(1R,2S)-5'-methoxy-2-(3-(4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one | 1247004-41-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (1R,2S)-5'-methoxy-2-(3-(4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one
• 英文别名: (2'S,3R)-2'-[3-[4-(4-fluoro-1-methylpiperidin-4-yl)phenyl]-1H-indazol-6-yl]-5-methoxyspiro[1H-indole-3,1'-cyclopropane]-2-one
• CAS: 1247004-41-6
• 化学式: C₃₀H₂₉FN₄O₂
• 分子量: 496.584
• InChiKey: MRRJIJBPTGTPLV-NGQVCNFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  37
• 可旋转键数：
  4
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  70.2
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  1-苄基-5-甲氧基-1,3-二氢-2H-吲哚-2-酮 在 四(三苯基膦)钯 、 potassium tert-butylate 、 碘 、 氧气 、 sodium hydride 、 sodium carbonate 、 potassium carbonate 作用下， 以 四氢呋喃 、 乙醇 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 20.0~120.0 ℃ 、101.33 kPa 条件下， 生成 (1R,2S)-5'-methoxy-2-(3-(4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one
  参考文献：
  名称：

  Design and optimization of (3-aryl-1 H -indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-ones as potent PLK4 inhibitors with oral antitumor efficacy

  摘要：

  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 Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl) spiro[cyclopropane-1,30-indolin]-20-ones.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. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.08.063

文献信息

• KINASE INHIBITORS AND METHOD OF TREATING CANCER
  申请人：Sampson Peter B.

  公开号：US20110263598A1

  公开（公告）日：2011-10-27

  The invention is directed to a compound represented by the following structural formula and pharmaceutically acceptable salts thereof: Compounds represented by this structural formula are kinase inhibitors and are therefore disclosed herein for the treatment of cancer. Definitions for the variables in the structural formula are provided herein.

  本发明涉及以下结构式和其药学上可接受的盐所代表的化合物：该结构式所代表的化合物是激酶抑制剂，因此本发明公开了用于治疗癌症的该类化合物。该结构式中变量的定义在此提供。
• KINASE INHIBITORS AND METHOD OF TREATING CANCER WITH SAME
  申请人：Sampson Peter B.

  公开号：US20120149686A1

  公开（公告）日：2012-06-14

  The invention is directed to a compound represented by the following structural formula and pharmaceutically acceptable salts thereof: Compounds represented by this structural formula are kinase inhibitors and are therefore disclosed herein for the treatment of cancer. Definitions for the variables in the structural formula are provided herein.

  本发明涉及以下结构式及其药物可接受的盐所表示的化合物：该结构式所表示的化合物是激酶抑制剂，因此在此披露用于治疗癌症。本结构式中变量的定义在此提供。
• SYNTHESIS OF CHIRAL 2-(1H-INDAZOL-6-YL)-SPIRO[CYCLOPROPANE-1,3'-INDOLIN]-2'-ONES
  申请人：University Health Network

  公开号：US20150133677A1

  公开（公告）日：2015-05-14

  The present invention is directed to novel synthetic methods for preparing a spiro cyclopropyl indolinone compound represented by Structural Formula (A): or its pharmaceutically acceptable salt thereof. Also included are synthetic intermediates described herein.

  本发明涉及一种新的合成方法，用于制备由结构式(A)所表示的螺环丙基吲哚酮化合物或其药学上可接受的盐。本发明还包括在此处描述的合成中间体。
• Synthesis of chiral 2-(1H-indazol-6-yl)-spiro[cyclopropane-1,3′-indolin]-2′-ones
  申请人：University Health Network

  公开号：US10077255B2

  公开（公告）日：2018-09-18

  The present invention is directed to novel synthetic methods for preparing cyclopropyl indolinone compound represented by Structural Formula (A): (A) or its pharmaceutically acceptable salt thereof. Also included are synthetic intermediates described herein.

  本发明涉及制备结构式（A）代表的环丙基吲哚啉酮化合物或其药学上可接受的盐的新合成方法。还包括本文所述的合成中间体。
• Kinase inhibitors and method of treating cancer
  申请人：University Health Network

  公开号：US10358436B2

  公开（公告）日：2019-07-23

  The invention is directed to a compound represented by the following structural formula and pharmaceutically acceptable salts thereof: Compounds represented by this structural formula are kinase inhibitors and are therefore disclosed herein for the treatment of cancer. Definitions for the variables in the structural formula are provided herein.

  本发明涉及由以下结构式代表的化合物及其药学上可接受的盐类： 由该结构式代表的化合物是激酶抑制剂，因此在此公开用于治疗癌症。本文提供了结构式中变量的定义。