DNA-PK inhibitors

Patent metadata

Field	Value
Publication number	US-9359380-B2
Application number	US-201414205508-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 12, 2013
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

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.

First claim

What is claimed is:

1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein Ring A is a ring system selected from

Ring B is a ring system selected from

wherein Ring B is optionally substituted with up to 4 fluorine atoms or up to two C 1-4 alkyl optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
X is NH or O;
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 , —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 3 is hydrogen, C 1-4 alkyl, fluoro, chloro, OC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, CN, C(O)NHC 1-2 alkyl, or C(O)NH 2 , wherein each of said R 3 alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, phenyl, a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, or quinoline, or a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from 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 Br, Cl, up to three fluorine atoms, up to three C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, an oxetane ring, a tetrahydrofuran ring, a dihydropyran ring, a tetrahydropyran ring, a pyrrolidine ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxadiazole ring, CN, CH 2 OR 5 , C(O)R 5 , C(O)N(R 5 ) 2 , C(O)OR 5 , NO 2 , NHC(O)R 5 , N(R 5 ) 2 , or up to two OR 5 , wherein each of said optional R 4 substituents is optionally substituted with up to 3 fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, or up to two SC 1-4 alkyl groups; and
each R 5 is, independently, hydrogen, C 1-4 alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, a 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, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups.

2. The compound according to claim 1 , wherein X is NH.

3. The compound according to claim 2 having the following formula:

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 having the following formula:

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 2 having the following formula:

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5 having the following formula:

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 , wherein
R 3 is hydrogen, C 1-4 alkyl, fluoro, chloro, OC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, CN, C(O)NHC 1-2 alkyl, or C(O)NH 2 , wherein each of said R 3 alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, phenyl, a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, or quinoline, or a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine;
each of said R 4 groups is optionally substituted with Br, Cl, up to three fluorine atoms, up to three C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, an oxetane ring, a tetrahydrofuran ring, a dihydropyran ring, a tetrahydropyran ring, a pyrrolidine ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxadiazole ring, CN, CH 2 OR 5 , C(O)R 5 , C(O)N(R 5 ) 2 , C(O)OR 5 , NO 2 , NHC(O)R 5 , N(R 5 ) 2 , or up to two OR 5 , wherein each of said optional R 4 substituents is optionally substituted with up to 3 fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, or up to two SC 1-4 alkyl groups; and
each R 5 is, independently, hydrogen, C 1-4 alkyl, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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, 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, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups.

8. The compound according to claim 7 having formula:

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein X is O.

10. The compound according to claim 9 having the following formula:

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10 having the following formula:

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 10 having the following formula:

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 9 having the following formula:

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 M
• Morris Mark A
• Waal Nathan D
• Court John J
• Gu Wenxin
• Deng Hongbo

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D491/08

  Bridged systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title