4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)-cyclopropyl]pyrimidin-2-yl}-1H-indole | 1233339-21-3

• 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: 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)-cyclopropyl]pyrimidin-2-yl}-1H-indole
• 英文别名: (3S)-4-[2-(1H-indol-4-yl)-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]-3-methylmorpholine
• CAS: 1233339-21-3
• 化学式: C₂₁H₂₄N₄O₃S
• 分子量: 412.513
• InChiKey: SCGCBAAYLFTIJU-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  96.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,6-二氯嘧啶-4-甲酸甲酯 在 bis-triphenylphosphine-palladium(II) chloride 、 锂硼氢 、 四丁基溴化铵 、 sodium carbonate 、 三乙胺 、 sodium hydroxide 、 lithium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇二甲醚 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 45.0h， 生成 4-{4-[(3S)-3-methylmorpholin-4-yl]-6-[1-(methylsulfonyl)-cyclopropyl]pyrimidin-2-yl}-1H-indole
  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

• [EN] PYRIMIDINE INDOLE DERIVATIVES FOR TREATING CANCER<br/>[FR] DÉRIVÉS DE PYRIMIDINE ET D'INDOLE POUR LE TRAITEMENT DU CANCER
  申请人：ASTRAZENECA AB

  公开号：WO2010073034A1

  公开（公告）日：2010-07-01

  There is provided pyrimidinyl indole compounds of Formula (I), or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly for treating cancer.

  提供了式（I）的嘧啶基吲哚化合物，或其药用盐，其制备方法，含有它们的药物组合物以及它们在治疗中的应用，特别是用于治疗癌症。
• CHEMICAL COMPOUNDS 610
  申请人：Foote Kevin Michael

  公开号：US20110053923A1

  公开（公告）日：2011-03-03

  There is provided pyrimidinyl indole compounds of Formula (I), or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

  提供了式(I)的嘧啶基吲哚化合物或其药学上可接受的盐，其制备过程，包含它们的制药组合物以及它们在治疗中的使用。
• PYRIMIDINE INDOLE DERIVATIVES FOR TREATING CANCER
  申请人：AstraZeneca AB

  公开号：EP2379530A1

  公开（公告）日：2011-10-26
• 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.