Substituted pyrazines as ATR kinase inhibitors

• US 9,701,674 B2
• Filed: 08/25/2014
• Issued: 07/11/2017
• Est. Priority Date: 12/19/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Durrant, Steven, Knegtel, Ronald, Mortimore, Michael, Charrier, Jean-Damien, MacCormick, Somhairle, Kay, David, Reaper, Philip Michael, Rutherford, Alistair, Young, Stephen, Virani, Anisa Nizarali, O'Donnell, Michael, Pinder, Joanne
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/467,175
• Publication Number:
  US 20150051187A1
• Time in Patent Office: 1,051 Days
• Field of Search: 51425506, 544407
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 241/28 in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention relates to pyrazine 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.

Certain compounds of this invention are of formula II, V, and/or VII:

• • wherein the variables are as defined herein.

Claims

1. A compound of Formula II:

2. The compound of claim 1, wherein R¹ and R², taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring containing 1-2 nitrogen atoms.

3. The compound of claim 2, wherein t is 1.

4. The compound of claim 2, wherein t is 0.

5. The compound of claim 2, wherein the heterocyclic ring formed by R¹ and R² is pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1,4-diazepanyl.

6. The compound of claim 5, wherein the heterocyclic ring formed by R¹ and R² is

7. The compound of claim 6, wherein the ring formed by R¹ and R² is optionally substituted with CH₂pyrrolidinyl, C₁-C₄alkyl, N(C₁-C₂alkyl)₂, or CH₂CH₂CN.

8. The compound of claim 7, wherein R³ and R⁴ are both C₁-C₂alkyl.

9. The compound of claim 7, wherein R³ and R⁴, taken together with the atom to which they are bound, form a ring selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and 1,4-diazepanyl.

10. The compound of claim 9, wherein said ring is pyrrolidinyl or piperidinyl.

11. The compound of claim 1, wherein R² is —

(C₂-C₆alkyl)-Z.

12. The compound of claim 1, wherein p is 0, q is 0, and -L-NR¹R² is C(O)-pyrrolidinyl, C(O)-piperidinyl, C(O)-piperazinyl, C(O)-azepanyl, C(O)-1,4-diazepanyl, or C(O)—

N(CH₃)CH₂CH₂N(CH₃)₂, wherein said pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1,4-diazepanyl is optionally substituted with CH₂pyrrolidinyl, C₁-C₄alkyl, N(C₁-C₂alkyl)₂, or CH-₂CH₂CN.

13. The compound of claim 1, the compound is:

14. A method if inhibiting ATR in a biological sample, comprising the step of contacting a compound of claim 1 with said biological sample.

15. The method of claim 14, wherein said biological sample is a cell.

20. The compound of claim 14, wherein Ring A is a 9-membered bicyclic heteroaryl ring.

21. The compound of claim 20, wherein L is C(O) or S(O)₂.

22. The compound of claim 21, wherein R¹ and R² are both C₁-C₄alkyl.

26. The compound of claim 14, wherein Ring A has 1-2 heteroatoms.

27. The compound of claim 26, wherein p is 1 and Ring Q is substituted in the para position with L-NR¹R² as shown in Formula V-a:

28. The compound of claim 20, wherein L is C(O) or S(O)_2.

29. The compound of claim 14, wherein Ring A is a 9-membered bicyclic heteroaryl ring.

30. The compound of claim 14, wherein Ring A is an 8-membered bicyclic heteroaryl ring.

33. The compound of claim 15, wherein Ring Q is pyridyl.

35. The compound of claim 33, wherein m is 1, and J² is CN.

46. The compound of claim 33, wherein Ring A is phenyl.

47. The compound of claim 46, wherein said phenyl is substituted with one occurrence of J¹.

48. The compound of claim 47, wherein J¹ is a C₁-C₆alkyl chain wherein 1 methylene unit is replaced with NR* or O.

56. A method of sensitizing cells of a patient to DNA damaging agents comprising administering to the patient a compound of any one of claims 1, 14, and 33.

59. The method of claim 56, wherein said cells are cancer cells expressing DNA damaging oncogenes.

16. A pharmaceutical composition comprising a compound of formula II,

34. The compound of claim 16, wherein p is 0.

44. The compound of claim 34, wherein Ring A is pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, triazolyl, thienyl, thiazolyl, thiadiazolyl, furanyl, oxazolyl, or oxadiazolyl.

17. A method of promoting cell death in cancer cells of a patient comprising administering to the patient a compound of formula II,

18. A method of preventing cell repair from DNA damage in a patient comprising administering to the patient a compound of formula II,

19. A compound of Formula V:

23. The compound of claim 19, wherein Ring A is benzimidazolyl, benzoxazolyl, indazolyl, benzothiazolyl, or indolyl.

24. The compound of claim 19, wherein Ring A is benzimidazolyl, benzoxazolyl, indazolyl, benzothiazolyl, indolyl, or pyrrolopyridinyl.

25. The compound of claim 24, wherein said 4-7 membered monocyclic heterocyclic ring is 1,4-diazepanyl.

31. The compound of claim 23, wherein said 4-7 membered monocyclic heterocyclic ring is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, and 1,4-diazepanyl.

32. The compound of claim 24, wherein said 4-7 membered monocyclic heterocyclic ring is 1,4-diazepanyl.

36. The compound of claim 19, wherein the compound is:

37. The compound of claim 19, wherein the compound is:

38. A method of inhibiting ATR in a biological sample comprising the step of contacting a compound of claim 19 with said biological sample.

49. The compound of claim 38, wherein J¹ is O(C₁-C₄alkyl) or —

(C₁-C₄alkyl)NH(C₁-C₄alkyl).

57. The method of claim 49, wherein said cells are cancer cells having defects in the ATM signaling cascade.

58. The method of claim 57, wherein said defect is altered expression or activity of one or more selected from the group consisting of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, and H2AX.

60. The method of claim 19, wherein said cancer cell has altered expression or activity of one or more selected from the group consisting of K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A, and Rb.

39. A pharmaceutical composition comprising a compound of formula V,

50. The compound of claim 39, wherein J¹ is —

(C₁-C₄alkyl)NH(C₁-C₄alkyl).

40. A method of promoting cell death in cancer cells of a patient comprising administering to the patient a compound of formula V,

41. A method of preventing cell repair from DNA damage in a patient, comprising administering to the patient a compound of formula V,

42. A compound of Formula VII:

43. The compound of claim 42, wherein Ring A is a 5-6 membered monocyclic heteroaryl having 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.

45. The compound of claim 43, wherein Ring A is pyridinyl, pyrazolyl, thiadiazolyl, or thiazolyl, wherein Ring A is optionally substituted with C_1-4alkyl.

51. The compound of claim 42, wherein the compound is:

52. A method of inhibiting ATR in a biological sample comprising the step of contacting a compound of claim 42 with said biological sample.

53. A pharmaceutical composition comprising a compound of formula VII,

54. A method of promoting cell death in cancer cells of a patient comprising administering to the patient a compound of formula VII,

55. A method of preventing cell repair from DNA damage in a patient comprising administering to the patient a compound of formula VII,

61. A compound selected from the group consisting of: