(Z)-N-[3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide | 1221433-99-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (Z)-N-[3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
• 英文别名: N-[(3Z)-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-2-oxo-1H-indol-5-yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide
• CAS: 1221433-99-3
• 化学式: C₂₈H₃₁N₅O₂
• 分子量: 469.586
• InChiKey: OAOIBNCLBKKVQA-JLPGSUDCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  80.5
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (3Z)-5-amino-3-(1H-pyrrol-2-ylmethylidene)-2,3-dihydro-1H-indol-2-one 、 4-(4-甲基-1-哌嗪基甲基)苯甲酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以21%的产率得到(Z)-N-[3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide
  参考文献：
  名称：

  Synthesis, structure–activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors

  摘要：

  The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped re. ne SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2010.01.011

文献信息

• Synthesis, structure–activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors
  作者：Luca Mologni、Roberta Rostagno、Stefania Brussolo、Phillip P. Knowles、Svend Kjaer、Judith Murray-Rust、Enrico Rosso、Alfonso Zambon、Leonardo Scapozza、Neil Q. McDonald、Vittorio Lucchini、Carlo Gambacorti-Passerini

  DOI：10.1016/j.bmc.2010.01.011

  日期：2010.2

  The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped re. ne SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers. (C) 2010 Elsevier Ltd. All rights reserved.