Compounds Useful as Protein Kinase Inhibitors

• US 20110263575A1
• Filed: 08/15/2008
• Published: 10/27/2011
• Est. Priority Date: 08/15/2007
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Pierard, Francoise
• Granted Patent: US 8,461,149 B2
• Time in Patent Office: Days
• US Class Current: 514/221
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 31/12 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
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/14 : Ortho-condensed 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.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein X is O and R² is —

CH₃.

3. The compound of claim 1, wherein X is NR⁵ and, R² and R⁵, together with the atoms to which they are attached, form a 1,2,4-triazole.

5. The compound of claim 1, wherein R³ and R⁴ are each methyl.

6. The compound of claim 1, wherein R³ is H and R⁴ is ethyl.

7. The compound of claim 1, wherein R³ and R⁴, together with the atoms to which they are attached, form a cyclopropyl ring.

8. The compound of claim 1, wherein R⁶ is cyclopropyl optionally substituted with 1 or 2 halogen atoms.

9. The compound of claim 1, wherein R⁶ is cyclopentyl optionally substituted with 1 or 2 halogen atoms.

10. The compound of claim 1, wherein R⁶ is cyclohexyl optionally substituted with 1 or 2 halogen atoms.

11. The compound of claim 1, wherein R⁶ is C_1-4 aliphatic optionally substituted with 1 or 2 halogen atoms.

12. The compound of claim 1, wherein the compound is

N-cyclopropyl-4-(9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;

4-(9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-fluorocyclopentyl)-3-methoxybenzamide;

N-(3,3-difluorocyclopentyl)-4-(9-(3,3-difluorocyclopentyl)-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzamide;

N-cyclopropyl-4-(9′

-(3,3-difluorocyclopentyl)-5′

-methyl-6′

-oxo-5′

,6′

,8′

,9′

-tetrahydrospiro[cyclopropane-1,7′

-pyrimido[4,5-b][1,4]diazepine]-2′

-ylamino)-3-methoxybenzamide;

N-(3,3-difluorocyclopentyl)-4-(9′

-(3,3-difluorocyclopentyl)-5′

-methyl-6′

-oxo-5′

,6′

,8′

,9′

-tetrahydrospiro[cyclopropane-1,7′

-pyrimido[4,5-b][1,4]diazepine]-2′

-ylamino)-3-methoxybenzamide;

4-((R)-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-N-ethyl-3-methoxybenzamide;

N-cyclopropyl-4-((R)-5-((R)-3,3-difluorocyclopentyl)-4-ethyl-4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridin-7-ylamino)-3-methoxybenzamide;

4-((R)-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-N-ethyl-3-methoxybenzamide;

or

N-cyclopropyl-4-((R)-8-((R)-3,3-difluorocyclopentyl)-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-ylamino)-3-methoxybenzamide.

13. A pharmaceutical composition comprising a compound of claim 1 or 12, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

14. A method of inhibiting protein kinase activity in a patient in need thereof, comprising administering to the patient a compound of claim 1 or 12 or a pharmaceutical composition of claim 13.

15. A method of inhibiting protein kinase activity in a biological sample, comprising contacting the biological sample with a compound of claim 1 or 12 or a pharmaceutical composition of claim 13.

16. The method of claim 14 or 15, wherein the protein kinase is a PLK.

17. The method of claim 16, wherein the 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 in need thereof, comprising the step of administering to the patient a compound of claim 1 or 12 or a pharmaceutical composition of claim 13.

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 the additional therapeutic agent is appropriate for the disease being treated and is administered together with the compound of claim 1 or 12 or the pharmaceutical composition of claim 13 as a single dosage form or separately from the compound or pharmaceutical 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 the patient a compound of claim 1 or 12 or a pharmaceutical composition of claim 13.

21. A method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of claim 1 or 12 or a pharmaceutical composition of claim 13.

22. The method of claim 21, wherein the method comprises the step of disrupting cancer cell mitosis by inhibiting PLK with the compound pharmaceutical composition.

4. (canceled)

23. A process for preparing a compound of formula I-A:

24. The process of claim 23, further comprising the step of reacting a compound of formula 4A:

25. The process of claim 24, further comprising the step of reductive cyclization of a compound of formula 3A:

26. The process of claim 24, further comprising cyclizing a compound of formula 3A-a:

27. The process of claim 26, further comprising the step of reacting a compound of formula 3A:

28. The process of claim 23 or 27, further comprising

a) reacting the compound of formula 3A-a with an alkylating agent to form a compound of formula 3A-b;

and

29. The process of claim 25, further comprising reacting a compound of formula 2a;

30. The process of claim 29, further comprising reacting a compound of formula 11;

31. The process of claim 29, further comprising

a) reacting compound of formula 11 to form hexahydro-1,3,5-triazine of formula 13;

and

32. A process for preparing a compound of formula I-C:

33. The process of claim 32, further comprising the step of reacting a compound of formula 4C:

34. The process of claim 33, further comprising the step of reductive cyclization of a compound of formula 3C:

35. The process of claim 34, further comprising cyclizing a compound of formula 3C-a:

36. The process of claim 35, further comprising the step of reacting a compound of formula 3C:

37. The process of claim 32 or 36, further comprising

a) reacting the compound of formula 3C-a with an alkylating agent to form a compound of formula 3C-b:

38. The process of claim 34 or 36, further comprising reacting a compound of formula 2b:

39. The process of claim 38, further comprising reacting a compound of formula 11;

40. A process for preparing a compound of formula I-B:

41. The process of claim 40, further comprising the step of reacting a compound of formula 9:

42. The process of claim 41, further comprising the step of reacting a compound of formula 8:

43. The process of claim 42, further comprising reacting a compound of formula 4C:

44. The process of any of claims 40-43, wherein R² and R⁵, together with the atoms to which they are attached, form a 1,2,4-triazole.