N-(4-((6-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | 1584220-27-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(4-((6-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• 英文别名: N-(4-((6-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide
• CAS: 1584220-27-8
• 化学式: C₂₁H₁₅ClF₂N₄O₃
• 分子量: 444.825
• InChiKey: IRIXDVLLDMWDAE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.56
• 重原子数：
  31.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  93.21
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-(4-((6-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 、 3-[(methylsulfonyl)methyl]aniline 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 1,4-二氧六环 为溶剂， 反应 2.0h， 以43%的产率得到N-(3-fluoro-4-((6-((3-((methylsulfonyl)methyl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
  参考文献：
  名称：

  Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

  摘要：

  Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 mu M. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.

  DOI：

  10.1021/ml500066m
• 作为产物：
  描述：

  1,1-环丙基二羧酸 在 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.5h， 生成 N-(4-((6-chloropyrimidin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
  参考文献：
  名称：

  Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity

  摘要：

  Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing an anilinopyrimidine scaffold. Two novel synthetic protocols were employed for rapid analoguing of the designed molecules for structure activity relationship (SAR) exploration. Some analogues displayed nanomolar potency against c-Met and VEGFR-2 at enzymatic level. Privileged compounds 3a, 3b, 3g, 3h, and 18a exhibited potent antiproliferative effect against c-Met addictive cell lines with IC50 values ranged from 0.33 to 1.7 mu M. In addition, a cocrystal structure of c-Met in complex with 3h has been determined, which reveals the binding mode of c-Met to its inhibitor and helps to interpret the SAR of the analogues.

  DOI：

  10.1021/ml500066m

文献信息

• Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors
  作者：Daowei Huang、Jixia Yang、Qingwei Zhang、Guan Wang、Zixue Zhang、Yue Zhang、Jianqi Li

  DOI：10.1016/j.ejmech.2021.113648

  日期：2021.11

  over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed

  HGF/Met 信号通路在许多类型的癌症中过度表达，并与肿瘤发生和转移密切相关。因此，我们开发了新的N-苯基嘧啶-2-胺衍生物来测试它们对 c-Met 激酶的抑制活性，大多数化合物（15a-i、15o-r、20和34a-c）可以通过 IC 抑制靶标从 550.8 nM 到 15.0 nM 的50 个值。随后，化合物15B，15D，15F，15I，15O，15R，20，34A和34B还在 c-Met 敏感的肿瘤细胞系（PC-3、Panc-1、HepG2、HCT116 和 Caki-1）中显示出高抗增殖活性，IC 50值从 0.53 到 1.37 μM。先导化合物34a显示出出色的c-Met抑制活性（IC 50：15.0 nM）和抗增殖活性。此外，34a在小鼠中也表现出良好的药代动力学特性（F%：59.3），并且在临床前研究中具有可接受的安全性。进一步的对接研究表明34a与 c-Met 在 ATP