N-(2-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-2-oxoethyl)-4-hydroxy-3-isopropylbenzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(2-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-2-oxoethyl)-4-hydroxy-3-isopropylbenzamide
• 英文别名: N-[2-[3-[[5-chloro-4-(2-propan-2-ylsulfonylanilino)pyrimidin-2-yl]amino]-4-methoxyanilino]-2-oxoethyl]-4-hydroxy-3-propan-2-ylbenzamide
• 化学式: C₃₂H₃₅ClN₆O₆S
• 分子量: 667.186
• InChiKey: BKGPJIJPJFIINT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  180
• 氢给体数：
  5
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  4-甲氧基-3-硝基苯胺 在 tris-(dibenzylideneacetone)dipalladium(0) 、 N-羟基-7-氮杂苯并三氮唑 、 三氯化硼 、 铁粉 、 氯化铵 、 caesium carbonate 、 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-) 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 N-(2-((3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)amino)-2-oxoethyl)-4-hydroxy-3-isopropylbenzamide
  参考文献：
  名称：

  Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation

  摘要：

  To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diary-laminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. (C) 2017 Published by Elsevier Masson SAS.

  DOI：

  10.1016/j.ejmech.2017.12.060

文献信息

• Discovery of 2,4-diarylaminopyrimidines bearing a resorcinol motif as novel ALK inhibitors to overcome the G1202R resistant mutation
  作者：Kaijun Geng、Zongjun Xia、Yinchun Ji、Ruisi (Ruthy) Zhang、Deqiao Sun、Jing Ai、Zilan Song、Meiyu Geng、Ao Zhang

  DOI：10.1016/j.ejmech.2017.12.060

  日期：2018.1

  To address drug resistance caused by ALK kinase mutations, especially the most refractory and predominant mutation G1202R for the second-generation ALK inhibitor, a series of new diary-laminopyrimidine analogues were designed by incorporating a resorcinol moiety (A-ring) to interact the ALK kinase domain where the G1202R is located. Compound 12d turns out as the most potent with IC50 values of 1.7, 3.5, and 1.8 nM against ALK wild type, gatekeeper mutant L1196M, and the G1202R mutant, respectively. More importantly, compound 12d has excellent inhibitory effects against the proliferation of BaF3 cells specifically expressing ALK wild type, gatekeeper L1196M, and the most challenging mutant G1202R, with IC50 values all less than 1.5 nM. Collectively, compound 12d is worthy of further investigation as a new more potent third-generation ALK inhibitor to circumvent drug resistance of both the first-generation and the second-generation inhibitors. (C) 2017 Published by Elsevier Masson SAS.