Substituted quinoxaline DNA-PK inhibitors

Patent metadata

Field	Value
Publication number	US-10973830-B2
Application number	US-201916372080-A
Country	US
Kind code	B2
Filing date	Apr 1, 2019
Priority date	Mar 12, 2013
Publication date	Apr 13, 2021
Grant date	Apr 13, 2021

Abstract

The present invention relates to 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 of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is:

Ring B is:

each optionally substituted with one, two, three, or four fluoro, one or two hydroxy, or one or two C 1-4 alkyl, wherein the C 1-4 alkyl is further optionally substituted with one, two, or three fluoro, one or two hydroxy, or one or two OC 1-2 alkyl;

Ring C is cyclohexyl;
X is —NH—, —O—, or —OC 1-4 alkylene-;
R 1 is hydrogen, C 0-4 alkyl-NHR 4 , C(O)NHR 4 , C(O)OR 4 , NHC(O)R 4 , NHC(O)NHR 4 , NHC(O)OR 4 , NHS(O) 2 R 4 , or OR 4 ;
R 2 is hydrogen, C 0-4 alkyl-NHR 4 , C(O)NHR 4 , C(O)OR 4 , NHC(O)R 4 , NHC(O)NHR 4 , NHC(O)OR 4 , NHS(O) 2 R 4 , or OR 4 ; or
R 1 and R 2 , together with the intervening carbon atom(s) to which they are attached, form a dioxane or dioxolane ring;
R 3 is hydrogen, fluoro, chloro, cyano, C 1-4 alkyl, C(O)H, C(O)NH 2 , C(O)NHC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, or OC 1-2 alkyl, wherein each C 1-4 alkyl, C(O)NHC 1-2 alkyl, C(O)OC 1-2 alkyl, and OC 1-2 alkyl is optionally substituted with one, two, or three fluoro, one or two hydroxy, or one or two OC 1-2 alkyl;
each R 4 is independently hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, or phenyl, wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl and phenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of:
(a) one, two, three, or four fluoro, chloro, bromo, or C 1-4 alkyl;
(b) one, two, or three cyano;
(c) one or two OR 5 ;
(d) NO 2 , CH 2 OR 5 , C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)NH 2 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-N(R 5 )2, C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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), C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, or C 3-6 cycloalkyl;
(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and
(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each C 1-4 alkyl, CH 2 OR 5 , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O)NH 2 , C 1-4 alkyl-C(O)N(R 5 ) 2 , C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-N(R 5 ) 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)N(C 1-4 alkyl) 2 , C 1-4 alkyl-C(O)OR 5 , C(O)OC 1-4 alkyl, C(O)OC 1-4 alkyl-C 3-5 cycloalkyl, C 3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro, one or two C 1-4 alkyl, one C(O)C 1-4 alkyl, one C(O)OC 1-4 alkyl, one C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, one or two hydroxy, one or two OC 1-4 alkyl, or one or two SC 1-4 alkyl; or
each R 4 is independently selected from the group consisting of:
(i) a heterocyclyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroisoxazolyl, pyrimidine-2,4-(1H,3H)-dionyl, dihydropyrrolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyranopyrimidinyl, tetrahydropteridinyl, and tetrahydropyridopyrimidinyl; and
(ii) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrimidinonyl, pyrazinyl, and quinolinyl;
wherein each heterocyclyl and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of:
(a) one, two, three, or four fluoro, chloro, bromo, or C 1-4 alkyl;
(b) one, two, or three cyano;
(c) one or two OR 5 ;
(d) NO 2 , CH 2 OR 5 , C 2-4 alkenyl, C 2-4 alkynyl, C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-N(R 5 ) 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 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), C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, or C 3-6 cycloalkyl;
(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, piperazinyl, and morpholinyl; and
(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each C 1-4 alkyl, CH 2 OR 5 , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkyl-C(O)R 5 , C 1-4 alkyl-C(O)NH 2 , c 1-4 alkyl-C(O)N(R 5 )2, C 1-4 alkyl-NHC(O)R 5 , C 1-4 alkyl-N(R 5 ) 2 , C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C(O)NHC 1-4 alkyl, C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), C(O)N(C 1-4 alkyl) 2 , C 1-4 alkyl-C(O)OR 5 , C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, C 3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro, one or two C 1-4 alkyl, one C(O)C 1-4 alkyl, one C(O)OC 1-4 alkyl, one C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, one or two hydroxy, one or two OC 1-4 alkyl, or one or two SC 1-4 alkyl; and
each R 5 is independently hydrogen, C 1-4 alkyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, wherein the C 1-4 alkyl, imidazolyl, triazolyl, thiazolyl, pyridinyl, pyrimidinyl, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl are each optionally and independently substituted with one, two, or three fluoro, one chloro, one cyano, one or two C 1-2 alkyl, one hydroxymethyl, one or two hydroxy, one or two OC 1-2 alkyl, one pyrrolidinyl, one spirooxetanyl, or one triazolyl; or
two R 5 , together with the intervening nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
with the proviso that R 1 and R 2 are not simultaneously hydrogen.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, C 1-4 alkyl, C(O)H, C(O)NH 2 , or OC 1-2 alkyl, wherein each C 1-4 alkyl and OC 1-2 alkyl is optionally substituted with one hydroxy.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

4. The compound of claim 1 , wherein the compound is of Formula (III):

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein the compound is of Formula (III-A-1):

or a pharmaceutically acceptable salt thereof

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