Inhibitors of JAK protein kinase

• US 7,271,179 B2
• Filed: 05/06/2003
• Issued: 09/18/2007
• Est. Priority Date: 05/06/2002
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Ledeboer, Mark, Bemis, Guy W., Harbeson, Scott L.
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US10/430,805
• Publication Number:
  US 20040038992A1
• Time in Patent Office: 1,596 Days
• Field of Search: 514/259, 514/260, 514/312, 544/284, 546/153
• US Class Current: 514/312
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular 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 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 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. 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.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein:

R¹ and R² are taken together to form an optionally substituted 5-7 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The compound according to claim 2, wherein:

R¹ and R² are taken together to form an optionally substituted benzo, thieno, cyclohexo, pyrido, tetrahydropyrido, or pyrimido ring.

4. The compound according to claim 1, wherein:

Q is —

C(O)—

, —

C(O)NR—

, —

CO₂—

, —

C(O)CO₂—

, —

SO₂—

, or an optionally substituted C_1-4 alkylidene chain wherein;

one or two non-adjacent methylene units of Q are optionally and independently replaced by —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

CO₂—

, or —

SO₂—

.

5. The compound according to claim 1, wherein:

R³ is an optionally substituted ring selected from;

(a) a 3-6 membered monocyclic carbocyclic saturated or aryl ring;

or

(b) a 5-6 membered monocyclic or a 9-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound according to claim 5, wherein:

R³ is an optionally substituted group selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, thienyl, furanyl, isoxazolyl, triazolyl, benzothienyl, or benzo[1,3]dioxolyl.

7. The compound according to any one of claims 1-6, wherein W is sulfur.

8. The compound according to claim 7, wherein X is sulfur.

9. The compound according to claim 8, wherein A is nitrogen.

10. The compound according to claim 8, wherein A is CH.

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

13. The composition according to claim 12, wherein:

R¹ and R² are taken together to form an optionally substituted 5-7 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

14. The composition according to claim 12, wherein:

Q is —

C(O)—

, —

C(O)NR—

, —

CO₂—

, —

C(O)CO₂—

, —

SO₂—

, or an optionally substituted C_1-4 alkylidene chain wherein;

one or two non-adjacent methylene units of Q are optionally and independently replaced by —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

CO₂—

, or —

SO₂—

.

15. The composition according to claim 12, wherein:

R³ is an optionally substituted ring selected from;

(a) a 3-6 membered monocyclic carbocyclic saturated or aryl ring;

or

(b) a 5-6 membered monocyclic or a 9-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

16. The composition according to any one of claims 12-15, wherein W is sulfur.

17. The composition according to claim 16, wherein X is sulfur.

18. The composition according to claim 16, wherein A is nitrogen.

19. The composition according to claim 16, wherein A is CH.

20. The composition according to claim 12, additionally comprising an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, or an agent for treating cardiovascular disease.

11. A compound selected from the following compounds:

21. A composition comprising a compound according to claim 11, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.