6-(tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline | 1581269-99-9

• 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: 6-(tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline
• 英文别名: 6-(Tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline；6-tert-butylsulfonyl-4-chloro-7-(2-methoxyethoxy)quinoline
• CAS: 1581269-99-9
• 化学式: C₁₆H₂₀ClNO₄S
• 分子量: 357.858
• InChiKey: XCFCLUQTWBNWPH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  73.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline 、 3,4-二甲基吡唑-5-胺 在 盐酸 乙腈 作用下， 以 乙醇 为溶剂， 反应 16.0h， 以to yield 6-(tert-butylsulfonyl)-N-(3,4-dimethyl-1H-pyrazol-5-yl)-7-(2-methoxyethoxy)quinolin-4-amine, hydrochloride (0.290 g, 0.618 mmol, 48.0% yield)的产率得到4-Quinolinamine, 6-[(1,1-dimethylethyl)sulfonyl]-N-(4,5-dimethyl-1H-pyrazol-3-yl)-7-(2-methoxyethoxy)-, hydrochloride
  参考文献：
  名称：

  Amino-quinolines as kinase inhibitors

  摘要：

  公开了具有以下式的化合物：其中R1、R2、R3、R4和R5如本文所定义，并公开了制备和使用这些化合物的方法。

  公开号：

  US09216965B2
• 作为产物：
  描述：

  6-溴-7-甲氧基喹啉-4(1H)-酮 在 2,4,6-三甲基吡啶 、 Oxone 、 四(三苯基膦)钯 、 sodium carbonate 、 potassium carbonate 、 lithium iodide 、 三氯氧磷 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 6-(tert-butylsulfonyl)-4-chloro-7-(2-methoxyethoxy)quinoline
  参考文献：
  名称：

  Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel

  摘要：

  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).

  DOI：

  10.1021/acsmedchemlett.8b00344

文献信息

• [EN] AMINO-QUINOLINES AS KINASE INHIBITORS<br/>[FR] AMINO-QUINOLÉINES SERVANT D'INHIBITEURS DE KINASE
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2014043437A1

  公开（公告）日：2014-03-20

  Disclosed are compounds having the formula: (Chemical formula should be inserted here.) wherein R1, R2, R3, R4 and R5 are as defined herein, and methods of making and using the same.

  揭示的是具有以下化学式的化合物：（化学式应在此处插入。）其中R1、R2、R3、R4和R5如本文所定义，并且制备和使用这些化合物的方法。
• Amino-quinolines as kinase inhibitors
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US09216965B2

  公开（公告）日：2015-12-22

  Disclosed are compounds having the formula: wherein R1, R2R3, R4 and R5 are as defined herein, and methods of making and using the same.

  公开了具有以下式的化合物：其中R1、R2、R3、R4和R5如本文所定义，并公开了制备和使用这些化合物的方法。
• US9216965B2
  申请人：——

  公开号：US9216965B2

  公开（公告）日：2015-12-22
• 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).
• AMINO-QUINOLINES AS KINASE INHIBITORS
  申请人：GlaxoSmithKline Intellectual Property Development Limited

  公开号：US20150094333A1

  公开（公告）日：2015-04-02

  Disclosed are compounds having the formula: wherein R 1 , R 2 R 3 , R 4 and R 5 are as defined herein, and methods of making and using the same.

  公开了具有以下式子的化合物：其中R1，R2，R3，R4和R5的定义如本文所述，并且公开了制备和使用这些化合物的方法。