PYRAZOLOPYRIDINES

• US 20120178778A1
• Filed: 11/04/2011
• Published: 07/12/2012
• Est. Priority Date: 05/06/2009
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Collier, Philip
• Granted Patent: US 8,541,445 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/06 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 471/04 Ortho-condensed systems

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 structural formula I or IA:

2. The compound of claim 1 wherein the structural formula is represented by Formula I.

3. The compound of claim 2 wherein:

each R₁ is independently —

H, halogen, or -T1-Q1.

4. The compound of claim 3 wherein:

T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, —

N(R′

)—

, or —

C(O)—

; and

T1 is optionally and independently substituted with one or more J_T1.

5. The compound of claim 4 wherein:

Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_Q1.

6. The compound of claim 5 wherein:

each J_T1 is independently —

OR^̂

, —

N(R^̂

)₂, or —

CN.

7. The compound of claim 6 wherein:

each J_Q1 is independently C1-10 alkyl, —

OR″

, —

N(R″

)₂, or acyl.

8. The compounds of claim 7 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nC(O)N(R*)₂, —

(CR⁺⁺₂).OR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen.

9. The compound of claim 8 wherein:

each R₃ and R₄ independently is —

H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —

CN, —

NO₂, —

N(R*)₂, and —

OR*;

or

R₃ and R₄ taken together with the carbon to which they are attached form C═

O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

10. The compound of claim 9 wherein:

each R₃ and R₄ independently is —

H, C1-10 aliphatic, cycloalkylalkyl, wherein R₃ and

R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —

CN, —

NO₂, —

N(R*)₂, and —

OR*;

or

R₃ and R₄ taken together with the carbon to which they are attached form C═

O, or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

11. The compound of claim 10 wherein:

J_T1 is —

OR^̂

.

12. The compounds of claim 11 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen.

13. The compound of claim 12 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a 3-8 membered saturated, or partially saturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

14. The compound of claim 13 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

15. The compound of claim 14 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, imidazolinyl, thiazolidinyl, or oxazolidinyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

16. The compound of claim 14 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

R₃ and R₄ taken together with the carbon to which they are attached form a monocyclic ring selected from the group consisting of cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl, wherein the ring is optionally and independently substituted with one or more selected from the group consisting of ═

O, ═

S, C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R*)₂, and —

OR*.

17. The compounds of claim 14 wherein:

R₂ is —

H, —

(CR⁺⁺₂)_nCN, —

(CR⁺⁺₂)_nOR*, —

(CR⁺⁺₂)_nN(R*)₂, or C1-3 aliphatic optionally substituted with one or more halogen; and

each R₃ and R₄ independently is —

H, C1-10 aliphatic, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, or aralkyl wherein R₃ and R₄ are optionally and independently substituted with one or more selected from the group consisting of halogen, —

CN, —

NO₂, —

N(R*)₂, and —

OR*.

18. The compounds of claim 17 wherein

R₅ is —

H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and

R₆ is —

H or C1-4 alkyl.

19. The compounds of claim 18 wherein

R₅ is —

H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and

R₆ is —

H.

20. The compounds of claim 18 wherein

R₅ is trifluoromethyl;

and

R₆ is —

H.

21. The compound of claim 1 wherein the structural formula is represented by Formula IA.

22. The compound of claim 21 wherein:

each R₁ is independently —

H, halogen, or -T1-Q1.

23. The compound of claim 22 wherein:

T1 is absent or a C1-10 aliphatic wherein up to three methylene units of T1 are optionally and independently replaced by G wherein G is —

O—

, —

N(R′

)—

, or —

C(O)—

; and

T1 is optionally and independently substituted with one or more J_T1.

24. The compound of claim 23 wherein:

Q1 is absent or a 3-8 membered saturated, partially saturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from the groups consisting of O, N, and S, wherein Q1 is optionally and independently substituted with one or more J_Q1.

25. The compound of claim 24 wherein:

each J_T1 is independently —

OR^̂

, —

N(R^̂

)₂, or —

CN.

26. The compound of claim 25 wherein:

each J_Q1 is independently C1-10 alkyl, —

OR″

, —

N(R″

)₂, or acyl.

27. The compounds of claim 26 wherein

R₅ is —

H, Cl, C1-4 haloalkyl, or C1-4 alkyl; and

R₆ is —

H or C1-4 alkyl.

28. The compounds of claim 27 wherein

R₅ is —

H, Cl, trifluoromethyl, methyl, ethyl, or cyclopropyl; and

R₆ is —

H.

29. The compounds of claim 28 wherein

R₅ is trifluoromethyl;

and

R₆ is —

H.

30. The compound of claim 29 wherein:

ring B is five- or six-membered saturated carbocyclic ring.

31. The compound of claim 30 wherein:

each R₇ is independently C1-10 aliphatic, C1-10 haloaliphatic, halogen, —

CN, —

N(R)₂, or —

OR**;

or two R₇ groups together with the carbon to which they are attached form C═

O.

32. The compound of claim 31 wherein:

A is —

C(R⁺)—

.

33. The compound of claim 32 wherein:

J_T1 is —

OR^̂

.

34. The compound of claim 33 wherein:

each J_Q1 is independently C1-10 alkyl, —

OR″

, —

N(R″

)₂, or acyl.

35. The compound of claim 24 wherein:

ring B is five-membered saturated carbocyclic ring.

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

38. A method of treating or preventing a protein kinase-mediated condition in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 or pharmaceutically acceptable salt thereof.

39. The method of claim 38, wherein the protein kinase-mediated condition is a PKC mediated condition.

40. The method of claim 39, wherein the PKC-mediated condition is a PKCtheta mediated condition.

41. The method of claim 40, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.

42. The method of claim 40, 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.

43. The method of claim 41, wherein the PKCtheta mediated condition is an autoimmune disease.

44. The method of claim 41, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease

45. The method of claim 41, wherein the autoimmune disease is multiple sclerosis.

46. The method of claim 41, wherein the autoimmune disease is rheumatoid arthritis.

47. The method of claim 41, wherein the autoimmune disease is irritable bowel disease.

48. The method of claim 40, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma.

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