Compositions useful as inhibitors of protein kinases

• US 7,446,199 B2
• Filed: 09/07/2004
• Issued: 11/04/2008
• Est. Priority Date: 09/04/2003
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Li, Pan, Lauffer, David J., Aronov, Alex, Tomlinson, Ronald C.
• Primary Examiner(s): Shiao; Rei-tsang
• Assistant Examiner(s): Young; Shawquia
• Application Number:
  US10/936,470
• Publication Number:
  US 20050137201A1
• Time in Patent Office: 1,519 Days
• Field of Search: 546/272.1
• US Class Current: 546/113
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful of 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 is optionally substituted with one or more halogen or —

OR^o, wherein each R^o is C_1-4aliphatic.

3. The compound according to claim 1, wherein Ring B is optionally substituted with one or more oxo;

chloro;

bromo;

fluoro;

—

CH₂OH;

—

OH;

—

OCH₃;

CH₃;

—

NHCH₃;

—

NHCH₂CH₃;

—

N(CH₃)₂;

—

NH—

CH₂-tetrahydrofuranyl, pyrrolidinyl;

piperidinyl;

—

COO(CH₃);

—

B(OH)₂;

phenyl;

benzyl;

pyrindinyl;

H;

cyclopropyl;

cyclohexyl;

cyclohexenyl;

—

CH₂CH₃;

—

CH₂N(CH₃)₂;

propynyl substituted with N(CH₃)₂;

ethenyl;

ethenyl substituted with triazolyl;

—

CH₂CH₂-triazolyl;

NH(CH₃);

NH(CH₂)phenyl;

N(CH₃)₂;

—

NHSO₂(CH₃);

—

CO(piperazinyl) or —

CO(pyrrolidinyl).

4. The compound according to claim 1, wherein Ring A is an optionally substituted isoxazolyl ring.

5. The compound according to claim 4, wherein Ring A is selected from the following rings:

6. The compound according to claim 1, wherein W is CH.

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

10. The composition according to claim 9, wherein said compound is in an amount sufficient to detectably inhibit c-Met, GSK3, JAK-3, SYK, or KDR protein kinase activity.

11. The composition according to claim 9, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease or, an agent for treating liver disease.

12. A method of inhibiting c-Met, GSK3, JAK-3, SYK, KDR, FLT-3, c-Kit, Aurora-2, or TAK-1kinase activity in a biological sample in vitro;

which method comprises contacting said biological sample with;

a) a composition according to claim 9;

or

b) a compound according to claim 1.

7. A compound selected from the group consisting of:

8. A compound selected from the group consisting of the following compounds: