Substituted pyrazin-2-amines as inhibitors of ATR kinase

• US 9,365,557 B2
• Filed: 03/24/2014
• Issued: 06/14/2016
• Est. Priority Date: 12/19/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: MacCormick, Somhairle, Charrier, Jean-Damien, Durrant, Steven, Kay, David, Knegtel, Ronald, Mortimore, Michael, O'Donnell, Michael, Pinder, Joanne, Rutherford, Alistair, Virani, Anisa Nizarali, Young, Stephen, Reaper, Philip Michael
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/223,109
• Publication Number:
  US 20150031661A1
• Time in Patent Office: 813 Days
• Field of Search: 514/255.06, 544/405, 546/268.1, 548/128, 548/131, 548/143, 548/247
• US Class Current: 1/1
• 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 have formula IA:

• • wherein the variables are as defined herein.

Claims

1. A compound of formula IA:

2. The compound of claim 1, wherein

Y is a C₁-C₆aliphatic chain wherein one methylene unit of the alkyl chain is optionally replaced with C(O) or —

NR⁰—

;

R⁵ is a 3-7 membered monocyclic fully saturated, partially unsaturated, or aromatic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or an 8-10 membered bicyclic fully saturated, partially unsaturated, or aromatic ring containing 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

wherein R⁵ is optionally substituted with 1-5 J⁵ groups;

J^Z1 is —

(X)_t—

CN, C₁-C₆alkyl, or —

(X)_r—

Z;

X¹ is C_1-10aliphatic;

wherein 1-3 methylene units of said C_1-10aliphatic are optionally replaced with —

NR′

—

, —

O—

, —

S—

, C(O), S(O)₂, or S(O);

wherein X¹ is optionally and independently substituted with 1-4 occurrences of NH₂, NH(C_1-4aliphatic), N(C_1-4aliphatic)₂, halogen, C_1-4aliphatic, OH, O(C_1-4aliphatic), NO₂, CN, CO₂H, CO₂(C_1-4aliphatic), C(O)NH₂, C(O)NH(C_1-4aliphatic), C(O)N(C_1-4aliphatic)₂, SO(C_1-4aliphatic), S(O)₂(C_1-4aliphatic), SO₂NH(C_1-4aliphatic), SO₂NH(C_1-4aliphatic), NHC(O)(C_1-4aliphatic), or N(C_1-4aliphatic)C(O)(C_1-4aliphatic), wherein said C_1-4aliphatic is optionally substituted with 1-3 occurrences of halo.

3. The compound of claim 1, wherein J³ is H.

4. The compound of claim 3, wherein Ring A is

5. The compound of claim 1, wherein Ring A is

6. The compound of claim 1, wherein J² is —

OCH₃, —

OCH₂CH₂N(CH₃)₂, —

NHCH₂CH₂N(CH₃)₂, or piperazinyl.

7. The compound of claim 1, wherein Q is substituted at the para position with J², wherein J² is a C_1-6aliphatic group wherein the methylene group bonded to Q is replaced with —

SO₂—

.

8. The compound of claim 1, wherein Q is substituted at the para position with —

S(O)₂(C_1-4alkyl), —

S(O)₂(C_1-4alkyl)N(C_1-4alkyl)₂, C(O)N(C_1-4alkyl)₂, C(O)(1,4-diazepanyl), CO(azepanyl), C(O)(piperazinyl), or C(O)(piperidinyl).

9. The compound of claim 1, wherein Q is phenyl.

10. The compound of claim 1, wherein Q is substituted at the ortho-position with one J², wherein J² is C₁-C₄alkyl, NH₂, NHC(O)CH₃, O(C₁-C₄alkyl), CH₂OH, CH₂OCH₃, CH₂CH₂OCH₃, CH₂CN, CN, CH₂C(O)NH₂, OH, OCF₃, CF₃, CHF₂, —

CH═

CHF, NHC(O)CH₃, C(O)CH₃, C(O)NH₂, SCH₃, S(O)CH₃, S(O)CH₂CH₃, S(O)₂CH(CH₃)₂, —

C≡

CH, oxazolyl, or phenyl.

11. The compound of claim 10, wherein Q is substituted at the ortho position with J², wherein J² is CH₂OH, CHF₂, S(O)CH₃, or S(O)CH₂CH₃.

12. The compound of claim 1, wherein Q is substituted at the ortho-position with J², wherein J² is C_1-4alkyl, —

C≡

C—

(C_1-4alkyl), CH═

CH₂, CH═

CHF, O(C_1-4alkyl), NH(C_1-4alkyl), N(C_1-4alkyl)₂, —

(C_1-4alkyl)OH, —

(C_1-4alkyl)O(C_1-4alkyl), —

(C_1-4alkyl)NH₂, —

(C_1-4alkyl)NH(C_1-4alkyl), —

(C_1-4alkyl)N(C_1-4alkyl)₂, —

(C_1-4alkyl)CN, CO(C_1-4alkyl), CON(C_1-4alkyl)₂, C(O)O(C_1-4alkyl), S(C_1-4alkyl), —

S—

(C_1-4alkyl)NH₂, S(O)(C_1-4alkyl)NH₂, S(O)₂(C_1-4alkyl)OH, NHS(O)₂(C_1-4alkyl), halo, or CN.

13. The compound of claim 1, wherein J² is CH₂CH₂OH, SCH(CH₃)₂, —

C≡

CCH₃, halo, CN, CON(CH₃)₂, CH₂CN, S(O)CH₂CH₂NH₂, SCH₂CH₂NH₂, C(O)OCH₃, CH₂N(CH₃)₂, N(CH₃)₂, NHSO₂CH₃, CH═

CHF, CH₂OCH₃, CH═

CH₂, SCH₂CH₃, or —

C≡

CH.

14. The compound of claim 1, wherein Q is substituted at the para position with J², wherein J² is —

SO₂(C_1-4alkyl), —

S(O)₂(C_3-6cycloalkyl), —

S(O)₂(3-6 membered heterocyclyl), —

S(O)₂(C_1-4alkyl)N(C_1-4alkyl)₂, —

C(O)(C_1-4alkyl), —

(C_1-4alkyl)N(C_1-4alkyl)₂, or —

NHC(O)(C_1-4alkyl).

15. The compound of claim 1, wherein Q is pyridyl.

16. The compound of claim 1, wherein Q is substituted at the ortho-position with one J², wherein J² is CN.

17. The compound of claim 1, wherein Q is substituted with one or two J², wherein J² is a C_1-6aliphatic group wherein up to two methylene units are optionally replaced with O or NR″

.

18. The compound of claim 17, wherein J² is —

OCH₃, —

OCH₂CH₂N(CH₃)₂, or —

NHCH₂CH₂N(CH₃)₂.

19. The compound of claim 1, wherein Ring A is

20. The compound of claim 19, wherein m is 0.

21. The compound of claim 19, wherein R¹ is H or C₁-C₆alkyl;

and R² is —

(C₂-C₆alkyl)-Z.

22. The compound of claim 21, wherein R³ and R⁴ are both C₁-C₂alkyl.

23. The compound of claim 1, wherein J³ is H.

24. The compound of claim 23, wherein J² is halo, CN, phenyl, oxazolyl, or a C_1-6aliphatic group wherein up to two methylene units are optionally replaced with O, NR″

, C(O), S, S(O), or S(O)₂;

wherein said C_1-6aliphatic group is optionally substituted with 1-3 fluoro or CN.

27. The compound of claim 1 having formula IIA:

28. The compound of claim 27 selected from the group consisting of:

29. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.

43. A method of inhibiting ataxia telangiectasia and Rad3-related kinase activity in a biological sample, comprising the step of contacting a compound of any one of claims 1 and 32, or a pharmaceutically acceptable salt thereof, with said biological sample.

44. A method of promoting cell death in cancer cells of a patient, comprising administering to said patient a compound of any one of claims 1 and 32, or a pharmaceutically acceptable salt thereof.

45. The method of claim 44, wherein said cell is a cancer cell expressing DNA damaging oncogenes.

46. The method of claim 45, wherein said cancer cell has altered expression or activity of one or more kinases 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.

47. A method of preventing cell repair from DNA damage in a patient, comprising administering to said patient a compound of any one of claims 1 and 32, or a pharmaceutically acceptable salt thereof.

48. A method of sensitizing cells to DNA damaging agents in a patient, comprising administering to said patient a compound of any one of claims 1 and 32, or a pharmaceutically acceptable salt thereof.

49. The method of claim 48, wherein said cell is a cancer cell having defects in the ataxia telangiectasia mutated kinase signaling cascade.

50. The method of claim 49, wherein said defect is altered expression or activity of one or more kinases selected from the group consisting of ataxia telangiectasia mutated, p53, checkpoint kinase 2, MRE11, RAD50, NBS1, 53BP1, MDC1 and H2AX.

25. The compound having formula IA′

;

26. The compound of claim 25, wherein J⁵ is halo, CN, phenyl, oxazolyl, or a C_1-6aliphatic group wherein up to two methylene units are optionally replaced with O, NR′

, C(O), S, S(O), or S(O)₂;

wherein said C_1-6aliphatic group is optionally substituted with 1-3 fluoro or CN.

30. A compound of formula IA:

31. The compound of claim 30, wherein q is 0.

32. A compound having formula IA-ii:

33. The compound of claim 32, 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 heteroatoms selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1,4-diazepanyl.

34. The compound of claim 33, wherein said 4-8 membered heterocyclic ring containing 1-2 nitrogen heteroatoms is

35. The compound of claim 33, wherein J^Z1 is (X)_r—

Z.

36. The compound of claim 33, wherein J^Z1 is C_1-4alkyl.

37. The compound of claim 32, wherein R³ and R⁴, taken together with the atom to which they are bound, form a 4-8 membered heterocyclic ring containing 1-2 nitrogen heteroatoms selected from pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, or 1,4-diazepanyl.

38. The compound of claim 37, wherein said 4-8 membered heterocyclic ring containing 1-2 nitrogen heteroatoms is pyrrolidinyl or piperidinyl.

39. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of claim 32 and a pharmaceutically acceptable carrier.

40. A compound having formula IA-iii:

41. The compound of claim 40, wherein Ring A is

42. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of claim 40 and a pharmaceutically acceptable carrier.

51. A compound selected from the group consisting of:

52. A compound selected from the group consisting of:

53. A compound selected from the group consisting of:

54. A compound selected from the group consisting of: