A new series of potent tricyclic pyrazole-based Chk1 inhibitors are described. Analogues disubstituted on the 6- and 7-positions show improved Chk1 inhibition potency compared with analogues with a single substituent on either the 6- or 7-position. Based on the lead compound 4'-(6,7-dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol (2), detailed SAR studies on the 6- and 7-positions were performed. 3'-morpholin-4'-yl-propoxy, pyridin-4'-ylmethoxy, pyridin-3'-ylmethoxy, 2'-(5''-ethyl-pyridin-2''-yl)-ethoxy, pyridin-2'-ylethoxy, (6'-methyl-pyridin-2'-yl)-propoxyethoxy, 2',3'-dihydroxyl-1'-yl-propoxy, and tetrahydro-furan-3'-yloxy have been identified as the best groups on the 6-position when the 7-position is substituted with methoxyl group. Pyridin-2'-ylmethoxy and pyridin-3'-ylmethoxy have been identified as the best substituents at the 7-position while the 6-position bearing methoxyl group. These compounds significantly potentiate the cytotoxicity of DNA-damaging antitumor agents in a cell-based assay and efficiently abrogate the doxorubicin-induced G2/M and the camptothecin-induced S checkpoints, suggesting that their potent biological activities are mechanism-based through Chk1 inhibition.

中文翻译：

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4'-（6,7-二取代-2,4-二氢-茚并[1,2-c]吡唑-3-基）-联苯-4-醇作为强效Chk1抑制剂的合成和生物学评估。

描述了一系列新的有效的三环吡唑基Chk1抑制剂。与在6或7位上带有单个取代基的类似物相比，在6和7位上双取代的类似物显示出改善的Chk1抑制能力。基于铅化合物4'-（6,7-二甲氧基-2,4-二氢-茚并[1,2-c]吡唑-3-基）-联苯-4-醇（2），对药物的详细SAR研究进行了6位和7位。3'-吗啉-4'-丙氧基，吡啶-4'-甲氧基，吡啶-3'-甲氧基，2'-（5''-乙基吡啶-2''-基）-乙氧基，吡啶-2 '-乙氧基，（6'-甲基吡啶-2'-基）-丙氧基乙氧基，2'，3'-二羟基-1'-丙氧基和四氢呋喃-3'-丙氧基被认为是最好的当7位被甲氧基取代时，其6位上的基团。吡啶2' 已经鉴定出-基甲氧基和吡啶-3'-基甲氧基是在7位上最好的取代基，而在6位上带有甲氧基。这些化合物在基于细胞的测定中显着增强了破坏DNA的抗肿瘤药的细胞毒性，并有效地消除了阿霉素诱导的G2 / M和喜树碱诱导的S检查点，表明它们的有效生物学活性是通过抑制Chk1来实现的。