Compounds useful as inhibitors of ATR kinase

• US 9,630,956 B2
• Filed: 05/12/2011
• Issued: 04/25/2017
• Est. Priority Date: 05/12/2010
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Grote, Matthew Paul, Charrier, Jean-Damien, Binch, Hayley Marie, Hurley, Dennis James, Cleveland, Thomas, Joshi, Pramod, Fanning, Lev Tyler Dewey, Pinder, Joanne, O'Donnell, Michael, Nizarali Virani, Anisa, Knegtel, Ronald Marcellus Alphonsus, Durrant, Steven John, Young, Stephen Clinton, Storck, Pierre-Henri, Kay, David, Reaper, Philip Michael
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US13/106,476
• Publication Number:
  US 20120027874A1
• Time in Patent Office: 2,175 Days
• Field of Search: 51425505, 544405
• 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 413/14 containing three or more hetero rings

Abstract

The present invention relates to pyrazine and pyridine 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 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

R¹ is H, C_1-6aliphatic, or tetrahydrofuranyl, wherein said C_1-6aliphatic is optionally substituted with one occurrence of OH and up to two occurrences of F;

R^3′

is H;

R⁴ is Q, —

(C_1-2alkyl)-Q, or a C_1-10aliphatic, wherein up to two methylene units of said C_1-10aliphatic are optionally replaced with O, NR′

, S, or CO;

Q is 3-6 membered saturated or partially unsaturated monocyclic ring having 0-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;

Q is optionally substituted with 1-3 occurrences of halo, CN, NRR′

, OR, or C_1-3aliphatic, wherein said C_1-3aliphatic is optionally substituted with up to 4 occurrences of F;

J² is H.

3. The compound of claim 1, wherein A is N.

4. The compound of claim 1, wherein R² is H.

5. The compound of claim 4, wherein Ring D is isoxazolyl.

6. The compound of claim 4, wherein Ring D is oxadiazolyl.

7. The compound of claim 5,

wherein

8. The compound of claim 7 having Formula Ib or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8, wherein R³ is H or methyl.

10. The compound of claim 9, wherein R³ is H.

11. The compound of claim 1, wherein R¹ is C_1-6aliphatic, phenyl, or tetrahydrofuranyl.

12. The compound of claim 11 wherein R¹ is C_1-6aliphatic or tetrahydrofuranyl.

13. The compound of claim 12, wherein R¹ is C_1-4alkyl or tetrahydrofuranyl.

14. The compound of claim 13, wherein R¹ is C_1-4alkyl.

15. The compound of claim 13, wherein R¹ is methyl, isopropyl, tert-butyl, or tetrahydrofuranyl.

16. The compound of claim 11, wherein R¹ is C_1-6aliphatic and wherein R¹ is optionally substituted with one occurrence of OH or 1-2 occurrences of fluoro.

17. The compound of claim 1, wherein q is 1.

18. The compound of claim 17, wherein J is bonded at the ortho position of the phenyl ring as shown in Formula Ic:

19. The compound of claim 18, wherein J is fluoro, C_1-3alkyl, O(C_1-3alkyl), or CN.

20. The compound of claim 19, wherein J is methyl or isopropyl.

21. The compound of claim 18, wherein J is fluoro, CH₃, OCH₃, or CN.

22. The compound of claim 1, wherein q is 0.

23. The compound according to claim 1, wherein R⁴ is Q, —

(C_1-2alkyl)-Q, or C_1-10aliphatic, wherein up to two methylene units of said C_1-10aliphatic are optionally replaced with O, NR′

, or CO; and

wherein one methylene unit of the C_1-2alkyl can optionally be replaced with C(═

O).

24. The compound of claim 23, wherein Q is a 5 membered heteroaryl having 1-2 heteroatoms selected from the group consisting of O, N, and S;

4-6 membered heterocyclyl having 1 heteroatoms selected from the group consisting of O and N;

or a 3-6 membered cycloalkyl.

25. The compound of claim 24, wherein Q is furanyl, thiazoyl, imidazolyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, or 3-6 membered cycloalkyl.

26. The compound of claim 23, wherein R⁴ is C_1-10aliphatic, —

(C_1-4alkyl)-CF₃, —

(C_1-2alkyl)-(C₃-C₆cycloaliphatic), —

(C_1-4alkyl)-N(C_1-3alkyl)₂, —

(C_1-4alkyl)-O(C_1-3alkyl), C₃-C₆cycloaliphatic, or tetrahydrofuranyl, wherein said alkyl group is optionally substituted.

27. The compound of claim 26, wherein R⁴ is C_1-6alkyl, —

(C_1-4alkyl)-CF₃, —

(C_1-2alkyl)-(C₃-C₆cycloaliphatic), C₃-C₆cycloaliphatic, or tetrahydrofuranyl.

28. The compound of claim 1, wherein R⁴ is methyl, ethyl, isopropyl, sec-butyl, isobutyl, CH(CH₃)C≡

CCH₃, CH(CH₃)COOH, CH₂CONH₂, CH(CH₃)CONH₂, CH(CH₃)CONHCH₃, CH(CH₃)CON(CH₂CH₃)₂, cyclobutyl, cyclopentyl, methylcyclopentyl, CH(CH₃)(cyclopropyl), CH₂(cyclopropyl), CH₂CH₂(cyclopropyl), CH₂CH₂(cyclopentyl), CH(CH₃)CH₂F, CH(CH₃)CF₃, CH₂CF₃, C(CH₃)₂CN, C(CH₂CH₃)₂CN, CH(CH₃)CN, CH₂CN, CH₂CH(CH₃)CH₂CH₃, CH(CH₂CH₃)₂ CH(CH₂OH)₂ CH(CH₃)CH₂OH, CH(CH₃)CH₂OCH₃, CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CH₂N(CH₃)₂, CH₂CH₂CH₂NH₂, tetrahydrofuranyl, tetrahydropyranyl, CH₂(furanyl), CH₂(thiazolyl), CH₂(imidazolyl), CH₂CH₂CN, CH₂CH(OCH₃)CH₂CH₃, CH₂CH₂CH(CH₃)CH₂CH₃,

29. The compound of claim 26, wherein R⁴ is methyl, ethyl, isopropyl, sec-butyl, isobutyl, CH(CH₃)C≡

CCH₃, CH(CH₃)COOH, cyclobutyl, cyclopentyl, CH(CH₃)(cyclopropyl), CH(CH₃)CH₂F, CH(CH₃)CF₃, CH₂CF₃, CH(CH₃)CN, CH₂CN, CH(CH₃)CH₂OH, CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CH₂N(CH₃)₂, CH₂CH₂CH₂NH₂, CH(CH₃)CH₂OCH₃, or tetrahydrofuranyl.

30. The compound of claim 28, wherein R⁴ is methyl, ethyl, isopropyl, sec-butyl, isobutyl, CH(CH₃)C≡

CCH₃, cyclobutyl, cyclopentyl, CH(CH₃)(cyclopropyl), CH(CH₃)CH₂F, CH(CH₃)CF₃, CH₂CF₃, CH(CH₃)CN, CH₂CN, or tetrahydrofuranyl.

31. The compound of claim 1, wherein J² is H, CN, F, Cl, Br, CH═

CH₂, methyl, ethyl, isopropyl, CH₂OH, CH(CH₂CH₃)CH₂CH₂CH₃, CH(CH₂CH₃)₂, cyclopentyl, cyclohexyl, cyclohexenyl, or phenyl.

32. The compound of claim 1, wherein

A is N;

J² is H;

R¹ is methyl;

R² is H;

R³ is H; and

R⁴ is C_1-10aliphatic, —

(C_1-4alkyl)-CF₃, —

(C_1-2alkyl)-(C₃-C₆cycloaliphatic), —

(C_1-4alkyl)-N(C_1-3alkyl)₂, —

(C_1-4alkyl)-O(C_1-3alkyl), C₃-C₆cycloaliphatic, or tetrahydrofuranyl, wherein said alkyl group is optionally substituted.

33. The compound of claim 32, wherein R⁴ is C_1-10aliphatic, —

(C_1-4alkyl)-CF₃, —

(C_1-2alkyl)-(C₃-C₆cycloaliphatic), C₃-C₆cycloaliphatic, or tetrahydrofuranyl.

34. The compound of claim 33, wherein said alkyl group of R⁴ is optionally substituted with CH₃, OH, OCH₃, NH₂, CN, or tetrahydrofuranyl.

35. A compound selected from the group consisting of:

36. A pharmaceutical composition comprising a compound of formula I: