N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-isobutyl-3-methyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-4-carboxamide | 1039046-38-2

• 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-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-isobutyl-3-methyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-4-carboxamide
• 英文别名: N-(3-fluoro-4-((7-methoxyquinolin-4-yl)oxy)phenyl)-1-isobutyl-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide；N-{3-fluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl}-5-methyl-1-(2-methylpropyl)-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide；N-[3-fluoro-4-(7-methoxyquinolin-4-yl)oxyphenyl]-5-methyl-1-(2-methylpropyl)-3-oxo-2-phenylpyrazole-4-carboxamide
• CAS: 1039046-38-2
• 化学式: C₃₁H₂₉FN₄O₄
• 分子量: 540.594
• InChiKey: AROMUEFGOQGFHF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  84
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-Bromo-4-hydroxy-7-methoxyquinoline-3-carboxylic acid 在 20 % Pd(OH)2/C 、 氢气 、 三乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氯氧磷 作用下， 以 二苯醚 、 乙醇 、 N,N-二甲基甲酰胺 、 氯苯 为溶剂， 反应 62.83h， 生成 N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-2-isobutyl-3-methyl-5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-4-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series

  摘要：

  As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.

  DOI：

  10.1021/jm201331s

文献信息

• Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series
  作者：Longbin Liu、Mark H. Norman、Matthew Lee、Ning Xi、Aaron Siegmund、Alessandro A. Boezio、Shon Booker、Debbie Choquette、Noel D. D’Angelo、Julie Germain、Kevin Yang、Yajing Yang、Yihong Zhang、Steven F. Bellon、Douglas A. Whittington、Jean-Christophe Harmange、Celia Dominguez、Tae-Seong Kim、Isabelle Dussault

  DOI：10.1021/jm201331s

  日期：2012.3.8

  As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of 1. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound 59e (AMG 458) was ultimately advanced into preclinical safety studies.