发明名称 1,7-DIAZACARBAZOLES AND METHODS OF USE
摘要 The invention relates to 1,7-diazacarbazole compounds of Formula (I), (I-a) and (I-b) which are useful as kinase inhibitors, more specifically useful as checkpoint kinase 1 (chk1) inhibitors, thus useful as cancer therapeutics. The invention also relates to compositions, more specifically pharmaceutical compositions comprising these compounds and methods of using the same to treat various forms of cancer and hyperproliferative disorders, as well as methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
申请公布号 US2014171407(A1) 申请公布日期 2014.06.19
申请号 US201414182190 申请日期 2014.02.17
申请人 Genentech, Inc. 发明人 Dyke Hazel Joan;Gazzard Lewis;Williams Karen;Chen Huifen;Kintz Samuel;Drobnick Joy;Lyssikatos Joseph P.;Goodacre Simon;Macleod Calum;Ellwood Charles
分类号 C07D471/14;A61K31/4375;C07D453/02;A61K45/06;A61K31/4545;A61K31/439;A61K31/55;A61K31/5377;A61K31/496 主分类号 C07D471/14
代理机构 代理人
主权项 1. A compound of formula (I), (I-a), or (I-b), or a solvate, hydrate or salt thereof: X is CR2 or N; Y is CR4 or N; Z is CR8 or N; provided that no more than one of X, Y and Z is N at the same time; R2 is H, halo, CN, CF3, —OCF3, OH, —NO2, C1-C5 alkyl, —O(C1-C5 alkyl), —S(C1-C5 alkyl), or N(R22)2; R3 is H, halo, CN, —O—R9, —N(R22)—R9, —S(O)p—R9, or R9; p is 0, 1 or 2; R4 is H, halo, CN, CF3, —OCF3, OH, —NO2, —(CR14R15)nC(═Y′)OR11, —(CR14R15)nC(═Y′)NR11R12, —(CR14R15)nNR11R12, —(CR14R15)nOR11, —(CR14R15)nS(O)pR11, —(CR14R15)nNR12C(═Y′)R11, —(CR14R15)nNR12C(═Y′)OR11, —(CR14R15)nNR12C(═Y′)NR11R12, —(CR14R15)nNR12SO2R11, —(CR14R15)nOC(═Y′)R11, —(CR14R15)nOC(═Y′)NR11R12, —(CR14R15)nS(O)2NR11R12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R13 groups; each n is independently 0-5; R5 is H, halo, CN, CF3, —OCF3, OH, —NO2, —(CR14R15)nC(═Y′)OR11, —(CR14R15)nC(═Y′)NR11R12, —(CR14R15)nNR12C(═Y′)R11, —(CR14R15)nNR11R12, —(CR14R15)nOR11, —(CR14R15)nS(O)pR11, —(CR14R15)nNR12C(═Y′)OR11, —(CR14R15)nNR12C(═Y′)NR11R12, —(CR14R15)nNR12SO2R11, —(CR14R15)nOC(═Y′)R11, —(CR14R15)nOC(═Y′)NR11R12, —(CR14R15)nS(O)2NR11R12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl wherein the said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R13 groups; R6 is H, CN, —CF3, —OCF3, halo, —C(═Y′)OR11, —C(═Y′)NR11R12, —OR11, —OC(═Y′)R11, —NR11R12, —NR12C(═Y′)R11, —NR12C(═Y′)NR11R12, —NR12S(O)qR11, —SR11, —S(O)R11, —S(O)2R11, —OC(═Y′)NR11R12, —S(O)2NR11R12, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one to four R13 groups; R7 is H, OH, CN, O(C1-C3 alkyl), or C1-C4 alkyl, wherein each said alkyl is optionally substituted with one to three groups independently selected from halo, N(R22)2 or OR22; R8 is H, halo, CN, NO2, N(R22)2, OH, O(C1-C3 alkyl), or C1-C3 alkyl, wherein each said alkyl is optionally substituted with one to three fluoro groups; each R9 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each member of R9 is independently substituted with one to three R10 groups; each R10 is independently H, CN, —CF3, —OCF3, —NO2, halo, R11, —OR11, —NR12C(═Y′)R11, —NR12C(═NR12)R11, —NR12S(O)qR11, —SR11, —NR11R12, oxo, —C(═Y′)OR11, —C(═Y′)NR11R12, —S(O)qR11, —NR12C(═Y′)OR11, —NR12C(═Y′)NR11R12, —OC(═Y′)R11, —OC(═Y′)NR11R12, or —S(O)2NR11R12; each q independently is 1 or 2; R11 and R12 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R13 groups, wherein two geminal R13 groups are optionally taken together with the atom to which they are attached to form a 3-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R18 groups; R11 and R12 are optionally taken together with the attached N atom to form a 4-7 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R13 groups; each R13 is independently halo, CN, CF3, —OCF3, —NO2, oxo, —(CR14R15)nC(═Y′)R16, —(CR14R15)nC(═Y′)OR16, —(CR14R15)nC(═Y′)NR16R17, —(CR14R15)nNR16R17, —(CR14R15)nOR16, —(CR14R15)nSR16, —(CR14R15)nNR16C(═Y′)R17, —(CR14R15)nNR16C(═Y′)OR17, —(CR14R15)nNR17C(═Y′)NR16R17, —(CR14R15)nNR17SO2R16, —(CR14R15)nOC(═Y′)R16, —(CR14R15)nOC(═Y′)NR16R17, —(CR14R15)nS(O)R16, —(CR14R15)nS(O)2R16, —(CR14R15)nS(O)2NR16R17, or R16; R14 and R15 are independently selected from H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R18 groups; R16 and R17 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R18 groups; R16 and R17 are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R18 groups; each R18 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF3, —OCF3, —NO2, oxo, —(CR19R20)nC(═Y′)R23, —(CR19R20)nC(═Y′)OR23, —(CR19R20)nC(═Y′)NR23R24, —(CR19R20)nNR23R24, —(CR19R20)nOR23, —(CR19R20)n—SR23, —(CR19R20)nNR24C(═Y′)R23, —(CR19R20)nNR24C(═Y′)OR23, —(CR19R20)nNR22C(═Y′)NR23R24, —(CR19R20)nNR24SO2R23, —(CR19R20)nOC(═Y′)R23, —(CR19R20)nOC(═Y′)NR23R24, —(CR19R20)nS(O)R23, —(CR19R20)nS(O)2R23, or —(CR19R20)nS(O)2NR23R24, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R21 groups; R19 and R20 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R25 groups; R23 and R24 are independently H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four R21 groups; R23 and R24 are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four R21 groups; each R21 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, CN, CF3, —OCF3, —NO2, oxo, —C(═Y′)R25, —C(═Y′)OR25, —C(═Y′)NR25R26, —NR25R26, —OR25, —SR25, —NR26C(═Y′)R25, —NR26C(═Y′)OR25, —NR22C(═Y′)NR25R26, —NR26SO2R25, —OC(═Y′)R25, —OC(═Y′)NR25R26, —S(O)R25, —S(O)2R25, or —S(O)2NR25R26, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one to four R25 groups; each R25 and R26 is independently H, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one to four groups selected from halo, —CN, —OCF3, —CF3, —NO2, —C1-C6 alkyl, —OH, oxo, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SO2(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —NHC(O)(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —SO2NH2, —SO2NH(C1-C6 alkyl), —SO2N(C1-C6 alkyl)2, —OC(O)NH2, —OC(O)NH(C1-C6 alkyl), —OC(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —NHC(O)O(C1-C6 alkyl), and —N(C1-C6 alkyl)C(O)O(C1-C6 alkyl); R25 and R26 are optionally taken together with the attached N atom to form a 5-6 membered ring having additional 0-2 heteroatoms selected from O, S, and N, said ring being optionally substituted with one to four groups selected from halo, —CN, —OCF3, CF3, —NO2, —C1-C6 alkyl, —OH, oxo, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SO2(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —NHC(O)(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —SO2NH2, —SO2NH(C1-C6 alkyl), —SO2N(C1-C6 alkyl)2, —OC(O)NH2, —OC(O)NH(C1-C6 alkyl), —OC(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —NHC(O)O(C1-C6 alkyl), and —N(C1-C6 alkyl)C(O)O(C1-C6 alkyl); Y′ is independently O, NR22, or S; each R22 is independently H or C1-C5 alkyl; and provided that (1) R2, R3, R4, R5, R6, and R8 are not H at the same time; and (2) when X is CH, Y is CH, R5 is H, Z is CR8, and R3 is H or alkyl, then R6 is not —C(═Y′)OR11.
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