1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-oxo-2-thiomorpholinoethyl)imidazolidin-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-oxo-2-thiomorpholinoethyl)imidazolidin-2-one
• 化学式: C₂₉H₃₄ClN₇O₅S₂
• 分子量: 660.2
• InChiKey: CNJHUOPURJMIPZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  44
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  171
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-(异丙基磺酰基)苯胺 在 iron(III) chloride hexahydrate 、 sodium hydride 、 甲烷 、 对甲苯磺酸 、 一水合肼 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 、 乙腈 为溶剂， 反应 31.5h， 生成 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-oxo-2-thiomorpholinoethyl)imidazolidin-2-one
  参考文献：
  名称：

  Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties

  摘要：

  Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6-33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15, showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3(G1202R) with IC50 values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALK(L1196M) and ALK(G1202R) mutants with IC50 values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profiles of 15 were obtained with quite satisfying AUC and C-max values. Besides, the binding models of 15 with ALK(WT), ALK(G1202R) and ROS1 clearly present the essential interactions within the active site. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.03.038

文献信息

• Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties
  作者：Hongrui Lei、Nan Jiang、Xiuqi Miao、Lingyun Xing、Ming Guo、Yang Liu、Haowen Xu、Ping Gong、Daiying Zuo、Xin Zhai

  DOI：10.1016/j.ejmech.2019.03.038

  日期：2019.6

  Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6-33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15, showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3(G1202R) with IC50 values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALK(L1196M) and ALK(G1202R) mutants with IC50 values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profiles of 15 were obtained with quite satisfying AUC and C-max values. Besides, the binding models of 15 with ALK(WT), ALK(G1202R) and ROS1 clearly present the essential interactions within the active site. (C) 2019 Elsevier Masson SAS. All rights reserved.