4-chloro-6-[(1,1-dimethylethyl)thio]quinoline | 1346549-09-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 4-chloro-6-[(1,1-dimethylethyl)thio]quinoline
• 英文别名: 6-tert-butylsulfanyl-4-chloroquinoline
• CAS: 1346549-09-4
• 化学式: C₁₃H₁₄ClNS
• 分子量: 251.78
• InChiKey: SNFOGVJMWLZQTR-UHFFFAOYSA-N

物化性质

• 沸点：
  360.2±22.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  38.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-chloro-6-[(1,1-dimethylethyl)thio]quinoline 在 Oxone 、 N-碘代丁二酰亚胺 、 溶剂黄146 、 三氯氧磷 作用下， 以 甲醇 、 水 为溶剂， 反应 2.0h， 生成 6-(tert-butylsulfonyl)-4-chloro-3-iodoquinoline
  参考文献：
  名称：

  QUINOLYL AMINES AS KINASE INHIBITORS

  摘要：

  揭示了具有下列化学式的化合物：其中R1、R2、R3、R4和R5如本文所定义，并提供了制备和使用这些化合物的方法。

  公开号：

  US20120041024A1
• 作为产物：
  描述：

  5-{[(4-iodophenyl)amino]methylidene}-2,2-dimethyl-1,3-dioxane-4,6-dione 在 四(三苯基膦)钯 sodium carbonate 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 二苯醚 为溶剂， 反应 2.5h， 生成 4-chloro-6-[(1,1-dimethylethyl)thio]quinoline
  参考文献：
  名称：

  QUINOLYL AMINES AS KINASE INHIBITORS

  摘要：

  揭示了具有下列化学式的化合物：其中R1、R2、R3、R4和R5如本文所定义，并提供了制备和使用这些化合物的方法。

  公开号：

  US20120041024A1

文献信息

• AMINO-QUINOLINES AS KINASE INHIBITORS
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：EP2566477B1

  公开（公告）日：2015-09-02
• The Identification and Pharmacological Characterization of 6-(<i>tert</i>-Butylsulfonyl)-<i>N</i>-(5-fluoro-1<i>H</i>-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase
  作者：Pamela A. Haile、Bartholomew J. Votta、Robert W. Marquis、Michael J. Bury、John F. Mehlmann、Robert Singhaus、Adam K. Charnley、Ami S. Lakdawala、Máire A. Convery、David B. Lipshutz、Biva M. Desai、Barbara Swift、Carol A. Capriotti、Scott B. Berger、Mukesh K. Mahajan、Michael A. Reilly、Elizabeth J. Rivera、Helen H. Sun、Rakesh Nagilla、Allison M. Beal、Joshua N. Finger、Michael N. Cook、Bryan W. King、Michael T. Ouellette、Rachel D. Totoritis、Maria Pierdomenico、Anna Negroni、Laura Stronati、Salvatore Cucchiara、Bartłomiej Ziółkowski、Anna Vossenkämper、Thomas T. MacDonald、Peter J. Gough、John Bertin、Linda N. Casillas

  DOI：10.1021/acs.jmedchem.6b00211

  日期：2016.5.26

  RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.
• Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel
  作者：Pamela A. Haile、Linda N. Casillas、Michael J. Bury、John F. Mehlmann、Robert Singhaus、Adam K. Charnley、Terry V. Hughes、Michael P. DeMartino、Gren Z. Wang、Joseph J. Romano、Xiaoyang Dong、Nikolay V. Plotnikov、Ami S. Lakdawala、Maire A. Convery、Bartholomew J. Votta、David B. Lipshutz、Biva M. Desai、Barbara Swift、Carol A. Capriotti、Scott B. Berger、Mukesh K. Mahajan、Michael A. Reilly、Elizabeth J. Rivera、Helen H. Sun、Rakesh Nagilla、Carol LePage、Michael T. Ouellette、Rachel D. Totoritis、Brian T. Donovan、Barry S. Brown、Khuram W. Chaudhary、Peter J. Gough、John Bertin、Robert W. Marquis

  DOI：10.1021/acsmedchemlett.8b00344

  日期：2018.10.11

  RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 mu M).
• US20140256949A1
  申请人：——

  公开号：US20140256949A1

  公开（公告）日：2014-09-11
• [EN] AMINO-QUINOLINES AS KINASE INHIBITORS<br/>[FR] AMINO-QUINOLÉINES EN TANT QU'INHIBITEURS DE KINASE
  申请人：GLAXO GROUP LTD

  公开号：WO2011140442A1

  公开（公告）日：2011-11-10

  Disclosed are quinoline compounds having the formula: wherein R1, R2 and A are as defined herein, and methods of making and using the same.