5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid
• 英文别名: 5-[[2,4-dichloro-5-(3-fluoropyridin-2-yl)benzoyl]amino]-1-phenylpyrazole-3-carboxylic acid
• 化学式: C₂₂H₁₃Cl₂FN₄O₃
• 分子量: 471.275
• InChiKey: BFRDZONOJMMAGO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  97.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid 、 1-氨基-2-甲基-2-丙醇 在 2-(2-pyridon-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.33h， 以66%的产率得到5-{[2,4-dichloro-5-(3-fluoropyridin-2-yl)benzoyl]amino}-N-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  [EN] TROPOMYOSIN-RELATED KINASE INHIBITORS
  [FR] INHIBITEURS DE KINASES APPARENTÉES À LA TROPOMYOSINE

  摘要：

  本发明涉及式I化合物及其药用可接受的盐，其中取代基如本文所述，并且在医学上的应用，特别是作为TrkA拮抗剂。

  公开号：

  WO2015170218A1
• 作为产物：
  描述：

  2-溴-3-氟吡啶 在 吡啶 、 四(三苯基膦)钯 、 potassium carbonate 、 1-丙基磷酸酐 、 lithium hydroxide 作用下， 以 2-甲基四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 21.0h， 生成 5-(2,4-dichloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid
  参考文献：
  名称：

  Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors

  摘要：

  Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.

  DOI：

  10.1021/acs.jmedchem.8b00280

文献信息

• [EN] TROPOMYOSIN-RELATED KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASES APPARENTÉES À LA TROPOMYOSINE
  申请人：PFIZER

  公开号：WO2015170218A1

  公开（公告）日：2015-11-12

  The present invention relates to compounds of Formula I and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine, in particular as TrkA antagonists.

  本发明涉及式I化合物及其药用可接受的盐，其中取代基如本文所述，并且在医学上的应用，特别是作为TrkA拮抗剂。
• TROPOMYOSIN-RELATED KINASE INHIBITORS
  申请人：PFIZER INC

  公开号：US20150322043A1

  公开（公告）日：2015-11-12

  The present invention relates to compounds of Formula I and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine, in particular as TrkA antagonists.

  本发明涉及公式I化合物及其药学上可接受的盐，其中取代基如本文所述，并且它们在医学上的应用，特别是作为TrkA拮抗剂。
• Tropomyosin-related kinase inhibitors
  申请人：PFIZER INC

  公开号：US09328096B2

  公开（公告）日：2016-05-03

  The present invention relates to compounds of Formula I and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine, in particular as TrkA antagonists.

  本发明涉及公式I的化合物及其药学上可接受的盐，其中取代基如本文所述，并且它们在医学上的用途，特别是作为TrkA拮抗剂。
• US9328096B2
  申请人：——

  公开号：US9328096B2

  公开（公告）日：2016-05-03
• Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors
  作者：Sharan K. Bagal、Kiyoyuki Omoto、David C. Blakemore、Peter J. Bungay、James G. Bilsland、Philip J. Clarke、Matthew S. Corbett、Ciaran N. Cronin、J. Jean Cui、Rebecca Dias、Neil J. Flanagan、Samantha E. Greasley、Rachel Grimley、Eric Johnson、David Fengas、Linda Kitching、Michelle L. Kraus、Indrawan McAlpine、Asako Nagata、Gareth J. Waldron、Joseph S. Warmus

  DOI：10.1021/acs.jmedchem.8b00280

  日期：2019.1.10

  Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are activated by hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical proof of concept for inhibition of the TrkA kinase pathway in pain leading to significant interest in the development of small molecule inhibitors of TrkA. However, achieving TrkA subtype selectivity over TrkB and TrkC via a Type I and Type II inhibitor binding mode has proven challenging and Type III or Type IV allosteric inhibitors may present a more promising selectivity design approach. Furthermore, TrkA inhibitors with minimal brain availability are required to deliver an appropriate safety profile. Herein, we describe the discovery of a highly potent, subtype selective, peripherally restricted, efficacious, and well-tolerated series of allosteric TrkA inhibitors that culminated in the delivery of candidate quality compound 23.