Heteroaryl compounds and uses thereof.

HETEROARYL COMPOUNDS AND USES OF THE

Field of Invention

The present invention relates to useful as protein kinase inhibitors.

also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods for using those compositions in the treatment of various disorders.

Background of the Invention

The search for new therapeutic agents has been greatly aided in recent years by a better understanding of the structure of enzymes and other biomolecules associated with diseases. An important class of enzymes that have been the subject of extensive study are protein kinases.

Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a variety of signal transduction processes within the cell. Protein kinases are believed to have evolved from a common ancestral gene due to the conservation of their catalytic structure and function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be categorized into families by the substrates they phosphorylate (eg, protein-tyrosine, protein-serine / threonine, lipids, etc.).

REF: 260043.

393

IMPI

<img file="MX360970B_D0001.tif" />

The title compound was prepared * "3S" ^ ar: uerd © --eon -— the reaction schemes, steps and intermediates described in Example 20 using 3- (2- (2-oxopyrrolidin-lyl) ethoxy) aniline instead of 4 in stage 2. ¹H NMR (DMSO-

<td>d₆) δ ppm:</td><td colspan="2">1.89 (quintet, J = 7.6</td><td>Hz, 2H),</td><td>2.21 (t, i</td><td> 7=8</td>

<td>Hz, 2H), 3.</td><td>40 (t, J =</td><td>6.8 Hz, 2H),</td><td>3.50 (t,</td><td>J = 5.6 Hz,</td><td>2H),</td>

<td>3.93 (t, J</td><td>= 5.2 Hz,</td><td>2H), 5.75 (dd,</td><td>J = 2 and</td><td>10 Hz, 1H),</td><td> 6.25</td>

<td>(dd, J = 2</td><td colspan="2">and 16.84 Hz, 1H), 6.42-6</td><td colspan="2">.49 (m, 2H), 7.05 (t</td><td>, J =</td>

<td>8.4 Hz, 1H)</td><td>, 7.28 (t,</td><td>J = 8 Hz, 2H),</td><td>, 7.33 (S,</td><td>1H), 7.43</td><td>(d, J</td>

<td>= 8 Hz, 1H)</td><td>, 7.57 (d,</td><td>J = 8 Hz, 1H),</td><td>, 7.92 (s,</td><td>1H), 8.12</td><td>(d, J</td>

<td>= 3.6 Hz,</td><td>1H), 9.15</td><td>(S, 1H), 9.45</td><td>(S, 1H),</td><td>10.13 (s,</td><td>1 HOUR) ;</td>

LCMS: m / e 475 (M-2).

Example 75

Preparation of N- (3- (5-fluoro-2- (6- (3 (methylsulfonyl) propoxy) pyridin-3-ylamino) pyrimidin-4ylamino) phenyl) acrylamide 1-80

<img file="MX360970B_D0002.tif" />

1-80

The title compound was prepared according to the reaction schemes, steps and intermediates described in Example 20 using 3-amino-6- (3 (methylsulfonyl) propoxy) pyridine instead of 4 in step 2.

IMPI

<img file="MX360970B_D0003.tif" />

In general, protein kinases mediate intracellular signaling by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein receptor that is involved in a signaling pathway. These phosphorylation events act as molecular quenchers / ignitors that can modulate or regulate the biological function of target proteins. These phosphorylation events are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of these stimuli include environmental and chemical stress signals (e.g., osmotic shock, term shock, ultraviolet radiation, bacterial endotoxins, and H₂0₂), cytokines (for example, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α)), and growth factors (for example, granulocyte-macrophage colony stimulating factor (GM-CCSF) and fibroblast growth factor (FGF)). An extracellular stimulus can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle.

Many diseases are associated with abnormal cellular responses triggered by protein kinase mediated events as described above. These diseases include, but are not

<img file="MX360970B_D0004.tif" />

INSTITUTO MEXICANO oe U raOMEDAD «fousntAi limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy and asthma, disease of diseases related to hormones.

Alzheimer's and

Consequently, there remains a need to find useful protein kinase inhibitors as therapeutic agents.

Brief Description of the Invention

Invention has been found, and compositions thereof, are effective general Ia and Ib:

<img file="MX360970B_D0005.tif" />

the ring is now defined that the compounds of this are pharmaceutically acceptable

These as protein kinase inhibitors.

compounds have

<img file="MX360970B_D0006.tif" />

acceptable formulas thereof,

A, ring B, m, p, R^x, R^Y, R^v, W¹, W² and R¹ at the moment.

The compounds of or more wherein they are as the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or

<img file="MX360970B_D0007.tif" />

<img file="MX360970B_D0008.tif" />

. IMPI ** MEXICAN INSTITUTE of industrial cold conditions associated with cellular responses triggered by protein kinase-mediated events. These diseases, disorders or conditions include those described herein.

The compounds provided by this invention are also useful for the study of kinases in biological and pathological phenomena. The study of intracellular signal transduction pathways mediated by these kinases and the comparative evaluation of new kinase inhibitors.

Brief Description of Figures

Figure 1 illustrates the dose response inhibition of phospho-plc gamma2 (T-PLC gamma 2) with compound 1-2 in Ramos cells and the results of compound 1-2 in a washout experiment.

Figure 2 illustrates dose response inhibition of p-plc gamma2 with compound 1-4 in Ramos cells; and the results of compound 1-4 in a wash experiment.

Figure 3 illustrates the dose response inhibition of p-plc gamma2 with compound 1-7 in Ramos cells, and the results of compound 1-7 in a washout experiment.

Figure 4 shows the dose response inhibition of p-plc gamma2 with compound 1-35 in Ramos cells.

Figure 5 illustrates the response inhibition of? Γ * «τ? Ϊΐβτ» η

<img file="MX360970B_D0009.tif" />

<img file="MX360970B_D0010.tif" />

ΤΜΤΠ

JLvjL jL jl INSTITUTO MEXICANO DI LA PROPIEDAD INDUSTRIAL dose of p-plc gamma2 with compound 1-38 in Harlot cells ·: ·

<td>The</td><td>figure 6</td><td>illustrates the</td><td>MS analysis</td><td>confirming</td><td>the</td>

<td>modification</td><td colspan="3">TEC kinase covalent in</td><td>Cys449 by</td><td>the</td>

<td>compound 1-2</td><td></td><td></td><td></td><td></td><td></td>

<td>The</td><td>figure 7</td><td>illustrates the</td><td>MS analysis</td><td>confirming</td><td>the</td>

<td>modification</td><td>covalent</td><td>kinase</td><td colspan="3">TEC on Cys449 by Composite</td>

<td> 1-4.</td><td></td><td></td><td></td><td></td><td></td>

<td>The</td><td>figure 8</td><td>illustrates the</td><td>MS analysis</td><td>confirming</td><td>the</td>

<td>modification</td><td>covalent</td><td>kinase</td><td colspan="3">TEC on Cys449 by Composite</td>

<td> 1-7.</td><td></td><td></td><td></td><td></td><td></td>

<td>The</td><td>figure 9 i</td><td>shows the</td><td>results</td><td>of the compound</td><td>I-</td>

in a wash experiment compared to the results of compound 1-4 and compound 1-7 in the same wash experiment in HCC827 cells containing EGFR deletion mutant.

Figure 10 shows the results of compound 1-7 in a wash experiment compared to results of an EGF control in A431 cells containing wild-type EGFR.

Figure 11 illustrates MS analysis confirming covalent modification of JAK-3 kinase at Cys999 by compound 1-7.

Figure 12 illustrates dose response inhibition of P-Stat5 with Compound 1-2 in IL-2 stimulated CTLL-2 cells; and dose response inhibition

<img file="MX360970B_D0011.tif" />

IMPI '^ TUTO MEXICANO DE U INDUSTRIAL PROPERTY

<img file="MX360970B_D0012.tif" />

of P-JAK-3 with Compound 1-2 in IL-2 stimulated CTLL-2 cells.

Figure 13 illustrates the dose response inhibition of P-Stat5 with compound 1-4 in CTLL-2 cells.

<td colspan="2">stimulated</td><td>with IL-2;</td><td colspan="2">and response inhibition</td><td>dose</td><td>from</td>

<td>P-JAK-3</td><td>with</td><td>compound</td><td>1-4 in CTLL-2 cells</td><td colspan="2">stimulated</td><td>with</td>

<td>IL-2.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>The</td><td>figure 14</td><td>illustrates inhibition</td><td>from</td><td>answer</td><td>from</td>

dose of P-Stat5 with compound 1-7 in IL-2 stimulated CTLL-2 cells.

Figure 15 shows MS analysis confirming covalent modification of BTK by compound 1-7.

Figure 16 illustrates a Western Blot showing available BTK protein for probe compound 1-215 after treatment with varying amounts of 1-7.

Figure 17 illustrates the quantification of the Western Blot results in Figure 16.

Figure 18 illustrates a Western Blot for a wash experiment with compound 1-7 and probe compound

1-215.

Figure 19 illustrates the quantification of the Western Blot results in Figure 18.

Figure 20 illustrates an amino acid sequence for BTK (SEQ ID 1): full-length BTK protein.

Figure 21 illustrates an amino acid sequence

<img file="MX360970B_D0013.tif" />

IMPI

INJTnyrO MEXICANO DE LA PROPERTY INDUSTRIAL for TEC (SEQ ID 2): Full-length TEC protein NP_003206 631 aa.

Figure 22 illustrates an amino acid sequence for ITK (SEQ ID 3): Full length ITK protein NP_005537 620 aa.

Figure 23 illustrates an amino acid sequence for BMX (SEQ ID 4): Full-length BMX protein NP_001712 675 aa.

Figure 24 illustrates an amino acid sequence for TXK (SEQ ID 5): full length TXK protein NP_003319 527 aa.

Figure 25 illustrates an amino acid sequence for JAK3 (SEQ ID 6): full length JAK3 protein NP_00206 1124 aa.

Detailed description of the invention

1. General description of the compounds of the invention

In certain embodiments, the present invention provides a compound of formula Ia or Ib:

<img file="MX360970B_D0014.tif" />

or a pharmaceutically acceptable salt thereof, wherein:

<img file="MX360970B_D0015.tif" />

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL ring A is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered saturated, partially unsaturated or aryl bicyclic ring, a monocyclic heteroaryl ring 5-6 membered having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen , oxygen or sulfur or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered saturated, partially unsaturated or aryl bicyclic ring, a 5-6 membered monocyclic heteroaryl ring that has 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-7 membered saturated or partially unsaturated heterocycid ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a saturated or

<img file="MX360970B_D0016.tif" />

IMPI

<img file="MX360970B_D0017.tif" />

<img file="MX360970B_D0018.tif" />

has partially unsaturated

<img file="MX360970B_D0019.tif" />

<img file="MX360970B_D0020.tif" />

<img file="MX360970B_D0021.tif" />

heteroatoms nitrogen, oxygen

<img file="MX360970B_D0022.tif" />

independently selected

<img file="MX360970B_D0023.tif" />

nitrogen, oxygen

<img file="MX360970B_D0024.tif" />

sulfur;

R¹ it is a leading group;

R^Y is hydrogen, halogen, -CN, -CF₃, Ci-4 aliphatic, Ci_ haloaliphatic₄, -OR, -C (O) R or -C (0) N (R)₂;

each R group is independently hydrogen or an optionally substituted group selected from aliphatic from Ci-₆, phenyl, a 4-7 membered heterocyclic ring having 1-2 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 ;

W¹ and W² are each independently a covalent bond or a Ci_ alkylene chain₃ bivalent where a methylene unit of W¹ or W² is optionally replaced by -NR²-, - (R²) C (O) -, C (O) N (R²) -, -N (R²)SW₂-, -SO₂N (R²) -, -O-,

-C (0) -, -0C (0) -, -C (0) 0-, -S-, -SO- or -S0₂-;

R² is hydrogen, aliphatic of Ci-₆ optionally substituted, or -C (O) R, or:

R² and a substituent on ring A are taken

WICKED

DCTrryTO MEXICANO V'iíC »r -: - &lt;DE LA PROHEDaD industrial or aromatic of 4 with its atoms together with its intervening atoms for fused saturated, partially unsaturated 6 members, or:

R² and R^Y interveners are taken together to form a 4-7 membered partially unsaturated or aromatic fused ring;

m and p are independently 0-4; Y

R^x and R^v are independently selected from -R, halogen, -OR, -O (CH₂)_whatOR, -CN, -N0₂, -SO₂R, -SO₂N (R)₂, -SOR, C (O) R, -CO₂R, -C (O) N (R)₂, -NRC (O) R, -NRC (O) NR₂, -NRSO₂R, or N (R)₂, where q is 1-4; or:

R^x and R¹ when present concurrently on ring B they are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with a head group and 0-3 groups independently selected from oxo, halogen, -CN or aliphatic from Ci-₆; or

R^v and R¹ when present concurrently in ring A they are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is replaced with a leading group and 0-3 groups

<img file="MX360970B_D0025.tif" />

<img file="MX360970B_D0026.tif" />

MEXICAN INSTITUTE

OF PROPERTY W

INDUSTRIAL independently selected from oxo, halogen, -CN or aliphatic Ci_₆.

two. Compounds and definitions

The compounds of this invention include those generally described above, and are further illustrated by the classes, subclasses, and species described herein. As used herein, the following definitions will apply unless otherwise stated. For the purposes of this invention, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in Organic Chemistry. Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5^to edition., Ed.; Smith, MB and March, J., John Wiley &amp; Sons, New York: 2001, the full contents of which are incorporated herein by reference.

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 fully saturated or contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or that contains one or more units of

<img file="MX360970B_D0027.tif" />

IMPI

Mu industrial PROPERTY

<img file="MX360970B_D0028.tif" />

unsaturation, but which is not aromatic (also known here as carbocycle, cycloaliphatic, or cycloalkyl), which 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, the aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in still other embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms.

In some embodiments, cycloaliphatic (or carbocycle or cycloalkyl) refers to a hydrocarbon of C₃-C₆monocyclic that is fully 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.

The term "lower alkyl" refers to a straight or branched C 3-4 alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

<img file="MX360970B_D0029.tif" />

<img file="MX360970B_D0030.tif" />

The lower haloalkyl term ιμρϊ ^BwS} nⁱor Mexican industrial property

<img file="MX360970B_D0031.tif" />

Ci_ alkyl group₄ straight or branched that is substituted with one or more halogen atoms.

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-2H-pyrrolyl), NH) as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term unsaturated, as used herein, means that a portion has one or more units of unsaturation.

As used herein, the term Ch-a (or Ci-₆) bivalent, straight or branched, saturated or unsaturated, refers to bivalent alkylene, alkenylene and alkynylene chains that are straight or branched as defined herein.

The term "alkylene" refers to a bivalent alkyl group. An alkylene chain is a polymethylene group, that is, - (CH₂)_n"" Where n is a positive integer, preferably 1 to 6, dela4, dela3, 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. The

<img file="MX360970B_D0032.tif" />

Suitable substituents include those described below for a substituted aliphatic group.

The term "alkenylene" refers to a divalent 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.

As used herein, the term "cyclopropylenyl" refers to a bivalent cyclopropyl group of the following structure:

The term halogen means F, Cl, Br or I.

The term aryl used alone or as part of a larger portion as in aralkyl, aralkoxy, or aryloxyalkyl, refers to monocyclic and 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 three to seven ring members. The term aryl can be used interchangeably with the term aryl ring. In certain embodiments of the present invention, aryl refers to an aromatic ring system that includes, but is not limited to, phenyl, biphenyl, naphthyl,

<img file="MX360970B_D0033.tif" />

<img file="MX360970B_D0034.tif" />

anthracil and the like, which may carry one or more substituents. Also included within the scope of the term aryl, as used herein, 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.

The terms heteroaryl and heteroar-, used alone or as part of a larger portion, eg, 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 arrangement; and what do they have?

<td>of atoms</td><td>carbon,</td><td>from one to</td><td>five heteroatoms.</td><td>The</td>

<td>finished </td><td>heteroatom</td><td>it means</td><td>to nitrogen, oxygen</td><td>or</td>

<td>sulfur, e</td><td colspan="2">includes any shape</td><td>oxidized nitrogen</td><td>or</td>

sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl pyrimidinyl, pyrazinyl, naphthyridinyl, and pteridinyl.

pyridyl, pyridazinyl, indolizinyl, purinyl,

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,

IMPI 'ΝίΤΠντρ MEXICAN OE LA PROPERTY INDUSTRIAL

<img file="MX360970B_D0035.tif" />

<img file="MX360970B_D0036.tif" />

wherein the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, tetraoliniazinyl, and tetraquininiazinyl, and tetraquinolinehydrozinehydrozinyl, phenylazinohydrozinyl, pyrido [2,3b] -1,4-oxazin-3 (4H) -one. A heteroaryl group can be mono- or bicyclic. The term heteroaryl can 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 moieties are independently optionally substituted.

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 7-10 membered bicyclic heterocyclic portion 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

<img file="MX360970B_D0037.tif" />

₁₇ IMPI '' MEXICAN INSTITUTE

INDUSTRIAL PROPERTY Reference to a ring atom of a heterocyclic 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 can be N (as in 3,4-dihydro-2Hpyrrolyl), NH (as in pyrrolidinyl), or⁺NR (as in N-substituted pyrrolidinyl).

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 these saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxoinylo, morzolidinyl, tinozepinyloxylinyl, morzolidinyl, diazepinyl, and ethylinepolinyl. 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, 3H-indolyl, chromanyl, phenanthridinyl, or

IMPI

<img file="MX360970B_D0038.tif" />

tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group can be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl moieties are optionally independently substituted.

As used herein, the term "partially unsaturated" refers to a ring portion that includes at least one double bond or one 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 defined herein.

As described herein, the compounds of the present 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 in the designated portion are replaced with a suitable substituent. Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each substitutable position in 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 can be either the go

IMPI

<img file="MX360970B_D0039.tif" />

same or different in each position. Combinations of substituents contemplated by this invention are preferably those that result in the formation of stable or chemically viable compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow their production, detection and, in certain embodiments, their recovery, purification and

<td>use for</td><td>one</td><td>0 more than the purposes</td><td>described</td><td>on</td><td>the</td>

<td>Present.</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>The</td><td>monovalent substituents</td><td>suitable</td><td>on</td><td>a</td>

<td>atom of</td><td colspan="2">replaceable carbon a</td><td colspan="3">substituted group</td>

optionally they are independently halogen; - (CH₂)₀.₄R °, (CH₂)or-₄OR °, -0 (CH₂) ₀-₄R^or , -0- (CH₂) or-₄C (0) 0R °; - (CH₂) ₀-₄CH (0R °) ₂ ;

(CH₂)or-₄SR °; - (CH₂) or -4Ph, which can be substituted with

R °; - (CH₂) 0-4O (CH₂) 0-1-pyridyl which can be substituted with R °; -N0₂; -CN-N₃; - (CH₂) ₀-₄N (R °) ₂; - (CH₂) ₀-₄N (R °) C (0) R °; N (R °) C (S) R °; - (CH₂) or-₄N (R °) C (O) NR °; -N (R °) C (S) NR °₂ ; - (CH₂) ₀.

₄N (R °) C (0) 0R °; -N (R °) N (R °) C (O) R °; -N (R °) N (R °) C (0) NR °;

N (R °) N (R °) C (0) 0R °; - (CH₂) ₀-₄C (0) R °; -C (S) R °; - (CH₂) ₀-₄C (0) 0R °; (CH₂) or.₄C (0) SR °; - (CH₂) 0-4C (O) 0SiR ° 3; - (CH₂)₀_₄OC (O) R °;

0C (0) (CH₂)or-₄MR⁰, SC (S) SR °; - (CH₂) ₀.₄OC (0) NR °; -C (0) N (0R °) R °; C (O) C (O) R °; -C (0) CH₂C (0) R °; -C (NOR °) R °; - (CH₂) ₀_₄SSR °; - (CH₂) ₀.

₄SW)₂R °; - (CH₂) ₀-₄S (0) ₂0R °; - (CH₂) ₀.₄OS (0) ₂R °; -SW)₂NR °₂; (CH₂) 0.4S (0) R °; -N (R °) S (0)₂NR °₂; -N (R °) S (0)₂R °; -N (0R °) R °; twenty

<img file="MX360970B_D0040.tif" />

.....

msn

C (NH) NR °₂; -P (0)₂R^or; -P (0) R^or₂; -OP (O) R °; -OP (O) (OR °)₂; SiR °₃; (Ci-₄ straight or branched) ON (R °)₂; or - (straight or branched alkylene of Ci-₄) C (O) ON (R °) ₂, where each R ° may be substituted as defined below and is independently hydrogen, aliphatic Ci-₆, -CH₂Ph, O (CH₂)₀-iPh, -CH₂- (5-6 membered heteroaryl ring), or a saturated, partially unsaturated or 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definition, two occurrences independent of R °, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring having 04 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

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 *), - (CH₂)₀-₂OH, - (CH₂)or-₂OR ·, - (CH₂) or.₂CH (OR '); -O (haloR '); -CN, -N₃, - (CH₂)₀₂c (o) r ·, - (ch₂)₀-2C (o) oh, - (ch₂)₀-₂c (o) or ·, - (ch₂)or-₂sr), - (ch₂)₀₂sh, - (CH₂) or-₂NH₂, - (CH₂)or-₂NHR ·, - (ch₂)₀.₂nr *₂, -not₂, -sír '₃, osir *₂,

-C (O) SR

- (alkylene of

Ci-₄ branched rectum) C (O) 0R ', or -SSR * where each R * is unsubstituted

IMPI

MEXICAN INSTITUTE

OttAfWOrtCDiAC

INDUSTRIAL or when preceded by halo is substituted only with one or more halogens, and is independently selected from aliphatic from Ch-4, -CH₂Ph, -0 (CH₂) ₀-iPh, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of R include = 0 and = S.

Suitable divalent substituents on a saturated carbon atom of an optionally substituted group include the following: = 0, = S, = NNR *₂, = NNHC (O) R *, = NNHC (0) 0R *, = NNHS (O)₂R *, = NR *, = N0R *, -O (C (R *₂)) 2-3O-, or S (C (R *₂)) 2-3S-, where each independent occurrence of R * is selected from hydrogen, aliphatic from Ω_χ-₆ which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially saturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents that are attached to vicinal substitutable carbons of an optionally substituted group include: -0 (CR *₂) ₂.₃OR-,

<td>where</td><td>each occurrence regardless of R * is</td>

<td>Choose</td><td>hydrogen, aliphatic Ci_₆ What can be</td>

<td>replaced</td><td>as defined below, 0 a saturated ring,</td>

partially unsaturated or unsubstituted 5-6 membered aryl having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

<img file="MX360970B_D0041.tif" />

<img file="MX360970B_D0042.tif" />

<img file="MX360970B_D0043.tif" />

Suitable substituents on the aliphatic group of R * include halogen, -R ', - (haloR *), -OH, -OR *,

0 (haloR *,), -CN, -C (O) OH, -C (O) OR *, -NH₂, -NHR *, -NR *₂, or not₂, wherein each R * is unsubstituted or when preceded by halo is substituted with only one or more halogens, and is independently aliphatic of Ci-₄, -CH₂Ph, -0 (CH₂) ₀-iPh, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on a substitutable nitrogen of an optionally substituted group include R^F, -NR^t2, -CYOR *, -C (O) 0R^F, -0 (0) 0 (0 ^, -C (0) CH2C (0) R^F, SÍOzR¹, -S (O) 2NR^t2, -CÍSjNR ^, -CÍNHjNRS, or -N (R^F) S (O) ₂R^F; wherein each R 'is independently hydrogen, Ci-6 aliphatic which may be substituted as defined below, -OPh unsubstituted, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R^F, taken together with their intervening atoms form a saturated, partially saturated or unsubstituted 3-12 membered mono- or bicyclic aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group

<img file="MX360970B_D0044.tif" />

<img file="MX360970B_D0045.tif" />

IΜ Ρ ί \ INSTITUTO MEXICANO 1 DE LA PROPERTY INDUSTRIAL de R^F are independently halogen, -R *, - (haloR *), -OH, OR *, -O (haloR '), -CN, -C (O) OH, -C (O) OR *, -NH₂, -NHR *, -NR '_2z or not₂, where each R * is unsubstituted or when preceded by halo is substituted with only one or more halogens, and is independently aliphatic of Ci-₄, -CH₂Ph, -0 (CH₂) ₀-iPh, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of correct medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, response. allergy and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM 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 non-toxic pharmaceutically acceptable acid addition salts are the salts of an amino group formed with inorganic acids such as hydrochloric acid, acid

<img file="MX360970B_D0046.tif" />

<img file="MX360970B_D0047.tif" />

<img file="MX360970B_D0048.tif" />

«

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL hydrobromic, 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 using other methods used in the techniques 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, glycoconaphonate, glucerophosulfonate, fumarate, glucoconaphonate, glucoconaphonate, glucoconaphonate heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate,

<img file="MX360970B_D0049.tif" />

nicotinate, nitrate,

<img file="MX360970B_D0050.tif" />

palmitate, pamoate,

<img file="MX360970B_D0051.tif" />

<img file="MX360970B_D0052.tif" />

<img file="MX360970B_D0053.tif" />

<img file="MX360970B_D0054.tif" />

pivalate, succ

<img file="MX360970B_D0055.tif" />

propionate, stearate,

<img file="MX360970B_D0056.tif" />

undecanoate, valerate, and the like.

Suitable base derived salts include the alkali metal, alkaline earth metal, ammonium and

N⁺(Ci_ alkyl₄)₄. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, the non-toxic ammonium cations of ammonium

IMPI

<img file="MX360970B_D0057.tif" />

quaternary and amine formed using contraidliyy LáléS δδπίο halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

Unless otherwise indicated, the structures illustrated herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational) forms) of the structure;

for example, the settings

S for each asymmetric center, double bond isomers

E and Z and E conformation isomers. Therefore, individual 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 indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise indicated, the structures illustrated herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures include the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a carbon enriched with¹³C or ¹⁴C are within the scope of this invention. These compounds are useful, for example, as analytical tools, as probes in assays i

<img file="MX360970B_D0058.tif" />

INSTITUTO MEXICANO DE LA PROPERTY INDUSTRIAL biological or as therapeutic agents of diet COTI ta? present invention. In some modalities, group R¹ of formula Ia or Ib comprise one or more deuterium atoms.

As used herein, the term "irreversible" or "irreversible inhibitor" refers to an inhibitor (ie, a compound) that is capable of being covalently linked to a target protein kinase in a substantially irreversible manner. That is, while a reversible inhibitor is capable of binding to (but is generally unable to covalently form) the target protein kinase, and thus can become dissociated from the target protein kinase, an irreversible inhibitor will remain substantially bound to the target protein kinase. target protein kinase once covalent bond formation has occurred.

Irreversible inhibitors normally display time dependence, whereby the degree of inhibition increases with the time that the inhibitor is in contact with the enzyme.

Methods for identifying whether a compound acts as an irreversible inhibitor are known to one of ordinary skill in the art.

These methods include, but are not limited to, enzymatic kinetic analysis of the compound's inhibition profile with the protein kinase target, the use of mass spectrometry of the modified protein drug target in the presence of the inhibitory compound, exposure

<img file="MX360970B_D0059.tif" />

discontinuous, also known as washout experiments, and the use of labeling, such as radiolabelled inhibitor, to show covalent modification of the enzyme, as well as other methods known to one skilled in the art.

One of ordinary skill in the art will recognize that certain reactive functional groups can act as heads. As used herein, the term "head" or "head group" refers to a functional group present in a compound of the present invention wherein that functional group is capable of being covalently attached to an amino acid residue (such as cysteine, lysine, histidine or other residues capable of being covalently modified) present in the binding cavity of the target protein, thereby irreversibly inhibiting the protein. It will be appreciated that the -ΣΥ group, as defined and described herein, provides these head groups to covalently and irreversibly inhibit the protein.

As used herein, the term "inhibitor" is defined as a compound that binds to and / or inhibits the target protein kinase with measurable affinity. In certain modalities, 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

ΙΜΡϊ @&gt;

Mexican INSWüTO

Ota * HióDtDW 'ryzyas. industrial '%_&gt;^tow^wa 100 nM, or less than about 10 nM. ...— »

The terms measurable affinity and measurably inhibit, as used herein, mean a measurable change in at least one of ErbBl, ErbB2, ErbB3, ErbB4 activity, a TEC-kinase, and / or JAK3 between a sample comprising a compound of the present invention, or composition thereof, and at least one of ErbBl, ErbB2, ErbB3, ErbB4, a TEC-kinase, and / or JAK3, and an equivalent sample comprising at least one of ErbBl, ErbB2, ErbB3 , ErbB4, a TEC-kinase, and / or JAK3, in the absence of the compound, or composition thereof.

3. Description of exemplary compounds

According to one aspect, the present invention provides a compound of

<img file="MX360970B_D0060.tif" />

<img file="MX360970B_D0061.tif" />

Ia or a pharmaceutically salt thereof, where:

Ring A is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered saturated, partially unsaturated or aryl bicyclic ring, a 5-6 membered monocyclic heteroaryl ring that have

<img file="MX360970B_D0062.tif" />

IMPI

Mexican Institute of Industrial Property

1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a bicyclic saturated or partially unsaturated heterocyclic ring of 7 -10 members having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a partially unsaturated or saturated bicyclic ring, or 8-10 membered aryl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a saturated heterocyclic ring or

<img file="MX360970B_D0063.tif" />

heteroatoms

<img file="MX360970B_D0064.tif" />

<img file="MX360970B_D0065.tif" />

<img file="MX360970B_D0066.tif" />

independently

<img file="MX360970B_D0067.tif" />

nitrogen, oxygen

<img file="MX360970B_D0068.tif" />

members

<img file="MX360970B_D0069.tif" />

have

<img file="MX360970B_D0070.tif" />

independently selected from nitrogen, oxygen or

IMPI

<img file="MX360970B_D0071.tif" />

z sulfur;

R¹ is -LY, where:

L is a covalent bond or a saturated or unsaturated, straight or branched hydrocarbon chain of Ci3 and bivalent, where one, two or three methylene units of L are optionally and independently replaced by cyclopropylene, -NR-, -N ( R) C (O) -, -C (O) N (R) -, -N (R) SO₂-, SO₂N (R) -, -O-, -C (O) -, -0C (0) -, -C (O) O-, -s-, -so-, -so₂-, C (= S) -, -C (= NR) -, -N = N-, or -C (= N₂)-;

Y is hydrogen, aliphatic Ci_₆ optionally substituted with oxo, halogen or CN, or a 3-10 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein the ring is substituted with 1-4 groups independently selected from -QZ, oxo, NO₂, halogen, CN or aliphatic Ci-₆, where:

Q is a covalent bond or a saturated or unsaturated hydrocarbon chain of Ci-₆, straight or branched and bivalent, where one or two methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -C (0) -, -SO- or -S0₂-; Y

Z is hydrogen or aliphatic Ci-₆ optionally substituted with oxo, halogen or CN;

R^Y is hydrogen, halogen, -CN, -CF₃, aliphatic of

<img file="MX360970B_D0072.tif" />

INSTITUTO MEXIUAí '.O DELAPROPIEi'AU INDUSTRIAL

Ci-4, Ci- haloaliphatic₄, -OR, -C (O) R or -C (0) N (R)₂;

each R group is independently hydrogen or an optionally substituted group selected from Ci_6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5- 6-membered having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

W¹ and W² are each independently a covalent bond or a bivalent Ci-3 alkylene chain wherein a methylene unit of W¹ or W² is optionally replaced by -NR²-, - (R²) C (0) -, C (O) N (R²) -, -N (R²) SO2-, -SO₂N (R²) -, -O-,

-C (0) -, -0C (0) -, -C (0) 0-, -S-, -SO- or -SO₂-;

R² is hydrogen, optionally substituted Cx-6 aliphatic, or -C (O) R, or:

<td></td><td>R² and a substituent</td><td>in the</td><td colspan="2">ring A are taken</td>

<td>With</td><td>its intervening atoms</td><td>in order to</td><td colspan="2">form a ring</td>

<td>merged</td><td>partially unsaturated</td><td colspan="2">or aromatic</td><td>from 4-6</td>

<td>members, or</td><td></td><td></td><td></td><td></td>

<td></td><td>R² and R^Y they take</td><td>together</td><td>with their</td><td>atoms</td>

interveners to form a 4-6 membered saturated, partially unsaturated or aromatic fused ring;

m and p are independently 0-4; Y

R^x and R^v are independently selected from -R,

IMPI

<img file="MX360970B_D0073.tif" />

halogen, -0R, -O (CH₂)_whatOR, -CN, -NO₂, -SO₂R, -SO₂N (R)_2/ SOR, -C (O) R, -CO₂R, -C (O) N (R)₂, -NRC (O) R, -NRC (O) NR₂, NRSO₂R, O -N (R)₂; OR:

R^x and R¹ when present concurrently on ring B they are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where the ring is substituted with a head group and 0-3 groups independently selected from oxo, halogen, -CN or aliphatic of Ci_₆; or.

R^v and R¹ when present concurrently on ring A they are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with a head group and 0-3 groups independently selected from oxo, halogen, -CN or aliphatic Ci-₆.

As generally defined above, Ring A is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a

<img file="MX360970B_D0074.tif" />

! IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

·. INDUSTRIAL

<img file="MX360970B_D0075.tif" />

saturated, partially unsaturated or aryl bicyclic

8-10 membered, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 8-10 membered bicyclic that a heteroaryl ring has 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In certain embodiments, the ring

A is an optionally substituted phenyl group.

In some embodiments, the ring is a naphthyl ring optionally substituted by a bicyclic 810 membered heteroaryl ring having

1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain other embodiments, Ring A is an optionally substituted 3-7 membered carbocyclic ring. In still other embodiments, Ring A is a heterocyclic ring of

4-7 optionally substituted members having

1-3 heteroatoms independently selected from nitrogen, oxygen

<img file="MX360970B_D0076.tif" />

or sulfur.

In certain embodiments, ring A is substituted as defined herein. In some embodiments, ring A is substituted with one, two, or three groups independently selected from halogen, R °, or - (CH₂) 0-4OR⁰ , or -O (CH₂) 0-4R⁰ / where each R ° is as defined herein. Exemplary substituents on ring A include Br, I, Cl, methyl, -CF₃, -CsCH, -OCH₂phenyl,

OCH₂(fluorophenyl) or -OCH₂pyridyl.

Exemplary ring A groups are shown in Table 1.

Table 1

Exemplary A ring groups

<img file="MX360970B_D0077.tif" />

v vi viii

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0078.tif" />

<img file="MX360970B_D0079.tif" />

xxvi xxvii xxviii

<img file="MX360970B_D0080.tif" />

<img file="MX360970B_D0081.tif" />

xxix xxx

<img file="MX360970B_D0082.tif" />

<img file="MX360970B_D0083.tif" />

<img file="MX360970B_D0084.tif" />

<img file="MX360970B_D0085.tif" />

<img file="MX360970B_D0086.tif" />

/

<img file="MX360970B_D0087.tif" />

<img file="MX360970B_D0088.tif" />

<img file="MX360970B_D0089.tif" />

Ixxxi, where each R °, R^F and R¹ is as defined above

<img file="MX360970B_D0090.tif" />

and described in classes and subclasses herein.

In certain embodiments, ring A is selected from i, ii, iv, v, vi, vii, ix, xiv, xvi, lii, lxiii, lxxi, lxxiv, lxxvi, lxxviii, and lxxxi.

As generally defined above, Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered saturated, partially unsaturated or aryl bicyclic ring, a monocyclic heteroaryl ring 5-6 membered having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a saturated or partially unsaturated 4-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, a saturated or partially unsaturated bicyclic 7-10 membered heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen , oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, Ring B is an optionally substituted phenyl group. In some embodiments, Ring B is an optionally substituted naphthyl ring or a bicyclic 8-10 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. On

IMPI

<img file="MX360970B_D0091.tif" />

In certain other embodiments, Ring B is an optionally substituted 3-7 membered carbocyclic ring. In still other embodiments, Ring B is an optionally substituted 4-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, ring B is phenyl. In some embodiments, Ring B is a 6-membered heteroaryl ring having 1-3 nitrogens. In some embodiments, Ring B is a 5-membered heteroaryl ring having 1 or 2 or 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring B is a 5-6 membered saturated heterocyclic ring having 1 nitrogen. In some embodiments, Ring B is a 9-10 membered partially saturated heteroaryl bicyclic ring having 1-3 nitrogens. In some embodiments, Ring B is a 9-10 membered partially saturated bicyclic heteroaryl ring having a nitrogen. In some embodiments, Ring B is a partially saturated, heteroaryl, bicyclic 9-10 membered ring having 1 nitrogen and 1 oxygen.

In some embodiments, Ring B is an optionally substituted group selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, pyrrolidinyl,

IMPI

<img file="MX360970B_D0092.tif" />

piperidinyl, indolinyl, indazolyl, and isoindolinyl.

Exemplary ring B groups are shown in Table 2.

Table 2

Ring groups B

<img file="MX360970B_D0093.tif" />

«I *

<img file="MX360970B_D0094.tif" />

xxii xxiii xxiv xxv xxvi xxvii xxviii xxix

XXX xxxi xxxii xxxiii

<img file="MX360970B_D0095.tif" />

IMPI

<img file="MX360970B_D0096.tif" />

Ivii

Iviii lix

Ix

<img file="MX360970B_D0097.tif" />

<img file="MX360970B_D0098.tif" />

<img file="MX360970B_D0099.tif" />

<img file="MX360970B_D0100.tif" />

bcxxvi ixxxu

Ixxxiv lxxxvii txxxviii

Ixxxix

<img file="MX360970B_D0101.tif" />

Ixxviii

Ιχχιχ

Ixxx

IXXXlll

<img file="MX360970B_D0102.tif" />

<img file="MX360970B_D0103.tif" />

where each R¹ and R^x it is as defined above and described in classes and subclasses herein.

In certain modalities, ring B is selected from i, ii, iii, iv, v, ix, x, xi, xiii, xvi, xvii, xix, xx, xxv, xxvi, xxxii, xxxiv, xxxv, xxxviii, xlii, xlvi, xlviii,

IMPI

<img file="MX360970B_D0104.tif" />

1, lviii, lxiv, lxxviii, lxxxiii, lxxxvi, xciv, c, ci, cii, ciii, civ and cv.

In some embodiments, the m portion of formula I is 1, 2, 3, or 4. In some embodiments, m is 1. In other embodiments, m is 0.

In some embodiments, the p portion of formula I is 1, 2, 3, or 4. In some embodiments, p is 1. In other embodiments, p is 0.

As generally defined above, each R group^xof formula I is independently selected from -R, halogen, -0R, -O (CH2) qOR, -CN, -NO2, -SO2R, -SO2N (R) 2, -SOR, C (0) R, -CO2R , -C (O) N (R) 2, -NRC (O) R, -NRC (0) NR2, -NRSO2R or N (R) 2, where q is 1-4, or R^x and R¹ when present concurrently on ring B they are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with a head group and 0-3 groups independently selected from oxo, halogen, CN or aliphatic of Ci_6.

In some modes, each instance of R^x is independently selected from -R, -0R, -O (CH₂)_whatOR, or halogen. In certain modalities, R^x is lower alkyl, lower alkoxy, lower alkoxyalkoxy or halogen. The R groups^x Exemplary include methyl, methoxy, methoxyethoxy, and

IMPI

<img file="MX360970B_D0105.tif" />

fluoro. In some modalities, R^x it is hydrogen.

As generally defined above, each R group^vof formula I is independently selected from -R, halogen, -0R, -0 (CH₂)_what0R, -CN, -N0₂, -SO₂R, -SO₂N (R)₂, -SOR, C (O) R, -CO₂R, -C (0) N (R)₂, -NRC (O) R, -NRC (O) NR₂, -NRS0₂R or N (R)₂, where q is 1-4, or R^v and R¹ when present concurrently on ring A they are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with a head group and 0-3 groups independently selected from oxo, halogen, CN or Cj aliphatic.₆.

In some modes, each instance of R^v is independently selected from -R, -0R, -O (CH₂)_whatOR, or halogen. In certain modalities, R^v is lower alkyl, lower alkoxy, lower alkoxyalkoxy or halogen.

The R groups^v Exemplary include methyl, methoxy, trifluoromethyl, methoxyethoxy, and chlorine. In some modalities, R^v it is hydrogen.

In some embodiments, the q portion is 1, 2, 3, or

4.

In certain embodiments, q is 1.

In certain other modes, q is 2.

As generally defined above,

R^Y is hydrogen, halogen, -CN,

-cf₃, aliphatic of

Cx-4,

IMPI

<img file="MX360970B_D0106.tif" />

haloaliphatic Ci-₄, -OR, -C (0) R or -C (0) N (R)₂, where R is as defined above and described herein. In certain modalities, R^Y is hydrogen, halogen, -CN, -CF3, lower alkyl or halo-lower alkyl, -C = CR and cyclopropyl. In other modalities, R^Y is -OR, -C (0) R, or C (0) N (R) 2. In certain modalities, R^Y is -C (O) CH₃. In certain other modalities, R^Y is -C (O) NHR. In some modalities, R^Y it is hydrogen. In certain modalities, R^Y it is fluorine. In certain other modalities, R^Y is methyl.

As generally defined above, W¹ and W² are each independently a covalent bond or alkylene chain of Ci-₃ bivalent where a methylene unit of W¹or W² is optionally replaced by -NR²-, -N (R²)CO)-,

C (O) N (R²) -, -N (R²) SO2-, -SO2N (R²) -, -O-, -C (0) -, -OC (O) -, C (0) 0-, -S-, -SO- or -S02-. In certain modes, W¹ and W² They are equal. In some modalities, W¹ and W² They are different.

In some modalities, W¹ it is a covalent bond. In certain modalities, W¹ is a bivalent Ci..3 alkylene chain where a methylene unit of W¹ is optionally replaced by -NR²-, -N (R²) C (0) -, -C (O) N (R²) -, -N (R²) SO2-,

-SW₂N (R²) -, -0-, -C (O) -, -0C (0) -, -C (0) 0-, -S-, -SO- or -SO₂-.

In certain modalities, W¹ is -C (= O), -NR²-, -S- or -0-. In some modalities, W¹ is -NR²-. In other modalities, W¹ that-. In certain modalities, W¹ is -NH-, -S- or -O-. In some modalities, W¹ is -CH₂0-, -CH₂S-, or -CH₂NH-. On

INSTITUTO MEXICANO D £ LA PROPERTY INDUSTRIAL some aspects, W¹ is -OCH₂-, -SCH₂-, -NHCH₂- or -CH₂CH₂-.

In certain modalities, W² it is a covalent bond.

In some modalities, W² is a divalent C1-3 alkylene chain where a methylene unit of W² is optionally replaced by -NR²-, -N (R²) C (O) -, -C (O) N (R²) -, -N (R²)SW₂-, /

-SW₂N (R²) -, -0-, -C (0) -, -OC (O) -, -C (0) 0-, -s-, -so- or -so₂-.

In certain modalities, W² is -C (= 0), -NR²-, -S- or -0-. In some modalities, W² is -NR²-. In other modalities, W² is -0-. In certain modalities, W² is -NH-, -S- or -0-. In some modalities, W² is -CH₂O-, -CH₂S- or -CH₂NH-. In some respects, W² is -OCH₂-, -SCH₂-, -NHCH₂- or -CH₂CH₂-.

In some embodiments, ring B is phenyl,

<img file="MX360970B_D0107.tif" />

or a pharmaceutically acceptable salt thereof, wherein each of the A, m, p, R ring^x, R^Y, R^v, W¹, W² and R¹ it is as defined above and described in the classes and subclasses above and herein.

In certain embodiments, Ring A is phenyl, thus forming a compound of the formula Ill-a or Ill-b:

<img file="MX360970B_D0108.tif" />

<img file="MX360970B_D0109.tif" />

<img file="MX360970B_D0110.tif" />

or a pharmaceutically acceptable salt thereof, wherein each of the B, m, p, R ring^x, R^Y, R^v, W¹, W² and R¹ it is as defined above and described in classes and subclasses above and herein.

In certain embodiments, ring A is phenyl and ring B is phenyl, thus forming a compound of the

<img file="MX360970B_D0111.tif" />

<img file="MX360970B_D0112.tif" />

or a pharmaceutically acceptable salt thereof, wherein each of m, p, R^x, R^Y, R^v, W¹, W² and R¹ it is as defined above and described in classes and subclasses above and herein.

As generally defined above, each R² is independently hydrogen, optionally substituted Cx-6 aliphatic, or -C (O) R, or R² and a substituent on the ring

<img file="MX360970B_D0113.tif" />

I

<img file="MX360970B_D0114.tif" />

A are taken together with their intervening atoms to form a 4-6 membered partially unsaturated or aromatic fused ring, or R² and R^Y they are taken together with their intervening atoms to form a 4-6 membered saturated, partially unsaturated or fused aromatic ring. According to one aspect, R² it is hydrogen. According to another aspect, R² is -C (O) R, where R is an aliphatic group of Ci₆ optionally substituted.

According to some aspects, R² and a substituent on ring A are taken together with its intervening atoms to form a 4-7 membered partially unsaturated or saturated ring, then forming a compound of the formula Iai or Ibi:

<img file="MX360970B_D0115.tif" />

<img file="MX360970B_D0116.tif" />

Ibz or a pharmaceutically acceptable salt thereof, wherein each of the A, R ring¹, R^x and m are as defined above and described in classes and subclasses above and herein.

Similar to the formation of compounds of the formulas Iai and Ibi above, it will be understood by one skilled in the art that compounds of the formulas Il-a, ΙΙ-b, Ill-a, Ill-b, IV-a, and ΙΙ-b, will form compounds II-ai,

<img file="MX360970B_D0117.tif" />

II-bi, III-bi, IV-ai and IV-b-ϊ corresponding when R² and a substituent on ring A are taken together with its intervening atoms to form a 4-7 membered saturated or partially unsaturated ring.

According to some aspects, R² and R^Y are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring, then forming a compound of formula Ia-ii or Ib-ii:

<img file="MX360970B_D0118.tif" />

<img file="MX360970B_D0119.tif" />

or a pharmaceutically acceptable salt thereof, wherein each of the A, R ring¹, R^x and m are as defined above and described in classes and subclasses above and herein.

Similar to the formation of the compounds of the formulas Ia-ií and Ib-ii above, it will be understood by one skilled in the art that compounds of the formulas Il-a, ΙΙ-b, Ill-a, ΙΙΙ-b, IV-a, and IV-b, will form compounds II-a-ii, Il-b-ií, III-a-íi, III-b-ii, IV-a-ií and IV-b-íi corresponding when R² and R^Y are taken together with their intervening atoms to form a 4-7 membered partially unsaturated ring.

As generally defined above, the R group¹ from

<img file="MX360970B_D0120.tif" />

IMPI formulas I and II is -LY, where: '---¹

L is a covalent bond or a straight or branched saturated or unsaturated Ci-g divalent hydrocarbon chain, where one, two or three methylene units of L are optionally and independently replaced by cyclopropylene, -NR-, -N ( R) C (0) -, -C (O) N (R) -, -N (R) SO₂-,

SW₂N (R) -, -o-, -C (0) -, -0C (0), -C (0) 0-, -s-, -so-, -so₂-, C (= S) -, -C (= NR) -, -N = N-, or -C (= N₂)-_;

And it is hydrogen, aliphatic of

Ci-6 optionally substituted with oxo, halogen, NO₂ or CN, or a 310-membered monocyclic or bicyclic, saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein the ring is substituted by 1-4 R groups^and; and each R^and is selected regardless of

-Qz, oxo, N0₂, halogen, CN, a suitable leaving group, or an aliphatic of Ci_₆ optionally substituted with oxo, halogen, N0₂ or CN, where:

Q is a covalent bond or a bivalent hydrocarbon chain of Ci-₆ saturated or unsaturated, straight or branched, where one or two methylene units of Q are optionally and independently replaced by -N (R) -, S-, -0-, -C (0) -, -0C (0 ) -, -C (0) 0-, -SO- or -S0₂-, -N (R) C (0) -,

-C (O) N (R) -, -N (R) S0₂-, bear₂N (R) -, - and

Z is hydrogen or aliphatic Ci_₆ replaced

<img file="MX360970B_D0121.tif" />

IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0122.tif" />

optionally with oxo, halogen, NO₂ or CN.

In certain embodiments, L is a covalent bond.

In certain embodiments, L is a divalent hydrocarbon chain of Ci-₈ saturated or unsaturated, straight or branched. In certain embodiments, L is -CH₂-.

In certain embodiments, L is a covalent bond, CH₂-, -NH-, -CH₂NH-, -NHCH₂-, -NHC (O) -, -NHC (O) CH₂OC (O) CH₂NHC (O) -, -nhso₂-, -NHSO₂CH₂-, -NHC (O) CH₂OC (O) or -so₂nh-.

In some embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched where L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by -NRC (O) -, -C (O) NR-, -N (R) SW₂-, -SO₂N (R) -, -S-, ~ S (0) -, -SO₂-, -0C (0) -, -C (0) 0-, cyclopropylene, -O-, N (R) or -C (0) -.

In certain embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched in which L has at least one double bond and at least one methylene unit of L is replaced by -C (0) -, -NRC (O) -, -C (O) NR-, -N ( R) SO₂-, -SO₂N (R) -, -S-, -S (O) -, -SO₂-, -0C (0) - or -C (0) 0-, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, -O-, N (R) -, or -C ( O) -.

In some embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched, where L

<img file="MX360970B_D0123.tif" />

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL has at least one double bond and at least one —methylene unit of L is replaced by -C (0) -, and one or two methylene units^- Additional L's are optionally and independently replaced by cyclopropylene, -0-, -N (R) -, or -C (0) -.

As described above, in certain embodiments, L is a divalent hydrocarbon chain of C₂-8 straight or branched where L has at least one double bond.

One of ordinary skill in the art will recognize that this double bond may exist within the hydrocarbon chain backbone or it may be exogenous to the backbone chain and then form an alkylidene group.

By way of example, this group L having a branched chain alkylidene includes

-CH₂C (= CH₂) CH₂- .

Thus, in some modalities,

L is a bivalent hydrocarbon chain of C₂_₈ straight or branched where L has at least one alkylidenyl double bond.

Exemplary L groups include

NHC (O) C (= CH₂) CH₂- .

In certain modalities,

L is a bivalent hydrocarbon chain of C₂-₈ straight or branched where L has at least one double bond and at least one methylene unit of

L is replaced by

-C (O) -.

In certain modalities,

L is

-C (O) CH = CH (CH₃) -,

-C (0) ch = chch₂nh (ch₃) -,

-C (0) CH = CH-,

-CH₂C (O) CH = CH-,

CH₂C (O) CH = CH (CH₃) -,

-CH₂CH₂C (O) CH = CH-,

-CH₂CH₂C (O) CH = CHCH₂- ,

CH₂CH₂C (O) CH = CHCH₂NH (CH₃) -, or -CH₂CH₂C (0) CH = CH (CH₃) IMPI

<img file="MX360970B_D0124.tif" />

CH (CH₃) OC (O) CH = CH-. ¹

In certain embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched where L has at least one double bond and at least one methylene unit of L is replaced by -OC (O) -.

In some embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched where L has at least one double bond and at least one methylene unit of L is replaced by -NRC (O) -, -C (O) NR-,

N (R) SO₂-, -SO₂N (R) -, -S-, -S (O) -, -SO₂-, -OC (O) - or -C (0) 0-, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, -O-, -N (R), or -C (O) -. In some embodiments, L is -CH₂OC (O) CH = CHCH₂-, -CH₂-OC (O) CH = CH-, or -CH (CH = CH₂) OC (O) CH = CH-.

In certain embodiments, L is -NRC (O) CH = CH-,

NRC (O) CH = CHCH₂N (CH₃) -NRC (O) CH = CHCH₂O-, -CH₂NRC (O) CH = CH-, NRSO₂CH = CH-, -NRSO₂CH = CHCH₂-, -NRC (O) (C = N₂)CO)-,

NRC (O) CH = CHCH₂N (CH₃) -, -NRSO₂CH = CH-, -NRSO₂CH = CHCH₂- ,

NRC (O) CH = CHCH₂O-, -NRC (O) C (= CH₂) CH₂-, -CH₂NRC (O) -,

CH₂NRC (O) CH = CH-, -CH₂CH₂NRC (O) -, or -CH₂NRC (O) cyclopropylene, where each r is independently hydrogen or optionally substituted Ci-6 aliphatic.

In certain embodiments, L is -NHC (O) CH = CH-,

NHC (O) CH = CHCH₂N (CH₃) -NHC (O) CH = CHCH₂O-, -CH₂NHC (O) CH = CH-, NHSO₂CH = CH-,

-NHSO₂CH = CHCH₂-,

-NHC (O) (C = N₂) C (O) -,

IMPIS

MEXICAN INSTITUTE OF INDUSTRIAL CURRENCY

NHC (O) CH = CHCH₂N (CH₃) -, -NHSO₂CH = CH-,

NHC (O) CH = CHCH₂O-, -NHC (O) C (= CH₂) CH₂- ,

-NHSQgGH-GHCHg -,

-CH₂NHC (O) -,

CH₂NHC (O) CH = CH-, -CH₂CH₂NHC (O) - or -CH₂NHC (O) cyclopropylene-.

In some embodiments, L is a divalent hydrocarbon chain of C₂-e straight or branched where L has at least one triple bond. In certain embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched, where L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by -NRC (O) -, -C (O) NR-, -S-, S (BEAR₂-, C (= S) -, -C (= NR) -, -0-, -N (R) -_Z or -C (0) -. In some embodiments, L has at least one triple bond and at least one methylene unit of L is replaced by -N (R) -, -N (R) C (0) -, -C (0) -, -C (0) 0-, or -0C (0) - or -O-.

Exemplary L groups include -CsC-, C = CCH₂n (isopropyl) -, -NHC (0) C = CCH₂CH₂-, -CH₂-CsC-CCH₂-, CsCCH₂0-, -CH₂C (O) C ^ C-, -C (0) CsC- or -CH₂OC (= O) C ^ C.

In certain embodiments, L is a divalent hydrocarbon chain of C₂.₈ straight or branched where one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by -C (0) -, -NRC (O) -, -C (0) NR-, - N (R) SO₂-, bear₂N (R) -. Exemplary L groups include -NHC (O) cyclopropylene-S0₂- and -NHC (O) -cyclopropylene-.

As generally defined above, Y is

<img file="MX360970B_D0125.tif" />

<img file="MX360970B_D0126.tif" />

<img file="MX360970B_D0127.tif" />

hydrogen, Cx-6 aliphatic optionally substituted with oxo, halogen, NO₂ or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein the ring is substituted with 1-4 R groups^and, each R^and is independently selected from -QZ, oxo, NO₂, halogen, CN, a suitable or aliphatic leaving group of Cx-6, wherein Q is a covalent bond or a bivalent hydrocarbon chain of Ci-₆ saturated or unsaturated, straight or branched, where one or two methylene units of Q are optionally and independently replaced by -N (R) -, -S-, -O-, -C (0) -, -0C (0) -, -C (0) 0-, -SO- or -SO₂-,

-N (R) C (O) -, -C (O) N (R) -, -N (R) SO₂-, or -S0₂N (R) -; and Z is hydrogen or Ci_ aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN.

In certain embodiments, Y is hydrogen.

In certain embodiments, Y is aliphatic of Ci_₆optionally substituted with oxo, halogen, N0₂ or CN. In some embodiments, Y is alkenyl of C₂.₆ optionally substituted with with oxo, halogen, N0₂ or CN. In other embodiments, Y is C alkynyl₂.₆ optionally substituted with oxo, halogen, N0₂ or CN. In some embodiments, Y is alkenyl of C₂-e In other embodiments, Y is C alkynyl₂.

In other embodiments, Y is Ci-₆

IMPI

<img file="MX360970B_D0128.tif" />

substituted with with oxo, halogen, N0₂ or CN. These Y groups include -CH₂F, -CH₂C1, -CH₂CN and -CH₂NOT₂.

In certain embodiments, Y is a 3-6 membered saturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or

<td colspan="4">sulfur, where Y is substituted with 1-4 R groups^and, where</td>

<td>each R^and it's how i know</td><td>defined above</td><td>and it is described</td><td>on the</td>

<td>Present.</td><td></td><td></td><td></td>

<td>In some</td><td>modalities,</td><td>And it is a</td><td>ring</td>

3-4 membered saturated heterocyclic having 1 heteroatom selected from oxygen or nitrogen, wherein the ring is substituted with 1-2 R groups^and, where each R^and it is as defined above and described herein. Examples of these rings are epoxide and oxoethane rings, where each ring is substituted with 1-2 R groups.^and, where

<td>each R^and</td><td>it is</td><td>What</td><td colspan="2">defined above and described in the</td>

<td>Present.</td><td></td><td></td><td></td><td></td>

<td></td><td>On</td><td>other</td><td>modalities, Y is a ring</td><td>heterocyclic</td>

<td>saturated</td><td>from</td><td> 5-6</td><td>members who have 1-2</td><td>heteroatoms</td>

selected from oxygen or nitrogen, where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein. These rings include piperidine and pyrrolidine, where each ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein. In certain

MEXICAN INSTITUTE · &lt;Ο

DELA PROPERTY 1 / -,

INDUSTRIAL modalities, and where it describes saturated each in the is

<img file="MX360970B_D0129.tif" />

as present.

R, Q, Z and are defined above and are 3-6 membered, wherein the ring is substituted with 1-4 groups and cyclopropyl is described,

R^and, where each R^and it is as defined above herein. In certain embodiments, Y is cyclobutyl, cyclopentyl, or cyclohexyl, where each ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and present. In certain modes, Y is

R^and it is as defined above and described herein.

In certain embodiments, it is cyclopropyl optionally substituted with halogen, CN, or NO₂.

In certain embodiments, Y is a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, R groups^and, where each R^and it is as defined above and described herein.

3-6 membered partially unsaturated, where the ring

In some embodiments, Y is a carbocyclic ring

IMPI

<img file="MX360970B_D0130.tif" />

is substituted with 1-4 R groups^and where each defined above and is described herein. In some embodiments, Y is cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, where each ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein. In certain modes, Y is

<img file="MX360970B_D0131.tif" />

where each R^and it is as defined above and described herein.

In certain modalities,

Y is a partially unsaturated heterocyclic ring having 1-2 heteroatoms selected from 4-6 members that independently of nitrogen, oxygen or sulfur, where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein.

In certain modalities, Y is

<img file="MX360970B_D0132.tif" />

<img file="MX360970B_D0133.tif" />

<img file="MX360970B_D0134.tif" />

(R^and) i-₂

OR

<img file="MX360970B_D0135.tif" />

where each R and R^and it is as defined above and described herein.

members having 0-2 nitrogens, where the ring is

In certain embodiments, Y is an aromatic ring of

IMPI

<img file="MX360970B_D0136.tif" />

substituted with 1-4 R groups^and, where each group R^and it is as defined above and described herein. In certain embodiments, Y is phenyl, pyridyl, or pyrimidinyl, where each ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein.

In some modalities, Y is selected from:

Μ M

<img file="MX360970B_D0137.tif" />

where each R^and it is as defined above and described herein.

In other embodiments, Y is a membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is substituted with 1-3 R groups^and, where each group R^and it is as defined above and described herein. In some embodiments, Y is a 5-membered aryl or partially unsaturated ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each group R^and it is as defined above and described herein. Examples of these rings are isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrrolyl, furanyl, thienyl, triazole, thiadiazole, and oxadiazole, where each ring is substituted with 1-3 R groups.^and, where each group R^and is as defined above and described in the

ΙΜΡΙ ^&gt; 5&gt;

MEXICAN INSTITUTE 1

DE LZ INDUSTRIAL PROPERTY present. In certain modalities, Y is selected from:

<img file="MX360970B_D0138.tif" />

ΛΛ.

<img file="MX360970B_D0139.tif" />

<img file="MX360970B_D0140.tif" />

I

<img file="MX360970B_D0141.tif" />

<img file="MX360970B_D0142.tif" />

<img file="MX360970B_D0143.tif" />

<img file="MX360970B_D0144.tif" />

σίτυ i

<img file="MX360970B_D0145.tif" />

<img file="MX360970B_D0146.tif" />

<img file="MX360970B_D0147.tif" />

where each R and R^and it is as defined above and described herein.

In certain embodiments, Y is a saturated, partially unsaturated, or aryl, bicyclic 8-10 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein. According to another aspect, Y is a bicyclic, partially unsaturated or aryl 9-10 membered ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where R^and it is as defined above and described herein. Examples of these bicyclic rings include 2,3-dihydrobenzo [d] isothiazole, where the ring is substituted

IMPI

INSTITUTO MEXICANO Jíj

DE LA TXCHEDAD rVeeMá / INDUSTRIAL with 1-4 R groups^and, where R^and it is as defined above and described herein.

As generally defined above, each R group^andis independently selected from -QZ, oxo, NO₂, halogen, CN, a suitable or aliphatic leaving group of Ci_₆ optionally substituted with oxo, halogen, N0₂ or CN, where Q is a covalent bond or a bivalent hydrocarbon chain of Ci_₆saturated or unsaturated, straight or branched, where one or two methylene units of Q are optionally and independently replaced by -N (R) -, -S-, -0-, -C (0) -, -0C ( 0) -, -C (0) 0-,

-SO- or -S0₂-, -N (R) C (O) -, -C (O) N (R) -, -N (R) SO₂-, or -S0₂N (R) -;

and Z is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN.

In certain modalities, R^and is Ci_6 aliphatic optionally substituted with oxo, halogen, NO2 or CN. In other modalities, R^and it is oxo, NO2, halogen or CN.

In some modalities, R^and is -QZ, where Q is a covalent bond and Z is hydrogen (that is, R^and is hydrogen). In other modalities, R^and is -QZ, where Q is a straight or branched saturated or unsaturated Cx-6 divalent hydrocarbon chain, where one or two methylene units of Q are optionally and independently replaced by -NR-, -NRC (O) -, -C (O) NR-, -S-, -0-, -C (0) -, -SO-, or -S0₂In other embodiments, Q is a hydrocarbon chain of C₂.₆straight or branched bivalent having at least one double

IMPI

<img file="MX360970B_D0148.tif" />

bond, where one or two methylene units of Q are optionally and independently replaced by -NR-, -NRC (O), -C (O) NR-, -S-, -0-, -C (0) -, -SO-, -S0₂-. In certain embodiments, the Z portion of the R group^and it is hydrogen. In some embodiments, -QZ is -NHC (0) CH = CH₂ or -C (0) CH = CH₂.

In certain modalities, each R^and is independently selected from oxo, N0₂, CN, fluoro, chloro, NHC (O) CH = CH₂, -C (O) CH = CH₂, -CH₂CH = CH₂, -C ^ CH, -C (O) OCH₂C1, C (O) OCH₂F, -C (O) OCH₂CN, -C (O) CH₂C1, -C (O) CH₂F, -C (O) CH₂CN or CH₂C (O) CH₃.

In certain modalities, R^and it is a suitable leaving group, that is, a group that is subject to nucleophilic displacement. A leaving group is a chemical group that is readily displaced by a desired input chemical moiety such as the thiol portion of a cysteine ​​of interest.

Suitable leaving groups are known in the art, for example, see Advanced Organic Chemistry, Jerry March, 5^toedition, p. 351-357, John Wiley and Sons, NY These leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium moieties.

Examples of suitable leaving groups include chlorine, iodine, bromine, fluoro, acetoxy, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, nitro-

<img file="MX360970B_D0149.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0150.tif" />

phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy).

In certain modalities, the following modalities and combinations of -LY apply:

(a) L is a divalent hydrocarbon chain of C₂.₈ straight or branched where L has at least one double bond and one or two methylene units of L are optionally and independently replaced by -NRC (O) -, -C (O) NR-,

N (R) SO₂-, -S0₂N (R) -, -S-, -S (O) -, -S0₂-, -0C (0) -, -C (0) 0-, cyclopropylene, -0-, -N (R) -, or -C (0) -; and Y is hydrogen or Ci-g aliphatic optionally substituted with oxo, halogen, NO₂ or CN; or (b) L is a divalent hydrocarbon chain of C₂_₈ straight or branched where L has at least one double bond and at least one methylene unit of L is replaced by -C (O) -, -NRC (O) -, -C (O) NR-, -N (R )SW₂-, -SO₂N (R) -, -S-, -S (O) -,

-S0₂-, -0C (0) -, or -C (0) 0-, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, -O-, -N (R) -, or -C ( 0) -; and Y is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN; or (c) L is a divalent hydrocarbon chain of C₂_₈straight or branched where L has at least one double bond and at least one methylene unit of L is replaced by -C (0), and one or more additional methylene units of L are

IΜ ΡI 5 ^

MEXICAN INSTITUTE

DE LA FROHEDAE 'S. ₄ « ^¿_Λ 'NDUSTRlAl' -'X · * »» * · * optionally and independently replaced by cyclopropylene, -0-, -N (R) -, or -C (0) -; and Y is hydrogen or Ci-6 aliphatic optionally substituted with oxo, halogen, NO₂ or CN; or (d) L is a divalent hydrocarbon chain of C₂_₈straight or branched where L has at least one double bond and at least one methyl unit of L is replaced by -C (0) -; and Y is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, NO₂ or CN; or (e) L is a divalent hydrocarbon chain of C₂.₈straight or branched where L has at least one double bond and at least one methylene unit of L is replaced by 0C (0) -; and Y is hydrogen or aliphatic Ci_₆ optionally substituted with oxo, halogen, NO₂ or CN; or (f) L is -NRC (0) CH = CH-, -NRC (O) CH = CHCH₂N (CH₃) - , -

NRC (O) CH = CHCH₂O-, -CH₂NRC (O) CH = CH-, -NRSO₂CH = CH-, nrso₂ch = chch₂-, -NRC (O) (C = N₂) -, -NRC (O) (C = N₂) C (0) NRC (O) CH = CHCH₂N (CH₃) -, -NRSO₂CH = CH-, -nrso₂ch = chch₂-,

NRC (O) CH = CHCH₂O-, -NRC (O) C (= CH₂) CH₂-, -CH₂NRC (O) -,

CH₂NRC (0) CH = CH-, -CH₂CH₂NRC (0) -, or -CH₂NRC (0) cyclopropylene-; wherein R is H or optionally substituted Cx-6 aliphatic and Y is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN; or (g) L is -NHC (0) CH = CH-, -NHC (0) CH = CHCH₂N (CH₃) - , -

NHC (0) CH = CHCH₂0-, -CH₂NHC (O) CH = CH-, -NHSO₂CH = CH-,

<img file="MX360970B_D0151.tif" />

<img file="MX360970B_D0152.tif" />

nhso₂ch = chch₂-, -NHC (O) (C = N₂) -, -NHC (O) (C ~ - ~ W₂) C (O) ', NHC (O) CH = CHCH₂N (CH₃) -, -NHS0₂CH = CH-, -NHSO₂CH = CHCH₂-, NHC (O) CH = CHCH₂O-, -NHC (O) C (= CH₂) CH₂-, -CH₂NHC (O) -,

CH₂NHC (O) CH = CH-, -CH₂CH₂NHC (O) -, or -CH₂NHC (0) cyclopropylene-; and Y is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN; or (h) L is a divalent hydrocarbon chain of C₂_₈ straight or branched where L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by -C (0) -, -NRC (O) -, -C (O) NR-, -N (R) SO₂-, SO₂N (R) -, -S-, -S (0) -, -S0₂-, -0C (0) - or -C (0) 0-, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, -O-, -N (R) -, or C ( 0) -; and Y is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN; or (i) L is a divalent hydrocarbon chain of C₂-₈ straight or branched where L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by -NRC (O) -, C (O) NR-, -N (R) SO₂-, -SO₂N (R) -, -S-, -S (0) -, -S0₂-, -0C (0) -, or

-C (0) 0-, and Y is hydrogen or Ci- aliphatic₆ optionally substituted with oxo, halogen, N0₂ or CN; or (j) L is -C = C-, -C ^ CCH₂N (isopropyl) -, NHC (O) C = CCH₂CH₂-, -CH₂-C ^ C-CH₂-, -C = CCH₂O-, -CH₂C (O) C = C-, C (O) C = C-, or -CH₂OC (= 0) C = C-; and Y is hydrogen or aliphatic of

<img file="MX360970B_D0153.tif" />

<img file="MX360970B_D0154.tif" />

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

Ci-6 optionally substituted with oxo, halogen, NO₂ or CN; or (k) L is a divalent hydrocarbon chain of

C₂-₈, straight or branched where one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by -NRC (O) -, -C (O) NR-, -N (R) SO₂-,

SW₂N (R) -, -S-, -S (0) -, -S0₂-, -0C (0) -, or -C (0) 0-; and Y is hydrogen or aliphatic Ci_₆ optionally substituted with oxo, halogen, N0₂ or CN; or (l) L is a covalent bond and Y is selected from:

(i) Ci- alkyl₆ substituted with oxo, halogen, N0₂ or CN;

(ii) C alkenyl₂_₆ optionally substituted with oxo, halogen, N0₂ or CN; or (iii) C alkynyl₂.₆ optionally substituted with oxo, halogen, N0₂ or CN; or (iv) a 3-4 membered saturated heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen, wherein the ring is substituted with 1-2 R groups^and, where each R^and it is as defined above and described herein; or (v) a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen, wherein the ring is substituted with 1-4 R groups^and, where each R^and is as defined above and described i

; t (R^and) i-2 (R^and) i-2

<img file="MX360970B_D0155.tif" />

at the moment; or

<img file="MX360970B_D0156.tif" />

where each R, Q, Z and R^and it is as defined above and described herein; or (vii) a saturated 3-6 membered carbocyclic ring, where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 f heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or 3-6 membered partially unsaturated, where the ring is substituted with

1-4 R groups^and, where each R^and it is as defined above and described herein; or

TO.

(x) j 7 '-' J (^R ) i-2 where each R^and it is as and described herein; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having

1-2 heteroatoms

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY . INDUSTRIAL independently selected from nitrogen, oxygen or sulfur, where the ring is substituted with

1-4 R groups^and, where each R^and it is as defined above described herein; or in

<img file="MX360970B_D0157.tif" />

(R *) l-2 is how I know where each R and R^and the present; or (xiii) a ring has 0-2 nitrogenous R groups^and, in describe where each present; or what has where where the each R^and is present; or (xiv)

R^and is (xv) independently where the ring is defined above and 6-membered aromatic is described which ring is substituted with 1-4 as defined above and is as defined above and described in a

1-3 5-membered heteroaryl ring heteroatoms selected from nitrogen, oxygen or sulfur, substituted with 1-3 R groups^and, where each R^and it is as defined above and described herein; or

<img file="MX360970B_D0158.tif" />

<img file="MX360970B_D0159.tif" />

(χνϊ)

<img file="MX360970B_D0160.tif" />

R

<img file="MX360970B_D0161.tif" />

<img file="MX360970B_D0162.tif" />

σνν i

<img file="MX360970B_D0163.tif" />

(R^and) l-2

I

<img file="MX360970B_D0164.tif" />

UVL I

<img file="MX360970B_D0165.tif" />

ι

<img file="MX360970B_D0166.tif" />

<img file="MX360970B_D0167.tif" />

<img file="MX360970B_D0168.tif" />

<img file="MX360970B_D0169.tif" />

<img file="MX360970B_D0170.tif" />

<img file="MX360970B_D0171.tif" />

<img file="MX360970B_D0172.tif" />

<img file="MX360970B_D0173.tif" />

<img file="MX360970B_D0174.tif" />

where each R^and it is as defined above and described herein; or (xvii) a bicyclic 8-10 membered ring.

saturated, partially unsaturated, or aryl that independently selected heteroatoms have 0-3 nitrogen, oxygen, or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein;

(m) L is -C (O) - and Y is selected from:

(i) Ci-6 alkyl substituted with oxo, halogen, N0₂ or CN; or (ii) alkenyl of C₂-6 optionally substituted with oxo, halogen, N0₂ or CN; or (iii) C alkynyl₂_₆optionally with oxo, halogen, N0₂ or CN; or replaced

IMP

<img file="MX360970B_D0175.tif" />

(iv) a 3-4 membered saturated heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen, wherein the ring is substituted with 1-2 groups

R^and, where each R^and it is as defined above and described herein; or (v) a 5-6 membered saturated heterocyclic ring which, or nitrogen, has 1-2 heteroatoms selected from oxygen where the ring is substituted with 1-4 groups

R^and, where each R^and it is as defined above and described herein; or in is

<img file="MX360970B_D0176.tif" />

as defined above and described herein; or (vii) a saturated 3-6 membered carbocyclic ring, where the ring is substituted with 1-4 R groups^and, where each

R^and it is as defined above and described herein; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and is as defined above and described in (ix) a 3-6 membered carbocyclic ring herein; or

IMPI

<img file="MX360970B_D0177.tif" />

where the ring is replaced with

1-4 R groups^and, where each

R^and it is as defined above and described herein; or

TO.

(x), _; where each R^and it is as defined above and described herein; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the

1-4 R groups^and, at the moment;

ring is substituted with where each R and

as defined above

<img file="MX360970B_D0178.tif" />

is described in (R^and) i-₂ (R^and) i-₂ (R^and) i-₂ defined above and described where each R and R as set forth herein; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (xiv)

<img file="MX360970B_D0179.tif" />

<img file="MX360970B_D0180.tif" />

<img file="MX360970B_D0181.tif" />

<img file="MX360970B_D0182.tif" />

where each R^and it is as defined above and described herein; or (xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-3 R groups^and, where each group R^and it is as defined above and described herein; or (xvi) in in

<img file="MX360970B_D0183.tif" />

<img file="MX360970B_D0184.tif" />

where each R and the present; or

R

<img file="MX360970B_D0185.tif" />

(R^and) l-2

I JW i

<img file="MX360970B_D0186.tif" />

<img file="MX360970B_D0187.tif" />

<img file="MX360970B_D0188.tif" />

R^and It's like I know (xvii) a ring

<img file="MX360970B_D0189.tif" />

i ^^Re rs- ^^Re h- ^^Re defined above and 8-10 membered describes bicyclic, saturated, partially unsaturated or aryl which heteroatoms independently selected from have 0-3 nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein;

<img file="MX360970B_D0190.tif" />

<img file="MX360970B_D0191.tif" />

IMPI

MEXICAN INSTITUTE

FROM INDUSTRIAL PROPERTY (n) L is -N (R) C (O) - and Y is selected from:

(i) Ci_ alkyl₆ substituted with oxo, halogen, N0₂ or CN;

(ii) C alkenyl₂.₆ optionally substituted with oxo, halogen, N0₂ or CN; or (iii) C alkynyl₂.₆ optionally substituted with oxo, halogen, N0₂ or CN; or (ivj a 3-4 membered saturated heterocycid ring having 1 heteroatom selected from oxygen or nitrogen, wherein the ring is substituted with 1-2 R groups^and, where each R^and it is as defined above and described herein; or (vj a 5-6 membered saturated heterocycid ring having 1-2 heteroatoms selected from oxygen or nitrogen, where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (R^and) i-₂ (R^and) i-2

<img file="MX360970B_D0192.tif" />

where each R, Q, Z and R^and it is as defined above and described herein; or (vi) a saturated 3-6 membered carbocyclic ring, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or

<img file="MX360970B_D0193.tif" />

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein the ring is substituted with

1-4 R groups^and, where each R^and it is as defined above and described herein; or where each R^and it is as defined above and described herein; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or where each R and R^and is as defined above and described

<img file="MX360970B_D0194.tif" />

<img file="MX360970B_D0195.tif" />

<img file="MX360970B_D0196.tif" />

Present;

<img file="MX360970B_D0197.tif" />

IMPI

<img file="MX360970B_D0198.tif" />

{xiii) a · 6- mi-embro aromatic ring — having 0-2 nitrogens where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (xiv)

<img file="MX360970B_D0199.tif" />

where each R^and it is as defined above and described herein; or (xv) a 5-membered heteroaryl ring having

1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where the ring is substituted with 1-3 R groups^and where each R^and it is as defined above and described herein; or (xvi)

<img file="MX360970B_D0200.tif" />

<img file="MX360970B_D0201.tif" />

<img file="MX360970B_D0202.tif" />

<img file="MX360970B_D0203.tif" />

<img file="MX360970B_D0204.tif" />

<img file="MX360970B_D0205.tif" />

<img file="MX360970B_D0206.tif" />

<img file="MX360970B_D0207.tif" />

»ΛΛ, I

<img file="MX360970B_D0208.tif" />

<img file="MX360970B_D0209.tif" />

<img file="MX360970B_D0210.tif" />

where each R^and is as defined above described in

<img file="MX360970B_D0211.tif" />

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL the present; or (xvii) a saturated, partially unsaturated or aryl bicyclic 8-10 membered ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein;

(o) L is a straight or branched saturated or unsaturated Ci-g divalent hydrocarbon chain; y Y is selected from:

(i) Ci_ alkyl₆ substituted with oxo, halogen, NO₂ or CN;

(ii) alkenyl of C_{2 6} optionally substituted with oxo, halogen, N0₂ or CN; or (iii) C alkynyl₂_₆ optionally substituted with oxo, halogen, N0₂ or CN; or (iv) a 3-4 membered saturated heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen, wherein the ring is substituted with 1-2 R groups^and, where each R^and it is as defined above and described herein; or (v) a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen, wherein the ring is substituted with 1-4 R groups^and, where each R^and is as defined above and described

<img file="MX360970B_D0212.tif" />

at the moment; or

<img file="MX360970B_D0213.tif" />

, or where each R, Q, Z, and R^and it is as defined above and described herein; or (vii) a saturated 3-6 membered carbocyclic ring, where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein the ring is substituted with

1-4 R groups^and, where each R^and it is as defined above and described herein; or (R^and) i-2 _on where each R^and it is as defined above and described herein; or (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or

<img file="MX360970B_D0214.tif" />

sulfur where the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or (xií)

<img file="MX360970B_D0215.tif" />

as where each R and R^and es was defined above and described herein; or (xiii a 6-membered aromatic ring having 0-2 nitrogens where the ring is substituted with 1-4 R groups^and, where each group R^andit is as defined above and described herein; o (xi v)

<img file="MX360970B_D0216.tif" />

where each R^and it is as defined above and described herein; or (xv) a 5-membered heteroaryl ring having

1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where the ring is substituted with 1-3 R groups^and, where each group R^and it is as defined above and described herein; or

<img file="MX360970B_D0217.tif" />

r * - '

<img file="MX360970B_D0218.tif" />

(xvi)

<img file="MX360970B_D0219.tif" />

R

<img file="MX360970B_D0220.tif" />

I

<img file="MX360970B_D0221.tif" />

(R^and) l-2 i

<img file="MX360970B_D0222.tif" />

<img file="MX360970B_D0223.tif" />

<img file="MX360970B_D0224.tif" />

<img file="MX360970B_D0225.tif" />

<img file="MX360970B_D0226.tif" />

<img file="MX360970B_D0227.tif" />

JVb i

<img file="MX360970B_D0228.tif" />

<img file="MX360970B_D0229.tif" />

<img file="MX360970B_D0230.tif" />

where each R and R^and it is as defined above and described herein; or saturated, (xvii) a partially unsaturated or aryl 8-10 membered ring that bicyclic, has 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein;

(p) L is a covalent bond, -CH₂-, -NH-, -C (O) -,

-CH₂NH-, -NHCH₂-, -NHC (O) -, -NHC (O) CH₂0C (O) -, -CH₂NHC (O) -, NHSO₂-, -NHSO₂CH₂-, -NHC (O) CH₂OC (O) -, or -SO₂NH ~; y Y is selected from:

(i) Ci- alkyl₆ substituted with oxo, halogen, N0₂ or CN; or (ii) C alkenyl₂.₆ optionally substituted

<img file="MX360970B_D0231.tif" />

<img file="MX360970B_D0232.tif" />

IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY with oxo, halogen, N0₂ or CN; or (iii) C alkynyl₂.₆ optionally substituted with oxo, halogen, N0₂ or CN; or (ivj a 3-4 membered saturated heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen, wherein the ring is substituted with 1-2 R groups^and, where each R^and it is as defined above and described herein; or (v) a 5-6 membered saturated heterocyclic ring which, or nitrogen, has 1-2 heteroatoms selected from oxygen where the ring is substituted with 1-4 groups

R^and, where each R^and it is as defined above and described herein; or where each R, Q, Z and R 'is

<img file="MX360970B_D0233.tif" />

as defined above and described herein; or {vil) a saturated 3-6 membered carbocyclic ring, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein; or {viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 R groups^and,

<img file="MX360970B_D0234.tif" />

where each R^and it is as defined above and described herein; or (ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein the ring is substituted with 1-4 R groups^and, where each R^and it is as defined above and described herein;

<img file="MX360970B_D0235.tif" />

each R^and is as defined above and described herein (xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 1-4 groups R^and, where each R^and it is as defined above and described herein;

(xii)

<img file="MX360970B_D0236.tif" />

as where each R and R^and es was defined above and described herein; or (xiii) a 6-membered aromatic ring having 0-2 nitrogens where the ring is

<img file="MX360970B_D0237.tif" />

<img file="MX360970B_D0238.tif" />

substituted with 1-4 R groups^and, where each group R^andit is as defined above and described herein; or

<img file="MX360970B_D0239.tif" />

(xi v)

<img file="MX360970B_D0240.tif" />

where each R^and it is as defined above and described herein; or (xv) a 5-membered heteroaryl ring having

1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, in substituted defined as above and described where the ring where each group

1-3 R groups^and,

<img file="MX360970B_D0241.tif" />

Λ

N

N ^;"Ñ- ^^Re

I /^NR- ^^R* in se where each R and R^and is as defined above and is

Γ A 1 »A JL Λ κπτυτο Mexican ¡OF THE PROPERTY

I INDUSTRIAL describes herein; or (xvii) an 8-10 membered bicyclic, saturated, partially unsaturated or aryl ring having

0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, where each R^and it is as defined above and described herein.

In certain embodiments, the group Y of formula la or Ib is selected from those shown in Table 3 below, where each wavy line indicates the point of attachment to the rest of the molecule.

Table 3

Groups AND specimens

<img file="MX360970B_D0242.tif" />

<img file="MX360970B_D0243.tif" />

IMPI

<img file="MX360970B_D0244.tif" />

<img file="MX360970B_D0245.tif" />

<img file="MX360970B_D0246.tif" />

aaaa bbbb cccc dddd

<img file="MX360970B_D0247.tif" />

<img file="MX360970B_D0248.tif" />

<img file="MX360970B_D0249.tif" />

<img file="MX360970B_D0250.tif" />

<img file="MX360970B_D0251.tif" />

<img file="MX360970B_D0252.tif" />

<img file="MX360970B_D0253.tif" />

rrrr oooo pppp qqqq ssss

<img file="MX360970B_D0254.tif" />

tttt

UUUU VVVV wwww xxxx

0 0 Me

<img file="MX360970B_D0255.tif" />

ccccc yyyy zzzz aaaaa bbbbb where every R^and is independently selected from a suitable leaving group, NO2 or CN or oxo.

In certain modalities, R¹ is -C ^ C-, -OCCH2N (isopropyl) -, -NHC (O) C = CCH2CH3, -CH2-C = C-CH3, -c ^ cch2oh, -CH2C (O) ChCH, -C (0) ChCH , or CH20C (= O) C ^ CH. In some modalities, R¹ is selected from NHC (O) CH = CH2, -NHC (O) CH = CHCH₂N (CH₃)₂ or -ch₂nhc (o) ch = ch₂.

In certain modalities, R¹ is selected from those

<img file="MX360970B_D0256.tif" />

<img file="MX360970B_D0257.tif" />

IMPI

INSTITUTO MEXICANO DE LA PROPERTY INDUSTRIAL e where each wavy line indicates shown in the following table 4,

<img file="MX360970B_D0258.tif" />

<img file="MX360970B_D0259.tif" />

IMPI MSMVRO MEXICAN PROPERTY

INDUSTRIAL

<img file="MX360970B_D0260.tif" />

rrr sss ttt uuu vvv

IMPI

<img file="MX360970B_D0261.tif" />

<img file="MX360970B_D0262.tif" />

<img file="MX360970B_D0263.tif" />

ssss uuuu

9999 rrrr

OO

<img file="MX360970B_D0264.tif" />

aaaaa wwww vvvv&gt; Oo ddddd ccccc

<img file="MX360970B_D0265.tif" />

bbbbb

<img file="MX360970B_D0266.tif" />

<img file="MX360970B_D0267.tif" />

JJJJJ ch₃ ch₃ kkkkk

OR'"

CH₂CH = CH₂ mil e * 3 vvvvv mmmmm ¿n'h cccccc tutu oooooo lililí ttnnnn

00000 ppppp qqqqq rrrrr

CH₃ "CH₃

WWWWW dddddd

1UW ¿&lt;or⁰

<img file="MX360970B_D0268.tif" />

h₃c ^xch₃ sssss ttttt uuuuu

O \ A ^ CI xxxxx o

&gt; A ^^ac eeeeee kkkkkk

OH O pppppp uuuuuu yyyyy zzzzz aaaaaa oo gggggg bbbbbb o ch₃ hhhhhh or ch₃ &gt; ry._0Ac

Oh

<img file="MX360970B_D0269.tif" />

<img file="MX360970B_D0270.tif" />

nnnnnn ssssss xxxxxx

<img file="MX360970B_D0271.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY where each R^and is independently a »~ -group ...... sa suitable, N0₂, CN or oxo.

As generally defined above, R¹ is a head group, or, when R¹ and R^x form a ring, so -QZ is a head group. Without wishing to be bound by any particular theory, it is believed that these R groups¹, i.e., head groups, are particularly suitable for covalently binding to a key cistern residue in the binding domain of certain protein kinases. Protein kinases that have a cysteine ​​residue known to someone of ability include ErbBl, ErbB2 and ErbB4, in the binding domain is ordinary in the art and a mutant thereof.

In certain embodiments, the compounds of the present head further characterized in that the compounds of the invention target one or more of the following cysteine ​​residues:

ITQLMPFGCLLDYVREH

VTQLMPYGCLLDHVREN VTQLMPHGCLLEYVHEH modalities, R¹ It is characterized -LY is able to bind cysteine ​​in this way the enzyme. In certain cysteine ​​it is Cys797 from ErbBl,

ERBB1

ERBB2

ERBB4

Thus, in some in addition because the portion covalently to a residue irreversibly inhibiting modalities, the residue of

ErbB2 Cys805 and ErbB4 Cys803, or a mutant of the

<img file="MX360970B_D0272.tif" />

same, where the residue numbering provided is in accordance with Uniprot (code POO533 for ErbBl; code PO4626 for ErbB2 and code Q15303 for ErbB4). It will be understood that the Cys of ErbBl (EGFR) is variably called 773 or 797 depending on whether the source sequence contains the signal peptide or not. thus, in accordance with the present invention, the relevant cysteine ​​residue of ErbBl can be described as Cys 773 or Cys 797 and these terms are used interchangeably.

One of ordinary skill in the art will recognize that a variety of head groups, as defined herein, are suitable for this covalent bond. These R groups¹ include, but are not limited to, those described herein and illustrated in Table 5 below.

As illustrated in formulas Ia and Ib above, the head group R¹ it can be in an ortho, goal or para position. In certain modalities the head group R¹ it is in a meta position of the phenyl ring relative to the rest of the molecule.

In certain modalities, R¹ it is further characterized in that the -LY portion is capable of covalently binding to a cysteine ​​residue of TEC, thus irreversibly inhibiting the enzyme. In some embodiments, the cysteine ​​residue is Cys 449.

IMPI

<img file="MX360970B_D0273.tif" />

In certain modalities, R¹ ffS Tarac t é ri zsl further because the -LY portion is able to covalently bind to a BTK cysteine ​​residue, thus irreversibly inhibiting the enzyme. In some embodiments, the cysteine ​​residue is Cys 481.

In certain modalities, R¹ it is further characterized in that the -LY portion is capable of covalently binding to a cysteine ​​residue of ITK ,. in this way irreversibly inhibiting the enzyme. In some embodiments, the cysteine ​​residue is Cys 442.

In certain modalities, R¹ it is further characterized in that the -LY portion is capable of covalently binding to a cysteine ​​residue of BMX, thus irreversibly inhibiting the enzyme. In some embodiments, the cysteine ​​residue is Cys 496.

In certain modalities, R¹ it is further characterized in that the -LY portion is capable of covalently binding to a cysteine ​​residue of JAK3, thus irreversibly inhibiting the enzyme. In some embodiments, the cysteine ​​residue is Cys 909.

In certain modalities, R¹ is characterized

IMPI

<img file="MX360970B_D0274.tif" />

also because the -LY portion is ca'p'az '-de — uni-í-se —...

covalently a cysteine ​​residue of

TXK, thus irreversibly inhibiting the enzyme.

In some embodiments, the cyst ein residue is Cys

One of ordinary skill in the art will recognize that a variety of head groups, as defined herein, are suitable for this covalent bond.

These R groups¹ include, but are not limited to, those described herein and illustrated in Table 5 below.

Empiary compounds of the present invention are shown in Table 5 below.

Table 5

Exemplary compounds

<img file="MX360970B_D0275.tif" />

<img file="MX360970B_D0276.tif" />

<img file="MX360970B_D0277.tif" />

1-1

<img file="MX360970B_D0278.tif" />

1-2

<img file="MX360970B_D0279.tif" />

1-3

<img file="MX360970B_D0280.tif" />

<img file="MX360970B_D0281.tif" />

<img file="MX360970B_D0282.tif" />

1-4 1-5 1-6

<img file="MX360970B_D0283.tif" />

1-10

<img file="MX360970B_D0284.tif" />

1-12

1-11

<img file="MX360970B_D0285.tif" />

1-13

<img file="MX360970B_D0286.tif" />

1-25

1-26

1-27 irw.wtn '· .w

<img file="MX360970B_D0287.tif" />

1-38

1-39

1-40

-Λ

<img file="MX360970B_D0288.tif" />

1-50

1-51

1-52

<img file="MX360970B_D0289.tif" />

101

<img file="MX360970B_D0290.tif" />

<img file="MX360970B_D0291.tif" />

1-70

<img file="MX360970B_D0292.tif" />

<img file="MX360970B_D0293.tif" />

1-74

<img file="MX360970B_D0294.tif" />

'Ν /

1-75

1-76

<img file="MX360970B_D0295.tif" />

1-83

1-84

1-85

103

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

<img file="MX360970B_D0296.tif" />

1-92

1-93

1-94

104

<img file="MX360970B_D0297.tif" />

1-104

1-105

105

<img file="MX360970B_D0298.tif" />

<img file="MX360970B_D0299.tif" />

1-108

1-106

1-107

<img file="MX360970B_D0300.tif" />

1-113

<img file="MX360970B_D0301.tif" />

<img file="MX360970B_D0302.tif" />

1-116

106

IMPI

<img file="MX360970B_D0303.tif" />

<img file="MX360970B_D0304.tif" />

1-117 1-118 1-119

<img file="MX360970B_D0305.tif" />

1-122

<img file="MX360970B_D0306.tif" />

1-123

<img file="MX360970B_D0307.tif" />

1-124

1-125

1-126

<img file="MX360970B_D0308.tif" />

107

<img file="MX360970B_D0309.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0310.tif" />

<img file="MX360970B_D0311.tif" />

1-130

<img file="MX360970B_D0312.tif" />

1-128 1-129

<img file="MX360970B_D0313.tif" />

Η H

1-131 1-132

<img file="MX360970B_D0314.tif" />

1-136

1-137

1-138

3Φ

108

<img file="MX360970B_D0315.tif" />

<img file="MX360970B_D0316.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0317.tif" />

<img file="MX360970B_D0318.tif" />

1-142

1-143

1-144

<img file="MX360970B_D0319.tif" />

1-145 1-146

<img file="MX360970B_D0320.tif" />

109

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0321.tif" />

<img file="MX360970B_D0322.tif" />

<img file="MX360970B_D0323.tif" />

110

<img file="MX360970B_D0324.tif" />

1-169

1-170

1-171

<img file="MX360970B_D0325.tif" />

1-173

IMPI

INDUSTRIAL

<img file="MX360970B_D0326.tif" />

<img file="MX360970B_D0327.tif" />

1-174

1-172

<img file="MX360970B_D0328.tif" />

1-175

1-176

1-177

<img file="MX360970B_D0329.tif" />

1-178

1-179

1-180

I 1 and WiHTftMMiMail

112

<img file="MX360970B_D0330.tif" />

<img file="MX360970B_D0331.tif" />

1-181 1-182

<img file="MX360970B_D0332.tif" />

1-189

1-187

<img file="MX360970B_D0333.tif" />

<img file="MX360970B_D0334.tif" />

<img file="MX360970B_D0335.tif" />

1-190

1-188

<img file="MX360970B_D0336.tif" />

<img file="MX360970B_D0337.tif" />

1-192

113

<img file="MX360970B_D0338.tif" />

1-193

1-194

1-195

<img file="MX360970B_D0339.tif" />

1-196

1-197

1-198

<img file="MX360970B_D0340.tif" />

1-199

1-201

1-200

<img file="MX360970B_D0341.tif" />

1-202

1-203

<img file="MX360970B_D0342.tif" />

1-204

<img file="MX360970B_D0343.tif" />

<img file="MX360970B_D0344.tif" />

<img file="MX360970B_D0345.tif" />

115

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0346.tif" />

<img file="MX360970B_D0347.tif" />

<img file="MX360970B_D0348.tif" />

<img file="MX360970B_D0349.tif" />

116

<img file="MX360970B_D0350.tif" />

1-234

1-235

1-236

117

<img file="MX360970B_D0351.tif" />

<img file="MX360970B_D0352.tif" />

<img file="MX360970B_D0353.tif" />

1-240

1-241

1-242

<img file="MX360970B_D0354.tif" />

118

<img file="MX360970B_D0355.tif" />

1-243

<img file="MX360970B_D0356.tif" />

<img file="MX360970B_D0357.tif" />

<img file="MX360970B_D0358.tif" />

<img file="MX360970B_D0359.tif" />

1-252

1-253

1-254

119

<img file="MX360970B_D0360.tif" />

<img file="MX360970B_D0361.tif" />

<img file="MX360970B_D0362.tif" />

1-256

<img file="MX360970B_D0363.tif" />

1-257

1-255

OR

<img file="MX360970B_D0364.tif" />

1-258

OR

HN '^

<img file="MX360970B_D0365.tif" />

<img file="MX360970B_D0366.tif" />

<img file="MX360970B_D0367.tif" />

1-260

<img file="MX360970B_D0368.tif" />

H

1-261

<img file="MX360970B_D0369.tif" />

<img file="MX360970B_D0370.tif" />

1-264

1-259

<img file="MX360970B_D0371.tif" />

1-262 1-263

<img file="MX360970B_D0372.tif" />

<img file="MX360970B_D0373.tif" />

120

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0374.tif" />

1-267 1-268 1-269

<img file="MX360970B_D0375.tif" />

1-270 1-271 1-272

<img file="MX360970B_D0376.tif" />

1-273 1-274 1-275

<img file="MX360970B_D0377.tif" />

1-276

<img file="MX360970B_D0378.tif" />

1-277

121

<img file="MX360970B_D0379.tif" />

1-285

1-286

1-287

IMPI

<img file="MX360970B_D0380.tif" />

122

<img file="MX360970B_D0381.tif" />

<img file="MX360970B_D0382.tif" />

<img file="MX360970B_D0383.tif" />

<img file="MX360970B_D0384.tif" />

<img file="MX360970B_D0385.tif" />

<img file="MX360970B_D0386.tif" />

IMPI

<img file="MX360970B_D0387.tif" />

123

<img file="MX360970B_D0388.tif" />

1-298

<img file="MX360970B_D0389.tif" />

1-299

OR

<img file="MX360970B_D0390.tif" />

<img file="MX360970B_D0391.tif" />

<img file="MX360970B_D0392.tif" />

<img file="MX360970B_D0393.tif" />

1-301

1-300

OR

<img file="MX360970B_D0394.tif" />

<img file="MX360970B_D0395.tif" />

HN

1-302

OR

<img file="MX360970B_D0396.tif" />

<img file="MX360970B_D0397.tif" />

1-304

<img file="MX360970B_D0398.tif" />

<img file="MX360970B_D0399.tif" />

1-303

<img file="MX360970B_D0400.tif" />

IMPI

MEXICAN INSTITUTE

Say THE PROPERTY

INDUSTRIAL

<img file="MX360970B_D0401.tif" />

124

<img file="MX360970B_D0402.tif" />

1-306 1-307

<img file="MX360970B_D0403.tif" />

1-308 1-309

<img file="MX360970B_D0404.tif" />

1-310 1-311 1-312

<img file="MX360970B_D0405.tif" />

1-313

1-314

1-315

<img file="MX360970B_D0406.tif" />

<img file="MX360970B_D0407.tif" />

1-336

1-337

1-338

<img file="MX360970B_D0408.tif" />

127

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0409.tif" />

1-339 1-340 1-341

<img file="MX360970B_D0410.tif" />

1-345

1-346

1-347

128

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0411.tif" />

1-354

1-355

<img file="MX360970B_D0412.tif" />

<img file="MX360970B_D0413.tif" />

130

INSTITUTO MEXICANO M LA MOHEDA »INDUSTRIAL

<img file="MX360970B_D0414.tif" />

<img file="MX360970B_D0415.tif" />

1-366

131

MEXICAN INSTITUTE

<img file="MX360970B_D0416.tif" />

In certain embodiments, the present invention provides any compound illustrated in Table 5, above, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention provides a compound selected from:

<img file="MX360970B_D0417.tif" />

1-7

<img file="MX360970B_D0418.tif" />

1-4

<img file="MX360970B_D0419.tif" />

132

<img file="MX360970B_D0420.tif" />

<img file="MX360970B_D0421.tif" />

1-96 1-182

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0422.tif" />

<img file="MX360970B_D0423.tif" />

1-342 or a pharmaceutically acceptable salt thereof.

As described herein, the compounds of the present invention are irreversible inhibitors of at least one of ErbBl, ErbB2, ErbB3, and ErbB4, or a mutant thereof. In some embodiments, the provided compounds are irreversible inhibitors of a TECkinase (eg, BTK) and JAK3. One of ordinary skill in the art will recognize that certain compounds of the present invention are reversible inhibitors. In certain embodiments, these compounds are useful as test comparator compounds.

In other modalities,

133

<img file="MX360970B_D0424.tif" />

these reversible compounds are useful as inhibitors of ErbBl, ErbB2, ErbB3 and ErbB4, a TEC-kinase and / or JAK3, or a mutant thereof, and therefore useful for treating one or more disorders as described herein. An exemplary reversible compound of the present invention has the following structure.

OR

<img file="MX360970B_D0425.tif" />

or a pharmaceutically acceptable salt thereof.

Four. Uses, formulation and administration

Pharmaceutically acceptable compositions

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 the compositions of this invention is such that it is effective to measurably inhibit a protein kinase, particularly at least one of ErbBl, ErbB2, ErbB3 and ErbB4, a TEC-kinase and / or JAK3, or a mutant thereof , in a biological sample or in a

134

<img file="MX360970B_D0426.tif" />

patient. In certain embodiments, the amount of compound in the compositions of this invention is such that it is effective to measurably inhibit at least one of ErbBl, ErbB2, ErbB3 and ErbB4, a TEC-kinase and / or JAK3 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 this composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic 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 can 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, pH regulating substances. such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids,

135

IMPI *^NST* TWTO MEXICAN

DELAIKOHBDAD

INDUSTRIAL

Τ 'water, salts or electrolytes, such as protamine sulfate, disodium acid phosphate, potassium acid phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, carboxymethylcellulose sodium, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol and wool grease.

A "pharmaceutically acceptable derivative" means any salt, ester, non-toxic ester salt or other derivative of a compound of this invention which, after administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof.

As used herein, the term "inhibitory active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of at least one of ErbBl, ErbB2, ErbB3, and ErbB4, a TEC-kinase, and / or JAK3. or a mutant of it.

The compositions of the present invention can 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, intraarticular, intrasynovial, intrasternal, intrathecal, injection or infusion techniques.

IMPI

<img file="MX360970B_D0427.tif" />

136 intrahepatic, intralesional and intracranial.

Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be an aqueous or oleaginous suspension. These suspensions can 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-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile and 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. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injections, since they are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially polyoxyethylated suspensions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as

137

Mexican INSTITUTE

FROM INDUSTRIAL PROPERTY carboxymethylcellulose 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 that are commonly used in the manufacture of solid-liquid or other pharmaceutically acceptable dosage forms can also be used for formulation purposes.

The pharmaceutically acceptable compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous solutions or suspensions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in 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 can also be added.

Alternatively, the pharmaceutically acceptable compositions of this invention may

138

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL 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 will therefore melt in the rectum to release the drug. These materials include cocoa butter, beeswax, and polyethylene glycols.

/

The pharmaceutically acceptable compositions of this invention can also be administered topically, especially when the treatment target includes areas or organs readily accessible for topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs.

Topical application to the lower gastrointestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Transdermal patches topically can also be used.

For topical applications, the pharmaceutically acceptable compositions provided can be formulated into a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, oil

<img file="MX360970B_D0428.tif" />

139 mineral, liquid petrolatum, white petrolatum, propylene glycol, polyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions provided may 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, ethyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

For ophthalmic use, the pharmaceutically acceptable compositions provided 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 chloride of benzylalkonium. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

The pharmaceutically acceptable compositions of this invention can also be administered by nasal spray or inhalation. These compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions.

IMPI

<img file="MX360970B_D0429.tif" />

140 in saline solution, using benzyl alcohol or other suitable preservatives, absorption promoters to increase bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration.

The amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dose form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated such that a dose of between 0.01100 mg / kg of body weight / day of the inhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, timing of administration, rate of administration. 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 and the composition will also depend on a particular compound in the

<img file="MX360970B_D0430.tif" />

<img file="MX360970B_D0431.tif" />

143 radioactive labeling of the inhibitor before * cle ^L binding, 'isolating the inhibitor / ErbBl, inhibitor / ErbB2, inhibitor / ErbB3, inhibitor / ErbB4, inhibitor / TEC-kinase complex (i.e., TEC,

BTK, ITK, RLK and BMX), or inhibitor / JAK3 and determining the amount of bound radiolabel.

How inhibitor binding can be terminated by running a competition experiment where new inhibitors are incubated with ErbBl, ErbB2, ErbB3 and ErbB4, a TECkinase and / or JAK3 bound to known radioligands.

The detailed conditions for testing a compound used in this invention as an inhibitor of ErbBl, ErbB2, ErbB3 and

ErbB4, a TEC-kinase and / or JAK3, or a mutant thereof, are shown in the following examples.

Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP or GTP to a tyrosine residue located on a protein substrate.

Receptor tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors through a phosphorylation event.

A variety of cellular processes are promoted by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth, cell survival.

<img file="MX360970B_D0432.tif" />

Ι1ΜΙ1ΡΙ

44 MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL (a) ErbB Family

The ErbB receptors, a major family of receptor tyrosine kinases, are composed of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular domain with tyrosine kinase activity. The ErbB family comprises ErbBl (commonly known as EGFR), ErbB2 (commonly known as HER2 or neu), ErbB3 (commonly known as HER3), and ErbB4 (commonly known as HER4). More than 10 ligands (including EGF, TGFOt, AR, BTC, EPR, HB-EGF, NRG-1, NRG-2, NRG-3, NRG-4) have been identified for the different members of the receptor families. After ligand binding, the extracellular domain undergoes a change in conformation, allowing the formation of homodimers or heterodimers with other members of the ErbB family. Dimerization induces tyrosine phosphorylation of specific residues in the intracellular domain that serve as docking sites for adapter proteins and downstream effectors. In some contexts, activation of the phosphatidyl-inositol 3-kinase (PI3K) and mitogen-activated protein kinase pathways occurs, leading to cell proliferation and survival (Lin, NU; Winer, EP, Breast Cancer Res 6: 204 -210,2004).

Interaction between family members is required by deficiencies in ErbB2, which has no ligand

145

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IMPI

MEXICAN INSTITUTE OF PROPERTY

Known INDUSTRIAL, and ErbB3, which is muprt-a— κπτη? Kinase, RrbR3 and ErbB4 bind to the ligand to induce ErbB receptor homodimerization or heterodimerization, while ErbB2 functions as the preferred dimerization partner. The composition of pairwise combinations is important for signal diversification, since the identity of the dimer determines which downstream days are activated. Representative downstream gene products in the ErbB signal transduction pathway include She, Grb2, SOS1, Ras, Rafl, Mek, ERK1, ERK2, ERa, Akt, mTOR, FKHR, p27, Cyclin DI, FasL, GSK-3, Bad and STAT3.

There is strong precedent for the involvement of EGFR and other members of the ErbB family in human cancer because more than 60% of all solid tumors overexpress at least one of these proteins or their ligands. Constitutively active tumorigenic EGFR vIII, a mutant possessing a truncated extracellular domain, has been reported to be present in up to 78% of breast carcinomas and has also been found in glioblastomas. EGFR overexpression is commonly found in tumors of the breast, lung, head and neck, bladder, while ErbB2 expression is frequently elevated in human tumors of epithelial origin. Activating mutations in the tyrosine kinase domain have been identified in patients with non-small cell lung cancer (Lin, NU; Winer, EP,

<img file="MX360970B_D0434.tif" />

; WSSB¿146

<img file="MX360970B_D0435.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

Breast Cancer Res 6: 204-210, 2004). Amplification of

ErbBl and / or ErbB2 have also been implicated in squamous cell carcinomas, salivary gland carcinomas, ovarian carcinomas, and pancreatic cancers (Cooper, GC Oncogenes. 2¹ edition, Sudbury: Jones and Bartlett, 1995; Zhang, Y., et al., Cancer Res 66: 1025-32, 2006). ErbB2 overexpression has potent transforming activity, perhaps due to its ability to cooperate with other ErbB receptors (Sherman, L., et al., Oncogene 18: 6692-99, 1999). In fact, some human cancers that overexpress both EGFR and ErbB2 have a poorer prognosis than cancers that overexpress either receptor alone.

The ErbB signaling network is commonly a key component in breast cancer pathogenesis. ErbB2 amplification is associated with an aggressive tumor phenotype that is characterized by relatively rapid tumor growth, metastatic spread to visceral sites, and drug resistance. ErbB2 has been shown to be amplified in 20% of axillary node negative (ANN) breast cancer cases, and this amplification has been identified as an independent prognostic factor for the risk of recurrence in ANN breast cancer. (Andrulis, IL, et al., J Clin Oncol 16: 1340-9, 1998).

Targeted blockade of ErbB signaling with

<img file="MX360970B_D0436.tif" />

₁₄₇ IMPI ¹ MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL trastuzumab (Herceptin), a monociohai aiTlgldO antibody to * ErbB2, has been shown to improve survival in women with ErbB2-positive advanced breast cancer. Other monoclonal antibodies directed against ErbB receptors include cetuximab (Erbitux) and panitumumab (Vectibix).

Several small molecule tyrosine kinase inhibitors (TKIs) have been found to act selectively on members of the ErbB family. Notable examples include gefitinib (Iressa) and erlotinib (Tarceva), both of which target EGFR. These small molecules compete with ATP for binding to the receptor's kinase domain. Compared to monoclonal antibodies, TKIs have several advantages in that they are orally bioavailable, well tolerated, and appear to be active against truncated forms of ErbB2 and EGFR receptors (eg, EGFR vIII) in vitro. Furthermore, the small size of small molecule TKIs could allow them to penetrate sanctuary sites such as the central nervous system. Finally, the homology between the ErbB receptor kinase domains allows the development of TKIs that target more than one member of the ErbB family simultaneously, the advantages of which are described herein.

Although certain malignancies have been linked to the overexpression of individual receptors, a transduction

148 IMPI ^

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL Efficient Signals is based on the co-exprgS'lúi'i do ίο &amp; members of the ErbB receptor family. This cooperation of members of the ErbB receptor family in signal transduction and malignant transformation may limit the success of agents that target individual receptors in treating cancer; a potential mechanism of resistance to agents that target a single ErbB receptor in the upregulation of other members of the receptor family (Britten, CD, Mol Cancer Ther 3j 1335-42, 2004).

Agents that target two or more ErbB receptors are called pan-ErbB regulators. ERRP is a pan-ErbB negative regulator that is expressed in most pancreatic ductal epithelial cells and benign islets. Tumors have been found to experience a progressive loss in ERRP expression. That Erbitux and Herceptin show success in a limited patient base (tumors that have increased expression of EGFR or ErbB2) could be partially due to the co-expression of various members of the ErbB family.

In both in vitro and in vivo models, strategies employing a dual ErbB approach appear to have greater antitumor activity than agents that target a single ErbB receptor. Thus, agents targeting various members of the ErbB family are likely

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<img file="MX360970B_D0437.tif" />

149 that provide therapeutic benefit to a broader Be ”patient population (Zhang, Y., et al., Cancer Res 66: 102532, 2006). In certain embodiments, the provided compounds inhibit one or more of ErbBl, ErbB2, ErbB3, and ErbB4. In some embodiments, the provided compounds inhibit two or more of ErbBl, ErbB2, ErbB3, and ErbB4 or a mutant thereof, and are therefore inhibitors of pan-ErbB.

Clearly, there is growing evidence to support the concurrent inhibition of two or more ErbB receptors (ie, pan-ErbB) in cancer therapy. Possible approaches to pan-ErbB with small molecules include the use of combinations of agents that target individual ErbB receptors, the use of individual agents that target multiple ErbB receptors, or the use of agents that interfere with interactions. of the ErbB receptor (eg, dimerization). Additional strategies include therapies using a small molecule in combination with antibodies, or chemoprevention therapies (Lin, NU; Winer, e. P., Breast Cancer Res 6: 204-210, 2004).

An example of a small molecule pan-ErbB inhibition is CI-1033, an irreversible pan-ErbB inhibitor that covalently binds to the ATP-binding site of the intracellular kinase domain. Another irreversible pan-Erbb receptor tyrosine kinase inhibitor is HKI

<img file="MX360970B_D0438.tif" />

150

272, which inhibits the growth of tumor cells expressing ErbB-1 (EGFR) and ErbB-2 (HER-2) in culture and xenografts, and has antitumor activity in HER-2 positive breast cancer (Andrulis, IL, et al., J Clin Oncol 16: 1340-9, 1998). Irreversible inhibitors have shown superior antitumor activity compared to reversible inhibitors.

Neurofibromatosis type I (NF1) is a primarily inherited human disease that affects one in 2,500-3,500 individuals. Various organ systems are affected, including bones, skin, iris, and the central nervous system, as manifested in learning disabilities and gliomas. A characteristic of NF1 is the development of benign tumors of the peripheral nervous system (neurofibromas), which vary widely in both number and size between patients. Neurofibromas are heterogeneous tumors composed of Schwann cells, neurons, fibroblasts, and other cells, with Schwann cells being the main cell type (60-80%).

Aberrant EGFR expression is associated with tumor development in NF1 and in animal models of NF1, suggesting a role in pathogenesis and representing a potential novel therapeutic approach. EGFR expression affects the growth of NF1 patient-derived tumor cell lines under conditions in which EGF is not the

<img file="MX360970B_D0439.tif" />

151 main factor that leads to the growth of these cells.

These data suggest that EGFR may play an important role in NF1 tumorigenesis and cell transformation.

Schwann (DeClue, JE, et al., J Clin Invest 105: 1233-41,

2000).

Patients with NF1 develop aggressive Schwann cell neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs). Schwann cells are the main supporting cell population in the peripheral nervous system. Neoplastic Schwann cells within these neoplasms variably express ErbB tyrosine kinases mediating responses to NRG-1 (ErbB2, ErbB3, ErbB4). Neuregulin-1 (NRG-1) proteins promote differentiation, survival, and / or proliferation of many cell types in the developing nervous system, and over-expression of NRG-1 in myelinating Schwann cells induces tumor formation. peripheral nerve sheath

<td>evil</td><td>(MPNSTs)</td><td colspan="5">(Fallón, KB, et al., J Neuro Oncol 66:</td>

<td> 273-84,</td><td> 2004).</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td colspan="2">Deregulation</td><td colspan="2">of growth</td><td>from</td><td>Schwann cells</td>

<td>it's a</td><td>default</td><td>principal</td><td>what</td><td>she drives</td><td>to the</td><td>development of</td>

Both benign and MPNST neurofibromas in patients with neurofibromatosis type 1 (NF1). The growth of MPNSTs and in vitro transformed mouse Schwann cells is highly dependent on EGF and can be blocked by inhibitors of

IMPI

<img file="MX360970B_D0440.tif" />

EGFR under conditions where EGF is the primary growth factor. Some human MPNST cell lines have been found to demonstrate constitutive ErbB phosphorylation. Although treatment with ErbB inhibitors stops ErbB phosphorylation and reduces DNA synthesis in these lines, effective chemotherapeutic regimens for MPNST remain elusive (Stonecypher, MS, et al., Oncogene 24: 5589-5605, 2005).

Schwannomas are peripheral nerve tumors that comprise almost entirely Schwann-like cells, and typically have mutations in the neurofibromatosis type II (NF2) tumor suppressor gene. Ninety percent of patients with NF2 develop bilateral vestibular schwannomas and / or spiral schwannomas. Increasingly large schwannomas can comprise adjacent structures, resulting in deafness and other neurological problems. Surgical removal of these tumors is difficult, commonly resulting in increased patient morbidity.

Both normal human Schwann cells and Schwannoma cells express neuregulin receptors (ie, ErbB receptor) and Schwannoma cells proliferate in response to neuregulin. It is possible that aberrant neuregulin production or response contributes to aberrant Schwannoma cell proliferation (Pelton, PD, et al., Oncogene 17: 2195-2209, 1998).

<img file="MX360970B_D0441.tif" />

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153

The NF2 tumor suppressor, Merlin, is a membrane / cytoskeletal associated protein involved in the regulation of tyrosine kinase activity. Genetic interactions between a Merlin mutation and mutations in the EGFR pathway have been documented in Drosophila (LaJeunesse, DR, et al., Genetics 158: 667-79, 2001). Other evidence suggests that Merlin may inhibit EGFR internalization and signaling after cell-to-cell contact by restricting EGFR within a membrane compartment from which it can neither signal nor be internalized.

<td colspan="4">(McClatehey, AI, et al., Genes and Development 19: 2265-</td>

<td>77, 2005; Curto, M.</td><td>C., et al. ,</td><td>J Cell Biol 177:</td><td> 893-903,</td>

<td> 2007) .</td><td></td><td></td><td></td>

<td>Is according</td><td>use in the</td><td>present, the</td><td>terms</td>

"treating, treating, and treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the disease or disorder, or one or more symptoms progressing one thereof, as described herein.

In some modalities, treatment can be given after one or more symptoms have developed.

treatment can be administered in

In other modalities, the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (eg, in view of a history of symptoms and / or in view of different genetic or susceptibility factors).

The treatment

RWB — K'IMPIOS

Rzl INSTITUTO MEXICANO JE ¹ SAY OWNERSHIP

INDUSTRIAL can also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

The compounds provided are inhibitors of one or more of ErbBl, ErbB2, ErbB3 and ErbB4 and are therefore useful for treating one or more disorders associated with the activity of one or more of ErbBl, ErbB2, ErbB3 and ErbB4. Thus, in certain embodiments, the present invention provides a method of treating an ErbBl-mediated, ErbB2-mediated, ErbB3-mediated, and / or ErbB4-mediated disorder, comprising the step of administering to a patient in need of a compound of the present invention, or a pharmaceutically acceptable composition thereof.

As used herein, the terms ErbBl-mediated, ErbB2-mediated, ErbB3-mediated, and / or ErbB4-mediated disorders or conditions as used herein mean any disease or other harmful condition in which one or more of ErbBl , ErbB2, ErbB3 and ErbB4, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which one or more of ErbBl, ErbB2, ErbB3 and ErbB4 or a mutant thereof are known to play a role. Specifically, the present invention relates to a method for treating or reducing the severity of a Mexican and industrial property after administering a composition of

155 disease or condition selected from proliferative, wherein the method comprises patient requiring a compound or according to the present invention.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more selected disorders of a cancer. — In some embodiments, the cancer is associated with a solid tumor. In certain modalities, the cancer is breast cancer, glioblastoma, lung cancer, head and neck cancer, colorectal cancer, bladder cancer, or non-small cell lung cancer. In some embodiments, the present invention provides a method of treating or reducing the severity of one or more disorders selected from squamous cell carcinoma, salivary gland carcinoma, ovarian carcinoma, or pancreatic cancer.

In certain embodiments, the present invention provides a method of treating or reducing the severity of neurofibromatosis type 1 (NF1), neurofibromatosis type II (NF2), Schwann cell neoplasms (eg, MPSNST's), or Schwannomas.

(b) TEC family

<td></td><td>The</td><td colspan="2">TEC family</td><td>tyrosine kinases</td><td>non-recipients,</td>

<td>referred</td><td>on</td><td>the</td><td>Present</td><td>as TEC-kinases,</td><td>plays a role</td>

<td>central</td><td>on</td><td>the</td><td colspan="2">signage through</td><td>receivers of</td>

<img file="MX360970B_D0443.tif" />

156 antigens such as the TCR, BCR, and Fe receptors (reviewed in Miller A, et al. Current Opinion in Immunology 14; 331-340 (2002). TEC-kinases are essential for T-cell activation. Three family members , Itk, Rlk and, are activated downstream of receptor to antigen coupling in T cells and transmit signals to downstream effectors, including PLC-γ. The combined suppression of Itk and Rlk in mice leads to profound inhibition of TCR responses including proliferation, cytokine production, and immune responses to an intracellular parasite (Toxoplasma gondii) (Schaeffer et al., Science 284; 638-641 (1999 )). Intracellular signaling after TCR coupling occurs in ITK / RLK-deficient T cells; Inositol triphosphate production, calcium mobilization, and MAP kinase activation are all reduced. Tec-kinases are also essential for B cell development and activation.

TEC-kinases include five family members, which are expressed primarily in hematopoietic cells: TEC, BTK, ITK (also known as TSK and EMT), RLK (also known as TXK), and BMX (also known as ETK). Additional related TEC-kinases have been found in Drosophila melanogaster, zebrafish (Danio reró), stingray (Raja eglanteria), and sea urchin (Anthocidaris crassispina).

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157

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

The compounds provided are inhibitors of one or more TEC-kinases and are therefore useful for treating one or more disorders associated with the activity of one or more TEC-kinases. Thus, in certain embodiments, the present invention provides a method of treating a disorder mediated by ECT which comprises the step of administering to a patient in need of it a compound of the present invention, or a pharmaceutically acceptable composition thereof.

The term "ECT-mediated condition" as used herein means any disease or other harmful condition in which TEC-kinases are known to play a role. These conditions include those described herein and in Melcher, M et al., The Role of TEC Family Kinases in Inflammatory Processes, Anti-Inflammatory &amp; AntiAllergy Agents iri Medicinal Chemistry, vol. 6, No. 1, p. 61-69 (February 2007). Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which TEC-kinases are known to play a role. Specifically, the present invention relates to a method of treating or reducing the severity of a disease or condition selected from autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically mediated disorders including organ or tissue rejection.

<img file="MX360970B_D0446.tif" />

158 transplanted patients and acquired immunodeficiency syndrome (AIDS) (also known as HIV), wherein the method comprises administering to a patient in need of it a composition of the present invention.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TECkinases, including respiratory tract diseases including, without limitation, reversible obstructive airway diseases including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (for example, airway hyperresponsiveness due to late asthma) and bronchitis.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TECkinases, including those conditions characterized by inflammation of the nasal mucous membrane, including acute rhinitis, allergic, atrophic rhinitis, and rhinitis. chronic including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and drug rhinitis;

membranous rhinitis including cuprous, fibrinous and pseudomembranous rhinitis and scrofulous rhinitis, seasonal rhinitis including nervous rhinitis (hay fever) and vasomotor rhinitis, sarcoidosis, farmer's lung and diseases

159

<img file="MX360970B_D0447.tif" />

related, fibroid lung and idiopathic interstitial pneumonia.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with ECT-kinases including bone and joint diseases including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behqet's disease, Sjógren's syndrome, systemic sclerosis, osteoporosis, bone cancer and bone metastases.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TEC-kinases including skin diseases and disorders, including, without limitation, psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, urticaria, angioderma, vasculitides, erythema, cutaneous eosinophilias, uveitis, alopecia, areata and vernacular conjunctivitis.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TEC-kinases.

<img file="MX360970B_D0448.tif" />

160 including diseases and disorders of the gastrointestinal tract, including, without limitation, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Crohn's disease, ulcerative colitis, food-related allergies that have effects beyond the intestine, eg, migraine, rhinitis and eczema.

In some embodiments, the present invention provides a method for treating or reducing the severity of one or more diseases and conditions associated with TEC-kinases including those diseases and disorders of other tissues and systemic disease, including, without limitation, multiple sclerosis, atherosclerosis, lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper IgE syndrome, Lepromatous leprosy, Sézary syndrome and idiopathic thrombocytopenic purpura, restenosis after angioplasty, tumors (eg, leukemia, lymphomas, and prostate cancers), and atherosclerosis.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TEC-kinases including allograft rejection including, without limitation, acute and chronic allograft rejection after eg transplantation of kidney, heart, liver, lung, bone marrow,

<img file="MX360970B_D0449.tif" />

IMPI

INSTITUTO MEXICANO j_and.i OF THE PROPERTY

1Ό1 INDUSTRIAL skin and cornea; and chronic graft versus host disease.

In some embodiments, the present invention relates to a method for treating or reducing the severity of one or more of the diseases or conditions associated with TECkinases, such as those described above, wherein the method comprises administering to a patient in need of it a compound or composition according to the present invention.

(c) Bruton's tyrosine kinase (BTK)

Bruton's tyrosine kinase (BTK), a member of the TEC-kinases, is a key signaling enzyme expressed in all types of hematopoietic cells except T lymphocytes and natural killer cells. BTK plays an important role in the B cell signaling pathway by binding cell surface B cell receptor (BCR) stimulation to downstream intracellular responses.

BTK is a key regulator of B cell development, activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000, 276-281; ​​Shaeffer and

Schwartzberg, Curr Op Imm 2000, 282-288). In addition, BTK plays a role in a number of other hematopoietic cell signaling pathways, for example, Toll-like receptor (TLR) and macrophage cytokine receptor-mediated TNF-α production, i.e., IgE receptor signaling.

162

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<img file="MX360970B_D0451.tif" />

(Fc_épsilon_RI) in mast cells, inhibition of Fas / APO-1 apoptotic signaling in B lineage lymphoid cells, and collagen-stimulated platelet aggregation. See, for example, CA Jeffries, et al., (2003), Journal of Biological Chemistry 278: 26258-26264; NJ Horwwod, et al., (2003), The Journal of Experimental Medicine 197: 1603-1611; Iwaki et al. (2005), Journal of Biological Chemistry 280 (48): 40261-40270, - Vassilev et al. (1999), Journal of Biological Chemistry 274 (3): 1646-1656 and Quek et al. (1998), Current Biology 8 (20): 1137-1140.

Patients with BTK mutations have a profound block in B cell development, resulting in the almost complete absence of mature B lymphocytes and plasma cells, severely reduced Ig levels, and profound inhibition of the humoral response to antigen remembering (reviewed in Vihinen et al Frontiers in Bioscience 5: d917-928). BTK-efficient mice also have reduced numbers of peripheral B cells and greatly reduced serum levels of IgM and IgG3. BTK suppression in mice has a profound effect on anti-IgM-induced B cell proliferation, and inhibits immune responses to thymus-independent type II antigens (Ellmeier et al, J Exp Med 192: 1611-1623 (2000)) . BTK also plays a crucial role in mast cell activation through the high affinity IgE receptor (Fe epsilon RI). Cells

<img file="MX360970B_D0452.tif" />

163 BTK-deficient murine baits have reduced degranulation and reduced production of pro-inflammatory cytokines after crosslinking to Fc_epsilon_RI (Kawakami et al.

Journal of Leukocyte Biology 65: 286-290).

<img file="MX360970B_D0453.tif" />

Compounds provided are inhibitors of

BTK and are therefore useful for treating one or more disorders associated with BTK activity. Thus, in some embodiments, the present invention provides a method for treating a BTK-mediated disorder comprising the step of administering to a patient in need of a compound of the present invention, or as a pharmaceutically acceptable composition thereof.

As used herein, the term "BTK-mediated disorders or conditions" as used herein means any disease or other harmful condition in which BTK, or a mutant thereof, is known to play a role.

Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which BTK, or a mutant thereof, is known to play a role. Specifically, the present invention relates to a method for treating or reducing the severity of a disease or condition selected from a proliferative disorder or an autoimmune disorder, wherein the method comprises administering to a patient in need of it a compound or composition according to the present

<img file="MX360970B_D0454.tif" />

<img file="MX360970B_D0455.tif" />

164 i nvenc i on. '

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with BTK. In some embodiments, the disease or condition is an autoimmune disease, eg, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, thyroiditis Ord's disease, Grave's disease, Sjógren's syndrome, multiple sclerosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, Alkylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu arteritis, temporal arteritis, tibial autoimmune hemolytic anemia, tibial granulomatosis, autoimmune hemolytic anemia Wegener's, psoriasis, universal alopecia, Behget's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, or vulvodynia. In some embodiments, the disease or condition is hyperproliferative disease or immunologically mediated diseases including rejection of transplanted organs or tissues and

<img file="MX360970B_D0456.tif" />

<img file="MX360970B_D0457.tif" />

I

165 acquired immunodeficiency syndrome (AIDS, also known as HIV).

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with BTK, wherein the disease or condition is selected from heteroimmune conditions or diseases, which include, but are not limited to graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (for example, allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites or cockroaches), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with BTK, wherein the disease or condition is selected from an inflammatory disease, eg, asthma, appendicitis, blepharitis, bronchiolitis. , bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis

<td></td><td colspan="2"> 166</td><td>IMPI MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY</td>

<td>suppurative,</td><td>laryngitis,</td><td>mastitis,</td><td>meningitis, myelitis</td>

<td>myocarditis,</td><td>myositis,</td><td>nephritis,</td><td>oophoritis, orchitis,</td>

osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, vasitis, oginitis.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with BTK, wherein the disease or condition is selected from cancer.

In one embodiment, the cancer is a B-cell proliferative disorder, eg, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / macroglobulinemia of Waldenstrom, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non

Hodgkin, Hodgkin lymphoma, plasmacytoma, cell lymphoma

Extranodal marginal zone B, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or granulomatosis lymphomatoid. On

IMPI

<img file="MX360970B_D0458.tif" />

167 In some modalities, the cancer is breast cancer, prostate cancer, or mast cell cancer (eg, mast cell cancer, mast cell leukemia, mast cell sarcoma, systemic mastocytosis). In one embodiment, the cancer is bone cancer. In another embodiment, the cancer is of another primary origin and metastasizes to the bone.

In some embodiments, the present invention provides a method for treating or reducing the severity of one or more diseases or conditions associated with BTK, including bone and joint diseases including, without limitation, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, arthritis psoriatic and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer and bone metastases.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with BTK, wherein the disease or condition is selected from a thromboembolic disorder, eg, myocardial infarction, angina pectoris. , reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, one upset

<img file="MX360970B_D0459.tif" />

168 peripheral arterial occlusive, pulmonary embolism or deep vein thrombosis.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with BTK, including infectious and non-infectious inflammatory events and autoimmune and other inflammatory diseases. These autoimmune inflammatory diseases, disorders and syndromes include pelvic inflammatory disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, collocystitis , agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue and 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 syndrome, atherosclerosis, Addison's disease, Parkinson's disease,

IMPI

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169

Alzheimer's, type I diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroid disease, atopic degeneration, atopic degeneration , vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome,

Behqet, scleraderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distention syndrome ischemia / reperfusion injury) and disease of

Graves.

In some embodiments, the present invention provides a method of treating one or more BTK-associated diseases and conditions selected from rheumatoid arthritis, multiple sclerosis, B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, hairy cell leukemia, non-Hodgkin lymphoma. , Hodgkin's lymphoma, multiple myeloma, bone cancer, bone metastasis, osteoporosis, irritable bowel syndrome, Crohn's disease, lupus, and kidney transplantation.

(d) ITK

Interleukin-2 inducible T cell kinase (ITK) is expressed in T cells, mast cells, and natural killer cells. It is activated in T cells after stimulation of the T cell receptor (TCR), and in cells

IMPI

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170 primed after activation of the aluea · affinity IgE receptor. After stimulation of the receptor in cells

T, Lck, a member of the Src tyrosine kinase family, phosphorylates Y511 at the ITK kinase domain activation loop (SD Heyeck et al., 1997, J. Biol. Chem, 272, 2540125408). Activated ITK, along with Zap-70 is required for phosphorylation and activation of PLC-gamma (SC Bunnell et al., 2000, J. Biol. Chem., 275, 2219-2230). PLC-gamma catalyzes the formation of inositol 1,4,5-triphosphate and diacylglycerol, leading to calcium mobilization and PKC activation, respectively.

These events activate numerous downstream pathways and ultimately lead to degranulation (mast cells) and expression of cytokine genes (T cells) (Y. Kawakami et al., 1999, J. Leukocyte Biol., 65, 286-290).

The role of ITK in T cell activation has been confirmed in ITK-suppressed mice. CD4 T cells⁺of mice suppressed in ITK have a reduced proliferative response in a mixed lymphocytic reaction or after challenge with Con A or anti-CD3. (XC Liao and DR Littman, 1995, Immunity, 3, 757-769). Also, ITK-suppressed mouse T cells produced little IL-2 after TCR stimulation resulting in reduced proliferation of these cells. In another study, CD4 T cells⁺ deficient in ITK produced levels

<img file="MX360970B_D0462.tif" />

IMPI

171 reduced cytokines including IL-4, IL-5 and IL-13 after TCR stimulation, even after priming with inducing conditions (DJ Fowell, 1999, Immunity, 11,

399-409).

The role of ITK in the activation of PLC-gamma and in the mobilization of calcium was also confirmed in the T cells of these suppressed mice, which had a generation of IP.₃ severely impaired and no extracellular calcium influx after TCR stimulation (K. Liu et al., 1998, J. Exp. Med. 187, 1721-1727) These studies support a key role for ITK in T-cell activation and mast cells. Thus, an ITK inhibitor would be of therapeutic benefit in diseases mediated by inappropriate activation of these cells.

It has been well established that T cells play an important role in the regulation of the immune response (Powrie and

Coffman, 1993, Immunology Today, 14, 270-274). In fact, T cell activation is commonly the initiating event in immune disorders.

After TCR activation, there is an influx of calcium that is required for T cell activation.

After activation, T cells produce cytokines, including

Til-

2, 4, 5, 9, 10 and 13 leading to T cell proliferation, differentiation and effector function. Clinical studies with IL-2 inhibitors have shown that interference with the

IMPI

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172 T cell activation and proliferation effectively suppresses the immune response in vivo. Consequently, agents that inhibit T lymphocyte activation and subsequent cytokine production are therapeutically useful to selectively suppress the immune response in a patient in need of this immunosuppression.

Mast cells play a critical role in asthma and allergic disorders by releasing pro-inflammatory mediators and cytokines. Antigen-mediated aggregation of Fc.epsilon.RI, the high affinity receptor for IgE, results in mast cell activation (DB Corry et al., 1999, Nature, 402, B18-23). This triggers a series of signaling events that result in the release of mediators, including histamine, proteases, leukotrienes, and cytokines (JR Gordon et al., 1990, Immunology Today, 11, 4S8-464). These mediators cause increased vascular permeability, mucus production, bronchoconstriction, tissue breakdown, and inflammation thus playing key roles in the etiology and symptoms of asthma and allergic disorders.

Published data using ITK-suppressed mice suggests that in the absence of ITK function, increased numbers of memory T cells are generated. One strategy to improve vaccination methods is to increase the number of memory T cells generated (S.

<img file="MX360970B_D0464.tif" />

<img file="MX360970B_D0465.tif" />

173

M. Kaech et al., Nature Reviews Immunology, 2, 251-262). Furthermore, ITK suppression in mice results in reduced T-cell receptor (TCR) -induced proliferation and secretion of the cytokines IL-2, IL-4, IL-5, IL-10, and IFN-y ( Schaeffer et al., Science 284; 638-641 (1999)), Fowell et al, Immunity 11, 399-409 (1999), Shaeffer et al, Nature Immunology 2 (12): 1183-1188 (2001))). Immunological symptoms of allergic asthma are attenuated in ITK / - mice. Lung inflammation, eosinophilic infiltration, and mucus production are dramatically reduced in ITK- / mice in response to attack with the OVA allergen (Mueller et al, Journal of Immunology 170: 5056-5063 (2003)). ITK has also been implicated in atopic dermatitis. This gene has been reported to be more highly expressed in peripheral blood T cells from patients with moderate and / or severe atopic dermatitis than in controls or patients with mild atopic dermatitis (Matsumoto et al., International Archives of Allergy and Immunology 129: 327 -340 (2002)).

Splenocytes from RLK - / - mice secrete half of the IL-2 produced by wild-type animals in response to TCR coupling (Schaeffer et al, Science 284: 638-641 (1999)), whereas the combined deletion of ITK and RLK in mice leads to profound inhibition of TCR-induced responses including proliferation and production of the cytokines IL-2, IL-4, IL-5, and IFN-y (Schaeffer et al,

<img file="MX360970B_D0466.tif" />

174

Nature Immunology 2 (12): 1183-1188 (2001), Schaeffer et al7 Science 284: 638-641 (1999)). Intracellular signaling after TCR coupling is effected in ITK / RLK-deficient T cells; Inositol triphosphate production, calcium mobilization, MAP kinase activation, and activation of the transcription factors NFAT and AP-1 are all reduced (Schaeffer et al, Science 284: 638-641 (1999), Schaeffer et al, Nature Immunology 2 (12): 1183-1188 (2001)).

The compounds provided are inhibitors of ITK and are therefore useful for treating one or more disorders associated with ITK activity. Thus, in some embodiments, the present invention provides a method of treating an ITK-mediated disorder comprising the step of administering to a patient in need of it a compound of the present invention, or a pharmaceutically acceptable composition thereof.

As used herein, the term ITK-mediated disorders or conditions as used herein means any disease or other harmful condition in which ITK, or a mutant thereof, is known to play a role. Accordingly, another embodiment in the present invention relates to treating or reducing the severity of one or more diseases in which ITK, or a mutant thereof, is known to play a role. Specifically, the present invention relates to a method of treating or reducing the

<img file="MX360970B_D0467.tif" />

<img file="MX360970B_D0468.tif" />

175 severity of a disease or condition selected from a mast cell-mediated condition, a basophil-mediated disorder, an immune or allergic disorder, wherein the method comprises administering to a patient in need of a compound or composition according to the present invention.

In some embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TKI, wherein the disease or condition is an immune disorder, including inflammatory diseases, autoimmune diseases, organ transplant rejection. and bone marrow and other disorders associated with T cell mediated immune response or mast cell mediated immune response.

In certain embodiments, the present invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TKI, wherein the disease or condition is acute or chronic inflammation, an allergy, contact dermatitis, psoriasis, rheumatoid arthritis. , multiple sclerosis, type I diabetes, inflammatory bowel disease, Guillain-Barré syndrome, Crohn's disease, ulcerative colitis, cancer, graft versus host disease (and other forms of organ or bone marrow transplant rejection) or lupus erythematosus.

Y

<img file="MX360970B_D0469.tif" />

₁₇₆ IMPI

INSTITUTO MEXICANO Di LA PROPERTY

INDUSTRIAL

In certain embodiments, the preseirbc · invention provides a method of treating or reducing the severity of one or more diseases and conditions associated with TKI, wherein the disease or condition is a mast cell-driven condition, a basophil-mediated disorder, or reversible obstructive airway, asthma, rhinitis, chronic obstructive pulmonary disease (COPD), Peripheral T-cell lymphoma or HIV [also known as Acquired Immune Deficiency Syndrome (AIDS)]. These conditions include those described in Readinger, et al., PNAS 105: 6684-6689 (2008).

(e) JAK family

Janus kinases (JAK) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3, and TYK2. JAKs play a critical role in cytokine signaling. Downstream substrates of the JAK family of kinases include signal transducer and activator of transcription (STAT) proteins. JAK / STAT signaling has been implicated in mediating many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, and multiple sclerosis as well as solid and hematologic malignancies such as leukemias. and lymph nodes. The pharmaceutical intervention in the JAK / STAT pathway has been reviewed [Frank, Mol. Med. 5: 432-456 (1999) &amp;

IMPI

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177

Seidel, et al, Oncogene 19: 2645-2656 (2000)].

JAK1, JAK2, and JYK2 are ubiquitously expressed, while JAK3 is predominantly expressed in hematopoietic cells. JAK3 binds exclusively to the common cytokine receptor (ye) gamma chain and is activated by IL-2, IL-4, IL-7, IL-9, and IL-15.

The proliferation and survival of murine mast cells induced by IL-4 and IL-9 have, in fact, been shown by JAK3 and ye [Suzuki et al, Blood 96: 2172-2180 (2000)].

Crosslinking of high-affinity immunoglobulin (Ig) E receptors from sensitized mast cells leads to a release of pro-inflammatory mediators, including a number of vasoactive cytokines, resulting in acute or immediate (type I) allergic hypersensitivity reactions

[Gordon et al, Nature

346: 274-276 (1990) &amp; Galli,

J.

Med., 328: 257-265 (1993)].

A crucial role for JAK3 in receptor-mediated mast cell responses to

IgE in vitro and in vivo has been established

[Malaviya, et al, bio chem. Biophys.

Res. Commun.

257:807-813 (1999)].

In addition, the prevention of hypersensitivity reactions type

I, including anaphylaxis, mediated by mast cell activation through inhibition of JAK3 has also been reported

[Malaviya et al, J. Biol. Chem. 274: 27028-27038 (1999)]. The

<img file="MX360970B_D0471.tif" />

178 targeting of mast cells with 'JÁK3 inhibitors modulated mast cell degranulation in vitro and prevented IgE / antigen receptor-mediated anaphylactic reactions in vivo.

A recent study described the successful targeting of JAK3 for immune suppression and allograft acceptance. The study demonstrated dose-dependent survival of buffalo heart allograft in Wistar Furth recipients after administration of JAK3 inhibitors indicating the possibility of regulating unwanted immune responses in graft versus host disease [Kirken, Transpl. Proc. 33: 3268-3270 82001)].

IL-4 mediated phosphorylation of STAT has been implicated as the mechanism involved in early and late stages of rheumatoid arthritis (RA). The upregulation of proinflammatory cytokines in RA synovium and synovial fluid is a characteristic of the disease. IL-4-mediated activation of the IL4 / STAT pathway has been shown to be mediated through Janus kinases (JAK 1 and 3) and that IL-4-associated JAK kinases are expressed in RA synovium [Muller -Ladner, et al, J. Immunol. 164: 38943901 (2000)].

Familial amyotrophic lateral sclerosis (FALS) is a fatal neurodegenerative disorder that affects approximately 10% of ALS patients. Rates of

179

IMPI

<img file="MX360970B_D0472.tif" />

Survival of FALS mice is increased after treatment with a specific JAK3 inhibitor. This confirmed that JAK3 plays a role in FALS [Trieu, et al, Biochem. Biophys. Res. Commun. 267: 22-25 (2000)].

Signal transducer and activator of transcription (STAT) proteins are activated by, among others, the kinases of the JAK family. The results of a recent study suggested the possibility of intervention in the JAK / STAT signaling pathway by targeting JAK family kinases with specific inhibitors for the treatment of leukemia [Sudbeck, et al., Clin. Cancer Res. 5: 1569-1582 (1999)]. JAK3-specific compounds were shown to inhibit the clonogenic growth of cell lines expressing JAK3 DAÜDI, RAMOS, LCI; 19, NALM-6, MOLT-3 and HL60. Inhibition of tyrosine phosphorylation abrogated by JAK3 and TYK 2 of STAT3, and inhibited cell growth

<td>of mycosis</td><td>fungoides,</td><td>a</td><td>shape</td><td>lymphoma</td><td>from</td><td>T cells</td>

<td>cutaneous.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>From</td><td>agreement</td><td>with</td><td>other</td><td>modality,</td><td>the</td><td>invention</td>

<td>provides</td><td>a method</td><td>in order to</td><td>try</td><td>or reduce the</td><td colspan="2">severity of</td>

a JAK3-mediated disease or condition in a patient, comprising the step of administering to the patient a composition according to the present invention.

The term "JAK3-mediated disease" as used herein means any disease or other

<img file="MX360970B_D0473.tif" />

<img file="MX360970B_D0474.tif" />

180 harmful condition in which JAK3 kinase is known to play a role. Accordingly, another embodiment of the present invention relates to treating or reducing the severity of one or more diseases in which JAK3 is known to play a role. Specifically, the present invention relates to a method of treating or reducing the severity of a disease or condition selected from immune responses such as type I allergic or hypersensitivity reactions, asthma, autoimmune diseases such as rejection of transplants, disease of graft versus host, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative disorders such as familial amyotrophic lateral sclerosis (FALS), as well as in solid and hematological malignancies such as leukemias and lymphores, wherein the method comprises administering to a patient requiring it a composition according to the present invention.

The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective to treat or reduce the severity of cancer, an autoimmune disease, a neurological neurodegenerative disorder, schizophrenia, a related disorder. with bone, liver disease or a heart disorder. The exact amount required will vary from subject to subject,

IMPI

<img file="MX360970B_D0475.tif" />

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. The compounds of the invention are preferably formulated in a single dose form for ease of administration and uniformity of dosage. The term "single dose form" as used herein refers to a physically discrete unit of agent suitable for the patient to be treated. However, it will be understood that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of correct medical judgment. The specific effective dose level for any particular patient or organism will depend on 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 used; 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 coincidentally with the specific compound employed, and similar factors well known in the medical art. The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

<img file="MX360970B_D0476.tif" />

182

The pharmaceutically acceptable compositions of this invention can be administered to humans or other animals orally, rectally, parenterally, intracisternally intravaginally, intraperitoneally, topically (as by powders, ointments or drops), buccally, 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 can be administered orally or parenterally at dosage levels of about 0.01 mg / kg or about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, by weight. subject's body per day, one or more times per day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to active compounds, 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, acetate. ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils

IMPI

<img file="MX360970B_D0477.tif" />

183 (in particular, cottonseed, walnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can 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 non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, USP sodium chloride solution, and isotonic. Furthermore, 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. Furthermore, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be • afjMir.jFbiiágx:

184

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0478.tif" />

sterilized, for example, by filtration through a bacteria retention 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 before use.

In order to prolong the effect of a compound of the present invention, it is commonly desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The absorption rate of the compound then depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil carrier. Injectable depot forms are made by forming microcapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapment of the compound in liposomes or microemulsions that

<img file="MX360970B_D0479.tif" />

185

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MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0480.tif" />

They are compatible with body tissues. —----- 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 that are solid to room temperature but liquids at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these 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) 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, solution retarding agents such as paraffin, f) alginic acid, certain silicates and sodium carbonate, e) absorption accelerators such as quaternary ammonium compounds,

g) wetting agents such as, for example,

186

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<img file="MX360970B_D0482.tif" />

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 can also comprise pH regulating agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. 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 formulation art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the gastrointestinal 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 can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well

<img file="MX360970B_D0483.tif" />

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187

I

MEXICAN OF INDUSTRIAL PROPERTY such as high molecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulation art. In these solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. These dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise pH regulating agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredients only, or preferably, in a certain part of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical administration or

Μ

<img file="MX360970B_D0486.tif" />

188 transdermal compound of this invention incioyerr ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservative or pH regulator as required. Ophthalmic formulations, eye drops, and ear drops are also contemplated as being within the scope of this invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. These dosage forms can be made by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled either by providing a rate control membrane or by dispersing the compound in a polymeric matrix or gel.

According to one embodiment, the invention relates to a method for inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound of this invention, or a composition comprising the compound .

According to another embodiment, the invention relates to a method for inhibiting the activity of ErbBl,

189

<img file="MX360970B_D0487.tif" />

ErbB2, ErbB3, ErbB4, a TEC-kinase and / or JAK3, or a mutant thereof, in a biological sample, comprising the step of contacting the biological sample with a compound of this invention, or a composition comprising the compound. In certain embodiments, the invention relates to a method for irreversibly inhibiting the activity of ErbBl, ErbB2, ErbB3, ErbB4, a TEC-kinase and / or JAK3 or a mutant thereof in a biological sample, comprising the step of putting contacting the biological sample with a compound of this invention, or a composition comprising the compound.

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.

Inhibition of protein kinase, or a protein kinase activity selected from ErbBl, ErbB2, ErbB3, ErbB4, a TEC-kinase and / or JAK3 or a mutant thereof in a biological sample is useful for a variety of known purposes. by someone of skill in the art. Examples of these purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens, and biological testing.

<img file="MX360970B_D0488.tif" />

190

IMPI $ s&gt;

ΒΟΠΤυΤΟ MEXICANO DELA INDUSTRIAL PROPERTY

Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient, comprising the step of administering to the patient a compound of the present invention, or a composition comprising the compound.

According to another embodiment, the invention relates to a method for inhibiting one or more of the activity of ErbBl, ErbB2, ErbB3, ErbB4, a TEC-kinase and / or JAK3, or a mutant thereof in a patient, which comprises the step of administering to the patient a compound of the present invention, or a composition comprising the compound. According to certain embodiments, the invention relates to a method for irreversibly inhibiting one or more of the activities of ErbBl, ErbB2, ErbB3, ErbB4, a TEC-kinase and / or JAK3, a mutant thereof in a patient, which comprises the step of administering to the patient a compound of the present invention, or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a disorder mediated by one or more of ErbBl, ErbB2, ErbB3, ErbB4, a TEC-kinase and / or JAK3, or a mutant thereof, in a patient requiring it. , which comprises the step of administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. These disorders are described in detail herein.

IMPI

<img file="MX360970B_D0489.tif" />

191

Depending on the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to

<td colspan="2">treat that condition, they can also &lt;</td><td>be present</td><td>on</td><td>the</td>

<td>compositions of this</td><td>invention.</td><td>As used</td><td>on</td><td>the</td>

<td>present, the agents</td><td>therapeutic</td><td>additional</td><td>what</td><td>I know</td>

normally administered to treat a particular disease or condition are known to be suitable for the disease or condition being treated.

For example, the compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with chemotherapeutic agents to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, platinum derivatives, taxane (eg, paclitaxel), vinca alkaloids (eg, vinblastine), anthracyclines (eg doxorubicin), epipodophyllotoxins (eg etoposide), cisplatin, an mTOR inhibitor (eg rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, metroprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents (eg chlorambucil), 5-fluorouracil, camphothecin, cisplatin,

192

IMPI ^ a

MEXICAN INSTITUTE

OF THE PROPERTY .50

INDUSTRIAL X ^ ST * and metronidazole and Gleevec ™ among others. In other embodiments, a compound of the present invention is administered in combination with a biological agent, such as Avastin or

VECTIBIX.

In certain embodiments, the compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of abarelix, aldesleucin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine. , anastrozole, arsenic trioxide, asparaginase, azacitidine, live BCG, bevacuzimab, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, calusterone, capecitabine, canftothecin, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoieet ina alfa, daunorubicin, denileucine, dexrazoxane, docetaxorine hydrochloride, doxeraubin (docetaubin), propirororin , epoetin alfa, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide,

193

INSTITUTO MEXICANO DE LA PRCNEDACINDUSTRIA !.

letrozole, leucovorin, leuprolrdag acetate - ^ - drevami so-lr lomustine, megestrol acetate, melphalan, mercaptopurine, 6MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, my t oxanthrone, oprelvekin, pamidronate, nandrolone Pegademase, Nelarabine, Paclitaxel, Pegaspargasse, Nofetumomab, Palifermin, Pegfilgastrim, Pemetrexed Disodium, Pentostatin, Pipobroman, Plicamycin, Porfimer Sodium, Procarbazine, Quinacrine, Rasburicase, Rituximab, Sargramibostim, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM

26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.

<td>Others</td><td>examples</td><td>from</td><td>agents</td><td>with the</td><td>that the</td>

<td>inhibitors</td><td colspan="2">this invention</td><td>also</td><td>they can</td><td>to combine</td>

<td>include, without</td><td>limitation:</td><td colspan="2">treatments</td><td colspan="2">for disease of</td>

Alzheimer's such as donepezil hydrochloride (Aricept®) and rivastigmine (Exelon⁸); Parkinson's disease treatments such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine; agents to treat Multiple Sclerosis (MS) such as interferon beta (for example, Avonex® and Rebif⁸), glatiramer acetate (Copaxone®), and mitoxantrone; asthma treatments such as albuterol and montelukast

<img file="MX360970B_D0490.tif" />

IMPI, _{Λ A} MEXICAN INSTITUTE

94 OE THE PROPERTY

INDUSTRIAL (Singulair^s); agents to treat schizophrenia such as ziprexa, 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 cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, 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, cholstyramine, interferons, and antiviral agents; agents for treating hematological disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

In certain embodiments, the compounds of the present invention, or a pharmaceutically acceptable composition thereof, are administered in combination with a monoclonal antibody or a siRNA therapeutic.

Those additional agents can be administered separately from a composition containing

IMPI

<img file="MX360970B_D0491.tif" />

195 compound of the invention, as part of a multiple dosage regimen.

Alternatively, those agents can 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 regimen, the two active agents can be subjected simultaneously, sequentially or within a period of time from each other typically within five hours of each other.

As used herein, the term "combination," combined 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 can be administered with another therapeutic agent simultaneously or sequentially in separate single dose forms or together in a single single dose form. Accordingly, the present invention provides a single single dose form comprising a provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both, a compound of the invention and additional therapeutic agent (in these compositions comprising an additional therapeutic agent as described above)) that can be combined with the carrier materials

<img file="MX360970B_D0492.tif" />

196 to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated such that a dose of between 0.01-100 mg / kg of body weight / day of a compound of the invention can be administered.

In those compositions comprising an additional therapeutic agent, that additional therapeutic agent and the compound of this invention can act synergistically. Therefore, the amount of additional therapeutic agent in these compositions will be less than that required in a monotherapy using only that therapeutic agent. In those compositions a dose of between 0.01-1,000 ug / kg of body weight / day of the additional therapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositions of this invention will be no greater than the amount that would normally be administered in a composition comprising the therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in presently described 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.

IMPI

<img file="MX360970B_D0493.tif" />

197

The compositions 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 walls after injury). However, patients using stents and other implantable devices are at risk for clot formation or platelet activation. These effects can be prevented or mitigated so unwanted can be precoated 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.

5. Probe compounds

In certain aspects, a compound of the present invention can be linked to a detectable moiety to form a probe compound. In one aspect, a probe compound of the invention comprises an irreversible protein kinase inhibitor of formula Ia or Ib, as described herein, a detectable portion and a binding portion that binds the inhibitor to the portion

<img file="MX360970B_D0494.tif" />

198 detectable.

In some embodiments, these probe compounds of the present invention comprise a compound of formula Ia or Ib provided attached to a detectable moiety, R¹, may be a bivalent binding portion, -T-. The binding portion can be attached to a compound of formula Ia or Ib via ring A, ring B or R¹. One of ordinary skill in the art will appreciate that when a binding portion is attached to R¹, R¹is a bivalent head group indicated as R¹'. In certain embodiments, a probe compound provided is selected from either a, Vl-b, VH-a, or VH-b:

of the formulas Va, Vb, VI-

<img file="MX360970B_D0495.tif" />

He

<img file="MX360970B_D0496.tif" />

<img file="MX360970B_D0497.tif" />

Vl-a

<img file="MX360970B_D0498.tif" />

IMPI

<img file="MX360970B_D0499.tif" />

199

<img file="MX360970B_D0500.tif" />

<img file="MX360970B_D0501.tif" />

where each of ring A, ring B, R¹, m, p, R^x, R^Y, R^v, W¹, and W² as defined above with respect to formulas Ia and Ib, and described in classes and subclasses herein, R¹'is a bivalent head group, T is a bivalent binding portion, and R^fc it is a detectable portion.

In some modalities, R^fc it is a detectable portion selected from a primary marker or a secondary marker. In certain modalities, R^fc is a detectable portion selected from a fluorescent marker (eg, a fluorescent dye or a fluorophore), a mass tag, a chemiluminescent group, a chromophore, an electron dense group, or an energy transfer agent.

As used herein, the term "detectable portion" is used interchangeably with the term "marker" and "reporter" and refers to any portion capable of being detected, eg, primary markers and secondary markers. A presence of a detectable portion can be measured using methods to quantify (in absolute, approximate, or relative terms) the detectable portion in

<img file="MX360970B_D0502.tif" />

<img file="MX360970B_D0503.tif" />

200 a system under study. In some embodiments, these methods are well known to one of ordinary skill in the art and include any method that quantifies a reporter portion (e.g., a marker, a dye, a photointerlacer, a cytotoxic compound, a drug, an affinity marker , a photoaffinity marker, a reactive compound, an antibody or antibody fragment, a biomaterial, a nanoparticle, a centrifugal marker, a fluorophore, a metal-containing portion, a radioactive portion, quantum dots, a novel functional group, a group that interacts covalently or non-covalently with other molecules, a photocaged portion, an actinic radiation excitable portion, a ligand, a photoisomerizable portion, biotin, a biotin analog (e.g. example, biotin sulfoxide), a portion incorporating a heavy atom, a chemically cuttable group, a photo-cuttable group, a redox active agent, an isotopically labeled portion, a biophysical probe, a phosphorescent group, a chemiluminescent group, an electron dense group, a magnetic group, an intercalating group, a chromophore, an energy transfer agent, a biologically active agent, a detectable label, and any combination of the above ).

Primary markers, such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵Yes, ¹⁴C, ¹²³I, ¹²⁴I, ¹²⁵I, or ¹³¹I),

<img file="MX360970B_D0504.tif" />

201

IMPI mass markers including, but not limited to, —isotopes -, - stable (for example, ¹³C, ²H, ¹⁷0, ¹⁸0, ¹⁵N, ¹⁹F, and ¹²⁷I), positron-emitting isotopes (for example, ^X1C, ¹⁸F, ¹³N, ¹²⁴I and ¹⁵0), and fluorescent markers are signal-generating reporter groups that can be detected without further modification. Detectable portions can be analyzed by methods including, but not limited to, fluorescence, positron emission tomography, and medical imaging SPECT, chemiluminescence, electron spin resonance, ultraviolet / visible absorbance spectroscopy, mass spectrometry, nuclear magnetic resonance, magnetic resonance imaging, flow cytometry, autoradiography, scintillation counting, phosphoforming of images and electrochemical methods.

The term "secondary marker" as used herein refers to portions such as biotin and various protein antigens that require the presence of a second intermediate for the production of a detectable signal. For biotin, the secondary intermediate can include streptavidin-enzyme conjugates. For antigenic markers, secondary intermediates can include antibody-enzyme conjugates. Some fluorescent groups act as secondary markers because they transfer energy to another group in the process of transferring

<img file="MX360970B_D0505.tif" />

202 non-radioactive fluorescent resonance energy (FRET), and the second group produces the detected signal.

The terms fluorescent marker, fluorescent dye, and fluorophore as used herein refer to portions that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent markers include, but are not limited to: Alexa Fluorine dyes (Alexa Fluorine 350, Alexa Fluorine 488, Alexa Fluorine 532, Alexa Fluorine 546, Alexa Fluorine 568, Alexa Fluorine 594, Alexa Fluorine 633, Alexa Fluorine 660 and Alexa Fluorine 680), AMCA, AMCA-S, BODIPY colorants ( BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 493/503, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650 / 650, BODIPY 630/650 / 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, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IR Dyes (IRD40, IRD 700, IRD 800), JOE, Lysamine Rhodamine B, Navy 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-bromosulfon-fluorescein, • ί WiUIM'JW

203

<img file="MX360970B_D0506.tif" />

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0507.tif" />

tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA),

Texas Red, Texas Red-X, 5 (6) -carboxyfluorescein, 2,7-dichlorofluorescein, N, N-bis (2,4,6-trimethylphenyl) -3,4: 9,10-perylenebis (dicarboximide, HPTS, ethyl eosine, DY -490XL MegaStokes, DY-485XL MegaStokes, Adirondack Green 520, ATTO 465, ATTO 488, ATTO 495, YOYO-1,5-FAM, BCECF, Dichlorofluorescein, Rhodamine 110, Rhodamine 123, YO-PRO-1, SYTOX Green, Green sodium, SYBR 1 green, Alexa Fluorine 5 00, PHYTO, Fluo-3, fluo-4, fluoro-emerald, YoYo-1 ssDNA, YoYo-1 dsDNA, YoYo-1, SYTO, RNASelect, Diversa-FP green, Dragon green, EvaGreen, Surf green EX, Spectrum green, NuroTrace 500525, NBD-X, MitoTracker FM green, LysoTracker green DND26, CBQCA, PA-GFP (post-activation), WEGFP (post-activation), FIASH-CCXXCC, Monomeric Azami Green, Azami Green, Green Fluorescent Protein (GFP), EGFP (Campbell Tsien 2003), EGFP (Patterson 2001), Kaede Green, 7-benzylamino-4-nitrobenz-2-oxa-1,3-diazole , Bexl, doxorubicin, Lumio green and SuperGlo

GFP.

The present term refers to mass marker as used in any portion that is capable of being detected solely by virtue of its mass using mass spectrometric (MS) detection techniques.

Example of markers of i

mass include electrophor release markers such as acid

N- [3- [4 '- [(p-methoxytetrafluorobenzyl) oxy] phenyl] -3IMPI

<img file="MX360970B_D0508.tif" />

204 methylglyceronyl] isonipecotic, 4 '- [2,3,5,6tetrafluoro-4- (pentafluorophenoxyl)] methyl acetophenone and its derivatives. The synthesis and utility of these mass markers is described in US 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 mass markers include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying composition and length and base, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomeric composition. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of a suitable mass range (100-2,000 Daltons) can also be used as mass markers. Stable isotopes (for example, ¹³C, ²H, ¹⁷OR, ¹⁸0 Y ¹⁵N) can also be used as mass markers.

The term "chemiluminescent group", as used herein, refers to a group that emits light as a result of a chemical reaction without the addition of heat. By way of example, luminol (5-amino-2,3-dihydro-1,4-phthalazinedione) reacts with oxidants such as hydrogen peroxide (H₂OR₂) in the presence of a base and a metal catalyst to produce a product in the excited state (3-aminophthalate, 3-APA).

The term chromophore, as used in the

<img file="MX360970B_D0509.tif" />

205

IMPI

INSTITUTE MBXlCiKNO

<td>Present,</td><td>I know</td><td>refers to a molecule that</td><td colspan="2">abSótbe</td><td>light</td><td>from</td>

<td>lengths</td><td colspan="2">visible wavelengths</td><td>from</td><td>wave</td><td>Uv</td><td>or</td>

<td>lengths</td><td>from</td><td>IR wave.</td><td></td><td></td><td></td><td></td>

<td colspan="2">The</td><td>coloring term, according to</td><td>I know</td><td>uses</td><td>on</td><td>the</td>

<td>Present,</td><td>I know</td><td colspan="2">refers to a coloring substance</td><td colspan="2">soluble</td><td>what</td>

contains a chromophore.

The term "electron dense group", as used herein, refers to a group that scatters electrons when irradiated with an electron beam. These groups include, but are not limited to, ammonium molybdate, bismuth subnitrate, cadmium iodide, carbohydrazide, ferric chloride hexahydrate, hexamethylenetetramine, anhydrous indium trichloride, lanthanum nitrate, lead acetate trihydrate, lead citrate trihydrate, lead, periodic acid, phosphomolybdic acid, phosphotungstic acid, potassium ferricyanide, potassium ferrocyanide, ruthenium red, silver nitrate, silver proteinate (Ag test: 8.0-8.5%) strong, silver tetraphenylporfin (S-TPPS), sodium chloroaurate, sodium tungstate, thallium nitrate, thiosemicarbazide (TSC), uranyl acetate, uranyl nitrate, and vanadyl sulfate.

The term "energy transfer agent", as used herein, refers to a molecule that either donates or accepts energy from another molecule. By way of example only, the transfer of energy by

ΙΜΡΙ ^&gt;

onft nn.A'wcwiRp »© tUD JwjusTRawi Fluorescence resonance (FRET) is a dipole-diplo coupling process whereby energy in the excited state of a fluorescence donor molecule is transferred non-radioactively to an unexcited receptor molecule which then emits fluorescently donated energy at a longer wavelength.

The term "heavy atom incorporating portion", as used herein, refers to a group incorporating atom bonding that is normally heavier than carbon. In some embodiments, these ions or atoms include, but are not limited to, silicon, tungsten, gold, lead, and uranium.

<td></td><td colspan="7">The term photoaffinity marker, as used</td>

<td>on the</td><td>Present,</td><td>I know</td><td>It refers to</td><td>a</td><td>. marker</td><td>with a group,</td><td>the</td>

<td>which,</td><td>after</td><td>the</td><td>exposition</td><td>to</td><td>light shape</td><td>a link with</td><td>a</td>

<td colspan="2">molecule for the</td><td colspan="3">which marker</td><td>has a</td><td>affinity.</td><td></td>

The term "photocaged portion", as used herein, refers to a group that, after illumination at certain wavelengths, binds covalently or non-covalently to other ions or molecules.

The term "photoisomerizable portion", as used herein, refers to a group in which after illumination with light it changes from one isomeric form to another.

The term radioactive portion, as used herein, refers to a group whose nuclei give rise

<img file="MX360970B_D0510.tif" />

207 spontaneously to nuclear radiation, such alpha, beta or gamma; where helium particles, beta particles are electrons

IMPIOUS

INSTITUTO MEXICANO DE LA PROPIEDAD INDUSTRIAL as alpha particles are nuclei and gamma particles are high-energy photons.

The term "centrifugal marker," as used herein, refers to molecules that contain an atom or group of atoms that exhibit an unpaired electronic centrifugation (i.e., a stable paramagnetic group) that in some embodiments are detected by resonance spectroscopy. electron centrifugation and in other embodiments are attached to another molecule. These centrifugal marker molecules include, but are not limited to, nitrile and nitroxide radicals and in some embodiments are single centrifugal labels or double centrifugal labels.

The term quantum dots, as used herein, refers to colloidal semiconductor nanocrystals that in some embodiments are detected on the near-infrared scale and have extremely high quantum fields (i.e., very bright after modest illumination).

One of ordinary skill in the art will recognize that a detectable moiety can be attached to a provided compound via a suitable substituent.

As used herein, the term substituent

IMPI

<img file="MX360970B_D0511.tif" />

208 "suitable" refers to a portion that is capable of covalent attachment to a detectable portion. These portions are well known to one of ordinary skill in the art and include groups containing, for example, a carboxylate portion, an amino portion, a thiol portion, or a hydroxyl portion, to name just a few. It will be appreciated that these moieties can be attached directly to a provided compound or through a linking moiety, such as a saturated or unsaturated hydrocarbon chain.

In some embodiments, the detectable moieties are attached to a provided compound by click chemistry. In some embodiments, these portions are linked by 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods for using simplified chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 5257. In some embodiments, a click ready inhibitory portion is provided and reacted with a -TR portion.^fc list for simplified chemistry. As used herein, "click ready" refers to a portion containing an azide or alkyne for use in a simplified chemistry reaction. In some modalities, the portion

IMPI

<img file="MX360970B_D0512.tif" />

209 simplified includes the -TR portion^fc list for a restricted cyclooctin inhibitory list for azide chemistry. In certain embodiments, simplified chemistry comprises for use in a simplified copper-free chemistry reaction (eg, using methods described in Baskin et al., Proc. Nati. Acad. Sci. USA 2007, 104, 16793-16797).

In certain embodiments, the simplified chemistry ready inhibitory portion is one of the following formulas:

<img file="MX360970B_D0513.tif" />

where ring A, ring B, W¹, W², R^Y, R^v, p, R^x, and m are as defined above with respect to formula I and are described herein, and q is 1, 2, or 3.

Ready Inhibitors for Simplified Chemistry

<img file="MX360970B_D0514.tif" />

210 specimens include:

<img file="MX360970B_D0515.tif" />

<img file="MX360970B_D0516.tif" />

In some embodiments, the -TR portion¹¹ list for simplified chemistry is of the formula:

<img file="MX360970B_D0517.tif" />

An exemplary reaction in which an inhibitory portion ready for simplified chemistry and a -TR portion^fc list for simplified chemistry bind via a [2 + 3] -cycloaddition is as follows:

<img file="MX360970B_D0518.tif" />

In some embodiments, the detectable portion, R^or,

MEXICAN INSTITUTE

OF TOOPIETY

INDUSTRIAL

<img file="MX360970B_D0519.tif" />

211 is selected from a marker, a dye, a photointerlacer, a cytotoxic compound, a drug, an affinity marker, a photoaffinity marker, a reactive compound, an antibody or antibody fragment, a biomaterial, a nanoparticle, a centrifugal marker, a fluorophore, a metal-containing moiety, a radioactive moiety, quantum dots, a novel functional group, a group that interacts covalently or non-covalently with other molecules, a photocaged portion, an actinic radiation excitable portion, a ligand, a photoisomerizable portion, biotin, a biotin analog (e.g. biotin sulfoxide), a portion incorporating a heavy atom, a chemically cuttable group, a photo-cuttable group, a redox-active agent, an isotopically-labeled portion, a biophysical probe, a phosphorescent group, a chemiluminescent group, an electron-dense group, a magnetic group, an intercalating group, a chromophore, an energy transfer agent, a biologically active agent, a detectable label, or a combination thereof.

In some modalities, R^fc it is biotin or an analog thereof. In certain modalities, R^fc it is biotin. In certain other modalities, R^t it is biotin sulfoxide.

In another mode, R^fc it is a fluorophore. In a further embodiment, the fluorophore is selected from dyes

212

IMPIC.e ^

INSTITUTO MEXICANO, ¡I

OF THE CURRENCY r

INDUSTRIAL -

Alexa Fluorine (Alexa Fluorine 350, Alexa FluorΤδ8, 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 493/503, 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, Dapoxy, Dialkylaminocoumarin, 4 ', 5'-dichloro-2', 7 'dimethoxy-fluorescein. DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IR Dyes (IRD40, IRD 700, IRD 800), JOE, Lysamine Rhodamine B, Navy 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-bromosulfon-fluorescein, Tetramethyl-Rhodamine (TMR), Carboxytetramethylrhodamine ( TAMRA), Texas Red, Texas Red-X, 5 (6) -carboxyfluorescein, 2,7-dichlorofluorescein, N, N-bis (2,4,6-trimethylphenyl) -3,4: 9,10perylenebis (dicarboximide, HPTS, ethyl eosin, DY-490XL MegaStokes, DY-485XL MegaStokes, Adirondack Green 520, ATTO 465 , ATTO 488, ATTO 495, YOYO-1,5-FAM, BCECF, Dichlorofluorescein, Rhodamine 110, Rhodamine 123, YO-PRO-1, SYTOX Green, Sodium Green, SYBR 1 Green, Alexa Fluorine 500,

IMPI

<img file="MX360970B_D0520.tif" />

213

FITC, Fluo-3, fluo-4, fluoro-emerald, YoYo-1 ssDNA, YoYo-1 dsDNA, YoYo-1, SYTO, RNASelect, Diversa-FP green, Dragon green, EvaGreen, Surf green EX, Espera green, NuroTrace 500525, NBD-X, MitoTracker Green FM, LysoTracker Green DND26, CBQCA, PA-GFP (post-activation), WEGFP (post-activation), FIASH-CCXXCC, Monomeric Azami Green, Azami Green, Green Fluorescent Protein (GFP), EGFP (Campbell Tsien 2003), EGFP (Patterson 2001), Kaede green, 7-benzylamino-4-nitrobenz-2 oxa-1,3-diazole, Bexl, doxorubicin, Lumio green and SuperGlo

GFP.

As generally described above, a probe compound provided comprises a binding moiety, -T-, that binds the irreversible inhibitor to the detectable moiety. As used herein, the term "linkage or linking portion" refers to any bivalent chemical spacer including, but not limited to, a covalent bond, a polymer, a water-soluble polymer, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl. , optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkylalkenylalkyl, a substituted amide portion

IMPI

<img file="MX360970B_D0521.tif" />

214 optionally, an ether portion, a ketone portion, an ester portion, an optionally substituted carbamate portion, an optionally substituted hydrazone portion, an optionally substituted hydrazine portion, an optionally substituted oxime portion, a disulfide portion, a optionally substituted imine portion, optionally substituted sulfonamide portion, sulfone portion, sulfoxide portion, a portion of thioether or any combination thereof.

In some embodiments, the linking portion, -T- is selected from a covalent bond, a polymer, a water soluble polymer, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted heterocycloalkylalkenyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocycloalkylalkenylalkyl. In some embodiments, the linking moiety is an optionally substituted heterocycle.

In other embodiments, the heterocycle is selected from aziridine, oxirane, episulfide, azetidine, oxetane, pyrroline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, pyrazole, pyrrole, imidazole, triazole, tetrazole, oxazole, isoxazole,

<img file="MX360970B_D0522.tif" />

215 oxiren, thiazole, isothiazole, dithiolane, furan, thiophene, piperidine, tetrahydropyran, thiano, pyridine, pyran, thiapyran, pyridazine, pyrimidine, pyrazine, piperazine, oxazine, thiazine, dithian and dioxane. In some embodiments, the heterocycle is piperazine. In additional embodiments, the linking moiety is optionally substituted with halogen, CN, -OH, -N0₂, alkyl, S (0) and S (0)₂. In other embodiments, the water soluble polymer is a PEG group.

In other embodiments, the binding portion provides sufficient spatial separation between the detectable portion and the protein kinase inhibitory portion. In additional embodiments, the binding portion is stable. In a further embodiment, the binding portion does not substantially affect the response of the detectable portion. In other embodiments, the binding portion provides chemical stability to the probe compound. In additional embodiments, the binding portion provides sufficient solubility to the probe compound.

In some embodiments, a binding portion, -T-, such as a water-soluble polymer is end-coupled to a provided irreversible inhibitor and a detectable portion, R¹, at the other end. In other embodiments, a water soluble polymer is coupled via a functional group or substituent of the provided irreversible inhibitor.

In additional embodiments, a polymer

IMPI

<img file="MX360970B_D0523.tif" />

216 Water soluble is coupled via a functional group or substituent on the reporter portion.

In some embodiments, examples of hydrophilic polymers, for use in the -T- linking portion, include but are not limited to: polyalkyl ethers and alkoxy end-blocked analogs thereof (eg, polyoxyethylene glycol, polyoxyethylene / propylene glycol , and methoxy or ethoxy-blocked analogs thereof, polyoxyethylene glycol, the latter is also known as polyethylene glycol or PEG); polyvinylpyrrolidones; polyvinyl alkyl ethers; polyoxazolines, polyalkyl oxazolines, and polyhydroxyalkyl oxazolines; polyacrylamides, polyalkyl acrylamides, and polyhydroxyalkyl acrylamides (eg, polyhydroxypropylmethacrylamide and derivatives thereof); polyhydroxyalkyl acrylates; polysialic acids and analogs thereof, hydrophilic peptide sequences; polysaccharides and their derivatives, including dextran and dextran derivatives, eg, carboxymethyldextran, dextran sulfates, aminodextran; cellulose and its derivatives, for example carboxymethyl cellulose; hydroxyalkyl celluloses; chitin and its derivatives, for example chitosan, succinyl chitosan, carboxymethylchitin, carboxymethylchitosan; hyaluronic acid and its derivatives; starches; alginates; Chondroitin Sulfate; albumin; pullulan and carboxymethyl pullulan; polyamino acids and derivatives

217

<img file="MX360970B_D0524.tif" />

thereof, for example, polyglutamic acids, polylysines, polyaspartic acids, polyaspartamides; maleic anhydride copolymers such as: styrene maleic anhydride copolymer, divinylethyl ether maleic anhydride copolymer; polyvinyl alcohols; copolymers thereof; terpolymers thereof; mixtures thereof, and derivatives of the above. In other embodiments, a water soluble polymer is any structural form including but not limited to linear, hairpin, or branched. In additional embodiments, multi-functional polymer derivatives include, but are not limited to, linear polymers having two terms, each term being attached to a functional group that is the same or different.

In some embodiments, a water soluble polymer comprises a poly (ethylene glycol) portion. In additional embodiments, the molecular weight of the polymer is over a wide range, including, but not limited to, between about 100 Da and about 100,000 Da or more. In further embodiments, the molecular weight of the polymer is between about 100 Da and about 100,000 Da, including but not limited to, about 100,000 Da, about 95,000 Da, about 90,000 Da, about 85,000 Da, about 80,000 Da, about 75,000 Da, about 70,000 Da, about 65,000 Da, about 60,000

<img file="MX360970B_D0525.tif" />

218

I<img file="MX360970B_D0526.tif" />ΡΙ ¢ 2 wíss w ·

INDUSTRIAL% tt¿

<td colspan="2">It gives, approximately 55,</td><td> 000</td><td>Da, around</td><td>from</td><td> 50,000</td><td>Gives,</td>

<td>approximately</td><td> 45,000</td><td>Gives,</td><td>around</td><td>from</td><td> 40,000</td><td>Gives,</td>

<td>approximately</td><td>35,000 Da</td><td> , 30,</td><td colspan="2">000 Day, around</td><td>of 25,000</td><td>Gives,</td>

<td>approximately</td><td> 20,000</td><td>Gives,</td><td>around</td><td>from</td><td> 15,000</td><td>Gives,</td>

<td>approximately</td><td> 10,000</td><td>Gives,</td><td>around</td><td>from</td><td> 9, 000</td><td>Gives,</td>

<td>approximately</td><td> 8,000</td><td>Gives,</td><td>around</td><td>from</td><td> 7,000</td><td>Gives,</td>

<td>approximately</td><td> 6,000</td><td>Gives,</td><td>around</td><td>from</td><td> 5,000</td><td>Gives,</td>

<td>approximately</td><td> 4,000</td><td>Gives,</td><td>around</td><td>from</td><td> 3,000</td><td>Gives,</td>

<td>approximately</td><td> 2,000</td><td>Gives,</td><td>around</td><td>from</td><td> 1,000</td><td>Gives,</td>

about 900 days, about 800 days, about 700 days, about 600 days, about 500 days, about 400 days, about 30 days, about 200 days, and about 100 days. In some embodiments, the molecular weight of the polymer is between about 100 Da and 50,000 Da. In some embodiments, the molecular weight of the polymer is between about 100 Da and 40,000 Da. In some embodiments, the molecular weight of the polymer is between about 1,000 Da and 40,000 Da. In some embodiments, the molecular weight of the polymer is between about 5,000 Da and 40,000 Da. In some embodiments, the molecular weight of the polymer is between about 10,000 and 40,000 Da. In some embodiments, the poly (ethylene glycol) molecule is a branched polymer. In additional embodiments, the molecular weight of branched-chain PEG is between about 1,000 Da and about 100,000.

<img file="MX360970B_D0527.tif" />

<img file="MX360970B_D0528.tif" />

<img file="MX360970B_D0529.tif" />

219

Gives, including but not limited to, approximately 100,000

Da, about 95,000 Da, about 90,000 Da, about 85,000 Da, about 80,000 Da, about 75,000 Da, about 70,000 Da, about 65,000

<td colspan="2">It gives, approximately 60,</td><td> 000</td><td>Da, around</td><td>from</td><td> 55,000</td><td>Gives,</td>

<td>approximately</td><td> 50,000</td><td>Gives,</td><td>around</td><td>from</td><td> 45,000</td><td>Gives,</td>

<td>approximately</td><td> 40,000</td><td>Gives,</td><td>around</td><td>from</td><td> 35,000</td><td>Gives,</td>

<td>approximately</td><td> 30,000</td><td>Gives,</td><td>around</td><td>from</td><td> 25,000</td><td>Gives,</td>

<td>approximately</td><td> 20,000</td><td>Gives,</td><td>around</td><td>from</td><td> 15,000</td><td>Gives,</td>

<td>approximately</td><td> 10,000</td><td>Gives,</td><td>around</td><td>from</td><td> 9,000</td><td>Gives,</td>

<td>approximately</td><td> 8,000</td><td>Gives,</td><td>around</td><td>from</td><td> 7, 000</td><td>Gives,</td>

<td>approximately</td><td> 6,000</td><td>Gives,</td><td>around</td><td>from</td><td> 5,000</td><td>Gives,</td>

<td>approximately</td><td> 4,000</td><td>Gives,</td><td>around</td><td>from</td><td> 3,000</td><td>Gives,</td>

<td>approximately</td><td>2,000 Da</td><td colspan="3">and about 1,000 Da.</td><td colspan="2">In some</td>

<td>modalities, the</td><td colspan="2">molecular weight</td><td>of a PEG of</td><td colspan="3">branched chain</td>

is between about 1,000

Da and about 50,000

Gives. In some embodiments, the molecular weight of a branched-chain PEG is between approximately 1,000 molecular around

Give and

<td>from</td><td>40,000 Da.</td><td>In some modalities,</td><td>the</td><td>weight</td>

<td>from</td><td>a PEG of</td><td>branched chain is</td><td>from</td><td>Come in</td>

<td>from</td><td>5,000 Day and</td><td>about 40,000</td><td>Gives.</td><td>On</td>

chain molecular weight of a PEG some embodiments, the branched is between approximately

5,000 Da and around 20,000 Da. The above list for substantially water soluble base structures for no reason is

<img file="MX360970B_D0530.tif" />

IMPI

220 It is exhaustive and merely illustrative, and in some embodiments, polymeric materials having the qualities described above are suitable for use in the methods and compositions described herein.

One of ordinary skill in the art will appreciate that when -TR * is attached to a compound of formula Ia or Ib via the head group R¹, then the resulting Union portion comprises the head group R¹. As used herein, the phrase "comprises a head group" means that the binding portion formed by -R^lz-T- of formula Va or Vb is either substituted with a head group or has this head group incorporated within the linking portion. For example, the binding portion formed by -R¹'-T- may be substituted with a head group -LY, where these groups are as described herein. Alternatively, the binding portion formed by -R¹'-T- has the suitable characteristics of a head group incorporated within the joint portion. For example, the binding portion formed by -R¹'-T- may include one or more unsaturation units and optional substituents and / or heteroatoms which, in combination, translate into a moiety that is capable of covalently modifying a protein kinase in accordance with the present invention. This junction portion -R¹-! '- illustrated below.

In some embodiments, a methylene unit of a

IMPI

<img file="MX360970B_D0531.tif" />

221 -R binding portion¹'-T- is replaced by a bivalent -LY'- moiety to provide a compound of formula Va-iii or Vb-xxx:

<img file="MX360970B_D0532.tif" />

Va-íw Vb-Hí where each of ring A, ring B, m, p, R^x, R^Y, R^v, W¹, W², T, L, Y 'and R^fc is as defined above and described in classes and subclasses herein and Y 'is a bivalent version of the group Y defined above and described in classes and subclasses herein.

In some embodiments, a methylene unit of a -R linking moiety¹'-!? - is replaced by a portion L (Y) - to provide a compound of the formula Va-xv or

Vb-XV:

<img file="MX360970B_D0533.tif" />

Va-iv

<img file="MX360970B_D0534.tif" />

where each ring A, ring B, m, p, R^x, R^Y, R^v, W¹, W², T, L, Y and R^fc it is as defined above and described in classes and subclasses herein.

<img file="MX360970B_D0535.tif" />

222

In some embodiments, a binding moiety is substituted with a LY moiety to provide a compound of the formula Vav or Vbv:

<img file="MX360970B_D0536.tif" />

Vbv

<img file="MX360970B_D0537.tif" />

where each of ring A, ring B, m, p, R^x, R^Y, R^v,

W¹, W², T, L, Y and R¹ it is as defined above and described in classes and subclasses herein.

has has has

In certain embodiments the joining portion, one of the following structures:

/'0'

0'

In some embodiments, the joining portion, the following structure:

Ό '

0‘ _N^

H

In other embodiments, the joining portion, the following structure:

H

-T-,

-T-,

-T-,

In certain other embodiments, the joining portion,

-T-, has the following structure:

IMPI

<img file="MX360970B_D0538.tif" />

223

<img file="MX360970B_D0539.tif" />

<img file="MX360970B_D0540.tif" />

In still other embodiments, the joining portion, -T-, has the following structure:

In some embodiments, the joining portion, -T-,

<img file="MX360970B_D0541.tif" />

In some modalities,

-TR^fc has the following structure:

OO

Η H

<img file="MX360970B_D0542.tif" />

-TR *³ have

In other modalities, the following

<img file="MX360970B_D0543.tif" />

<img file="MX360970B_D0544.tif" />

structure:

<img file="MX360970B_D0545.tif" />

224

<img file="MX360970B_D0546.tif" />

Formula Va, Vb, Vl-a, Vl-b, VH-a, or VH-b is derived from any compound in Table 5.

In certain embodiments, the probe compound is one of the following structures:

<img file="MX360970B_D0547.tif" />

Τ 3 '*

<img file="MX360970B_D0548.tif" />

1-366

1-367

<img file="MX360970B_D0549.tif" />

handle

IMPI

<img file="MX360970B_D0550.tif" />

<img file="MX360970B_D0551.tif" />

It will be appreciated that many -TR reagents^fc are commercially available. For example, numerous biotinylation reagents are available, for example, from Thermo Scientific with varying binding lengths. These reagents include NHS-PEG₄-Biotin and NHS-PEGi₂-Biotin.

In some embodiments, probe structures analogous to those exemplified above are prepared using inhibitory portions ready for simplified chemistry and -TR * portions ready for simplified chemistry, as described herein.

In some embodiments, a provided probe compound covalently modifies a phosphorylated conformation of a protein kinase. In one aspect, the phosphorylated conformation of the protein kinase is either a

1-- || lili m

227

IMPI

Mexican Institute of Industrial Property

<img file="MX360970B_D0552.tif" />

active or inactive form of protein kinase. In certain embodiments, the phosphorylated conformation of the protein kinase is an active form of the kinase. In certain embodiments, the probe compound is cell permeable.

In some embodiments, the present invention provides a method for determining the occupancy of a protein kinase by an irreversible inhibitor provided (i.e., a compound of formula Ia or Ib) in a patient, comprising providing one or more tissues, types of cells or a lysate thereof, obtained from a patient who was administered at least one dose of an irreversible inhibitor compound, contacting the cell, cell type or lysate thereof with a probe compound (i.e., a compound of the formula Va, Vb, Vl-a, Vl-b, VH-a, or Vll-b) to covalently modify at least one protein kinase present in the lysate and measure the amount of the protein kinase covalently modified by

<td>the compound of</td><td colspan="2">probe</td><td>in order to</td><td colspan="2">decide</td><td>the ocupation</td><td>from</td><td>the</td>

<td>protein kinase</td><td>for</td><td>the</td><td colspan="2">compound</td><td>of the</td><td>formula Ia or</td><td>Ib</td><td>on</td>

<td>compared to</td><td>the</td><td colspan="2">occupation</td><td>from</td><td colspan="2">protein kinase</td><td>for</td><td>the</td>

probe compound. In certain embodiments, the method further comprises the step of adjusting the dose of the compound of formula Ia or Ib to increase protein kinase occupancy. In certain other embodiments, the method further comprises the step of adjusting the dose of the compound,_r

228

<img file="MX360970B_D0553.tif" />

of formula Ia or Ib to reduce protein kinase occupancy.

As used herein, the terms "occupancy" refer to the degree to which a protein kinase is modified by a provided covalent inhibitory compound. One of ordinary skill in the art would appreciate that it is desirable to administer the lowest dose possible to achieve the desired efficient protein kinase occupancy.

In some embodiments, the protein kinase to be modified is BTK. In other embodiments, the protein kinase to be modified is EGFR. In certain embodiments, the protein kinase is JAK. In certain other embodiments, the protein kinase is one or more of ErbBl, ErbB2, or ErbB4. In still other embodiments, the protein kinase is TEC, ITK, or BMX.

In some embodiments, the probe compound comprises the irreversible inhibitor for which occupancy is being determined.

In some embodiments, the present invention provides a method of evaluating the efficacy of an irreversible inhibitor provided in a mammal, comprising administering an irreversible inhibitor provided to the mammal, administering a probe compound provided to isolated tissues or cells of the mammal, or a lysate. thereof, measure the activity of the detectable portion of the

<img file="MX360970B_D0554.tif" />

<img file="MX360970B_D0555.tif" />

229 probe compound and compare the activity of the detectable portion to a standard.

In other embodiments, the present invention provides a method of evaluating the pharmacodynamics of an irreversible inhibitor provided in a mammal, comprising administering an irreversible inhibitor provided to the mammal, administering a probe compound presented herein to one or more cell types, or a lysate thereof, isolated from the mammal, and measuring the activity of the detectable portion of the probe compound at different time points after administration of the inhibitor.

In still other embodiments, the present invention provides a method for in vitro labeling of a protein kinase, which comprises contacting the protein kinase with a probe compound described herein. In one embodiment, the step of incubating the protein kinase with a compound disclosed herein.

In certain embodiments, the present probe comprises protein kinase invention, which comprises contacting one or more

<td>cells or</td><td colspan="3">tissues, or a lysate thereof,</td><td colspan="2">that express the</td>

<td>protein</td><td>kinase with</td><td>a compound of</td><td>probe</td><td>described in</td><td>the</td>

<td>Present.</td><td></td><td></td><td></td><td></td><td></td>

In certain other embodiments, the present invention

<img file="MX360970B_D0556.tif" />

IMPI

INSTITUTO MEXICANO non ^{D £ W} PROPERTY

INDUSTRIAL provides a method for detecting a labeled protein kinase, which comprises separating proteins, the proteins comprising a protein kinase labeled by probe compound described herein, by electrophoresis and detecting the probe compound by fluorescence.

In some embodiments, the present invention provides a method for evaluating the pharmacodynamics of an irreversible inhibitor provided in vitro, comprising incubating the irreversible inhibitor provided with the target protein kinase, adding the probe compound presented herein to the target protein kinase, and Determine the amount of target modified by the probe compound.

In certain embodiments, the probe compound is detected by binding to avidin, streptavidin, neutravidin, or captavidin.

<td></td><td>On</td><td>some</td><td>modalities,</td><td>the probe</td><td>I know</td><td>detect</td><td>for</td>

<td>Western</td><td>Blot.</td><td colspan="3">In other modalities, the probe</td><td>I know</td><td>detect</td><td>for</td>

<td>ELISA.</td><td>On</td><td>certain</td><td>modalities,</td><td>the probe</td><td>I know</td><td>detect</td><td>for</td>

flow cytometry.

In other embodiments, the present invention provides a method of probing the kinome of irreversible inhibitors, which comprises incubating one or more cell types, or a lysate thereof, with a biotinylated probe compound to generate modified proteins with a

<img file="MX360970B_D0557.tif" />

<img file="MX360970B_D0558.tif" />

231 portion of biotin, digest the proteins, capture with avidin or an analog thereof, and perform multidimensional LC-MS-MS to identify probe compound-modified protein kinases and kinase adduction sites.

In certain embodiments, the present invention provides a method for measuring protein synthesis in cells, which comprises incubating cells with an irreversible inhibitor of the target protein, forming cell Uses at specific time points, and incubating the cell lysates with a probe compound of the invention to measure the appearance of free protein over an extended period of time.

In other embodiments, the present invention provides a method of determining a dosage schedule in a mammal to maximize the occupancy of a target protein kinase, comprising testing one or more cell types, or a lysate thereof, isolated from the mammal ( derived from, for example, splenocytes, peripheral B cells, whole blood, lymph nodes, intestinal tissue or other tissues) of a mammal to which a provided irreversible inhibitor of formula Ia or Ib was administered, wherein the test step comprises contacting the one or more tissues, cell types or a lysate thereof , with a probe compound provided

IMPI

<img file="MX360970B_D0559.tif" />

232 and measuring the amount of protein kinase covalently modified by the probe compound.

Exemplification

As illustrated in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods illustrate the synthesis of certain compounds of the present invention, the following general methods, and other methods known from

<td>someone</td><td>from</td><td>ability</td><td>ordinary</td><td>on</td><td colspan="2">technique, they can</td>

<td>apply</td><td colspan="2">to all</td><td>compounds</td><td colspan="2">and subclasses and species</td><td>from</td>

<td>each</td><td>from</td><td colspan="2">these compounds,</td><td>What</td><td>is described in</td><td>the</td>

<td>Present.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>The</td><td>numbers</td><td colspan="2">compound</td><td>used in</td><td>the</td>

The following examples correspond to the compound numbers shown in Table 5 above.

Example 1

Preparation of N- (3- (5-methyl-2- (phenylamino) pyimidin-4ylamino) phenyl) acrylamide 1-7

-TO

<img file="MX360970B_D0560.tif" />

1-7

233

The title compound was prepared according to

IMPI ^

INSTITUTO MEXICANO YT-éawlQ ​​DE LA PROPERTY CLjS industrial reaction schemes, stages and intermediates described below.

<img file="MX360970B_D0561.tif" />

minutes, minutes, temperature

C)

00 ° C, 10 minutes, MW;

A) DIPEA, n-BuOH, room 30 minutes.

Stage 1

<img file="MX360970B_D0562.tif" />

A solution of 1 (2.0 g, 0.012 mol), 1,3f enylenediamine (2.0 g, 0.018 minol), DIPEA (2.33 g, 0.018 mol) in n-BuOH (20 mL) was subjected to microwave irradiation at 120 ° C for 30 minutes. The reaction mixture was then quenched with water (100 mL), extracted with EtOAc (3x100 mL). The combined EtOAc extract was washed with water (100 mL), brine (100 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The residue obtained was further purified by column chromatography (SiO₂, 60-120

<img file="MX360970B_D0563.tif" />

IMPI

2. 3. 4 meshes, EtOAc / CHCl₃: 15/85) gave 3 (1.3 g, 45T) as a 'dark brown solid.

Stage 2

<img file="MX360970B_D0564.tif" />

<img file="MX360970B_D0565.tif" />

H

S

A solution of 3 (1.0 g, 4.27 mmol), 4 (1.5 g,

16.12 mmol) in NMP (10.0 mL) was subjected to microwave irradiation (200 ° C, 10 minutes). The reaction mixture was cooled, diluted with water (100 mL), and extracted with EtOAc (3x100 mL). The combined ethyl acetate extract was washed with water (100 mL), brine (100 mL), dried over Na₂SW₄ and concentrated under reduced pressure to give a residue. The crude residue was further purified by column chromatography (SiO₂, CHCl₃/ MeOH: 98/2) to give 5 (0.5 g, 40.3%) as a light brown solid.

Stage 3

<img file="MX360970B_D0566.tif" />

To a stirred solution of 5 (200 mg, 0.68 mmol)

235

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPERTY in NMP (2.0 mL) at 0 ° C acryloyl chloride (248 mg, 0.2.74 mmol) was added and the reaction mixture was stirred at 0 ° C for 60 minutes. The reaction mixture was then stirred with hexane for% hour and then the hexane was removed by decanting from the mixture and the residue was quenched with water (10 mL). The aqueous solution was pacified with saturated NaHCO solution₃ and then extracted with EtQAc (3x10 mL). The combined EtOAc extract was washed with water (10 mL), brine (10 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The obtained residue was further purified by column chromatography (S1Q2, 230-400,

MeOH / CHCl₃: 10/90) to give 1-7 (100 mg, 46.4%) as a brown solid. 'H NMR (EMSO-de) δ ppm: 2.10 (s, 3H), 5.73 (dd, 1.88 and 10.42 Hz, 1H), 6.24 (dd, &lt;7 = 1.88 and 17 Hz, 1H), 6.44 (dd, J = 10.08 and 16.92 Hz, 1H), 6.78 (t, J = 7.36 Hz, 1H), 7.06-7.11 (m, 2H), 7.26 (t, J = 8.08 Hz, 1H),

7.38-7.40 (bm, 2H), 7.65 (d, J = 8.52 Hz, 2H), 7.88 (s, 1H), 7.92 (s,

1H), 8.37 (s, 1H), 8.91 (s, 1H), 10.09 (s, 1H); LCMS: m / e 346.8 (M + 1).

Example 2

Preparation of N- (3- (4- (m-tolylamino) pyrimidin-2-

<img file="MX360970B_D0567.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described

IMPI

<img file="MX360970B_D0568.tif" />

236

<img file="MX360970B_D0569.tif" />

3 5

<img file="MX360970B_D0570.tif" />

A) DIEA, n-BuOH

110 ° C, 30 minutes microwave, B) NMP,

200 ° C, 10 minutes, microwave; C) acryloyl chloride, NMP, 0 ° C-30 minutes, room temperature 30 minutes.

Stage 1

<img file="MX360970B_D0571.tif" />

A solution of 1 (0.5 g, 3.35 mmol), m-toluidine (0.36 g, 3.35 mmol), DIEA (0.65 g, 5.0 mmol) in n-BuOH (2.0 mL) was subjected to microwave irradiation at 110 ° C for 30 min. The reaction mixture was then concentrated

<img file="MX360970B_D0572.tif" />

237 under reduced pressure, it was quenched with water (5 mL), extracted with

EtOAc (3x mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), dried over Na₂S0₄ concentrated under reduced pressure.

The obtained residue was further purified by mesh chromatography, as a yellow solid.

Stage 2

CHCl₃/ MeOH: 99/1)

<img file="MX360970B_D0573.tif" />

give column (SiO₂,

60-120 (0.4

54.2%) (0.2 g,

<img file="MX360970B_D0574.tif" />

(0.2 g

/ /

NMP (2.

<img file="MX360970B_D0575.tif" />

A solution

1.8 mmol) mL). 91 se mmol), subjected to microwave irradiation (200 ° C the reaction mixture was cooled, (10 mL) brine extract (5 min.). After it was diluted with water, it was extracted with CH₂C1₂ (3x15 mL).

with water (5

The mL), mL), were dried over Na₂SW₄ and under reduced pressure to obtain a crude residue was further purified by concentrated residue.

Column chromatography (SiO₂, CHC1₃/ MeOH: 9 8/2) and gave 5 (0.14 g,

53%) as a light yellow solid.

<img file="MX360970B_D0576.tif" />

238

Stage 3

<img file="MX360970B_D0577.tif" />

• r

0.25 nrnoles) in NMP

Acryloyl chloride (0.19 g, 2.0 turnol) was added to a stirred solution of 5 (0.075 (1.0 mL) at 0 ° C) and the reaction mixture was stirred at 0 ° C for 30 minutes followed by stirring at room temperature for 30 minutes The concentrated reaction mixture was subjected to purification by column chromatography (neutral AI2O3, CHCl₃/ MeOH: 98/2) to give 1-1 (0.04 g, 45%) as a white solid. ^TH NMR (EMSO-d ^) δ ppm: 2.56 (s, 3H), 5.71 (dd, J = 2.0 and 10.08 Hz, 1H), 6.20-6.25 (m, 2H), 6.45 (dd, J = 10.12 and 17.00 Hz, 1H), 6.78 (d, J = 7.52 Hz, 1H), 7.12-7.19 (m, 2H), 7.31 (d, J = 8.44 Hz, 1H), 7.46-7.53 (m, 3H), 7.87 (s , 1H), 7.99 (d, J = 5.76 Hz, 1H), 9.15 (s, 1H), 9.24 (s, 1H), 10.03 (s, 1H); LCMS: m / e 346.4 (M + 1).

Example 3

Preparation of N- (3- (5-methyl-4- (m-tolylamino) pyrimidin-2-

<img file="MX360970B_D0578.tif" />

1-2

IMPI

<img file="MX360970B_D0579.tif" />

239

The title compound was prepared according to the reaction schemes, steps and intermediates described

<img file="MX360970B_D0580.tif" />

A) DIPEA,

0 ° C-30 ambient temperature 30 min.

B) NMP,

MW; C) acryloyl chloride, n-BuOH, 110 ° C, 30 minutes;

200 ° C, 15 minutes,

<img file="MX360970B_D0581.tif" />

minutes,

Stage 1

<img file="MX360970B_D0582.tif" />

A solution of 1 (0.1 g,

0.613 mmol), 2 (0.066 g, 0.613 (2.0 mL) mmol), DIPEA (0.118 g, subjected to irradiation

0.919 mmol) in microwave to n-BuOH

110 ° C for 90 min.

The reaction mixture was cooled,

<img file="MX360970B_D0583.tif" />

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

240

<img file="MX360970B_D0584.tif" />

concentrated under reduced pressure and the obtained residue was further purified by column chromatography (SiO₂, methanol / chloroform mixtures) to give 3 (0.05 g, 34%) as an off-white solid.

Stage 2

<img file="MX360970B_D0585.tif" />

A solution of 3 (0.05 g, 0.213 mmol), 4 (0.046 g, 0.427 mmol in NMP (2.0 mL) was subjected to microwave irradiation (200 ° C, 15 minutes). After the reaction mixture was cooled, it was diluted with water (15 mL) and extracted with EtOAc (3x15 mL). The combined EtOAc extract was washed with water (10 mL), brine (10 mL), dried over Na₂SW₄ and concentrated under reduced pressure to give a residue. The crude residue was further purified by column chromatography (Si0₂, CHCl₃/ MeOH: 98/2) to give 5 (0.03 g, 46%) as a gray solid.

Stage 3

<img file="MX360970B_D0586.tif" />

1-2

IMPI

<img file="MX360970B_D0587.tif" />

241

Acryloyl chloride (0.073 g, 0.821 mmol) was added to a stirred solution of 5 (0.025 g, 0.082 mmol) in NMP (0.5 mL) at 0 ° C and the reaction mixture was stirred at 0 ° C for 30 minutes. followed by stirring at room temperature for 30 min. The crude reaction mixture was passed through an alumina column (mixtures of A1₂OR₃ neutral, chloroform / methanol) to give 1-2 (0.012 g, 41%) as a pale brown solid. ¹H NMR (DMSO-d₆) δ ppm: 2.10 (s, 3H), 2.27 (s, 3H), 5.72 (dd, J = 2 and 10.04 Hz, 1H), 6.22 (dd, J = 1.96 and 16.92 Hz, 1H), 6.45 (dd, J = 10.08 and 16.92 Hz, 1H),

6.83 (d, J = 7.36 Hz, 1H), 7.09 (t, J = 8.06 Hz, 1H), 7.17 (t, J = 7.78 Hz, 1H), 7.26 (d, J = 7.80 Hz, 1H), 7.47 (d, J = 1.08 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J = 8.60 Hz, 1H), 7.78 (s, 1H), 7.88 (s, 1H), 8.15 (s, 1H ), 9.01 (s, 1H), 9.99 (s,

1 HOUR); LCMS: m / e 360.1 (M + l).

Example 4

Preparation of N- (3- (5-fluoro-4- (m-tolylamino) pyrimidin-2-

<img file="MX360970B_D0588.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described

242

IMPI

Mexican wjwo ίΚίΑΜΜΜΕΟΛη wtoisium below.

<img file="MX360970B_D0589.tif" />

A) n-Butanol, DIPEA, 110 ° C, 45 minutes, MW; B) NMP,

200 ° C, 10 minutes, MW; C) NMP, DMAP, 0 ° C, 30 min.

Stage 1

<img file="MX360970B_D0590.tif" />

To a solution of 1 (0.5 g, 3 mmol) in n-butanol (5.0 mL) was added 2 (0.64 g, 0.6 mmol), DIPEA (0.116 g, 0.8 mmol) and the reaction mixture was irradiated under microwaves at 110 ° C for 45 minutes. It was cooled, quenched with water (50 mL), and extracted with EtOAc (2x25 mL).

<img file="MX360970B_D0591.tif" />

243

IMPI

MEXICAN WSTrnjTO

ΟείΛΜΟΗΚΟΑΟ

INDUSfittAL

<td>The extract from</td><td>EtOAc</td><td colspan="2">combined washed</td><td>with</td><td>water (2 5</td><td>mL),</td>

<td>brine (25 mL)</td><td>, I know</td><td>dried on</td><td>Na₂SW₄ Y</td><td>I know</td><td>concentrated</td><td>under</td>

<td>reduced pressure</td><td>in order to</td><td>give 3 (0.45</td><td>g, 63%)</td><td>what</td><td>took away</td><td>to</td>

next cap without further purification.

Stage 2

<img file="MX360970B_D0592.tif" />

A solution of 3 (0.45 g, 1.8 immoles) and 4 (0.41 g, 3.7 mmol) in NMP (4.5 mL) was subjected to microwave irradiation at 200 ° C for 10 min. It was cooled, diluted with water (25 mL) and extracted with

EtOAc (3x25 mL). The combined EtOAc extract was washed with water (2x25 mL), brine (25 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The obtained residue was further purified by column chromatography (SiO₂, 60-120, chloroform / ethyl acetate: 90/10) to give 5 (0.23 g, 41%) as a light yellow solid.

Stage 3

<img file="MX360970B_D0593.tif" />

To a stirred solution of 5 (0.075 g, 0.24 mmol)

IMPI

<img file="MX360970B_D0594.tif" />

244 In NMP (1.5 mL) at 0 ° C under a N2 atmosphere, T5FKP (0.059 g, 0.48 mmol) and acryloyl chloride (0.064 g, 0.725 mmol) were added and the reaction mixture was kept at this temperature.

<td colspan="2">for 30</td><td>min.</td><td colspan="4">It was quenched with water (7.5 mL)</td><td colspan="2">and it was extracted</td>

<td>with</td><td>EtOAc</td><td>(3x25</td><td>mL). The</td><td>abstract</td><td>from</td><td colspan="2">Combined EtOAc</td><td>He washed</td>

<td>with</td><td>5 of</td><td>acid</td><td>citric</td><td>(10 mL),</td><td colspan="2">water (2 x 10</td><td>mL),</td><td>brine</td>

<td> (10</td><td>mL),,</td><td colspan="2">dried on</td><td>Na₂SW₄ Y</td><td>I know</td><td>concentrated</td><td>under</td><td>Pressure</td>

<td colspan="2">reduced.</td><td>The</td><td>residue</td><td>raw</td><td>I know</td><td>purified</td><td>more</td><td>through</td>

<td colspan="2">chromatography</td><td>in column (A1₂OR₃,</td><td colspan="2">chloroform / methanol:</td><td> 98/2)</td>

<td>in order to</td><td>give 1-3</td><td>(0.01 g, 11.3%) as</td><td colspan="2">an off-white solid</td><td> . ^XH</td>

<td>NMR</td><td>(DMSO-de)</td><td>δ ppm: 2.27 (s, 3H),</td><td>5.72 (d, J = 9.84</td><td>Hz,</td><td>1 HOUR) ,</td>

<td> 6.22</td><td>(d, J =</td><td>16.92 Hz, 1H), 6.44</td><td>(dd, J = 10.2 and:</td><td colspan="2">17.02 Hz,</td>

<td>1 HOUR) ,</td><td>6.85 (d,</td><td>J = 7.12 Hz, 1H), 7.</td><td>12-7.19 (τη, 2H), 7</td><td> .29</td><td>(d, J</td>

<td> = 7.</td><td>68 Hz, 1H)</td><td>, 7.43 (d, J = 7.92</td><td>Hz, 1H), 7.61-7.63</td><td>(m,</td><td>2H),</td>

<td> 7.82</td><td>(s, 1H),</td><td>8.08 (s, 1H), 9.23</td><td>(bs, 2H), 10.03</td><td>(yes,</td><td>1 HOUR) ;</td>

<td>LCMS</td><td>: m / e 364.</td><td>2 (M + l).</td><td></td><td></td><td></td>

Example 5

Preparation of (E) -4- (dimethylamino) -N- (3- (5-fluoro-4- (mtolylamino) pyrimidin-2-ylamino) phenyl) but-2-enamide 1-4.

<img file="MX360970B_D0595.tif" />

<img file="MX360970B_D0596.tif" />

The title compound was prepared according to

IMPI

<img file="MX360970B_D0597.tif" />

245 the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0598.tif" />

A) n-Butanol, DIPEA, 110 ° C, 45 min, MW; B) NMP,

200 ° C, 10 minutes, MW; C) oxalyl chloride, CH₃CN,% hour at 0 ° C, 2 hours at 25 ° C, 5 minutes at 45 ° C; D) NMP, 0 ° C to 10 ° C, 30 minutes.

Stage 1

<img file="MX360970B_D0599.tif" />

A solution of 1 (0.5 g, 3.0 mmol), 2 (0.32 g,

3.0 mmol) in n-butanol (5.0 mL) was irradiated with

<img file="MX360970B_D0600.tif" />

246 microwave (110 ° C, 45 minutes). Water (50 mL) was cooled, ... iaagt.iv0. ~ Xxm.— extracted with EtOAc (2 x 25 mL). The combined EtOAc extract was washed with water (25 mL), brine (25 mL), dried over Na₂S0₄ and concentrated under reduced pressure to give 3 (0.45 g, 63%) which was carried to the next step without further purification.

Stage 2

<img file="MX360970B_D0601.tif" />

A solution of 3 (0.45 g, 1.8 mmol), 4 80.41 g,

3.7 mmol) in NMP (4.5 mL) was subjected to microwave irradiation (200 ° C, 10 minutes). It was cooled, diluted with water (25 mL), and extracted with EtOAc (3x25 mL). The combined ethyl acetate extract was washed with water (2x25 mL), brine (25 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO₂, chloroform / ethyl acetate: 90/10) to give 5 (0.23 g, 41%) as a light yellow solid.

Stage 3a

<img file="MX360970B_D0602.tif" />

COCI

<img file="MX360970B_D0603.tif" />

<img file="MX360970B_D0604.tif" />

247

To a stirred solution of 6 (0.13 g, 0.80 mmol) in CH₃CN (1.0 mL) was added oxalyl chloride (0.122 g,

0.96 mmol) at 0 ° C.

I read reaction mixture allowed to stir at

0 ° C for% hour and then at room temperature for 2

h. Finally it was heated at 45 ° C for 5 minutes, and the reaction mixture was further purified.

Stage 3

<td></td><td>TO</td><td>a</td>

<td>on</td><td>NMP (1.0</td><td>mL)</td>

<td>I know</td><td>shook</td><td>0 ° C</td>

<td>I know</td><td>inactive</td><td>with</td>

7 was added at 0 ° C.

got cold led to the next

<img file="MX360970B_D0605.tif" />

stirred solution of 5 for 30 minutes and to stage without

<img file="MX360970B_D0606.tif" />

(0.05 g, 0.16 mmol)

The mixture of

10 ° C during saturated bicarbonate solution with CH₂C1₂ (3x5 mL). The extract reaction min.

sodium (combined organic 5 washed over Na₂S0₄. The concentration by purification under reduced pressure followed by column chromatography (SIO2,

230-400, CHCla / MeOH, 95/5) gave

1-4 (0.02 g, 29.4%) as a white solid.

3H), 3.08 (bd,

6.67-6.74 (m, ^XH NMR (DMSO-ds)

J = 5.6 Hz, 2H)

1H), 6.86 (d, J δ ppm:

, 6.29

7.20

2.21 (s, 6H), (d, J = 15.60

2.28 (s,

Hz, 1H),

Hz, 1H), 7.12-7.20 (m,

248

IMPI

<img file="MX360970B_D0607.tif" />

<td colspan="2">2H), 7.27</td><td>(d,</td><td colspan="2">J = 8.00 Hz, 1H), 7.43</td><td>(d,</td><td>J »-8τθ« ···· Μζ;^Γ^ ΊΗΤ; ''</td>

<td> 7.62-</td><td> 7.64</td><td>(m,</td><td>2H), 7.82</td><td>(s, 1H), 8.08</td><td>(d,</td><td>J = 3.6 Hz, 1H),</td>

<td> 9.23</td><td>(yes,</td><td>1 HOUR) ,</td><td>9.24 (s,</td><td>1H), 9.96 (s,</td><td>1 HOUR)</td><td>; LCMS: m / e 421.2</td>

<td>(M + l)</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 6

Preparation of N- (3- (5-methyl-4- (phenylamino) pyrimidin-2ylamino) phenyl) acrylamide 1-5

<img file="MX360970B_D0608.tif" />

1-5

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0609.tif" />

A) DIPEA, n-BuOH, 110 ° C, 30 minutes, MW; B) NMP,

IMPI

<img file="MX360970B_D0610.tif" />

249

200 ° C, 15 minutes, MW; C) acryloyl chloride, NMP,

0 ° C-30 minutes, room temperature 30 minutes.

Stage 1 g, 1.226 (2.0 mL)

<img file="MX360970B_D0611.tif" />

A solution of 1 (0.1 g, 0.613 mmol), 2 mmol), DIPEA was subjected for 90 minutes.

concentrated under pressure by

La (0.114 (0.118 g, 0.919 mmol) in mixed microwave n-BuOH irradiation at

110 ° C reaction was cooled, reduced and converted to methanol / chloroform:

white solid.

Step 2 the residue was further purified on a column (SiO₂,

60-120,

1/9) to give 3 (0.08

<img file="MX360970B_D0612.tif" />

NH₂

A solution of 3 (0.08 g, 0.546 mmol) in NMP (2.0 mL) microwave cooled, was g, 0.364 (200 ° C, 15 minutes).

diluted with water (15 g, 59%) as a mmol), (0.059 was subjected to irradiation of

The reaction mixture was mL) and was extracted with EtOAc (3x15 mL). The combined ethyl acetate extract was washed i

<img file="MX360970B_D0613.tif" />

IMPI

250 with water (10 mL), brine (10 mL), dried over Na₂SW₄ and concentrated under reduced pressure to give a residue.

The crude residue was further purified by chromatography on

98/2) to give 5 (0.06

9 / column (SiO₂,

60-12 0, CHCl₃/ MeOH:

<td> 60%)</td><td>as a</td><td colspan="2">solid light gray.</td><td colspan="2">^XH NMR (DMSO-d₆) δ ppm:</td><td> 2.09</td>

<td>(yes,</td><td>3H), 4.74</td><td>(yes,</td><td>2H), 6.09-6.11</td><td>(m,</td><td>1H), 6.77-6.85 (m,</td><td>2H),</td>

<td> 6.91</td><td>(t, J =</td><td> 1.72</td><td>Hz, 1H), 7.02</td><td>(t,</td><td>J = 7.36 Hz, 1H),</td><td> 7.31</td>

<td>(t,</td><td>J = 7.52</td><td>Hz,</td><td>2H), 7.75 (d,</td><td>J =</td><td>7.68 Hz, 2H), 7.84</td><td>(yes,</td>

<td>1 HOUR) ,</td><td>8.18 (s,</td><td>1 HOUR) ,</td><td>8.65 (s, 1H);</td><td>LCMS</td><td>: m / e 293.2 (M + l).</td><td></td>

Stage 3

<img file="MX360970B_D0614.tif" />

agitated 5 (60

To a solution mg, 0.205 mmol) in

NMP (2.0 mL) at 0 ° C was added acryloyl chloride (0.148 g, 1.64 mmol) and the reaction mixture was stirred at 0 ° C for 30 min. Through a chloroform / methanol, the concentrated reaction mixture was transferred to an alumina column (A1₂OR₃ neutral,

99/1) to give 1-5 (0.013 g, 18.5%) as an off-white solid. ¹H NMR (DMSO-d₆) δ ppm: 2.11 (s, 3H),

<td> 5 .</td><td>72 (dd,</td><td>J = 1.92</td><td>and 10.04</td><td>Hz,</td><td>1 HOUR) ,</td><td> 6.22</td><td>(dd, J = 1</td><td> . 92</td><td>Y</td>

<td> 16</td><td>.92 Hz,</td><td>1H), 6.45</td><td>(dd, J =</td><td> 9.32</td><td>and 16</td><td>.92 Hz</td><td>, 1H), 7.00</td><td>(t,</td><td>J</td>

<td> =</td><td>7.28 Hz,</td><td>1H), 7.09</td><td>(t, J =</td><td> 8.04</td><td>Hz,</td><td>1H), 7</td><td>.23-7.30 (m,</td><td>3H)</td><td> !</td>

<img file="MX360970B_D0615.tif" />

251

7.43 (d, J = 8.04 Hz, 1H), 7.75-7.77 (m, 2H), 7.83 (s, 1H) TT'88 ~ Ts7

1H), 8.22 (s, 1H), 9.00 (s, 1H), 9.99 (s, 1H); LCMS: m / e 346 (M + 1).

Example 7 Preparation of N- (4-methyl-3- (5-methyl-4- (mtolylamino) pyrimidin-2-ylantino) phenyl) acrylamide 1-8

<img file="MX360970B_D0616.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0617.tif" />

<img file="MX360970B_D0618.tif" />

1-8

<img file="MX360970B_D0619.tif" />

252

A) DIPEA, n-BuOH, 120 ° C, minutes, MW; A ') (BOC)₂O, MeOH, -10 ° C, 4 hours; B)

Pd (OAc)₂, BINAP, Cs₂CO₃, toluene, 110 ° C, 12 hours; C) TFA,

CH₂C1₂,

0 ° C-30 minutes, room temperature 2 hours; D) acryloyl chloride, NMP,

0 ° C-30 minutes, room temperature

Stage 1'

NH (BOC)

<img file="MX360970B_D0620.tif" />

NH₂

To a stirred solution of

MeOH (75 mL) was added (BOC)₂Or slowly to -10 ° C. The reaction was for 4 hours and then under reduced pressure.

EtOAc (300 mL). Washed dried over Na₂SW₄. The

The with mix min.

A (5 (11.59 stirred residue

0.04 immoles) in

0.050 mmol), at this reaction temperature the concentrated obtained was collected in water (25 mL ·), brine (25 mL ·) and filtration followed by concentration under reduced pressure gave 4 (2.5 g, 27%) as an off-white solid.

Stage 1

<img file="MX360970B_D0621.tif" />

<img file="MX360970B_D0622.tif" />

253

<img file="MX360970B_D0623.tif" />

A solution of 1 (0.5 g, 3.06 minols), 2 (O. ~ 3.9 ~ g,

3.06 mmol), DIPEA (0.59 g, 4.5 mmol) in n-BuOH (5 mL) was subjected to microwave irradiation (120 ° C, 30 minutes). The reaction mixture was cooled, the solvents were removed under reduced pressure, and the residue obtained was quenched with water (5 mL). It was extracted with EtOAc (3 x 20 mL) and the combined EtOAc layer was washed with water (5 mL), brine (5 mL), and dried over Na₂SW₄. Filtration followed by concentration under reduced pressure gave a residue that was further purified by column chromatography (SiO₂, 60-120, CHCl₃/ MeOH: 9/1) to give 3 (0.35 g, 49%) as an off-white solid.

Stage 2

NH (BOC)

A solution of 3 (0.1 g, 0.43 mmol), 4 (0.14 g,

0.64 mmol), Pd (OAc)₂ (10 mg, 0.043 mmol), BINAP (0.013, 0.021 mmol) and Cs₂CO₃ (0.2 g, 1.06 mmol) in degassed toluene (toluene was purged with N₂ for 15 minutes) was refluxed for 2 hours under a N atmosphere₂. The reaction mixture was cooled and passed through a short pad of Celite.^and. The filtrate was diluted with EtOAc (25 mL) and washed with water (5 mL), brine (5 mL), and dried over

254

Na₂SW₄. Filtration followed by concentration under reduced pressure gave a residue that was further purified by column chromatography (SiO₂, 60-120, CHCl₃/ MeOH: 9/1) to give 5 (40 mg, 22%) as an off-white solid.

<img file="MX360970B_D0624.tif" />

Stage 3

To a stirred solution of 5 (0.04 g, 0.095 mmol) in CH₂C1₂ dry (2 mL) at 0 ° C CF was added₃COOH (0.2 mL, 5 vol) and the reaction mixture was kept at this temperature for 30 minutes. It was allowed to come to room temperature and stirred at this temperature for 2 hours. It was quenched with ice-cold water (2 mL), made basic with sodium carbonate solution, and extracted with EtOAc (2x10 mL). The combined EtOAc extract was washed with water (2 mL), brine (2 mL), and dried over Na₂SW₄. Filtration followed by concentration under reduced pressure gave 6 (22 mg, 73%) as a light brown solid.

Stage 4

1-8

255

To a stirred solution of 6 (0.2 g, 0.63 mmol

<img file="MX360970B_D0625.tif" />

on

NMP (4 mL) at 0 ° C was added acryloyl chloride (0.12 g, 1.25 mmol). The reaction was held at this temperature for 30 minutes and then at room temperature for 30 minutes. It was quenched with ice cold water (2 mL), and extracted with EtOAc (2x10 mL). The combined EtOAc extract was washed with water (2 mL), brine (2 mL), and dried over Na₂SW₄. Filtration followed by concentration under reduced pressure gave a residue that was further purified by column chromatography (SiO₂, 230-400, CHCl₃/ MeOH: 9/1) to give 1-8 (10 mg, 4%) as a white solid. ^ΧΗ NMR (DMSO-de) δ ppm: 2.07 (s, 3H), 2.13 (s, 6H), 5.70 (dd, J = 1.92 and 10.08 Hz, 1H), 6.20 (dd, J = 1.96 and 16.88 Hz, 1H ), 6.41 (dd, J = 10.16 and 16.96 Hz, 1H), 6.69 (d, J = 7.36 Hz, 1H), 6.98 (t, J = 7.76 Hz, 1H), 7.11 (d, J = 8.24 Hz, 1H ), 7.41 (q, J = 9.92 Hz, 1H), 7.49-7.51 (m, 2H), 7.73 (s, 1H), 7.80 (s, 1H), 7.97 (s, 1H), 8.16 (s, 1H) , 10.00 (s, 1H); LCMS: m / e 374 (M + 1).

Example 8

Preparation of N- (3- (4- (3-bromophenylamino) -5-methylpyrimidin2-ylamino) phenyl) acrylamide 1-9

Br

1-9

<img file="MX360970B_D0626.tif" />

IMPI

256

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0627.tif" />

A) DIPEA, n-butanol,

110 ° C, 1 hr, MW; B) 1.5 N HC1, ethanol, 90 ° C, 30 minutes, MW; C) acryloyl chloride, NMP,

0 ° C, 30 min.

Stage 1

<img file="MX360970B_D0628.tif" />

A solution of 1 (0.5 g, 3.06 mmol), 2 (0.53 g,

3.06 mmol) and DIPEA (0.80 mL, 4.06 mmol) in n-butanol (5 mL) was subjected to microwave irradiation (110 ° C, 1 hour).

257

IMPIAS

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL

The reaction mixture was cooled and concentrated under reduced pressure to give a residue. The residue was taken up in EtOAc (5 mL) and washed with NaHCO solution₃ (2 mL), water (2 mL) and with brine solution (2 mL). Drying over Na₂SW₄followed by concentration under reduced pressure offered crude 3 which was further purified by column chromatography (SiO₂, 60-120, chloroform / methanol, 9/1) to give 3 (0.125 g, 13%) as a brown solid.

Stage 2

<img file="MX360970B_D0629.tif" />

To a solution of 3 (0.15 g, 0.5 mmol) in EtOH (3 mL) was added 4 (0.081 g, 0.75 mmol) followed by 1.5 N HCl (0.055 g, 1.5 mmol). The reaction mixture was subjected to microwave irradiation (90 ° C, 30 min), cooled and concentrated under reduced pressure. The residue obtained was taken up in EtOAc (5 mL) and washed with NaHCO solution₃ (2 mL), water (2 mL), and brine (2 mL). It was dried over Na₂SW₄, filtered and concentrated under reduced pressure to give crude 5. It was further purified by column chromatography (SiO_2/ 60120, chloroform / methanol, 9/1) to give 5 (0.06 g, 32%) as a light brown solid.

IMPI

<img file="MX360970B_D0630.tif" />

258

Stage 3

<img file="MX360970B_D0631.tif" />

To a stirred solution of 5 (0.06 g, 0.16 mmol) in NMP (1 mL) was added acryloyl chloride (0.17 g, 1.29 mmol) at 0 ° C. The reaction mixture was allowed to stir at this temperature for 30 minutes and was then taken up in dichloromethane (2 mL). Washed with NaHCO solution₃ (1 mL), water (1 mL), and brine solution (1 mL). It was dried over Na₂SW₄, filtered and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO₂, 60-120, chloroform / methanol, 9/1) to give 1-9 (0.016 g, 23%) as a pale brown solid. ¹H

<td>NMR</td><td colspan="2">(DMSO-d₆)</td><td colspan="2">δ ppm: 2.16 (s, 3H),</td><td> 5.75</td><td>(dd,</td><td>J = 1.72</td>

<td>and 10</td><td>Hz,</td><td>1 HOUR)</td><td>, 6.2 3 (dd, J =</td><td> 1.76</td><td>and 16</td><td> . 88 ,</td><td>Hz, 1H),</td>

<td> 6.45</td><td>(dd,</td><td>J</td><td>= 10.08 and 16.92</td><td>Hz,</td><td>1 HOUR) ,</td><td> 7.22</td><td>-7.34 (m,</td>

<td>4H),</td><td> 7.38</td><td>(d,</td><td>J = 8.00 Hz, 1H)</td><td> , 7 .</td><td>63 (d,</td><td>J =</td><td>: 8.08 Hz,</td>

<td>1 HOUR) ,</td><td> 7.77</td><td>(yes,</td><td colspan="2">1H), 7.82 (s, 1H),</td><td> 7.93</td><td>(yes,</td><td>1H), 9.68</td>

<td>(yes,</td><td>1 HOUR) ,</td><td colspan="2">10.26 (s, 1H), 10.34</td><td>(yes,</td><td>1 HOUR) ;</td><td>LCMS</td><td>: m / e 426</td>

(M + l).

IMPI

<img file="MX360970B_D0632.tif" />

259

Example 9

Preparation of 3- (4- (2- (cyclopropylsulfonyl) -l, 2,3,4-tetrahydroisoquinolin-6-ylamino) -5-methylpyrimidin-2ylamino) benzenesulfonamide 1-10

<img file="MX360970B_D0633.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described

<img file="MX360970B_D0634.tif" />

1-10

260

A ') DDPA

<img file="MX360970B_D0635.tif" />

Benzyl alcohol, Et₃N toluene

110'C, 12 hours; B ') Pd (OH)₂, ammonium formate,

EtOH, reflux, 6 hours; A) DIPEA, n-BuOH, 120 ° C, 1 hour, MW; B) 1.5N HCl, EtOH, reflux 12 hours; C) cyclopropylsulfonyl chloride,

DIPEA

THF room temperature, 12 hours.

The procedure for synthesizing structure 7 is described in the experimental section for compound 1-11 herein.

Stage 5

<img file="MX360970B_D0636.tif" />

1-10

To a stirred solution of 7 (0.05 g, 0.0121 mmol) in THF (4 mL) at 0 ° C, DIPEA (0.023 g, 0.182 mmol) was added followed by cyclopropylsulfonyl chloride (0.031 g, 0.182 mmol) under an atmosphere of N₂ . The reaction mixture was allowed to come to room temperature and was kept at this temperature for 12 hours. It was taken up in EtOAc (10 mL), washed with water (5 mL), brine (5 mL), and dried over Na₂SW₄.

Filtration followed by

261

<img file="MX360970B_D0637.tif" />

Concentration under reduced pressure yielded a residue that was further purified by column chromatography (SiO₂, 60-120, pet ether / ethyl acetate, 6/4) to give 1-10 (0.035 g, 56%) as a yellow solid. ^ΧΗ NMR (DMSO-dg) δ ppm: 0.97-0.1.00 (m, 4H), 2.12 (s, 3H), 2.60-2.66 (m, 1), 2.90 (t, J = 5.2 Hz, 2H), 3.52 (t, J = 6 Hz, 2H), 4.42 (s, 2H), 7.16 (d, J = 8.4 Hz, 1H), 7.27 (s, 2H), 7.31-7.35 (m, 2H), 7.53 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 8.03-8.04 (m, 2H), 8.45 (S, 1H), 9.40 (s, 1H); LCMS: m / e 515 (M + 1).

Example 10

Preparation of 3 - (4 - (2- (2-chloroacetyl) -1,2,3,4-tetrahydroisoquinolin-6-ylamino) -5-methylpyrimidin-2 i lamino) benzenesulfonamide I-11

to.

.N

1-11

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

262

IMPI

<img file="MX360970B_D0638.tif" />

ZBCHN

<img file="MX360970B_D0639.tif" />

SW₂NH₂ hours;

110 ° C,

A ') DPPA,

B ') Pd (OH)₂, ammonium formate, EtOH, benzyl alcohol, Et₃N

SW₂NH₂ reflux, 6 hours; TO)

DIPEA, n-BuOH, 120 | C, 1 hour, MW; B)

HC1 1.5 N,

EtOH, reflux 12 hours; C) C1-CH₂-COC1, Et₃N, THF, room temperature, 12 hours.

Stage 1

<img file="MX360970B_D0640.tif" />

To a stirred solution of 1 (1.5 g, 5.4 mmol) in toluene (15 mL) was added DPPA (2.17 g, 8.11 mmol), Et₃N (1.05 mL, 8.11 mmol) and benzyl alcohol (0.876 g, 8.11 mmol) under N₂. The reaction mixture was allowed to reflux for 12 hours, cooled and diluted with acetate.

<img file="MX360970B_D0641.tif" />

263 dried over Na₂SO4.

<img file="MX360970B_D0642.tif" />

IMPI

MEXICAN INSTITUTE

OF THE INDUSTRIAL PROPERTY of ethyl (100 mL). Brine (5 mL) and

It was filtered and concentrated under reduced pressure and the residue was purified by column chromatography (SiO₂,

60-120, chloroform / methanol,

9/1) to give 2 (2.0 g, 97%) as a white solid.

Stage 2

H₂N

<img file="MX360970B_D0643.tif" />

xBOC

To a stirred solution of 2 (2.2 g, 5.75 mmol) in

EtOH (25 mL) was added to ammonium formate (3.68 g, 57.5 mmol) and the reaction mixture was refluxed for 6 hours. It was cooled, filtered, and the filtrate was collected under reduced pressure to give 3 (1.3 g, 91%) as a dark brown oil which was used without further purification.

Stage 3

<img file="MX360970B_D0644.tif" />

„BOC

A solution of 3 (1.4 g, 5.56 mmol), (0.912 g.

5.56 mmol) and DIPEA (1.077 g, 8.3 mmol) in n-BuOH (15 mL) was subjected to microwave irradiation at 120 ° C for 45

IMPI

<img file="MX360970B_D0645.tif" />

264 minutes. The reaction mixture was cooled and concentrated under reduced mp-eALOfT. The residue was taken up in ethyl acetate (20 mL) and washed with water (5 mL) and brine (5 mL). -Drying over Na₂SW₄ followed by concentration under reduced pressure yielded a residue which was purified by column chromatography (SiO₂, 60-120, chloroform / methanol, 9/1) to give 5 (1.1 g, 52%) as a cream colored solid.

Stage 4

<img file="MX360970B_D0646.tif" />

To a stirred solution of 5 (0.25 g, 0.66 mmol) in ethanol (5 mL) was added 6 (0.126 g, 0.73 itmoles) and a catalytic amount of aqueous HCl, and the reaction mixture was refluxed for 12 hours. at 100 ° C. It was cooled, the precipitated solid was filtered and washed with diethyl ether and dried under high vacuum to give 7 (0.24 g, 82%) as a light yellow solid.

Stage 5

<img file="MX360970B_D0647.tif" />

SW₂NH₂

1-11

<img file="MX360970B_D0648.tif" />

INSTITUTO MEXICANO t DE LA PROPERTY ir INDUSTRIAL, ·. '

265

To a stirred solution of 7 (0.2 g, 0.487 mmol) in NMP (5 mL) was added Et₃N (0.094 g, 0.731 mmol). The solution was cooled to 0 ° C - and chloroacetyl chloride (0.082 g, 0.731 mmol) was added. The reaction mixture was allowed to come to room temperature and stirred at this temperature for 12 hours. It was quenched with ice-cold water (2 mL) and extracted with ethyl acetate (3x5 mL). The combined ethyl acetate extract was washed with brine solution (2 mL), dried over Na₂SW₄ anhydrous, filtered and concentrated under reduced pressure. The obtained residue was further purified by column chromatography (SiQz, 60-120, chloroform / methanol, 9/1) to give 1-11 (0.038 g, 16%) as a light yellow solid.^ΧΗ NMR (DMSO-de) δ ppm: 2.11 (s, 3H), 2.77-2.89 (m, 2H), 3.70-3.72 (m, 2H), 4.49 (d, J = 2.92 Hz, 2H), 4.63 (d , J = 23.56 Hz, 2H), 7.15-7.17 (m, 1H), 7.24 (s, 2H), 7.30-7.3 (m, 2H), 7.50-7.65 (m, 2H), 7.91 (s, 1H), 8.04-8.05 (m, 2H), 8.27 (s, 1H), 9.31 (s, 1H), LCMS: m / e 486.8 (MfT).

Example 11

Preparation of N- (3- (5-methyl-4- (4-phenoxyphenylamino) pyrimidine-

2-ylamino) phenyl) acrylamide 1-23

<img file="MX360970B_D0649.tif" />

<img file="MX360970B_D0650.tif" />

1-23

<img file="MX360970B_D0651.tif" />

266

The title compound was prepared acueiilu

<img file="MX360970B_D0652.tif" />

the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0653.tif" />

A) DIPEA, n-butanol, 100 ° C, 1 hour, MW: B) concentrated HCl n-BuOH, 160 ° C, 20 minutes, MW: C) acryloyl chloride 0 ° C, room temperature, 1 hour.

Stage 1

<img file="MX360970B_D0654.tif" />

A solution of 1 (0.2 g, 1.2 mmol), 2 (0.12 g,

0.95 mmol) and DIPEA (0.23 g, 1.78 mmol) in n-BuOH (2 mL) was subjected to microwave irradiation (100 ° C for 1 hour).

After the reaction mixture was cooled, concentrated under reduced pressure, and the residue was taken up in EtOAc (5 mL). Washed with NaHCO solution₃ (2 mL), water (2 mL), brine (2 mL) and then dried over Na₂SW₄ anhydrous. It was concentrated under reduced pressure followed by purification by column chromatography (SiO₂,

60-120

267

<img file="MX360970B_D0655.tif" />

chloroform / methanol, 9/1) to give 3 (0.11 g, 28.9%) as a light brown solid.

Stage 2

Ph .O

<img file="MX360970B_D0656.tif" />

To a solution of 3 (0.11 g, 0.3 mmol), 4 (0.114 g, 1.05 mmol) in n-butanol (1 mL) was added concentrated HC1 (1 drop) and the mixture was subjected to microwave irradiation (165 ° C for 10 minutes). The reaction mixture was cooled, concentrated under reduced pressure, and the residue was taken up in EtOAc (5 mL). Washed with NaHCO solution₃ (2 mL), water (2 mL), and brine (2 mL). Drying over Na₂SW₄followed by concentration under reduced pressure yielded a residue which was purified by column chromatography (SiO₂, 60-120, chloroform / methanol, 9/1) to give 5 (0.08 g,

65%) as a solid brown.

Stage 3

<img file="MX360970B_D0657.tif" />

1-23

268

To a stirred solution of 5 (0.015 g, 0.03 mmol)

<img file="MX360970B_D0658.tif" />

In NMP (1 mL) acryloyl chloride (0.005 g, 0.05 mmol) was added at 0 ° C. The reaction mixture was allowed to come to room temperature and was kept at this temperature for 1 hour. It was diluted with dichloromethane (2 mL) and washed with NaHCO solution.₃ (1 mL), water (1 mL), and brine (1 mL).

Drying over Na₂S0₄ followed by concentration under reduced pressure yielded a residue that was further purified by column chromatography (SiO₂, 60-120, chloroform / methanol, 9/1) to give 1-23 (0.004 g, 23%) as a brown solid. 400 MHz, MeOD: δ 2.14 (s, 3H), 5.71 (d, J = 11.20 Hz, 1H), 6.306.44 (m, 2H), 6.94-6.99 (m, 4H), 7.07-7.15 (m, 2H ), 7.22 (d,

J = 7.2 Hz, 1H), 7.34-7.36 (m, 3H), 7.63 (d, J = 8.8 Hz, 2H),

7.79 (S, 2H); LCMS: m / e 437 (M + 1).

Example 12

Preparation of N- (3- (5-methyl-2- (3-sulfamoylphenylamino) pyrimidin-4-ylamino) phenyl) acrylamide 1-33

1-33

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

269

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0659.tif" />

B) HCI 1.5

DIPEA, n-BuOH temperature

100 ° C, hour.

Stage 1 (0.49

A solution

9 / of 1 (0.5 g,

3.06 mmol), ambient, 1.0 °

N, ethanol,

<img file="MX360970B_D0660.tif" />

4.59 mmol) and DIPEA (0.59 g, 4.59 mL) was irradiated for minute mmol) in n-butanol (8 microwaves (120 ° C, minutes). It was cooled, quenched with water (5 mL) and extracted with acetate of ethyl (3x20 mL) The combined ethyl acetate layer was washed with brine solution (5 mL), dried over Na₂S0₄, filtered and concentrated under reduced pressure. The residue was further purified by column chromatography (SiO₂, 60-120, chloroform / ethyl acetate, 9/1) to give 1 (0.25 g, 34.77%) as a light brown solid.

IMPI

<img file="MX360970B_D0661.tif" />

270

Stage 2

To a

<img file="MX360970B_D0662.tif" />

stirred mmol) in ethanol

0.42 mmol) and one (2 mL), catalytic quantity (0.1 g, 0.48 of heated at 100 ° C during

The reaction mixture was then cooled, solid, g, as such is mmol) which was crude),

Stage 3 was then stirred, filtered and washed which brought to the (0.070 g,

HC1 1.5 N hours.

separated the following with ether 5 (0.1 step

A in acryloyl NMP (0.037

<img file="MX360970B_D0663.tif" />

mL) chloride of this is /

hour, room temperature for

0.425 mmol)

<img file="MX360970B_D0664.tif" />

and then the reaction mixture was quenched with water (4

271

IMPI

<img file="MX360970B_D0665.tif" />

mL) and basified with NaHCO3, this was extracted with S pyreis ^ "with ethyl acetate (5 mL), the combined organic layer was washed with brine solution (1 mL), dried over

Na₂SW₄ anhydrous, filtered and then concentrated.

The off-white preparative crude.

in order to

7.26-7.43 (m, 5H), give

NMR and

was then purified using HPLC

<td>1-33 (0.07 g,</td><td> 6%)</td><td>What</td><td colspan="2">a solid</td>

<td>(MeOD) δ ppm:</td><td> 2 . 17</td><td>(yes,</td><td colspan="2">3H), 5.78</td>

<td>.52 Hz, 1H),</td><td colspan="2"> 6.34-6.48</td><td>(m,</td><td>2H),</td>

<td>7.87 (s, 1H),</td><td colspan="2"> 7.96-8.03</td><td>(m,</td><td>3H);</td>

LCMS: m / e 425 (M + l)

Example

Preparation of N- (3- (methy 1 (5-methy1-2 (phenylamino) pyrimidin-4-yl) amino) phenyl) acrylamide I34

<img file="MX360970B_D0666.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

272

WICKED

MEXICAN INSTITUTE 'J'-, 9

OF THE PROPERTY X * w ». 'J INDUSTRIAL

<img file="MX360970B_D0667.tif" />

hours; B) NaH, CH₃I,

THF,

0 ° C-30 minutes, room temperature 16 hours; C) aniline, concentrated HCl, ethanol, 90 ° C, minutes; D) H₂,

Pd / C, ethanol, 16 hours; E) acryloyl chloride

NMP,

0 ° C, 1 hour.

Stage 1

<img file="MX360970B_D0668.tif" />

To a stirred solution of 2 (1.0 g, 6.0 mmol), in toluene (30.0 mL) was added 1 (0.84 g, 6.0 mmol), BINAP (0.186 g, 0.3 mmol), Cs₂CO₃ (4.87 g, 15.0 mmol). The reaction mixture was degassed by purging with N₂ during 15 minutes. Then Pd (OAc) was added₂ (0.134 g, 0.6 mmol) to the reaction mixture and the reaction mixture heated to

100 ° C for 16 hours under N atmosphere₂.

He cooled

<img file="MX360970B_D0669.tif" />

273

IMPI «Nsmirro MEXICANO DE LA PROPERTY industrial

<img file="MX360970B_D0670.tif" />

then, it was diluted with ethyl acetate (30 mL) and filtered through CeUte®. The filtrate was washed with water (2x25 mL), brine (25 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The obtained residue was further purified by column chromatography (SiO₂, 60-120 mesh, ethyl acetate / hexane: 10/90) to give a solid which was washed with ether to give 3 (0.6 g, 37%) as a light yellow solid.

Stage 2

<img file="MX360970B_D0671.tif" />

To a stirred mixture of NaH (0.1 g, 2.5 mmol, 60% dispersion in paraffin oil) in dry THF (10.0 mL) was added 3 (0.5 g, 1.89 mmol) at 0 ° C, and the reaction mixture stirred at this temperature for 30 min. CH was added₃I (0.305 g, 2.15 mmol) and the reaction was allowed to come to room temperature and stir at this temperature for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x25 mL). The combined EtOAc extract was washed with water (25 mL), brine (25 mL), dried over Na₂SW₄ and concentrated under reduced pressure to give a residue. The crude residue was further purified by column chromatography (SiO₂CHCl₃/ MeOH: 99/1) to give 4

<img file="MX360970B_D0672.tif" />

IMPI

274 (0.12 g, 22.7%) as a light yellow solid.

Stage 3

<img file="MX360970B_D0673.tif" />

Concentrated HC1 (0.044 g, 1.2 mmol) and aniline (0.16 g, 1.72 mmol) were added to a solution of 4 (120 mg, 0.431 mmol) in EtOH (2 mL ·) and the reaction mixture was heated in a tube. pressure sealed at 90 ° C for 1 hour. The reaction mixture was cooled, the solvents were removed by concentration under reduced pressure and the residue obtained was diluted with 10% NaHCO₃ (10.0 mL). It was extracted with EtOAc (3x15 mL) and the combined EtOAc extract was washed with water (15 mL), brine (15 mL), dried over Na₂SW₄. Concentration under reduced pressure gave a residue which was further purified by column chromatography (SiO₂, CHCl₃/ MeOH: 99/1) to give 5 (0.11 g, 76%) as a light yellow solid.

Stage 4

<img file="MX360970B_D0674.tif" />

A solution of 5 (0.110 g, 0.328 mmol), in

<img file="MX360970B_D0675.tif" />

275 ethanol (50 mL)) 10% palladium on carbon (0.022 g) was added and the reaction mixture was stirred under an atmosphere of H₂ (1.5 Kg) at room temperature for 16 hours. Filter through Celite and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, 60-120, methanol / chloroform: 1/99) to give 6 (0.07 g, 69.9%) as a colorless viscous liquid.

Stage 5

<img file="MX360970B_D0676.tif" />

H

1-34

To a stirred solution of 6 (0.070 g, 0.23 mmol) in MP (1.5 mL) at 0 ° C was added acryloyl chloride (0.083 g, 0.916 mmol) and the reaction mixture was stirred at 0 ° C for 1 hour . It was quenched with 10% sodium bicarbonate solution (15 mL) and the precipitated solid was filtered, washed with cold water (5 mL), hexane (5 mL). The solid was dried for 2 hours under reduced pressure to give 1-34 (0.033 g, 40%) as a pale yellow solid.¹H NMR (DMSO-d₆) δ ppm: 1.47 (s, 3H), 3.45 (s, 3H), 5.74 (dd, J = Hz, 1H), 6.22 (dd, J = 2.0 and 16.98 Hz, 1H), 6.38 (dd, J = 10 and 16.94 Hz, 1H), 6.85-6.91 (m, 2H), 7.21-7.25 (m, 2H), 7.32 (t, J = 8.02 Hz, • yl

276

IMPI

MEXICAN INSTITUTE OF INDUSTRIAL PROPERTY

<img file="MX360970B_D0677.tif" />

1H), 7.43-7.47 (m, 2H), 7.77-7.79 (m, 2H), 7.90 (s, 1H), 9.22 (s, 1H), 10.18 (s, 1H); LCMS: m / e 360.8 (M + l).

Example 14

Preparation of N- (3- (5-methyl-2- (3- (prop-2yloxy) phenylamino) pyrimidin-4-ylamino) phenyl) acrylamide 1-35

<img file="MX360970B_D0678.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0679.tif" />

<img file="MX360970B_D0680.tif" />

<img file="MX360970B_D0681.tif" />

<img file="MX360970B_D0682.tif" />

1-35

277

<img file="MX360970B_D0683.tif" />

A) K₂CO₃, CH₃CN, 65 ° C, 8 hours; B) —dust — of — Fev

NH₄C1, MeOH, H₂O, 80 ° C, 4 hours; C) 1,3-phenylenediamine, DIPEA, n-BuOH, 120 ° C, 30 minutes, MW; D) concentrated HCl, absolute ethanol, 110 ° C, 2 hours; E) NMP, 0 ° C, 1 hour.

Stage 1

<img file="MX360970B_D0684.tif" />

To a stirred solution of the (4 g, 0.0287 mol) and K₂CO₃ (5.6 g, 0.0574 mole) in CH₃CN (15 mL) was added propargyl bromide (4.1 g, 0.0345 mol) and the resulting mixture was allowed to reflux for 8 hours. The reaction mixture was then cooled, quenched with water, and extracted with EtOAc (3x50 mL). The combined EtOAc extract was washed with water (20 mL), brine (20 mL), and dried over Na₂SW₄. Filtration stirred for concentration under reduced pressure gave 2b as a brownish solid which was used without further purification.

Stage 2

<img file="MX360970B_D0685.tif" />

NH was added to a stirred solution of 2b in a mixture of methanol (30 mL) and water (30 mL).₄C1 (10.3 g, 0.194 mol) and iron powder (6.8 g, 0.121 mol) respectively. The resulting mixture was refluxed at

IMPI

<img file="MX360970B_D0686.tif" />

278

80 ° C for 4 hours. The reaction mixture was cooled, diluted with methanol, and filtered through a pad of Celite.¹. The filtrate was concentrated under reduced pressure and the residue was taken up in EtOAc. Washed with water, brine, dried over Na₂S0₄ and concentrated under reduced pressure to give a residue. The residue was further purified by column chromatography (Si02, 60-120, gravity column chromatography, the expected product was eluted with CHCl₃/ MeOH: 96/4) to give 3 (3.2 g, 91%) as a brownish solid.

Stage 3

<img file="MX360970B_D0687.tif" />

A pyrimidine solution of 2,4-dichloro-5-methyl (0.3 g, 0.0018 mol), 1,3-phenylenediamine (0.24 g, 0022 mol), DIPEA (0.35 g, 0.0027 mol) in n-BuOH (3 mL ) was subjected to microwave irradiation (120 ° C, 30 minutes). The reaction mixture was cooled, quenched with water (15 mL), and extracted with EtOAc (3x15 mL). The combined EtOAc extract was washed with water (20 mL), brine (20 mL), dried over Na₂S0₄ and concentrated under reduced pressure. The obtained residue was further purified by column chromatography (SiO₂, 60-120) to give 2 (0.15 g, 35%) as a solid or

279

IMPI

<img file="MX360970B_D0688.tif" />

brownish.

Stage 4

<img file="MX360970B_D0689.tif" />

(0.15 g, 0.006 moles) AND 3 (0.37 g, 0.0025 moles) They were taken in a pressure tube and to this absolute EtOH (3 mL) were added followed by concentrated HC1 (0.04 g, 0.0012 moles). The tube was screwed tight and heated at 120 ° C for 2 hours. The reaction mixture was then cooled, the solvents were removed under reduced pressure, and the obtained residue was taken up in EtQAc (10 mL). It was washed with water (4 mL), NaHCCh (4 mL), and brine (5 mL). Drying over Na2SO4 followed by concentration under reduced pressure gave a residue that was further purified by column chromatography (SiO₂, 60-120, gravity column chromatography, the expected compound was eluted in CHC ^ / MeOH: 94/6) to give 4 (125 mg, 56%) as a light brown solid.

Stage 5

<img file="MX360970B_D0690.tif" />

<img file="MX360970B_D0691.tif" />

1-35

IMPI

<img file="MX360970B_D0692.tif" />

280

To a stirred solution of 4 (0.1 g, 0.002 mol) in MP (8 mL) was added acryloyl chloride (0.1 g, 0.001 mol) dropwise at 0 ° C. The reaction was kept at this temperature for 10 minutes and then allowed to come to room temperature and stirred at this temperature for 1.5 hours. It was then quenched with 10% sodium bicarbonate solution (8 mL) and extracted with EtOAc (2 x 15 mL). The combined EtOAc extract was washed with water (10 mL), brine (10 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The residue obtained was purified by column chromatography (S02, 60-120, gravity column chromatography, the expected compound was eluted in CHCl₃/ MeOH: 90/10) to give 1-35 (20 mg, 18%) as an off-white solid. '' 'H NMR (DMSO-dJ δ ppm: 2.11 (s, 3H), 3.51 (s, 1H), 4.61 (s, 2H), 5.74 (d, J = 9.08 Hz, 1H), 6.25 (d, J = 15.84 Hz, 1H), 6.45 (s, 2H), 7.02 (s, 1H), 7.27-7.45 (m, 5H), 7.91 (d, J = 8.84 Hz, 2H), 8.36 (s, 1H), 8.93 (s, 1H), 10.09 (s, 1H), LCMS: m / e 400 (M + 1).

Example 15

Preparation of (E) -4- (dimethylamino) -N- (3- (5-methyl-2 (phenylamino) pyridimidin-4-ylamino) phenyl) but-2-enamide 1-38

<img file="MX360970B_D0693.tif" />

1-38

281

The title compound was prepared according to the reaction schemes, steps below.

INSTITUTO MEXICANO V. DE LA PROPERTY \ INDUSTRIAL X intermediaries described

HOOC

<img file="MX360970B_D0694.tif" />

minutes

B) NMP,

A) n-BuOH, from oxalyl,

DIEA, minutes,

MW; C)) chloride

200 ° C, minutes hour.

mmol), submitted

CH₃CN, 3 0 to 0 ° C, 2 hours

Stage 1

A solution at 25 ° C, 5 minutes at 45 ° C,

<img file="MX360970B_D0695.tif" />

of 1

DIPEA (2.33 g, 18 minutes.

(100 mL), (2.0 g, 12 mmol), mmol) in n-BuOH

D)

NMP, 0 ° C, (2.0 g, (20.0 mL) was microwave irradiated at 120 ° C for

The reaction mixture was extracted with EtOAc

Combined EtOAc was washed with water then quenched with water (3x100 mL). The extract from (100 mL), brine (100 mL), was dried over Na₂S0₄ and concentrated under reduced pressure. The

IMPI

<img file="MX360970B_D0696.tif" />

282 The residue obtained was further purified by column chromatography (SiO₂, 60-120 mesh, EtOAc / CHCl₃: 15/85) to give (1.3 g,

45%) as a dark brown solid.

Stage 2

A solution

16.12 mmol) in microwave NMP (200 ° C, reaction was cooled, with EtOAc (3x100 mL) with water (100 mL), concentrated under crude residue column (SiO₂,

40.3%) as a se

<img file="MX360970B_D0697.tif" />

<img file="MX360970B_D0698.tif" />

of 3 (1.0 g, 4.27 mmol), 4 (1.5 (10 mL) se minutes).

was diluted with

The extract subjected to irradiation

After mixing water (10 0 mL) and combined EtOAc brine (100 mL), dried over

9, from extracted was washed

Na₂SW₄ and reduced pressure to give a residue.

further purified by chromatography

60-120, CHCl₃/ MeOH: 98/2) to give a light brown solid.

Stage 2'

CIOC

The in (0.5

9,

To a stirred solution in CH₃CN (1.0 mL) was added from 6 '(70 mg chloride, 0.42 mmol oxalyl) (8 0 mg,

0.62 mmol) at 0 ° C. The reaction mixture was allowed to stir at

IMPI

<img file="MX360970B_D0699.tif" />

283 room temperature for 2 to 45 ° C for 5 minutes, it was carried to the next stage

0 ° C for% hour and then hours. Finally, the reaction mixture was heated and cooled without further purification.

<img file="MX360970B_D0700.tif" />

<img file="MX360970B_D0701.tif" />

1-38

To a stirred solution of 5 (75 mg, 0.12 mmol) in NMP (1 mL) was added 6 at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour, quenched with cold water (5 mL), basified with Et₃N and extracted with CH₂C1₂ (3x10 mL). The combined organic extract was washed with water (5

<td colspan="2">mL), brine (5 mL)</td><td>and</td><td>dried on</td><td>Na₂SW₄ .</td><td>The</td>

<td>concentration</td><td>under</td><td>Pressure</td><td>reduced</td><td>followed</td><td>for</td>

<td>purification</td><td>on gel</td><td colspan="2">silica (60-120)</td><td>using</td><td>5 of</td>

Methanol in chloroform gave the crude compound (20 mg) as a brown gummy solid, which was taken up again in dichloromethane and stirred with 10% bicarbonate solution for 30 minutes, the dichloromethane layer separated, dried over Na₂SW₄ and concentrated to give 1-38 (8mg, 17%) as a brown solid. ¹H NMR (DMSO-d₆) δ ppm:

IMPI

<img file="MX360970B_D0702.tif" />

284

2.15 (s, 3H), 2.32 (s, 6H), 3.21 (d, J = 5.76 Hz, 2H),

6.27 (d, J = 15.36 Hz, 1H), 6.84-6.93 (m, 2H), 7.14 (t, J = 7.52 Hz, 2H), 7.27-7.33 (m, 2H), 7.44 (d, J = 2.04 Hz , Y

5.08 Hz, 1H), 7.53 (d, J = 7.72 Hz, 2H), 7.80 (s, 1H),

8.00 (s, 1H); LCMS: m / e 402.8 (M + 1).

Example 16

Preparation of N- (4- (5-methyl-2- (phenylamino) pyrimidin-4ylamino) phenyl) acrylamide 1-39

<img file="MX360970B_D0703.tif" />

The title compound was prepared according to the reaction schemes, steps and intermediates described below.

<img file="MX360970B_D0704.tif" />

A) DIPEA, n-BuOH,

110 ° C, 45 minutes, MW; B) concentrated HC1 n-BuOH, 150 ° C, minutes, MW; C) acryloyl chloride, NMP, 0 ° C-30 minutes, room temperature, 2 hours.

<img file="MX360970B_D0705.tif" />

285

IMPI

<img file="MX360970B_D0706.tif" />

Stage 1

A solution of 1 (0.4 g, 2.4 mmol), 2 (0.3

2.6 mmol), DIPEA (0.46 g, 3.6 mmol) in n-BuOH (10 mL) was subjected to microwave irradiation (110 ° C, 45 minutes).

The reaction mixture was cooled, quenched with water (20 mL), extracted with EtOAc (3x15 mL).

The combined EtOAc extract was washed with water (20 mL), brine (20 mL), dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂,

60-120,

CHCl₃/ MeOH: 99/1) to give 3 (350 mg, 62%) as an off-white solid.

Stage 2

A solution

<img file="MX360970B_D0707.tif" />

(0.2 g, 0.8 mmol),

4 (0.63 g,

6.8 mmol) and concentrated HC1 (0.03 g, 0.8 mmol) (10 mL) was subjected to microwave irradiation in n-BuOH (150 ° C, 10 minutes). After the reaction mixture was cooled, diluted with water (10 mL), made basic with sodium bicarbonate solution

286

IMPI

MEXICAN INSTITUTE

OF THE PROPERTY

INDUSTRIAL sodium al

10% and extracted with EtOAc (3x15

The combined EtOAc extract was washed with brine water concentrated under reduced pressure.

The crude residue was purified by column chromatography (SiO₂,

60-120,

CHCl₃/ MeOh: 97/3) to give (110 mg, 47%) as a brown gummy solid.

Stage 3

<img file="MX360970B_D0708.tif" />

To a stirred solution of 5 (0.06 g, 0.2 mmol) in NMP (2 mL) was added acryloyl chloride (0.03 g, 0.3 mmol) at 0 ° C. It was allowed to stir at the same temperature for minutes and then at room temperature for 2 hours.

The reaction mixture was quenched with water, made basic with 10% sodium bicarbonate solution, and extracted with EtOAc (3x10 mL). The combined EtOAc layer was washed with water (10 mL), brine (10 mL), dried over Na₂SW₄ and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, 60

120) and finally by preparative HPLC to give I-

<img file="MX360970B_D0709.tif" />

<img file="MX360970B_D0710.tif" />

287

9 (10 mg, 16%) as an off-white solid.

^XH NMR (DMSO-d₆) δ ppm: 2.10

3H), 5.71-5.76 (dd,

J 2.04 and

16.96

Hz,

1H), 6.45 (dd,

10.08 and

16.92

Hz, 1H), (t,