HETEROCYCLIC COMPOUNDS AND USES THEREOF

• US 20120122838A1
• Filed: 11/10/2011
• Published: 05/17/2012
• Est. Priority Date: 11/10/2010
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Ren, Pingda, Liu, Yi, Li, Liansheng, Chan, Katrina, Wilson, Troy Edward, Castro, Alfredo C., Evans, Catherine A., Snyder, Daniel A.
• Granted Patent: US 8,901,133 B2
• Time in Patent Office: Days
• US Class Current: 514/210.18
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein n is 1, 2, or 3.

3. The compound of claim 1, wherein each L is —

O—

, —

C(═

O)—

, —

S(═

O)—

, —

S(═

O)₂—

, —

S—

, alkylene, or a bond.

4. The compound of claim 1, wherein R^1′

is alkyl, hydroxy, aryl, heteroaryl, aralkyl, —

(C═

O)—

NR^a1R^a2, or NR^a1R^a2.

5. The compound of claim 4, wherein R^a1 is hydrogen or alkyl.

6. The compound of claim 4, wherein R^a2 is alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, acyl, or heterocycloalkylalkyl.

7. The compound of claim 4, wherein R^a1 and R^a2 are taken together with the nitrogen to which they are attached to form a cyclic moiety.

8. The compound of claim 1, wherein W⁵ is N or W⁵ is CR⁴ and R⁴ is hydrogen.

9. The compound of claim 1, wherein X is absent.

10. The compound of claim 1, wherein X is —

(CH(R¹⁰))_z— and

z is 1 or 2.

11. The compound of claim 1, wherein Y is absent, —

O—

, —

NH(R⁹)—

, or —

S(═

O)₂—

.

12. The compound of claim 1, wherein Cy is phenyl substituted with 0-4 occurrences of R³.

13. The compound of claim 1, wherein Cy is phenyl substituted with 1 occurrence of R³.

14. The compound of claim 1, wherein R³ is halo, alkyl, haloalkyl, acyl, or heteroaryl.

15. The compound of claim 1, wherein W_d is aryl or heteroaryl.

16. The compound of claim 1, wherein W_d is:

17. The compound of claim 16, wherein R¹⁰ is hydrogen.

18. The compound of claim 16, wherein R¹² is hydrogen, halo, haloalkyl, cyano, amino, or amido.

19. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (II):

20. The compound of claim 19, wherein R^1′

is hydrogen, amino, alkoxy, alkyl, heterocycloalkyl, aryl, or NR′

R″

, wherein R′ and

R″

are taken together with nitrogen to form a cyclic moiety.

21. The compound of claim 19, wherein R is amino, alkoxy, alkyl, or NR′

R″

, wherein R′ and

R″

are taken together with nitrogen to form a cyclic moiety.

22. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (IIIa):

23. The compound of claim 22, wherein R^a1 and R^a2 are taken together with nitrogen to form a cyclic moiety.

24. The compound of claim 23, wherein the cyclic moiety is 5- or 6-membered.

25. The compound of claim 22, wherein n is 1 and L is alkyl.

26. The compound of claim 25, wherein L is methylene or ethylene.

27. The compound of claim 22, wherein L is alkyl substituted by aryl, heteroaryl or halo.

28. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (IV):

29. The compound of claim 1, wherein:

W¹ is N, W² is CR⁶, W³ is CR⁷, W⁴ is CR⁸;

W¹ is CR¹⁴, W² is N, W³ is CR⁷, W⁴ is CR⁸;

W¹ is CR¹⁴, W² is CR⁶, W³ is N, W⁴ is CR⁸;

W¹ is N, W² is CR⁶, W³ is N, W⁴ is CR⁸;

W¹ is N, W² is N, W³ is CR⁷, W⁴ is CR⁸;

W¹ is N, W² is CR⁶, W³ is CR⁷, W⁴ is N;

W¹ is CR¹⁴, W² is N, W³ is N, W⁴ is CR⁸;

W¹ is CR¹⁴, W² is N, W³ is CR⁷, W⁴ is N;

W¹ is CR¹⁴, W² is CR⁶, W³ is N, W⁴ is N;

or

W¹ is CR¹⁴, W² is CR⁶, W³ is CR⁷, W⁴ is CR⁸.

30. The compound of claim 29, wherein W¹ is CR¹⁴, W² is CR⁶, W³ is CR⁷, and W⁴ is CR⁸.

31. The compound of claim 1, wherein R⁸ is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, sulfonamido, thio, sulfoxide, sulfone, halo, cyano, hydroxy, or NR′

R″

, wherein R′ and

R″

are taken together with nitrogen to form a cyclic moiety.

32. The compound of claim 1, wherein R⁸ is hydrogen or alkyl.

33. The compound of claim 32, wherein R⁸ is alkyl substituted with one or more fluoro.

34. The compound of claim 1, wherein X is —

CH₂—

, —

CH(CH₃)—

, —

CH(C₆H₅)—

, or —

CH(CH₂CH₃)—

.

35. The compound of claim 34, wherein the CH carbon of —

CH(CH₃)—

or —

CH(CH₂CH₃)—

has a predominately (S) stereochemical configuration.

36. The compound of claim 1, wherein Y is absent, —

O—

, —

N(R⁹)—

, N(R⁹)C(R¹⁰)₂—

, or —

S(═

O)₂—

.

37. The compound of claim 36, wherein R⁹ and R¹⁰ are independently hydrogen, methyl or ethyl.

38. The compound of claim 1, wherein X is —

CH(R¹⁰))_z—

, z is 1, Y is —

N(R⁹)—

, and R⁹ is hydrogen.

39. The compound of claim 1, wherein Y is —

N(CH₂CH₃)CH₂—

or —

N(CH₃)CH₂—

.

40. The compound of claim 1, wherein X—

Y is —

CH₂—

N(CH₃)—

, or —

CH₂—

N(CH₂CH₃)—

.

41. The compound of claim 1, wherein W_d is a monocyclic or polycyclic heteroaryl which is unsubstituted or substituted with one or more substituents selected from alkyl, alkynyl, alkenyl, halo, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cyano, amino, carboxylic acid, hydroxy, alkoxy, acyloxy, alkoxycarbonyl, and amido.

42. The compound of claim 41, wherein W_d is a bicyclic heteroaryl.

43. The compound of claim 42, wherein W_d is a pyrazolopyrimidine, thiazolo[5,4-d]pyrimidine, pyrido[3,2-d]pyrimidine, pyrazolo[1,5-a]pyrimidine, quinazoline, imidazo[1,2-b]pyridazine, or a purine.

44. The compound of claim 43, wherein W_d is purine, and X—

Y is —

(CH(R¹⁰))N(R⁹)—

.

45. The compound of claim 44, wherein R⁹ is hydrogen.

46. The compound of claim 43, wherein W_d is:

47. The compound of claim 46, wherein W_d is of Formula XIII:

48. The compound of claim 46, wherein W_d is of Formula XIV:

49. The compound of claim 46, wherein R¹¹ is amino.

50. The compound of claim 46, wherein R¹² is a monocyclic heteroaryl, a bicyclic heteroaryl, or a heterocycloalkyl.

51. The compound of claim 46, wherein R¹² is hydrogen.

52. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (V):

53. The compound of claim 52, or its pharmaceutically acceptable forms thereof, wherein:

R¹ is -(L)_n-R^1′

;

each L is —

O—

, —

C(═

O)—

, —

S(═

O)—

, —

S(═

O)₂—

, —

S—

, or alkylene;

R^1′

is alkyl, hydroxy, aryl, heteroaryl, aralkyl, —

(C═

O)—

NR^a1R^a2, or NR^a1R^a2;

W_d is;

54. The compound of claim 53, wherein L is —

O—

or alkylene; and

n is 0, 1, or 2.

55. A pharmaceutical composition comprising a compound according to claim 1, and one or more pharmaceutically acceptable excipients.

56. A method of inhibiting a phosphatidyl inositol-3 kinase (PI3 kinase), comprising:

contacting the PI3 kinase with an effective amount of a compound according to claim 1, or a pharmaceutical composition thereof.

57. The method of claim 56, wherein said step of contacting comprises contacting a cell that expresses said PI3 kinase.

58. The method of claim 56, wherein the PI3 kinase is PI3 kinase delta.

59. The method of claim 56, wherein the PI3 kinase is PI3 kinase gamma

60. The method of claim 57, further comprising contacting the cell with an effective amount of a second therapeutic agent.

61. A method of treating a PI3K mediated disorder in a subject, the method comprising administering a therapeutically effective amount of a compound according to claim 1, or a pharmaceutical composition thereof.

62. The method of claim 61, wherein the disorder is cancer, an inflammatory disease or an auto-immune disease.