4-(2-chloro-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)morpholine | 1101818-09-0

• 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-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)morpholine
• 英文别名: 4-[2-chloro-6-(1-methylsulfonylcyclopropyl)pyrimidin-4-yl]morpholine
• CAS: 1101818-09-0
• 化学式: C₁₂H₁₆ClN₃O₃S
• 分子量: 317.796
• InChiKey: FGZUAQCFSTYJLB-UHFFFAOYSA-N

物化性质

• 沸点：
  625.7±55.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  80.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(2-chloro-6-(1-(methylsulfonyl)cyclopropyl)pyrimidin-4-yl)morpholine 在 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 lithium hydroxide monohydrate 、 potassium acetate 、 联硼酸频那醇酯 、 三环己基膦 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 41.0h， 生成 4-{4-[1-(methylsulfonyl)cyclopropyl]-6-(morpholin-4-yl)pyrimidin-2-yl}-1H-indole-2-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：

  2,4-二氯-6-(甲基磺酰基甲基)嘧啶 在 四丁基溴化铵 、 三乙胺 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 4.0h， 生成 4-(2-chloro-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

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。
• Compounds - 945
  申请人：PIKE Kurt Gordon

  公开号：US20090018134A1

  公开（公告）日：2009-01-15

  A compound of formula (I) or a pharamaceutically acceptable salt thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, for example in the treatment of proliferative disease such as cancer and particularly in disease mediated by an mTOR kinase and/or one or more PI3K enzyme.

  公式（I）的化合物或其药用盐，其制备方法，含有它们的药物组合物以及它们在治疗中的用途，例如在治疗增殖性疾病如癌症，特别是由mTOR激酶和/或一个或多个PI3K酶介导的疾病。
• Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent
  作者：Kevin M. Foote、J. Willem M. Nissink、Thomas McGuire、Paul Turner、Sylvie Guichard、James W. T. Yates、Alan Lau、Kevin Blades、Dan Heathcote、Rajesh Odedra、Gary Wilkinson、Zena Wilson、Christine M. Wood、Philip J. Jewsbury

  DOI：10.1021/acs.jmedchem.8b01187

  日期：2018.11.21

  characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer

  激酶共济失调毛细血管扩张突变和 rad3 相关 (ATR) 是 DNA 损伤反应和顶端激酶的关键调节器，它协调修复停滞的复制叉（复制压力）和相关的 DNA 双链断裂的细胞过程。在替代途径不太活跃的情况下，抑制 ATR 介导的修复途径有望通过增加复制压力来帮助临床反应。在这里，我们描述了临床候选药物2 (AZD6738)的开发，这是一种有效且选择性的亚砜亚胺吗啉代嘧啶 ATR 抑制剂，具有出色的临床前理化和药代动力学 (PK) 特性。化合物2从早期描述的抑制剂1 (AZ20)开始，开发了改善水溶性和消除 CYP3A4 时间依赖性抑制的药物。临床候选2具有适合每天一次或两次给药的有利人体 PK，并在中等剂量下实现生物有效暴露。化合物2目前正在多个 I/II 期试验中作为抗癌剂进行测试。
• 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。
• 2-morpholin-4,6-disubstituted pyrimidine derivative, and preparation method and pharmaceutical use thereof
  申请人：Shanghai Haiyan Pharmaceutical Technology Co., Ltd.

  公开号：US10227324B2

  公开（公告）日：2019-03-12

  Disclosed is a 2-morpholin-4,6-disubstituted pyrimidine derivative as shown in formula (1) below, and a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof, and a pharmaceutical composition thereof and a use thereof, wherein the definition of each group is as shown in the description. The compound has a PI3K kinase inhibition activity, and has a relatively high inhibitive ability and a low cytotoxicity against PIK3CA mutant breast cancer cell strains T47D and MCF-7.

  公开了一种如下式（1）所示的2-吗啉-4,6-二取代嘧啶衍生物及其药学上可接受的盐、溶液剂、立体异构体或原药，以及其药物组合物及其用途，其中各基团的定义如说明书所示。该化合物具有 PI3K 激酶抑制活性，对 PIK3CA 突变乳腺癌细胞株 T47D 和 MCF-7 具有相对较高的抑制能力和较低的细胞毒性。