N-{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-2,6-difluorobenzenesulfonamide | 1244641-87-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: N-{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-2,6-difluorobenzenesulfonamide
• 英文别名: N-[3-[2-(2-chloropyrimidin-4-yl)acetyl]phenyl]-2,6-difluorobenzenesulfonamide
• CAS: 1244641-87-9
• 化学式: C₁₈H₁₂ClF₂N₃O₃S
• 分子量: 423.827
• InChiKey: VHVXGGUTTYSSCY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  97.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  N-{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-2,6-difluorobenzenesulfonamide 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 2,2,2-三氟乙醇 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 2,6-difluoro-N-{3-[2-(1-methylethyl)-5-(2-{[6-(4-morpholinyl)-3-pyridinyl]amino}-4-pyrimidinyl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide
  参考文献：
  名称：

  Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup

  摘要：

  A potent series of inhibitors against the B-RafV600E kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.06.021
• 作为产物：
  描述：

  3-氨基苯甲酸甲酯 在 吡啶 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 N-{3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}-2,6-difluorobenzenesulfonamide
  参考文献：
  名称：

  Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors

  摘要：

  Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(v600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(v600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.

  DOI：

  10.1021/ml4000063

文献信息

• Thiazole Sulfonamide And Oxazole Sulfonamide Kinase Inhibitors
  申请人：Adjabeng George

  公开号：US20110319392A1

  公开（公告）日：2011-12-29

  The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.

  本发明提供了噻唑磺酰胺和噁唑磺酰胺化合物，含有它们的组合物，以及制备它们的过程和作为药物剂的方法。
• Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity
  作者：Adam K. Charnley、Máire A. Convery、Ami Lakdawala Shah、Emma Jones、Philip Hardwicke、Angela Bridges、Michael Ouellette、Rachel Totoritis、Benjamin Schwartz、Bryan W. King、David D. Wisnoski、James Kang、Patrick M. Eidam、Bartholomew J. Votta、Peter J. Gough、Robert W. Marquis、John Bertin、Linda Casillas

  DOI：10.1016/j.bmc.2015.09.038

  日期：2015.11

  Receptor interacting protein 2 (RIP2) is an intracellular kinase and key signaling partner for the pattern recognition receptors NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2). As such, RIP2 represents an attractive target to probe the role of these pathways in disease. In an effort to design potent and selective inhibitors of RIP2 we established a crystallographic system and determined the structure of the RIP2 kinase domain in an apo form and also in complex with multiple inhibitors including AMP-PCP (beta,gamma-Methyleneadenosine 5'-triphosphate, a non-hydrolysable adenosine triphosphate mimic) and structurally diverse ATP competitive chemotypes identified via a high-throughput screening campaign. These structures represent the first set of diverse RIP2-inhibitor co-crystal structures and demonstrate that the protein possesses the ability to adopt multiple DFG-in as well as DFG-out and C-helix out conformations. These structures reveal key protein-inhibitor structural insights and serve as the foundation for establishing a robust structure-based drug design effort to identify both potent and highly selective inhibitors of RIP2 kinase. (C) 2015 Elsevier Ltd. All rights reserved.
• Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors
  作者：Tara R. Rheault、John C. Stellwagen、George M. Adjabeng、Keith R. Hornberger、Kimberly G. Petrov、Alex G. Waterson、Scott H. Dickerson、Robert A. Mook、Sylvie G. Laquerre、Alastair J. King、Olivia W. Rossanese、Marc R. Arnone、Kimberly N. Smitheman、Laurie S. Kane-Carson、Chao Han、Ganesh S. Moorthy、Katherine G. Moss、David E. Uehling

  DOI：10.1021/ml4000063

  日期：2013.3.14

  Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(v600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(v600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
• Development of potent B-RafV600E inhibitors containing an arylsulfonamide headgroup
  作者：John C. Stellwagen、George M. Adjabeng、Marc R. Arnone、Scott H. Dickerson、Chao Han、Keith R. Hornberger、Alastair J. King、Robert A. Mook、Kimberly G. Petrov、Tara R. Rheault、Cynthia M. Rominger、Olivia W. Rossanese、Kimberly N. Smitheman、Alex G. Waterson、David E. Uehling

  DOI：10.1016/j.bmcl.2011.06.021

  日期：2011.8

  A potent series of inhibitors against the B-RafV600E kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.