Azaindoles Useful as Inhibitors of Janus Kinases

• US 20100311743A1
• Filed: 05/07/2010
• Published: 12/09/2010
• Est. Priority Date: 01/17/2006
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Salituro, Francesco, Farmer, Luc, Wang, Tiansheng, Pierce, Albert, Wang, Jian, Wannamaker, Marion, Martinez-Botella, Gabriel
• Granted Patent: US 8,163,917 B2
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/10 : Spiro-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
• CPC Class Codes: C12N 9/12 : transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Y 207/10002 : Non-specific protein-tyrosine kinase (2.7.10.2), i.e. spleen tyrosine kinase

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Claims

1. A compound of formula (I):

2. The compound according to claim 1, wherein the compound has formula I-A:

4. The compound according to claim 2, wherein R³ is Cl.

6. The compound according to claim 4, wherein R² is H, F, R′

, OH or OR′

.

7. The compound according to claim 6, wherein R² is H or F.

8. The compound according to claim 2, wherein the compound is of formula I-A and R⁴ is H, F, R′

, OH or OR′

, or R² and R⁴ are taken together to form a 6-membered aryl ring.

9. The compound according to claim 8, wherein R⁴ is H or F.

10. The compound according to claim 9, wherein if R⁴ is F, then R² is H and if R² is F, then R⁴ is H.

11. The compound according to claim 9, wherein R² and R⁴ are both H.

14. The compound according to claim 2, wherein R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CH₃, CH₂CH₂CF₃, CH₂CH₂CH₂F or CH₂CH₂CHF₂.

15. The compound according to claim 14, wherein R⁷ is CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃ or CH₂CH₂CF₃.

16. The compound according to claim 15, wherein R⁷ is CH₂CF₃.

17. The compound according to claim 1, wherein R″

is H or CH₃.

18. The compound according to claim 17, wherein R″

is H.

19. The compound according to claim 2, wherein R¹⁴ is H.

20. The compound according to claim 2, wherein R¹⁵ is H.

21. The compound according to claim 1, wherein the compound is of formula II:

22. The compound according to claim 21, wherein R⁷ is CH₂CH₃, CH₂CF₃, CH₂CH₂CH₃ or CH₂CH₂CF₃.

23. The compound according to claim 22, wherein R⁷ is CH₂CF₃.

24. The compound according to claim 21, wherein R^1A is

25. The compound according to claim 24, wherein R^1A is

26. The compound according to claim 25, wherein R^1A is

27. The compound according to claim 21, wherein R^1A is

28. The compound according to claim 27, wherein R^1A is

29. The compound according to claim 28, wherein R^1A is

30. The compound according to claim 29, wherein R¹³ is absent.

31. The compound according to claim 29, wherein Ring A is substituted with one occurrence of R¹³.

32. The compound according to claim 31, wherein R¹³ is OH, CH₃, F, OR′

or NHR′

.

33. The compound according to claim 32, wherein R′

is C_1-2 alkyl or C_2-3 alkenyl.

34. The compound according to claim 32, wherein R¹³ is OH.

35. The compound according to claim 21, wherein R^1A is

36. The compound according to claim 21, wherein R^1A is

37. The compound according to claim 36, wherein R^1A is

38. The compound according to claim 37, wherein R^1A is

39. The compound according to claim 21, wherein X^1A is CH or CF.

41. A pharmaceutical composition comprising a compound according to claim 1, 21, or 40 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

42. The composition according to claim 41, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

43. A method of inhibiting JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound according to any one of claim 1, 21, or 40 or with a composition according to either of claims 41 or 42.

44. A method of inhibiting JAK kinase activity in a patient, comprising administering to said patient a compound according to any one of claims 1, 21, or 40 or with a composition according to either of claim 41 or 42.

45. A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplantation, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to said patient a compound according to any one of claims 1, 21, or 40 or with a composition comprising said compound.

46. The method of claim 45, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated.

47. The method according to claim 45, wherein the disease or disorder is allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig'"'"'s disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, a solid malignancy, a hematologic malignancy, a leukemia, a lymphoma and a myeloproliferative disorder.

48. The method according to claim 47, wherein said disease or disorder is asthma.

49. The method according claim 47, wherein said disease or disorder is transplant rejection.

50. The method according claim 47, wherein said disease or disorder is rheumatoid arthritis.

51. The method according to claim 47, wherein said disease is a myeloproliferative disorder selected from polycythemia vera, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome or systematic mast cell disease.

52. The compound according to claim 1, wherein R¹ is

53. The compound of claim 52, wherein R³ is Cl.

54. The compound of claim 52, wherein R³ is F.

55. The compound according to claim 52, wherein R¹ is

56. The compound according to claim 52, wherein R² is H or F, R⁴ is H or F, and R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CH₃, CH₂CH₂CF₃, CH₂CH₂CH₂F or CH₂CH₂CHF₂.

57. The compound according to claim 56, wherein R² is H, R⁴ is H or F, and R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂ or CH₂CH₂F.

58. The compound according to claim 57, wherein R² is H, R⁴ is H, and R⁷ is CH₂CF₃.

59. The compound according to claim 52, wherein R″

is H or CH₃ and R¹⁴ is H.

60. The compound according to claim 1, wherein R¹ is

61. The compound according to claim 60, wherein R¹ is

62. The compound according to claim 60, wherein R² is H or F, R⁴ is H or F, and R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CH₃, CH₂CH₂CF₃, CH₂CH₂CH₂F or CH₂CH₂CHF₂.

63. The compound according to claim 62, wherein R² is H, R⁴ is H or F, and R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂ or CH₂CH₂F.

64. The compound according to claim 63, wherein R² is H, R⁴ is H, and R⁷ is CH₂CF₃.

65. The compound according to claim 60, wherein R″

is H or CH₃ and R¹⁴ is H.

66. The compound according to claim 1, wherein R¹ is

67. The compound according to claim 66, wherein R¹ is

68. The compound according to claim 66, wherein R² is H or F, R⁴ is H or F, and R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂, CH₂CH₂F, CH₂CH₂CH₃, CH₂CH₂CF₃, CH₂CH₂CH₂F or CH₂CH₂CHF₂.

69. The compound according to claim 68, wherein R² is H, R⁴ is H or F, and R⁷ is CH₂CH₃, CH₂CF₃, CH₂CHF₂ or CH₂CH₂F.

70. The compound according to claim 69, wherein R² is H, R⁴ is H, and R⁷ is CH₂CF₃.

71. The compound according to claim 66, wherein R¹⁴ is H or CH₃.

3. (canceled)

5. (canceled)

12. (canceled)

13. (canceled)

40. A compound selected from