RS52291B

Cyclic protein tyrosine kinase inhibitors

Abstract

Use of a compound of formula IV or a salt thereof: for the manufacture of a medicament for the oral treatment of cancer, wherein the cancer is chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), acute myelogenous leukemia (AML), mastocytosis, germ cell tumor, small-cell carcinoma lung cancer (SCLC), melanoma, pancreatic cancer, prostate cancer or pediatric sarkom.Prijava further comprises 13 claims.

RS52291B, drawing sheet 1 — Sheet 1 of 215

Term

Term ended

Expired 23 March 2024, 2.5 years ago.

13 claims: 3 independent, 10 dependent

1
Patent claims Patentni zahtevi 1. Use of a compound of formula IV or a salt thereof:for the manufacture of a medicament for the oral treatment of cancer, wherein the cancer is chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), acute myelogenous leukemia (AML), mastocytosis, germ cell tumor, small cell cancer lung (SCLC), melanoma, pancreatic cancer, prostate cancer or pediatric sarcoma. 1. Primena jedinjenja formule IV ili njegove soli: za proizvodnju leka za oralni tretman kancera, pri čemu je kancer hronična mijelogena leukemija (CML), gastrointestinalni stromalni tumor (GIST), akutna mijelogena leukemija (AML), mastocitoza, tumor germinativnih ćelija, kancer malih ćelija pluća (SCLC), melanom, kancer pankreasa, kancer prostate ili pedijatrijski sarkom.
7
Use of a compound of formula IV or a salt thereof:7. Primena jedinjenja formule IV ili njegove soli: for the manufacture of a medicament for the oral treatment of cancer, wherein the cancer is resistant to STI571. za proizvodnju leka za oralni tretman kancera, pri čemu je kancer otporan na STI571.
8
The compound of formula IV or a salt thereof:8. Jedinjenje formule IV ili njegova so: for use in the oral treatment of cancer, wherein the cancer is chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), acute myelogenous za primenu u oralnom tretmanu kancera, pri čemu je kancer hronična mijelogena leukemija (CML), gastrointestinalni stromalni tumor (GIST), akutna mijelogena 195 195 52291Β leukemia (AML), mastocytosis, germ cell tumor, small cell lung cancer (SCLC), melanoma, pancreatic cancer, prostate cancer or pediatric sarcoma. 52291Β leukemija (AML), mastocitoza, tumor germinativnih ćelija, kancer malih ćelija pluća (SCLC), melanom, kancer pankreasa, kancer prostate ili pedijatrijski sarkom.

Independent claims3

1,699 paragraphs in 138 sections, as filed

Field of the invention

The present invention relates to cyclic compounds and their salts. to methods of administering such compounds in the treatment of disorders associated with protein tyrosine kinase, such as immunological and oncological disorders, as well as to pharmaceutical compositions containing such compounds.

The basis of the invention

Protein tyrosine kinases (PTKs) are enzymes that. together with ATP as a substrate. perform phosphorylation of tyrosine residues in peptides and proteins. These enzymes are key elements in the regulation of cell signaling, including cell proliferation and cell differentiation. PTKs contain, among other things, receptor tyrosine kinases (RPTKs). including members of the epidermal growth factor kinase family (e.g., HER1 and HER2). platelet-derived growth factor (PDGF), as well as kinases that play a role in angiogenesis (Tie-2 and KDR): in addition, also non-receptor tyrosine kinases, including members of the Syk, JAK and Src families (e.g. Src, Fyn, Lyn, Lck, and Blk) (see Bolen. JB, Rowley, RB, Spana. C., and Tsygankov, Α.Υ .. The src family of tyrosine protein kinases in hematopoietic signal transduction, FASEB J., 6.3403-3409 (1992); Ullrich, A. and Schlessinger.1. Signal transduction by receptors with tyrosine kinase activity, Cell. 61, 203-212 (1990); i Ihle. J.N.. The Janus protein tyrosine kinases in hematopoetic cytokine signaling. Sem. Immunol.. 7.247-254 (1995)).

Increased activity of PTKs is involved in a large number of different malignant and non-malignant proliferative diseases. In addition, PTKs play a central role in the regulation of immune system cells. PTK inhibitors can thus have an impact on a large number of different oncological and immune disorders. The health status of patients with such disorders can be improved by the use of selective inhibitors of certain receptors or non-receptor PTK. such as Lck. or due to homology among PTK classes. by inhibiting more than one PTK using an inhibitor.

52291B

ΡΤΚ Of particular interest to us is Lck which is found in T cells where it is involved in the phosphorylation of major protein substrates. It is required for abundant signaling of antigen receptors and activation of cells. In the absence of Lck activity. zeta chain T cell receptor (TCR) is not phosphorylated, ZAP-70 kinase is not activated. and Ca mobilization does not occur2+ koja je neophodna za aklivaciju T ćelija (pogledati Weiss. A. and Littman. D.R.. Signal transduction by lymphocyte antigen receptors. Cell. 16263-274 (1994); hvashima. M„ Irving, B.A., van Oers, N.S.C., Chan. A.C., and Weiss. A„ Sequential interactions of the TCR with two distinct cvtoplasmic tyrosine kinases. Science. 263.1136-1139 (1994): i Chan, A.C.. Dalton. M.. Johnson. R„ Kong. G.. Wang. T.. Thoma. R.. and Kurosaki. T.. Activation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor function, EMBO J .. 14. 2499-2508 (1995)). Lck inhibitors are therefore useful in the treatment of T cell-mediated disorders. such as chronic diseases with a significant T cell component, for example. rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases for which T cells are known to play a major role. for example acute transplant rejection and delayed-type hypersensitivity reactions (DTH).

Summary of the invention

The present invention provides cyclic compounds of the following formula 1 and salts thereof. for use as a protein tyrosine kinase inhibitor:

indicated by

Q you:

(1) 5-membered heteroaryl ring:

(2) a 6-membered heteroaryl ring; or (3) an aryl ring:

52291Β optionally substituted with one or more groups R1;

Z is:

(1) single bond;

(2) -RI5C = CH <ili (3) - (CH2)m-. where m is 1 to 2;

each X] and X2 is hydrogen. or together form = 0 or = S; Ri is:

(1) hydrogen or R6.

wherein Ib is alkyl, alkenyl. alkynyl, cycloalkyl. cycloalkylalkyl. cycloalkenyl. cycloalkenylalkyl. aryl, aralkyl. heterocycle. or heterocycloalkyl. wherein each is unsubstituted or substituted with Z 1. With2 and one or more (preferably one or two) groups Z3;

(2) -OH ili-OR6:

(3) -SH ili -SR6;

(4) -C(0)2H. -C(0)qR6 or-OC (O)qR6. where q is 1 or 2:

(5) -SO3H ili-S (O)qR6;

(6) halo;

(7) cyano;

(8) nitro;

(9) -Z4-NR7R8 ;

(10) -Z4-N (R9) -Zs-NRioRi i;

(11) -Z4-N(Ri2)-WITH5-R6;

(12) -P(O)(OR6)2:

R2 i R3 independently are:

(1) hydrogen or R6;

(2) -Z4-R6; or (3) -Z13-NR7R8;

R4 i R?:

(1) independently are hydrogen or R <,;

(2) -Z4-N (R9) -Z5-NRi0R11;

(3) -N (R9) Z4R6: or (4) together with the nitrogen atom to which they are attached form a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z 1. Z2 and Z3. wherein the heterocyclic ring may. as needed. to have for itself a fused benzene ring which is itself unsubstituted or substituted with Z1. With2 and Z3:

52291B

R-7- R8, R9, R10, R | 1 i Ri ?:

(1) each is independently hydrogen or R6:

(2) R7 i R8 may together form alkylene. alkenylene or heteroalkyl. building a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached. wherein said ring is unsubstituted or substituted with Z ,. Z2 and Z3; or (3) any two groups of Ry, R 10 and R 11 may together form an alkylene or alkenylene, forming a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, wherein such ring is unsubstituted or substituted with Z |, Z2 and Z3;

R | zje:

(1) cyano;

(2) nitro;

(3) -NH2;

(4) -NHOalkil;

(5) -OH;

(6) -NHOaril;

(7) -NHCOOalkil;

(8) -NHCOOaril;

(9) -NHSO2alkil;

(10) -NHSO2aril;

(11) aril;

(12) heteroaryl;

(13) -Oalkyl; or (14) -Oaryl;

Ri4is:

(1) -NO2;

(2) -COOalkyl; or (3) -COOaryl;

Ri5 is:

(1) hydrogen;

(2) alkil:

(3) aril:

(4) arylalkyl: il (5) cycloalkyl:

Z|. Z2 and Z3 independently are:

52291Β (1) hydrogen or Z („wherein Z <, (i) alkyl. Alkenyl. Alkynyl. Cycloalkyl. Cycloalkylalkyl. Cycloalkenyl. Cycloalkenylalkyl. Aryl. Aralkyl. Alkylaryl. Cycloalkylaryl. Heterocyclo or heterocycloalkyl; (ii) group i which is itself substituted by one or more of the same or different groups (i), or (iii) group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z 1. With2 and Z3;

(2) -OH or -OZ6;

(3) -SH i!i-SZ6;

(4) -C(O)qH, -C(O)qWITH6 or -OC (O)qWITH6;

(5) -SO3H. -S(O)qWITH6 ili S (O)qN(Z9)WITH6:

(6) halo:

(7) cyano;

(8) nitro;

(9) -Z4-NZ7WITH8;

(10) -Z4-N(Z9)-WITH5-NZ7WITH8;

(11) -Ζ4-Ν (Ζ10) -Ζ5-Ζ6;

(12) -Z4-N(Z10)-WITH5-H;

(13) oxo;

(14) -O-C(O)-Z6;

(15) any dxwithand groups from Z ,. FROM2 and Z3 may together form alkylene or alkenylene. building a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or (16) any two groups of Z 1, Z2 and Z3 can together form -O- (CH2)r-O-. wherein r is 1 to 5, building a 4- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

WITH4 and Z3 independently are:

(1) single bond;

(2) -ZH-S(O)q-WITHl2-:

(3) -Z |] -C (O) -Zi2-;

(4) -Zn-C (S) -Z12-:

(5) -Ζ ,, - 0-Ζ ,, -;

(6) -Zi iSZ)2-:

(7) -Zn-OC (O) -Z12-: ili (8) -Z) jC (O) -OZ12-:

WITH7. WITH8. WITH9 and Zjo:

52291 Β (1) are independently hydrogen or Zfti (2) Z7 and Ζχ. or Z 1, and Z 10, may together form an alkylene or alkenylene, forming a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, wherein such ring is unsubstituted or substituted with Z]. Z7 and Z3: or (3) Z7 or ili, together with Z9. may be alkylene or alkenylene forming a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms attached. wherein such a ring is unsubstituted or substituted with Z 1, Z2 and Z3;

Zii and Z] 2 are independently:

(1) single bond;

(2) alkylene;

(3) alkenylene; il (4) alkynylene; I

Z13 you:

(1) j single bond;

(2) -Zn-SCOVZio-;

(3) -Zn-C (O) -Zi2-;

(4) -Zn-C (S) -Z12-;

(5) -Z,i-O-Zl2-;

(6) -Zn-SZ ,, -;

(7) -Zn-OC (O) -Zl2-:

(8) -Zh-C (O) -OZ2-;

(9) -C(NR|3)-;

(10) -C (CHR|4) -; ili (11) -C (C (R14)2)-.

Compounds of formula 1 include compounds of the following formula II and their salts:

indicated by

52291 Β η is 1 or 2;

A is selected from carbon or nitrogen;

B is selected from nitrogen. oxygen and sulfur: Hz is oxygen or sulfur; and

Ri, R2, R> R4 and R5 are as described above.

Detailed description of the invention

The following is a definition of the terms used in this specification. The initial definition given for a group or term. here refers to that group or term throughout this specification. individually or as part of another group. unless otherwise indicated.

The terms alk or alkyl refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms. preferably 1 to 8 carbon atoms. The term lower alkyl refers to alkyl groups of 1 to 4 carbon atoms.

The term alkenyl refers to straight or branched chain hydrocarbon groups of 2 to 10. preferably 2 to 4 carbon atoms. which have at least one double bond. Where the alkenyl group is attached to a nitrogen atom. it is preferred that such a group not be attached directly via a carbon bearing a double bond.

The term alkynyl refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms, having at least one triangular bond. Where the alkynyl group is attached to a nitrogen atom. preferably such a group is not attached directly via a carbon bearing a triple bond.

The term "alkylene" refers to a straight chain bridge of 1 to 5 carbon atoms attached by single bonds (eg .- (CH2)X- wherein χ is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

The term "alkeniler" refers to a straight chain bridge of 2 to 5 carbon atoms. which has one or two double bonds that are bound by single bonds. which may be substituted with 1 to 3 lower alkyl groups. Examples of alkenylene groups are -CH = CH-CH = CH-. -CH2CH = CH-, -SNJ-SN = SN-SN2-. -C (CH3)2CH = CH- and -CH (C2H?)-CH=CH-,

The term alkynylene refers to a straight chain bridge of 2 to 5 carbon atoms having a triple bond bound by single bonds. which may be substituted with 1 to 3 lower alkyl groups. Examples of alkynylene groups are -C = C-. -CH2-C = C-. -CH (CH3) -C = C- i C = C-CH (C2H5) CH2-.

52291B

The terms ar or aryl refer to aromatic cyclic groups (for example 6-membered unicyclic, 10-membered two-cyclic or 14-membered tricyclic ring systems) containing 6 to 14 carbon atoms. Examples of aryl groups include phenyl. naphthyl, biphenyl and anthracene.

The terms cycloalkyl and cycloalkenyl refer to cyclic hydrocarbon groups of 3 to 12 carbon atoms.

The terms halogen and halo refer to fluorine. chlorine, bromine and iodine.

The term -'unsaturated ring includes partially unsaturated and aromatic rings.

The terms heterocyclic or heterocyclo refer to fully saturated or unsaturated, including non-aromatic (i.e. heterocycloalkyl) and aromatic (i.e. heteroaryl) cyclic groups. for example, 4 to 7-membered unicycles. 7 to 11-membered two-cyclic or 10 to 15-membered tricyclic ring systems. having at least one heteroatom in at least one ring of carbon atoms. Each ring of a heterocyclic group containing a heteroatom may have 1. 2. 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms are optionally oxidized. and nitrogen heteroatoms may be quaterized as needed. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system.

Examples of unicyclic heterocyclic groups include pyrrolidinyl. pyrrolyl. pyrazolyl. oxetanyl, pyrazolinyl. imidazolyl. imidazolinyl, imidazolidinyl. oxazolyl. oxazolidinyl. isoxazolinyl. isoxazolyl, thiazolyl. thiadiazolyl. thiazolidinyl. isothiazolyl. isothiazolidinyl. furil. tetrahydrofuryl. thienyl, oxadiazolyl. piperidinyl, piperazinyl. 2-oxopiperazinyl. 2-oxopiperidinyl, 2-oxopyrrolodinyl. 2-oxoazepinyl, azepinyl. 4-piperidonic pyridinyl. pyrazinyl. pyrimidinyl, pyridazinyl. tetrahydropyranyl, morpholinyl. thiamorpholinyl. thiamorpholinyl sulfoxide. thiamorpholinyl sulfone. 1,3-dioxolane and tetrahydro-11-dioxothienyl. triazolyl. triazinyl and the like.

Examples of bicyclic heterocyclic groups include indolyl. benzothiazolyl. benzoxazolyl. benzodioxolyl, benzothienyl. quinuclidinyl. quinolinyl. tetra-hidroizohinolinil. isoquinolinyl benzimidazolyl. benzopyranyl. indolizinyl. benzofuryl. chromonyl. coumarin. benzopyranyl, cinnolinyl. quinoxalinyl. indazolyl. pyrrolopyridyl. furopyridinyl (such as furo [2,3-b] pyridinyl. furo [3.2-b] pyridinyl or furo [2,3-b] pyridinyl). dihydroisoindol. dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl). tetrahydroquinolinyl and the like.

Examples of tricyclic heterocyclic groups include carbazolyl. benzidolyl. phenanthrolynyl. acridinyl. tenantridinyl, xanthenyl and the like.

The term heteroaryl refers to aromatic heterocyclic groups.

52291B

Examples of heteroaryl groups include pyrrolyl. pyrazolic imidazolyl. oxazolyl. isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl. furil. thienyl. oxadiazolyl. pyridinyl. pyrazinyl. pyrimidinyl, pyridazinyl. triazolyl, triazinyl and the like,

Where q = 1 or 2, ”-C (O)qH denotes -C (O) -H or -C (O) -OH: -C (O)qR6 ili C (O)qWITH6 denote, respectively, -C (O) -R6 ili -C (O) - (Zhb.ili-C (O) -Z6 ili -C (O) -OZ6: -OC (O) QR6, or -OC (O)qZ6 označavaju, redom. -O-C (O) -IB ili -O-C (O) - (Zhb.ili -OC (O) Z(, ili -OC (O) -OZ6; i -S (O)qR6 or -S (O)qZ (, denote. In order. -SO-R6 ili -SO2-R(,. or SO-Z6 ili -SO2-WITH6.

The compounds of formula I may in some cases form salts which are also within the meaning of the present invention. Reference to a compound of formula I herein includes reference to its salts. unless otherwise indicated. The term salt. as used herein, means acidic and / or base salts formed with inorganic and / or organic acids and bases. Zwitterions (amphotemic ions) (m-themes or internal salts) are encompassed by the term salt (s) as used herein (and may be formed, for example, where R substituents contain an acidic group such as a carboxyl group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred. although other salts may be useful. for example. in isolation and purification steps that can be applied during preparation. Salts of the compounds of formula I can be formed, for example. by reacting compound I with an amount of an acid or base, for example an equal amount, in a medium such as a salt-precipitated medium or in an aqueous medium, followed by lyophilization.

Examples of acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example trifluoroacetic acid). adipate, alginate. ascorbate. aspartates. benzoate. sulfonate. bisulfate. borates. butyrates. citrate. camphorate. camphorsulphonates. cyclopentanepropionate. digluconate. dodecyl sulfates, ethanesulfonates. fumarate. glucoheptonate. glycerophosphate. hemisulphate. heptanoate. hexanoates, hydrochlorides, hydrobromides. hydroiodide. 2-hydroxyethanesulfonate. lactate, maleate. methanesulfonates. 2-naftaJensuIfonati. nicotinates. nitrates. oxalates. pectinates. persulphates. 3-phenylpropionates, phosphates, picrates. pivalate. propionates. salicylates. succinate. sulfates (such as those formed with sulfuric acid). sulfonates (as mentioned herein). tartrate. thiocyanates. toluenesulfonates. undecanoates and the like.

Examples of base salts (which are formed, for example, wherein the R substituents contain an acidic group such as a carboxyl group) include ammonium salts. salts with alkali metals as

52291Β which are salts with sodium. lithium and potassium. alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g. organic amines) such as benzathines. dicyclohexylamine. hydrabamines. N-methyl-D-glucamine. N-methylD-glucamides. t-butyl amines and salts with amino acids such as arginine. lysine and the like. Nitrogen-containing base groups can be quaternized with agents such as lower alkyl haiogenides (e.g. methyl, ethyl. propyl and butyl chlorides. bromides and iodides). dialkylsulfates (e.g. dimethyl, diethyl. dibutyl and diamyl sulfates), long chain halides (e.g. decyl. lauryl. myristyl and stearyl chlorides, bromides and iodides). aralkyl halides (e.g. benzyl and phenethyl bromides) and others.

Prodrugs and solvates of the compounds of this invention are also contemplated herein. The term prodrug, as used herein. denotes a compound which. after its application to the subject, it is subject to chemical conversion through metabolic and chemical processes. to give a compound of formula I or a salt and / or solvate thereof. Solvates of the compounds of formula I are preferably hydrates.

All stereoisomers of the compounds of this invention. such as those containing asymmetric carbons on the R substituents of the compounds of formula I. including enantiomeric and diastereomeric forms. are contemplated in the present invention. The individual stereoisomers of the compounds of this invention may, for example. to be substantially free of other isomers, or may be mixed, for example. as racemates or with everything else. or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined in the IUPAC 1974 Recommendations.

In the specification. groups and their substituents are selected to provide stable groups and compounds.

Preferred compounds

Preferred compounds of the present invention are compounds of formula I. as well as their salts. where Q is thiazole and where they are one or more. and especially everyone. of Z. X |. X2. R|. R2. R3. R4 and R5 selected from the following definitions:

Z is a single bond;

Ri is selected from hydrogen. hello. alkyl. aryl. alkoxy. alkoxycarbonyl or aryloxycarbonyl. and more preferably hydrogen:

Xi i X2 together they build = 0 or = S. and more preferably grade = O:

R2 is hydrogen:

52291B

R3 is selected from -Z4-R6 or -Z |3-NR7R8. and more preferably -Z4-R(,. where is Z4 single bond and R6 is aryl or heteroaryl which is unsubstituted or substituted by Zp Z2 and one or more (preferably one or two) groups Z3:

R4 is hydrogen; and

R3 is selected from aryl groups or heteroaryl groups which are substituted with Z1. With2 and with one or more (such as one or two) group Z3.

Preparation procedures

The compounds of formula I can be prepared by methods as illustrated in the following Schemes A to E and I to XI. Solvents, temperature. pressure and other reaction conditions can be easily selected by a qualified professional. References are provided for all documents cited here. The starting materials are commercially available or can be easily prepared by qualified professionals. The components of the compound are as defined elsewhere in the specification or as specifically specified in the scheme.

The processes described herein may be performed with starting materials and / or reagents in solution or alternatively, where appropriate. with one or more starting materials or reagents bound to a solid support (see (1) Thompson. LA. Ellman. JA. Chemical Reviews. 96,555-600 (1996); (2) Terrett. NK. Gardner. M .. Gordon .DW. Kobylecki. RJ. Steele. J. „Tetrahedron. 51. 8135-8173 (1995): (3) Gallop. MA, Barrett. RW, Dower, WJ„ Fodor. SPA. Gordon. EM. Journal of Medicinal Chemistry, 37.1233-1251 (1994); (4) Gordon. E.M., Barrett. R.W., Dower. W.J.. Fodor. S.P.A.. Gallop, M.A., Journal of Medicinal Chemistry. 37, 1385-1401 (1994); (5) Balkenhohl. F„ von dem Bussche-Hiinnefeld. Lansky. A.. Zechel. C.. Angewandte Chemie International Edition in English. 35. 2288-2337 (1996): (6) Balkenhohl. F.. von dem Bussche-Hiinneield, Lansky. A., Zechel, C.. Angewandte Chemie, 108. 2436-2487 (1996); i (7) Sofia. M.J.. Drugs Discovery Today. 1.27-34 (1996)).

52291B

Scheme Α

for Rg and R3 = H (1) saponifikacija (2) R5'-N-R4

I

H iii

R3

52291B

Scheme Α illustrates a general procedure for forming a compound Ia, which is a compound of formula I. wherein X | and X2 together they form = 0. As shown in Scheme A. compound Ia, where FG and R3 hydrogen. it can be formed by saponification of compound i, (R * is a carboxyl protecting group such as alkyl or arylalkyl), followed by reaction with an amine iii using methods known in the art. Alternatively, it can react with R2L. where L is a leaving group such as halogen (for example, in equimolar parts). followed, if necessary, by reaction with R3L (e.g. in equimolar moieties) to form compound ii. Also alternatively. and may be subjected to reductive amination using an appropriate aldehyde or ketone to form compound ii. Compound ii can then be saponified and reacted with amine iii, under conditions known to those skilled in the art, to form compound Ia. where R2 and / or R3 they are not hydrogen.

Methods for preparing preferred substituents on compounds I are illustrated in the following Schemes I to XI.

52291B

Scheme Β

iii

52291B

Scheme Β illustrates the general procedure for the formation of compound Ib. which is a compound of formula I, wherein Z is -CH = CH- and X 1 and X2 together build = 0. As shown in Scheme B. 2-halo compound vi can be prepared by reacting the appropriately substituted 2-amino compound ia with copper (ii) halide and alkyl nitrite. such as tert-butyl nitrite. in an aprotic solvent such as acetonitrile. to form the 2-halo compound iv (see J. Hel. Chem. 22. 1621 (1985)). Compound iv can be reduced with a reducing agent such as sodium borohydride in ethanol or an aqueous solution of tetrahydrofuran. to form an alcohol, which can be oxidized by an oxidizing agent such as pyridinium chlorolyromate or pyridinium dichromate. to form an aldehyde in. Compound u can be reacted with alkyl (triphenylphosphorylidene) acetate to form carboxylate vi. Compound vi can be saponified and then reacted with an amine iii using methods known to those skilled in the art. to form compound vii. Compound vii can be reacted with amine R2R3NH to form compound Ib, where Z is -CH = CH-. and X | and X2 together they form 0. Alternatively. compounds of formula Ib, wherein R2 i R3 = H. can be formed by reacting compound vii with an appropriately substituted benzyl amine such as 4-methoxybenzyl amine, to form compound ix. which can be hydrogenolized or treated with an acid such as trifluoromethanesulfonic acid and trifluoroacetic acid in the presence of anisole. to form compound Ib, where R2 i R3 hydrogen.

Methods for preparing preferred substituents on compounds I are illustrated in the following Schemes I to XI.

52291Β §ema C

Bl5 xiii

R2 and / or R30 H

52291 Β

Scheme C illustrates the general procedure for forming compound Ic. which is a compound of formula I. wherein Z is -R 15 C = CH- and X 1 and X2 together they form = 0. As shown in Semi C. 2-Amino-Ia can be reacted with chloroformate or dicarbonate. to form compound h, which can be saponified and treated with an organolithium reagent. to form compound xi. Compound xi can be reacted with alkyl (triphenylphosphorylidene) acetate. followed by deprotection of the carbamate protecting group to form compound xii. Alternatively. compound Ic. where R2 i R3 hydrogen.can be formed by saponification of compound xii. followed by reaction with the amine R4R5NH using methods known to those skilled in the art. Alternatively, equation xii may react with R2L. where L is a leaving group such as halogen (for example, in equimolamic parts). after which as needed. a reaction with R may follow3L (for example, in equimolamic moieties) to form compound xiii. which can be saponified and reacted with the amine R4R5NH using methods known to those skilled in the art to form compound Ia. where R2 and / or R3 they are not hydrogen.

Methods for preparing the preferred substituents on compounds I are illustrated in the following Schemes I to XI.

Sema D

Scheme D illustrates the general procedure for forming compound Id. which is a compound of formula I. where X | and X2 together they form = S. The compounds of formula Ia obtained in Scheme A can be converted into the corresponding thioamide Id using reagents such as Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide) (see ViP. Soc. Chim. Belg .. 87. 223 (1978)).

Methods for preparing the preferred substituents on compounds I illustrated in the following Schemes I to XI.

52291B

Scheme Ε

Scheme Ε illustrates the general procedure for the formation of compound Ie. which is a compound of formula I, wherein X 1 and X2 individually hydrogen. As shown in Scheme E. the compound of formula Id obtained in Scheme D. can be converted to the corresponding amine by reduction. for example, by reaction with Reni-nickel.

Methods for preparing preferred substituents on compounds I are illustrated in the following Schemes I to XI.

52291Β \ /

(Α) synthesis of peptide bonds. ie ..

merging with r ^n,r4

I n

or iii (B) synthesis via acid chloride. ie ..

(1) thionilhlorida ili oxalilhlorida

H

R3 = COORg ^,> <2 = 0 starting from 2: R2 = alkyl. arylalkyl.

or cycloalkylalkyl starting from 3: R2 = H

52291 Β

As shown in Scheme I, carboxylate i can also react with chloroformate or dicarbonate. to form compound L Compound 1 can be treated with a base such as sodium hydride. sodium / potassium hexamethyldisilazide or lithium diisopropylamide (LDA) and also with an alkylating agent R2X. wherein X is halogen and R 1 is preferably alkyl, arylalkyl or cycloalkylalkyl. and the slurry is saponified with an aqueous base solution such as potassium hydroxide to give compound 2. Alternatively. the compound χ can be subjected to reductive amination using an appropriate aldehyde or ketone, after which it is saponified with an aqueous base solution. such as potassium hydroxide. to give compound 2. Compound 1 can, alternatively. to be simply saponified with an aqueous solution of the base. such as potassium hydroxide, to give compound 3. wherein R2 hydrogen.

Acid 2 can be reacted with an amine iii using reaction conditions well known in the art for peptide bond synthesis (see, e.g., Bodanszky and Bodanszky, The Practice of Peptide Chemistry, Springer-Verlag. 1984; Bodanszky. Principles of Peptide Synthesis. Springer-Verlag. 1984) to give compound Id. which is a compound of formula I, wherein X 1 and X2 together form = 0, R3 is C00R &. and since compound 2 is the starting material, R2 preferably alkyl. arylalkyl or cycloalkylalkyl. For example, reagents that activate the carboxyl group of compound 2 to react with amine iv include bis- (2-oxo-3-oxazolidinyl) phosphine chloride (BOP chloride). benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent). [O- (7azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate (HATU) and carbodiimides such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-3 '- (dimethylamino) propylcarbodiimide. either alone or together with hydroxybenzotriazole. Alternatively. the activated ester intermediate can be isolated and then treated with the appropriate amine iv in a non-acidic solvent, such as tetrahydrofuran (THF) or dimethylformamide (DMF), in the presence of a base. for example, organic bases such as sodium / potassium hexamethyldisilazide, triethylamine, diisopropylethylamine or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). or inorganic bases such as sodium, potassium or cesium carbonate or sodium or potassium hydride. Alternatively. acid halide 2 can be prepared. for example, by reaction with thionyl chloride or oxalyl chloride. followed by reaction with amine iii to give compound If. which is a compound of formula 1. wherein R3 COOR6. Xi i X2 together they form = 0. and R2 je alkyl. arylalkyl cycloalkylalkyl.

52291 Β

Similar reactions as those used above for the conversion of compound 2 to compound If can be used to convert compound 3 to compound If. where R.3 is COORft. Xi and X2 together they form = 0. and R2 is hydrogen.

Scheme II

Σ3 R5

Xi,X2=H

R2, R3 ln

52291B

As shown in Scheme II. acid 4. where R2 and R3 is not hydrogen (and is selected so that the nitrogen to which they are attached is not basic), it is reduced to aldehyde 5 using methods well known in the art (see March. Advanced Organic Chemistry. Wiley. 1985). For example, acid 4 can be converted to its corresponding ester. followed by reduction with diisobutylaluminum hydride. Alternatively, acid 4 can be reduced to the corresponding primary alcohol. for example. treatment with borane / THF. L1AIH4. or by reduction of the mixed anhydride. followed by oxidation to aldehyde 5 using Cr (VI) (eg pyridinium chlorochromate, PCC) or under Swem or Moffatt conditions (eg COCl)2/ dimethylsulfoxide). The starting acid 4 can be obtained. for example, by saponification of the compound ii.

Reductive amination (see Hudlicky. Reductions in Organic Chemistry. Wiley, 1984) of aldehyde 5 with amine iii in the presence of a reducing agent such as NaBHjCN. NaBH (OAc)3 (Ac = acetyl) or hydrogen and a palladium catalyst gave the amine Ig. which is a compound of formula I. wherein Xi and X2 individually hydrogen. and R2 and R3 are not hydrogen.

52291B

Sheema III

x1;x2 = n R2l R3 H

As shown in Scheme III, reduction of acid 4 to the primary alcohol (e.g., by treatment with borane / tetrahydrofuran, L1AIH4, or reduction of mixed anhydride), followed by conversion using methods well known in the art (see March, Advanced Organic Chemistry, Wiley, 1985). compound 6 containing a leaving group, such as a halide, is obtained. tosylate (OTs). mesylate (OMs) or triflate (OTf). Group R2 i R3 they are chosen so that the nitrogen obtained to which they are bound is not basic. Compound 6 can then be converted to compound Ih. which is a compound of formula I. wherein each X | and X2 hydrogen, and R2 and R3 is not hydrogen, by an amine exchange reaction iii. preferably where amine iii is used in excess.

52291Β §ema IV

R2 = any group as defined R3 = acyl or thioacyl

Amid/Tioamid

RbNCS 13b [Χ1, X2 * H]

52291B

Scheme IV illustrates methods that can be used to prepare compounds Ij, Ik. II. Im and In. Ij. Ik, II, Im and ln are compounds of formula I. wherein R2 any group as defined. R3 is an acyl or thioacyl group. Xi and X2 they are not hydrogen. and Ri is neither primami nor seconds amine. Ij, Ik, II. Im and In have other special substituents which are specified in this Scheme and hereinafter. The starting compound II can be prepared using the suitable procedures described in Schemes A and D.

Amide Ij can be prepared by treating amine Ii with carboxylic acid 7 in the presence of reagents that activate the carboxyl group for the reaction. as described above, for example BOP reagent, HATU and carbodiimides such as DCC or EDCl. either alone or together with hydroxybenztriazole. Alternatively. the acid halide 8 can be reacted with amine II in the presence of an acid acceptor such as diisopropylethylamine. The corresponding thioamide Ik can be prepared by treating amide Ii (where X 12 # O) with Lawesson's reagent. as described above.

Carbamate II can be prepared by treating the amine with chloroformate 9 or dicarbonate 10 in the presence of an acid acceptor such as diisopropylethylamine.

Urea Im can be prepared by treating the amine of compound Ii with any of the following compounds: 1) chloroformate 9, such as phenylchloroformate. followed by reaction with amine 11: 2) carbamoyl chloride 12 in the presence of an acid acceptor such as diisopropylethylamine; or 3) by reaction with isocyanate 13a (wherein Rc u Im = N). The corresponding thiourea In can be prepared by treating the amine of compound Ii with thioisocyanate 13b.

Ra is selected from those groups covered by the definition of R6. such as the group C (= A) -Ra acyl or thioacyl group within the definition of R3. Rb i Rc are selected from those groups covered by the definitions for R7 and R «. such as the group -C (= A) -Nb)(Rc) acyl or thioacyl group within the definition for R3.

52291B

Scheme V \ /

[Χι, Χ2 The]

52291 Β

Scheme B illustrates a process that can be used to prepare compound Ip. which is a compound of formula I, wherein R2 any group as defined. except the acyl group. which is chosen so that the nitrogen to which it is attached is basic. R3 is alkyl. cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl. aralkyl or a saturated heterocyclic ring. and X | and X2 they are not hydrogen. The starting compounds Io and Iq can be prepared using suitable methods described in Schemes A and D.

As shown in Scheme V. amine Io was reacted with an aldehyde or ketone 14 under reductive amination conditions. which have been described above, to give the amine Ip. Compound Ip can also be prepared by treating the amine Iq, where R2 i R3 hydrogen, with t-butyl nitrite or sodium nitrite in the presence of copper (II) halides. to give a halo-substituted compound 15, followed by substitution with an amine 16 in the presence of a base, such as sodium or potassium hydride or the like (see Lee et al. Heterocyclic Chemistry, 22, 1621 (1985)).

Rd and Re are independently selected from hydrogen. alkyl. aryl. cycloalkyl or cycloalkenyl, or together alkylene or alkenylene forming a 3- to 8-membered saturated or unsaturated ring, so that the group -CH (Rd) (Rc) is a group within the definition of R3.

52291 Β

Scheme VI

R2= any group as defined. except the acyl group

R3= Aryl. heteroaryl

As shown in Scheme VI. when R2 any group as specified. except the acyl group. which is chosen so that the nitrogen to which it is attached is basic. R3 is aril or heteroaril, and X 1 and X2 they are not hydrogen. the amine of compound Ir can be reacted with halophenyl or a haloheteroaromatic group of compound 17 in the presence of a palladium (O) catalyst (see J. Am. Chem. Soc. 118. 7215 (1996)). to obtain amine Is. which is a compound of formula I, and which has the special substituents described in this Scheme. The initial compound Ir can be prepared using the suitable procedures described in Schemes A and D.

Scheme VII

R2= any group as defined

R3= heteroaryl

52291B

As shown in Scheme VII. when R2 any group as defined and R3 is a heteroaromatic group. the amine of the compound It can be reacted, in the presence of a base if necessary, with a 2-halosubstituted heteroaromatic compound 17. wherein Qi, together with the atoms to which it is attached, forms a 5- or 6-membered monocyclic or 10- to 12-membered a bicyclic heteroaromatic group (such as 2-chloropyridine or 2-chloropyrimidine). to give amine Iu, wherein Iu is a compound of formula I having special substituents described in this Scheme. The initial compound It can be prepared using the suitable procedures described in Schemes A and D.

Scheme VIII

[Xi,X2* H]

As shown in Scheme VIII. thiourea In (where X, and X2 are not hydrogen) can be reacted with the corresponding amine in the presence of bis- (2-oxo-3-oxazolidinyl) phosphinic acid chloride (BOP chloride). benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent). [O- (7-azabenzotriazol-1-yl) -1,3,3-tetramethyluronium] hexafluorophosphate (HATU) and carbodiimide. such as dicyclohexylcarbodiimide (DCC) or 3-ethyl-3 '- (dimethylamino) propylcarbodiimide (EDCI) or diisopropylcarbodiimide (DIC), in the presence of an organic base such as triethylamine. diisopropylethylamine or dimethylaminopyridine in solvents such as dimethylformamide. dichloromethane or tetrahydrofuran. to form the compound Iv. which is a compound of formula I having special substituents described in this Sem.

Alternatively. compound In can be reacted with the corresponding amine in the presence of a mercury (II) salt such as mercuric chloride. or by applying other procedures known in the literature. to form the compound Iv.

52291B

Scheme IX

Rx - What2 alkil.CN,

CO2 aril

HN

As shown in Scheme IX. amine Ir (where X | and X2 are not hydrogen) may react with diphenylcyanocarbonimidate either alone or in the presence of a base, such as sodium hydride. sodium hexamethyldisilazide or dimethylaminopyridine in acetonitrile. tetrahydrofuran or dimethylformamide. at room temperature or elevated temperature. to form the intermediate compound Iw. Compound Iw can be reacted with amine R.7R.8NH to form compound Iv. which is a compound of formula I. and which has special substituents described in this Scheme.

52291B

Scheme X / \

Ιχ

Ιγ

[Χι. Хг * H]

52291B

As shown on Sherney X. compound Ir (where X | and X2 are not hydrogen) may react with compound 18 or compound 19 either alone or in the presence of a base. such as sodium hydride. sodium hexamethyldisilazide or dimethylaminopyridine. in dimethylformamide or tetrahydrofuran, at room temperature or at a higher temperature, to form compounds Ix or Iy, respectively, which can react with amine R2RsNH at room temperature or elevated temperature, to form compounds Iz or Iz *. in a row. Compound Iz is a compound of formula I having the specific substituents described in this Scheme. Compound Iz * is a compound of formula I having the particular substituents described in this Scheme.

§Ema XI

R2 = aryl, heteroaryl, dvociklični-heteroaryl

R3= H, alkyl, aryl, heteroaryl, bicyclic-heteroaryl

r4

As shown in Scheme XI. Compounds of formula I may also be prepared from compound 15 by treatment with a particular amine in the presence of an acid catalyst (e.g. see: Gunzenhauser et al. Heh. Chim. Acta. 71.33 (1988)).

The present invention further provides compounds of formula III:

gde:

each R |. R? and R4 is. independent. heterocyclic group or aryl group. optionally substituted with one or more substituents: i

52291 Β

R? is hydrogen or alkyl.

A preferred compound of the present invention has the formula IV:

Primena

The compounds of the present invention inhibit protein tyrosine kinase. especially Heart family kinases, such as Lck, Fyn. Lyn, Src, Yes. Hck. Fgr and Blk and accordingly. these compounds are useful for treatment, including prevention and treatment. disorders associated with protein tyrosine kinase. such as immune and oncological disorders. These compounds also inhibit receptor tyrosine kinases including HER1 and HER2 and are therefore useful in the treatment of proliferative disorders such as psoriasis and cancer. The ability of these compounds to inhibit HER1 and other receptor kinases will allow their use as antiangiogenic agents for the treatment of disorders such as cancer and diabetic retinopathy. Disorders associated with protein tyrosine kinases are those disorders that occur as a result of abnormal tyrosine kinase activity and / or those disorders that are alleviated by inhibition of one or more of these enzymes. For example, Lck inhibitors are useful in the treatment of some of these disorders (for example, the treatment of autoimmune diseases). since Lck inhibition stops T cell activation. Treatment of T cell-mediated diseases. including inhibition of T cell activation and proliferation. represents a particularly preferred form of the present invention. Compounds that selectively arrest T cell activation and proliferation are preferred. Compounds of the present invention that inhibit PTK endothelial cell activation. where that activation is caused by oxidative stress. and thus limit the surface expression of neutrophil-binding adhesion molecules. wherein the PTK-inhibiting compounds of the present invention are necessary for neutrophil activation. represent useful compounds. for example. in the treatment of ischemia and reperfusion injury.

52291B

The present invention thus provides methods for treating disorders associated with protein tyrosine kinase, comprising a method of administering to a subject in need thereof at least one compound of formula I in an amount effective therefor. Other therapeutic agents. such as those described below. can be used with the compounds of the invention in the given methods. In the methods of the present invention. such other therapeutic agents (one or more) may be administered before. simultaneously with or after administration of a compound (one or more) of the present invention.

Examples of the use of the compounds of this invention in the treatment of disorders associated with protein tyrosine kinase are. but the application is not limited to them. treatment of a range of disorders such as: transplant rejection (such as organ transplant, acute transplant or xenograft or allograft) (as used in the treatment of burns)); protection against ischemic or reperfusion injury that may occur during organ transplantation, as a consequence of myocardial infarction. stroke or other causes; induction of transplant tolerance; arthritis (such as rheumatoid arthritis. psoriatic arthritis or osteoarthritis); multiple sclerosis: chronic obstructive pulmonary disease (COPD). such as emphysema: an inflammatory bowel disease. including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosus); graft-versus-host disease; T cell-mediated hypersensitivity diseases. including contact hypersensitivity. delayed-type hypersensitivity and gluten-sensitive enteropathy (celiac disease): psoriasis; contact dermatitis (including contact dermatitis caused by poison ivy): Hashimoto's thyroiditis; Sjogren's syndrome; autoimmune hyperthyroidism. such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome): autoimmune baldness; pernicious anemia: vitiligo; autoimmune hypopituitarism: Guillain-Barre syndrome: other autoimmune diseases: cancers, including cancers in which Lck or other kinases of the Src family, such as Src. activated or overexpressed, such as colon cancer and thymic cancer. as well as cancers in which the activity of the kinase from the Src family facilitates the growth of the tumor or its survival; glomerulonephritis; serum sickness: urticaria: allergic diseases such as respiratory allergies (asthma. pollen fever. allergic rhinitis) or skin allergies: mvcosis fungoides (cutaneous T-cell lymphoma): acute inflammatory responses (such as acute respiratory distress syndrome and ischemic / reperfusion injury): dermatomyositis: alopecia areata: chronic actin dermatitis: eczema; Behcet's disease; Pustulosis palmoplanteris: Pvoderma gangrenosum: Cesarean syndrome: atopic dermatitis: systemic sclerosis: and scleroderma. The present invention also provides a method of treating the above

52291Β disorders. such as atopic dermatitis, by administering any compound capable of inhibiting protein tyrosine kinase.

Src-family kinases other than Lck, such as Hck and Fgr, are important in the Fc gamma receptor responses of monocytes and macrophages. The compounds of the present invention inhibit Fc gamma-dependent production of TNF alpha in a Lc-1 monocyte cell line that does not express Lck. The ability to inhibit Fc gamma receptor-dependent responses of monocytes and macrophages results in additional anti-inflammatory activity for the given compounds in addition to their effects on T cells. This activity is especially useful. for example. in the treatment of inflammatory diseases such as arthritis or inflammatory bowel disease. The compounds of the present invention are useful for the treatment of autoimmune glomerulonephritis and other cases of glomerulonephritis caused by the deposition of immune complexes in the kidney thereby triggering Fc gamma receptor responses leading to renal damage.

In addition, kinases of the Src family, except Lck. such as Lyn and Src. they are important in mast cell and basophil degranulation which is induced by the Fc epsilon receptor and which plays an important role in asthma, allergic rhinitis and other allergic diseases. Fc epsilon receptors are stimulated by IgE-antigen complex. The compounds of the present invention inhibit degranulation responses induced by Fc epsilon receptors. including in the RBL basophil cell line that does not express Lck. The ability to inhibit Fc epsilon receptor-induced mast cell and basophil responses results in additional anti-inflammatory activity for the compounds of the present invention in addition to their effect on T cells. Especially. the compounds of this invention are useful for the treatment of asthma. allergic rhinitis and other cases of allergic diseases.

The combined effect of a compound of the invention on monocytes, macrophages. T cells. etc .. can be useful in treating any of the above disorders.

In a special form. the compounds of the present invention are useful for treating the aforementioned disorders regardless of their cause. for example. for the treatment of transplant rejection. rheumatoid arthritis. multiple sclerosis, chronic obstructive pulmonary disease. inflammatory bowel disease. lupus. graft-versus-host disease. T cell-mediated hypersensitivity disease, psoriasis. Hashimoto's thyroiditis. Guillain-Barre syndrome. cancer. contact dermatitis. allergic diseases such as allergic rhinitis. asthma. ischemic or reperfusion injury or atopic dermatitis. which are related or unrelated to PTK.

Thanks to their ability to inhibit HER1 and HER2 kinases. the compounds of the present invention may also be used to treat proliferative diseases. including

52291 Β Psoriasis and cancer. HER1 receptor kinase has been shown to be expressed and activated in many solid tumors including non-small cell lung cancer, colorectal cancer, and breast cancer. Similarly, HER2 receptor kinase has been shown to be overexpressed in breast cancer. ovaries. lungs and stomach. Monoclonal antibodies that down-regulate I4ER2 receptor numbers or inhibit HER1 receptor signaling have shown anti-tumor activity in preclinical and clinical trials. Therefore, HER1 and HER2 kinase inhibitors are expected to be effective in treating tumors that are dependent on the signaling of either of the two receptors. These compounds are expected to be effective either alone or in combination with other chemotherapeutic agents such as placlitaxel (Taxol). doksorubicin hidrohlorid (adriamicin) i cisplatin (Platinol). Pogledati sledeće dokumente i reference koje su ovde citirane: Cobleigh. M.A. . Vogel, C.L.. Tripathy, D„ Robert, N.J.. Scholl, S.. Fehrenbacher. L„ Wolter. J.M., Paton, V,. Shak, S.. Lieberman, G.. and Slamon, D.J., Multinational study of the efficacv and safety of humanized anti-HER2 monoclonal antibody in women who ha\'e HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. of Clin. Oncol. 17 (9). p. 2639-2648 (1999); Baselga. J.. Pfister. D.. Cooper. M.R.. Cohen. R.. Burtness, B.. Bos. M.. D'Andrea. G.. Seidman. A.. Norton. L.. Gunnett. K... Falcev. J„ Anderson. V.. Waksal. H., and Mendelsohn. J.. Phase 1 studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. .1. Clin. Oncol. 18 (4), p. 904-914 (2000).

The compounds of the present invention are useful for the treatment of cancers such as chronic myelogenous leukemia (CML). gastrointestinal stromal tumor (GIST). small cell lung cancer (SCLC). non-small cell lung cancer (NSCLC). ovarian cancer. melanoma. mastocytosis. germ cell tumors. acute myelogenous leukemia (AML). pediatric sarcomas. breast cancer. colorectal cancer. pancreatic cancer. prostate cancer and others. which are known to be associated with protein tyrosine kinases such as. for example. SRC. BCR-ABL and c-KIT. The compounds of the present invention are also useful in the treatment of cancers that are susceptible to and resistant to chemotherapeutic agents acting on BCR-ABL and c-KJT. such as. for example. Glee \ ^ ec® (STI-571).

The present invention also provides pharmaceutical compositions comprising at least one of the compounds of formula 1 that can be used to treat a disorder associated with a protein tyrosine kinase. for that purpose. effective amount. as well as a pharmaceutically acceptable carrier or diluent. The compositions of the present invention may contain other therapeutic agents as described below. and can be formulated. for example. application

52291Β conventional solid or liquid carriers or diluents. as well as pharmaceutical additives of the type suitable for the desired mode of administration (for example. excipients. binders. preservatives. stabilizers. flavor enhancers. etc.) according to techniques such as those well known in the art of pharmaceutical formulations.

The compounds of formula I can be administered in any suitable manner. for example, orally, such as in the form of tablets, capsules. granules or powders; sublingually; buccal; parenterally, such as by applying subcutaneous techniques. intravenous, intramuscular or intrasternal injections or infusions (e.g. as sterile aqueous or non-aqueous solutions or suspensions for injection); nasal. such as applying an inhalation spray; locally. such as in the form of cream or rnasti; or rectally as in the form of suppositories: in unit dosage formulations containing non-toxic, pharmaceutically acceptable carriers or diluents. The compounds of this invention may be. for example. administered in a form suitable for immediate release or prolonged release. Immediate release or sustained release can be achieved by the use of suitable pharmaceutical compositions containing the compounds of this invention, or, in the case of sustained release, in particular by the use of devices such as subcutaneous implants or osmotic pumps. The compounds of this invention may also be administered liposomally.

Examples of compositions for oral administration include suspensions that may contain. for example, microcrystalline cellulose as a base. alginic acid or sodium malginate as a suspension agent, methylcellulose as a viscosity enhancing agent. as well as sweeteners and flavor enhancers. as they are known in the art; and immediate-release tablets that may contain. for example. microcrystalline cellulose. dicalcium phosphate. starch, magnesium stearate and / or lactose and / or other excipients, binders. chargers, disintegrants. diluents and lubricants. as they are known in the art. The compounds of the present invention may also be administered orally by sublingual and / or buccal administration. Molded tablets. compressed tablets or freeze-dried tablets are examples of forms that can be used. Examples of compositions include those in which the compound (s) of the present invention are formulated with rapidly dissolving diluents. such as mannitol, lactose. sucrose and / or cyclodextrins. High molecular weight excipients may also be included in these formulations. such as cellulose (avicel) or polyethylene glycols (PEG). Such formulations may also contain an inert filler which facilitates adhesion to the mucosa. such as hydroxypropylcellulose (HPC). hydroxypropylmethylcellulose (HPMC). sodium carboxymethylcellulose (SCMC). a copolymer of maleic anhydride (e.g. Gantres). and release control agents.

52291Β such as a polyacrylic copolymer (e.g. Carbopol 934). Lubricants. sliding means. flavor enhancers. colorants and stabilizers may also be added to facilitate production and application.

Examples of compositions for nasal aerosol or inhalation administration include saline solutions that may contain. for example. benzene or other suitable preservatives. absorption initiating agents to increase bioavailability and / or other solubilizing or dispersing agents such as those known in the art.

Examples of compositions for parenteral administration include solutions or suspensions for injection which may contain, for example. suitable non-toxic. parnelaterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water. Ringer's solution. isotonic sodium chloride solution or other suitable dispersing or wetting and suspending agents. including synthetic mono- or diglycerides, as well as fatty acids. including oleic acid.

Examples of compositions for rectal administration include suppositories that may contain. for example. suitable non-irritating excipient. such as cocoa butter. synthetic esters of glycerides or polyethylene glycols. which are at solid temperatures at normal temperatures. but become liquid and / or dissolve in the rectal cavity to release the drug.

Examples of compositions for topical administration include a topical carrier. such as Plastibase (a mineral oil that is gelatinized using polyethylene).

An effective amount of a compound of the present invention may be determined by one skilled in the art and includes. for example. dosage amounts for an adult human of about 0.1 to 100 mg / kg body weight, active compound per day, which may be administered in a single dose or in the form of single divided doses, such as from 1 to 4 times per day. It is clear that the specific dose level and frequency of dosing for each individual subject may be different and will depend on different factors including the effect of the specific compound used. metabolic stability and duration of action of that compound. species. age. body weight, general health. sex and nutrition of the subject. methods and times of application, excretion rates. combination with other drugs. as well as the severity of the specific condition. Preferred subjects for treatment include animals. most desirable mammalian species such as humans. as well as domestic animals such as dogs. cats and the like. and who have disorders associated with protein tyrosine kinase.

When administered intravenously. compounds of the present invention, including compounds of formula III and IV. it is preferably administered using the formulations of the present invention. In general. compounds o \withand finding. including compounds of formula III and IV. apply IV

52291Β by infusion over about 10 minutes to about 3 hours. preferably about 30 minutes to about 2 hours. more preferably about 45 minutes to 90 minutes. and most preferably about 1 hour. Typically, these compounds are administered intravenously at a dose of about 0.5 mg / m 22 up to 65 mg / m2. preferably about 1 mg / m 22 up to 50 mg / m2, more preferably about 2.5 mg / m 22 up to 30 mg / m2. and most preferably about 25 mg / m2

Qualified professionals will know how to translate doses of mg / kg to mg / nT given for a patient's height or weight (see, e.g., http: // \ aavvv. Fda. Gov / cder / cancer / animalfrarne. Htm).

As discussed above. the compounds of the present invention, including the compounds of formulas III and IV, may be administered orally. intravenously or both. The methods of the invention in particular comprise dosage protocols such as once daily for 2 to 10 days, preferably every 3 to 9 days, more preferably every 4 to 8 days and most preferably every 5 days. In one form, a period of 3 days to 5 weeks is given. preferably 4 days to 4 weeks. more preferably 5 days to 3 weeks, and most preferably 1 week to 2 weeks. between cycles without treatment. In another embodiment of the compounds of this invention. including compounds of formula III or IV, may be administered orally. intravenously or both, once daily for 3 days. with a period of preferably 1 week to 3 weeks between cycles during which there is no treatment. In another embodiment of the compounds of this invention. including compounds of formula III or IV. can be administered orally. intravenously or both. once daily for 5 days, with a period of preferably 1 week to 3 weeks between cycles during which there is no treatment.

In one preferred embodiment, a treatment cycle for administering a compound of the present invention. including compounds of formula III or IV. is once a day for 5 consecutive days and with a period between treatment cycles of 2 to 10 days. and preferably one week. In one form. a compound of the present invention. for example. a compound of formula III or formula IV. it is applied once a day for 5 consecutive days. followed by 2 days without treatment.

Compounds of the present invention. including compounds of formula III or IV. they can also be administered orally. intravenously or in both of these ways every 1 to 10 weeks, preferably every 2 to 8 weeks. more preferably every 3 to 6 weeks. even more preferably every 3 weeks.

In the following process of the invention. compounds of the present invention. including compounds of formula III or IV. are administered over a cycle of 28 days during which the compounds are administered intravenously on days 1. 7 and 14 and are administered orally on day 21. Alternatively. compounds of the present invention. including compounds of formula III or IV. are administered over a cycle of 28 days during which the compounds of formulas I and II are administered orally on day 1 and administered intravenously on days 7. 14 and 28.

52291B

According to the methods of the present invention. the compounds of the present invention, including the compounds of formulas III or IV, are administered until the patient shows a response. for example. reduction in tumor size. or until a dose that is at the toxicity limit is reached.

The compounds of the present invention may be used alone or in combination with other compounds of the present invention and / or other suitable therapeutic agents useful in the treatment of protein tyrosine kinase-related disorders. such as PTK inhibitors. other than those of the present invention. anti-inflammatory agents. antiproliferative agents, chemotherapeutic agents. immunosuppressants, anticancer agents and cytotoxic agents.

Examples of such other therapeutic agents include the following: cyclosporins (e.g., cyclosporine A). CTLA4-Ig. antibodies such as anti-ICAM-3. anti-IL-2 receptor (Anti-Tac). anti-CD45RB. anti-CD2. anti-CD3 (OKT-3). anti-CD4. anti-CD80. anti-CD86. OKTZ monoclonal antibody. agents that stop the interaction between CD40 and gp39. such as antibodies specific for CD40 and / or gp39 (i.e., CD154). fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39). inhibitors. such as single translocation inhibitors, NF-kappa B function inhibitors. such as deoxypergualin (DSG). non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. steroids such as prednisone or dexamethasone. gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus. Prograf). mycophenolate mofetic cytotoxic drugs such as azatiprine and cyclophosphamide, TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor such as etanercept (Enbrel), rapamycin (sirolimus or Rapamune). leflunimide (Arava) and cyclooxygenase-2 (SOH-2), inhibitors such as celecoxib (Celebrex) and rofecoxib (Vioxx) or derivatives thereof, as well as PTK inhibitors are provided in the following U.S. patent applications, the references of which are incorporated herein by reference in their entirety: serial no. 60 / 056,770. filed 25.08.1997. (lawyer's statement no. QA202 *). serial no. 60 / 069.159. filed 09.12.1997. (lawyer's statement no. QA202a *). serial no. 09 / 097.338. filed 15.06.1998. (lawyer's statement no. QA202b). serial no. 60 / 056,797. filed 25.08.1997. (lawyer's statement no. QA205 *). serial no. 09 / 094,797. filed 15.06.1998. (lawyer's statement no. QA205a). serial no. 60 / 065.042. filed 11/10/1997 (lawyer's statement no. QA207 *). serial no. 09 / 173.413, filed on 15.10.1998. (lawyer's statement no. QA207a), serial no. 60,076 th most common 789. filed on March 4, 1998. (lawyer's statement no. QA208 *) and serial no. 09,262 th most common 525. filed 04.03.1999. (lawyer's statement no. QA208a). See the following documents and references cited here: Hollenbaugh. D .. Douthwright. .1 .. McDonald. V .. and Arut'fo. A .. Cleavable CD40Ig fusion proteins and the binding to sgp39. J. Imimmol. Methods CNetherlands). 188 (1). p. 1-7 (Dec 15 1995): Hollenbaugh. D .. Grosmaire. LS. Kullas.

52291 Β

CD. Shabby. NJ, Braesch-Andersen, S .. Noelle. RJ. Stamenkovic, I., Ledbetter, JA. and Aruffo, A .. The human T cell antigen gp39. a member of the TNF gene family. is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell costimulatory activity, EMBO J (England). 11 (12). p 4313-4321 (Dec 1992): and Moreland. LW et al .. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75) -Fc fusion protein, New England J. of Medicine. 337 (3). p. 141-147 (1997).

Examples of classes of anticancer agents and cytotoxic agents include, but are not limited to: alkylating agents, such as nitrogen mustards, alkylsulfonates. nitrosouree. ethyleneimines and triazenes; antimetabolites, such as folate antagonists, purine analogs, and pyrimidine analogs; antibiotics. such as anthracyclines. bleomycins. mitomycin. dactinomycin and plicamycin; enzymes, such as L-asparaginase; farnesyl protein transferase inhibitors; hormonal agents. such as glucocorticoids. estrogens / antiestrogens. androgens / antiandrogens, progestins and luteinizing hormone release hormone antagonists. octreotidacetate: agents that destroy microtubules. such as ecteinascidins or their analogs and derivatives; microtubule stabilizing agents such as paclitaxel (Taxol®). docetaxel (Taxotere®) and epothilones AF or their analogs or derivatives; plant-derived products, such as vinca alkaloids. epipodophyllotoxins. taxanes: and topoisomerase inhibitors: prenyl protein transferase inhibitors; and various agents such as, hydroxyurea. procarbazine. mitotan. hexamethylmelamine. platinum coordination complexes such as cisplatin and carboplatin; and other agents used as anticancer agents and cytotoxic agents. such as biological response modifiers. growth factors: immune response modulators and monoclonal antibodies. The compounds of this invention may also be used in conjunction with radiotherapy.

Typical examples of these classes of anticancer agents and cytotoxic agents include. but are not limited to. mechloretamine hydrochloride. cyclophosphamide. chlorambucil. melphalan, ifosfamide. busulfan. karmustine. lomustine. semustin. streptozocin. thiotepa. dacarbazine. methotrexate. thioguanine. mercaptopurine. fludarabine. pentastatin. cladribine. cytarabine. fluorouracil. doxorubicin hydrochloride. daunorubicin. idarubicin. bleomycin sulfate. mitomycin C. actinomycin D. safracini, saframicini. quinocarcinoma. discodermolidi. vincristine. Adnblastin. vinorelbine tartrate. etoposide. teniposide. paclitaxel. tamoxifen. estramustine. estramustine phosphate sodium. flutamide. buserelin. leuprolide. pteridines. diinesi. levamisole. aflakon. interferon. interleukins. aldesleukin. filgrastim. sargramostim. rituximab. BCG.

52291 Β tretinoin. irinotecan hydrochloride. betamethosone. gemcitabine hydrochloride. altretamine and topoteca and any analogues and derivatives thereof.

Preferred members of these classes include, but are not limited to. paclitaxel. cisplatin. carboplatin. doxorubicin. carminomycin. daunorubicin. aminopterin. methotrexate. metopterin, mitomycin C. ecteinascidin 743. porphyromycin. 5-fluorouracil. 6-mercaptopurine. gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivatives such as etoposide, etoposide phosphate or teniposide. melfalan. vinblastine. vincristine, leurosidine. vindesine and leurosin.

Examples of anticancer agents and other cytotoxic agents include the following: epothilone derivatives as given in U.S. Pat. 09 / 506.481 filed on 17.02.2000. (lawyer's statement no. LD186): German Patent no. 4138042.8; WO 97/19086, WO 98/22461. WO 98/25929. WO 98/38192. WO 99/01124. WO 99/02224. WO 99/02514. WO 99/03848. WO 99/07692. WO 99/27890. WO 99/28324. WO 99/43653. WO 99/54330. WO 99/54318. WO 99/54319. WO 99/65913. WO 99/67252. WO 99/67253 and WO 00/00485: cyclin dependent kinase inhibitors as given in WO 99/24416; and prenyl protein transferase inhibitors as given in WO 97/30992 and WO 98/54966.

The above therapeutic agents. when used in conjunction with the compounds of this invention. can be used. for example. in those quantities as indicated in the doctor's notes (PDR) or as otherwise determined by a qualified professional.

The following assays can be used to determine the degree of activity of a compound (test compound) as a PTK inhibitor. The compounds described in the following examples were tested in one or more of these assays and showed activity.

Enzyme assay using Lck. Fyn. Lyn. Hck. Fgr. Src. Blk or Yes

The following assay was performed using protein tyrosine kinase Lck. Fvn. Lyn. Hck. Fgr. Src. Blk and Yes.

The protein tyrosine kinase of interest was incubated in kinase buffer (20 mM MOPS, pH 7. 10 mM MgCl 3) in the presence of test compound. The reaction was started by adding media to a final concentration of 1 μΜ ATP. 3.3 pCi / ml [33P] gamma-ATP and 0.1 mg / ml acid denatured enolase (prepared as described in Cooper. .Ι.Α .. Esch. FS. Tavlor. SS. And Hunter. T .. Phosphorvlation sites in cnolase and lactate dehydrogenase utilized by tvrosine protein kinases in \ 'ivo and in vitro., /. Biol. Chem .. 259. 7835-7841 (1984)). The reaction was quenched after 10 minutes by the addition of 10% trichloroacetic acid. 100 mM sodium pyrophosphate. followed by 2 mg / ml bovine serum albumin. Pad

52291 Β with protein-labeled enolase is precipitated at 4 degrees. collected on Packard Unifilter plates and counted in a Topcount scintillation device. to determine the inhibitory activity of the test compound against protein tyrosine kinase (an activity that is inversely proportional to the amount of labeled enolase protein was obtained). The exact reagent concentration and label amount can be varied as needed.

This test is suitable because it uses an exogenous substrate (enolase) to more accurately determine the kinetics of the enzyme. and it can be run in a 96-bit format that is easily automated. In addition. His-labeled protein tyrosine kinases (described below) give much higher production yields and higher purity compared to GST-protein tyrosine kinase fusion protein.

Protein tyrosine kinases can be obtained from commercial sources or can be prepared using the recombinant methods described herein. For the preparation of recombinant Lck, human Lck was prepared as a His-labeled fusion protein using Life Technologies (Gibco) vector baculovirus pFastBac Hta (commercially available) in insect cells. cDNA encoding human Lck. which was isolated by PCR (polymerization chain reaction) was inserted into the vector and the protein was expressed by the procedure described by the manufacturer. Lck was purified by affinity chromatography. For the production of Lck in insect cells using baculovirus. look at Span. C._ O'Rourke, EC, Bolen. JB. and Fargnoli. J .. Analysis of the tvrosine kinase p561ck expressed as a glutatione S-transferase protein in Spodoptera frugiperda cells. ” Protein expression andpurification. Vol. 4. p. 390-397 (1993). Similar methods can be used for the recombinant production of other kinases of the Src family.

Enzyme assay using HER1 or HER2

The compounds of interest were tested in kinase buffer containing 20 mM Tris.HCL pH 7.5, 10 mM MnCB. 0.5 mM dithiothreitol. bovine serum albumin in 0.1 mg / ml. poly (glu / tyr. 4: 1) at 0.1 mg / ml. 1 μΜ ATP and 4 pCi / ml [gamma-ZZR] ATP. Poly (glu / tyr. 4: 1) is a synthetic polymer that serves as an acceptor of the phosphoryl group and is available from Sigma Chemicals. The kinase reaction was initiated by the addition of enzymes and the reaction mixtures were incubated for 1 hour at 26 ° C. The reaction was quenched by the addition of EDTA to 50 mM. proteins were precipitated by the addition of trichloroacetic acid to 5%. The precipitated proteins were recovered by filtration on Packard Unifilter plates and the amount of incorporated radioactivity in the Topcount scintillation device was measured.

52291B

For the preparation of recombinant HER1. the cytoplasmic receptor sequence is expressed in insect cells as a GST fusion protein. which was purified by affinity chromatography, as described above for Lck. The cytoplasmic sequence of HER2 was cloned into the expression vector of the baculovirus pBlueBac4 (Invitrogen) and was expressed as an unlabeled protein in insect cells. The recombinant protein was partially purified by ion exchange chromatography.

Cellular tests

Cellular tyrosine phosphorylation

Jurkat T cells were incubated with the test compound and then stimulated by the addition of antibodies to CD3 (monoclonal antibody G19-4). Cells were lysed after 4 minutes or at another desired time by adding lysis buffer containing NP-40 delergent. Protein phosphorylation is detected by anti-phosphotyrosine immunoblotting. Phosphorylation detection of specific proteins of interest. such as ZAP-70. is performed by immunoprecipitation with anti-ZAP-70 antibody. followed by anti-phosphotyrosine immunoblotting. Such procedures are described in Schieven. GL. Mittler. RS, Nadler. SG. Kirihara. JM, Bolen. JB, Kanner. SB. and Ledbetter. YES. ZAP-70 tyrosine kinase. CD45 and T cell receptor involvement in UV and H2Oh2 induced T cell signal transduction. J. Biol. Chem .. 269. 20718-20726 (1994). as well as in the literature whose references are cited herein. Lck inhibitors inhibit cellular protein tyrosine phosphorylation induced by anti-CD3 antibodies.

To prepare G19-4. look at Hansen. YES. Martin. PJ. Beatty. PG. Clark. EA. and Ledbetter. YES. Human T lymphocyte cell surface molecules defined by the workshop monoclonal antibodies, Leukocy1e Typing 1. A. Bemard. J. Boumsell. .1. Dausett. C. Milstein, and S. Schlossman. eds. (New York: Springer Verlag). p. 195-212 (1984): and Ledbetter. YES. June. CH. Rabinovitch. PS. Grossman, A .. Tsu. TT. and Imboden. JB. Signal transduction through CD4 receptors: stimulatorv vs. inhibitory activity is regulated by CD4 proximity to the CD3 / T cell receptor. Eur. J. hnmitnoL · 18. 525 (1988).

Calcium analysis

Lck inhibitors stop the mobilization of calcium in T cells that is stimulated by anti-CD3 antibodies. The cells are filled with a color indicator for calcium. indo-1. treated with an anti-CD3 antibody such as monoclonal antibody G19-4 and calcium mobilization was measured using flow cylometry by recording changes in the blue / purple ratio

52291 Β indo-1. as described in Schieven, GL. Mittler. RS. Nadler. SG. Kirihara. JM. Sick. JB. Kanner, SB. and Ledbetter. YES. ZAP-70 tyrosine kinase. CD45 and T cell receptor involvement in UV and NJOz induced T cell signal transduction. .7. Biol. Chem .. 269. 20718-20726 (1994). as well as in the literature whose references are cited herein.

Proliferation analysis

Lck inhibitors inhibit the proliferation of normal human peripheral blood T cells that are stimulated to grow with anti-CD3 plus anti-CD28 antibodies. Monoclonal antibodies to CD3 (such as G19-4) were applied to the 96-well plate, the antibody was allowed to bind, and then the plate was washed. Plate antibody serves to stimulate cells. Normal human peripheral blood T cells are added to the ventricles along with the test compound plus anti-CD28 antibody, to provide costimulation. After the desired period of time (e.g. 3 days), [3H] -thymidine is added to the cells. and after additional incubation. which is needed to enable the incorporation of markers into newly synthesized DNA. cells are collected and counted in a scintillation device to measure cell proliferation.

The following examples illustrate embodiments of the present invention. without limiting the scope of patent claims. The abbreviations used in the examples are defined below. The compounds of the example are indicated by the number of examples and the step in which they are prepared (e.g., 1A denotes the title compound of step A of Example 1), or are indicated only by the example where the compound is the title compound of the example (e.g., 2 denotes the compound of the title of Example 2).

Abbreviations aq. = Water conc. = concentrated

DMSO = dimethylsulfoxide

EtOAc = ethyl acetate

Et2O = diethyl ether x = hours

HATU = N- [dimethylamino-1H1,2,3-triazolo- [4,5-b] pyridin-1-ylmethylene] -N-methyl methanamine hexafluorophosphate N-oxide

MeOH = methanol

52291B

MOPS = 4-morpholine-propanesulfonic acid

MS = mass spectrometry

Retention time = retention time

RT = room temperature satd. = saturated

TFA = trifluoroacetic acid

THF = tetrahydrofuran

DMF = N, N-dimethylformamide

52291 Β

Example 1

Preparation of 1,1-dimethyl ester of [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid

L. Ethyl 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate

Ethyl 2-amino-4-methyl-thiazole-5-carboxylate suspension (18.6 g, 100 mmol). of di-tbutyldicarbonate (26.2 g. 120 mmol) and 4-dimethylaminopyridine (800 mg. 6.55 mmol) in dry tetrahydrofuran (300 mL) was stirred under nitrogen for 18 hours. The solvent was evaporated in vacuo. The residue was suspended in dichloromethane (1 L) and filtered through a pad of celite. The filtrate was washed with 1N aqueous HCl (300 mL. 2x). with water and saline. dried (MgSCU) and concentrated in vacuo. The residue was triturated with hexanes. The solid was filtered and dried in vacuo to give the title compound (20 g, 72%) as a tan solid.

B. 2-tert-Butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid

A mixed solution of ethyl 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (10 g, 34.95 mmol) in tetrahydrofuran-ethanol (250 mL. 2: 3) was treated with 6N KOH solution (250 rnL). The mixture was heated to 55 ° C overnight. The solution was cooled to 0 ° C and acidified with concentrated HCl to pH 1. The solvent was evaporated in vacuo. The residue was washed with water. diethyl ether, dried in vacuo over anhydrous phosphorus pentoxide. to give the title acid (6 g, 89%) as a white solid.

C. 2-tert-Butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid chloride

A M solution of oxalyl chloride in dichloromethane (22.5 mL. 45 mmol) was added dropwise to a mixed suspension of 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid (10 g. 38.72 mmol) in dichloromethane (150 mL) and NN -dimethylformamide (150 niL) at 0 ° C. As the addition is complete, the suspension gradually becomes homogeneous. The solution was allowed to warm to room temperature and stirred at room temperature for 1.5 hours. The solvent was evaporated in vacuo and the residue was evaporated with toluene (300 mL. 2x). and then dried in vacno. to give the title acid chloride (10.7 g. 99%) as a tan solid.

52291B

D. 1,1-Dimethyl ester [5-1 [(2,4,6-trimethylphenyl) amino] carbonyl-4-methyl-2-thiazolyl] carboxylic acid

2,4,6-Trimethylaniline (6.3 mL. 38.66 mmol) was added dropwise to a stirred solution of 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid chloride (10.7 g, 38.66 mmol) in dichloromethane (150 mL) at 0 °. C. After 20 min, diisopropylethylamine (8.8 mL, 44.88 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for another 2 hours. The solvent was evaporated in vacuo. The residue was suspended in EtOAc (700 mL). washed with 1 N aqueous HCl (300 mL. 2x). water and saline; dried (MgSO4). filtered and concentrated. The residue was triturated with ether. to give the title compound (12.5 g. 86%) as a tan solid.

Example 2

Preparation of 2-amino-N- (2,4,6-trimethylphenyl) -4-methyl-5-thiazolecarboxamide

A solution of 1,1-dimethyl ester [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid (10 g. 26.63 mmol) in trifluoroacetic acid (100 mL) was stirred at room temperature for 3 hours. . The solution was concentrated under reduced pressure and the residue was diluted with EtOAc (700 mL). washed with 5% aqueous KHCO 3 (400 mL. 2x). water and saline; dried (MgSO4). filtered and concentrated. The residue was washed with ether (200 mL) and acetonitrile (100 mL). to give the title compound (6.7 g. 91%) as a white solid.

Example 3

Preparation of 5-[[(2,4,6-trimethylphenyl) amino] carbonyl] -4-trifluoromethyl2-thiazolyl] carbamic acid 1,1-dimethyl ester

52291B

Α. Ethyl 2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylate

Ethyl 2-amino-4-trifluoromethyl-thiazole-5-carboxylate suspension (5.05 g, 21.02 mmol). di-t-butyldicarbonate (4.82 g. 22.07 mmol) and 4-dimethylaminopyridine (260 mg. 2.1 mmol) in dichloromethane (209 mL) was stirred under nitrogen for 1.5 h. The solvent was evaporated in vacuo. The residue was chromatographed on silica gel. Elution with 5% EtOAc in hexanes followed by 15% EtOAc in hexanes gave the title compound (6.57 g, 92%) as a white solid.

B. 2-tert-Butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylic acid

A stirred solution of ethyl 2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylate (6.5 g, 19.1 mmol) in methanol (100 mL) was treated with 1N aqueous NaOH (573 mL). The mixture was stirred at room temperature overnight. The solution was cooled to 0 ° C and acidified with 6 M aqueous HCl to pH 1 and extracted with chloroform (150 mL. 6x). Chloroform extracts were combined. dried (Na 2 SO 4), filtered and concentrated under reduced pressure and in vacuo. to give the title acid (5.75 g. 96%) as a white solid.

C. ________ 1,1-Dimethyl ester _______ [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -4-trifluoromethyl] -2-thiazolylcarbamic acid

4-Methylmorpholine (40 pL, 0.39 mmol) was added to a mixture of 2-tert-butoxycarbonyloxyamino-4-trifluoromethyl-thiazole-5-carboxylic acid (100 mg. 0.32 mmol), 2,4,6-trimethylamine (45 pL. 0.32 mmol) and benzotriazole -1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP reagent. 380 mg. 0.4 mmol) in DMF (2 mL). The solution was stirred at room temperature for 72 hours. diluted with dichloromethane and washed with 0.25 M aqueous KHSO4. and then with saturated aqueous K.HCO3. The dichloromethane extracts were separated. dried (NaiSC ^). filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 5% EtOAc in hexanes. and then with 10% EtOAc in hexanes. to give the title compound (90 mg, 65%) as a white solid.

52291B

Example 4

Preparation of 2-amino-N- (2,4,6-trimethylphenyl) -4-trifluoromethyl-5-thiazolecarboxamide.

trifluoroacetate (1: 1)

A solution of 1,1-dimethylethyl ester [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -4-trifluoromethyl-2-thiazolyl] carbamic acid (120 mg, 0.28 mmol) in trifluoroacetic acid (5 mL) was stirred at 0 ° C 1 time. The solution was concentrated under reduced pressure and the residue was evaporated with ether to give a yellow solid which was converted to a powder with hexanes. to give the title compound (96 mg, 76%) as a light yellow solid.

Example 5

Preparation of 1,1-dimethyl ester r5-rf (2,4,6-trimethylphenyl) aminocarbonyl-4-phenyl-2-thiazolylcarbamic acid

A. Ethyl 2-tert-butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylate

Compound 5A was prepared by a method analogous to the procedure for preparing compound ZA. with the difference that ethyl 2-amino-4-phenyl-thiazole-5-carboxylate was used herein to give the title compound 5A as a white solid (90.5%).

B. 2-tert-Butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylic acid

52291B

Compound 5Β was prepared using a procedure analogous to that for compound ZV, except that compound 5A was used herein to give the title compound 5B as a white solid (99%).

C. 2-tert-Butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylic acid chloride

Compound 5C was prepared using a procedure analogous to that for compound 1C, except that compound 5B was used herein to give the title compound 5C as a white solid (90%).

D. ___________ 1,1-Dimethylethyl ester ___________ [5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -4-phenyl-2-thiazolylcarbamic acid

Compound 5D was prepared using a procedure analogous to the procedure for preparing compound 1D. with the proviso that compound 5C was used herein to give the title compound 5D as a light yellow solid (93%).

Example 6

Preparation of 2-amino-N- (2A6-trimethylphenyl) -4-phenyl-6-thiazolecarboxamide.

trifluoroacetate (1: 1)

Compound 6 was prepared using a procedure analogous to that for compound 4, except that compound 5D was used herein to give the title compound 6 as a white solid (68%).

Example 7

Preparation of 1,1-dimethylethyl ester of r5 - [[phenylamino] carbonyl] -4-phenyl-2-thiazolylcarbamic acid

52291B

The compound was prepared using a procedure analogous to the procedure for the preparation of compound 1D. with the difference that aniline is used here instead of 2.4.6 trimethylaniline and triethylamine instead of diisopropylethylamine. to give the title compound 7 as a beige solid (76%).

Example 8

Preparation of 2-amino-N- (phenyl) -4-methyl-5-thiazolecarboxamide. trifluoroacetate (1: 1)

Compound 8 was prepared using a procedure analogous to the process for the preparation of compound 4. except that compound 7 was used herein to give the title compound 8 as a white solid (68%).

Example 9

Preparation of 1,1-dimethylethyl ester of 5 - [[(2,4-dichlorophenyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid

Compound 9 was prepared using a procedure analogous to the procedure for preparing compound 1D. with the proviso that 2,4-dichloroaniline was used herein to give the title compound 9 as a white solid (28%).

Example 10

52291B

Preparation of 2-amino-N- (2,4-dichlorophenyl) -4-methyl-5-thiazolecarboxamide, trifluoroacetate

Compound 10 was prepared using a procedure analogous to the procedure for the preparation of compound 4. except that compound 9 was used herein to give the title compound 8 as a white solid (100%).

Example 11

Preparation of 5-[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolylcarbamic acid 1,1-dimethylethyl ester

A. Ethyl 2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylate

Compound 11A was prepared using a procedure analogous to the procedure for preparing compound ZA. with the difference that ethyl 2-amino-thiazole-5-carboxylate is used herein. to give the title compound 11A as a white solid (79.5%).

B. 2-tert-Butoxycarbonyloxyamino-thiazole-5-carboxylic acid

Compound 11Β was prepared using a procedure analogous to that for compound ZV. with the proviso that compound 11A was used herein to give the title compound 11Β as a white solid (95.5%).

C. 2-tert-Butoxycarbonyloxyamino-thiazole-5-carboxylic acid chloride

52291B

Compound 11C was prepared using a procedure analogous to the procedure for preparing compound 1C. with the proviso that compound 11Β is used herein to give the title compound 11C.

D. 5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] carbamic acid 11-dimethylethyl ester

Compound 11D was prepared using a procedure analogous to that for compound 1D, except that compound 11C was used herein to give the title compound 11D as a beige solid (70%).

Example 12

Preparation of 2-amino-N- (2,4,6-trimethylphenyl) -4-phenyl-5-thiazolecarboxanide trifluoroacetate (1: 1)

Compound 12 was prepared using a procedure analogous to the process for the preparation of compound 4. except that compound 11D was used herein to give the title compound 12 as a light yellow solid (88%).

Examples 13 to 53

General procedure

Compounds 13 to 53 were prepared following the procedure described below. The corresponding amines (0.40 mmol) and diisopropylethylamine (70 [mu] L. 0.40 mmol) were added to a suspension of compound 1C (100 mg. 0.36 mmol) in dichloromethane (3 mL). The solution was mechanically stirred in a sealed tube at room temperature for 16 hours. The reaction mixtures were diluted with methanol (200 [mu] L) and poured into Varian SCX ion exchange columns (2 g / 6 cc) previously treated with methanol-dichloromethane (8 mL. 1: 1). followed by dichloromethane (8 mL). SCX Column filtration was performed using a Gilson automatic unit. The column was washed sequentially with dichloromethane (9 mL). dichloromethane-methanol (9 mL. 4: 1). dichloromethane-methanol (9 mL. 1: 1). methanol (9 mL). 0.01 M

52291 Β with ammonium hydroxide in methanol (9 mL) and 0.05 M ammonium hydroxide in methanol (9 mL). The eluates were specially collected using an automatic device. and then concentrated using Speed Vac. and product-containing fractions were combined.

HPLC retention time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH, 90% H2O. 0.2% H3BY4) to 100% solvent B (90% MeOH. 10% H2O. 0.2% N3RO4). flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention time (min)</td>

<td> 13</td><td>ns «NzkSNz.... ά;</td><td>5-[- [[(2-methoxy-6-methyl-phenyl) amino] carbonyl] -4-methyl-2-thiazolyl] -carbamic acid 1,1-dimethylethyl ester</td><td> 3.79</td>

<td> 14</td><td>ΣΖ oNzZ <sNzH3Cy> _N NzSuAJ SN3</td><td>4-Methyl5 - [[[3-methyl-4- (1-methylethyl) phenyl] amino] carbonyl] -2-thiazolylcarbamic acid 1,1-dimethylethyl ester</td><td> 4.51</td>

<td> 15</td><td>No.3 HlAu θΓNV sA You nc HČGNzS SN3</td><td>1,1-dimethylethyl ester [5 - [[(4- bromo-2,6-dimethylphenyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid</td><td> 4.24</td>

<td> 16</td><td>oAgSNzSNzNz ^ SIz O άΥ</td><td>1,1-dimethylethyl ester [4-methyl5 - [[[2-methyl-6- (1-methylethyl) phenyl] amino] carbonyl] -2-thiazolylcarbamic acid</td><td> 4.17</td>

<td> 17</td><td>, јХ</td><td>5-[- ([(2,4-dimethylphenyl) amino] carbonyl] -4-methyl-2-thiazole] -carbamic acid 1,1-dimethylethyl ester</td><td> 4.05</td>

52291 Β

<td> 18</td><td>α:,</td><td>1,1-dimethylethyl ester [4-methyl- 5 - [[(2-methylethyl) amino] carbonyl] -2-thiazolylcarbamic acid</td><td> 3.87</td>

<td> 19</td><td>jLld sn3CI</td><td>5-[[(2-chloro-6-methylphenyl) amino] carbonyl] -4-methyl-2-thiazolecarbamic acid 1,1-dimethylethyl ester</td><td> 3.86</td>

<td> 20</td><td>Ll „SN3Nz <UoNzS Δ-Ν sNd0 US n3with 0 Ch.H. ^ h ^.SNz</td><td>1,1-dimethylethyl ester [5 - [[[2- (11-Dimethylethyl) -4methylphenyl] amino] -carbonyl4-methyl-2thiazolylcarbamic acid</td><td> 4.30</td>

<td> 21</td><td>sg SN3 ° SN3</td><td>5-[[(2-furanylmethyl) amino aminocarbonyl] -4-methyl-2-thiazolyl] carbamic acid 1,1-dimethylethyl ester</td><td> 3.54</td>

<td> 22</td><td>n s /SNzH3° Ao »3 ° W-N Ah N3cool3s' °</td><td>5-[[[3-methoxy-5 (trifluoromethyl) phenyl] amino] carbonyl] -4-methyl-2-thiazolyl] carbamic acid 1,1-dimethylethyl ester</td><td> 4.43</td>

<td> 23</td><td>n s ° Nz VH3<ψ0-λ ° qZT</td><td>5-[[(4-cyclohexyl-phenyl) amino] carbonyl] -4-methyl-2-thiazolyl] -carbamic acid 1,1-dimethylethyl ester</td><td> 4.78</td>

<td> 24</td><td>A $ Α Χγ.</td><td>1,1-dimethylethyl ester [5- [[(cyclohexylmethyl) amino] carbonyl] -4-methyl-2-thiazolyl] carbamic acid</td><td> 4.21</td>

52291B

<td> 25</td><td>N3S <xr</td><td>1,1-dimethylethyl ester [5 - [[(2,3- dihydro-1H-indenyl) amino] carbonyl] -4-methyl-2-thiazolyl] carbamic acid</td><td> 4.30</td>

<td> 26</td><td>CHj U SNz</td><td>[5 - [(2,5-dihydro-1H-pyrrol-1-yl) carbonyl] -4-methyl-2-thiazolyl] carbamic acid 1,1-dimethylethyl ester</td><td> 3.56</td>

<td> 27</td><td>NzS-L JL N ^ CH3 glčAA · CH3U SN3</td><td>1,1-dimethylethyl ester [5 - ((2,5-dihydro-2,5-dimethyl-1H-pyrrole- 1-yl) carbonyl] -4-methyl-2-thiazolylcarbamic acid</td><td> 3.86</td>

<td> 28</td><td>fAbs)</td><td>l - [[2 - [[(ll- dimethylethoxy) carbonyl] amino] -4-methyl-5-thiazolyl] carbonyl] L-prolinamide</td><td> 2.96</td>

<td> 29</td><td>CH3{) X— N /) 0</td><td>1,1-dimethylethyl ester [5 - ((4- formyl-1piperazinyl) carbonyl] -4-methyl2-thiazolyl] carbamic acid</td><td> 2.90</td>

<td> 30</td><td>VQy r = 0 S ^ nA ^ CH, SN3</td><td>1,1-Dimethylethyl ester (5- (1,4-dioxa-8-azaspiro [4.5] decan-8-ylcarbonyl) -4-methyl-2-thiazolylcarbamic acid)</td><td> 3.54</td>

<td> 31</td><td>n3snz <> \ = o <) N3S Ihluu SN3</td><td>1,1-dimethylethyl ester [5 - ((3- [(diethylamino) carbonyl] -1-piperidinyl] carbonyl] -4-methyl2-thiazolyl] carbamic acid</td><td> 3.66</td>

<td> 32</td><td>N3S ^ SN3</td><td>1,1-dimethylethyl ester [4-methyl- 5 - [(octahydro-quinolinyl) carbonyl] -2-thiazolylcarbamic acid</td><td> 4.37</td>

52291B

<td> 33</td><td>N3S NzS-E0143č žsg · SN3U SN3</td><td>2 - [[(1,1-dimethylethoxy) carbonyl hydrazide 2 - [[(1.1- dimethylethoxy) carbonyl] amino] -4-methyl-5-thiazolecarboxylic acid</td><td> 3.50</td>

<td> 34</td><td>VXh3rrNH5C'/ V</td><td>[5 - [(4 (methoxyphenyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid 11-dimethylethyl ester</td><td> 3.83</td>

<td> 35</td><td>m r 0 \ <SNzuu ° · Ω n3s</td><td>1,1-dimethylethyl ester [4-methyl- 5 - [[(4- methylphenyl) amino] carbonyl] -4methyl-2-thiazolyl] carbamic acid</td><td> 4.07</td>

<td> 36</td><td>n3sH3t mS NzS ^ /NzSN3 OG-SNz SNz</td><td>5 - [[(1,2-dimethylpropyl) amino] carbonyl] -4-methyl-2-liazolyl] carbamic acid 11-dimethylethyl ester</td><td> 3.87</td>

<td> 37</td><td>NzS-SIz GSN3 ž 3 ° sn3</td><td>5-[- ([(2,2-dimethylpropyl) amino] carbonyl] -4-methyl-2-thiazole] -carbamic acid 1,1-dimethylethyl ester</td><td> 3.97</td>

<td> 38</td><td>sn3 ^ Hsn, OuO zKt n3s</td><td>1,1-dimethylethyl ester [4-methyl- 5 - [(2- propynylamino) carbonyl] -2thiazolyl] carbamic acid</td><td> 3.22</td>

<td> 39</td><td>n2s ^ SN3 ° SNz</td><td>1,1-dimethylethyl ester (4-methyl- 5 - ((2- propenylamino) carbonyl] -2thiazolyl] carbamic acid</td><td> 3.41</td>

52291B

<td> 40</td><td>"- The H3VCHsSN’</td><td>1,1-dimethylethyl ester [4-methyl- five- [(methylphenylamino) carbonyl] -thiazolyl] carbamic acid</td><td> 3.75</td>

<td> 41</td><td>«· Ν rn3 V>N H3.χτΝN3sh°</td><td>1,1-dimethylethyl ester [4-methyl- 5 - [[(3,4,5-trimethoxyphenyl) amino] carbonyl] -2-thiazolylcarbamic acid</td><td> 3.84</td>

<td> 42</td><td>ns 2'V30,13NzS ^ SNru ^ s cL SN3</td><td>5-[[[2.6Bis [1-methylethylphenyl] amino] carbonyl] -4-methyl-2-thiazolyl] carbamic acid 1,1-dimethylethyl ester</td><td> 4.40</td>

<td> 43</td><td>NASNzN3S- <... 0 N nX NzL ( \ -Ν</td><td>1,1-dimethylethyl ester [5 - [[[3 (1H-imidazol-1- yl) propyl] amino] carbon and 1] -4-methyl-2-thiazolyl] carbamic acid</td><td> 2.45</td>

<td> 44</td><td>n3s sn3N3SG% X. HE HAS ' O F</td><td>5-[[[[(3,4-difluorophenyl) methyl] amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid 1,1-dimethylethyl ester</td><td> 3.97</td>

<td> 45</td><td>SN3 ® -SNz= G> sn % _l ° The J№ N H3C ^ NV0<X 3 n3s sn3</td><td>N;[[2 - [[(1,1-dimethylethoxy) carbonyl] amino] -4-methyl-2-thiazolyl] carbonyl] L-leucine methyl ester</td><td> 3.99</td>

52291B

<td> 46</td><td>M2cNOIzsLo σ = 4 (ΤΝ 0</td><td>methyl ester 5 - [[[2 - [[(1.1- dimethylethoxy) carbonyl] amino] -4-methyl-5-thiazolyl] carbonyl] amino] -4-oxovaleic acid</td><td> 3.27</td>

<td> 47</td><td>Nz ^ , S Ί_ CH3 ° SN3</td><td>5-[- [[[2 (ethylthio) ethyl] amino] carbonyl] 4-methyl-2-thiazolylcarbamic acid 1,1-dimethylethyl ester</td><td> 3.75</td>

<td> 48</td><td>sn3n3s \ n3s ~ T-0 / SN3 N3s SNz</td><td>1,1-dimethylethyl ester [5- [[Bis (3-methylbutyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid</td><td> 4.67</td>

<td> 49</td><td>The Nz? , The n3s; ^gd ₽Nz N3S O-tCH3SNz</td><td>1.1-dimethylethyl ester [5- [[ethyl (1-methylethyl) amino] carbonyl] -4-methyl-2-thiazolyl] carbamic acid</td><td> 3.84</td>

<td> 50</td><td>N3S SNz H3cX% a Froms yN s α The</td><td>2 - [[(3,5-dichlorophenyl) amino] thioxomethyl] 2 - [[(1-dimethylethoxy) carbonyl] amino] -4-methyl-2-thiazolecarboxylic acid hydrazide</td><td> 4.66</td>

<td> 51</td><td>^ SNzNzr o --0 NzS νχ \ NzS-ho 1 sn3 χ n3s</td><td>1.1-dimethylethyl ester [5- [[Bis (2-ethoxyethyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid</td><td> 3.83</td>

<td> 52</td><td>M=% SNz Nze + o 4 -h ·</td><td>4-methyl5 - [[3 - [(trifluoroacetyl) amino] 1-pyrrolidinyl] carbonyl] -2-thiazolylcarbamic acid 1,1-dimethylethyl ester</td><td> 3.47</td>

52291 Β

Examples 54 to 129

General procedure

Compounds 54 to 129 were prepared following the procedure described below. Diisopropylethylamine (60 [mu] L, 0.34 mmol) was added to a mixture of amine 2 (30 mg, 0.11 mmol). corresponding carboxylic acids (0.13 mmol). 1-Hydroxy-7-azabenzotriazole (19.5 mg. 0.14 mmol) and ethyl 3- (3-dimethylamino) -propylcarbodiimide hydrochloride (26.8 mg. 0.14 mmol) in THF (0.4 mL). The mixture was heated in a sealed tube under argon to 45 ° C. 24 hours. The reaction mixture was diluted with dichloromethane (4 mL) and washed with 2N aqueous HCl (2 mL. Zh). The solution in dichloromethane was passed through a Varian SCX cation exchange column (2 g. 6 cc) on a Gilson automatic device. The column was eluted sequentially with acetonitrile-methanol (10 mL. 4: 1). methanol-2M solution of ammonia in methanol (3 mL. 4: 1) and 2M solution of ammonia in methanol (3 mL. 4x). Fractions were collected individually using a Gilson automatic device. The product-containing fractions were concentrated and dried in vacuo. HPLC retention time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% NJO. 0.2% H3BY4) to 100% solvent B (90% MeOH, 10% NJO. 0.2% N3RO4). flow rate 4 mL / min. λ = 220 nM for compounds 54-127. For compounds 128-129 HPLC the conditions are: Zorbax S8-C18 4.5 mm x 7.5 s short column. 8 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3BY4) to 100% solvent B (90% MeOH. 10% NJO. 0.2% N3RO4). flow rate 2.5 mL / min. λ = 217 πΜ.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 54</td><td>ΛΖ SNz N3S * 0 ο o Jč. rcs N3S ^> ^ SNz LC!</td><td>2 - [[(2.2-dichloro-1- methylcyclopropyl) carbonyl] amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.22</td>

52291B

<td> 55</td><td>Ž</td><td>2 - [(cyclohexylacetyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.47</td>

<td> 56</td><td>^ zS ^^^ SNz</td><td>2 - [(2,5-difluoro-benzoyl) amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.15</td>

<td> 57</td><td>Αχ ·· v / T Rnwith .X.</td><td>2 - [(5-bromo-2-chlorobenzoyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.37</td>

<td> 58</td><td>OG », il n, s</td><td>2 - [(3-cyano-benzoyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.06</td>

<td> 59</td><td>N from ^ /CH3 the3ΜΎ X / -N QH3Wa° ^ Cjf Α · .. n-4 o</td><td>2 - [[4- (acetylamino) benzoyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.60</td>

<td> 60</td><td>n / CH3</td><td>4-methyl-2 - [[3- (trifluoromethyl) benzoyl] amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.45</td>

<td> 61</td><td>, SN3and rVTLS N - CH3n3S</td><td>4-methyl-2 - [[2- (2- phenylethyl) benzoyl] -amino] -N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.64</td>

52291B

<td> 62</td><td>n3with SNz gg4 /mA_ / SNz n3N^~~S ° I3 SSN3</td><td>2 - [(3,5-dimethyl-benzoyl) amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.49</td>

<td> 63</td><td>lN and Xjl Hg S N3 S SNz</td><td>2 - [(4-ethenyl-benzoyl) amino] -4methyl-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td></td>

<td> 64</td><td>snzAA ~ N SNz snAg> X SN3</td><td>2 - [(4-butyl-benzoyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.58</td>

<td> 65</td><td>/ SN3V - / - N Assoc S = N3</td><td>4-methyl-2 - [(4- pentylbenzoyl) amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.76</td>

<td> 66</td><td>nuSIz n, <> D NzS ^^ SNz</td><td>4-methyl-2 - [(2-methyl-1 - oxohexyl) amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.41</td>

<td> 67</td><td>N /CH3 H = (/ -4 9nwith a NzSgO ^ sNz</td><td>4-methyl-2 - [(1-oxo-3- phenoxypropyl) amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.21</td>

<td> 68</td><td>^ SNz / = \ g \ '?n'ž</td><td>4-Methyl-2 - [(1-oxo-3-phenylpropyl) amino] -N - (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.26</td>

52291B

<td> 69</td><td>, čS • sA Α N3S '^^' SN3</td><td>2 - [[3- (2-Methoxy-phenyl) -loxopropyl] amino] -4-methyl-N (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.31</td>

<td> 70</td><td>N3S '<^ SNz</td><td>4-methyl-2 - [(2-naphthalenylacetyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.43</td>

<td> 71</td><td>nzS sndHOO nz <Hd d) sn3</td><td>2 - [(diphenyl-acetyl) amino] -4-methyl- N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.13</td>

<td> 72</td><td>Ζ ^ Χ-οι / hfCHsV-νΛνν0Ф ^ -Ч & G?Nwith ž</td><td>2 - [[(2-chloro-6- fluorophenyl) acetyl] amino] -4-methylN- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.17</td>

<td> 73</td><td>sn3A g... , Α.</td><td>4-methyl-2 - [[(2-methylphenyl) - acetyl] amino] -N-2,4,6-trimethyl- phenyl) -5-thiazolecarboxamide</td><td> 3.95</td>

<td> 74</td><td>“ΆΆ>. ”Α ...</td><td>2 - [[(3-methoxyphenyl) acetyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.11</td>

<td> 75</td><td>SN3ό <> -SN3 χχ A.</td><td>2 - [[(3,4-dimethoxy- phenyl) acetyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 3.90</td>

52291B

<td> 76</td><td></td><td>2 - [[(4-chloro-phenyl) acetyl] amino-4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.34</td>

<td> 77</td><td>T r, ž.</td><td>2 - [[[1H-biphenyl] -4- ylacetyl) amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.60</td>

<td> 78</td><td>ćk-HSNz\ = / λ - ^^ 'ι *0 9nz A NzS ^^^ SNz</td><td>4-Methyl-2 - [(1-oxo-4-phenylbutyl) amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.40</td>

<td> 79</td><td>N3S-7 NzSG ^^ SNz</td><td>4-methyl-2 - [(1-oxooctyl) amino] - N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.65</td>

<td> 80</td><td>n ^SNzfrom + ν g. no TO CzsDAsN3</td><td>2 - [(2-hydroxy-2-phenyl-1- oxopropyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.13</td>

<td> 81</td><td>N - / *3NzS ^^^^ SNz</td><td>2 - [(2-hydroxy-loxohexyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.14</td>

<td> 82</td><td>j ^SNz h ° T 'NzS ^^^ SNz</td><td>4-methyl-2 - [[1-oxo-4- (2-thienyl) butyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.32</td>

<td> 83</td><td>., / You . .UjSg + H OD, o DL ° ° N3S ^^ SNz</td><td>4-methyl-2 - [(3- thienylcarbonyl) amino] -N- (2,4,6-trimethyl-phenyl) -5- thiazolecarboxamide</td><td> 4.04</td>

52291B

<td> 84</td><td>Μ ΧΗ3Ο ~ ο 0 “nzDAsn,</td><td>2 - [(2-benzofuranylcarbonyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.37</td>

<td> 85</td><td>l, sn3° ^ zsA ^ H ^ sNz</td><td>N- [4-methyl-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] 4-pyridinecarboxamide. N-oxide</td><td> 3.50</td>

<td> 86</td><td>m -SN3NJS ^^ SNz</td><td>6-chloro-N- [4-methyl-5 - [[(2.4.6- trimethyl-phenyl) amino] carbonyl] -2- thiazolyl] -3-pyridinecarboxamide</td><td> 4.08</td>

<td> 87</td><td>m /SN3 ^ zS ^^ SNd</td><td>N- [4-methyl-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] 3-pyridinecarboxamide</td><td> 3.56</td>

<td> 88</td><td>^ From sn 0 O jZ. jL ς rn3s ^^ sn3</td><td>N- [4-methyl-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] 3-quinolinecarboxamide</td><td> 4.11</td>

<td> 89</td><td>4¾ -d NzS ^^ SNz</td><td>4-methyl] -2 - [[(4-nitrophenyl) acetyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.08</td>

<td> 90</td><td></td><td>4-methyl-2 - [(2,4,6- trichlorobenzoyl) amino] -N- (2.4.6 trimethylphenyl) -5thiazolecarboxamide</td><td> 4.45</td>

<td> 91</td><td>R AjL /snwith 2> G0 N - Z SNzf AΛΝ '^ ΡγΝγ4 M VzAAn,</td><td>4-methyl-2 - [[2 - [[3- (trifluoromethyl) phenyl] amino] benzoyl] amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.86</td>

<td> 92</td><td>'Wi>. NzS ^^ SNz</td><td>4-methyl-2 - [[4- (4-nitrophenyl) -1 - oxobutyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.28</td>

52291B

<td> 93</td><td>1 Rnwith uGSNz ? G> -SN3A NzS '%</td><td>4-methyl-2 - [[4- (methylsulfonyl) - benzoyl] -amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 3.79</td>

<td> 94</td><td>_hSN3H3C ~ ^ Y SN3N sn3</td><td>2 - [(4-heptylbenzoyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td></td>

<td> 95</td><td></td><td>2 - [[(2,4-difluoro- phenyl) acetyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.15</td>

<td> 96</td><td>sn3 ® ž. ...</td><td>(S) -2 - [[2- (dipropylamino) -1 - oxopropyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 3.20</td>

<td> 97</td><td> ,snz N- \ / ~ SNz P GGUCH χγΧ, Λ '' ОН, С</td><td>2 - [(2-biphenylenecarbonyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.64</td>

<td> 98</td><td>M ^ /SNwith Lg °a ν Λ NdS-O n3s '^^' sn3</td><td>2 - [[3- (3-methoxyphenyl) -loxopropyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.26</td>

52291B

<td> 99</td><td>N3S YES N3S / snΧχ. 1 SN3D</td><td>4-methyl-N- (2,4,6-trimethylphenyl) -2- [[(2,4,6-trimethyl- phenyl) acetyl] amino] -5- thiazolecarboxamide</td><td> 4.52</td>

<td> 100</td><td>/ ASNz/ AJč N2S NzsAAsNz</td><td>4-methyl-2 - [(1-oxo-6-heptenyl) amino] -N- (2,4,6-trimethylphenyl) -5- you azolecarboxamide</td><td> 4.47</td>

<td> 101</td><td>° ž.</td><td>2 - [[(1,3-benzodioxol-5-yl) acetyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.07</td>

<td> 102</td><td>j јХ</td><td>4-methyl-2 - [[[2- (phenylmethoxy) phenyl] acetyl] amino- N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.46</td>

<td> 103</td><td>NzsH ^ SNj</td><td>4-methyl-2 - [[(3- phenoxyphenyl) acetyl] amino] -N (2,4,6-trimethylphenyl) -5- you azolecarboxams d</td><td> 4.56</td>

<td> 104</td><td>O-SNz n3sno / X №_ <SNzNzsA ^ SNz</td><td>2 - [(3,5-dimethoxy- phenyl) acetyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.13</td>

<td> 105</td><td>ACI/ -N ž.</td><td>2 - [[4- [4- [Bis (2-chloroethyl) amino] phenyl] -loxobutyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.75</td>

52291B

<td> 106</td><td>and3N3s-O α / sn A N3S o</td><td>4 - [[4 - [[[4-methyl-5-] methyl ester [[(2,4,6- trimethylphenyl) amino] carbonyl] -2thiazolyl] -amino] carbonyl] phenyl] amino] -4-oxanoic acid</td><td> 4.03</td>

<td> 107</td><td>Ol ° o snthe, AA,</td><td>4-methyl-2 - [[(phenyl- sulfonyl) acetyl] amino] -N- (2.4.6- trimethylphenyl) -5thiazolecarboxamide</td><td> 3.77</td>

<td> 108</td><td>> -Ν 0NzS eleven NzS ^^ SNz</td><td>2 - [[2- (acetylamino) -1-oxohexyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.99</td>

<td> 109</td><td>_LNJ the3ο ^ Ύ U4? N3snwithThe> A_ ^ 0. oO '</td><td>2 - [[4 - [(dipropylamino) sulfonyl] benzoyl] amino] -4methyl-N- (2,4,6-trimethyl-phenyl) -5- you azole -carboxamide</td><td> 4.51</td>

<td> 110</td><td>, sn3 NzsA n G sn3-N</td><td>2 - [(4-cyclohexyl-benzoyl) amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.94</td>

<td> 111</td><td>N3s</td><td>2 - [(4-bromo-3-methylbenzoyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.80</td>

52291B

<td> 112</td><td></td><td>2 - [[(2.3- difluorophenyl) acetyl] amino] -4- methyl-N- (2,4,6-trimethyl-phenyl) -5- thiazole-carboxamide</td><td> 4.14</td>

<td> 113</td><td>sn3 n3s -No. The oH -HSNzn, Hk „,</td><td>4-methyl-2 - [[[[4- (1-methylethyl) phenyl] acetyl] amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.56</td>

<td> 114</td><td>and3uG SNzNzS SN3</td><td>2 - [[[4- (1,1-dimethyl- ethyl) cyclohexyl] carbonyl] amino] - 4-Methyl-N- (2,4,6-trimethyl-phenyl) -5-thiazole-carboxamide</td><td> 4.85</td>

<td> 115</td><td>7VCH3n3s-L 1 1 SN3 NzS ^^ SNj</td><td>N, N-dimethyl-N '- [4-methyl-5- [[(2.4.6- trimethylphenyl) amino] carbonyl] -2- thiazolylbutanediamide</td><td> 3.50</td>

<td> 116</td><td>~ XX A-.</td><td>2 - [(1,6-dioxohexyl) amino] -4methyl-N- (2,4,6-trimethyl-phenyl) -5thiazolecarboxamide</td><td> 4.40</td>

<td> 117</td><td>σΧΧΧb N3S ^^ sn3</td><td>2 - [(benzo [b] thiophene-2- ylcarbonyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.53</td>

<td> 118</td><td>sn3jČ-ν H3In YtnNzS 4==7-VA ^ i1CHgCJ ^ S ^ hAo</td><td>2 - [(1-adamantyl-carbonyl) amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.66</td>

52291B

<td> 119</td><td>, sn3</td><td>4-methyl-2 - [[(4- methylcyclohexyl) carbonyl] amino] - N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.48</td>

<td> 120</td><td>hs, SND</td><td>2 - [(1,7-dioxooctyl) -amino] -4methyl-N- (2,4,6-trimethyl-phenyl) -5thiazole-carboxamide</td><td> 3.88</td>

<td> 121</td><td>Uo5r... 2 ž.</td><td>2 - [[2- (acetylamino) -4- (ethylthio) -1-oxobutyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.93</td>

<td> 122</td><td>«, <> O%sAA0Iz</td><td>1,5-dimethyl-N- [4-methyl-5 - [[(2,4,6- trimethylphenylamino] carbonyl] -2thiazolyl] -1H-pyrazole-3-carboxamide</td><td> 3.91</td>

<td> 123</td><td>θ4 hi NzSG ^^ SNz</td><td>2 - [[[4-methyl-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2thiazolyl] amino] carbonyl] benzoic acid</td><td> 3.70</td>

<td> 124</td><td>rn3 ^ LN ^ -sn, u n, s</td><td>N- [4-methyl-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] 6-benzo-thiazolecarboxamide</td><td> 4.18</td>

<td> 125</td><td> - ., withch3SN3 RN3WMf \ X 0 ° HaA> CH3sn,</td><td>1-ethyl-4-methyl-N- [4-methyl-5- [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] -1H-pyrazole-3-carboxamide</td><td> 4.09</td>

<td> 126</td><td> ., WITHCH3GH “s XIin NzS - ^^ SNz r N-4</td><td>4-methyl-2 - [[3 - [(3H-1.2.3- triazolo [4,5-b] pyridin-3-yloxy) methyl] benzoyl] amino] -N (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.15</td>

52291B

<td> 127</td><td>fu /CH3 GM s * 0 ° ° Nz <A \ n3</td><td>2 - [(2-furanyl-carbonyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.45</td>

<td> 128</td><td>// ° N. /SN3</td><td>2 - [(4-chloro-benzoyl) amino] -4methyl-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 8.85</td>

<td> 129</td><td>sn</td><td>2 - [(2,2-dimethyl-1- oxopropyl) amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.30</td>

Example 130

Preparation of N-dimethylethyl ester [4-methyl-5 [[(2-nitrophenyl) aminocarbonyl] -2-thiazolylcarbamic acid

2-Nitroaniline (55 mg. 0.4 mmol) and diisopropylethylamine (70 μL. 0.4 mmol) were added dropwise to a mixed solution of 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid chloride 1C (100 mg. 0.36 mmol) in dichloromethane (3 mL). After 16 hours at room temperature. 4-1H-Dimethylaminopyridine (22 mg, 0.18 mmol) was added and the mixture was stirred.

3.5 hours. The solvent was evaporated in vacuo. The residue was subjected to silica gel column chromatography. Elution with 5% EtOAc in hexanes. followed by 20% EtOAc in hexanes to give the title compound (15 mg, 11%) as a yellow solid.

Prirner 131

Preparation of [4-methyl-5 [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolylcarbamic acid phenylmethyl ester

52291 Β

Α. Ethyl 2-benzyloxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate

A ZM aqueous solution of NaHCO 3 (10 mL. 30 mmol) was added to a stirred solution of ethyl 2-amino-4-methyl-thiazole-5-carboxylate (372 mg. 2 mmol) in THF (20 mL) at 0-5cC. Benzyl chloroformate (500 [mu] L) was added. After 2 hours, a new amount of benzyl chloroformate (500 μL) was added and the biphasic solution was stirred for another 2 hours at 0-5 ° C. The mixture was diluted with dichloromethane (50 mL) and N (30 mL). The organic layer was separated, dried (MgSO 4). filtered and concentrated. The residue was subjected to silica gel column chromatography. Elution with 10% EtOAc in hexanes followed by 20% and 30% EtOAc in hexanes. the title compound was obtained (310 mg, 48%) as a white solid.

B. 2-Benzyloxycarbonyloxyamino-4-methyl-thiazole-5-carboxylic acid

Compound 131Β was prepared using a procedure analogous to the process for the preparation of compound ZV, except that compound 131A was used herein to give the title compound 131Β as a white powder (77%).

C. [4-methyl-5-yl (2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] carbamic acid phenylmethyl ester

Diisopropylethylamine (70 μL. 0.41 mmol) was added to a solution of compound 131Β (100 mg. 0.34 mmol), 2,4,6-trimethylaniline (60 μL, 0.41 mmol) and [O- (7-azabenzotriazol-1-yl) - l. 1.3.3tetramethyluronium] hexafluorophosphate (HATU. 160 mg. 0.41 mmol). The mixture was stirred at room temperature for 24 hours. diluted with EtOAc (20 mL) and washed with 2N aqueous HCl (Zh), brine. dried (Na ^ SCh). filtered and concentrated. The residue was triturated with ether (40 mL). to give the title compound (100 mg, 77%) as a beige solid.

Example 132

Preferred 1,1-dimethylethyl ester methyl [4-methyl-5-n (2,4,6-trimethylphenyl) amino] carbonyl]

2-thiazolylcarbamic acid

n ·

52291B

Compound 132 was prepared using a process analogous to that for compound 1, except that ethyl 2-tert-butoxycarbonyloxyaminomethyl-4-methyl-thiazole-5-carboxylate was used herein to give the title compound 132 as a tan solid. substances.

Example 133

Preparation of 4-methyl-2- (methylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide.

trifluoroacetate (1: 1)

Compound 133 was prepared using a procedure analogous to that for compound 4, except that compound 132 was used herein to give the title compound 133 as a white solid (91%).

Example 134

Preparation of 11-dimethylethyl ester [4-methyl-5-[[methyl (2,4,6-trimethylphenyl) amino] carbonyl] 2-thiazolyl] carbamic acid

Compound 134 was prepared using a process analogous to that for compound 1, except that N-methyl-2,4,6-trimethylaniline was used herein. to give the title compound 134 as a white solid (60%).

Example 135

Preparation of 2-amino-N.4-dimethyl-N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide.

trifluoroacetate (1: 1)

52291B

Compound 135 was prepared using a procedure analogous to the procedure for the preparation of compound 4. except that compound 134 was used herein to give the title compound 135 as a white solid (97%).

Example 136

Preparation of [4-methyl-5 - [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolylcarbamic acid methyl ester

A mixture of compound 2 (100 mg, 0.36 mmol). pyridine (87 μL, 1.08 mmol). methyl chloroformate (111 [mu] L 1.44 mmol) in dichloromethane (3 mL) was stirred at room temperature for 1.5 hours. The solution was diluted with dichloromethane and washed with aqueous NaHCO 33 (20 mL, 2x), brine: dried4). filtered and concentrated. The residue was triturated with ether to give the title compound (88 mg, 82%) as a white solid.

Example 137

Preparation of 11-dimethylethyl ester [4-ethyl-5n (2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolylcarbamic acid

52291 Β

Compound 137 was prepared using a process analogous to that for Compound 1. except that methyl 2-amine O'4-ethyl-thiazole-5-carboxylate was used herein. to give the title compound 137 as a white solid (70%).

Example 138

Preparation of 2-amino-4-ethyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide. trifluoroacetate

Compound 138 was prepared using a procedure analogous to the procedure for the preparation of compound 4. except that compound 137 was used herein to give the title compound 138 as a white solid (89%).

Example 139

Preparation of [5 [[(2,6-dichlorophenyl) amino] carbonyl] -4-methyl-2-thiazolylcarbamic acid 11-dimethylethyl ester

A 1M solution of sodium bis-trimethylsilyl amide (290 μL. 0.29 mmol) was added to a stirred solution of 2,6-dichloroaniline (13.4 nig. 0.08 mmol) in THF (1 mL). After 30 min. the mixture was cooled to 0 ° C and compound 1C (30 mg. 0.11 mmol) was added in one portion. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solution was diluted with dichloromethane and washed with 2N aqueous HCl (2 mL. Zh). dried (MgSO4). filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 30% EtOAc in hexanes. to give the title compound (20 mg, 45%) as a light yellow solid.

52291B

Example 140

Preparation of 2-amino-N- (2,6-dimethylphenyl) -4-methyl-5-thiazolecarboxamide.

trifluoroacetate (1: 1)

Compound 140 was prepared using a process analogous to that for compound 4, except that compound 53 was used herein to give the title compound 140 as a light yellow-brown solid (100%).

Example 141

Preparation of 2-amino-N- (2-methoxy-6-methylphenyl) -4-methyl-5-thiazolecarboxamide, trifluoroacetate (1: 1)

Compound 141 was prepared using a procedure analogous to the process for the preparation of compound 4. except that compound 13 was used herein to give the title compound 141 as a beige solid (100%).

Example 142

Preparation of 2-amino-N- (2-methylphenyl) -4-methyl-5-thiazolecarboxamide. trifluoroacetate

ŠP

52291B

Compound 142 was prepared using a procedure analogous to that for compound 4, except that compound 18 was used herein to give the title compound 142 as a light yellow-brown solid (90%).

Example 143

Preparation of 2-amino-N- (2,6-dimethyl-4-bromophenyl) -4-methyl-5-thiazolecarboxamide. trifluoroacetate (1: 1)

Compound 143 was prepared using a procedure analogous to that for compound 4. except that compound 15 was used herein to give the title compound 143 as a tan solid (70%).

Example 144

Preparation of 2-amino-N- (2-chloro-6-methylphenyl) -4-methyl-5-thiazolecarboxamide, trifluoroacetate (1: 1)

Compound 144 was prepared using a procedure analogous to the procedure for the preparation of compound 4. except that compound 19 was used herein to give the title compound 144 as a light yellow-brown solid (81%).

52291B

Example 145

Preparation of 2-amino-N- (2,4-dimethylphenyl) -4-methyl-5-thiazolecarboxamide. trifluoroacetate

Compound 145 was prepared using a procedure analogous to the procedure for the preparation of compound 4. except that compound 17 was used herein to give the title compound 145 as a light tan compound (68%).

Example 146

Preparation of 2-amino-N- (2-methyl-6-isopropylphenyl) -4-methyl-5-thiazolecarboxamide.

trifluoroacetate (1: 1)

Compound 146 was prepared using a procedure analogous to the procedure for the preparation of compound 4. except that compound 16 was used herein to give the title compound 146 as a light tan compound (100%).

Example 147

Preparation of 2- (acetylamino) -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

52291B

A mixture of compound 2 (54 mg. 0.2 mmol). acetic anhydride (22 [mu] L, 0.23 mmol), dimethylaminopyridine (3 mg) in dichloromethane (4.5 mL) was stirred at room temperature for 4.5 hours. The mixture was diluted with dichloromethane (65 mL) and washed with 1N aqueous HCl (20 mL). water; dried (MgSO4). filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 35% EtOAc in hexanes. to give the title compound (43 mg, 69%) as a white solid.

Example 148

Preparation of 2- (benzoylamino) -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

A solution of compound 2 (100 mg. 0.36 mmol) and benzoic anhydride (226 mg. 1 mmol) in dichloromethane (10 mL) and pyridine (2 mL) was stirred at room temperature overnight. The mixture was diluted with dichloroethane (50 mL) and washed with 2N aqueous HCl (15 mL, 2x), 10% aqueous NaHCO 3 (20 mL, 2x); dried (MgSO4). filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 30% EtOAc in hexanes. and then with 50% EtOAc in hexanes. to give the title compound which was contaminated with benzoic acid. The solid was dissolved in EtOAc (40 mL) and washed with saturated KNSO 2 solution (15 mL. 4x). dried (MgSO4). filtered and concentrated to give the title compound (110 mg, 80%) as a white solid.

Example 149

Preparation of 4-methyl-2 - [(1-oxopropyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

52291B

A mixture of compound 2 (100 mg, 0.36 mmol). propionic anhydride (332 [mu] L. 2.58 mmol) in dichloromethane (10 mL) and pyridine (4 mL) was stirred at room temperature for 3 hours. Dimethylaminopyridine (122 mg, 1 mmol) was added and the mixture was stirred for another 1.5 h. The mixture was diluted with dichloromethane and washed with 1N aqueous HCl (25 mL. Zh). aqueous NaHCO 3 (20 mL, 2x). water (20 mL), saline; dried (MgSO4). filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 20% EtOAc in hexanes. to give the title compound (81 mg. 68%) as a white solid.

Example 150

Preparation of 4-methyl-2 - [(1-oxobutyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

Compound 150 was prepared using a process analogous to that for compound 149, except that anhydrous anhydride was used herein. to give the title compound 150 as a white solid (76%).

Example 151

Preparation of 4-methyl-2 - [(1-oxopentyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

Compound 151 was prepared using a procedure analogous to that for compound 149. except that valemic anhydride was used herein to give the title compound 151 as a white solid (77%).

Example 152

52291 Β

Preparation of 4-methyl-2 - [(1-oxohexyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

Compound 152 was prepared using a process analogous to that for compound 149. except that caproic anhydride was used herein. to give the title compound 152 as a white solid (75%).

Example 153

Preparation of 4-methyl-2 - [(phenylcetyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

CH3

Amin 2 solution (50 mg, 0.18 mmol). diisopropylethylamine (101 pL. 0.58 mmol). phenylacetic acid (27.2 mg. 0.20 mmol). 1-Hydroxy-7-azabenzotriazole (29.4 mg. 0.22 mmol) and ethyl 3- (3-dimethylamino) -propyl carbodiimide hydrochloride (42.2 mg, 0.22 mmol) in dichloromethane (0.62 mL) were mechanically stirred in a sealed tube for 16 hours. The reaction mixture was passed through a Varian SCX ion exchange column (2 g / 6 cc) and eluted with acetonitrile-methanol (10 mL). 4: 1) followed by a 2M solution of ammonia in methanol (9 mL). The product-containing fractions were combined and then concentrated. The residue was dissolved in dichloromethane and washed with 2N aqueous HCl (Zh). dried SHazbOd). filtered and concentrated. to give the title compound (39 mg, 55%) as a tan solid.

Example 154

Preparation of 2- [r (acetylamino) acetyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -6-thiazolecarboxamide

52291B

Amin 2 solution (50 mg, 0.18 mmol). diisopropylethylamine (400 μL. 2.3 mmol). Nacetylglycine (42 mg, 0.36 mmol). 1-hydroxy-7-azabenzotriazole (49 mg. 0.36 mmol) and ethyl-

3- (3-Dimethylamino) -propyl carbodiimide hydrochloride (72 mg. 0.36 mmol) in THF (5 mL) was heated to 50 ° C overnight. The mixture was cooled, diluted with dichloromethane (60 mL) and washed with 2N aqueous HCl (20 mL), saturated aqueous KHCO.3 (20 mL), dried (MgSOA) filtered and concentrated The crude solid was triturated with ether (10 mL), filtered and washed with ether (5 mL, Zh) to give the title compound (40 mg, 59%). ) in the form of a beige solid.

Example 155

Preparation of 2-amino-4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarbothioamide

A suspension of compound 2 (50 mg. 0.18 mmol) and Lawesson's reagent (44 mg. 0.11 mmol) in toluene (0.23 mL) was heated to 100 ° C for 4 hours. A new amount of Lawesson's reagent (44 mg, 0.11 mmol) was added and the mixture was heated for another 3.5 hours. The crude mixture was subjected to silica gel column chromatography and eluted with 50% EtOAc in hexanes and then with 70% EtOAc in hexanes. to give a yellow solid which was triturated with hexanes (6 mL). to give the title compound (11 mg, 21%) as a yellow solid.

Examples 156 to 170

General procedure

Compounds 156 to 170 were prepared following the procedure described below. Diisopropylethylamine (60 [mu] L. 0.34 mmol) was added to a mixture of amine 2 (30 mg. 0.11 mmol). corresponding carboxylic acids (0.13 mmol). 1-hydroxy-7-azabenzotriazole (19.5

52291Β mg. 0.14 mmol) and ethyl 3- (3-dimethylamino) -propyl carbodiimide hydrochloride (26.8 mg. 0.14 mmol) in THF (1 mL). The mixture was heated in a sealed tube under argon to 45 ° C. 24 hours. The reaction mixture was diluted with dichloromethane (4 mL) and washed with 2N aqueous HCl (2 mL, Zh). dried (Na2SO4) and concentrated using Speedvac. The crude products were either converted to a powder with dichloromethane-ether (5 mL. 1: 1) or purified by chromatography on silica gel (elution solvent: 50% EtOAC in hexanes and EtOAc). HPLC retention time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% H2O, 0.2% H3BY4) to 100% solvent B (90% MeOH. 10% H2O. 0.2% N3RO4), flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Time Detentions (min)</td>

<td> 156</td><td>o / H3C | p = y · ν 'ε'γ'</td><td>2 - [(bromobenzoyl) amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-azo 1-carboxylamine</td><td> 5.03</td>

<td> 157</td><td>.CHa j? jp (m. α '/ Α ήΑ ™, ο</td><td>4-methyl-2 - [(4-nitrobenzoyl) amino] -N - (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.87</td>

<td> 158</td><td>, SN3aDDSNz</td><td>2 - [(4-cyanobenzoyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.70</td>

<td> 159</td><td>, SN3 sLHA> ° ff3cAAcH3όν; 0</td><td>4-methyl-2 - [[(5-nitro-2-furanyl) carbonyl]] amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.63</td>

<td> 160</td><td>WITHCH3Ο N - / CH3VzS ^^ SNz</td><td>4-methyl-2 - [(2- thienylcarbonyl) amino] -N- (2.4.6 trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.60</td>

<td> 161</td><td>__ / SNz ., Ύ'ΧΧ., The</td><td>4 - [[[4-methyl-5 [[(2,4,6-trimethylphenyl) amino] carbonyl] -2thiazolyl] amino] carbonyl] benzoic acid methyl ester</td><td> 4.99</td>

52291B

<td> 162</td><td>CH3</td><td>2 - [(isoxazolylcarbonyl) amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.87</td>

<td> 163</td><td>WITHCH3Ο N - Ζ CH, NzS ^^ SNz</td><td>2 - [(3-furanylcarbonyl) amino] -4- methyl N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.54</td>

<td> 164</td><td>, sn3n3s j? jp-f sn3H>S 83<H ^ sn3</td><td>2 - [[(2,4-dimethyl-5- thiazolyl) carbonyl] amino] -4-methyl- N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.74</td>

<td> 165</td><td>SN3NzS_eleven jnf l [{the Rj sHH sn3</td><td>2 - [[(4-methoxy-3-thienyl) carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.75</td>

<td> 166</td><td>r N— / SN3umHD-d</td><td>4-methyl 1-2 - [[(5-nitro-3-thienyl) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.78</td>

<td> 167</td><td>XX the H-c0· Sn,</td><td>2 - [[[4 - [(4-chlorophenyl) thio] -3-thienyl] carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.27</td>

<td> 168</td><td>-SN3n>s0 ? JP ('F'aHg 'ML5 J Hd</td><td>2 - [[(5-chloro-4-methoxy-3-thienyl) carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.04</td>

<td> 169</td><td>N ₽3 SN3clA-ch3SN3</td><td>2 - [[[2- (4,5-dihydro-4,4-dimethyl- 2-oxazolyl) -3-thienyl] carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 5.13</td>

<td> 170</td><td>5 ^ uSN3 NzSG ^^ SNz Oh</td><td>2 - [[(2-acetyl-3-thienyl) carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.54</td>

Examples 171 to 180

Opsii procedure

Compounds 171 to 180 were prepared following the procedure described below. A mixture of compound 2 (80 mg. 0.29 mmol). of the corresponding isocyanate (0.87 mmol) and pyridine (2 mL) in THF (3.5 mL) was stirred at room temperature overnight. In some cases, the reaction mixture was heated to 60-70 ° C. 5 hours. Some of these reactions are

52291Β performed overnight at room temperature in the presence of catalytic N, N-dimethylaminopyridine. The reaction mixture was diluted with dichloromethane and washed with 1N aqueous HCl (Zh). water, saline; dried (MgSO 3). filtered and concentrated. The crude product was purified either by powdering with ether or with a mixture of ether and hexane. or silica gel column chromatography (elution solvent 20-40% EtOAc in hexanes). followed by powdering or passing through a Varian cation exchange SCX charge and eluting sequentially with methanol (5 mL). dichloromethane (5 mL). acetonitrile-methanol (10 mL. 4: 1) and methanol-2M ammonia in methanol (10 mL, 4: 1) to give the title compound. HPLC Retention time is the HPLC retention time under the following conditions: For compounds 171-172. 175 and 177, HPLC conditions are: Zorbax S8-C18 4.5 mm h 7.5 cm short column, 30 min gradient starting from 100% solvent A (10% MeOH, 90% NJO. 0.2% H3PO4) to 100% solvent B % MeOH 10% H 2 O, 0.2% H 3 PO 4). flow rate 2.5 mL / min. λ = 217 nM. For other compounds. HPLC conditions are: Zorbax S8-C18 4.5 mm h 7.5 cm short column, 8 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3PO4) to 100% solvent B (90% MeOH, 10% H2O. 0.2% H3PO4). flow rate 2.5 mL / min. λ = 217 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention Time a (min)</td>

<td> 17 1</td><td></td><td>4-Methyl-2 - [[(methylamino) carbonyl] amino] -N (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 24.48</td>

<td> 17 2</td><td>NzS ^ O ^ z</td><td>4-methyl-2 - [[(phenylamino) carbonyl] amino] -N (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 30.45</td>

<td> 17 3</td><td>xl_withCH3 H3C 0 n3s</td><td>4-methyl-2 - [[[(4- methylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 8.81</td>

<td> 17 4</td><td>N3° NzS / 3</td><td>4-methyl-2 - [[[[phenylmethyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.52</td>

52291B

<td> 17 5</td><td></td><td>2 - [[(butylamino) carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 30.49</td>

<td> 17 6</td><td>N __ <H3 H3C N3(Č_ R 0 SN3N3s</td><td>4-methyl-2- [[(propylamino) carbonylamino] -N- (2.4.6- trimethylphenyl) -5thiazolecarboxamide</td><td> 7.41</td>

<td> 17 7</td><td>SN3 N3s NzS</td><td>2- | [(cyclohexylamino) carbonyl] -amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 27.21</td>

<td> 17 8</td><td>n3s</td><td>2 - [[[(2-chloro- phenyl) amino] carbonyl] amino] - 4-Methyl-N- (2,4,6-trimethylphenyl) -5-thiazole-carboxamide</td><td> 8.99</td>

<td> 17 9</td><td>N b n n3s</td><td>2 - [[[(3-fluorophenyl) amino] carbonyl] amino] 4methyl-N- (2/4,6-trimethylphenyl) 5-thiazolecarboxamide</td><td> 8.87</td>

<td> 18 0</td><td> .__/SNz l m_ /SNwith N3s SNz ° N3S ^</td><td>2 - [[[(2,6-dimethylphenyl) amino] carbonyl] amino] 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazole-carboxamide</td><td> 8.92</td>

Example 181

Preparation of phenyl ester [5-0 (2,4,6-trimethylphenyl) aminocarbonyl] -4-methyl-2-thiazolylcarbamic acid

52291B

10% aqueous KHCO solution3 (170 mL) was added to a stirred solution of compound 2 (1.02 g, 3.7 mmol) in THF (130 mL). Phenyl chloroformate (1.39 mL, 11.1 mmol) was added dropwise. The biphasic mixture was stirred at room temperature overnight. diluted with dichloromethane (200 mL) and washed with water (50 mL. 2x) and brine. The organic extract was separated. dried (MgSO4), filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 10% EtOAc in hexanes. to give the title compound (980 mg. 69%) as a solid.

Examples 182 to 236

General procedure

Compounds 182 to 236 were prepared following the procedure described below. A solution of phenylcarbamate 181 (20 mg. 0.054 mmol) and the corresponding amine (0.08 mmol) in THF-acetonitrile (3 mL. 1: 1) was stirred overnight at room temperature. Some of the reactions require heating to 60 ° C, 4 hours to overnight. The mixture was diluted with dichloromethane (4 mL) and washed with 1N aqueous HCl (1.5 mL. 2x). 1N aqueous NaOH (1.5 mL. 2x). The dichloromethane extracts were separated. dried (MgSO4). filtered and concentrated to give the title product. HPLC retention time is the HPLC retention time under the following conditions: For compounds 182-192 HPLC conditions are: Zorbax SB-C18 4.5 mm x 7.5 cm short column. 8 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3BY4) to 100% solvent B (90% MeOH. 10% H2O. 0.2% N3RO4), flow rate 2.5 mL / min. λ = 217 nM. For compounds 193-236 HPLC the conditions are: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3BY4) to 100% solvent B (90% MeOH. 10% H2O. 0.2% N3RO4). flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Time Detentions (min)</td>

<td> 18 2</td><td>n3s</td><td>4-methyl-2 - [[[(2phenylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 8.83</td>

52291B

<td> 18 3</td><td>HjC^ ~ x ^nAn 's+ pN--THE_CH3NzS</td><td>2 - [[(hexylamino) carbonyl] - amino] -4-methyl-N- (2.4.6- trimethylphenyl) -5thiazolecarboxamide</td><td> 9.01</td>

<td> 18 4</td><td>SN, m ^SN’ HS?Nz% G1 ΖΚτ-Ν-Χ Nz C ^ N- · SNzn3s</td><td>2 - [[[(11-dimethyl- ethyl) amino] carbonyl] amino] - 4-methyl-N-2,4,6-trimethyl- phenyl) -5-thiazole-carboxamide</td><td> 8.48</td>

<td> 18 5</td><td>o m- <SNz M N3st NzS F</td><td>2 - [[[(3-fluoro-4-methylphenyl) amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.92</td>

<td> 18 6</td><td>SNz--- * = - L> O </td><td>2 - [[[(4-methoxyphenyl) amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.57</td>

<td> 18 7</td><td>γχφκ. 'SN3 »3°</td><td>2 - [[(diethylamino) carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 8.19</td>

<td> 18 8</td><td>NzS ο NzsuLzKG '* i_SNzIzS ^ SNz N*S</td><td>2 - [[[bis (1-methyl- Ethyl) amino] carbonyl] -amino] 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazole-carboxamide</td><td> 8.90</td>

<td> 18 9</td><td>sn3 n3s</td><td>4-Methyl-2 - [[[methyl (phenylmethyl) amino] carbonyl] amino] -N-2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 8.56</td>

<td> 19 0</td><td> №<SNz Nz? O- κΙ-SNz sn3 N3S</td><td>4-methyl-2 - [[(methylphenylamino) carbonyl] amino] N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.39</td>

<td> 19 1</td><td>m __ /snz Hsj? C | L ^ LsNz SNz N3S</td><td>2 - [[(cyclohexylmethylamino) carbonyl] amino] -4methyl-N- (2,4,6-trinethylphenyl) 5-thiazolecarboxamide</td><td> 8.84</td>

<td> 19 2</td><td>“J ^ SNz n ^ s O + «LpH N3S</td><td>4-methyl-2 - [[[[(1-phenylethyl) amino] carbonyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 8.47</td>

<td> 19 3</td><td>t> 34Yr ° sn, »» Θ ώ NdS ^^ SNz</td><td>2 - [[[[(cyclopropylmethyl) propylamino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.36</td>

52291B

<td> 19 4</td><td>/ u ~ sn3J * m_ /SNzNzSG ^^ SNz</td><td>4-methyl-2 - [[[(2-methylcyclohexyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -5thiazole-carboxamide</td><td> 4.42</td>

<td> 19 5</td><td>a / w "· Ύ,.</td><td>4-methyl-2 - [[[(4- methylcyclohexyl) amino] carbonyl] amino] -N (2,4,6-trimethyl-phenyl) -5thiazole-carboxamide</td><td> 4.49</td>

<td> 19 6</td><td>, -χ, Ή Τ rnz <γ °% Α NzsAASNz</td><td>2 - [[[(cyclohexylmethyl) amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.49</td>

<td> 19 7</td><td>Τ SN3XX,</td><td>2 - [[[(2,3-dihydro-1H-indene) 1-yl) amino] carbonyl] amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.35</td>

<td> 19 8</td><td>N ^ /CH3 Material / * Ύ τ ρη „ Ž</td><td>4-methyl-2 - [[[(1- naphthalenylmethyl) amino] carbonyl] amino] -N (2,4,6-trimethyl-phenyl) -5thiazole-carboxamide</td><td> 4.43</td>

<td> 19 9</td><td>Χ <Γ J.</td><td>2 - [[[Bis (phenylmethyl) amino] carbonyl] amino] -4 ”methyl-N- (2,4,6-trimethylphenyl) 5-thiazolecarboxamide</td><td> 4.66</td>

<td> 20 0</td><td>NzS SNz THE! R {_ / Y = J ~CHs H3Cy ^ XXs 0H3C ° ·? sn3</td><td>2,6-dimethyl-N- [4-methyl-5- [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] 4-morpholinecarboxamide</td><td> 3.97</td>

52291B

<td> 20 1</td><td>.sNzS N-uu-SNz n3s SN3</td><td>2-ethyl-N- [4-methyl-5 - [[(2.4.6- trimethyl phenyl) amino] carbonyl] -2thiazolyl] -1-piperidinecarboxamide</td><td> 4.29</td>

<td> 20 2</td><td>rn3I HmH NN s N - D SN z W N3S (jAoAsNz</td><td>1 - [[[4-methyl-5 [[(2,4,6-trimethylphenyl) amino] carbonyl] -2thiazolyl] -amino] carbonyl] -3-piperidinecarboxylic acid ethyl ester</td><td> 4.10</td>

<td> 20 3</td><td>out RNz, ^ J_SNzn3s sn3</td><td>3,3-dimethyl-N- [4-methyl-5- [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] -1-piperidinecarboxamide</td><td> 4.32</td>

<td> 20 4</td><td>N3S SIz gSN = / SNz ls° Ί sn3</td><td>1 - [[[4-methyl-5-] ethyl ester [[(2,4,6-trimethylphenyl) amino] carbonyl] -2thiazolyl] -amino] carbonyl] -4-piperidinecarboxylic acids</td><td> 4.06</td>

<td> 20 5</td><td>THE-013T SNz ž,</td><td>4-methyl-2 - [[[[(3-methyl-2-pyridinyl) -amino] carbonyl] amino] -N- (2,4,6-trinethylphenyl) -5-thiazolecarboxamide</td><td> 3.51</td>

<td> 20 6</td><td>A; As5 [sn3D NzO ^^ SNz</td><td>4-methyl-2 - [[[1- (phenylmethyl) -4piperidinyl] amino] carbonyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 3.28</td>

<td> 20 7</td><td>S1G3Oh TRY S N - S_ / SNz xS nwiths</td><td>octahydro-N - [[4-methyl 1 -5 [[(2,4,6-trimethylphenyl) amino] carbonyl] -2thiazolyl] -1 (2H) quinolinecarboxamide</td><td> 4.55</td>

52291B

<td> 20 8</td><td>..χ £ s”= L H =SN“'Soll“</td><td>3,4-dihydro-N- [4-methyl-5 [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] 2 (1H) -isoquinoline carboxamide</td><td> 4.35</td>

<td> 20 9</td><td>x ° ά HjcA NzS ^^ SNz SN3</td><td>2 - [[[(1,5-dimethylhexyl) amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.72</td>

<td> 21 0</td><td>Hsn, ° SA X n3s> h^<sn3NzS</td><td>4-methyl-2 - [[[[(1-methylheptyl) amino] carbonyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.74</td>

<td> 21 1</td><td>-X ΑΧ0 n4 b T sn3 o / ° ΆF HaC '^^ CHg</td><td>2 - [[[[(2-fluorophenyl) methyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.17</td>

<td> 21 2</td><td>,, Λ χ Χχ</td><td>2 - [[[[(2-methoxyphenyl) methyl] amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.22</td>

<td> 21 3</td><td>sn3 ^ SNz H £ SR n3s'L^L'sn3</td><td>2 - [[[[(2-ethoxy- phenyl 1) methyl] amino] carbon and 1] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.36</td>

<td> 21 4</td><td>m- /SNzSIz hP S n θν sn3 % A NzsH ^ SNz</td><td>2 - [[[[(3-methoxyphenyl) methyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.13</td>

<td> 21 5</td><td>X = nHHn ..</td><td>2 - [[[[(4-chlorophenyl) methyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.36</td>

52291B

<td> 21 6</td><td>ΎΪ</td><td>2 - [[[[(4-methoxyphenyl) methyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.12</td>

<td> 21 7</td><td>give /SNzo ο ». Z <Vi HU NzS ^ AA-sNz</td><td>2 - [[[(2,2-diphenylethyl) amino] carbonyl] -amino] 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazole-carboxamide</td><td> 4.57</td>

<td> 21 8</td><td>Q: 100 n4 CH; h ° 'sAHzN 1J NzS ^^ SNz</td><td>2 - [[[(2-aminoethyl) phenylamino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 3.70</td>

<td> 21 9</td><td> /°SNz |^SNz χχχ. X ...</td><td>2 - [[[[2- (3-methoxyphenyl) ethyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.26</td>

<td> 22 0</td><td>sn3ό r_snz n- ~ /SNzоХХ A NzSG ^^ SNz</td><td>2 - [[[[2- (3,4-dimethoxyphenyl) ethyl] amino] carbonyl] amino] -4- methyl-N- (2.4.6- trimethylphenyl) -5thiazolecarboxamide</td><td> 4.05</td>

<td> 22 1</td><td>SN3</td><td>2 - [[[[2- (4-methoxyphenyl) ethyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.25</td>

<td> 22 2</td><td>hS n4 s T rn3, A ..</td><td>4-methyl-2 - [[[(3phenylpropyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.40</td>

<td> 22 3</td><td>M ^SNZJ.</td><td>2 - [[[[2- (cyclohex-1-en-1-yl) ethyl] amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.11</td>

52291B

<td> 22 4</td><td>IzrhSNzH3° Q k. / SNz L r... ž.</td><td>2 - [[[[4- (1.1- dimethylethyl) cyclohexyl] amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.85</td>

<td> 22 5</td><td>, -H Η, ^ ό-sn, NzS-7</td><td>2 - [[[(3-butoxypropyl) amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.33</td>

<td> 22 6</td><td>LLk THE " QCH3 NzsL ^ SNz</td><td>2 - [[[[2- (2-methoxyphenyl) ethyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.46</td>

<td> 22 7</td><td>»VCH3Λ lS'NzS ^^^ SNz</td><td>2 - [[[[(2-chloro-4- fluorophenyl) methyl] amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) - 5-thiazolecarboxamide</td><td> 4.39</td>

<td> 22 8</td><td>SNzN3 C-, Nz SN z</td><td>2 - [[(hexylmethylamino) carbonyl] amino] -4-methyl-N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.65</td>

<td> 22 9</td><td>sn_ ΛχΛ3_, mČ s 1G Iji "O ^ CHa0 ^ L ^ -SN,</td><td>2 - [[[[1- (4-chlorophenyl) ethyl] amino] carbonyl 1] amino] -4-methyl-1-N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.42</td>

<td> 23 0</td><td>RK /SNzCf_Q Η ^ Τγ0 SN30 l N3S ^ HN3</td><td>2 - [[[[2- (3-chlorophenyl) ethyl] amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.44</td>

<td> 23 1</td><td>W ^ zCH3 0 L® \Ohsn,0 l NzSG ^ - ^ SNz</td><td>4-methyl-2 - [[[[2- (2-thienyl) ethyl] amino] carbonyl] amino] -N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.18</td>

52291 Β

<td> 23 2</td><td>X.</td><td>2 - [[[[2- (2-fluorophenyl) ethyl] amino] carbonyl] amino] -4-methyl-N (2,4,6-trinethylphenyl) -5-thiazolecarboxamide</td><td> 5.85</td>

<td> 23 3</td><td>HD sn3 «N υ 0 'Ύ, Sg ° X,</td><td>4-Methyl-2 - [[[[2- (2-pyridinyloxy) ethyl] amino] carbonyl] amino] -N (2,4,6-trimethyl-phenyl) -5-thiazole-carboxamide</td><td> 4.28</td>

<td> 23 4</td><td>Br NzsAHnz</td><td>2 - [[[[(2-bromo-4,5-dimethoxyphenyl) methyl] methylamino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.87</td>

<td> 23 5</td><td>HNwith ON, X 0 “L N3SD SN3</td><td>(E) -2 - [[[(3,7-dimethyl-2,6octa-dienyl) amino] carbonyl] amino] -4-methyl-N (2,4,6-trimethyl-phenyl) -5thiazole-carboxamide</td><td> 4.34</td>

<td> 23 6</td><td>O-uČ Χχ. n3s' ^č <#^nosn3</td><td>2 - [[[[(2,3-dihydro-1,4-benzodioxin-2-yl) methyl] amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethyl-phenyl) -5-thiazolecarboxamide</td><td> 4.27</td>

Examples 237 to 285

General procedure

Compounds 237 to 285 were prepared following the procedure described below. A solution of phenylcarbamate 181 (20 mg. 0.054 mmol) and the corresponding amine (0.08 mmol) in THF-acetonitrile (3 mL. 1: 1) was stirred overnight at room temperature. The mixture was diluted with dichloromethane (4 mL) and washed with 1N aqueous HCl (1.5 mL. 2x). 1N aqueous NaOFI solution (1.5 mL. 2x). The dichloromethane extract was separated. dried (MgSCM- filtered and concentrated to give the title product. HPLC retention time is the HPLC retention time under the following conditions: for compounds 237-278 HPLC conditions are: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% FFO. 0.2% H3PO4) to 100% solvent B (90% MeOH, 10% FEO. 0.2% H3PO4). flow rate 4 mL / min. X = 220 nM. For compounds 279285 HPLC the conditions are: Zorbax S8-C18 4.5 mm x 7.5 cm short column. 8 min gradient

52291Β starting from 100% solvent A (10% MeOH. 90% NJO, 0.2% H3PO4) to 100% solvent B (90% MeOH, 10% NJO. 0.2% H3PO4) flow rate 2.5 mL / min, λ = 217 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention Time a (min)</td>

<td> 23 7</td><td></td><td>2 - [[[[3-methoxy-5 (trifluoromethyl) phenylamino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 5.36</td>

<td> 23 8</td><td> % ,N „.CH3G rNz NzS - ^^ SNz</td><td>2 - [[[(4-cyclohexylphenyl) amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.73</td>

52291B

<td> 23 9</td><td> 43n3'H ^SNz</td><td>4-methyl-2 - [[[(5.6.7.8- tetrahydro-1 - naphthalenyl) amino] carbonyl] amino] -N-2.4.6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 5.38</td>

<td> 24 0</td><td>AHJh α χ) HgC N— ^ -SNz n3s</td><td>2 - [[(1-anthracenylamino) carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.82</td>

<td> 24 1</td><td>4P J.</td><td>2 - [[[(4-chloro-1-naphthalenyl) amino] carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.76</td>

<td> 24 2</td><td>A As T rNz ž.</td><td>4-methyl-2 - [[(2-naphthalenylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.28</td>

<td> 24 3</td><td>- χΡ5in NzS .N-4 No.°NzN3S</td><td>2 - [[(1H-indole-5-amino) carbonyl] amino] 4-methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 5.00</td>

52291 Β

<td> 24 4</td><td>A Χχ. Τ SN3</td><td>2 - [[(1,3-benzodioxol-5-amino) carbonyl] amino] 4-methyl-N- (2,4-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.76</td>

<td> 24 5</td><td>a N gm Τ JNz l</td><td>4-methyl-2 - [[(2-pyrazinylamino) carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.84</td>

<td> 24 6</td><td>01X P- Ah,</td><td>2 - [[[(5-chloro-2-pyridinyl) amino] carbonylamino] -4-methyl-1H- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.38</td>

<td> 24 7</td><td>0 = / n- /SKz Ά ». J.</td><td>4-methyl-2 - [[[[(6-methyl-2-pyridinyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.44</td>

<td> 24 8</td><td>“D NzSAH ^ SNz</td><td>4-methyl-2 - [[[(2-methyl-4- quinolinyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.23</td>

52291B

<td> 24 9</td><td>1 sn3 η, 'ΧΧοη,</td><td>2 - [[[(2,3-dihydro-1.4- benzodioxin-6yl) amino] carbonyl] amino] 4-methyl-N- (2.4.6- trimethylphenyl) -5thiazolecarboxamide</td><td> 4.72</td>

<td> 25 0</td><td> ,Nm .SN3ž.</td><td>2 - [[[[1,1'-biphenyl] -2ylamino) carbonyl] amino] - 4-methyl-N - (2,4,6- trimethylphenyl) -5thiazolecarboxamide</td><td> 5.29</td>

<td> 25 1</td><td>HgC-O The ~SNz° ^ CS I SNz H3CWITH4^4CH3</td><td>2 - [[[(4-methoxy-2- methylphenyl) amino] carbonyl] -amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.80</td>

<td> 25 2</td><td>N3S u ^ ~snwith N3S, N gnNzS ^^ SNz</td><td>4-methyl-N- (2,4,6-trimethylphenyl) -2 - [[[(2,4,6-trimethylphenyl) amino] carbonyl] amino] -5-thiazolecarboxamide</td><td> 5.06</td>

<td> 25 3</td><td>C ^ v-oh n3s'L^A'sn3</td><td>2 - [[[[2- (2-hydroxyethyl) phenyl]] aminocarbonyl 1] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.02</td>

100

52291 Β

<td> 25 4</td><td>X £., NzH ^ SNz</td><td>2 - [[[(3-methoxyphenyl) amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.86</td>

<td> 25 5</td><td>NzS h3q / Υ \ ΛΑο SN3</td><td>2 - [[[(4-methoxy [1,1-biphenyl] -3-yl) amino] carbonyl] amino] 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.81</td>

<td> 25 6</td><td>OF COURSE ,,Ν .. .sn3νύ5ι NzSG ^^ SNz</td><td>2 - [[[(3-acetylphenyl) - amino] carbonyl] amino] -4methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.12</td>

<td> 25 7</td><td>, SN3dd H3C ^ N</td><td>2 - [[[(4-cyanophenyl) amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.15</td>

<td> 25 8</td><td>X twNO-4½ ž</td><td>2 - [[[[4-fluoro-2- (trifluoromethyl) phenyl] amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.99</td>

<td> 25 9</td><td>nz <\ - b J.</td><td>2 - [[[(4-hexyloxyphenyl) amino] carbonyl] amino] -4methyl-N- (2,4,6- trimethylphenyl) -5- thiazolecarboxamide</td><td> 4.42</td>

101

52291 Β

<td> 26 0</td><td>ah Τ? THE3</td><td>4 - [[[[4-methyl-5-] ethyl ester [[(2,4,6-trimethyl-phenyl) amino] carbonyl] -2-thiazolyl] -amino] carbonylamino] benzoic acid</td><td> 4.26</td>

<td> 26 1</td><td>Ζ-Υr 'andH1A</td><td>2 - [[[(4-decylphenyl) - amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td></td>

<td> 26 2</td><td>N3S Υ A'1- .Ž.</td><td>4-methyl-2 - [[[[(4-propylphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.71</td>

<td> 26 3</td><td>Q O-SNz Ύ Ah Τ? THE3Ž</td><td>4-methyl-2 - [[[(3,4,5-trimethoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.67</td>

<td> 26 4</td><td>Ν-ν /Ν ΥΗ3 * 4G NzS ^^ SNz</td><td>4-methyl-2 - [[[[4 - [[(5-methyl- 3-isoxazolyl) aminoylsulfonylphenyl] amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.27</td>

102

52291B

<td> 26 5</td><td>N3S »SN3</td><td>4 - [[[[4-methyl-5- butyl ester ” [[(2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl-aminocarbonyl] amino-benzoic acid</td><td> 4.75</td>

<td> 26 6</td><td> /m .. WITHCH3Υ SN3ž</td><td>2 - [[(1-isoquinolinylamino) carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.81</td>

<td> 26 7</td><td>Yr χ en3 0</td><td>4-methyl-2 - [[[[2 - [(phenylmethyl) thio] - phenyl] amino] carbonyl 1] amino] -N- (2.4.6 trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.42</td>

<td> 26 8</td><td>P J.</td><td>4-methyl-2 - [[[[4 - [(5phenoxypentyl) oxy] phenyl] amino] carbonyl] amino] -N (2,4,6-trimethyl-phenyl) -5thiazole-carboxamide</td><td> 4.96</td>

<td> 26 9</td><td>n3<? 'V ΥΧ “· n, cNZS ~ SH Νsn3</td><td>2 - [[[[5- (1,1-dimethylpropyl) -2-methoxyphenyl] amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.76</td>

<td> 27 0</td><td> « Nz% Ll SNz «^ J-SIz H3c</td><td>2 - [[[(1,2-dihydro-5-acenaphthylenyl) amino] carbonyl] amino] -4-methylN- (2,4,6-trimethyl-phenyl) -5- thiazolecarboxamide</td><td> 4.70 __________</td>

103

52291B

<td> 27 1</td><td> 7Ν μ zCH3 Τ rNzΝχ5χ THE3 s / ^^ SMz</td><td>4-methyl-2 - [[[[(3phenoxyphenyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.70</td>

<td> 27 2</td><td>χχΌ ° X _, SN3-X · r ž,</td><td>4-methyl-2 - [[[[2- (4-morpholinyl) phenyl] amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.01</td>

<td> 27 3</td><td> /Nk, / SN3ž</td><td>4-methyl-2 - [[[[2- (1piperidinyl) phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.55</td>

<td> 27 4</td><td>and hA f4 λ-sn, XSNzu / “snwith n3s</td><td>2 - [[[(1-acetyl-2,3-dihydro- 1H-indole-6- yl) amino] carbonyl] amino] - 4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.08</td>

<td> 27 5</td><td> /N k, zCH3 °> h ... THE3A-OH,</td><td>2 - [[[(2-bromo-5-methoxyphenyl) amino] carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.55</td>

104

52291B

<td> 27 6</td><td>Ν SN3S0N N SN - 4 SN3 <r-si3n3s</td><td>2 - [[[(2,3-dimethyl-1H-indole- 5-yl) amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.30</td>

<td> 27 7</td><td>AJ? s \ 0 1 ) - \ N3S SN3 m_ / SN3NzCh / ^ o yJ>snwith N3S</td><td>4-methyl-2 - [[[[2 - [[(1-methylethyl) amino] carbonyl] phenyl] amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.82</td>

<td> 27 8</td><td>lD.SNz^ Jn-SNz N3S</td><td>2 - [[[(3-bromo-2-methylphenyl) amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.60</td>

<td> 27 9</td><td>, sn3 n3s *. * '14-—ΛΥτΥ) - · «, NzS '^</td><td>2 - [[[(4-methoxybutyl) amino] carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 7.62</td>

<td> 28 0</td><td>sn r m- <SNz Nz9 H3SL3 u the3Υ— l SNzNzs' * ^</td><td>2 - [[[(3,3-dimethylbutyl) amino] carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 9.13</td>

<td> 28 1</td><td>0 g4_^SNz n3s izs ^ u4 rA M,^ QhrNY0 ^ CH SNz ° NzS ^</td><td>4-methyl-2 - [[[(2- methylbutyl) amino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.90</td>

<td> 28 2</td><td>SN l m-č <SNz N3? nl / ίτΎι NzS NNSU SNz N3S</td><td>4-methyl-2 - [[[[(3-methylbutyl) amino] carbonyl] amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.98</td>

<td> 28 3</td><td>SN3NzS ° - ^ Lm ^ £ ^ 14 ^^ _SNzN3s</td><td>2 - [[[(2-methoxyethyl) amino] carbonyl] amino] -4methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 7.30</td>

105

52291B

<td> 28 4</td><td>H3GXn3s</td><td>2 - [[[[2- (dimethylamino) ethyl] amino] carbonyl] amino] -4-methylN- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 5.73</td>

<td> 28 5</td><td>CH3S. S. N3^ = \ 0 UU n3s</td><td>4-methyl-2 - [[[[[2 (methylthio) ethylamino] carbonyl] amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 8.19</td>

Examples 286 to 311

General procedure

Compounds 286 to 311 in addition to compound 307 were prepared following the procedure described below. 2 - [[(butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxylic acid chloride solution (30 mg, 0.11 mmol). of the corresponding amine (0.12 mmol) in THF (1 mL) was treated with diisopropylethylamine (22.6 pL. 0.13 mmol). The mixture was purified by purging with argon and mechanically stirred in a vessel for 22 hours. diluted with dichloromethane (4 mL) and washed with 2N aqueous HCl (Zh). The organic extracts were separated, dried (NaiSCU). filtered and concentrated. The crude products were purified either by powdering with dichloromethane-ether (1: 1) or by chromatography on silica gel (elution solvent: 80% EtOAc in hexanes followed by EtOAc) or by automatic preparative HPLC (conditions: YMC S5 ODS A 20 h 100 mm Column 10 min gradient starting from 30% solvent B (90% MeOH. 10% NJO. 0.1% TFA) and 70% solvent A (10% MeOH, 90% FEO. 0.1% TFA) to 100% solvent B, flow rate 20 mL / min. λ = 220 nM.

Compound 307 was prepared following the procedure described below. A suspension of 2 - [[(butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxylic acid (100 mg. 0.36 mmol) and HATU (170 mg, 0.44 mmol) in DMF (3 mL) was treated with diisopropylethylamine (62 mL). 0.44 mmol). The mixture was heated to 60 ° C for 2 hours. refrigerated. diluted with dichloromethane (12 mL). washed with 8M aqueous urea in 2N aqueous HCl (6 mL, Zh). 5% aqueous KNSO 2 (6 mL, Zh). dried (NaTSOp. filtered and concentrated. The residue was triturated with EtOAc ether to give the mixed anhydrous intermediate (102 mg, 74%) as a white solid. A 1M solution of sodium bis (trimethylsilylamide) in THF (170 μL. 0.17 mmol) was added dropwise to a stirred solution of 2.6-dichloroaniline (19.4 mg. 0.12 mmol) in THF (1 mL). After 15 min. in one portion a mixed anhydrous intermediate (41.3 mg. 0.11 mmol) was added. A few drops of DMF were added and the solution was stirred for 16 hours. A new amount of 1M sodium solution was added

106

52291Β bis (trimethylsilylamide) (110 [mu] L) and the mixture was stirred for a further 2 hours. The mixture was diluted with dichloromethane (4 mL) and washed with 2N aqueous HCl (2 mL, Zh). saturated aqueous solution of K.HCO3 (Zh). dried (Na2SO4). filtered and concentrated. The solid was washed with hexanes (2x) and the residue was subjected to silica gel column chromatography. Elution with 80% EtOAc in hexanes. followed by EtOAc to give compound 307 (12 mg, 27%) as a light yellow-brown solid. HPLC retention time ”is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column, 4 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3PO4) to 100% solvent B (90% MeOH. 10% H2O. 0.2% H3BY4). flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Time Detentions (min)</td>

<td> 286</td><td>n g-sn3ζΜ-Α ασΝ</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2,3-dihydro-1H-inden-5-yl) -4-methyl-5-thiazolecarboxamide</td><td> 4.20</td>

<td> 287</td><td>ah</td><td>2 - [[(butylamino) carbonyl] amino] -N-2-naphthalenyl-4-methyl-5-thiazolecarboxamide</td><td> 4.20</td>

<td> 288</td><td>about ZCH3 OH i</td><td>2 - [[(butylamino) carbonyl] amino] -N- (3-hydroxy-2-naphthalenyl) -4-methyl-5-thiazolecarboxamide</td><td> 4.24</td>

<td> 289</td><td>n3sNzČ Vn 0 F</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2-fluoro-5-methylphenyl) -4-methyl-5-thiazolecarboxamide</td><td> 3.95</td>

107

52291B

<td> 290</td><td>η / SN3sn3 ι the</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2,6-dimethylphenyl) -4-methyl-5-thiazole-carboxamide</td><td> 3.78</td>

<td> 291</td><td>THE3 <\ ^ γ- · ΒΓ n3s-H u</td><td>N- (4-bromo-2- methylphenyl) -2- [[(butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 4.12</td>

<td> 292</td><td>H3Q Υ ^ -Ν °> S CH3NzS %sNOSNz</td><td>N- (3-bromo-2,4,6-trimethylphenyl) -2 [[[butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 4.28</td>

<td> 293</td><td>NZ ^ "VY" 'oJZ-L and3 sn ^ T sAh,</td><td>2 - [[(butylamino) carbonyl] amino] -N- [2,6-dimethyl-3- (1-methylethyl) phenyl] -4-methyl-5-thiazolecarboxamide</td><td> 4.28</td>

<td> 294</td><td>N3S CH3V / x The NzS“S ^ Vg</td><td>N- (2-bromo-4,6-dimethylphenyl) - [[[butylamino (carbonyl) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 4.00</td>

<td> 295</td><td>IzS '—N > -N ° ^ -s SOOSNz NzS O jL -; /5n3s</td><td>methyl ester 3 - [[[2- [[(butylamino) carbonyl 1] amino] -4-methyl 1 - 5-thiazolyl] carbonyl] amino] -4-methyl- 2 -thiophene-carboxylic acids</td><td> 3.83</td>

<td> 296</td><td>o / ~snwith γ-- Ž</td><td>2 - [[(butylamino) carbonyl] amino] -4-methylN- (2-methyl-6-quinolinyl) -5-thiazolecarboxamide</td><td> 2.98</td>

<td> 297</td><td>o / -sn3a; sn3</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2,6-dimethoxyphenyl) -4-methyl-5-azolecarboxamide</td><td> 3.39</td>

108

52291 Β

<td> 298</td><td>ns ο ASNzt + jC</td><td>2 - [[(butylamino) carbonyl] amino] -N- (4-methoxy-2-naphthalenyl) -4-methyl-5-thiazolecarboxamide</td><td> 4.31</td>

<td> 299</td><td>Msn3°</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2-methyl-1-naphthalenyl) -4-methyl-5-thiazolecarboxamide</td><td> 3.92</td>

<td> 300</td><td>SNz SN3Nz ιϊ ^SNz hrV ^ CHg »X SIz N, s - / ^ 0</td><td>2 - [[(butylamino) carbonyl] amino] -N- [4 (dimethylamino) -2,3,5,6tetramethyl-phenyl] -4-methyl5-thiazolecarboxamide</td><td> 4.14</td>

<td> 301</td><td>α ψΑ \ ž> CH3°</td><td>2 - [[(butylamino) carbonyl] amino] -N- (6methyl-5-quinolinyl) -4methyl-5-thiazolecarboxamide</td><td> 3.13</td>

<td> 302</td><td>_ / ~ sn3NzSa ν, Α C γΑΝ a;</td><td>2 - [[(butylamino) carbonyl] amino] -N- [2- (2-hydroxyethyl) -6methylphenyl] -4-methyl-5-thiazolecarboxamide</td><td> 3.50</td>

<td> 303</td><td>H3C '—Ν λ # ° U-s sn3 ρ- VvVSf% NwithS % CV</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2,6-dimethyl-3-nitrophenyl) -4-methyl-5-thiazolecarboxamide</td><td> 3.75</td>

<td> 304</td><td>H3C Vg</td><td>N- (2-bromo-3,4,6-trimethylphenyl) -2 [[[butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 4.12</td>

<td> 305</td><td>g> A1’L SNz PR ON 1 ss ». 0</td><td>N- (2-acetyl-6-hydroxyphenyl) -2 [[[butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 3.75</td>

109

52291B

<td> 306</td><td>m r rNz Hsn. that The SNz</td><td>1,1-dimethylethyl ester [4- [[[2 - [[(butylamino) carbonyl] amino] -4-methyl5-thiazolyl] carbonyl] amino] -2.3.5.6tetramethylphenylcarbamic acid</td><td> 4.10</td>

<td> 307</td><td>_SN3Ο N - Z CI Nz γΆ G?h So f ' θ JL</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2,6-dichlorophenyl) -4-methyl-5-thiazolecarboxamide</td><td> 4.42</td>

<td> 308</td><td>CH3</td><td>N- (4-amino-2.3.5.6- tetramethylphenyl) -2 [[[butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 3.15</td>

<td> 309</td><td>H3CyN THE</td><td>N- [5- (acetylamino) -2,4-dimethylphenyl] -2 [[[butylamino) carbonyl] amino] -4-methyl-5-thiazolecarboxamide</td><td> 3.52</td>

<td> 310</td><td>hsn3X JGH m Γ n3 «· N δ-γ- ο AJL H3C ^^ Sr.</td><td>N- (4-bromo-2,6-dimethylphenyl) -2 [[[butylamino) carbonylamino] -4-methyl-5-thiazolecarboxamide</td><td> 4.93</td>

<td> 311</td><td>, CH3Ο N - Ζ S! β, ΛΑ</td><td>2 - [[(butylamino) carbonyl] amino] -N- (2-chloro-6-methylphenyl) -4-methyl-5-thiazolecarboxamide</td><td> 4.51</td>

Example 312

Preparation of 4-methyl-2-1 (methylsulfonyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

A. Ethyl 2-[(ipetylsulfonyl) amino] -4-methyl-thiazole-5-carboxylate

A mixed solution of ethyl 2-amino-4-methyl-thiazole-5-carboxylate (558 mg. 3 mmol) in dichloromethane (15 mL) and pyridine (5 mL) was treated with methanesulfonyl chloride (687 mg. 6).

110

52291Β mmol) at room temperature and overnight. The solution was diluted with dichloromethane (50 mL) and washed with 2N aqueous HCl (15 mL. Zh). dried (MgSO4). filtered and concentrated. The crude residue was diluted with ether (25 mL) and the solid was filtered. washed with a 1: 1 mixture of ether: hexanes (10 mL. Zh) and dried in vacuo to give the title compound (687 mg. 87%) in the form of a beige solid.

B. 2-r (methylsulfonyl) amino1-4-methyl-thiazole-5-carboxylic acid

A mixed solution of ethyl 2 - [(methylsulfonyl) amino] -4-methylthiazole-5-carboxylate (300 mg. 1.14 mmol) in methanol (9 mL) was treated with 1N NaOH solution (28.4 mL. 28.4 mmol). The mixture was stirred at room temperature overnight. The solution was cooled to 0 ° C and acidified with 6N aqueous HCl to pH 1. The solution was extracted with a mixture of dichloromethanechloroform. The organic extract was dried (MgSO 4)4). filtered and concentrated in vacuo. to give the title acid (148 mg, 55%).

C. 4-methyl-2 - [(methylsulfonyl) amino] -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

Diisopropylethylamine (87 [mu] L 0.5 mmol) was added to a solution of compound 312 B (99 mg. 0.42 mmol). 2,4,6-Trimethylaniline (68 [mu] L 0.5 mmol) and [O- (7-azabenzotriazol-1-yl) -1,3,3,3-tetramethyluronium] hexafluorophosphate (HATU. 191 mg. 0.5 mmol) in DMF (3 mL). The mixture was stirred at room temperature overnight, diluted with EtOAc and washed with 0.5 N aqueous HCl (15 mL), 10% aqueous LiCl (25 mL. Zh). with water (930 mL. 2x). saline. dried (MgSO4). filtered and concentrated. The residue was subjected to silica gel column chromatography and eluted with 50% EtOAc in hexanes. followed by 75% EtOAc in hexanes and 2% MeOH in EtOAc. to give the title compound (19 mg, 13%) as a white solid.

Example 313

Preparation of 4-methyl-2 - [[(phenylamino) thiocarbonyl] amino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

111

52291B

A solution of compound 2 (45 mg. 0.16 mmol) and phenylisothiocyanate (43 mg. 0.32 mmol) in pyridine (2 mL) was heated to 80 ° C for 20 hours. The mixture was cooled. diluted with dichloromethane-THF (80 mL. 3: 1) and washed with 2N aqueous HCl (15 mL, 2x). The organic extract was dried (MgSO-t). filtered and concentrated. The residue was diluted with EtOAc (20 mL) and the solid was filtered, washed with ether (10 mL. Zh) and dried in vacuo. to give the title compound (35 mg. 52%) in the form of a beige solid.

Example 314

Preparation of 2 - [[(ethylamino) carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolecarboxamide

Compound 314 was prepared using a procedure analogous to the procedure for preparing compound 171-180. using ethyl isocyanates. to give the title compound 314 as a white solid (65%).

Example 315

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(cyclopropylcarbonyl) amino] -5-thiazolecarboxamide

A. Ethyl 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate

Suspension of ethyl 2-amino-thiazole-5-carboxylax (972 mg. 6 mmol. B. Plower. C.

Baillv. R. Houssin. jP. Henlchart Heterocyles 32 (4). 693-701. 1991 and HJ Becker. .1. de Jonge Rec. Trav. Chim. 61. 463.1942). of di-t-butyldicarbonate (1.94 g. 9 mmol) and 4-dimethylaminopyridine (73 mg. 0.6 mmol) in dry tetrahydrofuran (75 mL) was stirred under

112

52291Β nitrogen 24 hours. The solvent was evaporated in vacuo. The residue was suspended in ether (50 mL). The solid was washed with ether (10 mL. Zh) and dried in vacuo to give the title compound (1 g and 70%).

B. 2-tert-Butoxycarbonyloxyamino-thiazole-5-carboxylic acid

A mixed solution of ethyl 2-tert-butoxycarbonyloxyamino-4-methyl-thiazole-5-carboxylate (11 g, 4.2 mmol) in tetrahydrofuran-methanol (80 mL, 1: 1) was treated with 6N aqueous NaOH solution (20 mL, 120 mmol). The mixture was stirred at room temperature for 24 hours. Most of the THF and methanol were removed by distillation under reduced pressure and the aqueous solution was acidified with 6N aqueous HCl (22 mL). The precipitated solid was filtered off. washed with water and ether. air dried. and then dried in vacuo. to give the title acid (940 mg, 96%) as a beige solid.

5- [r (2-chloro-6-methylphenyl) amino] carbonyl] -2-thiazolyl] carbamic acid C 1 H-dimethylethyl

A 2M solution of oxalyl chloride in dichloromethane (1 mL. 2 mmol) was added dropwise to a mixed solution of 2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid (234 mg. 1 mmol) in THF (10 mL) and N, N-dimethylformamide (a few drops). . The solution was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure and in vacuo. to obtain crude acid chloride. 2-chloro-6-methylamine (212 mg. 1.5 mmol) was added dropwise to a stirred solution of crude 2-tert-butoxycarbonyloxyamino-thiazole-5-carboxylic acid chloride (1 mmol) in dichloromethane (10 mL) at 0 ° C. Diisopropylethylamine (516 mg, 4 mmol) was added. The solution was allowed to warm to room temperature and stirred for 24 hours. diluted with dichloromethane (60 mL) and washed with 2N aqueous HCl (15 mL). The organic extract was dried (MgSCU). filtered and concentrated. The residue was diluted with EtOAc ether (25 mL. 1: 4) and the solid was filtered and washed with ether (5 mL. 4x) and dried in vacuo. to give the title compound (175 mg, 48%) as a tan solid.

D. 2-Amino-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

Compound 315D was prepared using a procedure analogous to the process for the preparation of compound 2. except that compound 315C was used herein to give the title compound 315D as a tan solid.

E. 2 - [(cyclopropylcarbonyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

113

52291 Β

A solution of compound 315D (50.6 mg, 0.19 mmol) and cyclopropanecarboxylic acid anhydride (302 mg, 1.96 mmol) in dioxane (2 mL) was heated to 93 ° C overnight. The mixture was concentrated in vacuo. diluted with EtOAc and washed with saturated aqueous KNSO 2 (2x). The organic extract was dried (Na 2 SCU). filtered and concentrated. The residue was triturated with ether. to give the title compound (11 mg, 17%) as a white solid.

Example 316

Preparation of 2- [r [(11-dimethylethyl) amino] carbonyl] amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

Sodium hydride (19.2 mg, 0.8 mmol) was added to a solution of compound 315D (48.3 mg. 0.18 mmol) and t-butyl isocyanate (41 [mu] L 0.36 mrnol) in THF (5 mL) at 0 ° C. After 1 hour. the mixture was diluted with EtOAc and washed with cold saturated aqueous ammonium chloride solution. The aqueous layer was separated and extracted with EtOAc. The EtOAc extracts were combined, dried (Na 2 Cl 2), filtered and concentrated. The residue was purified using automatic preparative HPLC (conditions: YMC S5 ODS A 20 x 100 mm Column. ten min gradient starting from 10% solvent B (90% MeOH. 10% EhO. 0.1% TFA) and 90% solvent A (10% MeOH. 90% NJO. 0.1% TFA) to 100% solvent B. flow rate 20 mL / mm. λ = 220 nM. to give the title compound (18 mg, 28%) as a beige solid.

Example 317

Preparation of 2-r [(11-di-ethylenethoxy) carbonyl] amino] -4-methyl-N- (2,4,6-trimethylphenyl) -5thiazolacetamide

114

52291B

Compound 317 was prepared using a procedure analogous to that for compound 1, except that methyl 2-amino-4-methyl-thiazole-5-acetate was used herein to give the title compound 317 as a beige solid.

Example 31 8

Preparation of 2-amino-4-methyl-N- (2,4,6-trimethylphenyl) -5-thiazolacetamide

Compound 318 was prepared using a procedure analogous to that for compound 2. except that compound 317 was used herein to give the title compound 318 as a light brown solid.

Example 319

Preparation of N- (2-chloro-6-methylphenyl) -2- [4,6-dimethyl-2-pyridinyl) amino] -5-thiazolecarboxamide

A. 2-Bromo-N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

A solution of copper (II) bromide (2.68 g. 12 mmol) in acetonitrile (50 mL) was purified by purging with nitrogen and cooled to 0 ° C. T-Butyl nitrite (2 mL, 15 mmol) was added. followed by a solution of compound 315D (2.68 g. 10 mmol) in acetonitrile (50 mL). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in EtOAc.

115

52291Β was washed with saturated aqueous NaHCOl · and the precipitate was removed by filtration. The organic extract was dried (NaiSCU). filtered and concentrated. The residue was crystallized from EtOAc / ether / hexane to give the title compound (1.68 g, 51%) as a yellow solid.

B. N- (2-chloro-6-methylphenyl) -2- (4,6-dimethyl-2-pyridinyl) amino] -5-thiazolecarboxamide

95% sodium hydride (15 mg) was added to a mixture of compound 319Α (25 mg. 0.075 mmol) and 4,6-dimethyl-2-aminopyridine (37 mg, 0.302 mmol) in THF (1 mL). The mixture was heated to 60 ° C overnight, cooled to room temperature and diluted with saturated aqueous ammonium chloride solution. The mixture was extracted with EtOAc (2x). The organic extracts were combined, washed with water and dried (Na 2 SO 2). filtered and concentrated. The residue was triturated with ether. to give the title compound (17.5 mg, 63%) as a tan solid.

Example 320

Preparation of N- (2-chloro-6-methylphenyl) -2- [4-ethyl-2-pyridinyl) amino] -5-thiazolecarboxamide

Compound 320 was prepared using a procedure analogous to that for compound 319 31. with the difference that 4-ethyl-2-aminopyridine is used herein. to give the title compound 320.

Example 321

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(2,6-dimethyl-4-pyrimidinyl) amino] -5-thiazolecarboxane

116

52291B

Compound 321 was prepared using a procedure analogous to that for compound 319 31. with the proviso that 2,6-dimethyl-4aminopyrimidine is used herein to give the title compound 321.

Example 322

Preparation of N- (2-chloro-6-methylphenyl) -2- (3-pyridazinylamino) -5-thiazolecarboxamide

Compound 322 was prepared using a procedure analogous to the procedure for preparing compound 319B. with the difference that 3-aminopyridazine is used herein. to give the title compound 322.

Examples 323 to 335

General procedure

Compounds 323 to 335 were prepared following the procedure described below. Diisopropylethylamine (60 [mu] L. 0.34 mmol) was added to a mixture of amine 144 (31 mg. 0.11 mmol). corresponding carboxylic acids (0.13 mmol). 1-Hydroxy-7-azabenzotriazole (19.5 mg. 0.14 mmol) and ethyl 3- (3-dimethylamino) -propylcarbodiimide hydrochloride (26.8 mg. 0.14 mmol) in THF (0.4 mL). The mixture was heated in a sealed tube under argon to 50 ° C. 24 hours. The reaction mixture was diluted with dichloromethane (4 mL) and washed with 1N aqueous HCl. The dichloromethane solution was passed through a Varian Mega Bond Elut SCX cation exchange column (previously washed with methanol and equilibrated with acetonitrile-methanol (4: 1)). The column was eluted sequentially with acetonitrile methanol (4: 1). methanol-2M solution of ammonia in methanol (4: 1). Factions that

117

52291Β containing product were combined and concentrated in vacuo. HPLC retention time ”is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3PO4) to 100% solvent B (90% MeOH. 10% NJO, 0.2% H3PO4). flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 323</td><td>Ο, γζOH'CI no s</td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [(2-thienylcarbonyl) amino] -5thiazolecarboxamide</td><td> 3.70</td>

<td> 324</td><td>0 iuSNz P</td><td>N- (2-chloro-6-methylphenyl) -2 [[(cyclopropylcarbonyl) amino] -4-methyl-5-thiazolecarboxamide</td><td> 3.41</td>

<td> 325</td><td></td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [(2-furanylcarbonyl) amino] -5-thiazolecarboxamide</td><td> 3.49</td>

<td> 326</td><td> 0 /snz α V</td><td>N- (2-chloro-6-methylphenyl) -4methyl 1-2 - ((3-thienylcarbonyl) amino] -5thiazole-carboxamide</td><td> 3.71</td>

<td> 327</td><td>0 1~1(SNz f * AsA 'n»PV</td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [(3-furanylcarbonyl) amino] -5thiazolecarboxamide</td><td> 3.57</td>

<td> 328</td><td>S</td><td>trans-N- (2-chloro-6-methylphenyl) -4-methyl-2 - [[(2-phenylcyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 4.09</td>

<td> 329</td><td> „ m__DNz.</td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [[(2-methylcyclopropyl) carbonyl] amino] -5thiazolecarboxamide</td><td> 3.65</td>

118

52291 Β

<td> 330</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[(cyclobutylcarbonyl) amino] 4-methyl-5-thiazolecarboxamide</td><td> 3.63</td>

<td> 331</td><td>° inCH3 R</td><td>N- (2-chloro-6-methylphenyl) 2 - [(cyclopentylcarbonyl) amino] -4 methyl-5-thiazolecarboxamide</td><td> 3.82</td>

<td> 332</td><td>o NVCH3 R</td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [(2-methyl-loxopropyl) amino] -5-thiazolecarboxamide</td><td> 3.50</td>

<td> 333</td><td>The №- /SNz R</td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [(loxopentyl) amino] -5thiazolecarboxamide</td><td> 3.79</td>

<td> 334</td><td>ο N ___ /SNz us</td><td>N- (2-chloro-6-methylphenyl) -4methyl-2 - [(2-methyl-loxopentyl) amino] -5-thiazolecarboxamide</td><td> 3.90</td>

<td> 335</td><td></td><td>2- (benzoylamino) -N- (2- chloro-6-methylphenyl) -4-methyl- 5th azolecarboxamide</td><td> 3.79</td>

Examples 336 to 362

General procedure

Compounds 336 to 362 were prepared using a procedure analogous to the procedure for preparing compounds 323-335. with the difference that compound 315D was used here instead of compound 144. The crude products were purified using automatic preparative HPLC (conditions: YMC S5 ODS A 20 x 100 mm Column. 10 min gradient starting from 10% solvent B (90% MeOH, 10% H2O. 0.1% T FA) and 90% solvent A (10% MeOH. 90% NJO. 0.1% TFA) to 100% solvent B. flow rate 20 mL / min. λ = 220 nM. to give the compounds of headings 336-362. HPLC retention time is the FIPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H?BY4) to 100% solvent B (90% MeOH. 10% H2O. 0.2% N3RO4). flow rate 4 mL / min. λ = 220 nM.

<td>Pr.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC</td>

119

52291 Β

<td>no.</td><td></td><td></td><td>Retention Time (min)</td>

<td> 336</td><td>η μ__ Cls FTA</td><td>N- (2-chloro-6-methylphenyl) -2 [[(1-oxopropyl) amino] -5-thiazolecarboxamide</td><td>Z.JZ</td>

<td> 337</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[(1-oxobutyl) amino] -5-thiazolecarboxamide</td><td> 3.61</td>

<td> 338</td><td>ο N___ Cl / 'γ' γΑ ε'γ</td><td>N- (2-chloro-6-methylphenyl) -2 [(2-ethyl-1-oxobutyl) amino] 5-azo 1 carboxamide</td><td> 3.54</td>

<td> 339</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[[(1-phenylcyclopropyl) carbonyl] amino] -5thiazolecarboxamide</td><td> 3.86</td>

<td> 340</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[(1-methylcyclopropyl) carbonyl] amino] -5thiazolecarboxamide</td><td> 3.53</td>

<td> 341</td><td>θ Ν__ CIc'X0Me ff3c70</td><td>N- (2-chloro-6-methylphenyl) -2- [[(2,2-dichloro-1-methylcyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.53</td>

<td> 342</td><td>νχχ</td><td>N- (2-chloro-6-methylphenyl) -2 [[[(2-methylcyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.53</td>

<td> 343</td><td>0 Μ - π ρ u / Mg-D VOH ftc'M</td><td>N- (2-chloro-6-methylphenyl) -2 [[(1-hydroxycyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.58</td>

<td> 344</td><td>Me\ X HH «LΜζχ Ν sMe me</td><td>N- (2-chloro-6-methylphenyl) -2 [[(2.2.3.3-tetramethylcyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.69</td>

<td> 345</td><td></td><td>N- (2-chloro-6-methylphenyl) -2- [[(1-cyanocyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.53</td>

<td> 346</td><td>Ο N___ Cl I love youU fto'M</td><td>N- (2-chloro-6-methylphenyl) -2 [[(cyclobutylcarbonyl) amino] 5-thiazolecarboxamide</td><td> 3.52</td>

120

52291B

<td> 347</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[(cyclopentylcarbonyl) amino] 5-thiazolecarboxamide</td><td> 3.59</td>

<td> 348</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[(cyclohexylcarbonyl) amino] 5-thiazolecarboxamide</td><td> 3.78</td>

<td> 349</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [(phenylacetyl) amino] -5thiazolecarboxamide</td><td> 3.62</td>

<td> 350</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 [[(cyclohexylacetyl) amino] -5thiazolecarboxamide</td><td> 4.07</td>

<td> 351</td><td></td><td>N- (2-chloro-6-methylphenyl) -2- [(4-pyridinylacetyl) amino] -5thiazolecarboxamide</td><td> 3.75</td>

<td> 352</td><td>Me - Λ // Af Ν— \ R3C '\ ^ THE Μθ</td><td>N- (2-chloro-6-methylphenyl) -2 [[(2,5-dimethyl-1H-pyrrol-3-yl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.17</td>

<td> 353</td><td></td><td>N- (2-chloro-6-methylphenyl) -2- [(2-pyridinylcarbonyl) amino] - 5-thiazolecarboxamide</td><td> 3.07</td>

<td> 354</td><td>s / Lob</td><td>N- (2-chloro-6-methylphenyl) -2 [(3-pyridinylcarbonyl) amino] 5-thiazolecarboxamide</td><td> 3.07</td>

<td> 355</td><td>] Ν ___ C] ASh \ r'vS Μ</td><td>N- (2-chloro-6-methylphenyl) -2 [(4-pyridinylcarbonyl) amino] 5-thiazolecarboxamide</td><td> 3.61</td>

<td> 356</td><td>ο μ_ α ft</td><td>N- (2-chloro-6-methylphenyl) -2 [[(3-thienylcarbonyl) amino] -5thiazolecarboxamide</td><td> 3.60</td>

<td> 357</td><td>0 Ν -— π Ρ</td><td>N- (2-chloro-6-methylphenyl) -2- [(2-thienylcarbonyl) amino] -5thiazolecarboxamide</td><td> 3.61</td>

<td> 358</td><td>0 Ν_ι α no</td><td>N- (2-chloro-6-methylphenyl) -2 [(2-furanylcarbonyl) amino] -5thiazolecarboxamide</td><td> 3.61</td>

<td> 359</td><td><: Α: ώ</td><td>N- (2-chloro-6-methylphenyl) -2 [[(3-furan and 1-carbon and 1) amino] -5 thiazolecarboxamide</td><td> 3.69</td>

121

52291B

<td> 360</td><td></td><td>trans-N- (2-chloro-6-methylphenyl) -2 - [[(2-phenylcyclopropyl) carbonyl] amino] -5-thiazolecarboxamide</td><td> 3.98</td>

<td> 361</td><td>1</td><td>N- (2-chloro-6-methylphenyl) -2 [(2-methyl-1-oxopentyl) amino] -5-thiazolecarboxamide</td><td> 3.90</td>

<td> 362</td><td></td><td>2- (benzoylamino) -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 3.61</td>

Example 363

Preparation of 2 - [(cyclopropylcarbonyl ') amino] -N- (2,6-dirnethylphenyl) -5-thiazolecarboxarnide

Compound 363 was prepared using a process analogous to that for compound 315. except that 2,6-dimethylaniline was used herein to give the title compound 363.

Example 364

Preparation of 2 - [(cyclopropylcarbonyl) amino1-N- (2,4,6-trimethylphenyl) -5thiazolecarboxamide

122

52291B

Compound 364 was prepared using a procedure analogous to that for compound 315. except that 2,4,6-trimethylaniline was used herein to give the title compound 364.

Example 365

Preparation of N- (2-chloro-4,6-dimethylphenyl) -2 - [(cyclopropylcarbonyl) amino] -5-thiazolecarboxamide

with

Compound 365 was prepared using a procedure analogous to that for compound 315. except that 2-chloro-4,6-dimethylaniline was used herein to give the title compound 365.

Example 366

Preparation of 1,1-dimethylethyl ester [4- [2-oxo-2 - [(2,4,6-trimethylphenyl) amino] ethyl] -2-thiazolylcarbamic acid sn,

N3s sn3

Compound 366 was prepared using a process analogous to that for compound 1, except that 2-tert-butoxycarbonyloxyamino-thiazole-4-acetic acid was used herein to give the title compound 366 as a white solid.

Example 367

Preparation of 2-amino-N- (2,4,6-trimethylphenyl) -4-thiazolacetamide

123

52291B

Compound 367 was prepared using a procedure analogous to that for compound 4, except that compound 365 was used herein to give the title compound 367 as a white solid.

Example 368

Preparation of 2-methyl-5-nitro-N- (2,4,6-trimethylphenyl) benzarnide

Compound 368 was prepared using a process analogous to that for compound 3, except that 2-methyl-5-nitrobenzoic acid was used herein to give the title compound 368 as a white solid.

Example 369

Preparation of 5-amino-2-methyl-N- (2,4,6-trimethylphenylbenzamide

124

52291B

10% Palladium on carbon (30 mg) was added to a stirred solution of compound 368 (149 mg. 0.5 mmol) in EtOAc (50 mL). The reaction vessel is connected to a balloon filled with hydrogen via a shut-off valve with three outlets. The air inside the vessel was emptied under reduced pressure and the vessel was filled with hydrogen from a balloon. After 4 hours. the catalyst was filtered off. washed with EtOAc (5 mL. 5x). The filtrate was concentrated to give the title compound (133 mg, 99%) as a white solid.

Example 370

Preparation of 2-amino-5-chloro-N- (2,4,6-trimethylphenyl) -4-pyrimidinecarboxamide

Compound 370 was prepared using a process analogous to that for compound 3, except that 2-amino-5-chloro-pyrimidine was used herein.

4-carboxylic acid to give the title compound 370 as a white solid.

Example 371

Preparation of 1,1-dimethylethyl ester [4-methyl-5- [r (2,4,6-trimethylphenyl) amino] carbonyl] -2-oxazolylcarbamic acid

CH3

Compound 371 was prepared using a process analogous to that for compound 1, except that 2-tert-butoxycarbonyloxyamino-4-methyl-5-oxazolecarboxylic acid was used herein to give the title compound 371 as a light yellow foam.

125

52291B

Example 372

Preparation of 2-amino-4- (methyl) -N- (2,4,6-trimethylphenyl) -5-oxazolecarboxamide.

trifluoroacetate (1: 1)

Compound 372 was prepared using a procedure analogous to that for compound 4, except that compound 369 was used herein to give the title compound 372 as a white solid.

Example 373

Preparation of 2-amino-N- (2,4,6-trimethylphenyl) -5-pyridinecarboxamide

Compound 373 was prepared using a process analogous to that for compound 3, except that 6-aminonicotinic acid was used herein to give the title compound 373 as a white solid.

Example 374

Preparation of 3-amino-N- (2,4,6-trimethylphenyl) -4-pyridinecarboxarnide

126

52291B

Compound 374 was prepared using a process analogous to that for compound 3, except that 3-amino-4-pyridinecarboxylic acid was used herein to give the title compound 374 as a white solid.

Example 375

Preparation of 2-amino-4-methyl-N- (2,4,6-trimethylphenyl) -5-pyrimidinecarboxamide

Compound 375 was prepared using a process analogous to that for compound 3, except that 2-amino-4-methyl-5-pyrimidinecarboxylic acid was used herein to give the title compound 375 as a white solid.

Example 376

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(4-methyl-2-pyridinyl) amino] -5-thiazolecarboxamide

127

52291B

Compound 376 was prepared using a process analogous to that for compound 319, except that 2-amino-4-methyl-pyridine was used herein to give the title compound 376 as a beige solid.

Example 377

Preparation of 2 - [(6-amino-2-pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide

Compound 377 was prepared using a procedure analogous to that for compound 319B, except that 2,6-diaminopyridine was used herein to give the title compound 377 as a light brown solid.

Example 378

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(6-propyl-2-pyridinyl) amino] -5-thiazolecarboxamide

Compound 378 was prepared using a procedure analogous to the procedure for preparing compound 319Β. with the proviso that 2-amino-6-propyl-pyridine was used herein to give the title compound 378 as a beige solid.

Example 379

128

52291B

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(6-ethyl-4-pyrimidinyl) amino] -5-thiazolecarboxamide

Compound 379 was prepared using a procedure analogous to the procedure for preparing compound 3I9B. with the proviso that 4-amino-6-ethyl-pyrimidine was used herein to give the title compound 379 as a white solid.

Examples 380 to 409

General procedure

Compounds 380 to 409 were prepared using a procedure analogous to that for compound 319 31. For the following examples 380 to 527 HPLC retention time is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 50 mm Ballastic Column. 4 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.2% H3BY4) to 100% solvent B (90% MeOH. 10% Η, 0.2. 0.2% H3BY4). flow rate 4 mL / min,? v = 220 nM. Where used. PIPLC retention time'B '. it is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 33 mm Turbo Column. 2 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.1% TFA) to 100% solvent B (90% MeOH. 10% H2O. 0.1% TFA) with 1 min with 100% solvent B. flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 380</td><td> 44,0</td><td>'N- (2-chloro-6-methyl Ifeni 1) - 2- (2-pyridinylamino) -5thiazolecarboxamide</td><td>n l * 7</td>

129

52291 Β

<td> 381</td><td>What?</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(6-methyl-2- pyridinyl) amino] -5thiazolecarboxamide</td><td> 3.61</td>

<td> 382</td><td>Thu3s</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(5-methyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.487</td>

<td> 383</td><td>, <Η</td><td>'N- (2-chloro-6-methylphenyl) 2 - [(4-methyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.293</td>

<td> 384</td><td></td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(3-methyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.243</td>

<td> 385</td><td>.THE</td><td>'2 - [(5-bromo-3-methyl-2-pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 4.17</td>

<td> 386</td><td></td><td>'2 - [(6-amino-2-pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-diazolecarboxamide</td><td> 2.817</td>

<td> 387</td><td>N3s</td><td>'2 - [(5-bromo-2- pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 4.023</td>

130

52291B

<td> 388</td><td></td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[3- (phenylmethoxy) -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 4.143</td>

<td> 389</td><td>HdA NzS</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(5-chloro-2- pyridinyl) amino] -5thiazolecarboxamide</td><td> 3.957</td>

<td> 390</td><td>ΥαΥ</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(6-ethyl-2- pyridinyl) amino] -5- thiazolecarboxamide</td><td> 3.867</td>

<td> 391</td><td></td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(6-propyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 4.083</td>

<td> 392</td><td></td><td>'2 - [(6-bromo-5-methyl-2- pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 4.077</td>

<td> 393</td><td></td><td>'2 - [(2-amino-3- pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 2.343</td>

<td> 394</td><td>ΥΧ ^ -ΝΗ, CI NO</td><td>'2 - [(3-amino-2-pyridinyl) amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 2.777</td>

<td> 395</td><td>CI X ΑΎ ταΧ Υθ</td><td>'N- (2-chloro-6-methylphenyl) - 2- (4-pyridinylamino) -5- thiazolecarboxamide</td><td> 2.493</td>

131

52291B

<td> 396</td><td>mčD / L Ζ'-Α'ι ΧΡ</td><td>'N- (2-chloro-6-methylphenyl) - 2- (3-pyridinylamino) -5- thiazolecarboxamide</td><td> 2.47</td>

<td> 397</td><td></td><td>'N- (2-chloro-6-methylphenyl) 2 - [(6-chloro-3-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.75</td>

<td> 398</td><td>DhR X</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(2-chloro-3- pyridinyl) amino] -5thiazolecarboxamide</td><td> 3.443</td>

<td> 399</td><td>SN, 1 3'χρ</td><td>N- (2-chloro-6-methylphenyl) - 2 - [(6-methoxy-3-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.517</td>

<td> 400</td><td>U η. Α ΧΡ</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(3,5-dimethyl-2- pyrazinyl) amino] -5- thiazolecarboxamide</td><td> 3.583</td>

<td> 401</td><td>Q l,. Α ΧΡ</td><td>'N- (2-chloro-6-methylphenyl) - 2- (phenylamino) -5- thiazolecarboxamide</td><td> 3.697</td>

<td> 402</td><td>χ <χ ° H, X ^</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(3-ethylphenyl) amino] -5thiazolecarboxamide</td><td> 4.107</td>

<td> 403</td><td></td><td>N- (2-chloro-6-methylphenyl) - 2 - [(3.5- dimethylphenyl) amino] -5thiazolecarboxamide</td><td> 3.98 ____!</td>

132

52291B

<td> 404</td><td>SNz</td><td>N- (2-chloro-6-methylphenyl) - 2 - [(4,6-dimethyl-2-pyrimidinyl) amino] -5-thiazolecarboxamide</td><td> 3.51</td>

<td> 405</td><td></td><td>1 '- (2-chloro-6-methylphenyl) 2 - [(6-ethyl-4-pyrimidinyl) amino] -5-diazolecarboxamide</td><td> 2.943</td>

<td> 406</td><td>fyi Cl</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [(6-chloro-2pyrazinyl) amino] -5thiazolecarboxamide</td><td> 3.763</td>

<td> 407</td><td>Ч1, С</td><td>'2 - [(3-aminophenyl) amino] - N- (2-chloro-6-methylphenyl) ~ 5-lyazolecarboxamide</td><td> 2.633</td>

<td> 408</td><td>n ° -čA // 1 \ / 'Ua</td><td>N- (2-chloro-6-methylphenyl) - 2 - [(3- hydroxyphenyl) amino] -5- thiazolecarboxamide</td><td>- "nos 3.33 /</td>

<td> 409</td><td>Chs</td><td>'2 - [(3-bromophenyl) amino] - N- (2-chloro-6-methylphenyl) - 5-thiazolecarboxamide</td><td> 4.12</td>

Example 410

Preparation of 'N- (2,6-dimethylphenyl) -2- (phenylamino) -5-thiazolecarboxamide

133

52291B

Α. 1,1-dimethylethyl ester r5- [[(2,6-dimethylphenyl) amino] carbonyl] -2-thiazolyl] carbamic acid Compound 410Α was prepared using a procedure analogous to the process for the preparation of compound 315C, except that 2,6-dimethylaniline was used herein.

B. 2-Amino-N- (2,6-dimethylphenyl) -5-thiazolecarboxamide

Compound 410Β was prepared using a process analogous to the process for preparing compound 315D, except that compound 410Α was used herein.

C. The compound of the title

The title compound was prepared using a procedure analogous to that for compound 319B. with the difference that compound 41OB and aniline are used herein. HPLC retention time 3.69 min.

Examples 411 to 427

General procedure

Compounds 411 to 427 were prepared using a procedure analogous to the procedure for preparing compound 319Β.

<td>Pr. no.</td><td>The structure is one</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 411</td><td>H, C N-- • g3«</td><td>'N- (2,6-dimethylphenyl) -2- (methylphenylamino) -5- thiazolecarboxamide</td><td> 3.667</td>

<td> 412</td><td></td><td>'N- (2,6-dimethylphenyl) -2- (2- pyridinylamino) -5- thiazolecarboxamide</td><td> 3.297</td>

134

52291B

<td> 413</td><td></td><td>'N- (2,6-dimethylphenyl EH) 6-methyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.587</td>

<td> 414</td><td>JČ</td><td>1 'N- (2,6-dimethylphenyl) -2 [(4-methyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.222</td>

<td> 415</td><td></td><td>'N- (2,6-dimethylphenyl) -2 [(4-ethyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.54</td>

<td> 416</td><td></td><td>'N- (2,6-dimethylphenyl) -2- [(4,6-dimethyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.543</td>

<td> 417</td><td>Α \ N3Sthe2νΑ α ll αآυLLŠ H3C</td><td>'2 - [(2-amino-3-pyrimidinyl) amino] -N (2,6-dimethylphenyl) -5-thiazolecarboxamide</td><td> 2.807</td>

<td> 418</td><td>N3S</td><td>'N- (2,6-dimethylphenyl) -2- [(6-ethyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 3.847</td>

<td> 419</td><td>° H3c</td><td>'N- (2,6-dimethylphenyl) -2- [(6-propyl-2-pyridinyl) amino] -5-thiazolecarboxamide</td><td> 4,057</td>

<td> 420</td><td>Dept</td><td>'2 - [(2-amino-3- pyridinyl) amino] -N- (2,6-dimethylphenyl) -5-thiazolecarboxamide</td><td> 2.337</td>

135

52291B

<td> 421</td><td>CD</td><td>'2 - [(3-amino-2-pyrimidinyl) amino] -N (2,6-dimethylphenyl) -5-thiazolecarboxamide</td><td> 2.737</td>

<td> 422</td><td>h> g</td><td>'2 - [(6-amino-2-methyl-4pyrimidinyl) amino] -N (2,6-dimethylphenyl) -5-thiazolecarboxamide</td><td> 2.71</td>

<td> 423</td><td>A</td><td>'N- (2,6-dimethylphenyl) -2- [[6- (4-morpholinyl) -3pyridazinyl] amino] -5thiazolecarboxamide</td><td> 2.727</td>

<td> 424</td><td>AigC</td><td>'2 - [(6-chloro-3-pyridazinyl) amino] -N (2,6-dimethylphenyl) -5-thiazolecarboxamide</td><td> 3.46</td>

<td> 425</td><td>n, s νΛΛ115 Črr</td><td>1 'N- (2,6-dimethylphenyl) -2- (3-pyridazinylamino) -5-thiazolecarboxamide</td><td> 2.973</td>

<td> 426</td><td>η, νάα and l-Az Οθ</td><td>'2 - [(3-aminophenyl) amino] - N- (2,6-dimethylphenyl) -5thiazolecarboxamide</td><td> 2.63</td>

<td> 427</td><td></td><td>'2 - [(3-bromophenyl) amino] - N- (2,6-dimethylphenyl) -5thiazolecarboxamide</td><td> 4.143</td>

Example 428

Preparation of 2- (2-pyridinylamino) -N- (2,4,6-trimethylphenyl) -5-thiazolecarboxarnide

136

52291B

Α. 5-[- (2,4,6-trimethylphenyl) amino] carbonyl] -2-thiazolyl] carbamic acid 1,1-dimethylethyl ester

Compound 428A was prepared using a procedure analogous to that for 315C. with the difference that 2,4,6-trimethylaniline is used herein.

B. 2-amino-N- (2,6-dimethylphenib-5-thiazolecarboxamide

Compound 428B was prepared using a process analogous to the process for preparing compound 315D, except that compound 428A was used herein.

C. The title compound

The title compound was prepared using a procedure analogous to the process for the preparation of 319B, except that compound 428B and 2aminopyridine were used herein. HPLC retention time 3.66min.

Examples 429 to 443

General procedure

Compounds 429 to 443 were prepared using a procedure analogous to the procedure for preparing compound 319B.

<td>Pr. no.</td><td>The structure is one</td><td>The name of the dish</td><td>HPLC Time Detentions (min)</td>

<td> 429</td><td></td><td>'2 - [(6-methyl-2-pyridini]) amino' | -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.903</td>

137

52291B

<td> 430</td><td>I3S X</td><td>'2 - [(5-methyl-2-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.8</td>

<td> 431</td><td></td><td>'2 - [(4-methyl-2-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.603</td>

<td> 432</td><td>H \ -sn, n, s um / HN sx ϊχ ° N3S</td><td>'2 - [(3-methyl-2-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.56</td>

<td> 433</td><td>rijU</td><td>'2 - [(5-bromo-2- pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5thiazolecarboxamide</td><td> 4.263</td>

<td> 434</td><td></td><td>'2- [(5-chloro-2-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.203</td>

<td> 435</td><td>sn, .Ι XX</td><td>'2 - [(6-methoxy-3-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.8</td>

<td> 436</td><td>HE HAS Cjs</td><td>'2 - [(4-ethyl-2-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.86</td>

<td> 437</td><td>Χχχ</td><td>'2 - [(6-ethyl-2-pyridinyl) amino] -N (2,4,6-trimethylphenyl) -thiazolecarboxamide</td><td> 4.127</td>

138

52291B

<td> 438</td><td></td><td>'2 - [(6-chloro-3-pyridinyl) amino] -N (2,4,6-ylmethylphenyl) -5-thiazolecarboxamide</td><td> 4.017</td>

<td> 439</td><td></td><td>'2 - [(2,6-dimethyl-4pyrimidinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 2.943</td>

<td> 440</td><td></td><td>'2 - [(4-methyl-2-pyrimidinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 3.723</td>

<td> 441</td><td>N3S</td><td>'2- (2-pyrazynylamino) -N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 3.65</td>

<td> 442</td><td>THETheυ</td><td>'2 - [(6-chloro-2- pyrazinyl) amino] -N (2,4,6-trimethylphenyl) -5-thiazolecarboxamide</td><td> 4.05</td>

<td> 443</td><td>Vvch. CEO wool KAsn</td><td>'2 - [(3,5-dimethyl-2pyrazinyl) amino] -N- (2,4,6-trimethylphenyl) -5- thiazolecarboxamide</td><td> 3.877</td>

Example 444

Preparation of N- (2-chloro-6-methylphenyl) -2-n'2-methyl-6- ['[2- (4-morpholinyl) ethyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide

139

52291 Β

To a suspension of NaH (148mg, 6.17mmol) in THF (20mL) was added a solution of compound 315D (551mg. 2.06mmol) in THF (10 mL) and the mixture was stirred at room temperature for 0.5 h. A solution of 4.6-dichloro-2-methylpyrimidine (671.6 mg, 4.12 mmol) in THF (10 mL) was added and the mixture was stirred at room temperature overnight. The reaction was quenched with acetic acid and the solvent was removed in vacuo. Water was added to the residue and saturated NaHCO 3 solution was extracted with SNJSk. The organic layer was removed in vacuo and the crude material was purified by column chromatography to give compound 444A (494mg).

B. The compound of the title

To compound 444A (30 mg) was added N- (2-aminoethyl) -morpholine (300 [mu] L) and the mixture was heated to 80 [deg.] C. 2 hours. Water was added to the reaction and the product was collected by filtration. HPLC retention time 2.357 min.

Examples 445 to 461

General procedure

Compounds 445 to 461 were prepared using a procedure analogous to the procedure for preparing compound 444B by substituting the appropriate amine.

<td>Rg. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Time Detentions</td>

140

52291B

<td> 445</td><td>Jχ j-CCd χ co</td><td>'N- (2-chloro-6-methylphenyl) -2- [[2-methyl-6 - [[3- (4-morpholinyl) propyl] amino] 4-pyrimidinyl] amino] -5- thiazolecarboxamide</td><td> 2.253</td>

<td> 446</td><td>sn3</td><td>'N- (2-chloro-6-methylphenyl) -2 [[2-methyl-6- [methyl [3 (methylamino) propyl] amino] -4-pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.493</td>

<td> 447</td><td>Yes sn,</td><td>'N- (2-chloro-6-methylphenyl) -2 [[2-methyl-6 - [[2- (tetrahydro2-oxo-1H-imidazol-1-yl) ethyl] -amino] -4pyrimidinyl] amino] - 5thiazolecarboxamide</td><td> 2.71</td>

<td> 448</td><td>N- # 04,</td><td>1- (2-chloro-6-methylphenyl) -2- [[2-methyl-6 - [(2-1Himidazol-4-ylethyl) amino] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.303</td>

<td> 449</td><td>hey with,</td><td>'N- (2-chloro-6-methylphenyl) -2- [[2-methyl-6- (4-morpholinyl) 4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td>η H -> -7 Z.JZ /</td>

<td> 450</td><td>ρι chiral HTMnwiths sn3</td><td>'N- (2-chloro-6-methylphenyl) -2- [[6 - [[[(2R) -1-ethyl-2-pyrrolidinyl] methyl] amino] -2methyl-4-pyrimidinyl] amino] - 5-thiazolecarboxamide</td><td> 2.703</td>

<td> 451</td><td>sn PM? these n / Ln3</td><td>'N- (2-chloro-6-methylphenyl) -2 [[6 - [[[(2S) -1-ethyl-2-pyrrolidinyl] methyl] amino] -2-methyl-4-pyrimidinyl Jamino] 5-thiazolecarboxamide</td><td> 2.717</td>

<td> 452</td><td>Q., N * 4. _. chiral ® ':'in sn,</td><td>'2 - [[6 - [(2S) -2- (aminocarbonyl) -1-pyrrolidinyl] -2-methyl-4-pyrimidinyl] amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 2.81</td>

141

52291B

<td> 453</td><td>M '4 SNz</td><td>'N- (2-chloro-6-methylphenyl) -2 [[6 - [(2-hydroxyethyl) amino] 2-methyl-4- pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.677</td>

<td> 454</td><td>SNz</td><td>* N- (2-chloro-6-methylphenyl) 2 - [[6- [4- (hydroxymethyl) -1piperidinyl] -2-methyl-4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td> 3.05</td>

<td> 455</td><td>SNz</td><td>'N- (2-chloro-6-methylphenyl) -2 [[6- [4- (2-hydroxyethyl) -1piperazinyl] -2-methyl-4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td> 2.717</td>

<td> 456</td><td>sn></td><td>1- [6 - [[5 - [[(2-chloro-6-methylphenyl) amino] carbonyl] 2-thiazolyl] amino] -2-methyl-4-pyrimidinyl] -4-piperidinecarboxamide</td><td> 2.863</td>

<td> 457</td><td>N * ^ chiral 'b0 04 SC,</td><td>'N- (2-chloro-6-methylphenyl) -2 [[2-methyl-6 - [(3S) -3-methyl-piperazinyl] -4pyrimidinyl] amino] -5-thiazolecarboxamide</td><td> 2.823</td>

<td> 458</td><td>'IN sn3</td><td>2 - [[6- [3- (acetylamino) -1-pyrrolidinyl] -2-methyl-4-pyrimidinyl] amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 2.78</td>

<td> 459</td><td>D-HDb</td><td>N- (2-chloro-6-methylphenyl) -2 [[6 - [[2- (1-methyl-2-pyrrolidinyl) ethyl] amino] -2methyl-4-pyrimidinyl] amino] - 5-thiazolecarboxamide</td><td> 2.383</td>

<td> 460</td><td>, = gSH <1 n ~ 4 <4</td><td>'N- (2-chloro-6-methylphenyl) -2- [[2-methyl-6 - [[(5-methyl-2pyrazinyl) methyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td> 3.027</td>

142

52291B

'N- (2-chloro-6-methylphenyl) -2 [[2-methyl-6 - [[2- (1H-1,2,3-triazol-1-yl) ethyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide

2.78

Example 462

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6 - [[2- (4-morpholinyl) ethyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide

Compound 462A was prepared by a pressing procedure analogous to the procedure for preparing compound 444A. with the difference that 4.6-dichloropyrimidine is used here.

B. The title compound

The title compound was prepared using a procedure analogous to that for compound 444B. with the difference that compound 462A is used here instead of compound 444A. HPLC retention time 2.553 min.

Examples 463 to 472

General procedure

143

52291B

Compounds 463 to 472 were prepared using a process analogous to that for compound 444B by substituting the appropriate amine. HPLC retention time'B 'is the HPLC retention time under the following conditions: YMC S5 ODS 4.6 x 33 mm Turbo Column. 2 min gradient starting from 100% solvent A (10% McOH. 90% H2O. 0.1% TFA) to 100% solvent B (90% MeOH. 10% H2O. 0.1% TFA) with 1 min with 100% solvent B. flow rate 4 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention time (min)</td>

<td> 463</td><td>I ΎΎ CHS</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[2- (dimethyl- amino) -ethyl] amino] -4pyrimidinyl] -amino] -5thiazolecarboxamide</td><td> 2.527</td>

<td> 464</td><td>dM /C1</td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[2- (tetrahydro-2-oxo-1H-imidazol-1-yl) ethyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td> 2.797</td>

<td> 465</td><td><jČ Μ Μ /</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6- [methyl [2- (methylamino) ethyl] amino] -4pyrimidinyl] -amino] -5thiazolecarboxamide</td><td>1,137 B</td>

<td> 466</td><td></td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[2- (1-methyl-2-pyrrolidinyl) ethyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td>1.113 v</td>

<td> 467</td><td>'-' s ^ zz oY /CI</td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6 - [[2- (pyrrolidinyl) -ethyl] amino] 4-pyrimidinyl] -amino] -5-thiazolecarboxamide</td><td>1,150 Β</td>

144

52291 Β

<td> 468</td><td>OM-H</td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[(1-ethyl-2-pyrrolidinyl) methyl] amino] 4-pyrimidinyl] amino] -5-thiazolecarboxamide</td><td>1,237 B</td>

<td> 469</td><td>Q X</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [(4-piperidinylmethyl) amino] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td>1,160 B</td>

<td> 470</td><td>«M sj *</td><td>'2 - [[6 - [[2- (acetylamino) ethyl] amino] -4-pyrimidinyl] amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td>2,457 Β</td>

<td> 471</td><td>θΧ-m c |</td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6 - [[2- (1H- L2,3-triazol-1-yl) ethyl] amino] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.897</td>

<td> 472</td><td>input</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6- (4-morpholinyl) -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 3.437</td>

Example 473

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6 - [[2- (4-morpholinyl) ethyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide

145

52291B

To a suspension of NaH (2.83 g. 118 mmol) in DMF (350 mL) cooled to 0 ° C was added compound 319Α (31 g, 93.5 mmol). The mixture was stirred at 0 ° C for 45 min. then Bu was added4NI (6.9 g, 18.7 mmol), followed by the addition of 4-methoxybenzyl chloride (18 g, 115 mmol). The reaction was allowed to warm to room temperature. After stirring overnight at room temperature, the reaction was quenched with acetic acid. and then the solvent t vacuo was removed. Water was added to the residue and it was neutralized with saturated aqueous NaHCO 33. The mixture was extracted 3 times with EtOAc and the combined organic layers were washed with water. and then washed with saturated NaCl solution. The EtOAc layer was concentrated in vacuo and the residue was purified by column chromatography to give compound 473A (35 g).

To compound 473A (0.5 g. 1.1 mmol) dissolved in THF (50 mL) was slowly added NaH (0.13 g. 5.5 mmol). followed by 2-bromo-6-aminopyridine (0.76 g. 4.4 mmol). The reaction was heated to reflux for 2 hours. it is then cooled to room temperature and

146

52291Β quenched with acetic acid. The solvent was removed and vcicuo. water and hexane were then added and the mixture was stirred at room temperature. The solid precipitate was collected by filtration and washed with water and Et2O to give compound 473B (0.48 g)

To compound 473B (0.48 g) dissolved in TFA (5 mL) was added anisole (2 mL). followed by trifluoromethanesulfonic acid (1 mL). The reaction was stirred at room temperature for 3 hours and then slowly added to the ice mixture. saturated NaHCO3. Et2O and CH2C12 which is rapidly mixed. The mixture was stirred in the cold for 1 hour and then the solid precipitate was collected by filtration and washed with water and then with a mixture of Et2O / CH2Cl2 to give compound 473C (0.344 g). HPLC retention time 3.85 min.

D. The title compound

The title compound was prepared using a procedure analogous to the process for the preparation of compound 444B, except that compound 473C was used here instead of compound 444A. HPLC retention time 2.80 min.

Examples 474 to 480

General procedure

Compounds 474 to 480 were prepared using a procedure analogous to the procedure for preparing compound 473D by substituting the appropriate amine.

<td>Pr.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC</td>

<td></td><td></td><td></td><td>Detentions</td>

147

52291B

<td> 474</td><td>aA</td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6 - [[3 (4-morpholinyl) propyl] amino] -2-pyridinyl] -amino'] - 5-thiazolecarboxamide</td><td> 2.867</td>

<td> 475</td><td>ΜΙ l 's jG</td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6 [methyl [3- (methylaminopropylamino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 3.067</td>

<td> 476</td><td>hirahii ĆAss</td><td>'N- (2-chloro-6- methylphenyl) -2 - [[6- [(3S) -3-methyl-1piperazinyl] -2-pyridinyl] -amino] -5-thiazolecarboxamide</td><td> 2.827</td>

<td> 477</td><td></td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6 - [(3H-imidazol-1-ylpropyl) amino] -2-pyridinyl] amino] -5-azo 1-carboxylic acid</td><td> 2.83</td>

<td> 478</td><td></td><td>'N- (2-chloro-6- methylphenyl) -2 - [[6 - [(2-hydroxyethyl) amino] 2-pyridinyl] amino] -5thiazolecarboxamide</td><td> 3.077</td>

<td> 479</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 - [[6 - [(2H-imidazol-1-ylethyl) amino] -2-pyridinyl] -amino] -5-thiazolecarboxamide</td><td> 2.903</td>

<td> 480</td><td> 3</td><td>'N- (2-chloro-6- methylphenyl) -2 - [[6- (4-morpholinyl) -2-pyridinyl] amino] -5-azolecarboxamide</td><td> 3.727</td>

Example 481

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6 - [[2- (4-morpholinyl) ethyl] amino] -2pyrazinyl] amino] -5-thiazolecarboxamide

148

52291B

Compound 481Α was prepared using a procedure analogous to that for 473B. with the difference that the compound 2-chloro-6-aminopyrazine is used here instead of the compound 2-bromo-6-aminopyridine.

B. (alternative synthesis of compound 406)

S1

149

52291B

Compound 406 was prepared using a procedure analogous to the procedure for preparing compound 473C. with the difference that compound 481A is used here instead of compound 473B.

C. The title compound

The title compound was prepared using a procedure analogous to that for compound 444B. with the difference that compound 406 was used instead of compound 444A. HPLC retention time 2.69 min.

Examples 482 to 486

General procedure

Compounds 482 to 486 were prepared using a procedure analogous to that of compound 481C by substituting the appropriate amine.

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 482</td><td>% ll / \ JL ž X Υ Υ Ί</td><td>'N- (2-chloro-6- methylphenyl) -2 - [[6 - [[3- (4-morpholinyl) propyl] amino] -2pyrazinyl] -amino] -5-thiazolecarboxamide</td><td> 2.783</td>

<td> 483</td><td></td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6- (4-morpholinyl) -2-pyrazinyl] amino] -5-thiazolecarboxamide</td><td> 3.57</td>

<td> 484</td><td>N chiral</td><td>1- (2-chloro-6-methylphenyl) -2 - [[6 - [(3S) 3-methyl-1-pyrazinyl] -2-pyrazinyl] -amino] -5-thiazolecarboxamide</td><td> 2.743</td>

<td> 485</td><td></td><td>'N- (2-chloro-6-methylphenyl) -2 - [[6- (3-hydroxy-1-pyrrolidinyl) -2-pyrazinyl] -amino] -5-thiazolecarboxamide</td><td> 3.327</td>

150

52291B

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6- (3-hydroxy-1-pyrrolidinyl) -3-pyridazinyl] amino] -5-thiazolecarboxamide

Compound 487A was prepared using a procedure analogous to the procedure for preparing compound 473B. with the proviso that the compound 3-chloro-5-aminopyridazine is used herein instead of the compound 2-bromo-6-aminopyridine.

151

52291B

Compound 487Β was prepared using a procedure analogous to that for compound 473C. with the difference that compound 487A is used here instead of compound 473B.

C. The compound of the title

The title compound was prepared using a process analogous to that for compound 444B, except that compound 487B was used here instead of compound 444A and 3-hydroxypyrrolidine instead of N- (2-aminoethyl) -morpholine. HPLC retention time 2.493 min.

Example 488

Preparation of N- (2-chloro-6-methylphenyl) -2- [6- (1H-irnidazol-1-yl) -3-pyridazinylamino] -5-thiazolecarboxamide

Compound 488 was prepared using a procedure analogous to the procedure for preparing compound 487C. with the difference that imidazole is used here instead of 3-hydroxypyrrolidine. HPLC retention time 2.61 min.

152

52291 Β

Example 489

Preparation of N- (2-chloro-6-methylphenyl) -2-yl [3- (methylamino) -2-pyrazinyl] amino] -5-thiazolecarboxamide

Compound 489A was prepared using a procedure analogous to the procedure for preparing compound 473B. with the difference that the compound 2-chloro-3aminopyrazine is used here instead of the compound 2-bromo-6-aminopyridine.

Compound 489B was prepared using a procedure analogous to that for compound 473C. with the difference that compound 489A is used here instead of compound 473B.

153

52291B

S. The compound from the title

The title compound was prepared using a process analogous to that for compound 444B, except that compound 489B was used here instead of compound 444A and methylamine instead of N- (2-aminoethyl) -morpholine. HPLC retention time 2.81 min.

Examples 490 to 494

General procedure

Compounds 490 to 494 were prepared using a procedure analogous to the procedure for the preparation of compound 489C by substituting the appropriate amine.

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Time Detentions (min)</td>

<td> 490</td><td>V / If</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[3- (3-hydroxy-pyrrolidinyl) -2pyrazinyl] amino] -5thiazolecarboxamide</td><td> 2.82</td>

Example 495

Preparation of 'N- (2-chloro-6-ylmethylphenyl) -2- (cyclohexylamino) -6-thiazolecarboxamide

Compound 495 was prepared using a procedure analogous to the procedure for preparing compound 444B. with the difference that compound 319A is used here instead

154

52291Β compounds 444Α and cyclohexylamine instead of N- (2-aminoethyl) -morpholine. HPLC retention time 3.547 min.

Examples 496 to 500

General process Compounds 496 to 500 were prepared using a procedure analogous to the procedure for preparing compound 495 by replacing the corresponding amine.

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 496</td><td>Ν - // Ί? ' n3s' gUAuA</td><td>* N- (2-chloro-6-methylphenyl) - 2- (methylamino) -5- thiazolecarboxamide</td><td> 2.357</td>

Example 501

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6- (methoxymethyl) -4-pyrimidinyl] amino] -5-thiazolecarboxamide

155

52291B

To a mixture of methyl 4-methoxyacetoacetate (14.6 g. 0.1 moL) and formamidine hydrochloride salt (16.1 g. 0.2 moL) in 70 mL of dry MeOH was added a 25% solution of sodium methoxide (70 mL. 0.3 moL) in MeOH in portions. A white precipitate formed immediately. The reaction mixture was stirred at room temperature for 1.0 hour. Acetic acid (28.6 mL. 0.5 moL) was added and the reaction mixture was concentrated in vacuo. Water was added to the residue, and the mixture was saturated with NaCl and extracted with EtOAc (x5). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give 8.13 of compound 501A as a yellow solid.

A mixture of compound 501Α (5.3 g, 37.8 mmol) and POCl 3 (40 mL) was heated to reflux for 2.0 hours. Concentration was performed in vacuo and the residue was poured into an ice-CPBCb mixture. The pH was adjusted to 6.5 to 7 using concentrated NH4OH. The mixture was extracted with CH2C12 (hZ) and the combined extracts were dried over Na2SC> 4. Concentration in vacuo. followed by ..flash chromatography (CH2Cl2-EtOAc: 9: 1) 5.33 g of compound 501Β are obtained on silica gel in the form of a pale yellow oil.

THE3οοΎ ^ γNH2

A mixture of compound 501B (3.2 g. 20 mmol) and NH4OH (50 mL) was heated to 85 ° C in a tube under pressure for 3.0 hours. After cooling to room temperature. the reaction mixture was concentrated in vacuo and the residue was triturated with ether to give 2.81 g of compound 501C as a pale yellow solid.

156

52291B

Compound 501D was prepared from compound 501C using a procedure analogous to the procedure for preparing compound 473B.

E. The title compound

The title compound was prepared from compound 501D using a procedure analogous to that for compound 473C. HPLC retention time = 3.25 min.

Example 502

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6- (hydroxymethyl) -4-pyrimidinylamino] -5-thiazolecarboxamide

To a solution of compound 501 (56 mg, 0.144 mmol) in dry SNJSV (3.0 mL) cooled to 0 ° C was added pure BBr3 (0.054 mL. 0.574 mmol). The mixture was stirred for 1.0 hour at ambient temperature. MeOH was carefully added slowly at 0 ° C and the resulting mixture was concentrated in vacuo. Water was added to the residue and the pH was adjusted to 7 with saturated NaHCO3. The white precipitate was collected by filtration. washed with water / ether and dried under high vacuum to give 52 mg of compound 502 as a beige solid. HPLC retention time = 2.84 min.

157

52291B

Example 503

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[6- (4-morpholinylmethyl) -4-pyrimidinyl] amino] -thiazolecarboxamide

To a suspension of compound 502 (44.2 mg, 0.118 mmol) in 0.5 mL of dry SN 2 SV was added thionyl chloride (0.086 mL, 1.18 mmol). The reaction mixture was stirred for 5.0 hours. It was then concentrated in vacuo and the residue was azeotroped with SNJSV to give 56 mg of compound 503 as a yellow solid.

B. The title compound

A mixture of compound 503A (20 mg), morpholine (0.014 mL) and diisopropylethylamine (0.09 mL) in 0.5 mL of dry dioxane was heated to 85 ° C for 4.0 h. Concentration in vacuo. followed by flash chromatography (SNJSV-MeON-INdON: 95: 5: 0.5) on silica gel to give 15 mg of the title compound as a beige solid. HPLC retention time = 2.52 min.

Examples 504 to 513

General procedure

Compounds 504 to 513 were prepared from compound 503A using a procedure analogous to the procedure for preparing compound 503. The compounds of these examples have the following structure:

158

52291B

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Time Detentions (min)</td>

<td> 504</td><td>X</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[[2- (dimethylamino) ethyl] amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.083</td>

<td> 505</td><td>Α ο n.s- £)</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[2- (4-) morpholinyl) ethyl] amino] methyl] -4pyrimidinyl] amino] -5- thiazolecarboxamide</td><td> 2.593</td>

<td> 506</td><td>/ V1^ “Ο</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[[3- (4morpholinyl) propyl] amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.163</td>

<td> 507</td><td>zi - N Cl The \ / nЧЗ</td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[[3- (2-oxo-pyrrolidinyl) propyl] amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.693</td>

<td> 508</td><td>· Γγ · ^ N ^ NS ~ X 0Λ- \ ρι ν_THE</td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[(2-1H-imidazol-4-ethyl) amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td> 2.143</td>

<td> 509</td><td>nq '^ AQT15 ΧΑΧ4ο-θ</td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[(3-1H-imidazol-1-yl] propyl) amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td>1,103 B</td>

<td> 510</td><td>^ -O</td><td>'N- (2-chloro-6-methylphenyl) - 2- [| 6 - [[[2- (2-pyrylidinyl) ethyl] amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td>1,113 B</td>

159

52291B

<td> 511</td><td></td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[[2- (3-pyridinyl) ethyl] amino] methyl] -4pyrimidinyl] amino] -5thiazolecarboxamide</td><td>1,117 B</td>

<td> 512</td><td></td><td>1 - [[6 - [[5 - [[(2-chloro-6-methylphenyl) amino] carbonyl] 2-thiazolyl] amino] -4-pyrimidinyl] methyl] -4-piperidinecarboxamide</td><td>1,207 B</td>

<td> 513</td><td></td><td>'2 - [[6 - [[[2 (acetylamino) ethylamino] methyl] -4pyrimidinyl] amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td>1,193 and</td>

Example 514

Preparation of N- (2-chloro-6-methylphenyl) -2- (2-naphthalenylamino) -5-thiazolecarboxamide

160

52291B

Compound 514Α was prepared from compound 473A using a procedure analogous to the procedure for preparing compound 473B. with the difference that 2aminonaphthalene is used here instead of 2-bromo-6-aminopyridine.

B. The title compound

The title compound was prepared using a procedure analogous to the process for the preparation of compound 473C, except that compound 514Α was used here instead of compound 473B. HPLC retention time 4.11 min.

Example 515

Preparation of N- (2-chloro-6-methylphenyl) -2- (2-quinolinylamino) -5-thiazolecarboxamide

Compound 515A was prepared from compound 473A using a procedure analogous to the procedure for preparing compound 473B. with the difference that 2aminoquinoline is used here instead of 2-bromo-6-aminopyridine.

161

52291B

Β. The compound from the title

The title compound was prepared using a procedure analogous to the procedure for the preparation of compound 473C. with the difference that compound 515Α is used here instead of compound 473B. HPLC retention time 3.94 min.

Example 516

Preparation of 'N - (' 2-chloro-6-methylphenyl) -2- (3-isoquinolinylamino) -5-thiazolecarboxamide

Compound 516Α was prepared from compound 473A using a procedure analogous to the procedure for preparing compound 473B. with the difference that 3aminoisoquinoline is used here instead of 2-bromo-6-aminopyridine.

B. The title compound

The title compound was prepared using a procedure analogous to the procedure for the preparation of compound 473C. with the difference that compound 516Α is used here instead of compound 473B. HPLC retention time 3.94 min.

162

52291B

Example 517

Preparation of N- (2-chloro-6-methylphenyl) -2- (2-quinoxalinylamino) -5-thiazolecarboxamide

Compound 517Α was prepared from compound 473A using a procedure analogous to the procedure for obtaining compound 473B. with the difference that 2aminoquinoxaline is used here instead of 2-bromo-6-aminopyridine.

B, The compound from the title

The title compound was prepared using a procedure analogous to the procedure for the preparation of compound 473C. with the difference that compound 517Α is used here instead of compound 473B. HPLC retention time 3.927 min.

Example 518

Preparation of N- (2-chloro-6-methylphenyl) -4-methyl-2 - [[2-methyl-6- (4-morpholinyl) -4pyrimidinyl] amino] -5-thiazolecarboxamide

163

52291B

Compound 518Α was prepared from compound 144 using a procedure analogous to the procedure for preparing compound 319A.

Compound 518Β was prepared using a procedure analogous to the procedure for preparing compound 473A. with the difference that compound 518Α is used here instead of compound 319A.

164

52291B

Compound 518C was prepared using a process analogous to that for compound 473B, except that compound 518Β was used here instead of compound 473A and 4-amino-6-chloro-2-methylpyrimidine instead of 2-amino-6-bromopyridine.

Compound 518D was prepared using a procedure analogous to the procedure for preparing compound 473C. with the difference that compound 518C is used here instead of compound 473B.

E. The title compound

The title compound was prepared using a procedure analogous to that for compound 444B. with the proviso that compound 518D is used herein instead of compound 444A and morpholine instead of N- (2-aminoethyl) -morpholine. HPLC retention time 3.397 min.

165

52291B

Example 519

Preparation of N- (2-chloro-6-methylphenyl) -4-methyl-2 - [[2-methyl-6- [R- (4-morpholinyl) ethyl] amino] -4-pyrimidinyl] amino] -5-thiazolecarboxamide

Compound 519 was prepared using a procedure analogous to the procedure for preparing compound 518Ε. with the difference that N- (2-aminoethyl) -morpholine is used here instead of morpholine. HPLC retention time 2.493 min.

Example 520

Alternative procedure for preparation of compound 321

Compound 520A was prepared from 2-aminothiazole according to the procedure described in UK patent application GB 2323595A.

166

52291 Β

To a solution of compound 520Α (480 mg. 4.0 mmol) in dry THF (10 mL). which was cooled to -78 ° C. a 2.5M solution of n-BuLi (1.68 mL. 4.2 mmol) in hexane was added dropwise using a pipette while maintaining the internal temperature below -75 ° C. Upon completion of the addition. a beige suspension was obtained. The reaction mixture was stirred at -78 ° C for 15 min. A solution of 2-chloro-6-methylphenylisocyanate (0.6 mL, 4.4 mmol) in 5 mL of dry THF was added and the reaction mixture was stirred for another 2.0 hours at -78 ° C. Saturated aqueous NH was added4Cl (10 mL). the mixture was partitioned between EtOAc-water and extracted with EtOAc (x2). The combined extracts were dried over Na 2 SO 2 and concentrated in vacuo to give 0.99 g of the title compound as a pale yellow crystalline material after recrystallization from EtOAc-hexane.

Compound 520C was prepared using a procedure analogous to the procedure for preparing compound 473A, using compound 520B instead of compound 319A.

167

52291B

Compound 520D was prepared from compound 520C using a procedure analogous to the procedure for preparing compound 473B.

E. Unity of titles

Compound 321 was prepared using a procedure analogous to the procedure for preparing compound 473C.

Example 521

Preparation of 2-N, N-dimethyl-4-pyrimidinyl) amino] -N-phenyl-5-thiazolecarboxamide

168

52291B

Compound 521Α was prepared using a procedure analogous to that for compound 520B. with the difference that phenylisocyanate is used here instead of 2-chloro-6-methylphenylisocyanate.

Compound 521Β was prepared using a procedure analogous to the procedure for preparing compound 473A, using compound 521Α instead of compound 319Α.

sn3

Compound 521C was prepared from compound 521B using a procedure analogous to the procedure for preparing compound 473B.

D. The title compound

The title compound was prepared using a procedure analogous to the procedure for the preparation of compound 473C. HPLC retention time 1.3 min method B.

169

52291B

Example 522

Preparation of '2 - {(2,6-dimethyl-4-pyrimidinyl) methylamino] -N- (2-methylphenyl) -5-thiazolecarboxamide

Compound 522A was prepared using a procedure analogous to the procedure for preparing compound 520B. with the difference that 2-methylphenylisocyanate is used here instead of 2-chloro-6-methylphenylisocyanate.

Compound 522B was prepared using a procedure analogous to the procedure for preparing compound 473A. using compound 522A instead of compound 319Α.

170

52291B

Compound 522C was prepared from compound 522B using a procedure analogous to the procedure for preparing compound 473B.

Sodium hydride (60% in oil: 40 mg: 1 mmol) was added to a solution of compound 522C (280 mg; 0.61 mmol) in 2 mL of DMF at room temperature. After stirring for 30 minutes. iodomethane (0.2 μg 3 mmol) was added and the reaction was stirred for 4 hours. Since the reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). the organic layer was washed with water (2 x 50 mL) and brine (50 mL). Drying (MgSO 2)4) and concentrated to give an oil which was chromatographed on a 2.5 x 15 cm silica gel column using 50-75% ethyl acetate / hexane. The pure fractions were concentrated and the residue was crystallized from ethyl acetate / hexanes to give 100 mg of compound 522D as a light yellow solid.

171

52291B

Ε. The compound from the title

The title compound was prepared using a procedure analogous to the procedure for the preparation of compound 473C. HPLC retention time 1.21 min method B.

Example 523

Preparation of '2 - [(2,6-dimethyl-4-pyrimidinyl) amino] -N- (2-methylphenyl) -5-thiazolecarboxamide

Compound 523 was prepared using a procedure analogous to the process for preparing compound 473C, except that compound 522C was used here instead of compound 473B. HPLC retention time 1.24 min method B.

Example 524

Preparation of 'N- (3,5-dimethoxyphenyl) -2 - [(2,6-dimethyl-4-pyrimidinyl) amino] -5-thiazolecarboxamide

172

52291B

°nosn3

Compound 524Α was prepared using a procedure analogous to that for compound 520B. with the difference that 3,5dimethoxyphenylisocyanate is used here instead of methylphenylisocyanate.

Compound 524B was prepared using a procedure analogous to the procedure for preparing compound 473A. using compound 524A instead of compound 319Α.

C

52291B

Compound 524C was prepared from compound 524B using a procedure analogous to that for compound 473B.

D. The title compound

The title compound was prepared using a procedure analogous to the procedure for the preparation of compound 473C. with the difference that compound 524C is used here instead of compound 473B. HPLC retention time 1.28 min method B.

Example 525

Preparation of N- [2,6-Bis (1-methylethyl) phenyl] -2 - [(2,6-dimethyl-4-pyrimidinyl) amino] -5-thiazolecarboxamide

Compound 525A was prepared using a procedure analogous to the procedure for preparing compound 520B. with the difference that 2.2diisopropylphenylisocyanate is used here instead of methylphenylisocyanate.

174

52291B

Compound 525Β was prepared using a procedure analogous to that for compound 473A. using compound 525A instead of compound 319Α.

C

Compound 525C was prepared from compound 525B using a procedure analogous to that for compound 473B.

D. The compound of the title

The title compound was prepared using a procedure analogous to the procedure for preparing compound 473C. with the difference that compound 525C is used here instead of compound 473B. HPLC retention time 1.6 min procedure B.

Example 526

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(2,6-dimethyl] -4-pyrimidinyl) methylamino] -5-thiazolecarboxamide

175

52291B

A mixture of compound 321 (110 mg; 0.29 mmol). potassium carbonate (138 mg: 1 mmol) and iodomethane (0.06 μm 1 mmol) in DMF were stirred for 2 hours at room temperature. Since the reaction mixture was partitioned between ethyl acetate (25 ml) and water (25 ml). the organic layer was washed with water (2 x 25 mL) and brine (25 mL). Drying (MgSO 2)4) and concentration gave an oil which was chromatographed on a 2.5 x 15 cm silica gel column using 1-4% MeOH / SNJSR. and then fractions containing compound 526 were collected to give 20 mg of product. HPLC retention time 1.3 min method B.

Example 527

Preparation of N- (2-chloro-6-methylphenyl) -2- [2 (2,6-dimethyl-4-pyrimidinyl) amino] -N-methyl-5-thiazolecarboxamide

Compound 527 was prepared using a procedure analogous to the process for the preparation of compound 526. except that fractions containing compound 527 were collected here to give 60 mg of product. HPLC retention time 1.23 min method B.

Example 528

Preparation of 2-bromo-N- (2-chloro-6-methylphenyl) - (4-methoxybenzyl) -5-thiazolecarboxamide

176

52291B

A 1.0 M solution of lithium bis (trimethylsilyl) amide (42.2 mL. 42.2 mmol. 2.00 equiv.) Was added dropwise to the cooled (0 ° C) solution of 2-chloro-6-methylaniline (2.86 mL. 23.3 mmol. 1.10 equiv.) In THF. using a pipette. The homogeneous solution was allowed to stir for 5 minutes, and then a solution of ethyl 2-bromo-5-thiazolecarboxylate (5.00 g, 21.1 mmol. 1.00 equiv., Prepared in a similar manner as compound 319Α) in THF was added via cannula. The solution was allowed to stir for 15 minutes until TLC analysis showed no more starting material. To the reaction was then added 4-methoxybenzyl chloride (7.15 mL. 52.7 mmol. 2.5 equiv.). followed by a catalytic amount of tetrabutylammonium iodide (1.56 g. 4.22 mmol. 0.20 equiv.). The homogeneous mixture was allowed to stir overnight at ambient temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. and the organic extracts were washed with physiological saline and dried over Na2SO4. After filtration and removal of the solvent. the product was purified by flash chromatography (10-20% ethyl acetate in hexanes) to give the title compound as a tan solid (47%).

Example 529

Preparation of N- (2-chloro-6-methylphenyl) - (4-methoxybenzyl) -2- [6-bromo-2-pyridinyl) amino] -5-thiazolecarboxamide

Compound 529 was prepared analogously to compound 319Β. with the proviso that compound 528 and 6-bromo-2-aminopyridine are used herein as reactants.

177

52291B

Example 530

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(6-bromo-2-pyridinyl) amino] -5-thiazolecarboxamide

Compound 529 (0.500 g. 0.919 mmol. 1.00 equiv.) Was dissolved in 5 mL of trifluoroacetic acid. then 2 mL of anisole was added at ambient temperature. followed by 1 mL of trifluoromethanesulfonic acid. The dark red homogeneous solution was allowed to stir overnight and then quenched by carefully pouring the solution into an ice / sodium bicarbonate mixture. The white solid was filtered off and washed with water. 1: 1 with hexane / ether and ether to give the title compound (41%).

Examples 531-538

General procedure

Compounds 531 to 538 were prepared according to the general procedure described below. The 1,771-gram vial was filled with compound 530 and excess amine and heated to 90 ° C overnight. The residue was then purified using reverse-phase HPLC to give the pure compound. For the following examples 531 to 555 HPLC retention time is the HPLC retention time under the following conditions: YMC ODS-A CIS S7 3.0 h 50 mm, 2 min gradient starting from 100% solvent A (10% MeOH. 90% H2O. 0.1% TFA) to 100% solvent B (90% MeOH. 10% H2O, 0.1% TFA). flow rate 5 mL / min. λ = 220 nM.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention Time a (min)</td>

178

52291B

<td> 53 1</td><td> ¢0</td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6- [4- (2-furanylcarbonyl) -1-piperazinyl] -2-pyridinyl] amino] -5H and azo 1-carboxylamine</td><td> 1.56</td>

<td> 53 2</td><td>a</td><td>'2 - [[6 - [[3- (1N-benzimidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -N- (2-chloro-6-methylphenyl) -5-thiazolecarboxamide</td><td> 1.41</td>

<td> 53 3</td><td>ΜλΜ0 SGα SG</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[4- (1H-imidazol-yl) butyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.24</td>

<td> 53 4</td><td></td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[5- (1H-imidazol-yl) pentyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.25</td>

<td> 53 5</td><td></td><td>'N- (2-chloro-6-methylphenyl) 2 - [[6 - [[3- (4-methyl-piperidinyl) propyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.14</td>

<td> 53 6</td><td>CL ·</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[4- (1H-imidazol-yl) phenyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.29</td>

<td> 53 7</td><td>Q—</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [[6- (1H-imidazoll-yl) hexyl] amino] -2-pyridinyl] amino] -5thiazolecarboxamide</td><td> 1.27</td>

<td> 53 8</td><td>Ν<^Νg^> ^ ιΑ'Λ'ΝΑΛγΝνΑ | YES</td><td>'N- (2-chloro-6-methylphenyl) - 2 - [[6 - [(3-1H-imidazol-1-ylpropyl) amino] -2-pyridinyl] amino] -5- ti azo 1 k arbo k sam id</td><td> 1.24</td>

Example 539

179

52291B

Preparation of ethyl 2 - [(6-bronze-2-pyridinyl) amino] -5-thiazolecarboxylate

Compound 539 was prepared analogously to the preparation of compound 319Β. with the difference that ethyl 2-bromo-5-thiazolecarboxylate and 6-bromo2-aminopyridine are used as reactants here.

Examples 540-550

The general procedure of compounds 540 to 550 was prepared according to the general procedure described below. Compound 539 was condensed with the corresponding aniline according to the procedure for Example 528 to give the corresponding N- (4-methoxybenzyl) amide. The intermediate bromopyridine was then reacted with N- (3-aminopropyl) -imidazole according to the procedure for Examples 531 to 538 to give the corresponding diaminopyridine. By removing 4methoxybenzyl grape according to the procedure described for Example 530. followed by purification by reverse-phase preparative HPLC to give compounds 540 to 550.

<td>Pr. no.</td><td>The structure of the compound</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 540</td><td></td><td>'2 - [[6 - [[3- (1Himidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -N (4-methoxyphenyl) -5-thiazolecarboxamide</td><td> 1.12</td>

<td> 541</td><td></td><td>'2 - [[6 - [[3- (1Nimidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -N (4-phenoxyphenyl) -5-thiazolecarboxamide</td><td> 1.48</td>

180

52291B

<td> 542</td><td></td><td>'N- (4-chlorophenyl) -2- [[6- - [[3-</td><td> 1.31</td>

<td> 543</td><td>N 1 Ν Ν Ν S ΗΝ - ά \ Yes</td><td>'2 - [[6 - [[3- (1Nimidazol-1-yl) propyl] amino] -2-pyridinyl] amino | -N [1- (phenylmethyl) -1H-indazol-5-yl] -5-thiazolecarboxamide</td><td> 1.34</td>

<td> 544</td><td>Ν ^ -Ν N S λ--</td><td>'N- (2-ethylphenyl) -2 - [[6- [[3- (1H-imidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.18</td>

<td> 545</td><td>X Χλ? Dr.</td><td>'N- (2.6- dimethoxyphenyl) -2 - [[6 [[3- (1H-imidazol-lyl) propyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.11</td>

<td> 546</td><td>, sn></td><td>'N- (2,4-dimethoxyphenyl) -2 - [[6 [[3- (1H-imidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide</td><td> 1.06</td>

<td> 547</td><td>e - Xu4 +)</td><td>'2 - [[6 - [[3- (1Nimidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -Nphenyl-5-thiazolecarboxamide</td><td> 1.06</td>

<td> 548</td><td>g NL rXi F ¥ aj) U / Nv</td><td>'2 - [[6 - [[3- (1Nimidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -N (2-methylphenyl) -5-thiazolecarboxamide</td><td> 1.11</td>

<td> 549</td><td> 0 Cl\ μι JGuL 4 / ^, AAZ> nA'-></td><td>'N- (2-chlorophenyl) -2 [(6 - ((3- (1H-imidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -5-diazolecarboxamide</td><td> 1.16</td>

181

52291B

550

'N- (2,6-diethylphenyl) -2 [[6 - [[3- (1H-imidazol-yl) propyl] amino] -2-pyridinyl] amino] -5-thiazolecarboxamide

1.29

Example 551

Preparation of ethyl 2- [6- (6-bromo-2-pyridinyl) amino] 4-methyl-5-thiazolecarboxylate

Compound 551 was prepared in an analogous manner to the preparation of compound 319B. with the difference that ethyl 2-bromo-4-methyl-5-thiazolecarboxylate and 6bromo-2-aminopyridine are used here as reactants.

Examples 552 and 553

Compounds 552 and 553 were prepared using a process similar to that for preparing compounds 540 to 550, except that compound 551 was used as starting material herein.

<td>Pr. no.</td><td>Unity structure</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 552</td><td></td><td>N- (2-chloro-6-methylphenyl) -2 - [[6 - [[3 (1H-imidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -4-methyl-5- thiazolecarboxamide</td><td> 1.19</td>

182

52291B

'2 - [[6 - [[3- (1Nimidazol-1-yl) propyl] amino] -2-pyridinyl] amino] -4-methyl-N- [1- (phenylmethyl) 1H-indazol-5-yl] -5-azolcarboxamide

Example 554

Preparation of N- (2-chloro-6-methylphenyl) -2-G [3 - [[3- (1H-imidazol-1-yl) propyl] amino] phenyl] amino] -5-thiazolecarboxamide

Solution of compound 528 (0.127 g. 0.281 mmol. 1.00 equiv.) And 3- [N, N- (tert-butoxycarbonyl) - (3-aminopropyl) -imidazoyl] -1,3-phenylenediamine (0.178 g, 0. 563 mmol. 2.00 equiv) in 0.200 mL DMSO was heated to 120 ° C in a sealed vessel overnight. Purification by reverse-phase preparative HPLC. and then deprotection according to the procedure for compound 530 gave the title compound.

Example 555

Preparation of N- (2-chloro-6-methylphenyl) -2- [5 - [[3- (1H-trifluoro-1-yl) pyrropyl] amino] -2-nitrophenyl] amino-5-thiazolecarboxamide

To a solution of 2,4-difluoronitrobenzene (0.400 mL. 3. 65 mmol. 1.00 equiv) in acetonitrile was added K2WHAT2, (0.605 g. 4.38 mmol. 1.20 equiv). and then ethyl 2-amino-5-thiazolecarboxylate (0.628 g. 3.65 mmol. 1.00 equiv) in the solid state. The heterogeneous mixture was closed and heated to 120 ° C overnight. The solution was filtered. and then concentrated in vacuo. Purification by flash chromatography gave ethyl 2 - [(3-fluoro-6-nitro-1-phenyl) amino] -5183

52291Β Thiazolecarboxylate as a yellow solid (9%). This intermediate was combined with 2-chloro-6-methylaniline according to the procedure for compound 528 to give N- (2-chloro-6-methylphenyl) -2- [3- (fluoro-6-nitro-1-phenyl) amino] - 5-thiazolkab'b oxamide (21%). The title compound was synthesized by reacting this intermediate with excess N- (S-aminopropyl) imidazole at 80 ° C, followed by purification using reverse-phase preparative HPLC.

Examples 556-566

General procedure

Compounds 556 to 566 were prepared according to the general procedure described below. Mixture of 2-bromo-N- [2-chloro-6-methylphenyl] -5-thiazolecarboxamide 319A. aniline (1 eq.), 1.0 N aqueous solution of HCl (0.5 eq.) in n-BuOH was heated overnight at 120 ° C in a closed vessel. It was then diluted with methanol and the product was isolated by preparative HPLC (YMC S5 ODS 30 x 100 mm column. eluting with a gradient consisting of two mixtures of solvents (mixture A: 10% MeOH, 90% water and 0.1% TFA; mixture B: 90% MeOH, 10% water and 0.1% TFA). For anilines substituted with a carboxylic acid group, the reaction mixture was treated with 1 N aqueous NaOH (5 eq.). and before final purification of the product using HPLC. HPLC retention time is the HPLC retention time under the following conditions: YMC S5 OSD 4.6 x 30 mm (for 556 to 560) or YMC S7 ODS 3 x 50 mm column (for 561 to 566). 2 min gradient starting from 100% solvent A (10% MeOH. 90% NJO. 0.1% TFA) to 100% solvent B (90% MeOH. 10% FBO, 0.1% TFA), flow rate 5 mL / min, k = 220 nM.

<td>Pr. no.</td><td>The structure of the unit</td><td>The name of the compound</td><td>HPLC Retention Time (min)</td>

<td> 556</td><td>Cl</td><td>N- (2-chloro-6-methylphenyl) - 2 - [(3,4,5-trimethoxylenyl) amino] -5-diazolecarboxamide</td><td> 1.63</td>

<td> 557</td><td></td><td>N- (2-chloro-6-methyl-phenyl) - 2 - [(4-methoxyphenyl) amino] -5thiazolecarboxamide</td><td> 1.63</td>

<td> 558</td><td></td><td>N- (2-chloro-6-methyl-phenyl) - 2 - [(3-methoxylenyl) amino] -5thiazolecarboxamide</td><td> 1.70</td>

184

52291B

<td> 559</td><td>Cat</td><td>N- (2-chloro-6-methyl-phenyl) 2 - [(2-methoxyphenyl) amino] -5-thiazolecarboxamide</td><td> 1.65</td>

<td> 560</td><td>Cat</td><td>N- (2-chloro-6-methyl-phenyl) - 2 - [(3,5-dimethoxyphenyl) amino] -5thiazolecarboxamide</td><td> 1.55</td>

<td> 561</td><td></td><td>N- (2-chloro-6-methyl-phenyl) - 2 - [[4- (dimethylamino) phenyl] amino] -5-thiazolecarboxamide</td><td> 1.25</td>

<td> 562</td><td></td><td>N- (2-chloro-6-methylphenyl) 2 - [[4- (4-morpholinyl) phenylamino] -5-thiazolecarboxamide</td><td> 1.24</td>

<td> 563</td><td>CI</td><td>N- (2-chloro-6-methylphenyl) - 2 - [[3- (carboxymethyl) phenyl] amino] -5-thiazolecarboxamide</td><td> 1.36</td>

<td> 564</td><td></td><td>N- (2-chloro-6-methylphenyl) - 2 - [[3- (3-carboxypropyl) phenyl] amino] -5thiazolecarboxamide</td><td> 1.48</td>

<td> 565</td><td>Η 0 Ζ</td><td>N- (2-chloro-6-methylphenyl) - 2 - [[4- (carboxymethyl) phenyl] amino] -5thiazolecarboxamide</td><td> 1.35</td>

<td> 566</td><td></td><td>N- (2-chloro-6-methylphenyl) 2 - [(2-methyl-1H-benzimidazol-5-yl) amino] 5-thiazolecarboxamide</td><td> 1.27</td>

Example 567

Preparation of N- (2-chloro-6-methylphenyl) -2- [f 1 -13- (1H-imidazol-1-ylpropyl] -1H-benzimidazol-4-yl] amino] -5-thiazolecarboxamide

A mixture of 1-bromo-3-chloropropane (10 mL. 0.10 mmol) and imidazole (6.81 g. 0.10 mmol) in a solution of NaOEt (41.3 mL. 21 wt%. 1.1 mmol) in elanol was heated to reflux 1

185

52291 Β time. After cooling to room temperature. the mixture was filtered and the filter cake was washed with EtOH. The solvent was removed from the filtrate to give crude 3-chloro-1- (imidazo-1-yl) -propane as an oil. A portion of the crude chloride (1.07 g, 7.40 mmol) was added to a mixture of 4-nitrobenzimidazole (1.09 g, 6.66 mmol) and NaH (293 mg. 60% in oil. 8.14 mmol) in DMF (15 mL). After heating at 60 ° C overnight and then at 75 ° C for 3 hours. the solvent was removed. The residue was partitioned between water and a mixture of 10% MeOH in DCM. The organic phase is separated. dried (Na2SO4) and the solvents were removed. Radial chromatography (4 mm silica gel plate eluted with a DCM gradient containing 2. 3. 4 .... 10% MeOH) gave the main product, 1- [3-imidazo-1-ylpropyl] -4-nitro- solid benzimidazole (513 mg. 28%). A mixture of this material (250 mg) and 10% palladium on carbon (200 mg) in EtOH (10 mL) under a hydrogen atmosphere (balloon) was stirred vigorously for 1 hour. Removal of the catalyst by filtration and the solvent under reduced pressure gave the crude 4-amino-1- [3-imidazol-1-ylpropyl] benzimidazole in solid. A portion of this material (46 mg, 0.191 mmol) was added to a mixture of compound 319Α (63 mg. 1.0 eq.). aqueous HCl (0.24 mL. 1.0 M. 1.25 eq.) and nBuOH (1 mL). This mixture was heated in a closed vessel to 120 ° C. 44 hours. After cooling to room temperature, compound 567 (HPLC retention time (YMC ODS S5 4.6 x 30 mm): 1.20 min) was isolated by preparative HPLC.

Example 568

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[1- [2- (1H-imidazol-1-ipethyl-1H-indazol-6-yl] amino] -5-thiazolecarboxamide

A mixture of 1-bromo-2-chloroethane (4.6 mL. 0.055 mol) and imidazole (3.40 g. 0.050 mol) in a solution of NaOEt (19 mL, 21% by weight. 1 eq.) In ethanol was heated at reflux for 2 hours. After cooling to room temperature. the reaction was filtered and the filter cake was washed with EtOH. The solvent was removed from the filtrate to give crude 2-chloro-1- (imidazo-1-yl) -ethane. A portion of the crude chloride (2.24 g, 17.2 mmol) was added to a mixture of 6-nitro-indazole (1.63 g, 10.0 mmol). K2SO 2 (1.50 mg. 1.1 eq.) And KI (1.70 g. 1.1 eq.) In DMF (15 mL). After heating at 70 ° C overnight and then at 90 ° C for 4 hours. the solvent was removed. The rest is divided

186

52291Β between water and a mixture of 5% MeOH in DCM. The organic phase is separated. dried (NaiSCM and solvents were removed. Radial chromatography (4mm silica gel plate eluting with a DCM gradient containing 0. 1.2% MeOH) gave 659 mg of 1- [2-imidazo-1-ylethyl] 6-nitro-indazole and 450 mg of isomeric 2- [2-imidazol-1-ylethyl] -6-nitro-indazole. A mixture of 1- [2imidazo-1-ylethyl] -6-nitro-indazole (650 mg) and 10% palladium on carbon (600 mg) in EtOH (10 mL) under a hydrogen atmosphere (balloon) was stirred vigorously overnight. Removal of the catalyst by filtration and the solvent under reduced pressure gave the crude 6-amino-1- [2-imidazo-1-ylethyl] -indazole in the solid. A portion of this material (68.1 mg. 1.5 eq.) Was added to a mixture of compound 556 (99.3 mg, 0.300 mmol), aqueous HCl (0.45 mL. 1.0 Μ, 1.5 eq.) And n-BuOH (1.5 mL). The mixture was heated in a closed vessel at 120 ° C for 44 hours. After cooling to room temperature. compound 568 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.31 min) was isolated by preparative HPLC.

Example 569

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(2- [2- (1H-imidazol-1-yl) ethyl] -2H-indazol-6-yl] amino] -5-thiazolecarboxamide

Starting from the isomeric 2- [2-imidazol-1-ylethyl] -6-nitro-indazole, compound 569 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.28 min) was prepared in a similar manner as compound 568.

Example 570

Preparation of N- (2-chloro-6-methylphenyl) -2 - [(1-methyl-1H-benzimidazol-6-yl) amino] -5-thiazolecarboxamide

187

52291 Β i

Example 571

Preparation of N- (2-chloro-6-methylphenyl) -2- [1 (1-methyl-1H-benzimidazol-5-yl) amino] -5-thiazolecarboxamide

Starting with 5-nitrobenzimidazole and methyl iodide. Compounds 570 (HPLC retention time (YMC ODS S7 3 x 50 mm); 1.23 min) and 571 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.23 min) were prepared in the same manner as compounds 557 and 558.

Example 572

Preparation of N- (2-chloro-6-methylphenyl) -2- [[2- (3- (1H-imidazol-1-yl) propyl] -1H-benzimidazol-5-yl] amino] -5-thiazolecarboxamide

A mixture of 2-chloro-5-nitro-benzimidazole (985 mg. 5.0 mmol) and 1- (3-aminopropyl) imidazole (1.8 mL, 3 eq.) In toluene (15 mL) was heated at reflux for 5 hours. The reaction was partitioned between EtOAc and brine to give a precipitate which was then collected by filtration. Flash chromatography of this material (silica gel; gradient elution with DCM mixtures containing 1. 2, 3 .... 10% MeOH) gave 2- [3- [imidazo-1-yl] propylamino] -5-nitro -benzimidazole (550 mg) in the solid state. This material was combined with 10% Pd on charcoal (500 mg), suspended in EtOH and stirred under a hydrogen atmosphere (balloon) overnight. Removal of the catalyst by filtration and the solvent under reduced pressure was obtained

188

52291Β is crude 5-amino-2- [3-imidaz-1-ylpropylamino] -benzyrimidazole in the solid state. A portion of this material (77 mg. 0.30 mmol) was added to a mixture of compound 319Α (99 mg, 1.0 eq.), Aqueous HCl (0.60 mL. 1.0 M. 2 eq.) And n-BuOH (1.5 mL). This mixture was heated in a closed vessel at 120 ° C for 20 hours. After cooling to room temperature, compound 572 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.20 min) was isolated by preparative HPLC.

Example 573

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[2- (4-morpholinylphenyl) -1H-benzimidazol-5-yl] amino] -5-thiazolecarboxamide

Mixture of 3,4-diamino-nitrobenzene (15.3 g, 0.10 mol) and chloroacetic acid (14.18 g)

1.5 eq.) In 5.0 N aqueous HCl (80 mL) was heated at reflux for 1 hour. After cooling to room temperature, the reaction was filtered through celite and the filtrate was stored at 0 ° C. 2 days. Crystals formed. were collected and recrystallized from a mixture of EtOH and water to give 7.2 g of the hydrochloride salt of 2-chloromethyl-5-nitro-benzimidazole. A portion of this salt (528 mg, 2.13 mmol) and morpholine (1.31 mL. 7 eq.) In toluene (15 rnL) were heated at reflux for 4 hours. After cooling to room temperature, the reaction was filtered and the filter cake was washed with toluene. The solvent was removed from the filtrate to give crude 2- [N-morpholinylmethyl] -5nitro-benzimidazole as an oil. A portion of this material (657 mg) and 10% palladium on carbon (650 mg) in EtOH (10 mL) were stirred overnight under a hydrogen atmosphere (balloon). Removal of the catalyst by filtration and removal of the solvent gave crude 5-amino-2 [N-morpholinylmethyl] -benzimidazole as an oil. A portion of this material was combined with compound 556 as described for compound 570 to give compound 573 (HPLC retention time (YMC ODS S7 3 x 50 mm): 0.92 min).

Example 574

189

52291B

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[2- (1H-imidazol-1-ylmethyl) -1H-benzimidazole-

5-yl] amino] -5-thiazolecarboxamide

Starting with imidazole and 2-chloromethyl-5-nitro-benzimidazole. the compound was prepared

574 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.17 min) in a similar manner to compound 570.

Example 575

Preparation of N- (2-chloro-6-methylphenyl) -2- [1,3- [r5- (1H-irnidazol-1-yl) -2-pyridinyl] aminophenyl] amino] -5-thiazolecarboxamide

A mixture of 3-nitroaniline (2.91 g. 21.1 mmol) and 2.5-dibromopyridine (5.0 g. 1 eq.) Was heated to 185 ° C. 1 hour. After cooling to room temperature, the solid was fractionated (crushed) and treated with a mixture of saturated aqueous NaHCO 3 and 10% MeOH in DCM. The suspended solid was collected by filtration and washed with a little 10% MeOH in DCM. and then with water to give 3.72 g of crude N- [5-bromo-pyridin-2-yl] -5-nitroaniline after drying. Part of this material (500 mg. 1.70 mmol) was combined with imidazole (116 mg. 1 eq.). Cul (81 mg. 0.25 eq.) And K2SO 2 (235 mg. 1 eq.) In DMF (2 mL) and the mixture was heated to 130 ° C. 2 days. After cooling to room temperature. the solvent was removed and the residue was partitioned between water and a mixture of 20% MeOH in DCM. The organic phase was removed. dried (Na2SO4) and the solvents were removed to give crude N- [5-imidazo-190

52291 Solid-pyridin-2-yl] -5-nitroamine in the solid state. It was treated with 10% palladium on carbon (650 mg) in EtOH under a hydrogen atmosphere for 1.5 h. By removing the catalyst. and then the solvent gave crude N- [5-imidazol-1-yl] -pyridin-2-yl] -5-aminoaniline. It was purified by radial chromatography (4 mm silica gel plate eluting with a DCM gradient containing 1. 2. 3 .... 6% MeOH). Aniline was then combined with compound 319Α, as described in compound 570. to give compound 575 (HPLC retention time (YMC ODS S5 4.6 x 30 mm): 1.42 min).

Example 576

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[3- [3- (1H-imidazol-1-yl) pyripoxy] phenyl] amino] -

5-thiazolecarboxamide

Example 577

Preparation of N- (2-chloro-6-methylphenyl) -2- [T4- [3- (1H-imidazol-1-yl) propoxylphenylamino] -

5-thiazolecarboxamide

3-nitrophenol suspension (837 mg, 6.02 mmol). 1-chloro-3- [imidazol-1-yl] -propane (871 mg. 1 eq.). K2SO 2 (3.3 g, 4 eq) and Nal (1.0 g, 1.1 eq) in DMF were heated to 120 ° C. 6 hours. After cooling to room temperature. the reaction was filtered and the filter cake was washed with DMF. The solvent was removed from the filtrate and the residue was chromatographed (radial chromatography: 4 mm silica gel plate eluting with a DCM gradient which

191

52291Β contains Ο, 1, 2.5, 5. 7.5% MeOH) to give 400 mg of 3- [3-imidazol-1-ylpropyloxy] nitrobenzene. It was treated with 10% palladium on carbon (400 mg) in EtOH under a hydrogen atmosphere for 4 hours. Removal of the catalyst and solvent gave 3- [3-imidazolyl-propyloxy] -aniline, which was then combined with compound 319Α. as described for compound 570. to give compound 576 (HPLC retention time (YMC ODS S5 4.6 x 30 mm): 1.33 min). Starting from 4-nitrophenol and 1-chloro-3- [imidazol-1-yl] -propane, compound 577 (HPLC retention time (YMC ODS S5 4.6 x 30 mm): 1.42 min) was prepared in a similar manner as compound 576.

Example 578

Preparation of N- (2-chloro-6-methylphenyl) -2-n'4- [2- (1H-imidazol-1-yl) ethoxy] -3-methoxyphenyl] amino] -5-thiazolecarboxamide

Starting with 2-methoxy-4-nitrophenol and 1-chloro-3- [imidazol-1-yl] -ethane. compound 578 (HPLC retention time (YMC ODS S5 4.6 x 30 mm): 1.35 min) was prepared in a similar manner as compound 576.

Example 579

Preparation of N- (2-chloro-6-methylphenyl) -2- [r3 - [[3- (1H-imidazol-1-yl) propylamino] sulfonylphenyl] amino] -5-thiazolecarboxamide

192

52291B

Example 580

Preparation of N- (2-chloro-6-methylphenyl) -2 - [[4 - [[3- (1H-imidazol-1-yl) propyl] amino] sulfonylphenyl] amino1-5-thiazolecarboxamide

3-Imidazol-1-yl-propylamine (2.04 mL. 2.5 eq.) Was added to a solution of 3-nitrobenzenesulfonyl chloride (1.5 g. 6.77 mmol) in THF (20 mL) at room temperature. After 1 hour. the solvent was removed and the residue was partitioned between water and a mixture of 10% MeOH in DCM. The organic phase is separated. washed with water and dried (NaiSOs). The crude N- [3- [imidazol-1-yl] propyl] -3-nitro-benzenesulfonamide was treated with 10% palladium on carbon (2 g) in THF (60 mL) under a hydrogen atmosphere overnight. By removing the catalyst. followed by the solvent to give crude 3-amino-N- [3- [imidazol-1-yl] -propyl] -benzenesulfonamide which was then combined with compound 319Α. as described for compound 570. to give compound 579 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.22 min). Starting from 4-nitrobenzenesulfonyl chloride and 3- [imidazol-1-yl] -propylamine, compound 580 (HPLC retention time (YMC ODS S7 3 x 50 mm): 1.21 min) was prepared in a similar manner as compound 579.

Contents138

129 members in 41 offices

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39550303	United States of America	A	2003-03-24
39550303	United States of America	A	2003-03-24
2004008827	United States of America	W	2004-03-23
2004008827	United States of America	W	2004-03-23
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CA2366932A1	Canada	A1	2000-10-26
WO0062778A1	World Intellectual Property Organization (WIPO)	A1	2000-10-26
AU4233800A	Australia	A	2000-11-02
NO20014970D0	Norway	D0	2001-10-12
ID30460A	Indonesia	A	2001-12-06
KR20010108500A	Republic of Korea	A	2001-12-07
NO20014970L	Norway	L	2001-12-10
EP1169038A1	European Patent Office (EPO)	A1	2002-01-09
BR0009721A	Brazil	A	2002-02-13
CN1348370A	China	A	2002-05-08
CZ20013677A3	Czechia	A3	2002-06-12
IL144910D0	Israel	D0	2002-06-30
HK1042433A1	Hong Kong, China	A1	2002-08-16
TR200102969T2	Türkiye	T2	2002-08-21
MXPA01010292A	Mexico	A	2002-10-23
ZA200107204B	South Africa	B	2002-12-02
JP2002542193A	Japan	A	2002-12-10
HU0202708A2	Hungary	A2	2002-12-28
PL351126A1	Poland	A1	2003-03-24
US6596746B1	United States of America	B1	2003-07-22
US2004024208A1	United States of America	A1	2004-02-05
NZ513639A	New Zealand	A	2004-02-27
US2004054186A1	United States of America	A1	2004-03-18
US2004073026A1	United States of America	A1	2004-04-15
US2004077875A1	United States of America	A1	2004-04-22
AU2004223828A1	Australia	A1	2004-10-07
CA2519898A1	Canada	A1	2004-10-07
WO2004085388A2	World Intellectual Property Organization (WIPO)	A2	2004-10-07
EP1169038A4	European Patent Office (EPO)	A4	2004-10-13
HU0202708A3	Hungary	A3	2004-12-28
AU779089B2	Australia	B2	2005-01-06
PE20041068A1	Peru	A1	2005-01-21
TW200510403A	Taiwan Province of China	A	2005-03-16
CL2004000610A1	Chile	A1	2005-05-06
WO2004085388A3	World Intellectual Property Organization (WIPO)	A3	2005-06-30
AR044506A1	Argentina	A1	2005-09-14
RU2260592C2	Russian Federation	C2	2005-09-20
IS8038A	Iceland	A	2005-09-21
NO20054359L	Norway	L	2005-10-19
MXPA05010145A	Mexico	A	2005-11-16
US2005261305A1	United States of America	A1	2005-11-24
KR20050115305A	Republic of Korea	A	2005-12-07
US6979694B2	United States of America	B2	2005-12-27
US2005288303A1	United States of America	A1	2005-12-29
HRP20050826A2	Croatia	A2	2005-12-31
EP1610780A2	European Patent Office (EPO)	A2	2006-01-04
HK1078491A1	Hong Kong, China	A1	2006-03-17
BRPI0408782A	Brazil	A	2006-03-28
RU2005132408A	Russian Federation	A	2006-04-10
US2006079563A1	United States of America	A1	2006-04-13
CN1764454A	China	A	2006-04-26
EP1610780A4	European Patent Office (EPO)	A4	2006-05-03
US7091223B2	United States of America	B2	2006-08-15
RU2005107463A	Russian Federation	A	2006-08-27
NO322470B1	Norway	B1	2006-10-09
JP2006523216A	Japan	A	2006-10-12
US7125875B2	United States of America	B2	2006-10-24
US7153856B2	United States of America	B2	2006-12-26
KR20070020153A	Republic of Korea	A	2007-02-16
ZA200507718B	South Africa	B	2007-02-28
US7189854B2	United States of America	B2	2007-03-13
NO2007005I1	Norway	I1	2007-03-27
KR100710100B1	Republic of Korea	B1	2007-04-23
KR100722344B1	Republic of Korea	B1	2007-05-29
CN1989969A	China	A	2007-07-04
IL144910A	Israel	A	2007-07-24
JP3989175B2	Japan	B2	2007-10-10
GEP20074234B	Georgia	B	2007-11-12
RU2312860C2	Russian Federation	C2	2007-12-20
RS20050698A	Serbia	A	2008-04-04
AU2004223828B2	Australia	B2	2008-07-03
NZ542171A	New Zealand	A	2008-10-31
NO2007005I2	Norway	I2	2008-12-01
CN101481359A	China	A	2009-07-15
UA87456C2	Ukraine	C2	2009-07-27
CA2366932C	Canada	C	2009-08-25
RU2365372C2	Russian Federation	C2	2009-08-27
MY139730A	Malaysia	A	2009-10-30
EP1610780B1	European Patent Office (EPO)	B1	2010-04-21
AT464898T	Austria	T	2010-05-15
ATE464898T1	Austria	T1	2010-05-15
DE602004026703D1	Germany	D1	2010-06-02
PT1610780E	Portugal	E	2010-06-22
ES2342937T3	Spain	T3	2010-07-19
DK1610780T3	Denmark	T3	2010-08-09
PL1610780T3	Poland	T3	2010-09-30
SI1610780T1	Slovenia	T1	2010-11-30
EP2308833A2	European Patent Office (EPO)	A2	2011-04-13
IL170873A	Israel	A	2011-04-28
EP2308833A3	European Patent Office (EPO)	A3	2011-09-28
KR101070101B1	Republic of Korea	B1	2011-10-05
TWI351404B	Taiwan Province of China	B	2011-11-01
CZ302788B6	Czechia	B6	2011-11-09
CA2519898C	Canada	C	2012-07-10
EP1169038B1	European Patent Office (EPO)	B1	2012-08-08
PT1169038E	Portugal	E	2012-10-26
RS52291BThis record	Serbia	B	2012-10-31
DK1169038T3	Denmark	T3	2012-11-26
ES2391550T3	Spain	T3	2012-11-27
HK1042433B	Hong Kong, China	B	2012-12-14

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