COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS

• US 20140018352A1
• Filed: 04/26/2013
• Published: 01/16/2014
• Est. Priority Date: 08/15/2007
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Pierard, Francoise, Charrier, Jean-Damien
• Application Number:
  US13/871,174
• Publication Number:
  US 20140018352A1
• Time in Patent Office: Days
• US Class Current: 514/220
• 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

1-44. -44. (canceled)

45. A method of inhibiting protein kinase activity in a patient or a biological sample, comprising administering to the patient a compound of formula I:

46. The method of claim 45, wherein X is O and R² is —

CH₃.

47. The method of claim 45, wherein X is NR⁵ and, R² and R⁵, together with the atoms to which they are attached, form a 1,2,4-triazole.

48. The method of claim 45, wherein R⁶ is C_1-4 aliphatic or C_3-6 cycloaliphatic, and is optionally substituted with 1 or 2 halogen atoms.

49. The method of claim 45, wherein R³ and R⁴ are each methyl.

50. The method of claim 45, wherein R³ is H and R⁴ is ethyl.

51. The method of claim 45, wherein R³ and R⁴, together with the atoms to which they are attached, form a cyclopropyl ring.

52. The method of claim 45, wherein R⁶ is cyclopropyl optionally substituted with 1 or 2 halogen atoms.

53. The method of claim 45, wherein R⁶ is cyclopentyl optionally substituted with 1 or 2 halogen atoms.

54. The method of claim 45, wherein R⁶ is cyclohexyl optionally substituted with 1 or 2 halogen atoms.

55. The method of claim 45, wherein R⁶ is C_1-4 aliphatic optionally substituted with 1 or 2 halogen atoms.

56. The method of claim 45, 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.

57. The method of claim 45, wherein the protein kinase is a PLK.

58. The method of claim 57, wherein the protein kinase is PLK1.

59. 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 formula I:

60. The method according to claim 59, 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 formula I as a single dosage form or separately from the compound as part of a multiple dosage form.

61. 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 formula I: