benzyl 4-({[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]methyl}sulfonyl)piperidine-1-carboxylate | 1426154-26-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 4-({[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]methyl}sulfonyl)piperidine-1-carboxylate
• 英文别名: benzyl 4-[(2-chloro-6-morpholinopyrimidin-4-yl)methylsulfonyl]piperidine-1-carboxylate；Benzyl 4-[(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)methylsulfonyl]piperidine-1-carboxylate；benzyl 4-[(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)methylsulfonyl]piperidine-1-carboxylate
• CAS: 1426154-26-8
• 化学式: C₂₂H₂₇ClN₄O₅S
• 分子量: 494.999
• InChiKey: QVKKBSSZJHXAHC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  110
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  benzyl 4-({[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]methyl}sulfonyl)piperidine-1-carboxylate 在 bis-triphenylphosphine-palladium(II) chloride 、 四丁基溴化铵 、 sodium carbonate 、 sodium hydroxide 作用下， 以 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 19.0h， 生成 benzyl 4-(1-(2-(1H-indol-4-yl)-6-morpholinopyrimidin-4-yl)cyclopropylsulfonyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity

  摘要：

  ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

  DOI：

  10.1021/jm301859s
• 作为产物：
  描述：

  methyl 2-chloro-6-morpholinopyrimidine-4-carboxylate 在 锂硼氢 、 甲基磺酰氯 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 benzyl 4-({[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]methyl}sulfonyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Expedient synthesis of biologically important sulfonylmethyl pyrimidines

  摘要：

  Two novel synthetic strategies that allow rapid diversification of the sulfone moiety in sulfonylmethyl pyrimidines, a class of compounds with a wide range of biological activity, which are of interest in a wide variety of drug discovery programmes, are described. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2014.04.111

文献信息

• Discovery of 4-{4-[(3<i>R</i>)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1<i>H</i>-indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity
  作者：Kevin M. Foote、Kevin Blades、Anna Cronin、Shaun Fillery、Sylvie S. Guichard、Lorraine Hassall、Ian Hickson、Xavier Jacq、Philip J. Jewsbury、Thomas M. McGuire、J. Willem M. Nissink、Rajesh Odedra、Ken Page、Paula Perkins、Abid Suleman、Kin Tam、Pia Thommes、Rebecca Broadhurst、Christine Wood

  DOI：10.1021/jm301859s

  日期：2013.3.14

  ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.
• Expedient synthesis of biologically important sulfonylmethyl pyrimidines
  作者：Kevin Blades、Julie Demeritt、Shaun Fillery、Kevin M. Foote、Ryan Greenwood、Clare Gregson、Lorraine A. Hassall、Thomas M. McGuire、Kurt G. Pike、Emma Williams

  DOI：10.1016/j.tetlet.2014.04.111

  日期：2014.7

  Two novel synthetic strategies that allow rapid diversification of the sulfone moiety in sulfonylmethyl pyrimidines, a class of compounds with a wide range of biological activity, which are of interest in a wide variety of drug discovery programmes, are described. (C) 2014 Elsevier Ltd. All rights reserved.