DNA-PK inhibitors

Patent metadata

Field	Value
Publication number	US-10501439-B2
Application number	US-201815912074-A
Country	US
Kind code	B2
Filing date	Mar 5, 2018
Priority date	Apr 24, 2012
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

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 method of potentiating a therapeutic regimen for the treatment of breast cancer, colorectal cancer, gastric-esophageal cancer, fibrosarcoma, glioblastoma, hepatocellular cancer, head and neck cancer, melanoma, lung cancer, pancreatic cancer, or prostate cancer in a patient comprising administering to said patient an effective amount of a compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound of Structural Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
Q is N or CH;
R 1 is hydrogen, CH 3 , or CH 2 CH 3 , or R 1 and the carbon to which it is bound form a C═CH 2 group;
Ring A is a ring system selected from

R A1 is hydrogen, halogen, C 1-4 alkyl, C 0-4 alkyl-C 3-6 cycloalkyl, C 0-4 alkyl-OR A1a , C 0-4 alkyl-SR A1a , C 0-4 alkyl-C(O)N(R A1a ) 2 , C 0-4 alkyl-CN, C 0-4 alkyl-S(O)—C 1-4 alkyl, C 0-4 alkyl-S(O) 2 —C 1-4 alkyl, C 0-4 alkyl-C(O)OR A1b , C 0-4 alkyl-C(O)C 1-4 alkyl, C 0-4 alkyl-N(R A1b )C(O)R A1a , C 0-4 alkyl-N(R A1b )S(O) 2 R A1a , C 0-4 alkyl-N(R A1a ) 2 , C 0-4 alkyl-N(R A1b )(3-6 membered-cycloalkyl), C 0-4 alkyl-N(R A1b )(4-6 membered-heterocyclyl), N(R A1b )C 2-4 alkyl-N(R A1a ) 2 , N(R A1b )C 2-4 alkyl-OR A1a , N(R A1b )C 1-4 alkyl-(5-10 membered heteroaryl), N(R A1b )C 1-4 alkyl-(4-6 membered heterocyclyl), N(R A1b )C 2-4 alkyl-N(R A1b )C(O)R A1a , C 0-4 alkyl-N(R A1b )C(O)C 1-4 alkyl, C 0-4 alkyl-N(R A1b )C(O)OC 1-4 alkyl, C 0-4 alkyl-(phenyl), C 0-4 alkyl-(3-10 membered-heterocyclyl), C 0-4 alkyl-C(O)-(4-6 membered-heterocyclyl), C 0-4 alkyl-O—C 0-4 alkyl-(4-6 membered-heterocyclyl), C 0-4 alkyl-(5-6 membered-heteroaryl), C 0-4 alkyl-C(O)-(5-6 membered-heteroaryl), C 0-4 alkyl-O—C 0-4 alkyl-(5-6 membered-heteroaryl), C 0-4 alkyl-N(R A1a )(4-6 membered-heterocyclyl), or C 0-4 alkyl-N(R A1b )(5-6 membered-heteroaryl), wherein each of said R A1 heterocyclyl is a ring system selected from aziridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, tetrahydrothiophenedioxidyl, 1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.4]octanyl, and isoindolinonyl wherein each of said R A1 heteroaryl is a ring system selected from furanyl, thiophenyl, imidazolyl, benzoimidazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, and tetrazolyl, and wherein each of said R A1 alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two C 1-2 alkyl groups, a C 3-6 cycloalkyl group, a phenyl group, a benzyl group, an alkenyl-C 0-2 alkyl group, an alkynyl-C 0-2 alkyl group, up to two C 0-2 alkyl-OR A1b groups, a C 0-2 alkyl-N(R A1b ) 2 group, a SC 1-4 alkyl group, a S(O) 2 C 1-4 alkyl group, a C(O)R A1b group, a C(O)OR A1b group, a C(O)N(R A1b ) 2 group, a —CN group, or a C 4-6 heterocyclic ring system selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl;
each R A1a is, independently, hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, C 5-6 heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, or two R A1a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, and morpholinyl, wherein each of said R A1a alkyl, cycloalkyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to two C 1-2 alkyl groups, a C 3-6 cycloalkyl group, up to two C 0-2 alkyl-OR A1b groups, a C 0-2 alkyl-N(R A1b ) 2 group, a SC 1-4 alkyl group, a C(O)R A1b group, a C(O)OR A1b group, a C(O)N(R A1b ) 2 group, or a —CN group;
each R A1b is, independently, hydrogen, C 1-2 alkyl, or C 3-4 cycloalkyl;
R A2 is hydrogen, C 1-4 alkyl, C 0-4 alkyl-C 3-6 cycloalkyl, C 0-2 alkyl-(4-6 membered)heterocyclyl, C 2-4 alkyl-OR A2a , C 0-2 alkyl-C(O)N(R A2a ) 2 , C 0-2 alkyl-S(O) 2 —C 1-4 alkyl, C 0-2 alkyl-C(O)OC 1-4 alkyl, or C 0-2 alkyl-C(O)-(4-6 membered)heterocyclyl, wherein each of said heterocyclyl is selected from oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, and 1,1-dioxothietanyl, and each of said R A2 groups except hydrogen is optionally substituted with up to three F atoms, up to two C 1-2 alkyl groups, a C 3-6 cycloalkyl group, an alkenyl-C 0-2 alkyl group, an alkynyl-C 0-2 alkyl group, up to two OR A2b groups, a C 0-2 alkyl-N(R A2b ) 2 group, a SC 1-4 alkyl group, a S(O) 2 C 1-4 alkyl group, a C(O)R A2b group, a C(O)OR A2b group, a C(O)N(R A2b ) 2 group, or a —CN group;
each R A2a is, independently, hydrogen, C 1-4 alkyl, a C 5-6 heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, eo and pyrazinyl, or two R A2a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, and morpholinyl;
each R A2b is, independently, hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;
R A3 is hydrogen or C 1-2 alkyl;
each R A4 is, independently, deuterium, halogen, CN, C 1-4 alkyl, or OC 1-4 alkyl, wherein each R A4 alkyl is optionally substituted with up to 3 F atoms, up to three 2 H atoms, two non-geminal OH groups, or one OC 1-2 alkyl, or two R A4 together with an intervening saturated carbon atom form a spiro-linked cyclopropyl or cyclobutyl ring;
n is 0-3;
Ring B is a ring system selected from

R B1 is hydrogen, C 1-4 alkyl, (CH 2 ) 0-1 C 3-6 cycloalkyl, C(O)C 1-2 alkyl, (CH 2 ) 0-1 -(4-6 membered)heterocyclyl ring wherein said heterocyclic ring is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, and pyrrolidinonyl, phenyl, benzyl, or (CH 2 ) 1-2 (5-6 membered)heteroaryl ring wherein said heteroaryl ring is selected from pyridinyl, imidazolyl, and pyrazolyl, and wherein each of said R B1 alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl and heteroaryl groups is optionally substituted with up to 3 F atoms, up to two C 1-2 alkyl groups, two non-geminal OH groups, or one OC 1-2 alkyl;
R B2 is hydrogen, C 1-4 alkyl, or OC 1-4 alkyl;
each R B3 is, independently, hydrogen, deuterium, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)C 1-4 alkyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)NH(CH 2 ) 0-1 C 3-6 cycloalkyl, C(O)NHCH 2 oxetanyl, C(O)NHCH 2 tetrahydrofuranyl, C(O)NHCH 2 tetrahydropyranyl, C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH, C(O)NHOC 1-4 alkyl, C(O)NHO(CH 2 ) 0-1 C 3-6 cycloalky

Assignees

• Vertex Pharma

Inventors

• Charifson Paul S
• Cottrell Kevin Michael
• Deng Hongbo
• Duffy John P
• Gao Huai
• Giroux Simon
• Green Jeremy
• Jackson Katrina Lee
• Kennedy Joseph M
• Lauffer David J
• Ledeboer Mark Willem
• Li Pan
• Maxwell John Patrick
• Morris Mark A
• Pierce Albert Charles
• Waal Nathan D
• Xu Jinwang

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title