发明名称 DNA-PK INHIBITORS
摘要 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.
申请公布号 US2015111871(A1) 申请公布日期 2015.04.23
申请号 US201414515793 申请日期 2014.10.16
申请人 VERTEX PHARMACEUTICALS INCORPORATED 发明人 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
分类号 C07D239/42;C07D471/04;C07D413/10;C07D405/14;A61K41/00;C07D417/10;C07D413/14;C07D495/04;C07D491/048;C07D491/056;C07D401/04;C07D409/14 主分类号 C07D239/42
代理机构 代理人
主权项 1. A compound having the formula:wherein Q is N or CH; R1 is hydrogen, CH3, CH2CH3, or R1 and the carbon to which it is bound form a C═CH2 group; Ring A is a ring system selected from RA1 is hydrogen, halogen, C1-4alkyl, C0-4alkyl-C3-6cycloalkyl, C0-4alkyl-ORA1a, C0-4alkyl-SRA1a, C0-4alkyl-C(O)N(RA1a)2, C0-4alkyl-CN, C0-4alkyl-S(O)—C1-4alkyl, C0-4alkyl-S(O)2—C1-4alkyl, C0-4alkyl-C(O)ORA1b, C0-4alkyl-C(O)C1-4alkyl, C0-4alkyl-N(RA1b)C(O)RA1a, C0-4alkyl-N(RA1b)S(O)2RA1a, C0-4alkyl-N(RA1a)2, C0-4alkyl-N(RA1b)(3-6 membered-cycloalkyl), C0-4alkyl-N(RA1b)(4-6 membered-heterocyclyl), N(RA1b)C2-4alkyl-N(RA1a)2, N(RA1b)C2-4alkyl-ORA1a, N(RA1b)C1-4alkyl-(5-10 membered heteroaryl), N(RA1b)C1-4alkyl-(4-6 membered heterocyclyl), N(RA1b)C2-4alkyl-N(RA1b)C(O)RA1a, C0-4alkyl-N(RA1b)C(O)C1-4alkyl, C0-4alkyl-N(RA1b)C(O)OC1-4alkyl, C0-4alkyl-(phenyl), C0-4alkyl-(3-10 membered-heterocyclyl), C0-4alkyl-C(O)-(4-6 membered-heterocyclyl), C0-4alkyl-O—C0-4alkyl-(4-6 membered-heterocyclyl), C0-4alkyl-(5-6 membered-heteroaryl), C0-4alkyl-C(O)-(5-6 membered-heteroaryl), C0-4alkyl-O—C0-4alkyl-(5-6 membered-heteroaryl), C0-4alkyl-N(RA1a)(4-6 membered-heterocyclyl), or C0-4alkyl-N(RA1b)(5-6 membered-heteroaryl), wherein each of said RA1 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, or isoindolinonyl wherein each of said RA1 heteroaryl is a ring system selected from furanyl, thiophenyl, imidazolyl, benzoimidazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, or tetrazolyl, and wherein each of said RA1 alkyl, cycloalkyl, phenyl, heterocyclyl, or heteroaryl groups is optionally substituted with up to three F atoms, up to two C1-2alkyl groups, a C3-6cycloalkyl group, a phenyl group, a benzyl group, an alkenyl-C0-2alkyl group, an alkynyl-C0-2alkyl group, up to two C0-2alkyl-groups, a C0-2alkyl-N(RA1b)2 group, a SC1-4alkyl group, a S(O)2C1-4alkyl group, a C(O)RA1b group, a C(O)ORA1b group, a C(O)N(RA1b)2 group, a —CN group, or a C4-6heterocyclic ring system selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or morpholinyl; each RA1a is, independently, hydrogen, C1-4alkyl, C3-6cycloalkyl, C4-6heterocyclyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl, C5-6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, or two RA1a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl, wherein each of said RA1a alkyl, cycloalkyl, heterocyclyl, or heteroaryl groups is optionally substituted with up to three F atoms, up to two C1-2alkyl groups, a C3-6cycloalkyl group, up to two C0-2alkyl-groups, a C0-2alkyl-N(RA1b)2 group, a SC1-4alkyl group, a C(O)RA1b group, a C(O)ORA1b group, a C(O)N(RA1b)2 group, or a —CN group; each RA1b is, independently, hydrogen, C1-2alkyl, or C3-4cycloalkyl; RA2 is hydrogen, C1-4alkyl, C0-4alkyl-C3-6cycloalkyl, C0-2alkyl-(4-6 membered)heterocyclyl, C2-4alkyl-ORA2a, C0-2alkyl-C(O)N(RA2a)2, C0-2alkyl-S(O)2—C1-4alkyl, C0-2alkyl-C(O)OC1-4alkyl, C0-2alkyl-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, or 1,1-dioxothietanyl, and each of said RA2 groups except hydrogen is optionally substituted with up to three F atoms, up to two C1-2alkyl groups, a C3-6cycloalkyl group, an alkenyl-C0-2alkyl group, an alkynyl-C0-2alkyl group, up to two ORA2b groups, a C0-2alkyl-N(RA2b)2 group, a SC1-4alkyl group, a S(O)2C1-4alkyl group, a C(O)RA2b group, a C(O)ORA2b group, a C(O)N(RA2b)2 group, or a —CN group; each RA2a is, independently, hydrogen, C1-4alkyl, a C5-6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, or two RA2a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl; each RA2b is, independently, hydrogen, C1-4alkyl, or C3-4cycloalkyl; RA3 is hydrogen or C1-2alkyl; each RA4 is, independently, deuterium, halogen, CN, C1-4alkyl, or OC1-4alkyl, wherein each RA4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2alkyl, or two RA4 together with an intervening saturated carbon atom form a spiral cyclopropyl or cyclobutyl ring; n is 0-3; Ring B is a ring system selected from RB1 is hydrogen, C1-4alkyl, (CH2)04C3-6cycloalkyl, C(O)C1-2alkyl, (CH2)04-(4-6 membered)heterocyclyl ring wherein said heterocyclic ring is selected from selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, or pyrrolidinonyl, phenyl, benzyl, or (CH2)1-2(5-6 membered)heteroaryl ring wherein said heteroaryl ring is selected from pyridinyl, imidazolyl, or pyrazolyl, and wherein each of said RB1 alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl or heteroaryl groups is optionally substituted with up to 3 F atoms, up to two C1-2alkyl groups, two non-geminal OH groups, or one OC1-2alkyl; RB2 is hydrogen, C1-4alkyl, OC1-4alkyl; each RB3 is, independently, hydrogen, halogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, CN, C(O)H, C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)C1-4alkyl, C(O)NH2, C(O)NHC1-4alkyl, C(O)NH(CH2)0-1C3-6cycloalkyl, C(O)NHCH2oxetanyl, C(O)NHCH2tetrahydrofuranyl, C(O)NHCH2tetrahydropyranyl, C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH, C(O)NHOC1-4alkyl, C(O)NHO(CH2)0-1C3-6cycloalkyl, C(O)NHO(CH2)0-1oxetanyl, C(O)NHO(CH2)0-1tetrahydrofuranyl, C(O)NHO(CH2)0-1tetrahydropyranyl, C(O)NHOphenyl, C(O)NHObenzyl, NH2, NHC(O)C1-4alkyl, OC1-4alkyl, SC1-4alkyl, S(O)C1-4alkyl, or a 5-membered-heteroaryl ring system selected from furanyl, thiophenyl, imidazolyl, pyrrole, pyrazolyl, and oxadiazolyl, wherein each RB3 group except hydrogen or halogen is optionally substituted with Cl, up to three F atoms, up to two non-geminal OH groups, up to two OC1-2alkyl, one NH2, one NHC1-2alkyl, one NHC(O)C1-2alkyl, or one N(C1-2alkyl)2; each RB4 is, independently, hydrogen, halogen, C1-4alkyl, OC1-4alkyl, SC1-4alkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)C1-4alkyl, C(O)OH, C(O)OC1-4alkyl, C(O)NH2, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)2, CN, a morpholinyl ring, or an imidazolyl ring, wherein each RB4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2alkyl; RB5 is hydrogen, C1-4alkyl, C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)NH2, C(O)NHC1-4alkyl, or C(O)N(C1-4alkyl)2, wherein said RB5 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2alkyl and RB6 is F or C1-2alkyl, or two RB6 and an intervening carbon atom from a spirocyclopropyl or spirocyclobutyl ring.
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