IL304055A

Irak degraders and uses thereof

Abstract

This record has no abstract on file.

IL304055A, drawing sheet 1 — Sheet 1 of 3,141

Term

No projected expiry on record.

21 claims: 1 independent, 20 dependent

1
A compound of formula I:(1RAk)---L—(CbM^) I or a pharmaceutically acceptable salt thereof, wherein: IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4;Lisa bivalent moiety that connects IRAK to LBM;and LBM is a ligase binding moiety.
15
16. The pharmaceutical composition according to claim 15, further comprising an additional therapeutic agent.
18
19. The method according to claim 18, further comprising administration of an additional therapeutic agent.
21
22. The method of claim 21, wherein the MyD88 driven disorder is selected from ABC DLBCL, Waldenstrom’s macroglobulinemia, Hodgkin’s lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

Independent claims4

13,820 paragraphs in 939 sections, as filed

IRAK DEGRADERS AND USES THEREOF

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to compounds and methods useful for the modulation of one or more interleukin-1 receptor-associated kinases (“IRAK”) via ubiquitination and/or degradation by compounds according to the present invention. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

[0002] Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0003] There are over 600 E3 ubiquitin ligases which facilitate the ubiquitination of different proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle’s dynamics and signaling.”; Bemdsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligase mechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled“RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem. 2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures, new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) titled “Roles of F-box proteins in cancer.”

[0004] UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation. The pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases (including cystic fibrosis, Angelman’s syndrome, and Liddle syndrome), in immune surveillance/viral pathogenesis, and in the pathology of muscle wasting. Many diseases are associated with an abnormal UPP and negatively affect cell cycle and division, the cellular response to stress and to extracellular modulators, morphogenesis of neuronal networks, modulation of cell surface receptors, ion channels, the secretory pathway, DNA repair and biogenesis of organelles.

[0005] Aberrations in the process have recently been implicated in the pathogenesis of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function with the resultant stabilization of certain proteins, and (b) those that result from gain of function, i.e. abnormal or accelerated degradation of the protein target.

[0006] The UPP is used to induce selective protein degradation, including use of fusion proteins to artificially ubiquitinate target proteins and synthetic small-molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target proteinbinding ligand and an E3 ubiquitin ligase ligand, induced proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds are capable of inducing the inactivation of a protein of interest upon addition to cells or administration to an animal or human, and could be useful as biochemical reagents and lead to a new paradigm for the treatment of diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr, Chembiochem, 2005, 6(1):40-46).

[0007] An ongoing need exists in the art for effective treatments for disease, especially hyperplasias and cancers, such as multiple myeloma. However, non-specific effects, and the inability to target and modulate certain classes of proteins altogether, such as transcription factors, remain as obstacles to the development of effective anti-cancer agents. As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target cancer-associated proteins such as interleukin-1 receptor-associated kinases (“IRAK”) hold promise as therapeutic agents. Accordingly, there remains a need to find bifunctional compounds that are IRAK degraders useful as therapeutic agents.

SUMMARY OF THE INVENTION

[0008] The present application relates novel bifunctional compounds, which function to recruit IRAK kinases to E3 Ubiquitin Ligase for degradation, and methods of preparation and uses thereof. In particular, the present disclosure provides bifunctional compounds, which find utility as modulators of targeted ubiquitination of IRAK kinases, which are then degraded and/or otherwise inhibited by the bifunctional compounds as described herein. An advantage of the compounds provided herein is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of IRAK kinases. In addition, the description provides methods of using an effective amount of the compounds as described herein for the treatment or amelioration of a disease condition, such as cancer, e.g., multiple myeloma.

[0009] The present application further relates to targeted degradation of IRAK kinases through the use of bifunctional molecules, including bifunctional molecules that link a cereblon-binding moiety to a ligand that binds IRAK kinasses.

[0010] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as degraders of IRAK kinases. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0011] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with regulation of signaling pathways implicating IRAK kinases. Such diseases, disorders, or conditions include those described herein.

[0012] Compounds provided by this invention are also useful for the study of IRAK enzymes in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new IRAK inhibitors or IRAK degraders or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Certain Embodiments of the Invention:

[0013] Compounds of the present invention, and compositions thereof, are useful as degraders and/or inhibitors of one or more IRAK protein kinases. In some embodiments, a provided compound degrades and/or inhibits IRAK-1/2/3/4.

[0014] In certain embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4;

Lisa bivalent moiety that connects IRAK to LBM; and

LBM is a ligase binding moiety.

2. Compounds and Definitions:

[0015] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0016] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as carbocycle, “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0017] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0018] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0019] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0020] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2//-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[0021] The term unsaturated, as used herein, means that a moiety has one or more units of unsaturation.

[0022] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0023] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0024] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0025] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of

the following structure:

[0026] The term “halogen” means F, Cl, Br, or I.

[0027] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0028] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 47/ quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0029] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7 membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term nitrogen includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro2// pyrrol yl), NH (as in pyrrolidinyl), or +NR (as in TV-substituted pyrrolidinyl).

[0030] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3// indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0031] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0032] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0033] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)0-4R°; -(CH2)0-4OR°; -O(CH2)0-4R°, -O(CH2)0-4C(O)OR°; -(CH2)o-4CH(OR°)2; -(CH2)o-4SR°; -(CH2)0-4Ph, which may be substituted with R°; -(CH2)0-40(CH!)0-1 Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)0-4O(CH2)0 pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH2)o4N(Ro)C(O)NR°2; -N(Ro)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°;

N(R°)N(R°)C(0)R°; -N(Ro)N(R°)C(O)NR°2; -N(Ro)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; C(S)R°; -(CH2)o-4C(0)OR°; -(CH2)o-4C(0)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R°; OC(O)(CH2)0-4SR-, SC(S)SR°; -(CH2)o^SC(0)R°; -(CH2)o-4C(0)NR°2; -C(S)NRo2; -C(S)SR°; -SC(S)SR°, -(CH2)0-4OC(O)NR°2; -C(0)N(0R°)R°; -C(O)C(O)R°; -C(O)CH2C(O)Ro; C(N0R°)R°; -(CH2)o-4SSR°; -(CH2)o^S(0)2R°; -(CH2)o^S(0)20R°; -(CH2)o-40S(0)2R°; S(O)2NR°2; -(CH2)o-4S(0)R°; -N(Ro)S(O)2NR°2; -N(Ro)S(O)2R°; -N(0R°)R°; -C(NH)NRo2; P(O)2R°; -P(O)Ro2; -OP(O)Ro2; -OP(O)(ORo)2; SiR°3; -(C1-4 straight or branched alkylene)ON(R°)2; or —(C!=4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -O(CH2)01Ph, -CH2-(5-6 membered heteroaryl ring), or a 5 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0034] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0-2R*, -(haloR&#1524;), -(CH2)0-2OH, -(CH2)o-20R&#1524;, -(CH2)o-2CH(OR’)2; -O(haloR’), -CN, -N3, -(CH2)0

2C(O)R&#1524;, -(CH2)0-2C(O)OH, -(CH2)o-2C(0)OR&#1524;, -(CH2)o-2SR&#1524;, -(CH2)o-2SH, -(CH2)o-2NH2, (CH2)o-2NHR., -(CH2)o-2NR’2, -NO2, -SiR*3, -0SiR*3, -C(O)SR. -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Cim aliphatic, CH2Ph, -O(CH2)0-1Ph, or a 5 membered saturated, partially unsaturated, or aryl ring having 04 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0035] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(0)R*, =NNHC(0)0R*, =NNHS(O)2R*, =NR*, =NOR\ -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)230-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR&#1524;, -O(haloR&#1524;), -CN, -C(O)OH, -C(O)OR’, -NH2, -NHR&#1524;, -NR2&#1524;, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R', -NR^, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf,

C(O)CH2C(O)R^, -S(O)2Rf, -S(O)2NR^2, -C(S)NR^2, -C(NH)NR'2, or -N(Rt)S(O)2Rt; wherein each is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s) form an unsubstituted 3 membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] Suitable substituents on the aliphatic group of are independently halogen, R&#1524;, -(haloR&#1524;), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a 5-6membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0039] As used herein, the term pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C!^alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention

[0042] As used herein, the term “inhibitor” is defined as a compound that binds to and /or inhibits an IRAK kinase with measurable affinity. In certain embodiments, an inhibitor has an IC50 and/or binding constant of less than about 50 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0043] As used herein, the term “degrader” is defined as a heterobifunctional compound that binds to and /or inhibits both an IRAK kinase and an E3 ligase with measurable affinity resulting in the ubiqitination and subsequent degradation of the IRAK kinase. In certain embodiments, a degrader has an DC50 of less than about 50 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0044] A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chern. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chern., 2006, 17, 52-57.

[0045] As used herein, the term “detectable moiety” is used interchangeably with the term label and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, 32Ρ, 33P, 35S, or 14C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.

[0046] The term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavidin-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.

[0047] The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina

Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethylrhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0048] The term “mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4’-[(pMethoxytetrafluorobenzyl)oxy]phenyl] methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6Tetrafluoro (pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of masstags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.

[0049] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in an IRAK protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and an IRAK protein kinase, and an equivalent sample comprising an IRAK protein kinase, in the absence of said compound, or composition thereof.

3. Description of Exemplary Embodiments:

[0050] As described above, in certain embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4;

Lisa bivalent moiety that connects IRAK to LBM; and

LBM is a ligase binding moiety.

[0051] In some embodiments, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

IRAK is an IRAK-4 binding moiety;

Lisa bivalent moiety that connects IRAK to LBM; and

LBM is a cereblon ligase binding moiety.

[0052] In some embodiments, LBM is an E3 ligase ligand. Such E3 ligase ligands are well known to one of ordinary skill in the art and include those described in M. Toure, C. M. Crews, Angew. Chern. Int. Ed. 2016, 55, 1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO 2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO 2012/003281, US 2013/0190340, US 2016/0022642, WO 2014/063061, US 2015/0274738, WO 2016/118666, US 2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US 2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US 2017/0008904, WO 2017/011590, US 2017/0037004, WO 2017/079267, US 2017/0121321, WO 2017/117473, WO 2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, WO 2017/197046, WO 2017/197051, WO 2017/197055, and WO 2017/197056 each of, the entirety of each of which is herein incorporated by reference.

[0053] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

compound of formula I-a-1, I-a-2,

I-a-3, I-a-4, I-a-5, I-a-6, I-a-7, I-a-8, I-a-9, or I-a-10 respectively:

I-a-5

I-a-6

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables

, X, Xi, X2, Y, Ri,

R3, R3’, R4, R5, t, m and n is as defined and described in WO 2017/007612 and US 2018/0134684, the entirety of each of which is herein incorporated by reference.

[0054] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

compound of formula I-a&#1523;-l, I-a2,1-&#1523;-a3,1-&#1523;-a4,1-&#1523;-a5-&#1523;, I-a6,1-&#1523;-a7,1-&#1523;-a8,1-&#1523;-a9-&#1523;, or I-a10-&#1523; respectively:

I-a7-&#1523;

I-a8-&#1523;

I-a9-&#1523;

I-a10-&#1523; or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and a

described in embodiments herein, and wherein each of the variables b , X, X!, X2, Y, Ri, R3, R3’, R4, R5, t, m and n is as defined and described in WO 2017/007612 and US 2018/0134684, the entirety of each of which is herein incorporated by reference.

[0055] In certain embodiments, the present invention provides a compound of Formula I,

compound of formula I-a-l, I-a-2,I-a-3,1-a-4,1-a-5,1-a-6,1-a-7,I-a-8,1-a-9, or I-

I-a-5

I-a-6

L (R1)m

I-a7-&#1524; R4

R3 x2 (R3')n

I-a8-&#1524;

I-a-9

I-a-10 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables

, X, Xi, X2, Y, Ri,

R3, R3’, R4, R5, t, m and n is as defined and described in WO 2017/007612 and US 2018/0134684, the entirety of each of which is herein incorporated by reference.

[0056] In certain embodiments, the present invention provides a compound of Formula I,

R1' , &#974; wherein LBM is a VHL E3 ubiquitin ligase binding moiety R x X—R2 &#1497;

forming a compound of formula I-b-1,1-b-2,1-b-3,1-b-4, or I-b-5 respectively:

I-b-1

I-b-2

R3

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, X, and X’ is as defined and described in WO 2013/106643 and US 2014/0356322, the entirety of each of which is herein incorporated by reference.

[0057] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-c:

I-c or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR;

each R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

each R6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 47 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0058] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety (R thereby forming a compound of formula I-c&#1523;:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, deuterium, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or

-N(R)S(O)2R;

Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR;

each R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

[0059] In some embodiments, the compound of formala I-c&#1523; above is provided as a compound of formula I-c or formula I-c':

or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, R1, R2, X1, X2, X3, and m is as defined above.

[0060] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

I-d or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or + ;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or

-N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to

each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0061] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety _ R1 /—X3

D—K

-Y X1-NH (R2)m ; thereby forming a compound of formula I-d&#1523;:

I-d&#1523; or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

(R2)m XS &#1497; (R2)m NR5 &#1497; , or / ;

each R2 is independently hydrogen, deuterium, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to

IRAK each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[0062] In some embodiments, the compound of formala Ι-d' above is provided as a compound of formula I-d or formula I-d':

I-d&#1523; or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, Ring B, L, R1, R2, R3, X1, X2, X3, m, and p is as defined above.

[0063] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-e:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

R1 is hydrogen, deuterium, halogen, -CN,

-OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

Ring A is a mono- or bicyclic ring selected from

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0064] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-e&#1523;:

I-e&#1523; or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

[0065] In some embodiments, the compound of formala I-e&#1523; above is provided as a compound of formula I-e or formula I-e':

or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, Ring B, L, R1, R2, R3, X1, X2, X3, p, and m is as defined above.

[0066] In certain embodiments, the present invention provides a compound of Formula I,

wherein LBM is a VHL E3 ubiquitin ligase binding moiety

; thereby forming a compound of formula I-f-1,1-f-2,

I-f-3,1-f-4,1-f-5 or I-f-6 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, R5, R6, R7, R9, Rio, R11, R14, R15, R16, R17, R23, R25, E, G, Μ, X, X’, Y, Z1, Z2, Z3, Z4, and 0 is as defined and described in WO 2016/149668 and US 2016/0272639, the entirety of each of which is herein incorporated by reference.

As used herein, depiction of brackets around any LBM

LBM

- means that the

[0067]

moiety is covalently attached to said LBM at any available modifiable carbon, nitrogen, oxygen, or sulfur atom. For purposes of clarity and by way of example, such available modifiable carbon, nitrogen, oxygen, or sulfur atoms in the following LBM compound structure are depicted below, wherein each wavy bond defines the point of attachment to said

[0068] In certain embodiments, the present invention provides a compound of Formula I,

wherein LBM is a VHL E3 ubiquitin ligase binding moiety

I-g-1

I-g-2

I-g-3 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables Rp, R9, Rio, R11, R14a, R14b, R15, R16, W3, W4, W5, X1, X2, and 0 is as defined and described in WO 2016/118666 and US 2016/0214972, the entirety of each of which is herein incorporated by reference.

[0069] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

forming a compound of formula I-h-1,1-h-2,1-h-3,1-h-4,1-h-5, or I-h-6 respectively:

I-h-2

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein

W is independently selected from the group CH2, CHR, C=O, SO2, NH, and N-alkyl;

X is independently selected from the group O, S and H2;

Y is independently selected from the group NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, Nheterocyclyl, O, and S;

Z is independently selected from the group 0, and S or H2, except that both X and Z cannot be H2;

G and G' are independently selected from the group H, alkyl, OH, CH2-heterocyclyl optionally substituted with R&#1523;, and benzyl optionally substituted with R&#1523;;

Q1-Q4 represent a carbon C substituted with a group independently selected from R&#1523;, N or Noxide;

A is independently selected from the group H, alkyl, cycloalkyl, Cl and F;

R comprises, but is not limited to: —CONR'R, —OR', —NR'R, —SR', —S02R', — S02NRR, —CR&#1523;R&#1524;—, — CR'NR'R&#1524;—, -aryl, -hetaryl, -alkyl, -cycloalkyl, heterocyclyl, —P(0)(0R&#1523;)R, —P(0)R&#1523;R, —0P(0)(0R&#1523;)R, —0P(0)R&#1523;R, —Cl, —F, —Br, —I, —CF3, —CN, —NR&#1523;SO2NR&#1523;R, —NR'CONR'R, — CONR'COR&#1523;', — NR&#1523;C(=N—CN)NR&#1523;R, —C(=N—CN)NR&#1523;R, —NR&#1523;C(=N—CN)R, —NR&#1523;C(=C— N02)NR&#1523;R, — SO2NR&#1523;COR&#1523;&#1523;, —N02, —C02R&#1523;, — C(C=N—0R&#1523;)R, —CR&#1523;=CR&#1523;R, — CCR&#1523;, — S(C=O)(C=N—R&#1523;)R, —SF5 and —OCF3;

R' and R are independently selected from a bond, H, alkyl, cycloalkyl, aryl, hetaryl, heterocyclyl;

n is an integer from 1-4;

&#1524;&#1524;&#1524; represents a bond that may be stereospecific ((R) or (S)) or non-stereospecific; and

Rn comprises 1-4 independent functional groups or atoms;

as defined and described in WO 2016/197114 and US 2018/0147202, the entirety of each of which is herein incorporated by reference.

[0070] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3 ligase binding moiety

thereby forming a compound of formula I-i-1,1-i-2,1-i-3, I-i-4,1-i-5,1-i-6, I-i-7,1-i-8,1-i-9,1-i10,1-i-11,1-i-12,1-i-13,1-i-14,1-i-15,1-i-16,1-i-17, or I-i-18 respectively:

I-i-4

I-i-18 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables Ri, R2, R3, R4, R5, R6, R7, Rs, R9, Rio, Rll, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, Ri’, R2’, R3&#1470;, R4&#1470;, R5’, R6&#1470;, R7’, R8&#1470;, R9&#1470;, R10’, R11’, R12’, Ri”, A, A’, A”, X, Y, and Z is as defined and described in WO 2017/011371 and US 2017/0008904, the entirety of each of which is herein incorporated by reference.

[0071] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety selected from the group

consisting of

forming a compound of formula I-j-1,1-j-2,1-j-3,1-j-4,1-j-5,1-j-6, or I-j-7 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein

A1 is selected from the group consisting of -C(R16a)= and -N=;

A2 is selected from the group consisting of -C(R16b)= and -N=;

A3 is selected from the group consisting of -C(R16c)= and -N=;

G is selected from the group consisting of -C(R16d)= and -N=;

Z is selected from the group consisting of -CH2 and -C(=O)-;

R5 is selected from the group consisting of hydrogen, methyl, and fluoro;

R16a is selected from the group consisting of hydrogen, halo, and Ci_4 alkyl;

R16b is selected from the group consisting of hydrogen, halo, and Ci_4 alkyl;

R16c is selected from the group consisting of hydrogen, halo, and Ci_4 alkyl; and

R16d is selected from the group consisting of hydrogen, halo, and Ci_4 alkyl;

as defined and described in WO 2017/176958, the entirety of which is herein incorporated by reference.

[0072] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety selected from the group

O

consisting of

; thereby forming a compound of formula I-j&#1523;-l, I-j'-2, I-j-2,

I-j'-3,I-j''-3,I-j'-4,I-j''-4,I-j'-7 0rI-j-7 respectively:

L

I-j'-l

L

I-j7-&#1524; or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables A1, A2, A3, R5, G and Z is as defined and described in WO 2017/176958, the entirety of which is herein incorporated by reference.

[0073] In certain embodiments, the present invention provides a compound of Formula I,

wherein LBM is an IAP E3 ubiquitin ligase binding moiety

I-k-4 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, R4, R5, R6, and R7, is as defined and described in WO 2017/011590 and US 2017/0037004, the entirety of each of which is herein incorporated by reference.

[0074] In certain embodiments, the present invention provides a compound of Formula I,

; thereby forming a compound of formula I-k’-l,

-k’-2, Ik’-3, or I-k’-4 respectively:

I-k’-l

I-k’-3

I-k’-4 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R1, R3, R4, R5, R6, and R7, is as defined and described in WO 2017/011590 andUS 2017/0037004, the entirety of each of which is herein incorporated by reference.

[0075] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

(R2)m

1-1 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or ;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(0)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR;

each R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

L1 is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, , -NR-, S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -

C(O)NR-, -OC(O)NR-, -NRC(O)O-,

n , or L J n , wherein:

each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is 0, 1, 2, 3 or 4;

each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0076] Where a point of attachment of-(R2)n is depicted on Ring B, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of-(R2)n may be on Ring A and may also be at any available carbon or nitrogen atom on Ring A including the ring to which Ring B is fused. Where -R2 is attached to a nitrogen atom bound to R4 or R5, R4 or R5 is absent and -R2 takes the place of the R4 or R5 group. Where -R2 is attached to a carbon atom bound to R3, R3 is absent and -R2 takes the place of the R3 group.

[0077] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

Thereby forming a compound of formula Ι-Γ:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

wherein

R3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR;

each R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

C(O)NR-, -OC(O)NR-, -NRC(O)O-,

wherein:

m is 0, 1, 2, 3 or 4;

[0078] Where a point of attachment of-(R2)n is depicted on Ring B, it is intended, and one of ordinary skill in the art would appreciate, that the point of attachment of-(R2)n may be on Ring A and may also be at any available carbon or nitrogen atom on Ring A including the ring to which Ring B is fused. Where -R2 is attached to a nitrogen atom bound to R4 or R5, R4 or R5 is absent and -R2 takes the place of the R4 or R5 group. Where -R2 is attached to a carbon atom bound to R3, R3 is absent and -R2 takes the place of the R3 group.

[0079] In some embodiments, a compound of formala I-Γ above is provided as a compound of formula 1-1 or formula 1-1':

&#1523;&#1524;1-1 or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, L1, R1, R2, X1, and m is as defined above.

[0080] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

Thereby forming a compound of formula I-m:

or a pharmaceutically acceptable salt thereof, wherein, L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

R1 is hydrogen, deuterium, halogen, -CN,

-OR,

-SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

Ring A is a mono- or bicyclic ring selected from

halogen, -CN, -NO2, -OR, -SR, each R2 is independently hydrogen, -R6,

- NR2, -S(0)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

- C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

- NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

- C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to

each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0081] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

Thereby forming a compound of formula I-m':

I-m' or a pharmaceutically acceptable salt thereof, wherein, L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR,

-SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

C(O)NR-,-OC(O)NR-,-NRC(O)O-, q , q , q

, or L J , wherein:

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to

[0082] In some embodiments, a compound of formala I-m&#1523; above is provided as a compound of formula I-m or formula I-m':

or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, Ring B, L, L1, R1, R2, R3, X1, p, and m is as defined above.

[0083] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

Thereby forming a compound of formula I-n:

I-n or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

R1 is hydrogen, deuterium, halogen, -CN,

-OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

Ring A is a mono- or bicyclic ring selected from

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

C(O)NR-,-OC(O)NR-,-NRC(O)O-, q , q , q

, or L , wherein:

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1;

[0084] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

Ring A is a mono- or bicyclic ring selected from

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

- C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

- NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

- C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1;

[0085] two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur. [0086] In some embodiments, a compound of formala I-n&#1523; above is provided as a compound of formula I-n or formula I-n':

(R/m

I-n&#1524;&#1523; or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, Ring B, L, L1, R1, R2, R3, X1, p, and m is as defined above.

[0087] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula 1-0:

R5

1-0 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

Ar is aryl, heteroaryl, cycloalkyl, or heterocyclyl;

L1 is absent or a linker selected from the group consisting of -SO2, -SO2R ; SO2RR,- SO2NRR; SO2NR&#1523;R&#1524;C(=O); -NRSO2R&#1524;; -R&#1523;SO2NR&#1523;R&#1524;; -C(=O); -C(=O)R&#1523;; -OC(=O)R&#1523;; C(=O)NRR; -NRC(=O)R; -NR&#1523;C(=O)R&#1524;C(=O); -OR; -NRR; -SR; -N3-C(=O)OR&#1523;; O(CRR)rC(=O)R; -O(CR&#1523;R&#1524;)rNR&#1524;C(=O)R&#1523;; -O(CR&#1523;R&#1524;)rNR&#1524;SO2R&#1523;; -OC(=O)NR&#1523;R&#1524;; NR&#1523;C(=O)OR&#1523;; and substituted or unsubstituted C1-C6 aliphatic alkyl;

wherein R, R , and R are individually selected from hydrogen; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted ether; substituted or unsubstituted cycloalkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylheteroaryl, or substituted or unsubstituted amine; and r is an integer from 1 to 6;

R1, R2, and R3 are individually selected from the group consisting of hydrogen, halogen, hydroxyl, azide, alkoxyl, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, morpholino, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted alkylhalide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylheteroaryl, and combinations thereof; or wherein R1 and R2 combine to form a 5-7 membered heterocyclic ring; and wherein when R1 and R2 combine to form a 5-7 membered heterocyclic ring, Ar is optionally not fused to the 57 membered heterocyclic ring but is a substituent of the 5-7 membered heterocyclic ring;

R4 and R5 are individually selected from the group consisting of hydrogen, halogen, hydroxyl, azide, ether, alkoxyl, sulfhydryl, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, substituted or unsubstituted alkyl, substituted or unsubstituted alkylhalide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, and combinations thereof;

R8 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkylhalide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted alkylaryl, and combinations thereof; and x is 0, 1, or 2;

as described and defined in WO 2017/161119, the entirety of which is herein incorporated by reference.

[0088] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

; thereby forming a compound of formula I-p:

I-p or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and further wherein:

Ais C, S; substituted of unsubstituted C1-C8 alkyl, or combinations thereof;

R6 and R7 are individually =0, hydrogen, C1-C8 alkyl, or R6 and R7combine to form =0; and each of the variables Ar, R1, R2, R3, R4, R5, R8, x, and the bond — is as decribed above and as described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference.

[0089] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-q:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R1, R2, R3, R4, R5, R6, R7, R8, A, x, and the bond --- is as decribed above described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference.

[0090] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-r:

I-r or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables Ar, R1, R2, R3, R4, R5, R8, L, x, y, and the bond — is as decribed above and described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference.

[0091] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-s:

I-s or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

G comprises C, S, N, substituted of unsubstituted C1-C8 alkyl, or combinations thereof; R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, azide, alkoxyl, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, substituted or unsubstituted amine, substituted or unsubstituted amide, nitro, ester, morpholino, dioxolane, substituted or unsubstituted alkyl, substituted or unsubstituted alkylhalide, substituted or unsubstituted aralkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkylheteroaryl, and combinations thereof; and each of the variables R3, R4, R5, R6, R7, R8, x, and the bond — is as decribed above and described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference. [0092] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-t:

I-t or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R3, R4, R5, R6, R7, R8, x, and the bond --- is as decribed above for 1-0 and described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference.

[0093] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-u:

Rs 'N f

Λ&#1523;

IRAK

I-u or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R3, R4, R5, R8, L, and the bond —- is as decribed above forl-o and described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference.

[0094] In certain embodiments, the present invention provides a compound of formula I,

H N

R5

R3 wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety thereby forming a compound of formula I-v:

I-v or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R1, R3, R4, R5, L, y, and the bond -&#1470;&#1470; is as decribed above for 1-0 and described and defined in WO 2017/161119, the entirety of each of which is herein incorporated by reference.

[0095] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-x:

I-x or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables A, B, C, W, X, Y, and Z is as described and defined in US 5,721,246, the entirety of each of which is herein incorporated by reference.

[0096] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

DCAF15 E3 ubiquitin ligase binding moiety

or a VHL E3

ubiquitin ligase binding moiety OH ; thereby forming a compound of formula Iy-1,1-y-2, or I-y-3:

I-y-1

I-y-2

I-y-3 or a pharmaceutically acceptable salt thereof, wherein IRAK is as defined above and described in embodiments herein, and wherein:

each of X1, X2, and X3 is independently a bivalent moiety selected from a covalent bond, -CH2-, <0^

- C(O)-, -C(S)-, or \ Λ each of X4 and X5 is independently a bivalent moiety selected from -CH2-, -C(O)-, -C(S)-, or O

VY

&#1512;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

each of R2, R3, and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(0)NR2,

- C(0)N(R)0R, -OC(O)R, -0C(0)NR2, -N(R)C(0)0R, -N(R)C(0)R, -N(R)C(0)NR2, or -N(R)S(O)2R;

R5 is hydrogen or C1-6 aliphatic;

Ring A is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring C is a selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -S(O)2NR-, -NRC(O)-, -

m is 0, 1, 2, 3 or 4;

each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

p is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[0097] In certain embodiments, the present invention provides a compound of Formula I, R1/—\ &#1503;—χν~Λ /=0

X1&#1470;NH wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety or

I-y&#1524;-l or a pharmaceutically acceptable salt thereof, wherein IRAK, L, Ring A, X1, X2, X3, R1, R2 and m are as described above.

[0098] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

1,1-z-2, or I-z-3 respectively:

, thereby forming a compound of formula I-z-

I-z-1

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described herein, and wherein:

WHs CR6R7, C=O, C=S, C=CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2;

W2is CR8R9, C=O, C=S, C=CH2, SO2, S(O), P(O)Oalkyl, P(O)NHalkyl, P(O)N(alkyl)2, P(O)alkyl, P(O)OH, P(O)NH2;

X is independently selected from NH, NR3, CH2, CHR3, C(R3)2, O, and S;

n is 0, 1, 2, or 3;

is a single or double bond;

wherein when represents a single bond, n is 0, 1, 2, or 3;

wherein when represents a double bond, n is 0, 1, or 2;

R2 is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl, heteroaryl or heterocyclic;

or R1 and R2 are combined to form a 4, 5, 6, 7, 8, 9, or 10 membered heterocyclo or heteroaryl species, wherein the heterocyclo or heteroaryl species is substituted with R12 at any desired position, wherein the heterocyclo or heteroaryl species is optionally further substituted with one or more substituents selected from R5;

R3 is selected at each instance from: alkyl, -C(O)H, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, alkene, and alkyne, aliphatic, heteroaliphatic, aryl, heteroaryl and heteroalkyl;

R4 is selected at each instance from: alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), -N(aliphatic)2, -NHSO2(aliphatic), - N(aliphatic)SO2alkyl, NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic) NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, and haloalkyl; aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclic;

or two R4 substituents together with the carbon atom(s) to which they are bound can form a 3, 4, 5 or 6 membered ring; R5 and R14 are selected at each instance from: hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, -NH(aliphatic), N(aliphatic)2, -NHSO2(aliphatic), -N(aliphatic)SO2alkyl, -NHSO2(aryl, heteroaryl or heterocyclic), -N(alkyl)SO2(aryl, heteroaryl or heterocyclic) -NHSO2alkenyl, N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, and haloalkyl; aliphatic, heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclic;

or R5 is independently selected from C(O)R4, cyano, aryl, aryloxy, heterocyclo, heteroaryl, arylalkyl, alkoxy, hydroxyl, O-arylalkyl, or cycloalkyl;

R6, R7, R8, R9, R10, and R11, are independently selected from hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxyl, alkoxy, amine, -NH(aliphatic), and -N(aliphatic)2;

or R6 and R7 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R8 and R9 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R10 and R11 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6- membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;

or R6 and R8 form a 1 or 2 carbon bridged ring;

or R6 and R10 form a 1 or 2 carbon bridged ring;

or R8 and R10 form a 1 or 2 carbon bridged ring;

or R14 and R6 form a 3, 4, 5, or 6 carbon fused ring;

or R14 and R10 form a 3, 4, 5, or 6 carbon fused ring;

or R14 and R8 form a 1 or 2 carbon bridged ring;

or R14 and R4 form a 3, 4, 5, or 6 carbon fused ring wherein R5 is on the carbon alpha to R14 or a 1, 2, 3, or 4 carbon bridged ring wherein R5 is not on the carbon alpha to R14;

R12 is L;

Y is independently selected from N, CH, or CR101, wherein 0, 1, 2, or 3 instances of Y are selected to be N;

R101 is independently selected at each occurrence from hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryl oxy, heteroaryloxy, CN, -COOalkyl, COOH, NO2, F, Cl, Br, I, CF3, NH2, NHalkyl, N(alkyl)2, aliphatic, and heteroaliphatic as defined in WO 2017/197051, ( irak)—l— the entirety of which is herein incorporated by reference, and wherein is attached to R1, the ring formed by combining R1 and R2, or R17 at the site of attachment of

R12 as defined in WO 2017/197051 such that

takes the place of the R12 substituent.

[0099] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-aa:

I-aa or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or ;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

- C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

(R2)mX|> γΗ

Ring A is a bi- or tricyclic ring selected from O wherein Ring B is other than

wherein

R3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR;

each R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

[00100] In certain embodiments, the present invention provides a compound of Formula I, r1 /—χ3 \—( A ,/ Χχ\ /^° &#1503;~^ X1-NH wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety (R2)m ;

thereby forming a compound of formula I-aa&#1523;:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

<0^

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or Y ;

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, deuterium, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or

-N(R)S(O)2R;

Ring A is a bi- or tricyclic ring selected from O wherein Ring B is other than

wherein

Ring B is a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R3 is selected from hydrogen, halogen, -OR, -N(R)2, or -SR;

each R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, 2, 3 or 4; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[00101] In some embodiments, the compound of formala I-aa&#1523; above is provided as a compound of formula I-aa or formula I-aa&#1524;&#1523;:

or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, R1, R2, X1, X2, X3, and m is as defined above.

[00102] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

I-bb or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

R1 is hydrogen, deuterium, halogen, -CN,

-OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

(R2)m NR5, ,or /;

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to

IRAK ; and each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

[00103] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

I-bb&#1523; or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or &#1500; ;

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

Ring A is a mono- or bicyclic ring selected from

each R2 is independently hydrogen, deuterium, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -Si(R)3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or

-N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR,

-NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

p is 0 or 1, wherein when p is 0, the bond connecting Ring A and Ring B is connected to

[00104] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (cereblon) binding moiety

thereby forming a compound of formula I-cc:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

R1 is hydrogen, deuterium, halogen, -CN,

-OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

Ring A is a mono- or bicyclic ring selected from

each R2 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

[00105] In some embodiments, the compound of formala I-bb&#1523; above is provided as a compound of formula I-bb or formula I-bb&#1524;&#1523;:

(RJ)n (RQm

P

I-bb&#1524;

I-bb&#1524;&#1523; or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, Ring B, L, R1, R2, R3, X1, X2, X3, p, and m is as defined above.

[00106] wherein

In certain embodiments, the present invention provides a compound of Formula I, is an E3 ubiquitin ligase (cereblon) binding moiety

LBM

; thereby forming a compound of formula I-cc&#1523;:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or k

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(0)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

Ring B is selected from a 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each of R3 and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen, C1-4 aliphatic, or -CN;

m is 0, 1, or 2;

n is 0, 1, 2, 3, or 4;

[00107] In some embodiments, a compound of formala I-cc&#1523; above is provided as a compound of formula I-cc or formula I-cc':

or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, Ring B, L, R1, R2, R3, X1, X2, X3, p, n, and m is as defined above.

[00108] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK-4 inhibitor or

; thereby forming a compound of formula I dd-1 or I-dd-2 respectively:

I-dd-2 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

A is optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl-NRx—, optionally substituted heterocycloalkyl-NRx—, optionally substituted aryl-NRx—, optionally substituted heteroaryl-NRX—, optionally substituted cycloalkyl-0—, optionally substituted heterocycloalkyl-0—, optionally substituted aryl-0— or optionally substituted heteroaryl-0—; e.g., wherein each optional substituent independently represents an occurrence of Rz;

B is hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkoxy, —NRaRb, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted cycloalkyl-NRx—, optionally substituted heterocycloalkyl-NRx—, optionally substituted aryl-NRx—, optionally substituted heteroaryl-NRX—, optionally substituted cycloalkyl

Ο—, optionally substituted heterocycloalkyl-0—, optionally substituted aryl-0—, optionally substituted heteroaryl-0—; e.g., wherein each optional substituent independently represents an occurrence of Ry;

Q is absent or optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl, optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, —NR3R4, —O—R3 or —S—R; e.g., wherein each optional substituent independently represents an occurrence of Rz;

W is N or CH;

Riis hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heterocycloalkyl)alkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted (heteroaryl)alkyl-, optionally substituted alkoxyalkyl, optionally substituted aminoalkyl, or —(CH2)m—R2; e.g., wherein each optional substituent independently represents halo, hydroxy, alkoxy, amino, nitro, cycloalkyl, aryl, heterocycloalkyl or heteroaryl;

R2is hydrogen, —NRaRb, alkoxy, hydroxy, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; e.g., wherein each optional substituent independently represents an occurrence of Ry;

each R3 and R4 is independently selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl and optionally substituted (heterocycloalkyl)alkyl; e.g., wherein each optional substituent is independently selected from alkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, nitro, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl and (heteroaryl)alkyl;

each Ra and Rb is independently selected from hydrogen, alkyl, aminoalkyl, acyl and heterocyclyl; or Ra and Rb are taken together with the nitrogen to which they are attached to form an optionally substituted ring;

Rxis hydrogen, alkyl, hydroxy, hydroxyalkyl, acyl or cycloalkyl;

each Ry and Rxis independently selected from hydroxy, hydroxyalkyl, halo, alkyl, oxo, haloalkyl, alkoxy, alkenyloxy, amino, nitro, cyano, —SH, —S(alkyl), glycinate, ester, thioester, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, and (heteroaryl)alkyl; optionally wherein the hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are further substituted by one or more substituents selected from alkyl, halo, alkenyl, amino, nitro, cycloalkyl and (cycloalkyl)alkyl; or

Ry and Rz taken together with the atoms to which they are attached form an alkyl chain having 110 carbon atoms; optionally wherein 1-3 carbon atoms are replaced by O, NH or S;

m is 1, 2, or 3; and n is 1 or 2;

as defined and described in WO 2017/009798 and US 2018/0201609, the entirety of each of which is herein incorporated by reference.

[00109] In certain embodiments, the present invention provides a compound of Formula I,

or I-ee-4 respectively:

thereby forming a compound of formula I-ee-1, I-ee-2, I-ee-3,

I-ee-1

I-ee-2

R2

or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is selected from phenyl and 5- or 6-membered heteroaryl;

Ring B is selected from phenyl and 5- or 6-membered heteroaryl;

n is 0, 1, or 2;

p is 0, 1, or 2;

one of W and X is N, and the other of W and X is C;

Y is N or C—R2;

R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(Rla)=NR(ORla), —C(Rla)=N(Rla), —C(O)Rla, — C(O)2Rla, —C(O)N(Rla)2, —NO2, —N(Rla)2, —N(Rla)C(O)Rla, —N(Rla)C(O)2Rla, — N(Rla)C(O)N(Rla)2, —N(Rla)S(O)2Rla, —ORla, —OC(O)Rla, —OC(O)N(Rla)2, —SRla, —S(O)Rla, —S(O)2Rla, —S(O)N(Rla)2, and —S(O)2N(Rla)2, wherein said C1-6alkyl, C26alkenyl, C2-6alkynyl, C3-6cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R10; or two R1 substituents, together with their intervening atoms, form a C5-7cycloalkyl or a saturated 5- to 7-membered heterocyclic ring, wherein said C5-7cycloalkyl or a saturated 5- to 7-membered heterocyclic ring are optionally substituted with one or more R15;

Rlain each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;

R10in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, —CN, — C(R10a)=NR(OR10a), — C(R10a)=N(R10a), —C(O)R10a, —C(O)2R10a, —C(O)N(R10a)2, — NO2, —N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)C(O)2R10a, —N(R10a)C(O)N(R10a)2, — N(R10a)S(O)2R10a, — OR10a, —OC(O)R10a, —OC(O)N(R10a)2, —SR10a, —S(O)R10a, — S(O)2R10a, —S(O)N(R10a)2, and —S(O)2N(R10a)2;

R10ain each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl is optionally substituted with one or more halo;

R15 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, —CN, — C(R15a)=NR(OR15a), — C(R15a)=N(R15a), — C(O)R15a, —C(O)2R15a, —C(O)N(R15a)2, — NO2, —N(R15a)2, —N(R15a)C(O)R15a, —N(R15a)C(O)2R15a, —N(R15a)C(O)N(R15a)2, —

N(R15a)S(O)2R15a, —OR15a, —OC(O)R15a, —OC(O)N(R15a)2, —SR15a, —S(O)R15a, — S(O)2R15a, — S(O)N(R15a)2, and —S(O)2N(R15a)2;

R15ain each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl is optionally substituted with one or more halo;

R2is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 7-membered carbocyclyl, 3- to 7membered heterocyclyl, halo, —CN, —C(R2a)=NR(OR2a), —C(R2a)=N(R2), —C(O)R2a, —C(O)2R2a, —C(O)N(R2a)2, —NO2, —N(R2a)2, —N(R2a)C(O)R2a, —N(R2a)C(O)2R2a, — N(R2a)C(O)N(R2a)2, —N(R2a)S(O)2R2a, —OR2a, —OC(O)R2a, —OC(O)N(R2a)2, —SR2a, —S(O)R2a, —S(O)2R2a, —S(O)N(R2a)2, and —S(O)2N(R2a)2, wherein said C1-6alkyl, C26alkenyl, C2-6alkynyl, 3- to 7-membered carbocyclyl, and 3-7 membered heterocyclyl are optionally substituted with one or more R20;

R2ain each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl in each occurrence is optionally and independently substituted with one or more R20;

R20in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C37cycloalkyl, 3- to 7-membered saturated heterocyclyl, halo, —CN, —C(R20a)=NR(OR20a), _C(R20a)=N(R20a), —C(O)R20a, —C(O)2R20a, —C(O)N(R20a)2, —NO2, —N(R20a)2, — N(R20a)C(O)R20a, —N(R20a)C(O)2R20a, —N(R20a)C(O)N(R20a)2, —N(R20a)S(O)2R20a, — OR20a —OC(O)R20a, —OC(O)N(R20a)2, —SR20a, —S(O)R20a, —S(O)2R20a, — S(O)N(R20a)2, and —S(O)2N(R20a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C37cycloalkyl, and 3-7 membered saturated heterocyclyl in each occurrence are optionally and independently substituted with one or more R25;

R20ain each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl is optionally substituted with R25;

R25 is selected from halo and —OR25a;

R25ais selected from H and C1-6alkyl;

R3 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo, —CN, —C(R3a)=NR(OR3a), —C(R3a)=N(R3a), —C(O)R3a, — C(O)2R3a, —C(O)N(R3a)2, —NO2, —N(R3a)2, —N(R3a)C(O)R3a, —N(R3a)C(O)2R3a, — N(R3a)C(O)N(R3a)2, —N(R3a)S(O)2R3a, —OR3a, —OC(O)R3a, —OC(O)N(R3a)2, —SR3a, —S(O)R3a, —S(O)2R3a, —S(O)N(R3a)2, and —S(O)2N(R3a)2, wherein said C!-6alkyl, C2

6alkenyl, C2-6alkynyl, C3-6cycloalkyl, and 3- to 6-membered saturated heterocyclyl are optionally substituted with one or more R30;

R3ain each occurrence is independently selected from H, C1-6alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl, wherein said C1-6alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;

R30in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6membered carbocyclyl, 3- to 6-membered heterocyclyl, halo, —CN, —

C(R30a)=NR(OR30a), —C(R30a)=N(R30a), —C(O)R30a, —C(O)2R30a, —C(O)N(R30a)2, — NO2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)2R30a, —N(R30a)C(O)N(R30a)2, — N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —

S(O)R30a S(O)2R30a, — S(O)N(R30a)2, and —S(O)2N(R30a)2, wherein said C1-6alkyl, C26alkenyl, C2-6alkynyl, 3-6 membered carboy cl yl, 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R35;

R30ain each occurrence is independently selected from H and C1-4alkyl, wherein C!-4alkyl is optionally substituted with one or more R35;

R35 in each occurrence is independently selected from halo and —OR35a;

R35ain each occurrence is independently selected from H and C1-6alkyl;

R4is selected from H, halo, C1-6alkyl, N(R4a)2, and —OR4a; and

R4ain each occurrence is independently selected from H and C1-6alkyl;

as defined and described in WO 2016/011390 and US 2017/0204093, the entirety of each of which is herein incorporated by reference.

[00110] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

R2 ff-2,1-ff-3, or I-ff-4 respectively:

; thereby forming a compound of formula I-ff-1,1-

I-ff-1

I-ff-4 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is selected from phenyl and 5- or 6-membered heteroaryl;

Ring B is selected from phenyl and 5- or 6-membered heteroaryl;

Ring C is a 3- to 6-membered carbocyclyl, n is 1, 2 or 3;

p is 0, 1, or 2;

one of W and X is N, and the other of W and X is C;

Y is N or C-R2;

R1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, -CN, -C(Rla)=NR(ORla), C(Rla)=N(Rla), -C(O)Rla, -C(O)2Rla, -C(O)N(Rla)2, -NO2, -N(Rla)2, -N(Rla)C(O)Rla, N(Rla)C(O)2Rla, -N(Rla)C(O)N(Rla)2, -N(Rla)S(O)2Rla, -ORla, -OC(O)Rla, - OC(O)N(Rla)2, SRla, -S(O)Rla, -S(O)2Rla, -S(O)N(Rla)2, and -S(O)2N(Rla)2, wherein said C1-6alkyl, C26alkenyl, and C2-6alkynyl are optionally substituted with one or more R10;

Rla in each occurrence is independently selected from H or C!-6alkyl wherein said C!-6alkyl in each occurrence are optionally and independently substituted with one or more R10;

R10 in each occurrence is independently selected from halo, -CN, -C(R10a)=NR(OR)10a, C(R10a)=N(R10a), -C(O)R10a, -C(O)2R10a, -C(O)N(R10a)2, -NO2, -N(R10a)2, N(R10a)C(O)R10a, -N(R10a)C(O)2R10a, -N(R10a)C(O)N(R10a)2, -N(R10a)S(O)2R10a, -OR10a, OC(O)R10a, -OC(O)N(R10a)2, -SR10a, -S(O)R10a, -S(O)2R10a, -S(O)N(R10a)2, and S(O)2N(R10a)2;

R10a in each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl is optionally substituted with one or more halo;

R is selected from H, C!-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 7-membered carbocyclyl, 3-to 7membered heterocyclyl, halo, -CN, -C(R2a)=NR(OR2a), -C(R2a)=N(R2a), -C(O)R2a, C(O)2R2a, -C(O)N(R2a)2, -NO2, -N(R2a)2, -N(R2a)C(O)R2a, -N(R2a)C(O)2R2a, N(R2a)C(O)N(R2a)2, -N(R2a)S(O)2R2a, -OR2a, -OC(O)R2a, -OC(O)N(R2a)2, -SR2a, S(O)R2a, -S(O)2R2a, -S(O)N(R2a)2, and -S(O)2N(R2a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-to 7-membered carbocyclyl, and 3-7 membered heterocyclyl are optionally substituted with one or more R20;

R2a in each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl in each occurrence is optionally and independently substituted with one or more R 20 ;

R20 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyl, 3-to 7-membered saturated heterocyclyl, halo, -CN, -C(R20a)=NR(OR20a), - C(R20a)=N(R20a), -C(O)R20a, -C(O)2R20a, -C(O)N(R20a)2, -N02, -N(R20a)2, N(R20a)C(O)R20a, -N(R20a)C(O)2R20a, -N(R20a)C(O)N(R20a)2, -N(R20a)S(O)2R20a, -OR20a, OC(O)R20a, -OC(O)N(R20a)2, -SR20a, -S(O)R20a, -S(O)2R20a, -S(O)N(R20a)2, and S(O)2N(R20a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, and 3-7 membered saturated heterocyclyl in each occurrence are optionally and independently substituted with one or more R25;

R20a in each occurrence is independently selected from H and C1-6alkyl, wherein said C!-6alkyl is optionally substituted with R25;

R25 is selected from halo and -OR25a;

R25a is selected from H and C1-6alkyl;

R is selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-to 6-membered saturated heterocyclyl, halo, -CN, -C(R3a)=NR(OR3a), -C(R3a)=N(R3a), -C(O)R3a, - C(O)2R3a, C(O)N(R3a)2, -NO2, -N(R3a)2, -N(R3a)C(O)R3a, -N(R3a)C(O)2R3a, - N(R3a)C(O)N(R3a)2, 153

N(R3a)S(O)2R3a, -OR3a, -OC(O)R3a, -OC(O)N(R3a)2, -SR3a, - S(O)R3a, -S(O)2R3a, S(O)N(R3a)2, and -S(O)2N(R3a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C36cycloalkyl, and 3-to 6-membered saturated heterocyclyl are optionally substituted with one or more R30;

R3a in each occurrence is independently selected from H, C1-6alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl, wherein said C1-6alkyl, 3- to 6- membered carbocyclyl, and 3- to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R30;

R30 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 6membered carbocyclyl, 3-to 6-membered heterocyclyl, halo, -CN, - C(R30a)=NR(OR30a), C(R30a)=N(R30a), -C(O)R30a, -C(O)2R30a, -C(O)N(R30a)2, -NO2, - N(R30a)2, N(R30a)C(O)R30a, -N(R30a)C(O)2R30a, -N(R30a)C(O)N(R30a)2, - N(R30a)S(O)2R30a, -OR30a, OC(O)R30a, -OC(O)N(R30a)2, -SR30a, -S(O)R30a, -S(O)2R30a, - S(O)N(R30a)2, and S(O)2N(R30a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3-6 membered carbocyclyl, 3-to 6-membered heterocyclyl in each occurrence are optionally and independently substituted with one or more R35;

R30ain each occurrence is independently selected from H and C1-4alkyl, wherein C!-4alkyl is optionally substituted with one or more R35;

R35 in each occurrence is independently selected from halo and -OR35a; and

R35a in each occurrence is independently selected from H and C1-6alkyl;

as defined and described in WO 2017/127430, the entirety of which is herein incorporated by reference.

[00111] In certain embodiments, the present invention provides a compound of Formula I,

HN*

wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-gg-1:

I-gg-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, imidazolo[4,5-b]pyridinyl, and imidazolo[4,5-d]pyrimidinyl, wherein said heteroaryl is attached to the pyridinyl group in the compound of Formula (I) by a nitrogen ring atom in said heteroaryl and wherein said heteroaryl is substituted with zero to 2 Rb;

A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl or dihydroisoxazolyl, each substituted with Ra;

R3 is C2-3 alkyl, C2-3 fluoroalkyl, C3-4 hydroxyalkyl, or a cyclic group selected from C3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, wherein said cyclic group is substituted with zero to 2 substituents independently selected from F, —OH, C1-2 alkyl, and —CH2CHF2;

Rais:

(i) H, F, Ci, —OH, —CN, C1-6 alkyl, C1-6 fluoroalkyl, C1-4 cyanoalkyl, C1-6 hydroxyalkyl, Ci5 hydroxy-fluoroalkyl, C2-4 alkenyl, C1-6aminoalkyl, —(CH2)1-3NHRy, —(CH2)1-3NRyRy, —CH2CH(OH)(phenyl), —CH(CH2OH)(phenyl), —CH2CH(OH)CH2(phenyl), —

CH2CH(OH)CH2O(methoxyphenyl), —CH2CH(NH2)CH2(phenyl), —(CH2CH2O)4H, — (CH2)1-3O(C1-3 alkyl), — CH2CH(OH)CH2O(C1-3alkyl), — CH2C(O)(C1-3 alkyl), —

CH2C(O)NRyRy, — (CH2)1-3NRyC(O)(C1-3 alkyl), — CH2C(O)O(C1-3 alkyl), —C(O)NH2, —CH2NRyC(O)NH2, — (CH2)1-2NRyC(O)O(C1-2 alkyl), —(CRyRy)1-5OC(O)CH2NRyRy, —CH2CH2S(O)2CH3, —CH2S(O)2(C1-3 alkyl), —CH2S(O)2(phenyl), or —

NH(aminocyclohexyl); or (ii) —(CH2)0-3Rzor —(CH2)0-1C(O)Rz, wherein Rzis C3-6 cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, dioxopyrimidinyl, benzo[d]imidazolyl, benzo[d]thiazolyl, 1,3-dioxolanyl, or 8azabicyclo[3.2.1]octanyl, each substituted with zero to 4 substituents independently from F, —CN, —OH, —NRyRy, C1-3 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, —CH(phenyl)2, —O(C1-4 alkyl), —C(O)(C1-4 alkyl), —C(O)(C 1-4 deuteroalkyl), — C(O)(C1- hydroxyalkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)(C3-6cycloalkyl), —C(O)O(C 1-3 alkyl), —C(O)NRyRy, —C(O)(phenyl), —C(O)(pyridinyl), —C(O)CH2(C3-6 cycloalkyl), — C(O)O(C1-4 alkyl), —NH(C 1-4 alkyl), —NH(C 1-3 fluoroalkyl), —NHC(O)CH3, — NHC(O)O(C1-3 alkyl), —NHC(O)OC(CH3)3, —S(O)2(C 1-3 alkyl), —OS(O)2(C1-3 alkyl), methyl oxadiazolyl, and pyrimidinyl;

each Rbis independently selected from H, Cl, —CN, —NH2, and —C(O)NH2, wherein said heteroaryl is attached to the pyridinyl group by a nitrogen atom in said heteroaryl; and each Ry is independently H or C1-2 alkyl;

as defined and described in WO 2016/210034 and US 2018/0186799, the entirety of each of which is herein incorporated by reference.

[00112] In certain embodiments, the present invention provides a compound of Formula I,

thereby forming a compound of formula I-hh-1,1-hh-2,1-hh-3, or I-hh-4 respectively:

I-hh-1

I-hh-2

I-hh-3

I-hh-4 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

each Xi, X2 and X3 are independently CR2 or N;

A is O, S, S(O) or S(O)2;

Z!is optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted aralkyl-, optionally substituted heteroaralkyl-, optionally substituted (cycloalkyl)alkyl-, optionally substituted aryloxy-, optionally substituted heteroaryloxy-, optionally substituted heterocycloalkyloxy-, optionally substituted cycloalkyloxy-, optionally substituted aryl-NR'—, optionally substituted heteroaryl-NR'—, optionally substituted heterocycloalkyl-NR'—, optionally substituted cycloalkyl-NR'—, optionally substituted aryl-S—, optionally substituted heteroaryl-S—, optionally substituted heterocycloalkyl-S—, optionally substituted cycloalkyl-S—, optionally substituted (cycloalkyl)alkyl-NR'—, optionally substituted aralkyl-NR'—, optionally substituted (heterocycloalkyl)alkyl-NR'—, optionally substituted heteroaralkyl-NR'—, optionally substituted (cycloalkyl)alkyl-S—, optionally substituted aralkyl-S—, optionally substituted (heterocycloalkyl)alkyl-S—, optionally substituted heteroaralkyl-S—, optionally substituted (cycloalkyl)alkyl-O—, optionally substituted aralkyl-0—, optionally substituted (heterocycloalkyl)alkyl-O—, optionally substituted heteroaralkyl-O—; e.g., wherein each optional substituent independently represents an occurance of Rx;

Z2 is absent or optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryloxy-, optionally substituted heteroaryloxy-, optionally substituted cycloalkyloxy-, optionally substituted heterocycloalkyloxy-, optionally substituted (cycloalkyl)alkyl-, optionally substituted aralkyl-, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-, optionally substituted (cycloalkyl)alkyl-NR'&#1523;—, optionally substituted aralkyl-NR—, optionally substituted (heterocycloalkyl)alkyl-NR'&#1523;—, optionally substituted heteroaralkyl-NR—, optionally substituted (cycloalkyl)alkyl-O—, optionally substituted aralkyl-0—, optionally substituted (heterocycloalkyl)alkyl-O—, optionally substituted heteroaralkyl-O—, optionally substituted (cycloalkyl)alkyl-S—, optionally substituted aralkyl-S—, optionally substituted (heterocycloalkyl)alkyl-S— or optionally substituted heteroaralkyl-S—; e.g., wherein each optional substituent independently represents an occurance of Ry;

Z3is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aryloxy-, optionally substituted heteroaryloxy-, optionally substituted cycloalkyloxy-, optionally substituted heterocycloalkyloxy-, optionally substituted (cycloalkyl)alkyl-, optionally substituted aralkyl-, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-, optionally substituted (cycloalkyl)-NR'—, optionally substituted arylNR'—, optionally substituted heteroaryl-NR'—, optionally substituted heterocycloalkylNR'—, optionally substituted aryl-S—, optionally substituted heteroaryl-S—, optionally substituted cycloalkyl-S—, optionally substituted heterocycloalkyl-S—, optionally substituted (cycloalkyl)alkyl-NR'—, optionally substituted aralkyl-NR&#1523;—, optionally substituted (heterocycloalkyl)alkyl-NR'—, optionally substituted heteroaralkyl-NR&#1523;—, optionally substituted (cycloalkyl)alkyl-O—, optionally substituted aralkyl-0—, optionally substituted (heterocycloalkyl)alkyl-O—, optionally substituted heteroaralkylO—, optionally substituted (cycloalkyl)alkyl-S—, optionally substituted aralkyl-S—, optionally substituted (heterocycloalkyl)alkyl-S— or optionally substituted heteroaralkylS—; e.g., wherein each optional substituent independently represents an occurance of Rz;

each R2is independently selected from hydrogen, alkyl, haloalkyl, halo, cyano, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl-, optionally substituted cycloalkyloxy-, optionally substituted aryl, optionally substituted aralkyl-, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-, —NRaRb, —O—R3and —S—R3; e.g., wherein each optional substituent independently represents alkyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, —SH, —S(alkyl), cyano, amido, amino, carboxylate, glycinate, alaninate, oxo, aryl, cycloalkyl, heterocycloalkyl or heteroaryl;

each R&#1523;, R and R&#1523;&#1524; is independently selected from hydrogen, alkyl, hydroxy, hydroxyalkyl, acyl and cycloalkyl;

each Rx, Ry and Rz is independently selected from alkyl, alkenyl, alkynyl, halo, hydroxy, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, —SH, —S(alkyl), cyano, amido, carboxylic acid, carboxylate, ester, thioester, alkoxycarbonyl, —C(O)NH(alkyl), oxo, cycloalkyl, cycloalkyloxy, (cycloalkyl)alkyl-, aryl, aralkyl-, heterocycloalkyl, heteroaryl, (heterocycloalkyl)alkyl-, heteroaralkyl-, —NR;1Rb, —O—R4 or —S—R4; optionally wherein the cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are further substituted by one or more substituents selected from halo, haloalkyl, amino, hydroxy, alkyl, cyano, nitro, alkenyl, aminoalkyl, hydroxyalkyl and haloalkoxy;

each Ra and Rbis independently selected from hydrogen, alkyl, aminoalkyl, acyl, aminoacyl, halo, haloalkyl, hydroxy, haloalkoxy, hydroxyalkyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl-, (heterocycloalkyl)alkyl-, aralkyl-, and (heteroaryl)alkyl-; optionally wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are further substituted by one or more substituents selected from alkyl, halo, alkenyl, cyano, hydroxy, hydroxyalkyl, alkoxy, amino and nitro; or

Ra and Rbare taken together along with the atoms which they are attached to form a 3 to 8 membered optionally substituted ring; and each R3and R4is independently selected from hydrogen, alkyl, aminoacyl, phosphate, phosphonate, alkylphosphate, alkoxycarbonyl, cycloalkyl, (cycloalkyl)alkyl-, aryl, heteroaryl, heterocycloalkyl, aralkyl-, heteroaralkyl and (heterocycloalkyl)alkyl-;

as defined and described in WO 2017/009806 and US 2018/0208605, the entirety of each of which is herein incorporated by reference.

[00113] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of

I-ii-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

XisCR orN;

A is O, S, SO2, SO, —NRC(O), —NRSO2, or N(R); or A is absent;

R3 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(0)N(R)2, —NRC(0)R, —NRC(0)N(R)2, —NRSO2R, or —N(R)2; or when A is —NRC(O), —NRSO2, or N(R); then R and R3, together with the atoms to which each is attached, may form a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;

X'is CR orN;

Ring Z is a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;

R1 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(0)N(R)2, —NRC(0)R, —NRC(0)N(R)2, —NRSO2R, or —N(R)2;

Rais absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, — C(0)N(R)2, —NRC(0)R, —NRC(0)N(R)2, —NRSO2R, or —N(R)2;

Ring Y is an optionally substituted 5-6 membered monocyclic heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R2 is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(0)N(R)2, —NRC(0)R, —NRC(0)N(R)2, —NRSO2R, or —N(R)2;

Rbis absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, — C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —NRSO2R, or —N(R)2;

each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or two R groups on the same atom are taken together with the atom to which they are attached to form a C3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted;

as defined and described in WO 2016/081679 and US 2016/0145252, the entirety of each of which is herein incorporated by reference.

[00114] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor

or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is NH or O;

b is 0 or 1;

n is 0, 1, 2, 3 or 4;

R! and R2 are independently H, (C1-C4)alkyl and heterocyclyl, or R!and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic (fused, bridged or spirocyclic) heterocycle containing 3-8 carbon atoms optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said alkyl and heterocycle are optionally substituted with one or more substituents selected from Ra;

R3 is (C1-C4)alkyl wherein two adjacent alkyl groups can join together and form a bridged moiety of 3-6 carbon atoms;

R4is absent, halo or Ob(C1-C4)alkyl;

R5 is selected from C1-C4 alkyl and C2-C4 alkenyl which are optionally substituted with one or more substituents selected from Rb;

R6is absent, halo, or O(C!-C4)alkyl;

Rais halo, oxo, OH, Ob(C!-C4)alkyl, CF3, SO2(C!-C4)alkyl, or heterocyclyl, said heterocyclyl optionally substituted with one or more substituents independently selected from F, and (C!-C4)alkyl; and

Rbis independently selected from OH, halo, Ob(C!-C4)alkyl, and CN;

as defined and described in WO 2016/053769 and US 2017/0247388, the entirety of each of which is herein incorporated by reference.

[00115] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor

; thereby forming a compound of formula I-kk-1 or Ikk-2 respectively:

I-kk-1

I-kk-2 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

B is CH, N or S; D is CH or N; E is CH or N; F is CH or N; G is CH or N; and J is C or N, wherein when B is S then D is CH, E is N, F is CH, G is N and J is C;

X is O, S, CH2 or N;

m is 0 or 1; n is 0, 1 or 2;

Ring A is pyridinyl, pyrazolyl, thiophenyl, furanyl or phenyl;

R! is independently selected from (C1-C4)alkyl, pyrimidine, piperidine and phenyl, each optionally substituted with (C1-C4)alkyl, OH, halo, O(C1-C4)alkyl, methylpiperidine, S(O)2Rc, C(O)N(Rb)2, or C(O)O(C1-C4)alkyl;

R2is absent or H and R3is independently selected from: (C1-C4)alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl each optionally substituted with one or more substituents independently selected from halo, OH, oxo, N(Rb)2, oxopyrrolidinyl, or morpholinyl, or R2 and R3 can be taken together with the nitrogen to which they are attached to form piperazine or morpholine, each optionally substituted with oxo;

R4 is independently H or methyl;

Rbis independently selected from H and (C!-C4)alkyl; and

Reis methyl;

as defined and described in WO 2016/144844 and US 2018/0051027, the entirety of each of which is herein incorporated by reference.

[00116] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

forming a compound of formula I-kk’-l or I-kk’-2 respectively:

I-kk’-2

or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein each of the variables A, B, D, E, F, G, J, X, Ri, R2, R3 and n is as defined and described in WO 2016/144844 and US 2018/0051027, the entirety of each of which is herein incorporated by reference. Such IRAK4 inhibitors are well known to one of ordinary skill in the art and include those described in Smith et al., Bioorg. Med. Chem., 2017, 27(12): 2721-2726 and Lim et al., ACS Med. Chem. Lett., 2015, 6(6): 683-688.

[00117] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

; thereby forming a compound of formula 1 1 or respectively:

or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is aryl or heterocyclyl;

n is 0, 1, 2, 3 or 4;

Riis independently selected from: (C1-C4)alkyl, (C3-C6)cycloalkyl, heterocyclyl, CF3, CHF2, CN, halo, said alkyl, cycloalkyl and heterocyclyl optionally substituted with halo, OH, CH3, and OCH3;

R2is H and R3is independently selected from: (C1-C6)alkyl, (C3-C8)cycloalkyl, and heterocyclyl each optionally substituted with one or more halo, OH, N(Rb)2, or morpholinyl, or R2 and R3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, said heterocyclyl optionally substituted with one or more substituents selected from Ra;

Rais independently selected from (C!-C4)alkyl, (C3-C6)cycloalkyl, CF3, CHF2, OH, halo and NH2, said alkyl optionally substituted with (C3-C6)cycloalkyl and CF3; and

Rbis independently selected from H and (C!-C4)alkyl;

as defined and described in WO 2016/144847 and US 2018/0051029, the entirety of each of which is herein incorporated by reference.

[00118] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor thereby forming a compound of formula I-mm-1 or I-mm’-2 respectively:

I-mm-1

or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is aryl or heterocyclyl;

n is 0, 1, 2, 3 or 4;

Riis independently selected from: (C1-C4)alkyl, (C3-C6)cycloalkyl, heterocyclyl, CF3, CHF2, CN and halo, said alkyl, cycloalkyl and heterocyclyl optionally substituted with halo, OH, CH3, and OCH3;

Rais independently selected from (C!-C4)alkyl, (C3-C6)cycloalkyl, CF3, CHF2, OH, halo and NH2, said alkyl optionally substituted with (C3-C6)cycloalkyl or CF3; and

Rbis independently selected from H and (C!-C4)alkyl;

as defined and described in WO 2016/144846 and US 2018/0051028, the entirety of each of which is herein incorporated by reference.

[00119] In certain embodiments, the present invention provides a compound of Formula I,

an IRAK4 inhibitor or

; thereby forming a compound of formula I-nn-1 or I-nn’-2 respectively:

I-nn-1

I-nn’-2 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is aryl or heterocyclyl;

n is 0, 1, 2, 3 or 4;

Riis independently selected from: (C1-C4)alkyl, (C3-C6)cycloalkyl, heterocyclyl, CF3, CHF2, CN, halo, said alkyl, cycloalkyl and heterocyclyl optionally substituted with halo, OH, CH3, and OCH3;

Rais independently selected from (C!-C4)alkyl, (C3-C6)cycloalkyl, CF3, CHF2, OH, halo and NH2, said alkyl optionally substituted with (C3-C6)cycloalkyl and CF3; and

Rbis independently selected from H and (C!-C4)alkyl;

as defined and described in WO 2016/144848 and US 2018/0051030, the entirety of each of which is herein incorporated by reference.

[00120] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

or ; thereby forming a compound of formula 1 1 or I-oo’-2 respectively:

1 1

I-oo’-2 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is aryl or heterocyclyl;

n is 0, 1, 2, 3 or 4;

Riis independently selected from: (C1-C4)alkyl, (C3-C6)cycloalkyl, heterocyclyl, CF3, CHF2, CN, halo, said alkyl, cycloalkyl and heterocyclyl optionally substituted with halo, OH, CH3, and OCH3;

R2is H and R3is independently selected from: (C1-C6)alkyl, (C3-C8)cycloalkyl and heterocyclyl each optionally substituted with one or more halo, OH, N(Rb)2, or morpholinyl, or R2 and R3 can be taken together with the nitrogen to which they are attached to form a heterocyclyl, said heterocyclyl optionally substituted with one or more substituents selected from Ra;

Rais independently selected from (C!-C4)alkyl, (C3-C6)cycloalkyl, CF3, CHF2, OH, halo and NH2, said alkyl optionally substituted with (C3-C6)cycloalkyl and CF3; and

Rbis independently selected from H and (C!-C4)alkyl;

as defined and described in WO 2016/144849 and US 2018/0051035, the entirety of each of which is herein incorporated by reference.

[00121] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAKI and IRAK4 inhibitor forming a compound of formula I-pp-1:

; thereby

I-pp-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein represents the portion of the ring fused to the pyrimidine ring and # is -L2(R4)p-Rx; each R1 and R1 is independently -R2, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -N(R)C(O)OR, N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R'is selected from one of the following formulae:

,R X(CH2)77 nr2 (CH2)1_4 R; or two R1 groups are taken together with their intervening atoms to form an optionally substituted 47 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each Cy is independently an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-10 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;

each R2 is independently an optionally substituted group selected from Ci-6aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R4 is independently halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, - N(R)C(O)R,

-N(R)C(O)N(R)2, -C(O)N(R)OR, -N(R)C(O)OR, -N(R)S(O)2N(R)2, -N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Rx is hydrogen, -R2, -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2;

Rz is hydrogen, -R2, -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2;

[Ar] is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms indepently selected from nitrogen, oxygen, and sulfur, wherein [Ar] is substituted by m instances of R1;

L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, , -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

L2 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(0)-, - C(0)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, , -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

m is 0-4;

n is 0-4; and p is 0-2;

as defined and described in WO 2017/004133, the entirety of each of which is herein incorporated by reference.

[00122] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAKI and IRAK4 inhibitor thereby forming a compound of formula I-qq-1:

I-qq-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Y is N or C-Rx;

each R1 and Rv is independently -R2, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -S(O)2R, S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -N(R)C(O)OR, N(R)C(O)N(R)2, Cy, or -N(R)S(O)2R; or R1 is selected from one of the following formulas:

p O R O i&#1470;N\R —A i&#1470;Nx Ji (CH2)1-4 NR2 (CH2)T4 r . or two R1 groups are taken together with their intervening atoms to form an optionally substituted 47 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;

each of Rx and Ry is independently hydrogen, -R2, -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, C(O)R, -N(R)2, - H[Ar], -OR, or -S(O)2N(R)2; or

Rx and Ry are taken together together with their intervening atoms to form a 4-7 membered partially unsaturated carbocyclic ring or a partially unsaturated heterocyclic ring having 13 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Rz is hydrogen, -R2, -CN, -NO2, halogen, -C(O)N(R)2, -C(O)OR, -C(O)R, -N(R)2, -NH[Ar], -OR, or -S(O)2N(R)2;

[Ar] is phenyl or a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said [Ar] is substituted by m instances 0fRr;

L1 is a covalent bond or a Ci-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -N(R)-, -N(R)C(O)-, - C(O)N(R)-, -N(R)S(O)2-, -S(O)2N(R)-, , -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2-;

m is 0-4; and n is 0-4;

as defined and described in WO 2017/004134, the entirety of each of which is herein incorporated by reference.

[00123] In certain embodiments, the present invention provides a compound of Formula I,

thereby forming a compound of formula I-rr-1,1-rr-2, or I-rr-3:

I-rr-3 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

R is aliphatic, heteroaliphatic, heteroaryl, aryl, halo, amide or CN;

R1 is H, aliphatic or heteroaliphatic;

or R and R1, together with the atoms to which they are attached, form a heterocyclyl ring;

R2is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl or araliphatic;

each R3 independently is H, aliphatic, halogen, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate;

y is from 1 to 6;

as defined and described in WO 2016/172560 and US 2016/0311839, the entirety of each of which is herein incorporated by reference.

[00124] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

; thereby forming a compound of formula I-ss-1:

I-ss-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

R is hydrogen, R1, halogen, cyano, nitro, —OR1, —C(=O)—R1, —C(=O)O—R1, — C(=0)NRn—R1, —S(=0)2—R1, —NRnC(=0)—R1, —NR11C(=0)NR11R11, — NR110(=0)0-R1, —NRuS(=0)2R1 or —NRnRn;

RMs C1-6 alkyl substituted with 0-4 Rla, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Rla, C26alkynyl substituted with 0-3 Rla, C3-10 cycloalkyl substituted with 0-3 Rla, C6-10aryl substituted with 0-3 Rla, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rla, or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rla;

Rlais hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRnRn, — (CH2)IC(0)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRu, —S(O)pNRnRn, — NRbS(O)pRc, —S(O)RC, —S(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, — (CH2)r 14 membered carbocycle substituted with 0-3 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Ra;

R2is C6-10 aryl substituted with 0-4 R2a, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 1-4 R2a, or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;

R2aat each occurrence is independently selected from hydrogen, =0, halo, OCF3, CN, NO2, — (CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)rC(O)NR11R11, —(CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, — NRbC(0)NRuRu, —S(O)pNRnRu, —NRbS(O)pRc, —S(O)RC, —S(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6haloalkyl, —(CH2)r 14 membered carbocycle substituted with 0-1 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-2 Ra;

R3is C1-6 alkyl substituted with 0-3 R3a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R3a, C26 alkynyl substituted with 0-3 R3a, C3-10 cycloalkyl substituted with 0-3 R3a, C6-10aryl substituted with 0-3 R3a, a 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R3aor a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R3a;

R3ais hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, — (CH2)IC(O)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRuRn, — NRbS(O)pRc, —S(O)RC, —S(O)2RC, C1-6 alkyl substituted with 0-2 Ra, C!-6haloalkyl, — (CH2)r 14 membered carbocycle substituted with 0-1 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-1 Ra;

R4and R5are independently selected from hydrogen, C1-4 alkyl substituted with 0-1 Rf, (CH2)phenyl substituted with 0-3 Rd, and a —(CH2) 7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P;

R6 and R7 are independently at each occurrence is selected from hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, — (CH2)rOC(O)Rb, — (CH2)rNR11R11, —(CH2)rC(O)NR11R11, —(CH2)rNRbC(O)Rc, — (CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRnRu, —NRbS(O)pRc, —S(O)2RC, —S(O)2RC, C1-6 alkyl substituted with 0-2 Ra, C!-6haloalkyl, —(CH2)r 14 membered carbocycle substituted with 0-3 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Ra, provided R6 and R7are not both hydrogen;

Rnat each occurrence is independently hydrogen, Re, C1-4 alkyl substituted with 0-1 Rf, CH2phenyl substituted with 0-3 Rd, or —(CH2) 7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Rd; or

R11 and along with another R11, R1, or R2 on the same nitrogen atom may join to form an optionally substituted heterocycle;

Rais hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, —(CH2)rORb, —(CH2)rSRb, — (CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRnRn, — (CH2)rC(O)NRnRu, —(CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(O)NRnRu, —(O)pNRnRu, —NRbS(O)pRc, —S(O)RC, —S(O)2RC, C1-6 alkyl substituted with 0-1 Rf, C1-6 haloalkyl, —(CH2)r 14 membered carbocycle, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P; or two Raon adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH2)n—O—, or —O—CF2—O—, wherein n is selected from 1 or 2;

Rbis hydrogen, Re, C1-6 alkyl substituted with 0-2 Rd, C!-6haloalkyl, C3 cycloalkyl substituted with 0-2 Rd, or (CH2)r-phenyl substituted with 0-3 Rd;

Rc is C1-6 alkyl substituted with 0-1 Rf, C3 cycloalkyl, or (CH2)r-phenyl substituted with 0-3 Rf;

Rdis hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, —ORe, —(CH2)rC(O)Rc, —NReRe, — NReC(O)ORc, C1-6 alkyl, or (CH2)r-phenyl substituted with 0-3 Rf;

Reis selected from hydrogen, C1-6 alkyl, C3 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 Rf;

Rf is hydrogen, halo, NH2, OH, or O(C!-6alkyl);

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2;

as defined and described in WO 2013/106612 and US 2015/0011532, the entirety of each of which is herein incorporated by reference.

[00125] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-tt-1:

I-tt-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

A is a triazole optionally substituted by 0-2 R;

X is N or C—R7;

R is hydrogen, R&#1523;, halogen, cyano, nitro, —OR1, —C(=O)—R1, —C(=O)O—R1, — C(=0)NRn—R1, —S(=O)2—R1, —NRnC(=0)—R', —NR11C(=0)NR11R1, — NR11C(=0)0—R&#1523; —NR11S(=0)2R1 or —NR11R1;

R4s C1-6 alkyl substituted with 0-4 Rla, C!-6haloalkyl, C2-6 alkenyl substituted with 0-3 Rla, C26 alkynyl substituted with 0-3 Rla, C3-10cycloalkyl substituted with 0-3 Rla, C6-10aryl substituted with 0-3 Rla, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rla, or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rla;

Rlais hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)iC(0)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRuRn, — NRbS(O)pRc, —S(C)RC, —S(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, — (CH2)r 14 membered carbocycle substituted with 0-3 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Ra;

R2aat each occurrence is independently selected from hydrogen, =0, halo, OCF3, CN, NO2, — (CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)rC(O)NR11R11, —(CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, — NRbC(0)NRuRu, —S(O)pNRnRu, —NRbS(O)pRc, —S(O)RC, —S(O)2RC, C1-6 alkyl substituted with 0-2 Ra, C!-6haloalkyl, —(CH2)r 14 membered carbocycle substituted with 0-1 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, 0, and S(O)P substituted with 0-2 Ra;

R3is C1-6 alkyl substituted with 0-3 R3a, C!-6haloalkyl, C2-6 alkenyl substituted with 0-3 R3a, C26alkynyl substituted with 0-3 R3a, C3-10cycloalkyl substituted with 0-3 R3a, C6-10aryl substituted with 0-3 R3a, a 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R3 or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R3a;

R3ais hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)iC(O)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRuRn, — NRbS(O)pRc, —S(O)RC, —S(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C!-6haloalkyl, — (CH2)r-14 membered carbocycle substituted with 0-1 Ra, or —(CH2)r-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-1 Ra;

R6 and R7 are independently at each occurrence is selected from hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, — (CH2)rOC(O)Rb, — (CH2)rNRnRu, —(CH2)rC(O)NR11R11, —(CH2)rNRbC(O)Rc, — (CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRnRu, —NRbS(O)pRc, —S(O)RC, — S(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C!-6haloalkyl, —(CH2)r 14 membered carbocycle substituted with 0-3 Ra, or —(CH2)r-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Ra, provided R6 and R7 are not both hydrogen;

R11 and along with another R11, R1, or R2 on the same nitrogen atom may join to form an optionally substituted heterocycle;

Rais hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, —(CH2)rORb, —(CH2)rSRb, — (CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRnRn, — (CH2)rC(O)NRnRu, —(CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —SCOjpNR1^11, —NRbS(O)pRc, —S(O)RC, —S(O)2RC, C1-6 alkyl substituted with 0-1 Rf, C!-6haloalkyl, —(CH2)r 14 membered carbocycle, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P; or two Raon adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH2)n—O—, or —O—CF2—O—, wherein n is selected from 1 or 2;

Rbis hydrogen, Re, C1-6 alkyl substituted with 0-2 Rd, C!-6haloalkyl, C3 cycloalkyl substituted with 0-2 Rd, or (CH2)r-phenyl substituted with 0-3 Rd;

Rc is C1-6 alkyl substituted with 0-1 Rf, C3 cycloalkyl, or (CH2)r-phenyl substituted with 0-3 Rf;

Rdis hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, —ORe, —(CH2)rC(O)Rc, —NReRe, — NReC(O)ORc, C1-6 alkyl, or (CH2)r-phenyl substituted with 0-3 Rf;

Reis selected from hydrogen, C1-6 alkyl, C3 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 Rf;

Rf is hydrogen, halo, NH2, OH, or O(C!-6alkyl);

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2;

as defined and described in WO 2013/106614 and US 2015/0045347, the entirety of each of which is herein incorporated by reference.

[00126] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor compound of formula I-uu-1:

; thereby forming a

I-uu-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is N or C—R7;

R is R1, halogen, cyano, nitro, —O—R1, —C(=O)—R1, —C(=O)O—R1, —C(=O)NRn—R1, — S(=O)2—R1, —NRnC(=O)—R1, —NRuC(=O)NRn—R1, —NRnC(=O)O—R1, — NRUS(=O)2—R1, or—NR11—R1;

R4s C1-6 alkyl substituted with 0-4 Rla, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 Rla, C26 alkynyl substituted with 0-3 Rla, C3-10cycloalkyl substituted with 0-3 Rla, C6-10aryl substituted with 0-3 Rla, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rla, a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 Rla;

Rlais hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)IC(O)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRnRn, —

NRbS(O)pRc, —S(O)RC, —S(0)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, — (CH2)r 14 membered carbocycle substituted with 0-3 Ra, or —(CH2)r 7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)pSubstituted with 0-3 Ra;

R2is C6-10 aryl substituted with 0-4 R2a, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a, a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R2a;

R2aat each occurrence is independently selected from hydrogen, =0, halo, OCF3, CN, NO2, — (CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)rC(O)NR11R11, —(CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, — NRbC(0)NRuRu, —S(O)pNRnRu, —NRbS(O)pRc, —S(O)RC, —S(O)2RC, C1-6 alkyl substituted with 0-2 Ra, C1-6haloalkyl, —(CH2)r 14 membered carbocycle substituted with 0-1 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-2 Ra;

R3is C1-6 alkyl substituted with 0-3 R3a, C1-6 haloalkyl, C2-6 alkenyl substituted with 0-3 R3a, C26 alkynyl substituted with 0-3 R3a, C3-10cycloalkyl substituted with 0-3 R3a, C6-10aryl substituted with 0-3 R3a, a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R3a, or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R3a;

R3ais hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, —(CH2)rNRnRn, —(CH2)IC(0)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRnRn, — NRbS(O)pRc, —S(O)RC, —S(O)2RC, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, — (CH2)r 14 membered carbocycle substituted with 0-1 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-1 Ra;

R6 and R7 are independently at each occurrence is selected from hydrogen, =0, F, Cl, Br, OCF3, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)rC(O)Rb, —(CH2)rC(O)ORb, — (CH2)rOC(O)Rb, — (CH2)rNRnRu, — (CH2)rC(O)NR11R11, —(CH2)rNRbC(O)Rc, — (CH2)rNRbC(O)ORc, —NRbC(O)NRnRn, —S(O)pNRnRu, —NRbS(O)pRc, —S(O)RC, — S(O)2Rc, C1-6 alkyl substituted with 0-2 Ra, C1-6 haloalkyl, —(CH2)r 14 membered carbocycle substituted with 0-3 Ra, or —(CH2)r 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Ra, provided R6 and R7 are not both hydrogen;

Rnat each occurrence is independently Re, C1-4 alkyl substituted with 0-1 Rf, CH2-phenyl substituted with 0-3 Rd, or —(CH2) 7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P substituted with 0-3 Rd;

alternatively, R11 and along with another R11, R1, or R2 on the same nitrogen atom may join to form an optionally substituted azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or 4-(C!. 6 alkyl)piperazinyl;

Rais Rd, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2, —(CH2)rORb, —(CH2)rSRb, —(CH2)!C(O)Rb, — (CH2)rC(O)ORb, —(CH2)rOC(O)Rb, — (CH2)rNRnRn, —(CH2)iC(0)NR11R11, — (CH2)rNRbC(O)Rc, —(CH2)rNRbC(O)ORc, —NRbC(0)NRnRn, —S(O)pNRnRn, — NRbS(O)pRc, —S(O)2Rc, —S(O)2Rc, C1-6 alkyl substituted with 0-1 Rf, C1-6 haloalkyl, — (CH2)r 14 membered carbocycle, or —(CH2)r 7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)P; alternatively two Raon adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH2)n—O— , or —O—CF2—O—, wherein n is selected from 1 or 2;

Rbis Rc, C1-6 alkyl substituted with 0-2 Rd, C1-6 haloalkyl, C3cycloalkyl substituted with 0-2 Rd, or (CH2)r-phenyl substituted with 0-3 Rd;

Rc is C1-6 alkyl substituted with 0-1 Rf, C3 cycloalkyl, or (CH2)r-phenyl substituted with 0-3 Rf;

Rdis hydrogen, F, Cl, Br, OCF3, CF3, CN, NO2, —ORe, —(CH2)rC(O)Rc, —NReRe, — NReC(O)ORc, C1-6 alkyl, or (CH2)r-phenyl substituted with 0-3 Rf;

Reis selected from hydrogen, C1-6 alkyl, C3 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 Rf;

Rf is hydrogen, halo, NH2, OH, or O(C!-6alkyl);

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and m is 0, 1, or 2;

as defined and described in WO 2013/106641 and US 2015/0018344, the entirety of each of which is herein incorporated by reference.

[00127] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

; thereby forming a compound of formula I-vv-1 or I-vv-2:

I-vv-1

I-vv-2 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

RMs:

(a) C2-3 hydroxyalkyl substituted with zero to 4 Rla wherein Rlais independently selected from F, Cl, —OH, —CHF2, —CN, —CF3, —OCH3, and cyclopropyl;

(b) C1-3 alkyl substituted with —O(C!-3 alkyl) and zero to 4 Rlawherein Rlais independently selected from F, Cl, —OH, —CHF2, —CN, —CF3, and cyclopropyl;

F, Cl, —OH, —CHF2, —CF3, —CN—OCH3, cyclopropyl, and —OP(O)(OH)2;

(d) —(CH2)2-4NHC(O)(C 1-6 alkyl), — (CH2)2CH(CH3)NHC(O)(C1-6alkyl), — (CH2)2CH(CH3)NHC(O)(CH2)0-1NH(C 1-6 alkyl), or — (CH2)2CH(CH3)NHC(O)(CH2)0-1N(C1.4alkyl)2;

(e) cyclohexyl substituted with zero to 2 substituents independently selected from — OH, —OCH3, C1-6 alkyl, C!-6hydroxyalkyl, —C(O)NH2, —C(O)NH(C!-3 alkyl), — C(O)NH(C!-6hydroxyalkyl), —C(O)NH(C3-6 cycloalkyl), —C(O)NH(C3-6 fluoro cycloalkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)O(C1-3 alkyl), —NHS(O)2CH3, — S(O)2NH2, —S(O)2(C!-3 alkyl), —S(C1-3 alkyl), thiazolyl, methyl pyrazolyl, and Ci3 alkyl substituted with —OH and cyclopropyl;

(f) —(CH2)2(phenyl) wherein said phenyl is substituted with —C(O)NH2, —

C(O)NH(C1-3 alkyl), or —S(O)2NH2; or (g) piperidinyl substituted with —C(O)(C!-3 alkyl);

R2is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, or triazolyl, each substituted with zero to 2 substituents independently selected from F, Cl, —OH, —CN, C1-3 alkyl, — CH2C(O)OCH3, — O(C1-3alkyl), —NH2, —NH(C1-3 alkyl), —NH(cyclopropyl), — C(O)NH2, —NHC(O)(C1-3 alkyl), —NH(tetrahydropyranyl), hydroxypyrrolidinyl, =0, — O(piperidinyl), and pyridinyl; and

R3is:

(a) C1-6 alkyl substituted with zero to 4 substituents independently selected from F, —

OH, —CH3, —CF3, and C3-6cycloalkyl;

(b) C3-6 cycloalkyl substituted with zero to 2 substituents independently selected from

F, —OH, C1-3 hydroxyalkyl, —CH3, —CF2H, —NH2, and —C(O)OCH2CH3;

(d) phenyl substituted with zero to 2 substituents independently selected from —OH, —CN, —O(C!-3 alkyl), C1-3 hydroxyalkyl, —C(0)NH2, —S(O)2NH2, — NHS(O)2(C!-3 alkyl), pyrazolyl, imidazolyl, and methyl tetrazolyl; or

?—V—7 S--\/ (e) ξ J \/ as defined and described in WO 2014/074675 and US 2015/0284382, the entirety of each of which is herein incorporated by reference.

[00128] In certain embodiments, the present invention provides a compound of Formula I, s 1?

f ri« Rs * wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-xx-1 nr

LBM

I-xx-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

R1 is an optionally substituted aromatic heterocyclic group or an optionally substituted C6-14 aryl group;

R2 is a hydrogen atom or a substituent;

R3 and R4 are independently a hydrogen atom or a substituent, or R3and R4 in combination optionally form an optionally substituted ring;

R5 and R6 are independently a hydrogen atom or a substituent, or R5and R6 in combination optionally form an optionally substituted ring;

X is CR7R8, NR9, O or S;

R7and R8are independently a hydrogen atom or a substituent, or R7and R8in combination optionally form an optionally substituted ring; and

R9 is a hydrogen atom or a substituent;

as defined and described in WO 2015/068856 and US 2015/0133451, the entirety of each of which is herein incorporated by reference.

[00129] In certain embodiments, the present invention provides a compound of Formula I, wherein LBM is an E3 ubiquitin ligase (IAP) binding moiety ; thereby forming a compound of formula I-yy-1

i-yy-1 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein the variable Ris as defined and described in Ohoka, N. et al. (2017). In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (lAP)-dependent Protein Erasers (SNIPERs). Journal of Biological Chemistry, 292(11), 4556-4570,, the entirety of each of which is herein incorporated by reference. [00130] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor thereby forming a compound of formula I-zz-1

I-zz-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

R1 denotes absent, A or Q-Het,

z. O wherein

X denotes O, S or N,

Y denotes C or N,

T denotes C or N, or

Z denotes a pyridine or a pyridazine group,

Rais absent, OR3, CF3, Hal, orNO2,

Rb is absent, A, or COHet,

R2 denotes H, Het, Q-Het, Cyc, A or OA, each Het is independently a 4-9 membered monocyclic ring or a fused, spiro or bridged bicyclic ring, which is saturated, unsaturated, or aromatic, which contains 1 to 3 heteroatoms independently selected from N, O, and S, and a group CO, SO or S02, and wherein 1 or 2 H atoms may be replaced by A, OA, COA, CN, Hal, N02, OR3, SOA and/or S02A,

Cyc denotes a 4-8 saturated carbocyclic ring optionally containing a group SO, S02, or CO, and optionally substituted once or twice by a group selected from CO(NR3)2, COHet, OR3, Het1, A, CH2Het1, NH2, NHCOA, OCH2Cyc1, S02A and — SA(=NH)(=0), each Q is independently a linear or branched alkylene, having 1 to 6 carbon atoms wherein 1-5 H atoms may be replaced by a group independently selected from OR3, Hal, and N(R3)2, and wherein 1 or 2 CH2 groups may be replaced by a group independently selected from CO, SO, S02and NR3, or Q denotes a 4 membered bivalent heterocyclic ring, which is saturated, unsaturated or aromatic and which contains 1 to 3 heteroatoms independently selected from N, 0 and S, each A is independently a linear or branched alkyl having 1 to 10 carbon atoms wherein 1 to 7 H atoms may be replaced by a group independently selected from —OR3, Hal, NHS02A, SO2A, SOA, and N(R3)2, and wherein 1, 2 or 3 non-adjacent —CH2— groups may be replaced by a group independently selected from —CO—, NR3 and —O—, each Hal is independently F, Cl, Br or I, each R3 is independently H or C1-C6-alkyl wherein 1 H atom may be replaced by a group selected from OH, O—C1-C6-alkyl, and Hal, each Het1 is independently a five- or six membered saturated monocyclic heterocycle which contains 1-3 N- and/or O-atoms, which optionally is monosubstituted by A,

Cyc1 denotes cycloalkyl with 3-7 atoms; as defined and described in WO 2014/008992 and US 2015/0141396, the entirety of each of which is herein incorporated by reference.

[00131] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor a compound of formula I-aaa-1 ; thereby forming

I-aaa-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is a monocyclic heteroaryl;

R1 is one to three optionally substituted with R10 monocyclic or bicyclic heteroaryl;

R2 is, -C(O)NH2, -C(O)NH-R°, -C(O)NH-R00-OH, -C(O)NH-R00-OR°, -C(O)N(R°)2, -C(O)NH197 cycloalkyl, -C(O)NH-heterocycloalkyl, -C(O)NH-(pyrazolyl optionally substituted with R0)&#1523; -C(O)-R°, -C(O)-cycloalkyl, -S(O)2NH2, -S(O)2NH-R°, -S(O)2NH-cycloalkyl, -R00OH&#1523; -R00-OR°, -R00-( morpholin yl) phenyl, oxadiazolyl, or tetrazolyl optionally substituted with R0&#1523; wherein oxadiazolyl in R2 is, R°, R°°-OH or may be substituted with R°-OR°;

R3 is, H, R°, halogeno-lower alkyl, cycloalkyl, heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, -C(O)N(R°)2, -R°°-cycloalkyl, -R°°-heterocycloalkyl, -R°°-phenyl, -R°°-OH or a -R00 -OR0, wherein the cycloalkyl in R3, heterocycloalkyl, phenyl and pyridyl, R°, halogen, -C(O)OR°, -C(O)-R°, -OH, -OR0, -S(O)2-R°, -O-halogeno-lower alkyl, -OR00(morpholin yl), -R00-OH, -R00-OR°, morpholin yl or, -R00-(morpholin yl) may be substituted;

R10 may be the same or different from each other, R°, halogen, halogeno-lower alkyl, cycloalkyl, -OR0, optionally substituted amino, -O-halogeno-lower alkyl, -R00-OH, -R00-OR° or, -R00is optionally amino substituted,

R° is the same or different from each other, lower alkyl,

R00 are identical or different from each other, it is a lower alkylene;

as defined and described in WO 2011/043371, the entirety of which is herein incorporated by reference.

[00132] In some embodiments, the compound of formala I-aaa-1 above is provided as a compound of formula I-aaa-2,1-aaa-3, or I-aaa-4:

I-aaa-2

or a pharmaceutically acceptable salt thereof, wherein:

each of LBM, L, R1, R2, R3, and R10 is as defined above.

[00133] In some embodiments, In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

; thereby forming a compound of formula I bbb-1

I-bbb-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is selected from O, S, and NH;

A is selected from aryl or heteroaryl;

R at each occurrence is independently selected from hydrogen, cyano, halo, hydroxy, -N02, NR3R4, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyi, optionally substituted heterocycloalkyl or optionally substituted heteroaryl; wherein the optional substituent, in each occurrence, is independently selected from halo, alkyl, haloalkyl, cyano, -NR5R6or -C00R7;

R1 at each occurence is independently selected from hydrogen, halogen, alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyi, heteroaryl, Y-arylalkyl or -Y-cycloalkyl; wherein cycloalkyi, aryl, heterocycloalkyl, heterocycloalkylalkyi, heteroaryl and arylalkyl can be optionally substituted with hydroxy, alkyl, haloalkyl, cyano or halo;

Y is selected from direct bond, O, -C(0)- or NR7;

R2 at each occurence is independently selected from hydrogen, carboxy, cyano, hydroxy, hydroxyalkyl, alkyl, aryl, heteroaryl, -S02R5 or oxo;

R3 and R4 are independently selected from hydrogen, hydroxyalkyl, aminoalkyl, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl; wherein the optional substituent, in each occurrence, is independently selected from halo, haloalkyl or -C00R7;

R5 and R6 are independently selected from hydrogen, alkyl, COR7 or -C00R7;

R7at each occurrence is independently selected from hydrogen or alkyl; and m, n and p are selected from 1, 2 or 3;

as defined and described in WO 2013/042137, the entirety of which is herein incorporated by reference.

[00134] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an

IRAK4 inhibitor

I-ccc-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring Z! is an optionally substituted heteroaryl;

Ring Z2 is an optionally substituted heterocycloalkyl, optionally substituted heteroaryl or a direct bond;

Riis alkyl, cyano, —NRaRbor optionally substituted groups selected from cycloalkyl, aryl or heterocyclyl; wherein the substituent, at each occurrence, independently is alkyl, alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl, nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH2—O-alkyl, —OP(O)(O-alkyl)2 or —CH2—OP(O)(O-alkyl)2;

R2, at each occurrence, independently is an optionally substituted group selected from alkyl or cycloalkyl; wherein the substituent, at each occurrence, is independently halogen, alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;

R3, at each occurrence, independently is hydrogen, halogen, alkyl, haloalkyl, haloalkoxy, alkoxy, —NRaRb, hydroxyl or hydroxyalkyl;

Rais hydrogen or alkyl;

Rbis hydrogen, alkyl, acyl, hydroxyalkyl, —SO2-alkyl or optionally substituted cycloalkyl;

m and n are independently 1 or 2;

as defined and described in WO 2015/104662 and US 2016/0326151, the entirety of each of which is herein incorporated by reference.

[00135] In certain embodiments, the present invention provides a compound of Formula I,

; thereby forming a compound of formula I-ddd-1

I-ddd-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X! and X3 independently are CH or N; X2 is CR2 or N; provided one and not more than one of Xi, X2 or X3 is N;

A is O or S;

Y is —CH2— or O;

Ring Z is aryl or heterocyclyl;

Ri, at each occurrence, is independently halo or optionally substituted heterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or—NRaRb;

R2 is hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or —NRaRt>; wherein the substituent is alkyl, amino, halo or hydroxyl;

R3, at each occurrence, is alkyl or hydroxyl;

Ra and Rb are independently hydrogen, alkyl, acyl or heterocyclyl;

m and n are independently 0, 1 or 2;

p is 0 or 1;

as defined and described in WO 2015/104688 and US 2016/0340366, the entirety of each of which is herein incorporated by reference.

[00136] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-eee-1

I-eee-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Z!is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or is absent;

Z2 is optionally substituted cycloalkyl, aryl or heterocyclyl;

Riis hydrogen, optionally substituted alkyl, amino, halogen, cyano, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;

R2at each occurrence is hydrogen, halogen, amino, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;

R3 at each occurrence is hydroxy, halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl or —NRaRb;

Ra and Rb, independently for each occurrence, are hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;

m at each occurrence, is 0, 1 or 2; and n at each occurrence, is 0, 1, or 2;

as defined and described in WO 2015/193846 and US 2017/0152263, the entirety of each of which is herein incorporated by reference.

[00137] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor thereby forming a compound of formula I-fff-1

I-fff-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherei R° represents hydrogen or C1-C4-alkyl, where the C1-C4-alkyl radical may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy and halogen;

R1 represents hydrogen, halogen, cyano, C(=O)OH, C(=O)ORa, C(=O)NH2, C(=O)N(H)Ra, C(=O)N(Ra)Rb, C(=O)Rd, hydroxy or C1-C6-alkyl, where the C1-C6-alkyl radical is optionally mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6-alkyl, NH2, NHRa, N(Ra)Rb, C1-C6-alkoxy which is optionally mono- or polysubstituted by identical or different radicals from the group consisting of halogen, C3-C8-cycloalkoxy which is optionally mono- or polysubstituted by identical or different radicals from the group consisting of halogen, heterocycloalkyl which is optionally mono- or poly substituted by identical or different radicals from the group consisting of Rc, or represents C1-C6-alkoxy, where the C!-C6-alkoxy radical may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6-alkyl, NH2, NHRa, N(Ra)Rb, C3C8-cycloalkyl which is optionally mono- or poly substituted by identical or different radicals from the group consisting of halogen, C!-C6-alkoxy which is optionally mono- or polysubstituted by identical or different radicals from the group consisting of halogen, C3C8-cycloalkoxy which is optionally mono- or polysubstituted by identical or different radicals from the group consisting of halogen, heterocycloalkyl which is optionally monoor poly substituted by identical or different radicals from the group consisting of Rc, aryl which is optionally mono- or polysubstituted by identical or different radicals from the group consisting of Rc, or 5- or 6-membered heteroaryl which is optionally mono- or polysubstituted by identical or different radicals from the group consisting of Rc, or represents C3-C8-cycloalkoxy or heterocycloalkoxy which may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl, or represents aryloxy or 5- or 6-membered heteroaryloxy in which aryloxy and 5- or 6membered heteroaryloxy may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, C1-C6-alkyl and C1-C6-alkoxy, or represents C3-C8-cycloalkyl or heterocycloalkyl which may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl, or represents C2-C6-alkenyl or C2-C6-alkynyl, or represents aryl, 5- to 10-membered heteroaryl, aryl-C1-C4-alkyl or 5- or 6-membered heteroaryl-C1-C4-alkyl, where aryl and heteroaryl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of halogen, hydroxy, cyano, C(=O)OH, C(=O)ORa, C!-C6-alkyl, C3-C8-cycloalkyl and C!-C6-alkoxy; Rarepresents C!-C6-alkyl, C3-C10-cycloalkyl, heterocycloalkyl, aryl or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of halogen, hydroxy, cyano, C!-C3-alkyl, C!-C3-alkoxy, heterocycloalkyl, —C(=O)O—C!-C6-alkyl and S(=O)2—C1-C6-alkyl;

Rb represents C!-C6-alkyl or C3-C10-cycloalkyl;

or Raand Rb together with the nitrogen atom form a 5- or 6-membered heterocycle which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, and C!-C6-alkyl;

Rc represents hydroxy, halogen, cyano, C!-C3-alkyl or C!-C3-alkoxy;

Rd represents hydrogen, C!-C6-alkyl or C3-C10-cycloalkyl;

R2 represents hydrogen, C!-C6-alkyl or C3-C6-cycloalkyl;

R13 represents hydrogen or C!-C6-alkyl;

W represents 5-membered heteroaryl which contains one to three heteroatoms selected from the group consisting of N, O and S and may optionally be monosubstituted by R3 and optionally be mono- or poly substituted by identical or different radicals R4 or

W represents pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl or 1,3,5-triazinyl which may optionally be monosubstituted by R3 and optionally be mono- or poly substituted by identical or different radicals R4;

R3 represents hydrogen, halogen, cyano, C(=O)Ra, NH2, NHRa, N(Ra)Rb, N(H)C(=O)Ra or C1-C6alkyl, where C!-C6-alkyl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)Ra, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6-alkyl, NH2, NHRa, N(Ra)Rb, C1-C6-alkoxy, C3-C8cycloalkoxy, where C!-C6-alkoxy and C3-C8-cycloalkoxy may optionally be mono- or poly substituted by identical or different halogen radicals;

or C!-C6-alkyl is optionally mono- or poly substituted by identical or radicals from the group consisting of C3-C6-cycloalkyl and heterocycloalkyl, where C3-C6-cycloalkyl and heterocycloalkyl may optionally be mono-, di- or tri substituted by identical or different radicals from the group consisting of halogen, cyano, C!-C3-alkyl and C!-C3-alkoxy, or C!-C6-alkyl is optionally mono- or poly substituted by identical or different radicals from the group consisting of aryl and 5- or 6-membered heteroaryl, where aryl and 5- or 6-membered heteroaryl may optionally be mono-, di- or trisubstituted by identical or different radicals from the group consisting of halogen, cyano, C1-C3-alkyl and C1-C3-alkoxy, or R3 represents C1-C6-alkoxy, where C1-C6-alkoxy may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)ORa, S(=O)2—CiC6-alkyl, N(Ra)Rb, C3-C8-cycloalkyl, C1-C4-alkoxy, C3-C8-cycloalkoxy, or represents C3-C6-cycloalkyl, heterocycloalkyl or C5-Cn-spirocycloalkyl, where cycloalkyl, heterocycloalkyl and spirocycloalkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)Ra, C(=O)OH, C(=O)ORa, C1-C6-alkyl and C1-C4-alkoxy;

or represents aryl or 5- to 10-membered heteroaryl, where aryl and heteroaryl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, hydroxy, cyano, C(=O)ORa, S(=O)2—C1-C6-alkyl, NO2, NH2, NHRa, N(Ra)Rb, N(H)C(=O)Ra, C3-C8-cycloalkyl, CiC3-alkoxy and C!-C3-alkyl, where

C!-C3-alkyl may optionally be mono- or polysubstituted by identical or different halogen radicals; R4 represents halogen, hydroxy, cyano or C!-C6-alkyl, where C!-C6-alkyl may optionally be monoor poly substituted by identical or different radicals from the group consisting of halogen, C!-C6-alkoxy, where C!-C6-alkoxy may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, C2-C6-alkenyl, C2-C6alkynyl, C3-C10-cycloalkyl, 3- to 10-membered heterocycloalkyl and aryl, where aryl may optionally be mono- or polysubstituted by identical or different radicals R;

or R4 represents aryl or heteroaryl which may optionally be mono- or poly substituted by identical or different radicals R;

or R4 represents C(=O)Ra, C(=O)NH2, C(=O)N(H)Ra, C(=O)N(Ra)Rb, C(=O)ORa, NH2, NHRa, N(Ra)Rb, N(H)C(=O)Ra, N(Ra)C(=O)Ra, N(H)C(=O)NH2, N(H)C(=O)NHRa, N(H)C(=O)N(Ra)Rb, N(Ra)C(=O)NH2, N(Ra)C(=O)NHRa, N(Ra)C(=O)N(Ra)Rb, N(H)C(=O)ORa, N(Ra)C(=O)ORa, NO2, N(H)S(=O)Ra, N(Ra)S(=O)Ra, N(H)S(=O)2Ra, N(Ra)S(=O)2Ra, N=S(=O)(Ra)Rb, OC(=O)Ra, OC(=O)NH2, OC(=O)NHRa,

OC(=O)N(Ra)Rb, SH, SRa, S(=O)Ra, S(=0)2Ra, S(=O)2NH2, S(=O)2NHRa, S(=O)2N(Ra)Rb or S(=O)(=N—Ra)Rb;

R represents halogen, cyano, C!-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C10-cycloalkyl, 3- to 10-membered heterocycloalkyl, aryl, heteroaryl, C(=O)Ra, C(=O)NH2, C(=O)N(H)Ra, C(=O)N(Ra)Rb, C(=O)ORa, NH2, NHRa, N(Ra)Rb, N(H)C(=O)Ra, N(Ra)C(=O)Ra, N(H)C(=O)NH2, N(H)C(=0)NHRa, N(H)C(=O)N(Ra)Rb, N(Ra)C(=O)NH2, N(Ra)C(=O)NHRa, N(Ra)C(=O)N(Ra)Rb, N(H)C(=O)ORa, N(Ra)C(=O)ORa, NO2, N(H)S(=O)Ra, N(Ra)S(=O)Ra, N(H)S(=O)2Ra, N(Ra)S(=O)2Ra, N=S(=O)(Ra)Rb, OH, C1-C6-alkoxy, OC(=O)Ra, OC(=O)NH2, OC(=O)NHRa, OC(=O)N(Ra)Rb, SH, SRa, S(=O)Ra, S(=O)2Ra, S(=O)2NH2, S(=O)2NHRa, S(=O)2N(Ra)Rb or S(=O)(=NRa)Rb;

n represents 0 or 1;

Y represents a group selected from:

where * represents the point of attachment of the group to the remainder of the molecule;

R5 represents hydrogen, C!-C6-alkyl or C3-C10-cycloalkyl, where

C!-C6-alkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, S(=O)2— C!-C6-alkyl, N(Ra)Rb, C!-C4-alkoxy and C3-C8-cycloalkyl;

R6 represents hydrogen or C!-C6-alkyl, where

C!-C6-alkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C3-C10-cycloalkyl, C(=O)Ra, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6-alkyl, N(Ra)Rb, C1-C4-alkoxy and C3-C8cycloalkoxy, or represents C3-C10-cycloalkyl, where

C3-C10-cycloalkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl, where C!-C6-alkyl may optionally be substituted by hydroxy, or represents heterocycloalkyl, where heterocycloalkyl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, cyano, C!-C3-alkyl and C!-C3-alkoxy, or represents aryl or 5- or 6-membered heteroaryl, where aryl and 5- or 6-membered heteroaryl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, cyano, C!-C3-alkyl, CiC3-alkoxy, S(=O)2NH2, S(=O)2NHRa and S(=O)2N(Ra)Rb;

R7arepresents hydrogen, halogen, N(Ra)Rb, C!-C6-alkyl or C3-C10-cycloalkyl, where C!-C6-alkyl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6alkyl, N(Ra)Rb, C!-C4-alkoxy, C3-C8-cycloalkyl and heterocycloalkyl;

R7b represents hydrogen, halogen or C!-C6-alkyl, where C!-C6-alkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6-alkyl, N(Ra)Rb, C1-C4-alkoxy, C3C8-cycloalkyl and heterocycloalkyl;

or R7aand R7b together with the carbon atom form C3-C6-cycloalkyl which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl, or R7a and R b together represent an oxo group;

R7c represents hydrogen, halogen, N(Ra)Rb, C!-C6-alkyl or C3-C10-cycloalkyl, where

C!-C6-alkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=0)0H, C(=0)0Ra, S(=0)2— C!-C6-alkyl, N(Ra)Rb, C!-C4-alkoxy, C3-C8-cycloalkyl and heterocycloalkyl;

R7d represents hydrogen, halogen or C!-C6-alkyl, where

or R7cand R7d together with the carbon atom form C3-C6-cycloalkyl which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl, or R7c and R7d together represent an oxo group;

R8a represents hydrogen, halogen, N(Ra)Rb, C!-C6-alkyl or C3-C10-cycloalkyl, where

R8b represents hydrogen, halogen or C!-C6-alkyl, where

or R8aand R8b together with the carbon atom form C3-C6-cycloalkyl which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl,

R8c represents hydrogen, halogen, N(Ra)Rb, C!-C6-alkyl or C3-C10-cycloalkyl, where

R8d represents hydrogen, halogen or C!-C6-alkyl, where

or R8cand R8d together with the carbon atom form C3-C6-cycloalkyl which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano and C!-C6-alkyl, or R8c and R8d together represent an oxo group;

represents 0, 1 or 2, p represents 0, 1 or 2, q represents 0, 1 or 2, r represents 0, 1 or 2, s represents 0, 1 or 2, where 0, p, q, r and s do not simultaneously represent 0;

Z represents a group selected from C(=O), CR9R10, NR11, O, S, S(=O) and S(=O)2;

R9 represents hydrogen or C!-C6-alkyl,

R10 represents hydrogen, halogen, cyano, C(=O)Ra, C(=O)OH, C(=O)ORa, C(=O)NH2, C(=O)N(H)Ra, C(=O)N(Ra)Rb, N(H)C(=O)Ra, N(Rb)C(=O)Ra, S(=O)2Ra, hydroxy, N(Ra)Rb and C!-C6-alkyl, where

C!-C6-alkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)Ra, C(=O)OH, C(=O)ORa, S(=O)2—C1-C6-alkyl, N(Ra)Rb, C!-C4-alkoxy and C3-C8-cycloalkoxy, or represents CiC6-alkoxy, where

C!-C6-alkoxy may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, S(=O)2— C!-C6-alkyl, N(Ra)Rb, C3-C8-cycloalkyl, C!-C4-alkoxy, C3-C8-cycloalkoxy, heterocycloalkyl, aryl and 5- or 6-membered heteroaryl, where aryl and 5- or 6-membered heteroaryl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, cyano, C!-C3-alkyl and C!-C3-alkoxy, or represents aryloxy or 5- or 6-membered heteroaryloxy in which aryloxy and 5- or 6-membered heteroaryloxy may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)OH, C(=O)ORa, C!-C3-alkyl and C1-C3-alkoxy, or represents C3-C8-cycloalkyl, C3-C8-cycloalkyl-C1-C4-alkyl, heterocycloalkyl or heterocycloalkyl-C1-C4-alkyl, which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=O)Ra, C(=O)OH, C(=O)ORa, C1-C6-alkyl and C1-C6-alkoxy, where

C!-C6-alkoxy may optionally be mono- or poly substituted by identical or different halogen radicals or an oxo group;

or represents C2-C6-alkenyl or C2-C6-alkynyl, or represents aryl, 5- to 10-membered heteroaryl, aryl-C1-C4-alkyl or 5- or 6-membered heteroaryl-C1-C4-alkyl, where aryl and heteroaryl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, hydroxy, cyano, C(=0)0H, C(=0)0Ra, NHRa, N(Ra)Rb, C!-C3-alkyl, C3-C8-cycloalkyl and C1-C3-alkoxy;

or R9 and R10 together with the carbon atom form C3-C8-cycloalkyl or a 4- to 6-membered heterocycle, where the C3-C8-cycloalkyl radical or the 4- to 6-membered heterocycle may optionally be monoor polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C!-C6-alkyl, C(=O)Raand an oxo group;

R11 represents hydrogen, C(=0)Ra, C(=0)0Ra, C(=0)NH2, C(=0)N(H)Ra, C(=0)N(Ra)Rb, S(=O)2Ra, S(=0)2N(Ra)Rb or C1-C6-alkyl, where

C!-C6-alkyl may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C(=0)Ra, C(=0)0Ra, C(=0)NH2, C(=0)N(H)Ra, C(=0)N(Ra)Rb, S(=0)2—C1-C6-alkyl, N(Ra)Rb, C3-C8-cycloalkyl, C1-C4alkoxy and C3-C8-cycloalkoxy, where

C3-C8-cycloalkyl, C!-C4-alkoxy and C3-C8-cycloalkoxy may optionally be mono- or polysubstituted by identical or different radicals from the group consisting of hydroxy and halogen;

or represents C3-C8-cycloalkyl, heterocycloalkyl or heterocycloalkyl-C1-C4-alkyl which may optionally be mono- or poly substituted by identical or different radicals from the group consisting of hydroxy, halogen, cyano, C!-C6-alkyl, C!-C6-alkoxy, where alkyl and alkoxy may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen and an oxo group, or represents C2-C6-alkenyl or C2-C6-alkynyl, or represents aryl, 5- to 10-membered heteroaryl, aryl-C1-C4-alkyl or 5- or 6-membered heteroaryl-C1-C4-alkyl, where aryl and heteroaryl may optionally be mono- or poly substituted by identical or different radicals from the group consisting of halogen, hydroxy, cyano, C(=0)0H, C(=0)0Ra, C!-C3-alkyl, C3-C8-cycloalkyl and C!-C3-alkoxy;

as defined and described in WO 2015/091426 and US 2016/0311833, the entirety of each of which is herein incorporated by reference.

[00138] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of

formula I-ggg-1

i-ggg-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Ring A is phenylene or 5- to 6-membered heteroarylene containing 1-3 heteroatoms chosen from O, S, and N, wherein ring A is optionally substituted with lower alkyl that is further optionally substituted,

Ring B is phenylene, 5- to 6-membered heterocycloalkylene containing 1-3 heteroatoms chosen from O, S, and N, or 5- to 6-membered heteroarylene containing 1-3 heteroatoms chosen from 0, S, and N, wherein ring B is optionally substituted with lower alkyl that is further optionally substituted,

R3is chosen from hydrogen, lower alkyl optionally substituted with alkoxy, amino, N(alkyl)amino, N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl, wherein phenyl, heterocycloalkyl, and heteroaryl are optionally substituted with one or two groups independently chosen from lower alkyl and wherein alkoxy is optionally substituted with tri(alkyl)silyl,

R4is chosen from heteroarylene and arylene, each of which is optionally substituted, or R4and R3 taken together with the nitrogen to which they are bound, form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R4 is an alkylene chain having 1-3 carbon atoms that is optionally substituted with one or two groups independently chosen from lower alkyl and cycloalkyl, each of which groups is optionally substituted with hydroxyl or alkoxy, or R4is absent,

R5 is chosen from C(O)NR51, NR52, and O or R5 is absent, provided that if R4 is absent, then R5 is absent,

R6 is an alkylene or alkenylene chain having one or two double bonds, wherein the alkylene or alkenylene chain has 2 to 10 carbon atoms, wherein the alkylene or alkenylene chain is optionally substituted with one or two groups independently chosen from lower alkyl and cycloalkyl, each of which groups is optionally substituted with hydroxyl or alkoxy, and further wherein one or two of the carbon atoms in the alkylene chain is optionally replaced by an O, S, SO, SO2, or NR61, and wherein two of the carbon atoms in the alkylene chain, are optionally connected by a two or three carbon atom alkylene chain to form a 5- to 7-membered ring.

R7 is chosen from NR71 and O or R7 is absent,

R51 is chosen from hydrogen and lower alkyl,

R52 is chosen from hydrogen, lower alkyl, and —C(O)OR81,

R61 is chosen from hydrogen, lower alkyl, and —C(O)OR81,

R71 is chosen from hydrogen, lower alkyl, and —C(O)OR81, and

R81 is lower alkyl;

as defined and described in WO 2014/143672 and US 2016/0002265, the entirety of each of which is herein incorporated by reference.

[00139] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-hhh-1

I-hhh-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, imidazo[4,5b]pyridinyl, and purinyl, wherein said heteroaryl is substituted with Ra and Rb;

Ra is H, F, Cl, Br, —CN, —OH, C1-4 alkyl, C1-4 fluoroalkyl, C!-4hydroxyalkyl, C1-4 alkoxy, —NH2, —NH(C 1-4 alkyl), —N(C1-4 alkyl)2, —NH(C!-4 hydroxyalkyl), —NH(C!-4 fluoroalkyl), — NH(C1-6hydroxy-fluoroalkyl), —C(O)NH2, —CH2NHC(O)(C1-6 alkyl), —

CH2NHC(O)(C1-6hydroxyalkyl), —CH2NHC(O)NH(C 1-6 alkyl),—

CH2NHC(O)NHCH2(phenyl), — CH2NHC(O)N(C1-4 alkyl)2, — CH2NHC(O)O(C1-4 alkyl), —CH2NHC(O)(C3-6 cycloalkyl), —CH2NHC(O)(tetrahydrofuranyl),—

CH2NHC(O)CH2(C3-6 cycloalkyl), —CH2NHC(O)CH2(tetrahydropyranyl),—

CH2NHC(O)CH2(phenyl), —NHC(O)(C1-4 alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or pyridazinyl;

Rbis H or—NH2;

Riis:

(i) C1-6 alkyl, C1-6 fluoroalkyl, C1-6 hydroxyalkyl, C1-8 hydroxy-fluoroalkyl, —(Ci- alkylenyl)O(C1-4 alkyl), —(C1-6 alkylenyl)O(C1-4fluoroalkyl), —(Ci6 fluoroalkylenyl)O(C1-4 alkyl), —(C1-6fluoroalkylenyl)O(C1-4 deuteroalkyl), — (C1-6 fluoroalkylenyl)O(C1-4fluoroalkyl), —(C1-4 fluoroalkylenyl)C(C36 cycloalkyl)2(OH), —(C1-4alkylenyl)NHC(O)(C1-4 alkylenyl)OC(O)(C1-3 alkyl), —(C1-6alkylenyl)NHS(O)2(C1-4 alkyl), —(C1-6 alkyl enyl)P(O)(C 1-4 alkoxy)2, —(Ci6 fluoroalkylenyl)NH(C1-4 alkyl), —(C1-6 alkylenyl)C(O)NH(C1-4 alkyl), —(Ci6 fluoroalkylenyl)C(O)NH(C1-4 alkyl), —(C1-6fluoroalkylenyl)C(O)NH(C14 hydroxyalkyl), or —(C1-6fluoroalkylenyl)OP(O)(OH)2;

(ii) —(C1-3 alkyl enyl)Rx, —(C1-3 fluoroalkylenyl)Rx, —(C1-3alkylenyl)C(O)Rx, —(Ci- alkylenyl)C(O)NHRx, —(C1-3fluoroalkylenyl)C(O)Rx, or — CH2CF=(tetrahydropyranyl), wherein Rxis a cyclic group selected from C36 cycloalkyl, tetrazolyl, 1,1-dioxidotetrahydrothiophenyl, 1,1dioxidothiomorpholinyl, oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, imidazolyl, morpholinyl, phenyl, and triazinyl, wherein each cyclic group is substituted with zero to 3 substituents independently selected from F, —OH, —CH3, —C(CH2)2OH, — OCH3, —C(O)CH2CN, —S(O)2CH3, —S(O)2NH2, —NHC(O)CH3, — N(S(O)2CH3)2, —CH2CH2(acetamidophenyl), —CH2CH2(methoxyphenyl), — CH2CH2(sulfamoylphenyl), oxetanyl, benzyl, and morpholinyl;

(iii) C3-6 cycloalkyl or C4-6 cycloalkenyl, each substituted with zero to 3 substituents independently selected from F, —OH, —CN, C1-3alkyl, C1-3 alkoxy, —S(C!. 3 alkyl), —NO2, —S(O)2(C1-3 alkyl), C1-4hydroxyalkyl, — C(C1-3 alkyl)(OH)(C36 cycloalkyl), —CH2C(O)NH(C1-3 alkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)(C14hydroxyalkyl), —C(O)NH(C!-3 alkyl), —C(O)NH(C!-3 deuteroalkyl), — C(O)NH(C3-6 cycloalkyl), —NHC(O)O(C1-3 alkyl), —NHS(O)2(C1-3alkyl), pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl, methylpyrazolyl, and thiazolyl;

(iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl, pyridinyl, or pyrimidinyl, each substituted with zero to 1 substituent selected from —OH, C1-3 alkyl, Ci- fluoroalkyl, C1-4 hydroxyalkyl, C!-3alkoxy, —C(O)(C 1-4 alkyl), —S(O)2(C!. 4 alkyl), —S(O)2NH(C1-4 alkyl), —NH(C1-3 alkyl), —N(C1-3 alkyl)2, — O(C13 alkylenyl)N(C1-3 alkyl)2, —CH2(morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, methylpiperazinyl, methoxypiperidinyl, pyridinyl, pyrimidinyl, methyl sulfonyl azetidinyl, and — C(0)(methyl sulfonyl azetidinyl); or (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-l-ol, tetrahydrobenzo[d]thiazol-2amine, or l,3-diazaspiro[4.5]decane-2,4-dione; and

R2is:

(i) C1-7 alkyl or C2-6 alkenyl, each substituted with zero to three substituents independently selected from F, —OH, and —CN; —(C1-4 alkylenyl)O(C1-4 alkyl), —(C1-4alkylenyl)O(C1-4 fluoroalkyl), —(C1-6 alkyl enyl)NH2, —(Ci6 alkylenyl)S(O)2(C1-3 alkyl), —(C1-6fluoroalkylenyl)NH(C 1-3 alkyl), or —(Ci6 alkylenyl)NHC(O)(C1-4fluoroalkyl);

(ii) —(C1-4 alkylenyl)Ry wherein Ryis C3-6 cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl, tetrahydropyranyl, or morpholinyl, each substituted with zero to 2 substituents independently selected from F, —OH, and C1-3 alkyl;

(iii) C3-6 cycloalkyl, azetidinyl, oxetanyl, furanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl, each substituted with zero to 3 substituents independently selected from F, —OH, C1-3alkyl, C!-3hydroxyalkyl, —C(O)(C!. 3 alkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)(C 1-3 cyanoalkyl), —C(O)O(C 1-3 alkyl), —C(O)NH2, —C(O)NH(C 1-3 alkyl), —C(O)(difluorophenyl), —NH2, —NH(C13 alkyl), —NH(C 1-3 fluoroalkyl), —NH(oxetanyl), —NHC(O)(C 1-3 alkyl), — NHC(O)(C!-3 fluoroalkyl), —NHC(O)(C3-6 cycloalkyl), —NHC(O)(fluorophenyl), —S(O)2(C!-3 alkyl), imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, chloropyrimidinyl, and methoxypyrimidinyl;

(iv) adamantanyl, hydroxyadamantanyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl, bicyclo[ l.l.l]pentanyl, or hydroxybicyclo[2.2.1]heptanyl; or (v) phenyl, pyrazolyl, thiazolyl, thiadiazolyl, or indazolyl, each substituted with 0 to 2 substituents independently selected from F, Cl, —OH, —CN, C1-4 alkyl, Ci hydroxyalkyl, C1-4 fluoroalkyl, C!-4cyanoalkyl, C1-3 alkoxy, C3-6 cycloalkyl, — (C1-3 alkylenyl)O(C1-3alkyl), —(C1-3 alkyl enyl)O(C 1-3 fluoroalkyl), —C(O)NH2, — C(O)NH(C1-3 alkyl), —NHC(O)(C 1-3 alkyl), —NHC(O)S(O)2(C1-3alkyl), — S(O)2NH2, —S(O)2(C!-3 alkyl), pyrazolyl, methyl pyrazolyl, imidazolyl, triazolyl, methyl tetrazolyl, ethyl tetrazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl, and tetrahydropyranyl;

as defined and described in WO 2015/103453 and US 2015/0191464, the entirety of each of which is herein incorporated by reference.

[00140] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor a compound of formula I-iii-1

; thereby forming

I-iii-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein is a single or double bond;

W is selected from CH, CH—CH, O, S, NR6, and CO;

Y is N or CR9;

Z is N or C, and Z is N if W is CH and Y is CR9;

R4is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted carbocycle, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C!-C6heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, SO2R6 and SO2NR7R8;

R5 is selected from hydrogen, halogen, OR6, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C!-C6haloheteroalkyl, an optionally substituted C1-C6 alkenyl, and an optionally substituted C1-C6 alkynyl;

or R4 and R5 are linked to form an optionally substituted non-aromatic ring;

each R6 is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted C1-C10alkyl, an optionally substituted C1-C10 haloalkyl, and an optionally substituted CiC10 heteroalkyl;

each R7and R8is independently selected from an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, each optionally fused with a substituted aryl or a substituted heteroaryl, hydrogen, an optionally substituted CiC10 alkyl, an optionally substituted C1-C10 haloalkyl, an optionally substituted CiC10 alkenyl, an optionally substituted C1-C10 alkynyl, and an optionally substituted CiC10 heteroalkyl, or R7and R8 are linked to form an optionally substituted non-aromatic ring;

R9is selected from hydrogen, halogen, OR6, CN, NR7R8, CH2OR6, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted non-aromatic ring, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted C1-C6 alkenyl, an optionally substituted C1-C6 alkynyl, CO2R6, SO3R6, and SO2NR7R8;

A is an optionally substituted aryl or an optionally substituted heteroaryl group;

each optionally substituted group is either unsubstituted or substituted with one or more groups independently selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, Ncarbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, Nsulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, =0, =S, amino, and protected derivatives of amino groups;

as defined and described in WO 2012/068546 and US 2014/0155379, the entirety of each of which is herein incorporated by reference.

[00141] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor thereby forming a compound of formula I-jjj-1

i-jjj-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Q denotes Ar or Het;

E denotes —(CH2)mCO—, —(CH2)mSO2, —(CH2)q—, —(CH2)mNHCO—, or a single bond;

R1 denotes H, OH, NH—C1-C6-alkyl, OC!-C6-alkyl, C!-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cyc, Hal, Het1, O-Het1, CO-Het1, NH-Het1, CO—Ar1, O—Ar1, Ar1, NH—Ar1, — (CH2)qHet1, —CONH—(CH2)qHet1, —CONH-Het1, —(CH2)qO-Het1, —(CH2)qO—Ar1, —(CH2)qAr1, —CONH—(CH2)qAr1, —CONH—Ar1, —CONHC3-C6-cycloalkyl, — (CH2)qHal, —(CH2)qCyc, CF3, —(CH2)SNH—(CH2)q-Het1, —(CH2)SNH—(CH2)q—Ar1, wherein NH—C!-C6-alkyl, OC!-C6-alkyl, C!-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3C6-cycloalkyl may be substituted by 1 to 3 groups independently selected from OC1-C3alkyl, OH, CONH2, NH2;

R2 denotes H, C!-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Hal, CF3, preferably H;

R3denotes Het1, Ar1, NRaRb, COOH, —(CH2)qHet1, —(CH2)qAr1, —(CH2)qNRaRb, — (CH2)qCOOH, or C!-C6-alkyl wherein 1 to 3 hydrogen atoms may be independently replaced by OH or CF3;

R4 denotes H, C!-C6-alkyl, C2-C6-alkenyl, Hal;

Ra denotes H, linear, branched or cyclic C!-C6-alkyl;

Rb denotes H, Hetb, Arb, —CO-Hetb, —CO—Arb, a C3-C8-cycloalkyl or a linear or branched alkyl having 1 to 6 carbon atoms, wherein 1 to 3 hydrogen atoms may be replaced by Hetb, Arb, NH2, N(C1-C6-alkyl)2, NH(C1-C6-alkyl), N(C1-C6-alkyl)(C3-C8-cycloalkyl), NH(C3-C8cycloalkyl), O(C!-C6-alkyl), CN, OH, CF3, Hal;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2, 3 or 4;

q is 1, 2, or 3;

s is 0, 1, 2 or 3;

Hal denotes Cl, Br, I, F, preferably Cl or F;

Ar denotes a divalent monocyclic or fused bicyclic arylen group having 6 to 14 carbon atoms, which may be further substituted with 1 to 4 substitutents selected from Hal, C!-C6-alkyl, —(CH2)mOC1-C6-alkyl, CN, OH, NO2, CF3, —(CH2)mCOOH, — (CH2)mCOOC1-C6-alkyl;

Het denotes a divalent monocyclic or fused bicyclic unsaturated, saturated or aromatic heterocyclic group having 1 to 5 heteroatom independently selected from N, O, S and/or a group — C=O, which may be further substituted with 1 to 4 substituent selected from Hal, C1-C6alkyl, — (CH2)mOC1-C6-alkyl, CN, OH, NO2, CF3, —(CH2)mCOOH, —(CH2)mCOOC1-C6alkyl;

Ar1 denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or tri substituted by Hal, —CF3, —OCF3, —NO2, —CN, perfluoroalkyl, Hal, —CF3, —OCF3, —NO2, —CN, perfluoroalkyl, linear or branched C!-C6-alkyl, cycloalkyl, —OH, —OC!-C6-alkyl, — COC1-C6-alkyl, —NH2, —COH, —COOH, —CONH2, a group Rb such as —CH2O(C1C6-alkyl), —SO2NRaRb or SO2(C1-C6alkyl);

Het1 denotes a monocyclic or bicyclic (fused, bridged or spiro) saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 heteroatom independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or tri substituted by Hal, —CF3, —OCF3, —NO2, —CN, perfluoroalkyl, linear or branched C!-C6-alkyl, C3C8-cycloalkyl, —OH, —0C1-C6-alkyl, —NH2, —N(C1-C6-alkyl)2, —COH, —COOH, — C0NH2, —COC!-C6-alkyl, —NHCO(C3-C6cycloalkyl), a group Rb—SO2NRaRbor SO2(C!-C6alkyl);

Hetb denotes a monocyclic or bicyclic (fused or spiro) saturated, unsaturated or aromatic heterocyclic ring having 1 to 4 heteroatom independently selected from N, O, S and/or a CO group, which is unsubstituted or monosubstituted, disubstituted or tri substituted by Hal, —CF3, —0CF3, —N02, —CN, perfluoroalkyl, —OH, —0C1-C6-alkyl, —NH2, — COH, —COOH, —C0NH2, or by a linear or branched C!-C6-alkyl wherein 1 to 3 hydrogen atoms may be replaced by NH2, N(C1-C6-alkyl)2, NH(C!-C6-alkyl), N(C1-C6-alkyl)(C3-C8cycloalkyl), NH(C3-C8-cycloalkyl), 0(C!-C6-alkyl), CN, OH, CF3, Hal, C3-C8-cycloalkyl, or by a 4 to 8-membered heterocyclic ring containing an heteroatom selected from 0, S and N;

Arb denotes a monocyclic or bicyclic, aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or tri substituted by Hal, —CF3, —0CF3, —N02, —CN, perfluoroalkyl, Hal, —CF3, —0CF3, —N02, —CN, perfluoroalkyl, —OH, —0C!-C6-alkyl, —NH2, —COH, —COOH, —C0NH2, or by a linear or branched C!-C6-alkyl wherein 1 to 3 hydrogen atoms may be replaced by NH2, N(C1-C6-alkyl)2, NH(C1-C6-alkyl), N(C1-C6-alkyl)(C3-C8-cycloalkyl), NH(C3-C8cycloalkyl), 0(C!-C6-alkyl), CN, OH, CF3, Hal, C3-C8-cycloalkyl, or by a 4 to 8-membered heterocyclic ring containing an heteroatom selected from 0, S and N;

Cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, preferrably 5 or 6 carbon atoms, wherein 1 to 5 H atoms are replaced by Hal, —CF3, —OCF3, —NO2, —CN, perfluoroalkyl, Hal, —CF3, —OCF3, —NO2, —CN, perfluoroalkyl, linear or branched C!-C6-alkyl, cycloalkyl, —OH, —OC!-C6-alkyl, —COC!-C6-alkyl, —NH2, — COH, —COOH, —CONH2, a group Rbsuch as —CH2O(C1-C6-alkyl), —SO2NRaRbor SO2(C!-C6alkyl); or as defined and described in WO 2012/084704 and US 2013/0274241, the entirety of each of which is herein incorporated by reference.

[00142] In certain embodiments, the present invention provides a compound of Formula I,

; thereby wherein IRAK is an IRAK4 inhibitor forming a compound of formula I-kkk-1

I-kkk-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

R1 is aryl, heteroaryl, heterocyclyl or (C1-6 alkyl)R6, wherein said aryl, heteroaryl, and heterocyclyl groups are optionally substituted with one or two substituents selected from the group consisting of halo, cyano, R4, C3-8 cycloalkyl, C1-3 aminoalkyl, C!-3hydroxyalkyl, OR4, NR4R5, NR4COR6, NR4SO2R6, SO2NR4R5, CONR4R5and CONR4R5;

R2is aryl, heteroaryl, C3-8 cycloalkyl, heterocyclyl or (C1-6 alkyl)R6, wherein said aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally substituted with one or two substituents selected from the group consisting of halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R4, OR4, 0(03-8 cycloalkyl), (C=0)0R4, SOmR6, SOmR4, NR4R5, SO2NR4R5and NR4SO2R6;

R3is halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R4, OR4, C3-8cycloalkyl, SOmR6, SOmR4NR4R5 or (C=O)NR4R5, NR4(CO)R6, SOmNR4R5 and NR4SO2R6;

R4is hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with one to three halo or hydroxyl;

R5 is hydrogen or C1-6 alkyl, wherein said alkyl is optionally substituted with halo or hydroxyl;

R6is aryl, heteroaryl, C3-8 cycloalkyl or heterocyclyl;

m is an integer from zero to two;

as defined and described in WO 2012/129258 and US 2014/0194404, the entirety of each of which is herein incorporated by reference.

[00143] In certain embodiments, the present invention provides a compound of Formula I,

O

H wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula 1 1

1 1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is —N= or — CH=;

Y is selected from the group consisting of—NR2—, —CH2—, —CHR— and —O—, such that when Y is —CHR—, R and R3 together with the carbon to which they are attached optionally form a 4- to 6-membered cycloalkyl, cycloalkenyl or heterocyclic ring, wherein the 4- to 6-membered cycloalkyl, cycloalkenyl, or heterocyclic ring is optionally substituted with one to three substituents independently selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, phenyl, CF3, heterocyclyl, halogen, —COOR8, —NHR8, — SR8, —OR8, —SO2R8, —COR8, —NHCOR8, and —CONHR8; or when Y is —NR2—, R2and R3 together with the nitrogen to which they are attached optionally form a 4- to 6membered heterocyclic ring, wherein the 4- to 6-membered heterocyclic ring is optionally substituted with one to three substituents independently selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, phenyl, CF3, heterocyclyl, halogen, —COOR8, —NHR8, — SR8, —OR8, —SO2R8, —COR8, —NHCOR8, and —CONHR8;

R1 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-8cycloalkyl, aryl, heterocyclyl, halogen, —COOR7, —NHR7, —SR7, —OR7, —SO2R7, —COR7, —NHCOR7, and — CONHR7; wherein said alkyl, cycloalkyl, aryl and heterocyclyl are optionally substituted with one to three substituents independently selected from the group consisting of Ci4 alkyl, C3-6 cycloalkyl, CN, phenyl, CF3, heterocyclyl, halogen, —COOR8, —NHR8, —

SR8, —OR8, —SO2R8, —COR8, —NHCOR8, and —CONHRS, wherein said —NHR8 is optionally substituted with —N(C!-4alkyl)NH2 or —N(C3-6 cycloalkyl)NH2;

R2 is selected from the group consisting of hydrogen, C1-10 alkyl, and C3-8 cycloalkyl;

R3 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-8cycloalkyl, aryl, heterocyclyl, and —COOR7; wherein said alkyl, cycloalkyl, aryl and heterocyclyl are optionally substituted with one to three substituents independently selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, phenyl, CF3, heterocyclyl, halogen, —COOR8, —NHR8, — SR8, —OR8, —SO2R8, —COR8, —NHCOR8, and —CONHR8;

R6is selected from the group consisting of Ci-10 alkyl, C3-8 cycloalkyl, aryl, heterocyclyl, — COOR7, —SO2R7, and —COR7; wherein said alkyl, cycloalkyl, aryl and heterocyclyl are optionally substituted with one to three substituents independently selected from the group consisting of C1-4 alkyl, C3-6 cycloalkyl, phenyl, CF3, heterocyclyl, halogen, —COOR8, — NHR8, —SR8, —OR8, —SO2R8, —COR8, —NHCOR8, and —CONHR8;

R7is selected from the group consisting of hydrogen, C1-10 alkyl, C3-8cycloalkyl, aryl, and heteroaryl; wherein said alkyl, cycloalkyl, aryl and heterocyclyl are optionally substituted with one to three substituents independently selected from the group consisting of Ci4 alkyl, C3-6cycloalkyl, phenyl, CF3, heterocyclyl, halogen, —COOR8, —NHR8, —SR8, — OR8, —SO2R8, —COR8, —NHCOR8, and —CONHR8; and

R8 is selected from the group consisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl;

as defined and described in WO 2013/066729 and US 2014/0329799, the entirety of each of which is herein incorporated by reference.

[00144] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-mmm-1

l-mmin-l or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is independently CH or N;

Y is H or methyl;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4;

Ring A is (C3-C8)cycloalkenyl, aryl or heterocycle optionally substituted with one to three substituents independently selected from Ri;

Riis selected from: H, oxo, (C=O)aOb(C1-C10)alkyl, (C=O)aOb&#1470;aryl, (C=O)aOb(C2-C10)alkenyl, (C=O)aOb(C2-C10)alkynyl, CO2H, halo, OH, Ob(C1-C6)fluoroalkyl, (C=O)aNR5R6, CN, (C=O)aOb(C3-C8)cycloalkyl, S(O)mNR5R6, SH, S(O)m—(Ci-Cio)alkyl and (C=O)aObheterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from Ra;

R2and R3are independently selected from: H, (C=O)aObC1-C10 alkyl, (C=O)aObaryl, C2C10 alkenyl, C2-C10 alkynyl, (C=O)aOb heterocyclyl, CO2H, CN, ObC!-C6fluoroalkyl, Oa(C=O)bNR5R6, CHO, (N=O)R5R6, S(O)mNR5R6, SH, S(O)m—(Ci-Cio)alkyl, (C=O)aObC3-C8 cycloalkyl, optionally substituted with one or more substituents selected from Ri; or R2 and R3 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N,

O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from Ri;

R4is independently selected from: (C!-C6)alkyl, OH, methoxy, CF3and F, said alkyl optionally substituted with OH;

R5and R6are independently selected from H, (C=O)aOb(C1-C10)alkyl, (C=O)aOb-aryl, (C=O)aOb(C2-C10)alkenyl, (C=O)aOb(C2-C10)alkynyl, CO2H, Ob(C1-C6)fluoroalkyl, (C=O)aN(Ra)2, CN, (C=O)aOb(C3-C8)cycloalkyl, S(O)mN(Ra)2, SH, S(O)m—(Ci-Cio)alkyl and (C=O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from Ra;

R3is independently selected from Rb, OH, (C!-C6)alkoxy, halogen, cyclopropyl, CO2H, CN, Oa(C=O)b(C!-C6)alkyl, oxo, and N(Rb)2; and

Rbis independently selected from H and (C!-C6)alkyl;

as defined and described in WO 2014/058685 and US 2015/0299224, the entirety of each of which is herein incorporated by reference.

[00145] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor compound of formula I-nnn-1 thereby forming a

I-nnn-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is CH or N;

a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;

Ring A is (C3-C8)cycloalkyl, (C3-C8)cycloalkenyl, aryl or heterocycle optionally substituted with one to three substituents independently selected from Ri;

Riis selected from: H, oxo, (C=O)aOb(C1-C10)alkyl, (C=O)aOb&#1470;aryl, (C=O)aOb(C2-C10)alkenyl, (C=O)aOb(C2-C10)alkynyl, C02H, halo, OH, Ob(C1-C6)fluoroalkyl, (C=O)aNR5R6, CN, (C=O)aOb(C3-C8)cycloalkyl, S(O)mNR5R6, SH, S(O)m—(Ci-Cio)alkyl and (C=O)aObheterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from Ra;

R2and R3are independently selected from: H, (C=O)aObC1-C10 alkyl, (C=O)aObaryl, C2C10 alkenyl, C2-C10 alkynyl, (C=O)aOb heterocyclyl, CO2H, CN, ObC1-C6 fluoroalkyl, Oa(C=O)bNR5R6, CHO, (N=O)R5R6, S(O)mNR5R6, SH, S(O)m—(Ci-Cio)alkyl, (C=O)aObC3-C8 cycloalkyl, optionally substituted with one or more substituents selected from Ri; or R2 and R3 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 3-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from Ri;

R4is selected from: (C1-C6)alkyl and (C3-C6)cycloalkyl, optionally substituted with Ra;

R5and R6are independently selected from: H, oxo, (C=O)aOb(C1-C10)alkyl, (C=O)aOb&#1470;aryl, (C=O)aOb(C2-C10)alkenyl, (C=O)aOb(C2-C10)alkynyl, C02H, Ob(C1-C6)fluoroalkyl, (C=0)aN(Ra)2, CN, (C=O)aOb(C3-C8)cycloalkyl, S(0)mN(Ra)2, SH, S(0)m—(Ci-Cio)alkyl and (C=O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from Ra;

Rais independently selected from Rb, OH, (C!-C6)alkoxy, halogen, cyclopropyl, C02H, CN, Oa(C=O)b(C1-C6)alkyl, oxo, and N(Rb)2; and

Rbis independently selected from H and (C!-C6)alkyl;

as defined and described in WO 2014/058691 and US 2015/0274708, the entirety of each of which is herein incorporated by reference.

[00146] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-nnn’-l

I-nnn’-l or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein each of the variables R3, R4, X, and Ring A is as defined and described in WO 2014/058691, the entirety of each of which is herein incorporated by reference.

[00147] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

; thereby forming a compound of formula 1 1

1 1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Z denotes a group x rc ; wherein X is CH or N;

Y is CH or N;

Ra, Rc, Rl denote each independently H, Hal or Al;

Rb is H or alkyl;

Al is branched or linear alkyl having 1 to 12 C-atoms, wherein one or more, such as 1 to 7, H atoms may be replaced by Hal, ORb, COORb, CN or N(Rb)2 and wherein one or more, preferably 1 to 5 CH2-groups may be replaced by O, CO, NRb or S, SO, SO2, 1,2-, 1,3- or 1,4-phenylen, —CH=CH— or —C=C—; and

Hal denotes F, Cl, Br, I;

as defined and described in WO 2014/121931 and US 2015/0376167, the entirety of each of which is herein incorporated by reference.

[00148] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor ; thereby forming a compound of formula I-ppp-1

I-ppp-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Rl, R3 denote each, independently of one another H, (CH2)PCON(R5)2, OA, Hal, COOH, COO A, (CH2)PNHCOA, (CH2)PHetl, (CH2)PNR2R5, or OH;

R2 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms, wherein one or two H atoms of the alkyl group are optionally replaced by OR6, NR5R6, NHCOR5, CONR5R6;

R4 denotes H or A;

R5 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms;

R6 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms;

Z is absent or denotes Ar-diyl or Het-diyl;

L denotes (CH2)n wherein one or two CH2 groups are optionally replaced by O and/or a CH=CHgroup, and/or wherein one or two H atoms are optionally replaced by OR2, NR2R5 or Hetl;

Ar-diyl denotes 1,2-, 1,3- or 1,4-phenylen optionally substituted with from 1 to 5 groups independently selected from the group consisting of Hal, CN, —CF3, —OCF3, OH, O-A, SO2-A, COOH, COO A, —CO-A, O-phenyl, SO2-phenyl, SO2—CF3, Het2 and A;

Het-diyl denotes an unsaturated, saturated or aromatic 5- or 6-membered heterocycle comprising 1 to 2 N, O and/or S atoms, which are optionally unsubstituted or mono-, di- or trisubstituted by Hal, CN, —CF3, —OCF3, O-A, SO2-A, COOH, COOA, —CO-A, Ophenyl, S02-phenyl, SO2—CF3, Het2 and/or A;

A denotes an unbranched or branched alkyl comprising 1 to 10 C atoms, in which 1 to 5 H atoms are optionally replaced by F and/or in which one or two non-adjacent CH2 groups are optionally replaced by O;

Hetl denotes morpholinyl, piperidinyl or pyrrolidinyl;

Het2 denotes morpholinyl, piperidinyl or pyrrolidinyl;

Hal denotes F, Cl, Br, I;

n denotes 1, 2, 3, 4, 5 or 6;

p denotes 0, 1 or 2;

as defined and described in WO 2014/121942 and US 2015/0376206, the entirety of each of which is herein incorporated by reference.

[00149] In certain embodiments, the present invention provides a compound of Formula I,

I-qqq-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0-4;

each RUs independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, — SO2R, —SO2N(R)2, —SOR, — C(O)R, —CO1R, — C(O)N(R)2, —C(O)N(R)—OR, — NRC(O)R, —NRC(O)N(R)2, Cy, or —NRSO2R; or RUs selected from one of the following formulas:

0 ל > R n —^<R A X

I >ch2)1.4 nr2 I (CH2)T>R;

or two R1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, aryl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

Rzis —R, —CN, —NO2, halogen, — C(O)N(R)2, —C(O)OR, —C(O)R, —N(R)2, —OR, or — SO2N(R)2;

Ring B is an unsubstituted 4-8 membered partially unsaturated carbocyclic fused ring; and

L is a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, — N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —s—, —so— or—SO2—;

as defined and described in WO 2012/097013 and US 2012/0283238, the entirety of each of which is herein incorporated by reference.

[00150] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAKI and/or IRAK4 inhibitor

I-rrr-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

n is 0-4;

each RMs independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, — SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, — NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R; or Rhs selected from one of the following formulas:

Ring B is a cyclopento or cyclohexo fused ring;

m is 1-2;

p is 0-2;

WisN;

Rzis R, CN, NO2, halogen, —C(O)N(R)2, —C(O)OR, — C(O)R, —N(R)C(O)OR, — NRC(O)N(R)2, —OR, or —SO2N(R)2;

L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, — C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;

each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, — N(R)C(O)—, — C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, — OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;

each R4is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, — CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —

C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

as defined and described in WO 2013/106535 and US 2013/0231328, the entirety of each of which is herein incorporated by reference.

[00151] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAKI and/or IRAK4 inhibitor thereby forming a compound of formula I-sss-1

or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

n is 0-4;

each RMs independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, — S(O)2R, —S(O)2N(R)2, —SOR, —C(O)R, —CO2R, — C(O)N(R)2, —C(O)N(R)—OR, — N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, Cy, or —N(R)S(O)2R, or R1 is selected from one of the following formulas:

H a H1, 5 (CH2)b4 NR2 ξ (CH2)b4 R;

Ring B is selected from a benzo fused ring and a 5-6 membered heteroaromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;

m is 0-4;

p is 0-2;

W is N or — C(R3)—;

Rzis R, CN, NO2, halogen, — C(O)N(R)2, —C(O)OR, —C(O)R, —N(R)2, —N(R)C(O)OR, — N(R)C(O)N(R)2, —OR, or —S(O)2N(R)2;

R3is hydrogen, halogen, —CN, C1-4 aliphatic, C1-4haloaliphatic, —OR, —C(O)R, or — C(O)N(R)2;

L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, — C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, — C(O)O—, —S—, — S(O)— or —S(O)2—;

each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, — N(R)C(O)—, — C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, — OC(O)—, —C(O)O—, —S—, — S(O)— or —S(O)2—; and each R4is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, — S(O)2N(R)2, — S(O)R, — C(O)R, — CO2R, — C(O)N(R)2, —N(R)C(O)R, — N(R)C(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

as defined and described in WO 2014/011902 andUS 2014/0018343, the entirety of each of which is herein incorporated by reference.

[00152] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAKI and/or IRAK4 inhibitor thereby forming a compound of formula I-ttt-1

I-ttt-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

n is 0-4;

each R1 is independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, — S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)— OR, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, Cy, or —N(R)S(O)2R; or RHs selected from one of the following formulas:

two R1 groups are taken together with their intervening atoms to form an optionally substituted 47 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Ring B is selected from a 4-8 membered partially unsaturated carbocyclic fused ring and a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;

m is 0-4;

p is 0-2;

Rzis —R, —CN, —NO2, halogen, —C(O)N(R)2, —C(O)OR, —C(O)R, —N(R)2, — N(R)C(0)0R, —N(R)C(0)N(R)2, —OR, or —S(O)2N(R)2;

R3is hydrogen, halogen, —CN, C1-4 aliphatic, C1-4haloaliphatic, —OR, —C(O)R, or — C(O)N(R)2;

each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —

N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)2— —S(O)2N(R)—, —O—, —C(O)—, — OC(O)—, —C(O)O— —S—, — S(O)— or —S(O)2—; and each R4is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, — S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, —N(R)C(O)R, — N(R)C(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

as defined and described in WO 2014/011906 andUS 2014/0018357, the entirety of each of which is herein incorporated by reference.

[00153] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAKI and/or IRAK4 inhibitor thereby forming a compound of formula I-uuu-1

I-uuu-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

n is 0-4;

each R4s independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, — S(O)2R, — S(O)2N(R)2, —S(O)R, — C(O)R, —C(O)OR, —C(O)N(R)2, —C(O)N(R)— OR, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R)2, Cy, or —N(R)S(O)2R; or RHs selected from one of the following formulas:

each of Rx and Ry is independently —R, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, — S(O)R, — C(O)R, —C(O)OR, — C(O)N(R)2, —N(R)C(O)R, — N(R)C(O)N(R)2, or —N(R)S(O)2R, or:

Rxand Ryare taken together with their intervening atoms to form Ring B substituted with m occurrences of &#1500; ;

Ring B is selected from a benzo fused ring, a 4-8 membered partially unsaturated carbocyclic fused ring, a 4-8 membered partially unsaturated heterocyclic fused ring having one or two heteroatoms independently selected from nitrogen oxygen and sulfur, and a 5-6 membered heteroaromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;

m is 0-4;

p is 0-2;

Q is —O— or —N(R)—

W is N or — C(R3)—;

Rzis —R, —CN, —NO2, halogen, —C(0)N(R)2, —C(O)OR, —C(O)R, —N(R)2, — N(R)C(0)0R, —N(R)C(0)N(R)2, —OR, or —S(O)2N(R)2;

R3is hydrogen, halogen, —CN, C1-4 aliphatic, C1-4haloaliphatic, —OR, —C(O)R, or — C(O)N(R)2;

L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, — C(0)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, — C(O)O— —S—, — S(O)— or —S(O)2—;

each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, — N(R)C(0)—, — C(0)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, — OC(O)—, —C(O)O—, —S—, — S(O)— or —S(O)2—; and each R4is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, — S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(0)N(R)2, —N(R)C(0)R, — N(R)C(0)N(R)2, —C(0)N(R)0R, —N(R)C(0)0R, —N(R)S(O)2N(R)2, —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

as defined and described in WO 2014/011911 and US 2014/0018361, the entirety of each of which is herein incorporated by reference.

[00154] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAKI and/or IRAK4 inhibitor ; thereby forming a compound of formula I-vvv-1

I-vvv-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Qis CH, C—CN, orN;

X is C-L2(R4)p—Rx and Y is N; or

X is N and Y is C—Rx;

each R1 and R1 is independently —R2, halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, —S(O)2N(R)2, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)2, — C(O)N(R)OR, — N(R)C(O)OR, —N(R)C(O)N(R)2, Cy, or —N(R)S(O)2R; or R1 is selected from one of the following formulas:

each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-10 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R2is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R4is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —S(O)2R, — S(O)2N(R)2, — S(O)R, — C(O)R, —C(O)OR, — C(O)N(R)2, —N(R)C(O)R, —

N(R)C(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Rxis hydrogen, —R2, —CN, —NO2, halogen, — C(O)N(R)2, —C(O)OR, —C(O)R, —N(R)2, — NH[Ar], —OR, or —S(O)2N(R)2;

Rzis hydrogen, —R2, —CN, —NO2, halogen, —C(O)N(R)2, —C(O)OR, —C(O)R, —N(R)2, — NH[Ar], —OR, or —S(O)2N(R)2;

[Ar] is a phenyl or heteroaromatic ring substituted by m instances of R1;

L2 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, — C(O)N(R)—, —N(R)S(O)2—, —S(O)2N(R)—, —O—, —C(O)—, —OC(O)—, — C(O)O— —S—, — S(O)— or —S(O)2—;

m is 0-4;

n is 0-4; and p is 0-2;

as defined and described in WO 2015/048281 and US 2015/0094305, the entirety of each of which is herein incorporated by reference.

[00155] In some embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor R2 thereby forming a compound of formula I-vvv’-l:

I-vvv’-l or a pharmaceutically acceptable salt thereof, wherein

L and LBM are as defined above and described in embodiments herein;

each A, B, C, D, E, F, G, Η, X1, X2, and X3 are independently a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; and each R1, R2, R3, and R4 are independently hydrogen or a substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

R1 and R2 and R3 and R4 are each optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.

[00156] Such IRAK4 inhibitors are well known to one of ordinary skill in the art and include those described in Scott et al., J. Med. Chem., 2017, 60(24): 10071-10091 and Degorce et al., Bioorg. Med. Chem., 2018, 26(4): 913-924.

[00157] In certain embodiments, the present invention provides a compound of Formula I,

forming a compound of formula I-vvv’-2,1-vvv’-3,1-vvv’-4,1-vvv’-5,1-vvv’-6,I-vvv’-7,1-vvv’8, I-vvv’-9, I-vvv’-10, I-vvv’-11, I-vvv’-12, I-vvv’-13, I-vvv’-14, I-vvv’-15, I-vvv’-16, I-vvv’17,1-vvv’-18,1-vvv’-19,1-vvv’-20,1-vvv’-21,1-vvv’-22,1-vvv’-23,1-vvv’-24,1-vvv’-25, I-vvv’252

26,1-vvv’-27,1-vvv’-28,1-vvv’-29,1-vvv’-30,1-vvv’-31,1-vvv’-32,1-vvv’-33,1-vvv’-34,1-vvv’35,1-vvv’-36,1-vvv’-37,1-vvv’-38, and I-vvv’-39:

I-vvv’-2

I-vvv’-3

I-vvv’-4

I-vvv’-7

I-vvv’-9

I-vvv’-10

I-vvv’-12

I-vvv’-14

I-vvv’-18

I-vvv’-20

I-vvv’-23

I-vvv’-24

I-vvv’-25

I-vvv’-27

I-vvv’-28

I-vvv’-29

I-vvv’-32

I-vvv’-37

I-vvv’-38

I-vvv’-39 or a pharmaceutically acceptable salt thereof, wherein

L and LBM are as defined above and described in embodiments herein;

each X1, X2, and X3 are independently a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom; and each R1, R2, R3, and R4 are independently hydrogen or a substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

R1 and R2 or R3 and R4 are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur.

[00158] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAKI and/or IRAK4 inhibitor ; thereby forming a compound of formula I-www-1

I-www-1 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

Q is =N— or =CH ;

each R3is independently —R2, halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, — S(O)2NR2, — S(O)R, — C(O)R, —C(O)OR, —C(O)NR2, —C(O)N(R)OR, —

N(R)C(O)OR, —N(R)C(O)NR2, Cy, or —N(R)S(O)2R; or Rfis selected from one of the following formulas:

each of R5 and R6 is independently hydrogen or -L2(R4)P—Rx; or

R5 and R6 are taken together with their intervening atoms to form a 4-7 membered partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R4is independently halogen, —CN, —NO2, —OR, —SR, —NR2, —S(O)2R, —S(O)2NR2, —S(O)R, — C(O)R, —C(O)OR, —C(O)NR2, —N(R)C(O)R, —N(R)C(O)NR2, — C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2NR2, —N(R)S(O)2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

Rxis hydrogen, —R2, —CN, —NO2, halogen, —C(O)NR2, —C(O)OR, —C(O)R, —NR2, — NH[Ar], —OR, or —S(O)2NR2;

Rzis hydrogen, —R2, —CN, —NO2, halogen, —C(O)NR2, —C(O)OR, —C(O)R, —NR2, — NH[Ar], —OR, or —S(O)2NR2;

[Ar] is an optionally substituted phenyl or an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

m is 0-4;

n is 0-4; and p is 0-2;

as defined and described in WO 2015/164374 and US 2015/0329498, the entirety of each of which is herein incorporated by reference.

[00159] In certain embodiments, the present invention provides a compound of Formula I,

wherein IRAK is an IRAK4 inhibitor compound of formula I-xxx-1

; thereby forming a or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X and X' are each independently CR8, N or —N+—Ο; Y is independently N, —N+—0“ or CR8; provided that at least one of X, X' or Y is neither N nor —N+—0“ and that no more than one of X, X' or Y is —N+—0“;

R3is C!-C6alkyl; C2-C6alkenyl; C2-C6alkynyl; —(CR3aR3b)m-(3- to 7-membered cycloalkyl); — (CR3aR3b)m-(3- to 7-membered heterocycloalkyl) having one to three heteroatoms; — (CR3aR3b)m-(5- to 10-membered heteroaryl), having one to three heteroatoms; or — (CR3aR3b)m—C6-C!2aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five halogen, deuterium, —OR5, —SR5, —NRllaRllb, cyano, C!-C6alkyl, C3-C6cycloalkyl or —CiC6alkoxy;

R2is —(CR3aR3b)m-(3- to 10-membered cycloalkyl); —(CR3aR3b)m-(3- to 10-membered heterocycloalkyl) having one to three heteroatoms; —(CR3aR3b)m-(5- to 10 membered heteroaryl) having one to three heteroatoms; or —(CR3aR3b)m—C6-C!2aryl; wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to five R4; and wherein, if the heteroatom on said heterocycloalkyl and heteroaryl is N, said N is optionally substituted with R4 ; or R2is C!-C6alkyl, wherein said alkyl is optionally substituted with NH2, OH or cyano;

R3a and R3b for each occurrence are independently hydrogen or C!-C3alkyl;

R4for each occurrence is independently a bond, deuterium halogen, cyano, C!-C6alkyl, C2C6alkenyl, oxo, —OR5, —SR5, —S(O)R9, —S(O)2R9, —NRllaRllb, —C(O)R10, — (CR3aR3b)n-(3- to 7-membered cycloalkyl), —(CR3aR3b)n-(4- to 10-membered heterocycloalkyl), having one to three heteroatoms, —(CR3aR3b)n-(5- to 10 membered heteroaryl), having one to three heteroatoms, or —(CR3aR3b)n—C6-C12a1yl wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is each optionally and independently substituted with one to five deuterium, halogen, OR5, —SR5, —NRllaRllb, cyano, CiC6alkyl, C3-C6cycloalkyl or —C!-C6alkoxy; or two R4 taken together with the respective carbons to which each are bonded form a 3 - to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR5, —SR5, —NRllaRllb, cyano or C!-C6alkyl or CiC6alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR5, —SR5, —NRllaRllb, or cyano; and wherein, if a heteroatom on said heterocycloalkyl is N, said N is optionally substituted with R4;

R4 is independently C1-C6alkyl, C2-C6alkenyl, —C(O)R10, —S(O)2R9, —(CR3aR3b)n-(3- to 7membered cycloalkyl), —(CR3aR3b)n-(4- to 10-membered heterocycloalkyl) or C(O)(CH2)tCN; wherein said alkyl, alkenyl, cycloalkyl, or heterocycloalkyl is each optionally and independently substituted with one to five deuterium, halogen, OH, cyano or C!-C6alkoxy; or R4 and R4 taken together with the respective atoms to which each are bonded form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one to three halogen, deuterium, —OR5, —SR5, —NRllaRllb, cyano, C!-C6alkyl or C!-C6alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, —OR5, — SR5, —NRllaRllb, or cyano;

R5is independently hydrogen or C!-C6alkyl, wherein said alkyl is optionally substituted with halogen, deuterium, C!-C6alkoxy, C!-C6alkylthiolyl, —NRllaRllb, cyano, C!-C6alkyl or C3-C6cycloalkyl; or two R5 taken together with the oxygen atoms to which they are bonded form a 5- or 6-membered heterocycloalkyl;

R6 is —C(O)NHR7, CO2R7 or cyano;

R7is hydrogen or C!-C6alkyl;

each R8is independently hydrogen, halogen, cyano, —OR5, —SR5, —NRllaRllb, C6alkyl, C3C6cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is optionally substituted with one to three halogen, —NRllaRllb, OR5, —SR5, cyano, C1-C3 alkyl, —C(O)R10or oxo;

R8 is hydrogen, deuterium, halogen, cyano, —OR5, —SR5 or NRllaRllb;

R9is —(CR3aR3b)p—(C!-C3alkyl), —(CR3aR3b)p-(4- to 6-membered cycloalkyl), —(CR3aR3b)p-(4to 6-membered heterocycloalkyl) or —(CR3aR3b)p—(C5-C9aryl), wherein said alkyl, cycloalkyl, heterocycloalkyl or aryl are each optionally substituted with fluoro or CiC3 alkyl;

R10is C!-C6alkyl, wherein said alkyl is optionally substituted with deuterium, halogen, OH, CiC6alkoxy or cyano;

Rllaand Rllbare each independently hydrogen or C!-C6alkyl, wherein said alkyl is optionally substituted with deuterium, C!-C6alkoxy or cyano; and if C2-C6alkyl, said alkyl is optionally substituted with deuterium, C!-C6alkoxy, cyano, halogen or OH;

m is independently 0, 1, 2 or 3;

n is independently 0, 1, 2 or 3;

p is independently 0 or 1; and t is 1, 2 or 3;

as defined and described in WO 2015/150995 and US 2015/0284405, the entirety of each of which is herein incorporated by reference.

[00160] In certain embodiments, the present invention provides a compound of Formula I, wherein IRAK is an IRAK4 inhibitor

in or ; thereby forming a compound of formula I-yyy-1 or Iyyy2&#1470;

i-yyy-1

i-yyy-2 or a pharmaceutically acceptable salt thereof, wherein L and LBM are as defined above and described in embodiments herein, and wherein:

X is N or CH m is 1 or 2;

Ar is optionally substituted aryl or optionally substituted heteroaryl;

RUs hydrogen, C1-6alkyl, C!-6alkoxy, hydroxyl, hydroxy-C1-6alkyl, C1-6alkyl-amino, amino-C!. 6alkyl, amino-C 1-6alkyl-amino, hydroxy-C1-6alkylamino, C3-6cycloalkylamino, amino-C36cycloalkylamino, amino-C3-6heterocycloalkylamino, aminocarbonyl, halo, hydroxy-C!. 6alkyl, or hydroxy-C 1-6alkoxy; and

R2 is hydrogen or C1-6alkyl;

as defined and described in WO 2012/007375 and US 2012/0015962, the entirety of each of which is herein incorporated by reference.

[00161] As defined above and described herein, IRAK is an IRAK binding moiety capable of binding to one or more of IRAK-1, -2, -3, or -4.

[00162] In some embodiments, IRAK is an IRAK binding moiety capable of binding to IRAK1. In some embodiments, IRAK is an IRAK binding moiety capable of binding to IRAK-2. In some embodiments, IRAK is an IRAK binding moiety capable of binding to IRAK-3. In some embodiments, IRAK is an IRAK binding moiety capable of binding to IRAK-4.

[00163] In some embodiments, IRAK is selected from a moiety recited in Aurigene Discovery Tech. Ltd. Presentation: Novel IRAK-4 Inhibitors exhibit highly potent anti-proliferative activity inDLBCL cell lines with activation MYD88 L264P mutation, such as, for example: AU-5850, AU268

---L—( LBIVM

2807, AU-6686, and AU-5792, wherein is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00164] In some embodiments, IRAK is selected from a moiety recited in Scott, J.S. et al. Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88 Diffuse Large B-cell Lymphoma. J. Med. Chem. Manuscript, Nov, 29 2017, 10.1021/acs.jmedchem.7b01290 such as, for example:

Cmp 9

Cmp 10 Cmp 11 Cmp 12

Cmp 13 Cmp 14 Cmp 15

Cmp 16 Cmp 17 Cmp 18a/b

Cmp 29

Cmp31 Cmp 32

Cmp 35 Cmp 36 wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00165] In some embodiments, IRAK is selected from a moiety recited in Powers, J.P. et al.

Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4, Bioorg. Med

Chern Lett. (2006) 16(11): 2842-45, such as, for example:

Compound 1

Compound 2 Compound 3

Compound 4

Compound 6

Compound 7

Compound 9

Compound 11

Compound 12 Compound 13

OMe

Compound 15

Compound 14

Compound 16

Compound 17

O

Compound 19

MeO

Compound 20

Compound 21

Compound 22

Compound 24

Compound 25

Compound 26

Compound 27

Compound 28 Compound 29 Compound 30

Compound 31

Compound 32

<td> 4 #־־~N 0 4 //~N O '1 11 μγλ \ 1 11 N^N^^V 2 J H H IL J MeO EtO Compound 34 Compound 35 p-N 0 Μ/ J η 11 1 y 1 0^x 0^OEt 0-/ Compound 37 o~n ° Qi 1 5ANArvN°ט ץ ־ A .0,/ h || Ί > H yy \__/ HO Compound 39 Compound 40 0 V-H J 0^ / h Ν Ί p HO 0 (DH 4 #-N O ιί Ji J H H J 1 Compound 42 Compound 43</td><td> VzZ N o ,no2 nAtvNO2H l!^J EtO Compound 36 N 0 \^n°2 Compound 38 Vj/ N 0 ,no2 n^n^^n02 ___/ π U \ OH Compound 41 -N 0 XnV'YNO־ Η 0 J ,no2 Compound 44</td>

wherein

Compound 45

Compound 47

Compound 48 is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00166] In some embodiments, IRAK is selected from a moiety recited in Wang, et al. Crystal Structure of IRAK-4 Kinase in Complex with Inhibitors: Serine/Threonine Kinase with Tyrosine as a Gatekeeper, Structure, 2006, 14(12): 1835-44, such as, for example:

wherein

NO2

OH

Compound 1 is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00167] In some embodiments, IRAK is selected from a moiety recited in Wang, Z. et al. Discovery of potent, selective, and orally bioavailable inhibitors of interleukin-1 receptorassociated kinase 4, Bioorg. Med. Chern Lett., 2015, 25(23): 5546-50, such as, for example:

<td> X 0 / \ 1[ n n V OH Compound 1 F. O H HO Compound 4 F, HO*^</td><td> ° F\ A^.NO2 )=\ XX XX ϊ u XXa 2 h h F, O AAV־״ OH Compound 2 Compound 3 A X--N 0 4 X-N O Avo׳״׳ Hyq- HO^ HO^ Compound 5 Compound 6 F, \\AN 0 ^no2 n0! ΗΟ'־.θ</td>

Compound 7

Compound 8

HO

NO2

Compound 9

HO

Compound 10

Compound 13

Compound 14 wherein

Compound 15 Compound 16

Compound 17 Compound 18

, and

Compound 19 is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00168] In some embodiments, IRAK is selected from a moiety recited in Chaudhary, D. etal., Recent Advances in the Discovery of Small Molecule Inhibitors of Interleukin-1 ReceptorAssociated Kinase 4 (IRAK4) as a Therapeutic Target for Inflammation and Oncology Disorders, J. Med Chern., 2015, 58(1): 96-110, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00169] In some embodiments, IRAK is selected from a moiety recited in Zhang, D. et al.

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic

Ductal Adenocarcinoma, Clin. Can. Res., 2017, 23(7): 1748-59, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00170] In some embodiments, IRAK is selected from a moiety recited in Cushing, L. et al., IRAK4 kinase controls Toll-like receptor induced inflammation through the transcription factor IRF5 in primary human monocytes, J. Bio. Chem., 2017, 292(45): 18689-698, such as, for

O

PF-06426779

---L—i LBM J wherein is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00171] In some embodiments, IRAK is selected from a moiety recited in Li, N. etal. Targeting interleukin-1 receptor-associated kinase for human hepatocellular carcinoma, J. Ex. Clin. Can. Res., 2016, 35(1): 140-50, such as, for example:

wherein

1-5409 (Sigma) is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00172] In some embodiments, IRAK is selected from a moiety recited in Dudhgaonkar, S. et al., Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity, J. of Immun., 2017, 198(3): 1308-19, such as, for example:

BMS-986126 wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00173] In some embodiments, IRAK is selected from a moiety recited in Wang, Z. et al., IRAK

Inhibitors for Inflammation, Cur. Top. Med. Chem., 2009, 9(8): 724-37, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00174] In some embodiments, IRAK is selected from a moiety recited in Kelly, P.N. et al.

Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy, J. Exp. Med., 2015, 212(13): 2189-201, such as, for example:

wherein

ND-2158 is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00175] In some embodiments, IRAK is selected from a moiety recited in Dunne, A. et al., IRAKI and IRAK4 Promote Phosphorylation, Ubiquitation, and Degradation ofMyD88 Adaptorlike (Mal), J. Bio. Chern., 2010, 285(24): 18276-82, such as, for example:

IRAK1/4 inhibitor

---L—( LBM J wherein Q—Q is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00176] In some embodiments, IRAK is selected from a moiety recited in Kiippers, R., IRAK inhibition to shut down TLR signaling in autoimmunity andMyD88-dependent lymphomas, J. Exp.

Med, 2015, 212(13): 2184, such as, for example:

---L—( LBIVM wherein is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00177] In some embodiments, IRAK is selected from a moiety recited in Chiang, E.Y. et aL, Immune Complex-Mediated Cell Activation from Systemic Lupus Erythematosus and Rheumatoid Arthritis Patients Elaborate Different Requirements for IRAK1/4 Kinase Activity across human Cell Types, J. Immunol., 2011, 186(2): 1279-88, such as, for example:

IRAK1/4 inhibitor |---L—( LBMj wherein +-+ is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00178] In some embodiments, IRAK is selected from a moiety recited in Lee, K.L. et al., Discovery of Clinical Candidate 1-{[2S, 3S, 4S) ethyl fluoro oxopyrrolidin yl]methoxy}-7methoxyisoquinoine carboxamide (PF-06650833), aPotent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 9IRAK4), by Fragment-Based Drug Design, J. Med. Chern., 2017, 60(13): 5521-42, such as, for example:

Amgen 1 Amgen 2

Nimbus 8 10

[00179] In some embodiments, IRAK is selected from a moiety recited in Kondo, M. et al., Renoprotective effects of novel interleukin-1 receptor-associated kinase 4 inhibitor AS2444697 through anti-inflammatory action in 5/6 nephrectomized rats, Naunyn-Schmiedeberg’s Arch Pharmacol., 2014, 387(10): 909-19, such as, for example:

AS2444697

---L—( LBM J wherein 0-0 is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00180] In some embodiments, IRAK is selected from a moiety recited in Song, K.W. et al. The Kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells, Mol. Immunol., 2009, 46(7): 1458|---L—( LBM J

66, such as, for example: RO0884, RO 1679, or RO6245, wherein 0—is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00181] In some embodiments, IRAK is selected from a moiety recited in Vollmer, S. etal. The mechanism of activation of IRAKI and IRAK4 by interleukin-1 and Toll-like receptor agonists, Biochem. J., 2017, 474(12): 2027-38, such as, for example: IRAK-IN-1A, JNK-IN-7, and JNK--L—( LBM J

IN-8, wherein is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00182] In some embodiments, an IRAK ligand is selected from moiety recited in McElroy, W.T., et al., Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation, Med. Chem. Lett., 2015, 6(6): 677-82, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00183] In some embodiments, an IRAK ligand is selected from moiety recited in Seganish, W.M., et al. Discovery and Structure Enabled Synthesis of 2,6-diaminopyrimidine one IRAK4 Inhibitors, Med. Chem. Lett., 2015, 6(8): 942-47, such as, for example:

OH

OH

14 15

17 18

23 24

--L—&#943; LBMJ wherein is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00184] In some embodiments, an IRAK ligand is selected from moiety recited in Seganish, W.M., et al. Initial optimization and series evolution of diaminopyrimidine inhibitors of interleukin-1 receptor associated kinase 4, Bioorg. Med. Chem. Lett., 2015, 25(16): 3203-207, such as, for example:

OH

OH

OH

OH

OH

OH wherein

OH

OH

OH

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00185] In some embodiments, an

[00186] In some embodiments, IRAK is

In some IRAK ligand is selected from moiety recited in McElroy, W.T., et al. Discovery and hit-to-lead optimization of 2,6-diaminopyrimidine Inhibitors of interleukin-1 receptor-associated kinase 4,

Bioorg. Med. Chem. Lett., 2015, 25(9): 1836-41, such as, for example:

OH

OH

OH

--L—i LBMJ wherein X-X is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00187] In some embodiments, an IRAK ligand is selected from moiety recited in Tumey, L.N., et al. Identification and optimization of indolo[2,3-c]quinoline inhibitors ofIRAK4, Bioorg. Med. Chern. Lett., 2014, 24(9): 2066-72, such as, for example:

CN

wherein

(sic)

LBM is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

N

[00188] In some embodiments, IRAK is

In some embodiments, IRAK is

some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments,

[00189]

In some embodiments, IRAK is

<td> Y ״ δ^γχ^Ν,^^ΝΗ «χτ ιχ Ν^Χ> Ν>>\ y some embodiments, IRAK is . N</td><td> In some embodiments, IRAK is</td>

<td> // /Γη YL n / T y2 \־־ N-+ ' In some F F—/ aNH2>zxm-N An yr N sx__Z 1 11 L uJ'A ΑΆν n Τ ו s H ז In some nh2 W 0J\Ax A O r ץ x^x-0 IT x>N . In some embodiments, IRAK is F °Vv\nsn h JOL embodiments, IRAK is θ [00190] In some embodiments, IRAK is</td><td> embodiments, IRAK is embodiments, IRAK is \.<ΝΗ nA^Ox !1 JL JL ז . In some .0 h2n~# An YOn^x Υ/ό JO / h</td>

<td> Ν pY N F F H some embodiments, IRAK is F F H 0¾ embodiments, IRAK is FY N^Vk F H MN\ 0 ΗΝ-γ Vn H2N4־־ IRAK is 0 .0 H2N—-ץ An H/N (Zn0 XAy F HN־־־\ / F־V F .0 h2n-# An H o-# o</td><td> .0 h2n~# ^>1 An 0Ά Ό £ In some .0 h2n~a׳ An H/N ׳ x° to . In some embodiments, jOy In some embodiments, IRAK is In some embodiments, IRAK is In some embodiments, IRAK is</td>

<td> Ο H2N—/ °e ο ΕΕγ־ 0 h2n~# 0N N \__Ζ γ ך F H 0Έ Ό \Ey .0 H2N—-ץ 0N v0־\V/ n xy \ z \Ά f H 0-/Ό .0 H2N—Y F^mAEn FT h ' >4־־־ |l F 0-# 0 k^Ny [00191] In some embodiments, IRAK is F^XX F I H some embodiments, IRAK is F 1 H2N—ץ Xn ץ—< N v py \ z >r '׳ H 0E o 0 IRAK is</td><td> In some embodiments, IRAK is In some embodiments, IRAK is In some embodiments, IRAK is F F-/ Xn H 0J1) EE . In EN Y\T־־Vnh 79—F o In some embodiments, . In some embodiments, IRAK is</td>

<td> 0 h2n~# 0A o kky F F~/ Vn 0Jq k^k F F-Y /=N F f H 0ΑΆ kky F F-Y N^Vi YN ^NAJyN ™־־VNy^ H o-yid k^Ny YN [00192] In some embodiments, IRAK is O—y ״ty V Mk^N HN-y^N^ O-Yo In F F—/ ,N^ >N 0-# ό kk>/</td><td> In some embodiments, IRAK is In some embodiments, IRAK is In some embodiments, IRAK is V O . In some embodiments, IRAK is some embodiments, IRAK is In some embodiments, IRAK is</td>

In some embodiments, IRAK is some embodiments, IRAK is

In some embodiments, IRAK is

<td> N H [00193] In some embodiments, IRAK is ץכ V Hc some embodiments, IRAK is N-γ Y Z~~N embodiments, IRAK is י Ν-γ γ 0 ΥλΟΗ ο^νη2 /Ν''</td><td> Ν^\ !ΑΛ । q /ץ ΗΝ-γ / Vn f7\ F F . In R F F \ /=N לסל Γ7Λ ז In some )H ih2 In some embodiments, IRAK is _ A) NY כ ΥγΟΗ iZZ o^nh2 Z־NZ M-Z</td>

embodiments, IRAK is

<td> ' Z י ΧγΥ'׳־ Γ Η 5 In some embodiments, IRAK is NH2</td><td> In some embodiments, IRAK is</td>

<td> 9' ΝΗ Η some embodiments, IRAK is O jOl j0O Ϊ J H is HNX ־־־־O ΧχΛΊ Y=Z V=n HN— [00194] In some embodiments, IRAK is</td><td> . In some embodiments, IRAK In some embodiments, IRAK is -0 I HN—/ >NH // N N 7 In some embodiments,</td>

<td> HN—/ ^'״ΝΗ״ Y / 1Ν N IRAK is ^=7</td><td> J. HN—()1״γ hn--~X^n In some embodiments, IRAK is !n</td>

<td>HN,\ (Γ / / 1Ν Ν some embodiments, IRAK is HN—11 ׳Y Y— HN-^n I ״Y HN—/ YY Y— (f / / N N^ In N^ zr\ Y f Yy0 / Nπ /—N V^\. /\ ξ Γj f^^n vJa hn-7 ך F Ό h2n—/ N^^ >N כג^ס H [00195] In some embodiments, IRAK is</td><td> Y'N^ In some embodiments, IRAK is n some embodiments, IRAK is some embodiments, IRAK is In some embodiments, IRAK is y H aJ NH r F J. t / n . In some</td>

In some embodiments, IRAK is

In some embodiments, IRAK is some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is some embodiments, IRAK is

In some embodiments, IRAK is

[00196] In some embodiments, IRAK is selected from those depicted in Table 1, below.

[00197] As defined above and described herein, Lisa bivalent moiety that connects IRAK to LBM.

[00198] In some embodiments, Lisa bivalent moiety that connects IRAK to LBM.

[00199] In some embodiments, L is a covalent bond or a bivalent, saturated or unsaturated, straight or branched C1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by -Cy-, , -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -NRS(O)2-, -

S(O)2NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-,

, n , or &#1497;- n , wherein: each -Cy- is independently an optionally substituted bivalent ring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7 membered saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl, a 4-7 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur. [00200] In some embodiments, each -Cy- is independently an optionally substituted bivalent phenylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic arylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated spiro carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated carbocyclylenyl. In some embodiments, each -Cy- is independently an optionally substituted 47 membered saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated spiro heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclylenyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5-6 membered heteroarylenyl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00201] In some embodiments, -Cy- is '—' . In some embodiments, -Cy- is '—' . In some embodiments, -Cy- is

In some embodiments, -Cy- is

Xn/ X C some embodiments, -Cy- is ,&#1488;—/ . In some embodiments, -Cy- is + . In some

<td> embodiments, -Cy- is J . In</td><td> some embodiments, -Cy- is . In some</td>

<td> embodiments, -Cy- is + . In</td><td> some embodiments, -Cy- is + . In some</td>

<td> embodiments, -Cy- is + . In</td><td> some embodiments, -Cy- is + . In some</td>

embodiments, -Cy- is embodiments, -Cy- is embodiments, -Cy- is

. In some embodiments, -Cy- is . In some embodiments, -Cy- is

In some embodiments, -Cy- is

. In . In some some

In some

<td> An Y nA embodiments, -Cy- is ׳—א '—/ 0 | Xo In some embodiments, -Cy- is .</td><td> An γ\ιΑ In some embodiments, -Cy- is ׳—א v 0 Αν^Ί In some embodiments, -Cy- is A In</td>

<td> 0 N— some embodiments, -Cy- is . [00202] In some embodiments, y η h γ 0 γ 0 0 0 y η h \ γ 0 0 Y 0 ο o In Y Η Η H o o In 0 0 Y^ n n 0^'׳y י H Hr In some / H ״ 0 0 H H ז In some embodiments, L is ׳WY some embodiments, L is 0 . H ? /γΝχ^־־\/^ΝΑ^ A 0 . In some embodiments, L is</td><td> L is In some embodiments, L is some embodimentsn, L is some embodiments, L is embodiments, L is In some embodiments, L is 0 0 Y^ n N ׳^Xx'°y Η Η Z . in In some embodiments, L is A, 0</td>

[00203] In some embodiments, L is 0 in some embodiments, L is

In some embodiments, L is

<td> / H A״/N\z^ 0 In some embodiments, L is is 0 0 Z H 1 O / H 1 embodiments, L is 0 / h ז embodiments, L is 0 Η ί 0 [00204] In some 4tUv^0. 0</td><td> ZKzN. \ _ 1ץ° H . In some embodiments, L In some embodiments, L is y>- In some embodiments, L is H In some H In some N |_| In some embodiments, L is H ^Ny embodiments, L is H ^0^0^Ny . In some embodiments, L is</td>

<td> e H f Η \ ο o In / η ז s S H / / Η 1 ״ 0 X H f H % Z\/ N /0. Χλ , N . A ? Y 0 0 0 ץ λ 0 0 H f H ל /γΝΥ^Ο^θ^Ν^Υ In ס ס c Η Η % Ay Ν ^//Υ-^/Χ/Ο-^/Χ/־ Ν γ^οΑ. 0 0 1 0 \ / 0 \Α Ν Ν ΆγΥ Η 1. Η ז Α Η 1 4ν^/ [00206] In some embodiments, L is 0 / H II embodiments, L is O s Η H ל An^n^a Οθ . In some 4 H H />< NN 0 H</td><td> some embodiments, L is In some embodiments, L is /Oy . In some embodiments, L is In some embodiments, L is some embodiments, L is n some embodiments, L is Η V O . In some In some embodiments, L is embodiments, L is In some embodiments, L is</td>

<td> 0 H ל Ay N 0 0 Λ-/.ο-+^ογ F 0 . ο ? _ Π n ___ ex x\ /O. JU. 0 r H ץ 0 0 / H /γ׳Ύ [00207] In some embodiments, Lis 0 א H F L is 0 Ay N 0 Ay N 0 0 H j n ך/ 0</td><td> H \ ^x/NxA 0 In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is H T . In some embodiments, 1 1χ In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is</td>

<td> II H N N 0 Ζ H H [00208] In some embodiments, L is ί H ל N \</td><td> In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is H . In some embodiments, L is / H 1 5V-n, nA fl H י</td>

some embodiments, L is

<td> some embodiments, L is O 0 H / H embodiments, L is O 4 H ל NN A H In some embodiments, L is</td><td> H _____. h 'Νγ,^—===x—N .א^ . In some embodiments, L is . In some embodiments, Lis H . In some Ό N |_| In some embodiments, L is > H s k. N . In some embodiments, Lis ° י ν^Οχ^οχ^ O In some embodiments, L is O</td>

* &#908;’

[00209] In some embodiments, L is

&#908;

O . In some

&#908;&#1470;

In some embodiments, L is embodiments, L is embodiments, L is

In some embodiments, L is

some embodiments, L is O . In some embodiments, L is

<td> c H || 0 y H V- [00210] In some embodiments, L is 0 ל H א embodiments, L is 0 0 H 2 0 Γ Η H ל / γ 0 0 γ 0 % 0 0 0 H ז ל H . A׳ N N 0 H N X H N X H ל । , 55Χ<Νχ-־^Ο'/''^Ο^^Οχ^ S H / H /\xN [00211] In some embodiments, L is O</td><td> O . In some In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is H . In</td>

<td> / Η some embodiments, L is 0 embodiments, L is 0 r Η ί H Λ , Ν ν Λ/0.A / N ? Y Y o 0 0 /x H ל H 0 ' ' pH \ Αγ NN N A s H H \ 1 ל h , 0 H ίί 1 H \ h 1 z . Η H axo--oa 0 y Η ί H 0 0 An H [00212] In some embodiments, L is / H 1 embodiments, L is 0</td><td> xAxmAA^0^^' n H In some H 0 y In some embodiments, L is y In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is 1 H 1 N y 1 X ? >־ In some X/OxX^N-k |_| . In some embodiments, L is</td>

In some embodiments, L is

In some embodiments, L is

[00213] In some embodiments, L is O 0 . In embodiments, L is some embodiments.

In some

<td> AnAA ן ן_ן ר embodiments, L is F iAA0^^0^0 h 0 II V H I H F . Η H XzNK/\ ζ\ζΝχ? z 0 ץ y 0 H f H /AN \ N γ γ 0 /X H 0 [00214] In some embodiments, L is H AY H Λ״ Ν Ν N L is O > some embodiments, L is O N 0 H</td><td> O In some embodiments, L is O In some embodiments, L is H x0^Ny In some embodiments, L is H 7 In some embodiments, L is In some embodiments, L is H In some embodiments, L is Η H ל γΝ^^Ν^ΝΑ II η Ο . In some embodiments, Α°^λ . In some embodiments, L is H . In |_| In some embodiments, L is In some embodiments, L is</td>

In some embodiments, L is

<td> O In some O In some H י I o In some j־ Η H % , θ In some embodiments, L is C</td><td> embodiments, L is embodiments, L is embodiments, L is Η ΐ 5 In some</td>

<td> L/A n N H ׳ _ \ ? embodiments, L is NN [00215] In some embodiments, L is NN ח ן c J ') In some embodiments, L is N^ Ljki___, ~ 'N hn^/^n h N^N . In some embodiments, L is u N=N hN-4 In some embodiments, L is O 0 x H . In y H / In</td><td> H In some embodiments, L is ΛΑ^ -Λ 0 H . In some embodiments, L is some embodiments, L is some embodiments, L is</td>

H In some embodiments, L is

O In some embodiments, L is

<td> 0 YA .0./ H 0 |_| [00216] In some embodiments, L is Ay N embodiments, L is 0 5 H H embodiments, L is 0 0 , H lAj [00217] In some embodiments, Lis O j Η H ל ג״— O . In some embodiments, L is some embodiments, L is O m^0^-n^-na S׳ H . In some embodiment, Lis O / H ל some embodiment, L is O ל / O \ In some embodiments, L is</td><td> O . In some O H ץ . In some O H . In some embodiments, L is H . In In some embodiments, L is N ׳ . In In some embodiment, L is</td>

In some embodiments, L is embodiments, L is

In some embodiments, L is

some embodiments, Lis 0 . In some embodiments,

some embodiments,

some embodiments,

some embodiments, L is H . In some embodiments,

In some embodiments, L is

[00218]

In some embodiments, L is O

In some embodiments,

<td> 0 some embodiments, L is < H N N ^0 H H 0 H < H 1 Y ז Λ,N Χ/χ/χ Nx ע i H [00219] In some embodiments, Lis 0 3 H is ° 4 H -cy o n ך o k^Ny 4 H n ך 0</td><td> kkxNA H . In some embodiments, L is In some embodiments, L is In some embodiments, L is H ->Ny In some embodiments, L is . In some embodiments, L In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is</td>

[00220]

In some embodiments, L

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is some embodiments,

In some embodiments, L is

In some embodiments,

In some embodiments, L is

In some embodiments, L is

embodiments, L is 0

In some embodiments, L is

<td> some embodiments, L is , 1 some embodiments, L is 5 H X</td><td> θ In some embodiments, L is . In some embodiments, L is θ . In H ל O In some embodiments, L is 4 .A \</td>

In some embodiments, L is

<td> 3 H Ay N In some embodiments, L is I י H . 0 < H J 1 H o / H A+^ N ^0++^0^ N A H [00221] In some embodiments, L is A^</td><td> In some embodiments, L is In some embodiment, L is In some embodiment, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is H H Ν Ύ\ζ N N 7 ° In some</td>

embodiments, L is

In some embodiments, L is

In some embodiments, L is

some embodiments,

In some embodiments, L is

In some embodiments, L is some embodiments,

In some embodiments, L is

In some

embodiments,

In some embodiments, L is

O In some embodiments, L is

<td> ־ η Ο Y j ס >ך > O In some , Η ?Υ Ο In some < Η 9^Ί Ο . In some embodiments, L is</td><td> embodiments, L is embodiments, L is h 9^1 o</td>

<td> . η O . /χ N N In some embodiments, L is ° % ^9 1 ־ O In some embodiments, L is some embodiments, L is ° % 1 O ־ /x N N O In some embodiments, L is < 1 O v embodiments, L is ° . Ir ; H A 0 . In some embodiments, L is . H 9^ embodiments, L is O I 0 In some embodiments, L is</td><td> In some embodiments, L is ° °M . In In some embodiments, L is . 1 % O In some 1 some embodiments, L is I O . In some In some embodiments, L is h 9^1 o . In</td>

<td> some embodiments, L is O . 1 o o some embodiments, L is . H ?ty H e some embodiments, L is ־s H < H (A N A < Η Γ N=N « H N N Ά < Η Γ A> N n k Ά , H</td><td> H ?A H ' In some embodiments, L is / 1 o 4n^—γν In some embodiments, L is O . In H ?A H In some embodiments, L is . । ?Q AzNsXnxs^ In some embodiments, Lis H . In । ?A — ^X N ty/ H In some embodiments, L is H In some embodiments, L is ΐ^ΑΐΝ-Α t , ,. + τ 4 . In some embodiments, L is H In some embodiments, L is In some embodiments, L is In some embodiments, L is ׳°^nA H In some embodiments, L is</td>

In some embodiments, L is some embodiments, L is

In some embodiments, L is embodiments, L is

In some embodiments, L is

[00222] In some embodiments, L is HO . In some embodiments, L is

N H . In some enbodiments, L is

<td> x H 0 \ / VJ H HN—( / V0 0 H Y—Nx^O 0 A kf N h HO^ ' 0 H H H q F 0 >0^ S H H **—NxyO hnJ ץ^°<> [00223] In some embodiments, L is</td><td> In some embodiments, L is X In some embodiments, L is H In some embodiments, L is ^NX H / \ . In some embodiments, L</td>

<td> is 7 OH some embodiments, L is ־°1׳ \ some embodiments, L is some embodiments, L is</td><td> . In some embodiments, L is HO OH !n \ / θ . In some embodiments, L is 1 HOX OH . In some embodiments, Lis In \ / H \ / . In some embodiments, L is ' . In In some embodiments, L is</td>

[00224]

In some embodiments, L is

In some embodiments, L is embodiments,

In some embodiments, L is

In some embodiments,

In some

O embodiments, L is jn some embodiments, L is

<td>In 0 0 [00226] In some embodiments, L is T 0 embodiments, L is H 0 Jn jn some embodiments, L is 0 embodiments, L is ! Z ^o^x°x^o^/°x^X>\ In</td><td> some embodiments, L is . In some In some embodiments, L is some embodiments, L is O jn some n some embodiments, L is some embodiments, L is</td>

<td> 0 [00227] In some embodiments, L is Ln is A—/ . In some embodiments, L is / A In some embodiments, L is /xA,,, n LA zx^nY υ O . In some /'y’d d'N'd5' n LA /־xA-L υ O . In some</td><td> . In some embodiments, L 1 A/NnLJ In some embodiments, L is embodiments, L is embodiments, L is</td>

<td> Y Z^N׳,.^ Us J some embodiments, L is embodiments, L is some embodiments, L is Αχ/Χχ A0N__^ V־N^ embodiments, Lis</td><td> X/ In some embodiments, L is ^N/״cx . In some embodiments, L is in !η some embodiments, L is In some embodiments, L is ° x In some XX u In some embodiments, L is י . In some embodiments, L is r י . In x ז AUxX°\/\A r י . In some embodiments, L is ,5A/x/ .y\n__A In some embodiments, L is 1־—J In some ל ׳Νκχ\ A A/n׳׳-X\ A 7־־N ץ 7־־N ן —/ . In some embodiments, Lis 1—/</td>

<td> τ , ,. τ Λ nJ Ln In some embodiments, L is e A n J 1 In some embodiments, L is embodiments, L is Ά^Ν\χ</td><td> . In some embodiments, L is 1 τ ז In some In some embodiments, L is</td>

In some embodiments, L is

embodiments, L is

. In some embodiments, L is

In some

[00228] In some embodiments, Lis H . In some embodiments,

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is some embodiments, L is

In some embodiments,

some

L is

In some embodiments,

L is

<td> / H r-Ο < Η I V ΑΝΆΧτ N^־ H / ך > cH some embodiments, L is < Η Η ϊ Os/ \Z \Z z ז6 embodiments, L is 0 < Η Η ϊ ύννγν\ 0 / H embodiments, L is / H Λ/Ν embodiments, L is / H A/ N /O\ is 0 / H / H</td><td> A^ Η H in some embodiment, L is 5 H \ZOH ל . In some embodiments, L is * . In c Η Η ϊ Xn./x/x.nA 14 In some embodiments, L is 3 1 Η ϊ In some embodiments, L is O . In some Χ^Α In some embodiments, L is < Η Η ϊ ΧΝ^ογΝα In some embodiments, L is 0 . In some ז In some in some embodiments, L θ In some embodiments, L is In some embodiments, L is 0c u 0 H . In some embodiments, Lis H</td>

<td>0 1 ז ύ^.ΌΛΝ% In some embodiments, L is H y H j N / . In some embodiments, L is</td><td> In some embodiments, L is s 1 In</td>

some embodiments, L is

In some embodiments, L is

In some embodiments, L is embodiments,

In some embodiments, L is

In some embodiments, L

[00229]

In some embodiments, L is

In some

embodiments,

In some embodiments, L is

embodiments,

In some embodiments, L is

Q N— embodiments, L is . In some embodiments, Lis

Ο N—

. In some embodiments, L is

In some embodiments, L is embodiments, L is

embodiments, L is

In some embodiments, Lis

In some embodiments, L is

In some embodiments,

In some embodiments, L is

N

In some

In some embodiments,

L is

In some

In some embodiments, L is . In some embodiments, L is . In some embodiments, Lis 0

. In some embodiments, L is

N

In some embodiments, L is I

'0&#1470;

In some embodiments, L is

. In some embodiments, L is

. In some embodiments, . N

Lis *

[00230]

[00231]

O' . In some embodiments, L is

In some embodiments, L is selected from those depicted in Table 1, below.

As defined above and described herein, LBM is a ligase binding moiety.

[00232] In some embodiments, LBM is LBM is an E3 ubiquitin ligase (cereblon) binding

wherein each of X1, X2, and X3 is independently a bivalent moiety selected from a covalent bond, <0^

-CH2-, -C(O)-, -C(S)-, or \ Λ each of X4 and X5 is independently a bivalent moiety selected from -CH2-, -C(O)-, -C(S)-, or O vv

&#1512;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic;

each of R2, R3, and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2,

-C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R;

R5 is hydrogen or C1-6 aliphatic;

Ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring C is a selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

m is 0, 1, 2, 3 or 4;

each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

p is 0, 1, 2, 3 or 4;

[00233] In some embodiments, LBM is

O . In some embodiments, LBM is

In some

In some embodiments, LBM is

[00234] In some embodiments, LBM is O In some embodiments, LBM is

Ο . In some embodiments, LBM is

[00235] In some embodiments, LBM is

&#908;

N

N H

&#908;

N

N H

O . In some

O some embodiments, LBM

In is

<td> Ο ° \ /-- ZZ^N A [Γz'1' [00237] In some embodiments, LBM is Ο l. , YA /( nA /]ן Ί V A0 H A YN is OH in some embodiments, LBM is O __ ץ־־־ס il Ί V Ao , 1! J ZN ο H embodiments, LBM is + . Ir γ Λ״Ν ). il ί V Yo , J! J , Y+A OH \ + . In some embodiments, LBM is ' Arr [00238] In some embodiments, LBM is θ \ NH ...L HN 0 TjlW LBM is s In</td><td> Ao J 1 . In some embodiments, LBM OH in some 1 some embodiments, LBM is K° Ζ-Λ il Ί V Yo II J >ZN Ο H HN^ NH ¼/ 0נH ί 1 . In some embodiments, some embodiments, LBM is</td>

[00239] In some embodiments, LBM is a E3 Ubiquitin ligase (cereblon) binding moiety recited in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κΒ activation, and TNFa-Dependent Apoptosis, Cell, 2007, 131(4): 669-81, such as, for example:

wherein

BV6

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

[00240] In some embodiments, LBM is selected from those depicted in Table 1, below.

[00241] As defined above and described herein, each of X1, X2, and X3 is independently a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or

[00242]

In some embodiments, X1 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or

[00243] In some embodiments, X1 is selected from those depicted in Table 1, below.

[00244]

In some embodiments, X2 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or

[00245] In some embodiments, X2 is selected from those depicted in Table 1, below.

[00246]

In some embodiments, X3 is a covalent bond, -CH2-, -C(O)-, -C(S)-, or

[00247] In some embodiments, X3 is selected from those depicted in Table 1, below.

[00248] As defined above and described herein, each of X4 and X5 is independently a bivalent moiety selected from -CH2-, -C(O)-, -C(S)-, or

[00249] In some embodiments, X4 is -CH2-, -C(O)-, -C(S)-, or k A

[00250] In some embodiments, X4 is selected from those depicted in Table 1, below.

[00251] In some embodiments, X5 is -CH2-, -C(O)-, -C(S)-, or k A

[00252] In some embodiments, X5 is selected from those depicted in Table 1, below.

[00253] As defined above and described herein, R1 is hydrogen, deuterium, halogen, -CN, OR, -SR, -S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic.

[00254] In some embodiments, R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR,

-S(O)R, -S(O)2R, -NR2, or an optionally substituted C1-4 aliphatic.

[00255] In some embodiments, R1 is selected from those depicted in Table 1, below.

[00256] As defined above and described herein, each of R2, R3, and R4 is independently hydrogen, -R6, halogen, -CN, -NO2, -OR,

SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR,

C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[00257] In some embodiments, R2 is hydrogen, -R6, halogen, -CN, -NO2, -OR, SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR,

C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[00258] In some embodiments, R2 is selected from those depicted in Table 1, below.

[00259] In some embodiments, R3 is hydrogen, -R6, halogen, -CN, -NO2, -OR, SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR,

C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[00260] In some embodiments, R3 is methyl.

[00261] In some embodiments, R3 is selected from those depicted in Table 1, below.

[00262] In some embodiments, R4 is hydrogen, -R6, halogen, -CN, -NO2, -OR, SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR,

C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, or -N(R)S(O)2R.

[00263] In some embodiments, R4 is methyl.

[00264] In some embodiments, R4 is selected from those depicted in Table 1, below.

[00265] As defined above and described herein, R5 is hydrogen or C1-6 aliphatic.

[00266] In some embodiments, R5 is /-butyl.

[00267] In some embodiments, R5 is selected from those depicted in Table 1, below.

[00268] As defined above and described herein, each R6 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00269] In some embodiments, R6 is an optionally substituted C1-6 aliphatic group. In some embodiments, R6 is an optionally substituted phenyl. In some embodiments, R6 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R6 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00270] In some embodiments, R6 is selected from those depicted in Table 1, below.

[00271] As defined above and described herein, Ring A is a fused ring selected from 6membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered partially saturated carbocyclyl, 5 to 7-membered partially saturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00272] In some embodiments Ring A is a fused 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments Ring A is a fused 5 to 7-membered partially saturated carbocyclyl. In some embodiments Ring Ais a fused 5 to 7-membered partially saturated heterocyclyl with 12 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments Ring Ais a fused 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00273] In some embodiments, Ring Ais a fused phenyl.

[00274] In some embodiments, Ring Ais selected from those depicted in Table 1, below.

[00275] As defined above and described herein, Ring B is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00276] In some embodiments, Ring B is a 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, Ring B is a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[00277] In some embodiments, Ring Bis 1 'p.

[00278] In some embodiments, Ring B is selected from those depicted in Table 1, below.

[00279] As defined above and described herein, Ring C is selected from 6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00280] In some embodiments, Ring C is a 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, Ring C is a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00281] In some embodiments, Ring C is a

[00282] In some embodiments, Ring C is selected from those depicted in Table 1, below.

[00283] As defined above and described herein, m is 0, 1, 2, 3 or 4.

[00284] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[00285] In some embodiments, m is selected from those depicted in Table 1, below.

[00286] As defined above and described herein, each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[00287] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10.

[00288] In some embodiments, n is selected from those depicted in Table 1, below.

[00289] As defined above and described herein, p is 0, 1, 2, 3 or 4.

[00290] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[00291] In some embodiments, p is selected from those depicted in Table 1, below.

[00292] As defined above and described herein, q is 0, 1, 2, 3 or 4.

[00293] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[00294] In some embodiments, q is selected from those depicted in Table 1, below.

[00295] As defined above and described herein, each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[00296] In some embodiments, R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[00297] In some embodiments, R is selected from those depicted in Table 1, below.

[00298] As described above, in certain embodiments, the present invention provides a compound of formula I-zzz:

I-zzz or a pharmaceutically acceptable salt thereof, wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or ;

X2 is a carbon atom or silicon atom;

X3 is a bivalent moiety selected from -CH2- or -Si(R2)-;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

each R2 is independently hydrogen, -R3, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R)3, -S(O)2R, -S(O)2N(R)2, -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R;

each R3 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 47 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

(R2)m--D

Ring A is a tricyclic ring selected from , wherein each of Ring B, Ring C, and Ring D is independently a fused ring selected from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;

wherein L and IRAK are as described in embodiments herein.

[00299] In some embodiments, a compound of formala I-zzz above is provided as a compound of formula I-zzz' or formula I-zzz:

IRAK)----L

I-zzz'

I- zzz or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, R1, R2, X1, and m is as defined above.

[00300] As described above, in certain embodiments, the present invention provides a compound of formula I-aaaa:

I-aaaa or a pharmaceutically acceptable salt thereof, wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or Y ;

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R;

(R2)m

Ring A is a tricyclic ring selected from

, wherein each of Ring B, Ring C, and Ring D is independently a fused ring selected from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;

wherein L and IRAK are as described in embodiments herein.

[00301] In some embodiments, a compound of formala I-aaaa above is provided as a compound of formula I-aaaa&#1523; or formula I-aaaa:

I- aaaa or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, R1, R2, X1, and m is as defined above.

[00302]

As described above, in certain embodiments, the present invention provides a compound of formula I-bbbb:

I-bbbb or a pharmaceutically acceptable salt thereof, wherein:

<0^

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or k k

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

-N(R)S(O)2R;

each of Ring B and Ring C is independently a fused ring selected from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring D is a fused ring selected from aryl containing 0-3 nitrogens, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated heterocyclyl ring with 1-2 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur, or heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

— is a single or double bond;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;

wherein L and IRAK are as described in embodiments herein.

[00303] In some embodiments, a compound of formala I-bbbb above is provided as a compound of formula I-bbbb&#1523; or formula I-bbbb&#1523;&#1523;:

I- bbbb or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, R1, R2, X1, and m is as defined above.

[00304] As described above, in certain embodiments, the present invention provides a compound of formula I-cccc:

R1/—\ —L—( A ) \ /=° X1&#1470;NH (R2)m

I-cccc or a pharmaceutically acceptable salt thereof, wherein:

X1 is a bivalent moiety selected from a covalent bond, -CH2-, -C(O)-, -C(S)-, or X X

R1 is hydrogen, deuterium, halogen, -CN, -OR, -SR, -S(O)R, -S(O)2R, -N(R)2, -Si(R)3, or an optionally substituted C1-4 aliphatic;

-N(R)S(O)2R;

each of Ring B and Ring C is independently a fused ring selected from 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

— is a single or double bond;

m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;

wherein L and IRAK are as described in embodiments herein.

[00305] In some embodiments, a compound of formala I-cccc above is provided as a compound of formula I-cccc' or formula I-cccc:

I- CCCC&#1524; or a pharmaceutically acceptable salt thereof, wherein:

each of IRAK, Ring A, L, R1, R2, X1, and m is as defined above.

[00306] As defined above and described herein, X1 is a bivalent moiety selected from a covalent <0^ bond, -CH2-, -C(O)-, -C(S)-, or Λ

[00307] In some embodiments, X1 is a covalent bond. In some embodiments, X1 is -CH2-. In some embodiments, X1 is -C(O)-. In some embodiments, X1 is -C(S)-. In some embodiments, O xHs^ Λ

[00308] In some embodiments, X1 is selected from those depicted in Table 1, below.

[00309] As defined above and described herein, X2 is a carbon atom or silicon atom.

[00310] In some embodiments, X2 is a carbon atom. In some embodiments, X2is a silicon atom.

[00311] In some embodiments, X2 is selected from those depicted in Table 1, below.

[00312] As defined above and described herein, X3 is a bivalent moiety selected from -CH2or -Si(R2)-.

[00313] In some embodiments, X3 is -CH2- . In some embodiments, X2 is -Si(R2)-.

[00314] In some embodiments, X3 is selected from those depicted in Table 1, below.

[00315]

[00316] As defined above and described herein, R1 is hydrogen, deuterium, halogen, -CN, OR, -SR, -S(O)R, -S(O)2R, -NR2, -Si(R3), or an optionally substituted C1-4 aliphatic.

[00317] In some embodiments, R1 is hydrogen. In some embodiments, R1 is deuterium. In some embodiments, R1 is halogen. In some embodiments, R1 is -CN. In some embodiments, R1 is -OR. In some embodiments, R1 is -SR. In some embodiments, R1 is -S(O)R. In some embodiments, R1 is -S(O)2R. In some embodiments, R1 is -NR2. In some embodiments, R1 is Si(R3). In some embodiments, R1 is an optionally substituted C1-4 aliphatic.

[00318] In some embodiments, R1 is selected from those depicted in Table 1, below.

[00319] As defined above and described herein, each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or: two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[00320] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted C1-6 aliphatic. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

[00321] In some embodiments, R is selected from those depicted in Table 1, below.

[00322] As defined above and described herein, each R2 is independently hydrogen, -R3, halogen, -CN, -NO2, -OR, -SR, -N(R)2, -Si(R3), -S(O)2R, -S(O)2N(R)2,-S(O)R, -C(O)R, -C(O)OR, -C(O)N(R)2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)N(R)2, -OC(O)R, -OC(O)N(R)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R)2, or -N(R)S(O)2R.

[00323] In some embodiments, R2 is hydrogen. In some embodiments, R2 is -R3. In some embodiments, R2 is halogen. In some embodiments, R2 is -CN. In some embodiments, R2 is NO2. In some embodiments, R2 is -OR. In some embodiments, R2 is -SR. In some embodiments,

R2 is -NR2. In some embodiments, R2 is -Si(R3). In some embodiments, R2 is -S(O)2R. In some embodiments, R2 is -S(O)2NR2. In some embodiments, R2 is -S(O)R. In some embodiments, R2 is -C(O)R. In some embodiments, R2 is -C(O)OR. In some embodiments, R2 is -C(O)NR2. In some embodiments, R2 is -C(O)N(R)OR. In some embodiments, R2is -C(R)2N(R)C(O)R. In some embodiments, R2 is -C(R)2N(R)C(O)N(R)2. In some embodiments, R2 is -OC(O)R. In some embodiments, R2 is -OC(O)NR2. In some embodiments, R2 is -N(R)C(O)OR. In some embodiments, R2 is -N(R)C(O)R. In some embodiments, R2 is -N(R)C(O)NR2. In some embodiments, R2 is -N(R)S(O)2R.

[00324] In some embodiments, R2 is selected from those depicted in Table 1, below.

[00325] As defined above and described herein, each R3 is independently an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00326] In some embodiments, R3 is an optionally substituted C1-6 aliphatic. In some embodiments, R3 is an optionally substituted phenyl. In some embodiments, R3 is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[00327] In some embodiments, R3 is selected from those depicted in Table 1, below.

[00328] As defined above and described herein, Ring A is a tricyclic ring selected from

[00329] In some embodiments, Ring Ais L » J

[00330] In some embodiments, Ring Ais selected from those depicted in Table 1, below.

[00331] As defined above and described herein, each of Ring B, Ring C, and Ring D is independently a fused ring selected from 6-membered aryl containing 0-3 nitrogens, 5 to 7membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl ring with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00332] In some embodiments, each Ring B, Ring C, and Ring D is independently a 6membered aryl containing 0-2 nitrogen atoms. In some embodiments, each Ring B, Ring C, and Ring D is independently a 5 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each Ring B, Ring C, and Ring D is independently a 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each Ring B, Ring C, and Ring D is independently a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00333] In some embodiments, Ring B, Ring C, and Ring D is selected from those depicted in Table 1, below.

[00334] As defined above and described herein, Ring A is a tricyclic ring selected from

[00335] In some embodiments, Ring Ais embodiments, Ring A is (R2)m-In some embodiment, Ring A is

In some embodiments, Ring

In some

In some embodiments, Ring A is (R2)m--(c/

[00336] In some embodiments, Ring Ais selected from those depicted in Table 1, below.

[00337] As defined above and described herein, Ring D is a fused ring selected from aryl containing 0-3 nitrogens, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated heterocyclyl ring with 1-2 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur, or heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00338] In some embodiments, Ring D is an aryl containing 0-2 nitrogen atoms. In some embodiments, Ring D is a saturated or partially unsaturated carbocyclyl. In some embodiments, each Ring D is a saturated or partially unsaturated heterocyclyl with 1-2 heteroatoms independently selected from nitrogen, oxygen, silicon, or sulfur. In some embodiments, Ring D is a heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring D is

In some embodiments, Ring

[00339]

embodiments, Ring D is

embodiments, Ring D (R2)m

In some embodiments, Ring D is

In some

In some embodiments, Ring D is

<td> In some embodiments, Ring D is</td><td></td><td></td>

In some

In some embodiments, Ring D is (R2)m

In some embodiments, Ring D is (R2)m embodiments, Ring D is (R2)m

embodiments, Ring D is

In some

(R2)m

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D

In some embodiments, Ring D is

In some embodiments, Ring D

In some embodiments, Ring D is

embodiments, Ring D

embodiments, Ring D

In some embodiments, Ring D is

. In some

In some embodiments, Ring D is

I . In some

In some embodiments, Ring D is

[00341] In some embodiments, Ring D is selected from those depicted in Table 1, below.

[00342] As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,

14, 15, or 16.

[00343] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

[00344] In some embodiments, m is selected from those depicted in Table 1, below.

[00345] As defined above and described herein, Ring A is a tricyclic ring selected from

In some embodiments, Ring Ais (R2)m —

In some embodiments, Ring

[00346]

embodiments, Ring A is

In some embodiment, Ring A is

(R2)m —

In some

In some embodiments, Ring A is

(R2)m~ embodiments, Ring A

N

In some embodiments, Ring A is is

[00347]

[00348]

In some

In some embodiments, Ring A is (R2)m-h

. In some embodiments, Ring A is

In some embodiments, Ring Ais selected from those depicted in Table 1, below.

As defined above and described herein, each Ring B and Ring C is independently a fused ring selected from 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7-membered saturated or partially unsaturated carbocyclyl, 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00349] In some embodiments, each Ring B and Ring C is independently a 6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, each Ring B and Ring C is independently a 5 to 7-membered saturated or partially unsaturated carbocyclyl. In some embodiments, each Ring B and Ring C is independently a 5 to 7-membered saturated or partially unsaturated heterocyclyl with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, each Ring B and Ring C is independently a 5-membered heteroaryl with 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

(R2)m—s

[00350] In some embodiments, each Ring B and Ring C is independently V In (R2)mHft some embodiments, each Ring B and Ring C is independently Ν&#1470;&#902; . In some embodiments, each Ring B and Ring C is independently

In some embodiments, each (R )m A? A

Ring B and Ring C is independently Ν&#1470;&#902;. In some embodiments, Ring B and Ring C is independently

[00351] In some embodiments, Ring B and Ring C is independently is N &#1500; . In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

. In some embodiments, Ring B and Ring C is independently

(R )m-r .

AA

[00352] In some embodiments, Ring B and Ring C is independently H . In some

embodiments, Ring B and Ring C is independently H

In some embodiments, B and (R2)mE

Ring C is independently independently

HO

H In some embodiments, Ring B and Ring C is

In some embodiments, Ring B and Ring C is independently

[00353] In some embodiments, Ring B and Ring C is independently selected from those depicted in Table 1, below.

[00354] As defined above and described herein, is a single or double bond

[00355] In some embodiments, is a single bond. In some embodiments, is a double bond.

[00356] As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

[00357] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8.

[00358] In some embodiments, m is selected from those depicted in Table 1, below.

[00359] In some embodiments, In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, In some embodiments, LBM is

In some embodiments, LBM is

[00360] embodiments, LBM is

In some

In some

[00361] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety

thereby forming a compound of formula I-dddd:

I-dddd or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables R9, R10, R11, R14a, and R15 is as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, the entirety of each of which is herein incorporated by reference.

[00362] In certain embodiments, the present invention provides a compound of formula I,

M-%

V___*Vs;

HN x—I wherein LBM is a VHL binding moiety thereby forming a compound of formula I-eeee:

I-eeee or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables X, R9, R10, R11, R14a, and R15 is as described and defined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, the entirety of each of which is herein incorporated by reference.

[00363] In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an IAP binding moiety thereof;

thereby forming a compound of formula I-ffff:

I-ffff or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein each of the variables W, Y, Z, R1, R2, R3, R4, and R5 is as described and defined in WO 2014/044622, US 2015/0225449. WO 2015/071393, and US 2016/0272596, the entirety of each of which is herein incorporated by reference.

[00364] In certain embodiments, the present invention provides a compound of formula I,

wherein LBM is a MDM2 binding moiety I— -I or derivatives thereof;

thereby forming a compound of formula I-gggg:

1-gggg or derivative thereof, or a pharmaceutically acceptable salt thereof, as described and defined in Hines, J. et al., Cancer Res. (DOI: 10.1158/0008-5472.CAN 2918), the entirety of each of which is herein incorporated by reference.

[00365] In certain embodiments, the present invention provides a compound of formula I,

wherein LBM is a DCAF16 binding moiety derivatives thereof;

thereby forming a compound of formula I-hhhh:

I-hhhh or derivative thereof, or a pharmaceutically acceptable salt thereof, as described and defined in Zhang, X. et al., bioRxiv (doi: https://doi.org/10.1101/443804), the entirety of each of which is herein incorporated by reference.

[00366] In certain embodiments, the present invention provides a compound of formula I,

wherein LBM is a RNF114 binding moiety derivatives thereof;

thereby forming a compound of formula I-iiii:

I-iiii

[00367] or derivative thereof, or a pharmaceutically acceptable salt thereof, as described and defined in Spradin, J.N. et al., bioRxiv (doi: https://doi.org/10.1101/436998), the entirety of each of which is herein incorporated by reference.

[00368] In certain embodiments, the present invention provides a compound of formula I,

wherein IRAK is an IRAK4 binding moiety thereby forming a compound of formula I-jjjj:

or derivative thereof;

1-jjjj or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein X, Y, Ri, R2, and R3 are as defined and described in WO 2018/209012, the entirety of which is herein incorporated by reference.

[00369] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;

thereby forming a compound of formula I-kkkk:

I-kkkk or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ri, R2, R3, R4, R5, R6, and R7 are as defined and described in US 2018/0230157, the entirety of which is herein incorporated by reference.

[00370] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAKI and/or IRAK4 binding moiety

or derivative thereof;

thereby forming a compound of formula 1-1111:

1-1111 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ring Al, Ring B, Ring C, L1A, R1, R2, R3, R4, n, and p are as defined and described in WO 2018/098367, the entirety of which is herein incorporated by reference.

[00371] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety

derivative thereof;

thereby forming a compound of formula I-mmmm:

I-mmmm or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein R1, R2, R3, R4, R5, and R6 are as defined and described in WO 2018/052058, the entirety of which is herein incorporated by reference.

[00372] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAKI and/or IRAK4 binding moiety

- or derivative thereof;

thereby forming a compound of formula I-nnnn:

I-nnnn or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ring A, Ring B, R1, R2, and R3 are as defined and described in US 2017/0369476, the entirety of which is herein incorporated by reference.

[00373] In certain embodiments, the present invention provides a compound of formula I,

wherein IRAK is an IRAK4 binding moiety derivative thereof;

thereby forming a compound of formula 1-0000:

1-0000 or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein R1, R2, R3, and R4 are as defined and described in WO 2017/207385, the entirety of which is herein incorporated by reference.

[00374] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety derivative thereof;

thereby forming a compound of formula I-pppp:

I-PPPP or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ring A, X, Y, L1, Cy1, Cy2, R1 R8, R9, k, m, and n are as defined and described in WO 2017/205766, the entirety of which is herein incorporated by reference.

[00375] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety derivative thereof;

thereby forming a compound of formula I-qqqq:

I-qqqq or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ring A, L1, Cy1, Cy2, R1 R8, R9, m, and n are as defined and described in WO 2017/205762, the entirety of which is herein incorporated by reference.

[00376] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety thereof;

thereby forming a compound of formula I-rrrr:

or derivative

I-rrrr or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ring A, R1, R3, R4, R5, and R16 are as defined and described in WO 2017/108723, the entirety of which is herein incorporated by reference.

[00377] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAKI and/or IRAK4 binding moiety

or derivative thereof;

thereby forming a compound of formula I-ssss:

I-sss or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein Ring X, Z, R1, R2, R3, R4, Ra and p are as defined and described in WO 2017/049068, the entirety of which is herein incorporated by reference.

[00378] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety thereof;

thereby forming a compound of formula I-ssss:

or derivative

I-ssss or a pharmaceutically acceptable salt thereof, wherein L and IRAK are as defined above and described in embodiments herein, and wherein X, X’, Y, Y’, Z, R1, R2, R3, R4a, R4b, R5a, R5b and R6 are as defined and described in WO 2017/033093, the entirety of which is herein incorporated by reference.

[00379] In certain embodiments, the present invention provides a compound of formula I, wherein IRAK is an IRAK4 binding moiety thereof;

thereby forming a compound of formula I-ssss:

[00380] In certain embodiments, the present invention provides a compound of formula I,

wherein LBM is a RNF114 binding moiety or derivatives thereof;

thereby forming a compound of formula I-iiii:

I-iiii

[00381] or derivative thereof, or a pharmaceutically acceptable salt thereof, as described and defined in Ward, C.C., et al., bioRxiv (doi: https://doi.org/10.1101/439125), the entirety of each of which is herein incorporated by reference.

[00382] Exemplary compounds of the invention are set forth in Table 1, below.

<td> I32 1</td><td colspan="2"> V f8H[ _s Ά-ΝΗ2 Λ / יי. ,ט Υ-Ν N«\ £ irt'j 4 sq ϋ -t v = CCXrtrt'A.XA ACT'’״'A</td>

[00383] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof.

4. General Methods of Providing the Present Compounds

[00384] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

[00385] In the Schemes below, where a particular protecting group, leaving group, or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Μ. B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.

[00386] As used herein, the phrase “oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxycrotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[00387] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, the entirety of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, di chloroacetyl, tri chloroacetyl, phenylacetyl, tri fluoroacetyl, benzoyl, and the like.

[00388] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 1 set forth below:

Scheme 1: Synthesis of Compounds of Formula I

A-1

[00389] As depicted in Scheme 1, above, amine A-l is coupled to acid A-2 using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of formula I with a linker comprising an amide bond. The squiggly bond, represents the portion of the linker between IRAK and the terminal amino group of A-l or the portion of the linker between LBM and the terminal carboxyl group of A-2, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, ΒΟΡ-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[00390] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 2 set forth below:

Scheme 2: Synthesis of Compounds of Formula I

A-1

[00391] As depicted in Scheme 2, above, amine A-l is coupled to acid A-2 using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of formula I with a linker comprising an amide bond. The squiggly bond, represents the portion of the linker between IRAK and the terminal amino group of A-l or the portion of the linker between LBM and the terminal carboxyl group of A-2, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, ΒΟΡ-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[00392] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 3 set forth below:

Scheme 3: Synthesis of Compounds of Formula I

HATU, DIPEA, DMF I

A-3

[00393] As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 using the coupling agent HATU in the presence of the base DIPEA in DMF to form a compound of formula I with a linker comprising an amide bond. The squiggly bond, represents the portion of the linker between IRAK and the terminal carboxyl group of A-3 or the portion of the linker between LBM and the terminal amino group of A-4, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-CI, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[00394] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 4 set forth below:

Scheme 4: Synthesis of Compounds of Formula I

A-3

[00395] As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 using the coupling agent PyBOP in the presence of the base DIPEA in DMF to form a compound of formula I with a linker comprising an amide bond. The squiggly bond, &#1524;&#1524;&#1523;&#1524;&#1524;, represents the portion of the linker between IRAK and the terminal carboxyl group of A-3 or the portion of the linker between LBM and the terminal amino group of A-4, respectively. Additionally, an amide bond can be formed using coupling reagents known in the art such as, but not limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-CI, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

[00396] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 5 set forth below:

Scheme 5: Synthesis of Compounds of Formula I

A-5 I

[00397] As depicted in Scheme 5, above, an 8νΑγ displacement of fluoride A-6 by amine A-5 is effected in the presence of the base DIPEA in DMF to form a compound of formula I with a linker comprising a secondary amine. The squiggly bond, represents the portion of the linker between IRAK and the terminal amino group of A-5.

[00398] In certain embodiments, compounds of the present invention are generally prepared according to Scheme 6 set forth below:

Scheme 6: Synthesis of Compounds of Formula I

A-7

[00399] As depicted in Scheme 6, above, an SnAt displacement of fluoride A-7 by amine A-8 is effected in the presence of the base DIPEA in DMF to form a compound of formula I with a linker comprising a secondary amine. The squiggly bond, represents the portion of the linker between LBM and the terminal amino group of A-8.

Scheme 7: Synthesis of Compounds of Formula I

A-8

[00400] As depicted in Scheme 7, above, reductive amination of the mixture of aldehyde A-9 and amine A-10 is effected in the presence of NaHB(OAc)3 and KO Ac in DMF/THF to form a compound of formula I with a linker comprising a secondary amine. The squiggly bond, &#1524;ww, represents the portion of the linker between LBM and the terminal amino group of A-8.

[00401] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below in the Exemplification.

5. Uses, Formulation and Administration

Pharmaceutically acceptable compositions

[00402] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably degrade and/or inhibit an IRAK protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably degrade and/or inhibit an IRAK protein kinase, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[00403] The term “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[00404] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylenepolyoxypropylene-block polymers, polyethylene glycol and wool fat.

[00405] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily or degratorily active metabolite or residue thereof.

[00406] As used herein, the term inhibitorily active metabolite or residue thereof' means that a metabolite or residue thereof is also an inhibitor of an IRAK protein kinase, or a mutant thereof. [00407] As used herein, the term degratorily active metabolite or residue thereof means that a metabolite or residue thereof is also a degrader of an IRAK protein kinase, or a mutant thereof.

[00408] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanedi01. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[00409] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[00410] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[00411] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00412] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[00413] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[00414] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00415] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[00416] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques wellknown in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[00417] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[00418] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.

[00419] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

[00420] Compounds and compositions described herein are generally useful for the degradation and/or inhibition of kinase activity of one or more enzymes.

[00421] Examples of kinases that are degraded and/or inhibited by the compounds and compositions described herein and against which the methods described herein are useful include those of the interleukin-1 receptor-associated kinase (IRAK) family of kinases, the members of which include IRAK-1, IRAK-2, and IRAK-4, or a mutant thereof. Li et al., “IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase,” PNAS 2002, 99(8), 5567

5572, Flannery et al., “ The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling” Biochem Pharm 2010, 80(12), 1981-1991 incorporated by reference in its entirety .

[00422] The activity of a compound utilized in this invention as a degrader and/or inhibitor of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity and/or the subsequent functional consequences, or ATPase activity of activated IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to IRAK-1, IRAK-2 and/or IRAK-4. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/IRAK-1, inhibitor/IRAK-2, or inhibitor/IRAK-4 complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with IRAK-1, IRAK-2, and/or IRAK-4 bound to known radioligands. Representative in vitro and in vivo assays useful in assaying an IRAK-4 inhibitor include those described and disclosed in, e.g., Kim et al., “A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity,” J. Exp. Med. 2007 204(5), 1025-1036; Lebakken et al., “A Fluorescence Lifetime Based Binding Assay to Characterize Kinase Inhibitors,” J. BiomoL Screen. 2007, 12(6), 828-841; Maschera et al., “Overexpression of an enzymatically inactive interleukin1-receptor-associated kinase activates nuclear factor-κΒ,” Biochem. J. 1999, 339, 227-231; Song et al., “The kinase activities of interleukin-e receptor associated kinase (IRAK)-l and 4 are redundant in the control of inflammatory cytokine expression in human cells,” MoL Immunol. 2009, 46, 1458-1466, each of, the entirety of each of which is herein incorporated by reference. Detailed conditions for assaying a compound utilized in this invention as a degrader and/or inhibitor of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are set forth in the Examples below.

[00423] The best characterized member of the IRAK family is the serine/threonine kinase IRAK-4. IRAK-4 is implicated in signaling innate immune responses from Toll-like receptors (TLRs) and Toll/IL-1 receptors (TIRs).

[00424] Innate immunity detects pathogens through the recognition of pathogen-associated molecular patterns by TLRs, when then links to the adaptive immune response. TLRs recognize conserved structures of both microbes and endogenous molecules. TLRs which recognize bacterial and fungal components are located on the cell surface, whereas TLRs which recognize viral or microbial nucleic acids are localized to intracellular membranes such as endosomes and phagosomes. Cell surface TLRs can be targeted by small molecules and antibodies, whereas intracellular TLRs require targeting with oligonucleotides.

[00425] TLRs mediate the innate immune response by upregulating the expression of inflammatory genes in multiple target cells. See, e.g. Sen et al., “Transcriptional signaling by double-stranded RNA: role of TLR3,” Cytokine & Growth Factor Rev. 2005, 16, 1-14, incorporated by reference in its entirety. While TLR-mediated inflammatory response is critical for innate immunity and host defense against infections, uncontrolled inflammation is detrimental to the host leading to sepsis and chronic inflammatory diseases, such as chronic arthritis, atherosclerosis, multiple sclerosis, cancers, autoimmune disorders such as rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel diseases.

[00426] Upon binding of a ligand, most TLRs recruit the adaptor molecule MyD88 through the TIR domain, mediating the MyD88-dependent pathway. MyD88 then recruits IRAK-4, which engages with the nuclear factor-κΒ (NF-κΒ), mitogen-activated protein (MAP) kinase and interferon-regulatory factor cascades and leads to the induction of pro-inflammatory cytokines. The activation of NF-κΒ results in the induction of inflammatory cytokines and chemokines, such as TNF-a, IL-1 a, IL-6 and IL-8. The kinase activity of IRAK-4 has been shown to play a critical role in the TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of the innate immune response orchestrated by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs). Inactivation of IRAK-1 and/or IRAK-4 activity has been shown to result in diminished production of cytokines and chemokines in response to stimulation of IL-1 and TLR ligands. See, e.g., Picard et al., “Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency,” Medicine (Baltimore), 2010, 89(6), 043-25; Li, “IRAK4 in TLR/IL-1R signaling: Possible clinical applications,” Eur. J. Immunology 2008, 38:614-618; Cohen et al., “Targeting protein kinases for the development of antiinflammatory drugs,” Curr. Opin. Cell Bio. 2009, 21:317-324; Flannery et al., “The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signalling,” Biochem. Pharm. 2010, 80(12), 1981-1991; Gottipati et al., “IRAKI: A critical signaling mediator of innate immunity,” Cellular Signaling 2008, 20, 269-276; Kim et al., “A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity,” J. Exp. Med. 2007 204(5), 1025-1036;

Koziczak-Holbro et al., “IRAK-4 Kinase Activity Is Required for Interleukin-1 (IL-1) Receptorand Toll-like Receptor 7-mediated Signaling and Gene Expression,” J. Biol. Chem. 2007, 282(18), 13552-13560; Kubo-Murai et al., “IRAK dependent Degradation of IRAK-1 is a Negative Feedback Signal for TLR-mediated NF-κΒ Activation,” J. Biochem. 2008, 143, 295-302; Maschera et al., “Overexpression of an enzymatically inactive interleukin receptor-associated kinase activates nuclear factor-κΒ,” Biochem. J. 1999, 339, 227-231; Lin et al., “Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR /IL-1R signalling,” Nature 2010, 465(17), 885891; Suzuki et al., “IRAK-4 as the central TIR signaling mediator in innate immunity,” TRENDS in Immunol. 2002, 23(10), 503-506; Suzuki et al., “Severe impairment of interleukin-1 and Tolllike receptor signalling in mice lacking IRAK-4,” Nature 2002, 416, 750-754; Swantek et al., “IL1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin,” J. Immunol. 2000, 164, 4301-4306; Hennessy, E., et al., “Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010); Dinarello, C. “Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007), each of, the entirety of each of which is herein incorporated by reference. In fact, knockdown mice that express a catalytically inactive mutant IRAK-4 protein are completely resistant to septic shock and show impaired IL-1 activity. Moreover, these mice are resistant to joint and bone inflammation/destruction in an arthritis model, suggesting that IRAK-4 may be targeted to treat chronic inflammation. Further, while IRAK-4 appears to be vital for childhood immunity against some pyogenic bacteria, it has been shown to play a redundant role in protective immunity to most infections in adults, as demonstrated by one study in which patients older than 14 lacking IRAK4 activity exhibited no invasive infections. Cohen et al., “Targeting protein kinases for the development of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009, 21:317-324; Ku et al., “Selective predisposition to bacterial infections in IRAK deficient children: IRAK dependent TLRs are otherwise redundant in protective immunity,” J. Exp. Med. 2007, 204(10), 2407-2422; Picard et al., “Inherited human IRAK-4 deficiency: an update,” Immunol. Res. 2007, 38, 347-352; Song et al., “The kinase activities of interleukin-e receptor associated kinase (IRAK)-l and 4 are redundant in the control of inflammatory cytokine expression in human cells,” Mol. Immunol. 2009, 46, 1458-1466; Rokosz, L. et al., “Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges,” Expert Opinions on Therapeutic Targets, 12(7), pp: 883-903 (2008); Gearing, A. “Targeting toll-like receptors for drug development: a summary of commercial approaches,” Immunology and Cell Biology, 85, pp: 490-494 (2007); Dinarello, C. “IL-1: Discoveries, controversies and future directions,” European Journal of Immunology, 40, pp: 595-653 (2010), each of, the entirety of each of which is herein incorporated by reference. Because TLR activation triggers IRAK-4 kinase activity, IRAK-4 inhibition presents an attractive target for treating the underlying causes of inflammation in countless diseases.

[00427] Representative IRAK-4 inhibitors include those described and disclosed in e.g., Buckley et al., Bioorg. Med. Chern. Lett. 2008, 18, 3211-3214; Buckley et al., Bioorg. Med. Chern. Lett. 2008, 18, 3291-3295; Buckley et al., Bioorg. Med. Chern. Lett. 2008, 18, 3656-3660; Powers et al., “Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4,” Bioorg. Med. Chern. Lett. 2006, 16, 2842-2845; Wng et al., “IRAK-4 Inhibitors for Inflammation,” Curr. Topics in Med. Chern. 2009, 9, 724-737, each of, the entirety of each of which is herein incorporated by reference.

[00428] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[00429] Provided compounds are degraders and/or inhibitors of one of more of IRAK-1, IRAK2, and/or IRAK-4 and are therefore useful for treating one or more disorders associated with activity of one or more of IRAK-1, IRAK-2, and/or IRAK-4. Thus, in certain embodiments, the present invention provides a method for treating a IRAK mediated, a IRAK mediated, and/or a IRAK mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof.

[00430] As used herein, the terms “IRAK mediated”, “IRAK mediated”, and/or “IRAK-4mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which one or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which one or more of IRAK526

1, IRAK-2, and/or IRAK-4, or a mutant thereof, are known to play a role.

[00431] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition is a cancer, a neurodegenative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

[00432] Diseases and conditions treatable according to the methods of this invention include, but are not limited to, cancer (see, e.g., Ngo, V. et al., “Oncogenically activeMYD88 mutations in human lymphoma,” Nature, vol. 000, pp: 1-7 (2010); Lust, J. et al., “Induction of a Chronic Disease State in patients With Smoldering of Indolent Multiple Myeloma by Targeting Interleukin IB-Induced Interleukin 6 Production and the Myeloma Proliferative Component,” Mayo Clinic Proceedings, 84(2), pp: 114-122 (2009)), diabetes, cardiovascular disease, viral disease, autoimmune diseases such as lupus (see, e.g., Dinarello, C. “ Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen et al., “Targeting protein kinases for the development of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009, 21:317-324) and rheumatoid arthritis (see, e.g., Geyer, M. et al., “Actual status of antiinterleukin-1 therapies in rheumatic diseases,” Current Opinion in Rheumatology, 22, pp: 246251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H. et al., “Efficacy and Safety of Rilonacept (Interleukin-1 Trap) in Patients with Cryopyrin-Associated Periodic Syndromes,” Arthritis & Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease (see, e.g., Cario, E. “Therapeutic Impact of Toll-like Receptors on Inflammatory Bowel Diseases: A Multiple-edged Sword,” Inflamm. Bowel Dis., 14, pp: 411-421 (2008)), inflammation (see, e.g., Dinarello, C. “Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process, ” The American Journal of Clinical Nutrition, 83, pp: 447S-455S (2006)), acute and chronic gout and gouty arthritis (see, e.g., Terkeltaub, R. “Update on gout: new therapeutic strategies and options,” Nature, vol. 6, pp: 30-38 (2010); Weaver, A. “Epidemiology of gout,” Cleveland Clinic Journal of Medicine, vol. 75, suppl. 5, pp: S9-S12 (2008); Dalbeth, N. et al., “Hyperuricaemia and gout: state of the art and future perspectives,” Azwkz/s of Rheumatic Diseases, 69, pp: 1738-1743 (2010); Martinon, F. et al., “Goutassociated uric acid crystals activate the NALP3 inflammasome,” Nature, vol. 440, pp: 237-241 (2006); So, A. et al., “A pilot study of IL-1 inhibition by anakinra in acute gout,” Arthritis Research & Therapy, vol. 9, no. 2, pp: 1-6 (2007); Terkeltaub, R. et al., “The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study,” Annals of Rheumatic Diseases, 68, pp: 16131617 (2009); Torres, R. et al., “Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis,” Annals of Rheumatic Diseases, 68, pp: 1602-1608 (2009)), neurological disorders, metabolic syndrome (see, e.g., Troseid, M. “The role of interleukin-18 in the metabolic syndrome,” Cardiovascular Diabetology, 9:11, pp:l-8 (2010)), immunodeficiency disorders such as AIDS and HIV (see, e.g., lannello, A. et al., “Role of Interleukin-18 in the Development and Pathogenesis of AIDS,” AIDS Reviews, 11, pp: 115-125 (2009)), destructive bone disorders (see, e.g., Hennessy, E., et al., “Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010)), osteoarthritis, proliferative disorders, Waldenstrom’s Macroglobulinemia (see, e.g., Treon, et al., “Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenstrom’s Macroglobulinemia” 53rd ASH Annual Meeting; Xu, et al., “A somatic variant in MYD88 (L256P) revealed by whole genome sequencing differentiates lymphoplasmacytic lymphoma from marginal zone lymphomas” 53rd ASH Annual Meeting; Yang et al., “Disruption of MYD88 pathway signaling leads to loss of constitutive IRAKI, NK-kB and JAK/STAT signaling and induces apoptosis of cells expressing the MYD88 L265P mutation in Waldenstrom’s Macroglobulinemia” 53rd ASH Annual Meeting; Iriyama et al., “Clinical significance of genetic mutations of CD79B, CARD11, MYD88, and EZH2 genes in diffuse large B-cell lymphoma patients” 53rd ASH Annual Meeting; infectious diseases, conditions associated with cell death, pathologic immune conditions involving T cell activation, and CNS disorders in a patient. In one embodiment, a human patient is treated with a compound of the current invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound is present in an amount to measurably degrade and/or inhibit IRAK-1 only, IRAK only, IRAK only and/or IRAKI and IRAK4 kinase activity.

[00433] Compounds of the current invention are useful in the treatment of a proliferative disease selected from a benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, an MyD88 driven disorder, Smoldering of indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma).

[00434] In some embodiments the proliferative disease which can be treated according to the methods of this invention is an MyD88 driven disorder. In some embodiments, the MyD88 driven disorder which can be treated according to the methods of this invention is selected from ABC DLBCL, Waldenstrom’s macroglobulinemia, Hodgkin’s lymphoma, primary cutaneous T-cell lymphoma and chronic lymphocytic leukemia.

[00435] In some embodiments the proliferative disease which can be treated according to the methods of this invention is an IL-1 driven disorder. In some embodiments the IL-1 driven disorder is Smoldering of indolent multiple myeloma.

[00436] Compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as wheezy infants, an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[00437] Compounds according to the invention are useful in the treatment of heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[00438] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to morning dipping. Morning dipping is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[00439] Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[00440] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

[00441] Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[00442] Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acidinduced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, HenochSchonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[00443] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is an disease of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact dermatitits, atompic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.

[00444] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.

[00445] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a TH17 mediated disease. In some embodiments the TH17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).

[00446] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

[00447] Cardiovascular diseases which can be treated according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, and deep venous thrombosis.

[00448] In some embodiments, the neurodegenerative disease which can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation and graft versus host disease.

[00449] The loss of IRAK4 function results in decreased Αβ levels in an in vivo murine model of Alzheimer’s disease and was associated with diminished microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from the adult mouse brain revealed an altered pattern of gene expression associated with changes in microglial phenotype that were associated with expression of IRF transcription factors that govern microglial phenotype. Further, loss of IRAK4 function also promoted amyloid clearance mechanisms, including elevated expression of insulin-degrading enzyme. Finally, blocking IRAK function restored olfactory behavior (Cameron et al. “Loss of

Interleukin Receptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer’s Disease” Journal of Neuroscience (2012) 32(43), 15112-15123.

[00450] In some embodiments the invention provides a method of treating, preventing or lessening the severity of Alzheimer’s disease comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt or composition thereof.

[00451] In some embodiments the invention provides a method of treating a disease or condition commonly occurring in connection with transplantation. In some embodiments, the disease or condition commonly occurring in connection with transplantation is selected from organ transplantation, organ transplant rejection, and graft versus host disease.

[00452] In some embodiments the invention provides a method of treating a metabolic disease. In some embodiments the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

[00453] In some embodiments the invention provides a method of treating a viral disease. In some embodiments, the viral infection is HIV infection.

[00454] Furthermore, the invention provides the use of a compound according to the definitions herein, or a pharmaceutically acceptable salt, or a hydrate or solvate thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in connection with transplantation.

Combination Therapies

[00455] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[00456] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[00457] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[00458] Examples of agents the combinations of this invention may also be combined with include, without limitation: treatments for Alzheimer’s Disease such as Aricept® and Excel on®; treatments for HIV such as ritonavir; treatments for Parkinson’s Disease such as LDOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; agents for treating Multiple Sclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma such as albuterol and Singulair®; agents for treating schizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; agents that prolong or improve pharmacokinetics such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3 A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immunodeficiency disorders such as gamma globulin.

[00459] In certain embodiments, combination therapies of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or an siRNA therapeutic.

[00460] Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[00461] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[00462] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00463] One or more other therapeutic agent may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20,21,22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the invention are administerd as a multiple dosage regimen within greater than 24 hours aparts.

[00464] In one embodiment, the present invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent may be administered together with a compound of formula I, or may be administered prior to or following administration of a compound of formula I. Suitable therapeutic agents are described in further detail below. In certain embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[00465] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologic agents and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-l” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Haris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron ®) in combination with lenalidomide (Revlimid ®), or any combination(s) thereof.

[00466] In another embodiment, the present invention provides a method of treating gout comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol and febuxostat (Uloric®).

[00467] In another embodiment, the present invention provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®) and “anti-IL-6” agents such as tocilizumab (Actemra®).

[00468] In some embodiments, the present invention provides a method of treating osteoarthritis comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal antiinflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[00469] In some embodiments, the present invention provides a method of treating lupus comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[00470] In some embodiments, the present invention provides a method of treating inflammatory bowel disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[00471] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[00472] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®,

[00473] In some embodiments, the present invention provides a method of treating HIV comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), and combinations thereof.

[00474] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[00475] In another embodiment, the present invention provides a method of treating a solid tumor comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[00476] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of formula I and a Hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al “Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma” Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[00477] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[00478] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[00479] In another embodiment, the present invention provides a method of treating Waldenstrom’s macroglobulinemia comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/panJAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[00480] In some embodiments, one or more other therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors which may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for treatment of basal cell carcinoma.

[00481] In some embodiments, one or more other therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. In some embodiments, a PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, Abb Vie); and BGB-290 (BeiGene, Inc.).

[00482] In some embodiments, one or more other therapeutic agent is a histone deacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[00483] In some embodiments, one or more other therapeutic agent is a CDK inhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[00484] In some embodiments, one or more other therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[00485] In some embodiments, one or more other therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[00486] In some embodiments, one or more other therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[00487] In some embodiments, one or more other therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied which may be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[00488] In some embodiments, one or more other therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied which may be used in the present invention include CB-839 (Calithera Biosciences).

[00489] In some embodiments, one or more other therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens which may be used in the present invention include rituximab (Rituxan®, Genentech/Biogenldec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Peijeta®, Genentech); and brentuximab vedotin (antiCD30-drug conjugate, Adcetris®, Seattle Genetics).

[00490] In some embodiments, one or more other therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied which may be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[00491] In some embodiments, one or more other therapeutic agent is an inhibitor of antiapoptotic proteins, such as BCL-2. Approved anti-apoptotics which may be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins which have undergone clinical testing and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[00492] In some embodiments, one or more other therapeutic agent is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas/Medivation); approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

[00493] In some embodiments, one or more other therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[00494] In some embodiments, one or more other therapeutic agent is an inhibitor of bone resorption. An approved therapeutic which inhibits bone resorption is Denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, prevents binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with osseous metastases. Other approved therapeutics that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[00495] In some embodiments, one or more other therapeutic agent is an inhibitor of interaction between the two primary p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied which may be used in the present invention include ALRN6924 (Aileron), a stapled peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[00496] In some embodiments, one or more other therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-beta or TGFB). Inhibitors of TGF-beta proteins being studied which may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in the clinic for treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as described in Connolly et al. (2012) Int’l J. Biological Sciences 8:964-978. One therapeutic compound currently in clinical trials for treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific, anti-PDLl/TGFB trap compound (NCT02699515); and (NCT02517398). M7824 is comprised of a fully human IgGl antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFB “trap.”

[00497] In some embodiments, one or more other therapeutic agent is selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with cancer cells’ ability to metastasize.

[00498] In some embodiments, one or more other therapeutic agent is an antiproliferative compound. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17DMAG (17-dimethylaminoethylamino demethoxy-geldanamycin, NSC707545), IPI-504, CNF 1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[00499] In some embodiments, the present invention provides a method of treating Alzheimer’s disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[00500] In some embodiments, one or more other therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. In some embodiments, a taxane compound is selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[00501] In some embodiments, one or more other therapeutic agent is a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or will otherwise inhibit rapidly proliferating cells.

[00502] In some embodiments, a nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent 5-(3-methyltriazenl-yl)-imidazole carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolic cytidine analog, Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, believed to form interstrand DNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semisynthetic analog of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of deoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®, Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor, competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

[00503] In some embodiments, one or more other therapeutic agent is a kinase inhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech/Roche); Bruton’s tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[00504] Other kinase inhibitors and VEGF-R antagonists that are in development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/Takeda).

[00505] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft vs. host disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from a steroid, cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[00506] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still’s disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto’s thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune thyroiditis, Sjogren’s syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison’s disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture’s syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter’s syndrome, Takayasu’s arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener’s granulomatosis, psoriasis, alopecia universalis, Behcet’s disease, chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, a hyperproliferative disease, rejection of transplanted organs or tissues, Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1 diabetes, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,

Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorder, e.g., diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of the mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, diseases of the bone and joints including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter’s disease), Behcet’s disease, Sjogren’s syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, a thromboembolic disorder, (e.g., myocardial infarct, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transitory ischemia, a peripheral arterial occlusive disorder, pulmonary embolism, deep venous thrombosis), inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn’s disease, irritable bowel syndrome, ulcerative colitis, Sjogren’s disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture’s syndrome, atherosclerosis, Addison’s disease,

Parkinson’s disease, Alzheimer’s disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, Behcet’s disease, scleraderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury), and Graves’ disease.

[00507] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from a cancer, a neurodegenative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, and a CNS disorder.

[00508] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or a tumor of the neck and head, an epidermal hyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, a neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small-cell lung carcinoma, lymphomas, (including, for example, non-Hodgkin’s Lymphoma (NHL) and Hodgkin’s lymphoma (also termed Hodgkin’s or Hodgkin’s disease)), a mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or a leukemia, diseases include Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K/PKB pathway is aberrantly activated, asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection, acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy, bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis, pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophilrelated disorders affecting the airways occasioned by drug-reaction, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

[00509] In some embodiments, one or more other therapeutic agent is a phosphatidylinositol 3 kinase (ΡΙ3Κ) inhibitor. In some embodiments, a ΡΙ3Κ inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly ΙΡΙ-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[00510] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bonerelated disorder, liver disease, or a cardiac disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression dosage unit form as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[00511] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[00512] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00513] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanedi01. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00514] Injectable formulations can be sterilized, for example, by filtration through a bacterialretaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00515] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00516] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00517] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00518] Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00519] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00520] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00521] According to one embodiment, the invention relates to a method of inhibiting protein kinase activity or degading a protein kinase in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00522] According to another embodiment, the invention relates to a method of inhibiting or degrading IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00523] The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00524] Inhibition and/or degradation of a protein kinase, or a protein kinase selected from IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.

[00525] Another embodiment of the present invention relates to a method of degrading a protein kinase and/or inhibiting protein kinase activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.

[00526] According to another embodiment, the invention relates to a method of degrading and/or inhibiting one or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by one or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[00527] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[00528] A compound of the current invention may also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17demethoxy-geldanamycin, NSC707545), IPI-504, CNF 1010, CNF2024, CNF 1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[00529] The term aromatase inhibitor as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[00530] In some embodiments, one or more other therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis and glucose uptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[00531] In some embodiments, one or more other therapeutic agent is an aromatase inhibitor. In some embodiments, an aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

[00532] The term antiestrogen as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an anti estrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[00533] The term anti-androgen as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term gonadorelin agonist as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[00534] The term topoisomerase I inhibitor as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[00535] The term topoisomerase II inhibitor as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin ™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed, under the trade name

Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[00536] The term microtubule active agent relates to microtubule stabilizing, microtubule destabilizing compounds and microtublin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; cochicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

[00537] The term alkylating agent as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[00538] The term histone deacetylase inhibitors or HDAC inhibitors relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[00539] The term antineoplastic antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[00540] The term platin compound as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.

[00541] The term “Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic.

[00542] The term compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factorreceptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclindependent kinase family (CDK) including staurosporine derivatives, such as midostaurin;

examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR! ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, El.l, E2.4, E2.5, E6.2, E6.4, E2.ll, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; 0) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[00543] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[00544] In some embodiments, one or more other therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists which may be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists which may be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagri sso®, AstraZeneca).

[00545] The term “PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol kinase family, including, but not limited to PI3Ka, ΡΙ3Κγ, PI3K6, ΡΙ3Κβ, PI3K-C2a, ΡΙ3Κ-Ε2β, PI3KC2y, Vps34, pllO-a, pllO-β, ρ110-γ, pllO-δ, p85-a, ρ85-β, ρ55-γ, pl50, pl01, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF-1126, DS7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[00546] The term “BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[00547] The term “SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib

[00548] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.

[00549] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference. [00550] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973,

WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786,

WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.

[00551] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.

[00552] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.

[00553] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin gallate (EGCG), salinosporamide A, carfdzomib, ONX-0912, CEP-18770, andMLN9708.

[00554] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[00555] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, a- γ- or δ- tocopherol or a- γ- or δ-tocotrienol.

[00556] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl arylaminophenylacetic acid, such as 5-methyl (2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[00557] The term bisphosphonates as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[00558] The term heparanase inhibitor as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term biological response modifier as used herein refers to a lymphokine or interferons.

[00559] The term inhibitor of Ras oncogenic isoforms, such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a farnesyl transferase inhibitor such as L-744832, DK8G557 or Rl 15777 (Zamestra™). The term telomerase inhibitor as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

[00560] The term methionine aminopeptidase inhibitor as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[00561] The term proteasome inhibitor as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™),); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

[00562] The term matrix metalloproteinase inhibitor or (MMP inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251 , BAY 12-9566, TAA211 , MMI270B or AAJ996.

[00563] The term compounds used in the treatment of hematologic malignancies as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, Ι-β-D-arabinofuransyl cytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.

[00564] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the

Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SUI 1248 andMLN518.

[00565] The term HSP90 inhibitors as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HD AC inhibitors.

[00566] The term antiproliferative antibodies as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DMl, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity.

[00567] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

[00568] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy [4-[[[2-(2-methyl-lH-indol yl)-ethyl]- amino]methyl]phenyl]2E propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy [4-[(2hydroxyethyl){2-(lH-indol yl)ethyl]-amino]methyl]phenyl]-2E propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term ionizing radiation referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993). [00569] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term “ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-lH-isoindole-l ,3-dione derivatives.

[00570] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as l-(4-chloroanilino) (4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4-chloroanilino) (4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI4610) and Bevacizumab (Avastin™).

[00571] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[00572] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortex 01 one, 17a-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[00573] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[00574] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[00575] The compounds of the invention are also useful as co-therapeutic compounds for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs. A compound of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance. Accordingly the invention includes a combination of a compound of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said compound of the invention and said drug substance being in the same or different pharmaceutical composition.

[00576] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH351591 (Schering- Plough), Arofylline (Almirall Prodesfarma), PD189659 / PD168787 (ParkeDavis), AWD 281 (Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol, and especially, formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilatory drugs include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[00577] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[00578] Other useful combinations of compounds of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, e.g. CCR-1 , CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1 , CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH55700 and SCH-D, and Takeda antagonists such as N-[[4-[[[6,7-dihydro (4-methylphenyl)-5Hbenzo-cyclohepten yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4aminium chloride (TAK-770).

[00579] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium The Merck Index or from databases, e.g. Patents International (e.g. IMS World Publications).

[00580] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[00581] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[00582] Those additional agents may be administered separately from an inventive compoundcontaining composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[00583] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[00584] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.

[00585] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01 - 1,000 pg/kg body weight/day of the additional therapeutic agent can be administered.

[00586] The amount of one or more other therapeutic agent present in the compositions of this invention may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of one or more other therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, one or more other therapeutic agent is administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount normally administered for that agent. As used herein, the phrase “normally administered” means the amount an FDA approved therapeutic agent is approvided for dosing per the FDA label insert.

[00587] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention.

Exemplary Immuno-Oncology agents

[00588] In some embodiments, one or more other therapeutic agent is an immuno-oncology agent. As used herein, the term “an immuno-oncology agent” refers to an agent which is effective to enhance, stimulate, and/or up-regulate immune responses in a subject. In some embodiments, the administration of an immuno-oncology agent with a compound of the invention has a synergic effect in treating a cancer.

[00589] An immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biologic or small molecule. Examples of biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, an antibody is a monoclonal antibody. In some embodiments, a monoclonal antibody is humanized or human.

[00590] In some embodiments, an immuno-oncology agent is (i) an agonist of a stimulatory (including a co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including a coinhibitory) signal on T cells, both of which result in amplifying antigen-specific T cell responses. [00591] Certain of the stimulatory and inhibitory molecules are members of the immunoglobulin super family (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1 BBL, CD 137 (4-IBB), TRAIL/Ap02-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTpR, LIGHT, DcR3, HVEM, VEGI/TLIA, TRAMP/DR3, EDAR, EDAI, XEDAR, EDA2, TNFR1,

Lymphotoxin α/ΤΝ&#904;β, TNFR2, TNFa, ΕΓβΚ, Lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[00592] In some embodiments, an immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation, for stimulating an immune response.

[00593] In some embodiments, a combination of a compound of the invention and an immunooncology agent can stimulate T cell responses. In some embodiments, an immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors) such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM4; or (ii) an agonist of a protein that stimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[00594] In some embodiments, an immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells. In some embodiments, an immuno-oncology agent is an antagonists of KIR, such as lirilumab.

[00595] In some embodiments, an immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO 13/87699, WO 13/119716, WO 13/132044) or FPA-008 (WO 11/140249; WO13169264; WO14/036357).

[00596] In some embodiments, an immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that increase systemically the frequency of anti-tumor T cells, agents that overcome distinct immune suppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibit Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse/prevent T cell energy or exhaustion) and agents that trigger innate immune activation and/or inflammation at tumor sites.

[00597] In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[00598] In some embodiments, an immuno-oncology agent is a PD-1 antagonist. In some embodiments, a PD-1 antagonist is administered by infusion. In some embodiments, an immunooncology agent is an antibody or an antigen-binding portion thereof that binds specifically to a Programmed Death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, an immuno-oncology agent may be pidilizumab (CTOil). In some embodiments, an immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgGl, called AMP-224.

[00599] In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. In some embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS936559 (WO2007/005874), and MSB0010718C (WO2013/79174).

[00600] In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. In some embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

[00601] In some embodiments, an immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, a CD137 antibody is urelumab or PF-05082566 (WO12/32433).

[00602] In some embodiments, an immuno-oncology agent is a GITR agonist. In some embodiments, a GITR agonist is an agonistic GITR antibody. In some embodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116), or MK4166 (WO11/028683).

[00603] In some embodiments, an immuno-oncology agent is an indoleamine (2,3)dioxygenase (IDO) antagonist. In some embodiments, an IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer);

BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

[00604] In some embodiments, an immuno-oncology agent is an 0X40 agonist. In some embodiments, an OX40 agonist is an agonistic 0X40 antibody. In some embodiments, an 0X40 antibody is MEDI-6383 or MED1-6469.

[00605] In some embodiments, an immuno-oncology agent is an OX40L antagonist. In some embodiments, an OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

[00606] In some embodiments, an immuno-oncology agent is a CD40 agonist. In some embodiments, a CD40 agonist is an agonistic CD40 antibody. In some embodiments, an immunooncology agent is a CD40 antagonist. In some embodiments, a CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, a CD40 antibody is lucatumumab or dacetuzumab.

[00607] In some embodiments, an immuno-oncology agent is a CD27 agonist. In some embodiments, a CD27 agonist is an agonistic CD27 antibody. In some embodiments, a CD27 antibody is varlilumab.

[00608] In some embodiments, an immuno-oncology agent is MGA271 (to B7H3) (WO 11/109400).

[00609] In some embodiments, an immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[00610] In some embodiments, an immuno-oncology agent is an immunostimulatory agent. For example, antibodies blocking the PD-1 and PD-L1 inhibitory axis can unleash activated tumorreactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in increasing numbers of tumor histologies, including some tumor types that conventionally have not been considered immunotherapy sensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558), has shown potential to improve the overall survival in patients with RCC who had experienced disease progression during or after prior anti-angiogenic therapy.

[00611] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics which may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[00612] In some embodiments, an immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approved for treatment of asymptomatic, or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), a genetically modified oncolytic viral therapy approved for treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, an immuno-oncology agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enteric orphan virus (reovirus) which does not replicate in cells that are not RAS-activated, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and nonsmall cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAdl), an adenovirus engineered to express a full length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); GLONC1 (GLV-lh68/GLV-lhl53, Genelux GmbH), vaccinia viruses engineered to express betagalactosidase (beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter (hNIS), respectively, were studied in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, in bladder cancer (NCT02365818).

[00613] In some embodiments, an immuno-oncology agent is selected from JX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is able to convert the prodrug 5fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapy agents targeted for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5/3-E2F-delta24-hTNFa-IREShIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to raise an antigen-specific CD8+ T cell response.

[00614] In some embodiments, an immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor, or CAR. The T-cells engineered to express such chimeric antigen receptor are referred to as a CAR-T cells.

[00615] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell-surface antigens, fused to endodomains that are the functional end of the T-cell receptor (TCR), such as the CD3-zeta signaling domain from TCRs, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex.

[00616] For example, in some embodiments the CAR-T cell is one of those described in U.S. Patent 8,906,682 (June; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to comprise an extracellular domain having an antigen binding domain (such as a domain that binds to CD 19), fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in the T cell, the CAR is able to redirect antigen recognition based on the antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=l].

[00617] In some embodiments, an immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor y (RORyt). RORyt is a transcription factor with key roles in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (Tcl7) T cells, as well as the differentiation of IL-17 expressing innate immune cell subpopulations such as NK cells. In some embodiments, an activator of RORyt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[00618] In some embodiments, an immunostimulatory agent is an agonist or activator of a tolllike receptor (TLR). Suitable activators of TLRs include an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG which is being studied for B-cell, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 which may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamous cell cancer of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[00619] Other immuno-oncology agents that may be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (BristolMyers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[00620] In some embodiments, an immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORyt.

[00621] In some embodiments, an immunostimulatory therapeutic is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). In some embodiments, an immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, an IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, a recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[00622] In some embodiments, an immuno-oncology agent is selected from those descripted in Jerry L. Adams ET. AL., “Big opportunities for small molecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages 603-622, the content of which is incorporated herein by refenrece in its entirety. In some embodimetne, an immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams ET. AL. In some embodiments, an immuno-oncology agent is a small molecule targeting an immuno-oncoloby target selected from those listed in Table 2 of Jerry L. Adams ET. AL. In some embodiments, an immuno-oncology agent is a small molecule agent selectd from those listed in Table 2 of Jerry L. Adams ET. AL.

[00623] In some embodiments, an immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the content of which is incorporated herein by refenrece in its entirety. In some embodiments, an immuno-oncology agent is an agent targeting the pathways as described in Peter L. Toogood.

[00624] In some embodiments, an immuno-oncology agent is selected from those described in Sandra L. Ross et al., “Bispecific T cell engager (BiTE® ) antibody constructs can mediate bystander tumor cell killing”, PL0S ONE 12(8): 60183390, the conten of which is incorporated herein by reference in its entirety. In some embodiments, an immuno-oncology agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodimens, a bispecific T cell engager (BiTE®) antibody construct is a CD19/CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodimens, a bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodimens, a bispecific T cell engager (BiTE®) antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodimens, a bispecific T cell engager (BiTE®) antibody construct activates T cells which result in induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, the bystander cells being lysed are in proximity to the BiTE®-acticvated T cells. In some embodiment, the bystander cells comprises tumor-associated antigen (TAA) negatgive cancer cells. In some embodiment, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, an immunooncology agent is an antibody which blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncology agent is an ex-vivo expanded tumor-infiltrating T cell. In some embodiments, an immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptors (CARs) that directly connect T cells with tumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

[00625] In some embodiments, an immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[00626] The term “checkpoint inhibitor” as used herein relates to agents useful in preventing cancer cells from avoiding the immune system of the patient. One of the major mechanisms of anti-tumor immunity subversion is known as “T-cell exhaustion,” which results from chronic exposure to antigens that has led to up-regulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints in order to prevent uncontrolled immune reactions.

[00627] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cell Immunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3 (Lag-3; CD223), and others are often referred to as a checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[00628] In some embodiments, an immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thus overriding the ability of tumors to suppress the host anti-turn or immune response.

[00629] In one aspect, the checkpoint inhibitor is a biologic therapeutic or a small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In an additional aspect, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In an aspect, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In a specific aspect, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[00630] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner, the inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen binding fragments thereof, that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that may be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, γδ, and memory CD8+ (αβ) T cells), CD 160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7- 1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies, or antigen binding fragments thereof, other binding proteins, biologic therapeutics, or small molecules, that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab (anti-PDl antibody), CT-011 (anti-PDl antibody), BY55 monoclonal antibody, AMP224 (anti-PDLl antibody), BMS- 936559 (anti-PDLl antibody), MPLDL3280A (anti-PDLl antibody), MSB0010718C (anti-PDLl antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

[00631] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PDLI antibody, Tecentriq®, Genentech).

[00632] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[00633] In some embodiments, an immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgGl anti-PD-Ll antibody, in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple negative breast cancer and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been in studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell cancer of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[00634] In some embodiments, a checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that may be used in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which is being studied in advanced malignancies (NCT02608268).

[00635] In some embodiments, a checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that may be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[00636] In some embodiments, a checkpoint inhibitor is an inhibitor of Lymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be used in the present invention include BMS986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG Ig fusion protein, being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[00637] Checkpoint inhibitors that may be used in the present invention include OX40 agonists. OX40 agonists that are being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MED10562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705); and BMS-986178 (BristolMyers Squibb) an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[00638] Checkpoint inhibitors that may be used in the present invention include CD137 (also called 4-1BB) agonists. CD137 agonists that are being studied in clinical trials include utomilumab (PF-05082566, Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and neoplasms (NCT02554812 and

NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[00639] Checkpoint inhibitors that may be used in the present invention include CD27 agonists. CD27 agonists that are being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[00640] Checkpoint inhibitors that may be used in the present invention include glucocorticoidinduced tumor necrosis factor receptor (GITR) agonists. GITR agonists that are being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT 02740270);

INCAGN01876 (Incyte/Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgGl Fc domain, in advanced solid tumors (NCT02583165). [00641] Checkpoint inhibitors that may be used in the present invention include inducible Tcell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists that are being studied in clinical trials include MED1-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in Phase 1 (NCT02904226).

[00642] Checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors that are being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[00643] Checkpoint inhibitors that may be used in the present invention include CD47 inhibitors of interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa with the Fc domain of human IgGl, acts by binding human CD47, and preventing it from delivering its “do not eat” signal to macrophages, is in clinical trials in Phase 1 (NCT02890368 andNCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

[00644] Checkpoint inhibitors that may be used in the present invention include CD73 inhibitors. CD73 inhibitors that are being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[00645] Checkpoint inhibitors that may be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173, or TMEM173). Agonists of STINGthat are being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

[00646] Checkpoint inhibitors that may be used in the present invention include CSF1R inhibitors. CSF1R inhibitors that are being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-lR antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4[2((lR,2R) hydroxycyclohexylamino)-benzothiazol yloxyl]-pyridine carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[00647] Checkpoint inhibitors that may be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors that are being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[00648] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

EXEMPLIFICATION

[00649] Abbreviations

Ac: acetyl

AcOH: acetic acid

ACN: acetonitrile

Ad: adamantly

AIBN: 2,2'-azo bisisobutyronitrile

Anhyd: anhydrous

Aq: aqueous

B2Pin2: bis (pinacolato)diboron -4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2dioxaborolane)

BINAP: 2,2'-bi s(diphenylphosphino)-1,1 '-binaphthyl

BH3: Borane

Bn: benzyl

Boc: /<?/7-butoxy carbonyl

B0C20: di-tert-butyl dicarbonate

BPO: benzoyl peroxide nBuOH: n-butanol

CDI: carbonyldiimidazole

COD: cyclooctadiene d: days

DABCO: l,4-diazobicyclo[2.2.2]octane

DAST: diethylaminosulfur trifluoride dba: dibenzylideneacetone

DBU: 1, 8-diazobicyclo[5.4.0]undec ene

DCE: 1,2-di chloroethane

DCM: dichloromethane

DEA: diethylamine

DHP: dihydropyran

DIBAL-H: diisobutylaluminum hydride

DIPA: diisopropylamine

DIPEA or DIEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DME: 1,2-dimethoxy ethane

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMP: Dess-Martin periodinane

DMSO-dimethyl sulfoxide

DPPA: diphenylphosphoryl azide dppf :1,1’ -bi s(diphenylphosphino)ferrocene

EDC or EDCI: l-(3-dimethylaminopropyl) ethylcarbodiimide hydrochloride ee: enantiomeric excess

ESI: electrospray ionization

EA: ethyl acetate

EtOAc: ethyl acetate

EtOH: ethanol

FA: formic acid h or hrs: hours

HATU: N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate

HCI: hydrochloric acid

HPLC: high performance liquid chromatography

HO Ac: acetic acid

IBX: 2-iodoxybenzoic acid

IPA: isopropyl alcohol

KHMDS: potassium hexamethyldisilazide K2CO3: potassium carbonate

LAH: lithium aluminum hydride

LDA: lithium diisopropylamide m-CPBA: meta-chloroperbenzoic acid M: molar

MeCN: acetonitrile

MeOH: methanol

Me2S: dimethyl sulfide

MeONa: sodium methylate

Mel: iodomethane min: minutes mL: milliliters mM: millimolar mmol: millimoles

MPa: megapascal

MOMC1: methyl chloromethyl ether MsCl: methanesulfonyl chloride MTBE: methyl tert-butyl ether nBuLi: n-butyllithium

NaNO2: sodium nitrite

NaOH: sodium hydroxide

Na2SO4: sodium sulfate

NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide

NFSI: N-Fluorobenzenesulfonimide

NMO: N-methylmorpholineN-oxide

NMP: N-methylpyrrolidine

NMR: Nuclear Magnetic Resonance °C: degrees Celsius

Pd/C: Palladium on Carbon

Pd(0Ac)2: Palladium Acetate

PBS: phosphate buffered saline

PE: petroleum ether

POC13: phosphorus oxychloride

PPh3: triphenylphosphine

PyBOP: (Benzotriazol yl oxy )tripyrrolidinophosphonium hexafluorophosphate

Rei: relative

R.T. or rt: room temperature sat: saturated

SEMC1: chioromethyl trimethylsilylethyl ether

SFC: supercritical fluid chromatography

SOC12: sulfur dichloride tBuOK: potassium /c77-butoxide

TBAB: tetrabutylammonium bromide

TBAI: tetrabutyl ammonium iodide

TEA: triethylamine

Tf: trifluoromethanesulfonate

TfAA, TFMSAor Tf2O: trifluoromethanesulfonic anhydride

TFA: trifluoracetic acid

TIPS: triisopropylsilyl

THF: tetrahydrofuran

THP: tetrahydropyran

TLC: thin layer chromatography

TMEDA: tetramethylethylenediamine pTSA: para-toluenesulfonic acid wt: weight

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[00650] General Synthetic Methods

[00651] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[00652] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.

[00653] All reactions are carried out under nitrogen or argon unless otherwise stated.

[00654] Proton NMR (1H NMR) is conducted in deuterated solvent. In certain compounds disclosed herein, one or more 1H shifts overlap with residual proteo solvent signals; these signals have not been reported in the experimental provided hereinafter.

[00655] Table 2: Analytical instruments

<td> LCMS</td><td> Shimadzu UFLC MS: LCMS-2020 Agilent Technologies 1200 series MS: Agilent Technologies 6110 Agilent Technologies 1200 series MS: LC/MSD VL</td>

<td> NMR</td><td> BRUKER AVANCEIII/400; Frequency (MHz) 400.13; Nucleus: IH; Number of Transients: 8</td>

<td> Prep-HPLC</td><td> Gilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F, GX-G and GX-H</td>

<td> GCMS</td><td> SHIMADZU GCMS-QP2010 Ultra</td>

<td> Analytical</td><td> Agilent Technologies 1290 Infinity</td>

<td> Prep-cSFC</td><td> Waters SFC Prep 80</td>

[00656] For acidic LCMS data:

[00657] LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS2020 equipped with electro-spray ionization and quadruple MS detector [ES+ve to give MH+] and equipped with Chromolith Flash RP-18e 25*2.0 mm, eluting with 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). Other LCMS was recorded on an Agilent 1290 Infinity RRLC attached with Agilent 6120 Mass detector. The column used was BEH C18 50*2.1 mm, 1.7 micron. Column flow was 0.55 ml /min and mobile phase were used (A) 2 mM Ammonium Acetate in 0.1% Formic Acid in Water and (B) 0.1% Formic Acid in Acetonitrile.

[00658] For basic LCMS data:

[00659] LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS 2020 equipped with electro-spray ionization and quadruple MS detector [ES+ve to give MH+] and equipped with Xbridge C18, 2.1X50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C18 2.1X30mm columns packed with 5 mm C18-coated silica, eluting with 0.05 vol% NH3 H2O in water (solvent A) and acetonitrile (solvent B).

[00660] HPLC Analytical Method:

[00661] HPLC was carried out on X Bridge C18 150*4.6 mm, 5 micron. Column flow was 1.0 ml /min and mobile phase were used (A) 0.1 % Ammonia in water and (B) 0.1 % Ammonia in Acetonitrile.

[00662] Prep HPLC Analytical Method:

[00663] The compound was purified on Shimadzu LC-20AP and UV detector. The column used was X-BRIDGE C18 (250*19)mm, 5μ. Column flow was 16.0 ml/min. Mobile phase were used (A) 0.1% Formic Acid in Water and (B) Acetonitrile Basic method used (A) 5mM ammonium bicarbonate and 0.1% NH3 in Water and (B) Acetonitrile or (A) 0.1% Ammonium Hydroxide in Water and (B) Acetonitrile. The UV spectra were recorded at 202nm & 254nm.

[00664] NMR Method:

[00665] The IH NMR spectra were recorded on a Bruker Ultra Shield Advance 400 MHz/5 mm Probe (BBFO). The chemical shifts are reported in part-per-million.

[00666] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[00667] INTERMEDIATES:

[00668] l-azido-S-bromopentane (Intermediate A)

[00669] To a stirred solution of sodium azide (2.5 g, 38.5 mmol) in DMF (85 mL) was added 1,5-dibromopentane (8.4 g, 36.7 mmol) at room temperature. The resulting reaction mixture was then stirred at 50 °C for 16 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give l-azido bromopentane as colorless oil (5.0 g, 71 %). 1H NMR (400 MHz, DMSO) δ 3.44 (t,J = 6.8 Hz, 2H), 3.32 (t, J = 4 Hz, 2H), 1.95-1.91 (m, 2H), 1.67-1.62 (m, 2H), 1.56-1.46 (m, 2H).

[00670] /rrLbutvl_________(5J2J_2Jj_52mmnoj2£&#1524;tvl}oxy]etJ1oxy]eri1oxy]12£Ul^^ (Intermediate B) η2ν

BocHN

MsCI, TEA

&#908;Η ------DCM

MsO.

NHBoc

&#908;Η (Boc)2O

DCM

TBAB, NaOH, toluene

Pd(OH)2/C, H2

Boc

Acetic Acid, EtOH

THF, EtOAc

TBAB, NaOH, toluene

Pd(QH)2/C, H2 H2N^rt^rt^O^rto/rt^O^rt^rt^NHBoc

MeOH B

[00671] Step 1 - tert-butyl (5-hydroxypentyl)carbamate

[00672] To a stirred solution of 5-aminopentan-l-ol (10.0 g, 96.9 mmol) in DCM (75 mL) was added Boc-anhydride (25.4 g, 116.3 mmol) dropwise at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred at rt for 1 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give ter/-butyl (5-hydroxypentyl)carbamate as colorless oil (16 g, 81 %). 1HNMR (400 MHz, DMSO) δ 4.56 (bs, IH), 3.69-3.64 (m, 2H), 3.17-3.12 (m, 2H), 1.64-1.62 (m, 2H), 1.54-1.53 (m, 6H), 1.51-1.49 (m, IH), 1.46 (s, 9H), 1.43-1.37 (m, 2H).

[00673] Step 2 - 5-((tert-butoxycarbonyl)aminojpentyl methanesulfonate

[00674] To a stirred solution of tert-butyl (5-hydroxypentyl)carbamate (6.0 g, 29.5 mmol) and triethylamine (13 mL, 88.5 mmol) in DCM (100 mL) was added mesyl chloride (3.7 mL, 44.3 mmol) dropwise at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred at rt for 2 h. The reaction mixture was transferred into water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 5-((tertbutoxycarbonyl)amino)pentyl methanesulfonate as white solid (7.0 g, 84%). LCMS: (ES+) m/z (M+H)+

[00675] Step 3 - ter/-butyl (5-(2-(2-(benzyloxy)ethoxy)ethoxy)pentyl)carbamate

[00676] To a stirred solution of 2-(2-(benzyloxy)ethoxy)ethan-l-ol (3.3 g, 16.8 mmol, CAS#

2050 1) and 5-((/er/-butoxycarbonyl)amino)pentyl methanesulfonate (7.0 g, 25.2 mmol) in toluene (50 mL) and 8 N Aqueous NaOH solution (50 mL) was added TBAB (catalytic amount) at room temperature. The resulting reaction mixture was allowed to stir at 80 °C for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford the crude product. The crude product was purified using silica gel column chromatography (25% EtOAc-Hexanes) to give /er/-butyl (5-(2-(2-(benzyloxy)ethoxy)ethoxy)pentyl)carbamate as colorless oil (3.5 g, 55%). 1H NMR (400 MHz, DMSO) δ 7.36 (d, J = 4.4 Hz, 2H), 7.32-7.28 (m, 2H), 4.59 (s, IH), 3.71-3.70 (m, 2H), 3.69-3.67 (m, IH), 3.66-3.65 (m, IH), 3.13-3.11 (m, IH), 1.65-1.61 (m, 2H), 1.59-1.54 (m, 6H), 1.50-1.48 (m, IH).

[00677] Step 4 - te/7-butyl (5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate

[00678] To a stirred solution of /e/7-butyl (5-(2-(2-(benzyloxy)ethoxy)ethoxy)pentyl)carbamate (3.5 g, 9.2 mmol) in ethanol (30 mL), THF (30 mL), ethyl acetate (30 mL) and acetic acid (2 mL) was added 20% Pd(OH)2 (2.5 g) at room temperature under nitrogen atmosphere. The resulting reaction mixture was allowed to stir under hydrogen gas (20 kg/cm2 pressure) in an autoclave at 60 °C for 16 h. The reaction mixture was filtered through celite with a vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give /er/-butyl (5-(2-(2hydroxyethoxy)ethoxy)pentyl)carbamate as colorless oil (2.5 g, 93 %). 1H NMR (400 MHz, DMSO) δ 4.68 (bs, IH), 3.77-3.75 (m, 2H), (s, IH), 3.71-3.69 (m, 2H), 3.69-3.64 (m, 2H), 3.633.59 (m, 2H), 3.51-3.48 (m, 2H), 3.14-3.13 (m, 3H), 1.71-1.61 (m, 2H), 1.59-1.55 (m, 2H), 1.45 (s, 9H), 1.42-1.36 (m, 2H).

[00679] Step 5 - te/7-butyl (5-(2-(2-((5-azidopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate [00680] To a stirred solution of tert-butyl (5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate (1.4 g, 4.8 mmol) and l-azido bromopentane (2.8 g, 14.4 mmol, Intermediate A) in toluene (10 mL) and 8 N aqueous NaOH solution (10 mL) was added TBAB (catalytic amount) at rt. The resulting reaction mixture was then heated to 80 °C and stirred for 16 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give /er/-butyl (5-(2-(2-((5azidopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate as colorless oil (0.95 g, 50%). 1H NMR (400

MHz, DMSO) δ 4.56 (bs, IH), 3.69-3.61 (m, 4H), 3.50-3.46 (m, 3H), 3.33-3.27 (m, IH), 3.143.12 (m, IH), 1.68-1.61 (m, 4H), 1.53-1.42 (m, 7H).

[00681] Step 6 - te/7-butyl (5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate

[00682] To a stirred solution of ter/-butyl (5-(2-(2-((5azidopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate (0.45 g, 1.12 mmol) in methanol (30 mL) was added 20% Pd(OH)2 (0.45 g) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred under hydrogen gas (20 kg/cm2 pressure) in an auto clave at rt for 3 h. The reaction mixture was filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give /c77-butyl (5-(2-(2-((5aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate as colorless oil (0.35 g, 83 %).

[00683] (lR,4R) (6-((l,6-naDhthyridin vl)amino)-4(cvcloDroDvlamino)nicotinamido)cvclohexane-l-carboxylic acid (Intermediate C)

[00684] Step L Methyl(lR,4R) (6-((L6-naphthyridin yl)amino)-4(cy cl opropyl am i n 0 )n i coti nami do )cycl ohexane-1 -carb oxyl ate

[00685] To a stirred solution of 6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinic acid (1.85 g, 5.76 mmol, Intermediate N) and methyl (lR,4R)-4aminocyclohexane carboxylate hydrochloride (1.34 g, 6.91 mmol) in DMF (10 mL) was added DIPEA (5 mL, 28.8 mmol) and PyBOP (4.5 g, 8.64 mmol) at rt. The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was then transferred into ice water and the resulting precipitate was filtered off, and dried reduced pressure. The crude product was purified using silica gel column chromatography (7% MeOH-DCM) to give methyl (lr,4r) (6-((l,6-naphthyridin-2yl)amino) (cyclopropylamino)nicotinamido)cyclohexane-l-carboxylate as light a green solid (1.3 g, 49%). LC-MS (ESI+) m/z 460.54 (M+H)+

[00686] Step 2:(lR,4R) (6-((L6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclohexane-l -carboxylic acid

[00687] To a stirred solution of methyl (lR,4R) (6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylate (1.2 g, 2.6 mmol) in MeOH (20 mL) was added NaOH (2 g, 50 mmol) in 20 mL water dropwise at rt. The resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was then evaporated under vacuum, water (10 mL) was added and pH was adjusted to 6-7 using 10 % citric acid solution. The resulting mixture was stirred for 15 min, the solid precipitate was filtered off and dried under vacuum to give (1R,4R) (6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylic acid as a brown solid (0.9 g, 77%).

LC-MS (ESI+) m/z 446.51 (M+H)+

[00688] 2-((2-(2,6-dioxoDiDeridin vl)-l,3-dioxoisoindolin vl)oxy)acetic acid (Intermediate

[00689] Step 1 - ter/-butyl (2,6-dioxopiperidin yl)carbamate

[00690] To a stirred solution of (/e/7-butoxycarbonyl)-L-glutamine (6.0 g, 24 mmol) in THF (60 mL) was added CDI (4.2 g, 25.9 mmol) and DMAP (0.012 g, 0.098 mmol) at rt. The resulting reaction mixture heated to 70 °C and stirred for 16 h. The reaction precipitate was filtered and washed with THF (50 mL), and dried under reduced pressure to give /ert-butyl (2,6dioxopiperidin yl)carbamate as white solid (1.8 g, 32%). LCMS (ESI‘) m/z 227.2 (M-H)'.

[00691] Step 2 - 3-aminopiperidine-2,6-dione (TFA salt)

[00692] /<?/7-Butyl (2,6-dioxopiperidin yl)carbamate (1.8 g, 7.9 mmol) was dissolved in TFA (10 mL) and stirred at rt for 1 h. The reaction mixture was then evaporated under reduced pressure to give 3-aminopiperidine-2,6-dione as the TFA salt as a brown solid (1.7 g, 96%). LCMS (ESI+) m/z 129 (M+H)+.

[00693] Step 3 - 2-(2,6-dioxopiperidin yl) hydroxyisoindoline-L3-dione

[00694] To a stirred solution of 4-hydroxyisobenzofuran-l,3-dione (1.2 g, 7.3 mmol) in pyridine (25 mL) was added 3-aminopiperidine-2,6-dione-TFA salt (1.8 g, 7.3 mmol) at room temperature. The resulting reaction mixture was then warmed to 110 °C and stirred for 16 h. The reaction mixture was then evaporated under reduced pressure. The crude product was purified using silica gel column chromatography (4% MeOH-DCM) to give 2-(2,6-dioxopiperidin yl)-4hydroxyisoindoline-1,3-dione as yellow solid (1 g, 50%). LC-MS (ESI‘) m/z 273.2 (M-H)+.

[00695] Step 4 - te/7-butyl 2-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yl)oxy)acetate

[00696] To a stirred solution of 2-(2,6-dioxopiperidin yl) hydroxyisoindoline-l,3-dione (2.95 g, 10.76 mmol) and K2CO3 (2.22 g, 16.14 mmol) in DMF (40 mL) was added ter/-butyl 2bromoacetate (1.6 mL, 10.16 mmol) in DMF (10 mL) dropwise at rt. The resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (50% EAc-Hexanes) to give /c77-butyl 2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)oxy)acetate as white solid (3 g, 72%). LC-MS (ESI&#1470;) m/z 387.2 (M-H)+.

[00697] Step 5 - 2-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin yl)oxy)acetic acid [00698] tert-Butyl 2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)oxy)acetate (3.0 g,

7.7 mmol) was dissolved in TFA (30 mL) and stirred at rt for 1 h. The reaction mixture was then evaporated under reduced pressure and triturated with MTBE to give 2-((2-(2,6-di oxopiperi din-3yl)-l,3-dioxoisoindolin yl)oxy)acetic acid as white solid (2 g, 78%). 1H NMR. (400 MHz, DMSO) δ ppm 13.27 (s, IH), 11.12 (s, IH), 7.82-7.78 (m, IH), 7.48 (d, J = 7.6 Hz, IH), 7.40 (d, J = 8.4 Hz, IH), 5.13-5.04 (m, IH), 4.99 (s, 2H), 2.94-2.85 (m, IH), 2.73-2.57 (m ,2H), 2.07-2.02 (m, IH). LCMS (ESI+) m/z 333 (M+H)+.

[00699] tert-butyl (5-((5-amin0Dentyl)0xy)Dentyl)carbamate (Intermediate E) (Boc)2OA

H2N V OH --------&#9658; BocHN OH &#9658; DCM NaH, Nai, DMF

Pd/C, H2 BocHN'''''''''''''''/&#1523;'Y&#1499;'',^^ -------------&#9658; BocHN ONH

MeOH

[00700] Step 1 - tert-butyl (5-hydroxypentyl)carbamate

[00701] To a stirred solution of 5-aminopentan-l-ol (10.0 g, 96.9 mmol) in DCM (75 mL) was added Boc-anhydride (25.4 g, 116.3 mmol) dropwise at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give tert-butyl (5-hydroxypentyl)carbamate as colorless oil (16 g, 81 %). 1HNMR (400 MHz, DMSO) δ 4.56 (bs, IH), 3.69-3.64 (m, 2H), 3.17-3.12 (m, 2H), 1.64-1.62 (m, 2H), 1.541.53 (m, 6H), 1.51-1.49 (m, IH), 1.46 (s, 9H), 1.43-1.37 (m, 2H).

[00702] Step 2 - tert-butyl (5-((5-azidopentvl)oxv)pentyl)carbamate

[00703] To a stirred solution of tert-butyl (5-hydroxypentyl)carbamate (2.5 g, 12.3 mmol) in DMF (20 mL) was added Nai (catalytic amount) and NaH (0.74 g, 18.4 mmol, 60% dispersion in mineral oil) at room temperature. The resulting reaction mixture was stirred at room temperature for 0.5 h. To this reaction mixture l-azido bromopentane (3.55 g, 18.4 mmol, Intermediate A) in DMF (5 mL) was added dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified using silica gel column chromatography (6% EAcHexanes) to give tert-butyl (5-((5-azidopentyl)oxy)pentyl)carbamate as colorless oil (0.85 g,

22%). LC-MS (ESC) m/z 315.39 (M+H)+.

[00704] Step 3 - tert-butyl (5-((5-aminopentyl)oxy)pentyl)carbamate

[00705] To a stirred solution of tert-butyl (5-((5-azidopentyl)oxy)pentyl)carbamate (0.2 g, 0.6 mmol) in methanol (5 mL) was added 10% Pd/C (0.1 g, 50% wet) at room temperature under nitrogen atmosphere. The resulting reaction mixture was stirred under hydrogen gas (5 kg/cm2 pressure) in auto clave at rt for 5 h. The reaction mixture was filtered through a pad of celite under vacuum and washed with MeOH (20 mL). The filtrate was evaporated under reduced pressure to give tert-butyl (5-((5-aminopentyl)oxy)pentyl)carbamate as colorless oil (0.15 g, 82 %). LC-MS (ESC) m/z 289.43 (M+H)+.

[00706] tert-butyl (5-(2-((5-amin0Dentyl)0xy)eth0xy)Dentyl)carbamate (Intermediate F)

N H Boc

A ---------*&#1470; O v/W/

TBAB, NaOH, Tolune

HO

Pd/C, H2 (gas)

BocH N N H2

MeOH

[00707] Step 1 - ((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene

[00708] A solution of 2-(benzyloxy) ethan 01 (1.67 g, 10.96 mmol), 1,5-dibromopentane (10.0 g, 43.0 mmol), and ammonium bromide (0.5 g) in 8N NaOH (20 mL) was stirred at room temperature for 25 h. The reaction mixture was then transferred into ice water mixture, the pH was adjusted to 6-7, and resulting mixture was extracted using n-hexane (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated under vacuum to give ((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene as colorless liquid (23 g, 95%). LC-MS (ESI+) m/z 303 (M+H)+2.

[00709] Step 2 - ((2-((5-azidopentyl)oxv)ethoxv)methyl)benzene

[00710] A solution of ((2-((5-bromopentyl)oxy)ethoxy) methyl)benzene (23.0 g, 76.6 mmol) and sodium azide (7.47 g, 114.93 mmol) in DMF (125 mL) was heated to 60 °C and stirred for 18 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (10 % EtOAc-Hexane) to give ((2-((5azidopentyl)oxy)ethoxy)methyl)benzene as a colorless liquid (10.5 g, 82%). LC-MS (ESI+) m/z 281.2 (M+18)+.

[00711] Step 3 - ter/-butyl (5-(2-hydroxyethoxy)pentyl)carbamate

[00712] A solution of ((2-((5-azidopentyl)oxy)ethoxy) methyl)benzene (10.5 g, 39.9 mmol), 10 % Pd/(OH)2 (50% wet) (5 g) and Boc anhydride (13.04 g, 59.84 mmol) in MeOH (100 mL) and acetic acid (1 mL) was stirred in an autoclave. The reaction mixture was heated to 60 °C under hydrogen gas (30 kg/cm2 pressure) for 48 h. The reaction mixture was filtered through a pad of celite and washed with methanol (100 mL). The filtrate was evaporated under reduced pressure and the crude product (with tert-butyl (5-(2-(benzyloxy)ethoxy)pentyl)carbamate as a side product) was purified using silica gel column chromatography (20% EtOAc- hexane) to give tertbutyl (5-(2-hydroxyethoxy)pentyl)carbamate as colorless oil (1.6 g, 13%).

[00713] Step 4 - te/7-butyl (5-(2-((5-azidopentyl)oxy)ethoxy)pentyl)carbamate

[00714] A solution of ter/-butyl (5-(2-hydroxyethoxy)pentyl)carbamate (1.6 g, 6.5 mmol), TBAB (0.3 g, catalytic amount) and l-azido bromopentane (1.85 g, 9.71 mmol, Intermediate A) were dissolved in a mixture of toluene (30 mL) and 8 N NaOH (20 mL) and heated at 80 °C for 24 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (25 % EtOAc-Hexane) to give te/7-butyl (5-(2((5-azidopentyl)oxy)ethoxy)pentyl)carbamate as a colorless oil (0.7 g, 30%). LC-MS (ESI+) m/z 359.3 (M+H)+.

[00715] Step 5 - te/7-butyl (5-(2-((5-aminopentyl)oxy)ethoxy)pentyl)carbamate

[00716] A solution of tert-butyl (5-(2-((5-azidopentyl) oxy)ethoxy)pentyl)carbamate (0.7 g, 19.9 mmol) and 10 wt % Pd/C (50% wet) (0.05 g) was dissolved in MeOH (10 mL) in an autoclave. The reaction mixture was heated to 50 °C under hydrogen gas (20 kg/cm2 pressure) for 4 h. Upon completion, the reaction mixture was filtered through a pad of celite and washed with methanol (20 mL). The filtrate was evaporated under reduced pressure to give as ///&#1523;/-butyl (5-(2-((5aminopentyl)oxy)ethoxy)pentyl)carbamate as a colorless oil (0.55 g) which was used directly in the next step without further purification.

[00717] (2S.,4R)-l-((S) amino-3.,3-dimethylbutanoyl) hydroxy-N-(4-(4-methylthiazol5-vl)benzvl)Dvrrolidine carboxamide hydrochloride(Intermediate G)

HCI in dioxane

DCM

[00718] Step 1 - 4-(4-methylthiazol yl)benzonitrile

[00719] To a solution of 4-bromobenzonitrile (1.0 g, 5.5 mmol) and palladium acetate (0.061 g, 2.75 mmol) in dimethyl acetamide (5 mL) was added potassium acetate (1.08 g, 11.0 mmol) and 4-methylthiazole (1 mL, 11.0 mmol) at rt. The reaction mixture was then heated and stirred at 130 °C for 18 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using DCM (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (10% EtOAc-hexane) to give 4-(4-methylthiazol5-yl)benzonitrile as yellow solid (0.6 g, 55%). LC-MS (ESI+) m/z 200 (M+H)+.

[00720] Step 2 - te/7-butyl (4-(4-methylthiazol yl)benzyl)carbamate

[00721] To a stirred solution of 4-(4-methylthiazol yl)benzonitrile (0.6 g, 3.0 mmol) in methanol (50 mL) was added NiC12 6H2O (0.07 g, 0.3 mmol) and boc anhydride (1 mL, 4.5 mmol) at 0 °C and stirred for 15 minutes. After 15 minutes, NaBH4 (0.8 g, 21.0 mmol) was added in portions over 30 minutes at 0 °C and stirred additional for 30 minutes. Then triethylamine (0.8 mL, 6.0 mmol) was added and the mixture was stirred for a further 3 h. The reaction mixture was then evaporated under vacuum and diluted with ethyl acetate (50 mL) and filtered through celite. The filtrate was washed using water (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (15% EtOAc-Hexane) to give /c77-butyl (4-(4-methylthiazol yl)benzyl)carbamate as yellow semisolid (0.5 g, 55%). LC-MS (ESI+) m/z 305.2 (M+H)+.

[00722] Step 3 - (4-(4-methylthiazol yl)phenyl)methanamine hydrochloride

[00723] To a stirred solution of /erLbutyl (4-(4-methylthiazol yl)benzyl)carbamate (0.5 g, 1.6 mmol) in DCM (5 mL) was added 4N HCI in dioxane (1 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was then evaporated under vacuum and triturated using diethyl ether to give (4-(4-methylthiazol yl)phenyl)methanamine hydrochloride as yellow solid (0.35 g, 89%). LC-MS (ESI+) m/z 205.2 (M+H)+.

[00724] Step 4:te/7-butyl(2S,4R) hydroxy ((4-(4-methylthi azol-5yl)benzyl)carbamoyl )pyrrolidine-1 -carboxylate

[00725] To a solution of (2S,4R)-l-(/erLbutoxycarbonyl) hydroxypyrrolidine carboxylic acid (0.25 g, 1.08 mmol, CAS# 13726 7) in DCM (5 mL) was added N-hydroxysuccinimide (0.16 g, 1.40 mmol) and EDC HCI (0.25 g, 1.30 mmol) and the reaction was stirred at rt for 3 h. After 3 h, (4-(4-methylthiazol yl)phenyl)methanamine hydrochloride (0.31 g, 1.30 mmol) and DIPEA (0.6 mL, 3.24 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated NaHCO3 solution (50 mL) and extracted in DCM (50 mL χ 3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give /er/-butyl (2S,4R) hydroxy2-((4-(4-methylthiazol yl)benzyl)carbamoyl)pyrrolidine-l-carboxylate as yellow solid (0.3 g, 66%). LC-MS (ESI+) m/z 418.8 (M+H)+.

[00726] Step 5 - (2S,4R) hydroxy-N-(4-(4-methylthiazol yl)benzyl)pyrrolidine-2carboxamide hydrochloride

[00727] To a stirred solution of /ert-butyl (2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)pyrrolidine-l-carboxylate (0.3 g, 0.7 mmol) in DCM (10 mL) was added 4N HCI in dioxane (1 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was then evaporated under vacuum and triturated using diethyl ether to give (2S,4R) hydroxy-N-(4(4-methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride as yellow solid (0.2 g, 79 %). LC-MS (ESI+) m/z 318.0 (M+H)+.

[00728] Step 6 - terLbutyl ((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol-5yl )benzyl )carbamoyl )-pyrrolidin-l-yl )-3.3-dimethyl-l-oxobutan yl )carbamate

[00729] To a solution of (2S,4R) hydroxy-N-(4-(4-methylthiazol yl)benzyl)pyrrolidine-2carboxamide hydrochloride (0.2 g, 0.6 mmol), (S) ((/er/-butoxycarbonyl)amino)-3,3dimethylbutanoic acid (0.13 g, 0.57 mmol, CAS# 62965 9) and DIPEA (0.4 mL, 2.28 mmol) in DMF (2 mL), was added HATU (0.3 g, 0.63 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (4% MeOH-DCM) to give /er/-butyl ((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3dimethyl-l-oxobutan yl)carbamate as yellow semisolid (0.15 g, 44%). LC-MS (ESI+) m/z 531.81 (M+H)+.

[00730] Step 7 - (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4-(4methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride

[00731] To a stirred solution of tert-butyl ((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan yl)carbamate (0.15 g, 0.28 mmol) in DCM (10 mL) was added 4N HCI in dioxane (1 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was then evaporated under vacuum and solid was triturated using diethyl ether to give (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4-(4 methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride as yellow solid (0.12 g, 91 %). 1H NMR (400 MHz, DMSO) δ 9.10 (s, IH), 8.78 (t, J = 6 Hz, IH), 8.27-8.07 (m, 3H), 7.507.31 (m, 4H), 4.55 (t, J = 8.2 Hz, IH), 4.50-4.30 (m, 2H), 4.29-4.15 (m, IH), 4.05-3.85 (m, IH), 3.84-3.70 (m, IH), 3.65-3.45 (m, IH), 2.46 (s, 3H), 2.20-2.05 (m, IH), 1.95-1.80 (m, IH), 1.321.27 (m, IH), 1.03 (s, 9H). LC-MS (ESI+) m/z 431.85 (M+H)+.

[00732] tert-butyl ((lR,3R) ((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cvclobutyl) carbamate (Intermediate H)

'NH2 HCI (Boc)2O

LiBH4

THF

NHBoc

NHBoc

TEA, DCM

MsCI, TEA

DCM

Pd/C, H2 (gas)

.,, N HBoc

EtOH

MsCI, TEA

DCM

MsO

.,,NHBoc

NaN3

DMF

.,, N HBoc

Pd/C, H2 (gas)

EtOH

[00733] Step 1 - methyl (lR,3R) ((tert-butoxycarbonyl)amino)cyclobutane-l-carboxylate [00734] To a stirred solution of methyl (lR,3R) aminocyclobutane-l-carboxylate hydrochloride (1.0 g, 6.1 mmol), TEA (2 mL, 12 mmol) in DCM (5 mL) was added and Boc anhydride (1.7 g, 7.8 mmol) at 0 °C The reaction mixture was then stirred at rt for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give methyl (lR,3R) ((tertbutoxycarbonyl)amino)cyclobutane-l-carboxylate as a white solid (1.2 g, 72%). 1H NMR (400 MHz, DMSO) δ 7.26 (d, J=2.6 Hz, IH), 4.10 (m, IH), 3.62(s, 3H), 2.96-2.91(m, IH), 2.36-2.31 (m, 2H), 2.19-2.12 (m, 2H), 1.42 (s, 9H).

[00735] Step 2 - tert-butyl ((lRR) (hydroxymethyl)cvclobutyl)carbamate

[00736] To a stirred solution of methyl (lR,3R) ((tert-butoxycarbonyl)amino)cyclobutane-lcarboxylate (1.0g, 4.4 mmol) in THF (20 mL) was added 3M lithium borohydride (9 mL, 9 mmol) at 0 °C. Then the reaction mixture was heated and stirred at 60 °C for 3 h. The reaction mixture was then transferred into dilute NaOH and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and fdtered. The fdtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3 % MeOH-DCM) to give tert-butyl ((lr3r)-3(hydroxymethyl)cyclobutyl)carbamate as a white solid (0.8 g, 91%). 1HNMR (400 MHz, DMSO) δ 4.77 (bs, IH), 4.24 (d, J= 6.8 Hz, IH), 3.71 (d, J= 6.0 Hz, 3H), 2.39(s, IH), 2.25-2.21 (m, 2H), 2.05-1.98 (m, 2H), 1.67-1.29 (m, 13H).

[00737] Step 3 - (HR, 3R) ((te/7-butoxvcarbonyl) aminolcyclobutyl )methyl methane sulfonate

[00738] To a stirred solution of tert-butyl ((lR,3R) (hydroxymethyl)cyclobutyl)carbamate (0.8 g, 4.0 mmol) in dichloromethane (20 mL) was added triethylamine (1.67 mL, 11.91 mmol) at 0 °C. Mesyl chloride (0.82 mL, 5.96 mmol) was then added and the mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and fdtered. The fdtrate was evaporated under reduced pressure to give ((1R, 3 R) ((tert-butoxycarbonyl) amino)cyclobutyl)methyl methane sulfonate as yellow solid (0.9 g, 81%).

[00739] Step 4:tert-butyl((lR,3R) (12-phenyl-2,5,8,11tetraoxadodecyl)cyclobutyl)carbamate

[00740] A solution of 2-(2-(2-(benzyloxy)ethoxy) ethoxy)ethan-l-ol (0.43 g, 1.79 mmol, Intermediate T), ((lR,3R) ((tert-butoxycarbonyl)amino)cyclobutyl)methyl methanesulfonate (2.9 g, 10.39 mmol) and TBAB (20 mg,) in toluene:8N NaOH (1:1, 16 mL) was stirred at 90 °C for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and fdtered. The fdtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (45 % EtOAc-Hexane) to give tertbutyl ((lR,3R) (18-phenyl-2,5,8,ll,14,17-hexaoxaoctadecyl)cyclobutyl)carbamate as a light yellow liquid (0.7 g, 76%). LC-MS (ESI+) m/z 441.50 (M+H)+.

[00741] Step 5:tert-butyl((1R.3RY3-( (2-(2-(2hydroxyethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate

[00742] To a stirred solution of ter/-butyl ((lr,3r) (12-phenyl-2,5,8,ll-tetraoxadodecyl) cyclobutyl)carbamate (0.7 g, 1.65 mmol) in EtOH (20 mL) was added 10 % Pd/C (50% wet) (0.7 g) and the reaction mixture was stirred under hydrogen atmosphere at rt for 6 h. The reaction mixture was then filtered through celite and evaporated under reduced pressure to give ter/-butyl ((lR,3R) ((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate as a colorless liquid (0.5 g). LC-MS (ESI+) m/z 351.45 (M+H)+.

[00743] Step 6:2-(2-(2-(((lR3R) ((tertbutoxycarbonyl)amino)cyclobutyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate

[00744] To a stirred solution of ter/-butyl ((lR,3R) ((2-(2-(2hydroxyethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate (0.5 g, 1.5 mmol) and tri ethylamine (0.7 mL, 4.5 mmol) in di chloromethane (5 mL) was added mesyl chloride (0.15 mL, 1.8 mmol) at 0 °C. The reaction was allowed to warm to rt and stirred for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2-(2-(2-(((lR,3R) ((tertbutoxycarbonyl)amino)cyclobutyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate as a light yellow solid (0.53 g, 85%).

[00745] Step 7 - ter/-butyl ((lR3R) ((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl) cyclobutyDcarbamate

[00746] To a stirred solution of 2-(2-(2-(((lR,3R) ((tertbutoxycarbonyl)amino)cyclobutyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate (0.53 g, 1.30 mmol) in DMF (4 mL) was added sodium azide (0.13 g, 1.93 mmol) at rt. Then the reaction mixture was heated at 65°C for 5 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (2 % MeOH-DCM) to give ter/-butyl ((lR,3R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate as a light yellow liquid (0.45 g, 82%). LC-MS (ESI+) m/z 376 (M+18)+.

[00747] Step 8:tert-butyl((1R3RY3-((2-(2-(2aminoethoxy)ethoxy)ethoxy)methyl)cyclobutyl) carbamate

[00748] To a stirred solution of tert-butyl ((lR,3R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate (0.45 g, 1.25 mmol) in EtOH (20 mL) was added 10 % Pd/C (50% wet) (0.45 g) and the reaction mixture was stirred under hydrogen atmosphere for 5 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give tert-butyl((lr,3r) ((2-(2-(2aminoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate as a colorless liquid (0.35 g,). LC-MS (ESI+) m/z 334.45 (M+18)+.

[00749] 12-((tert-butoxvcarbonyl)amino)dodecanoic acid(Intermediate I) (Boc)2O h9 , ----------&#9658; n /. ^0/. a 0H TEA, MeOH Boc0H

I

[00750] A mixture of 12-aminododecanoic acid (2.0 g, 9.3 mmol, CAS# 693 2), Boc anhydride (2.4 mL, 10.2 mmol) and triethylamine (1.4 mL, 10.2 mmol) in methanol (50 mL) was refluxed for 18 h. The reaction mixture then cooled to rt and was concentrated under vacuum and diluted with ethyl acetate (200 mL). The organic layer was washed with 5% citric acid (100 mL x 2), water (100 mL), dried over anhydrous sodium sulphate, and evaporated to give \2-((tertbutoxycarbonyl)amino)dodecanoic acid as a white solid (2.5 g, 85%). LC-MS (ESI+) m/z 314.2 (M-H)+.

[00751] l-phenyl-2,5,8,ll-tetraoxatridecan ol (Intermediate J)

HO.

'0' '0'

NaH, BnBr

Un __________

DMF

HOx^Q^^O^^Q^/OBn

[00752] To a stirred solution of 2,2'-((oxybis(ethane-2,l-diyl))bis(oxy))bis(ethan-l-ol) (20.0 g, 103 mmol) in THF (150 mL) was added 60% NaH in paraffin (2.06 g, 51.5 mmol) at 10 °C in an ice water bath and the reaction mixture was stirred 0.5 h. To this reaction mixture benzyl bromide (5.9 mL, 51.49 mmol) in THF (50 mL) was added dropwise at 10 °C over 1.5 h. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give l-phenyl-2,5,8,ll-tetraoxatridecan ol as a yellow oil (15 g, 51%). LC-MS (ESI+) m/z 284.35 (M+H20)+.

[00753] tert-butyl ((lR,4R) (13-amino-2.,5.,8,ll-tetraoxatridecyl)cydohexyl)carbamate (Intermediate

KI

NH2 HCI

LIBH4

MsCI, TEA (Boc)2O

TEA, DCM

THF

TBAB, NaOH, toluene

DCM

Pd/C, H2 (gas)

Acetic Acid, EtOH

[00754] Step 1 - methyl (lR4R) ((tert-butoxycarbonyl)amino)cvclohexane-l-carboxylate [00755] To a stirred solution of methyl (lR,4R) aminocyclohexane-l-carboxylate hydrochloride (6.5 g, 31.0 mmol) and triethylamine (6.8 mL, 92.94 mmol) in DCM (100 mL) was added Boc-anhydride (8.1 g, 37.18 mmol) dropwise at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 1.5 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give methyl (lR,4R) ((tert-butoxycarbonyl)amino)cyclohexane-l-carboxylate as a white solid (6.6 g, 83 %). LC-MS (ESI+) m/z 258.2 (M+H)+.

[00756] Step 2 - ter/-butvl ((lR4R) (hydroxymethyl)cvclohexyl)carbamate

[00757] To a stirred solution of methyl (1 R,4R) ((tert-butoxycarbonyl)amino)cyclohexane1-carboxylate (5.5 g, 21.4 mmol) in THF (20 mL) was added 3 M LiBH4 in THF (16 mL, 43 mmol) dropwise at 0 °C. The resulting reaction mixture then heated to 75 °C and stirred for 1 h. The reaction mixture was then transferred into 5% citric acid solution. The pH of the reaction mixture was adjusted to pH 8 to 9 with 8 N NaOH solution. The resulting mixture was then extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (25% EAc-Hexanes) to give tert-butyl ((lr,4r)-4(hydroxymethyl)cyclohexyl)carbamate as white solid (1.5 g, 31%). LC-MS (ESI+) m/z 230.2 (M+H)+.

[00758] Step 3 - ((1 R,4R) ((tert-butoxycarbonyl)aminojcyclohexyl)methyl methanesulfonate [00759] To a solution of /c77-butyl ((lR,4R) (hydroxymethyl)cyclohexyl)carbamate (1.8 g, 7.8mmol) in DCM (50 mL) was added triethylamine (2.36 g, 23.4 mmol) and MsCl(0.9 mL, 11.7 mmol) at 0 °C and the reaction was stirred for 90 minutes. The reaction mixture was then diluted with water (50 mL) and product was extracted in DCM (50 mL x3). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuum to give ((lR,4R) ((tertbutoxycarbonyl)amino)cyclohexyl)methyl methanesulfonate as a light brown solid (1.8 g, 75%); LC-MS (ESI+) m/z 308.2 (M+H)+.

[00760] Step 4:tert-butyl((lR,4R) (15-phenyl-2,5,8,ll,14pentaoxapentadecyDcyclohexyDcarbamate

[00761] To a solution of l-phenyl-2,5,8,ll-tetraoxatridecan ol (1.4 g, 4.9 mmol, Intermediate J) in toluene (20 mL) and 8NNaOH (20 mL) was added a catalytic amount of TBAB and the reaction was stirred for 15 minutes at rt. After 15 minutes, ((lR,4R) ((tertbutoxycarbonyl)amino)cyclohexyl)methyl methanesulfonate (1.8 g, 5.9 mmol) was added and the reaction mixture was refluxed for 16 h. The reaction mixture was then diluted with water (200 mL) and extracted in ethyl acetate (250 mL x3). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (45-50% EtOAC-Hexane) to give tert-butyl ((lR,4R) (15-phenyl-2,5,8,ll,14pentaoxapentadecyl)cyclohexyl)carbamate as a yellow semisolid (0.8 g, 33%); LC-MS (ESI+) m/z 496.5 (M+H)+.

[00762] Step 5:tert-butyl((1 R,4R) ( 13 -hydroxy-2,5,8,11tetraoxatridecyl)cyclohexyl)carbamate

[00763] To a stirred solution of tert-butyl ((lR,4R) (15-phenyl-2,5,8,ll,14pentaoxapentadecyl)cyclohexyl)carbamate (0.8 g, 1.6 mmol) in ethanol (50 mL) was added 10%

Pd/C (50% wet) (0.8 g) and acetic acid (0.2 mL) at room temperature with hydrogen gas bubbling through the solution for 2h. The reaction mixture was then filtered through a pad of celite and the filtrate was evaporated to give /c77-butyl ((lR,4R) (13-hydroxy-2,5,8,lltetraoxatridecyl)cyclohexyl)carbamate as a brown oil (0.7 g, 64%); LC-MS (ESI+) m/z 406.4 (M+H)+.

[00764] Step 6 1-((1 R.4R ) ((/cv7-butoxvcarbonvl )aminojcycl ohexyl )-2.5.8JItetraoxatridecan-13 -yl methanesulfonate

[00765] To a stirred solution of /c77-butyl ((lR,4R) (13-hydroxy-2,5,8,lltetraoxatridecyl)cyclohexyl)carbamate (0.37 g, 0.91 mmol) in DCM (10 mL) was added triethylamine (0.3 mL, 2.7 mmol) at 0 °C followed by mesyl chloride (0.11 g, 1.37 mmol) then the reaction was stirred for 2h. The reaction was then quenched with water (50 mL) and product was extracted using DCM (50 mL x3). The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give l-((lR,4R) ((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,lltetraoxatridecan yl methanesulfonate as a yellow oil (0.37 g; 82%).

[00766] Step 7 - /c77-butyl ((lr,4r) (13-azido-2,5,8,ll-tetraoxatridecyl)cyclohexyl)carbamate [00767] To a stirred solution of l-((IR,4R) ((/c77-butoxycarbonyl)amino)cyclohexyl)2,5,8,ll-tetraoxatridecan yl methanesulfonate (0.36 g, 0.74 mmol) in DMF (5 mL) was added NaN3 (0.072 g, 1.11 mmol) and the reaction mixture was heated at 70 °C for 2h. The reaction mixture was then cooled to rt and diluted with water (250 mL) and extracted in ethyl acetate (100 mL x3). The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give and the crude product was purified by silica gel column chromatography (40% EtOAcHexane) to give /c77-butyl ((lr,4r) (13-azido-2,5,8,ll-tetraoxatridecyl)cyclohexyl)carbamate as a yellow semisolid (0.29 g; 90%); LC-MS (ESI+) m/z 448.8 (M+l8)+.

[00768] Step 8:ter/-butyl((lr,4r) (13-amino-2,5,8,lltetraoxatridecyl)cyclohexyl)carbamate

[00769] To a stirred solution of /c77-butyl ((lR,4R) (13-azido-2,5,8,ll-tetraoxatridecyl)cyclohexyl)carbamate (0.29 g, 0.67 mmols) in ethanol (20 mL) was added 10% Pd(OH)2/C (50% wet) (0.29 g) at rt and the reaction mixture was stirred in autoclave under hydrogen gas (20 kg/cm2 pressure) for 5h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated in vacuo to give tert-butyl ((lR,4R) (13-amino-2,5,8,lltetraoxatridecyl)cyclohexyl)carbamate as a yellow semisolid (0.17, 62%); LC-MS (ESI+) m/z

405.4 (M+H)+.

[00770] 6-(5-cyan0-lH-Dvraz010[3.,4-b]Dvridin-l-vl) (cvcl0Dr0Dvlamin0)nic0tinic acid (Intermediate L)

[00771] Step 1 - methyl 6-chloro (cyclopropylamino)nicotinate

[00772] A solution of methyl 4,6-dichloronicotinate (10.0 g, 48.5 mmol), DIPEA (6.26 g , 48.5 mmol, 8.23 mL) and cyclopropylamine (3.04 g, 53.4 mmol) in DMA(80 mL) was stirred at 90 °C for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (10 % EtOAc-Hexane) to give methyl 6-chloro (cyclopropylamino)nicotinate as a white solid (8.5 g, 77 %). 1H NMR (400 MHz, DMSO-d6) δ 8.538 (s, IH), 8.079 (s, IH), 7.040 (s, IH), 3.826 (s, 3H), 2.634-2.594 (m, IH), 0.892-0.846 (m, 2H), 0.595- 0.557 (m, 2H).

[00773] Step 2 - 6-chloro (cyclopropylamino)nicotinic acid

[00774] A stirred solution of methyl 6-chloro (cyclopropylamino)nicotinate (6.8 g, 30.0 mmol) in ethanol (70 mL) was cooled to 0-10°C. Then a solution of lithium hydroxide (3.6 g, 85.7 mmol in water (10 mL) was added. The reaction mixture was allowed to warm to rt and was stirred for 3h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (2 x 100 mL). The aqueous layer was acidified by addition of saturated citric acid solution until the pH = 3-4. The mixture was then extracted with ethyl acetate (3 x 250 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was triturated using hexane to give 6-chloro (cyclopropylamino)nicotinic acid as an off-white solid (5g, 78%). 1H NMR (400 MHz, DMSO-d6) δ 13.415 (bs, IH), 8.525 (s,lH) 8.318 (s, IH), 7.007 (s, IH), 2.616-2.592 (m, IH), 0.891-0.845 (m, 2H), 0.620- 0.564 (m, 2H).

[00775] Step 3 - tert-butyl 6-chloro (cyclopropylamino)nicotinate

[00776] A stirred solution 6-chloro (cyclopropylamino)nicotinic acid (2.5 g, 11.74 mmol) and

DMF-DTA (10.2 g, 50.3 mmol) in toluene (50 mL) was heated at 110 °C for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 250 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (6% EtOAc-Hexane) to give ter/-butyl 6-chloro-4(cyclopropylamino)nicotinate as a white solid (2.23 g, 70%). LC-MS (ESI+) m/z 269.3 (M+H)+. [00777] Step 4 - tert-butyl 6-(5-cyano-lH-pyrazolo[3,4-b1pyridin-l-yl) (cyclopropylamino) nicotinate

[00778] Under an atmosphere of argon, lH-pyrazolo[3,4-b]pyridine carbonitrile (1.0 g, 6.94 mmol), tert-butyl 6-chloro (cyclopropylamino)nicotinate (2.05 g, 7.63 mmol), potassium carbonate (2.9 g, 20.83 mmol), Xantphos (1.61g, 2.77mmol) and Pd(dba)2 (1.6g, 2.77mmol) in 1,4-dioxane (50 mL) was heated at 120 °C for 20 h. The reaction mixture was filtered through celite and washed with ethyl acetate (3 x 300 mL). The combined organic layer was washed with water (400mL), dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (1% MeOH-DCM) to give tert-butyl 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino) nicotinate as a brown solid (0.6 g, 21%). LC-MS (ESI+) m/z 377.3 (M+H)+ [00779] Step 5 - 6-(5-cyano-lH-pyrazolo[3,4-b1pyridin-l-yl) (cyclopropylamino)nicotinic acid (as the TFA salt)

[00780] A solution of tert-butyl 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotinate (0.4 g, 1.06 mmol) and TFA (4 mL) in DCM (10 mL) was stirred at rt for 6 h. The organic solvent was evaporated and the residue was triturated with MTBE (20 mL) to give 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)nicotinic acid as the TFA salt as a white solid (0.3 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ 13.38 (bs, IH), 9.10 (d, J= 2 Hz, IH), 9.04 (d, J= 2 Hz, IH), 8.76 (s, IH), 8.70 (s, IH), 8.43 (s, IH), 7.83 (s, IH), 2.66

2.60 (m, IH), 0.93-0.89 (m, 2H), 0.65- 0.62 (m, 2H).

[00781] l.,6-naDhthvridin amine(Intermediate M) (11 A Diphenyl phosphoryl azide I θ i ifi HCI in dioxane AAn ho. A-,A &#1490; -----------A A A A &#1490; -------A 1 J ( N TEA, f-BuOH Ο N N MeOH: DCM H2N

O H

M

[00782] Step 1 - tert-butyl (L6-naphthyridin yl)carbamate

[00783] To a stirred solution of l,6-naphthyridine carboxylic acid (20.0 g, 114 mmol) in tBuOH (200 mL) was added Et3N (16 mL, 114 mmol) and diphenyl phosphoryl azide (37.0 g, 137 mmol) respectively at rt. The resulting mixture then heated to 80 °C and stirred for 24 h. The reaction mixture was evaporated carefully under vacuum, diluted with ice water and resulting solid was collected by filtration. The solid was treated with hot ethanol and again filtered and dried under vacuum to give ter/-butyl (l,6-naphthyridin yl)carbamate as a light brown solid (13.1 g, 46 %). 1HNMR (400 MHz, DMSO-d6) δ 10.49 (s, IH), 9.20 (s, IH), 8.61 (d, J= 6 Hz, IH), 8.47 (d, 9.2 Hz, IH), 8.18 (d, J = 8.8 Hz, IH), 7.62 (s, IH), 1.50 (s, 9H). LC-MS (ESI+) m/z 246.2 (M+H)+

[00784] Step 2 - L6-naphthyridin amine

[00785] To a stirred solution of ter/-butyl (l,6-naphthyridin yl)carbamate (4.37 g, 17.8 mmol) in MeOH: DCM (40 mL, 3:1 ratio) was added 4N HCI in dioxane (15 mL) at 0 °C. The resulting reaction mixture was allowed to warm to rt and stirred for 18 h. The reaction mixture was then evaporated under vacuum and diluted with 30 mL of water. Saturated NaHCO3 solution (15 mL) was added and the resulting mixture was extracted using EtOAc (2 x 50 mL). The combined organic layers were dried under vacuum to give l,6-naphthyridin amine as a white solid (2.45 g, 94 %). 1HNMR (400 MHz, DMSO-d6) δ 9.03 (s, IH), 8.43 (d, J = 6 Hz, IH), 8.14 (d, J = 8.8 Hz, IH), 7.72 (bs, 2H), 7.45 (d, J= 6 Hz, IH), 6.96 (d, J= 8.8 Hz, IH); LCMS (ESI+) m/z 146.4 (M+H)+.

[00786] (6-((l6&#1524;-naDhthvridin vl)amin0) (cvd0Dr0Dvlamin0)nic0tinic acid (Intermediate N)

[00787] Step 1 - methyl 6-chloro (cyclopropylamino)nicotinate

[00788] To a stirred solution of methyl 4,6-dichloronicotinate (10.0 g, 48.5 mmol) in DMA (80 mL) was added DIPEA(6.6 mL, 48.5 mmol) and cyclopropylamine (3.7 mL, 53.0 mmol) at rt. The resulting mixture then heated at 90 °C for 3 h. After 3 h, the reaction mixture was cooled to rt and diluted with ice water. The resulting mixture was stirred for 20 min and the solid precipitate was collected by filtration and dried under vacuum. The crude product was purified by silica gel column chromatography (10% EtOAc-hexanes) to give methyl 6-chloro (cyclopropylamino)nicotinate as a white solid (9.5 g, 87 %). 1H NMR (400 MHz, CDCh) δ 8.67 (s, IH), 8.20 (bs, IH), 6.98 (s, IH), 3.89 (s, 3H), 2.51 (m, IH), 0.91 (q, J = 6.8 Hz, 2H), 0.61-0.65 (m, 2H); LC-MS (ESI+) m/z 227.2 (M+H)+.

[00789] Step 2 - methyl 6-((L6-naphthyridin yl)amino) (cyclopropylamino)nicotinate [00790] To a stirred solution of methyl 6-chloro (cyclopropylamino)nicotinate (2.5 g, 11.8 mmol) and l,6-naphthyridin amine (1.6 g, 11.76 mmol, Intermediate M) in DMA (50 mL) was added Xantphos (2.5 g, 4.4 mmol) and Cs2CO3 (5.76 g, 17.60 mmol) and resulting reaction mixture was degassed using argon for 30 min. Then of Pd2(dba)3 (2.0 g, 2.2 mmol) was added. The resulting mixture was heated at 120 °C for 18 h. The reaction mixture was cooled to rt and ice water was added. The resulting solid precipitate was collected by filtration and dried under vacuum. The crude product was purified by silica gel column chromatography (5% MeOH-DCM) to give methyl 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)nicotinate as a yellow solid (2.2 g, 59%). 1HNMR (400 MHz, DMSO-d6) δ 10.5 (s, IH), 9.08 (s, IH), 8.66 (s, IH), 8.58-8.60 (m, 2H), 8.31 (d,J = 8.8 Hz, IH), 8.03 (s, IH), 7.61 (d, J = 6 Hz, IH), 7.51 (d, J = 8.8 Hz, IH), 3.80 (s, 3H), 2.67-2.70 (m, IH), 0.99-1.02 (m, 2H), 0.65-0.67 (m, 2H). LC-MS (ESI+) m/z 336.6 (M+H)+.

[00791] Step 3 - 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)nicotinic acid

[00792] To a stirred solution of methyl 6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinate (1.6 g, 1.8 mmol) in methanol :water (30 mL, 1:1 ratio) was added NaOH (0.36 g, 5 mmol) at rt. The resulting reaction mixture was then heated at 70 °C for 16 h. Upon completion, the reaction mixture was in vacuo and the resulting solid was triturated using ethyl acetate and collected by filtration. The solid was taken in water and the pH was adjusted to 6-7 using dilute HCI and the resulting solid was collected by filtration and dried under vacuum to give 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)nicotinic acid as a dark yellow solid (0.45 g, 78 %). LC-MS (ESI+) m/z 322.6 (M+H)+

[00793] (lR,3R) (6-((l,6-naphthyridin vl)amino)-4(cyclopropylaminolnicotinamidolcyclobutane-l-carboxylic acid (Intermediate O) o

N

NaOH, H2O

THF, MeOH

O

[00794] Step 1 - methyl (lR,3R) (6-((L6-naphthyridin yl)amino) (cyclopropylamino) nicotinamidojcyclobutane carboxylate

[00795] To a stirred solution of methyl (lR,3R) aminocyclobutane-l-carboxylate-HCl (0.2 g, 1.6 mmol) and 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)nicotinic acid (0.5 g, 1.6 mmol, Intermediate N) in DMF (4 mL) was added DIPEA (0.9 mL, 4.7 mmol) and PyBOP (1.2 g, 2.3 mmol) at rt. The resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was filtered, dried and dried under reduced pressure. The crude product was triturated with MTBE and dried in vacuo to give methyl (lr,3r)3-(6-((1,6-naphthyridin yl)amino) (cyclopropylamino)nicotinamido)cyclo butane-1613 carboxylate as a yellow solid. (0.55 g, 81%). LC-MS (ESI+) m/z 433.2 (M+H)+.

[00796] Step 2:(1R, 3R)-3 -(6-(( 1, 6-naphthyridin yl)amino)-4(cycl opropyl am i η o )n i coti nami do)

[00797] cyclobutane carboxylic acid

[00798] To a stirred solution of methyl (lR,3R) (6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclobutane-l-carboxylate (0.55 g, 1.27 mmol) in THF:MeOH (15 mL, 1:1) was dropwise added NaOH (0.16 g, 3.82 mmol) in 5 mL water at rt. The resulting reaction mixture was stirred at rt for 3 h. The reaction mixture was then evaporated under vacuum, and water (10 mL) was added and the pH was adjusted to 6-7 using 10 % citric acid solution. The resulting mixture was then stirred for 15 min, and the solid precipitate was fdtered off and dried under vacuo to give (lR,3R) (6-((l,6-naphthyridin yl)amino) (cyclopropylamino)nicotinamido)cyclobutane-l-carboxylic acid as a yellow solid.(0.4 g, 75%). 1H NMR (400 MHz, DMSO) δ 11.18 (s, IH), 10.36 (s, IH), 9.05 (d, J = 12 Hz, IH), 8.59-8.45 (m, 4H), 8.28-8.23(m, IH), 7.58-7.03 (m, 4H), 4.52-4.46 (m, IH), 2.91 (t, J = 8.8 Hz, IH), 2.58-2.27 (m, 4H), 0.90 (m, 2H), 0.52(m, 2H).

[00799] Ethyl 2-(4-amin0DiDeridin-l-yl)acetate hydrochloride (Intermediate P)

[00800] Step 1 - methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-l-yl)acetate

[00801] A solution of tert-butyl piperidin ylcarbamate (0.5 g, 2.5 mmol), ethyl bromo acetate (0.45 g, 2.75 mmol) and DIPEA (0.65 mL, 3.76 mmol) in DCM (5 mL) was stirred at rt for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and fdtered. The fdtrate was evaporated under reduced pressure to give methyl 2-(4-((tertbutoxycarbonyl)amino)piperidin-l-yl)acetate as a colorless oil (0.55 g, 81 %). LC-MS (ESI+) m/z 287.2 (M+H)+.

[00802] Step 2 - ethyl 2-(4-aminopiperidin-l-yl)acetate hydrochloride

[00803] To a solution of ethyl 2-(4-((te/7-butoxycarbonyl)amino)piperidin- l-yl)acetate (0.55 g, 1.92 mmol) in DCM (10 mL) was added 4N HC1 in dioxane (3 mL) at 0 °C and then the reaction was allowed to warm to rt and stirred for 4 h. The reaction mixture was then evaporated under vacuum and the solid was triturated using MTBE (5 mL) to give ethyl 2-(4-aminopiperidin-lyl)acetate hydrochloride as white solid (0.3 g, 86 %). LC-MS (ESI+) m/z 187.2 (M+H)+.

[00804] Methyl 2-(3-aminoazetidin-l-yl)acetate 2,2,2-trifluoroacetate (Intermediate O)

[00805] Step 1 - methyl 2-(3-((tert-butoxycarbonyl)amino)azetidin-l-yl)acetate

[00806] To a mixture of tert-butyl azetidin ylcarbamate (0.5 g, 0.58 mmol) and K2CO3 (0.6 g, 0.87 mmol) in ACN (5 mL) at 0 °C was added a solution of methyl 2-bromoacetate (0.444 g, 0.58 mmol) in ACN (5 mL) at same temperature and the reaction mixture was stirred for 25 minutes. The reaction mixture was then diluted with water (100 mL) and product was extracted in ethyl acetate (50 mL x3). The organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (3% MeOH-DCM) to give methyl 2-(3-((tert-butoxycarbonyl)amino)azetidin-l-yl)acetate as a yellow semi-solid (0.15 g, 21%); LC-MS (ESI+) m/z 245.2 (M+H)+.

[00807] Step 2 - methyl 2-(3-aminoazeti din vDacetate 2,2,2-trifluoroacetate

[00808] To a stirred solution of methyl 2-(3-((tert-butoxycarbonyl)amino)azetidin-l-yl)acetate (0.15 g, 0.61 mmol) in DCM (10 mL) was added TFA (3 mL) at 0 °C and the reaction was stirred for 3h. The reaction mixture was then evaporated in vacuo and triturated with diethyl ether to give methyl 2-(3-aminoazeti din-l-yl)acetate 2,2,2-trifluoroacetate as a brown semisolid (0.1 g, 63%); LC-MS (ESF)&#1524;/z 145.16 (M+H)+.

[00809] 2-(2,6-dioxoDiDeridin vl) fluoroisoindoline-l,3-dione (Intermediate R)

[00810] Step 1 - 5-amino (4-fluoro-L3-dioxoisoindolin yl) oxopentanoic acid

[00811] To a stirred solution of 4-fluoroisobenzofuran-l,3-dione (25 g, 150 mmol, CAS# 65239-1) in DMF (100 mL) was added L-glutamine (22 g, 150 mmol) at rt. The resulting reaction mixture was heated to at 90 °C and stirred for 2 h. The reaction mixture was then evaporated under reduced pressure, transferred into 4 N aqueous HC1 solution and the resulting mixture was stirred for 36 h at rt. The solid precipitate was then filtered off, washed with cold water and dried under reduced pressure to give 5-amino (4-fluoro-l,3-dioxoisoindolin yl) oxopentanoic acid as a white solid (28 g, 63%). LC-MS (ESI+) m/z 295 (M+H)+.

[00812] Step 2 - 2-(2,6-dioxopiperidin yl) fluoroisoindoline-L3-dione

[00813] To a stirred solution of 5-amino (4-fluoro-l,3-dioxoisoindolin yl) oxopentanoic acid (28 g, 95 mmol) in acetonitrile (200 mL) was added CDI (19 g, 110 mmol) and DMAP (0.14 g, 1.1 mmol) at rt. The resulting reaction mixture then heated to 90 °C and stirred for 5 h. The reaction mixture was then evaporated under reduced pressure. The crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give 2-(2,6-dioxopiperidin yl)-4fluoroisoindoline-1,3-dione as a yellow solid (12 g, 46%). 1H NMR (400 MHz, DMSO) δ ppm 11.16 (s, IH), 7.98-7.93 (m, IH), 7.80-7.76 (m, 2H), 5.19-5.14 (m, IH), 2.94-2.85 (m, IH), 2.632.54 (m, 2H), 2.09-2.04 (m, IH).

[00814] tert-butyl(3-(3-aminopropoxv)propyl)carbamate(Intermediate S) (Boc)2O Η2Ν/Χ/^Ο/χ/^ΝΗ2 DCM

S

[00815] A solution of 3,3'-oxybis(propan-l-amine) (1.0 g, 7.6 mmol, CAS# 2157 6), and Boc anhydride (0.83 g, 3.78 mmol) in DCM (8 mL) was stirred at rt for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified using silica gel column chromatography (5% MeOH-DCM) to give tert-butyl (3-(3aminopropoxy)propyl)carbamate as a white solid (0.36 g, 21%). 1H NMR (400 MHz, DMSO) δ 10.34 (s, IH), 9.05 (s, IH), (d, J= 5.2 Hz, 3H), 8.42 (s, IH), 8.28 (d, J= 9.2 Hz, IH), 8.14 (d, J= 7.6 Hz, IH), 7.70-7.67 (m, IH), 6.76 (bs, IH), 3.70 (t, J = 2.8 Hz, IH), 3.00-3.05 (m, 2H), 2.892.86 (m, 2H), 2.06 (s, IH), 1.88 (d, J = 12.4 Hz, 2H), 1.77 (d, J = 11.6 Hz, 2H), 1.48-1.21 (m, 17H). LC-MS (ESI+) m/z 233.35 (M+H)+

[00816] 2-(2-(2-(benzvloxv)ethoxv)ethoxy)ethan-l-ol(Intermediate T) μη . Λ η Λ NaH, BnBr RnO Λ ο Λ

THF

[00817] To a stirred solution of 2,2'-(ethane-l,2-diylbis(oxy))bis(ethan-l-ol) (30 g, 200 mmol) in THF (125 mL) was added 60% NaH in paraffin (4 g, 100 mmol) at 10 °C. The resulting reaction mixture stirred at the same temperature for 0.5 h. To this reaction mixture was then added benzyl bromide (17 g, 100 mmol) in THF (125) dropwise at 10 °C over 1.5 h. The resulting reaction mixture then stirred at rt for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (4% MeOH-DCM) to give 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-l-ol as a yellow oil (20 g, 42%). LC-MS (ESI+) m/z 241.35 (M+H)+

[00818] tert-butyl((lR,3R) ((2-(2-(2aminoethoxv)ethoxv)ethoxv)methyl)cvcloDentvl)carbamate(Intermediate U)

(Boc)2O, tea

DCM

LiBH4

THF

MsCI, TEA

DCM

TBAB, NaOH, toluene

.»NHBoc

10% Pd/C, H2 (gas)

Acetic acid, EtOH

&#1524;NHBoc

NaN3

DMF

10% Pd/C, H2 (gas) 0^/^0/*^24NHB0c

EtOH H2N^&#1523;^O^/

U

[00819] Step 1 - methyl (lS,3S) ((te/7-butoxycarbonyl)amino)cyclopentane-l-carboxylate [00820] To a stirred solution of methyl (1S,3S)3&#1470;-aminocyclopentane carboxylate hydrochloride (4.5 g, 25 mmol) and TEA (10.5 mL, 75 mmol) in DCM (100 mL) was dropwise added Boc-anhydride (6.6 g, 30 mmol) at 0 °C. The resulting reaction mixture was then allowed to warm to rt and then stirred for 1.5 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (40% EAcHexanes) to give methyl (lS,3S) ((ter/-butoxycarbonyl)amino)cyclopentane-l-carboxylate as a white solid (5.1 g, 84 %). LC-MS (ESI+) m/z 261.3 (M+18)+.

[00821] Step 2 - te/7-butyl ((1 S.3 S) (hydroxymethyl)cyclopentyl)carbamate

[00822] To a stirred solution of methyl ( I S,3S) ((/c77-butoxycarbonyl)amino)cyclopentane1-carboxylate (2.5 g, 10.2 mmol) in THF (50 mL) was added 4 M LiBH4 in THF (5.13 mL, 20.4 mmol) dropwise at 0 °C. The resulting reaction mixture then heated to 75 °C and stirred for 1 h. The reaction mixture was then transferred into 5% citric acid solution. The pH of the solution was then adjusted to pH = 8 to 9 with 8 N NaOH solution. The resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give tert-butyl ((lS,3S)-3(hydroxymethyl)cyclopentyl)carbamate as a white solid (1.9 g, 86%). LC-MS (ESI+) m/z 233.15 (M+18)+.

[00823] Step 3:((1 S,3 S) ((tert-butoxycarbonyl)aminojcyclopentyl)methyl methanesulfonate

[00824] To a stirred solution of tert-butyl ((lS,3S) (hydroxymethyl)cyclopentyl)carbamate (1.6 g, 7.4 mmol) and TEA(3.1 mL, 22.3 mmol) in DCM (25 mL) was added Mesyl chloride (0.91 mL, 11.14 mmol) dropwise at 0 °C. The resulting reaction mixture was allowed warm to room temperature and then stirred for 1 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give ((lS,3S) ((tert-butoxycarbonyl)amino)cyclopentyl)methyl methanesulfonate as a white solid (1.9 g, 87%). LC-MS (ESI+) m/z 238.3 (M-56)+.

[00825] Step 4:tert-butyl((lRJR) (12-phenyl-2,5,8,11tetraoxadodecvljcvclopentyljcarbamate

[00826] To a stirred solution of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-l-ol (1.3 g, 5.4 mmol, Intermediate T) and ((lS,3S) ((tert-butoxycarbonyl)amino)cyclopentyl)methyl methanesulfonate (1.9 g, 6.5 mmol) in toluene (20 mL) and 8 N Aqueous NaOH solution (20 mL) was added TBAB (catalytic amount) at rt. The resulting reaction mixture was then heated to 90 °C and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give tert-butyl ((lR,3R) (12-phenyl-2,5,8,ll-tetraoxadodecyl)cyclopentyl)carbamate as a yellow oil (0.8 g, 41%). LC-MS (ESI+) m/z 338.4 (M-100)+.

[00827] Step 5:tert-butyl((1R,3R)2)-2)-2))- 3&#1470; hydroxyethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate

[00828] To a stirred solution of tert-butyl ((lR,3R) (12-phenyl-2,5,8,lltetraoxadodecyl)cyclopentyl)carbamate (0.8 g, 1.8 mmol) in ethanol (25 mL) and acetic acid (0.3 mL) was added 10% Pd/C (0.8 g, 50% wet) at rt under nitrogen atmosphere. The resulting reaction mixture was stirred under hydrogen gas (2 kg/cm2 pressure) in an autoclave at rt for 1.5 h. The reaction mixture was then filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl ((lR,3R) ((2-(2(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate as a yellow oil (0.6 g, 94 %). LCMS (ESI+) m/z 248.5 (M-100)+.

[00829] Step 6:2-(2-(2-(((lR3R) ((tertbutoxvcarbonvl)amino)cvclopentyl)methoxy)ethoxy)

[00830] ethoxy)ethyl methanesulfonate

[00831] To a stirred solution of tert-butyl ((lR,3R) ((2-(2-(2hydroxyethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate (0.6 g, 1.7 mmol) and TEA (0.75 mL, 5.18 mmol) in DCM (10 mL) was added Mesyl chloride (0.21 mL, 2.59 mmol) dropwise at 0 °C. The resulting reaction mixture then warmed to rt and stirred for 1 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2-(2-(2-(((lR,3R)-3 -((tertbutoxycarbonyl)amino)cyclopentyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate as a brown oil (0.72 g, 98%). LC-MS (ESI+) m/z 370.3 (M-56)+.

[00832] Step 7:tert-butyl((lR3R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cvclopentyl)

[00833] carbamate

[00834] To a stirred solution of 2-(2-(2-(((lR,3R) ((ter tbutoxycarbonyl)amino)cyclopentyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate (0.78 g, 1.83 mmol) in DMF (10 mL) was added NaN3 (0.18 g, 2.74 mmol) at rt. The resulting reaction mixture was then heated to 65 °C and stirred for 2 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3%

MeOH-DCM) to give tert-butyl ((lR,3R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate as a colorless oil (0.65 g, 95%). LCMS (ESI+) m/z 390.4 (M+18)+.

[00835] Step 8:tert-butyl((1R,3R)2)-2)-2))- 3&#1470;aminoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate

[00836] To a stirred solution of tert-butyl ((lR,3R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate (0.75 g, 2.01 mmol) in ethanol (20 mL) was added 10% Pd/C (0.75 g, 50% wet) at rt under nitrogen atmosphere. The resulting reaction mixture then stirred under hydrogen gas (15 kg/cm2 pressure) in autoclave at rt for 6 h. The reaction mixture was then filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl ((lR,3R)-3((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate as a yellow oil (0.48 g, 69 %). LC-MS (ESI+) m/z 347.5 (M+H)+.

[00837] tert-butyl(14-amino-3.,6.,9,12-tetraoxatetradecvl)(methvl)carbamate (Intermediate V)

Ag2O, Nai, TsCI

DCM

(Boc)2O

DCM

MeNH2 in THF

THF

MsO

Boc 1 N\

NaN3

DMF

MsCI, TEA

DCM

Pd/C, H2 (gas)

MeOH

Boc

V

[00838] Step 1 - 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate

[00839] To a solution of 3,6,9,12-tetraoxatetradecane-l,14-di 01 (10 g, 41.96 mmol, CAS# 479215-8), silver oxide (14.6 g, 62.94 mmol) and Nai (7 g, 46.56 mmol) in DCM (250 mL) was added tosyl chloride (8.5 g, 41.96 mmol) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 1 h. The reaction mixture was then filtered through celite and the filtrate was washed with 10% NaHCO3 solution (125 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give 14-hydroxy-3,6,9,12tetraoxatetradecyl 4-methylbenzenesulfonate as a yellow oil (13 g, 79%). LC-MS (ESI+) m/z 394.3 (M+H)+.

[00840] Step 2 - 5,8,lL14-tetraoxa azahexadecan ol

[00841] To a stirred solution of 14-hydroxy-3,6,9,12-tetraoxatetradecyl 4methylbenzenesulfonate (3.0 g, 7.7 mmol) in THF (10 mL) was added 2M methyl amine solution in THF (16 mL, 30.6 mmol) dropwise at rt. The resulting reaction mixture then heated to 65 °C and stirred for 16 h. The reaction mixture was filtered and the filter cake was washed with THF (20 mL). The filtrate was then evaporated under reduced pressure to give 5,8,ll,14-tetraoxa-2azahexadecan 01 as a yellow oil (1.8 g, 94 %). MASS (ESI+) m/z 252 (M+H)+.

[00842] Step 3 - tert-butyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate [00843] To a stirred solution of 5,8,ll,14-tetraoxa azahexadecan ol (1.8 g, 7.2 mmol) in DCM (50 mL) was added Boc-anhydride (9.36 g, 42.96 mmol) dropwise at 0 °C. The resulting reaction mixture then warmed to rt and stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give tert-butyl (14-hydroxy-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate as a light yellow oil (1.5 g, 59%). LC-MS (ESI+) m/z 351.44 (M+H)+.

[00844] Step 4 - 2,2,5-trimethyl oxo-3,8,lL14,17-pentaoxa azanonadecan yl methanesulfonate

[00845] To a stirred solution of tert-butyl (14-hydroxy-3,6,9,12tetraoxatetradecyl)(methyl)carbamate (1.5 g, 4.3 mmol) and TEA (1.8 mL, 12.8 mmol) in DCM (30 mL) was added mesyl chloride (0.5 mL, 6.4 mmol) dropwise at 0 °C. The resulting reaction mixture then warmed to rt and stirred for 1 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2,2,5-trimethyl oxo-3,8,ll,14,17-pentaoxa azanonadecan yl methanesulfonate as a yellow oil (1.5 g, 82%).

[00846] Step 5 - tert-butyl (l4-azido-3,6,9,l2-tetraoxatetradecyl)(methyl)carbamate

[00847] To a stirred solution of 2,2,5-trimethyl oxo-3,8,ll,14,17-pentaoxa azanonadecan19-yl methanesulfonate (1.5 g, 3.5 mmol) in DMF (15 mL) was added sodium azide (0.34 g, 5.23 mmol) at rt. The resulting reaction mixture was then heated to 65 °C and stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (40% EAc-Hexanes) to give tert-butyl (14-azido3,6,9,12-tetraoxatetradecyl)(methyl)carbamate as a light yellow oil (1.2 g, 92%). LC-MS (ESI+) m/z Μ&#906;2 (M+H)+.

[00848] Step 6 - tert-butyl (&#906;4-amino-3,6,9J 2-tetraoxatetradecyl )(methyl)carbarnate

[00849] To a stirred solution of tert-butyl (14-azido-3,6,9,12tetraoxatetradecyl)(methyl)carbamate (1.2 g, 3.2 mmol) in MeOH (30 mL) was added 10% Pd/C (1.2 g, 50% wet) at rt under nitrogen atmosphere. The resulting reaction mixture was then stirred under hydrogen gas (15 kg/cm2 pressure) in autoclave at rt for 2 h. The reaction mixture was then filtered through a pad of celite under vacuum and washed with MeOH (30 mL). The filtrate was then evaporated under reduced pressure to give tert-butyl (14-amino-3,6,9,12tetraoxatetradecyl)(methyl)carbamate as a colorless oil (1 g, 91 %). LC-MS (ESI+) m/z 351.7 (M+H)+.

[00850] tert-butyl((lR,4R) ((2-(2-(2aminoethoxv)ethoxv)ethoxv)methyl)cvclohexvl)carbamate (Intermediate W) ‘OH

BocHN,,

.NHBoc

OBn

TBAB, NaOH, toluene

[00851] Step 1:tert-butyl((lR,4R) (12-phenyl-2,5,8,11tetraoxadodecyl)cyclohexyl)carbamate

[00852] To a stirred solution of ((lR,4R) ((tert-butoxycarbonyl)amino)cyclohexyl)methyl methanesulfonate (1.1 g, 4.6 mmol, synthesized via Steps 1-3 of Intermediate K) and 2-(2-(2(benzyloxy)ethoxy)ethoxy)ethan-l-ol (1.7 g, 5.5 mmol, Intermediate T) in toluene (20 mL) and 8 N Aqueous NaOH solution (20 mL) was added TBAB (catalytic amount) at rt. The resulting reaction mixture was then heated to 90 °C and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give tert-butyl ((lr,4r) (12-phenyl-2,5,8,lltetraoxadodecyl)cyclohexyl)carbamate as a yellow oil (0.7 g, 28%). LC-MS (ESI+) m/z 452.5 (M+H)+.

[00853] Step 2:tert-butyl((lR,4R) ((2-(2-(2hydroxyethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate

[00854] To a stirred solution of tert-butyl ((lR,4R) (12-phenyl-2,5,8,lltetraoxadodecyl)cyclohexyl)carbamate (0.85 g, 1.88 mmol) in ethanol (25 mL) and acetic acid (0.3 mL) was added 10% Pd/C (0.85 g, wet) at rt under nitrogen atmosphere. The resulting reaction mixture was then stirred under hydrogen gas (2 kg/cm2 pressure) in autoclave at rt for 1.5 h. The reaction mixture was filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give ter/-butyl ((lR,4R) ((2-(2-(2 hydroxyethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate as a yellow oil (0.65 g, 95 %). LCMS (ESI+) m/z 362.4 (M+H)+.

[00855] Step 3:2-(2-(2-((( lr,4r) ((tertbutoxvcarbonvl)amino)cvclohexvl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate

[00856] To a stirred solution of tert-butyl ((lR,4R) ((2-(2-(2hydroxyethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate (0.65 g, 1.8 mmol) and TEA (0.8 mL, 5.4 mmol) in DCM (10 mL) was added mesyl chloride (0.21 mL, 2.7 mmol) dropwise at 0 °C. The resulting reaction mixture was allowed to warm to rt for 1 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2-(2-(2-(((lR,4R) ((tertbutoxycarbonyl)amino)cyclohexyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate as a brown oil (0.75 g, 95%). LC-MS (ESI+) m/z 440.5 (M+H)+.

[00857] Step 4:tert-butyl((lR,4R) ((2-(2-(2azidoethoxv)ethoxv)ethoxv)methyl)cvclohexvl)carbamate

[00858] To a stirred solution of 2-(2-(2-((( lR,4R) ((tertbutoxycarbonyl)amino)cyclohexyl)methoxy)ethoxy)ethoxy)ethyl methanesulfonate (0.75 g, 1.71 mmol) in DMF (10 mL) was added sodium azide (0.17 g, 2.55 mmol) at rt. The resulting reaction mixture was then heated to 65 °C and stirred for 2 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (35% EtOAc-Hexanes) to give tert-butyl ((lR,4R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate as a colorless oil (0.55 g, 83%). LC-MS (ESI+) m/z 387.4 (M+H)+.

[00859] Step 5:tert-butyl((lR,4R) ((2-(2-(2aminoethoxv)ethoxv)ethoxv)methyl)cvclohexvl)carbamate

[00860] To a stirred solution of tert-butyl ((lR,4R) ((2-(2-(2azidoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate (0.55 g, 1.42 mmol) in ethanol (15 mL) was added 10% Pd/C (0.55 g, wet) at rt under nitrogen atmosphere. The resulting reaction mixture was then stirred under hydrogen gas (15 kg/cm2 pressure) in autoclave at rt for 5 h. The reaction mixture was filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give /er/-butyl ((lR,4R) ((2-(2-(2aminoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate as a yellow oil (0.45 g, 88 %). LC-MS (ESI+) m/z 361.45 (M+H)+.

[00861] l-Dhenvl-2,5,8,ll,14-Dentaoxahexadecan vl

4-methvlbenzenesulfonate (Intermediate

HO

NaH,BnBr

THF

DCM

[00862] Step 1 - l-phenyl-2,5,8.1L14-pentaoxahexadecan ol

[00863] To a stirred solution of 3,6,9,12-tetraoxatetradecane-l,14-diol (10 g, 42 mmol, CAS# 4792 8) in THF (50 mL) was added 60% NaH in paraffin (0.84 g, 21 mmol) at 10 °C. The resulting reaction mixture was stirred at the same temperature for 0.5 h. To this reaction mixture benzyl bromide (3.6 g, 21 mmol) in THF (50) was added dropwise at 10 °C over 1.5 h. The resulting reaction mixture was allowed warm to rt and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give l-phenyl-2,5,8,ll,14-pentaoxahexadecan-1601 as a yellow oil (6 g, 43%). LC-MS (ESI+) m/z 347.4 (M+H20)+.

[00864] Step 2 - l-phenyl-2,5,8.1L14-pentaoxahexadecan yl 4-methylbenzenesulfonate [00865] To a stirred solution of methyl l-phenyl-2,5,8,ll,14-pentaoxahexadecan ol (6.0 g, 18.2 mmol) and TEA (8 mL, 55 mmol) in DCM (150 mL) was added tosyl chloride (5.2 g, 27.3 mmol) at rt. The resulting reaction mixture then stirred at rt for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give l-phenyl-2,5,8,ll,14-pentaoxahexadecan yl 4methylbenzenesulfonate as a yellow oil (7 g, 79%). LC-MS (ESI+) m/z 484.2 (M+H)+.

[00866] tert-butyl ((lR,4R) (16-amino-2,5,841,14pentaoxahexadecvDcyclohexyDcarbamate (Intermediate Y)

KOH, THF

BocHN,, BocHN,

Γ 1 NaNj | ]

[00867] Step 1 tert-butyl ((lR,4R) (18-phenyl-2X84L1447hexaoxaoctadecyl)cyclohexyl)carbamate

[00868] To a stirred solution of tert-butyl ((lR,4R) (hydroxymethyl)cyclohexyl)carbamate (1.5 g, 0.7 mmol, synthesized via Steps 1-2 of Intermediate K) and l-phenyl-2,5,8,11,14pentaoxahexadecan yl 4-methylbenzenesulfonate (4.74 g, 0.98 mmol, Intermediate X) in THF (30 mL) was added KOH (3.67 g, 65.4 mmol) at rt. The resulting reaction mixture then heated to 60 °C and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give tert-butyl ((lR,4R) (18-phenyl-2,5,8,ll,14,17-hexaoxaoctadecyl)cyclohexyl)carbamate as a yellow oil (0.92 g, 26%). LC-MS (ESI+) m/z 557.4 (M+18)+.

[00869] Step 2:tert-butyl((lR,4R) (16-hydroxy-2,5,8,ll,14pentaoxahexadecyDcyclohexyDcarbamate

[00870] To a stirred solution of tert-butyl ((lR,4R) (18-phenyl-2,5,8,ll,14,17hexaoxaoctadecyl)cyclohexyl)carbamate (0.91 g, 1.68 mmol) in ethanol (15 mL) was added 10% Pd/C (0.9 g, 50% wet) at rt under nitrogen atmosphere. The resulting reaction mixture was stirred under hydrogen gas (2 kg/cm2 pressure) in an autoclave at rt for 6 h. The reaction mixture was filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl ((lR,4R) (16-hydroxy-2,5,8,ll,14pentaoxahexadecyl)cyclohexyl)carbamate as a yellow oil (0.75 g, 99 %). LC-MS (ESI+) m/z 450.2 (M+H)+.

[00871] Step 3 - l-((lR,4R) ((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,lL14pentaoxahexadecan yl methanesulfonate

[00872] To a stirred solution of ter/-butyl ((lR,4R) (16-hydroxy-2,5,8,ll,14pentaoxahexadecyl)cyclohexyl)carbamate (0.8 g, 1.8 mmol) and TEA (0.75 mL, 5.33 mmol) in DCM (10 mL) was added mesyl chloride (0.2 mL, 2.66 mmol) dropwise at 0 °C. The resulting reaction mixture was allowed to warm to rt and stirred for 1 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give l-((lR,4R) ((tertbutoxycarbonyl)amino)cyclohexyl)-2,5,8,ll,14-pentaoxahexadecan yl methanesulfonate as a brown oil (0.9 g, 96%). LC-MS (ESI+) m/z 545.6 (M+18)+.

[00873] Step 4:tert-butyl((lR,4R) (16-azido-2,5,8,ll,14pentaoxahexadecyDcyclohexyDcarbamate

[00874] To a stirred solution of l-((lR,4R) ((tert-butoxycarbonyl)amino)cyclohexyl)2,5,8,11,14-pentaoxahexadecan yl methanesulfonate (0.9 g, 1.7 mmol) in DMF (10 mL) was added sodium azide (0.17 g, 2.55 mmol) at rt. The resulting reaction mixture was then heated to 65 °C and stirred for 2 h. The reaction mixture was then transferred into water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (45% EAc-Hexanes) to give tert-butyl ((lR,4R) (16-azido-2,5,8,ll,14-pentaoxahexadecyl)cyclohexyl)carbamate as a colorless oil (0.72 g, 90%).

[00875] Step 5:tert-butyl((lR,4R) (16-amino-2,5,8,ll,14pentaoxahexadecyDcyclohexyDcarbamate

[00876] To a stirred solution of tert-butyl ((lR,4R) (16-azido-2,5,8,ll,14pentaoxahexadecyl)cyclohexyl)carbamate (0.7 g, 1.47 mmol) in ethanol (20 mL) was added 10%

Pd/C (0.7 g, 50% wet) at rt under nitrogen atmosphere. The resulting reaction mixture was then stirred under hydrogen gas (15 kg/cm2 pressure) in an autoclave at rt for 4 h. The reaction mixture was then filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give ter/-butyl ((lR,4R) (16-amino2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate as a yellow oil (0.52 g, 78 %). LC-MS (ESI+) m/z 449.5 (M+H)+.

[00877] 4-((14-amino-3,6,9,12-tetraoxatetradecvl)amino) (2,6-dioxoDiDeridin

vl)isoindoline-l,3-dione hydrochloride (Intermediate

dioxane

HCI in dioxane

[00878] Step 1 - te/7-butyl (14-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)3,6,9,12-tetraoxatetradecyl)carb amate

[00879] To a stirred solution of 2-(2,6-dioxopiperidin yl) fluoroisoindoline-l,3-dione (0.95 g, 3.44 mmol, Intermediate R) and DABCO (0.5 g, 4.5 mmol) in DMF (25 mL) was added tertbutyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (1.5 g, 4.5 mmol, CAS # 811442 9) at rt. The resulting reaction mixture then heated at 80 °C for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (2% MeOH-DCM) to give /c77-butyl (14-((2-(2,6-dioxopiperidin yl)-l,3dioxoisoindolin yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate as a yellow oil (0.35 g, 17%). LCMS (ESI+) m/z 593.6 (M+H)+.

[00880] Step 2 - 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino) (2,6-dioxopiperidin-3yl)isoindoline-l,3-dione hydrochloride

[00881] To a stirred solution of tert-butyl (14-((2-(2,6-di oxopiperi din yl)-l, 3dioxoisoindolin yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate (0.35 g, 0.59 mmol) in 1,4 dioxane (10 mL) was added 4 M HC1 in dioxane (10 mL) at 0 °C. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was then evaporated under vacuum and triturated using MTBE to give 4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2(2,6-dioxopiperidin yl)isoindoline-l,3-dione hydrochloride as a yellow solid (0.28 g, 90%). LCMS (ESI+) m/z 493.45 (M+H)+.

[00882] tert-butyl 6-bromohexanoate(Intermediate AA) t-BuOH, pyridine

DMF, DCM DCM

AA

[00883] Step 1 - 6-bromohexanoyl chloride

[00884] To a stirred solution of 6-bromohexanoic acid (5.0 g, 25.6 mmol) and DMF (catalytic amount) in DCM (50 mL) was added oxalyl chloride (2.5 mL, 28.16 mmol) dropwise at 0 °C. The resulting reaction mixture was then warmed to rt and stirred for 16 h. The reaction mixture was then evaporated under reduced pressure to give 6-bromohexanoyl chloride as a brown oil (5 g, 91 %).

[00885] Step 2 - tert-butyl 6-bromohexanoate

[00886] To a stirred solution of 6-bromohexanoyl chloride (5.5 g, 25.8 mmol) and pyridine (2.55 mL, 30.9 mmol) in DCM (50 mL) was added tert-butanol (3.71 mLg, 38.62 mmol) dropwise at rt. The resulting reaction mixture stirred at rt for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and fdtered. The fdtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (6% EAc-Hexanes) to give tert-butyl 6-bromohexanoate as a colorless oil (4.5 g, 70%). 1HNMR (400 MHz, DMSO) δ 3.43 (/, J = 8 Hz, 2H), 2.25 (/, J = 7.2 Hz, 2H), 1.93-1.86 (m, 2H), 1.67-1.60 (m, 2H), 1.52-1.50 (m, 2H), 1.46 (s, 9H).

[00887] tert-butyl 6-((7-aminoheptyl)oxv)hexanoate(Intermediate AB)

NaN3, TBAB

Toluene

Nai, NaH, DMF

Pd(OH)2, H2

MeOH nh2

[00888] Step 1: 7-azidoheptan-l-ol

[00889] To a stirred solution of 7-bromoheptan-l-ol (0.5 g, 2.6 mmol) and TBAB (0.083 g, 0.25 mmol) in toluene (10 mL) was added sodium azide (0.35 g, 5.12 mmol) at rt. The resulting reaction mixture was then heated to 90 °C and stirred for 16 h. The reaction mixture was then filtered through celite, washed with DCM (25 mL), and filtrate was evaporated under reduced pressure. The crude product was purified using silica gel column chromatography (10% EAc-Hexanes) to give 7-azidoheptan-l-ol as a colorless oil (0.35 g, 87%). LC-MS (ESI+) m/z 157.2 (M+H)+.

[00890] Step 2 - tert-butyl 6-((7-azidoheptyl)oxy)hexanoate

[00891] To a stirred solution of 7-azidoheptan-l-ol (1.1 g, 7.2 mmol) in DMF (30 mL) was added Nai (0.18 g, 1.19 mmol) and 60% NaH (0.36 g, 8.9 mmol) at rt. The resulting reaction mixture was stirred at rt for 0.5 h then ter/-butyl 6-bromohexanoate (1.5 g, 5.97 mmol) in DMF (5 mL) was added dropwise at rt. The resulting reaction mixture then heated to 50 °C and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3% EAc-Hexanes) to give tert-butyl 6-((7-azidoheptyl)oxy)hexanoate as a colorless oil (0.3 g, 10 %). 1HNMR (400 MHz, DMSO) δ 3.43-3.39 (m, 4H), 3.27 (/, J= 7.2 Hz, 2H), 2.23 (t, J= 7.6 Hz, 2H), 1.66-1.48 (m, 8H), 1.46 (m, 9H), 1.44-1.41 (m, 8H).

[00892] Step 3 - tert-butyl 6-((7-aminoheptyl)oxy)hexanoate

[00893] To a stirred solution of tert-butyl 6-((7-azidoheptyl)oxy)hexanoate (0.3 g, 0.92 mmol) in methanol (30 mL) was added 20% Pd(OH)2 (0.3 g) at rt under nitrogen atmosphere. The resulting reaction mixture then stirred under hydrogen gas (20 kg/cm2 pressure) in an autoclave at rt for 4 h. The reaction mixture was then filtered through a pad of celite under vacuum and washed with MeOH (50 mL). The filtrate was then evaporated under reduced pressure to give tert-butyl 6 ((7-aminoheptyl)oxy)hexanoate as a colorless oil (0.25 g, 90 %). 1H NMR (400 MHz, DMSO) δ 3.42-3.38 (m, 4H), 2.69 (/, J= 7.2 Hz, 2H), 2.23 (t, J= 7.6 Hz, 2H), 1.65-1.56 (m, 8H), 1.46 (m, 10H), 1.42-1.33 (m, 8H).

[00894] tert-butvl(2-(2-(2-(methvlamino)ethoxv)ethoxv)ethyl)carbamate (Intermediate

AC)

[00895] Step 1 - tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate

[00896] A solution of 2-(2-(2-aminoethoxy)ethoxy)ethan-l-ol (1.5 g, 10.1 mmol), triethylamine (3.3 mL, 15.1 mmol), and Boc-anhydride (3.3 g, 15.1 mmol) in DCM (10 mL) was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (3 % MeOH-DCM) to give tert-butyl (2-(2-(2hydroxyethoxy)ethoxy)ethyl)carbamate as a colorless oil (1.8 g, 72%). LC-MS (ESI+) m/z 267.35 (M+H)+.

[00897] Step 2 - 2,2-dimethyl oxo-3,8,ll-trioxa azatridecan yl methanesulfonate [00898] To a stirred solution of tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.8 g, 7.2 mmol) and triethylamine (3.0 g, 4.15 mL, 21.7 mmol) in DCM (12 mL) was added of mesyl chloride (0.85 g, 10.8 mmol) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using DCM (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2,2-dimethyl oxo-3,8,ll-trioxa-5azatri decan yl methanesulfonate as a yellow semisolid (2.2 g, 93%).

[00899] Step 3 - tert-butyl (2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate

[00900] A stirred solution of tert-butyl(2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate (2.0 g, 6.1 mmol), 2M Methyl amine in THF (36.66 mL, 73.32 mmol) and DIPEA (3 mL, 3 eq) in DMF (20 mL) was heated at 90 °C for 10 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give ter/-butyl (2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate (1.2 g, 68%).

[00901] 2-azidoethan-l-ol (Intermediate AD) Br n3^

H2O 0H

[00902] To a stirred solution of 2-bromoethan-l-ol (10 g, 80 mmol) in water (100 mL) was added sodium azide (10.4 g, 160.1 mmol) and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was then extracted using diethyl ether (250 mLx3), dried over anhydrous sodium sulphate and evaporated in vacuum to give 2-azidoethan-l-ol as a light yellow oil (6.5 g, 93%); 1H NMR (400 MHz, DMSO) δ 5.00 (t, J= 52 Hz, IH), 3.7-3.5 (m, 2H), 3.3-3.2 (m, 2H).

[00903] 2-azidoethyl 4-methylbenzenesulfonate(Intermediate AE)

N3x /x TsCI, TEA N3x &#9658; ^^OTs

DCM

AD AE

[00904] To a stirred mixture of 2-azidoethan-l-ol (0.1 g, 1.2 mmol, Intermediate AD) in DCM (5 mL) was added TEA (0.5 mL, 3.5 mmol) and TsCI (0.286 g, 1.5 mmol) at 0 °C and the reaction mixture was stirred for 3h. The reaction mixture was then diluted with water (100 mL) and extracted using DCM (50 mL x3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo and the crude product was purified by silica gel column chromatography (10-15% EtOAc-Hexane) to give 2-azidoethyl 4-methylbenzenesulfonate as a colorless semisolid (0.15 g, 54%). 1H NMR (400 MHz, DMSO) δ 7.83 (d, J= 8.4 Hz, 2H), 7.52 (d, J= 8.0 Hz, 2H), 4.17 (t, J= 4.8 Hz, 2H), 3.56 (t, J= 4.8 Hz, 2H), 2.52 (d, J= 1.6 Hz, 2H).

[00905] tert-butyl (2-((6-((2-aminoethoxy)methyl)pyridin yl)methoxy)ethyl) carbamate (Intermediate AF)

p-TsOH, 2,3-DHP ---------&#9658;

DCM

Pd(OH)2, H2 (gas) (Boc)2O, EtOH

TBAB, NaOH, H2O, toluene

AF

[00906] Step 1 - methyl 6-(((tetrahydro-2H-pyran yl)oxy)methyl)nicotinate

[00907] To a stirred solution of methyl 6-(hydroxymethyl)nicotinate (0.5 g, 3.0 mmol) in DCM (50 mL), was added p-TsOH (0.63 g, 3.3 mmol) at 0 °C followed by 3,4-dihydro-2//-pyran (0.9 mL, 9.0 mmol) at same temperature. The mixture was allowed to warm to rt then stirred for 16 h. The reaction mixture was diluted with water (50 mL) and product was extracted using DCM (50 mL x3). The combined organic layer was dried over anhydrous sodium sulphate and vacuum evaporated and the crude product was purified by silica gel column chromatography (0-1% MeOHDCM to give methyl 6-(((tetrahydro-2H-pyran yl)oxy)methyl)nicotinate as a yellow semi solid (0.7 g, 90%); LC-MS (ESC) m/z 252.3 (M+H)+.

[00908] Step 2 - (6-(((tetrahydro-2H-pyran yl)oxy)methyl)pyridin vljmethanol

[00909] To a stirred solution of methyl 6-(((tetrahydro-2H-pyran yl)oxy)methyl)nicotinate (0.7 g, 2.79 mmol) in THF (25 mL) was added IM lithium aluminum hydride in THF (7 mL, 7 mmol) dropwise at -70 °C and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was then quenched with water (100 mL), filtered through celite and the filtrate was extracted in ethyl acetate (100 mL x3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo and the crude product was purified by silica gel column chromatography (70-80% EtOAc-Hexane) to give (6-(((tetrahydro-2H-pyran-2yl)oxy)methyl)pyridin yl)methanol as a yellow semisolid (0.3 g, 48%); LC-MS (ESI+) m/z 224.25 (M+H)+.

[00910] Step 3 - 5-(bromomethyl) (((tetrahydro-2H-pyran yl)oxy)methyl)pyridine

[00911] To a stirred solution of (6-(((tetrahydro-2H-pyran yl)oxy)methyl)pyridin-3yl)methanol (0.3 g, 1.34 mmol) in DCM (10 mL) was added carbon tetrabromide (0.668 g, 2.02 mmol) and triphenylphosphine (0.334 g, 1.47 mmol) at 0 °C and the reaction mixture was stirred for 4 h. The reaction mixture was then diluted with water (50 mL) and product was extracted using DCM (50 mL x3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (50% EtOAc-Hexane) to give 5-(bromomethyl) (((tetrahydro-2H-pyran-2yl)oxy)methyl)pyridine as a yellow oil (0.05 g, 13%); LC-MS (ESI+) m/z 288.2 (M+H)+.

[00912] Step 4:5-((2-azidoethoxy)methyl) (((tetrahydro-2H-pyran-2vl)oxy)methyl)pyridine

[00913] To a stirred solution of 2-azidoethan-l-ol (0.8 g, 9.1 mmol, Intermediate AD) in DMF (10 mL) was added 60% NaH in oil (0.363 g, 9.09 mmol) at 0 °C followed by addition of a solution of 5-(bromomethyl) (((tetrahydro-2H-pyran yl)oxy)methyl)pyridine (1.3 g, 4.54 mmol) in DMF (5 mL) and the reaction was stirred for 15 min. The reaction mixture was then quenched with water (50 mL) and product was extracted in ethyl acetate (250 mL). The organic layer was washed with water (250 mL x3) and dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (50% EtOAc-Hexane) to give 5-((2-azidoethoxy)methyl) (((tetrahydro-2H-pyran yl)oxy)methyl)pyridine as a yellow oil (1.1g, 83%); LC-MS (ESI+) m/z 293.3 (M+H)+.

[00914] Step 5 - (5-((2-azidoethoxy)methyl)pyridin yl)methanol

[00915] To a stirred solution of 5-((2-azidoethoxy)methyl) (((tetrahydro-2H-pyran-2yl)oxy)methyl)pyridine (1.1 g, 3.8 mmol) in methanol (25 mL) was added p-TsOH (0.648 g, 3.76 mmol) at 0 °C and the reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was then concentrated, diluted with water (250 mL) and extracted in ethyl acetate (200 mL x3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography u(10%

MeOH-DCM) to give (5-((2-azidoethoxy)methyl)pyridin yl)methanol as a yellow semisolid (0.55 g, 70%); LC-MS (ESI+) m/z 209.2 (M+H)+.

[00916] Step 6 - tert-butyl (2-((6-(hydroxymethyl)pyridin yl)methoxy)ethyl)carbamate [00917] To a stirred solution of (5-((2-azidoethoxy)methyl)pyridin yl)methanol (0.55 g, 2.64 mmol) in ethanol (50 mL) was added Boc anhydride (0.91 mL, 3.96 mmol) and 20% Pd(OH)2/C (50% wet) (0.55 g) in autoclave at rt under hydrogen gas (20 kg/cm2 pressure) and the reaction was stirred for 6 h. The reaction mixture was then filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (7080% EtOAc-Hexane) to give tert-butyl (2-((6-(hydroxymethyl)pyri din-3yl)methoxy)ethyl)carbamate as a yellow semisolid (0.4 g, 54%); LC-MS (ESI+) m/z 283.3 (M+H)+. [00918] Step 7:tert-butyl(2-((6-((2-azidoethoxy)methyl)pyridin-3yl)methoxy)ethyl)carbamate

[00919] To a stirred solution of tert-butyl (2-((6-(hydroxymethyl)pyri din-3yl)methoxy)ethyl)carbamate (0.15 g, 0.53 mmol), 8N NaOH in water (2 mL) and TBAB in toluene (2 mL) was added 2-azidoethyl 4-methylbenzenesulfonate (3 mL, 18 mmols, Intermediate AE) and the mixture was refluxed for 48 h. The reaction mixture was then diluted with water (100 mL) and extracted using ethyl acetate (50 mL x3). The combined organic layer was dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. The crude product was purified by silica gel column chromatography (2% MeOH-DCM) to give tert-butyl (2-((6-((2azidoethoxy)methyl)pyridin yl)methoxy)ethyl)carbamate as a colorless oil (0.065 g, 35%); LCMS (ESI+) m/z 352.3 (M+H)+.

[00920] Step 8 - tert-butyl (2-((6-((2-aminoethoxy)methyl)pyridin yl)methoxy)ethyl) carbamate

[00921] To a stirred solution of tert-butyl (2-((6-((2-azidoethoxy)methyl)pyri din-3yl)methoxy)ethyl)carbamate (0.145 g) in ethanol (10 mL) was added 20% Pd(OH)2/C (50% wet) (0.14 g) in an autoclave at rt and the reaction mixture was stirred under hydrogen gas (20 kg/cm2 pressure) for 4 h. The reaction mixture was then filtered through celite and the filtrate was concentrated and evaporated in vacuo to give tert-butyl (2-((6-((2-aminoethoxy)methyl)pyridin-3yl)methoxy)ethyl)carbamate as a yellow semisolid (0.1 g, 74%); LC-MS (ESI+) m/z 326.5 (M+H)+.

[00922] (lR4&#1524;R) (6-(5-cvano-lH-Dvrazolo [3.,4-b] Dvridin-l-yl)-4636 (cvcloDroDvlamino)nicotinamido)cvclohexane-l-carboxylic acid (Intermediate AG)

LiOHH2O

THF, H2O

[00923] Step 1 - methyl (lR,4R) (6-(5-cyano-lH-pyrazolo[3,4-b1pyridin-l-yl)-4 (cy cl opropyl amino)ni coti nami do)cy cl ohexane-1 -carb oxyl ate

[00924] A stirred solution of 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotinic acid (0.3 g, 0.94 mmol, Intermediate L), methyl (lR,4R)-4 aminocyclohexane carboxylate hydrochloride (0.18 g, 0.94 mmol), HATU (0.54 g, 1.41 mmol) and DIPEA (0.54 mL, 1.41 mmol) in DMF (5 mL) was stirred at rt for 4 h. The reaction mixture was transferred then into ice water and the resulting precipitate was filtered off and dried under vacuum to give methyl (lR,4R) (6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylate as an off white solid (0.38 g, 88%). LC-MS (ESI+) m/z 460.2 (M+H)+.

[00925] Step 2:(lR,4R) (6-(5-cvano-lH-pvrazolor3,4-b1pvridin-l-yl)-4(cyclopropylamino)nicotinamido)cyclohexane-1 -carboxylic acid

[00926] To a stirred solution of methyl (lr,4r) (6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)4-(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylate (0.38 g, 0.82 mmol) in THF: water (1:1, 10 mL) was added lithium hydroxide monohydrate (0. Ilg, 2.48 mmol) at rt and the reaction mixture was stirred for 2 h. The reaction mixture was then transferred into ice water and the pH was adjusted to 5-6 using 10% citric acid solution. The resulting precipitate was filtered off and dried under vacuum to give (lR,4R) (6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylic acid as an off-white solid (0.25 g,

76%). LC-MS (ESI+) m/z 446.4 (M+H)+.

[00927] 3-(DIBENZYLAMINO) FLUORO-PROPAN-l-OL (INTERMEDIATE AH)

[00928] Step 1 - Methyl 2-(dibenzylamino) hydroxy-propanoate

[00929] To a mixture of methyl 2-amino hydroxy-propanoate (15.0 g, 96.4 mmol, HCI salt) and benzyl bromide (36.3 g, 212 mmol, 25.2 mL) in acetonitrile (200 mL) was added potassium carbonate (66.6 g, 482 mmol). The mixture was stirred at rt for 12 h. On completion, the reaction mixture was filtered and washed with acetonitrile. The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography to give the title compound (16.1 g, 56% yield) as a white solid. 1H NMR (400MHz, DMSO-A) δ 7.39 - 7.28 (m, 8H), 7.27 - 7.20 (m, 2H), 4.80 (dd, J = 4.8, 6.0 Hz, IH), 3.84 - 3.80 (m, 2H), 3.69 (s, 3H), 3.56 (d, J = 14.4Hz, 2H), 3.40 - 3.30 (m, 2H); LC-MS (ESI+) m/z 300.1 (M +H)+.

[00930] Step 2 - Methyl 3-(dibenzylamino) fluoro-propanoate

[00931] To a solution of methyl 2-(dibenzylamino) hydroxy-propanoate (5.00 g, 16.7 mmol) in THF (20.0 mL) was added a solution of DAST (3.23 g, 20.0 mmol, 2.65 mL) in 10 mL THF. The reaction mixture was stirred at rt for 1 h. On completion, the reaction mixture was quenched by the addition of ice-water (50 mL) followed by ethyl acetate (200 mL). The mixture was rapidly stirred and solid NaHCO3 was added until effervescence ceased .The layers were then separated and the aqueous layer was extracted with ethyl acetate (2 X 50 mL). The combined organic phase was washed with water (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (3.63 g, 72% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.42 - 7.25 (m, 10H), 5.19 - 5.01 (m, IH), 3.88 (d, J= 13.6 Hz, 2H), 3.77-3.71 (s, 3H), 3.57 (d, J= 13.6 Hz, 2H), 3.16-2.96 (m, 2H); LC-MS (ESI+) m/z 302.1(M +H)+.

[00932] Step 3 - 3-(Dibenzylamino) fluoro-propan-l-ol

[00933] To a solution of lithium borohydride (50.6 mg, 2.3 mmol) in THF (5 mL) was added a solution of methyl 3- (dibenzylamino) fluoro-propanoate (500 mg, 1.66 mmol) in THF (10 mL) at -15 °C under nitrogen. The reaction was allowed to warm to rt and was stirred for 4 h. On completion, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) drop wise, and then extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.70 g, 96% yield) as a white oil. 1HNMR (400MHz, CDCh) δ 7.44 - 7.28 (m, 10H), 4.76 - 4.58 (m, IH), 3.82 - 3.67 (m, 4H), 3.66 - 3.60 (m, 2H), 3.11 - 3.08 (m, IH), 2.90 - 2.84 (m, 2H); LC-MS (ESI+) m/z 274.1 (M +H)+.

[00934] Tert-butyl (2-(2-(2-(3-amin0 flu0r0Dr0D0xv)eth0xv)eth0xv)ethyl)carbamate (Intermediate

AI)

BocHN

&#1470;0‘

OH

MsCI, TEA

DCM

BocHN

NaH, DMF

BocHN^/^Ο^θ/γχ^Βη Pd/C, Pd(OH)2/C, H2

F Bn THF Al F

[00935] Step 1 - 2,2-Dimethyl oxo-3,8,ll-trioxa azatridecan yl methanesulfonate [00936] To a solution of tert-butyl A-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (4.00 g, 16.0 mmol, CAS# 139115 7) in dichloromethane (5 mL) was added triethylamine (3.25 g, 32.0 mmol) and MsCI (2.21 g, 19.2 mmol) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 1 . On completion, the reaction mixture was quenched with water (10 mL) and extracted with di chloromethane (3 X 100 mL). The combined organic layer was washed with brine (2 X 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (5.23 g, 99% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 4.94 (s, IH), 4.44 - 4.37 (m, 2H), 3.83 - 3.75 (m, 2H), 3.69 - 3.65 (m, 2H), 3.64 - 3.59 (m, 2H), 3.54 (t, J= 5.2 Hz, 2H), 3.36 - 3.29 (m, 2H), 3.08 (s, 3H), 1.45 (s, 9H).

[00937] Step 2 - Tert-butyl (2-benzyl fluoro-l-phenvl-6,9,12-trioxa azatetradecan yl)

[00938] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (3.64 g, 13.3 mmol,

Intermediate AH) in DMF (5 mL) was added sodium hydride (1.60 g, 39.5 mmol, 60% oil dispersion) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 1 h. Then, 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methane sulfonate (5.23 g, 15.9 mmol) was added. The resulting reaction mixture was stirred at rt for 3 h. On completion, the reaction mixture was quenched with saturated NH4C1 (20 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase flash column (0.1% NH3*H2O) to give the title compound (2.95 g, 44% yield) as a colorless oil. 1H NMR (400MHz, CDC13) δ 7.40 - 7.28 (m, 10H), 5.02 (s, IH), 4.89 - 4.70 (m, IH), 3.72 - 3.61 (m, 12H), 3.60 - 3.56 (m, 2H), 3.54 (t, J= 5.2 Hz, 2H), 3.31 - 3.18 (m, 2H), 2.82 - 2.69 (m, 2H), 1.46 (s, 9H); LC-MS (ESI)+m/z 505.2. (M+H)+.

[00939] Step 3 - Tert-butyl (2-(2-(2-(3-amino fluoropropoxy)ethoxy)ethoxy)ethyl)carbamate

[00940] To a solution of tert-butyl 7V-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy]ethyl] carbamate (2.90 g, 5.75 mmol) in THF (5 mL) was added Pd(OH)2/C (1.00 g, 10 wt %) and Pd/C (1.00 g, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas 3 times. The mixture was then stirred under hydrogen gas (50 psi pressure) at rt for 24 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.70 g, 91% yield) as a white gum. LC-MS (ESI)+m/z 325.1. (M+H)+.

[00941] Benzyl N- [2- [2- [2- [2-(2-hvdroxvethoxv)ethoxy] ethoxy] ethoxy] ethyl] carbamate (Intermediate A J)

HO

OH

NaOH, TsCI

THF H°^^O'^+&#1523;'O^/^O&#1523;+^&#1470;'O^+^OTs

HO. /^/0.0

DMF

Pd/C, H2 (gas)

EtOH H ν H 2

CbzCI, NaHCO3

CH3CN, h20

HO

AJ

NHCbz

[00942] Step 1 - 2-r2-r2-r2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethoxy1ethyl 4640 methylbenzenesulfonate

[00943] To a solution of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (3.50 g, 14.7 mmol, CAS# 4792 8) in tetrahydrofuran (30 mL) was added a solution of sodium hydroxide (763 mg, 19.1 mmol) in water (30 mL) at 0 °C. Then a solution of TsCI (2.80 g, 14.7 mmol) in tetrahydrofuran (90 mL) was added slowly dropwise at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 12 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with di chloromethane (3 X 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (5.20 g, 87% yield) as a yellowish oil. LC-MS (ESI+) m/z 393.0 (M+H)+.

[00944] Step 2 - 2-r2-r2-[2-(2-Azidoethoxy)ethoxy1ethoxy1ethoxy1ethanol

[00945] To a mixture of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl 4methylbenzenesulfonate (4.50 g, 11.5 mmol) in DMF (30 mL) was added sodium azide (1.86 g, 28.6 mmol). Then the reaction mixture was stirred at 80 °C for 12 h. On completion, the reaction mixture was diluted with water (30 mL) and extracted with a mixture of di chloromethane and methanol (10:1, 3 X 30 mL). The organic layer was concentrated in vacuo to give the title compound (3.00 g, 99% yield) as a yellowish oil. LC-MS (ESI+) m/z 264.1 (M+H)+.

[00946] Step 3 - 2-[2-[2-[2-(2-Aminoethoxy)ethoxy1ethoxy1ethoxy1ethanol

[00947] To a mixture of 2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethanol (3.00 g, 11.4 mmol) in ethanol (30 mL) was added Pd/C (1.00 g, 11.4 mmol, 5 wt %). Then the reaction mixture was stirred at rt for 48 hours under hydrogen gas (15 psi pressure). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (2.70 g, 100% yield) as a yellowish oil. LC-MS (ESI+) m/z 238.1 (M+H)+.

[00948] Step 4:Benzyl Ν-Γ2-[2-Γ2-Γ2-(2hydroxvethoxv)ethoxy1 ethoxy] ethoxy] ethyl 1 carb am ate

[00949] To a mixture of 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethanol (1.20 g, 5.06 mmol) in acetonitrile (10 mL) and water (10 mL) was added sodium bicarbonate (1.27 g, 15.1 mmol) and CbzCl (1.04 g, 6.07 mmol). Then the reaction mixture was stirred at 25 °C for 12 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 X 100 mL). Then the organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound (1.50 g, 70% yield) as white solid. LC-MS (ESI+) m/z 372.1

[00950] Tert-butyl

N-[2-[2-[2-[2-[2-(3-amino fluoroDropoxyjethoxy] ethoxy] ethoxy] ethoxy] ethyl] carbamate (Intermediate AK)

CbzH N

Pd(OH)2/C, H2 (gas)

AJ (Boc)2O, EtOAc

BocHN

OH

MsCI, TEA

BocHN

DCM o^°^o^o^OMs

NaH,DMF

BocHN

F Bn

Pd/C, Pd(OH)2/C, H2 (gas)

MeOH

F

AK

[00951] Step 1:Tert-butyl Ν-Γ2-[2-Γ2-Γ2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[00952] To a solution of benzyl N-[2-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (3.40 g, 9.15 mmol, Intermediate AJ) in ethyl acetate (35.0 mL) was added Pd(OH)2/C (1.00 g, 10 wt %) and (Boc)2O (3.00 g, 13.7 mmol, 3.15 mL). The reaction mixture was stirred under hydrogen gas (15 psi pressure) at rt for 16 h. On completion, the mixture was fdtered through a pad of celite and washed with ethyl acetate (2X5 mL). Then the fdtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (DCM: MeOH = 20: 1) to give the title compound (2.45 g, 79% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 5.34 (s, IH), 3.76 - 3.70 (m, 2H), 3.70 - 3.58 (m, 14H), 3.57 - 3.50 (m, 2H), 3.39 - 3.20 (m, 2H), 1.43 (s, 9H).

[00953] Step 2:2-[2-Γ2-Γ2-Γ2-(Τ61&#912;butoxycarbonylamino)ethoxy1ethoxy1ethoxy1ethoxy1ethylmethane sulfonate

[00954] To a solution of tert-butyl N-[2-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (2.45 g, 7.26 mmol) and triethylamine (1.47 g, 14.5 mmol) in DCM (15.0 mL) was added mesyl chloride (998 mg, 8.71 mmol) at 0 °C. Then the reaction mixture was allowed to warm to rt and stirred for 1 hr. On completion, the mixture was diluted with water (30 mL), extracted with DCM (3 X 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.88 g, 95% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 4.94 (s, IH), 4.34 - 4.28 (m, 2H), 3.72 - 3.67 (m, 2H), 3.61 - 3.54 (m, 12H), 3.47 (t, J = 5.2 Hz, 2H), 3.28 - 3.20 (m, 2H), 3.01 (s, 3H), 1.38 (s, 9H).

[00955] Step 3 Tert-butyl N-r2-r2-r2-r2-[2-r3-(dibenzylamino) fluoropropoxy1ethoxy1ethoxy1ethoxy1 ethoxy1ethyl1carbamate

[00956] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (0.50 g, 1.83 mmoL Intermediate AH) in DMF (5.00 mL) was added sodium hydride (219 mg, 5.49 mmol, 60% purity) at 0 °C. The mixture was stirred at 0 °C for 1 h, then 2-[2-[2-[2-[2(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy] ethylmethanesulfonate (912 mg, 2.20 mmol) was added to the reaction and the reaction mixture was allowed to warm to rt and stirred for 16 hrs. On completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (0.26 g, 22% yield) as a colorless oil. LC-MS (ESI+) m/z 593.4 (M+H)+.

[00957] Step 4:Tert-butyl N-r2-r2-r2-r2-r2-(3-amino fluoropropoxy)ethoxy1ethoxy1ethoxy1ethoxy1ethyl1 carbamate

[00958] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethyl]carbamate (1.66 g, 2.80 mmol) in methanol (8.00 mL) was added Pd(OH)2/C (0.50 g, 10 wt %) and Pd/C (0.50 g, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas 3 times. The mixture was stirred under hydrogen (50 psi pressure) at rt for 16 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (0.80 g, 69% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 5.06 (s, IH), 4.63 - 4.43 (m, IH), 3.66 - 3.54 (m, 18H), 3.47 (t, J =5.2 Hz, 2H), 3.28 - 3.19 (m, 2H), 2.93 - 2.83 (m, 2H), 1.37 (s, 9H).

[00959] 4-(Dibenzvlamino) fluoro-butan ol (Intermediate AL)

LiOH»H2O

THF, H2O

N&#1523;Bn 1 Bn

HCI

DIPEA, HATU, DMF

MeMgBr ,Bn NaBH4 I

--------&#9658; Ο γ N ---------&#9658; HO N'

THF &#941;η THF’ Me0H i Bn

AL

[00960] Step 1 - 3-(Dibenzvlamino) fluoro-propanoic acid

[00961] To a mixture of methyl 3-(dibenzylamino) fluoro-propanoate (15.0 g, 49.7 mmol, synthesized via Steps 1-2 of Intermediate AH) in THF (150 mL) and water (50 mL) was added LiOH*H2O (4.18 g, 99.5 mmol). The reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was acidified with HCI (2 M) until the pH = 5 ~ 6 and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FA condition) to give the title compound (13.4 g, 92% yield) as a light yellow gum. LC-MS (ESI+) m/z 288.0 (M+H)+.

[00962] Step 2 - 3-(Dibenzvlamino) fluoro-N-methoxv-N-methyl-propanamide

[00963] To a mixture of A'-methoxymethanamine (9.10 g, 93.2 mmol, HCI salt) in DMF (150 mL) was added DIPEA(36.1 g, 279 mmol), then 3-(dibenzylamino) fluoro-propanoic acid (13.4 g, 46.6 mmol) and HATU (35.4 g, 93.2 mmol). The reaction mixture was stirred at rt for 2.5 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (15.0 g, 94% yield) as a light yellow oil. LCMS (ESI+) m/z 331.1 (M+H)+.

[00964] Step 3 - 4-(Dibenzylamino) fluoro-butan one

[00965] To a mixture of 3-(dibenzylamino) fluoro-A-methoxy-A-methyl-propanamide (7.00 g, 21.1 mmol) in THF (80 mL) was added methyl magnesium bromide (3 M, 21.1 mL, 63.3mmol) at 0 °C. The reaction mixture was then warmed to rt and stirred for 2 h. On completion, the reaction mixture was quenched with slow addition of saturated ammonium chloride solution (30 mL) under stirring. The reaction mixture was then poured into 3 mL of water and extracted with ethyl acetate (3 X 80 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (4.40 g, 72% yield) as a light yellow solid. 1H NMR (400MHz, CDC13) δ 7.29 - 7.15 (m, 10H), 4.93 - 4.77 (m, IH), 3.72 (d, J= 13.6 Hz, 2H), 3.49 (d, J= 13.6 Hz, 2H), 2.95 - 2.84 (m, 2H), 2.02 (d, J= 4.0 Hz, 3H); LC-MS (ESI+) m/z 286.1 (M+H)+.

[00966] Step 4 - 4-(Dibenzylamino) fluoro-butan ol

[00967] To a mixture of 4-(dibenzylamino) fluoro-butan one (4.40 g, 15.4 mmol) in THF (40 mL) and methanol (20 mL) was added sodium borohydride (1.17 g, 30.8 mmol) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 1 hour. On completion, the reaction mixture was quenched with slow addition of sat. NH4C1 solution (4 mL) under stirring. The reaction mixture was concentrated in vacuo. The residue was then poured into (5 mL) of water and extracted with ethyl acetate (3X10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (4.30 g, 93% yield) as a colorless oil. LC-MS (ESI+) m/z 288.1 (M+H)+.

[00968] Tert-butyl N-[2-[2-[2-(3-amino fluoro-l-methylpropoxvlethoxy] ethoxy] ethyl] carbamate(Intermediate AM)

Pd(OH)2/C, Pd/C

H2 (gas), MeOH

AM

[00969] Step 1 - 2-r2-r2-(Tert-butoxycarbonylamino)ethoxy1ethoxy1ethyl methanesulfonate

[00970] To a mixture of tert-butyl 7V-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (2.00 g, 8.02 mmol, CAS# 139115 7) and triethylamine (2.44 g, 24.0 mmol) in DCM (20 mL) was added mesyl chloride (1.10 g, 9.63 mmol) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 2 h. On completion, the reaction mixture was poured into water (15 mL) and extracted with DCM (3 X 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.60 g, 98% yield) as a light yellow oil. 1H

NMR (400MHz, CDC13) δ 4.87 (s, IH), 4.35 - 4.29 (m, 2H), 3.73 - 3.66 (s, 2H), 3.63 - 3.52 (m, 4H), 3.50 - 3.43 (m, 2H), 3.30 - 3.20 (s, 2H), 3.01 (s, 3H), 1.38 (s, 9H).

[00971] Step 2 - Tert-butyl N-r2-r2-r2-r3-(dibenzylamino) fluoro-l-methylpropoxy1ethoxy1ethoxy1ethyl1 carbamate

[00972] To a mixture of 4-(dibenzylamino) fluoro-butan ol (1.60 g, 5.57 mmol, Intermediate AL) in DMF (20 mL) was added sodium hydride (668 mg, 16.7 mmol, 60% oil dispersion) at 0 °C and the reaction was stirred for 0.5 h. Then 2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (2.60 g, 7.94 mmol) was added. The reaction mixture was allowed to warm to rt and stirred C for 2 h. On completion, the reaction mixture was quenched with slow addition of water (3 mL) under stirring. The reaction mixture was then poured into water (20 mL) and extracted with ethyl acetate (4 X 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% NH3*H2O condition) to give the title compound (1.25 g, 41% yield) as a light yellow oil. LC-MS (ESI+) m/z 519.3 (M+H)+.

[00973] Step 3:Tert-butyl N-r2-r2-r2-(3-amino fluoro-l-methylpropoxy )ethoxy 1 ethoxy] ethyl 1 carb am ate

[00974] To a mixture of tert-butyl 7V-[2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethoxy] ethyl]carbamate (1.30 g, 2.51 mmol) in MeOH (10 mL) was added Pd(OH)2/C (470 mg, 10 wt %) and Pd/C (470 mg, 10 wt %) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 14 h. On completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (820 mg, 96% yield) as a colorless oil. LC-MS (ESI+) m/z 339.3 (M+H)+.

[00975] 2-[3-(dibenzvlamin0) flu0r0-l,l-dimethvl-Dr0D0xy]ethan01 (Intermediate AN)

MeMgBr

N'Bn

Rh(OAc)2, DCM

LiAIH4 &#1470;*--------THF

[00976] Step 1 - 4-(Dibenzylamino) fluoro methyl-butan ol

[00977] To a mixture of methyl 3-(dibenzylamino) fluoro-propanoate (15.0 g, 49.7 mmol, , synthesized via Steps 1-2 of Intermediate AH) in THF (250 mL) was added MeMgBr (3 M, 41.4 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at rt for 1 h. On completion, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) at 0 °C and extracted with ethyl acetate (2 X 50 mL). The organic layers were collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (15.0 g, 89% yield) as a yellow solid. LC-MS (ESI+) m/z 302.1 (M+H)+.

[00978] Step 2 - Ethyl 2-r3-(dibenzylamino) fluoro-Ll-dimethyl-propoxy1acetate

[00979] To a solution of 4-(dibenzylamino) fluoro methyl-butan ol (30.0 g, 99.5 mmol) in DCM (200 mL) was added Rh(OAc)2 (440 mg, 1.99 mmol) then ethyl 2-diazoacetate (34.0 g, 298 mmol) in DCM (100 mL) was added. The reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (11.7 g, 28% yield) as a colorless oil. LC-MS (ESI+) m/z 388.1 (M+H)+

[00980] Step 3 - 2-[3-(Dibenzylamino) fluoro-Ll-dimethyl-propoxy1ethanol

[00981] To a solution of ethyl 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]acetate (8.00 g, 20.6 mmol) in THF (220 mL) was added lithium aluminum hydride(1.20 g, 30.9 mmol, 98% purity) at 0 °C, then reaction mixture was allowed to warm to rt and stirred for 3 h. On completion, the reaction mixture was quenched with water (2 mL) and NaOH solution (15%, 6 mL) at 0 °C and the reaction mixture was filtered. The filtrate was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give the title compound (5.90 g, 81% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.44 - 7.22 (m, 10H), 4.64 - 4.46 (dd, J= 7.6, 48.8 Hz, IH), 3.82 (d, J= 13.6 Hz, 2H), 3.58 (d, J= 13.6 Hz, 2H), 3.53 - 3.48 (m, 2H), 3.44 - 3.31 (m, 2H), 2.99 - 2.82 (m, IH), 2.75 - 2.61 (m, IH), 1.72 ( s, IH), 1.13 (s, 3H), 1.09 (s, 3H).

[00982] 2- [2- [2- [2-(tert-butoxvcarbonvlamino)ethoxy] ethoxy] ethoxy] ethyl methanesulfonate(Intermediate AO)

HO

OH

H0^/0^^0/^0^N3

MsCI, TEA

BocHN

DCM

TsCI, Ag2O, KI

DCM (Boc)2O, Pd/C

H2 (gas), EtOAc

&#1470;0‘

HO'

BocHN .OMs

&#1470;0‘

OTs

NaN3

DMF

AO

[00983] Step 1 - 2-[2-[2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethyl 4-methylbenzenesulfonate

[00984] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (20.0 g, 103 mmol, CAS# 112 7) and potassium iodide (1.71 g, 10.3 mmol) in DCM (2 L) was added 4methylbenzenesulfonyl chloride (19.6 g, 103 mmol) and silver oxide (28.6 g, 124 mmol). The reaction mixture was stirred at rt for 17 h. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (25.1 g, 70% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.83 - 7.78 (m, 2H), 7.37 - 7.33 (m, 2H), 4.19 - 4.14 (m, 2H), 3.74 - 3.60 (m, 14H), 2.45 (s, 3H); LC-MS (ESI+) m/z 349.0 (M+H)+.

[00985] Step 2 - 2-[2-[2-(2-Azidoethoxy)ethoxy1ethoxy1ethanol

[00986] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4methylbenzenesulfonate (13.5 g, 38.8 mmol) in DMF (100 mL) was added sodium azide (5.04 g, 77.5 mmol) slowly. The reaction mixture was stirred at 80 °C for 18 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (200 ml), filtered and the filtrate was concentrated in vacuo to a half volume(50 mL). The crude product ethyl acetate solution was used in next step directly.

[00987] Step 3 - Tert-butyl N-[2-[2-[2-(2-hydroxyethoxy)ethoxy1ethoxy1ethyl1carbamate [00988] To a solution of 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol (15.0 g, 68.4 mmol) and (Boc)2O (74.7 g, 342 mmol) in ethyl acetate (300 mL) was added Pd/C (5 g, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The reaction mixture was stirred under hydrogen gas (15 Psi pressure) at rt for 18 h. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, DCM/MeOH = 10/1) to give the title compound (5.1 g, 25% yield) as a light yellow oil. 1H NMR (400MHz, CDC13) δ 5.67 (s, IH), 3.78 - 3.72 (m, 4H), 3.69 3.63 (m, 8H), 3.55 (t, J = 4.8 Hz, 2H), 3.34 (d, J= 4.8 Hz, 2H), 3.07 (s, IH), 1.46 (s, 9H).

[00989] Step 4 - 2-r2-r2-r2-(tert-butoxvcarbonvlamino)ethoxy1ethoxy1ethoxy1ethyl methanesulfonate

[00990] To a solution of tert-butyl N-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (3.0 g, 10.2 mmol) and triethylamine (2.07 g, 2.77 mL, 20.5 mmol) in DCM (30 mL) was added mesyl chloride (1.41 g, 12.3 mmol) at 0 °C. The reaction mixture was stirred at rt for 17 h. On completion, the mixture was quenched with water (30 mL) and extracted with DCM (2 X 30 mL). The organic layer was washed with sat.NaHCO3 (40 mL), then washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (3.6 g, 95% yield) as a light yellow oil. 1H NMR (400MHz, CDC13) δ 5.05 (s, IH), 4.43 - 4.39 (m, 2H), 3.82 - 3.78 (m, 2H), 3.71-3.69 (m, 2H), 3.69 - 3.67 (m, 2H), 3.67 - 3.62 (m, 4H), 3.56 (t, J = 4.8 Hz, 2H), 3.34 (q, J= 4.8 Hz, 2H), 3.10 (s, 3H), 1.46 (s, 9H).

[00991] Tert-butyl N- [2- [2- [2- [2- [2-(3-amino fluoro-1,1-dimethylpropoxylethoxy] ethoxy] ethoxy]ethoxy] ethyl] carbamate(Intermediate AP)

Pd(OH)2/C, Pd/C, H2 (gas)

MeOH, ΝΗ3.Η2Ο

BocHN

NH2

AP

[00992] Step 1 - Tert-butyl N-r2-r2-r2-r2-[2-r3-(dibenzylamino) fluoro-L 1-dimethylpropoxy]ethoxy]ethoxy] ethoxy1ethoxy1ethyl1carbamate

[00993] To a mixture of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethanol (1.50 g, 4.34 mmol, Intermediate AN) in DMF (10 mL) was added sodium hydride (521 mg, 13.0 mmol, 60% oil dispersion) at 0 °C for 0.5 h. Then the 2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (2.42 g, 6.51 mmol, Intermediate AO) was added. The reaction mixture was allowed to warm to rt and stirred for 6 hours. On completion, the reaction mixture was quenched with slow addition of water (10 mL) under stirring. The mixture was extracted with DCM (3 X 20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% NH3*H2O condition) to give the title compound (1.10 g, 39% yield) as a light yellow oil. LC-MS (ESI+) m/z 621.5 (M+H)+.

[00994] Step 2 - Tert-butyl N-r2-r2-r2-r2-r2-(3-amino fluoro-Ll-dimethylpropoxy)ethoxy1ethoxy1ethoxy1 ethoxy1ethyl]carbamate

[00995] To a mixture of tert-butyl N-[2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.10 g, 1.77 mmol) in methanol (10 mL) was added Pd(OH)2/C (600 mg, 10 wt %), Pd/C (600 mg, 10 wt %) and ΝΗ3&#905;2Ο (455 mg, 12.9 mmol, 500 uL) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 15 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (750 mg, 96% yield) as a light yellow oil. LC-MS (ESI+) m/z 441.3 (M+H)+.

[00996] 2-[2-(2-Bromoethoxv)ethyl]isoindoline-l.,3-dione (Intermediate AQ)

AQ

[00997] A solution of (l,3-dioxoisoindolin yl)potassium (10.0 g, 53.9 mmol) and 1-bromo2-(2- bromoethoxy)ethane (37.5 g, 161 mmol) in acetone (250 mL) was stirred at 60 °C for 12 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (12.0 g, 74% yield) as a white solid. 1HNMR (400MHz. CDC13) δ 7.91 - 7.84 (m, 2H), 7.77 - 7.72 (m, 2H), 3.96 - 3.90 (m, 2H), 3.84 - 3 77 (m, 4H), 3.42 (t, J 6.0 Hz, 2H).

[00998] Tert-butvlN-[2-[2-[2-(3-amino fluoro-l,l-dimethylDropoxy)ethoxy] ethoxy] ethyl] carbamate (Intermediate AR)

AN

ΝΗ2ΝΗ2.Η2Ο

EtOH

Pd(OH)2/C, Pd/C

ΝΗ3.Η2Ο, MeOH

[00999] Step 1:2-Γ2-Γ2-Γ2-Γ3 -(Dibenzylamino) fluoro-1,1 -dimethyl propoxy]ethoxy]ethoxy]ethyl]iso indoline-L3-dione

[001000] To a solution of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethanol (2.00 g, 5.79 mmol, Intermediate AN) in DMF (35 mL) was added sodium hydride (694 mg, 17.3 mmol, 60% oil dispersion) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, and then 2[2-(2-bromoethoxy)ethyl]isoindoline-l,3-dione (2.76 g, 9.26 mmol, Intermediate AQ) was added and the reaction mixture was stirred allowed to warm to rt and stirred for 17 h. On completion, the reaction mixture was quenched with water (1 mL) at 0°C, and then concentrated in vacuo to give the product (5.00 g) as yellow oil. LC-MS (ESI)+ m/z 563.2. (M+H)+.

[001001] Step 2 - 3-r2-r2-(2-Aminoethoxy)ethoxy]ethoxy]-N,N-dibenzyl fluoro-3m ethyl-butan-1 -amine

[001002] To a solution of 2-[2-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethoxy]ethyl] isoindoline-1,3-dione (5.00 g, 8.89 mmol) in EtOH (40 mL) was added hydrazine (2.27 g, 44.4 mmol, 98% purity) and the reaction mixture was stirred at 80 °C for 38 h. On completion, the reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound (2.50 g) as a yellow oil. LC-MS (ESI)+ m/z 433.1. (M+H)+.

[001003] Step 3 - Tert-butyl N-r2-r2-r2-r3-(dibenzylamino) fluoro-Ll-dimethylpropoxy]ethoxy]ethoxy] ethyl]carbamate

[001004] To a solution of 3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-N,N-dibenzyl fluoro-3methyl-butan amine (2.50 g, 5.78 mmol, crude) in DCM (30 mL) was added (Boc)2O (2.52 g,

11.56 mmol) and the reaction mixture was stirred at rt for 3 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (950 mg, 30% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.42 (d, J= 7.2 Hz 4H), 7.31 (t, J= 7.2 Hz, 4H), 7.26 - 7.19 (m, 2H), 5.01 (s, IH), 4.64 (dd, J = 8.0, 49.2 Hz, IH), 3.75 (d, J = 13.6 Hz, 2H), 3.60 (d, J = 13.6 Hz, 2H), 3.57 3.38 (m, 10H), 3.31 (d, J = 3.6 Hz, 2H), 2.98 - 2.80 (m, IH), 2.79 - 2.65 (m, IH), 1.45 (s, 9H), 1.10 (d, J= 8.8 Hz, 6H); LC-MS (ESI)+ m/z 533.4. (M+H)+.

[001005] Step 4:Tert-butylN-r2-r2-r2-(3-amino fluoro-LI-dimethylpropoxy)ethoxy1ethoxy1ethyl1 carbamate

[001006] To a solution of tert-butyl N-[2-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy] ethoxy] ethylcarbamate (950 mg, 1.78 mmol) in MeOH (20 mL) was added Pd(OH)2/C (500 mg, 10 wt %), Pd/C (500 mg, 10 wt %) and ΝΗ3.Η2Ο (1.92 g, 20.7 mmol, 38 wt %) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen gas three times. The reaction mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 55 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (550 mg, 88% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ = 5.51 ( s, IH), 4.32 - 4.15 (m, IH), 3.67 - 3.57 (m, 8H), 3.54 (t, J = 5.2 Hz, 2H), 3.36 - 3.28 (m, 2H), 3.07 - 2.96 (m, IH), 2.95 - 2.85 (m, IH), 1.45 (s, 9H), 1.23 (dd, J= 1.6, 10 Hz, 6H); LC-MS (ESI)+ m/z 353.2. (M+H)+.

[001007] Tert-butyl N-[2-[2-[2-[2-[2-(3-amino fluoro-l-methylDropoxvlethoxy] ethoxy] ethoxy]ethoxy] ethyl] carbamate(Intermediate AS)

NaH, DMF F Bn

Pd(OH)2/C, Pd/C, H2 (gas)

AS

ΝΗ3.Η2Ο, MeOH

[001008] Step 1 -Tert-butyl N-r2-r2-r2-r2-r2-r3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethoxy] ethoxylethoxylethyllcarbamate

[001009] To a solution of 4-(dibenzylamino) fluoro-butan ol (968 mg, 3.37 mmol, Intermediate AL) in DMF (20 mL) was added NaH (404 mg, 10.1 mmol, 60% dispersion in mineral oil) and the reaction mixture was stirred at rt for 30 min. Then 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (2.10 g, 5.05 mmol, synthesized via Steps 1-2 of Intermediate AK) was added into the mixture and the reaction was stirred at rt for 12 h. On completion, the reaction mixture was quenched by addition H2O (20 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (0.1% ΝΗ3&#905;2Ο condition) to give the title compound (640 mg, 25% yield) as a yellow oil. LC-MS (ESI+) m/z 607.3 (M+H)+.

[001010] Step 2-Tert-butyl N-[2-[2-[2-[2-[2-(3 -amino fluoro-1 -methylpropoxy)ethoxv1ethoxv1ethoxv1 ethoxy1ethyl1carbamate

[001011] To a mixture of tert-butyl 7V-[2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethyl]carbamate (840 mg, 1.38 mmol) in MeOH (20 mL) and ΝΗ3&#905;2Ο (1 mL) was added Pd(OH)2/C (300 mg, 10 wt %) and Pd/C (300 mg, 10 wt %). The reaction mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 12 h. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (540 mg, 91% yield) as a colorless oil. LC-MS (ESI+) m/z 427.2 (M+H)+.

[001012] Tert-butyl N-i3-[3-(3-amino fluoro-l,l-dimethylpropoxv)propoxy]propyl]carbamate (Intermediate AT)

LiOH

THF, H2O

TMSCH2N2

THF, CH3CN

Ag2O

MeOH (COCI)2

DMF, DCM

LiAIH4

THF

(Boc)2O

DCM

Pd/C, Pd(OH)2/C

MeOH, NH3.H2O F

AT

[001013] Step 1 r3-(dibenzvlamino) fluoro-Ll-dimethyl-propoxv1acetic acid

[001014] To a solution of ethyl 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]acetate (5.00 g, 12.9 mmol, synthesized via Steps 1-2 of Intermediate AN) in THF (50.0 mL) and H2O (30.0 mL) was added LiOH (1.24 g, 51.6 mmol) and the reaction mixture was stirred at rt for 6 h. On completion, the mixture was concentrated and acidified with 5 N HCI (1 mL) until pH = 5 and was then concentrated in vacuo again. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (3.50 g, 64% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 7.50-7.31 (m, 1 OH), 4.64 - 4.44 (m, IH), 4.06 - 3.96 (m, 6H), 3.07 - 2.77 (m, 2H), 1.10 (s, 3H), 1.07 (s, 3H)

[001015] Step 2 - 2-[3-(dibenzvlamino) fluoro-Ll-dimethvl-propoxv1acetvl chloride [001016] To a solution of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]acetic acid (2.00 g, 5.56 mmol) in DCM (40.0 mL) was added DMF (4.07 mg, 55.6 umol, 4.28 uL) and (COC1)2 (2.12 g, 16.6 mmol, 1.46 mL) at 0 °C, then reaction mixture was allowed to warm to rt and stirred for 3 h. On completion, the mixture was concentrated in vacuo to give the title compound (2.00 g, 98% yield) as a light yellow oil. LC-MS (ESI+) m/z 388.2 (M +H)+ (+OEt from quench with ethanol).

[001017] Step 3 - l-diazo r3-(dibenzylamino) fluoro-Ll-dimethyl-propoxy1propan-2one

[001018] To a solution of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]acetyl chloride (3.40 g, 9.00 mmol) in THF (20.0 mL) and ACN (20.0 mL) was dropwise added TMSCHN2 (2 M, 9.00 mL) at 0 °C. Then the reaction mixture was allowed to warm to rt and stirred for 19 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE: EA= 5: 1) to give the title compound (2.30 g, 65% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.46 - 7.21 (m, 10H), 5.08 (s, IH), 4.61 - 4.45 (m, IH), 3.92 - 3.80 (m, 4H), 3.60 - 3.50 (m, 2H), 3.00 - 2.62 (m, 2H), 1.13 (s, 3H), 1.10 (s, 3H)

[001019] Step 4 - Methyl 3-r3-(dibenzylamino) fluoro-Ll-dimethyl-propoxy1propanoate [001020] To a solution of 1-diazo [3-(dibenzylamino) fluoro-1,1-dimethylpropoxy]propan one (2.00 g, 5.22 mmol) in MeOH (30 mL) was added Ag2O (120 mg, 521 umol) and the reaction mixture was stirred at 50 °C for 16 h. On completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 5: 1) to give the title compound (1.10 g, 48% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.43 - 7.20 (m, 10H), 4.61 - 4.42 (m, IH), 3.81 - 3.73 (m, 2H), 3.66 (s, 3H), 3.63 - 3.49 (m, 4H), 2.94 - 2.63 (m, 2H), 2.40 - 2.36 (m, 2H), 1.11 (s, 3H), 1.08 (s, 3H)

[001021] Step 5 - 3-r3-(dibenzylamino) fluoro-Ll-dimethyl-propoxy1propan-l-ol

[001022] To a solution of methyl 3-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]propanoate (900 mg, 2.32 mmol) in THF (15.0 mL) was added LiAlH4 (116 mg, 3.02 mmol, 98% purity) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to rt and stirred for 1 hr. On completion, the mixture was quenched with water (1 mL) and 15 % NaOH (1.5 mL) at 0 °C. The mixture was then filtered, dried over Na2SO4, filtered again and concentrated in vacuo to give the title compound (800 mg, 90% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.42 - 7.21 (m, 10H), 4.64 - 4.45 (m, IH), 3.82 - 3.77 (m, 2H), 3.66 - 3.56 (m, 4H), 3.55 - 3.41 (m, 2H), 2.96 - 2.63 (m, 2H), 2.28 (s, IH), 1.68 - 1.62 (m, 2H), 1.11 (s, 3H), 1.09 (s, 3H).

[001023] Step 6:3 -[3 -[3 -(dibenzylamino) fluoro-1,1 -dimethylpropoxylpropoxylpropanenitrile

[001024] To a mixture of 3-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]propan-l-ol (560 mg, 1.56 mmol) and prop enenitrile (1.60 g, 30.1 mmol, 2.00 mL) was added NaOMe (841 ug, 15.5 umol), and the reaction mixture was stirred at rt for 50 h. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 5: 1) to give the title compound (550 mg, 83% yield) as a colorless oil. 1H NMR. (400MHz, CDC13) δ 7.43 - 7.20 (m, 10H), 4.64 - 4.43 (m, IH), 3.80 - 3.77 (m, 2H), 3.66 - 3.52 (m, 4H), 3.44 - 3.28 (m, 4H), 3.00 - 2.62 (m, 2H), 2.56 - 2.53 (m, 2H), 1.70 - 1.60 (m, 2H), 1.11 (s, 3H), 1.07 (s, 3H).

[001025] Step 7 - 3-r3-(3-aminopropoxy)propoxy1-N,N-dibenzyl fluoro methyl-butanμ

[001026] A solution of BH3-Me2S (10 M, 145 uL) in THF (20.0 mL) was added to a solution of 3-[3-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]propoxy]propanenitrile (300 mg, 727 umol) in THF (5.00 mL) at 0 °C and stirred for 30 min. Then the reaction mixture was heated to 70 °C and stirred for 16 h. On completion, the mixture was quenched with MeOH (3 mL) and concentrated in vacuo to give the title compound (300 mg, 65% yield) as yellow oil. LC-MS (ESI+) m/z 417.4 (M+H)+.

[001027] Step 8 - Tert-butyl N-r3-r3-r3-(dibenzylamino) fluoro-Ll-dimethylpropoxy1propoxy1propyl1 carbamate

[001028] To a solution of 3-[3-(3-aminopropoxy)propoxy]-N,N-dibenzyl fluoro methylbutan-l-amine (300 mg, 720 umol) in DCM (5.00 mL) was added (Boc)2O (314 mg, 1.44 mmol, 330 uL) and the reaction mixture was stirred at rt for 2 h. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (180 mg, 45% yield) as a yellow solid. LCMS (M+l)+: 517.3. [001029] Step 9:Tert-butyl N-r3-[3-(3-amino fluoro-Ll-dimethylpropoxy )propoxy1propyl1carbamate

[001030] To a solution of tert-butyl N-[3-[3-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]propoxy] propyl]carbamate (180 mg, 348 umol) andNH3*H2O (151 mg, 1.30 mmol, 166 uL, 30 wt %) in MeOH (5.00 mL) was added Pd/C (90.0 mg, 348 umol, 10 wt %) and Pd(OH)2/C (90.0 mg, 348 umol, 10 wt %) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The reaction mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 16 h. On completion, the mixture was filtered and the filtrate concentrated in vacuo to give the title compound (70.0 mg, 59 % yield) as a yellow oil. LC-MS (ESI+) m/z 337.2 (M +H)+

[001031] Tert-butyl

N-[2-[2-(3-amino fluoro-l,l-dimethylpropoxv)ethoxy] ethyl] carbamate (Intermediate AU)

ΝΗ2ΝΗ2.Η2Ο

EtOH

(Boc)2O DCM

BocHN

F Bn

Pd(0H)2/C, Pd/C ___ η ___X

--------------&#9658; BocHN 0 &#1498;< NH2

MeOH, ΝΗ3.Η2Ο p

AU

[001032] STEP 1 - ETHYL 2&#1470;r2-[3-(DIBENZYLAMINO) FLUORO-Ll-DIMETHYLPROPOXY1ETHOXY1ACETATE

[001033] To a solution of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethanol (4.00 g, 11.6 mmol> Intermediate AN) and Rh(OAc)2 (128 mg, 579 umol) in DCM (80 mL) was added a solution of ethyl 2-diazoacetate (3.96 g, 34.7 mmol) in DCM (40 mL) dropwise at rt. The reaction mixture was stirred at rt for 20 h. On completion, the reaction mixture was diluted with H2O (60 mL) and extracted with DCM (2 X 50 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4.63 g, 93% yield) as a yellow oil. LC-MS (ESI+) m/z 432.2 (M+H)+.

[001034] Step 2 - 2-r2-r3-(Dibenzylamino) fluoro-Ll-dimethyl-propoxy1ethoxy1ethanol

[001035] To a mixture of LiAlH4 (611 mg, 16.1 mmol) in THF (20 mL) was added a solution of ethyl 2-[2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethoxy]acetate (4.63 g, 10.7 mmol) in THF (40 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. On completion, the reaction mixture was quenched with H2O (0.55 mL) at 0°C. Then 15% NaOH solution (1.5 mL) was added to the reaction mixture. The mixture was fdtered and the fdtrate was concentrated in vacuo to give the title compound (3.53 g, 84% yield) as a yellow oil.

[001036] Step 3 - 2-r2-[3-(Dibenzylamino) fluoro-Ll-dimethyl-propoxy1ethoxy1ethyl methanesulfonate

[001037] To a solution of 2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethanol (3.53 g, 9.06 mmol) and TEA (2.29 g, 22.7 mmol) in DCM (35 mL) was added MsCl (1.56 g, 13.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at rt for 1 hour. On completion, the mixture was quenched with H2O (30 mL) and extracted with DCM (2 X 30 mL). The organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4.50 g, 100% yield) as a yellow oil. 1HNMR (400MHz, CDCh) δ 7.44 - 7.24 (m, 10H), 4.63 - 4.46 (m, IH), 4.35 - 4.30 (m, 2H), 3.81-3.75 (m, 2H), 3.68 - 3.64 (m, 2H), 3.63 - 3.59 (m, 2H), 3.54 - 3.39 (m, 4H), 3.04 (s, 3H), 2.96 - 2.67 (m, 2H), 1.11 (s, 6H).

[001038] Step 4:2-Γ2-Γ2-Γ3 -(Dibenzylamino) fluoro-1,1 -dimethylpropoxy1ethoxy1ethyl1isoindoline-L3- dione

[001039] To a solution of 2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethyl methane sulfonate (4.50 g, 9.62 mmol) in DMF (45 mL) was added (1,3dioxoisoindolin yl)potassium (2.67 g, 14.4 mmol). The reaction mixture was stirred at 80 °C for 3 h. On completion, the mixture was diluted with H2O (30 mL) and extracted with EtOAc (3 X 40 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (5.90 g, 96% yield) as a yellowish oil. LC-MS (ESE) 519.3 2/&#1524; (M+H)+.

[001040] Step 5 - 3-r2-(2-Aminoethoxy)ethoxy1-N,N-dibenzyl fluoro methyl-butan-lamine

[001041] To a solution of 2-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethyl]isoindoline -1,3-dione (4.99 g, 9.62 mmol) in EtOH (60 mL) was added ΝΗ2ΝΗ2&#905;2Ο (2.41 g, 48.1 mmol). The reaction mixture was stirred at 80 °C for 15 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove solvent. The residue was diluted with DCM (30 mL), filtered and the filtrate was concentrated in vacuo to give the title compound (3.74 g, 100% yield) as a yellow oil. LC-MS (ESI+) m/z 389.2 (M+H)+.

[001042] Step 6 - Tert-butyl N-r2-r2-r3-(dibenzylamino) fluoro-Ll-dimethylpropoxy1ethoxy1ethyl1 carbamate

[001043] To a solution of 3-[2-(2-aminoethoxy)ethoxy]-N,N-dibenzyl fluoro methylbutan-l-amine (3.74 g, 9.63 mmol) in DCM (40 mL) was added (Boc)2O (4.20 g, 19.3 mmol). The reaction mixture was stirred at rt for 3 hours. On completion, the reaction mixture was concentrated in vacuo to remove solvent. The residue was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (3.10 g, 66% yield) as a yellow oil. LC-MS (ESI+) m/z 489.1 (M+H)+.

[001044] Step 7:Tert-butyl N-[2-r2-(3-amino fluoro-Ll-dimethylpropoxy)ethoxy1ethyl1carbamate

[001045] To a solution of tert-butyl N-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethyl] carbamate (3.10 g, 6.34 mmol) in MeOH (30 mL) was added Pd/C (1.5 g, 10 wt %), Pd(OH)2/C (1.5 g, 10 wt %) and ΝΗ3&#905;2Ο (910 mg, 6.49 mmol, 25 wt %). The reaction mixture was stirred at rt for 17 h under hydrogen atmosphere (15 psi pressure). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.82 g, 93% yield) as a yellow oil. LC-MS (ESI+) m/z 309.1 (M+H)+.

[001046] Tert-butyl N- [2-[2-(3-amin0 flu0r0-Dr0D0xy)eth0xy] ethyl] carbamate (Intermediate AV)

Pd(OH)2/C, Pd/C, H2 (gas) θ

---------------------&#9658; BocH N O &#1523;&#1498;^ N H2 MeOH,NH3&#1524;H2O F

AV

[001047] Step 1 - 2-r2-[2-r3-(Dibenzylamino) fluoro-propoxy1ethoxy1ethyl1isoindoline1,3-di one

[001048] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (1.00 g, 3.66 mmoL Intermediate AH) in DMF (15.0 mL) was added NaH (439 mg, 10.9 mmol, 60% dispersion in mineral oil) under 0 °C and the mixture was stirred at 0 °C for 30 minutes. Then 2-(2-(2bromoethoxy)ethyl]isoindoline-l,3-dione (1.64 g, 5.49 mmol, Intermediate AQ) was added and the mixture was allowed to warm to rt and stirred 4 h. On completion, the mixture was quenched with H2O (1 mL) and concentrated in vacuo to give the title compound (1.79 g, 80% yield) as yellow solid. LC-MS (ESI+) m/z 491.3 (M+H)+.

[001049] Step 2 - 3-[2-(2-Aminoethoxy)ethoxy1-N,N-dibenzyl fluoro-propan-l-amine [001050] To a solution of 2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethyl]isoindoline-l,3-dione (2.68 g, 5.46 mmol) in EtOH (30.0 mL) was added N2H4 H2O (5.58 g, 109 mmol, 5.42 mL, 98% purity). The reaction mixture was stirred at 80 °C for 40 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The solid was diluted with DCM(50 mL) and stirred for 15 minutes, filtered, and the organic layer was concentrated in vacuo to give the title compound (1.97 g, 80% yield) as a yellow oil. LC-MS (ESI+) m/z 361.2 (M+H)+.

[001051] Step 3:Tert-butyl N-r2-[2-r3-(dibenzylamino) fluoropropoxy1ethoxy1ethyl1carbamate

[001052] To a solution of 3-[2-(2-aminoethoxy)ethoxy]-N,N-dibenzyl fluoro-propan-lamine (1.97 g, 5.47 mmol) in DCM (20.0 mL) was added (Boc)2O (2.39 g, 10.9 mmol, 2.51 mL) and the reaction mixture was stirred at rt for 16 hours. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (930 mg, 36% yield) as a yellow oil. LC-MS (ESI+) m/z 461.2 (M+H)+.

[001053] Step 4 - Tert-butyl N-[2-[2-(3-amino fluoro-propoxy)ethoxy1ethyl1carbamate [001054] To a solution of tert-butyl N-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethyl]carbamate (930 mg, 2.02 mmol) in MeOH (10.0 mL) and NH3.H2O (200 uL) was added Pd/C (500 mg, 10 wt %) and Pd(OH)2/C (500 mg, 10 wt %) under nitrogen atmosphere. The suspension was degassed in vacuo and purged with hydrogen gas several times. The mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 16 hours. On completion, the mixture was filtered and concentrated in vacuo to give the title compound (560 mg, 98% yield) as a yellow oil. LC-MS (ESI+) m/z 281.1 (M+H)+.

[001055] Tert-butyl N-[2-(3-amin0 flu0r0-l,l-dimethvl-Dr0D0xv)ethyl]carbamate (Intermediate AW) o

AN

(Boc)2O

MeOH

F Bn

Pd(OH)2/C, Pd/C

ΝΗ3.Η2Ο, MeOH

Ν2Η4Η2Ο

EtOH

AW

[001056] Step 1 methanesulfonate

2- [3 -(Dibenzyl amino) fluoro-1,1 -dimethyl-propoxy] ethyl

[001057] To a mixture of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethanol (1.50 g, 4.34 mmol, Intermediate AN) and Et3N (1.32 g, 13.0 mmol, 1.81 mL) in DCM (10 mL) was added MsCl (746 mg, 6.51 mmol). The mixture was stirred at rt for 2 hours. On completion, the mixture was quenched with water (15 mL) and extracted with DCM (2 X 20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the title compound (1.90 g, 98% yield) as a yellow oil. LC-MS (ESI+) m/z 424.2 (M+H)+.

[001058] Step 2:2-Γ2-Γ3 -(Dibenzylamino) fluoro-1,1 -dimethylpropoxy1ethyl1isoindoline-L3[001059] To a solution of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethyl methanesulfonate (1.70 g, 4.01 mmol) in DMF (20 mL) was added (l,3-dioxoisoindolin yl) potassium (817 mg, 4.42 mmol). The mixture was heated at 60 °C for 16 hours. On completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (2 X 50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the title compound (1.90 g, 99% yield) as a yellow oil. LC-MS (ESI+) m/z 475.2 (M+H)+.

[001060] Step 3 - 3-(2-Aminoethoxy)-N,N-dibenzyl fluoro methyl-butan-l-amine

[001061] To a solution of 2-[2-[3-(dibenzylamino) fluoro-l, 1-dimethylpropoxy]ethyl]isoindoline-l,3-dione (1.90 g, 4.00 mmol) in EtOH (20 mL) was added ΝΗ2ΝΗ2&#905;2Ο (2.05 g, 40.0 mmol, 1.99 mL, 98% purity). The reaction mixture was stirred at 80 °C for 16 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.50 g, crude) as a white solid. LC-MS (ESI+) m/z 345.2 (M+H)+.

[001062] Step 4 - Tert-butyl N-r2-r3-(dibenzylamino) fluoro-Ll-dimethyl-propoxy1ethyl1 [001063] To a solution of 3-(2-aminoethoxy)-N,N-dibenzyl fluoro methyl-butan-lamine (1.00 g, 2.90 mmol) in MeOH (10 mL) was added (Boc)2O (1.27 g, 5.81 mmol). The mixture was stirred at rt for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (1.29 g, 90% yield). 1H NMR (400MHz, CDC13) δ 7.44 - 7.22 (m, 10H), 4.66 - 4.41 (m, 2H), 3.82 (d, J= 13.6 Hz, 2H), 3.60 (d, J = 13.6 Hz, 2H), 3.41 - 3.24 (m, 2H), 3.18 - 3.00 (m, 2H), 2.99 - 2.81 (m, IH), 2.77 - 2.61 (m, IH), 1.47 (s, 9H), 1.13-1.06 (m, 6H); LC-MS (ESI+) m/z 445.3 (M+H)+.

[001064] Step 5 - Tert-butyl N-r2-(3-amino fluoro-Ll-dimethyl-propoxy)ethyl1carbamate

[001065] To a solution of tert-butyl N-[2-[3-(dibenzylamino) fluoro-1,1-dimethylpropoxy]ethyl]carbamate (1.3 g, 2.9 mmol) in MeOH (15 mL) was added Pd/C (0.5 g, 10 wt %), Pd(OH)2/C (0.5 g, 10 wt %) and ΝΗ3&#905;2Ο (100 uL, 30 wt %, catalytic amount). The mixture was degassed and purged with hydrogen gas three times. The mixture was stirred at rt for 24 hours under hydrogen gas (50 psi pressure). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (700 mg, 90% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.93 (s, IH), 3.57 - 3.43 (m, 2H), 3.38 - 3.19 (m, 2H), 3.13 - 2.91 (m, 2H), 2.38 - 2.30 (m, 2H), 1.46 (s, 9H), 1.22 (dd, J= 1.2, 10.6 Hz, 6H); LC-MS (ESI+) m/z 265.1 (M+H)+.

[001066] Tert-butyl N-[2-(3-amin0 flu0r0-Dr0D0xv)ethyl]carbamate (Intermediate

AX)

nh2nh2&#1470;h2o

EtOH

F Bn (Boc)2O DCM

F Bn ,Bn

Pd(OH)2/C, Pd/C, H2 (gas)

MeOH, ΝΗ3.Η2Ο

BocHN^/0.

NH2

F

AX

[001067] Step 1 - Ethyl 2-r3-(dibenzvlamino) fluoro-propoxv1acetate

[001068] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (5.00 g, 18.2 mmoL Intermediate AH) in DCM (100 mL) was added [Rh(OAc)2]2 (80.8 mg, 365 umol) in DCM (50.0 mL) then and ethyl 2-diazoacetate (6.26 g, 54.8 mmol, 5.74 mL) was added dropwise. The reaction mixture was stirred at rt for 60 h. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase column (0.1% ΝΗ3&#905;2Ο) to give the title compound (7.23 g, 78% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.42 - 7.25 (m, 10H), 4.92 - 4.71 (m, IH), 4.28 - 4.18 (m, 2H), 4.13 - 4.08 (m, 2H), 3.79 - 3.53 (m, 6H), 2.82 - 2.71 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[001069] Step 2 - 2-[3-(Dibenzylamino) fluoro-propoxy1 ethanol

[001070] To a solution of LiAlH4 (1.15 g, 30.1 mmol) in THF (70.0 mL) was added a solution of ethyl 2-[3-(dibenzylamino) fluoro-propoxy] acetate (7.23 g, 20.1 mmol) dissolved in THF (30.0 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. On completion, the mixture was quenched with water (3 mL), then 15% NaOH (3 mL) was added until no precipitate formed. The reaction mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound (5.88 g, 92% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.39 - 7.26 (m, 10H), 4.86 - 4.64 (m, IH), 3.71 - 3.61 (m, 8H), 3.58 - 3.51 (m, 3H), 2.80 - 2.70 (m, 2H).

[001071] Step 3 - 2-r3-(Dibenzylamino) fluoro-propoxy1 ethyl methanesulfonate

[001072] To a solution of 2-[3-(dibenzylamino) fluoro-propoxy]ethanol (2.00 g, 6.30 mmol) and TEA (1.28 g, 12.6 mmol, 1.75 mL) in DCM (20.0 mL) was added MsCl (866 mg, 7.56 mmol, 585 uL) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 1 hr. On completion, the mixture was diluted with DCM (30 mL), then washed with H2O (3X30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.27 g, 90% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 7.41 - 7.25 (m, 10H), 4.83 - 4.63 (m, IH), 4.33 - 4.28 (m, 2H), 3.69 - 3.66 (m, 6H), 3.64 - 3.55 (m, 2H), 2.99 (s, 3H), 2.81 -2.69 (m, 2H)

[001073] Step 4 - 2-r2-r3-(Dibenzylamino) fluoro-propoxy1ethyl1isoindoline-L3-dione [001074] To a solution of 2-[3-(dibenzylamino) fluoro-propoxy]ethyl methanesulfonate (2.27 g, 5.74 mmol) in DMF (20.0 mL) was added (l,3-dioxoisoindolin yl)potassium (1.59 g, 8.61 mmol) and the reaction mixture was stirred at 80 °C for 3 h. On completion, the mixture was diluted with water (50 mL) then extracted with EtOAc (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.56 g, 80% yield) as a yellow oil. LC-MS (ESI+) m/z 447.2 (M+H)+.

[001075] Step 5 - 3-(2-Aminoethoxy)-N,N-dibenzyl fluoro-propan-l-amine

[001076] To a solution of 2-[2-[3-(dibenzylamino) fluoro-propoxy]ethyl]isoindoline-l,3dione (2.56 g, 5.73 mmol) in EtOH (25.0 mL) was added Ν2Η4.Η2Ο (1.46 g, 28.6 mmol, 1.42 mL, 98% purity) and the reaction mixture was stirred at 80 °C for 16 h. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was diluted with DCM (50 mL), stirred for 15 min, filtered, and the filtrate was concentrated in vacuo to give the title compound (1.50 g, 82% yield) as a yellow oil. LC-MS (ESI+) m/z 317.1 (M+H)+.

[001077] Step 6 - Tert-butyl N-r2-r3-(dibenzylamino) fluoro-propoxy1ethyl1carbamate [001078] To a solution of 3-(2-aminoethoxy)-Af,A-dibenzyl fluoro-propan-l-amine (1.50 g, 4.74 mmol) in DCM (15.0 mL) was added (Boc)2O (1.55 g, 7.11 mmol, 1.63 mL) and the reaction mixture was stirred at rt for 16 h. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο) to give the title compound (1.37 g, 67% yield) as a yellow oil. LC-MS (ESI+) m/z 417.2 (M+H)+.

[001079] Step 7 - Tert-butyl N-r2-(3-amino fluoro-propoxy)ethyl1carbamate

[001080] To a solution of tert-butyl 7V-[2-[3-(dibenzylamino) fluoropropoxy]ethyl]carbamate (1.30 g, 3.12 mmol) in a solvent mixed solution ofMeOH (15.0 mL) and ΝΗ3&#905;2Ο (300 uL) was added Pd/C (600 mg, 10 wt %) and Pd(OH)2/C (600 mg, 10 wt %) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 16 h. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (730 mg, 99% yield) as a yellow oil. LC-MS (ESI+) m/z 237.0 (M+H)+.

[001081] Tert-butyl N-[2-(3-amin0 flu0r0-l-methvl-Dr0D0xv)ethyl]carbamate (Intermediate AY)

AY

[001082] Step 1 - Ethyl 2-[3-(dibenzylamino) fluoro-l-methyl-propoxy1acetate

[001083] To a mixture of 4-(dibenzylammo) fluoro&#1470;butan ol (1.00 g, 3.48 mmol, Intermediate AL) and [Rh(OAc)2]2 (15.3 mg, 69.6 umol) in DCM (20 mL) was added a solution of ethyl 2-diazoacetate (1.19 g, 10.4 mmol) in DCM (10 mL) dropwise. The reaction mixture was stirred at rt for 20 h. On completion, the reaction mixture was poured into 30 mL of water and extracted with DCM (3 X 30 mL). The combined organic layer was dried over Na SO&#1470;, filtered and concentrated in vacuo to give a residue. The residue w7as purified by reverse phase chromatography (0.1% ΝΗ3.Η2Ο) to give the title compound (890 mg, 67% yield) as a light yellow oil. 1HNMR (400MHz, CDCh) δ 7.45 - 7.22 (m, 10H), 4.83 - 4.50 (m, IH), 4.25 - 4.00 (m, 4H), 3.81 - 3.57 (m, 5H), 2.99 - 2.75 (m, 2H), 1.31 - 1.26 (m, 3H), 1.12 - 1.02 (m, 3H); LC-MS (ESI+) m/z 374.1 (M+H)+.

[001084] Step 2 - 2-[3-(Dibenzylamino) fluoro-l-methyl-propoxy1ethanol

[001085] To a mixture of ethyl 2-[3-(dibenzylamino) fluoro-l-methyl-propoxy]acetate (890 mg, 2.38 mmol) in THF (3 mL) was added LiAlH4 (138 mg, 3.57 mmol, 98% purity) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred 30 min. On completion, the reaction mixture was quenched with water (0.5 mL) and NaOH solution (15 %, 0.5 mL) at 0 °C. Then the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (730 mg, 95% yield) as a light yellow oil. LC-MS (ESI+) m/z 332.1 (M+H)+.

[001086] Step 3 - 2-r3-(Dibenzylamino) fluoro-l-methyl-propoxy]ethyl methanesulfonate [001087] To a mixture of 2-[3-(dibenzylamino) fluoro-l-methyl-propoxy]ethanol (730 mg, 2.20 mmol) and TEA (668 mg, 6.61 mmol) in DCM (10 mL) was added MsCl (378 mg, 3.30 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 2 h. On completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3 X 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (900 mg, 100% yield) as a light yellow oil. LC-MS (ESI+) m/z 410.1 (M+H)+.

[001088] Step 4 - 2-r2-[3-(Dibenzylamino) fluoro-l-methyl-propoxy]ethyl]isoindolineL 3 -di one

[001089] To a mixture of 2-[3-(dibenzylamino) fluoro-l-methyl-propoxy]ethyl methanesulfonate (900 mg, 2.20 mmol) in DMF (10 mL) was added (l,3-dioxoisoindolin-2yl)potassium (610 mg, 3.30 mmol). The reaction mixture was stirred at 100 °C for 3 h. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.00 g, 95% yield) as a light yellow solid. LC-MS (ESI+) m/z 461.2 (M+H)+.

[001090] Step 5 - 3-(2-Aminoethoxy)-N,N-dibenzyl fluoro-butan-l-amine

[001091] To a mixture of 2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethyl]isoindoline-l,3-dione (1.00 g, 2.17 mmol) in EtOH (15 mL) was added ΝΗ2ΝΗ2.Η2Ο (869 mg, 17.3 mmol). The reaction mixture was stirred at 80 °C for 20 h. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was poured into 30 mL of DCM, filtered and concentrated in vacuo to give the title compound (800 mg, 73% purity, 75% yield) as a light yellow solid. LC-MS (ESI+) m/z 333.1 (M+H)+.

[001092] Step 6 - Tert-butyl N-r2-r3-(dibenzylamino) fluoro-l-methylpropoxy]ethyl]carbamate

[001093] To a mixture of 3-(2-aminoethoxy)-Af,Af-dibenzyl fluoro-butan-l -amine (800 mg, 2.42 mmol) in DCM (10 mL) was added (Boc)2O (1.06 g, 4.84 mmol). The reaction mixture was stirred at rt for 2 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο) to give the title compound (520 mg, 48% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 7.42 - 7.23 (m, 10H), 4.87 4.41 (m, 2H), 3.81 - 3.68 (m, 2H), 3.68 - 3.59 (m, 2H), 3.59 - 3.44 (m, 2H), 3.39 - 3.24 (m, IH), 3.19 (d, J = 5.2 Hz, 2H), 2.91 - 2.65 (m, 2H), 1.48 - 1.45 (m, 9H), 1.07 - 0.98 (m, 3H); LC-MS (ESC)/431.2 2&#1524; (M+H)+.

[001094] Step 7 - Tert-butyl N-r2-(3-amino fluoro-l-methyl-propoxy)ethyl1carbamate

[001095] To a mixture of tert-butyl Af-[2-[3-(di benzyl ami no) fluoro-l-methylpropoxy]ethyl]carbamate (520 mg, 1.21 mmol), Pd/C (300 mg, 10 wt %) and Pd(OH)2/C (300 mg, 10 wt %) in MeOH (10 mL) was added NH3*H2O (169 mg, 1.21 mmol 25% wt %) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 16 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (280 mg, 100% yield) as a light yellow oil. 1HNMR (400MHz, CDCh) δ 5.09 - 4.78 (m, IH), 4.41 - 4.07 (m, IH), 3.63 - 3.49 (m, 2H), 3.47 - 3.38 (m, IH), 3.26 - 3.16 ( m, 2H), 2.96 - 2.77 (m, 2H), 1.70 - 1.60 ( m, 2H), 1.38 (s, 9H), 1.14 - 1.10 (m, 3H).

[001096] Tert-butyl N-[2-[2-(3-amino fluoro-l-methylpropoxy)ethoxy] ethyl] carbamate(Intermediate AZ)

BocHN

F Bn

Pd/C, Pd(OH)2/C, H2 (gas)

MeOH, NH3-H2O

[001097] Step 1 - Ethyl 2-[2-r3-(dibenzylamino) fluoro-l-methyl-propoxy1ethoxy1acetate [001098] To a solution of 2-[3-(dibenzylamino) fluoro-l-methyl-propoxy]ethanol (3.30 g, 9.96 mmol, synthesized via Steps 1-2 of Intermediate AY) in DCM (50 mL) was added Rh(OAc)2 (44 mg, 199 umol), then a solution of ethyl 2-diazoacetate (3.41 g, 29.9 mmol, 3.13 mL) in DCM (50 mL) was added dropwise. The mixture was stirred at rt for 20 h. On completion, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give the title compound (2.70 g, 58% yield) as a colorless oil. LC-MS (ESI+) m/z 418.1 (M+H)+.

[001099] Step 2 - 2-r2-r3-(Dibenzvlamino) fluoro-l-methyl-propoxv1ethoxv1ethanol [001100] To a solution of ethyl 2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]acetate (1.00 g, 2.40 mmol) in THF (30 mL) was added LiAlH4 (136 mg, 3.59 mmol). The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was quenched by adding water (1 mL), 15% NaOH (3 mL) then more water (1 mL). A large quantity of white precipitate was formed, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (880 mg, 93% yield) as a colorless oil. LC-MS (ESI+) m/z 376.2 (M+H)+.

[001101] Step 3 - 2-r2-r3-(Dibenzylamino) fluoro-l-methyl-propoxy1ethoxy1ethyl methanesulfonate

[001102] To a solution of 2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethanol (2.40 g, 6.39 mmol) in DCM (25 mL) was added Et3N (1.94 g, 19.2 mmol, 2.67 mL) and MsCI (1.10 g, 9.59 mmol, 742 uL). The mixture was stirred at 0 °C for 1 hr. On completion, the reaction was quenched with water (20 mL) and extracted with DCM (2X30 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.90 g, 98% yield) as a yellow oil. LC-MS (ESI+) m/z 454.1 (M+H)+.

[001103] Step 4:2-r2-[2-r3-(Dibenzylamino) fluoro-l-methylpropoxv1ethoxv1ethyl1isoindoline-L3-dione

[001104] To a solution of 2-[2-[3-(dibenzylamino) fluoro-l-methyl-propoxy]ethoxy]ethyl methanesulfonate (2.90 g, 6.39 mmol) in DMF (30 mL) was added (l,3-dioxoisoindolin-2yl)potassium (1.30 g, 7.03 mmol). The mixture was stirred at 60 °C for 10 h. On completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (2 X 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo to give the title compound (3.8 g) as a light yellow oil. LC-MS (ESI+) m/z 505.2 (M+H)+.

[001105] Step 5 - 3-r2-(2-Aminoethoxy)ethoxy1-N,N-dibenzyl fluoro-butan-l-amine

[001106] To a solution of 2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethyl]isoindoline- 1,3-dione (3.80 g, 7.53 mmol) in EtOH (50 mL) was added ΝΗ2ΝΗ2.Η2Ο (3.85 g, 75.3 mmol, 3.73 mL, 98% purity). The mixture was stirred at 90 °C for 3 h. On completion, the mixture was concentrated in vacuo to give the title compound (3.00 g, 100%) as a white solid. LC-MS (ESI+) m/z 375.1 (M+H)+.

[001107] Step 6 - Tert-butyl N-r2-[2-r3-(dibenzvlamino) fluoro-l-methvlpropoxy1ethoxy1ethyl1carbamate

[001108] To a solution of 3-[2-(2-aminoethoxy)ethoxy]-N,N-dibenzyl fluoro-butan-lamine (3.00 g, 8.01 mmol) in MeOH (30 mL) was added (Boc)2O (3.50 g, 16.02 mmol, 3.68 mL). The mixture was stirred at rt for 16 h. On completion, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give the title compound (4.00 g, 100%) as a white solid. LC-MS (ESI+) m/z 475.2 (M+H)+.

[001109] Step 7:Tert-butyl Ν-Γ2- [2-(3 -amino fluoro-1 -methyl propoxy)ethoxy1ethyl1carbamate

[001110] To a solution of ///7-butyl 7V-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy] ethylcarbamate (2.00 g, 4.21 mmol) in MeOH (20 mL) was added Pd/C (400 mg, 10 wt %), Pd(OH)2/C (400 mg, 10 wt %), ΝΗ3.Η2Ο (404 mg, 3.46 mmol, 30 wt %). The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 36 h. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (400 mg, 32% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 5.36 - 5.13 (m, IH), 4.54 - 4.29 (m, IH), 3.79 - 3.46 (m, 7H), 3.33 (s, 2H), 3.08 - 2.73 (m, 2H), 1.71 (s, 2H), 1.57 - 1.38 (m, 9H), 1.36-1.14 (m, 3H).

[001111] Tert-butyl N- [2- [2- [2- [2-(3-amino fluoropropoxy)ethoxy] ethoxy] ethoxy] ethyl] carbamate(Intermediate BA)

BocHN

&#1523;&#1505;-

&#1497;&#1505;

OMs

NaH, DMF

BocH Ν n ' Bn

F Bn

AO

Pd(OH)2/C, Pd/C /CL /-,

-------------&#9658; BocHN '-X'-q^X/ '^z^O NH2

H2 (gas), MeOH ,1

BA

[001112] Step 1 Tert-butyl N-[2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy1ethoxy1ethoxy1ethoxy1ethyl1- carbamate

[001113] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (550 mg, 2.01 mmol, Intermediate AH) in A/A-dimethylform amide (16 mL) was added sodium hydroxide (241 mg, 6.04 mmol, 60% dispersion in mineral oil). The mixture was stirred at 0 °C for 30 minutes then 2-[2[2-[2-(tert-butoxycarbonylamino) ethoxy]ethoxy]-ethoxy]ethyl methanesulfonate (747 mg, 2.01 mmol, Intermediate AO) was added. Then, the reaction mixture was allowed to warm to rt and stirred for 4.5 hours under nitrogen atmosphere. On completion, the reaction mixture was quenched by addition of ice water (30 mL) and extracted with ethyl acetate (3 X 20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to get a residue. The residue was purified by reversed phase chromatography (0.1% NH3*H2O) to give the title compound (600 mg, 54% yield) as a colorless gum. 1H NMR (400MHz, CDCh) δ 7.40 - 7.23 (m, 10H), 5.08 (m, IH), 4.89 - 4.70 (m, IH), 3.69 - 3.60 (m, 17H), 3.57 3.52 (m, 3H), 3.36 - 3.29 (m, 2H), 2.77 (d, J= 5.4 Hz, IH), 2.72 (d, J= 5.4 Hz, IH), 1.46 (s, 9H). [001114] Step 2:Tert-butyl N-[2-[2-[2-[2-(3-amino fluoropropoxy )ethoxy 1 ethoxy] ethoxy] ethyl 1 carb am ate

[001115] To a solution of tert-butyl 7V-[2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy]ethoxy]- ethylcarbamate (600 mg, 1.09 mmol) in methanol (20 mL) was added Pd/C (300 mg, 10 wt %) and Pd(OH)2/C (300 mg, 10 wt %) under nitrogen gas atmosphere. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen gas (15 psi pressure) at rt for 18 h. On completion, the reaction mixture was filtered through a pad of celite and the filter cake was washed with methanol (3X10 mL). The filtrate was concentrated in vacuo to give the title compound (310 mg, 76% yield) as a colorless oil. LC-MS (ESI+) m/z 369.2 (M+H)+.

[001116] Tert-butyl N-[2-[2-[2-[2-(3-amino fluoro-l-methyl671 propox v )et hoxv I ethoxy] ethoxy] ethyl] carbamate(Intermediate BB)

Pd(OH)2/C, Pd/C

H2 (gas), MeOH

BB

[001117] Step 1 - Tert-butyl N-r2-r2-r2-r2-[3-(dibenzylamino) fluo1O-l-methylpropoxy] ethoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[001118] To a solution of 4-(dibenzylamino) fluoro-butan ol (476 mg, 1.66 mmol, Intermediate AL) in DMF (8 mL) was added NaH (199 mg, 4.97 mmol) at 0 °C for 0.5 h. Then 2[2-[2-[2-(tert -butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (800 mg, 2.15 mmol, Intermediate AO) was added into the above mixture. The reaction mixture allowed to warm to rt and stirred for 17 hrs. On completion, the reaction mixture was quenched with H2O (20 mL) and extracted with EA (3 X 20 mL). The organic layer was dried with Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο) to give the title compound (362 mg, 29% yield) as a yellow oil. LC-MS (ESI+) m/z 563.1 (M+H)+.

[001119] Step 2 - Tert-butyl N-r2-r2-[2-r2-(3-amino fluoro-l-methylpropoxy)ethoxy1ethoxy1ethoxy1ethyl1 carbamate

[001120] To a solution of tert-butyl N-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy] ethoxy]ethoxy]ethyl]carbamate (430 mg, 764 umol) in MeOH (10 mL) was added Pd/C (200 mg, wt %), Pd(OH)2/C (200 mg, wt %) and ΝΗ3&#905;2Ο (182 mg, 30 wt %, 1.30 mmol). The suspension was degassed and purged with hydrogen gas three times. The reaction mixture was stirred at rt for 17 h under hydrogen atmosphere (50 psi pressure). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (250 mg, 86% yield) as a yellow oil. LC-MS (ESI+) m/z 383.1 (M+H)+.

[001121] Tert-butyl N-[2-[2-[2-[2-(3-amino fluoro-l,l-dimethylpropoxv)ethoxy] ethoxy] ethoxy] ethyl] carbamate (Intermediate BC)

BocHN

NaH, DMF

Pd(OH)2/C, Pd/C, H2 (gas) ΝΗ3.Η2Ο, MeOH BC

[001122] Step 1 - Tert-butyl N-r2-r2-r2-r2-r3-(dibenzylamino) fluoro-Ll-dimethylpropoxy]ethoxy]ethoxy] ethoxylethyllcarbamate

[001123] To a solution of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethanol (800 mg, 2.32 mmol, Intermediate AN) in DMF (12 mL) was added NaH (277 mg, 6.95 mmol, 60% oil dispersion) at 0°C and the mixture was stirred at 0 °C for 0.5 h. Then 2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (834 mg, 2.55 mmol, synthesized via Step 1 of Intermediate AM) was added and the mixture was allowed to warm to rt and stirred for 5 hrs. On completion, the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 X 30 mL). The combined organic layer was dried over Na2SO4, fdtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (700 mg, 49% yield) as a colorless oil. LC-MS (ESI+) m/z 5112 (M+H)+.

[001124] Step 2 - Tert-butyl N-r2-r2-[2-r2-(3-amino fluoro-Ll-dimethylpropoxy)ethoxy1ethoxy1ethoxy1 ethyUcarbamate

[001125] To a solution of tert-butyl A-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l,ldimethyl-propoxy] ethoxy] ethoxy]ethoxy]ethyl]carbamate (450 mg, 780 umol) in MeOH (10 mL) was added Pd(OH)2/C (150 mg, 10 wt %), Pd/C (150 mg, 10 wt %) and ΝΗ3&#905;2Ο (455 mg, 4.93 mmol, 38 wt %) under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 62 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (200 mg, 64% yield) as colorless oil. 1H NMR (400MHz, CDC13) δ 5.24 (s, IH), 4.33 - 4.10 (m, IH), 3.70 - 3.58 (m, 12H), 3.54 (t, J= 4.8 Hz, 2H), 3.38 - 3.25 (m, 2H), 3.05 - 2.88 (m, 2H), 1.60 (br. s, 2H), 1.45 (s, 9H), 1.23 (d, J= 1.6 Hz, 3H), 1.20 (d, J = 1.2 Hz, 3H).

[001126] Tert-butyl N-[2-(2-aminoethoxv)ethvl]-N-[2-[2-[3-(benzyloxvcarbonvlamino)2-fluoro-l,l -dimethyl-propoxy] ethoxy] ethyl] carbamate (Intermediate BD)

BocHN

NHCbz

HCI/dioxang

DCM

CbzCI, NaHCO3

MeCN,H2O

NHCbz

NHCbz

NH2NH2H2O

EtOH

[001127] Step 1 - Tert-butyl N-r2-r2-r3-(benzyloxycarbonylamino) fluoro-Ll-dimethyl propoxy] ethoxy1ethyl1carbamate

[001128] To a solution of tert-butyl N-[2-[2-(3-amino fluoro-l,l-dimethylpropoxy)ethoxy]ethyl]carbamate (1.1 g, 3.57 mmol, Intermediate AU) in amixed solvent ofACN (10 mL) and H2O (10 mL) was added NaHCO3 (898 mg, 10.7 mmol, 416 uL) and CbzCI (730 mg, 4.28 mmol, 608 uL).The mixture was stirred at rt for 5 h. On completion, the mixture was extracted with DCM (2X20mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA=3:1) to give the title compound (1.50 g, 95% yield) as a colorless oil. LC-MS (ESI+) m/z 465.2(M + Na)+.

[001129] Step 2 - Benzyl N-r3-[2-(2-aminoethoxy)ethoxy1 fluoro methylbutyllcarbamate

[001130] To a solution of tert-butyl N-[2-[2-[3-(benzyloxycarbonylamino) fluoro-l,ldimethyl-propoxy] ethoxy] ethyl ]carbamate (1.5 g, 3.4 mmol) in DCM (15 mL) was added

HCl/dioxane (4 M, 3.00 mL). The mixture was stirred at rt for 1 h. On completion; the reaction mixture was concentrated in vacuo to give the title compound (1.3 g, 93% yield, HC1 salt) as a colorless oil. LC-MS (ESI+) m/z 343.1(M +H)+.

[001131] Step 3:Benzyl Ν-Γ3-Γ2-Γ2-Γ2-Γ2-(1,3-&#940;&#912;οχο&#912;5ο&#912;η&#940;ο1&#912;η-2yl)ethoxy1ethylamino1ethoxy1ethoxy1 fluoro methyl-butyl1carbamate

[001132] To a solution of benzyl N-[3-[2-(2-aminoethoxy)ethoxy] fluoro methylbutyl]carbamate (1.3 g, 3.80 mmol) in ACN (10 mL) was added K2CO3 (1.05 g, 7.59 mmol) and 2-[2-(2-bromoethoxy)ethyl]isoindoline 1,3-dione (1.08 g, 3.61 mmol, Intermediate AQ) .The mixture was stirred at 60 °C for 16 h. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.1 g, crude, 65% yield) as yellow oil. LC-MS (ESI+) m/z 560.3 (M +H)+.

[001133] Step 4 - Tert-butyl N-r2-r2-r3-(benzvloxvcarbonvlamino) fluoro-Ll-dimethylpropoxy] ethoxy] ethyl1-N-r2-r2-(L3-dioxoisoindolin yl)ethoxy1ethyl1carbamate

[001134] To a solution of benzyl N-[3-[2-[2-[2-[2-(l,3-dioxoisoindolin-2yl)ethoxy]ethylamino]ethoxy] ethoxy] fluoro methylbutyl]carbamate (2.1 g, 3.8 mmol) in ACN (20 mL) was added (Boc)2O (1.23 g, 5.63 mmol, 1.29 mL) and TEA (379 mg, 3.75 mmol, 522 uL). The mixture was stirred at rt for 3 h. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA=3:1) to give the title compound (700 mg, 27% yield) as a colorless oil. LC-MS (ESI+) m/z 682.3 (M +Na)+.

[001135] Step 5:Tert-butyl N-r2-(2-aminoethoxy)ethyl1-N-[2-r2-r3(benzyloxycarbonylamino) fluoro-Ll -dimethyl-propoxy1ethoxy1ethyl1carbamate

[001136] To a solution of tert-butyl N-[2-[2-[3-(benzyloxycarbonylamino) fluoro-1,1dimethyl-propoxy] ethoxy]ethyl]-N-[2-[2-(l,3-dioxoisoindolin yl)ethoxy]ethyl]carbamate (500 mg, 757 umol) in EtOH (30 mL) was added N2H4.H2O (193 mg, 3.79 mmol, 187 uL, 98% purity) and the reaction mixture was stirred at 80 °C for 16 h. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH =10/1).to give the title compound (340 mg, 84% yield) as a yellow oil. LC-MS (ESI+) m/z 530.3 (M +H)+.

[001137] Tert-butyl N-[2-[2-[2-(4-amino fluorobutoxy)ethoxy| ethoxy] ethyl] carbamate (Intermediate BE)

THF Ο O Bn

NaBH4

EtOH

N&#1523;Bn

TBDMSCI , imidazole

DCM

LAH

THF

BocHN

NaH, DMF

BocHN

OH Bn

DAST

THF

Pd/C, Pd(OH)2/C, H2, (gas) 0 /χ O

----------------------&#9658; BocHN 0 NH2 MeOH, NH3 H2O F

BE

[001138] Step 1 - Ethyl 4-(dibenzylamino) oxo-butanoate

[001139] To a mixture of N-benzyl-l-phenyl-methanamine (49.5 g, 251 mmol, 48.1 mL) ethyl 4-bromo oxo- butanoate(25 g, 119 mmol) in THF (200 mL) was added a solution of ethyl 4-bromo oxo-butanoate (25 g, 119 mmol) in THF (50 mL) dropwise. The reaction mixture was stirred at rt for 1.5 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (ACN/H2O) to give the title compound (27 g, 69 % yield) as a black brown oil. LC-MS (ESI+) m/z 326.1(M +H)+.

[001140] Step 2 - Ethyl 4-(dibenzylamino) hydroxy-butanoate

[001141] To a mixture of ethyl 4-(dibenzylamino) oxo-butanoate (4 g, 12.2 mmol) in EtOH (50 mL) was added NaBH4 (930 mg, 24.5 mmol) dropwise at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 2 h. On completion, the reaction mixture was quenched by saturated NH4C1 solution (5 mL) under stirring, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was poured into H2O (15 mL) and extracted with EtOAc (3 X 30mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (3.4 g, 85% yield) as a yellow oil. LC-MS (ESI+) m/z 328.1 (M +H)+.

[001142] Step 3 - Ethyl 3-rtert-butvl(dimethyl)silvl1oxv (dibenzylamino)butanoate

[001143] To a solution of ethyl 4-(dibenzylamino) hydroxy-butanoate (3.0 g, 9.2 mmol) in

DCM (30 mL) was added imidazole (2.5 g, 36.7 mmol) and TBDMSC1 (4.14 g, 27.4 mmol, 3.37 mL) dropwise at 0 °C. The mixture was then stirred at rt for 12 h. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1,) to give the title compound (3.6 g, 88% yield) as a colorless 011.¾ NMR (400MHz, CDCh) δ 7.30 - 7.20 (m, 10H), 4.23 - 4.13 (m, IH), 4.11 - 3.99 (m, 2H), 3.65 - 3.60 (m, 2H), 3.51 - 3.47 (m, 2H), 2.78 - 2.76 (m, IH), 2.47 - 2.43 (m, 2H), 2.22 - 2.18 (m, IH), 1.21 (t, J= 7.2 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H).

[001144] Step 4 - 3-[Tert-butyl(dimethyl)silyl1oxy (dibenzylamino)butan-l-ol

[001145] To a solution of ethyl 3-[tert-butyl(dimethyl)silyl]oxy (dibenzylamino)butanoate (3.6 g, 8.2 mmol) in THF (40 mL) was added LiBH4 (532 mg, 24.4 mmol) in portions at 0 °C. Then the reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was quenched by sat. NH4C1 (20 mL), and then diluted with H2O (20 mL) and extracted with EtOAc (2 X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE/EA = 5/1) to give the title compound (1.8 g, 51% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.37 7.26 (m, 10H), 3.97 - 3.89 (m, IH), 3.80 - 3.67 (m, 3H), 3.61 - 3.48 (m, 4H), 2.70 - 2.65 (m, IH), 2.50 - 2.46 (m, IH), 1.94 - 1.86 (m, IH), 1.79 - 1.72 (m, IH), 0.88 (s, 9H), 0.05 (d, J = 52 Hz, 6H).

[001146] Step 5 Tert-butyl N-[2-[2-[2-[4-(dibenzylamino) hydroxybutoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[001147] To a solution of 3-[tert-butyl(dimethyl)silyl]oxy (dibenzylamino)butan-l-ol (1.8 g, 4.50 mmol) in DMF (30 mL) was added NaH (540 mg, 13.5 mmol) and the mixture was stirred at rt for 30 mins. Then 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (2.21 g, 6.76 mmol, synthesized via Step 1 of Intermediate AM) was added. The reaction mixture was stirred at rt for 3 h. On completion, the reaction mixture was quenched with H2O (20 mL), and then extracted with EtOAc (2 X 50 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο condition) to give the title compound (250 mg, 11% yield) as a yellow oil. LC-MS (ESI+) m/z 517.2 (M +H)+.

[001148] Step 6:Tert-butyl N-[2-[2-[2-[4-(dibenzylamino) fluoro677 butoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[001149] To a solution of tert-butyl N-[2-[2-[2-[4-(dibenzylamino) hydroxybutoxy]ethoxy]ethoxy]ethyl] carbamate (230 mg, 445 umol) in THF (8 mL) was added DAST (86.1 mg, 534 umol, 70.5 uL) dropwise and the mixture was stirred at rt for 1 hr. On completion, the mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 71% yield) as a yellow oil. LC-MS (ESI+) m/z 519.3 (M +H)+.

[001150] Step 7:Tert-butyl N-r2-[2-r2-(4-amino fluorobutoxylethoxy] ethoxy] ethyl] carb amate

[001151] A mixture of tert-butyl N-[2-[2-[2-[4-(dibenzylamino) fluorobutoxy]ethoxy]ethoxy]ethyl] carbamate (0.28 g, 539.85 umol) in MeOH (10 mL) and NH3*H2O (0.5 mL) was added Pd(OH)2/C (100 mg, 539 umol, 10 wt %) and Pd/C (100 mg, 539 umol, 10 wt %). The reaction mixture was stirred at rt for 24 h under hydrogen atmosphere (50 psi pressure). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (140 mg, 68% yield) as a colorless oil. LC-MS (ESI+) m/z 339.0 (M +H)+.

[001152] Tert-butyl N-[2-(2-aminoethoxv)ethvl]-N-[2-[3-(dibenzylamino) fluoro-l,ldimethyl- propoxy] ethyl] carbamate (Intermediate BF)

[001153] Step 1:2-Γ2-Γ2-Γ2-Γ3 -(Dibenzylamino) fluoro-1,1 -dimethyl propoxy] ethyl amino] ethoxy] ethyl]i so- indoline-1,3 -di one

[001154] To a solution of 2-[2-(2-bromoethoxy)ethyl]isoindoline-l,3-dione (1.95 g, 6.53 mmol, Intermediate AQ) in acetonitrile (150 mL) was added potassium carbonate (3.01 g, 21.7 mmol) and 3-(2-aminoethoxy)-7V,/V&#1470;dibenzyl- 2-fluoro methyl-butan-1 -amine (2.50 g, 7.26 mmol, synthesized via Steps 1-3 of Intermediate AW). The mixture was stirred at 80 °C for 14 h. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (4.00 g, 51% purity, 50% yield) as a light yellow gum. LC-MS (ESI+) m/z 562.3 (M+H)+.

[001155] Step 2 - Tert-butyl N-r2-r3-(dibenzylamino) fluoro-Ll-dimethylpropoxy1ethyl1-N-[2-r2-(L3-di- oxoisoindolin yl)ethoxy1ethyl1carbamate

[001156] To a solution of 2-[2-[2-[2-[3-(dibenzylamino) fluoro-1,1-dimethylpropoxy]ethylamino]ethoxy]- ethyl]isoindoline-1,3-dione (4.00 g, 51% purity, 3.63 mmol) in acetonitrile (100 mL) was added B0C20 (2.38 g, 10.9 mmol, 2.50 mL).The mixture was stirred at 60 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to get a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 8:1 to 5:1) to give the title compound (2.20 g, 91% yield) as a colorless gum. 1H NMR (400MHz, CDCh) δ 7.88 - 7.82 (m, 2H), 7.74 - 7.68 (m, 2H), 7.40 - 7.38 (m, 4H), 7.32 - 7.29 (m, 4H), 7.26 - 7.19 (m, 2H), 4.57 - 4.40 (m, IH), 3.92 - 3.87 (m, 2H), 3.78 - 3.59 (m, 6H), 3.54 - 3.15 (m, 8H), 2.93 - 2.78 (m, IH), 2.76 - 2.63 (m, IH), 1.43 (s, 9H), 1.06 (s, 3H), 1.04 (s, 3H).

[001157] Step 3 - Tert-butyl N-r2-(2-aminoethoxv)ethvl1-N-r2-[3-(dibenzvlamino) fluoroL 1-dimethyl- propoxy1ethyl1carbamate

[001158] To a solution of tert-butyl W[2-[3-(dibenzylamino) fluoro-l, 1-dimethylpropoxy]ethyl]-7V-[2-[2- (l,3-dioxoisoindolin yl)ethoxy]ethyl]carbamate (1.00 g, 1.51 mmol) in ethanol (50 mL) was added hydrazine hydrate (1.51 g, 30.2 mmol, 1.47 mL). The mixture was stirred at 80 °C for 12 h. On completion, the reaction mixture was concentrated in vacuo to get a residue. Then the residue was diluted with (petroleum ether: ethyl acetate = 5:1, 25 mL). The insoluble substance was filtered and the filtrate was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (780 mg, 97% yield) as a colorless gum. 1HNMR (400MHz, CDCh) δ 7.34 - 7.28 (m, 4H), 7.26 - 7.20 (m, 4H), 7.18 - 7.11 (m, 2H), 4.50 - 4.34 (m, IH), 3.68 (d, J = 13.6 Hz, 2H), 3.53 (d, J = 13.6 Hz, 2H), 3.44 - 3.11 (m, 10H), 2.86 - 2.52 (m, 4H), 1.52 (br. s, 2H), 1.37 (s, 9H), 0.99 (s, 3H), 0.98 (s, 3H).

[001159] Tert-butyl N-[5-(3-amin0 flu0r0-Dr0D0xy)Dentvl]carbamate (Intermediate BG)

BocHN''''''++&#1523;+''''&#1470;^Ox^^ Pd/C’ pd(°H)2/C, H2 (gas) ΒοοΗΝ'^^/^&#1470;&#1523;^Ο&#1470;χγ&#1470;&#1523;χ^ΝΗ2

F Bn MeOH, ΝΗ3.Η2Ο F

BG

[001160] Step 1 - 2-(5-Bromopentyl)isoindoline-L3-dione

[001161] To a solution of 1,5-dibromopentane (55.9 g, 243 mmol, 32.9 mL) in acetone (250 mL) was added (l,3-dioxoisoindolin yl)potassium (15.0 g, 81.0 mmol) in portions over 30 minutes. The mixture was then stirred at rt for 30 minutes, and then heated to 60 °C and stirred for 15 hrs. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA= 15:1 to 10:1) to give the title compound (20.0 g, 82% yield) as a white solid. LC-MS (ESI+) m/z 296.0 (M+H)+.

[001162] Step 2 - 2-r5-r3-(Dibenzylamino) fluoro-propoxy1pentyl1isoindoline-L3-dione [001163] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (2.00 g, 7.32 mmol, Intermediate AH) in DMF (80 mL) was added NaH (878 mg, 22.0 mmol, 60% oil dispersion) and the mixture was stirred at rt for 0.5 h. Then 2-(5-bromopentyl)isoindoline-l,3-dione (5.20 g, 17.6 mmol) was added and the reaction mixture was stirred at 70 °C for a further 34.5 h. On completion, the reaction mixture was quenched by adding H2O (50 mL), and then extracted with ethyl acetate (3 X 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography to give the title compound (560 mg, 16% yield) as colorless oil. LC-MS (ESI+) m/z 489.3 (M+H)+.

[001164] Step 3 - 5-r3-(Dibenzylamino) fluoro-propoxy1 pentan amine

[001165] To a solution of 2-[5-[3-(dibenzylamino) fluoro-propoxy]pentyl]isoindoline-l,3dione (560 mg, 1.14 mmol) in EtOH (10 mL) was added ΝΗ2ΝΗ2.Η2Ο (676 mg, 13.5 mmol). The reaction mixture was stirred at 80 °C for 24 h. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (380 mg, 31% purity, 49% yield) as a light yellow solid. LC-MS (ESI+) m/z 359.1 (M+H)+.

[001166] Step 4 - Tert-butyl N-r5-r3-(dibenzylamino) fluoro-propoxy1pentyl1carbamate [001167] To a solution of 5-[3-(dibenzylamino) fluoro-propoxy] pentan amine (380 mg, 1.06 mmol) in DCM (10 mL) was added (Boc)2O (462 mg, 2.12 mmol) and the reaction mixture was stirred at rt for 3 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 12:1) to give the title compound (390 mg, 77% yield) as a colorless oil. LC-MS (ESI+) m/z 459.3 (M+H)+.

[001168] Step 5 - Tert-butyl N-r5-(3-amino fluoro-propoxy)pentyl1carbamate

[001169] To a solution of /c77-butyl N-[5-[3-(dibenzylamino) fluoropropoxy]pentyl]carbamate (390 mg, 816 umol) in MeOH (10 mL) was added Pd(OH)2/C (190 mg, 10 wt %), Pd/C (190 mg, 10 wt %) and NH3*H2O (91.0 mg, 779 umol, 30 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas several times. The mixture was stirred at rt for 12 h under hydrogen atmosphere (15 psi pressure). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (206 mg, 61% purity, 55% yield) as a light yellow oil. LC-MS (ESI+) m/z 279.1 (M+H)+.

[001170] Tert-butyl (2-(3-amin0 flu0r0Dr0D0xv)ethyl)(2-(2-(l.,3-di0x0is0ind01in-2yl)ethoxv)ethyl)carbamate(Intermediate BH)

[001171] Step 1 - 2-(3-(Dibenzylamino) fluoropropoxy)ethylmethanesulfonate

[001172] To a solution of 2-[3-(dibenzylamino) fluoro-propoxy]ethanol (2.00 g, 6.30 mmol, synthesized via Steps 1-2 of Intermediate AX) and TEA (1.28 g, 12.6 mmol, 1.75 mL) in DCM (20 mL) was added MsCl (866 mg, 7.56 mmol, 585 uL) at 0 °C. Then the mixture was allowed to warm to rt and stirred for 3 h. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 X 50 mL). The combined organic layers were washed with saturated NH4C1 solution (3 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.65 g, 90% purity, 96% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.45 - 7.25(m, 10H), 4.85 - 4.65 (m, IH), 4.38 - 4.27 (m, 2H), 3.70 - 3.59 (m, 8H), 2.99 (s, 3H), 2.80 - 2.70 (m, 2H).

[001173] Step 2 - 2-(2-(3-(Dibenzylamino) fluoropropoxy)ethyl)isoindoline-L3-dione

[001174] A mixture of 2-(3-(dibenzylamino) fluoropropoxy)ethylmethanesulfonate (2.65 g, 6.03 mmol, 90% purity) and potassium l,3-dioxoisoindolin ide (2.23 g, 12.1 mmol) in DMF (45 mL) was stirred at 85 °C for 12 h. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EA (200 mL). The combined organic layer was washed with brine (3 X 150 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (3.00 g, 90% yield) as a yellow oil. LC-MS (ESI)+ m/z 447.3. (M+H)+.

[001175] Step 3 - 3-(2-Aminoethoxy)-N,N-dibenzyl fluoropropan-l-amine

[001176] To a solution of 2-[2-[3-(dibenzylamino) fluoro-propoxy]ethyl]isoindoline-l,3di one (3.00 g, 1.34 mmol) in EtOH (150 mL) was added Ν2Η4&#905;2Ο (5 mL, 98% purity) at rt. The mixture was stirred at 85 °C for 12 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with DCM (100 mL) and white precipitate was filtered off. The filtrate was concentrated in vacuo to give the title compound (1.93 g, 85% purity, 86% yield) as a colorless oil. LC-MS (ESI)+ m/z 317.3. (M+H)+.

[001177] Step 4 - 2-(2-Benzyl fluoro-l-phenyl-6,12-dioxa-2,9-diazatetradecan-14yl)isoindoline-L3-dione

[001178] To a mixture of 3-(2-aminoethoxy)-7V,7V-dibenzyl fluoro-propan-l-amine(1.93 g, 5.19 mmol, 85% purity), K2CO3 (2.17 g, 15.6 mmol) and KI (86.2 mg, 519 umol) in MeCN (50 mL) was added dropwise a solution of 2-[2-(2-bromoethoxy)ethyl]isoindoline-l,3-dione (1.39 g, 4.67 mmol, 0.9 eq, Intermediate AQ) in MeCN (10 mL) at rt. The reaction mixture then heated to 80 °C and stirred for 12 h. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (3.33 g, 45% purity, 54% yield) as a colorless oil. LC-MS (ESI)+ m/z 534.3. (M+H)+.

[001179] Step 5 - Tert-butyl(2-(3-(dibenzylamino) fluoropropoxy)ethyl)(2-(2-(L3dioxoisoindolin yl) ethoxy)ethyl)carbamate

[001180] A mixture of 2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethylamino]ethoxy]ethyl]isoindoline -1,3-dione (3.22 g, 45% purity, 2.72 mmol ) and B0C20 (1.19 g, 1.25 mL) in MeOH (30 mL) was stirred at 60 °C for 6 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 1:0 to 5:1) to give the title compound (1.40 g, 79% purity, 65% yield) as a colorless oil. LC-MS (ESI)+ m/z 634.4. (M+H)+.

[001181] Step 6 - Tert-butyl (2-(3-amino fluoropropoxy)ethyl)(2-(2-(L3-dioxoisoindolin2-yl)ethoxy)ethyl) carbamate

[001182] A mixture of tert-butyl 7V-[2-[3-(dibenzylamino) fluoro-propoxy]ethyl]-7V-[2-[2(1,3-dioxoisoindo lin yl)ethoxy]ethyl]carbamate (400 mg, 79% purity), Pd/C (200 mg, 10 wt %) and Pd(0H)2/C (200 mg, 10 wt %) in MeOH (15 mL) was purged with hydrogen gas several times. The reaction mixture was stirred under hydrogen atmosphere (50 psi pressure) at 45 °C for 6 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (273 mg, 71.6% purity) as a colorless oil. LC-MS (ESI)+ m/z 454.3. (M+H)+.

[001183] Ethyl

2- [2- [2-(2-methylsulfonyloxyethoxy)ethoxy| ethoxy] acetate (Intermediate BI)

BF3&#1523;Et2O, DCM

MsCI, TEA

DCM

MsO

O

[001184] Step 1 -Ethyl 2-r2-r2-(2-hydroxyethoxy)ethoxy1ethoxy1acetate

[001185] A solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (10.0 g, 66.6 mmol) and

BF3«Et2O (205 mg, 665 umol) in DCM (150 mL) was cooled to 0°C. Then ethyl 2-diazoacetate (7.60 g, 66.9 mmol) was added to the mixture dropwise. After that, the mixture was stirred at rt for

h. On completion, the reaction mixture was quenched with saturated NH4C1 (5 mL), then diluted with water (100 mL) and extracted with DCM (3 X 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PEEA= 1:3) to give the title compound (5.00 g, 31% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 4.17 (q, J= 7.2 Hz, 2H), 4.11 (s, 2H), 3.72 - 3.60 (m, 10H), 3.59 - 3.54 (m, 2H), 2.82 (s, 2H), 1.24 (t, J= 7.2 Hz, 3H).

[001186] Step 2 - Ethyl 2-r2-r2-(2-methylsulfonyloxvethoxy)ethoxy1ethoxy1acetate [001187] A solution of ethyl 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]acetate (900 mg, 3.81 mmol) and TEA (1.16 g, 11.4 mmol) in DCM (10 mL) was cooled to 0°C. Then, MsCI (523 mg, 4.57 mmol) in DCM (2 mL) was added to the reaction mixture dropwise. The mixture was stirred at rt for 1 hour. On completion, the reaction mixture was quenched with water (8 mL) and then extracted with dichloromethane (3X5 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.10 g, 91% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.40 - 4.36 (m, 2H), 4.21 (q, J= 7.2 Hz, 2H), 4.13 (s,

2H), 3.79 - 3.74 (m, 2H), 3.74 - 3.65 (m, 8H), 3.08 (s, 3H), 1.28 (t, J= 7.2 Hz, 3H).

[001188] Ethyl

2-[2-[2-[2-[2-(3-amino fluoro-l,l-dimethylpropoxylethoxy] ethoxy] ethoxy] ethoxy] acetate (Intermediate BJ)

SOCI2

EtOH

Pd(OH)2/C, H2 (gas)

EtOH, TFA

O F

BJ

[001189] Step 1:2-r2-r2-r2-r2-r3-(Dibenzylamino) fluoro-Ll-dimethylpropoxy1ethoxy1ethoxy1ethoxy1 ethoxylacetic acid

[001190] To a mixture of 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]ethanol (3.66 g, 10.6 mmol, Intermediate AN) in DMF (40 mL) was added NaH (1.27 g, 31.8 mmol, 60% dispersion in mineral oil) at 0 °C and stirred for 0.5 hour. Then ethyl 2-(2-(2-(2methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (4.00 g, 12.7 mmol, Intermediate BI) was added and the reaction was allowed to warm to rt and stirred for 16 hours. On completion, the reaction mixture was quenched with water (1 mL) and concentrated in vacuo to give the title compound (5.00 g, 88% yield) as a yellow oil. LC-MS (ESI+) m/z 536.1 (M+H)+.

[001191] Step 2 - Ethyl 2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-Ll-dimethylpropoxy1ethoxy1ethoxy1ethoxy1 ethoxy] acetate

[001192] To a mixture of 2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethoxy] ethoxy]ethoxy]acetic acid (5.00 g, 9.33 mmol) in EtOH (50 mL) was added SOC12 (3.33 g, 28.0 mmol). The reaction mixture was stirred at 80 °C for 4 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and basified with NaHCO3 until the pH = 7-8, then the mixture was extracted with EA (3 X 20mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1 % ΝΗ3&#905;2Ο) to give the title compound (1.80 g, 34% yield) as a light yellow oil. LC-MS (ESI+) m/z 564.4 (M+H)+. [001193] Step 3:Ethyl 2-Γ2-Γ2-Γ 2 (3 -amino fluoro-1,1 -dimethylpropoxy)ethoxy]ethoxy]ethoxy]ethoxy] acetate

[001194] To a mixture of ethyl 2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l,l-dimethylpropoxy]ethoxy]ethoxy] ethoxy]ethoxy]acetate (900 mg, 1.60 mmol) and Pd(OH)2/C (600 mg, 10% purity) in EtOH (10 mL) was added TFA (161 mg, 1.60 mmol) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (610 mg, 90% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 4.54 - 4.37 (m, IH), 4.24 (q, J = 7.6 Hz, 2H), 4.15 (s, 2H), 3.80 - 3.50 (m, 18H), 3.31 -3.01 (t, 7= 7.6 Hz, 3H), 1.31 - 1.23 (m, 6H).

[001195] Ethyl 2- [2- [2- [2-(2-methylsulfonyloxyethoxy)ethoxy|ethoxvl ethoxy] acetate (Intermediate BK)

MsCI, TEA

DCM

BK

[001196] Step 1 - Ethyl 2-r2-r2-r2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate [001197] Asolution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (10.0 g, 51.5 mmol, CAS# 112 7) and BF3.Et2O (159 mg, 515 umol) in DCM (150 mL) was cooled to 0°C. Then ethyl 2-diazoacetate (5.87 g, 51.5 mmol) was added to the solution dropwise. After that, the mixture was stirred at rt for 12 h. On completion, the reaction mixture was quenched with saturated NH4C1 aqueous solution (5 mL), diluted with water (100 mL), then extracted with di chloromethane (3 X 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE:EA = 1:3) to give the title compound (2.90 g, 20% yield) as a colorless oil. 1H NMR (400 MHz, CDCh) δ 4.19 (q, 7= 7.2 Hz, 2H), 4.12 (s, 2H), 3.73 - 3.63 (m, 14H), 3.61 - 3.56 (m, 2H), 1.26 (t, 7= 7.2 Hz, 3H)

[001198] Step 2:Ethyl 2-[2-[2-[2-(2methyl sulfonyl oxy ethoxy)ethoxy1 ethoxy] ethoxy] acetate

[001199] A solution of ethyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate (800 mg, 2.85 mmol) and TEA (577 mg, 5.70 mmol) in DCM (30 mL) was cooled to 0 °C . Then, a solution of MsCl (392 mg, 3.42 mmol) in DCM (4 mL) was added to the mixture dropwise. The mixture was then allowed to warm to rt and stirred for 1 hour. On completion, the reaction mixture was quenched with water (25 mL), and extracted with di chloromethane (3 X 10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.90 g, 90% yield) as a yellowish oil.

[001200] Methyl 2-[2-[2-[2-[2-(3-amino fluoro-l-methylpropoxv)ethoxy| ethoxy] ethoxy] ethoxy] acetate (Intermediate BL)

BK

Pd/C, Pd(OH)2/C

H2 (gas), TFA, EtOH

BL

[001201] Step 1:2-[2-[2-[2-[2-[3 -(Dibenzylamino) fluoro-1 -methylpropoxy1ethoxy1ethoxy1ethoxy1ethoxy1 acetic acid

[001202] To a solution of 4-(dibenzylamino) fluoro-butan ol (600 mg, 2.09 mmol, Intermediate AL) in DMF (10 mL) was added NaH (209 mg, 5.22 mmol) at 0 °C. After 0.5 h, ethyl 2-[2-[2-[2-(2- methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate (898 mg, 2.51 mmol, Intermediate BK) was added to the reaction mixture. The reaction mixture was then allowed to warm to rt and stirred for 17 h. On completion, the mixture was acidified with IN HC1 solution until the pH = 4-5, then concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% TFA) to give the title compound (640 mg, 53% yield) as a yellow oil. LC

MS (ESI+) m/z 522.1 (M+H)+.

[001203] Step 2 - Methyl 2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy1ethoxy1ethoxy]ethoxy1 ethoxy] acetate

[001204] To a solution of 2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethoxy]ethoxy] ethoxy]acetic acid (640 mg, 1.11 mmol) in MeOH (10 mL) was added SOC12 (396 mg, 3.33 mmol). The reaction mixture then heated to 65 °C and stirred for 15 h. On completion, the mixture was concentrated in vacuo to remove the solvent MeOH then diluted with H2O (20 mL). The mixture was then basified with IN NaOH solution until the pH = 8-9, and extracted with DCM (3 X 20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (280 mg, 47% yield) as a yellow oil. LCMS (ESH) m/z 536.3 (M+H)+.

[001205] Step 3:Methyl 2-[2-[2-[2-[2-(3-amino fluoro-l -methylpropoxv)ethoxv1ethoxv1ethoxv]ethoxv1 acetate

[001206] To a solution of methyl 2-[2-[2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethoxy] ethoxy]ethoxy]acetate (280 mg, 522 umol) in EtOH (4 mL) was added Pd(OH)2/C (0.3 g, 10 wt %), Pd/C (0.3 g, 10 wt %) and TFA (59.6 mg, 523 umol, 0.59 mmol). The suspension was degassed and purged with hydrogen gas three times. The reaction mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 17 h. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (200 mg, 100% yield). 1HNMR (400MHz, CDCh) δ 4.68 - 4.29 (m, IH), 4.17 - 4.11 (m, IH), 3.75 - 3.53 (m, 21H), 3.27 - 3.14 (m, 2H), 1.21 - 1.18 (m, 3H).

[001207] Methyl 2-[2-[2-[3-[[6-(5-cvanopyrazolo[3.,4-b]pvridin-l-vl)-4(cvclopropylamino)pyridine carbonvl]amino] fluoro-l-methylpropoxy] ethoxy] ethoxy] acetate (Intermediate BM)

Pd/C, Pd(OH)2/C, H2 gas)

MeOH, HCI

MeOH O F

BM

[001208] Step 1 - Ethyl 2-[2-(2-hydroxy ethoxy)ethoxy1 acetate

[001209] To a mixture of 2-(2-hydroxyethoxy)ethanol (5.00 g, 47.1 mmol, 4.46 mL) and Rh2(OAc)4 (278 mg, 628 umol) in DCM (50 mL) was added a solution of ethyl 2-diazoacetate (3.58 g, 31.4 mmol, 3.29 mL) in DCM (35 mL) dropwise. Then, the reaction mixture was stirred at rt for 16 h. On completion, the reaction mixture was quenched by adding H2O (10 mL), and then extracted with DCM (2 X 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 10:1 to 0:1) to give the title compound (1.68 g, 28% yield) as a black-brown oil. 1HNMR (400MHz, CDCh-tZ) δ 4.22 (q, J = 7.2 Hz, 2H), 4.14 (s, 2H), 3.77 - 3.68 (m, 6H), 3.64 - 3.59 (m, 2H), 2.60 (s, IH), 1.29 (t, J = 7.2 Hz, 3H).

[001210] Step 2 - Ethyl 2-(2-(2-methylsulfonyloxyethoxy)ethoxy1acetate

[001211] To a solution of ethyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate (800 mg, 4.16 mmol) in DCM (8 mL) was added TEA (1.26 g, 12.5 mmol, 1.74 mL) and MsCl (715 mg, 6.24 mmol, 483 uL) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 30 minutes. On completion, the reaction mixture was quenched by adding H2O (10 mL) and then citric acid (5 mL). The mixture was then extracted with DCM (2X10 mL). The combined organic layers were washed with NaHCO3 solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.00 g, 88% yield) as a black-brown oil. 1HNMR. (400MHz, CDC13) δ 4.44 - 4.37 (m, 2H), 4.24 (q, J= 7.2 Hz, 2H), 4.17 - 4.12 (m, 2H), 3.84 - 3.78 (m, 2H), 3.77 - 3.69 (m, 4H), 3.10 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[001212] Step 3:2-r2-[2-r3-(Dibenzylamino) fluoro-l-methylpropoxy1ethoxy1ethoxy1acetic acid

[001213] To a solution of 4-(dibenzylamino) fluoro-butan ol (818 mg, 2.85 mmol, Intermediate AL) in DMF (10 mL) was addedNaH (341 mg, 8.54 mmol, 60% dispersion in mineral oil) at 0 °C and the reaction was stirred for 0.5 hour. Then, ethyl 2-(2-(2methylsulfonyloxyethoxy)ethoxy]acetate (1.00 g, 3.70 mmol) was added, and the reaction mixture was allowed to warm to rt and stirred for a further 16.5 h. On completion, the reaction mixture was adjusted to pH < 7 with 10% hydrochloride acid, and then concentrated in vacuo to give the title compound (3.00 g, 31% purity, 76% yield,) as a black-brown gum. LC-MS (ESI+) m/z 434.1 (M+H)+.

[001214] Step 4 - Methyl 2-r2-r2-[3-(dibenzylamino) fluoro-l-methylpropoxy] ethoxy] ethoxy] acetate

[001215] To a solution of 2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethoxy]acetic acid (3.00 g, 6.92 mmol) in MeOH (30 mL) was added SOC12 (2.47 g, 20.8 mmol, 1.51 mL) . The reaction mixture then heated to 65 °C and stirred for 15 h. On completion, the reaction mixture was concentrated in vacuo. The residue was then adjusted to pH > 8 with saturated NaHCO3 solution, and then extracted with ethyl acetate (2 X 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1) first, and then purified by reverse phase column chromatography (0.1% FA) to give the title compound (250 mg, 95% purity, 8% yield) as a brown oil. 1H NMR (400MHz, CDC13) δ 7.30 - 7.15 (m, 10H), 4.65 - 4.36 (m, IH), 4.07 (d, J = 3.2 Hz, 2H), 3.69 3.43 (m, 15H), 3.43 - 3.35 (m, IH), 2.77 - 2.62 (m, 2H), 0.99 - 0.92 (m, 3H).

[001216] Step 5:Methyl 2-[2-[2-(3-amino fluoro-l-methylpropoxy )ethoxy 1 ethoxy] acetate

[001217] To a solution of methyl 2-[2-[2-[3-(dibenzylamino) fluoro-l-methylpropoxy]ethoxy]ethoxy]acetate (250 mg, 559 umol) in MeOH (5 mL) was added Pd/C (120 mg, wt %) , Pd(0H)2/C (120 mg, 10 wt %) and HC1 (1 M, 2.5 mL). The reaction mixture was stirred at rt for 15 h under hydrogen atmosphere (15 psi pressure). On completion, the reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound (200 mg, 92% purity, 100% yield) as a light yellow oil. LC-MS (ESI+) m/z 254.1 (M+H)+.

[001218] Step 6 - Methyl 2-r2-r2-r3-rr6-(5-cyanopyrazolor3,4-b1pyridin-l-yl)-4(cyclopropylamino)pyridine carbonyl1amino1 fluoro-l-methylpropoxy] ethoxy] ethoxy] acetate

[001219] To a solution of 2-[2-[2-(3-amino fluoro-l -methylpropoxy)ethoxy]ethoxy]acetic acid (140 mg, 553 umol) in MeOH (3 mL) was added SOC12 (197 mg, 1.66 mmol, 120 uL). The reaction mixture was then heated to 65 °C and stirred for 3 h. On completion, the reaction mixture was concentrated in vacuo to give the title compound (120 mg, 85% purity, 69% yield) as a yellow oil. LC-MS (ESI+) m/z 268.1 (M+H)+.

[001220] Tert-butyl N-[2-[2-[2-(2-azidoethoxv)ethoxv]ethoxy]ethvl]carbamate (Intermediate BN)

NaN3

BocHN______3 » BocHN

DMF AO BN

[001221] To a solution of 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (3.6 g, 9.7 mmol, Intermediate AO) in DMF (20 mL) was added NaN3 (1.26 g, 19.4 mmol). The reaction mixture was then heated to 80 °C and stirred for 18 h. On completion, the solvent DMF was removed in vacuo. The residue was diluted with EtOAc (50 mL), fdtered and the fdtrate was removed under nitrogen gas sweep to give the title compound (3.2 g, 90% yield) as a yellow oil. LC-MS (ESI+) m/z 219.1 (M+H-100)+

[001222] 2-[2-[2-[2-[2-[2-(Tertbutoxycarbonylaminolethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl methanesulfonate (Intermediate BO)

HO

OH

TsCI, Ag20

KI, DCM

HO .o^O^o^,O^o^,OTs

NaN3 Pd/C&#1523; H2 (gas) -

&#1470;* 3 &#9658;

DMF EtOH

HO

NH2

Pd(0H)2/C (Boc)2O, EA

CbzCI, NaHC03

ACN, H20

HO. ___.x\ NHCbz

HO^^o/x^OXs^o/X^Ox^o/xxxNHBoc JYALZlAAiiL MsOX'^0/-^Ox^0/xQOX'^0/BO

[001223] Step 1 - 2-r2-r2-r2-r2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethoxy1ethoxy1ethyl4methylbenzene sulfonate

[001224] To a solution of 2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy ]ethanol (10.0 g, 35.4 mmol, CAS# 2615 8) in DCM (1.00 L) was added Ag2O (9.85 g, 42.5 mmol), KI (587 mg, 3.54 mmol) and 4methylbenzenesulfonylchloride (6.75 g, 35.4 mmol). The reaction mixture was stirred under nitrogen atmosphere at rt for 24 h. On completion, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica column chromatography (DCM : MeOH = 100 : 1) to give the title compound (15.0 g, 97% yield) as a yellowish oil. 1H NMR (400MHz, CDCh) δ 7.73 (d, J= 8.4 Hz, 2H), 7.27 (d, J= 8.4 Hz, 2H), 4.12 - 4.06 (m, 2H), 3.68 - 3.50 (m, 22H), 2.38 (s, 3H).

[001225] Step 2 - 2-r2-r2-r2-r2-(2-Azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol

[001226] To a solution of 2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy ]ethyl 4-methylbenzene sulfonate (15.0 g, 34.3 mmol) in DMF (75.0 mL) was added NaN3 (4.50 g, 69.2 mmol) and the mixture was heated to 80 °C and stirred for 12 h. On completion, the DMF solvent was removed under nitrogen gas sweep. Then the reaction mixture was diluted with water (100 mL) and extracted with DCM: MeOH (10 : 1) (2 X 200 mL). The organic layer was purged under nitrogen to give the title compound (10.0 g, 94% yield) as a colorless oil.

[001227] Step 3 - 2-r2-r2-r2-r2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol

[001228] To a solution of 2-[2-[2-[2-[2-(2azidoethoxy)ethoxy] ethoxy] ethoxy ]ethoxy] ethanol (10.0 g, 32.5 mmol) in EtOH (80.0 mL) was added Pd/C (4.00 g, 10 wt %). The reaction mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 12 h. On completion, the mixture was filtered and concentrated in vacuo to give the title compound (8.50 g, 92% yield) as a light yellow oil. LC-MS (ESI)+ m/z 282.1. (M+H)+. [001229] Step 4:Benzyl N-[2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[001230] To a solution of 2-[2-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol (4.00 g, 14.2 mmol) in ACN (40.0 mL) and H2O (40.0 mL) was added NaHCO3 (3.58 g, 42.6 mmol) and CbzCl (2.91 g, 17.0 mmol), and the mixture was stirred at rt for 12 h. On completion, the mixture was extracted with DCM (2 X 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM: MeOH = 10: 1) to give the title compound (4.00 g, 67% yield) as a colorless oil. 1HNMR (400MHz, CDC13) δ 7.38 - 7.33 (m, 5H), 5.56 (s, IH), 5.11 (s, 2H), 3.73 - 3.42 (m, 23H).

[001231] Step 5:Tert-butyl N-[2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[001232] To a solution of benzyl N-[2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy ]ethyl] carbamate (3.00 g, 7.22 mmol) in EtOAc (60.0 mL) was added Pd(OH)2/C (100 mg, 2.41 mmol, 10 wt%) and (Boc)2O (1.89 g, 8.66 mmol), and the mixture was stirred at rt for 12 h. On completion, the mixture was filtered and concentrated in vacuo. The residue was purified by silica column chromatography (DCM: MeOH = 10: 1) to give the title compound (2.00 g, 72% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 5.19 (s, IH), 3.84 - 3.82 (m, 2H), 3.80 - 3.34 (m, 20H), 3.33 (s, 2H), 1.46 (s, 9H).

[001233] Step 6:2-[2-[2-[2-[2-[2-(Tertbutoxycarbonylamino)ethoxy1 ethoxy] ethoxy] ethoxy] ethoxy] ethyl methanesulfonate

[001234] To a solution of tert-butyl N-[2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy ]ethyl] carbamate (1.70 g, 4.46 mmol) in DCM (5.00 mL) was added MsCl (765 mg, 6.68 mmol) and TEA (1.35 g, 13.3 mmol), and the mixture was stirred at 0 °C for 1 h. On completion, the mixture was quenched with water (20 mL) and extracted with DCM (3 X 30 mL). The combined organic layer was washed with brine (3 X 30 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.8 g, 87% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 5.07 (s, IH), 4.44 4.38 (m, 2H), 3.81 - 3.76 (m, 2H), 3.71 - 3.62 (m, 16H), 3.56 (t, J = 52 Hz, 2H), 3.39 - 3.29 (m, 2H), 3.11 (s, 3H), 1.46 (s, 9H).

[001235] Tert-butyl

N-[2-[2-[2-[2-[2-[2-(3

-amino fluoroDropoxvlethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl] carbamate (Intermediate BP)

MsO.

&#1523;&#1505;-

&#1497;&#1505; '0'

NHBoc

HO F

NaH, DMF

BO

BocHN

F Bn

Pd/C, Pd(OH)2/C, H2 (gas) --------------&#9658;

ΝΗ3.Η2Ο, MeOH

F

BP

[001236] Step 1 - Tert-butyl N-r2-r2-r2-r2-r2-r2-r3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethyl]carbamate

[001237] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (0.50 g, 1.83 mmol, Intermediate AH) in DMF (10.0 mL) was added NaH (219 mg, 5.49 mmol, 60% dispersion in mineral oil), and the mixture was stirred at 0 °C for 1 h. Then 2-[2-[2-[2-[2-[2(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylmethane sulfonate (1.01 g, 2.20 mmol, Intermediate BO) was added to the reaction mixture and the mixture was allowed to warm to rt and stirred for 16 h. On completion, the mixture was quenched with water (50 mL) and extracted with EA (3 X 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by reverse phase flash column chromatography (NH3 H2O, ACN 50% ~ 60%) to give the title compound (300 mg, 21% yield) as a colorless oil. LC-MS (ESI)+ m/z 637.4. (M+H)+.

[001238] Step 2 - Tert-butyl Ν-Γ2-Γ2-[2-Γ2-Γ2-Γ2-(3 -amino fluoropropoxy)ethoxy1ethoxy1ethoxy]ethoxy1 ethoxylethyl] carbamate

[001239] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2fluoropropoxy]ethoxy]ethoxy] ethoxy]ethoxy]ethoxy]ethyl]carbamate (0.40 g, 628 umol) in MeOH (5.00 mL) and NH3.H2O (0.2 mL) was added Pd(OH)2/C (0.10 g, 10 wt %) and Pd/C (0.10 g, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 12 h. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (210 mg, 73% yield) as a colorless oil. LC-MS (ESI)+ m/z 457.1. (M+H)+.

[001240] Tert-butyl

N-[2-[2-[2-[2-[2-(2azidoethoxv)ethoxy|ethoxy]ethoxy]ethoxy]ethyl]carbamate (Intermediate BQ)

BocHN q^x^OMs

NaN3

DMF

BocHN

BO

BQ

[001241] To a solution of 2-[2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethylmethane sulfonate (4.45 g, 9.68 mmol, Intermediate BO) in DMF (50 mL) was added NaN3 (1.26 g, 19.37 mmol). The reaction mixture then heated to 80 °C and stirred for 16 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (3.90 g, 99% yield) as a yellow oil. LC-MS (ESI+) m/z 424.1 (M+18)+.

[001242] Tert - butyl N-[2-[2-[2-[2-[2-[4-[2-(3-amin0 flu0r0-Dr0D0xv)ethyl]DiDerazin1-yllethoxy] ethoxy|ethoxy|ethoxvlethvl]carbamate (Intermediate BR)

HCI in dioxane

MeOH, DCM

K2CO3, DMF

Pd(OH)2, Pd/C

H2 (gas), MeOH

[001243] Step 1 - Tert-butyl 4-(2-methylsulfonyloxvethyl)piperazine-l-carboxylate [001244] To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-l-carboxylate (500 mg, 2.17 mmol, CAS# 77279 4) in DCM (10 mL) at 0° C was added TEA (329 mg, 3.26 mmol, 451 uL). After 5 minutes, MsCI (298 mg, 2.60 mmol, 201 uL) was added, and the reaction mixture was allowed to warm to rt and was stirred under nitrogen atmosphere for 3 hours. On completion, the reaction mixture was diluted with H2O (20 mL) and extracted with DCM (2 X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (620 mg, 93% yield) as a yellowish oil.

[001245] Step 2 - Tert-butyl 4-r2-r3-(dibenzylamino) fluoro-propoxy1ethyl1piperazine-lcarboxylate

[001246] To a mixture of tert-butyl 4-(2-methylsulfonyl oxy ethyl )piperazine-1 -carboxylate (620 mg, 2.01 mmol) in DMF (3.00 mL) was added NaH (110 mg, 2.74 mmol, 60% dispersion in mineral oil) at rt under nitrogen atmosphere. The mixture was stirred at rt for 30 minutes, then 3(dibenzylamino) fluoro-propan 01 (500 mg, 1.83 mmol, Intermediate AH) was added to the mixture at rt and the reaction mixture was stirred for 48 hours. On completion, the reaction mixture was quenched with sat. NH4C1 solution (20 mL), then diluted with H2O (20 mL) and extracted with EA (2 X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed phase flash chromatography (ΝΗ3&#905;2Ο) to give the title compound (160 mg, 18% yield) as a yellow oil. LCMS (ESI+) m/z 486.3 (M +H)+.

[001247] Step 3 - N,N-dibenzyl fluoro (2-piperazin-l-ylethoxy)propan-l -amine

[001248] To a mixture of tert-butyl 4-[2-[3-(dibenzylamino) fluoropropoxy]ethyl]piperazine-l-carboxylate (160 mg, 329 umol) in DCM (5.00 mL) and MeOH (1.00 mL) was added HCI in dioxane (329 umol, 2.00 mL). The mixture was stirred at rt for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (200 mg) as a yellow oil. LC-MS (ESI+) m/z 386.2 (M +H)+.

[001249] Step 4 - Tert - butyl N-r2-r2-r2-r2-r2-r4-r2-r3-(dibenzylamino) fluoropropoxy1ethyl1piperazin-l-yl1 ethoxy1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[001250] To a mixture of Ν,Ν-dibenzyl fluoro (2-piperazin-l-ylethoxy)propan-l-amine (200 mg, 518 umol) and 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (259 mg, 623 umol, synthesized via Steps 1-2 of Intermediate AK) inDMF (1.00 mL)andMeCN (3.00 mL)was added K2CO3 (215 mg, 1.56 mmol). The mixture was then heated to 80 °C and stirred for 12 hours. On completion, the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EA = 1:1) to give the title compound (220 mg, 60% yield) as a yellow oil. LC-MS (ESI+) m/z 705.3 (M +H)+

[001251] Step 5 - Tert - butyl N-r2-r2-r2-r2-r2-r4-[2-(3-amino fluoropropoxy)ethyl1piperazin-l-yl1ethoxy1 ethoxy1ethoxy1ethoxy1ethyl1carbamate

[001252] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[4-[2-[3-(dibenzylamino) fluoropropoxy]ethyl] piperazin-l-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (220 mg, 312 umol) in MeOH (7.00 mL) was added Pd(OH)2 (100 mg, 71.2 umol, 10 wt %) and Pd/C (100 mg, 312 umol, 10 wt %). The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was then stirred at rt for 192 hours under hydrogen atmosphere (50 psi pressure). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (100 mg, 61% yield) as a white oil.

[001253] Tert-butyl(15-amino fluoro-13,13-dimethvl oxo-3,6,12-trioxa-9azapentadecyl) carbamate (Intermediate

BS)

Pd/C, Pd(OH)2/C, H2 (gas)

MeOH

BS

[001254] Step 1 - N-(2-(2-(2-aminoethoxy)ethoxy)ethyl) ((4-(dibenzylamino) fluoro-2methylbutan- 2-yl)oxy)acetamide

[001255] A solution of ethyl 2-[3-(dibenzylamino) fluoro-l,l-dimethyl-propoxy]acetate (337 mg, 870 umol, synthesized via Steps 1-2 of Intermediate AN) and 2-(2-(2aminoethoxy)ethoxy]ethanamine (644 mg, 4.35 mmol, CAS# 929 9) in methanol (2 mL). The reaction mixture was heated to 80 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (850 mg, 40% yield) as a colorless oil. LC-MS (ESI+) m/z 490.3 (M+H)+.

[001256] Step 2 - Tert-butyl (2-benzyl fluoro-5,5-dimethyl oxo-l-phenyl-6,12,15trioxa-2,9- diazaheptadecan yl)carbamate

[001257] To a solution of 7V-[2-[2-(2-aminoethoxy)ethoxy]ethyl] [3-(dibenzylamino)-2fluoro-1,1- dimethyl- propoxy]acetamide (920 mg, 1.60 mmol) in DCM (5 mL) was added (Boc)2O (5.23 g, 24.0 mmol). The reaction mixture was stirred at rt for 14 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase chromatography (ΝΗ3&#905;2Ο, 0.1%) to give the title compound (440 mg, 44% yield) as a colorless oil. 1HNMR (400MHz, CDC13) δ = 7.42 - 7.37 (m, 4H), 7.35 - 7.33 (m, 4H), 7.28 - 7.23 (m, 2H), 6.80 (s, IH), 5.01 (s, IH), 4.66 - 4.45 (m, IH), 3.93 - 3.83 (m, 2H), 3.81-3.70 (m, 2H), 3.63 - 3.60 (d, J= 14.0 Hz, 2H), 3.60 - 3.44 (m, 10H), 3.32 - 3.31 (m, 2H), 2.91 - 2.67 (m, 2H), 1.46 (s, 9H), 1.10 (s, 6H). LC-MS (ESI+) m/z 590.4 (M+H)+.

[001258] Step-^^-J/erLbulM—QjLamjrioJjLdluOro^ azapentadecyl) carbamate

[001259] To a solution of tert-butyl W[2-[2-[2-[[2-[3-(dibenzylamino) fluoro-l,ldimethyl-propoxy] acetyl] amino]ethoxy]ethoxy]ethyl]carbamate (440 mg, 746 umol) in MeOH (5 mL) was added Pd(OH)2/C (200 mg, 10 wt %) and Pd/C (200 mg, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (55 psi pressure) at rt for 15 h. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (270 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m/z 410.2 (M+H)+.

[001260] Tert-butyl N-[2-[2-[2-(3-amin0 flu0r0-Dr0D0xv)-l-methylethoxy] ethoxy] ethyl]carbamate(Intermediate BT)

Boc2O

DCM

BocHN

Pd/C, H2 (gas) -------&#9658;

MeOH

BocHN

MsCI, TEA

DCM

BocHN

Pd/C, Pd(OH)2/C, H2 (gas)

MeOH, ΝΗ3.Η2Ο

BocHN

BT

[001261] Step 1 - 2-r2-r2-(2-Benzyloxy-l-methyl-ethoxy)ethoxy1ethyl1isoindoline-L3di one

[001262] To a solution of 1-benzyloxypropan ol (2.5 g, 15.0 mmol, synthesized via Step 1 of Intermediate BU) in DMF (40 mL) was added NaH (1.80 g, 45.12 mmol, 60% dispersion in mineral oil) and the mixture was stirred at rt for 30 min. Then 2-(2-(2Bromoethoxy)ethyl]isoindoline-1,3-dione (4.48 g, 15.0 mmol, Intermediate AQ) was added to the mixture and the mixture was stirred at rt for an additional 12 h. On completion, the reaction mixture was quenched with H2O (10 mL) and then concentrated in vacuo to give the title compound (5 g) as yellow solid. LC-MS (ESI+) m/z 384.1(M + H)+.

[001263] Step 2 - 2-[2-(2-Benzyloxy-l-methyl-ethoxy)ethoxy1ethanamine

[001264] To a solution of 2-[2-[2-(2-benzyloxy-l-methyl-ethoxy)ethoxy]ethyl]isoindoline1,3-dione (10 g, 26.0 mmol) in EtOH (100 mL) was added Ν2Η4.Η2Ο (6.66 g, 130 mmol, 6.47 mL, 98% solution), and the mixture was heated to 80 °C and stirred for 12 h. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (6 g) as a yellow oil. LC-MS (ESI+) m/z 254.1(M + H)+.

[001265] Step 3 - Tert-butyl N-r2-r2-(2-benzyloxy-l-methyl-ethoxy)ethoxy1ethyl1carbamate [001266] To a solution of 2-[2-(2-benzyloxy-l-methyl-ethoxy)ethoxy]ethanamine (6 g, 23.6 mmol) in DCM (40 mL) was added B0C20 (10.3 g, 47.3 mmol, 10.8 mL) and the mixture was stirred at rt for 2 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (NH3*H2O) to give the title compound (3 g, 32% yield over steps 1-3) as a white solid. LC-MS (ESI+) m/z 376.2(M + Na)+. [001267] Step 4 - Tert-butyl N-r2-r2-(2-hydroxy-l-methyl-ethoxy)ethoxy1ethyl1carbamate [001268] To a solution of tert-butyl N-[2-[2-(2-benzyl oxy-1 -methylethoxy)ethoxy]ethyl]carbamate (3 g, 8.49 mmol) in MeOH (30 mL) was added Pd/C (1.5 g, 10 wt %). The mixture was then heated to 40 °C and stirred under hydrogen atmosphere (50 psi pressure) for 18 h. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2 g, 45% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 5.14 (s, IH), 3.84 - 3.76 (m, IH), 3.68 - 3.55 (m, 7H), 3.54 - 3.45 (m, IH), 3.34 (, J= 4.8 Hz, 2H), 1.46 (s, 9H), 1.15 (d, J = 6.4 Hz, 3H).

[001269] Step 5:2-r2-r2-(Tert-butoxycarbonylamino)ethoxy1ethoxy1propyl methanesulfonate

[001270] To a solution of tert-butyl N-[2-[2-(2-hydroxy-l -methyl ethoxy)ethoxy]ethyl]carbamate (0.44 g, 1.67 mmol) in DCM (5 mL) was added TEA (507 mg, 5.01 mmol, 697 uL) and MsCl (287 mg, 2.51 mmol, 193 uL) dropwise at 0°C. The mixture was allowed to warm to rt and stirred for 3 h. On completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (2 x 20 mL). The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (0.56 g, 90% yield) as a yellow oil.

[001271] Step 6 - Tert-butyl N-r2-r2-r2-r3-(dibenzylamino) fluoro-propoxy]-l-methylethoxy] ethoxy] ethyl] carbamate

[001272] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (298 mg, 1.09 mmol, Intermediate AH) in DMF (8 mL) was added NaH (131 mg, 3.28 mmol, 60% dispersion in mineral oil) and the mixture was stirred at rt for 30 min. Then 2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]propyl methanesulfonate (0.56 g, 1.64 mmol) was added to the mixture and the mixture was stirred at rt for an additional 12 h. On completion, the reaction mixture was quenched with water (0.5 mL) and then concentrated in vacuo to give a residue. The residue was purified by reversed phase chromatography (0.1% NH3*H2O) to give the title compound (130 mg, 22% yield) as a yellow oil. LC-MS (ESI+) m/z 519.4(M + Na)+.

[001273] Step 7 - Tert-butyl N-r2-r2-r2-(3-amino fluoro-propoxy)-l-methylethoxy]ethoxy]ethyl] carbamate

[001274] To a solution of tert-butyl N-[2-[2-[2-[3-(dibenzylamino) fluoro-propoxy]-lmethyl-ethoxy]ethoxy] ethyl]carbamate (0.3 g, 578 umol) in MeOH (10 mL) and ΝΗ3.Η2Ο (1 mL) was added Pd(OH)2/C (0.2 g, 10 wt %) and Pd/C (0.2 g, 10 wt %), and the mixture was stirred at rt for 12 h under hydrogen atmosphere (15 psi pressure). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (140 mg, 71% yield) as a colorless oil. LC-MS (ESI+) m/z 339.2 (M + H)+.

[001275] 2-[2-[2-[2-(3-Amino fluoro-propoxv)ethoxy|ethoxy|propyl]isoindoline-l.,3dione(Intermediate BU)

[001276] Step 1 - 1-Benzyl oxypropan ol

[001277] To a solution of LiAlH4 (7.56 g, 199 mmol) in anhydrous tetrahydrofuran (100 mL) was added a solution of 2-(benzyloxymethyl)oxirane (21.8 g, 132 mmol, 20.1 mL) in anhydrous tetrahydrofuran (300 mL) dropwise at 0 °C under nitrogen atmosphere. The mixture was then stirred for 1 hour. On completion, the reaction mixture was quenched with water (15 mL), then 15% sodium hydroxide solution (15 mL) was added, and the mixture was stirred for a further 15 minutes until no precipitate formed. Next, the inorganic salt precipitate was filtered off and the filter cake was washed with ethyl acetate (2 X 100 mL). The combine organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 2:1) to give the title compound (21.3 g, 96% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.40 - 7.29 (m, 5H), 4.57 (s, 2H), 4.08 - 3.94 (m, IH), 3.49 (dd, J= 3.2, 9.2 Hz, IH), 3.30 (dd, J= 8.4, 9.2 Hz, IH), 2.40 (d, 7= 2.4 Hz, IH), 1.16 (d, J= 6.4 Hz, 3H).

[001278] Step 2 - 2-(2-(2-Bromoethoxy)ethoxy1propoxym ethylbenzene

[001279] A mixture of 1-benzyloxypropan ol (4.00 g, 24.0 mmol), l-bromo (2bromoethoxy)ethane (27.9 g, 120 mmol, 15.0 mL), tetrabutylammonium bromide (7.76 g, 24.0 mmol), potassium iodide (3.99 g, 24.0 mmol) and sodium hydride (2.89 g, 72.2 mmol, 60% dispersion in mineral oil) in AA-dimethylformamide (40 mL) was degassed and purged with nitrogen gas three times. Then the mixture was stirred at rt for 20 hours under nitrogen atmosphere. On completion, the reaction mixture was poured into ice water (100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to get a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 6:1) to give the title compound (4.20 g, 55% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.40 - 7.25 (m, 5H), 4.58 (s, 2H), 3.83 (t, J = 6.4 Hz, 2H), 3.75 - 3.66 (m, 5H), 3.56 - 3.42 (m, 4H), 1.20 (d, J= 6.4 Hz, 3H).

[001280] Step 3 - N,N-dibenzyl [2-[2-(2-benzyloxy-l-methyl-ethoxy)ethoxy1ethoxy1-2fluoro-propan amine

[001281] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (2.00 g, 7.32 mmol, Intermediate AH) in A; AMi methyl form am ide (40 mL) was added sodium hydride (878 mg, 21.9 mmol, 60% dispersion in mineral oil) at 0 °C and the reaction was stirred for 30 minutes. Then 2[2-(2-bromoethoxy)ethoxy]propoxy -methylbenzene (2.50 g, 7.88 mmol) was added and the reaction mixture was then allowed to warm to rt and stirred for a further 15.5 hours. On completion, the reaction mixture was quenched with ice water (120 mL) and extracted with ethyl acetate (3 X 50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to get a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to give the title compound (2.60 g, 69% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.40 - 7.34 (m, 15H), 4.91 - 4.71 (m, IH), 4.59 (d, J = 2.4 Hz, 2H), 3.74 - 3.60 (m, 16H), 3.48 - 3.42 (m, IH), 2.81 - 2.72 (m, 2H), 1.21 (d, J= 6.4 Hz, 3H).

[001282] Step 4 - 2-[2-[2-(3-Amino fluoro-propoxy)ethoxy1ethoxy1propan-l-ol

[001283] To a solution of Af,Af-dibenzyl [2-[2-(2-benzyloxy-l-methylethoxy)ethoxy]ethoxy] fluoro-propan- 1-amine (2.30 g, 4.51 mmol) in methanol (30 mL) was added Pd/C (1.00 g, 10 wt %) and Pd(OH)2/C (1.00 g, 10 wt %) under nitrogen gas atmosphere. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen gas (50 psi pressure) at rt for 18 h. On completion, the reaction mixture was filtered through a pad of celite and the pad and the filter cake was washed with methanol (3X10 mL). The filtration was concentrated in vacuo to give the crude product (930 mg, 86% yield) as a colorless oil. LC-MS (ESI)+ m/z 240.0. (M+H)+.

[001284] Step 5:Tert-butyl N-[2-fluoro r2-r2-(2-hydroxy-l-methylethoxy)ethoxy1ethoxy1propyl1carbamate

[001285] To a solution of 2-[2-[2-(3-amino fluoro-propoxy)ethoxy]ethoxy]propan-l-ol (850 mg, 3.55 mmol) in dichloromethane (30 mL) was added B0C20 (852 mg, 3.91 mmol, 897 uL) dropwise. The mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1) to give the title compound (930 mg, 77% yield) as a colorless gum. 1H NMR (400MHz, CDCh) δ 5.28 (m, IH), 4.83 - 4.60 (m, IH), 3.87 3.79 (m, IH), 3.73 - 3.58 (m, 11H), 3.50 - 3.36 (m, 3H), 3.13 (br s, IH), 1.45 (s, 9H), 1.13 (d,J = 6.4 Hz, 3H).

[001286] Step 6:2-Γ2-Γ2-Γ3 -(Tert-butoxycarbonylamino) fluoropropoxv1ethoxv1ethoxv1propyl methane- sulfonate

[001287] To a solution of tert-butyl 7V-[2-fluoro [2-[2-(2-hydroxy-l-methylethoxy)ethoxy]ethoxy]propyl]- carbamate (880 mg, 2.59 mmol) in dichloromethane (30 mL) was added triethylamine (787 mg, 7.78 mmol, 1.08 mL) and the reaction mixture was cooled to 0 °C. Then methyl sulfonyl chloride (445 mg, 3.89 mmol, 301 uL) was added dropwise at 0 °C. Then, the mixture was allowed to warm to rt and stirred for 30 minutes. On completion, the reaction mixture was quenched with ice water (30 mL), The organic phase was separated, washed with citric acid (30 mL), then dried over anhydrous magnesium, filtered and concentrated in vacuo to give the title compound (1.00 g, 92% yield) as a colorless gum. 1H NMR (400MHz, CDCh) δ 4.97 (m, IH), 4.80 - 4.60 (m, IH), 4.24 - 4.12 (m, 2H), 3.82 - 3.61 (m, 11H), 3.47 - 3.28 (m, 2H), 3.08 (s, 3H), 1.45 (s, 9H), 1.22 (d, J = 6.4 Hz, 3H).

[001288] Step 7 - Tert-butyl N-r3-r2-r2-r2-(L3-dioxoisoindolin yl)-l-methylethoxy]ethoxy]ethoxy] fluoro-propyllcarbamate

[001289] To a solution of 2-[2-[2-[3-(tert-butoxycarbonylamino) fluoropropoxy]ethoxy]ethoxy]propyl methanesulfonate (1.00 g, 2.40 mmol) in N,N-dimethylformamide (20 mL) was added (1,3-dioxoiso- indolin yl)potassium (532 mg, 2.87 mmol). The mixture then heated to 80 °C and stirred for 16 h. On completion, the reaction mixture was concentrated in vacuo to get a residue. The residue was diluted in ice water (20 mL) and extracted with ethyl acetate (3X15 mL). The organic phase was collected, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to give the title compound (730 mg, 65% yield) as a colorless gum. 1HNMR (400MHz, CDCh) δ 7.78 (m, 2H), 7.65 (m, 2H), 4.91 (m, IH), 4.70 - 4.49 (m, IH), 3.81 - 3.70 (m, 2H), 3.66 - 3.42 (m, 12H), 3.30 - 3.18 (m, IH), 1.37 (s, 9H), 1.14 (d, J = 6.4 Hz, 3H).

[001290] SRyUU^zlJULUIJQQAinilKENfLuOtOipropoxY)(^^

L 3 -di one

[001291] To a solution of tert-butyl N-[3-[2-[2-[2-(l,3-dioxoisoindolin yl)-l-methylethoxy]ethoxy]ethoxy]- 2-fluoro-propyl]carbamate (350 mg, 747 umol) in dichloromethane (14 mL) was added a solution of hydrochloric acid in dioxane (4 M, 14 mL). The mixture was stirred at rt for 30 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (300 mg, 99% yield, hydrochloride salt) as a colorless gum. LC-MS (ESI)+ m/z 369.1. (M+H)+.

[001292] Tert-butyl N-[3-[3-(3-amino fluoro-propoxv)propoxv]propyl]carbamate (Intermediate BV) ΗΟχχ&#910;χΟΗ

NC&#1524;^

MeONa

Raney Ni, H2 (gas)

Boc2O, MeOH

MsCI, TEA

DCM

BocHN 0 OMs

NaH, DMF

BocHN

Pd/C, Pd(OH)2

H2 (gas), MeOH

BocHN

NH2

BV

[001293] Step 1 - 3-(3-Hydroxypropoxy)propanenitrile

[001294] To a mixture of propane-1,3-di 01 (28.7 g, 377 mmol, 27.3 mL) and prop enenitrile (20.0 g, 377 mmol, 25.0 mL) was added NaOMe (204 mg, 3.77 mmol). The mixture was stirred at rt for 20 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica column chromatography to give the title compound (20.3 g, 41% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 3.70 (t, J = 6.0 Hz, 2H), 3.65 - 3.57 (m, 4H), 2.55 (t, J= 6.4 Hz, 2H), 1.99 (s, IH), 1.79 (m, 2H).

[001295] Step 2 - Tert-butyl N-r3-(3-hvdroxvpropoxv)propyl1carbamate

[001296] To a solution of 3-(3-hydroxypropoxy)propanenitrile (5.00 g, 38.7 mmol) in MeOH (50 mL) was added Raney-Ni (1.00 g) and (Boc)2O (12.7 g, 13.3 mL) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 72 h. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica column chromatography to give the title compound (6.5 g, 72% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.86 (s, IH), 3.79 (t, J = 5.6 Hz, 2H), 3.60 (t, J= 6.0 Hz, 2H), 3.50 (t, J= 6.0 Hz, 2H), 3.30 - 3.18 (m, 2H), 2.63 (s, IH), 1.87 - 1.70 (m, 4H), 1.45 (s, 9H).

[001297] Step 3 - 3-r3-(Tert-butoxvcarbonvlamino)propoxy1propyl methanesulfonate [001298] To a solution of tert-butyl 7V-[3-(3-hydroxypropoxy)propyl]carbamate (1.20 g, 5.14 mmol) in DCM (10 mL) was added Et3N (1.56 g, 2.15 mL, 15.4 mmol) and MsCI (884 mg, 7.72 mmol). The mixture was stirred at rt for 2 h. On completion, the reaction was quenched with water (10 mL) and extracted with DCM (2 X 30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.60 g, 99% yield) as a yellow oil. 1HNMR (400MHz, CDCh) δ 4.88 - 4.78 (s, IH), 4.36 (t, J= 6.0 Hz, 2H), 3.52 (m, 4H), 3.27 - 3.19 (m, 2H), 3.03 (s, 3H), 2.01 (t, J = 6.0 Hz, 2H), 1.76 (t, J = 6.0 Hz, 2H), 1.45 (s, 9H).

[001299] Step 4 - Tert-butyl N-[3-r3-(3-amino fluoro-propoxy)propoxy1propyl1carbamate [001300] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (1.00 g, 3.66 mmol, Intermediate AH) in DMF (20 mL) was added NaH (439 mg, 11.0 mmol, 60% dispersion in mineral oil) and the reaction mixture was stirred for 30 minutes at rt. Then, 3-[3-(tertbutoxycarbonylamino) propoxy]propyl methanesulfonate (1.48 g, 4.76 mmol) was added and the mixture was stirred at rt for an additional 12 h. On completion, the mixture was quenched with saturated NH4C1 solution and extracted with EA (3X50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase chromatography (0.1% NH3 H2O in water) to give the title compound (800 mg, 45% yield). LC706

MS (ESI+) m/z 489.4 (M+H)+.

[001301] Step 5 - Tert-butyl N-[3-[3-(3-amino fluoro-propoxy)propoxy1propyl1carbamate

[001302] To a solution of ter/-butyl Af-[3-[3-[3-(dibenzylamino) fluoropropoxy]propoxy]propyl]carbamate (600 mg, 1.23 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 10 wt %) and Pd(OH)2/C (200 mg, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 18 h. On completion, the mixture was filtered and concentrated in vacuo to give the title compound (370 mg, 98% yield) as a white gum. LC-MS (ESI+) m/z 309.0 (M+H)+.

[001303] Methyl 2- [2- [2 [2- r2-(3-amino fluoropropoxylethoxy] ethoxy] ethoxy] ethoxy]ethoxy] acetate(Intermediate BW)

HO

SOCI2

MeOH ,Bn N

Pd(OH)2/C, H2 (gas)

TFA, EtOH

BW

[001304] Step_____________1

Ethyl

2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy] acetate

[001305] To a mixture 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (14.0 g, 58.7 mmol, CAS# 4792 8) and BF3*Et2O (833 mg, 5.88 mmol) in DCM (200 mL) was added dropwise ethyl 2-diazoacetate (6.70 g, 58.7 mmol) in DCM (100 mL) at rt under nitrogen atmosphere. The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH = 100/1) to give the title compound (5.00 g, 26% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.20 (q, J = 7.2 Hz, 2H), 4.14 (s, 2H), 3.75 - 3.62 (m, 18H), 3.62 - 3.58 (m, 2H), 2.69 (s, IH), 1.27 (t, J= 7.2 Hz, 3H).

[001306] Step 2:Ethyl 2-[2-[2-[2-[2-(2methyl sulfonyl oxy ethoxy)ethoxy1 ethoxy] ethoxy] ethoxy] acetate

[001307] To a mixture of ethyl 2-[2-[2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethoxy] ethoxy ]acetate (5.00 g, 15.4 mmol) in DCM (50 mL) was added TEA (4.68 g, 46.2 mmol) and the reaction was cooled to 0 °C. Then MsCI (2.12 g, 18.4 mmol) was added dropwise at 0 °C and the reaction mixture was allowed to warm to rt and stirred for 3 hours. On completion, the reaction mixture was diluted with water (30 mL) and extracted with DCM (3 X 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (6.60 g, 95% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 4.39 - 4.35 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.14 (s, 2H), 3.79 - 3.60 (m, 18H), 3.08 (s, 3H), 1.27 (t, J =7.2 Hz, 3H).

[001308] Step 3:2-r2-r2-r2-r2-[2-r3-(Dibenzvlamino) fluoroPropoxy1ethoxy1ethoxy1ethoxy1ethoxy1ethoxy1 acetic acid

[001309] To a mixture of 3-(dibenzylamino) fluoro-propan-l-ol (67.9 mg, 248 umol, Intermediate AH) in DMF (4 mL) was added NaH (14.9 mg, 372 umol, 60% dispersion in mineral oil) at 0 °C. Then, the reaction mixture was allowed to warm to rt and stirred for 0.5 hour. Then ethyl 2-[2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]acetate (100 mg, 248 umol) was added and the reaction mixture was stirred at rt for an additional 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EA (2 X 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (DCM/MeOH= 10/1) to give the title compound (64.0 mg, 46% yield) as a colorless oil. LC-MS (ESI)+ m/z 552.2. (M+H)+.

[001310] Step 4 Methyl 2-[2-[2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy1ethoxy1ethoxy1ethoxy1ethoxy1 ethoxy] acetate

[001311] To a mixture of 2-[2-[2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy]ethoxy]ethoxy] ethoxy]acetic acid (2.10 g, 3.81 mmol) in MeOH (20 mL) was added S0C12 (3.28 g, 27.5 mmol). The reaction mixture was stirred at rt for 38 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was diluted with water (10 mL) and extracted with DCM (4 X 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography to give the title compound (550 mg, 25% yield) as alight yellow oil. 1HNMR (400MHz, CDCh) δ 7.30 - 7.21 (m, 8H), 7.18-7.13 (m, 2H), 4.10 (s, 2H), 3.69 -3.60 (m, 8H), 3.60-3.51 (m, 22H), 2.68 (d, J= 5.6 Hz, IH), 2.63 (d, J= 5.2 Hz, IH).

[001312] Step 5:Methyl 2-Γ2-[2-Γ2-Γ2-Γ2-(3^π1&#912;η0 &#943;1η0Γ0propoxy)ethoxy1ethoxy1ethoxy1ethoxy1 ethoxy] acetate

[001313] To a mixture of methyl 2-[2-[2-[2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy]ethoxy] ethoxy]ethoxy]acetate (10.0 mg, 17.6 umol) in EtOH (1 mL) was added TFA (15.4 mg, 10.0 uL, 135 umol) and Pd(OH)2/C (20.0 mg, 10 wt %) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (8 mL) and extracted with EA (3X15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (6.00 mg, 88% yield) as a light yellow oil. LC-MS (ESI)+ m/z 386.2. (M+H)+.

[001314] Methyl 2-(2-(2-(3-amin0 flu0r0Dr0D0xv)eth0xv)eth0xy)acetate (Intermediate BX)

Pd/C, Pd(OH)2/C, H2 (gas) Π O I IN Π ΙΝΠ2

O F Bn MeOH, AcOH O F

BX

[001315] Step 1 - 2-[2-[2-[3-(Dibenzylamino) fluoro-propoxy1ethoxy1ethoxy1acetic acid [001316] To a solution of 3-(dibenzylamino) fluoro-propan-l-ol (1.5 g, 5.49 mmol, Intermediate AH) in DMF (20 mL) was added NaH (658 mg, 60% dispersion in mineral oil) at rt. After stirred for 30 minutes, ethyl 2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate (1.93 g, 7.13 mmol, synthesized via Steps 1-2 of Intermediate BM) was added and the mixture was stirred at rt for 12 h. On completion, the mixture was poured into water (60 mL) and extracted with EA (3 X 50 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.00 g, 40% yield). LC-MS (ESI+) m/z 420.1 (M+H)+.

[001317] Step 2:Methyl 2-[2-[2-[3-(dibenzylamino) fluoropropoxy] ethoxy] ethoxy] acetate

[001318] A mixture of 2-[2-[2-[3-(dibenzylamino) fluoro-propoxy]ethoxy]ethoxy]acetic acid (2.00 g, 4.77 mmol), SOC12 (24.6 g, 15 mL) and MeOH (20 mL) was stirred at 70 °C for 1 hour under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: MeOH = 100 : 1 to 20 : 1) to give the title compound (900 mg, 39% yield) as a red oil. LC-MS (ESI+) m/z 434.1 (M+H)+.

[001319] Step 3 - Methyl 2-(2-(2-(3-amino fluoropropoxy)ethoxy)ethoxy)acetate

[001320] To a solution of methyl 2-[2-[2-[3-(dibenzylamino) fluoropropoxy]ethoxy]ethoxy]acetate (1.00 g, 2.31 mmol) in MeOH (20 mL) was added Pd(OH)2/C (100 mg, 10 wt %), Pd/C (100 mg, 10 wt %) and acetic acid (0.1 mL) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen atmosphere (50 psi pressure) at rt for 24 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 mL) and HCI (4M in EA, 5 mL) was added. The mixture was triturated with MTBE (100 mL) and the white solid was collected to give the title compound (400 mg, 60% yield). LC-MS (ESI+) m/z 254.0 (M+H)+.

[001321] 6-(l,3-Benz0thiaz01 vlamin0) (cvcl0Dr0Dvlamin0)Dvridine carb0xylic acid (Intermediate BY)

DI PEA, DMA

Xantphos, Pd2(dba)3, Na2CO3, dioxane, H2O

[001322] Step 1 - Ethyl 6-chloro (cyclopropylamino)pyridine carboxylate

[001323] To a mixture of ethyl 4,6-dichloropyridine carboxylate (30.0 g, 136 mmol) in DMA (300 mL) was added DIPEA (17.6 g, 136 mmol) and cyclopropanamine (8.56 g, 149 mmol). The reaction mixture was heated to 90 °C and stirred for 3 h. On completion, the reaction mixture was quenched with crushed ice. The resulting slurry was stirred and filtered. The filter cake was purified by flash chromatography (PE/EA= 3/l)to give the title compound (28.4 g, 86% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 8.53 (s, IH), 8.08 (s, IH), 7.02 (s, IH), 4.30 (q, J = 7.2 Hz, 2H), 2.63 - 2.57 (m, IH), 1.30 (t, J = 7.2 Hz, 3H), 0.87 - 0.84 (m, 2H), 0.58 - 0.56 (m, 2H).

[001324] Step 2 - Ethyl 6-(L3-benzothiazol vlamino) (cvclopropvlamino)pyridine-3carboxylate

[001325] To a solution of ethyl 6-chloro (cyclopropylamino)pyridine carboxylate (5.00 g, 20.7 mmol) in a mixed solvent of dioxane (30.0 mL) and H2O (5.00 mL) was added 1,3benzothiazol amine (3.12 g, 20.7 mmol), Xantphos (4.81 g, 8.31 mmol) and Na2CO3 (8.81 g, 83.1 mmol), followed by Pd2(dba)3 (7.61 g, 8.31 mmol) to the reaction mixture under nitrogen. The reaction mixture was then heated at 115 °C for 12 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 X 100 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM: MeOH = 100:1) to give the title compound (0.60 g, 6% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 8.91 (s, IH), 8.68 (s, IH), 8.13 (d, J= 2.0 Hz, IH), 8.09 (d, J = 8.8 Hz, 2H), 7.43 (dd, J = 2.0, 8.8 Hz, IH), 6.89 - 6.84 (m, IH), 6.46 (s, IH), 4.30 (q, J = 7.2 Hz, 2H), 2.45 - 2.36 (m, IH), 1.38 (t, J= 7.2 Hz, 3H), 0.80 - 0.74 (m, 2H), 0.62 - 0.57 (m, 2H).

[001326] Step 3 - 6-(L3-Benzothiazol ylamino) (cyclopropylamino)pyridine-3carboxylic acid

[001327] To a solution of ethyl 6-(1,3-benzothiazol ylamino)-4(cyclopropylamino)pyridine carboxylate (0.43 g, 1.21 mmol) in a mixed solvent of H2O (1.00 mL) and THF (3.00 mL) was added LiOH*H2O (152 mg, 3.64 mmol). The reaction mixture was stirred at 40 °C for 24 h. On completion, the reaction was acidified with 2 N HC1 until pH = 4. The reaction mixture was then concentrated in vacuo and lyophilized to give the title compound (500 mg, 79% yield, HC1 salt) as a white solid. LC-MS (ESI+) m/z 327.0 (M+H)+.

[001328] 6-[(5-Cvan0 flu0r0 Dvridvl)amin0] (cvcl0Dr0Dvlamin0)Dvridine-3carboxylic acid(Intermediate BZ)

[001329] Step 1 - 6-Amino fluoro-pyridine carbonitrile

[001330] To a solution of 5-bromo fluoro-pyridin amine (5.00 g, 26.1 mmol), potassium ferrocyanide (3.86 g, 10.4 mmol) and Pd(PPh3)4 (1.51 g, 1.31 mmol) in a mixed solvent of t-BuOH (40.0 mL) and H2O (40.0 mL) was added DBU (996 mg, 6.54 mmol, 986 uL) under nitrogen. The reaction mixture was heated to 85 °C and stirred for 16 h. On completion, the mixture was diluted with water (20.0 mL) and extracted with EA (3 X 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 5:1) to give the title compound (2.50 g, 69% yield) as a yellow solid. 1HNMR (400MHz, DMSO&#1470;d6) δ 8.23 (s, IH), 7.85 (dd, J = 1.6, 11.6 Hz, IH), 7.38 (s, 2H).

[001331] Step 2:Ethyl 6-((5 -cyano-3 -fluoro pyridyl)amino1 -4(cyclopropylamino)pyridine carboxylate

[001332] To a solution of 6-amino fluoro-pyridine carbonitrile (2.50 g, 18.2 mmol), ethyl 6-chloro (cyclopropylamino)pyridine carboxylate (4.39 g, 18.2 mmol, synthesized via Step 1 of Intermediate BY) and Na2CO3 (7.73 g, 72.9 mmol) in a mixed solvent of dioxane (40.0 mL) and H2O (8.00 mL) was added Xantphos (527 mg, 911 umol) and Pd2(dba)3 (834 mg, 911 umol) under nitrogen. The reaction mixture was then heated to 115°C and stirred for 16 h. On completion, the mixture was diluted with a mixed solvent of DCM and MeOH (80.0 mL, 10:1), and stirred for 1 h, then filtered. The solid was washed with water (50 mL) and triturated with a mixed solvent of DCM and MeOH (30 mL, 10: 1) to give the title compound (2.20 g, 35% yield) as a white solid. 1H NMR (400MHz, DMSO4) δ 9.83 (s, IH), 8.62 (d, J = 2.0 Hz, IH), 8.56 (s, IH), 8.21 (dd, J = 1.6, 11.2 Hz, IH), 8.05 - 7.98 (m, 2H), 4.27 (q, J = 7.2 Hz, 2H), 2.55 - 2.54 (m, IH), 1.31 (t, J = 7.2 Hz, 3H), 0.95 - 0.86 (m, 2H), 0.60 - 0.55 (m, 2H).

[001333] Step 3 - 6-[(5-Cyano fluoro pyridyl)amino1 (cyclopropylamino)pyridine-3carboxylic acid

[001334] To a solution of ethyl 6-[(5-cyano fluoro pyridyl)amino]-4(cyclopropylamino)pyridine carboxylate (500 mg, 1.46 mmol) in a mixed solvent of THF (3.00 mL), MeOH (1.00 mL) and H2O (1.00 mL) was added LiOH*H2O (307 mg, 7.32 mmol). The reaction mixture was stirred at 45 °C for 2 hrs. On completion, the mixture was acidified with IN HCI until the pH=3. The mixture was lyophilized to give the title compound (800 mg, 80% yield) as a yellow solid. LC-MS (ESI+) m/z 314.0 (M+H)+.

[001335] 2-[2-(2.,6-Dioxo DiDeridvl)-l.,3-dioxo-isoindolin vl]oxvacetic acid (Intermediate CA)

CA

[001336] Step 1 - 2-(2,6-Dioxo piperidyl) hydroxy-isoindoline-L3-dione

[001337] To a solution of 4-hydroxyisobenzofuran-l,3-dione (20.0 g, 122 mmol) in pyridine (100 mL) was added 3-aminopiperidine-2,6- dione (20.0 g, 122 mmol, HC1 salt). The reaction mixture was stirred at 110 °C for 16 h. On completion, the mixture was concentrated in vacuo. The residue was diluted with water (500 mL) and stirred for 16 h. The mixture was then filtered and the filter cake was dried in vacuo to give the title compound (24.8 g, 74% yield) as a white solid. LC-MS (ESI+) m/z 297.0 (M+Na)+.

[001338] Step 2 - Tert-butyl 2-[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl] oxy acetate

[001339] To a mixture of 2-(2,6-dioxo piperidyl) hydroxy-isoindoline-l,3-dione (20 g, 72.9 mmol) and tert-butyl 2-chloroacetate (16.5 g, 109 mmol) in DMF (50 mL) was added Ag2O (16.9 g, 72.9 mmol), K2CO3 (25.2 g, 182 mmol) and KI (1.21 g, 7.29 mmol). The reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was filtered and the filtrate was diluted with H2O (40 mL) and extracted with DCM (2 X 200 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.40 g, 8.5% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 11.13 (s, IH), 7.84 - 7.78 (m, IH), 7.49 (d, J = 7.2 Hz, IH), 7.38 (d, J = 8.8 Hz, IH), 5.12 (dd, 7=5.2, 12.8 Hz, IH), 4.98 (s, 2H), 2.60 - 2.54 (m, IH), 2.52 - 2.50 (m, 2H), 2.10-2.01 (m, IH), 1.43 (s, 9H).

[001340] Step 3 - 2-[2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin yl1oxyacetic acid [001341] To a mixture of tert-butyl 2-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]oxyacetate (2.40 g, 6.18 mmol) in DCM (10 mL) was added TFA (61.5 g, 539 mmol). Then the reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was concentrated in vacuo to give the title compound (3.10 g, 90% yield, TFA salt) as a white solid. 1H NMR. (400MHz, DMSO-76) δ 11.13 (s, IH), 7.80 (dd, J= 7.2, 8.4 Hz, IH), 7.48 (d, J= 7.2 Hz, IH), 7.40 (d, 7= 8.4 Hz, IH), 5.11 (dd,7=5.2, 12.8 Hz, IH), 5.00 (s, 2H), 2.95 - 2.84 (m, IH), 2.64 - 2.53 (m, 2H), 2.11-1.98 (m, IH); LC-MS (ESI+) m/z 332.9 (M+H)+.

[001342] (3S,4S.,5S) Ethvl fluoro (hvdroxvmethvl)Dvrrolidin one (Intermediate CB)

LDA, ΒΗΤ I) Λ TFA HN A, toluene ' ACN, H2° J ' (X HO^

CB

[001343] Step 1 - (S)-3,3-Dimethyltetrahydropyrrolo[L2-c]oxazol-5(3H)-one

[001344] To a mixture of (5S) (hydroxymethyl)pyrrolidin one (200 g, 1.74 mol) and 2,2dimethoxypropane (517 g, 4.97 mol) in toluene (2.4 L) was added TsOHH2O (13.2 g, 69.5 mmol). The reaction mixture was then stirred at 120 °C for 16 h. On completion, the reaction mixture was concentrated in vacuo and diluted with EA (5L). The mixture was washed with IN NaOH solution (2L) and extracted with EA (8 x IL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with PE (200 mL) to give the title compound (200 g, 74% yield) as a black brown crystal. 1H NMR (400MHz, CDCh) δ 4.29 - 4.19 (m, IH), 4.05 (dd, 7= 5.6, 8.4 Hz, IH), 3.42 (t, 7= 8.4 Hz, IH), 2.81 - 2.71 (m, IH), 2.58 - 2.44 (m, IH), 2.21 - 2.08 (m, IH), 1.82 - 1.66 (m, IH), 1.68 (s, 3H), 1.47 (s, 3H).

[001345] Step 2 - (S)-3,3-Dimethvl ((trimethvlsilvl)oxv)-L3,7,7a-tetrahvdropvrrolo[L2c] oxazole

[001346] To a solution of DIPA (119 g, 1.18 mol) in THF (1.3 mL) was added n-BuLi (2.5 M, 433 mL) at -25 °C. The reaction mixture was stirred for 30 min. Then, the reaction mixture was cooled to -70 °C. A solution of (S)-3,3-dimethyltetrahydropyrrolo[l,2-c]oxazol-5(3J7)-one (140 g, 902 mmol) in THF (500 mL) was added dropwise. The reaction mixture was stirred at -60 °C for 5 min. Then, TMSC1 (127 g, 1.17 mmol) was added dropwise at -60 °C. The reaction mixture was allowed to warm to -10 °C and stirred for 25 min. On completion, the reaction mixture was concentrated in vacuo. The residue was triturated with hexane (1 L), filtered and the filtrate was concentrated in vacuo to give the title compound (140 g, 68% yield) as a colorless oil. The product was unstable and was used for the next step directly without purification.

[001347] Step 3 (7aS)-3,3-dimethyl-L7a-dihydropyrrolo[L2-c1oxazol one

[001348] To a mixture of (S)-3,3-dimethyl ((trimethylsilyl)oxy)-l,3,7,7atetrahydropyrrole[l,2-c]oxazole (140 g, 616 mmol) and allyl methyl carbonate (107 g, 923 mmol) in THF (1.4 L) was added Pd(OAc)2 (41.5 g, 185 mmol). The reaction mixture was stirred at 65 °C for 8 h under nitrogen. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 5:1) to give the title compound (30 g, 32% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.00 (d, J= 5.6 Hz, IH), 6.04 (d, J = 5.6 Hz, IH), 4.67 - 4.49 (m, IH), 4.09 - 4.04 (m, IH), 3.27 (t, J= 8.8 Hz, IH), 1.61 (s, 3H), 1.50 (s, 3H).

[001349] Step 4 - (7R,7aS) Ethvl-3,3-dimethvltetrahvdropvrrolo[L2-c1oxazol-5(3H)-one [001350] To a mixture of bromocopper-methylsulfanylmethane (14.1 g, 68.6 mmol) in THF (200 mL) was added EtMgBr (3 M, 45.7 mL) at -10 °C dropwise. Then, the reaction mixture was cooled to -70 °C and TMSC1 (7.45 g, 68.6 mmol) was added dropwise over 15 min. The reaction mixture was then stirred at -70 °C for an additional 15 min. Then a solution of (7aS)-3,3-dimethyll,7a-dihydropyrrolo[l,2-c]oxazol one (6.00 g, 27.4 mmol) in THF (20 mL) was added dropwise over 10 min. Then the reaction mixture was stirred at 0 °C for 20 min. On completion, the reaction mixture was poured into cool saturated NH4C1 solution (100 mL) and extracted with EA (3 X 500 mL). The combined layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 3:1) to give the title compound (3 g, 60% yield). 1HNMR (400MHz, CDCh) δ 4.34 (td, J= 6.4, 9.6 Hz, IH), 3.90 (dd, J= 6.4, 8.4 Hz, IH), 3.72 (dd, 7= 8.4, 9.6 Hz, IH), 2.91 (dd,7=8.0, 16.8 Hz, 1H),2.31 (dd,7=1.6, 16.8 Hz, IH), 2.28 -2.18 (m, IH), 1.64 (s, 3H), 1.55 - 1.49 (m, IH), 1.48 (s, 3H), 1.37- 1.27 (m, IH), 0.91 (t,7=7.2

Hz, 3H).

[001351] Step 5 - (6S,7S,7aS) Ethyl fluoro-3,3-dimethyltetrahydropyrrolo[L2c1oxazol-5(3H)- one

[001352] A solution of (7R,7aS) ethyl-3,3-dimethyl-l,6,7,7a-tetrahydropyrrolo[l,2c]oxazol one (2.5 g, 13.6 mmol) in THF (10 mL) was treated at -78 °C with LiHMDS (1 M, 15.0 mL) and the mixture was kept for 0.5 h at -78 °C. A solution of NFSI (5.60 g, 17.8 mmol) in THF (10 mL) was added slowly. The mixture was kept at approximately -78° C for 0.5 h. On completion, the precipitated solid was filtered and washed with THF (20 mL). The filtrate was concentrated in vacuo to an oily residue. The oily residue was purified by silica gel chromatography (PE: EA = 10:1). Then, the residue was repurified by reversed phase chromatography (0.1% FA) to give the title compound (575 mg, 21% yield) as a colorless oil. 1H NMR (400MHz, CD3CN) δ 4.89 - 4.73 (m, IH), 4.42 (td, J= 6.4, 10.4 Hz, IH), 3.95 (dd, J= 5.6, 8.4 Hz, IH), 3.59 (dd, 7= 8.4, 10.4 Hz, IH), 2.49 - 2.33 (m, IH), 1.59 (s, 3H), 1.58-1.51 (m, IH), 1.45 (s, 3H), 1.44 - 1.37 (m, IH), 1.00 (t, J= 7.2 Hz, 3H).

[001353] Step 6 - (6S,7S,7aS) Eethyl fluoro-3,3-dimethyltetrahydropyrrolorL2c1oxazol-5(3H)[001354] To a solution of diisopropylamine (322 mg, 3.18 mmol) in toluene (5 mL) was added n-BuLi (2.5 M, 1.26 mL) dropwise at -30 °C. The mixture was maintained at -30 °C. for an additional 30 min, then a solution of (6R,7S,7aS) ethyl fluoro-3,3-dimethyl-l,6,7,7atetrahydropyrrolo[l,2-c]oxazol one (575 mg, 2.86 mmol) in toluene (2 mL) was added dropwise at -78 °C over 2 h. After the addition was completed, the mixture was kept at -78° C for 30 min more before a solution of BHT (1.30 g, 5.91 mmol) in toluene (2 mL) was added dropwise over 0.5 h, keeping the internal temperature below - 65° C. After the addition was completed, the mixture was kept at -78° C for 30 min. The mixture was then warmed to rt and stirred for 2 hrs. On completion, the reaction was quenched with water (5 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 10:1) to give the title compound (244 mg, 40% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 5.36 - 5.15 (m, IH), 4.12 - 4.01 (m, 2H), 3.79 - 3.68 (m, IH), 2.78 -2.64(m, IH), 1.80- 1.70 (m, IH), 1.69 (s, 3H), 1.50 (s, 3H), 1.42- 1.32 (m, IH), 0.98 (t, 7=7.2 Hz, 3H). LC-MS (ESH) m/z 202.1 (M+H)+.

[001355] Step 7 - (3S,4S,5S) Ethyl fluoro (hydroxymethyl)pyrrolidin one

[001356] (6S,7S,7aS) ethyl fluoro-3,3-dimethyl-l,6,7,7a-tetrahydropyrrolo[l,2c]oxazol one (330 mg, 1.64 mmol) in acetonitrile (1.5 mL)andH2O (0.15 mL) was treated with TFA (37.4 mg, 328 umol). The mixture was warmed to ~65 °C over 1 h, and held at that temperature for 3 hrs. On completion, the mixture was concentrated in vacuo. The residue was reversed phase chromatography to give the title compound (230 mg, 91% yield). 1H NMR (400MHz, CDCh) δ 7.59 (s., IH), 4.80 (dd, IH), 3.69-3.83 (m, 2H), 3.52-3.64 (m, IH), 3.48 (br. s, IH), 2.27-2.52 (m, IH), 1.57-1.73 (m, IH), 1.49 (dt, IH), 1.04 (t, 3H). LC-MS (ESL)&#1524;/z 162.1 (M+H)+

[001357] 7-Methoxy-l-oxo-l.,2-dihvdroisoquinoline carbonitrile (Intermediate CO

CuCN

DMSO

[001358] Step 1 - Methyl 4-iodo methoxybenzoate

[001359] To a solution of 3-hydroxy iodo-benzoic acid (25.0 g, 94.7 mmol) in acetone (350 mL) was added K2CO3 (52.4 g, 379 mmol) and CH3I (53.8 g, 379 mmol). The reaction mixture was stirred at 50 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate (150mL) and washed with water (150 mL).The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (24.5 g, 89% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.86 (d, J= 8.0 Hz, IH), 7.46 (d, J= 1.6 Hz, IH), 7.38 (dd, J= 1.6, 8.0 Hz, IH), 3.95 (s, 3H), 3.93 (s, 3H).

[001360] Step 2 - 4-Iodo methoxybenzoic acid

[001361] To a solution of methyl 4-iodo methoxy-benzoate (3.00 g, 10.3 mmol) in a mixture of methanol (20 mL) and water (5 mL) was added LiOHH2O (1.29 g, 30.8 mmol). The reaction mixture was stirred at rt for 2 h. On completion, the reaction mixture was concentrated in vacuo to remove the methanol. The aqueous phase was acidified with 2N HCI solution until the pH = 2, and filtered. The filter cake was dried in vacuo to give the title compound (2.70 g, 95% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 13.21 (s, IH), 7.91 (d, J= 8.0 Hz, IH), 7.42 (d, J= 1.6 Hz, IH), 7.30 (dd, J= 1.6, 8.0 Hz, IH), 3.89 (s, 3H).

[001362] Step 3 - N-(2,2-dimethoxyethyl) iodo methoxybenzamide

[001363] To a mixture of 4-iodo methoxy-benzoic acid (2.3 g, 8.3 mmol), HATU (3.77 g, 9.93 mmol) and DIPEA (3.21 g, 24.8 mmol) in DMF (40 mL) was added 2,2dimethoxyethanamine (1.04 g, 9.93 mmol). The reaction mixture was stirred at rt for 1 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (40mL), acidified with citric acid, and extracted with EA (3 X 100 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (PE/EA=l/2) to give the title compound (2.80 g, 93% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 7.83 (d, J= 8.0 Hz, IH), 7.34 (d, J= 2.0 Hz, IH), 6.99 (dd, 7 = 2.0, 8.0 Hz, IH), 6.33 (s, IH), 4.49 (t, J = 5.6 Hz, IH), 3.95 (s, 3H), 3.61 (t, J = 5.6 Hz, 2H), 3.45 (s, 6H).

[001364] Step 4 - 6-Iodo methoxyisoquinolin-l(2H)-one

[001365] A mixture of A-(2,2-dimethoxyethyl) iodo methoxy-benzamide (3.30 g, 9.04 mmol) in concentrated H2SO4 (15 mL) was stirred at 60 °C for 0.5 h. On completion, the reaction mixture was pour into ice water (200 mL) and extracted with DCM (3 X 200 mL). The combined organic layer was dried in vacuo to give the title compound (2.50 g, 92% yield) as a white solid. 1HNMR (400MHz, DMSO-d6) δ 11.29 (s, IH), 8.22 (s, IH), 7.54 (s, IH), 7.07 (d, 7= 7.2 Hz, IH), 6.48 (d, J= &#906;2 Hz, IH), 3.92 (s, 3H).

[001366] Step 5 - 7-Methoxy-l-oxo-L2-dihydroisoquinoline carbonitrile

[001367] A mixture of 6-iodo methoxy-2H-isoquinolin-l-one (2.4 g, 7.97 mmol) and CuCN (2.14 g, 23.9 mmol) in DMF (50 mL) was stirred at 125 °C for 1 h under nitrogen. On completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in DCM: MeOH = 10:1 (100 mL), filtered and concentrated in vacuo to give the title compound (1.40 g, 88% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.52 (s, IH), 8.24 (s, IH), 7.78 (s, IH), 7.17 (dd, J= 5.6, 7.2 Hz, IH), 6.57 (d, J= 7.2 Hz, IH), 4.02 (s, 3H).

[001368] l-(((2S,3S,4S) Ethvl fluoro oxoDvrrolidin vl)methoxy)-7methoxyisoquinoline carbonitrile(Intermediate CD)

[001369] Step 1 - l-Chloro methoxyisoquinoline carbonitrile

[001370] To a mixture of 7-methoxy-l-oxo-2H-isoquinoline carbonitrile (1.25 g, 6.24 mmol, Intermediate CC) in dioxane (50 mL) was added POC13 (3.83 g, 25.0 mmol). The reaction mixture was stirred at 110 °C for 2 h. On completion, the reaction mixture was concentrated to remove the solvent. The residue was dissolved in DCM (20 mL) and washed with NaHCO3 solution until the pH= 8. The reaction mixture was then extracted with DCM (3 X 100 mL). The combined layer was dried over Na2SO4, fdtered, and the fdtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: DCM = 1:5) to give the title compound (1.00 g, 60% yield) as an off-white solid. LC-MS (ESI+) m/z 219.0 (M+H)+.

[001371] Step 2 - l-(((2S,3S,4S) Ethyl fluoro oxopyrrolidin yl)methoxy)-7methoxyisoquinoline carbonitrile

[001372] A mixture of l-chloro methoxy-isoquinoline carbonitrile (50.0 mg, 229 umol) and (3S,4S,5S) ethyl fluoro (hydroxymethyl)pyrrolidin one (36.9 mg, 229 umol, Intermediate CB) were stirred in DMF (1 mL) and cooled to approximately -10° C. A solution of KHMDS (1 M, 503.11 uL) in THF was then added into the reaction mixture over ~15 minutes, maintaining the internal reaction temperature at approximately -10° C. After, the reaction was stirred at -10° C for approximately an additional 30 minutes. On completion, the reaction mixture was quenched with saturated NaH2PO4 (20 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo. The residue was purified by prep-TLC (EA) to give the title compound (50.0 mg, 49% yield) as a white solid. LC-MS (ESI+) m/z 344.0 (M+H)+

[001373] l-[[(2S.,3S.,4S) ethvl fluoro oxo-Dvrrolidin vl]methoxv] methoxvisociuinoline-6carboxylic acid (Intermediate

CE)

CE

[001374] Step 1 - 7-Methoxy-l-oxo-2H-isoquinoline carboxylic acid

[001375] To a solution of 7-methoxy-l-oxo-2H-isoquinoline carbonitrile (1.50 g, 7.49 mmol, Intermediate CC) in ethanol (30 mL) was added aqueous sodium hydroxide (10 M, 15.0 mL). The mixture was stirred at 80 °C for 15 h. On completion, the reaction mixture was concentrated in vacuo to remove the ethanol. The residue was acidified with saturated citric acid aqueous until the pH < 6. A fine light yellow precipitate formed and the precipitate was filtered and dried in vacuo to give the title product (1.20 g, 73% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 13.16 (br s, IH), 11.35 (br s, IH), 7.91 (s, IH), 7.70 (s, IH), 7.10 (dd, J= 5.6, 6.8 Hz, IH), 6.59 (d, J= 7.2 Hz, IH), 3.91 (s, 3H).

[001376] Step 2 - Methyl 7-methoxy-l-oxo-2H-isoquinoline carboxylate

[001377] To a solution of 7-methoxy-l-oxo-2H-isoquinoline carboxylic acid (1.10 g, 5.02 mmol) in methanol (50 mL) was added sulfonyl chloride (3.58 g, 30.1 mmol, 2.18 mL). The mixture was stirred at 70 °C for 15 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in ice water (30 mL) and basified with saturated sodium bicarbonate aqueous until the pH > 7 and a fine light yellow precipitate was formed. The precipitate was filtered and dried in vacuo to give the title compound (1.10 g, 93% yield) as a light yellow solid. 1HNMR (400MHz, CDCh) δ 10.79 (br s, IH), 7.89 (s, IH), 7.83 (s, IH), 7.03 (d, J = 6.8 Hz, IH), 6.49 (d, J= 7.2 Hz, IH), 3.96 (s, 3H), 3.89 (s, 3H).

[001378] Step 3 - Methyl l-chloro methoxy-isoquinoline carboxylate

[001379] Methyl 7-methoxy-l-oxo-2//-isoquinoline carboxylate (1.00 g, 4.29 mmol) was dissolved in POC13 (30 mL) and the mixture was stirred at 105°C for 14 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in ice water (50 mL) and basified with saturated sodium bicarbonate aqueous until the pH > 7, and a fine light yellow precipitate was formed. The precipitate was filtered and dried in vacuo to give the title compound (1.00 g, 92% yield) as a light yellow solid. 1H NMR (400MHz, CDCh) δ 8.25 (d, J= 5.6 Hz, IH), 8.23 (s, IH), 7.65 (s, IH), 7.60 (d, J= 5.6 Hz, IH), 4.09 (s, 3H), 4.00 (s, 3H).

[001380] Step 4 - l-Chloro methoxy-isoquinoline carboxylic acid

[001381] To a solution of methyl l-chloro methoxy-isoquinoline carboxylate (1.00 g, 3.97 mmol) in a mixed solution of tetrahydrofuran (20 mL) and water (10 mL) was added lithium hydroxide (380 mg, 15.8 mmol). The mixture was stirred at rt or 14 h. On completion, the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The resulting residue was acidified with 1 N hydrochloride acid until the pH = 6 and a white precipitate was formed. The precipitate was filtered and the filter cake was dried in vacuo to give the title compound (900 mg, 95% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 8.22 (d, J = 5.6 Hz, IH), 8.18 (s, IH), 7.89 (d, J= 5.6 Hz, IH), 7.53 (s, IH), 3.98 (s, 3H).

[001382] Step 5 - l-rr(2S,3S,4S) ethyl fluoro oxo-pyrrolidin yl1methoxy1-7methoxy-isoquinoline carboxylic acid

[001383] A mixture of l-chloro methoxy-isoquinoline carboxylic acid (200 mg, 841 umol), (35,45,55) ethyl fluoro (hydroxymethyl)pyrrolidin one (135 mg, 841 umol, Intermediate CB) in N,N- dimethylformamide (8 mL) was cooled to -10°C, and KHMDS (1 M, 3.53 mL) was added dropwise under nitrogen gas atmosphere to keep the temperature at -10 °C over 0.25 h. The mixture was stirred at 0 °C for 15 h. On completion, the reaction mixture was quenched with ice water (30 mL) and acidified with 1 N hydrochloride acid until the pH = 5, and then extracted with di chloromethane (3X15 mL). The combine organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.05% HC1)-ACN]) to give the title compound (95.0 mg, 28% yield, hydrochloride salt) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.91 (s, IH), 8.13 (s, IH), 7.92 (d, J= 5.6 Hz, IH), 7.74 (s, IH), 7.43 (d, J = 5.6 Hz, IH), 4.99 - 4.82 (m, IH), 4.55 (dd, J = 3.2, 11.2 Hz, IH),

4.26 (dd, 7=6.4, 11.2 Hz, IH), 4.10 - 4.09 (m, IH), 3.94 (s, 3H), 2.69 - 2.55 (m, IH), 1.66-1.56 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).

[001384] 22&#1524;,-(Pentane-l.,5-divlbis(oxv))diethanamine(Intermediate CF)

ΝΗ2ΝΗ2.Η2Ο o zx O zx

---------&#9658; H2N ^' ethanol CF

[001385] Step 1 - Diethyl 2,2'-(pentane-L5-diylbis(oxy))diacetate

[001386] To a solution of pentane-l,5-diol (20 g, 192 mmol, 20.2 mL) and Rh(OAc)2 (1.70 g, 7.68 mmol) in DCM (50 mL) was added a solution of ethyl 2-diazoacetate (21.9 g, 192 mmol) in DCM (200 mL), and the reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 X 200 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE/EA=5/1) to give the title compound (10 g, 19% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 4.24 - 4.20 (m, 4H), 4.05 (s, 4H), 3.55 3.51 (m, 4H), 1.67 - 1.64 (m, 4H), 1.48 - 1.46 (m, 2H), 1.30 - 1.26 (m, 6H).

[001387] Step 2 - 2,2'-(Pentane-L5-diylbis(oxy))diethanol

[001388] To a solution of LAH (3.43 g, 90.5 mmol) in THF (100 mL) was added slowly dropwise a solution of ethyl 2-[5-(2-ethoxy oxo-ethoxy)pentoxy]acetate (10.0 g, 36.2 mmol) in THF (100 mL) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 1 h under nitrogen. On completion, the reaction mixture was quenched with water (6 mL) and 15% sodium hydroxide solution (10 mL). Then, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (5.7 g, 83% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 3.69 - 3.62 (m, 4H), 3.49 - 3.45 (m, 4H), 3.42 (t, J = 6.0 Hz, 4H), 2.33 (t, J = 6.0 Hz, 2H), 1.60 - 1.52 (m, 4H), 1.44 - 1.35 (m, 2H).

[001389] Step 3 -(Pentane-L5-diylbis(oxy))bis(ethane-2,l-diyl) dimethanesulfonate

[001390] To a solution of 2-[5-(2-hydroxyethoxy)pentoxy]ethanol (5.7 g, 29.7 mmol) in DCM (60 mL) was added TEA (9.00 g, 89.0 mmol) and MsCl (8.49 g, 74.1 mmol). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was quenched with water (10 mL). Then, the mixture was washed with IN citric aqueous (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (10 g, 97% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 4.45 - 4.33 (m, 4H), 3.76 - 3.68 (m, 4H), 3.51 (t, J = 6.4 Hz, 4H), 3.08 (s, 6H), 1.67 - 1.60 (m, 4H), 1.48 - 1.41 (m, 2H).

[001391] Step 4 - 2,2'-((Pentane-L5-diylbis(oxy))bis(ethane-2,l-diyl))bis(isoindoline-L3di one)

[001392] A solution of 2-[5-(2-methylsulfonyloxyethoxy)pentoxy]ethyl methanesulfonate (10 g, 28.7 mmol) and (l,3-dioxoisoindolin yl)potassium (11.7 g, 63.1 mmol) in DMF (100 mL) was heated to 100 °C for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was dissolved ethyl acetate (300 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 5:1) to give the title compound (11 g, 77% yield). 1H NMR (400MHz, CDCh) δ 7.92 - 7.82 (m, 4H), 7.77 - 7.72 (m, 4H), 3.88 (t, J= 6.0 Hz, 4H), 3.64 (t, J= 6.0 Hz, 4H), 3.39 (t, J= 6.4 Hz, 4H), 1.54 - 1.44 (m, 4H), 1.30- 1.23 (m, 2H).

[001393] Step 5 - 2,2'-(Pentane-L5-diylbis(oxy))diethanamine

[001394] To a solution of 2-[2-[5-[2-(l,3-dioxoisoindolin-2yl)ethoxy]pentoxy]ethyl]isoindoline-l,3-dione (1.10 g, 2.44 mmol) in ethanol (20 mL) was added NH2NH2H2O (624 mg, 12.2 mmol). The reaction mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo. Then, the residue was diluted with DCM (20 mL) and filtered again. The filtrate was concentrated in vacuo to give the title compound (460 mg, 99% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 3.51 - 3.43 (m, 8H), 2.87 (t, J= 5.2 Hz, 4H), 1.68 - 1.57 (m, 4H), 1.50 - 1.39 (m, 2H).

[001395] Tert-butyl N-dl-aminoundecvDcarbamate(Intermediate CG) (Boc)2O

H2N +/+/+/+/+/ NH2 -------*&#1470; BocHN +/ +/\/ +/ +/ NH2 chci3

CG

[001396] To a mixture of undecane-1,11-diamine (512 mg, 2.75 mmol) in CHCh (25 mL) was added a solution of tert-butoxycarbonyl tert-butyl carbonate (120 mg, 549 umol) in CHC13 (5 mL) dropwise. The reaction mixture was stirred at rt for 20 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (120 mg, 76% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 4.54 (s, 1H), 3.12 (d, 6.0 Hz, 2H), 2.70 (t, J= 7.0 Hz, 2H), 1.70 - 1.55 (m, 4H), 1.46 (s, 9H), 1.32 &#1470;

1.25 (m, 14H).

[001397] Ethyl

2-[2-[2-[2-[2-(tertbutoxycarbonylaminolethoxy] ethoxy] ethoxy] ethoxy] acetate(Intermediate CH)

BF3&#1470;Et2O(cat ), DCM

MsCI, TEA

DCM

O

NaN3

DMF

Pd/C, H2 (gas) (Boc)2O, EA

CH

[001398] Step 1 - Ethyl 14-hydroxy-3A9,12-tetraoxatetradecan-l-oate

[001399] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (10.0 g, 51.5 mmol, CAS# 112 7) in DCM (150 mL) was added BF3*Et2O (159 mg, 515 umol) at 0 °C. Then, ethyl 2-diazoacetate (5.87 g, 51.5 mmol) was added to the reaction mixture dropwise. After that, the mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was quenched by ammonium chloride (5 mL), then diluted with water (100 mL), and extracted with DCM (3 X 50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give the title compound (2.60 g, 18% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.16 (<yJ = 7.2 Hz, 2H), 4.10 (s, 2H), 3.71 - 3.59 (m, 14H), 3.58 - 3.54 (m, 2H), 1.24 (t, J = 7.2 Hz, 3H).

[001400] Step_____________2

Ethyl 2-[2-[2-[2-(2methyl sulfonyl oxy ethoxy)ethoxy1 ethoxy] ethoxy] acetate

[001401] To a solution of ethyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate (6.86 g, 24.5 mmol) in DCM (50 mL) was added TEA (4.95 g, 48.9 mmol). The reaction mixture was cooled to 0 °C. Then MsCl (3.36 g, 29.4 mmol) was added into the solution slowly. The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was quenched with H2O (20 mL) and saturated citric acid solution (20 mL) was added until the pH = 5 - 6, then they organic layer was separated. The organic layer was washed with brine (4 X 50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (8.00 g, 91% yield) as a brown oil. 1H NMR (400MHz, CDCh) δ 4.43 - 4.37 (m, 2H), 4.23 (q, J = 7.2 Hz, 2H), 4.16 (s, 2H), 3.82 - 3.62 (m, 14H), 3.10 (s, 3H), 1.30 (t, J= 7.2 Hz, 3H).

[001402] Step 3 - Ethyl 2-r2-r2-r2-(2-azidoethoxy)ethoxv1ethoxv1ethoxv1acetate

[001403] To a solution of ethyl 2-[2-[2-[2-(2methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate (8.00 g, 22.3 mmol) in DMF (30 mL) was added NaN3 (2.90 g, 44.6 mmol). The reaction mixture was stirred at 80 °C for 15 h. On completion, the solvent DMF was removed in vacuo. Then the residue was diluted with EA (150 mL) and filtered. The filtrate was used for the next step directly without further purification or concentration. LC-MS (ESI+) m/z 278.1 (M+H-28)+.

[001404] Step 4:Ethyl 2-[2-[2-[2-[2-(tertbutoxycarbonylaminojethoxy] ethoxy] ethoxy] ethoxy] acetate

[001405] To a solution of ethyl 2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]acetate (6.81 g, 22.3 mmol) inEA(150 mL) was added Pd/C (700 mg, 10 wt %) and (Boc)2O (24.3 g, 112 mmol). The mixture was degassed and purged with hydrogen gas three times. Then the reaction mixture was stirred at rt for 15 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (DCM/MeOH = 10/1) to give the title compound (5.15 g, 61% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 5.05 (s, IH), 4.27 (q, J= 7.2 Hz, 2H), 4.17 (s, 2H), 3.79 - 3.60 (m, 12H), 3.56 (t, J= 5.2 Hz, 2H), 3.37 - 3.27 (m, 2H), 1.45 (s, 9H), 1.31 (t, J= 7.2 Hz, 3H).

[001406] Step 5:Ethyl 2-[2-[2-[2-[2-(tertbutoxycarbonylaminojethoxy] ethoxy] ethoxy] ethoxy] acetate

[001407] To a solution of ethyl 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate (0.40 g, 1.05 mmol) in THF (10 mL) and H2O (4 mL) was added LiOH (50.5 mg, 2.11 mmol). The reaction mixture was stirred at rt for 16 hours. On completion, the mixture was concentrated in vacuo to give a residue, then diluted with H2O. The aqueous phase was acidified with cone. HC1 until the pH = 6 and concentrated in vacuo to give the title compound (350 mg, 996 umol) as a yellow solid. 1HNMR (400MHz, CDCh) δ 4.18 (m, 2H), 3.80 - 3.63 (m, 14H), 3.46 - 3.17 (m, 2H), 1.46 - 1.41 (s, 9H).

[001408] (2S,4R)-l-[(2S) amino-3,3-dimethvl-butanovl] hydroxv-N-[[4-(4methvlthiazol vl)-Dhenvl]methvl]Dvrrolidine carboxamide(Intermediate CI)

[001409] Step 1 - 4-(4-Methylthiazol yl)benzonitrile

[001410] To a mixture of 4-bromobenzonitrile (32.0 g, 176 mmol), 4-methylthiazole (34.86 g, 352 mmol) and KOAc (34.5 g, 352 mmol) in DMA (100 mL) was added Pd(OAc)2 (820 mg, 3.65 mmol). The mixture was stirred at 150 °C under nitrogen atmosphere for 2 hours. On completion, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 X 200 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was triturated with PE (100 mL) and filtered to give the title compound (28.8 g, 82% yield) as a yellow solid. 1H NMR (400MHz, MeOD-A) δ 8.98 (s, IH), 7.85 - 7.81 (m, 2H), 7.71 - 7.66 (m, 2H), 2.53 (s, 3H); LC-MS (ESI+) m/z 201.0 (M+H)+.

[001411] Step 2 - [4-(4-Methylthiazol yl)phenyl1methanamine

[001412] To a solution of 4-(4-methylthiazol yl)benzonitrile (14.7 g, 73.4 mmol) in MeOH (460 mL) was added di chlorocob alt (14.3 g, 110 mmol) and the mixture was cooled to 0 °C. Then, NaBH4 (13.9 g, 367 mmol) was added in portions over 0.5 hour. Finally, the mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was quenched with NH3 H2O (20 mL, 30 wt %), then diluted with water (100 mL) and extracted with DCM (3 X 80 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase flash column (0.1% NH3.H2O in water) to give the title compound (3.50 g, 23.3% yield) as a yellowish oil. LC-MS (ESI+) m/z 205.1 (M+H)+.

[001413] Step 3 - Tert-butyl (2S,4R) hydroxy [[4-(4-methylthiazol-5yl)phenyl1methylcarbamoyl1

[001414] -pyrrolidine-1 -carboxylate

[001415] A solution of (2S,4R)-l-tert-butoxycarbonyl hydroxy-pyrrolidine carboxylic acid (3.36 g, 14.5 mmol, CAS# 13726 7) in DMF (50 mL) was cooled to 0 °C. Then, DIPEA (5.13 g, 39.7 mmol), [4-(4-methylthiazol yl) phenyl] methanamine (2.70 g, 13.2 mmol) and HATU (6.03 g, 15.9 mmol) were added. Finally, the mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was diluted with water (50 mL) and extracted with DCM (3 X 60 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase flash (0.1% NH3 H2O in water) column to give the title compound (1.70 g, 30% yield) as a yellowish solid. 1H NMR (400MHz, MeOD-J4) δ 8.91 (s, IH), 7.48 - 7.40 (m, 4H), 4.74 - 4.25 (m, 4H), 3.66 - 3.56 (m, IH), 3.54 - 3.43 (m, IH), 2.48 (s, 3H), 2.31 - 2.20 (m, IH), 2.08 - 1.98 (m, IH), 1.54 - 1.25 (m, 9H); LC-MS (ESI+) m/z 418.0 (M+H)+.

[001416] Step 4:(2S,4R) hydroxy-N-[[4-(4-methylthi azol-5yl)phenyl1methyl1pyrrolidine carboxamide

[001417] To a solution of tert-butyl (2S,4R) hydroxy [[4-(4-methylthiazol-5yl)phenyl]methylcarbamoyl] -pyrrolidine carboxylate (1.70 g, 4.07 mmol) in DCM (10 mL) was added HCI in dioxane (4 M, 10 mL) and the mixture was stirred at rt for 6 hours. On completion, the mixture was concentrated under reduced pressure to give the product (1.60 g, HCI salt, 96% yield) as a yellowish solid. LC-MS (ESI+) m/z 318.0 (M+H)+.

[001418] Step 5 - Tert-butyl N-[(lS)-l-[(2S,4R) hydroxy [[4-(4-methylthiazol-5 yl)phenyl1 methyl carbamoyl1pyrrolidine-l-carbonyl1-2,2-dimethyl-propyl1carbamate

[001419] A solution of (2S,4R) hydroxy-N-[[4-(4-methylthiazol-5yl)phenyl]methyl]pyrrolidine carboxamide (1.60 g, 4.52 mmol, HC1 salt) in DMF (25.00 mL) was cooled to 0 °C. Then, DIPEA (1.75 g, 13.6 mmol), (2S) (tert-butoxycarbonylamino)-3,3dimethyl-butanoic acid (1.31 g, 5.65 mmol) and HATU (2.06 g, 5.43 mmol) were added. Finally, the mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove the DMF. The residue was diluted with water (40 mL) and extracted with DCM (3 X 40 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase flash column (0.1% ΝΗ3&#905;2Ο in water) to give the title compound (1.70 g, 70% yield) as a light yellow solid. 1H NMR (400MHz, CDC13-77) δ 8.71 (s, IH), 7.43 (s, IH), 7.39 7.30 (m, 4H), 5.20 (d, J= 8.0 Hz, IH), 4.78 (t, J= 1.6 Hz, IH), 4.59 (m, IH), 4.33 (m, IH), 4.18 - 4.09 (m, 2H), 3.58 (m, IH), 2.60 (m, IH), 2.52 (s, 3H), 2.14 (m, IH), 1.41 (s, 9H), 0.92 (s, 9H); LC-MS (ESE)/77 2 531.1 (M+H)+.

[001420] Step 6 - (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl1 hydroxy-N-[[4-(4methylthiazol yl)-phenyl1methyl1pyrrolidine carboxamide

[001421] To a solution of tert-butyl N-[(l S)-l-[(2S,4R) hydroxy [[4-(4-methylthiazol-5yl)phenyl]-methyl carbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]carbamate (1.60 g, 3.01 mmol) in DCM (20 mL) was added HC1 in dioxane (4 M, 20 mL). Then, the mixture was stirred at rt for 6 hours. On completion, the mixture was concentrated under reduced pressure to give the title compound as a light yellow solid (1.90 g, HC1 salt, 95% yield). 1H NMR (400MHz, MeOD-i4) δ 9.98 (s, IH), 7.58 - 7.52 (m, 4H), 4.72 - 4.65 (m, IH), 4.60 - 4.50 (m, 2H), 4.46 - 4.38 (m, IH), 4.07 (s, IH), 3.86 -3.83 (m, IH), 3.75 - 3.68 (m, IH), 3.60 (s, IH), 2.61 (s, 3H), 2.33 2.28 (m, IH), 2.11 - 2.05 (m, IH), 1.14 (s, 9H); LC-MS (ESI+) 777/2 431.1 (M+H)+.

[001422] 4-Nitro-lH-Dvrazole carboxamide(Intermediate CJ)

O /— 0 y-0 νη3.η2ο V-nh2

N=/ N=<

HN^^NOz HN^A'NOz

CJ

[001423] A solution of ethyl 4-nitro-lH-pyrazole carboxylate (6.00 g, 32.4 mmol, CAS# 55864 4) in NH3eH2O (60 mL) was stirred at 100 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (5.10 g, 98% yield) as a light yellow solid. 1HNMR (400MHz, DMSO-d6) δ 8.71 (s, IH), 8.09 ( s, IH), 7.85 ( s, IH).

[001424] (E)-N,N-dimethvl nitro-ethenamine(Intermediate CK) MeV / MeNO2 A MeO X —N

CK

[001425] Amixture of l,l-dimethoxy-N,N-dimethyl-methanamine (20.0 g, 167 mmol, 22.30 mL) in MeNO2 (12.8 mL) was stirred at 80 °C for 30 minutes. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (14.0 g, 72% yield) as a red brown solid. 1H NMR (400MHz, DMSO-d6) δ 8.13 (d, J= 10.8 Hz IH), 6.62 (d, J= 10.8 Hz, IH), 3.21 (s, 3H), 2.88 (s, 3H).

[001426] Methyl 4-(4-amino carbamoyl-Dvrazol-l-vl)benzoate (Intermediate CL)

[001427] Step 1 - Ethyl (2E) r(4-bromophenyl)hydrazono1 chloro-acetate

[001428] To a mixture of 4-bromoaniline (50.0 g, 291 mmol) in a mixed solvent of HC1 (12 N, 72.6 mL) and H2O (150 mL) was added a solution of NaNO2 (22.1 g, 319 mmol) in H2O (50 mL) dropwise at -5°C. The mixture was stirred at 0°C for 0.5 hour. Then ethyl 2-chloro oxobutanoate (50.2 g, 305 mmol, 42.2 mL) and NaOAc (71.53 g, 872 mmol) were added to the solution at 0°C and the mixture was stirred for 30 minutes. The reaction mixture was then allowed to warm to rt and stirred for an additional for 2 hours. On completion, the reaction mixture was filtered and the filter cake was dried in vacuo. The residue was triturated with MeOH (500 mL) to give the title compound (50.0 g, 56% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.32 (s, IH), 7.45 - 7.20 (m, 2H), 7.14-7.11 (m, 2H), 4.40 (q, J= 7.2 Hz, 2H), 1.41 (t, J= 7.2 Hz, 3H).

[001429] Step 2 - Ethyl l-(4-bromophenyl) nitro-pyrazole carboxylate

[001430] Ethyl (2Z) [(4-bromophenyl)hydrazono] chloro-acetate (1.00 g, 3.27 mmol), (E)-N,N-dimethyl nitro-ethenamine (380 mg, 3.27 mmol, Intermediate CK) and Et3N (331 mg, 3.27 mmol) were taken up into a microwave tube in CHC13 (3 mL). The sealed tube was heated at 140 °C for 1 hour under microwave. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase flash (0.1% FA in water) to give the title compound (350 mg, 28% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 9.76 (s, IH), 7.97 - 7.90 (m, 2H), 7.85 - 7.78 (m, 2H), 4.43 (q, J= 7.2 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H).

[001431] Step 3 - l-(4-Bromophenyl) nitro-pyrazole carboxamide

[001432] To a solution of ethyl l-(4-bromophenyl) nitro-pyrazole carboxylate (0.50 g, 1.47 mmol) in THF (10 mL) was added ΝΗ3.Η2Ο (15.1 g, 129 mmol, 16.6 mL, 30 wt %). The mixture was stirred at 110 °C for 3 hours in a seal tube. On completion, the reaction mixture was concentrated in vacuo to give the title compound (500 mg, 98% yield) as pale solid. LC-MS (ESI+) m/z 310.9 (M+H)+.

[001433] Step 4 - 4-Amino-l-(4-bromophenyl)pyrazole carboxamide

[001434] To a solution of l-(4-bromophenyl) nitro-pyrazole carboxamide (500 mg, 1.61 mmol) in MeOH (10 mL) and H2O (4 mL) was added Fe (898 mg, 16.0 mmol) and NH4C1 (860 mg, 16.0 mmol). The mixture was stirred at 75 °C for 5 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EA (30 mL) and washed with water (10 mL). The organic layer was separated and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (230 mg, 49% yield) as a yellow solid. LC-MS (ESI+) m/z 304.9 (M+Na+2)+.

[001435] Step 5 - Methyl 4-(4-amino carbamoyl-pyrazol-l-yl)benzoate

[001436] A mixture of 4-amino-l-(4-bromophenyl)pyrazole carboxamide (0.23 g, 818 umol), dppf (18.2 mg, 32.0 umol), Pd(OAc)2 (7.35 mg, 32.0 umol) in DMF (5 mL) and MeOH (5 mL) was degassed and purged with nitrogen gas three times. Then the mixture was stirred at 80 °C for 16 h under CO atmosphere (50 psi pressure). On completion, the mixture was filtered and the filtrate was concentrated to remove MeOH. Then the residue was diluted with EA (200 mL) and washed with water (2 X 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (140 mg, 61% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.12 7.96 (m, 4H), 7.89 (s, IH), 7.62 (s, IH), 7.33 (s, IH), 4.95 (s, 2H), 3.87 (s, 3H); LC-MS (ESI+) m/z 261.0 (M+H)+.

[001437] 2-[2-[tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino] Dvridvl]oxazole-4carboxylic acid (Intermediate

CM)

Br (Boc)2O

LiHMDS, THF

H

Boc

Cs2CO3, DMF

(Bip)2, KOAc, Pd(dppf)CI2 dioxane

[001438] Step 1 - Tert-butyl N-(4-bromo pyridvl)carbamate

[001439] A solution of 4-bromopyridin amine (5.00 g, 28.9 mmol) in dry THF (100 mL) was treated with LiHMDS (1 M, 57.8 mL) at -5 °C and the solution was stirred at -5 °C for 10 minutes. Then (Boc)2O (6.31 g, 28.9 mmol) was added and the mixture was allowed to warm to rt and stirred for 1 h. On completion, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with EtOAc (3 X 100 mL). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (6.50 g, 82% yield) as a white solid. 1H NMR (400MHz, CDCh) δ = 8.92 (s, IH), 8.27 (d, 7= 0.8 Hz, IH), 8.13 (d,7= 5.2 Hz, IH), 7.12 (dd,7= 1.6, 5.2 Hz, IH), 1.55 (s, 9H).

[001440] Step 2 - Tert-butyl N-(4-bromo pyridyl)-N-(2,2,2-trifluoroethyl)carbamate [001441] To a mixture of tert-butyl 7V-(4-bromo pyridyl)carbamate (6.10 g, 22.3 mmol), cesium carbonate (11.0 g, 33.7 mmol) and DMF (60 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (5.18 g, 22.3 mmol). The reaction mixture was stirred at rt for 15 h. On completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3 X 100 mL). The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (5.70 g, 72% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ = 8.18 (d, J = 5.2 Hz, IH), 8.01 - 7.94 (m, IH), 7.24 (dd, J= 1.6, 5.2 Hz, IH), 4.81 (q, J= 8.8 Hz, 2H), 1.55 (s, 9H).

[001442] Step 3 - Tert-butyl N-r4-(4A5,5-tetramethyl-L3,2-dioxaborolan yl) pyridyl1N-(2,2,2-trifluoro ethyDcarbamate

[001443] To a solution of tert-butyl 7V-(4-bromo pyridyl)-7V-(2,2,2trifluoroethyl)carbamate (3.00 g, 8.45 mmol) in dioxane (60 mL) was added 4,4,5,5-tetramethyl2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)-l,3,2- dioxaborolane (10.7 g, 42.2 mmol), KOAc (1.66 g, 16.9 mmol) and Pd(dppf)C12*CH2C12 (345 mg, 423 umol) under nitrogen atmosphere. The reaction mixture was then heated to 65 °C and stirred for 2 h. On completion, the reaction mixture was diluted with ethyl acetate (100 mL) and fdtered. The fdtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (3.00 g, 96% yield) as a white solid. 1H NMR (400MHz, CDCh) δ = 8.38 (dd, J= 0.8, 4.8 Hz, IH), 7.91 (s, IH), 7.42 (d, J= 4.8 Hz, IH), 4.76 (q, J= 8.8 Hz, 2H), 1.52 (s, 9H), 1.35 (s, 12H).

[001444] Step 4 - Ethyl 2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carboxylate

[001445] To a solution of tert-butyl 7V“[4“(4,4,5,5“tetramethyl“l,3,2“d1oxaborolan-2“yl)“2“ pyridyl]-7V-(2,2,2- trifluoroethyl)carbamate (4.00 g, 9.94 mmol), ethyl 2-bromooxazole-4carboxylate (2.19 g, 9.94 mmol) in dioxane (40 mL) and H2O (8 mL) was added Cs2CO3 (6.48 g, 19.9 mmol) and Pd(dppf)C12 CH2C12 (406 mg, 497 umol) and the mixture was stirred at 80 °C for 16 h. On completion, the reaction mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (2.10 g, 51% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ = 8.50 (d, J= 5.2 Hz, IH), 8.38 (s, IH), 8.34 (s, IH), 7.79 (d, J= 5.2 Hz, IH),

4.85 (q, J= 8.8 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 1.56 (s, 9H), 1.43 (t, J= 7.2 Hz, 3H); LC-MS (ESC) 416.1 2/&#1524; (M+H)+.

[001446] Step 5 - 2-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1 pyridyl1oxazole

4-carboxylic acid

[001447] To a solution of ethyl 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylate (100 mg, 241 umol) in THF (1 mL) and H2O (200 uL) was added LiOH (11.5 mg, 482 umol). The mixture was stirred at rt for 0.5 h. On completion, the reaction mixture was acidified with IN HCI (3 mL) to pH = 5, then extracted with ethyl acetate (5 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (90.0 mg, 97% yield) as a white solid. 1HNMR (400MHz, CDCh) δ = 8.53 (dd, J = 0.8, 5.2 Hz, IH), 8.46 (s, IH), 8.40 (s, IH), 7.79 (dd, J= 1.2, 5.2 Hz, IH), 7.81 - 7.77 (m, IH), 4.86 (q, J= 8.8 Hz, 2H), 1.57 (s, 9H); LCMS (ESI+) m/z 388.1 (M+H)+

[001448] 4-[4-[[2-[2-[Tert-butoxvcarbonvl(2,2,2-trifluoroethyl)amino]-4 pyridyl]oxazole carbonyl] amino] carbamoyl-Dvrazol-l-vl]benzoic acid (Intermediate

CN)

CN

[001449] Step 1 - Methyl 4-r4-rr2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4 pyridyl1oxazole carbonyl1amino1 carbamoyl-pyrazol-l-yl1benzoate

[001450] To a mixture of methyl 4-(4-amino carbarnoyl-pyrazol-l-yl)benzoate (120 mg,

461 umol, Intermediate CL) and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (179 mg, 461, Intermediate CM) in DMF (5 mL) was added DIPEA (179 mg, 1.38 mmol) and HATU (210 mg, 553 umol) and the mixture was stirred at rt for 2 h. On completion, the mixture was diluted with water (20 mL), extracted with EA (2 X 50 mL), and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (223 mg, 72% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.07 (s, IH), 9.11 (s, IH), 9.06 (s, IH), 8.74 - 8.61 (m, IH), 8.26 (s, IH), 8.16 - 8.05 (m, 5H), 7.86 - 7.75 (m, 2H), 4.91 (m, 2H), 3.89 (s, 3H), 1.54 (s, 9H); LC-MS (ESI+) m/z 630.2 (M+H)+.

[001451] Step 2 - 4-r4-rr2-r2-rTert-butoxvcarbonvl(2,2,2-trifluoroethyl)amino1-4Pvridvl1oxazole carbonyl1 amino1 carbamovl-pyrazol-l-vl1benzoic acid

[001452] To a solution of methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoate (210 mg, 333 umol) in THF (5 mL) and H2O (5 mL) was added LiOH (40.0 mg, 1.67 mmol). The mixture was stirred at rt for 16 h. On completion, the mixture was adjusted to pH = 6 with IN HCI, then extracted with EA (2 X 100 mL). The organic layer was concentrated in vacuo to give the title compound (150 mg, 68% yield) as a white solid. 1HNMR (400MHz, DMSO-d6) δ 11.08 (s, IH), 9.12 (s, IH), 8.99 (s, IH), 8.67 (d, J = 5.2 Hz, IH), 8.26 (s, IH), 8.13 - 7.97 (m, 5H), 7.79 - 7.76 (m, 2H), 7.76 (s, IH), 4.91 (m, 2H), 1.54 (s, 9H); LC-MS (ESI+) m/z 616.2 (M+H)+.

[001453] 5-bromo (2.,6-dioxoDiDeridin vl)isoindoline-l.,3-dione (Intermediate CO):

[001454] To a solution of 4-bromophthalic anhydride (15.0 g, 66.1mmol, CAS# 86 8) in acetic acid (225mL) was added 2,6-di oxopiperi din amine hydrochloride (10.87 g, 66.1 mmol, CAS# 24666 6) and sodium acetate (5.42g, 66.07mmol) at rt. The reaction mixture was heated to 80 °C and stirred for 16 h. The resulting reaction mixture was cooled to rt and concentrated on a rotary evaporator. The obtained residue was suspended in water (255mL) and the resulting mixture was cooled to 0°C. The resulting slurry was stirred at 0 °C for 1 h. The resulting precipitate was filtered, washed with water (60mL) and dried under vacuum to give the title compound (20.44 g, 92%) as a purple solid. LC-MS (ESI+) m/z 336.9 (M+H)+.

[001455] 5-(3-(2-aminoethoxv)DroDvl) (2,6-dioxoDiDeridin vl)isoindoline-l,3-dione

[001456] Step 1 - Tert-butyl N-(2-prop vnoxvethyl)carbamate

[001457] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (1 g, 6.20 mmol) and 3bromoprop yne (775 mg, 6.51 mmol) in THF (30 mL) was added TBAI (137 mg, 372 umol) and KI (154 mg, 931 umol). Then KOH (409 mg, 6.20 mmol) was added into the above mixture and the reaction mixture was stirred at rt for 20 h. On completion, the mixture was concentrated in vacuo to remove the solvent. The residue was diluted with water (40 mL) and extracted with EA (3 X 30 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (0.84 g, 68% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 4.84 (s, IH), 4.09 (d, J= 2.4 Hz, 2H), 3.52 (t, J= 5.2 Hz, 2H), 3.28 - 3.26 (m, 2H), 2.38 (t, J= 2.4 Hz, IH), 1.38 (s, 9H).

[001458] Step 2 - Tert-butyl (2-((3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-5yl)prop yn-l-yl)oxy)ethyl)carbamate

[001459] 5-bromo (2,6-dioxopiperidin yl)isoindoline-l,3-dione (0.4 g, 1.19 mmol,

Intermediate CO), Cui (22.6 mg, 119 umol) and Pd(PPh3)2C12 (83.3 mg, 119 umol) were put into a microwave tube. Then tert-butyl N-(2-prop ynoxyethyl)carbamate (473 mg, 2.37 mmol), TEA (2.16 g, 2.98 mL, 21.4 mmol) and DMF (3 mL) were added into the tube. The mixture was degassed with nitrogen for 5 minutes. The sealed tube was then heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (510 mg, 94% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 8.16 (s, IH), 7.92 (s, IH), 7.87 - 7.78 (m, 2H), 5.03 - 4.96 (m, IH), 4.94 (s, IH), 4.43 (s, 2H), 3.67 (t, J = 5.2 Hz, 2H), 3.39 (d, J = 5.2 Hz, 2H), 2.96 - 2.90 (m, IH), 2.88 - 2.80 (m, IH), 2.79 - 2.71 (m, IH), 2.21-2.13 (m, IH), 1.45 (s, 9H).

[001460] Step 3 - Tert-butyl (2-(3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-5yl)propoxy)ethyl)carbamate

[001461] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]prop ynoxy] ethylcarbamate (490 mg, 1.08 mmol) in THF (5 mL) was added Pd/C (0.2 g, 329 umol, 10 wt %) and Pd(OH)2/C (0.2 g, 329 umol, 10 wt %). The reaction mixture was stirred at rt for 18 h under hydrogen atmosphere (15 Psi pressure). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (370 mg, 75% yield) as a yellow oil. LC-MS (ESI+) m/z 360.0 (M+H100&#1470;)+.

[001462] Step 4 - 5-(3-(2-aminoethoxy)propyl) (2,6-dioxopiperidin yl)isoindoline-L3di one

[001463] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]propoxy]ethyl] carbamate (120 mg, 26 umol) in DCM (1 mL) was added HCl/dioxane (4 M, 1 mL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (90 mg, 96% yield) as a yellow oil. LC-MS (ESI+) m/z 360.0 (M+H)+.

[001464] 5-(3-(2-(2-amin0eth0xv)eth0xy)Dr0Dvl) (2.,6-di0x0DiDeridin-3737 vl)isoindoline-l,3-dione (Intermediate

TBAI, Nai, KOH, THF

NHBoc

Pd(PPh3)2CI2, Cui, TEA, DMF, mw

NHBoc

Pd/C, Pd(OH)2/C

H2 (gas), THF

NHBoc

HCI in dioxane

DCM

CQ

[001465] Step 1 - Tert-butyl N-[2-(2-prop ynoxyethoxy)ethyl1carbamate

[001466] To a solution of /c77-butyl A-[2-(2-hydroxyethoxy)ethyl]carbamate (5.00 g, 24.4 mmol, CAS# 139115 6) and 3-bromoprop yne (2.90 g, 24.4 mmol, 2.10 mL) in THF (40 mL) was added TBAI (540 mg, 1.46 mmol), KI (606 mg, 3.65 mmol) and KOH (1.61 g, 24.4 mmol, 85% wt %). The reaction mixture was stirred at rt for 16 h. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was diluted with H2O (20 mL) and extracted with EA (2 X 50 mL). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 5:1) to give the title compound (4.00 g, 67% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 5.02 (s, IH), 4.17 (d, J = 2.4 Hz, 2H), 3.68 - 3.63 (m, 2H), 3.62 - 3.58 (m, 2H), 3.51 (t, J = 5.2 Hz, 2H), 3.28 (q, J= 5.2 Hz, 2H), 2.43 (t, J= 2.4 Hz, IH), 1.43 (s, 9H).

[001467] Step 2 -Tert-butyl (2-(2-((3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-5yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate

[001468] To a solution of 5-bromo (2,6-dioxopiperidin yl)isoindoline-l,3-dione (300 mg, 890 umol, Intermediate CO) and tert-butyl A-[2-(2-prop ynoxyethoxy)ethyl]carbamate (433 mg, 1.78 mmol) in DMF (8 mL)was added Pd(PPh3)2C12 (62.5 mg, 88.9 umol), TEA (1.62 g, 16.0 mmol, 2.23 mL) and Cui (16.9 mg, 88.9 umol). The reaction mixture was heated at 80 °C for 30 minutes under microwave. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether: Ethyl acetate = 5:1 to 1:0) to give the title compound (440 mg, 89% yield) as a yellow solid. LC-MS (ESI+) m/z 400.1 (M+H-100)+.

[001469] Step 3 - Tert-butyl (2-(2-(3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-5yl)propoxy)ethoxy)ethyl)carbamate

[001470] To a solution of tert-butyl 7V-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]prop ynoxy] ethoxy]ethyl]carbamate (580 mg, 1.16 mmol) in THF (10 mL) was added Pd/C (300 mg, 10 wt %) and Pd(OH)2/C (300 mg, 10 wt %). The reaction mixture was stirred at rt under hydrogen atmosphere (15 psi pressure) for 12 h. On completion, the residue was filtered and the filter was concentrated in vacuo to give the title compound (500 mg, 85% yield) as a yellow oil. LC-MS (ESI+) m/z 526.1 (M +Na)+.

[001471] Step 4- 5-(3-(2-(2-aminoethoxy)ethoxy)propyl) (2,6-dioxopiperidin-3yl)isoindoline-L3-dione

[001472] To a solution of tert-butyl 7V-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]propoxy] ethoxy]ethyl]carbamate (200 mg, 397umol) in DCM (2 mL) was added HCI in dioxane (4 M, 2.00 mL), and the reaction mixture was stirred at rt for 20 minutes. On completion, the mixture was concentrated in vacuo to give the title compound (160 mg, 99% yield) as a yellow solid. LC-MS (ESI+) m/z 404.0 (M+H)+.

[001473] 2- [2-[2- [(4-Methoxyphenvl)methvl-methvl-amino] ethoxy] ethoxy] ethanamine (Intermediate CR) ™&#1524;&#1524;'NN I HCI in dioxane .O. ///0 .OMs PMB_____z\ .0./0 /0 N. -----------&#9658;

BOCHN~ ^0^ K2CO3 DMF BOCHN&#1524;^ PMB DOM

I //.0./0 /\^NX

H2N 0 ^^ PMB

CR

[001474] Step 1 - Tert-butyl N-r2-r2-[2-r(4-methoxyphenyl)methyl-methylamino1ethoxy1ethoxy1ethyl1 carbamate

[001475] To a mixture of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (1.30 g, 3.97 mmol, synthesized via Step 1 of Intermediate AM) and 1-(4methoxyphenyl)-N-methyl-methanamine (600 mg, 3.97 mmol) in DMF (15 mL) was added K2CO3 (1.10 g, 7.94 mmol). The reaction mixture was stirred at rt for 16 hours. On completion, the mixture was diluted with water (10 mL) and extracted with DCM (3 X 20 mL). The organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (670 mg, 44% yield) as a light yellow oil. LC-MS (ESI+) m/z 383.2 (M +H)+.

[001476] Step 2:2-r2-[2-r(4-Methoxyphenvl)methyl-methylamino] ethoxy] ethoxy] ethanamine

[001477] To a mixture of tert-butyl N-[2-[2-[2-[(4-methoxyphenyl)methyl-methylamino]ethoxy]ethoxy]ethyl] carbamate (470 mg, 1.23 mmol) in DCM (4 mL) was added HCI in dioxane (4 M, 1.5 mL). The reaction mixture was stirred at rt for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (350 mg, 95% yield) as a light yellow oil. LC-MS (ESI+) m/z 283.1 (M +H)+.

[001478] 5-(l-amino-3,6,9,12-tetraoxaDentadec yn yl) (2,6-dioxoDiDeridin-3yl)isoindoline-l,3-dione hydrochloride(Intermediate CS)

EW

[001479] Step 1 - tert-butyl (15-(2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)3,6,9,12-tetraoxapentadec yn-l-yl)carbamate

[001480] In a flame dried reaction assembly equipped with nitrogen bubbler was prepared a solution of 5-bromo (2,6-dioxopiperidin yl)isoindoline-l,3-dione (1.0 g, 3.0 mmol, Intermediate CO) and tert-butyl (3,6,9,12-tetraoxapentadec yn-l-yl)carbamate (1.18 g, 3.56 mmol, Intermediate EW) in DMF (20mL) at rt. Cuprous iodide (0.11g, 0.59 mmol) and TEA (5.0 mL, 36.0 mmol) were sequentially added to the reaction mixture at rt. The resulting reaction mixture was degassed with argon for 10-15 min. Then Pd(PPh3)2C12 (0.02 g, 0.029 mmol) was added to the reaction mixture and argon purging was continued for 5-10 min. The reaction mixture was then heated at 70 °C and stirred for 0.5 h under argon atmosphere. The resulting reaction mixture was then cooled to rt and concentrated on a rotary evaporator. The obtained crude product was purified by gradient column chromatography using neutral alumina as stationary phase and DCM/IPAas a mobile phase. The title compound (1.1g, 63%) was isolated as a light yellow viscous oil which solidified upon standing overnight at 0-5 °C temperature. LC-MS (ESI+) m/z 488.0 (M100+H)+.

[001481] Step 2 - 5-(l-amino-3,6,9,12-tetraoxapentadec yn yl) (2,6741 dioxopiperidin yl)isoindoline-l,3-dione hydrochloride

[001482] To a solution of tert-butyl (15-(2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-5yl)-3,6,9,12-tetraoxapentadec yn-l-yl)carbamate (2.1 g, 35.8 mmol) in 1,4-dioxane (5 mL) was added 4N HCI in Dioxane (20 mL) at rt. The reaction mixture was stirred at rt for 5h. The resulting reaction mixture was concentrated under vacuum to get a brown color viscous liquid which was further triturated with diethyl ether (20 mL) followed by n-pentanes (30 mL) to give the title compound (1.9 g, 99%) as a yellowish hydroscopic solid. LC-MS (ESI+) m/z 488.0 (M+H)+.

[001483] 5-(l-amino-3.,6.,9,12-tetraoxapentadecan yl) (2.,6-dioxopiperidin-3yl)isoindoline-l.,3-dione hydrochloride(Intermediate CT) /9 9 ? J Pd/C, H2 (gas)

HnA

0=¢ +N I || H Et0H

O

[001484] Step-1 tert-butyl (15-(2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)3,6,9,12-tetraoxapentadecvl)carbamate

[001485] To a solution of tert-butyl (15-(2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-5yl)-3,6,9,12-tetraoxapentadec yn-l-yl)carbamate (3.0 g, 51.0 mmol, synthesized via Step 1 of Intermediate CS) in ethanol (100 mL) was added Pd/C (1.5 g, 10 wt %) under nitrogen atmosphere. Hydrogen gas was purged into the reaction mixture and the reaction was stirred for 6 h at rt. The resulting reaction mixture was filtered through a pad of celite and washed with ethanol (30 mL). The resulting filtrate was concentrated under vacuum to give the title compound (3.0 g, 96%) as a green viscous oil. LC-MS (ESI+) m/z 492.0 (M-100+H)+.

[001486] Step-2 5-(l-amino-3,6,9,12-tetraoxapentadecan yl) (2,6-dioxopiperidin-3yl)isoindoline-l,3-dione hydrochloride

[001487] To a solution of tert-butyl (15-(2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-5yl)-3,6,9,12-tetraoxapentadecyl)carbamate (3.0 g, 50.7 mmol) in 1,4-dioxane (20 mL) was added 4N HC1 in dioxane (25 mL) at rt. The reaction mixture was stirred at rt for 5h. The resulting reaction mixture was concentrated under vacuum to get a brown color viscous liquid which was further triturated with diethyl ether (30 mL) followed by n-pentanes (30 mL) to give the title compound (2.5 g, 93%) as a brown liquid. LC-MS (ESI+) m/z 492.4 (M+H)+.

[001488] 4- [4- [ [6- [2- [Tert-butoxvcarbonvl(2,2,2-trifluoroethyl)amino] -4pyridyl]Dyridine carbonyl] amino] carbamoyl-pyrazol-l-yl] benzoic acid (Intermediate

CU)

LiOH

THF, MeOH, H2O

[001489] Step 1 - Ethyl 6-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4 pyridyl1pyridine carboxylate

[001490] To a mixture of ethyl 6-bromopyridine carboxylate (1.50 g, 6.52 mmol) and tert743 butyl AL[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan yl) pyridyl]-7V-(2,2,2trifluoroethyl)carbamate (5.46 g, 6.52 mmol, synthesized via Steps 1-3 of Intermediate CM) in a mixed solvent of dioxane (40 mL) and H2O (8 mL) was added C82CO3 (6.37 g, 19.5 mmol) and Pd(dppf)C12 (238 mg, 326 umol). The reaction mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.90 g, 68% yield) as a light yellow oil. LC-MS (ESI+) m/z 448.0 (M+Na)+.

[001491] Step 2 - 6-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amin01 pyridyl1pyridine2-carboxylic acid

[001492] To a mixture of methyl 6-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]pyridine carboxylate (800 mg, 1.94 mmol) in a mixed solvent of THF (6 mL), H2O (1 mL) and MeOH (1 mL) was added Li OH (93.1 mg, 3.89 mmol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was acidified with HCI (1 N) until the pH = 5-6 and concentrated in vacuo to give the title compound (700 mg, 95% yield) as a white solid. LC-MS (ESI+) m/z 420.1 (M+Na)+.

[001493] Step 3 - Methyl 4-[4-IT6-[2-[tert-butoxvcarbonvl(2,2,2-trifluoroethvl)amino]-4Pvridvl1pvridine carbonvl1amino1 carbamoyl-pyrazol-l-yl1benzoate

[001494] To a mixture of methyl 4-(4-amino carbarn oyl-pyrazol-l-yl )benzoate (550 mg, 2.11 mmol, Intermediate CL) and DIPEA (975 mg, 7.55 mmol in DMF (8 mL) was added 6-[2[tert-butoxycarbonyl (2,2,2-trifluoroethyl)amino] pyridyl]pyridine carboxylic acid (600 mg, 1.51 mmol) and HATU (688 mg, 1.81 mmol).The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (4 X 10mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (0.1% FA) to give the title compound (140 mg, 14% yield) as a white solid. LC-MS (ESI+) m/z 640.2 (M+H)+.

[001495] Step 4 - 4-r4-rr6-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1pyridine carbonyl1 amino1 carbamoyl-pyrazol-l-yl1benzoic acid

[001496] To a mixture of methyl 4-[4-[[6-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] pyridine carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoate (80.0 mg, 125 umol) in a mixed solvent of THF (4 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH (14.9 mg, 625 umol). The reaction mixture was stirred at rt for 4 hours. On completion, the reaction mixture was acidified with HCI (1 N) until the pH =5-6 and concentrated in vacuo to give the title compound (120 mg, 100% yield) as a brown solid. LC-MS (ESI+) m/z 626.2 (M+H)+.

[001497] N-[l-[4-(bromomethvl)Dhenvl] carbamovl-Dvrazol yl] [2-(2,2,2trifluoroethylamino) Dvridyl]oxazole carboxamide (Intermediate CV)

[001498] Step 1 - Tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-(hydroxymethyl)phenyl1pyrazol-4yllcarbamoyU 0xaz0l yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[001499] To a solution of 4-[4-[[2-[2-[/er/-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (1.00 g, 1.62 mmol, Intermediate CN) in THF (30 mL) was added TEA (329 mg, 3.25 mmol) and isopropyl carbonochloridate (398 mg, 3.25 mmol). The mixture was stirred at -10 °C for 2 hours, then the mixture was filtered and washed with THF (30 mL). To the filtrate was then added NaBH4 (246 mg, 6.50 mmol) and H2O (5 mL) at 0 °C and the mixture was stirred at 0 °C for 1 hour. On completion, the mixture was extracted with DCM (200 mL). The organic layer was concentrated in vacuo and the residue was triturated in DCM to give the title compound (420 mg, 43% yield) as a white solid. LC-MS (ESI+) m/z 602.2 (M+H)+.

[001500] Step 2 - N-[l-[4-(bromomethyl)phenyl] carbamoyl-pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridyl1oxazole carboxamide

[001501] To a mixture of /c77-butyl N-[4-[4-[[3-carbamoyl-l-[4(hydroxymethyl)phenyl]pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (0.25 g, 416 umol) in DCM (5 mL) was added PBn (169 mg, 623 umol).

Then the reaction mixture was stirred at rt for 3 hours. On completion, the reaction mixture was quenched with water (20 mL), washed with saturated NaHCO3 (30 mL), and extracted with DCM (3X30 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to give the title compound (0.10 g, 34% yield) as a pale solid. LC-MS (ESI+) m/z 565.9 (M+H)+.

[001502] 4-[4-[[2-[2-[Tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino]-4pyridyl]oxazole-4 -carbonyl] amino] carbamovl-Dvrazol-l-vl]cvclohexanecarboxylic acid (Intermediate CW)

[001503] Step 1 - Methyl 4-methyl sulfonyl oxy cyclohexanecarboxylate

[001504] To a solution of methyl 4-hydroxy cyclohexanecarboxylate (5.00 g, 31.6 mmol) and

TEA (6.40 g, 63.2 mmol, 8.80 mL) in DCM (50 mL) was added MsCl (4.34 g, 37.9 mmol, 2.94 mL) dropwise at 0 °C. Then the reaction mixture was allowed to warm to rt and stirred for 3 hours. On completion, the mixture was diluted with H2O (20 mL), then extracted with DCM (2 X 40 mL). The combined organic phase was dried over by Na2SO4 and concentrated in vacuo to give the title compound (7.00 g, 93% yield) as a white solid.

[001505] Step 2 - Methyl 4-(3-carbamoyl nitro-pyrazol-l-yl)cyclohexanecarboxylate [001506] To a solution of 4-nitro-lH-pyrazole carboxamide (4.62 g, 29.6 mmol,

Intermediate CJ) and methyl 4-methylsulfonyloxycyclohexanecarboxylate (7.00 g, 29.6 mmol) in DMF (100 mL) was added Cs2CO3 (19.3 g, 59.2 mmol). The reaction mixture was stirred at 130 °C for 12 hours. On completion, the mixture was filtered, and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% NH3.H2O) to give the title compound (2.20 g, 25% yield) as a yellow oil. LC-MS (ESI+) m/z 297.2 (M+H)+.

[001507] Step 3 - Methyl 4-(4-amino carbarnoyl-pyrazol-l-yl)cyclohexanecarboxylate [001508] To a solution of methyl 4-(3-carbarn oyl nitro-pyrazol-lyl)cyclohexanecarboxylate (0.60 g, 2.03 mmol) in MeOH (10 mL) was added Pd/C (400 mg, 10 wt %). The reaction mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 16 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (490 mg, 90% yield) as a purple oil. LC-MS (ESI+) m/z 267.1 (M+H)+.

[001509] Step 4 - methyl 4-[4-l42-[2-[tert-butoxvcarbonvl(2,2,2-trifluoroethvl)amino]-4pyridyl1oxazole carbonyl1amino1 carbamoyl-pyrazol-l-yl1cyclohexanecarboxylate

[001510] To a solution of methyl 4-(4-amino carbarn oyl-pyrazol-1yl)cyclohexanecarboxylate (150 mg, 563 umol) and 2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl]oxazole carboxylic acid (218 mg, 563 umol, Intermediate CM) in DMF (5 mL) was added DIPEA (363 mg, 2.82 mmol, 490 uL). The mixture was stirred at rt for 12 minutes, then HATU (257 mg, 675 umol) was added and the reaction mixture was stirred at rt for 12 hours. On completion, the mixture was diluted with H2O (10 mL) and then extracted with EtOAc (2 X 20 mL). The organic phase was dried over Na2SO4, filtrated and concentrated in vacuo to give the title compound (400 mg, 83% purity, 92% yield) as a white solid. LC-MS (ESI+) m/z 636.2(M+H)+.

[001511] Step 5 - 4-r4-rr2-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole-4 -carbonyl] amino1 carbamoyl-pyrazol-l-yl1cyclohexanecarboxylic acid [001512] To a solution of methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole-4 -carbonyl]amino] carbamoyl-pyrazol-lyl]cyclohexanecarboxylate (400 mg, 629 umol) in THF (10 mL) and H2O (2 mL) was added LiOH (22.6 mg, 944 umol). The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was concentrated in vacuo to remove THF, then diluted with H2O (20 mL). The mixture was adjusted to pH = 5 with IN HCI, then extracted with EA (2 X 40 mL). The combined organic phase was dried with Na2SO4, filtered and concentrated in vacuo to give the title compound (330 mg, 84%) as a yellow solid. LC-MS (ESI+) m/z 644.2 (M+Na)+.

[001513] N-[3-carbamoyl-l-(4-DiDeridvl)pyrazol yl] [2-(2.,2.,2-trifluoroethylamino)4-pyridyl] oxazole carboxamide (Intermediate CX)

[001514] Step 1 - Tert-butyl 4-methvlsulfonvloxypiperidine-l-carboxylate

[001515] To a mixture of tert-butyl 4-hydroxypiperidine-l-carboxylate (5.00 g, 24.8 mmol) and TEA(5.03 g, 49.6 mmol) in DCM (50 mL) was added MsCl (4.27 g, 37.2 mmol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was diluted with water (10 mL) and acidified with citric acid solution until the pH = 5-6. Then the mixture was extracted with DCM (3 X 15 mL). The combined organic layers were diluted with water (10 mL) and basified with NaHCO3 solution until the pH = 7-8. Then the mixture was extracted with DCM (3 X 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.00 g, 90% yield) as a white solid. 1H NMR (400MHz, CDC13) δ 4.84 m 4.78 (m, IH), 3.68 - 3.59 (m, 2H), 3.26 - 3.20 (m, 2H), 2.97 (s, 3H), 1.94 - 1.84 (m, 2H), 1.80 - 1.69 (m, 2H), 1.39 (s, 9H).

[001516] Step 2 - Tert-butyl 4-(3-carbamoyl nitro-pyrazol-l-yl)piperidine-l-carboxylate

[001517] To a mixture of 4-nitro-lH-pyrazole carboxamide (3.91 g, 25.0 mmol, Intermediate CJ) and tert-butyl 4-methylsulfonyl oxypiperi dine-1 -carboxylate (7.00 g, 25.0 mmol) in DMF (70 mL) was added Cs2CO3 (16.3 g, 50.1 mmol). The reaction mixture was stirred at 130 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % ΝΗ3&#905;2Ο) to give the title compound (1.80 g, 21% yield) as a brown solid. 1H NMR (400MHz, DMSO4) δ = 8.95 (s, IH), 8.00 (s, IH), 7.76 (s, IH), 4.49 4.43 (m, IH), 4.06 (d, J = 11.6 Hz, 2H), 3.01 -2.70 (m, 2H), 2.04 (d, J = 9.6 Hz, 2H), 1.87 - 1.70 (m, 2H), 1.42 (s, 9H).

[001518] Step 3 - Tert-butyl 4-(4-amino carbamoyl-pyrazol-l-yl)piperidine-l-carboxylate [001519] To a mixture of tert-butyl 4-(3-carbarnoyl nitro-pyrazol-l-yl)piperidine-1carboxylate (1.80 g, 5.30 mmol) in MeOH (30 mL) was added Pd/C (1.00 g, 10 wt %) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (610 mg, 100% yield) as a light yellow solid. 1HNMR (400MHz, DMSO-d6) δ 7.17 (s, IH), 7.08 (s, IH), 6.98 ( s, IH), 4.70 - 4.53 (m, 2H), 4.25 - 4.17 (m, IH), 4.03 (d, J = 11.2 Hz, 2H), 2.99 2.80 (m, 2H), 1.94 (d, J = 10.0 Hz, 2H), 1.80 - 1.70 (m, 2H), 1.42 (s, 9H).

[001520] Step 4 - Tert-butyl4-r4-rr2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1amino1 carbamoyl-pyrazol-l-yl1piperidine-l-carboxylate

[001521] To a mixture of tert-butyl 4-(4-amino carbarnoyl-pyrazol-l-yl)piperidine-1carboxylate (159 mg, 516 umol) and DIPEA (200 mg, 1.55 mmol) in DMF (5 mL) was added 2[2-[tert-butoxycarbonyl (2,2,2-trifluoroethyl)amino] pyridyl]oxazole carboxylic acid (200 mg, 516 umol, Intermediate CM) and HATU (235 mg, 619 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (3 X 10mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (400 mg, 80% purity, 91% yield) as a light yellow solid. LC-MS (ESI+) m/z 679.3 (M+H)+.

[001522] Step 5:N-r3-carbamoyl-l-(4-piperidyl)pyrazol yl1 r2-(2,2,2trifluoroethylamino) pyridyl1 oxazole carboxamide

[001523] To a mixture of tert-butyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l yl]piperidine-l-carboxylate (400 mg, 589 umol) in DCM (4 mL) was added HC1 in dioxane (4 M, 2 mL). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (280 mg, HC1 salt) as a light yellow solid. LCMS (ESI+) m/z 479.2 (M+H)+.

[001524] Tert-butyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetate (Intermediate CY)

ΝΗ2ΝΗ2.Η2Ο

EtOH &#2404; O

CY

[001525] Step 1 - 2-(2-(2-Hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[001526] To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (50.0 g, 333 mmol, 44.6 mL) in DCM (1 L) was added Ag2O (84.9 g, 366 mmol) and KI (5.53 g, 33.3 mmol) and TsCl (63.5 g, 333 mmol). The reaction mixture was stirred at rt for 18 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (76.0 g, 74% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.81 (d, J= 8.0 Hz, 2H), 7.35 (d, J= 8.0 Hz, 2H), 4.20 - 4.15 (m, 2H), 3.74 3.69 (m, 4H), 3.64 - 3.56 (m, 6H), 2.45 (s, 3H); LC-MS (ESI+) m/z 305.0 (M+H)+.

[001527] Step 2 - 2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethyl)isoindoline-L3-dione

[001528] To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (20.0 g, 65.7 mmol) in DMF (200 mL) was added (l,3-dioxoisoindolin yl)potassium (12.8 g, 69.0 mmol). The resulting reaction mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (14.6 g, 80% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ

7.89 - 7.83 (m, 2H), 7.75 - 7.69 (m, 2H), 3.95 - 3.90 (m, 2H), 3.79 - 3.74 (m, 2H), 3.69 - 3.64 (m, 4H), 3.63 - 3.59 (m, 2H), 3.56 - 3.52 (m, 2H).

[001529] Step 3:Tert-butyl 2-(2-(2-(2-(L3-dioxoisoindolin-2yl)ethoxy)ethoxy)ethoxy)acetate

[001530] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]isoindoline-l,3-dione (10.0 g, 35.8 mmol) and Rh(OAc)2 (396 mg, 1.79 mmol) in DCM (50 mL) was added a solution of tert-butyl 2-diazoacetate (7.63 g, 53.7 mmol) in DCM (200 mL) dropwise. The reaction mixture was stirred at rt for 18 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (11.0 g, 78% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.88 - 7.82 (m, 2H), 7.75 - 7.69 (m, 2H), 3.99 (s, 2H), 3.94 - 3.88 (m, 2H), 3.77 - 3.72 (m, 2H), 3.68 - 3.58 (m, 8H), 1.47 (s, 9H).

[001531] Step 4 - Tert-butyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetate

[001532] To a solution of tert-butyl 2-[2-[2-[2-(l,3-dioxoisoindolin-2yl)ethoxy]ethoxy]ethoxy]acetate (11.0 g, 28.0 mmol) in ethanol (200 mL) was added NH2NH2 H2O (7.00 g, 140 mmol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was diluted with DCM (200 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (6.40g, 87% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.02 (s, 2H), 3.72 - 3.63 (m, 10H), 3.53 - 3.50 (m, 2H), 1.47 (s, 9H); LC-MS (ESI+) m/z 264.0 (M+H)+.

[001533] Ethyl 2-[2-(2-aminoethoxv)ethoxy] acetate (Intermediate CZ)

BocHN

N2

OEt

&#908;Η ---------Rh(OAc)2, DCM

BocHN

OEt

HCI in dioxane

DCM

O cz

[001534] Step 1 - Ethyl 2-r2-r2-(tert-butoxycarbonylamino)ethoxy1ethoxy1acetate

[001535] To a mixture of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (10.0 g, 48.7 mmol, CAS# 139115 6) and Rh(OAc)2 (215 mg, 974 umol) in DCM (150 mL) was added a solution of ethyl 2-diazoacetate (16.6 g, 146 mmol) in DCM (100 mL) dropwise. The reaction mixture was stirred at rt for 20 hours. On completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 X 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (12.0 g, 84% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 4.23 - 4.16 (m, 4H), 4.11 (s, IH), 4.05 - 3.97 (m, 2H), 3.67 - 3.58 (m, 3H), 3.51 - 3.41 (m, 2H), 1.47 - 1.37 (m, 9H), 1.28 - 1.26 (m, 3H).

[001536] Step 2 - Ethyl 2-[2-(2-aminoethoxy)ethoxy1 acetate

[001537] To a mixture of ethyl 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]acetate (3.00 g, 10.3 mmol) in DCM (20 mL) was added HC1 in dioxane (4 M, 10 mL). The reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (2.00 g, 100% yield) as a red brown oil. 1H NMR (400MHz, CDCh) δ 4.27 - 4.14 (m, 3H), 4.12 (s, IH), 4.07 - 3.93 (m, 2H), 3.75 - 3.69 (m, 3H), 3.67 (s, 2H), 3.45 - 3.36 (m, IH), 1.29 (t, J = 7.6 Hz, 3H).

[001538] Tert-butyl 2- [2-[2- [2-(2-aminoethoxv)ethoxy] ethoxy] ethoxy] acetate (Intermediate DA)

DA

[001539] Step 1 - 2-r2-r2-r2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethyl1isoindoline-L3-dione

[001540] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4methylbenzenesulfonate (20.0 g, 57.4 mmol, synthesized via Step 1 of Intermediate AO) in DMF (200 mL) was added (l,3-dioxoisoindolin yl)potassium (12.7 g, 68.8 mmol) and the mixture was stirred at 80 °C for 2 h. On completion, the mixture was concentrated in vacuo. The residue was then diluted with EA (200 mL) and stirred for 30 min, filtered, and the organic layer was concentrated in vacuo. The mixture was purified by silica gel chromatography (petroleum ether: ethyl acetate = 1: 2) to give the title compound (9.00 g, 48% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 7.90 - 7.84 (m, 2H), 7.78 - 7.70 (m, 2H), 3.97 - 3.89 (m, 2H), 3.81 - 3.74 (m, 2H), 3.73 - 3.69 (m, 2H), 3.69 - 3.65 (m, 2H), 3.65 - 3.61 (m, 6H), 3.61 - 3.57 (m, 2H).

[001541] Step 2:Tert-butyl 2-[2-[2-[2-[2-(L3-dioxoisoindolin-2vDethoxy] ethoxy] ethoxy] ethoxy] acetate

[001542] To a solution of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]isoindoline-l,3dione (1.00 g, 3.09 mmol) and Rh(OAc)2 (27.3 mg, 123 umol) in DCM (10.0 mL) was added a solution of tert-butyl 2-diazoacetate (1.32 g, 9.28 mmol) in DCM (20 mL) dropwise at rt for 1 hr. The reaction mixture was stirred at rt for 20 h. On completion, the mixture was extracted with H2O (3 X 30 mL), the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (petroleum ether: ethyl acetate = 3: 1) to give the title compound (1.00 g, 73% yield) as a yellow oil. 1H NMR (400MHz, CDC13) δ 7.81 - 7.76 (m, 2H), 7.68 - 7.63 (m, 2H), 3.95 (s, 2H), 3.87 - 3.82 (m, 2H), 3.70 - 3.66 (m, 2H), 3.66 - 3.61 (m, 2H), 3.61 - 3.57 (m, 4H), 3.56 - 3.52 (m, 6H), 1.42 (s, 9H).

[001543] Step 3 - Tert-butyl 2-[2-[2-[2-(2-aminoethoxy)ethoxy1ethoxy1ethoxy1acetate

[001544] To a solution of tert-butyl 2-[2-[2-[2-[2-(l,3-dioxoisoindolin-2yl)ethoxy]ethoxy]ethoxy] ethoxy]acetate (1.00 g, 2.29 mmol) in EtOH (15.0 mL) was added ΝΗ2ΝΗ2&#905;2Ο (233 mg, 4.57 mmol, 226 uL, 98% purity), and the mixture was stirred at 80 °C for 12 h. On completion, the mixture was concentrated in vacuo. The residue was diluted with DCM(30 mL), filtered and the organic layer was concentrated in vacuo to give the title compound (700 mg, 99% yield) as a yellow oil. 1H NMR (400MHz, CDC13) δ 4.04 (s, 2H), 3.75 - 3.64 (m, 12H), 3.57 - 3.51 (m, 2H), 2.94 - 2.84 (m, 2H), 2.08 - 1.95 (m, 2H), 1.52 - 1.45 (m, 9H).

[001545] N- il-(azetidin vl) carbamovl-Dvrazol yl] [2-(2,2.,2trifluoroethvlamino) Dvridyl]oxazole carboxamide(Intermediate DB)

MsCI, TEA

DCM

CS2CO3, DMF

[001546] Step 1 - Tert-butyl 3-methylsulfonyloxyazetidine-l-carboxylate

[001547] To a solution of tert-butyl 3-hydroxyazetidine carboxylate (10.0 g, 57.7 mmol) and TEA (17.5 g, 24.1 mL, 173 mmol) in DCM (80.0 mL) was added MsCI (9.92 g, 86.6 mmol) at 0 °C. The mixture was then allowed to warm to rt and stirred for 30 min. On completion, the mixture was washed with H2O (3 X 50 mL). The organic layer was washed with brine (3 X 30 mL), dried over anhydrous Na2SO4, fdtered and concentrated in vacuo to give the title compound (14.2 g, 97% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 5.25 - 5.17 (m, IH), 4.33 - 4.25 (m, 2H), 4.15 - 4.09 (m, 2H), 3.08 (s, 3H), 1.46 (s, 9H).

[001548] Step 2 - Tert-butyl 3-(3-carbamoyl nitro-pyrazol-l-yl)azetidine-l-carboxylate [001549] To a solution of tert-butyl 3-methylsulfonyloxyazetidine-l-carboxylate (8.85 g, 35.2 mmol) and 4-nitro-lH-pyrazole carboxamide (5.00 g, 32.0 mmol, Intermediate CJ) in DMF (110 mL) was added CS2CO3 (20.8 g, 64.0 mmol), and the mixture was stirred at 130°C for 16 h. On completion, the mixture was fdtered and the fdtrate was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% FA) to give the title compound (3.50 g, 35% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 9.04 (s, IH), 8.06 (s, IH), 7.83 (s, IH), 5.36 .22 (m, IH), 4.38 - 4.27 (m, 2H), 4.22 - 4.08 (m, 2H), 1.41 (s, 9H).

[001550] Step 3 - Tert-butyl 3-(4-amino carbamoyl-pyrazol-l-yl)azetidine-l-carboxylate [001551] To a solution of tert-butyl 3-(3-carbamoyl nitro-pyrazol-l-yl)azetidine-lcarboxylate (500 mg, 1.61 mmol) in MeOH (5.00 mL) was added Pd/C (50.0 mg, 10 wt %) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 14 hours. On completion, the mixture was concentrated in vacuo to give the title compound (335 mg, 74% yield) as a purple oil. LC-MS (ESI+) m/z 304.0 (M+Na)+

[001552] Step 4 - Tert-butyl 3-r4-rr2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl] oxazole carbonyl]amino] carbamoylpyrazol-l-yl]azetidine-l-carboxylate

[001553] To a solution of tert-butyl 3-(4-amino carbarnoyl-pyrazol-l-yl)azetidine-1carboxylate (145 mg, 516 umol), 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (200 mg, 516 umol, Intermediate CM) in DMF (3.00 mL) was added HATU (235 mg, 619 umol) and DIPEA (333 mg, 2.58 mmol, 449 uL), and the mixture was stirred at rt for 30 min. On completion, the mixture was diluted with H2O (20 mL) and stirred for 20 min. The mixture was filtered and the solid was dried in vacuo to give the title compound (250 mg, 74% yield) as a white solid. 1H NMR (400MHz, DMSO4) δ 11.01 (s, IH), 9.07 (s, IH), 8.66 (d, J = 5.2 Hz, IH), 8.49 (s, IH), 8.25 (s, IH), 7.83 (s, IH), 7.77 (d, J = 5.2 Hz, IH), 7.59 (s, IH), 5.42 - 5.32 (m, IH), 4.96 - 4.87 (m, 2H), 4.36 - 4.28 (m, 2H), 4.27 - 4.17 (m, 2H), 1.53 (s, 9H), 1.43 (s, 9H)

[001554] Step 5 - N-r1-(azetidin yl) carbamoyl-pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridyl] oxazole carboxamide

[001555] To a solution of tert-butyl 3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]azetidine1-carboxylate (220 mg, 338 umol) in DCM (5.00 mL) was added TFA (7.70 g, 67.5 mmol), and the mixture was stirred at rt for 30 min. On completion, the mixture was concentrated in vacuo to give the title compound (190 mg, 99% yield, TFA salt) as a white solid. LC-MS (ESI+) m/z 451.2 (M+H)+.

[001556] 2- [2- [2-(2-Aminoethoxy)ethoxy| ethoxy] ethanol(Intermediate DC)

BocHN.X .OH HCI in dioxane H2N .OH

--- Q --- Q Q -X/ Q 'X/

[001557] To a solution of tert-butyl N-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.82 mmol, synthesized via Steps 1-3 of Intermediate AO) in DCM (30 mL) was added HC1 in dioxane (4 M, 10.2 mL), and the mixture was stirred rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.30 g, 82% yield, HC1 salt) as a brown oil. 1H NMR (400MHz, DMSO-76) δ 8.03 (s, 2H), 3.57 - 3.50 (m, 13H), 3.43 - 3.41 (m, 2H), 2.97 - 2.90 (m, 2H).

[001558] 3-[4-[[2-[2-[tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino]-4 pyridyl]oxazole carbonyl] amino] carbamoyl-Dvrazol-l-vl]benzoic acid (Intermediate

DD)

NaNO2, con HCI

NaOAc, EtOH, H2O

NH3H2O

Fe, NH4CI

EtOH, H2O

CO, Pd(dppf)CI2

TEA , MeOH, DMF

TEA, CHCI3, mw

[001559] Step 1 - Ethyl (2Z) r(3-bromophenyl)hydrazono1 chloro-acetate

[001560] To a mixture of 3-bromoaniline (30.0 g, 174 mmol) in a mixed solvent of HCI (12 M, 43.6 mL) and H2O (30.0 mL) was added a solution of NaNO2 (13.2 g, 191 mmol) in H2O (10 mL) at -5 °C dropwise. Then the mixture was stirred at 0 °C for 0.5 hr. Ethyl 2-chloro oxobutanoate (30.1 g, 183 mmol) and NaOAc (42.9 g, 523mmol) were added to the solution and the mixture was stirred for 30 min. The reaction mixture was then allowed to warm to rt and stirred for an additional for 2 h. On completion, the mixture was filtered and the filter cake was dried in vacuo to give the title compound (46.6 g, 87% yield) as a yellow solid. 1H NMR. (400MHz, DMSO76) δ 10.68 (s, IH), 7.53 (t, J = 2.0 Hz, IH), 7.38 - 7.33 (m, IH), 7.29 (t, J = 8.0 Hz, IH), 7.19 7.14 (m, IH), 4.30 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[001561] Step 2 - Ethyl 1-(3-brom ophenvl) nitro-pyrazole carboxylate

[001562] Ethyl (2Z) [(3-bromophenyl)hydrazono] chloro-acetate (2.50 g, 8.18 mmol), (E)-N,N- dimethyl nitro-ethenamine (950 mg, 8.18 mmol) and TEA (827 mg, 8.18 mmol) were taken up into a microwave tube in CHCh (20 mL).The sealed tube was heated at 140 °C for 30 min under microwave. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica column chromatography (PE: EA=10: 1) to give the title compound (0.42 g, 15% yield) as a yellow solid. IH NMR (400MHz, CDCh) δ 8.63 (s, IH), 7.98 (t, J = 2.0 Hz, IH), 7.71 - 7.66 (m, IH), 7.64 - 7.61 (m, IH), 7.46 - 7.40 (m, IH), 4.54 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H).

[001563] Step 3 - 1-(3-brom ophenyl) nitro-pyrazole carboxamide

[001564] To a solution of ethyl 1-(3-bromophenyl) nitro-pyrazole carboxylate (3.00 g, 8.82 mmol) in THF (20.0 mL) was added ΝΗ3.Η2Ο (13.4 g, 115 mmol, 14.7 mL, 30 wt %), and the mixture was stirred at 110 °C for 16 h. On completion, the mixture was concentrated in vacuo to give the title compound (2.70 g, 90% yield) as a yellow solid. LC-MS (ESI+) m/z 312.9 (M+H)+. [001565] Step 4 - 4-amino (3-bromophenyl)pvrazole carboxamide

[001566] To a solution of 1-(3-bromophenyl) nitro-pyrazole carboxamide (2.70 g, 8.68 mmol) in MeOH (50.0 mL) and H2O (25.0 mL) was added Fe (4.85 g, 86.7 mmol) and NH4C1 (4.64 g, 86.7 mmol). The mixture was stirred at 80 °C for 3 h. On completion, the mixture was filtered and the filtrated was concentrated in vacuo to remove MeOH. The residue was extracted with EA (2 X 200 ml). The combined organic layer was then washed with water (200ml) and concentrated in vacuo to give the title compound (1.90 g, 77% yield) as a yellow solid. LC-MS 757 (ESI+) m/z 281.0 and 283.0 (M+H)+.

[001567] Step 5 - Methyl 3-(4-amino carbamoyl-pyrazol-l-yl)benzoate

[001568] To a solution of 4-amino (3-bromophenyl)pyrazole carboxamide (1.90 g, 6.76 mmol) in DMF (20 mL) and MeOH (20 mL) was added TEA (683 mg, 6.76 mmol) and Pd(dppf)C12 (494 mg, 675 umol). The mixture was stirred at 80 °C for 16 h under CO atmosphere (50 psi pressure). On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column chromatography (PE: EA=1: 1) to give the title compound (1.10 g, 62% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 8.38 (t, J = 2.0 Hz, IH), 8.12 - 8.06 (m, IH), 7.89 (s, IH), 7.88 - 7.84 (m, IH), 7.67 - 7.58 (m, 2H), 7.28 (s, IH), 4.91 (s, 2H), 3.90 (s, 3H).

[001569] Step 6 - Methyl 3-[4-IT2-[2-[tert-butoxvcarbonvl(2.2.2-trifluoroethvl)amino1-4pyridvHoxazole carbonvl1amino1 carbamovl-pyrazol-l-vl1benzoate

[001570] To a solution of methyl 3-(4-amino carbarnoyl-pyrazol-l-yl)benzoate (300 mg, 1.15 mmol), 2-[2-[tertbutoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole-4carboxylic acid (446 mg, 1.15 mmol, Intermediate CM) in DMF (5.00 mL) was added HATU (525 mg, 1.38 mmol) and DIPEA(446 mg, 3.46 mmol), and the mixture was stirred at 25 °C for 30 min. On completion, the mixture was diluted with H2O (40 mL) and stirred for 30 min. The mixture was then filtered and the solid was dried in vacuo to give the title compound (660 mg, 90% yield) as off-white solid. 1HNMR (400MHz, DMSO-76) δ 11.10 (s, IH), 9.11 (s, IH), 9.04 (s, IH), 8.67 (d, 7= 5.2 Hz, IH), 8.50 (s, IH), 8.31 - 8.25 (m, 2H), 8.18 (s, IH), 7.97 (d,7= 7.6 Hz, IH), 7.81 - 7.75 (m, 2H), 7.75 - 7.69 (m, IH), 4.95 - 4.87 (m, 2H), 3.93 (s, 3H), 1.54 (s, 9H).

[001571] Step 7 - 3-r4-rr2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1 amino1 carbamoyl-pyrazol-l-yl1benzoic acid

[001572] To methyl 3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoate (660 mg, 1.05 mmol) in a solution of THF (10.0 mL), H2O (1.00 mL) and MeOH (1.00 mL) was added LiOH (125 mg, 5.24 mmol), and the mixture was stirred at rt for 7 h. On completion, the mixture was diluted with H2O (50 mL) and then acidified with IN HCI solution until the pH = 5. The mixture was then extracted with EA (3 X 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (620 mg, 96% yield) as an off-white solid. 1HNMR (400MHz, DMSO-76) δ 13.33 (s, IH), 11.10 (s, IH), 9.11 (s, IH), 9.02 (s, IH), 8.66 (d, J = 52 Hz, IH), 8.49 (s, IH), 8.27 - 8.21 (m, 2H), 8.17 (s, IH), 7.95 (d, 7 = 7.6 Hz, IH), 7.80

7.74 (m, 2H), 7.71 - 7.65 (m, IH), 4.95 - 4.85 (m, 2H), 1.53 (s, 9H).

[001573] 4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)Dyridin-4yl)oxazole carboxamido) (trifluoromethyl)-lH-Dyrazol-l-yl)benzoic acid (Intermediate

HN03

H2SO4

Pd/C, H2 (gas)

MeOH

LiOH

THF, H2O

[001574] Step 1 - 4-Nitro (trifluoromethyl)-lH-pyrazole

[001575] To a solution of 3-(trifluoromethyl)-lH-pyrazole (5.0 g, 36.7 mmol) in concentrated sulfuric acid (75 mL) was carefully added dropwise at 0 °C 65% HNO3 (8.91 g, 91.86 mmol, 6.36 mL). After stirring for 10 min the reaction mixture was heated to 115 °C, and stirring was continued at 115 °C for 4 h. On completion, the reaction mixture was cooled to rt. Then, the reaction mixture was poured onto the 200 mL ice, and extracted with ethyl acetate (3 X 150 mL). The combined organic layers were washed with brine (2 X 100 mL), dried over with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 10:1) to give the title compound (5.9 g, 89% yield) as a white solid. 1H NMR (400MHz, DMSOd6) δ 14.72 (s, IH), 9.15 (s, IH).

[001576] Step 2 - Methyl 4-(4-nitro (trifluoromethvl)-lH-pyrazol-l-vl)benzoate

[001577] A mixture of 4-nitro (trifluoromethyl)-lH-pyrazole (5.70 g, 31.5 mmol), (4methoxycarbonylphenyl) boronic acid (7.00 g, 38.9 mmol), pyridine (9.96 g, 125.9 mmol) and Cu(OAc)2 (8.58 g, 47.2 mmol) in DCM (150 mL) was stirred at rt for 5 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 10:1) to give the title compound (4.5 g, 45% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.74 (d, J = 0.6 Hz, IH), 8.22 - 8.12 (m, 2H), 7.82 - 7.74 (m, 2H), 3.90 (s, 3H).

[001578] Step 3 - Methyl 4-(4-amino (trifluoromethyl)-lH-pyrazol-l-yl)benzoate [001579] To a solution of methyl 4-[4-nitro (trifluoromethyl)pyrazol-l-yl]benzoate (500 mg, 1.59 mmol) in a mixed solvent of DCM (20 mL) and MeOH (20 mL) was added Pd/C (100 mg, 10 wt %) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 14 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (450 mg, 97% yield) as a white solid. LC-MS (ESI+) m/z 286.0 (M+H)+.

[001580] Step 4:Methyl 4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2trifluoroethyl)amino)pyridin yl)oxazole-4yDbenzoate

[001581] To a solution of methyl 4-[4-amino (trifluoromethyl)pyrazol-l-yl]benzoate (150 mg, 526 umol) and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole-4carboxylic acid (204 mg, 526 umol, Intermediate CM) in DMF (5 mL) was added HATU (240 mg, 631 umol) and DIPEA (136 mg, 1.05 mmol, 183 uL). The mixture was stirred at rt for 1 hr. On completion, the reaction mixture was quenched with water 50 mL. A white precipitate formed which was filtered. The filter cake was dried over in vacuo to give the title compound (300 mg, 88% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 9.07 (s, IH), 8.98 (s, IH), 8.55 (d, J= 4.8 Hz, IH), 8.45 (s, IH), 8.37 (s, IH), 8.19 (d, J= 8.0 Hz, 2H), 7.87 (d, J= 8.0 Hz, 2H), 7.73 (d, J= 4.0 Hz, IH), 4.98 - 4.81 (m, 2H), 3.97 (s, 3H).

[001582] Step 5 - 4-(4-(2-(2-((Tert-butoxvcarbonvl)(2,2,2-trifluoroethyl)amino)pyridin-4yl)oxazole carboxamido) (trifluoromethyl)-IH-pyrazol-l-yl )benzoic acid

[001583] To a solution of methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl]oxazole carbonyl]amino] (trifluoromethyl)pyrazol-l yl]benzoate (300 mg, 458 umol) in THF (6 mL) and H2O (2 mL) was added L1OHH2O (38.5 mg, 917 umol). The mixture was stirred at rt for 12 h. On completion, the reaction mixture was concentrated in vacuo to remove THF. The residue was acidified with IN HCI until the pH = 4, then filtered. The filter cake was collected to give the title compound (460 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 641.0 (M+H)+.

[001584] 4-[4-[[2-[2-[Tert-but0xvcarb0nvl(cvcl0Dr0Dvlmethyl)amin0]-4 pyridyl]oxazole carbonyl] amino] carbamoyl-Dvrazol-l-vl]benzoic acid (Intermediate

DF)

(Boc)2O &#9633;HMDS, THF

NaH, DMF

tris-o-tolylphosphane, Pd(OAc)2, Cs2CO3 DMF

LiOH

THF, H2O, MeOH

[001585] Step 1 - Tert-butyl N-(4-bromo pyridyl)-N-(cyclopropylmethyl)carbamate [001586] To a solution of tert-butyl 7V-(4-bromo pyridyl)carbamate (5.0 g, 18.3 mmol, synthesized via Step 1 of Intermediate CM) in DMF (50 mL) was added NaH (1.10 g, 27.5 mmol) at 0 °C for 30 minutes. Then bromomethylcyclopropane (2.97 g, 22.0 mmol) was added into the mixture. The reaction mixture was stirred at rt for 17 h. On completion, the mixture was quenched with water (40 mL) and extracted with EA (2 X 50 mL). The organic phase was washed with brine (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.7 g, 45% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.18 (d, J = 5.2 Hz, IH), 7.98 (d, J = 1.6 Hz, IH), 7.17 (dd, J = 1.6, 5.2 Hz, IH), 3.88 (d, J= 7.2 Hz, 2H), 1.55 (s, 9H), 1.22-1.15 (m, IH), 0.47 - 0.40 (m, 2H), 0.28 - 0.23 (m, 2H).

[001587] Step 2 - Ethyl 2-r2-rtert-butoxycarbonyl(cyclopropylmethyl)amino1-4pyridyl1oxazole carboxylate

[001588] To a solution of ethyl oxazole carboxylate (1.16 g, 8.25 mmol) and tert-butyl N(4-bromo pyridyl)-N-(cyclopropylmethyl)carbamate (2.7 g, 8.25 mmol) in DMF (30 mL) was added tris-o-tolylphosphane (502 mg, 1.65 mmol), Pd(OAc)2 (185 mg, 825 umol) and Cs2CO3 (5.38 g, 16.5 mmol). The reaction mixture was stirred at 80 °C under nitrogen for 17 h. On completion, the mixture was diluted with water (50 mL) and extracted with EA (3 X 50 mL). The organic layer was washed with water (100 ml), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (1.8 g, 56% yield) as a white oil. 1H NMR (400MHz, CDCh) δ 8.50 (dd, J= 1.6, 5.2 Hz, IH), 8.38 (s, IH), 8.35 (s, IH), 7.71 (dd, J= 1.6, 5.2 Hz, IH), 4.46 (q, J= 7.2 Hz, 2H), 3.93 (d, J= 7.2 Hz, 2H), 1.57 (s, 9H), 1.44 (t, J= 7.2 Hz, 3H), 1.24-1.16 (m, IH), 0.46 - 0.40 (m, 2H), 0.28 - 0.24 (m, 2H).

[001589] Step 3 - 2-r2-Tert-butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1oxazole4-carboxylic acid

[001590] To a solution of ethyl 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylate (0.5 g, 1.29 mmol) in a mixed solvent of THF (5 mL) and H2O (1 mL) was added LiOH (92.7 mg, 3.87 mmol). The reaction mixture was stirred at rt for 2 h. On completion, the mixture was acidified with IN HC1 solution until the pH = 3-5, then extracted with EA (2 X 30 mL). The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (460 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 304.0 (M-56)+.

[001591] Step 4 - Methyl 4-r4-rr2-r2-rtert-butoxycarbonyl(cyclopropylmethyl)amino1-4pyridyl1oxazole carbonyl1amino1 carbamoyl-pyrazol-l-yl1benzoate

[001592] To a solution of 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylic acid (360 mg, 1.00 mmol) and methyl 4-(4-amino carbamoylpyrazol-l-yl)benzoate (443 mg, 1.70 mmol, Intermediate CL) in DMF (5 mL) was added DIPEA (647 mg, 5.01 mmol) and HATU (457 mg, 1.20 mmol). The reaction mixture was stirred at rt for

0.5 hr. On completion, the mixture was diluted with water (40 mL) and extracted with EA (2 X 30 mL). The combined organic layer was washed with brine (40 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (190 mg, 32% yield) as a white solid. LC-MS (ESI+) m/z 602.3 (M+H)+.

[001593] Step 5 - 4-r4-rr2-r2-rTert-butoxycarbonyl(cyclopropylmethyl)amino1-4Pvridvl1oxazole carbonyl1 amino1 carbamovl-pyrazol-l-vl1benzoic acid

[001594] To a solution of methyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino] carbamoylpyrazol-l-yl]benzoate (190 mg, 316 umol) in a mixed solvent of THF (3 mL), MeOH (2 mL) and H2O (1 mL) was added LiOH (37.8 mg, 1.58 mmol). The reaction mixture was stirred at rt for 17 h. On completion, the mixture was acidified with IN HC1 solution until the pH = 5-7, concentrated in vacuo to give the title compound (180 mg, 97% yield) as a yellow solid. LC-MS (ESI+) m/z 588.3 (M+H)+.

[001595] 4-[(l,3-Dioxoisoindolin vl)methyl]benzenesulfonvl chloride (Intermediate

DG chlorosulfonic acid

[001596] A mixture of 2-benzylisoindoline-1,3-dione (5.00 g, 21.0 mmol) and sulfurochloridic acid (17.1 g, 147 mmol, 9.82 mL) was stirred at 60 °C for 1.5 h until the evolution of hydrochloric gas ceased. On completion, the mixture was poured in a mixture of water and ice (100 mL), and a fine white precipitate was formed. The precipitate was filtered and washed with cold water. The precipitate was purified by column chromatography (dichloromethane: petroleum ether = 1:1) to give the title compound (5.20 g, 73% yield) as a white solid. 1H NMR (400MHz, DMSO-J6) δ 7.91 - 7.85 (m, 4H), 7.57 -7.55 (m, 2H), 7.30 - 7.25 (m, 2H), 4.77 (s, 2H).

[001597] 4-(Aminomethvl)-N-(3-cvano methyl-lH-indol vl)benzenesulfonamide (Intermediate DH)

Y^MgBr

KH, t-BuLi, C02

THF

DPPA, TEA t-BuOH

TFA

DCM

ΝΗ2ΟΗ&#905;ΟΙ, KOAc

EtOH

pyridine, DMAP, DCM

Ν2Η4.Η2Ο

EtOH

[001598] Step 1 - 7-Bromo methyl-lH-indole

[001599] To a solution of l-bromo methyl nitro-benzene (40.0 g, 185 mmol, 25.3 mL) in tetrahydrofuran (400 mL) was added bromo(vinyl)magnesium (1 M, 611 mL) at -60 °C under nitrogen gas atmosphere. The reaction mixture was then stirred at -30 °C for 1 hour. On completion, the reaction mixture was quenched with saturated ammonium chloride solution (150 mL), followed with water (100 mL). The mixture was concentrated in vacuo to remove the tetrahydrofuran. The residue was extracted with ethyl acetate (2 X 500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by column chromatography (petroleum ether: ethyl acetate = 100:1) to give the title compound (18.0 g, 42% yield) as a yellow oil. 1H NMR (400MHz, DMSO-Y) δ 11.27 (br s, IH), 7.37 (t, J= 2.8 Hz, IH), 7.18 (d, J= 7.6 Hz, IH), 6.75 (dd, J= 0.8, 7.6 Hz, IH), 6.57 (dd, J= 1.6, 3.2 Hz, IH), 2.44 (s, 3H).

[001600] Step 2 - 4-Methyl-lH-indole carboxylic acid

[001601] To a mixture of potassium hydride (4.47 g, 34.27 mmol, 30 wt %) suspended in anhydrous tetrahydrofuran (80 mL) was added 7-bromo methyl-l//-indole (6.00 g, 28.56 mmol) dissolved in tetrahydrofuran (30 mL) at 0 °C. After 15 minutes, the mixture was cooled to -70 °C and t-BuLi (1.3 M, 54.9 mL) was added dropwise, keeping the temperature below -65 °C. After further 15 minutes, carbon dioxide gas (15 psi pressure) was bubbled into the reaction and the reaction was slowly warmed to rt over 30 minutes. On completion, the reaction mixture was quenched with ice water (120 mL), and washed with ethyl acetate (3 X 60 mL). The aqueous phase was collected and acidified with 1 N hydrochloride acid solution until the pH < 7. Then, the mixture was extracted with ethyl acetate (3 X 60 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product as a brown solid. The crude product was triturated with petroleum ether: dichloromethane (10:1, 100 mL) to give the product (3.50 g, 69% yield) as a white solid. 1H NMR (400MHz, DMSO-<76) δ 12.82 (br s, IH), 11.02 (brs, IH), 7.67 (d, J =1.6 Hz, IH), 7.35 (t, J= 2.8 Hz, IH), 6.92 (d, J =1.6 Hz, IH), 6.56 (dd, J= 2.0, 3.2 Hz, IH), 2.54 (s, 3H).

[001602] Step 3 - Tert-butyl N-(4-methyl-lH-indol yl)carbamate

[001603] To a solution of 4-methyl-l//-indole carboxylic acid (2.20 g, 12.5 mmol) in tBuOH (36 mL) was added triethylamine (3.81 g, 37.6 mmol, 5.24 mL) and DPPA (4.49 g, 16.3 mmol, 3.54 mL). The mixture was stirred at 80 °C for 3 h. On completion, the reaction mixture was poured into ice water (150 mL) and extracted with ethyl acetate (3 X 80 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to get a residue. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1) to give the title compound (2.00 g, 64% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 9.80 (br s, IH), 7.14 (t, J= 2.8 Hz, IH), 6.70 (d, J = 7.6 Hz, IH), 6.60 (br s, IH), 6.52 (br s, IH), 6.45 (dd, J= 2.0, 2.8 Hz, IH), 2.44 (s, 3H), 1.48 (s, 9H).

[001604] Step 4 - Tert-butyl N-(3-formvl methyl-lH-indol vl)carbamate

[001605] Phosphorus oxychloride (2.61 g, 17.0 mmol, 1.58 mL) was added to anhydrous A/A-dimethyl- formamide (20 mL) at 0 °C under nitrogen atmosphere and the reaction mixture was stirred for 30 minutes. Tert-butyl 7V-(4-methyl-l//-indol yl)carbamate (2.80 g, 11.3 mmol) dissolved in A; AMi methyl form am ide (8 mL) was then added dropwise and the reaction mixture was allowed to warm to rt and then stirred for 1.5 hrs. Next, to the reaction mixture was added 30% sodium hydroxide (100 mL) and the mixture was heated to reflux for 30 minutes. On completion, the mixture was extracted with ethyl acetate (3 X 150 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 3:1 to 0:1) to give the title compound (2.70 g, 86% yield) as a white solid. 1H NMR (400MHz, DMSO4) δ 11.93 (br s, IH), 9.99 (s, IH), 9.04 (br s, IH), 8.27 (s, IH), 7.43 (br d, J = 6.0 Hz, IH), 6.96 (d, J= 8.0 Hz, IH), 2.76 (s, 3H), 1.55 (s, 9H).

[001606] Step 5 - Tert-butyl N-[3-(hydroxyiminomethyl) methyl-lH-indol yl1carbamate [001607] To a solution of tert-butyl N-(3-formyl methyl-lH-indol yl)carbamate (2.70 g, 9.84 mmol) in ethanol (80 mL) was added NH2OH*HC1 (1.03 g, 14.7 mmol) and anhydrous potassium acetate (2.90 g, 29.5 mmol). The mixture was stirred at 80 °C for 30 minutes. On completion, the reaction mixture was concentrated in vacuo to get a residue. The residue was diluted with water (60 mL) and extracted with ethyl acetate (3 X 60 mL). The organic phase was collected, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (2.80 g, 98% yield) as a white solid. LC-MS (ESI+) m/z 290.2 (M+H)+.

[001608] Step 6 - Tert-butyl N-(3-cyano methyl-lH-indol yl)carbamate

[001609] To a solution of tert-butyl 7V-[3-(hydroxyiminomethyl) methyl-l//-indol-7yl]carbamate (2.60 g, 8.99 mmol) in anhydrous tetrahydrofuran (70 mL) was added di(imidazoll-yl)methanthione (3.20 g, 17.9 mmol) and the mixture was stirred at rt for 2 h. The reaction mixture was then concentrated in vacuo to get a residue. The residue was diluted with ice water (60 mL) and extracted with ethyl acetate (3 X 40 mL). The combined organic phase was collected, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to get a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate = 5:1 to 2:1) to give the title compound (2.40 g, 98% yield) as a gray solid. 1H NMR (400MHz, CDCh) δ 10.98 (br s, IH), 7.74 (d, J = 3.2 Hz, IH), 6.89 (d, J = 7.6 Hz, IH), 6.81 (br s, IH), 6.66 (br d, J = 6.8 Hz, IH), 2.75 (s, 3H), 1.57 (s, 9H).

[001610] Step 7 - 7-Amino methyl-lH-indole carbonitrile

[001611] To a solution of tert-butyl N-(3-cyano methyl-lH-indol yl)carbamate (2.30 g, 8.48 mmol) in anhydrous dichloromethane (23 mL) was added trifluoroacetic acid (17.7 g, 155 mmol, 11.50 mL).The mixture was stirred at rt for 30 minutes. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 X 30 mL). The combined organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was triturated with petroleum ether: dichloromethane (30:1, 50 mL) to give the title compound (1.40 g, 96% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 11.73 (br s, IH), 8.12 (d, J= 3.2 Hz, IH), 6.67 (d, J = 7.6 Hz, IH), 6.37 (d, J = 7.6 Hz, IH), 5.09 (br s, 2H), 2.50 (br s, 3H).

[001612] Step 8 - N-(3-cyano methyl-lH-indol yl) [(L3-dioxoisoindolin-2yl)methyl1benzenesulfon- amide

[001613] To a solution of 4-[(l,3-dioxoisoindolin yl)methyl]benzenesulfonyl chloride (1.51 g, 4.50 mmol, Intermediate DG) in dichloromethane (30 mL) was added pyridine (646 mg, 8.18 mmol, 660 uL) and DMAP (49.9 mg, 408 umol) and 7-amino methyl-l//-indole-3carbonitrile (700 mg, 4.09 mmol). The mixture was stirred at rt for 3 h. On completion, the reaction mixture was concentrated in vacuo to get a residue. The residue was triturated with (dichloromethane: methanol = 10:1, 50 mL) to give the title compound (1.00 g, 51% yield) as a white solid. 1HNMR (400MHz, DMSO-t/6) δ 11.92 (d, J= 2.4 Hz, IH), 9.97 (s, IH), 8.15 (d, J= 3.2 Hz, IH), 7.93 - 7.84 (m, 4H), 7.67 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, IH), 6.59 (d, J= 8.0 Hz, IH), 4.83 (s, 2H), 2.55 (s, 3H).

[001614] Step 9:4-(Aminomethyl)-N-(3-cyano methyl-lH-indol-7yDbenzenesulfonamide

[001615] To a solution of 7V-(3-cyano methyl-lH-indol yl) [(l,3-dioxoisoindolin-2yl)methyl]-benzene sulfonamide (1.00 g, 2.13 mmol) in ethanol (30 mL) was added hydrazine hydrate (2.13 g, 2.07 mL). The mixture was stirred at 80 °C for 2 h. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.05 g, 92% yield) as a white solid. LC-MS (ESL)&#1524;/ z 341.1 (M+H)+.

[001616] 2-[2-[2-[2-[2-[2-(Tertbutoxvcarbonvlamino)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetic acid (Intermediate DI)

BocHN

Rh2(0Ac)4, DCM

BocHN

THF, MeOH, H2O

[001617] Step 1:Ethyl 2-[2-[2-[2-[2-[2-(tertbutoxycarbonylamino )ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate

[001618] To a mixture of tert-butyl N-[2-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (2.00 g, 5.93 mmol, synthesized via Step 1 of Intermediate AK) and Rh2(OAc)4 (52.4 mg, 119 umol) in dichloromethane (10 mL) was added a solution of ethyl 2-diazoacetate (1.01 g, 8.89 mmol, 931 uL) dissolved in dichloromethane (10 mL) dropwise at rt. Then the reaction mixture was stirred at rt for 17 h. On completion, the reaction mixture was quenched by adding water (15 mL) and was then extracted with di chloromethane (2 X 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether: Ethyl acetate = 5:1 to 1:1) to give the title compound (370 mg, 15% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 5.12 (s, IH), 4.23 (q, J= 7.2 Hz, 2H), 4.16 (s, 2H), 3.76 - 3.64 (m, 16H), 3.56 (t, J= 5.2 Hz, 2H), 3.33 (d, J= 4.8 Hz, 2H), 1.46 (s, 9H), 1.30 (t, 7= 7.2 Hz, 3H).

[001619] Step 2:2-Γ2-[2-Γ2-Γ2-Γ2-(Τ61&#912;butoxycarbonylam i n0 )ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetic acid

[001620] To a mixed solution of ethyl 2-[2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]- ethoxy]ethoxy]acetate (370 mg, 877 umol) in tetrahydrofuran (4 mL), methanol (1 mL) and H2O (1 mL) was added lithium hydroxide (41.8 mg, 1.75 mmol). The reaction mixture was stirred at rt for 0.5 hr. On completion, the reaction mixture was adjusted pH < 7 with 1 N hydrochloride acid solution, and then concentrated in vacuo to give the title compound (520 mg, 70% purity, 87% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 5.33 (s, IH), 4.67 (s, IH), 3.88 (s, 2H), 3.61 - 3.55 (m, 16H), 3.47 (t, 7= 5.2 Hz, 2H), 3.23 (d, 7= 5.2 Hz, 2H), 1.37 (s, 9H).

[001621] 4-(2-Aminoethylamino) (2.,6-dioxo DiDeridvl)isoindoline-l.,3-dione (Intermediate DJ)

[001622] Step 1 - Tert-butyl N-r2-r[2-(2,6-dioxo piperidyl)-l J-dioxo-isoindolin-4yl1amin01ethyl1carbamate

[001623] Amixture of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (2.07 g, 7.49 mmol, Intermediate R), /c77-butyl N-(2-aminoethyl)carbamate (1.00 g, 6.24 mmol) and DIPEA (1.61 g, 12.5 mmol, 2.17 mL) in dioxane (10 mL) was stirred at 115 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (0.90 g, 28% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 11.09 (s, IH), 7.58 (t, J = 7.6 Hz, IH), 7.15 (d, J = 8.8 Hz, IH), 7.08 6.96 (m, 2H), 6.71 (t, J = 5.6 Hz, IH), 5.05 (dd, J = 5.6, 12.8 Hz, IH), 3.41 - 3.35 (m, 2H), 3.13 (m, 2H), 2.97 - 2.82 (m, IH), 2.65 - 2.53(m, 2H), 2.07 - 1.96 (m, IH), 1.37 (s, 9H).

[001624] Step 2 - 4-(2-Aminoethylamino) (2,6-dioxo piperidyl)isoindoline-L3-dione

[001625] To a solution of /c77-butyl N-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]amino]ethyl] carbamate (0.30 g, 720 umol) in DCM (10 mL) was added HCI in dioxane (4 N, 3 mL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (0.25 g, 98% yield) as a yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 11.12 (s, IH), 7.63 (t, J= 7.8 Hz, IH), 7.20 (d, J= 8.4 Hz, IH), 7.10 (d, J = 6.8 Hz, IH), 6.84 (t, J = 6.4 Hz, IH), 5.05 (dd, J= 5.6, 12.8 Hz, IH), 3.62 - 3.57 (m, 2H), 3.01 - 2.89 (m, 2H), 2.90 - 2.89 (m, IH), 2.62 - 2.55 (m, 2H), 2.05 - 2.03 (m, IH).

[001626] 2-Chl0r0-N-cvcl0Dr0Dvl ethvnvl-Dvridin amine (Intermediate DL)

[001627] Step 1 - 5-Bromo chloro-N-cvclopropvl-pyridin amine

[001628] To a solution of 5-bromo-2,4-dichloro-pyridine (5 g, 22.0 mmol) and cyclopropanamine (1.32 g, 23.1 mmol) in DMF (50 mL) was added DIPEA (8.54 g, 66.1 mmol). The reaction mixture was stirred at 100 °C for 17 h. On completion, the mixture was diluted with H2O (40 mL) and extracted with EA (2 X 40 mL). The organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.10 g, 39% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.14 (s, IH), 6.90 (s, IH), 5.22 (s, IH), 2.56 - 2.49 (m, IH), 0.96 - 0.90 (m, 2H), 0.69 - 0.64 (m, 2H); LC-MS (ESI+) m/z 248.9 and 246.9 (M+H)+.

[001629] Step 2 - 2-Chloro-N-cyclopropyl (2-trimethylsilylethynyl)pyridin amine

[001630] 5-Bromo chloro-N-cyclopropyl-pyridin amine (1.0 g, 4.0 mmol), Cui (46.2 mg, 242 umol) and Pd(PPh3)2C12 (170 mg, 242 umol) was taken up into a microwave tube. Then ethynyl(trimethyl)silane (794 mg, 8.08 mmol), TEA (7.36 g, 72.7 mmol) and DMF (5 mL) were added into the above tube. The mixture was degassed with nitrogen gas for 5 minutes. The sealed tube was then heated to 120 °C for 1 h under microwave. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (900 mg, 45% yield) as a brown solid. LC-MS (ESI+) m/z 265.0 (M+H)+.

[001631] Step 3 - 2-Chloro-N-cyclopropyl ethynyl-pyridin amine

[001632] To a solution of 2-chloro-N-cyclopropyl (2-trimethylsilylethynyl)pyridin-4amine (1.0 g, 3.8 mmol) in a mixed solvent of MeOH (10 mL) and DCM (10 mL) was added K2CO3 (2.09 g, 15.1 mmol). The reaction mixture was stirred at rt for 15 h. On completion, the mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (268 mg, 35% yield) as a yellow solid. 1H NMR (300MHz, CDCh) δ 8.13 (s, IH), 6.88 (s, IH), 5.42 (s, IH), 3.50 (s, IH), 2.57-2.46 (m, IH), 0.96 - 0.84 (m, 2H), 0.70 - 0.58 (m, 2H); LC-MS (ESI+) m/z 193.0 (M+H)+.

[001633] 2- [2- [2- [2-(Tert-butoxvcarbonvlamino)ethoxy| ethoxy] ethoxy] acetic acid (Intermediate DM)

NHBoc

Rh(OAc)2, DCM

NHBoc

O

LiOH

THF, MeOH, H2O

BocHN

O

DM

[001634] Step 1 - Ethyl 2-r2-r2-r2-(tert-butoxycarbonylamino)ethoxy1ethoxy1ethoxy1

[001635] To a mixture of tert-butyl /V-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (3.00 g, 12.0 mmol, CAS# 139115 7) andRh(OAc)2 (106 mg, 481 umol) in DCM (70 mL) was added a solution of ethyl 2-diazoacetate (4.12 g, 36.1 mmol) in DCM (40 mL) dropwise. The reaction mixture was stirred at rt for 16 h. On completion, the reaction mixture was diluted with water (100 mL) and extracted with DCM (3 X 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (600 mg, 14% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 5.15 - 5.13 (m, IH), 4.23 (q, J = 7.2 Hz, 2H), 4.16 (s, 2H), 3.77 - 3.69 (m, 4H), 3.68 - 3.61 (m, 4H), 3.55 (t, J= 5.2 Hz, 2H), 3.32 (d, J = 4.8 Hz, 2H), 1.45 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

[001636] Step 2 - 2-r2-r2-r2-(Tert-butoxycarbonylamino)ethoxy1ethoxy1ethoxy1acetic acid

[001637] To a solution of ethyl 2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetate (300 mg, 894 umol) in a mixed solvent of MeOH (5 mL) and H2O (5 mL) was added LiOH*H2O (75.0 mg, 1.79 mmol). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was acidified with IN HC1 solution until the pH=7. The mixture was lyophilized to give the title compound (300 mg, 100% yield) as a white solid.

[001638] 2-(26&#1524;-Dioxo DiDeridvl) (DroD vnvlamino)isoindoline-l.,3-dione (Intermediate DN)

DN

[001639] To a solution of prop yn-l-amine (332 mg, 6.03 mmol, 386 uL) and DIPEA(3.90 g, 30.1 mmol, 5.25 mL) in dioxane (20.0 mL) was added 2-(2,6-dioxo piperidyl) fluoroisoindoline-1,3-dione (2.00 g, 7.24 mmol, Intermediate R), and the mixture was stirred at 115°C for 16 h. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% FA) to give the title compound (550 mg, 29% yield) as a yellow solid. 1H NMR (400MHz, CDC13) δ 8.00 (s, IH), 7.65 - 7.57 (m, IH), 7.23 (d, J = 7.2 Hz, IH), 7.06 (d, J = 8.4 Hz, IH), 6.50 - 6.48 (m, IH), 4.99 - 4.91 (m, IH), 4.14 - 4.10 (m, 2H), 2.91 - 2.77 (m, 2H), 2.31 - 2.28 (m, IH), 2.20 - 2.11 (m, IH), 2.07 (s, IH).

[001640] 4-(But vnvlamino) (2,6-dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate DO)

DIPEA, dioxane

DO

[001641] To a mixture of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (2.04 g, 7.39 mmoL Intermediate R) and but yn-I -amine (650 mg, 6.16 mmol, hydrochloride) in dioxane (20 mL) was added DIPEA (7.96 g, 61.5 mmol). The reaction mixture was stirred at 115 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA) to give the title compound (800 mg, 39% yield) as a green solid. LCMS (ESI+) m/z 326.0 (M+H)+.

[001642] 4-(3-AzidoDroDvlamino) (2,6-dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate DP)

Ο Ο

Ν3^χ-Χ^ΝΗ2

HCI

DIPEA, dioxane

R DP

[001643] To a solution of 3-azidopropan amine (198 mg, 1.45 mmol, HCI, CAS# 8819219-2) and 2-(2,6-di oxo piperi dyl) fluoro-isoindoline-1,3-dione (0.40 g, 1.45 mmol, Intermediate R) in DMF (10 mL) was added DIPEA (936 mg, 7.24 mmol, 1.26 mL). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (NH3*H2O) to give the title compound (200 mg, 38.4% yield) as a yellow solid. LC-MS (ESI+) m/z 357.0 (M +H)+.

[001644] Tert-butyl 4-(4-hvdroxvcvclohexvl)DiDerazine-l-carboxylate (Intermediate DO) HHCI Boc2O, NaOH ?oc ΗΟ'&#1524;<θ-ΝΗ2

HO1&#1470;&#1470;? )&#1524;N N-Boc:

Cl Cl DCM Cl Cl K2CO3, KI, dioxane '—' x—7

DQ

[001645] Step 1 - Tert-butyl N,N-bis(2-chloroethyl)carbamate

[001646] To a mixture of 2-chloro-A-(2-chloroethyl)ethanamine (20.0 g, 112 mmol, HCI salt) in a mixed solution of DCM (150 mL) and NaOH (13.5 g, 3 M, 110 mL) was added a solution of (Boc)2O (24.5 g, 112 mmol) in DCM (80 mL) dropwise. The reaction mixture was stirred at rt for 18 h. On completion, the mixture was separated and the organic layer was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (24.5 g, 90% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 3.71 - 3.58 (m, 8H), 1.49 (s, 9H).

[001647] Step 2 - Tert-butyl 4-(4-hydroxycyclohexyl)piperazine-l-carboxylate

[001648] To a solution of terLbutyl Af,Af-bis(2-chloroethyl )carbamate (10.0 g, 41.3 mmol) and 4- aminocyclohexanol (5.04 g, 43.8 mmol) in dioxane (200 mL) was added K2CO3 (17.1 g,

124 mmol) and KI (20.6 g, 124 mmol). The reaction mixture was stirred at 115 °C for 17 h. On completion, the reaction mixture was fdtered and the fdtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (3.50 g, 30% yield) as a red solid. 1H NMR (400MHz, MeOH&#1470;d4) δ 3.54 - 3.47 (m, IH), 3.47 - 3.39 (m, 4H), 2.60 2.51 (m, 4H), 2.37 - 2.27 (m, IH), 2.03 - 1.97 (m, 2H), 1.96 - 1.90 (m, 2H), 1.47 (s, 9H), 1.38 1.27 (m, 4H).

[001649] (2S) Hvdroxv [(8R)-l-(4-DiDerazin-l-vlcvclohexoxv)-7,8-dihydro-6Hcyclopenta[4,5]thieno[l,2-c]pvrimidin yl]propenamide(Intermediate DR)

NCCH2C00Et

Et2NH, S, EtOH

HCI in dioxane

DCM

DR

[001650] Step 1 - Ethyl 2-amino (2-ethoxy oxo-ethyl)-5,6-dihydro-4Hcyclopenta[b1thiophene carboxylate

[001651] To a solution of ethyl 2-(2-oxocyclopentyl)acetate (30.0 g, 169 mmol) in EtOH (300 mL) was added ethyl 2-cyanoacetate (17.2 g, 152 mmol), Et2NH (15.2 g, 208 mmol,) and sulphur (6.62 g, 206 mmol) at rt and the mixture was stirred for 90 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with EA (300 mL) and washed with brine (3 X 40 mL). The organic layer was dried over Na2SO4, fdtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE: EA = 10:1) to give the title compound (25.0 g, 47% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 5.95 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.15 (q, J = 7.2 Hz, 2H), 3.64 - 3.55 (m, IH), 2.87 - 2.11 (m, 6H), 1.35 (t, J= 7.2 Hz, 3H), 1.25 (t, J= 7.2 Hz, 3H); LC-MS (ESI+) m/z 298.0 (M+H)+.

[001652] Step 2 - Ethyl 2-(l-hydroxy-7.8-dihydro-6H-cyclopentar3.41thieno[L3c1pyrimidin yl)acetate

[001653] A mixture of ethyl 2-amino (2-ethoxy oxo-ethyl)-5,6-dihydro-4/7 cyclopenta[£]thiophene carboxylate (28.0 g, 94.1 mmol) and formamide (158 g, 3.51 mol) was stirred at 180 °C for 8 h. On completion, the reaction mixture was cooled to room temperature and then quenched with water/ice (200 mL). The mixture was extracted with ethyl acetate (3 X 100 mL) and the combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (15.0 g, 57% yield) as a yellow brown solid. 1H NMR (400MHz, DMSOA) δ 12.49 (s, IH), 8.03 (s, IH), 4.05 (q, J = 7.2 Hz, 2H), 3.66 - 3.52 (m, IH), 3.28 (dd, 7=3.6, 16 Hz, IH), 3.08 - 2.81 (m, 2H), 2.74 - 2.59 (m, IH), 2.40 - 2.30 (m, IH), 2.181.99 (m, IH), 1.15 (t, J = 7.2 Hz, 3H); LC-MS (ESI+) m/z 279.0 (M+H)+.

[001654] Step 3 - Ethyl 2-(l-chloro-7,8-dihydro-6H-cyclopentar3,41thieno[L3-d1pyrimidin8-yl)acetate

[001655] A mixture of ethyl 2-(l-hydroxy-7,8-dihydro-6H-cyclopenta[3,4]thieno[l,3c]pyrimidin yl)acetate (14.0 g, 50.3 mmol) in POC13 (165 g, 1.08 mol) was stirred at 85 °C for 16 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE: EA= 5:1) to give the title compound (12.0 g, 80% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 8.71 - 8.63 (m, IH), 4.07 (q, J = 7.2 Hz, 2H), 3.93 - 3.83 (m, IH), 3.16 - 3.04 (m, IH), 3.00 - 2.90 (m, IH), 2.85 (dd, J= 2.8, 12.8 Hz, IH), 2.73 -2.67 (m, IH), 2.42 (dd,7=10.4, 15.2 Hz, IH), 2.34 - 2.28 (m, IH), 1.15 (t, J= 7.2 Hz, 3H); LC-MS (ESI+) m/z 297.0 (M+H)+.

[001656] Step 4 - 2-(1-Chioro-7,8-dihydro-6H-cvclopenta[3,4]thieno[ L3-d1pvrimidin-8vDethanol

[001657] To a solution of ethyl 2-(l-chloro-7,8-dihydro-6//-cyclopenta[3,4]thieno[l,37]pyrimidin yl)acetate (18.0 g, 60.6 mmol) in THF (200 mL) was added DIBAL-H (1 M, 196 mL) at -50 °C dropwise. Then the mixture was stirred at -30 °C for 1 hour. On completion, the mixture was added to water (10 mL) and NaOH solution (15%, 20 mL) at 0 °C. The mixture was then filtered and dried over Na2SO4, then filtered again and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE: EA = 5:1) to give the title compound (12.0 g, 68% yield) as a light yellow solid. 1HNMR (400MHz, CDCh) δ 8.76 (s, IH), 3.85 - 3.71 (m, 2H), 3.62 (t, J = 8.8 Ηζ,ΙΗ), 3.21 - 3.07 (m, IH), 3.06 - 2.93 (m, IH), 2.70 - 2.60 (m, IH), 2.44 - 2.33 (m, IH), 2.20 - 2.08 (m, IH), 1.78 - 1.68 (m, IH); LC-MS (ESI+) m/z 254.9 (M+H)+.

[001658] Step 5 - 2-r(8R)-l-chloro-7,8-dihydro-6H-cvclopentar3,41thieno[L3-d1pvrimidin777

8-yl1 ethanol

[001659] The racemic 2-(1-chi oro-7,8-dihydro-6H-cyclopenta[3,4]thi eno[ l,3-i/]pyrimidin8-yl)ethanol (23.0 g, 90.2 mmol) was separated by SFC (column:

AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O MEOH]) to give to give two isomers. The first fraction was the desired product: 2-[(8J?)-l-chloro-7,8- di hydro-67/cyclopenta[3,4]thieno[l,3-d]pyrimidin yl]ethanol (10.9 g, 47% yield, tR = 2.562) which was isolated as a yellow solid. The second fraction is 2-[(85)-l-chloro-7,8-dihydro-6Hcyclopenta[3,4]thieno[l,3-d]pyrimidin yl] ethanol (11.5 g, 49% yield, tR = 3.522 ) was also isolated as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.72 (s, IH), 3.87 - 3.72 (m, 2H), 3.70 3.59 (m, IH), 3.21 - 3.09 (m, IH), 3.06 - 2.95 (m, IH), 2.71 - 2.61 (m, IH), 2.41 - 2.35 (m, IH), 2.19 - 2.09 (m, IH), 1.78 - 1.69 (m, IH) ; LC-MS (ESI+) m/z 255.0 (M+H)+.

[001660] Step 6 - Tert-butvl-r2-r(8R)-l-chloro-7,8-dihydro-6H-cvclopentar3,41thieno[L3d1pyrimidin yl1 ethoxyl-dimethyl-silane

[001661] To a solution of 2-[(8J?)-l-chioro-7,8-dihydro-6H-cyclopenta[3,4]thieno[ 1,3<7]pyrimidin yl] ethanol (5.9 g, 23.1 mmol) in DMF (60 mL) was added imidazole (2.21 g, 32.4 mmol) and TBSC1 (4.19 g, 27.7 mmol). The reaction mixture was stirred at rt for 13 h under nitrogen atmosphere. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3X30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 5:1) to give the title compound (7.80 g, 87% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 8.74 (s, IH), 3.82 - 3.70 (m, 2H), 3.68 - 3.58 (m, IH), 3.20 - 3.09 (m, IH), 3.05 - 2.95 (m, IH), 2.68 - 2.58 (m, IH), 2.48 - 2.37 (m, IH), 2.17 - 2.05 (m, IH), 1.70 - 1.63 (m, IH), 0.89 (s, 9H), 0.06 (d, J= 0.8 Hz, 6H); LC-MS (ESI+) m/z 369.0 (M+H)+.

[001662] Step 7 - Tert-butyl 4-r4-rr(8R) r2-rtert-butvl(dimethyl)silvl10xvethyl]-7,8dihydro-6H-cyclopenta r4,51thienorL2-c1pyrimidin-l-yl1oxy1cyclohexyl1piperazine-lcarboxylate

[001663] To a solution of ///7-butyl 4-(4-hydroxycyclohexyl)piperazine-l-carboxylate (4.32 g, 15.1 mmol, Intermediate DQ) in THF (80 mL) was added NaH (1.73 g, 43.3 mmol, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then a solution of ter/-butyl-[2-[(8J?)-l-chloro-7,8-dihydro-6/7-cyclopenta [3,4]thieno[l,3-d]pyrimidin8-yl]ethoxy]-dimethyl-silane (4.00 g, 10.8 mmol) in THF (40 mL) was added at 0 °C dropwise.

The reaction mixture was then heated to 60 °C and stirred for 14 h. On completion, the reaction mixture was quenched with water (50 mL) and the mixture was extracted with EA (3 X 80 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 3:1) to give the title compound (4.00 g, 42% yield) as a light yellow solid. 1HNMR. (400MHz, CDCh) δ 8.49 (s, IH), 5.27 - 5.14 (m, IH), 3.77 - 3.63 (m, 2H), 3.50 -3.40 (m, 5H), 3.14 - 3.01 (m, IH), 2.99 - 2.87 (m, IH), 2.68 - 2.57 (m, IH), 2.56 - 2.47 (m, 4H), 2.43 -2.37 (m, IH), 2.36 - 2.19 (m, 4H), 1.97 (d, J = 10.4 Hz, 2H), 1.64-1.51 (m, 5H), 1.47 (s, 9H), 0.90 (s, 9H), 0.05 (s, 6H); LC-MS (ESI+) m/z 617.2 (M+H)+.

[001664] Step 8 - Tert-butyl 4-r4-rr(8R) (2-hydroxyethyl)-7,8-dihydro-6Hcyclopentar4,51thieno[L2-c1 pyrimidin-l-yl1oxy1cyclohexyl1piperazine-l-carboxylate

[001665] To a solution of tert-butyl 4-[4-[[(8J?) [2-[tert-butyl(dimethyl)silyl]oxyethyl]7,8-dihydro-6H- cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-lcarboxylate (12.0 g, 19.4 mmol) in THF (120 mL) was added TBAF (1 M, 29.1 mL), and the mixture was stirred at rt for 14 h. On completion, the reaction mixture was quenched by addition of water (100 mL), and then extracted with EA (3 X 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA= 1:1) to give the title compound (9.7 g, 93% yield) as a light yellow oil. 1HNMR (400MHz, CDCh) δ 8.50 (s, IH), 5.29 - 5.16 (m, IH), 3.79 - 3.67 (m, 2H), 3.52 - 3.40(m, 5H), 3.14 - 3.02 (m, IH), 2.96 - 2.90 (m, IH), 2.71 - 2.62 (m, IH), 2.58 - 2.48 (m, 4H), 2.47 - 2.39 (m, IH), 2.38 - 2.25 (m, 3H), 2.21 - 2.12 (m, IH), 2.03 - 1.92 (m, 2H), 1.81 1.70 (m, 2H), 1.65 - 1.49 (m, 4H), 1.47 (s, 9H). LC-MS (ESI+) m/z 503.2 (M+H)+.

[001666] Step 9 - Tert-butyl 4-r4-rr(8R) (2-oxoethyl)-7,8-dihydro-6Hcyclopentar4,51thieno[L2-c1 pyrimidin-l-yl1oxy1cyclohexyl1piperazine-l-carboxylate

[001667] To a solution of tert-butyl 4-[4-[[(8J?) (2-hydroxyethyl)-7,8-dihydro-6Hcyclopenta[4,5]thieno [l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-l-carboxylate (9.70 g, 19.3 mmol) in DCM (160 mL) was added DMP (16.3 g, 38.5 mmol) at 0 °C. Then the mixture was allowed to warm to rt and stirred for 16 h. On completion, the reaction mixture was quenched by saturated NaHCO3 (200 mL) and then extracted with DCM (3 X 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (9.00 g, 72% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 9.84 (s, IH), 8.52 (s, IH), 5.28 - 5.17 (m, IH), 3.48 (t, J= 5.2 Hz, IH), 3.58 - 3.48 (m, 4H), 3.16 - 2.98 (m, 3H), 2.88 - 2.76 (m, IH), 2.74 - 2.52 (m, 6H), 2.38 - 2.27 (m, 2H), 2.18 - 2.11 (m, IH), 2.05 - 1.98 (m, 2H), 1.60 - 1.50 (m, 4H), 1.47 (s, 9H); LC-MS (ESI+) m/z 501.2 (M+H)+.

[001668] Step 10 - Tert-butyl 4-r4-rr(8R) (2-cyano trimethylsilyloxy-ethyl)-7,8dihydro-6H-cyclopenta[ thienorL2-c1pyrimidin-l-yl1oxy1cyclohexyl1piperazine-lcarboxylate and tert-butyl 4-[4-rr(8R) (2-cvano hydroxy-ethyl)-7,8-dihydro-6Hcvclopentar4,51thienorL2-c1pvrimidin-l-vl1oxv1cvclohexvl1piperazine-l-carboxylate

[001669] To a solution of tert-butyl 4-[4-[[(87?) (2-oxoethyl)-7,8-dihydro-6Hcyclopenta[4,5]thieno[l,2-c] pyrimidin-l-yl]oxy]cyclohexyl]piperazine-l-carboxylate (6.00 g, 11.98 mmol) and TEA (1.21 g, 11.9 mmol) in DCM (80 mL) was added TMSCN (3.57 g, 35.9 mmol), and the mixture was stirred at rt for 4 h. On completion, the reaction mixture was diluted with water (60 mL) and extracted with DCM (3 X 80 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-[4-[[(8R)8-(2-cyano trimethylsilyloxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5] thieno[l,2-c]pyrimidin-lyl]oxy]cyclohexyl]piperazine-l-carboxylate (5.5 g) and tert-butyl 4-[4-[[(8R) (2-cyano-2hydroxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[l,2-c]pyrimidin-lyl]oxy]cyclohexyl]piperazine-l-carboxylate (0.5 g) as a yellow oil, which were brought on to the next step as a mixture. LC-MS (ESI+) m/z 600.3 (M+H)+.

[001670] Step 11 - Tert-butyl 4-r4-rr(8R) (2-cvano hvdroxv-ethyl)-7,8-dihvdro-6Hcyclopenta[4,5]thieno Γ1,2-c1pyrimidin-1 -yl]oxylcyclohexyllpiperazine-1 -carboxylate

[001671] To a solution of tert-butyl 4-[4-[[(87?) (2-cyano trimethylsilyloxy-ethyl)-7,8dihydro-6H- cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-lcarboxylate (5.50 g, 9.17 mmol) and tert-butyl 4-[4-[[(87?) (2-cyano hydroxy-ethyl)-7,8dihydro-6H-cyclopenta[4,5]thieno [l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-lcarboxylate (500 mg, 947 umol) in THF (80 mL) was added TBAF (1 M, 13.75 mL), and the mixture was stirred at rt for 3 h. On completion, the reaction mixture was quenched with water (80 mL), and then extracted with EA (3 X 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA= 1:1) to give the title compound (4.20 g, 69% yield) as a light yellow oil. 1HNMR (400MHz, CDCh) δ 8.51 (d, J = 1.6 Hz, IH), 5.32 - 5.18 (m, IH), 4.58 - 4.50 (m,

IH), 3.69 - 3.37 (m, 5H), 3.17 - 2.92 (m, 2H), 2.80 - 2.66 (m, IH), 2.65 - 2.46 (m, 6H), 2.43 - 2.23 (m, 3H), 2.04 - 1.85 (m, 3H), 1.76 - 1.49 (m, 4H), 1.46 (s, 9H). LC-MS (ESI+) m/z 528.1 (M+H)+. [001672] Step 12 - 2-Hydroxy [(8R)-l-(4-piperazin-l-ylcyclohexoxy)-7,8-dihydro-6Hcyclopenta[4,51thieno [L2-c1pyrimidin yl1propanamide

[001673] To a solution of tert-butyl 4-[4-[[(87?) (2-cyano hydroxy-ethyl)-7,8-dihydro6H-cyclopenta[4,5] thieno[ 1,2-c]pyrimidin-1 -yl]oxy]cyclohexyl]piperazine-1 -carboxylate (4.20 g, 7.96 mmol) in DCM (80 mL) was added HC1 in dioxane (4 M, 33.6 mL), and the mixture was stirred at rt for 3 h. On completion, the reaction mixture was quenched with saturated sodium bicarbonate (30 mL). The mixture was concentrated in vacuo to give the title compound (4.00 g, 100% yield) as a light yellow solid. LC-MS (ESI+) m/z 446.2 (M+H)+.

[001674] Step 13 - Tert-butyl 4-[4-[[(8R) (3-amino hydroxy oxo-propyl)-7,8-dihydro6H-cyclopenta [4,51thieno[L2-c1pyrimidin-l-yl1oxy1cyclohexyl1piperazine-l-carboxylate [001675] To a solution of 2-hydroxy [(87?)-l-(4-piperazin-l-ylcyclohexoxy)-7,8-dihydro6//-cyclopenta[4,5] thieno[l,2-c]pyrimidin yl]propanamide (2.50 g, 5.61 mmol) in a mixed solvent of DCM (25 mL) and MeOH (25 mL) was added TEA (1.70 g, 16.8 mmol) and B0C20 (2.45 g, 11.2 mmol) , and the mixture was stirred at rt for 16 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο) to give the title compound (1.50 g, 47% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 8.49 (d, J = 5.2 Hz, IH), 6.70 - 6.50 (m, IH), 6.01 - 5.87 (m, IH), 5.29 - 5.13 (m, IH), 4.20 - 4.13 (m, IH), 3.72 - 3.53 (m, IH), 3.42 (t, J= 4.4 Hz, 4H), 3.15 3.04 (m, IH), 3.01 - 2.88 (m, IH), 2.78 - 2.60 (m, IH), 2.58 - 2.49 (m, 4H), 2.49 - 2.12 (m, 6H), 1.99 - 1.83 (m, 3H), 1.63 - 1.43 (m, 13H). LC-MS (ESE)&#1524;/ z 546.2 (M+H)+.

[001676] Step 14 - Tert-butyl 4-[4-[[(8R) [(2S) amino hydroxy oxo-propyl1-7,8dihydro-6H-cyclopenta[4,51thieno[L2-c1pyrimidin-l-yl1oxy1cyclohexyl1piperazine-lcarboxylate

[001677] The racemic tert-butyl 4-[4-[[(87?) (3-amino hydroxy oxo-propyl)-7,8dihydro-6H- cyclopenta [4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-lcarboxylate (1.50 g, 2.66 mmol) was separated by SFC (column: AD(250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH]) to give the two isomers. The first fraction is tert-butyl 4-[4-[[(87?) [(27?) amino hydroxy oxo-propyl]-7,8-dihydro-6/7cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-l-carboxylate (700 mg,

46% yield, tR = 1.034) which was isolated as a light yellow solid. 1H NMR (400MHz, CDCh) δ 8.46 (s, IH), 6.66 (d, J = 2.8 Hz, IH), 5.99 (d, J = 2.8 Hz, IH), 5.25 - 5.11 (m, IH), 4.21 - 4.10 (m, IH), 3.67 - 3.56 (m, IH), 3.47 - 3.29 (m, 4H), 3.13 - 3.01 (m, IH), 2.98 - 2.86 (m, IH), 2.70 2.57 (m, IH), 2.54 - 2.43 (m, 4H), 2.40 - 2.04 (m, 6H), 1.97 - 1.79 (m, 3H), 1.75 - 1.26 (m, 13H); LC-MS (ESI+) m/z 546.2 (M+H)+.

[001678] The second fraction was the desired 4-[4-[[(87?) [(25) amino hydroxy-3oxo-propyl]-7,8-dihydro-6H- cyclopenta[4,5]thieno[l,2-c]pyrimidin-lyl]oxy]cyclohexyl]piperazine-l-carboxylate (560 mg, 37% yield, tR = 1.238) was also isolated as a light yellow solid. 1H NMR (400MHz, CDCh) δ 8.50 (s, IH), 6.60 (d, J = 2.8 Hz, IH), 5.72 (d, 2.8 Hz, IH), 5.30 - 5.23 (m, IH), 4.18 - 4.10 (m&#1524; IH), 3.63 - 3.51 (m, IH), 3.48 - 3.36 (m, 4H), 3.18-3.05 (m, IH), 3.00 - 2.88 (m, IH), 2.81 -2.66 (m, IH), 2.55 - 2.59 (m, 4H), 2.45 - 2.23 (m, 6H), 2.05 - 1.81 (m, 3H), 1.66 - 1.44 (m, 13H) ; LC-MS (ESI+) m/z 546.3 (M+H)+.

[001679] Step 15 - (2S) Hydroxy r(8R)-l-(4-piperazin-l-ylcyclohexoxy)-7,8-dihydro6H-cyclopenta[4,51 thieno[L2-c1pyrimidin yl1propanamide

[001680] To a solution of tert-butyl 4-[4-[[(87?) [(25) amino hydroxy oxo-propyl]7,8-dihydro-6H- cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-lcarboxylate (80.0 mg, 143 umol) in DCM (2 mL) was added HCI in dioxane (4 M, 1.37 mL), and the mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (80 mg, 100% yield, HCI salt) as a white solid; LC-MS (ESI+) m/z 446.1 (M+H)+.

[001681] Tert-butyl 2-(2-aminoethoxy)acetate(Intermediate DS)

[001682] Step 1 - Tert-butyl 2-r2-(L3-dioxoisoindolin yl)ethoxy1acetate

[001683] To a solution of 2-(2-hydroxyethyl)isoindoline-l,3-dione (1.00 g, 5.23 mmol, CAS# 3891 4) and Rh(OAc)2 (46.2 mg, 209 umol) in DCM (20 mL) was added tert-butyl 2diazoacetate (1.64 g, 11.5 mmol) in DCM (20 mL) dropwise at rt over 1 hour. The reaction mixture was then stirred at rt for 20 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (0.76 g, 48% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.90 - 7.84 (m, 2H), 7.77 - 7.70 (m, 2H), 3.99 (s,

2H), 3.97 - 3.93 (m, 2H), 3.85 - 3.80 (m, 2H), 1.45 (s, 9H); LC-MS (ESI+) m/z 328.0 (M+Na)+.

[001684] Step 2 - Tert-butyl 2-(2-aminoethoxy)acetate

[001685] To a solution of tert-butyl 2-[2-(l,3-dioxoisoindolin yl)ethoxy]acetate (0.76 g, 2.49 mmol) in EtOH (20 mL) was added ΝΗ2ΝΗ2.Η2Ο (623 mg, 12.5 mmol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with DCM (20 mL), filtered and the filtrate was concentrated in vacuo to give the title compound (340 mg, 78% yield) as a yellow oil. LC-MS (ESI+) m/z 176.0 (M+H)+.

[001686] 2- [2 12- [2-(2-ethoxv oxo-ethoxv)ethoxy] ethoxy] ethoxy] ethoxy] acetic acid (Intermediate DT) &#970; P

ΗΟ&#1523;^Ο'^Ο&#1523;^Ο'^Ο&#1523;ΑΤ'°Ε‘ ° Rh(OAc)2, DCM °°

TFA

DCM 00

DT

[001687] Step 1:Ethyl 2- [2- [ 2-[2-[2-(2-tert-butoxy oxoethoxy)ethoxy1 ethoxy] ethoxy] ethoxy] acetate

[001688] To a solution of ethyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate (1.00 g, 3.57 mmol, synthesized via Step 1 of Intermediate BK) and Rh(OAc)2 (39.5 mg, 178 umol) in DCM (20 mL) was added a solution of tert-butyl 2-diazoacetate (1.01 g, 7.14 mmol) in DCM (30 mL) dropwise at rt over 30 minutes. The reaction mixture was then stirred at rt for an additional 17 hours. On completion, the mixture was washed with water (3X30 mL). The organic phase was separated and was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (0.64 g, 45% yield) as a yellow oil. 1HNMR (400MHz, CDCh) δ 4.23 (q, J= 7.2 Hz, 2H), 4.17 (s, 2H), 4.04 (s, 2H), 3.78 - 3.66 (m, 16H), 1.49 (s, 9H), 1.30 (t, J= 7.2 Hz, 3H).

[001689] Step 2:2-[2-[2-[2-[2-(2-ethoxy oxoethoxy)ethoxy1ethoxy1ethoxy1ethoxy1acetic acid

[001690] To a solution of ethyl 2-[2-[2-[2-[2-(2-tert-butoxy oxoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (200 mg, 507 umol) in DCM (1.5 mL) was added

TFA (1.5 mL). The reaction mixture was stirred at rt for 30 minutes. On completion, the mixture was concentrated in vacuo to give the title compound (170 mg, 99% yield) as a yellow oil.

[001691] (4-Hvdroxvcvclohexyl) 4-methylbenzenesulfonate (Intermediate DU) < &#1509; pyridine, TsCI _ <

HCT^ CHCI3 Η0&#902;Υ

DU

[001692] To a solution of pyridine (12.3 g, 155 mmol) in CHCh (150 mL) was added cyclohexane-1,4-di01 (15.0 g, 129 mmol) at rt. Then the mixture was then cooled to 0 °C and 4methylbenzenesulfonyl chloride (24.6 g, 129 mmol) was added into the mixture. The reaction mixture was then allowed to warm to rt and stirred for 18 hrs. On completion, the reaction mixture was acidified with IN HCI solution until the pH = 5-6, and extracted with EA (3 X 30 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (16.0 g, 46% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 7.85 - 7.76 (m, 2H), 7.36 (d, J= 8.0 Hz, 2H), 4.66 - 4.49 (m, IH), 3.80 - 3.70 (m, IH), 2.47 (s, 3H), 1.97 - 1.91 (m, 2H), 1.72 - 1.65 (m, 2H), 1.64 1.50 (m, 4H).

[001693] Tert-butyl 4-((4-(45,.5,.4&#1524;-tetramethvl-l.,3.,2-dioxaborolan vl)phenvl)sulfonvl) piperazine-l-carboxylate

TEA,THF

Pd(dppf)CI2, KOAc, dioxane

[001694] Step 1 - Tert-butyl 4-((4-bromophenyl)sulfonyl)piperazine-l-carboxylate

[001695] To a solution of tert-butyl piperazine-l-carboxylate (20.1 g, 108 mmol) in THF (250 mL) was added TEA (19.8 g, 196 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 minutes, then 4-bromobenzene sulfonylchloride (25.0 g, 97.8 mmol) was added to the reaction mixture. The reaction mixture was then allowed to warm to rt and stirred for 50 minutes. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was washed with water (100 mL) and 10 % HCI (50 mL), and then extracted with DCM (2 X 50 mL). The organic layer was washed with NaHCO3 (50 mL) until the pH = 8. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 0:1) to give the title compound (33 g, 83% yield)) as a white solid. 1HNMR (400MHz, CDCh) δ 7.72 - 7.70 (m, 2H), 7.64 - 7.62 (m, 2H), 3.54 (t, J= 4.8 Hz, 4H), 3.00 (t, J= 4.8 Hz, 4H), 1.43 (s, 9H).

[001696] Step 2 - Tert-butyl 4-((4-(4.4.5.5-tetramethyl-L3.2-dioxaborolan-2yl)phenyl)sulfonyl) piperazine carboxylate

[001697] To a solution of tert-butyl 4-(4-bromophenyl)sulfonylpiperazine-l-carboxylate (10.0 g, 24.7 mmol) and 4,4,5,5-tetramethyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)1,3,2-dioxaborolane (18.8 g, 74.0 mmol) in dioxane (100 mL) was added Pd(dppf)C12 (1.81 g, 2.47 mmol) and KOAc (4.84 g, 49.4 mmol). The reaction mixture was stirred at 80 °C for 3 hours. On completion, the mixture was filtered, and the filter was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate: Petroleum ether = 1/1) to give the title compound (8.00 g, 63% yield) as a gray solid. 1HNMR (400MHz, CDCh) δ 7.98 (d, 7 = 8.0 Hz, 2H), 7.74 (d, 7= 8.0 Hz, 2H), 3.52 (t, 7= 4.8 Hz, 4H), 2.98 (t, 7= 4.8 Hz, 4H), 1.42 (s, 9H), 1.37 (s, 12H), LC-MS (ESI+) m/z 397.0 (M+H-56)+.

[001698] Ethyl 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetate (Intermediate DW)

O DCM O

DW

[001699] To a solution of ethyl 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate (0.80 g, 2.11 mmol, synthesized via Steps 1-4 of Intermediate CH) in DCM (10 mL) was added HCI in dioxane (4 M, 2.67 mL). The reaction mixture was stirred at rt for 15 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (0.55 g, 83% yield, HCI) as a yellow oil.

[001700] Tert-butyl 2-(8-aminooctoxy)acetate(Intermediate DX)

EtOH O

DX

[001701] Step 1 - 8-Hydroxyoctyl 4-methylbenzenesulfonate

[001702] To a mixture of octane-1,8-di01 (23.5 g, 160 mmol, CAS# 629 4) and pyridine (10.1 g, 128 mmol) in DCM (360 mL) was added a solution of TsCl (24.5 g, 128 mmol) in DCM (240 mL) dropwise. The mixture was then stirred at rt for 16 hours. On completion, the mixture was washed with IN HC1 (2 X 50 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 3 : 1) to give the title compound (10.0 g, 20% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.80 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.02 (t, J = 6.4 Hz, 2H), 3.63 (t, J= 6.4 Hz, 2H), 2.45 (s, 3H), 1.69 - 1.60 (m, 2H), 1.56 - 1.53 (m, 2H), 1.36 1.23 (m, 8H); LC-MS (ESI+) m/z 323.0 (M+Na)+.

[001703] Step 2 - 2-(8-Hvdroxyoctvl)isoindoline-L3-dione

[001704] To a solution of 8-hydroxyoctyl 4-methylbenzenesulfonate (5.00 g, 16.6 mmol) in DMF (80 mL) was added (l,3-dioxoisoindolin yl)potassium (4.01 g, 21.6 mmol). The mixture was stirred at 100 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with DCM (50 mL), filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE/EA=3/1) to give the title compound (4.50 g, 98% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 3.69 - 3.59 (m, 4H), 1.76 - 1.46 (m, 6H), 1.32 .29 (m, 6H).

[001705] Step 3 - Tert-butyl 2-[8-(L3-dioxoisoindolin yl)octoxy1acetate

[001706] To a solution of 2-(8-hydroxyoctyl)isoindoline-l,3-dione (3.00 g, 10.9 mmol) and Rh(OAc)2 (120 mg, 544 umol) in DCM (20 mL) was added a solution of tert-butyl 2-diazoacetate (2.32 g, 16.3 mmol) in DCM (80 mL) dropwise. The reaction mixture was stirred at rt for 48 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE/EA= 2/1) to give the title compound (1.40 g, 26% yield) as a light yellow oil. LC-MS (ESI+) m/z 412.2 (M+Na)+.

[001707] Step 4 - Tert-butyl 2-(8-aminooctoxy)acetate

[001708] To a solution of tert-butyl 2-(8-(1,3-dioxoisoindolin yl)octoxy]acetate (1.4 g, 2.91 mmol) in EtOH (25 mL) was added Ν2Η4.Η2Ο (1.49 g, 29.1 mmol). Then the reaction mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (750 mg, 99% yield) as a light yellow oil. LC-MS (ESI+) m/z 260.2 (M+H)+.

[001709] Methyl 5-(4-amino carbamovl-pvrazol-l-vl)pvridine carboxylate

Intermediate DY)

DY

[001710] Step 1 - Ethyl l-(6-bromo pyridyl) nitro-pyrazole carboxylate

[001711] To a solution of ethyl 4-nitro-lH-pyrazole carboxylate (5.8 g, 31.3 mmol, CAS# 55864 4), pyridine (9.91 g, 125 mmol) and Cu(OAc)2 (8.54 g, 46.9 mmol) in DCM (120 mL) was added (6-bromo pyridyl)boronic acid (7.59 g, 37.5 mmol, CAS# 223463 7). The mixture was stirred at rt for 16 hours under an oxygen atmosphere (15 psi pressure). On completion, the reaction mixture was quenched by adding saturated NH3*H2O solution (40 mL). The organic layer was separated and dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE/EA=3/1) to give the title compound (2.30 g, 21% yield) as a white solid. 1H NMR (400MHz, DMSO4) δ 9.83 (s, IH), 9.00 (d, J= 2.8 Hz, IH), 8.31 (dd, 7=3.2, 8.8 Hz, IH), 7.91 (d, 7= 8.8 Hz, IH), 4.42 (q,7=7.2 Hz, 2H), 1.33 (t,7= 7.2 Hz, 3H).

[001712] Step 2 - l-(6-Bromo pyridvl) nitro-pyrazole carboxamide

[001713] To a solution of ethyl l-(6-bromo pyridyl) nitro-pyrazole carboxylate (2.30 g, 6.74 mmol) in THF (15 mL) was added ΝΗ3&#905;2Ο (1.03 mmol, 25 mL, 30% solution) in a sealed tube, and the mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.80 g, 72% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 9.74 (s, IH), 9.03 (d, 7= 3.2 Hz, IH), 8.32 (dd, 7= 2.8, 8.8 Hz, IH), 8.23 (s, IH), 7.96 (s, IH), 7.91 (d, 7= 8.8 Hz, IH); LC-MS (ESI+) m/z 311.9 (M+H)+.

[001714] Step 3 - 4-Amino-l-(6-bromo pyridyl)pyrazole carboxamide

[001715] To a solution of l-(6-bromo pyridyl) nitro-pyrazole carboxamide (1.80 g, 4.90 mmol) in a mixed solvent of MeOH (45 mL) and H2O (10 mL) was added Fe (2.74 g, 49.0 mmol) and NH4C1 (2.62 g, 49.0 mmol). The mixture was stirred at 70 °C for 36 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was triturated with water (20 mL), filtered and the filter cake was dried in vacuo to give the title compound (0.90 g, 65% yield) as a brown solid. LC-MS (ESI+) m/z 282.0 (M+H)+.

[001716] Step 4 - Methyl 5-(4-amino carbamoyl-pyrazol-l-yl)pyridine carboxylate [001717] To a solution of 4-amino-l-(6-bromo pyridyl)pyrazole carboxamide (450 mg, 1.60 mmol) in a mixed solvent of DMF (15 mL) and MeOH (15 mL) was added Pd(dppf)C12 (46.6 mg, 63.8 umol) and TEA (161 mg, 1.60 mmol). The suspension was degassed under vacuum and purged with CO three times. The mixture was stirred at 80 °C for 16 hours under CO (50 psi pressure). On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=l/l) to give the title compound (400 mg, 94% yield) as a brown solid. LC-MS (ESI+) m/z 262.0 (M+H)+.

[001718] 5-[4-[[2-[2-[Tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino]-4pyridyl] oxazole carbonyl] amino] carbamovlDvrazol-l-vl]Dvridine carboxylic acid (Intermediate DZ)

DY

DZ

[001719] Step 1 - Methyl 5-r4-rr2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1amino1 carbamoyl-pyrazol-l-yl1pyridine carboxylate

[001720] To a solution of 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (494 mg, 1.28 mmol, Intermediate CM) in DMF (6 mL) was added HATU (630 mg, 1.66 mmol) and DIPEA (494.54 mg, 3.83 mmol). The mixture was stirred at rt for 12 minutes, then methyl 5-(4-amino carbamoyl-pyrazol-l-yl)pyridine carboxylate (340 mg, 1.28 mmol, Intermediate DY) was added, and the mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give the title compound (500 mg, 49% yield) as a yellow solid. LC-MS (ESI+) m/z 631.2 (M+H)+.

[001721] Step 2 - 5-r4-rr2-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1 amino1 carbamoylpyrazol-l-yl1pyridine carboxylic acid

[001722] To a mixture of methyl 5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]pyridine2-carboxylate (500 mg, 792 umol) in a mixed solvent of THF (5 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH (94.9 mg, 3.96 mmol). The reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (500 mg, 90% yield) as a brown solid. LC-MS (ESI+) m/z 617.2 (M+H)+.

[001723] Tert-butyl N-[(lS,2R) [(2-br0m0Dvraz010[l,5-a]pyrimidin-5vDamino] carbamate(Intermediate EA)

[001724] Step 1 - (2-Bromopyrazolo[L5-a1pyrimidin yl)oxysodium

[001725] To a solution of Na (7.10 g, 309 mmol) in EtOH (125 mL) was added 3-bromo-lHpyrazol amine (5.00 g, 30.9 mmol, CAS# 1203705 8) and l,3-dimethylpyrimidine-2,4-dione (4.33 g, 30.9 mmol, CAS# 874 6). The reaction mixture was stirred at 80 °C for 3 hours. On completion, the mixture was cooled to 0-5°C, then fdtered. The fdter cake was washed with cold EtOH, and dried in vacuo to give the title compound (2.80 g, 38% yield) as a yellow solid. 1H NMR (400MHz, D2O) δ 8.02 (d, J= 7.6 Hz, IH), 5.98 (d, J= 7.6 Hz, IH), 5.85 (s, IH).

[001726] Step 2 - 2-Bromo chloro-pyrazolo[L5-a1pyrimidine

[001727] A mixture of (2-bromopyrazolo[l,5-a]pyrimidin yl)oxysodium (1.00 g, 4.24 mmol) in POC13 (10 mL) was stirred at 110 °C for 3 hours. On completion, the mixture was concentrated in vacuo. The residue was diluted with EA (20 mL), washed with NaHCO3 (10 ml), and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (0.67 g, 68% yield) as a white solid. 1H NMR (400MHz, CDC13) δ 8.51 (d, J= 7.2 Hz, IH), 6.84 (d, J= 7.2 Hz, IH), 6.69 (s, IH).

[001728] Step 3 - Tert-butyl N-r(lS,2R) r(2-bromopyrazolorL5-a1pyrimidin-5yl)amino1cyclohexyl1 carbamate

[001729] 2-bromo chloro-pyrazolo[l,5-a]pyrimidine (620 mg, 2.67 mmol), tert-butyl N[(lS,2R) amino cyclohexyl]carbamate (686 mg, 3.20 mmol, CAS#184954 4) and DIPEA (379 mg, 2.93 mmol) were taken up into a microwave tube in NMP (6 mL). The sealed tube was heated at 130 °C for 3 hours under microwave. On completion, the mixture was concentrated in vacuo to remove the solvent. Then the residue was purified by silica gel chromatography to give the title compound (1.00 g, 91% yield) as a white solid. 1H NMR. (400MHz, CDCh) δ 8.08 (d, J= 7.6 Hz, IH), 6.10 (s, IH), 5.98 (d, J = 7.6 Hz, IH), 5.76 (s, IH), 4.94 (br s, IH), 4.20 - 4.11 (m, IH), 4.01 - 3.92 (m, IH), 2.00 - 1.83 (m, IH), 1.75 - 1.49 (m, 6H), 1.45 (s, 9H), 1.39 - 1.22 (m, IH).

[001730] Methyl 4-[3-(difluoromethvl) (4,4,5,5-tetramethyl-l,3.,2-dioxaborolan-2yllpyrazol-l- yllbenzoate (Intermediate EB)

OH I

EB

[001731] Step 1 - Methyl 4-(3-formyl-lH-pyrazol-l-yl)benzoate

[001732] To a solution of lH-pyrazole carbaldehyde (10.0 g, 104 mmol, CAS# 3920-201) and (4-methoxy carbonyl-phenyl) boronic acid (22.5 g, 125 mmol, CAS# 99768 4) in DCM (50 mL) was added Cu(OAc)2 (22.7 g, 125 mmol) and pyridine (32.9 g, 416 mmol). The reaction mixture was stirred at rt for 18 hours under oxygen gas (balloon). On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (12.0 g, 50% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 10.10 (s, IH), 8.24 - 8.14 (m, 2H), 8.06 (d, J= 2.4 Hz, IH), 7.90 - 7.82 (m, 2H), 7.02 (d, J= 2.4 Hz, IH), 3.95 (s, 3H).

[001733] Step 2 - Methyl 4-(4-bromo formyl-lH-pyrazol-l-yl)benzoate

[001734] To a solution of methyl 4-(3-formylpyrazol-l-yl)benzoate (4.00 g, 17.4 mmol) in

DMF (40 mL) was added NBS (6.18 g, 34.8 mmol). The reaction mixture was stirred at rt for 1 hour. Then, the reaction mixture was heated to 50°C and stirred for 12 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA) to give the title compound (4.50 g, 82% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 10.02 (s, IH), 8.12 (d, J = 8.4 Hz, 2H) 8.04 (s, IH), 7.75 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H); LC-MS (ESI+) m/z 308.9, 310.9 (M+l)+.

[001735] Step 3 - Methyl 4-(4-bromo (difluoromethyl)-IH-pyrazol-l-yl )benzoate

[001736] To a solution of methyl 4-(4-bromo formyl-pyrazol-l-yl)benzoate (1.70 g, 5.50 mmol) in DCM (100 mL) was added DAST (7.98 g, 49.5 mmol) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 5 hours. On completion, the mixture was quenched with methanol (30 mL) at 0 °C then mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% HC1) to give the title compound (1.44 g, 78% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 8.17 (d, J = 8.8 Hz, 2H), 8.07 (s, IH), 7.76 (d, J = 8.8 Hz, 2H), 6.80 (t, J = 53.2 Hz, IH), 3.96 (s, 3H); LC-MS (ESI+) m/z 330.9 (M+H)+.

[001737] Step 4 - Methyl 4-r3-(difluoromethyl) (4A5,5-tetramethyl-L3,2-dioxaborolan2-yl)pyrazol-l- yllbenzoate

[001738] Methyl 4-[4-bromo (difluoromethyl)pyrazol-l-yl]benzoate (500 mg, 1.51 mmol), TEA (382 mg, 3.78 mmol), acetonitrile-dichloropalladium (58.8 mg, 227 umol), dicyclohexyl-[2-(2,6-dimethoxy phenyl)phenyl]phosphane (93.0 mg, 227 umol) and HBPin (1.93 g, 15.1 mmol) were taken up into a microwave tube in toluene (10 mL). The sealed tube was heated at 90°C for 60 minutes under microwave. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (440 mg, 54% yield) as a yellow solid. LC-MS (ESI+) m/z 379.2 (M+H)+.

[001739] 4-[4-[5-[[(lR,2S) (tertbutoxycarbonylamino)cyclohexyl]amino]Dyrazolo[l,5-a]Dyrimidin yl]-3(difluoromethyl)Dyrazol-l-yl]benzoic acid (Intermediate EC)

EB

F

EC

[001740] Step 1:Methyl 4-Γ4-[5-ΓΓ(1Κ25) (&#912;61&#912;butoxycarbonylamino)cyclohexyl1amino1pyrazolo[L5-a1pyrimidin yl1-3(difluoromethyl)pyrazol-1 -yllbenzoate

[001741] To a solution of methyl 4-[3-(difluoromethyl) (4,4,5,5-tetramethyl-l,3,2dioxaborolan yl)pyrazol -l-yl]benzoate (379 mg, 702 umol, Intermediate EB) and tert-butyl N[(lS,2R) [(2-bromopyrazolo[l,5-a]pyrimidin-5 -yl)amino]cyclohexyl]carbamate (160 mg, 390 umol, Intermediate EA) in a mixed solvent of H2O (0.6 mL) and dioxane (3 mL) was added K2CO3 (162 mg, 1.17 mmol) and XPHOS-PD-G2 (30.7 mg, 39.0 umol). The reaction mixture was stirred at 90 °C for 17 hours. On completion, the mixture was concentrated in vacuo to remove the solvent dioxane. The residue was purified by reverse phase chromatography (0.1% HCI) to give the title compound (80.0 mg, 35% yield) as a yellow solid. LC-MS (ESI+) m/z 582.1 (M+H)+.

[001742] Step 2:4-Γ4-[5-ΓΓ(1Κ25) (&#912;61&#912;butoxycarbonylamino)cyclohexyl1amino1pyrazolo[L5-a1pyrimidin yl1-3(difluoromethyl)pyrazol-1 -yllbenzoic acid

[001743] To a solution of methyl 4-[4-[5-[[(lR,2S) (tertbutoxycarbonylamino)cyclohexyl]amino]pyrazolo [l,5-a]pyrimidin yl]-3(difluoromethyl)pyrazol-l-yl]benzoate (80.0 mg, 138 umol) in a mixed solvent of THF (2 mL) and H2O (0.4 mL) was added Li OH (16.5 mg, 688 umol). The reaction mixture was stirred at rt for 17 hours. On completion, the mixture was acidified with IN HCI solution until the pH = 6-7, then concentrated in vacuo to give the title compound (75.0 mg, 96% yield) as a yellow solid. LC-MS (ESI+) m/z 568.3 (M+H)+.

[001744] 2-(4-Pvridvl)oxazole carboxylic acid (Intermediate ED)

[001745] Step 1 - Ethyl 2-(4-pyridyl)oxazole carboxylate

[001746] To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)pyridine (1.50 g, 7.31 mmol) and ethyl 2-bromooxazole carboxylate (1.61 g, 7.31 mmol, CAS# 460081 3) in a mixed solvent of dioxane (20 mL) and H2O (4 mL) was added Cs2CO3 (7.15 g, 21.9 mmol) and Pd(dppf)C12 (267 mg, 365 umol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate = 1/1, PE/EA=1/1) to give the title compound (200 mg, 12% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 8.82 - 8.77 (m, 2H), 8.37 (s, IH), 8.01 - 7.97 (m, 2H), 4.47 (q, J= 7.2 Hz, 2H), 1.44 (t, J= 7.2 Hz, 3H).

[001747] Step 2 - 2-(4-Pyridyl)oxazole carboxylic acid

[001748] To a solution of ethyl 2-(4-pyridyl)oxazole carboxylate (0.2 g, 916 umol) in THF (5 mL), MeOH (1 mL) and H2O (1 mL) was added LiOH (26.34 mg, 1.10 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was concentrated in vacuo to give a residue. The residue was then diluted with H2O and the aqueous phase was acidified with cone. HCI until the pH = 6. The mixture was concentrated in vacuo to give the title compound (220 mg) as a yellow solid.

[001749] 4-[3-Carbamovl [[2-(4-Dvridvl)oxazole carbonyl]amino]Dvrazol-lyl] benzoic acid(Intermediate EE)

EE

[001750] Step 1:Methyl 4-r3-carbamoyl rr2-(4-pyridyl)oxazole-4carbonyl1amino1pyrazol-1 -yllbenzoate

[001751] To a solution of 2-(4-pyridyl)oxazole carboxylic acid (200 mg, 1.05 mmol, Intermediate ED) and methyl 4-(4-amino carbamoyl-pyrazol-l-yl)benzoate (328 mg, 1.26 mmol, Intermediate CL) in DMF (5 mL) was added DIPEA (679 mg, 5.26 mmol, 915 uL). The mixture was stirred at rt for 12 minutes, and then HATU (479 mg, 1.26 mmol) was added. The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was diluted with H2O (10 mL) and extracted with EA (2 X 20 mL). The combined organic layers were concentrated in vacuo to give the title compound (60.0 mg, 13% yield) as a brown solid. LC-MS (ESI+) m/z 433.2 (M+H)+.

[001752] Step 2 - 4-r3-Carbamoyl IT2-(4-pyridyl)oxazole carbonyl1amino1pyrazol-lyUbenzoic acid

[001753] To a solution of methyl 4-[3-carbamoyl [[2-(4-pyridyl)oxazole-4carbonyl]amino]pyrazol-l-yl]benzoate (60.0 mg, 138 umol) in THF (8 mL) and H2O (2 mL) was added LiOH (4.99 mg, 208 umol). The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was concentrated in vacuo to give a residue. The residue was then diluted with H2O and the aqueous phase was acidified with cone. HCI until the pH = 6. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% HCI) to give the title compound (25.0 mg, 43% yield) as a white solid. LC

MS (ESI+) m/z 419.1(M+H)+.

[001754] Tert-butyl N-[3-(3-aminopropoxv)propyl]carbamate (Intermediate EF) (Boc)2O BocHN NH2

CHCI3

EF

[001755] To a mixture of 3-(3-aminopropoxy)propan amine (499 mg, 3.78 mmol, CAS#

2157 6) in CHCh (25 mL) was added a solution of tert-butoxycarbonyl tert-butyl carbonate (165 mg, 756 umol) in CHC13 (5 mL) dropwise. Then the reaction mixture was stirred at rt for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give the title compound (140 mg, 79% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 4.87 (s, IH), 3.42 (q, J= 6.4 Hz, 4H), 3.15 (q, J= 5.6 Hz, 2H), 2.76 (t, J= 6.4 Hz, 2H), 1.70 - 1.63 (m, 4H), 1.37 (s, 9H).

[001756] 4-(4-(2-(2-((Tert-butoxvcarbonvl)(cvclopropvlmethvl)amino)pyridin-4 yl)oxazole carboxamido) (trifluoromethvl)-lH-pyrazol-l-vl)benzoic acid (Intermediate

EG)

HATU, DIPEA, DMF

4-(4-(2-(2-((tertbutoxycarbonyl)(cyclopropylmethyl)amino)pyridin yl)oxazole carboxamido)-3(trifluoromethyl)- IH-pyrazol-1 -yDbenzoate

[001758] To a solution of methyl 4-[4-amino (trifluoromethyl)pyrazol-l-yl]benzoate (300 mg, 1.05 mmol, synthesized via Steps 1-3 of Intermediate DE) and 2-[2-[tert butoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carboxylic acid (378 mg, 1.05 mmol, synthesized via Steps 1-4 of Intermediate DF) in DMF (5 mL) was added DIPEA (408 mg, 3.16 mmol). Then, HATU (478 mg, 1.26 mmol) was added and the reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was quenched with water (20 mL) and filtered. The filtered cake was collected and dried in vacuo to give the title compound (659 mg, 100% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 9.09 (s, IH), 8.99 (s, IH), 8.55 (d, 5.2 Hz, IH),

8.44 (s, IH), 8.38 (s, IH), 8.21 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 8.8 Hz, 2H), 7.65 (dd, J= 1.2, 5.2 Hz, IH), 4.01 - 3.95 (m, 5H), 1.60 (s, 9H), 1.30 - 1.20 (m, IH), 0.50 - 0.43 (m, 2H), 0.30 (m, 2H); LC-MS (ESL)&#1524;/ z 627.1 (M+H)+.

[001759] Step 2 - 4-(4-(2-(2-((Tert-butoxvcarbonvl)(cvclopropvlmethvl)amino)pyridin-4yl)oxazole carboxamido) (trifluoromethyl)-IH-pyrazol-l-yl)benzoic acid

[001760] To a solution of methyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]- oxazole carbonyl]amino]-3(trifluoromethyl)pyrazol-l-yl]benzoate (659 mg, 1.05 mmol) in a mixed of solvent THF (30 mL), H2O (10 mL) and methanol (10 mL) was added LiOH (126 mg, 5.26 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (20 mL) and acidified with IN HCI until the pH = 4, then the mixture was filtered. The filtered cake was collected and dried in vacuo to give the title compound (700 mg, 91% yield) as a white solid. LC-MS (ESI+) m/z 613.0 (M+H)+.

[001761] [3-[4-Amino (trifluoromethvl)Dvrazol-l-vl]Dhenyl]methanol (Intermediate EH)

EH

[001762] Step 1 - r3-r4-Nitro (trifluoromethyl)pyrazol-l-yl1phenyl1methanol

[001763] To a solution of 4-nitro (trifluoromethyl)-lH-pyrazole (10.0 g, 55.2 mmol, synthesized via Step 1 of Intermediate DE) and [3-(hydroxymethyl) phenyl]boronic acid (12.9 g, 85.3 mmol) in DCM (200 mL) was added Cu(OAc)2 (15.0 g, 82.8 mmol) and pyridine (17.4 g,

220 mmol). The mixture was stirred at rt for 16 hours under oxygen (15 psi pressure). On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE: EA=1: 1) to give the title compound (8.00 g, 50% yield) as a white solid. 1HNMR (400MHz, DMSO-d6) δ 9.90 (s, IH), 7.93 (s, IH), 7.85 (d, J = 8.0 Hz, IH), 7.58 (t, J = 7.6 Hz, IH), 7.48 (d, J = 7.6 Hz, IH), 5.45 (t, J = 6.0 Hz, IH), 4.62 (d, J = 6.0 Hz, 2H).

[001764] Step 2 - r3-r4-Amino (trifluoromethyl)pyrazol-l-yl1phenyl1methanol

[001765] To a solution of [3-[4-nitro (trifluoromethyl)pyrazol-l-yl]phenyl]methanol (1.00 g, 3.48 mmol) in MeOH (20.0 mL) was added Pd/C (200 mg, 10 wt %) under hydrogen (15 psi pressure). The mixture was stirred at rt for 3 hours. On completion, the mixture was filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE: EA = 1: 1) to give the title compound (700 mg, 78% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 7.60 (s, IH), 7.47 (s, IH), 7.45 (s, IH), 7.36 (t, J = 8.0 Hz, IH), 7.24 (d, J = 7.2 Hz, IH), 4.70 (d, J = 3.2 Hz, 2H), 3.28 (s, 2H), 1.76 (s, IH).

[001766] Tert-butyl N-(cvclopropvlmethvl)-N-[4-[4-[[l-[3-(hvdroxvmethvl)phenvI|-3(trifluoromethyl) pyrazol vl]carbamoyl]oxazol yl] pvridvl]carbamate (Intermediate EI)

EH El

[001767] To a solution of [3-[4-amino (trifluoromethyl)pyrazol-l-yl]phenyl]methanol (400 mg, 1.56 mmol, Intermediate EH) and 2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino]4-pyridyl]oxazole carboxylic acid (558 mg, 1.56 mmol, Intermediate OM) in DMF (5.00 mL) was added HATU (709 mg, 1.87 mmol) and DIPEA (602 mg, 4.67 mmol). The mixture was stirred at rt for 30 minutes. On completion, the mixture was quenched with H2O (1 mL) and concentrated in vacuo. The mixture was purified by reverse phase prep-HPLC (0.1% FA) to give the title compound (320 mg, 34% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 9.08 (s, IH), 8.92 (s, IH), 8.55 (d, J = 5.2 Hz, IH), 8.44 (s, IH), 8.38 (s, IH), 7.83 (s, IH), 7.70 (d, J = 8.0 Hz, IH), 7.66 (dd, J = 1.2, 5.2 Hz, IH), 7.52 (t, J = 7.6 Hz, IH), 7.41 (d, J = 7.6 Hz, IH), 4.83 (d, J = 5.2 Hz, 2H), 3.97 (d, J = 7.2 Hz, 2H), 1.90 - 1.82 (m, IH), 1.59 (s, 9H), 1.28 - 1.25 (m, IH), 0.49

0.43 (m, 2H), 0.33 - 0.29 (m, 2H).

[001768] 4-[2-[2-[2-(Aminomethvl)morpholin vl]ethoxy]ethvlamino] (2.,6-dioxo-3piperidyl) isoindoline-l.,3-dione (Intermediate EJ)

nh2

EJ

[001769] Step 1 - Tert-butyl Ν-ΓΓ4-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-1,3-&#940;&#912;οχο-&#912;5ο&#912;η&#940;ο1&#912;η-4 yl1amino1ethoxy1 ethyl1morpholin yl1methyl1carbamate

[001770] To a solution of 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethyl methanesulfonate (195 mg, 443 umol, synthesized via Steps 1-2 of Example 184) and tert-butyl N-(morpholin ylmethyl)carbamate (287.92 mg, 1.33 mmol, CAS# 173341 1) in CH3CN (30 mL) was addedNaHCO3 (111 mg, 1.33 mmol, 51.7 uL). The mixture was stirred at 80 °C for 6 hours. On completion the mixture was concentrated and extracted with EA (3 X 30 mL). The combined organic layers were washed with brine (50 mL, dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The mixture was purified by column chromatography (TLC; PE: EA 1:1) to give the title compound (100 mg, 35% yield) as a yellow oil. LC-MS (ESI+) m/z 560.2 (M+H)+.

[001771] Step 2 - 4-r2-r2-r2-(Aminomethyl)morpholin yl1ethoxy1ethylamino1 (2,6dioxo piperidyl) isoindoline-L3-dione

[001772] To a solution of tert-butyl N-[[4-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethyl]morpholin yl]methyl]carbamate (50.0 mg, 89.3 umol) in DCM (2 mL) was added HCI in dioxane (4 M, 1 mL). The mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (44.3 mg, HCI salt, 90% yield) as a yellow oil. LC-MS (ESI+) m/z 460.2 (M+H)+.

[001773] Tert-butyl N-(5-oxopentyl)carbamate(Intermediate EK) oxalyl dichloride, DMSO .

NHB0C -------------------O' NHB0C

TEA, DCM EK

[001774] To a solution of oxalyl dichloride (312 mg, 2.46 mmol, 215 uL) in dichloromethane (5 mL) at -78°C was added dimethyl sulfoxide (384 mg, 4.92 mmol, 384 uL) dissolved in dichloromethane (0.5 mL) dropwise, while keeping the temperature below -65°C. Five minutes later, tert-butyl N-(5-hydroxypentyl)carbamate (500 mg, 2.46 mmol, 500 uL, CAS#: 75178 4) dissolved in dichloromethane (0.5 mL) was added slowly to the solution and the mixture was stirred at -78°C for 15 min. Finally, triethylamine (1.24 g, 12.3 mmol, 1.71 mL) was added dropwise and stirred the reaction was stirred for 15 min. The mixture was allowed to warm to rt and stirred for 1 hour. The reaction mixture was quenched with water (10 mL), and extracted with di chloromethane (3X5 mL). The combined organic layers were washed with brine (2X10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give title compound (450 mg, crude) as a brown oil. 1H NMR (400MHz, DMSO-d6) δ 6.76 - 6.60 (m, IH), 4.96 - 4.74 (m, IH), 3.13-3.02 (m, IH), 2.00 - 1.93 (m, 2H), 1.76- 1.68 (m, 2H), 1.43 (s, 9H), 1.20 (t, J= 7.2 Hz, IH).

[001775] 4-[2-(5-AminoDentvlamino)ethylamino] (2,6-dioxo DiDeridyl)isoindoline1.,3-dione (Intermediate EL)

[001776] Step 1 - Tert-butyl N-r5-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1amin01ethylamin01 pentvUcarbamate

[001777] To a solution of 4-(2-aminoethylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (100 mg, 283 umol, HCI, Intermediate DJ) and /c77-butyl N-(5-oxopentyl)carbamate (68.5 mg, 340 umol, Intermediate EK) in THF (20 mL) was added KOAc (55.6 mg, 567 umol). The mixture was stirred at rt for 30 minutes, then NaBH(OAc)3 (150 mg, 709 umol) was added in portions. The mixture was stirred at rt for 11.5 hours. The reaction mixture was quenched with water (1 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate = 5/1 to dichloromethane: methanol = 10/1) to give title compound (60.0 mg, 39% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ 11.11 (s, IH), 9.07 (s, 2H), 7.65 - 7.60 (m, IH), 7.31 (d, J= 8.8 Hz, IH), 7.10 (d, J = 6.8 Hz, IH), 6.87 (t, J= 6.8 Hz, IH), 5.08 (dd, J= 5.2, 12.8 Hz, IH), 3.77 - 3.67 (m, 2H), 3.14 - 3.04 (m, 2H), 2.97 - 2.85 (m, 3H), 2.81 - 2.72 (m, 2H), 2.64 - 2.56 (m, 2H), 2.10 - 1.98 (m, IH), 1.68 - 1.61 (m, 2H), 1.59 - 1.53 (m, 2H), 1.45 - 1.34 (m, 2H).

[001778] Step 2:4-r2-(5-Aminopentylamino)ethylamino1 (2,6-di oxo-3piperidyl)isoindoline-L3-dione

[001779] Tc77-butyl N-[5-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethyl amino]pentyl]carbamate (60.0 mg, 119 umol, HCI) was dissolved in 4 M HCI in dioxane (5 mL). The mixture was stirred at rt for 1 hour. The reaction mixture was then concentrated in vacuo to give title compound (60.0 mg, 95% yield) as a brown oil. 1H NMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 9.10 (s, 2H), 7.62 (t, J = 7.6 Hz, IH), 7.31 (d, J = 8.4 Hz, IH), 7.10 (d, J = 7.2 Hz, IH), 6.86 (s, IH), 5.07 (dd, J = 5.2, 12.4 Hz, IH), 3.98 - 3.86 (m, IH), 3.51 - 3.41 (m, 4H), 3.36 - 3.29 (m, IH), 3.11 - 3.03 (m, 2H), 2.96 - 2.86 (m, 3H), 2.76 - 2.73 (m, 2H), 2.69 - 2.59 (m, 2H), 2.07 - 1.99 (m, IH), 1.70 - 1.53 (m, 4H), 1.43 - 1.33 (m, 2H).

[001780] (2R) hvdroxv [(8R)-l-(4-DiDerazin-l-vlcvclohexoxy)-7.,8-dihvdro-6Hcyclopenta[4.,5] thieno[l.,2-c|pvrimidin vI|propanamide (Intermediate EM)

HCI in dioxane

DCM

[001781] To a mixture of tert-butyl 4-[4-[[(8R) [(2R) amino hydroxy oxo-propyl]7,8-dihydro-6H- cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazine-lcarboxylate (0.09 g, 164 umol, synthesized via Steps 1-14 of Intermediate DR) in DCM (2 mL) was added HCI in dioxane (4.0 M, 6.43 mL). Then the reaction mixture was stirred at rt for 20 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (79.5 mg, 100% yield) as white solid. LC-MS (ESI+) m/z 446.1 (M+H)+.

[001782] 22&#1524;-dimethyl oxo-3.,8,ll,14,17-pentaoxa azanonadecan oic acid (Intermediate EN) (Boc)2O, KOH

H0^ ^O^°^NH2 dioxane1 &#1524;,ο

&#1495;

HO

NaOH, Toluene, THF

O

EN

NHBoc

[001783] Step 1 - tert-butyl (2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate

[001784] To a stirred solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-l-ol (1.0 g, 5.2 mmol, CAS# 86770 3) and KOH (0.32 g, 5.6 mmol) in 1,4 dioxane (4 mL) and water ( 8 mL) was added Boc-anhydride (1.24 g, 5.6 mmol) dropwise at 10 °C. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (8% MeOH-DCM) to give tert-butyl (2-(2-(2-(2hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate as a colorless oil (1.2 g, 79%). LC-MS (ESI+) m/z 293.13 (M+H)+.

[001785] Step 2 - 2,2-dimethyl oxo-3,8,lL14,17-pentaoxa azanonadecan oic acid

[001786] To a stirred solution of tert-butyl (2-(2-(2-(2hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (0.38 g, 1.29 mmol) and 2-bromoacetic acid (0.54 g, 3.8 mmol) in toluene : THF (1:1, 4 mL) was added NaOH (0.31 g, 7.7 mmol) at 45 °C. The resulting reaction mixture stirred at 45 °C for 16 h. The reaction mixture was then evaporated, water (10 mL) was added and aqueous layer was acidified with 1 N HC1 solution. The resulting mixture was extracted using DCM (3 x 50 mL) and the combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2,2-dimethyl oxo-3,8,ll,14,17-pentaoxa azanonadecan oic acid as a colorless oil (0.24 g, 53%). LC-MS (ESI+) m/z 351.4 (M+H)+.

[001787] 6-((l,6-naDhthvridin vl)amin0) (cvcl0Dr0Dvlamin0)-N-(DiDeridin-4vDnicotinamide hydrochloride (Intermediate EO)

EO

[001788] Step 1:tert-butyl 4-(6-((L6-naphthyri din yl)amino)-4(cyclopropylamino)nicotinamido)piperidine-l-carboxylate

[001789] A solution of 6-((1,6-naphthyri din yl)amino) (cyclopropylamino)nicotinic acid (0.5 g, 1.56 mmol, Intermediate N), tert-butyl 4-aminopiperidine-l-carboxylate (0.32 g, 1.56 mmol, CAS# 87120 7), PyBOP (1.22 g, 2.34 mmol) and DIPEA (0.4 mL, 2.34 mmol) in DMF (3 mL) was stirred at rt for 2 h. On completion, the reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 30 mL). The combined organic layers were dried over anhydrous sodium sulfate and fdtered. The fdtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (5% MeOH-DCM) to give tert-butyl 4-(6-((1,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)piperidine-l-carboxylate as a yellow solid (0.6 g, 76%). LC-MS (ESI+) m/z 504.50 (M+H)+.

[001790] Step 2 - 6-((L6-naphthyridin yl)amino) (cyclopropylamino)-N-(piperidin-4yDnicotinamide hydrochloride

[001791] To the solution tert-butyl 4-(6-((1,6-naphthyri din yl)amino)-4(cyclopropylamino)nicotin amido)piperidine-l-carboxylate (0.6 g, 1.19 mmol) in DCM (10 mL) was added 4N HC1 in dioxane (3 mL) at 0 °C. Then the reaction mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was evaporated under reduced pressure to afford the crude product. The crude product was triturated using MTBE to give 6-((1,6-naphthyridin-2yl)amino) (cyclopropylamino)-N-(piperidin yl)nicotinamide hydrochloride as a white solid (0.45 g, 85%). LC-MS (ESI+) m/z 404.40 (M+H)+.

[001792] tert-butyl(2-(2-(2-aminoethoxv)ethoxv)ethvl)(methyl)carbamate (Intermediate EP) HO^O^o^OTs

TEA, (Boc)2O

DCM

Ag2O, Nai, TsCI

DCM

MeNH2

THF

NaN3

DMF

Pd/C, H2 (gas)

EtOH

MsCI, TEA

DCM

Boc

EP

[001793] Step 1 - 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

[001794] To a stirred solution of 2,2'-(ethane-l,2-diylbis(oxy))bis(ethan-l-ol) (15.0 g, 0.10 mmol, CAS# 112 6), silver oxide (34.65 g, 34.65 mmol), and sodium iodide (16.5 g, 1.1 mmol) in DCM (200 mL) was added tosyl chloride (19.06 g, 0.10 mmol) portion-wise at 0 °C, and the reaction mixture was stirred for 3 h. On completion, the reaction mixture was filtered through a pad of celite and the filtrate was extracted using DCM (3 x 20 mL). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to get the crude product. The crude product was purified using silica gel column chromatography (3 % MeOH: DCM) to give 2-(2-(2hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate as a yellow liquid (18 g, 59%). LC-MS (ESI+) m/z 305.34 (M+H)+.

[001795] Step 2 - 2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-l-ol

[001796] To a stirred solution of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4methylbenzenesulfonate (5.0 g, 16.4 mmol) in THF (15 mL) was added 2M Methylamine in THF (34 mL, 66 mmol) at rt, then the reaction mixture was heated to 90 °C and stirred for 8 h. The reaction mixture was then filtered and filtrate was evaporated under reduce pressure to give 2-(2(2-(methylamino)ethoxy)ethoxy)ethan-l-ol as a yellow oil (2.5 g, 93% yield). LC-MS (ESI+) m/z 164.21 (M+H)+.

[001797] Step 3 - ter/-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamate

[001798] To a stirred solution of 2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-l-ol (2.5 g, 15.3 mmol) in DCM (40 mL) was added boc anhydride (20 g, 92 mmol) and TEA (4.0 mL, 30.6 mmol) at 0 °C and the reaction mixture was stirred for 2h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (40 % EtOAc-Hexane) to give tert-butyl (2-(2-(2hydroxyethoxy)ethoxy)ethyl)(methyl)carbamate as a yellow semisolid (2.2 g, 54%). LC-MS (ESI+) m/z 264.32 (M+H)+.

[001799] Step 4 - 2,2,5-trimethyl oxo-3,8,ll-trioxa azatridecan yl methanesulfonate

[001800] To a stirred solution of ter/-butyl(2-(2-(2hydroxyethoxy)ethoxy)ethyl)(methyl)carbamate (2.2 g, 8.4 mmol) and triethylamine (3.5 g, 25.08 mmol) in DCM (15 mL) was added mesyl chloride (1.2 mL, 12.54 mmol) at 0 °C, then the reaction mixture was stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted with DCM (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2,2,5-trimethyl oxo-3,8,ll-trioxa azatridecan yl methanesulfonate as a yellow semisolid (2.8 g, 78%).

[001801] Step 5 - tert-butyl (2-(2-(2-azidoethoxy)ethoxy)ethyl)(methyl)carbamate

[001802] To a stirred solution of 2,2,5-trimethyl oxo-3,8,ll-trioxa azatridecan yl methanesulfonate (2.8 g, 8.2 mmol) in DMF (10 mL) was added sodium azide (0.8 g, 12.3 mmol) at rt. Then the reaction mixture was heated to 60 °C and stirred for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (30 % EtOAc-Hexane) to give tert-butyl (2-(2(2-azidoethoxy)ethoxy)ethyl)(methyl)carbamate as a yellow semisolid (1.6 g, 98%). LC-MS (ESI+) m/z 355.33 (M+FA adduct)+.

[001803] Step 6 - tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamate

[001804] To a stirred solution of tert-butyl(2-(2-(2-azidoethoxy) ethoxy)ethyl)(methyl)carbamate (1.6 g, 5.6 mmol) in EtOH (15 mL) in an autoclave was added % Pd/C (50% wet) (1.6 g) under hydrogen gas (5 kg/cm2 pressure) at rt for 3 h. The reaction mixture was filtered through celite and concentrated under reduced pressure to give tert-butyl (2(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamate a as colorless oil (1 g, 68 % yield). LC-MS (ESI+) m/z 263.32 (M+H)+

[001805] 2-(2-(benzvloxv)ethoxv)ethyl methanesulfonate (Intermediate EQ)

HO

OBn

TEA, MsCI

DCM

MsO'

OBn

EQ

[001806] To a stirred solution of 2-(2-(benzyloxy)ethoxy)ethan-l-ol (0.5 g, 2.5 mmol, CAS# 2050 1) and TEA(1.1 mL, 7.6 mmol) in DCM (10 mL) was added mesyl chloride (0.3 mL, 3.8 mmol) dropwise at 0 °C. The resulting reaction mixture stirred at 0 °C for 2 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate as a colorless oil (0.45 g, 64%).

[001807] tert-butyl (2-(2-aminoethoxv)ethyl)(2.,2-dimethvl oxo-3.,8,ll-trioxa-5azatridecan yl)carbamate (Intermediate ER)

EQ (Boc)2O, TEA

THF

Pd/C, H2 (gas)

AcOH, EtOH

Boc

Boc

MsCI, TEA

DCM

Sodium azide

DMF

Boc

OMs

Boc

Pd/C, H2 (gas)

EtOH

Boc

ER

[001808] Step 1 - tert-butyl (l-phenyl-2,5riL14-tetraoxa azahexadecan yl)carbamate

[001809] To a stirred solution of tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (3.0 g, 12.1 mmol. CAS # 153086 3, Supplier: Chem-Impex) and 2-(2(benzyloxy)ethoxy)ethyl methanesulfonate (5.0 g, 18.2 mmol, Intermediate EQ) in DMF (45 mL) was added K2CO3 (5 g, 36.2 mmol) at rt. The resulting reaction mixture heated to 80 °C and stirred for 5 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (5% MeOH-DCM) to give ter/-butyl (l-phenyl-2,5,ll,14-tetraoxa azahexadecan yl)carbamate as a yellow oil (2.4 g, 47%). LCMS (ESI+) m/z 426.55 (M+H)+.

[001810] Step 2 - tert-butyl (2-(2-(benzyloxy)ethoxy)ethyl)(2,2-dimethyl oxo-3,8,lltrioxa azatridecan-13 -yDcarbamate

[001811] To a stirred solution of tert-butyl (l-phenyl-2,5,ll,14-tetraoxa azahexadecan-16yl)carbamate (2.4 g, 5.6 mmol) and TEA (1.6 mL, 11.2 mmol) in THF (40 mL) was added Boc anhydride (1.47 g, 6.7 mmol) dropwise at 0°C. The resulting reaction mixture stirred at rt for 1 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give tert-butyl (2-(2(benzyloxy)ethoxy)ethyl)(2,2-dimethyl oxo-3,8,ll-trioxa azatridecan yl)carbamate as a colorless oil (2.9 g, 98%). LCMS (ESI+) m/z 526.67 (M+H)+.

[001812] Step 3 - tert-butyl (2,2-dimethyl oxo-3,8,ll-trioxa azatridecan yl)(2-(2hydroxyethoxy)ethyl)carbamate

[001813] To a stirred solution of tert-butyl (2-(2-(benzyloxy)ethoxy)ethyl)(2,2-dimethyl-4oxo-3,8,ll-trioxa azatridecan yl)carbamate (3.2 g, 6.1 mmol) in ethanol (60 mL) and acetic acid (0.1 mL) in autoclave was added 10% Pd/C (50% wet) (3.2 g) at rt under nitrogen atmosphere. The resulting reaction mixture stirred under hydrogen gas (2 kg/cm2 pressure) in autoclave at rt for 4 h. The reaction mixture was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl (2,2-dimethyl oxo-3,8,lltrioxa azatridecan yl)(2-(2-hydroxyethoxy)ethyl)carbamate as a yellow oil (2.4 g, 81 %). LC-MS (ESI+) m/z 436.55 (M+H)+.

[001814] Step 4 - 14-(tert-butoxycarbonyl)-2,2-dimethyl oxo-3,8,lL17-tetraoxa-5,14diazanonadecan yl methanesulfonate

[001815] To a stirred solution of tert-butyl (2,2-dimethyl oxo-3,8,ll-trioxa azatridecan13-yl)(2-(2-hydroxyethoxy)ethyl)carbamate (2.2 g, 5.0 mmol) and TEA (2.1 mL, 15.1 mmol) in dichloromethane (50 mL) was added mesyl chloride (0.6 mL, 7.7 mmol) dropwise at 0 °C. The resulting reaction mixture allowed to warm to rt and stirred for 4 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 14-(tert-butoxycarbonyl)-2,2-dimethyl oxo3,8,ll,17-tetraoxa-5,14-diazanonadecan yl methanesulfonate as a brown oil (2.5 g, 96%). LCMS (ESC) m/z 514.63 (M+H)+.

[001816] Step 5 - tert-butyl (2-(2-azidoethoxv)ethvl)(2.2-dimethvl oxo-3.8JI-trioxa-5azatridecan-13 -vDcarbamate

[001817] To a stirred solution of 14-(tert-butoxycarbonyl)-2,2-dimethyl oxo-3,8,ll,17tetraoxa-5,14-diazanonadecan yl methanesulfonate (2.5 g, 4.8 mmol) in DMF (25 mL) was added sodium azide (0.48 g, 7.2 mmol) at rt. The resulting reaction mixture was heated to 65 °C and stirred for 4 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (1% MeOH-DCM) to give tert-butyl (2-(2-azidoethoxy)ethyl)(2,2-dimethyl oxo-3,8,ll-trioxa-5azatridecan yl)carbamate as a yellow liquid (2 g, 89%). LCMS (ESI+) m/z 461.56 (M+H)+.

[001818] Step 6 - tert-butyl (2-(2-aminoethoxv)ethvl)(2.2-dimethvl oxo-3.8JI-trioxa-5azatridecan-13 -yl )carbamate

[001819] To a stirred solution of tert-butyl (2-(2-azidoethoxy)ethyl)(2,2-dimethyl oxo3,8,ll-trioxa azatridecan yl)carbamate (1.8 g, 3.9 mmol) in ethanol (100 mL) was added 10% Pd/C (50% wet) (1.8 g) at rt under nitrogen atmosphere. The resulting reaction mixture was stirred under hydrogen gas (2 kg/cm2 pressure) in an autoclave at rt for 4 h. The reaction mixture was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl (2-(2-aminoethoxy)ethyl)(2,2-dimethyl 0x0-3,8,11trioxa azatridecan yl)carbamate as a colorless oil (1.4 g, 82 %). LC-MS (ESI+) m/z 435.56 (M+H)+.

[001820] Tert-butyl ((lR,3R) (16-amino-2,5,841,14pentaoxahexadecvDcyclobutyDcarbamate (Intermediate ES)

Pd/C, H2 (gas)

AcOH, EtOH

BocHN/,

MsCI, TEA

DCM

BocHN

NaN3

DMF

BocHN/,

Pd/C, H2 (gas) BocHN,,,

EtOH

ES

[001821] Step 1 - tert-butyl ((lR,3R) (18-phenyl-2,5,8,lL14,17-hexaoxaoctadecvl) cyclobutyl) carbamate

[001822] To a stirred solution of ((lR,3R) ((tertbutoxycarbonyl)amino)cyclobutyl)methyl methanesulfonate (2.9 g, 10.4 mmol, synthesized via Steps 1-3 of Intermediate H) and l-phenyl-2,5,8,ll,14-pentaoxahexadecan ol (6.8 g, 20.78 mmol, synthesized via Step 1 of Intermediate X) in toluene (30 mL) and 8 N NaOH solution (30 mL) was added TBAB (500 mg, 2.1 mmol) at rt. The resulting reaction mixture then heated to 90 °C and stirred for 16 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product. The crude product was purified using silica gel column chromatography (1% MeOH-DCM) to give tert-butyl ((lR,3R) (18-phenyl-2,5,8,ll,14,17hexaoxaoctadecyl)cyclobutyl)carbamate as a colorless oil (2.4 g, 46%). LCMS (ESI+) m/z 511.66 (M+H20)+.

[001823] Step 2 - tert-butyl ((lR,3R) (16-hydroxy-2,5,8.1L14-pentaoxahexadecyl) cyclobutyDcarbamate

[001824] To a stirred solution of tert-butyl ((lr,3r) (18-phenyl-2,5,8,ll,14,17hexaoxaoctadecyl) cyclobutyl) carbamate (3.15 g, 6.16 mmol) in ethanol (40 mL) and acetic acid (0.3 mL) was added 10% Pd/C (50% wet) (3.15 g) at rt under nitrogen atmosphere. The resulting reaction mixture was stirred under hydrogen gas (2 kg/cm2 pressure) in autoclave at rt for 4 h. The reaction mixture was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give ter/-butyl ((lR,3R) (16-hydroxy-2,5,8,ll,14pentaoxahexadecyl)cyclobutyl)carbamate as a brown oil (2.1 g, 81 %). LC-MS (ESI+) m/z 421.53 (M+H)+.

[001825] Step 3 - l-((lR,3R) ((ter/-butoxycarbonyl)amino)cyclobutyl)-2,5,8.1L14pentaoxahexadecan yl methanesulfonate

[001826] To a stirred solution of tert-butyl ((lR,3R) (16-hydroxy-2,5,8,ll,14pentaoxahexadecyl) cyclobutyl) carbamate (2.1 g, 5.0 mmol) and TEA (2.1 mL, 15.0 mmol) in dichloromethane (50 mL) was added mesyl chloride (0.58 mL, 7.5 mmol) dropwise at 0°C. The resulting reaction mixture stirred at rt for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give l-((lR,3R) ((tert-butoxycarbonyl)amino)cyclobutyl)-2,5,8,ll,14pentaoxahexadecan yl methanesulfonate as a brown oil (2.3 g, 92%). LCMS (ESI+) m/z 499.62 (M+H)+.

[001827] Step 4 tert-butyl((lR,3R) (16-azido-2A8,lL14pentaoxahexadecyl)cyclobutyl)carbamate

[001828] To a stirred solution of l-((IR,3R) ((te/7-butoxycarbonyl)amino)cyclobutyl)2,5,8,11,14-pentaoxahexadecan yl methanesulfonate (2.0 g, 4.0 mmol) in DMF (20 mL) was added sodium azide (390 mg, 6.0 mmol) at rt. The resulting reaction mixture then heated to 65 °C and stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to afford crude product which was purified by silica gel column chromatography (2% MeOH-DCM) to give tert-butyl ((lR,3R) (16-azido-2,5,8,ll,14-pentaoxahexadecyl) cyclobutyl) carbamate as a colorless liquid (1.75 g, 98%). LCMS (ESI+) m/z 446.55 (M+H)+.

[001829] Step 5 - tert-butyl ((lR,3R) (16-amino-2,5,8,ll,14pentaoxahexadecvDcyclobutvDcarbamate

[001830] To a stirred solution of tert-butyl ((lR,3R) (16-azido-2,5,8,ll,14pentaoxahexadecyl) cyclobutyl) carbamate (1.8 g, 4.0 mmol) in ethanol (40 mL) was added 10% Pd/C (50% wet) (1.8 g) at rt under nitrogen atmosphere. The resulting reaction mixture was then stirred under hydrogen gas (2 kg/cm2 pressure) in autoclave at rt for 2 h. The reaction mixture was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was evaporated under reduced pressure to give tert-butyl ((lr,3r) (16-amino-2,5,8,ll,14-pentaoxahexadecyl) cyclobutyl)carbamate as a brown oil (1.41 g, 83 %). LC-MS (ESI+) m/z 420.55 (M+H)+

[001831] 4-(3-carbamovl (2-(2-((2,2,2-trifluoroethvl)amino)pyridin vl)oxazole-4carboxamido)-LH-Dyrazol-l-yl)benzoic acid (Intermediate ET)

[001832] Prepared a 5:4:1 mixture of DCM:TFA:H2O by combining DCM (5.6 mL), trifluoroacetic acid (4.5 mL), and water (1.1 mL). To this solution was added Intermediate CN (870 mg, 1.69 mmol) and the reaction mixture was stirred for 2.5 h at rt. On completion, the solvent was removed and the residue was placed under high vacuum to yield 1.07 g (quantitative yield) of the title compound as a brown solid. LC-MS (ESI+) m/z 516.1 (M+H)+.

[001833] 2-(4-iodobutyl)isoindoline-l,3-dione (Intermediate EU)

Nai acetone

EU

[001834] Step 1 - 2-(4-hydroxybutyl)isoindoline-L3-dione

[001835] To a suspension of 4-aminobutan-l-ol (5.05 g, 48.95 mmol) in toluene (200 mL) was added phthalic anhydride (7.25 g, 48.95 mmol). The reaction mixture was stirred under a Dean-Stark apparatus at 110 °C for 16 h at. The reaction mixture was then cooled to rt and washed with a IN aqueous solution of HCI. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (gradient of 25-75% Ethyl Acetate in Hexanes) to yield the title compound (8.62 g, 76%) as a colorless oil.

[001836] Step 2 - 4-(L3-dioxoisoindolin yl)butyl methanesulfonate

[001837] 2-(4-hydroxybutyl)isoindoline-l,3-dione (7.6 g, 32.6 mmol) was dissolved in di chloromethane (200 mL) and cooled to 0 °C. Triethylamine (5.9 mL, 42.4 mmol) and methane sulfonyl chloride (2.77 mL, 35.83 mmol) were added and the reaction was stirred for 1.5 hours. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3, and the layers were partitioned. The organic layer was washed with a saturated aqueous solution of NaHCO3 (3 times), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (9.9 g, 97%) as an off-white powder.

[001838] Step 3 - 2-(4-iodobutyl)isoindoline-L3-dione

[001839] 4-(1,3-dioxoisoindolin yl)butyl methanesulfonate (9.90 g, 31.82 mmol) was dissolved in acetone (200 mL). Then sodium iodide (14.4 g, 95.5 mmol) was added and the reaction mixture was heated to 58 °C for 2 hours. The reaction mixture was then concentrated in vacuo, then the residue was diluted with water and the aqueous layer was extracted with Ethyl Acetate (3 times). The combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The title compound was isolated as a yellow powder (10.22 g, 93%).

LC-MS (ESI+) m/z 344.0 (M+H)+.

[001840] 5-(2-(4-((tetrahvdro-2H-Dvran vl)oxv)butoxv)ethoxv)Dentan-l-amine (Intermediate EV) /x /x .Br THPO

HO '&#1523;&#1470;&#1470;''&#910;οη

NaH, KI

DMF

[001841] Step 1 - 2-(4-((tetrahydro-2H-pyran yl)oxy)butoxy)ethan-l-ol

[001842] To a suspension of NaH (2.9 g, 73.42 mmol, 60% dispersion in mineral oil) in dry DMF (150 mL) was added ethylene glycol (17.2 mL, 306 mmol) dropwise. The reaction mixture was stirred for 30 minutes at rt before the addition of potassium iodide (10.15 g, 61.19 mmol) and 2-(4-bromobutoxy)tetrahydro-2H-pyran (15.37 g, 61.19 mmol, CAS# 31608 7). The reaction was stirred at rt for 16 h. The reaction mixture was then quenched with a saturated aqueous solution of NH4C1. The aqueous layer was extracted with Ethyl Acetate (3 times). The combined organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient of 20-100% Ethyl Acetate in Hexanes). The title compound was isolated as a yellow powder (4.33 g, 30% yield).

[001843] Step 2:2-(5-(2-(4-((tetrahydro-2H-pyran-2yl)oxy)butoxy)ethoxy)pentyl)isoindoline-L3-dione

[001844] 2-(4-((tetrahydro-2H-pyran yl)oxy)butoxy)ethan-l-ol (2.2 g, 9.5 mmol) was dissolved in dry DMF (40 mL). Then NaH (0.41 g, 10.4 mmol, 60% dispersion in mineral oil) was carefully added. After stirring for 30 minutes at rt, 2-(4-iodobutyl)isoindoline-l,3-dione (3.9 g, 11.3 mmol, Intermediate EU) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was then was quenched with water and the aqueous layer was extracted with Ethyl Acetate (3 times). The combined organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (gradient of 0-100% Ethyl Acetate in Hexanes) to give the title compound (956 mg, 22% yield) as a colorless oil. LC-MS (ESI+) m/z 449.2 (M+H)+.

[001845] Step 3 - 5-(2-(4-((tetrahydro-2H-pyran yl)oxy)butoxy)ethoxy)pentan-l-amine

[001846] 2-(5-(2-(4-((tetrahydro-2H-pyran yl)oxy)butoxy)ethoxy)pentyl)isoindoline-l,3dione (200 mg, 0.44 mmol) was dissolved in methanol (3 mL) and hydrazine hydrate (64 pL, 1.32 mmol) was added. The reaction mixture was heated to 70 °C and stirred for 3 hours. The reaction mixture was then cooled to rt and concentrated in vacuo. The residue was triturated in diethyl ether, and the white precipitate was filtered off. The filtrate was then concentrated in vacuo to give the title compound as a colorless oil (120 mg, 87% yield).

[001847] Tert-butyl (39,12&#1524;6&#1524;-tetraoxaDentadec vn-l-vl)carbamate (Intermediate

[001848] To a solution of tert-butyl (2-(2-(2-(2hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (10.0 g, 34.1 mmol, Step 1 of Intermediate EN) in anhydrous THF (250mL) was added sodium hydride (1.63 g, 40.94 mmol, 60% dispersion in mineral oil) in one portion under nitrogen atmosphere. The reaction mixture was stirred at rt for

0.5 h and thereafter it was cooled to 0 °C. An 80% solution of 3-bromoprop yne in toluene (5.7 mL, 51.2 mmol) was added dropwise to the reaction mixture at 0°C over a period of 10 min. The resulting reaction mixture was stirred at 0°C for 1 h and thereafter it was allowed to warm to rt. The resulting reaction mixture was stirred overnight at rt. Then the reaction mixture was quenched with a small aliquot of methanol (1.6 mL) and concentrated on a rotary evaporator. The obtained crude material was suspended in DCM (100 mL) and was washed with water (2 x 30 mL) and brine (50 mL). The resulting organic layer was dried over anhydrous sodium sulphate, filtered and concentrated on a rotary evaporator. The obtained crude product was purified by silica gel chromatography (gradient Ethyl acetate/Hexanes) to give the title compound (6.25 g, 55%) as a light yellow viscous liquid.

[001849] 3-Benzyloxv methoxv-aniline (Intermediate EX)

NO, N02 N02 NH2

APd2(dba)3, tBuXphos J. BnBr&#1523; T. Fe, NH4CI,

KOH, dioxane, H20 A _A acetone II MeOH, H20 A A

Br Me(J &#908;Η MeO'^^^OBn MeO^^^ OBn

EX

[001850] Step 1 - 3-Methoxy nitro-phenol

[001851] A mixture of KOH (11.6 g, 206 mmol) and 1-bromo methoxy nitro-benzene (12.0 g, 51.7 mmol) in a mixed solvent of dioxane (80 mL) and H2O (80 mL) was degassed for 5 minutes. Then Pd2(dba)3 (473 mg, 517 umol) and tBuXphos (439 mg, 1.03 mmol) were added to the reaction mixture. The resulting reaction mixture was degassed for a further 0.5 hour, and then the reaction mixture was heated at 100° C for 12 hours under a nitrogen atmosphere. On completion, the mixture was cooled, then acidified with 5 M HCI until the pH = 1.0 and extracted with EtOAc (2 X 200 mL). The combined organic layer was washed with saturated brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 3:1) to give the title compound (8.60 g, 98% yield) as a yellow solid. 1H NMR (400MHz, DM SO-6/6) δ 10.46 (s, IH), 7.18 (d, J= 2.4 Hz, 2H), 6.75 (t, J= 2.4 Hz, IH), 3.81 (s, 3H).

[001852] Step 2 - l-Benzyloxy methoxy nitro-benzene

[001853] To a mixture of 3-methoxy nitro-phenol (4.00 g, 23.6 mmol) in acetone (150 mL) was added K2CO3 (8.17 g, 59.1 mmol) and BnBr (6.07 g, 35.4 mmol, 4.21 mL). Then the reaction mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to remove acetone. The residue was washed with water (100 mL) and extracted with EA (2 X 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PEEA = 8:1) to give the title compound (6.00 g, 97% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.52 - 7.34 (m, 7H), 6.84 (t, J = 2.4 Hz, IH), 5.13 (s, 2H), 3.87 (s, 3H).

[001854] Step 3 - 3-Benzyloxy methoxy-aniline

[001855] To a solution of l-benzyloxy methoxy nitro-benzene (2.00 g, 7.71 mmol) in MeOH (45 mL) and H2O (10 mL) was added Fe (4.31 g, 77.1 mmol) followed by NH4C1 (4.12 g, 77.1 mmol). Then, the reaction mixture was stirred at 75 °C for 14 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to remove MeOH. The residue was washed with water (100 mL) and extracted with EA (2 X 200 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.14 g, 64% yield) as black brown oil. 1H NMR (400MHz, CDCh) δ 7.47 - 7.28 (m, 5H), 6.04 (t, J= 2.0 Hz, IH), 5.98 (t, J= 2.0 Hz, IH), 5.92 (t, J = 2.0. Hz, IH), 5.03 (s, 2H), 3.76 (s, 3H); LC-MS (ESI+) m/z 230.1 (M+H)+.

[001856] 2- [2- [2- [2-(Benzvloxvcarbonvlamino)ethoxy] ethoxy] ethoxy] ethyl methanesulfonate (Intermediate EY) / CbzCI, NaHCO3 // // // // Xbz H0^

ACN, H2O DC

MsCI, TEA

N 'CbZ

DCM

EY

[001857] Step 1 - Benzyl N-r2-r2-r2-(2-hydroxyethoxy)ethoxy1ethoxy1ethyl1carbamate [001858] To a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethanol (6.00 g, 31.0 mmol, Intermediate DC) in ACN (50 mL) and H2O (50 mL) was added CbzCI (6.36 g, 37.2 mmol) and NaHCO3 (7.83 g, 93.1 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3X30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (9.20 g, 90% yield) as a colorless oil. LC-MS (ESI+) m/z 350.0 (M+Na)+.

[001859] Step 2 - 2-r2-r2-r2-(Benzyloxycarbonylamino)ethoxy1ethoxy1ethoxy1ethyl methanesulfonate

[001860] To a mixture of benzyl N-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (1.00 g, 3.05 mmol) in dichloromethane (10 mL) was added TEA (617 mg, 0.85 mL, 6.10 mmol) and MsCI (524 mg, 0.354 mL, 4.57 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture then allowed to warm to rt and stirred for 1 hour. On completion, the reaction mixture was poured into 5 mL of water and acidified with citric acid until the pH = 5-6. The mixture was extracted with di chloromethane (2X10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.10 g, 88% yield) as a light yellow oil. LC-MS (ESI+) m/z 406.0 (M+H)+.

[001861] 7-((3-Hvdroxv methoxvDhenvl)amino) (methylthio)imidazo[l,2clpyrimidine carbox amide (Intermediate EZ)

30% H2O2, NaOH

DMSO, EtOH

EZ

[001862] Step 1 - 4-(3-Benzyloxy methoxy-anilino) chloro methylsulfanylpyrimidine carbonitrile

[001863] To a mixture of 3-benzyloxy methoxy-aniline (6.90 g, 30.1 mmol, Intermediate : EX) and 4,6-dichloro methylsulfanyl-pyrimidine carbonitrile (6.62 g, 30.1 mmol, CAS# 33097 1) in THF (20 mL) was added DIPEA (5.83 g, 45.1 mmol, 7.88 mL) dropwise at 0 °C. : The reaction mixture was then allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was concentrated in vacuo to remove THF. The residue was washed with water : (100 mL) and extracted with EA (2 X 200 mL). The combined organic layers were dried over : Na2SO4, filtered and concentrated in vacuo to give the title compound (9.00 g, 72% yield) as a ; light yellow solid. 1HNMR (400MHz, DMSO-i/6) δ 7.51 - 7.29 (m, 5H), 6.93 (t, J= 2.0 Hz, IH), i 6.85 (t, J= 2.0 Hz, IH), 6.45 (t, J= 2.4 Hz, IH), 5.08 (s, 2H), 3.73 (s, 3H), 2.46 (s, 3H); LC-MS ; (ESC) mz 412.9 (M+H)L

[001864] Step 2 - 4-Amino (3-benzvloxv methoxv-anilino) methylsulfanvlpyrimidine carbonitrile

[001865] To a solution 4-(3-benzyloxy methoxy-anilino) chloro-2methylsulfanylpyrimidine carbonitrile (10.2 g, 24.7 mmol) in THF (50 mL) was added NH3*H2O (30 mL). The reaction mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with DCM (100 mL) and filtered. The filter cake was collected to afford a white solid. Then, the white solid was triturated with acetone (50 mL) to give the title compound (7.79 g, 80% yield) as an off-white solid. LC-MS (ESI+) m/z 394.0 (M+H)+.

[001866] Step 3 - 4-Amino (3-benzyloxy methoxy-anilino) methylsulfanylpyrimidine carboxamide

[001867] To a mixture 4-amino (3-benzyloxy methoxy-anilino)-2methylsulfanylpyrimidine carbonitrile (7.79 g, 19.8 mmol) in DMSO (80 mL) and EtOH (80 mL) was added NaOH (5 M, 19.8 mL) and H2O2 (11.2 g, 99.0 mmol, 9.51 mL, 30% solution) dropwise. The reaction mixture was stirred at rt of 2.5 hours. On completion, the reaction mixture was quenched by slow addition of saturated Na2S2O3 solution (50 mL) under stirring. The reaction mixture was concentrated in vacuo to remove the EtOH. The residue was poured into 100 mL of water and acidified with IM HCI until the pH = 7. The mixture was extracted with EA (2 X 200 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (10.0 g, 91% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 9.89 (s, IH), 7.56 (s, 2H), 7.47 - 7.31 (m, 5H), 6.91 (t, J = 2.0 Hz, IH), 6.88 (t, J = 2.0 Hz, IH), 6.85 (s, 2H), 6.25 (t, J = 2.0 Hz, IH), 5.07 (s, 2H), 3.72 (s, 3H), 2.46 (s, 3H); LC-MS (ESI+) m/z 412.0 (M+H)+.

[001868] Step 4 - 7-(3-Benzyloxy methoxy-anilino) methylsulfanvl-imidazo[L2c1pyrimidine carbox amide

[001869] To a mixture of 4-amino (3 -benzyl oxy-5 -methoxy-anilino)-2methylsulfanylpyrimidine carbox amide (8.00 g, 19.4 mmol) in DMF (50 mL) was added a solution of 2-chloroacetaldehyde (11.4 g, 58.3 mmol, 9.39 mL, 40% solution in water). The reaction mixture was stirred at 60 °C for 8 hours. On completion, the reaction mixture was concentrated in vacuo to remove the DMF. The residue was purified by silica gel chromatography (DCM: MeOH = 80:1) to give the title compound (2.30 g, 27% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 12.04 (s, IH), 10.04 (s, IH), 7.48 - 7.33 (m, 7H), 6.94 - 6.92 (m, IH), 6.88 6.85 (m, IH), 6.34 (t, J = 2.0 Hz, IH), 5.74 (s, IH), 5.07 (s, 2H), 3.81 (s, 3H), 2.80 (s, 3H); LCMS (ESI+) m/z 436.0 (M+H)+.

[001870] Step 5 - 7-((3-Hydroxy methoxyphenyl)amino) (methylthio)imidazo[L2c1pyrimidine carbox amide

[001871] To a solution of 7-(3-benzyloxy methoxy-anilino) methylsulfanyl imidazo[l,2-c]pyrimidine carboxamide (2.30 g, 5.28 mmol) in DCM (150 mL) was added a solution of BCh in DCM (1 M, 42.2 mL) under nitrogen atmosphere. The reaction mixture was stirred at rt for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 20:1) to give the title compound (1.42 g, 70% yield) as a yellow solid. 1HNMR (400MHz, DMSO-6/6) δ 11.98 (s, IH), 7.76 (d, J = 1.6 Hz, IH), 7.55 (d, J = 1.6 Hz, IH), 6.67 (d, J = 2.0 Hz, IH), 6.64 (d, J = 2.0 Hz, IH), 6.10 (d, J= 2.0 Hz, IH), 3.71 (s, 3H), 2.80 (s, 3H).

[001872] 7-(4-Hydroxv-3.,5-dimethoxv-anilino) methvlsulfanvl-imidazo[l.,2c]Dvrimidine-8 -carboxamide (Intermediate FA)

OH

OH

tert-butyl nitrite

THF

DIPEA, THF

ΝΗ3.Η2Ο

THF

Fe, NH4CI

H2O, EtOH

OBn

FA

[001873] STEP 1 - 2,6-DIMETHOXY NITRO-PHENOL

[001874] To a solution of 2,6-dimethoxyphenol (5.00 g, 32.4 mmol) in THF (50 mL) was added dropwise tert-butyl nitrite (10.0 g, 97.3 mmol). Then, the reaction mixture was stirred at rt for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.73 g, 58% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.57 (s, 2H), 6.06 (s, IH), 3.91 (s, 6H).

[001875] Step 2 - 2-Benzyloxy-L3-dimethoxy nitro-benzene

[001876] To a solution of 2,6-dimethoxy nitro-phenol (8.00 g, 40.2 mmol) in acetone (100 mL) was added K2CO3 (11.1g, 80.3 mmol) and KI (667 mg, 4.02 mmol) at rt. The suspension was stirred at rt for 1 hr. Then, bromomethylbenzene (10.3 g, 60.3 mmol) was added to the mixture dropwise. The reaction mixture was then heated to 60 °C and stirred for 12 hours. On completion, the reaction mixture was concentrated in vacuo to remove the acetone. The residue was diluted with water (100 mL) and extracted with EA (3 X 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (8.62 g, 74% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 7.51 (s, 2H), 7.45 (d, J = 6.8 Hz, 2H), 7.39 - 7.27 (m, 3H), 5.14 (s, 2H), 3.91 (s, 6H).

[001877] Step 3 - 4-Benzyloxy-3,5-dimethoxy-aniline

[001878] To a solution of 2-benzyloxy-l,3-dimethoxy nitro-benzene (8.62 g, 29.8 mmol) in a mixed solvent of H2O (50 mL) and EtOH (170 mL) was added Fe (16.6 g, 298 mmol) followed by NH4C1 (15.9 g, 298 mmol). Then, the reaction mixture was stirred at 75 °C under nitrogen for 1.5 hrs. On completion, the mixture was diluted with MeOH (150 mL), filtered through a pad of Celite and washed with MeOH (80 mL). The filtrate was concentrated, and the residue was washed with H2O (100 mL) and extracted with EA (2 X 150 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (7.27 g, 94% yield) as a black brown oil. LCMS (ESI+) m/z 260.0 (M+H)+.

[001879] Step 4 - 4-(4-Benzyloxy-3,5-dimethoxy-anilino) chloro methylsulfanylpyrimidine carbonitrile

[001880] To a solution of 4,6-dichloro methylsulfanyl-pyrimidine carbonitrile (6.17 g, 28.0 mmol) and 4-benzyloxy-3,5-dimethoxy-aniline (7.27 g, 28.0 mmol) in THF (150 mL) was added DIPEA (5.44 g, 42.1 mmol) dropwise. The reaction mixture was stirred at rt for 15 hours. On completion, the reaction mixture was diluted with water (150 mL) and filtered. Then, the filter cake was dried in vacuo to give the title compound (9.49 g, 76% yield) as a yellow solid. LC-MS (ESI+) m/z 464.9 (M+Na)+.

[001881] Step 5 - 4-Amino (4-benzyloxy-3,5-dimethoxy-anilino) methylsulfanyl pyrimidine carbonitrile

[001882] To a mixture of 4-(4-benzyloxy-3,5-dimethoxy-anilino) chloro-2methylsulfanyl-pyrimidine-5 -carbonitrile (4.49 g, 10.1 mmol) in THF (50 mL) was added NH3*H2O (7.11 g, 203 mmol). Then, the reaction mixture heated to 70 °C and stirred for 17 hours at autoclave. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with DCM to give the title compound (3.74 g, 87% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.54 - 7.48 (m, 2H), 7.41 - 7.30 (m, 3H), 6.88 (s, IH), 6.84 (s, 2H), 5.35 (s, 2H), 5.02 (s, 2H), 3.85 (s, 6H), 2.50 (s, 3H); LC-MS (ESI+) m/z 424.0 (M+H)+.

[001883] Step 6 - 4-Amino (4-benzyloxy-3,5-dimethoxy-anilino) methylsulfanylpyrimidine carboxamide

[001884] To a solution of 4-amino (4-benzyloxy-3,5-dimethoxy-anilino)-2methylsulfanyl-pyrimidine carbonitrile (5.60 g, 13.2 mmol) in DMSO (30 mL) and EtOH (30 mL) at 0 °C was added H2O2 (7.50 g, 66.1 mmol, 30% solution) and NaOH (5 M, 13.2 mL, 20% solution). The reaction mixture was stirred at rt for 3 hours. On completion, the reaction mixture was quenched with sat.Na2SO3. Then the mixture was fdtered through a pad of celite. After that, the fdter cake was washed with H2O (3 X 50 mL) and dried to give the title compound (5.70 g, 98% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 9.82 (s, IH), 7.54 (s, 2H), 7.46 (d, J= 6.8 Hz, 2H), 7.41 - 7.28 (m, 3H), 6.95 (s, 2H), 6.83 (s, 2H), 4.85 (s, 2H), 3.76 (s, 6H), 2.45 (s, 3H); LC-MS (ESI+) m/z 442.1 (M+H)+.

[001885] Step 7 - 7-(4-Benzyloxy-3.5-dimethoxy-anilino) methylsulfanyl-imidazo[L2c1pyrimidine carboxamide

[001886] A mixture of 4-amino (4-benzyloxy-3,5-dimethoxy-anilino) methylsulfanylpyrimidine carboxamide (5.00 g, 11.3 mmol) and 2-chloroacetaldehyde (3.33 g, 17.0 mmol) in DMF (20 mL) was heated at 60 °C for 6 hours under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (5.07 g, 96% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 11.88 (s, IH), 10.00 (s, IH), 7.42 (d, J = 7.2 Hz, 2H), 7.32 - 7.22 (m, 5H), 6.70 (s, 2H), 5.64 (m, IH), 4.94 (s, 2H), 3.75 (s, 6H), 2.64 (s, 3H); LC-MS (ESI+) m/z 466.0 (M+H)+.

[001887] Step 8 - 7-(4-Hydroxy-3.5-dimethoxy-anilino) methylsulfanyl-imidazo[L2 c&#1470;|pyrimidine-8 -carboxamide

[001888] To 7-(4-benzyl oxy-3,5-dimethoxy-anilino) methylsulfanyl-imidazo[ 1,2c]pyrimidine carboxamide (1.55 g, 3.33 mmol) was added HBr (22.4 g, 15 mL, 110 mmol, 40 % solution). The reaction mixture was stirred at 50 °C for 3 hours under nitrogen atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with dichloromethane: methanol = 10:1 to give the title compound (1.20 g, 96% yield) as a yellow solid. LC-MS (ESI+) m/z 376.0 (M+H)+.

[001889] 5,7-Dichl0r0Dvrid0[4,3-d]Dvrimidin-4(3H)-0ne (Intermediate FB)

FB

[001890] Step 1 - Tert-butyl N-tert-butoxvcarbonvl-N-(2.6-dichloro pvridvl )carbamate [001891] A solution of 2,6-dichloropyridin amine (28.0 g, 172 mmol, CAS# 2587 2) in

THF (400 mL) under nitrogen was cooled to 0 °C with an ice-water bath. To this mixture was added a solution of NaHMDS (1 M, 412 mL) in THF. After the reaction mixture was stirred at 0 °C for 0.5 h, a solution of (Boc)2O (82.5 g, 378 mmol, 86.8 mL) in THF (1.2 L) was added and the ice-water bath was then removed. The reaction mixture was then stirred at rt for 16 hrs. On completion, the reaction mixture was quenched with saturated NH4C1 (1000 mL) and extracted with ethyl acetate (3 X 500 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (42.0 g, 96% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.98 (s, IH), 8.34 (s, IH), 1.63 (s, 9H), 1.53 (s, 9H).

[001892] Step 2 - Tert-butyl 4-(tert-butoxycarbonylamino)-2,6-dichloro-pyridine-3carboxylate

[001893] To a solution of LDA (2 M, 169 mL) was added a solution of tert-butyl A'-tertbutoxycarbonyl-7V-(2,6-dichloro pyridyl)carbamate (35.0 g, 96.4 mmol) in THF (600 mL) under nitrogen at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 hr. On completion, the reaction mixture was quenched with saturated NH4C1, and extracted with ethyl acetate (3 X 100 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 200:1) to give the title compound (35.0 g, 100% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.99 (s, IH), 8.35 (s, IH), 1.64 (s, 9H), 1.54 (s, 9H).

[001894] Step 3 - 4-Amino-2,6-dichloro-pyridine carboxylic acid

[001895] To a solution of tert-butyl 4-(tert-butoxycarbonylamino)-2,6-dichloro-pyridine-3carboxylate (35 g, 96.4 mmol) in DCM (100 mL) was added TFA (139 g, 1.22 mol, 90 mL). The reaction mixture was stirred at 65 °C for 12 h. On completion, the reaction was mixture was concentrated in vacuo to give the title compound (31.0 g, 82% yield, TFA salt) as yellow solid. LCMS (ESI+) m/z 206.9 (M+H)+.

[001896] Step 4 - 4-amino-2,6-dichloro- pyridine carbonyl chloride

[001897] A solution of 4-amino-2,6-dichloro-pyridine carboxylic acid (26.0 g, 81.0 mmol, TFA) and SOC12 (164 g, 1.38 mol, 100 mL) was heated at 80 °C for 15 min. On completion, the reaction mixture was concentrated in vacuo and the title compound was used directly in the next step. LCMS (M+l)+: 221.0

[001898] Step 5 - 4-Amino-2,6-dichloro-pyridine carboxamide

[001899] To a solution of NH3/THF (7 M, 50.1 mL) was added a solution of 4-amino-2,6dichloro- pyridine carbonyl chloride (5.30 g, 15.6 mmol, TFA salt) in THF (100 mL) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 12 h. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM: MeOH = 50:1 to 10:1) to give the title compound (2.00 g, 58% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ = 7.99 (s, IH), 7.72 (s, IH), 6.61 (s, IH), 6.59 (s, 2H); LC-MS (ESI+) m/z 205.9 (M+H)+.

[001900] Step 6 - 5,7-Dichloropyrido[4,3-d1pyrimidin-4(3H)-one

[001901] A mixture of 4-amino-2,6-dichloro-pyridine carboxamide (3.00 g, 14.6 mmol) and triethyl orthoformate (53.4 g, 360 mmol, 60 mL) was heated to 150 °C for 3 hrs. On completion, the reaction mixture was concentrated in vacuo and the residue was triturated with PE/EA = 1:1 (5 mL) to give the title compound (2.0 g, 64% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 12.83 (s, IH), 8.33 (s, IH), 7.72 (s, IH).

[001902] 2- [2 12- [2-(Benzvloxvcarbonylamino)ethoxy| ethoxy] ethoxy] ethoxy] ethyl methane sulfonate (Intermediate FC)

MsCI, TEA

DCM

MsO^o^O^o/^O^NHCbz

AJ

FC

[001903] To a solution of benzyl N-[2-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (500 mg, 1.35 mmol, Intermediate AJ) in dichloromethane (6 mL) was added triethylamine (273 mg, 2.70 mmol, 374 uL) and MsCI (185 mg, 1.62 mmol, 125 uL) at 0 °C. The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was diluted with water (100 mL), and extracted with ethyl acetate (3 X 100 mL). Then the combined organic layer was dried over Na2SO4 and concentrated in vacuo to give the title compound (600 mg, 98% yield) as a yellowish oil.

[001904] 3-Oxo-l-Dhenvl-2,7,10-trioxa azadodecan yl methanesulfonate (Intermediate FD) ho^^o&#1523;^o^&#1524;^NH2

CbzCI, NaHCO3

CH3CN, h2o HO^x^O'^^'°^x^NHCbz

DCM

FD

[001905] Step 1 - Benzyl N-[2-r2-(2-hydroxyethoxy)ethoxy1ethyl1carbamate

[001906] To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (3.50 g, 23.5 mmol, CAS# 6338 2) in CH3CN (30 mL) and H2O (30 mL) was added CbzCI (4.80 g, 28.1 mmol) and NaHCO3 (5.91 g, 70.4 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum etherethyl acetate = 5:1 to 1:1) to give the title compound (5.00 g, 75% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.38 - 7.29 (m, 5H), 5.47 (s, IH), 5.11 (s, 2H), 3.71 (s, 2H), 3.65 3.56 (m, 8H), 3.43 - 3.37 (m, 2H).

[001907] Step 2 - 3-Oxo-l-phenvl-2,7,10-trioxa azadodecan vl methanesulfonate [001908] To a solution of benzyl A-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (2.00 g,

7.06 mmol) in DCM (30 mL) was added TEA (2.14 g, 21.2 mmol, 2.94 mL) and MsCI (1.05 g, 9.18 mmol, 710 uL) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 0.5 hr. On completion, the reaction mixture was quenched with saturated citric acid (5 mL), and extracted with dichloromethane (3 X 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.4 g, 94% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 7.39 - 7.31 (m, 5H), 5.24 (s, IH), 5.11 (s, 2H), 4.38 - 4.34 (m, IH), 4.38 - 4.34 (m, IH), 3.76 (dd, J= 3.6, 5.2 Hz, 2H), 3.67 - 3.64 (m, 2H), 3.64 - 3.60 (m, 2H), 3.59 - 3.54 (m, 2H), 3.40 (q, J = 52 Hz, 2H), 3.02 (s, 3H).

[001909] N-[2-[(2.,5-dichloroDvrimidin vl)amino] methoxvphenyllmethanesulfonamide (Intermediate FE)

BnBr, K2CO3 acetone

HNO3 HOAc

Fe/NH4CI

MeOH, H2O

DIPEA, IPA

MsCI pyridine

FE

[001910] Step 1 - 1-Benzyl oxy methoxy methyl-benzene

[001911] To a mixture of 2-methoxy methyl-phenol (25.0 g, 180 mmol) in acetone (460 mL) was added K2CO3 (62.5 g, 452 mmol) and BnBr (46.4 g, 271 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to remove the acetone. The residue was diluted with water (100 mL) and extracted with EA (2 X 200 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (40.0 g, 96% yield) as white solid. 1H NMR (400MHz, CDCh) δ 7.49 - 7.43 (m, 2H), 7.42 - 7.27 (m, 3H), 6.83 - 6.73 (m, 2H), 6.69 - 6.63 (m, IH), 5.15 (s, 2H), 3.90 (s, 3H), 2.32 (s, 3H).

[001912] Step 2 - 1-Benzyloxy methoxy methyl nitro-benzene

[001913] A stirred mixture of l-benzyloxy methoxy methyl-benzene (17.5 g, 76.6 mmol) in HOAc (60 mL) was cooled to 4-6°C and a mixture of concentrated HNO3 (49.0 g, 778 mmol) in HOAc (17 mL) was added dropwise. The reaction mixture was stirred at 4-6 °C for 3 hours. On completion, the reaction mixture was poured into 100 mL of an ice-H2O mixture. The mixture was filtered and the solid precipitate was washed with water. The solid was dried in vacuo to give the title compound (20.0 g, 95% yield) as a yellow solid. 1H NMR (400MHz, DMSOA) δ 7.73 (s, IH), 7.49 - 7.33 (m, 5H), 7.09 (s, IH), 5.17 (s, 2H), 3.90 (s, 3H), 2.54 (s, 3H).

[001914] Step 3 - 5-Benzyloxy methoxy methyl-aniline

[001915] To a mixture of l-benzyloxy methoxy methyl nitro-benzene (10.0 g, 36.5 mmol) in MeOH (100 mL) and H2O (60 mL) was added Fe (26.5 g, 475 mmol) and NH4C1 (25.4 g, 475 mmol). The reaction mixture was stirred at 65 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to remove the MeOH. The residue was diluted with water (50 mL), and neutralized with sat. NaHCO3 (20 mL) until the pH = 8-9. The residue was diluted with water (30 mL) and extracted with EA (2 X 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (1.60 g, 17% yield) as a white solid. LCMS (ESI+) m/z 244.1 (M+H)+.

[001916] Step 4 - Nl-(2,5-dichloropyrimidin yl) methoxy-benzene-L2-diamine [001917] Amixture of 4-methoxybenzene-l,2-diamine (25.0 g, 180 mmol) and DIPEA (28.0 g, 217 mmol) in IPA (150 mL) was stirred at 0°C. 2,4,5-trichloropyrimidine (33.1 g, 180 mmol) was then added dropwise and the mixture was allowed to warm to rt and stirred for 1 hour. On completion, the reaction mixture was concentrated in vacuo to remove the IPA. The residue was diluted with water (50 mL) and extracted with EA (2 X 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (44.0 g, 85% yield) as a pale solid. LC-MS (ESI+) m/z 284.9 (M+H)+.

[001918] Step 5:N- [2- [(2,5 -dichloropyrimidin yl)amino1 -5 -methoxyphenyllmethanesulfonamide

[001919] To a mixture of Nl-(2,5-dichloropyrimidin yl) methoxy-benzene-l,2-diamine (8.00 g, 28.0 mmol) in pyridine (20 mL) was added MsCl (3.54 g, 30.8 mmol) at 0 °C. Then the reaction mixture was then allowed to warm to rt and stirred for 4 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (7.00 g, 68% yield) as a pale solid. LC-MS (ESI+) m/z 362.9 (M+H)+.

[001920] 2-Methoxv methyl nitro-Dhenol(Intermediate FF)

OBn OH

YyOMe BCI3 Υγ0Μθ o2N^y dcm 02νΑ>

FF

[001921] To a mixture of l-benzyloxy methoxy methyl nitro-benzene (5.00 g, 18.3 mmol, synthesized via Steps 1-2 of Intermediate FE) in DCM (60 mL) was added BC13DCM (1.0 M, 91 mL). Then the reaction mixture was stirred at rt for 8 hours. On completion, the reaction mixture was concentrated in vacuo. The reaction mixture was washed with sat.NaHCO3 (150 mL) and extracted with DCM (3 X 100 mL). The organic layer was dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (2.80 g, 83% yield) as yellowish solid. LC-MS (ESI+) m/z 184.1 (M+H)+.

[001922] 23&#1524;-Dimeth0xy nitr0Dhen01 (Intermediate FG)

FG

[001923] Step 1 - 2,3-Dimethoxyphenyl benzenesulfonate

[001924] To a solution of 2,3-dimethoxyphenol (10.0 g, 64.8 mmol, 8.47 mL) in dichloromethane (200 mL) was added triethylamine (13.1 g, 129 mmol, 17.9 mL) at 0 °C. Then benzenesulfonyl chloride (13.7 g, 77.8 mmol, 9.96 mL) was added dropwise over 1 hour at 0 °C. The mixture was then allowed to warm to rt and stirred for 15 hours. On completion, the reaction mixture was diluted with water (700 mL), and then extracted with di chloromethane (4 X 250 mL). The combined organic layers were washed with brine (2 X 250 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum etherethyl acetate = 10:1) to give the title compound (17.0 g, 89% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 7.85 (t, J= 7.2 Hz, 2H), 7.57 (d, J= 7.6 Hz, IH), 7.45 (t, J = 8.0 Hz, 2H), 6.89 - 6.87 (m, IH), 6.78 - 6.75 (m, 2H), 3.75 (s, 3H), 3.61 (s,

3H).

[001925] Step 2 - 2J-Dimethoxy nitrophenyl benzenesulfonate

[001926] To a solution of (2,3-dimethoxyphenyl) benzenesulfonate (17.0 g, 57.7 mmol) in acetic acid (340 mL) was added nitrosoaphyllinic acid (17.0 g, 57.7 mmol, 61.2 mL) dropwise over 1 hour at 0°C. The mixture was then allowed to warm to rt and was stirred for 15 hours. On completion, the reaction mixture was diluted with water 50 mL and extracted with ethyl acetate (3 X 300 mL). The combined organic layers were washed with brine (2 X 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue purified by column chromatography (petroleum etherethyl acetate = 50:1 to 20:1) to give the title compound (17.0 g, 86% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 7.96 (t, J= 5.2 Hz, IH), 7.74 (d, J= 4.8 Hz, IH), 7.63 - 7.61 (m, 5H), 3.96 (s, 3H), 3.88 (s, 3H).

[001927] Step 3 - 2,3-Dimethoxy nitrophenol

[001928] To a solution of (2,3-dimethoxy nitro-phenyl) benzenesulfonate (2.80 g, 8.25 mmol) in methanol (28.2 mL) was added 20% potassium hydroxide solution (16.89 mL). The mixture was stirred at 50 °C for 4 hours. On completion, the reaction mixture was concentrated in vacuo to remove methanol. The residue was diluted with water (50 mL), and acidified with HCI until the pH = 5-6. The mixture was then filtered, and the solid precipitate was collected and dried in vacuo to give the title compound (1.40 g, 85% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 7.45 (d, J= 2.8 Hz, IH), 7.34 (d, J= 2.8 Hz, IH), 5.94 (s, IH), 3.95 (s, 3H), 3.83 (s, 3H). [001929] (±1-Tert-butyl 2-ethvl [5-(2-methvlsulfonvlpyrimidin vl)-2Dyridyllpiperazine-l- carboxylate (Intermediate FH)

HN N-Boc

DIPEA, ACN

H2O2, Na2W2O4 acetone

FH

[001930] Step 1 - (±)-Tert-butyl 4-(5-acetvl pvridvl) ethyl-piperazine-l-carboxvlate

[001931] To a solution of l-(6-chloro pyridyl)ethanone (4.00 g, 24.9 mmol; CAS# 3635738-7) in ACN (8 mL) was added DIPEA (9.67 g, 74.8 mmol) and (±)-tert-butyl 2-ethylpiperazine1-carboxylate (6.41 g, 29.9 mmol; CAS# 393781 0). The reaction mixture was stirred at 85 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 5:1) to give the title compound (8.30 g, 100% yield) as a yellow oil. 1H NMR (400 MHz, CDCh) δ 8.75 (d, J= 2.0 Hz, IH), 8.03 (dd, J= 2.4, 9.2 Hz, IH), 6.58 (d, J = 8.8 Hz, IH), 4.34 (d, J= 13.2 Hz, IH), 4.27 (d, J = 10.4 Hz, IH), 4.13 (q, J = 7.2 Hz, IH), 4.02 (s, IH), 3.27 (dd, J = 4.0, 13.2 Hz, IH), 3.20-3.04 (m, 2H), 2.51 (s, 3H), 1.63 - 1.50 (m, 2H), 1.49 (s, 9H), 0.90 (t, J= 7.2 Hz, 3H). [001932] Step 2 - »-Ethyl l-(4-bromo-3,5-dimethyl-phenyl) phenyl-pyrazole-4carboxylate

[001933] A mixture of (±)-tert-butyl 4-(5-acetyl pyridyl) ethyl-piperazine- 1-carboxylate (8.30 g, 24.9 mmol) and l,l-dimethoxy-N,N-dimethyl-methanamine (29.7 g, 249 mmol) was heated to 110 °C for 14 hours. LCMS showed that the starting material remained, thus the reaction was then heated to 120 °C for another 22 hours. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residue was purified by column chromatography (petroleum etherethyl acetate = 5:1 to ethyl acetate) to give the title compound (7.70 g, 80% yield) as a yellow oil. 1HNMR (400 MHz, CDCh) δ 8.73 (d, J= 2.4 Hz, IH), 8.07 (dd, J= 2.4, 8.8 Hz, IH), 7.79 (d, J= 12.4 Hz, IH), 6.59 (d, J= 8.8 Hz, IH), 5.66 (d, J= 12.4 Hz, IH), 4.31 -4.21 (m, 2H), 4.12 (q, J = 7.2 Hz, IH), 3.99 (d, J= 10.4 Hz, IH), 3.49 (s, IH), 3.24 - 2.97 (m, 8H), 1.67 1.52 (m, 2H), 1.49 (s, 9H), 0.90 (t, J= 7.2 Hz, 3H).

[001934] Step 3 - (±)-Tert-butyl 2-ethyl [5-(2-sulfanylpyrimidin yl)-2pyridyl1piperazine-l-carboxylate

[001935] To a solution of (±)-tert-butyl 4-[5-[(Z) (dimethylamino)prop enoyl]-2pyridyl] ethyl-piperazine carboxylate (7.70 g, 19.8 mmol) in ethanol (80 mL) was added thiourea (3.02 g, 39.6 mmol) and NaOMe (2.68 g, 49.6 mmol). The reaction mixture was stirred at 78 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (7.90 g, 99% yield) as a white solid. LC-MS (ESI+) m/z 401.9 (M+H)+.

[001936] Step 4 - (±)-Tert-butyl 2-ethyl [5-(2-methylsulfanylpyrimidin yl)-2pyridyl1piperazine-l- carboxylate

[001937] To a solution of (±)-tert-butyl 2-ethyl [5-(2-sulfanylpyrimidin yl)-2pyridyl]piperazine-l- carboxylate (7.90 g, 19.7 mmol) and iodomethane (11.2 g, 78.7 mmol) in THF (80 mL) was added NaOH (1 M, 29.5 mL). The reaction mixture was stirred at rt for 5 hours. On completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum etherethyl acetate = 5:1 to dichloromethane:methanol = 100:1) to give the title compound (7.70 g, 94% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.90 (d, J= 2.0 Hz, IH), 8.45 (d, J= 52 Hz, IH), 8.22 (dd, J= 2.4, 8.8 Hz, IH), 7.24 (d, J= 52 Hz, IH), 6.66 (d, 7= 8.8 Hz, IH), 4.31 (d, J= 13.2 Hz, IH), 4.25 (d, J= 11.6 Hz, IH), 4.18 - 4.08 (m, IH), 4.03 (s, IH), 3.25 (dd, 7=4.0, 13.2 Hz, IH), 3.21 -3.02(m, 2H), 2.63 (s, 3H), 1.70-1.64 (m, IH), 1.55 (dd, 7= 7.2, 14.4 Hz, IH), 1.50 (s, 9H), 0.91 (t, 7= 7.2 Hz, 3H).

[001938] Step 5 - (±)-Tert-butyl 2-ethyl [5-(2-methylsulfonylpyrimidin yl)-2pyridyl1piperazine-l- carboxylate

[001939] To a solution of (±)-tert-butyl 2-ethyl [5-(2-methylsulfanylpyrimidin yl)-2pyridyl]piperazine carboxylate (3.85 g, 9.26 mmol) in acetone (15.0 mL) was added H2O2 (5.90 g, 52.0 mmol) and disodium dioxide (dioxo) tungsten-dihydrate (306 mg, 926 umol). The reaction mixture was stirred at 40 °C for 12 hours. On completion, the reaction mixture was quenched with saturated Na2SO4 (20 mL) and extracted with di chloromethane (3 X 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 100:1) to give the title compound (4.00 g, 97% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 8.93 (d, J= 2.0 Hz, IH), 8.78 (d, J= 5.6 Hz, IH), 8.31 (dd, J = 2.4, 9.2 Hz, IH), 7.74 (d, J = 5.6 Hz, IH), 6.69 (d, J = 8.8 Hz, IH), 4.37 (d, J = 13.4 Hz, IH), 4.29 (d, J = 8.8 Hz, IH), 4.19 - 3.99 (m, 2H), 3.41 (s, 3H), 3.30 (dd, J= 3.6, 13.2 Hz, IH), 3.21 3.08 (m, 2H), 1.69 - 1.61 (m, IH), 1.53 (d, J= 7.2 Hz, IH), 1.50 (s, 9H), 0.92 (t, J= 7.2 Hz, 3H).

[001940] 4-[3-[(Tert-butoxvcarbonvlamino)methyl] [[2-[2-[tertbutoxvcarbonyl(2.,2.,2-trifluoroethvl)

1-yl] benzoic acid (Intermediate FI)

[001941] Step 1 - r4-Amino-l-(4-bromophenvl)pyrazol vl1methanol

[001942] To a solution of ethyl l-(4-bromophenyl) nitro-pyrazole carboxylate (3.70 g, 10.8 mmol, synthesized via Steps 1-2 of Intermediate CL) in THF (30.0 mL) was added LiBH4 (1.18 g, 54.3 mmol). The reaction mixture was stirred at 50 °C for 3 hrs under N2. On completion, the reaction mixture was quenched with water (100 mL), concentrated in vacuo to removed the THF, and filtered. The filtered cake was collected and dried under vaccuum to give the title compound (1.80 g, 61% yield) as yellow solid. 1HNMR (400MHz, DMSO-i/6) δ 7.72 (s, IH), 7.69 - 7.62 (m, 4H), 5.07-5.03 (m, IH), 4.51 (d, J = 5.6 Hz, 2H), 4.16 (s, 2H).

[001943] Step 2 - Methyl 4-r4-amino (hvdroxvmethvl)pyrazol-l-vl1benzoate

[001944] To a solution of [4-amino-l-(4-bromophenyl)pyrazol yl]methanol (1.60 g, 5.97 mmol) in a mixed solvent of DMF (30.0 mL) and MeOH (30.0 mL) was added Pd(dppf)C12.CH2C12 (487 mg, 596 umol) and TEA (1.81 g, 17.9 mmol, 2.49 mL) under N2. The suspension was degassed in vacuo and purged with CO several times. The mixture was stirred under CO (50 psi) at 80°C for 36 hours. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (0.1%, HCI) to give the title compound (800 mg, 54% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 8.62 (s, IH), 8.08 (d, J = 8.8 Hz, 2H), 8.03 - 7.93 (m, 2H), 4.63 (s, 2H), 3.87 (s, 3H).

[001945] Step 3 - Methyl 4-r4-rr2-r2-rtert-butoxvcarbonvl(2,2,2-trifluoroethyl)amino1-4Pvridvl1oxazole carbonvl1amino1 (hydroxymethyl)pyrazol-l-yl1benzoate

[001946] To a solution of methyl 4-[4-amino (hydroxymethyl)pyrazol-l-yl]benzoate (400 mg, 1.62 mmol) and 2-[2-[tertbutoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole-4carboxylic acid (626 mg, 1.62 mmol, Intermediate CM) in DMF (3.00 mL) was added DIPEA(418 mg, 3.24 mmol). The reaction mixture was stirred at 25 °C for 0.5 hr. Then, HATU (676 mg, 1.78 mmol) was added. The resulting reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was quenched with water (15 mL), and a white solid precipitation formed, which was filtered. The filter cake was dried in vacuo to give the title compound (920 mg, 92% yield) as white solid. 1HNMR (400MHz, DMSO-76) δ 9.08 (s, IH), 8.90 (s, IH), 8.66 (d, J = 52 Hz, IH), 8.10 - 8.04 (m, 2H), 8.02 - 7.96 (m, 2H), 7.73 - 7.70 (m, 2H), 7.83 - 7.75 (m, IH), 4.91 4.87 (m, 2H), 4.80 (d, J = 52 Hz, 2H), 3.87 (s, 3H), 1.53 (s, 9H).

[001947] Step 4 - Methyl 4-r3-(azidomethyl) rr2-r2-rtert-butoxvcarbonvl(2,2,2trifluoroethyl)amino1 pyridvl1oxazole carbonvl1amino1pyrazol-l-yl1benzoate

[001948] To a solution of methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] (hydroxymethyl)pyrazol-lyl]benzoate (500 mg, 810 umol) in THF (15.0 mL) was added DPPA (334 mg, 1.22 mmol) and DBU (308 mg, 2.03 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hr. On completion, the mixture was diluted with H2O (50 mL), then extracted with DCM (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (520 mg, 70% yield) as yellow solid. LC-MS (ESI+) m/z 642.3 (M+H)+.

[001949] Step 5 - Methyl 4-r3-r(tert-butoxvcarbonvlamino)methyl1 rr2-r2-[tertbutoxycarbonyl(2,2,2yllbenzoate

[001950] To a solution of methyl 4-[3-(azidomethyl) [[2-[2-[tert-butoxycarbonyl(2,2,2 trifluoroethyl)amino] pyridyl]oxazole carbonyl]amino]pyrazol-l-yl]benzoate (520 mg, 810 umol) and(Boc)2O (265 mg, 1.22 mmol) in MeOH (10.0 mL) was added Pd/C (100 mg, 810 umol). The mixture was stirred at 25 °C for 3 hrs under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (500 mg, 86% yield) as white solid. 1H NMR (400MHz, DMSO-/) δ 10.64 (s, IH), 9.05 (s, IH), 8.95 (s, IH), 8.64 (d, J = 5.2 Hz, IH), 8.35 (s, IH), 8.09 (s, IH), 8.07 (s, IH), 8.00 (s, IH), 7.98 (s, IH), 7.86 (d, J = 5.2 Hz, IH), 7.79 (s, IH), 4.91 (d, J = 8.8 Hz, 2H), 4.29 (d, 6.8 Hz, 2H), 3.88 (s, 3H), 1.52 (s, 9H), 1.36 (s, 9H).

[001951] Step 6:4-r3-r(Tert-butoxycarbonylamino)methyl1 IT2-r2-rtertbutoxycarbonyl(2,2,2-trifluoroethyl) vllbenzoic acid (8) - Notebook Page: EW7002-283

[001952] To a solution of methyl 4-[3-[(tert-butoxycarbonylamino)methyl] [[2-[2-[tertbutoxycarbonyl (2,2,2-trifluoroethyl)amino] pyridyl]oxazole carbonyl]amino]pyrazol-lyl]benzoate (160 mg, 223 umol) in a mixed solvent of THF (20.0 mL), H2O (5.00 mL) and MeOH (5.00 mL) was added LiOH (26.7 mg, 1.12 mmol). The mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was acidified with IN HCI solution until the pH = 5. The mixture was diluted with H2O (50 mL), and extracted with EA (3X30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (70.0 mg, 44% yield) as white solid. LC-MS (ESI+) m/z 702.4 (M+H)+.

[001953] 2- [2-[2- [2-(4-I0d0Dhen0xv)eth0xy] ethoxy] ethoxy] ethanamine (Intermediate

FJ)

AO

[001954] Step 1:Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-(4 i odophenoxy)ethoxy 1 ethoxy] ethoxy] ethyl 1 carb am ate

[001955] To a solution of 4-iodophenol (1 g, 4.55 mmol) and 2-[2-[2-[2-(tert butoxycarbonylamino)ethoxy] ethoxy]ethoxy]ethyl methanesulfonate (1.69 g, 4.55 mmol, Intermediate AO) in DMF (15 mL) was added K2CO3 (1.57 g, 11.3 mmol), and the reaction mixture was stirred at 100 °C for 12 hr. On completion, the mixture was diluted with H2O (30 mL), then extracted with EA(2 X 40 mL), and the organic phase was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.00 g, 44% yield) as yellow oil. LC-MS (ESI+) m/z 496.2 (M+H)+.

[001956] Step 2 - 2-r2-r2-r2-(4-Iodophenoxv)ethoxy]ethoxy]ethoxy]ethanamine

[001957] To a solution of tert-butyl N-[2-[2-[2-[2-(4iodophenoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (0.9 g, 1.82 mmol) in DCM (2 mL) was added HCl/dixoane (4 M, 2.00 mL), and the reaction mixture was stirred at 20 °C for 20 mins. On completion, the residue was concentrated in vacuo to give the title compound (800 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 396.1 (M + 1)+.

[001958] 2-[2-[2-[[2-(2.,6-Dioxo DiDeridvl)-l.,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] acetaldehyde (Intermediate FK)

FK

[001959] Step 1:2-(2,6-Dioxo piperidyl) [2-r2-(2hydroxyethoxy)ethoxy]ethylamino]isoindoline-L3- di one

[001960] To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (1.80 g, 12.0 mmol, CAS# 6338 2) and 2-(2,6-dioxo piperidyl) fluoroisoindoline-l,3-dione (4.00 g, 14.4 mmol, Intermediate R) in dioxane (35.0 mL) was added DIPEA(9.36 g, 72.3 mmol). The reaction mixture was stirred at 115 °C for 20 hrs. On completion, the mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (2.90 g, 59% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 8.28 (s, IH), 7.50 (dd, J = &#906;.2, 8.4 Hz, IH), 7.11 (d, J = 22 Hz, IH), 6.91 (d, J = 8.4 Hz, IH), 6.57 (t, J = 5.2 Hz, IH), 4.96 - 4.85 (m, IH), 3.77 - 3.67 (m, 8H), 3.64 - 3.59 (m, 2H), 3.48 (q, J= 52 Hz, 2H), 2.92 2.70 (m, 3H), 2.62 (s, IH), 2.17 - 2.08 (m, IH).

[001961] Step 2 - 2-r2-r2-rr2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin-4yl1amino1ethoxv1ethoxy1 acetaldehyde (11) - Notebook Page: EW7002-288

[001962] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-(2hydroxyethoxy)ethoxy]ethylamino]isoindoline- 1,3-dione (200 mg, 493 umol) in DCM (10.0 mL) was added DMP (209 mg, 493 umol). The mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was diluted with DCM (30 mL), and extracted with saturated Na2S2O3 (2 X 30 mL) and saturated NaHCO3 (2 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (140 mg, 70% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 9.74 (s, IH), 8.15 (s, IH), 7.52 (t, J = 2.6 Hz, IH), 7.14 (d, J = 7.2 Hz, IH), 6.97 - 6.90 (m, IH), 6.57 - 6.49 (m, IH), 4.97 - 4.89 (m, IH), 3.83 - 3.65 (m, 10H), 2.17 2.11 (m, IH), 1.91 - 1.87 (m, IH), 1.87 - 1.83 (m, IH), 1.31 - 1.03 (m, IH).

[001963] Tert-butyl 5-(45,.5,.4&#1524;-tetramethyl-l.,3.,2-dioxaborolan yl)isoindoline-2carboxylate (Intermediate FL)

FL

[001964] To a solution of tert-butyl 5-bromoisoindoline carboxylate (1.20 g, 4.02 mmol, CAS# 201940 1), 4,4,5,5-tetramethyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)-l,3,2dioxaborolane (1.12 g, 4.43 mmol) in DMSO (20.0 mL) was added KO Ac (1.18 g, 12.0 mmol) and Pd(PPh3)4 (139 mg, 120 umol). The mixture was stirred at 80 °C for 16 hours under N2. On completion, the mixture was diluted with H2O (50 mL), and extracted with EA (3 X 30 mL). The organic layers were washed with brine (3 X 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by prep-HPLC (reserve phase (0.1% FA)) to give the title compound (500 mg, 36% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 7.75 (s, IH), 7.32 - 7.29 (m, IH), 7.25 (d, J =2.6 Hz, IH), 4.74 - 4.66 (m, 4H), 1.54 (s, 9H), 1.37 (s, 12H).

[001965] Tert-butyl 5-[4-amino (trifluoromethyl)Dyrazol-l-yl]isoindoline-2carboxylate (Intermediate FM)

FL

FM

[001966] Step 1 - (2-Tert-butoxycarbonylisoindolin yl)boronic acid

[001967] To a solution of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)isoindoline carboxylate (500 mg, 1.45 mmol, Intermediate FL) in a mixed solvent of THF (20.0 mL) and H2O (4.00 mL) was added NaIO4 (929 mg, 4.34 mmol). The mixture was stirred at 25°C for 0.5 hr. HCI (3 M, 965 uL) was added to the mixture; and the mixture was stirred at 25°C for 1.5 hrs. On completion, the mixture was diluted with H2O (30 mL), and extracted with EA (3 X 30 mL). The organic layers were washed with brine (3 X 20 mL), the organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by prepHPLC (reverse phase (0.1% FA)) to give the title compound (260 mg, 68% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 8.05 (s, 2H), 7.72 (s, IH), 7.70 (s, IH), 7.29 (t, J = 6.4 Hz, IH), 4.64 - 4.53 (m, 4H), 1.46 (s, 9H).

[001968] Step 2 - Tert-butyl 5-r4-nitro (trifluoromethyl)pyrazol-l-yl1isoindoline-2carboxylate

[001969] To a solution of 4-nitro (trifluoromethyl)-lH-pyrazole (378 mg, 2.09 mmol, synthesized via Step 1 of Intermediate DE), (2-tert-butoxycarbonyl isoindolin yl)boronic acid (660 mg, 2.51 mmol) in DCM (20.0 mL) was added Cu(OAc)2 (569 mg, 3.14 mmol) and pyridine (661 mg, 8.36 mmol). The mixture was stirred at 25°C for 12 hrs under 02 (15 psi). On completion, the mixture was concentrated in vacuo then washed with ΝΗ3&#905;2Ο (5 mL), filtered and the solid was dried in vacuo. The mixture was triturated again with MeOH (5 mL), then filtered and the solid was dried in vacuo to give the title compound (400 mg, 48% yield) as white solid. 1H NMR (400MHz, DMSO-t/6) δ 9.86 (d, J = 6.8 Hz, IH), 7.93 (d, J = 12.8 Hz, IH), 7.90 - 7.85 (m, IH),

7.59 - 7.52 (m, IH), 4.71 - 4.60 (m, 4H), 1.47 (s, 9H).

[001970] Step 3 - Tert-butyl 5-r4-amino (trifluoromethyl)pyrazol-l-yl1isoindoline-2carboxylate (7) - Notebook Page: EW7002-281

[001971] To a solution of tert-butyl 5-[4-nitro (trifluoromethyl)pyrazol-l-yl]isoindoline-2carboxylate (260 mg, 652 umol) in a mixed solvent of DCM (10.0 mL) and MeOH (10.0 mL) was added Pd/C (50.0 mg). Then the reaction mixture was stirred at 25°C for 16 hrs under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (240 mg, 80% yield) as white solid. LC-MS (ESI+) m/z 369.2 (M+H)+.

[001972] 4-(4-Aminobutvlamino) (2,6-dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate

[001973] Step 1 - Tert-butyl N-r4-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1amin01butyl1carbamate

[001974] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (1.50 g, 5.43 mmol, Intermediate R) and tert-butyl N-(4-aminobutyl)carbamate (1.02 g, 5.43 mmol, CAS# 33545 1) in dioxane (15 mL) was added DIPEA (2.81 g, 23 mmol). The reaction mixture was stirred at 115 °C for 24 hours. On completion, the mixture was concentrated in vacuo to remove the solvent. The residue was purified by silica gel chromatography to give the title compound (0.96 g, 40% yield) as a yellow solid. LC-MS (ESI+) m/z 445.2 (M+H)+.

[001975] Step 2 - 4-(4-Aminobutylamino) (2,6-dioxo piperidyl)isoindoline-L3-dione [001976] To a solution of tert-butyl N-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]butyl] carbamate (0.96 g, 2.16 mmol) in DCM (5 mL) was added HCl/dioxane (4 M, 10 mL). The reaction mixture was stirred at 25 °C for 3 hours. On completion, the mixture was concentrated in vacuo to give the title compound (0.82 g, 100% yield, HCI) as a yellow solid. The crude product was used for the next step directly without further purification. LC-MS (ESI+) m/z 345.1 (M+H)+.

[001977] Tert-butyl N-(3-oxopropyl)carbamate (Intermediate FO) oxalyl dichloride, DMSO

HO NHBoc ----------------&#9658; O^^^ NHBoc

TEA, DCM FO

[001978] To a solution of DMSO (2.23 g, 28.53 mmol, 2.23 mL, 2.5 eq) in DCM (15 mL) was added a solution of (COC1)2 (2.90 g, 22.8 mmol) in DCM (10 mL) dropwise at -70°C. The mixture was stirred at -70°C for 10 minutes. Then a solution of tert-butyl N-(3hydroxypropyl)carbamate (2.00 g, 11.4 mmol, CAS# 58885 8) in DCM (15 mL) was added into the above mixture slowly. After stirred at -70°C for 50 minutes, TEA (6.93 g, 68.5 mmol) was added and the reaction mixture was stirred at -70°C for 0.5 hour. On completion, the mixture was quenched with water (30 mL) and separated. The aqueous phase was extracted with DCM (2X30 mL). Then the organic phase was combined and washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (1.70 g, 86% yield) as yellow oil. The residue was used for the next step directly without further purification. 1H NMR (400MHz, CDCh) δ 9.80 (s, IH), 5.01 -4.87 (m, IH), 3.41 (q, J =6.0 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 1.42 (s, 9H).

[001979] 4-[4-(3-Aminopropvlamino)butvlamino] (2,6-dioxo piperidyl)isoindoline1.,3-dione (Intermediate FP)

[001980] Step 1 - Tert-butyl Ν-Γ3-Γ4-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-1 J-dioxo-isoindolin-4yl1amin01butylamin01 propyllcarbamate

[001981] To a solution of tert-butyl N-(3-oxopropyl)carbamate (0.10 g, 577 umol, Intermediate FO) and 4-(4-aminobutylamino) (2,6-dioxo piperidyl)isoindoline-l,3-dione (264 mg, 693 umol, HCI, Intermediate FN) in THF (20 mL) was added KO Ac (113 mg, 1.15 mmol). One hour later, NaBH(OAc)3 (245 mg, 1.15 mmol) was added into the above mixture. The reaction mixture was stirred at 25°C for 72 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% HCI condition) to give the title compound (60.0 mg, 21% yield) as a yellow solid. LC-MS (ESI+) m/z 502.1 (M+H)+.

[001982] Step 2:4-r4-(3-Aminopropylamino)butylamino1 (2,6-di oxo-3piperidyl)isoindoline-L3-dione

[001983] To a solution of tert-butyl N-[3-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] butylamino]propyl]carbamate (60.0 mg, 120 umol) in DCM (2 mL) was added HCl/dioxane (4 mL). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (50.0 mg, 95% yield, HCI) as a yellow solid. The residue was used for the next step directly without further purification. LC-MS (ESI+) m/z 402.1 (M+H)+.

[001984] Tert-butyl N-[3-[4-(amin0methyl)imidaz01-l-vl]Dr0Dvl]carbamate (Intermediate FQ)

NHB0C

FQ

[001985] Step 1 - Methyl lH-imidazole carboxylate

[001986] To a mixture of lH-imidazole carboxylic acid (5.00 g, 44.6 mmol, CAS# 107284-0) in MeOH (50 mL) was added S0C12 (10.6 g, 89.2 mmol, 6.47 mL). The reaction mixture was stirred at 70 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (5.60 g, 99% yield) as white solid. The residue was used to the next step directly without further purification. 1H NMR (400MHz, DMSO-c#) δ 9.29 - 9.25 (m, IH), 8.37 (s, IH), 3.87 (s, 3H).

[001987] Step 2 - Methyl l-r3-(tert-butoxycarbonylamino)propyl1imidazole carboxylate [001988] To a mixture of methyl lH-imidazole carboxylate (3.10 g, 24.5 mmol) in ACN (50 mL) was added K2CO3 (11.2 g, 81.1 mmol) and tert-butyl N-(3-bromopropyl)carbamate (11.7 g, 49.1 mmol, CAS# 83948 2). The reaction mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA=5:1) to give the title compound (4.00 g, 57% yield) as colourless oil. 1H NMR (400MHz, DMSO4) δ 8.02 (s, IH), 7.83 (s, IH), 7.00 (s, IH), 4.10 - 4.08 (m, 2H), 3.80 (s, 3H), 2.99 - 2.88 (m, 2H), 1.90 - 1.88 (m, 2H), 1.45 (s, 9H).

[001989] Step 3 - Tert-butyl N-r3-r4-(hydroxymethyl)imidazol-l-yl1propyl1carbamate

[001990] To a mixture of methyl l-[3-(tert-butoxycarbonylamino)propyl]imidazole-4carboxylate (3.00 g, 10.5 mmol) in THF (50 mL) was added LiAlH4 (602 mg, 15.8 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was quenched with water (3 mL) and NaOH solution (15 %, 5 mL) at 0 °C, then Na2SO4 (20 g) was added. Then the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.50 g, 92% yield) as colourless oil. The residue was used to the next step directly without further purification. LC-MS (ESI+) m/z 256.2 (M+H) +.

[001991] Step 4 - Tert-butyl N-r3-r4-(azidomethyl)imidazol-l-yl1propyl1carbamate (6) Notebook Page: EW5435-653

[001992] To a mixture of tert-butyl N-[3-[4-(hydroxymethyl)imidazol-lyl]propyl]carbamate (1.00 g, 3.92 mmol) andDPPA(1.62 g, 5.88 mmol, 1.27 mL) in THF (20 mL) was added DBU (1.49 g, 9.79 mmol, 1.48 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EA (3X10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.10 g, 100% yield) as light yellow oil. The residue was used to the next step directly without further purification. LC-MS (ESI+) m/z 281.3 (M+H) +

[001993] Step 5 - Tert-butyl N-r3-r4-(aminomethyl)imidazol-l-yl1propyl1carbamate

[001994] To a mixture of tert-butyl N-[3-[4-(azidomethyl)imidazol-l-yl]propyl]carbamate (1.10 g, 3.92 mmol) in MeOH (50 mL) was added Pd/C (500 mg, 10 wt %). The reaction mixture was stirred at 25 °C for 3 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (950 mg, 95% yield) as light yellow oil. The residue was used in the next step directly without further purification. LC-MS (ESC) mz 255.3 (M+H)+.

[001995] 4 |2- [2-(Aminomethyl)-l-piperidvl] ethoxy] ethylamino] (2.,6-dioxo-3piperidylliso indoline-l.,3-dione (Intermediate FR)

FR

[001996] Step 1- Tert-butyl N-rr1-r2-r2-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yllaminolethoxy] ethyl1 piperidyl1methyl1carbamate

[001997] To a solution of 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethyl methanesulfonate (500 mg, 1.14 mmol, synthesized via Steps 1-2 of Example 184) in CH3CN (20 mL) was added tert-butyl N-(2-piperidylmethyl) carbamate (488 mg, 2.28 mmol, CAS# 141774 0), NaHCO3 (287 mg, 3.41 mmol) and KI (18.9 mg, 114 umol). The mixture was stirred at 80 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed phase flash to give the title compound (450 mg, 71% yield) as yellow solid. LC-MS (ESI+) m/z 558.4 (M+H)+.

[001998] Step 2 - 4-r2-r2-r2-(Aminomethvl)-l-piperidvl1ethoxv1ethvlamino1 (2,6-dioxo3-piperidyl)iso indoline-L3-dione

[001999] To a solution of tert-butyl N-[[l-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethyl] piperidyl]methyl]carbamate (450 mg, 807 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (360 mg, 91% yield) as yellow solid. LC-MS (ESI+) m/z 458.3 (M+H)+.

[002000] 4-[2-[2-(2-Aminoethoxv)ethvlamino]ethvlamino] (2,6-dioxo-3DiDeridyl)isoindoline-l,3 -dione (Intermediate FS)

HO'

NHBoc oxalyl dichloride, DMSO

KOAc, NaBH(OAc)3, THF

TEA, DCM

FS

[002001] Step 1 - Tert-butyl N-[2-(2-oxoethoxy)ethyl1carbamate

[002002] To a solution of DMSO (1.90 g, 24.4 mmol) in DCM (10 mL) was added a solution of (COC1)2 (2.47 g, 19.5 mmol) in DCM (10 mL) dropwise at -70 °C. The mixture was stirred at this temperature for 10 minutes. Then a solution of tert-butyl N-[2-(2hydroxyethoxy)ethyl]carbamate (2 g, 9.74 mmol, CAS# 139115 6) in DCM (15 mL) was added into the above mixture slowly. After stirring at -70°C for 50 minutes, TEA (7.89 g, 78.0 mmol) was added and the reaction mixture was stirred at -70°C for 0.5 hour. On completion, the mixture was quenched with water (30 mL) and separated. The aqueous phase was extracted with DCM (2 X 30 mL). Then the organic phase was combined and washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (1.30 g, crude) as yellow oil.

[002003] Step 2 - Tert-butyl N-r2-r2-r2-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yllaminolethyl aminolethoxylethyllcarbamate

[002004] To a solution of 4-(2-aminoethylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (202 mg, 572 umol, HC1, Intermediate DJ) and tert-butyl N-[2-(2oxoethoxy)ethyl]carbamate (90.0 mg, 443 umol) in THF (20 mL) was added KOAc (102 mg, 1.04 mmol). One hour later, NaBH(OAc)3 (220 mg, 1.04 mmol) was added into the above mixture. The reaction mixture was stirred at 25 °C for 17 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% HC1 condition) to give the title compound (80.0 mg, 31% yield) as a yellow solid. LC-MS (ESI+) m/z 504.1 (M+H)+.

[002005] Step 3 - 4-[2-[2-(2-Aminoethoxy)ethylamino1ethylamino1 (2,6-dioxo-3piperidyl)isoindoline-L3 -dione

[002006] To a solution of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethylamino]ethoxy]ethyl]carbamate (75.0 mg, 149 umol) in DCM (2 mL) was added HCl/dioxane (2 mL). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (65.0 mg, 99% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 404.1 (M+H)+.

[002007] 4-Bromo (2.,6-dioxo DiDeridvl)isoindoline-l.,3-dione (Intermediate FT)

FT

[002008] Step 1 - 4-Bromoisobenzofuran-L3-dione

[002009] A solution of 3-bromophthalic acid (5.00 g, 20.4 mmol, CAS# 116 8) in (Ac)2O (20.4 mmol, 20 mL) was stirred at 120 °C for 12 hours. The reaction mixture was then stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give the title compound (4.60 g, 99% yield) as yellow solid. LC-MS (ESI+) m/z 227.1 (M+H)+.

[002010] Step 2 - 4-Bromo (2,6-dioxo piperidyl)isoindoline-L3-dione

[002011] To a solution of 4-bromoisobenzofuran-l,3-dione (4.60 g, 20.2 mmol) and 3aminopiperidine-2,6- dione (3.67 g, 22.2 mmol, HCI, CAS# 24666 6) in HOAc (40 mL) was added KO Ac (6.16 g, 62.8 mmol), the reaction mixture was stirred at 90 °C for 16 hr. On completion, the mixture was cooled to 25 °C and diluted with ice water (800 mL), and then stirred at 0 °C for 0.5 hr. The reaction mixture was filtered and the filter cake was dried in vacuo to give the title compound (6.8 g, 99% yield) as gray solid. 1H NMR (400MHz, DMSO-6/6) δ 11.17 (s, IH), 8.19 - 7.65 (m, 3H), 5.41 - 4.91 (m, IH), 3.35 (s, IH), 3.05 - 2.85 (m, IH), 2.72 - 2.54 (m, , 2H), 2.09 (s, IH).

[002012] 4-(3-Amin0Dr0Dvl) (2.,6-di0x0 DiDeridvl)is0ind01ine-l.,3-di0ne (Intermediate FU)

[002013] Step 1 - Tert-butyl N-r3-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yl1prop ynyl1carbamate

[002014] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.00 g, 2.97 mmol, Intermediate FT) and tert-butyl N-prop ynylcarbamate (598 mg, 3.86 mmol, CAS# 92136 5) in DMF (6 mL) was added TEA (5.40 g, 53.3 mmol, 7.43 mL), Cui (56.4 mg, 296 umol) and Pd(PPh3)2C12 (208 mg, 296 umol). The reaction mixture was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.20 g, 98% yield) as yellow solid. LC-MS (ESI+) m/z 434.0 (M+Na)+.

[002015] Step 2 - Tert-butyl N-r3-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yUpropyl] carbamate

[002016] To a mixture of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]prop ynyl] carbamate (520 mg, 1.26 mmol) in THF (20 mL) was added Pd(OH)2/C (150 g, 10 wt %) and Pd/C (130 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (0.52 g, 99% yield) as light yellow solid. LC-MS (ESI+) m/z 438.3 (M+Na)+.

[002017] Step 3 - 4-(3-Aminopropyl) (2,6-dioxo piperidyl)isoindoline-L3-dione

[002018] To a mixture of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]propyl]carbamate (520 mg, 1.25 mmol) in DCM (3 mL) was added HCl/dioxane (4 M, 3 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (520 mg, 99% yield, HCI) as light yellow solid. LC-MS (ESI+) m/z 316.1 (M+H) + .

[002019] 4 (5-Amin0Dentvlamin0)Dr0Dvl] (2,6-di0x0 DiDeridyl)is0ind01ine-l,3dione (Intermediate FV)

[002020] Step 1 - Tert-butyl N-r5-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1propylamino1pentyl1 carbamate

[002021] To a mixture of 4-(3-aminopropyl) (2,6-dioxo piperidyl)isoindoline-l,3-dione (445 mg, 1.27 mmol, HCI, Intermediate FU) in THF (5 mL) was added TEA (85.4 mg, 844 umol, 117 uL) and tert-butyl N-(5-oxopentyl)carbamate (170 mg, 844 umol, Intermediate EK) and HO Ac (76.0 mg, 1.27 mmol, 72.4 uL), then NaBH(OAc)3 (358 mg, 1.69 mmol) was added. The reaction mixture was stirred at 25 °C for 5 hours under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (200 mg, 47% yield) as light yellow oil. LC-MS (ESI+) m/z 501.4 (M+H)+.

[002022] Step 2 - 4-r3-(5-Aminopentylamino)propyl1 (2,6-dioxo piperidyl)isoindolineL 3 -di one

[002023] To a mixture of tert-butyl N-[5-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]propylamino] pentyl]carbamate (170 mg, 339 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 8 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (170 mg, 99% yield) as light yellow solid. LC-MS (ESI+) m/z 401.2 (M+H)+.

[002024] Methyl 4-[4-amino (difluoromethyl)Dvrazol-l-vl]benzoate (Intermediate

FW)

[002025] Step 1 - Methyl 4-[4-(benzhydrylideneamino) (difluoromethyl)pyrazol-l yllbenzoate

[002026] Amixture of methyl 4-[4-bromo (difluoromethyl)pyrazol-l-yl]benzoate (0.15 g,

453 umol, synthesized via Steps 1-2 of Intermediate EB), diphenylmethanimine (205 mg, 1.13 mmol), Pd(OAc)2 (20.8 mg, 92.4 umol), Xantphos (26.2 mg, 45.3 umol) and Cs2CO3 (448 mg,

1.38 mmol) in dioxane (3 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 3 hrs under N2 atmosphere. On completion, the mixture was concentrated, then H2O (30 mL) was added and the mixture was extracted with EtOAc (3X30 mL). The organic phase was dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (0.24 g, 50% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.02 - 7.95 (m, 2H), 7.80 - 7.73 (m, 2H), 7.51 - 7.45 (m, 3H), 7.43 - 7.31 (m, 5H), 7.22 - 7.19 (m, 2H), 7.12 - 6.82 (m, IH), 6.37 (s, IH), 3.85 (s, 3H); LC-MS (ESI+) m/z 432.1 (M+H)+.

[002027] Step 2 - Methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl1benzoate

[002028] To a solution of methyl 4-[4-(benzhydrylideneamino) (difluoromethyl)pyrazoll-yl]benzoate (215 mg, 498 umol) in THF (2 mL) and MeOH (20 mL) was added HCI/MeOH (4 M, 124 uL). The mixture was stirred at 25 °C for 30 min. On completion, the mixture was concentrated to give the title compound (0.20 g, 90% yield) as a yellow solid. LC-MS (ESI+) m/z

268.1 (M+H)+.

[002029] 4-[4-[[2-[2-(Cvclopropvlmethvlamino) pvridvl]oxazole carbonyl]amino]3-(difluoro methyl)pvrazol-l-yl]benzoic acid (Intermediate FX)

FW

[002030] Step 1 - Methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino1-4pyridyl1oxazole carbonyl1amino1 (difluoromethyl)pyrazol-l-yl1benzoate

[002031] A mixture of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (340 mg, 1.27 mmol, Intermediate FW), 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylic acid (412 mg, 1.15 mmol, from Steps 1-4 of Intermediate DF), HATU (484 mg, 1.27 mmol), DIPEA(411 mg, 3.18 mmol, 554 uL) in DMF (10 mL) was degassed and purged with N2 3 times. Then the mixture was stirred at 25 °C for 6 hrs. On completion, the mixture was diluted with 50 mL H2O and then filtered. The filter cake was dried in vacuo to give the title compound (260 mg, 27% yield) as a yellow solid. LC-MS (ESI+) m/z 609.2 (M+H)+.

[002032] Step 2 - 4-[4-[[2-[2-(Cyclopropylmethylamino) pyridyl1oxazole-4carbonyl1amino1 (difluoro methyl)pyrazol-l-yl1benzoic acid

[002033] To a solution of methyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl] oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]benzoate (200 mg, 329 umol) in THF (5 mL) and H2O (5 mL) and MeOH (1 mL) was added LiOH (39.4 mg, 1.64 mmol). The mixture was stirred at 25 °C for 6 hrs. On completion, the mixture was concentrated, the residue was diluted with H2O (50 mL) and added

IM HCI to pH = 5-6, extracted with EA (3 X 30 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (0.13 g, 95% yield) as a yellow solid. LC-MS (ESI+) m/z 595.4 (M+H)+.

[002034] Tert-butyl N-methyl-N- [2-(2-Dr0D yn0xyeth0xy)ethyl] carbamate (Intermediate FY)

A n&#1524;n 0 h0-x++n+ EtO''^’&#1470; Η O LiAIH4, THFBoc

Λ EtO'''^' '&#1470;'&#1470;'&#1470;'''Ν''' &#9658; HO. ++10&#1524;

Boc Rh(OAc)2, DCMO

BrBoc

KOH, KI, TBAI, THF°

FY

[002035] Step 1 - Ethyl 2-r2-rtert-butoxvcarbonvl(methyl)amino1ethoxy1acetate

[002036] To a solution of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (10 g, 57.0 mmol) and Rh(OAc)2 (630 mg, 2.85 mmol) in DCM (100 mL) was added a solution of ethyl 2diazoacetate (13.0 g, 114 mmol, CAS# 623 4) in DCM (200 mL) dropwise, and the mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was washed with water (50 mL X 4), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (14.5 g, 97% yield) as light yellow liquid. 1H NMR (400MHz, CDCh) δ 4.21 (q, J= 7.2 Hz, 2H), 4.09 4.04 (m, 2H), 3.71 - 3.59 (m, 2H), 3.46 - 3.38 (m, 2H), 2.92 (s, 3H), 1.44 (s, 9H), 1.27 (t, J = 7.2 Hz, 3H).

[002037] Step 2 - Tert-butyl N-r2-(2-hydroxyethoxy)ethyl1-N-methyl-carbamate

[002038] To a solution of ethyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]acetate (12.4 g, 47.4 mmol) in THF (200 mL) was added LiAlH4 (2.76 g, 71.1 mmol, 98% purity) at 0 °C under N2 atmosphere. The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was quenched with water (4 mL) and NaOH aqueous solution (15%, 4 mL) at 0 °C, filtered and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (9.40 g, 90% yield) as colorless liquid. 1H NMR (400MHz, CDCh) δ 3.72 - 3.67 (m, 2H), 3.66 - 3.54 (m, 4H), 3.50-3.42 (m, 2H), 2.91 (s, 3H), 1.46 (s, 9H).

[002039] Step 3 - Tert-butyl N-methyl-N-r2-(2-prop ynoxyethoxy)ethyl1carbamate [002040] To a solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (8.70 g, 39.6 mmol) and 3-bromoprop yne (5.19 g, 43.6 mmol) in THF (100 mL) was added

TBAI (879 mg, 2.38 mmol), KI (987 mg, 5.95 mmol) and KOH (2.62 g, 39.6 mmol, 85%). The mixture was stirred at 20 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA=3:1) to give the title compound (4.20 g, 41% yield) as colorless oil. 1HNMR (400MHz, CDCh) δ 4.21 (d, J = 2.4 Hz, 2H), 3.72 - 3.67 (m, 2H), 3.67 - 3.62 (m, 2H), 3.61 - 3.55 (m, 2H), 3.45 - 3.35 (m, 2H), 2.92 (s, 3H), 2.43 (t, J = 2.4 Hz, IH), 1.46 (s, 9H).

[002041] 2-(2,6-Dioxo DiDeridvD [3- [2- [2(methvlamino)ethoxv]ethoxy]DroDvl]isoindoline-l.,3- dione (Intermediate FZ)

FZ

[002042] Step 1 - Tert-butyl N-r2-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl]prop ynoxy] ethoxy]ethyl]-N-methyl-carbamate

[002043] 4-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (0.60 g, 1.78 mmol,

Intermediate FT), Cui (33.9 mg, 178 umol) and Pd(PPh3)2C12 (125 mg, 178 umol) was taken up into a microwave tube. Then tert-butyl N-methyl-N-[2-(2-prop ynoxyethoxy)ethyl]carbamate (458 mg, 1.78 mmol, Intermediate FY), TEA (3.24 g, 32.0 mmol) and DMF (5 mL) were added into the above tube. The mixture was degassed with N2 for 5 minutes. The sealed tube was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (460 mg, 43% yield, 85% purity) as yellow oil. LC-MS (ESI+) m/z 536.3 (M+Na)+.

[002044] Step 2 - Tert-butyl N-r2-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4 yllpropoxylethoxyl ethyl1-N-methyl-carbamate

[002045] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]prop ynoxy]ethoxy]ethyl]-N-methyl-carbamate (460 mg, 761 umol) in THF (5 mL) was added Pd/C (0.2 g, 10% wt) and Pd(OH)2/C (0.2 g, 10% wt). The reaction mixture was stirred at 25 °C for 18 hrs under H2 (15 Psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (450 mg, 100% yield) as yellow oil. LC-MS (ESF)&#1524;/z 540.1 (M+Na)+.

[002046] Step 3:2-(2,6-Dioxo piperidvl) [3-r2-r2(methylamino)ethoxy1ethoxy1propyl1isoindoline-L3- dione

[002047] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]propoxy] ethoxy]ethyl]-N-methyl-carbamate (450 mg, 869 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 4 mL). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was concentrated in vacuo to give the title compound (330 mg, 84% yield, HCI) as yellow oil. LC-MS (ESI+) m/z 418.1 (M+H)+.

[002048] 5-Bromo (2,6-dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate GA) o

GA

[002049] To a solution of 3-aminopiperidine-2,6-dione (7.98 g, 48.4 mmol, HCI salt, CAS# 24666 6), KOAc (13.4 g, 136 mmol) in HOAc (200 mL) was added 5-bromoisobenzofuran1,3-dione (10.0 g, 44.0 mmol, CAS# 282 5). The mixture was then heated to 90 °C and stirred for 12 hours. On completion, the mixture was cooled down to 25°C and diluted with water (800 mL), and then filtered to give a filter cake. The filter cake was stirred in DCM (20 mL) for 1 hour and filtered to give a filter cake. The filter cake was dried in vacuo to give the title compound (9.00 g, 60% yield) as a blue solid. 1HNMR (400MHz, DMSO-75) δ 11.15 (s, IH), 8.15 (d, J = 1.2 Hz, IH), 8.10 (dd, 7= 1.6, 8.0 Hz, IH), 7.87 (d, 7= 8.0 Hz, IH), 5.17 (dd, J= 5.6, 12.8 Hz, IH), 2.95 - 2.83 (m, IH), 2.65 - 2.52 (m, 2H), 2.11 - 2.00 (m, IH).

[002050] 4-Amino-l-[4-(hvdroxvmethyl)Dhenvl]Dvrazole carboxamide (Intermediate GB)

[002051]

[002052]

Cu(OAc)2, Py, O2, DCM

ΝΗ3.Η2Ο sealed tube

Step 1 - Methyl l-r4-(hydroxymethyl)phenyl1 nitro-pyrazole carboxylate

To a mixture of methyl 4-nitro-lH-pyrazole carboxylate (8.00 g, 38.5 mmol, HC1 salt, Intermediate HL), [4-(hydroxymethyl)phenyl]boronic acid (7.03 g, 46.2 mmol, CAS# 5901693-2) and pyridine (18.2 g, 231 mmol) in DCM (130 mL) was added Cu(OAc)2 (8.40 g, 46.2 mmol). The mixture was stirred at 25 °C under 02 (15 psi) for 16 hours. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (4.00 g, 36% yield) as white solid. 1H NMR (400MHz, DMSO-d6) δ 9.68 (s, IH), 7.89 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.8 Hz, 2H), 5.37 (t, J = 5.6 Hz, IH), 4.57 (d, J= 5.6 Hz, 2H), 3.94 (s, 3H); LC-MS (ESI+) m/z 300.0 (M+Na)+.

[002053] Step 2 - l-[4-(Hvdroxvm ethyl )phenyl] nitro-pyrazole carboxamide

[002054] To a solution of methyl l-[4-(hydroxymethyl)phenyl] nitro-pyrazole-3carboxylate (2.30 g, 7.72 mmol) in THF (15 mL) was added NH3*H2O (22.7 g, 194 mmol, 30% w/w) in a sealed tube. The mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (2.20 g, 97% yield) as yellow solid. 1H NMR (400MHz, DMSO-d6) δ 9.60 (s, IH), 8.19 (s, IH), 7.90 (d, J = 8.4 Hz, 3H), 7.50 (d, J= 8.4 Hz, 2H), 5.37 (s, IH), 4.56 (d, J= 2.4 Hz, 2H).

[002055] Step 3 - 4-Amino [4-(hydroxymethyl)phenyl1pyrazole carboxamide

[002056] To a solution of l-[4-(hydroxymethyl)phenyl] nitro-pyrazole carboxamide (1.60 g, 6.10 mmol) in MeOH (120 mL) was added Pd/C (0.8 g, 10% w/w) under N2. The suspension was degassed in vacuo and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 20 °C for 40 minutes. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.40 g, 91% yield) as yellow solid; LC-MS (ESI+) m/z 233.1 (M+H)+.

[002057] Tert-butyl

N-[4-[4-[[3-carbamovl-l-(4-formylDhenvl)Dvrazol-4yl] carbamoyl] oxazol yl] Dvridvl]-N-(cvcl0Dr0Dvlmethyl)carbamate (Intermediate GC)

GC

[002058] Step 1 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-r4-(hydroxymethyl)phenyl1pyrazol-4yl1carbamoyl1 oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[002059] To a solution of 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylic acid (1.24 g, 3.44 mmol, from Steps 1-4 of Intermediate DF) in DMF (25 mL) was added DIPEA (1.67 g, 12.9 mmol), HATU (1.96 g, 5.17 mmol) and 4-amino-l-[4(hydroxymethyl)phenyl]pyrazole carboxamide (1.00 g, 4.31 mmol, Intermediate GB). The mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was diluted with water (80 mL), fdtered to give a fdter cake which was dried in vacuo to give the title compound (1.50 g, 60% yield) as brown solid. LC-MS (ESI+) m/z 574.1 (M+H)+.

[002060] Step 2 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-(4-formylphenyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[002061] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4(hydroxymethyl)phenyl]pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (1.5 g, 2.62 mmol) in a THF (300 mL) was added DMP (1.22 g, 2.88 mmol), and the mixture was stirred at 20 °C for 16 hours. On completion, the reaction mixture was quenched with saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL) at 25°C. This reaction mixture was then stirred for 30 minutes, then extracted with CH2C12 (80 mL X 3). The combined organic layers were fdtered and concentrated in vacuo to give the title compound (1 g,

67% yield) as gray solid. 1H NMR (400MHz, DMSO-76) δ 11.04 (s, IH), 10.04 (s, IH), 9.09 (s, 2H), 8.60 (d, J= 52 Hz, IH), 8.25 - 8.23 (m, 3H), 8.17 (s, IH), 8.07 (d, J= 8.4 Hz, 2H), 7.81 (br s, IH), 7.67 (d, J= 4.8 Hz, IH), 3.86 (br d, 7=7.2 Hz, 2H), 1.52 (s, 9H), 1.20-1.16 (m, IH), 0.46 - 0.35 (m, 2H), 0.25 -0.22 (m, 2H); LC-MS (ESI+) m/z 572.1 (M+H)+.

[002062] 2-(2,6-Dioxo piperidyl) [3- [2- [2(methylamino)ethoxy|ethoxv|propyl]isoindoline-l.,3- dione (Intermediate GD)

HCI/dioxane, DCM

[002063] Step 1 - Tert-butyl N-r2-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl1prop ynoxy1 ethoxy1ethyl1-N-methyl-carbamate

[002064] To a solution of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (3.73 g, 11.0 mmol, Intermediate GA) and tert-butyl N-methyl-N-[2-(2-prop-2ynoxyethoxy)ethyl]carbamate (3.70 g, 14.3 mmol, Intermediate FY) in DMF (30 mL) was added Pd(PPh3)2C12 (776 mg, 1.11 mmol), TEA (20.1 g, 199 mmol) and Cui (210 mg, 1.11 mmol). The mixture was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA=1:1) to give the title compound (5.50 g, 96% yield) as brown oil. 1H NMR (400MHz, CDCh) δ 8.09 (s, IH), 7.91 (s, IH), 7.87 - 7.78 (m, 2H), 4.99 (dd, 7= 5.6, 12.4 Hz, IH), 4.48 (s, 2H), 3.80 - 3.73 (m, 2H), 3.71 - 3.66 (m, 2H), 3.65 - 3.58 (m, 2H), 3.45 - 3.35 (m, 2H), 2.98 - 2.94 (m, IH), 2.93 (s, 3H), 2.88 - 2.70 (m, 2H), 2.21 - 2.13 (m, IH), 1.46 (s, 9H).

[002065] Step 2 - Tert-butyl N-r2-r2-r3-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-5 yl1propoxy1ethoxy1 ethyl1-N-methyl-carbamate (19) - Notebook Page: EW5417-733

[002066] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]prop ynoxy]ethoxy]ethyl]-N-methyl-carbamate (1.00 g, 1.95 mmol) in THF (20 mL) was added Pd/C (0.30 g, 10% w/w) and Pd(OH)2/C (0.30 g, 10% w/w) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20°C for 1 hour. On completion, the reaction mixture was filtered and the filterate was concentrated in vacuo to give the title compound (0.95 g, 95% yield) as brown oil. 1H NMR (400MHz, CDCh) δ 8.08 (s, IH), 7.79 (d, J= 8.0 Hz, IH), 7.72 (s, IH), 7.59 (dd, J = 1.2, 7.6 Hz, IH), 5.02 (dd, J = 5.2, 13.6 Hz, 1H),3.67 - 3.55 (m, 6H), 3.48 (t, J = 6.0 Hz, 2H), 3.44 - 3.36 (m, 2H), 2.92 (s, 3H), 2.91 - 2.89 (m, IH), 2.88 - 2.85 (m, 2H), 2.84 - 2.68 (m, 2H), 2.19-2.11 (m, IH), 2.00 - 1.91 (m, 2H), 1.46 (s, 9H); LC-MS (ESI+) m/z 540.3 (M+Na)+.

[002067] Step 3:2-(2,6-Dioxo piperidvl) [3-r2-r2(methylamino)ethoxy1ethoxy1propyl1isoindoline-L3- dione

[002068] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]propoxy] ethoxy]ethyl]-N-methyl-carbamate (0.95 g, 1.84 mmol) in DCM (20 mL) was added HCl/dioxane (4 M, 12 mL). The mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (0.83 g, 99% yield, HCI salt) as light yellow solid. LC-MS (ESI+) m/z 418.3 (M+H)+.

[002069] N-[3-carbamovl-l-(4-formvlDhenvl)Dvrazol vl] (4-Dvridyl)oxazole-4carboxamide (Intermediate GE)

GE

[002070] Step 1 - Isopropoxycarbonyl 4-r3-carbamoyl r[2-(4-pyridyl)oxazole-4carbonyl1amino1pyrazol-l-yl1 benzoate

[002071] To a mixture of 4-[3-carbamoyl [[2-(4-pyridyl)oxazole-4carbonyl]amino]pyrazol-l-yl]benzoic acid (500 mg, 1.20 mmol, Intermediate EE) in THF (20 mL) was added TEA (483 mg, 4.78 mmol, 665 uL) and isopropyl carbonochloridate (366 mg, 2.99 mmol, 414 uL). The reaction mixture was stirred at -10°C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was used to the next step directly without further purification to give the title compound (600 mg, 99% yield) as light yellow oil. LC-MS (ESI+) m/z 505.0 (M+H)+. [002072] Step 2 - N-r3-carbamoyl-l-r4-(hydroxymethyl)phenyl1pyrazol yl1 (4pyridyl)oxazole carboxamide

[002073] To a mixture of isopropoxycarbonyl 4-[3-carbamoyl [[2-(4-pyridyl)oxazole-4carbonyl]amino] pyrazol-l-yl]benzoate (600 mg, 1.19 mmol) in H2O (5 mL) and THF (50 mL) was added LiBH4 (155 mg, 7.14 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was quenched with water (30 mL) under stirring. Then the mixture was extracted with EA (3 X 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was triturated with DCM/PE (5 mL/30 mL) and filtered to give the title compound (250 mg, 51% yield) as light yellow solid. LC-MS (ESI+) m/z 405.2 (M+H)+.

[002074] Step 3 - N-[3-carbamoyl-l-(4-formylphenyl)pyrazol yl1 (4-pyridyl)oxazole-4carboxamide

[002075] To a mixture of N-[3-carbamoyl-l-[4-(hydroxymethyl)phenyl]pyrazol yl] (4pyridyl)oxazole carboxamide (250 mg, 618 umol) in DCM (10 mL) and THF (10 mL) was added DMP (524 mg, 1.24 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was diluted with Na2S2O3 (10 mL), NaHCO3 (10 mL) and stirred for 30 min. Then the mixture was extracted with DCM (3 X 10mL) and the combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (230 mg, 92% yield) as light yellow solid. LC-MS (ESI+) m/z 403.2 (M+H)+.

[002076] Tert-butyl

N-(cvcl0Dr0Dvlmethvl)-N-[4-[4-[[3-(diflu0r0methyl)-l-(4formylDhenvl)Dvrazol-4 -yl] carbamoyl] oxazol yl] Dvridvl] carbamate (Intermediate GF)

TEA, THF

[002077] Step 1:Isopropoxycarbonyl 4-(4-(12-(2-14611butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1 oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-1 -yllbenzoate

[002078] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (250 mg, 420 umol, Intermediate FX) in THF (10 mL) was added TEA (170 mg, 1.68 mmol) and isopropyl carbonochloridate (128 mg, 1.05 mmol). The mixture was stirred at -10°C for 1 hour. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (280 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 681.3 (M+H)+.

[002079] Step 2 - Tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l-[4 (hydroxymethyl)phenyll pyrazol yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[002080] To a solution of isopropoxycarbonyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl] amino]-3(difluoromethyl)pyrazol-l-yl]benzoate (280 mg, 411 umol) in THF (30.0 mL) and H2O (4.00 mL) was added NaBH4 (62.2 mg, 1.65 mmol). The mixture was stirred at 0°C for 1 hour. On completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was triturated with DCM: PE= 1:5 (30 mL), and filtered. The filter cake was dried in vacuo to give the title compound (200 mg, 83% yield) as white solid. LC-MS (ESI+) m/z 581.3 (M+H)+. [002081] Step 3 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-[r3-(difluoromethyl)-l-(4formvlphenvl)pyrazol-4 -yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[002082] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-(hydroxymethyl) phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (140 mg, 241 umol) in DCM (10.0 mL) was added DMP (204 mg, 482 umol). The mixture was stirred at 15 °C for 2 hours. On completion, the mixture was diluted with DCM (30 mL), and washed with saturated Na2S2O3 (2 X 30 mL) and saturated NaHCO3 (2 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (80.0 mg, 57% yield) as white solid. LC-MS (ESI+) m/z 579.1 (M+H)+.

[002083] Tert-butyl N-(5-Dr0D yn0xyDentyl)carbamate (Intermediate GG)

HO././.NH, Βθθ2θ12 &#1523; HO./0//.NHBOC -&#9658; -¾ o. NHBoc MeOH KOH, KI, TBAI, THF

GG

[002084] Step 1 - Tert-butyl N-(5-hydroxypentyl)carbamate

[002085] To a solution of 5-aminopentan-l-ol (21.3 g, 206 mmol) in MeOH (200 mL) was added 12 (2.63 g, 10.3 mmol) and tert-butoxycarbonyl tert-butyl carbonate (54.2 g, 248 mmol). The mixture was stirred at 25 °C for 12 hours. On completion, the mixture was concentrated to give a residue. The residue was purified by silica gel chromatograph to give the title compound (40.0 g, 95% yield) as yellow oil. 1HNMR (400MHz, CDCh) δ 4.60 (s, IH), 3.69 - 3.59 (m, 2H), 3.12 (d, 7=5.6 Hz, 2H), 1.9- 1.7 (m, IH), 1.61 - 1.36 (m, 15H).

[002086] Step 2 - Tert-butyl N-(5-prop ynoxypentyl)carbamate

[002087] To a solution of tert-butyl N-(5-hydroxypentyl)carbamate (5.00 g, 24.6 mmol) and 3-bromoprop yne (3.07 g, 25.8 mmol) in THF (100 mL) was added TBAI (545 mg, 1.48 mmol) and KI (612 mg, 3.69 mmol). Then KOH (1.38 g, 24.6 mmol) was added into the above mixture. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatograph (PE:EA= 5/1) to give the title compound (3.00 g, 50% yield) as a light yellow oil. 1HNMR (400MHz, DM SO-6/6) δ 4.12 (d, J = 2.4 Hz, 2H), 3.50 (t, J = 6.4 Hz, 2H), 3.11 (q, J = 6.4 Hz, 2H), 2.41 (t, J= 2.4 Hz, IH), 1.65 - 1.55 (m, 2H), 1.53 - 1.33 (m, 13H).

[002088] 4 (5-AminoDentoxy)DroDvl] (2.,6-dioxo DiDeridvl)isoindoline-l.,3-dione (Intermediate GH)

GG

Cui, Pd(PPh3)2CI2, TEA, DMF

HCI/dioxane

DCM

[002089] Step 1 - Tert-butyl N-r5-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1prop ynoxy1pentyl1 carbamate

[002090] 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (500 mg, 1.48 mmol,

Intermediate FT) ,Cui (28.2 mg, 148 umol) and Pd(PPh3)2C12 (104 mg, 148 umol) was taking up into a microwave tube. Then DMF (10 mL), TEA (2.70 g, 26.7 mmol) and tert-butyl N-(5-prop-2ynoxypentyl)carbamate (715 mg, 2.97 mmol, Intermediate GG) were added to the tube. The sealed tube was heated to 80 °C and stirred for 0.5 hours. On completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (5 X 10 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatograph (EA/PE=1/1) to give the title compound (1.10 g, 74 % yield) as a white solid. LC-MS (ESI+) m/z 498.1 (M+H)+.

[002091] Step 2 - Tert-butyl N-r5-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1propoxy1pentyl1 carbamate

[002092] To a solution of tert-butyl N-[5-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]prop ynoxy]pentyl]carbamate (0.50 g, 1.00 mmol) in THF (5 mL) was added Pd/C (50.0 mg, 10 wt%) and Pd(OH)2 (50 mg, 10 wt%). The mixture was purged with H2 gas several times. The mixture was stirred under H2 (15 psi) at 25°C for 12 minutes. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatograph to give the title compound (380 mg, 75% yield) as a yellow gum; LC-MS (ESI+) m/z 502.1 (M+H)+.

[002093] Step 3 - 4-r3-(5-Aminopentoxy)propyl1 (2,6-dioxo piperidyl)isoindoline-L3di one

[002094] To a solution of tert-butyl N-[5-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]propoxy] pentyl]carbamate (380 mg, 757 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the product (330 mg, 65% yield) as light yellow solid; LC-MS (ESI+) m/z 402.3 (M+H)+.

[002095] Tert-butyl methvl(5-(Dr0D vn-l-vl0xy)Dentvl)carbamate (Intermediate GI)

(Boc)2O, MeOH

KOH, KI, TBAI, THF

Boc

GI

[002096] Step 1 - N-(5-hydroxypentyl)formamide

[002097] A solution of 5-aminopentan 01 (CAS# 2508 4) (7 g, 67.9 mmol) in ethyl formate (20.1 g, 271 mmol) was heated to 90 °C for 6 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (8.9 g, 97% yield) as colorless oil. The residue was used for the next step without purification. LC-MS (ESI+) m/z 132.1 (M+H)+.

[002098] Step 2 - 5-(Methylamino)pentan-l-ol

[002099] To a solution of LiAlH4 (3.09 g, 81.4 mmol) in THF (100 mL) was added N-(5hydroxypentyl)formamide (8.9 g, 67.8 mmol) slowly at 0 °C. Then, the reaction mixture was heated to 80 °C for 2 hrs. On completion, the reaction mixture was quenched with a solution of 15% NaOH (20 mL). Thereafter, 50 g anhydrous sodium sulfate was added, and the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (7.95 g, 100% yield, crude) as colorless oil.

[002100] Step 3 - Tert-butyl (5-hydroxypentyl)(methyl)carbamate

[002101] To a solution of 5-(methylamino)pentan-l-ol (7.95 g, 67.8 mmol) in methanol (100 mL) was added tert-butoxycarbonyl tert-butyl carbonate (14.8 g, 67.8 mmol, 15.6 mL). The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 2:1) to give the title compound (9.6 g, 65% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 3.66 (t,/=6.4 Hz, 2H), 3.25-3.21 (m, 2H), 2.85 (s, 3H), 1.65 - 1.59 (m, 2H), 1.58-1.51 (m, 2H), 1.47 (s, 9H), 1.42 - 1.33 (m, 2H).

[002102] Step 4 - Tert-butyl methyl(5-(prop yn-l-yloxy)pentyl)carbamate

[002103] To a solution of tert-butyl N-(5-hydroxypentyl)-N-methyl-carbamate (1.00 g, 4.60 mmol) and 3-bromoprop yne (575 mg, 4.83 mmol) in THF (10 mL) was added KOH (334 mg, 5.06 mmol, 85% purity), KI (153 mg, 920 umol) and TBAI (340 mg, 920 umol). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the reaction mixture was extracted with ethyl acetate (3 X 50 mL). The combined organic layers was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 50:1) to give the title compound (530 mg, 45 % yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 4.15 (d, J = 2.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.24 -3.22 (m, 2H), 2.85 (s, 3H), 2.43 (t, J= 2.4 Hz, IH), 1.68 - 1.63 (m, 2H), 1.57- 1.53 (m, 2H), 1.47 (s, 9H), 1.41-1.34 (m, 2H).

[002104] 2-(2,6-Di0x0DiDeridin yl) (3-((5(methvlamino)Dentvl)oxy)DroDvl)isoindoline-l,3-dione (Intermediate GJ)

[002105] Step 1 - Tert-butyl (5-((3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yl)prop yn-l -yl)oxy) pentyl)(methyl)carbamate

[002106] 4-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (200 mg, 593 umol,

Intermediate FT), tert-butyl Af-methyl-Af-(5-prop ynoxypentyl)carbamate (152 mg, 593 umol, Intermediate GI), Pd(PPh3)2C12 (41.6 mg, 59.3 umol) , Cui (11.3 mg, 59.3 umol) and TEA (1.08 g, 10.7 mmol, 1.49 mL) were taken up into a microwave tube in DMF (3 mL) under N2. The reaction mixture was de-gassed with N2 and then the seal tube was heated to 80 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 2:1) to give the title compound (260 mg, 66% yield) as a yellow oil. 1HNMR (400MHz, CDC13) δ 8.47 (s, IH), 7.76 (d, J = 7.2 Hz, IH), 7.71 - 7.67 (m, IH), 7.65 7.60 (m, IH), 4.95 - 4.91 (m, IH), 4.38 (s, 2H), 3.60 (t, J = 6.8 Hz, 2H), 3.14 (t, J= 6.8 Hz, 2H), 2.83 - 2.66 (m, 7H), 1.66 - 1.56 (m, 2H), 1.49 - 1.43 (m, 2H), 1.38 (s, 9H), 1.36 - 1.30 (m, 2H); LC-MS (ESL)/&#1524;z 512.1 (M+H)+.

[002107] Step 2 - Tert-butyl (5-(3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yDpropoxy)pentyl) (methyl) carbamate

[002108] To a solution of tert-butyl 7V-[5-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]prop ynoxy]pentyl]-N-methyl-carbamate (260 mg, 391 umol) in THF (20 mL) was added Pd(OH)2/C (26 mg, 10% wt) and Pd/C (26 mg, 10% wt) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 Psi) at 25 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (260 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 538.1 (M+Na)+.

[002109] Step 3:2-(2,6-Dioxopiperidin yl) (3-((5(methylamino)pentyl)oxy)propyl)isoindoline-L3-dione

[002110] To a solution of tert-butyl /V-[5-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl] propoxy]pentyl]-N-methyl-carbamate (260 mg, 388 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL) under N2. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (175 mg, 99% yield) as a white solid which was used for the next step without purification. LC-MS (ESI+) m/z 416.1 (M+H)+.

[002111] Tert-butyl N-methvl-N-(2-Dr0D vn0xvethyl)carbamate (Intermediate GK)

Boc KOH, KI, TBAI, THF Boc

GK

[002112] To a solution of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (4 g, 22.8 mmol, CAS# 57561 4) and 3-bromoprop yne (2.72 g, 22.8 mmol, 1.97 mL) in THF (40 mL) was added TBAI (505 mg, 1.37 mmol), KI (568 mg, 3.42 mmol), and KOH (1.28 g, 22.8 mmol), and the reaction mixture was stirred at 25 °C for 16 hr. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (PE/EA=5/1, Rf =0.6) to give the title compound (2.9 g, 59% yield) as yellow oil. 1HNMR (400MHz, CDCh) δ 4.15 (d, J= 2.4 Hz, 2H), 3.64 (s, 2H), 3.41 (s, 2H), 2.92 (s, 3H), 2.53 - 2.35 (m, IH), 1.46 (s, 9H)

[002113] 2-(26&#1524;-Dioxo DiDeridvl) [3-[2-(methvlamino)ethoxv]DroDvl]isoindoline1.,3-dione (Intermediate GL)

[002114] Step 1 - Tert-butyl N-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl]prop ynoxy] ethyl] -N-methyl-carbamate

[002115] To a solution of tert-butyl N-methyl-N-(2-prop ynoxyethyl)carbamate (379 mg, 1.78 mmol, Intermediate GK) and 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (300 mg, 889 umol, Intermediate FT) in DMF (4 mL) was added TEA (1.62 g, 16.0 mmol, 2.23 mL), Cui (16.9 mg, 88.9 umol) and Pd(PPh3)2C12 (62.4 mg, 88.9 umol), the reaction mixture was heated at 80 °C for 30 min under microwave. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/l to 1/0, Rf = 0.29) to give the title compound (430 mg, 100% yield) as yellow oil. LCMS (ESI+) m/z 370.2 (M+H-100)+.

[002116] Step 2 - Tert-butyl N-r2-r3-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yl]propoxy]ethyl]-N- methyl-carbamate

[002117] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]prop ynoxy] ethyl]-N-methyl-carbamate (430 mg, 915 umol) in THF (10 mL) was added Pd(OH)2/C (250 mg, 10 wt%) and Pd/C (250 mg, 10 wt%), and the reaction mixture was stirred at 25 °C under H2 (15 psi) for 16 hr. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (350 mg, 80% yield) as brown solid. LC-MS (ESI+) m/z 496.2 (M + Na)+.

[002118] Step 3:2-(2,6-Dioxo piperidyl) [3-r2(methylamino)ethoxylpropyllisoindoline-l,3-dione

[002119] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo isoindolin yl]propoxy]ethyl] -N-methyl-carbamate (350 mg, 739 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL), and the reaction mixture was stirred at 25 °C for 20 mins. On completion, the mixture was concentrated in vacuo to give the title compound (300 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 374.2 (M+H)+.

[002120] Tert-butyl N-hex vnyl-N-methyl-carbamate (Intermediate GM) /X /X OH MsCI, DCM, TEA /&#1523;/\&#1523;\ OMs NH2CH3/THF, KI

(B0c)2O, MeOH

GM

[002121] Step 1 - Hex ynyl methanesulfonate

[002122] To a solution of hex yn-l-ol (2.00 g, 20.4 mmol, CAS# 928 5) and TEA(5.16 g, 51.0 mmol) in DCM (20 mL) was added MsCI (2.80 g, 24.5 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hrs. On completion, the mixture was quenched with water (20 mL), and extracted with DCM (2 X 20 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (3.20 g, 89% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 4.27 (t, J = 6.4 Hz, 2H), 3.02 (s, 3H), 2.30 2.24 (m, 2H), 1.98 (t, J = 2.8 Hz, IH), 1.93 - 1.84 (m, 2H), 1.70 - 1.64 (m, 2H).

[002123] Step 2 - N-methylhex yn-l-amine

[002124] A solution of hex ynyl methanesulfonate (0.60 g, 3.40 mmol) and KI (28.3 mg, 170 umol) in a solution of methanamine (2 M, 8.51 mL) was stirred at 55 °C for 15 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (0.25 g, 66% yield) as yellow oil. 1HNMR (400MHz, CDCh) δ 2.63 (t, J= 7.2 Hz, 2H), 2.45 (s, 3H), 2.23 - 2.19 (m, 2H), 1.94 (t, J= 2.4 Hz, IH), 1.68 - 1.56 (m, 4H).

[002125] Step 3 - Tert-butyl N-hex ynyl-N-methyl-carbamate

[002126] To a solution of N-methylhex yn-l-amine (500 mg, 4.50 mmol) in MeOH (10 mL) was added (Boc)2O (1.18 g, 5.40 mmol). The reaction mixture was stirred at 25 °C for 17 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (670 mg, 70% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 3.22 - 3.11 (m, 2H), 2.77 (s, 3H), 2.20 - 2.12 (m, 2H), 1.88 (t, J= 2.4 Hz, IH), 1.60 - 1.53 (m, 2H), 1.46 - 1.41 (m, 2H), 1.39 (s, 9H).

[002127] 2-(26&#1524;-Dioxo piperidvl) [6-(methvlamino)hexvl]isoindoline-l.,3-dione (Intermediate

[002128] Step 1 - Tert-butyl N-r6-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin yl1hex5-ynyl1-N-methyl- carbamate

[002129] 4-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (0.60 g, 1.78 mmol,

Intermediate FT), Cui (33.9 mg, 178 umol) and Pd(PPh3)2C12 (125 mg, 178 umol) was taken up into a microwave tube. Then tert-butyl N-hex ynyl-N-methyl-carbamate (602 mg, 2.85 mmol, Intermediate GM), TEA (3.24 g, 32.0 mmol) and DMF (5 mL) were added into the above tube. The mixture was degassed with N2 gas for 5 minutes. The sealed tube was heated at 80°C for 30 minutes under microwave. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% HCI condition) to give the title compound (720 mg, 78% yield) as a yellow gum. LC-MS (ESI+) m/z 490.1 (M+Na)+.

[002130] Step 2 - Tert-butyl N-r6-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yl 1 hexyl 1-N-methyl- carbamate

[002131] To a solution of tert-butyl N-[6-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]hex ynyl]-N- methyl-carbamate (720 mg, 1.39 mmol) in THF (8 mL) was added Pd/C (0.2 g, 10 wt%) and Pd(OH)2/C (0.2 g, 10 wt%). The reaction mixture was stirred at 25 °C for 18 hrs under H2 (15 Psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (620 mg, 95% yield) as a light yellow solid. LC-MS (ESI+) m/z 494.1 (M+Na)+.

[002132] Step 3 - 2-(2,6-Dioxo piperidvl) r6-(methylamino)hexyl1isoindoline-L3-dione [002133] To a solution of tert-butyl N-[6-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]hexyl]-N-methyl- carbamate (620 mg, 1.31 mmol) in DCM (4 mL) was added HCl/dioxane (6 mL). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (530 mg, 94% yield) as a yellow solid. LC-MS (ESI+) m/z 372.2 (M+H)+.

[002134] 4-(3-Amin0Dr0Dvl) (2.,6-di0x0DiDeridin vl)is0ind01ine-l.,3-di0ne (Intermediate

[002135] Step 1 - Tert-butyl (3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin yl)prop2-yn-l-yl)carbamate

[002136] 4-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (200 mg, 593 umol,

Intermediate FT), tert-butyl 7V-prop ynylcarbamate (CAS#: 92136 5) (92.0 mg, 593 umol),

Pd(PPh3)2C12 (41.6 mg, 59.3 umol) and TEA (1.08 g, 10.7 mmol, 1.49 mL) , Cui (11.3 mg, 59.3 umol) were taken up into a microwave tube in DMF (3 mL) under N2. The reaction mixture was de-gassed with N2 and then the seal tube was heated to 80 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 2:1) to give the title compound (200 mg, 73% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.07 (s, IH), 7.85 (dd, J = 1.2, 7.2 Hz, IH), 7.78 - 7.69 (m, 2H), 5.01 (dd, J= 5.2, 12.4 Hz, IH), 4.94 (s, IH), 4.28 (d, J= 5.2 Hz, 2H), 2.94 - 2.74 (m, 3H), 2.21 - 2.14 (m, IH), 1.50 (s, 9H); LC-MS (ESI+) m/z 434.0 (M+Na)+.

[002137] Step 2 - Tert-butyl (3-(2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yDpropyPcarbamate

[002138] To a solution of tert-butyl 7V-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]prop ynyl] carbamate (200 mg, 433 umol) in THF (20 mL) was added Pd/C (20 mg, 10% wt) and Pd(OH)2/C (20 mg, 10% wt) under N2. The suspension was degassed under vacuum and purged with H2 gas several times. The mixture was stirred under H2 (15 Psi) at 25 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (200 mg, 95% yield) as a white solid. LC-MS (ESI+) m/z 438.0 (M+Na)+.

[002139] Step 3 - 4-(3-AminopropyP (2,6-dioxopiperidin yl)isoindoline-l,3-dione [002140] To a solution of tert-butyl 7V-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]propyl]carbamate (200 mg, 404 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (142 mg, 100% yield) as a white solid.

[002141] Tert-butyl (4-(4-((3-carbamovl-l-(4-(methvl(5-oxopentvl)carbamovl)phenvDIH-pyrazol vl)carbamovl)oxazol vl)pvridin vl)(cvclopropvlmethvl)carbamate (Intermediate GP)

HATU, DIPEA, DMF

hydroxypentyl)(methyl)carbamoyl)phenyl)-lHDMP, DCM/THF (4-(4-((3 -carbamoyl-1 -(4-((5 vl)(cvclopropylmethvl)carbamate

[002143] To a solution of 5-(methylamino)pentan-l-ol (141 mg, 918 umol, HCI, synthesized via Steps 1-2 of Intermediate GI) and 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino] carbamoylpyrazol-l-yl]benzoic acid (539 mg, 918 umol, Intermediate DF) in DMF (25 mL) was added DIPEA (593 mg, 4.59 mmol, 799 uL). The reaction mixture was stirred at 0.5 hour. Then HATU (384 mg, 1.01 mmol) was added to the reaction mixture. The resulting reaction mixture was stirred at 25°C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (acidified condition: 0.1%, HC1) to give the title compound (300 mg, 48% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 10.97 (s, IH), 8.91 (s, IH), 8.58 - 8.49 (m, IH), 8.42 (s, IH), 8.36 (s, IH), 7.84 (d, J= 8.8 Hz, 2H), 7.79 (dd, J = 1.2, 5.2 Hz, IH), 7.62 - 7.54 (m, 2H), 6.91 (s, IH), 5.58 (s, IH), 3.95 (d, J = 7.2 Hz, 2H), 3.73 - 3.71 (m, IH), 3.63 - 3.61 (m, 2H), 3.33 - 3.31 (m, IH), 1.75 - 1.59 (m, 2H), 1.59 (s, 9H), 1.54 - 1.50 (m, 2H), 1.31 - 1.18 (m, 3H), 0.50 - 0.40 (m, 2H), 0.34 - 0.25 (m, 2H).

[002144] Step 2:Tert-butyl(4-(4-((3-carbamoyl-l-(4-(methyl(5oxopentyl)carbamoyl)phenyl)-lH-pyrazol yl)carbamoyl)oxazol yl)pyri din-2yl)(cyclopropylmethyl)carbamate (9) - Notebook Page: EW5356-822

[002145] To a solution of tert-butyl A-[4-[4-[[3-carbamoyl-l-[4-[5hydroxypentyl(methyl)carbamoyl]phenyl] pyrazol yl]carbamoyl]oxazol yl] pyridyl]-7V(cyclopropylmethyl)carbamate (300 mg, 437 umol) in DCM (10 mL) was added DMP (371 mg, 874 umol, 270 uL). The reaction mixture was stirred at 25 °C for 5 hrs. On completion, the reaction mixture was quenched with saturated NaS2O3 (30 mL), and extracted with DCM (3 X 100 mL). The combined organic layer was washed with saturated NaHCO3 (50 mL), then washed with brine (50 mL), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo to give the title compound (299 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 685.1 (M+H)+.

[002146] Tert-butyl N-tert-butoxvcarbonvl-N-non vnyl-carbamate (Intermediate

GO)

Boc^

NH

MsCI, TEA Boc

DCM Cs2CO3, ACN

GQ

[002147] Step 1 - Non ynyl methanesulfonate

[002148] To a mixture of non yn-l-ol (5.00 g, 35.6 mmol, CAS# 10160 8) and TEA (10.8 g, 106 mmol, 14.8 mL) in DCM (100 mL) was added MsCI (6.13 g, 53.4 mmol, 4.14 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with DCM (3 X 10 mL). The combined organic layers was dried over Na2SO4, fdtered and concentrated in vacuo to give the title compound (7.70 g, 98% yield) as light yellow oil. 1H NMR (400MHz, CDCh) δ 4.23 (t, J =6.4 Hz, 2H), 3.01 (s, 3H), 2.22-2.18 (m, 2H), 1.95 (t, 7= 2.4 Hz, IH), 1.80- 1.73 (m, 2H), 1.58 - 1.50 (m, 2H), 1.47 - 1.36 (m, 6H).

[002149] Step 2 - Tert-butyl N-tert-butoxvcarbonvl-N-non vnyl-carbamate

[002150] To a mixture of non ynyl methanesulfonate (1.00 g, 4.58 mmol) and tert-butyl Ntert- butoxycarbonylcarbamate (1.49 g, 6.87 mmol, CAS# 51779 9) in ACN (10 mL) was added Cs2CO3 (4.48 g, 13.7 mmol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (650 mg, 41% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 3.59 - 3.53 (m, 2H), 2.22 - 2.12 (m, 2H), 1.94 (t, J= 2.4 Hz, IH), 1.62 - 1.53 (m, 4H), 1.52 (s, 18H), 1.45 - 1.29 (m, 6H).

[002151] Tert-butyl N-methyl-N-non ynyl-carbamate (Intermediate GR)

BocHN— Boc

X/V^\zOMs -------&#9658; K /x /x \

NaH, DMF

GR

[002152] To a solution of tert-butyl N-methylcarbamate (300 mg, 2.29 mmol, CAS# 1606684-5) in DMF (10 mL) was added NaH (183 mg, 4.58 mmol, 60% purity) at 0 °C.The mixture was stirred at 25 °C for 2 hours. Then non ynyl methanesulfonate (0.5 g, 2.29 mmol, synthesized via Step 1 of Intermediate GQ) in dry DMF (2 mL) was added at 0°C, and then the mixture was stirred at 25 °C for 5 hours. On completion, the mixture was quenched by addtion H2O (30 mL), then extracted with EA(3 X 50 mL), and the organic phase was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography to give the title compound (410 mg, 70% yield) as colorless oil.1HNMR (400MHz, DMSO4) δ 3.14 (t, J= 7.6 Hz, 2H), 2.75 (s, 3H), 2.74-2.72 (m, IH), 2.17 - 2.11 (m, 2H), 1.48 - 1.42 (m, 4H), 1.39 (s, 9H), 1.35 - 1.18 (m, 6H).

[002153] 2-(2,6-Dioxo DiDeridvl) [9-(methvlamino)nonyl]isoindoline-l,3-dione (Intermediate GS)

[002154] Step 1 - Tert-butyl N-r9-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin yl1non8-ynyl1-N-methyl- carbamate

[002155] 4-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (300 mg, 889 umol,

Intermediate FT), Cui (16.9 mg, 88.9 umol) and Pd(PPh3)2C12 (62.4 mg, 88.9 umol) were taken up into a microwave tube. Then tert-butyl N-methyl-N-non ynyl-carbamate (405 mg, 1.60 mmol, Intermediate GR), TEA (1.62 g, 16.0 mmol, 2.23 mL) and DMF (3 mL) were added into the above tube. The mixture was degassed with N2 for 5 minutes. The sealed tube was heated at 80°C for 30 minutes under microwave. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (380 mg, 77% yield) as a white solid. LC-MS (ESI+) m/z 532.4 (M+Na)+.

[002156] Step 2 - Tert-butyl N-r9-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1nonyl1-N-methyl- carbamate

[002157] To a solution of tert-butyl N-[9-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]non ynyl]-N- methyl-carbamate (380 mg, 745 umol) in THF (10 mL) was added Pd(OH)2/C (100 mg, 10 wt%) and Pd/C (100 mg, 10 wt%). The reaction mixture was stirred under H2 (15 psi) at 25 °C for 12 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (380 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 536.2 (M + Na)+.

[002158] Step 3- 2-(2,6-Dioxo piperidyl) [9-(methylamino)nonyl1isoindoline-L3-dione

[002159] To a solution of tert-butyl N-[9-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl] nonyl]-N-methyl -carbamate (380 mg, 739 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 4 mL), and the reaction mixture was stirred at 25 °C for 20 min. On completion, the mixture was concentrated in vacuo to give the title compound (330 mg, 99% yield, HCI) as yellow solid. LC-MS (ESI+) m/z 414.3 (M+H)+.

[002160] 4-(9-Aminononyl) (2.,6-dioxo DiDeridvl)isoindoline-l.,3-dione

GQ

Cui, Pd(PPh3)2CI2, TEA, DMF

N(Boc)2

[002161] Step 1 - Tert-butyl N-tert-butoxycarbonyl-N-r9-r2-(2,6-dioxo piperidyl)-L3dioxo-isoindolin yl1 non ynyl1 carbamate

[002162] To a mixture of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (300 mg, 889 umol, Intermediate FT) and tert-butyl N-tert-butoxycarbonyl-N-non ynyl-carbamate (453 mg, 1.33 mmol, Intermediate GQ) in DMF (5 mL) was added Pd(PPh3)2C12 (62.4 mg, 88.9 umol), Cui (16.9 mg, 88.9 umol) and TEA(1.62 g, 16.0 mmol, 2.23 mL). The reaction mixture was heated at 80 °C for 30 mins under microwave. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) compound (340 mg, 64% yield) as brown oil. LC-MS (ESI+) m/z 618.4 (M+Na) + .

[002163] Step 2 - Tert-butyl N-tert-butoxvcarbonvl-N-r9-[2-(2,6-dioxo piperidvl)-L3dioxo-isoindolin yl1 nonyllcarbamate

[002164] To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[9-[2-(2,6-dioxo piperidyl)1,3-dioxo- isoindolin yl]non ynyl]carbamate (440 mg, 738 umol) in THF (5 mL) was added Pd/C (150 mg, 10 wt%) and Pd(OH)2/C (150 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 1 hour under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (442 mg, 99% yield) as white solid. LC-MS (ESI+) m/z 622.5 (M+Na)+.

[002165] Step 3 - 4-(9-Aminononyl) (2,6-dioxo piperidyl)isoindoline-L3-dione

[002166] To a mixture of tert-butyl N-tert-butoxycarbonyl-N-[9-[2-(2,6-dioxo piperidyl)1,3-dioxo-isoindolin yl]nonyl]carbamate (442 mg, 737 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (320 mg, 99% yield, HCI) as colourless oil. LC-MS (ESI+) m/z 400.3 (M+H)+.

[002167] ULLhEiUaiiHiioetJioxyfriniiiylJH-mxmiyoiiidonmUyHiH^^ (Intermediate GU)

[002168] Step 1 - tert-butyl (2-((3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin yl)prop-2yn-1 -yl )oxy )ethyl )carbamate

[002169] To a stirred solution of 3-(4-bromo-l-oxoisoindolin yl)piperidine-2,6-dione (0.5 g, 1.551 mmol, Intermediate IR) in DMF (6.0 ml) was added tert-butyl (2-(prop yn-lyloxy)ethyl)carbamate (0.46 g, 2.32 mmol, Intermediate IU) at rt. The reaction mixture was purged with N2 gas for 20 min. To this stirred reaction mixture were added Cui (0.014 g, 0.077 mmol), TEA (6.0 ml, 36.09 mmol), PdC12(PPh3)2(0.054 g, 0.0776 mmol) and the mixture was further purged with N2 gas for 20 min. The reaction mixture was heated at 80 °C for 3 h. The reaction mixture was then poured into water (100 ml) and the product was extracted with ethyl acetate (3 x 100 ml). The combined organic layer dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl (2-((3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin yl)prop2-yn-l-yl)oxy)ethyl)carbamate (0.28 g, 0.64 mmol). LCMS m/z: ES+ 386.17 (M-55)+.

[002170] Step 2 - tert-butyl (2-(3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin-4yl)propoxy)ethyl)carbamate

[002171] To a solution of tert-butyl (2-((3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin-4yl)prop yn-l-yl)oxy)ethyl)carbamate (1.5 g, 3.40 mmol) in methanol (50 ml) was added 10 wt%

Pd/C (0.2 g) at rt. Hydrogen gas was purged in to the reaction mixture at rt for 4 h. The resulting reaction mixture was filtered over a bed of celite and washed with methanol (50 ml). The obtained filtrate was concentrated under vacuum. The crude material was purified by silica gel flash chromatography (eluting at 4% MeOH in MDC) to afford tert-butyl (2-(3-(2-(2,6-di oxopiperi din3-yl)-l-oxoisoindolin yl)propoxy)ethyl)carbamate (0.6 g, 1.34 mmol). LCMS m/z: ES+ 346.2 (M-99)+. 1HNMR (400 MHz, DMSO-d6) δ 11.01 (s, IH), 7.58 (dd, J = 5.0, 3.6 Hz, IH), 7.49 7.45 (m, 2H), 6.80 (t, J = 5.7 Hz, IH), 5.15 (dd, J = 13.2, 5.1 Hz, IH), 4.47 (d, J = 17.2 Hz, IH), 4.31 (d, J = 17.1 Hz, IH), 3.38 (dd, J = 12.9, 6.4 Hz, 7H), 3.08 (q, J = 6.0 Hz, 2H), 2.94 (ddd, J = 17.3, 13.7, 5.4 Hz, IH), 2.69 (dd, J = 8.9, 6.5 Hz, 2H), 2.66 - 2.56 (m, IH), 2.42 (td, J = 13.2, 4.5 Hz, IH), 2.02 (dtd, J = 12.6, 5.3, 2.3 Hz, IH), 1.83 (p, J = 6.8 Hz, 2H), 1.37 (s, 9H).

[002172] Step 3 - 3-(4-(3-(2-aminoethoxy)propyl)-l-oxoisoindolin yl)piperidine-2,6di one

[002173] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-4yl]propoxy] ethylcarbamate (200 mg, 448 umol) in DCM (2.00 mL) was added HCl/dioxane (4 M, 2.00 mL). The mixture was stirred at 20 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (170 mg, 80% yield, HCI) as yellow solid. LCMS (ESH) m/z 346.3 (M+H)+.

[002174] 3-[3-[2-[2-(2-aminoethoxy)ethoxy]ethyl] oxo-benzimidazol-l-yl]piperidine2.,6- dione (Intermediate GV)

GV

[002175] Step 1: tert-butyl (2-(2-(2-((2-nitrophenyl)amino)ethoxy)ethoxy)ethyl)carbamate [002176] To a solution of tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (15.0 g, 0.060 mol, CAS# 153086 3) in DMF (30 mL) was added l-fluoro nitrobenzene (10.2 g, 0.072 mmol), and K2CO3 (25.1 g, 0.182 mmol) at r.t. The reaction was heated at 60 °C for 3 h. The mixture was quenched with water and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified via column chromatography (petroleum ether / EtOAc = 5% - 80%) to give the desired compound (12.8 g, 57% yield) as a yellow oil.LC-MS (ESI+): m/z 370.2 (M+H)+.

[002177] Step 2: tert-butyl (2-(2-(2-((2-aminophenyl)amino)ethoxy)ethoxy)ethyl)carbamate [002178] To a solution of tert-butyl (2-(2-(2-((2nitrophenyl)amino)ethoxy)ethoxy)ethyl)carbamate (12.8 g, 34.7 mmol) in MeOH (200 mL) was added Pd/C (720 mg) at r.t. The reaction mixture was degassed and purged with hydrogen three times. The reaction was stirred at r.t. for 12 hs under hydrogen. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the desired compound (11.2 g, 95% yield) as a yellow oil. LC-MS (ESI+): m/z 340.2 (M+H)+.

[002179] Step 3: tert-butyl (2-(2-(2-(2-oxo-2,3-dihydro-lH-benzo[d1imidazol-l yl)ethoxy)ethoxy)ethyl)carbamate

[002180] To a solution of tert-butyl (2-(2-(2-((2aminophenyl)amino)ethoxy)ethoxy)ethyl)carbamate (11.2 g, 33.04 mmol) in THF (100 mL) was added CDI (6.5 g, 40.37 mmol) at r.t. The reaction was stirred at r.t. overnight. The mixture was quenched with water and extracted with EtOAc (100 ml x 2). The combined organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified via column chromatography (petroleum ether / EtOAc =5% - 80%) to give the desired compound (3.7 g, 31% yield) as a yellow oil. 1HNMR (400 MHz, DM SO-6/6) δ ppm: 10.84 (s, IH), 7.20 - 7.13 (m, IH), 7.03 - 6.94 (m, 3H), 6.75 (t, J = 5.5 Hz, IH), 3.94 (t, J = 5.7 Hz, 2H), 3.66 (t, J = 5.7 Hz, 2H), 3.51 (d, J = 5.3 Hz, 2H), 3.44 (d, J = 5.2 Hz, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.02 (q, J = 5.9 Hz, 2H), 1.37 (s, 9H).

[002181] Step 4: tert-butyl (2-(2-(2-(3-(1 -(4-methoxybenzyl )-2,6-di oxopiperi din yl )-2oxo-2,3-dihvdro-IH-benzo[d]imidazol-l-vl)ethoxv)ethoxv)ethyl )carbamate

[002182] To a stirred solution of tert-butyl (2-(2-(2-(2-oxo-2,3-dihydro-lHbenzo[d]imidazol-l-yl)ethoxy)ethoxy)ethyl)carbamate (1.5 g, 4.12 mmol) in THF (300 ml) was added t-BuOK (370 mg, 3.3 mol) at room temperature portion-wise. After addition, the mixture was stirred at room temperature for 2 h. Then the 3-bromo-l-(4-m ethoxybenzyl )piperi dine-2,6dione (1.9 g, 6.16 mmol) in THF (20 ml) was added dropwise. The mixture was stirred at room temperature for 2 h. Then a second batch of t-BuOK (370 mg, 3.3 mmol) was added portion-wise, and the mixture was stirred for an additional 30 min. Then the mixture was poured into water, and extracted with EtOAc(3 x 200 ml). The combined organic layers were concentrated under reduced pressure, and the residue was purified by column on silica gel eluting with EtOAc : DCM =2:1 to get the title compound (600 mg, 24% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ ppm: 7.36 (m, J = 8.50 Hz, 2 H), 7.17 (d, J = 7.75 Hz, 1 H), 7.08 (t, J = 7.75 Hz, 1 H), 6.94 (t, J = 7.75 Hz, 1 H), 6.83 (m, J = 8.38 Hz, 2 H), 6.50 (d, J = 7.88 Hz, 1 H), 5.23 (dd, J = 13.13, 5.38 Hz, 1 H), 4.96 (d, J = 2.00 Hz, 2 H), 4.09 (t, J = 5.63 Hz, 2 H), 3.74 - 3.86 (m, 5 H), 3.57 - 3.62 (m, 2 H), 3.51 - 3.56 (m, 2 H), 3.41 - 3.49 (m, 2 H), 3.21 - 3.29 (m, 2 H), 2.95 - 3.07 (m, 1 H), 2.77 - 2.89 (m, 1 H), 2.54 - 2.68 (m, 1 H), 2.13 - 2.22 (m, 1 H), 1.46 (s, 9 H). LC-MS (ESI+): m/z 597.0 (M+H)+.

[002183] Step 5:3 -(3 -(2-(2-(2-aminoethoxy)ethoxy)ethyl) oxo-2,3 -dihydro-1Hbenzord]imidazol-l-yl)piperidine-2,6-dione

[002184] To a solution of tert-butyl (2-(2-(2-(3-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3yl) oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)ethoxy)ethoxy)ethyl)carbamate (640 mg, 1.074 mmol) in toluene (5 mL) was added MsOH (2.1 g, 21 mmol). The reaction was heated at 110 °C for 3 h. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure. The residue was poured into ice water, then basified with sat. NaHCO3 to pH = 7-8. Then the mixture was purified by prep HPLC eluting with ACN / H2O (0.1% HCOOH) = 0% -10% to give the desired formic acid salt compound as a colorless oil (62 mg, 15% yield). 1HNMR (400 MHz, DMSO4) δ ppm: 7.33 (d, J = 7.38 Hz, 1 H), 7.01 - 7.24 (m, 3 H), 5.45 (dd, J = 12.57, 5.07 Hz, 1 H), 4.27-4.54 (m, 2 H), 4.04 - 4.13 (m, 2 H), 3.68 - 3.86 (m, 2 H), 3.61 (br. s., 2 H) 3.34 3.58 (m, 4 H), 2.89 - 3.03 (m, 1 H), 2.63 - 2.84 (m, 2 H), 1.98 - 2.18 (m, 1 H) LC-MS (ESI+): m/z 377.0 (M+H)+.

[002185] 4-[3-(2-Aminoethoxy)DroDvl] (2.,6-dioxo DiDeridvl)isoindoline-l.,3-dione

[002186] Step 1 - Tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1prop ynoxy1 ethyl] carbamate

[002187] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.95 g, 5.79 mmol, Intermediate FT) and tert-butyl N-(2-prop ynoxyethyl)carbamate (1.50 g, 7.53 mmol, synthesized via Step 1 on Intermediate CP) in DMF (10 mL) was added Pd(PPh3)2C12 (406 mg, 579 umol), TEA (10.5 g, 104 mmol) and Cui (110 mg, 579 umol). The mixture was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (1.80 g, 68% yield) as light yellow oil; LC-MS (ESI+) m/z 478.0 (M+Na)+. [002188] Step 2 - Tert-butyl N-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yllpropoxylethyl] carbamate

[002189] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]prop ynoxy] ethylcarbamate (1.00 g, 2.20 mmol) in THF (30 mL) was added Pd/C (0.2 g, 10% w/w) and Pd(OH)2/C (0.2 g, 10% w/w) under N2. The suspension was degassed under vacuum and purged with H2 gas three times. The mixture was stirred under H2 (15 Psi) at 20 °C for 1 hour. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give title compound (600 mg, 60 % yield) as white solid; LC-MS (ESI+) m/z 482.2 (M+Na)+.

[002190] Step 3 - 4-r3-(2-Aminoethoxy)propyl1 (2,6-dioxo piperidyl)isoindoline-L3dione (7) - Notebook Page: EW5417-748

[002191] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]propoxy] ethylcarbamate (200 mg, 435 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 0.8 mL). The mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (156 mg, 90% yield, HCI salt) as white solid; LC-MS (ESL)&#1524;/ z 360.1 (M+H)+.

[002192] 4-[3-[2-(2-aminoethoxv)ethoxv]propvl] (2,6-dioxo piperidyl)isoindoline1.,3-dione (Intermediate GX)

[002193] Step 1 - Tert-butyl N-r2-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4 yl1prop ynoxy1 ethoxylethyllcarbamate

[002194] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1 g, 2.97 mmol, Intermediate FT) and tert-butyl N-[2-(2-prop ynoxyethoxy)ethyl]carbamate (1.44 g, 5.93 mmol, synthesized via Step 1 of Intermediate CQ) in DMF (8 mL) was added Pd(PPh3)2C12 (208 mg, 296 umol), TEA (5.4 g, 53.3 mmol, 7.43 mL) and Cui (56.4 mg, 296 umol). The reaction mixture was heated at 80 °C for 30 min under microwave. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/l to 1/0, Rf = 0.73) to give the title compound (1.20 g, 72% yield) as yellow solid. LC-MS (ESI+) m/z 500.1 (M+H)+.

[002195] Step 2 - Tert-butyl N-r2-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yllpropoxylethoxy] ethyllcarbamate

[002196] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]prop ynoxy]ethoxy]ethyl]carbamate (600 mg, 1.20 mmol) in THF (10 mL) was added Pd/C (300 mg, 1.20 mmol, 10 wt%) and Pd(OH)2/C (300 mg, 1.20 mmol, 10 wt%). The reaction mixture was stirred at 25°C under H2 (15 psi) for 12 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (600 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 526.4 (M + Na)+.

[002197] Step 3:4-r3-r2-(2-aminoethoxv)ethoxv1propvl1 (2,6-dioxo-3piperidyl)isoindoline-L3-dione

[002198] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]propoxy] ethoxy]ethyl]carbamate (600 mg, 1.19 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 2.00 mL), and the reaction mixture was stirred at 25 °C for 20 minutes. On completion, the mixture was concentrated in vacuo to give the title compound (500 mg, 95% yield) as yellow solid. LC-MS (ESI+) m/z 404.3 (M+H)+.

[002199] tert-butyl N-[4-[4-[[3-carbamoyl-l-(4-formylDhenvl)Dvrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (Intermediate GY)

DMP

DCM

GY

[002200] Tert-butyl N-[4-[4-[[3-carbamoyl-l-(4- formylphenyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate was synthesized as described below in Step 1 of Example 171.

[002201] Tert-butyl N-[2-[2-[2-(2-prop ynoxyethoxy)ethoxy]ethoxy]ethyl]carbamate (Intermediate GZ)

HO^'''/ n HBoc -----------------+ &#908; 0 NHBoc

KOH, KI, TBAI, THF GZ

[002202] To a solution of tert-butyl N-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.82 mmol, synthesized via Steps 1-3 of Intermediate AO) and 3-bromoprop yne (973 mg, 8.18 mmol, 705 uL) in THF (30 mL) was added TBAI (151 mg, 409 umol), KI (169 mg, 1.02 mmol), KOH (382 mg, 6.82 mmol). The reaction mixture was stirred at 25 °C for 16 hours. On completion, the mixture was filtered, and the filterate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography to give the title compound (0.85 g, 37% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 5.06 (s, IH), 4.21 (d, J= 2.4 Hz, 2H), 3.72 - 3.61 (m, 14H), 3.54 (t, J= 5.2 Hz, 2H), 2.46 - 2.43 (m, IH), 1.45 (s, 9H).

[002203] 4 12 [2-(2-Aminoethoxyjethoxy] ethoxy] ethoxy] propyl] (2.,6-dioxo-3piperidyl) isoindoline-l.,3-dione (Intermediate HA)

GZ

NHBoc

Pd(PPh3)2CI2, Cui, TEA, DMF

NHBoc

Pd(OH)2/C, Pd/C, H2

THF

HCI/dioxane, DCM

[002204] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-Γ3-Γ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-Ε3-&#940;&#912;οχοisoindolin yl1prop ynoxy1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[002205] To a mixture of tert-butyl N-[2-[2-[2-(2-prop-2ynoxyethoxy)ethoxy]ethoxy]ethyl]carbamate (690 mg, 2.08 mmol, Intermediate GZ) and 4bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (540 mg, 1.60 mmol, Intermediate FT) in DMF (6 mL) was added Pd(PPh3)2C12 (112 mg, 160 umol), Cui (30.5 mg, 160 umol) and TEA (2.92 g, 28.8 mmol, 4.01 mL). The reaction mixture was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (580 mg, 61% yield) as light yellow oil. LC-MS (ESI+) m/z 610.4 (M+Na)+.

[002206] Step 2 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-Γ3-Γ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-Ε3-&#940;&#912;οχοi soindolin yl1propoxy1 ethoxy] ethoxy] ethoxy] ethyl] carb amate

[002207] To a mixture of tert-butyl N-[2-[2-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] prop ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (380 mg, 646 umol) in THF (10 mL) was added Pd(OH)2/C (150 mg, 10 wt%) and Pd/C (150 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 0.5 hour under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (382 mg, 99% yield) as light yellow oil. LC-MS (ESI+) m/z 592.3 (M+H)+.

[002208] Step 3 - 4-r3-r2-r2-r2-(2-Aminoethoxy)ethoxy1ethoxy1ethoxy1propyl1 (2,6dioxo piperidyl) isoindoline-L3-dione

[002209] To a mixture of tert-butyl N-[2-[2-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (382 mg, 645 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (340 mg, 99% yield, HC1) as light yellow oil. LC-MS (ESI+) m/z 492.3 (M+H)+.

[002210] 3-[4-[3-[2-(2-aminoethoxv)ethoxv]DroDvl]-l-oxo-isoindolin yl]DiDeridine-

2,6- dione (Intermediate HB)

Pd/C, EtOAc

-->

HCI/dioxane, DCM

[002211] Step 1 - (2-(2-((3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin yl)prop yn-l yl)oxy)ethoxy)ethyl)carbamate

[002212] To a stirred solution of 3-(4-bromo-l-oxoisoindolin yl)piperidine-2,6-dione (0.3 g, 0.93 mmol, Intermediate IR) in DMF (6.0 ml) was added tert-butyl (2-(2-(prop yn-lyloxy)ethoxy)ethyl)carbamate (0.34 g, 1.39 mmol, Intermediate IT) at rt. The reaction mixture was purged with N2 gas for 20 min. To this stirred reaction mixture were added Cui (0.008 g, 0.0465 mmol), TEA (3.2 ml, 22.35 mmol), PdC12(PPh3)2(0.032 g, 0.0465 mmol) and the reaction was further purged with N2 gas for 20 min. Then the reaction mixture was heated at 80 °C for 3 h. On completion, the reaction mixture was poured into water (100 ml) and product was extracted with ethyl acetate (3 x 100 ml). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel flash chromatography (eluting at 3% MeOH in MDC) to afford tert-butyl (2-(2-((3-(2-(2,6dioxopiperidin yl)-l-oxoisoindolin yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate (0.2 g, 0.412mmol). LCMS m/z: (ES+) 508.2 (M+23)+.

[002213] Step 2 - tert-butyl (2-(2-(3-(2-(2,6-dioxopiperidin vl)-l-oxoisoindolin-4yl)propoxv)ethoxv)ethyl) carbamate

[002214] To a solution of tert-butyl (2-(2-((3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin4-yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate (1.4 g, 2.88 mmol) in methanol (50 ml) was added 10 wt% Pd/C (0.2 g) at rt. Hydrogen gas was purged in to the reaction mixture at rt for 4 h. The resulting reaction mixture was filtered over a bed of celite and washed with methanol (50ml). The obtained filtrate was concentrated under vacuum. The obtained crude material was purified by silica gel chromatography (eluting at 4% MeOH in MDC) to afford tert-butyl (2-(2-(3-(2-(2,6dioxopiperidin yl)-l-oxoisoindolin yl)propoxy)ethoxy)ethyl) carbamate (0.8 g, 1.63 mmol). LCMS m/z: ES+ 390.3 (M-99)+. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, IH), 7.58 (dd, J = 5.3, 3.3 Hz, IH), 7.51 - 7.42 (m, 2H), 5.15 (dd, J = 13.3, 5.0 Hz, IH), 4.47 (d, J = 17.2 Hz, IH), 4.30 (d, J = 17.1 Hz, IH), 3.49 (td, J = 5.2, 2.9 Hz, 3H), 3.38 (dd, J = 7.0, 4.4 Hz, 6H), 3.06 (q, J = 6.1 Hz, 2H), 3.00 - 2.86 (m, IH), 2.70 (d, J = 7.8 Hz, 2H), 2.61 (d, J = 17.6 Hz, 2H), 2.42 (d, J = 4.5 Hz, IH), 2.01 (dd, J = 9.4, 3.7 Hz, IH), 1.84 (t, J = 7.5 Hz, 2H), 1.36 (d, J = 4.6 Hz, 9H).

[002215] Step 3 - 3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-l-oxoisoindolin-2yl)piperidine-2,6-dione

[002216] To a solution of tert-butyl N-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin4-yl]propoxy]ethoxy] ethylcarbamate (200 mg, 408 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (155 mg, 89% yield) as yellow solid. LC-MS (ESI+) m/z 390.1 (M+H)+.

[002217] 3-[4-[3-[2-[2-(2-Aminoethoxv)ethoxv]ethoxv]DroDvl]-l-oxo-isoindolin-2yllpiperidine-2.,6- dione (Intermediate HC)

[002218] Step 1 - tert-butyl (2-(2-(2-((3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin-4vl)prop yn-l-yl)oxy)ethoxy)ethoxy)ethyl)carbamate

[002219] To a stirred solution of 3-(4-bromo-l-oxoisoindolin yl)piperidine-2,6-dione (0.5 g, 1.55 mmol, Intermediate IR) in DMF (6.0 ml) was added tert-butyl (2-(2-(2-(prop yn-lyloxy)ethoxy)ethoxy)ethyl)carbamate(0.6 g, 2.32 mmol, Intermediate IS) at rt. The reaction mixture was purged with N2 gas for 20 min. To the stirred reaction mixture were added Cui (0.014 g, 0.0776 mmol), TEA (5.5 ml, 37.26 mmol), PdC12(PPh3)2 (0.054 g, 0.0776 mmol) and further purged with N2 gas for 20 min. The reaction mixture was heated at 80 °C for 3 h. On completion, the reaction mixture was poured into water (200 ml) and product was extracted with ethyl acetate (3 x 200 ml). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel flash chromatography (eluting at 4% MeOH in MDC) to afford tert-butyl (2-(2-(2-((3-(2-(2,6-di oxopiperi din yl)-loxoisoindolin yl)prop yn-l-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (0.5 g, 1.0 mmol). LCMs m/z: (ES+) 528.4 (M-l)+.

[002220] Step 2 - tert-butyl (2-(2-(3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin-4yl)propoxy)ethoxy)ethyl) carbamate

[002221] To a solution of tert-butyl (2-(2-(2-((3-(2-(2,6-di oxopiperi din yl)-loxoisoindolin yl)prop yn-l-yl)oxy)ethoxy)ethoxy)ethyl)carbamate(1.5 g, 2.83 mmol) in methanol (50 ml) was added 10 wt% Pd/C (0.15g) at rt. Hydrogen gas was purged into the reaction mixture at rt for 4 h. The resulting reaction mixture was filtered over a bed of celite and washed with methanol (50 ml). The obtained filtrate was concentrated under vacuum. The crude material was purified by combi flash chromatography (eluting at 4% MeOH in MDC) to afford tert-butyl (2-(2-(3-(2-(2,6-dioxopiperidin yl)-l-oxoisoindolin yl)propoxy)ethoxy)ethyl) carbamate (0.3 g, 0.56 mmol). LCMS m/z: (ES+) 390.3 (M-99)+. 1HNMR (400 MHz, DMSO-d6) δ 11.03 (s, IH), 7.58 (dd, J = 5.6, 3.0 Hz, IH), 7.49 - 7.44 (m, 2H), 6.78 (t, J = 5.8 Hz, IH), 5.15 (dd, J = 13.3, 5.1 Hz, IH), 4.47 (d, J = 17.1 Hz, IH), 4.30 (d, J = 17.2 Hz, IH), 3.50 (tq, J = 8.2, 2.8 Hz, 8H), 3.05 (q, J = 6.0 Hz, 3H), 2.94 (ddd, J = 17.2, 13.6, 5.4 Hz, IH), 2.74 - 2.63 (m, 3H), 2.59 (s, 3H), 2.41 (td, J = 13.2, 4.5 Hz, IH), 2.05 - 1.92 (m, IH), 1.91 - 1.77 (m, 2H), 1.37 (d, J = 4.5 Hz, 9H).

[002222] Step 3 - 3-r4-r3-r2-r2-(2-Aminoethoxy)ethoxy1ethoxy1propyl1-l-oxo-isoindolin2-yl1piperidine-2,6- dione

[002223] To a solution of tert-butyl N-[2-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl] propoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 374 umol) in DCM (2.00 mL) was added HCl/dioxane (4 M, 4.00 mL). The mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (170 mg, 80% yield) as yellow solid. LC-MS (ESI+) m/z 434.3 (M+H)+.

[002224] 1 12- [2-(2-Aminoethoxv)ethoxy] ethoxy] ethyl] nitro-Dvrazole-3carboxamide (Intermediate HD)

BocHN

AO

HCI/dioxane, DCM

HD

[002225] Step 1 - Tert-butyl N-r2-r2-r2-r2-(3-carbamoyl nitro-pyrazol-lyl)ethoxy1ethoxy1ethoxy1ethyl1 carbamate

[002226] To a solution of 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (6.50 g, 17.5 mmol, Intermediate AO), 4-nitro-lH-pyrazole carboxamide (2.48 g, 15.9 mmol, Intermediate CJ) in DMF (80.0 mL) was added Cs2CO3 (10.3 g, 31.8 mmol). The mixture was stirred at 130 °C for 16 hours. On completion, the mixture was filtered and the organic layer was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (2.00 g, 29% yield) as yellow solid. LC-MS (ESI+) m/z 454.3 (M+Na)+.

[002227] Step 2 - l-[2-[2-[2-(2-Aminoethoxy)ethoxy1ethoxy1ethyl1 nitro-pyrazole-3carboxamide

[002228] To a solution of tert-butylN-[2-[2-[2-[2-(3-carbamoyl nitro-pyrazol-lyl)ethoxy]ethoxy]ethoxy] ethyl]carbamate (1.00 g, 2.32 mmol) in DCM (3.00 mL) was added HCI/dioxane (4 M, 5.00 mL). The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (500 mg, 80% yield, HCI) as yellow oil. 1HNMR (400MHz, MeODA) δ 8.64 (s, IH), 4.41 - 4.38 (m, 2H), 3.90 - 3.87 (m, 2H), 3.68 3.65 (m, 4H), 3.62 - 3.60 (m, 6H), 3.13 - 3.09 (m, 2H).

[002229] 4-Amino-l-[2-[2-[2-[2-[[2-(2.,6-dioxo DiDeridvl)-l.,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] ethoxy] ethyl] pyrazole carboxamide (Intermediate HE)

HD

HE

[002230] Step 1 - l-r2-[2-[2-[2-[[2-(2,6-Dioxo piperidvl)-L3-dioxo-isoindolin-4 yl1amino1ethoxy1ethoxy1 ethoxy1ethyl1 nitro-pyrazole carboxamide

[002231] To a solution of l-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl] nitro-pyrazole3-carboxamide (300 mg, 815 umol, HCI, Intermediate HD), 2-(2,6-di oxo piperi dyl) fluoroisoindoline-1,3-dione (247 mg, 897 umol, Intermediate R) in dioxane (5.00 mL) was added DIPEA (1.05 g, 8.16 mmol), and the mixture was stirred at 115 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (DCM: MeOH = 30: 1) to give the title compound (100 mg, 20% yield) as yellow oil. LC-MS (ESI+) m/z 588.3 (M+H)+.

[002232] Step 2 - 4-Amino-l-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin4-yl 1 amino] ethoxy] ethoxy] ethoxy] ethyl 1 pyrazole-3 -carboxamide

[002233] To a solution of l-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy] ethoxy]ethoxy]ethyl] nitropyrazole carboxamide (70.0 mg, 119 umol) in THF (5.00 mL) was added Pd/C (25.0 mg), and the mixture was stirred at 15 °C for 15 min under H2 (15 psi). On completion, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (60.0 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 558.2 (M+H)+.

[002234] 4-Amino-l-(2-hvdroxvethvl)Dvrazole carboxamide (Intermediate HF)

CJ

CS2CO3, DMF

LiBH4, THF, MeOH

HF

[002235] Step 1 - Ethyl 2-(3-carbarn oyl nitro-pyrazol-l-yl)acetate

[002236] To a solution of 4-nitro-lH-pyrazole carboxamide (1.5 g, 9.61 mmol,

Intermediate CJ) and ethyl 2-bromoacetate (1.68 g, 10.0 mmol) in DMF (20 mL) was added

Cs2CO3 (3.13 g, 9.61 mmol), the mixture was stirred at 20 °C for 16 hours. On completion, the mixture was filtered to give the filtrate and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give the title compound (1.60 g, 68% yield) as white solid. 1HNMR (400MHz, DMSO4) δ 8.87 (s, IH), 8.05 (s, IH), 7.78 (s, IH), 5.19 (s, 2H), 4.20 (q, J= 7.2 Hz, 2H), 1.23 (t, J= 7.2 Hz, 3H).

[002237] Step 2 - Ethyl 2-(4-amino carbarnoyl-pyrazol-l-yl)acetate

[002238] To a solution of ethyl 2-(3-carbarnoyl nitro-pyrazol-l-yl)acetate (1 g, 4.13 mmol) in MeOH (40 mL) was added Pd/C (0.3 g, 10% w/w) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (780 mg, 89% yield) as white solid. 1HNMR (400MHz, DMSO-d6) δ 7.13 (s, 2H), 7.00 (s, IH), 4.93 (s, 2H), 4.68 (s, 2H), 4.14 (q, J= 7.2 Hz, 2H), 1.20 (t, J= 7.2 Hz, 3H).

[002239] Step 3 - 4-Amino-l-(2-hydroxyethyl)pyrazole carboxamide

[002240] To a solution of ethyl 2-(4-amino carbarnoyl-pyrazol-l-yl)acetate (770 mg, 3.59 mmol) in a mixed solvent of THF (120 mL) and MeOH (15 mL) was added LiBH4 (156 mg, 7.18 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched with water (0.5 mL), and then concentrated in vacuo to give a residue. The residue was diluted with water 20 mL, and then extracted with DCM (100 mL X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (600 mg, 98% yield) as white solid. 1H NMR (400MHz, DMSO-t/6) δ 7.10 (s, 2H), 6.93 (s, IH), 4.97 (t, J= 5.6 Hz, IH), 4.61 (s, 2H), 4.01 (t, J= 5.6 Hz, 2H), 3.69 (q, J= 5.6 Hz, 2H).

[002241] Tert-butyl N-[4-[4-[[3-carbamoyl-l-(2-oxoethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (Intermediate HG)

[002242] Step 1 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-(2-hydroxyethyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[002243] To a solution of 4-amino-l-(2-hydroxyethyl)pyrazole carboxamide (500 mg, 2.94 mmol, Intermediate HF) in DMF (15 mL) was added 2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carboxylic acid (844 mg, 2.35 mmol, synthesized via Steps 1-4 of Intermediate DF), DIPEA(1.14g, 8.81 mmol) and HATU (1.23 g, 3.23 mmol). The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was diluted with water 80 mL, filtered to give the filter cake which was dried in vacuo to give the title compound (1.00 g, 67% yield) as light yellow solid; LC-MS (ESI+) m/z 512.4 (M+H)+.

[002244] Step 2 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-(2-oxoethyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[002245] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-(2-hydroxyethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (300 mg, 486 umol) in THF (50 mL) was added DMP (412 mg, 973 umol), and the mixture was stirred at 10 °C for 16 hours. On completion, the reaction mixture was filtered to give the filtrate, which was then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (90.0 mg, 33% yield) as light yellow solid; LC-MS (ESI+) m/z 528.3 (M+H+H2O)+.

[002246] 1- [2- [2- [2- [3-(2-Aminoethoxv)propoxy] ethoxy] ethoxy] ethyl] nitro-Dyrazole-

3- carboxamide (Intermediate HH)

BocHN^O^O&#1470;^O'^O/'''-&#1523;OH

BocHN

OMs

MsCI, TEA

DCM

HCI/dioxane ------&#9658;

DCM

HCI

HH

[002247] Step 1:2-[2-Γ2-Γ2-Γ2-(Τ61&#912;butoxycarbonylamino)ethoxy1ethoxy1ethoxy1ethoxy]ethyl methane sulfonate

[002248] To a solution of tert-butyl N-[2-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (4.00 g, 11.9 mmol, CAS# 1404111 6) and TEA(3.00 g, 29.6 mmol) in DCM (40 mL) was added MsCI (1.77 g, 15.4 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched with water (20 mL), and extracted with DCM. The organic layer was washed with water (50 mL) and brine (50 mL), dried with Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound (4.65 g, 94% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 5.05 (s, IH), 4.41-4.31 (m, 2H), 3.79 - 3.74 (m, 2H), 3.69 - 3.58 (m, 12H), 3.56 - 3.51 (m, 2H), 3.34 - 3.27 (m, 2H), 3.08 (s, 3H), 1.44 (s, 9H).

[002249] Step 2 - Tert-butyl N-r2-r2-r2-r2-r2-(3-carbamoyl nitro-pyrazol-lvDethoxy]ethoxy]ethoxy]ethoxy] ethyUcarbamate

[002250] To a solution of 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (4.59 g, 11.1 mmol) and 4-nitro-lH-pyrazole carboxamide (1.50 g, 9.61 mmol, Intermediate CJ) in DMF (25 mL) was added Cs2CO3 (7.20 g, 22.1 mmol). The reaction mixture was stirred at 125 °C for 15 hours.

On completion, the mixture was filtered and the filtrate was concentrated in vacuo, and the residue was purified by reverse phase (0.1% HC1 condition) to give the title compound (1.45 g, 31% yield) as yellow oil. LC-MS (ESI+) m/z 498.3 (M+Na)+.

[002251] Step 3 - l-[2-[2-[2-[3-(2-Aminoethoxy)propoxy1ethoxy1ethoxy1ethyl1 nitropyrazole carboxamide

[002252] To a solution of tert-butyl N-[2-[2-[2-[2-[2-(3-carbamoyl nitro-pyrazol-lyl)ethoxy]ethoxy]ethoxy] ethoxy]ethyl]carbamate (1.45 g, 2.99 mmol) in DCM (6 mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at 25 °C for 20 minutes. On completion, the mixture was concentrated in vacuo to give the title compound (1.19 g, 94% yield) as yellow oil. 1HNMR (400MHz, DMSO-76) δ 8.83 (s, IH), 8.02 (s, IH), 7.77 (s, IH), 4.40 - 4.30 (m, 2H), 3.81 (t, J= 5.2 Hz, 2H), 3.60 (t, J = 5.2 Hz, 2H), 3.56 - 3.53 (m, 8H), 3.49 - 3.46 (m, 4H), 2.98 2.91 (m, 2H); LC-MS (ESI+) m/z 376.2 (M+H)+.

[002253] 4-Amino-l- [2- [2-[2- [2- [2- [[2-(26&#1524;-dioxo DiDeridyl)-l.,3-dioxo-isoindolin-4vHamino] ethoxy|ethoxy|ethoxvlethoxvlethvI]DvrazoIe carboxamide (Intermediate HI)

[002254] Step 1 - l-[2-[2-[2-[2-[2-[[2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin-4yl1amino1ethoxy1ethoxy1 ethoxy1ethoxy1ethyl1 nitro-pyrazole carboxamide

[002255] To a solution of l-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethyl]-4 nitro-pyrazole carboxamide (0.50 g, 1.21 mmol, HCI, Intermediate HH) and 2-(2,6-dioxo-3piperidyl) fluoro-isoindoline-l,3-dione (352 mg, 1.27 mmol, Intermediate R) in dioxane (8 mL) was added DIPEA (785 mg, 6.07 mmol). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (280 mg, 37% yield) as yellow oil. LC-MS (ESI+) m/z 632.3 (M+H)+.

[002256] Step 2 - 4-Amino-l-r2-r2-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethoxy1ethoxy1ethoxy1ethoxy1ethyl1pyrazole carboxamide

[002257] To a solution of l-[2-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]amino]ethoxy] ethoxy]ethoxy]ethoxy]ethyl] nitro-pyrazole carboxamide (140 mg, 222 umol) in THF (5 mL) was added Pd/C (0.3 g, 20% wt). The reaction mixture was stirred at 25 °C for 0.4 hour under H2 (15 Psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 75% yield) as yellow oil. LC-MS (ESI+) m/z 602.1 (M+H)+.

[002258] 2-[2-(Tert-butoxvcarbonvlamino) pyridvl]oxazole carboxvlic acid (Intermediate HJ)

NHBoc

[002259] Step 1 - Ethyl 2-r2-(tert-butoxycarbonylamino) pyridyl1oxazole carboxylate

[002260] Amixture of tert-butyl N-(4-bromo pyridyl)carbamate (1.00 g, 3.66 mmol, CAS#

207799 8), ethyl oxazole carboxylate (517 mg, 3.66 mmol, CAS# 170487 4), tris-otolylphosphane (223 mg, 732 umol), Pd(OAc)2 (82.2 mg, 366 umol) and Cs2CO3 (2.39 g, 7.32 mmol) in DMF (10 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 70 °C for 17 hrs under N2 atmosphere. On completion, the mixture was diluted with water (300 mL), and extracted with EA (3 X 200 mL). The organic layer was washed with water (400 mL), dried over Na2SO4, filtrated and concentrated in vacuo to give the title compound (1.22 g, 50% yield) as a yellow solid. LC-MS (ESI+) m/z 278.2 (M+H-56)+.

[002261] Step 2 - 2-r2-(Tert-butoxycarbonylamino) pyridyl1oxazole carboxylic acid

[002262] To a solution of methyl 2-[2-(tert-butoxycarbonylamino) pyridyl]oxazole-4 carboxylate (1.17 g, 3.66 mmol) in MeOH (5 mL) and H2O (5 mL) was added LiOHH2O (439 mg, 18.3 mmol). The mixture was stirred at 15 °C for 6 hours. On completion, the mixture was concentrated, then IM HCI was added to the residue until the pH = 5-6, and then filtered. The filter cake was dried in vacuo to give the title compound (400 mg, 28% yield) as a yellow solid. 1H NMR (400MHz, DMSO&#1470;d6) δ 13.37 (br s, IH), 10.31 - 10.12 (m, IH), 9.13 - 8.95 (m, IH), 8.52 (s, IH), 8.50 (d, J = 5.4 Hz, IH), 7.63 - 7.58 (m, IH), 1.69 - 1.53 (m, 9H); LC-MS (ESI+) m/z 250.2 (M+H56&#1470;)+.

[002263] 4-[2-[2-[(2S) (aminomethvl)morDholin vl]ethoxv]ethylamino] (2,6dioxo-S-piperidyl) isoindoline-l,3-dione (Intermediate HK)

HK

[002264] Step 1 - Tert-butyl N-rr(2S) r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxo isoindolin yl1amino1 ethoxy1ethyl1morpholin yl1methyl1carbamate

[002265] To a solution of 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethyl methanesulfonate (460 mg, 1.05 mmol, synthesized via Steps 1-2 of Example 184) and tert-butyl N-[[(2R)-morpholin yl]methyl]carbamate (453 mg, 2.09 mmol, CAS# 186202 3) in ACN (15 mL) was added KI (17.4 mg, 105 umol) and NaHCO3 (264 mg, 3.14 mmol). The reaction mixture was stirred at 80 °C for 17 hrs. On completion, the mixture was concentrated m vacuo. The residue was purified by silica gel chromatography to give the title compound (530 mg, 91% yield) as a yellow solid. LC-MS (ESI+) m/z 560.2 (M+H)+.

[002266] Step 2 - 4-r2-r2-r(2S) (aminomethyl)morpholin yl1ethoxy1ethylamino1 (2,6dioxo piperidyl) isoindoline-L3-dione

[002267] To a solution of tert-butyl N-[[(2S) [2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo isoindolin yl] amino]ethoxy]ethyl]morpholin yl]methyl]carbamate (630 mg, 1.13 mmol) in DCM (6 mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at 15 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (550 mg, 99% yield) as a yellow solid. LC-MS (ESI+) m/z 460.4 (M+H)+.

[002268] Methyl 4-nitro-lH-Dvrazole carboxylate (Intermediate HL)

no2 no2

[002269] ML

[002270] To a solution of 4-nitro-lH-pyrazole carboxylic acid (50.0 g, 318 mmol, CAS#5334 7) in MeOH (250 mL) was added SOC12 (56.8 g, 477 mmol). The mixture was stirred at 70 °C for 5 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (54.0 g, 99% yield) as white solid. 1H NMR (400MHz, DMSO-d6) δ 14.40 (s, IH), 9.98 (s, IH), 3.89 (s, 3H).

[002271] Tert-butyl (cvcloDropvlmethvl)(4-(4-((l-(4-formvlphenvl) (trifluoromethyl)IH-pyrazol- 4-yl)carbamoyl)oxazol yl)pyridin yl)carbamate (Intermediate HM)

HM

[002272] Step 1 - 4-(4-(2-(2-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4yl)oxazole carboxamido)-3 -(trifluoromethyl)- IH-pyrazol-1 yl)b enzoi c(i sopropyl carb oni c)anhy dri de

[002273] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carbonyl]amino] (trifluoromethyl)pyrazol-l-yl]benzoic acid (700 mg, 960 umol, Intermediate EG) in THF (10 mL) was added TEA (194 mg, 1.92 mmol). Then, the reaction mixture was cooled to -10 °C. After, isopropyl carbonochloridate (235 mg, 1.92 mmol) was added and the reaction mixture was stirred at -10 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (720 mg, 91% yield) as white solid. LC-MS (ESI+) m/z 699.0 (M+H)+.

[002274] Step 2 - Tert-butyl (cy cl opropylmethyl)(4-(4-((l-(4-(hydroxym ethyl )phenyl)-3 (trifluoromethyl)-IH- pyrazol yl)carbamoyl)oxazol yl)pyridin yl)carbamate

[002275] To a solution of isopropoxycarbonyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(trifluoromethyl)pyrazol-l-yl]benzoate (720 mg, 876 umol) in THF (20 mL) was added NaBH4 (66.3 mg, 1.75 mmol) and water (63.1 mg, 3.50 mmol). The residue was mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched with water (5 mL) and the mixture was extracted with DCM (3 X 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (520 mg, 99 % yield) as a white solid. 1HNMR (400MHz, CDCh) δ 9.06 (s, IH), 8.88 (s, IH), 8.54 (d, J= 5.2 Hz, IH), 8.42 (s, IH), 8.36 (s, IH), 7.76 (d, J= 8.4 Hz, 2H), 7.64 (d, J= 4.8 Hz, IH), 7.51 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H), 3.96 (d, J= 7.2 Hz, 2H), 1.59 (s, 9H), 0.93 0.81 (m, IH), 0.47 - 0.42 (m, 2H), 0.30 - 0.26 (m, 2H); LC-MS (ESI+) m/z 599.2 (M+H)+.

[002276] Step 3 - Tert-butyl (cyclopropylmethyl)(4-(4-((l-(4-formylphenyl)-3(trifluoromethyl)-IH-pyrazol- 4-yl)carbamoyl)oxazol yl)pyridin yl)carbamate

[002277] To a solution of tert-butyl X-(cyclopropylmethyl)-7V-[4-[4-[[l-[4(hydroxymethyl)phenyl] (trifluoromethyl)pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]carbamate (320 mg, 535 umol) in DCM (10 mL) was added DMP (454 mg, 1.07 mmol). The reaction mixture was stirred at 25 °C for 5 hours. On completion, the reaction mixture was quenched with saturated Na2S2O3 (20 mL), and extracted with DCM (3 X 30 mL). The combined organic layers was washed with saturated NaHCO3 (2 X 20 mL), then washed with brine (30 mL), dried over with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% HC1) to give the title compound (123 mg, 39% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 10.08 (s, IH), 9.08 (s, IH), 9.01 (d, J= 5.2 Hz, IH), 8.98 (s, IH), 8.57 (s, IH), 8.06 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 7.45 (s, IH), 7.39 (s, IH), 3.35 (s, 2H), 1.67 (s, 9H), 1.15 - 1.05 (m, IH), 0.78 - 0.76 (m, 2H), 0.45 - 0.44 (m, 2H).

[002278] 3-(5-bromo methvl oxo-benzimidazol-l-yl)DiDeridine-2,6-dione (3-(5bromo methyl oxo-2,3-dihydro-lH-l,3-benzodiazol-l-yl)DiDeridine-2,6-dione)

HN

[002279] Step 1 - [l-[(4-Methoxyphenyl) methyl]-2,6-dioxo piperidyl] trifluoromethanesulfonate

[002280] To a solution of 3-hydroxy-l-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (43.0 g, 173 mmol, Intermediate IQ) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethyl sulfonyl trifluoromethanesulfonate (73.0 g, 258.74 mmol) dropwise at 0 °C. The mixture was stirred at 0-10 °C for 1.5 hours under N2. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (45.0 g, 68% yield) as light yellow gum. 1H NMR (400MHz, CDCh) δ 7.36 (d, J = 8.4 Hz, 2H), 6.85 - 6.82 (m, 2H), 5.32 - 5.28 (m, IH), 4.91 (s, 2H), 3.79 (s, 3H), 3.02 - 2.97 (m, IH), 2.79 - 2.74 (m, IH), 2.41 - 2.35 (m, 2H).

[002281] Step 2:3 -(5-Bromo-3 -methyl oxo-benzimidazol-1 -yl) 1(4methoxvphenvl)methyl1piperidine-2.6 -dione

[002282] To a solution of 5-bromo methyl-lH-benzimidazol one (4.90 g, 21.6 mmol, Intermediate IP) in THF (300 mL) was added t-BuOK (3.63 g, 32.3 mmol) at 0 °C. The mixture was stirred at 0-10°C for 1 hour under N2. Then a solution of [l-[(4-methoxyphenyl) methyl]-2, 6dioxo piperidyl] trifluoromethanesulfonate (9.87 g, 25.9 mmol) in THF (100 mL) was added to the reaction mixture at 0-10°C during 30 minutes. The mixture was stirred at 0-10°C for 30 minutes under N2. An additional solution of [l-[(4 -methoxyphenyl) methyl]-2, 6-dioxo piperidyl] trifluoromethanesulfonate (2.47 g, 6.47 mmol) in THF (20 mL) was added to the reaction mixture at 0-10°C dropwise. The mixture was then stirred at 0-10°C for another 30 minutes under N2. On completion, the reaction was quenched water (400 mL) and extracted with EA (3 X 200 mL). The combined organic layer was concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound (6.70 g, 67% yield) as light yellow solid. The filtrate was also concentrated in vacuo and the residue was purified by column chromatography to give another batch title compound (1.80 g, 18% yield) as light yellow solid. 1HNMR (400MHz, DMSO-A) δ 7.47 (d, J= 1.6 Hz, IH), 7.21-7.16 (m, 3H), 7.01 (d, J = 8.0 Hz, IH), 6.85 (d, J = 8.8 Hz, 2H), 5.55 - 5.51 (m, IH), 4.84 - 4.73 (m, 2H), 3.72 (s, 3H), 3.33 (s, 3H), 3.04 - 3.00 (m, IH), 2.83 - 2.67 (m, 2H), 2.07 - 2.05 (m, IH).

[002283] Step 3 - 3-(5-Bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione

[002284] To a mixture of 3-(5-bromo methyl oxo-benzimidazol-l-yl)-l-[(4methoxyphenyl)methyl] piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was added methanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15 °C). The mixture was stirred at 120 °C for 2 hours. On completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice/water (200 mL), and extracted with EA(3 X 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filtrate cake was collected and dried in vacuo to give the title compound (4.20 g, 67% yield) as off-white solid. 1HNMR (400MHz, DMSO-A) δ 11.12 (s, IH), 7.47 (d, J= 2.0 Hz, IH), 7.22 (d, J = 8.4 Hz, IH), 7.10 (d, J = 8.4 Hz, IH), 5.40 - 5.35 (m, IH), 2.34 (s, 3H), 2.92 - 2.88 (m, IH), 2.71 - 2.60 (m, 2H), 2.03 - 1.99 (m, IH).

[002285] 3-[5-[3-[2-(2-Aminoethoxv)ethoxv]DroDvl] methyl oxo-benzimidazol-lyllpiperidine-2.,6 -dione (Intermediate HO)

[002286] Step 1 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxylethoxylethyllcarbamate

[002287] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (350 mg, 1.04 mmol, Intermediate HN) and tert-butyl N-[2-(2-prop-2ynoxyethoxy)ethyl]carbamate (629 mg, 2.59 mmol, synthesized via Step 1 of Intermediate CQ) in DMF (10 mL) was added TEA (2.62 g, 25.8 mmol, 3.60 mL), Cui (98.5 mg, 517 umol) and Pd(PPh3)2C12 (363 mg, 517 umol). The reaction mixture was stirred at 80 °C for 1.5 hours under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in DCM (20 mL) and thiourea (resin) (300 mg) was added. The mixture was stirred at 20 °C for 12 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (208 mg, 40% yield) as yellow solid. LC-MS (ESI+) m/z 523.3 (M + Na)+. 1HNMR (400MHz, DMSO-i/6) δ 11.13 (s, IH), 7.34 (d, J= 0.8 Hz, IH), 7.227.12 (m, 2H), 6.83 - 6.70 (m, IH), 5.40 (dd, J = 5.6, 12.8 Hz, IH), 4.40 (s, 2H), 3.67 - 3.61 (m, 2H), 3.60 - 3.54 (m, 2H), 3.40 (t, J = 6.0 Hz, 2H), 3.35 (s, 3H), 3.08 (q, J = 6.0 Hz, 2H), 2.96 2.84 (m, IH), 2.73 - 2.60 (m, 2H), 2.09 - 2.00 (m, IH), 1.38 (s, 9H).

[002288] Step 2 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl]propoxy] ethoxy1ethyl1carbamate

[002289] To a solution of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]ethoxy]ethyl]carbamate (100 mg, 199 umol) in THF (10 mL) was added Pd(OH)2/C (50 mg, 10 wt%) and Pd/C (50 mg, 10 wt%), and the reaction mixture was stirred under H2 (15 psi) for 1 hr. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 99.2% yield) as yellow oil. LC-MS (ESI+) m/z 527.4 (M + Na)+.

[002290] Step 3- 3-r5-r3-r2-(2-Aminoethoxy)ethoxy]propyl] methyl oxo-benzimidazoll-yl]piperidine-2,6 -dione

[002291] To a solution of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]ethyl]carbamate (100 mg, 198.19 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL), and the reaction mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (85.0 mg, 97% yield) as yellow oil. LC-MS (ESI+) m/z 405.2(M+H)+. 1H NMR (400MHz, DMSO-d6) δ 7.09 6.96 (m, 2H), 6.88 (d, J= 7.6 Hz, IH), 5.34 (dd, J = 5.2, 12.8 Hz, IH), 3.57 - 3.49 (m, 6H), 3.41 (t, J = 6.4 Hz, 2H), 3.33 (s, 3H), 2.98 - 2.83 (m, 2H), 2.76 - 2.68 (m, IH), 2.64 - 2.68 (m, 2H), 2.63 - 2.54 (m, IH), 2.46 - 2.44 (m, IH), 2.04 - 1.97 (m, IH), 1.87 - 1.78 (m, 2H).

[002292] 3-(4-bromo methyl oxo-2.,3-dihvdro-lH-benzo[d1imidazol-lyl)Diperidine-2.,6-dione (Intermediate HP)

[002293] Step 1 - 2-Bromo-N-methyl nitro-aniline

[002294] To a solution of l-bromo fluoro nitro-benzene (40.0 g, 181 mmol, CAS#

58534 4) in THF (40 mL) was added MeNH2 (2 M, 400 mL). The reaction mixture was stirred at 60 °C for 12 hours. On completion, the reaction mixture was poured into sat.NaHCO3 (30 mL) and extracted with EA (3 X 200 mL). The combined organic layers were washed with brine (2 X 200 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (40.0 g, 95% yield) as red oil. LC-MS (ESI+) m/z 230.9 (M+H) +.

[002295] Step 2 - 3-B romo-N2-m ethyl-benzene-L2-diamine

[002296] To a mixture of 2-bromo-N-methyl nitro-aniline (23.0 g, 99.5 mmol) in EA (300 mL) and H2O (10 mL) was added AcOH (100 mL). The mixture was warmed to 50 °C. Then Fe (22.2 g, 398 mmol) was added to the reaction mixture and the mixture was heated to 80 °C about 4 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EA (3 X 200 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (20.0 g, 99% yield) as red oil. 1HNMR (400MHz, DM SO-6/6) δ 6.73 - 6.70 (m, IH), 6.68 - 6.60 (m, 2H), 5.02 (s, 2H), 3.67 (s, IH), 2.58 (s, 3H).

[002297] Step 3 - 4-Bromo methyl-lH-benzimidazol one

[002298] To a mixture of 3-bromo-N2-m ethyl-benzene-1,2-diamine (20.0 g, 99.4 mmol) in

ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reaction mixture was stirred at 85 °C for 12 hours under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo. The reaction mixture was diluted with water (200 mL), where a solid precipitate was formed, which was filtered off. The solid was washed with water (1 L) and dried in vacuo to give the title compound (20.0 g, 88% yield) as white solid. 1H NMR (400MHz, DM SO-6/6) δ 11.17 (s, IH), 7.14 (dd, J= 1.2, 8.0 Hz, IH), 7.00 - 6.95 (m, IH), 6.93 - 6.87 (m, IH), 3.55 (s, 3H).

[002299] Step 4:3 -(4-Bromo-3 -methyl oxo-benzimidazol-1 -yl) 1(4methoxvphenvDmethyllpiperidine- 2,6-dione

[002300] To a solution of 4-bromo methyl-lH-benzimidazol one (12.0 g, 52.8 mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reaction mixture was stirred at 0 °C for 0.5 hr. Subsequently, [l-[(4-methoxyphenyl)methyl]-2,6-dioxo piperidyl] trifluoromethanesulfonate (20.1 g, 52.8 mmol, Intermediate IQ) in a solution of THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at 20 °C for 0.5 hr under N2. On completion, the reaction mixture was quenched with saturated NH4C1 (100 mL), and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (2 X 100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (13.3 g, 55% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.38 (d, J= 8.8 Hz, 2H), 7.22 (d,J= 8.0 Hz, IH), 6.84 (d, J = 8.8 Hz, 2H), 6.80 (t, J = 8.0 Hz, IH), 6.48 - 6.40 (d, J = 8.0 Hz, IH), 5.22 (dd, J = 5.2, 12.8 Hz, IH), 5.04 - 4.93 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.12 - 2.98 (m, IH), 2.93 - 2.77 (m, IH), 2.62 (dq, J= 4.4, 13.2 Hz, IH), 2.20 - 2.17 (m, IH).

[002301] Step 5 - 3-(4-bromo methyl oxo-2,3-dihydro-lH-benzold1imidazol-lyl)piperidine-2,6-dione

[002302] A mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)-l-[(4methoxyphenyl)methyl]piperidine -2,6-dione (13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methane sulfonic acid (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 120 °C for 2 hrs under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to remove toluene. The residue was added 200 mL of ice water, and then white solid precipitate formed. The mixture was filtered and the filtered cake was collected and dried over in vacuo to give the title compound (7.30 g, 74% yield) as white solid. 1H NMR (400MHz, DMSO-/6) δ 11.13 (s, IH), 7.25 (d, J = 8.0 Hz, IH), 7.17 (d, J = 8.0 Hz, IH), 7.05 - 6.93 (m, IH), 5.41 (dd, J= 5.2, 12.8 Hz, IH), 3.64 (s, 3H), 2.96 - 2.83 (m, IH), 2.78 - 2.59 (m, 2H), 2.08 - 2.00 (m, IH).

[002303] 32142[3212ζ(22Αη1&#912;ηθ6&#943;11Ο2&#943;χ)6&#943;11Ο2&#943;χ12£Ο2χ11ζ32η16&#943;11χ1222Ο2&#943;Ο2Β6η2&#912;η1Μ32θ121:

yl] piperidine -2,6-dione (Intermediate HQ)

NHBoc

Pd(PPh3)CI2, Cui, TEA, DMF

NHBoc

Pd(OH)2/C, Pd/C, H2, THF

[002304] Step 1 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1prop ynoxy1ethoxy1ethyl1carbamate

[002305] To a mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (100 mg, 295 umol, Intermediate HP) and tert-butyl N-[2-(2-prop-2ynoxyethoxy)ethyl]carbamate (93.5 mg, 384 umol, synthesized via Step 1 of Intermediate CQ) in DMF (5 mL) was added Cui (5.63 mg, 29.5 umol), Pd(PPh3)2C12 (20.7 mg, 29.5 umol) and TEA (538 mg, 5.32 mmol, 740 uL). The reaction mixture was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Kromasil 150*25mm*10um; mobile phase: [water (0.225%FA)ACN]) to give the title compound (55.0 mg, 34% yield, FA) as brown solid. 1H NMR (400MHz, DMSO-76)5 11.12 (s, IH), 7.18 (d, 7= 7.6 Hz, IH), 7.13 (d, J= 7.6 Hz, IH), 7.08 - 7.00 (m, IH), 6.76 (s, IH), 5.41 (dd, J= 4.4, 12.4 Hz, IH), 4.47 (s, 2H), 3.69 - 3.65 (m, 2H), 3.65 (s, 3H), 3.57 (d, 7= 4.4 Hz, 2H), 3.40 (t, 7= 6.0 Hz, 2H), 3.08 (d, 7= 5.6 Hz, 2H), 2.96 - 2.84 (m, IH), 2.77 2.63 (m, 2H), 2.09 - 1.97 (m, IH), 1.37 (s, 9H). LC-MS (ESI+) m/z 501.4 (M+H)+.

[002306] Step 2 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1propoxy1 ethoxylethyllcarbamate

[002307] To a mixture of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]ethoxy]ethyl]carbamate (50.0 mg, 99.8 umol) in THF (4 mL) was added Pd/C (15 mg, 10 wt%) and Pd(OH)2/C (15 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 1 hour under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (50.0 mg, 99% yield) as brown oil. LC-MS (ESI+) m/z 505.4 (M+H)+.

[002308] Step 3 - 3-r4-r3-r2-(2-Aminoethoxy)ethoxy1propyl1 methyl oxobenzimidazol-l-yl1piperidine -2,6-dione

[002309] To a mixture of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]ethyl]carbamate (50.0 mg, 99.0 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (43.0 mg, 98% yield, HCI) as colourless oil. LC-MS (ESI+) m/z 405.3 (M+H)+.

[002310] 4-[2-[2-[(2R) (aminomethvl)morpholin vl]ethoxy]ethvlamino] (2,6dioxo Diperidyl) isoindoline-l,3-dione (Intermediate HR)

HCl/dioxane, DCM

[002311] Step 1 - Tert-butyl N-rr(2R) r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethoxy1ethyl1morpholin yl1methyl1carbamate

[002312] To a solution of 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4 yl]amino]ethoxy]ethyl methanesulfonate (500 mg, 1.14 mmol, synthesized via Steps 1-2 of Example 184), tert-butyl N-[[(2S)-morpholin yl]methyl] carbamate (492 mg, 2.28 mmol, CAS# 875551 0) in ACN (20.0 mL) was added KI (18.8 mg, 113 umol) and NaHCO3 (286 mg, 3.41 mmol). The mixture was stirred at 80 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (DCM: MeOH = 50: 1) to give the title compound (400 mg, 62% yield) as yellow solid. 1HNMR (400MHz, CDC13) δ 8.38 - 8.13 (m, IH), 7.46 - 7.40 (m, IH), 7.04 (d, J = 7.2 Hz, IH), 6.83 (d, J = 8.8 Hz, IH), 6.43 (s, IH), 4.94 - 4.81 (m, 2H), 3.80 - 3.72 (m, IH), 3.67 - 3.54 (m, 6H), 3.41 - 3.34 (m, 2H), 3.34 - 3.18 (m, IH), 3.07 2.94 (m, IH), 2.84 - 2.75 (m, 2H), 2.73 - 2.66 (m, 2H), 2.61 - 2.49 (m, 2H), 2.21 - 2.09 (m, IH), 2.08 - 2.01 (m, IH), 1.95 - 1.85 (m, IH), 1.69 - 1.55 (m, IH), 1.36 (s, 9H).

[002313] Step 2 - 4-r2-r2-r(2R) (aminomethyl)morpholin yl1ethoxy1ethylamino1-2(2,6-dioxo piperidyl) isoindoline-L3-dione

[002314] To a solution of tert-butyl N-[[(2R) [2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]ethoxy]ethyl]morpholin yl]methyl]carbamate (380 mg, 679 umol) in DCM (3.00 mL) was added HCl/dioxane (4 M, 5.00 mL). The mixture was stirred at 15 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (330 mg, 95% yield) as yellow solid. LC-MS (ESI+) m/z 460.1 (M+H)+.

[002315] 3-(Difluoromethvl) nitro-lH-Dvrazole (Intermediate HS)

[002316] Step 1 - l-Benzyl-lH-pyrazole carbaldehyde

[002317] To a solution of lH-pyrazole carbaldehyde (5.00 g, 52.0 mmol, CAS#: 3920-501) and BnBr (9.34 g, 54.6 mmol) in DMF (50 mL) was added Cs2CO3 (42.4 g, 130 mmol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was diluted with water, extracted with ethyl acetate (3 X 100 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (Petroleum ether: Ethyl acetate = 20:1) to give the title compound (8.00g, 83% yield) as a colorless oil. 1H NMR. (400MHz, CDCh) δ 10.02 (s, IH), 7.44 (d, J = 2.4 Hz, IH), 7.43 - 7.33 (m, 3H), 7.29 - 7.24 (m, 2H), 6.85 (d, J = 2.4 Hz, IH), 5.42 (s, 2H).

[002318] Step 2 - l-Benzyl (difluoromethyl)-lH-pyrazole

[002319] To a solution of 1-benzylpyrazole carbaldehyde (5.00 g, 26.9 mmol) in DCM (30 mL) was added DAST (17.3 g, 107 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 5 hours. On completion, the reaction mixture was quenched with methanol (30 mL) at 0 °C. After, the mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20:1) to give the title compound (3.30 g, 59% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 7.43 - 7.36 (m, 3H), 7.27 - 7.21 (m, 2H), 6.91 - 6.57 (m, IH), 6.55 - 6.51 (m, IH), 5.35 (s, 2H); LC-MS (ESI+) m/z 209.1 (M+H)+.

[002320] Step 3 - 3-(Difluoromethyl)-IH-pyrazole

[002321] To a solution of l-benzyl (difluoromethyl)pyrazole (1.00 g, 4.80 mmol) in methanol (20 mL) was added Pd(OH)2/C (0.1 g, 10% purity) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred at 40 °C for 12 hrs under H2 (50 Psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (470 mg, 83% yield) as colorless oil. 1H NMR (400MHz, DMSO-t/6) δ 13.16 (s, IH), 7.85 (s, IH), 7.14 - 6.82 (m, IH), 6.52 (s, IH).

[002322] Step 4 - 3-(Difluoromethyl) nitro-lH-pyrazole

[002323] To a solution of 3-(difluoromethyl)-lH-pyrazole (470 mg, 3.98 mmol) in H2SO4 (5 mL) was carefully added a 65% solution of HNO3 (965 mg, 9.95 mmol) dropwise at 0 °C. After stirring for 10 minutes, the reaction mixture was heated to 115 °C, and stirred for 12 hrs. On completion, the reaction mixture was cooled to 25 °C. Then, the reaction mixture was poured onto the (100 mL) ice, extracted with ethyl acetate (3 X 50 mL). The combined organic layers was washed with brine (2 X 50 mL), dried over with anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (530 mg, 82% yield). 1H NMR (400MHz, DMSO-t/6) δ 14.41 (s, IH), 9.04 (s, IH), 7.50 - 7.17 (m, IH), 7.50 - 7.17 (m, IH).

[002324] 142(32(&#971;&#912;&#943;111ΟΤΟ1η6&#943;11χ1)2Κ11&#912;&#943;£θΣ1ΗζΕ1£2&#943;θ1ζ1ζ11)ζ356595122&#943;6&#943;Τ3ΟΧ3&#943;6&#943;Τ3&#940;6£3Ι12 l-3mine (Intermedi3te HT)

[002325] Step 1 - Tert-butyl N-r2-r2-[2-r2-r2-r3-(difluoromethyl) nitro-pyrazol-lyl]ethoxy]ethoxy]ethoxy] ethoxylethyllcarbamate

[002326] To a solution of 3-(difluoromethyl) nitro-lH-pyrazole (200 mg, 1.23 mmol, Intermediate HS) and 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (560 mg, 1.35 mmol, synthesized via Step 1 of Intermediate HH) in DMF (5 mL) was added Cs2CO3 (799 mg, 2.45 mmol). The reaction mixture was stirred at 130 °C for 12 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by prepHPLC (condition: 0.1% HC1) to give the title compound (220 mg, 36% yield) as a yellow oil. 1H NMR (400MHz, DMSO-Y) δ 8.99 (s, IH), 7.51 - 7.16 (m, IH), 6.76 (s, IH), 4.41 (t, J = 5.2 Hz, 2H), 3.83 (t, J= 5.2 Hz, 2H), 3.61 - 3.44 (m, 13H), 3.61 - 3.44 (m, IH), 3.05 (q, J= 5.6 Hz, 2H), 1.37 (s, 8H); LC-MS (ESI+) m/z 505.4 (M+Na)+.

[002327] Step 2:14-(3 -(Difluoromethyl) nitro-1 H-pyrazol-1 -yl)-3,6,9,12tetraoxatetradecan-1 -amine

[002328] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[3-(difluoromethyl) nitro-pyrazol-lyl]ethoxy]ethoxy] ethoxy]ethoxy]ethyl]carbamate (220 mg, 456 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 114 uL). The reaction mixture was stirred at 20 °C for 15 min. On completion, the reaction mixture was concentrated in vacuo to give the title compound (191 mg, 100% yield) as yellow oil. LC-MS (ESI+) m/z 383.0 (M+H)+.

[002329] 4-((14-(4-Amino (difluoromethvl)-lH-Dvrazol-l-yl)-3.,6.,9,12912 tetraoxatetradecyl)amino) (26&#1524;-dioxoDiDeridin yl)isoindoline-l.,3-dione (Intermediate

HU

Pd/C, H2, MeOH

[002330] Step 1 - 4-((14-(3-(Difluoromethyl) nitro-lH-pyrazol-l-yl)-3,6,9,12tetraoxatetradecyl)amino) (2,6-dioxopiperidin yl)isoindoline-L3-dione

[002331] To a solution of 2-[2-[2-[2-[2-[3-(difluoromethyl) nitro-pyrazol-lyl]ethoxy]ethoxy]ethoxy]ethoxy] ethanamine (191 mg, 456 umol, Intermediate HT) and 2-(2,6dioxo piperidyl) fluoro-isoindoline-l,3-dione (139 mg, 502 umol, Intermediate R) in dioxane (10 mL) was added DIPEA (295 mg, 2.28 mmol). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (condition: 0.1% HCI) to give the title compound (170 mg, 58% yield) as a yellow oil. 1H NMR (400MHz, DMSO-t/6) δ 11.10 (s, IH), 8.98 (s, IH), 7.58 (t, J = 7.6 Hz, IH), 7.45 7.18 (m, IH), 7.14 (d, J = 8.4 Hz, IH), 7.04 (d, J = 6.8 Hz, IH), 6.60 (s, IH), 5.06 (dd, J = 4.8, 13.2 Hz, IH), 4.43 - 4.37 (m, 2H), 3.82 (t, J = 4.8 Hz, 2H), 3.64 - 3.59 (m, IH), 3.61 (d, J = 4.8 Hz, IH), 3.56 - 3.46 (m, 14H), 2.97 - 2.80 (m, IH), 2.65 - 2.55 (m, 2H), 2.09 - 1.98 (m, IH); LCMS (ESI+) m/z 639.1 (M+H) +.

[002332] Step 2 - 4-((14-(4-Amino (difluoromethyl)-lH-pyrazol-l-yl)-3,6,9,12tetraoxatetradecyl)amino) (2,6-dioxopiperidin yl)isoindoline-L3-dione

[002333] To a solution of 4-[2-[2-[2-[2-[2-[3-(difluoromethyl) nitro-pyrazol-lyl] ethoxy] ethoxy] ethoxy] ethoxy]ethylamino] (2,6-dioxo piperidyl)isoindoline-l,3-dione (170 mg, 266 umol) in methanol (20 mL) was added Pd/C (0.05 g, 10% wt) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred at 20 °C for 0.5 hr under H2 (15 Psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (130 mg, 80% yield) as yellow oil. LC-MS (ESI+) m/z 609.1 (M+H)+.

[002334] 4-Fluoro (2-oxo piperidyl)isoindoline-l.,3-dione (Intermediate HV

HV

[002335] To a solution of 4-fluoroisobenzofuran-l,3-dione (661 mg, 3.98 mmol, CAS#65239-1) ,KOAc (1.21 g, 12.3 mmol) in HO Ac (30 mL) was added 3-aminopiperi din one (0.50 g, 4.38 mmol CAS# 1892 4). Then the mixture was stirred at 90 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give a residue, which was then diluted with water 60 mL, and filtered to give the filter cake (0.60 g, 57% yield) as yellow solid. 1H NMR (400MHz, DMSOt/6) δ 7.97 - 7.86 (m, 2H), 7.79 - 7.66 (m, 2H), 4.60 (dd, J= 6.4, 12.0 Hz, IH), 3.26 - 3.14 (m, 2H), 2.27 - 2.13 (m, IH), 2.06 - 1.96 (m, IH), 1.95 - 1.86 (m, 2H).

[002336] 4-(2-Aminoethvlamino) (2-oxo piperidyl)isoindoline-l.,3-dione (Intermediate HW)

DIPEA, dioxane

NHBoc

HV

HW

[002337] Step 1 - Tert-butyl N-[2-[[L3-dioxo (2-oxo piperidyl)isoindolin-4yl1amin01ethyl1carbamate

[002338] To a solution of tert-butyl N-(2-aminoethyl)carbamate (366 mg, 2.29 mmol) in dioxane (20 mL) was added 4-fluoro (2-oxo piperidyl)isoindoline-l,3-dione (0.6 g, 2.29 mmol, Intermediate HV) and DIPEA (1.48 g, 11.4 mmol), and the mixture was stirred at 115 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (360 mg, 39.06% yield) as light yellow oil. 1H NMR (400MHz, DMSO4) δ 7.81 (s, IH), 7.55 (t, J = 8.0 Hz, IH), 7.11 (d, J= 8.4 Hz, IH), 7.07 - 6.95 (m, 2H), 6.68 (t, J= 5.6 Hz, IH), 4.50 (dd, J = 6.0, 12.6 Hz, IH), 3.44 - 3.34 (m, 2H), 3.24 - 3.16 (m, 2H), 3.14-3.09 (m, 2H), 2.25 - 2.14 (m, 2H), 1.98-1.81 (m, 3H), 1.37 (s, 9H).

[002339] Step 2 - 4-(2-Aminoethylamino) (2-oxo piperidyl)isoindoline-L3-dione

[002340] To a solution of tert-butyl N-[2-[[l,3-dioxo (2-oxo piperidyl)isoindolin-4yl]amino]ethyl] carbamate (350 mg, 869 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at 5 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (280 mg, 91% yield) as yellow solid; LC-MS (ESI+) m/z 303.2 (M+H)+.

[002341] 2-(26&#1524;-dioxo DiDeridvl) fluoro-isoindoline-l.,3-dione (Intermediate HX)

F

HX

[002342] To a mixture of 3-aminopiperidine-2,6-dione (10.8 g, 65.8 mmol, HCI) and KOAc (18.2 g, 185 mmol) in HOAc (160 mL) was added 5-fluoroisobenzofuran-1,3-dione (9.95 g, 59.9 mmol, CAS# 319 9). Then the mixture was stirred at 90 °C for 16 hours. On completion, the reaction mixture was cooled to 25 °C and diluted with water (600 mL), and then stirred at 0 °C for 0.5 hour then filtered. The filter cake was dried in vacuo to give the title compound (14.0 g, 84% yield) as black brown solid. 1HNMR (400MHz, DMSO-6/6) δ 11.15 (s, IH), 8.01 (dd, J= 4.4, 8.0 Hz, IH), 7.84 (dd, J = 2.4, 7.6 Hz, IH), 7.76 - 7.67 (m, IH), 5.17 (dd, J= 5.6, 12.8 Hz, IH), 2.97 - 2.83 (m, IH), 2.65 - 2.51 (m, 2H), 2.13 - 2.03 (m, IH).

[002343] Tert-butyl N-[2-[2-(2-oxoethoxv)ethoxy]ethvl]carbamate (Intermediate HY) _ klLjr, DMSO, (COCI)2, TEA .1UD

XX .NHBoc ’ ' u .NHBoc

HO O -------------------*&#1470; O O

DCM

HY

[002344] To a solution of DMSO (1.57 g, 20.0 mmol) in DCM (20 mL) was added a solution of (COC1)2 (2.04 g, 16.0 mmol) in DCM (15 mL) dropwise at -70 °C. The mixture was stirred at this temperature for 10 minutes. Then a solution of tert-butyl N-[2-[2-(2hydroxyethoxy)ethoxy]ethyl]carbamate (2 g, 8.02 mmol, CAS# 139115 7) in DCM (15 mL) was added into the above mixture slowly. After stirred at -70 °C for 50 minutes, TEA (6.49 g, 64.2 mmol) was added and the reaction mixture was stirred at -70 °C for 0.5 hr. On completion, the mixture was quenched with water (30 mL) and separated. The aqueous phase was extracted with DCM (2 X 30 mL). Then the organic phase was combined and washed with brine (2 X 50 mL), dried over Na2SO4, and concentrated in vacuo to give the title compound (1.36 g, 69% yield) as yellow oil. 1HNMR (400MHz, DM SO-0/6) δ 9.57 (s, IH), 6.80 - 6.74 (m, IH), 4.18 (s, 2H), 3.63 - 3.53 (m, 4H), 3.39 - 3.34 (m, 2H), 3.08 - 3.04 (m, 2H), 1.37 (s, 9H).

[002345] 52]JJ_flY]Y&#1509;γMLLLLLθ£lb*L&#970;Σl£lb*L&#970;Σl£ll.LΣUΞzL.12il2£LidΣlJillLLLLL*L^ piperidyl) isoindoline-l.,3-dione (Intermediate HZ)

HCI/dioxane

DCM

[002346] Step 1 - Tert-butyl 4-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-5yl1amin01piperidine-l- carboxylate

[002347] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (600 mg, 2.17 mmol, Intermediate HX) and tert-butyl 4-aminopiperidine-l-carboxylate (522 mg, 2.61 mmol, CAS# 502482 0) in DMSO (7 mL) was added DIPEA (1.40 g, 10.8 mmol, 1.89 mL). The reaction mixture was stirred at 130 °C for 1.5 hours. On completion, the mixture was diluted with H2O (10 mL), then filtered and the filtrate was concentrated in vacuo to give the title compound (250 mg, 25% yield) as a yellow solid. LC-MS (ESI+) m/z 479.2 (M+Na)+.

[002348] Step 2 - 2-(2,6-Dioxo piperidvl) (4-piperidylamino)isoindoline-L3-dione [002349] To a solution of tert-butyl 4-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]amino]piperidine-l- carboxylate (350 mg, 766 umol) in DCM (4 mL) was added HCl/dixoane (4 M, 4 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (300 m g, 99% yield) as a yellow solid. LC-MS (ESI+) m/z 357.3 (M+H)+.

[002350] Step 3 - Tert-butyl N-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1propoxv1ethyl1 carbamate

[002351] To a solution of 2-(2,6-dioxo piperidyl) (4-piperidylamino)isoindoline-l,3dione (200 mg, 509 umol, HC1) in THF (20 mL) was added TEA (103 mg, 1.02 mmol, 141 uL), the mixture was stirred at 20 °C for 10 mins, then tert-butyl N-[2-[2-(2oxoethoxy)ethoxy]ethyl]carbamate (163 mg, 661 umol, Intermediate HY), HOAc (91.7 mg, 1.53 mmol, 87.3 uL) and NaBH(OAc)3 (215 mg, 1.02 mmol) was added to the mixture, and the reaction mixture was stirred at 20 °C for 16 hr. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (110 mg, 37% yield) as a yellow solid. LC-MS (ESI+) m/z 588.1 (M+H)+.

[002352] Step 4 - 5-rr1-r2-r2-(2-Aminoethoxv)ethoxv1ethvl1 piperidvl1amino1 (2,6dioxo piperidyl) isoindoline-L3-dione

[002353] To a solution of tert-butyl N-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] -l-piperidyl]ethoxy]ethoxy]ethyl]carbamate (110 mg, 187umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (95.0 mg, 97% yield) as a yellow solid. LC-MS (ESI+) m/z 488.3 (M+H)+.

[002354] 4-[4-[2-[2-(2-Aminoethoxv)ethoxv]ethvl]piperazin-l-yl] (2,6-dioxo-3DiperidvDisoindoline -1,3-dione (Intermediate IA)

[002355] Step 1 - Tert-butyl 4-[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yllpiperazine-1 -carboxylate

[002356] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (500 mg, 1.81 mmol, Intermediate R), and tert-butyl piperazine carboxylate (404 mg, 2.17 mmol, CAS# 143238 4) in dioxane (5.00 mL) was added DIPEA (1.17 g, 9.05 mmol). The mixture was stirred at 115 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1 % HCI) to give the title compound (270 mg, 33% yield) as yellow solid. LC-MS (ESI+) m/z 465.2 (M+Na)+.

[002357] Step 2 - 2-(2,6-Dioxo piperidyl) piperazin-l-yl-isoindoline-L3-dione

[002358] To a solution of tert-butyl 4-(2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]piperazine-l -carboxylate (270 mg, 610 umol) in DCM (2.00 mL) was added HCl/dioxane (4.00 M, 3.00 mL). The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (230 mg, 95% yield, HCI) as a yellow solid. 1H NMR (400MHz, DMSO-» δ 11.12 (s, IH), 9.22 (s, IH), 7.80 - 7.74 (m, IH), 7.49 - 7.39 (m, 2H), 5.16 - 5.08 (m, IH), 3.53 - 3.48 (m, 4H), 3.33 - 3.19 (m, 4H), 2.95 - 2.83 (m, IH), 2.70 - 2.61 (m,

IH), 2.59 - 2.53 (m, IH), 2.10 - 1.97 (m, IH).

[002359] Step 3 - Tert-butyl N-r2-r2-r2-r4-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin4-yl1piperazin-l-yl1 ethoxv1ethoxv1ethyl1carbamate

[002360] To a solution of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (100 mg, 263 umol, HC1), 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (86.4 mg, 263 umol, synthesized via Step 1 of Intermediate AM) in ACN (5.00 mL) was added KI (4.38 mg, 26.4 umol) and NaHCO3 (66.5 mg, 791 umol). The mixture was stirred at 80 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give the title compound (100 mg, 60% yield) as yellow solid., LC-MS (ESI+) m/z 574.4 (M+H)+.

[002361] Step 4 - 4-r4-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1piperazin-l-yl1 (2,6-dioxo-3piperidyl)isoindoline -L3-dione

[002362] To a solution of tert-butyl N-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] piperazin-l-yl]ethoxy]ethoxy]ethyl]carbamate (70.0 mg, 122 umol) in DCM (2.00 mL) was added HCl/dioxane (4.00 M, 4.00 mL). The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (60.0 mg, 80% yield, HC1) as yellow solid. LC-MS (ESI+) m/z 474.3 (M+H)+.

[002363] 5-[4-[2-[2-(2-Aminoethoxv)ethoxv]ethvl]piperazin-l-yl] (2,6-dioxo-3DiperidvDisoindoline -1,3-dione (Intermediate IB)

Ruphos-Pd-G2, CsCO3, dioxane

HY

KOAc, NaB(OAc)3, THF

[002364] Step 1 - Tert-butyl 4-[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yllpiperazine-1 -carboxylate

[002365] 5-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (0.5 g, 1.48 mmol,

Intermediate GA), tert-butyl piperazine-l-carboxylate (552 mg, 2.97 mmol), Cs2CO3 (966 mg, 2.97 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6diisopropoxyphenyl)phenyl]-phosphane (115 mg, 148 umol, CAS# 1375325 0) in dioxane (10 mL) was degassed and then heated to 80 °C for 15 hours under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (100 mg, 14% yield) as a yellow solid. LC-MS (ESI+) m/z 465.1 (M+Na)+.

[002366] Step 2 - 2-(2,6-Dioxo piperidyl) piperazin-l-yl-isoindoline-L3-dione

[002367] To a solution of tert-butyl 4-(2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]piperazine-l- carboxylate (70 mg, 142 umol) in DCM (1 mL) was added HCl/dioxane (2 mL). The reaction mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (53.0 mg, 98% yield, HC1) as a yellow solid. LC-MS (ESI+) m/z 343.1 (M+H)+.

[002368] Step 3 - Tert-butyl N-r2-r2-r2-r4-r2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin5-yl1piperazin-l-yl1 ethoxy1ethoxy1ethyl1carbamate

[002369] To a solution of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (53 mg, 140 umol, HC1) and tert-butyl N-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (45 mg, 182 umol, Intermediate HY) in THF (10 mL) was added KO Ac (27.5 mg, 280 umol). One hour later, NaBH(OAc)3 (59.3 mg, 280 umol) was added and the reaction mixture was stirred at 20 °C for 14 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (70 mg, 87% yield) as yellow oil. LC-MS (ESI+) m/z 574.3 (M+H)+.

[002370] Step 4 - 5-r4-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1piperazin-l-yl1 (2,6-dioxo-3piperidyl)isoindoline -1,3-dione

[002371] To a solution of tert-butyl N-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] piperazin-l-yl]ethoxy]ethoxy]ethyl]carbamate (90.0 mg, 157 umol) in DCM (2 mL) was added HCl/dioxane (4 mL). The reaction mixture was stirred at 20 °C for 3 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (80 mg, 100% yield, HC1) as a yellow solid. LC-MS (ESI+) m/z 474.2 (M+H)+.

[002372] 5- [[1- [2-[2-(2-Aminoethoxv)ethoxy] ethyl] azetidin yl] amino] (2.,6-dioxo-3piperidyl) isoindoline-l.,3-dione (Intermediate IC)

HCI/dioxane, THF

Brettphos G3, Cs2CO3, dioxane

HOAc, NaBH(OAc)3, DCM

O

IC

[002373] Step 1 - Tert-butyl 3-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yllaminolazetidine carboxylate

[002374] A mixture of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (500 mg, 1.48 mmol, Intermediate GA), tert-butyl 3-aminoazetidine carboxylate (383 mg, 2.22 mmol, CAS# 193269 2), Brettphos-G3 (134 mg, 148 umol), and Cs2CO3 (1.45 g, 4.45 mmol) in dioxane (50 mL) was degassed and purged with N2 3 times. Then the mixture was stirred at 90 °C for 2 hours under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by pre-HPLC to give the title compound (90.0 mg, 13% yield) as yellow solid. LC-MS (ESI+) m/z 451.1 (M+Na)+.

[002375] Step 2 - 5-(Azetidin ylamino) (2,6-dioxo piperidyl)isoindoline-L3-dione [002376] To a solution of tert-butyl 3-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]amino]azetidine-l- carboxylate (100 mg, 233 umol) in THF (5 mL) was added HCI/dioxane (4 M, 5 mL). The mixture was stirred at 20 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (85.0 mg, 99% yield) as yellow solid. LC-MS (ESI+) m/z 329.0 (M+H)+.

[002377] Step 3 - Tert-butyl N-r2-r2-r2-r3-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin5-yl]amino] azetidin-1 -yl]ethoxy]ethoxy]ethyl]carbamate

[002378] To a mixture of 5-(azetidin ylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (85.0 mg, 233 umol), tert-butyl N-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (57.6 mg, 233 umol, Intermediate HY) in THF (10 mL) and DMF (10 mL) was added TEA (23.5 mg, 233 umol, 32.4 uL). The reaction mixture was stirred for 0.5 hour. Then HOAc (13.9 mg, 233 umol) and NaBH(OAc)3 (98.7 mg, 466 umol) was added to the reaction mixture, and the mixture was stirred at 20 °C for 48 hours under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (60.0 mg, 40% yield) as yellow oil. LC-MS (ESI+) m/z 560.4 (M+H)+.

[002379] Step 4 - 5-rr1-r2-r2-(2-Aminoethoxy)ethoxy]ethyl]azetidin yl]amino] (2,6dioxo piperidyl) isoindoline-L3-dione

[002380] To a solution of tert-butyl N-[2-[2-[2-[3-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] azetidin-l-yl]ethoxy]ethoxy]ethyl]carbamate (60.0 mg, 107 umol) in THF (5 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (50.0 mg, 95% yield) as yellow solid. LC-MS (ESI+) m/z 460.3 (M+H)+.

[002381] Tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (Intermediate ID) mud NaN3, DMF.

/x /x ,NHBoc J ,NHBoc

MsO 00

[002382]

[002383] To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (2.30 g, 7.03 mmol, synthesized via Step 1 of Intermediate AM) in DMF (20 mL) was added NaN3 (913 mg, 14.1 mmol). The reaction mixture was stirred at 80 °C for 12 hrs. On completion, the mixture was diluted with water (50 mL), and extracted with DCM (2 X 30 mL). The organic layer was washed with brine (50 mL), dried under N2 to give the title compound (1.60 g, 83% yield) as yellow oil. LC-MS (ESI+) m/z 297.1 (M+Na)+.

[002384] 4- [[1- [2-[2-(2-Aminoethoxy)ethoxy| ethyl]triazol yl] methylamino] (2.,6dioxo piperidyl)isoindoline-l.,3-dione (Intermediate IE)

copper(ll) sulfate; sodium L-ascorbate, water and tert-butanol

ID

[002385] Step 1 - Tert-butyl N-r2-r2-r2-r4-rrr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1methyl1 triazol-l-yl1ethoxy1ethoxy1ethyl1carbamate

[002386] To a solution of tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (348 mg, 1.27 mmol, Intermediate ID), CuSO4 (507 ug, 3.18 umol) and sodium;(2R) [(lS)-l,2dihydroxyethyl] hydroxy oxo-2H-furan- 3-olate (1.26 mg, 6.36 umol) in a mixed solvent of H2O (2 mL) and t-BuOH (2 mL) was added 2-(2,6-di oxo piperidyl) (prop-2ynylamino)isoindoline-l,3-dione (200 mg, 636 umol, Intermediate DN). The reaction mixture was stirred at 60 °C for 2 hours. On completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (20 mL X 3). The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE/EA=1/1) to give the title compound (0.30 g, 78% yield) as yellow solid. 1H NMR (400MHz, DMSO-/6) δ 11.11 (s, IH), 7.99 (s, IH), 7.57 (t,/=7.8 Hz, IH), 7.18 (d,/= 8.8 Hz, IH), 7.12 7.02 (m, 2H), 6.76 (t, /= 5.2 Hz, IH), 5.06 (dd, /= 5.2, 12.8 Hz, IH), 4.60 (d, /= 6.0 Hz, 2H), 4.48 (t, /= 5.2 Hz, 2H), 3.78 (t, /= 5.2 Hz, 2H), 3.52 - 3.38 (m, 4H), 3.33 - 3.28 (m, 2H), 3.03 (q, /=5 .6 Hz, 2H), 2.95 - 2.82 (m, IH), 2.63 - 2.52 (m, 2H), 2.08 - 1.99 (m, IH), 1.36 (s, 9H); LCMS (ESI+) m/z 586.4 (M+H)+.

[002387] Step 2 - 4 12 (2-Aminoethoxy)ethoxy1ethyl1triazol yl1methylamino1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[002388] To a solution of tert-butyl N-[2-[2-[2-[4-[[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] methyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (0.30 g, 502 umol) in DCM (6 mL) was added HCl/dioxane (4 M, 2.94 mL). The mixture was stirred at 5 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (0.22 g, 84% yield) as yellow solid. LC-MS (ESI+) m/z 486.3 (M+H)+.

[002389] 2-(2,6-Dioxo piperidvl) (prop vnylamino)isoindoline-l,3-dione (Intermediate IF)

DMSO, DIPEA

[002390] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (700 mg,

2.53 mmol, Intermediate HX) and prop yn-l-amine (209 mg, 3.80 mmol) in DMSO (10 mL) was added DIPEA (983 mg, 7.60 mmol). The reaction mixture was stirred at 130 °C for 1.5 hours. On completion, the mixture was diluted with water (40 mL), and extracted with DCM (2 X 30 mL). The organic layers were washed with brine (40 mL), and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (0.25 g, 27% yield) as a yellow solid. LC-MS (ESI+) m/z 312.2 (M+H)+.

[002391] 5- [[1- [2-[2-(2-Aminoethoxv)ethoxy] ethyl]triazol yl] methylamino] (2,6dioxo piperidyl) isoindoline-l,3-dione (Intermediate IG)

IF

NHBoc

[002392] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ4-ΓΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-Ε3-&#940;&#912;οχοisoindolin yl1amino1methyl1 triazol-l-yl1ethoxy1ethoxy1ethyl1carbamate

[002393] To a solution of 2-(2,6-dioxo piperidyl) (prop ynylamino)isoindoline-l,3dione (200 mg, 546 umol, Intermediate IF) and tert-butyl N-[2-[2-(2azidoethoxy)ethoxy] ethyl ]carb am ate (300 mg, 1.09 mmol, Intermediate ID) in a mixed solvent of H2O (3 mL) and t-BuOH (3 mL) was added CuSO4 (872 ug, 5.46 umol) and sodium;(2R) [(lS)l,2-dihydroxyethyl] hydroxy oxo-2H-furan olate (2.16 mg, 10.9 umol). The reaction mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was diluted with water (30 mL), and extracted with DCM (30 mL). The organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (240 mg, 75% yield) as a yellow solid. LC-MS (ESI+) m/z 586.1 (M+H)+.

[002394] Step 2 - 5-rr1-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1triazol yl1methylamino1-2(2,6-di oxo piperidyl) isoindoline-L3-dione

[002395] To a solution of tert-butyl N-[2-[2-[2-[4-[[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] methyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (240 mg, 410 umol) in DCM (2 mL) was added HCl/dioxane (4 mL). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (210 mg, 98% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 486.1 (M+H)+.

[002396] 4 |3 [2-(2-Aminoethoxy)ethoxy| ethylltriazol yl] ethylamino] (2.,6927 dioxo piperidyl) isoindoline-l.,3-dione (Intermediate IH

DIPEA, dioxane

Pentamethyl cyclopentane(PPh3)2RuCI, THF

NHBoc

HCI/dioxane, DCM

[002397] Step 1 - 4-(But yn-l-ylamino) (2,6-dioxopiperidin yl)isoindoline-L3-dione [002398] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (400 mg, 1.45 mmol, Intermediate R) and but yn-l-amine (120 mg, 1.74 mmol) in dioxane (10 mL) was added DIPEA (561 mg, 4.34 mmol). The reaction mixture was stirred at 115 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reversed phase (0.1% HC1 condition) to give the title compound (230 mg, 49% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.11 (s, IH), 7.63 - 7.56 (m, IH), 7.17 (d, J = 8.8 Hz, IH), 7.06 (d, J= &#906;.2 Hz, IH), 6.72 (t, J= 6.0 Hz, IH), 5.07 (dd, J= 5.2, 12.8 Hz, IH), 3.70 (t, J= IS Hz, IH), 3.48 (q, J = 6.8 Hz, 2H), 2.96 - 2.83 (m, 3H), 2.57 - 2.53 (m, 2H), 2.09 - 1.99 (m, IH); LC-MS (ESI+) m/z 326.1 (M+H)+.

[002399] Step 2 - Tert-butyl (2-(2-(2-(5-(2-((2-(2,6-dioxopiperidin yl)-L3dioxoisoindolin yl)amino)ethyl)- 1 H-L2.3-triazol-l-yl)ethoxy)ethoxy)ethyl )carbamate

[002400] To a solution of 4-(but ynylamino) (2,6-dioxo piperidyl)isoindoline-l,3di one (280 mg, 861 umol) and tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (472 mg, 1.72 mmol, Intermediate ID) in THF (5 mL) was added chlororuthenium(l+); 1,2,3,4,5pentamethylcyclopenta-1,3- diene;triphenylphosphane (13.7 mg, 17.2 umol, CAS: 92361 4).

The reaction mixture was stirred at 65 °C for 12 hrs under N2. On completion, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (EA: ACN = 1:1) to give the title compound (300 mg, 57% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.40 (s, IH), 7.57 - 7.52 (m, IH), 7.57 - 7.52 (m, IH), 7.28 (s, IH), 7.16 (d, J = 7.2 Hz, IH), 6.93 (d, J = 8.8 Hz, IH), 6.40 (t, J = 5.6 Hz, IH), 4.92 (d, J = 5.6 Hz, IH), 4.49 (t, J= 5.6 Hz, 2H), 3.93 (t, J= 5.6 Hz, 2H), 3.65 (q, J= 7.2 Hz, 2H), 3.55-3.51 (m, 4H), 3.44 (t, J= 5.2 Hz, 2H), 3.27 (d, J= 4.8 Hz, 2H), 3.11 (t, J= 7.2 Hz, 2H), 2.93 - 2.74 (m, 3H), 2.22 - 2.11 (m, IH), 1.45 (s, 9H); LC-MS (ESI+) m/z 600.1 (M+H)+.

[002401] Step 3 - 4-r2-r3-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1triazol yl1ethylamino1-2(2,6-di oxo piperidyl) isoindoline-L3-dione

[002402] To a solution of tert-butyl N-[2-[2-[2-[5-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]ethyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (300 mg, 500 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 7.50 mL). The reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (268 mg, 100% yield, HCI salt) as yellow solid. LC-MS (ESI+) m/z 500.1 (M+H)+.

[002403] 4- [[1- [2-[2-(2-Aminoethoxv)ethoxy] ethyl]triazol yl] methoxy] (2.,6-dioxo3-piperidvl) isoindoline-l.,3-dione (Intermediate II)

NHB0C

HCI/dioxane, DCM

[002404] Step 1 - 2-(2,6-Dioxo piperidyl) prop ynoxy-isoindoline-L3-dione

[002405] To a solution of 2-(2,6-dioxo piperidyl) hydroxy-isoindoline-l,3-dione (3.00 g, 10.9 mmol, synthesized via Step 1 of Intermediate CA) in DMF (30 mL) was added K2CO3 (1.66 g, 12.0 mmol). Then 3-bromoprop yne (1.43 g, 12.0 mmol) was added and the mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was diluted with water (200 mL), stirred and filtered. The filter cake was purified by reverse phase (0.1% HCI condition) to give the title compound (0.90 g, 26% yield) as a light yellow solid. LC-MS (ESI+) m/z 313.1 (M+H)+.

[002406] Step 2 - Tert-butyl N-r2-r2-r2-r4-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin4-yl 1 oxym ethyl 1 tri azol -1 -y 11 ethoxy] ethoxy] ethyl 1 carb am ate

[002407] To a solution of tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (527 mg, 1.92 mmol, Intermediate ID), CuSO4 (1.53 mg, 9.61 umol) and sodium;(2R) [(lS)-l,2dihydroxyethyl] hydroxy oxo-2H- furan olate (3.81 mg, 19.2 umol) in a mixed solvent of H2O (3 mL) and t-BuOH (3 mL) was added 2-(2,6-dioxo piperidyl) prop ynoxyisoindoline-1,3-dione (300 mg, 961 umol). The reaction mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was diluted with H2O (20 mL), and extracted with EA (2 X 30 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (460 mg, 82% yield) as a white solid. LC-MS (ESI+) m/z 587.3 (M+H)+.

[002408] Step 3 - 4-rr1-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1triazol yl1methoxy1 (2,6dioxo piperidyl) isoindoline-L3-dione

[002409] To a solution of tert-butyl N-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] oxymethyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (105 mg, 179 umol) in DCM (2 mL) was added HCI/dioxane (3 mL). The reaction mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (93.0 mg, 99% yield, HCI) as a white solid. LC-MS (ESI+) m/z 487.2 (M+H)+.

[002410] 4- [2-[3- [2- [2-(2-Aminoethoxylethoxy] ethylltriazol yl] ethoxy| (2.,6-dioxo3-piperidyl) isoindoline-l.,3-dione (Intermediate IJ)

HCI/dioxane, DCM

[002411] Step 1 - 4-But vnoxv (2,6-dioxo piperidyl)isoindoline-L3-dione

[002412] To a solution of 2-(2,6-dioxo piperidyl) hydroxy-isoindoline-l,3-dione (1 g, 3.65 mmol, synthesized via Step 1 of Intermediate CA) and but yn-l-ol (307 mg, 4.38 mmol, CAS# 927 2) in THF (10 mL) was added PPh3 (1.43 g, 5.47 mmol). Then a solution of DIAD (1.47 g, 7.29 mmol, 1.42 mL, 2.0 eq) in THF (10 mL) was added into the above mixture dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% HCI condition) to give the title compound (0.7 g, 59% yield) as an off-white solid. 1H NMR (300MHz, DMSO-A) δ 11.12 (s, IH), 7.86 - 7.76 (m, IH), 7.54 (d, J =8.4 Hz, IH), 7.47 (d, 7= 7.2 Hz, IH), 5.08 (dd,7=5.2, 12.8 Hz, IH), 4.31 (t, J = 6.8 Hz, 2H), 2.92 (t, J = 2.8 Hz, IH), 2.90 - 2.80 (m, IH), 2.75 - 2.66 (m, 2H), 2.64 - 2.52 (m, 2H), 2.09 - 1.97 (m, IH).

[002413] Step 2 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ5-Γ2-Γ2-(2,6-&#940;&#943;οχο ρ&#912;ρ6Γ&#938;&#940;ν1)-Τ3-&#940;&#943;οχοisoindolin yl1oxyethyl1 triazol-I&#1470;yl1ethoxy1ethoxy1ethyl1carbamate

[002414] To a solution of 4-but ynoxy (2,6-dioxo piperidyl)isoindoline-l,3-dione (0.25 g, 766 umol) and tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (420 mg, 1.53 mmol, Intermediate ID) in THF (8 mL) was added chlororuthenium(l+);l,2,3,4,5pentamethylcyclopenta-1,3- diene;triphenylphosphane (30.5 mg, 38.3 umol, CAS# 92361 4). The reaction mixture was stirred at 65 °C for 15 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (330 mg, 68% yield) as a white solid. LC-MS (ESI+) m/z 601.2 (M+H)+.

[002415] Step 3 - 4-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy1ethyl1triazol yl1ethoxy1 (2,6dioxo piperidyl) isoindoline-L3-dione

[002416] To a solution of tert-butyl N-[2-[2-[2-[5-[2-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] oxyethyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (330 mg, 522 umol) in DCM (2 mL) was added HCl/dioxane (4 mL). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (280 mg, 100% yield, HCI) as an off-white solid. LC-MS (ESI+) m/z 501.1 (M+H)+.

[002417] 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl methanesulfonate (Intermediate IK) h2n

CbzCI, NaHCO3

&#911;Η --------------’ ch3cn,h2o

CbzHN OH

MsCI, TEA, DCM

CbzHN OMs

IK

[002418] Step 1 - Benzyl N-[2-(2-hydroxyethoxy)ethyl1 carbamate

[002419] To a solution of 2-(2-aminoethoxy)ethanol (5.00 g, 47.5 mmol, 4.76 mL, CAS# 929 6) and NaHCO3 (11.9 g, 142mmol, 5.55 mL) in MeCN (50 mL) and H2O (50 mL) was added CbzCI (9.74 g, 57.07 mmol, 8.11 mL) dropwise at 0 °C. The reaction mixture was stirred at 20 °C for 12 hours. On completion, the mixture was filtered, the filtrate was extracted with EA (2 X 100 mL), and the organic phase was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography to give the title compound (10.0 g, 87.9% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 7.38 - 7.29 (m, 5H), 5.55 (s, IH), 5.10 (s, 2H), 3.73 3.69 (m, 2H), 3.57 - 3.51 (m, 4H), 3.40 (q, J= 52 Hz, 2H), 2.84 (s, IH).

[002420] Step 2 - 2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl methanesulfonate (3) Notebook Page: EW5765-602, EW5765-605

[002421] To a solution of benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (1 g, 4.18 mmol ) and TEA (1.27 g, 12.5 mmol, 1.75 mL) in DCM (10 mL) was added MsCI (574 mg, 5.02 mmol, 388 uL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was quenched with the addition of H2O (30 mL), then exacted with DCM (2 X 50 mL). The organic phase was concentrated in vacuo to give a title compound (1.30 g, 98% yield) as yellow oil. LCMS (ESH) m/z 318.2 (M +H)+.

[002422] Benzyl N-[2-(2-piperazin-l-ylethoxy)ethyl] carbamate (Intermediate IL)

CbzHN 'OMs

KI, NaHCO3, MeCN

HCI/dioxane, DCM

IK

CbzHN nA

A&#1523;nh

IL HCI

[002423] Step 1 - tert-butyl 4-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)piperazine1-carboxylate

[002424] To a solution of 2-[2-(benzyloxycarbonylamino)ethoxy]ethyl methanesulfonate (6.6 g, 20.8 mmol) and tert-butyl piperazine-l-carboxylate;hydrochloride (4.49 g, 17.3 mmol, HCI, CAS# 57260 6) in MeCN (100 mL) was added KI (287 mg, 1.73 mmol) andNaHCO3 (4.37 g, 51.9 mmol, 2.02 mL). The reaction mixture was stirred at 80 °C for 16 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (5.00 g, 71% yield) as yellow oil. 1HNMR (400MHz, CDCh) δ 7.39 - 7.28 (m, 5H), 5.58 (s, IH), 5.30 (s, IH), 5.10 (s, 2H), 3.58 (t, J= 5.6 Hz, 2H), 3.56 - 3.50 (m, 2H), 3.47 - 3.33 (m, 6H), 2.55 (t, J= 5.6 Hz, 2H), 2.42 (m, J= 4.8 Hz, 4H), 1.46 (s, 9H).

[002425] Step 2 - Benzyl N-r2-(2-piperazin-l-ylethoxy)ethyl1carbamate

[002426] To a solution of tert-butyl 4-[2-[2(benzyloxycarbonylamino)ethoxy]ethyl]piperazine-l-carboxylate (5.00 g, 12.2 mmol) in DCM (10 mL) was added HCI/dioxane (4 M, 25 mL). The reaction mixture was stirred at 25 °C for 3 hours. On completion, the mixture was concentrated in vacuo to give the title compound (3.80 g, 90% yield) as a yellow solid. LC-MS (ESI+) m/z 308.3 (M+H)+.

[002427] Tert-butyl N-[2-[2-[4-[2-(2-aminoethoxy)ethyl]DiDerazin-lyl]ethoxy]ethyl]carbamate (Intermediate IM)

CbzHN

N

BocHN

IL NH TEA, HOAc, NaBH(OAc)3, THF HCI

CbzHN

NHBoc

Pd/C, H2 H2N ++ ++ N +&#1503;

THY ^N^^^NHBoc

IM

[002428] Step 1:Tert-butyl Ν-[2-Γ2-Γ4-Γ2-Γ2(benzyloxycarbonylamino)ethoxy1ethyl1piperazin-l-yl1ethoxy1 ethyUcarbamate

[002429] To a solution of benzyl N-[2-(2-piperazin-l-ylethoxy)ethyl]carbamate (2.00 g, 6.51 mmol, Intermediate IL) in THF (50 mL) was added TEA (1.32 g, 13.0 mmol, 1.81 mL). The mixture was stirred at 25 °C for 30 min, then tert-butyl N-[2-(2-oxoethoxy)ethyl]carbamate (1.85 g, 9.11 mmol, synthesized via Step 1 of Intermediate FS), HOAc (1.17 g, 19.5 mmol, 1.12 mL) and NaBH(OAc)3 (2.76 g, 13.0 mmol) was added in the mixture. The reaction mixture was stirred at 25 °C for 24 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (2.00 g, 62% yield) as yellow oil. LC-MS (ESI+) m/z 495.4 (M+l)+.

[002430] Step 2 - Tert-butyl N-r2-r2-r4-r2-(2-aminoethoxy)ethyl1piperazin-lyl1ethoxy1ethyl1carbamate

[002431] To a solution of tert-butyl N-[2-[2-[4-[2-[2(benzyloxycarbonylamino)ethoxy]ethyl]piperazin-l-yl] ethoxy]ethyl]carbamate (1.00 g, 2.02 mmol) in THF (5 mL) was added Pd/C (500 mg, 202 umol, 10 wt %). The reaction mixture was stirred at 20 °C under H2 (15 psi) for 24 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (600 mg, 82% yield) as colorless oil. LC-MS (ESI+) m/z 361.3 (M + H)+.

[002432] 4 12 [2-(2-Aminoethoxyjethvl] piperazin-l-yl] ethoxy] ethylamino] (2.,6dioxo piperidyl)isoindoline-l.,3-dione (Intermediate IN

IM

O

Ο O HN HNk Xk' 0=( )—N |

ν I z\ .NHBoc

HCI/dioxane, DCM zNH2 0

HCI

[002433] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ4-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#943;οχο ρ&#912;ρ6Γ&#938;&#940;ν1)-Ε3-&#940;&#943;οχοisoindolin yl1amino1 ethoxy1ethyl1piperazin-l-yl1ethoxy1ethyl1carbamate

[002434] To a solution of tert-butyl N-[2-[2-[4-[2-(2-aminoethoxy)ethyl]piperazin-lyl]ethoxy]ethyl]carbamate (300 mg, 832 umol, Intermediate IM) and 2-(2,6-dioxo piperidyl)-4fluoro-isoindoline-1,3-dione (229 mg, 832 umol, Intermediate R) in DMSO (10 mL) was added DIPEA (537 mg, 4.16 mmol, 724 uL). The reaction mixture was stirred at 90 °C for 2 hours. On completion, the mixture was diluted with H2O (30 mL), then extracted with DCM (2 X 60 mL). The combined organic phase was washed with brine, and then concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (200 mg, 39% yield) as a yellow solid. LC-MS (ESI+) m/z 617.4 (M+H)+.

[002435] Step 2 - 4-r2-r2-r4-r2-(2-Aminoethoxy)ethyl1piperazin-l-yl1ethoxy1ethylamino12-(2,6-di oxo piperidyl)isoindoline-L3-dione

[002436] To a solution of tert-butyl N-[2-[2-[4-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]ethoxy]ethyl]piperazin-l-yl]ethoxy]ethyl]carbamate (200 mg, 324 umol) in DCM (4 mL) was added HCI/dioxane (4 M, 4 mL), and the reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 83% yield) as a yellow solid. LC-MS (ESI+) m/z 517.3 (M+H)+.

[002437] 4- [2 16- [2-(2-Aminoethoxv)ethyl]-2,6-diazaspiro [3.3] heptan-2935 yl] ethoxy] ethylamino] (2,6-dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate IO)

TFA, DCM

[002438] Step 1 - Tert-butyl 6-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1) -1 J-dioxo-isoindolin-4yllaminolethoxy] ethyl1-2.6-diazaspiro[3.31heptane carboxylate

[002439] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane carboxylate (0.40 g, 1.70 mmol, HCI, CAS# 1041026 3) and 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethyl methanesulfonate (899 mg, 2.04 mmol, synthesized via Steps 1-2 of Example 184) in CH3CN (80 mL) was added NaHCO3 (429 mg, 5.11 mmol). The mixture was stirred at 80 °C for 6 hr. On completion, the mixture was concentrated. The residue was purified by flash silica gel chromatography (DCM: MeOH = 10:1) to give the title compound (0.80 g, 69% yield, 80% purity) as a yellow solid. LC-MS (ESI+) m/z 542.4 (M+H)+.

[002440] Step 2 - 4-r2-r2-(2,6-Diazaspiror3.31heptan yl)ethoxy1ethylamino1 (2,6dioxo piperidyl) isoindoline-L3-dione

[002441] To a solution of tert-butyl 6-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethyl]-2,6-diazaspiro[3.3]heptane carboxylate (0.80 g, 1.48 mmol) in DCM (50 mL) was added TFA (6.16 g, 54.0 mmol). The mixture was stirred at 15 °C for min. On completion, the mixture was concentrated. The crude product was purified by reversedphase chromatography (0.1% FA condition) to give the title compound (0.34 g, 47% yield, FA salt) as a yellow solid. LC-MS (ESI+) m/z 442.3 (M+H)+.

[002442] Step 3 - Tert-butyl Ν-Γ2-Γ2-Γ6-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1) -L3-dioxoisoindolin yl1amino1ethoxy1ethyl1-2,6-diazaspiror3.31heptan yl1ethoxy1ethyl1carbamate [002443] To a solution of 4-[2-[2-(2,6-diazaspiro[3.3]heptan yl)ethoxy]ethylamino]-2(2,6-dioxo piperidyl) isoindoline-1,3-dione (0.29 g, 595 umol, FA) and tert-butyl N-[2-(2oxoethoxy)ethyl]carbamate (363 mg, 1.78 mmol, synthesized via Step 1 of Intermediate FS) in DCM (1 mL) and THF (1 mL) was added Et3N (181 mg, 1.78 mmol) and AcOH (71.5 mg, 1.19 mmol) and then added NaBH(OAc)3 (252 mg, 1.19 mmol). The mixture was stirred at 15 °C for 6 hrs. On completion, the mixture was concentrated. The crude product was purified by reversedphase chromatography (0.1% FA condition) to give the title compound (0.32 g, 68% yield, 80% purity) as a yellow solid. LC-MS (ESI+) m/z 629.4 (M+H)+.

[002444] Step 4 - 4-r2-r2-r6-r2-(2-Aminoethoxy)ethyl1-2,6-diazaspiro[3.31heptan-2yl1ethoxy1ethylamino1 (2,6-dioxo piperidyl)isoindoline-L3-dione

[002445] To a solution of tert-butyl N-[2-[2-[6-[2-[2-[[2-(2,6-dioxo piperidyl) -1,3-dioxoisoindolin yl] amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptan yl]ethoxy]ethyl]carbamate (0.22 g, 350 umol) in DCM (2 mL) was added TFA (39.9 mg, 350 umol). The mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated to give the title compound (0.10 g, 31% yield, 70% purity, TFA) as yellow oil. LC-MS (ESI+) m/z 529.4 (M+H)+.

[002446] 5-Bromo methvl-lH-benzimidazol one (Intermediate IP)

[002447] Step 1 - 5-Bromo-N-methyl nitro-aniline

[002448] 4-bromo fluoro-l-nitro-benzene (230 g, 1.05 mol, CAS#321 3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 °C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid.

1H NMR (400MHz, DMSO-6/6) δ 8.22 (s, IH), 7.98 (d, J= 9.2 Hz, IH), 7.16 (d, J= 1.6 Hz, IH), 6.82 (dd, J= 8.4, 1.6 Hz, IH), 2.95 (d, J= 4.8 Hz, 3H).

[002449] Step 2 - 4-Bromo-N2-m ethyl-benzene-1,2-diamine

[002450] To a mixture of 5-bromo-N-methyl nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and H2O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50 °C, and then Fe (174 g, 3.11 mol) was added to the reaction mixture. After that, the reaction mixture was stirred at 80 °C for 6 hours. On completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with aq.NaHCO3 and brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as black oil. 1H NMR (400MHz, DMSO-6/6) δ 6.55 - 6.52 (m, IH), 6.48 - 6.45 (m, IH), 6.43 - 6.42 (m, IH), 4.89 - 4.88 (m, IH), 4.61 (s, 2H), 2.70 (d, J= 4.0 Hz, 3H).

[002451] Step 3 - 5-Bromo methyl-lH-benzimidazol one

[002452] To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol) in CH3CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture was stirred at 80 °C for 6 hours under N2. On completion, the mixture was concentrated in vacuo. The mixture was diluted with H2O (1.0 L) and filtered. The filter cake was washed with water (3 X 200 mL) and dried in vacuo to give the title compound (106 g, 85% yield) as a white solid. 1H NMR (400MHz, DMSO-6/6) δ 11.00 (s, IH), 7.33 (s, IH), 7.13 (d, J= 8.0 Hz, IH), 6.92 (d, J= 8.0 Hz, IH), 3.27 (s, 3H).

[002453] [!-[(4-Methoxyphenvl)methyl]-2,6-dioxo piperidvl] trifluoromethanesulfonate (Intermediate IQ)

t-BuOK, THF

[002454] Step 1 - 5-Oxotetrahvdrofuran carboxylic acid

[002455] To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS# 617 2) in H2O (800 mL) and HC1 (12 M, 210 mL) was added a solution of NaNO2 (147 g, 2.13 mol) in H2O (400 mL) at - 5 °C. The mixture was stirred at 15 °C for 12 hrs. On completion, the mixture was concentrated and then dissolved in EA (500 mL) and filtered and washed with EA (3 X 100 mL). The filtrate and washed solution were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, crude) as yellow oil. 1H NMR (400MHz, CDCh) δ 6.43 (s, IH), 5.02 - 4.95 (m, IH), 2.67 - 2.38 (m, 4H)

[002456] Step 2 - N-r(4-methoxyphenyl)methyl1 oxo-tetrahydrofuran carboxamide [002457] To 5-oxotetrahydrofuran carboxylic acid (120 g, 922 mmol) was added SOCh (246 g, 2.07 mol) at 0 °C slowly. The mixture was stirred at 85 °C for 3 hrs, and then the mixture was stirred at 15 °C for 6 hrs. The mixture was concentrated in vacuo. The residue was dissolved in dry DCM (1 L) at 0 °C under N2. After that a solution of Et3N (187 g, 1.84 mol) and 4methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, then the mixture was stirred at 15 °C for 3 hrs. On completion, water (600 mL) was added and the mixture was extracted with DCM (3 X 300mL). The combined organic phase was washed with 0.5 M HC1 (500 mL), brine (500 mL), dried over with anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE: EA = 1:1) to give the title compound (138 g, 60% yield) as a yellow solid. 1H NMR (400MHz, CDC13) δ 7.22 - 7.20 (d, J = 8.0, IH), 6.89 - 6.87 (d, J = 8.0, IH), 4.90 - 4.86 (m, IH), 4.47 - 4.4.36 (m, 2H) 3.81 (s, 3H), 2.67 - 2.64 (m, IH), 2.59 - 2.54 (m, 2H), 2.40 - 2.38 (m, IH); LC-MS (ESI+) m/z 272.0 (M+Na)+.

[002458] Step 3 - 3-Hydroxy-l-r(4-methoxyphenyl)methyl1piperidine-2,6-dione

[002459] A solution of N-[(4-methoxyphenyl)methyl] oxo-tetrahydrofuran-2carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to -78 °C. Then, tBuOK (62.7 g, 559 mmol) in a solution of anhydrous THF (1000 mL) was added dropwise slowly at -78 °C under nitrogen atmosphere. The resulting reaction mixture was stirred at -40 °C for 1 hr. On completion, the reaction mixture was quenched with saturated NH4C1 solution (100 mL). The mixture was extracted with ethyl acetate (3 X 1500 mL). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (128 g, 92% yield) as a white solid. 1H NMR (400MHz, CDC13) δ 7.39

7.32 (m, 2H), 6.89 - 6.81 (m, 2H), 4.91 (s, 2H), 4.17 - 4.11 (m, IH), 3.80 (s, 3H), 3.54 (s, IH),

2.98 - 2.87 (m, IH), 2.73 - 2.60 (m, IH), 2.26 - 2.20 (m, IH), 1.80 (dq, J= 4.8, 13.1 Hz, IH).

[002460] Step 4 - r1&#1470;r(4&#1470;Methoxyphenyl) methyl1-2,6-dioxo piperidyl1 trifluoromethanesulfonate

[002461] To a solution of 3-hydroxy- l-[(4-methoxyphenyl) methyl] piperidine-2, 6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (73.0 g, 258 mmol) dropwise at 0 °C. The mixture was stirred at -10°C for 1.5 hours under N2. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA= 20:1/8:1) to give the title compound (45.0 g, 68% yield) as light yellow gum. 1HNMR (400MHz, CDCh) δ 7.36 (d, J= 8.4 Hz, 2H), 6.85 - 6.82 (m, 2H), 5.32 - 5.28 (m, IH), 4.91 (s, 2H), 3.79 (s, 3H), 3.02 - 2.97 (m, IH), 2.79 - 2.74 (m, IH), 2.41 - 2.35 (m, 2H).

[002462] 3-(4-bromo-l-oxoisoindolin yl)DiDeridine-2,6-dione (Intermediate IR)

NBS, BPO

Benzene

[002463] Step 1: 3-bromo (bromomethyl) benzoate

[002464] To a solution of methyl 3-bromo methylbenzoate (10.0 g, 43.64 mmol, CAS #:

99548 6) in benzene (60 ml) were added N-bromosuccinimide (6.1 g, 52.37 mmol) and benzoyl peroxide (1.05 g, 4.36 mmol) at rt. The reaction mixture was stirred at 80 °C for 12 h. The resulting reaction mixture was poured into EtOAc (260 mL) and the organic layer was washed with water (200 ml), separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the residue. The crude was purified by flash chromatography (eluting at 0-2% ethyl acetate in hexane) to afford 3-bromo (bromomethyl) benzoate (f 2.0 g, 39.33 mmol). 1H NMR (400 MHz, DMSO-d6) δ 7.92 (dd, J = 8.0, 1.3 Hz, IH), 7.85 (dd, J = 7.8, 1.3 Hz, IH), 7.41 (t, J = 7.9 Hz, IH), 5.02 (s, 2H), 3.87 (s, 3H).

[002465] Step 2: 3-(4-bromo-l-oxoisoindolin yl)piperidine-2,6-dione

[002466] To a solution of 3-bromo (bromomethyl) benzoate (12.0 g, 39.33 mmol) in ACN (100 ml) were added 3-aminopiperidine-2,6-dione hydrochloride (7.76 g, 47.20 mmol, CAS #:

24666 6), TEA (11.95 g, 117.9 mmol) at rt. The reaction mixture was heated 80 °C for 12 h then cooled to rt. EtOAc (250 ml) was added and the organic layer was washed with water (500 ml), separated, dried over anhydrous Na2SO4 and concentrated under vacuum. The obtained crude material was purified by flash chromatography (eluting at 4-6% Methanol in DCM) to give 3-(4bromo oxoisoindolin yl)piperidine-2,6-dione (5.60 g, 17.33 mmol). LCMS m/z: (ES+) 323.0 (M+l)+. 1HNMR (400 MHz, DMSO&#1470;d6) δ 11.04 (s, IH), 7.88 (dd, J = 7.9, 0.9 Hz, IH), 7.78 (dd, J = 7.5, 0.9 Hz, IH), 7.52 (t, J = 7.7 Hz, IH), 5.16 (dd, J = 13.3, 5.1 Hz, IH), 4.43 (d, J = 17.6 Hz, IH), 4.27 (d, J = 17.7 Hz, IH), 2.92 (ddd, J = 17.2, 13.7, 5.4 Hz, IH), 2.61 (dd, J = 17.5, 4.3 Hz, IH), 2.02 (dtd, J = 12.8, 5.4, 2.3 Hz, IH).

[002467] tert-butyl(2-(2-(2-(prop vn-l-vloxv)ethoxv)ethoxv)ethyl)carbamate (Intermediate IS)

[002468] To a stirred solution of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.0 g, 4.01 mmol, synthesized via Step 1 on Intermediate AC) in THF (50 ml) was added NaH (0.2 g, 4.81 mmol) at 0-5 °C. 3-bromoprop yne (0.9 ml, 6.02 mmol, CAS #: 106 7) was added dropwise at 0-5 °C. The reaction mixture was stirred at rt for 5 h. The resulting reaction mixture was poured into ice cold water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl (2-(2-(2-(prop yn-l-yloxy)ethoxy)ethoxy)ethyl)carbamate (1.1 g, 3.83mmol). LCMS m/z ( ES+): 188.2 (M99&#1470;)+.

[002469] tert-butyl (2-(2-(prop vn-l-vloxv)ethoxv)ethyl)carbamate (Intermediate IT)

NaH,THF

IT

[002470] To a stirred solution of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate (2.0 g, 9.74 mmol, CAS #; 139115 6) in THF (50 ml) was added NaH (0.47 g, 11.70 mmol) at 0-5 °C. 3bromoprop yne (2.1 ml, 14.62 mmol) was added dropwise at 0-5 °C. The reaction mixture was stirred at rt for 5 h. The resulting reaction mixture was poured into ice cold water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layer was dried over anhydrous

Na2SO4, filtered and concentrated under vacuum to afford tert-butyl (2-(2-(prop yn-lyloxy)ethoxy)ethyl)carbamate (2.1 g, 8.97 mmol). LCMS m/z: (ES+) 144.1 (M-99)+.

[002471] tert-butyl (2-(prop yn-l-yloxy)ethyl)carbamate (Intermediate IU)

O THF, NaH O

IU

[002472] To a stirred solution of tert-butyl (2-hydroxyethyl)carbamate (3.70 g, 22.96 mmol, CAS #: 26690 ) in THF (150 ml) was added NaH (1.1g, 27.55 mmol) at 0-5°C. Then 3bromoprop yne (3.3 ml, 34.44 mmol) was added dropwise at 0-5°C. The reaction mixture was stirred at rt for 3 h. The resulting reaction mixture was poured into ice cold water (200 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford crude material. The isolated crude material was further purified by column chromatography (eluting at 15% ethyl acetate in hexane) to afford tert-butyl (2-(prop yn-l-yloxy)ethyl)carbamate (4.12 g, 20.69 mmol). 1H NMR (400 MHz, DMSO-d6) δ 6.83 (t, J = 5.8 Hz, IH), 4.12 (d, J = 2.4 Hz, 2H), 3.42 (s, 2H), 3.08 (q, J = 6.0 Hz, 2H), 1.38 (s, 9H).

[002473] 2-(l-Methylpyrazol yl)oxazole carboxylic acid (Intermediate IV)

OEt OH

IV

[002474] Step 1 - Ethyl 2-(l-methylpyrazol yl)oxazole carboxylate

[002475] To a solution of ethyl 2-chlorooxazole carboxylate (1.87 g, 10.7 mmol, CAS# 4600081 9) and l-methyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)pyrazole (2.22 g, 10.7 mmol, CAS# 761446 0) in a mixed solvent of H2O (6 mL) and dioxane (30 mL) was added K2CO3 (2.94 g, 21.3 mmol) and Pd(dppf)C12*CH2C12 (870 mg, 1.07 mmol). The reaction mixture was stirred at 80 °C for 4 hours under nitrogen. On completion, the reaction mixture was diluted with EA (100 mL) and filtered. The organic layers were dried with anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica column chromatography (SiO2) to give the title compound (1.50 g, 64% yield) as a white solid. LC-MS (ESI+) m/z 222.1 (M+H)+.

[002476] Step 2 - 2-(l-Methylpyrazol yl)oxazole carboxylic acid

[002477] To a solution of ethyl 2-(l-methylpyrazol yl)oxazole carboxylate (1.20 g, 5.42 mmol) in THF (30 mL) was added a solution of LiOH*H2O (683 mg, 16.3 mmol) in H2O (6 mL). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with water (50 mL), acidified with HCI (IN, 10 mL), and filtered. The filter cake was washed with water (2X10 mL) and dried in vacuo to give the title compound (1.10g, 80% purity) as a white solid.

[002478] N-[3-(difluoromethvl)-l-(4-formvlphenvl)Dvrazol vl] (l-methvlpyrazol-4yl)oxazole carboxamide (Intermediate IW)

[002479] Step 1 - Methyl 4-r3-(difluoromethyl) rr2-(l-methylpyrazol yl)oxazole-4 carbonyllaminolpyrazol -l-yl1benzoate

[002480] To a solution of 2-(l-methylpyrazol yl)oxazole carboxylic acid (860 mg, 4.45 mmol, Intermediate IV) and methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (833 mg, 3.12 mmol, Intermediate FW) in DMF (30 mL) was added DIPEA (2.30 g, 17.8 mmol) and HATU (1.86 g, 4.90 mmol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was poured into water (50 mL), and filtered to give the filter cake. The cake was washed with water (2 X 20 mL) and dried in vacuo to give the title compound (1.40 g, 68% yield) as a white solid. LC-MS (ESI+) m/z 443.2 (M+H)+.

[002481] Step 2 - 4-[3-(Difluoromethyl) [[2-(l-methylpyrazol yl)oxazole-4carbonvl1amino1pyrazol-l-vl1 benzoic acid

[002482] To a solution of methyl 4-[3-(difluoromethyl) [[2-(l-methylpyrazol-4yl)oxazole carbonyl]amino] pyrazol-l-yl]benzoate (800 mg, 1.81 mmol) in THF (10 mL) was added a solution of LiOH*H2O (228 mg, 5.43 mmol) in H2O (2 mL). The reaction mixture was stirred at 40 °C for 12 hours. On completion, the reaction mixture was quenched with HC1 (IN, 3 mL) and concentrated in vacuo to give the title compound (900 mg, 59% purity) as a white solid. LC-MS (ESI+) m/z 429.0 (M+H)+.

[002483] Step 3 - N-[3-(difluoromethyl)-l-[4-(hydroxymethyl)phenyl1pyrazol yl1 (lmethylpyrazol yl)oxazole carboxamide

[002484] To a solution of 4-[3-(difluoromethyl) [[2-(l-methylpyrazol yl)oxazole-4carbonyl]amino] pyrazol-l-yl]benzoic acid (775 mg, 1.81 mmol) and TEA (732 mg, 7.24 mmol) in THF (30 mL) was added isopropyl carbonochloridate (443 mg, 3.62 mmol) at -10 °C. The reaction mixture was stirred at -10 °C for 2 hours. After that, H2O (3 mL) was added. The reaction mixture was warmed to 0 °C. Then LiBH4 (158 mg, 7.24 mmol) was added slowly. The reaction mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was diluted with THF (50 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica column chromatography (SiO2) to give the title compound (200 mg, 27% yield) as a white solid. LC-MS (ESI+) m/z 415.2 (M+H)+.

[002485] Step 4 - N-[3-(difluoromethyl)-l-(4-formylphenyl)pyrazol yl1 (lmethylpyrazol yl)oxazole carboxamide

[002486] To a solution ofN-[3-(difluoromethyl)-l-[4-(hydroxymethyl)phenyl]pyrazol yl]2-(l-methylpyrazol yl)oxazole carboxamide (180 mg, 434 umol) in THF (20 mL) was added DMP (184 mg, 434 umol). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched with water (5 mL) and concentrated in vacuo. The residue was dissolved in EA(200 mL), washed with water (50 mL), sat.NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 71% yield) as a white solid. LC-MS (ESI+) m/z 413.1 (M+H)+.

[002487] 5-[2-[2-(2-Aminoethoxv)ethoxv]ethvlamino] (2,6-dioxo-3piperidyl)isoindoline-l,3-dione (Intermediate IX)

[002488] Step 1 - Tert-butyl N-r2-r2-r2-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-5yl1amino1ethoxy1 ethoxylethyllcarbamate

[002489] To a mixture of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (100 mg,

362 umol, Intermediate HX) and tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (107 mg, 434 umol, CAS# 153086 3) in DMSO (5 mL) was added DIPEA (233 mg, 1.81 mmol, 315 uL). The reaction mixture was stirred at 130 °C for 1 hour. On completion, the reaction mixture was diluted with water (20 mL) and extracted with EA (3 X 30 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (90.0 mg, 49% yield) as light yellow solid. LC-MS (ESI+) m/z 505.1 (M+H)+.

[002490] Step 2 - 5-[2-[2-(2-Aminoethoxy)ethoxy1 ethyl amino] (2,6-di oxo-3piperidyl)isoindoline-l,3-dione

[002491] To a mixture of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethoxy]ethyl]carbamate (90.0 mg, 178 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 5 mL). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (72.0 mg, 91% yield, HCI) as light yellow solid. LC-MS (ESI+) m/z 405.3 (M+H)+.

[002492] Tert-butyl N-methyl-N-Drop ynyl-carbamate (Intermediate IY)

BocHN—

NaH,THF

Boc ;x 1

IY

[002493] To a solution of tert-butyl N-methylcarbamate (10.4 g, 79.2 mmol) in THF (120 mL) was added NaH (4.12 g, 103 mmol, 60% purity) under 0 °C. The mixture was stirred at 0 °C for 0.5 hour, then 3-bromoprop yne (13.2 g, 111 mmol) was added dropwise. The mixture was stirred at rt for 16 hours. On completion, the reaction mixture was quenched with water (10 mL) at 0°C, and then concentrated in vacuo to give a residue. The residue was diluted with water (80 mL) and extracted with DCM (4 X 60mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (4.50 g, 33% yield) as light yellow oil. 1H NMR (400MHz, DMSO4) δ 4.05 (s, 2H), 2.92 (s, 3H), 2.22 (t, J= 2.4 Hz, IH), 1.47 (s, 9H).

[002494] 2-(26&#1524;-Dioxo piperidyl) [3-(methvlamino)propvl]isoindoline-l.,3-dione (Intermediate

[002495] Step 1 - Tert-butyl N-r3-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin yl]prop2-ynyl]-N-methyl- carbamate

[002496] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.87 g, 5.54 mmol, Intermediate FT) and tert-butyl N-methyl-N-prop ynyl-carbamate (1.5 g, 8.86 mmol, Intermediate IY) in DMF (5 mL) was added Pd(PPh3)2C12 (388 mg, 554 umol), TEA (10.0 g, 99.7 mmol) and Cui (105 mg, 554 umol). The mixture was heated at 80 °C for 30 minutes under microwave. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA =1:1) to give the title compound (1.90 g, 71% yield) as light yellow solid. 1H NMR (400MHz, DMSO-A) δ 11.13 (s, IH), 7.93 - 7.89 (m, IH), 7.89 - 7.84 (m, 2H), 5.15 (dd, J = 5.4, 12.8 Hz, IH), 4.37 (s, 2H), 3.32 (s, 3H), 3.01 - 2.90 (m, 3H), 2.90 - 2.82 (m, IH), 2.64 - 2.51 (m, 2H), 2.11 - 2.00 (m, IH), 1.47 - 1.36 (m, 9H) ; LCMS (ESI+) m/z 448.2 (M+Na)+.

[002497] Step 2 - Tert-butyl N-r3-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4vl1propyl1-N-methyl- carbamate

[002498] To a solution of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]prop ynyl]-N- methyl-carbamate (0.50 g, 1.05 mmol) in THF (20 mL) was added Pd/C (0.2 g, 1.05 mmol, 10 wt%) and Pd(OH)2/C (0.2 g, 1.05 mmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20 °C for 2 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.4 g, 89% yield) as black brown solid. LC-MS (ESI+) m/z 452.3 (M+Na)+.

[002499] Step 3 - 2-(2,6-Dioxo piperidvl) r3-(methvlamino)propyl1isoindoline-L3di one

[002500] To a solution of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]propyl]-N- methyl-carbamate (0.40 g, 828 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 5 °C for 20 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (0.28 g, 92% yield) as black brown solid. LC-MS (ESI+) m/z 330.2 (M+H)+.

[002501] N-[3-carbamovl-l-(4-formvlDhenvl)Dvrazol vl] (4-Dvridyl)oxazole-4carboxamide (Intermediate JA)

JA

[002502] Step 1 - Isopropoxycarbonyl 4-r3-carbamoyl [r2-(4-pyridyl)oxazole-4carbonyl1amino1pyrazol-l-yl1 benzoate

[002503] To a mixture of 4-[3-carbamoyl [[2-(4-pyridyl)oxazole-4carbonyl]amino]pyrazol-l-yl]benzoic acid (500 mg, 1.20 mmol, Intermediate EE) in THF (20 mL) was added TEA (483 mg, 4.78 mmol, 665 uL) and isopropyl carbonochloridate (366 mg, 2.99 mmol, 414 uL). The reaction mixture was stirred at -10°C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated to give the title compound (600 mg, 99% yield) as light yellow oil. LC-MS (ESI+) m/z 505.0 (M+H)+.

[002504] Step 2 - N-r3-carbamoyl-l-r4-(hydroxymethyl)phenyl1pyrazol yl1 (4pyridyl)oxazole carboxamide

[002505] To a mixture of isopropoxy carbonyl 4-[3-carbamoyl [[2-(4-pyridyl)oxazole-4carbonyl]amino] pyrazol-l-yl]benzoate (600 mg, 1.19 mmol) in H2O (5 mL) and THF (50 mL) was added LiBH4 (155 mg, 7.14 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was quenched with water (30 mL) under stirring. Then the mixture was extracted with EA (3 X 50 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was triturated with DCM/PE (5 mL/30 mL) and filtered to give the title compound (250 mg, 51% yield) as light yellow solid. LC-MS (ESI+) m/z 405.2 (M+H)+.

[002506] Step 3 - Ν-Γ3-carbamoyl-l-(4-formylphenyl)pyrazol yl1 (4-pyridyl)oxazole-4carboxamide

[002507] To a mixture of N-[3-carbamoyl-l-[4-(hydroxymethyl)phenyl]pyrazol yl] (4pyridyl)oxazole carboxamide (250 mg, 618 umol)in DCM (10 mL) and THF (10 mL) was added DMP (524 mg, 1.24 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was diluted with Na2S2O3 (10 mL), NaHCO3 (10 mL) and stirred for 30 min. Then the mixture was extracted with DCM (3 X 10mL) and the combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (230 mg, 92% yield) as light yellow solid. LC-MS (ESI+) m/z 403.2 (M+H)+.

[002508] [4-[4-Amino (difluoromethvl)Dvrazol-l-vl]Dhenyllmethanol (Intermediate JB) 'NH2 ^/NH2 0ν-ΛΛ-Na LiAH&#1523; thf

MeO [ HO [

F F

FW JB

[002509] To a solution of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (1.30 g, 4.86 mmol, Intermediate FW) in a mixed solvent of THF (40 mL) was added LiAlH4 (369 mg, 9.73 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was quenched with water (0.8 mL) and NaOH aqueus solution (15 %, 0.8 mL) at 0 °C, then filtered and dried over Na2SO4, filtered again and concentrated in vacuo to give the title compound (1.10 g, 94% yield) as light yellow solid. 1H NMR (400MHz, DMSO4) δ 7.78 (s, IH), 7.67 (d, J= 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.05 (t, J = 13.6 Hz, IH), 5.25 (t, J = 5.6 Hz, IH), 4.51 (d, J = 5.6 Hz, 2H), 4.39 (s, 2H).

[002510] Tert-butyl N-[4-[4-[[3-(difluoromethvl)-l-(4-formylphenvl)pvrazol-4yl] carbamoyl] oxazol vl] pyridvl]-N-(2.,2.,2-trifluoroethvl)carbamate (Intermediate JC)

HATU, DIPEA, DMF

[002511] Step 1:Tert-butyl N-r4-r4-rr3-(difluoromethyl)-l-[4(hydroxymethyl )phenyl 1 pyrazol yl 1 carb amoyl 1 0xaz0l yl1 pyridyl1-N-(2,2,2trifluoroethyDcarbamate

[002512] To a solution of 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (1.42 g, 3.68 mmol, Intermediate CM) and HATU (1.92 g, 5.06 mmol) in DMF (20 mL) was added DIPEA (1.78 g, 13.7 mmol) and [4-[4-amino-3(difluoromethyl)pyrazol-l-yl]phenyl]methanol (1.1 g, 4.60 mmol, Intermediate JB). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was diluted with 80 mL water, filtered to give the filter cake and was dried in vacuo to give the product (1.90 g, 67% yield) as gray solid. 1H NMR (400MHz, DMSO-6/6) δ 10.06 (s, IH), 9.07 (s, IH), 8.80 (s, IH), 8.65 (d, J = 5.2 Hz, IH), 8.31 (s, IH), 7.87 - 7.77 (m, 3H), 7.48 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 14.4 Hz, IH), 5.30 (t, J= 5.6 Hz, IH), 4.90 (q, J= 92 Hz, 2H), 4.56 (d, J= 5.6 Hz, 2H), 1.52 (s, 9H).

[002513] Step 2 - Tert-butyl N-r4-r4-rr3-(difluoromethyl)-l-(4-formylphenyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[002514] To a solution of tert-butyl N-[4-[4-[[3-(difluoromethyl)-l-[4(hydroxymethyl)phenyl]pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (1.90 g, 3.12 mmol) in a THF (60 mL) was added DMP (1.59 g, 3.75 mmol). The mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was quenched by saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL) at 25 °C. The mixture was stirred for 30 minutes, then extracted with CH2C12 (3 X 100 mL). The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.30 g, 68% yield) as gray solid. 1HNMR (400MHz, DMSO-» δ 10.17 (s, IH), 10.05 (s, IH), 9.09 (s, IH), 8.99 (s, IH), 8.65 (d, J = 5.2 Hz, IH), 8.31 (s, IH), 8.12 (d, J= 8.4 Hz, 2H), 8.04 (d, J= 8.4 Hz, 2H), 7.80 (dd, J = 0.8, 5.2 Hz, IH), 7.33 (t, J = 14.0 Hz, IH), 4.90 (q, J = 8.8 Hz, 2H), 1.52 (s, 9H); LC-MS (ESH) m/z 607.1 (M+H)+.

[002515] N-[3-(difluoromethyl)-l-(4-formylDhenvl)pvrazol yl] (4-Dyridyl)oxazole4-carboxamide (Intermediate JD)

[002516] Step 1 - N-r3-(difluoromethyl)-l-r4-(hydroxymethyl)phenyl1pyrazol yl1 (4pyridvl)oxazole carboxamide

[002517] To a solution of 2-(4-pyridyl)oxazole carboxylic acid (1.27 g, 6.69 mmol, Intermediate ED) and HATU (3.18 g, 8.36 mmol) in DMF (60 mL) was added DIPEA (3.24 g, 25.0 mmol) and [4-[4-amino (difluoromethyl) pyrazol-l-yl]phenyl]methanol (2 g, 8.36 mmol, Intermediate JB). The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was diluted with water (80 mL), filtered to give the filter cake and dried in vacuo to give the title compound (3.00 g, 87% yield) as gray solid. 1HNMR (400MHz, DMSO-» δ 10.05 (s, IH), 9.04 (s, IH), 8.83 (d, J= 6.0 Hz, 2H), 8.78 (s, IH), 7.97 (d, J= 6.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H),

7.48 (d, J= 8.8 Hz, 2H), 7.29 (t, J= 54 Hz, IH), 5.30 (t, J= 5.2 Hz, IH), 4.56 (d, J= 4.8 Hz, 2H). [002518] Step 2 - N-[3-(difluoromethyl)-l-(4-formylphenyl)pyrazol yl1 (4pyridvl)oxazole carboxamide

[002519] To a solution ofN-[3-(difluoromethyl)-l-[4-(hydroxymethyl)phenyl]pyrazol yl]2-(4-pyridyl) oxazole carboxamide (2.50 g, 6.08 mmol) in THF (160 mL) was added DMP (3.09 g, 7.29 mmol). The mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was quenched with saturated Na2S2O3 (20 mL) and saturated NaHCO3 (20 mL) at 25°C, and then stirred for 30 minutes. The mixture was then extracted with CH2C12 (3 X 100 mL). The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.80 g, 73% yield) as gray solid. LC-MS (ESI+) m/z 410.2 (M+H)+.

[002520] 4-[4-[[2-[2-[Tert-butoxycarbonyl(2.,2.,2-trifluoroethyl)amino]-4pyridyl] amino] (difluoromethyl)pyrazol-l-yl]benzoic acid

[002521] Step 1 - Methyl 4-r4-rr2-r2-rtert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1amino1 (difluoromethyl)pyrazol-l-yl1benzoate

[002522] To a solution of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (340 mg, 1.27 mmol, Intermediate FW) and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (493 mg, 1.27 mmol, Intermediate CM) in DMF (8 mL) was added DIPEA (658 mg, 5.09 mmol) and HATU (581 mg, 1.53 mmol). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was quenched with water (80 mL), stirred and filtered. The filter cake was dried in vacuo to give the title compound (0.7 g, 86% yield) as an off-white solid. LC-MS (ESI+) m/z 637.3 (M+H)+.

[002523] Step 2 - 4-r4-rr2-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1 amino1 (difluoromethyl)pyrazol-l-yl1benzoic acid

[002524] To a solution of methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]benzoate (0.70 g, 1.10 mmol) in a mixed solvent of THF (10 mL) and H2O (2 mL) was added LiOH (132 mg, 5.50 mmol). The reaction mixture was stirred at 20 °C for 2 days. On completion, the mixture was acidified with 0.5 N HC1 solution until the pH = 3-4, then stirred and filtered. The filter cake was dried in vacuo to give the title compound (0.68 g, 99% yield) as a white solid. LCMS (ESI+) m/z 623.2 (M+H)+.

[002525] 3-(7-bromo oxo-l.,3-benzoxazol vl)DiDeridine-2.,6-dione (Intermediate JF

/ N-PMB

Br O

EtOH *

CDI

THF

JF

[002526] Step 1 - 3-(3-bromo hydroxyphenylamino)-l-(4-methoxybenzyl)piperidine-2,6di one

[002527] To a solution of 3-bromo-l-(4-methoxybenzyl)piperidine-2,6-dione (145 mg, 0.77 mmol, Intermediate LJ) in EtOH (10 mL) was added 2-amino bromophenol (200 mg, 0.64 mmol) and at r.t. The reaction mixture was heated and stirred under microwave irradiation at 140 °C for 25 mins. The reaction mixture was concentrated under reduced pressure. The residue was purified via reverse phase column chromatography (ACN/H2O with 0.1%TFA) to give title compound (80 mg, 30% yield) as a colorless oil. 1H NMR (400 MHz, DMSOQ) δ 8.94 (s, IH), 7.18 (d, J= 8.6 Hz,

2H), 6.85 (d, J= 8.7 Hz, 2H), 6.75 (dd, J= 6.9, 2.6 Hz, IH), 6.67 - 6.59 (m, 2H), 5.48 (d, J= 7.1 Hz, IH), 4.76 (q, J= 14.3 Hz, 2H), 4.58 - 4.40 (m, IH), 3.71 (s, 3H), 3.05 - 2.89 (m, IH), 2.83 - 2.61 (m, IH), 2.25 - 2.10 (m, IH), 2.02-1.97 (m, IH). LC-MS (ESI+): m/z 421.1 (M+H)+.

[002528] Step 2:3 -(7-bromo oxobenzo[ d] oxazol-3 (2H)-yl) (4methoxybenzyl)piperidine-2,6-dione

[002529] To a solution of 3-(3-bromo hydroxyphenylamino)-l-(4methoxybenzyl)piperidine-2,6-dione (80 mg, 0.19mmol) in THF (5 mL) was added a solution of CDI (46mg, 0.284 mmol) in THF (5 mL) at r.t. under N2. The reaction mixture was stirred at 35 °C for 12 h. The reaction mixture was then concentrated under reduced pressure and the residue was purified via column chromatography (Petroleum ether/EtOAc= 2 / 1) to give title compound (70 mg, 74% yield) as a white solid. 1HNMR (400 MHz, DMSO-0/6) δ 7.39 (dd, J= 8.0, 1.1 Hz, IH), 7.23 - 7.16 (m, 4H), 6.86 (d, J= 8.7 Hz, 2H), 5.56 (dd, J= 13.3, 5.3 Hz, IH), 4.89 - 4.70 (m, 2H), 3.72 (s, 3H), 3.04-3.01 (m, IH), 2.87-2.83 (m, IH), 2.71 - 2.65 (m, IH), 2.27 - 2.18 (m, IH). LC-MS (ESI+): m/z 445.1 (M+H)+.

[002530] Step 3 - 3-(7-bromo oxobenzord1oxazol-3(2H)-yl)piperidine-2,6-dione

[002531] To a solution of 3-(7-bromo oxobenzo[d]oxazol-3(2H)-yl)-l-(4methoxybenzyl)piperidine-2,6-dione (80 mg, 0.180 mmol) in CH3CN (2 mL) was added a solution of CAN (690 mg, 1.26 mmol) in 0.5 mL of water dropwise at r.t. The reaction mixture was stirred at r.t. for 2 hours. The reaction mixture was then extracted with EtOAc (15mL x 2), the organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified via Pre-TLC (Petroleum ether/EtOAc= 1 /1) to give the title compound (9.7mg, 17% yield) as a pale yellow solid. &#905; NMR (400 MHz, DMSO-0/6) δ 11.26 (s, IH), 7.39 (dd, J = 8.2, 0.8 Hz, IH), 7.33 - 7.27 (m, IH), 7.19 (t, J= 8.1 Hz, IH), 5.42-5.38 (m, IH), 2.97 - 2.79 (m, IH), 2.75 - 2.60 (m, 2H), 2.27 - 2.12 (m, IH). LC-MS (ESI+): m/z 325.1 (M+H)+.

[002532] 3-[7-[3-[2-(2-Aminoethoxv)ethoxy|DroDvl] oxo-l.,3-benzoxazol-3yl]DiDeridine-2.,6-dione (Intermediate JG)

JF

NHBoc

[002533] Step 1 - Tert-butyl N-r2-r2-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-7 yl1prop ynoxy1 ethoxy1ethyl1carbamate

[002534] To a solution of 3-(7-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (220 mg, 676 umol, Intermediate JF) and tert-butyl N-[2-(2-prop ynoxyethoxy)ethyl]carbamate (411 mg, 1.69 mmol, synthesized via Step 1 of Intermediate CQ) in DMF (10 mL) was added TEA (1.23 g, 12.1 mmol, 1.70 mL), Cui (64.4 mg, 338 umol) and Pd(PPh3)2C12 (237 mg, 338 umol). The reaction mixture was stirred at 80 °C for 1.5 hours under N2. On completion, the mixture was filtered; and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in DCM (20 mL) and thiourea (resin) (300 mg) was added. The mixture was stirred at 20 °C for 2 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (250 mg, 76% yield) as a yellow solid. LC-MS (ESI+) m/z 510.2 (M + Na)+.

[002535] Step 2 - Tert-butyl N-r2-r2-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-7yl1propoxy1ethoxy1 ethyUcarbamate

[002536] To a solution of tert-butyl N-[2-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop ynoxy]ethoxy]ethyl]carbamate (250 mg, 512umol) in THF (10 mL) was added PtO2 (58.2 mg, 256 umol). The reaction mixture was stirred at 20 °C under H2 (15 psi) for 1 hour. On completion, the residue was fdtered and the fdtrate was concentrated in vacuo to give the title compound (250 mg, 99%) as yellow oil. LC-MS (ESI+) m/z 514.2 (M + Na)+.

[002537] Step 3 - 3-r7-r3-r2-(2-Aminoethoxy)ethoxy1propyl1 oxo-L3-benzoxazol-3yl1piperidine-2,6-dione

[002538] To a solution of tert-butyl N-[2-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] ethoxy]ethyl]carbamate (250 mg, 508 umol) in DCM (4 mL) was added HCI/dioxane (4 M, 4 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (190 mg, 87% yield) as yellow oil. LC-MS (ESI+) m/z 392.3(M+H)+.

[002539] 2-(2,6-Dioxo DiDeridvl) [3-(methvlamino)DroDvl]isoindoline-l,3-dione

[002540] Step 1 - Tert-butyl N-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin yl1prop2-ynyl1-N-methyl- carbamate

[002541] To a mixture of tert-butyl N-methyl-N-prop ynyl-carbamate (1.00 g, 5.93 mmol, Intermediate IY) and 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.00 g, 2.97 mmol, Intermediate GA) in DMF (4 mL) was added Cui (56.4 mg, 296 umol), TEA (5.40 g, 53.3 mmol, 7.43 mL) and Pd(PPh3)2C12 (208 mg, 296 umol). The reaction mixture was heated at 80 °C for 0.5 hour under microwave. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3 X 50 mL). The combined organic layer was dried over Na2SO4, fdtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (1.20 g, 95% yield) as yellow solid. 1H NMR (400MHz, DMSO-6/6) δ 11.14 (s, IH), 7.96 - 7.88 (m, 3H), 5.16 (dd, J= 5.6, 12.8 Hz, IH), 4.33 (s, 2H), 3.33 (s, 3H), 2.89 - 2.83 (m, IH), 2.64 - 2.51 (m, 2H), 2.10 - 2.02 (m, IH), 1.42 (s, 9H).

[002542] Step 2 - Tert-butyl N-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl1propyl1-N-methyl -carbamate

[002543] To a mixture of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]prop ynyl]-N -methyl-carbamate (2.40 g, 5.64 mmol) in MeOH (50 mL) was added Pd/C (500 mg, 10 wt %) and Pd(OH)2/C (500 mg, 10 wt%). The reaction mixture was stirred at 20°C for 1 hour under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (2.40 g, 99% yield) as light yellow solid. LC-MS (ESC) m/z 452.3 (M+Na) +.

[002544] Step 3 - 2-(2,6-Dioxo piperidyl) r3-(methylamino)propyl1isoindoline-L3di one

[002545] To a mixture of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]propyl]-N-methyl -carbamate (2.40 g, 5.59 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 19.2 mL). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (2.00 g, 97% yield) as light yellow solid. LC-MS (ESI+) m/z 330.2 (M+H)+.

[002546] 5-(3-Amin0Dr0Dvl) (2.,6-di0x0 DiDeridvl)is0ind01ine-l.,3-di0ne

[002547] Step 1 - Tert-butyl N-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin yl1prop2-ynyl1carbamate

[002548] To a solution of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1 g, 2.97 mmol Intermediate GA) and tert-butyl N-prop ynylcarbamate (920 mg, 5.93 mmol) in DMF (4 mL) was added Pd(PPh3)2C12 (208 mg, 296 umol) TEA (5.40 g, 53 mmol, 7.43 mL) and Cui (57 mg, 296 umol). The mixture was stirred at 80 °C for 0.5 hr under microwave. On completion, the mixture was concentrated in vacuo, the residue was purified by silica gel chromatography to give the title compound (1.3 g, 95% yield) as yellow solid. 1HNMR (400MHz, DMSO-#6) δ 11.15 (s, IH), 8.01 -7.81 (m, 3H), 5.17 (dd, J= 5.2, 12.8 Hz, IH), 4.10-4.03 (m, 2H), 3.33 (s, IH), 2.942.84 (m, IH), 2.73- 2.53 (m, 2H), 2.13 - 2.02 (m, IH), 1.47 - 1.36 (m, 9H); LC-MS (ESI+) m/z 434.0 (M+Na)+.

[002549] Step 2 - Tert-butyl N-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl1propyl1 carbamate

[002550] A mixture of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]prop ynyl]carbamate (2.5 g, 6.08 mmol), Pd/C (400 mg), Pd(OH)2/C (400 mg) in THF (40 mL) was degassed and purged with H2 gas 3 times. The mixture was then stirred at 20 °C for 16 hrs under H2 atmosphere at 15 psi. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.4 g, 95% yield) as brown solid. 1H NMR (400MHz, DMSO-76) δ 11.12 (s, IH), 7.84 (d, J= 7.6 Hz, IH), 7.80 (s, IH), 7.72 (dd, J= 1.2, 7.6 Hz, IH), 6.94 -6.85 (m, IH), 5.14 (dd, J= 5.2, 12.8 Hz, IH), 2.99 - 2.84 (m, 3H), 2.82 - 2.72 (m, 2H), 2.65 - 2.54 (m, 2H), 2.11 - 2.01 (m, IH), 1.80 - 1.68 (m, 2H), 1.38 (s, 9H)LC-MS (ESI+) m/z 438.1 (M+Na)+.

[002551] Step 3 - 5-(3-Aminopropyl) (2,6-dioxo piperidyl)isoindoline-L3-dione [002552] To a solution of tert-butyl N-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]propyl]carbamate (2.4 g, 5.78 mmol) in DCM (25 mL) was added HCI/dioxane (4 M, 10 mL). The mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (1.2 g, 65% yield) as light yellow solid. 1H NMR (400MHz, DMSO76) δ 11.14 (s, IH), 8.01 (s, 3H), 7.88 (d, J = 7.6 Hz, IH), 7.84 (s, IH), 7.76 (d, J = 8.0 Hz, IH), 5.15 (dd, J= 5.2, 12.8 Hz, IH), 2.95 - 2.84 (m, 3H), 2.83 - 2.72 (m, 2H), 2.69 - 2.52 (m, 2H), 2.11 - 2.01 (m, IH), 1.97 - 1.89(m, 2H); LC-MS (ESI+) m/z 316.2 (M+H)+.

[002553] 5-(Aminomethvl) (2,6-dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate JJ)

JJ

[002554] Step 1 - 2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindoline carbonitrile

[002555] To a solution of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (450 mg,

1.33 mmol, Intermediate GA), Zn(CN)2 (94.0 mg, 800 umol) in DMF (15.0 mL) was added Pd(PPh3)4 (154 mg, 133 umol). The mixture was stirred at 100 °C for 3 hours under N2. On completion, the mixture was diluted with H2O (50 mL), filtered and the solid was dried in vacuo. The solid was triturated with PE: EA =5:1 (30 mL), filtered and the solid was dried in vacuo to give the title compound (200 mg, 52% yield) as purple solid. 1H NMR (400MHz, DM SO-0/6) δ 11.16 (s, IH), 8.49 (s, IH), 8.38 (dd, J = 1.2, 7.6 Hz, IH), 8.12 (d, J = 7.6 Hz, IH), 5.26 - 5.17 (m, IH), 2.97 - 2.89 (m, IH), 2.65 - 2.58 (m, IH), 2.57 - 2.52 (m, IH), 2.12 - 2.05 (m, IH).

[002556] Step 2 - Tert-butyl N-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yUmethyllcarbamate

[002557] To a solution of 2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindoline carbonitrile (200 mg, 706 umol) in THF (10.0 mL) and DMF (10.0 mL) was added (Boc)2O (169 mg, 776 umol) and Raney-Ni (50.0 mg, 583 umol). The mixture was stirred at 30 °C for 3 hours under H2 (50 psi). On completion, the mixture was filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE: EA=1: 1) to give the title compound (250 mg, 91% yield) as white solid. 1H NMR (400MHz, DM SO-0/6) δ 11.10 (s, IH), 7.88 (d, J = 7.6 Hz, IH), 7.76 (s, IH), 7.72 (d, J = 7.6 Hz, IH), 7.63 - 7.55 (m, IH), 5.18- 5.04 (m, IH), 4.33 - 4.24 (m, 2H), 2.95 - 2.88 (m, IH), 2.84 - 2.83 (m, IH), 2.64 - 2.57 (m, IH), 2.57 - 2.52 (m, IH), 2.11 - 2.01 (m, IH), 1.39 (s, 9H).

[002558] Step 3 - 5-(Aminomethyl) (2,6-dioxo piperidvl)isoindoline-L3-dione [002559] To a solution of tert-butyl N-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]methyl]carbamate (250 mg, 645 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 4.00 mL), and the mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (200 mg, 90% yield, HCI) as white solid. LCMS (ESI+) m/z 288.1 (M+H)+.

[002560] 2-(2,6-Dioxo piperidvl) [3-[2-(methvlamino)ethoxv]propyl]isoindoline

1.,3-dione (Intermediate JK)

Pd/C, Pd(OH)2/C

H2, THF

HCl/dioxane, DCM

Ο Ο H

HN—\ o=Q&#1470;\X J O JK

[002561] Step 1 - Tert-butyl N-r2-r3-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl]prop ynoxy]ethyl] -N-methyl-carbamate

[002562] To a solution of tert-butyl N-methyl-N-(2-prop ynoxyethyl)carbamate (2.53 g, 11.8 mmol, Intermediate GK) and 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (2.00 g, 5.93 mmol, Intermediate GA) in DMF (4.00 mL) was added TEA (10.8 g, 106 mmol), Cui (112 mg, 593 umol) and Pd(PPh3)2C12 (416 mg, 593 umol), and the reaction mixture was heated at 80 °C for 30 min under microwave. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE: EA=1: 1) to give the title compound (2.7 g, 96% yield) as yellow solid. IH NMR (400MHz, CDCh) δ 8.00 (s, IH), 7.93 (s, IH), 7.89 - 7.79 (m, 2H), 5.02 - 4.96 (m, IH), 4.44 (s, 2H), 3.73 (s, 2H), 3.48 (s, 2H), 2.97 (s, 3H), 2.96 - 2.91 (m, IH),

2.89 - 2.82 (m, IH), 2.82 - 2.73 (m, IH), 2.22 - 2.15 (m, IH), 1.48 (s, 9H).

[002563] Step 2 - Tert-butyl N-r2-r3-[2-(2Adioxo piperidyl)-lJ-dioxo-isoindolin-5yl1propoxy1ethyl1- N-methyl-carbamate

[002564] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin5-yl]prop ynoxy] ethyl]-N-methylcarbamate(2.70 g, 5.75 mmol) in THF (30.0 mL) was added Pd/C (400 mg) and Pd(OH)2/C (400 mg), and the mixture was stirred at 15 °C for 16 hr under H2 (15 psi). On completion, the mixture was concentrated in vacuo to give the title compound (2.70 g, 95% yield) as black solid. LC-MS (ESI+) m/z 496.1 (M+Na)+.

[002565] Step 3:2-(2,6-Dioxo piperidvl) [3-r2(methylamino)ethoxy1propyl1isoindoline-L3-dione

[002566] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin5-yl]propoxy] ethyl]-N-methyl-carbamate (2.70 g, 5.70 mmol) in DCM (20.0 mL) was added HCl/dioxane (4.00 M, 20.0 mL). The mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (2.37 g, 90% yield, HCI) as yellow solid., 1HNMR (400MHz, DMSO-A) δ 11.14 (s, IH), 9.02 (s, IH), 7.87 - 7.74 (m, 3H), 5.19 5.10 (m, IH), 3.67 - 3.63 (m, 2H), 3.57 (s, 3H), 3.46 - 3.42 (m, 2H), 3.12 - 3.03 (m, 2H), 2.91 2.86 (m, 2H), 2.64 - 2.58 (m, IH), 2.57 - 2.55 (m, IH), 2.55 - 2.54 (m, IH), 2.10 - 2.01 (m, IH), 1.94- 1.83 (m, 2H).

[002567] 4-[3-(Difluoromethvl) [[2-(4-Dvridvl)oxazole carbonyl]amino]Dvrazol-lyl] benzoic acid (Intermediate JL)

LiOH, THF/MeOH

[002568] Step 1 - Difluoromethyl) [[2-(4-pyridyl)oxazole carbonyl1amino1pyrazol-lyllbenzoate

[002569] A mixture of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (900 mg, 3.37 mmol, Intermediate FW), 2-(4-pyridyl)oxazole carboxylic acid (640 mg, 3.37 mmol, Intermediate ED), DIPEA (1.31 g, 10 mmol, 1.76 mL), and HATU (1.54 g, 4.04 mmol) in DMF (20 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at 20 °C for 1 hr under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (basic condition) to give the title compound (1.45g, 67% yield) as white solid. LC-MS (ESI+) m/z 440.2 (M+l)+.

[002570] Step 2:4-[3-(Difluoromethyl) [[2-(4-pyridyl)oxazole-4carbonyl1amino1pyrazol-l-yl1benzoic acid

[002571] To a solution of methyl 4-[3-(difluoromethyl) [[2-(4-pyridyl)oxazole-4carbonyl]amino]pyrazol-l-yl] benzoate (1.60 g, 3.64 mmol) in a mixed of THF (160 mL), MeOH (20 mL) and H2O (30 mL) was added LiOH (436 mg, 18.2 mmol). The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was adjusted to pH = 6 with IN HC1, and then filtered and the filter cake was dried in vacuo to give the title compound (1.5 g, 96% yield) as white solid. LC-MS (ESI+) m/z 426.1 (M+l)+.

[002572] N-[3-(difluoromethvl)-l-[4-[methvl(2-oxoethyl)carbamovl]Dhenvl]Dvrazol-4yl] (4-Dvridyl) oxazole carboxamide (Intermediate JM)

[002573] Step 1:N-r3-(difluoromethyl)-l-[4-r2hvdroxvethvl(methvl)carbamovl1phenvl1pyrazol vl1 (4-pyridyl)oxazole carboxamide [002574] A mixture of 4-[3-(difluoromethyl) [[2-(4-pyridyl)oxazole-4carbonyl]amino]pyrazol-l-yl]benzoic acid (500 mg, 1.18 mmol, Intermediate JL), 2(methylamino)ethanol (88.3 mg, 1.18 mmol, CAS# 109 1), DIPEA (456 mg, 3.53 mmol, 614 uL), and HATU (537 mg, 1.41 mmol) in DMF (20 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at 25 °C for 3 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (acid condition) to give the title compound (500 mg, 85% yield) as light yellow solid. 1H NMR (400MHz, DMSO76) δ 10.16 (s, IH), 9.07 (s, IH), 8.91 -8.74 (m, 3H), 8.03 -7.84 (m, 4H), 7.59 (d, J= 8.4 Hz, 2H), 7.48 - 7.10 (m, IH), 4.83 (s, IH), 3.64 -3.38 (m, 4H), 3.00 (s, 3H); LC-MS (ESI+) m/z 483.2 (M+l)+.

[002575] Step 2:N-r3-(difluoromethvl)-l-r4-[methvl(2oxoethvl)carbamovl1phenvl1pvrazol vl1 (4-pyridvl) oxazole carboxamide

[002576] To a solution of N-[3-(difluoromethyl)-l-[4-[2hydroxyethyl(methyl)carbamoyl]phenyl]pyrazol yl]- 2-(4-pyridyl)oxazole carboxamide (500 mg, 1.04 mmol) in THF (10 mL) was added Dess-Martin (528 mg, 1.24 mmol). The mixture was stirred at 25 °C for 3 hrs. On completion, the mixture was quenched with saturated Na2S2O3(10 mL), then extracted with DCM (2x150 mL). The organic layer was concentrated in vacuo to give the title compound (490 mg, 98% yield) as yellow solid. LC-MS (ESI+) m/z 481.2 (M+l)+.

[002577] 2-(2,6-Dioxo DiDeridvl) [2-(2-hvdroxvethoxv)ethvl]isoindoline-l,3-dione (Intermediate JN)

[002578] Step 1 - 2-(2,6-Dioxo piperidyl) r(E) (2-hydroxyethoxy)vinyl1isoindolineL 3-di one

[002579] To a solution of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (2.00 g, 5.93 mmol Intermediate GA), 2-vinyloxyethanol (1.05 g, 11.8 mmol) in dioxane (15.0 mL) was added P(t-Bu)3 (2.40 g, 1.19 mmol, 10 wt%), Pd2(dba)3 (543 mg, 593 umol) and N-cyclohexyl-Nmethyl-cyclohexanamine (1.51 g, 7.71 mmol), and the mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (EA) to give the title compound (2.00 g, 97% yield) as yellow solid. 1HNMR (400MHz, DMSO» δ 11.13 (s, IH), 7.91 (s, IH), 7.79 - 7.76 (m, IH), 7.72 (s, IH), 7.71 - 7.67 (m, IH), 6.08 (d, J = 12.8 Hz, IH), 5.17 - 5.10 (m, IH), 4.91 -4.86 (m, IH), 3.96 (t, J = 4.8 Hz, 2H), 3.70 -3.63 (m, 2H), 2.95 - 2.84 (m, IH), 2.65 - 2.57 (m, IH), 2.57 - 2.53 (m, IH), 2.11 - 2.01 (m, IH).

[002580] Step 2 - 2-(2,6-Dioxo piperidyl) [2-(2-hydroxyethoxy)ethyl1isoindoline-L3di one

[002581] To a solution of 2-(2,6-dioxo piperidyl) [(E) (2hydroxyethoxy)vinyl]isoindoline-l,3-dione (1.00 g, 2.90 mmol) in THF (40.0 mL) was added Pd/C (300 mg, 10 wt%) and Pd(OH)2/C (300 mg, 10 wt%). The mixture was stirred at 15 °C for 12 hours under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (1.00 g, 95% yield) as yellow solid. LC-MS (ESI+) m/z 347.2 (M+H)+.

[002582] 2-[2-[2-(2.,6-Dioxo DiDeridvl)-l.,3-dioxo-isoindolin vl]ethoxv]ethvl methanesulfonate (Intermediate JO)

[002583] To a solution of 2-(2,6-di oxo piperi dyl) [2-(2hydroxyethoxy)ethyl]isoindoline-l,3-dione (300 mg, 866 umol, Intermediate JN) in DCM (30.0 mL) was added MsCl (148 mg, 1.30 mmol) and TEA (262 mg, 2.60 mmol), and the mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was diluted with DCM (20 mL), and extracted with H2O (3 X 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (350 mg, 95% yield) as yellow oil. LC-MS (ESI+) m/z 425.2 (M+H)+.

[002584] 4-[3-(difluoromethvl) nitro-pvrazol-l-yl]piperidine (Intermediate JP)

[002585] Step 1 -Tert-butyl 4-[3-(difluoromethyl) nitro-pyrazol-l-yl1piperidine-lcarboxylate

[002586] To a solution of tert-butyl 4-methylsulfonyl oxypiperi dine-1 -carboxylate (3.43 g, 12.26 mmol, synthesized via Step 1 of Intermediate CX) and 3-(difluoromethyl) nitro-lHpyrazole (2 g, 12.26 mmol, Intermediate HS) in DMF (20 mL) was added Cs2CO3 (7.99 g, 24.5 mmol). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 5/1 to 1/1) to give the title compound (2.00 g, 44.1% yield) as a yellow solid. LC-MS (ESI+) m/z 291.0 (M+H-56)+.

[002587] Step 2 - 4-[3-(difluoromethyl) nitro-pyrazol-l-yl1piperidine

[002588] To a solution of tert-butyl 4-[3-(difluoromethyl) nitro-pyrazol-l-yl]piperidine-lcarboxylate (1 g, 2.89 mmol) in DCM (10 mL) was added HCI (4 M, 20 mL). The reaction mixture was concentrated in vacuo to give the title compound (830 mg, HCI, 85% purity) as a white solid.

LC-MS (ESI+) m/z 247.0(M+H)+.

[002589] 5-[2-[2-[4-[4-Amino (difluoromethvl)pvrazol-l-yl]-lpiperidyl]ethoxy]ethyl] (2,6 -dioxo piperidyl)isoindoline-l,3-dione (Intermediate JO)

[002590] Step 1:5 -[2- [2-[4- [3 -(Difluoromethyl) nitro-pyrazol-1 -yl] -1 piperidvl1ethoxy1ethyl1 (2,6-dioxo piperidyl)isoindoline-L3-dione

[002591] To a solution of 2-[2-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]ethoxy]ethyl methanesulfonate (225 mg, 530 umol, Intermediate JO), 4-[3-(difluoromethyl)-4nitro-pyrazol-l-yl]piperidine (100 mg, 353 umol, HCI, Intermediate JP) in ACN (2.00 mL) was added KI (5.87 mg, 35.3 umol) and NaHCO3 (89.1 mg, 1.06 mmol). The mixture was stirred at 80 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (DCM: MeOH=50: 1) to give the title compound (100 mg, 49% yield) as white solid. LC-MS (ESI+) m/z 575.1 (M+H)+.

[002592] Step 2:5-[2-[2-[ 4-[4-Amino-3 -(difluorometh yl)pyrazol-1 -yl] -1 piperidyl1ethoxy1ethyl1 (2,6 -dioxo piperidyl)isoindoline-L3-dione

[002593] To a solution of 5-[2-[2-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]-lpiperidyl]ethoxy]ethyl] (2,6- dioxo piperidyl)isoindoline-l,3-dione (90.0 mg, 156 umol) in THF (5.00 mL) was added PtO2 (3.56 mg, 15.6 umol), the mixture was stirred at 15 °C for 16 hrs under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (85.0 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 545.3

[002594] 5-(3-(2-Aminoethoxv)propyl] (2.,6-dioxo piperidvl)isoindoline-l.,3-dione (Intermediate JR)

Pd/C, Pd(OH)2/C, H2, THF

O O

JR

[002595] Step 1 - Tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl1prop ynoxy1 ethyl] carbamate

[002596] To a solution of tert-butyl N-(2-prop ynoxyethyl)carbamate (2.36 g, 11.8 mmol synthesized via Step 1 on Intermediate CP), 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3dione (2.00 g, 5.93 mmol, Intermediate GA) in DMF (4.00 mL) was added Cui (112 mg, 593 umol), Pd(PPh3)2C12 (416 mg, 593 umol), and TEA (10.8 g, 106 mmol). The mixture was stirred at 80 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE: EA =1: 1) to give the title compound (2.60 g, 96% yield) as yellow solid. 1H NMR (400MHz, DMSO-Y) δ 11.2 (s, IH), 8.01 (s, IH), 8.00 (s, 2H), 6.97 - 6.87 (m, IH), 5.28 - 5.17 (m, IH), 4.52 (s, 2H), 3.66 - 3.55 (m, 2H), 3.25 - 3.17 (m, 2H), 2.95 - 2.89 (m, IH), 2.71 - 2.63 (m, IH), 2.62 - 2.58 (m, IH), 2.17 - 2.09 (m, IH), 1.43 (s, 9H).

[002597] Step 2 - Tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl]propoxy]ethyl1 carbamate

[002598] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin5-yl]prop ynoxy] ethylcarbamate (2.60 g, 5.71 mmol) in THF (30.0 mL) was added Pd/C (500 mg, 10 wt%), and Pd(OH)2/C (500 mg, 10 wt%). The mixture was stirred at 15 °C for 16 hours under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (2.40 g, 91% yield) as yellow solid. LC-MS (ESI+) m/z 482.3 (M+Na)+.

[002599] Step 3 - 5-r3-(2-Aminoethoxy)propyl1 (2,6-dioxo piperidvl)isoindoline-L3di one

[002600] To a solution of tert-butyl N-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin5-yl]propoxy]ethyl] carbamate (2.40 g, 5.22 mmol) in DCM (15.0 mL) was added HCI/dioxane (4.00 M, 15.0 mL). The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (2.00 g, 90% yield, HCI) as yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 11.18 (s, IH), 8.14 (s, 2H), 7.91 (d, J = 7.6 Hz, IH), 7.87 (s, IH), 7.81 (d, J = 7.6 Hz, IH), 5.25 - 5.15 (m, IH), 3.66 - 3.63 (m, 2H), 3.52 - 3.47 (m, 2H), 3.07 - 2.98 (m, 2H), 2.97 - 2.94 (m, IH), 2.93 - 2.88 (m, 2H), 2.70 - 2.64 (m, IH), 2.62 - 2.58 (m, IH), 2.15 2.08 (m, IH), 1.99 - 1.90 (m, 2H).

[002601] Methyl 4-(3-bromo nitro-pyrazol-l-vl)benzoate (Intermediate JS

Cu(OAc)2, Pyridine O2, DCM

[002602] To a solution of 3-bromo nitro-lH-pyrazole (4.8 g, 25.0 mmol, CAS# 784193

37-9) and (4-methoxycarbonylphenyl) boronic acid (6.75 g, 37.5 mmol, CAS# 99768 4) in DCM (100 mL) was added Cu(OAc)2 (4.54 g, 25.0 mmol), and pyridine (7.91 g, 100 mmol) under 02 (15 Psi). The reaction mixture was stirred at 20 °C for 12 hours under 02 (15 Psi) atmosphere. On completion, the mixture was washed with ΝΗ3&#905;2Ο (50 mL), filtered and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with 2 N aq.HCl (60 mL) and brine (2 X 100 mL), dried over anhydrous sulfate sodium, filtered and concentrated in vacuo. The crude product was triturated with PE: EA= 10:1 (100 mL) to give the title compound (5.00 g, 61% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 9.82 (s, IH), 8.11 - 8.06 (m, 4H), 3.88 (s, 3H).

[002603] Methyl 4-[4-amino [3-(2-hvdroxvethvl) oxo-imidazolidin-l-vl]pyrazol-l yl] benzoate (Intermediate JT)

K2CO3, bis(tetrabutylammonium iodide) copper[!]

N,N'-dimethylethane-1,2-diamine , dioxane

[002604] Step 1 - Methyl 4-r3-r3-(2-hydroxyethyl) oxo-imidazolidin-l-yl1 nitropyrazol-l-yl1benzoate

[002605] A mixture of methyl 4-(3-bromo nitro-pyrazol-l-yl)benzoate (500 mg, 1.53 mmol, 1 eq, Intermediate JS), l-(2-hydroxyethyl)imidazolidin one (239 mg, 1.84 mmol, CAS# 3699 5), bis (tetrabutylammonium iodide) copper[!] (132 mg, 306 umol), K2CO3 (423 mg, 3.07 mmol) and Nl,N2-dimethyl ethane-1,2-diamine (27.0 mg, 306 umol) in dioxane (25 mL) was degassed and purged with N2 3 times. Then the mixture was stirred at 110 °C for 16 hours under N2 atmosphere. The mixture was fdtered and the fdtrate was concentrated in vacuo. The residue was purified by Pre-HPLC( acid condition) give the title compound (110 mg, 17% yield) as yellow solid; LC-MS (ESI+) m/z 316$ (M+H)+.

[002606] Step 2 - Methyl 4-r4-amino r3-(2-hydroxyethyl) oxo-imidazolidin-lyllpyrazol-1 -yllbenzoate

[002607] To a solution of methyl 4-[3-[3-(2-hydroxyethyl) oxo-imidazolidin-l-yl] nitropyrazol yl]benzoate (110 mg, 293 umol) in THF (10 mL) was added Pd/C (20 mg, 10 wt%). The mixture was stirred at 20 °C for 3 hours under H2 (15 Psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 98% yield) as yellow solid; LC-MS (ESI+) m/z 346.2 (M+H)+.

[002608] 3,3-DimethylDvrrolidin one (Intermediate JU) (Boc)2O, DMAP LiHMDS, Mel HCI/dioxane ^NH CH3CN N'Bqc THF *&#1497; [XM YnH

[002609] Step 1 - Tert-butyl 2-oxopyrrolidine-l-carboxylate

[002610] To a solution of pyrrolidin one (20 g, 235 mmol) in ACN (450 mL) was added (Boc)2O (61.5 g, 282 mmol) and DMAP (2.87 g, 23.50 mmol) at 0 °C. The mixture was stirred at 10 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE/EA=3/1) to give the title compound (38 g, 87% yield) as light yellow solid. 1H NMR (400MHz, CDCh) δ 3.74 (t, J= 7.2 Hz, 2H), 2.50 (t, J= 8.2 Hz, 2H), 2.06 - 1.93 (m, 2H), 1.52 (s, 9H).

[002611] Step 2 - Tert-butyl 3.3-dimethvl oxo-pyrrolidine-l-carboxylate

[002612] To a mixture of tert-butyl 2-oxopyrrolidine-l-carboxylate (4.5 g, 24.3 mmol) in THF (50 mL) was added LiHMDS (1.0 M, 25.5 mL) at -70 °C. Then the reaction mixture was stirred at -30°C for 0.5 hour. Mel (8.62 g, 60.7 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo. The residue was quenched with water (30 mL) and extracted with EtOAc (3 X 30 mL). The organic layer was dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE:EA = 5:1) to give the title product (2.80 g, 54% yield) as colorless solid. 1H NMR (400MHz, CDCh) δ 3.67 (t, J = 7.2 Hz, 2H), 1.85 (t, J = 7.2 Hz, 2H), 1.55 (s, 9H), 1.20 (s, 6H).

[002613] Step 3 - 3,3-Dimethylpyrrolidin one

[002614] To a mixture of tert-butyl 3,3-dimethyl oxo-pyrrolidine-l-carboxylate (2.0 g, 9.38 mmol,) in DCM (3 mL) was added HCl/dioxane (4 M, 2.00 mL). Then the reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.00 g, 94% yield) as yellowish solid. 1H NMR (400MHz, DMSO-d6) δ 3.06 (t, J= 6.8 Hz, 2H), 1.76 (t, J= 6.8 Hz, 2H), 0.93 (s, 6H).

[002615] Methyl 4-[4-amino (3.,3-dimethvl oxo-pvrrolidin-l-vl)Dvrazol-lyl] benzoate (Intermediate JV)

OMe

JV

[002616] Step 1 - Methyl 4-[3-(3,3-dimethyl oxo-pyrrolidin-l-yl) nitro-pyrazol-lyllbenzoate

[002617] A mixture of methyl 4-(3-bromo nitro-pyrazol-l-yl)benzoate (500 mg, 1.53 mmol, Intermediate JS), 3,3-dimethylpyrrolidin one (208 mg, 1.84 mmol, Intermediate JU), bis(tetrabutylammonium iodide) copper[!] (132 mg, 306 umol), K2CO3 (423 mg, 3.07 mmol) and Ν,Ν'-dimethylethane-1,2-diamine (27.0 mg, 306 umol) in dioxane (20 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at 110 °C for 16 hours under N2 atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by Pre-HPLC (acid condition) to give the title compound (200 mg, 18% yield) as yellow solid, LC-MS (ESI+) m/z 359.2 (M+H)+.

[002618] Step 2 - Methyl 4-[4-amino (3,3-dimethyl oxo-pyrrolidin-l-yl)pyrazol-lyllbenzoate

[002619] To a solution of methyl 4-(3-(3,3-dimethyl oxo-pyrrolidin-l-yl) nitro-pyrazoll-yl]benzoate (50 mg, 139 umol) in MeOH (5 mL) was added Pd/C (30 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 gas three times. The mixture was stirred at 20 °C for 3 hours under H2 (15 Psi). On completion, the reaction mixture was concentrated in vacuo to give the title compound (45 mg, 97% yield) as light yellow solid; LC-MS (ESI+) m/z 329.2 (M+H)+.

[002620] 2-(26&#1524;-Dioxo DiDeridvl) (4-DiDeridvlamino)isoindoline-l.,3-dione (Intermediate JW)

DIPEA, dioxane

HCI/Dioxane, DCM

[002621] Step 1 - Tert-butyl 4-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1amin01piperidine-l- carboxylate

[002622] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (2.5 g, 9.05 mmol, Intermediate R) and tert-butyl 4-aminopiperidine-l-carboxylate (1.81 g, 9.05 mmol, CAS# 502482 0) in dioxane (25 mL) was added DIPEA (4.68 g, 36.2 mmol). The reaction mixture was stirred at 115 °C for 15 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.16 g, 52% yield) as a yellow solid. LC-MS (ESI+) m/z 479.1 (M+Na)+.

[002623] Step 2 - 2-(2,6-Dioxo piperidyl) (4-piperidylamino)isoindoline-L3-dione [002624] To a solution of tert-butyl 4-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]piperidine-l- carboxylate (2.16 g, 4.73 mmol) in DCM (5 mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was concentrated in vacuo. The residue was triturated with DCM (50 mL), stirred and filtered. The filter cake was dried in vacuo to give the title compound (1.20 g, 65% yield, HCI) as a yellow green solid. LC-MS (ESI+) m/z 357.1 (M+H)+.

[002625] Tert-butyl

N- [2- [2- [2-(2-oxoethoxy)ethoxy| ethoxy] ethyl] carbamate (Intermediate JX)

NHBoc

DMSO, (COCI)2

TEA, DCM

NHBoc

JX

[002626] To a solution of DMSO (1.33 g, 17.0 mmol) in DCM (10 mL) was added a solution of (COC1)2 (1.73 g, 13.6 mmol) in DCM (15 mL) dropwise at -70 °C. The mixture was stirred at this temperature for 10 minutes. Then a solution of tert-butyl N-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.82 mmol, synthesized via Steps 1-3 of Intermediate AO) in DCM (15 mL) was added into the above mixture slowly. After stirred at -70 °C for 50 minutes, TEA (5.52 g, 54.5 mmol) was added and the reaction mixture was stirred at 70 °C for 0.5 hr. On completion, the mixture was quenched with water (30 mL), and then separated. The aqueous phase was extracted with DCM (2 X 30 mL). Then the organic phase was combined and washed with brine (2 X 30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (1.50 g, 76% yield) as yellow oil, which was used directly in the next step without further purification.

[002627] 4- [[1- [2-[2- [2-(2-Aminoethoxv)ethoxy] ethoxy] ethyll piperidyl] amino]-2 (2,6-dioxo piperidyl)isoindoline-l,3-dione (Intermediate JY)

[002628] Step 1 - Tert-butyl N-r2-r2-r2-r2-r4-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1-l- piperidyl1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[002629] To a mixture of tert-butyl N-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (386 mg, 1.32 mmol, Intermediate JX) and 2-(2,6-di oxo-3 -piperi dyl) (4piperidylamino)isoindoline-1,3-dione (400 mg, 1.02 mmol, HC1, Intermediate JW) in THF (20 mL) was added KOAc (200 mg, 2.04 mmol). One hour later, NaBH(OAc)3 (432 mg, 2.04 mmol) was added and the reaction mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% HC1 condition) to give the title compound (550 mg, 86% yield) as a yellow solid. LC-MS (ESI+) m/z 632.4 (M+H)+ [002630] Step 2 - 4-[[l-[2-[2-[2-(2-Aminoethoxy)ethoxy1ethoxy1ethyl1 piperidyl1amino12-(2,6-di oxo piperidyl)isoindoline-L3-dione

[002631] To a solution of tert-butyl N-[2-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]-l-piperidyl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (550 mg, 871 umol) in DCM (5 mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at 20 °C for 10 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (460 mg, 93% yield, HC1) as a yellow solid. LC-MS (ESI+) m/z 532.2 (M+H)+.

[002632] 5-[[l-[2-(2-Aminoethoxv)ethvl] DiDeridyl]amino] (2.,6-dioxo-3piperidyl)isoindoline-l.,3-dione (Intermediate JZ)

P 1 H O<^O^&#1523;^NHBoc hnA; )Art+wArt/A

0=/ / N JL J L ' ------------------------&#9658; '—' Y&#1523;NH KOAc, NaBH(OAc)3, THF/DCM

O

HCI/dioxane, DCM

[002633] Step 1 - Tert-butyl N-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yl1amin01-l- piperi dyl1ethoxy1ethyl1carbamate

[002634] To a solution of 2-(2,6-dioxo piperidyl) (4-piperidylamino)isoindoline-l,3dione (400 mg, 1.02 mmol, HC1, synthesized via Steps 1-2 of Intermediate HZ), tert-butyl N-[2 (2-oxoethoxy)ethyl]carbamate (310 mg, 1.53 mmol, synthesized via Step 1 of Intermediate FS) in a mixed solvent of THF (10.0 mL) and DCM (10.0 mL) was added KO Ac (199 mg, 2.04 mmol), the mixture was stirred at 15 °C for 0.5 hr, then NaBH(OAc)3 (431 mg, 2.04 mmol) was added, and the mixture was stirred at 15 °C for 16 hrs. On completion, the mixture was quenched with H2O (2.00 mL) and concentrated in vacuo. The crude product was purified by reverse phase: (0.1% HCI condition) to give the title compound (380 mg, 68% yield) as yellow solid. LC-MS (ESI+) m/z 544.4 (M+H)+.

[002635] Step 2 - 5-rr1-r2-(2-Aminoethoxy)ethyl1 piperidvl1amino1 (2,6-dioxo-3piperidyl)isoindoline -L3-dione

[002636] To a solution of tert-butyl N-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]-1 -piperi dyl ]ethoxy] ethyl ]carb am ate (380 mg, 699 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 5.00 mL), the mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (300 mg, 90% yield, HCI) as yellow solid. LC-MS (ESI+) m/z 444.1 (M+H)+.

[002637] 5- [[1- [2-[2- [2-(2-Aminoethoxv)ethoxy] ethoxy] ethyl] piperidyl] amino]-2(26&#1524;-dioxo piperidyl)isoindoline-l.,3-dione (Intermediate KA)

JX

HCl/dioxane, DCM

[002638] Ste£Y^^IertzbutYl^H2z]2d2d2dJz[12zi226zdioxoz3z2iperidYl)zL3zdioxoz isoindolin yl1amino1-l- piperidvl1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[002639] To a solution of 2-(2,6-dioxo piperidyl) (4-piperidylamino)isoindoline-l,3 dione (400 mg, 1.02 mmol, HCI, synthesized via Steps 1-2 of Intermediate HZ) in THF (20 mL) was added TEA (206 mg, 2.04 mmol, 283 uL). The mixture was stirred at 20 °C for 30 minutes, then tert-butyl N-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy] ethylcarbamate (385 mg, 1.32 mmol, Intermediate JX), HOAc (183 mg, 3.05 mmol, 174 uL) and NaBH(OAc)3 (431 mg, 2.04 mmol) was added to the mixture. The reaction mixture was stirred at 20 °C for 16 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (400 mg, 62% yield) as a yellow solid. LC-MS (ESI+) m/z 632.4 (M +H)+.

[002640] Step 2 - 5-rr1-r2-r2-r2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl] piperidyl]amino]2-(2,6-di oxo piperidyl)isoindoline-L3-dione

[002641] To a solution of tert-butyl N-[2-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]-l-piperidyl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 633 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 6.20 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (350 mg, 97% yield) as a yellow solid. LC-MS (ESI+) m/z 532.4 (M+H)+.

[002642] 4 12 [2-(2-Aminoethoxv)ethoxy] ethoxy] ethyl] piperazin-l-yl] (2,6dioxo piperidyl) isoindoline-l,3-dione (Intermediate KB)

[002643] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-Γ4-Γ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-1,3-&#940;&#912;οχοisoindolin yl]piperazin-l -yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

[002644] To a mixture of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (250 mg, 659 umol, HCL synthesized via Steps 1-2 Intermediate IA) and TEA (66.7 mg, 659 umol, 91.8 uL) in THF (10 mL) and DMF (5 mL) was added tert-butyl N-[2-[2-[2-(2oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (249 mg, 857 umol, Intermediate JX), HO Ac (39.6 mg, 659 umol, 37.7 uL) and NaBH(OAc)3 (279 mg, 1.32 mmol). The reaction mixture was stirred at 20 °C for 20 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA condition) to give the title compound (200 mg, 49% yield) as yellow solid. LC-MS (ESI+) m/z 618.4 (M+H) + .

[002645] Step 2 - 4-[4-[2-[2-[2-(2-Aminoethoxv)ethoxv1ethoxv1ethvl1piperazin-l-yl1-2(2,6-di oxo piperidyl) isoindoline-L3-dione

[002646] To a mixture of tert-butyl N-[2-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] piperazin-l-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 323 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 10 mL). The reaction mixture was stirred at 20 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (179 mg, 99% yield, HCI) light yellow gum. LC-MS (ESI+) m/z 518.3 (M+H)+.

[002647] 3-(5-Bromo-l-oxo-isoindolin yl)piperidine-2.,6-dione (Intermediate KC)

KC

[002648] Step 1 - Methyl 4-bromo (bromomethyl)benzoate

[002649] To a solution of methyl 4-bromo methyl-benzoate (5.00 g, 21.8 mmol, CAS# 99548 7) in CCL (50.0 mL), NBS (4.66 g, 26.1 mmol) and AIBN (358 mg, 2.18 mmol) were added. The reaction mixture was stirred at 80 °C for 24 hrs. On completion, the reaction was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 20: 1) to give the title compound (5.1 g, 76% yield) as colorless liquid. 1H NMR (400MHz, DMSO-d6) δ 7.86 (d, J = 8.4 Hz, IH), 7.59 (s, IH), 7.54 - 7.52 (m, IH), 4.92 (s, 2H), 3.96 (s, 3H). [002650] Step 2 - 3-(5-bromo-l-oxo-isoindolin yl)piperidine-2,6-dione

[002651] To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.1 mmol, HCI) and methyl

4-bromo (bromomethyl)benzoate (5.10 g, 16.5 mmol) in DMF (50.0 mL) was added TEA (4.92 g, 48.6 mmol). The reaction mixture was stirred at 75 °C for 12 hrs. On completion, the reaction mixture was diluted with water (200 mL) and filtered. The filtered cake was collected. The reaction mixture was concentrated in vacuo. The residue was triturated with EA: H2O =1:1 (50 mL) to give the title compound (1.70 g, 39% yield) as blue solid. 1H NMR (400MHz, DMSO-d6) δ 10.99 (s, IH), 7.90 (s, IH), 7.74 - 7.66 (m, 2H), 5.14 - 5.09 (m, IH), 4.50 - 4.33 (m, 2H), 2.95 - 2.86 (m, IH), 2.70 - 2.61 (m, IH), 2.42 - 2.36 (m, IH), 2.04 - 2.01 (m, IH).

[002652] 3-(l-Oxo piperazin-l-vl-isoindolin yl)piperidine-2,6-dione (Intermediate

KD

KC

,Boc

HCI/dioxane, DCM

Ruphis, Ruphou Pd G2, Cs2CO3, dioxane

KD

[002653] Step 1 - Tert-butyl 4-[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin yl1piperazine1-carboxylate

[002654] To a solution of 3-(5-bromo-l-oxo-isoindolin yl)piperidine-2,6-dione (500 mg, 1.55 mmol, Intermediate KC), and tert-butyl piperazine carboxylate (413 mg, 1.86 mmol, HCI) in dioxane (40.0 mL) was added Cs2CO3 (1.01 g, 3.09 mmol), RuPhos (144 mg, 309 umol), [2-(2aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6diisopropoxyphenyl)phenyl]phosphane (240 mg, 309 umol) and 4A molecular sieves (30.0 mg), and the mixture was stirred at 100 °C for 16 hr under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by reverse phase: (0.1% HCI) to give the title compound (350 mg, 95% yield) as yellow oil, LC-MS (ESI+) m/z 429.3 (M+H)+. [002655] Step 2 - 3-(l-Oxo piperazin-l-yl-isoindolin yl)piperidine-2,6-dione

[002656] To a solution of tert-butyl 4-(2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-5yl]piperazine-l-carboxylate (160 mg, 373 umol) in DCM (2.00 mL) was added HCI/dioxane (4.00 M, 4.00 mL), the mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (130 mg, 90% yield, HCI) as yellow solid. LCMS (ESI+) m/z 329.2 (M+H)+.

[002657] 3-[5-[4-[2-[2-(2-Aminoethoxv)ethoxv]ethvl]piperazin-l-vl]-l-oxo-isoindolin-2yl] piperidine -2,6-dione (Intermediate KE)

KD

[002658] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ4-Γ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1) οχο-&#912;5ο&#912;η&#940;ο1&#912;η-5yllpiperazin-1 -yl] ethoxv1ethoxv1ethyl1carbamate

[002659] To a solution of 3-(l-oxo piperazin-l-yl-isoindolin yl)piperidine-2,6-dione (130 mg, 356 umol, HCI, Intermediate KE), tert-butyl N-[2-[2-(2oxoethoxy)ethoxy]ethyl]carbamate (105 mg, 427 umol, Intermediate HY) in THF (10.0 mL) was added KO Ac (69.9 mg, 712 umol). The mixture was stirred at 15 °C for 0.5 hr, then NaBH(OAc)3 (151 mg, 712 umol) was added, and the mixture was stirred at 15 °C for 16 hrs. On completion, the mixture was diluted with H2O (1.00 mL) and concentrated in vacuo. The crude product was purified by reverse phase: (0.1% HCI) to give the title compound (130 mg, 65% yield) as yellow solid. LC-MS (ESI+) m/z 560.4 (M+H)+

[002660] Step 2 - 3-r5-r4-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1piperazin-l-yl1-l-oxoisoindolin yl1piperidine -2,6-dione

[002661] To a solution of tert-butyl N-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl]piperazin-l-yl]ethoxy]ethoxy]ethyl]carbamate (130 mg, 232 umol) in DCM (3.00 mL) was added HCI/dioxane (4.00 M, 4.00 mL), and the mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (110 mg, 90% yield, HCI) as yellow solid. LC-MS (ESI+) m/z 460.4 (M+H)+.

[002662] 5-[4-[2-(2-Aminoethoxv)ethvl]DiDerazin-l-yl] (2,6-dioxo-3piperidyl)isoindoline-l,3-dione (Intermediate KF)

NHB0C

TEA, HOAc, NaBH(OAc)3, DCM/DMF

[002663] Step 1 - Tert-butyl N-r2-r2-r4-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-5yllpiperazin-1 -yl] ethoxylethyllcarbamate

[002664] To a solution of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (500 mg, 1.32 mmol, HCI, synthesized via Steps 1-2 of Intermediate IB) in a mixed solvent of DCM (20 mL) and DMF (6 mL) was added TEA (200 mg, 1.98 mmol), HOAc (158 mg, 2.64 mmol) and tert-butyl N-[2-(2-oxoethoxy)ethyl]carbamate (804 mg, 3.96 mmol, synthesized via Step 1 of Intermediate FS) at 5 C. The mixture was stirred at 5 C for 30 minutes, and then NaBH(OAc)3 (559 mg, 2.64 mmol) was added at 0 ° C, the mixture was stirred at 10 ° C for 72 hours. On completion, the reaction mixture was quenched by water (0.1 mL), and then concentrated in vacuo. The residue was purified by prep-HPLC (FA condition) to give the title compound (0.40 g, 53% yield) as yellow solid. LC-MS (ESI+) m/z 530.2(M+H)+.

[002665] Step 2 - 5-[4-[2-(2-Aminoethoxy)ethyl1piperazin-l-yl1 (2,6-dioxo-3piperidyl)isoindoline-L3-dione

[002666] To a solution of tert-butyl N-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]piperazin-l- yl]ethoxy]ethyl]carbamate (0.37 g, 649 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 3 mL). The mixture was stirred at rt for 1.5 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (0.28 g, 91% yield, HCI) as yellow solid. LC-MS (ESI+) m/z 430.1 (M+H)+.

[002667] 2-[2-(Cvcl0Dr0Dvlmethvlamin0) Dvridvl]-N-[3-(diflu0r0methyl)-l-[4980 iii(2S.,4R) hvdroxv carboxamide (Intermediate KG)

KG

HCI/dioxane, DCM

[002668] Step 1:Tert-butyl N-r4-r4-rr1-[4-(azidomethyl)phenyl1-3(difluoromethyl)pyrazol yl1carbamoyl1 oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate

[002669] To a mixture of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4- (hydroxymethyl)phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (1 g, 1.72 mmol, synthesized via Step 1-2 of Intermediate GF) in THF (20 mL) was added DPPA (2.37 g, 8.61 mmol ) at 0 °C, then DBU (1.31 g, 8.61 mmol) was added. The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was quenched with water (10 mL), then extracted with EA (2 X 50 mL). The organic layer was concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give the title compound (700 mg, 67% yield) as white solid. LCMS (ESI+) m/z 606.3 (M+l)+.

[002670] Step 2:Tert-butyl N-r4-r4-rr1&#1470;r4-(aminomethyl)phenyl1-3(difluoromethyl)pyrazol yl1 carbamoyl1oxazol yl1 pyridyl1-N(cyclopropylmethyl)carbamate

[002671] To a solution of tert-butyl N-[4-[4-[[l-[4-(azidomethyl)phenyl]-3(difluoromethyl)pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (700 mg, 1.16 mmol) in THF (100 mL) was added Pd/C (50 mg, 10 wt%). The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at rt for 16 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (500 mg, 74% yield) as white solid. LC-MS (ESI+) m/z 580.3 (M+l)+.

[002672] Step 3:Tert-butyl(25ΑΚ) ΓΓ4-Γ4-ΓΓ2-Γ2-Γ&#912;61&#912;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1 oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenyl1methylcarbamoyl1 hydroxy-pyrrolidine-l-carboxylate

[002673] A mixture of (2S,4R)-l-tert-butoxycarbonyl hydroxy-pyrrolidine carboxylic acid (199 mg, 862 umol, CAS# 13726 7), tert-butyl N-[4-[4-[[l-[4-(aminomethyl)phenyl]-3(difluoromethyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (500 mg, 862 umol), HATU (393 mg, 1.04 mmol), and DIPEA (334 mg, 2.59 mmol) in DMF (3 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at rt for 2 hrs under N2 atmosphere. On completion, the reaction mixture was quenched with water 20 mL, and then extracted with EA (2 X 100 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC to give the title compound (460 mg, 67% yield) as white solid. LC-MS (ESI+) m/z 793.2 (M+l)+.

[002674] Step 4 - 2-r2-(Cyclopropylmethylamino) pyridyl1-N-l3-(difluoromethyl)-l-r41rr(2S,4R) hydroxy pyrrolidine carbonyl1amino1methyl1phenyl1pyrazol yl1oxazole-4 carboxamide

[002675] To a solution of tert-butyl (2S,4R) [[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3 (difluoromethyl)pyrazol-l-yl]phenyl]methylcarbamoyl] hydroxy-pyrrolidine-l-carboxylate (200 mg, 252 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at rt for 16 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 94% yield) as white solid. LC-MS (ESI+) m/z 593.4 (M+l)+.

[002676] N-[l-[4-[[[(2S.,4R)-l-[(2S) amino-3.,3-dimethvl-butanovl] hvdroxvDyrrolidine carbonvl]amino]methvl]phenvl] (difluoromethvl)pyrazol vl] [2(cvclopropvlmethvlamino) pyridvl]oxazole carboxamide (Intermediate KH)

KG

HCI/dioxane, DCM

KH

[002677] Step 1 - Tert-butyl N-r(lS)-l-r(2S,4R) rr4-r4-rr2-[2-(cyclopropylmethylamino)4-pyridyl1oxazole carbonyl1amino1 (difluoromethyl)pyrazol-lyl1phenyl1methylcarbamoyl1 hydroxy-pyrrolidine-l-carbonyl1-2,2-dimethyl-propyl1

[002678] A mixture of 2-[2-(cyclopropylmethylamino) pyridyl]-N-[3-(difluoromethyl)-l[42)]]] &#1470;S,4R) hydroxypyrrolidine carbonyl]amino]methyl]phenyl]pyrazol yl]oxazole-4carboxamide (70 mg, 111 umol, HCI, Intermediate KG), (2S) (tert-butoxycarbonylamino)-3,3dimethyl-butanoic acid (26 mg, 111 umol, CAS# 62965 9), HATU (51 mg, 133 umol), and DIPEA (43. mg, 334 umol) in DMF (5 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at rt for 2 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo, the residue was purified by prep-HPLC to give the title compound (65 mg, 65% yield) as white solid. LC-MS (ESI+) m/z 806.5 (M+l)+.

[002679] Step 2 - N-r1-r4-rr[(2SAR)-l-r(2S) amino-3 J-dimethyl-butanovl1 hydroxypyrrolidine carbonvl1amino1methyl1phenvl1 (difluoromethyl)pyrazol yl1 [2(cyclopropylmethylamino) pyridyl1oxazole carboxamide

[002680] To a solution of tert-butyl N-[(lS)-l-[(2S,4R) [[4-[4-[[2-[2(cyclopropylmethylamino) pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]phenyl]methylcarbamoyl] hydroxy-pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]carbamate (100 mg, 124 umol) in DCM (6 mL) was added HCI/dioxane (4 M, 2 mL). The mixture was stirred at rt for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (95 mg, 100% yield) as white solid. LC-MS (ESI+) m/z 706.2 (M+l)+

[002681] O1-Benzyl O2-[(3R5&#1524;S) [[4-[4-[[2-[2-(cvclopropvlmethvlamino)-4pyridyl] carbonyl]amino] (difluoromethyl)pyrazol-ly 1] phenyl] methylcarbamoyl] pyr rolidin yl] (2S)-pyrrolidine-1 .,2-dicarboxylate (Intermediate KI)

Cbz H°+b

DCC, DMAP, DCM

TFA, DCM

[002682] Step 1 - 01-benzyl O2-r(3R,5S)-l-tert-butoxycarbonyl rr4-r4-rr2-r2-[tertbutoxycarbonyl(cvclopropylmethyl)amino1 pyridvl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-1 -yl1phenvl1methylcarbamoyl1pyrrolidin-3 -yl] (2S)-pyrrolidine-1,2di carboxyl ate

[002683] To a solution of (2S)-l-benzyloxycarbonylpyrrolidine carboxylic acid (72.3 mg, 290 umol) in DCM (10 mL) was added EDCI (83.4 mg, 435 umol) and DMAP (3.54 mg, 29.0 umol) at 0 °C, then tert-butyl(2S,4R) [[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methylcarbamoyl] hydroxy-pyrrolidine-l-carboxylate (230 mg, 290 umol, synthesized via Steps 1-3 of Intermediate KG) was added to the mixture, and the reaction mixture was stirred at rt for 12 hr. On completion, the mixture was diluted with H2O (5 mL), then concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (280 mg, 94% yield) as a white solid. LC-MS (ESI+) m/z 1024.6 (M +H)+.

[002684] Step 2- Ol-benzyl O2-r(3R,5S) rr4-r4-rr2-r2-(cyclopropylmethylamino)-4pyridvHoxazole carbonvl1amino1 (difluoromethyl)pyrazol-lyl1phenyl1methylcarbamoyl1pyrrolidin yl1(2S)-pyrrolidine-L2-dicarboxylate

[002685] To a solution of Ol-benzyl O2-[(3R, 5S)-l-tert-butoxycarbonyl [[4-[4-[[2-[2[tert-butoxy carbonyl (cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-1 -yl]phenyl]methylcarbamoyl]pyrrolidin-3 -yl] (2S)-pyrrolidine-1,2dicarboxylate (260 mg, 253 umol) in DCM (2 mL) was added TFA(1.54 g, 13.5 mmol, 1 mL), and the reaction mixture was stirred at rt for 12 hr. On completion, the mixture was concentrated in vacuo to give the title compound (200 mg, 96% yield) as a white solid. LC-MS (ESI+) m/z 824.4(M+H)+.

[002686] 02- [(3R,5S) [(2S) amino-3,3-dimethyl-butanovl] [[4- [4- [[2- [2(cycloDroDylmethylamino) Dyridyl]oxazole carbonyl]amino]-3(difluoromethyl)Dyrazol-l-yl]Dhenyl]methylcarbamoyl]Dyrrolidin yl] Ol-benzyl (2S)pyrrolidine-l,2-dicarboxylate (Intermediate KJ)

[002687] Step 1- (S)-l-Benzyl 2-((3R,5S)-l-((S) ((tert-butoxycarbonyl)amino)-3,3dimethylbutanoyl) ((4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin yl)oxazole-4carboxamido) (difluoromethyl)-lH-pyrazol-l-yl)benzyl)carbamoyl)pyrrolidin yl) pyrrolidine-1,2-dicarboxylate

[002688] To a solution of 01-benzyl O2-[(3R,5S) [[4-[4-[[2-[2(cyclopropylmethylamino) pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]phenyl]methylcarbamoyl]pyrrolidin yl](2S)- pyrrolidine-1,2-dicarboxylate (140 mg, 169 umol, Intermediate KI) and (2S) (tert- butoxycarbonylamino)-3,3-dimethyl-butanoic acid (39.3 mg, 169 umol, CAS# 62965 9) in DMF (10 mL) was added DIPEA (21.9 mg, 169 umol, 29.6 uL) and HATU (77.5 mg, 203 umol), and the mixture was stirred at rt for 12 hr. On completion, the mixture was quenched by addition of H2O (5mL), and then concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (160 mg, 91% yield) as a white solid. LC-MS (ESI+) m/z 1037.3 (M+H)+.

[002689] Step 2 - O2-r(3R5S)-l-r(2S) amino-3,3-dimethyl-butanoyl] rr4-[4-rr2-r2(cyclopropylmethylamino) pyridyl1oxazole carbonyl1amino1 (difluoromethyl)pyrazol-lyl1phenyl1methylcarbamoyl1pyrrolidin yl1 Ol-benzyl (2S)-pyrrolidine-L2-dicarboxylate [002690] To a solution of Ol-benzyl O2-[(3R,5S)-l-[(2S) (tert-butoxycarbonylamino)3,3-dimethyl-butanoyl] [[4-[4-[[2-[2-(cyclopropylmethylamino) pyridyl]oxazole-4carbonyl]amino] (difluoromethyl)pyrazol-l-yl]phenyl]methylcarbamoyl]pyrrolidin yl] (2S)pyrrolidine-1,2-dicarboxylate (150 mg, 144 umol) in DCM (4 mL) was added TFA (3.08 g, 27.0 mmol, 2.0 mL), and the reaction mixture was stirred at rt for 3 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (130 mg, 96% yield) as a yellow solid. LC-MS (ESI+) m/z 937.5 (M+H)+.

[002691] 4- [[1- [2-[2-(2-Aminoethoxv)ethoxy] ethyl] DiDeridyl] amino] (2.,6-dioxo-3DiDeridyl)isoindoline-l.,3-dione (Intermediate KK)

[002692] Step 1 - Tert-butylN-r2-r2-r2-r4-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin

4-yl] amino] -1 -piperidyl] ethoxy] ethoxy] ethyl] carb amate

[002693] To a mixture of 2-(2,6-dioxo piperidyl) (4-piperidylamino)isoindoline-l,3dione (200 mg, 509 umol, HCI, Intermediate JW) in DCM (10 mL) was added KOAc (99.9 mg, 1.02 mmol) and stirred at 1 hr. Tert-butyl N-[2-[2-(3-oxopropoxy)ethoxy]ethyl]carbamate (133 mg, 509 umol, Intermediate HY) and NaBH(OAc)3 (216 mg, 1.02 mmol) was added into the mixture. The reaction mixture was stirred at rt for 11 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (165 mg, 55% yield) as a yellow solid. LC-MS (ESI+) m/z 588.2 (M+H)+.

[002694] Step 2 - 4-rr1-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1 piperidyl1amino1 (2,6dioxo piperidyl)isoindoline-L3-dione

[002695] To a mixture of tert-butyl N-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino]-l- piperidyl]ethoxy]ethoxy]ethyl]carbamate (165 mg, 281 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 0.7 mL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (136 mg, 92% yield, HCI) as brown oil. LC-MS (ESI+) m/z 488.2 (M+H)+.

[002696] 4-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-l-yl] (2.,6-dioxo-3DiDeridyl)isoindoline-l.,3-dione (Intermediate KL)

HCl/dioxane, DCM

[002697] Step 1 - Tert-butyl N-r2-r2-r2-r4-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin4-vl1piperazin-l-yl1 ethoxv1ethoxv1ethyl1carbamate

[002698] To a solution of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (250 mg, 660 umol, HC1, synthesized via Steps 1-2 Intermediate IA) and tert-butyl N-[2-[2-(2oxoethoxy)ethoxy]ethyl]carbamate (212 mg, 858 umol, Intermediate HY) in a mixed solvent of THF (15 mL) and DCM (5 mL) was added KOAc (130 mg, 1.32 mmol). Then one hour later, NaBH(OAc)3 (280 mg, 1.32 mmol) was added and the reaction mixture was stirred at rt for 17 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% HC1 condition) to give the title compound (110 mg, 29% yield) as a yellow solid. LC-MS (ESI+) m/z 574.2 (M+H)+.

[002699] Step 2 - 4-r4-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1piperazin-l-yl1 (2,6-dioxo-3piperidyl)isoindoline-L3-dione

[002700] To a solution of tert-butyl N-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] piperazin-l-yl]ethoxy]ethoxy]ethyl]carbamate (110 mg, 192 umol) in DCM (4 mL) was added HCI/dioxane (4 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (90 mg, 92% yield, HC1) as a yellow solid. LC-MS (ESI+) m/z 474.2 (M+H)+.

[002701] Tert-butyl N-[4-[4-[[3-carbamovl-l-[4-[methyl(2oxoethyDcarbamoyl] phenyl] pyrazol vl]carbamovl]oxazol vl] pyridvl]-N(cvclopropylmethvl)carbamate (Intermediate KM)

HO

I

NH

HATU. DIPEA, DMF

[002702] Step 1:Tert-butyl N-r4-r4-rr3-carbamoyl-l-[4-r2hydroxyethyl(methyl)carbamoyl1phenyl1pyrazol-4 (cyclopropylmethyl)carbamate

[002703] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (300 mg, 510 umol, Intermediate DF) and 2-(methylamino) ethanol (38.3 mg, 510 umol, 41.0 UI, CAS# 109 1 ) in DMF (2 mL) was added HATU (232 mg, 612 umol) and DIPEA (329 mg, 2.55 mmol, 444 uL), and the reaction mixture was stirred at rt for 12 hrs. On completion, the mixture was filtered, and the filter cake was dried in vacuo to give the title compound (210 mg, 64% yield) as a yellow solid. LC-MS (ESI+) m/z 645.4 (M +H)+.

[002704] Step 2:Tert-butyl N-r4-r4-rr3-carbamoyl-l-r4-[methyl(2oxoethyl)carbamoyl1phenyl1pyrazol yl1 carbamoyl1oxazol yl1 pyridyl1-N(cyclopropylmethyl)carbamate

[002705] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[2hydroxyethyl(methyl)carbamoyl]phenyl] pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (160 mg, 248 umol) in THF (5 mL) was added DMP (126 mg, 297 umol, 92.2 uL). The reaction mixture was stirred at rt for 2 hours. On completion, the mixture was diluted with H2O (20 mL), then extracted with DCM (2 X 30 mL). The combined organic layer was then washed with Na2S2O3 (30 mL), NaHCO3 (30 mL), and concentrated in vacuo to give the title compound (150 mg, 94% yield) as a yellow solid. LC-MS (ESI+) m/z 643.4 (M+H)+.

[002706] Tert-butyl N-[2-[3-(2-amin0eth0xv)Dr0D0xy]ethvl]carbamate (Intermediate

ΝΗ2ΝΗ2.Η2Ο, EtOH

(Boc)2O, CHCI3

H2N

NHBoc

KN

[002707] Step 1 - Ethyl 2-r3-(2-ethoxy oxo-ethoxy)propoxy1acetate

[002708] To a solution of propane-1,3-diol (15.0 g, 197 mmol, CAS# 126 7) and Rh(OAc)2 (435 mg, 1.97 mmol) in DCM (200 mL) was added a solution of ethyl 2-diazoacetate (67.4 g, 591 mmol) in DCM (100 mL) dropwise. The mixture was stirred at 10 °C for 16 hours. On completion, the mixture was diluted with H2O (150 mL) and extracted with DCM (3 X 150 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2) to give the title compound (30.0 g, 61% yield) as colorless liquid. 1H NMR (400MHz, CDC13) δ 4.21 (q, J = 7.2

Hz, 4H), 4.07 (s, 4H), 3.65 (t, J= 6.4 Hz, 4H), 1.99 - 1.89 (m, 2H), 1.28 (t, J= 7.2 Hz, 6H).

[002709] Step 2 - 2-[3-(2-Hydroxyethoxy )propoxy]ethanol

[002710] To a solution of ethyl 2-[3-(2-ethoxy oxo-ethoxy)propoxy]acetate (20.0 g, 80.5 mmol) in THF (300 mL) was added LiAlH4 (6.24 g, 161 mmol, 98% purity) at 0 °C. The mixture was then stirred at 10 °C for 1 hour. On completion, the mixture was quenched with water (10 mL) and NaOH aqueus solution (15 %, 10 mL) at 0 °C, and the reaction was filtered. The filtrate was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (12 g, 90% yield) as colourless oil. 1H NMR (400MHz, DMSO4) δ 4.53 (t, J= 52 Hz, 2H), 3.50 - 3.45 (m, 4H), 3.43 (t, J= 6.4 Hz, 4H), 3.37 (t, J= 52 Hz 4H), 1.75 - 1.68 (m, 2H)

[002711] Step 3 - 2-[3-(2-Methylsulfonyloxyethoxy)propoxy]ethyl methanesulfonate [002712] To a solution of 2-[3-(2-hydroxy ethoxy )propoxy] ethanol (12.0 g, 73.0 mmol) and TEA (44.3 g, 438 mmol) in DCM (160 mL) was added MsCl (25.1 g, 219 mmol) dropwise at 0 °C, then the mixture was stirred at 10 °C for 1 hour. On completion, the reaction mixture was quenched by water (50 mL) at 0 °C, and then extracted with DCM (3 X 150 mL). The combined organic layers were washed with saturated citric acid (2 X 30 mL), dried over Na2SO4, filtered and concentrated in vacuo to give title compound (23 g, 98% yield) as light yellow oil. &#1523;H NMR (400MHz,CDCh) δ 3.67 (t, J= 4.4 Hz, 4H)3.71 &#1524; (t, J= 4.4 Hz, 4H), 3.58 (t, J= 6.0 Hz, 4H), 3.06 (s, 6H), 1.93 - 1.79 (m, 2H).

[002713] Step 4 - 2-r2-r3-r2-(L3-Dioxoisoindolin yl)ethoxy]propoxy]ethyl]isoindolineL 3 -di one

[002714] To a solution of 2-[3-(2-methylsulfonyloxyethoxy)propoxy]ethyl methanesulfonate (16.0 g, 49.9 mmol) in DMF (280 mL) was added (l,3-dioxoisoindolin yl)potassium (27.7 g, 149 mmol). The mixture was stirred at 85 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was triturated with EA (30 mL) and filtered to give a filter cake. The filter cake was triturated with water (150 mL) and filtered again to give the filter cake as the title compound (19 g, 90% yield) as white solid. 1H NMR (400MHz, DMSO-6/6) δ 7.87 - 7.78 (m, 8H), 3.67 (t, J= 6.0 Hz, 4H), 3.47 (t, J= 6.0 Hz, 4H), 3.32 (t, J= 6.0 Hz, 4H), 1.59 - 1.52 (m, 2H).

[002715] Step 5 - 2-r3-(2-Aminoethoxy)propoxy]ethanamine

[002716] To a solution of 2-[2-[3-[2-(l,3-dioxoisoindolin-2yl)ethoxy]propoxy]ethyl]isoindoline-l,3-dione (18.0 g, 42.6 mmol) in EtOH (250 mL) was added

ΝΗ2ΝΗ2&#905;2Ο (21.7 g, 426 mmol, 98% purity). The mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was filtered to give the filtrate which was concentrated in vacuo to give the title compound (7.2 g, 100% yield) as colorless oil. 1H NMR (400MHz, DMSO-» δ 3.42 (t, J= 6.4 Hz, 4H), 3.31 (t, J= 5.6 Hz, 4H), 2.63 (t, 7=5.6 Hz, 4H), 2.46 - 2.09 (m, 4H), 1.75 - 1.68 (m, 2H).

[002717] Step 6 - Tert-butyl N-r2-[3-(2-aminoethoxy)propoxy1ethyl1carbamate

[002718] To a solution of 2-[3-(2-aminoethoxy)propoxy]ethanamine (7.20 g, 44.3 mmol) in CHCh (250 mL) was added a solution of (Boc)2O (3.23 g, 14.7 mmol) in CHCh (80 mL) dropwise. The mixture was stirred at rt for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2) to give the title compound (2.50 g, 64% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 4.98 (s, IH), 3.54 (t, 7= 6.0 Hz, 4H), 3.51 - 3.42 (m, 4H), 3.34 - 3.25 (m, 2H), 2.86 (t, 7= 5.2 Hz, 2H), 1.88 1.82 (m, 2H), 1.45 (s, 9H).

[002719] Benzyl N-[4-(4-amino carbamoyl-pyrazol-l-yl)phenyl]carbamate (Intermediate

[002720] Step 1

KO

Methyl carboxylate

[002721] To a solution of methyl 4-nitro-lH-pyrazole carboxylate (841 mg, 4.92 mmol,

CAS# 1345513 2, Intermediate HL), [4-(benzyloxycarbonylamino)phenyl]boronic acid (2.00 g, 7.38 mmol, CAS# 192804 7) in DCM (70.0 mL) was added pyridine (1.56 g, 19.6 mmol) and Cu(OAc)2 (1.34 g, 7.38 mmol), and the mixture was stirred at rt for 16 hrs under 02 (15 psi).

On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE: EA= 1: 1) to give the title compound (400 mg, 20% yield) as white solid. 1H NMR (400MHz, CDCh) δ 8.14 (s, IH), 7.50 - 7.45 (m, 2H), 7.40 - 7.36 (m, 2H), 7.35 - 7.30 (m, 5H), 6.79 (s, IH), 5.16 (s, 2H), 3.87 (s, 3H).

[002722] Step 2 -Benzyl N-r4-(3-carbamoyl nitro-pyrazol-l-yl)phenyl1carbamate [002723] To a solution of methyl l-[4-(benzyloxycarbonylamino)phenyl] nitro-pyrazole3-carboxylate (200 mg, 504 umol) in THF (10.0 mL) was added ΝΗ3.Η2Ο (4.55 g, 38.9 mmol, 30 wt%), and the mixture was stirred at 110 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (70.0 mg, 36% yield) as yellow solid. 1HNMR (400MHz, DMSO-76) δ 10.07 (s, IH), 9.54 (s, IH), 8.53 (s, IH), 7.88 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.48 - 7.36 (m, 5H), 5.19 (s, 2H).

[002724] Step 3 - Benzyl N-r4-(4-amino carbamoyl-pyrazol-l-yl)phenyl1carbamate [002725] To a solution of benzyl N-[4-(3-carbamoyl nitro-pyrazol-l-yl)phenyl]carbamate (70.0 mg, 183 umol) in MeOH (10.0 mL) and H2O (5.00 mL) was added NH4C1 (98.1 mg, 1.84 mmol) and Zn (60.0 mg, 917 umol), and the mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo. The mixture was diluted with H2O (10.0 mL) then extracted with EA (3 X 10 mL). The organic layers were dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (60.0 mg, 93% yield) as yellow solid, LC-MS (ESC)/352.1 2&#1524; (M+H)+

[002726] Tert-butyl N-[4-[4-[[l-(4-amin0DhenyD carbam0yl-Dyraz01-4yl] carbamoyl] oxazol yl] Dyridyl]-N-(cycl0Dr0Dylmethyl)carbamate (Intermediate KP)

KP

[002727] Step 1 - Tert-butyl N-r4-r4-rr1-r4-(benzyloxycarbonvlamino) phenvl1-3carbamoyl-pyrazol- 4-yl1carbamoyl1oxazol yl1 pyridyl1-N-(cvclopropylmethyl)carbamate [002728] To a solution of benzyl N-[4-(4-amino carbamoyl-pyrazol-lyl)phenyl]carbamate (60.0 mg, 170 umol, Intermediate KO), and 2-[2[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carboxylic acid (92.0 mg, 256 umol, synthesized via Steps 1-4 of Intermediate DF) in DMF (3.00 mL) was added DIPEA (66.2 mg, 512 umol) and HATU (97.4 mg, 256 umol), and the mixture was stirred at rt for 0.5 hr. On completion, the mixture was diluted with H2O (15 mL) and extracted with EA (3X15 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (70.0 mg, 59% yield) as yellow solid. LC-MS (ESI+) m/z 693.2 (M+H)+.

[002729] Step 2 - Tert-butyl N-r4-r4-rr1-(4-aminophenyl) carbamoyl-pyrazol-4vl1carbamoyl1oxazol yl1 pyridvl1-N-(cvclopropylmethyl)carbamate

[002730] To a solution of tert-butyl N-[4-[4-[[l-[4-(benzyloxycarbonylamino)phenyl]-3carbamoyl- pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (70.0 mg, 101 umol) in THF (10.0 mL) was added Pd/C (30.0 mg), the mixture was stirred at rt for 1 hr under H2 (15 Psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (55.0 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 559.4 (M+H)+.

[002731] Methyl 4-amino-l-methyl-Dvrazole carboxvlate (Intermediate KQ)

MeOH

Pd/C, H2 (15 Psi)

KQ

[002732] To a solution of methyl l-methyl nitro-pyrazole carboxylate (2 g, 10.8 mmol, CAS# 400877 8) in MeOH (20 mL) was added Pd/C (200 mg, 10% wt) under N2 atmosphere. The suspension was degassed and purged with H2 gas 3 times. The mixture was stirred under H2 (15 Psi) at rt for 12 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.68 g, 100% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 6.95 (s, IH), 3.92 (s, 3H), 3.86 (s, 3H).

[002733] 4-[[2-[2-[Tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino] Dvridvl]oxazole-

4- carbonyl] amino]-l-methyl-Dvrazole carboxvlic acid (Intermediate KR)

KQ

HATU, DIPEA, DMF

LiOH&#1524;H2O

THF, H2O

[002734] Step 1 - Methyl 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4 pyridyl1oxazole carbonyl1amino1-l-methyl-pyrazole carboxylate

[002735] To a solution of methyl 4-amino-l-methyl-pyrazole carboxylate (1.68 g, 10.8 mmol, Intermediate KQ) and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (4.19 g, 10.8 mmol, Intermediate CM) in DMF (20 mL) was added DIPEA (2.80 g, 21.7 mmol), The reaction mixture was stirred at rt for 0.5 hr. After, HATU (4.94 g, 13.0 mmol) was added and the resulting reaction mixture was stirred at rt for 0.5 hr. On completion, the reaction mixture was quenched with water (200 mL). White precipitate formed after the reaction was added to water, which was filtered and the filtered cake was dried in vacuo to give the title compound (5.1 g, 90% yield) as a white solid; 1H NMR (400MHz, DMSO-#6) δ 10.30 (s, IH), 9.09 (s, IH), 8.65 (s, IH), 8.43 (s, IH), 8.31 (s, IH), 7.76 (s, IH), 4.93 - 4.86 (m, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 1.53 (s, 9H). LC-MS (ESI+) m/z 547.1 (M+Na)+.

[002736] Step 2 - 4-l42-[2-[Tert-butoxvcarbonvl(2.2.2-trifluoroethvDamino]-4pyridyl1oxazole carbonyl] amino1-l-methyl-pyrazole carboxylic acid

[002737] To a solution of methyl 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]4-pyridyl]oxazole carbonyl]amino]-l-methyl-pyrazole carboxylate (500 mg, 953 umol) in a mixed solvent of THF (10 mL) and H2O (2 mL) was added L1OH.H2O (120 mg, 2.86 mmol). The reaction mixture was stirred at rt for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with water (50 mL) and acidified with HCI (2 N) to pH = 5, then filtered. The filtered cake was collected, ground up, and dried for 2 hours at 105-110 °C in the drying oven. This was then ground again to a fine powder to give the title compound (480 mg, 99% yield) as a white solid. 1H NMR (400MHz, DMSO4) δ 10.65 (s, IH), 9.07 (s, IH), 8.64 (d, 7=4.8 Hz, IH), 8.38 (s, IH), 8.24 (s, IH), 7.77 (dd, J= 1.2, 5.2 Hz, IH), 4.89 (q, J= 8.8 Hz, 2H), 3.95 (s, 3H), 1.52 (s, 9H).

[002738] 4 (3-Aminopropoxv)propvlamino] (2.,6-dioxo piperidvl)isoindoline1.,3-dione (Intermediate KS)

[002739] Step 1 - Tert-butyl Ν-Γ3-Γ3-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-1 J-dioxo-isoindolin-4yllaminolpropoxy] propyllcarbamate

[002740] To a mixture of tert-butyl N-[3-(3-aminopropoxy)propyl]carbamate (1.20 g, 5.17 mmol, Intermediate EF) and 2-(2,6- dioxo piperidyl) fluoro-isoindoline-l,3-dione (1.43 g, 5.17 mmol, Intermediate R) in dioxane (50 mL) was added DIPEA (6.68 g, 51.6 mmol, 9.00 mL). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA=1:1 PE: EA=1:1, Pl: Rf=0.08) to give the title compound (1.00 g, 39% yield) as yellow solid. LC-MS (ESL)&#1524;/z 511.3 (M+Na)+.

[002741] Step 2:4-r3-(3-Aminopropoxv)propylamino1 (2,6-dioxo-3piperidyl)isoindoline-L3-dione

[002742] To a mixture of tert-butyl N-[3-[3-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] propoxy]propyl]carbamate (1.20 g, 2.46 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 20 mL). The reaction micture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.00 g, 95% yield, HCI) as yellow solid. LC-MS (ESI+) m/z 389.1 (M+H)+.

[002743] Tert-butyl N-[4-[4-[[l-(4-formvlphenvl) (methvlcarbamovl)pyrazol vl] carbamovl]oxazol yl] Dvridvl]-N-(2.,2.,2-trifluoroethvl)carbamate (Intermediate KT)

DMP, THF

KT

[002744] Step 1 - l-r4-(Hydroxymethyl)phenvl1-N-methyl nitro-pyrazole carboxamide [002745] To a solution of methyl l-[4-(hydroxymethyl)phenyl] nitro-pyrazole-3carboxylate (200 mg, 721 umoL synthesized via Step 1 of Intermediate GB) in THF (5.00 mL) was added MeNH2 (2.00 M, 5.00 mL), and the mixture was stirred at 70 °C for 16 hrs in a sealed tube. On completion, the mixture was concentrated in vacuo. The mixture was diluted with H2O (30 mL), then extracted with EA (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (195 mg, 97% yield) as yellow solid. IH NMR (400MHz, DMSO4) δ 9.68 (s, IH), 8.81 - 8.68 (m, IH), 7.97 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 5.39 (t, J = 5.6 Hz, IH), 4.63 (d, J = 5.6 Hz, 2H), 2.87 (d, J = 4.8 Hz, 3H)

[002746] Step 2 - 4-Amino-l-r4-(hydroxymethyl)phenyl1-N-methyl-pyrazole-3carboxamide

[002747] To a solution of l-[4-(hydroxymethyl)phenyl]-N-methyl nitro-pyrazole-3carboxamide (195 mg, 705 umol) in MeOH (100 mL) was added Pd/C (10 wt%, 100 mg), and the mixture was purged with H2 several times and stirred at 15 °C for 0.5 hr under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (160

1000 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 247.1 (M+H)+.

[002748] Step 3 Tert-butyl N-r4-r4-rr1&#1470;r4-(hydroxymethyl)phenyl1-3(methylcarbamoyl)pyrazol yl1 carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2trifluoroethyDcarbamate

[002749] To a solution of 4-amino-l-[4-(hydroxymethyl)phenyl]-N-methyl-pyrazole-3carboxamide (160 mg, 649 umol), 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (251 mg, 649 umol, Intermediate CM) in DMF (3.00 mL) was added DIPEA (251 mg, 1.95 mmol) and HATU (296 mg, 779 umol), and the mixture was stirred at rt for 0.5 hr. On completion, the mixture was diluted with H2O (1.00 mL) and concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% NH3*H2O) to give the title compound (200 mg, 50% yield) as yellow solid. 1HNMR (400MHz, DM SO-0/6) δ 11.08 (s, IH), 9.10 (s, IH), 8.93 (s, IH), 8.67 (d, J = 5.2 Hz, IH), 8.62 - 8.56 (m, IH), 8.29 (s, IH), 7.93 (d, J = 8.8 Hz, 2H), 7.82 - 7.77 (m, IH), 7.50 (d, J = 8.8 Hz, 2H), 5.30 (t, J = 5.6 Hz, IH), 4.96 - 4.86 (m, 2H), 4.57 (d, J = 5.6 Hz, 2H), 2.87 (d, J = 4.8 Hz, 3H), 1.56 (s, 9H).

[002750] Step 4 - Tert-butyl N-r4-r4-ITl-(4-formylphenyl) (methylcarbamoyl)pyrazol-4yl] carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[002751] To a solution of tert-butyl N-[4-[4-[[l-[4-(hydroxymethyl)phenyl]-3(methylcarbamoyl)pyrazol- 4-yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (110 mg, 178 umol) in THF (20.0 mL) was added DMP (90.9 mg, 214 umol), and the mixture was stirred at rt for 1 hr. On completion, the mixture was quenched with saturated Na2S2O3 (30 mL) and washed with saturated NaHCO3 (2 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (105 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 614.3 (M+H)+.

[002752] l-[4-[4-Amino (difluoromethyl)Dvrazol-l-vl]Dhenvl]ethenone (Intermediate

[002753] Step 1- l-l4-r3-(difluoromethyl) nitro-pyrazol-l-yl1phenyl1ethanone

1001

[002754] To a mixture of 3-(difluoromethyl) nitro- IH-pyrazole (1.42 g, 8.69 mmol, Intermediate HS), 1- (4-fluorophenyl) ethanone (1.0 g, 7.24 mmol) in DMF (10 mL) was added K2CO3 (1.50 g, 10.8 mmol). The reaction mixture was stirred at 120 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2) to give the title compound (435 mg, 21% yield) as brown oil. 1HNMR (400MHz, DMSO4) δ 9.93 (s, IH), 8.17 - 8.13 (m, 4H), 7.59 - 7.32 (m, IH), 2.64 (s, 3H).

[002755] Step 2- l-r4-r4-Amino (difluoromethyl)pyrazol-l-yl1phenyl1ethanone

[002756] To a mixture of l-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]phenyl]ethanone (360 mg, 1.28 mmol) in MeOH (20 mL) and H2O (10 mL) was added Zn (837 mg, 12.8 mmol) and AcOH (769 mg, 12.8 mmol). The reaction mixture was stirred at rt for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (186 mg, 58% yield) as a yellow solid. LC-MS (ESI+) m/z 252.2 (M+H)+.

[002757] Tert-butyl N-[4-[4-[[l-(4-acetvlphenvl) (difluoromethyl)Dvrazol-4yl] carbamoyl] oxazol -2 -vl] pvridvl]-N-(cvclopropylmethvl)carbamate (Intermediate KV)

[002758] To a mixture of l-[4-[4-amino (difluoromethyl)pyrazol-l-yl]phenyl]ethanone (90 mg, 358 umol, Intermediate KU), 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylic acid (154 mg, 429 umol, synthesized via Steps 1-4 of Intermediate DF) in DMF (10 mL) was added DIPEA (139 mg, 1.07 mmol) and HATU (163 mg, 430 umol). The mixture and stirred at rt for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (165 mg, 75% yield) as a white solid. LC-MS (ESI+) m/z 593.2 (M+H)+.

[002759] Methyl 4-(4-amino (3-((tetrahvdro-2H-Dvran vl)oxy)DroDvl)-lH-Dvrazol1-vDbenzoate (Intermediate KW)

1002

[002760] Step 1 - Methyl 4-(3-(3-hydroxyprop-l-yn-l-yl) nitro-lH-pyrazol-l-yl)benzoate [002761] Methyl 4-(3-bromo nitro-pyrazol-l-yl)benzoate (1 g, 3.07 mmol, Intermediate JS), prop yn-l-ol (500 mg, 8.92 mmol), Pd(PPh3)2C12 (215 mg, 307 umol), TEA (3.10 g, 30.7 mmol), and Cui (58.4 mg, 307 umol) were taken up into a microwave tube in DMF (10 mL)under N2. The reaction mixture was de-gassed with N2 and then the sealed tube was heated to 80 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (PE: EA= 2:1) to give the title compound (920 mg, 100% yield) as a yellow solid. 1H NMR (400MHz, DM SO-6/6) 69.87 (s, IH), 8.18 (s, 4H), 5.62 (t, J = 6.0 Hz, IH), 5.49 - 5.43 (m, IH), 4.47 (d, J= 6.0 Hz, 2H), 3.94 (s, 3H).

[002762] Step 2 - Methyl 4-(4-nitro (3-((tetrahydro-2H-pyran yl)oxy)prop-l-yn-l-yl)IH-pyrazol-l-yl) benzoate

[002763] To a solution of methyl 4-[3-(3-hydroxyprop-l-ynyl) nitro-pyrazol-lyl]benzoate (600 mg, 1.99 mmol) and DHP (251 mg, 2.99 mmol) in a mixed solvent of DCM (100 mL) and THF (20 mL) was added PPTS (50.1 mg, 199 umol). The reaction mixture was stirred at rt for 12 hours under N2. On completion, the reaction mixture was concentrated in vacuo. The crude product purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1) to give the title compound (700 mg, 91% yield) as a white solid. 1H NMR (400MHz, DMSO-76) 6 9.83 (s, IH), 8.13 (s, 4H), 4.94 - 4.86 (m, IH), 4.66 - 4.50 (m, 2H), 3.90 (s, 3H), 3.79 (ddd, J = 3.2,8.4, 11.2 Hz, IH), 3.57 - 3.47 (m, IH), 1.75 - 1.65 (m, 2H), 1.59- 1.49 (m, 4H). LC-MS (ESI+) m/z 408.1 (M+Na)+.

[002764] Step 3 - Methyl 4-(4-amino (3-((tetrahydro-2H-pyran yl)oxy)propyl)-lHpyrazol-l-yl )benzoate

[002765] To a solution of methyl 4-[4-nitro (3-tetrahy dropyran yl oxyprop-1ynyl)pyrazol-l-yl]benzoate (930 mg, 2.41 mmol) in MeOH (10 mL) was added Pd/C (50 mg, 10

1003 wt%) and Pd(0H)2/C (50 mg, 10 wt%) under N2 atmosphere. The suspension was degassed and purged with H2 gas 3 times. The mixture was stirred under H2 (15 Psi) at rt for 24 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (760 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m/z 360.2 (M+H)+.

[002766] 4-(4-(2-(2-((Tert-butoxvcarbonvl)(2.,2.,2-trifluoroethvl)amino)Dvridin-4yl)oxazole-4vDbenzoic acid (Intermediate KX)

CM

KW

[002767] Step 1 - Tert-butyl 4-rr2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-5 yl1amin01piperidine-l- carboxylate

[002768] To a solution of 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (711 mg, 1.84 mmol, Intermediate CM) and methyl 4-[4-amino

3-(3-tetrahydropyran-2 -yloxypropyl)pyrazol-l-yl] benzoate (660 mg, 1.84 mmol, Intermediate KW) in DMF (5 mL) was added DIPEA(475 mg, 3.67 mmol), and the reaction mixture was stirred at rt for 0.5 hour. Then, HATU (838 mg, 2.20 mmol) was added and the resulting reaction mixture

1004 was stirred at rt for an additional 0.5 hour. On completion, the reaction mixture was quenched with water (50 mL) and filtered. The filtered cake was collected and dried over high vacuum to give (800 mg, 60% yield) as a yellow solid. LC-MS (ESI+) m/z 729.1 (M+H)+.

[002769] Step 2 - 4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4yl)oxazole carboxamido) (3-((tetrahydro-2H-pyran yl)oxy)propyl)-lH-pyrazol-lyDbenzoic acid

[002770] To a solution of methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] (3-tetrahydropyran-2yloxypropyl)pyrazol-l-yl]benzoate (800 mg, 1.10 mmol) in a mixed solvent of THF (9 mL) and H2O (3 mL) was added L1OH.H2O (138 mg, 3.29 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo to removed THF then diluted with water (10 mL) and acidified with 2 N aq.HCl to pH = 5, then extracted with ethyl acetate (3 X 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (740 mg, 94% yield) as a yellow solid. LC-MS (ESI+) m/z 715.1 (M+H)+.

[002771] Tert-butyl(4-(4-((l-(4-formvlphenvl) (3-((tetrahvdro-2H-pyran-2vl)oxv)propyl)-lH-pvrazol vl)carbamovl)oxazol vl)pyridin vl)(2.,2.,2trifluoroethyllcarbamate (Intermediate KY)

1005

KY

[002772] Step 1 - 4-(4-(2-(2-((Tert-butoxvcarbonvl)(2.2.2-trifluoroethvl)amino)pvridin-4yl)oxazole carboxamido) (3-((tetrahydro-2H-pyran yl)oxy)propyl)-lH-pyrazol-lyl )benzoic (isopropyl carbonic) anhydride

[002773] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole- 4-carbonyl]amino] (3-tetrahydropyran yloxypropyl)pyrazol-l-yl]benzoic acid (740 mg, 1.04 mmol, Intermediate KX) in THF (20 mL) was added TEA(419 mg, 4.14 mmol). Then, the reaction mixture was cooled to -10 °C and isopropyl carbonochloridate (254 mg, 2.07 mmol) was added. The resulting reaction mixture was stirred at -10 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (800 mg, 96% yield) as a white solid. LC-MS (ESI+) m/z 801.1 (M+H)+.

[002774] Step 2 - Tert-butyl (4-(4-(( l-(4-(hydroxymethyl)phenyl) (3-((tetrahydro-2Hpyran vl)oxy)propyl )- I H-pyrazol yl )carbamoyl )oxazol yl )pyridin yl )(2.2.2trifluoroethyPcarbamate

1006

[002775] To a solution ofisopropoxycarbonyl 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl]oxazole carbonyl]amino] (3-tetrahydropyran-2yloxypropyl)pyrazol-l-yl]benzoate (800 mg, 999 umol) in THF (50 mL) was added H2O (180 mg, 9.99 mmol) and LiBH4 (109 mg, 5.00 mmol). The reaction mixture was stirred at 0 °C for 10 minutes. On completion, the mixture was quenched with water (5 mL) and was extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (700 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 701.1 (M+H)+.

[002776] Step 3 - Tert-butyl (4-(4-(( l-(4-formylphenyl) (3-((tetrahydro-2H-pyran-2vl)oxy)propyl)-lH-pyrazol yl)carbamoyl)oxazol yl)pyridin yl)(2,2,2trifluoroethyDcarbamate

[002777] To a solution of tert-butyl N-[4-[4-[[l-[4-(hydroxymethyl)phenyl] (3tetrahydropyran yloxypropyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (700 mg, 999 umol) in DCM (20 mL) was added DMP (847 mg, 2.00 mmol). The reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was quenched with water (1 mL) and was concentrated in vacuo. The crude product was purified by prep-HPLC (condition: 0.1% FA) to give the title compound (270 mg, 30% yield) as colorless solid. LC-MS (ESI+) m/z 699.1 (M+H)+.

[002778] [4-[l-(Tert-but0xycarb0nylamin0)cycl0Dr0Dyl]Dhenyl]b0r0nic acid (Intermediate KZ)

THF/H2O 7

OH

KZ

[002779] Step 1 - Tert-butyl N-r1-r4-(4A5,5-tetramethyl-L3,2-dioxaborolan-2vl)phenyl1cvclopropvl1 carbamate

[002780] A mixture of tert-butyl N-[l-(4-bromophenyl)cyclopropyl]carbamate (3 g, 9.61 mmol, CAS# 360773 8), Pin2B2 (4.88 g, 19.2 mmol), KOAc (2.83 g, 28.8 mmol) and

1007 cyclopentyl(diphenyl) phosphane;dichloromethane;dichloropalladium;iron (392 mg, 480 umol) in DMSO (30 mL) was degassed and then heated to 70 °C for 12 hours under N2. On completion, the mixture was quenched with water (200 mL) and filtered. The filter cake was purified by silica gel chromatography (SiO2) to give the title compound (3.0 g, 87% yield) as a white solid. LC-MS (ESI+) m/z 398.2 (M+K)+.

[002781] Step 2 - r4-r1-(Tert-butoxycarbonylamino)cyclopropyl1phenyl1boronic acid [002782] To a solution of tert-butyl N-[l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl]cyclopropyl] carbamate (1.2 g, 3.34 mmol) in a mixed solvent of THF (30 mL) and H2O (6 mL) was added NaIO4 (2.14 g, 10.0 mmol). The reaction mixture was stirred at rt for 0.5 hour. Then, HCI (3 M, 2.23 mL) was added and the mixture was stirred at rt for 4 hrs. On completion, the mixture was diluted with water, then extracted with EA (30 mL x 2). The organic layer was washed with water and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (0.76 g, 82% yield) as a white solid. LC-MS (ESI+) m/z 278.1 (M+H)+.

[002783] Tert-butyl N-[l-[4-[4-amino (difluoromethyl)Dyrazol-lyl]phenyl]cycloDropyl]carbamate (Intermediate LA)

[002784] Step 1 - Tert-butyl N-r1-r4-r3-(difluoromethyl) nitro-pyrazol-lyl 1 phenyl 1 cy cl opropy 11 carb amate

[002785] To a solution of [4-[l-(tert-butoxycarbonylamino)cyclopropyl]phenyl]boronic acid (0.76 g, 2.74 mmol, Intermediate KZ) and 3-(difluoromethyl) nitro-lH-pyrazole (447 mg, 2.74

1008 mmol, Intermediate HS) in DCM (10 mL) was added Cu(0Ac)2 (747 mg, 4.11 mmol) and pyridine (4.34 g, 54.9 mmol). The reaction mixture was stirred at rt for 10 hours under oxygen (15 Psi) atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2), then the residue was repurified by reverse phase (0.1% FA condition) to give the title compound (550 mg, 51% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 9.71 (s, IH), 7.86 (d, J= 8.4 Hz, 2H), 7.78 (s, IH), 7.56 - 7.27 (m, 3H), 1.43 - 1.25 (m, 9H), 1.22-1.17 (m, 4H); LC-MS (ESI+) m/z 339.0 (M-56+H)+.

[002786] Step 2 - Tert-butyl N-r1-[4-r4-amino (difluoromethyl)pyrazol-lyl 1 phenyl 1 cy cl opropy 11 carb amate

[002787] To a solution of tert-butyl N-[l-[4-[3-(difluoromethyl) nitro-pyrazol-lyl] phenyl ]cyclopropyl] carbamate (0.55 g, 1.39 mmol) in THF (10 mL) was added Pd/C (0.2 g, 10 wt%). The reaction mixture was stirred at rt for 4 hours under H2 (15 Psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.42 g, 83% yield) as a yellow solid. LC-MS (ESI+) m/z 365.1 (M+H)+.

[002788] N-[l-[4-(l-amin0cvd0Dr0Dvl)Dhenvl] (diflu0r0methvl)Dvraz01 yl] [2(cycloDroDylmethylamino) Dyridyl]oxazole carboxamide (Intermediate LB)

[002789] Step 1:Tert-butyl Ν-Γ4-Γ4-ΓΓ1-[4-Γ1-(&#912;61&#912;butoxvcarbonvlamino)cvclopropyl1phenyl1-3yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[002790] To a solution of tert-butyl N-[l-[4-[4-amino (difluoromethyl)pyrazol-l

1009 yl] phenyl ]cyclopropyl] carbamate (220 mg, 604 umol, Intermediate LA) and 2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl] oxazole carboxylic acid (217 mg, 604 umol, synthesized via Steps 1-4 of Intermediate DF) in DMF (5 mL) was added DIPEA (234 mg, 1.81 mmol) and HATU (276 mg, 725 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the mixture was quenched with water (50 mL), filtered and the filter cake was dried in vacuo to give the title compound (0.27 g, 63% yield) as a brown solid. LC-MS (ESI+) m/z 706.4 (M+H)+.

[002791] Step 2 - N-[l-[4-(l-aminocyclopropyl)phenyl1 (difluoromethyl)pyrazol yl]-2[2- (cyclopropylmethylamino) pyridyl1oxazole carboxamide

[002792] To a solution of tert-butyl N-[4-[4-[[l-[4-[l-(tertbutoxycarbonylamino)cyclopropyl]phenyl] (difluoromethyl)pyrazol yl]carbamoyl]oxazol-2yl] pyridyl]-N-(cyclopropylmethyl)carbamate (250 mg, 354 umol) in DCM (1 mL) was added 4.0 M HCl/dioxane (1 mL). The reaction mixture was stirred at rt for 10 hours. On completion, the mixture was concentrated in vacuo to give the title compound (0.19 g, 99% yield, HC1) as a light yellow solid. LC-MS (ESI+) m/z 506.2 (M+H)+.

[002793] 2-(2-ProD vnoxyethoxv)ethanol (Intermediate LC)

[002794] To a mixture of t-BuOK (4.76 g, 42.5 mmol) in THF (120 mL) was added 2-(2hydroxyethoxy)ethanol (8.92 g, 84.0 mmol, CAS# 111 4) at 0 °C. The reaction mixture was stirred at rt for 30 minutes and then 3-bromoprop yne (5 g, 42.0 mmol) in THF (25 mL) was added dropwise. The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (3 g, 50% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 4.20 (d, J = 2.4 Hz, 2H), 3.76 - 3.65 (m, 6H), 3.63 - 3.56 (m, 2H), 2.44 (t, J = 2.4 Hz, IH), 2.41 (s, IH).

[002795] 22&#1524;-Dimethyl oxo-3.,8,ll,14-tetraoxa azahexadecan vl

4methylbenzenesulfonate (Intermediate LD)

HO

TsCI

TEA, DCM

Ts0^&#1523;^0^^0&#1523;°^^N&#1523;B0C

LD

1010

[002796] To a stirred solution of tert-butyl (2-(2-(2-(2hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (8 g, 27.30 mmol, synthesized via Step 1 of Intermediate EN) in DCM (100 mL) was added TEA (5.52 g, 54.60 mmol) at rt. To the above reaction mixture was added dropwise TsCl (10.41 g, 54.60 mmol) in DCM (5 mL) at 0 °C. After the addition, the reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified via column chromatography (Petroleum ether/EtOAc = 5%80%) to give the title compound (10.9 g, 73 %) as a yellow oil. LC-MS (ESI+): m/z 448.3 (M+H)+.

[002797] 2 |3- [l-(2,6-Dioxo piperidvl) methyl oxo-benzimidazol-4yl] propoxy] ethoxy] acetaldehyde (Intermediate LE)

LC

Pd/C, Pd(OH)2, H2, THF

[002798] Step 1 - 3-r4-r3-r2-(2-hydroxyethoxy)ethoxy1prop-l-ynyl1 methyl oxo benzimidazol yl1piperidine-2,6-dione

[002799] 2-(2-prop ynoxyethoxy)ethanol (384 mg, 2.66 mmol, Intermediate LC), Cui (84.5 mg, 444 umol) and Pd(PPh3)2C12 (311 mg, 444 umol) was taken up into a tube. Then 3-(4bromo methyl oxo-benzimidazol-l-yl) piperidine-2,6-dione (300 mg, 887 umol, Intermediate HP), TEA (1.62 g, 16 mmol) and DMF (5 mL) were added into the above tube. The mixture was degassed with N2 and the sealed tube was heated at 80 °C for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (0.12 g, 34% yield) as a brown solid. LC-MS (ESI+) m/z 402.1 (M+H)+.

1011

[002800] Step 2-3 -[4-[3-[ 2-(2-hydroxyethoxy)ethoxy1propyl1 -3 -methyl oxobenzimidazol-l-yl1piperidine- 2,6-dione

[002801] To a solution of 3-[4-[3-[2-(2-hydroxyethoxy)ethoxy]prop-l-ynyl] methyl-2oxo-benzimidazol-1 -yl]piperidine-2,6-dione (50 mg, 125 umol) in THF (4 mL) was added Pd/C (0.1 g, 10 wt%) and Pd(OH)2/C (0.1 g, 10 wt%). The reaction mixture was stirred at rt for 10 hours under H2 (15 Psi) atmosphere. On completion, the mixture was filtered and filtrate was concentrated in vacuo to give the title compound (50 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 406.1 (M+H)+.

[002802] Step 3 - 2-r2-r3-r1-(2,6-Dioxo piperidvl) methyl oxo-benzimidazol-4yl1propoxy1ethoxy1 acetaldehyde

[002803] To a solution of 3-[4-[3-[2-(2-hydroxyethoxy)ethoxy]propyl] methyl oxobenzimidazol-l-yl] piperidine-2,6-dione (50 mg, 123 umol) in THF (3 mL) was added DMP (78.5 mg, 185 umol). The reaction mixture was stirred at rt for 2 hours. On completion, the mixture was quenched with sat. Na2S2O3 (20 mL) and sat. NaHCO3 (20 mL) and stirred for 0.5 hour. The reaction mixture was then extracted with DCM (2 X 30 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (30 mg, 60% yield) as yellow oil. LC-MS (ESE) m/z 404.2 (M+H)+.

[002804] 3-[4-[3-(3-aminopropoxv)propvl] methvl oxo-benzimidazol-lyl]piperidine-2.,6- dione (Intermediate LF)

1012

HP

[002805] Step 1 - Tert-butyl N-r3-(r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihvdro-IH-L3-benzodiazol vHprop vn-l-vHoxy)propvHcarbamate

[002806] To a stirred solution of 3-(4-bromo methyl oxo-2,3-dihydro-1//-1,3benzodiazol-l-yl)piperidine-2,6-dione (221 mg, 0.65 mmol,), /c77-butyl 7V-[3-(prop yn-lyloxy)propyl]carbamate (209 mg, 0.98 mmol, Intermediate OH) and TEA(1 mL) in DMA (3 mL) were added Cui (12.4 mg, 0.07 mmol) and Pd(PPh3)2C12 (45.9 mg, 0.07 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C. The mixture was cooled down to room temperature and concentrated under reduced pressure to remove TEA. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 80 g; Eluent A: Water (plus 10 mmol/LFA); Eluent B: ACN; Gradient: 35% - 55% B in 15 min; Flow rate: 50 mL/min; Detector: 220/254 nm; desired fractions were collected at 50% B and concentrated under reduced pressure to afford tertbutyl /V-[3-([3-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-4yl]prop yn-l-yl]oxy)propyl]carbamate (90 mg, 29%) as a light pink solid. 1H NMR (400 MHz, CDCh) δ 8.12 (s, IH), 7.20 (d, J= 7.9 Hz, IH), 7.01 (t, J= 7.9 Hz, IH), 6.78 (d, J= 7.9 Hz, IH), 5.22 (dd, J = 12.5, 5.3 Hz, IH), 4.80 (s, IH), 4.42 (s, 2H), 3.80 (s, 3H), 3.68 (t, J = 6.0 Hz, 2H), 3.30-3.24 (m, 2H), 3.02-2.95 (m, IH), 2.91-2.69 (m, 2H), 2.28-2.26 (m, IH), 1.85 (q, J= 6.2 Hz,

1013

2H), 1.46 (s, 9H); LC/MS (ESI, m/z): [(M 469.5 = &#1470;[(1 &#1470;.

[002807] Step 2 - Tert-butyl N-(3-r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihvdro-IH-L3-benzodiazol vl1propoxv1propyl )carbamate

[002808] To a stirred solution of tert-butyl 7V-[3-([3-[l-(2,6-dioxopiperidin yl) methyl2-oxo-2,3-dihydro-l//-l,3-benzodiazol yl]prop yn-l-yl]oxy)propyl]carbamate (0.5 g, 1.06 mmol) in THF (10 mL) was added palladium on charcoal (100 mg, 10% w/w) at room temperature under nitrogen atmosphere. The resulting mixture was purged with H2 gas 3 times and stirred for 16 h at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford tert-butyl 7V-(3-[3-[l(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-4yl]propoxy]propyl)carbamate (430 mg, 85%) as a light green oil. 1HNMR (400 MHz, CDCh) δ 8.07 (s, IH), 7.01 (t, J = 7.8 Hz, IH), 6.92 (d, J = 7.8 Hz, IH), 6.69 (d, I = 7.7 Hz, IH), 5.22 (dd, J = 12.3, 5.5 Hz, IH), 4.88 (s, IH), 3.77 (s, IH), 3.71 (s, 3H), 3.50 (m, 3H), 3.26 (d, J = 6.3 Hz, 2H), 3.08-3.00 (m, 2H), 3.00-2.91 (m, IH), 2.91-2.71 (m, 2H), 2.32-2.19 (m, IH), 2.00-1.74 (m, 4H), 1.46 (s, 9H); LC/MS (ESI, m/z): [(M 473.3 = &#1470;[(1 &#1470;.

[002809] Step 3 - 3-[4-[3-(3-Aminopropoxy)propyl1 methyl oxo-2,3-dihydro-l//-L3benzodiazol-l-yl1piperidine-2,6-dione hydrochloride

[002810] To a stirred solution of tert-butyl 7V-(3-[3-[l-(2,6-dioxopiperidin yl) methyl-2oxo-2,3-dihydro-1/7-1,3-benzodiazol yl]propoxy]propyl)carbamate (430 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added a solution of HCI in 1,4-dioxane (4 M, 5 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in 1,4dioxane (15 mL) and re-concentrated under reduced pressure to afford 3-[4-[3-(3aminopropoxy )propyl] methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-l-yl]piperidine-2,6dione hydrochloride (310 mg, 91%) as a brown yellow solid. 1H NMR (400 MHz, DM SO-0/6) δ 11.10 (s, IH), 7.94 (s, 3H), 7.02-6.92 (m, 2H), 6.88 (dd, J= 6.4, 2.5 Hz, IH), 5.39 (dd, J = 12.6, 5.4 Hz, IH), 3.60-3.54 (s, 3H), 3.51-3.43 (m, 4H), 3.02-2.82 (m, 5H), 2.79-2.58 (m, 2H), 2.091.93 (m, IH), 1.90-1.80 (m, 4H); LC/MS (ESI, m/z): [(M + 1)]+ = 375.3.

[002811] 3-[5-[3-(3-amin0Dr0D0xv)Dr0DvH methvl oxo-benzimidazol-lyllpiperidine-2.,6- dione (Intermediate LG)

1014

[002812] Step 1 - Tert-butyl 7V-r3-(r3-r1-(2,6-dioxopiperidin vl) methyl oxo-2,3dihydro-l/M,3-benzodiazol yl]prop yn-l-yl]oxy)propyl]carbamate

[002813] To a stirred mixture of 3-(5-bromo methyl oxo-2,3-dihydro-1//-1,3benzodiazol-l-yl)piperidine-2,6-dione (2 g, 6 mmol, IntermediateHN), Pd(PPh3)4 (683.4 mg, 0.59 mmol) and Cui (225.3 mg, 1.18 mmol) in DMSO (10 mL) and TEA (5 mL) was added tert-butyl 7V-[3-(prop yn-l-yloxy)propyl]carbamate (3.8 g, 18 mmol, Intermediate OH) at room temperature under nitrogen atmosphere. The resulting mixture was purged with nitrogen three times and stirred for 16 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to remove TEA. The resulting mixture was diluted with a solution of AcOH (3 mL) in ice water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ Cl8-1, 20-40 pm, 330 g; Eluent A: Water (plus 10 mmol/LFA); Eluent B: ACN; Gradient: 50% - 60% B in 20 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions were collected at 57% B and

1015 concentrated under reduced pressure to afford tert-butyl 7V-[3-([3-[l-(2,6-dioxopiperidin yl)-3methyl oxo-2,3-dihydro-1//-1,3-benzodiazol yl]prop yn-l-yl]oxy)propyl]carbamate (1.5 g, 54%) as a light yellow solid: 1HNMR (400 MHz, DMSO-t/6) δ 11.12 (s, IH), 7.34 (s, IH), 7.237.11 (m, 2H), 6.80 (s, IH), 5.40 (dd, J= 12.7, 5.4 Hz, IH), 4.35 (s, 2H), 3.51 (t, 7= 6.4 Hz, 2H), 3.35 (s, 3H), 3.00 (q, J= 6.7 Hz, 2H), 2.95-2.83 (m, IH), 2.79-2.58 (m, 2H), 2.03 (dd, J= 9.3, 4.3 Hz, IH), 1.66 (p, J= 6.6 Hz, 2H), 1.37 (s, 9H); LC/MS (ESI, m/z); [(M + 1)]+ = 469.20.

[002814] Step 2 - Tert-butyl 7V-(3-r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-L3-benzodiazol yl1propoxy1propyl)carbamate

[002815] To a stirred solution of tert-butyl 7V-[3-([3-[l-(2,6-dioxopiperidin yl) methyl2-oxo-2,3-dihydro-l//-l,3-benzodiazol yl]prop yn-l-yl]oxy)propyl]carbamate (800 mg, 1.70 mmol) in THF (20 mL) was added palladium on charcoal (200 mg, 10% w/w) at rt under nitrogen atmosphere. The resulting mixture was purged with H2 gas 3 times and stirred for 4 h at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford tert-butyl //-(3-[3-[l-(2,6di oxopiperi din yl) methyl oxo-2,3-dihydro-1//-l,3-benzodiazol-5yl]propoxy]propyl)carbamate (730 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.08 (s, IH), 7.06-6.97 (m, 2H), 6.87 (d, J= 7.8 Hz, IH), 6.77 (s, IH), 5.34 (dd, J= 12.7, 5.3 Hz, IH), 3.61 (s, IH), 3.40-3.31 (m, 6H), 2.99 (q, J= 6.6 Hz, 2H), 2.90 (t, J= 15.0 Hz, IH), 2.73-2.58 (m, 4H), 2.01 (d, J = 12.7 Hz, IH), 1.83-1.73 (m, 2H), 1.66-1.58 (m, 2H), 1.38 (s, 9H); LC/MS (ESI, m/z); [(M 473.3 = &#1470;[(1 &#1470;.

[002816] Step 3 - 3-r5-r3-(3-Aminopropoxy)propyl1 methyl oxo-2,3-dihydro-l//-L3benzodiazol-l-yl1piperidine-2,6-dione hydrochloride

[002817] To a stirred solution of tert-butyl 7V-(3-[3-[l-(2,6-dioxopiperidin yl) methyl-2oxo-2,3-dihydro-1//-1,3-benzodiazol yl]propoxy]propyl)carbamate (730 mg, 1.54 mmol) in 1,4-dioxane (10 mL) was added a solution of HCI in dioxane (4 M, 10 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 1,4dioxane (20 mL) and re-concentrated under reduced pressure to afford 3-[5-[3-(3aminopropoxy )propyl] methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-l-yl]piperidine-2,6di one hydrochloride (600 mg, 99%) as a light brown solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.09 (s, IH), 7.74 (br s, 3H), 7.11-6.95 (m, 2H), 6.87 (d, J = 8.0 Hz, IH), 5.35 (dd, J = 12.8, 5.4 Hz,

1016

IH), 3.58 (s, 3H), 3.44 (t, J= 6.1 Hz, 2H), 3.39 (t, J= 6.5 Hz, 2H), 2.94-2.80 (m, 3H), 2.77-2.56 (m, 4H), 2.10-1.95 (m, IH), 1.90-1.76 (m, 4H); LC/MS (ESI, m/z[. [(M + 1)]+ = 375.10.

[002818] 3-(4-(3-(3-(3-Amin0Dr0D0xv)Dr0D0xv)Dr0Dvl) methvl 0x0-2,3-dihydr0lH-benzo[d1imidazol-l-yl)DiDeridine-2,6-dione (Intermediate LH) h Boc

OJ

[002819] Step 1 - ter/-butyl 7V-r3-r3-(r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-L3-benzodiazol yl1prop yn-l-yl1oxy)propoxy1propyl1carbamate

[002820] To a solution of 3-(4-bromo methyl oxo-2,3-dihydro-l/7-l,3-benzodiazol-lyl)piperidine-2,6-dione (2 g, 5.91 mmol, Intermediate HP) in DMA (30 mL) were added ter/-butyl A-[3-[3-(prop yn-l-yloxy)propoxy]propyl]carbamate (3 g, 11.06 mmol, Intermediate OJ), TEA (15 mL), Cui (113 mg, 0.59 mmol) and Pd(PPh3)4 (0.68 g, 0.59 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 5 h at 90 °C under nitrogen atmosphere. The resulting mixture was cooled down to rt and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 330 g; Eluent A: Water (plus 10 mmol/LHCOOH); EluentB: ACN; Gradient:

1017

35% - 60% B in 15 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions were collected at 55% B and concentrated under reduced pressure to afford tert-butyl 7V-[3-[3-([3-[l(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-l//-l,3-benzodiazol yl]prop yn-lyl]oxy)propoxy]propyl]carbamate (1.4 g, 45%) as a light brown solid. 1H NMR (400 MHz, DMSO4) δ 11.12 (br s, IH), 7.19-7.12 (m, 2H), 7.08-6.95 (m, IH), 6.75 (br s, IH), 5.41 (dd, J= 12.7, 5.4 Hz, IH), 4.43 (s, 2H), 3.64 (s, 3H), 3.63-3.55 (m, 4H), 3.42 (t, J= 6.4 Hz, 2H), 3.35 (d, J = 12.6 Hz, 2H), 3.00-2.83 (m, 3H), 2.71 (m, 2H), 2.10-1.97 (m, 2H), 1.78 (p, J = 6.4 Hz, 2H), 1.59 (p, J= 6.6 Hz, 2H), 1.37 (s, 9H); LC/MS (ESI, m/z): [(M + 1)]+ = 529.35.

[002821] Step 2 - tert-butyl 7V-r3-(3-r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-1,3-benzodi azol vl1propoxv1propoxy )propyl ]carbamate

[002822] To a stirred solution of tert-butyl 7V-[3-[3-([3-[l-(2,6-dioxopiperidin yl)-3methyl oxo-2,3-dihydro-1//-1,3-benzodiazol yl]prop yn-lyl]oxy)propoxy]propyl]carbamate (900 mg, 1.71 mmol) in THF (20 mL) was added palladium on charcoal (300 mg, 10% w/w) at rt under nitrogen atmosphere. The resulting mixture was purged with hydrogen for 3 times and was stirred for 4 h at rt under hydrogen atmosphere. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under reduced pressure to afford tert-butyl A-[3-(3-[3-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-l//-1,3benzodiazol yl]propoxy]propoxy)propyl]carbamate (800 mg, 88%) as a light brown solid. 1H NMR (400 MHz, DMSO4) δ 11.10 (br s, IH), 7.02-6.98 (m, 2H), 6.90-6.83 (m, IH), 6.76 (t, J= 5.7 Hz, IH), 5.37 (dd, J = 12.6, 5.4 Hz, IH), 3.56 (s, 3H), 3.52-3.33 (m, 6H), 3.01-2.83 (m, 5H), 2.72-2.58 (m, 2H), 2.00 (ddd, J = 11.1, 5.9, 3.6 Hz, IH), 1.89-1.68 (m, 6H), 1.60 (p, J = 6.6 Hz, 2H), 1.37 (s, 9H); LC/MS (ESI, m/z): [(M + 1)]+ = 533.40.

[002823] Step 3 - 3-(4-r3-r3-(3-Aminopropoxy)propoxy1propyl1 methyl oxo-2,3dihydro-1//-1,3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride

[002824] To a stirred solution of tert-butyl 7V-[3-(3-[3-[l-(2,6-dioxopiperidin yl)-3methyl oxo-2,3-dihydro-1//-1,3-benzodiazol yl]propoxy]propoxy)propyl]carbamate (800 mg, 1.50 mmol) in 1,4-dioxane (10 mL) was added a solution of hydrochloride in dioxane (4 M, 10 mL) dropwise at 0 °C. The resulting mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure to afford 3-(4-[3-[3-(3-aminopropoxy)propoxy]propyl]-3methyl oxo-2,3-dihydro-lH-l,3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride (640 mg, 91%) as a white solid. 1HNMR (400 MHz, DMSOQ) δ 11.11 (br s, IH), 7.83 (br s, 3H), 7.05

1018

6.93 (m, 2H), 6.88 (td, J= 6.8, 5.9, 3.1 Hz, IH), 5.38 (dd, J= 12.5, 5.4 Hz, IH), 3.57 (s, 3H), 3.453.31 (m, 8H), 3.04-2.77 (m, 5H), 2.77-2.57 (m, 2H), 1.99 (dd, J= 9.8, 4.9 Hz, IH), 1.90-1.70 (m, 6H); LC/MS (ESI, m/z[. [(M + 1)]+ = 433.30.

[002825] 3-(5-[3-[3-(3-Aminopropoxy)propoxy]propyl] methyl oxo-2.,3-dihydro1//-1.3-benzodiazol-l-vl)piperidine-2.6-dione (Intermediate LI)

Pd/C, H2 (2 atm)

THF

M HCI in dioxane

LI

[002826] Step 1 - tert-Butyl 7V-r3-r3-(r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-L3-benzodiazol yl1prop yn-l-yl1oxy)propoxy1propyl1carbamate

[002827] To a stirred solution of 3-(5-bromo methyl oxo-2,3-dihydro-1//-1,3benzodiazol-l-yl)piperidine-2,6-dione (2.0 g, 5.91 mmol, Intermediate HN) in DMSO (20 mL) were added tert-butyl 7V-[3-[3-(prop yn-l-yloxy)propoxy]propyl]carbamate (5.8 g, 21.4 mmol, Intermediate OJ), TEA (10 mL), Cui (0.2 g, 1 mmol) and Pd(PPh3)4 (0.7 g, 0.59 mmol) at rt under

1019 nitrogen atmosphere. The resulting mixture was stirred for 3 h at 90 °C. The resulting mixture was cooled to rt and concentrated under reduced pressure. The resulting mixture was diluted with 1% aqueous solution of AcOH (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 330 g; Eluent A: Water (plus 10 mmol/L AcOH); Eluent B: ACN; Gradient: 45% - 55% B in 10 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions were collected at 51% B and concentrated under reduced pressure to afford tert-butyl 7V-[3-[3-([3-[l-(2,6-dioxopiperidin yl)3-methyl oxo-2,3-dihydro-l/7-l,3-benzodiazol yl]prop yn-lyl]oxy)propoxy]propyl]carbamate (1.5 g, 48%) as a yellow solid. 1HNMR (400 MHz, CDCh) δ 8.21 (br s, IH), 7.22 (dd, J = 8.2, 1.5 Hz, IH), 7.14 (d, J = 1.4 Hz, IH), 6.77 (d, J = 8.1 Hz, IH), 5.22 (dd, J = 12.7, 5.3 Hz, IH), 4.89 (br s, IH), 4.39 (s, 2H), 3.69 (t, J= 6.3 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 3.51 (t, J = 5.9 Hz, 2H), 3.44 (s, 3H), 3.23 (q, J = 6.1 Hz, 2H), 3.03-2.64 (m, 3H), 2.34-2.24 (m, IH), 1.92 (p, J = 6.3 Hz, 2H), 1.76 (p, J= 6.3 Hz, 2H), 1.46 (s, 9H); LC/MS (ESI, m/z)&#1523;. [(M+ l)]+ = 529.25.

[002828] Step 2 - tert-Butyl 7V-r3-(3-[3-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l/7-L3-benzodiazol yl1propoxy1propoxy)propyl1carbamate

[002829] To a solution of tert-butyl 7V-[3-[3-([3-[l-(2,6-dioxopiperidin yl) methyl-2oxo-2,3-dihydro-l 7/-1,3-benzodiazol yl]prop yn-l-yl]oxy)propoxy]propyl]carbamate (200 mg, 0.38 mmol) in THF (10 mL) was added palladium on charcoal (402 mg, 10% w/w) under nitrogen atmosphere. The mixture was purged with hydrogenated for three times and was stirred at rt for 6 h under hydrogen atmosphere. The resulting mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to afford tert-butyl Λ-[3-(3-[3-[ Ι-(2,6di oxopiperi din yl) methyl oxo-2,3-dihydro-1/7-l,3-benzodiazol-5yl]propoxy]propoxy)propyl]carbamate (150 mg, 74%) as a white solid. 1H NMR (400 MHz, DMSO-» δ 11.09 (br s, IH), 7.93 (br s, IH), 7.06-6.98 (m, 2H), 6.87 (d, J = 8.0 Hz, IH), 5.36 (dt, J= 12.6, 6.0 Hz, IH), 3.57 (s, 5H), 3.47-3.34 (m, 8H), 3.04-2.84 (m, 2H), 2.82-2.66 (m, IH), 2.66-2.58 (m, 3H), 2.04-1.96 (m, IH), 1.86-1.68 (m, 4H), 1.65-1.53 (m, IH), 1.37 (s, 9H); LC/MS (ESI, m/z)&#1523;. [(M + 1)]+ = 533.25.

[002830] Step 3- 3-(5-r3-r3-(3-Aminopropoxv)propoxv1propvl1 methvl oxo-2,3

1020

dihydro-l//-L3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride

[002831] To a solution of /c77-butyl 7V-[3-(3-[3-[l-(2,6-dioxopiperidin yl) methyl oxo2,3-dihydro-l//-l,3-benzodiazol yl]propoxy]propoxy)propyl]carbamate (300 mg, 0.56 mmol) in dioxane (10 mL) was added a solution of hydrochloride in 1,4-dioxane (4 M, 10 mL). The resulting solution was stirred for 4 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford 3-(5-[3-[3-(3-aminopropoxy)propoxy]propyl] methyl-2oxo-2,3-dihydro-l//-l,3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride (200 mg, 76%) as a yellow solid. 1H NMR (400 MHz, DM SO-0/6) δ 11.09 (br s, IH), 7.93 (br s, 3H), 7.06-6.99 (m, 2H), 6.87 (d, J = 8.0 Hz, IH), 5.36 (dd, J = 12.7, 5.5 Hz, IH), 3.58 (s, 3H), 3.48-3.34 (m, 8H), 3.02-2.54 (m, 7H), 2.00 (dd, J = 11.4, 6.2 Hz, IH), 1.87-1.68 (m, 6H); LC/MS (ESI, m/z[ [(M + l)]+ = 433.15.

[002832] 3-Bromo-l-(4-methoxvbenzyl)DiDeridine-2,6-dione (Intermediate LJ)

9 PMB-OH

Br2, CHCI3 DEAD, PPh3

[002833] Step 1 - 3-bromopiperidine-2,6-dione

[002834] To a stirred solution of piperidine-2,6-dione (30 g, 0.266 mol) in CHC13 (60 mL) was added Br2 (13.5 mL, 0.265 mol) in a sealed glass tube, then the reaction mixture was heated to 113 °C for 1.5 h. The mixture was cooled to r.t. and transferred to a round bottom flask and concentrated. To the residue was added 100 mL ice water, and the solution was basified to pH = ~ 8 with saturated NaHCO3 aqueous, then extracted with DCM (100 mL x 5). The organic layer was dried with Na2SO4, filtered, and concentrated to give crude product, which was dissolved in a solution of DCM: EtOAc = 1:1 (~90 mL), then heated to 80 °C. After the solid was completely dissolved, the heating was stopped and the solution was cooled to r.t. for overnight. The solution was filtered, the solid was collected, and dried under vacuum to give desired compound (15.7 g) as a white solid. The filtrate was also concentrated to dry to give crude product, which was purified by column chromatography on silica gel eluting with DCM : Petroleum ether : EtOAc = 5:5:1 to DCM : Petroleum ether : EtOAc = 5:5:2 to obtain desired the second batch pure product (12 g) as a white solid (total yield: 54.5 %). 1H NMR (400 MHz, DM SO-0/6) δ 11.06 (s, IH), 5.00 - 4.78 (m, IH), 2.69-2.54 (m, 2H), 2.45 (dd, J = 10.0, 5.1 Hz, IH), 2.17-2.12 (m, IH).

1021

[002835] Step 2 - 3-bromo-l-(4-methoxybenzyl)piperidine-2,6-dione

[002836] To a solution of 3-bromopiperidine-2,6-dione (30 g, 156.3 mmol), (4methoxyphenyl)methanol (23.3 g, 168 mmol) and PPh3 (40.5 g, 154.5 mmol) in dry THF (450 mL) was added dropwise DEAD (26.9 g, 154.5 mmol) at 0 °C under N2 for 30 min. The mixture was stirred for another 1.5 hour at 0 °C under N2. The mixture was quenched with H2O (300 mL) at 0 °C, and extracted with EA (400 mLx3). The organic layer was concentrated to give a residue, which was purified by column chromatography on silica gel eluting with PE:EA = 5:1 to PE:EA = 4:1 to give crude product. The crude product was further purified by column chromatrography on silica gel eluting with DCM to give 3-bromo-l-(4-methoxybenzyl) piperidine-2,6-dione (26.8 g, 55 % yield) as a pale yellow solid. 1H NMR (400 MHz, CDCh) δ 7.32-7.29 (d, J= 8.8 Hz, 2H), 6.83-6.81 (d, J= 8.8 Hz, 2H), 4.96-4.83 (dd, J= 13.6 Hz, J= 38 Hz, 2H), 4.72-4.70 (m, IH), 3.78 (s, 3H), 3.06-2.99 (m, IH), 2.76-2.72 (m, IH), 2.36-2.32 (m, IH), 2.25-2.21 (m, IH).

[002837] 5-Chloro-l-methvl-N-(4-morpholinocvclohexvl)Dvrazolo[4,3-d]Dvrimidin-7amine (Intermediate LK)

Mel, K2CO3, acetone

NH3 H2O, THF

Pd/C, H2, MeOH

HL

Ν,Ν-Diethylaniline , POCI3

Na2CO3, ACN

LK

[002838] Step 1 - Methyl 2-methvl nitro-pyrazole carboxvlate

[002839] To a mixture of methyl 4-nitro-lH-pyrazole carboxylate (30.0 g, 175 mmol,

Intermediate HL) and K2CO3 (48.4 g, 350 mmol) in acetone (600 mL) was added Mel (49.7 g, 350 mmol, 21.8 mL). The reaction mixture was stirred at 70 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column

1022 chromatography to give the title compound (10.0 g, 30% yield) as light yellow solid. 1H NMR. (400MHz, CDCh) δ 7.99 (s, IH), 4.01 (s, 3H), 4.01 (s, 3H).

[002840] Step 2 - 2-Methyl nitro-pyrazole carboxamide

[002841] To a mixture of methyl 2-methyl nitro-pyrazole carboxylate (10.0 g, 54.0 mmol) in THF (20 mL) was added ΝΗ3.Η2Ο (27.3 g, 740 mmol, 30 mL, 95%). The reaction mixture was stirred at 100 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (8.80 g, 95% yield) as white solid. 1H NMR (400MHz, DMSOd6) δ 8.46 (s, IH), 8.29 (s, IH), 8.26 (s, IH), 3.86 (s, 3H).

[002842] Step 3 - 4-Amino methyl-pyrazole carboxamide

[002843] To a mixture of 2-methyl nitro-pyrazole carboxamide (8.80 g, 51.7 mmol) in MeOH (100 mL) was added Pd/C (6.00 g, 10 wt%). The reaction mixture was stirred at rt for 12 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (7.10 g, 97% yield) as red solid. 1H NMR (400MHz, DMSO-76) δ 7.37 (s, 2H), 7.02 (s, IH), 4.41 (s, 2H), 3.89 (s, 3H).

[002844] Step 4 - l-Methylpyrazolor4,3-d1pyrimidine-5,7-diol

[002845] To a mixture of 4-amino methyl-pyrazole carboxamide (11.3 g, 80.6 mmol) in DMF (120 mL) was added CDI (26.1 g, 161 mmol). The reaction mixture was stirred at 90 °C for 24 hours. On completion, the reaction mixture was diluted with water (400 mL) then the solid was formed, and filtered to afford solid. The solid was washed with water (1 L) to give the title compound (13.0 g, 97% yield) as off-white solid. 1H NMR (400MHz, DMSO-76) δ 11.08 (s, IH), 10.92 ( s, IH), 7.33 (s, IH), 4.04 (s, 3H).

[002846] Step 5 - 5,7-Dichloro-l-methyl-pyrazolor4,3-d1pyrimidine

[002847] To a mixture of l-methylpyrazolo[4,3-d]pyrimidine-5,7-diol (5.00 g, 30.1 mmol) in POCh (50.0 g, 326 mmol, 30.3 mL) was added Ν,Ν-diethylaniline (4.46 g, 29.8 mmol, 4.78 mL). The reaction mixture was stirred at 110 °C for 4 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.70 g, 60% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 8.48 (s, IH), 4.33 (s, 3H).

[002848] Step 6 - 5-Chloro-l-methyl-N-(4-morpholinocyclohexyl)pyrazolor4,3d1pyrimidin amine

[002849] To a solution of 5,7-dichloro-l-methyl&#1470;pyrazolo[4,3-d]pyrimidine (1.00 g, 4.93

1023 mmol) and 4-morpholinocyclohexanamine (1.27 g, 4.93 mmol, 2HC1, CAS# 558442 0) in ACN (30 mL) was added Na2CO3 (2.09 g, 19.70 mmol). The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated in vacuo, diluted with DCM (30 mL), and filtered. The filtrate was concentrated in vacuo. The crude product was triturated with ACN/DCM/PE = 1:0.2:10 (30 mL) to give the title compound (1.30 g, 75% yield) as a yellow solid. 1HNMR(400MHz, CDCh) δ 7.85 (s, IH), 5.18 (d, J= 6.8 Hz, IH), 4.30 (s, 3H), 4.28 - 4.17 (m, IH), 3.86 (s, 4H), 2.74 (s, 4H), 2.56 - 2.50 (m, IH), 2.36 (d, ./= 11.6 Hz, 2H), 2.13 (d, 7=11.6 Hz, 2H), 1.69 - 1.53 (m, 2H), 1.47 - 1.32 (m, 2H).

[002850] Tert-butyl N-[2-[2-[2-[2-[2-(4-amin0Dyraz01-lyDethoxy] ethoxy] ethoxy] ethoxy] ethyl] carbamate (Intermediate LL) no2

nh2

[002851] Step 1:Tert-butyl N-r2-r2-r2-r2-[2-(4-nitropyrazol-lyl)ethoxy1ethoxy1ethoxy1ethoxy1ethyl1 carbamate

[002852] To a solution of 2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (1.76 g, 4.24 mmol, synthesized via Step 1 of Intermediate HH) and 4-nitro-lH-pyrazole (0.40 g, 3.54 mmol, CAS# 2075 9) in DMF (15 mL) was added Cs2CO3 (2.31 g, 7.07 mmol). The reaction mixture was stirred at 130 °C for 3 hours. On completion, the mixture was diluted with H2O (50 mL), then extracted with EA (2 X 100 mL). The combined organic phase was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.20 g, 78% yield) as yellow oil. LC-MS (ESI+) m/z 455.2 (M+Na)+.

[002853] Step 2:Tert-butyl N-r2-r2-r2-r2-[2-(4-aminopyrazol-lvl)ethoxv1ethoxv1ethoxv1ethoxv1ethyl1 carbamate

[002854] To a mixture of tert-butyl N-[2-[2-[2-[2-[2-(4-nitropyrazol-lyl)ethoxy]ethoxy]ethoxy]ethoxy] ethylcarbamate (1.20 g, 2.77 mmol) in MeOH (20 mL) was added Pd/C (800 mg, 10 wt%). The reaction mixture was stirred at rt for 12 hours under H2 (15

1024

Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.00 g, 89% yield) as red oil. 1H NMR. (400MHz, CDCh) δ 7.16 (d, J= 5.2 Hz, 2H), 5.23 (s, IH), 4.17 (t, J= 5.2 Hz, 2H), 3.78 (t, J= 52 Hz, 2H), 3.65 - 3.51 (m, 14H), 3.30 (d, J= 4.8 Hz, 2H), 2.67 (s, 2H), 1.43 (s, 9H).

[002855] l-[2-[2-[2-(4-AminoDvrazol-l-vl)ethoxv]ethoxv]ethoxy]Dentan one (Intermediate LM)

LM

[002856] Step 1 - Ethyl 2-r2-r2-r2-(4-nitropyrazol-l-yl)ethoxy1ethoxy1ethoxy1acetate [002857] To a mixture of ethyl 2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (0.5 g, 1.59 mmol, Intermediate BI) and 4-nitro-lH-pyrazole (270 mg, 2.38 mmol) in DMF (10 mL) was added Cs2CO3 (1.04 g, 3.18 mmol). The reaction mixture was stirred at rt for 24 hours under N2 atmosphere. On completion, the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (0.5 g, 1.43 mmol, 90% yield, 95% purity) as a yellow solid. 1HNMR (400MHz, DMSO-d6) δ = 8.84 (s, IH), 8.27 (s, IH), 4.35 (t, J= 52 Hz, 2H), 4.19 - 4.04 (m, 4H), 3.82 (t, J= 5.2 Hz, 2H), 3.62 - 3.46 (m, 8H), 1.19 (t, J= 7.2 Hz, 3H) LC-MS (ESI+) m/z 332.2 (M+H)+.

[002858] Step 2 - l-r2-r2-r2-(4-Aminopvrazol-l-vl)ethoxv1ethoxv1ethoxy1pentan one

[002859] To a solution of ethyl 2-[2-[2-[2-(4-nitropyrazol-lyl)ethoxy]ethoxy]ethoxy]acetate (0.5 g, 1.51 mmol) in EtOH (10 mL) was added Pd/C (0.05 g, 50 wt%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at rt for 2 hours. On completion, the mixture was filtered with celite. The filtrate was concentrated in vacuo to give the title compound (0.34 g, 75% yield) as black red oil. 1H NMR (400MHz, DMSO-d6) δ 7.14 - 7.01 (m, IH), 6.96 - 6.83 (m, IH), 4.17 4.09 (m, 4H), 4.08 - 4.03 (m, 2H), 3.72 - 3.66 (m, 2H), 3.63 - 3.57 (m, 2H), 3.55 - 3.51 (m, 2H),

1025

3.49 (s, 4H), 1.25 - 1.17 (m, 3H).

[002860] 3-[4-[4-(4-aminobutoxv)butvl] methvI oxo-benzimidazoI-l-vI]DiDeridine2.,6-dione (Intermediate LN)

NHBoc

NHBoc

LN

[002861] Step 1 - Tert-butyl 7V-[4-([4-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-lJ/-L3-benzodiazol yl1but yn-l-yl1oxy)butyl1carbamate

[002862] To a stirred mixture of 3-(4-bromo methyl oxo-2,3-dihydro-lJ/-l,3benzodiazol-l-yl)piperidine-2,6-dione (1.5 g, 4.4 mmol, Intermediate HP), Pd(PPh3)2C12 (311.3 mg, 0.44 mmol) and Cui (84.5 mg, 0.44 mmol) in DMA (22 mL) and TEA (7 mL) was added tertbutyl 7V-[4-(but yn-l-yloxy)butyl]carbamate (5.4 g, 22.2 mmol, Intermediate OI) at rt under nitrogen atmosphere. The resulting mixture was purged with nitrogen three times and stirred for 16 h at 85 °C under nitrogen atmosphere. The resulting mixture was cooled and concentrated under reduced pressure to remove TEA. The resulting mixture was diluted with a solution of AcOH (3 mL) in ice water (50 mL). The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers was washed with brine (30 mL) and dried over anhydrous Na2SO4. After

1026 filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ Cl8-1, 20-40 pm, 120 g; Eluent A: Water (plus 10 mmol/LFA); Eluent B: ACN; Gradient: 50% - 60% B in 20 min; Flow rate: 60 mL/min; Detector: 220/254 nm; desired fractions were collected at 57% B and concentrated under reduced pressure to afford tert-butyl A-[4-([4-[ l-(2,6-dioxopiperidin yl)-3methyl oxo-2,3-dihydro-1//-1,3-benzodiazol yl]but yn-l-yl]oxy)butyl]carbamate (1.4 g, 63%) as a light yellow solid. 1H NMR (400 MHz, DMSO-6/6) δ 11.11 (s, IH), 7.12 (d, J= 7.7 Hz, IH), 7.05 (d, J= 7.7 Hz, IH), 7.00 (d, J= 7.8 Hz, IH), 6.79 (t, J= 5.7 Hz, IH), 5.39 (dd, J= 12.6, 5.4 Hz, IH), 3.65 (s, 3H), 3.63-3.54 (m, 2H), 3.43 (t, J = 6.3 Hz, 2H), 2.98-2.83 (m, 3H), 2.792.58 (m, 4H), 2.03 (dt, J= 10.8, 5.1 Hz, IH), 1.56-1.39 (m, 4H), 1.37 (s, 9H); LC/MS (ESI, m/z[. [(M- 1)]497.15 = &#1470;.

[002863] Step 2 - Tert-butyl //-(4 11-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-1//-1,3-benzodiazol yl]butoxy]butyl)carbamate

[002864] To a stirred solution of tert-butyl //-[4-([4-[l-(2,6-dioxopiperidin yl) methyl2-oxo-2,3-dihydro-l//-l,3-benzodiazol yl]but yn-l-yl]oxy)butyl]carbamate (800 mg, 1.60 mmol) in THF (20 mL) was added palladium on charcoal (80 mg, 10% w/w) at room temperature. The resulting mixture was stirred for 3 h at rt under hydrogen atmosphere. After filtration, the filter cake was washed with EtOAc (2x10 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 7V-(4-[4-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-l//-l,3benzodiazol yl]butoxy]butyl)carbamate (500 mg, 62%) as a white solid: 1H NMR (400 MHz, DMSO-6/6) δ 11.09 (s, IH), 6.96 (d, J = 5.0 Hz, 2H), 6.87 (q, J = 4.6 Hz, IH), 6.77 (t, J = 6.2 Hz, IH), 5.37 (dd, J = 12.5, 5.4 Hz, IH), 3.56 (s, 3H), 3.40 (t, J = 5.8 Hz, 2H), 3.37-3.29 (m, 2H), 3.00-2.82 (m, 5H), 2.78-2.57 (m, 2H), 2.06-1.95 (m, IH), 1.71-1.55 (m, 4H), 1.53-1.37 (m, 4H), 1.37 (s, 9H); LC/MS (ESI, m/z[ [(M + 1)]+ = 503.20.

[002865] Step 3 - 3-r4-r4-(4-Aminobutoxy)butyl] methyl oxo-2,3-dihydro-l//-l,3benzodiazol-l-yl]piperidine-2,6-dione hydrochloride

[002866] To a stirred solution of tert-butyl //-(4-[4-[l-(2,6-dioxopiperidin yl) methyl-2oxo-2,3-dihydro-1//-1,3-benzodiazol yl]butoxy]butyl)carbamate (500 mg, 0.99 mmol) in dioxane (4 mL) was added a solution of hydrochloride in 1,4-dioxane (4 M, 4 mL) dropwise at rt under nitrogen atmosphere. The resulting solution was stirred for 2 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3-[4-[4-(4

1027 aminobutoxy)butyl] methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-l-yl]piperidine-2,6-dione hydrochloride (420 mg, 96%) as a white solid. 1H NMR (400 MHz, DMSO-76) δ 11.08 (s, IH), 7.88 (br s, 3H), 7.02-6.92 (m, 2H), 6.87 (dd, J= 6.2, 2.6 Hz, IH), 5.38 (dd, J= 12.6, 5.4 Hz, IH), 3.57 (s, 3H), 3.47-3.28 (m, 4H), 2.99-2.84 (m, 3H), 2.79-2.58 (m, 4H), 2.00 (dt, J = 11.1, 5.2 Hz, IH), 1.69-1.50 (m, 8H); LC/MS (ESI, m/z[. [(M + 1)]+ = 403.25.

[002867] (2S,4R)-l-[(2S) [[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl1amino]-3.,3 dimethylcarboxamide (Intermediate LO)

HATU, DIPEA, DMF

NHBoc

HCI/dioxane, DCM

[002868] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-ΓΓ(18) [(28,4Κ) 11ν&#940;Γ0χν ΓΓ4-(4methylthiazol yl )phenyl]methylcarbamoyl1pyrrolidine-l-carbonyl]-2,2-dimethylpropyl] amino] oxo-ethoxy] ethoxy] ethoxy] ethyl 1 carbamate

[002869] To a solution of (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl] hydroxy-N[[4-(4-methylthiazol- 5-yl)phenyl]methyl]pyrrolidine carboxamide (250 mg, 535 umol, HCI,

1028

Intermediate CI) and 2-[2- [2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetic acid (164 mg, 535 umol, CAS# 462100 7) in DMF (5 mL) was added DIPEA (207 mg, 1.61 mmol) and HATU (244 mg, 642 umol). The mixture was stirred at rt for 1 hour. On completion, the reaction mixture was quenched with water 20 mL, and then extracted with EA (3X30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (300 mg, 77% yield) as brown solid. LC-MS (ESI+) m/z 720.4 (M+H)+.

[002870] Step 2:(28,4Κ) Γ(28) ΓΓ2-Γ2-Γ2-(2aminoethoxy)ethoxy1 ethoxy] acetyl] amino] -3.3 -dimethyl-butanoyl1 hydroxy-N-[r4-(4methylthiazol yl)phenyl1methyl1pyrrolidine carboxamide

[002871] To a solution of tert-butyl N-[2-[2-[2-[2-[[(lS)-l-[(2S,4R) hydroxy [[4-(4methylthiazol yl) phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethylpropyl]amino] oxo-ethoxy]ethoxy]ethoxy]ethyl]carbamate (240 mg, 333 umol) in DCM (12 mL) was added HCI/dioxane (4 M, 2.5 mL). The mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (0.21 g, 96% yield, HC1) as light yellow solid. LC-MS (ESI+) m/z 620.2 (M+H)+.

[002872] (2S,4R)-l-[(2S) [2- [2- [2-(2-aminoethoxv)ethoxy] ethoxy] ethylamino]-3,3dimethylcarboxamide (Intermediate LP)

1029

JX

NHBoc

TEA, NaBH(OAc)3, AcOH.THF

HCI/dioxane, THF

LP

[002873] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-ΓΓ(18) [(28,4Κ)-4^ν&#940;Γ0χν ΓΓ4-(4methylthiazol yl )phenyl]methylcarbamoyl1pyrrolidine-l-carbonyl]-2,2-dimethylpropyl 1 amino] ethoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[002874] To a mixture of tert-butyl N-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (500 mg, 1.72 mmol, Intermediate JX), (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl]-4hydroxy-N-[[4-(4-methyl thiazol yl)phenyl]methyl]pyrrolidine carboxamide (801 mg, 1.72 mmol, HCI, Intermediate CI), and TEA (174 mg, 1.72 mmol) in THF (20 mL) was added AcOH (103 mg, 1.72 mmol) and NaBH(OAc)3 (727 mg, 3.43 mmol). Then the mixture was stirred at rt for 72 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by Pre-HPLC (acid condition) to give the title compound (480 mg, 38% yield) as colorless solid. LC-MS (ESI+) m/z 706.5 (M+H)+.

[002875] Step 2 - (2S,4R)-l-ri2S) r2-r2-r2-(2-aminoethoxy)ethoxy1ethoxy1ethylamino1

1030

3,3-dimethylcarboxamide [002876] To a solution of tert-butyl N-[2-[2-[2-[2-[[(lS)-l-[(2S,4R) hydroxy [[4-(4methylthiazol yl) phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethylpropyl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (380 mg, 538 umol) in THF (10 mL) was added HCl/dioxane (4 M, 12 mL). The mixture was stirred at rt for 6 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (325 mg, 94% yield) as white solid. LC-MS (ESI+) m/z 606.4 (M+H)+.

[002877] Tert-butyl N- [3- [3-(3-amin0Dr0D0xy)Dr0D0xy]Dr0Dyl] carbamate (Intermediate LQ)

UA M M Raney-Ni, H2, MeOH

ΗΟ^χχ-,ΟΗ -------&#9658; NY-------------&#9658;

NaOMe O O (Boc)2O, DCM H2N&#1523;~'^O''~'^O&#1523;~''^NH2 -----------&#9658; H2N&#1470;^^&#1470;x^O&#1470;^&#1523;x^O'^^x^NHBoc

LQ

[002878] Step 1 - 3-r3-(2-Cyanoethoxy)propoxy1propanenitrile

[002879] NaOMe (71.00 mg, 1.31 mmol) was dissolved in a solution of propane-1, 3-diol (10 g, 131 mmol, CAS# 126 7). Then prop enenitrile (27.9 g, 525 mmol, CAS# 107 1) was added into the mixture. The reaction mixture was stirred at rt for 48 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (21.6 g, 90% yield) as a brown solid. 1HNMR (400MHz, DMSO-A) δ 3.57 (t, J= 6.4 Hz, 4H), 3.50 (t, J= 6.4 Hz, 4H), 2.74 (t, J= 6.4 Hz, 4H), 1.79 - 1.73 (m, 2H).

[002880] Step 2 - 3-r3-(3-Aminopropoxy)propoxy1propan-l-amine

[002881] To a mixture of 3-[3-(2-cyanoethoxy)propoxy]propanenitrile (10 g, 54.9 mmol) in MeOH (10 mL) was added Raney-Ni (9.40 g, 109 mmol), and the reaction mixture was stirred at 25 °C for 12 hrs under H2 (50 psi). On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (8.40 g, 80% yield) as brown oil. 1HNMR (400MHz, CDCh) δ 3.74 - 3.30 (m, 9H), 2.79 - 2.38 (m, 4H), 1.85 - 1.56 (m, 4H), 1.91 - 1.48 (m, IH).

[002882] Step 3 - Tert-butyl N-r3-r3-(3-aminopropoxy)propoxy1propyl1carbamate

[002883] To a solution of 3-[3-(3-aminopropoxy)propoxy]propan-l-amine (4.00 g, 21.0

1031 mmol) in DCM (40 mL) was dropwise added (Boc)2O (5.51 g, 25.2 mmol). The reaction mixture was stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (2.20 g, 36% yield) brown oil. 1HNMR (400MHz, CDCh) δ 3.66 - 3.60 (m, 3H), 3.66 - 3.60 (m, 3H), 3.49 - 3.45 (m, 4H), 2.61 - 2.53 (m, 4H), 1.88 - 1.68 (m, 6H), 1.41 (s, 9H).

[002884] 4-[3-[3-(3-Aminopropoxy)propoxy]propylamino] (2,6-dioxo-3piperidyl)isoindoline-l,3- dione (Intermediate LR)

LQ

LR

[002885] Step 1 - Tert-butyl N-r3-r3-r3-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yl1amino1propoxy1propoxy1propyl1carbamate

[002886] To a mixture of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (476 mg,

1.72 mmol, Intermediate R), tert-butyl N-[3-[3-(3-aminopropoxy)propoxy]propyl]carbamate (500 mg, 1.72 mmol, Intermediate LQ) in dioxane (10 mL) was added DIPEA (2.23 g, 17.2 mmol). The reaction mixture was stirred at 115 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (820 mg, 87% yield) as brown oil. LC-MS (ESI+) m/z 547.4 (M+H)+.

1032

[002887] Step 2 - 4-r3-r3-(3-Aminopropoxv)propoxv1propylamino1 (2,6-dioxo-3piperidyl)isoindoline-L3- dione

[002888] To a mixture of tert-butyl N-[3-[3-[3-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] propoxy]propoxy]propyl]carbamate (820 mg, 1.50 mmol) in DCM (5 mL) was added HCI/dioxane (4 M, 750 uL) and the reaction was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (695 mg, 96% yield, HCI) as yellow oil LC-MS (ESI+) m/z 447.1 (M+H) +.

[002889] Tert-butyl N-[4-[4-[(3-formvl-l-methvl-pvrazol vl)carbamoyl]oxazol vl]2-pyridyll-N- (22&#1524;2&#1524;-trifluoroethyl)carbamate (Intermediate LS)

[002890] Step 1 - Isopropoxycarbonyl 4-rr2-r2-rtert-butoxycarbonyl(2,2,2trifluoroethyl)amino1 pyridyl1 oxazole carbonyl1 amino] methyl-pyrazole carboxylate [002891] To a solution of 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole-4 -carbonyl]amino]-l-methyl-pyrazole carboxylic acid (3 g, 5.88 mmol, Intermediate KR) in THF (50 mL) was added TEA (595 mg, 5.88 mmol). Then, the reaction mixture was cooled to -10 °C. To the mixture was added isopropyl carbonochloridate (1.44 g, 11.8 mmol). The resulting reaction mixture was stirred at -10 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (3.51g, 82% yield) as a white solid. LC-MS (ESI+) m/z 597.1 (M+H)+.

[002892] Step 2 - Tert-butyl N-r4-r4-rr3-(hydroxymethyl)-l-methyl-pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[002893] To a solution of isopropoxycarbonyl 4-[[2-[2-[tert-butoxycarbonyl(2,2,2

1033 trifluoroethyl)amino]- 4-pyridyl]oxazole carbonyl]amino]-l-methyl-pyrazole carboxylate (3.51 g, 4.83 mmol) in THF (60 mL) was added LiBH4 (315 mg, 14.5 mmol) and H2O (1.37 g, 76.0 mmol). The reaction mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was quenched with water (5 mL) and the mixture was extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.92 g, 73% yield) as a white solid. LC-MS (ESI+) m/z 497.1 (M+H)+.

[002894] Step 3 - Tert-butyl N-r4-r4-r(3-formyl-l-methyl-pyrazol yl)carbamoyl1oxazol-2yl1 pyridyl1-N- (2,2,2-trifluoroethyl)carbamate

[002895] To a solution of tert-butyl N-[4-[4-[[3-(hydroxymethyl)-l-methyl-pyrazol-4yl]carbamoyl]oxazol- 2-yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (2.42 g, 4.19 mmol) in DCM (30 mL) was added DMP (3.56 g, 8.38 mmol). The reaction mixture was stirred at rt for 5 hrs. On completion, the reaction mixture was quenched with saturated Na2S2O3 (20 mL), and extracted with DCM (3 X 30 mL). The combined organic layer was washed with saturated NaHCO3 (2 X 20 mL) and brine (30 mL), dried over with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with methanol (10 mL) to give the title compound (1.60 g, 77% yield) as a white solid. 1H NMR(400MHz, DMSO-76) δ 10.32 (s, IH), 10.00 (s, IH), 9.11 (s, IH), 8.67 (d, J= 52 Hz, IH), 8.44 (s, IH), 8.29 (s, IH), 7.79 (dd, J = 1.2, 5.2 Hz, IH), 4.91 (q, J= 8.8 Hz, 2H), 4.02 (s, 3H), 1.54 (s, 9H). LC-MS (ESI+) m/z 495.1 (M+H)+.

[002896] 2-(2-Chloro Dvridvl)oxazole carboxylic acid (Intermediate LT)

[002897] Step 1 - Methyl 2-(2-chloro pyridyl)oxazole carboxylate

[002898] To a solution of methyl 2-amino hydroxy-propanoate; hydrochloride (1.10 g, 7.06 mmol, CAS# 2104 4) in DMA (20 mL) was added NaHCO3 (1.19 g, 14.1 mmol). The mixture was stirred at rt for 2 hours. Then, to the mixture was added 2-chloropyridine-3carbaldehyde (1 g, 7.06 mmol, CAS# 36404 3) in one portion. The mixture was stirred for 12 hours. Then, to the mixture was added bromo(trichloro)methane (4.20 g, 21.2 mmol) and DBU

1034 (3.23 g, 21.2 mmol) at 0 °C. Then, the mixture was stirred at rt for an additional 12 hours. On completion, the mixture was quenched with water (20 mL) and extracted with EA (2 X 100 mL). The organic layer was washed with brine (30 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (1.2 g, 71% yield) as a white solid. LC-MS (ESI+) m/z 238.9 (M+H)+.

[002899] Step 2 - 2-(2-Chl oro pyridyl)oxazole carboxylic acid

[002900] To a solution of methyl 2-(2-chl oro pyridyl) oxazole carboxylate (1.2 g, 5.03 mmol) in a mixed solvent of H2O (4 mL) and THF (20 mL) was added LiOHH2O (602 mg, 25.1 mmol). The mixture was stirred at rt for 5 hours. On completion, the mixture was adjusted to pH = 7 with IN aq.HCl, and filtered. The filter cake was dried in vacuo to give the title compound (0.7 g, 62% yield) as a white solid. LC-MS (ESI+) m/z 225.0 (M+H)+.

[002901] 3-(Difluoromethvl)-l-methvl-Dvrazol amine (Intermediate LU)

F F F

HS LU

[002902] Step 1 - 3-Difluoromethyl)-l-methyl nitro-pyrazole

[002903] A mixture of 3-(difluoromethyl) nitro-lH-pyrazole (1 g, 6.13 mmol, Intermediate HS), K2CO3 (1.69 g, 12.3 mmol), and Mel (1.74 g, 12.3 mmol) in acetone (20 mL) was degassed and purged with N2 gas 3 times. Then the mixture was stirred at 70 °C for 2 hours under N2 atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (0.5 g, 46% yield) as yellow oil.

[002904] Step 2 - 3-(Difluoromethyl) m ethyl-pyrazol amine

[002905] To a solution of 3-(difluoromethyl) methyl nitro-pyrazole (200 mg, 1.13 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 10 wt%). The mixture was stirred at rt for 3 hours under H2 atmosphere (15 Psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (0.2 g, crude) as red oil. 1H NMR (400MHz, CDCh) δ 6.89 (s, IH), 6.76 - 6.45 (m, IH), 3.72 (s, 3H), 2.86 (s, 2H).

[002906] 2-(2-Chloro Dvridvl)-N-[3-(difluoromethvl)-l-methvl-Dvrazol yl]oxazole4-carboxamide (Intermediate LV)

1035

LT

HATU, DIPEA, DMF

LV

[002907] A mixture of 3-(difluoromethyl)-l-methyl-pyrazol amine (350 mg, 2.38 mmol, Intermediate LU), 2-(2-chloro-3 -pyridyl)oxazole carboxylic acid (534 mg, 2.38 mmol, Intermediate LT), DIPEA (922 mg, 7.14 mmol), and HATU (1.09 g, 2.85 mmol) in DMF (3 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at rt for 3 hours under N2 atmosphere. On completion, the mixture was quenched with water (20 ml) and extracted with EA (2 X 20 mL). The organic layer was washed with brine (20 mL), then concentrated in vacuo to give the title compound (0.6 g, 96% yield) as a white solid. LC-MS (ESI+) m/z 354.1 (M+H)+.

[002908] 2- [2- [2- [2- [2-(2-Aminoethoxv)ethoxy] ethoxy] et h via m ino I Dvridvl]-N- [3(difluoromethyl) -l-methvl-Dvrazol vl]oxazole carboxamide (Intermediate LW)

1036

[002909] Step 1 - Tert-butyl N-[2-[2-[2-[2-[[3-[4-[[3-(difluoromethyl)-l-methyl-pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1amino1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[002910] To a solution of 2-(2-chloro pyridyl)-N-[3-(difluoromethyl)-l-methyl-pyrazol-4yl]oxazole carboxamide (200 mg, 565 umol, Intermediate LV) in NMP (2 mL) was added tertbutyl N-[2-[2-[2-(2-aminoethoxy) ethoxy]ethoxy]ethyl]carbamate (827 mg, 2.83 mmol, CAS# 101187 0). The mixture was stirred at 150 °C for 1 hour under microwave. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (acid condition) to give the title compound (0.2 g, 55% yield) as a white solid. LC-MS (ESI+) m/z 610.4 (M+H)+.

[002911] Step 2 - 2-[2-[2-[2-[2-(2-Aminoethoxy)ethoxy1ethoxy1ethylamino1 pyridyl1-N[3-(difluoromethyl) methyl-pyrazol yl1oxazole carboxamide

[002912] To a solution of tert-butyl N-[2-[2-[2-[2-[[3-[4-[[3-(difluoromethyl)-l-methylpyrazol yl] carbamoyl] oxazol yl] pyridyl] amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 328 umol) in THF (5 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at rt for 16 hours. On completion, the mixture was concentrated in vacuo to give the title compound (180 mg, 93% yield, HC1) as a yellow solid. LC-MS (ESI+) m/z 510.3 (M+H)+.

[002913] 7- [2-[2- [2- [2-(2-aminoethoxv)ethoxy] ethoxy] ethoxy|ethoxy| [(2S) [(2 methoxvacetvl)amino]-3,3-dimethvl-butanovl]-N-[(lR)-tetralin-l-vl]-3,4-dihydro-lHisoquinoline-3 -carboxamide (Intermediate LX)

1037

LX

[002914] 7-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy] [(2S) [(2methoxyacetyl)amino]-3,3-dimethyl-butanoyl]-N-[(lR)-tetralin-l-yl]-3,4-dihydro-lHisoquinoline carboxamide was synthesized as described for Intermediate LY, using 2,2dimethyl 0X0-3,8,11,14,17-pentaoxa azanonadecan yl4-methylbenzenesulfonate,

Intermediate ON, as the tosylate in Step 1 to couple with alcohol Intermediate MH. 1H NMR (400 MHz, DMSO-76) δ 8.21-8.15 (m, IH), 7.45-7.30 (m, IH), 7.14-6.77 (m, 7H), 5.11-4.40 (m, 5H), 4.07-4.02 (m, 2H), 3.90-3.72 (m, 4H), 3.60-3.41 (m, 12H), 3.36-3.20 (m, 7H), 3.05-2.93 (m, 2H), 2.76-2.61 (m, 4H), 1.87-1.52 (m, 4H), 1.03-0.93 (m, 9H). LC-MS (ESI+): m/z 727.2 (M+H)+ [002915] 7-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy] [(2S) [(2methoxyacetyl)amino]-3,3-dimethyl-butanoyl]-N-[(lR)-tetralin-l-yl]-3,4-dihydro-lHisoquinoline carboxamide (Intermediate LY)

1038

[002916] Step 1 - tert-butyl (2-(2-(2-(2-(((S) ((S) (2-methoxyacetamido)-3,3dimethylbutanoyl) (((R)-1,2,3,4-tetrah ydronaphthal en-1 -vDcarbamoyl)-1,2,3,4tetrahydroisoquinolin yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

[002917] To a mixture of (S) hydroxy ((S) (2-methoxyacetamido) -3,3dimethylbutanoyl) -N- ((R)-1,2,3,4-tetrahydronaphthalen-1 -yl)-1,2,3,4-tetrahydroisoquinoline-3carboxamide (1.75g, 3.45 mmol, Intermediate MH) and 2,2-dimethyl oxo-3,8,ll,14-tetraoxa-5azahexadecan yl 4-methyl benzenesulfonate (1.7 g, 3.8 mmol, Intermediate LD) in DMF (25 mL) was added K2CO3 (714 mg, 5.2 mmol), and the mixture was stirred at 110 °C for overnight. The solution was then poured into water(150 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, filtered, concentrated in vacuo and purified via column chromatography (Petroleum ether / EtOAc= 1 /1) to give the title compound (1.38 g, 51.1 % yield) as a colorless oil. LC-MS (ESI+): m/z 683.2 (M-99)+.

[002918] Step 2 - (S) (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy) ((8) (2

1039 methoxyacetamido) -3,3 -dimethylbutanoyl)-N-((R)-1,2,3,4-tetrah ydronaphthal en-I -yl )-1,2,3,4tetrahydroisoquinoline carboxamide

[002919] To a mixture of tert-butyl (2-(2-(2-(2-(((S) ((S) (2-methoxyacetamido) -3,3dimethyl butanoyl) (((R)-l,2,3,4-tetrahydronaphthalen -l-yl)carbamoyl)- 1,2,3,4tetrahydroisoquinolin yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (1.38 g, 1.76 mmol) in THF (15 mL) was added 4 M HCl/dioxane(10 mL), and the mixture was stirred at rt for overnight. Then the solution was poured into aq.NaHCO3 (100 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (50 mL x 3), dried over Na2SO4, fdtered, concentracted in vacuo and purified via column chromatography (DCM / MeOH= 10 / 1) to give the title compound (600 mg, 50 % yield) as a white solid. 1H NMR (400 MHz, DMSO4) δ (s, IH), 8.23-8.17 (m, IH), 7.46-7.30 (m, IH), 7.14-6.77 (m, 7H), 5.12-4.41 (m, 5H), 4.07-4.03 (m, 2H), 3.90-3.73 (m, 4H), 3.60-3.47 (m, 10H), 3.32-3.29 (m, 3H), 3.06-2.93 (m, 2H), 2.81-2.64 (m, 4H), 1.87-1.52 (m, 4H), 1.03-0.94 (m, 9H). LC-MS (ESI+): m/z 683.2 (M+H)+.

[002920] 3-[4-[3-[3-(3-amin0Dr0D0xv)-2,2-dimethvl-Dr0D0xv]Dr0Dvl] methyl 0x0benzimidazol-l-yl]DiDeridine-2,6-dione (Intermediate LZ)

LZ

[002921] Step 1 - Tert-butyl 7V-r3-r3-(r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-1/7-1,3-benzodiazol yl1prop yn-l-yl1oxy)-2,2-dimethylpropoxy1propyl1carbamate

[002922] To a stirred solution of 3-(4-bromo methyl oxo-2,3-dihydro-l/7-l,3benzodiazol-l-yl)piperidine-2,6-dione (2.45 g, 7.25 mmol, Intermediate HP) and te/7-butyl 7V-[3

1040

[2,2-dimethyl (prop yn-l-yloxy)propoxy]propyl]carbamate (1.5 g, 4.85 mmol, Intermediate OG) in DMA (25 mL) were added Cui (138.0 mg, 0.72 mmol), TEA (10 mL) andPd(PPh3)4 (837.2 mg, 0.72 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred for 5 h at 90 °C under nitrogen atmosphere. The resulting mixture was cooled and concentrated under reduced pressure to remove TEA. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 300 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 48% - 68% B in 25 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions were collected at 60% B and concentrated under reduced pressure to afford tert-butyl 7V-[3-[3-([3-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-l//-l,3benzodiazol yl]prop yn-l-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate (1.4 g, 33%) as a light brown solid: 1HNMR (400 MHz, DMSO4) δ 11.12 (s, IH), 7.20-7.16 (m, IH), 7.12 (dd, J = 8.0, 1.1 Hz, IH), 7.03 (t, J= 7.9 Hz, IH), 6.71 (s, IH), 5.41 (dd, J = 12.6, 5.4 Hz, IH), 4.44 (s, 2H), 3.65 (s, 3H), 3.36 (t, J = 62 Hz, 2H), 3.32-3.30 (m, 2H), 3.13 (s, 2H), 2.97 (q, J = 6.6 Hz, 2H), 2.94-2.84 (m, IH), 2.79-2.58 (m, 2H), 2.09-1.99 (m, IH), 1.59 (p, J = 6.5 Hz, 2H), 1.36 (s, 9H), 0.88 (s, 6H); LC/MS (ESI, m/z(. [(M - 100 + 1)]+ = 457.4.

[002923] Step 2 - 3-(4-r3-r3-(3-Aminopropoxy)-2,2-dimethylpropoxy1propyl1 methyl-2oxo-2,3-dihydro-l//-L3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride

[002924] To a solution of tert-butyl /V-[3-[3-([3-[l-(2,6-dioxopiperidin yl) methyl-2oxo-2,3-dihydro-l//-l,3-benzodiazol yl]prop yn-l-yl]oxy)-2,2dimethylpropoxy]propyl]carbamate (800 mg, 1.44 mmol) in THF (15 mL) was added palladium on charcoal (152.9 mg, 10% w/w) in a pressure tank. The mixture was purged with hydrogen gas 3 times at rt and the mixture was hydrogenated at rt under 1 psi for 16 h. After filtration, the filter cake was concentrated under reduced pressure. The residue was dissolved in dioxane (8 mL). To it was added a solution of HCI in 1,4-dioxane (4 M, 8 mL) dropwise at rt under nitrogen atmosphere. The resulting solution was stirred for 2 hours at rt under nitrogen atmosphere. The resulting solution was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ Cl8-1, 20-40 pm, 80 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 45% - 70% B in 25 min; Flow rate: 50 mL/min; Detector: 220/254 nm; desired fractions were collected at 63% B and concentrated under reduced pressure to afford 3-(4-[3-[3-(3-aminopropoxy)-2,2dimethylpropoxy]propyl] methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-l-yl)piperidine-2,6

1041 dione hydrochloride (72.8 mg, 10%) as a light yellow solid: 1H NMR (400 MHz, CDCh) δ 8.51 (br s, IH), 7.48 (br s, 3H), 6.99 (t, J = 7.8 Hz, IH), 6.90 (d, J = 7.8 Hz, IH), 6.74 (d, J = 7.8 Hz, IH), 5.22 (dd, J= 12.4, 5.5 Hz, IH), 3.69 (s, 3H), 3.51-3.38 (m, 4H), 3.20-3.08 (m, 4H), 3.06-2.93 (m, 4H), 2.89-2.66 (m, 3H), 2.22-2.13 (m, IH), 1.99-1.83 (m, 4H), 0.87 (s, 6H); LC/MS (ESI, m z): [(M + l)]+ = 461.35.

[002925] 3-[5-[3-[3-(3-aminopropoxy)-2,2-dimethyl-propoxy]propyl] methyl oxo benzimidazol-l-yl]piperidine-2,6-dione (Intermediate MA)

1) Pd-C, H2, THF

2) 2 M HCI in dioxane, dioxane

[002926] Step 1 - Tert-butyl A-r3-r3-(r3-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-L3-benzodiazol yl1prop yn-l-yl1oxy)-2,2-dimethylpropoxy1propyl1carbamate [002927] To a stirred solution of 3-(5-bromo methyl oxo-2,3-dihydro-l//-1,3benzodiazol-l-yl)piperidine-2,6-dione (1.68 g, 4.97 mmol, Intermediate HN) and tert-butyl 7V-[3[2,2-dimethyl (prop yn-l-yloxy)propoxy]propyl]carbamate (996.6 mg, 3.33 mmol, Intermediate OG) in DMA (15 mL) were added Cui (94.6 mg, 0.50 mmol), TEA (10 mL) and Pd(PPh3)4 (574.1 mg, 0.50 mmol) at room temperature under nitrogen atmosphere. The mixture was purged with nitrogen gas 3 times, and the resulting mixture was stirred for 5 h at 90 °C under nitrogen atmosphere. After cooling to rt, the mixture was purified by reverse phase flash

1042 chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 300 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 48% - 68% B in 20 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions were collected at 60% B and concentrated under reduced pressure to afford tert-butyl 7V-[3-[3-([3-[l-(2,6-dioxopiperidin yl)3-methyl oxo-2,3-dihydro-17/-l,3-benzodiazol yl]prop yn-l-yl]oxy)-2,2dimethylpropoxy]propyl]carbamate (600 mg, 22%) as a light brown solid. 1H NMR (400 MHz, DMSOA) ri 11.12 (brs, IH), 7.32 (d, J= 1.4 Hz, IH), 7.22-7.07 (m, 2H), 6.84-6.64 (m, IH), 5.40 (dd, 7= 12.8, 5.4 Hz, IH), 4.37 (s, 2H), 3.40-3.32 (m, 5H), 3.29 (s, 2H), 3.13 (s, 2H), 2.98 (q,7 = 6.6 Hz, 2H), 2.95-2.83 (m, IH), 2.76-2.59 (m, 2H), 2.04 (ddd, 7= 10.8, 6.0, 3.9 Hz, IH), 1.61 (t, 7= 6.7 Hz, 2H), 1.37 (s, 9H), 0.88 (s, 6H); LC/MS (ESI, m/zf [(M + 1)]+ = 557.25.

[002928] Step 2 - 3-(5-r3-r3-(3-Aminopropoxy)-2,2-dimethylpropoxy1propyl1 methyl-2oxo-2,3-dihydro-1//-L3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride

[002929] To a solution of tert-butyl 7V-[3-[3-([3-[l-(2,6-dioxopiperidin yl) methyl-2oxo-2,3-dihydro-1//-1,3-benzodiazol yl]prop yn-l-yl]oxy)-2,2dimethylpropoxy]propyl]carbamate (600 mg, 1.08 mmol) in THF (10 mL) was added palladium on charcoal (114.7 mg, 10% w/w) in a pressure tank. The mixture was purged with hydrogen gas 3 times and was hydrogenated at rt under 1 psi of hydrogen for 16 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (5 mL). To it was added a solution of HCI in 1,4-dioxane (4 M, 5 mL) dropwise at rt under nitrogen atmosphere. The resulting solution was stirred for 2 hours at rt under nitrogen atmosphere, then was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 80 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 45% - 70% B in 25 min; Flow rate: 50 mL/min; Detector: 220/254 nm; desired fractions were collected at 63% B and concentrated under reduced pressure to afford 3-(5-[3-[3-(3 -aminopropoxy)-2,2-dimethylpropoxy]propyl] -3 -methyl oxo-2,3 dihydro-1//-1,3-benzodiazol-l-yl)piperidine-2,6-dione hydrochloride (58.1 mg, 10%) as a light yellow solid. 1H NMR (400 MHz, CDCh) ri 8.47 (s, IH), 8.21 (br, 3H), 6.96-6.76 (m, 3H), 5.28 (dd, 7= 12.7, 5.4 Hz, IH), 3.47 - 3.39 (m, 5H), 3.39-3.32 (m, 2H), 3.19-3.08 (m, 4H), 2.96 (t, 7 = 6.9 Hz, 2H), 2.88-2.79 (m, 2H), 2.72 (q,7 = 11.8, 9.5 Hz, 3H), 2.22-2.12 (m, IH), 1.87 (q,7=6.4, 5.6 Hz, 4H), 0.87 (s, 3H), 0.86 (s, 3H); LC/MS (ESI, m/zf [(M + 1)]+ = 461.40.

[002930] N-[3-carbamovl-l-(4-formvlDhenvl)Dvrazol vl]oxazole carboxamide

1043 (Intermediate MB)

MB

[002931] Step 1 - N-r3-carbamoyl-l-r4-(hydroxymethyl)phenyl1pyrazol yl1oxazole-4carboxamide

[002932] To a solution of 4-amino-l-[4-(hydroxymethyl)phenyl]pyrazole carboxamide (200 mg, 861 umol, Intermediate GB) and oxazole carboxylic acid (97.3 mg, 861 umol, CAS# 23012 7) in DMF (3 mL) was added DIPEA (333 mg, 2.58 mmol) and HATU (392 mg, 1.03 mmol). The mixture was stirred at rt for 0.5 hour. On completion, the mixture was diluted with H2O (15 mL), the mixture was filtered and the solid was dried in vacuo to give the title compound (270 mg, 75% yield) as white solid. LC-MS (ESI+) m/z 350.2 (M+Na)+.

[002933] Step 2 - N-r3-carbamoyl-l-(4-formylphenyl)pyrazol yl1oxazole carboxamide

[002934] To a soluton of N-[3-carbamoyl-l-[4-(hydroxymethyl)phenyl]pyrazol-4yl]oxazole carboxamide (270 mg, 824 umol) in DCM (30 mL) was added DMP (419 mg, 989 umol). The mixture was stirred at rt for 2 hours. On completion, the mixture was quenched with saturated aq. Na2S2O3 (30 mL) and washed with saturated aq. NaHCO3 (2X30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (100 mg, 40% yield) as yellow solid. LC-MS (ESI+) m/z 326.1 (M+H)+.

[002935] l-Methyl [[2- [2-(22,.2&#1524;-trifluoroethvlamino) pvridvl] oxazole-4carbonyllaminolpyrazole carboxylic acid (Intermediate MC)

1044

KR

HCI CF3

MC

[002936] To a solution of 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4 pyridyl]oxazole carbonyl]amino]-l-methyl-pyrazole carboxylic acid (35 mg, 68.6 umol,

Intermediate KR) in DCM (2 mL) was added 4.0 M HCl/dioxane (2 mL). The reaction mixture was stirred at rt for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (30 mg, 98% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 411.5 (M+H)+.

[002937] (2S,4R)-l-[(2S) [[2-[2-[2-[2-[2-[2-(2aminoethoxy)ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] amino]-3,3-dimethyl-butanoyl] -4hydroxy-N-[[4-(4-methylthiazol yl)Dhenvl]methyl]Dyrrolidine carboxamide (Intermediate MD) s

NH

G HOy-o. 0

OF

&#1523;&#1505;-

&#1497;&#1505;

HO,,.

HATU,DIPEA

[002938]

Step 1 - tert-butyl ((S) ((2S,4R) hydroxy ((4-(4-methylthiazol-51045 yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-23,23-dimethyl oxo-3A9,12,15,18-hexaoxa21 -azatetracosyl )carbamate

[002939] To a solution of (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4(4-methylthiazol yl)benzyl)pyrrolidine carboxamide (1.0 g, 2.15 mmol, Intermediate G) in DMF (100 mL) was added 2,2-dimethyl oxo-3,8,ll,14,17,20,23-heptaoxa azapentacosan-25oic acid (1.083 g, 2.47 mmol, Intermediate OF), HATU (939.1 mg, 2.47 mmol), and DIPEA(693.4 mg, 5.4 mmol) at rt. The reaction mixture was stirred rt for 1 h. The reaction mixture was diluted with water, then extracted with EA (100 mL x 2). The combined organic layer was washed with brine (50 mLx 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH = 0%-10%) to give the desired compound (1.4 g, 76.5 %) as a colorless oil. LC-MS (ESI+): m/z 852.6 (M+H)+.

[002940] Step 2 - (2S,4R)-l-((S) amino (tert-butyl) oxo-6,9,12,15,18,21-hexaoxa-3azatricosan-l-oyl) hydroxy-N-(4-(4-methylthiazol yl)benzyl)pyrrolidine carboxamide [002941] A solution of tert-butyl ((S) ((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-23,23-dimethyl oxo-3,6,9,12,15,18-hexaoxa21-azatetracosyl)carbamate (1.4 g, 1.65 mmol) in dioxane (4 N HCI in dioxane, 20 mL) was stirred rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified via reverse phase column chromatography (H2O (0.1 % formic acid) /CH3CN = 0% -100%) to give the desired FA salt compound (545.1 g, 43.99 %) as a colorless oil. 1HNMR (400 MHz, DM SO-0/6) δ 8.88 (s, IH), 7.49 - 7.38 (m, 4H), 4.70 (s, IH), 4.59 - 4.48 (m, 3H), 4.36 (dd, J = 15.2, 3.4 Hz, IH), 4.09 (s, 2H), 3.83 (dt, J = 11.0, 7.4 Hz, 2H), 3.74 (dd, J = 6.4, 3.8 Hz, 2H), 3.72 - 3.60 (m, 20H), 3.13 (dd, J = 6.4, 3.9 Hz, 2H), 2.47 (s, 3H), 2.30 - 2.20 (m, IH), 2.09 (ddd, J = 13.3, 9.2, 4.4 Hz, IH), 1.05 (s, 9H). LC-MS (ESI+): m/z 752.4 (M+H)+.

[002942] (2S,4R)-l-[(2S) [[2-[2-[2-[2-(2-aminoethoxy)ethoxy] ethoxy] ethoxy] acetyl] amino] yl)phenyl] methyl] pyrrolidine carboxamide (Intermediate ME)

1046

ΛΝ

[002943] (2S,4R)-l-[(2S) [[2-[2-[2-[2-(2-aminoethoxy)ethoxy] ethoxy]ethoxy]acetyl]amino] -3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4-methylthiazol-5yl)phenyl]methyl]pyrrolidine carboxamide was synthesized as described for Intermediate MD, using 2,2-dimethyl oxo-3,8,ll,14,17-pentaoxa azanonadecan oic acid (Intermediate EN) as the acid which coupled with Intermediate G in the first step. 1H NMR (400 MHz, DMSO-6/6) δ 8.99 (s, IH), 8.61-8.58 (t, J = 6.0 Hz, IH), 7.79 (s, 3H), 7.51-7.38 (m, 5H), 4.58-4.55 (d, J = 9.6 Hz, IH), 4.45-4.23 (m, 4H), 3.98 (s, 2H), 3.69-3.51 (m, 16H), 2.99-2.95 (m, 2H), 2.44 (s, 3H), 2.09-2.04 (m, IH), 1.93-1.87 (m, IH), 0.95 (s, 9H). LC-MS (ESI+): m/z 664.2 (M+H)+.

[002944] l-Methyl (oxazole carbonylamino)Dyrazole carboxylic acid (Intermediate MF)

KQ

LiOH, H2O, MeOH, THF

[002945] Step 1 - Methyl l-methyl (oxazole carbonylamino)pyrazole carboxylate

1047

[002946] To a solution of methyl 4-amino-l-methyl-pyrazole carboxylate (100 mg, 645 umol, Intermediate KQ) and oxazole carboxylic acid (72.9 mg, 645 umol, CAS# 23012 7) in DMF (2 mL) was added DIPEA (333 mg, 2.58 mmol) and HATU (294 mg, 773 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the mixture was quenched with water (30 mL), filtered and the filter cake was dried in vacuo to give the title compound (100 mg, 62% yield) as a white solid. LC-MS (ESI+) m/z 251.2 (M+H)+.

[002947] Step 2 - l-Methyl (oxazole carbonylamino)pyrazole carboxylic acid

[002948] To a solution of methyl l-methyl (oxazole carbonylamino) pyrazole-3carboxylate (100 mg, 400 umol) in a mixed solvent of THF (2 mL), MeOH (1 mL) and H2O (0.4 mL) was added LiOH (47.9 mg, 2.00 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was acidified with IN aq.HCl to pH = 4-6, then stirred and filtered. The filter cake was dried in vacuo to give the title compound (50 mg, 53% yield) as a white solid. LC-MS (ESI+) m/z 237.1 (M+H)+.

[002949] 32(42(32Απ2η02Γ0211)ζ32Π16&#943;11χ12220Χ02Β6η2&#912;Π1&#912;&#940;320121-χ11Ε&#938;Ε£η&#940;&#912;η622262&#940;&#912;0η6

MG

[002950] Step 1 - Tert-butyl N-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1prop ynyl1 carbamate

[002951] To a mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6di one (150 mg, 444 umol, Intermediate HP), tert-butyl N-prop ynyl carbamate (172 mg, 1.11 mmol) in DMF (2.5 mL) was added TEA (808 mg, 7.98 mmol), Cui (25.3 mg, 133 umol), Pd(PPh3)2C12 (93.4 mg, 133 umol) under N2. The reaction mixture was stirred at 80 °C for 12 hrs. On completion, the reaction mixture was poured into water (10 mL). The aqueous phase was then

1048 extracted with ethyl acetate (2 X 20 mL). The combined organic phase was washed with brine (2 X 25 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=3:l) to give the title compound (96 mg, 52% yield) as brown oil. LC-MS (ESI+) m/z 357.2 (M-55)+.

[002952] Step 2- Tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1propyl1 carbamate

[002953] To a solution of tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynyl]carbamate (112 mg, 272 umol) in THF (5 mL) was added Pd/C (543 umol, 20 wt%) and Pd(OH)2/C (543 umol, 20 wt%) under N2. The suspension was degassed under vacuum and purged with H2 gas 3 times. The mixture was stirred (15 Psi) at rt for 12 hours under H2. On completion, the mixture was filtered and concentrated in vacuo to give the title compound (112 mg, 91% yield) as a white solid. LC-MS (ESI+) m/z 439.3 (M + Na) +.

[002954] Step 3- 3-[4-(3-Aminopropyl) methyl oxo-benzimidazol-l-yl1piperidine-2,6di one

[002955] To a solution of tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propyl] carbamate (112 mg, 269 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 134 uL). The mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo to get the title compound (92 mg, 97% yield, HC1) as a white solid. LC-MS (ESI+) m/z 217.2 (M+Na)+.

[002956] (S) hvdroxv ((S) (2-methoxvacetamido)-3,3-dimethylbutanovl)-N-((R)l,2,3^4-tetrahvdronaDhthalen-l-vl)-l,2,3^4-tetrahvdroisoquinoline carboxamide (Intermediate MH)

1049

ΜΗ

[002957] Step 1 - (S) hydroxy-6,8-diiodo-L2,3,4-tetrahydroisoquinoline carboxylic acid hydrochloride

[002958] To concentrate HCI (780 mL) was added (S) amino (4-hydroxy-3,5diiodophenyl)propanoic acid (65 g, 150 mmol, CAS# 18835 1), CH2O (37 % inH2O) andDME (65 mL). The mixture was heated to 72 °C slowly, and then stirred vemight. To the mixture was added another 20 mL of CH2O (37 % in H2O), and the reaction was stirred for another 4 h at 72 °C. The mixture was cooled to 0 °C and filtered. The filter cake was washed with DME (50 mL) give (S) hydroxy-6,8-diiodo-l,2,3,4-tetrahydroisoquinoline carboxylic acid hydrochloride HCI salt (32 g, 72 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-t/6) δ 9.89 (s, IH), 9.69 (s, IH), 7.73 (s, IH), 4.34-4.30 (dd, J = 4.8 Hz, J = 11.2 Hz, IH), 4.14-4.00 (dd, J = 16.4 Hz, J = 40 Hz, 2H), 3.24-3.18 (m, IH), 3.09-3.02 (m, IH). LC-MS (ESI+): m/z 482.5 (M+H)+.

[002959] Step 2 (S) (tert-butoxvcarbonvl) hydroxy-6,8-diiodo-L2,3,4

1050 tetrahydroisoquinoline carboxylic acid

[002960] A mixture of (S) hydroxy-6,8-diiodo-l,2,3,4-tetrahydroisoquinoline-3carboxylic acid hydrochloride (20 g, 41.6 mmolO, (Boc)2O (13.6 g, 62.4 mmol), TEA(16.8 g, 166 mmol), H2O (40 mL) and DMF (300 mL) was stirred overnight at rt. To the mixture was added H2O (200 mL), and the solution was washed with EA (200 mL). The aqueous layer adjusted with 1 N HCI to pH < 7, then extracted with EA (300 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by column to give (S) (tertbutoxycarbonyl) hydroxy-6,8-diiodo-l,2,3,4-tetrahydroisoquinoline carboxylic acid (15.5 g, 68 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-/) δ 12.77 (s, IH), 9.46 (s, IH), 7.64 (s, IH), 4.83-4.67 (m, IH), 4.49-4.39 (m, IH), 4.21-4.17 (d, J = 16.8 Hz, IH), 3.05-3.04 (d, J = 4 Hz, 2H), 1.47-1.40 (d, J = 24.4 Hz, 9H).

[002961] Step 3: (S) (tert-butoxvcarbonyl ) hydroxy-l .2.3.4-tetrahydroisoquinoline-3carboxylic acid

[002962] A mixture of (S) (tert-butoxycarbonyl) hydroxy-6,8-diiodo-l,2,3,4tetrahydroisoquinoline carboxylic acid (7 g, 12.8 mmol), Pd/C (10 wt%, 1.4 g), TEA (2.9 g, 28.3 mmol) and MeOH (100 mL) was stirred for overnight at rt under N2. The mixture was filtered to remove Pd/C, concentrated to dry, then H2O (100 mL) was added and the mixture was washed with EA (100 mL). The aqueous layer was adjusted with IN HCI to pH < 7, then extracted with EA (300 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give (S)-2(tert-butoxycarbonyl) hydroxy-l,2,3,4-tetrahydroisoquinoline carboxylic acid (3 g, 80 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-t/6) δ 12.58 (s, IH), 9.26 (s, IH), 6.97 (t, J = 8.4 Hz, IH), 6.58-6.52 (m, 2H), 4.83-4.25 (m, 3H), 3.01-2.96 (m, 2H), 1.45-1.39 (d, J = 26.4 Hz, 9H). LC-MS (ESI+): m/z 294.4 (M+H)+.

[002963] Step 4 - (S)-tert-butyl7-hydroxy (((R)-L2,3,4-tetrahydronaphthalen-lyl )carbamoyl )-3.4-dihy droisoquinoline-2(lH)-carboxylate

[002964] To a mixture of (S) (tert-butoxycarbonyl) hydroxy- 1,2,3,4tetrahydroisoquinoline carboxylic acid (32 g, 109 mmol) and (R)-l,2,3,4tetrahydronaphthalen amine (19.3 g, 131 mmol, CAS# 23357 2) in DMF (150 mL) was added HATU (54 g, 142 mmol) and DIPEA (42 g, 328 mmol), and the mixture was stirred at rt for 15 min. The solution was then poured into water(1500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was washed with brine (500 mL x 3), dried over Na2SO4, filtered,

1051 concentrated in vacuo and purified via column chromatography (Petroleum ether / EtOAc= 4/1) to give the title compound (40.2 g, 86.9 % yield) as a white solid. LC-MS (ESI+): m/z 423.1 (M+H)+

[002965] Step 5 - (S) hydroxy-N-((R)-L2,3,4-tetrahydronaphthalen-l-yl)-L2,3,4tetrahydroisoquino line -3 -carboxamide hydrochloride

[002966] To a mixture of (S)-tert-butyl7-hydroxy (((R)-l,2,3,4-tetrahydronaphthalen-l-yl) carbamoyl) -3,4-dihy droisoquinoline-2(lH)-carboxylate (44 g, 104 mmol) in THF (300 mL) was added 4N HCI in dioxane(300 mL), and the mixture was stirred at rt overnight. The solution was concentrated under reduced pressure to give the crude product, which was recrystallized by EAto give the title compound (33.3 g, 82.0 % yield) as a white solid. LC-MS (ESI+): m/z 323.1 (M+H)+. [002967] Step 6 - tert-butyl ((S)-l-((S) hydroxy (((R)-L2,3,4-tetrahydronaphthalen-l-yl) carbamoyl) -3,4-dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)carbamate

[002968] To a mixture of (S) hydroxy-N-((R)-l,2,3,4-tetrahydronaphthalen-l-yl) -1,2,3,4tetrahydroisoquinoline carboxamidehydrochloride(33.3 g, 92.8 mmol) and (S) ((tert- butoxy carbonyl)amino)-3,3-dimethylbutanoic acid (22.5, 97.4 mmol, CAS# 62963 9) in DMF (400 mL) was added HATU (42.3 g, 111.3 mmol) and DIPEA (48 g, 371 mmol), and the mixture was stirred at rt for 1.5 h. The solution was then poured into water (2500 mL) and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layer was washed with brine (500 mL x 3), dried over Na2SO4, filtered, concentrated in vacuo and purified via column chromatography (Petroleum ether/EtOAc= 2 / 1) to give the title compound (21.5 g, 43.9 % yield) as a white solid. LC-MS (ESI+): m/z 536.2 (M+H)+.

[002969] Step 7 - (S) ((S) amino-3,3-dimethylbutanoyl) hydroxy-N-((R)-L2,3,4tetrahydronaphthalen-l-yl)-L2,3,4-tetrahydroisoquinoline carboxamide hydrochloride

[002970] To a mixture of tert-butyl ((S)-l-((S) hydroxy (((R)-l,2,3,4tetrahydronaphthalen-l-yl) carbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-loxobutan yl)carbamate (21.5 g, 40 mmol) in THF (200 mL) was added 4N HCI in dioxane(200 mL), and the mixture was stirred at rt overnight. The solution was then poured into aq.NaHCO3 (1000 mL), and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layer was washed with brine (500 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound as the HCI salt (17 g, 97 % yield) as a white solid. LC-MS (ESI+): m/z 436.1 (M+H)+.

1052

[002971] Step 8 - (S) hydroxy ((S) (2-methoxyacetamido)-3,3-dimethylbutanoyl)-N((R)-L2,3,4-tetrahydronaphthalen-l-vl)-L2,3,4-tetrahydroisoquinoline carboxamide

[002972] To a mixture of (S) ((S) amino-3,3-dimethylbutanoyl) hydroxy-N- ((R)1,2,3,4- tetrahy dronaphthalen-l-yl)-l,2,3,4-tetrahydroisoquinoline carboxamide hydrochloride (14.4 g, 33 mmol) and 2-methoxyacetic acid (2.97 g, 131 mmol) in DMF (120 mL) was added HATU (15 g, 39.6 mmol) and DIPEA (6.4 g, 49.5 mmol), and the mixture was stirred at rt for 1 h. The solution was then poured into water (1500 mL), and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layer was washed with brine (500 mL x 3), dried over Na2SO4, filtered, concentrated in vacuo and purified via column chromatography (Petroleum ether / EtOAc= 1 / 1) to give the title compound (14 g, 83.8 % yield) as a white solid. LC-MS (ESI+): m/z 508.2 (M+H)+.

[002973] l-methvl [[2-(4-pvridvl)oxazole carbonvl]amino]pvrazole carboxylic acid (Intermediate MI)

[002974] Step 1 - Methyl l-methyl rr2-(4-pyridvl)oxazole carbonyl1amino1pyrazole-3carboxylate

[002975] A mixture of methyl 4-amino-l-methyl-pyrazole carboxylate (500 mg, 3.22 mmol, Intermediate KQ), 2-(4-pyridyl)oxazole carboxylic acid (612 mg, 3.22 mmol, Intermediate ED), HATU (1.47 g, 3.87 mmol), and DIPEA (1.25 g, 9.67 mmol) in DMF (10 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at rt for 2 hours under N2 atmosphere. On completion, the mixture was quenched with water (50 mL), filtered and the filter cake was dried in vacuo to give the title compound (900 mg, 85% yield) as white solid. LC-MS (ESI+) m/z 328.2 (M+H)+.

[002976] Step 2 - l-methyl rr2-(4-pyridyl)oxazole carbonyl1amino1pyrazole-3carboxylic acid

[002977] To a solution of methyl l-methyl [[2-(4-pyridyl) oxazole carbonyl] amino]

1053 pyrazole carboxylate (900 mg, 2.75 mmol) in H2O (4 mL) and THF (20 mL) was added LiOH (32 mg, 13.7 mmol). The mixture was stirred at rt for 4 hours. On completion, the mixture was adjusted to pH = 6 with IN aq.HCl, filtered and the filter cake was dried in vacuo to give the title compound (600 mg, 69% yield) as white solid. LC-MS (ESI+) m/z 314.1 (M+H)+.

[002978] [4-[(4-Tert-butoxvcarbonvlmorDholin vl)methoxvmethvl]Dhenyl]boronic acid (Intermediate MJ)

[002979] Step 1 - Tert-butyl 2-r(4-bromophenvl)methoxymethyl1morpholine carboxylate [002980] To a mixture of l-bromo (bromo1n ethyl )benzene (10.3 g, 41.4 mmol, CAS# 3433 5), tert-butyl 2-(hydroxymethyl)morpholine carboxylate (4.50 g, 20.7 mmol, CAS# 135065 9), TBAI (0.80 g, 2.07 mmol) in DMF (80 mL) was added NaH (1.70 g, 41.4 mmol, 60% oil dispersion) at 0 °C. The mixture was then stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The mixture was poured into a solution of saturated sodium bicarbonate (60 mL) and extracted with ethyl acetate (2 X 80 mL). The combined organic phase was washed with brine (2 X 80 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo at 45°C. The residue was purified by silica gel chromatography (petroleum ether : ethyl acetate = 20 : 1) to give the title compound (4.80 g, 61% yield) as a brown oil. 1H NMR (400 MHz, CDCh) δ 7.47 (d, J= 8.4 Hz, 2H), 7.23 - 7.18 (m, IH), 7.21 (d, J= 8.4 Hz, IH), 4.51 (s, 2H), 3.90 (d, J= 10.4 Hz, 3H), 3.64 - 3.43 (m, 4H), 2.94 (s, IH), 2.74 (s, IH), 1.47 (s, 9H).

[002981] Step 2 - Tert-butyl 2 (4.4.5.5-tetramethyl-L3.2-dioxaborolan-2yl)phenvl1methoxvmethyl1 morpholine carboxylate

[002982] To a mixture of tert-butyl 2-[(4-bromophenyl)methoxymethyl]morpholine-4carboxylate (460 mg, 11.9 mmol), 4,4,5,5-tetramethyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-l,3,2-dioxaborolane (363 mg, 14.3 mmol) in dioxane (50 mL) was added Pd(dppf)C12

1054 (972mg, 1.19 mmol) and KOAc (234 mg, 23.8 mmol). The reaction mixture was stirred at 100 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (480 mg, 93% yield) as brown oil. 1H NMR (400 MHz, CDCh) δ 7.72 (d, J= 7.8 Hz, 2H), 7.26 (d, J= 7.8 Hz, 2H), 4.51 (s, 2H), 3.83 (d, J= 8.8 Hz, 3H), 3.52 - 3.36 (m, 4H), 2.86 (s, IH), 2.66 (t, J = 12.0 Hz, IH), 1.39 (s, 9H), 1.27 (s, 12H).

[002983] Step 3:r4-r(4-Tert-butoxycarbonylmorpholin-2yl)methoxymethyl1phenyl1boronic acid

[002984] To a mixture of tert-butyl 2-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl]methoxymethyl] morpholine carboxylate (4.80 g, 11.1 mmol) in THF (40 mL) and H2O (8 mL) was added NaIO4 (7.10 g, 33.3 mmol). After that, to the reaction mixture was added 4M HC1 (7.4 mL) and the mixture was stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.50 g, 38% yield) as brown oil. 1H NMR (400MHz, DMSO-Y) δ 8.02 (s, 2H), 7.77 (d, 8.0 Hz, 2H), 7.28 (d, J= 7.9 Hz, 2H), 4.50 (s, 2H), 3.90 - 3.74 (m, 2H), 3.73 - 3.64 (m, IH),

3.53 - 3.37 (m, 7H), 1.41 (s, 9H).

[002985] Tert-butyl 2-[[4-(4-amino carbamovl-pyrazol-lvDphenyl] methoxymethyl] morpholine carboxylate (Intermediate MK)

[002986] Step 1 - Tert-butyl 2-rr4-(3-methoxycarbonyl nitro-pyrazol-l yl)phenyl1methoxymethyl1 morpholine carboxylate

[002987] To a mixture of methyl 4-nitro-lH-pyrazole carboxylate (0.80 g, 4.70 mmol,

1055

CAS# 170487 4), [4-[(4-tert-butoxycarbonylmorpholin yl)methoxymethyl]phenyl]boronic acid (1.50 g, 4.27 mmol, Intermediate MJ) in DCM (20 mL) was added pyridine (1.35 g, 17.1 mmol) and Cu(0Ac)2 (1.16 g, 6.41 mmol) under oxygen, and the mixture was stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.10 g, 54% yield) as brown oil. 1HNMR (400MHz, DMSO-» δ 9.74 (s, IH), 7.93 (s, IH), 7.52 (s, IH), 7.10 (s, IH), 6.73 (d, J= 8.4 Hz, IH), 4.60 4.57 (m, IH), 4.58 (s, IH), 4.35 (s, IH), 4.03 (q, J= 7.2 Hz, IH), 3.95 (s, 3H), 3.82 (d, J= 8.8 Hz, 2H), 3.70 (d, J= 12.4 Hz, IH), 3.48 - 3.36 (m, 4H), 1.41 (s, 9H).

[002988] Step 2:Tert-butyl 2-[[4-(3 -carbarn oyl nitro-pyrazol-1 yl)phenyl1methoxymethyl1morpholine carboxylate

[002989] To a sealed tube was added a solution of tert-butyl 2-[[4-(3-methoxycarbonyl-4nitro-pyrazol-l-yl) phenyl] methoxymethyl]morpholine carboxylate (1.10 g, 2.31 mmol), NH3.H2O (971 mg, 6.93 mmol, 25% solution) in THF (10 mL). The mixture was stirred at 80 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (840 mg, 79% yield) as brown oil. LC-MS (ESI+) m/z 484.1 (M+Na)+.

[002990] Step 3:Tert-butyl 2-rr4-(4-amino carbamovl-pyrazol-lyl)phenyl1methoxymethyl1morpholine carboxylate

[002991] To a mixture of tert-butyl 2-[[4-(3-carbamoyl nitro-pyrazol-lyl)phenyl]Methoxymethyl] morpholine carboxylate (300 mg, 650 umol) in MeOH (3 mL) was added Pd/C (150 mg, 1.30 mmol) under H2 (15 Psi), and the mixture was stirred at rt for 0.2 hr. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (275 mg, 98% yield) as brown oil. LC-MS (ESI+) m/z 454.1 (M+Na)+.

[002992] [4-[(l-Tert-butoxvcarbonvl DiDeridvl)methoxvmethvl]Dhenyl]boronic acid (Intermediate ML)

<td> ׳Ay־Br 1 TBAI, NaH, DMF 1( ΌΗ Boc 0ΆΑ NalO4, THF, H2O Y» II II I *A A N 1 1 Boc Boc</td><td> »Br J Pd(dppf)2CI2, KOAc, dioxane OH aAqh ML</td>

1056

[002993] Step 1 - Tert-butyl 2-r(4-bromophenvl)methoxymethyl]morpholine carboxylate [002994] To a mixture of l-bromo (bromom ethyl )benzene (1.15 g, 4.60 mmol, CAS# 3433 5), tert-butyl 2-(hydroxymethyl)morpholine carboxylate (0.50 g, 2.30 mmol, CAS# 157634 9) and TBAI (85.0 mg, 0.23 mmol) in DMF (10 mL) was added NaH (184 mg, 4.60 mmol, 60% oil dispersion) at 0 °C. The mixture was stirred at rt for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The mixture was poured into a solution of saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic phase was washed with brine (2X30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo at 45 °C. The residue was purified by silica gel chromatography to give the title compound (554 mg, 62% yield) as brown oil. 1H NMR (400MHz, CDCh) δ 7.39 (d, J= 8.4 Hz, 2H), 7.13 (d, J= 8.4 Hz, 2H), 4.43 (s, 2H), 3.96 - 3.63 (m, 3H), 3.41 (dd, J = 4.8, 8.0 Hz, 4H), 2.94 - 2.59 (m, 2H), 1.39 (s, 9H).

[002995] Step 2 Tert-butvl2-rr4-(4A5,5-tetramethyl-L3,2-dioxaborolan-2vl)phenyl]methoxymethyl]piperi dine- 1-carboxylate

[002996] To a mixture of tert-butyl 2-[(4-bromophenyl)methoxymethyl]piperidine-lcarboxylate (5.00 g, 13.0 mmol), 4,4,5,5-tetramethyl (4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)-l,3,2-dioxaborolane (3.30 g, 13.0 mmol) in dioxane (50 mL) was added dioxane (50 mL) and KO Ac (2.55 g, 26.0 mmol) and Pd(dppf)C12.CH2C12 (1.06 g, 1.30 mmol). The reaction mixture was stirred at 100 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.20 g, 57% yield) as brown oil. 1HNMR (400MHz, CDCh) δ 7.88 - 7.77 (m, 2H), 7.41 - 7.33 (m, 2H), 4.65 - 4.53 (m, 3H), 3.99 (d, J= 10.8 Hz, IH), 3.61 - 3.52 (m, IH), 3.63 - 3.47 (m, IH), 2.85 - 2.65 (m, IH), 1.90 - 1.72 (m, IH), 1.88 - 1.71 (m, IH), 1.66 - 1.53 (m, 3H), 1.47 (s, 9H), 1.37 (s, 12H).

[002997] Step 3 - r4-r(l-Tert-butoxycarbonyl piperidyl)methoxymethyl]phenyl]boronic acid

[002998] To a mixture of tert-butyl 2-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl]methoxymethyl] piperidine carboxylate (3.20 g, 7.42 mmol) in THF (60 mL) andH2O (12 mL) was added NaIO4 (4.76 g, 22.2 mmol, 1.2 mL). Then HCI (3 M, 4.95 mL) was added to the mixture. The reaction mixture was stirred at rt for 12 hrs. On completion, the mixture was diluted with H2O (30 mL), and extracted with EA (3 X 30 mL). The organic layers were washed with brine (3 X 20mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The

1057 residue was purified by column chromatography to give the title compound (1.50 g, 58% yield) as brown oil. 1H NMR (400MHz, DMSO-t/6) δ 8.02 (s, 2H), 7.76 (d, J= 8.0 Hz, 2H), 7.27 (d, J= 8.0 Hz, 2H), 4.58 - 4.44 (m, 2H), 4.30 (s, IH), 3.82 (d, J= 12.4 Hz, IH), 3.58 - 3.47 (m, 2H), 3.35 (s, 3H), 2.79 - 2.63 (m, IH), 1.70 (d, J = 7.2 Hz, IH), 1.59 - 1.41 (m, 4H), 1.37 (s, 9H), 1.32 - 1.21 (m, IH).

[002999] Tert-butyl 2-[[4-(4-amino carbamovl-pyrazol-lyl)phenyl] methoxy methyl] piperidine- 1-carboxylate (Intermediate MM)

Boc Boc

MM

[003000] Step 1 - Tert-butyl 2-rr4-(3-methoxycarbonvl nitro-pyrazol-lyl)phenyl1methoxymethyl1piperidine- 1-carboxylate

[003001] To a mixture of [4-[(l-tert-butoxycarbonyl-2piperidyl)methoxymethyl]phenyl]boronic acid (1.50 g, 4.30 mmol, Intermediate ML), and methyl 4-nitro-lH-pyrazole carboxylate (0.70 g, 4.08 mmol, CAS# 170487 4) in DCM (20 mL) was added pyridine (1.36 g, 17.2 mmol) and Cu(OAc)2 (1.17 g, 6.44 mmol) under oxygen. The reaction mixture was stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.50 g, 73% yield)) as a brown oil. 1HNMR (400MHz, DMSO-t/6) δ 9.75 (s, IH), 7.94 (d, J= 8.8 Hz, 2H), 7.55 - 7.50 (m, 2H), 4.64 - 4.51 (m, 2H), 4.41 - 4.29 (m, 2H), 3.95 (s, 3H), 3.63 - 3.50 (m, 2H), 3.45 (d, J = 7.6 Hz, IH), 1.61 - 1.42 (m, 6H), 1.38 (s, 9H).

[003002] Step 2:Tert-butyl 2-[[4-(3 -carbarn oyl nitro-pyrazol-1 vl)phenvl1methoxymethyl1piperidine-l- carboxylate

[003003] To a sealed tube was added a mixture of tert-butyl 2-[[4-(3-methoxycarbonyl-4nitro-pyrazol-l-yl) phenyl]methoxymethyl]piperidine carboxylate (1.50 g, 3.16 mmol) in

1058

MeOH (10 mL). Then NH3.H2O (1.33 g, 9.48 mmol, 1.46 mL) was added and the mixture was stirred at 80 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (850 mg, 58% yield) as brown oil. LC-MS (ESI+) m/z 482.2 (M+Na)+.

[003004] Step 3:Tert-butyl 2-rr4-(4-amino carbamoyl-pyrazol-lyl)phenyl1methoxymethyl1piperidine- 1-carboxylate

[003005] To a mixture of tert-butyl 2-[[4-(3-carbamoyl nitro-pyrazol-lyl)phenyl]methoxymethyl]piperidine- 1-carboxylate (300 mg, 653 umol) in MeOH (3 mL) was added Pd/C (120 mg, 652.89 umol) under H2 (15 Psi). The mixture was stirred at rt for 0.3 hour. On completion, the reaction mixture was fdtered and concentrated in vacuo to give the title compound (265 mg, 94% yield) as brown oil. LC-MS (ESI+) m/z 452.1 (M+Na)+.

[003006] 4 |2 [2-(2-Aminoethoxv)ethoxy| ethoxy] ethoxy] prop-l-vnyl] (2,6dioxo piperidyl) isoindoline-l,3-dione (Intermediate MN)

[003007] To a mixture of tert-butyl N-[2-[2-[2-[2-[3-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]prop- 2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (300 mg, 510 umol, synthesized via Step 1 of Intermediate HA) in DCM (3 mL) was added HCI/dioxane (4 M, 0.3 mL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (245 mg, 91% yield) as a brown solid. LC-MS (ESI+) m/z 488.3 (M+H)+.

[003008] 2-(2-Methvl pyridvl)oxazole carboxvlic acid (Intermediate MO)

1059

tris-o-tolylphosphane Pd(OAc)2, Cs2CO3, DMF

[003009] Step 1 - Ethyl 2-(2-methylpyridin yl)oxazole carboxylate

[003010] To a solution of 4-bromo methyl-pyridine (1.50 g, 8.72 mmol, from CAS# 22282 1) and ethyl oxazole carboxylate (1.23 g, 8.72 mmol, from CAS# 170487 4) in DMF (40 mL) was added tris-o-tolylphosphane (531 mg, 1.74 mmol), Pd(OAc)2 (196 mg, 872 umol) and Cs2CO3 (5.68 g, 17.4 mmol). The reaction mixture was stirred at 70 °C for 12 hours under nitrogen. On completion, the reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.10 g, 44% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 8.65 (d, J= 5.2 Hz, IH), 8.31 - 8.36 (m, IH), 7.86 (s, IH), 7.75 (d, J = 5.2 Hz, IH), 4.44 (q, J = 7.2 Hz, 2H), 2.64 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); LC-MS (ESI+) m/z 233.1 (M+H)+.

[003011] Step 2 - 2-(2-Methvl pvridvl)oxazole carboxylic acid

[003012] To a solution of ethyl 2-(2-methyl pyridyl)oxazole carboxylate (1.10 g, 4.74 mmol) in THF (20 mL) was added LiOH*H2O (795 mg, 19.0 mmol) in H2O (4 mL). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was filtered and the filter cake was dissolved in water (20 mL). The solution was acidified to pH = 4 and filtered. The filter cake was washed with water (2X5 mL) and dried in vacuo. The residue was purified by prep-HPLC to give the title compound (600 mg, 52% yield) as a white solid.

[003013] 4-[3-Carbamovl [[2-(2-methyl Dvridvl)oxazole-4carbonyllaminolpyrazol-l-yllbenzoic acid (Intermediate MP)

1060

MP

[003014] Step 1 - Methyl4-r3-carbamoyl rr2-(2-methyl pyridyl)oxazole-4carbonyl1amino1pyrazol-l-yl1 benzoate

[003015] To a solution of 2-(2-methyl pyridyl)oxazole carboxylic acid (200 mg, 831.11 umol, HCI, Intermediate MO) and methyl 4-(4-amino carbarnoyl-pyrazol-l-yl)benzoate (173 mg, 665 umol, Intermediate CL) in DMF (20 mL) was added DIPEA (322 mg, 2.49 mmol) and HATU (379 mg, 997 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was quenched with water (5 mL) and filtered. The filter cake was washed with water (3X3 mL) and dried in vacuo to give the title compound (200 mg, 53% yield) as a white solid. LC-MS (ESI+) m/z 447.3 (M+H)+.

[003016] Step 2:4-r3-Carbamoyl rr2-(2-methyl pyridyl)oxazole-4carbonyl1amino1pyrazol-l-yl1benzoic acid

[003017] To a solution of methyl 4-[3-carbamoyl [[2-(2-methyl pyridyl)oxazole-4carbonyl]amino]pyrazol- l-yl]benzoate (150 mg, 336 umol) in THF (20 mL) and MeOH (4 mL) was added LiOH H2O (42.3 mg, 1.01 mmol) in H2O (4 mL). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was poured into HCI (IN, 2mL) and concentrated in vacuo to give the title compound (200 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 433.2 (M+H)+.

[003018] 2-(2-Cvd0Dr0Dvl Dvridvl)0xaz01e carb0xylic acid (Intermediate MQ)

1061

tris-o-tolylphosphane

Pd(OAc)2, Cs2CO3, DMF

[003019] Step 1 - Ethyl 2-(2-cyclopropyl pyridyl)oxazole carboxylate

[003020] To a solution of 4-bromo cyclopropyl-pyridine (512 mg, 2.59 mmol, CAS# 1086381 3) and ethyl oxazole carboxylate (365 mg, 2.59 mmol, CAS# 170487 4) in DMF (5 mL) was added tris-o-tolylphosphane (157 mg, 517 umol), Pd(OAc)2 (58.0 mg, 259 umol) and Cs2CO3 (1.68 g, 5.17 mmol). The reaction mixture was stirred at 70 °C for 12 hours under nitrogen. On completion, the reaction mixture was diluted with EA (100 mL), poured into sat.NH4Cl (50 mL) and extracted with EA(3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 10/1 to 5/1) to give the title compound (380 mg, 55% yield) as a white solid. 1HNMR (400MHz, DM SO-0#) δ 8.57 (d, J= 4.8 Hz, IH), 8.33 (s, IH), 7.82 (s, IH), 7.67 (dd, 7= 1.6, 5.2 Hz, IH), 4.44 (q, 7= 7.2 Hz, 2H), 2.16 - 2.07 (m, IH), 1.42 (t, 7= 7.2 Hz, 3H), 1.12-1.02 (m, 4H). LC-MS (ESI+) m/z 259.1 (M+H)+.

[003021] Step 2 - 2-(2-Cyclopropyl pyridyl)oxazole carboxylic acid

[003022] To a solution of ethyl 2-(2-cyclopropyl pyridyl)oxazole carboxylate (370 mg, 1.43 mmol) in THF (20 mL) was added a solution of LiOH*H2O (150 mg, 3.57 mmol) in H2O (4 mL). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was quenched with 4 mL of HC1 (IN) and concentrated in vacuo to give the title compound (450 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 231.1 (M+H)+.

[003023] 2-(2-(2-Aminoethoxv)ethoxy)ethanol (Intermediate MR)

BocH N 0 H

HCI/dioxane, DCM

MR

[003024] To a solution of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (1.60 g, 6.42 mmol, from CAS# 139115 7 ) in DCM (10 mL) was added HCI/dioxane (4 M, 1.60 mL). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was

1062 concentrated in vacuo to give the title compound (1.19 g, 100% yield) as colorless oil.

[003025] 4-[2-[2-(2-Azidoethoxv)ethoxy|ethvlamino] (2.,6-dioxo-3DiDeridyl)isoindoline-l.,3-dione (Intermediate MS)

R

MS

[003026] Step 1:2-(2,6-Dioxopiperidin yl) ((2-(2-(2hydroxy ethoxy)ethoxy)ethyl)amino)isoindoline-1,3- dione

[003027] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (1.50 g, 5.43 mmol, Intermediate R) and 2-[2-(2-aminoethoxy)ethoxy]ethanol (1.01 g, 5.43 mmol, HC1, Intermediate MR) in DMF (5 mL) was added DIPEA (2.81 g, 21.7 mmol). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the reaction mixture was poured into sat.NaHCO3 (30 mL) and extracted with EA (3 X 100 mL). The combined organic layers were washed with brine (100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 1/1 to 0/1) to give the title compound (600 mg, 27% yield) as a yellow solid. LC-MS (ESI+) m/z 406.2 (M+H)+.

[003028] Step 2 - 2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethyl methanesulfonate

[003029] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-(2hydroxyethoxy)ethoxy]ethylamino]isoindoline -1,3-dione (100 mg, 247 umol) in DCM (5 mL) was added TEA (49.9 mg, 493 umol) and MsCI (37.0 mg, 323 umol) at 0 °C. The reaction mixture was then stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give title compound (130 mg, 100% yield) as a yellow solid. LC-MS (ESI+) m/z 484.2 (M+H)+.

1063

[003030] Step 3 - 4-r2-r2-(2-Azidoethoxy)ethoxy1ethylamino1 (2,6-dioxo-3piperidyl)isoindoline-L3-dione

[003031] To a solution of 2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy] ethyl methanesulfonate (60.0 mg, 124 umol) in DMF (3 mL) was added NaN3 (16.1 mg, 248 umol). The reaction mixture was stirred at 65 °C for 2 hours. On completion, the reaction mixture was poured into sat. NaHCO3 (30 mL) and extracted with DCM (2 X 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (60.0 mg, 100% yield) as a yellow solid. LC-MS (ESI+) m/z 453.2 (M+Na)+.

[003032] 4-Amino-l-DroD vnvl-Dvrazole carboxamide (Intermediate MT)

CJ MT

[003033] Step 1 - 4-Nitro-l-(prop yn-l-yl)-lH-pyrazole carboxamide

[003034] To a solution of 4-nitro-lH-pyrazole carboxamide (2.00 g, 12.8 mmol, Intermediate CJ) and 3-bromoprop yne (3.05 g, 25.6 mmol, 2.21 mL) in DMF (30 mL) was added K2CO3 (3.54 g, 25.6 mmol). The reaction mixture was stirred at 60 °C for 1 hour. On completion, the reaction mixture was diluted with EA (50 mL) and filtered, then the filtrate was concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 1/1 to 0/1) to give the title compound (1.30 g, 52% yield) as an off-white solid. 1H NMR (300 MHz, DMSO-76) δ 8.90 (s, IH), 8.07 (s, IH), 7.82 (s, IH), 5.14 (d, J= 2.4 Hz, 2H), 3.67 (t, J= 2.4 Hz, IH), 2.73 (s, IH).

[003035] Step 2 - 4-Amino-l-prop ynyl-pyrazole carboxamide

[003036] To a solution of 4-nitro-l-prop ynyl-pyrazole carboxamide (1.20 g, 6.18 mmol) in MeOH (30 mL) was added a solution of NH4C1 (1.65 g, 30.9 mmol) in H2O (10 mL) and Fe (1.73 g, 30.9 mmol). The reaction mixture was stirred at 80 °C for 12 hours under nitrogen. On completion, the reaction mixture was diluted with DCM (400 mL), stirred at rt for 10 min, then washed with brine (2 X 50 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (800 mg, 79% yield) as a light yellow solid.

[003037] 2-(2-Pr0D vn0xyeth0xv)ethanamine (Intermediate MU)

1064

BocHN

HCI

MU

[003038] To a mixture of tert-butyl N-[2-(2-prop ynoxyethoxy)ethyl]carbamate (2.50 g,

10.3 mmol, synthesized via Step 1 of Intermediate CQ) in DCM (20 mL) was added HCI/dioxane (4 M, 5.14 mL) and the reaction was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (1.80 g, 97% yield, HCI) as a brown solid. 1H NMR (400MHz, DMSOA) δ 8.27 (s, 2H), 4.14 (d, J= 2.4 Hz, 2H), 3.62 (t, J= 5.6 Hz, 2H), 3.59 - 3.54 (m, 4H), 3.45 (t, J = 2.4 Hz, IH), 2.91 (s, 2H).

[003039] 2-(26&#1524;-Dioxo piperidvl) [2-(2-prop-2vnoxvethoxv)ethylamino]isoindoline-l.,3-dione (Intermediate MV)

[003040] To a mixture of 2-(2-prop ynoxyethoxy)ethanamine (1.80 g, 10.0 mmol, HCI, Intermediate MU) in dioxane (30 mL) was added DIPEA (3.88 g, 30.0 mmol, 5.24 mL), and 2(2,6-dioxo piperidyl) fluoro-isoindoline-l,3- dione (2.77 g, 10.0 mmol, Intermediate R) into the mixture. The reaction mixture was stirred at 115°C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.10 g, 27% yield) as a brown solid. 1HNMR (400MHz, CDCh) δ 8.61 (s, IH), 7.49 (t, 7= 7.6 Hz, IH), 7.10 (d, 7= 7.2 Hz, IH), 6.93 (d, 7= 8.8 Hz, IH), 6.49 (t, 7= 5.6 Hz, IH), 4.98 - 4.89 (m, IH), 4.21 (d, 7= 2.4 Hz, 2H), 3.75 - 3.70 (m, 6H), 3.49 (q, 7= 5.6 Hz, 2H), 2.90 - 2.73 (m, 3H), 2.46 (t, 7= 2.4 Hz, IH), 2.18 - 2.06 (m, IH).

[003041] 4-(Azetidin ylamino) (2.,6-dioxo piperidvl)isoindoline-l.,3-dione (Intermediate MW)

1065

[003042] Step 1 - Tert-butyl 3-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-4yl1amin01azetidine-l- carboxylate

[003043] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (500 mg, 1.81 mmol, Intermediate R) and tert-butyl 3-aminoazetidine-l-carboxylate (374 mg, 2.17 mmol, CAS# 193269 2) in DMSO (20 mL) was added DIPEA (702 mg, 5.43 mmol). The reaction mixture was stirred at 90 °C for 15 hrs. On completion, the reaction mixture was filtered and acidified to pH = 5. The crude product was purified by reversed phase (0.1% HCI condition) to give the title compound (350 mg, 44% yield) as a yellow solid. 1H NMR (400MHz, DMSO-A) δ 11.12 (s, IH), 7.61 (t, J= 8.0 Hz, IH), 7.13 (d, J= 7.2 Hz, IH), 6.96 (d, J= 8.4 Hz, IH), 6.89 (d, J = 6.4 Hz, IH), 5.08 (dd, J = 5.2, 12.8 Hz, IH), 4.49 - 4.41 (m, IH), 4.19 - 4.23 (m, 2H), 3.80 3.84 (m, 2H), 2.95 - 2.84 (m, IH), 2.95 - 2.84 (m, IH), 2.65 - 2.60 (m, IH), 2.54 - 2.52 (m, IH), 2.09 - 1.99 (m, IH), 1.39 (s, 9H).

[003044] Step 2 - 4-(Azetidin ylamino) (2,6-dioxo piperidyl)isoindoline-L3-dione [003045] To a solution of tert-butyl 3-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]azetidine-l- carboxylate (430 mg, 1.00 mmol) in DCM (5 mL) was added HCl/dioxane (4 M, 5.12 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (430 mg, 100% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 329.0 (M+H)+.

[003046] 4- [[1- [2-[2-(2-aminoethoxv)ethoxy] ethyl] azetidin yl] amino] (2.,6-dioxo-3 piperidyl) isoindoline-l.,3-dione (Intermediate MX)

1066

HY

KOAc, NaBH(OAc)3, THF/DCM

[003047] Step 1 - Tert-butyl N-r2-r2-r2-r3-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin4-yl]amino] azetidin-1 -yl 1 ethoxy]ethoxy]ethyl]carbamate

[003048] To a solution of 4-(azetidin ylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (250 mg, 685 umol, Intermediate MW) and tert-butyl N-[2-[2-(2oxoethoxy)ethoxy]ethyl]carbamate (220 mg, 891 umol, Intermediate HY) in DCM (10 mL) and THF (20 mL) was added KOAc (135 mg, 1.37 mmol) and NaBH(OAc)3 (218 mg, 1.03 mmol). The reaction mixture was stirred at rt for 2 hrs. On completion, the reaction mixture was quenched with water (2 mL), and concentrated in vacuo. The crude product was purified by reversed phase (acidified condition: 0.1% FA) to give the title compound (270 mg, 66% yield) as yellow oil. 1H NMR (400MHz, DMSO-d6) δ 11.09 (s, IH), 7.72 - 7.54 (m, IH), 7.09 (d, J= 8.8 Hz, IH), 7.01 (d, J= 8.8 Hz, IH), 6.76 - 6.74 (m, IH), 6.61 (d, J= 6.8 Hz, IH), 5.07 (dd, /=5.2, 12.8 Hz, IH), 4.34 - 4.19 (m, IH), 3.70 (t, /= 6.8 Hz, 2H), 3.50 - 3.36 (m, 10H), 3.06 (q, /= 6.0 Hz, 2H), 3.00 - 2.96 (m, 2H), 2.92 - 2.84 (m, IH), 2.65 - 2.61 (m, 2H), 2.09 - 2.01 (m, IH), 1.37 (s, 9H); LC-MS (ESI+) m/z 560.1 (M+H)+.

[003049] Step 2 - 4-n&#1470;l-r2-r2-(2-aminoethoxy)ethoxy1ethyl1azetidin yl1amino1 (2,6dioxo piperidyl) isoindoline-L3-dione

1067

[003050] To a solution of tert-butyl N-[2-[2-[2-[3-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] azetidin-l-yl]ethoxy]ethoxy]ethyl]carbamate (270 mg, 483 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 121 uL). The reaction mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (239 mg, 100% yield, HC1 salt) as a yellow solid. LC-MS (ESI+) m/z 460.3 (M+H)+.

[003051] 5 |3 [2-(2-Aminoethoxv)ethoxy| ethyl]triazol yl] ethylamino] (2,6dioxo-S-piperidyl) isoindoline-l,3-dione (Intermediate MY)

DI PEA, DMSO

ID

NHBoc

Pentamethyl cyclopentane(PPh3)2RuCI, THF

HCI/dioxane, DCM

MY

[003052] Step 1 - 5-(But ynylamino) (2,6-dioxo piperidyl)isoindoline-L3-dione

[003053] To a mixture of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (650 mg,

2.35 mmol, Intermediate HX), but yn-l-amine (373 mg, HC1, CAS# 14044 4) in DMSO (10 mL) was added DIPEA (3.04 g, 23.5 mmol) and stirred at 130 °C for Ihr. On completion, the mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (2 X 20 mL). The combined organic phase was washed with brine (2X30 mL), dried with anhydrous Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l:l) to give the title compound (386 mg, 50% yield) as a brown solid; LC-MS (ESI+) m/z 326.0 (M+H)+.

[003054] Step 2 - Tert-butylN-r2-r2-r2-r5-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethyl1triazol-l-yl1ethoxy1ethoxy1ethyl1carbamate

1068

[003055] To a mixture of 5-(but ynylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (200 mg, 0.615 mmol), tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (506 mg, 1.84 mmol, Intermediate ID) in THF (5 mL) was added chlororuthenium( 1+); 1,2,3,4,5pentamethylcyclopenta-l,3-diene; triphenylphosphane (24.4 mg, 0.030 mmol). The mixture was stirred at 65 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=l:l) to give the title compound (210 mg, 54% yield) as a brown oil; LC-MS (ESI+) m/z 600.2 (M+H)+.

[003056] Step 3 - 5-r2-r3-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1triazol yl1ethylamino1-2(2,6-di oxo piperidyl) isoindoline-L3-dione

[003057] To a mixture of tert-butyl N-[2-[2-[2-[5-[2-[[2-(2, 6-dioxo piperidyl)-1,3-dioxoisoindolin yl] amino]ethyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (210 mg, 350 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 87.5 uL) and stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (185 mg, 98% yield, HCI) brown oil. LC-MS (ESI+) m/z 500.2 (M+H)+.

[003058] 2-(26&#1524;-Dioxo piperidvl) hvdroxv-isoindoline-l.,3-dione (Intermediate MZ) o

[003059] To a solution of 5-hydroxyisobenzofuran-l,3-dione (1.00 g, 6.09 mmol, CAS# 27550 0) and 3-aminopiperi dine-2,6-dione (1.05 g, 6.40 mmol, HCI) in HO Ac (20 mL) was added KO Ac (1.79 g, 18.3 mmol). The mixture was stirred at 90 °C for 6 hrs. On completion, the mixture was poured into ice water(100 mL), and solid was obtained and then filtered. The residue was washed with H2O (3 X 50 mL), dried in vacuo to give the title compound (1.40 g, 83% yield) as a light white solid. 1H NMR (400MHz, DMSO-76) δ 11.29 - 10.90 (m, 2H), 7.75 (d, J= 8.2 Hz, IH), 7.39 - 6.87 (m, 2H), 5.09 (dd, 7=5.4, 12.8 Hz, IH), 3.34 (s, IH), 2.96 - 2.82 (m, IH) , 2.69 2.58 (m, IH), 2.08 - 1.99 (m, IH).

[003060] 2-(26&#1524;-Dioxo piperidvl) prop vnoxv-isoindoline-l.,3-dione (Intermediatea NA)

1069

[003061] To a solution of 2-(2,6-dioxo piperidyl) hydroxy-isoindoline-l,3-dione (1.40 g, 5.11 mmol, Intermediate MZ) in DMF (20 mL) was added K2CO3 (847 mg, 6.13 mmol) and 3bromoprop yne (668 mg, 5.62 mmol, 484 uL). The mixture was stirred at 15 °C for 6 hrs. On completion, the residue was diluted with H2O (50 mL) and extracted with EA (3 X 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by reversed phase (FA condition) to give the title compound (0.700 g, 43% yield) as a light yellow solid. 1HNMR (400MHz, DMSO-t/6) δ 11.11 (s, IH), 7.89 (d, J = 8.4 Hz, IH), 7.53 (d, J = 2.4 Hz, IH), 7.41 (dd, J = 2.4, 8.4 Hz, IH), 5.14 (dd, J = 5.4, 12.8 Hz, IH), 5.07 (d, 7=2.0 Hz, 2H), 3.70 (t, 7= 2.4 Hz, IH), 3.41 - 3.35 (m, IH), 2.97 - 2.83 (m, IH), 2.65 - 2.52 (m, 2H), 2.11 - 2.01 (m, IH); LC-MS (ESI+) m/z 313.2 (M+H)+.

[003062] 5- [[1- [2-[2-(2-Aminoethoxv)ethoxy]ethyl]triazol yl]methoxy] (2.,6-dioxo

3-piperidyl) isoindoline-l.,3-dione (Intermediate NB)

ID

N H Boc θ

copper(ll) sulfate; sodium L-ascorbate water and tert-butanol

[003063] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ4-ΓΓ2-(2,6-&#940;&#943;οχο ρ&#943;ρ6Γ&#938;&#940;ν1) -L3-dioxo-isoindolin1070

-yl 1 oxym ethyl 1 tri azol -1 -y 11 ethoxy] ethoxy] ethyl 1 carb am ate

[003064] To a solution of 2-(2,6-dioxo piperidyl) prop ynoxy-isoindoline-l,3-dione (0.6 g, 1.92 mmol, Intermediate NA), CuSO4 (3.07 mg, 19.2 umol) and sodium;(2R) [(lS)-l,2dihydroxyethyl] hydroxy oxo -2H-furan 01ate (7.61 mg, 38.4 umol) in H2O (3 mL) and tBuOH (3 mL) was added tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (527.06 mg, 1.92 mmol, Intermediate ID). The mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was diluted with H2O (20 ml), extracted with EA (2 X 30ml), washed with brine (50ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reversed phase (FA condition) to give the title compound (0.800 g, 71% yield) as a yellow solid. 1H NMR (400MHz, DMS 0-76) δ 11.10 (s, IH), 8.25 (s, IH), 7.85 (d, J= 8.2 Hz, IH), 7.61 (s, IH), 7.45 (d, J= 8.2 Hz, IH), 6.72 (s, 2H), 5.38 (s, 2H), 5.17 - 5.09 (m, IH), 4.55 (s, 2H), 4.10 - 3.97 (m, 4H), 3.83 (s, 2H), 3.65 - 3.51 (m, 13H), 3.07 (d, J= 6.0 Hz, 4H), 2.88 (d, J= 13.6 Hz, IH), 2.70 - 2.57 (m, 4H), 1.38 (s, 9H).

[003065] Step 2 - 5-rr1-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1triazol yl1methoxy1 (2,6dioxo piperidyl) isoindoline-L3-dione

[003066] To a solution of tert-butyl N-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl) -1,3-dioxoisoindolin yl] oxymethyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (0.800 g, 1.36 mmol) in DCM (10 mL) was added HCl/dioxane (4 Μ, 1 mL).The mixture was stirred at rt for 30 minutes. On completion, the mixture was concentrated, to give the title compound (500 mg 70% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 487.3 (M+H)+.

[003067] 5-But vnoxv (2,6-dioxo DiDeridvl)isoindoline-l,3-dione (Intermediate

NC)

NC

[003068] To a mixture of 2-(2,6-dioxo piperidyl) hydroxy-isoindoline-l,3-dione (1.00 g,

3.65 mmol, Intermediate MZ) and but yn-l-ol (307 mg, 4.38 mmol, CAS# 927 2) in THF (10 mL) was added PPh3 (1.43 g, 5.47 mmol). Then DIAD (1.47 g, 7.29 mmol) was added into the mixture at 0 °C and the mixture was stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2) to give the title

1071 compound (568 mg, 48% yield) as a brown solid. LC-MS (ESI+) m/z 327.0 (M+H)+.

[003069] 5 13 [2-(2-aminoethoxv)ethoxy| ethyl] triazol yl] ethoxy] (2.,6-dioxo-3piperidyl) isoindoline-l.,3-dione (Intermediate ND)

ID

Pentamethyl cyclopentane(PPh3)2RuCI, THF

O

ND

[003070] Step 1 - Tert-butylN-r2-r2-r2-r5-r2-r2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1oxyethyl1 triazol-I&#1470;yl1ethoxy1ethoxy1ethyl1carbamate

[003071] To a mixture of 5-but ynoxy (2,6-dioxo piperidyl)isoindoline-l,3-dione (115 mg, 352 umol, Intermediate NC), tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (290 mg, 1.06 mmol, Intermediate ID) in THF (3 mL) was added chlororuthenium( 1+); 1,2,3,4,5pentamethylcyclopenta-l,3-diene;triphenylphosphane (14.0 mg, 17.6 umol). The mixture was stirred at 65 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2) to give the title compound (156 mg, 73% yield) as brown oil. LC-MS (ESI+) m/z 601.1(M+H)+.

[003072] Step 2 r2-r3-r2-r2-(2-aminoethoxy)ethoxy1ethyl1triazol yl1ethoxy1 (2,6dioxo piperidyl) isoindoline-L3-dione

[003073] To a mixture of tert-butyl N-[2-[2-[2-[5-[2-[2-(2,6-dioxo piperidyl)-l, 3-dioxoisoindolin yl] oxyethyl]triazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (156 mg, 259 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 129 uL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (135 mg, 96% yield, HCI) as brown oil. LC

1072

MS (ESI+) m/z 501.1 (M+H)+.

[003074] 5 12 [2-(2-Aminoethoxv)ethyl] piperazin-l-yl] ethoxy] ethylamino] (2.,6dioxo piperidyl)isoindoline-l,3-dione (Intermediate NE)

NHBoc

IM

NE

[003075] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ4-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-Ε3-&#940;&#912;οχοisoindolin yl1amino1 ethoxy1ethyl1piperazin-l-yl1ethoxy1ethyl1carbamate

[003076] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (250 mg, 905 umol, Intermediate HX) and tert-butyl N-[2-[2-[4-[2-(2-aminoethoxy)ethyl]piperazin-lyl]ethoxy]ethyl]carbamate (343 mg, 950 umol, Intermediate IM) in DMSO (8 mL) was added DIPEA (351 mg, 2.72 mmol). The reaction mixture was stirred at 130 °C for 13 hours. On completion, the reaction mixture was quenched with water (2 mL), concentrated in vacuo. The crude product was purified by reversed phase (acidified condition: 0.1% FA) to give the title compound (324 mg, 55% yield) as a yellow oil. LC-MS (ESI+) m/z 517.2 (M+H-100)+.

[003077] Step 2 - 5-r2-r2-r4-r2-(2-Aminoethoxy)ethyl1piperazin-l-yl1ethoxy1ethylamino12-(2,6-di oxo piperidyl)isoindoline-L3-dione

[003078] To a solution of tert-butyl N-[2-[2-[4-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]ethoxy]ethyl]piperazin-l-yl]ethoxy]ethyl]carbamate (350 mg, 534 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 133 uL). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound

1073 (290 mg, 98% yield) as a yellow solid. LC-MS (ESI+) m/z 517.2 (M+H)+.

[003079] 2-[2-[[2-(2.,6-Dioxo DiDeridvl)-l.,3-dioxo-isoindolin vl]amino]ethoxv]ethvl methanesulfonate (Intermediate NF)

DIPEA, DMSO

[003080] Step 1:2-(2,6-Dioxopiperidin yl) ((2-(2hydroxyethoxy)ethyl)amino)isoindoline-L3-dione

[003081] To a solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (500 mg,

1.81 mmol, Intermediate HX) and 2-(2-aminoethoxy)ethanol (210 mg, 2.00 mmol) in DMSO (10.0 mL) was added DIPEA (702 mg, 5.43 mmol). The reaction mixture was stirred at 130 °C for 15 hrs. On completion, the mixture was added H2O (10.0 mL) and extracted with DCM (3 X 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound (250 mg, 38% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.14 (s, IH), 7.62 (d, J= 8.4 Hz, IH), 7.01 (d, J= 2.0 Hz, IH), 6.79 (dd, J= 2.0, 8.4 Hz, IH), 5.05 (s, IH), 4.95 (dd, J = 5.2, 12.8 Hz, IH), 3.81 (d, J = 4.2 Hz, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.68 - 3.63 (m, 2H), 3.45 (t, J = 52 Hz, 2H), 2.95 - 2.70 (m, 3H), 2.19 - 2.11 (m, IH). LCMS (ESI+) m/z 362.1 (M+H)+.

[003082] Step 2:2-[2-[[2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin-5yl1amino1ethoxy1ethyl methanesulfonate

[003083] To a solution of 2-(2,6-dioxo piperidyl) [2-(2hydroxyethoxy)ethylamino]isoindoline-l,3-dione (300 mg, 830 umol) in DCM (20.0 mL) was added TEA (168 mg, 1.66 mmol) and MsCl (105 mg, 913 umol). The reaction mixture was stirred at rt for 2 hrs. On completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 X 100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (360 mg, 98% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.99 (s, IH), 7.64 (d, J = 8.4 Hz, IH), 7.02 (d, J

1074 = 2.0 Hz, IH), 6.83 (dd, J= 2.0, 8.4 Hz, IH), 5.03 - 4.89 (m, IH), 4.52 - 4.39 (m, 2H), 3.85 - 3.76 (m, 4H), 3.44 (t, J = 52 Hz, 2H), 3.10 (s, 3H), 2.96 - 2.72 (m, 3H), 2.24 - 2.10 (m, IH).

[003084] 5- [2 16- [2-(2-Aminoethoxy)ethyl]-2.,6-diazaspiro [3.3] heptan-2yl]ethoxy]ethylamino] (2,6-dioxo piperidyl)isoindoline-l,3-dione (Intermediate NG)

NF

HCI

O

NG

[003085] Step 1 - Tert-butyl 6-r2-r2-rr2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin-5yl]amino]ethoxy]ethyl]- 2,6-diazaspiro[3.3]heptane carboxvlate

[003086] To a solution of 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-5yl]amino]ethoxy]ethyl methanesulfonate (260 mg, 592 umol, Intermediate NF) and tert-butyl 2,6diazaspiro[3.3]heptane carboxylate (139 mg, 592 umol, HCI, CAS# 1041026 3) in ACN (15.0 mL) was addedNaHCO3 (149 mg, 1.77 mmol) and TBAI (21.9 mg, 59.2 umol). The reaction mixture was stirred at 80 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (DCM: MeOH = 20: 1) to give the title compound (159 mg, 45% yield) as a yellow solid., 1HNMR (400MHz, DM SO-6#) δ 11.07 (s, IH), 7.57 (d, 7= 8.4 Hz, IH), 7.16 (s, IH), 7.01 (s, IH), 6.90 (d, J= 8.4 Hz, IH), 5.04 (dd,7=5.2, 12.8 Hz, IH), 3.86 (s, 4H), 3.54 (t, J= 52 Hz, 2H), 3.44 - 3.35 (m, 10H), 2.96 - 2.80 (m, IH), 2.63 - 2.59 (m, 2H), 2.00 (d, J= 10.8 Hz, IH), 1.36 (s, 9H). LC-MS (ESI+) m/z 542.3 (M+H)+.

1075

[003087] Step 2 - 5-r2-r2-(2,6-Diazaspiror3.31heptan yl)ethoxy1ethylamino1 (2,6dioxo piperidyl) isoindoline-1,3-dione

[003088] To a solution of tert-butyl 6-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethyl]-2,6-diazaspiro[3.3]heptane carboxylate (177 mg, 327 umol) in DCM (5.00 mL) was added TFA (2.48 g, 21.7 mmol). The reaction mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo. Then, the residue was diluted with anhydrous toluene (30.0 mL). Then the mixture was concentrated in vacuo to give the title compound (181 mg, 100% yield, TFA) as a yellow solid. LC-MS (ESI+) m/z 442.3 (M+H)+.

[003089] Step 3 - Tert-butyl Ν-Γ2-Γ2-Γ6-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-1,3-&#940;&#912;οχοisoindolin yl1amino1 ethoxy1ethyl1-2,6-diazaspiro[3.31heptan yl1ethoxy1ethyl1carbamate [003090] To a solution of 5-[2-[2-(2,6-diazaspiro[3.3]heptan yl)ethoxy]ethylamino]-2(2,6-dioxo piperidyl) isoindoline-1,3-dione (181 mg, 327 umol, TFA) and tert-butyl N-[2-(2oxoethoxy)ethyl]carbamate (230 mg, 1.13 mmol, synthesized via Step 1 of Intermediate FS) in a mixed solvent of THF (15.0 mL) and DMF (5.00 mL) was added TEA (66.1 mg, 654 umol) and HO Ac (78.5 mg, 1.31 mmol). The reaction mixture was stirred at rt for 12 hrs. After, NaBH(OAc)3 (83.1 mg, 392 umol) was added and the resulting reaction mixture was stirred at rt for 24 hrs. On completion, the mixture was quenched with water (1.00 mL). The mixture was concentrated in vacuo. The crude product was purified by reversed phase (condition: 0.1% FA) to give the title compound (77 mg, 34% yield) as yellow solid. LC-MS (ESI+) m/z 629.4 (M+H)+.

[003091] Step 4 - 5-r2-r2-r6-r2-(2-Aminoethoxy)ethyl1-2,6-diazaspiro[3.31heptan-2yl1ethoxy1ethylamino1 (2,6-dioxo piperidyl)isoindoline-L3-dione

[003092] To a solution of tert-butyl N-[2-[2-[6-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptan yl]ethoxy]ethyl]carbamate (100 mg, 151 umol) in DCM (5.00 mL) was added TFA (86.2 mg, 756 umol). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (97 mg, 100% yield, TFA) as a yellow solid. LC-MS (ESI+) m/z 529.4 (M+H)+. [003093] 4-(Aminomethyl) (2.,6-dioxo DiDeridvl)isoindoline-l.,3-dione (Intermediate NH)

1076

KF3B

NHBoc

HCI/ dioxane, DCM

K2CO3, Pd(dppf)CI2«CH2CI2, dioxane, H2O

[003094] Step 1 - Tert-butyl N-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yllmethyllcarbamate

[003095] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (700 mg, 2.08 mmol, Intermediate FT) and potassium N-Boc-amino methyltrifluoroborate (738 mg, 3.11 mmol, CAS# 1314538 0) in dioxane (10 mL) and H2O (2 mL) was added K2CO3 (861 mg, 6.23 mmol) and Pd(dppf)C12.CH2C12 (170 mg, 208 umol). The reaction mixture was stirred at 85 °C for 6 hours under nitrogen. On completion, the reaction mixture was poured into brine (30 mL) and extracted with EA (3 X 80 mL). The combined organic layers were washed with brine (80 mL), dried with anhydrous Na2SO4, filtered, concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 3/1 to 1/1) to give the title compound (270 mg, 34% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-/6) δ 11.11 (s, IH), 7.88 - 7.77 (m, 2H), 7.74 - 7.64 (m, IH), 5.20 - 5.09 (m, IH), 4.69 - 4.54 (m, 2H), 3.02 - 2.79 (m, IH), 2.69 - 2.56 (m, 2H), 2.17 - 2.01 (m, IH), 1.41 (s, 9H).

[003096] Step 2 - 4-(Aminomethyl) (2,6-dioxo piperidyl)isoindoline-L3-dione

[003097] To a solution of tert-butyl N-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]methyl]carbamate (80.0 mg, 207 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 12.3 mL). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (60.0 mg, 90% yield) as yellow oil.

[003098] 5-[2-(2,6-Dioxo DiDeridvl)-l,3-dioxo-isoindolin yl]Dentvl methanesulfonate (Intermediate ND

1077

NI

[003099] Step 1 - 2-(2,6-Dioxo piperidyl) (5-hydroxypent-l-ynyl)isoindoline-L3-dione [003100] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.00 g, 2.97 mmol, Intermediate FT) and pent yn-l-ol (499 mg, 5.93 mmol, CAS# 5390 5) in DMF (10 mL) was added Pd(PPh3)2C12 (208 mg, 296 umol), TEA (5.40 g, 53.3 mmol, 7.43 mL), and Cui (56.4 mg, 296 umol) under N2. The reaction mixture was stirred at 80 °C for 30 min under microwave. On completion, the reaction mixture was diluted with EA (20 mL), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5:1 to 1:1) to give the title compound (800 mg, 76% yield) as a light yellow solid. LC-MS (ESI+) m/z 341.1 (M + H)+.

[003101] Step 2 - 2-(2,6-Dioxo piperidyl) (5-hydroxypentyl)isoindoline-L3-dione [003102] To a solution of 2-(2,6-dioxo piperidyl) (5-hydroxypent-l-ynyl)isoindoline1,3-dione (800 mg, 2.35 mmol) in THF (25 mL) was added Pd/C (100 mg, 2.35 mmol, 10 wt%) and Pd(OH)2/C (100 mg, 71.2 umol, 10 wt%). The reaction mixture was stirred at rt for 12 hours under H2 (15 psi). On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (810 mg, 95% yield) as a black brown solid. LC-MS (ESI+) m/z 345.3 (M + H)+.

[003103] Step 3 - 5-r2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin yl1pentyl methanesulfonate

[003104] To a solution of 2-(2,6-dioxo piperidyl) (5-hydroxypentyl)isoindoline-l,3dione (300 mg, 871 umol) and TEA (264 mg, 2.61 mmol, 363 uL) in DCM (5 mL) was added

1078

MsCI (119 mg, 1.05 mmol, 80.9 uL). The reaction mixture was stirred at rt for 0.5 hour. The mixture was quenched by addition of H2O (50 mL), then extracted with DCM (2 X 100 mL). The organic phase was concentrated in vacuo to give the title compound (370 mg, 90% yield) as a yellow solid. LC-MS (ESI+) m/z 423.2 (M+H)+.

[003105] 2-[2-[2-(2.,6-Dioxo DiDeridvl)-l.,3-dioxo-isoindolin vl]ethoxv]ethvl methanesulfonate (Intermediate NJ)

FT

NJ

[003106] Step 1 - 2-(2,6-Dioxo piperidyl) r(Z) (2-hydroxyethoxy)vinyl1isoindoline1,3-di one

[003107] To a solution of 4-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.5 g, 4.45 mmol, Intermediate FT) and 2-vinyloxyethanol (784 mg, 8.90 mmol, CAS# 764 7) in dioxane (100 mL) was added P(t-Bu)3 (1.80 g, 889 umol, 2.09 mL, 10% purity), DIPEA (690 mg, 5.34 mmol, 930 uL) and Pd2(dba)3 (407 mg, 444 umol). The reaction mixture was stirred at rt for 12 hours under N2. On completion, the reaction mixture was poured into sat.NH4Cl (30 mL) and extracted with EA (3 X 100 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 2:1 to 0:1) to give the title compound (600 mg, 33% yield) as a light yellow solid. LC-MS (ESI+) m/z 345.1 (M + H)+.

[003108] Step 2 - 2-(2,6-Dioxo piperidyl) r2-(2-hydroxyethoxy)ethyl1isoindoline-l,3di one

[003109] To a solution of 2-(2,6-dioxo piperidyl) [(Z) (2hydroxyethoxy)vinyl]isoindoline-l,3-dione (500 mg, 1.45 mmol) in THF (20 mL) was addedPd/C

1079 (50 mg, 1.45 mmol, 10 wt%). The reaction mixture was stirred at rt for 24 hours under H2 (15 Psi). Then Pd(OH)2/C (50 mg, 35.6 umol, 10 wt%) was added. The reaction mixture was stirred at rt for 12 hours under H2 (15 Psi). On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (600 mg, 85% purity) as a light yellow solid. LCMS (ESC) m/z 347.2 (M+H)+.

[003110] Step 3 - 2-r2-r2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin yl1ethoxy1ethyl methanesulfonate

[003111] To a solution of 2-(2,6-dioxo piperidyl) [2-(2hydroxyethoxy)ethyl]isoindoline-l,3-dione (250 mg, 721.85 umol) in DCM (10 mL) was added TEA(219 mg, 2.17 mmol, 301 uL) and MsCI (124 mg, 1.08 mmol, 83.8 uL) at 0 °C. The reaction mixture was stirred at rt for 30 min. The mixture was quenched by addition H2O (50 mL), then extracted with DCM (2 X 100 mL). The organic phase was concentrated in vacuo to give the title compound (310 mg, 63% purity) as a yellow solid. LC-MS (ESI+) m/z 425.0 (M+H)+.

[003112] 4-[2-[2-[4-[4-Amino (difluoromethyl)Dyrazol-l-yl]-lDiDeridyl]ethoxy]ethyl] (2.,6-dioxo- 3-DiDeridyl)isoindoline-l.,3-dione (Intermediate NK)

[003113] Step 1:4-[2- [2-[4- [3 -(Difluoromethyl) nitro-pyrazol-1 -yl] -1 piperidvl1ethoxv1ethyl1 (2,6-dioxo-3 -piperidyl)isoindoline-L3-dione

[003114] To a solution of 2-[2-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4

1080 yl] ethoxy] ethyl methanesulfonate (300 mg, 706 umol, Intermediate NJ) and 4-[3(difluoromethyl) nitro-pyrazol-l-yl]piperidine (199 mg, 706 umol, HCI, Intermediate JP) in CH3CN (20 mL) was added NaHCO3 (178 mg, 2.12 mmol) and KI (11.7 mg, 70.6 umol). The reaction mixture was stirred at 80 °C for 12 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (410 mg, 85% purity) as a yellow solid. LC-MS (ESI+) m/z 575.2 (M+H)+.

[003115] Step 2:4-(2-(2-( 4-[4-Amino-3 -(difluorometh yl)pyrazol-1 -yl] -1 piperidvl1ethoxy1ethyl1 (2,6-dioxo- 3-piperidyl)isoindoline-L3-dione

[003116] To a solution of 4-[2-[2-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]-lpiperidyl]ethoxy]ethyl] (2,6- dioxo piperidyl)isoindoline-l,3-dione (260 mg, 452 umol) in THF (10 mL) was added PtO2 (41.1 mg, 181 umol), the reaction mixture was stirred at rt under H2 (15 psi) for 16 hrs. On completion, the mixture was filtered, the filtrate was concentrated was concentrated in vacuo to give the title compound (40 mg, 16% yield) as a white solid. LC-MS (ESI+) m/z 545.3 (M+H)+.

[003117] 4-[5-[4-[4-Amino (difluoromethvl)Dvrazol-l-vl]-l-DiDeridvl]Dentvl] (2,6dioxo DiDeridyl)isoindoline-l,3-dione (Intermediate NL)

[003118] Step 1 - 4-r5-r4-r3-(Difluoromethvl) nitro-pvrazol-l-vl1-l-piperidvl1pentyl1-2(2,6-di oxo piperidyl) isoindoline-L3-dione

[003119] To a solution of 5-(2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl]pentyl

1081 methanesulfonate (260 mg, 615 umol, Intermediate NI) and 4-[3-(difluoromethyl) nitro-pyrazoll-yl]piperidine (133 mg, 473 umol, HCI, Intermediate JP) in ACN (15 mL) was added NaHCO3 (119 mg, 1.42 mmol, 55.2 uL) and KI (7.86 mg, 47.3 umol), the reaction micture was stirred at 80 °C for 16 hr. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/MeOH= 100/1 to 50/1) to give the title compound (140 mg, 51% yield) as a white solid. LC-MS (ESI+) m/z 573.3 (M+H)+.

[003120] Step 2 - 4-r5-r4-r4-Amino (difluoromethvl)pvrazol-l-vl1-l-piperidvl1pentvl1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[003121] To a solution of 4-[5-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]-lpiperidyl]pentyl] (2,6-dioxo piperidyl)isoindoline-l,3-dione (190 mg, 331 umol) in THF (5 mL) was added PtO2 (37.6 mg, 165 umol), and the reaction mixture was stirred at rt under H2 (15 psi) for 3 hrs. On completion, the mixture was filtered, the filtrate was concentrated in vacuo to give the title compound (180 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 543.4 (M+H)+.

[003122] 3-[2-(2.,6-Dioxo piperidvl)-l.,3-dioxo-isoindolin vl]propvl methanesulfonate (Intermediate NM)

[003123] Step 1- 2-(2,6-Dioxo piperidyl) (3-hydroxyprop-l-ynyl)isoindoline-L3-dione

[003124] 4-Bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.00 g, 2.97 mmol,

Intermediate FT), prop yn-l-ol (332 mg, 5.93 mmol, CAS# 107 7), Pd(PPh3)2C12 (208 mg, 296 umol), Cul(113 mg, 593 umol), and TEA (5.40 g, 53.4mmol) were taken up into a microwave tube in DMF (20 mL). The sealed tube was heated at 80 °C for 0.5 hr under microwave. On completion, the mixture was poured into water (100 mL). The aqueous phase was extracted with

1082 ethyl acetate (2 X 50 mL). The combined organic phase was washed with brine (2 X 40 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=O:l) to give the title compound (185 mg, 9% yield) as white solid. LC-MS (ESI+) m/z 335.0 (M+Na)+.

[003125] Step 2- 2-(2,6-Dioxo piperidyl) (3-hydroxypropyl)isoindoline-L3-dione

[003126] To a mixture of 2-(2, 6-dioxo piperidyl) (3-hydroxyprop-l-ynyl)isoindoline1,3-dione (320 mg, 1.02 mmol) in THF (10 mL) was added Pd/C (2.05 mmol, 10 wt%), and Pd(OH)2 (288 mg, 2.05 mmol) under H2 (15 Psi), and the reaction mixture was stirred at rt for 5 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (296 mg, 91% yield) as brown oil. LC-MS (ESI+) m/z 339.0 (M+Na)+.

[003127] Step 3 r2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin yl1propyl methanesulfonate

[003128] To a mixture of 2-(2,6-dioxo piperidyl) (3-hydroxypropyl)isoindoline-l,3dione (296 mg, 935 umol) in DCM (10 mL) was added DIPEA (362 mg, 2.81 mmol) and the mixture was cooled to 0 °C. MsCI (161 mg, 1.40 mmol) was added into the mixture. The reaction mixture was stirred at rt for 1 hr. On completion, the mixture was poured into water (15 mL). The aqueous phase was extracted with ethyl acetate (2 X 20 mL).The combined organic phase was washed with brine (2 X 20 mL), then dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give title compound (348 mg, 94% yield) as brown oil. LC-MS (ESI+) m/z 395.0 (M+H)+.

[003129] 4-[3-[4-[3-(Difluoromethvl) nitro-Dvrazol-l-vl]-l-DiDeridyl]DroDvl] (2,6dioxo DiDeridvl)isoindoline-l,3-dione (Intermediate NN)

1083

NM

PtO2, H2, THF

NN

[003130] !ytep_Jj_JIJ_32]_42]_32(DifhjoromelJ1Yl)242nilTO2p^^ (2,6-di oxo-3 -piperi dvDisoindoline-1,3 -di one

[003131] To a mixture of 3-[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl]propyl methanesulfonate (348 mg, 882 umol, Intermediate NM), 4-[3-(difluoromethyl) nitro-pyrazoll-yl]piperidine (274.36 mg, 970umol, HCI, Intermediate JP) in CH3CN (10 mL) was added NaHCO3 (296 mg, 3.53 mmol) and the mixture was stirred at 80 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=O: 1) to give title compound (190 mg, 30% yield) as a yellow solid. LC-MS (ESI+) m/z 545.3 (M+H)+.

[003132] Step 2 - 4-[3-r4-r3-(Difluoromethvl) nitro-pvrazol-l-vl1-l-piperidvl1propvl1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[003133] To a mixture of 4-[3-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]-lpiperidyl]propyl] (2,6-dioxo piperidyl)isoindoline-l,3-dione (20.0 mg, 36.7 umol) in THF (2 mL) was added PtO2 (1.67 mg, 7.35 umol) under H2 (15 Psi) and the reaction mixture was stirred at rt for 12 hrs. On completion, the mixture was concentrated in vacuo to give title compound (15 mg, 80% yield) as brown oil. LC-MS (ESI+) m/z 515.2 (M+H)+.

[003134] 5-[2-(2.,6-Dioxo DiDeridvl)-l.,3-dioxo-isoindolin vl]Dentvl

1084 methanesulfonate (Intermediate NO)

[003135] Step 1 - 2-(2,6-Dioxo piperidyl) (5-hydroxypent-l-ynyl)isoindoline-L3-dione

[003136] Amixture of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.00 g, 2.97 mmol, Intermediate GA), pent yn-l-ol (499 mg, 5.93 mmol), Pd(PPh3)2C12 (208 mg, 296 umol),

Cui (56.0 mg, 296 umol) and TEA (5.40 g, 53.3 mmol, 7.43 mL) in DMF (4 mL) was degassed and purged with N2 gas 3 times. The mixture was stirred at 80 °C for 0.5 hr under microwave. On completion, the mixture was extracted with EA(2 X 100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (900 mg, 89% yield) as light yellow solid. 1HNMR (400MHz, DMSO-76) δ 11.14 (s, IH), 7.94 - 7.78 (m, 3H), 5.17 (dd, J = 5.6, 12.8 Hz, IH), 4.57 (t, J = 5.2 Hz, IH), 3.55 (q, J = 6.0 Hz, 2H), 2.97 - 2.84 (m, IH), 2.67 2.55 (m, 4H), 2.15 - 2.02 (m, IH), 1.77 - 1.70 (m, 2H).

[003137] Step 2 - 2-(2,6-Dioxo piperidyl) (5-hydroxypentyl)isoindoline-L3-dione [003138] To a solution of 2-(2,6-dioxo piperidyl) (5-hydroxypent-l-ynyl)isoindoline1,3-dione (900 mg, 2.64 mmol) in THF (20 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%) under H2 atmosphere (15 psi). The mixture was stirred at rt for 2 hrs. On

1085 completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (800 mg, 87% yield) as light yellow solid. 1H NMR (400MHz, DMSO-76) δ 11.12 (s, IH), 7.89-7.65 (m, 3H), 5.14 (dd, J= 5.2, 12.8 Hz, IH), 4.38 - 4.33 (m, IH), 3.43 -3.34 (m, 2H), 2.89 (s, IH), 2.78 (t, J= 7.6 Hz, 2H), 2.65 - 2.52 (m, 2H), 2.12 - 2.00 (m, IH), 1.80- 1.72 (m, IH), 1.68 - 1.60 (m, 2H), 1.48 - 1.41 (m, 2H), 1.35 - 1.24 (m, 2H).

[003139] Step 3 - 5-[2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin yl1pentyl methanesulfonate

[003140] To a solution of 2-(2,6-dioxo piperidyl) (5-hydroxypentyl)isoindoline-l,3dione (200 mg, 580 umol) in DCM (20 mL) was added TEA (176 mg, 1.74 mmol) and MsCI (133 mg, 1.16 mmol, 89.9 uL). The mixture was stirred at rt for 3 hrs. On completion, the mixture was washed with citric acid (10 mL), and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vauco to give the title compound (240 mg, 97% yield) as yellow oil. LC-MS (ESI+) m/z 423.3 (M+l)+.

[003141] 5-[3-[4-[4-Amino (difluoromethvl)pvrazol-l-vl]-l-piperidvl]Dropyl] (2,6dioxo piperidyl)isoindoline-l,3-dione (Intermediate NP)

[003142] Step 1 - 5-r5-r4-r3-(Difluoromethyl) nitro-pyrazol-l-yl1-l-piperidyl1pentyl1-2(2,6-dioxo-3 -piperidyl) isoindoline-L3-dione

[003143] To a mixture of 5-(2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl]pentyl methanesulfonate (179 mg, 424 umol, Intermediate NO) and 4-[3-(difluoromethyl) nitro

1086 pyrazol-l-yl]piperidine (100 mg, 354 umol, HCI, , Intermediate JP) in ACN (8 mL) was added NaHCO3 (89.2 mg, 1.06 mmol) and KI (5.87 mg, 35.4 umol). The mixture was stirred at 80 °C for 16 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo, the residue was purified by Pre-HPLC (acid condition) to give the title compound (140 mg, 69% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 11.11 (s, IH), 9.08 (s, IH), 7.85 (d, J = 7.6 Hz, IH), 7.79 (s, IH), 7.73 (d, J = &#906;2 Hz, IH), 7.46 - 7.17 (m, IH), 5.14 (dd, J = 5.2, 12.8 Hz, IH), 4.38 - 4.27 (m, IH), 3.03 - 2.95 (m, 2H), 2.94 - 2.85 (m, IH), 2.83 - 2.77 (m, 2H), 2.71 - 2.53 (m, 2H), 2.38 -2.31 (m, 2H), 2.16-1.95 (m, 7H), 1.73 - 1.62 (m, 2H), 1.55 - 1.44 (m, 2H), 1.37- 1.28 (m, 2H).

[003144] Step 2 - 5-r3-r4-r4-Amino (difluoromethyl)pyrazol-l-yl1-l-piperidyl1propyl1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[003145] To a solution of 5-[5-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]-lpiperidyl]pentyl] (2,6-dioxo piperidyl)isoindoline-l,3-dione (140 mg, 244 umol) in THF (20 mL) was added PtO2 (11.1 mg, 48.9umol). The mixture was stirred at rt for 16 hrs under H2(15psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (130 mg, 98% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 11.11 (s, IH), 7.85 - 7.83 (m, 2H), 7.78 (s, IH), 7.74 - 7.71(m, 2H), 7.17 (s, IH), 7.03 - 6.61 (m, 3H), 5.14 (dd, J = 5.6, 12.8 Hz, IH), 3.99 - 3.94 (m, IH), 2.96 - 2.88 (m, 3H), 2.84 - 2.76 (m, 2H), 2.67 - 2.58 (m, 2H), 2.30 - 2.24 (m, 2H), 1.98 - 1.74 (m, 7H), 1.72 - 1.60 (m, 2H), 1.53 - 1.41 (m, 2H), 1.33 1.22 (m,2H).

[003146] 3-[2-(2,6-Dioxo DiDeridvl)-l,3-dioxo-isoindolin yl]DroDvl methanesulfonate (Intermediate NO)

1087

[003147] Step 1 - 2-(2,6-Dioxo piperidvl) (3-hydroxyprop-l-ynyl)isoindoline-L3-dione

[003148] Amixture of 5-bromo (2,6-dioxo piperidyl)isoindoline-l,3-dione (1.00 g, 2.97 mmol, Intermediate GA), prop yn-l-ol (333 mg, 5.93 mmol, CAS# 107 7), Pd(PPh3)2C12 (208 mg, 297 umol), Cui (56.5 mg, 297 umol) and TEA(5.40 g, 53.4 mmol, 7.43 mL) in DMF (4 mL) was degassed and purged with N2 gas 3 times, and then the mixture was stirred at 80 °C for 0.5 hr under microwave. On completion, the mixture was extracted with EA (2 X 100 mL), the organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (800 mg, 86% yield) as light white solid. 1H NMR (400MHz, DMSO-7) δ 11.15 (s, IH), 7.96 - 7.90 (m, 3H), 5.48 (t, J = 6.0 Hz, IH), 5.17(dd, J = 5.2, 12.8 Hz, IH), 4.38 (d, J= 6.0 Hz, 2H), 2.96 - 2.84 (m, IH), 2.70 - 2.54 (m, 2H), 2.13 - 2.03 (m, IH).

[003149] Step 2 - 2-(2,6-Dioxo piperidyl) (3-hydroxypropyl)isoindoline-L3-dione

[003150] To a solution of 2-(2,6-dioxo piperidyl) (3-hydroxyprop-l-ynyl)isoindoline1,3-dione (800 mg, 2.56 mmol) in THF (20 mL) was added Pd/C (200 mg, 10 wt%) and Pd(OH)2/C (200 mg, 10 wt%). The mixture was stirred at rt for 3 hrs under H2 (15 psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (800 mg, 98% yield) as light brown solid. 1H NMR (400MHz, DM SO-6#) δ 11.12 (s, IH), 7.86 - 7.69 (m, 3H), 5.14 (dd, J = 5.2, 12.8 Hz, IH), 4.54 (t, J= 5.2 Hz, IH), 3.45 - 3.38 (m, 2H), 2.96 - 2.90 (m, IH), 2.87 - 2.79 (m, 2H), 2.69 - 2.53 (m, 2H), 2.11 - 2.01 (m, IH), 1.83 - 1.72 (m, 2H).

[003151] Step 3 - 3-r2-(2,6-Dioxo piperidvl)-L3-dioxo-isoindolin yl1propyl methanesulfonate

[003152] To a solution of 2-(2,6-dioxo piperidyl) (3-hydroxypropyl)isoindoline-l,3dione (300 mg, 948 umol) in DCM (10 mL) was added MsCl (217 mg, 1.90 mmol) and TEA (288 mg, 2.85 mmol). The mixture was stirred at rt for 3 hrs. On completion, the mixture was washed with citric acid (10 mL), and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vauco to give the title compound (350 mg, 93% yield) as yellow solid. LC-MS (ESI+) m/z 412.2 (M+18)+.

[003153] 5-[3-[4-[4-Amino (difluoromethvDDvrazol-l-vH-l-DiDeridvllDroDvl| (2.,6dioxo DiDeridyl)isoindoline-l.,3-dione (Intermediate NR)

1088

Pto2, H2, THF

[003154] Step 1 - 5-[3-[4-[4-Amino (difluoromethyl)pyrazol-l-yl1-l-piperidyl1propyl1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[003155] To a mixture of 3-(2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl]propyl methanesulfonate (167 mg, 424 umol, Intermediate NQ) and 4-[3-(difluoromethyl) nitropyrazol-l-yl]piperidine (100 mg, 354 umol, HCI, Intermediate JP) in ACN (10 mL) was added NaHCO3 (89.0 mg, 1.06 mmol) and KI (5.87 mg, 35.4 umol). The mixture was stirred at 80 °C for 16 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo, the residue was purified by Pre-HPLC (acid condition) to give the title compound (100 mg, 52% yield) as white solid. 1H NMR (400MHz, DM SO-0/6) δ 11.11 (s, IH), 9.09 (s, IH), 7.87 - 7.80 (m, IH), 7.78-7.71 (m, IH), 7.46 - 7.17 (m, IH), 5.14 (dd, J= 5.2, 12.8 Hz, IH), 4.38 - 4.28 (m, IH), 3.00 - 2.93 (m, 2H), 2.91 - 2.79 (m, 3H), 2.65 - 2.53 (m, 2H), 2.39 - 2.29 (m, 2H), 2.12 - 2.00 (m, 7H), 1.88 - 1.76 (m, 2H).

[003156] Step 2 - 5-[3-[4-[4-Amino (difluoromethyl)pyrazol-l-yl1-l-piperidyl1propyl1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[003157] To a solution of 5-[3-[4-[3-(difluoromethyl) nitro-pyrazol-l-yl]-lpiperidyl]propyl] (2,6-dioxo piperidyl)isoindoline-l,3-dione (100 mg, 184 umol) in THF (15 mL) was added PtO2 (41.7 mg, 184 umol). The mixture was stirred at rt for 16 hrs under H2 (15 psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo

1089 to give the title compound (80 mg, 85% yield) as white solid. LC-MS (ESI+) m/z 515.3 (M+l)+.

[003158] 3-[l-Oxo (4-DiDeridvlamino)isoindolin yl]DiDeridine-2.,6-dione (Intermediate NS)

HCI/Dioxane, DCM

NS

[003159] Step 1 - Tert-butyl 4-rr2-(2,6-dioxo piperidvl)-l-oxo-isoindolin-4yl]amino]piperidine-l- carboxylate

[003160] To a solution of 3-(4-amino-l-oxo-isoindolin yl)piperidine-2,6-dione (400 mg, 1.54 mmol, CAS# 191732 6) and tert-butyl 4-oxopiperidine-l-carboxylate (615 mg, 3.09 mmol) in a mixed solvent of DCE (10 mL) and HOAc (1.05 g, 17.5 mmol) was added molecular sieves (200 mg, 386 umol, 4 A). The reaction mixture was stirred at 30 °C for 4 hrs. Then, NaBH(OAc)3 (327 mg, 1.54 mmol) was added . The resulting reaction mixture was stirred at 30 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give the crude product which was purified by reversed-phase chromatography (0.1% FA condition) to give the title compound (168 mg, 22% yield) as a white solid. 1H NMR (400MHz, DMS0-<7) δ 11.00 (s, IH), 7.29 (t, J = 7.6 Hz, IH), 6.95 (d, J = 7.6 Hz, IH), 6.86 (d, J = 8.4 Hz, IH), 5.35 (d, J = 8.4 Hz, IH), 5.12 (dd, 7= 5.2, 12.8 Hz, IH), 4.31 - 4.10 (m, 2H), 3.92 (d,7= 12.6 Hz, 2H), 3.02-2.85 (m, 3H), 2.71 - 2.59 (m, IH), 2.38 - 2.23 (m, IH), 2.09 - 2.00 (m, IH), 1.92 - 1.90 (m, 2H), 1.41 (s, 9H), 1.33 - 1.29 (m, 2H) LC-MS (ESI+) m/z 387.1 (M-56)+.

[003161] Step 2 - 3-r1-Oxo (4-piperidylamino)isoindolin yl]piperidine-2,6-dione [003162] To a solution of tert-butyl 4-[[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-4yl]amino]piperidine-l- carboxylate (210 mg, 475 umol) in dichloromethane (10 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (180 mg, 100% yield, HCI

1090 salt) as a white solid which was used for the next step without purification. LC-MS (ESI+) m/z

343.1 (M+H)+.

[003163] 3-[4-[[l-[2-[2-(2-Aminoethoxv)ethoxv]ethvl] piperidvl]amino]-l-oxoisoindolin yl]piperidine-2.,6-dione (Intermediate NT)

HY

KOAc, NaBH(OAc)3, THF/DCM

[003164] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ4-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1) οχο-&#912;5ο&#912;η&#940;ο1&#912;η-4yl]amin01-l-piperidyl] ethoxy] ethoxy] ethyl ]carbamate

[003165] To a solution of 3-[l-oxo (4-piperidylamino)isoindolin yl]piperidine-2,6dione (180 mg, 475 umol, HC1, Intermediate NS) and tert-butyl N-[2-[2-(2oxoethoxy)ethoxy]ethyl]carbamate (176.0 mg, 712 umol, Intermediate HY) in THF (20 mL) was added KOAc (93.2 mg, 949 umol) and NaBH(OAc)3 (111 mg, 522 umol). The reaction mixture was stirred at rt for 36 hrs. On completion, the reaction mixture was quenched with water (1 mL) and the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.1% FA) to give the title compound (130 mg, 45% yield) as a colorless oil. LC-MS (ESI+) m/z 574.2 (M+H)+. 1HNMR (400MHz, DMSO-Y) δ 11.03 (s, IH), 7.30 - 7.25 (m, IH), 6.93 (d, J =7 .6 Hz, IH), 6.82 - 6.75 (m, 2H), 5.33 (d, J = 7.6 Hz, IH), 5.13 (dd, J = 5.2, 13.2 Hz, IH), 4.26 4.11 (m, 2H), 4.26 - 4.10 (m, IH), 3.06 (d, J = 6.0 Hz, 2H), 2.99 - 2.89 (m, 3H), 2.68 - 2.59 (m,

1091

IH), 2.30 - 2.26 (m, IH), 2.20 - 2.14 (m, 2H), 2.06 - 2.00 (m, IH), 1.92 - 1.88 (m, 2H), 1.48 - 1.42 (m, 2H), 1.37 (s, 9H).

[003166] Step 2 - 3-r4-rr1-r2-r2-(2-Aminoethoxy)ethoxy]ethyl] piperidyl]amino]-l-oxoisoindolin yl1piperidine-2,6-dione

[003167] To a solution of tert-butyl N-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl]amino]-l- piperidyl]ethoxy]ethoxy]ethyl]carbamate (130 mg, 227 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (116 mg, 99% yield, HCI salt) as a white solid. LC-MS (ESI+) m/z 474.2 (M+H) +.

[003168] 4-[[l-[2-(2-Aminoethoxv)ethvl] DiDeridvl]amino] (2,6-dioxo

HCI

[003169] Step 1 - Tert-butyl N-r2-r2-r4-IT2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4yl1amin01-l- piperidyl1ethoxy1ethyl1carbamate

[003170] To a solution of 2-(2,6-dioxo piperidyl) (4-piperidylamino)isoindoline-l,3dione (300 mg, 764 umol, HCI, Intermediate JW) and tert-butyl N-[2-(2oxoethoxy)ethyl]carbamate (233 mg, 1.15 mmol, synthesized via Step 1 of Intermediate FS) in THF (10 mL) was added KOAc (150 mg, 1.53 mmol). One hour later, NaBH(OAc)3 (324 mg, 1.53 mmol) was added. The reaction mixture was stirred at rt for 16 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified reverse phase (0.1% HCI condition) to give the title compound (300 mg, 72% yield) as a white solid. LC-MS (ESI+) m/z 544.4 (M+H)+.

[003171] Step 2 - 4-n&#1470;l-r2-(2-Aminoethoxy)ethyl1 piperidyl1amino1 (2,6-dioxo-3

1092 piperidyl)isoindoline-L3 -dione

[003172] To a solution of tert-butyl N-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] piperidyl]ethoxy]ethyl]carbamate (300 mg, 552 umol) in DCM (5 mL) was added HCI/dioxane (10 mL). The reaction mixture was stirred at rt for 10 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (240 mg, 91% yield, HC1) as a yellow solid. LC-MS (ESI+) m/z 444.1 (M+H)+.

[003173] 3-(5-Amino-l-oxo-isoindolin yl)DiDeridine-2.,6-dione (Intermediate NV)

[003174] Step 1 - Methyl 2-(bromomethyl) nitro-benzoate

[003175] To a solution of methyl 2-methyl nitro-benzoate (3.00 g, 15.4 mmol) in CC14 (60.0 mL) was added NBS (3.28 g, 18.4 mmol) and BOP (68.0 mg, 154 umol). The reaction mixture was stirred at 85 °C for 12 hrs. On completion, the mixture was washed with saturated NaHCO3 (20.0 mL) and brine (50.0 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: AcOEt = 3: 1) to give the title compound (4.21g, 100% yield) as a colorless oil. 1HNMR (400MHz, CDCh) δ 8.30 (d, 7= 2.0 Hz, IH), 8.20 (dd, 7= 2.0, 6.4 Hz, IH), 8.10 (d, 7= 6.4 Hz, IH), 4.96 (s, 2H), 4.00 (s, 3H).

[003176] Step 2 - 3-(5-Nitro-l-oxo-isoindolin yl)piperidine-2,6-dione

[003177] To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.2 mmol, HC1) and methyl 2-(bromomethyl) nitro-benzoate (4.21 g, 15.4 mmol) in DMF (10.0 mL) was added TEA (3.07 g, 30.4 mmol). The reaction mixture was stirred at 75 °C for 12 hrs. On completion, the reaction mixture was diluted with water (200 mL), filtered. The filtered cake was collected. The reaction mixture was concentrated in vacuo. The residue was triturated EA: H2O = 1: 1 (50 mL) to give the title compound (1.7 g, 48% yield) as a blue solid. 1H NMR (400MHz, DMSO-76) δ 11.04 (s, IH),

1093

8.53 (d, J= 1.2 Hz, IH), 8.36 (dd, J= 2.0, 8.4 Hz, IH), 7.98 (d, J= 8.4 Hz, IH), 5.17 (dd, J= 5.2, 13.2 Hz, IH), 4.69 - 4.45 (m, IH), 3.01 - 2.86 (m, IH), 2.68 - 2.59 (m, IH), 2.48 - 2.35 (m, IH), 2.13 -2.02 (m, IH).

[003178] Step 3 - 3-(5-Amino-l-oxo-isoindolin yl)piperidine-2,6-dione

[003179] To a solution of 3-(5-nitro-l-oxo-isoindolin yl)piperidine-2,6-dione (500 mg, 1.73 mmol) in a mixed of solvent DMF (5.00 mL) and THF (10.0 mL) was added Pd/C (50.0 mg, 1.73 mmol, 10% wt) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at rt for 12 hours. On completion, the reaction mixture was filtered and the filter cake was collected and dried in vacuo to give the title compound (530 mg, 82% yield) as a brown solid. LC-MS (ESI+) m/z 260.2 (M+H)+.

[003180] 3-[l-Oxo (4-piperidylamino)isoindolin yl]piperidine-2.,6-dione (Intermediate NW)

NV

HCI/Dioxane, DCM

NW

[003181] Step 1 - Tert-butyl 4-rr2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-5 yl1amin01piperidine-l- carboxylate

[003182] To a solution of 3-(5-amino-l-oxo-isoindolin yl)piperidine-2,6-dione (448 mg, 1.73 mmol, Intermediate NV) and tert-butyl 4-oxopiperidine carboxylate (689 mg, 3.46 mmol) in a mixed solvent of DCE (10 mL) and HOAc (1.18 g, 19.6 mmol) was added molecular sieves (200 mg, 386 umol, 4A). The reaction mixture was stirred at 30 °C for 4 hrs. Then, NaBH(OAc)3 (366 mg, 1.73 mmol) was added. The resulting reaction mixture was stirred at 30 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give the crude product, which was purified by reversed-phase chromatography (0.1% FA condition) to give the title compound (120 mg, 15% yield) as a white solid. 1HNMR (400MHz, DMSO-» δ 10.93 (s, IH), 7.39 (d, J= 8.8 Hz, IH), 7.26-7.17 (m, IH), 6.69 (s, IH), 6.28 (d, J= 8.8 Hz, IH), 5.02 (dd,J=5.2, 13.2 Hz,

1094

IH), 4.34-4.10 (m, 2H), 3.89 (d, J= 12.4 Hz, 2H), 3.06 -2.82 (m, 3H), 2.71 -2.55 (m, IH), 2.41 - 2.29 (m, IH), 1.95 - 1.93 (m, IH), 1.92 - 1.89 (m, 2H), 1.41 (s, 9H), 1.27 - 1.24 (m, 2H); LC-MS (ESC) 443.1 2/&#1524; (M+H)+.

[003183] Step 2 - 3-r1-Oxo (4-piperidylamino)isoindolin yl1piperidine-2,6-dione

[003184] To a solution of tert-butyl 4-[[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-5yl]amino]piperidine-l- carboxylate (120 mg, 257.6 umol) in DCM (5.00 mL) was added HCI/dioxane (4.00 M, 2.83 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (97.6 mg, 100% yield, HC1) as a white solid. LC-MS (ESI+) m/z 343.1 (M+H)+.

[003185] 3-[5-[[l-[2-[2-(2-Aminoethoxv)ethoxv]ethvl] DiDeridvl]amino]-l-oxoisoindolin yl] DiDeridine-2,6-dione (Intermediate NX)

NW

NHBoc

KOAc, NaBH(OAc)3, THF/DCM

[003186] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ4-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1) οχο-&#912;5ο&#912;η&#940;ο1&#912;η-5yl1amin01-l-piperidyll ethoxy] ethoxy] ethyl ]carbamate

[003187] To a solution of 3-[l-oxo (4-piperidylamino)isoindolin yl]piperidine-2,6dione (97.0 mg, 256 umol, HC1, Intermediate NW) and 2-(2,6-dioxo piperidyl) piperazin-lyl-isoindoline-1,3-dione (82.3 mg, 333 umol, synthesized via Steps 1-2 of Intermediate IB) in a mixed of solvent DMF (3.00 mL) and DCM (20.0 mL) was added KOAc (50.3 mg, 512 umol) and NaBH(OAc)3 (81.4 mg, 384 umol). The reaction mixture was stirred at rt for 12 hrs. On completion, the reaction mixture was quenched with water (1.00 mL) and the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.1% FA) to give the

1095 title compound (60 mg, 33% yield) as a colorless oil. LC-MS (ESI+) m/z 574.2 (M+H)+.

[003188] Step 2 - 3-r5-rr1-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1 piperidyl1amino1-l-oxoisoindolin yl1 piperidine-2,6-dione

[003189] To a solution of tert-butyl N-[2-[2-[2-[4-[[2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl]amino]-l- piperidyl]ethoxy]ethoxy]ethyl]carbamate (60 mg, 105 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 5.00 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (53 mg, 99% yield, HCI) as a white solid. LC-MS (ESI+) m/z 474.2 (M+H)+.

[003190] Tert-butyl N-[2-[2-[4-[2-(2.,6-dioxo piperidvl)-l.,3-dioxo-isoindolin-4vllpiperazin -l-vl]ethoxy|ethvl]carbamate (Intermediate NY)

[003191] To a solution of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (0.5 g, 1.46 mmol, HCI, synthesized via Steps 1-2 Intermediate IA) and tert-butyl N-[2-(2oxoethoxy)ethyl]carbamate (445 mg, 2.19 mmol, synthesized via Step 1 of Intermediate FS) in THF (10 mL) was added Et3N (296 mg, 2.92 mmol, 407 uL) and AcOH (263 mg, 4.38 mmol, 251 uL) and then was added NaBH(OAc)3 (619 mg, 2.92 mmol). The mixture was stirred at rt for 6 hr. On completion, the mixture was concentrated in vacuo. The crude product was purified by reversed-phase chromatography (0.1% HCI condition) to give the title compound (0.3 g, crude) as a yellow solid. LC-MS (ESI+) m/z 530.4 (M+H)+.

[003192] 5 12 [2-(2-Aminoethoxv)ethoxy| ethoxy] ethyl] piperazin-l-yl] (2.,6dioxo piperidyl)isoindoline-l.,3-dione (Intermediate NZ)

1096

HCI

[003193] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-Γ4-Γ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-Ε3-&#940;&#912;οχοisoindolin yl1piperazin -l-yl1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[003194] A mixture of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (390 mg, 1.03 mmol, HCI, synthesized via Steps 1-2 of Intermediate IB), tert-butyl N-[2-[2-[2-(2oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (250 mg, 858 umol, Intermediate JX), TEA (86.8 mg, 858 umol) in THF (10 mL) was added HOAc (51.5 mg, 858 umol, 49.0 uL) and NaBH(OAc)3 (363 mg, 1.72 mmol), the mixture was stirred at rt for 72 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by Pre-HPLC (0.1% FA condition) to give the title compound (220 mg, 41% yield) as yellow solid. LC-MS (ESI+) m/z 618.4 (M+H)+.

[003195] Step 2 - 5-r4-r2-r2-r2-(2-Aminoethoxy)ethoxy1ethoxy1ethyl1piperazin-l-yl1-2(2,6-dioxo piperidyl)isoindoline-L3-dione

[003196] To a solution of tert-butyl N-[2-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl] piperazin-l-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (220 mg, 356 umol) in THF (10 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was stirred at rt for 3 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (190 mg, 96% yield) as yellow solid. LC-MS (ESI+) m/z 518.3 (M+H)+.

[003197] 5-[4-[2-[2-(2-Aminoethoxv)ethoxv]ethyl]DiDerazin-l-vl] (2.,6-dioxo-31097

DiDeridyl)isoindoline-l,3-dione (Intermediate OA)

[003198] Step 1 - Tert-butyl N-r2-r2-r2-r4-r2-(2,6-dioxo piperidvl)-L3-dioxo-isoindolin5-vl1piperazin-l-vl1 ethoxylethoxylethyllcarbamate

[003199] To a solution of 2-(2,6-dioxo piperidyl) piperazin-l-yl-isoindoline-l,3-dione (250 mg, 730 umol, HCI, synthesized via Steps 1-2 of Intermediate IB) and tert-butyl (2-(2-(2oxoethoxy)ethoxy)ethyl)carbamate (271 mg, 1.10 mmol, Intermediate HY) in THF (20.0 mL) was added KOAc (143 mg, 1.46 mmol) and NaBH(OAc)3 (170 mg, 803 umol). The reaction mixture was stirred at rt for 3 hrs. On completion, the reaction mixture was quenched with water (1.00 mL). The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.1% FA) to give the title compound (275 mg, 62% yield) as a yellow solid. LC-MS (ESI+) m/z 574.2 (M+H)+.

[003200] Step 2 - 5-r4-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1piperazin-l-yl1 (2,6-dioxo-3piperidyl)isoindoline -L3-dione

[003201] To a solution of tert-butyl N-[2-[2-[2-[4-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]piperazin-l-yl]ethoxy]ethoxy]ethyl]carbamate (275 mg, 455 umol) in DCM (10.0 mL) was added HCI/dioxane (4.00 M, 7.60 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (232 mg, 99% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 474.3 (M+H)+.

[003202] [(3R,5S) [[4-[4-[[2-[2-(Cycl0Dr0Dylmethylamin0) Dyridyl]0xaz01e-4carbonyllamino]- 3-(difluoromethyl)Dyrazol-l-yl]Dhenyl]methylcarbamoyl]Dyrrolidin yl]

1098 acetate (Intermediate OB)

HCI/dixoane, DCM

[003203] Step 1:Tert-butyl(2S,4R) acetoxv rr4-r4-rr2-[2-rtertbutoxvcarbonyl(cvclopropylmethyl)amino1 pyridvl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-1 -yl1phenyl1methylcarbamoyl1pyrrolidine-1 -carboxylate

[003204] To a solution of tert-butyl (2S,4R) [[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino]- 4-pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methylcarbamoyl] hydroxy-pyrrolidine-l-carboxylate (180 mg, 227 umol, synthesized via Steps 1-3 of Intermediate KG) in pyridine (5.00 mL) was added acetyl acetate (545 mg, 5.34 mmol). The reaction mixture was stirred at rt for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (0.1%, HCI) to give the title compound (180 mg, 95% yield) as colorless oil. LC-MS (ESI+) m/z 835.1 (M+H)+.

[003205] Step 2 - r(3R,5S) rr4-r4-rr2-r2-(Cyclopropylmethylamino) pyridyl1oxazole-41099 carbonvllaminol3-(difluoromethyl)pyrazol-l-yl1phenyl1methylcarbamoyl1pyrrolidin yl1 acetate

[003206] To a solution of tert-butyl (2S,4R) acetoxy [[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl) amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methylcarbamoyl]pyrrolidine carboxylate (110 mg, 132 umol) in DCM (3.00 mL) was added HCI/dioxane (4.00 M, 7.33 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (88.4 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 635.2 (M+H)+.

[003207] [(3R,5S)-l-[(2S) Amino-3,3-dimethvl-butanovl] n4-[4-[[2-[2(cvcloDroDvlmethvlamino)

-Dvridylloxazole carbonyllaminol-3(difluoromethyl)Dyrazol-l-yl]Dhenyl]methylcarbamoyl]Dyrrolidin yl] acetate

HATU, TEA, DMF

[003208] Step 1- r(3R5S)-l-r(2S) (Tert-butoxvcarbonvlamino)-3,3-dimethyl-butanoyl]1100

5-ΓΓ4-Γ4-ΓΓ2-Γ2-(cyclopropylmethylamino) pyridyl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenyl1methylcarbamoyl1pyrrolidin yl1 acetate

[003209] To a solution of [(3R,5S) [[4-[4-[[2-[2-(cyclopropylmethylamino)-4pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]phenyl]methylcarbamoyl]pyrrolidin yl] acetate (88.4 mg, 132 umol, Intermediate OB) and (2S) (tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (36.6 mg, 158 umol, CAS# 6296535-9) in DMF (3.00 mL) was added DIPEA (85.1 mg, 659 umol), The reaction mixture was stirred at rt for 0.5 hr. After, HATU (60.10 mg, 158.07 umol) was added. The resulting reaction mixture was stirred at rt for 0.5 hr. On completion, the reaction mixture was quenched with water (15.0 mL), and extracted with ethyl acetate (3 X 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sulfate sodium, filtered and concentrated in vacuo to give the title compound (110 mg, 99% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 9.07 (s, IH), 8.74 (s, IH), 8.30 (s, IH), 8.17 (d, J= 5.2 Hz, IH), 7.58 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 7.24 (s, IH), 7.13 (d, J= 5.2 Hz, IH), 7.05 - 6.73 (m, 2H), 5.28 (s, IH), 5.06 (d, J= 10.0 Hz, IH), 4.68 (t, J = 7.6 Hz, IH), 4.51 (dd, J = 6.4, 16 Hz, IH), 4.28 (dd, J= 5.2, 14.9 Hz, IH), 4.11 (d, J= 10.0 Hz, IH), 4.00 -3.98 (m, IH), 3.68 - 3.61 (m, IH), 3.17 (dd, J= 5.2, 6.8 Hz, 2H), 2.76 - 2.68 (m, IH), 1.98 (s, 3H), 1.34 (s, 9H), 1.08 (s, IH), 0.83 (s, 9H), 0.57 - 0.50 (m, 2H), 0.28 - 0.22 (m, 2H). LC-MS (ESI+) m/z 848.3 (M+H)+.

[003210] Step 2 - r(3R5S)-l-r(2S) Amino-3,3-dimethvl-butanovl1 rr4-[4-rr2-r2(cyclopropylmethylamino) yl1phenyl1methylcarbamoyl1pyrrolidin yl1 acetate

[003211] To a solution of [(3R,5S)-l-[(2S) (tert-butoxycarbonylamino)-3,3-dimethylbutanoyl] [[4- [4-[[2-[2-(cyclopropylmethylamino) pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methylcarbamoyl]pyrrolidin yl] acetate (110 mg, 130 umol) in DCM (5.00 mL) was added HCl/dioxane (4.00 M, 5.45 mL). The reaction mixture was stirred at rt for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (100 mg, 98% yield) as a white solid. LC-MS (ESI+) m/z 748.2 (M+H)+.

[003212] 3-[5-[4-(4-aminobutoxv)butvl] methvl oxo-benzimidazol-l-yl]DiDeridine2,6- dione (Intermediate OD)

1101

NHB0C

Pd-C, H2, THF

NHBoc

M HCI in dioxane

OD

[003213] Step 1- 7er/-butyl /V-r4-(r4-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-L3-benzodiazol yl1but yn-l-yl1oxy)butyl1carbamate

[003214] To a solution of 3-(5-bromo methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-lyl)piperidine-2,6-dione (2 g, 6 mmol, Intermediate HN) in DMSO (20 mL) were added tert-butyl 7V-[4-(but yn-l-yloxy)butyl]carbamate (4.3 g, 18 mmol, Intermediate OI), Pd(PPh3)4 (683.4 mg, 0.59 mmol), Cui (225.3 mg, 1.18 mmol) and TEA (10 mL) at rt under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 85 °C under nitrogen atmosphere. The reaction mixture was cooled to rt and concentrated under reduced pressure to remove the TEA. The resulting mixture was diluted with ice/water (50 ml, plus 3 ml AcOH) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: Column: WelFlash ™ C18-I, 20-40 pm, 330 g; Eluent A: Water (plus 10 mmol/LFA); Eluent B: ACN; Gradient: 5% B - 5% B in 10 min; 50% B - 60% B in 25 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions were collected at 57% B and concentrated under reduced pressure to afford tertbutyl /V-[4-([4-[l-(2,6-di oxopiperi din yl) methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-5

1102 yl]but yn-l-yl]oxy)butyl]carbamate (1.5 g, 51%) as ayellow solid. 1HNMR (400 MHz, DMSO76) ri 11.12 (s, IH), 7.24 (s, IH), 7.10 (s, 2H), 6.79 (s, IH), 5.41-5.34 (m, IH), 3.55 (t, J= 6.8 Hz, 2H), 3.44 (t, J = 6.3 Hz, 2H), 3.32 (s, 3H), 2.96-2.88 (m, 3H), 2.71-2.65 (m, 4H), 2.11-2.00 (m, IH), 1.49 (s, 2H), 1.48-1.40 (m, 2H), 1.37 (s, 9H); LC/MS (ESI, m/z[ [M - 1]497.2 = &#1470;.

[003215] Step 2 - 7er/-butyl 7V-(4-r4-r1-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-l//-L3-benzodiazol yl]butoxy]butyl)carbamate

[003216] To a solution of tert-butyl 7V-[4-([4-[l-(2,6-dioxopiperidin yl) methyl oxo2,3-dihydro-1//-1,3-benzodiazol yl]but yn-l-yl]oxy)butyl]carbamate (1.5 g, 3.01 mmol) in THF (50 mL) was added palladium on charcoal (0.15 g, 10% w/w) under nitrogen atmosphere. The mixture was hydrogenated at rt for 4 h using a hydrogen balloon. The resulting mixture was filtered through a celite pad and concentrated under reduced pressure to afford tert-butyl 7V-(4-[4[1-(2,6-di oxopiperi din yl) methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-5yl]butoxy]butyl)carbamate (1.2 g, 79%) as a white solid. 1HNMR (400 MHz, CDCh) ri 8.12 (br s, IH), 6.94-6.89 (m, IH), 6.87 (d, J = 1.5 Hz, IH), 6.73 (d, J = 8.0 Hz, IH), 5.23 (dd, J = 12.5, 5.4 Hz, IH), 4.73-4.60 (m, IH), 3.49-3.36 (m, 7H), 3.15 (d, J= 6.1 Hz, 2H), 2.97 (d, J= 16.7 Hz, IH), 2.87 (dd, J = 13.3, 5.0 Hz, IH), 2.70 (t, J = 7.6 Hz, 2H), 2.32-2.19 (m, IH), 1.76-1.50 (m, 9H), 1.46 (s, 9H); LC/MS (ESI, m/z[. [M + 1]+ = 503.4.

[003217] Step 3 - 3-r5-r4-(4-Aminobutoxy)butyl] methyl oxo-2,3-dihydro-l//-L3benzodiazol-l-yl]piperidine-2,6-dione hydrochloride

[003218] A solution of ter/-butyl /V-(4-[4-[l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-1//-1,3-benzodiazol yl]butoxy]butyl)carbamate (150 mg, 0.29 mmol) in dioxane (2 mL) was treated with a solution of HCI (gas) in 1,4-dioxane (4 M, 2 mL) for 16 h at rt under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3-[5-[4-(4aminobutoxy)butyl] methyl oxo-2,3-dihydro-l//-l,3-benzodiazol-l-yl]piperidine-2,6-dione hydrochloride (100 mg, 77%) as a light yellow solid. 1HNMR (400 MHz, DAI SO-0/6) ri 11.08 (s, IH), 7.86 (br s, 3H), 7.05-6.98 (m, 2H), 6.87 (d, J = 8.0 Hz, IH), 5.35 (dd, J= 12.7, 5.3 Hz, IH), 3.74-3.63 (m, IH), 3.57 (s, IH), 3.49 (dd, J = 11.6, 4.4 Hz, IH), 3.42-3.33 (m, 4H), 2.97-2.85 (m, IH), 2.82-2.59 (m, 6H), 2.06-1.96 (m, IH), 1.67-1.48 (m, 8H); LC/MS (ESI, m/z[. [(M + 1)]+ = 403.2.

[003219] (S) (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy) ((S) (2methoxyacetamido) -33&#1524;-dimethylbutanoyl)-N-((R)-l.,2.,3.,4-tetrahydronaDhthalen-l-yl)1103 l4,.3,.2&#1524;-tetrahvdroisoquinoline carboxamide (Intermediate OE)

K2CO3, DMF

OE

[003220] (S) (2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy) ((S) (2methoxyacetamido) -3,3 -dimethylbutanoyl)-N-((R)-1,2,3,4-tetrahydronaphthalen-1 -yl)-1,2,3,4tetrahydroisoquinoline carboxamide was synthesized as described for Intermediate LY, using 2,2-dimethyl oxo-3,8,ll,14,17,20-hexaoxa azadocosan yl 4-methylbenzenesulfonate, Intermediate 00, as the tosylate in Step 1 to couple with alcohol Intermediate MH. 1H NMR (400 MHz, DMSO-Y) δ 8.37 (br. s., 1 H), 8.17 - 8.23 (m, 1 H), 7.30-7.46 (m, 1 H), 6.77 - 7.14 (m, 7 H), 4.63-5.11 (m, 5H), 4.03 - 4.10 (m, 2 H), 3.70 - 3.92 (m, 4 H), 3.40 - 3.63 (m, 18 H), 3.28 - 3.35 (m, 3 H), 2.91 - 3.08 (m, 2 H), 2.78 - 2.88 (m, 2 H), 2.61 - 2.76 (m, 2 H), 1.52-1.88 (m, 4 H), 0.841.04 (m, 9 H). LC-MS (ESI+): m/z 771.2 (M+H)+.

[003221] 22&#1524;-dimethyl oxo-3.,8,ll,14,17.,20.,23-heDtaoxa azaDentacosan oic acid (Intermediate OF)

1104

HO

OH

Phthalimide

PPh3, DIPEA

OF

[003222] SttyD-LANOTzhyriiOXYzAL/J/LlApUlLiO)^^

[003223] To a stirred solution of 3,6,9,12,15-pentaoxaheptadecane-l,17-diol (10 g, 35.4 mmol, CAS# 2615 8) in THF (200 ml) was added phtalimide (6.253 g, 42.51 mmol), and PPh3 (12.06 g, 46.02 mmol) at room temperature. The reaction mixture was degassed and purged with nitrogen several times. The reaction mixture was cooled to 0 °C then DEAD (8.02 g, 46.02 mmol) was added dropwise to the reaction mixture at 0 °C. After the addition, the mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and the residue was purified via column chromatography (DCM / MeOH = 0% - 10%) to give the desired compound (6.4 g, 44.0 %) as a colorless oil. 1HNMR (400 MHz, DMSO4) δ 7.93 - 7.81 (m, 4H), 4.57 (t, J = 5.5 Hz, IH), 3.75 (t, J = 5.8 Hz, 2H), 3.63 (t, J = 5.8 Hz, 2H), 3.54 - 3.48 (m, 7H), 3.46 (ddd, J = 7.0, 4.7, 1.9 Hz, 7H), 3.43 - 3.38 (m, 6H).

[003224] Step 2 - tert-butyl 20-(L3-dioxoisoindolin yl)-3A9,12,15,18-hexaoxaicosan-loate

[003225] To a solution of 2-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)isoindoline-l,3dione (7.0 g, 17.03 mmol) in THF (200 mL) was added 60% NaH (885.6 mg, 22.14 mmol) at 0 °C. After stirring for 0.5 h at 0 °C, tert-butyl 2-bromoacetate (4.65 g, 23.84 mmol) was added

1105 dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 0 °C for 2hrs, then warmed to rt with stirring on for another 2 hrs. The reaction mixture was quenched with water at 0 °C, and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH = 0%-10%) to give the desired compound (4.5 g, 50.3 %) as a pale yellow solid. LC-MS (ESI+): m/z 526.3 (M+H)+.

[003226] Step 3 - 20-(1.3-dioxoisoindolin yl )-3.6.9.12.15.18-hexaoxaicosan-l-oic acid [003227] To a solution of tert-butyl 20-(l,3-dioxoisoindolin yl)-3,6,9,12,15,18hexaoxaicosan-l-oate (4.5 g, 8.571 mmol) in DCM (100 mL) was added TFA (50 mL) at rt. The reaction mixture was stirred at rt for 2 hs, then concentrated in vacuo to give the desired compound (3.5 g, 87.1 %) as a yellow solid. LC-MS (ESI+): m/z 470.2 (M+H)+.

[003228] Step 4: 2.2-dimethyl oxo-3.8.1L14.17.20.23-heptaoxa azapentacosan oic acid

[003229] To a solution of 20-(l,3-dioxoisoindolin yl)-3,6,9,12,15,18-hexaoxaicosan-l-oic acid (3.5 g, 7.463 mmol) in EtOH (50 mL) was added hydrazinium (716.8 mg, 22.4 mmol, 99 %) at r.t. The reaction mixture was heated to reflux for 3 hs. A white solid formed, then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in CH3CN (100 mL). (Boc)2O (9.8 g, 44.8 mmol) was added to the reaction mixture at rt and the mixture was stirred at room temperature for 2 hr. The reaction mixture was then concentrated in vacuo to give a residue which was purified by column chromatography (DCM/MeOH = 0%-10%) to give the desired compound (1.4 g, 42.7 %) as a colorless oil. LC-MS (ESI+): m/z 440.5 (M+H)+.

[003230] Tert-butyl N-[3-[2.,2-dimethvl (prop vn-lyloxvlpropoxy] propyl] carbamate (Intermediate OG)

NHBoc

NaH, DMF

OG

[003231] Step 1 - 2-r3-(3-Hydroxy-2.2-dimethylpropoxy)propyl1-2.3-dihydro-l//-isoindoleL 3 -di one

1106

[003232] To a solution of 2,2-dimethylpropane-l,3-diol (38.8 g, 373 mmol, CAS# 126 7) in DMF (400 mL) was added sodium hydride (60% dispersion in mineral oil, 15.0 g, 375 mmol) at 0 °C. The mixture was stirred for 15 min at the same temperature. Then a solution of 2-(3bromopropyl)-2,3-dihydro-l//-isoindole-l,3-dione (50 g, 187 mmol, CAS# 5460 7) in DMF (50 mL) was added dropwise and the mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched by the addition of a solution of HOAc (60 g) in water (1 L) at rt. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layer was washed with brine (500 mL) and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 50% ethyl acetate in petroleum ether to afford 2-[3-(3-hydroxy-2,2dimethylpropoxy)propyl]-2,3-dihydro-l//-isoindole-l,3-dione (7.4 g, 11%) as a light yellow solid. 1HNMR (400 MHz, CDCh) δ 7.81 (dd, J= 5.5, 3.1 Hz, 2H), 7.69 (dd, J= 5.5, 3.1 Hz, 2H), 3.77 (t, J= 6.6 Hz, 2H), 3.44-3.37 (m, 4H), 3.20 (s, 2H), 1.92 (p, J= 6.2 Hz, 2H), 0.86 (s, 6H); LC/MS (ESI, m/z): [(M + 18)]+ = 292.30.

[003233] Step 2 - Tert-butyl A-r3-(3-hydroxy-2,2-dimethylpropoxy)propyl1carbamate [003234] To a stirred solution of 2-[3-(3-hydroxy-2,2-dimethylpropoxy)propyl]-2,3-dihydrol//-isoindole-l,3-dione (6.1 g, 20.9 mmol) in EtOH (400 mL) was added hydrazine hydrate (2.1 g, 41.9 mmol, 98%) at rt under nitrogen atmosphere. The resulting solution was stirred for 2 h at 70 °C. The mixture was cooled down to room temperature. To the above mixture was added ditert-butyl dicarbonate (27.4 g, 125.6 mmol) at rt and the resulting mixture was stirred for additional 16 hours at rt. After filtration, the filter cake was washed with EtOH (50 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% ethyl acetate in petroleum ether, to afford tert-butyl 7V-[3-(3hydroxy-2,2-dimethylpropoxy)propyl]carbamate (5.6 g, 82%) as a light yellow oil. 1HNMR (400 MHz, CDCh) δ 5.00 (br s, IH), 3.45 (td, J= 5.8, 1.3 Hz, 2H), 3.40 (t, J= 2.0 Hz, 2H), 3.25-3.14 (m, 4H), 1.71 (p, J= 6.6, 6.1 Hz, 2H), 1.41 (s, 9H), 0.87 (s, 6H); LC/MS (ESI, m/z): [(M - 100 + l)]+= 162.35.

[003235] Step 3:Tert-butyl 7V-r3-[2,2-dimethyl (prop yn-lvloxv)propoxv1propyl1carbamate

[003236] To a solution of tert-butyl A-[3-(3-hydroxy-2,2dimethylpropoxy)propyl]carbamate (5.6 g, 21.4 mmol) in DMF (60 mL) was added sodium

1107 hydride (60% dispersion in mineral oil, 1.7 g, 42.5 mmol) at 0 °C. The mixture was stirred for 15 min at the same temperature. Then a solution of 3-bromoprop yne (2.5 g, 21.43 mmol) in DMF (20 mL) was added dropwise and the mixture was allowed to warm to rt and stirred for 16 hours. The reaction was quenched by the addition of saturated aqueous NH4C1 (300 mL) at room temperature. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers was washed with brine (500 mL) and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 10% ethyl acetate in petroleum ether, to afford ter/-butyl A-[3-[2,2-dimethyl (prop yn-l-yloxy)propoxy]propyl]carbamate (2.9 g, 45%) as a light yellow oil: 1HNMR (400 MHz, DMSO-t/6) δ 6.71 (t, J= 5.7 Hz, IH), 4.10 (d, J = 2.4 Hz, 2H), 3.41-3.31 (m, 3H), 3.20 (s, 2H), 3.10 (s, 2H), 2.98 (q, J = 6.6 Hz, 2H), 1.61 (p, J= 6.6 Hz, 2H), 1.38 (s, 9H), 0.84 (s, 6H); LC/MS (ESI, m/z); [(M + 1)]+ = 300.20.

[003237] Tert-butyl V-|3-(1)ro1) vn-l-vloxv)1)ropvl|carba111ate (Intermediate OH) w&#1523;&#1470;/

ΗΟ^^^ΝΗΒοο --------&#9658; 0 NHBoc

THF, NaH

OH

[003238] A solution of /ert-butyl 77-(3-hydroxypropyl)carbamate (1 g, 6 mmol, CAS# 5888558-8) in THF (40 mL) was treated with NaH (60% dispersion in mineral oil, 0.3 g, 14 mmol) for 30 min at 0 °C under nitrogen atmosphere. Next, a solution of 3-bromoprop yne (0.7 g, 6.28 mmol) in THF (5 mL) was added dropwise at 0 °C. The resulting mixture was stirred for 16 h at rt. The reaction was quenched with saturated aqueous NH4HCO3 (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 5%-20% ethyl acetate in petroleum ether, to afford tert-butyl 7V-[3-(prop yn-l-yloxy)propyl]carbamate (0.6 g, 49%) as a yellow oil: 1H NMR (400 MHz, DMSO-t/6) δ 6.77 (t, J = 5.7 Hz, IH), 4.10 (t, J = 2.0 Hz, 2H), 3.44-3.39 (m, 3H), 2.99-2.91 (m, 2H), 1.64-1.59 (m, 2H), 1.38 (s, 9H); LC/MS (ESI, m/z); [(M &#1470;

.212.2 = &#1470;[(1

[003239] Tert-butyl 7V-[4-(but vn-l-vloxy)butvl]carbamate (Intermediate QI)

1108

Cs2CO3, acetone

NaN3

DMSO

PPh3 .¾. Boc2O, NaHCO3 .ILID THF- h2O O DCM, h20

[003240] Step 1 - 4-(4-Bromobutoxv)but-l-yne

[003241] To a stirred solution of 1,4-dibromobutane (201 g, 933 mmol) in acetone (IL) were added Cs2CO3 (223 g, 685 mmol) and but yn-l-ol (43.6 g, 622.05 mmol) at rt. The resulting mixture was stirred for 16 h at rt under nitrogen atmosphere. After filtration, the filter cake was washed with acetone (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 1% ethyl acetate in petroleum ether to afford 4-(4-bromobutoxy)but-l-yne (29 g, 23%) as a light yellow oil. 1HNMR. (400 MHz, CDCh) δ 3.54 (t, J = 6.9 Hz, 2H), 3.49 (t, J = 6.2 Hz, 2H), 3.44 (t, J = 6.6 Hz, 2H), 2.45 (td, J= &#906; Q, 2.6 Hz, 2H), 2.02-1.88 (m, 3H), 1.80-1.65 (m, 2H).

[003242] Step 2 - 4-(4-Azidobutoxy)but-l-yne

[003243] A mixture of 4-(4-bromobutoxy)but-l-yne (29 g, 141 mmol) and NaN3 (14 g, 212 mmol) in DMSO (300 mL) was stirred for 4 h at rt under nitrogen atmosphere. The resulting mixture was diluted with ice water (IL) and extracted with petroleum ether/EtOAc (5/1, v/v, 2 x 500 mL). The combined organic layers was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-(4azidobutoxy)but-l-yne (22.2 g, 94%) as a light yellow oil: 1H NMR (400 MHz, CDCh) δ 3.53 (td, J = 6.9, 1.6 Hz, 2H), 3.47 (td, J = 6.0, 1.7 Hz, 2H), 3.29 (t, J= 6.2 Hz, 2H), 2.44 (tt, J = 7.0, 2.2 Hz, 2H), 1.97 (t, J= 22 Hz, IH), 1.73-1.57 (m, 4H); LC/MS (ESI, m/z] [(2M + 1)]+ = 335.25.

[003244] Step 3 - 4-(But yn-l-yloxy)butan-l-amine

[003245] A solution of 4-(4-azidobutoxy)but-l-yne (22.2 g, 132.8 mmol) and Ph3P (52.2 g, 199.2 mmol) in THF (400 mL) and H2O (80 mL) was stirred for 4 h at 50 °C under nitrogen atmosphere. The resulting mixture was cooled and concentrated under reduced pressure to remove THF. The residue was acidified to pH = 1 with 4 M aqueous HCI. The resulting mixture was extracted with EtOAc (2 x 500 mL). The water layer was neutralized to pH = 7 with 2 M aqueous NaOH, and extracted with DCM (2 x 500 mL). The combined organic layers was washed with

1109 brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude product (18 g). LC/MS (ESI, m z)\ [(M + 1)]+ = 142.1.

[003246] Step 4 - 7c77-butyl Af-[4-(but vn-l-vloxy)butvl1carbamate

[003247] To a stirred solution of 4-(but yn-l-yloxy)butan-l-amine (18 g, 127.5 mmol) in DCM (500 mL) and H2O (500 mL) were added NaHCO3 (21.4 g, 254.9 mmol) and B0C20 (33.4 g, 152.9 mmol) at rt. The resulting mixture was stirred for 16 h at rt under nitrogen atmosphere. The resulting mixture was extracted with CH2C12 (2 x 500 mL). The combined organic layers was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 20% ethyl acetate in petroleum ether to afford ter/-butyl Af-[4-(but3-yn-l-yloxy)butyl]carbamate (30 g, 98%) as a light yellow oil. 1H NMR (400 MHz, CDC13) δ 4.67 (s, IH), 3.54 (td, J= 6.9, 3.6 Hz, 2H), 3.51-3.42 (m, 2H), 3.13 (q, J= 5.6, 4.7 Hz, 2H), 2.45 (dh, J= 22, 4.0, 3.5 Hz, 2H), 1.98 (q, J= 2.8 Hz, IH), 1.58 (td, J= *.2, 2.2, 4.4 Hz, 4H), 1.42 (s, 9H); LC/MS (ESI, m/z[. [(M + 1)]+ = 242.3.

[003248] tert-butyl A-[3-[3-(Dr0D vn-l-vl0xv)Dr0D0xy]Dr0Dvl]carbamate (Intermediate OJ)

MsCI, TEA HO^_,OH h°//&#1523;\/NHBoc -------.- MsO^^/NHBoc -----------&#9658; ΗΟ^^^,Ο^-^/NHBoc

DCM NaH, DMF

NaH,THF

OJ

[003249] Step 1 - tert-butyl TV (methanesulfonyloxy)propyl1 carbamate

[003250] To a stirred solution of tert-butyl TV-(3-hydroxypropyl)carbamate (92.6 g, 528.4 mmol, CAS# 58885 8) in DCM (800 mL) were added TEA (80.2 g, 792.7 mmol) and a solution of MsCI (60.5 g, 528.5 mmol) in DCM (200 mL) dropwise at 0 °C over 30 min under nitrogen atmosphere. The resulting mixture was stirred for 30 min at rt under nitrogen atmosphere. The resulting mixture was diluted with water (2 L) and extracted with CH2C12 (3 x 800 mL). The combined organic layers was washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 40% ethyl acetate in petroleum ether to afford tert-butyl TV-[3-(methanesulfonyloxy)propyl]carbamate (112 g, 84%) as a light brown solid. 1HNMR (400

1110

MHz, CDCh) δ 4.91 (br s, IH), 4.24 (td, J = 6.9, 6.4, 2.9 Hz, 2H), 3.21 (d, J = 7.9 Hz, 2H), 3.062.92 (m, 3H), 1.89 (pd, J = 6.3, 2.6 Hz, 2H), 1.39 (d, J= 3.0 Hz, 9H).

[003251] Step 2 - tert-butyl Af-[3-(3-hvdroxvpropoxv)propyl]carbamate

[003252] To a solution of propane-1,3-diol (50 g, 657 mmol) in DMF (500 mL) was added sodium hydride (4.79 g, 200 mmol, 60% dispersed in mineral oil) at 0 °C. The mixture was stirred for 15 min at rt. To the above mixture was added a solution of tert-butyl 7V-[3(methanesulfonyloxy)propyl]carbamate (25.3 g, 100 mmol) in DMF (150 mL) dropwise rt and the mixture was stirred for 16 hours at rt. The reaction was quenched with sat. NH4C1 (200 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with brine (1.5 L) and extracted with EtOAc (3 x 500 mL). The combined organic layers was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 30% ethyl acetate in petroleum ether to afford tert-butyl 7V-[3-(3hydroxypropoxy)propyl]carbamate (13.7 g, 59%) as a light yellow oil. 1H NMR (400 MHz, CDCh) δ 4.11 (s, IH), 3.57 (td, J= 6.3, 1.9 Hz, 2H), 3.50-3.42 (m, 4H), 3.19 (q, J= 6.5 Hz, 2H), 1.88-1.78 (m, 2H), 1.71 (p, J= 6.5 Hz, 2H), 1.41 (s, 9H); LC/MS (ESI, m/zf [(M + 1)]+ = 234.15. [003253] Step 3 - tert-butyl Af-[3-[3-(prop vn-l-vloxv)propoxv]propvl]carbamate

[003254] To a solution of tert-butyl 7V-[3-(3-hydroxypropoxy)propyl]carbamate (12.5 g, 53.6 mmol) in THF (300 mL) was added sodium hydride (2.6 g, 108.3 mmol, 60% dispersion in mineral oil) at 0 °C. The mixture was stirred for 15 min. To the mixture was added a solution of 3bromoprop yne (6.4 g, 53.8 mmol) in THF (50 mL) dropwise and the mixture was warmed to rt and stirred for 16 hours. The reaction was quenched with sat. NH4C1 (200 mL) at 0 °C, diluted with brine (500 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers was washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with 25% ethyl acetate in petroleum ether to afford tert-butyl N-[3-[3(prop yn-l-yloxy)propoxy]propyl]carbamate (9.2 g, 60%) as a light yellow solid. 1H NMR (400 MHz, CDCh) δ 4.90 (br s, IH), 4.11 (d, J = 2.4 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.50-3.40 (m, 4H), 3.18 (t, J= 7.2 Hz, 2H), 2.42 (t, J= 2.4 Hz, IH), 1.83 (p, J= 6.2 Hz, 2H), 1.71 (p, J= 6.2 Hz, 2H), 1.41 (s, 9H).

[003255] 4-[2-[2-(2-aminoethoxv)ethoxy]ethvlamino] (2.,6-dioxo-31111 piperidyl)isoindoline-l.,3-dione (Intermediate OK)

[003256] 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino] (2,6-di oxo-3 piperidyl)isoindoline-l,3-dione was synthesized as described in Steps 1-2 of Example 127.

[003257] 2-[2-[2-[2-H2-(2,6dioxo piperidyl)-l.,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] ethoxy] acetic acid (Intermediate OL)

[003258] 2-[2-[2-[2-[[2-(2,6di oxo-3 -piperidyl)-1,3 -dioxo-isoindolin-4 yl]amino]ethoxy]ethoxy]ethoxy]acetic acid was synthesized via Steps 1-2 of Example 152.

1112

[003259] 2-[2-[tert-butoxycarbonyl(cycloproDylmethyl)amino] Dyridyl]oxazole-4carboxylic acid (Intermediate OM)

OM

[003260] 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole-4carboxylic acid was synthesized via Steps 1-4 of Intermediate DF.

[003261] 2,2-dimethvl oxo-3,8,ll,14,17-pentaoxa azanonadecan yl 4methylbenzenesulfonate (Intermediate ON)

TsCI

NaN3 Pd/C, H2, (Boc)2O

-----» DMF MeOH

ON

[003262] Step 1 - 3,6,9,12-tetraoxatetradecane-l, 14-diyl bis(4-methylbenzenesulfonate)

[003263] To a mixture of 3,6,9,12-tetraoxatetradecane-l, 14-diol (10 g, 42 mmol, CAS# 75506 4) and TsCI (17.56 g,92.4 mmol) in DCM(200 ml) was added TEA (17 g, 168 mmol) dropwise at rt and the mixture was stirred at rt overnight. Then the reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (100 ml) and washed with water (100 ml x 2), brine (100 ml), dried with Na2SO4, and filtered. The organic phase was evaporated and

1113 the residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (19.17 g, 83.35 yield) as a yellow solid LC-MS (ESI+): m/z 547.1 (M+H)+.

[003264] Step 2 - 3.6.9.12-tetraoxatetradecane- L I4-diyl bis(4-methylbenzenesulfonate)

[003265] To a solution of 3,6,9,12-tetraoxatetradecane-l,14-diyl bis(4methylbenzenesulfonate) (19.17 g, 35.1 mmol) in DMF (100 ml) was added NaN3(2.51 g, 38.62 mmol). The mixture was stirred rt for 2 days. The mixture was poured into water (300 ml) and extracted with EtOAc (3 x 300 ml). The combined organic layers were washed with water (300 ml x 3) and brine (300 ml), dried with Na2SO4, and filtered. The organic phase was evaporated and the residue was purified by silica gel chromatography (PE: EA) to give the title compound as a colorless oil (6.5 g, 44% yield). LC-MS (ESI+): m/z 418.2 (M+H)+.

[003266] £ep£^££2dirnedTyL£0x02X£JJJJ£22penL10xa2%azim0nadecim£92Yl jL methylbenzenesulfonate

[003267] Amixture of 14-azido-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate (10 g,

20.4 mmol), Pd/C (20 %, 1 g), (Boc)2O (6.7 g, 30.6 mmol) and MeOH (200 mL) was stirred for overnight at rt under H2. The mixture was filtered and concentrated in vacuo. To the mixture was added H2O (200 mL) then it was extracted with EA (300 mL). The organic layer was concentrated and purified by column chromatography (PE/EA = 2/1 to 1/1 to EA) to give 2,2-dimethyl oxo3,8,ll,14,17-pentaoxa azanonadecan yl 4-methylbenzenesulfonate (8.2 g, 69 % yield) as a yellow oil. 1HNMR (400 MHz, CDCh) δ 7.81-7.79 (d, J = 8 Hz, 2H), 7.35-7.33 (d, J = 8 Hz, 2H), 4.17-4.13 (t, J = 4.8 Hz, 2H), 3.70-3.47 (m, 16H), 3.31-3.29 (t, J = 5.2 Hz, 2H), 2.45 (s, 3H), 1.44 (s, 9H). LC-MS (ESI+): m/z 492.7 (M+H)+.

[003268] 22&#1524;-dimethyl oxo-3.,8,ll,14,17.,20-hexaoxa azadocosan vl 4methylbenzenesulfonate (Intermediate OO) (Boc)2O ηο&#1470;^ο^ο^ο^ο^ο^νη2 -----*

NaHCO3,THF

[003269]

NHBoc

TsO^°^O^°^O^0^

NHBoc

OO

Step 1TsCI ------&#9658;

TEA, DCM tert-butyl tert-butyl(17-hydroxy-3,6,9,12,151114 pentaoxaheptadecyPcarbamate

[003270] To a stirred solution of 17-amino-3,6,9,12,15-pentaoxaheptadecan-l-ol (4.0 g, 14.22 mmol, CAS# 39160-708&#1470;) in THF (50 mL) was added (Boc)2O (3.72 g, 17.06 mmol) and NaHCO3 (saturated solution, 2 mL) at rt. The reaction mixture was stirred at rt for 3 h. The mixture was concentrated in vacuo and the residue was purified by column to give the desired compound (4.96 g, yield, 73%) as a yellow oil. LC-MS (ESI+): m/z 382.43 (M+H)+.

[003271] Step 2 - 2,2-dimethyl oxo-3,8,lL14,17,20-hexaoxa azadocosan yl 4methylbenzenesulfonate

[003272] To a stirred solution of tert-butyl (17-hydroxy-3,6,9,12,15pentaoxaheptadecyl)carbamate (2.0 g, 5.25 mmol) in DCM (10 mL) was added TEA (1.06 g, 10.5 mmol) at rt. To the above reaction mixture was added dropwise TsCl (2.0 g, 10.5 mmol) in DCM (5 mL) at 0 °C. After the addition, the reaction was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was purified via column chromatography (Petroleum ether/EtOAc = 5% - 80%) to give the desired compound (1.85 g, 66 %) as a yellow oil. LC-MS (ESI+): m/z 536.50 (M+H)+.

[003273] N-(4-piperazin-l-vlcvclohexvl) tetrahvdropvran vl-pyrrolo[2,lf|[L2.,4]triazin amine (Intermediate OP)

1115

NaBH(OAc)3, HOAc, DCM

Boc-N NH

Pd/C, H2, MeOH

[003274] Step 1 - Tert-butyl 4-(trans (((benzvloxv)carbonvl)amino)cvclohexyl)piperazine1-carboxylate (3)

[003275] The reaction was performed in parallel for two batches: to a solution of tert-butyl piperazine carboxylate (24.0 g, 129 mmol) in DCM (400 mL) was added benzyl N-(4oxocyclohexyl)carbamate (31.9 g, 129 mmol, CAS#16801 l), HOAc (3.15 g, 52.5 mmo) and NaBH(OAc)3 (81.9 g, 387 mmol) successively at 0-10 °C, and the mixture was stirred at 15 °C for 16 hours under N2. On completion, the mixture of two bathces was combined, basified to pH = 8 with sat.aq.NaHCO3, and partitioned. The aqueous phase was extracted with DCM (2 X 200 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18 250*50mm*10 um;mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN];B%: 50%75%,26MIN,40%min) to give two fractions. The first fraction is the title compound (20.0 g, 18%

1116 yield) as white solid. 1H NMR (400MHz, CDCh) δ ppm 7.46-7.29 (m, 5H), 5.09 (s, 2H), 4.57 (s, IH), 3.43 (m, 5H), 2.50 (m, 4H), 2.28 (m, IH), 2.10 (d, J = 12.0 Hz, 2H), 1.90 (d, J = 11.6 Hz, 2H), 1.46 (s, 9H), 1.40-1.27 (m, 2 H), 1.22-1.08 (m, 2H). The second fraction is undesired cisisomer (12.7 g, 11% yield).

[003276] Step 2 - Tert-butyl 4-(trans aminocy cl ohexyl )piperazine-1 -carboxylate (4)

[003277] A mixture of tert-butyl 4-[4-(benzyloxycarbonylamino)cyclohexyl]piperazine-lcarboxylate (8.00 g, 16.4 mmol) and Pd/C (800 mg, 10% purity) in MeOH (80 mL) was stirred at 25°C for 2 hours under H2 (15 Psi). On completion, the mixture was filtered, and the cake was washed with MeOH (50 mL). The filtrate and washings were combined and concentrated in vacuum to give the title compound (5.3 g, crude) as white solid. 1H NMR (400 MHz, CDCh) δ ppm 3.49-3.21 (m, 4H), 2.64-2.58 (m, IH), 2.54 (m, 4H), 2.31-2.20 (m, IH), 1.88 (t, J= 15.2 Hz, 4H), 1.45 (s, 9H), 1.34-1.22 (m, 2H), 1.17-1.05 (m, 2H).

[003278] Step 3 - Tert-butyl 4-[4-[(5-bromopyrrolo[2,l-f][L2,41triazin-4yl)amino1cyclohexyl1piperazine-l- carboxylate (6)

[003279] 5-bromo chloro-pyrrolo[2,l-f][l,2,4]triazine (250 mg, 1.08 mmol, CAS#1403767 8), DIPEA (555 mg, 4.30 mmol) and tert-butyl 4-(4aminocyclohexyl)piperazine-l-carboxylate (350 mg, 1.23 mmol) were suspended in IPA (5 mL) under nitrogen and sealed into a microwave tube. The resulting suspension was heated to 150 °C for 3 hours under microwave irradiation. On completed, the mixture was concentrated in vacuo. The crude product was triturated with methanol (5 mL) to give the title compound (300 mg, 58% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 7.92 (s, IH), 7.72 (d, J = 2.8 Hz, IH), 6.80 (d, J= 2.8 Hz, IH), 6.61 (d, J= 6.8 Hz, IH), 4.08 - 4.00 (m, IH), 3.32 - 3.20 (m, 4H), 2.93 2.91 (m, IH), 2.45 - 2.41 (m, 2H), 2.11 - 2.07 (m, 2H), 1.84 - 1.80 (m, IH), 1.57-1.16 (m, 16H); LC-MS (ESI+) m/z 481.2 & 479.2 (M+H)+.

[003280] Step 4 - Tert-butyl 4-[4-[[5-(3,6-dihydro-2H-pyran yl)pyrrolo[2,lf1[L2,41triazin yl1amin01 cyclohexyl1piperazine-l-carboxylate (8)

[003281] A mixture of tert-butyl 4-[4-[(5-bromopyrrolo[2,l-f][l,2,4]triazin-4yl)amino]cyclohexyl]piperazine- 1-carboxylate (300 mg, 625 umol), 2-(3,6-dihydro-2H-pyran-4yl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (394 mg, 1.88 mmol, CAS#287944 5), BrettphosPd-G3 (56.7 mg, 62.5 umol) and K2CO3 (173 mg, 1.25 mmol) in a mixed solvent of THF (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at

1117 °C for 12 hrs under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo. The residue was washed with water (60 mL), extracted with ethyl acetate (3 X 50 mL). The organic layer was dried with Na2SO4, filtrated and concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (220 mg, 73% yield) as yellow oil. 1HNMR (400MHz, DM SO-0/6) δ 7.89 (s, IH), 7.62 (d, J= 2.8 Hz, IH), 6.66 (d, 7= 2.8 Hz, IH), 6.20 (d, 7= 8.0 Hz, IH), 5.82 (s, IH), 4.22 - 4.19 (m, 2H), 3.98 - 3.94 (m, IH), 3.84 (t, 7= 5.2 Hz, 2H), 3.28 - 3.26 (m, 4H), 2.46 - 2.44 (m, 4H), 2.36 (t, 7= 10.8 Hz, IH), 2.10 2.07 (m, 2H), 1.83 - 1.80 (m, 2H), 1.39 (s, 9H), 1.37 - 1.23 (m, 4H); LC-MS (ESI+) m/z 483.4 (M+H)+.

[003282] Step 5 - Tert-butyl 4-r4-r(5-tetrahydropyran ylpyrrolo[2,l-f]rL2,41triazin-4vl)amino1cvclohexyl1 piperazine carboxylate (9)

[003283] To a solution of tert-butyl 4-[4-[[5-(3,6-dihydro-2H-pyran yl)pyrrolo[2,lf][l,2,4]triazin yl] amino]cyclohexyl]piperazine-l-carboxylate (220 mg, 455 umol) in methanol (30 mL) was added Pd/C (100 mg, 10%, wt) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 hours. On completion, the reaction mixture was fdtered. The fdtrate was concentrated in vacuo to give the title compound (190 mg, 86% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 7.78 (s, IH), 7.54 (d, 7= 2.8 Hz, IH), 6.53 (d,7=2.8Hz, IH), 6.21 (d, 7= 8.0 Hz, IH), 4.17 - 3.97 (m, IH), 3.92 - 3.88 (m, 2H), 3.57 - 3.51 (m, 2H), 3.44 - 3.38 (m, IH), 3.29 - 3.27 (m, 4H), 2.45 - 2.43 (m, 4H), 2.35 - 2.29 (m, IH), 2.01 - 1.98 (m, 2H), 1.84 - 1.81 (m, 2H), 1.79 - 1.72 (m, 2H), 1.66 1.63 (m, 2H), 1.57 - 1.47 (m, 2H), 1.39 (s, 9H), 1.37 - 1.28 (m, 2H); LC-MS (ESI+) m/z 485.4 (M+H)+.

[003284] Step 6 - N-(4-piperazin-l-ylcy cl ohexyl) tetrahydropyran yl-pyrrolo[2,lf1[L2,41triazin amine (Intermediate OP)

[003285] To a solution of tert-butyl 4-[4-[(5-tetrahydropyran ylpyrrolo[2,lf][l,2,4]triazin yl)amino] cyclohexyl]piperazine-l-carboxylate (180 mg, 345 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 50 mL). The reaction mixture was stirred at 20 °C for 20 minutes. On completion, the mixture was fdtered and concentrated in vacuo to give the title compound (145 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 385.3 (M+H)+.

[003286] Step 7 - l-r4-r4-r(5-Tetrahydropyran ylpyrrolor2,l-f]rL2,41triazin-4yl)amino1cyclohexyl1 piperazin yl]ethanone (10)

1118

[003287] To a solution of N-(4-piperazin-l-ylcyclohexyl) tetrahydropyran ylpyrrolo[2,l-f][l,2,4]triazin- 4-amine (153 mg, 363 umol, HCI salt) and AcOH (24.0 mg, 399 umol) in DMF (3 mL) was added HATU (165 mg, 436 umol). Then, DIPEA (187 mg, 1.45 mmol) was added. The reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 3%-33%, 10 min) to give the title compound (94.0 mg, 61% yield) as white solid. 1H NMR (400MHz, DMSO-t/6) δ 7.79 (s, IH), 7.54 (d, J = 2.8 Hz, IH), 6.54 (d, J = 2.8 Hz, IH), 6.20 (d, J = 8.0 Hz, IH), 4.14 4.01 (m, IH), 3.91 (dd, J= 3.2, 10.8 Hz, 2H), 3.55 (t, J= 10.8 Hz, 2H), 3.44 - 3.40 (m, 6H), 2.58 - 2.54 (m, 2H), 2.43 - 2.39 (m, IH), 2.04 - 2.00 (m, 2H), 1.98 (s, 3H), 1.87 - 1.85 (m, 2H), 1.78 1.72 (m, 2H), 1.71 - 1.59 (m, 2H), 1.58 - 1.47 (m, 2H), 1.44-1.31 (m, 2H); LC-MS (ESI+) m/z 427.3 (M+H)+.

[003288] Nl-methvl-N4-(5-tetrahvdropvran vl-7H-pyrrolo[2,3-d]pvrimidin-4vDcyclohexane-1.,4- diamine (Intermediate OQ)

1119

Intermediate OQ

[003289] Step 1 - Tert-butyl N-[4-(dibenzvlamino)cvclohexvl]carbamate (2)

[003290] To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (3.00 g, 14.0 mmol, CAS#177906 8) in ACN (50 mL) was added K2CO3 (5.80 g, 42.0 mmol) and BnBr (7.18 g, 42.0 mmol). The mixture was stirred at 60°C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (4.60 g, 83% yield) as white solid. 1H NMR (400MHz, DMSO4) δ 7.38 - 7.26 (m, 8H), 7.24 - 7.14 (m, 2H), 6.58 (d, J= 8.0 Hz, IH), 3.56 (s, 4H), 3.16 (d, 7= 8.4 Hz, IH), 2.32 (t, J= 12.0 Hz, IH), 1.78 (d, J= 10.4 Hz, 4H), 1.49- 1.38 (m, 2H), 1.35 (s, 9H), 1.08 - 0.91 (m, 2H); LC-MS (ESI+) m/z 395.3 (M+H)+.

[003291] Step 2 - Tert-butyl N-[4-(dibenzvlamino)cvclohexvl]-N-methyl-carbamate (3) [003292] To a solution of tert-butyl N-[4-(dibenzylamino)cyclohexyl]carbamate (4.00 g, 10.1 mmol) in DMF (80 mL) was added NaH (810 mg, 20.2 mmol, 60% purity) at 0°C. The

1120 mixture was stirred at 0°C for 0.5 hour, and then Mel (2.88 g, 20.2 mmol) was added. The mixture was stirred at 20°C for 16 hours. On completion, the reaction mixture was quenched by water (60 mL) at 0°C, and then extracted with EA (3 X 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was triturated with DMF (8 mL) to give the title compound (3.70 g, 89% yield) as white solid. 1H NMR (400MHz, CDCh) δ 7.38 (d, J= 7.2 Hz, 4H), 7.30 (t, J= 7.2 Hz, 4H), 7.25 - 7.18 (m, 2H), 3.63 (s, 4H), 2.66 (s, 3H), 2.52 -2.39 (m, IH), 1.96 (d, J = 11.6 Hz, 2H), 1.72 (d, J = 11.2 Hz, 2H), 1.58 - 1.30 (m, 14H); LC-MS (ESI+) m/z 409.2 (M+H)+.

[003293] Step 3 - Tert-butyl N-(4-aminocvclohexvl)-N-methvl-carbamate (4)

[003294] To a solution of tert-butyl N-[4-(dibenzylamino)cyclohexyl]-N-methyl-carbamate (2.60 g, 6.36 mmol) in a mixed solvent of MeOH (10 mL) and EA (50 mL) was added Pd(OH)2/C (200 mg, 10% purity), Pd/C (200 mg, 10% purity) and ΝΗ3.Η2Ο (182 mg, 0.2 mL, 38% purity) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred at 20°C for 16 hours under H2 (15 psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.40 g, 96% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 2.70 (s, 3H), 2.64 - 2.57 (m, IH), 1.91 (d, J= 12.0 Hz, 2H), 1.67 (d, J= 12.0 Hz, 2H), 1.58 - 1.48 (m, 2H), 1.45 (s, 9H), 1.32-1.17 (m, 3H).

[003295] Step 4:Tert-butyl N-[4-n5-bromo (2trimethvlsilvlethoxvmethyl)pvrrolo[2.,3-d]pvrimidin vl] carbamate (6)

[003296] To a solution of tert-butyl N-(4-aminocyclohexyl)-N-methyl-carbamate (1.25 g, 5.47 mmol) and 2-[(5-bromo chloro-pyrrolo[2,3-d]pyrimidin yl)methoxy]ethyl-trimethylsilane (2.18 g, 6.02 mmol, from 1-442) in ACN (50 mL) was added Na2CO3 (1.16 g, 10.9 mmol). The mixture was stirred at 85°C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give the title compound (2.40 g, 79% yield) as light yellow oil. 1H NMR (400MHz, DM SO-0/6) δ 8.21 (s, IH), 7.55 (s, IH), 6.06 (d, J= 8.0 Hz, IH), 5.46 (s, 2H), 4.06 (s, IH), 3.49 (t, J= 8.0 Hz, 2H), 3.32 - 3.29 (m, IH), 2.69 (s, 3H), 2.08 (d, J= 10.0 Hz, 2H), 1.73 - 1.54 (m, 4H), 1.54 - 1.44 (m, 2H), 1.40 (s, 9H), 0.81 (t, J= 8.0 Hz, 2H), -0.09 (s, 9H); LC-MS (ESI+) m/z 554.2 (M+H)+.

1121

[003297] Step 5 - Tert-butyl N-[4-[[5-(3,6-dihydro-2H-pyran yl) (2trimethylsilylethoxymethyl)pyrrolo[2,3-d] pyrimidin yl] amino] cyclohexyl]-N-methylcarbamate (8)

[003298] To a mixture of tert-butyl N-[4-[[5-bromo (2trimethylsilyl ethoxymethyl)pyrrolo[2,3-d]pyrimidin- 4-yl]amino]cyclohexyl]-N-methylcarbamate (1.20 g, 2.16 mmol) and 2-(3,6-dihydro-2H-pyran yl)- 4,4,5,5-tetramethyl-l,3,2dioxaborolane (1.36 g, 6.49 mmol, CAS#287944 5) in a mixed solvent of THF (20 mL) and H2O (4 mL) was added BrettPhos-Pd-G3 (196 mg, 216 umol) and K2CO3 (598 mg, 4.33 mmol). The mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 55 °C for 16 hours under N2 atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was washed with water (30 mL) and extracted with EA (6 X 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography to give the title compound (0.92 g, 76% yield) as light yellow solid. 1HNMR (400MHz, DMSO-t/6) δ 8.20 (s, IH), 7.36 (s, IH), 5.81 (s, IH), 5.62 (d, J = 8.0 Hz, IH), 5.47 (s, 2H), 4.24 (d, J = 2.4 Hz, 2H), 4.07 - 3.94 (m, IH), 3.84 (t, J = 5.6 Hz, 2H), 3.49 (t, J = 8.0 Hz, 2H), 2.69 (s, 3H), 2.44 (s, 2H), 2.09 (d, J = 10.4 Hz, 2H), 1.73 - 1.55 (m, 4H), 1.45 - 1.35 (m, 11H), 0.81 (t, J = 8.0 Hz, 2H), -0.08 (s, 9H); LC-MS (ESI+) m/z 558.4 (M+H)+.

[003299] Step 6 - Tert-butyl N-methyl-N-[4-[[5-tetrahydropyran yl (2trimethylsilylethoxymethyl)pyrrolo [23&#1524;-d]pyrimidin yl]amino]cyclohexyl]carbamate (9) [003300] To a solution of tert-butyl N-[4-[[5-(3,6-dihydro-2H-pyran yl) (2trimethylsilyl ethoxymethyl) pyrrolo[2,3-d]pyrimidin yl]amino]cyclohexyl]-N-methylcarbamate (200 mg, 358 umol) in MeOH (10 mL) was added Pd/C (60.0 mg, 10% purity) under N2. The suspension was degassed in vacuo and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25°C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (195 mg, 88% yield) as light yellow solid. LCMS (ESI+) m/z 560.3 (M+H)+.

[003301] Step 7- [4-[[4-(Methylamino)cyclohexyl]amino] tetrahydropyran ylpyrrolo [2,3-d] pyrimidin yllmethanol (10)

[003302] To a solution of tert-butyl N-methyl-N-[4-[[5-tetrahydropyran yl (2trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidin yl]amino]cyclohexyl]carbamate (190 mg,

1122

339 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 45°C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (120 mg, 63% yield) as light yellow solid. LC-MS (ESI+) m/z 360.1 (M+H)+.

[003303] Step 8 - Nl-methyl-N4-(5-tetrahydropyran yl-7H-pyrrolo[2,3-d]pyrimidin4-yl)cyclohexane-l,4- diamine (Intermediate OQ)

[003304] To a solution of [4-[[4-(methylamino)cyclohexyl]amino] tetrahydropyran ylpyrrolo[2,3-d] pyrimidin yl]methanol (120 mg, 303 umol) in a mixed solvent of THF (6 mL) and H2O (1.5 mL) was added LiOH*H2O (50.8 mg, 1.21 mmol). The mixture was stirred at 25°C for 16 hours. On completion, the reaction mixture was acidified with IN HCI solution till pH = 7, and then concentrated in vacuo give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.04%NH3H20+10mM NH4HCO3) to give the title compound (12.1 mg, 12% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 11.31 (s, IH), 8.07 (s, IH), 6.83 (s, IH), 5.53 (d, J = 8.0 Hz, IH), 4.13 - 3.99 (m, IH), 3.90 (dd, 7=3.2, 11.2 Hz, 2H), 3.54 (t, J= 11.6 Hz, 2H), 3.28 -3.19 (m, 2H), 2.32 - 2.21 (m, 4H), 2.01 - 1.80 (m, 6H), 1.60 - 1.49 (m, 2H), 1.47 - 1.32 (m, 2H), 1.20 - 1.01 (m, 2H); LC-MS (ESI+) m/z 330.3 (M+H)+.

[003305] 3-(l-(2,6-Dioxopiperidin vl) methvl oxo-2,3-dihydro-lHbenzo[d]imidazol yl) propanal (Intermediate OR)

OR

1123

[003306] Step 1 - (E) (4-(3-hydroxyprop-l-en-l-yl) methyl oxo-2,3-dihydro-lHbenzo[d1imidazol-l-yl) piperi dine-2,6-dione

[003307] A mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, Intermediate HP), prop en-l-ol (0.500 g, 8.61 mmol), DIPEA (764. mg, 5.91 mmol), Pd2(dba)3 (271 mg, 296 umol) and P(t-Bu)3 (1.20 g, 591 umol, 10% purity in hexane solution) in dioxane (50 mL) was de-gassed and then heated to 30 °C for 24 hours under N2. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA condition) to give the title compound (860 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m/z 316.1 (M + H)+.

[003308] Step 2:3-(4-(3-Hydroxypropyl) methyl oxo-2,3-dihydro-lHbenzo[d1imidazol-l-vl)piperidine- 2,6-dione

[003309] To a solution of 3-[4-[(E) hydroxyprop-l-enyl] methyl oxo-benzimidazol-lyl]piperidine- 2,6-dione (860 mg, 2.73 mmol) in THF (10 mL) was added Pd/C (100 mg, 163 umol) (10%, wt) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 °C for 48 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reversed-phase chromatography (0.1% FA condition) to give the title compound (450 mg, 44% yield) as a yellow solid. LC-MS (ESI+) m/z 318.1 (M + H) +.

[003310] Step 3 - 3-(1-(2,6-Dioxopiperidin vl) methvl oxo-2,3-dihydro-lHbenzo[d1imidazol yl) propanal

[003311] To a solution of 3-[4-(3-hydroxypropyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (250 mg, 788 umol) in DCM (10 mL) was added DMP (400 mg, 945 umol). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched with saturated sodium thiosulfate (50 mL) and saturated aq.NaHCO3, then extracted with DCM (3 X 150 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound (240 mg, 96% yield) as a white solid. 1HNMR (400MHz, CDC13) δ 9.80 (s, IH), 8.33 - 8.04 (m, IH), 6.96 - 6.91 (m, IH), 6.82 (d, J= 8.0 Hz, IH), 6.62 (d, J= 8.0 Hz, IH), 5.13 (dd, J = 5.6, 12.4 Hz, IH), 3.61 (s, 3H), 3.21 (t, J= 7.6 Hz, 2H), 2.81 (t, J= 7.6 Hz, 2H).

1124

[003312] 3-(4-(3-(((6-(Aminomethyl)hexahvdrofuro[3.,2-b]furan-3vl)methvl)amino)propvl)-3methyl oxo-2.,3-dihvdro-lH-benzo[d]imidazol-lyl)piperidine-2.,6-dione (Intermediate OS)

OR

[003313] To a solution of 3-[1 -(2,6-dioxo piperidyl) methyl oxo-benzimidazol-4yl]propanal (120 mg, 380 umol, Intermediate OR) and [6-(aminomethyl)-2,3,3a,5,6,6ahexahydrofuro[3,2-b]furan yl]methanamine (328 mg, 1.90 mmol, Intermediate OT) in DMF (5 mL) was added 4A MS (100 mg) and HOAc (45.7 mg, 761 umol). The reaction mixture was stirred at 80 °C for 1 hour. Then, NaBH3CN (47.8 mg, 761 umol) was added. The resulting reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Shim-pack Cl8 150*25*lOum; mobile phase: [water (0.225%FA)-ACN]; B%: l%-25%, lOmin) to give the title compound (50.0 mg, 23% yield) as a white solid. LC-MS (ESI+) m/z 472.3 (M + H) +.

[003314] [6-(Aminomethyl)-2.,3.,3a.,5.,6.,6a-hexahvdrofuro[3.,2-b]furan-3yl]methanamine (Intermediate OT)

BH3Me2S &#943; AAh2 ___1_&#943;_&#9658; Η2Ν^Αγ j THF

OT

[003315] Step 1 - r(3R,3aS,6R,6aS) (Trifluoromethylsulfonyloxy)-2,3,3a,5A6ahexahydrofuro[3,2-b1 furan yl] trifluoromethanesulfonate

[003316] To a solution of (3R,3aR,6R,6aR)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6diol (25.0 g, 171 mmol, CAS# 641 7) and pyridine (32.4 g, 410 mmol) in DCM (250 mL) at 0

1125 °C was added Tf20 (115 g, 410 mmol, 67.74 mL) dropwise. Then the mixture was stirred at rt for 3 hours. On completion, the reaction mixture was acidified with IN aq.HCl until the pH= 3. The mixture was washed with H2O (3 X 50 mL). The organic layer was basified with saturated NaHCO3 solution until the pH= 8. The organic layer was then washed with brine (2 X 30 mL) and dried over Na2SO4, then filtered. The filtrate was concentrated in vacuo to give the title compound (70.0 g, 99% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 5.28 - 5.19 (m, 2H), 4.82 - 4.75 (m, 2H), 4.22-4.12 (m, 4H).

[003317] Step 2 - 2,3,3A,5,6,6a-Hexahydrofuro[3,2-b1furan-3,6-dicarbonitrile

[003318] To a mixture of 18-crown-6 (58.9 g, 223 mmol) and KCN (48.4 g, 743 mmol) in THF (400 mL) was added a solution of [(3R,3aS,6R,6aS) (trifluoromethylsulfonyloxy)2,3,3a,5,6,6a -hexahydrofuro[3,2-b]furan yl]trifluorom ethanesulfonate (61.0 g, 148 mmol) in THF (400 mL). Then the reaction mixture was stirred at 0 °C for 3 hours. On completion, the reaction was warmed to room temperature, then the mixture was poured into cold water (200 mL) and extracted with chloroform (5 X 100 mL). The combined organic layers were dried over Mg2SO4, then filtered. The filtrate was decolorized with activated carbon. After filtration through celite, the filtrate was concentrated in vacuo. The residue was purified by Prep-TLC (SiO2, PE: EA = 1: 1) to give the title compound (5.00 g, 20% yield) as yellowish solid. 1H NMR (400MHz, CDCh) δ 5.03 (s, 2H), 4.14 - 4.07 (m, 4H), 3.22 - 3.19 (m, 2H).

[003319] Step 3 - [6-(Aminomethyl)-2,3,3a,5,6,6a-hexahvdrofuro[3,2-b1furan-3vHmethanamine

[003320] To a solution of 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-dicarbonitrile (2.50 g, 15.2 mmol) in THF (25.0 mL) was added BH3-Me2S (10.0 M, 25.0 mL) dropwise. The mixture was stirred at 20 °C for 16 hours under N2. On completion, the reaction mixture was quenched with MeOH (50 mL). The mixture was concentrated in vacuo to give the title compound (2.62 g, 100% yield) as white solid. 1H NMR (400MHz, D2O) δ 4.30 - 3.86 (m, IH), 3.71 - 3.47 (m, 4H), 3.12 - 2.91 (m, 3H), 2.68 - 2.50 (m, 2H), 1.68 - 1.40 (m, 2H).

[003321] 3-[l-(2.,6-Dioxo DiDeridvl) methvl oxo-benzimidazol vl]DroDanal (Intermediate OU)

1126

ΗΝ

OU

[003322] Step 1 - 3-r5-(3-Hydroxyprop-l-enyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione

[003323] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (1.00 g, 2.96 mmol, Intermediate HN) and prop en-l-ol (350 mg, 6.03 mmol) in dioxane (10.0 mL) was added P(t-Bu)3 (1.20 g, 591 umol, 10 wt %), Pd2(dba)3 (270 mg, 295 umol) and DIPEA (496 mg, 3.84 mmol). The mixture was stirred at 20 °C for 16 hours under N2. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (750 mg, 80% yield) as yellow solid. 1H NMR (400MHz, DMSO-76) δ 12.74 (s, IH), 11.08 (s, IH), 9.80 - 9.62 (m, IH), 7.11 - 7.07 (m, IH), 7.01 (d, J = 8.0 Hz, IH), 6.95 - 6.93 (m, IH), 6.96 - 6.83 (m, IH), 5.41 - 5.25 (m, IH), 3.31 (s, 3H), 2.94 - 2.89 (m, 2H), 2.81 - 2.76 (m, IH), 2.75 - 2.65 (m, IH), 2.65 - 2.54 (m, IH), 2.04 1.94 (m, IH).

[003324] Step 2 - 3-r5-(3-Hydroxypropyl) methyl oxo-benzimidazol-l-yl1piperidine2,6-dione

[003325] To a solution of 3-[5-[(E) hydroxyprop-l-enyl] methyl oxo-benzimidazol-lyl] piperidine-2, 6-dione (750 mg, 2.38 mmol) in THF (30.0 mL) was added PtO2 (54.0 mg, 237 umol). The mixture was stirred at 20 °C for 16 hours under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (220 mg, 29% yield) as white solid. 1H NMR (400MHz, DM SO-6/6) δ 11.08 (s, IH), 7.06 - 6.96 (m, 2H), 6.90 - 6.82 (m, IH), 5.38 - 5.27

1127 (m, IH), 3.45 - 3.42 (m, 2H), 3.33 (s, 3H), 2.98 - 2.78 (m, 2H), 2.76 - 2.68 (m, IH), 2.64 - 2.60 (m, IH), 2.59 - 2.52 (m, IH), 2.05 - 1.93 (m, IH), 1.83 - 1.66 (m, 2H).

[003326] Step 3 - 3-[l-(2,6-Dioxo piperidvl) methvl oxo-benzimidazol yl1propanal

[003327] To a solution of 3-[5-(3-hydroxypropyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (220 mg, 693 umol) in DCM (10.0 mL) was added DMP (352 mg, 831 umol). The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was quenched with saturated Na2S2O3 (30 mL) and washed with saturated NaHCO3 (2 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 91% yield) as yellow solid. LC-MS (ESI+) m/z 316.1(M+H)+.

[003328] 3-[5-[3-[[3-(Aminomethyl)-2.A3a.,5.,6.,6a-hexahydrofuro[3.,2-b]furan-6yl] Dropyl] methyl oxo-benzimidazol-l-yl]piperidine-2.,6-dione (Intermediate OV)

OU ov

[003329] To a solution of 3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl]propanal (190 mg, 602 umol, Intermediate OU), [6-(aminomethyl)-2,3,3a,5,6,6ahexahydrofuro[3,2-b]furan yl]methanamine (518 mg, 3.01 mmol, Intermediate OT) in DMF (6.00 mL) was added HO Ac (72.3 mg, 1.21 mmol) and 4A molecular sieves (10.0 mg). The mixture was stirred at 80 °C for 1 hour. The mixture was cooled to 25 °C, then NaBH3CN (75.7 mg, 1.21 mmol) was added, and the mixture was stirred at 25 °C for 16 hours. On completion, the mixture was quenched with H2O (1 mL), filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Shim-pack Cl8 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: l%-30%, 10 min) to give the title compound (120 mg, 42% yield) as yellow solid. 1HNMR (400MHz, DMSO-A) δ 8.19 (s, IH), 8.04 (s, IH), 7.07 - 6.98 (m, 2H), 6.87 (d, J = 7.2 Hz, IH), 5.42- 5.28 (m, IH), 4.42 - 4.35 (m, 2H), 4.31 - 4.22 (m, 2H), 3.85-3.78 (m, 2H), 3.33 (s, 3H), 3.12-3.06 (m, 2H), 3.02 - 2.94 (m, 2H), 2.79 - 2.73 (m, IH), 2.66 - 2.64 (m, IH), 2.47 - 2.46 (m, IH), 2.32 - 2.24 (m, 6H), 2.07 - 1.94 (m, IH), 1.79 - 1.70 (m, 2H).

[003330] 4-Amino-l-[4-(hvdroxvmethyl)Dhenvl]Dvrazole carbonitrile (Intermediate OW) (IRW-598)

1128

no2

Cu(OAc)2, Py, 02, DCM

HO

NO2

CN

Fe, NH4CI

EtOH, H2O

CN

[003331] Step 1- l-r4-(Hydroxymethyl)phenyl1 nitro-pyrazole carbonitrile

[003332] To a mixture of 4-nitro-lH-pyrazole carbonitrile (3.00 g, 21.7 mmol, CAS# 61241 4) and [4-(hydroxylmethyl)phenyl] boronic acid (2.20 g, 14.4 mmol, CAS# 59012-932) in mixed solvents of pyridine (25 mL) and DCM (75 mL) was added Cu(OAc)2 (3.94 g, 21.7 mmol) under 02 (15 psi), then the mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2) to give the title compound (3.00 g, 78% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 9.90 (s, IH), 7.95 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 4.62 (s, 2H), 4.39 (s, IH).

[003333] Step 2- 4-Amino-l-r4-(hydroxymethyl)phenyl1pyrazole carbonitrile

[003334] To a mixture of l-[4-(hydroxymethyl)phenyl] nitro-pyrazole carbonitrile (3.00 g, 12.3 mmol) in a mixed solvents of EtOH (120 mL) and H2O (30 mL) was added NH4C1 (6.57 g, 123 mmol). The mixture was heated to 65 °C. Then Fe (6.86 g, 123 mmol) was added in portions. The reaction mixture was stirred at 65 °C for 1 hour. On completion, the reaction mixture was cooled to 25 °C, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2) to give the title compound (1.20 g, 42% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 7.84 (s, IH), 7.70 (d, J = 8.8 Hz, 2H), 7.41 (d, J= 8.8 Hz, 2H), 5.25 (t, J= 5.6 Hz, IH), 5.00 (s, 2H), 4.50 (d, J= 5.6 Hz, 2H).

[003335] Tert-butyl N-[4-[4-[[3-cvano-l-(4-formylDhenvl)Dvrazol-4yl] carbamoyl] oxazol yl] Dvridvl]-N-(cvcl0Dr0Dvlmethyl)carbamate (Intermediate OX)

1129

[003336] Step 1- Tert-butyl N-r4-r4-rr3-cyano-l-[4-(hydroxymethyl)phenyl1pyrazol-4vl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[003337] To a mixture of 4-amino-1 -[4-(hydroxymethyl)phenyl]pyrazole carbonitrile (300 mg, 1.40 mmol, Intermediate OW) and 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylic acid (503 mg, 1.40 mmol, Intermediate OM) in DMF (10 mL) was added DIPEA (543 mg, 4.20 mmol) and HATU (639 mg, 1.68 mmol). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (453 mg, 52% yield) as a yellow solid. 1HNMR (400MHz, DMSO-76) δ 10.73 (s, IH), 9.08 (s, IH), 8.85 (s, IH), 8.61 (d, J= 5.2 Hz, IH), 8.36 (s, IH), 7.86 (d, J= 8.8 Hz, 2H), 7.72 (d, 7= 1.2, 4.0 Hz, IH), 7.51 (d, 7= 8.4 Hz, 2H), 5.34 (t, 7= 5.6 Hz, IH), 4.58 (d, 7= 5.6 Hz, 2H), 3.88 (d, 7= 6.8 Hz, 2H), 1.52 (s, 9H), 1.20 - 1.15 (m, IH), 0.46 - 0.37 (m, 2H), 0.30 - 0.20 (m, 2H).

[003338] Step 2- Tert-butyl N-r4-r4-rr3-cyano-l-(4-formylphenyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[003339] To a mixture of tert-butyl N-[4-[4-[[3-cyano-l-[4-(hydroxymethyl)phenyl]pyrazol4-yl]carbamoyl] oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (350 mg, 630 umol) in DCM (15 mL) was added DMP (294 mg, 693 umol). The reaction was stirred at 20 °C for 1 hour. On completion, a solution of sodium thiosulfate aqueous solution (20 mL) and saturated sodium bicarbonate (20 mL) was added into the mixture and stirred for 10 minutes. Then the mixture was

1130 extracted with DCM (2 X 20 mL). The combined organic layer was washed with brine (2 X 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give title compound (320 mg, 91% yield) as a yellow solid. 1HNMR (400MHz, DMSO-t/6) δ 10.85 (s, IH), 10.07 (s, IH), 9.14 - 9.02 (m, 2H), 8.61 (d, J = 52 Hz, IH), 8.36 (s, IH), 8.23 - 8.15 (m, 2H), 8.14 - 8.08 (m, 2H), 7.72 (d, J = 52 Hz, IH), 3.88 (d, J = 7.2 Hz, 2H), 1.52 (s, 9H), 1.26 - 1.11 (m, IH), 0.49 0.37 (m, 2H), 0.30 - 0.21 (m, 2H).

[003340] 6-Bromo-3H-l,3-benzoxazol one (Intermediate OY)

[003341] To a solution of 2-amino bromo-phenol (4.50 g, 23.9 mmol, CAS# 38191 3) in THF (120 mL) was added CDI (4.66 g, 28.7 mmol). The reaction mixture was stirred at 70 °C for 2 hours. On completion, the reaction mixture was added to water (240 mL) and the mixture was adjusted pH = 6 ~ 7 with 2.0 M aq.HCl, then ethyl acetate (150 mL) was added. The organic layer was separated and washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized in toluene (60 mL) to give the title compound (3.75 g, 90% yield) as an off-white solid. 1H NMR (400MHz, DMSO-d6) δ 7.58 (d, 7= 1.6 Hz, IH), 7.32 (dd, J= 1.8, 8.4 Hz, IH), 7.06 (s, IH), 7.04 - 7.01 (m, IH). LC-MS (ESI+) m/z 216.0 & 214.0 (M + Na)+.

[003342] 3-(6-Bromo oxo-l.,3-benzoxazol vl)DiDeridine-2.,6-dione (Intermediate OZ)

1131

O. QTf

PMB-N

1Q o t-BuOK, THF

methoxyphenyl)methyl1piperidine-2,6-dione

[003344] To a solution of 6-bromo-3H-l,3-benzoxazol one (2.00 g, 9.35 mmol, Intermediate OY) in THF (50 mL) was added t-BuOK (1.26 g, 11.2 mmol). The reaction mixture was stirred at 0 °C for 0.5 hour. Subsequently, [l-[(4-methoxyphenyl)methyl]-2,6-dioxo-3piperidyl] trifluoromethanesulfonate (4.81 g, 12.6 mmol, Intermediate IQ) in a solution of THF (30 mL) was added dropwise. The resulting reaction mixture was stirred at 20 °C for 0.5 hour under N2. On completion, the reaction mixture was quenched with saturated NH4C1 (100 mL), and extracted with ethyl acetate (100 mL). The combined organic layer was washed with brine (2 X 100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA: DCM = 5:1:2) to give the title compound (3.75 g, 90% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 7.22 - 7.20 (d, J= 8.0 Hz, IH), 6.89 - 6.87 (d, J= 8.0 Hz, IH), 4.90 - 4.86 (m, IH), 4.47 - 4.36 (m, 2H) 3.81 (s, 3H), 2.67 - 2.64 (m, IH), 2.59 - 2.54 (m, 2H), 2.40 - 2.38 (m, IH). LC-MS (ESI+) m/z 466.9 & 468.9 (M + Na)+.

[003345] Step 2 - 3-(6-Bromo oxo-L3-benzoxazol yl)piperidine-2,6-dione

[003346] To a mixture of 3-(6-bromo oxo-l,3-benzoxazol yl)-l-[(4methoxyphenyl)methyl]piperidine- 2,6-dione (2.00 g, 4.49 mmol) in ACN (60 mL) was added

1132

CAN (7.39 g, 13.4 mmol) in solution of H2O (20 mL), and the reaction mixture was degassed and purged with N2 for 3 times. Then the mixture was stirred at 20 °C for 3 hours under N2 atmosphere. On completion, the reaction mixture was filtered. The filtered cake was collected and dried in vacuo to give the title compound (900 mg, 61% yield) as a white solid. 1HNMR(400MHz, DMSOd6) δ 11.24 (s, IH), 7.74 (d, J = 1.6 Hz, IH), 7.48 - 7.41 (m, IH), 7.27 (d, J = 8.4 Hz, IH), 5.39 (dd, J= 5.2, 12.8 Hz, IH), 3.00 - 2.80 (m, IH), 2.76 - 2.60 (m, 2H), 2.18 - 2.15 (m Hz, IH). LCMS (ESI+) m/z 325.0 &327.0 (M+H)+.

[003347] 2 [6-[3-[2-(2-Aminoethoxv)ethoxv]DroDvl] oxo-l,3-benzoxazol-3vllDiperidine-2,6- dione (Intermediate PA)

Cs2CO3, Cui, Pd(PPh3)2CI2, DMF

Pd/C, Pd(OH)2/C, H2

THF

HCI/dioxane

DCM

[003348] Step 1 - Tert-butyl N-r2-r2-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-6yllpropoxylethoxy] ethyUcarbamate

[003349] 3-(6-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (400 mg, 1.23 mmol, Intermediate OZ), tert-butylN-[2- (2-prop ynoxyethoxy)ethyl]carbamate (898 mg, 3.69 mmol, synthesized via Step 1 of Intermediate CQ), Pd(PPh3)2C12 (86.3 mg, 123 umol), Cui (23.4 mg, 123

1133 umol), 4A MS (400 mg, 307 umol) and Cs2CO3 (2.00 g, 6.15 mmol) in DMF (6 mL) was stirred at 80 °C for 2 hours under N2. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (ACN) to give an impure product. The impure product was re-purified by reverse phase (0.1% FA condition) to give the title compound (340 mg, 54% yield) as yellow oil. 1HNMR (400MHz, DMSO-76) δ 11.23 (s, IH), 7.53 (s, IH), 7.37 - 7.33 (m, IH), 7.31 - 7.27 (m, IH), 6.82 - 6.75 (m, IH), 5.40 (dd, J= 5.2, 12.8 Hz, IH), 4.39 (s, 2H), 3.65 - 3.60 (m, 2H), 3.57 - 3.53 (m, 2H), 3.41 - 3.38 (m, 2H), 3.07 3.02 (m, 2H), 2.93 - 2.81 (m, IH), 2.72 - 2.61 (m, 2H), 2.18 - 2.16 (m, IH), 1.37 (s, 9H), 1.37 1.36 (m, IH). LC-MS (ESI+) m/z 510.2 (M + Na)+.

[003350] Step 2 - Tert-butyl N-r2-r2-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-6yllpropoxylethoxy] ethyllcarbamate

[003351] To a solution of tert-butyl N-[2-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop- 2-ynoxy]ethoxy]ethyl]carbamate (420 mg, 861 umol) in THF (30 mL) was added Pd/C (0.1 g, 10% =wt) and Pd(OH)2/C (0.1 g, 10% =wt) under N2. The suspension was degassed under vacuum and purged with H2 gas several times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (440 mg, 93% yield) as yellow oil. 1H NMR (400MHz, DM SO-6/6) δ 11.25 (s, IH), 7.32 (s, IH), 7.22 (d, J= 8.0 Hz, IH), 7.11 (d, J = 8.0 Hz, IH), 6.79 (s, IH), 5.40 (dd, J = 5.2, 12.8 Hz, IH), 3.57 - 3.53 (m, 4H), 3.46 - 3.43 (m, 4H), 3.13 (d, J= 6.0 Hz, 2H), 3.00 - 2.89 (m, IH), 3.00 - 2.89 (m, IH), 2.80 - 2.67 (m, 4H), 2.25 - 2.20 (m, IH), 1.88 - 1.83 (m, 2H), 1.43 - 1.42 (m, 9H). LC-MS (ESI+) m/z 514.2 (M+ Na)+.

[003352] Step 3 3-r6-r3-r2-(2-Aminoethoxy)ethoxy1propyl1 oxo-L3-benzoxazol-3vl1piperidine-2,6- dione

[003353] To a solution of tert-butyl N-[2-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] ethoxy]ethyl]carbamate (150 mg, 305 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 7.50 mL). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (130 mg, 99% yield, HCI salt) as a white solid. LC-MS (ESI+) m/z 392.2 (M+H)+.

[003354] 2-[2-(Cvcl0Dr0Dvlmethvlamin0) Dvridvl]-N-[3-(diflu0r0methvl)-l-(4formylphenyl)pyrazol vl]oxazole carboxamide (Intermediate PB)

1134

GF

[003355] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl) -1(4-formylphenyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (100 mg, 172 umol, Intermediate GF) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 3.00 mL), and the mixture was stirred at 25 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (80.0 mg, 96% yield) as yellow solid. LC-MS (ESI+) m/z 479.2 (M+H)+.

[003356] Tert-butyl N-(4-hvdroxv methyl-heDt envl)carbamate (Intermediate PC)

PC

[003357] Step 1 - Tert-butyl N-(4-oxopentyl)carbamate

[003358] To a solution of tert-butyl 2-oxopyrrolidine-l-carboxylate (5.00 g, 26.9 mmol) in THF (50.0 mL) was added MeMgBr (3.00 M, 10.8 mL) dropwise at -78 °C under N2, and the mixture was stirred at -78 °C for 3 hrs. On completion, the mixture was poured into cool water (50 mL) and then extracted with MTBE (2 X 50 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE: EA= 5: 1) to give the title compound (4.45 g, 81% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 4.67 (s, IH), 3.19 - 3.02 (m, 2H), 2.51 - 2.47 (m, 2H), 2.14 (s, 3H), 1.80 - 1.70 (m, 2H), 1.42 (s, 9H).

[003359] Step 2 - Tert-butyl N-(4-hydroxy methyl-hept enyl)carbamate

[003360] To a solution of tert-butyl N-(4-oxopentyl)carbamate (2.00 g, 9.94 mmol) in THF (20.0 mL) was added allyl (brom o)magnesium (1.00 M, 12.9 mL) dropwise at -78 °C, and the mixture was stirred at 0 °C for 3 hrs under N2. On completion, the mixture was quenched with saturated NH4C1 (30 mL), then extracted with MTBE (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE: EA= 5: 1) to give the title compound (770 mg, 31% yield) as yellow oil. 1H NMR

1135 (400MHz, DMSO-76) δ 6.74 (s, IH), 5.91 - 5.74 (m, IH), 5.03 (s, IH), 4.99 (d, J = 3.6 Hz, IH), 4.15 (s, IH), 2.91 -2.83 (m, 2H), 2.15 - 2.05 (m, 2H), 1.46- 1.39 (m, 2H), 1.38 (s, 9H), 1.31 -1.24 (m, 2H), 1.00 (s, 3H).

[003361] 3-[5-(7-Amino hvdroxv methvl-heptvl) methvl oxo-benzimidazol-lyl] piperidine -2,6-dione (Intermediate PD)

PD

[003362] Step 1 - Tert-butyl N-r(E) r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 hydroxy methyl-hept enyl1carbamate

[003363] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6di one (200 mg, 591 umol, Intermediate HN), tert-butyl N-(4-hydroxy methyl-hept-6enyl)carbamate (287 mg, 1.18 mmol, Intermediate PC) in dioxane (12.0 mL) was added tris-otolylphosphane (36.0 mg, 118 umol), Pd(OAc)2 (13.2 mg, 59.1 umol) and DIPEA (1.53 g, 11.8 mmol) under N2. The mixture was stirred at 120 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% FA) to give the title compound (180 mg, 60% yield) as yellow solid. 1H NMR (400MHz, DMSO-76) δ

1136

11.10 (s, IH), 7.27 (s, IH), 7.04 (s, 2H), 6.76 (s, IH), 6.45 - 6.34 (m, IH), 6.33 - 6.21 (m,IH),

5.40 - 5.30 (m, IH), 4.26 (s, IH), 2.92 - 2.89 (m, IH), 2.89 - 2.84 (m, 2H), 2.71 - 2.67 (m,IH),

2.64 - 2.56 (m, IH), 2.30 - 2.20 (m, 2H), 2.08 (s, 3H), 2.05 - 1.96 (m, IH), 1.52 - 1.41 (m,2H),

1.36 (s, 9H), 1.35-1.31 (m, 2H), 1.07 (s, 3H).

[003364] Step 2 - Tert-butyl N-r7-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1 hydroxy methyl-heptyl1carbamate

[003365] To a solution of tert-butyl N-[(E) [l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] hydroxy methyl-hept enyl]carbamate (160 mg, 319 umol) in THF (8.00 mL) was added Pd(OH)2/C (50.0 mg, 10% wt) and Pd/C (50 mg, 10% wt), and the mixture was stirred at 25 °C for 3 hrs under H2 gas (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (160 mg, 99% yield) as white solid. 1H NMR (400MHz, DMSO4) δ 11.13 (s, IH), 7.08 (s, IH), 7.05 (d, J = 8.0 Hz, IH), 6.92 (s, 2H), 6.79 (s, IH), 5.44 - 5.34 (m, IH), 4.03 (s, IH), 3.38 (s, 3H), 3.01 - 2.95 (m, IH), 2.94 - 2.87 (m, 2H), 2.80 - 2.69 (m, 2H), 2.68 - 2.64 (m, IH), 2.64 - 2.60 (m, IH), 2.11 - 2.01 (m, IH), 1.69 1.59 (m, 2H), 1.48 - 1.43 (m, 2H), 1.42 (s, 9H), 1.40 - 1.36 (m, 2H), 1.40 - 1.35 (m, 2H), 1.05 (s, 3H).

[003366] Step 3 - 3-r5-(7-Amino hydroxy methyl-heptyl) methyl oxobenzimidazol-l-yl1piperidine -2,6-dione

[003367] To a solution of tert-butyl N-[7-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] hydroxy methylheptyl]carbamate (150 mg, 298 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 1.00 mL) at 0 °C, and the mixture was stirred at 0 °C for 3 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% FA) to give the title compound (50.0 mg, 41% yield) as yellow solid. 1H NMR (400MHz, DMSO4) δ 8.43 (s, IH), 7.05 - 6.98 (m, 2H), 6.87 (d, J = 7.6 Hz, IH), 5.40 5.28 (m, IH), 3.33 (s, 3H), 2.96 - 2.87 (m, IH), 2.74 - 2.68 (m, 2H), 2.69 - 2.63 (m, 2H), 2.62 2.56 (m, 2H), 2.06 - 1.98 (m, IH), 1.67 - 1.46 (m, 4H), 1.40 - 1.28 (m, 4H), 1.02 (s, 3H).

[003368] Benzyl ((S)-l-(((S)-l-((S) hydroxy (((R)-l.,2.,3.,4-tetrahydronaphthalen-lyl)carbamoyl)-3.,4-dihydroisoquinolin-2(lH)-yl)-3.,3-dimethyl-l-oxobutan yl)amino)-l0x0Dr0pan yl)(methyl)carbamate (Intermediate PE)

1137

PE

[003369] To a solution of (S) ((S) amino-3,3-dimethylbutanoyl) hydroxy-N-((R)l,2,3,4-tetrahydronaphthalen-l-yl)-l,2,3,4-tetrahydroisoquinoline carboxamide (13.45 g, 30.92 mmol, synthesized via Steps 1-7 of Intermediate MH), (S)-2(((benzyloxy)carbonyl)(methyl)amino)propanoic acid (7.70 g, 32.47 mmol, CAS# 21691 8) in DMF (150 mL) was added HOBT (4.59 g, 34.01 mmoL), EDCI (6.53 g, 34.01 mmoL), and DIPEA (9.97 g, 77.30 mmoL) at rt. The reaction mixture was stirred at r.t. for 4 h. The mixture was then concentrated under reduce pressure. Then the mixture was poured into H2O (200 mL), extracted with EA (3 x 100 mL), and the combined organic layers were dried over anhydrous Na2SO4. The solid was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with DCM/MEOH=10:1 to give the title compound (13.7 g, 63% yield) as a white solid. LC/MS (ESI, m/z): [M +1]+ = 655.4.

[003370] Benzyl N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-(2aminoethoxv)ethoxv]ethoxv]ethoxy]-3 isoquinoline carbonyl]-2.,2-dimethvl-propvl]amino]-l-methvl oxo-ethvl]-N-methvlcarbamate (Intermediate PF)

1138

PF

[003371] Step 1 - benzyl ((S)-l-(((S)-l-((S) ((2,2-dimethyl oxo-3,8,ll,14-tetraoxa-5azahexadecan yl)oxy) (((R)-1,2,3,4-tetrahydronaphthalen-l-yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate

[003372] To a solution of benzyl ((S)-l-(((S)-l-((S) hydroxy (((R)-l,2,3,4tetrahydronaphthalen-l-yl)carbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-loxobutan yl)amino)-l-oxopropan yl)(methyl)carbamate (1.50 g, 2.29 mmol, Intermediate PE) in CH3CN (20 mL) was added 2,2-dimethyl oxo-3,8,ll,14-tetraoxa azahexadecan yl 4methylbenzenesulfonate (1.23 g, 2.75 mmoL, Intermediate LD), and K2CO3 (475 mg, 3.44 mmoL). The mixture was stirred at 82 °C overnight. The reaction mixture was then concentrated under reduced pressure and purified by silica gel chromatography eluted with DCMZEA=1:1 to give the title compound (1.64 g, 77% yield) as a yellow oil. LC/MS (ESI, m/z); [M +1]+ = 931.4.

[003373] Step 2:benzyl((S)-1 -(((S)-1 -((S) (2-(2-(2-(2aminoethoxy)ethoxy)ethoxy)ethoxy) (((R)-l,2,3,4-tetrahydronaphthalen-l-yl)carbamoyl)-3,4

1139 dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate

[003374] A solution of benzyl ((S)-l-(((S)-l-((S) ((2,2-dimethyl oxo-3,8,ll,14tetraoxa azahexadecan yl)oxy)-3 -(((R)-1,2,3,4-tetrahydronaphthalen-1 -yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.37 g, 1.47 mmoL) in TFA/DCM=10 mL/5 mL was stirred at rt for 1 h. The mixture was then concentrated under reduced pressure to give the title compound (900 mg, 74% yield) as a white solid. LC/MS (ESI, m/z[ [M +1]+ = 830.7. 1H NMR (400 MHz, DMSO4) δ 8.23 (dd, J = 49.6, 8.8 Hz, IH), 7.81 - 7.56 (m, 4H), 7.35 (s, 5H), 7.16 - 6.71 (m, 7H), 5.29 4.58 (m, 8H), 4.06 (d, J= 3.2 Hz, 2H), 3.76 - 3.73 (m, 2H), 3.64 - 3.52 (m, 10H), 3.05 - 2.91 (m, 3H), 2.87 - 2.80 (m, 2H), 2.78 - 2.61 (m, 3H), 1.91 - 1.50 (m, 4H), 1.20 (d, J = 7.2 Hz, 2H), 1.12 (d, J = 7.2 Hz, IH), 0.99 (s, 6H), 0.92 (s, 3H).

[003375] Tert-butyl N-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl] oxazole oxopentyDcarbamate (Intermediate PG)

1140

HOAc, NaBH(OAc)3, DCM/THF

[003376] Step 1 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-[4-r(5hydroxypentyl amino)methyl1phenyl1pyrazol yl1carbamoyl1oxazol yl1 pyridyl1

[003377] A solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l-(4formylphenyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (700 mg, 1.21 mmol, Intermediate GF) and 5-aminopentan-l-ol (187 mg, 1.81 mmol, CAS# 2508 4) in DMF (4 mL) and dioxane (20 mL) was stirred at 100 °C for 30 min. Then the reaction mixture was cooled to 25 °C, and AcOH (217 mg, 3.63 mmol, 207 uL) and NaBH(OAc)3 (769 mg, 3.63 mmol) were added . The reaction mixture was stirred at 25 °C for 1 hour. Then another batch NaBH(OAc)3 (256 mg, 1.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 °C for another 2 hours. On completion, the reaction was quenched with sat.NaHCO3 (50 mL) and

1141 extracted with EA (2 X 300 mL). The organic layers were washed with brine (2 X 70 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound (500 mg, 62% yield) as a white solid. 1HNMR (400MHz, DMSO-76) δ 10.09 (s, IH), 9.06 (s, IH), 8.82 (s, IH), 8.60 (d, J= 4.8 Hz, IH), 8.32 (s, IH), 8.28 (s, IH), 7.85 (d, J= 8.8 Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.44 - 7.15 (m, IH), 3.91 - 3.78 (m, 4H), 3.38 (t, J = 6.4 Hz, 2H), 2.63 (t, 7= 6.4 Hz, 2H), 1.54- 1.28 (m, 13H), 1.25 - 1.13 (m, IH), 0.48 - 0.39 (m, 2H), 0.27 - 0.20 (m, 2H).

[003378] Step 2:Tert-butyl Ν-ΓΓ4-Γ4-ΓΓ2-Γ2-Γ&#912;61&#912;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenyl1methyl1-N-(5-hydroxypentyl)carbamate

[003379] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[(5- hydroxypentylamino)methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]carbamate (450 mg, 675 umol) in DCM (5 mL) was added (Boc)2O (147 mg, 675 umol) and TEA (136 mg, 1.35 mmol). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was poured into sat.NaHCO3 (60 mL) and extracted with EA (2 X 150 mL). The combined organic layers were washed with brine (70 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 4/1 to 1/1) to give the title compound (370 mg, 483 umol, 71% yield) as a white solid. 1HNMR (400MHz, DMSO-76) δ 10.06 (s, IH), 9.05 (s, IH), 8.80 (s, IH), 8.60 (d, 7= 5.2 Hz, IH), 8.32 (s, IH), 7.84 (d,7 = 8.4 Hz, 2H), 7.70 (dd,7= 1.2, 5.2 Hz, IH), 7.45 - 7.11 (m, 2H), 4.42 (s, 2H), 3.87 (d, 7= 6.8 Hz, 2H), 3.33 (s, 9H), 2.59 - 2.52 (m, 3H), 1.52 (s, 9H), 1.48 - 1.40 (m, 8H), 1.27 - 1.23 (m, IH), 0.49 - 0.32 (m, 2H), 0.32 - 0.16 (m, 2H).

[003380] Step 3:Tert-butyl Ν-ΓΓ4-Γ4-ΓΓ2-Γ2-Γ&#912;61&#912;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenyl1methyl1-N-(5-oxopentyl)carbamate

[003381] To a solution of tert-butyl N-[[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl] oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methyl]-N-(5-hydroxypentyl)carbamate (370 mg, 483 umol) in DCM (20 mL) was added DMP (225 mg, 531 umol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was quenched sat.Na2S2O3 (10mL) and extracted with EA (2 X 100). The combined organic layers were washed with brine (70 mL), dried with

1142 anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound (350 mg, 458 umol, 94% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 10.06 (s, IH), 9.08 - 8.99 (m, IH), 8.83 - 8.74 (m, IH), 8.65 - 8.52 (m, IH), 8.36 - 8.27 (m, IH), 8.02 - 7.93 (m, IH), 7.87 - 7.77 (m, 2H), 7.73 - 7.69 (m, IH), 7.50 - 7.44 (m, IH), 7.42 - 7.37 (m, IH), 7.30 7.20 (m, IH), 4.42 (s, 2H), 3.91 - 3.82 ( m, 2H), 3.33 (s, 9H), 2.56 - 2.52 (m, 2H), 2.47 - 2.34 (m, IH), 1.55 - 1.41 (m, 15H), 0.92 - 0.70 (m, IH), 0.45 - 0.36 (m, 2H), 0.30 - 0.18 (m, 2H).

[003382] 3-[5-(Aminomethvl) methvl oxo-benzimidazol-l-yl]DiDeridine-2.,6-dione (Intermediate

[003383] Step 1 - l-(2,6-Dioxo piperidyl) methyl oxo-benzimidazole carbonitrile

[003384] To a mixture of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (3.00 g, 8.87 mmol, Intermediate HN) in DMF (30 mL) was added Zn(CN)2 (1.04 g, 8.87 mmol) and Pd(PPh3)4 (1.03 g, 887 umol). The reaction mixture was stirred at 100 °C for 3 hours under N2. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EA (3 X 100 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (1.50 g, 59% yield) as a white solid. 1HNMR (400 MHz, DMSO-t/6) δ 11.31 - 11.00 (m, IH), 11.15 (s, IH), 7.75 (d, J = 1.2 Hz, IH), 7.57 - 7.52 (m, IH), 7.34 (d, J= 8.4 Hz, IH), 5.49 - 5.42 (m, IH), 3.38 (s, 3H), 2.95 - 2.83 (m, IH), 2.79 - 2.59 (m, 2H), 2.10 - 2.01 (m, IH).

[003385] Step 2 - 3-r5-(Aminomethyl) methyl oxo-benzimidazol-l-yl1piperidine-2,6di one

1143

[003386] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-5carbonitrile (1.40 g, 4.92 mmol) in THF (150 mL) was added Raney-Ni (421 mg, 4.92 mmol) and HCl/dioxane (4 M, 4.92 mL). The reaction mixture was stirred at 25 °C for 36 hours under H2 (50 Psi). On completion, the reaction mixture was filtered. The filter cake was washed with DMF (3 X 10 mL). The combined organic layers were concentrated in vacuo to give the title compound (1.40 g, 98% yield) as a green solid. LC-MS (ESI+) m/z 289.0 (M +H)+.

[003387] 2- [2- [Tert-butoxycarbonyl- [[4- [4- [[2- [2- [tertbutoxvcarbonvl(cvcloDroDylmethyl)amino] Dyridvl]oxazole carbonyl]amino]-3(difluoromethyl)Dyrazol-l-yl]Dhenyl]methyl]amino]ethoxy]ethyl methanesulfonate (Intermediate PI)

1144

[003388] Step 1 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-[4-rr2(2-hydroxyethoxy)ethylamino1methyl1phenyl1pyrazol yl1carbamoyl1oxazol yl1-2pyridvUcarb amate

[003389] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l(4-formylphenyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (600 mg, 1.04 mmol, Intermediate GF) in a mixed solvent of DMF (10 mL) and THF (100 mL) was added 2-(2aminoethoxy)ethanol (141 mg, 1.35 mmol, CAS# 929 6) and HOAc (124 mg, 2.07 mmol). The reaction mixture was stirred at 25 °C for 0.5 hr. Then, NaBH(OAc)3 (659 mg, 3.11 mmol) was added. The resulting reaction mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was quenched with water (1 mL) and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography (FA, 0.1 %) to give the title compound (400 mg, 57% yield) as a yellow solid. 1H NMR (400MHz, DMSO-76) δ 10.06 (s, IH), 9.05 (s, IH), 8.82 (s, IH), 8.60 (d, J= 5.2 Hz, IH), 8.32 (s, IH), 7.86 (d, J= 8.8 Hz, 2H), 7.70 (dd, J= 1.6, 5.2 Hz, IH), 7.55 (d, J= 8.8 Hz, 2H), 7.43 - 7.15 (m, IH), 5.75 (s, IH), 3.92 (s, 2H), 3.87 (d, J= 6.8 Hz, 2H), 3.56 (t, J = 5.6 Hz, 2H), 3.53 -3.50 (m, 2H), 3.45 - 3.42 (m, 2H), 2.81 (t, J= 5.6 Hz, 2H), 1.52 (s, 9H), 1.24 - 1.12 (t, J= 7.8 Hz, IH), 0.45 - 0.38 (m, 2H), 0.27 - 0.22 (m, 2H).

[003390] Step 2:Tert-butyl Ν-ΓΓ4-[4-ΓΓ2-Γ2-Γ&#912;61&#912;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenvl1methyl1-N-r2-(2-hydroxyethoxy)ethyl1carbamate

[003391] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[[2-(2- hydroxyethoxy)ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]carbamate (400 mg, 599 umol) in DCM (20 mL) was added TEA (181 mg, 1.80 mmol) and B0C20 (156 mg, 718 umol). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was poured into sat. NaHCO3 (30 mL) and extracted with EA (3 X 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound (450 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 768.1 (M+H)+.

[003392] Step 3:2-r2-rTert-butoxvcarbonvl-rr4-r4-rr2-r2-[tertbutoxycarbonyl(cyclopropylmethyl)amino1 pyri dyl 1 oxazol e carb onyl 1 amino] -3 (difluoromethyl)pyrazol-1 -yl1phenyl1methyl1amino1ethoxy1ethyl methanesulfonate

1145

[003393] To a solution of tert-butyl N-[[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl] oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-1 -yl]phenyl]methyl]-N-[2-(2-hydroxyethoxy)ethyl]carbamate (400 mg, 520 umol) in DCM (20 mL) was added TEA (158 mg, 1.56 mmol). The reaction mixture was cooled to 0 °C. Then, MsCI (119 mg, 1.04 mmol) was dropwise into the mixture slowly. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was poured into sat.NaHCO3 (30 mL) and extracted with EA (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound (400 mg, 100% yield) as a yellow solid. LC-MS (ESI+) m/z 846.2 (M+H)+.

[003394] Benzyl Ν-[(15) [[(15) [(35) [2-[2-[2-[2-(2aminoethoxylethoxy]ethoxy]ethoxy] ethoxy| [[(17?)-tetralin-l-yl]carbamoyl]-3,4-dihydrolH-isoquinoline carbonvl]-2,2-dimethvl-DroDvl]amino]-l-methvl oxo-ethvl]-N-methylcarbamate (Intermediate PJ)

PJ

1146

[003395] Step 1 - benzyl ((S)-l-(((S)-l-((S) ((2,2-dimethyl oxo-3,8,ll,14,17-pentaoxa5-azanonadecan yl)oxy)-3 -(((R)-1,2,3,4-tetrahydronaphthalen-1 -yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate

[003396] To a solution of benzyl ((S)-l-(((S)-l-((S) hydroxy (((R)-l,2,3,4tetrahydronaphthalen-l-yl)carbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-loxobutan yl)amino)-l-oxopropan yl)(methyl)carbamate (1.0 g, 1.53 mmol, Intermediate PE) in CH3CN (50 mL) was added 2,2-dimethyl oxo-3,8,ll,14,17-pentaoxa azanonadecan yl 4-methylbenzenesulfonate (901 mg, 1.84 mmol, Intermediate ON) andK2CO3 (317 mg, 2.3 mmol) at rt. The reaction mixture was then stirred at 80 °C for 12 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated under reduced pressure. The residue was purified via column chromatography (EtOAc / petroleum ether) to give the title compound (1.08 g, 73% yield) as a pale yellow oil. LC/MS (ESI, m/z); [M+l]+ = 974.68.

[003397] Step 2 - benzyl ((S)-l-(((S)-l-((S) ((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)3 -(((R)-1,2,3,4-tetrahydronaphthalen-1 -yl)carbamoyl)-3,4-dihydroi soquinolin-2( 1 H)-yl)-3,3 dimethyl-l-oxobutan yl)amino)-l-oxopropan yl)(methyl)carbamate 2,2,2-trifluoroacetate [003398] To a solution of benzyl ((S)-l-(((S)-l-((S) ((2,2-dimethyl oxo-3,8,ll,14,17pentaoxa azanonadecan yl)oxy)-3 -(((R)-1,2,3,4-tetrahydronaphthalen-1 -yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.4 g, 1.43 mmol) in DCM (20 mL) was added TFA (20 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was purified via reverse phase column chromatography (ACN / H2O) to give the title compound (1.341 g, 94.8 % yield) as as a white solid. 1H NMR (400 MHz, DMSOd6) δ; 8.30 - 8.15 (m, IH), 7.77 - 7.56 (m, 4H), 7.40 - 7.35 (m, 5H), 7.18 - 6.70 (m, 7H), 5.28 4.23 (m, 9H), 4.13 - 4.00 (m, 2H), 3.74 (t, J = 4.5 Hz, 2H), 3.69 - 3.23 (m, 14H), 3.02 - 2.64 (m, 8H), 1.95- 1.45 (m, 4H), 1.21-1.11 (m, J3H), 0.99-0.91 (m, 9H). LC/MS (ESI, m/z); [M+l]+ = 874.55.

[003399] 3-(Tert-butoxvcarbonvlamino)propyl(4-nitrophenyl)carbonate (Intermediate PK)

1147

Η 0^^ Ν H Boc

[003400] To a solution of tert-butyl N-(3-hydroxypropyl)carbamate (0.600 g, 3.42 mmol, CAS# 58885 8) and (4-nitrophenyl) carbonochloridate (759 mg, 3.77 mmol, CAS# 7693-461) in DCM (25 mL) was added TEA(866 mg, 8.56 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 1 hr. On completion, the mixture was quenched with water (10 mL), then concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (520 mg, 45% yield) as colorless oil. 1HNMR (300MHz, CDCh) δ 8.34 - 8.25 (m, 2H), 7.44 - 7.35 (m, 2H), 4.77 (s, IH), 4.36 (t, J = 6.4 Hz, 2H), 3.29 (q, J = 6.4 Hz, 2H), 2.03 1.90 (m, 2H), 1.45 (s, 9H).

[003401] .LMllilLlLLLElLULL^illlzi^XwHoxmViriiieindHJzVirmTliyLUoxmber^^ yl] methyl] carbamate (Intermediate PL)

[003402] Step 1 - 3-(Tert-butoxycarbonylamino)propyl Ν-ΓΓ1 -(2,6-dioxo piperidyl)-3 methyl oxo- benzimidazol yl1methyl1carbamate

[003403] To a solution of 3-[5-(aminomethyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (120 mg,

416 umol, Intermediate PH) and 3-(tert

1148 butoxycarbonylamino)propyl (4-nitrophenyl) carbonate (170 mg, 500 umol, Intermediate PK) in DMF (2 mL) was added TEA (84.2 mg, 832 umol). The reaction mixture was stirred at 25 °C for 3 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (110 mg, 54% yield) as a white solid. 1H NMR (400 MHz, DMSO-76) δ 11.05 (s, IH), 7.64 (s, IH), 7.10 - 7.01 (m, 2H), 6.98 - 6.91 (m, IH), 6.86 - 6.78 (m, IH), 5.43 - 5.29 (m, IH), 4.19 (d, J = 6.0 Hz, 2H), 3.95 (t, J = 6.4 Hz, 2H), 3.30 (s, 3H), 3.02 - 2.94 (m, 2H), 2.94 - 2.84 (m, IH), 2.69 - 2.56 (m, 2H), 2.09 - 1.94 (m, IH), 1.73 - 1.58 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 512.3 (M+Na)+.

[003404] Step 2 - 3-Aminopropyl N-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1methyl1 carbamate

[003405] To a solution of 3-(tert-butoxycarbonylamino)propyl N-[[l-(2,6-dioxo-3piperidyl) methyl oxo- benzimidazol yl]methyl]carbamate (140 mg, 286 umol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (140 mg, 97% yield, TFA) as a white solid. LC-MS (ESI+) m/z 390.2 (M+H)+

[003406] Tert-butyl 4-(3-methvl oxo-lH-benzimidazol vl)piperazine-l-carboxylate (Intermediate PM)

IP PM

[003407] To a solution of 5-bromo methyl-lH-benzimidazol one (4.00 g, 17.6 mmol, Intermediate IP), tert-butyl piperazine carboxylate (4.92 g, 26.4 mmol, CAS# 1433238 4) and t-BuOK (4.35 g, 38.8 mmol), was added RuPhos (822 mg, 1.76 mmol) and [2-(2aminophenyl)phenyl] -chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl) phenyl]phosphane (1.37 g, 1.76 mmol) in dioxane (100 mL), and the mixture was stirred at 90 °C for 1 hr at N2. On completion, the residue was diluted with H2O (50 mL) and extracted with EtOAc (3 X 100 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE: EA (10:1, 50 mL), filtered and filtered caked was dried under reduced pressure to give the title

1149 compound (3.80 g, 65% yield) as a yellow solid. 1HNMR (400 MHz, DM SO-0/6) δ 10.54 (s, 1 H), 6.83 (d, J= 8.4 Hz, 1 H), 6.78 (d, J= 2.20 Hz, 1 H), 6.60 (dd, J= 8.4, Hz, 1 H), 3.43 - 3.50 (m, 4 H), 3.24 (s, 3 H), 2.98 - 3.03 (m, 4 H), 1.42 (s, 9 H), LC-MS (ESI+) m/z 333.1 (M+H)+.

[003408] 3-(3-Methvl oxo DiDerazin-l-vl-benzimidazol-l-yl)DiDeridine-2.,6-dione (Intermediate PN)

TFA DCM

CF3SO3H, DCM

[003409] Step 1 - Tert-butyl 4-r1-r1-r(4-methoxyphenyl)methyl1-2,6-dioxo piperidyl1-3methyl oxo- benzimidazol yl1piperazine-l-carboxylate

[003410] To a solution of tert-butyl 4-(3-methyl oxo-lH-benzimidazol yl)piperazine-lcarboxylate (3.80 g, 11.4 mmol, Intermediate PM) in THF (100 mL) was added t-BuOK (2.57 g, 22.9 mmol); then [l-[(4-methoxyphenyl)methyl]-2,6-dioxo piperidyl] trifluoromethanesulfonate (8.72 g, 22.86 mmol, Intermediate IQ) in THF (20 mL) was added at 0 °C.The mixture was stirred at 0 °C for 2 hrs. On completion, the residue was diluted with H2O (50 mL) and extracted with EtOAc (3 X 50mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE: EA (10:1, 50 mL), filtered and the filtered cake was dried in vacuo to give the title compound (3.00 g, 37% yield, 80% purity) as a blue solid. LC-MS (ESI+) m/z 564.3 (M+H)+.

[003411] Step 2 - 3-(3-Methyl oxo piperazin-l-yl-benzimidazol-l-yl)piperidine-2,6di one

1150

[003412] To a solution of tert-butyl 4-[l-[l-[(4-methoxyphenyl)methyl]-2,6-dioxo-3piperidyl] methyl oxo-benzimidazol yl]piperazine-l-carboxylate (2.50 g, 4.44 mmol) in DCM (40 mL) was added TFA (38.5 g, 338 mmol, 25.0 mL), and the mixture was stirred at 15 °C for 1 hr. Then methanesulfonic acid (33.8 g, 351 mmol, 25 mL) was added and the mixture was stirred at 15 °C for 25 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (700 mg, 40% yield) as a blue solid. 1H NMR (400 MHz, DM SO-0#) δ 10.89 - 11.20 (m, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 6.67 (dd, J = 8.4, 1.6 Hz, 1 H), 5.31 (dd, J = 12.8, 5.6 Hz, 1 H), 3.21 (d, J= 3.6 Hz, 4 H), 3.15 (s, 4 H), 2.85 - 2.95 (m, 1 H), 2.63 - 2.75 (m, 2 H), 1.96 - 2.04 (m, 1 H), LC-MS (ESI+) m/z 344.1 (M+H)+.

[003413] Tert-butyl N-methvl-N-(3-Dr0D yn0xvDr0Dvl)carbamate (Intermediate PO)

KOH, TBAI, KI, THF

PO

[003414] To a solution of 3-bromoprop yne (1.32 g, 11.1 mmol, CAS# 106 7) and tertbutyl N-(3-hydroxypropyl)-N-methyl-carbamate (2.00 g, 10.6 mmol, CAS# 98642 5) in THF (20 mL) was added TBAI (234 mg, 634 umol) and KI (263 mg, 1.59 mmol). Then KOH (698 mg, 10.6 mmol, 85% purity) was added into the above mixture. The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to remove the solvent, the residue was diluted with water (30 mL), then extracted with EA (3 X 40 mL). The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (1.15 g, 48% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 4.15 - 4.11 (m, 2H), 3.57 - 3.49 (m, 2H), 3.29 (t, J = 6.8 Hz, 2H), 2.86 (s, 3H), 2.42 (t, J= 2.4 Hz, IH), 1.85 - 1.76 (m, 2H), 1.46 (s, 9H).

[003415] 3-[3-Methyl [3-[3-(methvIamin0)Dr0D0xy|Dr0DvI 0x0-benzimidaz0I-lyl] piperidine- 2.,6-dione (Intermediate PP)

1151

PO

[003416] Step 1 - Tert-butyl N-r3-r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1prop ynoxy1propyl1-N-methyl-carbamate

[003417] 3-(4-bromo methyl oxo-benzimidazol-l-yl )piperi dine-2,6-di one (300 mg, 887 umol, Intermediate HP), tert-butyl N-methyl-N-(3-prop ynoxypropyl)carbamate (504 mg, 2.22 mmol, Intermediate PO), Pd(PPh3)2C12 (125 mg, 177 umol), Cs2CO3 (1.45 g, 4.44 mmol), Cui (33.8 mg, 177 umol) and 4A molecular sieves (150 mg) in DMF (8 mL) was heated at 80 °C for 2 hrs under N2. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (200 mg, 40% yield) as a yellow solid. LC-MS (ESI+) m/z 507.3 (M+Na)+.

[003418] Step 2 - Tert-butyl N-r3-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propoxv1 propyl-N-methyl-carbamate

[003419] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]propyl]-N-methyl-carbamate (200 mg, 351 umol) in THF (6 mL) was added Pd/C (0.100 g, 10% wt) and Pd(OH)2/C (0.100 g, 10% wt). The reaction mixture was stirred at 25 °C for 10 hrs under H2 (15 Psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (200 mg, 93% yield) as a yellow solid. 1H NMR (400MHz, DMSO-» δ 11.10 (s, IH), 7.00 - 6.92 (m, 2H), 6.90 - 6.84

1152 (m, IH), 5.44 - 5.24 (m, IH), 3.56 (s, 3H), 3.44 - 3.40 (m, 4H), 3.22 (t, J= 7.2 Hz, 2H), 2.99 - 2.92 (m, 2H), 2.76 (s, 3H), 2.74 - 2.69 (m, IH), 2.65 - 2.58 (m, 2H), 2.04 - 1.96 (m, IH), 1.87 - 1.79 (m, 2H), 1.74 - 1.65 (m, 2H), 1.38 (s, 9H); LC-MS (ESI+) m/z 511.3 (M+Na)+.

[003420] Step 3 - 3-[3-Methyl r3-r3-(methvlamino)propoxv1propyl oxo-benzimidazoll-yl1piperidine- 2,6-dione

[003421] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]propyl]-N-methyl-carbamate (200 mg, 327 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 3.20 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (160 mg, 100% yield, HCI) as a white solid. 1H NMR (400MHz, DMSO-A) δ 11.08 (s, IH), 7.02 - 6.92 (m, 2H), 6.90 - 6.83 (m, IH), 5.44-5.24 (dd, J= 5.6, 12.4 Hz, IH), 3.57 (s, 3H), 3.49 - 3.43 (m, 4H), 3.00 2.91 (m, 4H), 2.74 - 2.53 (m, 6H), 2.04 - 1.94 (m, IH), 1.90 - 1.81 (m, 4H); LC-MS (ESI+) m/z 389.2 (M+H)+.

[003422] Tert-butyl N-(3-Dr0D yn0xvDr0Dvl)carbamate (Intermediate PX)

HO-^-^NHBoc -----------&#9658; ^U^O^^^^NHeoc

TBAI, KI, KOH, THF

PX

[003423] To a mixture of tert-butyl N-(3-hydroxypropyl)carbamate (10.0 g, 57.1 mmol, CAS# 58885 8), 3-bromoprop yne (8.15 g, 68.5 mmol, CAS# 106 7) in THF (150 mL) was added TBAI (1.26 g, 3.42 mmol) KOH (3.20 g, 57.07 mmol) and KI (1.42 g, 8.56 mmol). The mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give residue. The residue was purified by column chromatography to give the title compound (6.80 g, 55% yield) as yellow solid. 1HNMR (400MHz, CDCh) δ 4.76 (s, IH), 4.10 4.05 (m, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.16 (q, J = 6.0 Hz, 2H), 2.37 (t, J = 2.4 Hz, IH), 1.74 1.65 (m, 2H), 1.37 (s, 9H).

[003424] 3-[7-[3-(3-Aminopropoxy)propyl] oxo-l.,3-benzoxazol yl]piperidine-2.,6dione (Intermediate PY)

1153

JF

PY

[003425] Step 1 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidvl) oxo-L3-benzoxazol-7vl1prop ynoxy1propyl1 carbamate

[003426] To a mixture of 3-(7-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (3.00 g, 9.23 mmol, Intermediate JF) and tert-butyl N-(3-prop ynoxypropyl)carbamate (4.92 g, 23.0 mmol, Intermediate PX) in DMF (30 mL) was added Cs2CO3 (15.0 g, 46.1 mmol), Cui (175 mg, 922 umol) and Pd(PPh3)2C12 (647 mg, 922 umol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EA (3 X 100 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (2.70 g, 63 % yield) as light yellow solid. 1HNMR (400MHz, DM SO-6/6) δ 11.23 (s, IH), 7.32 (dd, J= 2.0, 7.2 Hz, IH), 7.27-7.19 (m, 2H), 6.81 -6.77 (m, IH), 5.39 (dd, J= 5.6, 13.2 Hz, IH), 4.43 (s, 2H), 3.53 (t, J= 6.4 Hz, 2H), 3.02 - 2.97 (m, 2H), 2.92 - 2.81 (m, IH), 2.73 - 2.58 (m, 2H), 2.22 - 2.13 (m, IH), 1.70 - 1.64 (m, 2H), 1.36 (s, 9H); LC-MS (ESI+) m/z 480.2 (M+Na)+.

[003427] Step 2 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidvl) oxo-L3-benzoxazol-7yl1propoxy1propyl1 carbamate

1154

[003428] To a mixture was tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop ynoxy]propyl]carbamate (2.30 g, 5.03 mmol) in THF (200 mL) was added Pd/C (0.6 g, 10% wt) and Pd(0H)2/C (0.6 g, 10% wt). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (2.30 g, 99% yield) as off-white solid. LCMS (ESI+) m/z 484.2 (M+Na) +.

[003429] Step 3 - 3-r7-r3-(3-Aminopropoxy)propyl1 oxo-L3-benzoxazol yl1piperidine2,6-dione

[003430] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] propyl]carbamate (2.30 g, 4.98 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 10 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.80 g, 90% yield, HCI salt) as off-white solid. 1H NMR (400MHz, DMSO-/6) δ 11.20 (s, IH), 7.86 (s, 2H), 7.17 - 7.09 (m, 2H), 7.04 - 7.00 (m, IH), 5.37 (dd, J = 5.2, 13.2 Hz, IH), 3.47 - 3.43 (m, 2H), 3.43 - 3.41 (m, 2H), 2.90 - 2.84 (m, 2H), 2.83 - 2.79 (m, IH), 2.78 - 2.72 (m, 2H), 2.70 - 2.61 (m, 2H), 2.20 - 2.10 (m, IH), 1.91 - 1.84 (m, 2H), 1.83 - 1.78 (m, 2H).

[003431] 3-[6-[3-(3-Amin0Dr0D0xv)Dr0Dvl] 0x0-l,3-benz0xaz01 yl]DiDeridine-2,6dione (Intermediate PZ)

1155

PX

Cs2CO3, Cui, Pd(PPh3)2CI2, DMF, 3A molecular sieves

[003432] Step 1 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidvl) oxo-L3-benzoxazol-6vl1prop ynoxy1propyl1 carbamate

[003433] To a mixture of 3-(6-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (1.20 g, 3.69 mmol, Intermediate OZ) and tert-butyl N-(3-prop ynoxypropyl)carbamate (1.57 g, 7.38 mmol, Intermediate PX) in DMF (30 mL) was added Cui (210 mg, 1.11 mmol), Pd(PPh3)2C12 (777 mg, 1.11 mmol), Cs2CO3 (6.01 g, 18.5 mmol) and 3A molecular sieves (100 mg, 3.69 mmol) under N2. The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was cooled to 25 °C. Then the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (868 mg, 42% yield) as brown solid. 1H NMR (400MHz, CDCh) δ 8.49 (s, IH), 7.74 - 7.65 (m, IH), 7.61 7.54 (m, IH), 7.36 (d, J = 1.0 Hz, IH), 7.30 - 7.27 (m, IH), 6.79 (d, J= 8.4 Hz, IH), 5.07 (d, J = 5.6, 13.2 Hz, IH), 4.37 (s, 2H), 3.66 (t, J= 6.0 Hz, 2H), 3.27 ( d, J= 6.0 Hz, 2H), 3.05 - 2.95 (m,

1156

IH), 2.92 - 2.80 (m, IH), 2.79 - 2.65 (m, IH), 2.40 - 2.26 (m, IH), 1.85 - 1.80 (m, 2H), 1.45 (s, 9H).

[003434] Step 2 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidvl) oxo-L3-benzoxazol-6vllpropoxylpropyllcarbamate

[003435] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop ynoxy]propyl]carbamate (868 mg, 1.90 mmol) in THF (30 mL) was added Pd/C (200 mg, 10 wt%) and Pd(OH)2/C (200 mg, 10 wt%). The suspension was degassed under vacuum and purged with H2 gas 3 times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (835 mg, 95% yield) as brown solid. 1HNMR. (400 MHz, DMSOd6) δ 11.22 (s, IH), 7.66 - 7.59 (m, IH), 7.27 (s, IH), 7.16 (s, IH), 7.05 (s, IH), 5.37 - 5.32 (m, IH), 2.98 (d, J = 6.4 Hz, 2H), 2.71 - 2.64 (m, 5H), 2.34 (d, J = 1.6Hz, 3H), 2.16 - 2.15 (m, 2H), 1.88 - 1.72 (m, 2H), 1.66 - 1.54 (m, 2H), 1.37 (s, 9H).

[003436] Step 3 - 3-r6-r3-(3-Aminopropoxy)propyl1 oxo-L3-benzoxazol yl1piperidine2,6-dione

[003437] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] propyl]carbamate (680 mg, 1.47 mmol) in DCM (20 mL) was added HCI/dioxane (4 M, 0.7 mL). The reaction mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give title compound (580 mg, 98% yield) as a white solid. LC-MS (ESI+) m/z 362.1 (M+H)+.

[003438] 3-[7-[3-[3-(Methvlamino)propoxv]propyl] oxo-l.,3-benzoxazol-3yl]piperidine-2.,6-dione (Intermediate QA)

1157

QA

[003439] Step 1 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-7yl]prop ynoxy]propyl] -N-methyl-carbamate

[003440] To a solution of tert-butyl N-methyl-N-(3-prop ynoxypropyl)carbamate (1.05 g, 4.61 mmol, Intermediate PO) and 3-(7-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (500 mg, 1.54 mmol, Intermediate JF) in DMF (10 mL) was added Pd(PPh3)2C12 (215 mg, 307 umol), Cui (58.5 mg, 307 umol) and Cs2CO3 (2.51 g, 7.69 mmol). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (440 mg, 60% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 11.21 (s, IH), 7.35 - 7.28 (m, IH), 7.28 - 7.19 (m, 2H), 5.39 (dd, J = 5.2, 12.8 Hz, IH), 4.45 (s, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H), 2.94 - 2.82 (m, IH), 2.77 (s, 3H), 2.71 - 2.60 (m, 2H), 2.22 - 2.13 (m, IH), 1.81 - 1.68 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 372.1 (M+H-100)+.

[003441] Step 2 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-7vl]propoxy]propyl]-N- methyl-carbamate

[003442] To a solution of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop ynoxy] propyl]-N-methyl-carbamate (440 mg, 933 umol) in THF (10

1158 mL) was added Pd(0H)2/C (150 mg, 10 wt%) and Pd/C (150 mg, 10 wt%). The reaction mixture was stirred at 25 °C under H2 (15 psi) for 12 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (400 mg, 90% yield) as a white solid. 1HNMR (400MHz, DMSO4) δ 1HNMR (400MHz, DMSO-Y) δ 11.21 (s, IH), 7.18 - 7.06 (m, 2H), 7.01 (d, J= 7.2 Hz, IH), 5.35 (dd, J= 5.2, 12.8 Hz, IH), 3.42 - 3.38 (m, 2H), 3.35 - 3.30 (m, 2H), 3.21 (t, J = 7.2 Hz, 2H), 2.93 - 2.83 (m, IH), 2.78 - 2.71 (m, 5H), 2.70 - 2.61 (m, 2H), 2.19 - 2.10 (m, IH), 1.91 - 1.79 (m, 2H), 1.74 - 1.63 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 489.2 (M+Na)+.

[003443] Step 3 - 3-r7-r3-r3-(Methylamino)propoxy1propyl1 oxo-L3-benzoxazol-3yl1piperidine-2,6-dione

[003444] To a solution of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy]propyl] -N-methyl-carbamate (400 mg, 841 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL).The reaction mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (340 mg, 98% yield, HC1) as a white solid. LC-MS (ESI+) m/z 376.2(M+H)+.

[003445] 2-Tert-butyl N-[2-[2-[2-(2-oxo-3H-benzimidazol-lvDethoxy]ethoxy]ethyl]carbamate (Intermediate QB)

QB

[003446] Step 1 - Tert-butyl N-r2-r2-r2-(2-nitroanilino)ethoxy1ethoxy1ethyl1carbamate

[003447] To a mixture of l-fluoro nitro-benzene (2.84 g, 20.1 mmol, 2.12 mL, CAS# 127723 7) and tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (5.00 g, 20.1 mmol, CAS# 153086 3) in DMF (50 mL) was added K2CO3 (8.35 g, 60.4 mmol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (2 X 100 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.40 g, 99% yield) as red oil. 1H

1159

NMR (400 MHz, CDCh) δ 8.25 (s, IH), 8.20 - 8.14 (m, IH), 7.48 - 7.40 (m, IH), 6.86 (d, J= 8.4 Hz, IH), 6.71 -6.61 (m, IH), 5.07 (s, IH), 3.80 (t, 7= 5.2 Hz, 2H), 3.71 -3.62 (m, 4H), 3.59 - 3.49 (m, 4H), 3.88 - 3.27 (m, 2H), 1.43 (s, 9H).

[003448] Step 2 - Tert-butyl N-r2-r2-r2-(2-aminoanilino)ethoxy1ethoxy1ethyl1carbamate

[003449] To a mixture of tert-butyl N-[2-[2-[2-(2nitroanilino)ethoxy]ethoxy]ethyl]carbamate (7.00 g, 18.9 mmol) in THF (100 mL) was added Pd/C (3.00 g, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (6.40 g, 99% yield) as red oil. 1H NMR (400 MHz, CDCh) δ 6.84 - 6.78 (m, IH), 6.74 - 6.64 (m, 3H), 5.32 (s, IH), 3.76 (t, 7= 5.2 Hz, 2H), 3.67 - 3.60 (m, 4H), 3.54 (t, 7 = 5.2 Hz, 2H), 3.35 - 3.27 (m, 4H), 1.45 (s, 9H).

[003450] Step 3:2-Tert-butyl N-r2-r2-r2-(2-oxo-3H-benzimidazol-lyl)ethoxy1ethoxy1ethyl1carbamate

[003451] To a mixture of tert-butyl N-[2-[2-[2-(2aminoanilino)ethoxy]ethoxy]ethyl]carbamate (6.70 g, 19.7 mmol) in THF (100 mL) was added CDI (11.8 g, 73.0 mmol) and DIPEA (9.44 g, 73.0 mmol, 12.7 mL). The mixture was stirred at 25 °C for 3 hours. On completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (2 X 100 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (7.20 g, 99% yield) as red oil. 1HNMR (400 MHz, DMSO-76) δ 10.86 (s, IH), 7.02 - 6.94 (m, 4H), 6.74 (s, IH), 3.93 (t, 7= 5.6 Hz, 2H), 3.65 (t, 7= 5.6 Hz, 2H), 3.52 - 3.41 (m, 4H), 3.32 (t, 7= 6.0 Hz, 2H), 3.10 - 2.94 (m, 2H), 1.36 (s, 9H).

[003452] 3-[3-[2-[2-(2-Aminoethoxv)ethoxv]ethvl] oxo-benzimidazol-l-yl]piperidine2.,6-dione (Intermediate OC)

1160

NHBoc

NHBoc

O

QC

[003453] Step 1 - Tert-butyl N-[2-[2-[2-[3-[l-[(4-methoxyphenyl)methyl1-2,6-dioxo-3piperidyl1 oxo- benzimidazol-l-yl1ethoxy1ethoxy1ethyl1carbamate

[003454] To a mixture of tert-butyl N-[2-[2-[2-(2-oxo-3H-benzimidazol-lyl)ethoxy]ethoxy]ethyl]carbamate (3.00 g, 8.21 mmol, Intermediate QB) in THF (50 mL) was added t-BuOK (1.38 g, 12.3 mmol), the mixture was stirred at 0 °C for 0.5 hour. Then [l-[(4methoxyphenyl)methyl]-2,6-dioxo piperidyl]trifluoromethane sulfonate (4.70 g, 12.3 mmol, Intermediate IQ) in THF (20 mL) was added to the mixture. The reaction mixture was stirred at 0 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (2 X 200 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prepHPLC (0.1 % FA condition) to give the title compound (4.00 g, 81% yield) as brown oil. 1H NMR (400 MHz, DMSO4) δ 7.26 (d, J = 7.6 Hz, IH), 7.21 (d, J = 8.8 Hz, 2H), 7.09 - 7.04 (m, IH), 7.02 - 6.95 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.70 (s, IH), 5.57 - 5.48 (m, IH), 4.87 - 4.73 (m, 2H), 4.02 - 3.98 (m, 2H), 3.72 (s, 3H), 3.68 (d, J = 5.2 Hz, 2H), 3.54 - 3.49 (m, 2H), 3.46 - 3.41 (m, 2H), 3.33 (s, 2H), 3.12 - 3.05 (m, IH), 3.04 - 2.97 (m, 2H), 2.86 - 2.69 (m, 2H), 2.10 - 2.01 (m, IH), 1.36 (s, 9H).

[003455] Step 2 - 3-[3-[2-[2-(2-Aminoethoxy)ethoxy1ethyl1 oxo-benzimidazol-lyl1piperidine-2,6-dione

1161

[003456] To a mixture of tert-butyl N-[2-[2-[2-[3-[l-[(4-methoxyphenyl)methyl]-2,6-dioxo3-piperidyl] oxo- enzimidazol-l-yl]ethoxy]ethoxy]ethyl]carbamate (1.00 1.68 mmol) in DCM (10 mL) was added TFA (7.70 g, 67.5 mmol, 5.00 mL). The mixture was stirred at 25 °C for 0.5 hour. Then CF3SO3H (4.25 g, 28.3 mmol, 2.50 mL) was added to the mixture. The mixture was stirred at 25 °C for 30 hours. On completion, the reaction mixture was diluted with water (20 mL) and basified with saturated aqueous K2CO3 till pH = 8-9, then the solution was extracted with DCM (3 X 50 mL). The aqueous phase was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (0.1 % HCI condition) to give the title compound (330 mg, 52% yield) as brown oil. 1HNMR (400 MHz, DMSOA) δ 11.10 (s, IH), 7.74 (s, 2H), 7.25 (d, J = 7.2 Hz, IH), 7.15 - 7.09 (m, IH), 7.09 - 7.00 (m, 2H), 5.41 - 5.33 (m, IH), 4.01 (t, J = 5.4 Hz, 2H), 3.70 (t, 7= 5.4 Hz, 2H), 3.58 - 3.55 (m, 2H), 3.53 - 3.50 (m, 4H), 2.94 - 2.85 (m, 3H), 2.78 - 2.63 (m, 2H), 2.06- 1.97 (m, IH).

[003457] Benzyl((S)-l-(((S)-l-cvclohexvl ((S) (4-(3-hvdroxvbenzoyl)thiazol-2vl)pvrrolidin-l-vl) oxoethvl)amino)-l-oxopropan vl)(methyl)carbamate

QD)

1162

Boc

Lawessons's Reagent

DCM

2) TFAA, 2,4,6-Collidine

DME

QD

[003458] Step 1 - (S)-tert-butyl 2-carbamothioylpyrrolidine-l-carboxylate

[003459] To a stirred solution Boc-D-prolinamide (50.0 g, 234.0 mmol) in CH2CI2 (25 mL) at rt was added Lawesson's reagent (62.2 g, 140.0 mmol). The mixture was stirred overnight, then washed with NaHCO3 (sat., 500 mL). The organic layer was washed with brine, and dried over anhydrous Na2SO4. The oily residue was purified by column chromatography on silica gel, eluted with a 0-10 percent MeOH in CH2CI2 gradient, to afford the title compound (42 g, 78% yield) as

1163 a white solid. 1H NMR (400 MHz, DM SO-0/6) δ 9.51 (s, IH), 9.08 (m, IH), 4.41 (dd, J= 8.4, 3.3 Hz, IH), 3.47-3.46 (m, IH), 3.27 (s, IH), 2.27 - 2.09 (m, IH), 1.92- 1.65 (m, 3H), 1.37 (m, 9H). [003460] Step 2 - ethyl (S) (l-(tert-butoxycarbonyl)pyrrolidin yl)thiazole carboxylate [003461] Ethyl bromopyruvate (4.15 g, 21.3 mmol) was added dropwise via syringe to a mixture of (S)-tert-butyl 2-carbamothioylpyrrolidine-l-carboxylate (3.5 g, 15.2 mmol) and potassium bicarbonate (50.5 g, 504 mmol) in 35 mL of dimethoxyethane at 23c°C. The resulting mixture was stirred vigorously for 25 minutes, and then the mixture was cooled to 0 °C. A mixture of trifluoroacetic anhydride (TFAA) (3.19 g, 15.2 mmol, 1 equiv.) and 2,4,6-collidine (2.94 g, 24.3 mmol, 1.6 equiv.) was then added dropwise via canula to the yellow mixture prepared above at 0 °C. Following this addition, an additional three portions of neat TFAA (3.19 g, 15.2 mmol, 1 equiv.) and 2,4,6-collidine (2.94 g, 24.3 mmol, 1.6 equiv.) were prepared and added in sequence dropwise via canula to the yellow reaction mixture at 0° C. The resulting yellow mixture was stirred vigorously at 0 °C. for 3 h. Then water (1,000 mL) was added and the solution was extracted with dichloromethane (2 x 50 mL). The organic phases were combined, washed with 0.5 N aqueous HC1 (100 mL), washed with brine (100 mL), and dried over anhydrous sodium sulfate. The solution was fdtered and concentrated to afford a light yellow solid. This solid was purified by flash column chromatography on silica gel (1:9 to 2:3 ethyl acetate :hexanes) providing a light yellow solid. This solid was triturated with ether (20 mL) to afford the title compound as a white solid (2.2 g, 44% yield). 1HNMR (400 MHz, DMSO-76) δ 8.41 (d, J= 9.8 Hz, IH), 5.08 (d, J= 7.3 Hz, IH), 4.33 - 4.25 (m, 2 H), 3.53 - 3.34 (m, 2H), 2.38-2.27 (m, IH), 2.04-1.99 (m, IH), 1.93 - 1.79 (m, 2H), 1.43 (s, 6H), 1.30 (t, J= 7.1 Hz, 3H), 1.24 (s, 3H). LC/MS (ESI, m/z): [M +1]+ = 327.3.

[003462] Step 3 - (S) (l-(tert-butoxycarbonyl)pyrrolidin yl)thiazole carboxylic acid [003463] A solution of (S)-ethyl 2-(l-(tert-butoxycarbonyl)pyrrolidin yl)thiazole-4carboxylate (14.5 g, 44.5 mmol, 1 equiv.) in tetrahydrofuran (60 mL) was added to a solution of sodium hydroxide (5.33 g, 134.5 mmol, 3 equiv.) in water (40 mL) at 23 °C. The resulting mixture was stirred vigorously at 23 °C. for 3 h. Then the mixture was concentrated to 20 mL. The concentrated mixture was cooled to 0 °C and the pH was adjusted to 3 by the addition of concentrated HC1 solution dropwise. A lot of white solid was formed and the solid was collected by filtration to provide the title compound as a white solid (10.4 g, 74% yield). LC/MS (ESI, m/z): [M+1]+= 299.4.

1164

[003464] Step 4 - tert-butyl (S) (4-(methoxy(methyl)carbamoyl)thiazol yl)pyrrolidine1-carboxylate

[003465] (S) (l-(tert-butoxycarbonyl)pyrrolidin yl)thiazole carboxylic acid (22.6 g,

75.8 mmol), Ο,Ν-dimethylhydroxylamine hydrochloride (11.9 g, 122.7 mmol), diisopropyl ethyl amine (45.0 mL, 243 mmol) and HATU (46.2 g, 122.0 mmol) in DMF (200 mL) were stirred at rt for 12 hours. The reaction mixture was quenched with water, and the layers were separated. The aqueous layer was extracted with EtOAc (100 mLx3), and the combined organic layers were dried, filtered and concentrated. The crude product was purified via column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1) to give the title compound as an oil (23.0 g, 89% yield). LC/MS (ESI, mzy [M +1]+ = 342.2. 1HNMR (400 MHz, DMSO-76) δ 8.11 (s, IH), 5.08 (m, IH), 3.72 (s, 3H), 3.52 - 3.35 (m, 2H), 3.29 (s, 3H), 2.32 (m, IH), 2.06 (m, IH), 1.96 - 1.77 (m, 2H), 1.50-1.20 (d, 9H).

[003466] Step 5 - (S)-tert-butyl 2-(4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)thiazol-2yDpyrrolidine-1 -carboxylate

[003467] To a solution of tert-butyl(3-iodophenoxy)dimethylsilane (6.9 g, 20.6 mmol) in THF (50 mL) was added isopropylmagnesium chloride solution (9.27 mL, 2.0 M in THF) dropwise at -10 °C under N2. The reaction mixture was stirred at 0 °C for 30 min. Then this resulting mixture, which formed (3-((tert-butyldimethylsilyl)oxy)phenyl)magnesium iodide, was added dropwise via syringe to a solution of the weinreb amide tert-butyl (S) (4-(methoxy(methyl)carbamoyl)thiazol2-yl)pyrrolidine-l-carboxylate (3.9 g, 11.4 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 0 ° C for 30 min then warmed up to rt and stirred for 4 h. The mixture was then cooled to -5 °C and quenched with saturated ammonium chloride solution (20 mL). The mixture was partitioned between water (30 mL) and ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was further extracted with ethyl acetate (3x 100 mL). The organic phases were combined, washed with brine (50 mL) and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated to give a light yellow oil. This oil was purified by flash column chromatography on silica gel (1:30 to 1:10 ethyl acetate :hexanes) providing the title compound as a colorless oil (5.13 g, 92.1%). 1H NMR (400 MHz, CDCh) δ 8.10 (s, IH), 7.76 (d, J = 7.7 Hz, IH), 7.71 - 7.66 (m, IH), 7.34 (t, J = 7.9 Hz, IH), 7.07 (d, J = 7.0 Hz, IH), 5.30-5.19 (m, IH), 3.66 - 3.41 (m, 2H), 2.42 - 2.19 (m, 2H), 2.01 - 1.90 (m, 2H), 1.50 (s, 3H), 1.35 (s, 6H), 1.02 0.98 (m, 9H), 0.28 - 0.14 (m, 6H); LC/MS (ESI, m/zf [M +1]+ = 489.5.

1165

[003468] Step 6 - (S)-(3-((tert-butyldimethylsilyl)oxy)phenyl)(2-(pyrrolidin yl)thiazol-4yDmethanone

[003469] To a solution of (S)-tert-butyl 2-(4-(3-((tertbutyldimethylsilyl)oxy)benzoyl)thiazol yl)pyrrolidine-l-carboxylate (12.0 g, 20.5 mmol) in 1,4-dioxane (60 mL) was added HCl-dioxane (40 mL) (4 M in dioxane) dropwise. The reaction mixture was stirred at rt for 3 h. The reaction mixture concentrated in vacuo and used directly without further purification to afford (S)-(3-hydroxyphenyl)(2-(pyrrolidin yl)thiazol-4yl)methanone HCI salt (8.0 g). To a solution of (S)-(3-hydroxyphenyl)(2-(pyrrolidin yl)thiazol4-yl)methanone HCI salt (8.00 g, 25.7 mmol) in DCM (80 mL) was added imidazole (5.2 g, 57.2 mmol) slowly at 0° C. Then TBSC1 (3.89 g, 34.3 mmol, in 20 mLDCM) was added slowly at 0 °C. The resulting mixture was stirred at rt for 130 min. The reaction mixture was quenched with water, extracted with ethyl acetate (3x 100 mL), washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and purified by flash column chromatography on silica gel (1:100 to 1:40 methanol / DCM) to give the title compound as a yellow oil (8.0 g, 84% yield). 1HNMR (400 MHz, DMSO-t/6) δ 8.38 (s, IH), 7.71 - 7.64 (m, 2H), 7.43 (t, J = 8.0 Hz, IH), 7.14 (ddd, J= 8.0, 2.4, 1.1 Hz, IH), 4.51 (dd, J = 8.3, 4.9 Hz, IH), 3.56 (s, IH), 3.00-2.89 (m, 2H), 2.27 - 2.10 (m, IH), 1.75-1.70 (m, IH), 1.77- 1.65 (m, 2H), 0.97 (s, 9H), 0.22 (s, 6H).

[003470] Step 7:benzyl((S)-1 -(((S) ((S) (4-(3 -((tertbutyl dimethylsilyl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-l-cy cl ohexyl oxoethyl)amino)-loxopropan yl)(methyl)carbamate

[003471] In a 250-mL round-bottom flask, was placed (S)-(3-((tertbutyldimethylsilyl)oxy)phenyl)(2-(pyrrolidin yl)thiazol yl)methanone (7.5 g, 19.3 mmol), (S) ((S) (((benzyloxy)carbonyl)(methyl)amino)propanamido) cyclohexylacetic acid (9.5 g, 25.1 mmol, Intermediate UU), and 4-methylmorpholine (3.90 g, 38.60 mmol) in EtOAc (100 mL) at 0°C. DMT-MM (6.94 g, 25.1 mmol) was then added and the resulting solution was stirred for 3 h at 0 °C. Then H2O (40 mL) was added, and the resulting solution was extracted with EtOAC (3 x 50 mL) . The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1 :2) to give the title compound as a yellow solid. (7.3 g, 60% yield). 1H NMR (400 MHz, DMSO-t/6) δ 8.49 (s, IH), 7.95 (d, J = 39.4 Hz, IH), 7.74

1166

7.63 (m, 2H), 7.43 (t, J = 7.9 Hz, IH), 7.35 - 7.31 (m, 5 H), 7.16 (dd, J = 8.0, 2.5 Hz, IH), 5.37 (dd, J= 7.6, 2.2 Hz, IH), 5.08 - 5.01 (m, IH), 4.66 (d, J= 6.6 Hz, IH), 4.37 (t, J = 7.5 Hz, IH), 3.83-3.75 (m, 2H), 2.83 (s, 3H), 2.33-2.14 (m, 2 H), 2.07- 1.98 (m, 2H), 1.67-1.48 (m, 6H), 1.25 (s, 3H), 1.07 - 0.89 (m, 14H), 0.22 (s, 6H). LC/MS (ESI, m/z[. [M +1]+ = 747.6.

[003472] Step 8 - benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3-hydroxybenzoyl)thiazol2-yl)pyrrolidin-l-yl) oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate

[003473] To a stirred solution of benzyl ((S)-l-(((S) ((S) (4-(3-((tertbutyl dimethylsilyl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-l-cy cl ohexyl oxoethyl)amino)-loxopropan yl)(methyl)carbamate (5.0 g, 6.68 mmol) in THF (20 mL) was added TBAF (8.0 mL, 8.0 mmol) a rt. The reaction mixture was stirred at rt for 4 h. Then H2O (20 mL) was added and the mixture was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine, dried and concentrated in vacuo. The mixture was purified via column chromatography (DCM / EtOAc = 5% - 80%) to give the title compound (3.2 g, 76% yield) as a yellow solid. 1H NMR (400 MHz, MeOD-/4) δ 8.26 (s, IH), 7.59 - 7.53 (m, IH), 7.51 (dd, J = 2.3, 1.7 Hz, IH), 7.37 - 7.28 (m, 6H), 7.05 (ddd, J = 8.1, 2.6, 0.9 Hz, IH), 5.50 - 5.39 (m, IH), 5.13 (s, 2H), 4.69 (s, IH), 4.54 - 4.38 (m, IH), 4.02 - 3.93 (m, IH), 3.90 - 3.86 (m, IH), 2.94 (s, 3H), 2.23 - 2.10 (m, 4H), 1.72 - 1.56 (m, 6H), 1.37 (d, J = 5.2Hz, 3H ), 1.16 - 0.88 (m, 5H); LC-MS (ESI+): m/z 633.5(M+H)+.

[003474] Benzyl N-[(lS) [[(lS) [(2S) [4-[3-[2-[2-[2-[2-[2-(2-aminoethoxv)ethoxy] ethoxy] ethoxy] ethoxy|ethoxy|benzovl]thiazol vl]Dvrrolidin-l-vl]-l-cvclohexvl oxoethvl]amino]-l-methvl oxo-ethvl]-N-methyl-carbamate (Intermediate QE)

1167

QE

[003475] Step 1 - benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3-((2,2-dimethyl oxo3,8,lL14,17,20-hexaoxa azadocosan yl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-2oxoethvl)amino)-l-oxopropan vl)(methyl)carbamate

[003476] To a solution of benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3hydroxybenzoyl)thiazol yl)pyrrolidin-l-yl) oxoethyl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.3 g, 2.06 mmol, Intermediate QD) in CH3CN (100 mL) was added 2,2dimethyl oxo-3,8,ll,14,17,20-hexaoxa azadocosan yl 4-methylbenzenesulfonate (1.32 g, 2.47 mmol, Intermediate OO) and K2CO3 (340.9 mg, 2.47 mmol) at rt. Then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture solvent was removed under reduced pressure. The residue was purified via column chromatography (EtOAc / Petroleum ether) to give the title compound (1.71 g, 84 % yield) as a pale yellow oil. LC/MS (ESI, m/z): [M +1]+ = 997.56.

1168

[003477] Step 2 - benzyl ((S)-l-(((S) ((S) (4-(3-((17-amino-3,6,9,12,15pentaoxaheptadecyDoxy )benzoyl )thiazol yl)pyrrolidin-1 -yl)-1 -cyclohexyl oxoethyl)amino)1 -oxopropan yl)(methyl)carbamate 2,2,2-trifluoroacetate

[003478] To a solution of benzyl ((S)-1 -(((S)-1 -cyclohexyl ((S) (4-(3 -((2,2-dimethyl-4oxo-3,8,ll,14,17,20-hexaoxa azadocosan yl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate (1.6 g, 1.61 mmol) in DCM (30 mL) was added TFA (30 mL) and the reaction mixture was stirred at rt for 3 h. Then the reaction mixture solvent was removed under reduced pressure and the residue was purified via reverse phase column chromatography (ACN / H2O) to give the title compound (1.4 g, 86% yield) as a pale yellow oil. 1HNMR (400 MHz, MeOD) δ; 8.32 (s, IH), 7.86 - 7.67 (m, 2H), 7.45 (t, J= 7.9 Hz, IH), 7.41 7.13 (m, 6H), 5.62- 5.47 (m, IH), 5.13 (s, 2H), 4.73 -4.68 (m, IH), 4.59-4.34 (m, IH), 4.244.22 (m, 2H), 4.07 - 3.79 (m, 4H), 3.79 - 3.52 (m, 18H), 3.19-3.05 (m, 2H), 2.94 - 2.77 (m, 3H), 2.62 - 1.91 (m, 4H), 1.88 - 1.49 (m, 6H), 1.37 - 1.35 (m, 3H), 1.23 - 0.82 (m, 5H). LC/MS (ESI, m/z): [M+l]+ = 896.57.

[003479] Benzyl N-[(lS) [[(lS) [(2S) [4-[3-[2-[2-[2-(2aminoethoxv)ethoxy] ethoxy] oxo-ethyl]amino]-l-methyl oxo-ethyl]-N-methyl-carbamate (Intermediate OF)

1169

[003480] Step 1 - benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3-((2,2-dimethyl oxo3,8,lL14-tetraoxa azahexadecan vl)oxv)benzovl)thiazol vl)pyrrolidin-l-vl)-2oxoethvl)amino)-l-oxopropan vl)(methyl)carbamate

[003481] To a solution of benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3hydroxybenzoyl)thiazol yl)pyrrolidin-l-yl) oxoethyl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.50 g, 2.38 mmol, Intermediate QD) in CH3CN (100 mL) was added 2,2dimethyl oxo-3,8,ll,14-tetraoxa azahexadecan yl 4-methylbenzenesulfonate (1.30 g, 3.09 mmol, Intermediate LD) and K2CO3 (346.4 mg, 2.51 mmol) at rt. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified via column chromatography on silica gel (EtOAc / petroleum ether=l/l-EA) to give the title compound (1.80 g, 80% yield) as a white solid. 1H NMR (400 MHz, DMSO-» δ 8.49 (s, IH), 7.97 (d, J = 40.8 Hz, IH), 7.69 - 7.64 (m, 2H), 7.46 (t, J = 7.9 Hz, IH), 7.39 - 7.29 (m, 5H), 7.26 (dd, J= 8.2, 1.9 Hz, IH), 6.73 (t, J = 5.1 Hz, IH), 5.40 - 5.37 (m, IH), 5.09 - 5.06 (m, 2H), 4.70 - 4.65 (m, IH), 4.38 (t, J = 7.5 Hz, IH), 4.23 - 4.12 (m, 2H), 3.85 - 3.73 (m, 4H), 3.62 - 3.59 (m, 2H), 3.55 -3.47 (m, 6H), 3.36 (t, J= 6.2 Hz, 2H), 3.05 (q, J= 5.9 Hz, 2H), 2.84 (s,

1170

3H), 2.28 - 2.14 (m, 2H), 2.08 -2.01 (m, 2H), 1.66 - 1.44 (m, 6H), 1.36 (s, 9H), 1.26 (br s, 3H), 1.09 - 0.86 (m, 5H). LC/MS (ESI, m/z[. [M +1]+ = 908.6.

[003482] Step 2 - benzyl ((S)-l-(((S) ((S) (4-(3-(2-(2-(2-(2aminoethoxy)ethoxy)ethoxy)ethoxy )benzoyl )thiazol yl)pyrrolidin-1 -yl)-1 -cyclohexyl-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate

[003483] To a solution of benzyl ((S) (((S) cyclohexyl ((S) (4-(3-((2,2-dimethyl-4oxo-3,8,11,14-tetraoxa azahexadecan yl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate (1.8 g, 1.47 mmol) in DCM (30 mL) was added TFA (30 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.8 g, 100% yield, TFA salt) as a light yellow oil. 1H NMR (400 MHz, CD3OD) δ 8.32 (s, IH), 7.80 (br s, IH), 7.76 - 7.70 (m, 2H), 7.44 (t, J= 7.9 Hz, IH), 7.38 - 7.30 (m, 5H), 7.26 - 7.20 (m, IH), 5.47-5.46 (m, IH), 5.13 (s, 2H), 4.73-4.65 (m, IH), 4.53 - 4.40 (m, IH), 4.22 (dd, J = 5.3, 3.8 Hz, 2H), 4.00 - 3.94 (m, IH), 3.89 - 3.86 (m, 3H), 3.76 - 3.72 (m, 2 H), 3.70 - 3.66 (m, 8H), 3.12-3.08 (m, 2H), 2.94 (s, 3H), 2.40 -2.19 (m, 3 H), 2.17-2.09 (m, 1 H), 1.72 - 1.57 (m, 6H), 1.36 (d, J = 7.2 Hz, 3H), 1.19-0.94 (m, 5H). LC/MS (ESI, m/zf [M +1]+ = 808.6.

[003484] Benzyl N-[(l S) [[(1 S) [(2S) [4- [3-[2-[2- [2- [2-(2-aminoethoxv)ethoxy] ethoxy] ethoxy] ethoxy|benzovl]thiazol vl]Dvrrolidin-l-vl]-l-cvclohexvl oxoethvl]amino]-l-methvl oxo-ethvl]-N-methyl-carbamate (Intermediate OG)

1171

QG

[003485] Step 1 - benzyl ((S) (((S) cy cl ohexyl ((S) (4-(3-((2,2-dimethyl oxo3,8,11,14,17-pentaoxa azanonadecan yl)oxy )benzoyl )thiazol yl)pynOlidin-1 -yl)-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate

[003486] To a solution of benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3hydroxybenzoyl)thiazol yl)pyrrolidin-l-yl) oxoethyl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.32 g, 2.09 mmol, Intermediate QD) in CH3CN (100 mL) was added 2,2dimethyl oxo-3,8,ll,14,17-pentaoxa azanonadecan yl 4-methylbenzenesulfonate (1.23 g, 2.51 mmol, Intermediate ON) and K2CO3 (346.4 mg, 2.51 mmol) at rt. Then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was then concentrated under reduced pressure. The residue was purified via column chromatography on silica gel (EtOAc / petroleum ether) to give the title compound (1.68 g, 85% yield) as a pale yellow oil. LC/MS (ESI, m/z): [M+l]+ = 953.7.

[003487] Step 2 - benzyl ((S)-l-(((S) ((S) (4-(3-((14-amino-3,6,9,12tetraoxatetradecvl)oxv)benzoyl)thiazol yl)pyrrolidin-1 -yl)-1 -cvclohexyl oxoethyl)amino)-1 oxopropan yl)(methyl)carbamate 2,2,2-trifluoroacetate

1172

[003488] To a solution of benzyl ((S) (((S) cy cl ohexyl ((S) (4-(3-((2,2-dimethyl-4oxo-3,8,ll,14,17-pentaoxa azanonadecan yl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate (1.4 g, 1.47 mmol) in DCM (30 mL) was added TFA (30 mL) and the reaction mixture was stirred at rt for 3 h. Then the reaction mixture was concentrated under reduced pressure and the residue was purified via reverse phase column chromatography (ACN / H2O) to give the title compound (1.2 g, 84% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD) ri: 8.33 (s, IH), 7.90 - 7.68 (m, 3H), 7.50 - 7.40 (m, IH), 7.40 - 7.19 (m, 5H), 5.67 - 5.30 (m, IH), 5.13 (s, 2H), 4.73-4.67 (m, IH), 4.50 - 4.40 (m, IH), 4.29 - 4.12 (m, 2H), 4.05 - 3.79 (m, 4H), 3.78 - 3.52 (m, 14H), 3.10 - 3.07 (m, 2H), 2.94 (s, 3H), 2.57 - 1.95 (m, 4H), 1.85 - 1.46 (m, 6H), 1.40-1.29 (m, 3H), 1.27-0.86 (m, 5H). LC/MS (ESI, m/z[ [M+l]+ = 852.7.

[003489] Benzyl N-[(lS) [[(lS) [(2S) [4-[3-[2-[2-(2aminoethoxv)ethoxy] thiazol vl]pvrrolidin-l-vl]-l-cvclohexvl oxoethyllaminol-l-methyl oxo-ethyll-N-methyl-carbamate (Intermediate OH)

1173

[003490] Step 1 - benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3-((2,2-dimethyl oxo3,8,ll-trioxa azatridecan yl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl) oxoethyl)amino)l-oxopropan vl)(methyl)carbamate

[003491] To a solution of benzyl ((S)-l-(((S)-l-cyclohexyl ((S) (4-(3hydroxybenzoyl)thiazol yl)pyrrolidin-l-yl) oxoethyl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.30 g, 2.05 mmol, Intermediate QD) in CH3CN (25 mL) was added 2,2dimethyl oxo-3,8,ll-trioxa azatridecan yl 4-methylbenzenesulfonate (1.20 g, 2.46 mmol, Intermediate UV) and K2CO3 (368 mg, 2.67 mmol) at rt. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified via column chromatography on silica gel (EtOAc / Petroleum ether=l/l-EA) to give the title compound (1.30 g, 68 % yield) as a white solid. 1HNMR (400 MHz, CD3OD) δ 8.32 (s, IH), 7.73 - 7.71 (m, 2H), 7.43 (t, J= 8.0 Hz, IH), 7.39 - 7.29 (m, 5H), 7.26 - 7.20 (m, IH), 5.47 - 5.46 (m, IH), 5.13 (s, 2H), 4.69 (br s, IH), 4.52 - 4.41 (m, IH), 4.22 - 4.18 (m, 2H), 4.00 - 3.93 (m, IH), 3.89 - 3.87 (m, 3H), 3.73 - 68 (m, 2H), 3.66 - 3.61 (m, 2H), 3.52 - 3.49 (m, 2H), 3.23-3.19 (m, 2H), 2.94 (s, 3H), 2.36 - 2.20 (m, 3H), 2.18 - 2.06 (m, IH), 1.76- 1.50 (m, 6H), 1.41 (s, 9H), 1.36 (d, J= 7.2 Hz, 3H), 1.17 - 0.96 (m, 5H). LC/MS (ESI, m/z[. [M +1]+ = 864.6.

[003492] Step 2 benzyl((S)-1 -(((S) ((S) (4-(3 -(2-(2-(2aminoethoxy)ethoxy)ethoxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-l-cyclohexyl-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate

[003493] To a solution of benzyl ((S) (((S) cyclohexyl ((S) (4-(3-((2,2-dimethyl-4oxo-3,8,ll-trioxa azatridecan yl)oxy)benzoyl)thiazol yl)pyrrolidin-l-yl)-2oxoethyl)amino)-l-oxopropan yl)(methyl)carbamate (1.2 g, 1.39 mmol) in DCM (5mL) was added TFA (5 mL) and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give the title compound (1.2 g, 100 % yield, TFA salt) as a light yellow oil. 1HNMR (400 MHz, CDsOD)^ 8.33 (s, IH), 7.79 - 7.71 (m, 2H), 7.45 (t, J = 8.0 Hz, IH), 7.38 - 7.28 (m, 5H), 7.25 - 7.22 (m, IH), 5.47 - 5.46 (m, IH), 5.13 (s, 2H), 4.73 4.64 (m, IH), 4.52 - 4.40 (m, IH), 4.24 - 4.21 (m, 2H), 4.01 - 3.94 (m, IH), 3.90 - 3.88 (m, 3H), 3.77 - 3.74 (m, 2H), 3.72 - 3.69 (m, 4H), 3.1 l(t, J = 4.8 Hz, 2H), 2.94 (s, 3H), 2.39 - 2.11 (m, 4H), 1.75 - 1.54 (m, 6H), 1.36 (t, J = 8.0 Hz, 3H), 1.16 - 0.99 (m, 5H). LC/MS (ESI, m/zf [M +l]+ = 764.6.

1174

[003494] [3-Methvl [3-[3-(methvlamin0)Dr0D0xv]Dr0Dvl] 0x0-benzimidaz01-lyl]piperidine-2.,6-dione (Intermediate QI)

PO

Pd/C, Pd(OH)2/C, H2

THF

Cs2CO3, Cui, Pd(PPh3)2CI2, DMF

QI

[003495] Step 1 - Tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1prop ynoxy1propyl1-N-methyl-carbamate

[003496] To a solution of tert-butyl N-methyl-N-(3-prop ynoxypropyl)carbamate (604 mg, 2.66 mmol, Intermediate PO) and 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (450 mg, 1.33 mmol, Intermediate HN) in DMF (10 mL) was added Pd(PPh3)2C12 (186 mg, 266 umol), Cui (50.6 mg, 266 umol) and Cs2CO3 (2.17 g, 6.65 mmol). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (550 mg, 85% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 11.13 (s, IH), 7.65 - 7.52 (m, 3H), 5.39 (dd, J = 5.6, 12.8 Hz, IH), 4.45 - 4.18 (m,

1175

2H), 3.62 - 3.44 (m, 2H), 3.22 (t, J= 7.2 Hz, 2H), 2.92 - 2.83 (m, IH), 2.80 - 2.59 (m, 7H), 2.08 2.00 (m, IH), 1.77 - 1.70 (m, 2H), 1.38 (s, 9H); LC-MS (ESI+) m/z 507.1 (M+Na)+.

[003497] Step 2 - Tert-butyl N-r3-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1 propyl1-N-methyl-carbamate

[003498] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]propyl]-N-methyl-carbamate (530 mg, 1.09 mmol) in THF (10 mL) was added Pd(OH)2/C (200 mg, 10 wt%) and Pd/C (200 mg, 10 wt% ). The reaction mixture was stirred at 25 °C under H2 (15 Psi) for 12 hrs. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobilephase: [water (0.225%FA)-ACN]; B%: 38%-65%, 9 min) to give the title compound (300 mg, 56% yield) as yellow oil. 1H NMR (400MHz, DMSO4) δ 11.08 (s, IH), 7.05 - 6.98 (m, 2H), 6.87 (d, J= 8.0 Hz, IH), 5.33 (dd, J= 5.6, 12.8 Hz, IH), 3.36 - 3.33 (m, 4H), 3.32 (s, 3H), 3.22 (t, J= 7.2 Hz, 2H), 2.95 - 2.85 (m, IH), 2.77 (s, 3H), 2.73 - 2.60 (m, 4H), 2.03 - 1.98 (m, IH), 1.86 - 1.78 (m, 2H), 1.73 - 1.69 (m, 2H), 1.38 (s, 9H); LC-MS (ESI+) m/z 389.2 (M + H-100)+.

[003499] Step 3 - 3-r3-Methyl r3-r3-(methylamino)propoxy1propyl1 oxo-benzimidazoll-yl1piperidine -2,6-dione

[003500] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy] propyl]-N-methyl-carbamate (50.0 mg, 102 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (40.0 mg, 92% yield, HC1) as a white solid. 1HNMR (400MHz, DMSO-Y) δ 11.09 (s, IH), 7.06 - 6.97 (m, 2H),6.90 6.84 (m, IH), 5.34 (dd, J = 5.2, 12.8 Hz, IH), 3.56 (s, 2H), 3.43 (t, J= 6.0 Hz, 2H), 3.32 (s, 3H), 2.96 - 2.86 (m, 3H), 2.72 - 2.58 (m, 4H), 2.56 - 2.52 (m, 3H), 2.02 - 1.97 (m, IH), 1.90 - 1.78 (m, 4H); LC-MS (ESI+) m/z 389.2(M+H)+.

[003501] Tert-butyl(2-methvl (prop vn-l-vloxv)butan yl)carbamate (Intermediate

[003502] Step 1 - Tert-butyl (4-hydroxy methylbutan yl)carbamate

1176

[003503] To a solution of 3-amino methylbutan-l-ol (4.0 g, 38.8 mmol, CAS# 42514-501) and TEA(3.92 g, 38.8 mmol, 5.4 mL) in THF (50 mL) added dropwise (Boc)2O (9.31g, 9.8 mL, 42.6 mmol) at 20 °C and the mixture was stirred at 20 °C for 16 hours. Once completion, the reaction mixture was quenched by water (15 mL), and then extracted with EA (3 X 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE/EA = 10:1) to give the title compound (1.50 g, 19% yield) as a light yellow oil. 1H NMR (400 MHz, CDCh) δ 4.90 (s, IH), 3.76 (q, 2H), 2.04 (s, IH), 1.88 (t, J= 6.4 Hz, 2H), 1.43 (s, 9H), 1.32 (s, 6H).

[003504] Step 2 - Tert-butyl (2-methyl (prop yn-l-yloxy)butan yl)carbamate [003505] To a solution of tert-butyl (4-hydroxy methylbutan yl)carbamate (1.40 g, 6.89 mmol) and 3-bromoprop yne (1.23 g, 10.3 mmol) in THF (20 mL) was added KI (171 mg, 1.03 mmol), TBAI (152 mg, 0.41 mmol) and KOH (463 mg, 8.26 mmol) at 30 °C. Then the mixture was stirred at 30 °C for 16 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the residue. The residue was purified by column chromatography (SiO2, PE/EA = 30:1) to give the title compound (1.40 g, 84% yield) as a light yellow liquid. 1HNMR (400 MHz, CDCh) δ 4.84 (s, IH), 4.12 (d, J= 2.4 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2H), 2.42 (t, J= 2.4 Hz, IH), 1.91 (t, J= 6.4 Hz, 2H), 1.42 (s, 9H), 1.31 (s, 6H).

[003506] 3-[7-[3-(3-Amino methvl-butoxy)DroDvl] oxo-l.,3-benzoxazol-3yl]DiDeridine-2.,6-dione (Intermediate OK)

1177

Pd(OH)2/C, Pd/C, H2

THF

QK

[003507] Step 1 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidyl) oxo-l,3-benzoxazol-7yl1prop ynoxy1-l, 1- dimethyl-propyllcarbamate

[003508] To a solution of 3-(7-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (320 mg, 0.98 mmol, Intermediate JF) and tert-butyl (2-methyl (prop yn-l-yloxy)butan-2yl)carbamate (593 mg, 2.46 mmol, Intermediate QJ) in DMF (20 mL) was added Cs2CO3 (1.28 g, 3.94 mmol), Cui (37.49 mg, 0.2 mmol), Pd(PPh3)2C12 (138 mg, 0.2 mmol) and 4A molecular sieves (80 mg) at 25 °C under N2. Then the reaction mixture was heated to 80 °C and stirred for 2 hours. On completion, the reaction mixture was quenched by addition of water (10 m)L, and then extracted with EA (30 mL, 3X10 mL). The combined organic layers and dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 2/1 to 1/1) to give the title compound (330 mg, 69% yield) as a white solid. 1HNMR (400 MHz, CDCh) δ 8.18 (s, IH), 7.25 - 7.19 (m, IH), 7.13 (t, J= 8.0 Hz, IH), 6.82 - 6.75 (m, IH), 5.08 - 5.01 (m, IH), 4.91 (s, IH), 4.41 (s, 2H), 3.73 (t, 7= 6.4 Hz, 2H), 3.04 - 2.95 (m, IH), 2.91 - 2.66 (m, 2H), 2.40 - 2.27 (m, IH), 1.97 (t, 7= 6.2 Hz, 2H), 1.41 (s, 9H), 1.35 (s, 6H); LC-MS (ESI+) m/z 386.0 (M+H-100)+.

[003509] Step 2 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidyl) oxo-l,3-benzoxazol-7yUpropoxyl-1,1- dimethyl-propyllcarbamate

1178

[003510] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop-2 -ynoxy]-1,1-dimethyl-propyl]carbamate (130 mg, 0.27 mmol) in THF (15 mL) was added Pd/C (10 wt%) and Pd(OH)2/C (10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 gas several times. The mixture was stirred at 25 °C for 16 hours under H2 (15 psi). On completion, the reaction mixture was fdtered and concentrated in vacuo to give the title compound (127 mg, 85% yield) as a white solid. LC-MS (ESI+) m/z 390.2 (M+H100)+.

[003511] Step 3 - 3-r7-r3-(3-Amino methyl-butoxy)propyl1 oxo-L3-benzoxazol-3yl1piperidine-2,6-dione

[003512] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] -l,l-dimethyl-propyl]carbamate (127 mg, 0.26 mmol) in DCM (5 mL) was added TFA (591 mg, 0.52 mmol, 0.38 mL) at 25 °C. The mixture was stirred at 25 °C for 60 min. On completion, the reaction mixture was concentrated in vacuo to give the title compound (126 mg, 96% yield, TFA) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 9.05 (s, IH), 7.13 (t, J= 16 Hz, IH), 7.03 - 6.98 (m, IH), 6.78 (d, J= 8.0 Hz, IH), 5.14 - 5.09 (m, IH), 3.67 (t, J= 5.6 Hz, 2H), 3.56 (t, J = 5.6 Hz, 2H), 2.99 - 2.71 (m, 6H), 2.37 - 2.33 (m, IH), 2.04 - 1.96 (m, 2H), 1.84 (t, J= 5.6 Hz, 2H), 1.40 (s, 6H); LC-MS (ESI+) m/z 390.1 (M+H)+.

[003513] 2- [2- [2-(Tert-butoxycar bonylaminolethoxy] ethoxy] ethyl(4-nitrophenyl) carbonate (Intermediate QL)

[003514] To a solution of (4-nitrophenyl) carbonochloridate (711 mg, 3.53 mmol, CAS# 7693 1) and tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (800 mg, 3.21 mmol, CAS# 139135 7) in DCM (20 mL) was added TEA (812 mg, 8.02 mmol) at 0 °C. The reaction mixture was stirred at this temperature for 1 hr. On completion, the mixture was quenched with water (10 mL), and concentrated in vacuo to give the title compound (1.2 g, 90% yield) as a yellow oil. LC-MS (ESI+) m/z 437.2 (M+Na)+.

[003515] 3-[5-(Aminomethvl)-l-oxo-isoindolin yl]piperidine-2,6-dione (Intermediate QM)

1179

HCl/dioxane

DCM

[003516] Step 1 - 2-(2,6-Dioxo piperidyl)-l-oxo-isoindoline carbonitrile

[003517] To a solution of 3-(5-bromo-l-oxo-isoindolin yl) piperidine-2,6-dione (1.70 g,

5.26 mmol, Intermediate KC) and Zn(CN)2 (370 mg, 3.16 mmol) in DMF (30.0 mL) was added Pd(PPh3)4 (607 mg, 526 umol). The mixture was stirred at 100 °C for 3 hour under N2. On completion, the mixture was diluted with H2O (50 mL), then mixture was filtered and the solid was dried in vacuo. The solid was triturated with PE: EA=5: 1 (50 mL), filtered and the solid was dried in vacuo to give the title compound (1.10 g, 77% yield) as purple solid. 1H NMR (400MHz, DMSO-76) δ 11.02 (s, IH), 8.16 (s, IH), 8.01 - 7.90 (m, 2H), 5.20 - 5.09 (m, IH), 4.59 - 4.37 (m, 2H), 2.99 - 2.87 (m, IH), 2.70 - 2.57 (m, IH), 2.46 - 2.37 (m, IH), 2.11-1.98 (m, IH).

[003518] Step 2 - Tert-butyl N-rr2-(2,6-dioxo piperidyl)-l-oxo-isoindolin-5vHmethyllcarbamate

[003519] To a solution of 2-(2,6-dioxo piperidyl)-l-oxo-isoindoline carbonitrile (1.50 g,

5.57 mmol) in THF (15.0 mL) and DMF (15.0 mL) was added (Boc)2O (1.34 g, 6.13 mmol) and Raney-Ni (750 mg, 8.75 mmol). The mixture was stirred at 30 °C for 40 hour under H2 (50 psi). On completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE: EA = 1: 2) to give the title compound (900 mg, 43% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 10.99 (s, IH), 7.68 (d, J = 7.6 Hz, IH), 7.52 (t, J = 6.0 Hz, IH), 7.45 (s, IH), 7.38 (d, J = 7.6 Hz, IH), 5.17 - 5.03 (m, IH), 4.48 - 4.27 (m, 2H), 4.24 (d, J = 6.0 Hz, 2H), 2.98 - 2.85 (m, IH), 2.65 - 2.55 (m, IH), 2.44 - 2.31 (m, IH), 2.06 - 1.96 (m, IH), 1.40 (s, 9H).

[003520] Step 3 - 3-r5-(Aminomethyl)-l-oxo-isoindolin yl1piperidine-2,6-dione

1180

[003521] To a solution of tert-butyl N-[[2-(2, 6-dioxo piperidyl)-l-oxo-isoindolin yl] methyl]carbamate (200 mg, 535 umol) in DCM (5.00 mL) was added HCI/dioxane (4.00 M, 5.00 mL). The mixture was stirred at rt for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (160 mg, 90% yield, HCI) as white solid. LC-MS (ESI+) m/z 274.1 (M+H)+.

[003522] 2- [2-(2-Aminoethoxy)ethoxy| ethyl N-[[2-(2,6-dioxo DiDeridyl)-l-oxoisoindolin yl]methyl]carbamate (Intermediate ON) %NH

Q°

N—>

0Ax °2NX* n &#1512; &#1509; HCI || &#906; H QM \A/NH2 /0.NHBoc ________»

0 0

TEA, DMF QL

[003523] Step 1 - 2-r2-r2-(Tert-butoxvcarbonvlamino)ethoxy1ethoxy1ethylN-rr2-(2,6-dioxo3-piperidyl) oxo-isoindolin yl1methyl1carbamate

[003524] To a solution of 3-[5-(aminomethyl)-l-oxo-isoindolin yl]piperidine-2,6-dione (100 mg, 323 umol, HCI, Intermediate QM) and 2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethyl (4-nitrophenyl) carbonate (268 mg, 646 umol, Intermediate QL) in DMF (3 mL) was added TEA (163 mg, 1.61 mmol) under N2 atmosphere. The reaction mixture was stirred at 25 °C for 1 h. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (110 mg, 62% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 11.00 (s, IH), 7.93 - 7.86 (m, IH), 7.70 - 7.65 (m, IH), 7.47 (s, IH), 7.42 - 7.36 (m, IH), 6.82 - 6.72 (m, IH), 5.14 - 5.06

1181 (m, IH), 4.47 - 4.40 (m, IH), 4.34 - 4.25 (m, 3H), 4.12 - 4.03 (m, 2H), 3.60 - 3.55 (m, 2H), 3.50 3.47 (m, 4H), 3.38 - 3.36 (m, 2H), 3.05 (q, J = 5.6 Hz, 2H), 2.97 - 2.85 (m, IH), 2.59 - 2.53 (m, 2H), 2.04 - 1.93 (m, IH), 1.36 (s, 9H); LC-MS (ESI+) m/z 549.3 (M+H)+.

[003525] Step 2 - 2-[2-(2-Aminoethoxy)ethoxy1ethyl N-rr2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl1methyl1carbamate

[003526] To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl N-[[2(2,6-dioxo piperidyl)-l-oxo-isoindolin yl]methyl]carbamate (150 mg, 273 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (130 mg, 98% yield, HCI) as a white solid. LC-MS (ESI+) m/z 449.2 (M+H)+.

[003527] 2-(Tert-butoxycarbonylamino)ethyl (4-nitrophenyl) carbonate (Intermediate

[003528] To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (500 mg, 3.10 mmol), (4nitrophenyl)carbonochloridate (687 mg, 3.41 mmol) in DCM (20.0 mL) was added TEA(784 mg, 7.75 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (1.00 g, 90% yield) as yellow solid. LC-MS (ESI+) m/z 349.1 (M+Na)+.

[003529] 2-Aminoethyl

N-[[2-(2.,6-dioxo piperidyl)-l-oxo-isoindolin-5 yl] methyl] carbamate (Intermediate OP)

1182

[003530] Step 1 - 2-(Tert-butoxvcarbonvlamino)ethyl N-rr2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl] methyl]carbamate

[003531] To a solution of 3-[5-(aminomethyl)-l-oxo-isoindolin yl]piperidine-2,6-dione (200 mg, 645umol, HCI, Intermediate QM) and 2-(tertbutoxycarbonylamino)ethyl (4-nitrophenyl) carbonate (421 mg, 1.29 mmol, Intermediate QO) in DMF (10.0 mL) was added TEA (326 mg, 3.23 mmol). The reaction mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA) - ACN]; B%: 26%-56%, 10 min) to give the title compound (160 mg, 53% yield) as white solid. 1HNMR (400MHz, DMSOY) δ 11.00 (s, IH), 7.82 (t, J = 6.0 Hz, IH), 7.68 (d, J = 8.0 Hz, IH), 7.49 (s, IH), 7.41 (d, J = 8.0 Hz, IH), 6.94 - 6.87 (m, IH), 5.16 - 5.07 (m, IH), 4.49 - 4.31 (m, 2H), 4.30 (d, J = 6.4 Hz, 2H), 3.99 - 3.90 (m, 2H), 3.18-3.09 (m, 2H), 2.97 - 2.89 (m, IH), 2.64 - 2.58 (m, IH), 2.44 - 2.35 (m, IH), 2.05 - 1.95 (m, IH), 1.38 (s, 9H).

[003532] Step 2 - 2-Aminoethyl N-rr2-(2,6-dioxo piperidvl)-l-oxo-isoindolin-5yl]methyl]carbamate

[003533] To a solution of 2-(tert-butoxycarbonylamino) ethyl N-[[2-(2,6-dioxo piperidyl)1-oxo- isoindolin yl]methyl]carbamate (140 mg, 304 umol) in DCM (2.00 mL) was added HCl/dioxane (4.00 M, 14.0 mL). The mixture was stirred at 25 °C for 0.5 hr. On completion, the

1183 mixture was concentrated in vacuo to give the title compound (120 mg, 99% yield) as yellow solid.

LC-MS (ESI+) m/z 361.2 (M+H)+.

[003534] 3-[7-[3-(2-Aminoethoxy)DroDvl] oxo-l.,3-benzoxazol vl]DiDeridine-2.,6 dione (Intermediate OR)

[003535] Step 1 - Tert-butyl N-r2-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol yl1 prop ynoxy1 ethyllcarbamate

[003536] To a solution of tert-butyl N-(2-prop ynoxyethyl)carbamate (689 mg, 3.46 mmol, synthesized via Step 1 on Intermediate CP) and 3-(7-bromo oxo-l,3-benzoxazol-3yl)piperidine-2,6-dione (450 mg, 1.38 mmol, Intermediate JF) in DMF (10 mL) was added Pd(PPh3)2C12 (194 mg, 276 umol), Cui (52.7 mg, 277 umol) and Cs2CO3 (2.25 g, 6.92 mmol). The reaction was stirred at 80 °C for 3 hrs under N2. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (510 mg, 83% yield) as a brown solid. 1H

1184

NMR (400 MHz, DMSO-A) δ 11.23 (s, IH), 7.31 (dd, J = 7.2 Hz, IH), 7.26 - 7.19 (m, 2H), 6.92 - 6.77 (m, IH), 5.46 - 5.32 (m, IH), 4.45 (s, 2H), 3.52 (t, J= 6.0 Hz, 3H), 3.12 (q, J= 5.6 Hz, 2H), 2.93 - 2.82 (m, IH), 2.66 - 2.57 (m, IH), 2.22 - 2.13 (m, IH), 1.36 (s, 9H); LC-MS (ESI+) m/z 344.1 (M + H- 100)+.

[003537] Step 2 - Tert-butylN-r2-r3-r3-(2,6-dioxo piperidyl) oxo-l,3-benzoxazol-7yUpropoxylethyl] carbamate

[003538] To a solution of tert-butyl N-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop ynoxy]ethyl]carbamate (340 mg, 766 umol ) in THF (20 mL) was added Pd(OH)2/C (150 mg, 10 wt%) and Pd/C (150 mg, 50 wt%). The reaction mixture was stirred at 25 °C for 2 hrs under H2 (15psi). On completion, the reaction mixture was filtered through celite and concentrated in vacuo to give the title compound (350 mg, 90% yield) as gray solid. LC-MS (ESI+) m/z 348.1 (M + H-100)+.

[003539] Step 3 - 3-[7-r3-(2-Aininoethoxy)propyl1 oxo-L3-benzoxazol yl1piperidine2,6-dione

[003540] To a solution of tert-butyl N-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] ethylcarbamate (70.0 mg, 156 umol ) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo to give the title compound (60.0 mg, 99 % yield, HCI) as a white solid. LC-MS (ESI+) m/z 348.1(M+H)+.

[003541] 4-[[2-[2-[Tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino] Dvridvl]oxazole4-carbonyl] amino]-l-(4-formylDhenvl)Dvrazole carboxylic acid (Intermediate QU)

1185

HO

QU

[003542] Step 1 - Methyl 4-amino-l-»(hydroxymethyl )phenvl]pvrazole carboxylate [003543] To a solution of methyl l-[4-(hydroxymethyl)phenyl] nitro-pyrazole-3carboxylate (15.0 g, 54.1 mmol, synthesized via Step 1 of Intermediate GB) in MeOH (200 mL) was added Pd/C (5.00 g, 10 wt%). The reaction mixture was stirred at 25 °C for 2 hours under H2 (15 Psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (13.0 g, 97% yield) as a light yellow solid. 1H NMR (400MHz, DMSO-» δ 7.82 (s, IH), 7.74 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 5.27 (t, J = 5.6 Hz, IH), 4.89 (s, 2H), 4.53 (d, J=5 .6 Hz, 2H), 3.83 (s, 3H).

[003544] Step 2 - Methyl 4-rr2-r2-rtert-butoxvcarbonvl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1amino1-l-[4-(hydroxymethyl)phenyl1pyrazole carboxylate [003545] To a solution of methyl 4-amino-l-[4-(hydroxymethyl)phenyl]pyrazole-3carboxylate (4.10 g, 16.5 mmol) and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (5.14 g, 13.2 mmol, Intermediate CM) in DMF (100 mL) was added DIPEA (4.29 g, 33.1 mmol) and HATU (6.31 g, 16.5 mmol). The reaction mixture was

1186 stirred at 25 °C for 0.5 hour. On completion, the reaction was quenched with water (500 mL) and the reaction mixture was filtered. The filter cake was washed with water (2 X 100 mL), MeOH (2 X 10 mL) and then dried in vacuo to give the title compound (10.0 g, 100% yield) as a yellow solid. LC-MS (ESI+) m/z 639.0 (M+Na)+.

[003546] Step 3 - Methyl 4-[[2-[2-[tert-butoxvcarbonvl(2.2.2-trif1uoroethyl)amino1-4pyridyl1oxazole carbonyl1amino1-l-(4-formylphenyl)pyrazole carboxylate

[003547] To a solution of methyl 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]4-pyridyl]oxazole- 4-carbonyl]amino]-l-[4-(hydroxymethyl)phenyl]pyrazole carboxylate (7.00 g, 11.3 mmol) in THF (250 mL) was added DMP (5.78 g, 13.6 mmol). The reaction mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was diluted with DCM (300 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (7.00 g, 100% yield) as a yellow solid. 1H NMR (400MHz, DMSO-/6) δ 10.39 (s, IH), 10.05 (s, IH), 9.15 (d, J = 3.6 Hz, IH), 8.66 (d,/= 5.2 Hz, IH), 8.33 (s, IH), 8.19 (d,/= 8.8 Hz, IH), 8.11 -8.03 (m, 2H), 8.03 - 7.95 (m, IH), 7.78 -7.75 (m, IH), 4.91 (q, / = 8.8 Hz, 2H), 1.54 (s, 9H), 1.35 (s, 3H); LC-MS (ESI+) m/z 637.0 (M +Na)+.

[003548] Step 4 - 4-l42-[2-[Tert-butoxvcarbonvl(2.2.2-trifluoroethvl)amino1-4pyridyl1oxazole carbonyl1 amino1-l-(4-formylphenyl)pyrazole carboxylic acid

[003549] To a solution of methyl 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]4-pyridyl]oxazole carbonyl]amino]-l-(4-formylphenyl)pyrazole carboxylate (4.00 g, 6.51 mmol) in THF (10 mL) and H2O (2 mL) was added LiOH (467 mg, 19.5 mmol). The reaction mixture was stirred at 25 °C for 3 hours. On completion, the reaction mixture was acidified with HCI (0.5 N) to pH=6 and filtered to give the title compound (3.00 g, 76% yield) as a white solid. LC-MS (ESI+) m/z 601.0 (M+H)+.

[003550] Tert-butyl N-[4-[4-[[l-(4-formvlDhenvl) (4-methylDiDerazine-lcarbonyl)Dvrazol vl] (Intermediate QV)

1187

[003551] To a solution of 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino]-l-(4-formylphenyl)pyrazole carboxylic acid (1.50 g, 2.50 mmol, Intermediate QU) and 1-methylpiperazine (200 mg, 2.00 mmol, CAS# 109 3) in DMF (50 mL) was added DIPEA (968 mg, 7.49 mmol) and HATU (949 mg, 2.50 mmol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched with water (100 mL), filtered and washed with water (2X30 mL) to give the filter cake. The filter cake was then purified by reverse phase (0.1% FA) to give the title compound (1.00 g, 58% yield) as a white solid. 1HNMR (400MHz, DM SO-0#) δ 11.17 - 11.06 (m, IH), 10.05 (s, IH), 9.15 (s, IH), 9.11 (s, 1H),8.66 (d, J= 5.2 Hz, IH), 8.16 (s, 3H), 8.12 - 8.05 (m, 2H), 7.78 - 7.74 (m, IH), 4.91 (q, 7 = 8.8 Hz, 2H), 4.39 - 4.32 (m, 2H), 3.85 - 3.70 (m, 2H), 2.48 - 2.40 (m, 4H), 2.24 (s, 3H), 1.54 (s, 9H); LC-MS (ESI+) m/z 683.1 (M+H)+.

[003552] 4-[4-[[2-[2-[Tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino]-4pyridyl] oxazole carbonyl] acid (Intermediate QW)

[003553] To a solution of tert-butyl N-[4-[4-[[l-(4-formylphenyl) (4-methylpiperazine-lcarbonyl)pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (100 mg, 146 umol, Intermediate QV) and NaH2PO4 (87.8 mg, 732 umol) in ACN (1 mL) was added H2O2 (33.2 mg, 292 umol, 30% sol) at 0 °C. Then sodium chlorite (92.7 mg, 1.03 mmol) in

1188

H2O (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was acidified by HC1 (0.5 N) to pH = 6 and filtered. The filter cake was collected and dried in vacuo to give the title compound (100 mg, 97% yield) as a white solid. LC-MS (ESI+) m/z 699.1 (M+H)+.

[003554] Tert-butyl N-[4-[4-[[3-[2-(dimethvlamino)ethylcarbamovl]-l-(4formylDhenvl)Dvrazol vl]carbamovl]oxazol vl] pyridvl]-N-(2.,2.,2trifluoroethyDcarbamate (Intermediate OX)

QU ZN~

QX

[003555] To a solution of 4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino]-l-(4-formylphenyl)pyrazole carboxylic acid (800 mg, 1.33 mmol, Intermediate QU) and Ν',Ν'- dimethyl ethane-1,2-diamine (117 mg, 1.33 mmol, 145 uL, CAS# 108 9) in DMF (10 mL) was added HATU (607 mg, 1.60 mmol) and DIPEA (860 mg, 6.66 mmol, 1.16 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (230 mg, 25% yield) as a white solid. 1H NMR (400 MHz, DMS0-76) δ 10.99 (s, IH), 10.05 (s, IH), 9.12 (s, IH), 8.70 (t, J= 5.2, IH), 8.66 (d, 7 = 5.2 Hz, IH), 8.29 (s, IH), 8.26 - 8.08 (m, 5H), 7.80 - 7.74 (m, IH), 4.90 (q, 7= 8.8 Hz, 2H), 3.54 - 3.48 (m, 2H), 2.71 - 2.63 (m, 2H), 2.36 (s, 6H), 1.54 (s, 9H); LC-MS (ESI+) m/z 671.3 (M +H)+.

[003556] 4-[4-[[2-[2-[Tert-butoxvcarbonyl(2.,2.,2-trifluoroethvl)amino]-4pyridyl] amino] [2-(dimethvlamino)ethvlcarbamovl]pyrazol-lyl] benzoic acid (Intermediate OY)

1189

[003557] To a solution of tert-butyl N-[4-[4-[[3-[2-(dimethylamino)ethylcarbamoyl]-l-(4formylphenyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (150 mg, 223 umol, Intermediate QX) in CH3CN (10 mL) was added a solution of NaH2PO4 (134 mg, 1.12 mmol and NaClO2 (141 mg, 1.57 mmol) in H2O (10 mL) at 0 °C, then H2O2 (126 mg, 1.12 mmol, 107 uL, 30% sol) was added to the mixture. The reaction mixture was stirred at 25 °C for 3 hrs . On completion, the mixture was diluted with 0.5N HCI (10 mL) and extracted with EA (2 X 40 mL). The organic phase was concentrated in vacuo to give the title compound (120 mg, 78% yield) as a white solid. LC-MS (ESI+) m/z 687.2(M +H)+.

[003558] 12-[[(lS)-l-[(2S,4R) hvdroxv [[4-(4-methylthiazol-5yl)Dhenvl]methylcarbamovl] dodecanoic acid (Intermediate QZ)

1190

QZ

[003559] Step 1 - methyl 12-(((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol-5 yl)benzyl)carbamoyl)pyrrohdin-l-yl)-3,3-dimethyl-l-oxobutan yl)amino) oxododecanoate

[003560] To a solution of 12-methoxy oxododecanoic acid (0.623 g, 2.55 mmol, CAS# 3909 0) in DMF (20 mL) was added HATU (0.989 g, 2.55 mmol) and DIPEA (0.599 g, 4.64 mmol). The mixture was stirred for 10 min at rt. Then to the mixture was added a solution of (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4-(4-methylthi azol-5yl)benzyl)pyrrolidine carboxamide HC1 salt (1 g, 2.32 mmol, Intermediate G) in DMF (10 mL) and the mixture was stirred for 3 h at rt. On completion, H2O (50 mL) was added to the mixture, then extracted with EA (100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated and purified by column (PE/EA= 1/1 to EA) to give the title compound (700 mg, 50 % yield) as a white solid. 1HNMR (400 MHz, CDCh) δ 8.80 (s, 1 H), 7.39-7.31 (m, 5H), 6.10 (d, 7= 8.8 Hz, IH), 4.73 (t, J= 8.0 Hz, IH), 4.61-4.48 (m, 3H), 4.34 (dd, J= 1.6 Hz, 7= 14.8 Hz, IH), 4.15-4.10 (m, IH), 3.66 (s, 3H), 3.60 (dd, 7= 3.6 Hz, 7= 11.6 Hz, IH), 2.56-2.53 (m,

1191

4H), 2.29 (t, J= 7.6 Hz, 2H), 2.21-2.10 (m, 3H), 1.62-1.57 (m, 4H), 1.28-1.26 (m, 11H), 0.93 (s, 9H). LC/MS (ESI, m/z[. [M +1]+ = 657.6.

[003561] Step 2:12-(((S)-l-((2S,4R) hydroxy ((4-(4-methylthi azol-5yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan yl)amino) oxododecanoic acid

[003562] To a solution of methyl 12-(((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan yl)amino) oxododecanoate (2.4 g, 3.65 mmol) in MeOH (30 mL), H2O (30 mL) and THF (30 mL) was added NaOH (877 mg, 21.9 mmol). The mixture was stirred for 3 h at rt. To the mixture was added then added 0.06 N HCI until the pH = 6.5, then the mixture was extracted with EA (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated to the title compound (2.3 g, 100% yield) as a white solid. 1HNMR (400 MHz, CDCh) δ 8.89 (s, IH), 7.39 (s, 4H), 7.20 (t, J= 7.2 Hz, IH), 7.12 (d, J = 9.2 Hz, IH), 4.74-4.64 (m, 3H), 4.58 (s, IH), 4.33 (dd, J= 4.8 Hz, J = 14.8 Hz, IH), 4.21 (d, J= 11.2 Hz, IH), 3.69 (dd, J= 4.0 Hz, J= 12 Hz, IH), 2.58 (s, 3H), 2.512.45 (m, IH), 2.35 (t, J= 6.0 Hz, 2H), 2.26-2.19 (m, 3H), 1.69-1.56 (m, 4H), 1.34-1.28 (m, 12H), 0.95 (s, 9H). LC/MS (ESI, m/z[. [M +1]+ = 643.3.

[003563] 2-[2-[2-[2-[2-[2-[[(lS)-l-[(2S,4R) hvdroxv n4-(4-methylthiazol-5vDphenyl] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetic acid (Intermediate RA)

1192

[003564] Step 1:(S) ((2S,4R) hydroxy ((4-(4-methylthi azol-5yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-20,20-dimethyl oxo-3,6,9,12,15-pentaoxa-18azahenicosanoic acid

[003565] To a mixture of 3,6,9,12,15-pentaoxaheptadecanedioic acid (1.04 g, 3.36 mmol, Intermediate UF), DIPEA(289 mg, 2.24 mmol) in DMF(15 mL) was added HATU (511 mg, 1.344 mmmol). Then the (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4-(4methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride (500 mg, 1.12 mmol, Intermediate G) in DMF (5 mL) was added dropwise to the solution. After the addition, the mixture was stirred at rt for 30 min. Then the mixture was poured into water, acidified to pH< 6 by addition of IM HCI, then extracted with EtOAc (3 x 30 mL). The combined organic layers was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (311 mg, 38% yield) as a white solid. 1H NMR (400 MHz, METHANOL-6/4) δ 9.05 (s, IH), 7.53 - 7.44 (m, 4H), 4.74 - 4.70 (m, IH), 4.61 -4.51 (m, 3H), 4.38 (d, 7=15.51 Hz, IH), 4.13 (s, 2H), 4.08 (d, 7=3.13 Hz, 2H), 3.90

1193

3.81 (m, 2H), 3.73 - 3.63 (m, 16H), 2.52 (s, 3H), 2.27 - 2.08 (m, 2H), 1.07 (s, 9H); LC/MS (ESI, mzy. [M+l]+ = 723.2.

[003566] 2- [2-[2- [2- H(1 S)-l- [(2S,4R) hydroxv [[4-(4-methvlthiazol vDDhenvl] methvlcarbamovl]Dvrrolidine-l-carbonvl]-2,2-dimethvl-DroDvl]amino] oxoethoxy] ethoxy] ethoxy] acetic acid Intermediate RB)

[003567] Step 1:(S) ((2S,4R) hydroxy ((4-(4-methylthi azol-5yl)benzyl)carbamoyl)pyrrolidine-l-carbonyl)-14,14-dimethyl-ll-oxo-3,6,9-trioxa-12azapentadecanoic acid

[003568] To a mixture of 2,2'-((oxybis(ethane-2,l-diyl))bis(oxy))diacetic acid (1.36 g, 4.3 mmol, CAS# 13887 4), DIPEA (415 mg, 3.23 mmol) in DMF(5 mL) was added HATU (488 mg, 1.29 mmmol). Then (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4-(4methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride (500 mg, 1.12 mmol, Intermediate G) in DMF(5 mL) was added dropwise into the mixture. After the addition, the mixture was stirred at rt for 30 min. Then the mixture was poured into water, acidified to pH<6 by the addition of IM HCI, then extracted with EtOAc (3 x 30 mL). The combined organic layers was washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (125 mg, 18%) as a white solid. 1HNMR (400 MHz, METHANOL-74) δ 9.10 (br. s., IH), 7.45 - 7.25 (m, 4H), 4.60 (s, IH), 4.50 - 4.40 (m, 3H), 4.26 (d, 7=15.51 Hz, IH), 4.03 - 3.94 (m, 4H), 3.79 - 3.68 (m, 2H), 3.63 - 3.58 (m, 8H), 2.41 (s, 3H), 2.16 - 1.93 (m, 2H), 0.94 (s, 9H); LC/MS (ESI, mzy [M +1]+ = 635.1.

1194

[003569] 5-(4-Tert-butoxvcarbonylpiperazin- 1-vDpyrazolo [ 1 5&#1524;-a] Dyrimidine-3carboxylic acid (Intermediate RC)

RC

[003570] Step 1 - Ethyl 5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[L5-a1pyrimidine3-carboxylate

[003571] To a mixture of ethyl 5-chloropyrazolo[l,5-a]pyrimidine carboxylate (0.50 g, 2.22 mmol, CAS# 1224944 7) and tert-butyl piperazine-l-carboxylate (619 mg, 3.32 mmol) in MeCN (6 mL) was added DIPEA (857 mg, 6.63 mmol, 1.16 mL), and the resulting mixture was stirred at 60 °C for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and acidified with HC1 (1 N) until the pH = 5, then the mixture was extracted with EA (3 X 50 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the compound (0.81 g, 97% yield) as white solid; 1H NMR (400MHz, CDCh) δ 8.32 - 8.31 (m, IH), 8.29 (s, IH), 6.43 - 6.41 (m, IH), 4.38 - 4.32 (m, 2H), 3.90 - 3.80 (m, 4H), 3.59 - 3.56 (m, 4H), 1.49 (s, 9H), 1.41 - 1.37 (m, 3H).

[003572] Step 2 - 5-(4-Tert-butoxycarbonylpiperazin-l-yl)pyrazolorL5-a1pyrimidine-3carboxylic acid

[003573] To a solution of ethyl 5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[l,5-a] pyrimidine carboxylate (0.80 g, 2.13 mmol) in THF (16.0 mL) was added a solution of LiOH*H2O (223 mg, 5.33 mmol) in H2O (4.00 mL). The reaction mixture was stirred at 20 °C for 16 hours, then an additional solution of LiOH*H2O (1.00 g, 23.8 mmol) in H2O (4.00 mL) was added, and the reaction mixture was stirred at 20 °C for 8 hours. The mixture was then heated to 45 °C and stirred for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was extracted with EA (20 mL) to remove organic impurities. Then the water phase was acidified with 1 N HC1 (aq.) until pH = 4, and extracted with EA/MeOH (10/1, 2 X 20 mL). The combined

1195 organic layer was dried 0verNa2S04, filtered and concentrated in vacuo to give the title compound (0.72 g, 97% yield) as yellowish solid. 1H NMR (400MHz, CDCh) δ 8.74 - 8.72 (m, IH), 8.17 (s, IH), 6.84 - 6.82 (m, IH), 3.75 - 3.74 (m, 4H), 3.46 - 3.43 (m, 4H), 1.42 (s, 9H).

[003574] N-[3-(difluoromethvl)-l-methvl-pvrazol vl] piperazin-l-vl-pyrazolo[l.,5alpyrimidine carboxamide (Intermediate RD)

RC RD

[003575] Step U Tert-butyl 4-[3-rr3-(difluoromethyl)-l-methyl-pyrazol-4vl1carbamoyl1pyrazolo[L5-a1 pyrimidin-5 - yl1piperazine-l-carboxylate

[003576] To a mixture of 3-(difluoromethyl) methyl-pyrazol amine (847 mg, 5.76 mmol, Intermediate LU), 5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[l,5-a]pyrimidine-3carboxylic acid (2.00 g, 5.76 mmol, Intermediate RC) in DMF (20 mL) was added DIPEA (2.23 g, 17.3 mmol) and HATU (2.63 g, 6.91 mmol). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (2X30 mL). The combined organic phase was washed with brine (2 X 30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Ethyl acetate) to give the title compound (734 mg, 26% yield) as reddish brown solid. 1H NMR (400MHz, CDCh) δ 9.42 (s, IH), 8.37 (s, IH), 8.32 - 8.25 (m, 2H), 6.70 (t, J= 54.0 Hz, IH), 6.35 (d, J= 8.0 Hz, IH), 3.83 (s, 3H), 3.75 (s, 4H), 3.59 - 3.49 (m, 4H), 1.44 (s, 9H).

[003577] Step 2- N-[3-(difluoromethyl)-l-methyl-pyrazol yl1 piperazin-l-ylPvrazolo[L5-a1pvrimidine carboxamide

[003578] To a mixture of tert-butyl 4-[3-[[3-(difluoromethyl)-l-methyl-pyrazol-4yl]carbamoyl]pyrazolo[l,5-a] pyrimidin yl]piperazine-l-carboxylate (684 mg, 1.44 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 717 uL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (575 mg, 91% yield, HCI) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 9.65 (s, 2H), 9.33 (s,

1196

IH), 8.90 (d, J= 8.0 Hz, IH), 8.35 (d, J= 12.4 Hz, IH), 7.13 (t, J= 53.6 Hz, IH), 6.96 (d, J= 7.6 Hz, IH), 4.08 (s, 4H), 3.89 (s, 3H), 3.23 (s, 4H). LC-MS (ESI+) m/z 377.2(M + H)+.

[003579] 3- [5- [ 4- [2-(2-Aminoethoxv)ethyl] piperazin- 1-yl] methyl oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate RG)

PN

NHBoc

[003580] Step 1 - Tert-butyl Ν-[2-[2-[4-|&#906;-(2.6-dioxo piperidvl) methyl oxobenzimidazol yl1piperazin -I&#1470;zyl1ethoxy1ethyl1carbamate

[003581] To a mixture of 3-(3-methyl oxo piperazin-l-yl-benzimidazol-l-yl)piperidine2,6-dione (20.0 mg, 582 umol, Intermediate PN) in THF (4 mL) and DMF (4 mL) was added TEA (589 mg, 5.82 mmol, 811 uL). The reaction mixture was stirred at 25°C for 0.5 hour. Then tertbutyl N-[2-(2-oxoethoxy) ethylcarbamate (500 mg, 2.46 mmol, synthesized via Step 1 of Intermediate FS) and HOAc (385 mg, 6.41 mmol, 366 uL) were added to the above solution. The reaction mixture was stirred at 25°C for 0.5 hour. Then NaBH(OAc)3 (247 mg, 1.16 mmol) was added to the reaction mixture. Then the mixture was stirred at 25 °C for 6 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (60.0 mg, 19% yield) as a yellow solid. LC-MS (ESI+) m/z 531.3 (M+H)+.

[003582] Step 2 - 3-r5-r4-r2-(2-Aminoethoxy)ethyl1piperazin-l-yl1 methyl oxobenzimidazol-l-yl] piperi dine-2.6-di one

1197

[003583] To a solution of tert-butyl N-[2-[2-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] piperazin-l-yl]ethoxy]ethyl]carbamate (60.0 mg, 113 umol) in DCM (10 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL). The mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (50.0 mg, 95% yield) as yellow oil. LC-MS (ESI+) m/z 431.2 (M+H)+.

[003584] 3-[5-[3-(2-Aminoethoxv)DroDvl] methvl oxo-benzimidazol-lyl]piperidine-2,6-dione (Intermediate RH)

Pd/C, Pd(OH)2/C, H2

THF

[003585] Step 1 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1prop ynoxy1ethyl1carbamate

[003586] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (600 mg, 1.77 mmol, Intermediate HN) and tert-butyl N-(2-prop ynoxyethyl)carbamate (883 mg, 4.44 mmol, synthesized via Step 1 on Intermediate CP) in DMF (10 mL) was added Cs2CO3 (2.31 g, 7.10 mmol), Cui (67.5 mg, 354 umol), 4A molecular sieve (20 mg) and Pd(PPh3)2C12 (249 mg, 354. umol). The mixture was heated at 80 °C for 2 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted

1198 with water (30 mL), and then extracted with EA (3 X 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (650 mg, 80% yield) as light yellow solid. 1HNMR (400MHz, DMSO4) δ 11.12 (s, IH), 7.32 (s, IH), 7.19-7.10 (m, 2H), 6.90-6.78 (m, IH), 5.39 (dd, 7= 5.6, 12.8 Hz, IH), 4.37 (s, 2H), 4.11 (d, 7=2.4 Hz, IH), 3.50 (t, 7= 6.0 Hz, 2H), 3.34 (s, 3H), 3.18 - 3.09 (m, 2H), 2.95 - 2.82 (m, IH), 2.73 - 2.55 (m, 2H), 2.09 - 1.99 (m, IH), 1.37 (s, 9H); LC-MS (ESI+) m/z 357.2 (M+H-100)+.

[003587] Step 2 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl]propoxy] ethyl]carbamate

[003588] To a solution of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]ethyl]carbamate (600 mg, 1.31 mmol) in THF (20 mL) was added Pd(OH)2/C (150 mg, 10 wt%) and Pd/C (150 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 gas three times. The mixture was stirred at 25°C for 16 hours under H2 (15 PSI). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (500 mg, 82% yield) as white solid. 1H NMR (400MHz, DMSO-t/6) δ 11.07 (s, IH), 7.08 - 6.92 (m, 2H), 6.86 (dd, 7= 1.2, 8.4 Hz, IH), 6.77 (t, 7= 5.2 Hz, IH), 5.33 (dd, 7= 5.2, 12.8 Hz, IH), 3.39 - 3.33 (m, 4H), 3.32 (s, 3H), 3.15 - 3.03 (m, 2H), 2.97 - 2.81 (m, IH), 2.73 - 2.58 (m, 4H), 2.03 - 1.95 (m, IH), 1.86 - 1.74 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 483.1 (M+Na)+.

[003589] Step 3 - 3-r5-r3-(2-Aminoethoxy)propyl] methyl oxo-benzimidazol-lyl]piperidine-2,6-dione

[003590] To a solution of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethyl]carbamate (150 mg, 325 umol) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 30 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (150 mg, 97% yield, TFA) as light yellow solid. LC-MS (ESI+) m/z 361.1 (M+H)+.

[003591] 4 [4-[3-(2-Aminoethoxv)DroDvl] methvl oxo-benzimidazol-lyl]Diperidine-2.,6-dione (Intermediate RI)

1199

[003592] Step 1 - Tert-butyl N-r2-r3-r1-(2»dioxo piperidvl) methyl oxobenzimidazol yl1prop ynoxylethyllcarbamate

[003593] To a mixture of tert-butyl N-(2-prop ynoxyethyl)carbamate (4.42 g, 22.1 mmol, synthesized via Step 1 on Intermediate CP) and 3-(4-bromo methyl oxo-benzimidazol-lyl)piperidine-2,6-dione (3.00 g, 8.87 mmol, Intermediate HP) in DMF (50 mL) was added Cs2CO3 (14.4 g, 44.3 mmol), Cui (168 mg, 887 umol) and Pd(PPh3)2C12 (622 mg, 887 umol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EA (3 X 100 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (2.70 g, 66% yield) as brown solid. 1H NMR (400 MHz, DMSO-» δ 11.13 (s, IH), 7.23 - 7.09 (m, 2H), 7.08 - 6.99 (m, IH), 6.92 - 6.82 (m, IH), 5.45 - 5.36 (m, IH), 4.44 (s, 2H), 3.64 (s, 3H), 3.52 (t, J= 6.0 Hz, 2H), 3.16 - 3.08 (m, 2H), 2.96 - 2.83 (m, IH), 2.78 - 2.60 (m, 2H), 2.07 - 1.95 (m, IH), 1.36 (s, 9H).

[003594] Step 2 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1 ethyllcarbamate

[003595] To a mixture of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]ethyl]carbamate (200 mg, 438 umol) in THF (5 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%). The reaction mixture was stirred at 25

1200 °C for 12 hours under H2 (15 PSI) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (200 mg, 99% yield) as light yellow oil. 1H NMR (400 MHz, DMSO-76) δ 11.08 (s, IH), 7.00 - 6.92 (m, 2H), 6.91 - 6.84 (m, IH), 6.79 (s, IH), 5.39 - 5.32 (m, IH), 3.56 (s, 3H), 3.44 (t, J = 6.0 Hz, 2H), 3.40 - 3.38 (m, 2H), 3.09 (d, J = 5.6 Hz, 2H), 2.98 - 2.93 (m, 2H), 2.90 - 2.83 (m, IH), 2.71 - 2.60 (m, 2H), 2.03 - 1.94 (m, IH), 1.88 - 1.76 (m, 2H), 1.37 (s, 9H).

[003596] Step 3 - 4 [4-[3-(2-Aminoethoxy)propyl1 methyl oxo-benzimidazol-lyl1piperidine-2,6-dione

[003597] To a mixture of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethyl]carbamate (200 mg, 434 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (172 mg, 99% yield) as light yellow solid. LC-MS (ESI+) m/z 361.1 (M+H)+.

[003598] 3-[5-[3-[(2R) (aminomethvl)morDholin vl]DroDvl] methyl oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate RJ)

1201

HN

Pd(PPh3)2CI2, Cui

CS2CO3, DMF

[003599] Step 1 - Tert-butyl N-rr(2R) prop vnvlmorpholin vl1methvl1carbamate [003600] To a solution of tert-butyl N-[[(2S)-morpholin yl]methyl]carbamate (1.00 g, 4.62 mmol, CAS# 875551 0) and 3-bromoprop yne (550 mg, 4.62 mmol) in THF (20 mL) was added K2CO3 (1.28 g, 9.25 mmol). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the mixture was diluted with water (30 mL) and extracted with EA (3 X 80 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 10/1 to 2/1) to give the title compound (800 mg, 68% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.93 (s, IH), 3.93 - 3.87 (m, IH), 3.68 (dt, J = 2.4, 11.2 Hz, IH), 3.64 - 3.57 (m, IH), 3.31 (d, J = 2.4 Hz, 2H), 3.15 - 3.05 (m, IH), 2.78 - 2.72 (m, IH), 2.70 - 2.65 ( IH), 2.39 (dt, J = 3.6, 11.2 Hz, IH), 2.27 (t, J =2.4 Hz, IH), 2.13 (t, J= 10.8 Hz, IH), 1.87 (s, IH), 1.45 (s, 9H).

[003601] Step 2 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop- 2-ynyl1morpholin yl1methyl1carbamate

1202

[003602] To a solution of tert-butyl N-[[(2R) prop ynylmorpholin-2yl]methyl]carbamate (846 mg, 3.33 mmol) and 3-(5-bromo methyl oxo-benzimidazol-lyl)piperidine-2,6-dione (450 mg, 1.33 mmol, Intermediate HN) in DMF (15 mL) was added Cs2CO3 (2.17 g, 6.65 mmol), Cui (25.3 mg, 133 umol) and Pd(PPh3)2C12 (93.4 mg, 133 umol). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (550 mg, 80% yield) as a yellow solid. 1HNMR (400 MHz, DMSO-76) δ 11.11 (s, IH), 7.28 (s, IH), 7.16 - 7.10 (m, 2H), 6.86 6.83 (m, IH), 5.38 (dd, J= 5.2, 12.4 Hz, IH), 3.79 (t, J= 13.2 Hz, 2H), 3.52 (s, 2H), 3.34 (s, 3H), 3.01 - 2.92 (m, 3H), 2.80 - 2.70 (m, 2H), 2.69 - 2.65 (m, 2H), 2.35 - 2.27 (m, IH), 2.25 - 2.15 (m, IH), 2.06 - 1.95 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 512.2 (M + H)+.

[003603] Step 3 - Tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1carbamate

[003604] To a solution of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynyl]morpholin yl]methyl]carbamate (300 mg, 586 umol) in THF (10 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%). The reaction mixture was stirred at 25 °C under H2 (15 psi) for 12 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prepHPLC (column: Phenomenex Synergi Cl8 150*25*lOum; mobile phase: [water (0.225%FA)ACN]; B%: 1%-31%, lOmin) to give the title compound (120 mg, 39% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 11.08 (s, IH), 7.04 (s, IH), 7.00 (d, J= 8.0 Hz, IH), 6.87 (d,J=8.0 Hz, IH), 6.82 (t, J= 5.6 Hz, IH), 5.33 (dd, J= 5.2, 12.8 Hz, IH), 3.43 - 3.40 (m, 3H), 3.32 (s, 3H), 3.03 - 2.87 (m, 3H), 2.73 - 2.58 (m, 6H), 2.36 - 2.25 (m, 2H), 2.03 - 1.95 (m, 2H), 1.79 - 1.66 (m, 3H), 1.36 (s, 9H); LC-MS (ESI+) m/z 516.3 (M+H)+.

[003605] Step 4 - 3-[5-[3-[(2R) (aminomethyl)morpholin yl1propyl1 methyl oxobenzimidazol-l-yl] piperi dine-2,6-di one

[003606] To a solution of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]carbamate (120 mg, 232 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (100 mg, 95% yield) as a white solid. LC-MS (ESI+) m/z 416.2(M+H)+.

1203

[003607] 32]52[32Ι&#943;Ζ8)222(3η1&#912;η0η16&#943;11χ1)η10τβ1101&#912;η242χ1]ρτ0ρχ1]232η16&#943;11χ12220χ02 benzimidazol-l-yl] piperidine-2,6-dione (Intermediate RK)

K2CO3, THF

Pd(PPh3)2CI2, Cui, Cs2CO3, 4A MS, DMF

[003608] Step 1 -Tert-butyl N-rr(2S) prop ynylmorpholin yl1methyl1carbamate

[003609] To a mixture of tert-butyl N-[[(2R)-morpholin yl]methyl]carbamate (3 g, 13.8 mmol, CAS# 186202 3) and 3- bromoprop yne (1.98 g, 16.6 mmol) in THF (60 mL) was added K2CO3 (3.83 g, 27.7 mmol). The reaction mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=4/l) to give the title compound (2.4 g, 68% yield) as light yellow solid. 1H NMR (400MHz, CDCh) δ 4.90 (s, IH), 3.96 - 3.83 (m, IH), 3.74 - 3.50 (m, 2H), 3.33 -3.25 (m, 3H), 3.13 - 3.08 (m, IH), 2.78 - 2.62 (m, 2H), 2.41 - 2.33 (m, IH), 2.26 (t, J= 2.4 Hz, IH), 2.13 (t, J= 10.4 Hz, IH), 1.44 (s, 9H).

[003610] Step 2 - Tert-butyl N-rr(2S) r3-r1-(2.6-dioxo piperidvl) methyl oxobenzimidazol yl1prop ynyl1morpholin yl1methyl1carbamate

1204

[003611] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (265 mg, 784 umol, Intermediate HN) and tert-butyl N-[[(2S) prop ynylmorpholin-2yl]methyl]carbamate (299 mg, 1.18 mmol) in DMF (15 mL) was added Cui (29.9 mg, 157 umol), Pd(PPh3)2C12 (110 mg, 157 umol), Cs2CO3 (1.02 g, 3.13 mmol) and 4A molecular sieves (20 mg) at 25 °C. The reaction mixture was stirred at 80 °C for 3 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was diluted with water (30 mL), and then extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (50 mL), then dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (270 mg, 67% yield) as a white solid. IH NMR (400 MHz, CDCh) δ 8.18 ( s, IH), 7.17 (d, 7= 1.2 Hz, IH), 7.10 (s, IH), 6.73 (d, 7= 8.4 Hz, IH), 5.20 - 5.16 (m, IH), 4.93-4.89 ( m, IH), 3.95 - 3.89 ( m, IH), 3.72 - 3.71 ( m&#1524; IH), 3.54 - 3.49 (m, 2H), 3.43 (s, 3H), 3.15 - 3.07 (m, IH), 2.99 - 2.99 (m, IH), 2.99 - 2.92 (m, IH), 2.89 - 2.61 (m, 6H), 2.48 - 2.40 (m, IH), 2.28 2.22 (m, IH), 2.17 (t, 7= 3.6 Hz, IH), 1.43 (s, 9H); LC-MS (ESI+) m/z 512.3 (M+H)+.

[003612] Step 3 - Tert-butyl N-rr(2S) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1 propyl1morpholin yl1methyl1carbamate

[003613] To a solution of tert-butyl N-[[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]prop ynyl]morpholin yl]methyl]carbamate (270 mg, 528 umol) in THF (15 mL) was added Pd/C (120 mg, 528umol, 10 wt%) and Pd(OH)2/C (110 mg, 528 umol, 10 wt%) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours under H2 (15 PSI). On completion, the reaction mixture was filtered with celite and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (230 mg, 85% yield) as a brown solid. LC-MS (ESI+) m/z 516.1 (M+H)+.

[003614] Step 4 - 3-r5-r3-r(2S) (aminomethyl)morpholin yl1propyl1 methyl oxobenzimidazol-l-yl] piperidine-2,6-dione

[003615] To a solution of tert-butyl N-[[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]carbamate (130 mg, 252 umol) in DCM (2 mL) was added TFA (1.67 g, 14.6 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (100 mg, 95% yield, TFA) as a brown oil. LC-MS (ESI+) m/z 416.3(M+H)+.

[003616] 2- [(2S) prop vnylmorpholin vl]acetonitrile (Intermediate RL)

1205

[003617] Step 1 - Tert-butyl (2R) (methylsulfonyloxymethyl)morpholine carboxylate [003618] To a solution of tert-butyl (2R) (hydroxymethyl)morpholine carboxylate (10.0 g, 46.0 mmol, CAS# 135065 3) and TEA (9.32 g, 92.0 mmol) in DCM (100 mL) was added MsCI (6.36 g, 55.5 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was poured into sat.NaHCO3 (50 mL) and extracted with EA (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (13.5 g, 99% yield) as colorless oil, 1H NMR (400MHz, CDCh) δ 4.23 (d, J = 4.8 Hz, 2H), 4.06 - 3.77 (m, 3H), 3.74 3.64 (m, IH), 3.59 - 3.49 (m, IH), 3.06 (s, 3H), 3.01 - 2.88 (m, IH), 2.81 - 2.67 (m, IH), 1.49 1.42 (m, 9H).

[003619] Step 2 - Tert-butyl (2S) (cyanomethyl)morpholine carboxylate

[003620] To a solution of tert-butyl (2R) (methylsulfonyloxymethyl)morpholine-4carboxylate (13.0 g, 44.0 mmol) and KI (10.9 g, 66.0 mmol) in DMSO (200 mL) was added KCN (3.15 g, 48.4 mmol, 2.07 mL). The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was then stirred at 100 °C for 4 hours. On completion, the reaction mixture was poured into sat.NaHCO3 (100 mL) and extracted with EA (3 X 500 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA= 10/1 to 6/1) to give the title compound (8.00 g, 80% yield) as a white solid. 1HNMR (400MHz, CDCh) δ 4.10 - 3.78 (m, 3H), 3.72-3.62 (m, IH), 3.60 - 3.50 (m, IH), 2.97 (t, J= 11.2 Hz, IH), 2.84 - 2.65 ( s, IH), 2.62 - 2.50 (m, 2H), 1.47 (s, 9H).

[003621] Step 3 - 2-r(2S)-Morpholin yl1acetonitrile

[003622] To a solution of tert-butyl (2S) (cyanomethyl)morpholine carboxylate (4.50 g, 19.8 mmol) in DCM (10 mL) was added TFA (138 g, 1.22 mol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title

1206 compound (4.70 g, 98% yield) as colorless oil. 1HNMR. (400MHz, DMSO-6/6) δ 9.29 - 8.83 (m, 2H), 4.05 -3.88 (m, 2H), 3.77-3.63 (m, IH), 3.31 -3.15 (m, 2H), 3.03 -2.76 (m, 3H), 2.41 - 2.18 (m, IH).

[003623] Step 4 - 2-r(2S) prop ynylmorpholin yl1acetonitrile

[003624] To a solution of 2-[(2S)-morpholin yl]acetonitrile (4.70 g, 19.5 mmol, TFA) and 3-bromoprop yne (3.49 g, 29.3 mmol) in THF (100 mL) was added KI (324 mg, 1.96 mmol) and K2CO3 (8.11 g, 58.7 mmol). The reaction mixture was stirred at 25 °C for 48 hours. On completion, the reaction mixture was diluted with EA(500 mL) and filtered to give the filtrate. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica column chromatography (PE/EA= 10/1 to 6/l)to give the title compound (1.50 g, 46% yield) as a light yellow oil. 1HNMR (400MHz, CDCh) δ 3.97 -3.90 (m, IH), 3.87 - 3.78 (m, IH), 3.70 (dt,7=2.4, 11.2 Hz, IH), 3.33 (d, 7= 2.0 Hz, 2H), 2.85 - 2.80 (m, IH), 2.67 - 2.60 (m, IH), 2.56 (d, 7= 6.0 Hz, 2H), 2.44 (dt, 7 = 3.2, 11.2 Hz, IH), 2.29 (t, 7= 2.4 Hz, IH), 2.35 (t, 7= 10.0 Hz, IH).

[003625] 3- [5-[3- [(2S) (2-aminoethvl)morDholin yI| Dr0Dvl] methyl 0x0benzimidazol yl]DiDeridine-2,6-dione (Intermediate RM)

RL

Raney-Ni, AcOH

THF

1207

[003626] Step 1 - 2-[(2S) [3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl1prop ynyl1 morpholin yl1 acetonitrile

[003627] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (1.00 g, 2.96 mmol, Intermediate HN) and 2-[(2S) prop ynylmorpholin yl]acetonitrile (971 mg, 5.91 mmol, Intermediate RL) in DMSO (50 mL) was added Pd(PPh3)2C12 (415 mg, 591 umol), DIPEA (1.91 g, 14.7 mmol) and Cui (112 mg, 591 umol). The reaction mixture was stirred at 85 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was diluted with EA (30 mL), poured into water (300 mL) and extracted with EA (2 X 200 mL). The organic layer was washed with water (2 X 200 mL), brine (200 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by reversed-phase chromatography (FA, 0.1%) to give the title compound (1.00 g, 80% yield) as a yellow solid. LCMS (ESI+) m/z 422.2 (M+H)+.

[003628] Step 2 - 3-[5-[3-[(2S) (2-aminoethyl)morpholin yl1prop-l-ynyl1 methyl-2oxo-benzimidazol yl1piperidine-2,6-dione

[003629] To a solution of 2-[(2S) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynyl]morpholin yl]acetonitrile (600 mg, 1.42 mmol) and AcOH (170 mg, 2.85 mmol) in THF (40 mL) was added Raney-Ni (50.0 mg, 583 umol). The reaction mixture was stirred at 25 °C for 4 hours under H2 (50 Psi). On completion, the reaction mixture was filtered. The filter cake was triturated with water (3X30 mL) and filtered to give the filtrate. The filtrate was concentrated in vacuo to give the title compound (600 mg, 100% yield, HOAc) as light yellow oil. LC-MS (ESI+) m/z 426.1 (M+H)+.

[003630] Step 3 - 3-[5-[3-[(2S) (2-aminoethyl)morpholin yl1propyl1 methyl oxobenzimidazol yl1piperidine-2,6-dione

[003631] To a solution of 3-[5-[3-[(2S) (2-aminoethyl)morpholin yl]prop-l-ynyl]-3methyl oxo- benzimidazol yl]piperidine-2,6-dione (550 mg, 1.13 mmol, HOAc) in THF (30 mL) was added PtO2 (51.4 mg, 226 umol). The reaction was stirred at 25 °C for 4 hours under H2 (15 Psi). On completion, the reaction mixture was filtered to give the filtrate and concentrated in vacuo to give the title compound (400 mg, 100% yield, HOAc) as yellow oil. LC-MS (ESI+) m/z 430.2 (M+H)+.

[003632] 2-[(2R) Pr0D vnylm0rDh01in vl]acetonitrile (Intermediate RN)

1208

MsCI, TEA

DCM

NaCN, KI

DMSO

K2CO3, DMF

RN

TFA [ 0

DCM HnA,&#1523;,/CN TFA

[003633] Step 1 - Tert-butyl (2S) (methylsulfonyloxymethyl)morpholine carboxylate [003634] To a mixture of tert-butyl (2S) (hydroxymethyl)morpholine carboxylate (5.00 g, 23.0 mmol, CAS# 135065 8) in DCM (50 mL) was added TEA (3.03 g, 29.9 mmol) and MsCI (6.06 g, 52.9 mmol) at 0°C. Then the reaction mixture was stirred at 25°C for 2 hours. On completion, the reaction mixture was poured into the ice-water (50 mL), and extracted with DCM (2 X 30 mL).The combined organic phase was washed with brine (2 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (6.50 g, 95% yield) as a white oil. 1H NMR (400 MHz, CDCh) δ 4.23 (d, J= 4.8 Hz, 2H), 3.92 - 3.85 (m, 3H), 3.69- 3.65 (m, IH), 3.57 - 3.51 (m, IH), 3.06 (s, 3H), 3.01 - 2.95 (m, IH), 2.82 - 2.76 (m, IH), 1.46 (s, 9H).

[003635] Step 2 - Tert-butyl (2R) (cyanomethyl)morpholine carboxylate

[003636] To a mixture of tert-butyl (2S) (methylsulfonyloxymethyl)morpholine-4carboxylate (6.50 g, 22.0 mmol) in DMSO (80mL) was added KCN (1.50 g, 23.1 mmol) and KI (5.48 g, 33.0 mmol) at 25 °C. The reaction mixture was then stirred at 100 °C for 4 hours. On completion, the reaction mixture was poured into the ice-water (50 mL), and extracted with DCM (2 X 30 mL). The combined organic phase was washed with brine (2 X 50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=3:l) to give the title compound (2.30 g, 46% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 4.04-3.83 (m, 3H), 3.62-3.59 (m, IH), 3.51-3.48 (m, IH), 2.93 - 2.90 (m, IH), 2.68 (m, IH), 2.50 - 2.43 (m, 2H), 1.40 (s, 9H). [003637] Step 3 - 2-r(2R)-Morpholin yl1acetonitrile

[003638] To a solution of tert-butyl (2R) (cyanomethyl) morpholine carboxylate (1.00 g, 4.42 mmol) in DCM (6 mL) was added TFA (3 mL) at 25 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (1.06 g, 95% yield, TFA) as light yellow gum. 1H NMR (400 MHz, DMSO-6/6) δ 9.11 (s, 2H), 4.04

1209

4.01 (m, IH), 4.00 - 3.91(m, IH), 3.79 - 3.67 (m, IH), 3.34 - 3.16 (m, 2H), 3.07 - 2.89 (m, 2H), 2.87-2.73 (m, 2H).

[003639] Step 4 - 2-[(2R) Prop ynylmorpholin yl1acetonitrile

[003640] To a mixture of 2-[(2R)-morpholin yl]acetonitrile (1.06 g, 4.41 mmol, TFA) and K2CO3 (1.83 g, 13.2 mmol) in DMF (15 mL) was added 3-bromoprop yne (577 mg, 4.85 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was filtered and the cake was washed with EA (20 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA= 20:15:1) to give the title compound (650 mg, 89% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 3.93 (m, IH), 3.88 - 3.81 (m, IH), 3.72 (m, IH), 3.36 - 3.30 (m, 2H), 2.88 (s, IH), 2.68 (m, IH), 2.57 (d, J = 6.0 Hz, 2H), 2.46 (m, IH), 2.32 - 2.21 (m, 2H).

[003641] 3-[5-[3-[(2R) (2-Aminoethvl)morDholin vl]DroDvl] methyl oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate RO)

Raney-Ni, H2, HOAc

THF

HOAc

RO

[003642] Step 1- 2-[(2R) [3-[l-(2,6-Dioxo piperidyl) methyl oxo-benzimidazol-5 yl1prop ynyl1 morpholin yl1 acetonitrile

1210

[003643] A mixture of 2-[(2R) prop ynylmorpholin yl]acetonitrile (588 mg, 3.58 mmol, Intermediate RN), 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (480 mg, 1.42 mmol, Intermediate HN), Cui (58 mg, 304 umol), Pd(PPh3)2C12 (201 mg, 286 umol), 4A MS (300 mg) and Cs2CO3 (2.31 g, 7.10 mmol) in DMF (15 mL) was stirred at 80°C for 2 hours under N2. On completion, the mixture was filtered and the filter cake was washed with EA (10 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by reversed phase (FA condition) and prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.1%TFA)- ACN]; B%: 2%-30%, lOmin) to give the title compound (280 mg, 47% yield) as yellow solid. 1HNMR (400 MHz, DMSO-76) δ 11.13 (s, IH), 7.35 (d, J= 1.2 Hz, IH), 7.27 - 7.20 (m, IH), 7.20 - 7.13 (m, IH), 5.42 - 5.38 (m, 1 H), 4.17 (s, 2H), 4.08 (d, J= 12.4 Hz, IH), 3.91 m, IH), 3.77 - 3.67 (m, IH), 3.35 (s, 3H), 3.34-3.31 (m, IH), 3.02-2.81 (m, 5H), 2.77 - 2.58 (m, 3H), 2.06 - 1.97 (m, IH).

[003644] Step 2 - 3-r5-r3-r(2R) (2-Aminoethyl)morpholin yl1prop-l-enyl1 methyl-2oxo-benzimidazol -l-yl1piperidine-2,6-dione

[003645] A mixture of 2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynyl]morpholin yl]acetonitrile (270 mg, 640 umol) , Raney-Ni (100 mg) and HOAc (210 mg, 3.50 mmol) in THF (6 mL) was stirred at 25 °C for 16 hours under H2 (45 Psi). On completion, the mixture was fdtered and the cake was washed with THF (10 mL). The combined organic layer was concentrated in vacuo to give the title compound (320 mg, 100% yield, HOAc) as light yellow gum. LC-MS (ESI+) m/z 428.3 (M+H)+.

[003646] Step 3 - 3-r5-r3-r(2R) (2-Aminoethyl)morpholin yl1propyl1 methyl oxobenzimidazol-l-yl] piperi dine-2,6-di one

[003647] A mixture of 3-[5-[3-[(2R) (2-aminoethyl) morpholin yl] prop-l-enyl]-3methyl oxo -benzimidazol yl] piperidine-2,6-dione (320 mg, 640 umol) and PtO2 (50.0 mg, 220 umol) in THF (10 mL) was stirred at 25 °C for 3 hours under H2 (15 Psi). On completion, the mixture was fdtered and the fdter cake was washed with THF (10 mL). The fdtrate and washing were combined and concentrated in vacuo to give the title compound (280 mg, 98% yield, HOAc) as light yellow gum. LC-MS (ESI+) m/z 430.3 (M+H)+.

[003648] 4-[3-(Difluoromethvl) [[2-[2-(2,2,2-trifluoroethvlamino) pyridvl]oxazole4-carbonyl] aminolpyrazol-l-yllbenzoic acid (Intermediate RP)

1211

[003649] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (70.0 mg, 112 umol, Intermediate JE) in DCM (4 mL) was added TFA (4 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (71.5 mg, 100% yield, TFA) as a white solid. LC-MS (ESI+) m/z 523.2 (M+H)+.

[003650] l-(4-methoxvDhenvl)-N-methvl-N-[[(2S) DroD vnylmorDholin-2yl] methyl] methanamine (Intermediate RO)

N b°c^n A'^oh dmp Bo% pmb Boc'n A'n&#1523;pmb

A-O DCM A-0 HOAc, NaBH(OAc)3, DCM* A&#1523;° '

HCI/dioxane

DCM

K2CO3, DMF

RQ

[003651] Step 1-Tert-butyl (2R) formvlmorpholine carboxylate

[003652] To a solution of tert-butyl (2» (hydroxymethyl)morpholine carboxylate (2.00 g, 9.21 mmol, CAS# 135065 3) in DCM (40 mL) was added DMP (4.69 g, 11.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched with aq. Na2S2O3 (50 mL) and aq. NaHCO3 (50 mL). The mixture was stirred for 15 minutes and extracted with EA (2 X 50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, and concentrated in vacuo to give the title compound (1.50 g, 76% yield) as colorless oil. 1HNMR (400 MHz, CDCh) δ 9.65 (s, IH), 4.08 - 4.00 (m, IH), 3.95 - 3.85 (m, 2H), 3.83 - 3.75 (m, IH), 3.68 - 3.53 (m, 2H), 3.12-3.03 (m, IH), 1.47 (s, 9H).

1212

[003653] Step 2 - Tert-butyl (2S) rr(4-methoxyphenyl)methyl-methylamino1methyl1morpholine carboxylate

[003654] To a solution of tert-butyl (2J?) formylmorpholine carboxylate (1.5 g, 6.97 mmol) and l-(4-methoxyphenyl)-N-methyl-methanamine (1.05 g, 6.97 mmol) in DCM (30 mL) was added HOAc (418 mg, 6.97 mmol) and the reaction was stirred at 25 °C. Thirty minutes later, NaBH(OAc)3 (1.77 g, 8.36 mmol) was added and the reaction mixture was stirred at 25 °C for 10 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reversed phase (0.1% FA) to give the title compound (1.4 g, 57% yield) as a yellow solid. 1H NMR (300 MHz, CDCh) δ 7.22 (d, J= 8.4 Hz, 2H), 6.85 (d, J= 8.4 Hz, 2H), 4.07 - 3.94 (m, IH), 3.93 - 3.83 (m, 2H), 3.90 (s, 3H), 3.58 - 3.43 (m, 4H), 3.01 - 2.80 (m, IH), 2.62 - 2.46 (m, 2H), 2.41 2.31 (m, IH), 2.26 (s, 3H), 1.48 (s, 9H); LC-MS (ESI+) m/z 351.1 (M+H)+.

[003655] Step 3:1 -(4-Methoxvphenvl)-N-methvl-N-[r (2R)-morpholin-2yllmethyllmethanamine hydrochloride

[003656] To a solution of tert-butyl (25) [[(4-methoxyphenyl)methyl-methylamino]methyl]morpholine carboxylate (1.40 g, 3.99 mmol) in HCI/dioxane (10 mL) was added DCM (10 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (1.15g, 100% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 251.1 (M+H)+.

[003657] Step 4 - l-(4-methoxyphenvl)-N-methyl-N-rr(2S) prop ynylmorpholin-2yllmethyllmethanamine

[003658] To a solution of l-(4-methoxyphenyl)-N-methyl-N-[[(2/?)-morpholin-2yl]methyl]methanamine (1.15 g, 4.01 mmol, HCI) and 3-bromoprop yne (525 mg, 4.41 mmol) in DMF (20 mL) was added K2CO3 (1.66 g, 12.0 mmol). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the mixture was diluted with water (100 mL), and extracted with EA (2 X 50 mL). The organic layer was washed with brine (100 mL), then concentrated in vacuo. The residue was purified by reversed phase chromatography (0.1% FA condition) to give the title compound (700 mg, 61% yield) as colourless oil. LC-MS (ESI+) m/z 289.2 (M+H)+.

[003659] 3-[3-Methvl [3-[(2S) (methvlaminomethvl)morpholin vl]propyl] oxobenzimidazol- l-yl]piperidine-2.,6-dione (Intermediate RR)

1213

RQ

Pd(PPh3)2CI2, Cui, Cs2CO3, 4A MS, DMF

Pd(OH)2/C, Pd/C, H2

EA/IPA, (Boc)2O

0&#910;Υ TFA

HN /

RR

[003660] Step 1:3-r5-r3-r(2S) r1(4-methoxyphenyl)methyl-methylamino1methvl1morpholin yl1prop-ldi one

[003661] l-(4-methoxyphenyl)-N-methyl-N-[[(25) prop ynylmorpholin-2yl]methyl]methanamine (1.01 g, 3.51 mmol, Intermediate RQ), 3-(5-bromo methyl oxobenzimidazol-l-yl)piperidine-2,6-dione (660 mg, 1.95 mmol, Intermediate HN), Pd(PPh3)2C12 (274 mg, 390 umol), Cui (74.3 mg, 390 umol), 4A molecular sieves (200 mg) and Cs2CO3 (2.54 g, 7.81 mmol) in DMF (12 mL) was degassed with N2 and then heated at 80 °C for 2 hours under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo and purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 5%-35%, 28 mins) to give the title compound (850 mg, 80% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-76) δ 11.13 (s, IH), 7.33 -7.23 (m, 3H), 7.17-7.12 (m, 2H), 6.89 - 6.84 (m, 2H), 5.44 - 5.35 (m, IH), 3.87 - 3.79 (m, IH), 3.78 - 3.72 (m, IH), 3.71 - 3.69 (m, 3H), 3.68 - 3.56 (m, 4H), 3.53 (s, 2H), 3.34 (s, 3H), 2.93 - 2.80 (m, IH), 2.74 - 2.60 (m, 2H),

1214

2.30 (s, 3H), 2.28 - 2.24 (m, IH), 2.21 - 2.18 (m, IH), 2.18 - 2.15 (m, IH), 2.05 - 2.00 (m, 2H), 1.98 - 1.96 (m, IH); LC-MS (ESI+) m/z 546.3 (M+H)+.

[003662] Step 2 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1-N-methyl-carbamate

[003663] To a mixture of 3-[5-[3-[(25) [[(4-methoxyphenyl)methyl-methylamino]methyl]morpholin yl] prop-l-ynyl] methyl oxo-benzimidazol-l-yl]piperidine-2,6dione (200 mg, 367 umol) and (Boc)2O (96.0 mg, 440 umol) in a mixed solvent of IP A (5 mL) and EA (10 mL) was added Pd(OH)2/C (0.1 g, 20 wt%) and Pd/C (0.1 g, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hours under H2 (50 Psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase (0.1% FA) to give the title compound (85.0 mg, 44% yield) as a white solid. LC-MS (ESI+) m/z 530.3 (M+H)+.

[003664] Step 3 - 3-r3-Methyl r3-r(2S) (methylaminomethyl)morpholin yl1propyl1-2oxo-benzimidazol- l-yl1piperidine-2,6-dione

[003665] To a solution of tert-butyl N-[[(2J?) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]propyl]morpholin yl]methyl]-N-methyl-carbamate (85.0 mg, 160 umol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (87.0 mg, 100% yield, TFA) as a yellow solid. LC-MS (ESI+) m/z 430.3 (M+H)+.

[003666] Tert-butyl N-(4-but ynoxybutyl)-N-methyl-carbamate (Intermediate RS) _ NaH, Mel . q . ,Boc

NHBoc -----------&#9658;N'

THF syRS

[003667] To a solution of tert-butyl N-(4-but ynoxybutyl)carbamate (5.00 g, 20.7 mmol, Intermediate SY) in THF (100 mL) was added NaH (1.24 g, 31.0 mmol, 60% oil dispersion) at 0 °C. The mixture was stirred 20 °C for 1 hour. Then Mel (4.41 g, 31.0 mmol) was added. The mixture was stirred at 20 °C for 15 hrs. On completion, the mixture was quenched by water (10 mL) and extracted with EA (2 X 250 mL). The combined organic layers were concentrated in vacuo to give the title compound (5.00 g, 94% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 3.57 (t, J = 7.2 Hz, 2H), 3.50 (t, J = 6.0 Hz, 2H), 3.24 (s, 2H), 2.85 (s, 3H), 2.48 (dt, J = 2.8, 6.8 Hz, 2H), 2.03 - 1.96 (m, IH), 1.62 - 1.56 (m, 4H), 1.47 (s, 9H).

1215

[003668] 3-[3-Methvl [4-[4-(methvlamino)butoxv]butvl1 oxo-benzimidazol-lyl] piperidine- 2.,6-dione (Intermediate RT)

Pd(OH)2/C, Pd/C, H2

THF

[003669] Step 1 - Tert-butyl N-r4-r4-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1 but ynoxy] butyl1-N-methyl-carbamate

[003670] A mixture of tert-butyl N-(4-but ynoxybutyl)-N-methyl-carbamate (3.06 g, 12.0 mmol, Intermediate RS), 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (1.50 g, 4.44 mmol, Intermediate HN), Pd(PPh3)2C12 (934 mg, 1.33 mmol), Cui (253 mg, 1.33 mmol) and TEA (8.08 g, 79.8 mmol) in DMF (30 mL) was degassed and purged with N2 for 3 times. Then the mixture was stirred at 85 °C for 4 hrs under N2 atmosphere. On completion, the mixture was diluted with water (100 mL) and extracted with EA (2 X 200 mL). The organic layer was concentrated in vacuo. The residue was purified by reversed phase (0.1% FA) to give the title compound (1.1g, 46% yield) as yellow solid. 1HNMR (400MHz, DM SO-0/6) δ 11.12 (s, IH), 7.24 (s, IH), 7.14 - 7.05 (m, 2H), 5.38 (dd, J = 5.2, 12.8 Hz, IH), 3.56 (t, J = 6.8 Hz, 2H), 3.46 (t, J= 6.0 Hz, 2H), 3.33 (s, 3H), 3.17 (t, J = 6.4 Hz, 2H), 2.93 - 2.90 (m, IH), 2.74 (s, 3H), 2.69 - 2.63

1216 (m, 2H), 2.53 - 2.51 (m, 2H), 2.08 - 2.00 (m, IH), 1.56 - 1.45 (m, 4H), 1.37 (s, 9H); LC-MS (ESI+) m/z 535.3 (M+Na)+.

[003671] Step 2 - Tert-butyl N-r4-r4-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl]butoxy] butyl]-N-methyl-carbamate

[003672] To a solution of tert-butyl N-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] but ynoxy]butyl]-N-methyl-carbamate (1.10 g, 2.15 mmol) in THF (30 mL) was added Pd/C (0.10 g, 10 wt%) and Pd(OH)2/C (0.10 g, 10 wt%). The mixture was stirred at 30 °C for 16 hrs under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.10 g, 100% yield) as yellow solid. 1H NMR (400MHz, DM SO-0/6) δ 11.09 (s, IH), 7.06 - 6.94 (m, 2H), 6.90 - 6.83 (m, IH), 5.34 (dd, J= 5.2, 12.8 Hz, IH), 3.40 - 3.34 (m, 4H), 3.32 (s, 3H), 3.15 (t, J= 6.8 Hz, 2H), 2.92 - 2.88 (m, IH), 2.74 (s, 3H), 2.64 - 2.58 (m, 4H), 2.07 - 1.95 (m, IH), 1.67 - 1.58 (m, 2H), 1.57 - 1.43 (m, 6H), 1.37 (s, 9H); LC-MS (ESI+) m/z 539.2 (M+Na)+.

[003673] Step 3 - 3-r3-Methyl r4-r4-(methylamino)butoxy]butyl] oxo-benzimidazol-lyl]piperidine- 2,6-dione

[003674] To a solution of tert-butyl N-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] butoxy]butyl]-N-methyl-carbamate (1.10 g, 2.13 mmol) in DCM (20 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 3 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (1.10 g, 100% yield) as yellow solid. LC-MS (ESI+) m/z 417.2 (M+H)+.

[003675] 4-(4-(2-(2-((CycloDropylmethyl)amino)pyridin yl)oxazole carboxamido)3- (difluoromethyl)-lH-pyrazol-l-yl)benzoic acid (Intermediate RU)

FX RU

[003676] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole- 4-carbonyl]amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (44.6 mg, 75.1 umol, Intermediate FX) in DCM (1 mL) was added TFA (770 mg, 6.75 mmol) under N2

1217 atmosphere. The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (41.0 mg, 100% yield, TFA) as colorless oil. LCMS (ESI+) m/z 495.2 (M+H) +.

[003677] (S)-tert-butyl methyl((4-(DroD yn-l-yl)morDholin yl)methyl)carbamate (Intermediate RV)

RV

[003678] Step 1 - (S)-morpholin ylmethanol

[003679] To a solution of tert-butyl (2S) (hydroxymethyl)morpholine carboxylate (25.0 g, 115 mmol, CAS# 135065 8) in DCM (40 mL) was added HCI/dioxane (4 M, 57.5 mL), the reaction mixture was stirred at 25 °C for 2 hrs. On completed, the reaction mixture was concentrated in vacuo to give the title compound (17.0 g, 96% yield, HCI) as yellow oil. 1HNMR (400MHz, CDCh) δ 4.47 (s, IH), 3.92 - 3.89 (m, IH), 3.75 - 3.72 (m, 2H), 3.40 - 3.37 (m, 2H), 3.13 (t, J= 2.4, 2H), 2.92 - 2.6(m, 2H).

[003680] Step 2 - (S)-(4-(prop vn-l-vl)morpholin yl)methanol

[003681] To a solution of [(2S)-morpholin yl]methanol (12.0 g, 78.1 mmol, HCI) and 3bromoprop yne (9.29 g, 78.1 mmol) in DMF (200 mL) was added K2CO3 (32.4 g, 234 mmol). The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was diluted with water (300 mL) and extracted with EA (3 X 80 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/l to 2/1) to give the title compound (10.5 g, 86% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 3.98 - 3.91 (m, IH), 3.76 - 3.63 (m, 3H), 3.62 - 3.56 (m, IH), 3.31 (d, J= 2.4 Hz, 2H), 2.76 - 2.66 (m, 2H), 2.41 (dt, J= 3.6, 11.2 Hz, IH), 2.28 (t, J= 2.4 Hz, IH), 2.22 (t, J= 10.4 Hz, IH), 1.97 - 1.66 (m, IH). [003682] Step 3 - (S)-(4-(prop yn-l-yl)morpholin yl)methyl methanesulfonate

1218

[003683] To a solution of [(2S) prop ynylmorpholin yl]methanol (2 g, 12.8 mmol) in DCM (30 mL) was added TEA (2.61 g, 25.7 mmol) and MsCI (1.62 g, 14.1 mmol). The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched with water (2 mL), and then extracted with DCM (3 X 100 mL). The combined organic layers were washed with brine (2X30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (3.00 g, 99% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 4.28 - 4.20 (m, 2H), 3.99 - 3.91 (m, IH), 3.91 - 3.81 (m, IH), 3.71 (dt,7=2.4, 11.2 Hz, IH), 3.33 (d,7=2.4 Hz, 2H), 3.09 (s, 3H), 2.82 - 2.75 (m, IH), 2.69 (dd, 7= 1.2, 11.2 Hz, IH), 2.51 - 2.36 (m, IH), 2.33 -2.19 (m, 2H).

[003684] Step 4^^(S)4ertzbutyl jnethylX(42(prop=22yn212yl)mmpholin=22 yl)methyl)carbamate

[003685] To a solution of tert-butyl N-methylcarbamate (1.69 g, 12.8 mmol) and Nai (192 mg, 1.29 mmol) in DMF (30 mL) was added NaH (771 mg, 19.2 mmol, 60% oil dispersion). The reaction mixture was stirred at 25 °C for 0.5 hr. After, [(2S) prop ynylmorpholin yl]methyl methanesulfonate (3.00 g, 12.8 mmol) was added into the mixture. The resulting reaction mixture was stirred 90 °C for 12 hrs. On completion, the reaction mixture was quenched with water (0.1 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA = 5:1) to give the title compound (250 mg, 7% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 3.95 - 3.86 (m, IH), 3.77 - 3.61 (m, 2H), 3.47 - 3.38 (m, IH), 3.32 - 3.30 (m, 2H), 3.17 (dd, 7= 2.4, 10.8 Hz, IH), 2.93 (s, 3H), 2.79 - 2.65 (m, 2H), 2.39 (dt, 7= 2.4, 11.2 Hz, IH), 2.28 - 2.26 (m, IH), 2.11 (t, 7= 10.8 Hz, IH), 1.46 (s, 9H).

[003686] 3-(3-Methvl (3-((R) ((methvlamino)methvl)morDholino)DroDvl) oxo2,3-dihydro-lH- benzo[d]imidazol-l-vl)DiDeridine-2,6-dione (Intermediate RW)

1219

[003687] Step 1 - Tert-butyl (((2S) (3-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-lH-benzo[d1 imidazol yl)prop yn-l-yl)morpholin yl)methyl)(methyl)carbamate [003688] To a mixture of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (180 mg, 532 umol, Intermediate HN), tert-butyl N-methyl-N-[[(2S) prop-2ynylmorpholin yl]methyl]carbamate (214 mg, 798 umol, Intermediate RV), Pd(PPh3)2C12 (37.3 mg, 53.2 umol), Cui (10.1 mg, 53.2 umol), 4A molecular sieves (200 mg) and Cs2CO3 (693 mg, 2.13 mmol) in DMF (10 mL) was de-gassed with N2 and then heated to 80°C for 2 hours under N2. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% FA, condition) to give the title compound (150 mg, 42% yield) as yellow oil. LC-MS (ESI+) m/z 526.1 (M+ H) +.

[003689] Step 2 - Tert-butyl (((2S) (3-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-lH-benzo[d1 imidazol yl)propyl)morpholin yl)methyl)(methyl)carbamate

[003690] To a solution of tert-butyl N-[[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol- 5-yl]prop ynyl]morpholin yl]methyl]-N-methyl-carbamate (150 mg, 228 umol) in THF (20 mL) was added PtO2 (13.8 mg, 6.10 umol) under N2 atmosphere. The suspension was degassed and purged with H2 seven times. The mixture was stirred under H2 (15 Psi) at 25 °C for 2 hrs. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (40.0 mg, 31% yield) as colorless oil. LC-MS (ESI+) m/z 530.3 (M+H)+.

[003691] Step 3 - 3-(3-Methyl (3-((R) ((methylamino)methyl)morpholino)propyl)-2oxo-2,3-dihydro-lH- benzo[d1imidazol-l-yl)piperidine-2,6-dione

1220

[003692] To a solution of tert-butyl N-[[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]-N-methyl-carbamate (40.0 mg, 75.5 umol) in DCM (3 mL) was added TFA (308 mg, 2.70 mmol) under N2 atmosphere. The mixture was stirred at 25 °C for 15 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (41.0 mg, 100% yield, TFA) as colorless. LC-MS (ESI+) m/z 430.2 (M+H)+.

[003693] 2-[2-[2-[2-[3-[l-(2.,6-dioxo piperidvl) methvl oxo-benzimidazol-4yl] propoxy] ethoxy] ethoxy] ethoxy] acetic acid (Intermediate RX)

HP

Pd(PPh3)2CI, Cui, Cs2CO3, DMF

[003694] Step 1 - Tert-butyl 2-r2-r2-r2-r3-r1-(2,6-dioxo piperidvl) methyl oxo benzimidazol yl1prop ynoxy]ethoxy]ethoxy]ethoxy]acetate

[003695] To a mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (600 mg, 1.77 mmol, Intermediate HP), tert-butyl 2-[2-[2-(2-prop-2ynoxyethoxy)ethoxy]ethoxy]acetate (1.07 g, 3.55 mmol, synthesized via Steps 1-2 of Example

1221

441, 1-447) in DMF (10 mL) was added Cui (67.6 mg, 355 umol), Cs2CO3 (2.89 g, 8.87 mmol) and Pd(PPh3)2C12 (249.08 mg, 355 umol) under N2. The reaction mixture was stirred at 80 °C for 3 hours. On completion, the mixture was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (2X30 mL). The combined organic phase was washed with brine (2 X 30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase (0.1% FA condition) to give the title compound (598 mg, 60% yield) as brown oil. 1H NMR (400MHz, CDCh) δ 8.29 (s, IH), 7.16 (d, J= 7.6 Hz, IH), 6.97 (t, 7= 8.0 Hz, IH), 6.75 (d, 7= 8.0 Hz, IH), 5.23 - 5.15 (m, IH), 4.46 (s, 2H), 4.01 (s, 2H), 3.76 (s, 3H), 3.76 - 3.66 (m, 12H), 2.99 - 2.68 (m, 3H), 2.29 - 2.16 (m, IH), 1.46 (s, 9H).

[003696] Step 2 - Tert-butyl 2-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 propoxy] ethoxy]ethoxy]ethoxy]acetate

[003697] To a solution of tert-butyl 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynoxy]ethoxy]ethoxy]ethoxy]acetate (578 mg, 1.03 mmol) in THF (5 mL) was added Pd/C (100 mg, 20 wt%) and Pd(OH)2/C (100 mg, 20 wt%) under N2. The suspension was degassed under vacuum and purged with H2 gas three times. The mixture was stirred at 20 °C for 12 hours under H2 (15 psi). On completion, the mixture was filtrated and the filtrate was concentrated in vacuo to give a title compound (540 mg, 92% yield) as brown oil. LCMS (ESI+) m/z 586.3 (M+Na)+.

[003698] Step 3 - 2-r2-r2-r2-r3-r1-(2,6-Dioxo piperidyl) methyl oxo-benzimidazol-4yl]propoxy]ethoxy1 ethoxy]ethoxy]acetic acid

[003699] To a mixture of tert-butyl 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop oxy] ethoxy ]ethoxy ]ethoxy ]acetate (520 mg, 922 umol) in DCM (2 mL) was added TFA (210 mg, 1.85 mmol). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (436 mg, 93% yield) as brown oil. LC-MS (ESI+) m/z 508.3 (M+H) +.

[003700] Step 2 - Tert-butyl 4-(trans aminocyclohexyl)piperazine-l-carboxylate

[003701] A mixture of tert-butyl 4-[4-(benzyloxycarbonylamino)cyclohexyl]piperazine-lcarboxylate (8.00 g, 16.4 mmol) and Pd/C (800 mg, 10 wt%) in MeOH (80 mL) was stirred at 25 °C for 2 hours under H2 (15 Psi). On completion, the mixture was filtered, and the cake was washed with MeOH (50 mL). The filtrate and washings were combined and concentrated in vacuo to give

1222 the title compound (5.30 g, 100% crude yield) as white solid. 1H NMR (400 MHz, CDCh) δ 3.49 - 3.21 (m, 4H), 2.64 - 2.58 (m, IH), 2.54 (m, 4H), 2.31 - 2.20 (m, IH), 1.88 (t, J= 15.2 Hz, 4H), 1.45 (s, 9H), 1.34 - 1.22 (m, 2H), 1.17-1.05 (m, 2H).

[003702] 2-[4-[4-[l-(2.,6-Dioxo DiDeridvl) methyl oxo-benzimidazol-5yl] butoxy] butylamino] acetic acid (Intermediate SB)

TFA

DCM

[003703]

SB

Step 1 - Tert-butyl 2-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1butoxy1 butylaminolzacetate

[003704] A mixture of 3-[5-[4-(4-aminobutoxy)butyl] methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (200 mg, 455 umol, HC1, Intermediate OD), tert-butyl 2-bromoacetate (80.0 mg, 410 umol, CAS# 5292 3) and TEA (100 mg, 988 umol) in DMF (2 mL) was stirred at 25 °C for 16 hours. On completion, the mixture was purified by reverse phase flash chromatography (FA condition) to give the title compound (100 mg, 31% yield) as light yellow gum. 1H NMR (400 MHz, DMSO-76) δ 11.09 (s, IH), 7.02 - 6.98 (m, 2H), 6.86 (d, J = 8.0 Hz, IH), 5.37 - 5.28 (m, IH), 3.62 - 3.57 (m, 2H), 3.34 (s, 3H), 3.32 (m, 4H), 2.91 - 2.83 (m, IH), 2.65 - 2.56 (m, 6H), 2.04 - 1.95 (m, IH), 1.77 - 1.73 (m, IH), 1.63 - 1.47 (m, 8H), 1.41 (s, 9H).

[003705] Step 2 - 2-[4-[4-[ 1-(2, 6-Dioxo piperidyl) methyl oxo-benzimidazol-5yl1butoxy1butylamino1 acetic acid

[003706] To a solution of tert-butyl 2-[4-[4-[ 1-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] butoxy]butylamino]acetate (125 mg, 176 umol) in DCM (2 mL) was added TFA (1 mL) at 25 °C. The mixture was stirred at 25 °C for 6 hours. On completion, the mixture

1223 was concentrated in vacuo to give the title compound (120 mg, crude, TFA) as yellow gum. LCMS (ESI+) m/z 461.2 (M+H)+

[003707] Tert-butyl N-(3-but yn0xvDr0Dvl)carbamate (Intermediate SD)

^CN

1) Et2SiH2, B(C6F5)3, DCM

NaOMe, THF

2) HCI/dioxane, DCM (Boc)2O, TEA ^^O&#1523;^^NH2 ~ * \^O&#1523;^-^NHBOC

SD

[003708] Step 1 - 3-But ynoxypropanenitrile

[003709] To a solution of prop enenitrile (2.00 g, 37.6 mmol) and but yn-l-ol (7.93 g, 113 mmol) in THF (40.0 mL) was added NaOMe (203 mg, 3.77 mmol). The mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (4.60 g, 99% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 3.71 (t, J = 6.4 Hz, 2H), 3.63 (t, J = 6.8 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.52 - 2.45 (m, 2H), 2.00 (t, J = 2.4 Hz, IH).

[003710] Step 2 - 3 -But-3 -ynoxypropan-1 -amine

[003711] To a mixture of diethylsilane (3.58 g, 40.6 mmol) and tris(perfluorophenyl)borane (83.1 mg, 162 umol) in DCM (30.0 mL) was added 3-but ynoxypropanenitrile (2.00 g, 16.2 mmol). The mixture was stirred at 25 °C for 16 hours. Then HCI/dioxane (4.00 M, 20.0 mL) was added, and the mixture was stirred for 1 hour. On completion, the mixture was concentrated in vacuo. The residue was dissolved in water (10.0 mL), and then extracted with EA (10.0 mL). The aqueous layer was concentrated in vacuo to give the title compound (2.30 g, 86% yield, HCI) as colorless oil. 1HNMR (400MHz, CDCh) δ 8.06 (s, 2H), 3.80 - 3.76 (m, 2H), 3.63 - 3.59 (m, 2H), 3.24 (s, 2H), 2.64 - 2.57 (m, 2H), 2.21 - 2.15 (m, IH), 2.08 - 2.04 (m, 2H).

[003712] Step 3 - Tert-butyl N-(3-but ynoxypropyl)carbamate

[003713] To a solution of 3-but ynoxypropan amine (300 mg, 1.83 mmol, HCI) in MeOH (10.0 mL) was added (Boc)2O (1.00 g, 4.58 mmol) and TEA (371 mg, 3.67 mmol). The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA= 5: 1) to give the title compound (200 mg, 48% yield) as colorless oil. 1H NMR (400MHz, DMSO-6/6) δ 4.85 (s, IH), 3.51 - 3.44

1224 (m, 4H), 3.21 - 3.10 (m, 2H), 2.43 - 2.38 (m, 2H), 1.95 - 1.90 (m, IH), 1.75 - 1.63 (m, 2H), 1.37 (s, 9H).

[003714] 34(55) (3bromoDhenvl) oxo-oxazolidin yl]DiDeridine-2.,6-dione (Intermediate SE)

OTf

SE

[003715] Step 1 - (S) bromo (3-brom ophenyDethanol

[003716] To a stirred solution of (S)-l-methyl-3,3-diphenylhexahydropyrrolo[l,2c][l,3,2]oxazaborole (1 g, 3.61 mmol, CAS# 112022 8) in THF (50 mL) was added BH3DMS (10 M, 2.5 mL, 25.3 mmol) at 0 °C. The mixture was stirred for 0.5 h at 0 °C. To the reaction mixture was added a solution of 2-bromo (3-bromophenyl)ethanone (10 g, 36.1 mmol) in THF (30 mL) dropwise at 0 °C. The mixture was stirred for 12 h at rt. To the mixture was added MeOH dropwise, where the mixture released bubbles of gas. Addition of MeOH was halted after bubbling stopped. Then the mixture was concentrated and purified by column (PE/EA = 50/1 to 20/1 to 10/1 to 5/1) to give the title compound (10 g, 100 % yield) as a white solid. 1H NMR (400 MHz, CDCh) ri 7.56 (t, J = 1.8 Hz, 1 H), 7.47-7.45 (m, 1 H), 7.32-7.30 (m, 1 H), 7.26-7.22 (m, 1 H), 4.90 (d, J = 8.7 Hz, 1 H), 3.63 (dd, J = 10.5, 3.4 Hz, 1 H), 3.51 (dd, J = 10.5, 8.8 Hz, 1 H), 2.68 (d, 7 = 1.6 Hz, 1 H).

[003717] Step 2 - (S) amino (3-brom ophenyDethanol

[003718] To a solution of (S) bromo (3-bromophenyl)ethanol (11 g, 90.3 mmol) in MeOH (80 mL) was added ΝΗ3&#905;2Ο (25%, 200 mL) at 0 °C under N2. The reaction mixture was stirred for 12 h under N2 at room temperature. The mixture was concentrated. The solid was washed with EA to give the title compound (6.2 g, 74% yield) as a white solid. 1H NMR (400

1225

MHz, DMSO4) δ 7.70 (br s, 2 H), 7.60 (t, J= 1.9 Hz, 1 H), 7.54-7.51 (m, 1 H), 7.42-7.34 (m, 2 H), 6.17 (d, J= 3.8 Hz, 1 H), 4.81-4.79 (m, 1 H), 3.09 (dd, J = 12.8, 3.2 Hz, 1 H), 2.87 (dd, J= 12.8, 9.6 Hz, 1 H).

[003719] Step 3 - (S) (3-bromophenyl)oxazolidin one

[003720] Amixture of (S) amino (3-bromophenyljethan01 (1 g, 4.63 mmol), CDI (1.1 g, 6.94 mmol) and THF (30 mL) was heated to 80 °C and stirred for overnight at 80 °C under N2. To the mixture was added H2O (20 mL), then the mixture was extracted with EA(50 mL). The organic layer was concentracted and purified by column chromatography on silica gel (PE/EA = 2/1 to 1/1) to give the title compound (300 mg, 27% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) δ 7.55-7.54 (m, 1 H), 7.51 (dt, J = 6.9, 2.0 Hz, 1 H), 7.32-7.29 (m, 2 H), 5.60 (t, J = 8.0 Hz, 1 H), 5.09 (br s, 1 H), 4.00 (dt, J= 0.6, 8.7 Hz, 1 H), 3.53-3.49 (m, 1 H).

[003721] Step 4 - (R) ((S) (3-bromophenyl) oxooxazolidin yl) (4methoxybenzyl)piperidine-2,6-dione

[003722] To a solution of (S) (3-bromophenyl)oxazolidin one (8.1 g, 33.5 mmol) in THF (100 mL) was added /-BuOK (5.6 g, 50.3 mmol) at 0 °C under N2. The mixture was stirred for 1 h at 0 °C. Then to the mixture was added l-(4-methoxybenzyl)-2,6-dioxopiperidin yl trifluoromethanesulfonate (14 g, 36.8 mmol) at 0 °C under N2. The mixture was stirred for 2 h at 0 °C~10 °C. To the mixture was added EA (100 mL), then the solution was washed with H2O (100 mL), brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (PE/EA = 2/1) to give a mixture of desired product and starting material. Then the mixture was re-purified by flash column chromatography (210 nm, 30 % MeCN in H2O) to give product (R) ((S) (3-bromophenyl) oxooxazolidin yl)-l-(4methoxybenzyl)piperidine-2,6-dione (4.0 g, 25% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ &#906;.66-&#906;.5&#906; (m, 2 H), 7.39-7.36 (m, 2 H), 7.32-7.28 (m, 2 H), 6.81-6.77 (m, 2 H), 5.48 (t, J= 8.4 Hz, 1 H), 4.87 (s, 2 H), 4.69 (dd, J = 13.5, 5.2 Hz, 1 H), 3.79 (t, J = 8.4 Hz, 1 H), 3.76 (s, 3 H), 3.42 (t, J= 8.0 Hz, 1 H), 2.95 (ddd, J= 17.8, 4.5, 2.4 Hz, 1 H), 2.77 (ddd, J= 17.8, 13.5, 5.5 Hz, 1 H), 2.24-2.07 (m, 2 H).

[003723] Step 5 - (R) ((S) (3-bromophenyl) oxooxazolidin yl)piperidine-2,6-dione [003724] To a solution of (R) ((S)-5 -(3 -bromophenyl) oxooxazolidin yl) (4methoxybenzyl)piperidine-2,6-dione (4.0 g, 8.47 mmol) in MeCN (90 mL) was added dropwise a solution of CAN (18.6 g, 33.9 mmol) in H2O (20 mL) at 0 °C. The mixture was stirred for 3 h at 0

1226 °C~10 °C. To the mixture was added H2O (50 mL), then the solution was extracted with EA (100 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, concentrated to give a yellow solid. The solid was washed with EA (30 mL) to give the title compound (1.2 g, 40% yield) as a white solid. The filtrate was concentrated and purified by flash (210 nm, 30 % MeCN in H2O) to give another portion of the title compound (0.2 g, 7% yield) as a white solid, the total yield is 47%. 1H NMR (400 MHz, DMSO&#1470;» δ 11.00 (s, IH), 7.72 (t, J = 1.6 Hz, IH), 7.63-7.60 (m, 1 H), 7.50-7.49 (m, IH), 7.42 (t, J= 8 Hz, IH), 5.63 (dd, J= 7.6, 8.8 Hz, IH), 4.71 (dd, J = 5.2, 13.2 Hz, IH), 3.94 (t, J = 8.8 Hz, IH), 3.29-3.25 (m, IH), 2.92-2.82 (m, IH), 2.592.57 (m, IH), 2.25-2.14 (m, IH), 2.03-2.01 (m, 1H).LC/MS (ESI, m/z[. [M+l]+ = 355.0.

[003725] 3-[(5S) [3-[4-(3-aminopropoxv)but-l-vnvl]phenvl] oxo-oxazolidin-3yllpiperidine-2.,6- dione (Intermediate SF)

SF

[003726] Step 1 - Tert-butyl N-[3-[4-[3-[(5S) (2,6-dioxo piperidvl) oxo-oxazolidin-5vl1phenyl1but ynoxylpropyllcarbamate

[003727] To a solution of tert-butyl N-(3-but ynoxypropyl)carbamate (146 mg, 645 umol, Intermediate SD) and 3-((55) (3- bromophenyl) oxo-oxazolidin yl]piperidine-2,6-dione (190 mg, 537 umol, Intermediate SE) in DMF (8.00 mL) was added Pd(PPh3)2C12 (37.7 mg, 53.8 umol), Cui (10.2 mg, 53.8 umol), Cs2CO3 (701 mg, 2.15 mmol) and 4A molecular sieves (30 mg) under N2, and the mixture was stirred at 80 °C for 3 hrs. On completion, the mixture was filtered

1227 and the filtrate was concentrated in vacuo. The mixture was purified by prep-HPLC (reverse phase: 0.1% FA) to give the title compound (140 mg, 52% yield) as yellow solid. 1H NMR (400MHz, DMSO-/6) δ 11.0 (s, IH), 7.51 - 7.39 (m, 4H), 6.79 (s, IH), 5.73 - 5.58 (m, IH), 4.76 - 4.63 (m, IH), 3.97 - 3.84 (m, IH), 3.59-3.51 (m, 2H), 3.46 - 3.43 (m, 2H), 3.30 - 3.22 (m, IH), 3.03 - 2.95 (m, 2H), 2.92 - 2.76 (m, IH), 2.70 - 2.67 (m, 2H), 2.61 - 2.54 (m, IH), 2.28 - 2.14 (m, IH), 2.05 1.93 (m, IH), 1.68 - 1.57 (m, 2H), 1.38 (s, 9H).

[003728] Step 2 - 3-r(5S) r3-r4-(3-aminopropoxy)but-l-ynyl1phenyl1 oxo-oxazolidin-3yl1piperidine-2,6- dione

[003729] To a solution of tert-butyl N-[3-[4-[3-[(55) (2,6-dioxo piperidyl) oxooxazolidin yl]phenyl] but ynoxy]propyl]carbamate (110 mg, 220 umol) in DCM (4.00 mL) was added TFA (6.16 g, 54.0 mmol). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (110 mg, 97% yield, TFA) as yellow solid. LC-MS (ESI+) m/z 400.2(M+H)+.

[003730] But ynyl methanesulfonate (Intermediate SG) MSC1, TEA ^^x^OMs DCM SG

[003731] To a solution of but yn-l-ol (10.0 g, 142 mmol, CAS# 927 2) and TEA (43.3 g, 428 mmol) in DCM (250 mL) was added MsCI (21.2 g, 185 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by water (150 mL) at 0 °C. The organic layers were washed with water (150 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (20.0 g, 95% yield) as light yellow oil. 1HNMR (400MHz, CDCh) 4.31 (t, J= 6.4 Hz, 2H), 3.06 (s, 3H), 2.68 -2.64 (Μ, 2H), 2.07 (t, /=2.8 Hz, IH).

[003732] Tert-butyl N-[(l-but vnvl DiDeridvl)methvl]-N-methyl-carbamate (Intermediate SH)

SH

[003733] To a solution of tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate (3.00 g, 13.1 mmol, CAS# 138200- 04-5) in a mixed solvent of CHCh (25 mL) and ACN (25 mL) was added K2CO3 (3.63 g, 26.2 mmol) and but ynyl methanesulfonate (2.53 g, 17.0 mmol, Intermediate

1228

SG). The mixture was stirred at 70 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE/EA=6/1) to give the title compound (2.30 g, 62% yield) as light yellow oil. 1H NMR (400MHz, CDCh) δ 3.09 (d, J= 6.8 Hz, 2H), 2.97 - 2.97 (m, 2H), 2.84 (s, 3H), 2.59 (t, 7= 8.0 Hz, 2H), 2.45 - 2.32 (m, 2H), 2.04 - 1.93 (m, 3H), 1.65 - 1.55 (m, 3H), 1.45 (s, 9H), 1.30 - 1.20 (m, 2H).

[003734] 3-[3-Methvl [4-[4-(methvlaminomethvl)-l-piperidvl]but-l-vnyl] oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate SI)

TFA

DCM

[003735] Step 1 - Tert-butyl N-rr1-r4-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1but ynyl1 piperidvl1methvl1-N-methyl-carbamate

[003736] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6 dione (500 mg, 1.48 mmol, Intermediate HN) and tert-butyl N-[(l-but ynyl piperidyl)methyl]N-methyl-carbamate (1.04 g, 3.70 mmol, Intermediate SH) in DMF (15 mL) was added Cs2CO3 (1.93 g, 5.91 mmol), Cui (56.3 mg, 295 umol), 4A molecular sieves (500 mg) and Pd(PPh3)2Ch (207 mg, 295 umol). The mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo&#1523;, the residue was diluted with water (30 mL), and then extracted with EA (3 X 40 mL). The combined organic layers were dried over Na2SO4, filtered

1229 and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (80.0 mg, 10% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 8.16 (s, IH), 7.14 (dd, J = 1.6, 8.4 Hz, IH), 7.07 (s, IH), 6.72 (d, J = 8.0 Hz, IH), 5.19 (dd, J= 5.6, 12.8 Hz, IH), 3.42 (s, 3H), 3.12 (d, J= 6.8 Hz, 2H), 3.07 -2.92 (m, 3H), 2.89 2.81 (m, 4H), 2.80 - 2.58 (m, 5H), 2.29 - 2.21 (m, IH), 2.19 - 2.00 (m, 2H), 1.46 (s, 9H), 1.39 1.24 (m, 2H); LC-MS (ESI+) m/z 538.3 (M+H)+.

[003737] Step 2 - 3-r3-Methyl r4-r4-(methylaminomethyl)-l-piperidvl1but-l-vnyl1 oxobenzimidazol-l-yl] piperidine-2,6-dione

[003738] To a solution of tert-butyl N-[[l-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]but ynyl] piperidyl]methyl]-N-methyl-carbamate (60.0 mg, 111 umol) in DCM (3 mL) was added TFA (924 mg, 8.10 mmol). The mixture was stirred at 30 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (60.0 mg, 97% yield, TFA) as light yellow oil. LC-MS (ESI+) m/z 438.3 (M+H)+.

[003739] Tert-butyl N-[3-(2-DiDerazin-l-ylethoxy)cyclobutyl]carbamate (Intermediate SJ) ff ΗΟ&#1523;&#1523;^ O A n,, _ LiBH4 hO^°'&#1523;T3

--------------&#9658; Eto ^XHBoc Rh(OAc)2,DCM *A THF ^AhBoc

MsCI, Et3N

DCM

MsO

NHBOC

Et3N, KI,AON

Pd/C, H2

MeOH

[003740] Step 1 - Ethyl 2-r3-(tert-butoxvcarbonvlamino)cvclobutoxv1acetate

[003741] To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (8.00 g, 43.0 mmol, CAS# 389890 0) in DCM (80 mL) was added diacetoxy rhodium (0.38 g , 0.85 mmol), the mixture was stirred at 25 °C for 0.5 hour. Then a solution of ethyl 2-diazoacetate (5.90 g, 51.0 mmol, CAS# 623 4) in DCM (20 mL) was added to the reaction mixture and stirred at 25 °C

1230 for 12 hours. On completion, the reaction mixture was diluted with saturated sodium bicarbonate solution (100 mL) and extracted with DCM (2 X 150 mL). The combined organic layers were washed with brine (2 X 200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (9.00 g, 77% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 4.23 - 4.19 (m, 4H), 3.97 (s, 2H), 2.45 2.41 (m, 2H), 2.17 - 2.14 (m, 2H), 1.43 (m, 9H), 1.30-1.28 (m, 3H).

[003742] Step 2 - Tert-butyl N-r3-(2-hydroxyethoxy)cvclobutyl1carbamate

[003743] To a solution of ethyl 2-[3-(tert-butoxycarbonylamino)cyclobutoxy]acetate (9.00 g, 33.0 mmol) in THF (100 mL) was added LiBH4 (1.20 g, 53.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was quenched by H2O (60 mL) at 25 °C, and then extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with (2 X 200 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.0 g, 92% yield) as colorless oil.

[003744] Step 3 - 2-r3-(Tert-butoxycarbonylamino)cyclobutoxy1ethyl methanesulfonate [003745] To a solution of tert-butyl N-[3-(2-hydroxyethoxy)cyclobutyl]carbamate (2.00 g, 8.70 mmol) in DCM (20 mL) was added Et3N (1.80 g, 17.0 mmol) and MsCI (1.50 g, 13.0 mmol) at 0 °C. Then the reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with DCM (2 X 50 mL). The combined organic layers were washed with brine (2 X 100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.00 g, 75% yield) as colorless oil.

[003746] Step 4 - Benzyl 4-r2-r3-(tert-butoxycarbonylamino)cyclobutoxy1ethyl1piperazine1-carboxylate

[003747] To a solution of 2-[3-(tert-butoxycarbonylamino)cyclobutoxy]ethyl methanesulfonate (2.00 g, 6.50 mmol) and benzylpiperazine carboxylate (2.90 g, 13.0 mmol, CAS# 31166 6) in ACN (40 mL) was added Et3N (2.00 g, 19.0 mmol) and KI (1.30 g, 7.80 mmol). Then the reaction mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (2.00 g, 77% yield) as colorless oil. 1HNMR (400MHz, DMSO-t/6) δ 7.39 - 7.33 (m, 5H), 7.18 (d, J= 6.0 Hz, IH), 5.11 (s, 2H), 4.06 - 4.00 (m, 3H), 3.57 (d, J = 4.0 Hz, 2H), 3.31 (s, 3H), 3.11 (d, J = 9.2 Hz, 2H), 2.52 (s, 4H), 2.22 - 2.18 (m, 2H), 2.12 - 2.08 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 434.3 (M+H)+.

1231

[003748] Step 5 - Tert-butyl N-[3-(2-piperazin-l-ylethoxy)cyclobutyl1carbamate

[003749] To a solution of benzyl 4-[2-[3-(tertbutoxycarbonylamino)cyclobutoxy]ethyl]piperazine-l- carboxylate (1.50 g, 3.50 mmol) in MeOH (20 mL) was added Pd/C (0.200 g, 3.50 mmol, 10 wt%). Then the reaction mixture was degassed and purged with H2 gas 3 times and stirred at 25 °C for 12 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.0 g, 97% yield) as colorless oil.

[003750] ]^226Ξ1)&#912;0χ0Ξ3Ξ12&#912;12££&#944;!11}Ξ3Ξ”1£1Ι&#943;Σ&#943;Ξ220χ0ΞΙ)£11Ηιη2(Ι<ιζ010Ξ5Ξ£^^ (Intermediate SK)

Y^bf3k

Cs2CO3,Pd(dppf))CI2,dioxane

NalO4, OsO4, NMO dioxane/water

[003751] Step 1 - 3-(3-Methvl oxo vinvl-benzimidazol-l-vl)piperidine-2,6-dione

[003752] A mixture of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (3.00 g, 8.87 mmol, Intermediate HN), potassium hydride, trifluoro (vinyl)boron (3.57 g, 26.6 mmol), Cs2CO3 (2 M solution, 8.87 mL), Pd(dppf)C12 CH2C12 (724 mg, 887 umol) and in dioxane (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 3 hours under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (TFA condition) to give the title compound (1.60 g, 58% yield) as a yellow solid. LC-MS (ESI+) m/z 286.0 (M+H)+.

[003753] Step 2 - l-(2,6-Dioxo piperidyl) methyl oxo-benzimidazole carbaldehyde

[003754] To a solution of 3-(3-methyl oxo vinyl-benzimidazol-l-yl)piperidine-2,6dione (0.30 g, 1.05 mmol) in a mixed solvent of dioxane (20 mL) and H2O (2 mL) was added NaIO4 (449 mg, 2.10 mmol), OsO4 (267 mg, 1.00 mmol) and NMO (61.0 mg, 525 umol). The mixture was stirred at 25 °C for 0.5 hr. On completion, the residue was diluted with water (10 mL)

1232 and extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (TFA condition) to give the title compound (0.1 g, 32% yield) as a gray solid. LC-MS (ESI+) m/z 288.0 (M+H)+.

[003755] 3-[5-[[4-[2-(3-Aminocvclobutoxv)ethvl]DiDerazin-l-vl]methvl] methyl-2oxo-benzimidazol-l-yl]piperidine-2,6-dione (Intermediate SL)

NHB oc

SL

[003756] Step 1 - Tert-butylN-r3-r2-r4-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1methyl1piperazin-l-yl1ethoxy1cyclobutyl1carbamate

[003757] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-5carbaldehyde (0.20 g, 696 umol, Intermediate SK) and tert-butyl-N-[3-(2-piperazin-lylethoxy)cyclobutyl]carbamate (0.420 g, 1.40 mmol, Intermediate SJ) in THF (4 mL) was added HO Ac (84.0 mg, 1.40 mmol) and stirred at 40 °C for 1 hour. Then NaBH(OAc)3 (0.440 g, 2.10 mmol) was added to the reaction mixture and stirred at 40 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prepHPLC (column: LunaC18 150*25 5u; mobile phase: [water (0.075%TFA)-ACN]; B%: 15%-45%, 9 min) to give the title compound (0.21 g, 46% yield) as a colorless oil. LC-MS (ESI+) m/z 571.2 (M+H)+.

[003758] Step 2 - 3-r5-rr4-r2-(3-Aminocyclobutoxy)ethyl1piperazin-l-yl1methyl1 methyl2-oxo-Benzimidazol-l-yl1piperidine-2,6-dione

[003759] To a solution of tert-butylN-[3-[2-[4-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl]piperazin-l-yl]ethoxy]cyclobutyl]carbamate (0.35 g, 0.61 mmol) in DCM (6 mL) was added HCl/dioxane (4 M, 3.1 mL). Then the reaction mixture was stirred at 25

1233 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (0.1 g, 34% yield, HC1) as colorless oil. LC-MS (ESI+) m/z 471.2 (M+H)+.

[003760] 3-[(5S) [3-[3-[(2S) (aminomethvl)morDholin vl]DroD-l-vnyl]Dhenvl]-2oxo-oxazolidin yl]DiDeridine-2.,6-dione (Intermediate SM)

[003761] Step 1 - Tert-butyl N-[[(2S) [3-[3-[(5S) (2,6-dioxo piperidyl) oxo0xaz0lidin yl1phenyl1 prop ynyl1morpholin yl1methyl1carbamate

[003762] To a mixture of tert-butyl N-[[(25) prop ynylmorpholin-2yl]methyl]carbamate (540 mg, 2.12 mmol, synthesized via Step 1 of Intermediate RK) and 3-((55)5-(3-bromophenyl) oxo-oxazolidin yl]piperidine-2,6-dione (300 mg, 849 umol, Intermediate SE) in DMF (5 mL) was added Pd(PPh3)2C12 (59.6 mg, 84.9 umol), Cui (16.1 mg, 84.9 umol) and Cs2CO3 (1.38 g, 4.25 mmol). The reaction mixture was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with EA (3 X 30 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (450 mg, 95% yield) as light yellow solid. LC-MS (ESI+) m/z 527.3 (M+H)+.

[003763] Step 2 - 3-[(5S) [3-[3-[(2S) (aminomethyl)morpholin yl1prop-lynyl1phenyl1 oxo-oxazolidin yl1piperidine-2,6-dione

[003764] To a mixture of tert-butyl N-[[(25) [3-[3-[(5JS) (2,6-dioxo piperidyl) oxooxazolidin yl] phenyl]prop ynyl]morpholin yl]methyl]carbamate (180 mg, 341 umol) in DCM (3 mL) was added TFA (4.62 g, 40.5 mmol, 3 mL). The reaction mixture was stirred at 25

1234 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (184 mg, 99% yield, TFA) as red oil. LC-MS (ESI+) m/z 427.1 (M+H)+.

[003765] 3-[(5ty) (4-bromophenvl) oxo-oxazolidin yl]piperidine-2.,6-dione (Intermediate SN)

Br Br Br

[003766] Step 1 - (S) bromo-l-(4-bromophenyl)ethanol

[003767] To a stirred solution of (S)-l-methyl-3,3-diphenylhexahydropyrrolo[l,2

c][l,3,2]oxazaborole (0.5 g, 1.81 mmol) in THF (25 mL) was added BH3DMS (10 M, 1.3 mL, 12.7 mmol) at 0 °C. The mixture was stirred for 0.5 h at 0 °C. To the reaction mixture was then added a solution of 2-bromo-l-(4-bromophenyl)ethanone (5 g, 18.1 mmol) in THF (15 mL) dropwise at 0 °C. The mixture was stirred for 12 h at rt. To the mixture was then added MeOH dropwise where gas evolved. MeOH was added until no more bubbling occurred. The mixture was concentrated and purified by column chromatography on silica gel (PE/EA= 50/1 to 20/1 to 10/1 to 5/1) to give the title compound (5 g, 100 % yield) as a white solid. 1H NMR (400 MHz, DMSO4) δ 7.55-7.52 (m, 2 H), 7.38-7.34 (m, 2 H), 5.89 (d, J= 4.9 Hz, 1 H), 4.82-4.78 (m, 1 H), 3.66 (dd, J= 10.2, 4.6 Hz, 1 H), 3.57 (dd, J= 10.2, 6.8 Hz, 1 H).

[003768] Step 2 - (S) amino-l-(4-bromophenyl)ethanol

[003769] To a solution of (S) bromo-l-(4-bromophenyl)ethanol (15 g, 123 mmol) in MeOH (100 mL) was added ΝΗ3&#905;2Ο (25 %, 250 mL) at 0 °C under N2. The reaction mixture was stirred at rt for 12 h under N2. Then the mixture was concentrated. The solid was washed with EA to give the title compound (8.4 g, 74 % yield) as a white solid. 1H NMR (400 MHz, DMSO-7) δ

1235

7.54 (d, J= 8.4 Hz, 2 H), 7.32 (d, J= 8.4 Hz, 2 H), 5.51 (br s, 3 H), 4.64 (dd,7=8.4, 3.6 Hz, 1 H), 2.83 (dd, 7= 12.8, 3.4 Hz, 1 H), 2.69 (dd, 7= 12.6, 6.8 Hz, 1 H).

[003770] Step 3 - (S) (4-bromophenyl)oxazolidin one

[003771] A mixture of (S) amino-l-(4-bromophenyl)ethanol (22 g, 102 mmol), CDI (24.2 g, 153 mmol) and THF (500 mL) was heated to 80 °C and stirred for overnight at 80 °C under N2. To the mixture was then added H2O (200 mL), and the mixture was extracted with EA (300 mL). The organic layer was concentracted and purified by column (PE/EA= 2/1 to 1/1) to give the title compound (8.0 g, 33% yield) as a yellow solid.

[003772] Step 4 - (R) ((S) (4-bromophenyl) oxooxazolidin yl) (4methoxvbenzyl)piperidine-2.6-dione

[003773] To a solution of (S) (3-bromophenyl)oxazolidin one (8.0 g, 30.2 mmol) in THF (100 mL) was added /-BuOK (5.5 g, 49.8 mmol) at 0 °C under N2. The mixture was stirred for 1 h at 0 °C. Then to the mixture was added l-(4-methoxybenzyl)-2,6-dioxopiperidin yl trifluoromethanesulfonate (13.9 g, 36.8 mmol) at 0 °C under N2. The mixture was stirred at 0 °C~10 °C for 2 h. To the mixture was then added EA (100 mL), the solution was then washed with H2O (100 mL), brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (PE/EA = 2/1) to give a mixture of desired product (R) ((S) (4bromophenyl) oxooxazolidin yl)-l -(4-methoxybenzyl)piperidine-2,6-dione and starting material. Then the mixture was re-purified by flash column chromatography (210 nm, 30 % MeCN in H2O) to give the title compound (4.5 g, 28% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 7.57-7.52 (m, 2 H), 7.34-7.29 (m, 2 H), 7.26-7.24 (m, 2 H), 6.86-6.80 (m, 2 H), 5.89 (dd, 7= 8.7, 7.1 Hz, 1 H), 4.89 (s, 2 H), 4.58 (dd, 7= 12.8, 6.0 Hz, 1 H), 3.94 (t, 7= 8.4 Hz, 1 H), 3.78 (s, 3 H), 3.80 (dd, 7= 17.9, 7.1 Hz, 1 H), 2.97-2.90 (m, 1 H), 2.79-2.70 (m, 1 H), 2.20-2.04 (m, 2 H).

[003774] Step 5 - (R) ((S) (4-bromophenyl) oxooxazolidin yl)piperidine-2,6-dione [003775] To a solution of (R) ((S) (4-bromophenyl) oxooxazolidin yl) (4methoxybenzyl)piperidine-2,6-dione (50 mg, 0.106 mmol) in MeCN (5 mL) was added dropwise a solution of CAN (232 mg, 0.424 mmol) in H2O (1 mL) at 0 °C. The mixture was stirred for 3 h at 0 °C~10 °C. To the mixture was then added H2O (100 mL), and the solution was extracted with EA (200 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column (PE/EA = 1/1) to give the title compound (5 mg, 14 % yield)

1236 as a white solid. 1H NMR (400 MHz, CDCh) δ 8.20 (s, 1 H), 7.56 (d, J= 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 5.49 (t, J= 8.2 Hz, 1 H), 4.74 (dd, J= 13.0, 5.2 Hz, 1 H), 3.84 (t, J= 8.4 Hz, 1 H), 3.48 (t, J= 7.8 Hz, 1 H), 2.91-2.87 (m, 1 H), 2.82-2.73 (m, 1 H), 2.22-2.11 (m, 2 H). LC/MS (ESI, m/z): [M+l]+ = 355.0.

[003776] Step 6 - (S) ((S) (4-bromophenyl) oxooxazolidin yl)piperidine-2,6-dione [003777] To a solution of (S) ((S) (4-bromophenyl) oxooxazolidin yl) (4methoxybenzyl)piperidine-2,6-dione (80 mg, 0.169 mmol) in MeCN (10 mL) was added dropwise a solution of CAN (372 mg, 0.678 mmol) in H2O (2 mL) at 0 °C. The mixture was stirred for 3 h at 0 °C~10 °C. To the mixture was added H2O (100 mL), then the mixture was extracted with EA (200 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column (PE/EA= 1/1) to give the title compund (1.5 mg, 3% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 7.86 (s, 1 H), 7.56 (d, J= 8.2 Hz, 2 H), 7.26-7.22 (m, 2 H), 5.60 (t, J= 7.8 Hz, 1 H), 4.64 (dd, J= 12.0, 5.2 Hz, 1 H), 4.00 (t, J= 8.2 Hz, 1 H), 3.41 (t, J= 7.4 Hz, 1 H), 2.91-2.86 (m, 1 H), 2.78-2.73 (m, 1 H), 2.24-2.20 (m, 2 H). LC/MS (ESI, m/z): [M+l]+= 355.0.

[003778] 3-[(5S) [4-[3-[(2S) (aminomethvl)morpholin vl]prop-l-vnyl]phenvl]-2oxo- oxazolidin yl]piperidine-2.,6-dione (Intermediate SO)

1237

[003779] Step 1 - Tert-butyl N-rr(2S) r3-r4-r(5S) (2,6-dioxo piperidyl) oxo0xaz0lidin yl1phenyl1 prop ynyl1morpholin yl1methyl1carbamate

[003780] To a solution of tert-butyl N-[[(25) prop ynylmorpholin-2yl]methyl]carbamate (648 mg, 2.55 mmol, synthesized via Step 1 of Intermediate RK) and 3-^55)5-(4-bromophenyl) oxo-oxazolidin yl]piperidine-2,6-dione (300 mg, 849 umol, Intermediate SN) in DMF (15 mL) was added Pd(PPh3)2C12 (119 mg, 169 umol), Cui (32.3 mg, 169 umol) and Cs2CO3 (1.38 g, 4.25 mmol). The reaction mixture was stirred at 80 °C for 2 hours under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (440 mg, 80% yield) as a yellow solid. 1HNMR (400 MHz, DMSO4) 511.00 (d, J= 6.0 Hz, IH), 7.53 - 7.40 (m, 4H), 6.88 - 6.84 (m, IH), 5.73 - 5.61 (m, IH), 4.75 - 4.63 (m, IH), 3.94 (t, J = 8.8 Hz, IH), 3.89 (t, J = 8.8 Hz, IH), 3.80 (t, J = 7.2 Hz, 2H), 3.50 - 3.40 (m, 4H), 3.30 - 3.21 (m, 2H), 2.60 - 2.52 (m, 2H), 2.37 - 2.15 (m, 3H), 2.02 - 1.92 (m, 2H), 1.36 (s, 9H); LC-MS (ESI+) m/z 527.3 (M +H)+.

[003781] Step 2 - 3-r(5S) r4-r3-r(2S) (aminomethyl)morpholin yl1prop-lynyl1phenyl1 oxo- oxazolidin yl1piperidine-2,6-dione

[003782] To a solution of tert-butyl N-[[(2JS) [3-[4-[(5S) (2,6-dioxo piperidyl) oxooxazolidin yl] phenyl] prop ynyl]morpholin yl]methyl]carbamate (150 mg, 284 umol) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the residue concentrated in vacuo to give the title compound (150 mg, 97% yield) as yellow oil. LC-MS (ESI+) m/z 427.2 (M+H)+.

[003783] 3-[3-Methvl [3-[2-[2-(methvlamino)ethoxv]ethoxy]DroDvl] oxobenzimidazol-l-yl] DiDeridine-2,6-dione (Intermediate SP)

1238

Pd(OH)2/C, Pd/C, H2

THF

SP

[003784] Step 1 - Tert-butyl N-r2-r2-r3-r1-(2»dioxo piperidvl) methyl oxobenzimidazol yl1prop ynoxy1ethoxy1ethyl1-N-methyl-carbamate

[003785] To a mixture of tert-butyl N-methyl-N-[2-(2-prop ynoxyethoxy)ethyl]carbamate (1.37 g, 5.32 mmol, Intermediate FY), 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (600 mg, 1.77 mmol, Intermediate HP) in DMF (30 mL) was added Cs2CO3 (2.89 g, 8.87 mmol), Pd(PPh3)2C12 (249 mg, 354 umol) and Cui (67.5 mg, 354 umol) under N2. The reaction mixture was stirred at 80 °C for 2 hours. On completion, the mixture was filtered, the filtrate was poured into water (100 mL), and the aqueous phase was extracted with ethyl acetate (2 X 40 mL). The combined organic phase was washed with brine (2 X 40 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to get residue. The residue was purified by reverse phase (0.1% FA condition) to get title compound (480 mg, 52% yield) as a brown solid. 1H NMR (400 MHz, CDCh) δ 8.29 (s, IH), 7.22 - 7.16 (m, IH), 7.03 - 7.00 (m, IH), 6.78 (d, J= 8.0 Hz, IH), 5.28 5.17 (m, IH), 4.49 (s, 2H), 4.20 - 4.08 (m, IH), 3.81 - 3.78 (m, 3H), 3.71 - 3.67 (m, 2H), 3.62 (s, 3H), 3.61 - 3.55 (m, 4H), 2.93 (s, 3H), 2.92 (s, 2H), 2.30 - 2.20 (m, IH), 2.03 (s, IH), 1.47 (s, 9H). [003786] Step 2 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1ethoxy1ethyl1-N-methyl-carbamate

1239

[003787] To a mixture of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]ethoxy]ethyl]-N-methyl-carbamate (480 mg, 933 umol) in THF (20 mL) was added Pd/C (100 mg, 1.87 mmol, 10 wt%) and Pd(OH)2/C (100 mg, 1.87 mmol, 10 wt%) under N2. The suspension was degassed in vacuo and purged with H2 gas three times. The mixture was stirred at 20 °C for 12 hours under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (360 mg, 74% yield) as brown oil. LC-MS (ESI+) m/z 541.2 (M+Na)+.

[003788] Step 3 - 3-r3-Methyl r3-r2-r2-(methylamino)ethoxy1ethoxy1propyl1 oxobenzimidazol-l-yl1 piperi dine-2,6-di one

[003789] To a mixture of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]ethyl]-N-methyl-carbamate (350 mg, 675 umol) in DCM (2 mL) was added TFA (154 mg, 1.35 mmol). The reaction mixture was stirred at 25 °C for 0.1 hour. On completion, the mixture was concentrated in vacuo to get title compound (365 mg, 100% yield) as brown oil. LC-MS (ESI+) m/z 419.1 (M+H)+.

[003790] 3-[4-[3-[(2R) (aminomethvl)morpholin vl]propyl] methvl oxobenzimidazol yl]piperidine-2.,6-dione (Intermediate SO)

Pd/C, Pd(OH)2/C, H2

THF

1240

[003791] Step 1 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynyl1morpholin yl1methyl1carbamate

[003792] To a solution of tert-butyl N-[[(2R) prop ynylmorpholin-2yl]methyl]carbamate (940 mg, 3.70 mmol, synthesized via Step 1 of Intermediate RJ) and 3-(4bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate HP) in DMF (15 mL) was added Cs2CO3 (2.41 g, 7.39 mmol), Cui (28.1 mg, 147 umol) and Pd(PPh3)2C12 (103 mg, 147 umol). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (500 mg, 66% yield) as a yellow solid. LC-MS (ESI+) m/z 512.3 (M +H)+.

[003793] Step 2 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1carbamate

[003794] To a solution of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol- 4-yl]prop ynyl]morpholin yl]methyl]carbamate (500 mg, 977 umol) in THF (20 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%). The reaction mixture was stirred at 25 °C under H2 (15 psi) for 12 hrs. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (370 mg, 73% yield) as a white solid. 1H NMR (400MHz, DMSO-6/6) δ 11.09 (s, IH), 7.04 - 6.91 (m, 2H), 6.91 - 6.79 (m, 2H), 5.36 (dd, J = 5.2, 12.4 Hz, IH), 3.76 (d, J= 10.4 Hz, IH), 3.56 (s, 3H), 3.46 (t, J= 10.8 Hz, IH), 3.40 - 3.35 (m, IH), 3.02 - 2.79 (m, 6H), 2.75 - 2.61 (m, 3H), 2.45 - 2.31 (m, 2H), 2.06 - 1.94 (m, 2H), 1.82 1.63 (m, 3H), 1.37 (s, 9H); LC-MS (ESI+) m/z 516.3 (M+H)+.

[003795] Step 3 - 3-[4-[3-[(2R) (aminomethyl)morpholin yl1propyl1 methyl oxobenzimidazol yl1piperidine-2,6-dione

[003796] To a solution of tert-butyl N-[[(27?) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]carbamate (370 mg, 717 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 3.08 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (320 mg, 98% yield, HCI) as a white solid. LC-MS (ESI+) m/z 416.3 (M+H)+.

[003797] .ΥΙΑ^υΚΤ^^Τ^^&#912;η&#912;&#912;η&#912;&#912;η&#912;Τ&#912;Ι&#943;Σ&#912;Ι&#912;ΙΙΙΙΗ&#912;Ι&#943;θΙ&#943;Ι&#912;ΞζΕΣ&#912;^^ benzimidazol yl]piperidine-2.,6-dione (Intermediate SR)

1241

Pd(PPh3)2CI2, Cui, Cs2CO3, 4A MS, DMF

SR

[003798] Step 1 - Tert-butyl N-rr(2S) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1 prop ynyl1morpholin yl1methyl1carbamate

[003799] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (500 mg, 1.48 mmol, Intermediate HP) and tert-butyl N-[[(2JS)4&#1470;-prop ynylmorpholin-2yl]methyl]carbamate (564 mg, 2.22 mmol, synthesized via Step 1 of Intermediate RK) in DMF (20 mL) was added Cs2CO3 (1.93 g, 5.91 mmol), Cui (56.3 mg, 295 umol), 4A molecular sieves (20 mg) and Pd(PPh3)2C12 (207 mg, 295 umol), and the mixture was heated at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (40 mL), and then extracted with EA (50 mL X 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (430 mg, 56% yield) as light yellow solid. 1H NMR (400MHz, CDCh) δ 8.35 (s, IH), 7.18 (dd, J= 0.8, 8.0 Hz&#1524; IH), 7.98 (t, J = 8.0 Hz, IH), 6.77 (dd, J = 0.8, 8.0 Hz, IH), 5.22 (dd, J = 5.2, 12.8 Hz, IH), 4.90 (s, IH), 3.94 (dd, 7= 0.8, 11.6 Hz, IH), 3.77 (s, 3H), 3.74 - 3.70 (m, IH), 3.68 - 3.62 (m, IH), 3.58 (d, 7= 2.0 Hz, 2H), 3.40 - 3.31 (m, IH), 3.18 - 3.08 (m, IH), 3.01 - 2.91 (m, IH), 2.90 - 2.73 (m, 4H), 2.50 2.44 (m, IH), 2.31 - 2.17 (m, 2H), 1.44 (s, 9H). LC-MS (ESI+) m/z 512.3 (M+H)+.

1242

[003800] Step 2 - Tert-butyl N-rr(2S) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1carbamate

[003801] To a solution of tert-butyl N-[[(25) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]prop ynyl]morpholin yl]methyl]carbamate (360 mg, 703 umol) in THF (5 mL) was added Pd(OH)2/C (40.0 mg, 10 wt%) and Pd/C (40.0 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 4 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (280 mg, 77% yield) as light yellow solid. 1HNMR (400MHz, CDCh) δ 8.32 (s, IH), 7.89 (t, J= 8.4 Hz, IH), 7.18 (d, J= 0.8, 8.0 Hz&#1524; IH), 6.67 (d, J= 7.6 Hz, IH), 5.22 (dd,/=5.2, 12.4 Hz, IH)4.90 &#1524; (s, IH), 3.87 (d,/= 10.8 Hz, IH), 3.72 - 3.52 (m, 5H), 3.40 - 3.25 (m, IH), 3.17 - 3.03 (m, IH), 3.01 - 2.91 (m, 3H), 2.87 - 2.66 (m, 4H), 2.41 (t, /= 6.8 Hz, 2H), 2.26 - 2.08 (m, 2H), 1.94 - 1.83 (m, 3H), 1.45 (s, 9H); LC-MS (ESI+) m/z 516.2 (M+H)+.

[003802] Step 3 - 3-r4-r3-r(2S) (aminomethyl)morpholin yl1propyl1 methyl oxobenzimidazol yl1piperidine-2,6-dione

[003803] To a solution of tert-butyl N-[[(25) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]carbamate (200 mg, 387 umol) in DCM (3 mL) was added TFA (924 mg, 8.10 mmol). The mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (200 mg, 98% yield, TFA) as light yellow oil. LC-MS (ESI+) m/z 416.3 (M+H)+.

[003804] 3-[7-[3-[(2S) (aminomethvl)morpholin vl]propvl] oxo-l,3-benzoxazol3-yl]piperidine -2,6-dione (Intermediate SS)

1243

Pd/C, Pd(OH)2/C, H2

THF

[003805] Step 1 - Tert-butyl (((2S) (3-(3-(2,6-dioxopiperidin yl) oxo-2,3dihydrobenzo[d1oxazol yl) prop yn-l-yl)morpholin yl)methyl)carbamate

[003806] To a solution of 3-(7-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione 2 (600 mg, 1.85 mmol, Intermediate JF) and tert-butyl N-[[(25) prop ynylmorpholin-2yl]methyl]carbamate (704 mg, 2.77 mmol, synthesized via Step 1 of Intermediate RK) in DMF (15 mL) was added Cs2CO3 (2.41 g, 7.38 mmol), Cui (70.3 mg, 369 umol), 4A molecular sieves (30.0 mg) and Pd(PPh3)2C12 (259 mg, 369 umol) at 25 °C under N2. Then the mixture was heated at 80 °C for 2 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 1:2 to 1:3) to give the title compound (684 mg, 74% yield) as a yellow solid. 1HNMR (400 MHz, CDCh) δ 8.18 (s, IH), 7.43 (s, IH), 7.23 - 7.20 (m, IH), 7.14 - 7.10 (t, J = 8.0 Hz, IH), 6.80 - 6.77 (m, IH), 5.07 - 5.02 (m, IH), 4.91 - 4.90 (m, IH), 3.96 - 3.92 (m, IH), 3.74 - 3.60 (m, 4H), 3.16 - 3.09 (m, IH), 3.02 - 2.97 (m, IH), 2.89 - 2.68 (m, 4H), 2.54 - 2.47 (m, IH), 2.37 - 2.21 (m, 2H), 1.44 (s, 9H); LC-MS (ESI+) m/z 499.1 (M+H)+.

[003807] Step 2 - Tert-butylN-rr(2S) r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol7-yl1propyl1mor pholin- 2-yl1methyl1carbamate

1244

[003808] To a mixture of tert-butyl N-[[(25) [3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop- 2-ynyl]morpholin yl]methyl]carbamate (250 mg, 501 umol) in THF (5 mL) was added Pd/C (75.0 mg, 10 wt%) and Pd(OH)2 (75.0 mg, 10 wt%) under N2. The suspension was degassed in vacuo and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 hours. On completion, the reaction mixture was filtered to remove Pd/C and Pd(OH)2/C, and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (120 mg, 55% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 8.38 (s, IH), 7.10 (t, J= 8.0 Hz, IH), 7.00 (d, J= 7.8 Hz, IH), 6.70 (d, J= 7.8 Hz, IH), 5.08 - 5.04 (m, IH), 4.89 (s, IH), 3.92 - 3.76 (m, 3H), 3.34 - 3.29 (m, IH), 3.18 - 3.09 (m, IH), 3.01 - 2.69 (m, 8H), 2.57 (d, J = 5.4 Hz, 2H), 2.36 - 2.30 (m, 2H), 2.04 - 1.99 (m, 2H), 1.45 (s, 9H); LC-MS (ESI+) m/z 503.1 (M+H)+.

[003809] Step 3 - 3-r7-r3-r(2S) (aminomethyl)morpholin yl1propyl1 oxo-L3benzoxazol yl1piperidine -2,6-dione

[003810] To a mixture of tert-butyl N-[[(25) [3-[3-(2,6-dioxo piperidyl) oxo-l,3-ben zoxazol yl]propyl] orpholin yl]methyl]carbamate (140 mg, 278 umol) in DCM (2 mL) was added TFA (317 mg, 2.79 mmol) in one portion at 25 °C. The mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (139 mg, 96% yield, TFA) as light yellow oil. 1H NMR (400 MHz, DMSO4) δ 11.22 (s, IH), 8.06 (s, 2H), 7.23 - 7.12 (m, 2H), 7.10 - 7.00 (m, IH), 5.40 - 5.35 (m, IH), 5.41 - 5.34 (m, IH), 4.11 ( d, J= 10.4 Hz, IH), 4.01 -3.89 (m, IH), 3.74 (t,J= 12.0 Hz, IH), 3.64-3.43 (m, 2H), 3.32 -3.11 (m, 2H), 3.11 -2.98 (m, 2H), 2.97-2.59 (m, 7H), 2.18 -2.11 (m, IH), 2.09-2.00 (m, 2H); LC-MS (ESI+) m/z 403.2 (M+H)+.

[003811] 3-[7-[3-[(2R) (aminomethvl)morpholin vl]propvl] oxo-l,3-benzoxazol3-yl]piperidine -2.,6-dione (Intermediate ST)

1245

ST

[003812] Step 1 - Tert-butyl N-[[(2R) [3-[3-(2,6-dioxo piperidyl) oxo-L3benzoxazol yl1prop ynyl1 morpholin yl1methyl1carbamate

[003813] To a solution of tert-butyl N-[[(27?) prop ynylmorpholin-2yl]methyl]carbamate (488 mg, 1.92 mmol, synthesized via Step 1 of Intermediate RJ) and 3-(7bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (250 mg, 768 umol, Intermediate JF) in DMF (15 mL) was added Pd(PPh3)2C12 (53.9 mg, 76.9 umol), Cui (14.6 mg, 76.9 umol) and Cs2CO3 (1.25 g, 3.84 mmol). The reaction mixture was stirred at 80 °C for 2 hrs under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (350 mg, 91% yield) as a yellow solid. LC-MS (ESI+) m/z 499.2 (M +H)+.

[003814] Step 2 - Tert-butyl N-[[(2R) [3-[3-(2,6-dioxo piperidyl) oxo-L3benzoxazol yl1propyl1 morpholin yl1methyl1carbamate

[003815] To a solution of tert-butyl N-[[(27?) [3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl] prop- 2-ynyl]morpholin yl]methyl]carbamate (350 mg, 702 umol) in THF (20 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%). The reaction mixture was stirred at 25 °C under H2 (15 psi) for 12 hrs. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (290 mg, 82% yield) as a white solid. 1H NMR

1246 (400MHz, DMSO-76) δ 11.21 (s, IH), 7.17 - 7.07 (m, 2H), 7.02 (d, J = 6.8 Hz, IH), 6.82 (t, J = 5.6 Hz, IH), 5.38 - 5.32 (m, IH), 3.77 (d, J= 10.2 Hz, IH), 3.47 (d, J= 11.2 Hz, IH), 3.43 - 3.39 (m, IH), 2.99 - 2.87 (m, 3H), 2.79 - 2.65 (m, 6H), 2.44 - 2.31 (m, 2H), 2.21 - 2.07 (m, 2H), 1.87 1.69 (m, 3H), 1.36 (s, 9H); LC-MS (ESI+) m/z 503.3 (M+H)+.

[003816] Step 3 - 3-r7-r3-r(2R) (aminomethyl)morpholin yl1propyl1 oxo-L3benzoxazol yl1piperidine -2,6-dione

[003817] To a solution of tert-butyl N-[[(2J?) [3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propyl] morpholin yl]methyl]carbamate (290 mg, 577 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 2.48 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (250 mg, 98% yield, HCI) as a white solid. LC-MS (ESI+) m/z 403.2(M+H)+.

[003818] 3-(6-((2-(2-(2-Aminoethoxv)ethoxv)ethvl)amino)-9H-pyrido[2,3-b]indol-9vl)Diperidine- 2,6-dione (Intermediate SU)

Dess-Martin periodinane . q. NHBoc &#1523;^0 ------------AcOH, DCM

NaCNBH3, THF, AcOH

HCI/dioxane

DCM

[003819] Step 1 - tert-butyl (2-(2-(2-oxoethoxv)ethoxv)ethyl)carbamate

[003820] To a solution of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (2 g,

8.03 mmol, synthesized via Step 1 on Intermediate AC) in DCM (20 mL) was added Dess-Martin

1247 periodinane (5.1 g, 12.04 mmol) and AcOH (1 mL) portion wise. After addition, the mixture was stirred at rt overnight. The mixture was then concentrated in vacuo. The residue was purified by flash chromatography to give the title compound (300 mg, 15%) as an oil. LC/MS (ESI, m/z): [M +l]+ = 248.2.

[003821] Step 2 - tert-butyl (2-(2-(2-((9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3-b1indol-6yl)amino)ethoxy)ethoxy)ethyl)carbamate

[003822] To a mixture of 3-(6-amino-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione (200 mg, 0.68 mmol, Intermediate UG), tert-butyl (2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (176.3 mg, 0.714 mmol) in THF(5 mL) was added AcOH (5 drops). The mixture was stirred at rt for 2 h. Then sodium cyanoborohydride (85.4 mg, 1.36 mmol) was added, and the mixture was heated to 40 °C and stirred overnight. Then the mixture was poured into water, and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound (70 mg, 20% yield) as a white solid. 1HNMR (400 MHz, DMSO-76) δ 11.09 (br. s., IH), 8.52 - 8.26 (m, 2H), 7.36 - 7.32 (m, 2H), 7.15 (dd, 7=7.63, 4.88 Hz, IH), 6.93 - 6.90 (m, IH), 6.78 - 6.76 (m, IH), 5.91 (br. s., IH), 5.30 (br. s., IH), 3.64 (t, 7=5.82 Hz, 2H), 3.51 - 3.59 (m, 4H), 3.40 (t, 7=6.13 Hz, 2H), 3.30 - 3.28 (m, 2H), 3.09 - 2.98 (m, 4H), 2.69 - 2.66 (m, IH), 2.00 - 2.12 (m, IH), 1.37 (s, 9H); LC/MS (ESI, m/z): [M +1]+ = 526.55.

[003823] Stepty_22Y!(ldi/1122172Amlnoe7T0>2dfdlK20}L!lL\d)a1nlnoj21^^

9-71)niperidine- 2,6-dione

[003824] To a solution of tert-butyl N-[2-[2-[2-[[9-(2,6-dioxo piperidyl)pyrido[2,3b]indol yl]amino] ethoxy] ethoxy] ethyl ]carb am ate (20.0 mg, 38.0 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 2 mL). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in 7acuo to gi7e the title compound (17.5 mg, 100% yield, HC1) as a white solid. LC-MS (ESI+) m/z 426.2 (M+H)+.

[003825] 3-[4-[3-[2-(2-aminoethoxv)ethoxv]DroDvl] methyl oxo-benzimidazol-lvl]-l-methvl-DiDeridine-2,6-dione (Intermediate SV)

1248

Mel, K2CO3

4A MS, DMF

NHBoc

Pd(PPH3)2CI2, Cui, Cs2CO3, 4A MS, DMF

HCl/dioxane

DCM

SV

[003826] Step 1 - 3-(4-Bromo methyl oxo-benzimidazol-l-yl)-l-methyl-piperidine-2,6di one

[003827] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (4.00 g, 11.8 mmol, Intermediate HP) and 4A molecular sieves (300 mg) in DMF (40 mL) was added Mel (1.68 g, 11.8 mmol) and K2CO3 (1.63 g, 11.8 mmol). The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (3.70 g, 89% yield) as a white solid. IH NMR (400 MHz, DMSO&#1470;d6) δ 7.24 (d, J = 8.0 Hz, IH), 7.17 (d, J = 7.8 Hz, IH), 7.00 - 6.94 (m, IH), 5.46 (dd, J = 5.2, 12.8 Hz, IH), 3.63 (s, 3H), 3.03 (s, 3H), 3.00 - 2.90 (m, IH), 2.83 - 2.66 (m, 2H), 2.08 - 1.97 (m, IH).

[003828] Step 2 - Tert-butyl N-r2-r2-r3-r3-methyl-l-(l-methyl-2,6-dioxo piperidyl)-2oxo-benzimidazol yl]prop ynoxy]ethoxy]ethyl]carbamate

[003829] A mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)-l-methylpiperidine-2,6-dione (800 mg, 2.27 mmol), tert-butyl N-[2-(2-prop-2

1249 ynoxyethoxy)ethyl]carbamate (1.38 g, 5.68 mmol, synthesized via Step 1 of Intermediate CQ), Pd(PPh3)2C12 (319 mg, 454 umol), Cui (86.5 mg, 454 umol), Cs2CO3 (3.70 g, 11.4 mmol), and 4A molecular sieve (800 mg) in DMF (40 mL) was de-gassed and then heated at 80 °C for 2 hrs under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (650 mg, 45% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-76) δ 7.18 (d, J = 7.6 Hz, IH), 7.13 (d, J= 7.2 Hz, IH), 7.05 - 6.98 (m, IH), 6.82 - 6.75 (m, IH), 5.51 - 5.43 (m, IH), 4.46 (s, 2H), 3.67 - 3.64 (m, 2H), 3.64 (s, 3H), 3.57 - 3.54 (m, 2H), 3.47 - 3.42 (m, 2H), 3.10 - 3.06 (m, 2H), 3.03 (s, 3H), 2.99 - 2.90 (m, IH), 2.79 - 2.63 (m, 2H), 2.06 - 1.92 (m, IH), 1.36 (s, 9H); LC-MS (ESI+) m/z 537.3 (M+Na)+.

[003830] Step 3 - Tert-butyl N-r2-r2-r3-r3-methyl-l-(l-methyl-2,6-dioxo piperidyl)-2oxo-benzimidazol yl1propoxy1ethoxy1ethyl1carbamate

[003831] To a solution of tert-butyl N-[2-[2-[3-[3-methyl-l-(l-methyl-2,6-dioxo-3piperidyl) oxo- benzimidazol yl]prop ynoxy]ethoxy]ethyl]carbamate (1.30 g, 2.02 mmol) in THF (20 mL) was added Pd/C (300 mg, 10% wt) and Pd(OH)2/C (300 mg, 10% wt). The reaction mixture was stirred at 25 °C for 10 hrs under H2 (15 psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.30 g, 99% yield) as a yellow solid. LC-MS (ESI+) m/z 541.3 (M+Na)+.

[003832] Step 4 - 3-r4-r3-r2-(2-Aminoethoxy)ethoxy1propyl1 methyl oxobenzimidazol-l-yl1-l-methyl- piperi dine-2,6-di one

[003833] To a solution of tert-butyl N-[2-[2-[3-[3-methyl-l-(l-methyl-2,6-dioxo-3piperidyl) oxo- benzimidazol yl]propoxy]ethoxy]ethyl]carbamate (1.20 g, 1.85 mmol) in DCM (10 mL) was added HCl/dioxane (10 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (1.10 g, 98% yield, HCI salt) as a yellow solid. LC-MS (ESI+) m/z 419.2 (M+H)+

[003834] Tertbutyl N-methvl-N-[3-(2-DiDerazin-l-vlethoxv)cvclobutyl1carbamate (Intermediate SW)

1250

MsCI, Et3N

DCM

Pd/C, H2 MeOH sw

[003835] Step 1 - Ethyl 2-r3-rtert-butoxycarbonyl(methyl)amino1cyclobutoxy1acetate [003836] To a solution of ethyl 2-[3-(tert-butoxycarbonylamino)cyclobutoxy]acetate (5.00 g, 18 mmol, synthesized via Step 1 of Intermediate SJ) in DMF (50 mL) at 0 °C was added NaH (1.50 g, 36 mmol, 60% oil dispersion) and stirred at 0 °C for 0.5 hour. Then a solution of CH3I (3.10 g, 22 mmol) in DMF (5 mL) was added to the reaction mixture and stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched by H2O (20 mL) at 0 °C, and then extracted with ethyl acetate (2 X 20 mL). The combined organic layers were washed with brine (2 X 25 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (5.00 g, 95% yield) as yellow oil. 1H NMR (400MHz, DMSO4) δ 4.66 - 4.59 (m, IH), 4.29 - 4.00 (m, 5H), 2.73 (s, 3H), 2.33 - 2.28 (m, 2H), 2.15 - 2.07 (m, 2H), 1.38 (s, 9H), 1.22 - 1.16 (m, 3H).

[003837] Step 2 - Tert-butyl N-r3-(2-hydroxyethoxy)cvclobutvl1-N-methyl-carbamate

[003838] To a solution of ethyl 2-[3-[tertbutoxycarbonyl(methyl)amino]cyclobutoxy]acetate (2.50 g, 8.7 mmol) in THF (30 mL) was added LiBH4 (0.57 g, 26mmol) at 0 °C, then the reaction mixture was stirred at 25 °C for 2 hour. On completion, the reaction mixture was quenched by water (20 mL) at 25 °C, and then extracted with ethyl acetate (2 X 30 mL). The combined organic layers were washed with brine (2 X 40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.00 g, 93% yield) as colorless oil.

[003839] Step 3 - 2-r3-rTert-butoxycarbonyl(methyl)amino1cyclobutoxy1ethyl

1251 methanesulfonate

[003840] To a solution of tert-butyl N-[3-(2-hydroxyethoxy)cyclobutyl]-N-methylcarbamate (2.00 g, 8.20 mmol) andEt3N (1.7 g, 16 mmol) in DCM (20 mL) was added MsCl (1.40 g, 12 mmol), then the reaction mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched by water (25 mL) at 25 °C, and extracted with DCM (2 X 30 mL). The combined organic layers were washed with brine (2 X 40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.50 g, 94% yield) as colorless oil.

[003841] Step 4:Benzyl 4-[2-Γ3-Γ&#912;61&#912;butoxycarbonyl(methyl)amino1cyclobutoxy1ethyl1piperazine-1 - carboxylate

[003842] To a solution of 2-[3-[tert-butoxycarbonyl(methyl)amino]cyclobutoxy]ethyl methanesulfonate (2.50 g, 7.70 mmol) and benzyl piperazine carboxylate (3.40 g, 15.0 mmol) in ACN (30 mL) was added Et3N (2.4 g) and KI (1.50 g, 9.3 mmol), then the reaction mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (0.60 g, 16% yield) as a white solid. LC-MS (ESI+) m/z 448.1 (M+H)+.

[003843] Step 5 - Tertbutyl N-methyl-N-r3-(2-piperazin-l-ylethoxy)cvclobutyl1carbamate

[003844] To a solution of benzyl 4-[2-[3-[tertbutoxycarbonyl(methyl)amino]cyclobutoxy]ethyl]piperazine-l- carboxylate (0.60 g, 1.3 mmol) in MeOH (5 mL) was added Pd/C (60 mg, 10% wt), then the mixture was degassed and purged with H2 gas three times. The mixture was stirred at 25 °C for 2 hours under H2 atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (0.40 g, 95% yield) as colorless oil.

[003845] 3-[3-Methvl [[4-[2-[3-(methvlamino)cvclobutoxv]ethyl]DiDerazin-lyl]methyl] oxo- benzimidazol-l-yl]DiDeridine-2.,6-dione (Intermediate SX)

1252

SW

[003846] Step 1 - Tert-butyl N-r3-r2-r4-rr1-(2»dioxo piperidvl) methyl oxobenzimidazol yl1 methyl1piperazin-l-yl1ethoxy1cyclobutyl1-N-methyl-carbamate

[003847] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-5carbaldehyde (0.15 g, 0.52 mmol, Intermediate SK) and tertbutyl N-methyl-N-[3-(2-piperazin-lylethoxy)cyclobutyl] carbamate (0.16 g, 0.52 mmol, Intermediate SW) in a mixed solvent of THF (2 mL) and DMF (2 mL) was added Ti(i-PrO)4 (0.22 g, 0.78 mmol) and stirred at 50 °C for 4 hour, then NaBH(OAc)3 (0.22 g, 1.0 mmol) was added at 25 °C. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% TFA condition) to give the title compound (40.0 mg, 8.7% yield) as colorless oil. LC-MS (ESI+) m/z 585.4 (M+H)+.

[003848] Step 2 - 3-r3-Methyl rr4-r2-r3-(methylamino)cyclobutoxy1ethyl1piperazin-lyl1methyl1 oxo- benzimidazol-l-yl1piperidine-2,6-dione

[003849] To a solution of tert-butyl N-[3-[2-[4-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl]piperazin-l-yl]ethoxy]cyclobutyl]-N-methyl-carbamate (30.0 mg, 51.3 umol) in TFA (1.5 mL) was added DCM (2 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (30.7 mg, 100% yield) as yellow oil. LC-MS (ESI+) m/z 485.3 (M+H)+.

[003850] Tert-butyl N-(4-but ynoxybutyl)carbamate (Intermediate SY)

1253

(Boc)2O

MeOH

SY

[003851] Step 1 - l-bromo but ynoxy-butane

[003852] A mixture of but yn-l-ol (40 g, 571 mmol, 43.2 mL, CAS# 927 2), 1,4dibromobutane (185 g, 856 mmol, 103 mL, CAS# 110 1), Cs2CO3 (204 g, 627 mmol) in acetone (500 mL) was degassed and purged with N2 for 3 times. Then the mixture was stirred at 70 °C for 72 hrs under N2 atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (40.0 g, 34% yield) as colorless oil. 1H NMR (400MHz, CDC13) δ 3.57 (t, J = 6.8 Hz, 2H), 3.52 (t, J = 6.2 Hz, 2H), 3.49 - 3.45 (m, 3H), 2.48 (dt, J = 2.8, 6.8 Hz, 2H), 2.08 - 2.04 (m, IH), 2.03 - 1.96 (m, 2H), 1.80 - 1.71 (m, 2H).

[003853] Step 2 - 2-(4-But vnoxybutvl)isoindoline-L3-dione

[003854] To a solution of l-bromo but ynoxy-butane (27.0 g, 131 mmol) in DMF (300 mL) was added (l,3-dioxoisoindolin yl)potassium (29.3 g, 158 mmol). The mixture was stirred at 60 °C for 6 hrs. On completion, 1500 mL H2O was added to the mixture, and the mixture was extracted with EA (2 X 800 mL). The organic layer was washed with brine (300 mL), and then concentrated in vacuo to give the title compound (30.0 g, 84% yield) as white solid. 1H NMR (400MHz, CDCh) δ 7.87 - 7.83 (m, 2H), 7.75 - 7.70 (m, 2H), 3.73 (t, J = 7.2 Hz, 2H), 3.53 (td, J = 6.8, 19.2 Hz, 4H), 2.45 (dt, J = 2.8, 7.2 Hz, 2H), 1.98 (t, J = 2.8 Hz, IH), 1.83 - 1.71 (m, 2H), 1.69- 1.59 (m, 2H).

[003855] Step 3 - 4-But ynoxybutan-l-amine

[003856] To a solution of 2-(4-but ynoxybutyl)isoindoline-l,3-dione (50.0 g, 184 mmol)

1254 in EtOH (1000 mL) was added ΝΗ2ΝΗ2&#905;2Ο (92.3 g, 1.84 mol, 89.6 mL). The mixture was stirred at 80 °C for 4 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (21.0 g, 31% yield) as colorless oil. 1HNMR (400MHz, CDCh) δ 3.49 (t, J = 7.2 Hz, 2H), 3.43 - 3.38 (m, 2H), 2.65 (t, J= 7.2 Hz, 2H), 2.39 (dt, J= 2.8, 6.8 Hz, 2H), 1.91 (t, J= 2.8 Hz, IH), 1.89 (s, 2H), 1.60 - 1.52 (m, 2H), 1.49 - 1.40 (m, 2H).

[003857] Step 4 - Tert-butyl N-(4-but ynoxybutyl)carbamate

[003858] To a solution of 4-but ynoxybutan-l-amine (30.0 g, 212 mmol) in MeOH (300 mL) was added (Boc)2O (69.6 g, 318 mmol, 73.2 mL). The mixture was stirred at 25 °C for 4 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (50.0 g, 97% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 4.68 (s, IH), 3.57 (t, J= 6.8 Hz, 2H), 3.49 (t, J= 6.0 Hz, 2H), 3.20 - 3.11 (m, 2H), 2.48 (dt, J= 2.8, 6.8 Hz, 2H), 1.99 (t, J= 2.8 Hz, IH), 1.68 - 1.59 (m, 4H), 1.46 (s, 9H).

[003859] 3-[3-methvl [3-[(2R) (methvlaminomethvl)morDholin vl]DroDvl] oxobenzimidazol-l-yl]DiDeridine-2,6-dione (Intermediate SZ)

TO

Pd(PPh3)2CI2, Cui, Cs2CO3, MS-4A, DMF

Pd(OH)2/C, Pd/C, H2, , (Boc)2O

EA/IPA

HCI/dioxane

DCM

3-Γ5-Γ3-Γ (2R) [r(4-methoxyphenyl)m ethyl-methyl1255 amino1methyl1morpholin yl1prop-ldi one

[003861] To a solution of l-(4-methoxyphenyl)-N-methyl-N-[[(2R) prop-2ynylmorpholin yl]methyl] methanamine (900 mg, 3.12 mmol, Intermediate TO) and 3-(5bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6 -dione (703 mg, 2.08 mmol, Intermediate HN) in DMF (20 mL) was added 4A molecular sieves (300 mg), Pd(PPh3)2C12 (146 mg, 208 umol), Cs2CO3 (2.71 g, 8.32 mmol) and Cui (39.6 mg, 208 umol). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.10 g, 96% yield) as a yellow solid. LC-MS (ESI+) m/z 546.4 (M+H)+.

[003862] Step 2 - Tert-butyl N-rr(2S) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1-N-methyl-carbamate

[003863] To a solution of 3-[5-[3-[(2R) [[(4-methoxyphenyl)methyl-methylamino]methyl]morpholin yl] prop-l-ynyl] methyl oxo-benzimidazol-l-yl]piperidine-2,6dione (500 mg, 916 umol) in IPA (15 mL) and EA (30 mL) was added Pd(OH)2/C (200 mg, 10 wt%), Pd/C (200 mg, 10 wt%) and (Boc)2O (300 mg, 1.37 mmol, 315 uL). The reaction mixture was stirred at 25 °C for 48 hr under H2 (50 psi). On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (300 mg, 62% yield) as a yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 11.08 (s, IH), 7.08 - 6.93 (m, 2H), 6.86 (d, J = 8.0 Hz, IH), 5.75 (s, IH), 5.33 (dd, J= 5.2, 12.8 Hz, IH), 3.63 - 3.56 (m, 4H), 3.52 - 3.46 (m, 2H), 3.31 (s, 3H), 3.26 - 3.12 (m, 3H), 2.93 - 2.85 (m, IH), 2.72 - 2.58 (m, 6H), 2.07 - 1.96 (m, 2H), 1.81-1.69 (m, 3H), 1.37 (s, 9H); LC-MS (ESI+) m/z 530.3 (M + H)+.

[003864] Step 3 - 3-r3-Methyl r3-r(2R) (methylaminomethyl)morpholin yl1propyl1-2oxo-benzimidazol -l-yl1piperidine-2,6-dione

[003865] To a solution of tert-butyl N-[[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]-N-methyl-carbamate (300 mg, 566 umol) in DCM (8 mL) was added HCI/dioxane (4 M, 4 mL). The reaction mixture was stirred at 25 °C for 2 hr. On completion, the mixture was concentrated in vacuo to give the title compound (260 mg, 98% yield, HCI) as a white solid. LC-MS (ESI+) m/z 430.2 (M+H)+.

1256

[003866] tert-butyl 4-[3-[[3-(difluoromethvl)-l-(4-formylDhenvl)Dvrazol-4vl]carbamoyl]Dvrazolo[l.,5-a]Dvrimidin vl]DiDerazine-l-carboxvlate (Intermediate TA)

4-r3&#1470;rr3-(difluoromethyl)-l-(4 methoxycarbonylphenyl)pyrazol yl1carbamoyl1 pyrazolorL5-a1pyrimidin yl1piperazine-l

1257 carboxylate

[003868] To a solution of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (650 mg, 2.43 mmol, Intermediate FW), 5-(4-tertbutoxycarbonylpiperazin-l-yl)pyrazolo[l,5a]pyrimidine carboxylic acid (650 mg, 1.87 mmol, Intermediate RC) in ACN (15.0 mL) was added DIPEA (725 mg, 5.61 mmol), HATU (1.42 g, 3.74 mmol). The mixture was stirred at 60 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (700 mg, 62% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 9.60 (s, IH), 9.05 (s, IH), 8.48 (s, IH), 8.38 (d, J = 8.0 Hz, IH), 8.17 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.09 - 6.76 (m, IH), 6.46 (d, J = 8.0 Hz, IH), 3.96 (s, 3H), 3.86 (s, 4H), 3.65 (s, 4H), 1.54 (s, 9H).

[003869] Step 2 - 4-r4-rr5-(4-Tert-butoxycarbonylpiperazin-l-yl)pyrazolo[L5-a1pyrimidine3-carbonyl1amino1 (difluoromethyl)pyrazol-l-yl1benzoic acid

[003870] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-(4methoxycarbonylphenyl)pyrazol yl] carbamoyl]pyrazolo[l,5-a]pyrimidin yl]piperazine-lcarboxylate (1.00 g, 1.68 mmol) in THF (40.0 mL) and H2O (8 mL) was added LiOH (200 mg, 8.38 mmol). The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was diluted with H2O (30 mL), then the mixture was acidified with IN HC1 solution until the pH = 5. The mixture was filtered and the filter cake was dried in vauco to give the title compound (900 mg, 92% yield) as yellow solid. 1H NMR (400MHz, DMSOd6) δ 12.01 (s, IH), 9.48 (s, IH), 9.08 (s, IH), 8.82 (d, J = 8.0 Hz, IH), 8.32 (s, IH), 8.07 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 7.52 - 7.16 (m, IH), 6.89 (d, J = 8.0 Hz, IH), 3.82 (s, 4H), 3.50 (s, 4H), 1.44 (s, 9H).

[003871] Step 3:Tert-butyl 4-r3-r[3-(difluoromethyl)-l-(4isopropoxycarbonyloxycarbonylphenyl) yllpiperazine-1 -carboxylate

[003872] To a solution of 4-[4-[[5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[l,5a]pyrimidine carbonyl] amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (900 mg, 1.54 mmol), TEA (625 mg, 6.18 mmol) in THF (30.0 mL) was added isopropyl carbonochloridate (473 mg, 3.86 mmol) at -10 °C. The mixture was stirred at -10 °C for 1 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.00 g, 90% yield) as yellow solid. LC-MS (ESI+) m/z 669.2 (M+H)+.

1258

[003873] Step 4:Tert-butyl 4-r3-rr3-(difluoromethyl)-l-[4(hydroxymethyl)phenyl1pyrazol yl1carbamoyl1 carboxylate

[003874] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-(4isopropoxycarbonyloxycarbonylphenyl) pyrazol yl]carbamoyl]pyrazolo[l,5-a]pyrimidin-5yl]piperazine-l-carboxylate (1.00 g, 1.50 mmol) in THF (50.0 mL) and H2O (10.0 mL) was added LiBH4 (195 mg, 8.97 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was quenched with H2O (10 mL), then extracted with DCM (2 X 30 mL). The organic layers were dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was triturated with DCM (5 mL) to give the title compound (700 mg, 82% yield) as yellow solid. 1H NMR (400MHz, DMSO4) δ 9.49 (s, IH), 8.98 (s, IH), 8.85 (d, J = 8.0 Hz, IH), 8.33 (s, IH), 7.80 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.34 - 6.96 (m, IH), 6.91 (d, J = 8.0 Hz, IH), 5.35 - 5.24 (m, IH), 4.56 (d, J = 4.4 Hz, 2H), 3.84 (s, 4H), 3.50 (s, 4H), 1.45 (s, 9H).

[003875] Step 5 - Tert-butyl 4-r3-rr3-(difluoromethyl)-l-(4-formylphenyl)pyrazol-4yllcarbamoyllpyrazolo rL5-a1pyrimidin yl1piperazine-l-carboxylate

[003876] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-[4(hydroxymethyl )phenyl]pyrazol yl] carbamoyl]pyrazolo[l,5-a]pyrimidin yl]piperazine-lcarboxylate (700 mg, 1.23 mmol) in THF (30.0 mL) was added DMP (626 mg, 1.48 mmol). The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was quenched with saturated Na2S2O3 (30 mL) and washed with saturated NaHCO3 (2 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (680 mg, 90% yield) as yellow solid. 1HNMR (400MHz, DMSO4) δ 10.04 (s, IH), 9.52 (s, IH), 9.17 (s, IH), 8.86 (d, J = 8.0 Hz, IH), 8.35 (s, IH), 8.15 - 8.10 (m, 2H), 8.09 - 8.03 (m, 2H), 7.54 - 7.23 (m, IH), 6.96 - 6.86 (m, IH), 3.85 (s, 4H), 3.51 (s, 4H), 1.45 (s, 9H).

[003877] NffLj^NJJ.dLh^DioxmUjiillLLidvlliUiiietJiyLNoxmbenziiiHdazoLS;

1259 yl] vinyl oxy] ethyl methanesulfonate (Intermediate TB)

P(t-bu)3, Pd2(dba)3, dioxane, DIPEA

MsCI, TEA

DCM

[003878] Step 1 - 3-r5-r(E) (2-Hydroxyethoxy)vinyl] methyl oxo-benzimidazol-lyl]piperidine-2,6-dione

[003879] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (1.00 g, 2.96 mmol, Intermediate HN), 2-vinyloxyethanol (782 mg, 8.88 mmol, CAS# 76448-7) in dioxane (25 mL) was added P(t-Bu)3 toluene solution (2.08 mL, 591 umol, 10 wt%), Pd2(dba)3 (542 mg, 591 umol) and DIPEA (497 mg, 3.84 mmol) under N2. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column to give the title compound (500 mg, 49% yield) as yellow solid. 1H NMR (400MHz, DMSOY) δ 11.08 (s, IH), 7.25 - 7.19 (m, IH), 7.19 - 7.09 (m, IH), 6.99 (d, J= 8.4 Hz, IH), 6.95 - 6.90 (m, IH), 6.35 (d, J = 7.2 Hz, IH), 5.88 (d, J = 12.8 Hz, IH), 5.38 - 5.29 (m, IH), 5.25 (d, J = 7.2 Hz, IH), 3.99 - 3.83 (m, IH), 3.85 (t, J = 52 Hz, IH), 3.69 - 3.61 (m, 2H), 3.39 (s, 3H), 2.97 - 2.82 (m, IH), 2.66 - 2.58 (m, IH), 2.53 (d, J = 1.6 Hz, IH), 2.06 - 1.99 (m, IH).

[003880] Ste2_^_^^YJj(E)222]4Y2i62Di02i02322i2eridyl)232n1ethyl-2202i02benzimidaz01-52 yl]vinyloxy]ethyl methanesulfonate

[003881] To a solution of 3-[5-[(E) (2-hydroxyethoxy)vinyl] methyl oxobenzimidazol-l-yl]2i2eridine-2,6-dione (750 mg, 2.17mmol) in DCM (100 mL) was added TEA (659 mg, 6.52 mmol) and MsCI (373 mg, 3.26 mmol) at 0 °C. The reaction mixture was stirred at

1260 °C for 2 hours. On completion, the reaction mixture was poured into water (30 mL) and extracted with DCM (2 X 100 mL). The combined organic layers were washed with brine (80 mL) and sat. aq. NaHCO3 (2 X 70 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (800 mg, 70% yield, 75% purity) as a brown solid. LC-MS (ESI+) m/z 423.9 (M+H)+.

[003882] 3-[5-[2-[2-[(2S) (Aminomethvl)morpholin vl]ethoxy]ethvl] methvl-2oxo-benzimidazol-l-yl]piperidine-2,6-dione (Intermediate TC)

Pd(OH)2/C, Pd/C, H2

THF

[003883] Step 1 - Tert-butylN-rr(2S) r2-r(E) r1-(2,6-dioxo piperidyl) methyl-2 oxo-benzimidazol yl1 vinyl 0xy1ethyl1m0rph0lin yl1methyl1carbamate

[003884] To a solution of 2-[(E) [l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]vinyloxy]ethyl methanesulfonate (350 mg, 827 umol, Intermediate TB), tert butyl N-[[(2R)-morpholin yl]methyl]carbamate (268 mg, 1.24 mmol, CAS# 186202 3) in DMF (5 mL) was added DIPEA (320 mg, 2.48 mmol) at 20 °C. The mixture was stirred at 110 °C for 1 hour. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (reverse phase: 0.1% FA) to give the title compound (270 mg, 60% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.28 (s, IH), 6.97 - 6.82 (m, 2H), 6.82 - 6.69 (m, IH), 6.12 (d,

1261

J = 7.2 Hz, IH), 5.95 (d, 7=12.8 Hz, IH), 5.43 (d, 7= 7.1 Hz, IH), 5.26 - 5.18 (m, IH), 4.89 (s, IH), 4.39 - 4.18 (m, 2H), 4.06 (d, 7= 7.2 Hz, 2H), 3.98 - 3.87 (m, IH), 3.68 - 3.54 (m, 2H), 3.46 3.43 (m, 3H), 3.41 - 3.36 (m, 2H), 3.33 - 3.24 (m, 2H), 2.99 - 2.91 (m, 2H), 2.87 - 2.81 (m, IH), 2.79 - 2.75 (m, IH), 2.74 - 2.68 (m, IH), 2.31 - 2.21 (m, IH), 1.47 (s, 9H).

[003885] Step 2 - Tert-butyl N-[[(2S) [2-[2-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 ethoxy1ethyl1morpholin yl1methyl1carbamate

[003886] To a solution of tert-butyl N-[[(2S) [2-[(E) [l-(2,6-dioxo piperidyl)-3methyl oxo -benzimidazol yl]vinyloxy]ethyl]morpholin yl]methyl]carbamate (270 mg, 496 umol) in THF (20 mL) was added Pd/C (50.0 mg, 10 wt%) and Pd(OH)2/C (50.0 mg, 10 wt%) at 25 °C. The mixture was stirred at 25 °C for 2 hours under H2 (15 psi). On competion, the mixture was filtered. The filtrate was concentrated in vacuo. The mixture was purified by prep-HPLC (reverse phase: 0.1%FA) to give the title compound (150 mg, 30% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 7.09 (s, IH), 7.04 - 6.94 (m, 2H), 6.65 (s, IH), 5.37 5.33 (m, IH), 3.68 (s, 3H), 3.65 - 3.59 (m, 4H), 3.34 (s, 3H), 3.04 - 2.93 (m, 4H), 2.91 - 2.79 (m, 4H), 2.75 - 2.70 (m, IH), 2.66 - 2.61 (m, IH), 2.55 - 2.53 (m, IH), 2.04 - 1.96 (m, IH), 1.78 - 1.75 (m, 2H), 1.36 (s, 9H).

[003887] Step 3 - 3-[5-[2-[2-[(2S) (Aminomethyl)morpholin yl1ethoxy1ethyl1-3methyl oxo -benzimidazol-l-yl1piperidine-2,6-dione

[003888] To a solution of tert-butyl N-[[(2S) [2-[2-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]ethoxy]ethyl]morpholin yl]methyl]carbamate (100 mg, 184 umol) in DCM (2 mL) was added TFA (1 mL) at 15 °C. The mixture was stirred at 15 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (80.0 mg, 98% yield, TFA salt) as a white solid. LC-MS (ESI+) m/z 446.3 (M+H)+.

[003889] 3-[6-[3-[2-[2-(MethvIamino)ethoxy|ethoxv|propvI] oxo-l.,3-benzoxazoI-3yl] piperidine- 2.,6-dione (Intermediate TF)

1262

Pd/C, Pd(OH)2/C, H2

THF

TFA

DCM

[003890] Step 1 - Tert-butyl N-r2-r2-r3-r3-(2,6-dioxo piperidvl) oxo-L3-benzoxazol-6vl1prop ynoxy1 ethoxy1ethyl1-N-methyl-carbamate

[003891] A mixture of tert-butyl N-methyl-N-[2-(2-prop ynoxyethoxy)ethyl]carbamate (427 mg, 1.66 mmol, Intermediate FY), 3-(6-bromo oxo-l,3-benzoxazol yl)piperidine-2,6dione (300 mg, 923 umol, Intermediate OZ), 4A molecular sieves (40 mg), Pd(PPh3)2C12 (129 mg, 185 umol), Cui (35.2 mg, 184 umol) and Cs2CO3 (1.50 g, 4.61 mmol) in DMF (10 mL) was de-gassed and then heated at 80 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (280 mg, 61% yield) as yellow oil. LC-MS (ESI+) m/z 524.3 (M+Na)+.

[003892] Step 2 - Tert-butyl N-r2-r2-r3-r3(2,6-dioxo piperidvl) oxo-L3-benzoxazol-6yl1propoxy1ethoxy1 thyl1-N-methyl-carbamate

[003893] To a solution of tert-butyl-[2-[2-[3-[3-(2,6-dioxo piperidyl) xo-l,3benzoxazol l]prop noxy]ethoxyethyl]-N-methyl-carbamate (280 mg, 558 umol) in THF (20 mL) was added Pd/C (50 mg, 10% wt) and Pd(OH)2/C (50 mg, 10% wt) under N2 atmosphere. The

1263 suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred at 25 °C for 4 hrs under H2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (150 mg, 53% yield) as yellow oil. 1HNMR (400 MHz, DMSO-i/6) δ 11.19 (s, IH), 7.25 - 7.23 (m, IH), 7.15 -7.11 (m, IH), 7.03 (d, J = 7.6 Hz, IH), 5.34 (dd, J = 5.2, 12 Hz, IH), 3.5 - 3.48 (m, 4H), 3.42 - 3.39 (m, 2H), 3.37 3.35 (m, 3H), 3.31 - 3.27 (m, 4H), 2.81 - 2.80 (m, 2H), 2.69 - 2.61 (m, IH), 2.63 - 2.61 (m, 2H), 2.13 - 2.10 (m, IH), 1.80 - 1.75 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 528.3 (M+Na)+.

[003894] Step 3 - 3-r6-r3-r2-r2-(Methylamino)ethoxy1ethoxy1propyl1 oxo-L3benzoxazol yl1piperidine- 2,6-dione

[003895] To a solution of tert-butyl N-[2-[2-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] ethoxy]ethyl]-N-methyl-carbamate (140 mg, 277 umol) in DCM (3 mL) was added TFA (2 mL). The mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo to give the title compound (11.9 mg, 39% yield) as white solid. LC-MS (ESI+) m/z 406.2 (M+H)+.

[003896] 3- [6- [3- [3-(Methvlamino)propoxy] propyl] pyrido [2.,3-b] indol yl] piperidine-

1264

[003897] Step 1 - tert-butyl (3-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3-b1indol-6yl)prop yn-l-yl)oxy)propyl)(methyl)carbamate

[003898] A mixture of 3-(6-bromo-9H-pyrido[2,3-b]indol yl )piperi dine-2,6-dione (100 mg, 0.279 mmol, Intermediate UH), tert-butyl methyl(3-(prop yn-l-yloxy)propyl)carbamate (190 mg, 0.838 mmol, Intermediate UI), Pd(PPh3)2C12 (30 mg, 0.0419 mmol), Cui (4 mg, 0.0223 mmol), Cs2CO3 (455 mg, 1.40 mmol), 4A MS (200 mg) and DMF (5 mL) was heated to 80 °C under microwave for 1.5 h under N2. The mixture was then poured into IN HCI (20 mL), then extracted with EA (3 x 20 mL). The organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography on silica gel (PE/EA = 10/1 to 5/1 to 2/1) to give the title compound (50 mg, 35% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 8.57 (d, J = 7.2 Hz, IH), 8.46 (dd, J = 1.2 Hz, J = 5.6 Hz, IH), 8.25 (d, J = 1.2 Ηζ,ΙΗ), 8.13 (s, IH), 7.65 (dd, J= 1.6 Hz, J = 4.0 Hz, IH), 7.25-7.19 (m, 2 H), 5.90 (dd, J = 2.8 Hz, J= 6.0 Hz, IH), 4.41 (s, 2H), 3.63 (t, J= 6.4 Hz, 2H), 3.34 (t, J= 7.2 Hz, 2H), 3.02-2.91 (m, 3H), 2.89 (s, 3H), 2.50-2.47 (m, IH), 1.88 (t, J= 6.8 Hz, 2H), 1.46 (s, 9H). LC/MS (ESI, m/z(. [M +l]+ = 505.2.

[003899] Step 2 - tert-butyl (3-(3-(9-(2,6-di oxopiperi din vl)-9H-pvridor2,3-b1indol-6yl)propoxy)propyl)(methyl)carb amate

[003900] A mixture of tert-butyl (3-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3-b]indol6-yl)prop yn-l-yl)oxy)propyl)(methyl)carbamate (320 mg, 0.634 mmol), Pd/C (320 mg) and EA (10 mL) was stirred for overnight at rt under H2. The mixture was filtered, concentrated and purified by column (PE/EA = 1/1) to give the title product (170 mg, 53 % yield) as a white solid. 1HNMR (400 MHz, CDCh) δ 8.41 (dd, J= 1.6 Hz, J= 4.8 Hz, IH), 8.32 (d, J= 7.6 Hz, IH), 8.15 (s, IH), 7.91 (d, J = 0.8 Hz, IH), 7.33 (dd, J = 1.2 Hz, J = 8.0 Hz, IH), 7.22-7.16 (m, 2H), 5.94 (br s, IH), 3.45 (dd, J= 6.4 Hz, J= 11.6 Hz, 4H), 3.13 (t, J = 5.8 Hz, 2H), 3.07-2.95 (m, 3H), 2.882.84 (m, 5H), 2.33-2.29 (m, IH), 2.01-1.93 (m, 2H), 1.85-1.78 (m, 2H), 1.46 (s, 9H). LC/MS (ESI, mzy. [M -BOC+H]+ = 409.2 and [M-56+H] = 453.2.

[003901] Step 3 - 3-r6-r3-r3-(Methylamino)propoxy1propyl1pyridor2,3-b1indol-9vl1piperidine-2,6-dione

[003902] To a solution of tert-butyl N-[3-[3-[9-(2,6-dioxo piperidyl)pyrido[2,3-b]indol-6yl]propoxy]propyl]- N-methyl-carbamate (85.0 mg, 167 umol) in DCM (6 mL) was added TFA (381 mg, 3.34 mmol). The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction

1265 mixture was concentrated in vacuo to give the title compound (87 mg, 95% yield, TFA salt) as light yellow oil. LC-MS (ESI+) m/z 409.3 (M+H)+.

[003903] 2-(2-Pr0D vn0xveth0xv)ethyl 4-methylbenzenesulfonate (Intermediate TI) / TsCI, TEA, DMAP χχ toAx/X/x+H ---------&#9658; ^^0^^ /x^OTs

DCM LC TI

[003904] To a solution of 2-(2-prop ynoxyethoxy)ethanol (2.00 g, 13.8 mmol, Intermediate LC), TEA (4.21 g, 41.6 mmol) and DMAP (170 mg, 1.39 mmol) in DCM (60 mL) was added 4methylbenzenesulfonyl chloride (5.29 g, 27.7 mmol) at 0 °C. The mixture was then stirred at 25 °C for 16 hours. On completion, the mixture was washed with 2.0 M aq.HCl (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (3.40 g, 82% yield) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 7.81 (d, J= 8.4 Hz, 2H), 7.35 (m, J = 8.0 Hz, 2H), 4.23 - 4.14 (m, 4H), 3.73 - 3.68 (m, 2H), 3.67 - 3.59 (m, 4H), 2.46 (s, 3H), 2.44 (t, J= 2.4 Hz, IH).

[003905] N-[6-(l-hvdroxv-l-methvl-ethvl)-2H-indazol yl]-6(trifluoromethyl)Dvridine carboxamide (Intermediate TJ)

ΑΑτ&#902; °2Ν&#902;ν+ ΑχζΧ^χ &#1524; Ν ΗΝΟ3 Ι II Ν Fe, NH4CI TO&#1524;

MeO^AA &#1523; ---MeoA^A / -------- ΜβΟχΧΛ/ q H2SO4 11 H MeOH, THF, H2O Π &#1524;

[003906] Step 1 - Methyl 5-nitro-lH-indazole carboxylate

[003907] To a solution of methyl lH-indazole carboxylate (10.0 g, 56.7 mmol) in H2SO4 (100 mL) was added a solution of HNO3 (12.1 g, 125 mmol, 65% purity) in H2SO4 (20 mL) at 10-0°C during 30 minutes. The mixture was stirred at 0°C for 1 hour. On completion, the mixture was poured into ice/water (1.0 L) slowly. The mixture was filtered and the filter cake was washed with water (2 X 200 mL). Then the cake was collected and dried in vacuo to give the title

1266 compound (11.9 g, 94% yield) as yellow solid. 1H NMR (400 MHz, DMSO-76) δ 8.69 (s, IH), 8.44 (s, IH), 7.97 (s, IH), 3.86 (s, 3H).

[003908] Step 2 - Methyl 5-amino-lH-indazole carboxylate

[003909] To a solution of methyl 5-nitro-lH-indazole carboxylate (10.9 g, 49.2 mmol) in MeOH (100 mL) and THF (60 mL) was added a solution of NH4C1 (26.3 g, 492 mmol) in H2O (100 mL) at 25 °C. Then Fe (13.7 g, 245 mmol) was added to the mixture in portions at 70 °C, and the mixture was stirred at 70 °C for 1 hour. On completion, the mixture was filtered and the filter cake was washed with EA (200 mL). The filtrate was concentrated in vacuo. The residue was washed with water (100 mL), and extracted with EA (3 X 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to the title compound (7.30 g, 77% yield) as yellow solid. 1H NMR (400 MHz, DM SO-0/6) δ 12.82 (s, IH), 7.99 (s, IH), 7.85 (s, IH), 6.99 (s, IH), 6.00 (s, 2H), 3.85 (s, 3H).

[003910] Step 3 - Methyl 5-rr6-(trifluoromethyl)pyridine carbonyl1amino1-lH-indazole-6carboxylate

[003911] To a solution of methyl 5-amino-lH-indazole carboxylate (7.20 g, 37.6 mmol), 6-(trifluoromethyl)pyridine carboxylic acid (6.48 g, 33.9 mmol, CAS# 131747 7) and DIPEA (7.35 g, 56.8 mmol) in THF (70 mL) was added T3P (47.9 g, 44.8 mL, 50 wt%) slowly at 0 °C. Then the mixture was stirred at 0-5°C for 2 hours. On completion, the reaction was quenched with cold water (0.1 mL). The mixture was diluted with water (280 mL), and stirred at 25 °C for 0.5 hour. The mixture was filtered and the filter cake was washed with water (30 mL). The filter cake was collected and dried in vacuo to give the title compound (12.3 g, 99% yield) as yellow solid. 1HNMR (400 MHz, DM SO-0/6) δ 12.58 (s, IH), 9.15 (s, IH), 8.47 (d, J= 7.6 Hz, IH), 8.39 (t, J= 7.6 Hz, IH), 8.30 (s, IH), 8.25 (s, IH), 8.20 (d, J= 8.0 Hz, IH), 3.97 (s, 3H).

[003912] Step 4:N-[6-(T-hydroxy methyl-ethyl)-2H-indazol yl1-6(trifluoromethyl)pyridine carboxamide

[003913] To a solution of methyl 5-[[6-(trifluoromethyl)pyridine carbonyl]amino]-lHindazole carboxylate (4.00 g, 10.9 mmol) in THF (40 mL) was added MeMgBr-Et2O solution (3.0 M, 29.3 mL) slowly at 0°C. The mixture was stirred at 0 - 25 °C for 16 hours. On completion, the reaction was quenched with sat.NH4Cl (40 mL) slowly at 0 - 10 °C. The mixture was extracted with EA (3 X 40 mL). The combined organic layer was concentrated in vacuo. The residue was purified by reverse phase chromatography (FA condition) to give the title compound (1.50 g, 37%

1267 yield) as light yellow solid. 1H NMR (400 MHz, CDCh) δ 12.23 (s, IH), 8.96 (s, IH), 8.52 (d, J= 7.6 Hz, IH), 8.12 (t, J = 7.6 Hz, IH), 8.07 (s, IH), 7.85 (d, J= 7.6 Hz, IH), 7.50 (s, IH), 1.80 (s, 6H).

[003914] N-[6-(l-hvdroxv-l-methvl-ethvl) [2-(2-DroD vnoxvethoxv)ethvl1indazol-5vl1 (trifluoromethvl)Dvridine carboxamide (Intermediate TK)

(trifluoromethyl)pyridine carboxamide (300 mg, 823 umol, Intermediate TJ) and DIPEA (532 mg, 4.12 mmol) in toluene (10 mL) was added a solution of 2-(2-prop ynoxyethoxy)ethyl 4methylbenzenesulfonate (983 mg, 3.29 mmol, Intermediate ΤΙ) in toluene (5 mL) at 110 °C during 1 hour. Then, the mixture was stirred at 110 °C for 35 hours. On completion, after cooled to 25°C, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (130 mg, 32% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 12.26 (s, IH), 8.83 (s, IH), 8.47 (d, J = 8.0 Hz, IH), 8.08 (t, J = 8.0 Hz, IH), 8.00 (s, IH), 7.82 (m, J= 7.6 Hz, IH), 7.67 (s, IH), 4.57 (t, J= 5.2 Hz, 2H), 4.16 (d, J= 2.4 Hz, 2H), 3.97 (t, J= 5.2 Hz, 2H), 3.66 - 3.58 (m, 4H), 2.47 (t, J= 2.4 Hz, IH), 1.79 (s, 6H).

[003916] 3 13- [2-(2-Aminoethoxv)ethoxy| propyl] pyrido [2,3-b] indol yl] piperidine

2,6-dione (Intermediate TL)

1268

[003917] Step 1 - tert-butyl (2-(2-((3-(9-(2,6-di oxopiperi din vl)-9H-pvrido[2,3-b1indol-6yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate

[003918] A mixture of 3-(6-bromo-9H-pyrido[2,3-b]indol yl )piperi dine-2,6-dione (600 mg, 1.68 mmol, Intermediate UH), tert-butyl (2-(2-(prop yn-l-yloxy)ethoxy)ethyl)carbamate (1.2 g, 5.03 mmol, Intermediate IT), Pd(PPh3)2C12 (179 mg, 0.252 mmol), Cui (26 mg, 0.134 mmol), Cs2CO3 (55 g, 16.8 mmol), 4A MS (1 g) and DMF (10 mL) was heated to 80 °C under microwave for 1.5 h under N2. The mixture was then poured into IN HCI (400 mL), and extracted with EA (100 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column (PE/EA = 10/1 to 5/1 to 2/1) to give the title compound (250 mg, 29 % yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 8.45 (dd, J= 1.2 Hz, J= 4.8 Hz, IH), 8.34 (dd, J= 1.2 Hz, J= 7.6 Hz, IH), 8.21 (d, J= 0.8 Hz, IH), 8.15 (s, IH), 7.59 (dd, J= 1.2 Hz, 7= 8.4 Hz, IH), 7.27-7.22 (m, 2H), 5.95 (br s, IH), 5.01 (br s, 1 H), 4.47 (s, 2H), 3.81-3.79 (m, 2H), 3.71-3.69 (m, 2H), 3.58 (t, 7= 5.2 Hz, 2H), 3.33-3.34 (m, 2H), 3.09-2.96 (m, 2H), 2.352.31 (m, IH), 2.02-1.99 (m, IH), 1.44 (s, 9H). LC/MS (ESI, m/z); [M -Boc+1]+ = 421.3.

[003919] Step 2 - tert-butyl (2-(2-(3-(9-(2,6-di oxopiperi din yl)-9H-pyridor2,3-b1indol-6

1269 yl)propoxy)ethoxy)ethyl)carbamate

[003920] A mixture of tert-butyl (2-(2-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3b]indol yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate (250 mg, 0.481 mmol), Pd/C (100 mg) and EA (15 mL) was stirred for overnight at rt under H2. The mixture was filtered, concentrated and purified by column (PE/EA = 1/1) to give the title compound (150 mg, 60% yield) as a white solid. 1HNMR (400 MHz, CDCh) δ 8.41 (dd, J= 1.2 Hz, J= 4.8 Hz, IH), 8.31 (dd, J= 1.6 Hz, J = 7.6 Hz, IH), 8.22 (s, IH), 7.92 (d, J= 0.8 Hz, IH), 7.33 (dd, J = 1.6 Hz, J = 8.4 Hz, IH), 7.217.16 (m, 2H), 5.92-5.88 (m, IH), 5.04 (br s, IH), 3.64-3.50 (m, 8H), 3.33 (d, J= 4.8 Hz, 2H), 3.082.85 (m, 5H), 2.32-2.28 (m, IH), 2.04-1.97 (m, 2H), 1.43 (s, 9H); LC/MS (ESI, m/z[. [M - Boc +l]+ = 425.2.

[003921] Step 3 - 3-r6-r3-r2-(2-Aminoethoxy)ethoxy1propyl1pyrido[2,3-b1indol-9vl1piperidine-2,6-dione

[003922] To a solution of tert-butyl N-[2-[2-[3-[9-(2,6-dioxo piperidyl)pyrido[2,3-b]indol6-yl]propoxy] ethoxy]ethyl]carbamate (54.0 mg, 102 umol) in DCM (3 mL) was added TFA (352 mg, 3.09 mmol). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (55.0 mg, 95% yield, TFA salt) as light yellow oil. LC-MS (ESI+) m/z 425.3 (M+H)+.

[003923] Step 1 - Tert-butyl 4-prop ynoxypiperidine-l-carboxylate (Intermediate TM) pN&#1523;Boc &#902;Βγ pA00 HO NaH, THF

TM

[003924] To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (2.00 g, 9.94 mmol, CAS# 109384 2) in anhydrous THF (10 mL) was cooled to 0 °C, and subsequently NaH (477 mg, 11.9 mmol, 60% oil dispersion) was added. The reaction mixture was stirred at 0 °C for 0.5 hr. Then, 3-bromoprop yne (1.18 g, 9.94 mmol, 856 uL) was added. The resulting reaction mixture was stirred at 25 °C for 12 hrs. On completed, the reaction mixture was quenched with water (1 mL), then diluted with ethyl acetate (100 mL). The organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (2.38 g, 100%

1270 yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 4.22 (d, J= 2.4 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.73 - 3.70 (m, IH), 3.15 - 3.09 (m, 2H), 2.43 (t, J= 2.4 Hz, IH), 1.93 - 1.82 (m, 2H), 1.61 - 1.50 (m, 2H), 1.47 (s, 9H).

[003925] 3-[3-Methvl oxo [3-(4-DiDeridvloxv)DroDvl]benzimidazol-l-yl]DiDeridine2,6-dione (Intermediate TN)

TM

HCI/dioxane

DCM

TN

[003926] Step 1 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1prop ynoxy1 piperidine-l-carboxylate

[003927] A suspension of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (300 mg, 887 umol, Intermediate HP), tert-butyl 4-prop ynoxypiperidine-l-carboxylate (318 mg, 1.33 mmol, Intermediate TM), Pd(PPh3)2C12 (124 mg, 177 umol), Cui (33.8 mg, 177 umol), 4A molecular sieves (400 mg) and Cs2CO3 (1.16 g, 3.55 mmol) in DMF (5 mL) was degassed under vacuum and purged with N2 several times and then heated to 80 °C for 2 hours under N2. On completion, the reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with EA (50 mL) and water (20 mL). After, the organic layer was separated and washed with brine (5 mL X 2), dried over anhydrous Na2SO4, fdtered and the fdtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase to give the title compound (222

1271 mg, 48% yield) as a yellow solid. 1H NMR (400MHz, CDCh) δ 8.09 (s, IH), 7.10 (d, J= 8.0 Hz, IH), 6.92 (t, J = 8.0 Hz, IH), 6.69 (d, J = 8.0 Hz, IH), 5.13 (dd, J = 52, 12.8 Hz, IH), 4.39 (s, 2H), 3.76 - 3.66 (m, 6H), 3.09 - 3.03(m, 2H), 2.94 - 2.84 (m, IH), 2.82 - 2.71 (m, IH), 2.71 - 2.59 (m, IH), 2.22 - 2.11 (m, IH), 1.83 - 1.78 (m, 2H), 1.57 - 1.49 (m, 2H), 1.39 (s, 9H), LC-MS (ESI+) m/z 441.2 (M+H-56)+.

[003928] Step 2 - Tert-butyl4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1propoxy1 piperidine-1 -carboxylate

[003929] To a solution of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop- 2-ynoxy]piperidine carboxylate (370 mg, 745 umol) in THF (10 mL) was added Pd/C (0.1 g, 10% wt) and Pd(OH)2/C (0.1 g, 10% wt). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (330 mg, 88% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.03 (s, IH), 6.91 (d, J = 8.0 Hz, IH), 6.83 (d, J= 8.0 Hz, IH), 6.59 (t, J= 8.0 Hz, IH), 5.20 - 5.09 (m, IH), 3.70 - 3.64 (m, 2H), 3.62 (s, 3H), 3.44 (t, J= 5.6 Hz, 2H), 3.41 - 3.34 (m, IH), 3.06 - 3.04(m, 2H), 2.98 - 2.93 (m, 2H), 2.91 - 2.80 (m, IH), 2.79 - 2.63 (m, 2H), 2.19 - 2.10 (m, IH), 1.89 - 1.81 (m, 2H), 1.80 - 1.73 (m, 2H), 1.47 - 1.39 (m, 2H), 1.39 (s, 9H); LC-MS (ESI+) m/z 523.1 (M+Na)+.

[003930] Step 3 - 3-r3-Methyl oxo r3-(4-piperidyloxy)propyl1benzimidazol-lyl1piperidine-2,6-dione

[003931] To a solution of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] piperidine carboxylate (100 mg, 199 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (87.0 mg, 100% yield, HCI salt) as a white solid. LC-MS (ESI+) m/z 401.1 (M+H)+.

[003932] l-(4-MethoxvDhenvl)-N-methvl-N-[[(2R) DroD vnylmorDholin-2yl]methyl] methanamine (Intermediate TO)

1272

[003933] Step 1 - (2S) prop ynylmorpholine carbaldehyde

[003934] To a solution of [(2S) prop ynylmorpholin yl]methanol (5.00 g, 32.2 mmol, synthesized via Steps 1-2 of Intermediate RV) in DCM (250 mL) was added DMP (17.0 g, 40.0 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs. On completion, the reaction mixture was quenched with saturated NaS2O3 (30 mL), then extracted with DCM (3 X 100 mL). The combined organic layers was washed with saturated NaHCO3 (50 mL), then washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give the title compound (2.80 g, 56% yield) as yellow oil.

[003935] Step 2 - l-(4-Methoxyphenyl)-N-methyl-N-rr(2R) prop ynylmorpholin-2yllmethyll methanamine

[003936] To a solution of (2S) prop ynylmorpholine carbaldehyde (2.80 g, 18.2 mmol) and l-(4-methoxyphenyl)-N-methylmethanamine(2.76 g, 18.2 mmol, CAS# 702 9) in DCM (50 mL) was added NaBH(OAc)3 (4.65 g, 21.9 mmol), 4A molecular sieves (1g) and HO Ac (1.10g, 18.2 mmol, 1.05 mL). The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% NH3*H2O condition) to give the title compound (1.50 g, 25% yield) as yellow oil. 1HNMR (400 MHz, CDCh) δ 7.25 - 7.18 (m, 2H), 6.90 - 6.82 (m, 2H), 3.96 - 3.88 (m, IH), 3.81 (s, 3H), 3.78 -3.73 (m, IH), 3.73 -3.65 (m, IH), 3.56-3.44 (m, 2H), 3.31 (t, J= 2.4 Hz, 2H), 2.86 - 2.80 (m, IH), 2.73 - 2.67 (m, IH), 2.55 - 2.48 (m, IH), 2.41 - 2.33 (m, 2H), 2.27 (t, J= 2.4 Hz, IH), 2.25 (s, 3H), 2.09 - 2.03 (m, IH); LC-MS (ESI+) m/z 289.2 (M+H)+.

[003937] 3-[(5S) [4-[4-(3-amin0Dr0D0xv)but-l-vnvl]Dhenvl] 0x0-0xaz01idin-3yllDiperidine-2.,6 -dione (Intermediate TP)

1273

SD

[003938] Step 1 - Tert-butyl N-r3-r4-r4-r(5S) (2,6-dioxo piperidyl) oxo-oxazolidin-5yl1phenyl1but ynoxylpropyllcarbamate

[003939] To a solution of tert-butyl N-(3-but ynoxypropyl)carbamate (250 mg, 1.10 mmol,

Intermediate SD) and 3-[(5S) (4-bromophenyl) oxo-oxazolidin yl]piperidine-2,6-dione (323 mg, 916 umol, Intermediate SN) in DMF (15 mL) was added Pd(PPh3)2C12 (64.3 mg, 91.6 umol), Cui (17.4 mg, 91.6 umol) andCs2CO3 (1.19 g, 3.67 mmol). The reaction mixture was stirred at 80 °C for 2 hrs under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (250 mg, 54% yield) as a yellow solid. 1H NMR (400 MHz, DMSO4) δ 1HNMR (400 MHz, DMSO-Y) δ 11.00 (m, IH), 7.50 - 7.35 (m, 4H), 6.79 (t, J= 52 Hz, IH), 5.72 - 5.59 (m, IH), 4.78 - 4.61 (m, IH), 3.97 - 3.83 (m, IH), 3.59 - 3.51 (m, 2H), 3.44 (t, J = 6.0 Hz, 2H), 3.25 (t, J = 8.4 Hz, IH), 2.99 (q, J = 6.8 Hz, 2H), 2.92 - 2.77 (m, IH), 2.70 2.64 (m, 2H), 2.59 - 2.54 (m, IH), 2.29 - 2.14 (m, IH), 2.05 - 1.91 (m, IH), 1.67 - 1.58(m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 522.3 (M +Na)+.

[003940] Step 2 - 3-r(5S) r4-r4-(3-aminopropoxy)but-l-ynyl1phenyl1 oxo-oxazolidin-3yl1piperidine-2,6 -dione

[003941] To a solution of tert-butyl N-[3-[4-[4-[(5S) (2,6-dioxo piperidyl) oxooxazolidin yl]phenyl] but ynoxy]propyl]carbamate (100 mg, 200 umol) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL). The reaction mixture was stirred at 25 °C for 2 hr. On

1274 completion, the residue concentrated in vacuo to give the title compound (100 mg, 97% yield) as yellow oil. LC-MS (ESI+) m/z 400.2 (M + H)+.

[003942] 3-[3-Methvl [3-[(2S) (methvlaminomethvl)morDholin vl]DroDvl] oxobenzimidazol- l-yl]DiDeridine-2.,6-dione (Intermediate TT)

[003943] Step 1:3-[4-[3-[(2S) [[(4-Methoxyphenyl)m ethyl-methyl amino1methyl1morpholin yl1prop-l di one

[003944] To a mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (300 mg, 887 umol, Intermediate HP) and l-(4-methoxyphenyl)-N-methyl-N-[[(2S) prop2-ynylmorpholin yl] methyl]methanamine (383 mg, 1.33 mmol, Intermediate RQ) in DMF (20 mL) was added Cs2CO3 (1.45 g, 4.44 mmol), Cui (50.7 mg, 266 umol), Pd(PPh3)2C12 (187 mg, 266 umol) and 4A molecular sieves (20 mg). The reaction mixture was stirred at 80 °C for 2 hours under N2. On completion, the reaction mixture was filtered. The filtrate was washed with water (100 mL) and extracted with ethyl acetate (2 X 40 mL). The combined organic phase was washed with brine (2 X 40 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give residue. The residue was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (285 mg, 58% yield) as brown solid. 1HNMR (400 MHz, DMSO-/) δ 11.13 (s, IH),

1275

8.15 (s, 2H), 7.21 - 7.15 (m, 3H), 7.13 - 7.09 (m, IH), 6.83 - 6.79 (m, 2H), 5.41 (d, J= 5.6, 12.8 Hz, IH), 3.83 - 3.77 (m, 2H), 3.69 (s, 4H), 3.64 (s, 4H), 3.56-3.51 (m, 5H), 2.39 (d, J = 6.0 Hz, 2H), 2.35 - 2.26 (m, 2H), 2.15 (s, 3H), 2.10 - 2.05 (m, IH), 2.03 - 1.96 (m, 2H).

[003945] Step 2 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl]propyl] morpholin yl]methyl]-N-methyl-carbamate

[003946] To a mixture of 3-[4-[3-[(2S) [[(4-methoxyphenyl)methyl-methylamino]methyl]morpholin yl] prop-l-ynyl] methyl oxo-benzimidazol-l-yl]piperidine-2,6dione (285 mg, 522 umol) in EA (20 mL) and IPA (10 mL) was added Pd/C (50.0 mg, 10 wt%), Pd(OH)2/C (50.0 mg, 10 wt%) and (Boc)2O (171 mg, 783 umol). The suspension was degassed under vacuum and purged with H2 three times. The mixture was then stirred at 25 °C for 16 hours under H2 (50 psi) atmosphere. On completion, the reaction mixture was filtrated and filtrate was concentrated in vacuo to give residue. The residue was purified by reverse phase HPLC (0.1% FA condition) to give title compound (130 mg, 45% yield) as a brown solid. LC-MS (ESI+) m/z 530.4(M+H)+.

[003947] Step 3 - 3-r3-Methyl r3-r(2S) (methylaminomethyl)morpholin yl]propyl]-2oxo-benzimidazol- l-yl]piperidine-2,6-dione

[003948] To a mixture of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]-N-methyl-carbamate (130 mg, 245 umol) in DCM (2 mL) was added TFA (83.9 mg, 736 umol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give title compound (133 mg, 100% yield, TFA salt) as brown oil. LC-MS (ESI+) m/z 430.4 (M+H)+.

[003949] 3-[3-Methvl [3-[(2R) (methvlaminomethvl)morDholin vl]DroDvl] oxobenzimidazol -l-yl]DiDeridine-2.,6-dione (Intermediate TU)

1276

[003950] Step 1:3 - [4- [3 -[ (2R) [ [ (4-methoxyphenyl )methyl -methylamino1methyl1morpholin yl1prop-ldi one

[003951] To a solution of l-(4-methoxyphenyl)-N-methyl-N-[[(2R) prop-2ynylmorpholin yl]methyl] methanamine (450 mg, 1.56 mmol, Intermediate TO) and 3-(4bromo methyl-2 -oxo-benzimidazol yl) piperidine - 2,6-dione (352mg, 1.04 mmol, Intermediate HP) in DMF (10 mL) was added Cs2CO3 (1.36 g, 4.16 mmol), Cui (39.6 mg, 208 umol), 4A molecular sieves (50 mg) and Pd(PPh3)2C12 (146.03 mg, 208.1 umol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was diluted with water 30 mL, and then extracted with EA (3 X 50 mL). The combined organic layers were washed with brine and dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (355 mg, 63% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.12 (s, IH), 8.15 (s, IH), 7.20 - 7.14 (m, 4H), 7.13 - 7.08 (m, IH), 7.02 (t, J = 8.0 Hz, IH), 6.80 (d, J = 8.8 Hz, 3H), 5.40 (dd, 5.2 Hz, IH), 3.79 (d, J= 10.0 Hz, 2H), 3.68 (s, 4H), 3.63 (s, 3H), 3.60 (d, J= 7.2 Hz, 2H), 2.91 (d, J= 11.6 Hz, 2H), 2.74-2.64 (m, 4H), 2.37 (d, J=6.Q Hz, 2H), 2.30 -2.25 (m, IH), 2.14

1277 (s, 3H), 2.03 - 1.97 (m , IH); LC-MS (ESI+) m/z 546.3 (M +H)+.

[003952] Step 2 - Tert-butyl N-rr(2S) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1-N-methyl-carbamate

[003953] To a solution of 3-[4-[3-[(2R) [[(4-methoxyphenyl)methyl-methylamino]methyl]morpholin yl] prop-l-ynyl] methyl oxo-benzimidazol-l-yl]piperidine-2,6dione (355 mg, 651 umol) in EA (20 mL) and IPA (10 mL) was added Pd/C (180 mg, 20 wt%), Pd(OH)2/C (dry) (180 mg, 10 wt%) and (Boc)2O (213 mg, 976 umol, 224 uL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs under H2 (50 Psi) atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (225 mg, 65% yield) as a white solid. 1H NMR (400 MHz, DM SO-6/6) δ 11.08 (s, IH), 7.00 - 6.91 (m, 2H), 6.89 - 6.84 (m, IH), 5.36 (dd, J= 5.2 Hz, IH), 3.78 (d, J = 11.2 Hz, IH), 3.55 (s, 3H), 3.47 ( s, IH), 3.22 (d, J= 4.8 Hz, IH), 3.17 (d, J= 6.8 Hz, IH), 2.96 - 2.87 (m, 3H), 2.80 (d, J= 8.8 Hz, 3H), 2.73 - 2.58 (m, 4H), 2.42 - 2.31 (m, 3H), 2.06 - 1.94 (m, 2H), 1.79 - 1.68 (m, 3H), 1.37 (s, 9H); LC-MS (ESI+) m/z 530.3 (M+H)+.

[003954] Step 3 - 3-r3-Methyl r3-r(2R) (methylaminomethyl)morpholin yl1propyl1-2oxo-benzimidazol -l-yl1piperidine-2,6-dione

[003955] To a solution of tert-butyl N-[[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]-N-methyl-carbamate (120 mg, 227 umol ) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (95.0 mg, 98% yield) as a white solid. LC-MS (ESI+) m/z 430.3 (M+H)+.

[003956] Benzyl N-methyl-N - [ 2- [(2R) Dr0D vnylm0rDh01in vl] ethyl] carbamate (Intermediate TV)

1278

Raney-Ni, H2

NH3 H2O, MeOH

CbzCI, TEA

DCM

TFA

K2CO3, THF 1

TV

[003957] Step 1 - Tert-butyl (2R) (2-aminoethyl)morpholine carboxylate

[003958] A mixture of tert-butyl (2R) (cyanomethyl)morpholine carboxylate (3.86 g, 17.0 mmol, synthesized via Steps 1-2 of Intermediate RN) and Raney-Ni (3.00 g, 35.0 mmol) in MeOH (120 mL) and ΝΗ3&#905;2Ο (12 mL) was stirred at 25 °C for 4 hours under H2 (45 Psi). On completion, the mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate and washing were combined and concentrated in vacuo to give the title compound (3.90 g, 99% yield) as light yellow gum. 1H NMR (400 MHz, CDCh) δ 3.87 - 3.84 (m, 3H), 3.53-3.44 (m, 2H), 2.87 - 2.81 (m, 3H), 2.65 (m, IH), 1.65 - 1.56 (m, 4H), 1.47 (s, 9H).

[003959] Step^^JTert=butyl(2Rj=22]22ibenzylO2iycarbonylumino)ethyl]morpholine=42 carboxylate

[003960] To a solution of tert-butyl (2R) (2-aminoethyl) morpholine carboxylate (3.90 g, 16.9 mmol) and TEA (3.55 g, 35.0 mmol) in DCM (50 mL) was added CbzCI (3.03 g, 17.7 mmol) at 0 °C. The mixture was stirred at 0 - 10 °C for 1 hour. On completion, the mixture was washed with water (20 mL) and concentrated in vacuo. The residue was dissolved in EA (50 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (6.00 g, 97% yield) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 7.41 - 7.33 (m, 5H), 5.18- 5.16 (m, IH), 5.10 (s, 2H), 4.12 - 3.83 (m, 3H), 3.48 - 3.40 (m, 4H), 2.90 (m, IH), 2.62 -2.61 (m, IH), 1.44 (s, 9H).

[003961] Step 3:Tert-butyl(2R) [2[benzyl oxycarbonyl(methyl)amino1ethyl1morpholine carboxylate

[003962] To a solution of tert-butyl (2R) [2-(benzyloxycarbonylamino)ethyl]morpholine

1279

4-carboxylate (6.00 g, 16.4 mmol) in THF (60 mL) was added NaH (1.32 g, 33.0 mmol, 60% oil disperion) at 0 °C. The mixture was stirred at 0 °C for 30 minutes. Then Mel (7.01 g, 49.3 mmol) was added to the reaction mixture at 0 °C. The mixture was stirred at 0 - 25 °C for another 3 hours. On completion, the reaction was quenched with sat. aq. NH4C1 (10 mL). The mixture was diluted with water (50 mL), then extracted with EA(3 X 50 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (5.20 g, 83% yield) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 7.37 - 7.31 (m, 5H), 5.13 (s, 2H), 3.86 - 3.82 (m, 3H), 3.43 - 3.40 (m, 4H), 2.99 - 2.83 (m, 4H), 2.69 - 2.52 (m, IH), 1.74 - 1.62 (m, 2H), 1.47 (s, 9H).

[003963] Step 4 - Benzyl N-methyl-N-r2-r(2R)-morpholin yl1ethyl1carbamate

[003964] To a solution of tert-butyl (2R) [2[benzyloxycarbonyl(methyl)amino]ethyl]morpholine carboxylate (5.20 g, 13.7 mmol) in DCM (30 mL) was added TFA (10 mL) at 25 °C. The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (5.30 g, 98% yield, TFA salt) as light yellow gum.

[003965] Step 5 - Benzyl N-methyl-N-r2-r(2R) prop ynylmorpholin-2yllethyUcarbamate

[003966] To a mixture of benzyl N-methyl-N-[2-[(2R)-morpholin yl]ethyl]carbamate (5.30 g, 13.5 mmol, TFA salt) and K2CO3 (7.59 g, 54.9 mmol) in THF (60 mL) was added 3bromoprop yne (1.63 g, 13.7 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was fdtered, and the fdter cake was washed with EA (20 mL). The fdtrate and washing were combined and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (2.90 g, 67 % yield) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 7.37 - 7.31 (m, 5H), 5.13 (d, J= 3.2 Hz, 2H), 3.87 (t, J= 13.2 Hz, IH), 3.70 - 3.46 (m, 2H), 3.40 (t, J = 7.6 Hz, 2H), 3.28 (d, J= 10.8 Hz, 2H), 2.94 (s, 3H), 2.79 2.63 (m, 2H), 2.44 - 2.33 (m, IH), 2.27 (t, J = 2.4 Hz, IH), 2.16 - 2.06 (m, IH), 1.76 - 1.63 (m, 2H).

[003967] 3- [3-Methyl [3- [(2R) [2-(methvlamino)ethyl] morpholin vl] propyl]-!oxo- benzimidazol-l-yl]piperidine-2,6-dione (Intermediate TW)

1280

Pd(OH)2/C, Pd/C, H2

THF

TW

[003968] Step 1 - Benzyl N-[2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop-2 -ynyl1morpholin yl1ethyl1-N-methyl-carbamate

[003969] A mixture of benzyl N-methyl-N-[2-[(2R) prop ynylmorpholin-2yl]ethyl]carbamate (1.93 g, 6.11 mmol, Intermediate TV), 3-(5-bromo methyl oxobenzimidazol-l-yl)piperidine-2,6-dione (1.38 g, 4.08 mmol, Intermediate HN), Cui (165 mg, 866 umol), Pd(PPh3)2C12 (580 mg, 826 umol), Cs2CO3 (6.65 g, 20.4 mmol) and 4A molecular sieves (1.00 g) in DMF (30 mL) was stirred at 80 °C for 2 hours under N2. On completion, the reaction mixture was cooled to 25 °C. The mixture was filtered and the filter cake was washed with EA (20 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by reversed phase flash (FA condition) to give the title compound (1.50 g, 64% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-76) δ 11.13 (s, IH), 7.36-7.29 (m, 6H), 7.17-7.09 (m, 2H), 5.41 - 5.36 (m, IH), 5.05 (s, 2H), 3.85 - 3.76 (m, IH), 3.49 (s, 3H), 3.42 - 3.38 (m, 3H), 3.26 (m, IH), 2.86 - 2.82 (m, 4H), 2.76 - 2.68 (m, 2H), 2.65 - 2.62 (m, IH), 2.52 - 2.52 (m, 3H), 2.31 2.25 (m, IH), 2.06 - 1.98 (m, 2H), 1.61 - 1.57 (m, 2H).

[003970] Step 2 - Benzyl N-[2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propyl1 morpholin yl1ethyl1-N-methyl-carbamate

[003971] A mixture of benzyl N-[2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl oxo

1281 benzimidazol yl]prop ynyl]morpholin yl]ethyl]-N-methyl-carbamate (1.50 g, 2.61 mmol), Pd/C (400 mg, 10 wt%), and Pd(0H)2/C (400 mg, 10 wt%) in THF (60 mL) was stirred at 25 °C for 2 hours under H2 (15 psi). On completion, the mixture was filtered, and the filter cake was washed with EA (10 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by reversed phase flash chromatography (FA condition) to give the title compound (960 mg, 58% yield) as light yellow solid. 1H NMR (400 MHz, CDCh) δ 8.21 (s, IH), 7.37 - 7.31 (m, 5H), 6.92 - 6.84 (m, 2H), 6.72 (d, J = 8.0 Hz, IH), 5.26 - 5.18 (m, IH), 5.13 (s, 2H), 3.92 - 3.81 (m, IH), 3.75 - 3.58 (m, 2H), 3.42 (s, 3H), 3.41 - 3.35 (m, 2H), 2.93 (s, 3H), 2.80 - 2.68 (m, 7H), 2.56 - 2.46 (m, 2H), 2.29 - 2.19 (m, 2H), 2.08 - 1.96 (m, IH), 1.95 - 1.85 (m, 2H), 1.71 - 1.58 (m, 2H).

[003972] Step 3 - 3-r3-Methyl r3-r(2R) r2-(methylamino)ethyl1morpholin yl1propyl12-oxo- benzimidazol-l-yl1piperidine-2,6-dione

[003973] To a solution of benzyl N-[2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]ethyl]-N-methyl-carbamate (950 mg, 1.52 mmol) in DCM (10 mL) was added a solution of hydrogen bromide (2.30 mL, 13.9 mmol, 33% solution) in HO Ac at 20 °C. The mixture was stirred at 20 °C for 3 hours. On completion, the mixture was concentrated in vacuo at 20°C. The residue was diluted with water and lyophilized to give the title compound (790 mg, 98% yield, HBr salt) as light yellow solid. LC-MS (ESE) m/z 444.3 (M+H)+. [003974] Benzyl N-methvl-N-[2-[(2S) prop vnvlmorpholin vl]ethyl]carbamate (Intermediate TX)

Raney-Ni, H2 J'9 CbzCI, NaHCO3 &#1524; /L.CN D

Boc v NH3.H2O, MeOH Boc NH2 ACN

TFA

K2CO3, THF

TX

[003975] Step 1 - Tert-butyl (2S) (2-aminoethyl)morpholine carboxylate

1282

[003976] To a solution of tert-butyl (2S) (cyanomethyl)morpholine carboxylate (4.00 g, 17.6 mmol, synthesized via Steps 1-2 of Intermediate RL) in MeOH (20 mL) was added NH3.H2O (2.08 g, 19.5 mmol, 2.29 mL, 33% solution) and Raney-Ni (1.51 g, 17.6 mmol). The reaction mixture was stirred at 25 °C for 12 hours under H2 (50 psi). On completion, the reaction mixture was filtered and the filter cake was washed with MeOH. Then the filtrate was concentrated in vacuo to give the title compound (4.00 g, 98% yield) as colorless oil. 1HNMR (400MHz, DMSOd6) δ 3.84 - 3.60 (m, 4H), 3.43 - 3.33 (m, 4H), 2.90 - 2.77 (m, IH), 2.59 (s, 2H), 1.51 - 1.25 (m, 11H).

[003977] Step 2 - Tert-butyl (2S) r2-(benzyloxycarbonylamino)ethyl1morpholine-4carboxylate

[003978] To a solution of tert-butyl (2S) (2-aminoethyl)morpholine carboxylate (3.50 g,

15.2 mmol) and TEA (3.08 g, 30.3 mmol, 4.23 mL) in DCM (40 mL) was added CbzCl (2.85 g, 16.7 mmol, 2.38 mL). The mixture was stirred at 25 °C for 3 hrs. On completion, the mixture was diluted with H2O (20 mL) and extracted with DCM (2 X 40 mL). The organic phase was dried over Na2SO4, and then concentrated in vacuo to give the title compound (5.50 g, 99% yield) as yellow oil. 1HNMR (400 MHz, CDCh) δ 7.40 - 7.32 (m, 5H), 5.25 - 5.06 (m, 2H), 4.01 - 3.69 (m, 3H), 3.57 - 3.34 (m, 3H), 3.34 - 3.22 (m, IH), 2.98 - 2.82 (m, IH), 2.61 (s, IH), 2.10 - 1.78 (m, IH), 1.76 - 1.55 (m, 2H), 1.47 (s, 9H).

[003979] Step 3 - Tert-butyl (2S) r2-rbenzyloxycarbonyl(methyl)amino1ethyl1morpholine4-carboxylate

[003980] To a solution of tert-butyl (2S) [2-(benzyloxycarbonylamino)ethyl]morpholine4-carboxylate (2.00 g, 5.49 mmol) in THF (40 mL) was added NaH (439 mg, 10.9 mmol, 60% oil dispersion) at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes, and then Mel (1.95 g, 13.7 mmol, 854 uL) was added to the mixture. The mixture was stirred at 25 °C for 3 hrs. On completion, the reaction mixture was quenched with H2O (20 mL) and extracted with EA (2 X 40 mL). The organic phase was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (1.30 g, 62% yield) as yellow oil. 1HNMR (400 MHz, CDCh) 67.40 - 7.28 (m, 5H), 5.14 (s, 2H), 4.02 - 3.72 (m, 3H), 3.56 - 3.27 (m, 4H), 3.00 - 2.81 (m, 4H), 2.71 - 2.50 (m, IH), 1.79 - 1.63 (m, 2H), 1.47 (s, 9H).

[003981] Step 4 - Benzyl N-methyl-N-r2-r(2S)-morpholin yl1ethyl1carbamate

1283

[003982] To a solution of tert-butyl (2S) [2[benzyloxycarbonyl(methyl)amino]ethyl]morpholine carboxylate (1.20 g, 3.17 mmol) in DCM (10 mL) was added TFA (4.62 g, 40.5 mmol, 3.00 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (1.20 g, 96% yield, TFA) as yellow oil. LC-MS (ESI+) m/z 279.1(M+H)+.

[003983] Step 5 - Benzyl N-methyl-N-r2-r(2S) prop ynylmorpholin-2vllethyllcarbamate

[003984] To a solution of benzyl N-methyl-N-[2-[(2S)-morpholin yl]ethyl]carbamate (1.30 g, 3.31 mmol, TFA) and 3-bromoprop yne (394 mg, 3.31 mmol, 285 uL) in THF (20 mL) was added K2CO3 (1.37 g, 9.94 mmol). The reaction mixture was stirred at 25 °C for 16 hrs. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3 X 80 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (900 mg, 85% yield) as a yellow solid. 1HNMR (400 MHz, CDCh) 57.42 - 7.28 (m, 5H), 5.13 (s, 2H), 3.87 (t, J = 12.4 Hz, IH), 3.70 - 3.47 (m, 2H), 3.40 (t, J = 7.2 Hz, 2H), 3.28 (d, J = 9.6 Hz, 2H), 2.94 (s, 3H), 2.79 - 2.62 (m, 2H), 2.39 (t, J = 10.8 Hz, IH), 2.30 - 2.23 (s, IH), 2.16 - 2.06 (m, IH), 1.75 - 1.63 (m, 2H).

[003985] 3-[3-Methvl [3-[(2S) [2-(methvlamino)ethvl]morDholin yl]DroDvl]-2oxo-benzimidazol -l-yl]DiDeridine-2.,6-dione (Intermediate TY)

1284

TY

[003986] Stty3_L_2_J3en2wl_%J/2Jj(2j»42»]J»27)2di0x02»^^ benzimidazol 7Hprop 7n7l1morpholin 7l1eth7H-N-meth7l-carbamate

[003987] To a solution of benzyl N-methyl-N-[2-[(2S) prop ynylmorpholin-2yl]ethyl]carbamate (350 mg, 1.11 mmol, Interme4iate TX) an4 3-(5-bromo methyl oxobenzimi4azol-l-yl)piperi4ine-2,6-4ione (249 mg, 737 umol, Interme4iate HN) in DMSO (10 mL) was a44e4DIPEA(476 mg, 3.69 mmol, 642uL), CuI(14.0 mg, 73.7 umol) an4P4(PPh3)2C12 (51.7 mg, 73.7 umol). The reaction mixture was stirre4 at 80 °C for 2 hrs un4er N2. On completion, the mixture was filtere4, an4 the filtrate was concentrate4 in vacuo to gi7e a resi4ue. The resi4ue was purifie4 by re7erse phase (0.1% FA con4ition) to gi7e the title compoun4 (120 mg, 28% yield) as a yellow solid. 1H NMR (400MHz, DMSO-» δ 11.14 (s, IH), 7.38 - 7.28 (m, 6H), 7.24 - 7.09 (m, 2H), 5.40 (dd, J = 5.2, 12.8 Hz, IH), 5.06 (s, 2H), 3.72 - 3.39 (m, 6H), 3.35 (s, 6H), 2.92 - 2.80 (m, 5H), 2.77 - 2.71 (m, IH), 2.66 - 2.59 (m, 2H), 2.07 - 2.00 (m, IH), 1.74 - 1.55 (m, 2H); LCMS (ESH) m/z 574.3 (M +H)+.

[003988] Step 2 - Benz71 N-r2-r(2S) r3-r1-(2,6-dioxo piperid71) meth71 oxobenzimidazol 7l1prop7H morpholin 7l1eth7l1-N-meth7l-carbamate

[003989] To a solution of benzyl N-[2-[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynyl]morpholin yl]ethyl]-N-methyl-carbamate (100 mg, 174

1285 umol) in THF (20 mL) was added Pd(0H)2/C (2 mg, 10 wt%) and Pd/C (2 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hrs under H2 (15 psi). On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (80.0 mg, 79% yield) as a yellow solid. LC-MS (ESI+) m/z 578.3 (M+H)+.

[003990] Step 3 - 3-r3-Methyl r3-r(2S) r2-(methylamino)ethyl1morpholin yl1propyl12-oxo-benzimidazol -l-yl1piperidine-2,6-dione

[003991] To a solution of benzyl N-[2-[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]ethyl]-N-methyl-carbamate (80.0 mg, 138 umol) in DCM (2 mL) was added HBr/CH3COOH (8.66 umol, 1 mL, 35% solution). The reaction mixture was stirred at 20 °C for 4 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (70.0 mg, 96% yield, HBr) as a white solid. LC-MS (ESI+) m/z 444.3(M+H)+.

[003992] l-[4-(l-Amino-2.,2.,2-trifluoro-ethyl)phenvl] nitro-pyrazole carboxamid (Intermediate TZ)

1286

PPh3

H2O,THF

TZ

[003993] Step 1 - Methyl l-(4-formylphenyl) nitro-pyrazole carboxylate

[003994] To a solution of methyl l-[4-(hydroxymethyl)phenyl] nitro-pyrazole-3carboxylate (5.00 g, 18.0 mmol, synthesized via Step 1 of Intermediate GB) in DCM (100 mL) was added DMP (9.18 g, 21.6 mmol). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was quenched with sat. Na2S2O3 (100 mL) and sat. NaHCO3 (100 mL), stirred and extracted with DCM (2 X 100 mL). The organic layer was washed with brine (200 mL), dried with Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was triturated with PE/DCM =2:1 (50 mL), filtered and the filter cake was dried in vacuo to give the title compound (4.30 g, 87% yield) as a yellow solid. 1HNMR (400MHz, DMSO-t/6) δ 10.08 (s, IH), 9.90 (s, IH), 8.25 - 8.19 (m, 2H), 8.17 - 8.09 (m, 2H), 3.96 (s, 3H).

1287

[003995] Step 2 - Methyl 4-nitro-l-(4-(2.2.2-trifluoro-l-hydroxy-ethyl)phenyl1pyrazole-3carboxylate

[003996] To a solution of methyl l-(4-formylphenyl) nitro-pyrazole carboxylate (4.30 g, 15.6 mmol) in THF (80 mL) was added TMSCF3 (4.44 g, 31.3 mmol) and Cs2CO3 (10.2 g, 31.3 mmol). The reaction mixture was stirred at 20 °C for 2 hrs. Then HCl/dioxane (30 mL) was added and the mixture was stirred at 20 °C for 10 hrs. On completion, the mixture was quenched with water, extracted with EA (2 X 70 mL). The organic layer was washed with water, then concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (1.20 g, 22% yield) as yellow oil. 1H NMR (400MHz, DMSO4) δ 9.75 (s, IH), 8.03 - 7.97 (m, 2H), 7.70 (d, J= 8.8 Hz, 2H), 7.02 (d, J= 5.6 Hz, IH), 5.37 - 5.27 (m, IH), 3.95 (s, 3H).

[003997] Step 3 - 4-Nitro-l-[4-(2,2,2-trifluoro-l-hvdroxv-ethvl)phenvl1pvrazole-3carboxamide

[003998] To a solution of methyl 4-nitro-l-[4-(2,2,2-trifluoro-l-hydroxyethyl)phenyl]pyrazole carboxylate (1.20 g, 3.48 mmol) in THF (20 mL) was addNH3*H2O (9.75 g, 69.5 mmol, 25% solution). The reaction mixture was stirred at 75 °C for 10 hrs. On completion, the mixture was diluted with water (40 mL), then extracted with EA (2 X 40 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (720 mg, 63% yield) as an off-white solid. 1H NMR (400MHz, DMSOd6) 9.65 (s, IH), 8.19 (s, IH), 8.06 - 7.96 (m, 2H), 7.91 (s, IH), 7.73 - 7.65 (m, 2H), 7.00 (d, J = 5.6 Hz, IH), 5.34 - 5.26 (m, IH).

[003999] Step 4 - r1-r4-(3-Carbamoyl nitro-pyrazol-l-yl)phenyl1-2,2,2-trifluoro-ethyl1 methanesulfonate

[004000] To a solution of 4-nitro-l-[4-(2,2,2-trifluoro-l-hydroxy-ethyl)phenyl]pyrazole-3carboxamide (720 mg, 2.18 mmol) and TEA (662 mg, 6.54 mmol) in a mixed solvent of DCM (10 mL) and THF (10 mL) was added MsCl (500 mg, 4.36 mmol) at 0 °C. Then the reaction mixture was stirred at 20 °C for 3 hrs. On completion, the mixture was quenched with water (50 mL), then extracted with DCM (2 X 50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (850 mg, 95% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 9.69 (s, IH), 8.22 (s, IH), 8.13 - 8.08 (m, 2H), 7.94 (s, IH), 7.83 - 7.74 (m, 2H), 6.70 - 6.60 (m, IH), 3.33 (s, 3H).

1288

[004001] Step 5 - l-r4-(l-Azido-2,2,2-trifluoro-ethyl)phenyl1 nitro-pyrazole-3carboxamide

[004002] To a solution of [l-[4-(3-carbamoyl nitro-pyrazol-l-yl)phenyl]-2,2,2-trifluoroethyl] methanesulfonate (500 mg, 1.22 mmol) and TBAI (45.2 mg, 122 umol) in DMF (10 mL) was added NaN3 (159 mg, 2.45 mmol). The reaction mixture was stirred at 25 °C for 1 hr and then heated at 80 °C for 12 hrs. On completion, the mixture was diluted with water (30 mL), then extracted with DCM (2 X 30 mL). The organic layer was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (130 mg, 30% yield) as a white solid. LC-MS (ESI+) m/z 356.1 (M+H)+.

[004003] Step 6 - l-r4-(l-Amino-2,2,2-trifluoro-ethyl)phenvl1 nitro-pyrazole-3carboxamide

[004004] To a solution of l-[4-(l-azido-2,2,2-trifluoro-ethyl)phenyl] nitro-pyrazole-3carboxamide (130 mg, 366 umol) in a mixed solvent of H2O (0.2 mL) and THF (10 mL) was added PPh3 (192 mg, 732 umol). The mixture was stirred at 20 °C for 2 hrs, then the mixture was heated at 80 °C for 10 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (90.0 mg, 72% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 9.64 (s, IH), 8.19 (s, IH), 8.01 - 7.94 (m, 2H), 7.91 (s, IH), 7.74 - 7.68 (m, 2H), 4.62 (s, IH), 2.65 - 2.54 (m, 2H); LC-MS (ESI+) m/z 330.1 (M+H)+.

[004005] 3-[5-[3-[2-(2-Hvdroxvethoxv)ethoxy|propvl] methvl oxo-benzimidazol-lyl] piperidine- 2.,6-dione (Intermediate UA)

1289

[004006] Step 1 - 3-r5-r3-r2-(2-Hydroxyethoxy)ethoxy1prop-l-ynyl1 methyl oxobenzimidazol-l-yl] piperi dine-2,6-di one

[004007] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (500 mg, 1.48 mmol, Intermediate HN) and 2-(2-prop ynoxyethoxy)ethanol (639 mg, 4.44 mmol, Intermediate LC) in DMSO (15 mL) was added Cui (56.3 mg, 295 umol), Pd(PPh3)2C12 (103 mg, 147 umol), DIPEA(955 mg, 7.39 mmol), 4Amoleculare sieves (0.5 g) andP(t-Bu)3 (2.30 g, 1.48 mmol, 13 wt%). The reaction mixture was heated at 80 °C for 2 hours. On completion, the reaction mixture was quenched by water (30 mL), and then extracted with EA (3 X 40 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA condition) to give the title compound (590 mg, 99% yield) as light yellow solid. 1HNMR (400MHz, DMSO-76) δ 11.11 (s, IH), 7.33 (d, J= 0.8 Hz, IH), 7.20 - 7.09 (m, 2H), 5.40 (dd, J= 5.2, 12.4 Hz, IH), 4.43 - 4.37 (m, 2H), 3.67 - 3.62 (m, 2H), 3.61 - 3.56 (m, 2H), 3.52 - 3.49 (m, 2H), 3.46 - 3.42 (m, 3H), 3.34 (s, 3H), 2.96 - 2.81 (m, IH), 2.76 - 2.59 (m, 2H), 2.07 - 1.94 (m, IH); LC-MS (ESI+) m/z 402.1 (M+H)+.

[004008] Step 2 - 3-r5-r3-r2-(2-Hydroxyethoxy)ethoxy1propyl1 methyl oxobenzimidazol-l-yl1piperidine- 2,6-dione

[004009] To a solution of 3-[5-[3-[2-(2-hydroxyethoxy)ethoxy]prop-l-ynyl] methyl-2oxo-benzimidazol yl]piperidine-2,6-dione (650 mg, 1.62 mmol) in THF (20 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%) under N2. The suspension was degassed

1290 under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) at 25 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (570 mg, 86% yield) as light yellow solid. 1H NMR (400MHz, DMSO-/6) δ 11.08 (s, IH), 7.04 (s, IH), 7.00 (d, J = 8.0 Hz, IH), 6.92 - 6.82 (m, IH), 5.33 (dd, J = 5.2, 12.8 Hz, IH), 4.58 (t, J= 5.2 Hz, IH), 3.54 - 3.37 (m, 10H), 2.97 - 2.82 (m, IH), 2.76 - 2.57 (m, 4H), 2.01 (s, IH), 1.87 - 1.72 (m, 2H); LC-MS (ESI+) m/z 406.2 (M+H)+.

[004010] 2 |3- [l-(2,6-dioxo piperidvl) methvl oxo-benzimidazol-5yl]propoxy]ethoxy]ethyl methanesulfonate (Intermediate UB)

o 0

UA UB

[004011] To a solution of 3-[5-[3-[2-(2-hydroxyethoxy)ethoxy]propyl] methyl oxobenzimidazol-l-yl] piperidine-2,6-dione (100 mg, 246 umol) and TEA (74.8 mg, 739 umol) in DCM (4 mL) was added MsCI (42.3 mg, 369 umol) at 0 °C, the mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was quenched by water (15 mL), and then extracted with DCM (3X15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (110 mg, 92% yield) as light yellow oil. LC-MS (ESI+) m/z 484.1 (M+H)+.

[004012] 2 |3- [l-(2,6-Dioxo piperidvl) methvl oxo-benzimidazol-5yl] propoxy] ethoxy] acetaldehyde (Intermediate UC)

UB UC

[004013] To a solution of 3-[5-[3-[2-(2-hydroxyethoxy)ethoxy]propyl] methyl oxobenzimidazol-l-yl] piperidine-2,6-dione (270 mg, 666 umol, Intermediate UA) in THF (10 mL) was added DMP (339 mg, 799 umol). The mixture was stirred at 25 °C for 4 hrs. On completion,

1291 the reaction mixture was quenched by saturated Na2S2O3 (6 mL) and saturated NaHCO3 (6 mL) at 25°C, stirred for 30 minutes. Then the mixture was extracted with DCM (3 X 30 mL). The combined organic layers dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (0.1% FA condition) to give the title compound (150 mg, 56% yield) as a light yellow solid. 1H NMR (400MHz, DM SO-0/6) δ 11.08 (s, IH), 9.62 (s, IH), 7.10 - 6.92 (m, 2H), 6.85 - 6.72 (s, IH), 5.41 - 5.38 (m, IH), 4.18 (s, IH), 3.72 - 3.65 (m, IH), 3.60 - 3.35 (m, 6H), 3.34 - 3.25 (m, 3H), 2.99 - 2.81 (m, IH), 2.75 - 2.55 (m, 4H), 2.05 - 1.91 (m, IH), 1.88 - 1.70 (m, 2H); LC-MS (ESI+) m/z 404.2 (M+H)+.

[004014] 42ΔlL!iLL*Ll.lΞH&#1489;lJxl2&#1489;12&#1489;l^&#1489;llΞ&#943;24&#1497;ΞdiθΔθΞ^Ξ12il2£LidΣUΞ^ΞlLL£ll.LΣ&#943;Ξ2ΞθΔθΞ benzimidazol yl] carboxamide (Intermediate UP)

[004015] Step 1 - l-[4-[l-[2-[2-[3-[l-(2,6-Dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1 ethoxy1ethylamino1-2,2,2-trifluoro-ethyl1phenyl1 nitro-pyrazole1292

3-carboxamide

[004016] To a solution of 2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl]propoxy] ethoxy]acetaldehyde (98.0 mg, 243 umol, Intermediate UC) and 1-(4-(1-amino2,2,2-trifluoro-ethyl)phenyl] nitro- pyrazole carboxamide (80.0 mg, 243 umol, Intermediate TZ) in THF (3 mL) was added HOAc (14.6 mg, 243 umol). The mixture pH was adjusted to 5-6 and NaBH(OAc)3 (103 mg, 486 umol) was added into the mixture. The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (25.0 mg, 14% yield) as a white solid. 1H NMR (400MHz, DM SO-6/6) δ 11.08 (s, IH), 9.63 (s, IH), 8.18 (s, IH), 7.99 (d, J = 8.8 Hz, 2H), 7.92 (s, IH), 7.68 (d, J= 8.8 Hz, 2H), 7.02 - 6.96 (m, 2H), 6.84 (d, J= 8.0 Hz, IH), 6.54 (s, IH), 5.32 (dd, J= 5.2, 12.8 Hz, IH), 4.70 - 4.55 (m, IH), 3.50 - 3.44 (m, 6H), 3.37 (t, J= 6.4 Hz, 2H), 3.30 (s, 3H), 2.93 - 2.82 (m, 2H), 2.72 - 2.66 (m, IH), 2.66 - 2.62 (m, 4H), 2.03 -1.95 (m, IH), 1.84 - 1.74 (m, 2H); LC-MS (ESI+) m/z 717.0 (M+H)+.

[004017] Step 9 - 4-Amino-l-[4-[l-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 propoxy1ethoxy1ethylamino1-2,2,2-trifluoro-ethyl1phenyl1pyrazole-3carboxamide

[004018] To a solution of 1-(4-(1-(2-(2-(3-(1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]ethylamino]-2,2,2-trifluoro-ethyl]phenyl] nitro-pyrazole3-carboxamide (22.0 mg, 29.2 umol) in THF (4 mL) was added PtO2 (6.62 mg, 29.2 umol). The reaction mixture was stirred at 25 °C for 4 hrs under H2 (15 psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo io give the title compound (20.0 mg, 100% yield) as a yellow solid. LC-MS (ESI+) m/z 687.3 (M+H)+

[004019] 4- [2- [2- [2- [2- [2-(2-Aminoethoxv)ethoxy] ethoxy] ethoxy] ethoxy] ethylamino] 2-(26&#1524;-dioxo-3 -DiDeridyl)isoindoline-l.,3-dione (Intermediate UE)

1293

UE

[004020] Step 1 - Tert-butyl Ν-Γ2-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#943;οχο ρ&#912;ρ6Γ&#938;&#940;ν1)-Ε3-&#940;&#943;οχοisoindolin yl1 amino] ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

[004021] A solution of 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (550 mg, 1.99 mmol, Intermediate R), tert-butyl N-[2-[2-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (500 mg, 1.31 mmol, CAS# 18920927-6) and DIPEA (1.36 g, 10.5 mmol) in DMSO (20 mL) was stirred at 120-130 °C for 16 hours. On completion, the reaction mixture was cooled to rt and diluted with water (150 mL), then extracted with EA (3 X 80 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give crude product (800 mg). The crude product was purified by reversed phase chromatography (phase A: 0.1% FA water, B: CH3CN, 53% CH3CN) to the title compound (490 mg, 58% yield) as yellow gum. 1H NMR (400MHz, CDC13) δ 8.29 (s, IH), 7.50 (dd, J= &#906;2 Hz, J= 8.4 Hz, IH), 7.12 (d, J= 7.2 Hz, IH), 6.93 (d, J= 8.4 Hz, IH), 6.51 (m, IH), 5.09 (m, IH), 4.94-4.90 (m, IH), 3.74-3.63 (m, 18H), 3.55-3.54 (m, 4H), 3.32-3.31 (m, 2H), 2.832.77 (m, 3H), 2.15 (m, IH), 1.45 (s, 9H). LC-MS (ESI+) m/z 659.3 (M+Na), 537.3 (M&#1470;Boc+l)+.

1294

[004022] Step 2:4-[2- [2- [ 2-[2-[2-(2-Aminoethoxy)ethoxy1 ethoxy] ethoxy1ethoxy1ethylamino1 (2,6-dioxo-3 -piperi dyDisoindoline-1,3-di one

[004023] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3dioxo-isoindolin-4 -yl] amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (490 mg, 770 umol) in DCM (10 mL) was added 4.0 M HCI/dioxane (5 mL) at rt, and the mixture was stirred at rt for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (530 mg, quant, crude yield, HC1) as yellow gum. LC-MS (ESI+) m/z 537.3 (M+H)+.

[004024] 3,6,9,12,15-pentaoxaheptadecanedioic acid (Intermediate UF)

o 0

M HCI in dioxane 11 q Ο zv O JL

-------------* HO O 0 — OH

UF

[004025] Step 1 - di-tert-butyl 3,6,9,12,15-pentaoxaheptadecanedioate

[004026] To a solution of NaH (60% dispersion in mineral oil, 4.54 g, 113.4 mmol) in THF (200 mL) was added 2,2'-((oxybis(ethane-2,l-diyl))bis(oxy))diethanol (10 g, 51.5 mmol, CAS# 112 7) portion wise at 0 °C. After addition, the mixture was stirred at 0 °C for Ih, then tertbutyl 2-bromoacetate (22 g, 113.4 mmol) was added. After addition, the mixture was warmed to rt and stirred overnight. The mixture was quenched by addition of water, then extract with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (100 mLx 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with PEZEA=4/1 to give the title compound (5.5 g, 25.2%) as an colorless oil. LC/MS (ESI, mzy [M+l]+ = 423.1.

[004027] Step 2 - 3,6,9,12,15-pentaoxaheptadecanedioic acid

[004028] To a solution of di-tert-butyl 3,6,9,12,15-pentaoxaheptadecanedioate (5.5 g, 13 mmol) in DCM( 2 mL) was added 4M HCI in dioxane (18 mL). The mixture was stirred at rt overnight. The mixture was concentrated in vacuo to give the the title compound (3.5 g, 87% yield). LC/MS (ESI, mzy [M +1]+ = 311.0.

[004029] 3-(6-Amino-9H-pvrido[2,3-b]indol yl)piperidine-2,6-dione (Intermediate

1295

[004030] Step 1 - 6-nitro-9H-Dyrido [2.,3-b] indole

[004031] To a mixture 68%-70% nitric acid in H2O (20 mL) and fuming nitric acid (20 mL) was added 9H-pyrido[2,3-b]indole (2.5 g, 14.88 mmol) in portions at room temperature and the temperature was maintained under 30 °C. The mixture was stirred at 25 °C for 1 h. Then the mixture was set aside overnight at 0 °C. A lot of solid was formed. The resulting solid was filtered off and stirred with dilute ammonium hydroxide solution (50 mL) (33% in H2O). It was then filtered off and washed with water to leave the crude compound. The crude compound was triturated with EA and filtrated to give 6-nitro-9H-pyrido[2,3-b]indole as a grey solid. (2.6 g, yield:82%). LC/MS (ESI, mzy. [M+l]+ = 214.2

[004032] Step C: l-(4-methoxvbenzvl) (6-nitro-9H-pyrido [2.,3-b] indol-9yl)piperidine-2,6-dione

[004033] To a solution of 6-nitro-9H-pyrido[2,3-b]indole (2.6 g, 12.2 mmol) in THF (50 mL) was added t-BuOK (2.05 g, 18.3 mmol) at 0 °C. The mixture was stirred at 0-10 °C for 1 hour under N2. Then a solution of [l-[(4-methoxyphenyl) methyl]-2, 6-dioxo piperidyl] trifluoromethanesulfonate (6.98 g, 18.3 mmol) in THF (50 mL) was added to the reaction mixture at 0-10 °C during 30 minutes. The mixture was stirred at 0-10 °C for 30 minutes under N2. The reaction was quenched water (40 mL) and extracted with EA (3 X 50 mL). The combined organic layers were concentrated under reduced pressure. The residue was triturated with EA and filtrated to give l-(4-methoxybenzyl) (6-nitro-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione as a grey solid (4.95 g, yield 91%). LC/MS (ESI, m/z[. [M +1]+ = 445.1

1296

[004034] Step D: 3-(6-nitro-9H-Dvrido [2,3-b] indol yl)DiDeridine-2,6-dione

[004035] To a solution of l-(4-methoxybenzyl) (6-nitro-9H-pyrido[2,3-b]indol-9yl)piperidine-2,6-dione (400 mg, 0.90 mmol) in ACN (10 mL) was added CAN (2.46 g, 0.45 mmol) in water (3 mL) at 0 °C. After the addition, the mixture was warmed up to room temperature and stirred overnight. The reaction mixture was poured into water (50 mL), extract with EtOAc (3 x 50 mL), the combined organic layers were concentrated under reduced pressure. The residue was triturated with DMF/EA and filtrated to give 3-(6-nitro-9H-pyrido[2,3-b]indol yl)piperidine2,6-dione as a grey solid (130 mg, yield:44.4%). LC/MS (ESI, m/z): [M +1]+ = 325.1

[004036] Step E: 3-(6-amino-9H-Dvrido [2.,3-b] indol yl)DiDeridine-2,6-dione

[004037] To a solution of 3-(6-nitro-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione (130 mg, 0.401 mmol) in THF (5 mL) and EA (5 mL) was added Palladium on activated carbon 10% Pd (50 mg). The mixture was stirred at room temperature under H2 balloon overnight. The reaction mixture was filtered, the filtrate was concentrated under reduce pressure, the residue was triturated with DMF/EA and filtrated to give 3-(6-amino-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione as a grey solid (55 mg, yield:46.4%). 1HNMR (400 MHz, DMSO-76) rill.08 (s, IH), 8.26 - 8.39 (m, 2H), 7.24 - 7.36 (m, 2H), 7.14 (dd, J = 7.63, 4.88 Hz, IH), 6.85 (dd, 7=8.63, 2.13 Hz, IH), 5.90 (br. s., IH), 4.87 (s, 2H), 2.93 - 3.08 (m, 2H), 2.68 (d, 7=12.26 Hz, IH), 2.01 - 2.11 (m, IH). LC/MS (ESI, m/z): [M +1]+ = 295.1.

[004038] 3-(6-bromo-9H-Dvrido [2,3-b] indol yl)DiDeridine-2,6-dione (Intermediate

UH

1297

[004039] Step 1 - 6-bromo-9H-pyrido[2,3-b1indole

[004040] To a stirred solution of 9H-pyrido[2,3-b]indole (3 g, 17.9 mmol, CAS# 26148-685) in DCM (50 mL) was added Br2 (3.4 g, 21.4 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. To the mixture was added aq. NaHCO3 (100 mL), then the solution was extracted with EA (200 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, concentrated to give the title compound (2.7 g, 61% yield) as yellow solid. 1HNMR (400 MHz, DMSO-6/6) δ 12.02 (s, 1 H), 8.60 (dd, J= 1.2 Hz, J= 7.6 Hz, IH), 8.48-8.44 (m, 2H), 7.607.58 (m, IH), 7.48 (d, J = 8.4 Hz, IH), 7.26 (dd, J = 4.8 Hz, J= 7.6 Hz, IH). LC/MS (ESI, m/z); [M+l]+ = 247.8

[004041] Step 2:3 -(6-bromo-9H-pyrido[2,3 -b1indol yl)-1 -(4methoxvbenzyl)piperidine-2.6-dione

[004042] To a stirred solution of 6-bromo-9H-pyrido[2,3-b]indole (200 mg, 0.810 mmol) and

18-crown-6 (43 mg, 0.162 mmol) in THF (10 mL) was added NaHMDS (0.6 mL, 2 M in THF) dropwise at -30 °C under N2. The mixture was stirred for 1 h at -30 °C under N2. Then to the mixture was added a solution of l-(4-methoxybenzyl)-2,6-dioxopiperidin yl trifluoromethanesulfonate (463 mg, 1.21 mmol) in THF (5 mL) dropwise at - 30 °C under N2. The mixture was stirred for 2 h at -30 °C. The mixture was added to aq. NH4C1 (20 mL), then extracted with EA (50 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, concentrated and purified by column (PEZEA/DCM = 10/1/1 to 3/1/1) to give the title compound (220 mg, 57% yield) as a yellow oil. 1HNMR (400 MHz, CDCh) δ 8.41 (dd, J = 1.6 Hz, J = 52 Hz, IH), 8.29 (dd, J = 1.2 Hz, J= 7.6 Hz, IH), 8.20 (d, J= 1.6 Hz, IH), 7.45 (dd, J= 2.0 Hz, J= 8.8 Hz, IH), 7.40 (d, J = 8.8 Hz, 2H), 7.24-7.21 (m, IH), 6.84 (d, J = 8.8 Hz, 3H), 5.90-5.87 (m, IH), 5.01 (dd, J= 13.6 Hz, J = 20.4 Hz, 2H), 3.79 (s, 3H), 3.09-2.88 (m, 3H), 3.27-2.24 (m, IH). LC/MS (ESI, m/z); [M +1]+ = 479.1.

[004043] Step 3 - 3-(6-bromo-9H-pyridor2,3-b1indol yl)piperidine-2,6-dione

[004044] A mixture of 3-(6-bromo-9H-pyrido[2,3-b]indol yl)-l-(4methoxybenzyl)piperidine-2,6-dione (1.3 g, 2.72 mmol), MsOH (10 mL) and toluene (20 mL) was heated to 110 °C and stirred for 3 h under N2. The solvent was concentrated to remove toluene. Then to the mixture was added EtOAc (50 mL), and the solution was washed with brine (50 mL) to remove MsOH. The organic layer was dried over Na2SO4. The solid was filter and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel

1298 (PE/EA = 1/1) to give the title compound (500 mg, 51% yield) as a white solid. 1H NMR (400 MHz, DMSO-t/6) ri 11.17 (s, IH), 8.64 (dd, J = 1.6 Hz, 7= 7.6 Hz, IH), 8.52 (d, 7= 2.0 Hz, IH), 8.47 (dd, 7= 1.6 Hz, 7= 4.8 Hz, IH), 7.68-7.64 (m, 2H), 7.32 (dd, 7= 4.8 Hz, 7= 7.6 Hz, IH), 6.06 (br s, IH), 3.16-2.96 (m, 2H), 2.73-2.67 (m, IH), 2.16-2.13 (m, IH). LC/MS (ESI, m/z[ [M +l]+ = 358.0.

[004045] tert-butyl methyl(3-(prop yn-l-yloxy)propyl)carbamate (Intermediate UI) &#910;^,Βγ Boc Boc

HO. /\.N. ” &#910;./Ο.

TBAHS, NaOH, DCM

UI

[004046] To a solution of tert-butyl (3-hydroxypropyl)(methyl)carbamate (2 g, 10.6 mmol, CAS# 98642 5) in DCM (30 mL) was added aq. NaOH (40 %, 20 mL), 3-bromoprop yne (1.9 g, 15.9 mmol) and TBAHS (180 mg, 0.530 mmol) at rt. The mixture was stirred at rt for 3 h. To the mixture was added H2O (100 mL), then the mixture was extracted with DCM (3x30 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by column (PE/EA = 20/1 to 10/1 to 4/1) to give the title compound (1.4 g, 58% yield) as a yellow oil. 1HNMR (400 MHz, CDCh) ri 4.14 (d,7= 2.4 Hz, 2H), 3.53 (t, 7= 6.4 Hz, 2H), 3.29 (t, 7= 6.8 Hz, 2H), 2.86 (s, 3H), 2.42 (t, 7= 2.4 Hz, IH), 1.83-1.80 (m, 2H), 1.46 (s, 9H). LC/MS (ESI, m/z[. [M +1]+ = 227.9.

[004047] 2- [2-[2- [2-(4-Nitropyrazol-l-vl)ethoxy| ethoxy] ethoxy] ethanamine (Intermediate UJ)

no2

no2

[004048] Step 1:Tert-butyl N-r2-r2-r2-[2-(4-nitropyrazol-lvhethoxy] ethoxy] ethoxy] ethyl] carbamate

[004049] To a solution of 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl

1299 methanesulfonate (3 g, 8.08 mmol, Intermediate AO) and 4-nitro-lH-pyrazole (608 mg, 5.38 mmol) in DMF (40 mL) was added Cs2CO3 (3.51 g, 10.7 mmol). The reaction mixture was stirred at 130 °C for 2 hours. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.20 g, 57% yield) as yellow oil. LC-MS (ESI+) m/z 411.2 (M+Na)+.

[004050] Step 2 - 2-r2-r2-r2-(4-Nitropyrazol-l-yl)ethoxy1ethoxy1ethoxy1ethanamine

[004051] To a solution of tert-butyl N-[2-[2-[2-[2-(4-nitropyrazol-lyl)ethoxy]ethoxy]ethoxy]ethyl]carbamate (750 mg, 1.93 mmol) in DCM (6 mL) was added HCl/dioxane (4 M, 4.50 mL). The reaction mixture was stirred at 20 °C for 1.5 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (620 mg, 99% yield, HCI salt) as a yellow solid. LC-MS (ESI+) m/z 289.2 (M+H)+.

[004052] 4 |2 [2-(4-AminoDvrazol-l-vl)ethoxy|ethoxvl ethoxy] ethylamino] (2,6dioxo DiDeridvl)isoindoline-l,3-dione (Intermediate UK)

[004053] Step 1:2-(2,6-Dioxo piperidyl) r2-r2-r2-r2-(4-nitropyrazol-l

1300 vDethoxy]ethoxy]ethoxy]ethyl amino]isoindoline-L3-dione

[004054] To a solution of 2-[2-[2-[2-(4-nitropyrazol-l-yl)ethoxy]ethoxy]ethoxy]ethanamine (670 mg, 2.06 mmol, HCI salt, Intermediate UJ) and 2-(2,6-dioxo piperidyl) fluoroisoindoline-1,3-dione (570 mg, 2.06 mmol, Intermediate R) in dioxane (20 mL) was added DIPEA (1.33 g, 10.3 mmol). The reaction mixture was stirred at 120 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reversed phase (0.1%, FA condition) to give the title compound (400 mg, 36% yield) as yellow oil. 1H NMR (400MHz, DMSO-76) δ 11.11 (s, IH), 8.82 (s, IH), 8.26 (s, IH), 7.62-7.52 (m, IH), 7.14 (d, J= 8.8 Hz, IH), 7.04 (d, J= &#906;.2 Hz, IH), 6.59 (t, J= 6.0 Hz, IH), 5.06 (dd, J= 5.2, 12.8 Hz, IH), 4.33 (t, J= 5.2 Hz, 2H), 3.79 (t, J= 5.2 Hz, 2H), 3.62 - 3.59 (m, 2H), 3.56 - 3.46 (m, 10H), 3.56 - 3.44 (m, IH), 2.94 - 2.83 (m, IH), 2.63 - 2.56 (m, IH), 2.57 - 2.54 (m, IH), 2.07 - 1.99 (m, IH). LC-MS (ESI+) m/z 545.2 (M+H)+.

[004055] Step 2 - 4-r2-r2-r2-r2-(4-Aminopyrazol-l-yl)ethoxy]ethoxy]ethoxy]ethylamino]2-(2,6-di oxo piperidyl)isoindoline-L3-dione

[004056] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-[2-[2-(4-nitropyrazol-lyl)ethoxy]ethoxy]ethoxy] ethylamino]isoindoline-l,3-dione (400 mg, 735 umol) in THF (40 mL) was added PtO2*H2O (50 mg, 220 umol) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (370 mg, 98% yield) as yellow oil. 1HNMR (400MHz, DMSO-76) δ 11.10 (s, IH), 7.63 -7.53 (m, IH), 7.15 (d, J= 8.8 Hz, IH), 7.07-7.01 (m, 2H), 6.89 (s, IH), 6.60 (t, J= 5.8 Hz, IH), 5.06 (dd, J= 5.2, 12.8 Hz, IH), 4.03 (t, J = 5.6 Hz, 2H), 3.66 (t, J = 5.6 Hz, 2H), 3.57 - 3.54 (m, 2H), 3.54 - 3.45 (m, 10H), 2.96 - 2.82 (m, IH), 2.63 - 2.60 (m, IH), 2.59 - 2.57 (m, IH), 2.05 1.98 (m, IH).

[004057] 2- [2- [2- [2-(2-Tert-butoxy oxo-ethoxy)ethoxy| ethoxy] ethoxy] acetic acid (Intermediate UM)

1301

Ο LiOH H2O -----------*&#1470; HO THF, H2O

UM

[004058] Step 1-Ethyl 2-r2-r2-r2-(2-tert-butoxv oxoethoxy )ethoxy] ethoxy] ethoxy] acetate

[004059] To a solution of ethyl 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]acetate (150 mg, 635 umol, synthesized via Step 1 of Intermediate BI) and diacetoxyrhodium (6.00 mg, 13.6 umol) in anhydrous DCM (4 mL) was added a solution of tert-butyl 2-diazoacetate (271 mg, 1.91 mmol, CAS# 35059 8) in DCM (4 mL) dropwise at 0-10°C. The mixture was stirred at 25 °C for 16 hours under N2. On completion, the reaction was quenched with HOAc (0.1 mL). The mixture was stirred at 25°C for 15 minutes. The mixture was then concentrated in vacuo. The residue was purified over column chromatography on silica gel (PE: EA= 5:1-3:1) to give the title compound (130 mg, 58% yield) as light green oil. 1H NMR (400MHz, CDCh) δ 4.22 (q, J = 7.2 Hz, 2H), 4.16 (s, 2H), 4.03 (s, 2H), 3.74 - 3.68 (m, 12H), 1.48 (s, 9H), 1.29 (t, J= 7.2 Hz, 3H).

[004060] Step 2 - 2-r2-r2-r2-(2-Tert-butoxv oxo-ethoxv)ethoxv1ethoxv1ethoxv1acetic acid [004061] To a solution of ethyl 2-[2-[2-[2-(2-tert-butoxy oxoethoxy)ethoxy]ethoxy]ethoxy]acetate (130 mg, 371 umol) in THF (3 mL) was added a solution of lithium hydroxide hydrate (17.0 mg, 405 umol) in H2O (1 mL) at 25 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was diluted with water (20 mL), acidified to pH = 5 with 1.0 M aq. HCI, then extracted with EA (3 X 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (110 mg, 92% yield) as light green oil. 1HNMR (400MHz, CDCh) δ 4.17 (s, 2H), 4.03 (s, 2H), 3.77 - 3.70 (m, 12H), 1.48 (s, 9H).

[004062] 2-[2-[2-[2-[2-n(lS)-l-[(2S,4R) Hvdroxv n4-(4-methvlthiazol vDDhenvl] methylcarbamoyl]Dyrrolidine-l-carbonyl]-2,2-dimethyl-DroDyl]amino] oxoethoxy]ethoxy] ethoxy]ethoxy]acetic acid (Intermediate UN)

1302

UM

HATU, DIPEA, DMF

O

O

UN

[004063] Step 1 - Tert-butyl 2-r2-r2-r2-r2-rr(lS)-l-r(2S,4R) hydroxy-2&#1470;rr4-(4methylthiazol yl )phenyl]methyl carbamoyl1pyrrolidine-l-carbonyl1-2,2-dimethylpropyl] amino] oxo-ethoxy1 ethoxy] ethoxy] ethoxy] acetate

[004064] A mixture of (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl] hydroxy-N-[[4(4-methylthiazol yl)phenyl]methyl]pyrrolidine carboxamide (180 mg, HCI, Intermediate CI), 2-[2-[2-[2-(2-tert -butoxy oxo-ethoxy)ethoxy]ethoxy]ethoxy]acetic acid (100 mg, 310 umol, Intermediate UM), HATU (155 mg, 408 umol) and DIPEA (121 mg, 936 umol) in DMF (5 mL) was stirred at 25 °C for 2 hours. On completion, the reaction mixture was diluted with water (50 mL), then extracted with EA (3X30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified over column chromatography on silica gel (DCM: MeOH = 50:1-20:1) to give the title compound (130 mg, 48% yield, 84% purity) as light yellow gum. LC-MS (ESI+) m/z 735.3 (M+H)+, 757.3 (M+Na)+.

[004065] Step 2 - 2-r2-r2-r2-r2-rr(lS)-l-r(2SAR) Hydroxy-2&#1470;rr4-(4-methylthiazol-5yl)phenyl1 methylcarbamoyl1pyrrolidine-l-carbonyl1-2,2-dimethyl-propyl1amino1 oxoethoxy] ethoxy] ethoxy] ethoxy] aceti c aci d

1303

[004066] To a solution of tert-butyl 2-[2-[2-[2-[2-[[(lS)-l-[(2S,4R) hydroxy [[4-(4methylthiazol yl) phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethylpropyl]amino] oxo-ethoxy]ethoxy] ethoxy]ethoxy]acetate (110 mg, 125 umol) in DCM (4 mL) was added TFA (2 mL) at 25 °C. The mixture was stirred at 25 °C for 3 hours. On completion, the mixture was concentrated in vacuo to give the title compound (140 mg, quant, crude yield, TFA) as light yellow gum. LC-MS (ESI+) m/z 679.4 (M+H)+.

[004067] 2-[2-[2-(2-Tert-butoxy oxo-ethoxy)ethoxy]ethoxy]acetic acid (Intermediate UP)

UQ

[004068] Step 1 - Ethyl 2-r2-r2-(2-tert-butoxv oxo-ethoxy)ethoxy1ethoxy1acetate

[004069] To a stirring mixture of ethyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate (0.80 g, 4.16 mmol, synthesized via Step 1 of Intermediate BM) and diacetoxyrhodium (33.6 mg, 76.0 umol) in DCM (10 mL) was added a solution of tert-butyl 2-diazoacetate (1.78 g, 12.49 mmol, CAS# 35059 8) in DCM (10 mL) drop-wise under ice-cooling bath (0 °C). After the addition, the resulting mixture was stirred at 20 °C for 16 hours. Diacetoxyrhodium (33.6 mg, 76.02 umol) and tert-butyl 2-diazoacetate (1.78 g, 12.49 mmol) were supplied subsequently, and the resulting mixture was stirred at 20 °C for another 4 hours. On completion, the mixture was quenched with AcOH (1.2 mL) and concentration in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 5/1 to 3/1) to give the title compound (1.11 g, 87% yield) as blue oil. 1HNMR (400MHz, CDCh) δ 4.28 (q, J= 7.2 Hz, 2H), 4.02 (s, 2H), 4.15 (s, 2H), 3.73 - 3.70 (m, 8H), 1.48 (m, 9H), 1.28 (t, J= 7.2 Hz, 3H).

[004070] Step 2 - 2-r2-r2-(2-Tert-butoxv oxo-ethoxv)ethoxv1ethoxv1acetic acid

[004071] To a solution of ethyl 2-[2-[2-(2-tert-butoxy oxo-ethoxy)ethoxy]ethoxy]acetate (1 g, 3.26 mmol) in THF (40 mL) was added a solution of LiOH.H2O (170 mg, 4.05 mmol) in H2O (20 mL). The mixture was stirred at 20 °C for 16 hours. On completion, the mixture was diluted with H2O (30 mL), adjusted to pH = 4-5 with IM aq. HCI, extracted with EA (2 X 50 mL). The

1304 organic phases were combined and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (800 mg, 88% yield) as yellowish oil.

[004072] 2- [2-[2- [2- [[(1 S)-l- [(2S,4R) Hydroxy [[4-(4-methylthiazol-5vDphenyl] methylcarbamoyl] ethoxy]ethoxy] ethoxy]acetic acid (Intermediate UR)

o—

UR

OH

[004073] Step 1 - Tert-butyl 2-r2-r2-r2-rr(lS)-l-r(2S,4R) hydroxy [r4-(4-methylthiazol5-yl) phenyl] methylcarbamoyl1pyrrolidine-l-carbonvl]-2,2-dimethyl-propyl]amino1 oxoethoxy] ethoxy] ethoxy] acetate

[004074] To a mixture of 2-[2-[2-(2-tert-butoxy oxo-ethoxy)ethoxy]ethoxy]acetic acid (200 mg, 718 umol, Intermediate UQ) and HATU (327 mg, 862 umol) in DMF (20 mL) was added

1305

DIPEA (278 mg, 2.16 umol, 375 uL) and (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl]-4hydroxy-N-[[4-(4-methylthiazol yl)phenyl] methyl]pyrrolidine carboxamide (335 mg, 718 umol, HCI, Intermediate CI) subsequently, then the resulting mixture was stirred at 20 °C for 16 hours. On completion, the mixture was diluted with H2O (20 mL), then extracted with EA (2 X 50 mL ), the organic phase was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE/EA=1/1, EA/MeOH=40/l to 10/1) to give the title compound (400 mg, 70% yield) as yellowish solid. LC-MS (ESI+) m/z 691.3(M+H)+.

[004075] Step 2 - (S)-Methyl 13- ((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)pyrrolidine carbonyl)-14,14-dimethyl-l 1-oxo-3 A9-trioxa-12azapentadecan-1 -oate

[004076] To a solution of tert-butyl 2-[2-[2-[2-[[(lS)-l-[(2S,4R) hydroxy [[4-(4methylthiazol yl )phenyl] methyl carbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethylpropyl]amino] oxo-ethoxy]ethoxy]ethoxy]acetate (100 mg, 144 umol) in MeOH (5 mL) was added HCI/dioxane (4 M, 2 mL). The mixture was stirred at 20 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (150 mg, quant, crude yield) as colorless oil. LC-MS (ESI+) m/z 649.3 (M+H)+.

[004077] Step 3 - 2-r2-r2-r2-rr(lS)-l-r(2SAR) Hydroxy [r4-(4-methylthiazol-5yl)phenyl1methylcarbamoyl1 pyrrolidine-l-carbonyl1-2,2-dimethyl-propyl1amino1 oxoethoxy]ethoxy]ethoxy]acetic acid

[004078] To a solution of (S)-methyl 13- ((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl) pyrrolidine-1 -carbonyl)-14,14-dimethyl-l 1 -oxo-3,6,9-trioxa-12azapentadecan oate (150 mg) in THF (10 mL) was added a solution of LiOH.H2O (200 mg, 4.77 mmol) in H2O (5 mL). The mixture was stirred at 20 °C for 20 mins. On completion, the mixture was concentrated in vacuo to remove THF, then diluted with H2O (20 mL) and the pH was adjusted to 5 with 1.0 M aq. HCI, extracted with EA (2 X 40 mL). The organic phases were concentrated in vacuo to give the title compound (80 mg, 96%) as yellowish oil. LC-MS (ESI+) m/z 635.4 (M+H)+.

[004079] Tert-butyl N-[2-[2-[2-(4-aminoDvrazol-l-vl)ethoxv]ethoxy]ethvl]carbamate (Intermediate US)

1306

nh2

Pd/C, H2 /

MeOH . o nA

BocHN O N

US

[004080] Step 1 -Tert-butyl N-r2-r2-r2-(4-nitropyrazol-l-yl)ethoxy1ethoxy1ethyl1carbamate

[004081] To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (2.08 g, 6.37 mmol, synthesized via Step 1 of Intermediate AM) and 4-nitro-lHpyrazole (0.600 g, 5.31 mmol, CAS# 2075 9) inDMF (40 mL) was added Cs2CO3 (3.46 g, 10.6 mmol). The mixture was stirred at 130 °C for 2 hours. On completion, after cooling to 25 °C , the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (1.50 g, 82% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 8.29 (s, IH), 8.00 (s, IH), 4.90 (s, IH), 4.28 (t, J= 4.8 Hz, 2H), 3.84 3.77 (m, 2H), 3.56 - 3.50 (m, 4H), 3.46 (t, J= 5.2 Hz, 2H), 3.30 - 3.21 (m, 2H), 1.37 (s, 9H). LCMS (ESI+) m/z 367.2(M+Na)+.

[004082] Step 2:Tert-butyl N-r2-r2-[2-(4-aminopyrazol-lyl)ethoxy1ethoxy1ethyl1carbamate

[004083] To a solution of tert-butyl N-[2-[2-[2-(4-nitropyrazol-lyl)ethoxy]ethoxy]ethyl]carbamate (500 mg, 1.45 mmol) in MeOH (10 mL) was added Pd/C (220 mg, 10 wt%). The mixture was stirred at 20 °C for 12 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (400 mg, 87.6% yield) as red oil. LC-MS (ESI+) m/z 315.2(M+H)+.

[004084] N5-[l-[2-[2-(2-aminoethoxv)ethoxv]ethvl]pvrazol vl]-l-methyl-N7-(4morpholinocyclohexyllpyrazolo [4.,3-d] pyrimidine-5.,7-diamine (Intermediate UT)

1307

UT

[004085] Step 1:Tert-butyl Ν-Γ2-Γ2-Γ2-[4-ΓΓ1^6Φν1 Γ(4morpholinocyclohexyl)amino1pyrazolo[4,3-d1 pyrimidin yl1amino1pyrazol-lyl 1 ethoxy] ethoxy] ethyl 1 carb am ate

[004086] Tert-butyl N-[2-[2-[2-(4-aminopyrazol-l-yl)ethoxy]ethoxy]ethyl]carbamate (300 mg, 954 umol, Intermediate US), 5-chloro-l-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3d]pyrimidin amine (223 mg, 636 umol, Intermediate LK) and TsOH (21.9 mg, 127 umol) were taken up into a microwave tube in NMP (10 mL). The sealed tube was heated at 150 °C for 2 hours under microwave. On completion, after cooled to 25 °C , the reaction mixture was diluted with water (50 mL) and extracted with DCM (2 X 80 mL). The combined organic layer was concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (100 mg, 25% yield) as a white solid. LC-MS (ESI+) m/z 629.2 (M+H)+.

[004087] Step 2 - N5-r1-r2-r2-(2-aminoethoxy)ethoxy1ethyl1pyrazol yl1-l-methyl-N7-(4morpholinocyclohexyl)pyrazolor4,3-d1pyrimidine-5,7-diamine

[004088] To a solution of tert-butyl N-[2-[2-[2-[4-[[l-methyl [(4morpholinocyclohexyl)amino]pyrazolo [4,3-d] pyrimidin yl]amino]pyrazol-lyl]ethoxy]ethoxy]ethyl]carbamate (80.0 mg, 127 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL). The reaction mixture was stirred at 25 °C for 14 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (70 mg, 97.3%, HCI) as a white

1308 solid. LC-MS (ESI+) m/z 529.5 (M+H)+.

[004089] (S) ((S) (((benzvloxv)carbonvl)(methvl)amino)DroDanamido)-2cyclohexylacetic acid (Intermediate UU)

[004090] Step 1:methyl(S) ((S)-2(((benzyloxy)carbonyl)(methyl)amino)propanamido) cyclohexylacetate

[004091] To a solution ofN-((benzyloxy)carbonyl)-N-methyl-L-alanine (13.04 g, 55 mmol) and methyl (S) amino cyclohexylacetate hydrochloride (10.4 g, 50 mmol) in DMF (100 mL) was added HATU (24.72 g, 65 mmol) and DIPEA (19.35 g, 150 mmol). The reaction mixure was stirred at room temperature for 8 h. Water (300 mL) was then added, and the mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. The solid was filtered and the filtrate was concentrated under reduced pressure, the resulting residue was purified by column chromatography on silica gel to give the title compound as an oil (18 g, 96% yield). 1H NMR (400 MHz, CDC13) δ 7.37 - 7.27 (m, 5H), 5.19 (s, 2H), 4.81 (br s, 1 H), 4.49 (dd, J= 10.8, 5.3 Hz, IH), 3.72 (s, 3H), 2.88 (s, 3H), 1.76-1.50 (m, 6H), 1.36 (d, 7= 7.1 Hz, 3 H), 1.27-1.13 (m, 2H), 1.08-0.90 (m, 3H).

[004092] Step 2 - (S) ((S) (((benzyloxy)carbonyl)(methyl)amino)propanamido)-2cyclohexylacetic acid

[004093] To a solution of methyl (S) ((S)-2(((benzyloxy)carbonyl)(methyl)amino)propanamido) cyclohexylacetate (18.0 g, 46.15 mmol) in THF (60 mL) and H2O (12 mL) was added LiOH (1.44 g, 60 mmol) at 0 °C. The reaction mixure was stirred at 0 °C for 1 h then at rt for 4 h. THF was removed under reduced pressure, then the mixture was adjusted with critic acid to pH = 2~3, and the mixture was extracted with

1309

EtOAc (3 x 200 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. The solid was filtered and the filtrate was concentrated under reduced pressure to give the title compound (14 g, 81% yield). 1H NMR (400 MHz, DMSO-76) δ 12.55 (s, IH), 7.39 - 7.28 (m, 5H), 5.07 (d, J = 9.3 Hz, 2H), 4.69 (br s, IH), 4.10-4.07 (m, 1 H), 2.85 (s, 3H), 1.65-1.56 (m, 6 H), 1.35 - 1.28 (m, 3H), 1.19-1.08 (m, 5H).

[004094] 2,2-dimethvl oxo-3,8,ll-trioxa azatridecan yl 4methylbenzenesulfonate (Intermediate UV) _ TosCI, Et3N _ _ n ^^0^^ N HBoc *&#1470; °S N HBoc

UV

[004095] To a solution of tert-butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (Ilg, 44.12 mmol, CAS# 139115 7) in DCM (100 mL) was added Et3N (8.91 g, 88.24 mmol), then TosCI (16.82 g, 88.24 mmol) was added portions at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography on silica gel to give the product 2,2-dimethyl oxo-3,8,ll-trioxa azatridecan yl 4-methylbenzenesulfonate as an oil (17 g, yield 96%). 1H NMR (400 MHz, CDCh) δ 7.81 - 7.79 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.90 (br s, 1 H), 4.19-4.16 (m, 2 H), 3.72 - 3.68 (m, 2 H), 3.61 - 3.57 (m, 2 H), 3.56 - 3.53 (m, 2 H), 3.50 (t, J= 5.2 Hz, 2 H), 3.29 (t, J = 5.1 Hz, 2 H), 2.45 (s, 3 H), 1.42 (s, 9 H).

[004096] 3 13 [2-[2-(2-Aminoethoxv)ethoxy] ethoxy] ethoxy] propyl] methvl-2oxo- benzimidazol-l-yl]piperidine-2.,6-dione (Intermediate UX)

1310

GZ

Pd/C, Pd(OH)2/C, H2

THF

HCI/dioxane

DCM

UX

[004097] Step 1 - Tert-butyl N-r2-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 prop ynoxy1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[004098] To a mixture of tert-butyl N-[2-[2-[2-(2-prop-2ynoxyethoxy)ethoxy]ethoxy]ethyl]carbamate (0.500 g, 1.51 mmol, Intermediate GZ), 3-(4-bromo3-methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (170 mg, 502 umol, Intermediate HP), Cui (47.8 mg, 251 umol) and Pd(PPh3)2C12 (176 mg, 251 umol) in DMF (10 mL) was added TEA (916 mg, 9.05 mmol, 1.26 mL) in a glove box. Then the resulting mixture was stirred at 80 °C for 2 hours. On completion, the mixture was diluted with water (90 mL), then extracted with EA (2 X 100 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (131 mg, 30% yield) as brown liquid. LC-MS (ESI+) m/z 611.1 (M+Na)+.

[004099] Step 2 - Tert-butyl N-r2-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 propoxy1ethoxy1ethoxy1ethoxy1ethyl1carbamate

1311

[004100] To a mixture tert-butyl N-[2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (110 mg) in THF (15 mL) was added Pd/C (0.04 g, 10 wt%) and Pd(OH)2/C (0.04 g, 284 umol). The reaction mixture was stirred at 20 °C for 40 hours under H2 (15 psi). On completion, the reaction mixture was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EA) to give the title compound (100 mg, 59% yield) as brown liquid. LCMS (ESH) m/z 615.1 (M+Na)+.

[004101] Step 3 - 3-r4-r3-r2-r2-r2-(2-Aminoethoxy)ethoxy1ethoxy1ethoxy1propyl1-3methyl oxo- benzimidazol-l-yl1piperidine-2,6-dione

[004102] To a solution of tert-butyl N-[2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (0.10 g, 168 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 20 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse flash (0.1 % FA condition) to give the title compound (25.0 mg, 30% yield) as gray solid. LC-MS (ESH) m/z 493.3 (M+H)+.

[004103] 2-[2-[2-(2-ProD ynoxyethoxy)ethoxy]ethoxy]ethanol (Intermediate UY)

TBAI, KOH, KI, THF

UY

[004104] To a mixture of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (20.0 g, 102 mmol, 17.7 mL, CAS# 25322 3) and 3-bromoprop yne (14.7 g, 123 mmol) in THF (200 mL) was added TBAI (2.28 g, 6.18 mmol), KI (2.56 g, 15.45 mmol) and KOH (5.78 g, 102 mmol). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 5/1 to 0/1) to give the title compound (16.0 g, 67% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 4.18 (d, J = 2.4 Hz, 2H), 3.70 (d, J= 4.8 Hz, 2H), 3.67 (d, J= 3.2 Hz, 2H), 3.69 - 3.61 (m, 10H), 3.60-3.57 (m, 2H), 2.73 (s, IH), 2.42 (t, J = 2.4 Hz, IH).

[004105] 2 12 [(4-Methoxyphenyl)methyl-methylamino] ethoxy] ethoxy] ethoxy] ethanamine (Intermediate UZ)

1312

I

BocHΝ---PMB-------&#9658;

K2CO3, DMF

BocH Ν N ' PM B

AO

HCl/dioxane

DCM

[004106] Step 1 - Tert-butyl N-r2-r2-r2-[2-r(4-methoxyphenyl)methyl-methylamino]ethoxy]ethoxy]ethoxy] ethyl]carbamate

[004107] To a solution of 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (1.65 g, 4.44 mmol, Intermediate AO), l-(4-methoxyphenyl)-N-methylmethanamine (671 mg, 4.44 mmol) in DMF (20.0 mL) was added K2CO3 (1.23 g, 8.88 mmol). The mixture was stirred at 20 °C for 15 hours. On completion, the mixture was diluted with H2O (60 mL), then extracted with EA (3X30 mL). The organic layers were washed with brine (3X30 mL) and dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (700 mg, 36% yield) as yellow oil. IH NMR (400MHz, CDCh) δ 8.52 (s, IH), 7.33 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.87 (s, 2H), 3.83 (s, 3H), 3.81-3.75 (m, 2H), 3.68 - 3.61 (m, 8H), 3.56 - 3.48 (m, 2H), 3.38 - 3.25 (m, 2H), 2.96 - 2.84 (m, 2H), 2.48 (s, 3H), 1.46 (s, 9H).

[004108] Step 2:2-r2-[2-r2-r(4-Methoxyphenvl)m ethyl-methylamino] ethoxy] ethoxy] ethoxy] ethanamine

[004109] To a solution of tert-butyl N-[2-[2-[2-[2-[(4-methoxyphenyl) methyl-methylamino]ethoxy]ethoxy] ethoxy]ethyl]carbamate (700 mg, 1.64 mmol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 10.0 mL). The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (590 mg, 90% yield, HCI salt) as yellow oil. LC-MS (ESI+) m/z 327.3 (M+H)+.

[004110] 2-(2,6-Dioxo DiDeridyD [2- [2- [2- [2(methylamino)ethoxy]ethoxy]ethoxy]ethylamino] isoindoline-1 3-dione (Intermediate VA)

1313

VA

[004111] Step 1 - 2-(2,6-Dioxo piperidyl) [2-[2-[2-[2-[(4-methoxyphenyl)methylmethylaminolethoxyl ethoxy1ethoxy1ethylamino1isoindoline-L3-dione

[004112] To a solution of 2-[2-[2-[2-[(4-methoxyphenyl)methyl-methylamino]ethoxy]ethoxy]ethoxy] ethanamine (590 mg, 1.63 mmol, HC1, Intermediate UZ), 2-(2,6dioxo piperidyl) fluoro-isoindoline-l,3-dione (494 mg, 1.79 mmol, Intermediate R) in dioxane (10.0 mL) was added DIPEA (2.10 g, 16.2 mmol). The mixture was stirred at 115 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (500 mg, 52% yield) as yellow solid. LC-MS (ESI+) m/z 583.3 (M+H)+.

[004113] Step 2:2-(2,6-Dioxo piperidyl) [2-[2-[2-[2(methylamino)ethoxy1ethoxy1ethoxy1ethylamino1 isoindoline-L3-di one

[004114] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-[2-[2-[(4methoxyphenyl)methyl-methylamino] ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-l,3-dione (400 mg, 686 umol) in MeOH (10.0 mL) was added Pd/C (200 mg) and Pd(OH)2/C (200 mg) and HC1 (1.00 M, 686 uL). The mixture was stirred at 15 °C for 1 hour under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by reverse phase (0.1% HC1) to give the title compound (160 mg, 50% yield) as yellow solid. LC-MS (ESI+) m/z 463.3 (M+H)+.

[004115] 3-[4-[3-[2-[2-[2-(2-Hvdroxvethoxv)ethoxv]ethoxv]ethoxy]DroDvl] methvl-2oxo- benzimidazol-l-yl]DiDeridine-2.,6-dione (Intermediate VB)

1314

Pd(PPh3)2CI2, Cui, DIPEA, DMSO, P(t-Bu)3

Pd/C, Pd(OH)2/C, H2

THF

[004116] Step 1 - 3-r4-r3-r2-r2-r2-(2-Hvdroxvethoxv)ethoxv1ethoxv1ethoxv1prop-l-vnyl13-methyl oxo- benzimidazol-l-yl1piperidine-2,6-dione

[004117] To a mixture of 2-[2-[2-(2-prop ynoxyethoxy)ethoxy]ethoxy]ethanol (1.03 g, 4.44 mmol, Intermediate UY) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (0.50 g, 1.48 mmol, Intermediate HP) in DMSO (20 mL) was added Cui (56.3 mg, 295umol), P(t-Bu)3 (2.30 g, 1.48 mmol, 2.67 mL, 13% solution of toluene), DIPEA (955 mg, 7.39 mmol) and Pd(PPh3)2C12 (103 mg, 147 umol). The reaction mixture was stirred at 80 °C for 3 hours. On completion, the reaction mixture was diluted with water (60 mL) and extracted with EA (4 X 60 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC (0.1 % FA condition) to give the title compound (0.50 g, 69% yield) as brown oil. 1HNMR (400MHz, DMSO-t/6) δ 11.11 (s, IH), 7.17 (d, 7= 8.0 Hz, IH), 7.15-7.11 (m, IH), 7.06-7.00 (m, IH), 5.40 (dd,7=5.2, 12.8 Hz, IH), 4.55 (t, 7= 5.2 Hz, IH), 4.46 (s, 2H), 3.70-3.61 (m, 5H), 3.60-3.57 (m, 2H), 3.53 - 3.51 (m, 6H), 3.49 - 3.47 (m, 4H), 3.41 - 3.39 (m, 2H), 2.95 - 2.84 (m, IH), 2.77 - 2.58 (m, 2H), 2.07 - 1.99 (m,

1315

IH).

[004118] Step 2 - 3-r4-r3-r2-r2-r2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethoxy1propyl1-3methyl oxo- benzimidazol-l-yl1piperidine-2,6-dione

[004119] To a mixture of 3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]prop-lynyl] methyl oxo-benzimidazol-l-yl]piperidine-2,6-dione (200 mg, 408 umol) in THF (10 mL) was added Pd/C (100 mg, 10% wt) and Pd(OH)2/C (100 mg, 10% wt). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtrated and concentrated in vacuo to give the title compound (180 mg, 89% yield) as white solid. 1H NMR (400MHz, DMSO4) δ 11.09 (s, IH), 6.96 (d, J = 4.4 Hz, 2H), 6.90 6.86 (m, IH), 5.36 (dd, J= 5.2, 12.4 Hz, IH), 4.57 (t, J = 5.2 Hz, IH), 4.03 (q, J = 7.2 Hz, IH), 3.56 (s, 3H), 3.52 (d, J = 5.6 Hz, 10H), 3.48 - 3.45 (m, 4H), 3.40 (d, J = 5.2 Hz, 2H), 2.98 - 2.93 (m, 2H), 2.89 - 2.84 (m, IH), 2.72 - 2.63 (m, 2H), 2.61 - 2.58 (m, 2H), 2.02 - 1.96 (m, 2H), 1.85 1.81 (m, IH); LC-MS (ESI+) m/z 494.3 (M+H)+.

[004120] 2-[[2-[[2-[Benzvloxvcarbonvl(methvl)amino]acetvl]-methyl-amino]acetvl]methyl-amino] acetic acid (Intermediate VC)

HCI

HATU, DIPEA, DMF

LiOH

THF/H2O

[004121] Step 1 -Methyl 2-rr2-rbenzyloxycarbonyl(methyl)amino1acetyl1-methylamino] acetate

[004122] To a solution of 2-[benzyloxycarbonyl(methyl)amino]acetic acid (4.30 g, 19.2 mmol, CAS# 39608 6) and methyl 2-(methylamino)acetate (2.69 g, 19.2 mmol, HCI, CAS # 5473 1) in DMF (25 mL) was added DIPEA (4.98 g, 38.5 mmol) and HATU (8.79 g, 23.1 mmol). The reaction mixture was stirred at 25 °C for 1 hours. On completion, the reaction mixture was quenched with water (100 mL) and extracted with EA (3 X 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried with anhydrous Na2SO4, filtered and

1316 concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (5.00 g, 84% yield) as colorless oil. LC-MS (ESI+) m/z 309.1 (M+H)+.

[004123] Step 2 - 2-rr2-[Benzyloxycarbonyl(methyl)amino1acetyl1-methyl-amino1acetic acid

[004124] To a solution of methyl 2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methylamino] acetate (2.00 g, 6.49 mmol) in THF (20 mL) and H2O (4 mL) was added LiOH (310 mg, 12.9 mmol). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was acidified to pH = 5 with 1.0 M aq. HCI and concentrated in vacuo. The residue was purified by flash (0.1 %, HCI) to give the title compound (1.80 g, 91% yield) as colorless oil. LCMS (ESI+) m/z 295.1 (M+H)+.

[004125] Step 3 - Methyl 2-rr2-rr2-[benzyloxycarbonyl(methyl)amino1acetyl1-methylaminolacetyll-methyl- aminolacetate

[004126] To a solution of methyl 2-(methylamino)acetate (1.02 g, 7.34 mmol, HCI, CAS # 5473 1) and 2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetic acid (1.80 g, 6.12 mmol) in DMF (20 mL) was added DIPEA (2.37 g, 18.3 mmol ) and HATU (2.56 g, 6.73 mmol). The reaction mixture was stirred at 25 °C for 30 minutes. On completion, the reaction mixture was quenched with water (30 mL) and extracted with EA (3 X 100 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography (PE/EA, 5/1 to 1/1) to give the title compound compound (1.30 g, 56% yield) as colorless oil. 1HNMR (400MHz, METHANOL-6/4) δ 7.40 - 7.26 (m, 5H), 5.11 (d, J= 17.1 Hz, 2H), 4.44 - 4.00 (m, 6H), 3.81 - 3.68 (m, 3H), 3.11 -2.91 (m, 9H).

[004127] Step 4 - 2-rr2-rr2-rBenzvloxvcarbonvl(methvl)amino1acetvl1-methylamin01acetyl1-methyl-amin01 acetic acid

[004128] To a solution of methyl 2-[[2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]methyl-amino] acetyl]-methyl-amino]acetate (1.00 g, 2.64 mmol) in THF (20 mL) and H2O (4 mL) was added LiOH (126 mg, 5.27 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL) and acidified to pH = 5 with 1.0 M aq.HCl. The reaction mixture was concentrated in vacuo. The residue was purified by flash (0.1 %, HCI) to give the title compound (600 mg, 62% yield) as a white solid. 1HNMR (400MHz, DMSO4) δ 7.41 - 7.23 (m, 5H), 5.13 - 5.01 (m, 2H), 4.35-3.88

1317 (m, 5H), 4.35 - 3.87 (m, IH), 3.04 - 2.74 (m, 9H).

[004129] 3-[3-Methvl [3-(methvlamino)DroDvl] oxo-benzimidazol-l-yl]DiDeridine

2,6-dione (Intermediate VD)

VD

[004130] Step 1 - Tert-butyl N-r3-r1-(2,6-dioxo piperidvl) methyl oxo-benzimidazol4-yl1prop ynyl1- N-methyl-carbamate

[004131] To a solution of tert-butyl N-methyl-N-prop ynyl-carbamate (450 mg, 2.66 mmol, Intermediate IY) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (300 mg, 887 umol, Intermediate HP) in DMF (15 mL) was added Cs2CO3 (1.45 g, 4.44 mmol), Cui (33.7 mg, 177 umol) and Pd(PPh3)2C12 (124 mg, 177 umol). The reaction mixture was stirred at 80 °C for 2 hours under N2. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (200 mg, 58% yield) as yellow solid. LC-MS (ESI+) m/z 449.2 (M+Na)+.

[004132] Step 2 - Tert-butyl N-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-vl1propyl1-N- methyl-carbamate

[004133] To a solution of tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynyl]-N-methyl-carbamate (220 mg, 515 umol) in THF (20 mL) was added Pd/C (250 mg, 10 wt%) and Pd(OH)2/C (250 mg, 10 wt%). The mixture was stirred at 25 °C under H2 (15 psi) for 2 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (210 mg, 94% yield) as a white solid. 1H NMR

1318 (400MHz, DMSO-/6) δ 11.08 (s, IH), 7.00 - 6.93 (m, 2H), 6.91 - 6.86 (m, IH), 5.36 (dd, J= 5.2, 12.4 Hz, IH), 3.55 (s, 3H), 3.28 - 3.21 (m, 2H), 2.91 - 2.83 (m, 3H), 2.80 (s, 3H), 2.75 - 2.61 (m, 2H), 2.01 - 1.96 (m, IH), 1.86 - 1.72 (m, 2H), 1.36 (s, 9H). LC-MS (ESI+) m/z 453.1(M + Na)+.

[004134] Step 3 - 3-r3-Methyl r3-(methylamino)propyl1 oxo-benzimidazol-lyl1piperidine-2,6-dione

[004135] To a solution of tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propyl] -N-methyl-carbamate (210 mg, 487 umo)in DCM (3 mL) was added HCl/dioxane (4 M, 3 mL). The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (178 mg, 99% yield, HCI) as a white solid. LC-MS (ESI+) m/z 331.1 (M+H)+.

[004136] N-[2-[[2-[3-[l-(2,6-dioxo DiDeridvl) methvl oxo-benzimidazol-4yl] amino] oxo-ethvl]-methvl-amino] oxo-ethvl]-N-methyl-2(methylamino)acetamide (Intermediate VE)

[004137] Step 1 - Benzyl N-r2-rr2-IT2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propylamino1 oxo-ethyl1-N-methyl-carbamate

[004138] To a solution of 3-[3-methyl [3-(methylamino)propyl] oxo-benzimidazol-lyl]piperidine -2,6-dione (100 mg, 272 umol, HCI, Intermediate VD) and 2-[[2-[[2[benzyloxycarbonyl(methyl)amino]acetyl] -methyl-amino]acetyl]- methyl-amino]acetic acid

1319 (99.6 mg, 272 umol, Intermediate VC) in DMF (5 mL) was HATU (124 mg, 327 umol) and DIPEA (176 mg, 1.36 mmol, 237 uL). The mixture was stirred at 25 °C for 1.5 hours. On completion, the reaction mixture was diluted with H2O (5 mL) and then concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (140 mg, 75% yield) as a white solid. 1HNMR (400 MHz, DMSO-76) δ 11.08 (s, IH), 7.41-7.19 (m, 5H), 7.03 - 6.81 (m, 3H), 5.36 (dd, J= 5.2, 12.4 Hz, IH), 5.10 - 4.94 (m, 2H), 4.35 - 4.13 (m, 4H), 4.08 - 3.85 (m, 2H), 3.61 - 3.51 (m, 3H), 3.46 - 3.26 (m, 5H), 2.98 - 2.76 (m, 14H), 2.72 - 2.59 (m, 2H), 2.04 - 1.71 (m, 3H). LC-MS (ESI+) m/z 678.3(M+H)+.

[004139] Step 2 - N-r2-rr2-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-4yllpropyl-methyl-amino1 oxo-ethyl1-methyl-amino1 oxo-ethyl1-N-methyl-2(methylamino)acetamide

[004140] To a solution of benzyl N-[2-[[2-[[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propyl-methyl-amino] oxo-ethyl]-methyl-amino] oxo-ethyl]-methylamino] oxo-ethyl]-N-methyl-carbamate (200 mg, 295 umol) in THF (10 mL) was added Pd/C (100 mg, 915 umol, 10 wt%) and Pd(OH)2/C (100 mg, 915 umol, 10 wt%). The mixture was stirred at 25 °C under H2 (15 psi) for 12 hours. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (140 mg, 87% yield) as a white solid. LCMS (ESI+) m/z 544.3(M+H)+.

[004141] 2-[[2-[[2-[Tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]methyl- amino] acetic acid (Intermediate VF)

HO.Boc

1 ° N &#1495;

O &#2404; MeO. z\ A Υχ .Boc __L1OH__^

-----------------&#9658; N &#1498;< N κ . 1 κ κι . Al Al THF/H2O isobutyl carbonochloridate O' O' 2

HATU, TEA, THF

VF

[004142] Step 1 - Methyl 2-rr2-rTert-butoxycarbonyl(methyl)amino1acetyl1-methyl amino] acetate

[004143] To a solution of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (5.00 g, 26.4

1320 mmol, CAS# 13734 6) in THF (25 mL) was added CDI (4.28 g, 26.4 mmol) under ice-cooling bath. The resulting mixture was stirred for 1 hour; then methyl 2-(methylamino)acetate (3.69 g, 26.4 mmol, HC1) was added followed by addition of a solution of TEA (2.94 g, 29.0 mmol, 4.05 mL) in THF (20 mL). The resulting mixture was stirred at 20 °C for 20 hours. On completion, the mixture was concentrated in vacuo. The residue was diluted with EA (100 mL), washed with 10% aq. NaHCO3 and 1 M aq. HC1 subsequently; dried with Na2SO4 filtered and concentrated in vacuo to give the title compound (3.73g, 51% yield) as yellow oil. 1HNMR (400MHz, DMSO-Y) δ 4.35 - 4.23 (m, 4H), 3.55 - 3.45 (m, 3H), 3.05 (s, 3H), 2.89 - 2.93 (m, 3H), 1.47 - 1.25 (m, 9H).

[004144] Step 2 - Methyl 2-rmethvl-[2-(methvlamino)acetvl1amino1acetate

[004145] To a solution of methyl 2-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]-methylamino] acetate (3.73 g, 13.60 mmol) in DCM (10 mL) was added TFA(7.70 g, 67.53 mmol, 5 mL) under 0 °C. The resulting mixture was stirred at 20 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give to give the title compound (3.85 g, 98% yield, TFA salt) as yellow oil.

[004146] Step 3 -Methyl 2-rr2-rr2-rtert-butoxycarbonyl(methyl)amino1acetyl]-methylaminolacetyl] -methyl- aminolacetate

[004147] To a solution of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (1.31 g, 6.94 mmol, CAS #13734 6) and TEA (3.51 g, 34.7 mmol, 4.83 mL) in THF (50 mL) was isobutyl carbonochloridate (2.37 g, 17.3 mmol, 2.28 mL, CAS# 543 1) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour, then methyl 2-[methyl-[2- (methylamino)acetyl]amino]acetate (2.00 g, 6.94 mmol, TFA) was added, and the mixture was stirred at 25 °C for 3 hours. On completion, the reaction mixture was diluted with H2O (50 mL), and extracted with EA (2 X 100 mL), then concentrated in vacuo. The residue was purified by prep-HPLC (column: Kromasil 150*25mm*10um; mobile phase: [water(0.225%FA)-ACN];B%: 17%-47%,10min) to give the title compound (400 mg, 16% yield) as yellow oil. 1H NMR (400MHz, CD3C1) δ 4.15 - 4.12 (m, 3H), 3.78 (s, IH), 3.82 - 3.77 (m, IH), 3.75 - 3.73 (m, 2H), 3.09 - 3.05 (m, 5H), 2.99 - 2.95 (m, 2H), 2.92 (s, 3H), 2.95 - 2.88 (m, 3H), 1.46 (s, 9H).

[004148] Step 4 - 2-rr2-rr2-rTert-butoxycarbonyl(methyl)amino1acetyl]-methylamino]acetyl]-methyl- amino] acetic acid

[004149] To a solution of methyl 2-[[2-[[2-[tert-butoxycarbonyl(methyl)amino] acetyl]methyl-amino] acetyl]-methyl -amino]acetate (200 mg, 579 umol) in THF (4 mL) and H2O (2 mL)

1321 was added LiOH (27.7 mg, 1.16 mmol). The reaction mixture was stirred at 25 °C for 12 hr. On completion, the mixture was concentrated in vacuo. The residue was diluted with H2O (4 mL), and then adjusted to pH = 5 with 1.0 M aq.HCl to give the title compound (190 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 232.1 (M +H)+.

[004150] 3-[3-Methvl [3-(methvlamino)DroDvl] oxo-benzimidazol-l-yl]DiDeridine-

[004151] Step 1 - Tert-butyl N-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1prop ynyl1 -N-methyl-carbamate

[004152] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6di one (400 mg, 1.18 mmol, Intermediate HN), tert-butyl N-methyl-N-prop ynyl-carbamate (400 mg, 2.37 mmol, Intermediate IY) and Pd(PPh3)2C12 (83.0 mg, 118 umol) in DMF (4 mL) was added PPh3 (62.0 mg, 236 umol), TEA (2.15 g, 21.2 mmol) and Cui (22.5 mg, 118 umol). The reaction mixture was stirred at 80 °C for 3 hours under N2. On completion, the reaction mixture was quenched with aq. NH4C1 (30 mL) and extracted with EA (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash (0.1%, FA) to give the title compound (200 mg, 37% yield) as a yellow solid. LC-MS (ESI+) m/z 427.1 (M+H)+.

[004153] Step 2 - Tert-butyl N-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1 propyl 1-N- methyl-carbamate

[004154] To a solution of tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynyl]-N-methyl-carbamate (200 mg, 468 umol) in THF (20 mL) was

1322 added Pd(0H)2 (25.0 mg, 178 umol) and Pd/C (25.0 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 psi). On completion, the reaction mixture was diluted with EA (20 mL), filtered through a short of silica column and washed with EA (2 X 50 mL). The organic layers were concentrated in vacuo. The residue was purified by flash chromatography (0.1%, FA) to give the title compound (200 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 331.0 (M100+H)+.

[004155] Step 3 - 3-r3-Methyl r3-(methylamino)propyl1 oxo-benzimidazol-lyl1piperidine-2,6-dione

[004156] To a solution of tert-butyl N-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propyl]- N-methyl-carbamate (200 mg, 464 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25 °C for 20 min. On completion, the reaction mixture was concentrate in vacuo to give the title compound (150 mg, 97% yield) as a white solid. LC-MS (ESI+) m/z 331.1 (M+H)+.

[004157] N-[2-[[2-[3-[l-(2,6-dioxo DiDeridvl) methvl oxo-benzimidazol-5yl] amino] oxo-ethvl]-methvl-amino] oxo-ethvl]-N-methyl-2(methylamino)acetamide (Intermediate VH)

1323

VF

HATU, DIPEA, DMF

HCI/dioxane

DCM

VH

[004158] Step 1 - Tert-butyl N-r2-rr2-rr2-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol-5amino1 oxo-ethyl1-N-methyl-carbamate

[004159] To a solution of 3-[3-methyl [3-(methylamino)propyl] oxo-benzimidazol-lyl]piperidine-2,6-dione (100 mg, 272 umol, HCI, Intermediate VG) and 2-[[2-[[2-[tertbutoxycarbonyl(methyl)amino]acetyl]-methyl- amino]acetyl]-methyl-amino]acetic acid (108 mg, 327 umol, Intermediate VF) in DMF (5 mL) was added DIPEA (105 mg, 817 umol) and HATU (124 mg, 327 umol). The reaction mixture was stirred at 25 °C for 30 mines. On completion, the reaction mixture was quenched with water (5 mL), concentrated in vacuo. The residue was purified by flash chromatography (0.1%, FA) to give the title compound (50.0 mg, 28% yield) as a white solid. LC-MS (ESI+) m/z 644.2 (M+H)+.

[004160] Step 2 - N-r2-rr2-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5vllpropyl-methyl-amino1 oxo-ethyl1-methyl-amino1 oxo-ethyl1-N-methyl-2(methylamino)acetamide

[004161] To a solution of tert-butyl N-[2-[[2-[[2-[3-[l-(2,6-dioxo piperidyl) methyl-2

1324 oxo-benzimidazol yl]propyl-methyl-amino] oxo-ethyl]-m ethyl-amino] oxo-ethyl]-methylamino] oxo-ethyl]-N-methyl-carbamate (50.0 mg, 77.6 umol) in DCM (4 mL) was added HCI/dioxane (4 M, 10 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (40.0 mg, 88% yield, HCI) as a white solid. LC-MS (ESI+) m/z 544.2 (M+H)+.

[004162] N-[3-carbamovl-l-(4-formvlDhenvl)pvrazol vl] cvano-pyridine-2carboxamide (Intermediate VI)

GB

DMP

DCM

VI

[004163] Step 1 - N-r3-carbamoyl-l-r4-(hydroxymethyl)phenyl1pyrazol yl1 cyanopyridine-2 -carboxamide

[004164] To a solution of 4-amino-l-[4-(hydroxymethyl)phenyl]pyrazole carboxamide (200 mg, 861 umol, Intermediate GB) and 4-cyanopyridine carboxylic acid (102 mg, 688 umol, CAS# 640296 1) in DMF (5 mL) was added DIPEA (222 mg, 1.72 mmol) and HATU (327 mg, 861 umol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was poured into water (10 mL), the solid was filtered and washed with water (2X5 mL). Then the solid was dried in vacuo to give the title compound (200 mg, 42% yield) as a white solid. LC-MS (ESI+) m/z 385.0 (M+Na)+.

[004165] Step 2 - N-r3-carbamoyl-l-(4-formylphenyl)pyrazol yl1 cyano-pyridine-2carboxamide

[004166] To a solution of N-[3-carbamoyl-l-[4-(hydroxymethyl)phenyl]pyrazol yl]-4cyano-pyridine carboxamide (130 mg, 358 umol) in THF (10 mL) was added DMP (152 mg,

1325

358 umol) at 0 °C. Then the reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (100 mg, 277 umol, 77% yield) as a white solid. LC-MS (ESI+) m/z 383.0 (M+Na)+.

[004167] 2-[2-[2-[2-[3-[l-(2.,6-Dioxo DiDeridvD methvl oxo-benzimidazol-4yl]propoxy]ethoxy] ethoxy]ethoxy]ethyl methanesulfonate (Intermediate VJ)

VB

VJ

[004168] To a solution of 3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]3-methyl-2 -oxo-benzimidazol-l-yl]piperidine-2,6-dione (150 mg, 304 umol, Intermediate VB) in DCM (10 mL) was added TEA (92 mg, 911 umol) and MsCI (104 mg, 911 umol). The mixture was stirred at 25 °C for 4 hours. On completion, the mixture was concentrated in vacuo to give the title compound (170 mg, 98% yield) as yellow oil. LC-MS (ESI+) m/z 572.3 (M+l)+.

[004169] 3-[4-[3-[2-[2-[2-[2-(4-Amino-lpiperidvDethoxy] ethoxy] ethoxy] ethoxy] propyl] methvl oxo-benzimidazol-1yl]piperidine-2.,6-dione (Intermediate VK)

1326

NHBoc

HCl/dioxane

DCM

VK

[004170] Step 1 - Tert-butyl Ν-|&#906;-[2-[2-[2-[2-[3-|&#906;-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl] piperidyl]carbamate

[004171] To a solution of 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy] ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (250 mg, 437 umol, Intermediate VJ) in ACN (10 mL) was added KI (7.26 mg, 43 umol), NaHCO3 (110 mg, 1.31 mmol) and tert-butyl N-(4-piperidyl)carbamate (175 mg, 875 umol, CAS# 73874 0). The mixture was stirred at 80 °C for 16 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed phase flash chromatography to give the title compound (200 mg, 66% yield) as light yellow oil. LC-MS (ESI+) m/z 676.4 (M+l)+. [004172] Step 2:3-Γ4-Γ3-Γ2-[2-Γ2-Γ2-(4-Αιη&#912;ηο-1piperidyl)ethoxy]ethoxy]ethoxy]ethoxy]propyl] methyl-2 2,6-dione

[004173] To a solution of tert-butyl N-[l-[2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl2-oxo- benzimidazol yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl] piperidyl]carbamate (200 mg,

1327

295 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 3 hours. On completion, the mixture was concentrated in vacuo to give the title compound (180 mg, 99% yield) as yellow solid. LC-MS (ESI+) m/z 576.4 (M+l)+.

[004174] [4-(47,.6,.5&#1524;-Tetrahvdr0Dvraz010[4.,3-b]Dvridin vl)Dhenvl]methan01 (Intermediate

[004175] Step 1 - Tert-butyl 2,5A7-tetrahydropyrazolo[4,3-b1pyridine carboxylate [004176] To a mixture of 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (500 mg, 3.13 mmol, HCI, CAS# 1187830 2) and (Boc)2O (752 mg, 3.45 mmol) inMeOH (15 mL) was added aq.K2CO3 (3 M, 2.09 mL). The reaction mixture was stirred at 20 °C for 15 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2) to give the title compound (500 mg, 71% yield) as a white solid. 1H NMR (400MHz, DMSO-» δ 12.05 (s, IH), 7.55 (s, IH), 3.66 - 3.55 (m, 2H), 2.65 (t, J= 6.4 Hz, 2H), 1.94 - 1.82 (m, 2H), 1.51 (s, 9H).

[004177] Step 2 - Tert-butyl 2-[4-(hvdroxvmethvl)phenvl]-6.7-dihvdro-5H-pyrazolo[4.3b1pyridine carboxylate

[004178] To a solution of [4-(hydroxymethyl)phenyl]boronic acid (112 mg, 739 umol, CAS#

59016 2) and tert-butyl 2,5,6,7-tetrahydropyrazolo[4,3-b]pyridine carboxylate (110 mg, 493 umol) in DCM (5 mL) was added Cu(OAc)2 (179 mg, 985 umol) and pyridine (2 mL). The reaction mixture was stirred at 25 °C for 12 hours under oxygen (15 psi) atmosphere. On completion, the mixture was quenched with ammonia water (20 mL), stirred and separated. The organic layer was acidified to pH = 5 with IN aq.HCl (20 mL), separated and washed with brine (20 mL), then concentrated in vacuo. The mixture was purified by silica gel chromatography (SiO2) to give the title compound (80.0 mg, 49% yield) as colorless oil. 1H NMR (400MHz, DMSO-» δ 8.16 (s,

1328

IH), 7.64 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 4.93 (t, J = 5.6 Hz, IH), 4.53 (d, J= 5.6 Hz, 2H), 3.72 - 3.62 (m, 2H), 2.78 - 2.71 (m, 2H), 2.00 -1.91 (m, 2H), 1.54 (s, 9H); LC-MS (ESI+) m/z 330.2 (M+H)+.

[004179] Step 3 - r4-(4,5,6,7-Tetrahvdropvrazolor4,3-b1pvridin vl)phenyl1methanol

[004180] To a solution of tert-butyl 2-[4-(hydroxymethyl)phenyl]-6,7-dihydro-5Hpyrazolo[4,3-b]pyridine carboxylate (60.0 mg, 182 umol) in DCM (4 mL) was added HCI/dioxane (4 mL). The reaction mixture was stirred at 25 °C for 12 hours. On completion, the mixture was concentrated in vacuo to give the title compound (45 mg, 93% yield, HCI) as a yellow solid. LC-MS (ESI+) m/z 230.1 (M+H)+.

[004181] Tert-butyl N-[4-[4-[2-(4-formvlDhenvl)-6,7-dihydro-5H-Dvrazolo[4,3b]Dyridine carbonyl]oxazoLUylJXiivHdylJXJTXUtnfhuinietln^^ (Intermediate VM)

VL

VM

[004182] Step 1 - Tert-butyl N-r4-r4-r2-r4-(hydroxymethyl)phenyl1-6,7-dihydro-5Hpyrazolo[4,3-b1pyridine carbonyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate [004183] To a solution of [4-(4,5,6,7-tetrahydropyrazolo[4,3-b]pyridin-2yl)phenyl]methanol (45.0 mg, 169 umol, HCI, Intermediate VL) and 2-[2-[tertbutoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole carboxylic acid (52.5 mg, 135 umol, Intermediate CM) in DMF (4 mL) was added HATU (64.4 mg, 169 umol) and DIPEA (109 mg, 847 umol). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the mixture was quenched with water (50 mL), stirred and filtered. The filter cake was dried in vacuo to give the title compound (70 mg, 69% yield) as a brown solid. LC-MS (ESI+) m/z 599.3 (M+H)+

1329

[004184] Step 2 - Tert-butyl N-r4-r4-r2-(4-formylphenyl)-6,7-dihydro-5H-pyrazolo[4,3b1pyridine carbonyl1 0xaz0l yl1 pyridyl1-N-(2,2,2-trifluoroethyl )carbamate

[004185] To a solution of tert-butyl N-[4-[4-[2-[4-(hydroxymethyl)phenyl]-6,7-dihydro-5Hpyrazolo[4,3-b] pyridine carbonyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (70.0 mg, 117 umol) in DCM (4 mL) was added DMP (74.4 mg, 175 umol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched with sat.NaHCO3 (20 mL) and sat. Na2S2O3 (20 mL) and extracted with DCM (2 X 30 mL). The organic layer was washed with brine (40 mL), dried over Na2SO4, fdtered and the fdtrate was concentrated in vacuo to give the title compound (65 mg, 93% yield) as a yellow solid. LC-MS (ESI+) m/z 597.3 (M+H)+.

[004186] (4-Nitrophenyl)N-[2-[2-[2-(tertbutoxycarbonylaminolethoxylethoxy]ethyl]carbamate (Intermediate VN)

TEA, DCM H

VN

[004187] To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (500 mg, 2.01 mmol, CAS# 153086 3), (4-nitrophenyl)carbonochloridate (446 mg, 2.21 mmol) in DCM (20.0 mL) was added TEA (509 mg, 5.03 mmol). The mixture was stirred at 0 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (800 mg, 90% yield) as yellow solid. LC-MS (ESI+) m/z 314.1 (M+H-100)+

[004188] l-[2-[2-(2-Aminoethoxv)ethoxv]ethvl] [[2-(2,6-dioxo piperidyl)-l-oxoisoindolin yl]methyl]urea (Intermediate VO)

1330

[004189] Step 1 - Tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin yl1 methyl carb amoylami no] ethoxy] ethoxy] ethyl 1 carb amate

[004190] To a solution of 3-[5-(aminomethyl)-l-oxo-isoindolin yl]piperidine-2,6-dione (130 mg, 419 umol, HC1, Intermediate QM), (4-nitrophenyl) N-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethyl]carbamate (347 mg, 839 umol, Intermediate VN) in DMF (15.0 mL) was added TEA (212 mg, 2.10 mmol). The mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% FA) to give the title compound (170 mg, 73% yield) as white solid. 1HNMR (400MHz, DMSO-76) δ 10.99 (s, IH), 7.67 (d, J = 7.6 Hz, IH), 7.45 (s, IH), 7.38 (d, J = 7.6 Hz, IH), 6.78 (s, IH), 6.56 (t, J = 6.0 Hz, IH), 6.04 (t, J = 5.6 Hz, IH), 5.16 - 5.05 (m, IH), 4.47 - 4.24 (m, 4H), 3.53 - 3.36 (m, 8H), 3.24 - 3.13 (m, 2H), 3.10 - 3.02 (m, 2H), 2.99 - 2.85 (m, IH), 2.65 - 2.55 (m, IH), 2.46 - 2.36 (m, IH), 2.05 - 1.94 (m, IH), 1.37 (s, 9H).

1331

[004191] Step 2 - l-r2-r2-(2-Aminoethoxy)ethoxy1ethyl1 rr2-(2,6-dioxo piperidyl)-loxo-isoindolin yUmethyllurea

[004192] To a solution of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l-oxo-isoindolin5-yl] methylcarbamoylamino]ethoxy]ethoxy]ethyl]carbamate (170 mg, 310 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 8.00 mL). The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 90% yield, HCI) as white solid. LC-MS (ESI+) m/z 448.1 (M+H)+.

[004193] Methyl 5-[4-amino (difluoromethvl)Dvrazol-l-vl]Dvridine carboxylate (Intermediate VP)

VP

[004194] Step 1 - Methyl 5-[3-(difluoromethyl) nitro-pyrazol-l-yl1pyridine carboxylate [004195] To a solution of 3-(difluoromethyl) nitro-lH-pyrazole (200 mg, 1.23 mmol, Intermediate HS), (6-methoxycarbonyl-3 -pyridyl)boronic acid (266 mg, 1.47 mmol, CAS# 1072945 8) in DCM (20 mL) was added Cu(OAc)2 (334 mg, 1.84 mmol) and pyridine (388 mg, 4.91 mmol). The mixture was stirred at 15 °C for 6 hrs under 02 (15 psi). On completion, the mixture washed with NH3*H2O (100 mL) and then the layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with PE: EA = 1:1 (50 mL) and filtered. The filtered cake was dried in vacuo to give the title compound (100 mg, 27 % yield) as a yellow solid. 1H NMR (400 MHz, CDCh) δ 9.23 - 9.08 (m, IH), 8.85 (s, IH), 8.35 (s, 2H), 7.26 - 7.06 (t, J= 52 Hz, IH), 4.08 (s, 3H).

[004196] Step 2 - Methyl 5-[4-amino (difluoromethyl)pyrazol-l-yl1pyridine-2carboxylate

[004197] To a solution of methyl 5-[3-(difluoromethyl) nitro-pyrazol-l-yl]pyridine-2carboxylate (100 mg, 335 umol) in DCM (10 mL) was added Pd/C (50.0 mg, 50 wt%). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred

1332 under H2 (15 psi) at 15 °C for 2 hours. On completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (89.0 mg, 332 umol, 99% yield) as a yellow solid. 1HNMR (400 MHz, DMSO-76) δ 9.13 (d, 7=2.0 Hz, IH), 8.32-8.29 (m, IH), 8.16 (d, 7=8.4 Hz, IH), 7.29 - 6.97 (t, 7=5.2 Hz, IH), 8.00 (s, IH), 3.91 (s, 3H), 4.62 (s, 2H).

[004198] 5-[4-[[2-[2-[Tert-but0xvcarb0nvl(cvcl0Dr0Dvlmethyl)amin0]-4 pyridyl] oxazole carbonyl] amino] (difluoromethyl)Dvrazol-l-vl] pvridine carboxvlic acid (Intermediate VO)

VQ

[004199] Step 1 - Methyl 5-r4-rr2-r2-rtert-butoxycarbonyl(cyclopropylmethyl)amino1-4 pyridyl1oxazole-4 -carbonyl1amino1 (difluoromethyl)pyrazol-l-yl1pyridine carboxylate

[004200] To a solution of methyl 5-[4-amino (difluoromethyl)pyrazol-l-yl]pyridine-2carboxylate (0.300 g, 1.12 mmol, Intermediate VP) and 2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carboxylic acid (402 mg, 1.12 mmol, Intermediate OM) in DMF (2 mL) was added HATU (510 mg, 1.34 mmol) and DIPEA (361 mg, 2.80 mmol). The mixture was stirred at 15 °C for 2 hrs. On completion, to the mixture was added into H2O and a precipitate formed. The mixture was filtered and the filter cake was dried in vacuo to give the title compound (50.0 mg, 820 umol, 73% yield) as a yellow solid. LC-MS (ESI+) m/z 610.3 (M+H)+.

[004201] Step 2 - 5-r4-rr2-r2-rTert-butoxycarbonyl(cyclopropylmethyl)amino1-4pyridyl1oxazole carbonyl1 amino1 (difluoromethyl)pyrazol-l-yl1pyridine carboxylic acid [004202] To a solution of methyl 5-[4-[[2-[2-[tert1333 butoxycarbonyl(cyclopropylmethyl)amino] pyridyl] oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]pyridine carboxylate (500 mg, 820 umol) in THF (50 mL), H2O (50 mL) and MeOH (10 mL) was added LiOH H2O (172 mg, 4.10 mmol). The mixture was stirred at 15 °C for 6 hrs. On completion, the mixture was adjusted to pH=6-7 with 1.0 M aq.HCl and a precipitate formed. The mixture was filtered and the filter cake was dried in vacuo to give the title compound (500 mg, 90% yield, 90% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-Y) δ 10.16 (s, IH) 9.28 (d, J = 2.4 Hz, IH) 9.07 (s, 2H) 8.60 (d, J = 5.2 Hz, IH) 8.44 - 8.52 (m, IH) 8.32 (s, IH) 8.18 - 8.25 (m, IH) 7.64 - 7.78 (m, IH) 7.19 - 7.52 (m, IH) 1.52 (s, 9H) 1.09 - 1.28 (m, IH) 0.35 - 0.50 (m, 2H) 0.24 (q, J= 4.8 Hz, 2H); LC-MS (ESI+) m/z 596.2 (M+H)+.

[004203] 3-[5-[3-[2-(2-Aminoethoxv)ethoxy|propvl] methvl oxo-benzimidazol-lyl] piperidine- 2.,6-dione (Intermediate VR)

NHBoc -----------------------*

Pd(PPh3)2CI2, Cui, DIPEA, DMSO

Pd/C, Pd(OH)2, H2

THF

HCI/dioxane

DCM

O

VR

[004204] Step 1 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1prop-2 -ynoxy1ethoxy1ethyl1carbamate

1334

[004205] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (250 mg, 739 umol, Intermediate HN) and tert-butyl N-[2-(2-prop-2ynoxyethoxy)ethyl]carbamate (540 mg, 2.22 mmol, synthesized via Step 1 of Intermediate CQ) in DMSO (10 mL) was added Cui (28.2 mg, 148 umol), DIPEA (478 mg, 3.70 mmol) and Pd(PPh3)2C12 (104 mg, 148 umol). The mixture was stirred at 80 °C for 2 hrs in a glove box. On completion, the reaction mixture was purified by reverse phase chromatography (0.1% FA condition) to give the title compound (140 mg, 35 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-76) δ 11.12 (s, IH), 7.33 (s, IH), 7.22 - 7.09 (m, 2H), 6.86 - 6.71 (m, IH), 5.42-5.37 (m, IH), 4.40 (s, 2H), 3.67 - 3.61 (m, 2H), 3.59 - 3.53 (m, 2H), 3.08 (m, 2H), 2.95 - 2.86 (m, IH), 2.08 - 2.00 (m, IH), 1.37 (s, 9H). LC-MS (ESI+) m/z 506.3 (M+4)+.

[004206] Step 2 - Tert-butyl N-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 propoxy] ethoxylethyllcarbamate

[004207] To a solution of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]ethoxy]ethyl]carbamate (120 mg, 240 umol) in THF (20 mL) was added Pd/C (50 mg, 50 wt%) and Pd(OH)2/C (50 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 15 °C for 2 hours. On completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo to give the title compound (100 mg, 80% yield) as a yellow solid. LC-MS (ESI+) m/z 505.3 (M+H)+.

[004208] Step 3 - 3-r5-r3-r2-(2-Aminoethoxy)ethoxy1propyl1 methyl oxobenzimidazol-l-yl1piperidine- 2,6-dione

[004209] To a solution of tert-butyl N-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]ethyl]carbamate (100 mg, 198 umol) in DCM (10 mL) was added HCI/dioxane (4 M, 5 mL). The mixture was stirred at 15 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (80.0 mg, 95% yield) as a yellow solid. LC-MS (ESI+) m/z 405.2 (M+H)+.

[004210] Tert-butyl N-[2-[2-(2-DroD vnoxvethoxv)ethoxy]ethvl]carbamate (Intermediate VS)

NHB0C

TBAI, KI, KOH, THF

VS

1335

[004211] Amixture of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (3.00 g, 12.0 mmol), 3-bromoprop yne (1.72 g, 14.4 mmol, 1.24 mL), TBAI (356 mg, 962 umol), KI (299 mg, 1.81 mmol) and KOH (675 mg, 12.0 mmol) in THF (30 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16 hrs under N2 atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.50 g, 72% yield) as light yellow oil. 1H NMR (400MHz, CDCh) δ 5.05 (s, IH), 4.22 (d, J= 2.4 Hz, 2H), 3.76 - 3.60 (m, 8H), 3.55 (t, J= 5.2 Hz, 2H), 3.35 - 3.27 (m, 2H), 2.44 (t, J= 2.4 Hz, IH), 1.47 (s, 9H).

[004212] 3 13 [2-(2-Aminoethoxvlethoxy] ethoxv]propyl] methvl oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate VT)

H2, Pd/C, Pd(OH)2/C

THF

NHBoc

HCI/dioxane

DCM

VT

[004213] Step 1 - Tert-butyl N-r2-r2-r2-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1prop- 2-ynoxy1ethoxy1ethoxy1ethyl1carbamate

1336

[004214] A mixture of tert-butyl N-[2-[2-(2-prop ynoxyethoxy)ethoxy]ethyl]carbamate (849 mg, 2.96 mmol, Intermediate VS), 3-(5-bromo methyl oxo-benzimidazol-lyl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate HN), Pd(PPh3)2C12 (311 mg, 443 umol), Cui (84 mg, 443 umol) and TEA(2.69 g, 26.6 mmol, 3.70 mL) in DMF (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 °C for 3 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (400 mg, 49% yield) as light yellow solid. 1H NMR (400MHz, DMSO4) δ 11.12 (s, IH), 7.33 (s, IH), 7.21 - 7.12 (m, 2H), 6.77 - 6.71 (m, IH), 5.39 (dd, J= 5.2, 12.8 Hz, IH), 4.40 (s, 2H), 3.68 - 3.62 (m, 2H), 3.61 3.56 (m, 2H), 3.55 - 3.47 (m, 6H), 3.35 (s, 3H), 3.07 (q, J= 6.0 Hz, 2H), 2.96 - 2.80 (m, IH), 2.72 - 2.58 (m, 2H), 2.08 - 1.99 (m, IH), 1.37 (s, 9H).

[004215] Step 2 - Tert-butyl N-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxob enzimi dazol - 5 -yl 1 propoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[004216] To a solution of tert-butyl N-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo- benzimidazol yl]prop ynoxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 734 umol) in THF (100 mL) was added Pd/C (300 mg, 10 wt%) and Pd(OH)2/C (300 mg, 10 wt%). The mixture was stirred at 20 °C for 4 hrs under H2 (15 psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (270 mg, 67% yield) as light yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 11.07 (s, IH), 7.08 - 6.96 (m, 2H), 6.87 (d, J= 7.2 Hz, IH), 6.73 (s, IH), 5.34 (dd, J= 5.2, 12.4 Hz, IH), 3.69 - 3.35 (m, 15H), 3.09 - 3.01 (m, 2H), 2.97 - 2.81 (m, IH), 2.77 - 2.57 (m, 4H), 2.08 - 1.94 (m, IH), 1.89 - 1.71 (m, 2H), 1.37 (s, 9H).

[004217] Step 3 - 3-r5-r3-r2-r2-(2-Aminoethoxy)ethoxy1ethoxy1propyl1 methyl oxobenzimidazol-l-yl1 piperi dine-2,6-di one

[004218] To a solution of tert-butyl N-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]propoxy]ethoxy]ethoxy]ethyl]carbamate (270 mg, 492 umol) in DCM (10 mL) was added HCI/dioxane (4 M, 5 mL). The mixture was stirred at 25 °C for 3 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (220 mg, 92% yield) as light yellow solid. 1HNMR (400MHz, DMSO&#1470;d6) δ 11.08 (s, IH), 7.86 (s, 3H), 7.07 - 6.97 (m, 2H), 6.91 - 6.84 (m, IH), 5.40 - 5.29 (m, IH), 3.61 (t, J= 5.2 Hz, 2H), 3.59 - 3.56 (m, 4H), 3.55 3.53 (m, 2H), 3.52 - 3.48 (m, 2H), 3.43 - 3.40 (m, 2H), 3.33 (s, 3H), 3.02 - 2.84 (m, 3H), 2.76 2.58 (m, 4H), 2.05 - 1.97 (m, IH), 1.87 - 1.73 (m, 2H).

1337

[004219] 3 13 [2-(2-Aminoethoxv)ethoxy| ethoxv]propyl] methvl oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate VU)

Pd(PPh3)2CI2, Cui, Cs2CO3, DMF

VS

Pd/C, Pd(OH)2/C, H2

THF

HCl/dioxane

DCM

VU

[004220] Step 1 - Tert-butyl N-r2-r2-r2-r3-r1-(2,6-dioxo piperidvl) methyl oxob enzimi dazol yl 1 prop ynoxy 1 ethoxy] ethoxy] ethyl 1 carb am ate

[004221] A mixture of tert-butyl N-[2-[2-(2-prop ynoxyethoxy)ethoxy]ethyl]carbamate (1.27 g, 4.44 mmol, Intermediate VS), 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (500 mg, 1.48 mmol, Intermediate HP), Cui (85 mg, 446 umol), Pd(PPh3)2C12 (311 mg, 443 umol) and Cs2CO3 (2.41 g, 7.39 mmol) in DMF (12 mL) was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, after cooled to 25 °C, the mixture was filtered through a pad of celite and the cake was washed with EA (50 mL). The filtrate and washing were combined, diluted with water (100 mL), and extracted with EA (3 X 40 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was

1338 purified by reversed phase chromatography (0.1 % FA condition) to give the title compound (420 mg, 52% yield) as light yellow gum. 1HNMR (400 MHz, DMSO-/6) δ 11.11 (s, IH), 7.17 (d, J = 8.0 Hz, IH), 7.10-7.15 (m, IH), 7.00 - 7.06 (m, IH), 5.39 (dd, J= 12.4, 5.6 Hz, IH), 4.46 (s, 2H), 3.61 - 3.69 (m, 5H), 3.55 - 3.60 (m, 2H), 3.46 - 3.55 (m, 6H), 3.05 (q, J= 6.0 Hz, 2H), 2.83 - 2.93 (m, IH), 2.58 - 2.76 (m, 3H), 2.04 - 2.02 (m, IH), 1.36 (s, 9 H).

[004222] Step 2 - Tert-butyl N-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol vl1 propoxy1ethoxy1ethoxy1ethyl1carbamate

[004223] To a solution of tert-butyl N-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynoxy]ethoxy]ethoxy]ethyl]carbamate (500 mg, 918 umol) in THF (10 mL) was added Pd/C (200 mg, 918 umol, 10 wt%) and Pd(OH)2 (200 mg, 1.42 mmol). The mixture was stirred at 25 °C for 16 hours under H2 (15 psi). On completion, the mixture was filtered through a pad of celite, and the cake was washing with EA (20 mL). The filtrate and washing were combined and concentrated in vacuo to give the title compound (500 mg, 90% yield) as light yellow gum. LC-MS (ESI+) m/z 549.2 (M+H)+.

[004224] Step 3 - 3-r4-r3-r2-r2-(2-Aminoethoxy)ethoxy1ethoxy1propyl1 methyl oxobenzimidazol-l-yl] piperi dine-2,6-di one

[004225] To a mixture of tert-butyl N-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 182 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 4.00 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (100 mg, 98% yield, HCI) as light yellow solid. LC-MS (ESI+) m/z 449.3 (M+H)+.

[004226] Tert-butyl 2-(2-allyloxvethoxv)acetate (Intermediate VV)

[004227] To a mixture of 2-allyloxyethanol (3.00 g, 29.3 mmol) and diacetoxyrhodium (520 mg, 1.18 mmol) in DCM (30 mL) was added a solution of tert-butyl 2-diazoacetate (12.5 g, 88.1 mmol, CAS# 35059 8) in DCM (30 mL) at 25 °C dropwise during 2 hours. The mixture was stirred at 25 °C for 16 hours under N2. On completion, to the mixture was added HO Ac (5.0 mL). Then, the mixture was stirred at 25 °C for 0.5 hour. The mixture was concentrated in vacuo. The

1339 residue was purified by column chromatography over silica gel to give the title compound (6.80 g, 100% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 6.00 - 5.85 (m, IH), 5.29 (dd, J = 17.2, 2.0 Hz, IH), 5.19 (dd, J= 10.4, 1.6 Hz, IH), 4.07 - 4.02 (m, 4H), 3.77 - 3.71 (m, 2H), 3.67 -3.59(m, 2H), 1.49 (s, 9H).

[004228] 2-[2-[3-[l-(2,

6-Dioxo piperidvl) methyl oxo-benzimidazol-5yl] propoxy] ethoxy] acetic acid (Intermediate VW)

Pd2(dba)3, t-Bu3P DIPEA,dioxane

[004229] Step 1 - Tert-butyl 2-r2-r(E) r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol-5 -yllallyloxyl ethoxy]acetate

[004230] A mixture of tert-butyl 2-(2-allyloxyethoxy)acetate (1.50 g, 4.62 mmols, Intermediate VV), 3-(5-bromo methyl oxo- benzimidazol-l-yl)piperidine-2,6-dione (600 mg, 1.77 mmol, Intermediate HN), Pd2(dba)3 (168 mg, 183 umol), t-Bu3P (720 mg, 355 umol, 10 wt%) and DIPEA (468 mg, 3.62 mmol) in dioxane (30 mL) was stirred at 25 °C for 16 hours under N2. On completion, the mixture was filtered. The filtrate was concentrated in vacuo. The residue was

1340 purified by reversed phase (0.1% FA condition) to give the title compound (500 mg, 59% yield) as light yellow oil. LC-MS (ESI+) m/z 496.1 (M+Na)+.

[004231] Step 2 -Tert-butyl 2-r2-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propoxy1 ethoxy] acetate

[004232] A mixture of tert-butyl 2-[2-[(E) [l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]allyloxy]ethoxy]acetate (500 mg), Pd/C (200 mg, 10 wt%) and Pd(OH)2 (200 mg, 1.42 mmol) in THF (10 mL) was stirred at 25 °C for 16 hours under H2 (15 psi). On completion, the mixture was filtered, and the cake was washed with EA (20 mL). The filtrate and washings were combined and concentrated in vacuo. The residue was purified by reversed phase (0.1% FA condition) to give the title compound (400 mg) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 8.14 (s, IH), 6.93 - 6.87 (m, 2H), 6.72 (d, J = 8.0 Hz, IH), 5.25 - 5.20 (m, IH), 4.05 (s, 2H), 3.75 - 3.72 (m, 2H), 3.66 - 3.62 (m, 2H), 3.49 (t, J = 6.4 Hz, 2H), 3.45 (s, 3H), 2.96 - 2.83 (m, 2H), 2.76 - 2.71 (m, 2H), 2.29 - 2.19 (m, 2H), 1.95 - 1.90 (m, 2H) 1.49 (s, 9H).

[004233] Step 3 - 2-Γ2-Γ3-Γ 1-(2, 6-Dioxo piperidvl) methyl oxo-benzimidazol-5yl]propoxy]ethoxy] acetic acid

[004234] To a solution of tert-butyl 2-[2-[3-[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]acetate (400 mg, 815 umol) in DCM (4 mL) was added TFA (4 mL) at 25 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase flash (0.1% TFA condition) to give the title compound (180 mg, 42% yield) as light yellow gum. 1H NMR (400 MHz, CDCh) δ 8.35 (s, IH), 6.94-6.87 (m, 2H), 6.74 (d, J= 8.0 Hz, IH), 5.26 - 5.22 (m, IH), 4.18 (s, 2H), 3.81 3.74 (m, 2H), 3.64 - 3.62 (m, 2H), 3.55 (t, J= 6.4 Hz, 2H), 3.44 (s, 3H), 2.92 - 2.72 (m, 6H), 2.29 - 2.19 (m, IH), 2.00 - 1.90 (m, 2H).

[004235] Methyl 4-[4-amino (difluoromethvl)Dvrazol-l-yl] fluoro-benzoate (Intermediate VX)

1341

Cu(OAc)2, pyridine O2, DCM

F

VX

[004236] Step 1 - Methyl 4-[3-(difluoromethyl) nitro-pyrazol-l-yl] fluoro-benzoate [004237] To a solution of 3-(difluoromethyl) nitro-lH-pyrazole (1.00 g, 6.13 mmol, Intermediate HS) and (3-fluoro methoxycarbonyl-phenyl)boronic acid (1.58 g, 7.97 mmol, CAS# 3505083 5) in DCM (20 mL) was added Cu(OAc)2 (2.23 g, 12.3 mmol) and pyridine (10 mL). The reaction mixture was stirred at 25 °C for 12 hrs under oxygen (15 psi) atmosphere. On completion, the mixture was quenched with ammonia water (30 mL), then the mixture was stirred and separated. The organic layer was acidified with IN HCI (20 mL) to pH < 5, separated and washed with brine (20 mL), concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2), and then triturated with PE/EA= 10/1 (50 mL), filtered and the filter cake was concentrated in vacuo to give the title compound (360 mg, 19% yield) as a white solid. 1H NMR (400MHz, DMSOY) δ 9.92 (s, IH), 8.16 - 8.04 (m, 2H), 8.02 - 7.94 (m, IH), 7.61 - 7.30 (m, IH), 3.89 (s, 3H).

[004238] Step 2 - Methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl] fluoro-benzoate [004239] To a solution of methyl 4-[3-(difluoromethyl) nitro-pyrazol-l-yl] fluorobenzoate (350 mg, 1.11 mmol) in THF (10 mL) was added Pd/C (0.1 g, 10% wt). The reaction mixture was stirred at 25 °C for 10 hrs under H2 (15 psi) atmosphere. On completion, the mixture was concentrated in vacuo to give the title compound (310 mg, 98% yield) as a white solid. LCMS (ESI+) m/z 286.1 (M+H)+.

[004240] 4-[4-[[2-[2-[Tert-but0xycarb0nyl(cycl0Dr0Dylmethyl)amin0]-41342 pyridyl! oxazoIe carbonyi! amino! (difluoromethvl)pvrazol-l-v1! fluoro-benzoic acid (Intermediate VY)

LiOH«H2O

THF, H2O

[004241] Step 1 - Methyl 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino1-4 pyridyl1oxazole carbonyl1amino1 (difluoromethyl)pyrazol-l-yl1 fluoro-benzoate

[004242] To a solution of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl] fluorobenzoate (310 mg, 1.09 mmol, Intermediate VX) and 2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carboxylic acid (391 mg, 1.09 mmol, Intermediate OM) in DMF (6.00 mL) was added HATU (496 mg, 1.30 mmol) and DIPEA (421 mg, 3.26 mmol). The reaction mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was quenched with water (50 mL), and filtered. The filter cake was dried in vacuo to give the title compound (600 mg, 88% yield) as a white solid. 1H NMR (400MHz, DMSO-76) δ 10.15 (s, IH), 9.06 (s, IH), 9.01 (s, IH), 8.60 (d, J = 5.2 Hz, IH), 8.32 (s, IH), 8.06 (t, J = 8.4 Hz, IH), 8.00 - 7.94 (m, IH), 7.94 - 7.88 (m, IH), 7.75 - 7.66 (m, IH), 7.46 - 7.16 (m, IH), 3.88 (s, 3H), 3.86 (s, 2H), 1.52 (s, 9H), 1.22 - 1.12 (m, IH), 0.45 - 0.37 (m, 2H), 0.28 - 0.21 (m, 2H); LC-MS (ESI+) m/z 627.0 (M+H)+.

[004243] Step 2 - 4-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino1-4 pyridyl1oxazole carbonyl1 amino1 (difluoromethyl)pyrazol-l-yl1 fluoro-benzoic acid

[004244] To a mixture of methyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl] fluoro-benzoate (600 mg, 958 umol) in a mixed solvent of THF

1343 (10 mL) and H2O (2 mL) was added LiOH*H2O (160 mg, 3.83 mmol). The reaction mixture was stirred at 25 °C for 10 hrs. On completion, the mixture was concentrated in vacuo to remove the THF. The residue was diluted with water (30 mL), acidified with IN HCI to pH = 3-5, filtered and the filter cake was dried in vacuo to give the title compound (570 mg, 97% yield) as a yellow solid. 1HNMR (400MHz, DMSO-» δ 10.15 (s, IH), 9.15 - 8.95 (m, 2H), 8.60 (d, J= 5.2 Hz, IH), 8.32 (s, IH), 8.03 (t, J= 8.0 Hz, IH), 7.94-7.83 (m, 2H), 7.71 (d, J= 4.8 Hz, IH), 7.47-7.15 (m, IH), 3.87 (d, J = 6.8 Hz, 2H), 1.52 (s, 9H), 0.80 - 0.69 (m, IH), 0.49 - 0.36 (m, 2H), 0.29 - 0.15 (m, 2H); LC-MS (ESH) m/z 613.2 (M+H)+.

[004245] Tert-butyl N-(cvclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l-(3-fluoro-4 formyl-phenyl) pyrazol yl] carbamoyl] oxazol yl] pyridyl] carbamate (Intermediate

VZ

F

VZ

[004246] Step 1:Isopropoxycarbonyl 4-Γ4-ΓΓ2-[2-Γ&#970;6γ&#970;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1 oxazole carbonyl1amino1-3

1344 (difluoromethvl)pyrazol-1 -yl1 fluorc>-benzoate

[004247] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-l-yl] fluoro-benzoic acid (1.00 g, 1.63 mmol, Intermediate VY) and TEA (413 mg, 4.08 mmol) in THF (30 mL) was added isopropyl carbonochloridate (400 mg, 3.27 mmol) dropwise. The reaction mixture was stirred at 0 °C for 2 hrs. On completion, the mixture was filtered and the filtrate was used for the next step directly without further purification. LC-MS (ESI+) m/z 699.0 (M+H)+.

[004248] Step 2 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-[3fluoro (hydroxymethyl) phenvl1pvrazol yl1carbamoyl1oxazol yl1 pyridyl1carbamate [004249] To a solution of isopropoxycarbonyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl] fluoro-benzoate (1.14 g, 1.63 mmol) in a mixed solvent of THF (60 mL) and H2O (1 mL) was added LiBH4 (178 mg, 8.16 mmol). The reaction mixture was stirred at 0 °C for 2 hrs. On completion, the mixture was quenched with water (50 mL), then extracted with EA (2 X 50 mL). The organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with DCM/ΡΕ = 1/10 (50 mL), filtered and the filter cake was dried in vacuo to give the title compound (0.91 g, 93% yield) as a white solid. 1H NMR (300MHz, DMSO-t/6) δ 10.09 (s, IH), 9.05 (s, IH), 8.87 (s, IH), 8.60 (d, J = 5.1 Hz, IH), 8.32 (s, IH), 7.80 - 7.68 (m, 3H), 7.61 (t, J= 8.4 Hz, IH), 7.30 (t, J= 54.3, Hz, IH), 5.37 (t, J = 5.7 Hz, IH), 4.58 (d, J = 52 Hz, 2H), 3.86 (d, J = 7.2 Hz, 2H), 1.51 (s, 9H), 1.20 - 1.10 (m, IH), 0.44 - 0.37 (m, 2H), 0.27 - 0.20 (m, 2H); LC-MS (ESI+) m/z 599.2 (M+H)+.

[004250] Step 3 - Tert-butyl N-(cvclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-(3fluoro formyl-phenyl) pvrazol yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[004251] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[3-fluoro (hydroxymethyl)phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (0.91 g, 1.52 mmol) in DCM (20 mL) was added DMP (774 mg, 1.82 mmol). The reaction mixture was stirred at 25 °C for 10 hrs. On completion, the mixture was quenched with Na2S2O3 (30 mL) and NaHCO3 (30 mL), stirred for 10 minutes, then extracted with DCM (2 X 30 mL). The organic layers were washed with brine (50 mL), dried with Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was triturated with PE/DCM (10/1, 50 mL), filtered and the filter cake was dried in vacuo to give the title compound (840 mg, 93% yield) as a yellow solid.

1345

1H NMR (400MHz, DMSO-Y) δ 10.43 (s, IH), 10.20 (s, IH), 9.07 (s, IH), 9.05 (s, IH), 8.59 (d, 7= 5.2 Hz, IH), 8.31 (s, IH), 8.06-7.91 (m, 3H), 7.70 (dd,7= 1.2, 5.2 Hz, IH), 7.35 (t,7= 107.6 Hz, IH), 3.86 (d, 7= 6.8 Hz, 2H), 1.52 (s, 9H), 1.21 - 1.14 (m, IH), 0.44 - 0.38 (m, 2H), 0.28 0.20 (m, 2H); LC-MS (ESI+) m/z 597.2 (M+H)+.

[004252] 2- Methyl 4-amino-l-methvl-pyrazole carboxvlate (Intermediate WA) ’d/C, H2 ------&#9658; MeO MeOH

O NO2 O NH2

WA

[004253] To a mixture of methyl 2-methyl nitro-pyrazole carboxylate (0.5 g, 2.70 mmol, synthesized via Step 1 of Intermediate LK) in MeOH (20 mL) was added Pd/C (300 mg, 10% wt). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (400 mg, 95% yield) as white solid. 1H NMR (400MHz, DMSO-Y) δ 7.12 (s, IH), 4.67 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H).

[004254] l [[5-(4-Tert-butoxvcarbonvlpiperazin-l-vl)pyrazolo[l.,5-a]pvrimidine-3carbonyl] aminol-l-methyl-pvrazole carboxylic acid (Intermediate WB)

LiOH

THF, H2O, MeOH

WB

1346

[004255] Step 1 - Tert-butyl 4-r3-r(3-methoxycarbonyl-l-methyl-pyrazol-4yl)carbamoyl1pyrazolo[L5-a1 pyrimidin yl1piperazine-l-carboxylate

[004256] To a mixture of methyl 4-amino-l-methyl-pyrazole carboxylate (232 mg, 1.50 mmol, Intermediate WA) and 5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[l,5-a]pyrimidine3-carboxylic acid (400 mg, 1.15 mmol, Intermediate RC) in ACN (10 mL) was added DIPEA (446 mg, 3.45 mmol, 601 uL) and HATU (875 mg, 2.30 mmol,). The reaction mixture was stirred at 60 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (250 mg, 44% yield) as white solid. 1HNMR (400MHz, DM SO-0/6) δ 10.17 (s, IH), 8.80 (d, J= 8.0 Hz, IH), 8.44 (s, IH), 8.29 (s, IH), 6.88 (d, J= 8.0 Hz, IH), 4.02 - 3.92 (m, 7H), 3.86 (s, 3H), 3.61 - 3.49 (m, 4H), 1.42 (s, 9H).

[004257] Step 2 - l rr5-(4-Tert-butoxycarbonylpiperazin-l-yl)pyrazolo[L5-a1pyrimidine3-carbonyl] amino1-l-methyl-pyrazole carboxylic acid

[004258] To a mixture of tert-butyl 4-[3-[(3-methoxycarbonyl-l-methyl-pyrazol-4yl)carbamoyl]pyrazolo [l,5-a]pyrimidin yl]piperazine-l-carboxylate (200 mg, 412 umol) in a solution of THF (10 mL), MeOH (2 mL) and H2O (2 mL) was added LiOH (98.8 mg, 4.13 mmol). The reaction mixture was stirred at 25 °C for 12 hours. On compound, the reaction mixture was acidified with HCI (1 N) until pH = 5-6, then the mixture was concentrated in vacuo to give the title compound (194 mg, 99% yield) as white solid. 1H NMR (400MHz, DMSO-/) δ 10.53 (s, IH), 8.76 (d, J= 7.2 Hz, IH), 8.28 (d, J = 17.6 Hz, 2H), 6.85 (d, J = 7.6 Hz, IH), 4.12 - 3.87 (m, 4H), 3.86 (s, 3H), 3.55 - 3.49 (m, 4H), 1.43 (s, 9H).

[004259] Methyl 5-(4-amino-l-methvl-pyrazol vl)pyridine carboxylate (Intermediate WC)

1347

WC

[004260] Step 1 - 3-Bromo nitro-lH-pyrazole

[004261] To a solution of 3-bromo-lH-pyrazole (10 g, 68.0 mmol) in H2SO4 (50 mL) was added HNO3 (10.7 g, 170 mmol) at 0~10 °C. Then, the mixture was stirred at 80 °C for 2 hours. On completion, the mixture was cooled to 25 °C. Then, the mixture was poured into ice/water (300 mL), then extracted with EA (3 X 150 mL). The combined organic layer was washed with sat. aq. NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the title compound (11.2 g, 85% yield) as yellow solid. 1H NMR (400MHz, DMSO-76) δ 8.94 (s, 1 H).

[004262] Step 2 - 3-Bromo-l-methvl nitro-pyrazole

[004263] To a mixture of 3-bromo nitro-lH-pyrazole (6.20 g, 32.3 mmol) and K2CO3 (5.36 g, 38.7 mmol) in DMF (40 mL) was added Mel (5.50 g, 38.7 mmol) at 0 °C. Then, the mixture was stirred at 25 °C for 2 hours. On completion, the mixture was diluted with water (200 mL), then extracted with EA (3 X 80 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (PE: EA= 20:1-3:1) to give the title compound (3.90 g, 58% yield) as light yellow solid. 1HNMR (400MHz, CDCh) δ 8.16 (s, IH), 3.97 (s, 3H).

[004264] Step 3 - Methyl 5-(l-methvl nitro-pyrazol vl) pyridine carboxylate

[004265] A mixture of 3-bromo-l-methyl nitro-pyrazole (3.80 g, 18.4 mmol), (5methoxycarbonyl-3 -pyridyl)boronic acid (4.67 g, 25.8 mmol, CAS# 871329 2), Pd(dppf)C12.CH2C12 (800 mg, 979 umol) and NaHCO3 (3.10 g, 36.8 mmol) in dioxane (50 mL) and H2O (10 mL) was stirred at 80 °C under N2 for 2 hours. On completion, the mixture was cooled

1348 to 25 °C. The mixture was diluted with water (100 mL), then extracted with EA (3 X 80 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, fdtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EA = 5:1-DCM: EA = 2:1) to give the title compound (2.95 g, 61% yield) as light yellow solid. 1H NMR (400MHz, CDCh) δ 9.29 (s, IH), 9.12 (s, IH), 8.68 (s, IH), 8.31 (s, IH), 4.05 (s, 3H), 4.00 (s, 3H).

[004266] Step 4 - Methyl 5-(4-amino-l-methyl-pyrazol yl) pyridine carboxylate

[004267] A mixture of methyl 5-(l-methyl nitro-pyrazol yl)pyridine carboxylate (2.90 g, 11.0 mmol) and Pd/C (500 mg, 11.0 mmol, 10% wt) in DCM (80 mL) and MeOH (40 mL) was stirred at 25 °C for 6 hours under H2 (15 psi). On completion, the mixture was filtered, and the cake was washed with MeOH (50 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by reversed phase flash (NH3.H2O condition) to give crude product (1.8 g). The crude product was purified by prep-HPLC (column: Xbridge BEH C18, 250*50mm, lOum; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 1%26%, 32MIN; 45% min) to give the title compound (470 mg, 18% yield) as light yellow solid. 1H NMR (400 MHz, CDCh) δ 9.23 (d, J = 1.6 Hz, IH), 9.13 (d, J= 1.6 Hz, IH), 8.70 (t, J= 1.6 Hz, IH), 7.10 (s, IH), 3.97 (s, 3H), 3.88 (s, 3H).

[004268] 5-[4-[[2-[2-[Tert-butoxvcarbonvl(2,2,2-trifluoroethyl)amino]-4pyridyl] oxazole carbonyl] amino]-l-methvl-Dvrazol vl]Dvridine carboxylic acid (Intermediate WD)

1349

WC

WD

[004269] Step 1 - 5-r4-rr2-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole-4 -carbonyl1amino1-l-methyl-pyrazol yl1pyridine carboxylate

[004270] A mixture of methyl 5-(4-amino-l-methyl-pyrazol yl)pyridine carboxylate (90.0 mg, 387 umol, Intermediate WC), 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid (153 mg, 395 umol, Intermediate CM), HATU (192 mg, 504 umol) and DIPEA (101 mg, 781 umol) in DMF (3 mL) was stirred at 25 °C for 1 hour. On completion, the mixture was combined with another identical batch. The combined mixture quenched with water (1 mL) and purified by reverse phase flash (FA condition) to give the title compound (200 mg, 86% yield) as light yellow solid. 1H NMR (400 MHz, CDCh) δ 9.24 (s, IH), 9.18 (d, 7 = 1.6 Hz, IH), 8.83 (s, IH), 8.69 (s, IH), 8.51 (d, 7= 4.8 Hz, IH), 8.42 (s, IH), 8.36 (s, IH), 8.19 (s, IH), 7.73 (d, J = 52 Hz, IH), 4.88 (q, J = 8.8 Hz, 2H), 4.02 (s, 3 H), 3.97 (s, 3 H), 1.55 (s, 9H).

[004271] Step 2 - 5-r4-rr2-r2-rTert-butoxycarbonyl(2,2,2-trifluoroethyl)amino1-4pyridyl1oxazole carbonyl1 amino1-l-methyl-pyrazol yl1pyridine carboxylic acid

[004272] To a solution of methyl 5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino]-4 -pyridyl]oxazole carbonyl]amino]-l-methyl-pyrazol yl]pyridine-3carboxylate (200 mg, 332 umol) in THF (6 mL) was added a solution of LiOHH2O (21 mg, 500 umol) in H2O (2 mL) at 25 °C. Then, the mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was quenched with TFA (60 mg). The mixture was concentrated in vacuo. The residue was purified by reversed phase flash (TFA condition) to give the title compound (190

1350 mg, 81% yield) as light yellow solid. 1HNMR (400 MHz, DMSO-76) δ 13.47 (s, IH), 10.11 (s, IH), 9.08 (d, J = 2.0 Hz, IH), 8.98 (s, 2H), 8.64 (d, J = 5.2 Hz, IH), 8.54 (s, IH), 8.30 (s, IH), 8.03 (s, IH), 7.80 (d, J= 5.2 Hz, IH), 4.89 (q, J= 9.2 Hz, 2H), 3.95 (s, 3H), 1.50 (s, 9H).

[004273] Benzyl

N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-[2-[2-(2 aminoethoxylethoxy] ethoxy] ethoxy] ethoxy] ethoxy] [[(lR)-tetralin-l-yl] carbamoyl] -3,4 dihvdro-lH-isoquinoline carbonvl] 2-dimethvl-DroDvl]amino]-l-methvl oxo-ethyl]-Nmethyl-carbamate (Intermediate WE)

PE

WE

[004274] Step 1 - benzyl ((S)-1 -(((S)-1 -((S) ((2,2-dimethyl oxo-3,8,11,14,17,20hexaoxa azadocosan yl)oxy) (((R)-L2,3,4-tetrahydronaphthalen-l-yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate

[004275] To a solution of benzyl ((S)-l-(((S)-l-((S) hydroxy (((R)-l,2,3,4tetrahydronaphthalen-l-yl)carbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l

1351 oxobutan yl)amino)-l-oxopropan yl)(methyl)carbamate (1.6 g, 2.45 mmol, Intermediate PE) in CH3CN (75 mL) was added 2,2-dimethyl oxo-3,8,ll,14,17,20-hexaoxa azadocosan yl 4-methylbenzenesulfonate (1.57 g, 2.94 mmol, Intermediate 00) and K2CO3 (507.2 mg, 3.68 mmol) at rt. Then the reaction mixture was stirred at 80 °C for 12 h. The solid was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via column chromatography (DCM / MeOH) to give the title compound(!.58 g, 61% yield) as a colorless oil. LC-MS (ESI+): m/z 510.01 (M+H)+.

[004276] Step 2 - benzyl ((S)-l-(((S)-l-((S) ((17-amino-3,6,9,12,15pentaoxaheptadecyl)oxy) (((R)-L2,3,4-tetrahydronaphthalen-l-yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate 2,2,2-trifluoroacetate

[004277] To a solution of benzyl ((S) (((S) ((S) ((2,2-dimethyl 0x0-3,8,11,14,17,20hexaoxa azadocosan yl)oxy) (((R)-l,2,3,4-tetrahydronaphthalen-l-yl)carbamoyl)-3,4dihydroisoquinolin-2(lH)-yl)-3,3-dimethyl-l-oxobutan yl)amino)-l-oxopropan-2yl)(methyl)carbamate (1.3 g, 1.28 mmol) in DCM (20 mL) was added TFA (20 mL) at rt. The reaction mixture was stirred at rt for 3 h. The reaction mixture was then concentration under reduced pressure and the residue was purified via reverse phase column chromatography (ACN / H2O) to give the title compound (1.05 g, 89% yield) as a white solid. 1H NMR (400 MHz, DMSO76) δ 8.22 (dd, J= 49.8, 8.6 Hz, IH), 8.00 - 7.48 (m, 4H), 7.35 (s, 5H), 7.23 - 6.61 (m, 7H), 5.31 - 4.23 (m, 9H), 4.11 - 4.03 (m, 2H), 3.75 - 3.73 (m, 2H), 3.62 - 3.27 (m, 18H), 2.99 - 2.94 (m, 3H), 2.92 - 2.80 (m, 2H), 2.79 - 2.62 (m, 3H), 1.96 - 1.47 (m, 4H), 1.21 - 1.11 (m, 3H), 0.99 (s, 6H), 0.92 (s, 3H). LC/MS (ESI, m/z): [M +1]+ = 918.7.

[004278] 2-[2-(Tert-butoxycarbonylamino)ethoxy] acetic acid (Intermediate WF)

O LiOH 0

EtO'x^^/°'x/^NHBoc THF/H2O h0'^^&#1470;/°^/^nhB0c

WF

[004279] Step 1 - Ethyl 2-r2-(tert-butoxvcarbonvlamino)ethoxv1acetate

[004280] To a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (10.0 g, 62.0 mmol, 9.62 mL, CAS# 26690 2) and Rh(OAc)2 (274 mg, 1.24 mmol) in DCM (200 mL) was added a solution of ethyl 2-diazoacetate (10.6 g, 93.0 mmol, 9.74 mL, CAS# 623 4) in DCM (250 mL)

Rh(OAc)2, DCM

1352 dropwise slowly. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with water (200 mL) and extracted with DCM (2 X 200 mL). The combined organic layers was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (12.0 g, 78% yield) as light yellow oil. 1H NMR (400MHz, CDCh) δ 5.25 (s, IH), 4.19 (q, J= 7.2 Hz, 2H), 4.05 (s, 2H), 3.58 (t, J= 5.2 Hz, 2H), 3.31 (q, J= 5.2 Hz, 2H), 1.42 (s, 9H), 1.26 (t, J= 7.1 Hz, 3H).

[004281] Step 2 - 2-r2-(Tert-butoxycarbonylamino)ethoxy1acetic acid

[004282] To a mixture of ethyl 2-[2-(tert-butoxycarbonylamino)ethoxy]acetate (1.00 g, 4.04 mmol) in a mixed solvent of THF (10 mL) and H2O (5 mL) was added LiOH (193 mg, 8.09 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was acidified with HCI (1 N) until the pH = 5 - 6, then the mixture was concentrated in vacuo to removed THF, and the residue was extracted with EA (5x10 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (886 mg, 99% yield) as light yellow gum. 1H NMR (400MHz, DMSO-/6) δ 7.37 (s, IH), 3.57 (s, 2H), 3.43 - 3.40 (m, 2H), 3.06 (q, J= 5.2 Hz, 2H), 1.37 (s, 9H).

[004283] 3-[5-(aminomethvl) methvl oxo-benzimidazol-l-yl] DiDeridine-2,6-dione (Intermediate WG)

1353

[004284]

[004285]

Step 1 - 5-bromo-N-methyl nitroaniline

To a solution of 4-bromo fluoro-l-nitrobenzene (23 g, 105 mmol) in EtOH (50 mL) was added MeNH2 (250 ml, 33% in EtOH). After the addition, the mixture was stirred at rt overnight. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in EtOAc (300 mL), washed with water (200 mL x 2) and brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (23 g, 95% yield) as a yellow solid. 1HNMR (400 MHz, CDCh) δ 8.03 (d, J= 9.2 Hz, 2H), 7.01(s, IH), 6.76 (d, J= 9.2 Hz, IH), 3.02 (s,3H). LC/MS (ESI, m/z] [M+l]+ = 231.1 [004286] Step 2 - 5-bromo-Nl-methylbenzene-L2-diamine

[004287] To a solution of 5-bromo-N-methyl nitroaniline (23.0 g, 0.10 mol) in AcOH (230 mL)/ EtOAc (230 mL)/(50 mL) was added Fe (20 g, 0.36 mol) at 50 °C. After the addition, the reaction mixture was heated to 80 °C and stirred for 1 h. Then the mixture was cooled to rt and filtered. The filtrate was concentrated under reduce pressure. The residue was diluted with EtOAc (300 mL) and H2O (300 mL). The organic layer was washed with H2O (500 mL x 2) and brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was

1354 purified with column (EA: PE = 1:2) to afford the title compound (14 g, 70% yield) as a yellow solid. LC/MS (ESI, m/z); [M+l]+ = 201.1.

[004288] Step 3 - 6-bromo-l-methvl-L3-dihvdro-2H-benzo[d1imidazol one

[004289] To a solution of 5-bromo-Nl-methylbenzene-l,2-diamine (14 g, 69.3 mmol) in THF (200 mL) was added CDI (13.4 g, 83.2 mmol). The reaction mixture was heated for reflux 2 h under N2 atmosphere. The reaction mixture was cooled to rt and concentrated under reduce pressure. The residue was purified with column (EA : PE = 1 : 2) to afford the title compound (10 g, 63% yield) as a white solid. 1HNMR (400 MHz, DMSO-t/6) ¢511.0 (s, IH), 7.33 (s, IH), 7.13 (t, J= 8.0 Hz IH), 6.92 (d, J= 8.0 Hz, IH), 3.26 (s, 3H). LC/MS (ESI, m/z); [M+l]+ = 227.1.

[004290] Step 4 - 3-(5-bromo methyl oxo-2,3-dihydro-lH-benzo[d1imidazol-l-yl)-l-(4methoxvbenzyl)piperidine-2.6-dione

[004291] To a solution of 6-bromo-l-methyl-l,3-dihydro-2H-benzo[d]imidazol one (5.0 g, 22.1 mmol) in THF (50 mL) was added /-BuOK (2.48 g, 22.1mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then 3-bromo-l-(4-methoxybenzyl)piperidine-2,6-dione (6.9 g, 22.1 mmol) was added. After addition, the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with sat.aq. Ammonia chloride, extracted with EA (80 mL x 2). The combined organic lays were washed with H2O (80 mL x 2) and brine (80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified with column (EtOAc : DCM = 1 : 1) to afford 3-(5-bromo methyl oxo-2,3-dihydro-lHbenzo[d]imidazol-l-yl)-l-(4-m ethoxybenzyl )piperi dine-2,6-dione (3.7 g, 36.6% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-t/6) δ LAL (d, J = 1.9 Hz, IH), 7.23 - 7.13 (m, 3H), 7.00 (d, J = 8.4 Hz, IH), 6.88 - 6.81 (m, 2H), 5.53 (dd, J= 13.0, 5.4 Hz, IH), 4.78 (q, J= 14.3 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H), 3.12-2.95 (m, IH), 2.86-2.63 (m, 2H), 2.12-2.01 (m, IH). LC/MS (ESI, m/z); [M+l]+ = 458.1.

[004292] Step 5 - 3-(5-bromo methyl oxo-2,3-dihydro-lH-benzo[d1imidazol-lyl)piperidine-2,6-dione

[004293] To a solution of 3-(5-bromo methyl oxo-2,3-dihydro-lH-benzo[d]imidazol-lyl)-l-(4-methoxybenzyl)piperidine-2,6-dione (7.6 g, 16.6 mmol) in toluene (50 mL) was added methanesulfonic acid (20 mL). The reaction solution was heated to 110 °C and stirred for 3 h. The reaction mixture was cooled to rt and concentrated to remove toluene. The residue was diluted with CH3CN and purified via reverse phase column chromatography (CH3CN/H2O = 5%-80%) to

1355 give the title compound (3.4 g, 61% yield) as a white solid. 1H NMR. (400 MHz, DMSO) δ 11.11 (s, IH), 7.47 (d, J= 1.9 Hz, IH), 7.21 (dd,7=8.4, 1.9 Hz, IH), 7.10 (d, 7= 8.4 Hz, IH), 5.38 (dd, 7= 12.8, 5.4 Hz, IH), 3.34 (s, 3H), 2.93 -2.83 (m, IH), 2.74-2.60 (m, 2H), 2.03 - 1.97 (m, IH). LC/MS (ESI, m/z); [M +1]+ = 338.1.

[004294] Step 6 - l-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-lHbenzo[d1imidazole carbonitrile

[004295] A mixture of 3-(5-bromo methyl oxo-2,3-dihydro-lH-benzo[d]imidazol-lyl)piperidine-2,6-dione (5 g, 14. 8 mmol), zinc cyanide (6.9 g, 59.2 mmol), tris(dibenzylideneacetone)dipalladium (1.4 g, 1.5 mmol) and 1,1'Ferrocenebis(diphenylphosphine) (1.6 g, 3.0 mmol) in DMF (100 mL) was heated to 120 °C and stirred for 19 h under nitrogen atmosphere in sealed tube. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/DCM = 2/1) to give the title compound (3 g, 71%) as a white solid. 1H NMR (400 MHz, DMSO-76) δ 11.16 (s, 1 H), 7.75 (d, 7= 1.5 Hz, 1 H), 7.55 (dd, 7= 8.2, 1.5 Hz, 1 H), 7.34 (d, 7= 8.2 Hz, 1 H), 5.46 (dd, J = 12.8, 5.4 Hz, 1 H), 3.38 (s, 3 H), 2.83 - 2.94 (m, 1 H), 2.59 - 2.78 (m, 2 H), 2.01 - 2.09 (m, 1 H). LC/MS (ESI, m/z); [M+l]+ = 284.9.

[004296] Step 7 - 3-(5-(aminomethyl) methyl oxo-2.3-dihydro-lH-benzo[d1imidazol-lyl)piperidine-2,6-dione acetate

[004297] To a solution of 1-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydro-lHbenzo[d]imidazole carbonitrile (2.3 g, 8.1 mmol) in AcOH (20 mL) was added PtO2 (98.8 mg, 0.41 mmol) and 10 wt% palladium on activated carbon (850 mg, 0.81 mmol). The mixture was hydrogenated for 1 h at 85 psi at rt. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and dried to give the title compound (2.8 g, quant, yield) as a salt with AcOH. 1HNMR (400 MHz, DMSO-76) δ 7.24 (s, 1 H), 7.01 - 7.10 (m, 2 H), 5.36 (dd, 7=12.76, 5.38 Hz, 1 H), 3.84 (s, 2 H), 3.33 (s, 3 H), 2.83 - 2.96 (m, 1 H), 2.57 - 2.78 (m, 2 H), 1.97 - 2.05 (m, 1 H), 1.85 (br. s., 6 H). LC/MS (ESI, m/z); [M- NH2]+ = 272.17.

[004298] 2-(2-Aminoethoxv)-N-[[l-(2,6-dioxo DiDeridvl) methyl oxobenzimidazol yl] methyl] acetamide (Intermediate WH)

1356

NHBoc

WF

HATU, DIPEA, DMF

HCl/dioxane

DCM

WH

[004299] Step 1 - Tert-butyl N-r2-r2-rr1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl] methylamino] oxo-ethoxy]ethyl]carbamate

[004300] To a mixture of 2-[2-(tert-butoxycarbonylamino)ethoxy]acetic acid (405 mg, 1.85 mmol, Intermediate WF) and DIPEA (994 mg, 7.70 mmol, 1.34 mL) in DMF (5 mL) was added HATU (702 mg, 1.85 mmol). The reaction mixture was stirred at 0 °C Then, 3-[5-(aminomethyl)3-methyl oxo-benzimidazol-l-yl] piperidine-2,6-dione (0.50 g, 1.54 mmol, HCI, Intermediate WG) was added. The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (500 mg, 66% yield) as white solid. LC-MS (ESI+) m/z 390.2 (M+H-100)+.

[004301] Step 2 - 2-(2-Aminoethoxy)-N-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl]acetamide

[004302] To a mixture of tert-butyl N-[2-[2-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methylamino] oxo-ethoxy]ethyl]carbamate (400 mg, 817 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 20 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC (0.1 % FA condition) to give the title compound (240 mg, 75% yield) as white solid. 1H NMR (400MHz, DMSOY) δ 11.08 (s, IH), 8.53 ( t, J = 6.0 Hz, IH), 8.03 (s, 2H), 7.12 (s, IH),

1357

7.08 - 6.95 (m, 2H), 5.36 (dd, J= 5.2, 12.8 Hz, IH), 4.36 (d, J= 6.0 Hz, 2H), 3.98 (s, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.37 (s, 3H), 3.02 (d, J = 4.4 Hz, 2H), 2.97 - 2.85 (m, IH), 2.77 - 2.59 (m, 2H), 2.07 - 1.92 (m, IH); LC-MS (ESI+) m/z 390.2 (M+H)+.

[004303] 3-[4-[4-(4-Aminobutoxv)butvl1 methvl oxo-benzimidazol-l-yl]piperidine2.,6-dione (Intermediate WI)

Pd/C, Pd(OH)2/C, H2

THF

HCI/dioxane

DCM

WI

[004304] Step 1 - Tert-butyl N-r4-r4-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1but ynoxy1 butvllcarbamate

[004305] A mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate HP), tert-butyl N-(4-but ynoxybutyl)carbamate (1.07 g, 4.44 mmol, Intermediate SY), Cui (84 mg, 443 umol), Pd(PPh3)2C12 (311 mg, 443 umol) and TEA (2.69 g, 26.6 mmol) in DMF (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 85 °C for 4 hrs under N2 atmosphere. On completion, the mixture was dilute with H2O (20 mL), then extracted with EA (2 X 60 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and then concentrated in vacuo. The residue was purified by reversed phase flash to give the title compound (460 mg, 58% yield) as light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.12 (s, IH), 7.12 (d, J= 7.6 Hz, IH), 7.09 - 7.04 (m, IH), 7.02

1358

6.97 (m, IH), 6.79 (s, IH), 5.39 (dd, J= 5.2, 12.8 Hz, IH), 3.65 (s, 3H), 3.58 (t, J= 6.4 Hz, 2H), 3.43 (t, J= 6.0 Hz, 2H), 2.96 - 2.86 (m, 3H), 2.77 - 2.58 (m, 4H), 2.06 - 1.99 (m, IH), 1.51-1.40 (m, 4H), 1.37 (s, 9H); LC-MS (ESI+) m/z 499.3 (M+l)+.

[004306] Step 2 - Tert-butyl N-r4-r4-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1butoxy1butyl1 carbamate

[004307] To a solution of tert-butyl N-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]but- 3-ynoxy]butyl]carbamate (460 mg, 922 umol) in THF (50 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%). The mixture was stirred at 25 °C for 4 hrs under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (463 mg, 99% yield) as white solid. 1H NMR (400MHz, DMSOd6) δ 11.09 (s, IH), 6.99 - 6.95 (m, 2H), 6.89 - 6.87 (m, IH), 6.80 - 6.75 (m, IH), 5.37 (dd, J= 5.2, 12.4 Hz, IH), 3.55 (s, 3H), 3.40 (t, J= 5.6 Hz, 2H), 3.36 - 3.33 (m, 2H), 2.96 - 2.85 (m, 5H), 2.77 - 2.58 (m, 2H), 2.05 - 1.96 (m, IH), 1.69 - 1.57 (m, 4H), 1.52 - 1.40 (m, 4H), 1.37 (s, 9H).

[004308] Step 3 - 3-r4-r4-(4-Aminobutoxy)butyl1 methyl oxo-benzimidazol-lyl1piperidine-2,6-dione

[004309] To a solution of tert-butyl N-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] butoxy]butyl]carbamate (460 mg, 915 umol) in DCM (20 mL) was added HCl/dioxane (4 M, 10 mL). The mixture was stirred at 25 °C for 3 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (360 mg, 90% yield) as light yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.01 (s, IH), 7.68 (s, 2H), 6.94 - 6.85 (m, 2H), 6.81 - 6.79 (m, IH), 5.30 (dd, J= 5.2, 12.8 Hz, IH), 3.49 (s, 3H), 3.37 - 3.35 (m, 2H), 3.31 - 3.28 (m, 2H), 2.89 2.77 (m, 3H), 2.76 - 2.55 (m, 4H), 1.97 - 1.88 (m, IH), 1.61 - 1.45 (m, 8H); LC-MS (ESI+) m/z 403.1 (M+l)+.

[004310] Tert-butyl N- [4- [4- [ [3-(5-formvl pyridvl)- l-methyl-pyrazol-4yl] carbamoyl] oxazol yl] pyridvl]-N-(2.,2.,2-trifluoroethvl)carbamate (Intermediate WJ)

1359

[004311] Step 1 - Isopropoxycarbonyl 5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino1 pyridyl1 carboxylate

[004312] To a solution of 5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl] oxazole carbonyl]amino]-l-methyl-pyrazol yl]pyridine carboxylic acid (640 mg, 1.09 mmol, Intermediate WD) and TEA(560 mg, 5.53 mmol) in THF (20 mL) was added isopropyl carbonochloridate (340 mg, 2.77 mmol) at 0 °C. Then, the mixture was stirred at 0-10 °C for 2 hours. On completion, the mixture was filtered and the filter cake was washed with THF (10 mL). The filtrate and washing were combined and used directly in the next step. LC-MS (ESI+) m/z 674.3 (M+H)+.

[004313] Step 2 - Tert-butyl N-[4-[4-[[3-[5-(hydroxymethyl) pyridyl1-l-methyl-pyrazol4-yl1carbamoyl1 0xaz0l yl1 pyridyl1-N-(2,2,2-trifluoroethyl )carbamate

[004314] To a solution of isopropoxycarbonyl 5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl) amino] pyridyl]oxazole carbonyl]amino]-l-methyl-pyrazol yl]pyridine-3carboxylate in THF (30 mL) was added LiBH4 (147 mg, 6.75 mmol) at 0 °C. Then, the mixture was stirred at 0-10 °C for 1 hour. On completion, the mixture was added water (100 mL). The mixture was extracted with EA (3 X 60 mL). The combined organic layer was concentrated in vacuo. The residue was purified by reversed phase flash (0.1% FA condition) to give the title compound (380 mg, 60% yield via two steps) as light yellow solid. 1H NMR (400 MHz, CDCh) δ 8.94 - 8.92 (m, 2H), 8.59 (m, IH), 8.51 (d, J= 5.2 Hz, IH), 8.41 - 8.39 (m, 2H), 8.24 (s, IH), 8.14

1360 (s, IH), 7.68 - 7.66 (m, IH), 4.89 (q, J= 8.8 Hz, 2H), 4.81 (s, 2H), 4.01 (s, 3H), 1.59 (s, 9H).

[004315] Step 3 - Tert-butyl N-r4-r4-rr3-(5-formyl pyridyl)-l-methyl-pyrazol-4vl&#1470;|carbamoyl&#1470;|oxazol yl1 pvridvH-N-(2.2,2-trifluoroethyl )carbamate

[004316] To a solution of tert-butyl N-[4-[4-[[3-[5-(hydroxymethyl) pyridyl]-l-methylpyrazol yl] carbamoyl] oxazol yl] pyridyl]-N-(2, 2, 2-trifluoroethyl) carbamate (360 mg, 573 umol) in DCM (20 mL) was added Dess-Martin (360 mg, 848 umol) at 0 °C. Then, the mixture was stirred at 3 hours at 0-10 °C. On completion, the mixture was diluted with DCM (20 mL), washed with sat. aq. Na2S2O3 (10 mL). The organic layer was washed with sat.NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (320 mg, 97% yield) as light yellow solid. 1H NMR (400 MHz, CDC13) δ 10.21(s, IH), 9.26 (d, J = 2.0 Hz, IH), 9.08 (d, J= 2.0 Hz, IH), 8.82 (s, IH), 8.54 - 8.52 (m, 2H), 8.41 (s, IH), 8.38 (s, IH), 8.18 (s, IH), 7.73 (d, J= 1.6 Hz, IH), 4.87 (q, J= 8.8 Hz, 2H), 4.01 (s, 3H), 1.56 (s, 9H).

[004317] 2-[2-(Methvlamino)ethoxy] ethanol (Intermediate WK) .0. _Boc HCl/dioxane 0 HCI

HO N --------&#9658; HCT^ NH

I DCM I

WK

[004318] To a solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (3.00 g, 13.7 mmol, synthesized via Steps 1-2 of Intermediate FY) in DCM (20 mL) was added HCl/dioxane (4 M, 20 mL). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (2.10 g, 99% yield, HCI salt) as a white solid. 1HNMR (400 MHz, DMSO-76) δ 3.67 (t, J= 5.2 Hz, 2H), 3.57 - 3.51 (m, 2H), 3.50 3.46 (m, 2H), 3.13 - 3.02 (m, 2H), 2.55 (t, J= 5.2 Hz, 3H).

[004319] Tert-butyl 4-(2-prop vnoxvethoxv)piperidine-l-carboxylate (Intermediate WM)

1361

LAH

THF

Boc

Rh2(OAc)4, DCM

NaH,THF

[004320]

[004321]

WM

Step 1 - Tert-butyl 4-(2-ethoxy oxo-ethoxy)piperidine-l-carboxylate

To a mixture of tert-butyl 4-hydroxypiperidine-l-carboxylate (5.00 g, 24.8 mmol,

CAS# 109384 2) and diacetoxyrhodium (274 mg, 1.24 mmol) in DCM (80 mL) was added a solution of ethyl 2-diazoacetate (8.50 g, 74.5 mmol) in DCM (60 mL) at 0 - 10 °C during 2 hours. The mixture was stirred at 25 °C for 40 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (7.00 g, 98% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 4.28 - 4.20 (m, 2H), 4.12 (s, 2H), 3.81 - 3.75 (m, 2H), 3.57 (m, IH) 3.12 - 3.05 (m, 2H), 1.87 - 1.86 (m, 2H), 1.59 - 1.52 (m, 2H), 1.46 (s, 9H), 1.33 - 1.28 (s, 3H).

[004322] Step 2 - Tert-butyl 4-(2-hydroxyethoxy)piperidine-l-carboxylate

[004323] To a suspension of LAH (1.59 g, 41.8 mmol) in THF (40 mL) was added a solution of tert-butyl 4-(2-ethoxy oxo-ethoxy)piperidine-l-carboxylate (6.00 g, 16.5 mmol) in THF (20 mL) slowly at 0-10 °C. The mixture was stirred at 0-10 °C for 3 hours. On completion, the reaction was quenched with water (1.60 mL) slowly at 0-10°C. Then 10% aq.NaOH (1.60 mL) and water (4.80 mL) were added to the mixture. The mixture was fdtered and the fdter cake was washed with EA(50 mL). The fdtrate and washing were combined and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound (4.00 g, 67% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 3.76 - 3.75 (m, 2H), 3.74 - 3.73 (m, 2H), 3.60 3.58 (m, 2H), 3.50 (m, IH), 3.13 - 3.07 (m, 2H), 1.85 - 1.84 (m, 2H), 1.57 - 1.52 (m, 2H), 1.47 (s, 9H).

[004324] Step 3 - Tert-butyl 4-(2-prop ynoxyethoxy)piperidine-1 -carboxylate

[004325] To a solution of tert-butyl 4-(2-hy droxy ethoxy )piperi dine-1 -carboxylate (3.80 g, 15.4 mmol) in THF (40 mL) was added NaH (1.86 g, 46.5 mmol, 60% oil dispersion) at 0 °C. The mixture was stirred at 25 °C for 0.5 hour. Then 3-bromoprop yne (2.76 g, 23.2 mmol) was added

1362 to the mixture at 25 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the reaction was quenched with sat.aq.NH4Q (20 mL). The mixture was diluted with water (100 mL), then extracted with EA (3 X 80 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (3.70 g, 84% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 4.22 (d, J= 2.4 Hz, 2H), 3.86 - 3.75 (m, 2H), 3.73 - 3.62 (m, 4H), 3.53 - 3.45 (m, IH), 3.10 - 3.00 (m, 2H), 2.44 (t, J = 2.4 Hz, IH), 1.90 - 1.80 (m, 2H), 1.56 - 1.48 (m, 2H), 1.46 (s, 9H).

[004326] 3- |3-M et hvl oxo [3- [2-(4-piperidvloxy)ethoxy|propyl] benzimidazol-1yllpiperidine-2.,6 -dione (Intermediate WN)

Pd/C, Pd(OH)2/C

H2, THF

[004327] Step 1 - Tert-butyl 4-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop-2 -vnoxv1ethoxv1piperidine-l-carboxylate

[004328] A mixture of tert-butyl 4-(2-prop ynoxyethoxy)piperidine- 1-carboxylate (800 mg, 2.82 mmol, Intermediate WM), 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (400 mg, 1.18 mmol, Intermediate HN), Cui (45.0 mg, 236 umol), Pd(PPh3)2Ch (166 mg, 236 umol), Cs2CO3 (1.93 g, 5.91 mmol) and 4A MS (400 mg) in DMF (15 mL) was stirred at

1363 °C for 2 hours. On completion, the reaction mixture was cooled to 20 °C. The mixture was diluted with EA (50 mL), filtered and the cake was washed with EA (30 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by reversed phase flash (FA condition) to give the title compound (420 mg, 65% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-/6) δ 11.13 (m, IH), 7.33 (s, IH), 7.19 - 7.08 (m, 2H), 5.41 -5.37 (m, IH), 4.40 (s, 2H), 4.18 - 4.11 (m, IH), 3.63 - 3.59 (m, 4H), 3.56 - 3.51 (m, 2H), 3.50 - 3.41 (m, 2H), 3.36 (s, 3H), 2.93 - 2.83 (m, IH), 2.76 - 2.61 (m, 2H), 2.07 - 1.99 (m, IH), 1.80 - 1.75 (m, 2H) 1.38 (s, 9H), 1.35 - 1.30 (m, 2H).

[004329] Step 2 - Tert-butyl 4-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1 ethoxy1piperidine-l-carboxylate

[004330] A mixture of tert-butyl 4-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]ethoxy]piperidine-l-carboxylate (400 mg, 739 umol), Pd(OH)2/C (100 mg, 739 umol, 10 wt%) and Pd/C (100 mg, 739 umol, 10 wt%) in THF (20 mL) was stirred at 25 °C for 20 hours under H2 (15 psi). On completion, the mixture was filtered, and the cake was washed with EA (10 mL). The filtrate and washing were combined and concentrated in vacuo to give the title compound (400 mg, 99 % yield) as light yellow gum. 1H NMR (400 MHz, CDCh) δ 8.11 (s, IH), 6.94 - 6.89 (m, IH), 6.88 (s, IH), 6.72 (d, J= 8.0 Hz, IH), 5.25 - 5.18 (m, IH), 3.75 - 3.70 (m, IH), 3.60 - 3.56 (m, 2H), 3.52 - 3.46 (m, 4H), 3.43 (s, 3H), 3.11 - 3.02 (m, 3H), 2.90 - 2.83 (m, IH), 2.77 - 2.70 (m, 3H), 2.27 - 2.21 (m, IH), 1.93 - 1.91 (m, 2H), 1.88 - 1.81 (m, 3H), 1.64 - 1.60 (m, IH), 1.55-1.51 (m, 2H), 1.46 (s, 9H).

[004331] Step 3 - 3-r3-Methyl oxo r3-r2-(4-piperidyloxy)ethoxy1propyl1benzimidazoll-yl1piperidine-2,6 -dione

[004332] To a solution of tert-butyl 4-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethoxy]piperidine-l-carboxylate (100 mg, 183 umol) in DCM (3.0 mL) was added TFA (1.0 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (81.0 mg, 99% yield) as light yellow gum. LC-MS (ESI+) m/z 445.3 (M+H)+.

[004333] Tert-butyl N-methvl-N-[[(2R) Dr0D vnylm0rDh01in-2yl] methyl] carbamate (Intermediate WP)

1364

CbzCI, NaHCO3 MsCI, TEA *

ACN, H2O DCM

Cbz.

MeNH2

EtOH

(Boc)2O, tea

MeOH

MeOH

Pd/C, H2

,Boc

WP

[004334] Step 1 - Benzyl (2R) (hydroxymethyl)morpholine carboxylate

[004335] To a solution of [(2R)-morpholin yl]methanol (2.50 g, 16.2 mmol, HCI, CAS# 156925 3), NaHCO3 (4.10 g, 48.8 mmol) in a mixed solvent of ACN (80.0 mL) and H2O (80.0 mL) was added CbzCI (4.16 g, 24.4 mmol, 3.47 mL) at 0 °C dropwise. The mixture was then stirred at 25 °C for 16 hrs. On completion, the mixture was concentrated in vacuo to remove ACN. Then the mixture was extracted with EA (2 X 20 mL), and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1: 1) to give the title compound (3.7 g, 90% yield) as colorless oil. 1HNMR (400MHz, CDC13) δ 7.42 - 7.33 (m, 5H), 5.17 (d, J = 2.0 Hz, 2H), 4.08 - 3.88 (m, 3H), 3.77 - 3.65 (m, IH), 3.63 - 3.46 (m, 3H), 3.13 - 2.73 (m, 2H), 2.07 - 1.96 (m, IH).

[004336] Step 2 - Benzyl (2R) (methylsulfonyloxymethyl)morpholine carboxylate [004337] To a solution of benzyl (2R) (hydroxymethyl)morpholine carboxylate (3.70 g, 14.7 mmol), and TEA(4.47 g, 44.1 mmol) in DCM (40.0 mL) was added MsCI (2.53 g, 22.0 mmol) at 0°C, then the mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with DCM (20 mL) and washed with H2O (3 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4.85 g, 100% yield) as yellow oil. 1HNMR (400MHz, CDCh) δ 7.43 - 7.33 (m, 5H), 5.20 - 5.15 (m, 2H), 4.26 (d, J = 4.8 Hz, 2H), 4.10 - 3.83 (m, 3H), 3.80 - 3.65 (m, IH), 3.63 - 3.48 (m, IH), 3.08 (s, 3H), 3.07 - 2.75 (m, 2H).

[004338] Step 3 - Benzyl (2S) (methylaminomethyl)morpholine carboxylate

[004339] To a solution of benzyl (2R) (methylsulfonyloxymethyl)morpholine-4

1365 carboxylate (4.3 g, 13.0 mmol) in EtOH (10.0 mL) was added MeNH2 (40.5 g, 391 mmol, 30% solution in ethanol), and the mixture was stirred at 80 °C for 16 hrs in a 100 mL of autoclave. On completion, the mixture was concentrated in vacuo to give the title compound (3.45 g, 100% yield) as yellow oil. LC-MS (ESI+) m/z 265.1 (M+H)+.

[004340] Step 4 - Benzyl (2S) rrtert-butoxycarbonyl(methyl)amino1methyl1morpholine-4carboxylate

[004341] To a solution of benzyl (2S) (methylaminomethyl)morpholine carboxylate (3.45 g, 13.0 mmol) in MeOH (50.0 mL) was added TEA (1.58 g, 15.6 mmol, 2.18 mL). Then (Boc)2O (4.27 g, 19.5 mmol, 4.50 mL) was added into the above mixture dropwise. The mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 5: 1) to give the title compound (4.10 g, 86% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 7.43 - 7.30 (m, 5H), 5.24 - 5.09 (m, 2H), 4.11 - 3.83 (m, 3H), 3.68 - 3.34 (m, 3H), 3.30 - 3.14 (m, IH), 3.09 - 2.97 (m, IH), 2.94 (s, 3H), 2.80 - 2.62 (m, IH), 1.47 (s, 9H).

[004342] Step 5 - Tert-butyl N-methyl-N-rr(2R)-morpholin yl1methyl1carbamate

[004343] To a solution of benzyl (2S) [[tertbutoxycarbonyl(methyl)amino]methyl]morpholine carboxylate (4.10 g, 11.2 mmol) in MeOH (40.0 mL) was added Pd/C (1.00 g, 10% wf), and the mixture was stirred at 25 °C for 16 hrs under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.54 g, 98% yield) as colorless oil. 1H NMR (400MHz, DMSO-t/6) δ 3.75 - 3.65 (m, IH), 3.50 - 3.42 (m, IH), 3.41 - 3.37 (m, IH), 3.24 - 3.13 (m, IH), 3.10 - 3.03 (m, IH), 2.85 - 2.75 (m, 3H), 2.70 - 2.53 (m, 4H), 2.37 - 2.23 (m, IH), 1.39 (s, 9H).

[004344] Step 6 - Tert-butyl N-m ethyl-N-rr(2R) prop ynylmorpholin-2yllmethyllcarbamate

[004345] To a solution of tert-butyl N-methyl-N-[[(2R)-morpholin yl]methyl]carbamate (1.00 g, 4.34 mmol), 3-bromoprop yne (516 mg, 4.34 mmol, CAS# 106 7) in DMF (10.0 mL) was added K2CO3 (3.00 g, 21.7 mmol). The mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was diluted with H2O (20 mL), then extracted with EA (2 X 20 mL). The combined organic layers were washed with brine (2 X 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 5: 1) to give the title compound (960 mg, 82% yield) as yellow oil. 1H NMR (400MHz,

1366

DMSO4) δ 3.85 - 3.76 (m, IH), 3.63 - 3.52 (m, IH), 3.50 - 3.40 (m, IH), 3.30 - 3.24 (m, 2H), 3.20 - 3.14 (m, 2H), 2.84 - 2.78 (m, 3H), 2.68 - 2.55 (m, 2H), 2.54 - 2.52 (m, IH), 2.30 - 2.16 (m, IH), 2.03 - 1.90 (m, IH), 1.39 (s, 9H).

[004346] 3-[3-Methvl [3-[(2S) (methvlaminomethvl)morDholin vl]DroD-l-vnyl]2-oxo -benzimidazol-l-yl]DiDeridine-2.,6-dione (Intermediate WO)

WP

Pd(PPh3)2CI2, Cui, Cs2CO3, 4A MS, DMF

[004347] Step 1 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidyl) methyl oxo benzimidazol yl1 prop ynyl1morpholin yl1methyl1-Nmethyl-carbamate

[004348] To a solution of tert-butyl N-methyl-N-[[(2R) prop ynylmorpholin-2yl]methyl]carbamate (571 mg, 2.13 mmol, Intermediate WP), 3-(5-bromo methyl oxo benzimidazol-l-yl)piperidine-2,6-dione (400 mg, 1.18 mmol, Intermediate HN) in DMF (15.0 mL) was added Pd(PPh3)2C12 (83.0 mg, 118 umol), 4A molecular sieves (50.0 mg), Cs2CO3 (1.93 g, 5.91 mmol) and Cui (22.5 mg, 118 umol). The mixture was stirred at 80 °C for 2 hrs under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (400 mg, 64% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 8.28 (s, IH), 7.17 (d, J = 8.0 Hz, IH), 7.10 (s, IH), 6.74 (d, J = 8.0 Hz, IH), 5.25 - 5.14 (m, IH), 3.99 - 3.90 (m, IH), 3.82 - 3.65 (m, 2H), 3.57 - 3.47 (m, 2H), 3.43 (s, 3H), 3.25-3.14 (m, IH), 3.00 - 2.94 (m, IH), 2.94 (s, 3H), 2.89 - 2.82 (m, 2H), 2.82 - 2.74 (m, 2H), 2.74 - 2.63 (m, IH), 2.50 - 2.38 (m, IH), 2.30 - 2.21 (m, IH), 2.20 - 2.13 (m, IH), 1.45

1367 (s, 9H).

[004349] Step 2 - 3-r3-Methyl r3-r(2S) (methylaminomethyl)morpholin yl]prop-lynyl] oxo -benzimidazol-l-yl]piperidine-2,6-dione

[004350] To a solution of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynyl]morpholin yl]methyl]-N-methyl-carbamate (150 mg, 285 umol) in DCM (5.00 mL) was added TFA (7.70 g, 67.5 mmol, 5.00 mL). The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 97% yield, TFA salt) as yellow solid. 1H NMR (400MHz, DMSO4) δ 11.15 (s, IH), 8.83 (s, IH), 7.37 (d, J = 1.2 Hz, IH), 7.27 - 7.22 (m, IH), 7.22 - 7.17 (m, IH), 5.47 - 5.37 (m, IH), 4.39 - 4.21 (m, 3H), 4.18 - 4.14 (m, IH), 4.09 - 4.03 (m, IH), 3.84 - 3.73 (m, IH), 3.58 - 3.44 (m, 2H), 3.36 (s, 3H), 3.27 - 3.17 (m, IH), 3.12 - 3.02 (m, 2H), 2.95 - 2.84 (m, 2H), 2.68 - 2.62 (m, IH), 2.60 - 2.57 (m, 3H), 2.09 - 2.00 (m, IH).

[004351] 3-[3-methvl [4-[4-(methvlamino)butoxv]butvl] oxo-benzimidazol-lyllpiperidine-2.,6- dione (Intermediate WR)

Pd(OH)2/C, Pd/C

H2, THF

WR

[004352] Step 1 Tert-butyl N-r4-r4-r1-(2,6-dioxo piperidvl) methyl oxo benzimidazol yl]but ynoxy] butyl]-N-methyl-carbamate

[004353] To a solution of tert-butyl N-(4-but ynoxybutyl)-N-methyl-carbamate (500 mg, 1.96 mmol, Intermediate RS) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6

1368 dione (221 mg, 653 umol, Intermediate HP) in DMF (10 mL) was added Cui (24.8 mg, 131 umol), Cs2CO3 (213 mg, 653 umol), Pd(PPh3)2C12 (91.6 mg, 131 umol) and 4A molecular sieves (200 mg, 653 umol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (30 mL), and then extracted with EA (3 X 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (320 mg, 95% yield) as a purple solid. LC-MS (ESI+) m/z 413.2 (M +H-100)+.

[004354] Step 2 - Tert-butyl N-r4-r4-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1butoxy1 butyl1-N-methyl-carbamate

[004355] To a solution of tert-butyl N-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] but ynoxy]butyl]-N-methyl-carbamate (300 mg, 585 umol) in THF (20 mL) was added Pd(OH)2/C (500 mg, 585 umol, 20 wt%) and Pd/C (500 mg, 585 umol, 10 wt%) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours under H2 (15 psi). On completion, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound (280 mg, 92% yield) as colorless oil. LC-MS (ESI+) m/z 417.3(M+H-100)+.

[004356] Step 3 - 3-r3-methyl r4-r4-(methylamino)butoxy1butyl1 oxo-benzimidazol-lyl1piperidine-2,6-dione

[004357] To a solution of tert-butyl N-[4-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] butoxy]butyl]-N-methyl-carbamate (140 mg, 271 umol) in DCM (10 mL) was added TFA (5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (110 mg, 97% yield) as colorless oil. LC-MS (ESI+) m/z 417.2 (M+H)+.

[004358] Tert-butyl (3R) DroD vnoxvDvrrolidine-l-carboxylate (Intermediate WU)

[004359] To a mixture of tert-butyl (3R) hydroxypyrrolidine carboxylate (5.00 g, 26.7 mmol, CAS# 109431 0) and TBAI (493 mg, 1.34 mmol) in THF (50 mL) was added sodium hydride (1.28 g, 32.0 mmol, 60% oil dispersion) in portions at 0 °C. After 0.5 hour, 3-bromoprop

1369

1-yne (6.35 g, 53.4 mmol) was added to the mixture. The reaction mixture was stirred at 0 - 25 °C for 12.5 hours. On completion, the reaction was quenched with water (1.0 mL). The mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography on silica gel to give the title compound (6.00 g, 99% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.28 (s, IH), 4.24 - 4.06 (m, 2H), 3.55 - 3.32 (m, 4H), 2.44 (t, J = 2.4 Hz, IH), 2.13 - 1.88 (m, 2H), 1.46 (s, 9H).

[004360] 3- [3-Methyl oxo [3- [ (3R)-pyr rolidin yl] oxypropyl] benzimidazol-1 yl]piperidine-2,6- dione (Intermediate WV)

Pd(OH)2/C, Pd/C

H2, THF

TFA

DCM

TFA

WV

[004361] Step 1 - Tert-butyl (3R) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1prop ynoxy1pyrrolidine-l -carboxylate

[004362] A mixture of tert-butyl (3R) prop ynoxypyrrolidine-l-carboxylate (666 mg, 2.96 mmol, Intermediaet WU), 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (400 mg, 1.18 mmol, Intermediate HP), Pd(PPh3)2C12 (166 mg, 236 umol), Cui (45.0 mg, 236 umol), 4A MS (100 mg, 1.18 mmol) and Cs2CO3 (1.93 g, 5.91 mmol) in DMF (8 mL) was stirred at 80 °C for 2 hours under N2. On completion, the reaction mixture was filtered and the

1370 filtrate was concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (330 mg, 57% yield) as brown solid. 1H NMR (400 MHz, DMSO-76) δ 11.13 (s, IH), 7.18 (d, J = 7.6 Hz, IH), 7.13 (d, J = 7.6 Hz, IH), 7.06 - 7.00 (m, IH), 5.42 - 5.38 (m, IH), 4.48 (s, 2H), 4.34 - 4.24 (m, IH), 3.63 (s, 3H), 3.37 - 3.35 (m, IH), 3.27 - 3.17 (m, 2H), 2.95 - 2.82 (m, IH), 2.77 - 2.63 (m, 2H), 2.07 - 1.89 (m, 4H), 1.38 (d, J= 9.6 Hz, 9H).

[004363] Step 2 - Tert-butyl (3R) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 propoxy] pyrrolidine carboxylate

[004364] To a solution of tert-butyl (3R) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]pyrrolidine-l-carboxylate (300 mg, 621 umol) in THF (10 mL) was added Pd/C (150 mg, 10 wt%) and Pd(OH)2/C (150 mg, 20 wt%) at 20 °C. The reaction mixture was stirred at 20 °C for 12 hours under H2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (300 mg, 99% yield) as brown solid. 1HNMR (400 MHz, DM SO-6/6) δ 11.09 (s, IH), 6.99 - 6.92 (m, 2H), 6.90 6.82 (m, IH), 5.42 - 5.38 (m, IH), 4.06 -3.96 (m, IH), 3.55 (s, 3H), 3.50 - 3.39 (m, 2H), 3.32 3.30 (m, IH), 3.30 - 3.26 (m, 2H), 3.26 - 3.20 (m, IH), 2.98 - 2.91 (m, 2H), 2.90-2.82 (m, IH), 2.75 - 2.57 (m, 2H), 2.03 - 1.95 (m, IH), 1.94 - 1.86 (m, 2H), 1.85 - 1.74 (m, 2H), 1.40 (s, 9H).

[004365] Step 3 - 3-[3-Methyl oxo [3-[(3R)-pyrrolidin yl1oxypropyl1benzimidazol-lyl1piperidine-2,6- dione

[004366] To a solution of tert-butyl (3R) [3-[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy] pyrrolidine carboxylate (300 mg, 616 umol) in dichloromethane (3 mL) was added TFA (3 mL) at 15 °C. The reaction mixture was stirred at 15 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (330 mg, 100% yield, TFA salt) as yellow semisolid. LC-MS (ESI+) m/z 387.2 (M+H)+.

[004367] l-(26&#1524;-dioxo DiDeridvl) methvl oxo-benzimidazole carbaldehyde (Intermediate WW)

[004368] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6

1371 dione (500 mg, 1.48 mmol, Intermediate HP) in DMF (20 mL) was added TEA (448 mg, 4.44 mmol), Pd(dppf)C12 (162 mg, 221 umol) and Et3SiH (515 mg, 4.44 mmol). The reaction mixture was stirred at 80 °C for 16 hours under CO (50 Psi). On completion, the reaction mixture was concentrated in vacuo and purified by reverse phase (0.1% FA) to give the title compound (400 mg, 47% yield) as a white solid. LC-MS (ESI+) m/z 288.0 (M+H)+.

[004369] 3-[3-Methvl [[4-(methvlamino)-l-DiDeridvl]methvl] oxo-benzimidazol-lyl]piperidine-2,6-dione (Intermediate WX)

HOAc, NaBH(OAc)3, THF/DMF

TFA

DCM

WX

[004370] Step 1 - Tert-butyl N-r1-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1methyl1 piperidyl1-N-methyl-carbamate

[004371] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-4carbaldehyde (160 mg, 556 umol, Intermediate WW) and tert-butyl N-methyl-N-(4piperidyl)carbamate (119 mg, 556 umol) in a mixed solvents of THF (3 mL) and DMF (1.5 mL) was added AcOH until the pH = 5 - 7. After the reaction mixture was stirred at 20 °C for 3 hours. NaBH(OAc)3 (177mg, 835 umol) was added to the reaction mixture. The mixture was stirred at 20 °C for 12 hours. On completion, the reaction mixture was quenched by water (3 drops) and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (220 mg, 46% yield) as white solid. LC-MS (ESI+) m/z 486.2 (M+H)+.

[004372] Step 2 - 3-r3-Methyl rr4-(methylamino)-l-piperidyl1methyl1 oxobenzimidazol-l-yl1piperidine-2,6-dione

[004373] To a solution of tert-butyl N-[l-[[l-(2,6-dioxo piperidyl) methyl oxo

1372 benzimidazol yl]methyl] piperidyl]-N-methyl-carbamate (200 mg, 235 umol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at 15 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (220 mg, 100% yield, TFA salt) as yellow oil. LC-MS (ESI+) m/z 386.2 (M+H)+.

[004374] 3-[3-Methvl [4-[4-(methvlaminomethvl)-l-DiDeridvl]but-l-vnyl] oxobenzimidazol-l-yl] DiDeridine-2,6-dione (Intermediate WZ)

[004375] Step 1 - 3-r4-(4-Hydroxybut-l-ynyl) methyl oxo-benzimidazol-lyl1piperidine-2,6-dione

[004376] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6di one (1.00 g, 2.96 mmol, Intermediate HP) and but yn 01 (518 mg, 7.39 mmol, 559 uL, CAS# 927 2) in DMSO (15 mL) was added Pd(PPh3)2C12 (207 mg, 295 umol), Cui (56.3 mg, 295 umol) and DIPEA (1.91 g, 14.7 mmol, 2.58 mL). The reaction mixture was stirred at 80 °C for 2 hrs under N2. On completion, the mixture was fdtered, and the fdtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (600 mg, 62% yield) as a white solid. 1H NMR (400 MHz, DMSO-76) δ 11.13 (s, IH), 7.15 - 6.97 (m, 3H), 5.39 (dd, J = 4.8, 12.4 Hz, IH), 4.94 (s, IH), 3.65 (s, 3H), 3.34 (s, 2H), 2.95

1373 .84 (m, IH), 2.69 - 2.59 (m, 4H), 2.06 - 2.00 (m, IH); LC-MS (ESI+) m/z 328.1 (M +H)+.

[004377] Step 2 - 4-[ l-(2,6-Dioxo piperi dyl) methyl oxo-benzimidazol yl1but-3ynyl methane sulfonate

[004378] To a solution of 3-[4-(4-hydroxybut-l-ynyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (600 mg, 1.83 mmol) and TEA (556 mg, 5.50 mmol, 765 uL) in DCM (20 mL) was added MsCI (314 mg, 2.75 mmol, 212 uL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was quenched with H2O (30 mL), then extracted with DCM (2 X 50 mL). The organic phase was dried with Na2SO4, filtrated and concentrated in vacuo to give the title compound (500 mg, 67% yield) as a yellow solid. LC-MS (ESH) m/z 406.2 (M+H)+.

[004379] Step 3 - Tert-butyl N-rr1-r4-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol vl1but vnyl1- 4-piperidvl1methvH-N-methvl-carbamate

[004380] To a solution of 4-[ 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-4yl]but ynyl methanesulfonate (400 mg, 986umol) and tert-butyl N-m ethyl -N-(4piperidylmethyl)carbamate (270 mg, 1.18 mmol, CAS# 138022 5) in MeCN (10 mL) and CHCh (10 mL) was added K2CO3 (409 mg, 2.96 mmol). The reaction mixture was stirred at 65 °C for 16 hrs. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3 X 50 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (140 mg, 26% yield) as a yellow solid. 1H NMR (400MHz, DMSO-» δ 11.11 (s, IH), 7.11 (d, J= 7.2 Hz, IH), 7.07-7.02 (m, IH), 7.01 - 6.96 (m, IH), 5.38 (dd, J= 5.2, 12.8 Hz, IH), 3.67 (s, 3H), 3.05 (d, J= 6.4 Hz, 2H), 2.96 - 2.87 (m, 3H), 2.69 - 2.58 (m, 9H), 2.05 - 1.94 (m, 3H), 1.58 - 1.51 (m, 3H), 1.38 (s, 9H), 1.18 - 1.08 (m, 2H);LC-MS (ESI+) m/z 538.4 (M+H)+.

[004381] Step 4 - 3-[3-Methyl [4-[4-(methylaminomethyl)-l-piperidyl1but-l-ynyl1 oxobenzimidazol-l-yl1 piperi dine-2,6-di one

[004382] To a solution of tert-butyl N-[[l-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] but ynyl] piperidyl]methyl]-N-methyl-carbamate (140 mg, 260 umol) in DCM (3 mL) was added ZnBr2 (293 mg, 1.30 mmol, 65.1 uL). The reaction mixture was stirred at 20 °C for 48 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (100

1374 mg, 87% yield) as a white solid. LC-MS (ESI+) m/z 438.2 (M+H)+.

[004383] Tert-butyl(22&#1524;-diflu0r0 (Dr0D vn-l-vl0xv)Dr0Dvl)(methyl)carbamate (Intermediate XA)

NaH, Mel

KOH, TBAI, THF

THF (B0C)2O thf/h2o

XA

[004384] Step 1 - Tert-butyl (2,2-difluoro hydroxypropyl)carbamate

[004385] To a solution of 3-amino-2,2-difluoro-propan-l-ol (2.00 g, 18.0 mmol, CAS# 155310 5) in a mixed solvents of THF (75 mL) and H2O (75 mL) was added B0C20 (3.93 g, 18.0 mmol) slowly at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was diluted with 1.0 M aq.HCl (100 mL) and extracted with EA (2 X 150 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (3.76 g, 98% yield) as white solid. 1H NMR (400 MHz, CDCh) δ 5.04 (s, IH), 4.10 - 3.87 (m, IH), 3.76 - 3.63 (m, 2H), 3.60 - 3.54 (m, 2H), 1.48 (s, 9H).

[004386] Step 2 - Tert-butyl (2,2-difluoro (prop yn-l-yl oxy )propyl )carbamate

[004387] To a solution of tert-butyl N-(2,2-difluoro hydroxy-propyl)carbamate (5.00 g, 23.7 mmol) in THF (100 mL) was added KOH (1.33 g, 23.7 mmol), KI (393 mg, 2.37 mmol), TBAI (1.31 g, 3.55 mmol) and 3-bromoprop yne (4.22 g, 28.41 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. On completion, the reaction mixture was diluted with sat. aq. NH4C1 (100 mL) and extracted with EA (2 X 150 mL). The combined organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA = 40:1) to give title compound (3.27 g, 55% yield) as colorless oil. 1HNMR (400 MHz, CDCh) δ 4.95 - 4.73 (m, IH), 4.30 - 4.24 (m, 2H), 3.84 - 3.74 (m, 2H), 3.72 - 3.58 (m, 2H), 2.56 - 2.46 (m, IH), 1.47 (s, 9H).

[004388] Step 3 - Tert-butyl (2,2-difluoro (prop vn- l-yl oxy )propyl )(methyl )carbamate [004389] To solution of tert-butyl N-(2,2-difluoro prop ynoxy-propyl)carbamate (3.00 g, 12.1 mmol) in THF (50 mL) was added NaH (578 mg, 14.4 mmol, 60% dispersion in mineral

1375 oil) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour, then Mel (3.42 g, 24.1 mmol) was added. The reaction mixture stirred at 0 - 25 °C for 2 hours. On completion, the reaction was queched with water (100 mL). The mixture was extracted with EA (2 X 100 mL). The combined organic phase was concentrated in vacuo to give the title compound (3.00 g, 95% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.25 - 4.18 (m, 2H), 3.72 - 3.58 (m, 4H), 2.89 (s, 3H), 2.42 (s, IH), 1.40 (s, 9H).

[004390] 3-(4-(3-(2.,2-Diflu0r0 (methvlamin0)Dr0D0xv)Dr0Dvl) methvl 0x0-2.,3dihydro-ΙΗ -benzo[d]imidazol-l-yl)DiDeridine-2.,6-dione (Intermediate XB)

Pd/C, Pd(OH)2/C

THF

HCI/dioxane

DCM

[004391] Step 1 - Tert-butyl (3-((3-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-lH-benzo[d1 imidazol yl)prop yn-l-yl)oxy)-2,2-difluoropropyl )(methyl )carbamate [004392] To a solution of tert-butyl N-(2,2-difluoro prop ynoxy-propyl)carbamate (442 mg, 1.77 mmol, Intermediate XA) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (300 mg, 887 umol, Intermediate HP) in DMF (6 mL) was added Pd(PPh3)2C12 (125 mg, 177 umol), Cui (33.8 mg, 177 umol), Cs2CO3 (1.45 g, 4.44 mmol) and 4A molecular sieves (100 mg) at 20 °C. The mixture was stirred at 80 °C for 2 hours under N2. On completion, the reaction mixture was cooled to 20 °C. The mixture was diluted with EA (50 mL) and filtered. The filtrate was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (160 mg, 35% yield) as

1376 brown solid. 1H NMR (400 MHz, DMSO&#1470;d6) δ 11.11 (s, IH), 7.24 - 7.17 (m, IH), 7.17 - 7.11 (m, IH), 7.08 - 7.01 (m, IH), 5.46 - 5.35 (m, IH), 4.58 (s, 2H), 3.89 - 3.78 (m, 2H), 3.78 - 3.68 (m, 2H), 3.67 - 3.59 (m, 3H), 1.38 (s, 9H). LC-MS (ESI+) m/z 543.1(M+Na)+.

[004393] Step 2 - Tert-butyl (3-(3-(l-(2,6-dioxopiperidin vl) methvl oxo-2,3-dihydrolH-benzo[d1 imidazol yl)propoxy)-2,2-difluoropropyl)(methyl)carbamate

[004394] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]-2,2-difluoro-propyl]-N-methyl-carbamate (200 mg, 384 umol) in THF (10 mL) was added Pd/C (50.0 mg, 10 wt%) and Pd(OH)2/C (50.0 mg, 10 wt%) at 25 °C. The mixture was stirred at 25 °C for 18 hours under H2 (15 psi). On completion, the reaction mixture was diluted with THF (40 mL), filtrated and concentrated in vacuo to give the title compound (195 mg, 97% yield) as yellow solid. 1HNMR (400 MHz, DMSO-76) δ 11.08 (s, IH), 7.01 - 6.94 (m, 2H), 6.91 - 6.84 (m, IH), 5.40 - 5.33 (m, IH), 3.64 - 3.58 (m, 6H), 3.58 - 3.56 (m, 3H), 3.02 - 2.93 (m, 2H), 2.87 (s, 3H), 1.91 - 1.82 (m, 2H), 1.79 - 1.74 (m, 4H), 1.40 (s, 9H); LCMS (ESI+) m/z 547.3(M+Na)+.

[004395] Step 3 - 3-(4-(3-(2,2-Difluoro (methylamino)propoxy)propyl) methyl oxo2,3 -dihydro- IH -benzo[dlimidazol-1 -yl)piperidine-2,6-dione

[004396] To the solution of tert-butyl N-[3-[3-[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]-2, 2-difluoro-propyl]-N-methyl-carbamate (180 mg, 343 umol) in DCM (3 mL) was added HCl/dioxane (3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo to give the title compound (155 mg, 98% yield, HCI salt). LC-MS (ESI+) m/z 425.1(M+H)+ .

[004397] 3-[6-[3-[3-(Methylamino)propoxy]propyl] oxo-l.,3-benzoxazol-3yl]piperidine-2.,6-dione (Intermediate XC)

1377

PO

H2, THF &#1524;Boc

Cs2CO3, Cui, Pd(PPh3)2CI2, 4A MS, DMF

Pd/C, Pd(OH)2/C

[004398] Step 1 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-6yl1prop ynoxy1propyl1 -N-methyl-carbamate

[004399] To a mixture of 3-(6-bromo oxo-l,3-benzoxazol yl)piperidine-2,6-dione (450 mg, 1.38 mmol, Intermediate OZ), tert-butyl N-methyl-N-(3-prop ynoxypropyl)carbamate (566 mg, 2.49 mmol, Intermediate PO) in DMF (10 mL) was added Cs2CO3 (2.25 g, 6.92 mmol), Cui (79.08 mg, 415.24 umol), Pd(PPh3)2C12 (97.1 mg, 138 umol) and molecular sieves 4A (50 mg). The reaction mixture was stirred at 80 °C for 2 hours under N2. On completion, the reaction was filtered. And the filtrate was poured into water (100 mL), then the aqueous phase was extracted with ethyl acetate (2 X 40 mL). The combined organic phase was washed with brine (2 X 40 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (350 mg, 49% yield) as a brown solid. 1HNMR (300 MHz, CDCh) δ 8.24 - 8.11 (m, IH), 7.35 (s, 2H), 6.78 (d, J= 8.4 Hz, IH), 5.06 (d, J= 52, 12.8 Hz, IH), 4.37 (s, 2H), 3.60 (d, J= 6.4 Hz, 2H), 3.34 (d, J= 6.8 Hz, 2H), 2.89 (s, 3H), 1.94 - 1.78 (m, 3H), 1.75 - 1.61 (m, 3H), 1.47 (s, 9H).

[004400] Step 2 - Tert-butyl N-r3-r3-r3-(2,6-dioxo piperidyl) oxo-L3-benzoxazol-6yl1propoxy1propyl1-N- methyl-carbamate

[004401] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]prop ynoxy] propyl]-N-methyl-carbamate (350 mg, 742 umol) in THF (10 mL) was added Pd/C (50 mg, 10 wt%) and Pd(OH)2/C (50 mg, 10 wt%) under N2. The suspension was

1378 degassed under vacuum and purged with H2 three times. The mixture was stirred at 25 °C for 12 hours under H2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (330 mg, 93% yield) as brown oil. 1H NMR (400 MHz, CDCh) δ 8.19 (s, IH), 7.12 (s, IH), 7.00 (d,/=8.0 Hz, IH), 6.73 (d,/= 8.0 Hz, IH), 5.06 (d, /= 5.6, 13.2 Hz, IH), 3.41 (q, /= 6.4 Hz, 4H), 3.30 (s, 2H), 3.03 - 2.94 (m, IH), 2.89 - 2.84 (m, 3H), 2.78 - 2.68 (m, 3H), 2.37 - 2.26 (m, IH), 1.94 - 1.72 (m, 4H), 1.63 (d, /= 6.8 Hz, 2H), 1.46 (s, 8H).

[004402] Step 3 - 3-r6-r3-r3-(Methylamino)propoxy1propyl1 oxo-L3-benzoxazol-3yl1piperidine-2,6-dione

[004403] To a mixture of tert-butyl N-[3-[3-[3-(2,6-dioxo piperidyl) oxo-l,3benzoxazol yl]propoxy] propyl]-N-methyl-carbamate (320 mg, 673 umol) in DCM (10 mL) was added TFA (153 mg, 1.35 mmol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (320 mg, 97% yield, TFA salt) as a white solid. LC-MS (ESI+) m/z 376.2 (M+H)+.

[004404] 3-[3-Methvl [3-[3-(methvlamino)propoxy|prop-l-vnvl] oxobenzimidazol-l-yl] piperidine -2,6-dione (Intermediate XD)

[004405] To a mixture of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop- 2-ynoxy]propyl]-N-methyl-carbamate (180 mg, 371 umol, synthesized via Step 1 of Intermediate PP) in DCM (5 mL) was added TFA (7.70 g, 67.5 mmol, 5.00 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (180 mg, 97% yield, TFA salt) as a yellow solid. 1HNMR (400 MHz, DMSO-/6) δ 11.13 (s, IH), 8.35 (s, 2H), 7.19 (d,/= 7.6 Hz, IH), 7.14-7.11 (m, IH), 7.06 - 7.01 (m, IH), 5.40 (dd, /= 12.8 Hz, IH), 4.45 (s, 3H), 3.65 (s, 3H), 3.60 (s, 2H), 2.97 (m, 2H), 2.91 - 2.83 (m, IH), 2.73 - 2.60 (m, 2H), 2.52 - 2.50 (m, 2H), 2.06 - 1.99 (m, IH), 1.90- 1.83 (m, 2H).

[004406] 2-(Methvlamino)ethvlN-[[l-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl] methyl]carbamate (Intermediate XE)

1379

[004407] Step 1 - 2-rTert-butoxycarbonyl(methyl)amino1ethyl (4-nitrophenyl) carbonate [004408] To a mixture of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (1.00 g, 5.71 mmol, CAS # 57561 4) and (4-nitrophenyl) carbonochloridate (1.15 g, 5.71 mmol, CAS #769346-1) in DCM (20 mL) was added TEA (1.44 g, 14.27 mmol) at 0 °C for 1 hour. On completion, the reaction was poured into the ice-water (50 mL) and extracted with DCM (2 X 30 mL). The combined organic phase was washed with brine (2 X 50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.80 g, 92% yield) as a white solid. 1HNMR (300 MHz, CDCh) δ 8.30 (d, J = 9.2 Hz, 2H), 7.41 (d, J = 92 Hz, 2H), 4.41 (t, J = 5.6 Hz, 2H), 3.61 (s, 2H), 2.98 (s, 3H), 1.48 (s, 9H).

[004409] Step 2 - Tert-butylN-r2-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1methylcar bamoyloxy1ethyl1-N-methyl-carbamate

[004410] To a mixture of 2-[tert-butoxycarbonyl(methyl)amino]ethyl (4-nitrophenyl) carbonate (172 mg, 507 umol), 3-[5-(aminomethyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (102 mg, 253 umol, TFA salt, Intermediate PH) in DMF (10 mL) was added TEA (128 mg, 1.27 mmol). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (105 mg, 84%

1380 yield) as brown solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.08 (s, IH), 7.69 (s, IH), 7.09 - 7.02 (m, 2H), 6.95 (d, J = 8.4 Hz, IH), 5.39 - 5.32 (m, IH), 4.21 (d, J = 6.0 Hz, 2H), 4.10 - 4.03 (m, 2H), 3.36 (t, J= 5.6 Hz, 2H), 2.97 - 2.85 (m, IH), 2.80 (s, 2H), 2.74 (d, J= 4.4, 8.8 Hz, IH), 2.67 - 2.59 (m, IH), 2.10 - 1.59 (m, 3H), 1.37 (s, 9H).

[004411] Step 3 - 2-(Methylamino)ethylN-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 methyllcarbamate

[004412] To a mixture of tert-butyl N-[2-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methylcarbamoyloxy]ethyl]-N-methyl-carbamate (105 mg, 214 umol) in DCM (10 mL) was added TFA (24.4 mg, 214 umol). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (107 mg, 99% yield, TFA salt) as brown oil. LC-MS (ESI+) m/z 390.1 (M+H)+.

[004413] 3-(5-bromo-9H-Dvrido [2.,3-b] indol yl)DiDeridine-2.,6-dione (Intermediate

XF)

1381

PPA

TFA

NaHMDS, 18-crown-6, THF

toluene

MsOH

DCM

XF

[004414] Step 1 - N-(3-bromophenyl) nitro-pyridin amine

[004415] To a solution of 2-chl oro nitro-pyridine (5.00 g, 315 mmol, CAS# 34515 7) and 3-bromoaniline (5.97 g, 34.7 mmol, CAS# 591 5) in dioxane (40 mL) was added DIPEA (12.2 g, 94.6 mmol). The reaction mixture was stirred at 115 °C for 2 days. Then the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (8.00 g, 86% yield) as a red solid. LC/MS (ESI, m/z[. [M +1]+ = 295.1.

[004416] Step 2 - 7V2-(3-bromophenyl)pyridine-2,3-diamine

[004417] To a solution of 7V-(3-bromophenyl) nitro-pyridin amine (5.00 g, 17.0 mmol) and NH4C1 (9.09 g, 170 mmol) in a mixed solvent of H2O (80 mL) and EtOH (80 mL) was added Fe (9.49 g, 170 mmol). The reaction mixture was stirred at 80 °C for 1 h. The mixture was then diluted with water (80 mL) and extracted with EA (2 x 80 mL). The organic layers were washed with brine (2x30 mL), dried with Na2SO4, filtered and the filtrate was concentrated under reduced

1382 pressure to give the title compound (4.00 g, 89% yield) as a brown solid. LC/MS (ESI, m/z): [M +1]+ = 265.1.

[004418] Step 3 - 3-(3-Bromophenvl)triazolo[4,5-Z>1pvridine

[004419] To a solution of 7V2-(3-bromophenyl)pyridine-2,3-diamine (4.00 g, 15.1 mmol) in a mixed solvent of HO Ac (25 mL) and DCM (25 mL) was added a solution of NaNO2 (1.36 g, 19.7 mmol) in H2O (15 mL) dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 30 minutes. On completion, the mixture was diluted with water (50 mL), and extracted with DCM (2 X 50 mL). The organic layers were washed with brine (2 X 50 mL), dried with Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the title compound (4.10 g, 98% yield) as a brown solid. LC/MS (ESI, m/z): [M +1]+ = 276.1.

[004420] Step 4 - 5-Bromo-9H-pyrido[2,3-Z>1indole

[004421] Amixture of 3-(3-bromophenyl)triazolo[4,5-Z>]pyridine (3.60 g, 13.1 mmol) in PPA (20 mL) was heated at 170 °C for 3 h. On completion, the mixture was poured into the ice water (200 mL), stirred for 1 h, then filtered. The filter cake was dried under reduced pressure. The filter cake contained two isomers 5-bromo-9H-pyrido[2,3-b]indole and its isomer 7-bromo-9Hpyrido[2,3-b]indole, which were brought on to the next step directly.

[004422] Step 5 - tert-butyl 5-bromo-9rt-pyrido[2,3-Z>1indole carboxylate

[004423] To a mixture of 5-bromo-9rt-pyrido[2,3-b]indole and 7-bromo-9H-pyrido[2,3b]indole (10.0 g, 40.0 mmol) in THF/H2O (100 mL /100 mL) was added B0C20 (17.4 g, 80.0 mmol) and NaOH (4.8 g, 120.0 mmol), and the mixture was stirred at rt for 3 h. On completion, the mixture was poured into the water (200 mL), and extracted with EA(2 X 100 mL). The organic layers were washed with brine (2 X 100 mL), dried over Na2SO4, filtered and the filtrate was concentrated to give crude product which was purification by column chromatography to give tertbutyl 5-bromo-9//-pyrido[2,3-6]indole carboxylate (4.10 g, 7% yield for two steps) as brown product. LC/MS (ESI, m/z): [M +1]+ = 348.2.

[004424] Step 6 - 5-Bromo-9rt-pyrido[2,3-Z>1indole

[004425] Amixture of tert-butyl 5-bromo-9//-pyrido[2,3-6]indole carboxylate (9.0 g, 25.9 mmol) in DCM (20 mL) was added TFA (15 mL), and the mixture was stirred at rt for 16 h. On completion, the mixture was concentrated to give the title product (6.0 g, 94% yield) as brown solid.

[004426] Step 7:3-(5-Bromopyridor2,3-b1indol yl)-l-[(4

1383 methoxyphenyl)methyl1piperidine-2,6-dione

[004427] To a mixture of 5-bromo-9//-pyrido[2,3-Z>]indole (250 mg, 1.01 mmol) and 18crown-6 (53 mg, 0.2 mmol) in THF (5 mL) was added NaHMDS (0.75 mL, 1.5 mmol) (2 M in THF) at -30 °C. After stirring for 1 h at -30 °C, a solution of [l-[(4-methoxyphenyl)methyl]-2,6dioxo piperidyl] trifluoromethanesulfonate (579 mg, 1.5 mmol) in THF (2 mL) was added into the above mixture dropwise at -30 °C. The reaction mixture was stirred at -30 °C for 2 h. On completion, the mixture was quenched with NH4C1 aqueous, then extracted with EAThe combined EA layers were concentrated and purified by reverse phase (0.1% FA) to give the title compound (286 mg, 60% yield) as a brown solid. 1H NMR (400 MHz, DMSOY) δ 8.91 (dd, J= 1.2, 7.6 Hz, IH), 8.59 - 8.46 (m, IH), 7.57 - 7.50 (m, IH), 7.49 - 7.42 (m, IH), 7.41 - 7.35 (m, IH), 7.33 - 7.23 (m, 2H), 7.22 - 7.05 (m, IH), 6.94 - 6.86 (m, 2H), 6.32 - 5.97 (m, IH), 4.92 - 4.75 (m, 2H), 3.75 (s, 3H), 3.24 - 3.06 (m, 2H), 2.97 - 2.84 (m, IH), 2.27 - 2.15 (m, IH).

[004428] Step 8 - 3-(5-Bromopyrido[2,3-Z>]indol yl)piperidine-2,6-dione

[004429] To a solution of 3-(5-bromopyrido[2,3-Z>]indol yl)-l-[(4methoxyphenyl)methyl]piperidine-2,6-dione (6.0 g, 12.5 mmol) in toluene (50 mL) was added MsOH (10 mL). The reaction mixture was stirred at 110 °C for 4 h. On completion, the mixture was quenched with water (20 mL), then extracted with EA (2 X 20 mL). The organic layers were concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 38%68%, 10 min) to give the title compound (2.8 g, 62% yield) as a white solid. 1H NMR (400 MHz, DMSOY) δ 11.19 (s, IH), 8.91 (dd, J= 1.5 ,8.ד Hz, IH), 8.53 (dd, J= 4.7, 1.3 Hz, IH), 7.72 (br s, IH), 7.54 - 7.53 (m, IH), 7.49 - 7.45 (m, IH), 7.38 (dd, J = 7.9, 4.8 Hz, IH), 6.19 - 6.00 (m, IH), 3.16 - 2.98 (m, 2H), 2.74 - 2.67 (m, IH), 2.17 - 2.14 (m, IH); LC/MS (ESI, m/z[ [M +1]+ = 358.0/360.0.

[004430] 3 13- [2-(2-Aminoethoxy)ethoxy| propyl] pyrido [2,3-b] indol yl] piperidine2.,6-dione (Intermediate XG)

1384

NHBoc

Cs2CO3,Cul,PdCI2(PPh3)2

XG

[004431] Step 1 - tert-butyl (2-(2-((3-(9-(2,6-dioxopiperidin yl)-9H-pyridor2,3-b1indol5-yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate

[004432] A mixture of 3-(5-bromo-9/7-pyrido[2,3-b]indol yl)piperidine-2,6-dione (270 mg, 0.75 mmol), tert-butyl (2-(2-(prop yn-l-yloxy)ethoxy)ethyl)carbamate (270 mg, 2.25 mmol, Intermediate IT) Cs2CO3 (270 mg, 2.25 mmol), PdC12(PPh3)2 (105 mg, 0.15 mmol) and Cui (14 mg, 0.075 mmol) in DMF (10 mL) was stirred at 80 °C for 1 h under N2 with microwave . The mixture was cooled to rt, poured into water (100 mL), extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1) to give the title product (180 mg, 41% yield) as a white solid. LC/MS (ESI, m/z): [M +1]+ = 360.28. &#905; NMR (400 MHz, DMSOY6)(511.18 (s, IH), 8.81 (dd,7=7.8, 1.6 Hz, IH), 8.50 (dd, 7= 4.8, 1.7 Hz, IH), 7.73-7.68 (m, 1 H), 7.54 (t, 7= 7.9 Hz, IH), 7.45 - 7.28 (m, 2H), 6.80-6.76 (m, 1 H), 6.08 (s, IH), 4.65 (s, 2H), 3.81 - 3.70 (m, 2H), 3.62 (dd, 7= 5.7, 3.6 Hz, 2H), 3.43 (t, 7= 6.1 Hz, 2H), 3.17 - 2.96 (m, 3H), 2.76-2.64 (m, IH), 2.50 -2.45 (m, 1 H), 2.17-2.13 (m, 1 H), 1.35 (s, 9H).

[004433] Step 2 - tert-butyl (2-(2-(3-(9-(2,6-dioxopiperidin yl)-9H-pyridor2,3-b1indol-5yl)propoxy)ethoxy)ethyl)carbamate

[004434] To a mixture of tert-butyl (2-(2-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3b]indol yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate (180 mg, 0.34 mmol), Pd/C (100 mg) in EA (10 mL) was stirred at rt under H2 for 16 h. The mixture was fdtered and the solid was washed

1385 with EA, the filtrate was concentrated under reduced pressure. Then the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1) to give the title compound (100 mg, 56% yield) as a white solid. LC/MS (ESI, m/z): [M +1]+ =525.1. 1H NMR (400 MHz, DMSO-76) δ 11.15 (s, IH), 8.54 (dd, J = 7.9, 1.5 Hz, IH), 8.42 (dd, J = 4.9, 1.5 Hz, IH), 7.52-7.40 (m, 2 H), 7.28 (dd, J= 7.8, 4.9 Hz, IH), 7.11 (d, J= 7.4 Hz, IH), 6.77-6.74 (m, 1 H), 6.10-6.00 (m, 1 H), 3.61 - 3.50 (m, 6H), 3.43 (t, J = 6.1 Hz, 2H), 3.23-3.20 (m, 2 H), 3.12 2.96 (m, 4H), 2.72-2.65 (m, IH), 2.12-2.06 (m, 1 H), 1.99-1.89 (m, 2 H), 1.34 (s, 9H).

[004435] Step 3 - 3-[5-[3-[2-(2-Aminoethoxy)ethoxy1propyl1pyrido[2,3-b1indol-9yl1piperidine-2,6-dione

[004436] To a solution of tert-butyl N-[2-[2-[3-[9-(2,6-dioxo piperidyl)pyrido[2,3-b]indol5-yl]propoxy] ethoxy]ethyl]carbamate (100 mg, 190 umol) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (100 mg, 97% yield, TFA) as a white solid. LC-MS (ESI+) m/z 425.2(M+H)+.

[004437] Tert-butyl N-methvl-N-(l-Dr0D vnyl DiDeridvl)carbamate (Intermediate XH)

HN^A &#1503; K2CO3, THF &#1503;

XH

[004438] To a solution of tert-butyl N-methyl-N-(4-piperidyl)carbamate (1.50 g, 7.00 mmol,

CAS# 108612 0) and 3-bromoprop yne (915 mg, 7.70 mmol, 663 uL, CAS# 106 70) in THF (30 mL) was added K2CO3 (2.90 g, 21.0 mmol). The reaction mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was diluted with water (30 mL) and extracted with EA (3 X 80 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.50 mg, 85% yield) as yellow solid. 1H NMR (400 MHz, CDCh) δ 4.16 - 3.61 (m, IH), 3.29 (d, J = 2.0 Hz, 2H), 3.01 - 2.90 (m, 2H), 2.73 (s, 3H), 2.35 - 2.21 (m, 3H), 1.81 - 1.72 (m, 2H), 1.69 - 1.63 (m, 2H), 1.46 (s, 9H).

[004439] 3-[3-Methvl [3-[4-(methvlamino)-l-piperidvl1propyl] oxo-benzimidazol1-yllpiperidine- 2.,6-dione (Intermediate XI)

1386

XH

Pd(PPh3)2CI2, Cui, Cs2CO3, DMF

Pd(OH)2/C, Pd/C, H2

THF

HCI/dioxane

DCM

XI

[004440] Step 1 - Tert-butyl N-r1-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol vl1prop vnyl1 piperidvl1-N-methyl-carbamate

[004441] To a solution of tert-butyl N-methyl-N-(l-prop ynyl piperidyl)carbamate (559 mg, 2.22 mmol, Intermediate XH) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (500 mg, 1.48 mmol, Intermediate HP) in DMF (5 mL) was added Pd(PPh3)2C12 (103 mg, 147 umol), Cui (28.1 mg, 147 umol) and Cs2CO3 (955 mg, 2.93 mmol, 2.58 mL). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (700 mg, 93% yield) as a gray solid. 1HNMR (400 MHz, DMSO-t/6) δ 11.13 (s, IH), 7.20 - 6.93 (m, 3H), 5.40 (dd, J = 5.2, 12.8 Hz, IH), 3.66 (s, 3H), 3.58 (s, 2H), 2.98 - 2.84 (m, 3H), 2.68 (s, 3H), 2.66 - 2.59 (m, 2H), 2.25 (t, J= 10.8 Hz, 2H), 2.07 - 1.99 (m, IH), 1.75 - 1.50 (m, 5H), 1.40 (s, 9H); LC-MS (ESI+) m/z 510.3 (M+H)+.

[004442] Step 2 - Tert-butyl N-r1-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propyl1 piperidyl1-N-methyl-carbamate

[004443] To a solution of tert-butyl N-[l-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynyl] piperidyl]-N-methyl-carbamate (650 mg, 1.28 mmol) in THF (20 mL) was added Pd/C (150 mg, 1.28 mmol, 10 wt%) and Pd(OH)2/C (150 mg, 10 wt%). The

1387 reaction mixture was stirred at 25 °C under H2 (15 psi) for 2 hrs. On completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (480 mg, 73% yield) as a white solid. 1HNMR (400MHz, DMSO-76) δ 11.08 (s, IH), 6.96 (d, J= 4.8 Hz, 2H), 6.93 - 6.86 (m, IH), 5.36 (dd, 7= 5.6, 12.8 Hz, IH), 3.93 - 3.65 (m, IH), 3.56 (s, 3H), 3.08 - 2.97 (m, 2H), 2.96 - 2.81 (m, 3H), 2.76 - 2.67 (m, IH), 2.66 (s, 3H), 2.64 - 2.58 (m, IH), 2.49 - 2.39 (m, 2H), 2.14 - 2.05 (m, 2H), 2.03 - 1.94 (m, IH), 1.83 - 1.62 (m, 4H), 1.56 - 1.48 (m, 2H), 1.39 (s, 9H); LC-MS (ESI+) m/z 514.3 (M+H)+.

[004444] Step 3 - 3-r3-Methyl r3-r4-(methylamino)-l-piperidyl1propyl1 oxobenzimidazol-l-yl1piperidine- 2,6-dione

[004445] To a solution of tert-butyl N-[l-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propyl] piperidyl]-N-methyl-carbamate (100 mg, 194 umol) in DCM (2 mL) was added HCI/dioxane (4 M, 1 mL). The reaction mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (85.0 mg, 97% yield, HCI) as a white solid. LC-MS (ESI+) m/z 414.3(M+H)+.

[004446] Tert-butyl N-methyl-N-[2-(4-DiDeridvlmethoxv)ethyl] carbamate (Intermediate XJ) o

DPPA, DBU toluene

PPh3, H2O toluene

B0c2O, TEA

THF

XJ

[004447] Step 1 - Benzyl 4-((2-ethoxy oxoethoxy)methyl)piperidine-l-carboxylate

[004448] A solution of benzyl 4-(hydroxymethyl) piperidine carboxylate (15.0 g, 60.2 mmol, CAS# 122860 7) in DCM (15 mL) was added diacetoxyrhodium (1.33 g, 3.01 mmol,

1388

CAS# 623 4). The mixture was stirred at 25 °C for 0.5 hour. Then ethyl 2-diazoacetate (13.7 g, 120 mmol) in DCM (15 mL) was added dropwise slowly to the solution. The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched by water (10 mL), and extracted with DCM (3 X 20 mL). The combined organic layers dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (16.8 g, 83% yield) as yellow oil. LC-MS (ESI+) m/z 336.2 (M+H)+.

[004449] Step 2 - Benzyl 4-((2-hydroxyethoxy)methyl)piperidine-1 -carboxylate

[004450] To a solution of benzyl 4-[(2-ethoxy oxo-ethoxy)methyl]piperidine-lcarboxylate (16.8 g, 50.1 mmol) in THF (180 mL) was added LiBH4 (2.18 g, 100 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched with H2O (200 mL) and then extracted with ethyl acetate (2 X 300 mL). Then the organic layers were washed with brine (2 X 150 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (13.2 g, 90% yield) as colorless oil. LC-MS (ESI+) m/z 294.2 (M+H)+.

[004451] Step 3 - Benzyl 4-((2-azidoethoxy)methyl)piperidine-l-carboxylate

[004452] To a solution of benzyl 4-(2-hydroxyethoxymethyl)piperidine-l-carboxylate (4.00 g, 13.6 mmol) in toluene (40 mL) was added DPPA (4.50 g, 16.4 mmol) and DBU (2.49 g, 16.4 mmol). The mixture was stirred at 100 °C for 12 hours. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (4.34 g, 98% yield) as yellow oil.

[004453] Step 4 - Benzyl 4-(2-aminoethoxymethyl)piperidine-l-carboxylate

[004454] To a solution of benzyl 4-(2-azidoethoxymethyl)piperidine-l-carboxylate (4.34 g, 13.6 mmol) in a mixed solvent of THF (45 mL) and H2O (5 mL) was added PPh3 (3.58 g, 13.6 mmol). The mixture was stirred at 66 °C for 12 hours. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 X 50 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (3.99 g, 99% yield) as yellow oil. LC-MS (ESI+) m/z 293.2 (M+H)+.

[004455] Step 5 - Benzyl 4-r2-(tert-butoxycarbonylamino)ethoxymethyl1piperidine-lcarboxylate

1389

[004456] To a solution of benzyl 4-(2-aminoethoxymethyl)piperidine-l-carboxylate (3.99 g, 13.7 mmol) in THF (40 mL) was added B0C20 (4.47 g, 20.5 mmol) and TEA(4.14 g, 40.9 mmol). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with H2O (100 mL) and extracted with (2 X 100 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (4.70 g, 80% yield) as yellow oil. LC-MS (ESI+) m/z 415.3 (M+Na)+.

[004457] Step 6:Benzyl 4-r2-[tertbutoxycarbonyl(methyl)amino1ethoxymethyl1piperidine-l- carboxylate

[004458] To a solution of benzyl 4-[2-(tert-butoxycarbonylamino)ethoxymethyl]piperidine1-carboxylate (4.60 g, 11.7 mmol) in DMF (50 mL) was added NaH (938 mg, 23.4 mmol, 60% dispersion in oil) at 0 °C. Then CH3I (3.33 g, 23.4 mmol) was added dropwise to the solution. The mixture was stirred at 0-25 °C for 2 hours. On completion, the reaction mixture was quenched with saturated NH4C1 (20 mL). Then H2O (50 mL) and ethyl acetate (100mL) was added. The aqueous layer was extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (3.80 g, 79% yield) as yellow oil.

[004459] Step 7 - Tert-butyl N-methvl-N-r2-(4-piperidvlmethoxy) ethyUcarbamate

[004460] To a solution of benzyl 4-[2-[tertbutoxycarbonyl(methyl)amino]ethoxymethyl]piperidine-l- carboxylate (3.80 g, 9.35 mmol) in MeOH (80 mL) was added Pd/C (400 mg, 377 umol, 10 wt%) . The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (3.30 g, 98% yield) as yellowish oil. LC-MS (ESI+) m/z 273.2 (M+H)+.

[004461] 3-(3-methvl (4-((2-(methvlamino)ethoxv)methvl)piperidin-l-vl)-2oxo-2,3-dihydro -lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione methanesulfonate (Intermediate XK)

1390

[004462] Step 1 - Tert-butyl N-methyl-N-r2-rr1-r3-(methylamino) nitro-phenyl1-4piperidyl] methoxy] ethyUcarbamate

[004463] To a solution of tert-butyl N-methyl-N-[2-(4piperidylmethoxy)ethyl]carbamate (3.30 g, 12.1 mmol, Intermediate XJ) in DMF (30 mL) was added 5-fluoro-N-methyl nitro-aniline (2.06 g, 12.1 mmol) and K2CO3 (5.02 g, 36.4 mmol). Then the mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (3 X 100 mL). The organic layers were washed with brine (3 X 50 mL). Then the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (4.40 g, 85% yield) as orange oil. LC-MS (ESI+) m/z 423.5 (M+H)+.

[004464] Step 2 - Tert-butyl (2-((l-(4-amino (methylamino)phenyl)piperidin-4yl)methoxy)ethyl) (methyl)carbamate

[004465] To a solution of tert-butyl N-methyl-N-[2-[[l-[3-(methylamino) nitrophenyl] piperidyl] methoxy]ethyl]carbamate (3.6 g, 8.52 mmol) in MeOH (100 mL) was

1391 added Pd/C (0.7 g, 10 wt%) under N2. The suspension was degassed in vacuo and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 4 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (3.2 g, 97% yield) as brown oil. 1H NMR (400 MHz, CDCh) δ 6.63 (d, J = 8.2 Hz, IH), 6.34 (d, J= 2.4 Hz, IH), 6.28 (dd, J= 2.6, 8.2 Hz, IH), 3.52 (d, J= 12.0 Hz, 4H), 3.45-3.31 (m, 4H), 2.93 (s, 3H), 2.86 (s, 3H), 2.62 (dt, J= 2.0, 11.6 Hz, 2H), 1.83 (d, J = 12.6 Hz, 2H), 1.73 - 1.60 (m, IH), 1.49 - 1.40 (m, 11H); LC-MS (ESI+) m/z 393.2 (M+H)+. [004466] Step 3 - Tert-butyl (2-((l-(4-amino (methylamino)phenyl)piperidin-4yl)methoxy)ethyl) (methyl)carbamate

[004467] To a mixture of tert-butyl N-[2-[[l-[4-amino (methylamino)phenyl]-4piperidyl]methoxy] ethyl]-N-methyl-carbamate (1.5 g, 3.82 mmol) in MeCN (30 mL) was added CDI (1.24 g, 7.64 mmol) under N2. The mixture was stirred for at 85 °C 16 hours. On completion, the reaction mixture was concentrated in vacuo to remove THF. The residue was diluted with water (20 mL) and extracted with EA (3 X 20 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA condition) to give the title compound (1.10 g, 69% yield) as a purple solid. 1HNMR (400 MHz,CDCh) δ 9.06 (s, IH), 6.95 (d, J= 8.4 Hz, IH), 6.74 - 6.69 (m, IH), 6.62 (d, J= 2.2 Hz, IH), 3.60 - 3.52 (m, 4H), 3.39 (s, 3H), 3.37 3.31 (m, 2H), 2.93 (s, 3H), 2.73 - 2.65 (m, 2H), 1.86 (d, J = 11.8 Hz, 2H), 1.77 - 1.67 (m, 2H), 1.47 - 1.33 (m, 13H; LC-MS (ESI+) m/z 419.2 (M+H)+.

[004468] Step 4 - Tert-butyl (2-((l-(4-amino (methylamino)phenyl)piperidin-4yl)methoxy)ethyl) (methyl)carbamate

[004469] To a mixture of tert-butyl N-methyl-N-[2-[[l-(3-methyl oxo-lHbenzimidazol yl) piperidyl]methoxy]ethyl]carbamate (1.10 g, 2.63 mmol) in THF (20 mL) was added /-BuOK (442 mg, 3.94 mmol) at 0 °C under N2. Then a solution of [l-[(4methoxyphenyl)methyl]-2,6 -dioxo piperidyl] trifluoromethanesulfonate (1.50 g, 3.94 mmol, Intermediate IQ) in THF (20 mL) was added dropwise at 0 °C. The mixture was warmed slowly to 25 °C and stirred at 25 °C for 24 hours. On completion, the reaction mixture was quenched by addition water (10 mL) at 25 °C, and then extracted with EA (3 X 20 mL). The combined organic layers, dried over Na2SO4, filtered and concentrated in vacuo

1392 to give a residue. The residue was purified by column chromatography to give the title compound (800 mg, 24% yield) as brown oil. LC-MS (ESI+) m/z 650.2 (M+H)+.

[004470] Step 5 - 3-(3-methyl (4-((2-(methylamino)ethoxy)methyl)piperidin-l-vl)2-0X0-2,3-dihydro -lH-benzord1imidazol-l-yl)piperidine-2,6-dione methanesulfonate

[004471] To a mixture of tert-butyl N-[2-[[l-[l-[l-[(4-methoxyphenyl)methyl]-2,6di oxo piperidyl] methyl oxo-benzimidazol yl] piperidyl]methoxy]ethyl]-Nmethyl-carbamate (500 mg, 769 umol) in toluene (10 mL) was added CH3SO3H (2.22 g, 23.1 mmol) at 25 °C. The mixture was stirred at 120 °C for 3 hours. On completion, the reaction mixture was quenched by addition water (2 mL) at 25°C, and then neutralized by adding NEt3 to pH = 5. Then the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA condition) to give the title compound (100 mg, 25% yield, CH3SO3H) as yellow oil. LC-MS (ESI+) m/z 430.1 (M+H)+.

[004472] Tert-butyl 4-(2-prop ynoxyethyl)piperazine-l-carboxylate (Intermediate

[004473] A mixture of tert-butyl 4-(2-hydroxyethyl)piperazine-l-carboxylate (5.00 g, 21.7 mmol, CAS# 77279 4), 3-bromoprop yne (2.58 g, 21.7 mmol, CAS# 106 7) in THF (35 mL) was added TBAI (802 mg, 2.17 mmol), KI (541 mg, 3.26 mmol) and KOH (1.22 g, 21.7 mmol). The mixture was stirred at 25 °C for 12 hrs under N2 atmosphere. On completion, the reaction mixture was diluted with water (2 X 100 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, PE: EA = 10:1 to 3:1) to give the title compound (1.30 g, 18% yield) as yellow oil. 1H NMR (400 MHz, DMSO4) δ 4.12 (d, J = 2.4 Hz, 2H), 3.54 (t, J = 5.6 Hz, 2H), 3.41 (s, IH), 3.30 - 3.26 (m, 4H), 2.49 - 2.47 (m, 2H), 2.36 - 2.33 (m, 4H), 1.39 (s, 9H).

[004474] 3-[3-Methvl oxo [3-(2-DiDerazin-l-vlethoxy)DroDvl]benzimidazol-lyl]piperidine-2.,6-dione (Intermediate XM)

1393

XL

Pd(PPh3)2CI2, Cui, 4A MS, Cs2CO3, DMF

[004475] Step 1 - Tert-butyl 4-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxy1ethyl1piperazine-l-carboxylate

[004476] A mixture of tert-butyl 4-(2-prop ynoxyethyl)piperazine-l-carboxylate (476 mg,

1.77 mmol, Intermediate XL), 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (300 mg, 887 umol, Intermediate HP), Cs2CO3 (1.45 g, 4.44mmol), 4A molecular sieves (50 mg), Pd(PPh3)2C12 (124 mg, 177 umol) and Cui (33.8 mg, 177 umol) in DMF (8 mL) under N2 atmosphere. The mixture was de-gassed and then heated at 80 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (400 mg, 77% yield) as brown oil. 1H NMR (400 MHz, DMSO-/6) δ 11.12 (s, IH), 7.19 (d, J = 7.2 Hz, IH), 7.13 (d, J = 7.6 Hz, IH), 7.06 6.94 (m, IH), 5.41 (dd, J = 4.8, 12.4 Hz, IH), 4.47 (s, 2H), 3.74 (s, 2H), 3.64 (s, 3H), 3.56 - 3.52 (m, 4H), 2.94 - 2.89 (m, IH), 2.85 - 2.71 (m, 4H), 2.63 - 2.58 (m, 4H), 2.09 - 1.97 (m, IH), 1.39 (s, 9H); LC-MS (ESI+) m/z 526.3 (M+H)+.

[004477] St ep 2 - Tert-butyl 4-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol yl1propoxy1 ethyllpiperazine-1 -carboxylate

1394

[004478] To a solution of tert-butyl 4-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]ethyl]piperazine-l-carboxylate (400 mg, 679 umol) in THF (20 mL) was added Pd/C (50.0 mg, 10 wt%) and Pd(OH)2 (50.0 mg) under N2 atmosphere. The mixture was stirred at 25 °C for 12 hrs under H2 (15 Psi). On completion, the reaction mixture was concentrated in vacuo. The product was filtered under reduced pressure to give the title compound (395 mg, 99% yield) as brown solid. 1HNMR (400 MHz, DMSO-Y) δ 11.08 (s, IH), 6.97 (d, J= 5.2 Hz, 2H), 6.90 -6.85 (m, IH), 5.37 (dd, J= 5.2, 12.4 Hz, IH), 4.26 (t, J= 7.2 Hz, IH), 4.15 (t, J= 6.5 Hz, IH), 3.69 - 3.62 (m, 2H), 3.56 (s, 3H), 3.50 - 3.45 (m, 4H), 2.98 - 2.95 (m, 2H), 2.75 2.71 (m, 2H), 2.69 - 2.66 (m, 2H), 2.65 - 2.59 (m, 4H), 2.19 - 2.13 (m, IH), 1.88 - 1.82 (m, 2H), 1.77 - 1.71 (m, IH), 1.40 (s, 9H). LC-MS (ESI+) m/z 530.3 (M+H)+.

[004479] Step 3 - 3-r3-Methyl oxo r3-(2-piperazin-l-ylethoxy)propyl1benzimidazol-lyl1piperidine-2,6-dione

[004480] To a solution of tert-butyl 4-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy]ethyl]piperazine-l-carboxylate (100 mg, 189 umol) in DCM (4 mL) was added HCl/dioxane (2 mL). The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (87 mg, 58% yield, HC1) as brown solid. LC-MS (ESI+) m/z 430.3 (M+H)+.

[004481] Tert-butyl N-is0Dr0Dvl-N-(3-Dr0D yn0xvDr0Dvl)carbamate (Intermediate XN) nh2

HO^^+^NH (Boc)2O, TEA HO^^^N'800

HO +/ Br --------&#9658; T ----------&#9658; 7 /+- DCM /\

XN

[004482] Step 1 - 3-(Isopropylamino)propan-l-ol

[004483] A solution of 3-bromopropan 01 (5.00 g, 36.0 mmol) in propan amine (6.19 g, 105 mmol) was stirred at 50 °C for 12 hours. On completion, the mixture was concentrated to give the title compound (7.00 g, 90% yield, 50% purity) as colorless oil. 1H NMR (400 MHz, CDCh) δ 3.84 (t, J= 5.6 Hz, 2H), 3.40 - 3.33 (m, IH), 3.12 (t, J = 6.4 Hz, 2H), 2.11 - 1.99 (m, 2H), 1.39

1395 (d, J =6.6 Hz, 6H).

[004484] Step 2 - Tert-butyl N-(3-hydroxypropyl)-N-isopropyl-carbamate

[004485] To a solution of 3-(isopropylamino)propan-l-ol (7.00 g, 30.0 mmol, 50% purity) in

DCM (10 mL) was added (Boc)2O (13.0 g, 59.7 mmol, 13.7 mL) and Et3N (8.00 g, 79.0 mmol) at 15 °C. The mixture was stirred at 15 °C for 6 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (3.60 g, 50% yield) as yellow oil. 1HNMR (400 MHz, CDCh) δ 3.58 (m, 2H), 3.35 (m, 2H), 1.67 (m, 2H), 1.48 (s, 9H), 1.16 (d, J= 6.8 Hz, 6H), 0.91 - 0.86 (m, IH).

[004486] Step 3 - Tert-butyl N-isopropvl-N-(3-prop vnoxvpropyl)carbamate

[004487] To a solution of tert-butyl N-(3-hydroxypropyl)-N-isopropyl-carbamate (3.40 g, 15.7 mmol) and TBAI (57.8 mg, 156 umol) in THF (100 mL) was addedNaH (750 mg, 18.7 mmol, 60% dispersion in oil) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. 3-bromoprop yne (2.79 g, 23.5 mmol) was added at 0 °C. The mixture was stirred at 0 - 15 °C for 6 hours. On completion, the reaction mixture was quenched with sat. aq. NH4C1 (30 mL) at 0 °C. The mixture was extracted with EA (3 X 100 mL). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (3.50 g, 80% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.13 (d, J = 2.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.14 (m, 2H), 2.41 (t, J = 2.4 Hz, IH), 1.86 - 1.77 (m, 2H), 1.46 (s, 9H), 1.12 (d, J= 6.8 Hz, 6H), 0.90 - 0.80 (m, IH).

[004488] 3-[4-[3-[3-(Is0Dr0Dvlamin0)Dr0D0xy|Dr0Dvl] methvl 0x0-benzimidaz01-lyl] piperidine -2.,6-dione (Intermediate XO)

1396

XN

[004489] Step 1 - Tert-butyl N-r3-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1prop-2 -ynoxy1propyl1-N-isopropyl-carbamate

[004490] To a solution of tert-butyl N-isopropyl-N-(3-prop ynoxypropyl)carbamate (755 mg, 2.96 mmol, Intermediate XN) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (400 mg, 1.18 mmol, Intermediate HP) in DMF (10 mL) was added Pd(dppf)C12 (173 mg, 237 umol) and Cs2CO3 (1.54 g, 4.73 mmol) and Cul(45.1 mg, 237 umol) at 20 °C. The mixture was stirred at 80 °C for 2 hours under N2. On completion, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by reversed-phase HPLC (FA condition) to give the title compound (350 mg, 55% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, IH), 7.18 (d, J= 7.6 Hz, IH), 7.14 - 7.10 (m, IH), 7.08 - 6.99 (m, IH), 5.43 - 5.38 (m, IH), 4.44 (s, 2H), 3.09 (m, 2H), 2.95 - 2.84 (m, IH), 2.09 - 1.97 (m, IH), 1.82 - 1.69 (m, 2H), 1.38 (s, 9H), 1.08 (d, J= 6.0 Hz, 6H).

[004491] Step 2 - Tert-butyl N-r3-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propoxv1 propyll-N-isopropyl-carbamate

[004492] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]propyl]-N-isopropyl-carbamate (350 mg, 683 umol) in THF (20

1397

mL) was added Pd(0H)2/C (350 mg, 683 umol, 10 wt%) and Pd/C (350 mg, 682 umol, 10 wt%). The mixture was stirred at 15 °C for 2 hours. On completion, the mixture was filtered with celite and the filtrate was concentrated in vacuo to give the title compound (350 mg, 99% yield) as yellow oil. LC-MS (ESI+) m/z 539.4 (M+23)+

[004493] Step 3 - 3-r4-r3-r3-(Isopropylamino)propoxy]propyl] methyl oxobenzimidazol-l-yl]piperidine -2,6-dione

[004494] To a solution of tert-butyl N-[3-[3-[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]propyl]-N-isopropyl-carbamate (320 mg, 619 umol) in DCM (4 mL) was added TFA (10.7 mL) at 15 °C. The mixture was stirred at 15 °C for 0.5 hour. On completion, the mixture was concentrated in vacuo to give the title compound (320 mg, 97% yield, TFA salt) as yellow oil. LC-MS (ESI+) m/z 417.3 (M+H)+.

[004495] Tert-butyl N-cycloDropyl-N-(3-prop ynoxypropyl)carbamate (Intermediate XP) nh2

A HO'^^'^NH (Boc)2O, TEA HO

HO^^Br ----&#9658; I ------&#9651; DCM

NaH,THF A

XP

[004496] Step 1 - 3-(Cyclopropylamino)propan-l-ol

[004497] A mixture of 3-bromopropan 01 (5.00 g, 35.9 mmol, 3.25 mL, CAS# 627 9) in cyclopropanamine (10.2 g, 179 mmol, 12.4 mL, CAS# 765 0) was stirred at 50 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (4.00 g, 96% yield) as light yellow oil. 1H NMR (400 MHz, DMSO-6#) δ 3.45 (t, J= 6.0 Hz, 2H), 3.01 (t, J= 7.6 Hz, 2H), 2.75 - 2.68 (m, IH), 1.81 - 1.73 (m, 2H), 0.88 - 0.82 (m, 2H), 0.74 - 0.70 (m, 2H).

[004498] Step 2 - Tert-butyl N-cyclopropyl-N-(3-hydroxypropyl)carbamate

[004499] To a mixture of 3-(cyclopropylamino)propan-l-ol (4.00 g, 34.7 mmol) in DCM (60 mL) was added TEA (10.5 g, 104 mmol, 14.5 mL) and B0C20 (15.1 g, 69.4 mmol, 15.9 mL). The

1398 reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (3X 50 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (3.70 g, 49% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 3.54 (d, J= 5.0 Hz, 2H), 3.36 (t, J= 6.0 Hz, 2H), 2.49 - 2.41 (m, IH), 1.74 - 1.65 (m, 2H), 1.45 (s, 9H), 0.75 - 0.68 (m, 2H), 0.62 - 0.55 (m, 2H).

[004500] Step 3 - Tert-butyl N-cyclopropyl-N-(3-prop ynoxypropyl)carbamate

[004501] To a mixture of tert-butyl N-cyclopropyl-N-(3-hydroxypropyl)carbamate (3.20 g, 14.8 mmol) in THF (30 mL) was added NaH (1.19 g, 29.7 mmol, 60% dispersion in oil) at 0 °C for 0.5 hour. Then 3-bromoprop yne (3.54 g, 29.7 mmol, 2.56 mL) was added to the mixture. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched with sat. NH4C1 solution (10 mL) under stirring. The mixture was diluted with water (30 mL) and extracted with EA (3 X 50 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (3.70 g, 98% yield) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 4.13 (d, J = 2.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.32 - 3.25 (m, 2H), 2.54-2.46 (m, 1H),2.41 (t, J= 2.4 Hz, IH), 1.89-1.81 (m, 2H), 1.45 (s, 9H), 0.75-0.70 (m, 2H), 0.61 - 0.57 (m, 2H).

[004502] 3-[4-[3-[3-(Cvclopropvlamino)propoxv]propvl] methyl oxobenzimidazol-l-yl]piperidine -2.,6-dione (Intermediate XQ)

1399

XO

XQ

[004503] Step 1 - Tert-butyl N-cyclopropyl-N-r3-r3-r1-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl1prop ynoxy1propyl1carbamate

[004504] To a mixture of tert-butyl N-cyclopropyl-N-(3-prop ynoxypropyl)carbamate (599 mg, 2.37 mmol, Intermediate XP) and 3-(4-bromo methyl oxo-benzimidazol-lyl)piperidine-2,6-dione (400 mg, 1.18 mmol, Intermediate HP) in DMF (5 mL) was added Cui (22.5 mg, 118 umol), Cs2CO3 (1.93 g, 5.91 mmol), Pd(PPh3)2C12 (83.0 mg, 118 umol) and 4A molecular sieves (10 mg). The reaction mixture was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (240 mg, 39% yield) as brown solid. 1H NMR (400 MHz, DMSO-76) δ 11.14 (s, IH), 7.18 (d, J = 7.6 Hz, IH), 7.13 - 7.09 (m, IH), 7.05 - 7.00 (m, IH), 5.43 - 5.37 (m, IH), 4.43 (s, 2H), 3.64 (s, 3H), 3.53 (t, 7= 6.3 Hz, 2H), 3.44 - 3.37 (m, 2H), 3.21 (t, 7= 7.2 Hz, 2H), 2.94 - 2.83 (m, IH), 2.75 - 2.55 (m, 3H), 2.07 - 1.98 (m, IH), 1.80 - 1.70 (m, 2H), 1.39 (s, 2H), 1.37 (s, 9H), 0.70 - 0.63 (m, 2H), 0.57 - 0.49 (m, 2H).

[004505] Step 2 - Tert-butyl N-cyclopropyl-N-r3-r3-r1-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl1propoxy1propyl1carbamate

[004506] To a mixture of tert-butyl N-cyclopropyl-N-[3-[3-[l-(2,6-dioxo piperidyl)-3

1400 methyl oxo- benzimidazol yl]prop ynoxy]propyl]carbamate (180 mg, 352 umol) in THF (20 mL) was added Pd(0H)2/C (30.0 mg, 10 wt%) and Pd/C (30.0 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 2.5 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (181 mg, 99% yield) as light yellow solid. The residue was used to the next step directly without further purification. 1HNMR (400 MHz, DMSO-t/6) δ 11.09 (s, IH), 6.96 (d, J= 4.4 Hz, 2H), 6.89 - 6.84 (m, IH), 5.39 - 5.33 (m, IH), 3.56 (s, 3H), 3.41 (d, J= 6.0 Hz, 2H), 3.38 (t, J= 6.0 Hz, 2H), 3.21 (t, 7= 7.2 Hz, 2H), 2.99 - 2.93 (m, 2H), 2.91 - 2.84 (m, IH), 2.72 - 2.62 (m, 3H), 2.02 - 1.99 (m, IH), 1.85 - 1.79 (m, 2H), 1.77 - 1.70 (m, 2H), 1.38 (s, 9H), 0.70 - 0.64 (m, 2H), 0.56 - 0.50 (m, 2H).

[004507] Step 3 - 3-r4-r3-r3-(Cvclopropylamino)propoxy1propyl1 methyl oxobenzimidazol-l-yl1piperidine -2,6-dione

[004508] To a mixture of tert-butyl N-cyclopropyl-N-[3-[3-[l-(2,6-dioxo piperidyl)-3methyl oxo- benzimidazol yl]propoxy]propyl]carbamate (190 mg, 369 umol) in DCM (1 mL) was added TFA(4.62 g, 40.5 mmol, 3.00 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (195 mg, 99% yield, TFA salt) as red oil. LC-MS (ESI+) m/z 415.3 (M+H)+.

[004509] Tert-butyl 4-(4-piperidylmethyl)piperidine-l-carboxylate (Intermediate XS)

2) Pd(dppf)CI2 DCM, K2CO3 DMF, H2O

[004510] Step 1 - Tert-butyl 4-(4-pyridylmethyl)piperidine carboxylate

[004511] To a solution of tert-butyl 4-methylenepiperidine- 1-carboxylate (6.00 g, 30.4 mmol, CAS# 159635 1) was added 9-BBN THF solution (0.5 M, 60.5 mL) at 25 °C. The reaction mixture was stirred at 80 °C for 1 hour under N2. After cooling to 25 °C, 4-bromopyridine (4.33 g, 27.4 mmol, CAS# 1120 2), K2CO3 (5.04 g, 36.5 mmol), Pd(dppf)C12 CH2C12 (683 mg, 836 umol), DMF (50 mL) and H2O (5 mL) were added to the reaction mixture was added. The reaction mixture was stirred at 60 °C for 3 hours. After cooling to 25 °C, another charge of Pd(dppf)C12 CH2C12 (683 mg, 836 umol) was added to the reaction mixture. The mixture was stirred at 60 °C for 24 hours. On completion, the mixture was cooled to 25 °C and poured into

1401 water (60 mL). The pH was adjusted to 11 with 10% aq. NaOH. The mixture was extracted with ethyl acetate (2 X 100 mL). The combined organic layers were dried over NaSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (5.80 g, 76% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 8.53 - 8.47 (m, 2H), 7.08 (d, J= 6.0 Hz, 2H), 2.64 (t, J= 12.0 Hz, 2H), 2.54 (d, J = 7.6 Hz, 2H), 1.77 - 1.64 (m, 2H), 1.63 - 1.56 (m, 2H), 1.54 - 1.47 (m, IH), 1.45 (s, 9H), 1.21 - 1.09 (m, 2H).

[004512] Step 2 Tert-butyl 4-(4-piperidylmethyl)piperidine-l-carboxylate

[004513] To a solution of tert-butyl 4-(4-pyridylmethyl)piperidine-1 -carboxylate (5.80 g, 20.9 mmol) in EtOH (100 mL) and HO Ac (1.26 g, 20.9 mmol) was added PtO2 (1.02 g, 4.48 mmol) at 20 °C. The reaction mixture was stirred at 20 °C for 54 hours under H2 (50 Psi). On completion, the reaction mixture was filtered with celite and the filtrate was concentrated in vacuo to give the title compound (4.68 g, 79% yield) as black oil. 1H NMR (400 MHz, CDCh) δ 4.26 - 4.00 (m, 4H), 3.16 (d, 7= 9.6 Hz, 2H), 2.70 - 2.60 (m, 3H), 1.69 (d,7= 12.8 Hz, 2H), 1.65 - 1.56 (m, 2H), 1.54 - 1.46 (m, 2H), 1.44 (s, 9H), 1.29 - 1.20 (m, 2H), 1.20-1.13 (m, 2H), 1.11 - 0.97(m, 2H); LC-MS (ESI+) m/z 283.0 (M + H)+.

[004514] 3-[3-methvl oxo [[4-(4-DiDeridvlmethyl)-lDiDeridvl]methyl]benzimidazol-l- yl]DiDeridine-2,6-dione (Intermediate XT)

HCI/dioxane

DCM

[004515] Step 1 -Tert-butyl 4-rr1-rr1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol

4-yl1methyl1 piperidyllmethyUpiperidine-1 -carboxylate

[004516] To a solution of tert-butyl 4-(4-piperidylmethyl)piperidine-l-carboxylate (128 mg,

1402

452 umol, Intermediate XS) in THF (10 mL) and DMF (5 mL) was added TEA (45.8 mg, 452 umol). The mixture was stirred at 25 °C for 10 minutes. HOAc (27.2 mg, 452 umol) and 1-(2,6di oxo piperi dyl) methyl oxo -benzimidazole carbaldehyde (195 mg, 679 umol , Intermediate WW) were added to the above mixture. The reaction mixture was stirred at 25 °C for 20 minutes. Then NaBH(OAc)3 (192 mg, 905 umol) was added. The reaction mixture was stirred at 25 °C for 16 hours. On completion, the reaction was quenched with H2O (1 mL). The mixture was concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (250 mg, 99% yield) as a yellow solid. 1HNMR (400 MHz, DMSOY) δ 11.09 (s, IH), 7.19 (d, J = 6.4 Hz, IH), 6.95 (t, J = 7.6 Hz, IH), 6.86 (d, J = 7.2 Hz, IH), 5.36 (d, J = 5.6 Hz, IH), 3.97 - 3.81 (m, 2H), 3.66 (s, 3H), 3.60 (s, 2H), 2.96 - 2.83 (m, 2H), 2.83 - 2.69 (m, 4H), 2.66 - 2.58 (m, 3H), 2.06 - 1.89 (m, 4H), 1.58 (d, J = 12.4 Hz, 4H), 1.37 (s, 9H), 1.14 - 0.98 (m, 4H), 0.96 - 0.81 (m, 2H); LC-MS (ESI+) m/z 554.4(M+H)+.

[004517] Step 2:3-r3-methyl oxo [r4-(4-piperidylmethyl)-lpiperidyl1methyl1benzimidazol-l- yl1piperidine-2,6-dione

[004518] To a solution of tert-butyl 4-[[l-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]methyl] piperidyl]methyl]piperidine-l-carboxylate (100 mg, 181 umol) in DCM (2 mL) was added 4 M HCI/dioxane (1 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase (FA condition) to give the title compound (65.0 mg, 79 % yield) as a white solid. LC-MS (ESI+) m/z 454.5 (M+H)+.

[004519] 3-(7-bromo-9H-Dvrido [2,3-b] indol yl)DiDeridine-2,6-dione (Intermediate

XU)

1403

NH2

O

Ζ -ΡΜΒ N

O2N

Pd(OAc)2, Xanphos t-BuONa, DMF

H

O γ o

OTf

Ζ .ΡΜΒ N

Pd(OAc)2, DCHPB no2

DBU.DMA

CAN

ACN, h2o

NO2

Pd/C, H2

HOAc

[004520]

[004521]

Step 1 - 3-bromo-N-(3-nitrophenyl)pyridin amine

To a mixture of 3-bromopyridin amine (5 g, 28.9 mmol), l-iodo nitrobenzene (7.2 g, 28.9 mmol), Xanphos (1.07 g, 2.89 mmol), and Cs2CO3(18.9 g, 57.8 mmol) in DMF (50 mL) was added Pd(OAc)2 (323.7 mg, 1.44 mmol). The mixture was degrassed with N2 and stirred at 130 °C overnight. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc (3 x 200 mL). The combined organic layers was washed with water (200 mL x 2) and brine (200 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with EA/PE=20% to give the title compound (5.6 g, 66% yield) as a light yellow solid. LC/MS (ESI, m/z): [M +1]+ = 294.0, 296.0.

[004522] Step 2 - 7-nitro-9H-pyrido[2,3-b1indole

[004523] To a mixture of 3-bromo-N-(3-nitrophenyl)pyridin amine (4 g, 6.78 mmol), DCPHB (474 mg, 1.356 mmol), and DBU (4.12 g, 27.12 mmol) in DMA (12 mL) was added Pd(OAc)2 (152 mg, 0.678 mmol). The mixture was degrassed with N2 and stirred at 170 °C for 1 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc (3 x 50 mL).

1404

The combined organic layers was washed with water(100 mL x 2) and brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with EA/PE=1:1 to give the title compound (1 g, 34% yield) as a light yellow solid. 1HNMR (400 MHz, DMSO-/6) δ 12.40 (s, IH), 8.73 - 8.70 (m, IH), 8.60 - 8.58 (m, IH), 8.44 (d, /=8.63 Hz, IH), 8.33 (d,/=2.00 Hz, IH), 8.13 - 8.10 (m, IH), 7.35 (dd,/=7.75, 4.75 Hz, IH); LC/MS (ESI, m/z[. [M +1]+ = 214.1.

[004524] Step 3 - l-(4-methoxybenzyl) (7-nitro-9H-pyridor2,3-b1indol yl)piperidine2,6-dione

[004525] To a solution of 7-nitro-9H-pyrido[2,3-b]indole (910 mg, 4.27 mmol) in THF (10mL) and DMF (2 mL) was added t-BuOK (718 mg, 6.41 mmol) portion wise at 0 °C under N2 atmosphere. After addition, the mixture was stirred at 0 °C-5 °C for 1 h. Then 1-(4methoxybenzyl)-2,6-dioxopiperidin yl trifluoromethanesulfonate (2.44 g, 6.41 mmol) in THF(10 mL) was added dropwise at 0 °C-5 °C over 20 min. After addition, the reaction mixture was stirred at 0 °C-5 °C for an additional 1 h. The reaction mixture was quenched by the addition of water, then extracted with EtOAc (3 x 20 mL). The combined organic layers was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc and dried to give (1.3 g, 69% yield) as a light yellow solid. LC/MS (ESI, mz)\ [M+l]+ = 445.2.

[004526] Step 4 - 3-(7-nitro-9H-pyridor2,3-b1indol yl)piperidine-2,6-dione

[004527] To a solution of l-(4-methoxybenzyl) (7-nitro-9H-pyrido[2,3-b]indol-9yl)piperidine-2,6-dione (1.7 g, 3.83 mmol) in CH3CN(20 mL) was added CAN (10.5 g, 19.15 mmol) in water (5 mL) at 0 °C dropwise. After addition, the mixture was stirred at rt overnight. The mixture was poured into water (50 mL), then extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc and dried to give the title compound (850 mg, 69% yield) as a light yellow solid. LC/MS (ESI, m z)\ [M +1]+ = 325.2.

[004528] Step 5 - 3-(7-amino-9H-pyridor2,3-b1indol yl)piperidine-2,6-dione

[004529] To a solution of 3-(7-nitro-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione (850 mg, 2.62 mmol) in EtOAc(15 mL) was added 10% palladium on activated carbon (170 mg). The mixture was hydrogened at rt overnight. The reaction mixture was filtered, the filtrate was concentrated in vacuo to give the title compound (764 mg, 99% yield) as a white solid. LC/MS

1405 (ESI, m/z): [M+l]+ = 295.2.

[004530] Step 6 - 3-(7-bromo-9H-pyridor2,3-b1indol yl)piperidine-2,6-dione

[004531] To a solution of 3-(7-amino-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione (661m g, 2.26 mmol) in 40% HBr solution (10 mL) was added NaNO2 (156 mg, 2.26 mmol) portion wise at 0 °C. After addition, the mixture was stirred at 0 °C for 30 min. Then the diazonium solution was added dropwise to CuBr (972 mg, 6.78 mmol) in 40% HBr solution (10 mL). The mixture was stirred at rt for 2 h. Then the mixture was poured into water (50 mL), basified to pH > 8 with saturated NaHCO3 solution, then extracted with EtOAc (3 x 50 mL). The combined organic layers was washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (382 mg, 47% yield) as a yellow solid. LC/MS (ESI, m/z): [M +1]+ = 358.1, 360.1.

[004532] 3 13- [2-(2-Aminoethoxy)ethoxy| propyl] pyrido [2,3-b] indol yl] piperidine-

TFA

O XV

[004533] Step 1 - tert-butyl (2-(2-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3-b1indol-7vl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate

[004534] To a mixture of 3-(7-bromo-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione (461 mg, 1.29 mmol, Intermediate XU), tert-butyl (2-(2-(prop yn-l-yloxy)ethoxy)ethyl)carbamate (941 mg, 3.87 mmol, Intermediate IT), and Cs2CO3(2.1 g, 6.45 mmol) in DMF was added Cui (49 mg, 0.258 mmol) and PdC12(PPh3)2(181 mg, 0.258 mmol). The mixture was degrassed with N2 and stirred at 80 °C for 1 h under microwave condition. The reaction mixture was cooled to rt,

1406 poured into water, then extracted with EtOAc (3 x 20 mL). The combined organic layers was washed with water (20 mL x 2) and brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with EA/DCM=1:1 to the title compound (410 mg, 68% yield) as yellow solid. LC/MS (ESI, m/z); [M -55+H]+= 466.1.

[004535] Step 2 - tert-butyl (2-(2-(3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3-b1indol-7yl)propoxy)ethoxy)ethyl)carbamate

[004536] To a solution of tert-butyl (2-(2-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3b]indol yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate (400 mg, 0.77 mmol) in EtOAc(5 mL) was added 10% palladium on activated carbon (81 mg). The mixture was hydrogened at rt overnight. The reaction mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by P-TLC eluting with EA/DCM=1:2 firstly, then the crude compound was purified by prep HPLC to give the title compound (132 mg, 66% yield) as a white solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.13 (s, IH), 8.49 (dd, 7=7.63, 1.50 Hz, IH), 8.38 - 8.35 (m, IH), 8.11 (d, 7=7.88 Hz, IH), 7.47 (br. s., IH), 7.24 (dd, 7=7.63, 4.88 Hz, IH), 7.12 - 7.18 (m, IH), 6.77 - 6.74 (m, IH), 6.01 (br. s., IH), 3.47 - 3.55 (m, 4H), 3.45 - 3.37 (m, 4H), 3.15 - 3.02 (m, 4H), 2.80 (t, 7=7.69 Hz, 2H), 2.73 -2.68 (m, IH), 2.13-2.07 (m, IH), 1.94 - 1.88 (m, 2H), 1.36(s, 9H); LC/MS (ESI, m/z); [M+l]+ = 525.3.

[004537] Step 3 - 3-r7-r3-r2-(2-Aminoethoxy)ethoxy1propyl1pyrido[2,3-b1indol-9yl1piperidine-2,6-dione

[004538] To a solution of tert-butyl N-[2-[2-[3-[9-(2,6-dioxo piperidyl)pyrido[2,3-b]indol7-yl]propoxy] ethoxy]ethyl]carbamate (95.0 mg, 181 umol) in DCM (3 mL) was added TFA (722 mg, 6.34 mmol). The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (95 mg, 95% yield, TFA) as light yellow oil. LC-MS (ESI+) m/z 425.2 (M+H)+.

[004539] 2- [2-(Cvcl0Dr0Dvlmethvlamin0) Dvridyl] oxazole carboxylic acid (Intermediate XW)

OM XW

1407

[004540] To a mixture of 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carboxylic acid (400 mg, 1.11 mmol, Intermediate OM) in DCM (10 mL) was added TFA (127 mg, 1.11 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (397 mg, 95% yield, TFA salt) as brown oil. LC-MS (ESI+) m/z 260.1(M+H)+.

[004541] 3-(4-Bromo-9H-pyrido [2.,3-b] indol yl)piperidine-2.,6-dione (Intermediate

XY)

XY

[004542] Step 1 - 9H-pyrido[2,3-b1indole 1-oxide

[004543] To a stirred solution of 9H-pyrido[2,3-b]indole (10 g, 59.5 mmol) in AcOH (100 mL) was added 30% H2O2 (50 mL) dropwise. After the addition, the reaction mixture was heated to 110 °C and stirred for 6 h. Then the reaction mixture was cooled to rt and concentrated in vacuo. To the residue was added sat. aq. K2CO3 to basify to pH = 8. The mixture was stirred at rt overnight and filtered. The solid was washed with water and dried to afford the title compound (7.3 g, 67% yield) as a yellow solid. 1HNMR (400 MHz, DMSO4) δ 12.58 (s, IH), 8.36-8.34 (m, IH), 8.25 - 8.14 (m, 2H), 7.58 - 7.50 (m, 2H), 7.35 - 7.18 (m, 2H). LC/MS (ESI, m/z): [M+l]+ = 185.1 [004544] Step 2 - 4-bromo-9H-pyrido[2,3-b1indole

[004545] To a solution of 9H-pyrido[2,3-b]indole 1-oxide (9.3 g, 50.5 mmol) in DMF (100 mL) was added phosphorusoxybromide (29.0 g, 101.1 mmol) at rt. The reaction mixture was stirred at rt overnight and filtered. The solid was washed with water and dried to afford the title compound (9.0 g, 73% yield) as a yellow solid. 1HNMR (400 MHz, CDC13) δ 9.28 (s, IH), 8.61

1408 (d, 7= 8.0 Hz, IH), 8.25 (d, 7= 5.4 Hz, IH), 7.59 - 7.52 (m, 2H), 7.43 - 7.33 (m, 2H). LC/MS (ESI, m z)\ [M+l]+ = 247.3, 249.3.

[004546] Step 3 - 3-(4-bromo-9H-pyrido[2,3-b1indol yl)-l-(4-methoxybenzyl)piperidine2,6-dione

[004547] To a solution of 4-bromo-9H-pyrido[2,3-b]indole (8.8 g, 35.6 mmol) and 18-crown6 (1.9 g, 7.13 mmol) in THF (100 mL) was added NaHMDS (26.7 mL, 53.4 mmol, 2N in THF) dropwise at -30 °C under N2 atmosphere. After addition, the reaction mixture was stirred at -30 °C for 1 h. Then l-(4-methoxybenzyl)-2,6-di oxopiperi din-3 -yl trifluoromethanesulfonate (20.4 g in 30 mL THF, 53.4 mmol) was added to solution dropwise. After addition, the reaction mixture was stirred at -30 °C for 2 h and quenched by sat. aq. NH4C1 (100 mL), then extracted with EA (150 mLx 2). The combined organic layers were washed with brine (100 mLx 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column to give the title compound (10.0 g, 59% yield) as a white solid. LC/MS (ESI, m/z): [M+l]+ = 478.3.

[004548] Step 4 - 3-(4-bromo-9H-pyrido[2,3-b1indol yl)piperidine-2,6-dione

[004549] To a solution of 3-(4-bromo-9H-pyrido[2,3-b]indol yl)-l-(4methoxybenzyl)piperidine-2,6-dione (10 g, 20.9 mmol) in toluene (50 mL) was added methanesulfonic acid (20 mL). The reaction solution was heated to 110 °C and stirred for 2 h. The reaction mixture was cooled to rt and concentrated to remove toluene. The residue was diluted with CH3CN and purified via reverse phase column chromatography (CH3CN/H2O = 5%-80%) to give the title compound (3.7 g, 50% yield) as a white solid. 1H NMR (400 MHz, DMSO-76) δ 11.19 (s, IH), 8.57 (d, 7= 7.9 Hz, IH), 8.30 (d, 7= 5.3 Hz, IH), 7.73 - 7.69 (m, IH), 7.63 (t, 7 = 7.9 Hz, IH), 7.56 (d, 7= 5.3 Hz, IH), 7.41 (t, 7= 7.9 Hz, IH), 6.10 (s, IH), 3.14 - 2.98 (m, 2H), 2.73 -2.68 (m, IH), 2.18 - 2.12 (m, IH). LC/MS (ESI, m/z): [M+1]+= 358.0.

[004550] 3- [4- [3- [2-(2-Aminoethoxv)ethoxy| propyl] pyrido [2.,3-bl indol yl] piperidine2.,6-dione (Intermediate XZ)

1409

[004551] Step 1 - tert-butyl (2-(2-((3-(9-(2,6-di oxopiperi din yl)-9H-pyrido[2,3-b1indol-4yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate

[004552] To a mixture of 3-(4-bromo-9H-pyrido[2,3-b]indol yl)piperidine-2,6-dione (0.3 g, 0.84 mmol, Intermediate XY), tert-butyl (2-(2-(prop yn-l-yloxy)ethoxy)ethyl)carbamate (0.31 g, 1.26 mmol, Intermediate IT), Cs2CO3(2.7 g, 8.38 mmol) in DMF(10 mL) was added Cui (16 mg, 0.084 mmol) and PdC12(PPh3)2 (0.12 g, 0.17 mmol). The mixture was degrassed with N2 and stirred at 80 °C for 1 h under microwave condition. The reaction mixture was cooled to rt, poured into water, then extracted with EtOAc (3 x 20 mL). The combined organic layers was washed with water (20 mL x 2) and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with EA/DCM=1:1 to give the title compound (0.16 g, 37% yield) as yellow solid. LC/MS (ESI, m/z): [M -55+H]+ = 466.1. [004553] Step 2 - tert-butyl (2-(2-(3-(9-(2,6-dioxopiperidin vl)-9H-pvrido[2,3-b1indol-4yl)propoxy)ethoxy)ethyl)carbamate

[004554] To a solution of tert-butyl (2-(2-((3-(9-(2,6-dioxopiperidin yl)-9H-pyrido[2,3b]indol yl)prop yn-l-yl)oxy)ethoxy)ethyl)carbamate (0.16 g, 0.31 mmol) in EtOAc(5 mL) was added 10% palladium on activated carbon (32 mg). The mixture was hydrogened at rt overnight. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by P-TLC eluting with EA/DCM=1:2 firstly, then the crude compound was

1410 purified by prep HPLC to give the title compound (60 mg, 38% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 8.32 (d, J = 5.1 Hz, IH), 8.20 (d, J = 7.9 Hz, IH), 8.12 (s, IH), 7.53 - 7.46 (m, IH), 7.34 - 7.28 (m, 2H), 7.06 - 7.04(m, IH), 5.96 (s, IH), 5.00 (s, IH), 3.66 - 3.56 (m, 8H), 3.41-3.24 (m, 4H), 3.09 - 2.99 (m, 3H), 2.33 -2.29 (m, IH), 2.18-2.11 (m, 2H), 1.43 (s, 9H). LC/MS (ESI, mzy [M +1]+ = 525.4.

[004555] Step 3 - 3-r4-r3-r2-(2-Aminoethoxy)ethoxy1propyl1pyrido[2,3-b1indol-9yl1piperidine-2,6-dione

[004556] To a solution of tert-butyl N-[2-[2-[3-[9-(2,6-dioxo piperidyl)pyrido[2,3-b]indol4-yl]propoxy] ethoxy]ethyl]carbamate (66.0 mg, 125 umol) in DCM (2 mL) was added TFA (573 mg, 5.03 mmol). The mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (67.0 mg, 95% yield, TFA) as light yellow oil. LC-MS (ESI+) m/z 425.0 (M+H)+.

[004557] Tert-butyl 3-(prop vnoxvmethyl)azetidine-l-carboxvlate (Intermediate YA) / An b°c —Ay— H0 NaH, DMF 'Boc

YA

[004558] To a solution of tert-butyl 3-(hydroxymethyl)azetidine-l -carboxylate (2.00 g, 10.7 mmol, CAS# 142253 3) in DMF (20 mL) was added NaH (641 mg, 16.0 mmol, 60% oil dispersion) at 0 °C. Thirty minutes later, 3-bromoprop yne (1.40 g, 11.8 mmol, 1.01 mL, CAS# 106 7) was added and the reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was quenched with water (50 mL), then extracted with EA (2 X 30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, PE: EA = 15:1) to give the title compound (0.60 g, 25% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.17 (d, J= 2.4 Hz, 2H), 4.00 (t, J= 8.4 Hz, 2H), 3.71 - 3.64 (m, 4H), 2.87 - 2.69 (m, IH), 2.45 (t, 7= 2.4 Hz, IH), 1.44 (s, 9H).

[004559] 3-[4-[3-(Azetidin vlmethoxv)propvl] methvl oxo-benzimidazol-lyl]piperidine-2.,6-dione (Intermediate YB)

1411

YB

[004560] Step 1 - Tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1prop ynoxymethyllazetidine-l-carboxylate

[004561] To a solution of tert-butyl 3-(prop ynoxymethyl)azetidine carboxylate (480 mg, 2.13 mmol, Intermediate YA) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (400 mg, 1.18 mmol, Intermediate HP) in DMF (8 mL) was added Pd(PPh3)2C12 (166 mg, 236 umol), Cs2CO3 (1.93 g, 5.91 mmol), and Cui (45.1 mg, 236 umol) under N2 atmosphere. The mixture was de-gassed and then heated at 80 °C for 2 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was washed with ethyl acetate (60 mL), the filtrate was concentrated in vacuo. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (450 mg, 63% yield) as brown solid. 1H NMR (400 MHz, DMSO-» δ 11.12 (m, IH), 7.20 - 7.10 (m, 2H), 7.06 - 6.99 (m, IH), 5.39 (dd, J= 5.6, 12.8 Hz, IH), 4.47 (s, 2H), 3.64 (s, 3H), 3.60 - 3.56 (m, 4H), 2.80 - 2.70 (m, 4H), 2.61 - 2.59 (m, 2H), 2.06 - 1.98 (m, IH), 1.35 (s, 9H); LC-MS (ESI+) m/z 505.2 (M+Na)+.

[004562] St ep 2 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidvl) methvl oxo-benzimidazol-4vllpropoxymethyU azetidine-1 -carboxylate

[004563] To a solution of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxymethyl]azetidine-l-carboxylate (400 mg, 829 umol) in THF (8

1412 mL) was added Pd/C (80.0 mg, 10% wt) and Pd(0H)2/C (80.0 mg, 10% wt) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was filtered and then the filtrate was concentrated in vacuo to give the title compound (400 mg, 79% yield) as brown solid. 1H NMR (400 MHz, DMSO-76) δ 11.09 (s, IH), 6.99 - 6.95 (m, 2H), 6.87 - 6.85 (m, IH), 5.37 (dd, J= 5.2, 12.4 Hz, IH), 3.56 (s, 3H), 3.52 - 3.46 (m, 4H), 3.33 (s, 3H), 3.00 - 2.92 (m, 2H), 2.91 - 2.84 (m, IH), 2.78 - 2.55 (m, 4H), 2.04 - 1.96 (m, IH), 1.89 - 1.77 (m, 2H), 1.38 - 1.36 (m, 9H). LC-MS (ESI+) m/z 509.3 (M+Na)+

[004564] St ep 3 di one

[004565] To a solution of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxymethyl]azetidine-l-carboxylate (313 mg, 514 umol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (230 mg, 89% yield, TFA salt) as yellow solid. LC-MS (ESI+) m/z 387.2 (M+H)+

[004566] Tert-butyl N-but vnyl-N-methyl-carbamate (Intermediate YC) ¾- TEA, (Boc)2O ¾. Mel, NaH Αχ -Boc ^^NHzHCI * N HBoc Y

DCM THF I

YC

[004567] Step 1 - Tert-butyl N-but ynylcarbamate

[004568] To a solution of but yn-l-amine (4.30 g, 40.7 mmol, HCI) and TEA (4.12 g, 40.7 mmol) in DCM (150 mL) was added (Boc)2O (9.16 g, 41.9 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. Then TEA (4.12 g, 40.7 mmol) added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was diluted with DCM (400 mL) and washed with water (2 X 100 mL) and HCI (0.5 N, 3 X 300 mL). The organic layers were dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography to give the title compound (4.00 g, 58% yield) as colorless oil. 1HNMR (300MHz, CDCh) δ 4.93 (s, IH), 3.25 (q, J = 6.0 Hz, 2H), 2.35 (dt, J= 2.7, 6.0 Hz, 2H), 1.98 (t, J= 2.7 Hz, IH), 1.41 (s, 9H).

[004569] Step 2 - Tert-butyl N-but ynyl-N-methyl-carbamate

1413

[004570] To a solution of tert-butyl N-but ynylcarbamate (1.00 g, 5.91 mmol) in THF (20 mL) was added NaH (354 mg, 8.86 mmol, 60% oil dispersion) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hour, then Mel (1.26 g, 8.86 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched with sat. NH4C1 (30 mL) and extracted with EA (2 X 100 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (1.00 g, 92% yield) as colorless oil. 1H NMR (300MHz, CDCh) δ 3.43 - 3.28 (m, 2H), 2.87 (s, 3H), 2.44 - 2.33 (m, 2H), 1.95 (t, J = 2.4 Hz, IH), 1.44 (s, 9H).

[004571] 3-[3-Methvl [4-(methvlamino)butvl] oxo-benzimidazol-l-yl]piperidine

2.,6-dione (Intermediate YD)

YD

[004572] Step 1 - Tert-butyl N-r4-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1but ynyl1-N- methyl-carbamate

[004573] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (500 mg, 1.48 mmol, Intermediate HP) and 4A molecular sieves (50 mg) in DMF (5 mL) was added Pd(PPh3)2C12 (103 mg, 147 umol), Cui (56.3 mg, 295 umol) and Cs2CO3 (1.93 g, 5.91 mmol). The reaction mixture was degassed with N2 for three times. Then tert-butyl N-but ynylN-methyl-carbamate (487 mg, 2.66 mmol, Intermediate YC) was added. The reaction mixture was stirred at 85 °C for 2 hours. On completion, the reaction mixture was filtered. The organic layer

1414 was diluted with EA (300 mL), washed with sat.NH4Cl (2 X 100 mL) and brine (100 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash (0.1%, FA) to give the title compound (400 mg, 61% yield) as a light yellow solid, LC-MS (ESI+) m/z 463.1 (M+Na)+.

[004574] Step 2 - Tert-butyl N-r4-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1butyl1-N- methyl-carbamate

[004575] To a solution of tert-butyl N-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]but ynyl]-N-methyl-carbamate (400 mg, 908 umol) in THF (25 mL) was added Pd/C (200 mg, 10 wt%) and Pd(OH)2/C (1.28 g, 10 wt%). The reaction mixture was stirred at 25 °C under H2 (15 psi) for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (400 mg, 99% yield) as a white solid, 1H NMR (400MHz, DMSO4) δ 11.08 (s, IH), 6.99 - 6.93 (m, 2H), 6.89 - 6.84 (m, IH), 5.40 - 5.32 (m, IH), 3.55 (s, 3H), 3.24 - 3.14 (m, 2H), 2.99 - 2.82 (m, 3H), 2.75 (s, 3H), 2.72 - 2.59 (m, 2H), 2.04 - 1.94 (m, IH), 1.63 - 1.48 (m, 4H), 1.36 (s, 9H).

[004576] Step 3 - 3-r3-Methyl r4-(methylamino)butvl1 oxo-benzimidazol-lyl1piperidine-2,6-dione

[004577] To a solution of tert-butyl N-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]butyl]- N-methyl-carbamate (390 mg, 877 umol) in DCM (15 mL) was added HCI/dioxane (4 M, 15 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (300 mg, 89% yield, HCI) as a white solid. LC-MS (ESI+) m/z 345.2 (M+H)+.

[004578] 2-[2-[Tert-butoxvcarbonvl(methvl)amino] Dvridvl]oxazole carboxylic acid (Intermediate YE)

YE

[004579] Step 1 - 4-Bromo-N-methyl-pyridin amine

1415

[004580] To a solution of 4-bromo fluoro-pyridine (5.00 g, 28.4 mmol, CAS# 128071-987) in THF (50.0 mL) was added a solution of MeNH2 in EtOH (2.00 M, 42.6 mL). The mixture was stirred at 120 °C for 2 hrs under seal tube. The mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE: EA = 80: 1) to give the title compound (4.50 g, 84% yield) as white solid. 1H NMR (400 MHz, DMSO-t/6) δ 7.87 - 7.84 (m, IH), 6.75 - 6.74 (m, IH), 6.66 6.65 (m, IH), 6.64 (s, IH), 2.75 (s, 3H).

[004581] Step 2 - Tert-butyl N-(4-bromo pyridvl)-N-methyl-carbamate

[004582] To a solution of 4-bromo-N-methyl-pyridin amine (4.00 g, 21.4 mmol) in THF (30.0 mL) was added LiHMDS (1.00 M, 47.1 mL) dropwise at - 5 °C. Then a solution of (Boc)2O (4.67 g, 21.4 mmol, 4.91 mL) in THF (10.0 mL) was added into the above mixture slowly. The reaction mixture was stirred at - 5 °C for 10 minutes, then heated to 20 °C and stirred for 1 hr. The reaction mixture was quenched with sat. NH4C1 (100 ml), extracted with EA (2 X 50 mL), then concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (PE: EA = 100:1-8:1) to give the title compound (5.00 g, 81% yield) as a yellow liquid. 1H NMR (400 MHz, DMSO-t/6) δ 8.16 (d, J = 5.6 Hz, IH), 8.02-8.01 (m, IH), 7.13 (dd, J= 5.2 Hz, J= 5.6 Hz, IH), 3.39 (s, 3H), 1.53 (s, 9H).

[004583] Step 3 - Ethyl 2-r2-rtert-butoxycarbonyl(methyl)amino1 pyridyl1oxazole-4carboxylate

[004584] A mixture of tert-butyl N-(4-bromo pyridyl)-N-methyl-carbamate (4.00 g, 13.9 mmol), ethyl oxazole carboxylate (1.97 g, 13.9 mmo, CAS# 170487 4), Pd(OAc)2 (313 mg, 1.39 mmol), tris-o-tolylphosphane (848 mg, 2.79 mmol) and K2CO3 (5.78 g, 41.8 mmol) in DMF (60.0 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 70 °C for 16 hrs under N2 atmosphere. On completion, the reaction mixture was diluted by addition H2O (30 mL) and extracted with EA (3 X 50 mL). The combined organic layers were washed with saturated NaCl (2 X 100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The crude product was purified by reverse phase (0.1% FA condition) to give the title compound (2.20 g, 45% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.49 (d, J = 6.8 Hz, IH), 8.42 (s, IH), 8.33 (s, IH), 7.71 - 7.69 (m, IH), 4.47-4.41 (m, 2H), 3.45 (s, 3H), 1.56 (s, 9H), 1.42 (t, 7= 13.2 Hz, 3H).

[004585] Step 4 - 2-r2-rTert-butoxycarbonyl(methyl)amino1 pyridyl1oxazole carboxylic acid

1416

[004586] To a solution of ethyl 2-[2-[tert-butoxycarbonyl(methyl)amino] pyridyl]oxazole4-carboxylate (200 mg, 575 umol) in THF (10.0 mL) and H2O (2.00 mL) was added LiOH (68.9 mg, 2.88 mmol). The mixture was stirred at 20 °C for 15 hrs. On completion, the reaction mixture was quenched with water (1 mL), and the mixture was acidified with IN HCI solution until the pH = 5. The aqueous phase was extracted with EA (3X10 mL). The combined organic layer was washed with brine (2X10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (160 mg, 87 % yield) as an off-white solid. 1H NMR (400MHz, DMSOd6) δ 8.96 (s, IH), 8.57 (d, J = 52 Hz, IH), 8.35 (s, IH), 7.65 (dd, 71 = 4.8 Hz, 7= 5.2 Hz, IH), 3.37 (s, 3H), 1.52 (s, 9H).

[004587] Tert-butyl 3-prop vnoxvpyrrolidine-l-carboxvlate (Intermediate YG)

.Bqg zY^Br / N NaH, TBAI, THF

YG

[004588] To a solution of tert-butyl (3S) hydroxypyrrolidine carboxylate (5.00 g, 26.7 mmol, CAS# 101469 5) in THF (150 mL) was added NaH (1.60 g, 40.0 mmol, 60% oil dispersion) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. Then TBAI (986 mg, 2.67 mmol) and 3-bromoprop yne (4.37 g, 29.3 mmol, CAS# 106 7) was added. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was diluted with EA(300 mL) and quenched with sat. NH4C1 (100 mL). The organic layer was washed with water (2 X 30 mL) and brine (50 mL). The organic layer was dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica column chromatography to give the title compound (5.90 g, 98% yield) as light yellow oil, 1H NMR (300MHz, CDC13) δ 4.29 - 4.21 (m, IH), 4.17 - 4.10 (m, 2H), 3.51 - 3.32 (m, 4H), 2.50 - 2.34 (s, IH), 2.02 - 1.90 (m, 2H), 1.43 (s, 9H).

[004589] 3- [3-Methyl oxo [3- [ (3S)-pyrrolidin vl] oxypropyl] benzimidazol-1 yl] piperidine- 2,6-dione (Intermediate YH )

1417

Pd(PPh3)2CI2, Cui, Cs2CO3, DMF

Pd(OH)2/C, Pd/C

H2, THF

dioxane/HCI

DCM

YH

[004590] Step 1 - Tert-butyl (3S) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxy1pyrrolidine-l -carboxylate

[004591] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (600 mg, 1.77 mmol, Intermediate HP) in DMF (10 mL) was added Pd(PPh3)2C12 (124 mg, 177 umol), Cui (33.7 mg, 177 umol) and Cs2CO3 (2.31 g, 7.08 mmol). The reaction mixture was degassed with N2 three times. Then tert-butyl 3-prop ynoxypyrrolidine-l-carboxylate (598mg, 2.66 mmol, Intermediate YG) was added. The reaction mixture was stirred at 80 °C for 8 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by reversed-phase flash (FA, 0.1%) to give the title compound (450 mg, 52% yield) as a yellow solid, 1H NMR (400MHz, DMSOA) δ 11.13 (s, IH), 7.19 - 7.10 (m, 2H), 7.04 (d, J= 8.0 Hz, IH), 5.44 - 5.34 (m, IH), 4.48 (s, 2H), 4.32 - 4.25 (m, IH), 3.63 (s, 3H), 3.29 - 3.07 (m, 4H), 2.94 - 2.82 (m, IH), 2.77 - 2.62 (m, 2H), 2.56 - 2.52 (m, IH), 2.04 - 1.92 (m, 3H), 1.38 (d, J =9.2 Hz, 9H).

1418

[004592] Step 2 - Tert-butyl (35) 13 (2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] pyrrolidine-l-carboxylate

[004593] To a solution of tert-butyl (3S) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]pyrrolidine-l-carboxylate (400 mg, 828 umol) in THF (25 mL) was added Pd/C (200 mg, 10 wt%) and Pd(OH)2/C (200 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (400 mg, 99% yield) as a yellow solid. 1H NMR (400MHz, DMSOY) δ 11.08 (s, IH), 6.98 - 6.94 (m, 2H), 6.88 - 6.84 (m, IH), 5.39 - 5.31 (m, IH), 4.05 - 4.00 (m, IH), 3.55 (s, 3H), 3.47 - 3.39 (m, 2H), 3.30 - 3.22 (m, 4H), 2.96 - 2.84 (m, 3H), 2.76 - 2.60 (m, 2H), 2.55 - 2.52 (m, 2H), 2.02 - 1.96 (m, IH), 1.93 - 1.87 (m, 2H), 1.84 1.78 (m, 2H), 1.40 (s, 10H).

[004594] Step 3 - 3-r3-Methyl oxo r3-r(3S)-pvrrolidin yl]oxypropyl]benzimidazol-lyl]piperidine- 2,6-dione

[004595] To a solution of tert-butyl (3S) [3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]pyrrolidine-l-carboxylate (395 mg, 811 umol) in DCM (15 mL) was added HCl/dioxane (4 M, 15 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (300 mg, 87% yield, HCI) as a white solid. LC-MS (ESI+) m/z 387.2 (M+H)+.

[004596] [3-Methvl [[4-(methvlaminomethvl)-l-piperidvl]methyl] oxobenzimidazol-l-yl]piperidine-2.,6-dione (Intermediate Yl)

HOAc, NaBH(OAc)3, THF/DMF

1419

[004597] !Α^2!^ΠΑΑιι1υ ΑΑ^Α1Χ1Α2ΑΑθΝθ=22Ι&#943;Ι|2Α&#970;1γ[12^^ benzimidazol yl1methyl1 piperidyl1methyl1-N-methyl-carbamate

[004598] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-4carbaldehyde (150 mg, 522 umol, Intermediate WW) and tert-butyl N-methyl-N-(4piperidylmethyl)carbamate (119 mg, 522 umol, CAS# 138022 5) in THF (2 mL) and DMF (0.5 mL) was added HO Ac (31.4 mg, 522 umol) at 25°C. The mixture was stirred for 0.5 hour, then NaBH(OAc)3 (221 mg, 1.04 mmol) was added. The mixture was stirred at 25 °C for 2 hours. On completion, the mixture was quenched by water (0.2 mL), and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (180 mg, 69% yield) as a white solid. 1H NMR (400 MHz, CDCh) δ 8.48 (s, IH), 8.24 (s, IH), 7.08 - 6.97 (m, 2H), 6.85 - 6.72 (m, IH), 5.28 - 5.22 (m, IH), 3.78 (d, J= 5.0 Hz, 5H), 3.68 - 3.51 (m, 2H), 3.10 (s, 2H), 3.04 - 2.94 (m, 2H), 2.94 - 2.90 (m, IH), 2.86 (s, 4H), 2.81 - 2.72 (m, IH), 2.27 - 2.20 (m, IH), 1.71 - 1.62 (m, 2H), 1.46 (s, 9H), 1.39 - 1.21 (m, 2H); LC-MS (ESI+) m/z 500.4 (M+H)+.

[004599] Step 2 - r3-Methyl IT4-(methylaminomethyl)-l-piperidyl1methyl1 oxobenzimidazol-l-yl1piperidine 2,6-dione

[004600] To a mixture of tert-butyl N-[[l-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl] piperidyl]methyl]-N-methyl-carbamate (106 mg, 212 umol) in DCM (2 mL) was added TFA (483 mg, 4.24 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo give the title compound (108 mg, 99% yield, TFA). LC-MS (ESI+) m/z 399.9 (M+H)+.

[004601] 3-[3-Methvl [[(2S) (methvlaminomethvl)morDholin vl]methyl] oxobenzimidazo

[004602] l-l-yl]DiDeridine-2,6-dione (Intermediate YJ)

1420

HCI/dioxane

DCM

[004603] Step 1 - Tert-butvl-N-rr(2R) rr1-(2,6-dioxo piperidvl) methyl oxo benzimidazol yl1methyl1morpholin yl1 methyl1-N-methyl-carbamate

[004604] To a solution of tert-butyl N-methyl-N-[[(2R)-morpholin yl]methyl]carbamate (158 mg, 689 umol, synthesized via Steps 1-5 of Intermediate WP), l-(2,6-dioxo piperidyl)-3methyl oxo-benzimidazole carbaldehyde (180 mg, 626 umol, Intermediate WW) in DMF (3.00 mL) and THF (10.0 mL) was added HOAc (75.2 mg, 1.25 mmol). The mixture was stirred at 20 °C for 0.5 hr, then NaBH(OAc)3 (265 mg, 1.25 mmol) was added, and the mixture was stirred at 20 °C for 14 hrs. On completion, the reaction mixture was quenched with H2O (3 mL) at 20 °C, and extracted with EA 60 mL (3 X 20 mL). The combined organic layers were washed with brine (2X10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (215 mg, 68% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.07 (s, IH), 6.88 - 6.86 (m, IH), 6.82 - 6.80 (m, IH), 6.69 (d, J= 7.6 Hz, IH), 5.19 - 5.07 (m, IH), 3.79 - 3.72 (m, IH), 3.72 - 3.71 (m, 3H), 3.57 (s, 2H), 3.53 - 3.47 (m, 2H), 3.39 - 3.36 (m, 2H), 2.87 (s, 2H), 2.83 (s, 3H), 2.73 - 2.72 (m, IH), 2.63 - 2.54 (m, 2H), 2.19 - 2.12 (m, 2H), 1.87 - 1.80 (m, IH), 1.36 (s, 9H).

[004605] Step 2 - 3-r3-Methyl rr(2S) (methylaminomethyl)morpholin yl1methyl1-2oxo-benzimidazol-1 -yl1piperidine-2,6-dione

[004606] To a solution of tert-butyl N-[[(2R) [[ 1-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl] morpholin yl] methyl]-N-methyl-carbamate (100 mg, 199 umol) in DCM (3.00 mL) was added HCI/dioxane (4.00 M, 5.00 mL). The mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound

1421 (87.0 mg, quant, crude yield, HCI) as yellow solid. LC-MS (ESI+) m/z 401.2 (M+H)+.

[004607] 3-[3-Methvl [[(2R) (methvlaminomethvl)morDholin vl]methyl] oxobenzimidazol yl]DiDeridine-2,6-dione (Intermediate YK)

TEA, HOAc, NaBH(OAc)3, THF

HCI/dioxane

DCM

YK

[004608] Step 1 - N-rr(2S) rr1-(2,6-dioxo piperidvl) methyl oxo-benzimidazol-4yllmethyllmorpholin- 2-yl1methyl1-N-methyl-carbamate

[004609] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-4carbaldehyde (249 mg, 868 umol, Intermediate WW) and tert-butyl N-methyl-N-[[(2S)morpholin yl]methyl]carbamate (200 mg, 868 umol, Intermediate YM) in THF (15 mL) was added TEA (87.8 mg, 868 umol). The reaction mixture was stirred at 25 °C for 15 minutes. Then AcOH (156 mg, 2.61 mmol) and NaBH(OAc)3 (552 mg, 2.61 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction was quenched with water (3 mL) and the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (250 mg, 57% yield) as a white solid. LC-MS (ESI+) m/z 502.1 (M+H)+.

[004610] Step 2 - 3-r3-Methyl rr(2R) (methylaminomethyl)morpholin yl1methyl1-2oxo-benzimidazol yl1piperidine-2,6-dione

[004611] To a solution of tert-butyl N-[[(2S) [[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl]morpholin yl]methyl]-N-methyl-carbamate (100 mg, 199 umol) in DCM (1 mL) was added HCI/dioxane (4 M, 20.0 mL). The reaction mixture was stirred at 25 °C for 30 minutes. On completely, the reaction mixture was concentrated in vacuo to give the title compound (80.0 mg, 91% yield, HCI) as a white solid. LC-MS (ESI+) m/z 402.1 (M+H)+.

1422

[004612] 3-[3-Methvl oxo [2-(4-DiDeridvl)ethvnvl]benzimidazol-l-yl]DiDeridine2.,6-dione (Intermediate YL)

Pd(PPh3)2CI2, Cui, 4A-MS CS2CO3, DMF

[004613] Step 1 - Tert-butyl 4-r2-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1ethynyl1 piperidine carboxylate

[004614] To a solution of 3-(4-bromo methyl oxobenzimidazol-l-yl)piperidine-2,6di one (400 mg, 1.18 mmol, Intermediate HP), and tert-butyl 4-ethynylpiperidine-l-carboxylate (446 mg, 2.13 mmol, CAS# 287192 6) in DMF (5.00 mL) was added Cs2CO3 (1.93 g, 5.91 mmol), 4A molecular sieves (100 mg), Pd(PPh3)2C12 (83.0 mg, 118 umol) and Cui (22.5 mg, 118 umol). The mixture was stirred at 80 °C for 2 hrs under N2. On completion, the reaction mixture was filtered and the filter cake was washed with ACN (10 mL). The filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (330 mg, 707 umol, 60% yield) as yellow solid. 1H NMR (400MHz, DMSO- de) δ 11.11 (s, IH), 7.13-7.11 (m, IH), 7.07 - 7.05 (m, IH), 7.01 - 6.97 (m, IH), 5.40 - 5.36 (m, IH), 3.72 - 3.66 (m, 2H), 3.63 (s, 3H), 3.12 - 3.07 (m, 2H), 2.93 - 2.87 (m, 2H), 2.75 - 2.68 (m, IH), 2.65 - 2.60 (m, IH), 2.04 - 1.99 (m, IH), 1.88 - 1.85 (m, 2H), 1.8 - 1.50 (m, 2H), 1.40 (s, 9H).

[004615] Step 2 - 3-r3-Methyl oxo r2-(4-piperidyl)ethynyl1benzimidazol-lyl1piperidine-2,6-dione

[004616] To a solution of tert-butyl 4-[2-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]ethynyl] piperidine carboxylate (300 mg, 643 umol) in DCM (3.00 mL) was added ZnBr2 (2.17 g, 9.65 mmol). The mixture was stirred at 20 °C for 20 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (235 mg, 99% yield) as

1423 yellow gum. LC-MS (ESI+) m/z 367.2 (M+H)+.

[004617] Tert-butyl N-methvl-N-[[(2S)-morDholin vl]methyl]carbamate (Intermediate YM)

ΗΝγ^ΟΗ CbzCI, NaHCO3 * 01’2'N'^Y^OH MsCI, &#1470;TEA 002'Ν'&#910;'&#910;οΜε

Y/O ACN/H2O Y0&#1470; DCM Y&#1523;°

MeNH2 tea&#1523; (b°c)2O Cbz'N+^v^N'B0C H2’ Pd/C HN^Y^N'600

----------------------------1 ' 1 -----------------------------------------1 &#2404; 1 -----------------------------L &#1505; '

THF \+° DCM Y/O MeOH ^&#1523;&#1523;

YM

[004618] Step 1 - Benzyl (2S) (hydroxymethyl)morpholine carboxylate

[004619] To a solution of [(2S)-morpholin yl]methanol (5 g, 32.5 mmol, HC1; CAS# 132073 7) and NaHCO3 (6.84 g, 81.4 mmol) in a mixed solvent of ACN (10 mL) and H2O (10 mL) was added CbzCI (8.33 g, 48.8 mmol). The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to remove ACN. The residue was extracted with EA (2 X 20 mL), then the combined organic layers were concentrated in vacuo. The residue was purified by silica gel column (PE: EA=1: 1) to give the title compound (7.1 g, 87% yield) as colorless oil. 1H NMR (400MHz, CDCh) δ 7.42 - 7.33 (m, 5H), 5.17 (d, J = 2.0 Hz, 2H), 4.08 3.88 (m, 3H), 3.77 - 3.65 (m, IH), 3.63 - 3.46 (m, 3H), 3.13 - 2.73 (m, 2H), 2.07 - 1.96 (m, IH). LC-MS (ESI+) m/z 274.1 (M+Na)+.

[004620] Step 2 - Benzyl (2S) (methylsulfonyloxymethyl)morpholine carboxylate [004621] To a solution of benzyl (2S) (hydroxymethyl)morpholine carboxylate (7.1 g, 28.2 mmol) and triethylamine (5.72 g, 56.5 mmol) in dichloromethane (70 mL) was added methanesulfonyl chloride (4.86 g, 42.3 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hr. On completion, the mixture was diluted with dichloromethane (20 mL) and washed with water (3 X 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (9.31 g, 100% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 7.43 - 7.33 (m, 5H), 5.20 - 5.15 (m, 2H), 4.26 (d, J = 4.8 Hz, 2H), 4.10 - 3.83 (m, 3H), 3.80 - 3.65 (m, IH), 3.63 - 3.48 (m, IH), 3.08 (s, 3H), 3.07 - 2.75 (m, 2H).

[004622] Step 3 - Benzyl (2R) (methylaminomethyl)morpholine carboxylate

[004623] A solution of benzyl (2S) (methylsulfonyloxymethyl)morpholine carboxylate (9.31 g, 28.2 mmol) in EtOH (10 mL) saturated with methanamine (58.5 g, 565 mmol) was stirred

1424 under 50 Psi at 80 °C for 12 hrs in a 100 mL of autoclave. On completion, the mixture was concentrated in vacuo to give the title compound (7.47 g, 100% yield) as yellow oil, which was used for the next step without purification.

[004624] Step 4 - Benzyl (2R) rrtert-butoxycarbonyl(methyl)amino1methyl1morpholine-4carboxylate

[004625] To a solition of benzyl (2R) (methylaminomethyl)morpholine carboxylate (7.47 g, 28.2 mmol) in MeOH (100 mL) was added (Boc)2O (9.25 g, 42.4 mmol, 9.74 mL) and TEA (4.29 g, 42.4 mmol). The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column (PE: EA =5:1) to give the title compound (9.10 g, 88% yield) as yellow oil, 1H NMR (400MHz, CDCh) δ 7.43 7.30 (m, 5H), 5.24 - 5.09 (m, 2H), 4.11 - 3.83 (m, 3H), 3.68 - 3.34 (m, 3H), 3.30 - 3.14 (m, IH), 3.09 - 2.97 (m, IH), 2.94 (s, 3H), 2.80 - 2.62 (m, IH), 1.47 (s, 9H).

[004626] Step 5 - Tert-butyl N-methyl-N-rr(2S)-morpholin yl1methyl1carbamate

[004627] To a solution of benzyl (2R) [[tertbutoxycarbonyl(methyl)amino]methyl]morpholine carboxylate (9.1 g, 24.9 mmol) in THF (100 mL) was added Pd/C (1.00 g, 10% wf) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 25 °C for 12 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (5.7 g, 99% yield) as colorless oil. 1HNMR (400MHz, CDCh) δ 3.91 - 3.83 (m, IH), 3.68 - 3.55 (m, 2H), 3.48 - 3.33 (m, IH), 3.12 (dd, J= 6.2, 14.4 Hz, IH), 2.94 (s, 3H), 2.92 - 2.88 (m, IH), 2.86 (dd, J = 3.2, 10.8 Hz, IH), 2.84 - 2.78 (m, IH), 2.57 (dd, J = 10.3, 12.0 Hz, IH), 1.47 (s, 9H).

[004628] 3-[4-(Aminomethvl) methvl oxo-benzimidazol-l-yl]DiDeridine-2.,6-dione (Intermediate YN)

1425

[004629] Step 1 - l-(2,6-Dioxo piperi dyl) methyl oxo-benzimidazole carbonitrile [004630] To a solution of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6di one (500 mg, 1.48 mmol, Intermediate HP) in DMF (10 mL) was added Zn(CN)2 (190 mg, 1.62 mmol) and Pd(PPh3)4 (180 mg, 155 umol) at 25°C. The mixture was stirred at 100 °C for 3 hours under N2. On completion, the mixture was cooled to 25 °C. The mixture was filtered, and the cake was washed with EA (30 mL). The filtrate and washing were combined and concentrated in vacuo. The residue was purified by reversed phase flash (FA condition) to give the title compound (100 mg, 24% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-» δ 11.17 (s, IH), 7.48 (d, J= 7.6 Hz, 2H), 7.19 (t, J= 8.0 Hz, IH), 5.47 - 5.44 (m IH), 3.61 (s, 3H), 2.72 - 2.69 (m, IH), 2.66 2.62 (m, 2H), 2.07 - 2.03 (m, IH); LC-MS (ESI+) m/z 285.1 (M+H)+.

[004631] Step 2 - Tert-butyl N-rr1-(2,6-dioxo piperidvl) methvl oxo-benzimidazol-4yllmethyll carbamate

[004632] To a solution of 1-(2, 6-dioxo piperidyl) methyl oxo-benzimidazole-4carbonitrile (100 mg, 351 umol) and B0C20 (85.0 mg, 389 umol) in THF (2 mL) and DMF (2 mL) was added Raney-Ni (100 mg) at 20 °C. The mixture was stirred at 30 °C for 16 hours under H2 (50 Psi). On completion, the mixture was filtered, and the filter cake was washed with THF (20 mL). The filtrate and washing were combined and concentrated in vacuo to give the title compound (120 mg, 87% yield) as light yellow gum. LC-MS (ESI+) m/z 411.2 (M+Na)+.

[004633] Step 3 - 3-[4-(Aminomethvl) methvl oxo-benzimidazol-l-yl1piperidine-2,6di one

1426

[004634] To a solution of tert-butyl N-[[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl]carbamate (120 mg, 308 umol) in DCM (2 mL) was added TFA (1 mL) at 20 °C. The mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (120 mg, 96% yield, TFA) as light yellow solid. LC-MS (ESI+) m/z 311.2 (M+Na)+.

[004635] Tert-butyl N-methvl-N-(3-Dr0D vn0xycvcl0butvl)carbamate (Intermediate YO)

HQ, HO, un zA^Br &#1503;—1&#1470; LAH '.γ\ (Boc)2O H°'''Y\ __________

-X. VX _B0C \hBoc THF &#1503; MeOH N NaH, TBAI , THF

An.B0c I YO

[004636] Step 1 - 3-(Methylamino)cyclobutanol

[004637] To a stirred solution of LAH (2.43 g, 64.1 mmol) in THF (100 mL) was added a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (10.0 g, 53.4 mmol, CAS# 389890-420) in THF (100 mL) at 0 °C. Then the reaction mixture was stirred at 60 °C for 24 hrs. On completion, the reaction mixture was concentrated in vacuo. On completion, the mixture was cooled to 0 °C, quenched with H2O (2.4 mL) and added 15%NaOH (2.4 mL). After stirred for 15 minutes, H2O (2.4 mL X 3) was added into the above mixture. Then the mixture was warmed to rt and added anhydrous Na2SO4. The mixture was stirred for 10 minutes, filtered and the filtrate was concentrated in vacuo to give the title compound (4.90 g, 91% yield) as colorless oil. 1H NMR (400 MHz, DMSO-76) δ 5.01 (s, IH), 4.23 - 4.20 (m, IH), 3.13 - 3.00 (m, IH), 2.13 (s, 3H), 1.93 - 1.84 (m, 4H), 1.70 - 1.47 (m, IH).

[004638] Step 2 - Tert-butyl N-(3-hvdroxvcvclobutvl)-N-methyl-carbamate

[004639] To a solution of 3-(methylamino)cyclobutanol (4.90 g, 48.4 mmol) in methyl alcohol (50 mL) was added (Boc)2O (11.6 g, 53.3 mmol, 12.2 mL) for 3 hr at 25 °C. Then another batch of (Boc)2O (10.6 g, 48.4 mmol) was added. The mixture was stirred at 25 °C for another 19 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 1:1) to give the title compound

1427 (2.85 g, 30% yield) as yellow oil. 1H NMR (DMSO-76) δ 4.94 (s, IH), 4.25 - 4.21 (m, IH), 4.10 4.19 (m, IH), 2.72 (s, 3H), 2.23 - 2.35 (m, 2H), 1.91 - 2.03 (m, 2H), 1.38 (s, 9H).

[004640] Step 3 - Tert-butyl N-methyl-N-(3-prop ynoxycyclobutyl)carbamate

[004641] To a solution of tert-butyl N-(3-hydroxycyclobutyl)-N-methyl-carbamate (450 mg, 2.24 mmol) in THF (15 mL) was added NaH (107 mg, 2.68 mmol, 60% dispersion in oil), TBAI (82.6 mg, 223 umol) at 0 °C, and the mixture was stirred for 30 minutes. Then 3-bromoprop yne (3.35 mmol, 289 uL) was added to the mixture at 0 °C. The reaction mixture was stirred at 10 °C for 18 hrs. On completion, the reaction mixture was quenched 30 mL sat.aq NH4C1 at 10°C and diluted with 30 mL water. Then the reaction mixture was then extracted with EA (3 X 50 mL). The combined organic layers were washed with 50 mL brine, dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound (500 mg, 93% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.68 (s, IH), 4.27 - 4.19 (m, IH), 4.08 (d, J= 2.4 Hz, 2H), 2.83 (s, 3H), 2.41 (t, J= 2.4 Hz, IH), 2.38 - 2.26 (m, 4H), 1.46 (s, 9H).

[004642] 3-[3-methvl [3-[3-(methvlamino)cvclobutoxvlDroDvl] oxo-benzimidazoll-yl]piperidine-2,6-dione (Intermediate YP)

[004643] Step 1 - Tert-butyl N-r3-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxy] cyclobutyl1-N-methyl-carbamate

[004644] To a solution of tert-butyl N-methyl-N-(3-prop ynoxycyclobutyl)carbamate (500

1428 mg, 2.09 mmol, Intermediate YO) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (353 mg, 1.04 mmol, Intermediate HP) in DMF (15 mL) was added Cui (39.8 mg, 209 umol), Cs2CO3 (1.70 g, 5.22 mmol), Pd(PPh3)C12 (153 mg, 209 umol) and 4A molecular sieves (600 mg) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was diluted with 30 mL water, and then extracted with EA (3X30 mL). The combined organic layers were washed with brine (30 mL), and then dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (380 mg, 73% yield) as a white solid. 1H NMR (400 MHz, DMSO-6/6)5 11.11 (s, IH), 7.17 (d, 7= 7.6 Hz, IH), 7.12 (d, 7= 7.6 Hz, IH), 7.06 - 7.00 (m, IH), 5.39 (dd, 7= 5.2, 12.8 Hz, IH), 4.39 (s, 2H), 4.22 (t, 7= 6.8 Hz, IH), 3.63 (s, 3H), 3.29 (s, IH), 2.95 - 2.83 (m, IH), 2.75 (s, 3H), 2.65 - 2.64 (m, IH), 2.70 - 2.64 (m, IH), 2.36 - 2.30 (m, 2H), 2.26 - 2.16 (m, 2H), 2.09 - 1.98 (m, IH), 1.38 (s, 9H); LC-MS (ESI+) m/z 397.0 (M+H-100/.

[004645] Step 2 - Tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxv1 cvclobutvl1-N-methyl-carbamate

[004646] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]cyclobutyl]-N-methyl-carbamate (340 mg, 685 umol) in THF (15 mL) was added Pd(OH)2/C (400 mg, 685 umol, 10 wt%) and Pd/C (400 mg, 685 umol, 20 wt%) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs under H2 (15 psi). On completion, the reaction mixture was filtered with celite and the filtrate was concentrated in vacuo to give the title compound (330 mg, 96% yield) as black oil. LC-MS (ESI+) m/z 501.2(M+H)+.

[004647] Step 3 - 3-[3-methyl [3-[3-(methylamino)cyclobutoxy1propyl1 oxobenzimidazol-l-yl1piperidine-2,6-dione

[004648] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]cyclobutyl]-N-methyl-carbamate (300 mg, 599 umol) in DCM (8 mL) was added HCI/dioxane (4 M, 5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (220 mg, 91% yield) as a white solid. 1H NMR (400 MHz, DMSO-A) δ 11.08 (s, IH), 9.06 (s, IH), 6.98 - 6.96 (m, IH), 6.90-6.87(m, IH), 5.37 (dd, 7= 5.2, 12.8 Hz, IH), 4.23 - 4.14 (m, IH), 3.57 (s, 3H), 3.35 (s, 3H), 3.00 - 2.92 (m, 3H), 2.91 - 2.84 (m, IH), 2.75 - 2.70 (m, IH), 2.60 (s, 2H), 2.45 (t, 7= 5.6 Hz, 4H),

1429

2.27 - 2.17 (m, 2H), 2.03 - 1.95 (m, IH), 1.88 - 1.77 (m, 2H); LC-MS (ESI+) m/z 401.3 (M+H)+.

[004649] 3-[3-Methvl [3-[(2S) (methvlaminomethvl)morDholin vl]DroDvl] oxobenzimidazol-l-yl]DiDeridine-2,6-dione (Intermediate YQ)

WP

Boc

N \

Pd(OH)2/C, Pd/C

H2, THF

YQ

[004650] Step 1 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynyl1morpholin yl1methyl1-N-methyl-carbamate

[004651] To a solution of tert-butyl N-methyl-N-[[(2R) prop ynylmorpholin-2yl]methyl]carbamate (400 mg, 1.49 mmol, Intermediate WP) and 3-(4-bromo methyl oxobenzimidazol-l-yl)piperidine -2,6-dione (336 mg, 994 umol, Intermediate HP) in DMF (15 mL) was added Cs2CO3 (1.62 g, 4.97 mmol), 4A molecular sieves (500 mg, 994 umol), Cui (37.8 mg, 199 umol) and Pd(PPh3)2C12 (139mg, 199 umol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was diluted with water 30 mL, and then extracted with EA (3 X 20 mL). The combined organic layers were washed with brine (20 mL), and then dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (340 mg, 65% yield) as a white solid. 1H NMR (400 MHz, DMSO-6% δ 11.10 (s, IH), 7.18-7.13 (m, IH), 7.12 - 7.06 (m,

1430

IH), 7.04 - 6.99 (m, IH), 5.39 (dd, J = 5.2, 12.4 Hz, IH), 3.83 (d, J= 9.6 Hz, IH), 3.64 (s, 3H), 3.62 - 3.46 (m, 4H), 3.34 (s, 3H), 3.15 (s, IH), 2.86 - 2.78 (m, 4H), 2.75 - 2.66 (m, 3H), 2.11 1.98 (m, 2H), 1.35 (s, 9H); LC-MS (ESI+) m/z 526.3 (M+H)+.

[004652] Step 2 - Tert-butyl N-rr(2R) r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1propyl1 morpholin yl1methyl1-N-methyl-carbamate

[004653] To a solution of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] prop ynyl]morpholin yl]methyl]-N-methyl-carbamate (300 mg, 571 umol) in THF (20 mL) and Pd/C (200 mg, 20 wt%) was added Pd(OH)2/C (200 mg, 10 wt%) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs under H2 (15 psi). On completion, the reaction mixture was filtered with celite and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (130 mg, 43% yield) as a white solid. 1HNMR (400 MHz, DMSO-t/6) δ 11.10 (s, IH), 6.99 - 6.91 (m, 2H), 6.89 - 6.83 (m, IH), 5.36 (dd, J= 5.2, 12.4 Hz, IH), 3.77 (d, J = 11.2 Hz, IH), 3.55 (s, 3H), 3.46 (t, J= 10.4 Hz, 2H), 3.22 (d, J = 5.2 Hz, IH), 3.18 - 3.15 (m, IH), 2.94 - 2.88 (m, 2H), 2.84 - 2.76 (m, 3H), 2.72 - 2.62 (m, 4H), 2.52 (s, 3H), 2.39 - 2.34 (m, IH), 2.05 - 1.95 (m, 2H), 1.77 1.71 (m, 2H), 1.37 (s, 9H); LC-MS (ESI+) m/z 530.4 (M+H)+.

[004654] Step 3 - 3-r3-Methyl r3-r(2S) (methylaminomethyl)morpholin yl1propyl1-2oxo-benzimidazol-1 -yl1piperidine-2,6-dione

[004655] To a solution of tert-butyl N-[[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]methyl]-N-methyl-carbamate (110 mg, 208 umol) in DCM (6 mL) was added HCI/dioxane (4 M, 3 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (80.0 mg, 89% yield) as a white solid. LC-MS (ESI+) m/z 430.2(M+H)+.

[004656] 3-[3-Methvl [3-[(2S) [2-(methvlamino)ethvl]morDholin yl]DroDvl]-2oxo-benzimidazol -l-yl]DiDeridine-2.,6-dione (Intermediate YR)

1431

TX

[004657] Step 1 - Benzyl N-r2-r(2S) r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynyl1morpholin yl1ethyl1-N-methyl-carbamate

[004658] To a solution of benzyl N-methyl-N-[2-[(2S) prop ynylmorpholin-2yl]ethyl]carbamate (426 mg, 1.35 mmol, Intermediate TX) and 3-(4-bromo methyl oxobenzimidazol-l-yl)piperidine-2,6-dione (350 mg, 1.04 mmol, Intermediate HP) in DMF (15 mL) was added Cs2CO3 (1.69 g, 5.18 mmol), Cui (39.4 mg, 207 umol), 4A molecular sieves (500 mg, 147.86 umol) and Pd(dppf)C12 (151 mg, 207 umol) at 25 °C. The reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the residue. The residue was diluted with water 30 mL, and then extracted with EA (3 X 20 mL). The combined organic layers were washed with brine (20 mL), and then dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (400 mg, 67% yield) as a white solid. 1H NMR (400 MHz, DM SO-0/6) δ 11.11 (s, IH), 7.34 (d, J = 2.0 Hz, 5H), 7.18 7.08(m, 2H), 7.05 - 6.98 (m, IH), 5.39 (dd, J = 5.2, 12.8 Hz, IH), 5.05 (s, 2H), 3.84 - 3.74 (m, IH), 3.63 (s, 3H), 3.56 (s, 3H), 3.46 - 3.41 (m, 2H), 2.94 - 2.87 (m, IH), 2.88 - 2.80(m, 4H), 2.77 - 2.70 (m, 2H), 2.67 - 2.58 (m, 2H), 2.31 - 2.25 (m, IH), 2.08 - 1.98 (m, 2H), 1.65 - 1.55 (m, 2H); LC-MS (ESI+) m/z 574.1 (M+H)+.

[004659] Step 2 - 3-[3-Methyl [3-[(2S) [2-(methylamino)ethyl1morpholin yl1propyl12-oxo-benzimidazol -l-yl1piperidine-2,6-dione

[004660] To a solution of benzyl N-[2-[(2S) [3-[l-(2,6-dioxo piperidyl) methyl-2

1432 oxo-benzimidazol yl] prop ynyl]morpholin yl]ethyl]-N-methyl-carbamate (370 mg, 645 umol) in THF (15 mL) was added Pd/C (300 mg, 20 wt%) and Pd(0H)2/C (300 mg, 10 wt%) at 25 °C. The mixture was stirred at 25 °C for 2.5 hrs under H2 (15 psi). On completion, the reaction mixture was fdtered with celite and the fdtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (140 mg, 48% yield) as a brown solid. LC-MS (ESI+) m/z 444.3 (M+H)+.

[004661] Tert-butyl 4-(prop vnoxvmethyl)piperidine-l-carboxvlate (Intermediate YS)

YS

[004662] To a mixture of tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (5.00 g, 23.2 mmol, CAS# 123855 6) was added NaH (1.11 g, 27.8 mmol, 60% oil dispersion) at 0 °C for 0.5 hour. Then 3-bromoprop yne (4.14 g, 27.8 mmol, 3.00 mL, CAS# 106 7) and TBAI (857 mg, 2.32 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was quenched by addition sat. H2O (10 mL), and extracted with EA (50 mL X 2). The combined organic layers were dried over Na2SO4, fdtered and concentrated in vacuo to give the title compound (5.00 g, 84% yield) as yellow oil. 1H NMR (400 MHz, CDCh) δ 4.12 (d, J= 2.4 Hz, 2H), 3.36 (d, J= 6.2 Hz, 2H), 2.69 (t, J= 12.2 Hz, 2H), 2.41 (t, 7= 2.4 Hz, IH), 1.81 - 1.74 (m, IH), 1.73 - 1.67 (m, 2H), 1.45 (s, 9H), 1.15 - 1.10 (m, 2H).

[004663] 3- [3-Methyl oxo [3-(4-DiDeridvlmeth0xy)Dr0Dvl] benzimidazol-1yl]piperidine-2,6-dione (Intermediate YT)

1433

YS

Pd(PPh3)2CI2, Cui, Cs2CO3, 4A MS, DMF

Pd/C, Pd(OH)2/C

H2, THF

[004664] Step 1 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl]prop ynoxy methyl]piperidine-l-carboxylate

[004665] To a mixture of tert-butyl 4-(prop ynoxymethyl)piperidine-l-carboxylate (749 mg, 2.96 mmol, Intermediate YS) and 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (400 mg, 1.18 mmol, Intermediate HN) in DMF (1 mL) was added Pd(PPh3)2C12 (83.0 mg, 118 umol), Cui (22.5 mg, 118 umol), Cs2CO3 (1.93 g, 5.91 mmol) and 4A molecular sieves (10.0 mg, 147 umol). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (320 mg, 52% yield) as a yellowish solid. 1H NMR (400 MHz, DMSOY) δ 11.19 - 11.03 (m, IH), 7.66 - 7.52 (m, IH), 7.32 (d, J = 0.8 Hz, IH), 7.16 - 7.13 (m, IH), 5.39 (dd, J = 12.8 Hz, IH), 4.36 (s, 2H), 3.40 (t, J = 2.4 Hz, IH), 3.37 (d, J = 6.2 Hz, 2H), 3.34 (s, 3H), 3.30 - 3.27 (m, 2H), 2.97 - 2.82 (m, IH), 2.76 - 2.64 (m, 4H), 2.11 - 1.96 (m, IH), 1.64 (s, 2H), 1.38 (s, 9H), 1.07 - 1.01 (m, 2H).

[004666] Step 2 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidvl) methyl oxo-benzimidazol5-yl]propoxymethyl] piperidine carboxylate

[004667] To a mixture of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxo

1434 benzimidazol yl]prop ynoxymethyl]piperidine-l-carboxylate (320 mg, 626umol) in THF (5 mL) was added Pd/C (100 mg, 626 umol, 10% wt) and Pd(OH)2/C (100 mg, 626 umol, 10% wt). The mixture was stirred at 25 °C for 12 hours under H2 (15 psi). On completion, the mixture was filtered and concentrated in vacuo to give the title compound (320 mg, 99 yield) as a white solid. 1HNMR (400 MHz, DMSO-76) δ 11.07 (s, IH), 7.69 - 7.50 (m, IH), 7.03 - 7.00 (m, IH), 6.87 6.84 (m, IH), 5.33 (dd, J = 12.8 Hz, IH), 3.92 (d, J = 12.0 Hz, 2H), 3.38 - 3.34 (m, 3H), 3.31 3.27 (m, 2H), 3.20 (t, J = 6.6 Hz, 4H), 1.86 - 1.76 (m, 2H), 1.73 - 1.67 (m, IH), 1.64 - 1.60 (m, 2H), 1.55 - 1.44 (m, 2H), 1.38 (s, 9H), 1.35 (s, 2H).

[004668] Step 3 - 3-r3-Methyl oxo r3-(4-piperidylmethoxy)propyl1benzimidazol-lyl1piperidine-2,6-dione

[004669] To a mixture of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxymethyl]piperidine-l-carboxylate (310 mg, 602 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 4.00 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (220 mg, 88% yield) as a white solid. 1H NMR (400 MHz, DMSO4) δ 11.07 (s, IH), 7.07 - 6.97 (m, 2H), 6.89 - 6.82 (m, IH), 5.34 (dd, J= 12.8 Hz, IH), 3.57 (s, 4H), 3.40 - 3.37 (m, 2H), 3.22 - 3.21 (m, 2H), 2.96 - 2.70 (m, 6H), 2.67 - 2.64 (m, 2H), 1.85 - 1.81 (m, 2H), 1.52 - 1.47 (m, IH), 1.41 - 1.33 (m, 4H), 0.90 - 0.81 (m, IH), 0.86 (t, J= 7.2 Hz, IH).

[004670] 3- |3-M et hvl oxo [3-(4-piperidvlmethoxv)propyl] benzimidazol-1yl]piperidine-2.,6-dione (Intermediate YU)

1435

YU

[004671] Step 1 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1prop ynoxymethyllpiperidine-1 -carboxylate

[004672] To a mixture of tert-butyl 4-(prop ynoxymethyl)piperidine-l-carboxylate (749 mg, 2.96 mmol, Intermediate YS) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine2,6-dione (400 mg, 1.18 mmol, Intermediate HP) in DMF (5 mL) was added Cui (22.5 mg, 118 umol), Cs2CO3 (1.93 g, 5.91 mmol), Pd(PPh3)2C12 (83.0 mg, 118 umol) and 4A molecular sieves (20.0 mg). The reaction mixture was stirred at 80 °C for 4 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (300 mg, 49% yield) as brown solid. 1HNMR (400 MHz, DMSO-t/6) δ 11.11 (s, IH), 7.20 - 7.09 (m, 2H), 7.06 - 7.00 (m, IH), 5.43 - 5.36 (m, IH), 4.43 (s, 2H), 4.10 (d, J= 2.4 Hz, IH), 3.93 (d, J= 10.8 Hz, 2H), 3.64 (s, 3H), 3.40 - 3.38 (m, 2H), 3.28 (d, J= 6.4 Hz, IH), 2.95 - 2.83 (m, IH), 2.70 - 2.65 (m, 2H), 2.06 - 1.99 (m, IH), 1.81 - 1.70 (m, IH), 1.67 - 1.60 (m, 2H), 1.38 (s, 9H), 1.08 - 1.01 (m, 2H).

[004673] Step 2 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1propoxymethyl1 piperidine carboxylate

[004674] To a mixture of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxymethyl]piperidine-l-carboxylate (300 mg, 587 umol) in THF (30 mL) was added Pd/C (100 mg, 10 wt%) and Pd(OH)2/C (100 mg, 10 wt%). The reaction mixture

1436 was stirred at 25 °C for 12 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (302 mg, 99% yield) as light yellow solid. 1H NMR (400 MHz, DMSO-76) δ 11.08 (s, IH), 6.96 (d, J= 4.4 Hz, 2H), 6.88 - 6.83 (m, IH), 5.41 - 5.30 (m, IH), 3.96 - 3.91 (m, 2H), 3.55 (s, 3H), 3.42 (t, J= 5.6 Hz, 2H), 3.28 - 3.18 (m, 4H), 2.99 - 2.92 (m, 2H), 2.90 - 2.83 (m, IH), 2.71 - 2.66 (m, 2H), 2.05 - 1.94 (m, IH), 1.86 - 1.78 (m, 2H), 1.66 - 1.62 (m, 2H), 1.51-1.46 (m, IH), 1.39 (s, 9H), 1.06 - 0.99 (m, 2H).

[004675] Step 3 - 3-r3-Methvl oxo r3-(4-piperidvlmethoxv)propyl1benzimidazol-lvl1piperidine-2,6-dione

[004676] To a mixture of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxymethyl]piperidine-l-carboxylate (290 mg, 563 umol) in DCM (2 mL) was added HCI/dioxane (4 M, 29.00 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (254 mg, 99% yield, HCI salt) as white solid. LC-MS (ESI+) m/z 415.3 (M+H)+.

[004677] Tert-butyl 3-Dr0D yn0xyazetidine-l-carb0xylate (Intermediate YV)

YV

[004678] To a mixture of tert-butyl 3-hydroxyazetidine carboxylate (5.00 g, 28.8 mmol, CAS# 141699 0) in THF (5 mL) was added NaH (1.39 g, 34.6 mmol, 60% oil dispersion) at 0 °C for 0.5 hour. Then 3-bromoprop yne (5.15 g, 34.6 mmol, 3.73 mL) and TBAI (1.07 g, 2.89 mmol) were added to the mixture. The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was quenched with sat. NH4C1 (50 mL), diluted with water (100 mL) and extracted with EA (2 X 100 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (5.70, 93 % yield) as a yellow solid. 1H NMR (400 MHz, CDCh) δ 4.45 - 4.37 (m, IH), 4.13 (d, J = 2.4 Hz, 2H), 4.12 - 4.07 (m, 2H), 3.89 (dd, J = 9.6 Hz, 2H), 2.45 - 2.43 (m, IH), 1.43 (s, 9H).

[004679] 3-[5-[3-(Azetidin vloxv)DroDvl] methvl oxo-benzimidazol-lyl]piperidine-2,6-dione (Intermediate YW)

1437

YV

[004680] Step 1 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1prop ynoxy1 azetidine-1 -carboxylate

[004681] To a mixture of ert-butyl 3-prop ynoxyazetidine-l-carboxylate (499 mg, 2.37 mmol, Intermediate YV) and 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (400 mg, 1.18 mmol, Intermediate HN) in DMF (20 mL) was added Cs2CO3 (1.93 g, 5.91 mmol), Cui (22.5 mg, 118 umol), Pd(PPh3)2C12 (83.0 mg, 118 umol) and 4A molecular sieves (100 mg). The reaction mixture was stirred at 80 °C for 2 hours. On completion, the mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (300 mg, 54% yield) as colorless oil. 1H NMR (400 MHz, DMSO-7) δ 11.11 (s, IH), 7.66 - 7.59 (m, IH), 7.58 -7.49 (m, IH), 7.18-7.13 (m, IH), 4.49 - 4.43 (m, IH), 4.10 - 3.97 (m, 4H), 3.77 - 3.76 (m, IH), 3.77 - 3.72 (m, IH), 3.46 (t, J= 2.4 Hz, IH), 3.34 (s, 3H), 2.97 - 2.83 (m, IH), 2.77 - 2.58 (m, 2H), 2.09 - 1.94 (m, IH), 1.37 (s, 9H).

[004682] Step 2 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1propoxy1 azetidine-1 -carboxylate

[004683] To a solution of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]azetidine-l-carboxylate (300 mg, 640 umol) in THF (5 mL) was added Pd/C (100 mg, 71.2 mmol, 10% w/f) and Pd(OH)2/C (100 mg, 71.2 mmol, 10% w/f) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture

1438 was stirred at 25 °C for 17 hours under H2 (15 psi). On completion, the mixture was fdtered and concentrated in vacuo to give the title compound (240 mg, 79% yield) as a white solid. 1H NMR (400 MHz, DMSO-76) δ 11.07 (s, IH), 7.07 - 6.98 (m, 2H), 6.87 (td, J= 8.0 Hz, IH), 5.33 (dd, J = 12.8 Hz, IH), 4.24 - 4.17 (m, 2H), 4.06 - 4.01 (m, 2H), 3.63 (s, IH), 3.32 (s, 3H), 3.27 - 3.24 (m, 2H), 2.68 - 2.64 (m, 2H), 1.99 (s, 2H), 1.86 - 1.79 (m, 2H), 1.50 (t, J= 7.2 Hz, 2H), 1.37 (s, 9H). [004684] Step 3 - 3-r5-r3-(Azetidin yloxy)propyl1 methyl oxo-benzimidazol-lyl1piperidine-2,6-dione

[004685] To a mixture of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] azetidine carboxylate (220 mg, 465 umol) in DCM (5 mL) was added TFA (33.8 g, 297 mmol, 22.0 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (150 mg, 86% yield) as a yellow solid. LC-MS (ESI+) m/z 373.2 (M+H)+.

[004686] 4-(l-(2,6-DioxoDiDeridin vl) methvl oxo-2,3-dihydro-lHbenzo[d]imidazol yl)but- 3-yn-l-yl methanesulfonate (Intermediate YX)

MsCI

TEA, DCM

YX

[004687] Step 1 - 3-(5-(4-Hydroxybut-l-yn-l-yl) methyl oxo-2,3-dihydro-lHbenzo[d1imidazol-l-yl) piperi dine-2,6-dione

[004688] To a solution of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (500 mg, 1.48 mmol, Intermediate HN) and but yn-l-ol (207 mg, 2.96 mmol, CAS# 92774-2) in DMF (8 mL) was added Pd(PPh3)2C12 (207 mg, 295 umol), Cs2CO3 (1.93 g, 5.91 mmol), Cui (56.3 mg, 295 umol) and 4A molecular sieves at 25 °C under N2. The mixture was then heated

1439 to 80 °C and stirred for 2 hours. On completion, the reaction mixture was quenched by addition water (10 mL) at 25 °C, and then diluted with CH2C12 (20 mL) and extracted with CH2C12 (3 X 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA condition) to give the title compound (355 mg, 73% yield) as a yellow solid. 1HNMR (400 MHz, DMSO-76) δ 11.10 (s, IH), 7.24 (s, IH), 7.09 (s, 2H), 5.41 - 5.33 (m, IH), 4.88 (s, IH), 3.58 (t, J = 7.0 Hz, 2H), 3.33 (s, 3H), 2.91 2.84 (m, IH), 2.73 - 2.64 (m, 2H), 2.55 (t, J = &#906;Λ Hz, 2H), 2.05 - 1.99 (m, IH); LC-MS (ESI+) m/z 328.1 (M+H)+.

[004689] Step 2 - 4-(l-(2,6-Dioxopiperidin yl) methyl oxo-2,3-dihydro-lHbenzo[d1imidazol yl)but- 3-yn-l-yl methanesulfonate

[004690] To a mixture of 3-[5-(4-hydroxybut-l-ynyl) methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (350 mg, 1.07 mmol) in DCM (10 mL) was added TEA (324 mg, 3.21 mmol) and MsCI (159 mg, 1.39 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. On completion, the reaction mixture was quenched by addition water (20 mL) at 25 °C, and then extracted with DCM (3 X 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (400 mg, 92% yield) as yellowish oil. 1H NMR (400 MHz, CDCh) δ 8.16 (s, IH), 7.09 - 7.06 (m, IH), 7.00 (s, IH), 6.67 (d, J = 8.2 Hz, IH), 5.14 - 5.09 (m, IH), 4.33 (t, J = 6.8 Hz, 2H), 3.35 (s, 3H), 3.00 (s, 3H), 2.82 (t, J = 6.8 Hz, 2H); LC-MS (ESI+) m/z 406.3 (M+H)+.

[004691] 32]321^ζΙ4ζ£Α21&#912;11θΙ11£&#943;11χ1)21-2&#912;2££&#938;&#973;χ11^η&#943;212χηχ1]232Π16&#943;11χ12220χ02 benzimidazol-l-yl] DiDeridine-2,6-dione (Intermediate YY)

1440

[004692] Step 1 - Tert-butyl N-rr1-r4-[l-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1but ynyl1 piperidyl1methyl1carbamate

[004693] To a solution of 4-(1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl]but ynyl methanesulfonate (350 mg, 863 umol, Intermediate YX) and tert-butyl N-(4piperidylmethyl)carbamate (222 mg, 1.04 mmol, CAS# 135632 0) in a mixed solvent of CHCh (5 mL) and ACN (5 mL) was added K2CO3 (239 mg, 1.73 mmol). The reaction mixture was stirred at 65 °C for 12 hrs. On completion, the mixture was diluted with water (50 mL), then extracted with EA (2 X 50 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 150*50mm*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 10%-40%, 10 min) to give the title compound (165 mg, 37% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-» δ 11.11 (s, IH), 7.23 (s, IH), 7.11 - 7.06 (m, 2H), 6.83 (t, J = 5.6 Hz, IH), 5.37 (dd, J = 5.2, 12.8 Hz, IH), 3.32 (s, 3H), 2.95 - 2.84 (m, 3H), 2.79 (t, J= 6.4 Hz, 2H), 2.74 - 2.54 (m, 6H), 2.06 - 1.96 (m, 3H), 1.64 - 1.54 (m, 2H), 1.36 (s, 9H), 1.35-1.31 (m, IH), 1.17-1.04 (m, 2H).

[004694] Step 2 - 3-[5-[4-[4-(Aminomethvl)-l-piperidvl1but-l-vnvl1 methyl oxobenzimidazol-l-yl] piperi dine-2,6-di one

[004695] To a solution of tert-butyl N-[[l-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] but ynyl] piperidyl]methyl]carbamate (90.0 mg, 172 umol) in DCM (5

1441 mL) was added ZnBr2 (387 mg, 1.72 mmol). The reaction mixture was stirred at 20 °C for 10 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (70.0 mg, 96% yield) as a white solid. LC-MS (ESI+) m/z 424.3 (M+H)+.

[004696] 2-[2-[2-(Methvlamino)ethoxy]ethvl]isoindoline-l,3-dione (Intermediate YZ)

HO n&#1523;Boc

(Boc)2O

MeOH

MsCI, TEA

DCM

YZ

[004697] Step 1 - N-r2-(2-hydroxyethoxy)ethyl1formamide

[004698] A solution of 2-(2-aminoethoxy)ethanol (5.00 g, 47.5 mmol, CAS# 929 6) in ethyl formate (18.4 g, 248 mmol, CAS# 109 4) was stirred at 90 °C for 6 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (6.30 g, 99% yield) as yellow oil. LC-MS (ESI+) m/z 134.1 (M+H)+.

[004699] Step 2 - 2-l2-(Methylamino)ethoxy1ethanol

[004700] To a solution of LiAlH4 (2.16 g, 56.7 mmol) in THF (30.0 mL) was added a solution of N-[2-(2-hydroxyethoxy)ethyl]formamide (6.30 g, 47.3 mmol) in THF (30.0 mL) dropwise at 0 °C. The mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was quenched with a solution of 15% NaOH (20 mL). Thereafter, 50 g anhydrous sodium sulfate was added, and the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (5.64 g, 100% yield) as yellow oil.

[004701] Step 3 - Tert-butyl N-r2-(2-hydroxyethoxy)ethyl1-N-methyl-carbamate

[004702] To a solution of 2-[2-(methylamino)ethoxy]ethanol (5.60 g, 46.9 mmol) in MeOH (70.0 mL) was added (Boc)2O (15.3 g, 70.4 mmol), the mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column

1442 (PE: EA=2: 1) to give the title compound (8.00 g, 77% yield) as colorless oil. 1H NMR. (400MHz, CDCh) δ 3.80 - 3.68 (m, 2H), 3.67 - 3.52 (m, 4H), 3.48 - 3.33 (m, 2H), 2.92 (s, 3H), 1.47 (s, 9H). [004703] Step 4 - 2-r2-rTert-butoxvcarbonvl(methyl)amino1ethoxy1ethyl methanesulfonate [004704] To a solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (1.00 g, 4.56 mmol), TEA(1.38 g, 13.6 mmol) in DCM (10.0 mL) was added MsCl (783 mg, 6.84 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 hr. On completion, the mixture was diluted with DCM (20 mL), washed with H2O (3 X 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.28 g, 94% yield) as yellow oil. 1HNMR (400MHz, CDCh) δ 4.33 - 4.26 (m, 2H), 3.68 - 3.62 (m, 2H), 3.59 - 3.48 (m, 2H), 3.39 - 3.28 (m, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 1.39 (s, 9H).

[004705] Step 5 -Tert-butyl N-r2-r2-(L3-dioxoisoindolin yl)ethoxy1ethyl1-N-methylcarbamate

[004706] To a solution of 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethyl methanesulfonate (1.08 g, 3.63 mmol) in DMF (10.0 mL) was added (l,3-dioxoisoindolin-2yl)potassium (1.01 g, 5.45 mmol). The mixture was stirred at 80 °C for 3 hrs. On completion, the mixture was diluted with H2O (40 mL), then extracted with EA (3 X 30 mL). The organic layers were washed with brine (2 X 30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column (PE: EA= 5: 1) to give the title compound (1.2 g, 94% yield) as white solid. 1HNMR (400MHz, DMSO4) δ 7.89 - 7.83 (m, 4H), 3.81-3.71 (m, 2H), 3.68 - 3.56 (m, 2H), 3.54 - 3.42 (m, 2H), 3.28 - 3.20 (m, 2H), 2.69 (s, 3H), 1.32 (s, 9H). [004707] Step 6 - 2-r2-r2-(Methylamino)ethoxy1ethyl1isoindoline-L3-dione

[004708] To a solution of tert-butyl N-[2-[2-(l,3-dioxoisoindolin yl)ethoxy]ethyl]-Nmethyl-carbamate (200 mg, 574 umol) in DCM (3.00 mL) was added HCI/dioxane (4.00 M, 4.00 mL). The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (160 mg, 97% yield, HCI) as white solid. 1H NMR (400MHz, DMSO4) δ 8.84 (s, IH), 7.92 - 7.84 (m, 4H), 3.84 - 3.76 (m, 2H), 3.73 - 3.65 (m, 4H), 3.10 2.92 (m, 2H), 2.49 (s, 3H).

[004709] Tert-butyl N-[[(2S) (2-aminoethvl)morDholin vl]methvl]-N-methylcarbamate (Intermediate ZA)

1443

H2N^^n^^n.B0c A° '

ZA

[004710] Step 1 - Tert-butyl Ν-ΓΓ(25) [2-(1 J-dioxoisoindolin yl)ethyl1morpholin-2yl1methyl1-N-methyl- carbamate

[004711] To a solution of tert-butyl N-methyl-N-[[(2S)-morpholin yl]methyl]carbamate (1.00 g, 4.34 mmol, Intermediate YM) in ACN (30 mL) was added K2CO3 (535 mg, 13.0 mmol) and 2-(2-bromoethyl)isoindoline-1,3-dione (1.21 g, 4.77 mmol, CAS# 574 1) and KI (72.1 mg, 434 umol). The reaction mixture was stirred at 80 °C for 12 hrs. On completion, the mixture was diluted with H2O (20 mL), then extracted with EA (2 X 20 mL). The combined organic layers were washed with brine (2 X 20 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column (PE: EA = 1:1) to give the title compound (1.75 g, 100% yield) as yellow oil. 1HNMR. (400 MHz, CDC13) δ 7.89 - 7.81 (m, 2H), 7.77 - 7.67 (m, 2H), 3.96 - 3.75 (m, 3H), 3.65 - 3.48 (m, 2H), 3.42 - 3.29 (m, IH), 3.14 (dd, J= 6.4, 14.4 Hz, IH), 2.89 (s, 3H), 2.86 - 2.73 (m, 2H), 2.70 - 2.51 (m, 2H), 2.17 (t, J= 10.4 Hz, IH), 1.93 - 1.90 (m, IH), 1.45 (s, 9H).

[004712] Step 2 - Tert-butyl N-rr(2S) (2-aminoethyl)morpholin yl1methyl1-N-methylcarbamate

[004713] To a solution of tert-butyl N-[[(2S) [2-(l,3-dioxoisoindolin-2yl)ethyl]morpholin yl]methyl]-N- methyl-carbamate (1.00 g, 2.48 mmol) in EtOH (10 mL) was added ΝΗ2ΝΗ2&#905;2Ο (633 mg, 12.4 mmol). The reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (650 mg, 96% yield) as yellow solid. 1HNMR (400MHz, CDC13) δ 3.94 - 3.81 (m, IH), 3.76 - 3.60 (m, 2H), 3.53 - 3.30 (m, IH), 3.24 - 3.09 (m, IH), 2.92 (s, 3H), 2.82 - 2.78 (m, 2H), 2.75 - 2.71 (m, IH), 2.68 - 2.65 (m, IH), 2.43 (t, J= 6.0 Hz, 2H), 2.51 - 2.35 (m, IH), 2.17

1444

2.15 (, IH), 1.88 (t, J= 10.4 Hz, IH), 1.46 (s, 9H).

[004714] Benzyl N-[[l-(2.,6-dioxo piperidvl) methvl oxo-benzimidazol-5yl]methyl]-N-[2-[(2R) (methylaminomethyl)morDholin yl] ethyl] carbamate (Intermediate ZB)

ZA

HCI

[004715] Step 1 - Tert-butyl N-rr(2S) r2-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 methylamino1ethyl1morpholin yl1methyl1-N-methyl-carbamate

[004716] To a solution of 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-5carbaldehyde (400 mg, 1.04 mmol, Intermediate SK) and tert-butyl N-[[(2S) (2aminoethyl)morpholin yl]methyl]-N- methyl-carbamate (428 mg, 1.57 mmol, Intermediate ZA) in a mixed solvent of THF (5 mL) and DMF (2 mL) was added HO Ac (62 mg, 1.04 mmol). The reaction mixture was stirred at 25 °C for 0.5 hr. Then, NaBH(OAc)3 (266 mg, 1.25 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was quenched with water (0.5 mL) and concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (410 mg, 61% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 11.10(s, IH), 7.24 (s, IH), 7.16 - 7.02 (m, 2H), 5.37 (dd, J = 5.6, 12.8 Hz, IH), 4.53 - 4.50 (m, IH), 3.91 (s, 2H), 3.80 - 3.75 (m, 2H), 3.35 (s, 3H), 3.23 1445

3.17 (m, 2H), 2.92 - 2.87 (m, IH), 2.80 - 2.73 (m, 4H), 2.69 - 2.58 (m, 7H), 2.06 - 1.98 (m, 2H), 1.82- 1.74 (m, IH), 1.36 (s, 9H).

[004717] Step 2 - Tert-butyl N-rr(2S) r2-rbenzvloxvcarbonvl-rr1-(2,6-dioxo piperidyl)3-methyl oxo-benzimidazol yl1methyl1amino1ethyl1morpholin yl1methyl1-N-methylcarbamate

[004718] To a solution of tert-butyl N-[[(2S) [2-[[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol- 5-yl]methylamino]ethyl]morpholin yl]methyl]-N-methyl-carbamate (100 mg, 184 umol) in THF (5 mL) was added TEA (55.7 mg, 550 umol). Then, CbzCl (47.0 mg, 275 umol) was added. The reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (50.0 mg, 38% yield) as white solid. 1HNMR (400MHz, DMSO-t/6) δ 11.09 (s, IH), 7.49 - 7.26 (m, 5H), 7.11 - 6.90 (m, 3H), 5.36 (dd, J = 5.2, 12.8 Hz, IH), 5.13 (s, 2H), 4.52 (s, 2H), 3.75 - 3.67 (m, IH), 3.57 - 3.44 (m, 5H), 3.22 3.11 (m, 4H), 2.96 - 2.90 (m, IH), 2.79 (s, 2H), 2.73 - 2.66 (m, 2H), 2.62 - 2.55 (m, 3H), 2.43 2.37 (m, 2H), 2.06 - 1.96 (m, 2H), 1.80 - 1.68 (m, IH), 1.37 (s, 9H); LC-MS (ESI+) m/z 679.2 (M+H)+.

[004719] Step 3 - Benzyl N-rr1-(2,6-dioxo piperidvl) methyl oxo-benzimidazol-5yl1methyl1-N-[2-r(2R) (methylaminomethyl)morpholin yl1ethyl1carbamate

[004720] To a solution of tert-butyl N-[[(2S) [2-[benzyloxycarbonyl-[[l-(2,6-dioxo-3piperi dyl) methyl oxo-benzimidazol yl]methyl]amino]ethyl]morpholin yl]methyl]-Nmethyl-carbamate (50.0 mg, 73.6 umol) inDCM (2 mL) was addedHCI/dioxane (4 M, 1 mL). The reaction mixture was stirred at 20 °C for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (45.0 mg, 99% yield) as white solid. LC-MS (ESI+) m/z 579.2 (M+H)+.

[004721] 3-[3-Methvl oxo [2-(4-DiDeridvl)ethvnvl]benzimidazol-l-yl]DiDeridine2.,6-dione (Intermediate ZD)

1446

[004722] Step 1 - Tert-butyl 4-[2-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1ethynyl1 piperidine carboxylate

[004723] To a solution of tert-butyl 4-ethynylpiperidine carboxylate (743 mg, 3.55 mmol CAS# 287192 6) and 3-(5- bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (600 mg, 1.77 mmol, Intermediate HN) in DMF (20 mL) was added Pd(PPh3)2C12 (249 mg, 355 umol), Cui (67.6 mg, 355 umol), 4A molecular sieves (80 mg) and Cs2CO3 (2.89 g, 8.87 mmol). The mixture was de-gassed and then heated at 80 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (500 mg, 58% yield) as brown solid. 1H NMR (400 MHz, DMSO-6#)5 11.11 (s, IH), 7.25 (s, IH), 7.09 (s,, 2H), 5.37 (dd, J= 5.6, 12.8 Hz, IH), 3.70-3.59 (m, 2H), 3.33 - 3.33 (m, 3H), 3.19 - 3.08 (m, 2H), 2.95 - 2.80 (m, 2H), 2.75 - 2.62 (m, 2H), 2.07 1.98 (m, IH), 2.00 - 1.81 (m, 2H), 1.56 - 1.45 (m, 2H), 1.40 (s, 9H); LC-MS (ESI+) m/z 489.3 (M+Na)+.

[004724] Step 2 - 3-[3-Methyl oxo [2-(4-piperidyl)ethynyl1benzimidazol-lyl1piperidine-2,6-dione

[004725] To a solution of tert-butyl 4-[2-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]ethynyl] piperidine carboxylate (60.0 mg, 129 umol) in DCM (5 mL) was added ZnBr2 (347 mg, 1.54 mmol, 77.2 uL). The mixture was stirred at 25 °C for 24 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (40.0 mg, 68%

1447 yield) as yellow solid. LC-MS (ESI+) m/z 367.1 (M+H)+.

[004726] Tert-butyl (SRl-S-piperazin-l-ylpyrrolidine-l-carboxylate (Intermediate ZE) n _ Cbz-l/ \1H &#1498;&#1470;-/ .&#1524; oc X/ Cbz-N \ Boc^&#1470;&#1470;C ,B0C TFA . Z^m

N MSL.!, I LA * MsO&#1524;./ N _________________&#1498;___N

DCM '— TEA, KI, AON

Pd/C, H2

MeOH

ZE

[004727] Step 1 - Tert-butyl (3 S) methylsulfonyloxypyrrolidine-l -carboxylate

[004728] To a solution of tert-butyl (3S) hydroxypyrrolidine carboxylate (5.00 g, 26.7 mmol, CAS# 101469 5) in DCM (80 mL) was added TEA(8.11 g, 80.1 mmol) and MsCI (3.98 g, 34.7 mmol) at 0 °C. The mixture was then stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was washed with water (3 X 60 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.00 g, 95% yield) as light yellow oil. 1H NMR (400 MHz, CDCh) δ 5.30 - 5.23 (m, IH), 3.70 - 3.42 (m, 4H), 3.05 (s, 3H), 2.38 - 2.08 (m, 2H), 1.47 (s, 9H).

[004729] Step 2 - Benzyl 4-r(3R)-l-tert-butoxvcarbonvlpvrrolidin yl]piperazine-lcarboxylate

[004730] To a solution of tert-butyl (3S) methylsulfonyloxypyrrolidine-l-carboxylate (3 g, 11.3 mmol) and benzyl piperazine-l-carboxylate (4.98 g, 22.61 mmol, CAS# 31166 6) in ACN (30 mL) was added TEA (3.43 g, 33.9 mmol) and KI (2.82 g, 16.9 mmol). The mixture was stirred as 80 °C for 40 hrs. On completion, the mixture was concentrated in vacuo to give a residue. The reaction mixture was diluted with water (30 mL) and extracted with EA (3 X 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, PE/EA =3/1) to give the title compound (1.35 g, 30% yield) as light yellow oil. 1HNMR (400 MHz, CDCh) δ 7.43 - 7.28 (m, 5H), 5.14 (s, 2H), 3.75 - 3.38 (m, 6H), 3.34 - 3.20 (m, IH), 3.09 - 3.05(m, IH), 2.86 - 2.70 (m, IH), 2.61 - 2.31 (m, 4H), 2.12 - 2.05 (m, IH), 1.85 - 1.75 (m, IH), 1.46 (s, 9H).

[004731] Step 3 - Tert-butyl (3R) piperazin ylpyrrolidine-l-carboxylate

[004732] To a solution of benzyl 4-[(3R)-l-tert-butoxycarbonylpyrrolidin yl]piperazine-lcarboxylate (1.20 g, 3.08 mmol) in MeOH (20 mL) was added Pd/C (400 mg, 10 wt%) under N2.

1448

The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred at 25 °C for 16 hours under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (780 mg, 96% yield) as colorless oil. 1HNMR (400 MHz, CDCh) δ 3.76 - 3.48 (m, 2H), 3.30 - 3.19 (m, IH), 3.08 (t, J = 92 Hz, IH), 2.90 (t, J= 4.4 Hz, 3H), 2.83 - 2.69 (m, IH), 2.62 - 2.34 (m, 4H), 2.13 - 2.02 (m, IH), 1.73 - 1.67 (m, IH), 1.45 (s, 9H).

[004733] 3- [3-Methyl oxo [[4- [(3R)-pyrrolidin vl] piperazin-lyl]methyl]benzimidazol-l- yl]piperidine-2.,6-dione (Intermediate ZF)

HCI/dioxane

DCM

[004734] Step 1 - Tert-butyl (3R) r4-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1methyl1 piperazin-1 -yllpyrrolidine-1 -carboxylate

[004735] To a mixture of tert-butyl (3R) piperazin ylpyrrolidine-l-carboxylate (200 mg, 783 umol, Intermediate ZE) in a mixed solvent of THF (4 mL) and DMF (0.2 mL) was added 1 (2,6-dioxo piperidyl) methyl oxo-benzimidazole carbaldehyde (225 mg, 783 umol, Intermediate SK) and HOAc (9.41 mg, 156 umol). The mixture was stirred at 25 °C for 30 minutes. After that, NaBH(OAc)3 (331 mg, 1.57 mmol) was added. The mixture was stirred 25 °C for 72 hours. On completion, the reaction mixture was quenched by water (10 mL), and then extracted with EA (3 X 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column:

1449

Phenomenex Synergi Max-RP 150*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound (290 mg, 70% yield) as white solid. 1H NMR (400 MHz, DM SO-0/6) δ 11.08 (s, IH), 7.11 - 6.91 (m, 3H), 5.35 (dd, J= 5.2, 12.8 Hz, IH), 3.48 (s, 2H), 3.45 (s, IH), 3.42 - 3.34 (m, IH), 3.33 (s, 3H), 3.21 - 3.10 (m, IH), 2.98 - 2.84 (m, 2H), 2.75 - 2.59 (m, 3H), 2.45 2.3 (m, 8H), 2.06 - 1.93 (m, 2H), 1.71 - 1.51 (m, IH), 1.38 (s, 9H); LC-MS (ESI+) m/z 527.2 (M+H)+.

[004736] Step 2 - 3-r3-Methyl oxo rr4-r(3R)-pyrrolidin yl1piperazin-lyl1methyl1benzimidazol-l- yl1piperidine-2,6-dione

[004737] To a solution of tert-butyl (3R) [4-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl]piperazin-l-yl]pynOlidine-l-carboxylate (120 mg, 227 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 2.28 mL). The mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (105 mg, 99% yield, HCI) as white solid. LC-MS (ESI+) m/z 427.5 (M+H)+.

[004738] Tert - butyl methyl(3-oxopropyl)carbamate (Intermediate ZG)

DMP 0HC\___ ^-BOC ------&#9658; N-B0C / DCM /

ZG

[004739] To a solution of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (1.00 g, 5.28 mmol, CAS# 98642 5) in DCM (20 mL) was added DMP (3.36 g, 7.93 mmol) at 20 °C. Then the reaction mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was diluted with petroleum ether (10 mL) and stirred for 10 minutes, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (750 mg, 50% yield) as colorless oil. 1HNMR (400 MHz, CDCh) δ 9.78 (s, IH), 3.53 - 3.47 (m, 2H), 2.85 (s, 3H), 2.66 - 2.62 (m, 2H), 1.43(s, 9H).

[004740] 3-(3-Methvl oxo (piperidin vl)-2,3-dihydro-lH-benzo[d]imidazol-lyl)piperidine-2,6-dione hydrochloride (Intermediate ZH)

1450

Pd/C, H2

THF

[004741] Step 1 - Tert - butyl4-(l-(2,6-di oxopiperi din yl) methyl oxo-2,3-dihydrolH-benzo[d1imidazol yl)-5,6-dihydropyridine-l(2H)-carboxylate

[004742] A mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, Intermediate HP), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan yl)3,6-dihydro-2H-pyridine-l-carboxylate (1.19 g, 3.84 mmol, CAS# 286961 6), XPhos-Pd-G3 (376 mg, 0.444 mmol), K3PO4 (1.88 g, 8.87 mmol) in dioxane (20 mL) and water (2 mL) was degassed and purged with N2 three times. The mixture was stirred at 60 °C for 3 hours under N2 atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (1.00 g, 75% yield) as white solid. 1HNMR (400 MHz, DMSO4) δ 11.09 (s, IH), 7.10 - 6.95 (m, 2H), 6.82 (d, J = &#906;2 Hz, IH), 5.40 - 5.35 (m, IH), 3.99 (s, 3H), 3.67 - 3.50 (m, 3H), 2.95 - 2.83 (m ,IH), 2.80 - 2.55 (m, 3H), 2.43 - 2.30 (m ,3H), 2.05 - 1.95 (m, IH), 1.44 (s, 9H); LC-MS (ESI+) m/z 441.0 (M+H)+.

[004743] Step 2 - Tert - butyl 4-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3-dihydrolH-benzo[d1imidazol- 4-yl)piperidine-l-carboxylate

[004744] To a solution of tert - butyl 4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]-3,6- dihydro-2H-pyridine-l-carboxylate (900 mg, 2.04 mmol) in THF (270 mL)was added Pd/C (180 mg, 10 wt%) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 30 °C for 48 hours under H2 (50 Psi.). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (900 mg, 92% yield) as white solid. LC-MS (ESI+) m/z 387.2 (M+H-56)+.

1451

[004745] Step 3 - 3-(3-Methyl oxo (piperidin yl)-2,3-dihydro-lH-benzo[d1imidazoll-yl)piperidine-2,6-dione hydrochloride

[004746] To a solution of tert-butyl 4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]piperidine-l-carboxylate (1.00 g, 2.26 mmol) in DCM (10 mL) was added HCl/dioxane (4mol/L, 5 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (900 mg, 88% yield) as white solid. LC-MS (ESI+) m/z 343.2 (M+H)+.

[004747] 32(32ν[6(11ν12£()£32(ηΗΜ11ν1η2η&#912;ηο)2Π1[!Σ1)12&#912;12££&#944;1&#912;2Ξ£Σ1)222£&#970;θΞ232&#1524;^ lH-benzo[d]imidazol-l-yl)DiDeridine-2.,6-dione hydrochloride (Intermediate ZI)

ZG

[004748] Step 1- Tert - butyl (3-(4-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3 dihydro-lH-benzord1imidazol yl)piperidin-l-yl)propyl)(methyl)carbamate

[004749] To a solution of 3-[3-methyl oxo (4-piperidyl)benzimidazol-l-yl]piperidine2,6-dione (350 mg, 0.924 mmol, Intermediate ZH) in THF (5 mL) and DMF (1 mL) was added Et3N (140 mg, 1.39 mmol). Then the reaction mixture was stirred at 20 °C for 0.5 hour. Then HOAc (83.2 mg, 1.39 mmol) and tert-butyl N-methyl-N-(3-oxopropyl)carbamate (580 mg, 2.04 mmol, Intermediate ZG) were added to the above mixture. The reaction mixture was stirred at 20°C for 0.5 hour. NaBH(OAc)3 (392 mg, 1.85 mmol) was added to the reaction mixture and stirred at 20 °C for 16 hours. On completion, the reaction mixture was quenched with water (0.5 mL) and concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (450 mg, 83% yield) as off-white solid. LC-MS (ESI+) m/z 514.4 (M+H)+.

1452

[004750] Step 2 - 3-(3-Methyl (l-(3-(methylamino)propyl)piperidin yl) oxo-2,3dihydro-lH-benzord1imidazol-l-yl)piperidine-2,6-dione hydrochloride

[004751] To a solution of tert-butyl N-[3-[4-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]-l- piperidyl]propyl]-N-methyl-carbamate (450 mg, 0.876 mmol) in DCM (5 mL) was added HC1/EA (4 mol/L, 2 mL), the the reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (390 mg, 99% yield) as a white solid. LC-MS (ESI+) m/z 414.3 (M+H)+.

[004752] 3-(3-Methvl (3-((R) (2-(methvlamino)ethvl)morDholino)DroDvl) oxo2,3-dihvdro-lH-benzo[d]imidazol-l-vl)DiDeridine-2,6-dione hydrobromide (Intermediate

Pd(OH)2/C, Pd/C

H2, THF

HBr/HOAc

DCM

[004753] Step 1 - Benzyl (2-((2R) (3-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3 dihydro- IH-benzo[ d1imidazol yl)prop yn-1 -yl)morpholin yl)ethyl)(methyl)carbamate

[004754] A mixture of benzyl N-methyl-N-[2-[(2R) prop ynylmorpholin-2

1453 yl]ethyl]carbamate (700 mg, 2.07 mmol, Intermediate TV), 3-(4-bromo methyl oxo-2,3dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione (982 mg, 3.11 mmol, Intermediate HP), Pd(PPh3)2C12 (145 mg, 0.207 mmol), Cui (39.4 mg, 0.207 mmol) and Cs2CO3 (1.35 g, 4.14 mmol) in DMF (10 mL) was degassed and purged with N2 three times.Then the mixture was stirred at 80 °C for 2 hours under N2 atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% of FA condition) to give the title compound (1.10 g, 73%yield) as a yellow solid. 1H NMR (400 MHz, CDCh) 511.11 ( s, IH), 7.40 - 7.30 (s, 5H), 7.13 (dd, 7=16.0 Hz, 7= 7.6 Hz, 2H), 7.06 - 6.95 (m, IH), 5.47 - 5.32 (m, IH), 5.05 (s, 2H), 3.90 - 3.75 (m, IH), 3.63 (s, 3H), 3.56 (s, 3H), 3.27 - 3.15 (m, 2H), 2.90 - 2.80 (m, 5H), 2.75 - 2.55 (m, 4H), 2.35 - 2.25 (m, IH), 2.10 - 1.95 (m, 2H), 1.76 1.72 (m, IH), 1.65-1.55 (m, 2H); LC-MS (ESI+) m/z 574.1 (M+H)+.

[004755] Step 2 - Benzyl (2-((2R) (3-(l-(2,6-dioxopiperidin yl) methyl oxo-2,3dihydro-lH-benzo[d1 imidazol yl)propyl)morpholin yl)ethyl)(methyl)carbamate

[004756] To a solution of benzyl N-[2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]prop ynyl]morpholin yl]ethyl]-N-methyl-carbamate (1.00 g, 1.74 mmol) in THF (200 mL) was added Pd/C (200 mg, 5 wt%) and Pd(OH)2/C (200 mg, 10 wt%) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C for 48 hours under H2 (15 psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.00 g, 99% yield) as yellow-white solid. LC-MS (ESI+) m/z 578.2 (M+H)+.

[004757] Step 3 - 3-(3-Methyl (3-((R) (2-(methylamino)ethyl)morpholino)propyl)-2oxo-2,3-dihydro-lH-benzo[d1imidazol-l-yl)piperidine-2,6-dione hydrobromide

[004758] To a solution of benzyl N-[2-[(2R) [3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propyl]morpholin yl]ethyl]-N-methyl-carbamate (1.00 g, 1.73 mmol) in DCM (10 mL) was added HBr/HOAc (4 mL, 40% solution). The mixture was stirred at 20 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo. Then the residue was purified by reverse phase (0.1% of FA condition) to give the title compound (700 mg, 64% yield) as off-white solid. LC-MS (ESI+) m/z 444.4 (M+H)+.

[004759] 3-[3-Methvl oxo [3-(4-piperidvloxv)propyl]benzimidazol-l-vl]piperidine2,6-dione (Intermediate ZM)

1454

[004760] Step 1 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1prop ynoxy1 piperidine-l-carboxylate

[004761] To a mixture of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (350 mg, 1.04 mmol, Intermediate HN) and tert-butyl 4-prop ynoxypiperidine-lcarboxylate (371 mg, 1.55 mmol, Intermediate TM) in DMF (20 mL) was added Pd(PPh3)2C12 (72.6 mg, 103 umol), Cui (39.4 mg, 207 umol), Cs2CO3 (1.35 g, 4.14 mmol) and 4A molecular sieves (200 mg, 1.04 mmol) in one portion at 25 °C under N2. The reaction mixture was stirred at 80 °C for 2 hours. On completion, the reaction mixture was quenched by addition water (0.5 mL) at 25 °C, and then extracted with EA (3 X 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA condition) to give the title compound (300 mg, 58% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) δ 8.14 (s, IH), 7.23 -7.17(m, IH), 7.12 (d, J= 1.2 Hz, IH), 6.75 (d, J= 8.1 Hz, IH), 5.24 - 5.17 (m, IH), 4.43 (s, 2H), 3.85 - 3.72 (m, 3H), 3.43 (s, 3H), 3.18 - 3.09 (m, 2H), 3.01 - 2.92 (m, IH), 2.90 - 2.67 (m, 2H), 2.30 - 2.20 (m, IH), 1.94 - 1.86 (m, 2H), 1.64 - 1.57 (m, 2H), 1.47 (s, 9H); LC-MS (ESI+) m/z 519.3 (M+Na)+.

[004762] Step 2 - Tert-butyl 4-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1propoxy1piperi dine carboxylate

[004763] To a solution of tert-butyl 4-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy] piperidine-l-carboxylate (300 mg, 604 umol) in THF (4 mL)

1455 was added Pd/C (50 mg, 10 wt%) and Pd(0H)2/C (50 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred at 25 °C for 2 hours under H2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA condition) to give the title compound (300 mg, 84% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) δ 8.24 (s, IH), 6.95 - 6.85 (m, 2H), 6.73 (d, J = 8.2 Hz, IH), 5.26 - 5.18 (m, IH), 3.81 - 3.73 (m, 2H), 3.49 - 3.42 (m, 6H), 3.15 - 3.05 (m, 2H), 2.99 - 2.82 (m, 2H), 2.75 (t, J= 7.6 Hz, 3H), 2.28 2.19 (m, IH), 1.95 - 1.77 (m, 4H), 1.53 (d, J= 8.8 Hz, 2H), 1.47 (s, 9H); LC-MS (ESI+) m/z 401.0 (M+H-100)+.

[004764] Step 3 - 3-r3-Methyl oxo [3-(4-piperidyloxy)propyl1benzimidazol-lyl1piperidine-2,6-dione

[004765] To a mixture of tert-butyl 4-[3-[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] piperidine carboxylate (270 mg, 539 umol) in DCM (4 mL) was added TFA (1.84 g, 16.2 mmol) at 25 °C. The mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (TFA condition) to give the title compound (162 mg, 58% yield, TFA salt) as a yellow solid. LC-MS (ESI+) m/z 401.0 (M+H)+.

[004766] 3-[4-[3-(Azetidin vloxv)DroDvl] methvl oxo-benzimidazol-lyl]DiDeridine-2.,6-dione (Intermediate ZN)

[004767] Step 1 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol

1456

4-yl1prop ynoxy1 azetidine-1 -carboxylate

[004768] To a mixture of tert-butyl 3-prop ynoxyazetidine-l-carboxylate (499 mg, 2.37 mmol, Intermediate YV) and 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (400 mg, 1.18 mmol, Intermediate HP) in DMF (3 mL) was added Cui (22.5 mg, 118 umol), Cs2CO3 (1.93 g, 5.91 mmol), Pd(PPh3)2C12 (83.0 mg, 118 umol) and 4A molecular sieves (100 mg). The reaction mixture was stirred at 80 °C for 4 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase (0.1 % FA condition) to give the title compound (400 mg, 72% yield) as brown solid. 1H NMR (400 MHz, DMSOQ) δ 11.11 (s, IH), 7.21 - 7.16 (m, IH), 7.14-7.11 (m, IH), 7.06 - 7.01 (m, IH), 5.42 5.37 (m, IH), 4.49 - 4.45 (m, 3H), 4.09 - 4.04 (m, 2H), 3.77 - 3.72 (m, 2H), 3.63 (s, 3H), 2.92 2.84 (m, IH), 2.73 - 2.62 (m, 2H), 2.07 - 2.00 (m, IH), 1.37 (s, 9H).

[004769] Step 2 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol4-yl1propoxy1 azetidine-1 -carboxylate

[004770] To a mixture of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]azetidine-l-carboxylate (400 mg, 853 umol) in THF (10 mL) was added Pd/C (150 mg, 10 wt%) and Pd(OH)2/C (150 mg, 10 wt%). The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 Psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (300 mg, 74% yield) as light yellow solid. LC-MS (ESI+) m/z 417.2 (M+H-56)+.

[004771] Step 3 - 3-r4-r3-(Azetidin yloxy)propyl1 methyl oxo-benzimidazol-lyl1piperidine-2,6-dione

[004772] To a mixture of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] azetidine-l-carboxylate (290 mg, 613.71 umol) in DCM (3 mL) was added TFA (44.6 g, 391 mmol, 29.0 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (298 mg, 99% yield, TFA salt) as red oil. LC-MS (ESI+) m/z 373.2 (M+H)+.

[004773] 3- [4-[3-(4-Piperidvloxv)propvl]pyrido [2,3-b] indol yl] piperidine-2,6-dione (Intermediate ZO)

1457

ZO

[004774] Step 1 - Tert-butyl 4-r3-r9-(2,6-dioxo piperidyl)pyridor2,3-b1indol yl1prop-2ynoxylpiperidine carboxylate

[004775] To a solution 3-(4-bromopyrido[2,3-b]indol yl)piperidine-2,6-dione (400 mg, 1.12 mmol, Intermediate XY) and tert-butyl 4-prop ynoxypiperidine carboxylate (534 mg, 2.23 mmol, Intermediate TM) in DMF (8 mL) was added Pd(PPh3)2C12 (157 mg, 223 umol), Cui (42.5 mg, 223 umol), Cs2CO3 (1.82 g, 5.58 mmol) and 4A molecular sieves (40 mg). The mixture was de-gassed and then heated at 80 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (200 mg, 34% yield) as brown solid. 1H NMR (400 MHz, DMSO-76) δ 11.15 (s, IH), 8.49 (d, J= 7.6 Hz, IH), 8.42 (d,7=5.2 Hz, IH), 7.72 - 7.64 (m, IH), 7.62 - 7.56 (m, IH), 7.36 - 7.33 (m, IH), 7.32 - 7.29 (m, IH), 6.06 (s, IH), 4.71 (s, 2H), 3.88 - 3.84 (m, IH), 3.70 - 3.65 (m, 2H), 3.10 - 3.05 (m, 2H), 3.05 - 2.95 (m, IH), 2.77 - 2.68 (m, IH), 2.61 (s, IH), 2.20 - 2.11 (m, IH), 1.96 - 1.88 (m, 2H), 1.52 - 1.44 (m, 2H), 1.39 (s, 9H); LC-MS (ESI+) m/z 539.3 (M+Na)+.

[004776] Step 2 - Tert-butyl 4-r3-r9-(2,6-dioxo piperidvl)pvrido[2,3-b1indol-4yl1propoxy1piperidine-l - carboxylate

1458

[004777] To a solution of tert-butyl 4-[3-[9-(2,6-dioxo piperidyl)pyrido[2,3-b]indol-4yl]prop ynoxy] piperidine carboxylate (200 mg, 387 umol in THF (5 mL) was added Pd(OH)2 (40.0 mg, 10wt%), Pd/C (40.0 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 15 hours under H2 (15 psi). On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (120 mg, 59% yield) as white solid. 1H NMR (400 MHz, DMSO-c/) δ 11.13 (s, IH), 8.31 (d, 7= 5.2 Hz, IH), 8.24 (d, J= 7.6 Hz, IH), 7.67-7.58 (m, IH), 7.55 -7.47 (m, IH), 7.28 (t, J= 7.6 Hz, IH), 7.10 (d, J= 5.2 Hz, IH), 6.18-5.92 (m, IH), 3.67 - 3.47 (m, 6H), 3.29 (s, IH), 3.28 - 3.21 (m, 2H), 3.17 - 2.93 (m, 4H), 2.15 - 2.07 (m, IH), 2.03 - 1.93 (m, 2H), 1.86 - 1.76 (m, 2H), 1.39 (s, 9H), 1.35 (s, IH); LC-MS (ESI+) m/z 521.3 (M+Na)+.

[004778] St ep 3 - 3-r4-r3-(4-Piperidvloxv)propvl1pvridor2,3-b1indol yl1piperidine-2,6-dione

[004779] To a mixture of tert-butyl 4-[3-[9-(2, 6-dioxo piperidyl)pyrido[2,3-b]indol yl] propoxy]piperidine carboxylate (100 mg, 192 umol) in DCM (2 mL) was added HCI/dioxane (2 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (80.0 mg, 91% yield) as brown solid. LCMS (ESI+) m/z 421.3 (M+H)+.

[004780] 3-[3-Methvl [3-[2-(methvlamino)ethoxv]DroDvl] oxo-benzimidazol-lyl]DiDeridine-2.,6-dione (Intermediate ZP)

1459

HCI/dioxane

DCM

Pd/C, Pd(OH)2/C

H2, THF

[004781] Step 1 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxy1ethyl1-N-methyl-carbamate

[004782] 3-(4-bromo methyl oxo-benzimidazol-l-yl )piperi dine-2,6-dione (400 mg,

1.18 mmol, Intermediate HP), tert-butyl N-methyl-N-(2-prop ynoxyethyl)carbamate (440 mg, 2.06 mmol, Intermediate GK), Pd(PPh3)2C12 (166 mg, 237 umol), Cui (45.1 mg, 237 umol), 4A molecular sieves (400 mg) and Cs2CO3 (1.54 g, 4.73 mmol) in DMF (5 mL) was de-gassed and then heated at 80 °C for 2 hours under N2. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reversed-phase (0.1% FA condition) to give the title compound (310 mg, 39% yield) as a yellow solid. LC-MS (ESI+) m/z 415.1 (M+H-56)+.

[004783] Step 2 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1 ethyl1-N-methyl-carbamate

[004784] To a solution of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop- 2-ynoxy]ethyl]-Nmethyl-carbamate (390 mg, 829 umol) in THF (10 mL) was added Pd/C (0.1 g, 10% wt) and Pd(OH)2/C (0.1 g, 20% wt). The suspension was degassed under vacuum and purged with H2 several times. The reaction mixture was stirred at 25 °C for 12 hours under H2 (15 psi). On completion, the mixture was filtered and the filtrate was concentrated

1460 in vacuo to give the title compound (390 mg, 99% yield) as a yellow solid. 1H NMR (400 MHz, DMSOA) δ 8.25 (s, IH), 7.12 - 6.96 (m, IH), 6.95 - 6.86 (m, IH), 6.72 - 6.60 (m, IH), 5.30 5.15 (m, IH), 3.48 (s, 3H), 3.65 - 3.58 (m, 2H), 3.52 - 3.45 (m, 2H), 3.45 - 3.35 (m, 2H), 3.08 2.95 (m, 3H), 2.92 (s, 3H), 2.85 - 2.60 (m, 2H), 2.25 - 2.15 (m, IH), 1.96 - 1.85 (m, 2H), 1.50 (s, IH); LC-MS (ESI+) m/z 375.1 (M+H-100/.

[004785] Step 3-3 -[3-Methyl [3-[2-(methylamino)ethoxy1propyl1 oxo-benzimidazoll-vl1piperidine-2,6- di one

[004786] To a solution of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethyl]-N-methyl-carbamate (100 mg, 211 umol) in DCM (2 mL) was added HCI/dioxane (2 mL). The reaction mixture was stirred at 20 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (85.0 mg, 98% yield, HC1 salt) as a yellow solid. LC-MS (ESI+) m/z 375.1 (M+H)+.

[004787] 3-[3-Methvl [3-[3-(methvlamino)propoxv]prop-l-vnyl] oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate ZQ)

[004788] To a solution of tert-butyl N-[3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]propyl]-N-methyl-carbamate (200 mg, 412 umol, synthesized via Step 1 of Intermediate QI) in DCM (3.00 mL) was added ZnBr2 (1.39 g, 6.19 mmol). The mixture was stirred at 20 °C for 20 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (158 mg, 99% yield) as yellow solid. LC-MS (ESI+) m/z 385.2 (M+H)+.

[004789] 3-[3-Methvl [[4-(methvlaminomethvl)-l-piperidvl1methyl] oxobenzimidazol-l-yl] piperidine-2.,6-dione (Intermediate ZR)

1461

HCI/dioxane

DCM

[004790] Step 1 - Tert-butyl N-rr1-rr1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1methyl1 piperidyl1methyl1-N-methylcarbamate

[004791] To a solution of tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate (119 mg, 522 umol, CAS# 138022 5) and 1-(2,6-dioxo piperidyl) methyl oxo-benzimidazole-5carbaldehyde (150 mg, 522 umol, Intermediate SK) in a mixed solvents of DMF (1.2 mL) and

THF (2.4 mL) was added HO Ac until the pH = 5~ 6. After the reaction mixture was stirred at 10 °C for 1 hr, then NaBH(OAc)3 (221 mg, 1.04 mmol) was added. Then the reaction mixture was stirred at 10 °C for 48 hrs. On completion, the reaction mixture was quenched by H2O (0.5 mL), filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (230 mg, 88% yield) as a white solid. 1HNMR (400 MHz, CDCh) δ 8.53 (s, IH), 7.21 (d, J= 16.0 Hz, IH), 7.01 (J = 8.0 Hz, IH), 6.76 (d, J= 8.0 Hz, IH), 5.24 (dd, J= 5.2, 12.8 Hz, IH), 4.06 - 3.80 (m, 2H), 3.43 (s, 3H), 3.24 (d, J= 8.0 Hz, 2H), 3.13 (s, 2H), 2.98 - 2.87 (m, IH), 2.87 (s, 3H), 2.79 (d, J = 4.8 Hz, IH), 2.77 - 2.63 (m, IH), 2.57 - 2.39 (m, IH), 2.37 - 2.16 (m, 2H), 1.91 - 1.78 (m, IH), 1.78 - 1.60 (m, 2H), 1.60 1.48 (m, IH), 1.44 (s, 9H); LC-MS (ESI+) m/z 500.4 (M+H)+.

[004792] Step 2 - 3-r3-Methyl rr4-(methylaminomethyl)-l-piperidyl1methyl1 oxobenzimidazol-l-yl1 piperi dine-2,6-di one

[004793] To a solution of tert-butyl N-[[l-[[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] methyl] piperidyl]methyl]-N-methyl-carbamate (230 mg, 460 umol) in DCM (3 mL) was added HCI/dioxane (4 M, 3 mL). The reaction mixture was stirred at 20 °C for

1462 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (200 mg, 99% yield, HCI) as a white solid. LC-MS (ESI+) m/z 400.3 (M+H)+.

[004794] 3-[3-Methvl [3-[2-(methvlamino)ethoxv]DroDvl] oxo-benzimidazol-lyl]DiDeridine-2,6-dione (Intermediate ZS)

Pd/C, Pd(OH)2/C

H2, THF

HCI/dioxane

DCM

ZS

[004795] Step 1 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol vl1prop- 2-ynoxy1ethyl1-N-methyl-carbamate

[004796] To a solution tert-butyl N-methyl-N-(2-prop ynoxyethyl)carbamate (946 mg, 4.44 mmol, Intermediate GK) and 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (600 mg, 1.77 mmol, Intermediate HN) in DMF (10 mL) was added Pd(PPh3)2C12 (249 mg, 355 umol), Cui (67.6 mg, 355 umol), 4A molecular sieves (80.0 mg, 305 umol) and Cs2CO3 (2.89 g, 8.87 mmol). The reaction mixture was stirred at 80 °C for 4 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (540 mg, 52% yield) as yellow solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.10 (s, IH), 7.31 (s, IH), 7.18-7.12 (m, 2H), 5.38 (dd, J= 5.6, 12.4 Hz, IH), 4.39 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.38 - 3.36 (m, 2H), 3.34 (s, 3H), 2.82 (s, 3H), 2.77 - 2.70 (m, IH), 2.65 - 2.58 (m, 2H), 2.08 - 2.00 (m, IH), 1.39 (s, 9H); LC-MS (ESI+) m/z 493.3 (M+Na)+.

1463

[004797] Step 2 - Tert-butyl N-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1propoxy1 ethyl1-N-methyl-carbamate

[004798] To a solution of tert-butyl N-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop ynoxy]ethyl]-N-methyl-carbamate (530 mg, 1.13 mmol) in THF (5 mL) was added Pd/C (40.0 mg, 10 wt%), Pd(OH)2 (40.0 mg, 10 wt%) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 15 hours under H2 (15 psi). On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (450 mg, 84% yield) as yellow oil. 1H NMR (400 MHz, DMSO-/6) δ 11.07 (s, IH), 7.04 - 6.97 (m, 2H), 6.85 (d, J = 8.0 Hz, IH), 5.33 (dd, J = 4.8, 12.4 Hz, IH), 3.48 - 3.43 (m, 2H), 3.38 - 3.30 (m, 3H), 2.82 (s, 3H), 2.72 - 2.61 (m, 4H), 2.33 (s, IH), 2.07 (s, 4H), 2.04 - 1.96 (m, IH), 1.86 - 1.74 (m, 2H), 1.38 (s, 9H); LC-MS (ESI+) m/z 497.3 (M+Na)+.

[004799] St ep 3 2,6-dione

[004800] To a solution of tert-butyl N-[2-[3-[l-(2, 6-dioxo piperidyl) methyl oxobenzimidazol yl] propoxy]ethyl]-N-methyl-carbamate (430 mg, 906 umol) in DCM (2 mL) was added HCl/dioxane (2 mL). The mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (330 mg, 78% yield) as white solid. LC-MS (ESI+) m/z 375.2 (M+H)+

[004801] Tert-butyl N-methvl-N-(3-vinyl0xvDr0Dvl)carbamate (Intermediate ZT) 0 // // ,Boc // // // ,Boc

HO V N ----------------► Q> N । [lr(COD)C]2, NaOAc, toluene '

ZT

[004802] To a mixture of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (5.00 g, 26.4 mmol, CAS# 98642 5) and vinyl acetate (3.41 g, 39.6 mmol, CAS# 108 4) in toluene (20 mL) was added chloroiridium (lZ,5Z)-cycloocta-l,5-diene (177 mg, 264 umol, CAS# 12112-673) and Na2CO3 (1.68 g, 15.8 mmol) at 25 °C under N2 in glove box. The mixture was stirred at 100 °C for 2 hours. On completion, the reaction mixture was quenched with water (20 mL), filtered and the filtrate was extracted with EA (2 X 25 mL). The combined organic layers were washed

1464 with brine (10 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate= 30/1) to afford the title compound (2.40 g, 42% yield) as a yellow oil. 1HNMR (400 MHz, CDCh) δ 6.51 -6.42 (m, IH), 4.21 -4.13 (m, IH), 4.02 - 3.96 (m, IH), 3.69 (t, J= 6.2 Hz, 2H), 3.32 (s, 2H), 2.86 (s, 3H), 1.94 - 1.80 (m, 2H), 1.46 (s, 9H).

[004803] 3-[3-Methyl [2-[3-(methylamino)propoxy]ethyl] oxo-benzimidazol-lyl]piperidine-2.,6-dione (Intermediate ZU)

1) 9&#1470;BBN,THF

2) Pd(dtbpf)CI2, K3PO4, DMF/H2O ,B0C

ZU

[004804] Step 1 - Tert-butyl N-r3-r2-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1ethoxy1 propyl1-N-methyl-carbamate

[004805] To a solution of tert-butyl N-methyl-N-(3-vinyloxypropyl)carbamate (900 mg, 4.18 mmol, Intermediate ZT) in THF (10 mL) was added 9-BBN (0.5 M, 8.36 mL). The mixture was stirred at 25 °C for 2 hours. Then a solution of 3-(5-bromo methyl oxo-benzimidazol-lyl)piperidine-2,6-dione (471 mg, 1.39 mmol, Intermediate HN), K3PO4 (739 mg, 3.48 mmol) and ditert-butyl(cyclopentyl)phosphane; dichloro palladium; iron (90.8 mg, 139 umol) in DMF (15 mL) and H2O (3 mL) was added to the above mixture. The reaction mixture was stirred at 75 °C for 20 minutes under N2. On completion, the reaction mixture was diluted with EA (100 mL), poured into water (50 mL) and extracted with EA (2 X 50 mL). The combined organic layers were dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound (300 mg, 45% yield) as a light yellow solid. LC-MS (ESI+) m/z 375.3 (M+H-100)+.

[004806] Step 2 - 3-r3-Methyl r2-r3-(methylamino)propoxy1ethyl1 oxo-benzimidazol1465

-yl&#1470;|piperidine-2,6-dione

[004807] To a solution of tert-butyl N-[3-[2-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] ethoxy]propyl]-N-methyl-carbamate (200 mg, 421 umol) in DCM (2 mL) was added TFA (30.8 g, 270 mmol, 20 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound (200 mg, 91% yield, 94% purity, TFA) as yellow oil. LC-MS (ESI+) m/z 375.3 (M+H)+.

[004808] METHODS:

[004809] Example 1 (Method 1):6-((l6&#1524;-naphthvridin vl)amino)-4(cvclopropylamino)-N-((lR.,4R) ((l-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4vl)oxv) oxo-9,12,15-trioxa azaicosan vl)carbamovl)cvclohexyl)nicotinamide, 1-1

1466

B C

[004810] Step 1 - te/7-butyl (l-((lR,4R) (6-((L6-naphthyridin vl)amino)-4 (cyclopropylamino)-nicotinamido)-cyclohexyl)-l-oxo-8,lL14-trioxa azanonadecan-19yDcarbamate

[004811] To a stirred suspension of (lR,4R) (6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylic acid (0.2 g, 0.5 mmol, Intermediate C) and tert-butyl (5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate (0.25 g, 0.67 mmol, Intermediate B) in DMF (2 mL) was added DIPEA (0.4 mL, 2.2 mmol) and PyBOP (0.35 g, 0.67 mmol) at rt. The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The

1467 filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (10% MeOH-DCM) to give ter/-butyl (l-((lr,4r) (6-((l,6naphthyridin yl)amino) (cyclopropylamino)nicotinamido)cyclohexyl)-1 -oxo-8,11,14-trioxa2-azanonadecan yl)carbamate as a brown solid (0.18 g, 50%). LC-MS (ESI+) m/z 804.1 (MΗ)&#1470;

[004812] Step 2 - 6-((1,6-naphthyridin yl)amino)-N-((lR,4R) ((5-(2-(2-((5aminopentvl)oxv)ethoxv)-ethoxv)-pentvl)carbamoyl)cvclohexvl)-4(cyclopropylamino)nicotinamide hydrochloride

[004813] To a stirred solution of te/7-butyl (l-((lr,4r) (6-((l,6-naphthyridin yl)amino)4-(cyclopropylamino)nicotinamido)cyclohexyl)-1 -oxo-8,11,14-trioxa azanonadecan yl)carbamate (0.18 g, 0.22 mmol) in 1,4 dioxane (3 mL) was added 4N HCI in dioxane (1 mL) at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was evaporated under vacuum and triturated using diethyl ether to give 6-((1,6-naphthyridin-2yl)amino)-N-((lr,4r) ((5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamoyl)cyclohexyl) (cyclopropylamino)nicotinamide hydrochloride as yellow solid (0.16 g, 96%). LCMS (ESI+) m/z 706.6 (M+H)+.

[004814] Step 3 - 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lR,4R)-4((1-((2-(2,6-di oxopiperi din yl)-l,3-di ox oisoindolin yl)oxy) oxo-9,12,15-tri oxa-3azaicosan yl)carbamoyl)cyclohexyl)nicotinamide

[004815] To a solution of 2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)oxy)acetic acid (0.085 g, 0.24 mmol, Intermediate D) in DMF (5 mL) was added HATU (0.14 g, 0.36 mmol) at 0 °C and the reaction mixture was stirred for 30 minutes. To this reaction mixture, 6-((1,6-naphthyri din yl)amino)-N-((lr,4r) ((5-(2-(2-((5aminopentyl)oxy)ethoxy)ethoxy)pentyl)-carbamoyl)-cyclohexyl)-4(cyclopropylamino)nicotinamide hydrochloride (0.18 g, 0.24 mmol) and DIPEA (0.15 mL, 0.72 mmol) was added at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was transferred into ice water, and the resulting precipitate was fdtered off and washed with water and dried under reduced pressure. The crude product was purified using preparative HPLC (0.1% formic acid in water/ACN) to give 6-((1,6-naphthyridin yl)amino)-4(cyclopropylamino)-N-((lr,4r) ((l-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)oxy) oxo-9,12,15-trioxa azaicosan yl)carbamoyl)cyclohexyl)-nicotinamide 1-1 as off

1468 white solid (0.04 g, 16 %). 1HNMR (400 MHz, DMSO) δ 11.11 (s, IH), 10.34 (s, IH), 9.02 (s, IH), 8.55-8.53 (m, 3H), 8.40 (s, IH), 8.24 (d, J = 9.2 Hz, IH), 8.13-8.11 (m, IH), 7.96-7.93 (m, IH), 7.79 (t, J = 7.6 Hz, IH), 7.78-7.69 (m, IH), 7.54 (d, J = 5.6 Hz, IH), 7.49-7.46 (m, 2H), 7.36 (d,J = 8.4 Hz, IH), 5.12-5.09 (m, IH), 4.75 (s, 2H), 3.72 (bs, IH), 3.48-3.47 (m, 7H), 3.14-3.09 (m, 2H), 2.99-2.98 (m, 2H), 2.96-2.94 (m, IH), 2.59-2.52 (m, 2H), 2.03-2.0 (m, 2H), 1.85-1.83 (m, 2H), 1.73-1.71 (m, 2H), 1.45-1.42 (m, 6H), 1.40-1.38 (m, 2H), 1.36-1.34 (m , 2H), 1.31-1.28 (m, IH), 1.25-1.24 (m, 4H), 0.92-0.91 (m, 2H), 0.56 (s, 2H). LC-MS (ESI+) m/z 1020.2 (M+H)+.

[004816] Table 2: Compounds synthesized via Method 1, with the coupling of various amines with acid Intermediate C in Step 1, followed by coupling with acid Intermediate D in

Step 3.

<td> Ex-#</td><td> I-#</td><td> Intermediate Amine</td><td> LCMS (ES+) m/z (M+H)+</td><td> HNMR (400MHz, DMSO-d6) δ</td>

<td> 3</td><td> 1-3</td><td> tert-butyl (5aminopentyl)c arbamate (CAS# 51644-96-3)</td><td> 845.8</td><td> 11.14 (s, IH), 10.37 (s, IH), 9.04 (s, IH), 8.65-8.45 (m, 3H), 8.40 (s, IH), 8.23 (d, J= 9.2 Hz, IH), 8.18-8.05 (m, 2H), 7.98-7.88 (m, IH), 7.81 (t, J= 8.0 Hz, IH), 7.75-7.65 (m, IH), 7.63-7.53 (m, IH), 7.52-7.42 (m, 2H), 7.38 (d, J= 8.4 Hz, IH), 5.055.15 (m, IH), 4.76 (s, 2H), 3.75-3.61 (m, IH), 3.18-3.08 (m, 2H), 3.15-2.95 (m, 2H), 2.94-2.81 (m, IH), 2.61-2.51 (m, 3H), 2.11-1.97 (m, 2H), 1.90-1.80 (m, 2H), 1.79-1.70 (m, 2H), 1.50-1.20 (m, 10H), 0.92 (d, J= 5.2 Hz, 2H), 0.57 (s, 2H)</td>

<td> 4a</td><td> 1-4</td><td> tert-butyl (5aminopentyl)c arbamate (CAS# 51644-96-3)</td><td> 845.0</td><td> 11.18 (s, IH), 10.38 (s, IH), 9.05 (s, IH), 8.57-8.56 (m, 3H), 8.42(s, IH), 8.28 (d, J = 9.2 Hz, IH), 8.15 (s, IH), 8.14 (d, J = 2.8 Hz, IH), 7.96 (t, J = 5.2 Hz, IH), 7.83 (t, J = 7.2 Hz, IH), 7.72 (t, J = 5.2 Hz, IH), 7.57 (d, J = 6 Hz, IH), 7.51 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 8.8 Hz, IH), 5.16-5.12 (m, IH), 4.77 (s, 2H), 3.67 (bs, 2H), 3.41-3.12 (m, 2H), 3.02-2.94 (m, 2H), 2.90-2.86 (m, 2H), 2.602.51 (m, 3H), 2.08-2.03 (m, 2H), 1.87 (d, J = 10 Hz, 2H), 1.76 (d, J = 10.4 Hz, 2H), 1.46-1.23 (m, 11H), 0.95-0.93 (m, 2H), 0.59 (s, 2H)</td>

1469

<td> 6b</td><td> 1-6</td><td> tert-butyl (2- ־2) aminoethoxy) ethyl)carbama te (CAS# 127828-22-2)</td><td> 847.8</td><td> 11.1 (s, IH), 9.51 (s, IH), 8.94 (s, IH), 8.81 (d, J= 6.0 Hz, IH), 8.8-8.7 (m, IH), 8.65 (d, J= 8.8 Hz, IH), 8.50 (s, IH), 8.32-8.22 (m, IH), 8.05 (d, J= 5.4 Hz, IH), 7.83-7.78 (m, 2H), 7.61 (d, J= 8.8 Hz, IH), 7.49 (d, J= 7.6 Hz, IH), 7.39 (d, J= 8.8 Hz, 2H), 5.12 (dd, J= 12.8 Hz & 5.4 Hz, IH), 4.79 (s, 2H), 3.7-3.6 (m, 2H), 3.46-3.43 (m, 2H), 3.413.37 (m, 2H), 3.33-3.30 (m, 2H), 3.22-3.15 (m, 2H), 3.22-3.15 (m, 2H), 3.95-3.80 (m, IH), 3.703.55 (m, IH), 2.15-2.01 (m, 2H), 1.90-1.81 (m, 2H), 1.80-1.70 (m, 2H), 1.49-1.22 (m, 4H), 0.93 (d, 7= 5.6 Hz, 2H), 0.67 (s, 2H)</td>

<td> 7a</td><td> 1-7</td><td> tert-butyl (3aminopropyl) carbamate (CAS# 75178-96-0)</td><td> 816.9</td><td> 11.18 (s, IH), 9.50 (s, IH), 8.57-8.56 (m, 3H), 8.42 (s, IH), 8.27(d, J = 8.8 Hz, IH), 8.15-8.13 (m, 2H), 8.00 (t, J = 6 Hz, IH), 7.82 (t, J = 8 Hz, IH), 7.75 (t, J = 1.3 Hz, IH), 7.57 (d, J = 5.6 Hz, IH), 7.51 ( d, J = 7.6 Hz, IH), 7.41 (d, J = 8.8 Hz, IH), 5.155.10 (m, IH), 4.79 (s, 2H), 3.68 (bs, IH), 3.15 (d, J = 1.3 Hz, 2H), 3.05 (d, J = 6 Hz, 2H), 2.94-2.87 (m, 3H), 2.05-2.02 (m, 2H), 1.87-1.85 (m, 2H), 1.77-1.74 (m, 2H), 1.57 (t, J = 6.4 Hz, 2H), 1.471.30 (m, 5H), 0.94 (d, J = 5.2 Hz, 2H), 1.94 (s, 2H)</td>

<td> 8b</td><td> 1-8</td><td> tert-butyl (2aminoethyl)ca rbamate (CAS# 57260-73-8)</td><td> (M-Η)' 801.8</td><td> 11.14 (s, IH), 10.36 (s, IH), 9.05 (s, IH), 8.65-8.55 (m, 3H), 8.42 (s, IH), 8.27 (d, J= 9.2 Hz, IH), 8.18-8.08 (m, 2H), 8.1-8.0 (m, IH), 7.89-7.79 (m, 2H), 7.57 (d, J= 5.6 Hz, IH), 7.55-7.45 (m, IH), 7.40 (d, J= 8.4 Hz, IH), 5.15-5.10 (m, IH), 4.78 (s, 2H), 3.19-3.11 (m, 3H), 3.0-2.75 (m, 3H), 2.652.55 (m, IH), 2.11-2.95 (m, 3H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 2H), 1.50-1.20 (m, 5H), 0.94 (d, 7= 5.6 Hz, 2H), 0.58 (s, 2H)</td>

<td> 9b</td><td> 1-9</td><td> tert-butyl (4aminobutyl)ca rbamate (CAS#</td><td> 831.7</td><td> 11.12 (s, IH), 10.34 (s, IH), 9.03 (s, IH), 8.86-8.53 (m, 2H), 8.40 (s, IH), 8.25 (d, J= 92 Hz, IH), 8.15-8.05 (m, 2H), 7.97 (t, J= 5.6 Hz, IH), 7.81 (t, J= 7.8 Hz, IH), 7.72 (t, J= 5.6 Hz, 2H), 7.54 (d, J</td>

1470

*The intermediate formed in Step 1-2 could be triturated with diethyl ether, MBTE, or n-pentanes.

Step 1 was run for 1-2 h. aStep 2 started at 0 °C then run at rt for 6 h; Step 3 was run for 4 h at rt. bOnce water was added to quench the reaction in Step I, the product precipitated out of solution and was collected, dried and used directly in the next step. For Step 3, PyBOP was used as the coupling reagent instead of HATU and the reaction was nm at rt for 1 hr.

[004817] Example 10 (Method 2): 6-((l.,6-naphthvridin vl)amino)-4 (cvclopropylamino)-N-((lS.,4r) ((7-(((S)-l-((2S.,4R) hvdroxv ((4-(4-methvlthiazol-5 vl)benzvl)carbamovl)-pyrrolidin-l-vl)-3.,3-dimethvl-l-oxobutan vl)amino)-7oxoheptyllcarbamovDcvclohexvll-nicotinamide,

[004818] Step 1 - tert-butyl (7-(((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)-pynOlidin-l-yl)-3,3-dimethyl-l-oxobutan yl)amino)-7oxoheptvDcarbamate

1471

[004819] To a solution of 7-((tert-butoxycarbonyl)amino)heptanoic acid (0.3 g, 1.2 mmol, CAS# 60142 4), (2S,4R)-l-((S) amino-3,3-dimethylbutanoyl) hydroxy-N-(4-(4methylthiazol yl)-benzyl)pyrrolidine carboxamide hydrochloride (0.74 g, 1.59 mmol, Intermediate G) and DIPEA (1.1 mL, 6.1 mmol) in DMF (2 mL) was added PyBOP (0.95 g, 1.5 mmol) at rt and the mixture was stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel column chromatography (4% MeOH-DCM) to give tert-butyl (7-(((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol-5yl)benzyl)carbamoyl)-pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan yl)amino)-7oxoheptyl)carbamate as brownish yellow semisolid (0.8 g, 99%). LC-MS (ESI+) m/z 658.7 (M+H)+.

[004820] Step 2 - (2S,4R)-l-((S) (7-aminoheptanamido)-3,3-dimethylbutanoyl)-4hydroxy-N-(4-(4-methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride

[004821] To a stirred solution of tert-butyl (7-(((S)-l-((2S,4R) hydroxy ((4-(4methylthiazol yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan yl)amino)-7oxoheptyl)carbamate (0.8 g, 1.2 mmol) in DCM (10 mL) was added 4N HCI in dioxane (2 mL) at 0 °C. The resulting reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was then evaporated under vacuum and triturated using diethyl ether to give (2S,4R)-l-((S) (7aminoheptanamido)-3,3-dimethylbutanoyl) hydroxy-N-(4-(4-methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride as yellow solid (0.5 g, 70%). LCMS (ESI+) m/z 558.61 (M+H)+.

[004822] Step 3 - 6-((L6-naphthyridin yl)amino) (cvclopropylamino)-N-((lS,4f) ((7(((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3dimethyl-l-oxobutan yl)amino) oxoheptyl)carbamoyl)cyclohexyl)nicotinamide

[004823] To a stirred suspension of (lR,4R) (6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylic acid (0.2 g, 0.5 mmol, Intermediate C) and (2S,4R)-l-((S) (7-aminoheptanamido)-3,3-dimethylbutanoyl) hydroxy-N-(4-(4methylthiazol yl)benzyl)pyrrolidine carboxamide hydrochloride (0.34 g, 0.58 mmol) in DMF (5 mL) was added DIPEA (0.5 mL, 2.3 mmol) and PyBOP (0.35 g, 0.68 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was then transferred into ice water and the

1472 resulting mixture was extracted using ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using preparative HPLC (0.1% formic acid in water/ACN) to give 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lS,4r) ((7(((S)-l-((2S,4R) hydroxy ((4-(4-methylthiazol yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3dimethyl-l-oxobutan yl)amino) oxoheptyl)carbamoyl)cyclohexyl)nicotinamide 1-10 as light yellow solid (0.21 g, 37 %). 1H NMR (400 MHz, DMSO) δ 10.36 (s, IH), 9.05 (s, IH), 8.99 (s, IH), 8.63-8.51 (m, 3H), 8.42 (s, IH), 8.27 (d, J =92 Hz, IH), 8.15 (d, 7= 7.6 Hz, IH), 7.88 (d, J = 9.2 Hz, IH), 7.71-7.63 (m, IH), 7.57 (d, J= 5.6 Hz, IH), 7.51 (d, J= 8.8 Hz, IH), 7.48-7.31 (m, 3H), 4.55 (d, J= 9.2 Hz, IH), 4.49-4.41 (m, IH), 4.40-4.31 (m, 2H), 4.30-4.15 (m, IH), 3.75-3.61 (m, 2H), 3.05-2.95 (m, 2H), 2.65-2.55 (m, IH), 2.45 (s, 3H), 2.41-1.71 (m, 8H), 1.51-1.21 (m, 10H), 0.94 (s, 9H), 0.55 (s, 2H). LC-MS (ESI+) m/z 987.25 (M+H)+.

[004824] Table 3: Compounds synthesized via Method 2&#1524; with the coupling of various amines with acids in Step I, followed by coupling with acids in Step 3.

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermedi ate Amine</td><td> Step 1 Intermedi ate Acid</td><td> Step 3 Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td> HNMR (400MHz, DMSO-d6) δ</td>

<td> 11</td><td> 1-11</td><td> tert-butyl (2-(2-(2-(2aminoethox y)-ethoxy)ethoxy)eth yl)carbama te (CAS# 153086-783)</td><td> D</td><td> C</td><td> 936.0</td><td> 11.13 (s, IH), 10.35 (s, IH), 9.05 (s, IH), 8.56 (t, J= 4 Hz, 3H), 8.42 (s, IH), 8.28 (d, J= 8.8 Hz, IH), 8.17 (s, IH), 8.14 (d, 7= 7.6 Hz, IH), 8.03 (t, 7= 5.6 Hz, IH), 7.83-7.79 (m, 2H), 7.57 (d, 7= 6 Hz, IH), 7.52 (m, 2H), 7.41 (d, 7 = 8.4 Hz, IH) 5.14-5.10 (m, IH), 4.79 (s, 2H), 3.70 (bs, IH), 3.523.17 (m, 20H), 2.93-2.87 (m, IH), 2.67-2.50 (m, 4H), 2.082.03 (m, 2H), 1.87 (d, 7= 10 Hz, 2H), 1.76 (d, 7= 12.4 Hz, 2H), 1.46-1.30 (m, 4H), 0.96-0.93 (m, 2H), 0.58 (s, 2H)</td>

1473

<td> 15c</td><td> 1-15</td><td> G</td><td> 5-((tertbutoxycar bonyl)ami no)pentan oic acid</td><td> C</td><td> 959.3</td><td> 9.03 (s, IH), 8.96 (s, IH), 8.588.53 (m, 4H), 8.40 (s, IH), 8.25 (d, J = 4.8 h, IH), 8.13-8.11 (m, IH), 7.87 (d, J = 9.2 h, IH), 7.71 (t, J = 5.2 Hz, IH), 7.55 (d, J =</td>

1474

<td> 16a</td><td> 1-16</td><td> tert-butyl (2-(2-(2aminoethox y)ethoxy)et hyl)carbam ate (CAS# 153086-78- 3)</td><td> D</td><td> O</td><td> 863.7</td><td> 12.80 (bs, IH), 11.12 (s, IH), 10.35 (s, IH), 9.03 (s, IH), 8.548.50 (m, 3H), 8.44 (s, IH), 8.26 (d, 7= 8.8 Hz, IH), 8.11 (s, IH), 8.01 (t, 7= 5.2 Hz, IH), 7.827.77 (m, 2H), 7.55-7.47 (m, 3H), 7.38 (d, 7= 8.4 Hz, IH), 5.125.08 (m, IH), 4.78 (s,2H), 4.53-4.47 (m, IH), 3.50 (s, 3H), 3.46-3.32 (m, 4H), 3.32-3.29 (m, merged with water peak of DMSO, 3H), 3.22-3.17 (m, 2H), 2.91-2.85 (m, 2H), 2.65-2.48 (m, 3H), 2.35-2.30 (m, 2H), 2.262.19 (m, 2H), 2.03-2.01 (m, IH), 0.91 (s, 2H), 0.54 (s, 2H)</td>

<td> 17d</td><td> 1-17</td><td> tert-butyl (2-(2-(2-(2aminoethox y)ethoxy)et hoxy)ethyl) carbamate (CAS# 101187-400)</td><td> D</td><td> AG</td><td> 934.0</td><td> 11.03 (s, IH), 9.07-9.04 (m, 2H), 8.67 (s, IH), 8.60 (s, IH), 8.55 (s, IH), 8.40 (d, 7= 7.6 Hz, IH), 8.05-8.02 (m, IH), 7.84-7.80 (m, 2H), 7.68 (s, IH), 7.51 (d, 7= 7.2 Hz, IH), 7.41 (d, 7= 8.4 Hz, IH), 5.15-5.11 (m, IH), 4.80 (s, 2H), 3.73-3.71 (m, IH), 3.53-3.48 (m, 11H), 3.46-3.39 (m, 3H), 3.383.35 (m, IH), 3.20-3.18 (m, 2H), 2.95-2.86 (m, IH), 2.68-2.63 (m, 2H), 2.63-2.59 (m, 2H), 2.112.04 (m, 2H), 1.92-1.89 (m, 2H), 1.78-1.76 (m, 2H), 1.48-1.24 (m, 4H), 0.86 (d, 7= 5.2 Hz, 2H), 0.58 (s, 2H)</td>

1475

aHATU used instead of PyBOP as the coupling reagent in Step 1 and the reaction was run for 2 h at rt in DCM. In Step 2, the reaction was run for 3 h and the product was triturated with MBTE. Step 3 was run for 3 h. bTFA was used instead of HCI for the deprotection in Step 2 and was added at 0 °C, then the reaction was stirred at rt for 16 h. The product triturated using n-pentanes. In Step 3, HATU was used instead of PyBOP as the coupling reagent and the final product was purified using preparative HPLC (0.1% ammonia in water/ACN). CHATU was used as the coupling agent in Step 1 instead of PyBOP. In Step 2, the intermediate was triturated using MTBE. dThe final product was purified by silica gel column chromatography (7% MeOH-DCM).

[004825] Example 19 (Method 3):6-((l6&#1524;-naDhthvridin vl)amino)-4(cvcloDroDvlamino)-N-(l-(2-((2-(2-(2-((2-(2.,6-dioxoDiDeridin vl)-l.,3-dioxoisoindolin-4vl)amino)ethoxv)ethoxv)ethvl)amino) oxoethvl)DiDeridin yl)nicotinamide, 1-19

1476

[004826] Step 1 Ethyl 2-(4-(6-(( L6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)-piperidin-1 -vDacetate

[004827] A solution of 6-((1,6-naphthyri din yl)amino) (cyclopropylamino)nicotinic acid (0.19 g, 0.58 mmol, Intermediate N), ethyl 2-(4-aminopiperidin-l-yl)acetate hydrochloride (0.13 g, 0.58 mmol, Intermediate P), PyBOP (0.45 g, 0.87 mmol) and DIPEA (0.23 mL, 1.73 mmol) in DMF (3 mL) was stirred at rt for 3 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to and the crude product was purified using silica gel column chromatography (50 % EtOAc-Hexane) to give ethyl 2-(4-(6-((1,6-naphthyri din yl)amino)-4(cyclopropylamino)nicotinamido)piperidin-l-yl)acetate as a light yellow solid (0.15 g, 39%). 1H NMR (400 MHz, DMSO) δ 10.74 (bs, IH), 9.11 (s, IH), 8.61-8.32 (m, 5H), 7.75-7.60 (m, IH), 7.53 (d, J = 8.8 Hz, IH), 4.22-4.18 (m, 2H), 4.10-3.80 (m, 3H), 3.00-2.93 (m, 2H), 2.67-250 (m, 2H), 2.08-1.65 (m, 4H), 1.26-1.15 (m, 4H), 0.95 (d, J = 4.8Hz, 2H), 0.86-0.81 (m, IH), 0.59 (s, 2H).

[004828] Step 2:2-(4-(6-((L6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)-piperidin-1 -vDacetic acid

1477

[004829] A solution of ethyl 2-(4-(6-((1,6-naphthyridin yl)amino) (cyclopropylamino) nicotinamido)piperidin-l-yl)acetate (0.15 g, 0.31 mmol) and LiOHH2O (0.04 g, 0.93 mmol) in THF:MeOH (5 mL, 1:1) was stirred at rt for 5 h. The reaction mixture was then adjusted to pH of 4-5 using citric acid solution. The solid precipitate was collected using filtration and the solid was dried under vacuum to give 2-(4-(6-(( 1,6-naphthyri din yl)amino)-4(cyclopropylamino)nicotinamido)piperidin-l-yl)acetic acid as a light yellow solid (0.065 g, 53%). LC-MS (ESI+) m/z 462.04 (M+H)+.

[004830] Step 3 - 6-((L6-naphthyridin yl)amino) (cyclopropylamino)-N-(l-(2-((2-(2(2-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)amino)-2oxoethyl)piperidin yl)nicotinamide

[004831] A solution of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl) amino) (2,6di oxopiperi din yl) isoindoline-1,3-dione (0.06 g, 0.14 mmol, synthesized via Method 4, Step 12 of Example 23), 2-(4-(6-(( 1,6-naphthyri din yl)amino)-4(cyclopropylamino)nicotinamido)piperidin-l-yl)acetic acid (0.06 g, 0.14 mmol), PyBOP (0.11 g, 0.20 mmol) and DIPEA (0.05 mL, 0.4 mmol) in DMF (3 mL) was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and resulting solid was filtered and purified by preparative HPLC (0.1% formic acid in water/ACN) purification to give 6-((1,6-naphthyridin-2yl)amino) (cyclopropylamino)-N-(l-(2-((2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)amino) oxoethyl)piperidin yl)ni cotinamide 1-19 as a light yellow solid (0.022 g, 19%). 1H NMR (400 MHz, DMSO) δ 11.10 (s, IH), 9.67 (bs, IH), 9.18 (s, IH), 8.63-8.37 (m, 4H), 7.73 (bs, IH), 7.59-7.49 (m, 2H), 7.14 (d, J = 8.4 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 6.59 (s, IH), 5.06-5.02 (m, IH), 3.86-3.71 (m, IH), 3.60-3.54 (m, 6H), 3.46-3.33 (m, 6H), 3.11-3.08 (m, IH), 2.90-2.83 (m, IH), 2.59-2.52 (m, 2H), 2.16-1.98 (m, 5H), 1.89-1.82 (m, 3H), 0.94 (d, J= 5.6 Hz2 &#1524;H), 0.58 (s, 2H); LC-MS (ESI+) m/z (M+H)+ = 848.93

[004832] Example 20: 6-((l6&#1524;-naphthvridin vl)amino) (cvclopropvlamino)-N-(l(2-((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4vl)amino)ethoxv)ethoxv)ethvl)amino) oxoethvl)azetidin yl)nicotinamide, 1-20

1-20

1478

[004833] 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-(l-(2-((2-(2-(2-((2(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)amino)-2oxoethyl)azetidin yl)nicotinamide was synthesized via Method 3 starting with Intermediate Q as the amine and Intermediate N as the acid in Step 1. Step 1 was started at 0 °C then allowed to warm to rt and stirred for 16 h. After the water quench, the product was extracted using 5% methanol in DCM and the product was purified by silica gel column chromatography (8-9% MeOH-DCM). Step 2 was run at 0 °C for 2 h. Upon completion, the reaction mixture was acidified with Dowex 50 Resin and the reaction mixture was filtered through celite and used directly in the subsequent step. In Step 3, the amine 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl) amino) (2,6di oxopiperi din yl) isoindoline-1,3-dione (synthesized via Method 4, Step 1-2 of Example 23) was coupled under the conditions described at 0 °C and stirred for 45 min. Purification by HPLC (5mM ammonium bicarbonate with 0.1% ammonia in water/ACN) gave the title product 1-20. 1H NMR (400 MHz, DMSO-t/6) δ 11.11 (s, IH), 10.38 (s, IH), 9.06 (s, IH), 8.66 (d, 7= 6.8 Hz, IH), 8.65-8.50 (m, 3H), 8.48 (s, IH), 8.28 (d, J= 1.6 Hz, IH), 7.70-7.55 (m, 3H), 7.51 (d, J= 8.8 Hz, IH), 7.14 (d, J= 8.4 Hz, IH), 7.03 (d, J = 22 Hz, IH), 6.69-6.59 (m, IH), 5.06 (dd, J = 12.8 Hz & 5.2 Hz, IH), 4.55-4.45 (m, IH), 3.70-3.60 (m, 3H), 3.59-3.40 (m, 8H), 3.30-3.20 (m, 2H), 3.152.95 (m, 4H), 2.94-2.80 (m, 2H), 2.65-2.55 (m, IH), 2.10-1.95 (m, 2H), 1.80-1.70 (m, IH), 0.94 (d, J= 4.8 Hz, 2H), 0.58 (s, 2H), LC-MS (ESI+) m/z 820.21 (M+H+).

[004834] Example 21:6-(5-cvano-lH-pyrazolo[3.,4-b]pvridin-l-vl)-4(cyclopropylamino)-N-((lr.,3r) ((14-((2-(2.,6-dioxopiperidin yl)-l.,3-dioxoisoindolin-4yl)amino)-3.,6.,9,12-tetraoxatetradecyl)carbamoyl)cyclobutyl)nicotinamide,1-21

1-21

[004835] 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)-N-((lr,3r)-3((14-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)-3,6,9,12tetraoxatetradecyl)carbamoyl)cyclobutyl)nicotinamide was synthesized via Method 3 starting with methyl trans aminocyclobutane carboxylate hydrochloride (CAS# 74316 3) as the amine

1479 and Intermediate L as the acid in the first step. In Step 1, HATU was used at the coupling reagent instead of PyBOP and the reaction mixture was stirred with acid Intermediate L for 30 min at 0 °C then the amine and base were added and the reaction was stirred at rt for 1 h. After the aqueous work up, the solid precipitate was collected and used directly in the subsequent reaction. Step 2 was run in a 1:1 mixture of THF :water as the solvent. In Step 3 the starting material amine used was Intermediate Z and the final product was purified using silica gel column chromatography (4% MeOH-DCM) to give the title compound 1-21. 1H NMR (400 MHz, DMSO) δ 11.12 (s, IH), 9.07 (d, J= 2 Hz, IH), 9.04 (d, J = 2 Hz, IH), 8.80 (d, J= 7.2 Hz, IH), 8.65 (d, J= 11 Hz, 2H), 8.56 (s, IH), 7.87-7.84 (m, IH), 7.68 (s IH), 7.58 (t, J = 7.2 Hz, IH), 7.14 (d, J= 8.8 Hz, IH), 7.03 (d, J= 6.8 Hz, IH), 6.61 (t, J = 5.6 Hz, IH), 5.08-5.03 (m, IH), 4.56-4.54 (m, IH), 3.63-3.60 (m, 2H), 3.56-3.55 (m, 13H), 3.47-3.42 (m, 2H), 3.24-3.20 (m, 2H), 2.93-2.85 (m, 2H), 2.60-2.56 (m, 3H), 2.40-2.35 (m, 2H), 2.33-2.30 (m, 2H), 2.26-2.01 (m, IH), 0.87-0.83 (m, 2H), 0.58-0.56 (m, 2H). LC-MS (ESI+) m/z 892.8 (M+H)+.

[004836] Example 22:6-(5-cvano-lH-pvrazolo[3.,4-b]Dvridin-l-vl)-4(cvcloproDvlamino)-N-((lr.,4r) ((14-((2-(2.,6-dioxoDiDeridin vl)-l.,3-dioxoisoindolin-4vl)amino)-3.,6.,9,12-tetraoxatetradecvl)carbamovl)cvclohexvl)nicotinamide,1-22

[004837] 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)-N-((lr,4r)-4((14-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)-3,6,9,12tetraoxatetradecyl)carbamoyl)cyclohexyl)nicotinamide 1-22 was synthesized via Step 3 of Method 3 starting with acid Intermediate AG and amine Intermediate Z.

[004838] 1H NMR (400 MHz, DMSO) δ 11.12 (s, IH), 9.07 (s, IH), 9.05 (s, IH), 8.67 (s, IH), 8.67 (s, IH), 8.56 (s, IH), 8.42 (d, J= 8 Hz, IH), 7.81 (d, J= 5.2 Hz, IH), 7.68 (s, IH), 7.59 (t, 7 = 8 Hz, IH), 7.17 (d, 7= 8.4 Hz, IH), 7.05 (d, 7= 7.2 Hz, IH), 6.62 (s, IH), 5.09-5.04 (m, IH), 3.73-3.34 (m, 19H), 3.35-3.25 (m, 2H), 3.03-3.02 (m, 2H), 2.94-2.86 (m, 2H), 2.68-2.51 (m, 3H), 2.11-2.02 (m,3H), 1.98-1.89 (m, 2H), 1.79-1.74 (m, 4H), 1.46-1.33 (m, 4H), 0.87 (d, 7= 5.2

1480

Hz, 2H), 0.57 (s, IH). LC-MS (ESI+) m/z 921.5 (M+H)+.

[004839] Example 23 (Method 4):6-((l.,6-naphthvridin vl)amino)-4(cvclopropylamino)-N-((lR.,4R) ((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3dioxoisoindolin yl)amino)ethoxy)ethoxy)-ethyl)carbamoyl)cyclohexyl)nicotinamide.,

[004840] Step 1 - terrtbutyl (2-(2-(2-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethyl)carbamate

[004841] To a stirred solution of 2-(2,6-dioxopiperidin yl) fluoroisoindoline-l,3-dione (2.6 g, 9.4 mmol, Intermediate R) and DABCO (1.4 g, 12.2 mmol) in DMF (15 mL) was added te/7-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (2.8 g, 11.3 mmol, CAS# 153086 3) at rt. The resulting reaction mixture heated to 80 °C and stirred for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using silica gel

1481 column chromatography (2% MeOH-DCM) to give ter/-butyl (2-(2-(2-((2-(2,6-di oxopiperi din-3yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)carbamate as a yellow oil (0.6 g, 13%). LCMS (ESI+) m/z 505.5 (M+H)+.

[004842] Step 2 - 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino) (2,6-dioxopiperidin-3yl)isoindoline-L3-dione hydrochloride

[004843] To a stirred solution of ter/-butyl (2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)carbamate (0.6 g, 1.2 mmol) in 1,4 dioxane (15 mL) was added 4 M HCI in dioxane (10 mL) at 0 °C. The resulting reaction mixture was allowed to warm to rt and stirred for 16 h. The reaction mixture was then evaporated under vacuum and the residue was triturated using MTBE to give 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino) (2,6dioxopiperidin yl)isoindoline-l,3-dione hydrochloride as yellow solid (0.48 g, 91%). LCMS (ESI+) m/z 405.4 (M+H)+.

[004844] Step 3 - 6-((L6-naphthyridin yl)amino) (cyclopropylamino)-N-((lR,4R)-4((2-(2-(2-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-cyclohexyl)nicotinamide

[004845] To a stirred suspension of (lR,4R) (6-((l,6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)cyclohexane-l-carboxylic acid (0.4 g, 0.9 mmol, Intermediate C) and 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino) (2,6-dioxopiperidin yl)isoindoline-l,3dione hydrochloride (0.48 g, 1.07 mmol) in DMF (15 mL) was added DIPEA (0.8 mL, 4.5 mmol) and PyBOP (0.7 g, 1.3 mmol) at rt. The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was then transferred into ice water and the resulting solid was filtered off and dried reduced pressure. The crude product was purified using silica gel column chromatography (6% MeOH-DCM) to give 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lR,4R)4-((2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide 1-23 as a yellow oil (0.41 g, 55%). 1H NMR (400 MHz, DMSO) δ ppm 11.09 (s, IH), 10.34 (s, IH), 9.03 (s, IH), 8.55-8.54 (m, 3H), 8.39 (s, IH), 8.24 (d, J = 8.8 Hz, IH), 8.12 (d, J = 7.6 Hz, IH), 7.73-7.77 (m, IH), 7.57-7.53 (m, 2H ), 7.49-7.47 (m, IH), 7.13 (d,/=8.8 Hz, IH), 7.02 (d,/= 7.2 Hz, IH), 6.60 (m, IH), 5.03-4.96 (m, IH), 3.61-3.59 (m, 3H), 3.55-3.54 (m, 2H), 3.51-3.50 (m, 2H), 3.47-3.44 (m, 2H), 3.39-3.36 (m, 2H), 3.16-3.14 (m, 2H), 2.90-2.82 (m, IH), 2.58-2.55 (m, IH), 2.03 (m, 2H), 1.84-1.82 (m, 2H), 1.73-1.71 (m ,2H), 1.42-1.38 (m, 2H), 1.35-1.33 (m, 4H), 0.92-0.91(m, 2H), 0.56 (s, 2H). LC-MS (ESI+) m/z

1482

833.8 (M+H)+.

[004846] Example 24: 6-((l.,6-naphthvridin vl)amino) (cvclopropvlamino)-N((lR.,4R) ((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4vl)amino)ethoxv)ethoxv)ethvl)carbamovl)cvclohexyl)nicotinamide,1-24

[004847] 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lr,4r) ((2-(2-(2((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl) carbamoyl)cyclohexyl)nicotinamide 1-24 was synthesized via Method 4 with Intermediate R as the fluorine and tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (CAS# 811442 9) as the amine in Step 1. Intermediate C was used as the acid in Step 3. 1H NMR (400 MHz, DMSO) δ ppm 11.09 (s, IH), 10.34 (s, IH), 9.03 (s, IH), 8.55-8.54 (m, 3H), 8.40 (s, IH), 8.24 (d, J= 8.8 Hz, IH), 8.11 (d, J= 7.6 Hz, IH), 7.81-7.73 (m, IH), 7.58-7.47 (m, 3H), 7.13 (d, J= 8.8 Hz, IH), 7.02 (d, J= 7.2 Hz, IH), 6.60-6.58 (m, IH), 4.96 (m, IH), 3.68-3.61 (m, 3H), 3.60-3.59 (m, 3H), 3.54-3.52 (m, 7H), 3.37-3.34 (m, 2H), 3.17-3.15 (m, 2H), 3.17-3.15 (m, 2H), 2.91-2.82 (m, IH), 2.65-2.58 (m, IH), 2.06-1.99 (m, 2H), 1.85-1.82 (m, 2H), 1.74-1.70 (m ,3H), 1.45-1.21 (m, 4H), 0.92-0.84 (m, 2H), 0.56 (s, 2H). LC-MS (ESI+) m/z 922.2 (M+H)+

[004848] Example 25: 6-((l.,6-naphthvridin vl)amino) (cvclopropvlamino)-N((lr.,4r) ((2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4vl)amino)ethoxv)ethvl)carbamovl)cvclohexvl)nicotinamide.,1-25

[004849] 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lr,4r) ((2-(2-((2(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-41483 yl)amino)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide 1-25 was synthesized via Method 4 using Intermediate R as the fluorine and tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (CAS# 127828 2) as the amine in Step 1. The product of Step 2 was triturated with diethyl ether instead of MBTE. Intermediate C was used as the acid in Step 3 and the final product was purified by HPLC (0.1% formic acid in water/ACN). 1H NMR (400 MHz, DMSO - /6) δ 11.1 (s, IH), 10.34 (s, IH), 9.03 (s, IH), 8.56-8.54 (m, 3H), 8.40 (s, IH), 8.25 (d, J = 92 Hz, IH), 8.15-8.05 (m, 2H), 7.81-7.75 (m, IH), 7.60-7.5 (m, 2H), 7.50 (d, J = 8.8 Hz, IH), 7.14 (d, J= 8.4 Hz, IH), 7.04 (d, J = 7.2 Hz, IH), 6.59 (d, J = 6.0 Hz, IH), 5.04(dd, J = 13.0 Hz & 5.4 Hz, IH), 3.7-3.55 (m, 3H), 3.50-3.40 (m, 4H), 3.25-3.15 (m, 2H), 2.90-2.80 (m, IH), 2.55-2.65 (m, 2H), 2.10-1.95 (m, 2H), 1.85-1.65 (m, 4H), 1.45-1.21 (m, 4H), 0.92 (d, J = 52 Hz, 2H), 0.57 (s, 2H); LC-MS (ESI+) m/z %92&#1512; (M+H)+.

[004850] Example 26: 6-((l,6-naphthvridin vl)amino) (cvclopropylamino)-N((lr,3r) ((2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclobutyDnicotinamide,1-26

[004851] 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lr,3r) ((2-(2-(2((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl) carbamoyl) cyclobutyl)nicotinamide 1-26 was synthesized via Method 4 using Intermediate R as the fluorine and tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS# 153086 3) as the amine in Step 1. Intermediate O was used as the acid in Step 3. In Step 3, HATU was used as the coupling reagent instead of PyBOP and the reaction was run at rt for 4 h. 1H NMR (400 MHz, DMSO) δ 11.09 (s, IH), 10.36 (s, IH), 9.03 (s, IH), 8.55-8.50 (m, 3H), 8.44 (s, IH), 8.26 (d,/=8.8 Hz, IH), 7.79 (t, J = 5.6 Hz, IH), 7.58-7.54 (m, 2H), 7.49 (d, J = 92 Hz, IH), 7.14 (d, J = 8.4 Hz, IH), 7.00 (d,/=7.2 Hz, IH), 6.60 (s, IH), 5.06-5.02 (m, IH), 4.51-4.49 (m, IH), 3.62-3.32 (m, 10H), 3.20-3.14 (m, 3H), 2.87-2.83 (m, 2H), 2.58-2.48 (m, IH), 2.33-2.21 (m, 4H), 2.02-1.97 (m, 2H), 1.21 (m, IH), 0.92 (d, /= 5.2 Hz, 2H), 0.55 (s, 2H). LC-MS (ESI+) m/z 805.68 (M+H)+

[004852] Example 27:6-(5-cvano-lH-pvrazolo[3,4-b]pyridin-l-vl)-41484 (cvclopropylamino)-N-((lR.,3R) ((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3dioxoisoindolin vl)amino)ethoxv)ethoxv)ethyl) carbamovDcvclobutvDnicotinamide., 1-27

[004853] 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)-N-((lr,3r)-3((2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl) carbamoyl)cyclobutyl)nicotinamide 1-27 was synthesized via Method 4 using Intermediate R as the fluorine and ter/-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS# 153086 3) as the amine in Step 1. (lR,3R) (6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotinamido)cyclobutane-l-carboxylic acid (synthesized via Steps 1-2 of Method 3 for Example 21) was used as the acid in Step 3 which was run at rt for 2 h. The final compound was purified by prep HPLC (0.1% formic acid in water/ACN). 1H NMR (400 MHz, DMSO) δ 11.13 (s, IH), 9.07 (d, J = 2 Hz, IH), 9.04 (d, J = 2 Hz, IH), 8.81 (d, J= 7.2 Hz, IH), 8.67 (s, IH), 8.64 (s, IH), 8.56 (s, IH), 7.84 (t, J = 6 Hz, IH), 7.68 (s, IH), 7.59 (t, J = 7.2 Hz, IH), 7.16 (d, 7= 8.4 Hz, IH), 7.05 (d, 7= 7.2 Hz, IH), 6.62 (t, 7= 5.6 Hz, IH), 5.09-5.04 (m, IH), 4.56-4.52 (m, IH), 3.64-3.50 (m, 6H), 3.48-3.35 (m, 5H), 3.24-3.20 (m, 2H), 2.92-2.84 (m, 2H), 2.61-2.51 (m, 2H), 2.39-2.23 (m, 4H), 2.04-2.02 (m, IH). LC-MS (ESI+) m/z 804.5.

[004854] Example 29:6-(5-cvano-lH-pyrazolo[3.,4-b]pvridin-l-vl)-4(cvdopropylamino)-N-((lr.,4r) ((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin4-vl)amino)ethoxv)ethoxy)ethyDcarbamovDcyclohexyDnicotinamide.,1-29

[004855] 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)-N-((lr,4r)-4

1485 ((2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy) ethyl)carbamoyl)cyclohexyl)nicotinamide 1-29 was synthesized via Method 4 using Intermediate R as the fluorine and tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS# 153086-783) as the amine in Step 1. Intermediate AG was used as the acid in Step 3 which was run at rt for 2 h. The final product was purified using preparative HPLC (0.1% formic acid in water/ACN). Characterization of the final product: 1H NMR (400 MHz, DMSO) δ 11.13 (s, IH), 9.08 (dd, 71 = 2 Hz, 72 = 13 Hz, IH), 8.67 (s, 2H), 8.60 (d, 7= 18.4 Hz, IH), 8.42 (d, 7= 7.6 Hz, IH), 7.82-7.76 (m, IH), 7.69 (s, IH), 7.60 (t, 7= 7.6 Hz, IH), 7.18 (d, 7= 8.4 Hz, IH), 7.07 (d, 7= 6.8 Hz, IH), 6.63 (t, 7= 5.6 Hz, IH), 5.10-5.05 (m, IH), 3.71-3.36 (m, 9H) 3.22-3.19 (m, 2H), 3.04-3.00 (m, IH), 2.94-2.85 (m, IH), 2.62-2.51 (m, 2H), 2.11-1.91 (m, 2H), 1.88-1.78 (m, 2H), 1.76-1.73 (m, 2H), 1.48-1.24 (m, 3H), 1.39-1.32 (m, 2H), 0.87-0.58 (m, 2H). LC-MS (ESL)&#1524;/ z 832.78 (M+H)+. [004856] Example 30 (Method 5):6-((l6&#1524;-naphthvridin vl)amino)-4(cvclopropylamino)-N-((lR.,4R) ((3-(3-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4yl)amino)propoxy)propyl)carbamoyl)cyclohexyllnicotinamide.,1-30

[004857] Step 1 - tert-butyl (3-(3-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4 yl)amino)propoxy)propyl)carbamate

1486

[004858] A solution of tert-butyl (3-(3-aminopropoxy)propyl)carbamate (0.36 g, 1.55 mmol, Intermediate S), 2-(2,6-dioxopiperidin yl) fluoroisoindoline-l,3-dione (0.47 g, 1.70 mmol, Intermediate R) and DIPEA (0.4 mL, 2.3 mmol) in DMF (3 mL) was stirred at 80 °C for 1 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure. The crude product was purified using silica gel column chromatography (3% MeOH-DCM) to give tert-butyl (3-(3-((2-(2,6dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)propoxy)propyl)carbamate as a yellow semi-solid (0.1 g, 13%). LC-MS (ESI+) m/z 489.5 (M+H)+.

[004859] Step 2 - 4-((3-(3-aminopropoxy)propyl)amino) (2,6-dioxopiperidin-3yl)isoindoline-L3-dione hydrochloride

[004860] To a solution of tert-butyl (3-(3-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin4-yl)amino)propoxy)propyl)carbamate (0.1 g, 0.2 mmol) in DCM (5 mL) was added 4N HC1 in dioxane (2 mL) at 0 °C. The reaction mixture was then allowed to come to rt and was stirred for 3 h. The reaction mixture was then evaporated under vacuum to afford the crude product which was triturated using MTBE (5 mL) to give 4-((3-(3-aminopropoxy)propyl)amino) (2,6dioxopiperidin yl)isoindoline-l,3-dione hydrochloride as a yellow solid (0.06 g, 69%). LC-MS (ESI+) m/z 389.4 (M+H)+.

[004861] Step 3 - 6-((L6-naphthyridin yl)amino) (cyclopropylamino)-N-((lR,4R)-4((3-(3-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin yl)amino)propoxy)propyl)carbamoyl) cyclohexyDnicotinamide

[004862] A solution of 4-((3-(3-aminopropoxy )propyl)amino) (2,6-di oxopiperi din-3yl)isoindoline-l,3-dione hydrochloride (0.06 g, 0.14 mmol), (lR,4R) (6-((l,6-naphthyridin-2yl)amino) (cyclopropylamino)nicotineamido)cyclohexane-l-carboxylic acid (0.063 g, 0.14 mmol, Intermediate C), PyBOP (0.11 g, 0.21 mmol) and DIPEA (0.1 mL, 0.42 mmol) in DMF (3 mL) was stirred at rt for 2 h. The reaction mixture was then poured in ice water mixture (50 mL) and the solid precipitated was filtered. The crude solid was then purified by prep HPLC (0.1% formic acid in water/ACN) to give 6-((l,6-naphthyridin yl)amino) (cyclopropylamino)-N((lR,4R) ((3-(3-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)propoxy) propyl)carbamoyl) cyclohexyl)nicotinamide 1-30 as a yellow solid (0.018 g, 16%). 1H NMR (400 MHz, DMSO) δ 11.11 (s, IH), 10.36 (s, IH), 9.05 (s, IH), 8.57 (d, J= 52 Hz, 2H), 8.42 (s, IH),

1487

8.28 (d, J= 8.8 Hz, IH), 8.15 (d, J= 4.4 Hz, IH), 7.73-7.71 (m, IH), 7.59-7.49 (m, 3H), 7.12 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 7.2 Hz, IH), 6.75-6.65 (m, IH), 5.14-5.10 (m, IH), 3.60-3.70 (m, 2H), 3.45 (t, J= 5.6 Hz, 2H), 3.39-3.34 (m, 3 H), 3.11-3.09 (m, 2H), 3.00-2.80 (m, 2H), 2.67-2.50 (m, 4H), 2.33 (s, IH), 2.10-2.00 (m, 2H), 2.05- 1.63 (m, 7H), 1.45-1.25 (m, 4H), 0.95 (d, J = 4.8 Hz, 2H), 0.58 (s, 2H). LC-MS (ESI+) m/z 817.8 (M+H)+.

[004863] Table 4: Compounds synthesized via Method 5 with the addition of various amines to fluoride Intermediate R in Step 1, followed coupling with various acids in Step 3

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediate Amine</td><td> Step 3 Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td> HNMR (400MHz, DMSO-d6) δ</td>

1488

1489

<td> 37</td><td> 1-37</td><td> EP</td><td> (lR,3R)-3-(6(5-cyano-IHpyrazolo[3,4b]pyridin-lyl)-4(cyclopropylamino)nicotinamido)cyclobutane1-carboxylic acid (synthesized via Steps 1-2 of Method 3 for Example 21)</td><td> 818.7</td><td> 11.13 (s, IH), 9.09-9.05 (m, 2H), 8.84 (t, 7= 7.2 Hz, IH), 868 (d, 7 = 7.6 Hz, 2H), 8.56 (s, IH), 7.69 (d, 7= 2.4 Hz, IH), 7.59-7.57 (m, IH), 7.15 (t, 7= 9.2 Hz, IH), 7.04 (t, 7= 7.2 Hz, IH), 6.65-6.60 (m, IH), 2.10-5.04 (m, IH), 4.42-4.35 (m, IH), 3.66-3.28 (m, 11H), 2.93-2.85 (m, 4H), 2.69-2.35 (m, 5H), 2.33-2.26 (m, 2H), 2.06-2.02 (m, IH), 0.88-0.84 (m, 2H), 0.59 (d, 7=6.8Hz, 2H)</td>

1490

<td> 39</td><td> 1-39</td><td> V</td><td> (lR,3R)-3-(6(5-cyano-IHpyrazolo[3,4b]pyridin-lyl)-4(cyclopropylamino)nicotinamido)cyclobutane1-carboxylic acid (synthesized via Step 1-2 of Method 3 for Example 21)</td><td> 906.8</td><td> 11.12 (s, IH), 9.07-9.04 (m, 2H), 8.87-8.84 (m, IH), 8.68-8.67 (m, 2H), 8.57 (s, IH), 7.70 (s, IH), 7.58-7.56 (m, IH), 7.16-7.12 (m, 1 Hz, IH), 7.05-7.02 (m, IH), 6.61-6.59 (m, IH), 5.08-5.04 (m, IH), 4.42-4.40 (m, IH), 3.64-3.62 (m, 2H), 3.61-3.54 (m, 11H), 3.53-3.50 (m, 3H), 2.91 (s, 2H), 2.86 (s, IH), 2.68-2.57 (m, 4H), 2.51-2.46 (m, 3H), 2.34-2.29 (m, 3H), 2.05-0.02 (m, IH), 0.87-0.85 (m, 2H), 0.57 (s, 2H)</td>

*Step 1 was run at 80-90 °C for 1-1.5 h. The intermediate of Step 2 could also be triturated with similar solvents to MBTE, such as diethyl ether. The final product of Step 3 was often purified by silica gel column chromatography (10% MeOH-DCM) first, then preparative HPLC (0.1% formic acid in water/ACN). aStep 2 was run for 16 h at rt and the intermediate was not triturated.

[004864] Example 40 (Method 6):6-((l.,6-naphthvridin vl)amino)-4(cvclopropylamino)-N-((lR.,4R) ((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)(methyl) carbamoyDcyclohexyDnicotinamide., 1-40

1491

[004865] Step 1 - tert-butyl (2-(2-(2-((lR,4R) (6-((L6-naphthyridin yl)amino)-4(cyclopropylamino)nicotinamido)-N-methylcyclohexane-l-carboxamido)ethoxy)ethoxy) ethyl )carbamate

[004866] A solution of (lR,4R) (6-((l,6-naphthyridin yl)amino) (cyclopropylamino) nicotinamido)cyclohexane-l-carboxylic acid (0.7 g, 1.57 mmol, Intermediate C), tert-butyl(2-(2(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate (0.42 g, 1.57 mmol, Intermediate AC), PyBOP (1.23 g, 2.40 mmol) and DIPEA (0.7 mL, 2.5 mmol) in DMF (10 mL) was stirred at rt for 2 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 30 mL). The combined organic layer was dried over anhydrous sodium sulfate

1492 and filtered. The filtrate was evaporated under reduced pressure and the crude product which was purified using silica gel column chromatography (5% MeOH-DCM) to give tert-butyl (2-(2-(2((lR,4R) (6-((l,6-naphthyridin yl)amino) (cyclopropylamino)nicotinamido)-Nmethylcyclohexane-l-carboxamido)ethoxy)ethoxy) ethyl)carbamate as a yellow solid (0.3 g, 24%) [004867] LC-MS (ESI+) m/z 494.5 (M+H)+.

[004868] Step 2 - 6-((L6-naphthyridin yl)amino)-N-((lR,4R) ((2-(2-(2-aminoethoxy) ethoxy)ethyl)(methyl)carbamovl)cvclohexvl) (cvclopropylamino)nicotinamide hydrochloride [004869] To the solution of tert-butyl (2-(2-(2-((lR,4R) (6-((l,6-naphthyridin-2yl)amino) (cyclopropyl amino)nicotinamido)-N-methylcyclohexane-lcarboxamido)ethoxy)ethoxy)ethyl)-carbamate (0.3 g, 0.43 mmol) in DCM (3 mL) was added 4N HCI in dioxane (2 mL) at 0 °C. The reaction mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was then evaporated under vacuum to afford the crude product which was triturated using MTBE (5 mL) to give 6-((1,6-naphthyridin yl)amino)-N-((lR,4R) ((2-(2-(2aminoethoxy) ethoxy)ethyl)-(methyl)carbamoyl)cyclohexyl) (cyclopropylamino)nicotinamide hydrochloride as a light yellow solid (0.25 g, 97%). LC-MS (ESI+) m/z 591.4 (M+H)+.

[004870] Step 3 - 6-((L6-naphthvridin vl)amino) (cvclopropylamino)-N-((lR,4R)-4((2-(2-(2-((2-(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethyD(methyl) carbamoyl)cyclohexyl)nicotinamide

[004871] A solution of 6-((1,6-naphthyridin yl)amino)-N-((lR,4R) ((2-(2-(2aminoethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl) (cyclopropylamino) nicotinamidehydrochloride (0.25 g, 0.42 mmol), 2-(2,6-dioxopiperidin yl) fluoroisoindoline1,3-dione (0.13 g, 0.46 mmol, Intermediate R) and DIPEA (0.22 mL, 1.26 mmol) in DMF (2 mL) was heated at 90 °C for 1 h. The reaction mixture was then transferred into ice water and the resulting mixture was extracted using ethyl acetate (3 x 20 mL). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the crude product was purified using preparative HPLC (0.1% formic acid in water/ACN) to give 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lR,4R) ((2(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethyl)(methyl) carbamoyl)cyclohexyl)nicotinamide 1-40 as yellow solid (0.01 g, 5%). 1HNMR (400 MHz, DMSO) δ 11.11 (s, IH), 10.35 (s, IH), 9.05 (s, IH), 8.57-8.56 (m, 3H), 8.42 (d, J= 5.2 Hz, IH), 8.28 (d, J= 9.2 Hz, IH), 7.16 (s, IH), 8.14-8.11 (m, IH), 7.61

1493

7.50 (m, 3H), 7.16-7.13 (m, IH), 7.06-7.03 (m, IH), 6.62 (t, J = 5.6 Hz, IH), 5.03 (t, J= 8.4 Hz, IH), 3.64-3.34 (m, 11H), 3.03 (s, 2H), 2.85 (s, 2H), 2.67-2.50 (m, 3H), 2.04 (bs, IH), 1.90-1.80 (m, 2H), 1.46-1.38 (m, 4H), 0.95 (t, J= 5.2 Hz, IH), 0.57 (s, IH). LC-MS (ESI+) m/z 848 (M+H)+. [004872] Example 41: 6-((l6&#1524;-naphthvridin vl)amino) (cvclopropvlamino)-N((lr4&#1524;r) ((2-((5-((2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4vl)amino)ethoxv)methvl)pvridin vl)methoxv)ethvl)carbamovl)cvclohexyl)nicotinamide, I41

H

[004873] 6-((1,6-naphthyri din yl)amino) (cyclopropylamino)-N-((lr,4r) ((2-((5-((2((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)methyl)pyridin-2yl)methoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide 1-41 was synthesized via Method 6 using Intermediate AF as the amine and Intermediate C as the acid in Step 1. In Step 3, Intermediate R was used as the fluorine and the reaction was run for 2 h at 90 °C. The final product was purified first by silica gel column chromatography (15% MeOH-DCM) followed by preparative HPLC (0.1% formic acid in water/ACN). Characterization of the final product: 1H NMR (400 MHz, DMSO4) δ 11.13 (s, IH), 10.37 (s, IH) 9.06 (s, IH), 8.60-8.55 (m, 3H), 8.49 (s, IH), 8.43 (s, IH), 8.28 (d, J = 92 Hz, IH), 8.15 (d, J = 8.0 Hz, IH), 7.91 (t, J = 52 Hz, IH), 7.76 (d, J = 6.4 Hz, IH), 7.61-7.55 (m, 2H), 7.52 (d, J= 92 Hz, IH), 7.43 (d, J= 7.6 Hz, IH), 7.17 (d, J= 8.4 Hz, IH), 7.05 (d, J= 7.2 Hz, IH), 6.70-6.60 (m, IH), 5.11-5.06 (m, IH), 4.65-4.50 (m, 4H), 3.75-3.65 (m, 3H), 3.60-3.50 (m, 4H), 3.33-3.25 (m, 2H), 3.30-2.80 (m, 2H), 2.70-2.60 (m, 2H), 2.22-2.00 (m, 2H), 1.95-1.85 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.25 (m, 4H), 0.95 (d, J = 52 Hz, 2H), 0.59 (s, 2H), LC-MS (ESI+) m/z 909.8 (M+H)+.

[004874] Example 42:6-(5-cvano-lH-pyrazolo[3.,4-b]pvridin-l-vl)-4(cvdopropylamino)-N-((lr.,4r) ((2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin4-vl)amino)ethoxv)ethoxv)ethyl) (methvl)carbamovl)cvclohexyl)nicotinamide, 1-42

1494

[004875] 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)-N-((lr,4r)-4((2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl) (methyl)carbamoyl)cyclohexyl)nicotinamide 1-42 was synthesized via Method 6 using Intermediate AC as the amine and Intermediate AG as the acid in Step 1. In Step 3, Intermediate R was used as the fluorine. Characterization of the final product: 1H NMR (400 MHz, DMSO) δ 11.13 (s, IH), 9.07 (s, IH), 9.04 (d, J = 2 Hz, IH), 8.67 (s, IH), 8.60 (t, J = 4.4 Hz, IH), 8.53 (s, IH), 8.45-8.39 (m, IH), 7.68 (s, IH), 7.62-7.57 (m, IH), 7.18-7.14 (m, IH), 7.07-7.03 (m, IH), 6.63 (bs, IH), 5.10-5.05 (m, IH), 3.70 (bs, IH), 3.63-3.39 (m, 11H), 3.04 (s, 2H), 2.93-2.85 (m, IH), 2.80 (s, 2H), 2.68-2.51 (m, 4H), 2.09-2.04 (m, IH), 1.92-1.85 (m, 2H), 1.74-1.72 (m, 2H), 1.47-1.40 (m, 4H), 0.87(d, J= 52 Hz, IH), 0.58 (s, 2H). LC-MS (ESI+) m/z 846.2

[004876] Example 43: 6-((l.,6-naphthvridin vl)amino) (cvclopropvlamino)-N-(l-(2(2-(2-(2-((2-(2.,6-dioxopiperidin vl)-l.,3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethoxy)acetyl)piperidin yl)nicotinamide.,1-43

[004877] 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-(l-(2-(2-(2-(2-((2(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethoxy)acetyl) piperidin yl)nicotinamide 1-43 was synthesized via Method 6 using Intermediate EO as the amine and 2,2-dimethyl oxo-3,8,ll,14-tetraoxa azahexadecan oic acid (CAS # 46210006-7) as the acid in Step 1. In Step 3, Intermediate R was used as the fluorine. Characterization of the final product: 1HNMR (400 MHz, DMSO) δ 11.11 (s, IH), 10.36 (s, IH), 9.05 (s, IH), 8.578.54 (m, 3H), 8.43 (s, IH), 8.28 (d, J = 92 Hz, IH), 8.22-8.16 (m, IH), 7.59-7.49 (m, 3H), 7.14 (d,J= 8.4 Hz, IH), 7.04 (d, J= 6.8 Hz, IH), 6.61 (t, J= 5.6 Hz, IH), 5.08-5.03 (m, IH), 4.30-4.27

1495 (m, IH), 4.19-4.08 (m, 2H), 3.99-3.97 (m, IH), 3.83-3.80 (m, IH), 3.83-3.61 (m, 2H), 3.57-3.33 (m, 8H), 3.10-3.00 (m, IH), 2.88-2.85 (m, IH), 2.70-2.50 (m, 5H), 2.04-2.01 (m, IH), 1.90-1.75 (m, 2H), 1.55-1.30 (m, 2H), 0.95 (d, J = 52 Hz, IH), 0.58 (s, IH). LC-MS (ESI+) m/z 849.4 (M+H)+.

[004878] Example 44:6-(5-cvano-lH-pyrazolo[3.,4-b]pvridin-l-vl)-4(cyclopropylamino)-N-((lr.,4r) ((2-(2-(2-((2-(2.,6-dioxopiperidin yl)-l.,3-dioxoisoindolin4-yl)amino)ethoxy)ethoxy)ethyl) (methyl)carbamoyl)cydohexyl)nicotinamide., 1-44

[004879] 6-((1,6-naphthyridin yl)amino) (cyclopropylamino)-N-((lr,3r) ((2-(2-(2((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethyl)(methyl) carbamoyl)cyclobutyl)nicotinamide 1-44 was synthesized via Method 6 using Intermediate AC as the amine and Intermediate O as the acid in Step 1. In Step 3, Intermediate R was used as the fluorine. Characterization of the final product: 1H NMR (400 MHz, DMSO) δ 11.10 (s, IH), 10.36 (d, J = 4 Hz, IH), 9.05 (s, IH), 8.57-8.56 (m, 3H), 8.47 (s, IH), 8.28 (d, J = 92 Hz, IH), 7.60-7.50 (m, 3H), 7.16 (t, J = 8.4 Hz, IH), 7.05-7.02 (m, IH), 6.63-6.60 (m, IH), 5.08-5.03(m, IH), 4.38-4.30 (m, IH), 3.64-3.44 (m, 12H), 2.91 (s, 3H), 2.67-2.54 (m, 3H), 251-2.50 (m, 3H), 2.42-2.24 (m, 3H), 2.04-2.01 (m, IH), 0.94 (t, J = 6.4 Hz, IH), 0.57 (t, J = 6.4 Hz, IH). LC-MS (ESI+) m/z 818.92 (M+H)+.

[004880] Example 45:6-(5-cvano-lH-pyrazolo[3.,4-b]pvridin-l-vl)-4(cyclopropylamino)-N-((lR.,4R) ((14-((2-(2.,6-dioxopiperidin yl)-l.,3-dioxoisoindolin-4yl)amino)-3.,9,12-trioxa azatetradecyl)carbamoyl)cyclohexyl)nicotinamide, 1-45

1496

[004881] 6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)-N-((lR,4R)-4((14-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin yl)amino)-3,9,12-trioxa-6azatetradecyl)carbamoyl)cyclohexyl)nicotinamide 1-45 was prepared via Method 6 using Intermediate ER as the amine and Intermediate AG as the acid in Step 1. In Step 2, the BOC intermediate was deprotected using TFA at rt in DCM for 2 h. In Step 3, Intermediate R was used as the fluorine and the reaction was run at 80 °C for 2 h. Characterization of the final product: 1H NMR (400 MHz, DMSO-7,) δ 11.05 (s, IH), 9.08-9.04 (m, 2H), 8.67 (s, IH), 8.61 (s, IH), 8.56 (s, IH), 8.42 (d, J = 7.2 Hz, IH), 7.86-7.83 (m, IH), 7.69 (s, IH), 7.61-7.57 (m, IH), 7.17-7.15 (m, IH), 7.06-7.04 (m, IH), 6.64-6.61 (m, IH), 5.09-5.05 (m, IH), 3.74-3.72 (m, 2H), 3.65-3.63 (m, 5H), 3.60-3.59 (m, 6H), 3.41-3.38 (m, 4H), 3.23-3.20 (m, 2H), 2.94-2.90 (m, IH), 2.76-2.74 (m, 4H), 2.69-2.62 (m, 2H), 2.15-2.09 (m, 2H), 2.03-1.93 (m, 2H), 1.90-1.79 (m, 2H), 1.50-1.31 (m, 5H), 0.89-0.86 (m, 2H), 0.58 (s, 2H), LC-MS (ESI+) m/z 919.09 (M+H)+.

[004882] Example 46 (Method 7): 6-(5-Cvanopvrazolo[3,4-b]pyridin-l-vl)-4(cvclopropvlamino)-N-[3-[2-[2-[2-[[2-(2,6-dioxo piperidvl)-l,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] ethoxy] fluoro-propyl] pyridine carboxamide, 1-46

1497

BocHN

HATU, DIPEA, DMF

HCI in dioxane

DCM

[004883] Step 1 - Tert-butyl N-r2-r2-r2-r3-rr6-(5-cvanopvrazolo[3,4-b1pvridin-l-vl)-4(cyclopropylamino)pyridine carbonyl1amino1 fluoropropoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[004884] To a solution of tert-butyl N-[2-[2-[2-(3-amino fluoropropoxy)ethoxy]ethoxy]ethyl]carbamate (200 mg, 617 umol, Intermediate AI), 6-(5cyanopyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino) pyridine carboxylic acid (268 mg, 617 umol, Intermediate L, as the TFA salt) and DIPEA (398 mg, 3.08 mmol) in DMF (3 mL) was added HATU (281 mg, 740 umol). The mixture was stirred at rt for 1 h. On completion, the reaction mixture was diluted with H2O (30 mL), extracted with EA (3 X 20 mL), dried with Na2SO4, filtered

1498 and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% ΝΗ3&#905;2Ο) to give the title compound (82.0 mg, 21% yield) as a yellow oil. LC-MS (ESI+) m/z 627.4 (M+H)+.

[004885] Step 2 - N-r3-r2-r2-(2-aminoethoxy)ethoxy1ethoxy1 fluoro-propyl1 (5cyanopyrazolo[3,4-b1 pyridin yl) (cy cl opropylamino)pyridine carboxamide

[004886] To a solution of tert-butyl N-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-l-yl)4-(cyclopropylamino)pyridine carbonyl]amino] fluoropropoxy]ethoxy]ethoxy]ethyl]carbamate (90.0 mg, 144 umol) in DCM (2 mL) was added HCI in dioxane (4 M, 2 mL). The mixture was stirred at rt for 15 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (75.0 mg, 93% yield) as a yellow oil. LC-MS (ESI+) m/z 527.4 (M+H)+.

[004887] Step 3 - 6-(5-Cyanopyrazolor3,4-b1pyridin-l-yl) (cyclopropylamino)-N-[3-r2Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο-3 fluoro-propyl1pyridine carboxamide

[004888] To a solution of N-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy] fluoro-propyl] (5cyanopyrazolo[3,4 -b]pyridin-l-yl) (cyclopropylamino)pyridine carboxamide (75.0 mg, 133 umol, HCI salt) in dioxane (4 mL) was added DIPEA (172 mg, 1.33 mmol) and 2-(2,6-dioxo-3piperidyl) fluoro- isoindoline-1,3-dione (36.8 mg, 133 umol, Intermediate R). The mixture was heated to 115 °C and stirred for 60 h. On completion, the mixture was concentrated in vacuo. The residue was further purification by pre-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]; B%: 32%-62%, lOmin) to give the title compound 1-46 (42.0 mg, 38% yield) as yellow solid. 1HNMR (400MHz, DMSO-t/6) δ 11.16 - 11.08 (m, IH), 9.09 9.06 (m, IH), 9.05 - 9.02 (m, IH), 8.85 (t, J= 52 Hz, IH), 8.68 (s, IH), 8.64 (s, IH), 8.59 - 8.54 (m, IH), 7.71 (s, IH), 7.59 - 7.53 (m, IH), 7.15 (d, J= 8.8 Hz, IH), 7.04 (d, J= 6.8 Hz, IH), 6.63 - 6.59 (m, IH), 5.09 - 5.02 (m, IH), 4.87 - 4.70 (m, IH), 3.71 - 3.65 (m, IH), 3.64 - 3.61 (m, 2H), 3.60 - 3.52 (m, 10H), 3.50 - 3.46 (m, 2H), 2.91 - 2.83 (m, IH), 2.63 - 2.56 (m, 2H), 2.56 - 2.54 (m, 2H), 2.07 - 1.99 (m, IH), 0.90 - 0.83 (m, 2H), 0.57 - 0.55 (m, 2H); LC-MS (ESI+) m/z 783.2 (M+H)+.

[004889] Table 5: Compounds synthesized via Method 7&#1524; with the coupling of amines and acids in Step I, followed by the addition to fluoride Intermediate R in Step 3

<td> Ex-#</td><td> I-#</td><td> Intermediat e Amine</td><td> Intermediat e Acid</td><td> LCMS (ES+) m/z</td><td> HNMR (400MHz, DMSO-d6) δ</td>

1499

1500

<td> 53</td><td> 1-53</td><td> tert-butyl N[2-[2-[2-[2- ־2) aminoethoxy )ethoxy]ethoxy] ethox yl. ethyl ]carb am ate (CAS# 01187-40-0)</td><td> CN</td><td> 1012.0a</td><td> 11.10 (s, IH), 11.01 (s, IH), 9.03 (d, J= 4.8 Hz, 2H), 8.65 (t, J= 52 Hz, IH), 8.26 (d, J= 5.2 Hz, IH), 8.18 8.00 (m, 5H), 7.78 (s, IH), 7.70 (t, J = 6.8 Hz, IH), 7.61 - 7.53 (m, IH), 7.27 (s, IH), 7.18 (d, J =6.0 Hz, IH), 2.12 (d, J = 8.4 Hz, IH), 7.03 (d, J= 7.2 Hz, IH), 6.58 (t, J= 6.0 Hz, IH), 5.05 (dd, J= 5.2, 12.8 Hz, IH), 4.31 - 4.19 (m, 2H), 3.69 - 3.46 (m, 20H), 2.95 - 2.82 (m, IH), 2.63 2.57 (m, 2H), 2.10 - 1.97 (m, IH)</td>

1501

1502

1503

1504

1505

1506

1507

<td> 78c</td><td> 1-78</td><td> tert-butyl N[2-[2-[2-[2- ־2) aminoethoxy )-ethoxy]-</td><td> CE</td><td> 837.3</td><td> (CD3CN) δ 9.08 (br s, IH), 8.43 (s, IH), 8.17(br s, IH), 7.89 (d,7=5.6 Hz, IH), 7.74 (s, IH), 7.54 - 7.48 (m, IH), 7.34 (d, 7= 5.6 Hz, IH), 7.09 (br s, IH), 7.03 - 6.97 (m, 2H),</td>

1508

<td></td><td></td><td> ethoxy] ethox yl. ethyl ]carb am ate (CAS# 01187-40-0)</td><td></td><td></td><td> 6.45 (t, J= 5.6 Hz, IH), 4.98 - 4.81 (m, 2H), 4.68 - 4.64 (m, IH), 4.36 (dd, J= 6.4, 11.2 Hz, IH), 4.19 4.13 (m, IH), 4.06 (s, 3H), 3.66 3.52 (m, 18H), 3.42 (q, J= 5.6 Hz, 2H), 2.79 - 2.59 (m, 4H), 2.13 - 2.08 (m, IH), 1.80 - 1.62 (m, 2H), 1.10 (t, 7= 7.2 Hz, 3H)</td>

1509

1510

<td> 87</td><td> 1-87</td><td> tert-butyl N[2-[2-(2aminoethoxy ־( ethoxy] ethyl] -carbamate (CAS# 153086-783)</td><td> CE</td><td> 749.1</td><td> 11.10 (s, IH), 8.88 (s, IH), 8.43 (t, J = 5.6 Hz, IH), 8.15 (s, IH), 7.90 (d, J= 5.6 Hz, IH), 7.72 (s, IH), 7.58 7.51 (m, IH), 7.42 (d, J= 5.6 Hz, IH), 7.10 (d, J =8.4 Hz, IH), 6.99 (d, J= 7.2 Hz, IH), 6.59 (t, J= 5.6 Hz, IH), 5.05 (dd, J= 5.6, 12.8 Hz, IH), 4.99 - 4.82 (m, IH), 4.54 (dd, J = 3.6, 11.2 Hz, IH), 4.25 (dd, J= 6.4, 11.2 Hz, IH), 4.13 - 4.04 (m, IH), 3.96 (s, 3H), 3.68 - 3.56 (m, 8H), 3.50 - 3.43 (m, 4H), 2.94 - 2.81 (m, IH), 2.62 - 2.53 (m, 3H), 2.07 1.97 (m, IH), 1.65 - 1.56 (m, 2H), 1.02 (t, J =7.2 Hz, 3H)</td>

Variations of temperature and time for Method 7 were as follows: Step 1 was run a from 0.5-3 hrs;

Step 2 was run from 15-60 minutes; Step 3 was run at 110-115 °C for 14-136 hrs, with most

1511 complete within 40-60 h. 3mass is (M+Na)+. bStep 1 was run at rt for 12 h. cStep 3 was run at 90 °C for 12 h. dThe product of Step 1 was purified by silica gel chromatography (DCM: MeOH = 25:1) instead of prep-HPLC.

[004890] Further Examples using synthetic methods similar to Method 7:

[004891] Example 89: l-[[(2S,3S,4S)-l-[2-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyD-l,3dioxo-isoindolin vl]amino]

Pvrrolidin vl]methoxy| methoxv-isoquinoline carboxamide.,

[004892] Step 1 - Tert-butyl (14-((2S.3S.4S) (((6-cyano methoxyisoquinolin-lvl)oxy)methyl) ethyl fluoro oxopyrrolidin-l-vl )-3.6.9.12-tetraoxatetradecyl )carbamate [004893] To a solution of l-[[(2S,3S,4S) ethyl fluoro oxo-pyrrolidin yl]methoxy]7-methoxy- isoquinoline carbonitrile (50 mg, 145.6 umol, Intermediate CD) in DMF (3 mL) was added NaH (11.7 mg, 291 umol, 60% dispersion in mineral oil) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. Then, 2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (90.8 mg, 218 umol, synthesized via Steps 1-2 of Intermediate AK) was added. The resulting reaction mixture was allowed to warm to rt and stirred for 12 h. On completion, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 X 200 mL). The combined organic layers were washed with

1512 saturated brine solution (50 mL), dried over with anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 15%-75%) to give the title compound (25 mg, 25% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 8.03 (s, IH), 7.93 (d, J= 5.6 Hz, IH), 7.75 (s, IH), 7.20 (d, J= 5.6 Hz, IH), 5.10 - 4.92 (m, 2H), 4.85 (dd, /=3.2, 12.4 Hz, IH), 4.45 (dd,/=2.4, 12.4 Hz, IH), 4.32 - 4.25 (m, IH), 4.03 (s, 3H), 3.68 - 3.50 (m, 18H), 3.32-3.31 (m, 2H), 2.65 - 2.42 (m, IH), 1.88 - 1.76 (m, IH), 1.69 - 1.63 (m, IH), 1.44 (s, 9H), 1.11 (t, J = 7.2 Hz, 3H). LC-MS (ESI+) m/z 663.2 (M+H)+.

[004894] Step 2 - Tert-butyl (14-((2S,3S,4S) (((6-carbamoyl methoxyisoquinolin-lyl)oxy)methyl) ethyl fluoro oxopyrrolidin- l-yl )-3.6.9.12-tetraoxatetradecyl)carbarnate [004895] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[(2S,3 S,4S) [(6-cyano methoxy-1isoquinolyl) oxymethyl] ethyl fluoro oxo-pyrrolidinlyl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (20 mg, 30.2 umol) in DMSO (1 mL) was added K2CO3 (4.17 mg, 30.2 umol) at rt. Then, H2O2 (6.84 mg, 60.4 umol, 30% solution) was added slowly. The reaction mixture was stirred at rt for 3 h. On completion, the reaction mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (18 mg, 88% yield) as a colorless oil. LC-MS (ESI+) m/z 703.2 (M+H)+.

[004896] Step 3 - l-(((2S,3S,4S)-l-(14-amino-3A9,12-tetraoxatetradecyl) ethyl fluoro5- oxopyrrolidin- 2-yl)methoxy) methoxyisoquinoline carboxamide

[004897] To a solution of tert-butyl N-[2-[2-[2-[2-[2-[(2S,3S,4S) [(6-carbamoyl-7methoxy isoquinolyl) oxymethyl] ethyl fluoro oxo-pyrrolidin-lyl]ethoxy]ethoxy]ethoxy]ethoxy]-ethyl]carbamate(18.0 mg, 26.44 umol) in DCM (2 mL) was added HCI in dioxane (4 M, 1 mL). The reaction mixture was stirred at rt for 30 min. On completion, the reaction mixture was concentrated in vacuo to give the title compound (16.3 mg, 99% yield, hydrochloride salt). LC-MS (ESI+) m/z 603.2 (M+H)+.

[004898] Step 4 - 1-ΓΓ(28,38,48) Γ2-Γ2-Γ2-Γ2-Γ2-Γ[2-(2,6-&#940;&#912;οχο ρ&#912;ρ6Γ&#938;&#940;ν1)-1,3-&#940;&#912;οχοisoindolin yl1amino1 yl1methoxy1 methoxy-isoquinoline carboxamide

[004899] To a solution of l-[[(2S,3S,4S)-l-[2-[2-[2-[2-(2

1513 aminoethoxy)ethoxy]ethoxy]ethoxy]ethyl] ethyl- 4-fluoro oxo-pyrrolidin yl]methoxy]-7methoxy-isoquinoline carboxamide (16.3 mg, 26.5 umol, HCI salt) and 2-(2,6-dioxo-3piperidyl) fluoro-isoindoline-l,3-dione (9.50 mg, 34.4 umol, Intermediate R) in dioxane (5 mL) was added DIPEA (34.2 mg, 46 uL, 264 umol). The reaction mixture was stirred at 120 °C for 76 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water(0.225%FA)ACN];B%: 35%-65%) to give the title compound 1-89 (10.0 mg, 42% yield,) as a yellow solid. 1H NMR (400MHz, CD3CN) δ 9.09 (s, IH), 8.45 (s, IH), 7.91 (d, J= 6.0 Hz, IH), 7.73 (s, IH), 7.64 (s, IH), 7.57 - 7.50 (m, IH), 7.36 (d, J= 6.0 Hz, IH), 7.04 (s, IH), 7.02 (d, J = 1.6 Hz, IH), 6.48 (t, J= 52 Hz, IH), 6.39 (s, IH), 5.08 - 4.95 (m, IH), 4.92 (dd, J= 6.0, 8.4 Hz, IH), 4.81 (dd, J= 3.6, 12.4 Hz, IH), 4.46 (dd, J= 3.2, 12.4 Hz, IH), 4.30 -3.80(m, IH), 4.02 (s, 3H), 3.82 - 3.80 (m, IH), 3.71 - 3.42 (m, 18H), 3.41 - 3.33 (m, IH), 2.84 - 2.48 (m, 4H), 2.14 - 2.09 (m, IH), 1.81 1.63 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). LC-MS (ESI+) m/z 837.1 (M+H)+.

[004900] Example 90: (2S) [(8R)-l-[4-[4-[2-[2-[2-[[2-(2,6-dioxo piperidvD-l,3 dioxo-isoindolin yl]amino]

6H-cvclopenta[4,5]thieno[l,2-c]pvrimidin vl] hvdroxy-propanamide,

1-90

BocHN

K2CO3, DMF

1514

[004901] To a solution of (25) hydroxy [(8J?)-l-(4-piperazin-l-ylcyclohexoxy)-7,8di hydro-67/- cyclopenta[4,5]thieno[l,2-c]pyrimidin yl]propanamide (80.0 mg, 160 umol, HCI salt, Intermediate DR) in DMF (2 mL) was added K2CO3 (89.0 mg, 643 umol) and 2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy] ethyl methanesulfonate (79.0 mg, 241 umol, synthesized via Step 1 of Intermediate AI), and the mixture was stirred at 60 °C for 20 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% ΝΗ3.Η2Ο) to give tert-butyl N-[2-[2-[2-[4-[4-[[(8R) [(2S)-3amino hydroxy oxo-propyl]-7,8-dihydro -6H-cyclopenta[4,5]thieno[l,2-c]pyrimidin-lyl]oxy]cyclohexyl]piperazin-l-yl]ethoxy]ethoxy]ethyl]carbamate 1-90 (60.0 mg, 53% yield) as a light yellow solid (LC-MS (ESI+) m/z 677.5 (M+H)+). Steps 2 & 3 followed Method 7, where Step 2 was run at rt for 1 h and Step 3 used fluoride Intermediate R for the coupling at 115 °C for 20 h. Characterization of the final product: 1H NMR (400MHz, DMSO-t/6) δ 11.13 (s, IH), 8.52 (m, IH), 7.59 (dd, J = 7.6, 8.4 Hz, IH), 7.23 - 7.09 (m, 3H), 7.05 (d, J= 22 Hz, IH), 6.60 (t, J = 5.6 Hz, IH), 5.17 - 5.09 (m, IH), 5.05 (dd, J= 52, 12.8 Hz, IH), 3.91 (t, J= 6.8 Hz, IH), 3.64 -3.61 (m, 3H), 3.59 - 3.53 (m, 7H), 3.18 - 3.14 (s, 2H), 3.11 - 2.80 (m, 4H), 2.64 - 2.54 (m, 3H), 2.43 2.25 (m, 10H), 2.20 - 1.97 (m, 4H), 1.84 - 1.81 (m, 2H), 1.70 - 1.43 (m, 4H), 1.41 - 1.27 (m, 2H). LC-MS (ESI+) m/z 833.4 (M+H)+.

[004902] Example 91: (2R) [(8R)-l-[4-[4-[2-[2-[2-n2-(2,6-dioxo piperidvD-L3dioxo-isoindolin vl]amino]

6H-cvclopenta[4.,5]thieno[l.,2-c|pvrimidin vl] hvdroxv-propanamide, 1-91

1515

[004903] To a mixture of (2R) hydroxy [(8R)-l-(4-piperazin-l-ylcyclohexoxy)-7,8dihydro-6H-cyclopenta [4,5]thieno[l,2-c]pyrimidin yl]propanamide (60.0 mg, 124 umol, Intermediate EM) in DMF (2 mL) was added K2CO3 (68.8 mg, 497 umol) and 2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (81.5 mg, 248 umol, synthesized via Step 1 of Intermediate AI). Then the reaction mixture was stirred at 60°C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by revered phase (FA) to give ter/-butyl N-[2-[2-[2-[4-[4-[[(8R) [(2R) amino hydroxy oxopropyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazin-lyl]ethoxy]ethoxy]ethyl]carbamate 1-91 (75.0 mg, 63% yield) as yellowish oil. LC-MS (ESI+) m/z 677.2 (M+H)+. Steps 2 & 3 followed Method 7, where Step 2 was run at rt for 30 min and Step 3 used fluoride Intermediate R for the coupling at 115 °C for 12 h. Characterization of the final product: 1HNMR (400MHz, DMSO-d6) δ 11.13 (s, IH), 8.60 - 8.48 (m, IH), 7.66 - 7.50 (m, IH), 7.21-7.14 (m, 2H), 7.12 (s, IH), 7.06 (d,/=7.2 Hz, IH), 6.61 (t,/= 5.6 Hz, IH), 5.19 - 5.11 (m, IH), 5.06 (dd, / = 5.6, 13.2 Hz, IH), 3.86 - 3.84 (m, IH), 3.72 - 3.57 (m, 10H), 2.98 - 2.85 (m, 2H), 2.66 - 2.55 (m, 2H), 2.48 - 2.40 (m, 8H), 2.37 - 2.23 (m, 4H), 2.18-1.99 (m, 4H), 1.85 (d, J = 11.6 Hz, 2H), 1.74 - 1.46 (m, 4H), 1.44 - 1.26 (m, 2H); LC-MS (ESI+) m/z 833.1 (M+H)+.

1516

[004904] Example 92: N-[3-carbamovl-l-[4-[2-[2-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin vl]amino] trifluoroethvlamino) pvridvl]oxazole carboxamide.,1-92

1517

HCI in dioxane

DCM

[004905] To a solution of ter/-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (88.0 mg, 354 umol, CAS# 139115 7) in THF (10 mL) was added Na metal (20 mg, 886 umol). After stirring for 30 minutes at rt, N-[l-[4-(bromomethyl)phenyl] carbamoyl-pyrazol yl] [2

1518 (2,2,2-trifluoroethylamino) pyridyl]oxazole carboxamide (200 mg, 354 umol, Intermediate CV) was added. The mixture was stirred at rt for 30 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography to give tertbutyl N-[2-[2-[2-[[4-[3-carbamoyl [[2-[2-(2,2,2-trifluoroethylamino) pyridyl] oxazole-4carbonyl]amino]-pyrazol-l-yl]phenyl]methoxy]ethoxy]ethoxy]ethyl]carbamate (30.0 mg, 12% yield) as white solid. LC-MS (ESI+) m/z 733.3 (M+H)+.

[004906] Steps 2 & 3 followed Method 7 as described above where the deprotection was run at rt for 2 h. Intermediate R was used as the fluorine coupling partner in the last step, where the reaction was run at 115 °C for 72 hours. The final product was purified by pre-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 40%70%, 22 min) to give the title compound 1-92 (5.03 mg, 14% yield) as yellow solid. 1H NMR (400MHz, DMSO-d6) δ = 11.10 (s, IH), 11.01 (s, IH), 9.03 (s, IH), 8.93 (s, IH), 8.26 (d, J= 5.2 Hz, IH), 8.06 (s, IH), 7.99 - 7.88 (d, J = 8.0 Hz, 2H)7.66 - 7.81 &#1524; (m, 2H), 7.57 (t, J = 7.6 Hz, IH), 7.50-7.46 (m, 2H), 7.27 (s, IH), 7.20-7.12 (m, 2H), 7.03 (d, J= 7.2 Hz, IH), 6.61 (m, IH), 5.05 (dd, J= 5.2, 12.8 Hz, IH), 4.54 (s, 2H), 4.35 - 4.16 (m, 2H), 3.69 - 3.46 (m, 12H), 2.95 - 2.81 (m, IH), 2.60 - 2.57 (m, 2H), 2.06 - 1.97 (m, IH); LC-MS (ESI+) m/z 889.8 (M+H)+.

[004907] Example 93: 4-(Cvclopropvlamino)-N-[3-[2-[2-[2-[[2-(2.,6-dioxo piperidvl)l.,3-dioxo-isoindolin-4 naphthvridin vlamino)pvridine carboxamide,1-93

1519

HATU, DIPEA, DMF

[004908] 4-(cycl opropylamino)-7V-[3-[2-[2-[2-(l,3-di ox oisoindolin yl)-l-methyl-ethoxy]ethoxy]ethoxy] fluoro-propyl] (l,6-naphthyridin ylamino)pyridine carboxamide was synthesized via Step 1 of Method 7, coupling amine BU with acid Intermediate N. This compound was then deprotected in Step 2 using hydrazine hydrate dissolved in EtOH and stirring at 80 °C for 14 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reversed phase chromatography (0.1% NH3*H2O) to give the title compound 1-93 (120 mg, 65% yield) as a brown solid. (LC-MS (ESI)+ m/z 542.3. (M+H)+). Step 3 followed Method 7, where fluoride Intermediate R was utilized. Final product characterization: 1HNMR (400MHz, DMSO-» δ 11.10 (brs, IH), 10.37 (s, IH), 9.06 (s, IH), 8.60 - 8.51 (m, 4H), 8.31 - 8.24 (m, 2H), 7.60 - 7.54 (m, 2H), 7.51 (d, J = 8.8 Hz, IH), 7.14 (d, J = 8.8 Hz, IH), 7.03 (d, J= 7.2 Hz, IH), 6.60 (t, J= 5.6 Hz, IH), 5.06 (dd, J= 5.6, 12.8 Hz, IH), 4.83 - 4.65 (m, IH),

1520

3.72 - 3.20 (m, 15H), 2.95 - 2.84 (m, IH), 2.65 - 2.54 (m, 3H), 2.08 - 1.99 (m, IH), 1.15 (d, J =

6.4 Hz, 3H), 0.98 - 0.91 (m, 2H), 0.62 - 0.56 (m, 2H); LC-MS (ESI)+ m/z 798.3. (M+H)+.

[004909] Example 94:6-(5-Cvano-lH-pvrazolo[3,4-b]pyridin-l-vl)-4(cvclopropvlamino)-N-(3-(2-((2-(2-((2-(2,6-dioxopiperidin vl)-l,3-dioxoisoindolin-4vl)amino)ethoxv)ethvl)amino)ethoxv) fluoropropyl)nicotinamide.

1-94

νη2νη2.η2ο

EtOH

DIPEA, dioxane

[004910] Tert-butyl (2-(3-(6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotin amido) fluoropropoxy)ethyl)(2-(2-(l,3-dioxoisoindolin-2yl)ethoxy)ethyl)carbamate was synthesized using Step 1 of Method 7 by coupling amine Intermediate BH with acid Intermediate L. For Step 2, the amine was deprotected Ν2Η4&#905;2Ο (54.8 mg, 1.07 mmol) in EtOH (4 mL). The mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 4/1) to give tert-butyl (2-(2aminoethoxy)ethyl)(2-(3-(6-(5-cyano-lH-pyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)nicotinamido) fluoropropoxy)ethyl)carbamate (45.0 mg, 92.2% yield) as colorless oil (LC-MS (ESI)+ m/z 626.2. (M+H)+). Step 3 coupled Intermediate R as the fluoride

1521 under the conditions described for Method 7. The final compound was deprotected by dissolving tert-butyl (2-(3-(6-(5-cyano-l//-pyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)nicotin amido) fluoropropoxy)ethyl)(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)amino)ethoxy)ethyl)carbamate (39 mg, 44.2 mg) in DCM (2 mL) and adding HCI in dioxane (4 M, 0.5 mL). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was diluted with MeCN (2 mL) and basified with NaHCO3 solid until the pH = 7. After filtration, the mixture was purified directly by prep-HPLC (column: Phenomenex Synergi Cl8150*25* 10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-94 (2.06 mg, 3.7% yield, FA salt) as a yellow solid. 1H NMR (400MHz, DMSO) δ 11.1 (s, IH), 9.05 (d, 7 = 2.0 Hz, IH), 9.01 (d, 7= 2.0 Hz, IH), 8.83 (t, 7= 5.6 Hz, IH), 8.65 (s, IH), 8.61 (s, IH), 8.53 (s, IH), 8.34 (s, IH), 7.70 (s, IH), 7.55 (s, 7= 7.2 Hz, IH), 7.11(d, 7= 8.8 Hz, IH), 7.01(d,7 = 7.2 Hz, IH), 6.61(d, 7= 6.0 Hz, IH), 5.09 - 5.00 (m, IH), 4.88 - 4.70 (m, IH), 3.70 - 3.50 (m, 5H), 2.95 - 2.84 (m, 2H), 2.80 - 2.63 (m, 9H), 2.37 - 2.30 (m, 4H), 2.05 - 1.98 (m, IH), 0.85 (dd, 7= 6.8, 11.6 Hz, 2H), 0.55 (dd, 7= 6.8, 11.6 Hz, 2H); LC-MS (ESI)+ m/z 804.2. (M+Na)+.

[004911] Example 95 (Method 8): 6-(5-Cyanopyrazolo[3.,4-b]pyridin-l-yl)-4(cyclopropylamino)-N-[3-[2-[2-[[2-[2-(2.,6-dioxo piperidyl)-l.,3-dioxo-isoindolin-4yl]oxyacetyl]amino]ethoxy]ethoxy] fluoro-propyl]pyridine carboxamide.,1-95

<td> o BocHN־''''''-''' L______________N______________ F HATU, DIPEA, DMF AV Ο HN^^ HCI in dioxane η2Ν'^^°'^^Ο'Α^Ν'[|ϊ1 N־ DCM F N=/ Ο /—NH mA a Ο Ο HN M H F H A J F LA 1</td><td>1 A 0 hn׳^ - BocHN~°—O^—cnF AnA 1 f NY κ H °^N^° 0 T J /? A0H aIM CA X7\ \^CN ------------------► JI HATU, DIPEA, DMF A׳</td>

1522

[004912] Step 1 - Tert-butyl N-r2-r2-r3-rr6-(5-cyanopyrazolo[3,4-b1pyridin-l-yl)-4(cyclopropylamino)pyridine carbonyl1amino1 fluoropropoxy1ethoxy1ethyl1carbamate [004913] To a solution of tert-butyl N-[2-[2-(3-amino fluoropropoxy)ethoxy]ethyl]carbamate (100 mg, 356 umol, Intermediate AV) and 6-(5cyanopyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)pyridine carboxylic acid (171 mg, 535 umol, Intermediate L) in DMF (3.00 mL) was added HATU (162 mg, 428 umol) and DIPEA (138 mg, 1.07 mmol, 186 uL). The mixture was stirred at rt for 1 hour. On completion, the mixture was diluted with water (30 mL) and extracted with EA (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase (0.1% ΝΗ3&#905;2Ο) to give the title compound (80.0 mg, 38% yield) as a yellow oil. LC-MS (ESI+) m/z 583.3 (M+H)+.

[004914] Step 2:N-r3-r2-(2-aminoethoxy)ethoxy1 fluoro-propyl1 (5cyanopyrazolor3,4-b1pyridin-l-yl) (cyclopropylamino)pyridine carboxamide

[004915] To a solution of tert-butyl N-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino) pyridine carbonyl]amino] fluoro-propoxy]ethoxy]ethyl]carbamate (80.0 mg, 137 umol) in DCM (4.00 mL) was added HC1 in dioxane (4 M, 2.00 mL) and the mixture was stirred at rt for 30 minutes. On completion, the mixture was concentrated in vacuo to give the title compound (70.0 mg, 98% yield) as white solid. LC-MS (ESI+) m/z 483.2 (M+H)+.

[004916] Step 3 - 6-(5-Cyanopyrazolor3,4-b1pyridin-l-yl) (cyclopropylamino)-N-[3-r2Γ2-ΓΓ2-[2-(2,6-&#940;&#943;οχο-3 fluoro-propyl1pyridine carboxamide

[004917] To a solution of N-[3-[2-(2-aminoethoxy)ethoxy] fluoro-propyl] (5cyanopyrazolo[3,4-b]pyridin- l-yl) (cyclopropylamino)pyridine carboxamide (50.0 mg, 96.3 umol, HC1) and 2-[2-(2,6-dioxo piperidyl)-1,3-dioxo-isoindolin yl]oxyacetic acid (32.0 mg, 96.3 umol, Intermediate CA) in DMF (2.00 mL) was added HATU (43.9 mg, 115 umol) and DIPEA (62.2 mg, 481 umol, 83.9 uL). The mixture was stirred at rt for 1 hour. On completion, the mixture was diluted with H2O (30 mL) and extracted with EA (3X15 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)ACN]; B%: 20%-50%, 10 min) to give the title compound 1-95 (35.36 mg, 43% yield, FA) as a white solid. 1H NMR (400MHz, DMSOQ) δ 11.1 (s, IH), 9.06 (d, J = 1.6 Hz, IH), 9.02 (d, J =

1523

1.6 Hz, IH), 8.91 - 8.81 (m, IH), 8.66 (s, IH), 8.62 (s, IH), 8.54 (s, IH), 8.07 - 7.98 (m, IH), 7.82 - 7.76 (m, IH), 7.71 (s, IH), 7.48 (d, J = 7.2 Hz, IH), 7.39 (d, J = 8.8 Hz, IH), 5.13 - 5.09 (m, IH), 4.79 (s, 2H), 4.88 - 4.71(m, IH), 3.61 - 3.46 (m, 12H), 2.95 - 2.83 (m, IH), 2.63 - 2.54 (m, 3H), 2.09 - 2.02 (m, IH), 0.89 - 0.83 (m, 2H), 0.60 - 0.53 (m, 2H); LC-MS (ESI+) m/z 797A (M+H)+.

[004918] Table 6: Compounds synthesized via Method 8 with the coupling of various amines and acids in Step I, followed by coupling with acid Intermediate CA in Step 3.

<td> Ex-#</td><td> I-#</td><td> Intermediat e Amine</td><td> Intermediat e Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td> HNMR (400MHz, DMSO-d6) δ</td>

1524

1525

<td> 103</td><td> 1-103</td><td> tert-butyl N[2-(2-(2-(2- ־2) aminoethoxy )-ethoxy]ethoxy] ethox yl. ethyl ]carb am ate (CAS# 01187-40-0)</td><td> CE</td><td> 895.4</td><td> 11.12 (br s, IH), 8.88 (s, IH), 8.46 (t, 7= 5.6 Hz, IH), 8.16 (s, IH), 8.01 (t, 7= 5.2 Hz, IH), 7.91 (d, 7 = 5.6 Hz, IH), 7.84 - 7.78 (m, IH), 7.75 (s, IH), 7.49 (d, 7 = 7.2 Hz, IH), 7.44 (d, 7= 5.6 Hz, IH), 7.39 (d, 7 = 8.4 Hz, IH), 5.12 (dd, 7= 5.2, 12.8 Hz, IH), 4.99 - 4.82 (m, IH), 4.79 (s, 2H), 4.54 (dd, 7= 3.2, 11.2 Hz, IH), 4.26 (dd, 7= 6.4, 11.2 Hz, IH), 4.10 - 4.08 (m, IH), 3.97 (s, 3H), 3.60 - 3.43 (m, 18H), 3.32 - 3.27 (m, 2H), 2.96 - 2.84 (m, IH), 2.70 - 2.57 (m, 3H), 2.09 - 2.00 (m, IH), 1.66 1.55 (m, 2H), 1.02 (t, 7= 7.2 Hz, 3H)</td>

1526

Variations in reaction time for Method 8 were as follows: Step 1 was run anywhere from 0.5-16 h, Step 2 anywhere from 0.5-3 h, Step 3 anywhere from 0.5-12 h.

[004919] Further Examples using synthetic methods similar to Method 8:

[004920] Example 105: N-[3-carbamovl-l-[4-[2-[2-[2-[2-[[2-[2-(2,6-dioxo piperidvDl.,3-dioxo-isoindolin vl] oxyacetyll amino] ethoxy] ethoxy] ethoxy] ethoxymethyl] phenyl] pyrazoI vI] [2-(2,2.,2trifluoroethvlamino) pvridvl1oxazole carboxamide,1-105

1527

CV

NHBoc

Na ,THF

h2n

[004921] To a mixture of ter/-butyl N-[2-[2-[2-(2hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (31.0 mg, 106 umol, synthesized via Steps 1-3 of Intermediate AO) in THF (15 mL) was added Na metal (6.00 mg, 267 umol) and N-[l-[4(bromomethyl)phenyl] carbamoyl-pyrazol yl] [2-(2,2,2-trifluoroethylamino)-4pyridyl]oxazole carboxamide (60.0 mg, 106 umol, Intermediate CV). The mixture was stirred at rt for 18 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA in water) to give the tert-butyl N-[2-[2-[2-[2-[[4-[3carbamoyl [[2-[2-(2,2,2-trifluoroethylamino) pyridyl]oxazole carbonyl]amino]-pyrazol-l

1528 yl]phenyl]methoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate compound (15.0 mg, 18% yield) as a white solid. LC-MS (ESI+) m/z 799.4 (M+Na)+.

[004922] Steps 2 & 3 followed Method 8 as described above where the deprotection was run at rt for 30 min. Intermediate CA was used as the acid coupling partner in the last step, where the reaction was run at rt for 18 h. The final product was purified by Pre-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 10 min) to give the title compound 1-105 (1.20 mg, 6% yield) as white solid. 1HNMR (400MHz, DMSOd6) δ 11.08 (s, IH), 10.99 (s, IH), 9.01 (s, IH), 8.93 (s, IH), 8.26 (d, J = 52 Hz, IH), 8.11 - 7.86 (m, 4H), 7.83 - 7.76 (m, IH), 7.74 - 7.64 (m, 2H), 7.50 - 7.47 (m, 3H), 7.42 - 7.34 (m, 2H), 7.27 (s, IH), 7.18 (d, J= 5.2 Hz, IH), 5.11 (dd, J =52, 12.8 Hz, IH), 4.78 (s, 2H), 4.55 (s, 2H), 4.31 4.19 (m, 2H), 3.61 - 3.38 (m, 16H), 2.95 - 2.88 (m, IH), 2.61 - 2.58 (m, 2H), 2.06 - 2.03 (m, IH); LC-MS (ESL)&#1524;/z 1013.3 (M+Na)+.

[004923] Example 106 (Method 9): N-[3-carbamoyl-l-[4-[5-[[2-[2-(2,6-dioxo-3 piperidyl)-l.,3-dioxo-isoindolin yl]oxyacetyl1 yl] [2-(2.,2.,2-trifluoroethylamino) pyridyl1oxazole carboxamide,

1-106

[004924] Step 1 - Tert-butyl N-r5-rr2-r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4 yl]oxyacetvl]amino] pentyl]carbamate

1529

[004925] To a mixture of tert-butyl N-(5-aminopentyl)carbamate (1.50 g, 7.41 mmol, CAS # 51644 3) and DIPEA (3.83 g, 29.6 mmol) in DMF (15 mL) was added 2-[2-(2,6-dioxo-3piperidyl)-l,3-dioxo-isoindolin yl]oxyacetic acid (2.46 g, 7.41 mmol, Intermediate CA) and HATU (3.38 g, 8.90 mmol). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % NH3*H2O) to give the title compound (2.10 g, 54% yield) as a white solid. LC-MS (ESI+) m/z 417.0 (M+H-100)+.

[004926] Step 2 - N-(5-aminopentyl) r2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4ylloxy-acetamide

[004927] To a mixture of tert-butyl N-[5-[[2-[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]oxyacetyl] amino]pentyl]carbamate (500 mg, 967 umol) in DCM (4 mL) was added HCI in dioxane (4 M, 2 mL). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC (0.1 % NH3*H2O) to give the title compound (400 mg, 99% yield) as white solid. LC-MS (ESL) &#1524;/ζ 417.1 (M+H)+.

[004928] Step 3 - Tert-butyl N-r4-r4-rr3-carbamovl-l-r4-r5-rr2-r2-(2.6-dioxo piperidyl)L3-dioxo-isoindolin yl1oxyacetyl1amino1pentylcarbamoyl1phenyl1pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[004929] To a mixture of N-(5-aminopentyl) [2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]oxy- acetamide (250 mg, 552 umol, HCI) and DIPEA (356 mg, 2.76 mmol) in DMF (4 mL) was added 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (339 mg, 552 umol, Intermediate CN) and HATU (251 mg, 662 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was diluted with water (5 mL) and filtered and concentrated in vacuo to give the title compound (400 mg, 80% yield) as light yellow solid. LCMS (ESI+) m/z 1014.3 (M+H)+.

[004930] Step 4 - N-r3-carbamoyl-l-r4-r5-rr2-r2-(2,6-dioxo piperidyl)-L3-dioxoi soindolin yl1 oxyacetyl 1 amino1pentylcarbamoyl1phenyl1pyrazol yl1 r2-(2,2,2trifluoroethylamino) pyridyl1oxazole carboxamide

[004931] To a mixture of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[5-[[2-[2-(2,6-dioxo-3

1530 piperidyl)-l,3-dioxo- isoindolin yl]oxyacetyl]amino]pentylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (400 mg, 394 umol) in DCM (3 mL) was added HCI in dioxane (4 M, 2 mL). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex lunaC18 250*50 mm* 10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-106 (79.4 mg, 20% yield) as white solid. 1H NMR (400MHz, DMSO-d6) δ 11.13 (s, IH), 11.03 (s, IH), 9.04 (s, 2H), 8.56 (t, J= 5.6 Hz, IH), 8.26 (d, J= 5.2 Hz, IH), 8.15 (s, IH), 8.12 - 8.08 (m, 2H), 8.04 - 7.94 (m, 3H), 7.85 - 7.76 (m, 2H), 7.71 (t, J= 6.4 Hz, IH), 7.49 (d, J= 7.2 Hz, IH), 7.40 (d, J= 8.4 Hz, IH), 7.28 (s, IH), 7.21 - 7.16 (m, IH), 5.14 (dd, J = 5.2, 12.8 Hz, IH), 4.81 (s, 2H), 4.29 - 4.21 (m, 2H), 3.30 - 3.27 (m, 2H), 3.18 (d,J = 6.0 Hz, 2H), 2.96 - 2.86 (m, IH), 2.66- 2.61 (m, IH), 2.60 - 2.56 (m, IH), 2.10 - 2.01 (m, IH), 1.60 - 1.46 (m, 4H), 1.40 - 1.29 (m, 2H); LC-MS (ESI+) m/z 914.3 (M+H)+.

[004932] Table 7: Compounds synthesized via Method 9 with the coupling of various amines and acids in Step I, followed by coupling with acid Intermediate CN in Step 3

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediat e Amine</td><td> Step 1 Intermediat e Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td> HNMR (400MHz, DMSO-d6) δ</td>

1531

<td> 108</td><td> 1-108</td><td> tert-butyl N[2-[2-[2-(2aminoethoxy ־( ethoxy] ethox yl. ethyl ]carb am ate (CAS# 101187-40-0)</td><td> CA</td><td> 1026.3a</td><td> 11.12 (brs, IH), 11.01 (s, IH), 9.04 (d, J = 4.0 Hz, 2H), 8.65 (t, J = 5.2 Hz, IH), 8.27 (d, J = 5.2 Hz, IH), 8.19 8.07 (m, 3H), 8.06 - 7.97 (m, 3H), 7.85 - 7.75 (m, 2H), 7.70 (t, J = 6.4 Hz, IH), 7.49 (d, J = 7.2 Hz, IH), 7.39 (d, J = 8.4 Hz, IH), 7.28 (s, IH), 7.19 (d, J = 5.2 Hz, IH), 5.19 - 5.05 (m, IH), 4.78 (s, 2H), 4.35 - 4.17 (m, 2H), 3.59 - 3.49 (m, 12H), 3.48 - 3.45 (m, 4H), 2.97 - 2.83 (m, IH), 2.66 - 2.61 (m, IH), 2.60 - 2.56 (m, IH), 2.07 - 2.00 (m, IH)</td>

<td> 109</td><td> 1-109</td><td> tert-butvl N(8aminooctyl)carbamate (CAS# 88829-82-7)</td><td> CA</td><td> 956.4</td><td> 11.12 (s, IH), 11.01 (s, IH), 9.03 (d, J = 4.8 Hz, 2H), 8.55 (t, J= 5.6 Hz, IH), 8.26 (d, J = 5.6 Hz, IH), 8.14 (s, IH), 8.12 - 8.07 (m, 2H), 8.05 - 7.98 (m, 2H), 7.93 (t, J = 5.6 Hz, IH), 7.85 7.79 (m, IH), 7.77 (s, IH), 7.69 (t, J = 6.4 Hz, IH), 7.50 (d, J = 7.2 Hz, IH), 7.40 (d, J= 8.4 Hz, IH), 7.27 (s, IH), 7.19 (d, J = 52 Hz, IH), 5.14 - 5.08 (m, IH), 4.77 (s, 2H), 4.30 - 4.20 (m, 2H), 3.29 - 3.22 (m, 2H), 3.18 - 3.11 (m, 2H), 2.96 - 2.85 (m, IH), 2.64 2.56 (m, 2H), 2.08-2.01 (m, IH), 1.60 - 1.38 (m, 4H), 1.29 (s, 8H)</td>

<td> 110</td><td> 1-110</td><td> tert-butyl N[2-(2aminoethoxy ־( ethyl ]carb am ate (CAS# 127828-222)</td><td> CA</td><td> 915.9</td><td> 11.12 (s, IH), 11.03 (s, IH), 9.05 (s, IH), 9.03 (s, IH), 8.60 (t, J= 5.2 Hz, IH), 8.27 (d, J = 52 Hz, IH), 8.14 (s, IH), 8.09 - 8.05 (m, 2H), 8.05 - 7.98 (m, 3H), 7.83 - 7.76 (m, 2H), 7.71 (t, J = 6.4 Hz, IH), 7.47 (d, J= 7.2 Hz, IH), 7.39 (d, J = 8.8 Hz, IH), 7.28 (s, IH), 7.19 (dd, J= 1.6, 5.2 Hz, IH), 5.15 5.12 (m, IH), 4.79 (s, 2H), 4.31 - 4.20 (m, 2H), 3.61 - 3.56 (m, 2H), 3.55 3.51 (m, 2H), 3.50 -3.44 (m, 2H), 3.40 - 3.37 (m, 2H), 2.95 - 2.84 (m, IH), 2.64 - 2.55 (m, 2H), 2.10 - 2.01 (m, IH)</td>

1532

<td> 111</td><td> 1-111</td><td> tert-butyl N- ־4) aminobutyl)carbamate (CAS# 68076-36-8)</td><td> CA</td><td> 900.3</td><td> 11.12 (s, IH), 11.02 (s, IH), 9.04 (d, J = 4.0 Hz, 2H), 8.59 (t, J= 5.6 Hz, IH), 8.26 (d, J= 5.2 Hz, IH), 8.15 - 8.08 (m, 3H), 8.02 (m, 3H), 7.85 - 7.80 (m, IH), 7.78 (s, IH), 7.70 (t, J = 6.8 Hz, IH), 7.49 (d, J = 7.2 Hz, IH), 7.40 (d, J = 8.4 Hz, IH), 7.28 (s, IH), 7.21 7.17 (m, IH), 5.12 (dd, J = 5.6, 13.2 Hz, IH), 4.79 (s, 2H), 4.31 - 4.20 (m, 2H), 3.30 - 3.26 (m, 2H), 3.24-3.18 (m, 2H), 2.95 - 2.84 (m, IH), 2.64 2.54 (m, 2H), 2.07 - 2.00 (m, IH), 1.53 (m, 4H)</td>

<td> 112</td><td> 1-112</td><td> tert-butyl N- ־3) aminopropyl) -carbamate (CAS# 75178-96-0)</td><td> CA</td><td> 886.5</td><td> 11.12 (s, IH), 11.02 (s, IH), 9.04 (d, J = 2 Hz, 2H), 8.59 (t, J = 6 Hz, IH), 8.26 (d, J = 52 Hz, IH), 8.17 - 8.07 (m, 3H), 8.07 - 7.98 (m, 3H), 7.83 (dd, J= Ί2, 8.4 Hz, IH), 7.78 (s, IH), 7.70 (t, J= 6.4 Hz, IH), 7.50 (d, J= 7.2 Hz, IH), 7.42 (d, J = 8.4 Hz, IH), 7.28 (s, IH), 7.19 (dd, J = 1.6, 5.2 Hz, IH), 5.13 (dd, J = 52, 12.8 Hz, IH), 4.80 (s, 2H), 4.31 - 4.19 (m, 2H), 3.27 (m, 2H), 3.25 (m, 2H), 2.98 - 2.84 (m, IH), 2.65 - 2.54 (m, 2H), 2.09 - 2.00 (m, IH), 1.78 - 1.68 (m, 2H)</td>

1533

Variations in reaction time for Method 9 were as follows: Step 1 was run anywhere from 0.5-12 h, Step 3 anywhere from 0.5-12 h, and Step 4 anywhere from 0.5-12 hr. 3mass measured as (M+Na)+.

[004933] Further Examples using synthetic methods similar to Method 9:

[004934] Example 116: N-(3-carbamoyl-l-(4-((2-((5-(2-(2-((2-(2.,6-dioxopiperidin yl)l.,3-dioxoisoindolin yl)oxy) pyrazol yl) (2-((2.,2.,2-trifluoroethyl)amino)pyridin yl)oxazole carboxamide, 1-116

1534

CF

HATU, DIPEA, DMF

[004935] N-(3-carbamoyl-l-(4-((2-((5-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3dioxoisoindolin yl)oxy) acetamido)ethoxy)pentyl)oxy)ethyl)carbamoyl)phenyl)-lH-pyrazol-4yl) (2-((2,2,2-trifluoroethyl)amino)pyridin yl)oxazole carboxamide 1-116 was synthesized via Method 9, by coupling amine Intermediate CF with acid Intermediate CN in Step 1. Step 2 was not performed as the amine did not have a BOC group for deprotection. In Step 3, Intermediate CA was employed as the acid for the coupling. Characterization of the final product: 1H NMR (400MHz, DMSO-d6) δ 11.12 (s, IH), 11.00 (s, IH), 9.02 (d, J= 8.4 Hz, 2H), 8.64 (t, J= 5.2 Hz,

1535

IH), 8.26 (d, J = 5.2 Hz, IH), 8.14 (s, IH), 8.11 - 8.06 (m, 2H), 8.05 - 8.00 (m, 2H), 7.97 (t, J = 6.4 Hz, IH), 7.82 - 7.75 (m, 2H), 7.69 (t, J= 6.4 Hz, IH), 7.48 (d, J= &#906;2 Hz, IH), 7.38 (d, J = 8.4 Hz, IH), 7.26 (s, IH), 7.20 - 7.16 (m, IH), 5.10 (dd, J = 5.2, 12.8 Hz, IH), 4.78 (s, 2H), 4.30 4.18 (m, 2H), 3.40 - 3.28 (m, 12H), 2.94 - 2.84 (m, IH), 2.65 - 2.60 (m, IH), 2.52 - 2.44 (m, IH), 2.08 - 2.02 (m, IH), 1.53 - 1.44 (m, 4H), 1.35 - 1.27 (m, 2H). LC-MS (ESI+) m/z 1002.4 (M+H)+. [004936] Example 117: N-(3-carbamovl-l-(4-((2-(2-(2-((2-(2,6-dioxopiperidin yl)-loxoisoindolin yl)amino) ((2,2,2-trifluoroethvl)amino)pvridin yl)oxazole carboxamide,1-117

1536

[004937] Tert-butyl (2-(2-(2-((2-(2,6-dioxopiperidin yl)-l-oxoisoindolin-4yl)amino)ethoxy)ethoxy) ethyl)carbamate was synthesized in Step 1 as follows: To a mixture of 3-(4-amino-l-oxo-isoindolin yl)piperidine-2,6-dione (0.10 g, 385 umol, CAS# 191732 6) in DMA (2 mL) was added 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate (151 mg, 462 umol, synthesized via Step 1 of Intermediate AI), Nai (17.3 mg, 115 umol) and DIPEA (149 mg, 1.16 mmol, 201 uL). Then the reaction mixture was stirred at 80

1537 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (PE:EA = 0:1) to give the title compound 1-117 (0.18 g, 50% purity, 47% yield) as a yellowish solid (LC-MS (ESI+) m/z 513.1 (M+Na)+).

[004938] Steps 2-4 followed Method 9, where Intermediate CN was used as the acid in Step 3 which was coupled with the amine at rt for 12 hours. Characterization of the final product: 1H NMR (400MHz, DMSO&#1470;d6) δ 11.13 - 10.90 (m, 2H), 9.04 (s, 2H), 8.65 (t, J = 5.2 Hz, IH), 8.26 (d, 7 = 5.2 Hz, IH), 8.16 - 8.07 (m, 3H), 8.05 - 7.99 (m, 2H), 7.78 (s, IH), 7.70 (t, J= 6.4 Hz, IH), 7.32 - 7.24 (m, 2H), 7.19 (dd, J = 1.2, 5.2 Hz, IH), 6.94 (d, J = 7.2 Hz, IH), 6.79 (d, J = 8.0 Hz, IH), 5.58 (s, IH), 5.11 (dd,7=5.2, 13.2 Hz, IH), 4.29 - 4.11 (m, 4H), 3.77 - 3.52 (m, 8H), 3.49 3.41 (m, 4H), 2.97 - 2.87 (m, IH), 2.64 - 2.59 (m, 2H), 2.05 - 2.03 (m, IH). LC-MS (ESI+) m/z 888.1 (M+H)+.

[004939] Example 118 (Method 10): [2-[2-[[(lS)-l-[(4R) hydroxv [[4-(4methvlthiazol vl)phenvl]methvlcarbamovl]pvrrolidine-l-carbonvl]-2,2-dimethylpropyl] amino] oxo-ethoxy| ethoxy] ethoxy] ethoxy] ethoxyl methyl-butyl] pyridine-3carboxamide,1-118

1538

HATU, DIPEA, DMF

[004940] Step 1 - Ethyl 2-r2-r2-r2-r2-r3-rr6-(5-cyanopyrazolo[3,4-b1pyridin-l-yl)-4(cyclopropylamino)pyridine-3 -carbonyl1amino1 fluoro-1,1dimethylpropoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate

[004941] To a mixture of ethyl 2-[2-[2-[2-[2-(3-amino fluoro-l,l-dimethylpropoxy)ethoxy]ethoxy]ethoxy] ethoxy]acetate (200 mg, 521 umol, Intermediate BJ) and DIPEA (337 mg, 2.61 mmol) in DMF (3 mL) was added 6-(5-cyanopyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino)pyridine carboxylic acid (271 mg, 625 umol, Intermediate L as the TFA salt) and HATU (257 mg, 678 umol). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 %

1539

FA) to give the title compound (80.0 mg, 22% yield) as a red oil. LC-MS (ESI+) m/z 686.6 (M+H)+.

[004942] Step 2 - 2-[2-[2-[2-[2-[3-[[6-(5-Cvanopvrazolo[3,4-b1pvridin-l-vl)-4(cvclopropvlamino)pyri dine carbonyl1amino1 fluoro-1,1 -dimethylpropoxy1ethoxy1ethoxy1ethoxy1ethoxy1acetic acid

[004943] To a mixture of ethyl 2-[2-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-l-yl)-4(cyclopropylamino) pyridine carbonyl]amino] fluoro-l,l-dimethylpropoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate (70.0 mg, 102 umol) in THF (4 mL) and MeOH (1 mL) was added a solution of LiOH (4.89 mg, 204 umol) in H2O (1 mL). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was acidified with HC1 (1 N) until the pH = 5-6, then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water (0.05% HC1)-ACN]) to give the title compound (20.0 mg, 29% yield) as a light yellow oil. LC-MS (ESI+) m/z 658.1 (M+H)+.

[004944] Step 3 - 6-(5-Cyanopyrazolo[3,4-b1pyridin-l-yl) (cyclopropylamino)-N-[2fluoro [2-[2-[2-[2-[2-[[(lS)-l-[(4R) hvdroxv [[4-(4-methylthi azol-5yl)phenyl1methylcarbamoyl1pyrrolidine-l-carbonyl1-2,2-dimethyl-propyl1amino1 oxoethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -3 -m ethyl -butyl 1 pyri dine-3 -carb oxami de

[004945] To a mixture of (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl] hydroxy-N[[4-(4-methylthiazol- 5-yl)phenyl]methyl]pyrrolidine carboxamide (21.3 mg, 45.6 umol, Intermediate CI, as the HC1 salt) and DIPEA (29.4 mg, 228 umol) in DMF (3 mL) was added 2[2-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b] pyri din- l-yl) (cy cl opropylamino)pyri dine-3carbonyl]amino] fluoro-1,1 -dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (30.0 mg, 45.6 umol) and HATU (20.8 mg, 54.7 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*lOum; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-118 (10.9 mg, 21% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 9.07 (s, IH), 9.03 (d, J = 2.0 Hz, IH), 8.98 (s, IH), 8.87 (t, J = 5.2 Hz, IH), 8.72 - 8.58 (m, 4H), 7.76 (s, IH), 7.49 - 7.34 (m, 5H), 4.57 ( d, J = 9.6 Hz, IH), 4.48 - 4.43 (m, IH), 4.43 - 4.37 (m, IH), 4.35 (s, IH), 4.30 - 4.21 (m, IH), 3.97 (s, 2H), 3.66 - 3.50 (m, 20H), 2.59 (s, IH), 2.54 - 2.53 (m, IH), 2.44 (s, 3H), 2.10 - 2.01 (m, IH), 1.93 - 1.87 (m, IH), 1.21 (s, 6H), 0.94 (s, 9H), 0.89 - 0.84 (m, 2H), 0.58 (d, J= 2.0 Hz, 2H). LC-MS (ESI+) m/z 1070.1 (M+H)+.

1540

[004946] Table 8: Compounds synthesized via Method 10 with the coupling of various acids and amines in Step I, followed by coupling with an amine in Step 3.

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermedi ate Amine</td><td> Step 1 Intermedi ate Acid</td><td> Step 3 Intermediate Amine</td><td> LCMS (ES+) m/z (M+H)+</td><td> HNMR (400MHz, DMSO-d6) δ</td>

1541

1542

Variations in reaction time for Method 10 were as follows: Step 1 was run anywhere from 0.5-12 h, Step 2 anywhere from 0.5-3.5 h, and Step 3 anywhere from 0.5-3 hr. 3Product isolated as the FA salt.

[004947] Further Examples using synthetic methods similar to Method 10:

[004948] Example 124: (2S,4R)-l-[(2S) [[2-[2-[2-[2-[2-[2-[4-[4-[[(8R) [(2S)-3amino hydroxy oxo-propyl] yl] oxy] cyclohexyl] piper azin yl] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] amino] -3.,3dimethvl-butanovl] hvdroxv-N-[[4-(4-methvlthiazol vl)phenvl]methvl]pyrrolidine-2carboxamide,1-124

1543

OMs

K2CO3, DMF

[004949] Ethyl 2-[2-[2-[2-[2-[2-[4-[4-[[(8R) [(2S) amino hydroxy oxo-propyl]

7,8-dihydro-6 H-cyclopenta[4,5]thieno[l,2-c]pyrimidin-l-yl]oxy]cyclohexyl]piperazin-l yl] ethoxy ]ethoxy ]ethoxy ]ethoxy] ethoxy ]acetate was synthesized as follows: to a solution of (2S)2-hydroxy [(87?)-l-(4-piperazin-l-ylcyclohexoxy)-7,8-dihydro-6//-cyclopenta [4,5]thieno[l,2c]pyrimidin yl]propanamide (90.0 mg, 187 umol, Intermediate DR) in DMF (5 mL) was added

K2CO3 (129 mg, 933 umol) and ethyl 2-[2-[2-[2-[2-(2methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy] ethoxy]acetate (113 mg, 280 umol, synthesized via Steps 1-2 of Intermediate BW). The reaction mixture was stirred at 60 °C for 25 h. On completion, the reaction mixture was concentrated in vacuo to give the title compound (130 mg,

1544

92% yield) as a yellow solid (LC-MS (ESI+) m/z 752.4 (M+H)+). The final product was then synthesized via Steps 2-3 of Method 10, where Step 2 was run for 15 h at rt and Step 3 was run for 3 h at rt using acid Intermediate CI. Characterization of the final product 1-124: 1H NMR (400MHz, DMSO-A) δ 8.98 (s, IH), 8.60 (t, J= 6.0 Hz, IH), 8.52 (s, IH), 8.22 (s, IH), 7.42 (d, J = 9.6 Hz, 2H), 7.39 (s, 2H), 7.15 (s, IH), 7.11 (s, IH), 5.18 - 5.12 (m, IH), 4.57 (d, J = 9.6 Hz, IH), 4.47 - 4.40 (m, 2H), 4.40 - 4.33 (m, 2H), 4.25 (dd, J= 5.6, 15.8 Hz, 2H), 3.97 (s, 2H), 3.95 3.90 (m, 2H), 3.68 - 3.48 (m, 20H), 3.05 - 2.98 (m, IH), 2.94 - 2.87 (m, IH), 2.61 - 2.53 (m, 2H), 2.44 (s, 12H), 2.16 - 2.04 (m, 3H), 1.92 - 1.83 (m, 3H), 1.69 - 1.58 (m, 2H), 1.57 - 1.41 (m, 2H), 1.41 - 1.32 (m, 2H), 0.94 (s, 9H); LC-MS (ESI+) m/z 1136.1 (M+H)+.

[004950] Example 125: N-[3-carbamoyl-l-[4-[8-[2-[[(lS)-l-[(2S,4R) hydroxy [[4(4-methylthiazol yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethylpropyl] amino] oxo-ethoxy] octylcarbamoyl] phenyl] pyrazol yl] 12-(2,2.,2trifluoroethylamino) pyridyl]oxazole carboxamide,1-125

1545

[004951] Tert-butyl 2-[8-[[4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-41546 pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoyl]amino]octoxy]acetate was synthesized via Method 10, Stepl, where amine Intermediate DX and acid Intermediate CN were coupled at rt for 2 hours. In Step 2, the Boc groups were removed as follows: to a solution of tert-butyl 2-[8-[[4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoyl]amino]octoxy]acetate (120 mg, 134 umol) in DCM (3 mL) was added TFA (760 mg, 6.75 mmol). The mixture was stirred at rt for 3 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (110 mg, 100% yield, TFA salt) as light yellow oil (LC-MS (ESI+) m/z 701.4 (M+H)+). The third step followed Method 10, where amine Intermediate CI was coupled with the acid at rt for 3 hours. Characterization of the final product 1-125: 1H NMR (400MHz, DMSO-d6) δ 11.02 (s, IH), 9.04 (d, J = 2.0 Hz, 2H), 8.97 (s, IH), 8.61 (t, J = 6.0 Hz, IH), 8.54 (t, J = 6.0 Hz, IH), 8.25 (d, J= 5.6 Hz, IH), 8.13 (s, IH), 8.08 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.77 (s, IH), 7.70 (t, J = 6.4 Hz, IH), 7.47 - 7.31 (m, 5H), 7.27 (s, IH), 7.20 - 7.16 (m, IH), 5.16 (d, J = 3.6 Hz, IH), 4.56 (d, J= 9.6 Hz, IH), 4.48 - 4.32 (m, 3H), 4.29 - 4.19 (m, 3H), 3.91 (s, 2H), 3.71 - 3.57 (m, 2H), 3.49 - 3.44 (m, 2H), 3.29 - 3.21 (m, 2H), 2.43 (s, 3H), 2.11 - 2.01 (m, IH), 1.95 1.84 (m, IH), 1.59 - 1.47 (m, 4H), 1.36 - 1.23 (m, 8H), 0.93 (s, 9H); LC-MS (ESI+) m/z 1113.5 (M+H)+.

[004952] Example 126: 4-[2-[4-[2-[2-[2-[2-[[2-(2,6-Dioxo piperidvD-l,3-dioxoisoindolin vl]amino]ethoxy|ethoxy|ethoxy|ethvlcarbamovl]phenvl]ethvnyl]-ln(2S,3S,4S) ethvl fluoro oxo-pvrrolidin vl]methoxy| methoxv-isoquinoline-6carboxamide,1-126

1547

[004953] Step 1 - 4-bromo-l-[r(2S,3S,4S) ethyl fluoro oxo-pyrrolidin yl1methoxy17-methoxy-iso quinoline carbonitrile

[004954] To a solution of l-[[(2S,3S,4S) ethyl fluoro oxo-pyrrolidin yl]methoxy]7- methoxy-isoquinoline carbonitrile (200 mg, 582 umol, Intermediate CD) in ACN (7.00 mL) was added NBS (228 mg, 1.28 mmol), and the mixture was stirred at 60 °C for 2 hours. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-TLC (EA) to give the title compound (130 mg, 52% yield) as a yellow solid. 1HNMR (400MHz, CDCh) δ 8.31 (s, IH), 8.06 (s, IH), 7.68 (s, IH), 7.57 (s, IH), 4.99 - 4.79 (m, IH), 4.71 (d, J = 11.6 Hz, IH), 4.41 - 4.32 (m, IH), 4.21 - 4.14 (m, IH), 4.07 (s, 3H), 2.70 - 2.47 (m, IH), 1.86 - 1.66 (m, 2H), 1.13 (t, J = 7.2 Hz, 3H).

[004955] Step 2 - 4-Bromo-l-[r(2S,3S,4S) ethvl fluoro oxo-pvrrolidin-2

1548 yl1methoxy1 methoxy- isoquinoline carboxamide

[004956] To a solution of 4-bromo-l-[[(2S,3S,4S) ethyl fluoro oxo-pyrrolidin-2yl]methoxy] methoxy- isoquinoline carbonitrile (300 mg, 710 umol) inDMSO (3.00 mL) was added K2CO3 (39.2 mg, 284 umol) and H2O2 (241 mg, 2.13 mmol, 30% solution). The mixture was stirred at rt for 16 hours. On completion, the mixture was diluted with H2O (30 mL) and extracted with EA (3 X 30 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (300 mg, 80% yield) as a white solid. 1H NMR (400MHz, DMSO&#1470;d6) δ 8.88 (s, IH), 8.24 (s, IH), 8.16 (s, IH), 7.95 (s, IH), 7.85 (s, IH), 7.80 (s, IH), 5.00 - 4.82 (m, IH), 4.56 - 4.50 (m, IH), 4.30 - 4.23 (m, IH), 4.10 (s, IH), 4.00 (s, 3H), 1.64 - 1.53 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H).

[004957] Step 3 - Methyl 4-r2-r6-carbamoyl-l-[r(2S,3S,4S) ethyl fluoro oxopyrrolidin yl1methoxy1-7 -methoxy isoquinolyl1ethynyl1benzoate

[004958] 4-bromo-l-[[(2S,3S,4S) ethyl fluoro oxo-pyrrolidin yl]methoxy]-7methoxy-isoquinoline carboxamide (100 mg, 227 umol), Pd(PPh3)2C12 (15.9 mg, 22.7 umol) and Cui (8.65 mg, 45.4 umol) were placed in a microwave tube. Then methyl 4-ethynylbenzoate (72.7 mg, 454 umol, CAS# 10602 6), TEA (229 mg, 2.27 mmol) and DMF (2.00 mL) were added into the above tube. The mixture was degassed with nitrogen for 5 minutes. The sealed tube was heated at 120 °C for 3 hours under microwave. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase chromatography (0.1% FA) to give the title compound (40.0 mg, 33% yield) as a black solid. LC-MS (ESI+) m/z 520.3 (M+H)+.

[004959] Step 4 - 4-r2-r6-Carbamoyl-l-[r(2S,3S,4S) ethyl fluoro oxo-pyrrolidin-2yl1methoxy1 methoxy isoquinolyl1ethynyl1benzoicacid

[004960] To a solution of methyl 4-[2-[6-carbamoyl-l-[[(2S,3S,4S) ethyl fluoro oxopyrrolidin yl] methoxy] methoxy isoquinolyl]ethynyl]benzoate (40.0 mg, 76.9 umol) in a mixed solvent of THF (3.00 mL), MeOH (1.00 mL) and H2O (1.00 mL) was added LiOH (9.22 mg, 384 umol). The mixture was stirred at rt for 16 hours. On completion, the mixture was acidified with IN HCI solution until the pH = 5. The mixture was concentrated in vacuo to give the title compound (38.0 mg, 85% yield) as a black solid. LC-MS (ESI+) m/z 506.2 (M+H)+.

[004961] Step 5 - 4-Γ2-Γ4-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-Ρ&#912;οχο ρ&#912;ρ61&#906;&#940;ν1)-Ε3-&#940;&#912;οχο-&#912;5ο&#912;η&#940;ο1&#912;η-4yl1amino1ethoxy1 ethoxy] ethoxy] ethyl carb amoyl 1 phenyl 1 ethynyl 1-l-[r(2S,3S,4S)-3 -ethyl -4fluoro oxo-pyrrolidin yl1methoxy1 methoxy-isoquinoline carboxamide

1549

[004962] To a solution of 4-[2-[6-carbamoyl-l-[[(2S,3S,4S) ethyl fluoro oxopyrrolidin yl]methoxy] methoxy isoquinolyl]ethynyl]benzoic acid (28.0 mg, 55.3 umol) and 4-[2-[2-[2-(2-aminoethoxy)ethoxy] ethoxy]ethylamino] (2,6-dioxo-3piperidyl)isoindoline-l,3-dione (26.8 mg, 55.3 umol, HCI, synthesized via Steps 1-2 of Example 128) in DMF (2.00 mL) was added HATU (25.2 mg, 66.4 umol) and DIPEA(28.6 mg, 221 umol). The mixture was stirred at rt for 30 minutes. On completion, the mixture was quenched with H2O (2 mL), and the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Boston Green ODS 150*30 5 u; mobile phase: [water (0.225% FA) - ACN]; B%: 37%67%, 10 min) to give the title compound 1-126 (13.3 mg, 25% yield) as yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 8.91 (s, IH), 8.65 (t, J = 5.2 Hz, IH), 8.39 (s, IH), 8.27 (s, IH), 7.95 (s, 2H), 7.93 (s, IH), 7.82 (s, IH), 7.80 (s, IH), 7.74 (s, IH), 7.71 (s, IH), 7.60 - 7.54 (m, IH), 7.13 (d, J = 8.4 Hz, IH), 7.03 (d, J = 8.0 Hz, IH), 6.60 (t, J = 5.6 Hz, IH), 5.09 - 5.02 (m, IH), 5.01 - 4.84 (m, IH), 4.63 - 4.57 (m, IH), 4.35 - 4.28 (m, IH), 4.16 - 4.09 (m, IH), 4.00 (s, 3H), 3.63 - 3.59 (m, 2H), 3.56 - 3.44 (m, 14H), 2.89 - 2.85 (m, IH), 2.63 - 2.61 (m, IH), 2.58 2.58 (m, IH), 2.57 - 2.56 (m, IH), 2.05 - 2.00 (m, IH), 1.65 - 1.58 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H); LC-MS (ESI+) m/z 936.2 (M+H)+.

[004963] Example 127 (Method 11): N-[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-1 ,3-dioxo-isoindolin yl] amino] ethoxy] ethoxy] ethylcarbamoyl] phenyl] pyrazol4-yl] [2-(2.,2.,2-trifluoroethylamino) pyridvl]oxazole carboxamide,1-127

1550

HCI in dioxane

DCM

[004964] Step 1 - Tert-butyl n-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin-4 yllaminolethoxy] ethoxylethyllcarbamate

[004965] A solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (2.50 g, 10.1 mmol, CAS# 153086 3), 2-(2,6- dioxo piperidyl) fluoro-isoindoline-l,3-dione (3.34 g, 12.1 mmol, Intermediate R) and diisopropyl ethylamine (2.60 g, 20.1 mmol) in dioxane (120 mL) was stirred at 115 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether : ethyl acetate =1:1) to give the title compound (2.10 g, 40% yield) as a yellow gum. 1H NMR (400MHz, CDCh) δ 8.50 (s, IH), 7.54 - 7.48 (m, IH), 7.12 (d, J = 7.2 Hz, IH), 6.92 (d, J = 8.4 Hz, IH), 6.59 - 6.48

1551 (m, IH), 5.15 - 5.00(m, IH), 4.95 - 4.85 (m, IH), 3.79 - 3.71 (m, 2H), 3.70 - 3.62(m, 4H), 3.60 3.54 (m, 2H), 3.52 - 3.45 (m, 2H), 3.35 - 3.25 (m, 2H), 2.92 - 2.71 (m, 3H), 2.19 - 2.09 (m, IH), 1.44 (s, 9H); LC-MS (ESI+) m/z 527.1 (M+Na)+.

[004966] Step 2 - 4-[2-[2-(2-Aminoethoxy)ethoxy1 ethyl amino] (2,6-di oxo-3piperidyl)isoindoline-L3-dione

[004967] To a solution of tert-butyl N-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethoxy]ethyl]carbamate (200 mg, 396 umol) in DCM (5 mL) was added HCI in dioxane (4 M, 5 mL). The reaction mixture was stirred at rt for 10 minutes. On completion, the reaction mixture was concentrated in vacuo to give the title compound (200 mg, 90% yield) as a yellow solid. LC-MS (ESI+) m/z 405.2 (M +H)+.

[004968] Step 3 - Tert-butyl N-[4-[4-l73-carbamovl-l-[4-[2-[2-[2-l72-(2,6-dioxo-3piperidyl)-l,3-dioxoyl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[004969] To a solution of 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino] (2,6-dioxo-3piperidyl)isoindoline-l,3 -dione (200 mg, 418 umol) and 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2trifluoroethyl)amino] pyridyl] oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (257 mg, 418 umol, Intermediate CN) in DMF (5 mL) was added DIPEA (270 mg, 2.09 mmol, 364 uL). The mixture was stirred at rt for 12 minutes, and then HATU (191 mg, 502 umol) was added to the mixture. The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was quenched with H2O (10 mL) and filtered. The filter cake was dried in vacuo to give the title compound (400 mg, 95% yield) as a yellow solid. LC-MS (ESI+) m/z 902.2 (M +H-100)+.

[004970] Step 4 - N-r3-carbamoyl-l-r4-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl1amino1 ethoxy1ethoxy1ethylcarbamoyl1phenyl1pyrazol yl1 [2-(2,2,2trifluoroethylamino) pyridyl1oxazole carboxamide

[004971] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo -isoindolin yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (400 mg, 399 umol) in DCM (3 mL) was added HCI in dioxane (4 M, 3 mL). The reaction mixture was stirred at rt for 20 minutes. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50mm*10 um; mobile phase: [water

1552 (0.225% FA)-ACN]; B%: 35 ACN%63&#1470;ACN%) to give the title compound 1-127 (121 mg, 31% yield) as a yellow solid. 1HNMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 11.02 (s, IH), 9.05 (s, IH), 9.04 (s, IH), 8.63 (t, J =5.2 Hz, IH), 8.26 (d,/=5.2 Hz, IH), 8.14 (m, IH), 8.11 - 8.06 (m, 2H), 8.05 - 7.99 (m, 2H), 7.79 (m, 2H), 7.56 (dd, /= 7.2, 8.4 Hz, IH), 7.29 (s, IH), 7.19 (dd, / = 1.2,5.2 Hz, IH), 7.12 (d,/= 8.4 Hz, IH), 7.02 (d,/= 7.2 Hz, IH), 6.60 (s, IH), 5.06 (dd,/=5.6, 13.2 Hz, IH), 4.34 - 4.20 (m, 2H), 3.67 - 3.52 (m, 12H), 2.96 - 2.82 (m, IH), 2.64 - 2.58 (m, IH), 2.57 - 2.55 (m, IH), 2.13 - 1.96 (m, IH); LC-MS (ESI+) m/z 902.3 (M +H)+.

[004972] Table 9: Compounds synthesized via Method 11 with the addition of various amines to fluoride Intermediate R in Step 1, followed by coupling with various acids in Step

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediate Amine</td><td> Step 3 Intermediate Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td>1HNMR (400MHz, DMSO-d6) δ</td>

<td> 128a</td><td> 1-128</td><td> tert-butyl N[2-[2-[2-(2aminoethoxy) ethoxy]ethoxy] ethyl]carbamate (CAS# 101187-40-0)</td><td> CN</td><td> 946.5</td><td> 11.15 - 11.04 (s, IH), 11.02 (s, IH), 9.04 (s, 2H), 8.64 (t, /= 5.2 Hz, IH), 8.27 (d, /= 5.2 Hz, IH), 8.14 (s, IH), 8.12 (s, IH), 8.10 (s, IH), 8.04 (s, IH), 8.02 (s, IH), 7.78 (s, IH), 7.71 (t, / = 6.4 Hz, IH), 7.60 - 7.55 (m, IH), 7.28 (s, IH), 7.19 (dd, / = 5.2 Hz, IH), 7.12 (d,/= 8.4 Hz, IH), 7.03 (d, / = 7.2 Hz, IH), 6.59 (t, /= 5.6 Hz, IH), 5.09 - 5.03 (m, IH), 4.30 4.21 (m, 2H), 3.63 - 3.41 (m, 16H), 2.94 - 2.83 (m, IH), 2.64 2.55 (m, 2H), 2.07 - 1.98 (m, IH)</td>

1553

<td> 130b</td><td> 1-130</td><td> tert-butyl N[2-(2aminoethoxy) ethyl]carbama te (CAS# 127828-22-2)</td><td> CN</td><td> 858.0</td><td> 11.09 (s, IH), 11.02 (s, IH), 9.04 (d, 7= 1.6 Hz, 2H), 8.63 (t,7=5.2 Hz, IH), 8.26 (d, 7= 5.2 Hz, IH), 8.15 (s, IH), 8.11 - 8.06 (m, 2H), 8.03 - 7.97 (m, 2H), 7.79 (s, IH), 7.71 (t, 7= 6.4 Hz, IH), 7.60 - 7.54 (m, IH), 7.28 (s, IH), 7.21 - 7.14 (m, 2H), 7.02 (d, 7= 6.8 Hz, IH), 6.64 (t, 7 = 5.6 Hz, IH), 5.04 (dd, 7 = 5.6, 12.8 Hz, IH), 4.31 - 4.19 (m, 2H), 4.12 (s, 2H), 3.70 - 3.59 (m, 4H), 3.52 - 3.49 (m, 2H), 2.90 - 2.83 (m, IH), 2.63 -2.52 (m, 2H), 2.06 - 1.97 (m, IH)</td>

<td> 132c</td><td> 1-132</td><td> tert-butyl N- ־8) aminooctyl)carbamate (CAS# 88829-82-7)</td><td> CN</td><td> 898.3</td><td> 11.08 (s, IH), 11.02 (s, IH), 9.04 (d, 7= 3.2 Hz, 2H), 8.56 (t, 7= 5.6 Hz, IH), 8.26 (d, 7= 5.2 Hz, IH), 8.13 (s, IH), 8.11 - 8.07 (m, 2H), 8.06 - 7.99 (m, 2H), 7.77 (s, IH), 7.70 (t, 7= 6.4 Hz, IH), 7.62 - 7.54 (m, IH), 7.27 (s, IH), 7.18 (dd, 7 = 1.2, 5.2 Hz, IH), 7.09 (d,7=8.4 Hz, IH), 7.02 (d, 7= 7.2 Hz, IH), 6.52 (t, 7= 5.6 Hz, IH), 5.05 (dd, 7= 5.2, 12.8 Hz, IH), 4.31 - 4.20 (m, 2H), 3.31-3.25 (m, 4H), 2.94 - 2.83 (m, IH), 2.63 - 2.58 (m, IH), 2.56 - 2.53 (m, IH), 2.08 1.98 (m, IH), 1.61 - 1.52 (m, 4H), 1.33 (s, 8H)</td>

1554

<td> 133d</td><td> 1-133</td><td> undecane1,11-diamine (CAS# 82208-2)</td><td> CN</td><td> 940.0</td><td> 11.09 (br s, IH), 11.01 (s, IH), 9.06 - 8.99 (m, 2H), 8.56 (t, J = 5.6 Hz, IH), 8.26 (d, J= 5.6 Hz, IH), 8.13 (s, IH), 8.11 - 8.06 (m, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.77 (s, IH), 7.69 (t, J = 6.4 Hz, IH), 7.61 - 7.53 (m, IH), 7.27 (s, IH), 7.21 7.16 (m, IH), 7.08 (d, J = 8.4 Hz, IH), 7.01 (d, J =7.2 Hz, IH), 6.50 (t, J = 5.6 Hz, IH), 5.04 (dd, J = 5.6, 12.8 Hz, IH), 4.30 - 4.20 (m, 2H), 3.30-3.14 (m, 2H), 2.94 2.80 (m, IH), 2.63 - 2.54 (m, 2H), 2.09 - 1.97 (m, IH), 1.55 - 1.50 (m, 4H), 1.35 - 1.19 (m, 16H)</td>

<td> 134</td><td> 1-134</td><td> tert-butyl N[2-[2-(2aminoethoxy) -ethoxy]ethyl]carbamate (CAS# 153086-78-3)</td><td> DE</td><td> 926.9</td><td>1H NMR (400MHz, DMSO־d6) δ 11.09 (s, IH), 9.98 (s, IH), 8.99 (d, J= 4.8 Hz, 2H), 8.63 (s, IH), 8.24 (d, 7= 4.8 Hz, IH), 8.10-7.92 (m, 4H), 7.68 - 7.49 (m, 2H), 7.25 (s, IH), 7-21 (d, 7= 4.0 Hz, IH), 7.10 (d, 7= 8.8 Hz, IH), 7.01 (d, 7= 6.4 Hz, IH), 6.58 (s, IH), 5.05 (d,7 = 7.2 Hz, IH), 4.34 - 4.15 (m, 2H), 3.65 - 3.44 (m, 12H), 2.92 - 2.82 (m, IH), 2.61 - 2.59 (m, IH), 2.57 -2.54(m, IH), 2.10-1.95 (m, IH)</td>

<td> 135</td><td> 1-135</td><td> tert-butyl N[2-[2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> DD</td><td> 902.7</td><td> 11.07 (s, IH), 11.02 (s, IH), 9.03 (s, IH), 9.00 (s, IH), 8.74 (s, IH), 8.35 (s, IH), 8.26 (d, 7 = 5.2 Hz, IH), 8.12 (d, 7= 8.0 Hz, IH), 8.07 (s, IH), 7.85 (d, 7 = 8.0 Hz, IH), 7.74 (s, IH), 7.70 - 7.60 (m, 2H), 7.55 - 7.50 (m, IH), 7.27 (s, IH), 7.18 (d, 7 = 4.4 Hz, IH), 7.06 (d, 7 = 8.8 Hz, IH), 7.00 (d, 7 =6.8 Hz, IH), 6.56 (s, IH), 5.07 - 4.98 (m, IH), 4.31 - 4.19 (m, 2H), 3.66 3.52 (m, 12H), 2.88 - 2.80 (m, IH), 2.63 - 2.57 (m, IH), 2.57 2.55 (m, IH), 2.03 - 1.99 (m, IH)</td>

<td> 136</td><td> 1-136</td><td> ter/-butyl (14amino- 3,6,9,12tetraoxatetradecyl)-</td><td> DD</td><td> 990.3</td><td> 11.08 (s, IH), 11.03 (s, IH), 9.05 (s, IH), 9.02 (s, IH), 8.76 (s, IH), 8.37 (s, IH), 8.26 (d, 7 = 5.2 Hz, IH), 8.14 (d, 7 =7.2 Hz, IH), 8.08 (s, IH), 7.87 (d, 7 = 7.2 Hz, IH),</td>

1555

<td></td><td></td><td> carbamate (CAS# 811442-84-9)</td><td></td><td></td><td> 7.75 (s, IH), 7.70 - 7.61 (m, 2H), 7.58 - 7.52 (m, IH), 7.27 (s, IH), 7.18 (d, J = 4.4 Hz, IH), 7.11 (d, J = 8.4 Hz, IH), 7.02 (d, J =6.8 Hz, IH), 6.57 (s, IH), 5.07 - 5.01 (m, IH), 4.28 - 4.21 (m, 2H), 3.55 3.43 (m, 20H), 2.94 - 2.80 (m, IH), 2.62 - 2.59 (m, IH), 2.59 2.57 (m, IH), 2.02 - 1.97 (m, IH)</td>

<td> 137</td><td> 1-137</td><td> tert-butyl N[2-(2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> CU</td><td> 912.4</td><td> 12.09 (s, IH), 11.08 (s, IH), 9.12 (s, IH), 8.63 - 8.60 (m, IH), 8.28 8.21 (m, 4H), 8.14 (s, IH), 8.13 8.09 (m, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.88 (s, IH), 7.65 (d, J = 5.6 Hz, IH), 7.60 - 7.53 (m, IH), 7.50 (s, IH), 7.19 (t, J = 6.8 Hz, IH), 7.12 (d, 7= 8.4 Hz, IH), 7.02 (d, J = 7.2 Hz, IH), 6.60 (t, J= 5.6 Hz, IH), 5.06 (dd, J = 5.2, 13.2 Hz, IH), 4.41 - 4.22 (m, 2H), 3.65 3.60(m, 2H), 3.61 - 3.56 (m, 6H), 3.45 (d, J = 5.6 Hz, 4H), 2.93 2.82 (m, IH), 2.63 - 2.55 (m, IH), 2.55 -2.53 (m, IH), 2.08- 1.99 (m, IH)</td>

<td> 138e</td><td> 1-138</td><td> tert-butyl N[2-(2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> DF</td><td> 874.4</td><td> 10.84 (s, IH), 10.77 (s, IH), 8.79 (s, IH), 8.77 (s, IH), 8.40 - 8.36 (m, IH), 7.93 (d, J = 5.6 Hz, IH), 7.90 - 7.82 (m, 3H), 7.80 - 7.76 (m, 2H), 7.53 (s, IH), 7.35 - 7.30 (m, IH), 6.94 - 6.86 (m, 3H), 6.80 6.75 (m, 2H), 6.35 (t, J = 6.0 Hz, IH), 4.81 (dd, J = 5.6, 13.2 Hz, IH), 3.42 - 3.30 (m, 8H), 3.23 3.19 (m, 2H), 2.99 - 2.92 (m, 2H), 2.69 - 2.58 (m, IH), 2.37 - 2.28 (m, 4H), 1.83 - 1.75 (m, IH), 0.87 0.77 (m, IH), 0.26 - 0.18 (m, 2H), 0.02 - 0.04 (m, 2H)</td>

1556

<td> 139</td><td> 1-139</td><td> tert-butyl N[2-[2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> CW</td><td> 908.4</td><td> 11.09 (s, IH), 10.94 (d, J= 3.6 Hz, IH), 8.96 (d, J= 6.4 Hz, IH), 8.34 (d, J = 16.8 Hz, IH), 8.25 (d, J = 5.2 Hz, IH), 7.87 - 7.74 (m, IH), 7.72 - 7.61 (m, 2H), 7.61 - 7.55 (m, IH), 7.51 (s, IH), 7.26 (s, IH), 7.19-7.10 (m, 2H), 7.04 (t, J= 7.2 Hz, IH), 6.65 - 6.56 (m, IH), 5.06 - 5.04 (m, IH), 4.35 - 4.27 (m, IH), 4.26 - 4.19 (m, 2H), 3.66 3.53 (m, 6H), 3.51 - 3.44 (m, 4H), 3.30-3.14 (m, 2H), 2.94 - 2.83 (m, IH), 2.64 - 2.57 (m, IH), 2.56 2.53 (m, IH), 2.46 - 2.37 (s, IH), 2.24-2.17 (m, IH), 2.13 - 2.02 (m, 2H), 1.94 - 1.76 (m, 4H), 1.66 1.53 (m, 2H)</td>

<td> 140h</td><td> 1-140</td><td> tert-butyl N[2-[2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> EE</td><td> 805.4</td><td> 11.18 - 11.06 (m, 2H), 9.10 (s, IH), 9.03 (s, IH), 8.85 (d, J= 6.0 Hz, 2H), 8.62 (t, J = 5.4 Hz, IH), 8.15 (s, IH), 8.11 - 8.06 (m, 2H), 8.05 - 8.00 (m, 2H), 7.97 (d, J = 6.0 Hz, 2H), 7.82 (s, IH), 7.60 7.52 (m, IH), 7.12 (d, J = 8.4 Hz, IH), 7.02 (d, J= 7.2 Hz, IH), 6.59 ([J= 6.0 Hz, IH), 5.05 (dd, J = 5.4, 12.8 Hz, IH), 3.65 - 3.53 (m, 8H), 3.43-3.41 (m, 4H), 2.94 2.82 (m, IH), 2.63 - 2.57 (m, IH), 2.58-2.56 (m, IH), 2.03- 1.99 (m, IH)</td>

1557

<td> 142</td><td> 1-142</td><td> tert-butyl N[2-[2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> EC</td><td> 854.1</td><td> 9.12 (s, IH), 8.62 (t, J = 5.6 Hz, IH), 8.48 (d, J= 7.2 Hz, IH), 8.37 (s, IH), 8.05 - 7.98 (m, 4H), 7.83 (d, J= 5.6 Hz, IH), 7.67 - 7.35 (m, 2H), 7.11 (d, J= 8.4 Hz, IH), 7.01 (d,J= 7.2 Hz, IH), 6.59 (t, J= 5.6 Hz, IH), 6.45 (d, J= 7.2 Hz, IH), 6.31 (s, IH), 5.08 - 5.01 (m, IH), 4.33 -4.24 (m, IH), 3.65 - 3.62 (m, 2H), 3.57 - 3.54 (m, 11H), 2.92 2.81 (m, IH), 2.62 - 2.55 (m, IH), 2.54 - 2.52 (m, IH), 2.07- 1.97 (m, IH), 1.83 - 1.73 (m, 2H), 1.70 1.53 (m, 4H), 1.46 - 1.30 (m, 2H)</td>

<td> 143</td><td> 1-143</td><td> tert-butyl N[2-[2-(2aminoethoxy) ethoxy] ethyl]carbamate (CAS# 153086-78-3)</td><td> DZ</td><td> 903.0</td><td> 11.09 (s, IH), 11.03 (s, IH), 9.24 (d, 7= 2.4 Hz, IH), 9.14 (s, IH), 9.05 (s, IH), 8.71 (t, J = 5.6 Hz, IH), 8.56 (dd, J= 2.8, 8.4 Hz, IH), 8.26 (d, J= 5.6 Hz, IH), 8.20 (s, IH), 8.16 (d, 7= 8.4 Hz, IH), 7.84 (s, IH), 7.71 (t, J= 6.4 Hz, IH), 7.54 (t, J = 1.6Hz, IH), 7.27 (s, IH), 7.18 (d, 7= 5.2 Hz, IH), 7.11 (d, 7= 8.8 Hz, IH), 6.99 (d, 7= 7.2 Hz, IH), 6.58 (t, 7= 5.6 Hz, IH), 5.04 (dd, 7 = 5.2, 12.8 Hz, IH), 4.28 - 4.22 (m, 2H), 3.64 (d, J = 5.6 Hz, 2H), 3.61 - 3.58 (m, 6H), 3.51 -3.46 (m, 4H), 2.92 - 2.82 (m, IH), 2.61 - 2.59 (m, IH), 2.57 2.55 (m, IH), 2.03 - 2.01 (m, IH)</td>

Variations in reaction time for Method 11 were as follows: Step 1 was run anywhere from 12-16 h, Step 2 anywhere from 10 min-12 h, Step 3 anywhere from 0.5-12 h, and Step 4 was run anywhere from 20 min-10 h. The product of Step 3 was also extracted with EtOAc when it did not precipitate out of solution. aThe product of Step 1 was purified by prep-TLC (SiO2, PE:EA = 1:2). bThe product of Step 3 was purified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 55%-85%). cThe final product was purified by prepHPLC under basic conditions (column: Phenomenex Luna Phenyl-Hexyl 150_30_ 5 um; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 45%-90%). dStep 2, the first deprotection step with HCI was skipped as there was no BOC group to deprotect from the amine intermediate. 6Step 4 was run in a mixed solvent of DCM (1 mL) and DMF (2 mL). fThe deprotection of the CBZ group

1558 in Step 2 was achieved with a hydrogenation using Pd(OH)2/C and hydrogen gas (15 psi pressure) in THF at rt for 16 h. gThe deprotection of the benzyl groups in Step 2 was achieved with a hydrogenation using Pd(OH)2/C, Pd/C and hydrogen gas (15 psi pressure) in THF and a catalytic amount of HCI at rt for 20 h. After fdtration and concentration, the intermediate was purified by reversed phase chromatography (0.1% NH3*H2O). The final product was also purified by reversed phase chromatography using TFA not FA as the acidic modifier. hStep 4 was skipped as no deprotection was required.

[004973] Further Examples using synthetic methods similar to Method 11:

[004974] Example 144: N-[3-carbamovl-l-[4-[2-[5-[[2-(2,6-dioxo piperidyl)-l,3dioxo-isoindolin yl]amino] trifluoroethvlamino) pyridvl]oxazole carboxamide,1-144

1559

HCI in dioxane

DCM

NHBoc

KOAc, NaH(OAc)3, THF

[004975] 4-(5-aminopentylamino) (2,6-dioxo piperidyl)isoindoline-l,3-dione was synthesized via Steps 1-2 of Method 11, where fluoride Intermediate R was coupled with amine tert-butyl N-(5-aminopentyl)carbamate (CAS#51644 3) in the first step, and Step 2 was run at rt for 1 hr. Step 3 involved a reductive amination performed as follows: to a solution of 4-(5aminopentylamino) (2,6-dioxo piperidyl)isoindoline-l,3-dione (300 mg, 759 umol, HCI) and tert-butyl N-(2-oxoethyl)carbamate (193 mg, 1.22 mmol, CAS# 89711 0) in THF (60 mL) was added KOAc (149 mg, 1.52 mmol) and NaBH(OAc)3 (402 mg, 1.90 mmol). The mixture was

1560 stirred at rt for 20 hours. On completion, the reaction mixture was added to ice water (100 mL) and extracted with DCM (3 X 60 mL). The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% FA) to give tert-butyl N-[2-[5-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl]amino]pentylamino] ethylcarbamate (180 mg, 42% yield) as a yellow solid gum (LC-MS (ESI+) m/z 502.2 (M+H)+). [004976] Step 4 followed Method 11 with deprotection of the Boc group with HCI in dioxane. This intermediate was carried on without purification to the final step which was performed as follows: to a mixture of 4-[5-(2-aminoethylamino)pentylamino] (2,6-dioxo-3piperidyl)isoindoline-l,3- dione (110 mg, 251 umol, HCI salt) and DIPEA (162 mg, 1.26 mmol) in DMF (3 mL) was added 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (123 mg, 200 umol, Intermediate CN) and HATU (114 mg, 301 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% HCI), then it was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-144 (11.4 mg, 4% yield, FA) as yellow solid. 1H NMR (400MHz, DMSO-» δ 11.02 (s, IH), 9.05 (d, J = 2.4 Hz, 2H), 8.70 (s, IH), 8.33 (s, IH), 8.27 (d, J= 5.6 Hz, IH), 8.14 (s, IH), 8.13 - 8.00 (m, 4H), 7.78 (s, IH), 7.71 (t, J = 6.4 Hz, IH), 7.61 - 7.55 (m, IH), 7.28 (s, IH), 7.20 - 7.16 (m, IH), 7.10 (d, J= 8.4 Hz, IH), 7.04 - 6.99 (m, IH), 6.54 (t, J= 5.8 Hz, IH), 5.06 (dd, J = 5.5, 13.2 Hz, IH), 4.32 - 4.21 (m, 2H), 3.40 - 3.27 (m, 4H), 2.95 - 2.84 (m, 3H), 2.81 (t, J= 6.0 Hz, 2H), 2.66 - 2.61 (m, 3H), 2.06 - 2.00 (m, IH), 1.64 - 1.47 (m, 4H), 1.44 - 1.35 (m, 2H); LC-MS (ESI+) m/z 899.4 (M+H)+.

[004977] Example 145: N-[3-carbamovl-l-n-[2-[2-[2-[[2-(2,6-dioxo DiDeridvD-l,3dioxo-isoindolin vl]amino] (22,.2&#1524;-trifluoroethvlamino) Dvridvl]oxazole carboxamide,1-145

1561

[004978] To a solution of triphosgene (14.4 mg, 48.5 umol) in DCM (2 mL) was added a solution of 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino] (2,6-dioxo piperidyl)isoindoline1,3-dione (42.8 mg, 97.1 umol, HCI salt, synthesized via Steps 1-2 of Example 127) in DCM (3 mL) at 0 °C. Then TEA (49.1 mg, 485 umol) was added to the solution dropwise at 0°C, followed by N-[3-carbamoyl-l-(4-piperidyl)pyrazol yl] [2-(2,2,2-tri fluoroethyl amino)-4pyridyl]oxazole carboxamide (50.0 mg, 97.1 umol, HCI salt, Intermediate CX). The reaction mixture was then stirred at 0°C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue w7as purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-145 (20.4 mg, 22% yield, FA) as a yellow solid. 1HNMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 10.95 (s, IH), 8.98 (s, IH), 8.39 (s, IH), 8.25 (d, J = 5.2 Hz, IH), 7.75 - 7.67 (m, 2H), 7.62 - 7.55 (m, IH), 7.52 (s, IH), 7.26 (s, IH), 7.17 (d, J 1.2 Hz, IH), 7.16 - 7.13 (m, IH), 7.12 - 7.12 (m, IH), 7.04 (d, J 7.2 Hz, IH), 6.62 - 6.60 (m, 2H), 5.07 (dd, J= 5.6, 12.8 Hz, IH), 4.50 - 4.41 (m, IH), 4.30 - 4.19 (m, 2H), 4.09 (d, J= 12.8 Hz, 2H), 3.65 - 3.61 (m, 2H), 3.59 - 3.52 (m, 4H), 3.48 - 3.45 (m, 2H), 3.44 - 3.41 (m, 2H), 3.24 - 3.13 (m, 2H), 2.95 - 2.86 (m, IH), 2.86 - 2.78 (m, 2H), 2.62 - 2.57 (m, IH), 2.56 m 2.53 (m, IH), 2.05 - 1.96 (m, 3H), 1.89 - 1.78 (m, 2H); LC-MS (ESI+) m/z 909.1 (M+H)+

[004979] Example 146 (Method 12): N-(3-carbamovl-l-(4-((2-(3-(2-(2,6

1562 dioxoDiDeridin yl)-l,3-dioxoisoindolin yl)DroDoxy)ethyl)carbamoyl)Dhenyl)-lHDyrazol yl) (2-((2,2,2-trifluoroethyl)amino)Dyridin yl)oxazole carboxamide,

[004980] Step 1 - Tert-butyl (4-(4-((3-carbamoyl-l-(4-((2-(3-(2-(2,6-dioxopiperidin yl)L3-dioxoisoindolin yl)propoxy)ethyl)carbamoyl)phenyl)-lH-pyrazol yl)carbamoyl)oxazol2-yl)pyridin yl)(2,2,2-trifluoroethyl)carbamate

[004981] To a solution of 4-[3-(2-aminoethoxy)propyl] (2,6-dioxo-3 piperidyl)isoindoline-l,3-dione (90 mg, 250 umol, Intermediate CP) and (154 mg, 250 umol, Intermediate CN) in DMF (2 mL) was added DIPEA (162 mg, 1.25 mmol). Ten minutes later, HATU (114 mg, 300 umol) was added into the above mixture. The reaction mixture was stirred at rt for 0.5 h. On completion, the mixture was diluted was water (30 mL), stirred and filtered. The filter cake was dried in vacuo to give the title compound (110 mg, 43% yield) as a white solid. LC

1563

MS (ESI+) m/z 957.3 (M+H)+.

[004982] Step 2 - N-(3-carbamoyl-l-(4-((2-(3-(2-(2,6-dioxopiperidin yl)-L3dioxoisoindolin yl)propoxy)ethyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide

[004983] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[2-[3-[2-(2,6-dioxo-3piperidyl)-l,3-dioxo -isoindolin yl]propoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (110 mg, 115 umol) in DCM (2 mL) was added HCI in dioxane (4 M, 2 mL). The reaction mixture was stirred at rt for 17 h. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobilephase: [water (0.225%FA)-ACN]; B%: 32%-62%) to give the title compound 1-146 (13.3 mg, 13% yield, FA) as a white solid. 1H NMR (400MHz, DMS 0-76) δ 11.11 (s, IH), 11.02 (s, IH), 9.04 (d, J= 5.2 Hz, 2H), 8.71 - 8.62 (m, IH), 8.26 (d, J= 5.2 Hz, IH), 8.15 - 8.07 (m, 3H), 8.07 - 8.02 (m, 2H), 7.84 - 7.75 (m, 3H), 7.73 - 7.67 (m, 2H), 7.28 (s, IH), 7.19 (d, J = 52 Hz, IH), 5.14 (dd, J = 5.2, 13.2 Hz, IH), 4.32 - 4.19 (m, 2H), 3.54 (t, J= 5.2 Hz, 2H), 3.48 - 3.43 (m, 4H), 2.96 - 2.87 (m, IH), 2.86 - 2.83 (m, 2H), 2.63 2.59 (m, 2H), 2.11 - 2.02 (m, IH), 1.93 - 1.84 (m, 2H); LC-MS (ESI+) m/z 857.3 (M+H)+

[004984] Table 10: Compounds synthesized via Method 12 with the coupling of various amines and acids in Step 1.

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediate Amine</td><td> Step 1 Intermediate Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td>1HNMR (400MHz, DMSO-d6) δ</td>

1564

1565

Variations in reaction time for Method 12 were as follows: Step 1 was run anywhere from 0.5-12 h, and Step 2 anywhere from 10 min-17 h. If the product of Step 1 was not a precipitate, a standard work up with water and extraction with ethyl acetate was used to isolate the product.

[004985] Example 152 (Method 13): N-[3-carbamovl-l-[l-[2-[2-[2-[2-H2-(2,6-dioxo-3piperidyl)-l.,3-dioxo-isoindolin yl]amino] ethoxy] ethoxy] ethoxy] acetyl] -4piperidyl]pyrazol yl] [2-(2.,2.,2-trifluoroethylamino) pyridyl]oxazole carboxamide, 1-152

1566

[004986] Step 1 - Tert-butyl 2-(2-(2-(2-((2-(2,6-Dioxopiperidin yl)-L3-dioxoisoindolin-4 yl)amino)ethoxy) ethoxy)ethoxy)acetate

[004987] To a solution of tert-butyl 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetate (6.40 g, 24.3 mmol, Intermediate CY) and 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (6.71 g, 24.3 mmol, Intermediate R) in dioxane (100 mL) was added DIPEA (9.42 g, 72.9 mmol). The reaction mixture was stirred at 115 °C for 24 hours. On completion, the reaction mixture was concentrated in vacuo to give yellow oil. The yellow oil was purified by prep-HPLC (water (0.1% FA)-ACN) to give the title compound (6.00 g, 48% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 8.19 (s, IH), 7.54-7.45 (m, IH), 7.11 (d, J= 8.4 Hz, IH), 6.93 (d, J= 8.4 Hz, IH), 6.52 - 6.48 (m, IH), 4.99 - 4.87 (m, IH), 4.02 (s, 2H), 3.75 - 3.68 (m, 10H), 3.50 - 3.46 (m, 2H), 2.93 2.69 (m, 3H), 2.17 - 2.10 (m, IH), 1.49 (s, 9H).

[004988] Step 2 - 2-(2-(2-(2-((2-(2,6-Dioxopiperidin yl)-L3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy) ethoxyiacetic acid

[004989] To a solution of tert-butyl 2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino] ethoxy]ethoxy]ethoxy]acetate (6.00 g, 11.6 mmol) in DCM (30 mL) was

1567 added TFA (30.8 g, 270 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give the title compound (5.60 g, 99%yield) as a yellow oil. LC-MS (ESI+) m/z 464.0 (M+H)+.

[004990] Step 3 - N-r3-carbamoyl-l-r1-r2-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1 amino1ethoxy1ethoxy1ethoxy1acetyl1 piperidyl1pyrazol yl1 [2-(2,2,2trifluoroethylamino) pyridyl1oxazole carboxamide

[004991] To a mixture of N-[3-carbamoyl-l-(4-piperidyl)pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridyl]oxazole carboxamide (50.0 mg, 97.1 umol, Intermediate CX) and DIPEA(125 mg, 971 umol) inDMF (5 mL) was added 2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)l,3-dioxo-isoindolin yl]amino]ethoxy]ethoxy] ethoxy]acetic acid (54.0 mg, 116 umol) and HATU (44.3 mg, 116 umol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-152 (55.7 mg, 59% yield, FA) as a yellow solid. 1HNMR (400MHz, DM SO-0/6) δ 11.10 (s, IH), 10.94 (s, IH), 8.96 (s, IH), 8.39 (s, IH), 8.25 (d, J= 5.6 Hz, IH), 7.74 - 7.66 (m, 2H), 7.62 - 7.54 (m, IH), 7.51 (s, IH), 7.26 (s, IH), 7.16 (d, J= 5.2 Hz, IH), 7.13 (d, J = 8.4 Hz, IH), 7.03 (d, J = &#906;2 Hz, IH), 6.59 (s, IH), 5.05 (dd, J = 5.6, 12.8 Hz, IH), 4.61 - 4.39 (m, 2H), 4.32 - 4.21 (m, 2H), 4.20 - 4.12 (m, 2H), 3.94 (d, J= 13.6 Hz, IH), 3.63 - 3.59 (m, 2H), 3.58 - 3.53 (s, 8H), 3.46 (d, J = 5.2 Hz, 2H), 3.18 - 3.10 (m, IH), 2.94 - 2.83 (m, IH), 2.83 - 2.71 (m, IH), 2.63 - 2.56 (m, IH), 2.56 - 2.53 (m, IH), 2.07 - 1.92 (m, 4H), 1.85 (d, J = 9.6 Hz, IH); LC-MS (ESI+) m/z 924.3 (M+H)+.

[004992] Table 11: Compounds synthesized via Method 13 with the addition of various amines to fluoride Intermediate R in Step 1, followed by coupling with various amines in Step 3.

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediate Amine</td><td> Step 3 Intermediate Amine</td><td> LCMS (ES+) m/z (M+H)+</td><td> 1HNMR (400MHz, DMSO-d6) δ</td>

1568

1569

1570

IH)

Variations in reaction time for Method 13 were as follows: Step 1 was run anywhere from 16-24 h and Step 2 was run anywhere from 0.5-16 h. 3Since the product of Step 1 was the ethyl ester, not BOC ester, the deprotection for Step 2 used (Bu3Sn)2O in toluene and the reaction mixture was stirred at 115 °C for 4 hours. This intermediate was then purified by prep-HPLC (0.1 % FA.) [004993] Further Examples using synthetic methods similar to Method 13:

[004994] Example 159: N-[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6-dioxo piperidyD-l,3dioxo-isoindolin yl]amino]

2-[2-(2.,2.,2-trifluoroethylamino) pyridyl]oxazole carboxamide, 1-159

1571

[004995] Step 1 - 2-(2,6-Dioxo piperidyl) r2-r2-r2-r(4-methoxyphenyl)methyl-methylamino] ethoxy] ethoxy] ethyl aminoli soindoline-1,3 -dione

[004996] To a solution of 2-[2-[2-[(4-methoxyphenyl)methyl-methylamino]ethoxy]ethoxy]ethanamine (350 mg, 1.24 mmol, Intermediate CR) and 2-(2,6-dioxo-3piperidyl) fluoro-isoindoline-l,3-dione (342 mg, 1.24 mmol, Intermediate R) in dioxane (5 mL) was added DIPEA (1.60 g, 12.3 mmol, 2.16 mL). The reaction mixture was stirred at 115 °C for

1572 hours. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% NH3*H2O) to give the title compound (600 mg, 89% yield) as a yellow oil. LC-MS (ESI+) m/z 539.4 (M +H)+.

[004997] Step 2:2-(2,6-Dioxo piperidvl) [2-r2-r2(methylamino)ethoxy1ethoxy1ethylamino1isoindoline -L3-dione

[004998] To a mixture of 2-(2,6-dioxo piperidyl) [2-[2-[2-[(4-methoxyphenyl)methylmethyl-amino]ethoxy] ethoxy]ethylamino]isoindoline-l,3-dione (0.10 g, 185 umol) in MeOH (3 mL) and IN HCI (0.05 mL) was added Pd/C (0.05 g, 10 wt %) and Pd(OH)2/C (0.05 g, 10 wt %). Then the reaction mixture was stirred at rt for 2 hours under hydrogen atmosphere (15 psi pressure). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (60.0 mg, 77% yield) as a yellowish oil. LC-MS (ESI+) m/z 419.1 (M +H)+.

[004999] Step 3 - Tert-butyl N44444r3-carbamovl-l4442424241242.6-dioxo-3piperidyl)-L3-dioxo-i soindolin yl1 amino] ethoxy] ethoxy] ethyl-methyl carbamovl1phenvl1pvrazol vl1carbamovl1oxazol vl1 pvridvl1-N42.2.2trifluoroethyDcarbamate

[005000] To a mixture of 2-(2,6-dioxo piperidyl) [2-[2-[2(methylamino)ethoxy]ethoxy]ethylamino]isoindoline -1,3-dione (77.0 mg, 169 umol, HCI) and 4[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole-4carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (88.5 mg, 143 umol, Intermediate CN) in DMF (3 mL) was added DIPEA(109 mg, 846 umol, 147 uL). Then HATU (83.6 mg, 220 umol) was added to the mixture. The reaction mixture was stirred at rt for 12 hours. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 50%-80%) to give the title compound (0.05 g, 23% yield) as white solid. LC-MS (ESI+) m/z 1016.0 (M+H)+.

[005001] Step 4 - N43-carbamoyl-1444242424r2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 trifluoroethylamino) pyridyl1oxazole carboxamide

[005002] To a mixture of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-!,3-dioxo- isoindolin yl]amino]ethoxy]ethoxy]ethyl-methyl1573 carbamoyl]phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (42.0 mg, 41.3 umol) in DCM (3 mL) was added HCI in dioxane (4 M, 0.3 mL). Then the reaction mixture was stirred at rt for 0.5 hour. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 31% -61%) to give the title compound 1-159 (20.0 mg, 50% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) 511.15 - 10.96 (m, 2H), 9.18 - 8.78 (m, 2H), 8.27 (s, IH), 8.12 - 7.96 (m, 3H), 7.78 - 7.50 (m, 5H), 7.31 - 7.00 (m, 4H), 6.58 (s, IH), 5.05 (s, IH), 4.25 (s, 2H), 3.70 - 3.62 (s, 8H), 3.55 - 3.49 (m, 4H), 2.98 (s, 3H), 2.87 (s, IH), 2.65 - 2.58 (m, 2H), 2.02 - 2.00 (m, IH); LC-MS (ESI+) m/z 916.3 (M +H)+.

[005003] Example 160: (2S) [(8R)-l-[4-[4-[2-[2-[2-[[2-(2,6-dioxo DiDeridvD-l,3dioxo-isoindolin vl]amino]

6H-cvclopenta[4.,5]thieno[l.,2-c]Dvrimidin vl] hvdroxv-DroDanamide,1-160

<td> /9 O F HNX 1 1 ד° R q V θ DIPEA, dioxane CZ H o BBTO((n-Bu3Sn)2O) \ L A H/N^^O ----------► toluene λ—4 u O \ 0' n O א—\ /—λ Γ )° 0 IT \ 0 0X</td><td>H Ω a ד \—א \=< Άν J 0X^QEt O IT O 11 T Νχ/ך Γ Ί \.>ΟΗ Ο 0Α HNxX DR ΝΗ2 ^ΟΗ * HATU, DIPEA, DMF S ΟΗ</td>

1574

[005004] The title compound was synthesized via Method 13, using fluoride Intermediate R and amine intermediate CZ in the first step which was run at 115 °C for 18 hours. In Step 2, the ester was deprotected as follows: to a mixture of (Bu3Sn)2O (1.17 g, 1.97 mmol) in toluene (5 mL) was added ethyl 2-[2-[2-[[2-(2,6- dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy]acetate (440 mg, 983 umol). The reaction mixture was stirred at 115 °C for 4 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA) to give 2-[2-[2-[[2-(2,6-Dioxo piperidyl)-l,3-dioxoisoindolin yl]amino]ethoxy]ethoxy]acetic acid (230 mg, 55% yield) as a yellow solid (LC-MS (ESI+) m/z 420.1 (M+H)+; 1HNMR (400MHz, DMSO-» δ = 13.39 -11.73 (m, IH), 11.10 (s, IH), 7.65 - 7.52 (m, IH), 7.16 (d, J = 8.4 Hz, IH), 7.05 (d, J = 7.2 Hz, IH), 7.08 - 7.02 (m, IH), 6.62 (t, 5.6 Hz, IH), 5.06 (dd, J= 5.2, 12.8 Hz, IH), 4.02 (s, 2H), 3.67 - 3.56 (m, 6H), 3.52 - 3.46 (m, 2H), 2.95 - 2.81 (m, IH), 2.69 - 2.54 (m, 2H), 2.07 - 1.99 (m, IH)). Intermediate DR was used as the amine in Step 3 to give the final compound 1-160. Characterization data: 1H NMR (400MHz, DMSO-» δ = 11.12 (s, IH), 8.52 (s, IH), 7.59 (t, J = 7.6 Hz, IH), 7.15 (dd, J = 9.6, 18.4 Hz, 3H), 7.05 (d, J= 6.8 Hz, IH), 6.60 (s, IH), 5.11 (d, J = 11.2 Hz, IH), 5.06 (dd, J = 5.2, 12.8 Hz, IH), 4.14 (s, 2H), 3.95 - 3.90 (m, 5H), 3.64 (d, J= 4.8 Hz, 2H), 3.59 - 3.55 (m, 4H), 3.52 - 3.34 (m, 8H), 3.02 (dd, J= 8.4, 16.0 Hz, IH), 2.94 - 2.86 (m, 2H), 2.65 - 2.54 (m, 3H), 2.41 (d, J = 9.6 Hz, 2H), 2.33 - 2.26 (m, IH), 2.16 - 2.04 (m, 3H), 1.82 (d, J = 10.0 Hz, 2H), 1.64 - 1.47 (m, 3H), 1.43-1.31 (m, 2H). LC-MS (ESI+) m/z 847.1 (M+H)+.

[005005] Example 161: (2S) [(8R)-l-[4-[4-[2-[2-[2-[2-[2-[[2-(2,6-dioxo piperidvDl.,3-dioxo-isoindolin vl]amino] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] piperazin-1yl] cvclohexoxy] -78&#1524;-dihydro-6H-cvclopenta [4,5] thieno [1 .,2-cl pyrimidin yl] hydroxypropanamide,1-161

1575

nh2

[005006] The title compound was synthesized via Method 13, using fluoride Intermediate R and amine Intermediate DW in the first step which was run at 115 °C for 16 hours. In Step 2, the ester was deprotected as follows: to a solution of (Bu3Sn)2O (779 mg, 1.31 mmol) in toluene (20 mL) was added ethyl 2-[2-[2-[2-[2- [[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetate (0.35 g, 654 umol). The reaction mixture was stirred at 115 °C for 12 hours. On completion, the reaction mixture was quenched with 1 N sodium fluoride solution. The mixture was extracted with DCM (100 mL), then dried and concentrated in vacuo. The crude was purified by reverse phase flash chromatography (0.1% FA) to give 2-(2-(2[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl]amino]ethoxy]ethoxy] ethoxy]ethoxy]acetic acid_(0.175 g, 53% yield) as yellow oil (LCMS (M+l)+: 508.2). Intermediate DR was used as the amine in Step 3 to give the final compound 1-161. Characterization data: 1H NMR (400MHz, DMSO-t/6) δ 11.10 (s, IH), 8.52 (s, IH), 7.58 (t, J = 7.6 Hz, IH), 7.21 -7.07 (m, 3H), 7.04 (d, J = 7.2 Hz, IH), 6.61 (t, J = 5.6 Hz, IH), 5.21 - 5.11 (m, IH), 5.10 - 5.01 (m, IH), 4.12 (s, 2H), 3.93 (t, J = 6.4 Hz, IH), 3.66 - 3.62 (m, 2H), 3.60 - 3.49 (m, 20H), 3.07 - 3.00 (m, IH), 2.94 - 2.84 (m, 2H), 2.63 - 2.56 (m, 2H), 2.55 - 2.53 (m, 2H), 2.47 - 2.36 (m, 5H), 2.32 - 2.26 (m, IH), 2.20 - 2.08 (m, 2H), 2.06 - 1.99 (m, IH), 1.90 - 1.79 (m, 2H), 1.70 - 1.57 (m, 2H), 1.56

1576

1.47 (m, IH), 1.45 - 1.33 (m, 2H); LC-MS (ESI+) m/z 957.4 (M+Na)+.

[005007] Example 162 (Method 14): 5-[[(lS,2R) aminocvclohexvl]amino] [3-[2-[2[2-[2-[[(lS)-l-[(2S,4R) hvdroxy [[4-(4-methylthiazol-5vl)phenvl]methvlcarbamovl]pyrrolidine-l-carbonvl]-2.,2-dimethvl-propvl]amino] oxoethoxv]ethoxv]ethoxv]ethoxv] methoxy-anilino]imidazo[l.,2-c]pvrimidine carboxamide, 1-162

1577

1578

[005008] Step 1 - Ethyl 2-r2-r2-r2-r3-r(8-carbamoyl methylsulfanyl-imidazo[L2c1pyrimidin vDamino] -5 -methoxy-phenoxy] ethoxy] ethoxy] ethoxy] acetate

[005009] To a solution of ethyl 2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (819 mg, 2.61 mmol, Intermediate BI) and 7-(3-hydroxy methoxy-anilino) methylsulfanylimidazo[l,2-c]pyrimidine carboxamide (300 mg, 868 umol, Intermediate EZ) in DMF (10 mL) was added K2CO3 (360 mg, 2.61 mmol). The mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to remove solvent. The residue was diluted with water (5 mL) and extracted with DCM (3X10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (320 mg, 65% yield) as a yellowish oil. LC-MS (ESI+) m/z 564.0 (M+H)+.

[005010] Step 2 - Ethyl 2-r2-r2-r2-r3-rr5-rr(lS,2R) aminocyclohexyl1amino1-8carbamoyl-imidazo[L2-c1 pyrimidin yl1amino1 methoxyphenoxy] ethoxy] ethoxy] ethoxy] acetate

[005011] A solution of ethyl 2-[2-[2-[2-[3-[(8-carbamoyl methylsulfanyl-imidazo[l,2-c] pyrimidin yl)amino] methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate (220 mg, 390 umol) and (lR,2S)-cyclohexane-l,2- diamine (89.1 mg, 781 umol, CAS# 1436 5) in DMF (2 mL) was stirred at 90 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with water (5 mL) and extracted with DCM (3X10 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (220 mg, 65% yield) as a yellowish oil. LC-MS (ESL)/630.1 2 &#1524; (M+H)+.

1579

[005012] Step 3:Ethyl 2-Γ2-Γ2-Γ2-Γ3-ΓΓ5-ΓΓ(15,2Β) (&#912;61&#912;butoxycarbonylamino)cyclohexyl1amino1-8methoxy-phenoxy] ethoxy] ethoxy] ethoxy] acetate

[005013] To a solution of ethyl 2-[2-[2-[2-[3-[[5-[[(lS,2R) aminocyclohexyl]amino]-8carbamoyl-imidazo [l,2-c]pyrimidin yl]amino] methoxyphenoxy]ethoxy]ethoxy]ethoxy]acetate (220 mg, 349 umol) and (Boc)2O (152 mg, 699 umol) in MeOH (3 mL) was added 12 (17.7 mg, 69.9 umol). The reaction mixture was stirred rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo to remove solvent. The residue was diluted with water (5 mL) and extracted with DCM (3X5 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (150 mg, 58% yield) as a yellowish solid. LC-MS (ESI+) m/z 730.1 (M+H)+.

[005014] Step 4:2-Γ2-Γ2-Γ2-Γ3-ΓΓ5-ΓΓ(15,2Β) (&#912;61&#912;butoxycarbonylamino)cyclohexyl1amino1 carbamoyl -imidazo[ L2-c1pyrimidin yl1amin01-5methoxy-phenoxy1ethoxy1ethoxy1ethoxy1acetic acid

[005015] To a solution of ethyl 2-[2-[2-[2-[3-[[5-[[(lS,2R) (tertbutoxycarbonylamino)cyclohexyl]amino] carbamoyl-imidazo[l,2-c]pyrimidin yl]amino]-5methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate (150 mg, 205 umol) in a mixed solvent of THF (2 mL) and H2O (2 mL) was added LiOH (19.7 mg, 822 umol). Then the mixture was stirred at rt for 0.5 hour. On completion, saturated citric acid aqueous solution was added to the mixture to adjust the pH = 5.0. The residue was diluted with water (3 mL) and extracted with DCM (3X5 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (135 mg, 94% yield) as white solid. LC-MS (ESI+) m/z 702.3 (M+H)+.

[005016] Step 5 - Tert-butyl N-r(lR,2S) rr8-carbamoyl r3-r2-r2-[2-r2-rr(lS)-lr(2S,4R) hydroxy [r4-(4-methylthiazol yl)phenyl1methylcarbamoyl1pyrrolidine-lcarbonyl1-2,2-dimethyl-propyl1amino1 oxo-ethoxy1ethoxy1ethoxy1ethoxy1 methoxyanilino1imidazorL2-c1pyrimidin yl1amino1cyclohexyl1carbamate

[005017] A solution of 2-[2-[2-[2-[3-[[5-[[(lS,2R) (tertbutoxycarbonylamino)cyclohexyl]amino] carbamoyl -imidazo[l,2-c]pyrimidin yl]amino]-5methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetic acid (135 mg, 192 umol) in DMF (2 mL) was cooled to 0 °C. Then, DIPEA (67.8mg, 525 umol), (2S,4R)-l-[(2S) amino-3,3- dimethyl

1580 butanoyl] hydroxy-N-[[4-(4-methylthiazol yl)phenyl] methyl]pyrrolidine carboxamide (75.3 mg, 175 umol, Intermediate CI) and HATU (79.8 mg, 210 umol) were added. Then the mixture allowed to warm to rt and stirred for 6 hours. On completion, the mixture was diluted with water (5 mL) and extracted with EA (3X5 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FAin water) to give the title compound (90.0 mg, 46% yield) as a yellowish solid. LC-MS (ESI+) m/z 1114.2 (M+H)+.

[005018] Step 6 - 5-[[(lS,2R) aminocyclohexyl1amino1 [3-[2-[2-[2-[2-[[(lS)-l[(2S,4R) hydroxy [[4-(4-methylthiazol yl)phenyl1methylcarbamoyl1pyrrolidine-lcarbonvl1-2,2-dimethyl-propyl1amino1 oxo-ethoxy1ethoxy1ethoxy1ethoxy1 methoxyanilino1imidazo[L2-c1pvrimidine carboxamide

[005019] To a solution of tert-butyl N-[(lR,2S) [[8-carbamoyl [3-[2-[2-[2-[2-[[(lS)-l[(2S,4R) hydroxy [[4-(4-methylthiazol yl)phenyl]methylcarbamoyl]pyrrolidine-lcarbonyl]-2,2-dimethyl-propyl] amino] oxo-ethoxy]ethoxy]ethoxy]ethoxy] m ethoxyanilino]imidazo[l,2-c]pyrimidin yl]amino]cyclohexyl]carbamate (90.0 mg, 80.8 umol) in MeOH (2 mL) was added HCI in dioxane (4 M, 2 mL). Then the mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-162 (20.0 mg, 24% yield, FA salt) as white solid. 1HNMR (400MHz, DM SO-0/6) δ 12.39 (s, IH), 9.56 (d, J= 3.2 Hz, IH), 8.96 (s, IH), 8.59 (t, J = 5.6 Hz, IH), 8.14(s, IH), 7.48 - 7.36 (m, 6H), 7.32 (s, IH), 6.92 (s, IH), 6.67 (s, IH), 6.21 (s, IH), 4.59 - 4.52 (d, J= 9.6 Ηζ,ΙΗ), 4.45 - 4.31 (m, 4H), 4.29 - 4.18 (m, 2H), 4.12 - 4.00 (m, 3H), 3.96 (s, 2H), 3.74 (s, 4H), 3.72 - 3.64 (m, 7H), 3.61 - 3.57 (m, 10H), 2.53 - 2.51 (m, 2H), 2.43 (s, 3H), 2.10 - 1.98 (m, 2H), 1.92 - 1.80 (m, 2H), 1.76 - 1.70 (m, 2H), 1.47 - 1.34 (m, 2H), 0.94 (s, 9H); LC-MS (ESE)&#1524;/z 1014.2 (M+H)+.

[005020] Table 12: Compounds synthesized via Method 14 with the displacement of various mesylates with alcohols in Step I, followed by coupling of various amines in Step 5.

<td> Ex-#</td><td> I-#</td><td> Step 1 Mesylate</td><td> Step 1 Alcohol</td><td> Step 5 Amine</td><td> LCMS (ES+) m/z (M+H)+</td><td>1HNMR (400MHz, DMSO-d6) δ</td>

1581

<td> 163</td><td> 1-163</td><td> ethyl 2-[2[2-[2-[2-(2methyl sulfo nyloxyethoxy)e thoxy]ethoxy] etho xy]ethoxy] acet ate (synthesized via Steps 12 of Intermediate BW)</td><td> EZ</td><td> CI</td><td> 1124.6a</td><td> 12.39 (s, IH), 9.56 (s, IH), 8.96 (s, IH), 8.59 (t, J = 5.6 Hz, IH), 8.14 (s, IH), 7.48 7.34 (m, 6H), 7.31 (s, IH), 6.93 (s, IH), 6.66 (s, IH), 6.21 (s, IH), 4.57 - 4.55 (d, 7= 9.6 Hz, IH), 4.48-4.31 (m, 3H), 4.29-4.19 (m, 2H), 4.06 (s, 3H), 3.95 (s, 2H), 3.80 - 3.74 (m, 4H), 3.73 - 3.65 (m, 8H), 3.58 (m, 18H), 2.43 (s, 3H), 2.10 - 1.98 (m, 2H), 1.94- 1.83 (m, 2H), 1.73 - 1.65 (m, 3H), 1.59 - 1.35 (m, 3H), 0.93 (s, 9H)</td>

Variations in temperature and time for Method 14 were as follows: Step 1 was run at 50-90 C for anywhere from 4-24 h, Step 3 was run at rt anywhere from 2-12 hours, Step 4 was run at rt anywhere from 0.5-2.5 h, Step 5 was run at rt anywhere from 6-16 h, and Step 6 was run at rt for anywhere from 0.5-1 h. aLCMS measure as (M+Na)+.

[005021] Example 166 (Method 15) 4-[2-[2-[2-[2-[4-[[7-[[(lR,2S)-21582 aminocyclohexyll amino] oxo-3H-pvrido [4.,3-dl pyrimidin

-yl] amino I indol-1yl] ethoxy] ethoxy] ethoxy] ethylamino] (2.,6-dioxo DiDeridvl)isoindoline-1 ,3-dione., 1-166

1583

EY /\ // // XT // .Cbz

MsO //^.q ^z // N&#1523;

Fe, NH4CI

EtOH, H2O

NHCbz

1584

yDethoxy] ethoxy] ethoxy] ethyl] carbamate

N-r2-[2-[2-[2-(4-nitroindol-l[005023] To a mixture of 2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (100 mg, 246 umol, Intermediate EY) in DMF (2 mL) was added K2CO3 (68.1 mg, 493 umol) and 4-nitro-lH-indole (39.9mg, 246 umol). The reaction mixture was stirred at 100 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with water (4 mL) and extracted with dichloromethane (2X6 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EA = 1:1) to give the title compound (67.0 mg, 57% yield) as a light yellow oil. LC-MS (ESI+) m/z 494.1 (M+Na)+.

[005024] Step 2:Benzyl N-r2-[2-[2-[2-(4-aminoindol-lyDethoxy] ethoxy] ethoxy] ethyl] carbamate

[005025] To a mixture of benzyl N-[2-[2-[2-[2-(4-nitroindol-lyl)ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.30 g, 2.76 mmol) in EtOH (10 mL) and H2O (4 mL) was added NH4C1 (1.48 g, 27.6 mmol) andFe (1.54 g, 27.6 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 3 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to remove EtOH. The residue was diluted with water (10 mL) and neutralized with sat. NaHCO3 until the pH = 8-9. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layer was dried over Na2SO4,

1585 filtered and concentrated in vacuo to give the title compound (1.14 g, 93% yield) as a light yellow oil. LC-MS (ESI+) m/z 442.1 (M+H)+.

[005026] Step 3 - Benzyl N-r2-r2-r2-r2-r4-r(7-chloro oxo-3H-pvrido[4,3-d1pvrimidin-5yl)amino1indol-l-yl1 ethoxy1ethoxy1ethoxy1ethyl1carbamate

[005027] To a mixture of benzyl N-[2-[2-[2-[2-(4-aminoindol-lyl)ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.14 g, 2.58 mmol) and 5,7-dichloro-3H-pyrido[4,3d]pyrimidin one (550 mg, 2.55 mmol, Intermediate FB) in NMP (10 mL) was added TEA (774 mg, 7.65 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 140 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to remove the NMP. The residue was diluted with water (8 mL) and extracted with ethyl acetate (2X10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FA in water) to give the title compound (800 mg, 50% yield) as a yellow solid. 1HNMR (400MHz, MeOD) δ 8.26 (dd, J= 2.4, 6.0 Hz, IH), 8.15 (s, IH), 7.34 - 7.25 (m, 6H), 7.20 - 7.17 (m, 2H), 6.78 (s, IH), 6.68 (d, J = 3.2 Hz, IH), 5.03 (s, 2H), 4.63 (s, IH), 4.34 (t, J= 52 Hz, 2H), 3.83 (t, 7=5.2 Hz, 2H), 3.53 (s, 4H), 3.49 - 3.44 (m, 5H), 3.25 (t, 7= 5.6 Hz, 2H); LC-MS (ESI+) m/z 621.1 (M+H)+.

[005028] Step 4 - Benzyl N-r2-r2-r2-r2-r4-rr7-rr(lR,2S) aminocyclohexyl1amino1 oxo3H-pyrido[4,3-d1 pyrimidin yl1amino1indol-l-yl1ethoxy1ethoxy1ethoxy1ethyl1carbamate [005029] A mixture of benzyl N-[2-[2-[2-[2-[4-[(7-chloro oxo-3H-pyrido[4,3d]pyrimidin yl)amino]indol- l-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (550 mg, 886 umol) and (lR,2S)-cyclohexane-l,2 -diamine (1.01 g, 8.86 mmol) in NMP (3 mL) was heated in a microwave at 150 °C for 1.5 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to remove the NMP. The residue was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250 * 50 mm * 10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound (200 mg, 32% yield) as a yellowish solid. LC-MS (ESI+) m/z 699.6 (M+H)+.

[005030] Step 5 - Tert-butyl Ν-Γ(18^) ΓΓ5-ΓΓ1-[2-Γ2-Γ2-Γ2(benzyl oxycarbonylamino)ethoxy1ethoxy1ethoxy1 d1pyrimidin yl1amino1cyclohexyl1carbamate

[005031] To a mixture of benzyl N-[2-[2-[2-[2-[4-[[7-[[(lR,2S) aminocyclohexyl]amino]4-oxo-3H-pyrido [4,3-d]pyrimidin yl]amino]indol-l-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

1586 (200 mg, 286 umol) in dichloromethane (1 mL) was added (Boc)2O (62.4 mg, 286 umol) under a nitrogen atmosphere. The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was diluted with water (5 mL) and extracted with dichloromethane (2X10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (dichloromethane: methanol = 20:1) to give the title compound (150 mg, 65% yield) as a yellowish solid. LC-MS (ESI+) m/z 799.5 (M+H)+.

[005032] Step 6 - Tert-butyl Ν-Γ(15,2Κ) ΓΓ5-ΓΓ1-[2-Γ2-Γ2-(2aminoethoxy)ethoxy1ethoxy1ethyl1indol yl1 amino1 oxo-3H-pyridor4,3-d1pyrimidin-7yl1amino1cvclohexyl1carbamate

[005033] To a mixture of tert-butyl N-[(lS,2R) [[5-[[l-[2-[2-[2-[2(benzyloxycarbonylamino)ethoxy]ethoxy] ethoxy]ethyl]indol yl]amino] oxo-3H-pyrido[4,3d]pyrimidin yl]amino]cyclohexyl]carbamate (10.0 mg, 12.5 umol) in EtOAc (5 mL) was added Pd(OH)2/C (17.5 mg, 12.5 umol, 10 wt ) under a hydrogen atmosphere (50 psi pressure). The reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (3.00 mg, 36% yield) as a yellowish solid. LCMS (ESI+) m/z 665.3 (M+H)+.

[005034] Step 7 - Tert-butyl Ν-Γ(15,2Ε) ΓΓ5-ΓΓ1-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#943;οχο ρ&#943;ρ6Γ&#938;&#940;ν1)L3-dioxo-isoindolin yl1amino1ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino1 oxo-3HPvridor4,3-d1pvrimidin yl1amino1cvclohexvl1carbamate

[005035] To a mixture of tert-butyl N-[(lS,2R) [[5-[[l-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethyl]indol yl]amino] oxo-3H-pyrido[4,3-d]pyrimidin-7yl]amino]cyclohexyl]carbamate (50.0 mg, 75.2 umol) and 2-(2,6-dioxo piperidyl) fluoroisoindoline-1,3-dione (24.9 mg, 90.2 umol, Intermediate R) in DMF (2 mL) was added DIPEA (19.4 mg, 150 umol) under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 12 hours. On completion, the reaction mixture was purified by prep-HPLC (Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]) to give the title compound (18.0 mg, 25% yield) as a yellow solid. LC-MS (ESI+) m/z 921.2 (M+H)+.

[005036] Step 8 - 4-r2-r2-r2-r2-r4-rr7-rr(lR,2S) aminocvclohexyl1amino1 oxo-3Hpyridor4,3-d1pyrimidin

3-piperidyl)isoindoline-L3-dione

1587

[005037] To a mixture of tert-butyl N-[(lS,2R) [[5-[[l-[2-[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo- isoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol yl]amino]-4oxo-3H-pyrido[4,3-d]pyrimidin yl]amino]cyclohexyl]carbamate (33.0 mg, 35.8 umol) in dichloromethane (8 mL) was added TFA (3.08 g, 27.0 mmol). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to remove the di chloromethane. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl 8 150*25*10 um; mobile phase: [water (0.1% TFA)-ACN]) to give the title compound 1-166 (24.8 mg, 84% yield) as a yellow solid. 1HNMR (400MHz, DMSO-76) δ 11.69 (s, IH), 11.11 (s, IH), 8.16 (s, IH), 8.03 (s, IH), 7.79 (s, 3H), 7.54 (t, J= 12 Hz, IH), 7.39 (s, IH), 7.20 - 7.16 (m, IH), 7.15 - 7.06 (m, 3H), 7.02 (d, J = 6.0 Hz, IH), 6.56 (s, 2H), 6.06 (s, IH), 5.05 (d, J= 8.0 Hz, IH), 4.32 (s, 4H), 3.74 (s, 2H), 3.64 - 3.53 (m, 13H), 2.85 (d, J = 12.8 Hz, IH), 2.62 - 2.59 (m, IH), 2.01 (s, IH), 1.88 - 1.57 (m, 6H), 1.47 (s, 2H); LC-MS (ESI+) m/z 821.2 (M+H)+.

[005038] Example 167: 4-[2-[2-[2-[2-[2-[4-[[7-[[(lR,2S) Aminocvdohexyl]amino]-4oxo-3H-pyrido [4,3-dl

Pvrimidin vllaminolindol-l yl] ethoxy] ethoxy] ethoxy] ethoxy] ethylamino] (2,6-dioxo piperidyl)isoindoline-1,3-dione.

1-167

[005039] 4-[2-[2-[2-[2-[2-[4-[[7-[[(lR,2S) Aminocyclohexyl]amino] oxo-3H1588 pyrido[4,3-d] pyrimidin yl]amino]indol-l-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2(2,6-dioxo piperidyl)isoindoline-l,3-dione 1-167 was synthesized via Method 15, using Intermediate FC as the mesylate in Step 1. Variations in time and temperature were as follows: Step 3 was run at 140 °C for 4 h, Step 5 was run at rt for 7 h, Step 6 was run at rt for 4 h with 15 psi pressure of hydrogen, Step 7 was run at 100 °C for 8 h, and Step 8 was run at rt for 1 h. The intermediate formed from Step 5 was purified by prep-HPLC (column: Phenomenex luna Cl8 250*50mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35ACN%-65ACN%, 33 min). Characterization of the final product: 1HNMR (400MHz, DMSO-d6) δ 11.7 (s, IH), 11.1 (s, IH), 8.18 (br s, IH), 7.99 (s, IH), 7.78 - 7.76 (m, 3H), 7.56 (dd, J = 7.2, 8.4 Hz, IH), 7.39 (d, J = 3.2 Hz, IH), 7.22 - 7.16 (m, IH), 7.16 - 7.06 (m, 3H), 7.03 (d, J = 2.0 Hz, IH), 6.64 - 6.50 (m, 2H), 6.06 (s, IH), 5.05 (dd, J = 5.6, 12.8 Hz, IH), 4.47 - 4.17 (m, 4H), 3.67 - 3.65 (m, 2H), 3.63 - 3.56 (m, 4H), 3.55 - 3.53 (m, 4H), 3.52 - 3.47 (m, 10H), 2.96 - 2.80 (m, IH), 2.06 - 1.95 (m, IH), 1.94 - 1.55 (m, 6H), 1.47 - 1.45 (m, 2H); LC-MS (ESI+) m/z 865.2 (M+H)+.

[005040] Example 168: 4-[2-[2-[2-[4-[[7-[[(lR,2S) Aminocvclohexvl]amino] oxo3H-pyrido [4,3-d] pyrimidin- 5-yl] amino] indol- 1-yl] ethoxy] ethoxy] ethylamino] (2,6-dioxo3-piperidyl)isoindoline-l,3-dione, 1-168

[005041] 4-[2-[2-[2-[4-[[7-[[(lR,2S) Aminocyclohexyl]amino] oxo-3H-pyrido[4,3d]pyrimidin- 5-yl]amino]indol-l-yl]ethoxy]ethoxy]ethylamino] (2,6-di oxo-3piperidyl)isoindoline-l,3-dione 1-168 was synthesized via Method 15, using Intermediate FD as the mesylate in Step 1. Variations in time and temperature were as follows: Step 1 & 2 were run at 70 °C for 2 h, and Step 6 was run at rt for 6 h with 15 psi pressure of hydrogen. Characterization

1589 of the final product: 1HNMR (400MHz, DMSO-7,) δ 11.72 (s, IH), 8.38 (s, IH), 8.24 (d, J= 5.2 Hz, IH), 7.93 (s, IH), 7.53 (dd, J= 7.2, 8.4 Hz, IH), 7.36 (d, J= 3.2 Hz, IH), 7.18 - 7.12 (m, IH), 7.11 - 7.05 (m, 2H), 7.02 (d, J= &#906;2 Hz, IH), 6.60 - 6.53 (m, 2H), 6.02 (s, IH), 5.05 (dd, J= 5.6, 12.8 Hz, IH), 4.31 (t, J = 52 Hz, 2H), 3.75 (t, J = 52 Hz, 2H), 3.64 - 3.58 (m, 10H), 3.40 - 3.11 (m, 2H), 2.91 - 2.81 (m, 2H), 2.59 - 2.58 (m, IH), 2.53 - 2.52 (m, IH), 2.46 - 2.43 (m, IH), 2.05 1.96 (m, IH), 1.89 - 1.82 (m, 2H), 1.75 - 1.57 (m, 4H), 1.45 - 1.33 (m, 2H); LC-MS (ESI+) m/z 3&#1512;&#1512;&#1512; (m+h)+.

[005042] Further Examples:

[005043] Example 169: N-[3-carbamovl-l-[l-[2-[2-[2-[2-[[2-(2,6-dioxo piperidvD-l,3 dioxo-isoindolin vl]amino] (2,2,2-trifluoroethvlamino) pvridvl]oxazole carboxamide,

[005044] Step 1:2-(2.6-Dioxo piperidvl) [2-r2-r2-(2 hydroxy ethoxy )ethoxy] ethoxy] ethyl ami no]

[005045] isoindoline-L3-dione

1590

[005046] To a mixture of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethanol (0.60 g, 2.61 mmol, HCI salt, Intermediate DC) and DIPEA (2.70 g, 20.9 mmol) in dioxane (15 mL) was added 2-(2,6-dioxo piperidyl) fluoro- isoindoline-1,3-dione (721 mg, 2.61 mmol, Intermediate R). The reaction mixture was stirred at 115 °C for 24 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum etherethyl acetate = 0:1) to give the title compound (0.80 g, 68% yield) as a brown solid. 1H NMR (400MHz, DMSO-76) δ 11.11 (s, IH), 7.59 (dd, J= 3.2, 4.4 Hz, IH), 7.16 (d, J= 8.4 Hz, IH), 7.05 (d, 7 = 7.2 Hz, IH), 6.61 (t, 7=5.6 Hz, IH), 5.06 (dd, 7= 5.2, 12.8 Hz, IH), 4.58 - 4.56 (m, IH), 3.62 (t, 7= 5.6 Hz, 2H), 3.59 - 3.56 (m, 2H), 3.55 - 3.53 (m, 2H), 3.51 - 3.44 (m, 8H), 3.42 - 3.38 (m, 2H), 2.95 - 2.81 (m, IH), 2.64 - 2.53 (m, 2H), 2.09 - 2.00 (m, IH).

[005047] Step 2 - 2-r2-r2-r2-rr2-(2,6-Dioxo piperidvl)-L3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy] ethoxy]acetaldehyde

[005048] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-[2-(2hydroxy ethoxy )ethoxy] ethoxy] ethyl ami no] isoindoline-1,3-dione (250 mg, 556 umol) in DCM (10 mL) was added DMP (471 mg, 1.11 mmol) at 0 °C. Then the mixture was allowed to warm to rt and stirred for 2 hours. On completion, the reaction mixture was quenched with saturated NaHCO3 (10 mL) and saturated Na2S2O3 (10 mL) at rt, and then stirred for an additional 30 minutes. The mixture was then extracted with DCM (3 X 20 mL). The combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo to give the title compound (226 mg, 91% yield) as a yellow solid. LC-MS (ESI+) m/z 448.0 (M+H)+.

[005049] Step 3 - N-r3-carbamoyl-l-r1-r2-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethyl]azetidin yl]pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridvl]oxazole carboxamide

[005050] To a mixture of N-[l-(azetidin yl) carbamoyl-pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridyl] oxazole carboxamide (44.1 mg, 78.2 umol , TFA salt, Intermediate DB) in DCM (2 mL) was added TEA (11.8 mg, 117 umol), HOAc (9.39 mg, 156 umol) and 2-[2-[2-[2-[[2- (2,6-dioxo piperidyl)-l,3-dioxo- isoindolin-4yl]amino]ethoxy]ethoxy]ethoxy]acetaldehyde (35.0 mg, 78.2 umol), and the mixture was stirred for 30 minutes at rt. Then NaBH(OAc)3 (24.8mg, 117 umol) was added and the mixture was stirred rt for 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Kromasil 150*25mm *10 um; mobile phase:

1591

[water (0.225%FA)-ACN]) to give the title compound 1-169 (16.4 mg, 21% yield) as a yellow solid. 1H NMR (400MHz, DMSO-76) δ 11.10 (s, IH), 10.93 (s, IH), 8.96 (s, IH), 8.28 - 8.20 (m, 2H), 7.76 (s, IH), 7.68 (t, J= 6.4 Hz, IH), 7.61 - 7.49 (m, 2H), 7.25 (s, IH), 7.18 - 7.08 (m, 2H), 7.02 (d, J = 6.8 Hz, IH), 6.58 (t, J= 5.6 Hz, IH), 5.07 (dd, J = 6.4, 12.8 Hz, 2H), 4.25 - 4.21 (m, 2H), 3.70 (t, J = 7.6 Hz, 2H), 3.61 (t, J = 52 Hz, 2H), 3.57 - 3.47 (m, 14H), 2.92 - 2.84 (m, IH), 2.68 - 2.64 (m, 2H), 2.62 - 2.54 (m, 2H), 2.06 - 1.99 (m, IH). LC-MS (ESI+) m/z 904.3 (M+Na)+.

[005051] Example 170: N-[3-carbamovl-l-[l-[2-[2-[2-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin yl]amino] ethoxy] ethoxy] ethoxy] ethyl] piperidyl1 pyrazol vl] [2(22,.2&#1524;-trifluoroethvlamino) pvridvl1oxazole carboxamide, 1-170

mixture of N-[3-carbamoyl-l-(4-piperidyl)pyrazol yl] [2-(2,2,2 trifluoroethylamino) pyridyl]oxazole carboxamide (100 mg, 194 umol, HC1 salt, Intermediate CX) in DCM (4 mL) was added TEA (29.4 mg, 291 umol), HOAc (23.3 mg, 388 umol) and 2-[2-[2-[2-[[2-(2,6-dioxo n piperidyl)-!,3-dioxo-isoindolin-4 yl]amino]ethoxy]ethoxy]ethoxy]acetaldehyde (86.9 mg, 194 umol, synthesized via Steps 1-2 of Example 169) and the reaction was stirred at rt for 30 minutes. Then, NaBH(OAc)3 (61.7 mg, 291 umol) was added to the reaction mixture and the mixture was stirred at rt for an additional 16 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*lOum; mobile phase: [water (0.1% TFA)-ACN]) to give the title compound 1-170 (31.4 mg, 15% yield) as a

1592 yellow solid. 1H NMR (400MHz, DMSO-76) δ = 11.11 (s, IH), 10.92 (m, IH), 9.64 ( s, IH), 8.97 (s, IH), 8.39 (m, IH), 8.24 (d, J= 5.2 Hz, IH), 7.76 (t, J= 52 Hz, IH), 7.61 - 7.54 (m, 2H), 7.26 (s, IH), 7.20 - 7.14 (m, IH), 7.14 - 7.08 (m, IH), 7.07 - 6.99 (m, IH), 6.57 (s, IH), 5.05 (dd, J = 6.4, 12.8 Hz, IH), 4.80 - 4.48 (m, IH), 4.37 - 4.15 (m, 2H), 3.76 - 3.53 (m, 14H), 3.49 - 3.37 (m, 4H), 3.35 - 3.29 (m, IH), 3.22 - 3.11 (s, IH), 2.99 - 2.78 (m, IH), 2.62 - 2.51 (m, 2H), 2.41 - 2.17 (m, 4H), 2.09 - 1.97 (m, IH). LC-MS (ESI+) m/z 910.0 (M+H)+.

[005053] Example 171: N-[3-carbamovl-l-[4-[[2-[2-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin vl]amino] (22&#1524;2&#1524;-trifluoroethvlamino) pvridvl]oxazole carboxamide, 1-171

HOAc, NaBH(OAc)3, DCM

HCI in dioxane

THF

[005054] Step 1 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-(4-formylphenyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[005055] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4(hydroxymethyl)phenyl]pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (200 mg, 332 umoL synthesized via Step 1 of Intermediate CV) in THF

1593 (5 mL) and DCM (5 mL) was added DMP (282 mg, 665 umol) at 0 °C and the mixture was stirred at 0 °C for 2 hours. On completion, the mixture was quenched with saturated NaHCO3/Na2S2O3 (1: 1,30 mL) and stirred for an additional 30 min. The aqueous layer was then separated from the organic and extracted with DCM (3 X 20 mL). The combined organic solutions were washed with H2O (3 X 20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% FA in water) to give the title compound (100 mg, 48% yield) as a white solid. LC-MS (ESI+) m/z 600.4 (M+H)+.

[005056] Step 2 - Tert-butyl N-[4-[4-IT3-carbamovl-l-r4-IT2-[2-[2-IT2-(2.6-dioxo-3piperidyl)-L3-dioxo4-vl1carbamovl1oxazol vl1 pvridvl1-N-(2,2,2-trifluoroethvl)carbamate

[005057] A mixture of tert-butyl N-[4-[4-[[3-carbamoyl-l-(4-formylphenyl)pyrazol-4yl]carbamoyl] oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (40.5 mg, 66.7 umol), 4[2-[2-(2-amino ethoxy)ethoxy]ethylamino] (2,6-dioxo piperidyl)isoindoline-l,3-dione (40.0 mg, 100 umol, synthesized via Steps 1-2 of Example 127) in a mixed solvent of DCM (5 mL) and THF (5 mL) was added HO Ac (6.01 mg, 100 umol) and NaBH(OAc)3 (42.4 mg, 200 umol). The mixture was stirred at rt for 72 hours under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo and the residue was purified by reverse phase flash chromatography (0.1% FA in water) to give the title compound (50.0 mg, 76% yield) as a yellow solid. LC-MS (ESI+) m/z 988.5 (M+H)+.

[005058] Step 3 - N-r3-carbamoyl-l-r4-rr2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethoxy1ethoxy1ethylamino1methyl1phenyl1pyrazol yl1 [2-(2,2,2trifluoroethvlamino) pvridvl1oxazole carboxamide

[005059] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo- isoindolin yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol4-yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (50.0 mg, 50.6 umol) in THF (5 mL) was added HCI in dioxane (4 N, 2 mL). The mixture was stirred at rt for 2 hours. On completion, the mixture was concentrated in vacuo, and the residue was purified Pre-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 25%52%, 10 min) to give the title compound 1-171 (23.0 mg, 51% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.00 (s, IH), 9.01 (s, IH), 8.91 (s, IH), 8.29 - 8.21 (m, 2H), 8.03 (s, IH), 7.89 (d, J = 8.4 Hz, 2H), 7.76 - 7.66 (m, 2H), 7.61 - 7.54 (m, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.27

1594 (s, IH), 7.18 (d, J= 5.2 Hz, IH), 7.13 (d, J= 8.8 Hz, IH), 7.02 (d, J= 7.2 Hz, IH), 6.59 (t, J= 5.6

Hz, IH), 5.05 (dd, J = 5.2, 12.8 Hz, IH), 4.32 - 4.19 (m, 2H), 3.81 (s, 2H), 3.72 - 3.53 (m, 10H),

2.93 - 2.80 (m, IH), 2.75 - 2.67 (m, 2H), 2.56 - 2.53 (m, 3H), 2.09 - 1.97 (m, IH); LC-MS (ESI+) m/z 888.4 (M+H)+.

[005060] Example 172: N-[3-carbamoyl-l-[4-[5-[2-[[2-(2.,6-dioxo piperidvl)-l.,3dioxo-isoindolin yl]amino] ethvlamino]pentvlcarbamovl]phenvl]pvrazol yl] [2-(2.,2.,2-

h2n

hydroxyp entyl carb amoyDphenyl 1 pyrazol yl 1 carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2trifluoroethyDcarbamate

1595

[005062] To a mixture of 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (100 mg, 162 umol, Intermediate CN) and 5-aminopentan-l-ol (22.0 mg, 211 umol) in DMF (5 mL) was added DIPEA (63.0 mg, 487 umol, 85 uL) and HATU (74.0 mg, 195 umol). The mixture was stirred at rt for 2 hours. On completion, the mixture was quenched by water (15 mL), and then filtered. The filter cake was dried in vacuo. The residue was purified by reverse phase flash chromatography (0.1% FA in water) to give the title compound (80.0 mg, 67% yield) as a white solid. LC-MS (ESI+) m/z 701.3 (M+H)+.

[005063] Step 2:Tert-butyl N-r4-r4-rr3-carbamoyl-l-[4-(5oxopentylcarbamoyl)phenyl1pyrazol yl1 carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2trifluoroethyllcarbamate

[005064] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-(5hydroxypentylcarbamoyl)phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (80.0 mg, 114 umol) in THF (5.0 mL) and DCM (5.0 mL) was added DMP (54.0 mg, 125. umol) at 0 °C. The mixture was stirred at 0 °C for 2 hours. On completion, the reaction mixture was quenched with saturated NaHCO3/Na2S2O3 solution (1: 1, 10 mL) and stirred for 30 minutes. The aqueous layer was separated from the organic and extracted with DCM (3 X 20 mL). The combined organic layers were washed with H2O (3X10 mL) and brine (20 mL), dried over MgSO4, then filtered and concentrated in vacuo to give the title compound (80.0 mg, crude) as a yellowish solid. LC-MS (ESI+) m/z 599.2 (M+H-100)+.

[005065] Step 3 - Tert-butyl N-r4-r4-rr3-carbamovl-l-r4-r5-r2-rr2-(2.6-dioxo piperidyl)L3-dioxo-isoindolin yl1amino1ethylamino1pentvlcarbamoyl1phenvl1pyrazol-4vl1carbamovl1oxazol vl1 pvridvl1-N-('2.2.2-trifluoroethvl )carbamate

[005066] To a mixture of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-(5oxopentylcarbamoyl)phenyl]pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (60.0 mg, 86.0 umol) and 4-(2- aminoethylamino) (2,6-dioxo-3piperidyl)isoindoline-l,3-dione (34.0 mg, 95.0 umol, HCI salt, Intermediate DJ) in THF (5 mL) was added AcOH (7.00 mg, 112 umol) and NaBH(OAc)3 (27.0 mg, 128 umol). The mixture was stirred at rt for 24 hours under nitrogen atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (0.1% FA in water) to

1596 give the title compound (30.0 mg, 35% yield) as a yellow solid. LC-MS (ESI+) m/z 999.0 (M+H)+.

[005067] Step 4 - N-r3-carbamoyl-l-r4-r5-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethylamino1pentylcarbamoyl1phenyl1pyrazol yl1 r2-(2,2,2trifluoroethylamino) pyridyl1oxazole carboxamide

[005068] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[5-[2-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo- isoindolin yl]amino]ethylamino]pentylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (40.0 mg, 40.0 umol) in THF (5 mL) was added HCI in dioxane (4 N, 2 mL). The mixture was stirred at rt for 1 hour. On completion, the mixture was concentrated in vacuo, and the residue was purified by Pre-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 27%57%, 10 min).to give the title compound 1-172 (20.0 mg, 56% yield) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 11.01 (s, IH), 9.03 (d, J = 5.6 Hz, 2H), 8.65 - 8.54 (m, IH), 8.38 - 8.23 (m, 2H), 8.16 - 7.98 (m, 5H), 7.82 - 7.73 (m, IH), 7.69 (t, J= 6.4 Hz, IH), 7.59 (t, J= 7.6 Hz, IH), 7.27 (s, IH), 7.21 - 7.12 (m, 2H), 7.05 (d, J = 7.2 Hz, IH), 6.82 (m, IH), 5.06 (dd, J = 5.2, 12.8 Hz, IH), 4.32 - 4.16 (m, 2H), 3.48 - 3.47 (m, 2H), 3.29 (m, 2H), 2.97 - 2.85 (m, 3H), 2.77 - 2.66 (m, 2H), 2.64 - 2.53 (m, 3H) , 2.09 - 1.98 (m, IH), 1.56 (m, 4H), 1.38 (m, 2H); LC-MS (ESI+) m/z 899.4 (M+H)+.

[005069] Example 173: 6-(5-Cvanopvrazolo[3,4-b]pvridin-l-vl) (cvclopropylamino)N-[3-[2-(2,6-dioxo-3carboxamide, 1-173

1597

DIAD, PPh3, THF

[005070] Step 1:4-r3-(Dibenzylamino) fluoro-propoxy1 (2,6-di oxo-3piperidyl)isoindoline-L3-dione

[005071] To a mixture of 2-(2,6-dioxo piperidyl) hydroxy-isoindoline-l ,3-dione (2.00 g, 7.29 mmol, synthesized via Step 1 of Intermediate CA) in THF (200 mL) was added 3&#1470; (dibenzylammo) fluoiO-propan-l-ol (1.99 g, 7.29 mmol, Intermediate AH) and PPh3 (3.83 g, 14.5 mmol). Then DIAD (2.21 g, 10.9 mmol) was added to the mixture dropwise at 0°C. The reaction mixture was allowed to warm to rt and stirred for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm* 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 25ACN%-50ACN%, 30 min, 50% min) to give the title compound (2.70 g, 60% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) δ 11.13 (s, IH), 7.97 - 7.73 (m, IH), 7.47 (d, J = 7.2 Hz, IH), 7.41 (d, 7= 8.4 Hz, IH), 7.37-7.21 (m, 8H), 7.21 -7.08 (m, 2H), 5.21 -4.88 (m, 2H), 4.47 4.17 (m, 2H), 3.73 - 3.53 (m, 4H), 3.06 - 2.75 (m, 3H), 2.70 - 2.54 (m, 2H), 2.14 - 1.92 (m, IH); LC-MS (ESI+) m/z 530.0 (M+H)+.

[005072] !%££^2^ζβ%Δ111&#943;11θ222£Ιιι0Γ^£1&#908;££^)222(2^^^χ%£&#943;£6Γ^^ di one

[005073] To a mixture of 4-[3-(dibenzylamino) fluoro-propoxy] (2,6-di oxo-3piperidyl)isoindoline-l,3- dione (100 mg, 188 umol), Pd(OH)2/C (60.0 mg, 10 wt %) and Pd/C

1598 (60.0 mg, 10 wt %) in MeOH (6 mL) was added HCI (IM, 100 uL) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 18 hours. On completion, the reaction mixture was fdtered and concentrated in vacuo to give the compound (68.0 mg, HCI salt, 95% yield) as a colorless solid. LC-MS (ESI+) m/z 350.0 (M+H)+.

[005074] Step 3 - 6-(5-Cyanopyrazolor3.4-b1pyridin-l-yl) (cyclopropylamino)-N-[3-r2(2,6-dioxo piperidyl)-L3-dioxo-isoindolin yl1oxy fluoro-propyl1pyridine carboxamide [005075] To a mixture of 4-(3-amino fluoro-propoxy) (2,6-di oxo-3piperidyl)isoindoline-l,3-dione (48.0 mg, 124 umol, HCI salt) in DMF (2 mL) was added 6-(5cyanopyrazolo[3,4-b]pyridin-l-yl) (cyclopropylamino)pyridine carboxylic acid (64.8 mg, 149 umol, TFA salt, Intermediate L) and DIPEA (96.4 mg, 746 umol). Then HATU (70.9 mg, 186 umol) was added to the mixture and the mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-173 (24.0 mg, 28% yield) as a white solid. 1HNMR (400MHz, DMSOd6) δ 11.13 (s, IH), 9.08 (d, J= 2.0 Hz, IH), 9.04 (d, J= 2.0 Hz, IH), 8.95 (t, J= 5.6 Hz, IH), 8.72 - 8.62 (m, 2H), 8.55 (s, IH), 7.88 - 7.84 (m, IH), 7.72 (s, IH), 7.57 - 7.50 (m, 2H), 5.18 - 5.01 (m, 2H), 4.69 - 4.44 (m, 2H), 3.80 - 3.66 (m, 2H), 2.93 - 2.82 (m, IH), 2.71 - 2.56 (m, 3H), 2.09 - 1.99 (m, IH), 0.99 - 0.81 (m, 2H), 0.58 - 0.56 (m, 2H); LC-MS (ESI+) m/z 652.2 (M+H)+.

[005076] Example 174: 4-(Cvclopropvlamino)-N-[3-[2-(2,6-dioxo piperidyl)-l,3dioxo-isoindolin vl]oxy fluoro-propvl] (l,6-naphthvridin vlamino)pyridine-3carboxamide, 1-174

[005077] To a mixture of 4-(3-amino fluoro-propoxy) (2,6-dioxo-3piperidyl)isoindoline-l,3-dione (100 mg, 259 umol, HCI salt, synthesized via Steps 1-2 of Example 173) andDIPEA(167 mg, 1.30 mmol) in DMF (2 mL) was added 4-(cyclopropylamino)

1599

6-(l,6-naphthyridin ylamino)pyridine carboxylic acid (83.3 mg, 259 umol, Intermediate N) and HATU (118 mg, 311 umol). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo. Then the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-174 (44.7 mg, 26% yield) as a white solid. lH NMR (400MHz, DMSOd6) δ 11.13 (s, IH), 10.37 (s, IH), 9.06 (s, IH), 8.67 (t, J= 5.2 Hz, IH), 8.62 - 8.56 (m, 2H), 8.49 (s, IH), 8.28 (d, 8.8 Hz, IH), 8.18 (s, IH), 7.86 (t, 7= 7.6 Hz, IH), 7.65 - 7.44 (m, 4H), 5.15 4.98 (m, 2H), 4.60 - 4.43 (m, 2H), 3.76 - 3.70 (m, 2H), 2.97 - 2.86 (m, IH), 2.71 - 2.56 (m, 3H), 2.08 - 2.00 (m, IH), 1.01 - 0.87 (m, 2H), 0.60 - 0.58 (m, 2H). LC-MS (ESI+) m/z 653.2 (M+H)+. [005078] Example 175: l-[4-(cyclopropylamino) [l-[2-[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l.,3-dioxo-isoindolin yl] amino] ethoxy] ethoxy] ethoxy] ethyl] triazol yl] -2pyridyl] pyrazolo [3.,4-b] pyridine carbonitrile.,1-175

sodium L-ascorbate

BN h2O, t-BuOH

Tert-butvl

[005079] Step 1

N-[2-[2-[2-[2-[4-[6-chloro (cyclopropylamino)-31600 pyridylltriazol-1 -yl1 ethoxy] ethoxy]ethoxy]ethyl]carbamate

[005080] To a solution of tert-butyl N-[2-[2-[2-(2azidoethoxy)ethoxy]ethoxy]ethyl]carbamate (1.65 g, 5.19 mmol, Intermediate BN), CuSO4 (4.14 mg, 26.0 umol) and sodium (2R) [(lS)-l,2-dihydroxyethyl] hydroxy oxo-2H-furan olate (10.3 mg, 51.9 umol) in a mixed solvent of H2O (5 mL) and t-BuOH (5 mL) was added 2-chloroN-cyclopropyl ethynyl-pyridin amine (500 mg, 2.60 mmol, Intermediate DL). The reaction mixture was stirred at 60 °C for 2 h. On completion, the mixture was diluted with H2O (20 mL) and extracted with EA (2 X 30 mL). The organic layer was washed with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο) to give the title compound ( 1.02 g, 77% yield) as a yellow oil. LC-MS (ESI+) m/z 511.4 (M+H)+.

[005081] Step 2 - Tert-butyl N-r2-r2-r2-r2-r4-r6-(5-cyanopyrazolor3,4-b1pyridin-l-yl)-4(cyclopropylamino) pyridylltriazol-1 -yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

[005082] Tert-butyl N-[2-[2-[2-[2-[4-[6-chloro (cyclopropylamino) pyridyl]triazol-lyl]ethoxy]ethoxy] ethoxy]ethyl]carbamate (250 mg, 489 umol), lH-pyrazolo[3,4-b]pyridine-5carbonitrile (177 mg, 1.22 mmol, CAS# 1234616 1), Pd2(dba)3 (179 mg, 196 umol), K3PO4 (312 mg, 1.47 mmol) and t-Bu Xphos (83.1 mg, 196 umol) were taken up into a microwave tube. Then dioxane (5 mL) and H2O (0.5 mL) were added into the microwave tube. The mixture was degassed and purged with nitrogen gas three times, and then the sealed tube was heated to 100 °C and stirred for 8 hrs under microwave. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 36%-66%) to give the title compound (30 mg, 9.4% yield) as a white solid. LC-MS (ESI+) m/z 619.0 (M+H)+.

[005083] Step 3 - l-r5-r1-r2-r2-r2-(2-aminoethoxy)ethoxy1ethoxy1ethyl1triazol yl1-4(cyclopropylamino) pyridyl1pyrazolo[3,4-b1pyridine carbonitrile

[005084] To a solution of tert-butyl N-[2-[2-[2-[2-[4-[6-(5-cyanopyrazolo[3,4-b]pyridin-lyl) (cyclopropylamino) pyridyl]triazol-l-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (30 mg, 48.5 umol) in DCM (1.5 mL) was added HCI in dioxane (4 M, 1.5 mL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (26.9 mg, 100% yield, HCI salt). LC-MS (ESI+) m/z 519.3 (M+H)+

[005085] Step 4 - l-r4-(cyclopropylamino) r1-r2-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3

1601 dioxo-isoindolin b1pyridine carbonitrile

[005086] To a solution of l-[5-[l-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]triazol-4yl] (cyclopropylamino) pyridyl]pyrazolo[3,4-b]pyridine carbonitrile (26.9 mg, 48.5 umol, HC1 salt) and 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (14.7 mg, 53.3 umol, Intermediate R) in dioxane (3 mL) was added DIPEA (62.6 mg, 485 umol). The reaction mixture was stirred at 115 °C for 60 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10um; mobile phase: [water (0.225%FA) -ACN]; B%: 20%-50%) to give the title compound 1-175 (13 mg, 35% yield) as a yellow solid. 1H NMR (400MHz, DMSOA) 6 11.1611.03 (m, IH), 9.06 - 9.03 (m, IH), 9.03 - 9.00 (m, IH), 8.75 (s, IH), 8.64 (s, IH), 8.60 (s, IH), 8.44 - 8.41 (m, IH), 7.69 (s, IH), 7.57 - 7.43 (m, IH), 7.07 - 7.02 (m, IH), 7.01 - 6.97 (m, IH), 6.57 - 6.48 (m, IH), 5.07 - 5.00 (m, IH), 4.66 - 4.59 (m, 2H), 3.92 - 3.86 (m, 2H), 3.58 - 3.54 (m, 4H), 3.53 - 3.49 (m, 6H), 3.42 - 3.40 (m, 2H), 2.96 - 2.81 (m, IH), 2.62 - 2.59 (m, IH), 2.57 - 2.55 (m, 2H), 2.06 - 1.99 (m, IH), 0.94 - 0.87 (m, 2H), 0.65 - 0.57 (m, 2H); LC-MS (ESI+) m/z 775 A (M+H)+.

[005087] Example 176: l-[4-(Cvclopropvlamino) [l-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo3-piperidyl)-l.,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl] triazol vl] pyr idyll pyrazolo [34&#1497;blpyridine carbonitrile.,1-176

[005088] l-[4-(Cyclopropylamino) [l-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3dioxo- isoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol yl]-2pyridyl]pyrazolo[3,4-b]pyridine carbonitrile 1-176 was synthesized as described above for Example 175 except that Intermediate BQ was used as the azide in Step 1. 1H NMR (400MHz, CD3CN) 6 9.07 (s, IH), 8.92 (d, J = 2.0 Hz, IH), 8.70 (d, J = 2.0 Hz, IH), 8.56 (s, IH), 8.49 (s, IH), 8.45 (s, IH), 8.39 (s, IH), 7.82 (s, IH), 7.55 - 7.50 (m, IH), 7.02 (dd, J = 4.0, 5.2 Hz, 2H),

1602

6.49 - 6.40 (m, IH), 5.00 - 4.90 (m, IH), 4.63 (t, J= 4.8 Hz, 2H), 3.95 - 3.92 (m, 2H), 3.66 - 3.55 (m, 8H), 3.54 - 3.50 (m, 10H), 3.45 - 3.38 (m, 2H), 2.75 - 2.67 (m, 3H), 2.14 - 2.13 (m, IH), 1.82 .77 (m, IH), 0.95 - 0.90 (m, 2H), 0.72 - 0.63 (m, 2H); LC-MS (ESI+) m/z 863.4 (M+H)+.

[005089] Example 177: N-[3-carbamovl-l-[4-[6-[[2-(2,6-dioxo piperidvl)-l,3-dioxoisoindolin vl] amino] hexa-2,4-divnvlcarbamoyl] phenyl] pyrazol vl] [2-(2,2,2trifluoroethvlamino) pyridvl]oxazole carboxamide,

1-177

CN

Cui , NiCI2 , TMEDA , THF

[005090] Step 1:Tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-(prop-2ynylcarbamoyl)phenyl1pyrazol yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2 trifluoroethyDcarbamate

[005091] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole-4 -carbonyl]amino] carbamoyl-pyrazol-l-yl]benzoic acid (200 mg, 324 umol, Intermediate CN) and prop yn-l-amine (21.4 mg, 389 umol, 24.9 uL) in DMF (5.00 mL) was added HATU (148 mg, 389 umol) and DIPEA (125 mg, 974 umol, 169 uL), and the mixture was stirred at rt for Ihr. On completion, the mixture was diluted with H2O (30 mL) and extracted with

1603

EA (3X15 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (210 mg, 99% yield) as a white solid. 1H NMR (400MHz,

MeOD-d4) δ 11.04 (s, IH), 9.07 (s, IH), 9.04 - 8.99 (m, 2H), 8.63 (d, J = 52 Hz, IH), 8.22 (s,

IH), 8.12 - 8.06 (m, 3H), 8.03 - 7.98 (m, 2H), 7.77 - 7.73 (m, 2H), 4.92 - 4.82 (m, 2H), 4.08 - 4.03 (m, 2H), 3.11 (t, J = 2.4 Hz, IH), 1.50 (s, 9H).

[005092] Step 2 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-r4-r6-rr2-(2,6-dioxo piperidyl)-L3dioxo-isoindolin

2-vl1 pvridvl1-N-(2,2,2-trifluoroethyl)carbamate

[005093] A solution of Cui (5.84 mg, 30.6 umol), N1C12 6H2O (1.82 mg, 7.66 umol) and Ν,Ν,Ν',N'-tetram ethyl ethane-1,2-diamine (356 ug, 3.06 umol) were dissolved in THF (4.00 mL) and stirred at rt for 5 min. Tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-(prop ynylcarbamoyl)phenyl] pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (100 mg, 153 umol) and 2-(2,6-dioxo piperidyl) (prop ynylamino)isoindoline-l,3-dione (238 mg, 766 umol, Intermediate DN) in THF (4.00 mL) was then added and the reaction mixture was stirred at rt for 16 h. On completion, the reaction mixture was filtered through a pad of celite, and the celite layer was washed with AcOEt (30 mL). The combined filtrate was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*lOum; mobile phase: [water (0.225%FA)-ACN]; B%: 50%-80%) to give the title compound (25.0 mg, 16% yield) as a yellow solid. LC-MS (ESI+) m/z 962.0 (M+H)+.

[005094] Step 3 - N-r3-carbamoyl-l-r4-r6-rr2-(2,6-dioxo piperidyl)-L3-dioxo-isoindolin4-yl] pyridyl1oxazole carboxamide

[005095] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[6-[[2-(2,6-dioxo-3piperidyl)-l,3- dioxo-isoindolin yl]amino]hexa-2,4-diynylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (20.0 mg, 19.75umol) in DCM (2.00 mL) was added HCI in dioxane (4 M, 2.00 mL), and the mixture was stirred at rt for 30 min. On completion, the mixture was concentrated in vacuo. The mixture was purified by prepHPLC (column: Phenomenex Synergi Cl8 150*25*lOum; mobile phase: [water (0.225%FA)ACN]; B%: 40%-70%, 13min) to give the title compound 1-177 (2.94 mg, 16% yield, FA) as a yellow solid. 1HNMR (400MHz, DMSO-d6) δ 11.11 (s, IH), 11.01 (s, IH), 9.14 - 9.08 (m, IH), 9.05 (s, IH), 9.03 (s, IH), 8.26 (d, J = 5.2 Hz, IH), 8.16 (s, IH), 8.11 (d, J = 8.8 Hz, 2H), 8.01 (d,

1604

J = 8.8 Hz, 2H), 7.78 (s, IH), 7.72 - 7.65 (m, 2H), 7.27 (s, IH), 7.20 - 7.12 (m, 3H), 7.02 (t, J =

6.2 Hz, IH), 5.12 - 5.02 (m, IH), 4.36 - 4.30 (m, 2H), 4.28 - 4.22 (m, 2H), 4.21 - 4.17 (m, 2H),

2.99 - 2.81 (m, IH), 2.64 - 2.56 (m, 2H), 2.09 - 1.99 (m, IH), LC-MS (ESI+) m/z 862.1 (M+H)+.

[005096] Example 178: N-[3-carbamoyl-l-[4-[7-[[2-(2.,6-dioxo piperidvl)-l.,3-dioxoisoindolin yl]amino]hepta-24&#1524;-divnvlcarbamovl]phenvl]pvrazol yl] [2-(2.,2.,2trifluoroethvlamino) pvridvl]oxazole carboxamide.,1-178

[005097] N-[3-carbamoyl-l-[4-[7-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]hepta- 2,4-diynylcarbamoyl]phenyl]pyrazol yl] [2-(2,2,2-trifluoroethylamino)-4pyridyl]oxazole carboxamide 1-178 was synthesized as described for Example 177, using Intermediate CN as the acid and prop yn-l-amine as the alkyne in Step 1 and Intermediate DO as the alkyne in Step 2, which was run for 80 h at rt. Characterization of the final product: 1H NMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 11.02 (s, IH), 9.12 (t, J = 5.2 Hz, IH), 9.06 (d, J = 7.6 Hz, 2H), 8.26 (d, J = 5.2 Hz, IH), 8.16 (s, IH), 8.14 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.79 (s, IH), 7.70 (t, J = 6.4 Hz, IH), 7.62 - 7.56 (m, IH), 7.28 (s, IH), 7.19 (s, IH), 7.19 7.17 (m, IH), 7.06 (d, J = 7.2 Hz, IH), 6.76 (t, J = 6.0 Hz, IH), 5.10 - 5.04 (m, IH), 4.28 - 4.22 (m, 2H), 4.20 (d, J = 5.2 Hz, 2H), 3.73 - 3.45 (m, 2H), 2.95 - 2.81 (m, IH), 2.65 (s, IH), 2.61 2.58 (m, IH), 2.57 - 2.50 (m, 2H), 2.07 - 1.97 (m, IH); LC-MS (ESI+) m/z 876.2 (M+H)+.

[005098] Example 179: N-[3-carbamoyl-l-[4-[8-[[2-(2.,6-dioxo piperidvl)-l.,3-dioxoisoindolin yl]amino]octa-3,5-divnylcarbamoyl] phenyl] pyrazol yl] 12-(2,2,2trifluoroethvlamino) pvridvl]oxazole carboxamide.,1-179

1605

[005099] N-[3-carbamoyl-l-[4-[8-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]octa- 3,5-diynylcarbamoyl]phenyl]pyrazol yl] [2-(2,2,2-trifluoroethylamino)-4pyridyl]oxazole carboxamide 1-179 was synthesized as described for Example 177, using Intermediate CN as the acid and but yn-l-amine( hydrochloride salt) as the alkyne in Step 1 and Intermediate DO as the alkyne in Step 2, which was run for 80 h at rt. Characterization of the final product: 1HNMR (400MHz, DMSO-d6) δ 11.10 (s, IH), 11.02 (s, IH), 9.05 (d, J= 6.8 Hz, 2H), 8.83 (t, J = 5.6 Hz, IH), 8.26 (d, J = 5.6 Hz, IH), 8.13 (d, J = 8.8 Hz, 3H), 8.03 (d, J = 8.8 Hz, 2H), 7.78 (s, IH), 7.70 (t, J = 6.4 Hz, IH), 7.62 - 7.55 (m, IH), 7.28 (s, IH), 7.18 (d, J= 8.8 Hz, 2H), 7.05 (d, J= 7.2 Hz, IH), 6.74 (t, J= 6.0 Hz, IH), 5.07 (dd, J= 5.2, 13.2 Hz, IH), 4.30 - 4.21 (m, 2H), 3.53 - 3.48 (m, 4H), 2.93 - 2.86 (m, IH), 2.65 - 2.60 (m, 6H), 2.03 (d, J = 7.6 Hz, IH); LC-MS (ESI+) m/z 890.2 (M+H)+.

[005100] Example 180: N-[3-carbamoyl-l-[4-[[l-[3-[[2-(2.,6-dioxo piperidyl)-l.,3dioxo-isoindolin yl]amino]

[2-(2.,2.,2-trifluoroethylamino) pyridyl1oxazole carboxamide,1-180

1606

DP

copper(ll) sulfate, sodium L-ascorbate, H2O, t-BuOH

[005101] Step 1 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-r4-rr1-r3-rr2-(2,6-dioxo piperidyl)1,3-dioxo-isoindolin yl1amino1propyl1triazol yl1methylcarbamoyl1phenyl1pyrazol-4vl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[005102] To a solution of 4-(3-azidopropylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (131 mg, 368 umol, Intermediate DP) and tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-(prop-2ynylcarbamoyl)phenyl]pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (120 mg, 184 umol, synthesized via Step 1 of Example 177) in tertbutanol (4 mL) and H2O (4 mL) was added sodium (2R) [(lS)-l,2-dihydroxyethyl] hydroxyl5-oxo-2H-furan olate (728 ug, 3.68 umol) and CuSO4 (293 ug, 1.84 umol). The reaction mixture was heated to 60 °C and stirred for 12 hours. On completion, the mixture was concentrated in

1607 vacuo to give a residue, and the residue was triturated with H2O (50 mL). Then the solid the filtered and dried in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi

C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 48%-78%, 10 min) to give the title compound (60.0 mg, 32% yield) as a yellow solid. LC-MS (ESI+) m/z 1009.5 (M+H)+.

[005103] Step 2 - N-r3-carbamoyl-l-r4-rr1-r3-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 trifluoroethylamino) pyridyl1oxazole carboxamide

[005104] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[l-[3-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo- isoindolin yl]amino]propyl]triazol-4yl]methylcarbamoyl]phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (60.0 mg, 59.5 umol) in DCM (2 mL) was added HCI in dioxane (4 M, 2 mL). The reaction mixture was stirred at rt for 30 minutes. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min) to give the title compound 1-180 (14.2 mg, 24% yield) as yellow solid. 1H NMR (400MHz, DMSOd6) δ 11.02 (s, IH), 9.20 - 9.20 (m, IH), 9.05 (d, J = 4.4 Hz, 2H), 8.26 (d, J= 5.2 Hz, IH), 8.23 7.98 (m, 7H), 7.79 (s, IH), 7.75 - 7.68 (m, IH), 7.57 (t, J= 8.0 Hz, IH), 7.27 (s, IH), 7.18 (d, J= 4.8 Hz, IH), 7.04 (t, J = 8.0 Hz, 2H), 6.72 (m, IH), 5.05 (dd, J = 4.8, 12.8 Hz, IH), 4.54 (d, J = 4.8 Hz, 2H), 4.44 (t, J= 6.8 Hz, 2H), 4.30 - 4.20 (m, 2H), 3.49 - 3.43 (m, 2H), 2.95 - 2.83 (m, IH), 2.61 (m, IH), 2.58 - 2.56 (m, IH), 2.15 - 2.09 (m, , 2H), 2.05 - 2.00 (m, IH); LC-MS (ESI+) m/z 909.4 (M+H)+.

[005105] Example 181: N-[3-carbamoyl-l-[4-[2-[l-[3-[[2-(2.,6-dioxo piperidvl)-l.,3dioxo-isoindolin yl] amino] propyl] triazol yl] ethylcarbamoyl] phenyl] pyrazol yl] [2(22,.2&#1524;-trifluoroethvlamino) pvridvl]oxazole carboxamide,1-181

1608

[005106] N-[3-carbamoyl-l-[4-[2-[l-[3-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl] amino]propyl]triazol yl]ethylcarbamoyl]phenyl]pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridyl]oxazole carboxamide 1-181 was synthesized as described for Example 180, using azide Intermediate DP and alkyne tert-butyl N-[4-[4-[[l-[4-(but-3ynylcarbamoyl)phenyl] carbamoyl-pyrazol yl] carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate (synthesized via Step 1 of Example 179) in the first step. Characterization of the final product: 1HNMR (400MHz, DMSO-d6) δ 11.11 (s, IH), 11.03 (s, IH), 9.05 (s, IH), 9.04 (s, IH), 8.74 (t, J = 5.6 Hz, IH), 8.27 (d, J = 5.2 Hz, IH), 8.15 (s, IH), 8.12 - 8.08 (m, 2H), 8.02 (s, 2H), 8.00 (s, IH), 7.79 (s, IH), 7.74 - 7.68 (m, IH), 7.60 - 7.54 (m, IH), 7.28 (s, IH), 7.21 - 7.17 (m, IH), 7.06 - 7.01 (m, 2H), 6.69 (t, J = 6.0 Hz, IH), 5.10 - 5.02 (m, IH), 4.46 - 4.41 (m, 4H), 4.34 - 4.28 (m, 2H), 3.57 - 3.53 (m, 2H), 2.95 - 2.91 (m, 2H), 2.89 2.84 (m, IH), 2.64 - 2.59 (m, 2H), 2.13 - 2.08 (m, 2H), 2.07 - 2.05 (m, IH); LC-MS (ESI+) m/z 923.4 (M+H)+.

[005107] Example 182: N-[3-carbamovl-l-[4-[3-[4-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin vl]amino] (2,2,2-trifluoroethvlamino) pvridvl]oxazole carboxamide, 1-182

1609

&#1524; ___CF3

Boc 5

[005108] Step 1 - Tert-butyl N-)4-)4-))l-)4-(3-azidopropylcarbamoyl)phenyl1 carbamoylpyrazol yll carbamovl1oxazol vl1 pvridvH-N-(2.2.2-trifluoroethyl)carbamate

[005109] To a solution of 3-azidopropan amine (44.3 mg, 324 umol, HCI salt) and 4-[4[[2-[2-[tert -butoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole carbonyl]amino]-3carbamoyl-pyrazol-l-yl]benzoic acid (0.20 g, 324 umol, Intermediate CN) in DMF (4 mL) was added DIPEA (209 mg, 1.62 mmol, 282 uL). The mixture was stirred at rt for 12 minutes, and then HATU (148 mg, 389 umol) was added to the mixture. The reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (ΝΗ3&#905;2Ο) to give the title compound (180 mg, 77% yield) as a white solid. LC-MS (ESI+) m/z 698.2 (M +H)+.

[005110] Step 2 - Tert-butyl N-)4-)4-))3-carbamoyl-l-)4-)3-)4-)2-))2-/2.6-4^0-3

1610 piperidyl)-L3-dioxo

4-vl1carbamovl1oxazol vl1 pvridvl1-N-(2,2,2-trifluoroethyl)carbamate

[005111] To a solution of 4-(but ynylamino) (2,6-dioxo piperidyl)isoindoline-l,3dione (35.0 mg, 107 umol, Intermediate DO) and tert-butyl N-[4-[4-[[l-[4-(3azidopropylcarbamoyl) phenyl] carbamoyl- pyrazol yl]carbamoyl]oxazol yl] pyridyl]N-(2,2,2-trifluoroethyl)carbamate (112 mg, 161 umol) in H2O (1.00 mL) and tert-butanol (3.00 mL) was added CuSO4 (171 ug, 1.08 umol) and sodium (2R) [(lS)-l,2-dihydroxyethyl]-4hydroxy oxo-2H -furan olate (426 ug, 2.15 umol), and the mixture was heated to 60 °C and stirred for 16 hr. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]; B%: 50%-80%, lOmin) to give the title compound (30.0 mg, 27% yield) as a yellow solid. LC-MS (ESI+) m/z 1045.2 (M+Na)+.

[005112] Step 3 - N-r3-carbamoyl-l-r4-r3-r4-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethvl1triazol-l-l1propvlcarbamovl1phenvl1pvrazol vl1 r2-(2,2,2trifluoroethvlamino) pvridvl1oxazole carboxamide

[005113] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[3-[4-[2-[[2-(2,6-dioxo-3piperidyl)-l,3 -dioxo-isoindolin yl]amino]ethyl]triazol-l-yl]propylcarbamoyl]phenyl]pyrazol4-yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (30.0 mg, 29.3 umol) in DCM (2.00 mL) was added HCI in dioxane (4 M, 5.00 mL), and the mixture was stirred at rt for 30 min. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]; B%: 35%-65%) to give the title compound 1-182 (11.8 mg, 43% yield) as a yellow solid. 1H NMR (400MHz, DMSO-J6) δ 11.10 (s, IH), 11.02 (s, IH), 9.08 - 9.05 (m, IH), 9.04 (s, IH), 8.68 (s, IH), 8.26 (d, J = 5.2 Hz, IH), 8.13 (d, J = 3.2 Hz, 2H), 8.10 (s, IH), 8.03 (s, IH), 8.02 - 8.01 (m, 2H), 7.79 (s, IH), 7.74 - 7.68 (m, IH), 7.61 - 7.57 (m, IH), 7.27 (s, IH), 7.20 - 7.17 (m, IH), 7.12 (d, J = 8.8 Hz, IH), 7.03 (d, J = 7.2 Hz, IH), 6.75 - 6.71 (m, IH), 5.06 - 5.02 (m, IH), 4.43 - 4.39 (m, 2H), 4.32 - 4.21 (m, 2H), 3.64 - 3.57 (m, 2H), 3.30 - 3.28 (m, 2H), 2.97 - 2.93 (m, 2H), 2.88 2.84 (m, IH), 2.62 - 2.59 (m, IH), 2.57 - 2.56 (m, IH), 2.12 - 2.07 (m, 2H), 2.04 - 1.98 (m, IH), LC-MS (ESI+) m/z 944.9 (M+Na)+.

[005114] Example 183: N-[3-carbamoyl-l-[4-[3-[4-[[[2-(2,6-dioxo piperidyl)-l,3dioxo-isoindolin yl]amino] methyl]triazol-l-yl]propylcarbamoyl]phenyl]pyrazol yl]-21611

[2-(22,.2&#1524;-trifluoroethylamino) pyridyl]oxazole carboxamide,1-183

hn^cf3

[005115] N-[3-carbamoyl-l-[4-[3-[4-[[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino] methyl]triazol-l-yl]propylcarbamoyl]phenyl]pyrazol yl] [2-(2,2,2trifluoroethylamino) pyridyl]oxazole carboxamide 1-183 was synthesized as described above for Example 182, using alkyne Intermediate DN in the second step. Characterization of the final product: 1HNMR (400 MHz, DMSO-d6) δ 11.09 (s, IH), 11.02 (s, IH), 9.04 (d, J= 5.2 Hz, 2H), 8.64 (t, J = 5.2 Hz, IH), 8.26 (d, J = 5.2 Hz, IH), 8.15 - 8.07 (m, 4H), 8.02 (d, J = 8.8 Hz, 2H), 7.77 (s, IH), 7.70 (t, J = 6.4 Hz, IH), 7.63 - 7.55 (m, IH), 7.28 (s, IH), 7.21 - 7.14 (m, 2H), 7.12 - 7.02 (m, 2H), 5.07 (dd, J= 5.6, 12.8 Hz, IH), 4.61 (d, J = 6.0 Hz, 2H), 4.43 (t, J= 7.2 Hz, 2H), 4.25 (dd, J= 6.4, 9.8 Hz, 2H), 3.29 - 3.24 (m, 2H), 2.95 - 2.82 (m, IH), 2.64 - 2.55 (m, 2H), 2.13 - 2.00 (m, 3H); LC-MS (ESI+) m/z 909.2 (M+H)+.

[005116] Example 184: T(2R) [(8R)-l-[4-[4-[2-[2-[[2-(2,6-dioxo piperidyD-L3dioxo-isoindolin yl]amino]V cyclopenta [4,5] thieno[l.,2-c]pyrimidin yl] hydroxy-propanamide, 1-184

1612

[005117] Step 1 (2,6-Dioxo piperidyl) r2-(2-hydroxyethoxy)ethylamino1isoindoline1,3-di one

[005118] To a solution of 2-(2-aminoethoxy)ethanol (500 mg, 3.53 mmol, HCI salt) in dioxane (15 mL) was added DIPEA (3.65 g, 28.2 mmol) and 2-(2,6-dioxo piperidyl) fluoroisoindoline-1,3-dione (1.07 g, 3.88 mmol, Intermediate R), and the mixture was stirred at 115 °C for 16 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EA = 1:1) to give the title compound (500 mg, 37% yield) as a yellow solid. 1H NMR (400MHz, DMSO-/6) δ 11.10 (s, IH), 7.59 (dd, J = 7.6, 8.4 Hz, IH), 7.15 (d, J= 8.8 Hz, IH), 7.04 (d, J= 6.8 Hz, IH), 6.61 (t, J= 5.6 Hz, IH), 5.06 (dd, J= 5.6, 12.8 Hz, IH), 4.63 (t, J= 5.6 Hz, IH), 3.61 (t, J = 5.6 Hz, 2H), 3.55 - 3.44 (m, 6H), 2.94 - 2.80 (m, IH), 2.64 - 2.52 (m, 2H), 2.08 - 1.97 (m, IH); LC-MS (ESI+) m/z 362.0 (M+H)+.

[005119] Step 2:2-r2-rr2-(2,6-Dioxo piperidyl)-L3-dioxo-isoindolin-4yllaminolethoxylethyl methane- sulfonate

[005120] To a solution of 2-(2,6-di oxo piperi dyl) [2-(2hydroxyethoxy)ethylamino]isoindoline-l,3-dione (200 mg, 525 umol) and TEA (159 mg, 1.58 mmol) in DCM (20 mL) was added MsCI (120 mg, 1.05 mmol) at 0°C. Then the mixture was allowed to warm to rt and stirred for 3 h. On completion, the reaction mixture was quenched by adding water (30 mL) at 0 °C, and then the mixture was extracted with DCM (3 X 40 mL). The combined organic layers were washed with saturated citric acid (2 X 20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 mg, 86% yield) as a yellow

1613 solid. LC-MS (ESI+) m/z 440.0 (M+H)+.

[005121] Step 3 - Τ(2Κ) Γ(8Κ) Γ4-Γ4-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;γ1)-Ε3-&#940;&#912;οχοisoindolin yl1amino1V ethoxy1ethyl1piperazin-l-yl1cyclohexoxy1-7,8-dihydro-6Hcyclopentar4,51thienorL2-c1pyrimidin yl1 hydroxy-propanamide

[005122] To a solution of (2/?) hydroxy [(8/?)-l-(4-piperazin-l-ylcyclohexoxy)-7,8dihydro-6/7- cyclopenta[4,5]thieno[l,2-c]pyrimidin yl]propanamide (40 mg, 82.9 umol HCI salt, Intermediate DR) in DMF (3 mL) was added K2CO3 (45.8 mg, 331 umol) and 2-[2-[[2-(2,6dioxo piperidyl)-l,3- dioxo-isoindolin yl] amino]ethoxy]ethyl methanesulfonate (48.6 mg, 99.5 umol), and the mixture was stirred at 60 °C for 24 h. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.05% ammonia hydroxide v/v)ACN]) to give the title compound 1-184 (23.5 mg, 35% yield, FA salt) as a yellow solid. 1H NMR (400MHz, DMSO-76) δ 11.11 (s, IH), 8.53 (s, IH), 7.64 - 7.53 (m, IH), 7.20 - 7.13 (m, 2H), 7.11 (s, IH), 7.05 (d, J= 6.8 Hz, IH), 6.60 (t, J = 5.6 Hz, IH), 5.20 - 5.11 (m, IH), 5.07 (dd, J = 5.6, 12.8 Hz, IH), 3.93 (t, J = 6.4 Hz, IH), 3.60 - 3.55 (m, 6H), 3.10 - 2.99 (m, 2H), 2.95 - 2.87 (m, 2H), 2.72 - 2.56 (m, 3H), 2.48 - 2.39 (m, 10H), 2.38 - 2.26 (m, 4H), 2.20 - 2.01 (m, 3H), 1.85 1.82 (m, 2H), 1.63 - 1.49 (m, 3H), 1.41 - 1.30 (m, 2H); LC-MS (ESI+) m/z 789.3 (M+H)+.

[005123] Example 185: 3 (2-((Cvclopropvlmethvl)amino)pvridin vl)-N-(l-(4-(((2(2-(2-((2-(2,6-dioxopiperidin vl)-l,3-dioxoisoindolin-4vl)amino)ethoxv)ethoxv)ethvl)amino)methvl)phenvl) (trifluoromethvl)-lH-pyrazol-4yl)oxazole carboxamide,1-185

1614

[005124] Step 1 - 4-(4-(2-(2-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4vl)oxazole carboxamido)-3 -(trifluoromethyl)- IH-pyrazol-1 yl)b enzoi c(i sopropyl carb oni c)anhy dri de

[005125] To a solution of 4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carbonyl]amino] (trifluoromethyl)pyrazol-l-yl]benzoic acid (700 mg, 960 umol, Intermediate EG) in THF (10 mL) was added TEA (194 mg, 1.92 mmol). Then, the reaction mixture was cooled to -10 °C. Next, isopropyl carbonochloridate (235 mg, 1.92 mmol) was added and the reaction mixture was stirred at -10 °C for 2 hours. On completion, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (720 mg, 91% yield) as white solid. LC-MS (ESI+) m/z 699.0 (M+H)+.

1615

[005126] Step 2 - Tert-butyl (cy cl opropylmethyl)(4-(4-((l-(4-(hydroxym ethyl )phenvl)-3(trifluoromethyl)-IH- pyrazol yl)carbamoyl)oxazol yl)pyridin yl)carbamate

[005127] To a solution of isopropoxycarbonyl 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(trifluoromethyl)pyrazol-l-yl]benzoate (720 mg, 876 umol) in THF (20 mL) was added NaBH4 (66.3 mg, 1.75 mmol) and water (63.1 mg, 3.50 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. On completion, the reaction mixture was quenched with water (5 mL) and the mixture was extracted with DCM (3 X 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (520 mg, 99 % yield) as a white solid. 1HNMR (400MHz, CDCh) δ 9.06 (s, IH), 8.88 (s, IH), 8.54 (d, J= 5.2 Hz, IH), 8.42 (s, IH), 8.36 (s, IH), 7.76 (d, J= 8.4 Hz, 2H), 7.64 (d, J= 4.8 Hz, IH), 7.51 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H), 3.96 (d, J= 7.2 Hz, 2H), 1.59 (s, 9H), 0.93 0.81 (m, IH), 0.47 - 0.42 (m, 2H), 0.30 - 0.26 (m, 2H); LC-MS (ESI+) m/z 599.2 (M+H)+.

[005128] Step 3 - Tert-butyl (cvclopropylmethyl)(4-(4-((l-(4-formylphenvl)-3(trifluoromethyl)-IH-pyrazol- 4-yl)carbamoyl)oxazol yl)pyridin yl)carbamate

[005129] To a solution of tert-butyl 7V-(cyclopropylmethyl)-7V-[4-[4-[[l-[4(hydroxymethyl)phenyl] (trifluoromethyl)pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]carbamate (320 mg, 535 umol) in DCM (10 mL) was added DMP (454 mg, 1.07 mmol). The reaction mixture was stirred at rt for 5 hours. On completion, the reaction mixture was quenched with saturated Na2S2O3 (20 mL) and extracted with DCM (3X30 mL). The combined organic layers were washed with saturated NaHCO3 (2 X 20 mL), then washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (0.1% HCI) to give the title compound (123 mg, 39% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 10.08 (s, IH), 9.08 (s, IH), 9.01 (d, J= 5.2 Hz, IH), 8.98 (s, IH), 8.57 (s, IH), 8.06 (d, J= 8.4 Hz, 2H), 7.95 (d, J= 8.8 Hz, 2H), 7.45 (s, IH), 7.39 (s, IH), 3.35 (s, 2H), 1.67 (s, 9H), 1.15 - 1.05 (m, IH), 0.78 - 0.76 (m, 2H), 0.45 - 0.44 (m, 2H).

[005130] Step 4 - Tert-butyl (cyclopropylmethyl)(4-(4-((l-(4-(((2-(2-(2-((2-(2,6dioxopiperidin yl)-L3-dioxoi soindolin-4yl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenyl) (trifluoromethyl)-lH-pyrazol-4yl)carbamoyl)oxazol yl)pyridin yl)carbamate

1616

[005131] To a solution of 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino] (2,6-dioxo-3piperidyl)isoindoline- 1,3-dione (67.8 mg, 154 umol, HCI) in a mixed solvent of DCM (30 mL) and THF (30 mL) was added TEA (17.0 mg, 168 umol). The reaction mixture was stirred at rt for 0.5 hour. Then, tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[l-(4-formylphenyl)-3(trifluoromethyl)pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (100 mg, 168 umol, synthesized via Steps 1-2 of Example 127), HO Ac (20.1 mg, 335 umol, 19.2 uL) and NaBH(O Ac)3 (71.1 mg, 335 umol) were added to the mixture. The resulting reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine, dried over with anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (150 mg, 91% yield) as a yellow solid. LC-MS (ESI+) m/z 885.1 (M+H-100)+.

[005132] Step 5 2-(2-((Cyclopropylmethyl)amino)pyridin yl)-N-(l-(4-(((2-(2-(2-((2(2,6-dioxopiperidin yl)-L3-dioxoisoindolin-4vl)amino)ethoxv)ethoxv)ethvl)amino)methvl)phenvl) (trifluoromethvl)-lH-pyrazol-4yl)oxazole carboxamide

[005133] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[l-[4-[[2-[2-[2-[[2(2,6-di oxo piperidyl)- l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl] (trifluoromethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (150 mg, 152 umol) in DCM (4 mL) was added HCI in dioxane (4 M, 4 mL). The reaction mixture was stirred at rt for 0.5 hour. On completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.225% FA)- ACN]; B%: 10%-40%) to give the title compound 1-185 (61.0 mg, 45% yield) as a yellow solid. 1H NMR (400MHz, DMSO-» δ 10.88 (s, IH), 9.70 (s, IH), 8.75 (s, IH), 8.63 (s, IH), 8.03 (s, IH), 7.94 (d, J= 52 Hz, IH), 7.58 (d, J= 8.4 Hz, 2H), 7.37 - 7.30 (m, IH), 7.27 (d, J= 8.4 Hz, 2H), 6.92 - 6.89 (m, 2H), 6.87 (t, J= 5.6 Hz, IH), 6.83 - 6.77 (m, 2H), 6.38 (t, J= 5.6 Hz, IH), 4.83 (dd, J = 5.6, 12.8 Hz, IH), 3.55 (s, 2H), 3.43 - 3.39 (m, 2H), 3.38 - 3.35 (m, 2H), 3.33 - 3.30 (m, 2H), 3.29 - 3.27 (m, 2H), 3.24 (d, J= 5.6 Hz, 2H), 2.96 (t, J= 5.6 Hz, 2H), 2.72 2.59 (m, IH), 2.48 - 2.42 (m, 2H), 2.38 - 2.31 (m, IH), 2.30 - 2.85 (m, IH), 1.83 - 1.76 (m, IH), 0.89 - 0.81 (m, IH), 0.27 - 0.21 (m, 2H), 0.01 (m, 2H); LC-MS (ESI+) m/z 885.1 (M+H)+.

[005134] Example 186: 2-[2-(Cvcl0Dr0Dvlmethvlamin0) Dvridvl]-N-[l-[3-[[2-[2-[21617

[[2-(2,6-dioxo DiDeridyl)-l,3 vl1amino1ethoxv1ethoxv1ethvlamino1methvllDhenvl1 (trifluoromethyl)Dvrazol-4ylloxazole carboxamide., 1-186

DMP

DCM

[005135] Step 1 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-[r1-(3-formylphenyl)-3(trifluoromethyl)pyrazol-4 -yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[005136] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[l-[3(hydroxymethyl)phenyl] (trifluoro methyl)pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]carbamate (320 mg, 534 umol. Intermediate EI) in DCM (8.00 mL) was added DMP (105 mg, 249 umol), and the mixture was stirred at 25°C for 20 hours. On completion, the mixture was quenched with saturated Na2S2O3 (2 X 30 mL) and extracted with DCM (30 mL). The organic layer was washed with saturated NaHCO3 (2 X 30mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (280 mg, 87% yield) as a red solid. 1H NMR (400MHz, CDCh) δ 10.04 (s, IH), 9.01 (s, IH), 8.92 (s, IH), 8.46 (d, J = 52 Hz, IH), 8.36 (s, IH), 8.30 (s, IH), 8.22 (s, IH), 8.03 - 7.98 (m, IH), 7.83 (d, J = 7.6 Hz, IH), 7.66 - 7.60 (m, IH), 7.56 (dd, 7= 1.2, 5.2 Hz, IH), 3.88 (d, 7 = 7.2 Hz, 2H), 1.51 (s, 9H), 1.18- 1.11 (m, IH), 0.390.34 (m, 2H), 0.24 - 0.20 (m, 2H).

1618

[005137] Step 2 - Tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[l-[3-[[2-[2-[2-[[2-(2,6-dioxo3-piperidyl) (trifluoromethyl)pyrazol yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[005138] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[l-(3-formylphenyl)-3(trifluoromethyl) pyrazol yl]carbamoyl]oxazol yl] pyridyl]carbamate (100 mg, 167 umol) and 4-[2-[2-(2-amino ethoxy)ethoxy]ethylamino] (2,6-dioxo piperidyl)isoindoline-l,3-dione (88.6 mg, 201 umol, HC1, synthesized via Steps 1-2 of Example 127) in THF (30.0 mL) was added KOAc (32.9 mg, 335 umol) and NaBH(OAc)3 (71.0 mg, 335 umol). The mixture was stirred at rt for 16 hours. On completion, the mixture was quenched with water (2 mL) and extracted with ethyl acetate (3 X 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by reverse phase prep-HPLC (0.1% FA) to give the title compound (80.0 mg, 48% yield) as a yellow solid. LC-MS (ESI+) m/z 985.4 (M+H)+.

[005139] Step 3 - 2-[2-(Cyclopropylmethylamino) pyridyl1-N-[l-[3-[[2-[2-[2-[[2-(2,6dioxo piperidyl)-L3

3-(trifluoromethyl)pyrazol yl1oxazole carboxamide

[005140] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[l-[3-[[2-[2-[2-[[2(2,6-di oxo piperidyl)- l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl] (trifluoromethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (80.0 mg, 81.2 umol) in DCM (2.00 mL) was added HC1 in dioxane (4 M, 2.00 mL). The mixture was stirred at rt for 15 minutes. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%40%, 10 min) to give the title compound 1-186 (41.2 mg, 57% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 11.11 (s, IH), 9.92 (s, IH), 8.98 (s, IH), 8.88 (s, IH), 8.23 (s, IH), 8.16 (d, J = 5.2 Hz, IH), 7.86 (s, IH), 7.73 (d, J = 8.4 Hz, IH), 7.55 (dd, J = 7.2, 8.4 Hz, IH), 7.48 (t, J = 8.0 Hz, IH), 7.37 (d, J = 7.6 Hz, IH), 7.13 - 7.08 (m, 3H), 7.06 - 7.01 (m, 2H), 6.64 - 6.54 (m, IH), 5.08 - 5.01 (m, IH), 3.82 (s, 2H), 3.59 - 3.53 (m, 10H), 3.23 - 3.16 (m, 2H), 2.92 - 2.84 (m, IH), 2.69 - 2.66 (m, 2H), 2.62 - 2.58 (m, IH), 2.57 - 2.55 (m, IH), 2.06 - 1.94 (m, IH), 1.12-1.01 (m, IH), 0.50 - 0.43 (m, 2H), 0.27 - 0.20 (m, 2H); LC-MS (ESI+) m/z 885.1 (M+H)+.

[005141] Example 187: 2-[2-(Cvcl0Dr0Dvlmethvlamin0) Dvridvl1-N-[l-[4-[[2-[2-[31619

[2-(2,6-dioxo piperidvl)-l,3dioxo-isoindolin-5yl] propoxy! ethoxy] ethylamino] methyl] phenyl] (trifluoromethvl)pyrazol vl] oxazole-4carboxamide,

1-187

[005142] To a solution of 5-[3-[2-(2-aminoethoxy)ethoxy]propyl] (2,6-dioxo-3 piperidyl)isoindoline-l,3- dione (45.0 mg, 102 umol, HC1 salt, Intermediate CQ) and 2-[2(cyclopropylmethylamino) pyridyl]-N-[l-(4-formylphenyl) (trifluoromethyl)pyrazol-4 yl]oxazole carboxamide (54.5 mg, 102 umol, synthesized via Steps 1-3 of Example 185) in THF (10 mL) was added KOAc (20.1 mg, 205 umol) and the reaction mixture was stirred for 30 minutes at rt. Then NaBH(OAc)3 (54.2 mg, 256 umol) was added in portions and the mixture was stirred at rt for 2 hours. Then HO Ac (1.23 g, 20.5 mmol, 1.17 mL) was added and the mixture was stirred for 30 minutes. Finally, more NaBH(OAc)3 (54.2 mg, 256 umol) was added and the reaction was stirred for 2 hours. On completion, the reaction mixture was quenched by addition water (2 mL), and then concentrated in vacuo. The residue was purified by prep-HPLC (reserve phase (ACNwater/0.1%FA)) and lyophilized to give the title compound 1-187 (21.5 mg, 22% yield) as a white solid. 1HNMR (400MHz, DMSO-d6) δ 11.12 (s, IH), 9.92 (s, IH), 8.98 (s, IH), 8.86 (s, IH), 8.26 (s, IH), 8.16 (d, J = 5.2 Hz, IH), 7.84 - 7.79 (m, 3H), 7.77 (s, IH), 7.70 (d, J = 7.6 Hz, IH), 7.51

1620 (d, 7= 8.4 Hz, 2H), 7.14 - 7.07 (m, 2H), 7.06 -7.02 (m, IH), 5.14 (dd, J= 5.6, 13.2 Hz, IH), 3.79 (s, 2H), 3.53 - 3.50 (m, 4H), 3.41 - 3.75 (m, 2H), 3.19 (t, J= 6.4Hz, 2H), 2.95 -2.76 (m, 4H), 2.71 .60 (m, 4H), 2.59 - 2.53 (m, 2H), 2.08 - 2.01 (m, IH), 1.90 - 1.81 (m, 2H), 1.11 - 1.04 (m, IH),

0.49 - 0.43 (m, 2H), 0.26 - 0.20 (m, 2H); LC-MS (ESI+) m/z 884.0 (M+H)+.

[005143] Example 188: N-(3-carbamovl-l-(4-((5-(2-((5-(((S)-l-((2S,4R) hydroxv-2((4-(4-methvlthiazol vl)benzvl)carbamovl)pvrrolidin-l-vl)-3,3-dimethvl-l-oxobutan-2vl)amino)pentvl)oxv)ethoxv)pentvl)carbamovl)phenvl)-lH-pvrazol vl) (2-((2,2,2trifluoroethvl)amino)pvridin vl)oxazole carboxamide, 1-188

1621

TH Ν H2

HATU, DIPEA, DMF

EV

[005144] Step 1:N-(3-carbamoyl-l-(4-((5-(2-(4-((tetrahydro-2H-pyran-2yl)oxy)butoxy)ethoxy)pentyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide

[005145] 5-(2-(4-((tetrahydro-2H-pyran yl)oxy)butoxy)ethoxy)pentan-l-amine (122 mg,

1622

0.38 mmol, Intermediate EV) was dissolved in DMF (2 mL). 4-(3-carbamoyl (2-(2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamido)-l//-pyrazol-l-yl)benzoic acid (198 mg, 0.38 mmol, Intermediate ET), HATU (159 mg, 0.42 mmol) and Ν,Ν-diisopropylethylamine (0.13 mL, 0.76 mmol) were then added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was then diluted with a saturated aqueous solution of NaHCO3 and extracted with Ethyl Acetate (3 times). The combined organic was washed with water, dried over magnesium sulfate and filtered. The mixture was then concentrated in vacuo and the residue was purified by silica gel chromatography (gradient of 0-10% methanol in dichloromethane) to give the title compound (161 mg, 50%) as a yellow powder.

[005146] Step 2:N-(3-carbamoyl-l-(4-((5-(2-(4hydroxybutoxy)ethoxy)pentyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide

[005147] N-(3-carbamoyl-l-(4-((5-(2-(4-((tetrahydro-2H-pyran-2yl)oxy)butoxy)ethoxy)pentyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide (161 mg, 0.19 mmol) was dissolved in a 1.25 M solution of HCI in methanol (1.6 mL) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was then concentrated in vacuo to give the title compound as an orange solid (142 mg, quantitative yield). LC-MS (ESI+) m/z 731.4 (M+H)+.

[005148] Step 3:N-(3-carbamoyl-l-(4-((5-(2-(4oxobutoxy)ethoxy)pentyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide

[005149] To a suspension of N-(3-carbamoyl-l-(4-((5-(2-(4hydroxybutoxy)ethoxy)pentyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide (142 mg, 0.19 mmol) in acetone (10 mL) was added 2-iodoxybenzoic acid (156 mg, 0.57 mmol) and the reaction mixture was heated at 55 °C in a sealed tube for 16 h. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3 and extracted with Ethyl Acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound which was used directly in the subsequent step. LC-MS (ESI+) m/z 729.4 (M+H)+.

[005150] Step 4 - N-(3-carbamoyl-l-(4-((5-(2-((5-(((S)-l-((2S,4R) hydroxy ((4-(4methylthiazol yl)benzyl)carbamoyl)pyrrolidin-l-yl)-3,3-dimethyl-l-oxobutan-2

1623 yl)amino)pentyl)oxy)ethoxy)pentyl)carbamoyl)phenyl)-lH-pyrazol yl) (2-((2,2,2trifluoroethyl)amino)pyridin yl)oxazole carboxamide

[005151] N-(3-carbamoyl-l-(4-((5-(2-(4-oxobutoxy)ethoxy)pentyl)carbamoyl)phenyl)-lHpyrazol yl) (2-((2,2,2-trifluoroethyl)amino)pyridin yl)oxazole carboxamide (177 mg, 0.24 mmol) and (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4methylthiazol yl)-phenyl]methyl]pyrrolidine carboxamide (125 mg, 0.29 mmol, Intermediate CI) was dissolved in a mixture of methanol (1.4 mL) and dichloromethane (0.8 mL) and stirred for 5 minutes before the addition of borane pyridine complex (49 pL, 0.48 mmol). The reaction mixture was stirred at rt until completion. The reaction mixture was then concentrated in vacuo, diluted in Ethyl Acetate and partitioned with a saturated aqueous solution of NaHCO3. The precipitate was filtered off and the mixture was extracted with Ethyl Acetate (3 times). The combined organic layer was concentrated in vacuo. Purification with silica gel chromatography (gradient mixture of 0-60% methanol in dichloromethane) gave 74 mg of the impure product. A second purification was performed using silica gel chromatography (gradient of 10-40% methanol in dichloromethane) to give the title compound 1-188 (20 mg, 7%) as a yellow powder. 1H NMR (400 MHz, DMSO): δ 11.00 (s; 1 H); 9.02 (d; J = 2.46 Hz; 2 H); 8.95-8.96 (m; 1 H); 8.52-8.56 (m; 2 H); 8.24 (d; J = 5.29 Hz; 1 H); 8.12 (s; 1 H); 8.08 (d; J = 8.51 Hz; 2 H); 7.99 (d; J = 8.39 Hz; 2 H); 7.76 (s; 1 H); 7.68 (t; J = 6.53 Hz; 1 H); 7.34-7.42 (m; 4 H); 7.25 (s; 1 H); 7.16 (d; J = 5.39 Hz; 1 H); 5.02 (d; J = 3.19 Hz; 1 H); 4.50 (t; J = 8.16 Hz; 1 H); 4.30-4.39 (m; 3 H); 4.17-4.28 (m; 4 H); 3.48-3.57 (m; 2 H); 3.44 (s; 4 H); 3.20-3.40 (m; 6 H); 2.99 (s; 1 H); 2.41-2.43 (m; 4 H); 2.222.32 (m; 2 H); 1.41-1.57 (m; 6 H); 1.28-1.37 (m; 6 H); 0.88 (s; 9 H). LC-MS (ESI+) m/z [M+2H]2+: 572.3.

[005152] Example 189:(2S,4R)-l-[(2S) [[2-[2-[2-[4-[[7-[[(lR,2S)-2aminocvdohexvl]amino] oxo-3H-pyrido[43&#1524;-d]pvrimidin vl]amino]indol-lvl]ethoxv]ethoxy]acetvl1amino]-3.,3-dimethvl-butanovl] hvdroxv-N-[[4-(4-methvlthiazol5-yl)phenyl] methyl] pyrrolidine carboxamide.,1-189

1624

[005153] Step 1 - Ethyl 2-r2-[2-(4-nitroindol-l-yl)ethoxy1ethoxy1acetate and 2-[2-[2-(4nitroindol-l-yl) ethoxy]ethoxy]acetic acid

1625

[005154] To a solution of 4-nitro-lH-indole (649 mg, 4.01 mmol) and Cs2CO3 (3.26 g, 10.0 mmol) in DMF (15.0 mL) was added ethyl 2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate (1.30 g, 4.81 mmol, synthesized via Steps 1-2 of Intermediate BM), then the reaction mixture was stirred at 80°C for 12 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue, the residue was diluted with water (40 mL) and acidified with the saturated citric acid aqueous solution (10 mL) until the pH = 2. Then the mixture was extracted with EA (30 mL X 5). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a mixture of ethyl 2-[2-[2-(4-nitroindol-l-yl) ethoxy]ethoxy]acetate (800 mg, 59% yield) and 2-[2-[2-(4-nitroindol-l-yl)ethoxy]ethoxy]acetic acid (500 mg, 40% yield). LC-MS (ESI+) m/z 359.0 (M+Na)+ and LC-MS (ESI+) m/z 309.0 (M+H)+.

[005155] Step 2 - Ethyl 2-r2-r2-(4-nitroindol-l-vl)ethoxv]ethoxy]acetate

[005156] To a mixture of ethyl 2-[2-[2-(4-nitroindol-l-yl) ethoxy]ethoxy]acetate (800 mg, 2.38 mmol) and 2-[2-[2-(4-nitroindol-l-yl)ethoxy]ethoxy]acetic acid (500 mg, 1.62 mmol) in EtOH (10.0 mL) was added SOC12 (1.00 g, 8.44 mmol), and the reaction mixture was stirred at 80°C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted water (15 mL) and extracted with EA (20 mL X 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (950 mg, 66% yield). 1HNMR (400MHz, CDCh) δ 8.12 (d, J= 8.0 Hz, IH), 7.71 (d, J= 8.0 Hz, IH), 7.44 (d, J = 3.2 Hz, IH), 7.25 (d, J = 1.6 Hz, IH), 7.22 (d, J = 3.2 Hz, IH), 4.38 (t, J = 5.6 Hz, 2H), 4.19 (q, J= 7.2 Hz, 2H), 4.01 (s, 2H), 3.82 (t, J= 52 Hz, 2H), 3.64 - 3.60 (m, 2H), 3.59 - 3.54 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H); LC-MS (ESI+) m/z 337.1 (M+H)+.

[005157] Step 3 - Ethyl 2-r2-r2-(4-aminoindol-l-yl)ethoxy]ethoxy]acetate

[005158] To a solution of ethyl 2-[2-[2-(4-nitroindol-l-yl)ethoxy]ethoxy]acetate (950 mg, 2.82 mmol) in EA (12.0 mL) was added Pd/C (600 mg, 2.82 mmol) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas 3 times. The mixture was stirred under hydrogen atmosphere (15 psi pressure) at rt for 2 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (850 mg, 98% yield). 1H NMR (400MHz, CDCh) δ 7.09 (d, J= 3.6 Hz, IH), 7.03 (t, J= 8 Hz, IH), 6.83 (d, J= 8.0 Hz, IH), 6.41 - 6.39 (m, 2H), 4.27 (t, J = 6.0 Hz, 2H), 4.23 (q, 7= 7.2 Hz, 2H), 4.09 (s, 2H), 3.91 (s, 2H), 3.81 (t, 7= 6.0 Hz, 2H), 3.69 - 3.64 (m, 2H), 3.60 - 3.56 (m, 2H), 1.30 (t, 7= 7.2 Hz, 3H); LC-MS (ESC)/307.1 2&#1524; (M+H)+.

1626

[005159] Step 4- Ethyl 2-r2-r2-r4-r(7-chloro oxo-3H-pyridor4,3-d1pyrimidin-5yDaminolindol-1 -yUethoxy] ethoxy]acetate

[005160] To a solution of ethyl 2-[2-[2-(4-aminoindol-l-yl)ethoxy]ethoxy]acetate (500 mg, 1.63 mmol) and 5,7-dichloro-3H-pyrido[4,3-d]pyrimidin one (352 mg, 1.63 mmol, Intermediate FB) in NMP (4 mL) was added TEA (329 mg, 3.26 mmol), and the reaction mixture was stirred at 140 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE/EA = 1/2) to give the title compound (500 mg, 63% yield) as a yellow solid. 1H NMR (400MHz, DMSO-76) δ 12.95 (s, IH), 11.75 (s, IH), 8.31 (s, IH), 8.17 (d, J= 7.6 Hz, IH), 7.44 (d, J= 3.2 Hz, IH), 7.28 (d, J= 8.0 Hz, IH), 7.17 (t, J= 8.0 Hz, 2H), 6.91 (s, IH), 6.56 (d, J= 3.2 Hz, IH), 4.36 (t, J= 5.6 Hz, 2H), 4.10 (q, J= 7.2 Hz, 2H), 4.05 (s, 2H), 3.76 (t, J= 5.2 Hz, 2H), 3.53 (d, J= 3.6 Hz, 4H), 1.18 (t, J= 7.2 Hz, 3H); LC-MS (ESI+) m/z 486.0 (M+H)+.

[005161] Step 5 - 2-r2-r2-r4-r(7-Chloro oxo-3H-pyridor4,3-d1pyrimidin-5yl)amino1indol-l-vl1ethoxv1 ethoxylacetic acid

[005162] To a solution of ethyl 2-[2-[2-[4-[(7-chloro oxo-3H-pyrido[4,3-d]pyrimidin-5yl)amino]indol-l-yl] ethoxy]ethoxy]acetate (260 mg, 535 umol) in THF (3.00 mL) and H2O (3.00 mL) was added LiOH (51.2 mg, 2.14 mmol), and the mixture was stirred at rt for 2 hours. On completion, the mixture was acidified with IN HCI solution (1 mL) until the pH = 3, then diluted with water (5 mL) and extracted with DCM (50 mL X 3). The combined organic layers were dried over sodium sulfate, filtrated and concentrated in vacuo to give the product (230 mg, 93% yield) as a light yellow solid. LC-MS (ESI+) m/z 458.1 (M+H)+.

[005163] Step 6 - (2S,4R)-l-r(2S) rr2-r2-r2-r4-r(7-chloro oxo-3H-pvrido[4,3d1pyrimidin yl)amino1indo hydroxy-N-rr4-(4-methylthiazol yl)phenyl1methyl1pyrrolidine carboxamide

[005164] A solution of 2-[2-[2-[4-[(7-chloro oxo-3H-pyrido[4,3-d]pyrimidin-5yl)amino]indol-l-yl]ethoxy] ethoxy]acetic acid (180 mg, 393 umol) in DMF (3.00 mL) was cooled to 0 °C. Then, (2S,4R) [(2S)- 2-amino-3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4methylthiazol yl)phenyl]methyl]pyrrolidine carboxamide (166 mg, 357 umol, HCI salt, Intermediate CI), DIPEA (277 mg, 2.14 mmol) and HATU (163 mg, 428 umol) were added. Then the mixture was stirred at rt for 6 hours. On completion, the reaction mixture was concentrated in vacuo to remove the DMF. The residue was diluted with water (40 mL) and extracted with EA (40

1627 mL X 3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (reverse phase (0.1% FA)) to give the title compound to (255 mg, 81% yield) as light yellow solid. LC-MS (ESI+) m/z 870.4 (M+H)+.

[005165] Step 7 - (2S,4R)-l-[(2S) [[2-[2-[2-[4-[[7-[[(lR,2S) aminocyclohexyl1amino14-oxo-3H-pyrido[4/-d1pyrimidin yl1amino1indol-l-yl1ethoxy1ethoxy1acetyl1amino1-3,3dimethyl-butanoyl1 hydroxy-N-rr4-(4-methylthiazol yl)phenyl1methyl1pyrrolidine-2carboxamide

[005166] A mixture of (2S,4R)-l-[(2S) [[2-[2-[2-[4-[(7-chloro oxo-3H-pyrido[4,3d]pyrimidin yl) amino]indol-l-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4hydroxy-N-[[4-(4-methylthi-azol yl)phenyl]methyl]pyrrolidine carboxamide (100 mg, 114 umol) and (lR,2S)-cyclohexane- 1,2-diamine (52.4 mg, 459 umol) in NMP (2 mL) were placed in a sealed tube and stirred at 140°C for 1.5 hours under microwave. On completion, the mixture was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]) to give the title compound 1-189 (21.0 mg, 18% yield) as a white solid. 1H NMR (400MHz, DMSO-/6) δ 11.71 (s, IH), 8.94 (s, IH), 8.61 (t, J = 5.6 Hz, IH), 8.35 (s, 2H), 8.308.24 (m, IH), 7.91 (s, IH), 7.47 - 7.30 (m, 6H), 7.17 (d, J = 8.0 Ηζ,ΙΗ), 7.08 (t, J= 5.6 Hz, IH), 6.57 (d, J = 3.2 Hz, IH), 6.00 (s, IH), 4.60 (d, J = 9.6 Hz, IH), 4.46 (t, J = 8.0 Hz, IH), 4.39 4.31(m, 4H), 4.27 - 4.22 (m, IH), 3.99 - 3.94 (m, 2H), 3.77 (t, J = 5.4 Hz, 2H), 3.71 - 3.65 (m, 2H), 3.63 - 3.60(m, 2H), 3.58 - 3.56 (m, 2H), 3.54 - 3.53 (m, 2H), 2.53 - 2.52 (m, 2H), 2.41 (s, 3H), 2.07 (s, IH), 1.97 - 1.87 (m, 2H), 1.80 - 1.74 (m, 2H), 1.68 - 1.60 (m, 4H), 1.44 - 1.36 (m, 2H), 1.00 - 0.92 (s, 9H). LC-MS (ESI+) m/z 948.3 (M+H)+.

[005167] Example 190:(2S,4R)-l-[(2S) [[2-[2-[2-[2-[2-[4-n7-H(lR,2S)-2aminocyclohexyl] amino] 0X0-3H-pyr ido [4,3-d] pyrimidin yl] amino] indol-1yl] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] amino] -3,3-dimethvl-butanovl] hydroxv-N- [ [ 4-(4methvlthiazol vl)phenvl]methvl]pyrrolidine carboxamide,1-190

1628

[005168] The title compound 1-190 was synthesized as described in the method above for Example 189, using Intermediate BK as the mesylate in the first step which was run at 80 °C for 8 h. Time and temperature variations were as follows: Step 2 was run at 80 °C for 6 h, Step 3 was run at rt for 6 h and Step 7 was run at 150 °C for 1.5 h. Characterization data of the final compound: 1HNMR (400MHz, DMSO-i/6) δ 11.25 (s, IH), 9.18 (s, IH), 9.09 (s, IH), 8.68 (t, J= 5.6 Hz, IH), 8.30 - 8.28 (m, 3H), 8.20 (s, IH), 8.10 (d, J = 7.2 Hz, IH), 7.46 - 7.35 (m, 6H), 7.24 (d, J = 7.6 Hz, IH), 7.12 (t, J= 7.6 Hz, IH), 6.51 (d, J= 2.8 Hz, IH), 6.33 (s, IH), 4.44 - 4.17 (m, 1 OH), 3.90 (s, 2H), 3.79 - 3.37 (m, 18H), 2.44 (s, 3H), 2.13 - 1.83 (m, 4H), 1.79 - 1.56 (m, 4H), 1.48 - 1.34 (m, 2H), 0.92 (s, 9H); LC-MS (ESI+) m/z 1036.3 (M+H)+.

[005169] Example 191: N-[2-[[5-chloro [5-[2-[2-[2-[2-[2-[[2-(2,6-dioxo DiDeridvDl.,3-dioxo-isoindolin vl] anilino]Dvrimidin vl]amino] methoxv-phenvl]methanesulfonamide,1-191

1629

OBn

HCI in dioxane, IPA, mw

OBn

OH

MsO

NHCbz

FC

K2CO3, DMF

[005170] Step 1 - N-r2-rr2-(5-benzyloxy methoxy methyl-anilino) chloro-pyrimidin4-yl1amin01 methoxy-phenyllmethanesulfonamide

[005171] A mixture of N-[2-[(2,5-dichloropyrimidin yl)amino] methoxyphenyl]methanesulfonamide (1.00 g, 2.75 mmol, Intermediate FE), 5-benzyloxy methoxy-2methyl-aniline (735 mg, 3.03 mmol, synthesized via Steps 1-3 of Intermediate FE), HCI in dioxane

1630 (4 Μ, 996 uL) and IPA(lOmL) was heated in a microwave at 120°C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-column chromatography to give the title compound (1.50 g, 95% yield) as a yellowish solid. LC-MS (ESI+) m/z 570.0 (M+H)+.

[005172] Step 2 - N-r2-rr5-chloro (5-hydroxy methoxy methyl-anilino)pyrimidin-4yl1amin01 methoxy-phenvl]methanesulfonamide

[005173] To a mixture of N-[2-[[2-(5-benzyloxy methoxy methyl-anilino) chloropyrimidin yl]amino] methoxyphenyl]methanesulfonamide (2.50 g, 4.39 mmol) in DCM (20 mL) was added BC13 DCM (1 M, 26.34 mL) dropwise at rt. Then the reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was washed with sat.NaHCO3 (100 mL) and extracted with DCM (3 X 200 mL). Then the combined organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-column chromatography to give the title compound (1.70g, 80% yield) as a pale solid. LC-MS (ESI+) m/z 480.1 (M+H)+.

[005174] Step 3 - Benzyl N-r2-r2-r2-r2-r2-r5-rr5-chloro [2-(methanesulfonamido)-4methoxy-anilinol pyrimidin yl]amino] methoxy methylphenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl 1 carb am ate

[005175] To a mixture of N-[2-[[5-chloro (5-hydroxy methoxy methylanilino)pyrimidin yl]amino] methoxy-phenyl]methanesulfonamide (150 mg, 312 umol) and 2-[2-[2-[2-[2-(benzyloxycarbonyl amino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (168 mg, 375 umol, Intermediate FC) in DMF (10 mL) was added K2CO3 (64.7 mg, 468 umol). Then the reaction mixture was stirred at 100 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. Then the reaction mixture was purified by reverse phase chromatography to give the title compound (120 mg, 46% yield) as a yellowish oil. LC-MS (ESI+) m/z 833.4 (M+H)+.

[005176] Step 4 - N-r2-rr2-r5-r2-r2-r2-r2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-4methoxy methyl-anilino] -5 -chi oro-pyrimidin yl] amino] -5 -methoxyphenyUmethanesulfonamide

[005177] To a mixture of benzyl N-[2-[2-[2-[2-[2-[5-[[5-chloro [2-(methanesulfonamido)4-methoxy-anilino] pyrimidin yl]amino] methoxy methyl

1631 phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethyl]carbamate (90.0mg, 108 umol) in ACN (500 uL) was added 40% HBr solution (4.47 g, 55.2 mmol, 3.00 mL). Then the reaction mixture was stirred at 60 °C for 6 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was washed with sat.NaHCO3 (30 mL) and extracted with DCM (3 X 50 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to give the title compound (55.0 mg, 62% yield) as a yellowish oil. LC-MS (ESI+) m/z 699.1 (M+H)+.

[005178] Step 5 -Ν-Γ2-ΓΓ5-0Μ0Γ0 Γ5-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;0χ0 ρ&#912;ρ6&#942;&#940;ν1)-1,3-&#940;&#912;0χ0isoindolin yl1 amino] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] methoxy methylanilino]pyrimidin yl1amino1 methoxy-phenyl]methanesulfonamide

[005179] To a mixture of N-[2-[[2-[5-[2-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy] methoxy methyl-anilino] chloro-pyrimidin4-yl]amino] methoxy-phenyl]methanesulfonamide (50.0 mg, 71.5 umol) and 2-(2,6-dioxo-3piperidyl) fluoro-isoindoline-l,3-dione (23.7 mg, 85.8 umol, Intermediate R) in DMF (2 mL) was added DIPEA (27.7 mg, 214 umol, 37.4 uL). Then the reaction mixture was stirred at 90 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase:[water (0.225% FA)-ACN]) to give the title compound 1-191 (14.0 mg, 19% yield) as a white solid. 1H NMR (400MHz, DMSO-Y) δ 11.11 ( s, IH), 8.66 (s, IH), 8.40 (s, IH), 8.23 (s, IH), 7.96 (s, IH), 7.81 (d, 7= 8.8 Hz, IH), 7.62-7.54 (m, IH), 7.13 (d, J= 8.8 Hz, IH), 7.04 (d, J= 7.2 Hz, IH), 6.90 (s, IH), 6.83 (d, J = 2.8 Hz, IH), 6.80 (s, IH), 6.60 (t, J = 5.6 Hz, IH), 6.31 (s, IH), 5.08 - 4.99 (m, IH), 3.93 - 3.86 (m, 2H), 3.76 (s, 3H), 3.68 (s, 3H), 3.67 - 3.63 (m, 3H), 3.62 - 3.58 (m, 4H), 3.56 - 3.52 (m, 8H), 3.50 (s, 3H), 3.05 (s, IH), 2.95 - 2.84 (m, 2H), 2.79 (s, 3H), 2.09 (s, 3H), 2.04 2.00 (m, IH); LC-MS (ESI+) m/z 955.4 (M+H)+.

[005180] Example 192:(2S,4R) [(2S1 [[2-[2-[2- [2- [2-[5- [[5-chloro [2(methanesulfonamido) methoxyphenoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] amino] -33&#1524;-dimethvl-butanovl] hvdroxy-N[[4-(4-methvlthiazol vl)phenvl]methvl]pyrrolidine carboxamide,1-192

1632

[005181] Step 1:Ethyl2-r2-r2-r2-r2-(2-methoxy methyl nitrophenoxyjethoxy 1 ethoxy] ethoxy] ethoxy] acetate

[005182] To a mixture of 2-methoxy methyl nitro-phenol (500 mg, 2.73 mmol, Intermediate FF) and K2CO3 (1.13 g, 8.19 mmol) in DMF (15 mL) was added ethyl 2-[2-[2-[2-(2methylsulfonyloxyethoxy)ethoxy] ethoxy] ethoxy]acetate (978 mg, 2.73 mmol, Intermediate BK) at rt. The reaction mixture was then heated to 100 °C and stirred for 1 hour. On completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 X 50 mL). The

1633 combined layer was washed with brine (50 mL), dried over Na2SO4, fdtered and the fdtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1) to give the title compound (900 mg, 74% yield) as a yellow oil. 1HNMR (400MHz, CDCh) δ 7.73 (s, IH), 6.71 (s, IH), 4.27 - 4.18 (m, 4H), 4.15 (s, 2H), 3.94 (s, 3H), 3.93 - 3.88 (m, 2H), 3.76 - 3.66 (m, 12H), 2.62 (s, 3H), 1.29 (t, J= 7.2 Hz, 3H).

[005183] Step 2:Ethyl 2-[2-[2- [ 2 (5 -amino methoxy methylphenoxylethoxy 1 ethoxy] ethoxy] ethoxy] acetate

[005184] To a mixture of ethyl 2-[2-[2-[2-[2-(2-methoxy methyl nitrophenoxy)ethoxy]ethoxy]ethoxy] ethoxy]acetate (550 mg, 1.23 mmol) in EtOAc (10 mL) was added Pd/C (450 mg, 10 wt %) under hydrogen atmosphere (15 psi pressure). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was fdtered and concentrated in vacuo to give the title compound (470 mg, 91% yield) as a light yellow oil. LC-MS (ESI+) m/z 416.2 (M+H)+.

[005185] Step 3 - Isopropyl 2-r2-r2-r2-r2-r5-rr5-chloro [2-(methanesulfonamido)-4methoxy-anilinol pyrimidin yl1amino1 methoxy methylphenoxy 1 ethoxy] ethoxy] ethoxy] ethoxy] acetate

[005186] To a mixture of ethyl 2-[2-[2-[2-[2-(5-amino methoxy methylphenoxy)ethoxy] ethoxy] ethoxy] ethoxy] acetate (470 mg, 1.13 mmol) and N-[2-[(2,5dichloropyrimidin yl)amino] methoxy-phenyl] methanesulfonamide (410 mg, 1.13 mmol, Intermediate FE) in IPA (10 mL) was added HCI in dioxane (4 M, 409 uL). The reaction mixture was stirred at 120 °C for 1 hour in a microwave. On completion, the reaction mixture was concentrated in vacuo to remove the IPA. The residue was poured into 5 mL of water and basified with sat. Na2CO3 until the pH = 7-8, then the mixture was extracted with di chloromethane (2X10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (dichloromethane:methanol = 100:1) to give the title compound (226 mg, 26% yield) as a light yellow oil. LC-MS (ESI+) m/z 742.1 (M+H)+.

[005187] Step 4 - 2-r2-r2-r2-r2-r5-rr5-Chloro r2-(methanesulfonamido) methoxyanilin01pyrimidin yl1 amino] methoxy m ethylphenoxy 1 ethoxy] ethoxy] ethoxy] ethoxy] aceti c aci d

[005188] To a mixture of ethyl 2-[2-[2-[2-[2-[5-[[5-chloro [2-(methanesulfonamido)-41634 methoxy-anilino] pyrimidin yl]amino] methoxy methylphenoxy ]ethoxy ]ethoxy ]ethoxy ]ethoxy] acetate (226 mg, 304 umol) in THF (4 mL) and H2O (2 mL) was added LiOHH2O (51.1 mg, 1.22 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo to remove THF. The residue was poured into 5 mL of water and acidified with HCI until the pH = 6-7, then the mixture was extracted with dichloromethane (3 X 10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (162 mg, 74% yield) as a yellowish solid. 1H NMR (400MHz, CDCh) δ 8.23 (s, IH), 7.92 (s, IH), 7.70 (s, IH), 7.38 (d, J= 8.8 Hz, IH), 6.99 (s, IH), 6.94 (d, J = 2.4 Hz, IH), 6.70 (dd, J = 2.8, 8.8 Hz, IH), 6.64 (s, IH), 4.12 (s, 2H), 3.82 - 3.80 (m, 8H), 3.75 - 3.71 (m, 4H), 3.69 - 3.61 (m, 10H), 2.87 (s, 3H), 2.10 (s, 3H); LC-MS (ESI+) m/z 714.1 (M+H)+.

[005189] Step 5 - (25^) Γ(25) ΓΓ2-Γ2-Γ2-Γ2-Γ2-[5-ΓΓ5-Η11ογο Γ2(methanesulfonamido) methoxy-anilino1pyrimidin yl1amino1 methoxy methylphenoxy 1 ethoxy] ethoxy] ethoxy] ethoxy] acetyl 1 amino] -3,3 -dimethyl -butanoyl 1 -4 -hy droxy-N - [ [4(4-methvlthiazol vl)phenvl1methvl1pyrrolidine carboxamide

[005190] To a mixture of 2-[2-[2-[2-[2-[5-[[5-chloro [2-(methanesulfonamido)-4methoxy-anilino]pyrimidin yl]amino] methoxy methylphenoxy ]ethoxy ]ethoxy ]ethoxy ]ethoxy] acetic acid (80.0 mg, 112 umol) and (2S,4R)-l-[(2S)-2amino-3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4-methylthiazol yl) phenyl]methyl]pyrrolidine carboxamide (48.2 mg, 103 umol HCI, Intermediate CI) in DMF (3 mL) was added HATU (51.1 mg, 134 umol) and DIPEA (72.3 mg, 560 umol) under nitrogen atmosphere. The reaction mixture was stirred at rt for 3.5 hours. On completion, the reaction mixture was purified prep-HPLC (Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]) to give the title compound 1-192 (24.5 mg, 19% yield) as a white solid. 1H NMR (400MHz, DM SO-6/6) δ 9.00 (s, IH), 8.62 (t, J = 5.6 Hz, IH), 8.55 (s, IH), 8.40 (s, IH), 7.97 (s, IH), 7.77 (d, J = 8.8 Hz, IH), 7.47 - 7.35 (m, 6H), 6.88 (s, IH), 6.84 (d, J= 2.4 Hz, IH), 6.79 (s, IH), 6.40 (s, IH), 5.18 (d, J = 2.4 Hz, IH), 4.56 (d, J= 9.6 Hz, IH), 4.46 - 4.42 (m, IH), 4.41 - 4.33 (m, 2H), 4.28 - 4.22 (m, IH), 3.96 (s, 2H), 3.87 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.65 ( d, J= 3.2 Hz, 2H), 3.59 (s, 2H), 3.55 - 3.49 (m, 11H), 3.03 - 2.96 (m, IH), 2.82 (s, 3H), 2.44 (s, 3H), 2.08 (s, 3H), 1.92 - 1.90 (m, IH), 1.66 - 1.54 (m, IH), 0.94 (s, 9H); LC-MS (ESL)&#1524;/ z 1148.2 (M+H)+.

1635

[005191] Example 193: 3-[[(lR,2S) aminocvclohexvl]amino] [[l-[2-[2-[2-[2-[[2(26&#1524;-dioxo piperidyl)-l ,3-dioxo-isoindolin yl] amino] ethoxy] ethoxy] ethoxy] ethyl] indol-4yl]amino]-l.,2.,4-triazine carboxamide,1-193

EtO

HCI/dioxane

DCM

[005192] Step 1:Ethyl 5-[[1-[2-[2-[2-[2 (benzyloxycarbonylamino)ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino1 methylsulfanylL2,4-triazine carboxylate

[005193] A mixture of benzyl

N-[2-[2-[2-[2-(4-aminoindol-1 1636 yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate (250 mg, 566 umol, synthesized via Steps 1-2 of

Example 166) and ethyl 5-chloro methylsulfanyl-l,2,4-triazine carboxylate (140 mg, 599 umol, CAS# 75824 2) in NMP (3 mL) was stirred at rt for 1 hour. On completion, the residue was purified by reverse phase chromatography (0.1% FA) to afford the title compound (220 mg, % yield) as a yellow oil. LC-MS (ESI+) m/z 639.1 (M+H)+.

[005194] Step 2 - Benzyl N-r2-r2-r2-r2-r4-r(6-carbamoyl methylsulfanyl-L2,4-triazin-5yl)amino1indol-l- yl1ethoxy1ethoxy1ethoxy1ethyl1carbamate

[005195] A mixture of ethyl 5-[[l-[2-[2-[2-[2(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol yl

[005196] ]amino] methylsulfanyl-l,2,4-triazine carboxylate (220 mg, 344 umol) in MeOH (15 mL) and 70 Ν NH3 in MeOH (15 mL) was stirred at -40 °C for 1 hour. On completion, the mixture was concentrated in vacuo at 45 °C to afford the title compound (180 mg, 81 % yield) as a yellow solid. LC-MS (ESI+) m/z 610.2 (M+H)+.

[005197] Step 3 Tert-butyl Ν-Γ(15,2Κ) ΓΓ5-ΓΓ1-[2-Γ2-Γ2-Γ2(benzyloxycarbonylamino)ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino1 carbamoyl-L2,4triazin yl1amino1cyclohexyl1carbamate

[005198] To a mixture of benzyl N-[2-[2-[2-[2-[4-[(6-carbamoyl methylsulfanyl-1,2,4triazin yl)amino]indol-l-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (180 mg, 295 umol) in DMF (3 mL) was added m-CPBA (150 mg, 869 umol) in one portion at 0 °C under nitrogen. The mixture was stirred at rt for 1 hour. On completion, TEA (255 mg, 2.52 mmol) and tert-butyl N-[(1S,2R)2-aminocyclohexyl]carbamate (100 mg, 466 umol) was added to above solution. Then the reaction mixture was heated to 65 °C and stirred for 0.5 hour. On completion, the mixture was poured into water (50 mL) and stirred for 2 minutes. The aqueous phase was extracted with ethyl acetate (3 X 50 mL). The combined organic phase was washed with brine (1 X 50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to afford the title compound (120 mg, 49% yield) as yellow solid. LCMS (ESI+) m/z 776.5 (M+H)+.

[005199] Step 4 - Tert-butyl Ν-Γ(18^) ΓΓ5-ΓΓ1-[2-Γ2-Γ2-(2aminoethoxy)ethoxy1ethoxy1ethyl1indol yl1amino1 carbamoyl-L2,4-tri azin-3yl1amino1cyclohexyl1

1637

[005200] To a mixture of tert-butyl N-[(lS,2R) [[5-[[l-[2-[2-[2-[2(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol yl]amino] carbamoyl-l,2,4triazin yl]amino]cyclohexyl]carbamate (120 mg, 154 umol) in EA (10 mL) was added Pd(OH)2/C (270 mg, 10 wt %) and ΝΗ3&#905;2Ο (100 uL) in one portion at rt under a hydrogen atmosphere (15 psi pressure). The mixture was stirred at rt for 16 hours. LCMS showed 30% starting material was not consumed. More Pd(OH)2/C (150 mg, 10 wt %) was added to above solution, and the mixture was stirred at rt under a hydrogen atmosphere (15 psi pressure)for another 16 hours. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound (100 mg, 70% yield) as a yellow solid. LC-MS (ESI+) m/z 642.3 (M+H)+.

[005201] StepJXIerLhltynHiMSRY^JJXcarbampyLS^^ piperidyl)-L3-dioxo-isoindolin yl1amino1ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino1L2.4-triazin yl1amino1cvclohexyl1carb amate

[005202] To a solution of tert-butyl N-[(lS,2R) [[5-[[l-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethyl]indol yl]amino] carbamoyl-l,2,4-tri azin-3yl]amino]cyclohexyl]carbamate (82.0 mg, 128 umol) and 2-(2,6- dioxo piperidyl)-4fluoroisoindoline-1,3-dione (38.8 mg, 141 umol, Intermediate R) in DMF (3 mL) was added DIPEA(33.0 mg, 256 umol) under nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 7 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (DCM:MeOH = 10:1) to afford the title compound (100 mg, 57% yield) as a yellow solid. LC-MS (ESI+) m/z 898.3 (M+H)+.

[005203] Step 6 - 3-rr(lR,2S) aminocyclohexyl1amino1 rr1-r2-r2-r2-r2-rr2-(2,6-dioxo3-piperidyl)-L3-dioxo-isoindolin yl1amino1ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino11,2,4-triazine carboxamide

[005204] To a solution of tert-butyl N-[(lS,2R) [[6-carbamoyl [[l-[2-[2-[2-[2-[[2-(2,6di oxo piperidyl)-1, 3-dioxo-isoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4yl]amino]-l,2,4-triazin yl]amino]cyclohexyl]carbamate (100 mg, 111 umol) in DCM (3 mL) was added HCI in dioxane (4N, 2 mL) under a nitrogen atmosphere. The reaction mixture was stirred at rt for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase [water (0.225% FA)-ACN]; B%:24%-48%, 10 min) to afford the title compound 1-193 (10.0 mg, 11%

1638 yield). 1HNMR (400MHz, DMSO-» δ 12.92 (s, IH), 8.39 (d, J= 12.8 Hz, 3H), 7.95 - 7.85 (m, IH), 7.79 - 7.71 (m, IH), 7.69 - 7.52 (m, IH), 7.45 - 7.32 (m, IH), 7.31 - 7.21 (m, IH), 7.20 - 7.09 (m, 2H), 7.09 - 7.01 (m, IH), 6.62 - 6.50 (m, IH), 6.49 - 6.40 (m, IH), 5.10 - 5.01 (m, IH), 4.45 4.32 (m, 2H), 3.95 - 3.82 (m, IH), 3.80 - 3.60 (m, 2H), 3.55 - 3.45 (m, 14H), 2.93 - 2.81 (m, IH), 2.59 - 2.63 (m, 2H), 2.06 - 1.95 (m, IH), 1.89 - 1.72 (m, 2H), 1.68 - 1.49 (m, 4H), 1.45 - 1.25 (m, 3H); LC-MS (ESI+) m/z 798.6 (M+H)+.

[005205] Example 194: 3-n(lR,2S) aminocvdohexvl]amino] n1-[2-[2-[2-[2-[2-H2(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] ethyl] indol yl] amino]-1 ,2,4-tr iazine-6carboxamide,1-194

NHCbz

[005206] 3-[[(lR,2S) aminocyclohexyl]amino] [[l-[2-[2-[2-[2-[2-[[2-(2,6-di oxo-31639 piperidyl)-l,3-dioxo-isoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4yl]amino]-l,2,4-triazine carboxamide was synthesized as described for Example 193, using benzyl N-[2-[2-[2-[2-[2-(4-aminoindol-l-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (synthesized via Steps 1-2 of Example 167) as the starting material in the first step. In Step 4, the hydrogenation was run at rt with 50 psi pressure of hydrogen. In Step 6, TFA not HCI was used for the Boc deprotection. The procedure was as follows:

[005207] A mixture of tert-butyl N-[(lS,2R) [[6-carbamoyl [[l-[2-[2-[2-[2-[2-[[2-(2,6dioxo piperidyl)-l,3-dioxo-isoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4yl]amino]-l,2,4-triazin yl]amino]cyclohexyl]carbamate (72 mg, 76.4 umol) in TFA (300 uL) and DCM (500 uL) was stirred at rt for 0.5 hour. On completion, the mixture was concentrated in vacuo. The residue was purified by column (Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.05% HCCOH)-ACN]; B%: 10%-40%, 12 min) to afford the title compound I194 (20 mg, 30% yield) as a yellow solid. 1HNMR (400 MHz, CD3OD) δ 8.53 (br s, IH), 7.45 (dd, J = 7.2, 8.8 Hz, IH), 7.33 (d, J = 3.2 Hz, IH), 7.27 (d, J = 8.0 Hz, IH), 7.21 - 7.12 (m, IH), 7.00 - 6.95 (m, 2H), 6.55 (d, J = 3.2 Hz, IH), 4.34 (t, J = 4.8 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.63 (t, J = 5.6 Hz, 2H), 3.60 - 3.55 (m, 4H), 3.55 - 3.49 (m, 6H), 3.50 - 3.47 (m, 2H), 3.39 (t, J = 5.2 Hz, 2H), 2.85 - 2.64 (m, 2H), 2.16 - 1.93 (m, 2H), 1.90 -1.75 (m, 5H), 1.73 - 1.47 (m, 3H), 1.41 1.25 (m, 2H). LC-MS (ESI+) m/z 842.5(M+H)+.

[005208] Example 195: (2S,4R)-l-[(2S) [[2-[2-[2-[2-[2-[[2-[4-[[7-[[(lR,2S)-2Aminocvclohexyl amino] oxo-3H-pyrido[4.,3-d]pvrimidin vl]amino]indol-lyl] acetyl] amino] ethoxy] ethoxy] ethoxy] ethoxy] acetyl] amino]-3.,3-dimethyl-butanoyl]-4hvdroxv-N-[[4-(4-methvlthiazol vl)phenvl]methvl]pyrrolidine carboxamide,1-195

1640

LiOH, THF, H2O

1641

[005209] Step 1 - Ethyl 2-(4-nitroindol-l-yl)acetate

[005210] To a solution of 4-nitro-lH-indole (5.00 g, 30.8 mmol, CAS# 4769 5) in DMF (100 mL) was added ethyl 2-bromoacetate (7.73 g, 46.3 mmol, 5.12 mL), K2CO3 (12.8 g, 92.5 mmol) and Nai (462 mg, 3.08 mmol). The reaction mixture was stirred at 40 °C for 12 hrs. On completion, the reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3 X 200 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated

1642 with ethyl acetate (30 mL) to give the title compound (6.50 g, 85% yield) as a yellow solid. 1H

NMR (400MHz, CDCh) δ 8.17 (dd, J= 0.8, 8.2 Hz, IH), 7.59 (d, J= 8.2 Hz, IH), 7.38 - 7.36 (m,

IH), 7.35 - 7.29 (m, 2H), 4.94 (s, 2H), 4.24 (q, J= 7.2 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H).

[005211] Step 2 - Ethyl 2-(4-aminoindol-l-yl)acetate

[005212] To a solution of ethyl 2-(4-nitroindol-l-yl)acetate (2.60 g, 10.5 mmol) in THF (20 mL) was added Pd/C (260 mg, 10 wt %), and the suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen (15 psi pressure) at rt for 12 hrs. On completion, the reaction was filtered and concentrated in vacuo to give the title compound (2.20 g, 96% yield) as a colorless oil. 1H NMR (400MHz, CDCh) δ 7.06 (t, J= 8.0 Hz, IH), 7.02 (d, J= 3.2 Hz, IH), 6.72 (d, J= 8.0 Hz, IH), 6.49 (dd, J= 0.8, 3.2 Hz, IH), 6.43 (dd, J = 0.8, 8.0 Hz, IH), 4.81 (s, 2H), 4.22 (q, J= 7.2 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H).

[005213] Step 3 - Ethyl 2-[4-[(7-chloro oxo-3H-pyrido[4,3-d1pyrimidin yl)amino]indoll-yl1 acetate

[005214] To a solution of ethyl 2-(4-aminoindol-l-yl)acetate (2.20 g, 10.1 mmol) in NMP (40 mL) was added 5,7-dichloro-3H-pyrido[4,3-d]pyrimidin one (2.18 g, 10.1 mmol, Intermediate FB) under nitrogen. The reaction mixture was stirred at 140 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo. The residue was triturated with DMF/MeOH = (5 mL/10 mL) to give the title compound (3.20 g, 80% yield) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ 12.95 (s, IH), 11.76 (s, IH), 8.32 (s, IH), 8.22 - 8.15 (m, IH), 7.41 (d, 7= 3.2 Hz, IH), 7.21 -7.15(m, 2H), 6.92 (s, IH), 6.60 (d, J = 3.2 Hz, IH), 5.16 (s, 2H), 4.16 (q, J= &#906;2 Hz, 2H), 1.22 (t, J= 7.2 Hz, 3H).

[005215] Step 4 - 2-[4-[(7-Chloro oxo-3H-pyrido[4,3-d1pyrimidin yl)amino]indol-lyllacetic acid

[005216] To a solution of ethyl 2-[4-[(7-chloro oxo-3H-pyrido [4,3-d]pyrimidin-5yl)amino]indol-l-yl]acetate (2.00 g, 5.03 mmol) in THF (30 mL) and H2O (10 mL) was added LiOHH2O (633 mg, 15.0 mmol). The reaction mixture was stirred at rt for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was acidified with HC1 (2 N, 20 mL) to pH = 3. The precipitate was collected by filtration and the solid was dried in vacuo to give the title compound (1.80 g, 87% yield) as a yellow solid. 1H NMR (400MHz, DMSO-76) δ 12.98 (s, 2H), 11.78 (s, IH), 8.31 (s, IH), 8.22 - 8.13 (m, IH), 7.41 (d, J = 3.2 Hz, IH), 7.22 7.13 (m, 2H), 6.91 (s, IH), 6.59 (d, J= 3.2 Hz, IH), 5.04 (s, 2H); LC-MS (ESI+) m/z 370.0 (M+H)+.

1643

[005217] Step 5 - Ethyl 2-Γ2-Γ2-Γ2-Γ2-ΓΓ2-Γ4-Γ(7-Η110Γ0 0χ0-3Η-ρν&#912;&#906;&#940;0Γ4,3-&#940;1ρν&#912;&#906;&#912;η&#912;&#940;&#912;η-5yl)amino1indol-l-yl1acetyl1amino1ethoxy1ethoxy1ethoxy1ethoxy1acetate

[005218] To a solution of ethyl 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetate (287 mg, 1.03 mmol, Intermediate DW) and 2-[4-[(7-chloro oxo-3H-pyrido[4,3-d]pyrimidin-5yl)amino]indol-l-yl]acetic acid (380 mg, 1.03 mmol) in DMF (10 mL) was added DIPEA (398 mg, 3.08 mmol). After stirring for 30 minutes, HATU (430 mg, 1.13 mmol) was added. The mixture was stirred at rt for 2 hours. On completion, 50 mL water was added to the mixture. A large quantity of yellow precipitate formed, which was collected by filtration to give the title compound (575 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m/z 631.2 (M+H)+.

[005219] Step 6 - 2-r2-r2-r2-r2-rr2-r4-r(7-Chloro oxo-3H-pyrido[4,3-d1pyrimidin-5yl)amino1indol-l[005220] yl 1 acetyl 1 amino] ethoxy] ethoxy] ethoxy] ethoxy] acetic acid

[005221] To a mixture of ethyl 2-[2-[2-[2-[2-[[2-[4-[(7-chloro oxo-3H-pyrido[4,3d]pyrimidin yl)amino] indol-l-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetate (600 mg, 950 umol) in THF (10 mL) and H2O (10 mL), was added LiOH (228 mg, 9.51 mmol). Then, the mixture was stirred at rt for 5 hours. On completion, the mixture was adjusted to pH = 5 with HCI (IN), then the mixture was extracted with DCM (2 X 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (400 mg, 69% yield) as a yellow solid. LC-MS (ESI+) m/z 603.1 (M+H)+.

[005222] Step 7 - (25,4Κ) Γ(25) ΓΓ2-Γ2-Γ2-Γ2-Γ2-ΓΓ2-Γ4-Γ(7-0Μ0Γ0 0χ0-3Η-ρν&#942;&#940;0[4,3d1pyrimidin yl)

3,3-dimethyl-butanoyl1 hydroxy-N-rr4-(4-methylthiazol yl)phenyl1methyl1pyrrolidine-2carboxamide

[005223] A mixture of 2-[2-[2-[2-[2-[[2-[4-[(7-chloro oxo-3H-pyrido[4,3-d]pyrimidin-5yl)amino]indol-l-yl] acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (400 mg, 597 umol), (2S,4R)-l-[(2S) amino -3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4-methylthiazol-5yl)phenyl]methyl]pyrrolidine carboxamide (279 mg, 597 umol, HCI salt, Intermediate CI), and DIPEA (308 mg, 2.39 mmol) in DMF (20 mL) was degassed and purged with nitrogen gas three times. Then HATU (249 mg, 657 umol) was added, and the mixture was stirred at rt for 2 hours under a nitrogen atmosphere. On completion, the mixture was poured into water (50 mL) and

1644 extracted with DCM (2 X 40 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by silica column chromatography to give the title compound (110 mg, 18% yield) as a yellow solid. LC-MS (ESI+) m/z 1037.6 (M+Na)+.

[005224] Step 8 - (28,4Κ) Γ(28) ΓΓ2-Γ2-Γ2-Γ2-Γ2-ΓΓ2-Γ4-ΓΓ7-ΓΓ(1Κ,28)-2Aminocyclohexyl amino] oxo-3H-pyridor4,3-d1pyrimidin yl1amino1indol-lyl1acetyl1amino1ethoxy1ethoxy1ethoxy1ethoxy1acetyl1amino1-3,3-dimethyl-butanoyl1 hydroxyN-rr4-(4-methylthiazol yl)phenyl1methyl1pyrrolidine carboxamide

[005225] A mixture of (2S,4R)-l-[(2S) [[2-[2-[2-[2-[2-[[2-[4-[(7-chloro oxo-3Hpyrido[4,3-d]pyrimidin yl)amino]indol-lyl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl] hydroxyN-[[4-(4-methylthiazol yl)phenyl]methyl]pyrrolidine carboxamide (60.0 mg, 59.0 umol) and (lR,2S)-cyclohexane-l,2-diamine (67.4 mg, 590 umol) in NMP (0.5 mL) was heated under microwave irradiation at 150 °C for 1.5 hours. On completion, the mixture was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)ACN]) to give the title compound 1-195 (26.0 mg, 40% yield) as a yellow solid. 1H NMR (400MHz, DMSO-6Z6) δ 11.75 (s, IH), 9.06 - 8.91 (m, IH), 8.62 (t, J= 6.0 Hz, IH), 8.39 - 8.32 (m, 2H), 7.93 (s, IH), 7.49 - 7.29 (m, 6H), 7.14 - 6.99 (m, 2H), 6.58 (d, J= 3.2 Hz, IH), 6.03 (s, IH), 4.83 (s, 2H), 4.57 (d, J = 9.6 Hz, IH), 4.49 - 4.33 (m, 3H), 4.25 (m, 2H), 3.97 (s, 2H), 3.71 -3.40 (m, 17H), 3.25 (m, 2H), 2.57 - 2.52 (m, 4H), 2.45 (s, 3H), 2.12 - 2.01 (m, IH), 1.96- 1.78 (m, 3H), 1.65 (d, 7= 11.2 Hz, 4H), 1.41 (s, 2H), 1.00 - 0.88 (m, 9H); LC-MS (ESI+) m/z 1093.2 (M+H)+.

[005226] Example 196: 3-[[(lR,2S) aminocvdohexvl]amino] [H-[2-[2-[2-[2-[[(lS)l-[(2S.,4R) hvdroxv [[4carbonyl]-2.,2-dimethvl-propvl] amino] oxo-ethoxy] ethoxy] ethoxy] ethyl] indol-4yl]amino]-l.,2.,4-triazine carboxamide,1-196

1645

[005227] Step 1 - 2-r2-r2-r2-(4-Nitroindol-l-vl)ethoxy]ethoxy]ethoxy]acetic acid

[005228] To a mixture of ethyl 2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (1.10 g, 3.51 mmol, Intermediate BI) and 4-nitro-lH-indole (500 mg, 3.08 mmol) in DMF (10 mL) was added Cs2CO3 (2.51 g, 7.70 mmol) in one portion at rt under nitrogen. The mixture was stirred at 100 °C for 16 hours. Next, LiOHH2O (129 mg, 3.08 mmol) in MeOH (3 mL) was then added to above solution, and the solution was stirred at rt for 4 hours. On completion, the mixture was poured into water (50 mL) and stirred for 2 minutes. The aqueous phase was extracted with ethyl

1646 acetate (4 X 50 mL). The combined organic phase was washed with H2O (2 X 20 mL), the combined aqueous phase was adjusted to pH = 5 with citric acid. The aqueous phase was then extracted with ethyl acetate (4 X 50 mL). The combined organic phase was washed with brine (2 X 50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.00 g, 92% yield) as a brown oil. 1H NMR (400 MHz, CDCh) δ 8.15 (d, J= 8.0 Hz, IH), 7.75 (d, J = 8.0 Hz, IH), 7.47 (d, J = 3.2 Hz, IH), 7.31 - 7.28 (m, IH), 7.27 - 7.23 (m, IH), 4.41 (t, J= 5.6 Hz, 2H), 4.15 (s, 2H), 3.84 (t, J= 5.6 Hz, 2H), 3.72 - 3.64 (m, 2H), 3.63 - 3.47 (m, 6H).

[005229] Step 2 - (2S,4R)-l-r(2S)-3,3-dimethyl rr2-r2-r2-[2-(4-nitroindol-lvl)ethoxy1ethoxy1ethoxy1acetvl1amino1butanovl1 hydroxy-N-[r4-(4-methylthi azol-5yl)phenyl1methyl1pyrrolidine carboxamide

[005230] To a mixture of 2-[2-[2-[2-(4-nitroindol-l-yl)ethoxy]ethoxy]ethoxy]acetic acid (171 mg, 484 umol) and (2S,4R)-l-[(2S) amino-3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4methylthiazol yl)phenyl] methyl]pyrrolidine carboxamide (200 mg, 428 umol, HCI, Intermediate CI) in DMF (2 mL) was added TEA (183 mg, 1.80 mmol) and HATU (299 mg, 787 umol) in one portion at rt. The mixture was stirred at rt for 3 hours. On completion, the mixture was poured into water (30 mL) and stirred for 2 minutes. The aqueous phase was extracted with ethyl acetate (3 X 30 mL). The combined organic phase was washed with brine (1 X 20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound (270 mg, 82% yield) as a yellow solid. 1H NMR (400 MHz, CDCh) δ 8.68 (s, IH), 8.14 (d, J= 7.2 Hz, IH), 7.69 (d, J = 8.0 Hz, IH), 7.45 (d, J = 3.2 Hz, IH), 7.34 (q, J = 8.4 Hz, 5H), 7.24 (d, J = 4.0 Hz, 2H), 4.73 (t, J = 8.0 Hz, IH), 4.59 - 4.51 (m, 2H), 4.48 (d, J = 8.4 Hz, IH), 4.41 - 4.29 (m, 3H), 4.18-4.11 (m, IH), 4.05 -3.94 (m, 2H), 3.81 (t,7=5.2 Hz, 2H), 3.77 -3.68 (m, IH), 3.63 -3.53 (m, 8H), 2.82 (br s, IH), 2.63 - 2.55 (m, IH), 2.52 (s, 3H), 2.12 (dd, 7= 8.0, 13.6 Hz, IH), 0.94 (s, 9H).

[005231] Step 3:(2S,4R)-l-r(2S) rr2-r2-[2-r2-(4-aminoindol-lyl)ethoxy1ethoxy1ethoxy1acetyl1amino1-3.3-dimethyl-butanoyl1 hydroxy-N-[r4-(4methylthiazol yl)phenyl1methyl1pyrrolidine carboxamide

[005232] To a mixture of (2S,4R)-l-[(2S)-3,3-dimethyl [[2-[2-[2-[2-(4-nitroindol-lyl)ethoxy] ethoxy] ethoxy] acetyl]amino]butanoyl] hydroxy-N-[[4-(4-methylthiazol-5yl)phenyl]methyl]pyrrolidine carboxamide (270 mg, 353 umol) in EA(10 mL) was added Pd/C

1647 (100 mg, 10 wt %) in one portion at rt under hydrogen (15 psi pressure). The mixture was stirred at rt for 16 hours. On completion, the mixture was filtered and concentrated in vacuo to afford the title compound (200 mg, 77.1% yield) as a yellow solid. LC-MS (ESI+) m/z 757.1 (M+Na)+.

[005233] Step 4 - Ethyl 5-ΓΓ1-Γ2-Γ2-Γ2-Γ2-ΓΓ(18) Γ(28,4Κ)-4^γ&#940;Γ0χγ Γ[4-(4methylthiazol yl)phenyl]methylcarbamoyl1pyrrolidine-l-carbonyl1-2,2-dimethylpropyl1amino1 oxo-ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino1 methylsulfanyl-L2,4triazine carboxylate

[005234] A mixture of (2S,4R)-l-[(2S) [[2-[2-[2-[2-(4-aminoindol-lyl)ethoxy]ethoxy]ethoxy]acetyl]amino]- 3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4methylthiazol yl)phenyl]methyl]pyrrolidine carboxamide (200 mg, 272 umol) and ethyl 5chloro methylsulfanyl-l,2,4-triazine carboxylate (64.8 mg, 278 umol) in NMP (2 mL) was stirred at rt for 1 hour. On completion, the mixture was purified by reverse phase flash column (0.1% FA) to afford the title compound (200 mg, 79% yield) as a blue oil. LC-MS (ESI+) m/z 932.7 (M+H)+.

[005235] Step 5 - 5-rr1-r2-r2-r2-r2-rr(lS)-l-r(2S,4R) hydroxy [r4-(4-methylthiazol-5yl)phenyl1methylcarbamoyl1pyrrolidine-l-carbonyl1-2,2-dimethyl-propyl1amino1 oxoethoxy1ethoxy1ethoxy1ethyl1indol yl1amino1 methylsulfanyl-L2,4-triazine carboxamide [005236] To a mixture of ethyl 5-[[l-[2-[2-[2-[2-[[(lS)-l-[(2S,4R) hydroxy [[4-(4methylthiazol yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethylpropyl]amino] oxo-ethoxy]ethoxy]ethoxy]ethyl]indol yl]amino] 1nethylsulfanyl-l,2,4triazine carboxylate (200 mg, 215 umol) in MeOH (300 uL) was added 17 Ν NH3 in MeOH (300 uL) in one portion at -40 °C under nitrogen. The mixture was stirred at -40 °C for 1 hour. On completion, the mixture was concentrated at reduced pressure at 45°C. The residue was purified by reverse phase flash column (0.1% FA) to afford the title compound (160 mg, 78% yield) as a yellow solid. LC-MS (ESI+) m/z 903.4 (M+H)+.

[005237] Step 6 - 3-rr(lR2S) aminocvclohexvl1amino1 rr1-r2-r2-[2-r2-rr(lS)-lr(2S,4R) hvdroxv-2&#1470;rr4-(4-methvlthiazol vl)phenvl1methvlcarbamovl1pyrrolidine-lcarbonyl1-2,2-dimethyl-propyl1amino1 oxo-ethoxy1ethoxy1ethoxy1ethyl1indol yl1amino11,2,4-triazine carboxamide

[005238] 5-[[l-[2-[2-[2-[2-[[(lS)-l-[(2S,4R) hydroxy [[4-(4-methylthiazol-5

1648 yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2-dimethyl-propyl]amino] oxoethoxy]ethoxy]ethoxy]ethyl]indol yl]amino] methylsulfanyl-l,2,4-triazine carboxamide (150 mg, 166 umol) and (lR,2S)-cyclohexane-l,2-diamine (200 mg, 1.75 mmol) dissolved in a microwave tube in NMP (3 mL). The sealed tube was heated at 150 °C for 1.5 hours under microwave. On completion, the residue was purified by column (Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.05% HC1)-ACN]; B%: 10%-40%, 12 min) to afford the title compound 1-196 (107 mg, 60% yield) as a red solid. 1HNMR (400 MHz, DMSO-/6) δ 12.91 (s, IH), 9.24 (d, J = 7.2 Hz, IH), 9.15 - 9.08 (m, IH), 8.90 - 8.70 (m, IH), 8.70 - 8.60 (m, IH), 8.49 - 8.39 (m, IH), 8.44 - 8.34 (m, 2H), 7.94 (d, J= 7.6 Hz, IH), 7.51 - 7.37 (m, 7H), 7.27 - 7.18 (m, IH), 6.52 (d, J = 2.4 Hz, IH), 4.55 (d, J = 10.8 Hz, IH), 4.44 (t, J = 8.2 Hz, 2H), 4.40 - 4.34 (m, 5H), 4.30 - 4.24 (m, IH), 4.20 - 1.12 (m, IH), 3.73 (d, J = 4.8 Hz, 2H), 3.66 - 3.60 (m, 2H), 3.59 - 3.47 (m, 12H), 2.43 (s, 3H), 2.11 - 2.03 (m, IH), 1.93 - 1.80 (m, 4H), 1.70 -1.60 (m, 3H), 1.45 - 1.30 (m, 2H), 0.93 (s, 9H); LC-MS (ESI+) m/z 969.5 (M+H)+.

[005239] Example 197: 3-[[(lR,2S) aminocvclohexvl]amino] [[l-[2-[2-[2-[2-[2[[(lS)-l-[(2S,4R) hydroxv [[4-(4-methylthiazol-5vl)phenvl]methvlcarbamovl]pvrrolidine-l-carbonvl]-2,2-dimethvl-propyl] ethoxy] ethoxy] ethoxy] ethoxy] ethyl] indol yl] amino] -1,2,4-triazine carboxamide, 1-197

OH

[005240] 3-[[(lR,2S) aminocyclohexyl]amino] [[l-[2-[2-[2-[2-[2-[[(lS)-l-[(2S,4R)-4hydroxy [[4-(4-methylthiazol yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2dimethyl-propyl] amino] oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol yl]amino]-l,2,4triazine carboxamide 1-197 was synthesized as described for Example 196, using Intermediate BK as the mesylate in the first step. Characterization of the final compound: 1H NMR (400 MHz, DMSO-/6) δ 12.93 (s, IH), 9.26 (d,/=8.0 Hz, IH), 9.21 - 9.17 (m, IH), 8.77 - 8.65 (m, IH), 8.67 (t, /= 5.6 Hz, IH), 8.45 (br s, IH), 8.36 (br s, 2H), 7.94 (d, /= 7.6 Hz, IH), 7.52 - 7.42 (m, 4H), 7.40 (s, 5H), 7.37 - 7.27 (m, IH), 6.52 (d, /= 2.8 Hz, IH), 4.55 (d, /= 9.6 Hz, IH), 4.46 - 4.38

1649 (m, 2H), 3.95 (s, 2H), 3.73 (d, J= 5.2 Hz, 2H), 3.71 - 3.65 (m, IH), 3.68 - 3.26 (m, 20H), 2.46 2.40 (m, 3H), 2.10 - 2.03 (m, IH), 1.95 - 1.75 (m, 5H), 1.68 - 1.58 (m, 4H), 1.45 - 1.25 (m, 2H),

0.92 (s, 9H); LC-MS (ESI+) m/z 1013.3 (M+H)+.

[005241] Example 198: 5-[[(lS,2R) aminocyclohexyl]amino] [3-[2-[2-[2-[2-[[2-(2,6dioxo piperidvl)-1 ,3dioxo-isoindolin yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] -5methoxv-anilino]imidazo[l.,2-c|pvrimidine carboxamide, 1-198

EA

Pd(OH)2/C, H2

DIPEA, DMF

[005242] Step 1 - Benzyl (2-(2-(2-(2-(3-((8-carbamoyl (methylthio)imidazo[L2c]pyrimidin yl)amino)- 5-methoxyphenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

[005243] To a solution of 7-(3-hydroxy methoxy-anilino) methylsulfanyl-imidazo[l,2c]pyrimidine carboxamide (300 mg, 869 umol, Intermediate EZ) in DMF (10 mL) was added K2CO3 (480 mg, 3.47 mmol) and 2-[2-[2-[2

1650 (benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (1.76 g, 4.34 mmol, Intermediate EY) under nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate (100 mL) and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% ΝΗ3&#905;2Ο) to give the title compound (380 mg, 67% yield) as a yellow oil. LC-MS (ESI+) m/z 655.1 (M+H)+.

[005244] Step 2 - Benzyl (2-(2-(2-(2-(3-((5-(((1 S.2R) aminocvclohexyl)amino)-8carbamoylimidazo[L2-c1pvrimidin yl)amino)-5methoxyphenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

[005245] A solution of benzyl 2V-[2-[2-[2-[2-[3-[(8-carbamoyl methylsulfanylimidazo[l,2-c]pyrimidin yl)- amino] methoxyphenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 305 umol) and (lR,2S)-cyclohexane1,2-diamine (38.4 mg, 336 umol) in DMF (5 mL) was heated to 90 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (220 mg, 100% yield) as a yellow oil. LC-MS (ESI+) m/z 721.1 (M+H)+.

[005246] Step 3:Tert-butyl Ν-Γ(1Κ28) ΓΓ7-Γ3-[2-Γ2-Γ2-Γ2(benzyl oxycarbonylamino)ethoxy1ethoxy1ethoxy1 imidazorL2-c1pvrimidin yl1amino1cvclohexyl1carbmate

[005247] To a solution of benzyl 2V-[2-[2-[2-[2-[3-[[5-[[(l S,2R) aminocyclohexyl]amino]8-carbamoyl- imidazo[l,2-c]pyrimidin yl]amino] methoxyphenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (220 mg, 305 umol) in methanol (3 mL) was added 12 (7.75 mg, 30.5 umol) and (Boc)2O (133 mg, 610 umol) at rt. The reaction mixture was stirred at rt for 6 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 20:1) to give the title compound (230 mg, 91% yield) as a yellow oil. LC-MS (ESI+) m/z 821.1 (M+H)+.

[005248] Step 4:Tert-butyl Ν-Γ(1Κ28) ΓΓ7-[3-Γ2-Γ2-Γ2-(2aminoethoxy)ethoxy1ethoxy1ethoxy1 m ethoxy5-yl1amino1cvclohexyl1carbamate

[005249] To a solution of tert-butyl 7V-[(lR,2S) [[7-[3-[2-[2-[2-[2(benzyl oxycarbonylamino)ethoxy]ethoxy] ethoxy]ethoxy] methoxy-anilino] carbamoyl

1651 imidazo[l,2-c]pyrimidin yl]amino]cyclohexyl]carbamate (230 mg, 280 umol) in ethyl acetate (3 mL) was added Pd(0H)2/C (120 mg, 280 umol, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen three times. The mixture was stirred under hydrogen gas (15 psi pressure) at rt for 12 h. On completion, the reaction mixture was fdtered and the fdtrate was concentrated in vacuo to give the title compound (130 mg, 65% yield) as yellow oil. LC-MS (ESI+) m/z 687.2 (M+H)+.

[005250] Step 5 - Tert-butyl Ν-Γ(1Κ28) ΓΓ8^^π1ον1 Γ3-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο-3piperidyl)-L3-dioxo-isoindolin yl1amino1ethoxy1ethoxy1ethoxy1ethoxy1 methoxyanilino1imidazorL2-c1pyrimidin yl1amino1cyclohexyl1carbamate

[005251] To a solution of tert-butyl 7V-[(lR,2S) [[7-[3-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethoxy] methoxy-anilino] carbamoyl-imidazo[l,2-c]pyrimidin5-yl]amino]cyclohexyl]carbamate (130 mg, 189 umol) and 2-(2,6-diox0 piperidyl) fluoroisoindoline-1,3-dione (57.5 mg, 208 umol, Intermediate R) in DMF (4 mL) was added DIPEA (73.4 mg, 568 umol) under nitrogen. The reaction mixture was stirred at 90 °C for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography to give the title compound (70.0 mg, 39% yield) as a yellow solid. LC-MS (ESE) 943.1 2/&#1524; (M+H)+.

[005252] Step 6 - 5-rr(lS,2R) aminocyclohexyl1amino1 r3-r2-r2-r2-r2-rr2-(2,6-dioxo-3piperidyl)-L3-dioxo-isoindolin yl1amino1ethoxy1ethoxy1ethoxy1ethoxy1 methoxyanilino1imidazo[L2-c1pyrimidine carboxamide

[005253] To a solution of tert-butyl 7V-[(lR,2S) [[8-carbamoyl [3-[2-[2-[2-[2-[[2-(2,6dioxo piperidyl)-l,3- dioxo-isoindolin yl]amino]ethoxy]ethoxy]ethoxy]ethoxy] methoxyanilino]imidazo[l,2-c]pyrimidin yl]amino]cyclohexyl]carbamate (70.0 mg, 74.2 umol) in DCM (4 mL) was added HCI in dioxane (4 M, 4.00 mL) at rt. The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Boston pH-lex 150*25 lOum; mobile phase: [water (0.225%FA)-ACN]; B%: 20%-50%) to give the title compound 1-198 (13.5 mg, 21% yield) as a white solid. 1HNMR (400MHz, DMSO-76) δ 12.39 (s, IH), 9.55 (d, J = 3.2 Hz, IH), 8.36 (s, IH), 8.12 (s, IH), 7.57 7.53 (m, IH), 7.40 (d, J= 3.6 Hz, IH), 7.32 (d, J = 1.6 Hz, IH), 7.10 (d, J= 8.4 Hz, IH), 7.01 (d, J = 6.8 Hz, IH), 6.93 (s, IH), 6.67 (s, IH), 6.58 (t, J = 5.6 Hz, IH), 6.20 (s, IH), 5.06 - 5.02 (m, IH), 4.20 (d, J= 11.2 Hz, IH), 4.08 - 4.04 (m, 2H), 3.74 (s, 3H), 3.71 (s, 2H), 3.62 (s, 2H), 3.59 1652

3.50 (m, 12H), 2.92 - 2.81 (m, IH), 2.62 - 2.58 (m, 2H), 2.28 - 2.26 (m, IH), 2.04 - 1.94 (m, 2H),

1.82 - 1.64 (m, 4H), 1.56 - 1.53 (m, 2H), 1.46 - 1.33 (m, 2H); LC-MS (ESI+) m/z 843.4 (M+H)+.

[005254] Example 199: Tert-butyl ((lR,2S) ((8-carbamovl ((3-((14-((2-(2,6dioxopiperidin yl)-l,3-dioxoiso methoxvphenvl)amino)imidazo[l,2-c]pvrimidin vl)amino)cvclohexyl)carbamate, 1-199

[005255] Tert-butyl ((lR,2S) ((8-carbamoyl ((3-((14-((2-(2,6-di oxopiperi din yl)-l, 3dioxoiso indolin yl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)-5methoxyphenyl)amino)imidazo[l,2-c]pyrimidin yl)amino)cyclohexyl)carbamate 1-199 was synthesized as described above for Example 198 using Intermediate FC as the mesylate. Step 1 was run at 60 C for 12 h. Characterization of the final product: 1H NMR (400MHz, DMSO-#6) δ 12.39 (s, IH), 9.55 (s, IH), 8.36 (s, 2H), 8.13 (s, IH), 7.58 - 7.53 (m, IH), 7.39 (s, IH), 7.32 (s, IH), 7.11 (d, J = 8.4 Hz, IH), 7.02 (d, J = 6.8 Hz, IH), 6.93 (s, IH), 6.67 (s, IH), 6.58 (s, IH), 6.21 (s, IH), 5.04 (dd, J= 5.2, 13.2 Hz, IH), 4.22 (d, J = 10.4 Hz, IH), 4.07 (s, 2H), 3.74 (s, 3H), 3.71 (s, 2H), 3.64 - 3.56 (m, 18H), 2.89 - 2.85 (m, 2H), 2.63 - 2.60 (m, 2H), 2.27- 2.65 (m, IH), 1.80 - 1.72 (m, IH), 1.71 -1.65 (m, 4H), 1.56 - 1.52 (m, 2H), 1.45-1.51 (m, 2H); LC-MS (ESI+) m/z 887.4 (M+H)+.

[005256] Example 200: 5-(((1 S,2R) aminocvclohexvl)amino) ((4-(2-(2-(2-(2-((2(2,6-dioxopiperidin yl)-l,3dimethoxvphenvl)amino)imidazo[l,2-c]pyrimidine carboxamide, 1-200

1653

MsO.O. N HCbz

HBr/HOAc ch3cn

OH

K2CO3, DMF

[005257] Step 1 - Benzyl (2-(2-(2-(2-(4-((8-carbamoyl (methylthio)imidazo[L2 c1pyrimidin yl)amino)-2, 6-dimethoxyphenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate [005258] To a mixture of 7-(4-hydroxy-3,5-dimethoxy-anilino) methylsulfanylimidazo[l,2-c]pyrimidine carboxamide (200 mg, 532 umol, Intermediate FA) in DMF (3 mL) was added 2-[2-[2-[2-(benzyloxycarbonylamino) ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (237 mg, 586 umol, Intermediate EY) and K2CO3 (220 mg, 1.60 mmol). Then the reaction mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was washed with water (50

1654 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic layer was dried with

Na2SO4, filtrated and concentrated in vacuo. The residue was purified by prep-column chromatography (PE:EA= 3:1 to DCM:MeOH = 20:1) to give the title compound (172 mg, 47% yield) as a yellow oil. LC-MS (ESI+) m/z 685.0 (M+H)+.

[005259] Step 2 - 7-((4-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethoxy)-3,5dimethoxyphenyl)amino) (methylthio)imidazo[L2-c1pyrimidine carboxamide

[005260] To a mixture of benzyl N-[2-[2-[2-[2-[4-[(8-carbamoyl methylsulfanylimidazo[l,2-c]pyrimidin yl)amino]-2,6dimethoxyphenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 292 umol) in CH3CN (2 mL) was added HBr in HOAc (32.9 mg, 292 umol, 1 mL). Then the reaction mixture was stirred at 50 °C for 1 hour. On completion, the reaction mixture was quenched with sat. NaHCO3 (3X30 mL) and extracted with DCM (3 X 30 mL). The organic layer was dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA in water) to give the title compound (70.0 mg, 43% yield) as a yellowish oil.

[005261] Step 3 - 7-((4-(2-(2-(2-(2-((2-(2,6-Dioxopiperidin vl)-L3-dioxoisoindolin-4yl)amino)ethoxy)ethoxv)ethoxv)ethoxv)-3.5-dimethoxyphenvl)amino)-5(methylthio)imidazo[ 1,2-c1pyrimidine carboxamide

[005262] To a mixture of 7-[4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-3,5dimethoxy-anilino] methylsulfanyl-imidazo[l,2-c]pyrimidine carboxamide (70.0 mg, 127 umol) and 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (38.6 mg, 139 umol, Intermediate R) in DMF (1.5 mL) was added DIPEA (32.8 mg, 254 umol). Then the reaction mixture was stirred at 90 °C for 8 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-TLC (PE:EA = 0:1) to give the title compound (30.0 mg, 23% yield) as a yellowish solid. LC-MS (ESI+) m/z 829.1 (M+Na)+.

[005263] Step 4 - 5-(((1 S,2R) aminocyclohexyl)amino) ((4-(2-(2-(2-(2-((2-(2,6dioxopiperidin yl)-L3-dioxoisoindolin yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,5dimethoxyphenyl)amino)imidazo[ 1,2-c1pyrimidine carboxamide

[005264] To a mixture of 7-[4-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin4-yl]amino]ethoxy] ethoxy]ethoxy]ethoxy]-3,5-dimethoxy-anilino] methylsulfanylimidazo[l,2-c]pyrimidine carboxamide (30.0 mg, 37.1 umol) in DMF (1 mL) was added (lR,2S)-cyclohexane-l,2-diamine (8.49 mg, 74.3 umol). Then the reaction mixture was stirred at

1655 °C for 8 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 20%-44%, 10 min) to give the title compound 1-200 (6.00 mg, 18% yield) as a yellowish oil. 1H NMR (400MHz, DMSO-de) δ 12.19 (s, IH), 9.53 (d, J= 2.8 Hz, IH), 8.36 (s, IH), 8.12 (s, IH), 7.57 (t, J= 7.6 Hz, IH), 7.37 (d, J= 3.2 Hz, IH), 7.32 (s, IH), 7.14 (d, J= 8.4 Hz, IH), 7.03 (d, J= 7.2 Hz, IH), 6.91 - 6.76 (m, 2H), 6.61 (t, J= 5.6 Hz, IH), 5.05 (dd, J = 5.6, 12.0 Hz, IH), 4.19 (d, J= 10.4 Hz, IH), 4.12-4.06 (m, IH), 4.05 - 3.99 (m, IH), 3.93 (d, J = 4.8 Hz, IH), 3.79 (s, 6H), 3.64 - 3.63 (m, 4H), 3.56 - 3.50 (m, 8H), 2.94 - 2.88 (m, 2H), 2.08 1.85 (m, 3H), 1.76 - 1.19 (m, 9H); LC-MS (ESI+) m/z 873.1 (M+H)+.

[005265] Example 201: (±) (2,6-Dioxo piperidyD [2-[2-[2-[2-[2-[5-[[4-[6-(3ethylpiperazin-l-yl) pyridyl]pyrimidin yl] amino] -2.,3dimethoxyphenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethylamino] isoindoline-1,3-dione, 1-201

1656

1657

[005266] Step 1:Benzyl N-r2-r2-r2-r2-r2-(2,3-dimethoxy nitrophenoxy)ethoxy1 ethoxy ]ethoxy ]ethoxy] ethyl] carbamate

[005267] To a mixture of 2-[2-[2-[2-[2(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methane sulfonate (606 mg, 1.35 mmol, Intermediate FC) in DMF (10 mL) was added 2,3-dimethoxy nitro-phenol (268 mg, 1.35 mmol, Intermediate FG) and potassium carbonate (559 mg, 4.05 mmol). Then the reaction mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was washed with water (20 mL) and extracted with ethyl acetate (3 X 30 mL). The combined organic layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column (petroleum etherethyl acetate = 1:1 to dichloromethane:methanol = 20:1) to give the title compound (610 mg, 74% yield) as a yellowish oil. LC-MS (ESI+) m/z 553.1 (M+H)+.

[005268] Step 2:Benzyl N-r2-r2-r2-r2-r2-(5-amino-2,3-dimethoxyphenoxylethoxy]ethoxy]ethoxy]ethoxy] ethyllcarbamate

[005269] To a solution of benzyl N-[2-[2-[2-[2-[2-(2,3-dimethoxy nitrophenoxy)ethoxy]ethoxy]ethoxy] ethoxy]ethyl]carbamate (460 mg, 832 umol) in water (2 mL) and ethanol (8 mL) was added ammonium chloride (445 mg, 8.32 mmol) and Fe (464 mg, 8.32 mmol). The reaction mixture was stirred at 78 °C for 1 hour. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanaol = 50:1) to give the title compound (430 mg, 98% yield) as a yellow

1658 oil. 1HNMR (400MHz, CDCh) δ 7.37 - 7.35 (m, 5H), 6.03 - 5.82 (m, 2H), 5.52 (br s, IH), 5.16 5.07 (m, 2H), 4.19 - 4.08 (m, 2H), 3.84 (d, J= 5.6 Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.74 - 3.70 (m, 2H), 3.68 - 3.63 (m, 10H), 3.59 - 3.55 (m, 3H), 3.44 - 3.39 (m, 2H); LC-MS (ESI+) m/z 523.1 (M+H)+.

[005270] Step 3:(±)-Tert-butyl 4-[5-[2-[3-[2-[2-[2-[2-[2(b enzyl oxy carb onyl am i n 0 )eth ox y] ethoxy] ethoxy]ethoxy] ethoxy] -4,5dimethoxyanilino1pyrimidin yl1 pyridyl1 ethyl-piperazine-l-carboxylate

[005271] To a solution of (±)-tert-butyl 2-ethyl [5-(2-methylsulfonylpyrimidin yl)-2pyridyl]piperazine-l- carboxylate (200 mg, 446 umol, Intermediate FH) and benzyl N-[2-[2-[2-[2[2-(5-amino-2,3-dimethoxyphenoxy)ethoxy] ethoxy]ethoxy]ethoxy]ethyl]carbamate (233 mg, 446 umol) in toluene (3 mL) was added Pd(OAc)2 (10.0 mg, 44.6 umol), BINAP (41.7 mg, 67.0 umol), cesium carbonate (436 mg, 1.34 mmol) and 4AMS (1.00 g, 446 umol) under nitrogen. The reaction mixture was stirred at 100 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA in water) to give the title compound (160 mg, 32% yield) as a yellow oil. 1H NMR (400MHz, CDCh) δ 8.87 (d, J = 2.4 Hz, IH), 8.34 (d, J = 5.2 Hz, IH), 8.20 (dd, J = 2.4, 9.2 Hz, IH), 7.37 - 7.29 (m, 5H), 7.19 (d, J= 2.0 Hz, IH), 7.03 (d, J= 5.2 Hz, IH), 6.92 (s, IH), 6.65 (d, J= 92 Hz, IH), 5.59 (br s, IH), 5.09 (s, 2H), 4.36 - 4.24 (m, 2H), 4.20 (t, J= 4.8 Hz, 2H), 4.16 3.97 (m, 2H), 3.91 (s, 3H), 3.87 (t, J= 4.8 Hz, 2H), 3.84 (s, 3H), 3.72 (d, J = 4.8 Hz, 2H), 3.63 3.61 (m, 10H), 3.57 - 3.53 (m, 2H), 3.42 - 3.36 (m, 2H), 3.24 (dd, J = 4.0, 13.2 Hz, IH), 3.18 3.01 (m, 2H), 1.66 - 1.56 (m, 2H), 1.50 (s, 9H), 0.92 (t, J= 7.2 Hz, 3H).

[005272] Step 4:(±)-Tert-butyl 4-[5-[2-[3-[2-[2-[2-[2-(2aminoethoxyjethoxyl ethoxy] ethoxy] ethoxy]-4,5-di

2-ethyl-piperazine-l-carboxylate

[005273] To a mixture of (±)-tert-butyl 4-[5-[2-[3-[2-[2-[2-[2-[2(benzyl oxycarbonylamino)ethoxy]ethoxy] ethoxy] ethoxy] ethoxy]-4,5-dimethoxyanilino]pyrimidin yl] pyridyl] ethyl-piperazine-l-carboxylate (160 mg, 179 umol) in NH3 H2O (50 uL) and methanol (6 mL) was added Pd(OH)2/C (60.0 mg, 10 wt %). Then the reaction mixture was stirred at rt for 10 hours under hydrogen (50 psi pressure). On completion, the reaction mixture was concentrated in vacuo to give the title compound (130 mg, 95% yield) as a yellowish oil. LC-MS (ESI+) m/z 756.4 (M+H)+.

1659

[005274] Step 5 - (±)-Tert-butyl 4-Γ5-Γ2-Γ3-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο ρ&#912;ρ6&#942;&#940;ν1)-1,3dioxo-isoindolin yl]amino] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -4,5 -dimethoxyanilino]pyrimidin yl] pyridyl] ethyl-piperazine-l-carboxylate

[005275] To a mixture of (±)-tert-butyl 4-[5-[2-[3-[2-[2-[2-[2-(2aminoethoxy)ethoxy] ethoxy] ethoxy] ethoxy]-4, 5-dimethoxyanilino]pyrimidin yl] pyridyl]2-ethyl-piperazine-l-carboxylate (70.0 mg, 92.6 umol) in DMF (2 mL) was added (+) (2,6dioxo piperidyl) fluoro-isoindoline-l,3-dione (28.1 mg, 101 umol, Intermediate R) and DIPEA (29.9 mg, 231 umol, 40.4 uL). Then the reaction mixture was stirred at 90 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prepTLC (di chi orom ethane :methanaol = 20:1) to give the title compound (40.0 mg, 40% yield) as a yellowish solid. LC-MS (ESI+) m/z 1012.2 (M+H)+.

[005276] Step 6 - (±) (2.6-Ρ&#943;οχο ρ&#943;ρ61&#906;&#940;ν1) Γ2-Γ2-Γ2-Γ2-Γ2-Γ5-ΓΓ4-[6-(3ethylpiperazin-l-yl) pyridyl]pyrimidin yl]amino]-2,3dimethoxyphenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl amino]i soindoline-1.3 -di one

[005277] To a mixture of (±)-tert-butyl 4-[5-[2-[3-[2-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)1,3-dioxo-iso indolin yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy]-4,5-dimethoxyanilino]pyrimidin yl] pyridyl] ethyl-piperazine-l-carboxylate (73.0 mg, 72.1 umol) in a mixture of methanol (1 mL) and dichloromethane (1 mL) was added 4M HCI in dioxane (72.1 umol, 1.00 mL) at 0 °C. Then the reaction mixture was allowed to warm to rt and stirred for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 27%-48%, 10 min) to give the title compound 1-201 (35.0 mg, 53% yield) as a yellowish solid. 1H NMR (400MHz, DM SO-0/6) δ 11.12 (s, IH), 9.39 (s, IH), 8.93 (s, IH), 8.42 (d, J = 5.6 Hz, IH), 8.26 (d, J = 9.2 Hz, IH), 7.56 (t, J = 7.6 Hz, IH), 7.34 - 7.22 (m, 3H), 7.16 - 7.09 (m, IH), 7.06 - 6.99 (m, IH), 6.98 - 6.88 (m, IH), 6.67 - 6.54 (m, IH), 6.58 (t, J = 5.6 Hz, IH), 5.05 (dd, 7= 5.2, 13.2 Hz, IH), 4.39-4.19 (m, 2H), 4.11 (d, 7= 3.6 Hz, 2H), 3.79 (s, 3H), 3.65 (s, 3H), 3.63 - 3.57 (m, 6H), 3.56 - 3.52 (m, 2H), 3.54 - 3.50 (m, 6H), 3.47 - 3.41 (m, 4H), 3.00 (d, 7= 11.6 Hz, 2H), 2.86 (d, 7= 12.0 Hz, 3H), 2.75 - 2.64 (m, 3H), 2.10 - 1.95 (m, IH), 1.50 - 1.34 (m, 2H), 0.95 (t, 7= 7.6 Hz, 3H); LC-MS (ESI+) m/z 912.2 (M+H)+.

[005278] Example 202: (2S,4R)-l-[(2S) [[2-[2-[2-[2-[2-[5-[[4-[6-(3-ethylpiperazin-lyl) pyridyl] pyrimidin yl]amino]-2,3-dimethoxy1660 phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetyl! amino] -33&#1524;-dimethvl-butanovl] hvdroxy-Nn4-(4-methvlthiazol vl)phenvl]methvl]pyrrolidine carboxamide,

1-202

K2CO3, DMF

1661

[005279] Step 1 - Ethyl2-r2-r2-r2-r2-r2-r3-r(8-carbamoyl methylsulfanyl-imidazo[L2c1pyrimidin yl)

[005280] amino] -5 -methoxy-phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate

[005281] To a solution of 2,3-dimethoxy nitro-phenol (510 mg, 2.56 mmol, Intermediate FG) and ethyl 2-[2-[2-[2-(2-methyl sulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate (1.10 g, 3.07 mmol, Intermediate BK) in DMF (15 mL) was added K2CO3 (1.06 g, 7.68 mmol). The mixture was stirred at 50 °C for 12 hours. On completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (3X30 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA = 1:1) to give the title compound (1.10 g, 93% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 7.55 (d, J = 2.4 Hz, IH), 7.50 (d, J = 2.4 Hz, IH), 4.26 - 4.16

1662 (m, 4H), 4.13 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.90 (m, 2H), 3.74 - 3.63 (m, 12H), 1.27 (t, J =

14.4 Hz, 3H); LC-MS (ESI+) m/z 431.1 (M+18)+.

[005282] Step 2:ethyl 2-[2-[2-[2-[2-(5-amino-2,3-dimethoxyphenoxy)ethoxy 1 ethoxy] ethoxy] ethoxy] acetate

[005283] To a solution of ethyl 2-[2-[2-[2-[2-(2,3-dimethoxy nitrophenoxy)ethoxy]ethoxy]ethoxy]ethoxy] acetate (600 mg, 1.30 mmol) in MeOH (8 mL) was added Pd/C (300 mg, 10 wt %) under nitrogen atmosphere. The suspension was degassed and purged with hydrogen gas three times. The mixture was stirred under hydrogen (15 psi pressure) at rt for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (400 mg, 71% yield) as a red oil. 1H NMR (400MHz, CDCh) δ 5.97 (s, IH), 5.94 (s, IH), 4.26 - 4.18 (m, IH), 4.22 (q, J = 7.2 Hz, IH), 4.16 - 4.09 (m, 4H), 3.87 - 3.83 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 3.74 - 3.65 (m, 12H), 1.31-1.27 (t, J= 7.2 Hz, 3H); LC-MS (ESI+) m/z 432.1 (M+H)+.

[005284] Step 3:ΕΦν1 Γ2-Γ2-Γ2-Γ2-Γ2-Γ3-Γ[5-ΓΓ(18^) (&#943;6Γ&#943;butoxycarbonylamino)cyclohexyl1amino1 carbamoyl-imidazo[L2-c1pyrimidin yl1amino1-5methoxy-phenoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] acetate

[005285] To a solution of ethyl 2-[2-[2-[2-[2-(5-amino-2,3-dimethoxyphenoxy)ethoxy]ethoxy]ethoxy] ethoxy]acetate (300 mg, 695 umol) and tert-butyl 2-ethyl [5(2-methylsulfonylpyrimidin yl) pyridyl]piperazine-l-carboxylate (311 mg, 695 umoL Intermediate FH) in toluene (10 mL) was added 4 A MS (600 mg), Cs2CO3 (679 mg, 2.09 mmol), BINAP (64.9 mg, 104 umol) and Pd(OAc)2 (15.6 mg, 69.5 umol) under nitrogen atmosphere. The suspension was degassed and purged with nitrogen three times. The mixture was stirred at rt for 1 h, and then heated to 100 °C for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove the toluene. The residue was diluted with water (5 mL) and extracted with DCM (3X6 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FAin water) to give the title compound (400 mg, 72% yield) as a yellowish solid. LC-MS (ESI+) m/z 799.2 (M+H)+.

[005286] Step 4 - 2-r2-r2-r2-r2-r5-rr4-r6-(4-tert-butoxvcarbonvl ethyl-piperazin-l-yl)-3pyridyllpyrimidin- 2-yl1amino1-2,3-dimethoxy-phenoxy1ethoxy1ethoxy1ethoxy1ethoxy1acetic

1663 acid

[005287] To a solution of tert-butyl 4-[5-[2-[3-[2-[2-[2-[2-(2-ethoxy oxoethoxy)ethoxy] ethoxy] ethoxy] ethoxy]-4,5-dimethoxy-anilino]pyrimidin yl] pyridyl]-2ethyl-piperazine carboxylate (200 mg, 250 umol) in THF (6 mL) was added a solution of Li OH (52.5 mg, 1.25 mmol) in H2O (1 mL). The reaction mixture was stirred at rt for 3 hours. On completion, the mixture saturated citric acid aqueous solution (0.3 mL) was added to the mixture to adjust the pH to 5. The residue was diluted with 3 mL water and extracted with DCM (3X5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give title compound (193 mg, 100% yield) as a yellowish oil.

[005288] Step 5 - Tert-butyl 2-6Φγ1 Γ5-Γ2-Γ3-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ(18) Γ(28,4Κ)-4^γ&#940;Γ0χγ2&#1470;rr4-(4-methyl propyl1amino1 oxo-ethoxy1ethoxy1ethoxy1ethoxy1ethoxy1-4,5-dimethoxy-anilino1pyrimidin-4yl1 pyridyl1piperazine-1 -carboxylate

[005289] To a solution of 2-[2-[2-[2-[2-[5-[[4-[6-(4-tert-butoxycarbonyl ethyl-piperazinl-yl) pyridyl] pyrimidin yl]amino]-2,3-dimethoxyphenoxy ]ethoxy ]ethoxy ]ethoxy ]ethoxy] acetic acid (192 mg, 250 umol), (2S,4R)-l-[(2S) amino3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4-methylthiazol yl) phenyl]methyl]pyrrolidine-2carboxamide (129 mg, 300 umol, Intermediate CI), and DIPEA (96.9 mg, 750 umol) in DMF (5 mL) was added HATU (114 mg, 300 umol) at 0 °C. The reaction mixture was then allowed to warm to rt and stirred for 16 hours. On completion, the reaction mixture was concentrated under reduced pressure to remove DMF, then diluted with water (15 mL) and extracted with DCM (3 X 10 mL). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FA in water) to give the title compound (210 mg, 71 % yield). LC-MS (ESI+) m/z 1183.2 (M+H)+.

[005290] Step 6 - (2S,4R)-l-r(2S) rr2-r2-r2-r2-r2-r5-rr4-[6-(3-ethylpiperazin-l-yl)-3pyridyl1pyrimidin yl1 amino] -2,3 -dimethoxyphenoxy 1 ethoxy] ethoxy] ethoxy] ethoxy] acetyl 1 amino] -3,3 -dimethyl -butanoyl 1 -4 -hy droxy-N - [ [4(4-methylthiazol yl)phenyl1methyl1pyrrolidine carboxamide

[005291] To a solution of tert-butyl 2-ethyl [5-[2-[3-[2-[2-[2-[2-[2-[[(lS)-l-[(2S,4R)-4hydroxy [[4-(4-methylthiazol yl)phenyl]methylcarbamoyl]pyrrolidine-l-carbonyl]-2,2dimethyl-propyl]amino] oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy

1664 anilino]pyrimidin yl] pyridyl]piperazine-l-carboxylate (210 mg, 177 umol) in MeOH (3 mL) was added HCI in dioxane (4 M, 5 mL). Then the mixture was stirred at rt for 15 mins. On completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give a residue. The residue was purified by prep-HPLC (column: Luna C18 150*25 5u; mobile phase: [water (0.225%FA)-ACN]) to give the title compound 1-202 (118 mg, 61% yield). 1HNMR (400MHz, DMSO-76) δ 9.40 (s, IH), 8.95 (s, IH), 8.93 (d, J= 1.6 Hz, IH), 8.61 (7= 4.0 Hz, IH), 8.42 (d, 7= 5.6 Hz, IH), 8.32 - 8.22 (m, 2H), 7.47 - 7.34 (m, 5H), 7.29 (d, 7= 5.6 Hz, IH), 7.25 (d, 7= 6.4 Hz, 2H), 6.97 (d, 7= 9.6 Hz, IH), 4.55 (d, 7= 9.6 Hz, IH), 4.47 - 4.32 (m, 4H), 4.29 4.19 (m, 2H), 4.13 - 4.04 (m, 2H), 3.94 (s, 2H), 3.81 - 3.72 (m, 6H), 3.68 - 3.58 (m, 14H), 3.13 3.04 (m, IH), 2.98 (m, IH), 2.83 - 2.73 (m, IH), 2.67 (d, 7= 6.4 Hz, 2H), 2.42 ( 3H), 2.10 - 2.01 (m, IH), 1.94 - 1.84 (m, IH), 1.49 - 1.43 (m, 2H), 1.01 - 0.85 (m, 12H); LC-MS (ESE)&#1524;/ z 1083.2 (M+H)+.

[005292] Example 203: PBMC degradation assay

[005293] Protocol summary of PBMC degradation studies from compound treatment through quantitation.

[005294] Table 13. Cell Culture Materials

<td> Reagent</td><td> Vendor</td><td> Catalogue no.</td>

<td> 6 well plate</td><td> Falcon</td><td> 353046</td>

<td> Frozen PBMCs</td><td> AllCells</td><td> PB006F, PB005F or PB004F</td>

<td> FBS, certified one-shot</td><td> Gib co</td><td> A31604-02</td>

<td> Pen/Strep lOOOunits/mL</td><td> Gib co</td><td> 10378016</td>

<td> DMSO</td><td> Sigma</td><td> D8418-50mL</td>

<td> 2.0mL centrifuge tubes</td><td> Coming</td><td> 311-10-051</td>

[005295] PBMC culture medium: Human peripheral blood mononuclear cells (PBMCs):

RPMI+10%FBS (Heat-inactivated) +1%P/S.

[005296] Table 14. Lysate preparation and Western Reagents.

<td> Reagent</td><td> Vendor</td><td> Catalogue no.</td>

<td> LDS Sample Buffer (4x)</td><td> Life Technologies</td><td> NP0008</td>

<td> Reducing Agent (lOx)</td><td> Invitrogen</td><td> NP0009</td>

<td> Molecular Grade diH2O</td><td> Corning</td><td> 46-000-CV</td>

<td> 96 well PCR plate</td><td> Eppendorf</td><td> 951020346 EA</td>

1665

<td> SDS-Page protein gel (4-12% Bis-Tris) 20 well</td><td> Invitrogen</td><td> WG1402BOX</td>

<td> 20x MES running buffer (20x)</td><td> Invitrogen</td><td> NP0002</td>

<td> TransBlot Turbo RTAMidi LF PVDF transfer kit, for 40 blots</td><td> BioRad</td><td> 1704275</td>

<td> lOx RIPA buffer</td><td> Cell Signaling Technologies</td><td> 9806</td>

<td> HALT Protease and Phosphatase Inhibitor Cocktail (lOOx)</td><td> Thermo Scientific</td><td> 1861281</td>

<td> Odyssey Blocking buffer (TBS)</td><td> Licor</td><td> 927-50000</td>

<td> TBST lOx</td><td> Cell Signaling Technologies</td><td> 9997</td>

<td> Molecular Weight Markers</td><td> Licor</td><td> 928-40000</td>

[005297] Table 15. Antibodies.

<td> Antibody</td><td> Vendor</td><td> Catalogue no.</td>

<td> IRAKI</td><td> Cell Signaling Technologies</td><td> 4504S</td>

<td> IRAK4</td><td> Cell Signaling Technologies</td><td> 4363S</td>

<td> IRAK3</td><td> Cell Signaling Technologies</td><td> 4369S</td>

<td> MYD88</td><td> Abeam</td><td> 133739</td>

<td> Actin</td><td> Licor</td><td> 926-42212</td>

<td> Goat anti-rabbit IRDye 800CW</td><td> Licor</td><td> 926-32211</td>

<td> Goat anti-mouse IRDye 680CW</td><td> Licor</td><td> 926-68070</td>

[005298] Table 16. Equipment.

<td> Equipment</td><td> Vendor</td><td> Catalogue no.</td>

<td> XCell Surelock Midi Cell</td><td> Invitrogen</td><td> WR0100</td>

<td> TransBlot Turbo transfer system</td><td> BioRad</td><td> 1704150</td>

<td> Odyssey CLx</td><td> Licor</td><td></td>

[005299] Protocol Summary • Frozen human PBMCs were thawed into culture medium.

1666 • A cell count/viability assessment by trypan blue exclusion was performed. Cells were cultured at a minimum of 2.5xl06 c/mL.

• PBMCs were incubated @ 37 °C/5% CO2 and allowed to rest overnight.

• Following overnight recovery, a cell count/viability assessment by trypan blue exclusion was performed. Cells densities were adjusted back to 2.5xl06 c/mL (proceed with plating only if viability >80%).

• In a 6 well plate, 2.0 mL of cells were added to each well for a minimum of 5xl06 CT per treatment condition. Compounds dilltutions were prepared from 20 mM stock and were added at a final lOOOx dilution (0.1% DMSO concentration).

• At the end of treatment, cells were harvested and spun @ 1800 rpm for 5 min. IxPBS wash and spun again @ 1800 rpm for 5min. Cell pellets were frozen and stored at -80 °C until further processing.

• Lysates were generated by resuspending in lysis buffer. Protein quantification was performed with a BCA kit.

• 20 pg of protein were loaded per lane and run on a 26-well 4-12% Bis-Tris SDS-page gel.

• Transfers were performed on PVDF membranes using the BioRad Mixed MW turbo program for 7 min.

• Membranes were blocked for one hour on a rocker at room temperature.

• Primary antibodies were incubated overnight at 4 °C on a rocker.

• Membranes were washed 3x TBST, 5 min each.

• Secondaries were added and incubated for one hour on a rocker at room temperature.

• Membranes were washed 3x TBST, 5 min each and rinsed well with deionized H2O. Membranes were scanned using the Licor Odessey CLx and bands were quantified using Image Studio Lite Version 5.2 software.

[005300] PBMC results at 4 hours. The letter codes indicate the percentage of IRAK4 degraded after 4 hours: A (>50% degradation), B (>20-50% degredation) and C (<20% degredation)

[005301] Table 17. PBMC % IRAK4 Degradation Results.

<td> Compound Number</td><td> PBMC % IRAK4 Degradation</td>

1667

1668

[005302] Example 204: THP-1 and OCI-LY-10 degradation assay

[005303] Methods

[005304] Compound treatment:

[005305] Compounds were reconstituted in DMSO to make stock solutions at concentration of 60 mM. THP-1 and OCI-LY10 cells were maintained in RPMI-1640 medium containing 10% FBS, 0.5 μΜ 2-ME or 20% FBS, 55 μΜ 2-ME, and 1% L-Glutamine respectively.

[005306] Cells were seeded into 6-well plates with 5e6 cells per well. 200 pL of diluted compounds were added to cells to the final concentration of 0.003 - 10 μΜ. After 4 or 24 hourincubation at 37 °C, cells were collected into 2 mL Eppendorf tubes and centrifuged at 1,000 rpm for 5 min. The cell pellets were washed with 1 *DPBS once and resuspended in 60 pL lysis buffer. The cells were lysed on ice for 10 min, then centrifuged at 14,000 rpm for 10 min at 4 °C and the supernatants were collected for western blots. For THP-1 cells, the lysis buffer contained 40 mM pH 7.4 HEPES, 140 mM NaCl, 2.5 mM EDTA, 1% NP-40, 0.1% SDS, and protease inhibitor cocktail (Roche, Cat. No.05892791001). For OCI-LY10 cells, RIPA buffer (Thermo Fisher, 89900) with Halt Protease and Phophatase Inhibitor Cocktail (Thermo Fisher, 78446) was applied.

[005307] Protein concentration determination:

[005308] The protein concentration of cell lysates was quantified with Pierce™ BCA Protein Assay Kit (Pierce, 23227). Albumin standards at different concentrations were prepared, involving 2,000 ug/mL, 1,500 ug/mL, 1,000 ug/mL, 750 ug/mL, 500 ug/mL, 250 ug/mL, 125 ug/mL, and 25 ug/mL. BCA working reagents were prepared by mixing BCA reagent A with reagent B in 50 : 1 ratio. 200 pL of the BCA working reagents were added to 25 pL of BCA standard or cell lysates in microplate, and mixed thoroughly on a plate shaker for 30 seconds. After incubation at 37 °C

1669 for 30 min, the absorbance of samples at 562 nm were measured with EnVision Plate Reader.

[005309] Western blot assay:

[005310] Protein lysates were prepared in NuPAGE™ LDS sample buffer and NuPAGE™ sample reducing agent, and incubated at 95 °C for 5 min. For western blots, 20 - 25 pg of total proteins were resolved in 4 - 12% Bis-Tris gels (Introgen, WG1403A) or 10% Bis-Tris Midi gels (Invitrogen, WG1202BOX) running with IxMOPS SDS running buffer (Invitrogen, NP0001) or IxMES SDS running buffer (Invitrogen, NP0002). The proteins were transferred to low fluorescence PVDF membranes using the Trans-Blot Turbo Transfer System. Membranes were then blocked in Odyssey blocking buffer at RT for 1 h followed by primary incubation at 4 °C overnight. The primary antibodies were IRAKI rabbit monoclonal antibody (CST, #4504S, 1:500), IRAK3 rabbit polyclonal antibody (CST, #4369, 1:500), IRAK4 rabbit polyclonal antibody (CST, #4363S, 1:1,000), MyD88 rabbit monoclonal antibody (Abeam, Abl33739, 1:2,000), β-actin mouse monoclonal antibody (Sigma, A5441, 10,000), and Gapdh mouse monoclonal antibody (Millipore, MAB374, 1:5,000). Membranes were washed three times with IxTBST, and then incubated with IR Dye 800 CW Goat anti-rabbit (Licor, #926-32211) and IR Dye 700 CW Goat anti-mouse (Licor, #926-68070) secondary antibodies in 1:10,000 dilution at RT for 1 h. The western blot images were obtained using Odyssey Imaging System.

[005311] THP-1 results at 24 hours. The letter codes indicate the percentage of IRAK4 degraded after 24 hours: A (>50% degradation), B (>20-50% degredation) and C (<20% degredation)

[005312] Table 18. THP-1 % IRAK4 Degradation Results.

<td> Compound Name</td><td> THP-1 24 h % IRAK4 Degradation</td>

1670

1671

[005313] OCI-LY-10 results at 4 hours. The letter codes indicate the percentage of IRAK4 degraded after 4 hours: A (>50% degradation), B (>20-50% degredation) and C (<20% degredation)

[005314] Table 19. OCI-LY-10 % IRAK4 Degradation Results.

<td> Compound Name</td><td> OCI-LY10 % IRAK4 Degradation</td>

1672

1673

1674

1675

[005315] OCI-LY-10 results at 4 hours. The letter codes for % IRAK4 degradation indicate the percentage of IRAK4 degraded after 4 hours across three different concentrations: A (>50% degradation), B (>20-50% degredation) and C (<20% degredation).

[005316] Table 19a. OCI-LY-10 % IRAK4 Degradation

<td> Compound Name</td><td> OCI-LY10 % IRAK4 Degradation (0.01 uM)</td><td> OCI-LY10 % IRAK4 Degradation (0.1 uM)</td><td> OCI-LY10 % IRAK4 Degradation (1 uM)</td>

1676

1677

1678

1679

1680

1681

[005317] Example 204a: OCI-LY-10 PC50

[005318] A MSD assay was run to determine the concentration of compound required to degrade 50% of protein (DC50).

[005319] MSD Assay DC50 Protocol

[005320] Day 1 • Compounds were reconstituted to 10 mM in stock solutions. The stock solutions were diluted to 5mM and 45 pL of each dilution was transferred to a 384 pp-plate. A 3 fold, 8-point serial dilution was performed by transferring 15 pL of compound into 30 pL DMSO using Janus.

• 20 nL of each compounds were added into each well of a 96-well plate (Corning3799).

• OCI-LylO cells were seeded into the 96-well plate at 3.0*10e5 cells/100 pL/well.

• The cell plate was shaken at 720 rpm for 5 min and incubated for 4 hr.

• The 100 pL of cells were transferred into the 96-PCR plate and spun down at high speed for 5 mins.

• The supernatant was discarded and 100 pL of RIPA lysis buffer with proteinase inhibitors

1682 was added per well. The plate was then sealed and shaken at 600 rpm and 4 °C for about 20 min.

• The plate was then spun down at high speed (about 3200g) for 30 min and then frozen in a °C fridge.

• A bare MSD plate (Ll 5XA-3) was coated with 2 pg/mL of capture antibody (mouse AntiIRAK4 antibody [2H9], abl 19942) in PBS to 40 pL/well and incubated overnight at 4 °C.

[005321] Day 2 • The MSD coated plate was washed 3x (150 pL/well) with lx TBST (CST#9997S).

• The MSD plate was then blocked with 150 pL of blocking buffer [3% Blocker A (MSD,

R93BA-4) in TBST]/well and shaken for 1 hr at RT and 600 rpm.

• The MSD plate was washed 3x (150 pL/well) with lx TBST. The sample RIPA lysates were then added to the MSD plate (50 pL/well) and shaken for 1 hr at RT and 600 rpm.

• The MSD plate was washed 3x (150 pL/well) with lx TBST and the primary detection antibody (Rabbit Anti-IRAK4 antibody [Y279], ab32511) was added to a final concentration of 1 pg/ml with 25 pL/well. The plate was then shaken for 1 hr at RT and 600 rpm.

• The MSD plate was washed 3x (150 pL/well) with lx TBST and the secondary detection antibody, SULFO-TAG anti-species antibody (Anti Rabbit Antibody (R32AB-5) MSD,R32AB-1) was added to a volume of 25 pL/well at a final concentration of 1 pg/ml. The plate was then shaken for 1 hr at RT and 600 rpm.

• The MSD plate was then washed 3x (150 pL/well) with lx TBST.

• lx MSD reading buffer was then added (150 pL/well) and the plate was diluted with 4x water. (MSD, R92TC-2) • The MSD instrument was then read.

[005322] Data analysis • The remaining activity was calculated following the formula below:

' - WW ~

[005323] Calculate • The DC50 was calculated by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom)/(1 + 10A((LogIC50 - X)*HillS10pe))

[005324] OCI-LY-10 DC50 results. The letter codes for IRAK4 DC50 indicate the concentration of compound required to degrade 50% of protein: A (<0.05 pM), B (0.05 - 0.1 pM), C (0.1 - 0.5 pM), D (0.5 - 1.0 pM), and E (>1.0 pM).

1683

[005325] Table 19b. OCI-LY-10 % IRAK4 DC50 Results

<td> Compound Name</td><td> OCI-LY10 IRAK4 DC50 (μΜ)</td>

1684

1685

1686

1687

1688

1689

1690

[005326] Example 204b: OCI-LY-10 EC50

1691

[005327] A CTG cell viability assay using OCI-LY-10 cells was run to determine compoundmediated cell viability (EC50).

[005328] Cell Viability Protocol

[005329] Compound-mediated viability effect on OCI-LY10 was quantitatively determined using the CellTiter-Glo® Luminescent Cell Viability Assay kit from Promega (Catalog number G7570) following manufacturer’s recommended procedures. Briefly, OCI-LY10 cells were seeded into 384 well plates (Grenier Bio-One, Catalog number 781080) with a density of 10,000 cells per well. Compounds were then added to the assay plate with final top concentration of 10μΜ and 1:3 dilution series with total of 9 doses. The final DMSO concentration was normalized to 0.2%. The assay plates were incubated at 37 °C for 4 days under 5% CO2. Then the assay plate was equilibrated at room temperature for 10 minutes. To determine cell viability, 30 pL CellTiter Gio reagent was added to each well and the assay plate was centrifuged at 1000 rpm for 30 second, incubated at room temperature for 10 min, and analyzed by detecting the luminescence using a multimode plate reader (EnVision 2105, PerkinElmer). The data was then analyzed by software Prism 7.0 from GraphPad and the dose response curves were fit using a three-parameter logistic equation to calculate EC50.

[005330] OCI-LY-10 EC50 results. The letter codes for IRAK4 EC50 indicate the concentration of compound required to affect 50% of cells: A (<0.05 μΜ), B (0.05 - 0.1 μΜ), C (0.1 - 0.5 μΜ), D (0.5 - 1.0 μΜ), and E (>1.0 μΜ).

[005331] Table 19c. OCI-LY-10 IRAK4 EC50 Results

<td> Compound Name</td><td> OCI-LY10 IRAK4 EC50 (μΜ)</td>

1692

1693

1694

1695

1696

[005332] Table 20: Compounds synthesized via Method 11 with the addition of various amines to fluoride Intermediate R in Step 1, followed by coupling with various acids in Step

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediat e Amine</td><td> Step 3 Intermediat e Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td> 1HNMR (400MHz, DMSO-d6) δ</td>

1697

<td> 206</td><td> 1-211</td><td> tert-butyl N[2-(2aminoethoxy ־( ethyl ]carb am ate CAS# 127828-222)</td><td> FX</td><td> 837.5</td><td> 11.08 (s, IH), 10.03 (s, IH), 8.98 (s, IH), 8.91 (s, IH), 8.62 (t, 7= 5.6 Hz, IH), 8.16 (d, 7= 5.2 Hz, IH), 8.04 - 7.92 (m, 4H), 7.59 - 7.53 (m, IH), 7.47-7.18 (m, IH), 7.177.00 (m, 5H), 6.63 (t, 7= 5.6 Hz, IH), 5.10-4.98 (m, IH), 3.693.63 (m, 2H), 3.63 - 3.58 (m, 2H), 3.53 - 3.43 (m, 4H), 3.19 (t, 7= 6.0 Hz, 2H), 2.95 - 2.79 (m, IH), 2.61 2.52 (m, 2H), 2.08 - 1.96 (m, IH), 1.12-1.01 (m, IH), 0.49 - 0.42 (m, 2H), 0.27-0.19 (m, 2H)</td>

<td> 207</td><td> 1-212</td><td> tert-butyl N[2-[2-[2-[2- ־2) aminoethoxy )-ethoxy]ethoxy] ethox yl. ethyl ]carb am ate (CAS# 811442-849)</td><td> FX</td><td> 991.0 (M+23)+</td><td> 11.08 (s, IH), 10.03 (s, IH), 8.98 (s, IH), 8.92 (s, IH), 8.63 (t, 7= 5.2 Hz, IH), 8.16 (d, 7= 5.2 Hz, IH), 8.07 - 7.95 (m, 4H), 7.61 - 7.53 (m, IH), 7.47-7.17 (m, IH), 7.157.06 (m, 3H), 7.06 - 7.00 (m, 2H), 6.59 (t, 7= 5.6 Hz, IH), 5.05 (dd, J = 5.6, 12.8 Hz, IH), 3.63 - 3.58 (m, 2H), 3.56 - 3.48 (m, 14H), 3.47 3.42 (m, 4H), 3.18 (t, 7 = 6.0 Hz, 2H), 2.94 - 2.82 (m, IH), 2.63 2.52 (m, 2H), 2.06 - 1.97 (m, IH), 1.12-1.02 (m, IH), 0.50 - 0.41 (m, 2H), 0.27 - 0.20 (m, 2H)</td>

1698

<td> 209</td><td> 1-214</td><td> tert-butyl N[2-[2-[2-[2[2-(2aminoethoxy )ethoxy]ethoxy] ethox yl. ethoxy] ethyl] -carbamate (CAS# 189209-27- 6)</td><td> KR</td><td> 929.1</td><td> 11.09 (s, IH), 10.82 (s, IH), 9.02 (s, IH), 8.44-8.38 (m, 2H), 8.258.23 (m, 2H), 7.56(dd, J = 12 Hz, J = 8.4 Hz, IH), 7.41 (s, IH), 7.25 (d, 7= 5.6 Hz, IH), 7.11 (d,7=8.4 Hz, IH), 7.01 (d, 7= 6.8 Hz, IH), 6.58 (bs, IH), 5.06-5.03 (m, IH), 4.37-4.36 (m, 2H), 3.93-3.91 (m, 6H), 3.53-3.44 (m, 22H), 2.88 (m, IH), 2.60-2.54 (m, 2H), 2.03-2.01 (m, IH)</td>

aFor varations in Method 11, see Table 9 footnotes.

[005333] Table 21: Compounds synthesized via Method 12 with the coupling of various amines and acids in Step 1.

<td> Ex-#</td><td> I-#</td><td> Step 1 Intermediat e Amine</td><td> Step 1 Intermediat e Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td> 1HNMR (400MHz, DMSO-d6) δ</td>

1699

1700

1701

1702

1703

1704

1705

1706

1707

1708

<td> 240</td><td> 1-245</td><td> tert-butyl N[2-[5-[[2(2,6-di oxo-3piperidyl)1,3-di oxoisoindolin-4yl]amino]pentylamino] ethyl ]carb am ate (synthesized via Steps 1-4 of Example 144)</td><td> FX</td><td> 878.2</td><td> 11.24- 11.01 (m, IH), 10.09 (s, IH), 9.00 (s, IH), 8.93 (s, IH), 8.69 (s, IH), 8.34 (s, IH), 8.17 (d, 7 = 5.2 Hz, IH), 8.02 (d, J= 10.4 Hz, 3H), 7.58 (s, IH), 7.33 (s, IH), 7.21 - 7.03 (m, 4H), 6.55 (s, IH), 5.05 (s, IH), 3.19 (s, 6H), 2.95-2.91 (m, IH), 2.87 (d, J = 14.8 Hz, 2H), 2.83 - 2.80 (m, IH), 2.78 - 2.74 (m, IH), 2.68 - 2.65 (m, 2H), 2.04 2.02 (m, IH), 1.66 - 1.33 (m, 6H), 1.08 - 1.05 (m, IH), 0.47 (d, J= 7.2 Hz, 2H), 0.24 (s, 2H)</td>

1709

1710

1711

1712

1713

1714

1715

1716

1717

1718

1719

1720

1721

1722

1723

<td> 286</td><td> 1-291</td><td> KP</td><td> 2-[2-[2-[[2(2,6-dioxo-3piperidyl)1,3-di oxoisoindolin-4yl]amino]ethoxy] ethox y]acetic acid (synthesized via Steps 1-2 of Example 160)</td><td> 860.4</td><td> 11.1 (s, IH), 10.3 (s, IH), 9.88 (s, IH), 8.98 (s, IH), 8.37 (s, IH), 8.22 (s, IH), 8.17 (d, J = 5.6 Hz, IH), 7.78 (d, J = 8.8 Hz, 2H), 7.58 (t, J = 7.6 Hz, IH), 7.43 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, IH), 7.14 - 7.08 (m, 2H), 7.05 - 7.01 (m, 2H), 6.69 - 6.59 (m, IH), 5.10 - 5.00 (m, IH), 4.13 (s, 2H), 3.75 - 3.63 (m, 6H), 3-56-3.51 (m, 2H), 3.25 3.02 (m, 2H), 2.93 - 2.86 (m, IH), 2.63 - 2.59 (m, IH), 2.59 - 2.56 (m, IH), 2.03 - 1.99 (m, IH), 1.13 1.07 (m, IH), 0.49 - 0.43 (m, 2H), 0.27 - 0.21 (m, 2H)</td>

<td> 287</td><td> 1-292</td><td>]-2]-2]-4 ־2) aminoethoxy ־( ethoxy] ethox yl. ethylamino]2-(2,6-dioxo3-piperidyl)isoindoline1,3-di one (synthesized via Steps 1-2 of Example 128)</td><td> KR</td><td> 841.1</td><td> 11.08 (s, IH), 10.81 (s, IH), 8.97 (s, IH), 8.38 (s, IH), 8.25 (d, J= 5.6 Hz, IH), 8.21 (s, IH), 7.71 7.65 (m, IH), 7.56 (t, J= 8.0 Hz, IH), 7.25 (s, IH), 7.17 (d, J= 5.6 Hz, IH), 7.11 (d, J= 8.4 Hz, IH), 7.02 (d, J= 7.2 Hz, IH), 6.58 (s, IH), 5.04 (dd, 7=5.6, 12.8 Hz, IH), 4.33 - 4.17 (m, 2H), 3.93 (s, 3H), 3.61 (t, J= 5.2 Hz, 2H), 3.55 (d, J= 4.8 Hz, 10H), 3.46 (d, J = 4.8 Hz, 4H), 2.91 - 2.83 (m, IH), 2.60 - 2.56 (m, IH), 2.56 - 2.52 (m, IH), 2.08 - 2.00-(m, IH)</td>

1724

1725

1726

<td> 295b</td><td> 1-300</td><td>]-2]-2]-4 ־2) aminoethoxy ־( ethoxy] ethox y]ethylamino ]-2-(2,6di oxo-3piperidyl)isoindoline1,3- dione (synthesized via Steps 1-2 of Example 128)</td><td> MF</td><td> 667.3</td><td> 11.10 (s, IH), 10.82 (s, IH), 8.82 (d, 7= 0.8 Hz, IH), 8.60 (d, 7= 0.8 Hz, IH), 8.33 (s, IH), 8.21 (t,7 = 5.6 Hz, IH), 7.56 (dd, 7= 7.2, 8.4 Hz, IH), 7.11 (d,7= 8.4 Hz, IH), 7.02 (d, 7= 7.2 Hz, IH), 6.59 (t, 7 = 5.6 Hz, IH), 5.05 (dd, 7= 5.2, 12.8 Hz, IH), 3.91 (s, 3H), 3.63 - 3.57 (m, 2H), 3.57-3.49 (m, 10H), 3.47 - 3.39 (m, 4H), 2.93 - 2.82 (m, IH), 2.63 - 2.52 (m, 2H), 2.08 - 1.97 (m, IH)</td>

<td> 296b</td><td> 1-301</td><td>]-2]-2]-4 ־2) aminoethoxy )-ethoxy] ethoxy]ethylamino]2-(2,6-dioxo3-piperidyl)isoindoline1,3-di one (synthesized via Steps 1-2 of Example 128)</td><td> MI</td><td> 744.1</td><td> 11.08 (s, IH), 10.89 (s, IH), 9.07 (s, IH), 8.83 (d, 7 = 6.4 Hz, 2H), 8.38 (s, IH), 8.25 - 8.22 (m, IH), 7.94 (d, 7 = 6.0 Hz, 2H), 7.57 7.53(m, IH), 7.10 (d, 7= 8.8 Hz, IH), 7.01 (d, 7 = 6.4 Hz, IH), 6.59 - 6.56 (m, IH), 5.07 - 5.02 (m, IH), 3.93 (s, 3H), 3.61 - 3.59 (m, 2H), 3.55 - 3.54 (m, 1 OH), 3.46 - 3.43 (m, 4H), 2.87 - 2.86 (m, IH), 2.82 2.56 (m, 2H), 2.04 - 2.01 (m, IH)</td>

aFor variations on Method 12, see Table 10. bN0 deprotection Step 2 was required.

[005334] Further Examples using synthetic methods similar to Method 12:

[005335] Example 281:[(3R,5S) [[4-[4-[[2-[2-(cvclopropylmethvlamino)-41727

Pvridvlloxazole carbonvl]aminol-3

-(difluoromethvl)pvrazol-lvl1phenvl1methvlcarbamovl]-l-[(2S) [[2-[2-[2-[2-[[2-(2.,6-dioxo piperidvl)-l.,3-dioxoisoindolin yl] amino] ethoxy] ethoxy] ethoxy] acetyl] amino]-3.,3-dimethvlbutanoyl] pyrrolidin yl] (2S)-pvrrolidine carboxylate, 1-286

[005336] To a solution of 01-benzyl O2-[(3R,5S) [[4-[4-[[2-[2(cyclopropylmethylamino) pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]phenyl]methylcarbamoyl]-l-[(2S) [[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxoisoindolin yl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]pyrrolidin-3yl] (2S)-pyrrolidine-l,2-dicarboxylate (140 mg, 101 umol, synthesized via Method 12 with Intermediate KJ as the amine and 2-(2-(2-(2-((2-(2,6-dioxopiperidin yl)-l,3-dioxoisoindolin-4yl)amino)ethoxy)ethoxy)ethoxy)aceticacid, syntheisized via Steps 1-2 of Example 152, as the acid in Step 1) in DCM (4 mL) was added HBr/HOAc (101 umol, 2 mL, 33% solution), and the reaction

1728 mixture was stirred at rt for 1.5 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10um;mobile phase: [water(0.225%FA)-ACN];B%: 21%-41%,8min) to give the title compound (42.9 mg, 32% yield) as a white solid. 1HNMR (400MHz, DMSO-t/6) 11.07 (s, IH), 9.95 (s, IH), 8.96 (s, IH), 8.78 (s, IH), 8.64 (t, J = 6.0 Hz, IH), 8.16 (d, J = 52 Hz, IH), 7.85 7.71 (m, 2H), 7.55 (t, J = 8.0 Hz, IH), 7.48 - 7.14 (m, 4H), 7.14 - 7.09 (m, 2H), 7.08 - 7.05 (m, IH), 7.04 - 6.98 (m, 2H), 6.62 - 6.53 (m, IH), 5.30 (s, IH), 5.04 (dd, J= 52, 12.8 Hz, IH), 4.54 4.35 (m, 3H), 4.32 - 4.24 (m, IH), 3.98 - 3.89 (m, 3H), 3.87 - 3.82(m, IH), 3.70 - 3.58 (m, 11H), 3.48 - 3.40 (m, 2H), 3.19 (t, J= 6.0 Hz, 2H), 2.93 - 2.83 (m, 2H), 2.80 - 2.72 (m, IH), 2.63 - 2.54 (m, 2H), 2.29 - 2.22 (m, IH), 2.18 - 1.87 (m, 4H), 1.77 - 1.69 (m, IH), 1.68 - 1.53 (m, IH), 1.09 1.02 (m, IH), 1.00 - 0.90 (m, 9H), 0.49 - 0.41 (m, 2H), 0.26 - 0.19 (m, 2H); LC-MS (ESI+) m/z 1248.3 (M+H)+.

[005337] Example 284:[(3R.,5S) [[4-[4-[[2-[2-(cvclopropvlmethvlamino)-4Pvridvl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]phenyl]methylcarbamoyl]-l-[2-[2-[2-[2-[[2-(2.,6-dioxo piperidyl)-l.,3-dioxo-isoindolin4-yl] amino] ethoxy] ethoxy] ethoxy] acetyl] pyrrolidin yl] (2S)-pyrrolidine carboxylate., I289

1729

F

[005338] To a solution of Ol-benzyl O2-[(3R,5S) [[4-[4-[[2-[2(cyclopropylmethylamino) pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-lyl]phenyl]methylcarbamoyl]-l-[2-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy]ethoxy]acetyl]pyrrolidin yl](2S)-pyrrolidine-l,2-dicarboxylate (70 mg, 55.1 umol, synthesized via Step 1 of Method 12, coupling amine intermediate KI with 2-(2(2-(2-((2-(2,6-Dioxopiperidin yl)-l,3-di ox oisoindolin yl)amino)ethoxy)ethoxy) ethoxy)acetic acid (synthesized via Steps 1-2 of Example 152) as the acid) in DCM (2 mL) was added HBr/AcOH (4 M, 1 mL, 33 wt%), and the reaction mixture was stirred at rt for 4 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um;mobile phase: [water(0.225%FA)-ACN];B%: 10%-37%,2min) to give the title compound (40.7 mg, 61% yield) as a yellow solid. 1H NMR (400MHz, DM SO-6/6) δ 1H NMR (400MHz, DMSO-/6) δ 11.07 (s, IH), 9.95 (s, IH), 8.96 (s, IH), 8.79 (s, IH), 8.57 (t, J= 5.6 Hz, IH), 8.16 (d, J= 5.2 Hz, IH), 7.85

1730 .76 (m, 2H), 7.61 - 7.53 (m, IH), 7.43 (d, J= 8.4 Hz, 2H), 7.41 - 7.09 (m, 3H), 7.09 - 6.97 (m, 3H), 6.64 - 6.52 (m, IH), 5.29 (s, IH), 5.04 (dd, J = 5.6, 12.8 Hz, IH), 4.42 (t, J = 7.6 Hz, IH), 4.38 - 4.30 (m, 2H), 4.14 - 4.03 (m, 2H), 3.85 - 3.64 (m, 4H), 3.63 - 3.59 (m, 4H), 3.51 - 3.41 (m, 8H), 3.22 - 3.02 (m, 2H), 2.92 - 2.84 (m, 2H), 2.80 - 2.74 (m, IH), 2.64 - 2.55 (m, 2H), 2.27 - 2.20 (m, IH), 2.15-2.06 (m, IH), 2.04- 1.92 (m, 2H), 1.77- 1.69 (m, IH), 1.68 - 1.57 (m, 2H), 1.11 1.01 (m, IH), 0.49 - 0.42 (m, 2H), 0.23 (q, J= 4.8 Hz, 2H); LC-MS (ESI+) m/z 1135.7 (M+l)+.

[005339] Example 297: N-[3-carbamovl-l-[4-[[4-[2-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin vl]amino]

4-yl] [2-(2.,2.,2-trifluoroethvlamino) pvridvl]oxazole carboxamide, 1-302

NaHCO3, CH3CN

1731

[005340] To a mixture of N-[3-carbamoyl-l-[4-(morpholin-2ylmethoxymethyl)phenyl]pyrazol yl] [2-(2,2,2-trifluoroethylamino) pyridyl]oxazole-4carboxamide (70.0 mg, 109.89 umol, HCI, synthesized via Steps 1-2 of Method 12 coupling amine tert-butyl 2-[[4-(4-amino carbamoyl-pyrazol-l-yl)phenyl]methoxymethyl] morpholine-4carboxylate, Intermediate MK, and acid 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4pyridyl]oxazole carboxylic acid, Intermediate CM, in Step 1) in MeCN (10 mL) was added NaHCO3 (36.93 mg, 439.55 umol). Then 2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo- isoindolin4-yl]amino]ethoxy]ethyl methanesulfonate (48.29 mg, 109.89 umol, synthesized via Steps 1-2 of Example 184) was added into the mixture. The mixture was stirred at 80 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)ACN]; B%: 25%-42%, 6 min) to give the title compound (42.0 mg, 35% yield) as a yellow solid. 1HNMR (400MHz, DMSO-76) δ 11.09 (s, IH), 11.00 (s, IH), 9.02 (s, IH), 8.92 (s, IH), 8.24 (s, IH), 8.06 - 8.02 (m, IH), 8.04 (s, IH), 7.94 (d, J = 8.4 Hz, 2H), 7.74 - 7.66 (m, 2H), 7.60 - 7.53 (m, IH), 7.46 (d, J= 8.4 Hz, 2H), 7.26 (s, IH), 7.19 - 7.10 (m, 2H), 7.02 (d, J= 7.2 Hz, IH), 6.59 (t, 7= 5.6 Hz, IH), 5.09-5.01 (m, IH), 4.51 (s, 2H), 4.29 - 4.18 (m, 2H), 3.79-3.68 (m, IH), 3.58 (d, 7= 5.6, 15.2 Hz, 9H), 3.39 (d, 7= 4.8 Hz, 4H), 2.92 - 2.75 (m, 2H), 2.72 - 2.53 (m, 3H), 2.33 (td, 7= 1.8, 9.2 Hz, IH), 2.08 - 1.97 (m, IH), 2.10 - 1.97 (m, IH); LC-MS (ESI+) m/z 944.1 (M+H)+.

[005341] Example 298: N-[3-carbamovl-l-[4-[n-[2-[2-[[2-(2,6-dioxo DiDeridvD-l,3dioxo-isoindolin vl]amino] vl] [2-(2,2,2-trifluoroethvlamino) pvridvl]oxazole carboxamide, 1-303

1732

[005342] To a mixture of N-[3-carbamoyl-l-[4-(2-piperidylmethoxymethyl)phenyl]pyrazol4-yl] [2-(2,2,2- trifluoroethylamino) pyridyl]oxazole carboxamide (70.0 mg, 110.2 umol, HCI, synthesized via Method 12 coupling amine tert-butyl 2-[[4-(4-amino carbamoyl-pyrazoll-yl)phenyl]methoxymethyl]piperidine carboxylate, Intermediate MM and acid 2-[2-[tertbutoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl] oxazole carboxylic acid, Intermediate CM in Step 1) in CH3CN (10 mL) was added NaHCO3 (37.0 mg, 441 umol). Then 2-[2-[[2-(2,6

1733 dioxo piperidyl)-l,3-dioxo-isoindolin- 4-yl]amino]ethoxy]ethyl methanesulfonate (48.4 mg, 110 umol, synthesized via Steps 1-2 of Example 184) was added into the mixture. The mixture was stirred at 80 °C for 24 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 22%-42%, 7 min) to give the title compound (32.8 mg, 30% yield) as a yellow solid. 1H NMR (400MHz, DM SO-0/6) δ 11.09 (s, IH), 11.00 (s, IH), 9.03 (s, IH), 8.92 (s, IH), 8.28 - 8.25 (m, 3H), 8.04 ( s, IH), 7.93 (d, J = 8.4 Hz, 2H), 7.74 - 7.66 (m, 2H), 7.59 -7.53 (m, IH), 7.46 (d, J= 8.4 Hz, 2H), 7.28 (s, IH), 7.19 (d, J= 4.0 Hz, IH), 7.12 (d, 7 = 8.4 Hz, IH), 7.02 (d, 7= 7.2 Hz, IH), 6.58 (s, IH), 5.05 (dd, 7= 5.6, 12.8 Hz, IH), 4.49 (s, 2H), 4.25 (dd, 7= 6.0, 9.2 Hz, 2H), 3.60 - 3.55 (m, 6H), 3.51 (s, 7H), 2.87 - 2.85 (m, 4H), 2.70 2.64 (m, 3H), 2.34 - 2.14 (m, 2H), 1.60 (s, 3H), 1.36 - 1.24 (m, IH). LC-MS (ESI+) m/z 942.2 (M+H)+.

[005343] Example 299: N-[3-carbamovl-l-[[l-[2-[2-[2-[[2-(2,6-dioxo DiDeridvD-l,3dioxo-isoindolin vl]amino] (cvcloDroDvlmethvlamino) Dvridvl]oxazole carboxamide., 1-304

1734

[005344] Step 2 - Tert-butyl N-[4-[4-IT3-carbamovl-l-ITI-[2-[2-[2-IT2-(2.6-dioxo-3piperidyl)-L3-dioxovl1carbamoyl1oxazol yl1 pyridvl1-N-(cyclopropylmethyl)carbamate

To a solution of tert-butyl N-[4-[4-[(3-carbamoyl-l-prop ynyl-pyrazol yl)carbamoyl]oxazol2-yl]- 2-pyridyl]-N-(cyclopropylmethyl)carbamate (106 mg, 209 umol, synthesized via Step 1 of Method 12 coupling amine 4-amino-l-prop ynyl-pyrazole carboxamide, Intermediate MT with acid 2-[2-[tert- butoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carboxylic acid, synthesized via Steps 1-4 of Intermediate DF) and 4-(2-(2-(2azidoethoxy)ethoxy]ethylamino] (2,6-dioxo- 3-piperidyl)isoindoline-l,3-dione (60.0 mg, 139

1735 umol, Intermediate MS) in t-BuOH (5 mL) was added CuSO4 (4.6 mg, 28.8 umol, 4.42 uL) and sodium;(2R) [(lS)-l,2-dihydroxyethyl] hydroxy oxo-2H-furan 01 ate (11.1 mg, 55.8 umol) in H20 (5 mL). The reaction mixture was stirred at 60 °C for 2 hours under nitrogen. On completion, the reaction mixture was poured into brine (30 mL) and extracted with EA (3 X 50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (140 mg, 99% yield) as a light yellow solid. LC-MS (ESI+) m/z 936.5 (M+H)+.

[005345] Step 3 - N-r3-carbamoyl-l-rr1-r2-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 ethoxy1ethoxy1ethyl1triazol yl1methyl1pyrazol yl1 [2(cyclopropylmethylamino) pyridyl1oxazole carboxamide

To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[[l-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3dioxo -isoindolin yl]amino]ethoxy]ethoxy]ethyl]triazol yl]methyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (140 mg, 150 umol) in DCM (5 mL) was added HCI/dioxane (4 M, 10 mL). The reaction mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo and purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 18%-3 5%, 6 min). The purity of product was only 85%. Then the impure product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl) - ACN]; B%: 16%-36%, 7.8 min) to give the title compound (6.40 mg, 5% yield) as a yellow solid. 1HNMR (400 MHz, DM SO-6/6) δ 11.09 (s, IH), 10.99 (s, IH), 9.47 (s, IH), 9.09 (s, IH), 8.44 (s, IH), 8.13 (s, IH), 8.06 (d, J= 6.0 Hz, IH), 7.81 (s, IH), 7.63 (s, IH), 7.58 - 7.50 (m, 2H), 7.18 - 7.23 (m, IH), 7.07 (d, J= 8.8 Hz, IH), 6.99 (d, J= 6.4 Hz, IH), 6.54 (s, IH), 5.50 (s, 2H), 5.10 - 4.94 (m, IH), 4.51 (t, J = 4.8 Hz, 2H), 3.93 - 3.66 (m, 2H), 3.55 - 3.52 (m, 6H), 3.45-3.28 (m, 4H), 2.90 - 2.78 (m, IH), 2.61 - 2.56 (m, IH), 2.05 - 1.96 (m, IH), 1.19 - 1.09 (m, IH), 0.60 - 0.53 (m, 2H), 0.36 - 0.29 (m, 2H). LC-MS (ESI+) m/z 836.1 (M+H)+.

[005346] Example 300: (Method 16) N-[3-carbamovl-l-[4-[[[4-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l.,3-dioxo-isoindolin vl]amino]ethoxy] ethyl] morpholin-2yl] methylamino] methyl] phenyl] pvrazol vl] [2-(22,.2&#1524;-trifluoroethvlamino)-4pyridyl] oxazole car boxamide., 1-305

1736

[005347] Step 1- Tert-butyl Ν-Γ4-[4-ΓΓ3^Α^ιηον1 Γ4-ΓΓΓ4-Γ2-Γ2-ΓΓ2-(2,6-&#940;&#912;οχο-3piperidyl)-L3-dioxo-isoindolin yl1amino1ethoxy1ethyl1morpholin-2yl1methylamino1methyl1phenyl1pyrazol yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2trifluoroethyDcarbamate

[005348] To a mixture of 4-[2-[2-[2-(aminomethyl)morpholin yl]ethoxy]ethylamino]-2(2,6-dioxo piperidyl)isoindoline-l,3-dione (60.0 mg, 120 umol, HCI salt, Intermediate EJ) in DCM (5 mL) was added TEA (18.3 mg, 181 umol), HOAc (14.5 mg, 241 umol) and tert-butyl N[4-[4-[[3-carbamoyl- l-(4-formylphenyl)pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N(2,2,2-trifluoroethyl)carbamate (96.7 mg, 120 umol, Intermediate GY). The mixture was stirred for 30 minutes, and then NaBH(OAc)3 (51.2 mg, 241 umol) was added. The mixture was then stirred rt for 16 hours. On completion, the reaction mixture was quenched by addition water (0.4 mL), and then concentrated in vacuo to give the title compound (120 mg, 95% yield) as yellow solid. LC-MS (ESI+) m/z 1043.6 (M+H)+.

1737

[005349] Step 2 - N-r3-carbamoyl-l-r4-rrr4-r2-r2-rr2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl]amino]

2-r2-(2,2,2-trifluoroethylamino) pyridvl]oxazole carboxamide

To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[[4-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3dioxo-isoindolin yl]amino]ethoxy]ethyl]morpholin yl]methylamino]methyl]phenyl]pyrazol4-yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (120 mg, 115 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 1.03 mL). The mixture was stirred at rt for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]) to give the title compound (72.2 mg, 63% yield) as yellow solid. 1H NMR (400MHz, DMSO4) δ 11.01 (s, IH), 9.03 (s, IH), 8.92 (s, IH), 8.25 (d, J= 5.2 Hz, IH), 8.20 (s, IH), 8.06 (s, IH), 7.91 (d, J= 8.4 Hz, 2H), 7.73 - 7.69 (m, IH), 7.59 - 7.55 (m, IH), 7.49 (d, J = 8.4 Hz, 2H), 7.26 (s, IH), 7.20 - 7.11 (m, 2H), 7.03 (d, J = 6.8 Hz, IH), 6.60 (t, J = 5.6 Hz, IH), 5.05 (dd, J= 5.6, 12.8 Hz, IH), 4.33 - 4.19 (m, 2H), 3.78 (s, 2H), 3.72 (d, J = 12 Hz, 2H), 3.59 (t, J= 5.2 Hz, 2H), 3.55 (t, J= 6.0 Hz, 2H), 3.48 - 3.44 (m, 3H), 2.89 - 2.77 (m, 2H), 2.70 (d, J= 12.4 Hz, IH), 2.62 - 2.55 (m, 2H), 2.49 - 2.43 (m, 4H), 2.07 - 1.97 (m, 2H), 1.80 (t, J= 10.8 Hz, IH); LC-MS (ESE)/&#1524; z 943.1 (M+H)+.

[005350] Table 22: Compounds synthesized via Method 16 with the reductive amination of various amines with aldehydes in Step 1.

<td> Ex- #a’e</td><td> I-#</td><td> Step 1 Intermediat e Amine</td><td> Step 1 Intermediat e Aldehyde</td><td> LCMS (ES+) m/z (M+H)+</td><td> 1HNMR (400MHz, DMSO-d6) δ</td>

1738

1739

1740

1741

1742

1743

1744

1745

1746

1747

<td> 328</td><td> 1-333</td><td> HV</td><td> Tert-butyl N[4-[4-[[3carbamoyl-1[4-(5oxopentylcarbamoyl)phenyl]pyrazol-4-yl] carbamoyl]oxazol-2-yl]2-pyridyl]-N(2,2,2trifluoroethyl )-carbamate (synthesized via Steps 1-2 of Example 172)</td><td> 885.1</td><td> 11.02 (s, IH), 9.03 (s, 2H), 8.56 (t, J = 5.6 Hz, IH), 8.29 - 8.23 (m, 2H), 8.13 (s, IH), 8.10 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.79 (d, J= 15.2 Hz, 2H), 7.70 (t, J = 6.0 Hz, IH), 7.60 - 7.52 (m, IH), 7.27 (s, IH), 7.18 (dd, J = 1.2 Hz, IH), 7.09 (d, J= 8.2 Hz, IH), 6.99 (d, J= 7.2 Hz, IH), 6.78 (t, J = 5.6 Hz, IH), 4.51 (dd, J= 6.0, 12.0 Hz, IH), 4.30 - 4.20 (m, 2H), 3.42 3.16 (m, 6H), 2.83 (t, J= 5.6 Hz, 2H), 2.69 - 2.59 (m, 2H), 2.27 2.17 (m, IH), 2.03 - 1.82 (m, 3H), 1.61 - 1.45 (m, 4H), 1.42 - 1.34 (m, 2H)</td>

1748

1749

1750

1751

1752

1753

1754

1755

1756

1757

1758

1759

1760

1761

1762

1763

1764

1765

1766

1767

1768

1769

1770

1771

1772

<td> 403</td><td> 1-408</td><td>]-2]-2]-4 ־2) aminoethoxy ־( ethoxy] ethox yl. ethylamino]2-(2,6-dioxo3-piperidyl)isoindoline1,3-di one (synthesized via Steps 1-2 of Example 128)</td><td> LS</td><td> 827.5</td><td> 11.08 (s, 1 H), 10.09 (s, 1 H), 8.92 (s, 1 H), 8.88 (s, 2 H), 8.23 (d, / = 5.2 Hz, 1 H), 8.03 (s, 1 H), 7.63 7.55 (m, 2 H), 7.24 - 7.21 (m, 2 H), 7.11 (d,/= 8.8 Hz, 1 H), 7.03 (d, / = 6.8 Hz, 1 H), 6.56 (s, 1 H), 5.06 5.01 (m, IH), 4.30-4.13 (m, 5 H), 3.87 (s, 2 H), 3.70 - 3.67 (m, 3 H), 3.60 - 3.57 (m, 3 H), 3.54 - 3.52 (m, 4 H), 3.46 - 3.36 (m, 3 H), 3.18 (m, 2 H), 2.94 - 2.83 (m, 1 H), 2.63 2.53 (m, 2 H), 2.05 - 1.96 (m, 1 H)</td>

<td> 404</td><td> 1-409</td><td> 4-[2-[3-(2aminoethoxy )-propoxy]ethylamino]2-(2,6-dioxo3-piperidyl)isoindoline - 1,3-di one (synthesized via Steps 1-2 of Example 208,1-213)</td><td> GC</td><td> 874.3</td><td> 10.99 (s, 1 H), 8.99 (s, 1 H), 8.94 8.89 (m, IH), 8.23 (s, IH), 8.16 (d, /= 5.2 Hz, IH), 8.03 (s, IH), 7.90 (d, /= 8.4 Hz, 2H), 7.72 (s, IH), 7.59 - 7.54 (m, IH), 7.48 (d, /= 8.4 Hz, 2H), 7.19 - 7.11 (m, 3H), 7.05 6.98 (m, 2H), 6.59 (m, IH), 5.05 (m, IH), 3.78 (s, 2H), 3.59 - 3.54 (m, 11H), 3.19 (m, 2H), 2.92-2.83 (m, IH), 2.67 (m, 2 H), 2.61 - 2.55 (m, 2 H), 2.06 - 1.98 (m, 1 H), 1.74 (t,/= 6.36 Hz, 2 H), 1.11 - 1.03</td>

1773

1774

1775

1776

1777

aFor Method 16, when the amine is the HC1 salt, TEA was added to free base the salt, followed by

HOAc to adjust the pH to 3-4. KOAc could also be used in place of the TEA/HOAc combination. bTFA not HC1 was used for the deprotection in Step 2. 0No deprotection Step 2 required. dCoupling partner was a ketone not aldehyde. 6Steps 1-2 was run anywhere from 0.5-48 hrs.

[005351] Further Examples:

[005352] Example 419: N-[3-carbamovl-l-[4-[2-[2-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin yl]amino]ethoxy] ethoxy] ethylcarbamoyl] phenyl] pyrazoI vI] (2cvclopropvl pyridvl)oxazole carboxamide, 1-424

1778

[005353] N-[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino] ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol yl] (2-cyclopropyl-4pyridyl)oxazole carboxamide was synthesized via Method 10, coupling amine methyl 4-(4amino carbarn oyl-pyrazol yl )benzoate (Intermediate CL) and acid 2-(2-cyclopropyl-4pyridyl)oxazole carboxylic acid (Intermediate MQ) in Step 1, and coupling amine 4-(2-(2-(2aminoethoxy)ethoxy]ethylamino] (2,6-dioxo piperidyl)isoindoline-l,3-dione (synthesized via Steps 1-2 of Example 127) in Step 3. The final product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 33%53%, 7 min) to give the title compound (29.0 mg, 14% yield) as a yellow solid. 1H NMR (400 MHz, DMSO4) δ 11.14 - 11.04 (m, 2H), 9.10 (s, IH), 9.03 (s, IH), 8.66 - 8.61 (m, 2H), 8.15 (s, IH), 8.11 - 8.06 (m, 2H), 8.04 - 7.98 (m, 2H), 7.88 - 7.81 (m, 2H), 7.69 (dd, J= 1.2, 5.6 Hz, IH),

1779

7.58 - 7.52 (m, IH), 7.11 (d, J= 8.8 Hz, IH), 7.01 (d, J= 6.8 Hz, IH), 6.60 (t, J= 5.6 Hz, IH),

5.11 - 4.90 (m, IH), 3.64 - 3.53 (m, 8H), 3.49 - 3.40 (m, 5H), 2.92 - 2.83 (m, IH), 2.68 - 2.53 (m,

IH), 2.34-2.26 (m, 2H), 2.15 -1.89 (m, 2H), 1.07-0.96 (m, 4H). LC-MS (ESI+)m/z 845.2 (M+H)+.

[005354] Example 420: 4-[2-[4-[2-[2-[2-[2-n2-(2,6-Dioxo piperidyD-L3-dioxoisoindolin vl]amino]ethoxy] 4-fluoro oxo-pvrrolidin vl]methoxy| methoxv-isoquinoline carboxamide, 1-425

1780

FJ

1781

[005355] Step 1:2-(2,6-Ρ&#912;οχο ρ&#912;ρ6Γ&#938;&#940;ν1) [2-Γ2-Γ2-Γ2-(4iodophenoxylethoxy] ethoxy] ethoxy] ethyl amino] i soindoline-1,3 -di one

[005356] To a solution of 2-[2-[2-[2-(4-iodophenoxy)ethoxy]ethoxy]ethoxy]ethanamine (800 mg, 1.85 mmol, HCI, Intermediate FJ) and 2-(2,6-dioxo piperidyl) fluoro-isoindoline1,3-dione (511 mg, 1.85 mmol, Intermediate R) in dioxane (10 mL) was added DIPEA (1.20 g, 9.27 mmol, 1.61 mL), and the reaction mixture was stirred at 115 °C for 16 hr. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (900 mg, 75% yield) as yellow solid. LC-MS (ESI+) m/z 652.3 (M+H)+.

[005357] Step 2:2-(2,6-Ρ&#943;οχο ρ&#943;ρ6Γ&#938;&#940;ν1) Γ2-Γ2-Γ2-Γ2-Γ4-(2trimethyl silylethynyl)phenoxv1 ethoxy] ethoxy] ethoxy] ethyl aminoli soindoline-1.3 -dione

[005358] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-[2-[2-(4iodophenoxy)ethoxy]ethoxy]ethoxy] ethylamino]isoindoline-1,3-dione (800 mg, 1.23 mmol), Pd(PPh3)2C12 (25.8 mg, 36.8 umol) and Cui (7.02 mg, 36.8 umol) in TEA (10 mL) was added ethynyl(trimethyl)silane (241 mg, 2.46 mmol, 340 UI, CAS# 1066 2), and the reaction mixture was stirred at 80 °C for 12 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (800 mg, 93% yield) as yellow oil. LC-MS (ESI+) m/z 622.2 (M+H)+.

[005359] Step 3:2-(2,6-Ρ&#912;οχο ρ&#912;ρ6Γ&#938;&#940;ν1) [2-Γ2-Γ2-Γ2-(4ethynylphenoxylethoxy]ethoxy]ethoxy]ethyl aminolisoindoline-1.3-dione

[005360] To a solution of 2-(2,6-dioxo piperidyl) [2-[2-[2-[2-[4-(2trimethylsilylethynyl)phenoxy]ethoxy] ethoxy]ethoxy]ethylamino]isoindoline-l,3-dione (700 mg, 1.13 mmol) in THF (10 mL) was added TBAF (883 mg, 3.38 mmol), and the reaction mixture was stirred at 20 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (500 mg, 81% yield) as a yellow solid. LC-MS (ESI+) m/z 550.3 (M+l)+.

[005361] Step 4 - 4-Γ2-Γ4-Γ2-Γ2-Γ2-Γ2-ΓΓ2-(2,6-Ρ&#912;οχο ρ&#912;ρ61&#906;&#940;ν1)-Ε3-&#940;&#912;οχο-&#912;5ο&#912;η&#940;ο1&#912;η-4yl1amino1ethoxy1 pyrrolidin yl1methoxy1 methoxy-isoquinoline carboxamide

[005362] To a solution of 4-bromo-l-[[(2S,3S,4S) ethyl fluoro oxo-pyrrolidin-2yl]methoxy] methoxy -isoquinoline carboxamide (20.0 mg, 45.4 umol, synthesized via Steps

1782

1-2 of Example 126), Cui (4.33 mg, 22.7 umol), Pd(PPh3)2C12 (15.9 mg, 22.7 umol) in DMF (2 mL) was added 2-(2,6-dioxo piperidyl) [2-[2-[2-[2- (4ethynylphenoxy)ethoxy]ethoxy]ethoxy]ethylamino]-isoindoline-l,3-dione (50.0 mg, 90.9 umol) and TEA (82.8 mg, 818 umol, 113 uL). The reaction mixture was degassed with N2 for 5 minutes, and then heated at 120 °C for 3 hours under microwave. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in DCM (20 mL) and thiourea (resin) (50 mg) was added. The mixture was stirred at 20 °C for 2 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min) to give the title compound (4.19 mg, 9.85% yield) as yellow solid. 1HNMR (400MHz, DMSO-6/% δ 11.10 (s, IH), 8.89 (s, IH), 8.18 (s, IH), 7.95 (s, IH), 7.79 (s, 2H), 7.61 - 7.40 (m, 4H), 7.12 (d, J= 8.4 Hz, IH), 7.01 (d, J = 8.0 Hz, 3H), 6.61 - 6.54 (m, IH), 5.04 (dd, J= 4.8, 12.4 Hz, IH), 4.99 - 4.82 (m, IH), 4.60 4.52 (m, IH), 4.30 (dd, J = 5.6, 10.8 Hz, IH), 4.16 - 4.06 (m, 3H), 3.98 (s, 3H), 3.75 - 3.68(m, 3H), 3.60-3.55 (m, 12H), 2.93 - 2.75(m, IH), 2.63 - 2.60 (m, IH), 2.59 - 2.57 (m, IH), 2.08 - 1.94 (m, IH), 1.67 - 1.50 (m, 2H), 1.01 (t, J= 7.2 Hz, 3H); LC-MS (ESI+) m/z 909.5 (M+H)+.

[005363] Example 421: 2-[2-(Cvcl0Dr0Dvlmethvlamin0) Dvridvl]-N-[l-[2-[2-[2-[2[[2-(2,6-dioxo piperidyl)

5-vl] (trifluoromethvl)pvrazol yl]oxazole carboxamide, 1-426

1783

FM

HATU, DIPEA, DMF

[005364] To a solution of 2-[2-(cyclopropylmethylamino) pyridyl]-N-[l-isoindolin yl3-(trifluoromethyl) pyrazol yl]oxazole carboxamide (190 mg, 348 umol, HCI, synthesized via Method 12 coupling 5-[4-amino (trifluoromethyl)pyrazol-l-yl]isoindoline carboxylate (Intermediate FM) and 2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole4-carboxylic acid (from Steps 1-4 of Intermediate DF) in Step 1), 2-[2-[2-[[2-(2,6-dioxo-3piperidyl)- l,3-dioxo-isoindolin yl]amino]ethoxy]ethoxy]acetaldehyde (116 mg, 290 umol, Intermediate FK) in THF (30.0 mL) was added KO Ac (56.9 mg, 580 umol) and NaBH(OAc)3 (122 mg, 580 umol). The reaction mixture was stirred at 25 °C for 16 hours. On completion, the mixture was diluted with H2O (1 mL) and then concentrated in vacuo. The mixture was purified by prep

1784

HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)ACN]; B%: 10%-40%, 10 min) to give the title compound (16.1 mg, 5.9% yield) as yellow solid. 1H NMR (400MHz, DMSO-» δ 11.1 (s, IH), 9.94 (s, IH), 8.97 (s, IH), 8.83 (s, IH), 8.15 (d, J = 5.2 Hz, IH), 7.72 (s, IH), 7.68 (d, J = 8.4 Hz, IH), 7.57 (t, J = 7.8 Hz, IH), 7.37 (d, J = 8.4 Hz, IH), 7.17 - 7.08 (m, 3H), 7.06 - 7.00 (m, 2H), 6.69 - 6.53 (m, IH), 5.08 - 5.00 (m, IH), 4.00 - 3.85 (m, 4H), 3.68 - 3.55 (m, 6H), 3.50 - 3.47 (m, 4H), 3.20 - 3.15 (m, 2H), 2.95 - 2.86 (m, IH), 2.86 2.80 (m, 2H), 2.61 - 2.55 (m, IH), 2.54 - 2.53 (m, IH), 2.05 - 1.92 (m, IH), 1.08 - 1.00 (m, IH), 0.49 - 0.43 (m, 2H), 0.25 - 0.20 (m, 2H); LC-MS (ESI+) m/z 897.4 (M+H)+.

[005365] Example 422: 2-(2-Amino DyridvD-N-[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6dioxo Diperidvl)-l.,3-dioxo-isoindolin-4vl]amino]ethoxv]ethoxv]ethvlcarbamovl]Dhenvl]Dvrazol yl]oxazole carboxamide, 1-427

1785

[005366] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[2-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo- isoindolin yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (50.0 mg, 54.4 umol, synthesized via Method 10,

1786 coupling acid Intermediate HI and amine Intermediate CL in Step 1, and coupling amine 4-[2-[2(2-aminoethoxy)ethoxy]ethyl amino] (2,6-dioxo piperidyl)isoindoline-l,3-dione synthesized via Steps 1-2 of Example 127 in Step 3) in DCM (5 mL) was added HCI/dioxane (4 M, 13.6 uL). The mixture was stirred at 15 °C for 30 minutes. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Luna C18 150*25 5u; mobile phase: [water (0.225% FA)-ACN]; B%: 29%-49%, 7.8 min) to give the title compound (22.0 mg, 44% yield) as a yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 11.11 (s, IH), 11.01 (s, IH), 9.04 (s, IH), 9.02 (s, IH), 8.63 (t, J = 5.2 Hz, IH), 8.17 - 8.14 (m, IH), 8.17 - 8.14 (m, IH), 8.13 (d, J = 5.6 Hz, IH), 8.11 - 8.06 (m, 2H), 8.05 - 8.00 (m, 2H), 7.80 (s, IH), 7.59 - 7.54 (m, IH), 7.59 - 7.54 (m, IH), 7.12 (d, J = 8.8 Hz, IH), 7.07 (s, IH), 7.05 (s, IH), 7.03 - 7.01 (m, IH), 7.03 - 7.01 (m, IH), 7.02 (d, J = 7.2 Hz, IH), 6.60 (t, J = 5.6 Hz, IH), 6.42 (s, 2H), 5.06 (dd, J = 52, 12.8 Hz, IH), 3.65 - 3.61 (m, 2H), 3.61 - 3.55 (m, 6H), 3.48 - 3.43 (m, 2H), 3.43 (s, 2H), 2.92 - 2.85 (m, IH), 2.61 (s, IH), 2.56 (s, IH), 2.06 - 2.00 (m, IH); LC-MS (ESI+) m/z 820.5 (M+H)+.

[005367] Example 423: N-n-[4-[2-[2-[2-[[2-(2,6-dioxo piperidyD-l,3-dioxoisoindolin vl]amino]ethoxv]ethoxy] imidazolidin-l-vl]pvrazol vl] [2-(2,2,2-trifluoroethvlamino) pyridvl]oxazole-4carboxamide, 1-428

1787

HATU, DIEA, DMF

[005368] Tert-butylN-[4-[4-[[l-[4-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo1788 isoindolin yl] amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl] [3-(2-hydroxyethyl) oxoimidazolidin-l-yl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2trifluoroethyl)carbamate was synthesized via Method 10 with methyl 4-[4-amino [3-(2hydroxyethyl) oxo-imidazolidin-l-yl]pyrazol-l-yl] benzoate (Intermediate JT) as the amine and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole carboxylic acid (Intermediate CM) as the acid in Step 1, and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino] (2,6dioxo piperidyl)isoindoline-l,3- dione (50.3 mg, 114 umol, HCI, synthesized via Steps 12&#1470; of Example 127) as the amine in Step 3. In the final step, to a solution of tert-butylN-[4-[4-[[l-[4-[2[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin yl] amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl] [3-(2-hydroxyethyl) oxo-imidazolidin-lyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (100 mg, 91.9 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 2 mL). The mixture was stirred at 20 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by Pre-HPLC (column: Phenomenex Synergi C18 150*30mm*4um; mobile phase: [water (0.225%FA) -ACN]) to give the title compound (30 mg, 33% yield) as yellow solid. 1H NMR (400MHz, DMSO&#1470;/) δ 11.65 (s, IH), 11.09 (s, IH), 8.97 - 8.93 (m, 2H), 8.54 (s, IH), 8.25 - 8.24 (d, J= 5.6 Hz, IH), 7.98 (d, J= 8.8 Hz, 2H), 7.88 (d, J= 8.8 Hz, 2H), 7.60- 7.50 (m, 2H), 7.23 (d, /=8.4 Hz, 2H), 7.12 (d,/= 8.4 Hz, IH), 7.01 (d,/= 7.2 Hz, IH), 6.59 (s, IH), 5.05 (dd,/=5.2, 13.2 Hz, IH), 4.95 (s, 1H),4.27- 4.24 (m, 2H), 4.06 - 3.96(m, 2H), 3.64 - 3.54 (m, 10H), 3.44 3.40 (m, 6H), 2.95 - 2.85 (m, IH), 2.60 - 2.54 (m, 2H), 2.04 - 2.01 (m, IH); LC-MS (ESI+) m/z 987.8 (M+H)+.

[005369] Example 424: N-[3-(3,3-dimethvl oxo-pvrrolidin-l-vD-l-[4-[2-[2-[2-[[2-(2,6dioxo piperidyl)-1,3-dioxo-isoindolin-4vl]amino]ethoxv]ethoxv]ethvlcarbamovl]phenvl]pvrazol yl] [2-(2,2,2trifluoroethvlamino) pyridvl] oxazole carboxamide., 1-429

1789

Boc

[005370] Tert-butyl N-[4-[4-[[3-(3,3-dimethyl oxo-pyrrolidin-l-yl)-l-[4-[2-[2-[2-[[2(2,6-dioxo-3piperidyl)-!,3-dioxo-isoindolin-4

1790 yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]-N-(2,2,2-trifluoroethyl)carbamate was synthesized via Method 10, with methyl 4-[4amino (3,3-dimethyl oxo-pyrrolidin-l-yl)pyrazol-l-yl]benzoate (Intermediate JV) as the amine and 2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino] pyridyl]oxazole carboxylic acid (Intermediate CM) as the acid in Step 1, and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2(2,6-dioxo piperidyl)isoindoline-l,3-dione (synthesized via Steps 1-2 of Example 127) as the amine in Step 3. In the final step, to a solution of tert-butyl N-[4-[4-[[3-(3,3-dimethyl oxopyrrolidin-l-yl)-l-[4-[2-[2-[2-[[2-(2,6-dioxo piperidyl)-l,3-dioxo-isoindolin-4yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (42 mg, 39.2 umol) in DCM (2 mL) was added HCI/dioxane (4 M, 196 uL). The mixture was stirred at 20 °C for 3 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.05%HCl) -ACN]) to give the title compound (11.6 mg, 29% yield) as yellow solid. 1H NMR (400MHz, DMSO-76) δ 11.14 (s, IH), 11.08 (s, IH), 8.99 (s, IH), 8.96 (s, IH), 8.55 (s, IH), 8.26 (d, J = 5.2 Hz, IH), 7.98 (d, J = 8.4 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 7.78 (s, IH), 7.55 (t, J= 7.6 Hz, IH), 7.26 (s, IH), 7.22 (d, 7= 5.2 Hz, IH), 7.11 (d, J= 8.8 Hz, IH), 7.01 (d, J= 7.2 Hz, IH), 6.59 (s, IH), 5.05 (dd,7=5.2, 13.2 Hz, IH), 4.32- 4.23 (m, 2H), 3.98 (t, J = 6.8 Hz, 2H), 3.64 - 3.54 (m, 6H), 3.51 - 3.47 (m, 4H), 2.94 - 2.81 (m, IH), 2.62 - 2.53 (m, 4H), 2.11 (t, J= 6.8 Hz, 2H), 2.02 (d, J= 11.2 Hz, IH), 1.27 (s, 6H); LC-MS (ESI+) m/z 970.5 (M+H)+.

[005371] Example 427: N-[3-(difluoromethvl)-l-methvl-pvrazol yl] [2-[2-[2-[2-[2[[2-(26&#1524;-dioxo piperidvl)-l.,3-dioxo-isoindolin-4yl] amino] ethoxy] ethoxy] ethoxy] ethylamino] pyridvl] oxazole carboxamide., 1-432

1791

[005372] To a solution of 2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-3pyridyl]-N-[3- (difluoromethyl)-l-methyl-pyrazol yl]oxazole carboxamide (160 mg, 293 umol, HCI, Intermediate LW) in dioxane (20 mL) was added DIPEA (379 mg, 2.93 mmol) and 2(2,6-dioxo piperidyl) fluoro-isoindoline -1,3-dione (121 mg, 440 umol, Intermediate R). The mixture was stirred at 115 °C for 48 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 lOu; mobile phase: [water (0.225%FA)-ACN]; B%: 22%-52%, lOmin) to give the title compound (60 mg, 26% yield) as a yellow solid. 1H NMR (400MHz, DM SO-0/6) δ 11.10 (s, IH), 9.98 (s, IH), 8.86 (s, IH), 8.40 - 8.32 (m, IH), 8.26- 8.22 (m, IH), 8.18 - 8.12 (m, 2H), 7.60- 7.49 (m, IH), 7.25 - 6.98 (m, 3H), 6.75 - 6.68 (m, IH), 6.60 - 6.52 (m, IH), 5.08 - 4.92 (m, IH), 3.90 (s, 3H), 3.82 - 3.69 (m, 2H), 3.68 - 3.58 (m, 2H), 3.57 - 3.35 (m, 12H), 2.94 - 2.78 (m, IH), 2.60 - 2.52 (m, 2H), 2.08 1.94 (M, IH); LC-MS (ESI+) m/z 766.3 (M+H)+.

[005373] Example 429: N-[3-carbamoyl-l-[6-[2-[2-[[2-(2,6-dioxo piperidyD-l,3dioxo-isoindolin vl]amino]ethoxy]ethoxy]hexa-2.,4-diynyl]pyrazol yl] [2(cyclopropylmethylamino) pyridyl]oxazole carboxamide., 1-434

1792

[005374] Step 1 - Tert-butyl N-r4-r4-rr3-carbamoyl-l-r6-r2-r2-rr2-(2,6-dioxo piperidyl)L3-dioxo-isoindolin yl1amino1ethoxy1ethoxy1hexa-2,4-diynyl1pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[005375] To a solution of Cui (6.33 mg, 33.2 umol), TMEDA (1.38 mg, 11.87 umol) in acetone (2 mL) was added 2-(2,6-di oxo piperi dyl) [2-(2-prop-2ynoxyethoxy)ethylamino]isoindoline-l,3-dione (118 mg, 297 umol, Intermediate MV) and tertbutyl N-[4-[4-[(3-carbamoyl-l-prop ynyl-pyrazol yl)carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (15.0 mg, 29.7 umol, synthesized via Step 1 of of Example 299, 1-304). The reaction mixture was stirred at rt for 48 hrs under an oxygen atmosphere. On

1793 completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give title compound (20.0 mg, 74% yield) as a yellow solid. LC-MS (ESI+) m/z 903.1 (M+H)+.

[005376] Step 2 - N-[3-carbamoyl-l-[6-[2-[2-[[2-(2,6-dioxo piperidvl)-L3-dioxoisoindolin yl1amino1 ethoxy1ethoxy1hexa-2,4-diynyl1pyrazol yl1 [2(cyclopropylmethylamino) pyridyl1oxazole carboxamide

[005377] To a mixture of tert-butyl N-[4-[4-[[3-carbamoyl-l-[6-[2-[2-[[2-(2,6-dioxo-3piperidyl)-l,3-dioxo- isoindolin yl]amino]ethoxy]ethoxy]hexa-2,4-diynyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (20.0 mg, 22.1 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 5.54 uL) and the reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)ACN]; B%: 15%-45%, 10 min) to give the title compound (2.00 mg, 14% yield, FA) as a yellow solid. 1H NMR (400MHz, DMSO-76) δ 11.09 (s, IH), 10.97 (s, IH), 8.95 (s, IH), 8.49 - 8.44 (m, 2H), 8.15 (d, J = 5.6 Hz, IH), 7.84 (s, IH), 7.60 - 7.54 (m, 2H), 7.16 - 7.09 (m, 3H), 7.05 - 6.97 (m, 2H), 6.60 (t, J = 5.6 Hz, IH), 5.35 (s, 2H), 5.05 (dd, J = 5.6, 13.2 Hz, IH), 4.30 (s, 2H), 3.62 - 3.58 (m, 3H), 3.49 - 3.43 (m, 2H), 3.18 (t, J= 6.0 Hz, 2H), 2.94 - 2.81 (m, IH), 2.69 - 2.65 (m, 2H), 2.34 - 2.31 (m, 2H), 2.08 - 1.98 (m, 2H), 1.06 ( s, IH), 0.48 - 0.42 (m, 2H), 0.22 (d, J = 4.8 Hz, 2H); LC-MS (ESI+) m/z 803.3 (M+H)+.

[005378] Example 430: N-[3-carbamoyl-l-[6-[2-[2-[[2-(2,6-dioxo piperidvD-l,3dioxo-isoindolin yl]amino]ethoxy] ethoxy] hexyl] pyrazol yl] [2(cvclopropylmethylamino) pyridyl]oxazole carboxamide, 1-435

1794

butoxycarbonylamino)ethoxy1ethoxy1hexa-2,4-diynyl1-3 carbamoyl-pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[005380] To a solution of Cui (84.4 mg, 443 umol), TMEDA(18.4 mg, 158 umol) in acetone (5 mL) was added tert-butyl N-[4-[4-[(3-carbamoyl-l-prop ynyl-pyrazol-4

1795 yl)carbamoyl]oxazol yl] pyridyl]-N- (cyclopropylmethyl)carbamate (200 mg, 396 umol, synthesized via Step 1 of Example 299, 1-304) and tert-butyl N-[2-(2-prop-2ynoxyethoxy)ethyl]carbamate (962 mg, 3.96 mmol, synthesized via Step 1 of Intermediate CQ). The reaction mixture was stirred for 12 hours under an oxygen atmosphere. On completion, the mixture was concentrated in vacuo to give the title compound (1.80 g, 97% yield, HC1) as a brown solid. LC-MS (ESI+) m/z 747.2 (M+H)+.

[005381] Step 2:Tert-butylN-[4-[4-[[l-[6-[2-[2-(tertbutoxvcarbonvlamino)ethoxv1ethoxv1hexyl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[005382] To a mixture of tert-butyl N-[4-[4-[[l-[6-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]hexa-2,4- diynyl] carbarn oyl-pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (160 mg, 214 umol) in THF (10 mL) was added Pd/C (428.49 umol) and the suspension was degassed under vacuum and purged with H2 gas 3 times. The mixture was stirred at rt for 1 hr under H2 (15 Psi). On completion, the mixture was concentrated in vacuo to give the title compound (160 mg, 99% yield) as a brown solid. 1HNMR (400MHz, DMSO-76) δ 11.01 (s, IH), 9.02 (s, IH), 8.60 (d, J = 5.2 Hz, IH), 8.38 (s, IH), 8.25 (s, IH), 7.73 - 7.64 (m, 2H), 7.49 (s, IH), 6.87 (s, IH), 5.31 (s, IH), 4.57 (t, J = 5.6 Hz, IH), 4.18 (t, J= 6.8 Hz, 2H), 3.86 (d, J= 6.4 Hz, 2H), 2.18 (s, IH), 1.82 (d, J= 6.8 Hz, 3H), 1.46 (s, 19H), 0.91 - 0.82 (m, 2H), 0.41 (d, J= 7.6 Hz, 2H), 0.24 (d, J= 4.0 Hz, 2H), -0.06 (s, 4H). [005383] Step 3 - N-[l-[6-[2-(2-aminoethoxy)ethoxy1hexyl1 carbamoyl-pyrazol yl1-2[2-(cyclopropyl methyl amino) pyridyl1oxazole carboxamide

[005384] To a mixture of tert-butyl N-[4-[4-[[l-[6-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]hexyl] carbamoyl-pyrazol yl]carbamoyl]oxazol yl]2-pyridyl]-N-(cyclopropylmethyl)carbamate (100 mg, 132 umol) in DCM (2 mL) was added HCI/dioxane (4 M, 6.7 mL). The reaction mixture was stirred at rt for 0.5 hr. On completion, the mixture was concentrated in vacuo to give the title compound (75.0 mg, 95% yield, HC1) as brown oil. LC-MS (ESI+) m/z 555.2 (M+H)+.

[005385] Step 4 - N-[3-carbamoyl-l-[6-[2-[2-[[2-(2,6-dioxo piperidyl)-L3-dioxoisoindolin yl1amino1 pyridyl1oxazole carboxamide

[005386] To a mixture of N-[l-[6-[2-(2-aminoethoxy)ethoxy]hexyl] carbamoyl-pyrazol-41796 yl] [2-(cyclo propylmethylamino) pyridyl]oxazole carboxamide (45.0 mg, 76.1umol, HC1), 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (21.0 mg, 76.1 umol, Intermediate R) in DMSO (2 mL) was added DIEA (98.4 mg, 761 umol). The mixture was stirred at 130 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B%: 23%-43%,7 min and column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl)-ACN]; B%: 25%-45%, 9 min) to give the title compound (8.50 mg, 12% yield) as a yellow solid. 1H NMR (400MHz, DMSOQ) δ 11.14 - 11.09 (m, IH), 11.00 (s, IH), 9.08 (s, IH), 8.38 (s, IH), 8.10 (d, J= 6.4 Hz, IH), 7.76 (s, IH), 7.61 - 7.48 (m, 3H), 7.24 - 7.11 (m, 2H), 7.03 (d, 7 = 7.2 Hz, IH), 6.60 (s, IH), 5.10 - 5.00 (m, IH), 4.17 (t, 7= 7.2 Hz, 2H), 3.65 - 3.44 (m, 12H), 3.28 (d, 7= 6.8 Hz, 4H), 2.95 - 2.82 (m, IH), 2.71 - 2.65 (m, IH), 2.37 - 2.31 (m, IH), 2.08 - 1.98 (m, IH), 1.86 - 1.69 (m, 2H), 1.52 - 1.39 (m, 2H), 1.35 - 1.08 (m, 5H), 0.56 (d, 7= 6.8 Hz, 2H), 0.39 - 0.25 (m, 2H); LC-MS (ESI+) m/z 811.1 (M+H)+.

[005387] Example 431: 3-[3-Methvl oxo [3-[3-[4-[4-[(5-tetrahvdropyran-4ylpyrrolo [21 &#1524;-f] [1 .,2.,4] triazin yl)amino]cvdohexyl]piperazin-lvl]propoxv]propyl]benzimidazol-l-vl]piperidine-2,6-dione (1-436)

1797

[005388] Step 1 - 3-Prop ynoxypropan-l-ol (3),

[005389] To a solution of propane-1,3-di01 (10.0 g, 131 mmol, 9.52 mL, CAS#126 7) and

3-bromoprop yne (15.6 g, 131 mmol, 11.3 mL, CAS#106 7) in THF (250 mL) was added KOH (7.37 g, 131 mmol), KI (3.27 g, 19.7 mmol) and TBAI (2.91 g, 7.88 mmol). The reaction mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was filtered, and the filter was concentrated in vacuo to give a residue, the residue was diluted with H2O (50 mL), and then extracted with EA (2 X 100 mL). The organic phase was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography to give the title compound (8.00 g, 53% yield) as yellow oil. 1H NMR (400MHz, DMSO-d6) δ 4.14 (d, J = 2.4 Hz, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.68 (t, J= 5.6 Hz, 2H), 2.44 (t, J= 2.4 Hz, IH), 2.23 (s, IH), 1.88 - 1.81 (m, 2H).

[005390] Step 2 - 3-r5-r3-(3-Hydroxypropoxy)prop-l-ynyl1 methyl oxo-benzimidazoll-yl1piperidine-2,6- di one (5),

[005391] To a solution of 3-prop ynoxypropan-l-ol (506 mg, 4.44 mmol) and 3-(5-bromo3-methyl oxo- benzimidazol-l-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate HN) in DMSO (10 mL) was added DIEA (955 mg, 7.39 mmol, 1.29 mL), Cui (56.3 mg, 295 umol) and

1798

Pd(PPh3)2C12 (207 mg, 295 umol). The reaction mixture was stirred at 80 °C for 2 hr under N2. On completion, the mixture was filtered; the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase column (0.1% FA condition) to give the title compound (370 mg, 67% yield) as a yellow solid. LC-MS (ESI+) m/z 372.1(M+H)+.

[005392] Step 3 - 3-r5-r3-(3-Hydroxypropoxy)propyl] methyl oxo-benzimidazol-lyl]piperidine-2,6-dione (6),

[005393] To a solution of 3-[5-[3-(3-hydroxypropoxy)prop-l-ynyl] methyl oxobenzimidazol-l-yl] piperidine-2,6-dione (370 mg, 996 umol) in THF (20 mL) was added Pd/C (100 mg, 10% purity) and Pd(OH)2/C (100 mg, 10% purity). The reaction mixture was stirred at 25 °C for 12 hrs under H2 (15 psi). On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (340 mg, 90% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 11.07 (s, IH), 7.06 - 6.96 (m, 2H), 6.86 (d, J= 8.0 Hz, IH), 5.33 (dd, J= 5.2, 12.8 Hz, IH), 4.36 (s, IH), 3.47 (t, J= 6.4 Hz, 2H), 3.43 - 3.40 (m, 2H), 3.37 - 3.34 (m, 2H), 3.34 (s, 3H), 2.95 - 2.85 (m, IH), 2.76 - 2.57 (m, 4H), 2.04 - 1.96 (m, IH), 1.85 - 1.76 (m, 2H), 1.69 - 1.62 (m, 2H); LC-MS (ESI+) m/z 376.2 (M +H)+.

[005394] Step 4 - 3-r3-r1-(2,6-Dioxo piperidvl) methyl oxo-benzimidazol-5yl]propoxy]propyl methanesulfonate (7),

[005395] To a solution of 3-[5-[3-(3-hydroxypropoxy)propyl] methyl oxobenzimidazol-l-yl]piperidine- 2,6-dione (100 mg, 266 umol) and TEA (80.8 mg, 799 umol, 111 uL) in DCM (5 mL) was added MsCI (36.6 mg, 319 umol, 24.7 uL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hr. On completion, the mixture was quenched by water (20 mL), and then extracted with DCM (2X50 mL). The organic phase was concentrated in vacuo to give the title compound (100 mg, 83% yield) as yellow oil. 1HNMR (400MHz, DMSO-t/6) δ 11.09 (s, IH), 7.03 (s, IH), 7.00 (d, J= 8.0 Hz, IH), 6.90 - 6.84 (m, IH), 5.34 (dd, J= 5.2, 12.8 Hz, IH), 4.27 (t, J = 6.4 Hz, 2H), 3.47 - 3.43 (m, 2H), 3.38 (t, J = 6.4 Hz, 2H), 3.34 (m, 3H), 3.17 (s, 3H), 2.95 2.84 (m, IH), 2.73 - 2.57 (m, 4H), 2.04 - 1.96 (m, IH), 1.94 - 1.88 (m, 2H), 1.86 - 1.78 (m, 2H); LC-MS (ESI+) m/z 454.2 (M+H)+.

[005396] Step 5 - 3-r3-Methyl oxo r3-r3-r4-r4-r(5-tetrahydropyran ylpyrrolo[2,lf1rL2,4]triazin yl)amino]cyclohexyl]piperazin-l-yl]propoxy]propyl]benzimidazol-lyl]piperidine-2,6-dione. (1-436)

1799

[005397] To a solution of 3-[3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl]propoxy]propyl methanesulfonate (90.4 mg, 199 umol) and N-(4-piperazin-l-ylcyclohexyl)-5tetrahydropyran yl -pyrrolo[2,l-f][l,2,4]triazin amine (70.0 mg, 166 umol, Intermediate OP) in CH3CN (10 mL) was added KI (276 ug, 1.66 umol) and NaHCO3 (41.9 mg, 498 umol). The reaction mixture was stirred at 130 °C for 12 hrs. On completion, the residue was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)ACN]; B%: ll%-35%, 8 min) to give the title compound (20.8 mg, 16% yield) as a yellow solid. 1HNMR (400MHz, DMSO-» δ 11.10 (s, IH), 7.79 (s, IH), 7.54 (d, J= 2.4 Hz, IH), 7.08 - 6.97 (m, 2H), 6.87 (d, J= 8.0 Hz, IH), 6.53 (d, J= 2.8 Hz, IH), 6.21 (d, J= 8.0 Hz, IH), 5.34 (dd, J= 5.2, 12.8 Hz, IH), 4.12 - 3.99 (m, IH), 3.94 - 3.86 (m, 2H), 3.59 - 3.50 (m, 2H), 3.46 - 3.33 (m, 6H), 3.33 (s, 3H), 2.95 - 2.85 (m, IH), 2.72 - 2.67 (m, IH), 2.66 - 2.62 (m, 2H), 2.61 - 2.57 (m, IH), 2.56 - 2.51 (m, 4H), 2.44 - 2.34 (m, 3H), 2.34 - 2.30 (m, 2H), 2.29 - 2.25 (m, IH), 2.04 - 1.94 (m, 3H), 1.88 - 1.73 (m, 6H), 1.70 - 1.61 (m, 4H), 1.51 (q, J= 12.0 Hz, 2H), 1.33 (q, J= 11.6 Hz, 2H); LC-MS (ESI+) m/z 742.5 (M+H)+.

[005398] Example 432: 3-[3-Methyl oxo [3-[3-oxo [4-[4-[(5-tetrahydropyran-4vlpyrrolo[2,l-f] [l.,2.,4]triazin yl)amino]cvclohexyl] piperazin-1yl]propoxy|propyl]benzimidazol-l-yl]piperidine-2.,6-dione (1-437)

1800

[005400] Amixture of tert-butyl prop enoate (2 g, 15.6 mmol, 2.27 mL, CAS#1663 4), prop yn-l-ol (2.62 g, 46.8 mmol, 2.77 mL, CAS#107 7) in THF (10 mL) was added NaOMe (84.3 mg, 1.56 mmol), and then the mixture was stirred at 25 °C for 16 hrs under N2 atmosphere. On completion, the mixture was diluted with water (30 mL), and then extracted with EA (2 X 100 mL). The organic layer was dried with Na2SO4, filtrated and concentrated in vacuo to give the title compound (1.80 g, 63% yield) as light yellow oil. 1H NMR (400MHz, CDCh) δ 4.18 (d, J = 2.4 Hz, 2H), 3.78 (t, J= 6.4 Hz, 2H), 2.54 (t, J= 6.4 Hz, 2H), 2.45 (s, IH), 1.47 (s, 9H).

[005401] Step 2 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1prop ynoxy1 propanoate (5)

[005402] A mixture of 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (400 mg, 1.18 mmol, Intermediate HN), tert-butyl 3-prop ynoxypropanoate (654 mg, 3.55 mmol), Pd(PPh3)2C12 (166 mg, 236 umol), Cui (45.0 mg, 236 umol) and TEA (2.15 g, 21.0 mmol,

1801

2.96 mL) in DMF (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 4 hrs under N2 atmosphere. On completion, the mixture was diluted with water (50 mL), and then extracted with EA (2 X 100 mL). The organic layer was washed with brine (20 mL), dried with Na2SO4, filtrated and concentrated in vacuo. The residue was purified by reverse phase flash to give the title compound (300 mg, 49% yield) as light yellow solid. LC-MS (ESI+) m/z 386.1 (M+l-56)+.

[005403] Step 3 - Tert-butyl 3-r3-r1-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl1propoxy1 propanoate (6)

[005404] To a solution of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]prop ynoxy]propanoate (250 mg, 566 umol) in THF (50 mL) was added Pd/C (50 mg, 10% purity) and Pd(OH)2/C (50 mg, 10% purity). The mixture was stirred at 25 °C for 5 hrs under H2 atmosphere (15 psi). On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (200 mg, 79% yield) as white solid. 1H NMR (400MHz, DMSO-t/6) δ 11.09 (s, IH), 7.07 - 6.98 (m, 2H), 6.90 - 6.83 (m, IH), 5.34 (dd, J= 5.2, 12.8 Hz, IH), 3.63 - 3.53 (m, 2H), 3.39 - 3.37 (m, 2H), 3.33 (s, 3H), 3.02 - 2.83 (m, IH), 2.78 2.58 (m, 4H), 2.43 (t, J = 6.0 Hz, 2H), 2.07 - 1.94 (m, IH), 1.85 - 1.74 (m, 2H), 1.41 (s, 9H).

[005405] Step 4 - 3-r3-r1-(2,6-Dioxo piperidyl) methyl oxo-benzimidazol-5yl1propoxy1propanoic acid (7)

[005406] To a solution of tert-butyl 3-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] propanoate (150 mg, 336 umol) in DCM (4 mL) was added TFA(4.62 g, 40.0 mmol, 3.00 mL). The mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (120 mg, 91% yield) as brown solid. 1H NMR (400MHz, DMSO^/6) δ 11.08 (s, IH), 7.11 - 6.95 (m, 2H), 6.87 (dd, J = 1.2, 8.0 Hz, IH), 5.34 (dd, J= 5.2, 12.8 Hz, IH), 3.58 (t, J= 6.4 Hz, 2H), 3.38 (t, J= 6.4 Hz, 2H), 3.33 (s, 3H), 2.99 - 2.84 (m, IH), 2.76 - 2.57 (m, 4H), 2.46 (t, J= 6.4 Hz, 2H), 2.03 - 1.98 (m, IH), 1.86 - 1.74 (m, 2H).

[005407] Step 5 - 3-r3-Methyl oxo r3-r3-oxo r4-[4-r(5-tetrahydropyran-4ylpyrrolor2,l-f]rL2,41triazin yl)amino1cyclohexyl1piperazin-lyl1propoxy1propyl1benzimidazol-l-yl1piperidine-2,6-dione (1-437)

[005408] A mixture of 3-[3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl]propoxy]propanoic acid (120 mg, 308 umol), N-(4-piperazin-l-ylcyclohexyl)-5

1802 tetrahydropyran yl-pyrrolo[2,l-f][l,2,4] triazin amine (129 mg, 308 umol, HCI, Intermediate OP), DIEA (119 mg, 924 umol), HATU (140 mg, 369 umol) in DMF (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo. The residue was purified by Pre-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: ll%-39%, 9 min) to give the title compound (55.0 mg, 24% yield) as white solid. 1HNMR (400MHz, DMSO-de) δ 11.09 (s, IH), 7.79 (s, IH), 7.55 (d, J= 2.8 Hz, IH), 7.08 - 6.97 (m, 2H), 6.87 (d, J= 7.6 Hz, IH), 6.54 (d, J= 2.4 Hz, IH), 6.21 (d, J= 7.6 Hz, IH), 5.34 (dd, J= 5.2, 12.8 Hz, IH), 4.10 - 4.01 (m, IH), 3.95 - 3.85 (m, 2H), 3.64 - 3.48 (m, 8H), 3.34 - 3.30 (m, 7H), 2.96 2.86 (m, IH), 2.70 - 2.54 (m, 7H), 2.48 - 2.42 (m, 2H), 2.38 - 2.28 (m, IH), 2.03 - 1.96 (m, 3H), 1.88 - 1.71 (m, 6H), 1.71 - 1.59 (m, 2H), 1.57 - 1.46 (m, 2H), 1.43 - 1.27 (m, 2H), LC-MS (ESI+) m/z 756.5 (M+l)+.

[005409] Example 433: 3-[3-Methvl 0x0 [7-0x0 [4-[4-[(5-tetrahydr0Dvran-4vlpvrrolo[2,l-f][l,2,4]triazin-4vlJj2il2£ridm£22%<H011eJJ2^B

1803

[005410] Step 1 - 7-r1-(2,6-Dioxo piperidvl) methvl oxo-benzimidazol yl1hept-6ynoic acid (3)

[005411] A mixture of hept ynoic acid (224 mg, 1.77 mmol, CAS#30964 2), 3-(5bromo methyl oxo- benzimidazol-l-yl)piperidine-2,6-dione (200 mg, 591 umol, Intermediate HN), Pd(PPh3)2C12 (12.5 mg, 17.7 umol), Cui (1.13 mg, 5.91 umol) and DIEA (1.53 g, 11.8 mmol) in DMSO (5 mL) was degassed and purged with N2 for 3 times in glove box. The mixture was stirred at 80 °C for 2 hrs under N2 atmosphere. On completion, the crude product was purified by reverse phase column (0.1% FA condition) to give the title compound (180 mg, 60% yield) as a yellow solid. 1H NMR (400MHz, DMSO-t/6) δ = 11.12 (s, IH), 7.97 - 7.67 (m, IH), 7.29-7.18 (m, IH), 7.17-7.03 (m, 2H), 5.37 (d, J= 13.2 Hz, IH), 3.43 -3.38 (m, 3H), 2.93 - 2.81

1804 (m, 2H), 2.74 - 2.65 (m, IH), 2.46 - 2.39 (m, 2H), 2.30 - 2.23 (m, 2H), 2.02 (d, J = 4.4 Hz, IH), 1.72- 1.43 (m, 4H).

[005412] Step 2 - Tert-butyl 6-r2-r2-rr2-(2,6-dioxo piperidyl) -L3-dioxo-isoindolin-4yl1amino1ethoxy1 ethyl1-2.6-diazaspiro[3.31heptane carboxylate (4)

[005413] To a solution of 7-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl]hept ynoic acid (160 mg, 417 umol) in THF (50 mL) was added Pd/C (200 mg, 417 umol, 50% purity) and Pd(OH)2/C (200 mg, 417 umol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 15 °C for 2 hours under H2 (15 psi). On completion, the mixture was fdtered with Clite and the filtrate was concentrated in vacuo to give the title compound (100 mg, 40% yield) as a yellow solid. LC-MS (ESI+) m/z 388.2 (M+H)+.

[005414] Step 3 - 3-r3-Methyl oxo r7-oxo r4-r4-r(5-tetrahydropyran ylpyrrolo[2,lf1rL2,41triazin-4dione (1-438)

[005415] To a solution of 7-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-5yl]heptanoic acid (100 mg, 258 umol) and N-(4-piperazin-l-ylcyclohexyl) tetrahydropyran-4yl-pyrrolo[2,l-f][l,2,4] triazin amine (100 mg, 258 umol, Intermediate OP) in DMF (5 mL) was added HATU (118 mg, 310 umol) and DIEA(83.4 mg, 645 umol, 112 uL). The mixture was stirred at 25 °C for 6 hrs. On completion, the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl)-ACN]; B%: 17%-35%, 9 min) to give the title compound (26.0 mg, 12.0% yield) as a light yellow solid. 1H NMR (400MHz, DMSO/6) δ 11.16 (s, IH), 11.10 (s, IH), 7.97 (s, IH), 7.80 (s, IH), 7.05 - 7.00 (m, 2H), 6.87 (d, J = 8.0 Hz, IH), 6.71 (d, J= 2.4 Hz, IH), 5.35 (dd, J= 5.6, 12.8 Hz, IH), 4.49 (d, J= 14.4 Hz, IH), 4.06 (d, J = 11.2 Hz, 2H), 3.92 (d, J = 8.0 Hz, 4H), 3.50 - 3.48 (m, 3H), 3.33 (s, 3H), 3.21 - 3.06 (m, 4H), 2.98 - 2.84 (m, 2H), 2.70 - 2.67 (m, IH), 2.66 - 2.59 (m, 4H), 2.40 - 2.34 (m, 2H), 2.25 (s, 2H), 2.09 (s, 2H), 2.04 - 1.97 (m, IH), 1.80 - 1.64 (m, 10H), 1.50 (s, 2H), 1.33 - 1.30 (m, 4H); LCMS (ESI+) m/z 754.5 (M+H)+.

[005416] Example 434: 3-[3-Methvl [3-[2-[2-[2-[2-[methvl-[4-[(5-tetrahvdropvran-4vl-7H-Dvrrolo[2,3-d]pyrimidin-4vl)amino]cvclohexvl]amino]ethoxv]ethoxv]ethoxv]ethoxv]DroDvl] oxo-benzimidazol-lvl]Diperidine-2,6-dione (1-439)

1805

[005417] To a mixture of Nl-methyl-N4-(5-tetrahydropyran yl-7H-pyrrolo[2,3d]pyrimidin yl)cyclohexane -1,4-diamine (80.0 mg, 242 umol, Intermediate OQ) in a mixed solvent of THF (6 mL) and DMF (1.5 mL) was added TEA (36.8 mg, 364 umol), HO Ac (21.8 mg, 364 umol) and 2-[2-[2-[2-[3-[l-(2,6-dioxo piperi dyl) methyl oxo-benzimidazol-4yl]propoxy]ethoxy]ethoxy]ethoxy]acetaldehyde (119 mg, 242 umol, from Example 437). The mixture was stirred for 30 minutes, and then NaBH(OAc)3 (102 mg, 485 umol) was added. The mixture was stirred 25°C for 48 hours. On completion, the reaction mixture was quenched by water (15 mL), and then extracted with EA (3 X 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl)ACN]) to give the title compound (6.12 mg, 2% yield) as yellow solid. 1H NMR (400MHz, DMSOJ6+D2O) δ 8.30 (s, IH), 7.19 (s, IH), 6.96 (d, J= 4.8 Hz, 2H), 6.91 - 6.83 (m, IH), 5.30 (dd, J = 5.6, 12.4 Hz, IH), 3.89 - 3.86 (m, 2H), 3.69 - 3.34 (m, 24H), 3.24 - 3.16 (m, 2H), 2.98 - 2.79 (m, 3H), 2.74 (s, 3H), 2.70 - 2.57 (m, 2H), 2.15 - 1.94 (m, 5H), 1.85 - 1.75 (m, 4H), 1.71 - 1.49 (m, 6H); LC-MS (ESI+) m/z 805.6 (M+H)+.

[005418] Example 435:2-[2-[2-[2-[3-[l-(2.,6-Dioxo piperidvl) methvl oxobenzimidazol yl] propoxy] ethoxy]ethoxy|ethoxy|-N-[4-[(5-tetrahydropyran yl-7Hpyrrolo [2.,3-d] pyrimidin yl)amino] cyclohexyl] acetamide (1-440)

1806

[005419] To a solution of 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] ethoxy]ethoxy]ethoxy]acetic acid (70.7 mg, 113 umol, from Example 447) and N4-(5-tetrahydropyran yl-7H-pyrrolo[2, 3-d]pyrimidin yl)cyclohexane-l,4diamine (40.0 mg, 113 umol, HCI, from 1-442) in DMF (5 mL) was HATU (51.9 mg, 136 umol) and DIPEA (73.5 mg, 568 umol, 99.0 uL). The mixture was stirred at 25 °C for 1.5 hrs. On completion, the mixture was quenched with H2O (5 mL), then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 7%-37%, 10 min) to give the title compound (33.2 mg, 36% yield) as a white solid. 1H NMR (400MHz, DMSO-t/6) δ 11.31 (s, IH), 11.10 (s, IH), 8.06 (s, IH), 7.47 (d, J= 8.4 Hz, IH), 6.99 - 6.90 (m, 2H), 6.90 - 6.81 (m, 2H), 5.57 (d, J = 8.0 Hz, IH), 5.35 (dd, 7=5.2, 12.4 Hz, IH), 4.15 - 4.00 (m, IH), 3.93 -3.87 (m, 2H), 3.85 (s, 2H), 3.60 - 3.52 (m, 17H), 3.47 - 3.44 (m, 2H), 3.28-3.19 (m, 2H), 2.96 - 2.91 (m, 2H), 2.90 - 2.83 (m, IH), 2.71 - 2.58 (m, 2H), 2.03 - 1.93 (m, 3H), 1.87 - 1.76 (m, 6H), 1.59 - 1.36 (m, 6H); LC-MS (ESI+) m/z 805.5 (M+H)+.

[005420] Example 436: N-[3-(difluoromethyl)-l-[4-[[4-[4-[l-(2.,6-dioxo piperidvl)-3methyl oxo-benzimidazol yl] butoxy] butylamino] methyl] phenyl] pyrazol vl]-5piperazin-l-vl-pyrazolo[l.,5-a]pvrimidine carboxamide (1-441)

1807

HCI/dioxane, DCM

[005421] Step 1:Tert-butyl 4-r3-rr3-(difluoromethyl)-l-(4methoxycarbonylphenyl)pyrazol yl1carbamoyl1 carboxylate (3)

1808

[005422] To a solution of methyl 4-[4-amino (difluoromethyl)pyrazol-l-yl]benzoate (650 mg, 2.43 mmol, Intermediate FW), 5-(4-tertbutoxycarbonylpiperazin-l-yl)pyrazolo[l,5a]pyrimidine carboxylic acid (650 mg, 1.87 mmol) in ACN (15.0 mL) was added DIEA (725 mg, 5.61 mmol), HATU (1.42 g, 3.74 mmol). The mixture was stirred at 60 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (700 mg, 62% yield) as yellow solid. 1H NMR (400MHz, CDCh) δ 9.60 (s, IH), 9.05 (s, IH), 8.48 (s, IH), 8.38 (d, J = 8.0 Hz, IH), 8.17 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 6.92 (t, J = 54.0 Hz, IH), 6.46 (d, J = 8.0 Hz, IH), 3.96 (s, 3H), 3.91 - 3.80 (m, 4H), 3.70 - 3.60 (m, 4H), 1.54 (s, 9H).

[005423] Step 2 - 4-r4-rr5-(4-Tert-butoxycarbonylpiperazin-l-yl)pyrazolo[L5-a1pyrimidine3-carbonyl1amino1 (difluoromethyl)pyrazol-l-yl1benzoic acid (4)

[005424] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-(4-methoxycarbonylphenyl) pyrazol yl] carbamoyl]pyrazolo[l,5-a]pyrimidin yl]piperazine-l-carboxylate (1.00 g, 1.68 mmol) in THF (40.0 mL) and H2O (8 mL) was added LiOH (200 mg, 8.38 mmol). The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The mixture was diluted with H2O (30 mL). The mixture was acidified with IN HCI solution till pH = 5, filtered and the filter cake was dried in vauco to give the title compound (900 mg, 92% yield) as yellow solid. 1H NMR (400MHz, DMSO-d6) δ 12.01 (s, IH), 9.48 (s, IH), 9.08 (s, IH), 8.82 (d, J = 8.0 Hz, IH), 8.32 (s, IH), 8.07 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 53.6 Hz, IH), 6.89 (d, J = 8.0 Hz, IH), 3.90 - 3.75 (m, 4H), 3.50 - 3.45 (m, 4H), 1.44 (s, 9H).

[005425] Step 3:Tert-butyl 4-[3-[ [3-(difluoromethyl) (4isopropoxycarbonyloxycarbonylphenyl)pyrazol-4yl1piperazine-l-carboxylate (6)

[005426] To a solution of 4-[4-[[5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[l,5a]pyrimidine carbonyl] amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (900 mg, 1.54 mmol), TEA (625 mg, 6.18 mmol) in THF (30.0 mL) was added isopropyl carbonochloridate (473 mg, 3.86 mmol) at -10 °C. The mixture was stirred at -10 °C for 1 hr. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.00 g, 90% yield) as yellow solid. LC-MS (ESI+) m/z 669.2 (M+H)+.

[005427] Step 4 - Tert-butyl 4-[3-rr3-(difluoromethyl)-l-r4-(hydroxymethyl)phenyl1pyrazol4-yl1carbamoyl1 pyrazolorL5-a1pyrimidin yl1piperazine-l-carboxylate (7)

1809

[005428] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-(4isopropoxycarbonyloxycarbonylphenyl) pyrazol yl]carbamoyl]pyrazolo[l,5-a]pyrimidin-5yl]piperazine carboxylate (1.00 g, 1.50 mmol) in THF (50.0 mL) and H2O (10.0 mL) was added LiBH4 (195 mg, 8.97 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. On completion, the mixture was quenched with H2O (10 mL), then extracted with DCM (2 X 30 mL). The organic layers were dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The mixture was triturate with DCM (5 mL) to give the title compound (700 mg, 82% yield) as yellow solid. 1H NMR (400MHz, DMSO-t/6) δ 9.49 (s, IH), 8.98 (s, IH), 8.85 (d, J = 8.0 Hz, IH), 8.33 (s, IH), 7.80 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 53.2 Hz, IH), 6.91 (d, J = 8.0 Hz, IH), 5.35 - 5.24 (m, IH), 4.56 (d, J = 4.4 Hz, 2H), 3.95 - 3.75 (m, 4H), 3.55 - 3.45 (m, 4H), 1.45 (s, 9H).

[005429] Step 5 - Tert-butyl 4-r3-rr3-(difluoromethyl)-l-(4-formylphenvl)pvrazol-4yllcarbamoyUpyrazolo rL5-a1pyrimidin yl1piperazine-l-carboxylate (8)

[005430] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-[4(hydroxymethyl )phenyl]pyrazol yl] carbamoyl]pyrazolo[l,5-a]pyrimidin yl]piperazine-lcarboxylate (700 mg, 1.23 mmol) in THF (30.0 mL) was added DMP (626 mg, 1.48 mmol). The mixture was stirred at 20 °C for 1 hour. On completion, the mixture was quenched with saturated Na2S2O3 (30 mL) and washed with saturated NaHCO3 (2 X 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (680 mg, 90% yield) as yellow solid. 1HNMR (400MHz, DMSO-t/6) δ 10.04 (s, IH), 9.52 (s, IH), 9.17 (s, IH), 8.86 (d, J = 8.0 Hz, IH), 8.35 (s, IH), 8.15 - 8.10 (m, 2H), 8.09 - 8.03 (m, 2H), 7.39 (t, J = 52.8 Hz, IH), 6.96 - 6.86 (m, IH), 3.90 - 3.80 (m, 4H), 3.50 - 3.40 (m, 4H), 1.45 (s, 9H).

[005431] Step 6 - Tert-butyl 4-[3-rr3-(difluoromethyl)-l-r4-rr4-r4-r1-(2,6-dioxo-3piperi dyl) methyl oxoyllcarbamoyUpyrazolo[ L5-a1pyrimidin yl1piperazine carboxylate (10)

[005432] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-(4-formylphenyl)pyrazol-4yl]carbamoyl] pyrazolo[l,5-a]pyrimidin yl]piperazine-l-carboxylate (129 mg, 227 umol), 3-[5[4-(4-aminobutoxy) butyl] methyl oxo-benzimidazol-l-yl]piperidine-2,6-dione (100 mg, 227 umol, HCI, Intermediate OD) in THF (40.0 mL) was added TEA (46.1 mg, 455 umol) and HOAc (41.0 mg, 683 umol). The mixture was stirred at 20 °C for 0.5 hr, then NaBH(OAc)3 (144 mg, 683 umol) was added. The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was

1810 diluted with H2O (2 mL) and concentrated in vacuo. The mixture was purified by reverse phase column (0.1% FA) to give the title compound (60.0 mg, 27% yield) as yellow solid. LC-MS (ESI+) m/z 953.4 (M+H)+.

[005433] Step 7 - N-[3-(difluoromethyl)-l-[4-[[4-[4-[l-(2,6-dioxo piperidvl) methyl-2oxo-benzimidazol yl1butoxy1butylamino1methyl1phenyl1pyrazol yl1 piperazin-l-ylpyrazolo[L5-a1pyrimidine carboxamide (1-441)

[005434] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-[4-[[4-[4-[l-(2,6-dioxo-3piperidyl) methyl oxo-benzimidazol yl]butoxy]butylamino]methyl]phenyl]pyrazol-4yl]carbamoyl]pyrazolo[l,5-a]pyrimidin yl]piperazine-l-carboxylate (60.0 mg, 62.9 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 5.00 mL). The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The mixture was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)ACN]; B%: 8%-32%, 8 min) to give the title compound (31.2 mg, 54% yield) as white solid. 1H NMR (400MHz, DMSO-76) δ 11.00 (s, IH), 9.51 (s, IH), 9.01 (s, IH), 8.80 (d, J = 8.0 Hz, IH), 8.32 (s, IH), 8.28 (s, IH), 7.83 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 53.6 Hz, IH), 7.04 - 6.96 (m, 2H), 6.92 (d, J = 8.0 Hz, IH), 6.86 (d, J = 8.0 Hz, IH), 5.42 - 5.26 (m, IH), 3.90 - 3.86 (m, 4H), 3.67 - 3.54 (m, 4H), 3.40 - 3.33 (m, 4H), 3.31 (s, 3H), 2.88 (s, 4H), 2.75 - 2.70 (m, IH), 2.70 - 2.65 (m, 2H), 2.65 - 2.61 (m, IH), 2.61 - 2.59 (m, IH), 2.05 - 1.95 (m, IH), 1.66 1.48 (m, 8H); LC-MS (ESI+) m/z 853.3 (M+H)+.

[005435] Example 437: 3-[3-Methyl oxo [3-[2-[2-[2-[2-[[4-[(5-tetrahydropyran-4yl-7H-pyrrolo[2.,3-d]pyrimidin-4yl)amino]cvclohexvl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-lyl]piperidine-2.,6-dione (1-442)

1811

1812

TBAI, KOH, KI, THF

[005436] Step 1 - 2-r(5-Bromo chloro-pyrrolor2Xd1pyrimidin yl)methoxy1ethyltrimethyl-silane (2)

[005437] NaH (2.1 g, 52.5 mmol, 60% purity) was suspended in dimethylformamide (50 mL). The mixture was stirred for 10 min and then cooled at 0 °C with an ice bath. 5-bromo-4chloro-7H-pyrrolo[2,3-d] pyrimidine (10 g, 43.0 mmol) dissolved in dimethylformamide (50 mL) was added drop-wise and the mixture was stirred for 30 min. At the same temperature 2(chloromethoxy)ethyl-trimethyl-silane (9.00 g, 53.9 mmol, 9.55 mL) dissolved in dimethylformamide (50 mL) was added drop-wise and stirred for 30 min at 0 °C. On completed,

1813 the mixture was quenched with water (30 mL), extracted with ethyl acetate (3 X 30 mL). The combined organic layers was washed with brine (2X10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction mixture was purified by silica gel chromatography (PE: EA= 30:1) to give the title compound (13.2 g, 85% yield) as a white solid. 1H NMR (400MHz, CD3OD) δ 8.71 - 8.50 (m, IH), 7.81 (s, IH), 5.67 (s, 2H), 3.69 - 3.54 (m, 2H), 0.94 - 0.83 (m, 3H), -0.06 (s, 9H), LC-MS (ESI+) m/z 361.9 (M+H)+.

[005438] Step 2 - Tert-butyl N-r4-[[5-bromo (2-trimethylsilylethoxymethyl)pyrrolo[2,3d1pyrimidin yl1 aminolcyclohexyllcarbamate (4)

[005439] To a solution of 2-[(5-bromo chloro-pyrrolo[2,3-d]pyrimidin-7yl)methoxy]ethyl-trimethyl-silane (1 g, 2.76 mmol) and tert-butyl N-(4aminocyclohexyl)carbamate (591 mg, 2.76 mmol, CAS# 177906 8) in ACN (20 mL) was added Na2CO3 (585 mg, 5.52 mmol). The reaction mixture was stirred at 80 °C for 12 hrs. On completion, the reaction mixture was filtered and concentrated in vacuo. The crude product was triturated with ethyl acetate (10 mL) to give the title compound (1.48 g, 95% yield) as a white solid. 1H NMR (400MHz, CDCh) δ 8.33 (s, IH), 7.06 (s, IH), 5.91 (d, J = 7.2 Hz, IH), 5.52 (s, 2H), 4.45 (s, IH), 4.14 (d, J = 7.2 Hz, IH), 3.60 - 3.46 (m, 3H), 2.25 (d, J = 9.8 Hz, 2H), 2.16 2.05 (m, 2H), 1.47 (s, 9H), 1.44 - 1.34 (m, 4H), 0.98 - 0.86 (m, 2H), -0.03 (s, 9H). LC-MS (ESI+) m/z 540.1; 542.1 (M+H, M+3)+.

[005440] Step 3 - Tert-butyl N-r4-rr5-(3,6-dihydro-2H-pyran yl) (2trimethylsilylethoxymethyl)pyrrolo [2,3-d1pyrimidin yl1amino1cyclohexyl1carbamate (6)

[005441] A mixture of tert-butyl N-[4-[[5-bromo (2trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin yl] amino]cyclohexyl]carbamate (1.34 g, 2.48 mmol), 2-(3,6-dihydro-2H-pyran yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (1.56 g, 7.44 mmol, CAS# 287944 5), Berttphos-Pd-G3 (224 mg, 247 umol, CAS# 1470372 8) and K2CO3 (685 mg, 4.96 mmol) in a mixed solvent of THF (20 mL) and H2O (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 55 °C for 3 hrs under N2 atmosphere. On completion, the reaction mixture was concentrated in vacuo. The residue was washed with ethyl acetate (50 mL). After, the organic layer was concentrated in vacuo. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (1.06 g, 78% yield) as a yellow solid. 1H NMR (400MHz, DMSOQ) δ 8.28 (s, IH), 7.44 (s, IH), 6.81 (d, J= 7.6 Hz, IH), 5.89 (s, IH), 5.68 (d, J = 7.6 Hz, IH), 5.55 (s, 2H), 4.32 (d, J= 2.0 Hz,

1814

2H), 4.04 (s, IH), 3.92 (t, J= 5.2 Hz, 2H), 3.58 (t, J = 8.0 Hz, 2H), 3.37 - 3.30 (m, IH), 2.52 (s, 2H), 2.10 (d, J = 8.0 Hz, 2H), 1.90 (s, 2H), 1.46 (s, 9H), 1.45 - 1.36 (m, 4H), 0.90 (t, J= 8.0 Hz, 2H), 0.00 (s, 9H); LC-MS (ESI+) m/z 544.4 (M+H)+.

[005442] Step 4:Tert-butyl N-r4-rr5-tetrahvdropyran vl (2trimethylsilylethoxymethyl)pyrrolo[2,3-d1 pyrimidin yl1amino1cyclohexyl1carbamate (7)

[005443] To a solution of tert-butyl N-[4-[[5-(3,6-dihydro-2H-pyran yl) (2trimethylsilylethoxymethyl) pyrrolo[2,3-d]pyrimidin yl]amino]cyclohexyl]carbamate (1.06 g, 1.95 mmol) in methanol (5 mL) was added Pd/C (100 mg, 163 umol, 10%, wt) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 20 °C for 36 hrs. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (1.00 g, 94% yield) as a white solid. 1H NMR (400MHz, DMSO-» δ 8.23 (s, IH), 7.12 (s, IH), 6.83 (d, J = 7.6 Hz, IH), 5.81 (d, J = 7.6 Hz, IH), 5.52 (s, 2H), 4.13 (d, J = 7.6 Hz, IH), 4.00 (dd, 7=2.8, 11.2 Hz, 2H), 3.65 (t, 7= 11.2 Hz, 2H), 3.56 (t, 7= 8.0 Hz, 2H), 3.38 - 3.32 (m, IH), 2.04 (d, 7= 10.8 Hz, 2H), 1.98 - 1.92 (m, 3H), 1.70 - 1.54 (m, 4H), 1.48 (s, 9H), 1.46 - 1.27 (m, 4H), 0.91 - 0.83 (m, 2H), 0.00 (s, 9H); LC-MS (ESI+) m/z 546.4 (M+H) +.

[005444] Step 5 - [4-[(4-Aminocyclohexyl)amino1 tetrahydropyran yl-pyrrolo[2,3d1pyrimidin yl1 methanol (8)

[005445] To a solution of tert-butyl N-[4-[[5-tetrahydropyran yl (2trimethylsilylethoxymethyl)pyrrolo [2,3-d]pyrimidin yl]amino]cyclohexyl]carbamate (1.00 g, 1.83 mmol) in DCM (20 mL) was added HCl/dioxane (4 M, 30 mL). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (633 mg, 100% yield) as a white solid. LC-MS (ESI+) m/z 346.2 (M+H)+.

[005446] Step 6 - N4-(5-tetrahvdropvran vl-7H-pvrrolo[2,3-d1pyrimidin-4yl)cyclohexane-L4-diamine (9)

[005447] To a solution of [4-[(4-aminocyclohexyl)amino] tetrahydropyran ylpyrrolo[2,3-d]pyrimidin- 7-yl]methanol (633 mg, 1.83 mmol) in a mixed solvent of THF (3 mL), H2O (1 mL) and MeOH (1 mL) was added L1OH.H2O (384 mg, 9.16 mmol). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the reaction mixture was acidified with HCI (2 N) to pH = 2. The reaction mixture was concentrated in vacuo. The crude product was purified by

1815 reversed-phase HPLC (0.1% NH3*H2O condition) to give the title compound (250 mg, 43% yield) was added as a green solid. LC-MS (ESI+) m/z 316.2 (M+H)+.

[005448] Step 7 - 2-(2-(2-(2-Prop vnoxyethoxv)ethoxv1 ethoxy]ethanol (12)

[005449] To a mixture of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (20.0 g, 102 mmol, 17.7 mL) and 3-bromoprop yne (14.7 g, 123 mmol) in THF (200 mL) was added TBAI (2.28 g, 6.18 mmol), KI (2.56 g, 15.45 mmol) and KOH (5.78 g, 102 mmol). The mixture was stirred at 25 °C for 12 hours. On completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA= 5/1 to 0/1) to give the title compound (16.0 g, 67% yield) as a light yellow oil. 1H NMR (400MHz, CDCh) δ 4.18 (d, J= 2.4 Hz, 2H), 3.70 (d, J = 4.8 Hz, 2H), 3.67 (d, J= 3.2 Hz, 2H), 3.69 - 3.61 (m, 10H), 3.60 - 3.57 (m, 2H), 2.73 (s, IH), 2.42 (t, J= 2.4 Hz, IH).

[005450] Step 8 - 3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethoxy1prop-l-ynyl13-methyl oxo- benzimidazol-l-yl1piperidine-2,6-dione (14)

[005451] To a mixture of 2-[2-[2-(2-prop ynoxyethoxy)ethoxy]ethoxy]ethanol (1.03 g, 4.44 mmol) and 3-(4-bromo m ethyl oxo-benzimidazol-l-yl )piperi dine-2,6-dione (0.50 g, 1.48 mmol, Intermediate HP) in DMSO (20 mL) was added Cui (56.3 mg, 295umol), P(t-Bu)3 (2.30 g, 1.48 mmol, 2.67 mL, 13% purity, a solution of toluene), DIEA (955 mg, 7.39 mmol) and Pd(PPh3)2C12 (103 mg, 147 umol). The reaction mixture was stirred at 80 °C for 3 hours. On completion, the reaction mixture was diluted with water (60 mL) and extracted with EA (4 X 60 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to give a residue. The crude product was purified by prep-HPLC (0.1 % FA condition) to give the title compound (0.50 g, 69% yield) as brown oil. 1H NMR (400MHz, DMSOA) δ = 11.11 (s, IH), 7.17 (d, 7= 8.0 Hz, IH), 7.15-7.11 (m, IH), 7.06-7.00 (m, IH), 5.40 (dd,7=5.2, 12.8 Hz, IH), 4.55 (t, 7= 5.2 Hz, IH), 4.46 (s, 2H), 3.70-3.61 (m, 5H), 3.60-3.57 (m, 2H), 3.53 - 3.51 (m, 6H), 3.49 - 3.47 (m, 4H), 3.41 - 3.39 (m, 2H), 2.95 - 2.84 (m, IH), 2.77 - 2.58 (m, 2H), 2.07 - 1.99 (m, IH).

[005452] Step 9 - 3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy1ethoxy1ethoxy1propyl1-3methyl oxo- benzimidazol-l-yl1piperidine-2,6-dione (15)

[005453] To a mixture of 3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]prop-lynyl] methyl oxo-benzimidazol-l-yl]piperi dine-2,6-dione (200 mg, 408 umol) in THF (10 mL) was added Pd/C (100 mg, 10% wf) and Pd(OH)2/C (100 mg, 10% wt). The reaction mixture

1816 was stirred at 25 °C for 12 hours under H2 (15 Psi) atmosphere. On completion, the reaction mixture was concentrated in vacuo to give the title compound (180 mg, 89% yield) as white solid which was used for the next step without purification. 1H NMR (400MHz, DMSO-/6) δ 11.09 (s, IH), 6.96 (d, J= 4.4 Hz, 2H), 6.90 - 6.86 (m, IH), 5.36 (dd, J= 5.2, 12.4 Hz, IH), 4.57 (t, J= 52 Hz, IH), 4.03 (q,/= 7.2 Hz, IH), 3.56 (s, 3H), 3.52 (d,/= 5.6 Hz, 10H), 3.48 - 3.45 (m, 4H), 3.40 (d, /= 5.2 Hz, 2H), 2.98 - 2.93 (m, 2H), 2.89 - 2.84 (m, IH), 2.72 - 2.63 (m, 2H), 2.61 - 2.58 (m, 2H), 2.02 - 1.96 (m, 2H), 1.85-1.81 (m, IH); LC-MS (ESI+) m/z 494.3 (M+H)+.

[005454] Step 10 - 2-[2-[2-[2-[3-[l-(2,6-Dioxo piperidyl) methyl oxo-benzimidazol4-yl1propoxy1ethoxy1 ethoxylethoxylacetaldehyde (16)

[005455] To a mixture of 3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]3-methyl oxo- benzimidazol-l-yl]piperidine-2,6-dione (180 mg, 364 umol) in THF (20 mL) was added DMP (309 mg, 729 umol). The reaction mixture was stirred at 25 °C for 1.5 hours. On completion, the reaction mixture was quenched by saturated Na2S2O3 (15 mL) and saturated NaHCO3 (15 mL) at 25 °C, and then stirred for 30 minutes, then the organic layers were separated and concentrated in vacuo to give the title compound (179 mg, 100% yield) as a red oil. 1H NMR (400MHz, DMSO&#1470;/) δ 11.07 (s, IH), 9.56 (s, IH), 6.96 (d, /= 8.8 Hz, 2H), 6.88 (d, /= 8.8 Hz, IH), 5.41 - 5.31 (m, IH), 4.16 (s, 2H), 3.60 - 3.43 (m, 15H), 3.01 - 2.92 (m, 2H), 2.90 - 2.84 (m, IH), 2.74 - 2.54 (m, 4H), 2.04 - 1.96 (m, IH), 1.85 - 1.81 (m, 2H). LC-MS (ESI+) m/z 492.3 (M+H)+.

[005456] Step 11 - 3-[3-Methyl oxo [3-[2-[2-[2-[2-[[4-[(5-tetrahydropyran yl-7Hpyrrolo[2,3-d1 pyrimidin-4yl)amino1cyclohexyl1amino1ethoxy1ethoxy1ethoxy1ethoxy1propyl1benzimidazol-l-yl1piperidine2,6-dione (1-442)

[005457] To a solution of N4-(5-tetrahydropyran yl-7H-pyrrolo[2,3-d]pyrimidin-4yl)cyclohexane- 1,4-diamine (50.0 mg, 158 umol) and 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl)-3methyl oxo- benzimidazol yl]propoxy]ethoxy]ethoxy]ethoxy]acetaldehyde (77.9 mg, 158 umol) in a mixed solvent of THF (5 mL) and DMF (1 mL) was added HOAc (9.52 mg, 158. umol) and NaBH(OAc)3 (40.3 mg, 190 umol). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 13%-31%, 6 min) to give the title compound (11.0 mg, 8% yield) as

1817 white solid. 1H NMR (400MHz, DMSO-de) δ 11.35 (s, 2H), 8.35 (s, IH), 8.08 (s, IH), 7.05 - 6.80 (m, 4H), 5.60 (d, J = 7.6 Hz, IH), 5.36 (dd, J= 4.8, 12.0 Hz, IH), 4.05 (s, IH), 3.90 (d, J= 8.4

Hz, 2H), 3.59 - 3.49 (m, 20H), 3.45 (t, J= 5.6 Hz, 2H), 3.26 - 3.21 (m, IH), 3.01 - 2.91 (m, 4H),

2.90 - 2.84 (m, IH), 2.76 - 2.67 (m, IH), 2.62 (m, IH), 2.13 - 1.78 (m, 9H), 1.60 - 1.34 (m, 6H).

LC-MS (ESI+)m/z 791.5 (M+H)+.

[005458] Example 438: 3-[3-Methvl oxo [3-[2-[2-[2-[2-oxo [4-[4-[(5 tetrahvdropvran vl-7H-pvrrolo[2,3-d]pyrimidin yl)amino] cvclohexyl] piperazin-1yl] ethoxy] ethoxy] ethoxy] ethoxy] propyl] benzimidazol- 1-yl] piperidine-2,6-dione (1-444)

1-444

[005459] Step 1 - Tert-butyl 2-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxylethoxy]ethoxy]ethoxy]acetate (3)

[005460] To a mixture of 3-(4-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6dione (600 mg, 1.77 mmol, Intermediate HP), tert-butyl 2-[2-[2-(2-prop-2ynoxyethoxy)ethoxy]ethoxy]acetate (1.07 g, 3.55 mmol, from Example 441) in DMF (10 mL) was added Cui (67.6 mg, 355 umol), Cs2CO3 (2.89 g, 8.87 mmol) and Pd(PPh3)2C12 (249 mg, 355 umol) under N2. The reaction mixture was stirred at 80 °C for 3 hours. On completion, the mixture

1818 was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (2 X 30 mL).The combined organic phase was washed with brine (2 X 30mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by reversedphase (0.1% FA condition) to give the title compound (598 mg, 60% yield) as brown oil. 1H NMR (400MHz, CDCh) δ 8.29 (s, IH), 7.16 (d, J = 7.6 Hz, IH), 6.97 (t, J = 8.0 Hz, IH), 6.75 (d, J = 8.0 Hz, IH), 5.23 - 5.15 (m, IH), 4.46 (s, 2H), 4.01 (s, 2H), 3.76 (s, 3H), 3.76 - 3.66 (m, 12H), 2.99 - 2.68 (m, 3H), 2.29 - 2.16 (m, IH), 1.46 (s, 9H).

[005461] Step 2 - Tert-butyl 2-r2-r2-r2-r3-r1-(2,6-dioxo piperidvl) methyl oxobenzimidazol yl1 propoxy]ethoxy]ethoxy]ethoxy]acetate (4)

[005462] To a solution of tert-butyl 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol- 4-yl]prop ynoxy]ethoxy]ethoxy]ethoxy]acetate (578 mg, 1.03 mmol) in THF (5 mL) was added Pd/C (100 mg, 20% purity) and Pd(OH)2/C (100 mg, 20% purity) under N2. The suspension was degassed under vacuum and purged with H2 3 times. The mixture was stirred at 20 °C for 12 hours under H2 (15 psi). On completion, the mixture was concentrated in vacuo to give a title compound (540 mg, 92% yield) as brown oil. LC-MS (ESI+) m/z 586.3 (M+Na)+.

[005463] Step 3 - 2-r2-r2-r2-r3-r1-(2,6-Dioxo piperidyl) methyl oxo-benzimidazol-4yl1propoxy1ethoxy1 ethoxy]ethoxy]acetic acid (5)

[005464] To a mixture of tert-butyl 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl] prop oxy] ethoxy ]ethoxy ]ethoxy ]acetate (520 mg, 922 umol) in DCM (2 mL) was added TFA (210 mg, 1.85 mmol). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (436 mg, 93% yield) as brown oil. LC-MS (ESI+) m/z 508.3 (M+H) +.

[005465] Step 4 - 3-r3-Methyl oxo r3-r2-r2-r2-r2-oxo r4-[4-r(5-tetrahydropyran yl7H-pyrrolo[2,3-d1 pyrimidin yl)amino1cyclohexyl1piperazin-lvl1ethoxv1ethoxv1ethoxv1ethoxv1propvl1benzimidazol-l-vl1piperidine-2,6-dione (1-444)

[005466] To a mixture of 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] ethoxy]ethoxy]ethoxy]acetic acid (39.6 mg, 78.0 umol), N-(4piperazin-l-ylcyclohexyl) tetra hydropyran yl-7H-pyrrolo[2,3-d]pyrimidin amine (30.0 mg, 78.0 umol, Intermediate OP) in DMF (1.5 mL) was added DIEA (30.2 mg, 234 umol) and

1819

HATU (35.6 mg, 93.6 umol). The reaction mixture was stirred at 20 °C for 1 hr. On completion, water (1.5 mL) was added into the reaction mixture and the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.05% HC1)-ACN]; B%: 7%-27%) to give the title compound (2.00 mg, 2% yield) as a white solid. 1HNMR (400MHz, DMSO-d6) δ 11.08 (s, IH), 9.07 (s, IH), 8.10 (s, IH), 7.07 - 6.80 (m, 4H), 5.36 (d, J= 5.2, 12.4 Hz, IH), 4.18 (s, 2H), 3.90 ( d, J= 10.4 Hz, 2H), 3.66 - 3.50 (m, 22H), 3.48 - 3.40 (m, 6H), 3.17 - 3.06 (m, 4H), 3.00 - 2.83 (m, 5H), 2.75 - 2.56 (m, 3H), 2.25 - 1.94 (m, 4H), 1.84 (d, J = 8.0 Hz, 4H), 1.60 - 1.46 (m, 4H); LCMS (ESI+) m/z 874.5 (M+H)+.

[005467] Example 439: N-[3-(difluoromethyl)-l-[4-[4-[4-[l-(2.,6-dioxo piperidvl)-3methvl oxo-benzimidazol vl]butoxy|butvlcarbamovl]phenvl1pvrazol vl] piperazinl-vl-pyrazolo[l.,5-a1pvrimidine carboxamide (1-445)

HCI/dioxane, DCM

1820

[005468] Step 1 - Tert-butyl 4-[3-[[3-(difluoromethyl)-l-[4-[4-[4-[l-(2,6-dioxo piperidyl)3-methyl oxo-benzimidazol yl1butoxy1butylcarbamoyl1phenyl1pyrazol-4vl1carbamoyl1pyrazolo[L5-a1pyrimidin yl1piperazine-l-carboxylate (3)

[005469] To a solution of 4-[4-[[5-(4-tert-butoxycarbonylpiperazin-l-yl)pyrazolo[l,5a]pyrimidine carbonyl] amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (66.3 mg, 113 umol, from Example 436), 3-[5-[4- (4-aminobutoxy)butyl] methyl oxobenzimidazol-lyl]piperidine-2,6-dione (50.0 mg, 113 umol, HCI, Intermediate OD) in DMF (3.00 mL) was added HATU (51.9 mg, 136 umol) and DIEA (73.6 mg, 569 umol). The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was diluted with H2O (15 mL), filtered and the filter cake was concentrated in vacuo to give the title compound (90.0 mg, 81% yield) as yellow solid. LC-MS (ESI+) m/z 967.4 (M+H)+.

[005470] Step 2 - N-[3-(difluoromethyl)-l-[4-[4-[4-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl1butoxy1butylcarbamoyl1phenyl1pyrazol yl1 piperazin-l-ylPvrazolo[L5-a1pvrimidine carboxamide (1-445)

[005471] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-[4-[4-[4-[l-(2,6-dioxo-3piperi dyl) methyl oxo-benzimidazol yl]butoxy]butylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]pyrazolo[l,5-a]pyrimidin yl]piperazine-l-carboxylate (150 mg, 155 umol) in DCM (5.00 mL) was added HCI/dioxane (4 M, 7.50 mL). The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The mixture was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)ACN]; B%: 17%-41%, 8 min) to give the title compound (67.5 mg, 49% yield) as off-white solid. 1H NMR (400MHz, DMSO-76) δ 11.07 (s, IH), 9.53 (s, IH), 9.10 (s, IH), 8.79 (d, J = 8.0 Hz, IH), 8.56 (t, J = 5.6 Hz, IH), 8.32 (s, IH), 8.26 (s, IH), 8.04 - 7.98 (m, 2H), 7.97 - 7.92 (m, 2H), 7.31 (t, J = 5.6 Hz, IH), 7.02 (s, IH), 7.00 (d, J = 8.0 Hz, IH), 6.91 (d, J = 8.0 Hz, IH), 6.88 6.83 (m, IH), 5.37 - 5.28 (m, IH), 3.77 - 3.70 (m, 4H), 3.33 - 3.29 (m, 9H), 2.93 - 2.88 (m, IH), 2.86 - 2.83 (m, 4H), 2.75 - 2.68 (m, IH), 2.65 - 2.62 (m, 2H), 2.61 - 2.57 (m, IH), 2.06 - 1.97 (m, IH), 1.64 - 1.52 (m, 8H); LC-MS (ESI+) m/z 867.3 (M+H)+.

[005472] Example 440: N-[3-(difluoromethvD-l-[4-[[2-[2-[3-[l-(2.,6-dioxo piperidvD3-methyl oxo- benzimidazol yl] propoxy] ethoxy] ethylamino] methyl] phenyl] pyrazol-4yl] piperazin-l-yl-pyrazolo[l.,5-a]pyrimidine carboxamide (1-446)

1821

TEA, HOAc, NaBH(OAc)3, THF

[005473] Step 1 - Tert-butyl 4-Γ3-Γ[3-(&#940;&#943;Αυοτοη16&#912;&#943;1ν1) Γ4-ΓΓ2-Γ2-Γ3-Γ1-(2.6-(1&#912;οχο-3piperi dyl) methyl oxo-benzimidazol-4vl]propoxy]ethoxy]ethylamino]methyl]phenvl]pvrazol yl]carbamoyl]pyrazolo[L5a]pvrimidin yl]piperazine-l-carboxylate (3)

[005474] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-(4-formylphenyl)pyrazol-4yl]carbamoyl] pyrazolo[l,5-a]pyrimidin yl]piperazine-l-carboxylate (128 mg, 226 umol, from Example 436), 3-[4-[3-[2-(2-aminoethoxy)ethoxy]propyl] methyl oxobenzimidazol-lyl]piperidine-2,6-dione (100 mg, 226 umol, HCI, from Intermediate IQ) in THF (20.0 mL) was added TEA (45.9 mg, 453 umol) and HOAc (40.8 mg, 680 umol).The mixture was stirred at 20 °C for 0.5 hr, then NaBH(OAc)3 (144 mg, 680 umol) was added. The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was diluted with H2O (2.00 mL). The mixture was concentrated in vacuo. The mixture was purified by reverse phase column (0.1% FA) to give the title compound (180 mg, 83% yield) as yellow solid. LC-MS (ESI+) m/z 955.3 (M+H)+.

1822

[005475] Step 2 -N-r3-(difluoromethyl)-l-r4-rr2-r2-r3-r1-(2,6-dioxo piperidyl) methyl2-oxol-yl-pyrazolorL5-a1pyrimidine carboxamide (1-446)

[005476] To a solution of tert-butyl 4-[3-[[3-(difluoromethyl)-l-[4-[[2-[2-[3-[l-(2,6-dioxo3-piperi dyl) methyl oxo-benzimidazol-4yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]pyrazolo[l,5a]pyrimidin yl]piperazine-l-carboxylate(180 mg, 188 umol) in DCM (2 mL) was added HCI/dioxane (4 M, 6 mL). The mixture was stirred at 20 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 12%-33%, 7 min) to give the title compound (89.5 mg, 53% yield) as white solid. 1H NMR (400MHz, DMSO-t/6) δ 11.10 (s, IH), 9.50 (s, IH), 9.50 (s, IH), 8.98 (s, IH), 8.82 (d, J = 8.0 Hz, IH), 8.33 (s, IH), 8.23 (s, IH), 7.79 (d, 7=8.4 Hz, 2H), 7.51 (d, 7 = 8.4 Hz, 2H), 7.29 (t, 7= 54 Hz, IH), 6.95 (d, 7 = 6.4 Hz, 2H), 6.92 (s, IH), 6.88 - 6.83 (m, IH), 5.43 - 5.29 (m, IH), 3.89 (s, 3H), 3.84 (s, 4H), 3.59 3.54 (m, 8H), 3.49 - 3.44 (m, 2H), 2.94 (s, 4H), 2.94 - 2.91 (m, 2H), 2.91 - 2.85 (m, IH), 2.83 2.77 (m, 2H), 2.76 - 2.66 (m, IH), 2.66 - 2.58 (m, IH), 2.04 - 1.94 (m, IH), 1.89 - 1.76 (m, 2H); LC-MS (ESL)/&#1524;z 855.5 (M+H)+.

[005477] Example 441: 3- [3-Methyl oxo [3- [2- [2- [2- [2-0X0 [4-[4-[(5-tetrahvdropvran4-vl-7H-pyr rolo d] pvrimidin yl)amino] cyclohexyl] piperazin-1yl]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol- 1-yl]piperidine-2,6-dione (1-447)

1823

1-447

[005478] Step 1 - 2 (2-Prop ynoxyethoxy)ethoxy1ethanol (3)

[005479] To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (10.0 g, 66.5 mmol, 8.93 mL, CAS#112 6) and 3-bromoprop yne (7.92 g, 66.5 mmol, 5.74 mL, CAS#106 7) in THF (100 mL) was added KI (1.66 g, 9.99 mmol), TBAI (1.48 g, 4.00 mmol) and KOH (3.74 g, 66.5 mmol). The reaction mixture was stirred at 25 °C for 16 hrs. On completion, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, the residue was diluted with H2O (50 mL), and then extracted with EA (2 X 80 mL), the organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (10.0 g, 79% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 4.19 - 4.12 (m, 2H), 3.74 - 3.57 (m, 10H), 3.57 - 3.52 (m, 2H), 2.42 (s, IH), 2.38 (t, J= 2.4 Hz, IH).

1824

[005480] Step 2 - Tert-butyl 2-r2-r2-(2-prop ynoxyethoxy)ethoxy1ethoxy1acetate (5) [005481] To a solution of 2-[2-(2-prop ynoxyethoxy)ethoxy]ethanol (4.0 g, 21.25 mmol) in THF (50 mL) was added NaH (1.28 g, 31.8 mmol, 60% purity) at 0 °C, the mixture was stirred at 25 °C for 30 min, then tert-butyl 2-chloroacetate (6.40 g, 42.5 mmol, 6.10 mL, CAS#107 5) was added to the mixture, the reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was quenched by H2O (50 mL), and extracted with EA (2 X 100 mL). The organic phase was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (3.60 g, 56% yield) as yellow oil. 1H NMR (400MHz, CDCh) δ 4.20 (d, J= 2.4 Hz, 2H), 4.01 (s, 2H), 3.72 - 3.65 (m, 12H), 2.42 (t, J= 2.4 Hz, IH), 1.47 (s, 9H).

[005482] Step 3 - Tert-butyl 2-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1prop ynoxy] ethoxy] ethoxy] ethoxy] acetate (6)

[005483] To a solution of tert-butyl 2-[2-[2-(2-prop ynoxyethoxy)ethoxy]ethoxy]acetate (1.16 g, 3.84 mmol) and 3-(5-bromo methyl oxo-benzimidazol-l-yl)piperidine-2,6-dione (650 mg, 1.92 mmol, Intermediate HN) in DMF (10 mL) was added Cui (73.2 mg, 384 umol), Pd(PPh3)2Ch (269 mg, 384 umol) and Cs2CO3 (3.13 g, 9.61 mmol). The reaction mixture was stirred at 80 °C for 2 hrs under N2. On completion, the mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (550 mg, 51% yield) as a yellow solid. 1H NMR (400MHz, DMSO-t/6)6 11.11 (s, IH), 7.33 (s, IH), 7.21 - 7.09 (m, 2H), 5.39 (dd, J= 5.2, 12.8 Hz, IH), 4.39 (s, 2H), 3.97 (s, 2H), 3.68 - 3.61 (m, 2H), 3.59 - 3.52 (m, 10H), 3.34 (s, 3H), 2.97 - 2.82 (m, IH), 2.76 - 2.57 (m, 2H), 2.06 - 2.00 (m, IH), 1.41 (s, 9H); LC-MS (ESI+) m/z 582.3 (M+Na)+.

[005484] Step 4 - Tert-butyl 2-r2-r2-r2-r3-r1-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl1 propoxy]ethoxy]ethoxy]ethoxy]acetate (7)

[005485] To a solution of tert-butyl 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]prop ynoxy]ethoxy]ethoxy]ethoxy]acetate (550 mg, 982 umol) in THF (20 mL) was added Pd(OH)2/C (250 mg, 915 umol, 10% purity) and Pd/C (250 mg, 915 umol, 10% purity), the reaction mixture was stirred at 25 °C for 12 hrs under H2 (15 Psi). On completion, the residue was filtered and the filtrate was concentrated in vacuo to give the title compound (500 mg, 90% yield) as a white solid. LC-MS (ESI+) m/z 508.2 (M + H-56)+.

[005486] Step 5 - 2-r2-r2-r2-r3-r1-(2,6-Dioxo piperidyl) methyl oxo-benzimidazol-5yllpropoxylethoxy] ethoxy]ethoxy]acetic acid

1825

[005487] To a solution of tert-butyl 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl] propoxy]ethoxy]ethoxy]ethoxy]acetate (100 mg, 177 umol)in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL), the reaction mixture was stirred at 25 °C for 12 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (110 mg,

95% yield) as colorless oil. LC-MS (ESI+) m/z 508.3 (M+H)+.

[005488] Step 6 - 3-[3-Methyl oxo [3-[2-[2-[2-[2-oxo [4-[4-[(5-tetrahydropyran yl7H-pyrrolo[2,3-d1pyrimidin yl)amino1cyclohexyl1piperazin-lvl1ethoxv1ethoxv1ethoxv1ethoxv1propvl1benzimidazol- l-yl1piperidine-2,6-dione (1-447)

[005489] To a solution of 2-[2-[2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxobenzimidazol yl]propoxy] ethoxy]ethoxy]ethoxy]acetic acid (15.0 mg, 24.1 umol) and N-(4piperazin-l-ylcyclohexyl) tetrahydropyran yl-7H-pyrrolo[2,3-d]pyrimidin amine (9.28 mg, 24.1 umol, Intermediate OP) in DMF (5 mL) was DIPEA (15.5 mg, 120 umol, 21.0 uL) and HATU (11.0 mg, 28.9 umol). The mixture was stirred at 25 °C for 1.5 hrs. On completion, the mixture was quenched with H2O ( 5 mL), then concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 8%-32%, 8 min) to give the title compound (6.09 mg, 28% yield) as a white solid. 1HNMR (400MHz, DMSO-A) δ 11.29 (s, IH), 11.07 (s, IH), 8.06 (s, IH), 7.05 - 6.96 (m, 2H), 6.92 - 6.78 (m, 2H), 5.51 ( d, J= 8.0 Hz, IH), 5.32 (dd, J= 5.2, 12.8 Hz, IH), 4.12 (s, 2H), 4.08 - 3.98 (m, IH), 3.94 - 3.85 (m, 2H), 3.61-3.45 (m, 18H), 3.31 (s, 3H), 3.29 - 3.18 (m, 3H), 2.92 - 2.84 (m, IH), 2.71 - 2.57 (m, 4H), 2.49 - 2.39 (m, 4H), 2.36 - 2.28 (m, IH), , 2.07 - 1.94 (m, 3H), 1.89 - 1.69 (m, 6H), 1.63 1.28 (m, 6H); LC-MS (ESI+) m/z 874.5 (M+H)+.

[005490] Table 23: Compounds synthesized via Method 12 with the coupling of various amines and acids in Step 1.

<td> Ex-#a</td><td> I-#</td><td> Step 1 Intermediate Amine</td><td> Step 1 Intermediate Acid</td><td> LCMS (ES+) m/z (M+H)+</td><td>1HNMR (400MHz, DMSO-d6) δ</td>

1826

1827

1828

1829

1830

<td> 461b</td><td> 1-466</td><td> RD</td><td> 2-[2-[2-[2-[3[1-(2,6-di oxo3-piperidyl)3-methyl-2oxobenzimidazol -5yl]propoxy]ethoxy] ethox yl. ethoxy] acetic acid (synthesized via Steps 1-5 of Example 441,1-447)</td><td> 866.1</td><td> 11.07 (s, IH), 9.38 (s, IH), 8.79 (d, J= 8.0 Hz, IH), 8.35 (s, IH), 8.29 (s, IH), 7.26 - 6.95 (m, 3H), 6.88 (d, J= 8.0 Hz, IH), 6.85 6.80 (m, IH), 5.32 (dd, 7= 5.2, 12.8 Hz, IH), 4.21 (s, 2H), 3.87 (s, 3H), 3.84-3.81 (m, 2H), 3.63 -3.55(m, 8H), 3.53 - 3.48 (m, 6H), 3.46 - 3.40 (m, 4H), 3.34 3.32 (m, 2H), 3.30 (s, 3H), 2.96 2.82 (m, IH), 2.74 - 2.57 (m, 4H), 2.05 - 1.95 (m, IH), 1.82 - 1.70 (m, 2H)</td>

<td> 462b</td><td> 1-467</td><td> RD</td><td> 2-[2-[2-[2-[2[[2-(2,6di oxo-3piperidyl)1,3-di oxoisoindolin-4yl]amino]etho xy]ethoxy] ethox yl. ethoxy] acetic acid (synthesized via Steps 1-2 of Example 161,1-161)</td><td> 866.4</td><td> 11.08 (s, IH), 9.39 (s, IH), 8.82 (d, 7= 7.6 Hz, IH), 8.42-8.26 (m, 2H), 7.65 - 7.50 (m, IH), 7.21 -6.85 (m, 4H), 6.58 (d, 7= 5.2 Hz, IH), 5.05 (d,7= 5.2, 12.8 Hz, IH), 4.22 (s, 2H), 3.94 - 3.81 (m, 7H), 3.64-3.51 (m, 18H), 3.44 (d, 7= 5.6 Hz, 2H), 2.99 2.77 (m, IH), 2.61 (d, 7= 2.4 Hz, 2H), 2.14 - 1.92 (m, IH)</td>

1831

<td> 463b</td><td> 1-468</td><td> RD</td><td> 2-[2-[2-[2[[2-(2,6di oxo-3piperidyl)1,3-di oxoisoindolin-4yl]amino]ethoxy] ethox yl. ethoxy] acetic acid (synthesized via Steps 1-2 of Example 152,1-152)</td><td> 822.2</td><td> 11.08 (s, IH), 9.37 (s, IH), 8.80 (d, J= 8.0 Hz, IH), 8.36 (s, IH), 8.29 (s, IH), 7.53 (d, J= 7.2, 8.4 Hz, IH), 7.15-6.96 (m, 3H), 6.89 (d, J= 8.0 Hz, IH), 6.57 (t, J = 5.6 Hz, IH), 5.05 (d,J=5.6, 12.8 Hz, IH), 4.21 (s, 2H), 3.89 (s, 3H), 3.84 (s, 2H), 3.63 - 3.55 (m, 14H), 3.44 (d, J= 5.6 Hz, 2H), 3.29 (s, 2H), 2.93 - 2.82 (m, IH), 2.62 - 2.53 (m, 2H), 2.06 1.98 (m, IH)</td>

1832

<td> 466</td><td> 1-471</td><td> 4-[2-[2-[2-(2aminoethoxy) ethoxy] ethox yl. ethylamino]2-(2,6-dioxo3-piperidyl) isoindoline- 1,3-di one (synthesized via Steps 1-2)</td><td> WB</td><td> 801.1</td><td> 10.5 (s, IH), 8.71 (d, J= 8.0 Hz, IH), 8.38 (s, IH), 8.28 - 8.20 (m, 2H), 8.05 (t, J= 5.6 Hz, IH), 7.54 (dd, J= Ί2, 8.4 Hz, IH), 7.08 (d, J= 8.8 Hz, IH), 7.01 (d, J= 7.2 Hz, IH), 6.83 (d, J= 8.0 Hz, IH), 6.57 (t, J= 5.6 Hz, IH), 5.04 (dd, J= 5.6, 12.8 Hz, IH), 4.05 - 3.85 (m, 7H), 3.61 - 3.57 (m, 2H), 3.55 -3.50(m, 10H), 3.45 - 3.38 (m, 4H), 2.93 - 2.88 (m, 4H), 2.87 2.80 (m, IH), 2.62 - 2.52 (m, 2H), 2.06 - 1.98 (m, IH)</td>

1833

1834

1835

1836

1837

1838

1839

1840

1841

1842

3Variations in reaction time for Method 12 were as follows: Step 1 was run anywhere from 0.5-12 h, and Step 2 anywhere from 10 min-17 h. If the product of Step 1 was not a precipitate, a standard work up with water and extraction with ethyl acetate was used to isolate the product. Step 2 deprotection could also be achieved under a variety of standard conditions if not with HCI/dioxane in DCM, including with TFA in DCM at rt. bN0 Step 2 deprotection required. cStep 2 deprotection was achieved using HBr/HOAc in DCM at rt for 12 h.

[005491] Further Examples using synthetic methods similar to Method 12:

Example 514: 2-[2-(Cvclopropvlmethvlamino) pvridvl]-N-[3-(difluoromethyl)-l-[4-[2-[2[2-[2[[(lR)-tetralin-l-vl]carbamovl]-3,4-dihvdro-lH-isoquinolin-7yl] oxy] ethoxy] ethoxy] ethoxy] ethoxy] ethylcarbamoyl] phenyl] pyrazol yl] oxazole-4carboxamide, 1-519

1843

[005492] Step 1 - Tert-butyl Ν-Γ4-Γ4-ΓΓ1-Γ4-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ(35) Γ(25) ΓΓ(25)-2[benzyloxycarbonyl(methyl) l-yl1carbamoyl1-3,4-dihydro-lH-isoquinolin-71844 yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1ethylcarbamoyl1phenyl1 (difluoromethyl)pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[005493] To a mixture of benzyl N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy] ethoxy]ethoxy] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinoline carbonyl]-2,2-dimethyl-propyl]amino]-l-methyl oxo-ethyl]-N-methylcarbamate (30.0 mg, 30.3 umol, TFA, Intermediate PJ) and DIPEA (19.6 mg, 151 umol, 26.4 uL) in DMF (2 mL) was added 4-[4-[[2-[2- [tert-butoxycarbonyl(cyclopropylmethyl)amino]-4pyridyl]oxazole carbonyl]amino] (difluoromethyl)pyrazol-l-yl]benzoic acid (18.0 mg, 30.3 umol, Intermediate FX) and HATU (13.8 mg, 36.4 umol). The reaction mixture was stirred at 25 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (0.1 % FA condition) to give the title compound (25.0 mg, 56% yield) as white solid. LC-MS (ESI+) m/z 1451.8 (M+H)+.

[005494] Step 2 - Tert-butyl N-(cvclopropylmethyl)-N-r4-r4-[r3-(difluoromethyl)-l-r4-r2[2-[2-[2-[2-[[(35)

[ [(1 R)-tetralin-1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7 yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol yl]carbamoyl]oxazol-2yl] pyridyl]carbamate

[005495] To a mixture of tert-butyl N-[4-[4-[[l-[4-[2-[2-[2-[2-[2-[[(3S) [(2S) [[(2S)-2[benzyloxycarbonyl (methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl] [[(lR)-tetralin1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl] (difluoromethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (30.0 mg, 20.6 umol) in THF (3 mL) was added Pd/C (30 mg, 10% wt). The reaction mixture was stirred at 25 °C for 2 hours under H2 (15 psi) atmosphere. On completion, the reaction mixture was filtered and the filtrate concentrated in vacuo to give the title compound (27.0 mg, 99% yield) as light yellow oil. LC-MS (ESE)&#1524;/z 1316.6 (M+H)+.

[005496] Step 3 - 2-r2-(Cvclopropylmethylamino) pyridvl1-N-[3-(difluoromethyl)-l-r4[2-Γ2-Γ2-Γ2-r2-rr(3S) r(2S)-3,3-dimethyl rr(2S)-2(methylamino)propanoyl1amino1butanoyl1 rr(lR)-tetralin-l-yl1carbamoyl1-3,4-dihydro-lHisoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]oxazole carboxamide

1845

[005497] To a mixture of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[2-[2-[2-[2-[2- [[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methylamino)propanoyl]amino]butanoyl] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (27.0 mg, 20.5 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 5.13 uL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 13%43%, lOmin) to give the title compound (10.7 mg, 42% yield) as white solid. 1HNMR (400MHz, DMSO-» δ 10.06 (s, IH), 8.98 (s, IH), 8.92 (s, IH), 8.65 (t, J= 5.2 Hz, IH), 8.33 (s, IH), 8.20 8.15 (m, 2H), 8.06 - 7.95 (m, 4H), 7.95 - 7.84 (m, IH), 7.48 - 7.16 (m, IH), 7.13 - 6.97 (m, 7H), 6.91 (d, J= 2.4 Hz, IH), 6.81 - 6.75 (m, IH), 4.99 - 4.81 (m, 2H), 4.79 - 4.61 (m, 2H), 4.08 - 4.01 (m, 2H), 3.73 (d, J = 3.6 Hz, 2H), 3.61-3.47 (m, 17H), 3.18 (t, J = 6.0 Hz, 2H), 3.02 - 2.90 (m, 3H), 2.74 - 2.62 (m, 2H), 2.16 (s, IH), 2.12 (s, 2H), 1.89 - 1.73 (m, 2H), 1.72 - 1.62 (m, IH), 1.60 - 1.50 (m, IH), 1.12 - 0.99 (m, 10H), 0.98 - 0.88 (m, 3H), 0.48 - 0.43 (m, 2H), 0.26 - 0.20 (m, 2H). LC-MS (ESL)/&#1524;z 1216.6 (M+H)+.

[005498] Example 515:2-[2-(Cvclopropylmethylamino) pyridyl]-N-[3(difluoromethyl)-l-[4-[2-[2-[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methylamino)propanovl]amino]butanovl] [[(lR)-tetralin-l-yl]carbamoyl]-3.,4-dihydrolH-isoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]Pvrazol yl]oxazole carboxamide., 1-520

1846

[005499] Step 1- Tert-butyl Ν-Γ4-Γ4-ΓΓ1-Γ4-Γ2-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ(35) Γ(25) ΓΓ(25)-2[benzyloxycarbonyl

-yl] carb amoyl] -3 .4-dihydro-1 H-i soquinolin-7vl]oxv]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenvl] (difluoromethyl)pyrazol

1847

4-yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[005500] To a mixture of benzyl N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-[2-[2-(2aminoethoxy)ethoxy] ethoxy] ethoxy]ethoxy]ethoxy] [[(lR)-tetralin-l-yl]carbamoyl]-3,4dihydro-lH-isoquinoline carbonyl] 2-dimethyl-propyl]amino]-l-methyl oxo-ethyl]-Nmethyl-carbamate (70.0 mg, 76.2 umol, Intermediate WE), 4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl] amino]- 3(difluoromethyl)pyrazol-l-yl]benzoic acid (45.3 mg, 76.2 umol, Intermediate FX) in DMF (2 mL) was added DIPEA (29.6 mg, 229 umol) and HATU (34.8 mg, 91.5 umol). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (2 X 20 mL). The combined organic phase was washed with brine (2X30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (70 mg, 57% yield) as black solid. LC-MS (ESI+) m/z 1494.9 (M+H)+.

[005501] Step 2- Tert-butyl N-(cyclopropylmethyl)-N-[4-r4-rr3-(difluoromethyl)-l-r4-r2-r2r2-r2-r2-r2-rr(3S) r(2S)-3,3-dimethvl rr(2S) (methvlamino)propanovl1amino1butanoyl1-3Γ [(1 R)-tetralin-1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7 yl 1 oxy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] ethyl carb amoyl 1 phenyl 1 pyrazol -4yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[005502] To a mixture of tert-butyl N-[4-[4-[[l-[4-[2-[2-[2-[2-[2-[2-[[(3S) [(2S) [[(2S)2-[benzyl oxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl] [[(lR)tetralin-l-yl]carbamoyl]-3,4-dihydro-lH-isoquinolin-7yl ] °xy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -ethyl carb amoyl ] phenyl ] -3 (difluoromethyl)pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (35.0 mg, 23.4 umol) in THF (2 mL) was added Pd/C (20 mg, 20% wf). The suspension was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred under H2 (15 psi) at 20 °C for 1 hour. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (32.0 mg, crude quant, yield) as brown solid. LC-MS (ESI+) m/z 1360.6 (M+H)+.

[005503] Step 3- 2-r2-(Cyclopropylmethylamino) pyridyl1-N-[3-(difluoromethyl)-l-r4[2-Γ2-Γ2-Γ2-Γ2-Γ2-rr(3S) [(2S)-3J-dimethyl rr(2S)-2(methylamino)propanoyl1amino1butanoyl1 rr(lR)-tetralin-l-yl1carbamoyl1-3,4-dihydro-lH

1848 isoquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1-ethoxy1ethylcarbamoyl1phenyl1pyrazol-4yl&#1470;|oxazole carboxamide

[005504] To a mixture of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[2-[2-[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methylamino)propanoyl]amino]butanoyl] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (32.0 mg, 23.5 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 20 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um;mobile phase: [water(0.225%FA)ACN]; B%: 16%-46%,10min) to give the title compound (8 mg, 6.17 umol, 26% yield) as a green solid. LC-MS (ESI+) m/z 1260.9 (M+H)+. 1HNMR (400 MHz, DMSO&#1470;d6) δ 10.07 (s, IH), 9.03 8.90 (m, 2H), 8.66 (s, IH), 8.25 - 8.13 (m, 2H), 8.07 - 7.85 (m, 5H), 7.48 - 7.17 (m, IH), 7.16 6.99 (m, 8H), 6.92 (s, IH), 6.82 - 6.77 (m, IH), 5.01 - 4.82 (m, 2H), 4.80 - 4.61 (m, 2H), 4.05 (s, 2H), 3.73 (s, 2H), 3.58 - 3.51 (m, 18H), 3.19 - 3.17 (m, 4H), 3.00 - 2.97(m, 4H), 2.69 - 2.68(m, 3H), 2.22 - 2.04 (m, 3H), 1.92 - 1.74 (m, 2H), 1.73-1.51 (m, 3H), 1.14-1.00 (m, 10H), 0.94 (s, 2H), 0.47 - 0.45 (m, 2H), 0.23 - 0.22 (m, 2H).

[005505] Example 516:2-[2-(Cvclopropvlmethvlamino) pyridvl]-N-[3(difluoromethvl)-l-[4-[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methvlamino)propanovl]amino]butanovl] [[(lR)-tetralin-l-vl]carbamovl]-3,4-dihydrolH-isoquinolin vl]oxv]ethoxv]ethoxv]ethoxv]ethvlcarbamovl]-phenvl]pyrazol-4vl]oxazole carboxamide, 1-521

1849

[005506] Step 1 - Tert-butyl N-[4-[4-[[l-[4-[2-[2-[2-[2-[[(3S) [(2S) [[(2S)-2[benzyloxycarbonyl(methyl)

-yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7yl1oxy1ethoxy1ethoxy1ethoxy1ethylcarbamoyl1phenyl1 (difluoromethyl)pyrazol-4

1850 yl1carbamoyl1oxazol yl1 pyridyl1-N-(cyclopropylmethyl)carbamate

[005507] To a solution of benzyl N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-(2aminoethoxy)ethoxy] ethoxy] ethoxy] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinoline carbonyl]-2,2-dimethyl-propyl]amino-l-methyl oxo-ethyl]-N-methylcarbamate (50 mg, 52.9 umol, TFA, Intermediate PF) and 4-[4-[[2-[2- [tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]benzoic acid (31.5 mg, 52.9 umol, Intermediate FX) in DMF (3 mL) was added DIPEA (34.2 mg, 264 umol, 46.1 uL) and HATU (24.1 mg, 63.5 umol). The mixture was stirred at 25 °C for 1.5 hr. On completion, the reaction mixture was quenched with H2O (1 mL) and then concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (40 mg, 53% yield) as a white solid. LC-MS (ESI+) m/z 1406.7 (M+H)+.

[005508] Step 2 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-[4-r2[2-[2-[2-[[(35)-2Γ Γ (1 R)-tetralin-1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7 yl1oxy1ethoxy1ethoxy1ethoxy1ethylcarbamoyl1-phenyl1pyrazol yl1carbamoyl1oxazol yl1-2pyridyllcarbamate

[005509] To a solution of tert-butyl N-[4-[4-[[l-[4-[2-[2-[2-[2-[[(3S) [(2S) [[(2S)-2[benzyloxycarbonyl (methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl] [[(lR)-tetralinl-yl]carbamoyl]-3,4-dihydro-lH-isoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethyl carbamoyl]phenyl] (difluoromethyl)pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethyl)carbamate (40.0 mg, 28.4 umol) in THF (5 mL) was added Pd/C (20 mg, 10% wf), the reaction mixture was stirred at 25 °C for 40 mins under H2. On completion, the mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (35 mg, 96% yield) as a yellow solid. LC-MS (ESI+) m/z 1272.8 (M+H)+.

[005510] Step 3 - 2-r2-(Cyclopropylmethylamino) pyridyl1-N-[3-(difluoromethyl)-l-r4[2-[2-[2-[2-[[(35)-2Γ Γ (1 R)-tetralin-1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7 yl1oxy1ethoxy1ethoxy1ethoxy1ethylcarbamoyl1-phenyl1pyrazol yl1oxazole carboxamide [005511] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2

1851 (methylamino)propanoyl]amino]butanoyl] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (35.0 mg, 27.5 umol) in DCM (2 mL) was added HCI/dioxane (4 M, 2 mL), the reaction mixture was stirred at 20 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water(0.225%FA)ACN]; B%: 15%-45%,10min) to give the title compound (23.0 mg, 71% yield, FA) as a white solid. 1H NMR (400MHz, DMSO-J6) δ 10.05 (s, IH), 8.97 (s, IH), 8.91 (s, IH), 9.71 - 8.60 (m, IH), 8.21 - 8.13 (m, 2H), 8.04 - 8.00 (m, 2H), 7.99 - 7.95 (m, 2H), 7.94 - 7.85 (m, IH), 7.45 - 7.17 (m, IH), 7.14 - 7.00 (m, 8H), 6.91 - 6.76 (m, 2H), 5.09 - 4.47 (m, 6H), 4.06 - 4.01 (m, 2H), 3.74 3.68 (m, 2H), 3.55 (s, 9H), 3.48 - 3.45 (m, 2H), 3.18 (t, J= 6.0 Hz, 2H), 3.03 - 2.91 (m, 4H), 2.73 -2.64 (m, 2H), 2.16 (s, IH), 2.11 (s, 2H), 1.88 - 1.73 (m, 2H), 1.70 - 1.63 (m, IH), 1.60 - 1.50 (m, IH), 1.11 - 1.02 (m, 10H), 0.93 (s, 3H), 0.47 - 0.42 (m, 2H), 0.24 - 0.20 (m, 2H); LC-MS (ESI+) m/z 1172.8(M+H)+.

[005512] Table 23: Compounds synthesized via Method 16 with the reductive amination of various amines with aldehydes in Step 1

<td> Ex#</td><td> I-#</td><td> Step 1 Intermediat e Amine</td><td> Step 1 Intermediat e Aldehyde</td><td> LCMS (ES+) m/z (M+H)+</td><td> 1HNMR (400MHz, DMSO-d6) δ</td>

1852

1853

1854

1855

1856

1857

1858

1859

1860

1861

1862

1863

1864

1865

1866

1867

1868

1869

1870

1871

1872

1873

<td> 592</td><td> 1-597</td><td> 2-(2methoxyethoxy)ethan-amine (CAS# 31576-51-9)</td><td> GF</td><td> 603.3</td><td> 11.01 (s, IH), 9.03 (s, IH), 8.99 (s, IH), 8.26 (d, J= 52 Hz, IH), 8.06 (d, J= 8.4 Hz, 3H), 7.77 (s, IH), 7.70 (t, J = 6.4 Hz, IH), 7.64 (d, J= 8.8 Hz, 2H), 7.26 (s, IH), 7.18 (d, J = 52 Hz, IH), 4.28 - 4.20 (m, 2H), 4.15 (s, 2H), 3.65 (t, J= 5.2 Hz, 2H), 3.59 - 3.56 (m, 2H), 3.49 - 3.47 (m, 2H), 3.26 (s, 3H), 3.05 (t, J= 5.2 Hz, 2H)</td>

1874

aFor Method 16, when the amine is the HCI salt, TEA was added to free base the salt, followed by

HO Ac to adjust the pH to 3-4. KO Ac could also be used in place of the TEA/HOAc combination. Other standard deprotections conditions could be used for the deprotection in Step 2, including often with TFA. Steps 1-2 was run anywhere from 0.5-48 hrs. bN0 deprotection Step 2 required. cIn Step 1, Intermediates OS and were heated at 80 °C for 1 hr with HO Ac and 4 A MS, then

1875

NaBH3CN was added and the reaction mixture was stirred at rt for 1 h. dIn Step 2, the deprotection was achieved using HBr/HOAc in THF at rt for 96-160 hrs. For Example 617, 1-622 the reaction was run in DCM with HBr/HOAc for 12 hr. eIn Step 2, the deprotection was achieved using ZnBr2 in DCM at rt.

[005513] Further Examples using synthetic methods similar to Method 16:

Example 675: 2-[2-(Cvclopropvlmethvlamino) pvridvl]-N-[3-(difluoromethyl)-l-[4-[[2-[2[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methvlamino)propanovl]amino]butanovl] [[(lR)-tetralin-l-vl]carbamoyl]-3.,4-dihvdrolH-isoquinolin vl]oxv]ethoxv]ethoxv]ethoxv]ethoxv]ethoxy]ethvlamino]methvl]phenyl] pvrazol vl]oxazole carboxamide., 1-680

1876

[005514] Step 1 - Tert-butyl Ν-Γ4-Γ4-ΓΓ1-Γ4-ΓΓ2-Γ2-Γ2-Γ2-Γ2-Γ2-ΓΓ(35) Γ(25) ΓΓ(25)-2[benzyloxycarbonyl l-yl1carbamoyl1-3,4-dihydro-lH-isoquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1ethoxy1ethylamino1methyl1phenyl1 (difluoromethyl)pyrazol yl1carbamoyl1oxazol yl1 pyridyl11877

N-(cyclopropylmethyl)carbamate

[005515] To a solution of benzyl-N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-[2-[2-(2aminoethoxy)ethoxy] ethoxy] ethoxy]ethoxy]ethoxy] [[(lR)-tetralin-l-yl]carbamoyl]-3,4dihydro-lH-isoquinoline carbonyl]-2,2-dimethyl-propyl]amino]-l-methyl oxo-ethyl]-Nmethyl-carbamate (100 mg, 96.9 umol, TFA, Intermediate WE) and tert-butyl-N(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l-(4-formylphenyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (56.1 mg, 96.9 umol; Intermediate GF) in THF (4 mL) was added KO Ac (19.0 mg, 194 umol) and NaBH(OAc)3 (41.1 mg, 194 umol). The reaction mixture was stirred at 25 °C for 17 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (90.0 mg, 63% yield) as a white solid. LC-MS (ESI+) m/z 1481.7 (M+H)+.

[005516] Step 2 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-[4-rr2[2-[2-[2-[2-[2-[[(35) r(2S)-3,3-dimethyl [r(2S)-2(methylamino)propanoyl1amino1butanoyl1 rr(lR)-tetralin-l-yl1carbamoyl1-3,4-dihydro-lHisoquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1-ethoxy1ethylamino1methyl1phenyl1pyrazol4-yl1carbamoyl1oxazol yl1 pyridyl1carbamate

[005517] To a solution of tert-butyl N-[4-[4-[[l-[4-[[2-[2-[2-[2-[2-[2-[[(3S) [(2S)-2[[(2S) [benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl] [[(lR)tetralin-l-yl]carbamoyl]-3,4-dihydro-lH-isoquinolin-7yl ] °xy] ethoxy] ethoxy] ethoxy] ethoxy] ethoxy] -ethyl amino] methyl ] phenyl] -3 (difluoromethyl)pyrazol yl]carbamoyl]oxazol yl] pyridyl]-N(cyclopropylmethylcarbamate (40 mg, 27.0 umol) in THF (5 mL) was added Pd(OH)2/C (0.1 g, 20% wf). The reaction mixture was stirred at 25 °C for 2 hrs under H2 (15 psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (35.0 mg, 96% yield) as a white solid. LC-MS (ESI+) m/z 1346.8 (M+H)+.

[005518] Step 3 - 2-r2-(Cyclopropylmethylamino) pyridyl1-N-[3-(difluoromethyl)-l-r4ΓΓ2-Γ2-Γ2-Γ2-Γ2-Γ2-rr(3S) [(2S)-3J-dimethyl rr(2S)-2(methylamino)propanoyl1amino1butanoyl1 rr(lR)-tetralin-l-yl1carbamoyl1-3,4-dihydro-lHisoquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1-ethoxy1ethylamino1methyl1phenyl1pyrazol4-yl1oxazole carboxamide

1878

[005519] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[[2-[2-[2-[2-[2 -[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methylamino)propanoyl]amino]butanoyl] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol4-yl]carbamoyl]oxazol yl] pyridyl]carbamate (30.0 mg, 22.3 umol) in DCM (2 mL) was added HCI/dioxane (2 mL). The reaction mixture was stirred at 25 °C for 2 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 12%39%, 9min) to give the title compound (4.00 mg, 14% yield, FA) as a brown solid. 1H NMR (400MHz, DMSOY) δ 10.00 (s, IH), 8.96 (s, IH), 8.78 (s, IH), 8.28 - 8.25 (m, IH), 8.20 - 8.10 (m, 2H), 8.03 - 7.89 (m, IH), 7.80 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 54.8 Hz IH), 7.12 - 7.01 (m, 7H), 6.90 (s, IH), 6.80 - 6.77 (m, IH), 5.19 - 4.86 (m, 2H), 4.78 - 4.62 (m, 2H), 4.10 - 4.00 (m, 2H), 3.80 (s, 2H), 3.75 - 3.70 (m, 2H), 3.61 - 3.50 (m, 21H), 3.18 (t, J= 6.0 Hz, 2H), 3.09 - 3.02 (m, IH), 3.01 - 2.92 (m, 2H), 2.76 - 2.63 (m, 4H), 2.21 - 2.12 (m, 3H), 1.92 1.72 (m, 2H), 1.70 - 1.49 (m, 2H), 1.10 (d, J=6.8Hz, 3H), 1.07 - 1.05 (m, IH), 1.05 - 0.91 (m, 9H), 0.50 - 0.41 (m, 2H), 0.27 - 0.18 (m, 2H); LC-MS (ESI+) m/z 1246.8 (M+H)+.

[005520] Example 676:2-[2-(Cvclopropvlmethvlamino) pyridvl]-N-[3(difluoromethvl)-l-[4-[[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methvlamino)propanovl]amino]butanovl] [[(lR)-tetralin-l-vl]carbamovl]-3,4-dihydrolH-isoquinolin vl]oxv]ethoxv]ethoxv]ethoxv]ethvlamino]methyl]phenvl]pvrazol-4ylloxazole carboxamide., 1-681

1879

PF TFA

[005521] Step 1 - Tert-butyl Ν-Γ4-Γ4-ΓΓ1-Γ4-ΓΓ2-Γ2-Γ2-Γ2-ΓΓ(35) Γ(25) ΓΓ(25)-21880

[benzyloxycarbonyl(methyl)

-yl1 carb amoyl] -3 .4-dihydro-1 H-i soquinolin vl]oxv]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenvl] (difluoromethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate

[005522] To a solution of benzyl N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-(2aminoethoxy)ethoxy] ethoxy] ethoxy]-3 -[[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinoline carbonyl]-2,2-dimethyl-propyl]amino]-l-methyl oxo-ethyl]-N-methylcarbamate (150 mg, 158 umol, TFA, Intermediate PF) and tert-butyl N-(cyclopropylmethyl)-N-[4[4-[[3-(difluoromethyl)-l-(4-formylphenyl)pyrazol yl]carbamoyl]oxazol yl]-2pyridyl]carbamate (91.9 mg, 158 umol, Intermediate GF) in THF (30 mL) was added TEA (16.0 mg, 158 umol, 22.1 uL). The mixture was stirred at 20 °C for 30 mins, then HOAc (25.6 mg, 426 umol, 24.3 uL) and NaBH(OAc)3 (67.3 mg, 317 umol) was added into the mixture, and the reaction mixture was stirred at 20 °C for 48 hrs. On completion, the reaction mixture was quenched with H2O (0.5 mL) and then concentrated in vacuo to give a residue. The residue was purified by reverse phase chromatography (0.1% FA condition) to give the title compound (90 mg, 40% yield) as a white solid. LC-MS (ESI+) m/z 1392.3 (M +H)+.

[005523] Step 2 - Tert-butyl N-(cyclopropylmethyl)-N-r4-r4-rr3-(difluoromethyl)-l-[4-rr2[2-[2-[2-[[(35)-2Γ [(1 R)-tetralin-1 -yl] carb amoyl] -3 .4-dihydro-1 H-i soquinolin-7 yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl]2-pyridyl] carbamate

[005524] To a solution of tert-butyl N-[4-[4-[[l-[4-[[2-[2-[2-[2-[[(3S) [(2S) [[(2S)-2[benzyloxycarbonyl (methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl] [[(lR)-tetralin1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl] (difluoromethyl)pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(cyclopropylmethyl)carbamate (70.0 mg, 50.2 umol) in THF (1 mL) was added Pd(OH)2/C (50 mg, 3.59 umol, 10% wt), and the reaction mixture was stirred at 25 °C for 40 min under H2 gas (15 Psi). On completion, the mixture was filtered, the filtrate was concentrated in vacuo to give the residue, and the residue was purified by prepHPLC(column: Phenomenex Synergi Cl8 150*25* 10um;mobile phase: [water(0.225%FA)ACN];B%: 32%-50%, 6 min) to give the title compound (20 mg, 31% yield) as a yellow solid.

1881

LC-MS (ESI+) m/z 1258.8 (M+H)+.

[005525] Step 3 - 2-[2-(Cyclopropylmethylamino) pyridyl1-N-[3-(difluoromethyl)-l-[4[[2-[2-[2-[2-[[(3S) [[(lR)-tetralin-l-yl1carbamoyl1-3,4-dihydro-lH-isoquinolin-7yl1oxy1ethoxy1ethoxy1ethoxy1ethylamino1methyl1phenyl1pyrazol yl1oxazole carboxamide [005526] To a solution of tert-butyl N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-l[4-[[2-[2-[2-[2- [[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methylamino)propanoyl]amino]butanoyl] [[(lR)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]carbamate (20 mg, 15.8 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL), and the reaction mixture was stirred at 25 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prepHPLC (column: Shim-pack C18 150*25*10um;mobile phase: [water(0.225%FA)-ACN];B%: 12%-42%, lOmin) to give the title compound (1.57 mg, 8.0% yield) as a white solid. 1H NMR (400MHz, DMSO&#1470;/) δ 10.01 (s, IH), 8.92 (s, IH), 8.74 (s, IH), 8.33 (s, 2H), 8.20 - 8.09 (m, 2H), 8.02 - 7.87 (m, IH), 7.78 (d, J= 8.4 Hz, 2H), 7.52 - 7.42 (m, 2H), 7.25 (t, J = 54.8 Hz, IH), 7.11 - 6.92 (m, 8H), 6.90 - 6.73 (m, 2H), 4.96 - 4.82 (m, 2H), 4.74 - 4.58 (m, 2H), 4.05 - 3.99 (m, 2H), 3.78 (s, 3H), 3.73 - 3.69 (m, 4H), 3.67 - 3.61 (m, 9H), 3.16 (t, J= 6.0 Hz, 2H), 3.05 - 2.91 (m, 3H), 2.70 - 2.65 (m, 4H), 2.20 - 2.15 (m, IH), 2.13 (s, 2H), 1.89 - 1.71 (m, 2H), 1.70 - 1.61 (m, IH), 1.59 - 1.52 (m, IH), 1.11 - 1.05 (m, 3H), 1.04 - 0.89 (m, 9H), 0.47 - 0.41 (m, 2H), 0.24 - 0.18 (m, 2H); LC-MS (ESI+) m/z 1158.7(M+H)+.

[005527] Example 677: N-[3-[[2-[2-[2-[2-[2-[[(3S) [(2S)-3,3-dimethyl [[(2S)-2(methylamino)propanovl] amino] lH-isoquinolin vl]oxv]ethoxv]ethoxv]ethoxv]ethoxy]ethvlamino]methvl]-l-methvlPvrazol vl] [2-(2,2,2-trifluoroethvlamino) pyridvl]oxazole carboxamide, 1-682

1882

1883

[005528] Step 1 - Tert-butyl Ν-Γ4-Γ4-ΓΓ3-ΓΓ2-Γ2-Γ2-Γ2-Γ2-ΓΓ(38) [(28) ΓΓ(28)-2[benzyloxycarbonyl(methyl)

-yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1ethylamino1methyl1-l-methyl-pyrazol-4yl1carbamoyl1oxazol yl1 pyridyl1-N-(2,2,2-trifluoroethyl)carbamate

[005529] To a solution of benzyl N-[(lS) [[(lS)-l-[(3S) [2-[2-[2-[2-(2aminoethoxy)ethoxy]ethoxy]ethoxy] ethoxy] [[(U?)-tetralin-l-yl]carbamoyl]-3,4-dihydro-lHisoquinoline carbonyl]-2,2-dimethyl-propyl]amino]-l-methyl oxo-ethyl]-N-methylcarbamate (55.0 mg, 55.7 umol, TFA, Intermediate PJ) and tert-butyl N-[4-[4-[(3-formyl-lmethyl-pyrazol yl)carbamoyl]oxazol yl] pyridyl]-N-(2,2,2- trifluoroethyl)carbamate (27.5 mg, 55.7 umol, Intermediate LS) in a mixed solvent of DMF (1 mL) and THF (5 mL) was added KOAc (10.9 mg, 111 umol). The mixture was stirred at 25 °C for 0.5 hour. NaBH(OAc)3 (23.6 mg, 111 umol) was then added into the mixture and the reaction mixture was stirred at 25 °C for 24 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA condition) to give the title compound (35.0 mg, 46% yield) as a brown solid. LC-MS (ESI+) m/z 1352.7 (M+H)+.

[005530] Step 2 - Tert-butyl Ν-Γ4-Γ4-ΓΓ3-ΓΓ2-Γ2-Γ2-Γ2-Γ2-ΓΓ(38) [(28)-3>άίη16ΐ11ν1-2rr(2S) (methylamino)propanoyl1amino1butanoyl1 rr(lR)-tetralin-l-yl1carbamoyl1-3,4dihydro-lH-isoquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1ethylamino1methyl1-l-methylPvrazol yl1carbamoyl1oxazol yl1 pyridvl1-N-(2,2,2-trifluoroethyl)carbamate

[005531] To a solution of tert-butyl N-[4-[4-[[3-[[2-[2-[2-[2-[2-[[(3S) [(2S) [[(2S)-2[benzyloxycarbonyl (methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl] [[(lR)-tetralin1 -yl] carb amoyl] -3,4-dihydro-1 H-i soquinolin-7yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-l-methyl-pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (30.0 mg, 22.2 umol) in THF (3 mL) was added Pd(OH)2/C (0.05 g, 20% wt). The reaction mixture was stirred at 25 °C for 1 hour under H2 (15 Psi) atmosphere. On completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA condition) to give the title compound (15.0 mg, 56% yield) as a yellow solid. LC-MS (ESI+) m/z 1218.8 (M+H)+.

[005532] Step 3 - Ν-Γ3-ΓΓ2-Γ2-Γ2-Γ2-[2-ΓΓ(38) Γ(28)-3,3-&#940;&#912;π16Α1ν1 ΓΓ(28)-21884 (methylamino)propanoyllaminol isoquinolin yl1oxy1ethoxy1ethoxy1ethoxy1ethoxy1ethylamino1methyl&#1470;|-l-methyl-pyrazol yl&#1470;|2-[2-(2,2,2-trifluoroethylamino) pyridvl1oxazole carboxamide

[005533] To a solution of tert-butyl N-[4-[4-[[3-[[2-[2-[2-[2-[2-[[(35) [(25)-3,3-dimethyl2-^(25) (methylamino)propanoyl]amino]butanoyl] [[(17?)-tetralin-l-yl]carbamoyl]-3,4dihydro-lH-isoquinolin yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-l-methylpyrazol yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (14.0 mg, 11.5 umol) in DCM (3 mL) was added HCl/dioxane (3 mL). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*lOum; mobile phase: [water (0.225%FA)-ACN]; B%: 17%-41%, 8min) to give the title compound (2.00 mg, 15% yield, FA) as a yellow solid. 1H NMR (400MHz, DMSO4) δ 10.92 (s, IH), 8.88 (s, IH), 8.25 - 8.18 (m, 2H), 8.13 - 8.10 (m, IH), 7.98 - 7.88 (m, IH), 7.61 - 7.54 (m, IH), 7.20 (s, IH), 7.18 - 7.16 (m,

IH), 7.12 - 7.07 (m, 2H), 7.07 - 7.01 (m, 2H), 6.89 (s, IH), 6.82 - 6.72 (m, 2H), 5.23 - 4.92 (m,

2H), 4.90 - 4.80 (m, 2H), 4.71 - 4.60 (m, 2H), 4.29 - 4.18 (m, 3H), 4.05 - 3.97 (m, 2H), 3.92 (s,

2H), 3.79 - 3.56 (m, 16H), 3.00 - 2.93 (m, 3H), 2.75 - 2.71 (m, 2H), 2.20 - 2.04 (m, 6H), 1.90 -

1.73 (m, 2H), 1.71 - 1.60 (m, 2H), 1.57 -1.49 (m, IH), 1.13-1.07 (m, 3H), 1.07 - 1.04 (m, IH), 1.03 - 0.92 (m, 9H); LC-MS (ESI+) m/z 1118.7 (M+H)+.

[005534] Further Examples:

[005535] Example 679:2-[2-(cvclopropylmethylamino) pyridyl]-N-[3(difluoromethyl)-l-[4-[[2-[2-[[l-(2.,6-dioxoyl]methylamino]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]oxazole carboxamide., I684

1885

PI

[005536] Step 1:Tert-butyl Ν-ΓΓ4-[4-ΓΓ2-Γ2-Γ&#912;61&#912;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenyl1methyl1-N-r2-r2-rr1-(2,6-dioxo piperidyl) methyl-20x0-benzimidaz0l yl1methylamin01eth0xy1ethyl1carbamate

[005537] To a solution of 2-[2-[tert-butoxycarbonyl-[[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl) amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methyl]amino]ethoxy]ethyl methanesulfonate (200 mg, 236 umol, Intermediate PI) and 3-[5-(aminomethyl) methyl oxo- benzimidazol-l-yl]piperidine2,6-dione (160 mg, 492 umol, HCI, Intermediate PH) in ACN (10 mL) was added KI (39.2 mg, 236 umol) and NaHCO3 (59.5 mg, 709 umol). The reaction mixture was stirred at 25 °C for 48 hours. On completion, the reaction mixture was diluted with ACN (100 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by reversed-phase flash chromatography (FA, 0.1%) to give the title compound (60.0 mg, 24% yield) as a white solid. LCMS (ESI+) m/z 1038.6 (M +H)+.

[005538] Step 2 - 2-r2-(cyclopropylmethylamino) pyridyl1-N-[3-(difluoromethyl)-l-r4

1886

ΓΓ2-Γ2-ΓΓ1-&#943;2,6-(&#971;οχο piperidyl) methyl oxo-benzimidazol-5yl1methylamino1ethoxy1ethylamino1methyl1phenyl1pyrazol yl1oxazole carboxamide [005539] To a solution of tert-butyl N-[[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methyl]-N-[2-[2-[[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]methylamino]ethoxy]ethyl]carbamate (50.0 mg, 48.1 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 10 mL). The reaction mixture was stirred at 25 °C for 1 hour. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prepHPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.05%HCl)ACN]; B%: 9%-29%, 10 min) to give the title compound (6.50 mg, 14% yield, HCI) as a yellow solid. 1HNMR (400MHz, DMSO-i/6) δ 11.12 (s, IH), 10.16 (s, IH), 9.50 (s, 2H), 9.37 (s, 2H), 9.12 (s, IH), 8.88 (s, IH), 8.16 - 8.06 (m, IH), 7.98 - 7.88 (m, 2H), 7.78 (d, J= 6.8 Hz, 2H), 7.54 (s, IH), 7.36 - 7.12 (m, 4H), 5.47 - 5.32 (m, IH), 4.27 - 4.22 (m, 2H), 3.73 (s, 3H), 3.30 - 3.23 (m, 6H), 3.16-3.06 (m, 4H), 2.97 - 2.83 (m, IH), 2.62 - 2.58 (m, 2H), 2.04 - 1.90 (m, IH), 1.18- 1.07 (s, IH), 0.62 - 0.48 (m, 2H), 0.36 - 0.25 (m, 2H); LC-MS (ESI+) m/z 838.4 (M+H)+.

[005540] Example 680:2-[2-(Cvclopropvlmethvlamino) pyridvl]-N-[3(difluoromethvl)-l-[4-[[2-[2-[4-[l-(2,6vl]piperazin-l-vl]ethoxv]ethvlamino]methvl]phenvlpvrazol yl]oxazole carboxamide, I685

1887

[005541] Step 1:Tert-butyl Ν-ΓΓ4-[4-ΓΓ2-Γ2-Γ&#912;61&#912;butoxycarbonyl(cyclopropylmethyl)amino1 pyridyl1oxazole carbonyl1amino1-3(difluoromethyl)pyrazol-l-yl1phenyl1methyl1-N-r2-r2-r4-r1-(2,6-dioxo piperidyl) methyl-20x0-benzimidaz0l yl1piperazin-l-yl1eth0xy1ethyl1carbamate

[005542] To a solution of 3-(3-methyl oxo piperazin-l-yl-benzimidazol-l-yl)piperidine2,6-dione (50.0 mg, 146 umol, Intermediate PN), 2-[2-[tert-butoxycarbonyl-[[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl) amino] pyridyl]oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methyl]amino]ethoxy]ethyl methanesulfonate (148 mg, 175 umol, Intermediate PI) in CH3CN (8 mL) was added NaHCO3 (36.7 mg, 437 umol), and then the mixture was stirred at 80 °C for 6 hrs under N2 atmosphere. On completion, the mixture was concentrated in vacuo, and the residue was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (30.0 mg, 15% yield) as a yellow solid. LC-MS (ESI+) m/z 1093.6

1888 (M+H)+.

[005543] Step 2 - 2-r2-(Cyclopropylmethylamino) pyridyl1-N-r3-(difluoromethyl)-l-[4[[2-[2-[4-[1-(26&#1497;-dioxo piperidyl) methyl oxo-benzimidazol yl1piperazin-lyl1ethoxy1ethylamino1methyl1phenylpyrazol yl1oxazole carboxamide

[005544] To a solution of tert-butyl N-[[4-[4-[[2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino] pyridyl] oxazole carbonyl]amino]-3(difluoromethyl)pyrazol-l-yl]phenyl]methyl]-N-[2-[2-[4-[l-(2,6-dioxo piperidyl) methyl-2oxo-benzimidazol yl]piperazin-l-yl]ethoxy]ethyl]carbamate (20.0 mg, 18.3 umol) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol, 1.00 mL). The mixture was stirred at 15 °C for 0.5 hr. The mixture was then concentrated in vacuo, and the residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um;mobile phase: [water(0.225%FA)-ACN];B%: 1%31%,10min) to give the title compoud (13.6 mg, 83% yield) as a yellow solid. 1HNMR (400 MHz, DMSO4) δ 10.96 - 11.11 (m, 2H), 9.01 (s, IH), 8.91 (s, IH), 8.23 - 8.34 (m, 3H), 8.04 (s, 1 H), 7.91 (d, J = 8.4 Hz, 2H), 7.65 - 7.77 (m, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.27 (s, IH), 7.14 - 7.21 (m, IH), 6.91 (d, J = 8.6 Hz, IH), 6.80 (d, 7 = 1.6 Hz, 1 H), 6.60 (dd, J = 8.4, 2.20 Hz, IH), 5.26 (dd, 7= 13.2 Hz, IH), 4.23 - 4.30 (m, 2H), 3.81 (s, 2H), 3.55 (s, 4H), 3.29 (s, 3H), 3.06 (m, 4H), 2.83 - 2.91 (m, IH), 2.70 (m, 2H), 2.67 - 2.69 (m, 2H), 2.61 - 2.65 (m, 2H), 2.58 (m, 4H), 2.07 (s, 3H), 1.96 - 2.01 (m, IH), LC-MS (ESI+) m/z 893.5 (M+H)+.

[005545] Example 683: N-[2-[2-[2-[3-[l-(2,6-dioxo DiDeridvl) methyl oxobenzimidazol yl] prop vnoxv] ethoxy] ethyl] (1 -hydroxy- l-methvl-ethyl)indazol vl]6-(trifluoromethvl)pvridine carboxamide, 1-688

1889

[005546] A mixture of N-[6-(l-hydroxy-l-methyl-ethyl) [2-(2-prop-2ynoxyethoxy)ethyl]indazol yl] (trifluoromethyl)pyridine carboxamide (300 mg, 611 umol, Intermediate TK), 3-(4-bromo methyl oxo -benzimidazol-l-yl)piperidine-2,6-di one (130 mg, 384 umol, Intermediate HP), Cui (15.0 mg, 78.7 umol), Pd(PPh3)2C12 (54.0 mg, 76.9 umol), Cs2CO3 (630 mg, 1.93 mmol) and 4A molecular sieves (100 mg) in DMF (4 mL) was stirred at 80 °C for 2 hours under N2. On completion, the reaction mixture was cooled to 20 °C and then filtered. The filter cake was washed with EA (10 mL) and the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min) to give the title compound (74.2 mg, 25% yield) as yellow solid. 1H NMR (400 MHz, DMSO-» δ 12.36 (s, IH), 11.12 (s, IH), 8.72 (m, IH), 8.44 (d, J= 8.0 Hz, IH), 8.37 (d, J= 7.6 Hz, IH), 8.34 (s, IH), 8.16 (d, J= 8.0 Hz, IH), 7.57 (s, IH), 7.15 (d, J = 7.6 Hz, IH), 7.11 (d, J = 7.6 Hz, IH), 7.00 (t, J = 8.0 Hz, IH), 5.95 (s, IH), 5.41 - 5.36 (m, IH), 4.57 (t, J= 5.2 Hz, 2H), 4.41 (s, 2H), 3.93 (t, J= 5.2 Hz, 2H), 3.65 - 3.55 (m, 7H), 2.93 - 2.82 (m, IH), 2.74 - 2.68 (m, IH), 2.65 - 2.57 (m, IH), 2.06 - 1.96 (m, IH), 1.61 (s, 6H); LC-MS (ESI+) m/z 748.1 (M+H)+.

[005547] Example 684 & 685: N-[3-carbamoyl-l-[4-[[2-[2-[3-[(lR)-l-(2,6-dioxo-3piperidyl) methyl oxo-benzimidazol-4yl] propoxy] ethoxy] ethylamino] methyl] phenyl] pyrazol yl] [2-(2,2.,2trifluoroethylamino) pyridvl]oxazole carboxamide, 1-686 and N-[3-carbamoyl-l-[4-[[21890

[2-[3-[(lS)-l-(2,6-dioxo piperidyl) methyl oxo benzimidazol-4yl] propoxy] ethoxy] ethylamino] methyl] phenyl] pyrazol yl] [2-(2,2.,2trifluoroethvlamino) pvridyl] oxazole carboxamide, 1-690

1891

[005548] Step 1 - Tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[3-[(lS)-l-(2,6-dioxo-3piperi dyl) methyl oxo-benzimidazol-4yl1propoxy1ethoxy1ethylamino1methyl1phenyl1pyrazol yl1carbamoyl1oxazol yl1 pyridyl1N-(2,2,2-trifluoroethyl)carbamate & Tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[3-[(lR)-l(2,6-di oxo piperi dyl) methyl oxo-benzimidazol-4yl1propoxy1ethoxy1ethylamino1methyl1phenyl1pyrazol yl1carbamoyl1oxazol yl1 pyridyl1Ν-(2.2.2-trifluoroethyl )carbamate

[005549] Tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[3-[l-(2,6-dioxo piperidyl)-3methyl oxo- benzimidazol yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4yl]carbamoyl]oxazol yl] pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (190 mg, 192 umol, Example 324, 1-329) was separated by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm,10um);mobile phase: [0.1% DEA,IPA];B%: 70%-70%,5.7min;lOOminmin) to give the title compound tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[3-[(lS)-l-(2,6-dioxo-3piperi dyl) methyl- 2-oxo-benzimidazol-4yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]N-(2,2,2-trifluoroethyl)carbamate (95 mg, 50% yield) as a white solid and tert-butyl N-[4-[4-[[3carbamoyl-l-[4-[[2-[2-[3-[(lR)-l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol-41892 yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]N-(2,2,2-trifluoroethyl)carbamate (95 mg, 50% yield) as a white solid. LC-MS (ESI+) m/z 988.5 (M+H)+ for both isomers.

[005550] Step 2 - N-r3-carbamovl-l-r4-rr2-r2-r3-r(lR)-l-(2,6-dioxo piperidvl) methyl2-oxotrifluoroethylamino) pyridyl1oxazole carboxamide

[005551] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[3-[(lR)-l-(2,6di oxo piperi dyl) methyl oxo-benzimidazol -4yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]N-(2,2,2-trifluoroethyl)carbamate (75.0 mg, 75.9 umol) in DCM (1 mL) was added TFA (1.15 g, 10.1 mmol). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B%: 16%43%, 9 min) to give the title compound (36.6 mg, 52% yield, ee 81%, FA salt) as a white solid. 1H NMR (400 MHz, DMSO-t/6) δ 11.09 (s, IH), 11.01 (s, IH), 9.02 (s, IH), 8.90 (s, IH), 8.26 (d, J= 5.2 Hz, IH), 8.04 (s, IH), 7.89 (d, J= 8.8 Hz, 2H), 7.76 - 7.67 (m, 2H), 7.49 (d, J= 8.8 Hz, 2H), 7.27 (s, IH), 7.18 (dd, J= 1.2, 5.2 Hz, IH), 6.99-6.91 (m, 2H), 6.89-6.83 (m, IH), 5.36 (dd, J= 5.2, 12.8 Hz, IH), 4.32 - 4.19 (m, 2H), 3.81 (s, 2H), 3.63 - 3.52 (m, 11H), 2.98 - 2.91 (m, 2H), 2.91 - 2.83 (m, IH), 2.72 (t, J= 5.6 Hz, 2H), 2.69 - 2.65 (m, IH), 2.64 - 2.58 (m, IH), 2.04 - 1.95 (m, IH), 1.87 - 1.77 (m, 2H); LC-MS (ESI+) m/z 888.2 (M+H)+.

[005552] Step 3 - N-r3-carbamoyl-l-r4-rr2-r2-r3-r(lS)-l-(2,6-dioxo piperidyl) methyl2-oxotrifluoroethylamino) pyridvl1oxazole carboxamide

[005553] To a solution of tert-butyl N-[4-[4-[[3-carbamoyl-l-[4-[[2-[2-[3-[(lS)-l-(2,6di oxo piperi dyl) methyl oxo-benzimidazol-4yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol yl]carbamoyl]oxazol yl] pyridyl]N-(2,2,2-trifluoroethyl)carbamate (75.0 mg, 75.9 umol) in DCM (1 mL) was added TFA (1.15 g, 10.1 mmol). The reaction mixture was stirred at 25 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo. The crude product was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B%: 16%46%, 10 min) to give the title compound (38.0 mg, 51% yield, ee value = 85%, FA salt) as a white

1893 solid. 1HNMR (400 MHz, DMSO-Y) δ 11.09 (s, IH), 11.01 (s, IH), 9.02 (s, IH), 8.90 (s, IH), 8.26 (d, J = 5.2 Hz, IH), 8.04 (s, IH), 7.89 (d, J = 8.8 Hz, 2H), 7.76 - 7.67 (m, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.27 (s, IH), 7.18 (dd, J= 1.2, 5.2 Hz, IH), 6.99 - 6.91 (m, 2H), 6.89 - 6.83 (m, IH), 5.36 (dd, J= 5.2, 12.8 Hz, IH), 4.32 - 4.19 (m, 2H), 3.81 (s, 2H), 3.63 - 3.52 (m, 11H), 2.98 - 2.91 (m, 2H), 2.91 - 2.83 (m, IH), 2.72 (t, J = 5.6 Hz, 2H), 2.69 - 2.65 (m, IH), 2.64 - 2.58 (m, IH), 2.04 - 1.95 (m, IH), 1.87 - 1.77 (m, 2H); LC-MS (ESI+) m/z 888.2 (M+H)+.

[005554] Example 686: 2-(2,6-Dioxo piperidvD [2-[2-[2-[2-[4-[H-methyl [(4morpholinocyclohexyDamino]pyrazolo[4.,3-d]pvrimidin vl]amino]pvrazol-lyl] ethoxy] ethoxy] ethoxy] ethylamino] isoindoline-1 .,3-dione, 1-691

[005555] To a solution of 5-chloro-l-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3d]pyrimidin amine (100 mg, 285 umol, Intermediate LK), 4-[2-[2-[2-[2-(4-aminopyrazol-lyl)ethoxy]ethoxy]ethoxy] ethylamino] (2,6-dioxo piperidyl)isoindoline-l,3-dione (220 mg, 427 umol, Intermediate UK) in dioxane (6 mL) was added TFA(650 mg, 5.70 mmol). The reaction mixture was stirred at 120 °C for 2 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi Cl8 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 7%-28%, 7min) to give the title

1894 compound (26.0 mg, 11% yield) as yellow solid. 1HNMR. (400MHz, DM SO-0/6) δ 11.10 (s, IH), 8.57 (s, IH), 7.91 (s, IH), 7.57 (s, IH), 7.57 - 7.51 (m, IH), 7.47 (s, IH), 7.07 (d, J= 8.8 Hz, IH), 7.02 (d, J= 6.8 Hz, IH), 6.56 (t, J= 5.6 Hz, IH), 6.45 (d, J= 6.8 Hz, IH), 5.04 (dd, J= 52, 12.8 Hz, IH), 4.16 (t, J= 5.6 Hz, 2H), 4.13 (s, 3H), 4.07 (d, J = 8.0 Hz, IH), 3.72 (t, J = 5.6 Hz, 2H), 3.63 - 3.59 (m, 4H), 3.57 - 3.49 (m, 12H), 2.92 - 2.81 (m, IH), 2.62 - 2.58 (m, 4H), 2.57 -2.53 (m, 2H), 2.39 - 2.35 (m, IH), 2.10 - 2.06 (m, 2H), 2.03 - 1.99 (m, IH), 1.96 - 1.92 (m, 2H), 1.55 - 1.46 (m, 2H), 1.42 - 1.32 (m, 2H). LC-MS (ESI+) m/z 829.5 (M+H)+.

[005556] Example 687: 2-(2,6-Dioxo piperidyD [2-[2-[2-[4-[[l-methyl [(4morpholinocyclohexvDamino]pyrazolo[4.,3-d]pvrimidin vl]amino]pvrazol-lyl] ethoxy] ethoxy] ethylamino] isoindoline-1 ,3-dione., 1-692

[005557] To a solution of N5-[l-[2-[2-(2-aminoethoxy)ethoxy]ethyl]pyrazol yl]-lmethyl-N7-(4- morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidine-5,7-diamine (60.0 mg, 106 umol, HCI, Intermediate UT) and 2-(2,6-dioxo piperidyl) fluoro-isoindoline-l,3-dione (29.3 mg, 106 umol, Intermediate R) in DMF (2 mL) was added DIPEA (68.6 mg, 530 umol, 92.4 uL). The mixture was stirred at 90 °C for 16 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10um; mobile phase: [water (0.225%FA)-ACN]; B%: 9%-30%, 7min) to give the

1895 title compound (13.2 mg, 15% yield, FA) as yellow solid. 1HNMR (400MHz, OMSO-cf) δ 11.09 (s, IH), 8.55 (s, IH), 7.92 (s, IH), 7.56 (s, IH), 7.54 - 7.43 (m, 2H), 7.05 - 6.96 (m, 2H), 6.55 (t, J = 5.6 Hz, IH), 6.43 (d, J = 7.6 Hz, IH), 5.04 (dd, J= 52, 12.8 Hz, IH), 4.17 (t, J = 52 Hz, 2H), 4.12 (s, 3H), 4.10 - 4.04 (m, IH), 3.74 (t, J = 52 Hz, 2H), 3.57 - 3.51 (m, 14H), 2.94 - 2.78 (m, 2H), 2.63 - 2.58 (m, IH), 2.57 - 2.54 (m, IH), 2.28 - 2.21 (m, IH), 2.13 - 1.82 (m, 6H), 1.56 - 1.45 (m, 2H), 1.39 - 1.29 (m, 2H); LC-MS (ESI+) m/z 785.4 (M+H)+.

[005558] Example 688: (2S,4R)-l-[(2S)-3,3-dimethvl [[2-[2-[2-[2-[2-[H-methvl [(4morpholinocyclohexyl)amino]pyrazolo[4.,3-d]pvrimidin-5yl] amino] ethoxy] ethoxy] ethoxy] ethoxy] acetyl! amino] butanoyl] hydroxy-N- [ [4-(4methvlthiazol vl)phenv1!methv1!pyrrolidine carboxamide, 1-693

[005559] To a solution of (2S,4R)-l-[(2S) [[2-[2-[2-[2-(2-aminoethoxy) ethoxy]ethoxy]ethoxy]acetyl] amino]-3,3-dimethyl-butanoyl] hydroxy-N-[[4-(4-methylthiazol5-yl)phenyl]methyl]pyrrolidine carboxamide (30.0 mg, 45.1 umol, Intermediate ME), 5-chloro1-methyl -N-(4-morpholinocyclohexyl) pyrazolo[4,3-d]pyrimidin amine (14.4 mg, 41.0 umol, Intermediate LK) in NMP (2.00 mL) was added TsOH (707 ug, 4.11 umol). The mixture was stirred at 150 °C for 6 hours under microwave. On completion, the mixture was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.04% NH3.H2O+10mM NH4HCO3)-ACN]; B%: 30%- 58%, min). The

1896 residue was re-purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.04% NH3.H2O+10mM NH4HCO3) - ACN]; B%: 30%-54%, min) to give the title compound (2.39 mg, 5% yield) as brown solid. 1H NMR (400MHz, DMSO-i/6) δ 8.97 (s, IH), 8.59 (t, J = 5.6 Hz, IH), 7.49 (s, IH), 7.42 (s, IH), 7.39 (m, 4H), 6.31 (d, J = 8.0 Hz, IH), 5.96 (t, J = 5.6 Hz, IH), 5.16 (d, J = 3.2 Hz, IH), 4.56 (d, J = 9.6 Hz, IH), 4.48 - 4.38 (m, 2H), 4.37 - 4.32 (m, IH), 4.29 - 4.23 (m, IH), 4.10 (s, 3H), 4.05 - 3.98 (m, IH), 3.96 (s, 2H), 3.66 - 3.57 (m, 6H), 3.56 - 3.48 (m, 14H), 2.49 - 2.45 (m, 6H), 2.44 (s, 3H), 2.26 - 2.16 (m, IH), 2.07 - 1.98 (m, 3H), 1.95 - 1.83 (m, 3H), 1.54 - 1.40 (m, 2H), 1.34 - 1.22 (m, 2H), 0.94 (s, 9H), LC-MS (ESI+) m/z 978.7(M+H)+.

[005560] Example 689: N-[3-(difluoromethvl)-l-methvl-pvrazol yl] [4-[2-[2-[3-[l(26&#1524;-dioxo piperidyl) methvl oxo-benzimidazol yl] propoxy] ethoxy] ethyl] piperazinl-vl]pyrazolo[l.,5-a]pvrimidine carboxamide, 1-694

[005561] To a mixture of 2-[2-[3-[l-(2,6-dioxo piperidyl) methyl oxo-benzimidazol5-yl]propoxy]ethoxy] ethyl methanesulfonate (70 mg, 144 umol, Intermediate UB) and N-[3(difluoromethyl)-l-methyl-pyrazol yl] piperazin -l-yl-pyrazolo[l,5-a]pyrimidine-3carboxamide (59.7 mg, 144 umol, HCI, Intermediate RD) in ACN (3 mL) was added NaHCO3 (36.4 mg, 434 umol) and KI (2.40 mg, 14.4 umol), and the mixture was stirred at 80 °C for 16 hours. On completion, the reaction mixture was quenched with water (15 mL), and then extracted

1897 with EA (4 X 20 mL). The combined organic layers were dried over Na2SO4, fdtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 lOu; mobile phase: [water (0.225%FA)-ACN]) to give the title compound (8.68 mg, 10.7 umol, 7% yield, FA) as yellow solid. 1HNMR. (400MHz, DMSO-0/6) δ 11.07 (s, IH), 9.39 (s, IH), 8.74 (d,/=7.6 Hz, IH), 8.34 (s, IH), 8.26 (s, IH), 7.22 - 6.91 (m, 3H), 6.88 - 6.74 (m, 2H), 5.32 (dd, /= 5.2, 12.8 Hz, IH), 3.87 (s, 3H), 3.84 - 3.70 (m, 4H), 3.58 (t, / = 5.6 Hz, 2H), 3.55 - 3.50 (m, 4H), 3.30 (s, 3H), 2.94 - 2.82 (m, IH), 2.74 - 2.53 (m, 10H), 2.05 1.92 (m, IH), 1.88 - 1.71 (m, 2H); LC-MS (ESE) m/z 764.1 (M+H)+.

[005562] Examples 694 and 695: 2-[2-(Cvclopropvlmethvlamino) pyridvl]-N-[3(difluoromethvl)-l-[4-[[4-[4-[l-[(3S)-2,65-yl]butoxy]butylamino]methyl]phenyl]pvrazol yl]oxazole carboxamide, 1-699 & 2-[2(cvclopropvlmethvlamino) pvridyl]-N-[33-piperidvl] methvl oxo-benzimidazol vl]butoxv]butvlamino]methyl]phenvl]pvrazol4-yl]oxazole carboxamide, 1-700

1898

1-411

[005563] The 2-[2-(cyclopropylmethylamino) pyridyl]-N-[3-(difluoromethyl)-l-(4-((4[4-(1-(2,6-dioxo-3piperidyl) methyl oxo-benzimidazol-5 yl]butoxy]butylamino]methyl]phenyl]pyrazol yl]oxazole carboxamide (50.0 mg, 54.9 umol, FA salt, Example 406, 1-411) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H2O MeOH]; B%: 70%-70%, 13.7 min; 160 min) to give the two enantiomers. Then the two enantiomers were purified by prep-HPLC (column: Shim-pack C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%) respectively to give 2-[2-(cyclopropylmethylamino) pyridyl]-N-[3-(difluoromethyl)-l-[4-[[4[4-[l-[(3S)-2,6- dioxo piperidyl] methyl oxo-benzimidazol-5yl]butoxy]butylamino]methyl]phenyl]pyrazol yl]oxazole carboxamide (3.40 mg, 12% yield, ee value = 91 %) as a white solid and 2-[2-(cyclopropylmethylamino) pyridyl]-N-[3(difluoromethyl)-l-(4-((4-(4-( l-[(3R)-2,6-dioxo piperidyl] methyl oxo-benzimidazol-5yl]butoxy]butylamino]methyl]phenyl]pyrazol yl]oxazole carboxamide (3.80 mg, 14% yield,

1899 ee value = 77 %) as a white solid. The absolute configuration of the enantiomers was arbitratily assigned. Characterization of 2-[2-(cyclopropylmethylamino) pyridyl]-N-[3-(difluoromethyl)1-(4-((4-(4-[ 1-[(3 S)-2,6- dioxo piperidyl] methyl oxo-benzimidazol-5yl]butoxy]butylamino]methyl]phenyl]pyrazol yl]oxazole carboxamide: 1H NMR (400 MHz, DMSO-» δ 11.22 (s, IH), 9.99 (s, IH), 8.97 (s, IH), 8.78 (s, IH), 8.36 (s, IH), 8.16 (d, J = 52 Hz, IH), 7.79 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.42 - 7.15 (m, IH), 7.13 - 7.07 (m, 2H), 7.06 - 6.96 (m, 3H), 6.88 - 6.82 (m, IH), 5.33 (d, J= 52, 12.8 Hz, IH), 3.73 (s, 2H), 3.31 (s, 6H), 3.21 - 3.16 (m, 3H), 2.97 - 2.82 (m, IH), 2.75 - 2.55 (m, 6H), 2.03 - 1.94 (m, IH), 1.66 - 1.57 (m, 2H), 1.55 - 1.43 (m, 6H), 1.11 - 1.03 (m, IH), 0.49 - 0.41 (m, 2H), 0.26 - 0.19 (m, 2H); LCMS (ESI+) m/z 865.5(M+H)+. Characterization of 2-[2-(cyclopropylmethylamino) pyridyl]-N[3- (difluoromethyl)-l-[4-[[4-[4-[l-[(3R)-2,6-dioxo piperidyl] methyl oxo-benzimidazol5-yl]butoxy]butylamino]methyl]phenyl]pyrazol yl]oxazole carboxamide: 1H NMR (400 MHz, DMSO-» δ 11.05 (s, IH), 9.96 (s, IH), 8.95 (s, IH), 8.76 (s, IH), 8.35 (s, IH), 8.14 (d, J = 52 Hz, IH), 7.76 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.40 - 7.12 (m, IH), 7.11 - 7.05 (m, 2H), 7.04 - 6.94 (m, 3H), 6.83 (d, J= 8.0 Hz, IH), 5.30 (d, J= 52, 12.8 Hz, IH), 3.70 (s, 2H), 3.29 (s, 6H), 3.16 (d, J = 6.4 Hz, 3H), 2.93 - 2.81 (m, IH), 2.73 - 2.55 (m, 6H), 2.02 - 1.92 (m, IH), 1.65 - 1.55 (m, 2H), 1.53 - 1.40 (m, 6H), 1.11 -0.99 (m, IH), 0.47 - 0.39 (m, 2H), 0.23-0.17 (m, 2H); LC-MS (ESI+) m/z 865.5(M+H)+.

[005564] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

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33 members in 12 offices

This recordMember, by publication datePriority claim2 more offices are in the list below

Priority claims9

Priority claims
Document	Office	Kind	Date
62610397	United States of America	–	2017-12-26
201762610397	United States of America	P	2017-12-26
62653178	United States of America	–	2018-04-05
201862653178	United States of America	P	2018-04-05
62694955	United States of America	–	2018-07-06
201862694955	United States of America	P	2018-07-06
62712377	United States of America	–	2018-07-31
201862712377	United States of America	P	2018-07-31
2018067304	United States of America	W	2018-12-21

Members33

Family members, oldest first
Document	Office	Kind
US2019192668A1	United States of America	A1	2019-06-27
CA3086763A1	Canada	A1	2019-07-04
WO2019133531A1	World Intellectual Property Organization (WIPO)	A1	2019-07-04
AU2018396142A1	Australia	A1	2020-07-16
SG11202005912PA	Singapore	A	2020-07-29
IL275649A	Israel	A	2020-08-31
IL275649D0	Israel	D0	2020-08-31
EP3731869A1	European Patent Office (EPO)	A1	2020-11-04
MX2020006812A	Mexico	A	2020-11-06
MX2020006812A	Mexico	A	2020-11-06
BR112020012997A2	Brazil	A2	2020-12-01
CN112105385A	China	A	2020-12-18
US10874743B2	United States of America	B2	2020-12-29
JP2021508703A	Japan	A	2021-03-11
EA202091231A1	Eurasian Patent Organization (EAPO)	A1	2021-03-22
EP3731869A4	European Patent Office (EPO)	A4	2021-09-22
US11318205B1	United States of America	B1	2022-05-03
US2023106066A1	United States of America	A1	2023-04-06
IL275649B1	Israel	B1	2023-08-01
IL304055AThis record	Israel	A	2023-08-01
US11723980B2	United States of America	B2	2023-08-15
IL275649B2	Israel	B2	2023-12-01
US2023398223A1	United States of America	A1	2023-12-14
JP2024038329A	Japan	A	2024-03-19
JP7554672B2	Japan	B2	2024-09-20
IL304055B1	Israel	B1	2024-10-01
IL315310A	Israel	A	2024-10-01
US12168057B2	United States of America	B2	2024-12-17
US2025000985A1	United States of America	A1	2025-01-02
IL304055B2	Israel	B2	2025-02-01
EP3731869B1	European Patent Office (EPO)	B1	2025-07-23
EP4613773A2	European Patent Office (EPO)	A2	2025-09-10
US2025325673A1	United States of America	A1	2025-10-23