(E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde | 1168722-42-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde
• 英文别名: (E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-indazole-6-carbaldehyde；3-[(E)-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]ethenyl]-1-(2-trimethylsilylethoxymethyl)indazole-6-carbaldehyde
• CAS: 1168722-42-6
• 化学式: C₂₆H₃₅N₅O₂Si
• 分子量: 477.682
• InChiKey: RSSSDMUZZBIUKF-RMKNXTFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.48
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  63.5
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde 在 哌啶 、 盐酸 、 三氟化硼乙醚 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 反应 11.0h， 生成 (E)-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one dihydrochloride
  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
• 作为产物：
  描述：

  2-(4-甲基哌嗪-1-基)吡啶-5-硼酸频那醇酯 在 palladium diacetate 、 N,N-二异丙基乙胺 、 三(邻甲基苯基)磷 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 反应 26.17h， 生成 (E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde
  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
• 作为试剂：
  描述：

  Phosphorsaeure-bis-aethylenamid-<2-iod-benzoylamid> 、 1-methyl-4-(5-vinylpyridin-2-yl)piperazine 、 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde 在 (E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde 、 SiO2 作用下， 以to provide the title compound to as a pale orange material (46 mg, 39%)的产率得到(E)-3-(2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde
  参考文献：
  名称：

  Indazolyl, benzimidazolyl, benzotriazolyl substituted indolinone derivatives as kinase inhibitors useful in the treatment of cancer

  摘要：

  本发明涉及一种由结构式（A）表示的化合物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）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癌症患者的方法，其中该方法包括给予上述结构式（A）表示的化合物或其药学上可接受的盐的治疗有效量。

  公开号：

  US08765748B2

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。
• 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。
• Kinase inhibitors and method of treating cancer
  申请人：University Health Network

  公开号：US08263596B2

  公开（公告）日：2012-09-11

  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.

  该发明涉及以下结构式及其药学上可接受的盐所表示的化合物：此结构式所表示的化合物是激酶抑制剂，因此在此透露用于治疗癌症。此处提供了结构式中变量的定义。
• Kinase inhibitors and method of treating cancer with same
  申请人：Sampson Peter Brent

  公开号：US08481525B2

  公开（公告）日：2013-07-09

  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.

  本发明涉及一种由以下结构式表示的化合物及其药学上可接受的盐：该结构式表示的化合物是激酶抑制剂，因此在此披露用于治疗癌症。该结构式中各变量的定义在此提供。