KINASE INHIBITORS

• US 20120149680A1
• Filed: 10/18/2011
• Published: 06/14/2012
• Est. Priority Date: 11/02/2007
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Mortimore, Michael, Miller, Andrew, Collier, Philip, Young, Stephen, Brenchley, Guy, Davis, Chris, Twin, Heather, Mak, Chau, Boyall, Dean, Keily, Shazia, Settimo, Luca
• Granted Patent: US 8,367,697 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• 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 37/02 Immunomodulators
• 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: 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 IA:

5. The compound of claim 1 wherein:

A is —

N—

or —

C(R⁺)—

; and

A′

is —

C(R⁺)—

.

6. The compound of claim 1 wherein:

R⁺ is —

H.

7. The compound of claim 1 wherein:

R₁ is halogen, or -T1-Q1.

8. The compound of claim 1 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.

9. The compound of claim 1 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.

10. The compound of claim 1 wherein:

each J_T1 is independently —

OR̂

, —

N(R̂

)₂, or —

CN.

11. The compound of claim 1 wherein:

each J_Q1 is independently C1-10 alkyl, —

OR″

, —

N(R″

)₂, or acyl.

15. The compound of claim 1 wherein:

A is —

C(R⁺)—

.

16. The compound of claim 1 wherein:

J_T1 is —

OR̂

.

24. The compounds of claim 1 wherein

R₅ is —

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

R₆ is —

H or C1-4 alkyl.

25. The compounds of claim 1 wherein

R₅ is —

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

R₆ is —

H.

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

43. A process for preparing a compound of claim 1 comprising:

a) boronation of a compound represented by a structural formula selected from the group consisting of;

56. A process for preparing a compound of claim 1, comprising:

a) cyclization of compound represented by represented by the following structural formula;

69. 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.

70. The method of claim 69, wherein the protein kinase-mediated condition is a PKC mediated condition.

71. The method of claim 70, wherein the PKC-mediated condition is a PKCtheta mediated condition.

72. The method of claim 71, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.

73. The method of claim 72, 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.

74. The method of claim 71, wherein the PKCtheta mediated condition is an autoimmune disease.

75. The method of claim 74, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease

76. The method of claim 75, wherein the autoimmune disease is multiple sclerosis.

77. The method of claim 75, wherein the autoimmune disease is rheumatoid arthritis.

78. The method of claim 75, wherein the autoimmune disease is irritable bowel disease.

79. The method of claim 72, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma.

2. (canceled)

3. The compound of claim 2, represented by structural formula IA:

4. (canceled)

12-14. -14. (canceled)

17-23. -23. (canceled)

26-40. -40. (canceled)

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

44-55. -55. (canceled)

57-68. -68. (canceled)