Indolyl-pyridone derivatives having checkpoint kinase 1 inhibitory activity

摘要

Compounds of formula (I) have checkpoint kinase 1 (CHK1) inhibitory activity: wherein R1, R2, R5 and R6 are independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R3, and R4 are independently selected from hydrogen, hydroxy, C1-C3 alkyl, fluoro-(C1-C3)-alkyl, hydroxy-(C1C3)-alkyl, C1-C3 alkoxy, fluoro-(C1-C3)-alkoxy, hydroxy-(C1-C3)-alkoxy, -AIk-N(R11)—R12, -0-AIk-N(R11)—R12, —C(═O)OH, carboxy-(C1-C3)-alkyl, or —C(═O)—NH—R13; AIk is a straight or branched chain divalent C1-C6 alkylene radical; R7 and R8 are independently selected from hydrogen, hydroxy, or C1-C3 alkoxy; X is a straight chain divalent C1-C3 alkylene radical, optionally substituted on one or more carbons by R9 and/or R10; W is selected from —C(═O)—N(—R16)— or —N(—R17)—C(═O)—; Y is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halo; and Q is selected from optionally substituted phenyl, optionally substituted cyclohexyl, or an optionally substituted 6-membered monocyclic heteroaryl ring.;

主权项

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein R1, R2, R5 and R6 are independently selected from hydrogen, hydroxy, methyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, methylamino and dimethylamino; R3, and R4 are independently selected from hydrogen, hydroxy, C1-C3 alkyl, fluoro-(C1-C3)-alkyl, hydroxy-(C1-C3)-alkyl, C1-C3 alkoxy, fluoro-(C1-C3)-alkoxy, hydroxy-(C1-C3)-alkoxy, —N(R11)—R12, -Alk-N(R11)—R12, —O-Alk-N(R11)—R12, —C(═O)OH, carboxy-(C1-C3)-alkyl, or —C(═O)—NH—R13; Alk is a straight or branched chain divalent C1-C6 alkylene radical; R7 and R8 are independently selected from hydrogen, hydroxy, or C1-C3 alkoxy; X is a straight chain divalent C1-C3 alkylene radical, optionally substituted on one or more carbons by R9 and/or R10; R9 and R10 are independently selected from methyl, hydroxy, or fluoro; R11 is hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl, and R12 is C1-C3 alkyl or hydroxy-(C1-C6)-alkyl, either of which may be optionally substituted on the alkyl portion by phenyl, C1-C3 alkoxy-(C1-C3)-alkyl-, halo-(C1-C4)-alkyl, C3-C6 cycloalkyl, methylsulfonyl-(C1-C3)-alkyl or —N(R18)—R19; R13 is hydrogen, C1-C3 alkyl, fluoro-(C1-C3)-alkyl, or a radical of formula -Alk-N(R14)—R15; R14 and R15 are independently selected from hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl; W is selected from —C(═O)—N(—R16)— or —N(—R17)—C(═O)—; R16 or R17 is selected from hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl; R18 and R19 are selected from hydrogen, C1-C3 alkyl, or fluoro-(C1-C3)-alkyl; Y is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, or halo; and Q is selected from optionally substituted phenyl or optionally substituted cyclohexyl; wherein optionally substituted means optionally substituted by at least one substituent selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), oxo, phenyl, —COOH, —COORA, —CORA, —SO2RA, —CONH2, —SO2NH2, —CONHRA, —SO2NHRA, —CONRARB, —SO2NRARB, —NH2, —NHRA, —NRARB, —OCONH2, —OCONHRA, —OCONRARB, —NHCORA, —NHCOORA, —NRBCOORA, —NHSO2ORA, —NRBSO2ORA, —NHCONH2, —NRACONH2, —NHCONHRB, —NRACONHRB, —NHCONRARB, and —NRACONRARB wherein RA and RB are independently a (C1-C6)alkyl group.