Pyrazolopyridine kinase inhibitors

• US 9,137,973 B2
• Filed: 12/01/2011
• Issued: 09/22/2015
• 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
• Primary Examiner(s): Zarek, Paul
• Assistant Examiner(s): Kosturko, George W
• Application Number:
  US13/308,609
• Publication Number:
  US 20120184524A1
• Time in Patent Office: 1,391 Days
• Field of Search: 514/303, 514/210.21, 514/218, 514/252.11, 514/253.04, 540/575, 544/357, 544/362, 544/405, 546/119
• US Class Current: 1/1
• 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 a structural formula selected from the group consisting of:

2. The compound of claim 1 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.

3. The compound of claim 2 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.

4. The compound of claim 3 wherein:

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

5. The compound of claim 3 wherein:

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

6. The compound of claim 4 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 independently optionally and independently substituted with one Z and independently further and optionally substituted with one or more J_b.

7. The compound of claim 4 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 independently optionally and independently substituted with one Z and independently further and optionally substituted with one or more J_b.

8. The compound of claim 4 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 independently optionally and independently substituted with one Z and independently further and optionally substituted with one or more J_b.

9. The compound of claim 4 wherein

ring C is selected from the group consisting of cyclohexyl, phenyl, piperidinyl, piperazinyl, diazapanyl, pyrrolidinyl, azetidinyl, and azepanyl, wherein each ring is independently optionally and independently substituted with one Z and independently further and optionally substituted with one or more J_b.

10. The compound of claim 5 wherein ring C is represented a structural formula selected from the group consisting of:

11. The compound of claim 5 wherein ring C is represented by a structural formula selected from the group consisting of:

12. The compound of claim 11 wherein ring C is represented by a structural formula represented by:

13. The compound of claim 4 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 13 wherein ring C is represented by a structural formula represented by:

16. The compound of claim 15 wherein:

R₄ is a C1-10 aliphatic, wherein up to three methylene units of R₄ are optionally and independently replaced by G′

wherein G′

is —

O—

, —

C(O)—

, —

N(R′

)—

, or —

S(O)_p—

; and

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

17. The compound of claim 16 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.

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

19. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

20. A method of treating a protein kinase c theta mediated condition in a subject, wherein the condition is selected from the group consisting of psoriasis or transplant rejection, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof or composition of any one of claims 1-4, 6, 13 and 15-19.