Substituted benzooxadiazole DNA-PK inhibitors

Patent metadata

Field	Value
Publication number	US-9987284-B2
Application number	US-201615133378-A
Country	US
Kind code	B2
Filing date	Apr 20, 2016
Priority date	Mar 12, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

Provided are compounds of Formula (I):

wherein R 1 , R 2 , 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.

First claim

What is claimed is:

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

wherein:
Ring A is

Ring B is

wherein Ring B is optionally substituted with up to four fluorine atoms, up to two OH, or up to two C 1-4 alkyl which is optionally substituted with up to three fluorine atoms, up to two OH, or up to two —OC 1-2 alkyl groups;
Ring C is cyclohexane or cyclobutane;
X is —NH—, —O—, or —OC 1-4 alkyl-;
each of R 1 and R 2 is independently hydrogen, —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —C 0-4 alkyl-NHR 4 , or —OR 4 , wherein R 1 and R 2 cannot simultaneously be hydrogen, and wherein R 1 and R 2 and the intervening carbon atom can form a dioxane or dioxolane ring;
R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, phenyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinoline, oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine, wherein each of said R 4 groups is optionally substituted with up to four Br, Cl, F, or C 1-4 alkyl; up to three CN; NO 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), CH 2 OR 5 , C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-N(R 5 ) 2 , oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine, piperazine, furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole, or tetrazole; or up to two OR 5 , wherein each of said optional R 4 substituents is optionally substituted with up to four fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, up to two SC 1-4 alkyl groups, a C(O)C 1-4 alkyl, a C(O)OC 1-4 alkyl, or a C(O)OC 0-4 alkyl-C 3-5 cycloalkyl; and
each R 5 is independently hydrogen, C 1-4 alkyl, imidazole, triazole, thiazole, pyridine, oxetane, tetrahydrofuran, or tetrahydropyran, and each R 5 group is optionally substituted with chloro, up to three fluorine atoms, up to two C 1-2 alkyl, CH 2 OH, CN, up to two OH, up to two OC 1-2 alkyl, spirooxetane, pyrrolidine, or triazole, or two R 5 groups together with the intervening nitrogen atom form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring.

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-NHR 4 or —OR 4 .

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 R 1 is —C 0-4 alkyl-NHR 4 or —OR 4 .

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein is R 1 is —NHR 4 .

18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein is R 1 is —OR 4 .

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:

or a pharmaceutically acceptable salt thereof.

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:

or a pharmaceutically acceptable salt thereof.

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

Assignees

• Vertex Pharma

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

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title