Dna-pk inhibitors

Patent metadata

Field	Value
Publication number	US-2021069203-A1
Application number	US-202017023597-A
Country	US
Kind code	A1
Filing date	Sep 17, 2020
Priority date	Mar 12, 2013
Publication date	Mar 11, 2021
Grant date	—

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

1 - 22 . (canceled)

23 . A method of potentiating a therapeutic regimen for the treatment of cancer in a patient comprising the step of administering to said patient an effective amount of a compound of formula:

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 or up to two C 1-4 alkyl optionally substituted with up to three 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, 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 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 three 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, imidazole, triazole, thiazole, pyridine, pyrimidine, 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 three fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt thereof.

24 . The method of claim 23 , wherein X is NH.

25 . The method of claim 23 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

26 . The method of claim 25 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

27 . The method of claim 24 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

28 . The method of claim 27 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

29 . The method of claim 28 , 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 three 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, 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; 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 three 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, imidazole, triazole, thiazole, pyridine, pyrimidine, 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 three fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups.

30 . The method of claim 28 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

31 . The method of claim 23 , wherein X is O.

32 . The method of claim 31 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

33 . The method of claim 32 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

34 . The method of claim 32 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

35 . The method of claim 31 , wherein the compound is of formula:

or a pharmaceutically acceptable salt thereof.

36 . The method of claim 35 , wherein the compound is of formula:

or a pharmaceutically acc

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

• C07D413/02

  containing two hetero rings · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D498/08 Primary

  Bridged systems · CPC title

• C07D491/08

  Bridged systems · CPC title