NZ795495A

NZ795495A - Aminothiazole compounds as c-Kit inhibitors

Info

Publication number: NZ795495A
Application number: NZ795495A
Authority: NZ
Inventors: Nicholas E Bencivenga; David C Dalgarno; Joseph M Gozgit; Wei Sheng Huang; Anna Kohlmann; Feng Li; Jiwei Qi; William C Shakespeare; Ranny M Thomas; Yihan Wang
Original assignee: Ariad Pharmaceuticals Inc
Priority date: 2016-12-15
Filing date: 2017-12-14
Publication date: 2022-12-23

Abstract

The invention relates to c-Kit inhibitors useful in the treatment of cancers, and other -threonine kinase mediated diseases, having the Formula: (I) wherein A, L, R1, R2, R3, and n are described herein.

Description

The ion relates to c-Kit inhibitors useful in the treatment of cancers, and other -threonine kinase mediated diseases, having the Formula: (I) wherein A, L, R1, R2, R3, and n are described herein.

NZ 795495 AMINOTHIAZOLE COMPOUNDS AS C-KIT INHIBITORS Cross Reference to Related Applications This application claims priority to United States Provisional Patent Application serial number 62/434,845 filed on er 15, 2016, the entirety of which is hereby incorporated by reference. The present application is a divisional of New Zealand patent application 755196, which is the national phase entry of PCT international application (published as Field of Invention The present invention is directed to inhibitors of tyrosine-protein kinase Kit (c-Kit) useful in the treatment of diseases or disorders associated with c-Kit. Specifically, the invention is concerned with compounds and compositions ting c-Kit, methods of treating diseases or disorders ated with c-Kit, and methods of synthesis of these compounds.

Background of the Invention The discovery that the tyrosine kinase inhibitor (TKI) imatinib inhibits KIT, and its introduction as a treatment, transformed the clinical ment of gastrointestinal stromal tumors (GIST) (Corless, C.L. et al., Nat. Rev. Cancer 2011, 11: ). Nonetheless, most imatinibtreated patients ultimately relapse due to outgrowth of clones with secondary, drug-resistant KIT mutations ich, M.C., et al., J. Clin. Oncol. 2006, 24: 4). Secondary mutations typically occur in the ATP binding pocket encoded by exons 13 and 14, and the activation loop (A-loop) encoded by exons 17 and 18. The challenge of treating imatinib resistant GISTs is compounded by mutational heterogeneity, as ts can harbor multiple different secondary mutations in distinct tumor lesions, or even within different regions of the same lesion (Wardelmann E., et al., Clin.

Cancer Res. 2006, 12: 1743-9).

GIST patients with imatinib-resistant tumors are treated with sunitinib, which potently inhibits KIT ATP-pocket s (Heinrich, M.C., et al., J Clin Oncol 2008; 26: 5352-9). However, sunitinib is ctive against A-loop mutants, which t for 50% of imatinib-resistance mutations. This may explain why overall response rates (ORR) are low (7%) and median progression-free survival (PFS) is short (6.2 months; Demetri, G.D., et al., Lancet 2006; 368: 1329- 38). Regorafenib was recently approved as third line therapy, but also shows only moderate activity, with ORR of 4.5% and median PFS of 4.8 months (Demetri, G.D., et al., Lancet 2013; 381: 295-302). The KIT inhibitory properties of regorafenib have not yet been ed extensively, but both al and initial preclinical data suggest a limited spectrum of sensitive KIT mutants (George, S., et al., J. Clin. Oncol. 2012, 30: , and Serrano-Garcia, C., et al., ASCO g Abstracts 2013, 31(15_supp1): 10510). Thus, additional agents are needed to overcome resistance mutations in KIT, in particular those in the A-loop.

The KIT inhibitors imatinib, sunitinib and regorafenib are effective GIST therapies, though most patients develop resistance to these drugs due to c acquisition of polyclonal secondary KIT mutants. The lack of efficacy of any single agent against the te set of potential nding pocket and A-loop secondary mutants makes achievement of prolonged complete disease l in late stage ts challenging. To address this unmet medical need, presented herein are compounds that target a broad range of primary and secondary KIT mutants, including those within the .

Summary of the Invention The present disclosure provides novel aminothiazole compounds and pharmaceutically acceptable salts as effective c-Kit inhibitors.

A ﬁrst aspect of the invention relates to compounds of Formula (I): and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein: L is —C(O)NR5- or —NR5C(O)-, A is (C3-C8) cycloalkyl, o) aryl, or 5- to 10-membered heteroaryl wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R4, R1 is H, (C1-C6)alkyl, -(CH2)qC(O)OH, or —C(O)N(R7)2; R2 is (C1-C6) alkyl, -C(O)Rg, or —C(O)NR9R10, each R3 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) kyl, (C1-C6) haloalkoxy, halogen, or OH, each R4 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) koxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S or -(C(R6)2)p-heteroaryl n the heteroaryl comprises a 5- or 6-membered ring and l to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally tuted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino, R5 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, each R6 is independently H or (C1-C6) alkyl, each R7 is independently H or ) alkyl, R8 is (C1-C6) alkyl, (C3-C7) lkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, (C1-C6) kyl, (C1-C6) haloalkoxy, or 4 to ered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) kyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more tuents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is ally substituted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to ered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1-C6) alkylamino, q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, R“ is ) alkoxy, -OH, -NH2, (C1-C6) alkylamino, ) dialkylamino, 5— or 6- membered heteroaryl comprising 1 to 3 heteroatoms ed from N, O, or S, or 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and each n, p, and q is independently O, l or 2, and provided that when A is phenyl and R1 is H, then R2 is not —C(O)CH3.

A second aspect of the invention relates to a method of treating a c-Kit-mediated disease or disorder. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, e, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of preventing a c-Kit-mediated disease or disorder. The method comprises administering to a patient in need thereof an effective amount of a compound of a (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. r aspect of the ion relates to a method of inhibiting c-Kit. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a e or disorder associated with inhibiting c-Kit. The method comprises administering to a patient in need thereof an effective amount of a nd of Formula (I), or a pharmaceutically able salt, hydrate, e, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of preventing a disease or disorder associated with inhibiting c-Kit. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically able salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating cancer. The method comprises stering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or er thereof.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically able carrier. The pharmaceutical acceptable r may further include an excipient, diluent, or tant.

Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with inhibiting c- r aspect of the present invention s to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for preventing a disease associated with inhibiting c-Kit.

Another aspect of the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with inhibiting c-Kit.

Another aspect of the present invention relates to the use of a compound of Formula (I), or a ceutically acceptable salt, hydrate, e, prodrug, stereoisomer, or tautomer thereof, in the prevention of a disease ated with inhibiting c-Kit.

The present invention further provides methods of treating or preventing a disease or disorder associated with modulation of c-Kit including, cancer, metastasis, inflammation and auto-immune pathogenesis, comprising administering to a patient ing from at least one of said diseases or er a nd of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, g, isomer, or tautomer thereof.

The present invention provides inhibitors of c-Kit that are therapeutic agents in the treatment of diseases such as cancer, asis, inflammation and auto-immune pathogenesis.

The present disclosure provides agents with novel mechanisms of action toward c- Kit enzymes in the treatment of various types of diseases including cancer and cell proliferative disorders, multiple sclerosis, asthma, mastocytosis, inflammatory disorders, allergic reactions, fibrotic ers, auto-immune pathogenesis and metabolic disorders. tely the present ion provides the medical ity with a novel pharmacological strategy for the [FOLLOWED BY PAGE 5a] treatment of diseases and disorders associated with c-Kit. [0021A] ular features of the present disclosure are set out in the following numbered aphs: 1. A compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or er thereof, wherein: L is –C(O)NR5- or –NR5C(O)-; A is ) cycloalkyl, (C6-C10) aryl, or 5- to 10-membered heteroaryl wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R4; R1 is H, (C1-C6) alkyl, -(CH2)qC(O)OH, or –C(O)N(R7)2; R2 is ) alkyl, -C(O)R8, or –C(O)NR9R10; each R3 is independently at each occurrence (C1-C6) alkyl, ) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or OH; each R4 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to ered ring and 1 to 3 heteroatoms selected from N, O, and S , or )2)p-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino; R5 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl; each R6 is independently H or (C1-C6) alkyl; [FOLLOWED BY PAGE 5b] each R7 is ndently H or (C1-C6) alkyl; R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, ) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, ) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S; R9 is H, (C1-C6) alkyl, (C1-C6) kyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S; R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently selected from ) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R11; or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring sing 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C 1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH 2, -(CH2)q-(C 1-C6) alkylamino, -(CH 2)q-(C 1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl; R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl is optionally substituted with one or more substituents each ndently selected from (C1-C6) alkyl and OH; and each n, p, and q is independently 0, 1 or 2; and provided that when A is phenyl and R1 is H, then R2 is not H3. 2. The compound of paragraph 1, wherein L is a –C(O)NR5-. 3. The compound of paragraph 1, wherein L is a –NR5C(O)-. 4. The compound of any one of the preceding paragraphs, wherein R3 is (C1-C6) alkyl or n.

. The compound of any one of the preceding paragraphs, wherein n is 1 and R3 is methyl or F.

[FOLLOWED BY PAGE 5c] 6. The compound of any one of the preceding paragraphs, wherein n is 1 and R3 is methyl. 7. The compound of any one of the preceding paragraphs, wherein A is (C6-C10) aryl optionally tuted with one or more R4. 8. The compound of any one of the preceding paragraphs, wherein A is 6- membered heteroaryl optionally substituted with one or more R4; 9. The compound of any one of the preceding paragraphs, wherein A is phenyl or pyridinyl optionally substituted with one or more R4.

. The nd of any one of the preceding aphs, wherein A is phenyl or pyridinyl substituted with one or more R4. 11. The compound of any one of the preceding paragraphs, wherein R5 is H. 12. The compound of any one of the preceding paragraphs, wherein n is 0. 13. The compound of any one of the preceding paragraphs, wherein n is 1. 14. The compound of any one of the preceding aphs, wherein n is 1 and R3 is ortho to the alkyne.

. The compound of any one of the preceding paragraphs, wherein R1 is H, - CH3)2 or –CH2CH2C(O)OH. 16. The compound of any one of the preceding paragraphs, wherein R1 is H. 17. The compound of paragraph 1, having one of the ing formulae (Ia) or (Ib): (Ia), or (Ib), [FOLLOWED BY PAGE 5d] or a pharmaceutically acceptable salt, e, solvate, prodrug, stereoisomer, or tautomer thereof. 18. The compound of paragraph 1, having one of the following formulae (Ic) or (Id) : (Ic), or (Id), or a pharmaceutically acceptable salt, hydrate, e, prodrug, stereoisomer, or tautomer thereof. 19. The compound of paragraph 1, having one of the following formulae (Ie) or (If): (Ie), or [FOLLOWED BY PAGE 5e] (If), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

. The compound of aph 19, wherein R5 is H. 21. The compound of paragraph 19 or 20, wherein one R4 is (C1-C6) haloalkyl and the other R4 is (C1-C6) alkoxy, CN, or -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S. 22. The compound of any one of paragraphs 19 to 21, wherein at least one R4 is CF3 and the other R4 is (C1-C6) alkoxy, CN, or -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl ses a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S. 23. The compound of any one of aphs 19 to 22, wherein at least one R4 is CF3 and the other R4 is –OCH3, CN, or -(CH2)-pyrrolyl. 24. The compound of any one of paragraphs 19-23, wherein R1 is H and R2 is – C(O)NR9R10.

. The compound of paragraph 24, wherein R9 is H and R10 is (C1-C6) alkyl. 26. The compound of paragraph 24, wherein R9 is H and R10 is (C1-C6) alkyl tuted with one R11. 27. The compound of paragraph 26, wherein R11 is (C1-C6) alkoxy. 28. The compound of paragraph 27, wherein the ) alkoxy is –OCH3. 29. The compound of aph 24, wherein R9 is (C1-C6) alkyl and R10 is (C1-C6) alkyl.

. The compound of paragraph 24, wherein R9 is ) alkyl and R10 is (C1-C6) [FOLLOWED BY PAGE 5f] alkyl tuted with one R11. 31. The compound of paragraph 30, wherein R11 is (C1-C6) alkoxy. 32. The compound of paragraph 31, wherein the (C1-C6) alkoxy is –OCH3. 33. The compound of aph 1, having one of the following formulae (Ig) or (Ih): (Ig), or (Ih), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. 34. The compound of paragraph 33, wherein R5 is H.

. The compound of paragraph 33 or 34, wherein R4 is (C1-C6) haloalkyl. 36. The compound of any one of paragraphs 33 to 35, wherein R4 is CF3. 37. The compound of any one of paragraphs 33 to 36, wherein n is 1 and R3 is 38. The compound of any one of paragraphs 33 to 37, wherein R1 is H and R2 is (C1-C6) alkyl. 39. The compound of paragraph 38, n the (C1-C6) alkyl is selected from [FOLLOWED BY PAGE 5g] methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl , entyl, neo-pentyl, sec-pentyl, 3-pentyl, n-hexane, 2-methyl pentane, yl pentane, 2,2-dimethyl butane, and 2,3-dimethyl butane. 40. The compound of paragraph 39, wherein the (C1-C6) alkyl is ethyl. 41. The compound of aph 39, wherein the (C1-C6) alkyl is . 42. The compound of any one of aphs 33 to 37, n R1 is H and R2 is – C(O)R 8. 43. The compound of paragraph 42, wherein R8 is (C1-C3) alkoxy. 44. The compound of paragraph 43, wherein the (C1-C3) alkoxy is OCH3. 45. The nd of any one of paragraphs 33 to 37, wherein R1 is H and R2 is – C(O)NR 9R10 . 46. The compound of paragraph 45, n R9 is H and R10 is (C1-C6) alkyl. 47. The compound of paragraph 45, wherein R9 is H and R10 is (C1-C6) alkyl substituted with one R11 . 48. The compound of paragraph 47, wherein R11 is (C1-C6) alkoxy. 49. The compound of paragraph 48, wherein the (C1-C6) alkoxy is –OCH3. 50. The compound of paragraph 47, wherein R11 is (C1-C6) dialkylamino. 51. The compound of paragraph 50, wherein the (C1-C6) dialkylamino is – N(CH 3)2 or –N(CH2CH 3)2. 52. The compound of paragraph 47, wherein R11 is (C1-C6) alkylamino. 53. The compound of paragraph 52, n the ) alkylamino is –N(H)CH3. 54. The compound of paragraph 47, wherein R11 is –NH2. 55. The compound of paragraph 47, n R11 is 5- or 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, optionally substituted with (C1-C6) alkyl or OH. 56. The compound of paragraph 47, wherein R11 is 6-membered heteroaryl comprising 1 to 3 atoms selected from N, O, or S. 57. The compound of paragraph 47, wherein R11 is -OH. 58. The compound of paragraph 45, wherein R9 is (C1-C6) alkyl and R10 is (C1-C6) alkyl. 59. The compound of paragraph 45, wherein R9 is (C1-C6) alkyl and R10 is (C1-C6) alkyl substituted with one R11 . 60. The compound of paragraph 59, wherein R11 is (C1-C6) alkoxy.

[FOLLOWED BY PAGE 5h] 61. The nd of paragraph 60, wherein the (C1-C6) alkoxy is –OCH3. 62. The compound of paragraph 59, wherein R11 is -OH. 63. The compound of aph 59, wherein R11 is (C1-C6) dialkylamino. 64. The compound of aph 63, wherein the (C1-C6) dialkylamino is – N(CH 3)2 or –N(CH2CH 3)2. 65. The compound of paragraph 59, wherein R11 is –NH2. 66. The compound of paragraph 59, wherein R11 is 5- or ered cycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, optionally substituted with (C1-C6) alkyl or OH. 67. The compound of aph 59, wherein R11 is 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S. 68. The compound of paragraph 45, n R9 is H and R10 is (C3-C7) cycloalkyl optionally substituted with –OH or -NH2. 69. The compound of paragraph 68, wherein the (C3-C7) cycloalkyl is cyclopropyl or cyclohexyl optionally substituted with –OH or -NH2. 70. The compound of paragraph 45, wherein R9 is H and R10 is 4 to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, optionally substituted with methyl. 71. The compound of paragraph 45, wherein R9 is ) alkyl and R10 is 4 to 6- membered heterocycloalkyl sing 1 to 3 heteroatoms selected from N, O, or S, optionally substituted with methyl. 72. The compound of paragraph 45, wherein R9 and R10 together with the nitrogen atom to which they are ed form a 4- to 6-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q- (C 1-C6) dialkylamino, -C(O)(C1-C6) alkyl, OH, or 6-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with (C1-C6) alkyl. 73. The compound of any one of paragraphs 33 to 37, wherein R1 is –C(O)N(R7)2 and R2 is –C(O)NR9R10 . 74. The compound of paragraph 74, wherein R7 is (C1-C6) alkyl, R9 is ) alkyl and R10 is (C1-C6) alkyl. 75. The compound of any one of paragraphs 33 to 37, wherein R1 is - (CH 2 is –C(O)R 2)qC(O)OH and R 8.

[FOLLOWED BY PAGE 5i] 76. The nd of paragraph 75, wherein R8 is (C2-C3) alkenyl. 77. The compound of any one of paragraphs 33 to 36, wherein n is 1 and R3 is F. 78. The compound of paragraph 77, wherein R1 is H and R2 is –C(O)NR9R10 . 79. The compound of paragraph 78, wherein R9 is H and R10 is (C1-C6) alkyl. 80. The compound of any one of paragraphs 33 to 36, wherein n is 0, R1 is H, and R2 is –C(O)NR9R10 . 81. The compound of paragraph 78, wherein R9 is H and R10 is (C1-C6) alkyl. 82. The compound of aph 1, wherein the compound is selected from: 3-((2-(3,3-dimethylureido)thiazolyl)ethynyl)methyl-N-(4-(trifluoromethyl)pyridin yl)benzamide; 4-methyl-N-(4-(trifluoromethyl)pyridinyl)((2-ureidothiazolyl)ethynyl)benzamide; methyl (5-((2-methyl((4-(trifluoromethyl)pyridinyl)carbamoyl)phenyl)ethynyl)thiazol- arbamate; 4-methyl((2-(3-methylureido)thiazolyl)ethynyl)-N-(4-(trifluoromethyl)pyridin yl)benzamide; 3-((2-(3-(2-methoxyethyl)ureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-(2-morpholinoethyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 3-((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 3-((2-(3-ethylmethylureido)thiazolyl)ethynyl)methyl-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide; 3-((2-(3-(2-(dimethylamino)ethyl)methylureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; (3-(2-hydroxyethyl)methylureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; (3-(2-(dimethylamino)ethyl)ureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; [FOLLOWED BY PAGE 5j] 4-methyl((2-(3-(2-(pyrrolidinyl)ethyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-((1-methylpiperidinyl)methyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-(2-(4-methylpiperazinyl)ethyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 3-((2-(3-(2-hydroxymethylpropyl)ureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-methyl(2-(4-methylpiperazinyl)ethyl)ureido)thiazolyl)ethynyl)-N- ifluoromethyl)pyridinyl)benzamide; 3-((2-(3-cyclopropylureido)thiazolyl)ethynyl)methyl-N-(4-(trifluoromethyl)pyridin yl)benzamide; 3-((2-(3-(2-(3-hydroxypyrrolidinyl)ethyl)ureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-methyl(2-(pyrrolidinyl)ethyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-methyl((1-methylpyrrolidinyl)methyl)ureido)thiazolyl)ethynyl)- N-(4-(trifluoromethyl)pyridinyl)benzamide; (3-(2-hydroxymethylpropyl)methylureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 3-((2-(3-(4-hydroxycyclohexyl)methylureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)piperazinecarboxamide; 3-hydroxymethyl-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)azetidinecarboxamide; 4-methyl-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)piperidinecarboxamide; [FOLLOWED BY PAGE 5k] yl((2-(3-(pyridinylmethyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-(2-hydroxyethyl)-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)piperazinecarboxamide; 4-methyl((2-(3-methyl(2-(methylamino)ethyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-methyl((2-(3-methyl(1-methylpiperidinyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; N-(5-((2-methyl((4-(trifluoromethyl)pyridinyl)carbamoyl)phenyl)ethynyl)thiazol yl)piperazinecarboxamide; 3-((2-(3-(4-aminobutyl)ureido)thiazolyl)ethynyl)methyl-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide; 4-methyl((2-(3-methyl(1-methylpiperidinyl)ureido)thiazolyl)ethynyl)-N-(4- (trifluoromethyl)pyridinyl)benzamide; 3-((2-(3-(4-aminocyclohexyl)methylureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 2-((dimethylamino)methyl)-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)morpholinecarboxamide; N-(5-((2-methyl((4-(trifluoromethyl)pyridinyl)carbamoyl)phenyl)ethynyl)thiazol yl)morpholinecarboxamide; 3-((2-(3-(3-aminopropyl)ureido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 4-acetyl-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)piperazinecarboxamide; 3-((2-(3-(2-aminoethyl)ureido)thiazolyl)ethynyl)methyl-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide; 4-methyl((2-(3-methyl(1-methylazetidinyl)ureido)thiazolyl)ethynyl)-N-(4- uoromethyl)pyridinyl)benzamide; [FOLLOWED BY PAGE 5L] 3-(dimethylamino)-N-(5-((2-methyl((4-(trifluoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)pyrrolidinecarboxamide; N-(5-((2-methyl((4-(trifluoromethyl)pyridinyl)carbamoyl)phenyl)ethynyl)thiazolyl)- 4-(4-methylpiperazinyl)piperidinecarboxamide; 2-fluoro((2-(3-methylureido)thiazolyl)ethynyl)-N-(4-(trifluoromethyl)pyridin yl)benzamide; 2-fluoro-N-(4-(trifluoromethyl)pyridinyl)((2-ureidothiazolyl)ethynyl)benzamide; (3-methylureido)thiazolyl)ethynyl)-N-(4-(trifluoromethyl)pyridinyl)benzamide; 4-fluoro((2-(3-methylureido)thiazolyl)ethynyl)-N-(4-(trifluoromethyl)pyridin yl)benzamide; 3-((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)methyl-N-(4-(pyrrolidin- 1-ylmethyl)(trifluoromethyl)phenyl)benzamide; N-(2-methoxy(trifluoromethyl)phenyl)((2-(3-(2-methoxyethyl)methylureido)thiazol- -yl)ethynyl)methylbenzamide; N-(4-cyano(trifluoromethyl)phenyl)((2-(3-(2-methoxyethyl)methylureido)thiazol yl)ethynyl)methylbenzamide; 3-((2-(cyclopropanecarboxamido)thiazolyl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide; 3-((2-(cyclopropanecarboxamido)thiazolyl)ethynyl)methyl-N-(4-((4-methylpiperazin hyl)(trifluoromethyl)phenyl)benzamide; 3-((2-acetamidothiazolyl)ethynyl)methyl-N-(4-(trifluoromethyl)pyridin yl)benzamide; 4-methyl((2-pivalamidothiazolyl)ethynyl)-N-(4-(trifluoromethyl)pyridin yl)benzamide; N-(4-methyl((2-(3-methyl(1-methylpiperidinyl)ureido)thiazolyl)ethynyl)phenyl)- 4-(trifluoromethyl)picolinamide; N-(3-((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)methylphenyl) (trifluoromethyl)picolinamide; [FOLLOWED BY PAGE 5m] N-(4-methyl((2-(3-methyl(2-(4-methylpiperazinyl)ethyl)ureido)thiazol yl)ethynyl)phenyl)(trifluoromethyl)picolinamide; (2-(3,3-dimethylureido)thiazolyl)ethynyl)methylphenyl) (trifluoromethoxy)benzamide; N-(4-methyl((2-(3-methylureido)thiazolyl)ethynyl)phenyl) (trifluoromethyl)picolinamide; N-(3-((2-(3-(2-(dimethylamino)ethyl)methylureido)thiazolyl)ethynyl)methylphenyl)- 4-(trifluoromethyl)picolinamide; N-(3-((2-(3-(2-(diethylamino)ethyl)methylureido)thiazolyl)ethynyl)methylphenyl)- 4-(trifluoromethyl)picolinamide; N-(3-((2-(3-(2-hydroxyethyl)methylureido)thiazolyl)ethynyl)methylphenyl) (trifluoromethyl)picolinamide; N-(3-((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)phenyl) (trifluoromethyl)picolinamide; and N-(4-fluoro((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)phenyl) (trifluoromethyl)picolinamide. 83. A pharmaceutical composition comprising a compound of any one of paragraphs 1 to 82, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically able diluent, excipient or carrier. 84. A method of treating a c-Kit-mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of paragraphs 1 to 82, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. 85. The method of paragraph 84, n the ediated disease or disorder is selected from cell erative disorder, a fibrotic disorder, and a metabolic disorder. 86. The method of paragraph 85, wherein said cell proliferative disorder is cancer. 87. The method of paragraph 86, wherein said cancer is selected from the group consisting of leukemia, mast cell tumor, small cell lung cancer, testicular , cancer of the intestinal tract, cancer of the central nervous system, cancer of the female genital tract, sarcoma of neuroectodermal origin, and Schwann cell neoplasia ated with [FOLLOWED BY PAGE 5n] neurofibromatosis. 88. The method of paragraph 87, wherein said cancer is selected from the group consisting of small cell lung carcinoma, acute myeloid ia (AML), neuroblastoma, malignant melanomas, colorectal cancer,systemic mastocytosis (SM), and gastrointestinal stromal tumors (GISTs). 89. The method of paragraph 84, wherein said ediated disease or er is multiple sclerosis. 90. The method of paragraph 84, wherein said cKit-mediated disease or disorder is asthma. 91. The method of paragraph 84, wherein said cKit-mediated disease or disorder is an allergic reaction. 92. The method of paragraph 84, wherein said ediated disease or disorder is inflammatory arthritis. 93. The method of paragraph 84, wherein said cKit-mediated disease or disorder is mastocytosis. 94. A method of modulating c-Kit sing administering to a subject a compound of any one of paragraphs 1 to 82. 95. A method of inhibiting c-Kit comprising administering to a subject a compound of any one of paragraphs 1 to 82. 96. A method of treating or preventing a disease in which c-Kit plays a role, sing administering to a subject in need thereof an effective amount of a compound of any one of aphs 1 to 82.

[FOLLOWED BY PAGE 6] Detailed Description of the Invention The present invention relates to compounds and compositions that are capable of inhibiting the activity of c-Kit. The invention features methods of treating, preventing or ameliorating a disease or disorder in which c-Kit plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of a (I), or a pharrnaceutically acceptable salt, e, solvate, prodrug, stereoisomer, or tautomer f.

The s of the t invention can be used in the treatment of a variety of c-Kit dependent diseases and disorders by inhibiting the activity of c-Kit enzymes. Inhibition of c- Kit provides a novel approach to the treatment, prevention, or ration of diseases including, but not limited to, cancer and metastasis.

In a ﬁrst aspect of the invention, the nds of Formula (I) are described: and pharrnaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein A, L, R1, R2, R3, and n are as described herein above.

The details of the invention are set forth in the accompanying description below.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other es, objects, and advantages of the invention will be nt from the ption and from the . In the speciﬁcation and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless deﬁned otherwise, all technical and scientiﬁc terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this ion belongs. All patents and publications cited in this speciﬁcation are incorporated herein by reference in their entireties.

Definitions The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

The term “optionally substituted” is understood to mean that a given chemical moiety (e. g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a n atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally tuted” means that a given chemical moiety has the ial to contain other functional groups, but does not necessarily have any r functional groups. Suitable substituents used in the optional substitution of the described groups e, without limitation, halogen, oxo, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6) alkyl, (C1-C6) alkyl, ) alkoxy, (C1-C6) haloalkyl, ) koxy, -O- (C2-C6) alkenyl, -O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6) alkyl, -C(O)(C1-C6) alkyl, -OC(O)O(C1-C6) alkyl, -NH2, -NH((C1-C6) alkyl), -C6) alkyl)2, -NHC(O)(C1-C6) alkyl, -C(O)NH(C1-C6) alkyl, (C1-C6) alkyl, H(C1-C6) alkyl, and S(O)N((C1-C6) alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

As used herein, the term ituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the speciﬁed group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 ic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where ning two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e. g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., l to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6) alkyl, (C1-C6) alkyl, -O-(C2-C6) alkenyl, -O-(C2-C6) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, (C1-C6) alkyl, -C(O)(C1-C6) alkyl, O(C1-C6) alkyl, NHZ, NH((C1-C6) alkyl), N((C1-C6) alkyl)2, -S(O)2-(C1-C6) alkyl, -S(O)NH(C1-C6) alkyl, and S(O)N((C1-C6) alkyl)2. The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein deﬁned may have an unsaturated or partially saturated ring fused with a fully saturated ring.

Exemplary ring systems of these aryl groups include, but are not d to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, l, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless otherwise speciﬁcally deﬁned, "heteroaryl" means a lent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, or S, the ing ring atoms being C. Heteroaryl as herein deﬁned also means a bicyclic heteroaromatic group wherein the atom is selected from N, O, or S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophenyl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, azole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, o[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2- c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, obenzoxanyl, quinolinyl, isoquinolinyl, l,6-naphthyridinyl, benzo[de]isoquinolinyl, [4,3-b][l,6]naphthyridinyl, [2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3- a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2- b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2- a]pyrimidinyl, 3,4-dihydro-2H-lkz-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridinone, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4] thiazinyl, xazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, phthyridinyl, ,2-b]pyridine, ]triazolo[l,5-a]pyridinyl, benzo [1,2,3]triazolyl, imidazo[l,2- a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,2,5]oxadiazole, l,3-dihydro-2H-benzo[d]imidazolone, 3,4-dihydro-2H- pyrazolo [l,5-b][l,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4- d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, olyl, and derivatives thereof. Furthermore when containing two fused rings the aryl groups herein deﬁned may have an unsaturated or partially saturated ring fused with a fully saturated ring.

Exemplary ring systems of these heteroaryl groups e indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, nyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3- dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl. n or “halo” refers to ﬂuorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1-C6) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “0” in the chain, i.e., yl). Examples of alkoxy groups e, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a ht or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, nyl, isobutenyl , pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted.

Alkenyl, as herein d, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group ns at least one triple bond in the chain. Examples of l groups include ethynyl, propargyl, nyl, iso-butynyl, pentynyl, or hexynyl. An l group can be unsubstituted or substituted.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without tions, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

WO 12136 “Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not lized TE electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be ally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, zinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as deﬁned above, where the alkyl group is substituted with one or more -OH groups. Examples of hydroxyalkyl groups include HO-CH2-, HO-CHz-CHz- and CH3-CH(OH)-.

The term “haloalkyl” as used herein refers to an alkyl group, as deﬁned herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, triﬁuoromethyl, diﬁuoromethyl, pentaﬁuoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, as deﬁned , which is tuted one or more halogen. Examples of haloalkyl groups include, but are not limited to, triﬁuoromethoxy, diﬁuoromethoxy, pentaﬁuoroethoxy, trichloromethoxy, etc.

The term “amine” as used herein refers to primary (R-NHz, R 7: H), secondary (Rz-NH, R2 7: H) and tertiary (R3-N, R 7: H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at least one nitrogen atom. Speciﬁcally, NHZ, -NH(alkyl) or mino, -N(alkyl)2 or dialkylamino, , carbamide-, urea, and sulfamide tuents are ed in the term “amino”.

The term “alkylamino” as used herein refers to an amino or NH2 group where one of the hydrogens has been replaced with an alkyl group, as deﬁned herein above, i.e., - NH(alkyl). Example of alkylamino groups include, but are not limited to, methylamino (1'. e., -NH(CH3)), ethylamino, propylamino, iso-propylamino, n-butylamino, sec-butylamino, tert- butylamino, etc.

The term “dialkylamino” as used herein refers to an amino or NHZ group where both of the hydrogens have been replaced with alkyl groups, as deﬁned herein above, 1'. e., - N(alkyl)2. The alkyl groups on the amino group can be the same or different alkyl . e of alkylamino groups include, but are not limited to, dimethylamino (i.e., - N(CH3)2), diethylamino, dipropylamino, diiso-propylamino, utylamino, di-sec- butylamino, t-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

The term “oxo” as used herein refers to an “=0” group.

The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not ere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing le amounts of water.

The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more tric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

The sure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" e, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, , bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, ariate, dihydrochloride, edetate, edisylate, estolate, e, fumerate, f1unarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexaﬂuorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, e, magnesium, malate, maleate, mandelate, mesylate, bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N—methylglucamine ammonium salt, 3-hydroxy naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bishydroxynaphthoate, einbonate), pantothenate, phosphate/diphosphate, e, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, te, teoclate, tosylate, triethiodide, and valerate salts.

A "patient" or “subject” is a , e. g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human e, such as a monkey, nzee, baboon or rhesus.

An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a e in a subject as described herein.

The term "carrier", as used in this disclosure, encompasses rs, excipients, and diluents and means a material, composition or e, such as a liquid or solid flller, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a ceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

As used herein, ing” or “treat” describes the management and care of a patient for the purpose of reversing, ting, or combating a disease, condition, or disorder and es the administration of a compound of the present disclosure (1'.e., a nd of Formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, to reverse the disease, condition, or disorder, eliminate the disease, condition, or disorder, or inhibit the process of the e, condition, or disorder.

A compound of the t disclosure (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, can also be used to prevent a disease, condition, or er or one or more symptoms of such disease, condition, or disorder. As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition, or disorder.

The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

The present ion relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting c-Kit, which are useful for the treatment of es and disorders associated with modulation of a c-Kit enzyme. The invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for inhibiting c-Kit.

In one embodiment, the compounds of Formula (I) have the structure of Formula (Ia): and pharmaceutically acceptable salts, es, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the compounds of a (I) have the structure of Formula (Ib): R5 A (Ib), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the nds of a (I) have the structure of Formula (Ic): RKNA Nl \ : R2 \ A (Io), and ceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another ment, the compounds of a (I) have the structure of Formula (Id): R1\N/T|\\ : 0 IL2 / 4< R5 A (Id), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ie): WO 12136 and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structure of Formula (If): (If), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ig): — (1g), and pharmaceutically acceptable salts, hydrates, solvates, gs, stereoisomers, and ers thereof.

In another ment, the compounds of Formula (I) have the structure of Formula (Ih): / \ R4 — (Ih), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In some embodiments of the Formulae above, A is (C6-C10) aryl. In another ment, A is 5- or 6-membered heteroaryl. In yet r embodiment, A is 6- membered aryl. In another embodiment, A is 6-membered heteroaryl. In yet r embodiment, A is phenyl. In a further embodiment, A is pyridinyl.

In some embodiments of the Formulae above, L is —C(O)NR5—. In another embodiment, L )NH—.

In some embodiments of the Formulae above, L is —NR5C(O)—. In another embodiment, L is —NHC(O)—.

In some embodiments of the Formulae above, R1 is H, (C1-C6) alkyl, - (CH2)qC(O)OH, or —C(O)N(R7)2. In another embodiment, R1 is (C1-C6) alkyl, - (CH2)qC(O)OH, or —C(O)N(R7)2. In another embodiment, R1 is H, -(CH2)qC(O)OH, or — C(O)N(R7)2. In yet another embodiment, R1 is H, (C1-C6) alkyl, or (R7)2. In another embodiment, R1 is H, (C1-C6) alkyl, or -(CH2)qC(O)OH. In r embodiment, R1 is - (CH2)qC(O)OH, or —C(O)N(R7)2. In yet another embodiment, R1 is H or ) alkyl. In another embodiment, R1 is H or -(CH2)qC(O)OH. In yet another embodiment, R1 is H or — C(O)N(R7)2. In another ment, R1 is H or (C1-C6) alkyl. In yet r embodiment, R1 is H.

In some embodiments of the Formulae above, R2 is (C1-C6) alkyl, -C(O)Rg, or — C(O)NR9R10. In another embodiment, R2 is (C1-C6) alkyl or -C(O)Rg. In yet another embodiment, R2 is -C(O)Rg or —C(O)NR9R10. In another embodiment, R2 is (C1-C6) alkyl or —C(O)NR9R10. In another embodiment, R2 is (C1-C6) alkyl. In yet another embodiment, R2 is -C(O)Rg. In r embodiment, R2 is R9R10. In yet another embodiment, R2 is - C(O)OCH3. In another embodiment, R2 is -C(O)CH3. In yet r embodiment, R2 is - C(O)—l—butyl.

In some embodiments of the Formulae above, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) lkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S. In another embodiment, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, or (C3-C7) cycloalkyl. In yet another embodiment, R9 is H, (C1-C6) alkyl, or (C1- C6) kyl. In another embodiment, R9 is H or (C1-C6) alkyl. In yet another embodiment, R9 is (C1-C6) alkyl. In r embodiment, R9 is H, methyl, ethyl, n-propyl, iso-propyl, n- butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, n-hexane, 2-methyl pentane, 3-methyl pentane, 2,2-dimethyl , or 2,3- dimethyl butane. In another embodiment, R9 is H. In yet another embodiment, R9 is methyl.

In some embodiments of the Formulae above, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each ndently selected from (C1- C6) alkyl, -NH2, ) alkylamino, ) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more RH. In another embodiment, R10 is H, (C1- C6) alkyl, (C3-C7) lkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is ally substituted with one or more substituents each independently selected from (C1- C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more RH. In yet another embodiment, R10 is H, (C1-C6) alkyl, or (C3-C7) cycloalkyl, n the cycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, ) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R”. In another embodiment, R10 is H or (C1-C6) alkyl, wherein the (C1-C6) alkyl is optionally substituted with one or more R”. In yet another ment, R10 is (C1-C6) alkyl is optionally substituted with one or more R”. In another embodiment, R10 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, ne, yl pentane, 3- methyl pentane, 2,2-dimethyl butane, or 2,3-dimethyl butane, wherein the methyl, ethyl, npropyl , iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, ntyl, 3-pentyl, n-hexane, 2-methyl pentane, 3-methyl e, 2,2-dimethyl butane, or 2,3-dimethyl butane is optionally substituted with one or more R”. In yet another ment, R10 is H. In another embodiment, R10 is methyl, ethyl, n-propyl, or n-butyl, wherein the methyl, ethyl, n-propyl, or n-butyl is optionally substituted with one or more In an embodiment, R10 is (C3-C7) cycloalkyl, wherein the lkyl is ally tuted with one or more substituents each independently selected from (C1-C6) alkyl, - NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and —OH. In another embodiment, R10 is cyclopropyl or exyl, wherein the cyclopropyl or cyclohexyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and —OH.

In an ment, R10 is 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and —OH. In another embodiment, R10 is azetidinyl or piperidinyl, wherein the azetidinyl or dinyl is ally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1- C6) dialkylamino, and —OH.

In some embodiments of the Formulae above, R9 and R10 together with the nitrogen atom to which they are attached form a 4- to ered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from ) alkyl, (C1-C6) hydroxyalkyl, - (CH2)q-NH2, -(CH2)q-(C1-C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, C1-C6) alkyl, -OH, and 4- to ered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl. In another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form azetidinyl, morpholinyl, dinyl, or piperazinyl, ally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, - (CH2)q-(C1-C6) mino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl. In yet another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form azetidinyl, morpholinyl, piperidinyl, or piperazinyl, optionally substituted with one or more substituent each independently ed from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom ed from N, O, and S, and ally substituted with one or more (C1- C6) alkyl.

In some embodiments of the Formulae above, R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, ) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, n the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH. In another embodiment, R“ is (C1-C6) alkoxy, (cl—c6) alkylamino, (cl—c6) dialkylamino, 5- or 6- membered aryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each ndently selected from (C1-C6) alkyl and OH. In yet another embodiment, R11 is (C1-C6) alkoxy, (C1-C6) alkylamino, or (C1-C6) dialkylamino. In another embodiment, R11 is 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from ) alkyl and OH. In yet another embodiment, R11 is OH.

In r embodiment, R11 is -OCH3. In yet r embodiment, R11 is -NH2, -NHCH3, - N(CH3)2, or -N(CH2CH3)2. In yet another embodiment, R11 is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or pyridinyl, wherein the pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl and OH.

In some embodiments of the Formulae above, R3 is independently at each ence (C1-C6) alkyl, (C1-C6) , (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or OH. In another embodiment, R3 is independently at each occurrence (C1-C6) alkyl, halogen, or OH. In yet another embodiment, R3 is independently at each occurrence (C1-C6) alkyl or halogen. In another embodiment, R3 is independently at each ence methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tyl, tert-butyl, yl, iso-pentyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, n-hexane, 2-methyl pentane, 3-methyl pentane, 2,2-dimethyl butane, or 2,3-dimethyl butane. In yet r embodiment, R3 is independently at each occurrence ﬂuoro, chloro, bromo, or iodo. In another ment, R3 is independently at each occurrence methyl or ﬂuoro. In another embodiment, R3 is . In another embod1ment, R. 3 . 1s ﬂuoro.

In some embodiments of the Formulae above, R4 is independently at each ence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, ) haloalkoxy, halogen, - OH, CN, )2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7- membered ring and l to 3 heteroatoms ed from N, O, and S or -(C(R6)2)p-heteroaryl wherein the aryl comprises a 5- or 6-membered ring and l to 3 heteroatoms selected from N, O, and S, and n the heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino. In another embodiment, R4 is independently at each occurrence (C1-C6) , (C1-C6) kyl, (C1-C6) haloalkoxy, CN, or -(C(R6)2)p- heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, - NH2, (C1-C6) alkylamino, and (C1-C6) lamino. In another embodiment, R4 is independently at each occurrence (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, - OH, CN, or -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 5- or 6- membered ring and l to 3 atoms selected from N, wherein the heterocycloalkyl is optionally substituted with one or more substituents each ndently ed from (C1- C6) alkyl. In another embodiment, R4 is —CF3. In yet another embodiment, R4 is —OCF3. In another embodiment, R4 is —OCH3. In yet another embodiment, R4 is -(C(R6)2)p- heterocycloalkyl n the heterocycloalkyl comprises pyrrolidinyl or piperazinyl, wherein the pyrrolidinyl or piperazinyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl.

In some ments of the Formulae above, R5 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl. In another embodiment, R5 is H or (C1-C6) alkyl. In yet another embodiment, R5 is H or (C1-C6) haloalkyl. In another embodiment, R5 is (C1-C6) alkyl or (C1-C6) haloalkyl. In another embodiment, R5 is (C1-C6) alkyl. In yet another embodiment, R5 is methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, ntyl, 3-pentyl, n-hexane, 2-methyl pentane, 3-methyl pentane, 2,2-dimethyl butane, or methyl butane. In another embodiment, R5 is (C1-C6) haloalkyl. In yet another embodiment, R5 is H.

In some embodiments of the Formulae above, R6 is H or (C1-C6) alkyl. In another embodiment, R6 is (C1-C6) alkyl. In yet another ment, R6 is H, methyl, ethyl, npropyl , iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, ntyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, n-hexane, yl pentane, 3-methyl pentane, 2,2-dimethyl butane, or 2,3-dimethyl butane. In another embodiment, R6 is H. In yet another embodiment, R6 is methyl.

In some embodiments of the Formulae above, R7 is H or (C1-C6) alkyl. In another embodiment, R7 is (C1-C6) alkyl. In yet another embodiment, R7 is H, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, n-hexane, 2-methyl pentane, 3-methyl pentane, 2,2-dimethyl , or 2,3-dimethyl butane. In another embodiment, R7 is H. In yet another embodiment, R7 is methyl.

In some ments of the Formulae above, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C2-C6) l, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7- membered cycloalkyl comprising 1 to 3 heteroatoms ed from N, O, and S. In another embodiment, R8 is ) alkyl or (C1-C3) alkoxy. In yet another embodiment, R8 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso- pentyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, ne, 2-methyl pentane, 3-methyl pentane, 2,2-dimethyl , or 2,3-dimethyl butane. In another embodiment, R8 is methyl or tert-butyl. In yet another embodiment, R8 is ) alkoxy. In another embodiment, R8 is methoxy.

In some embodiments of the Formulae above, each n, p, and q is independently O, l or 2. In another embodiment, n is O or 1. In yet another embodiment, n is O. In yet another embodiment, n is 1. In another embodiment, p is O or 1. In yet another embodiment, p is O.

In another embodiment, p is 1. In another embodiment, q is O or 1. In yet another embodiment, q is O. In another embodiment, q is l.

In some embodiments of the Formulae above, L is —C(O)NR5-.

In some embodiments of the Formulae above, L is —NR5C(O)-.

In some embodiments of the Formulae above, R3 is (C1-C6) alkyl or halogen.

In some ments of the Formulae above, 11 is l and R3 is methyl or F.

In some embodiments of the ae above, 11 is l and R3 is methyl.

In some embodiments of the Formulae above, A is (Cs-(:10) aryl optionally substituted with one or more R4.

In some embodiments of the Formulae above, A is 6-membered heteroaryl optionally substituted with one or more R4.

In some embodiments of the Formulae above, A is phenyl or pyridinyl optionally substituted with one or more R4.

In some embodiments of the Formulae above, A is phenyl or pyridinyl substituted with one or more R4.

In some embodiments of the Formulae above, R5 is H.

In some ments of the Formulae above, 11 is O.

In some embodiments of the Formulae above, 11 is l.

In some embodiments of the ae above, 11 is l and R3 is ortho to the .

In some embodiments of the Formulae above, R1 is H, -C(O)N(CH3)2 or — CHZCH2C(O)OH.

In some embodiments of the Formulae above, R1 is H.

In some embodiments of the Formulae above, one R4 is (C1-C6) haloalkyl and the other R4 is (C1-C6) alkoxy, CN, or -(C(R6)2)p-heterocycloalkyl n the heterocycloalkyl ses a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S.

In some embodiments of the Formulae above, at least one R4 is CF3 and the other R4 is (C1-C6) , CN, or -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S.

In some embodiments of the Formulae above, at least one R4 is CF3 and the other R4 is —OCH3, CN, or -(CH2)-pyrrolyl.

In another embodiment, R1 is H and R2 is —C(O)NR9R10.

In some embodiments of the Formulae above, R9 is H and R10 is (C1-C6) alkyl.

In some embodiments of the Formulae above, R9 is H and R10 is (C1-C6) alkyl substituted with one R11.

In some embodiments of the Formulae above, R11 is (C1-C6) alkoxy.

In some embodiments of the ae above, the (C1-C6) alkoxy is —OCH3.

In some embodiments of the ae above, R9 is (C1-C6) alkyl and R10 is (C1- C6) alkyl.

In some embodiments of the ae above, R9 is (C1-C6) alkyl and R10 is (C1- C6) alkyl substituted with one R11.

In some embodiments of the Formulae above, R4 is (C1-C6) haloalkyl.

In some embodiments of the Formulae above, R4 is CF3.

In some embodiments of the Formulae above, 11 is l and R3 is methyl.

In some ments of the ae above, R1 is H and R2 is (C1-C6) alkyl.

In some embodiments of the Formulae above, (C1-C6) alkyl is selected from methyl, ethyl, yl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso- pentyl, tert-pentyl, neo-pentyl, sec-pentyl, 3-pentyl, n-hexane, 2-methyl pentane, 3-methyl pentane, 2,2-dimethyl butane, and 2,3-dimethyl butane.

In some embodiments of the Formulae above, (C1-C6) alkyl is ethyl.

In some ments of the Formulae above, (C1-C6) alkyl is methyl.

In some embodiments of the Formulae above, R1 is H and R2 is —C(O)R8.

In r embodiment, R8 is (C1-C3) alkoxy.

In some embodiments of the Formulae above, ) alkoxy is OCH3.

In some embodiments of the Formulae above, R1 is H and R2 is —C(O)NR9R10.

In some embodiments of the Formulae above, R9 is H and R10 is (C1-C6) alkyl substituted with one R”.

In some embodiments of the ae above, R11 is ) lamino.

In some embodiments of the Formulae above, (C1-C6) dialkylamino is —N(CH3)2 or —N(CH2CH3)2.

In some embodiments of the Formulae above, R11 is (C1-C6) alkylamino.

In some ments of the Formulae above, (C1-C6) alkylamino is —N(H)CH3.

In some embodiments of the Formulae above, R11 is —NH2.

In some embodiments of the Formulae above, R11 is 5- or 6-membered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, optionally substituted with (C1-C6) alkyl or OH.

In some embodiments of the Formulae above, R11 is 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S.

In some embodiments of the Formulae above, R11 is -OH.

In some embodiments of the Formulae above, R9 is H and R10 is (C3-C7) cycloalkyl optionally substituted with —OH or -NH2..

In some embodiments of the Formulae above, (C3-C7) cycloalkyl is cyclopropyl or cyclohexyl optionally substituted with —OH or -NH2.

In some embodiments of the Formulae above, R9 is H and R10 is 4 to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, optionally substituted with methyl In some embodiments of the Formulae above, R9 is (C1-C6) alkyl and R10 is 4 to 6- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, optionally substituted with methyl.

In some embodiments of the ae above, R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl, (C1-C6) yalkyl, - (CH2)q-(C1-C6) dialkylamino, C1-C6) alkyl, OH, or 6-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with (C1- C6) alkyl.

In some embodiments of the Formulae above, (R1 is —C(O)N(R7)2 and R2 is R9R10.

In some embodiments of the Formulae above, R1 is -(CH2)qC(O)OH and R2 is —C(O)Rg.

In some embodiments of the Formulae above, R8 is ) alkenyl.

In some embodiments of the Formulae above, 11 is l and R3 is F.

In some embodiments of the Formulae above, R1 is H and R2 is R9R10.

In some embodiments of the Formulae above, 11 is O, R1 is H, and R2 is — C(O)NR9R10.

In some ments of the Formulae above, when A is phenyl and R1 is H, then R2 is not —C(O)CH3.

In some embodiments of the ae above, A is phenyl and R1 is H, an R2 is (C1-C6) alkyl, -C(O)Rg, or R9R10, and R8 is (Cz—Cé) alkyl, (C3-C7) cycloalkyl, (Cz—Cé) alkenyl, (C1-C3) alkoxy, (C1-C6) kyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S.

In some embodiments of the Formulae above, L is —C(O)NR5- or —NR5C(O)-, A is (C3-C8) cycloalkyl, (Cs-Clo) aryl, or 5- to lO-membered heteroaryl wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more R4, R1 is H, (C1-C6) alkyl, - C(O)OH, or —C(O)N(R7)2, R2 is ) alkyl, -C(O)Rg, or —C(O)NR9R10, each R3 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or OH, each R4 is independently at each occurrence (C1-C6) alkyl, (C1- C6) , (C1-C6) haloalkyl, ) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p- heterocycloalkyl wherein the heterocycloalkyl ses a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S or , -(C(R6)2)p-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and l to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or aryl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and ) dialkylamino, R5 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, each R6 is independently H or (C1-C6) alkyl, each R7 is ndently H or (C1-C6) alkyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, ) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, ) haloalkyl, (C3-C7) cycloalkyl, or 4 to ered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently ed from (C1- C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally tuted with one or more R”, or R9 and R10 together with the en atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q- NH2, -(CH2)q-(C1-C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more ) alkyl, R11 is (C1-C6) alkoxy, -OH, - NHz, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and each n, p, and q is independently O, l or 2, and provided that when A is phenyl and R1 is H, then R2 is not —C(O)CH3.

] In some embodiments of the Formulae above, L is —C(O)NR5-, A is (Cs-Clo) aryl wherein the aryl is optionally substituted with one or more R4, R1 is H, R2 is (C1-C6) alkyl, - C(O)Rg, or —C(O)NR9R10, R3 is ) alkyl, R4 is (cl—c6) haloalkyl, R5 is H, (C1—C6) alkyl, or (C1-C6) haloalkyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl sing 1 to 3 heteroatoms selected from N, 0, or s, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl sing 1 to 3 heteroatoms selected from N, O, or S, wherein the lkyl or cycloalkyl is ally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) mino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring sing 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more tuent each independently selected from (C1-C6) alkyl, (C1- C6) hydroxyalkyl, q-NH2, -(CH2)q-(C1-C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, - C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom ed from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, R“ is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5— or 6- ed heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In some embodiments of the Formulae above, L is —C(O)NR5-, A is 5- to 10- membered heteroaryl wherein the heteroaryl is optionally substituted with one or more R4, R1 is H, R2 is (C1-C6) alkyl, -C(O)Rg, or —C(O)NR9R10, R3 is (C1-C6) alkyl, R4 is (C1-C6) haloalkyl, R5 is H, (C1-C6) alkyl, or (C1-C6) haloalkyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, (C1-C6) kyl, ) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, ) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3- C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each ndently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered cycloalkyl ring sing 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1- C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, R11 is ) alkoxy, -OH, -NH2, (C1- C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 atoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, wherein the heterocycloalkyl is optionally tuted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In r embodiment, L is —C(O)NR5- wherein R5 is is 7 H, A pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is (C1-C6) alkyl, - C(O)Rg, or —C(O)NR9R10, R3 is methyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, ) l, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) koxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3- C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally tuted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is ally tuted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, q-NH2, -(CH2)q-(C1- C6) alkylamino, -(CH2)q-(C1-C6) lamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, R11 is (C1-C6) alkoxy, -OH, -NH2, (C1- WO 12136 C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is 7 H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is g, R3 is methyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, ) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is is 7 H, A pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is -C(O)Rg, R3 is methyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C1-C3) alkoxy, and n is 1. In another embodiment, R8 is methoxy. In another embodiment, R8 is . In another ment, R8 is l—butyl. In another embodiment, R8 is ropyl.

] In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl ally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is H and R10 is H, (C1-C6) alkyl, or (C3-C7) lkyl, wherein the (C1-C6) alkyl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, - OH, -NH2, (C1-C6) alkylamino, (C1-C6) lamino, 5- or 6- membered aryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is is 7 H, A pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10 n R9 is H and R10 is H, , methyl, ethyl, propyl, n-butyl, isobutyl, or ropyl, wherein the , ethyl, propyl, n-butyl, or isobutyl is optionally substituted with one or more R“, n R“ is (C1-C6) , -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1. In another embodiment, R10 is H. In another embodiment, R10 is cyclopropyl,.

In another embodiment, L is —C(O)NR5-, n R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is , R2 is — C(O)NR9R10, wherein R9 is H and R10 is , ethyl, , n-butyl, or isobutyl, wherein the methyl, ethyl, propyl, n-butyl, or isobutyl is substituted with one or more R”, wherein R11 is (C1-C6) , -OH, -NH2, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to ered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, n R9 is H and R10 is , wherein the methyl is optionally substituted with one or more R”, wherein R11 is 5- or 6- membered heteroaryl comprising 1 to 3 atoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from ) alkyl and OH, and n is 1. In another embodiment, R10 is . In another embodiment, R10 is methyl, wherein the methyl is substituted with R11 wherein R11 is N-methylpiperidinyl. In another embodiment, R10 is methyl, wherein the methyl is substituted with R11, wherein R11 is pyridinyl.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is H and R10 is ethyl, wherein the ethyl is substituted with one or more R”, wherein R11 is ) alkoxy, -NH2, (C1-C6) dialkylamino, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1. In another embodiment, R10 is ethyl, wherein the ethyl is tuted with R11 wherein R11 is methoxy. In another embodiment, R10 is ethyl, wherein the ethyl is substituted with R11, wherein R11 is ylamino. In another embodiment, R10 is ethyl, wherein the ethyl is substituted with one or more R”, wherein R11 is —NH2, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is H and R10 is ethyl, wherein the ethyl is substituted with one or more R”, wherein R11 is 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally tuted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1. In another embodiment, R10 is ethyl, wherein the ethyl is substituted with R11, and n R11 is morpholinyl. In another embodiment, R10 is ethyl, wherein the ethyl is substituted with R11, and wherein R11 is pyrrolidinyl. In another embodiment, R10 is ethyl, wherein the ethyl is substituted with R11, and wherein R11 is N-methylpiperazinyl. In another embodiment, R10 is ethyl, wherein the ethyl is substituted with R11, and wherein R11 is 3-hydroxypyrrolidinyl.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10 wherein R9 is H and R10 is H, 7 methyl, ethyl, propyl, l, isobutyl, or cyclopropyl, wherein the methyl, ethyl, propyl, n-butyl, or isobutyl is optionally substituted with one or more R”, wherein R11 is —OH or -NH2, and n is 1. In another embodiment, R10 is isobutyl, wherein the isobutyl is substituted with R11, wherein R11 is —OH. In another ment, R10 is n-butyl, wherein the n-butyl is substituted with R11, wherein R11 is -NH2.

In another embodiment, R10 is n-propyl, wherein the n-propyl is substituted with R11, wherein R11 is -NH2.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is H, ) alkyl, (C1-C6) haloalkyl, ) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or cycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R11 wherein R11 is (C1-C6) alkoxy, -OH, -NH2, 7 (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- ed heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to ered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, n the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is H, A is 7 pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10 wherein R9 is methyl and R10 is , ethyl, , n-butyl, or isobutyl, n the , ethyl, propyl, n-butyl, or yl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is methyl, ethyl, or yl, wherein the , ethyl, or isobutyl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, -OH, -NH2, ) mino, (C1-C6) dialkylamino, 5- or 6- ed heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl sing 1 to 3 heteroatoms ed from N, O, or S, wherein the heterocycloalkyl is optionally tuted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1. In another embodiment, R10 is methyl, wherein the methyl is substituted with R11, wherein R11 is 2-methylpyrrolidinyl. In another embodiment, R10 is isobutyl, wherein the isobutyl is substituted with R11, wherein R11 is -OH.

In another embodiment, R10 is methyl. In another embodiment, R10 is ethyl.

In r embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is ethyl, n the ethyl is substituted with one or more R11 wherein R“ is 7 (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another ment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl substituted with one or more R4, n R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is ethyl, wherein the ethyl is substituted with one or more RH, wherein R11 is (C1-C6) alkoxy, -OH, ) alkylamino, (C1-C6) dialkylamino, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, wherein the heterocycloalkyl is ally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1. In another embodiment, R11 is y. In another embodiment, R11 is dimethylamino. In another embodiment, R11 is -OH. In another embodiment, R11 is —NHCH3. In another embodiment, R11 is N- methylpiperazinyl. In another embodiment, R11 is pyrrolidinyl.

In another embodiment, L is —C(O)NR5- n R5 is H, A is pyridinyl ally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10 wherein R9 is methyl and R10 is 7 (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) mino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R”, n R“ is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) mino, (C1-C6) dialkylamino, 5— or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from ) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is (C3-C7) cycloalkyl, wherein the cycloalkyl is optionally substituted with one or more substituents each independently selected from (C1- C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10 wherein R9 is methyl and R10 is cyclohexyl, wherein the cyclohexyl is ally tuted with one or more substituents each independently ed from (C1- C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and n is 1. In another embodiment, R10 is cyclohexyl, wherein the cyclohexyl is substituted with -OH. In another embodiment, R10 is cyclohexyl, wherein the cyclohexyl is substituted with -NH2.

In another embodiment, L is —C(O)NR5- wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — 9R10, wherein R9 is methyl and R10 is 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms ed from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl, - NH2, (C1-C6) alkylamino, ) dialkylamino, and -OH, and n is 1.

In another embodiment, L is —C(O)NR5- wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10 wherein R9 is methyl and R10 is piperidinyl, n the piperidinyl is optionally substituted with one or more substituents each independently selected from (C1- C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and —OH, and n is 1. In another embodiment, R10 is piperidinyl, wherein the piperidinyl is substituted with methyl. In another embodiment, R10 is azetidinyl, wherein the azetidinyl is substituted with methyl.

In another ment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, n R4 is —CF3, R1 is H, R2 is —C(O)NR9R10, R3 is , R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, ally substituted with one or more substituent each independently selected from (C1- C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1-C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1- C6) alkyl, and n is 1. In another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form an azetidine ring, wherein the azetidine ring is substituted with methyl. In r embodiment, R9 and R10 together with the en atom to which they are attached form a pyrrolidine ring, wherein the pyrrolidine ring is substituted with dimethylamino.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is R9R10, R3 is methyl, R9 and R10 together with the nitrogen atom to which they are attached form a piperazine ring, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1-C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more ) alkyl, and n is 1. In another embodiment, R9 and R10 together with the en atom to which they are attached form a piperazine ring. In another embodiment, R9 and R10 together with the en atom to which they are ed form a zine ring, wherein the piperazine ring is substituted with methyl. In another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form a piperazine ring, wherein the piperazine ring is substituted with hydroxyethyl. In another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form a piperazine ring, n the piperazine ring is substituted with C(O)CH3.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is R9R10, R3 is methyl, R9 and R10 er with the nitrogen atom to which they are attached form a piperidine ring, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1-C6) mino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl sing 1 to 3 heteroatom selected from N, O, and S, and ally substituted with one or more (C1-C6) alkyl, and n is 1. In another embodiment, R9 and R10 together with the en atom to which they are attached form a piperidine ring, n the piperidine ring is substituted with methyl. In another embodiment, R9 and R10 together with the nitrogen atom to which they are ed form a piperidine ring, n the piperidine ring is substituted with N-methylpiperazine.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is —C(O)NR9R10, R3 is methyl, R9 and R10 together with the nitrogen atom to which they are attached form a morpholine ring, optionally substituted with one or more substituent each independently ed from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1-C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered cycloalkyl comprising 1 to 3 atom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, and n is 1. In another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form a morpholine ring. In another embodiment, R9 and R10 together with the nitrogen atom to which they are attached form a morpholine ring, wherein the morpholine ring is substituted with -(CH2)q-(C1-C6) dialkylamino, wherein q is l and the -(CH2)q-(C1-C6) dialkylamino is —CH2N(CH3)2.

In another embodiment, L is —C(O)NR5- wherein R5 is H, A is 7 pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is (C1-C6) alkyl, - C(O)Rg, or —C(O)NR9R10, R3 is ﬂuoro, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (Cz—Cé) alkenyl, (C1-C3) , (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) kyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3- C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl sing 1 to 3 heteroatoms selected from N, O, or S, wherein the lkyl or cycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the ) alkyl is optionally substituted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom ed from N, O, and S, optionally tuted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1- C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7- membered heterocycloalkyl comprising 1 to 3 atom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, R11 is (C1-C6) alkoxy, -OH, -NH2, (C1- C6) alkylamino, (C1-C6) lamino, 5- or 6- membered aryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered cycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is nyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is ﬂuoro, R2 is — C(O)NR9R10, wherein R9 is H and R10 is H or (C1-C6) alkyl, wherein the (C1-C6) alkyl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, -OH, -NH2, (C1- C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, n R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is ﬂuoro, R2 is — C(O)NR9R10, wherein R9 is H and R10 is H or (C1-C6) alkyl, and n is 1. In another embodiment, R10 is H. In r embodiment, R10 is methyl.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is ) alkyl, - C(O)Rg, or —C(O)NR9R10, R8 is ) alkyl, ) lkyl, (oz—c6) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to ered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, ) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or cycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the ) alkyl is optionally substituted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each ndently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1-C6) mino, - (CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and ally substituted with one or more (C1-C6) alkyl, R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms ed from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 0.

In another embodiment, L is —C(O)NR5-, n R5 is H, A is pyridinyl ally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is —C(O)NR9R10, wherein R9 is H and R10 is H or (C1-C6) alkyl, wherein the (C1-C6) alkyl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) mino, (C1-C6) dialkylamino, 5- or 6- membered aryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered cycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, n the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 0.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is —C(O)NR9R10, wherein R9 is H and R10 is (C1-C6) alkyl, and n is O. In another embodiment, L is —C(O)NR5- wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is — CF3, R1 is H, R2 is —C(O)NR9R10, wherein R9 is H and R10 is methyl, and n is 0.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl optionally substituted with one or more R4, wherein R4 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) kyl, (C1-C6) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl ses a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S or -(C(R6)2)p-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and l to 3 atoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more tuents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) mino, and (C1-C6) dialkylamino, R1 is H, R2 is (c1— C6) alkyl, -C(O)Rg, or R9R10, R3 is methyl, R8 is (C1-C6) alkyl, ) cycloalkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, ) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3- C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, ) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally tuted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1- C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and ally substituted with one or more (C1-C6) alkyl, R11 is (C1-C6) alkoxy, -OH, -NH2, (C1- C6) alkylamino, ) dialkylamino, 5- or 6- membered aryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to ered heterocycloalkyl comprising 1 to 3 heteroatoms ed from N, O, or S, wherein the cycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl ally substituted with one or more R4, wherein R4 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and l to 3 heteroatoms selected from N, O, and S or -(C(R6)2)p-heteroaryl n the heteroaryl comprises a 5- or 6-membered ring and l to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino, R1 is H, R2 is — C(O)Rg, R3 is methyl, R8 is (C1-C6) alkyl, (C3-C7) lkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl optionally substituted with one or more R4, n R4 is selected from —CF3 and —CH2-N- methylpiperazinyl, R1 is H, R2 is g, R3 is methyl, R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, or (C1-C3) alkoxy, and n is 1.

In another embodiment, L is —C(O)NR5-, n R5 is H, A is phenyl ally substituted with one or more R4, wherein R4 is selected from —CF3 and —CH2-N- methylpiperazinyl, R1 is H, R2 is -C(O)Rg, R3 is methyl, R8 is (C3-C7) cycloalkyl, and n is 1.

In another embodiment, R8 is cyclopropyl.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl optionally substituted with one or more R4, wherein R4 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl n the cycloalkyl ses a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S or -(C(R6)2)p-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino, R1 is H, R3 is methyl, R2 is R9R10, wherein R9 is H, (C1-C6) alkyl, ) haloalkyl, ) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, 0, or s, R10 is H, (C1-C6) alkyl, (C1-C6)haloa1ky1, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, ) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R”, wherein R“ is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5— or 6- ed heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered cycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl ally substituted with one or more R4, wherein R4 is (C1-C6) alkyl, ) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S or -(C(R6)2)p-heteroaryl wherein the heteroaryl ses a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino, R1 is H, R3 is methyl, R2 is —C(O)NR9R10, wherein R9 is methyl and R10 is (C1-C6) alkyl, wherein the (C1- C6) alkyl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) lamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl and OH, and n is 1.

In r embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl optionally substituted with one or more R4, n R4 is selected from —CF3, CN, methoxy, and - (C(R6)2)p-heterocycloalkyl, wherein p is 1 and -(C(R6)2)p-heterocycloalkyl is CH2- pyrrolidinyl, R1 is H, R3 is methyl, R2 is —C(O)NR9R10, wherein R9 is methyl and R10 is (C1- C6) alkyl, wherein the (C1-C6) alkyl is optionally substituted with one or more R”, wherein R“ is ) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5— or 6- membered heteroaryl comprising 1 to 3 atoms selected from N, O, or S, or 4- to 7- membered cycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —C(O)NR5-, wherein R5 is H, A is phenyl optionally substituted with one or more R4, wherein R4 is selected from —CF3, CN, methoxy, and - (C(R6)2)p-heterocycloalkyl, n p is 1 and -(C(R6)2)p-heterocycloalkyl is CH2- pyrrolidinyl, R1 is H, R3 is methyl, R2 is R9R10, wherein R9 is methyl and R10 is ethyl, wherein the ethyl is optionally tuted with one or more R”, wherein R11 is methoxy, and n is 1. In another embodiment, R4 is selected from —CF3 and yrrolidinyl. In another embodiment, R4 is selected from —CF3 and methoxy. In another embodiment, R4 is selected from —CF3 and —CN.

In another embodiment, L is — NR5C(O)-, wherein R5 is H, A is phenyl optionally substituted with one or more R4, wherein R4 is —OCF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is methyl, and n is 1.

In r embodiment, L is —NR5C(O)-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is (C1-C6) alkyl, - C(O)Rg, or —C(O)NR9R10, R3 is methyl, R8 is ) alkyl, (C3-C7) cycloalkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, ) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S, R9 is H, ) alkyl, (C1-C6) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising l to 3 heteroatoms selected from N, O, or S, R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3- C7) lkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each ndently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R”, or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring sing 1 to 3 atom selected from N, O, and S, optionally substituted with one or more substituent each independently ed from (C1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH2, -(CH2)q-(C1- C6) alkylamino, -(CH2)q-(C1-C6) dialkylamino, C1-C6) alkyl, -OH, and 4- to 7- membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl, R11 is (C1-C6) alkoxy, -OH, -NH2, (C1- C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 atoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —NR5C(O)-, wherein R5 is H, A is pyridinyl optionally tuted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is H, (C1-C6) alkyl, ) haloalkyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R11 wherein R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) lamino, 5- or 6- membered heteroaryl sing 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms ed from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from ) alkyl and OH, and n is 1. In another embodiment, R10 is H.

In another embodiment, L is —NR5C(O)-, wherein R5 is H, A is pyridinyl optionally substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is , R2 is — C(O)NR9R10, wherein R9 is methyl and R10 is 4 to 7-membered heterocycloalkyl sing 1 to 3 heteroatoms selected from N, O, or S, wherein the heterocycloalkyl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, - NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and n is 1. In another embodiment, R10 is N-methylpiperidinyl.

In r embodiment, L is O)-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is H and R10 is H, methyl, ethyl, propyl, n-butyl, isobutyl, or cyclopropyl, wherein the methyl, ethyl, propyl, n-butyl, or isobutyl is optionally substituted with one or more R“, wherein R“ is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, wherein the heterocycloalkyl is optionally tuted with one or more substituents each independently selected from (C1-C6) alkyl and OH, and n is 1.

In another embodiment, L is —NR5C(O)-, n R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is H and R10 is ethyl, wherein ethyl is optionally substituted with one or more R”, wherein R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl sing 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7-membered heterocycloalkyl sing 1 to 3 heteroatoms selected from N, O, or S, wherein the cycloalkyl is optionally substituted with one or more substituents each independently ed from (C1-C6) alkyl and OH, and n is 1. In another embodiment, R11 is y. In r embodiment, R11 is N-piperazinyl. In another embodiment, R11 is -OH.

In another embodiment, L is —NR5C(O)-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is methyl, R2 is — C(O)NR9R10, wherein R9 is H and R10 is ethyl, wherein ethyl is optionally substituted with one or more RH, n R11 is (C1-C6) dialkylamino, and n is 1. In another embodiment, R11 is dimethylamino. In another embodiment, R11 is diethylamino.

In another ment, L is —NR5C(O)-, n R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or OH,, R2 is —C(O)NR9R10, n R9 is H and R10 is ethyl, wherein the ethyl is optionally substituted with one or more R”, wherein R11 is methoxy, and n is O or 1.

In another embodiment, L is —NR5C(O)-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R3 is ﬂuoro, R2 is — C(O)NR9R10, wherein R9 is H and R10 is ethyl, wherein the ethyl is optionally substituted with one or more RH, wherein R11 is methoxy, and n is 1.

] In r embodiment, L is —NR5C(O)-, wherein R5 is H, A is pyridinyl substituted with one or more R4, wherein R4 is —CF3, R1 is H, R2 is —C(O)NR9R10, wherein R9 is H and R10 is ethyl, wherein the ethyl is optionally substituted with one or more R”, wherein R11 is methoxy, and n is 0. miting illustrative compounds of the invention include: 3 -((2-(3 ,3 -dimethylureido)thiazol-S -yl)ethynyl)methyl-N-(4-(triﬂuoromethyl)pyridin yl)benzamide (I— 1), 4-methyl-N-(4-(triﬂuoromethyl)pyridinyl)-3 -((2-ureidothiazol-5 -yl)ethynyl)benzamide (1- methyl (5 -((2-methyl -5 -((4-(triﬂuoromethyl)pyri dinyl)carbamoyl)phenyl)ethynyl)thiazol - 2-yl)carbamate (1-3), 4-methyl-3 -((2-(3 -methylureido)thiazol-5 -yl)ethynyl)-N-(4-(triﬂuoromethyl)pyridin yl)benzamide (1-4), 3 -((2-(3 -(2-methoxyethyl)ureido)thiazol -5 -yl)ethynyl)methyl -N-(4- (triﬂuoromethyl)pyridinyl)benzamide (1-5), 4-methyl-3 3 -(2-morpholinoethyl)ureido)thiazol-S -yl)ethynyl)-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (1-6), 3 -((2-(3 -(2-methoxyethyl)-3 -methylureido)thiazol -5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (1-7), 3 -((2-(3 -3 -methylureido)thiazol-5 -yl)ethynyl)methyl-N-(4-(triﬂuoromethyl)pyridin- 2-yl)benzamide (1-8), 3 -((2-(3 -(2-(dimethylamino)ethyl)-3 -methylureido)thiazol-5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (1-9), 3 -((2-(3 -(2-hydroxyethyl)-3 lureido)thiazol -5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (I— 1 0), 3 -((2-(3 -(2-(dimethylamino)ethyl)ureido)thiazol -5 hynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (I— 1 1), 4-methyl-3 -((2-(3 -(2-(pyrrolidin- l hyl)ureido)thiazol-5 -yl)ethynyl)-N-(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-12); 4-methyl-3 -((2-(3 -(( l -methylpiperidinyl)methyl)ureido)thiazol-S -yl)ethynyl)-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (I— 13); 4-methyl-3 -((2-(3 -(2-(4-methylpiperazin- l -yl)ethyl)ureido)thiazol-5 -yl)ethynyl)-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (I— 1 4); 3 -((2-(3 -(2-hydroxymethylpropyl)ureido)thiazol -5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (I— 1 5); 4-methyl-3 -((2-(3 -methyl -3 -(2-(4-methylpiperazin- l -yl)ethyl)ureido)thiazol-S -yl)ethynyl)-N- (4-(triﬂuoromethyl)pyridinyl)benzamide (I— 1 6); 3 -((2-(3 propylureido)thiazol-5 -yl)ethynyl)methyl-N-(4-(triﬂuoromethyl)pyridin yl)benzamide (I— 1 7); 3 -((2-(3 -(2-(3 -hydroxypyrrolidin- l -yl)ethyl)ureido)thiazol -5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (I— 1 8); 4-methyl-3 -((2-(3 -methyl -3 -(2-(pyrrolidin- l -yl)ethyl)ureido)thiazol -5 -yl)ethynyl)-N-(4- oromethyl)pyridinyl)benzamide (1-1 9); 4-methyl-3 -((2-(3 -methyl -3 -((l -methylpyrrolidinyl)methyl)ureido)thiazol -5 -yl)ethynyl )- N—(4-(triﬂuoromethyl)pyridin-Z-yl)benzamide (1-20); 3 -((2-(3 droxymethylpropyl)-3 -methylureido)thiazol -5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (1-2 1); 3 -((2-(3 -(4-hydroxycyclohexyl)-3 -methylureido)thiazol-5 -yl)ethynyl)methyl-N-(4- (triﬂuoromethyl)pyridinyl)benzamide (1-22); yl-N—(5-((2-methyl((4-(triﬂuoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)piperazine- l xamide (1-23); 3 -hydroxy-3 -methyl-N—(5-((2-methyl-5 -((4-(triﬂuoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)azetidine- l -carboxamide (1-24); 4-methyl-N—(5-((2-methyl((4-(triﬂuoromethyl)pyridin yl)carbamoyl)phenyl)ethynyl)thiazolyl)piperidine- l xamide (1-25); 4-methy1-3 -((2-(3 -(pyridiny1methyl)ureido)thiazol-5 -y1)ethyny1)—N—(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-26); 4-(2-hydroxyethyl)-N—(5-((2-methy1((4-(triﬂuoromethyl)pyridin yl)carbamoyl)pheny1)ethyny1)thiazoly1)piperazine-1 -carboxamide (1-27); 4-methy1-3 -((2-(3 -methy1-3 ethy1amino)ethy1)ureido)thiazol-5 -y1)ethyny1)-N—(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-28); 4-methy1-3 -((2-(3 -methy1-3 -(1-methy1piperidiny1)ureido)thiazoly1)ethyny1)—N—(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-29); (2-methy1((4-(triﬂuoromethy1)pyridiny1)carbamoyl)pheny1)ethyny1)thiazol y1)piperazinecarboxamide (1-30); 3 -((2-(3 -(4-aminobuty1)ureido)thiazol-S -y1)ethyny1)methy1-N-(4-(triﬂuoromethyl)pyridin- 2-y1)benzamide (1-31); 4-methy1-3 -((2-(3 -methy1-3 -(1 -methy1piperidin-3 -y1)ureido)thiazol-5 -y1)ethyny1)—N—(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-32); 3 3 -(4-aminocyclohexy1)-3 -methy1ureido)thiazoly1)ethyny1)methy1-N—(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-33); 2-((dimethylamino)methyl)—N—(5-((2-methyl ((4-(triﬂuoromethy1)pyridin yl)carbamoy1)phenyl)ethynyl)thiazoly1)morpholinecarboxamide ; N—(5-((2-methy1((4-(triﬂuoromethy1)pyridiny1)carbamoyl)pheny1)ethyny1)thiazol yl)morpholinecarboxamide ; 3 -((2-(3 -(3 -aminopropy1)ureido)thiazoly1)ethyny1)—4-methy1-N-(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide ; 4-acetyl-N—(5-((2-methyl((4-(triﬂuoromethyl)pyridin yl)carbamoy1)pheny1)ethyny1)thiazoly1)piperazine-1 -carboxamide ; 3 -((2-(3 -(2-aminoethy1)ureido)thiazoly1)ethynyl)—4-methy1-N-(4-(triﬂuoromethyl)pyridin- 2-y1)benzamide (1-38); 4-methy1-3 -((2-(3 -methy1-3 -(1 -methy1azetidin-3 -y1)ureido)thiazol-5 -y1)ethyny1)-N—(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-39); 3 -(dimethy1 amino)—N—(5-((2-methy1((4-(triﬂuoromethy1)pyridin yl)carbamoyl)pheny1)ethyny1)thiazoly1)pyrrolidine-1 -carboxamide (1-40); N—(5-((2-methy1((4-(triﬂuoromethy1)pyridiny1)carbamoyl)phenyl)ethynyl)thiazoly1)- 4-(4-methy1piperazin-1 -y1)piperidinecarboxamide (1-41); 2-ﬂuoro—5 -((2-(3 -methylureido)thiazol-5 -y1)ethyny1)-N-(4-(triﬂuoromethy1)pyridin zamide ; 2-ﬂuoro—N—(4-(triﬂuoromethy1)pyridinyl)((2-ureidothiazoly1)ethyny1)benzamide (I- 43)‘7 3-((2-(3 -methy1ureido)thiazoly1)ethynyl)-N—(4-(triﬂuoromethy1)pyridinyl)benzamide (1-44); 4-ﬂuoro—3 -((2-(3 -methy1ureido)thiazol-5 -y1)ethyny1)-N-(4-(triﬂuoromethy1)pyridin yl)benzamide (1-45); 3 3 -(2-methoxyethy1)-3 -methy1ureido)thiazol-5 -y1)ethyny1)methy1-N-(4-(pyrrolidin- 1-y1methy1)—3 -(triﬂuoromethy1)pheny1)benzamide (1-46); N—(2-methoxy-3 -(triﬂuoromethyl)pheny1)-3 -((2-(3 thoxyethy1)—3 1ureido)thiazol- -y1)ethyny1)methylbenzamide (1-47); N—(4-cyano-3 -(triﬂuoromethyl)pheny1)-3 -((2-(3 -(2-methoxyethy1)-3 -methy1ureido)thiazol -5 - yl)ethyny1)methylbenzamide (1-48); 3-((2-(cyclopropanecarboxamido)thiazoly1)ethyny1)—4-methy1-N-(4- (triﬂuoromethyl)pyridin-Z-yl)benzamide (1-49); 3 -((2-(cyc1opropanecarboxamido)thiazoly1)ethyny1)—4-methy1-N-(4-((4-methy1piperazin yl)methy1)—3-(triﬂuoromethy1)pheny1)benzamide (1-50); 3-((2-acetamidothiazoly1)ethyny1)methyl-N-(4-(triﬂuoromethy1)pyridinyl)benzamide (1-51); 4-methy1-3 -((2-piva1ami dothiazol-S -y1)ethyny1)—N—(4-(triﬂuoromethy1)pyridin-Z- yl)benzamide (1-52); ethy1-3 -((2-(3 -methy1-3 -(1-methy1piperidiny1)ureido)thiazoly1)ethyny1)pheny1)— 4-(triﬂuoromethyl)picolinamide (1-53); N—(3 -((2-(3 -(2-methoxyethyl)—3 -methylureido)thiazolyl)ethynyl)methylphenyl) (triﬂuoromethyl)picolinamide (1-54), N—(4-methyl-3 -((2-(3 -methyl-3 -(2-(4-methylpiperazin- l -yl)ethyl)ureido)thiazol yl)ethynyl)phenyl)(triﬂuoromethyl)picolinamide (1-55), N—(3 -((2-(3 ,3 -dimethylureido)thiazol-5 -yl)ethynyl)methylphenyl)-3 - (triﬂuoromethoxy)benzamide (1-56), N—(4-methyl-3 -((2-(3 -methylureido)thiazol-5 hynyl)phenyl) (triﬂuoromethyl)picolinamide (1-57), N—(3 -((2-(3 -(2-(dimethyl amino)ethyl)-3 -methylureido)thiazol-5 hynyl)methylphenyl)- 4-(triﬂuoromethyl)picolinamide (1-58), N—(3 -((2-(3 -(2-(diethylamino)ethyl)-3 -methylureido)thiazolyl)ethynyl)methylphenyl)- 4-(triﬂuoromethyl)picolinamide (1-59), N—(3 -((2-(3 droxyethyl)-3 -methylureido)thiazol-5 -yl)ethynyl)methylphenyl) (triﬂuoromethyl)picolinamide (1-60), N—(3 3 -(2-methoxyethyl)—3 -methylureido)thiazolyl)ethynyl)phenyl) (triﬂuoromethyl)picolinamide (1-61), and uoro-3 -((2-(3 -(2-methoxyethyl)-3 -methylureido)thiazolyl)ethynyl)phenyl) (triﬂuoromethyl)picolinamide .

In another embodiment of the invention, the compounds of Formula (I) are enantiomers. In some embodiments the compounds are the antiomer. In other embodiments the compounds are the (R)-enantiomer. In yet other ments, the nds of Formula (I) may be (+) or (-) enantiomers.

It should be understood that all isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z conﬁguration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans conﬁguration. All tautomeric forms are also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof may eXist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

] The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention es all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reﬂect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry. reomeric mixtures can be separated into their dual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by ting the enantiomeric e into a reomeric mixture by reaction with an appropriate optically active compound (e. g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the reomers and converting (e.g., hydrolyzing) the individual diastereomers to the ponding pure omers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC .

It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the nds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the e of asymmetric carbons), rotameric forms, atropisomers, WO 12136 2017/066291 and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans- forms, as well as mixtures, are embraced within the scope of the invention. Also, for e, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R conﬁguration as deﬁned by the IUPAC 1974 Recommendations. The use of the terms “salt77 (L solvate77 (L 77 (4 7 7 ester, prodrug” and the like, is intended to y apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The compounds of Formula (I) may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts f, unless otherwise indicated.

The present invention relates to compounds which are modulators of c-Kit. In one embodiment, the compounds of the present invention are inhibitors of c-Kit.

The invention is directed to compounds as described herein and ceutically acceptable salts, es, solvates, gs, stereoisomers, or tautomers f, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds The compounds of the present ion may be made by a variety of methods, ing standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic s. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where ary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard s of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are d at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of nds of Formula (I).

Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (1). Accordingly, the present invention includes both possible stereoisomers (unless ed in the synthesis) and includes not only c compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospeciﬁc synthesis or by resolution of the ﬁnal product or any convenient intermediate. Resolution of the ﬁnal product, an ediate, or a starting material may be affected by any suitable method known in the art.

See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.

Preparation of compounds The compounds of the present invention can be prepared in a number of ways well known to those d in the art of organic synthesis. By way of example, compounds of the present invention can be sized using the methods described below, er with synthetic methods known in the art of synthetic organic chemistry, or variations n as appreciated by those skilled in the art. Preferred methods e but are not limited to those methods described below. Starting materials are either commercially ble or made by known procedures in the reported literature or as illustrated. Compounds of the present invention can be synthesized by following the steps outlined in General Scheme 1 which comprise the assembling of (thiazolyl)-carbamates or -ureas. Starting materials are either commercially ble or made by known procedures in the reported literature or as illustrated.

General Scheme 1 (Boc)n HN’ n = 1,2 Boc —N Boc‘N s)—/ _N Pd(PPh3)4, Cul s / (i-Pr)2NEt, DMF H H / R5 | I 3/\ \A 1a-1 1b-1 (R )n O RZ-N' _, —, (R3)n o wherein L is _C(O)NR5_ wherein A, Rl-R3, and R5 and n are deﬁned as in a (I).

The general manner of preparing target compounds of Formula (I) wherein L is —C(O)NR5- by using intermediates 121-1 and 1b-1, is outlined above in General Scheme 1.

Coupling of 121-1 to 1b—1 in the presence of a palladium (0) catalyst and a base, e.g., ropylethylamine (DIPEA), in a solvent (e.g., ylformamide (DMF), dimethylsulfoxide (DMSO), etc.) optionally at elevated temperature provides intermediate 1c—1. Deprotection in the presence of a strong acid (e.g., triﬂuoroacetic acid) and a solvent (e. g., dichloromethane (DCM)). Derivatization before or after the coupling step provides the desired product of Formula (I).

Compounds of Formula (I) can exist as enantiomeric or reomeric stereoisomers. Enantiomerically pure compounds of Formula (I) can be prepared using enantiomerically pure chiral ng blocks. Alternatively, racemic mixtures of the ﬁnal compounds or a racemic mixture of an advanced intermediate can be ted to chiral puriﬁcation as described herein below to r the desired enantiomerically pure intermediates or ﬁnal compounds. In the instances where an advanced intermediate is d into its individual enantiomers, each individual enantiomer can be carried on separately to r the ﬁnal enantiomerically pure nds of Formula (I).

It should be understood that in the description and formula shown above, the various groups Rl-RH, L, A, n, p, and q and other variables are as deﬁned above, except where otherwise indicated. Furthermore, for synthetic es, the compounds of General Scheme 1 are merely entative with elected radicals to illustrate the general synthetic methodology of the compounds of Formula (I) as deﬁned .

Methods of Using the Disclosed Compounds Another aspect of the invention relates to a method of ng a disease or disorder associated with modulation of c-Kit. The method comprises administering to a patient in need of a treatment for a disease or disorder associated with modulation of c-Kit an effective amount the compositions and compounds of Formula (I).

Another aspect of the invention relates to a method of ting a disease or disorder ated with tion of c-Kit. The method comprises administering to a t in need of a treatment for a disease or disorder associated with modulation of c-Kit an effective amount the compositions and compounds of Formula (I).

Another aspect of the invention relates to a method of treating a c-Kit-mediated disease or disorder. The method comprises administering to a patient in need of a treatment of a disease or disorder associated with modulation of c-Kit an effective amount the compositions and compounds of Formula (I). r aspect of the invention relates to a method of preventing a c-Kit-mediated disease or disorder. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of c-Kit an effective amount the compositions and compounds of Formula (I).

] In another aspect, the present invention is directed to a method of inhibiting c-Kit.

The method involves administering to a patient in need thereof an effective amount of a nd of Formula (I).

Another aspect of the present invention relates to a method of treating a e or disorder in a patient associated with the inhibition of c-Kit, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I).

In one embodiment, the disease or disorder is selected from the group consisting of cancer and cell proliferative disorders, multiple sclerosis, asthma, ytosis, inﬂammatory disorders, allergic reactions, fibrotic disorders, and metabolic ers.

Another aspect of the present invention s to a method of preventing a e or er in a patient associated with the inhibition of c-Kit, the method comprising administering to a patient in need thereof an ive amount of a compound of Formula (I).

The t invention also relates to the use of an inhibitor of c-Kit for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or disorder mediated by c-Kit, wherein the ment comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or disorder mediated by c-Kit, wherein the medicament comprises a nd of Formula (I).

Another aspect of the present invention s to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease or disorder associated with inhibiting c-Kit.

In another aspect, the t invention relates to the use of a compound of Formula (I) in the treatment of a disease or disorder associated with inhibiting c-Kit.

In another aspect, the present invention relates to the use of a compound of Formula (I) in the prevention of a disease or disorder associated with inhibiting c-Kit.

In some embodiments of the methods above, the disease or er is selected from the group consisting of cancer, metastasis, inﬂammation and auto-immune pathogenesis.

In some embodiments of the methods above, the disease or disorder is selected from the group ting of cell proliferative disorder, a f1brotic disorder, and a lic disorder.

In an embodiment of the methods above, the disease or disorder is multiple sclerosis.

In an embodiment of the methods above, the disease or disorder is asthma. In another embodiment of the methods above, the disease or disorder is mastocytosis.

In an embodiment of the methods above, the disease or disorder is an allergic reaction.

In an embodiment of the methods above, the disease or disorder is inﬂammatory arthritis.

Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

In some embodiments, the cancer is selected from liposarcoma, neuroblastoma, glioblastoma, bladder cancer, adrenocortical cancer, multiple myeloma, colorectal cancer, non-small cell lung cancer, oropharyngeal cancer, penis cancer, anal cancer, thyroid cancer, vaginal cancer, gastric cancer, rectal cancer, thyroid cancer, Hodgkin ma and diffuse large B-cell ma.

In some ments, the cancer is selected from ia, mast cell tumor, small cell lung , testicular cancer, cancer of the gastrointestinal tract, cancer of the l nervous system, cancer of the female genital tract, sarcoma of neuroectodermal origin, and Schwann cell neoplasia associated with neurof1bromatosis.

In some ments, the cancer is selected from small cell lung carcinoma, acute myeloid leukemia (AML), thymic oma, desmoid tumor, neuroblastoma, malignant melanomas, colorectal cancer, systemic mastocytosis (SM), and gastrointestinal stromal tumors (GISTs).

Another aspect of the invention relates to a method of inducing cell cycle arrest, sis in tumor cells, and/or enhanced tumor-speciﬁc T cell immunity. The method comprises contacting the cells with an effective amount of a compound of Formula (I).

In one embodiment, the t invention relates to the use of an inhibitor of c-Kit for the preparation of a medicament used in treatment, prevention, inhibition or elimination of a disease or disorder associated with associated with cancer and metastasis.

In some embodiments, administration of a nd of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier s a change in the cell cycle or cell viability. r aspect of the invention relates to a method of treating inﬂammation. The method comprises administering to a patient in need thereof an ive amount of a nd of a (I).

Another aspect of the invention relates to a method of treating auto-immune pathogenesis. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

Another aspect of the invention is directed to ceutical compositions comprising a compound of Formula (I) and a pharmaceutically able carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease or disorder ated with modulation of c-Kit including, , metastasis, inﬂammation and auto- immune pathogenesis, comprising administering to a patient suffering from at least one of said diseases or disorder a nd of Formula (I).

In one embodiment, are provided methods of treating a disease or disorder associated with modulation of c-Kit including, cancer and metastasis, comprising administering to a patient suffering from at least one of said diseases or er a compound of Formula (I).

One therapeutic use of the compounds or itions of the present invention which inhibit c-Kit is to provide treatment to patients or subjects suffering from cancer, asis, inﬂammation and auto-immune pathogenesis.

Another therapeutic use of the compounds or compositions of the present invention which inhibit c-Kit is to provide treatment to patients or subjects suffering from cancer and metastasis.

The disclosed compounds of the invention can be administered in effective s to treat or prevent a er and/or prevent the development thereof in subjects.

Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, aneous, vaginal, buccal, rectal or topical administration modes.

Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, elease capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in enous (both bolus and infusion), intraperitoneal, aneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and n capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., puriﬁed water, ceride oils, such as hydrogenated or partially hydrogenated ble oil, or mixtures thereof, corn oil, olive oil, sunﬂower oil, safﬂower oil, ﬁsh oils, such as EPA or DHA, or their esters or triglycerides or es thereof, omega- 3 fatty acids or derivatives thereof, lactose, se, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine, b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol, for tablets also, c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, anth, methylcellulose, sodium carboxymethylcellulose, magnesium ate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or nylpyrrolidone, if desired, d) a egrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures, e) absorbent, colorant, ﬂavorant and sweetener, f) an emulsiﬁer or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labraﬁl, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, re, vitamin E TGPS or other acceptable emulsifier, and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, itions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to y form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also ated as a suppository that can be ed from fatty emulsions or sions, using polyalkylene glycols such as propylene glycol, as the carrier.

The disclosed compounds can also be stered in the form of liposome ry systems, such as small unilamellar vesicles, large ellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or atidylcholines. In some embodiments, a ﬁlm of lipid ents is hydrated with an s solution of drug to a form lipid layer encapsulating the drug, as described in US. Pat. No. 564 which is hereby incorporated by reference in its entirety.

Disclosed compounds can also be red by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The sed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or hyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the Disclosed nds can be coupled to a class of biodegradable polymers useful in achieving lled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not ntly bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can n from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, seX and medical condition of the t; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Effective dosage s of the disclosed nds, when used for the indicated s, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, , 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.

Examples The disclosure is r illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate n embodiments and that no limitation to the scope of the disclosure is ed thereby. It is to be further understood that resort may be had to s other embodiments, modiﬁcations, and equivalents thereof which may suggest lves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Analytical s, Materials, and Instrumentation Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on Bruker spectrometers at 400 MHz. Spectra are given in ppm (6) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using a Waters ZQ Single Quad Mass Spectrometer (ion trap electrospray tion (ESI)). Purity and low resolution mass spectral data were measured using Waters Acquity i-class ultra-performance liquid tography (UPLC) system with Acquity Photo Diode Array Detector, Acquity Evaporative Light Scattering Detector (ELSD) and Waters ZQ Mass Spectrometer. Data was ed using Waters MassLynX 4.1 re and purity characterized by UV wavelength 220 nm, evaporative light scattering detection (ELSD) and electrospray positive ion (ESI). (Column: Acquity UPLC BEH C18 1.7 pm 2.1 X 50 mm; Flow rate 0.6 mL/min; Solvent A 0.l%: 10 mM Ammonium e/Acetonitrile/Formic Acid), Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); nt: 5-100% B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21 mins. Abbreviations used in the following examples and ere herein are: br broad CDI 1,1’ -carbonyldiimidazole DCM dichloromethane DIPEA MN—diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF N,N—dimethylformamide DMSO dimethyl sulfoxide EI electron ionization ESI electrospray ionization Et ethyl Et3N triethylamine EtOAc ethyl e EtOH ethanol GCMS gas chromatography—mass spectrometry h hour(s) HATU 2-(7-Aza- lH-benzotriazole- l -yl)- l , 1,3 , 3 -tetramethyluronium hexaﬂuorophosphate HPLC high-performance liquid chromatography LCMS liquid chromatography—mass spectrometry m multiplet Me methyl MeOH methanol MHz megahertz min minutes MS molecular sieves NMR nuclear magnetic resonance ppm parts per million PSI Pounds per square inch s singlet TBAF tetra-n-butylammonium e TFA triﬂuoroacetic acid THF tetrahydrofuran Methods for the Synthesis of Compounds of Formula (1) Method A Example 1: 3-((2-(3,3-dimethylureido)thiazol-S-yl)ethynyl)methyl-N-(4- (trifluoromethyl)pyridinyl)benzamide (I-1) HZN N ' | 800i2 N F3 N\ I) / o 0 ii) 1a 1b 1c 3°C H — TMS HBr BocHN iaoc H2N >—_N Pd(PPh3)2CI2. Cul ‘N 8):!“ (Boc)20 (Boc)20 >—N (i_pr)2NEt, DMF >—N / Ill) fr N) r ) r H 1a' 1b' 1d 16' MS (Boc)n HN’ n =1,2 BOG Boc intermediate 1c Boc—N' $>=N HN / TBAF —N S / Ffd(PP[\rli|3£)t4.DC|\:lilF (I-Pr)2 .

+ S / H VI) T H H H 1e 1e' 1f / H2N o f“ H96 / 8):“! H CDI/DCM (CH3)2N"I / 'X) X) H X = NH, 0 viii) N N \ H 0 | N / N\ Steps 1' and ii. 3-iodomethyl-N-(4-(trifluoromethyl)pyridinyl)benzamide (1c) 15.72 g (0.06 mol, 1.0 eq) of methylbenzoic acid (121) in 60 m1 of thionyl chloride was d for 1 h. The reaction mixture was evaporated by rotary evaporation to give a brown solid, 1b, which was further dried under high vacuum for 1 h. The solid 1b was then dissolved in 36 ml of THF and carried onto the next step without ation.

To a ﬂask under N2 atmosphere and with stirring was added DMAP (366 mg, 3.0 mmol, 0.05 eq), DIPEA (12.6 ml, 9.36 g, 72 mmol, 1.2 eq), o (triﬂuoromethyl)pyridine (9.9 g, 61.2 mmol, 1.02 eq) and THF (120 ml). To this solution was then slowly added solution of an acid chloride (1b, freshly prepared as above) using a funnel under a N2 atmosphere and the reaction mixture was stirred at rt overnight. Water (60 ml) was added, followed by EtOAc (150 ml). The organic layer was ted, and the aqueous layer was ted with EtOAc (2x100 ml). The combined organic layers were dried, ﬁltered, and concentrated in vacuo. The resulting crude product was puriﬁed by ﬂash column tography on silica gel ng with EtOAc/Heptane 20%) to give intermediate 1c as a white solid.

Steps iii to vi. -S-ethynylthiazol-Z-amine (Id) Di-tert-butyl dicarbonate [(Boc)20, 100.7 g, 0.461 mol, 1.2 eq] was added to a ﬂask containing a mixture of 2-aminobromothiazole monohydrobromide (1a', 100 g, 0.385 mol, 1.0 eq) and 4-(dimethylamino)pyridine (DMAP, 1.18 g, 9.7 mmol, 0.025 eq) in 900 mL of THF and 135 mL of Et3N and cooled to 0 0C using an ice bath. The on mixture was d at r.t. overnight and then concentrated in vacuo. The residue was stirred in EtOAc/Heptane (1:10, 250 ml) at rt overnight and then ﬁltered. The ﬁltrate was washed with brine, dried, ﬁltered, and concentrated in vacuo to furnish intermediate 1b' as a yellow solid (91% yield).

Di-tert-butyl dicarbonate [(Boc)20, 90.4 g, 0.414 mol, 1.2 eq] was added to a ﬂask containing a mixture of intermediate lb' (97.9 g, 0.351 mol, 1.0 eq) and 4- (dimethylamino)pyridine (DMAP, 1.07 g, 8.7 mmol, 0.025 eq) in 880 ml of THF and 121 ml of Et3N and cooled to 0 0C using an ice bath. The reaction mixture was stirred at rt overnight.

Water (200 ml) and DCM were added and the resulting mixture was d at rt for 30 min.

The organic layer was separated and the aqueous layer was extracted with DCM (2 x 150 ml).

The combined organic layers were washed with brine, dried over Na2S04, ﬁltered and concentrated in vacuo. The crude residue was puriﬁed with a short silica gel column (eluting with EtOAc/Heptane 1:20) to give intermediate lc' as an off-white solid (113 g, 85% yield).

A mixture of the di-Boc material lb' (48.5 g, 0.128 mol, 1.0 eq), trimethylsilylacetylene (21.8 ml, 15.1 g, 154 mmol, 1.29 eq), Pd(PPh3)2Clz (4.7 g), CuI (1.5 g), and Et3N (50 ml) in 200 ml of DMF was heated at 70 0C in a sealed tube under an N2 atmosphere and the resulting mixture was stirred for 1.5 h. After concentrating the reaction mixture in vacuo, sat. aq. N212CO3 and DCM were added to the crude residue. The c layer was separated and the combined organic layers were concentrated in vacuo.

Puriﬁcation by ﬂash column chromatography on silica gel (eluting with EtOAc/Heptane 1:10) gave intermediate 1d as a brown solid (37 g, 78% yield).

TBAF (1.0 M in THF, 108 ml) was slowly dropped to a solution of 1d (37 g, 0.1 mol) in 108 ml of DCM at rt. The resulting mixture was d at rt for 1 h and then water and DCM were added. The organic layer was separated and the combined organic layers were concentrated in vacuo. Puriﬁcation by ﬂash column chromatography on silica gel (eluting with EtOAc/Heptane 10% to 30%) ed a mixture of intermediates 1e (di—Boc- -ethynylthiazolamine, 24.5 g, 75% yield) and le' (Bocethynylthiazolamine, 2.1 g, 9% yield).

Steps vii to x. 3-((2-(3,3-dimethylureid0)thiaz01yl)ethynyl)—4-methyl-N-(4- (triflu0r0methyl)pyridinyl)benzamide (I-1) ] A mixture of 1e and le' (24.5 g, 75.5 mmol, 1.0 eq), intermediate 1c (31.4 g, 77.3 mmol, 1.02 eq), Pd(PPh3)4 (7.2 g), CuI (2.05 g), and DIPEA (72.5 ml) in 153 ml ofDMF was heated at 100 0C under an atmosphere of N2 and stirred for 3 h. After g to r.t., the mixture was evaporated in vacuo. Water and DCM were added with ng. The organic layer was separated and the aqueous layer was extracted with DCM (2 x 100 ml). The ed organic layers were washed with brine, dried, ﬁltered, and concentrated in vacuo to furnish a yellow solid (1f, 50 g).

The yellow solid 1f obtained above was dissolved in 200 ml of DCM and 200 ml of TFA was then added. The resulting mixture was stirred at rt for 1 h and then concentrated in vacuo. DCM and sat. aq. Na2CO3 were added with stirring and cooling using an ice bath until a pH of 9 — 10 was obtained. The organic layer was separated and the aqueous layer was ted with DCM (2 x 100 ml). The combined organic layers were washed with brine, dried, ﬁltered, and concentrated to give a yellow solid, which was puriﬁed by ﬂash column chromatography on silica gel (MeOH/DCM 1:20) hing intermediate 1g as a yellow solid (20 g, 62% yield for two steps). 1H NMR (CD3OD): 5 2.33 (3H, s), 7.03 (1H, s), 7.21 (1H, d), 7.24 (1H, d), 7.67 (1H, d), 7.85 (1H, d), 8.39 (2H, d). ESI—MS m/z: 401.1 [M-1]'.

A solution of intermediate 1g (80 mg) and l,l’-carbonyldiimidazole (CD1, 80 mg) in DCM (4 ml) was stirred at 50 oC overnight and then cooled to r.t. To the resulting suspension was added dimethylamine (2.0 M in THF, 5 eq.). The mixture was stirred at rt for 2 h, and then d. The ﬁltrate was concentrated and then puriﬁed by prep HPLC to furnish the title compound I-1 (52% yield).

The compounds in Table 1 were synthesized as described in Method A above using the corresponding ridinyl- or iodophenylbenzamides and di-Boc-S- ethynylthiazolamine in step Vii, and the corresponding l or amine in step X.

TABLE 1: 1H NMR (400 Amine/alcohol in MHz) ppm; ESI— step x.

MS m/z (CDgOD): 8.45 — 8.51 (m, 2 H), 7.98 (d, J: 2.01 Hz, 1 H), 7.78 (dd, J : 7.97, 1.94 Hz, 1 H), 7.46 (s, 1 H), 7.33 (d, J: 8.44 Hz, 1 H), 7.30 (d, J : 5.30 Hz, 1 H), 2.95 (s, 6 H), 2.44 (s, 3 H), [M+H]+ (CDgOD): 8.61 (d, J : 4.69 Hz, 2 H), 8.12 (d, J: 521 Hz, 1 H), 7.92 (dd, J : 7.55 Hz, 1 H), 7.58 (s, 1 H), 7.42 — 7.51 (m, 2 H), 2.58 (s, 3 H), [M+H]+ 446.

(CDgOD): 8.61 (d, J : 3.68 Hz, 2 H), 8.13 (d, J: 201 Hz, 1 H), 7.94 (d, J: 1.88 Hz, 1 H), 7.61 (s, 1 H), 7.47 (s, 1 H), 7.43 (d, J : 4.86 Hz, 1 H), 3.87 (s, 3 H) 2.58 (s, 3 H), [M+H]+ WO 12136 . . . H NMR (400 Amlne/alcohol 1n Compound Structure 33;]? MHz) ppm; ESI— step x. 0 MS m/z (CD3OD)I 8.44 (br s, 2 H), 7.95 (d, J : 1.76 Hz, 1 H), 7.75 (dd, J: 8.03, 2.01 Hz, 1 H), 7.39 (s, 1 H), 7.32 (d, J : 8.44 Hz, 1 H), 7.26 (d, J: 5.30 Hz, 1 H), 2.68 (s, 3 H), 2.41 (s, 3 H), [M+H]+ 460.

(CD3OD)I 8.60 (s, 2 H), 8.12 (d,J: 2.01 Hz, 1 H), 7.87 — 7.93 (m, 1 H), 7.57 (s, 1 H), 7.48 (d, J: 8.03 Hz, 1 CH30CH2CH2NH2 39 H), 7.43 (d, J : .65 Hz, 1 H), 3.55 (d, J : 7.98 Hz, 2H), 3.46 (d, J : 7.99 Hz, 2 H), 3.41 (s, 3H), 2.58 (s, 3 H), [M+H]+ 504.

(CD3OD)I 8.61 (s, 1 H), 8.11 (d,J: 2.01 Hz, 1 H), 7.92 (dd, J : 8.20 Hz, 1 H), 7.66 (s, 1 H), 7.59 (s, 1 H), 7.41 fNN — 7.49 (m, 2 H), \2 4.09 (br s, 2 H), 3.81 (br. s., 2 H), 3.71 (t, J: 5.77 Hz, 4 H), 3.38 (t, J : 5.70, 2 H), 3.23 (br s, 2 H), 2.57 (s, 3 H), [M+H]+ 559.

(CDC13): 9.58 (br s, 1H), 8.76 (br s., 1 H), 8.61 (s, 1 H), 8.40 (d, J: 5.14 \o/\/N\ 63 Hz, 1 H), 7.93 (d, J: 1.88 Hz, 1 H), 7.72 (dd, J: 7.97, 1.94 Hz, 1 H), 7.51 (s, 1 H), 7.30 (d, J 1H NMR (400 Amlne/alcohol 1n Compound ure MHz) ppm; ESI— step x. : 8.03 Hz, 1 H), 7.22 (d, J: 5, 19 Hz, 1H), 3.51 — 3.59 (m, 2 H), 3.42 — 3.49 (m, 2 H), 3.39 (s, 3 H), 3.00 (s, 3 H), 2.47 (s, 3 H), [M+H]+ 518.

(CDC13): 9.01 (s, 1 H), 8.60 (s, 1 H), 8.40 (d, J: 5.02 Hz, 1 H), 7.94 (d, J: 1.76 Hz, 1 H), 7.74 (dd, J: 7.97, 1.94 Hz, 1 H), 7.52 (s, 1 H), 7.31 (d, J CH3CH2NHCH3 : 8.16 Hz, 1 H), 7.23 (d, J: 5.36 Hz, 1 H), 3.30 — 3.46 (q, J: 7.96 Hz, 2 H), 2.95 (s, 3 H), 2.47 (s, 3 H), 1.14 (t, J: 7.96 Hz, 3 H), [M+H]+ (CDC13): 8.85 (s, 1 H), 8.71 (s, 1 H), 8.49 (d, J: 5.14 Hz, 1 H), 8.03 (d, J: 2.01 Hz, 1 H), 7.81 (dd, J: 7.91, 2.01 Hz, 1 H), 7.59 (s, 1 H), 7.39 (d, J : 8.03 Hz, 1 H), 7.29 (d, J: 5.46 Hz, 1 H), 3.32 — 3.46 (m, 2 H), 3.07 (s, 3 H), 2.61 — 2.74 (m, 2 H), 2.56 (s, 3 H), 2.47 (s, 6 H), [M+H]+ 531. 1H NMR (400 Amlne/alcohol 1n MHz) ppm; ESI— step x.

(CDC13): 8.59 — 8.63 (m, 2 H), 8.41 (d, J: 2.01 Hz, 1 H), 7.74 (dd, J : 7.78, 2.01 Hz, 1 H), 7.48 (s, 1 H), 7.31 (d, J: 7.99 HO(CH2)2NHCH3 38 Hz, 1H), 7.22 (d, J : 5.42 Hz, 1 H), 3.88 (t, J: 7.89 HZ, 2 H), 3.49 (t, J : 7.99 Hz, 2 H), 3.04 (s, 3 H), 2.49 (s, 3 H), [M+H]+ (DMSO-dg): 11.30 (s, 1H), 10.82 (s, 1H), 8.66 (d, J : .14 Hz, 1 H), 8.49 (s, 1 H), 8.19 (d, J : 2.01 Hz, 1 H), 7.96 (dd, J: 8.03, \ NH2 N/\/ 23 2.01 Hz, 1 H), 7.62 (s, 1 H), 7.44 — 7.50 (m, 2 H), 3.10 (d, J: 5.65 Hz, 2 H), 2.53 (s, 3 H), 2.38 — 2.47 (m, 2 H), 2.17 — 2.30 (m, 6 H), [M+H]+ 517.

(CDgOD): 12.04 — 12.16 (m, 2 H), 9.50 (d, J: 5.14 Hz, 1 H), 9.34 (s, 1 H), 9.00 (d, J : 1.76 Hz, 1 H), 8.78 (dd, J: 6.16 Hz, 1 H), 8.54 (s, 1 H), 8.29 — 8.38 (m, 2 H), 7.86 (br s, 1 H), 4.30 — 4.37 (m, 4 H), 3.85 (br s, 2 H), 2.82 (br s, 2 H), 2.69 (br s, 2 H), [M+H]+ 543. 1H NMR (400 Amine/alcohol in Compound Structure MHz) ppm; ESI— step x.

MS m/z (DMSO-dg): 11.30 (s, 1 H), 10.70 (s, 1 H), 8.69 (d, J: .14 Hz, 1H), 8.53 (s, 1 H), 8.21 (s, 1 H), 7.96 (dd, J : 7.97, 1.82 Hz, 1 H), 7.70 (s, 1 H), 7.58 (d, J: 2.08 Hz, 1H), 7.51 (d, J : 7.99 Hz, 1 H), 6.67 (br s, 1 H), 3.06 (t, J: 8.01 Hz, 2 H), 2.77 (d, J : 8.00, 2 H), 2.15 (s, 3 H), 1.81 (t, d=8.06 Hz, 2 H), 1.61 (d, J: 8.05 Hz, 2 H), 1.40 (m, 1 H), 1.11 — 1.24 (In, 2 H), [M+H]+ 557. dg): 11.30 (s, 1 H), 10.92 ( s, 1 H), 8.69 (d, J: .14 Hz, 1 H), 8.53 (s, 1 H), 8.20 (d, J : 2.01 Hz, 1 H), 7.96 (dd, J: 7.97, 1.94 Hz, 1 H), 7.70 (s, 1 H), 7.54 (dd, J : 5.02,1.00 Hz, 1 H), 7.49 (d, J : 8.03 Hz, 1 H), 6.58 (s, 1 H), 3.20 — 3.29 (m, 4 H), 2.28 — 2.37 (m, 8 H), 2.17 (s, 3 H) , [M+H]+ 572. 1H NMR (400 Amlne/alcohol 1n nd Structure MHz) ppm; ESI— step x.

(DMSO-dg)2 11.30 (s, 1 H), .72 (s, 1 H), 8.69 (d, J: 5.14 Hz, 1 H), 8.53 (s, 1 H), 8.20 (d, J : 2.01 Hz, 1 H), 7.96 (dd, J: 8.03,1.88 Hz, 1 H), 7.70 (s, 1 H), 7.64 (d, J : 2.02 Hz, 1 H), 7.48 (d, J : 7.98 Hz, 1 H), 6.66 (s, 1 H), 3.10 (d,J: 5.65 Hz, 2H), 1.11 (s, 6 H), [M+H]+ 518.

(CD3OD)I 8.60 (s, 2H), 8.11 (d,J: 2.01 Hz, 1 H), 7.91 (dd, J: 8.03, 2.01 Hz, 1 H), 7.60 (s, 1 H), 7.47 (d, J : 7.62 Hz, 1 H), 7.43 (d, J : 5.27 Hz, 1 H), 3.52 (m, 2 H), 3.06 (s, 3 H) 2.63 — 2.82 (m, 8 H), 2.58 (s, 3 H), 2.37 (s, 3 H), [M+H]+ 586.

(CD30D): 8.59 — 8.63 (m, 2 H), 8.12 (d, J: 2.01 Hz, 1 H), 7.92 (dd, J : 7.78, 2.01 Hz, 1 H), 7.58 (s, 1 H), 7.42 — 7.50 (m, 2 H), 2.63- 2.69 (m, 1 H), 2.58 (s, 3 H), 0.78 — 0.83 (m, 2 H), 0.58 (dd, J: 3.51, 2.01 Hz, 2 H), [M+H]+ 486. 1H NMR (400 Amine/alcohol in Compound ure MHz) ppm; ESI— step x.

MS m/z (DMSO-dg): 11.31 (s, 1H), 10.85 (s., 1 H), 8.69 (d, J: .14 Hz, 1 H), 8.53 (s, 1 H), 8.19 (s,1 H), 7.92 - 7.98 (m, 1 H), 7.69 (s, 1 H), 7.47 - 7.56 (m, 2 H), 6.66 (s, 1 H), 4.72 (br s, 2 H), 4.23 (br s, 2 H), 2.78 (br s, 2 H), 2.62 - 2.72 (m, 2 H), 2.40 (br s, 3 H), 2.34 (d, J : 1.76 Hz, 2 H), 2.19 (In, 1 H), 1.58 (br s, 2 H), [M+H]+ (DMSO-dg): 11.30 (s, 1 H), 8.69 (d, J : 5.14 Hz, 1 H), 8.53 (s, 1 H), 8.19 (d,J: 1.88 Hz,1 H), 7.95 (dd, J : 7.91,1.88 Hz,1 H), 7.70 (s, 1 H), 7.54 (d, J: 5.07 Hz, 1 H), 7.49 (d, J: 8.16 Hz, 1 H), 3.46 (t, J: 5.33 Hz, 2 H), 2.97 (s, 3 H), 2.75 (s, 2 H), 2.67 (br s, 4 H), 1.81 (br s, 4 H), [M+H]+ 557. 1H NMR (400 Amlne/alcohol 1n Compound Structure MHz) ppm; ESI— step x.

(DMSO-dg): 11.30 (s, 1 H), 8.69 (d, J : 5.14 Hz, 1 H), 8.53 (s, 1 H), 8.19 (d,J: 1.88 Hz,1 H), 7.95 (dd, J : 7.97,1.94 Hz,1 H), 7.70 (s, 1 H), 7.55 (d, J: 5.23 Hz, 1 H), 7.49 (d, J: 8.16 Hz, 1 H), 3.60 (br s, 1H), 3.06 (br s, 2H) 2.98 (s, 3 H), 1.94 (br s, 2H), 1.79 (br s, 2 H), 1.63 (br s, 2 H), [M+H]+ 557.

(DMSO-dg) 11.30 (s, 1 H), 8.69 (d, J : 5.14 Hz, 1 H), 8.53 (s, 1 H), 8.20 (d,J: 1.88 Hz,1 H), 7.96 (dd, J : .94 Hz,1 H), 7.73 (s, 1 H), 7.47 - 7.56 (m, 2 H), 3.34 (s, 2 H), 3.04 (br s, 3 H), 1.08 - 1.26 (m, 6 H), [M+H]+ 532.

(DMSO-dg) 11.31 (s, 1 H), 11.20 (s, 1H), 8.69 (d, J : .14 Hz, 1 H), 8.54 (s, 1 H), 8.20 (d, J : 2.01 Hz, 1 H), 7.96 (dd, J: 7.91, 1.88 Hz, 1 H), 7.75 (s, 1 H), 7.48 - 7.56 (m, 2 H), 4.55 (d, J: 4.64 Hz, 1 H), 3.28 (s, 1 H), 2.83 (s, 3 H), 1.87 (d, J: 11.54 Hz, 2 H), 1.55 (d, J: 7.03 Hz, 4 H), 1.30 (dd, J: 11.29, . . . H NMR (400 C1310pd Amlne/alcohol 1n Compound Structure MHz) ppm; ESI— (CD3OD)I 8.60 (s, 2 H), 8.10 (d, J: 1.88 Hz, 1 H), 7.92 (dd, J: 7.97, 1.94 Hz, 1 H), 7.56 (s, 1 H), 7.41 - 7.49 (m, 2 H), 4.53 (br s, 2 H), 3.57 (br s, 2 H), 3.15 (br s, 2 H), 2.97 (s, 3 H), 2.57 (s, 3 H), [M+H]+ 529.

(CD3OD)I 8.59 (s, 1 H), 8.58 (s, 1 H), ,J:1.88 Hz, 1 H), 7.91 (dd, J : 7.97, 1.95 Hz, 1 H), 7.59 (s, 1 H), 7.42 — 7.48 (m, 2 H), 4.01 (s, 4 H), 2.56 (s, 3 H), 1.52 (s, 3 H), [M+H]+ (CDgOD): 8.48 — 8.56 (m, 2 H), 8.02 (d, J: 2.01 Hz, 1 H), 7.83 (dd, J : 8.03, 2.01 Hz, 1 H), 7.45 (s, 2 H), 7.30 — 7.43 (m, 2 H), 3.77 — 3.87 (m, 1 H), 3.46 — 3.57 (m, 2 H), 3.02 — 3.23 (m, 2 H), 2.85 (s, 3H), 2.48 (s, 3 H), 2.19 (d, J: 14.93 Hz, 2 H), 1.73(m, 2 H), [M+H]+ 543. 1H NMR (400 Amine/alcohol in Compound ure MHz) ppm; ESI— step x.

MS m/z (CDgOD): 8.60 (d, J : 4.81 Hz, 2 H), 8.51 (d, J: 5.03 Hz, 2 H), 8.12 (d, J: 2.01 Hz, 1 H), 7.92 (dd, J: 8.03, 2.01 Hz, 1 H), 7.59 (s, 1 H), 7.48 (d, J : 8.03 Hz, 1 H), 7.41 — 7.44 (m, 3 H), 4.53 — 4.55 (m, 2 H), 2.57 (s, 3 H), [M+H]+ 537.

(CDgOD): 8.59 — 8.63 (m, 2 H), 8.11 (d, J: 2.01 Hz, 1 H), 7.92 (dd, J : 7.97, 1.94 Hz, 1 H), 7.57 (s, 1 H), 7.47 (d, J: 7.73 Hz, 1 H), 7.42 — 7.44 (m, 1 H), 3.69 — 3.91 (m, 6 H), 2.99 (br s, 6 H) 2.57 (s, 3 H), [M+H]+ 559.

(CDgOD): 8.61 (d, J : 4.52 Hz, 2 H), 8.10 (d,J: 1.76 Hz, 1 H), 7.92 (dd, J: 8.03, 2.01 Hz, 1 H), 7.60 (s, 1 H), 7.48 (d, J: 7.75 Hz, 1 H), 7.42 — 7.45 (m, 1 H), 3.77 (t, J: 5.52 Hz, 2 H), 3.27 (t, J : .52 Hz, 2H), 3.15 (s, 3 H), 2.77 (s, 3 H), 2.57 (s, 3 H), [M+H]+ 517. 1H NMR (400 Amlne/alcohol 1n Compound Structure MHz) ppm; ESI— step x. ): 8.37 — 8.41 (m, 2 H), 7.89 (d, J: 2.01 Hz, 1 H), 7.69 (dd, J : 8.03, 2.01 Hz, 1 H), 7.37 (s, 1 H), 7.25 (d, J: 7.75 Hz, 1 H), 7.21 (d, J : 5.20 Hz, 1 H), 3.93 — 4.02 (m, 1 H), 2.73 — 2.80 (m, H), 2.36 (s, 3 H), 2.10 (s, 3 H), 1.93 — 2.05 (m, 2 H), 1.60 — 1.74 (m, 2 H), 1.37 — 1.54 (m, 2 H), [M+H]+ 557.

(CD30D): 8.60 (d, J : 4.70 Hz, 1 H), 8.59 (s, 1 H), 8.10 (d, J: 2.01 Hz, 1 H), 7.91 (dd, J : 8.03, 2.01 Hz, 1 H), 7.55 (s, 1 H), 7.46 (d, J: 8.35 Hz, 1 H), 7.42 (d, J: 5.31 Hz, 1 H), 3.85 — 3.95 (m, 4 H), 3.33 (s, 3H), 3.28 — 3.31 (m, 4 H), 2.56 (s, 3 H), [M+H]+ 515.

(CD3OD)I 8.61 (s, 1 H), 8.60 (s, 1 H), 8.11 (d,J: 2.01 Hz, 1 H), 7.92 (dd, J : 8.03,1.88 Hz, 1 H), 7.58 (s, 1 H), 7.47 (d, J: 7.75 Hz, 1 H), 7.43 (d, J : 5.16 Hz, 1 H), 3.00 (t, J: 7.28 Hz, 2 H), 2.57 (s, 3 H), 1.62 — 1.78 (m, 4 H), [M+H]+ 517. 1H NMR (400 Amine/alcohol in Compound Structure MHz) ppm; ESI— step x.

MS m/z (CDgOD): 8.58 — 8.63 (s, 2 H), 8.11 (d, J: 2.01 Hz, 1 H), 7.92 (dd, J : 7.91,1.88 Hz, 1 H), 7.60 (s, 1 H), 7.39 — 7.52 (m, 2 H), 4.51 (m, 1 H), 3.50 (m, 2 H), 3.20 (t,J: 11.92 Hz, 2 H), 3.05 (s, 3 H), 2.93 (s, 3 H), 2.57 (s, 3 H), 2.15 (d, J : 8.28 Hz, 1 H), 1.81 — 2.02 (m, 3 H), [M+H]+ 557.

(CD30D): 8.50 — 8.54 (m, 2 H), 8.03 (d, J: 2.01 Hz, 1 H), 7.83 (dd, J : 8.03, 2.01 Hz, 1 H), 7.53 (s, 1 H), 7.34 — 7.42 (m, 2 H), 4.06 — 4.15 (m, 1 H), 3.01 — 3.23 (m, 1 H), 2.94 (s, 3 H), 2.49 (s, 3 H), 2.08 (d, J: 12.55 Hz, 2 H), 1.72 — 1.90 (m, 4 H), 1.53— 1.65 (m, 2 H), [M+H]+ 557. 1H NMR (400 alcohol in Compound Structure MHz) ppm; ESI— step x.

MS m/z (DMSO-dg) 11.71 (hrs, 1 H), 11.30 (s, 1 H), 8.69 (d, J : 5.14 Hz, 1 H), 8.52 — 8.58 (m, 1 H), 8.20 (d, J : 1.88 Hz, 1 H), 7.96 (dd, J: 8.03,1.88 Hz, 1 H), 7.76 (s, 1 H), 7.64 (s, 1 H), 7.43 — 7.57 (m, 2 H), 6.99 — 7.05 (br s, 1H), 4.16 (d,J : 12.92 Hz, 1 H), 4.04 (d, J: 12.92 Hz, 1 H), 3.86 (dd, J: 11.61, 2.20 Hz, 1 H), 3.34 — 3.57 (m, 3 H), 2.92 —3.14 (m, 1 H), 2.68 (dd, J: 13.05, 10.67 Hz, 1 H), 2.28 — 2.39 (m, 2 H), [M+H]+ 585.

(CD30D): 8.57 — 8.64 (m, 2 H), 8.11 (d, J: 2.01 Hz, 1 H), 7.91 (dd, J : 8.03, 2.01 Hz, 1 H), 7.59 (s, 1 H), 7.42 — 7.45 (m, 2 H), 3.68 — 3.77 (m, 4 H), 3.55 — 3.64 (m, 4 H), 2.57 (s, 3 H), [M+H]+ 516. 1H NMR (400 Amine/alcohol in step x. MHzg/[gpnnllizESI )I 8.60 (s, 1 H), 8.59 (s, 1 H), 8.10 (d, J: 2.01 Hz, 1 H), 7.91 (dd, J : 7.91, 1.88 Hz, 1 H), 7.58 (s, 1 H), 7.46 (d, J: 7.76 Hz, 1 H), 7.43 (d, J : 5.27 Hz, 1 H), 3.40 (t, J: 6.65 Hz, 2 H), 3.03 (t, J : 7.28 Hz, 2 H), 2.56 (s, 3 H) 1.85 — 2.01 (In, 2 H), [M+H]+503.

(CDgOD): 8.58 — 8.64 (m, 2 H), 8.12 (d, J: 1.76 Hz, 1 H), 7.92 (dd, J : 6.71 Hz, 1 H), 7.60 (s, 1 H), 7.43 — 7.50 (m, 2 H), 3.61 — 3.71 (m, 8 H), 2.58 (s, 3 H), 2.16 (s, 3 H), [M+H]+ (CD3OD)I 8.60 (s, 1 H), 8.59 (s, 1 H), 8.09 (d, J: 2.01 Hz, 1 H), 7.91 (dd, J : 7.97, 1.94 Hz, 1 H), 7.58 (s, 1 H), 7.46 (d, J: 8.31 Hz, 1 H), 7.42 (d, J : 5.28 Hz, 1 H), 3.57 (t, J: 5.83 Hz, 2 H), 3.14 (t, J : 5.77 Hz, 2 H), 2.56 (s, 3 H), [M+H]+ 489. 1H NMR (400 Amine/alcohol in Compound Structure MHz) ppm; ESI— step x.

MS m/z (CD3OD)I 8.58 (s, 2 H), 8.09 (d, J: 1.76 Hz, 1H), 7.90 (dd, J: 8.03, 2.01 Hz, 1 H), 7.62 (s, 1 H), 7.34 — 7.53 (m, 2 H), 4.26 — 4.40 (m, 1 H), 4.09 — 4.21 (m, 1 H), 4.03 (dd, J : .79, 6.02 Hz, 1 H), 3.39 — 3.52 (m, 2 H), 2.99 (s, 3 H), 2.84 (s, 3 H), 2.55 (s, 3 H), [M+H]+ (CD3OD)I 8.60 (s, 2 H), 8.10 (d,J: 2.01 Hz, 1 H), 7.91 (dd, J: 8.03, 2.01 Hz, 1 H), 7.55 — 7.66 (m, 1 H), 7.47 (d, J : 7.70 Hz, 1 H), 7.43 (d, J : .28 Hz, 1 H), 3.97 — 4.09 (m, 2 H), 3.84 (ddd, J: .54, 8.78, 3.51 Hz, 1 H), 3.57 — 3.74 (m, 2 H), 3.00 (s, 6 H), 2.47 — 2.65 (m, 4 H), 2.18 - 2.41 (m, 1H), [M+H]+ 543. 1H NMR (400 Amine/alcohol in Compound Structure MHz) ppm; ESI— step x.

(CD3OD)I 8.60 (s, 1 H), 8.59 (s, 1 H), 8.10 (d,J: 1.76 Hz, 1 H), 7.91 (dd, J : 7.91, 1.88 Hz, 1 H), 7.58 (s, 1 H), 7.46 (d, J: 8.30 Hz, 1 H), 7.43 (d, J : 5.23 Hz, 1 H), 4.44 (d, J: 13.80 Hz, 2 H), 3.57 (br s, 4 H), 3.47 — 3.54 (m, 4 H), 3.35 — 3.45 (m, 1 H), 2.95 — 3.04 (m, 5 H), 2.56 (s, 3 H), 2.16 (d, J: 10.79 Hz, 2 H), 1.62 — 1.78 (m, 2 H), [M+H]+ 612 (CD30D): 8.59 — 8.63 (m, 2 H), 7.96 (dd, J: 6.78, 2.26 Hz, 1 H), 7.73 (ddd, J : 8.60, 4.83, 2.13 Hz, 1 H), 7.55 (s, 1 H), 7.45 — 7.47 (m, 1 H), 7.33 — 7.36 (m, 1 H), 2.85 (s, 3 H), [M+H]+ 464.

(CDgOD): 8.59 — 8.62 (m, 2 H), 7.96 (dd, J: 6.90, 2.13 Hz, 1 H), 7.74 (ddd, J : 6.02 Hz, 1 H), 7.57 (s, 1 H), 7.46 (d, J: 5.38 Hz, 1 H), 7.34 (d, J: 2.01 Hz, 1 H), [M+H]+ 450. 1H NMR (400 Amine/alcohol in MHz) ppm; ESI— step x.

(CDgOD): 8.59 — 8.64 (m, 2 H), 8.14 (s, 1 H), 8.00 (d, J : 7.80 Hz, 1 H), 7.74 (d, J: 7.66 Hz, 1 H), 7.55 — 7.60 (m, 2 H), 7.44 (d, J: 5.10 Hz, 1 H), 3.37 (s, 1 H), 2.85 (s, 3 H), [M+H]+ 446.0.

(DMSO-dg): 11.39 (s, 1 H), 10.97 (s, 1 H), 8.70 (d, J: .27 Hz, 1 H), 8.51 — 8.54 (m, 1 H), 8.34 (dd, J: 6.90, 2.38 Hz, 1 H), 8.10 (ddd, J : 8.72, 4.96, 2.38 Hz, 1 H), 7.75 (s, 1 H), 7.48 — 7.59 (m, 2 H), 2.72 (d, J : 4.52 Hz, 3 H), [M+H]+ 464.0.

(CDC13) 12.48- 12.73 (m, 1H), 8.70 (s, 1H), 8.47 (d, J: 1.76 Hz, 1H), 8.04 (d, J : 1.51 Hz, 1H), 7.93 (d, J: 8.53 Hz, 1H), 7.86 (dd, J : 1.76, 8.03 Hz, 1H), 7.73 (br d, J : 6.78 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J : 8.03 Hz, 1H), 4.43 (s, 2H), 3.66- 3.74 (m, 2H), 3.66-3.74 (m, 2H), 3.60-3.68 (m, 4H), 3.58-3.72 (m, 6H), 1H NMR (400 MHz) ppm; ESI— 3.36-3.44 (m, 3H), 3.11-3.26 (m, 3H), 2.82-2.98 (m, 2H), 2.50-2.60 (m, 3H), 2.04—2.20 (m, 4H), [M+H]+ 600.2.

(CDC13) 8.57 (dd, J : 1.26, 8.03 Hz, 1H), 8.29 (s, 1H), 7.90 (d, J : 2.01 Hz, 1H), 7.69 (dd, J : 2.01, 7.78 Hz, 1H), 7.52 (br s, 1H), 7.25—7.35 (m, 2H), 7.20—7.23 (m, 1H), 3.84 (s, 3H), 3.52—3.59 (m, 2H), 3.43—3.49 (m, 2H), 3.40 (s, 3H), 3.01 (s, 3H), 2.48 (s, 3H), [M+H]+ 547.3.

(CDC13) 9.60 (br s, 1H), 8.78 (s, 1H), 8.22 (d, J: 2.01 Hz, 1H), 8.14 (dd, J : 2.01, 8.53 Hz, 1H), 7.95 (d, J : 2.01 Hz, 1H), 7.84 (d, J : 8.67 Hz, 1H), 7.79 (d, J : 7.64 Hz, 1H), 7.53-7.63 (m, 1H), 7.37 (d, J: 8.03 Hz, 1H), 3.59-3.64 (m, 2H), 3.46-3.54 (m, 2H), 3.43-3.46 (m, 3H), 3.05 (s, 3H), 2.54 (s, 3H), [M+H]+ 542.3.

Method B Example 2: 3-((2-(cyclopropanecarboxamid0)thiazolyl)ethynyl)—4-methyl-N-(4- (trillu0r0methyl)pyridinyl)benzamide (I-49) I «“40H N N _N HBr \ o o | S / H2N / N HN HN _ I: 1c F3 H / :Cl fN H — TMS / s):N/ r —>Et3NDCM E) —> TBAF H ’ r Ed(PPhs)4:CUI II s)4.CU' N N\ (l_pr)2NEt, DMF (i_pr)2NEt, DMF I 0 MS / 50 0 100°C 1a. 49b 49c |-49 F3 Step 1. N-(S-bromothiazolyl)cyclopropanecarboxamide (49b) To a on of 2-aminobromothiazole monohydrobromide (1a') (5.2 g, 20.0 mmol, 1.0 eq) in 40 ml of DCM was added 4.2 ml of Et3N. To the resulting mixture was slowly added a solution of cyclopropanecarbonyl chloride (1.83 ml, 2.09 g, 20.0 mmol, 1.0 eq) in 10 ml of DCM at -78 CC. After stirring at rt for 30 min, an additional 0.5 ml of cyclopropanecarbonyl de in 5 ml of DCM was added at -78 oC and the mixture was then stirred at rt for an additional 1h. Sat. aq. N212CO3 (15 ml) was added with stirring at rt over 15 min. The organic layers were separated and the s layer was extracted with DCM (1 x 20 ml). The combined organics were washed with brine, dried over Na2S04, ﬁltered, and concentrated by rotary evaporation to give a white solid (49b) which was washed with EtOAc, dried under vacuum and then used directly in the next step without puriﬁcation (3 g, 60%).

Step 2. N-(S-((trimethylsilyl)ethynyl)thiazol-Z-yl)cyclopropanecarboxamide (49c) A sealed tube was charged with N—(5-bromothiazol yl)cyclopropanecarboxamide (49b) (3.0 g, 12.1 mmol, 1.0 eq), Pd(PPh3)4 (583 mg), CuI (191 mg), trimethylsilylacetylene (2.25 ml, 1.57 g, 15.9 mmol, 1.3 eq), DIPEA (2.57 ml) and DMF (25 mL). After degassing with N2, the reaction mixture was stirred at 50 oC overnight. The solvents were removed by rotary evaporation and sat. aq. Na2CO3 and DCM were added. The combined organic layers from extraction were concentrated and the crude mixture was puriﬁed by ﬂash column chromatography on silica gel (eluting with EtOAc/Heptane 1:5) to provide intermediate 49c as a yellow solid.

Step 3. 3-((2-(cyclopropanecarboxamid0)thiazol-S-yl)ethynyl)—4-methyl-N-(4- u0r0methyl)pyridinyl)benzamide (I-49) A mixture of intermediate 1c (1.727 g, 4.25 mmol, 1.0 eq), intermediate 49c (1.238 g, 4.68 mmol, 1.14 eq), Pd(PPh3)4 (489 mg), CuI (126 mg), DIPEA (6.3 ml) and TBAF (1.0 M in THF, 5.2 ml) in 10 ml of DMF was degassed with N2 and then heated with stirring at 100 OC overnight. After removing volatiles by rotary ation, sat. aq. Na2CO3 and DCM were added. The combined organic layers from extraction were concentrated and the crude mixture was puriﬁed by ﬂash column chromatography on silica gel (eluting with EtOAc/Heptane 1:5) to provide a yellow solid, which was washed with EtOAc, ﬁltered, and further washed with MeOH to give the title compound I-49 as a light yellow solid.

] The nds in Table 2 were synthesized according to Method B above using the corresponding acyl chloride in step 1 and the ponding iodopyridinyl- or iodophenylbenzamides.

TABLE 2: Acyl 1H NMR (400 MHz) (5 chloride in ste n 1 (DMSO-dg): 12.74 (br s, 1 H), 11.31 (s, 1 H), 8.69 (d, J : 5.15 Hz, 1 H), 8.53 (s, 1 H), 8.21 (d, J: 1.76 Hz, 1 H), 7.97 (dd, J : 6.16 Hz, 1 H), 7.84 (s, 1 H), 7.42 — 7.62 (m, 2 H), 1.93 — 2.04 (m, 1 H), 0.86 — 1.04 (m, 4 H). ) 8.15 (d, J: 2.13 Hz, 1H), 8.08 (d, J: 2.01 Hz, 1H), 7.95 (dd, J : 2.07, 8.60 Hz, 1H), 7.87 (dd, J : 1.95, 7.97 Hz, 1H), 7.77 (d, J : 8.41 Hz, 1H), 7.66 (s, 1H), 7.45 (d, J : 8.16 Hz, 1H), 3.69 (s, 2H), 2.69 — 2.51 (br, s, 11H), 2.39 (s, 3H), 1.88- 1.95 (m, 1H), 0.86-1.11 (m, (DMSO-dg) 12.45 (s, 1 H), 11.30 (s, 1 H), 8.70 (br s, 1 H), 8.54 (s, 1 H), 8.22 (d, J : 1.63 Hz, 1 H), 7.95 — 8.03 (m 1 H), 7.84 (s, 1 H), 7.47 — 7.62 (m, 2 H), 2.19 (s, 3 H).

(CDC13): 9.28 (br s, 1 H), 8.79 (br s, 1 H), 8.61 (s, 1 H), 8.41 (br s, 1 H), 7.96 (s, 1 H), 7.74 (d, J : 7.98 Hz, 1 H), 7.66 (br s, 1 H), 7.32 (d, J : 8.03 Hz, 1 H), 7.22 (d, J : .34, 1 H), 2.48 (s, 3 H), 1.28 (s, 9 H).

Method C Example 3: N-(3-((2-(3-(2-(dimethylamino)ethyl)—3-methylureid0)thiazol-S-yl)ethynyl)— 4-methylphenyl)—4-(trifluoromethyl)picolinamide (I-61) O BocgN Boc HO IN\ | S>=N Boc-N' | / aO EN/ U 61b 1e F3 “ —> N IN‘ —> \\ NH2 / HATU, Et3N, DMF pd(pph3)4, Cul 0 61a (I'_pr)2NEt DMF' N 60 o0 ﬂ \ H2N o )=N H? l l CDI/DCM \o/\/N\ / o H O 50 C / N N\ H | 61e CF3 / Step I. N-(3-i0d0methylphenyl)(trifluoromethyl)picolinamide (61c) To a solution of 4-(triﬂuoromethyl)pyridinecarboxylic acid (61b, 11 g) and 3- iodomethyl-aniline (6121, 13.4 g) in DMF (70 mL) was added HATU (26.3 g) and triethylamine (29.6 mL). The resulting mixture was stirred at room temperature overnight and then diluted with water (400 mL). After stirring for 15 min., the solid was collected by ﬁltration and washed with water. The solid product was dried in vacuo to give a white solid (61c, 22 g, 94%).

Step 2. tert—butyl N-tert-butoxycarbonyl-N-[5-[2-[2-methyl[[4- (triflu0r0methyl)pyridine—2-carb0nyl]amin0]phenyl] ethynyl]thiazolyl]carbamate (61d) A mixture of bis-tert-butyl (5-bromothiazolyl)carbamate 1e (6.2 g), N—(3-iodo- 4-methylphenyl)(triﬂuoromethyl)picolinamide 61c (7.4 g), tetrakis(triphenylphosphine) palladium(0) (1.3 g), and CuI (0.2 g) in DMF (100 mL) was degassed and DIPEA (4.7 mL) was then added. After stirring at 60 0C for 2 h, the mixture was concentrated by rotary ation. The resulting e was dissolved in DCM (200 mL) and washed with water (100 mL). The organic layer was dried, ﬁltered, and concentrated in vacuo. The crude t was puriﬁed by ﬂash column chromatography on silica gel (eluting with 10% EtOAc in heptane) to give a solid (61d, 7.5 g, 68%).

Step 3. N-(3-((2-amin0thiaz01yl)ethynyl)—4-methylphenyl)—4-(triflu0r0methyl) picolinamide (61e) To a solution of tert-butyl N—tert-butoxycarbonyl-N-[5-[2-[2-methyl[[4- (triﬂuoromethyl)pyridinecarbonyl]amino]phenyl]ethynyl]thiazolyl]carbamate 61d (12 g) in DCM (30 ml) was added TFA (30 ml) at room temperature and the resulting mixture was stirred for 1 h. Volatile components were removed by rotary evaporation and the resulting residue was dissolved in DCM (300 mL) and washed with water (100 mL). The organic layer was dried, ﬁltered, and concentrated in vacuo. The crude product was puriﬁed by ﬂash column chromatography on silica gel (eluting with 5% MeOH in romethane) to give ediate 61e as a light brown solid (7.3 g, 91%). 1H NMR (400 MHz, CD3OD) 5 8.97-8.99 (d, J : 5.15 Hz, 1 H), 8.45 (s, 1 H), 7.92 : 8.28, — 7.96 (m, 2 H), 7.65-7.68 (dd, J 2.38 Hz, 1 H), 7.28-7.30 (d, J : 8.41 Hz, 1 H), 7.22 (s, 1 H), 2.45 (s, 3 H). EI—MS: [M+H]+ 403.1.

Steps 4 and 5. N-(3-((2-(3-(2-(dimethylamin0)ethyl)methylureid0)thiaz01 yl)ethynyl)—4-methylphenyl)—4-(trifluoromethyl)picolinamide (I-61) ] To a solution of intermediate 61e (0.07 g,) in DCM (20 ml) was added CDI (0.07 g). After the reaction mixture was stirred at 50 oC overnight, N,N,N’- trimethylethylenediamine (0.35 g) was added and then stirred for additional 1 h. After ﬁltration and tration of the ﬁltrates, the crude product was d by ﬂash column chromatography on silica gel (eluting with 5% MeOH in dichloromethane) to give the title compound I-61 (0.049 g, .

The compounds in Table 3 were synthesized according to Method C above using the corresponding N-(iodophenyl)(triﬂuoromethyl)picolinamide or N—(3-iodo methylphenyl)(triﬁuoromethoxy)benzamide in step 2, and the corresponding amine in step TABLE 3: 1H NMR (400 MHz): 5 (ppm) (CDClg): 9.80 (s, 1 H), 8.74 (d, J : .02 Hz, 1 H), 8.34 — 8.59 (m, 1 H), 8.08 (s, 1 H), 7.77 (d, J : 2.26 Hz, 1 H), 7.62 — 7.67 (m, 2 H), 7.46 (s, 1 H), 7.18 (d, J : 8.00 Hz, 2 H), 4.12 WO 12136 Cmpd 1H NMR (400 MHz): 5 (ppm) Compound Structure (br s, 1 H), 2.81 — 2.90 (m, 5 H), 2.39 (s, 3 H), 2.18 (s, 3 H), 1.92 — 2.09 (m, 2 H), 1.75 (m, 2 H), 1.59 — 1.67 (m, 2 (CDC13) 9.89 (s, 1 H), 9.54 (br s, 1 H), 8.83 (d, J : 5.02 Hz, 1 H), 8.56 (s, 1 H), 7.84 (d, J : 2.38 Hz, 1 H), 7.72 — 7.78 (m, 2 H), 7.56 (s, 1 H), 7.26 — 7.30 (m, 1 H), 3.44 — 3.66 (m, 7 H), 3.08 (s, 3 H) 2.49 (s, 3 H).

(CD30D) 8.98 (d, J : 5.02 Hz, 1 H), 8.46 (s, 1 H), 7.98 (s, 1 H), 7.93 (d, J : 5.05 Hz, 1 H), 7.70 (dd, J: 8.28, 2.26 Hz, 1 H), 7.57 (s, 1 H), 7.31 (d, J : 8.41 Hz, 1 H), 3.49 — 3.57 (m, 2 H), 3.05 (s, 3 H), 2.59 — 2.84 (m, 10 H), 2.48 (s, 3 H), 2.36 (s, 3 H).

(DMSO-dg): 11.06 (br. s., 1H), 10.38 (s, 1H), 8.03 (dt, J : 7.8, 1.2 Hz, 1H), 7.93 (d, J : 2.3 Hz, 2H), .75 (m, 4H), 7.33 (s, 1H), 2.98 (s, 6H), 2.41 (s, 3H).

(DMSO-dg): 10.85 (s, 2 H) 9.04—9.05 (d, J : 5.14 Hz, 1 H) 8.35-8.36 (m, 1 H) 8.09-8.11 (d, J : 5.56 Hz, 2 H) 7.80-7.83 (dd, J : 8.28, 2.26 Hz, 1 H) 7.67 (s, 1 H) 7.32—7.34 (d, J: 8.41 Hz, 1 H) 2.72 (d, J : 4.64 Hz, 3 H) 2.41 (s, 3 H).

(CDgOD): 8.98 (d, J : 5.02 Hz, 1H), 8.39-8.51 (m, 1H), 7.97 (s, 1H), 7.93 (d, J : 5.27 Hz, 1H), 7.69 (dd, J : 2.26, 8.28 Hz, 1H), 7.54 (s, 1H), 7.30 (d, J : 8.28 Hz, 1H), 3.60 (t, 2H), 3.06 (s, 3H), 2.69 (t, J : 5.33 Hz, 2H), 2.36-2.53 (m, 9H).

(CD30D): 8.98 (d, J : 5.02 Hz, 1H), 8.44-8.47 (m, 1H), 7.96 (s, 1H), 7.92 (d, J : 5.07 Hz, 1H), 7.69 (dd, J : 2.32, 8.22 Hz, 1H), 7.54 (s, 1H), 7.30 (d, J : 8.41 Hz, 1H), 3.57 (t, 2H), 3.05 (s, 3H), 2.72-2.85 (m, 6H), 2.47 (s, 3H), 1.17 (t, J : 7.22 Hz, 6H).

(DMSO-dg): 10.96 (br d, J : 1.25 Hz, 1H), 10.85 (s, 1H), 9.05 (d, J: 5.02 Hz, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 8.10 (d, J: 5.41 Hz, 2H), 7.82 (dd, J 1H NMR (400 MHz): 5 (ppm) nd Structure : 2.26, 8.28 Hz, 1H), 7.73 (s, 1H), 7.33 (d, J : 8.53 Hz, 1H), 3.52-3.62 (m, 2H), 3.50 (t, 2H), 3.28 (t, 1H), 3.02 (s, 3H), 2.41 (s, 3H).

(DMSO-dg): 10.99 (br s, 1H), 10.93 (s, 1H), 9.06 (d, J : 5.02 Hz, 1H), 8.36-8.38 (m, 1H), 8.10-8.16 (m, 2H), 7.93 (ddd, J: 1.00, 2.13, 8.28 Hz, 1H), 7.74 (s, 1H), 7.44 (t, J : 7.97 Hz, 1H), 7.31 (td, J: 1.19, 7.91 Hz, 1H), 3.42-3.63 (m, 4H), 3.29 (s,3H), 3.01 (s, 3H).

(CDgOD): 8.98 (d, J : 5.02 Hz, 1H), 8.46 (s, 1H), 8.04 (dd, J : 2.70, 6.21 Hz, 1H), 7.93 (d, J : 5.06 Hz, 1H), 7.83 (ddd, J : 2.76, 4.52, 9.03 Hz, 1H), 7.60 (s, 1H), 7.22 (t, J : 9.03 Hz, 1H), 3.59-3.67 (m, 4H), 3.43 (s, 3H), 3.10 (s, 3H).

Biochemical Assays Example 4: c-Kit Assay Generation of Ba/F3 KIT mutant engineered cell lines KIT cDNAs were synthesized by GenScript and cloned into the pLVX-IRES-Puro vector (Clontech). Viral particles were produced by transfecting pLVX-IRES-puro vectors containing KIT mutant genes into HEK293 cells (Invitrogen) using the Trans-Lentiviral ORF Packaging Kit (Thermo Scientiﬁc). 48 hours post-transfection, virus-containing supernatants were harvested and incubated for another 48-72 hours with parental Ba/F3 cells (DSMZ) in the presence of 10 ng/mL lL-3 (R&D Systems). uced Ba/F3 cells were then ed by IL-3 withdrawal and puromycin (0.5-1 ug/mL, ogen).

Viability assays Cell lines (e.g., EXl lDEL, EXl 1DEL/D816H, EXl 1DEL/T67OI, and L/V654A) were plated into 384 well plates using RPMI 1640 supplemented with % PBS at densities that produced linear growth and incubated at 37 0C in 5% (v/v) C02.

Cells were d with eight concentrations of compound over a 4-fold dilution (10 11M to 0.61 nM) and viability was assessed using Cell Titer-Glo assay (Promega) after 72 hours.

Data were plotted as percent viability relative to vehicle-treated cells. Dose-responses curves were generated and used to ate IC50 values.

Table 4: c-Kit activity of compounds of the invention in the c-Kit assay. ++++ indicates an IC50 of less than about 10 nM, +++ indicates an IC50 between about 10 nM and about 50 nM, ++ indicates an IC50 between about 50 nM and about 100 nM, and + indicates an IC50 greater than about 100 nM and less than about 10 uM.

TABLE 4: cKit Assay.

Hag BAF3 FL KIT BAF3 FL KIT BAF3 FL KIT 9‘0 BAF3 FL KIT EXllDEL/D816H EXllDEL/T6701 EXllDEL/V654A EXl1DEL (nM) l—t ++++ ’T‘.5———— ’T‘u: ’T‘\l ’7‘co ’7‘so ’T‘ p—x C lI—l p—x p—x ’T‘ p—x N ’T‘ p—x DJ ’T‘ p—x .k ’T‘ p—x U] ’T‘ p—x OK———— 1-17———— ’T‘ p—x 0Q ’T‘ p—x \D .~.~ NN HO ’T‘NN ’T‘N03 ’T‘N .5 ’7‘N u: ’7‘Na ’7‘N \l ’7‘N co ’7‘N so ’T‘m c: T103 p—x ’T‘03N ’T‘mm BAF3 FL KIT BAF3 FL KIT BAF3 FL KIT BAF3 FL KIT EXllDEL/D816H EXllDEL/T6701 EXllDEL/V654A EXl1DEL (nM) ’T‘93 IR ’7‘m u: ’T‘ma ’T‘m \1 ’T‘(a co ’7‘w v:———— ’7‘ .Bc T1 .5 p—x ’T‘ .5N ’7‘ IR(A ’T‘ IR .5 ’T‘T‘ .54; chm———— 1-47———— ’7‘ .B so ’7‘ .B so ’7‘ u:c FI—l U] p—x ’7‘ u:N ’T‘ u:m ’7‘ an IR ’7‘ u: u: ’7‘ an ax ’7‘ u: \l ’7‘ u: so ’7‘ u: so ’7‘ac FI—l OK p—x ’7‘aN Eguivalents Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the speciﬁc embodiments bed cally herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of a (I): or a pharmaceutically acceptable salt thereof, wherein: L is –C(O)NR5- or –NR5C(O)-; A is (C6-C10) aryl optionally substituted with one or more R4; R1 is H, (C1-C6) alkyl, -(CH2)qC(O)OH, or –C(O)N(R7)2; R2 is ) alkyl, -C(O)R8, or –C(O)NR9R10; each R3 is ndently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or OH; each R4 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, -OH, CN, -(C(R6)2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S , or -(C(R6)2)p-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1 to 3 heteroatoms selected from N, O, and S, and wherein the heterocycloalkyl or aryl is optionally substituted with one or more substituents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, and (C1-C6) dialkylamino; R5 is H, (C1-C6) alkyl, or ) haloalkyl; each R6 is independently H or (C1-C6) alkyl; each R7 is independently H or (C1-C6) alkyl; R8 is (C1-C6) alkyl, (C3-C7) cycloalkyl, (C2-C6) alkenyl, (C1-C3) alkoxy, ) haloalkyl, (C1-C6) haloalkoxy, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S; R9 is H, (C1-C6) alkyl, (C1-C6) kyl, (C3-C7) cycloalkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, or S; R10 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, ) lkyl, or 4 to 7-membered heterocycloalkyl comprising 1 to 3 atoms selected from N, O, or S, wherein the cycloalkyl or cycloalkyl is optionally substituted with one or more tuents each independently selected from (C1-C6) alkyl, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, and -OH, and wherein the (C1-C6) alkyl is optionally substituted with one or more R11 ; or R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatom selected from N, O, and S, optionally substituted with one or more substituent each independently selected from (C 1-C6) alkyl, (C1-C6) hydroxyalkyl, -(CH2)q-NH 2, -(CH2)q-(C 1-C6) alkylamino, -(CH 2)q-(C 1-C6) lamino, -C(O)(C1-C6) alkyl, -OH, and 4- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatom selected from N, O, and S, and optionally substituted with one or more (C1-C6) alkyl; R11 is (C1-C6) alkoxy, -OH, -NH2, (C1-C6) alkylamino, (C1-C6) dialkylamino, 5- or 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, or S, or 4- to 7- membered cycloalkyl sing 1 to 3 heteroatoms selected from N, O, or S, n the heterocycloalkyl is optionally substituted with one or more tuents each ndently selected from (C1-C6) alkyl and OH; and each p and q is independently 0, 1 or 2; each n is 0; provided that when A is phenyl and R1 is H, then R2 is not –C(O)CH3.

2. The compound of claim 1, wherein L is a –C(O)NR5-.

3. The compound of claim 1, wherein L is a –NR5C(O)-.

4. The compound of any one of claims 1 to 3, wherein n is 1 and R3 is methyl or F.

5. The compound of any one of claims 1 to 4, wherein A is phenyl substituted with one or more R4.

6. The compound of any one of claims 1 to 5, wherein R5 is H.

7. The compound of any one of claims 1 to 6, having one of the following ae (Ia) or (Ib): (Ia), or (Ib), or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1 to 7, having one of the following formulae (Ic) or (Id) : (Ic), or (Id), or a pharmaceutically acceptable salt tautomer thereof.

9. The compound of any one of claims 1 to 8, having one of the following formulae (Ie) or (If): (Ie), or (If), or a pharmaceutically acceptable salt tautomer thereof.

10. The compound of any one of claims 1 to 9, wherein one R4 is (C1-C6) kyl and the other R4 is (C1-C6) alkoxy, CN, or -(C(R6)2)p-heterocycloalkyl n the heterocycloalkyl comprises a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S.

11. The compound of any one of claims 1 to 10, wherein at least one R4 is CF3 and the other R4 is (C1-C6) alkoxy, CN, or )2)p-heterocycloalkyl wherein the heterocycloalkyl comprises a 4- to 7-membered ring and 1 to 3 heteroatoms selected from N, O, and S.

12. The compound of any one of claims 1 to 11, wherein at least one R4 is CF3 and the other R4 is –OCH3, CN, or -(CH2)-pyrrolyl.

13. The compound of any one of claims 1 to 12, wherein R1 is H and R2 is –C(O)NR9R10.

14. The compound of claim 13, wherein R9 is H and R10 is (C1-C6) alkyl.

15. The compound of claim 13, wherein R9 is H and R10 is (C1-C6) alkyl substituted with one R11.

16. The compound of claim 15, wherein R11 is (C1-C6) alkoxy.

17. The compound of claim 16, wherein the (C1-C6) alkoxy is –OCH3.

18. The compound of claim 13, wherein R9 is (C1-C6) alkyl and R10 is (C1-C6) alkyl.

19. The compound of claim 18, wherein R9 is (C1-C6) alkyl and R10 is (C1-C6) alkyl tuted with one R11.

20. The compound of claim 19, n R11 is (C1-C6) .

21. The compound of claim 20, wherein the (C1-C6) alkoxy is –OCH3.

22. The compound of claim 1, wherein the nd is selected from: 3-((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)methyl-N-(4-(pyrrolidin- 1-ylmethyl)(trifluoromethyl)phenyl)benzamide (I-46); N-(2-methoxy(trifluoromethyl)phenyl)((2-(3-(2-methoxyethyl)methylureido)thiazol- 5-yl)ethynyl)methylbenzamide ; N-(4-cyano(trifluoromethyl)phenyl)((2-(3-(2-methoxyethyl)methylureido)thiazol yl)ethynyl)methylbenzamide (I-48); 3-((2-(cyclopropanecarboxamido)thiazolyl)ethynyl)methyl-N-(4-((4-methylpiperazin yl)methyl)(trifluoromethyl)phenyl)benzamide (I-50); and N-(3-((2-(3,3-dimethylureido)thiazolyl)ethynyl)methylphenyl) (trifluoromethoxy)benzamide (I-56); N-(3-((2-(3-(2-methoxyethyl)methylureido)thiazolyl)ethynyl)phenyl) (trifluoromethyl)picolinamide (I-61 ); or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent, excipient or carrier.

24. Use of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition of claim 23, in the manufacture of a medicament for treating a c- diated disease or disorder.

25. The use of claim 24, wherein the cKit-mediated disease or disorder is selected from cell erative disorder, a fibrotic er, and a lic disorder.

26. The use of claim 25, wherein said cell erative disorder is cancer.

27. The use of claim 26, wherein said cancer is selected from the group consisting of leukemia, mast cell tumor, small cell lung cancer, testicular cancer, cancer of the gastrointestinal tract, cancer of the central nervous system, cancer of the female genital tract, sarcoma of neuroectodermal origin, and Schwann cell neoplasia associated with ibromatosis.

28. The use of claim 27, wherein said cancer is selected from the group ting of small cell lung carcinoma, acute d leukemia (AML), neuroblastoma, malignant melanomas, colorectal , systemic mastocytosis (SM), and gastrointestinal stromal tumors (GISTs).

29. The use of claim 24, wherein said cKit-mediated disease or disorder is multiple sclerosis, asthma, an allergic reaction, inflammatory arthritis, or mastocytosis.

30. Use of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition of claim 23, in the manufacture of a medicament for modulating c-Kit.

31. Use of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition of claim 23, in the cture of a medicament for inhibiting c-

32. Use of a compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or the composition of claim 23, in the manufacture of a medicament for treating or preventing a disease in which c-Kit plays a role.