Tri-cyclic pyrazolopyridine kinase inhibitors

• US 8,563,576 B2
• Filed: 12/01/2011
• Issued: 10/22/2013
• Est. Priority Date: 07/23/2008
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Brenchley, Guy, Boyall, Dean, Fraysse, Damien, Jimenez, Juan-Miguel, Settimo, Luca
• Primary Examiner(s): Zarek, Paul
• Assistant Examiner(s): Kosturko, George W
• Application Number:
  US13/308,612
• Publication Number:
  US 20120184534A1
• Time in Patent Office: 691 Days
• Field of Search: 514/303, 514/218, 514/253.04, 546/275.4, 546/119, 548/356.1, 548/360.1, 548/360.5, 540/575, 544/362
• 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 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 of tricyclic pyrazolopyridine useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising such 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:

ring B is imidazolyl, 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.

3. The compound of claim 2 wherein:

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

4. The compound of claim 2 wherein:

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

5. The compound of claim 2 wherein:

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

6. The compound of claim 2 wherein:

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

7. The compound of claim 5 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.

8. The compound of claim 7 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.

9. The compound of claim 8 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.

10. The compound of claim 9 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.

11. The compound of claim 2 wherein ring C is represented a structural formula selected from the group consisting of:

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

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

14. The compound of claim 7 wherein ring C is represented by a structural formula selected from the group consisting of:

15. The compound of claim 14 wherein ring C is represented by a structural formula represented by:

16. The compound of claim 14 wherein ring C is represented by a structural formula represented by:

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

18. A composition comprising a compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 5, 7, 10, 12 and 17, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

19. 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 1-18.