benzyl 4-({1-[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}sulfonyl)piperidine-1-carboxylate | 1426154-31-5

• 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-({1-[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}sulfonyl)piperidine-1-carboxylate
• 英文别名: Benzyl 4-[1-(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylpiperidine-1-carboxylate；benzyl 4-[1-(2-chloro-6-morpholin-4-ylpyrimidin-4-yl)cyclopropyl]sulfonylpiperidine-1-carboxylate
• CAS: 1426154-31-5
• 化学式: C₂₄H₂₉ClN₄O₅S
• 分子量: 521.037
• InChiKey: CWDCMSIMNNDNMB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.54
• 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-({1-[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}sulfonyl)piperidine-1-carboxylate 、 吲哚-4-硼酸 在 bis-triphenylphosphine-palladium(II) chloride 、 碘代三甲硅烷 、 sodium carbonate 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 为溶剂， 反应 4.0h， 生成 4-[2-(1H-indol-4-yl)-6-(1-piperidin-4-ylsulfonylcyclopropyl)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：

  methyl 2-chloro-6-morpholinopyrimidine-4-carboxylate 在 锂硼氢 、 四丁基溴化铵 、 sodium carbonate 、 N,N-二异丙基乙胺 、 sodium iodide 、 sodium hydroxide 、 sodium sulfite 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 丙酮 、 甲苯 为溶剂， 反应 58.5h， 生成 benzyl 4-({1-[2-chloro-6-(morpholin-4-yl)pyrimidin-4-yl]cyclopropyl}sulfonyl)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