Novel heterocyclic compounds and uses therof

• US 20100003246A1
• Filed: 03/19/2009
• Published: 01/07/2010
• Est. Priority Date: 03/21/2008
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Chen, Zheng, Machajewski, Timothy, Antonios-McCrea, William R., Xu, Yongjin, Shafer, Cynthia, McKenna, Maureen, Hunag, Zilin, Renhowe, Paul A., Sendzik, Martin, Jin, Jeff, Poon, Daniel, Zhang, Qiong, Smith, Aaron
• Granted Patent: US 8,129,394 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

New substituted heterocyclic compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.

Claims

1. A compound of Formula I, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein X or Y, whichever is present, is NR⁴.

3. The compound of claim 1 or 2, wherein R⁴ is hydrogen or an optionally substituted C1-C6 alkyl.

4. The compound of claim 2, wherein NR⁴ is NH or NMe.

5. The compound of claim 1, wherein X or Y, whichever is present, is O.

6. The compound of claim 1, wherein X or Y, whichever is present, is S.

7. The compound of any one of claims 1-6, wherein R¹ is optionally substituted pyridyl or pyrazinyl.

8. The compound of claim 7, wherein R¹ is optionally substituted 3-pyridyl.

9. The compound of claim 7, wherein R¹ is optionally substituted 2-pyrazinyl.

10. The compound of any one of claims 1-9, wherein the optional substituents for R¹ are selected from the group consisting of halo, D, cyano, hydroxy, —

C(O)R′

, —

NR″

C(O)R′

, —

C(O)NR″

₂, —

OS(O)₂NR″

₂, optionally substituted alkyl, optionally substituted amino, and optionally substituted C1-C4 alkoxy including C1-C4-haloalkoxy, and wherein R′

is optionally substituted alkyl, and wherein each R″

is independently hydrogen or optionally substituted C1-C4 alkyl.

11. The compound of any one of claims 1-6, wherein R¹ is selected from

12. The compound of any one of claims 1-10, which is a compound of Formula II:

13. The compound of claim 12, wherein R⁶ is NH₂.

14. The compound of claim 12 or 13, wherein R⁷ is —

OMe or —

OCD₃.

15. The compound of any one of claims 12-14, wherein Z¹ is CH and R⁵ is H or D.

16. The compound of any one of claims 12-14, wherein Z¹ is N.

17. The compound of any one of claims 1-16, wherein R² is optionally substituted pyridinyl or optionally substituted pyrimidinyl.

18. The compound of claim 17, wherein R² is optionally substituted 4-pyridinyl.

19. The compound of claim 17, wherein R² is optionally substituted 4-pyrimidinyl.

20. The compound of any one of claims 1-16, wherein R² is selected from:

21. The compound of claim 17, which a compound of Formula III:

22. The compound of claim 21, wherein R¹⁰ is selected from the group consisting of hydrogen, optionally substituted alkyl, and optionally substituted amino.

23. The compound of claim 21, wherein R¹⁰ is —

NHR¹³, wherein R¹³ is selected from the group consisting of optionally substituted alkyl, optionally substituted heterocyclyl, —

C(O)R′

, optionally substituted cycloalkyl, optionally substituted amino, optionally substituted aryl, and optionally substituted heteroaryl.

24. The compound of any one of claims 21-23, wherein Z² is CH or CD.

25. The compound of any one of claims 21-23, wherein Z² is N.

26. The compound of any one of claims 21-25, wherein R¹¹ and R¹² are both H.

27. The compound of any one of claims 21-26, wherein R⁴ is H.

28. The compound of any one of claims 1-27, wherein R³ is optionally substituted phenyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

29. The compound of claim 28, wherein R³ is unsubstituted phenyl or phenyl substituted with one, two or three substituents.

30. The compound of claim 28, wherein the optional substituents on the optionally substituted phenyl represented by R³ are selected from the group consisting of halo, hydroxyl, cyano, formyl, optionally substituted pyridyl, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, —

C(O)OR′

, —

S(O)₂R′

, —

S(O)₂NR″

₂, and —

C(O)NR″

₂, and wherein R′

is optionally substituted alkyl and each R″

is independently hydrogen or optionally substituted C1-C4 alkyl.

31. The compound of claim 28, wherein R³ is substituted or unsubstituted C1-C6 alkyl.

32. The compound of claim 28, wherein R³ is optionally substituted C3-C6 cycloalkyl.

33. The compound of claim 28, wherein R³ is optionally substituted heterocyclyl.

34. The compound of claim 28, wherein R³ is selected from

35. The compound of any of claims 7-34, wherein X is present, and X is NMe.

36. The compound of any of claims 7-34, wherein Y is present, and Y is NMe.

37. The compound of any of claims 7-34, wherein X is present, and X is O.

38. The compound of any of claims 7-34, wherein Y is present, and Y is O.

39. The compound of any of claims 7-34, wherein X is present, and X is S.

40. The compound of any of claims 7-33, wherein Y is present, and Y is S.

46. The compound of claim 1, which is selected from the group consisting of the compounds in Table 1.

47. The compound of claim 1, which is selected from the group consisting of

N-(2-(4-(5-(6-amino-5-methoxypyridin-3-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl)pyrimidin-2-ylamino)ethyl)-2-methoxyacetamide;

N-(2-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)ethyl)-2-methoxyacetamide;

(S)—

N-(1-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(3-(trifluoromethoxy)phenyl)pyrimidin-2-amine;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine;

(S)—

N-(1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

(S)—

N-(1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide,

(S)—

N-(1-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

(S)—

N-(1-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

(S)—

N-(1-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

(S)—

N-(1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(4-chloro-3-(trifluoromethyl)phenyl)pyrimidin-2-amine;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1-methyl-1H-imidazol-5-yl)-N-isobutylpyrimidin-2-amine;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine;

(S)-methyl 1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

(S)—

N—

((S)-1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxypropanamide;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-ethyl-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine;

4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-tert-butyl-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-methyl-1H-imidazol-5-yl)-N-(2-methoxypyridin-4-yl)pyrimidin-2-amine;

(S)—

N-(1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-cyclopropyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

(S)-methyl 1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-(1-methylcyclopropyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-fluorophenyl)-1H-imidazol-5-yl)pyrimidin-2-amine;

(S)—

N-(1-(4-(2-tert-butyl-4-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide;

(S)-methyl 1-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate;

3-methoxy-5-(2-phenyl-4-(pyridin-4-yl)-1H-imidazol-5-yl)pyridin-2-amine;

5-(2-(4-fluorophenyl)-5-(pyridin-4-yl)-1H-imidazol-4-yl)-3-methoxypyridin-2-amine;

3-methoxy-5-(4-(pyridin-4-yl)-2-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)pyridin-2-amine;

5-(2-(2,4-difluorophenyl)-4-(pyridin-4-yl)-1H-imidazol-5-yl)-3-methoxypyridin-2-amine;

3-methoxy-5-(2-phenyl-5-(pyridin-4-yl)oxazol-4-yl)pyridin-2-amine;

(S)—

N-(1-(4-(4-(6-amino-5-methoxypyridin-3-yl)-2-(4-fluorophenyl)oxazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide; and

(S)—

N-(1-(4-(4-(5-amino-6-methoxypyrazin-2-yl)-2-(4-fluorophenyl)oxazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide.

48. A pharmaceutical composition comprising a compound of any one of claims 1-47, admixed with at least one pharmaceutically acceptable excipient.

49. The pharmaceutical composition of claim 48, wherein the excipient is selected from the group consisting of corn starch, potato starch, tapioca starch, starch paste, pre-gelatinized starch, sugars, gelatin, natural gums, synthetic gums, sodium alginate, alginic acid, tragacanth, guar gum, cellulose, ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium aluminum silicate, polyvinyl pyrrolidone, talc, calcium carbonate, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, agar-agar, sodium carbonate, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, clays, sodium stearate, calcium stearate, magnesium stearate, stearic acid, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, sodium lauryl sulfate, hydrogenated vegetable oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, zinc stearate, sodium oleate, ethyl oleate, ethyl laureate, silica, and combinations thereof.

50. The pharmaceutical composition of claim 48, further comprising an additional therapeutic agent.

51. The pharmaceutical composition of claim 48, wherein the additional therapeutic agent is selected from an anticancer compound, an analgesic, an antiemetic, an antidepressant, and an anti-inflammatory agent.

52. A compound according to any one of claims 1-47 for treatment of cancer.

53. The compound according to claim 52, wherein the cancer to be treated is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, and adenomas.

54. A method to treat cancer, comprising administering to a subject in need of such treatment an effective amount of a compound of any of claims 1-47 or a pharmaceutical composition of any one of claims 48-51.

55. The method of claim 54, wherein the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, melanomas, and adenomas.

56. The method of claim 54 or 55, further comprising administering to the subject an additional therapeutic agent.

57. The method of claim 56, wherein the additional therapeutic agent comprises an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent.

58. The method of claim 56, wherein the additional therapeutic agent is a different Raf kinase inhibitor or an inhibitor of MEK, mTOR, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK.

59. The method of claim 56, wherein the additional therapeutic agent is administered to the subject concurrently with the compound.

60. The method of claim 57, wherein the anticancer drug is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, oxaliplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab and trastuzumab.

61. A method to treat a condition mediated by Raf kinase, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-47, or a pharmaceutical composition according to any one of claims 48-51.

62. The method of claim 61 wherein the Raf kinase is a mutant b-Raf kinase.

63. The method of claim 62, wherein the mutant b-Raf kinase is b-Raf(V600E).

41. A compound of Formula IV:

42. The compound of claim 41, wherein X or Y, whichever is present, is NH or NMe.

43. The compound of claim 41 or claim 42, wherein R⁶ is NH₂.

44. The compound of any of claims 41-43, wherein R⁷ is —

OCH₃ or a deuterated version of —

OCH₃.

45. The compound of any of claims 41-44, wherein R¹⁵ is substituted alkyl or substituted aryl.