4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile
• 英文别名: 4-(2,4-dichloro-5-methoxyanilino)-6,7-dimethoxyquinoline-3-carbonitrile
• 化学式: C₁₉H₁₅Cl₂N₃O₃
• 分子量: 404.252
• InChiKey: VPAAYYSCJUHANG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  76.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,4-二氯-5-甲氧基苯胺 、 4-氯-3-氰基-6,7-二甲氧基喹啉 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以69%的产率得到4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile
  参考文献：
  名称：

  Optimization of 4-Phenylamino-3-quinolinecarbonitriles as Potent Inhibitors of Src Kinase Activity

  摘要：

  Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM), several additional analogues were prepared. Optimization of the C-4 anilino group of la led to le, which contains a 2,4-dichloro-5-methoxy-substituted aniline. Replacement of the methoxy group at C-7 of le with a 3-(morpholin-4-yl)propoxy group provided 2c, resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c, with other trisubstituted anilines at C-4 were also potent Src inhibitors, and the propoxy group of 2c was preferred over ethoxy, butoxy, or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a, which had an IC50 of 1.2 nM in the Src enzymatic assay, an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a, which had higher 1 and 4 h plasma levels than 2c, effectively inhibited tumor growth in xenograft models.

  DOI：

  10.1021/jm0102250

文献信息

• PROTEIN DEGRADERS AND USES THEREOF
  申请人：Kymera Therapeutics, Inc.

  公开号：US20210002296A1

  公开（公告）日：2021-01-07

  The present invention provides compounds, compositions thereof, and methods of using the same for the targeted degradation of proteins, and the treatment of target protein-mediated disorders.