TRI-CYCLIC PYRAZOLOPYRIDINE KINASE INHIBITORS

• US 20120136000A1
• Filed: 01/27/2010
• Published: 05/31/2012
• Est. Priority Date: 07/23/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Fraysse, Damien, Boyall, Dean, Miller, Andrew, Studley, John, Knegtel, Ronald, Settimo, Luca, Collier, Philip N., Brenchley, Guy, Twin, Heather, Young, Stephen
• Granted Patent: US 8,569,337 B2
• Time in Patent Office: Days
• US Class Current: 514/252.11
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 239/24 having three or more double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 241/10 having three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 471/04 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

The present invention relates to compounds useful as inhibitors of protein kinase. 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. The invention also provides processes for preparing compounds of the inventions.

Claims

1. A compound represented by the following structural formula:

2. A compound of claim 1, represented by the following structural formula:

3. A compound of any one of claim 1 or 2, represented by the following structural formula:

4. A compound of claim 3, represented by the following structural formula:

5. The compound of any one of claims 1-4 wherein:

R₁ is —

H, halogen, C1-C10 aliphatic optionally and independently substituted with one or more J_a, or C3-C8 cycloaliphatic optionally and independently substituted with one or more J_b; and

R₂ is —

H, halogen, C1-C10 aliphatic optionally and independently substituted with one or more J_a, or C3-C8 cycloaliphatic optionally and independently substituted with one or more J_b.

6. The compound of any one of claims 1-5 wherein:

R₂ is —

H.

7. The compound of any one of claims 1-6 wherein:

R₁ is —

H, halogen or C1-C10 haloalkyl.

8. The compound of any one of claim 1, 2, 3, 4, 5 or 7 wherein the compound represented by the following structural formula:

9. The compound of any one of claims 1-8 wherein:

ring B is pyridyl, pyrazinyl, pyrimidinyl, isoquinolyl, quinazolinyl, pyridopyridyl, pyridopyradazinyl, pyrrolopyridiyl, pyrazolopyridiyl, pyrolopyrimidinyl, or pyrrolopyrazinyl, wherein ring B is optionally substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

10. The compound of any one of claims 1-9 wherein:

ring B is pyridyl, pyrazinyl, pyrimidinyl, isoquinolyl, pyrrolopyridiyl, pyrazolopyridiyl, pyrolopyrimidinyl, or pyrrolopyrazinyl, wherein ring B is optionally substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

11. The compound of any one of claims 1-10 wherein:

ring B is pyridyl optionally substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

12. The compound of any one of claims 1-10 wherein:

ring B is pyrazinyl optionally substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

13. The compound of any one of claim 11 or 12 wherein:

ring C is selected from the group consisting of cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, thiadiazolyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, indolyl, indazolyl, benzimidazolyl, quinolyl, quinoxalyl, indolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, azabicyclopentyl, azabicyclohexyl, azabicycloheptyl, azabicyclooctyl, azabicyclononyl, azabicyclodecyl, diazabicyclohexyl, diazabicycloheptyl, azetidinyl, isoindolinyl, isoindolyl, dihydroindazolyl, dihydrobenzimidazolyl, morpholinyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydropyrazolyl, dihydroimidazolyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, diazabicyclooctyl, diazabicyclononyl, diazabicyclodecyl, thiazepanyl, and thiazocanyl wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more J_b.

14. The compound of any one of claim 11 or 12 wherein

ring C is selected from the group consisting of cyclohexyl, diazabicyclooctyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazalolyl, oxadiazolyl, thiazolyl, azetidinyl, morpholinyl, azepanyl, diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, dihydropyridyl, octahydropyrrolopyrazyl, octahydropyrrolopyridyl, octahydropyridopyrazyl, octahydropyridopyridyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl, diazepanyl, and oxazepanyl wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more J_b.

15. The compound of any one of claim 11 or 12 wherein

ring C is selected from the group consisting of cyclohexyl, 3,8-diazabicyclo[3.2.1]octane, phenyl, pyridyl, piperidinyl, piperazinyl, diazepanyl, pyrrolidinyl, pyrrolyl, pyrrazolyl, azetidinyl, morpholinyl, azepanyl, 2,5 diazabicycloheptyl, diazabicyclooctyl, indolyl, tetrahydropyridyl, octahydro-1H-pyrrolo[2,3-b]pyrazyl, octahydropyrrolo[1,2-a]pyrazyl, and oxazepanyl wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more J_b.

16. The compound of any one of claim 11 or 12 wherein

ring C is selected from the group consisting of piperidinyl, piperazinyl, diazapanyl, pyrrolidinyl, azetidinyl, and azepanyl, wherein each ring is optionally substituted with one Z and independently further and optionally substituted with one or more J_b.

17. The compound of any one of claim 11 or 12 wherein ring C is represented a structural formula selected from the group consisting of:

18. The compound of any one of claim 11 or 12 wherein ring C is represented by a structural formula selected from the group consisting of:

19. The compound of claim 18 wherein ring C is represented by a structural formula represented by:

20. The compound of any one of claim 11 or 12 wherein ring C is represented by a structural formula selected from the group consisting of:

21. The compound of claim 20 wherein ring C is represented by a structural formula represented by:

22. The compound of claim 20 wherein ring C is represented by a structural formula represented by:

23. The compound of any one of claims 8 to 22 wherein:

R₁ is halogen or C1-C10 haloalkyl.

24. The compound of claim 23 wherein:

ring B is pyridyl substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

25. The compound of claim 24 wherein:

ring B is pyridyl substituted with one Y.

26. The compound of any one of claims 23-25 wherein:

ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z and independently further and optionally substituted with one or more J_b.

27. The compound of claim 26 wherein:

ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z.

28. The compound of any one of claims 8 to 22 wherein the compound represented by the following structural formula:

29. The compound of claim 28 wherein:

ring B is pyridyl substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

30. The compound of claim 29 wherein:

ring B is pyridyl substituted with one Y.

31. The compound of any one of claims 28-30 wherein:

ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z and independently further and optionally substituted with one or more J_b.

32. The compound of claim 31 wherein:

ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z.

33. The compound of any one of claims 8 to 22 wherein the compound represented by the following structural formula:

34. The compound of claim 33 wherein:

ring B is pyridyl independently and optionally and independently substituted with one or more J_c.

35. The compound of claim 34 wherein:

ring B is pyridyl.

36. The compound of any one of claims 33-35 wherein:

ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z and independently further and optionally substituted with one or more J_b.

37. The compound of claim 35 wherein:

ring C is selected from the group consisting of piperidinyl, piperazinyl, or diazepanyl, substituted with one Z.

38. The compound of any one of claims 8 to 22 wherein the compound represented by the following structural formula:

39. The compound of claim 38 wherein the compound represented by the following structural formula:

40. The compound of any one of claims 8 to 22 wherein the compound represented by the following structural formula:

41. The compound of claim 40 wherein:

T is —

CHNH₂—

, or —

NH—

42. The compound of any one of claims 8 to 22 wherein the compound represented by the following structural formula:

43. The compound of claim 42 wherein:

T is —

CHNH₂—

, or —

NH—

44. The compound of any one of claims 8 to 22 wherein the compound represented by the following structural formula:

45. The compound of claim 40 wherein:

T is —

CHNH₂—

, or —

NH—

46. The compound of claim 45, wherein the compound is represented by the following structural formula:

48. A composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-47, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

49. A method of treating or preventing a protein kinase-mediated condition in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof or composition of any one of claims 1-47.

50. The method of claim 49, wherein the protein kinase-mediated condition is a PKC mediated condition.

51. The method of claim 50 wherein the PKC-mediated condition is a PKCtheta mediated condition.

52. The method of claim 51, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.

53. The method of claim 52, wherein the PKCtheta mediated condition is selected from the group consisting of asthma, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, multiple sclerosis, diabetes, inflammatory bowel disease, transplant rejection, T-cell leukaemias, lymphomas, and lupus.

54. The method of claim 53, wherein the PKCtheta mediated condition is an autoimmune disease.

55. The method of claim 54, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease

56. The method of claim 55, wherein the autoimmune disease is multiple sclerosis.

57. The method of claim 55, wherein the autoimmune disease is rheumatoid arthritis.

58. The method of claim 55, wherein the autoimmune disease is irritable bowel disease.

59. The method of claim 54, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma.

47. A compound represented by a structural formula selected Table 1, or a pharmaceutically acceptable salt thereof.