methyl 4-{4-[1-(methylsulfonyl)cyclopropyl]-6-(morpholin-4-yl)pyrimidin-2-yl}-1H-indole-6-carboxylate | 1426154-37-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: methyl 4-{4-[1-(methylsulfonyl)cyclopropyl]-6-(morpholin-4-yl)pyrimidin-2-yl}-1H-indole-6-carboxylate
• CAS: 1426154-37-1
• 化学式: C₂₂H₂₄N₄O₅S
• 分子量: 456.522
• InChiKey: SMJMYBPSEMZBCG-UHFFFAOYSA-N

物化性质

• 沸点：
  687.6±55.0 °C(Predicted)
• 密度：
  1.48±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.28
• 重原子数：
  32.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  114.48
• 氢给体数：
  1.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  methyl 4-{4-[1-(methylsulfonyl)cyclopropyl]-6-(morpholin-4-yl)pyrimidin-2-yl}-1H-indole-6-carboxylate 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 18.0h， 以93%的产率得到4-{4-[1-(methylsulfonyl)cyclopropyl]-6-(morpholin-4-yl)pyrimidin-2-yl}-1H-indole-6-carboxylic acid
  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：

  6-(氯甲基)脲嘧啶 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 四丁基溴化铵 、 potassium acetate 、 三乙胺 、 联硼酸频那醇酯 、 sodium hydroxide 、 三氯氧磷 、 三环己基膦 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 43.0h， 生成 methyl 4-{4-[1-(methylsulfonyl)cyclopropyl]-6-(morpholin-4-yl)pyrimidin-2-yl}-1H-indole-6-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