DNA-PK inhibitors

• US 10,076,521 B2
• Filed: 02/07/2017
• Issued: 09/18/2018
• Est. Priority Date: 04/24/2012
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charifson, Paul S., Cottrell, Kevin Michael, Deng, Hongbo, Duffy, John P., Gao, Huai, Giroux, Simon, Green, Jeremy, Jackson, Katrina Lee, Kennedy, Joseph M., Lauffer, David J., Ledeboer, Mark Willem, Li, Pan, Maxwell, John Patrick, Morris, Mark A., Pierce, Albert Charles, Waal, Nathan D., Xu, Jinwang
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US15/426,150
• Publication Number:
  US 20170258789A1
• Time in Patent Office: 588 Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• 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 405/14 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 413/10 : linked by a carbon chain containing aromatic rings
• 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 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/056 : with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 521/00 : Heterocyclic compounds containing unspecified hetero rings

Abstract

The present invention relates to compounds useful as inhibitors of DNA-PK. 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. A compound having the formula:

2. The compound according to claim 1 having the formula

3. The compound or salt according to claim 2, wherein R^A1 is C_1-4alkyl, OC_1-4alkyl, or N(R^A1a)₂, wherein each R^A1a is, independently, hydrogen or C_1-4alkyl, or two R^A1a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl, wherein each of said R^A1 alkyl or heterocyclyl groups is optionally substituted with up to three F atoms, up to three ²H atoms, up to two C₁-2alkyl groups, a C_3-6cycloalkyl group, up to two C_0-2alkyl-OR^A1b groups, a C_0-2alkyl-N(R^A1b)₂ group, a SC_1-4alkyl group, a C(O)R^A1b group, a C(O)OR^A1b group, a C(O)N(R^A1b)₂ group, or a —

CN group, wherein each R^A1b is, independently, hydrogen, C_1-2alkyl, or C_3-4cycloalkyl.

4. The compound or salt according to claim 1 having a formula selected from

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein

6. The compound or salt according to claim 5, wherein Q is CH.

7. The compound or salt according to claim 6, wherein Ring A comprises a heterocyclyl or heteroaryl ring.

8. The compound or salt according to claim 4, wherein Ring A is selected from

9. The compound according to claim 4, wherein Ring A is selected from

10. The compound or salt according to claim 9, wherein

R^A2 is hydrogen, C_1-4alkyl, C_0-2alkyl-C_3-6cycloalkyl, C_0-2alkyl-(4-6 membered)heterocyclyl, C_2-4alkyl-OR^A2a, C_0-2alkyl-C(O)N(R^A2a)₂, C_0-2alkyl-S(O)₂—

C_1-4alkyl, or C_0-2alkyl-C(O)OC_1-4alkyl, wherein each of said heterocyclyl is selected from oxetan-2-yl, azetidin-2-yl, piperidin-4-yl, or 1,1-dioxothietan-2-yl, and each of said R^A2 groups is optionally substituted with up to three F atoms, up to two C_1-2alkyl groups, up to two OR^A2b groups, a C_0-2alkyl-N(R^A2b)₂ group, a C(O)R^A2b group, a C(O)OR^A2b group, a C(O)N(R^A2b)₂ group, or a —

CN group;

each R^A2a is, independently, H, C_1-4alkyl, or two R^A2a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl;

each R^A2b is, independently, H or C_1-4alkyl; and

n is 0.

11. The compound or salt according to claim 4, wherein Ring A is selected from

12. The compound or salt according to claim 11, wherein

R^A2 is a hydrogen, C_1-4alkyl, C_0-2alkyl-C_3-6cycloalkyl, C_0-2alkyl-(4-6 membered)heterocyclyl, C_2-4alkyl-OR^A2a, C_0-2alkyl-C(O)N(R^A2a)₂, C_0-2alkyl-S(O)₂—

C_1-4alkyl, or C_0-2alkyl-C(O)OC_1-4alkyl, wherein each of said heterocyclyl is selected from oxetan-2-yl, azetidin-2-yl, piperidin-4-yl, or 1,1-dioxothietan-2-yl, and each of said R^A groups is optionally substituted with up to three F atoms, up to two C_1-2alkyl groups, up to two OR^A2b groups, a C_0-2alkyl-N(R^A2b)₂ group, a C(O)R^A2b group, a C(O)OR^A2b group, a C(O)N(R^A2b)₂ group, or a —

CN group;

each R^A2a is, independently, H, C_1-4alkyl, or two R^A2a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl;

each R^A2b is, independently, H or C_1-4alkyl; and

n is 0.

13. The compound or salt according to claim 4, wherein Ring A is

14. The compound or salt according to claim 13, wherein

R^A1 is C_1-4alkyl, C_0-4alkyl-C_3-6cycloalkyl, C_0-4alkyl-OR^A1a, C_0-4alkyl-C_3-6cycloalkyl, C_0-4alkyl-N(R^Ala)₂, N(R^A1a)C_2-4alkyl-N(R^A1a)₂, wherein each of said R^A1 alkyl or cycloalkyl is optionally substituted with up to three F atoms, up to three ²H atoms, or up to two C_0-2alkyl-OR^A1b groups;

each R^A1a is, independently, hydrogen, C_1-4alkyl, a C(O)R^A1b group, or two R^A1a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl, wherein each of said alkyl or heterocyclyl group of R^A1a is optionally substituted with up to three F atoms, up to two C_1-2alkyl groups, up to two OR^A1b groups, or a —

CN group;

each R^A1b is, independently, hydrogen or C_1-2alkyl;

each R^A4 is, independently, halogen, ²H, C_1-4alkyl, N(R^1a)₂, or OC_1-4alkyl, wherein each R^A4 alkyl is optionally substituted with up to 3 F atoms, up to two non-geminal OH groups, or up to two OC_1-2alkyl; and

n is 0-3.

15. The compound or salt according to claim 4, wherein Ring A is selected from

16. The compound or salt according to claim 6, wherein Ring B comprises a heterocyclyl or heteroaryl ring.

17. The compound or salt according to claim 16, wherein Ring B is selected from

18. The compound or salt according to claim 17, wherein Ring B is selected from

19. The compound or salt according to claim 17, wherein Ring B is selected from

20. The compound or salt according to claim 19, wherein Ring A is

21. A pharmaceutical composition comprising a compound or salt according to claim 1 and a pharmaceutically acceptable excipient.