Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein ‘directly-linked’ aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.

中文翻译：

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设计和优化（3-芳基-1H-吲唑-6-基）螺[环丙烷-1,3'-吲哚啉] -2'-酮类作为具有口服抗肿瘤功效的有效PLK4抑制剂

我们实验室的先前研究表明，（E）-3-（（3-（E）-乙烯基芳基）-1H-吲唑-6-基）亚甲基）-吲哚啉-2-酮是有效的PLK4抑制剂，具有体内抗癌作用IP剂量。作为开发选择性和口服有效抑制剂的持续努力的一部分，我们研究了这一主题的变化，其中吲哚核侧基的“直接连接”芳烃取代了芳基乙烯基部分。在这里，我们描述了该系列的设计和优化，最终被（3-芳基-1H-吲唑-6-基）螺[环丙烷-1,3'-吲哚啉] -2'-取代。后一种化合物是PLK4的有效和选择性抑制剂，可在啮齿动物中口服并具有体内抗癌活性。在MDA-MB-468异种移植研究中，化合物13b特别具有22％的生物利用度，并实现了96％的肿瘤生长抑制。