4-(2-chloro-6-(1-methyl-4-(methylsulfonyl)piperidin-4-yl)pyrimidin-4-yl)morpholine | 1426154-29-1

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4-(2-chloro-6-(1-methyl-4-(methylsulfonyl)piperidin-4-yl)pyrimidin-4-yl)morpholine
• 英文别名: 4-[2-Chloro-6-(1-methyl-4-methylsulfonylpiperidin-4-yl)pyrimidin-4-yl]morpholine；4-[2-chloro-6-(1-methyl-4-methylsulfonylpiperidin-4-yl)pyrimidin-4-yl]morpholine
• CAS: 1426154-29-1
• 化学式: C₁₅H₂₃ClN₄O₃S
• 分子量: 374.892
• InChiKey: VVRJBNAPMMFHJV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  84
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-(2-chloro-6-(1-methyl-4-(methylsulfonyl)piperidin-4-yl)pyrimidin-4-yl)morpholine 、 吲哚-4-硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 sodium carbonate 作用下， 以 乙二醇二甲醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以30%的产率得到4-[2-(1H-indol-4-yl)-6-(1-methyl-4-methylsulfonylpiperidin-4-yl)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：

  2,4-二氯-6-(甲基磺酰基甲基)嘧啶 在 N-甲基吡咯烷酮 、 1-氯乙基氯甲酸酯 、 四丁基溴化铵 、 三乙酰氧基硼氢化钠 、 sodium hydride 、 溶剂黄146 、 三乙胺 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 6.83h， 生成 4-(2-chloro-6-(1-methyl-4-(methylsulfonyl)piperidin-4-yl)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

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.