Tri-cyclic pyrazolopyridine kinase inhibitors

• US 8,569,337 B2
• Filed: 01/27/2010
• Issued: 10/29/2013
• Est. Priority Date: 07/23/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Studley, John, Knegtel, Ronald, Settimo, Luca, Davis, Christopher John, Fraysse, Damien, Collier, Philip N., Brenchley, Guy, Boyall, Dean, Miller, Andrew, Twin, Heather, Young, Stephen
• Primary Examiner(s): Shen, Wu-Cheng Winston
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US12/670,989
• Publication Number:
  US 20120136000A1
• Time in Patent Office: 1,371 Days
• Field of Search: 546/119, 514/303
• US Class Current: 514/303
• 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 of tri-cyclic pyrazolopyridine useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions containing such 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 claim 2, represented by the following structural formula:

4. The compound of claim 3 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.

5. The compound of claim 4 wherein:

R₂ is —

H.

6. The compound of claim 5 wherein:

R₁ is —

H, halogen or C1-C10 haloalkyl.

7. The compound of claim 6 wherein the compound represented by the following structural formula:

8. The compound of claim 7, 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, piperazinyl, 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.

9. The compound of claim 7, 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.

10. The compound of claim 7, 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.

11. The compound of claim 7, 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.

12. The compound of claim 7, wherein ring C is represented a structural formula selected from the group consisting of:

13. The compound of claim 7, wherein ring C is represented by a structural formula selected from the group consisting of:

14. The compound of claim 13 wherein ring C is represented by a structural formula represented by:

15. The compound of claim 7, wherein ring C is represented by a structural formula selected from the group consisting of:

16. The compound of claim 15 wherein ring C is represented by a structural formula represented by:

17. The compound of claim 15 wherein ring C is represented by a structural formula represented by:

18. The compound of claim 17 wherein:

R₁ is halogen or C1-C10 haloalkyl.

19. The compound of claim 18 wherein:

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

20. The compound of claim 19 wherein:

ring B is pyridyl substituted with one Y.

21. The compound of claim 7 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.

22. The compound of claim 21 wherein:

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

23. The compound of claim 7 wherein the compound represented by the following structural formula:

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 claim 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 claim 7 wherein the compound represented by the following structural formula:

29. The compound of claim 28 wherein:

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

30. The compound of claim 29 wherein:

ring B is pyridyl.

31. The compound of claim 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 30 wherein:

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

33. The compound of claim 7 wherein the compound represented by the following structural formula:

34. The compound of claim 33 wherein the compound represented by the following structural formula:

35. The compound of claim 7 wherein the compound represented by the following structural formula:

36. The compound of claim 35 wherein:

T is —

CHNH₂—

, or —

NH—

.

37. The compound of claim 7 wherein the compound represented by the following structural formula:

38. The compound of claim 37 wherein:

T is —

CHNH₂—

, or —

NH—

.

39. The compound of claim 7 wherein the compound represented by the following structural formula:

40. The compound of claim 35 wherein:

T is —

CHNH₂—

, or —

NH—

.

41. The compound of claim 40, wherein the compound is represented by the following structural formula:

43. A composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

42. A compound represented by a structural formula selected from the group consisting of: