Substituted benzooxadiazole DNA-PK inhibitors

• US 9,987,284 B2
• Filed: 04/20/2016
• Issued: 06/05/2018
• Est. Priority Date: 03/12/2013
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Maxwell, John Patrick, Charifson, Paul S., Tang, Qing, Ronkin, Steven M., Jackson, Katrina Lee, Pierce, Albert Charles, Lauffer, David J., Li, Pan, Giroux, Simon, Xu, Jinwang, Cottrell, Kevin Michael, Morris, Mark A., Waal, Nathan D., Court, John J., Gu, Wenxin, Deng, Hongbo
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/133,378
• Publication Number:
  US 20160340341A1
• Time in Patent Office: 776 Days
• Field of Search: 514361, 548126
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5386 spiro-condensed or forming part of bridged ring systems
• 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 241/40 Benzopyrazines
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 271/12 condensed with carbocyclic rings or ring systems
• 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 403/12 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 405/12 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 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 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 475/00 : Heterocyclic compounds containing pteridine ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/052 : the oxygen-containing ring being six-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 491/08 : Bridged systems
• CPC Class Codes: C07D 498/08 : Bridged systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Provided are compounds of Formula (I):

wherein R¹, R², X, Ring A, Ring B, and Ring C are as defined herein. Compounds of Formula (I) are useful as inhibitors of DNA-PK. Also provided are pharmaceutical compositions comprising said compounds and methods of using the compounds and compositions in the treatment of various diseases, conditions, and disorders.

Claims

1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is cyclobutane.

3. The compound of claim 2, represented by Formula (II), or a pharmaceutically acceptable salt thereof:

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is cyclohexane.

6. The compound of claim 5, represented by Formula (III), or a pharmaceutically acceptable salt thereof:

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein X is —

NH—

.

8. The compound of claim 7, represented by Formula (III-A-2), or a pharmaceutically acceptable salt thereof:

9. The compound of claim 7, represented by Formula (III-B-2), or a

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein

11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R is —

C_0-4 alkyl-NHR⁴ or —

OR⁴.

12. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein X is —

O—

.

13. The compound of claim 12, represented by Formula (III-C-2), or a pharmaceutically acceptable salt thereof:

14. The compound of claim 12, represented by Formula (III-D-2), or a pharmaceutically acceptable salt thereof:

15. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein

16. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein is R¹ is —

C_0-4 alkyl-NHR⁴ or —

OR⁴.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein is R¹ is —

NHR⁴.

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein is R¹ is —

OR⁴.

19. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A compound of the formula:

21. A pharmaceutical composition comprising a compound of claim 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. A compound of the formula:

23. A pharmaceutical composition comprising a compound of claim 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.