COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS

• US 20100099686A1
• Filed: 12/14/2007
• Published: 04/22/2010
• Est. Priority Date: 12/14/2006
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Knegtel, Ronald, Kay, David, Charrier, Jean-Damien
• Granted Patent: US 8,129,387 B2
• Time in Patent Office: Days
• US Class Current: 514/250
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• 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 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: C07D 475/00 Heterocyclic compounds containing pteridine ring 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 of formula I:

2. The compound of claim 1, wherein X¹ is O, NR⁸, or S.

3. The compound of claim 1, wherein X¹ is NR⁸.

4. The compound of claim 1, wherein X² is N.

5. The compound of claim 1, wherein R¹ is optionally substituted C_6-10 aryl or optionally substituted 5- to 10-membered heteroaryl.

6. The compound of claim 5, wherein each R¹ is optionally substituted C_6-10 aryl.

7. The compound of claim 1, wherein R⁴ is C_3-10 cycloaliphatic.

8. The compound of claim 1, wherein R⁵ is H or CO₂R.

9. The compound of claim 1, wherein one of R² and R³ is H and the other is optionally substituted C_1-6 aliphatic or optionally substituted C_3-8 cycloaliphatic.

10. The compound of claim 1, wherein R⁸ is H.

11. The compound of claim 1, wherein:

L is a bond;

X² is N;

R′

is optionally substituted C_6-10 aryl or optionally substituted 5-10 membered heteroaryl; and

each R² and R³ is independently H, C_1-10aliphatic, or

C_3-10 cycloaliphatic;

wherein each R² and R³ is optionally substituted with 0-5 J² and J³ respectively;

or

R² and R³, together with the carbon atom to which they are attached, can form an optionally substituted 3- to 6-membered saturated or partially unsaturated monocyclic ring.

12. The compound according to claim 1, wherein

each J² and J³ is independently C_1-6 aliphatic, C_3-6 cycloaliphatic, or —

(C_1-4alkyl)_n-V¹;

wherein

n is 0 or 1;

V¹ is halo(C_1-4 aliphatic), —

O(haloC_1-4 aliphatic), halo, NO₂, CN, OH, OR″

, SH, SR″

, NH₂, NHR″

, N(R″

)₂, COH, COR″

, CO₂H, CO₂R″

, CONH₂, CONHR″

, CONR″

₂, OCOR″

, OCONH₂, OCONHR″

, OCON(R″

)₂, NHCOR″

, NR″

COR″

, NHCO₂R″

, NR″

CO₂R″

, NHCO₂H, NR″

CO₂H, NHCONH₂, NHCONHR″

, NHCON(R″

)₂, SO₂NH₂, SO₂NHR″

, SO₂N(R″

)₂, NHSO₂R″

, or NR″

SO₂R″

;

R″

is unsubstituted C_1-4 aliphatic;

or two of the same J³, J⁴, J⁵, or J⁶, bonded to the same atom, together can optionally form ═

O.

13. The compound according to claim 1 selected from the following:

14. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

15. A method of inhibiting protein kinase activity in a patient comprising administering to said patient a compound of claim 1.

16. A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with a compound of claim 1.

17. The method of claim 15, wherein said protein kinase is PLK1.

18. A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising administering to said patient in need thereof a compound of claim 1.

19. The method according to claim 18, further comprising administering to said patient an additional 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, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:

a) said additional therapeutic agent is appropriate for the disease being treated; and

b) said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

20. A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof, comprising administering to said patient a compound of claim 1.

21. A method of treating cancer in a patient in need thereof, comprising administering to said patient a compound of claim 1.

22. The method of claim 16, wherein said protein kinase is PLK1.

23. A composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

24. A method of inhibiting protein kinase activity in a patient comprising administering to said patient a compound of claim 13.

25. A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with a compound of claim 13.

26. A method of treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising administering to said patient in need thereof a compound of claim 13.

27. The method according to claim 26, further comprising administering to said patient an additional 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, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:

c) said additional therapeutic agent is appropriate for the disease being treated; and

d) said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

28. A method of treating melanoma, myeloma, leukemia, lymphoma, neuroblastoma, or a cancer selected from colon, breast, gastric, ovarian, cervical, lung, central nervous system (CNS), renal, prostate, bladder, or pancreatic, in a patient in need thereof, comprising administering to said patient a compound of claim 13.

29. A method of treating cancer in a patient in need thereof, comprising administering to said patient a compound of claim 13.