N-(4-chloro-2-fluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)propane-1-sulfonamide | 1396310-84-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-(4-chloro-2-fluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)propane-1-sulfonamide
• 英文别名: N-[4-chloro-2-fluoro-3-[methyl-(3-methyl-4-oxoquinazolin-6-yl)amino]phenyl]propane-1-sulfonamide
• CAS: 1396310-84-1
• 化学式: C₁₉H₂₀ClFN₄O₃S
• 分子量: 438.91
• InChiKey: XEUDESATLDVKQV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  90.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  、 6-溴-3-甲基喹唑啉-4(3H)-酮 在 tris-(dibenzylideneacetone)dipalladium(0) 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 sodium t-butanolate 作用下， 以 甲苯 为溶剂， 生成 N-(4-chloro-2-fluoro-3-(methyl(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)propane-1-sulfonamide
  参考文献：
  名称：

  Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-RafV600E kinase

  摘要：

  Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.03.007

文献信息

• [EN] HETEROCYCLIC SULFONAMIDES AS RAF INHIBITORS<br/>[FR] SULFONAMIDES HÉTÉROCYCLIQUES EN TANT QU'INHIBITEURS DE RAF
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2012118492A1

  公开（公告）日：2012-09-07

  Compounds of Formula (I) are useful for inhibition of Raf kinases. Methods of using compounds of Formula (I), stereoisomers, tautomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

  化合物的化学式（I）对于抑制Raf激酶很有用。本文披露了使用化合物的方法（I），立体异构体，互变异构体及其药用可接受的盐，用于体外、体内和体内诊断、预防或治疗哺乳动物细胞中的这类疾病，或相关的病理状况。
• Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-RafV600E kinase
  作者：Steve Wenglowsky、Li Ren、Jonas Grina、Joshua D. Hansen、Ellen R. Laird、David Moreno、Victoria Dinkel、Susan L. Gloor、Gregg Hastings、Sumeet Rana、Kevin Rasor、Hillary L. Sturgis、Walter C. Voegtli、Guy Vigers、Brandon Willis、Simon Mathieu、Joachim Rudolph

  DOI：10.1016/j.bmcl.2014.03.007

  日期：2014.4

  Herein we describe the design of a novel series of ATP competitive B-Raf inhibitors via structure-based methods. These 3-N-methylquinazoline-4(3H)-one based inhibitors exhibit both excellent cellular potency and striking B-Raf selectivity. Optimization led to the identification of compound 16, a potent, selective and orally available agent with excellent pharmacokinetic properties and robust tumor growth inhibition in xenograft studies. Our work also demonstrates that by replacing an aryl amide with an aryl sulfonamide, a multikinase inhibitor such as AZ-628, can be converted to a selective B-Raf inhibitor, a finding that should have broad application in kinase drug discovery. (C) 2014 Elsevier Ltd. All rights reserved.