N-(4-((2-carbamoyl-6-((3-((methylsulfonyl)methyl)phenyl)amino)pyridin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide | 1584220-12-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-(4-((2-carbamoyl-6-((3-((methylsulfonyl)methyl)phenyl)amino)pyridin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• 英文别名: 1-N'-[4-[2-carbamoyl-6-[3-(methylsulfonylmethyl)anilino]pyridin-4-yl]oxy-3-fluorophenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
• CAS: 1584220-12-1
• 化学式: C₃₁H₂₇F₂N₅O₆S
• 分子量: 635.648
• InChiKey: GCQNVCGQLNSPFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  45
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  178
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-(4-((2-carbamoyl-6-((3-((methylsulfonyl)methyl)phenyl)amino)pyridin-4-yl)oxy)-3-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide 在 sodium hypochlorite 、 sodium hydroxide 作用下， 以 水 、 异丙醇 为溶剂， 反应 1.5h， 以27%的产率得到N-(4-((2-amino-6-((3-((methylsulfonyl)methyl)phenyl)amino)pyridin-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
• 作为产物：
  描述：

  1,1-环丙基二羧酸 在 tris-(dibenzylideneacetone)dipalladium(0) 、 过氧化脲素 、 potassium carbonate 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 5.5h， 生成 N-(4-((2-carbamoyl-6-((3-((methylsulfonyl)methyl)phenyl)amino)pyridin-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

• Discovery of Anilinopyrimidines as Dual Inhibitors of c-Met and VEGFR-2: Synthesis, SAR, and Cellular Activity
  作者：Zhengsheng Zhan、Jing Ai、Qiufeng Liu、Yinchun Ji、Tiantian Chen、Yechun Xu、Meiyu Geng、Wenhu Duan

  DOI：10.1021/ml500066m

  日期：2014.6.12

  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.