(3R)-3-ethyl-4-{2-(methylsulfanyl)-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-4-yl}morpholine | 1426154-34-8

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: (3R)-3-ethyl-4-{2-(methylsulfanyl)-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-4-yl}morpholine
• 英文别名: (3R)-3-ethyl-4-[2-methylsulfanyl-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]morpholine
• CAS: 1426154-34-8
• 化学式: C₁₅H₂₃N₃O₃S₂
• 分子量: 357.498
• InChiKey: GQOFUSZKHUJSIQ-LLVKDONJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  106
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (3R)-3-ethyl-4-{2-(methylsulfanyl)-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-4-yl}morpholine 、 吲哚-4-硼酸 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 噻吩-2-甲酸亚铜(I) 、 三(2-呋喃基)膦 作用下， 以 四氢呋喃 为溶剂， 以54%的产率得到(3R)-3-ethyl-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]morpholine
  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：

  4,6-二氯-二甲硫基嘧啶 在 sodium hydride 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 62.5h， 生成 (3R)-3-ethyl-4-{2-(methylsulfanyl)-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-4-yl}morpholine
  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