(E)-3-((1H-indazol-6-yl)methylene)-5-chloroindolin-2-one | 1168721-87-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: (E)-3-((1H-indazol-6-yl)methylene)-5-chloroindolin-2-one
• 英文别名: (3E)-5-chloro-3-(1H-indazol-6-ylmethylidene)-1H-indol-2-one
• CAS: 1168721-87-6
• 化学式: C₁₆H₁₀ClN₃O
• 分子量: 295.728
• InChiKey: ULXYLHILBRICFA-WLRTZDKTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.71
• 重原子数：
  21.0
• 可旋转键数：
  1.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  57.78
• 氢给体数：
  2.0
• 氢受体数：
  2.0

反应信息

• 作为产物：
  描述：

  2-吲哚酮 、 5-氯氧化吲哚 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以29%的产率得到(E)-3-((1H-indazol-6-yl)methylene)-5-chloroindolin-2-one
  参考文献：
  名称：

  The Discovery of PLK4 Inhibitors: (E)-3-((1H-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents

  摘要：

  The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.

  DOI：

  10.1021/jm400380m

文献信息

• INDAZOLYL, BENZIMIDAZOLYL, BENZOTRIAZOLYL SUBSTITUTED INDOLINONE DERIVATIVES AS KINASE INHIBITORS USEFUL IN THE TREATMENT OF CANCER
  申请人：Pauls Heinz W.

  公开号：US20110065702A1

  公开（公告）日：2011-03-17

  The present invention is directed to a compound is represented by Structural Formula (A):or a pharmaceutically acceptable salt therof. The present invention is also directed to a pharmaceutical composition comprising a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. Also disclosed is a method of treating a subject having cancer, wherein the method comprises administering a therapeutically effective amount of a compound represented by Structural Formula (A) described above or a pharmaceutically acceptable salt thereof.

  本发明涉及一种化合物，其结构式表示为(A)或其药学上可接受的盐。本发明还涉及一种药物组合物，包括上述结构式(A)所表示的化合物或其药学上可接受的盐，以及药学上可接受的载体或稀释剂。本发明还揭示了一种治疗患有癌症的受试者的方法，其中该方法包括给予上述结构式(A)所表示的化合物或其药学上可接受的盐的治疗有效量。
• US8765748B2
  申请人：——

  公开号：US8765748B2

  公开（公告）日：2014-07-01
• The Discovery of PLK4 Inhibitors: (<i>E</i>)-3-((1<i>H</i>-Indazol-6-yl)methylene)indolin-2-ones as Novel Antiproliferative Agents
  作者：Radoslaw Laufer、Bryan Forrest、Sze-Wan Li、Yong Liu、Peter Sampson、Louise Edwards、Yunhui Lang、Donald E. Awrey、Guodong Mao、Olga Plotnikova、Genie Leung、Richard Hodgson、Irina Beletskaya、Jacqueline M. Mason、Xunyi Luo、Xin Wei、Yi Yao、Miklos Feher、Fuqiang Ban、Reza Kiarash、Erin Green、Tak W. Mak、Guohua Pan、Henry W. Pauls

  DOI：10.1021/jm400380m

  日期：2013.8.8

  The family of Polo-like kinases is important in the regulation of mitotic progression; this work keys on one member, namely Polo-like kinase 4 (PLK4). PLK4 has been identified as a candidate anticancer target which prompted a search for potent and selective inhibitors of PLK4. The body of the paper describes lead generation and optimization work which yielded nanomolar PLK4 inhibitors. Lead generation began with directed virtual screening, using a ligand-based focused library and a PLK4 homology model. Validated hits were used as starting points for the design and discovery of PLK4 inhibitors of novel structure, namely (E)-3-((1H-indazol-6-yl)methylene)indolin-2-ones. Computational models, based on a published X-ray structure (PLK4 kinase domain), were used to understand and optimize the in vitro activity of the series; potent antiproliferative activity was obtained. The kinase selectivity profile and cell cycle analysis of selected inhibitors are described. The results of a xenograft study with an optimized compound 50 (designated CFI-400437) support the potential of these novel PLK4 inhibitors for cancer therapy.