PYRAZOLOPYRIDINE KINASE INHIBITORS

• US 20140148434A1
• Filed: 09/18/2013
• Published: 05/29/2014
• Est. Priority Date: 07/23/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Boyall, Dean, Brenchley, Guy, Fraysse, Damien, Jimenez, Juan-Miguel, Settimo, Luca
• Granted Patent: US 9,029,546 B2
• Time in Patent Office: Days
• US Class Current: 514/210.21
• CPC Class Codes: A01K 39/01 Feeding devices, e.g. chainfeedersA01K39/04 takes precedence; panfeeding systems, feeding pans A01K39/0125
• 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 17/06 Antipsoriatics
• 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 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 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 37/06 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 9/00 : Drugs for disorders of the cardiovascular system
• 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 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.

8. The compound of claim 6, 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.

9. The compound of claim 8 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.

10. The compound of claim 9 wherein:

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

11. The compound of claim 9 wherein:

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

23. The compound of claim 1 wherein:

R₄ is a C2-10 aliphatic, wherein up to three methylene units of R₄ are optionally and independently replaced by G′

wherein G′

is —

O—

, or —

N(R′

)—

; and

R₄ is optionally and independently substituted with one or more J_a.

24. The compound of claim 1, wherein the compound is represented by a structural formula selected from the group consisting of:

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

26. 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 of claim 1.

27. The method of claim 26, wherein the protein kinase-mediated condition is a PKC mediated condition.

28. The method of claim 27, wherein the PKC-mediated condition is a PKCtheta mediated condition.

29. The method of claim 28, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.

30. The method of claim 29, 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.

36. The method of claim 30, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma.

7. (canceled)

12-22. -22. (canceled)

31. (canceled)

32. The method of claim 31, wherein the PKCtheta mediated condition is an autoimmune disease and the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease

33-35. -35. (canceled)