(S)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide | 1039046-42-8

• 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: (S)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
• 英文别名: (S)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide；N-{3-fluoro-4-[(7-methoxyquinolin-4-yl)oxy]phenyl}-1-[(2S)-2-hydroxypropyl]-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide；N-[3-fluoro-4-(7-methoxyquinolin-4-yl)oxyphenyl]-1-[(2S)-2-hydroxypropyl]-5-methyl-3-oxo-2-phenylpyrazole-4-carboxamide
• CAS: 1039046-42-8
• 化学式: C₃₀H₂₇FN₄O₅
• 分子量: 542.567
• InChiKey: OHLUERTUZNIQEE-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide 在 4-二甲氨基吡啶 、 palladium 10% on activated carbon 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 23.0h， 生成 (S)-((S)-1-(4-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenylcarbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl) 2-aminopropanoate fumarate
  参考文献：
  名称：

  AMINO ESTER DERIVATIVES, SALTS THEREOF AND METHODS OF USE

  摘要：

  公开号：

  EP2408300B1
• 作为产物：
  描述：

  benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate 在 magnesium(II) perchlorate 、 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-) 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 5.66h， 生成 (S)-N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-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

• AMINO ESTER DERIVATIVES, SAILTS THEREOF AND METHODS OF USE
  申请人：Xi Ning

  公开号：US20100239576A1

  公开（公告）日：2010-09-23

  The present invention provides amino ester compounds, salts, and pharmaceutical formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

  本发明提供了氨基酯化合物、盐及其药物配方，用于调节蛋白酪氨酸激酶活性，以及调节细胞间和/或细胞内信号传导。该发明还提供了包含这些化合物的药用合适组合物，以及使用这些组合物治疗哺乳动物，特别是人类的增生性疾病的方法。
• Amino ester derivatives, sailts thereof and methods of use
  申请人：——

  公开号：US08232294B2

  公开（公告）日：2012-07-31

  The present invention provides amino ester compounds, salts, and pharmaceutical formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.

  本发明提供了氨基酯化合物、盐和药物配制物，用于调节蛋白酪氨酸激酶活性，以及调节细胞内和/或细胞间信号传导。本发明还提供了包含这种化合物的药学上可接受的组合物，并使用这些组合物治疗哺乳动物，特别是人类的增殖过度性疾病的方法。
• US8232294B2
  申请人：——

  公开号：US8232294B2

  公开（公告）日：2012-07-31
• 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.
• AMINO ESTER DERIVATIVES, SALTS THEREOF AND METHODS OF USE
  申请人：Sunshine Lake Pharma Co., Ltd.

  公开号：EP2408300B1

  公开（公告）日：2016-05-11