COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE

• US 20120046295A1
• Filed: 06/23/2011
• Published: 02/23/2012
• Est. Priority Date: 06/23/2010
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Pinder, Joanne, Fraysse, Damien, Knegtel, Ronald Marcellus Alphonsus, Durrant, Steven John, MacCormick, Somhairle, Virani, Anisa Nizarali, Reaper, Philip Michael
• Granted Patent: US 8,623,869 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61N 2005/1098 Enhancing the effect of the particle by an injected agent or implanted device
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention relates to pyrrolopyrazines compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

The compounds of this invention have formula I:

wherein the variables are as defined herein.

Claims

1. A compound of formula I:

2. The compound of claim 1 wherein

A¹ is

3. The compound of claim 1, wherein A is

4. The compound of claim 1, wherein A is

5. The compound of claim 3, wherein A¹ is selected from the following:

6. The compound of claim 3, wherein A¹ is

7. The compound of claim 6, wherein X¹ is S.

8. The compound of claim 3, wherein A¹ is

9. The compound of claim 8, wherein X¹ is S or O.

10. The compound of claim 9, wherein X¹ is O.

11. The compound of claim 1 wherein Z¹ is C_1-6alkyl

12. The compound of claim 1, wherein Z¹ is a 5-6 membered aromatic ring.

13. The compound of claim 6, wherein Z¹ is COOH.

14. The compound of claim 12, wherein Z¹ is phenyl.

15. The compound of claim 12, wherein Z¹ is optionally substituted with 1-2 J¹ groups.

16. The compound of claim 15, wherein J¹ is —

CH₂NHR′

or CHC_1-6alkyl)NHR′

.

17. The compound of claim 16, wherein R′

is H.

18. The compound of claim 1, wherein A is

19. The compound of claim 18, wherein A² is phenyl and Z² is CN, CH₂OH, CH₂OCH₃, CONH₂, CON(CH₃)₂, OCH₃, or tretrazolyl.

20. The compound of claim 18, wherein A² is a 6-membered heteroaryl having 1-2 nitrogen atoms.

21. The compound of claim 20, wherein A² is pyridinyl or pyrimidinyl.

22. The compound of claim 21, wherein A² is selected from the following:

23. The compound of claim 1, wherein A is

24. The compound of claim 23, wherein A³ is an 8-10 membered bicyclic heteroaromatic ring having 1-2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.

25. The compound of claim 24, wherein said heteroaromatic ring is benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, azaindolyl, indolyl, indazolyl, benzothienyl, benzofuranyl, dihydrothienodioxinyl, quinolinyl, or isoquinolinyl.

26. The compound of claim 25, wherein A is

27. The compound of claim 24, wherein A is selected from the following:

28. The compound of claim 24, wherein A is selected from the following:

29. The compound of claim 1, wherein A is

30. The compound of claim 29, wherein Z⁴ is a 5-6 membered aromatic ring.

31. The compound of claim 30, wherein Z⁴ is phenyl.

32. The compound of claim 1, wherein R¹ is C_1-6alkyl.

33. The compound of claim 1, wherein R¹ is a monocyclic ring.

34. The compound of claim 33, wherein R¹ is a 3-7 membered cycloaliphatic or heterocyclyl.

35. The compound of claim 33, wherein R¹ is a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

36. The compound of claim 35, wherein R¹ is phenyl, pyridinyl, or pyrimidinyl.

37. The compound of claim 36, wherein R¹ is phenyl.

38. The compound of claim 1, wherein R¹ is substituted by one to two occurrences of J.

39. The compound of claim 38, wherein R¹ is substituted in the para position with J.

40. The compound of claim 39, wherein J is V.

41. The compound of claim 40, wherein V is a C_1-6aliphatic group wherein one methylene unit is optionally replaced with S(O)₂.

42. The compound of claim 41, wherein V is —

S(O)₂(C_1-4allyl).

43. The compound of claim 42, wherein V is S(O)₂CH(CH₃)₂.

44. The compound of claim 38, wherein J is CN and substituted in the ortho position.

45. The compound of claim 39, wherein J is —

(V)_t—

R².

46. The compound of claim 45, wherein V is —

S(O)₂.

47. The compound of claim 46, wherein R² is a C_3-7 cycloalkyl or a 3-7 membered heterocyclyl having 1-3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.

48. The compound of claim 1, wherein R¹ is phenyl substituted in the para position with J, wherein J is —

S(O)₂(C_1-4alkyl).

50. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

51. A method for treating cancer in a patient comprising administering a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

52. The method of claim 50, further comprising administering to said patient an additional therapeutic agent selected from a DNA-damaging agent;

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

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

53. The method of claim 51, wherein said DNA-damaging agent is selected chemotherapy or radiation treatment.

60. The method of claim 51, wherein said cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.

49. A compound selected from the following:

54-59. -59. (canceled)

61-73. -73. (canceled)