TRI-CYCLIC PYRAZOLOPYRIDINE KINASE INHIBITORS

• US 20120184534A1
• Filed: 12/01/2011
• Published: 07/19/2012
• Est. Priority Date: 07/23/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Brenchley, Guy, Boyall, Dean, Fraysse, Damien, Jimenez, Juan-Miguel, Settimo, Luca
• Granted Patent: US 8,563,576 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• 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 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• 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

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. The compound of claim 1 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.

3. The compound of either claim 1 or 2 wherein:

R₂ is —

H.

4. The compound of any one of claims 1-3 wherein:

R₁ is —

H, halogen or C1-C10 haloalkyl.

5. The compound of any one of claim 1 or 4 wherein the compound represented by the following structural formula:

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

ring B is imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, oxadiazolyl, thiazolyl, indazolyl, isoindolyl, pyrrolopyridinyl, pyrazolopyridinyl, azaindolyl, pyrolopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, pyrazolo pyrazinyl, pyrrolopyridazinyl, pyrazolopyridazinyl or thiadiazolyl wherein ring B is optionally substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

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

ring B is imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, indolyl, isoindolyl, indazolyl, pyrrolopyridinyl, pyrazolopyridinyl, azaindolyl, pyrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, or thiadiazolyl wherein ring B is optionally substituted with one Y and independently further and optionally and independently substituted with one or more J_c.

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

ring B is pyrazolyl optionally substituted with one Y and independently further and optionally substituted with one J_c.

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

ring B is imidazolyl optionally substituted with one Y and independently further and optionally substituted with one J_c.

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

ring B is thiazolyl, optionally substituted with one Y or one J_c.

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

ring B is indazolyl 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 8-11 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.

13. The compound of any one of claims 8-11 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.

14. The compound of any one of claims 8-11 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.

15. The compound of any one of claims 8-11 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.

16. The compound of any one of claims 8-11 wherein ring C is represented a structural formula selected from the group consisting of:

17. The compound of any one of claims 8-11 wherein ring C is represented by a structural formula selected from the group consisting of:

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

19. The compound of any one of claims 8-110 wherein ring C is represented by a structural formula selected from the group consisting of:

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

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

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

23. A composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-22, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

24. 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 1-23.

25. The method of claim 24, wherein the protein kinase-mediated condition is a PKC mediated condition.

26. The method of claim 25, wherein the PKC-mediated condition is a PKCtheta mediated condition.

27. The method of claim 26, wherein the PKCtheta mediated condition is an autoimmune disease, an inflammatory disease or a proliferative or hyperproliferative disease.

28. The method of claim 27, wherein the PKCtheta mediated condition is sleected 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.

29. The method of claim 27, wherein the PKCtheta mediated condition is an autoimmune disease.

30. The method of claim 29, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, irritable bowel disease

31. The method of claim 30, wherein the autoimmune disease is multiple sclerosis.

32. The method of claim 30, wherein the autoimmune disease is rheumatoid arthritis.

33. The method of claim 30, wherein the autoimmune disease is irritable bowel disease.

34. The method of claim 28, wherein the PKCtheta mediated condition is selected from the group consisting of T-cell leukaemia and lymphoma.