4-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)morpholine | 944058-89-3

• 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-(methylsulfonylmethyl)pyrimidin-4-yl)morpholine
• 英文别名: 2-Chloro-4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidine；4-[2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl]morpholine
• CAS: 944058-89-3
• 化学式: C₁₀H₁₄ClN₃O₃S
• 分子量: 291.758
• InChiKey: GUACFAIZFHQZLF-UHFFFAOYSA-N

物化性质

• 沸点：
  610.8±55.0 °C(Predicted)
• 密度：
  1.423±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 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-(methylsulfonylmethyl)pyrimidin-4-yl)morpholine 在 N-甲基吡咯烷酮 、 1-氯乙基氯甲酸酯 、 四丁基溴化铵 、 sodium hydride 作用下， 以 二氯甲烷 为溶剂， 反应 5.5h， 生成 4-(2-chloro-6-(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
• 作为产物：
  描述：

  methyl 2-chloro-6-morpholinopyrimidine-4-carboxylate 在 锂硼氢 、 甲基磺酰氯 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 4-(2-chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)morpholine
  参考文献：
  名称：

  Expedient synthesis of biologically important sulfonylmethyl pyrimidines

  摘要：

  Two novel synthetic strategies that allow rapid diversification of the sulfone moiety in sulfonylmethyl pyrimidines, a class of compounds with a wide range of biological activity, which are of interest in a wide variety of drug discovery programmes, are described. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2014.04.111

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 of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway
  作者：Heather Hobbs、Gianpaolo Bravi、Ian Campbell、Maire Convery、Hannah Davies、Graham Inglis、Sandeep Pal、Simon Peace、Joanna Redmond、Declan Summers

  DOI：10.1021/acs.jmedchem.9b00348

  日期：2019.8.8

  4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding

  4-（嘧啶-4-基）吗啉由于吗啉氧而成为抑制PI3K和PIKKs的特权药效基团，既形成了关键的氢键相互作用，又在更广泛的kinome上传递了选择性。吗啉作为激酶铰链结合剂的关键在于它能够与相邻的芳香核形成共面构象，而该芳香核受吗啉氮非键电子与缺电子的嘧啶π系统相互作用而受到促进。迄今为止，几乎没有发现选择性吗啉替代品。本文中，我们描述了一种具有强大的非氮的吗啉类异构体的能力，该异构体具有模仿这种构象的能力，并将其应用在mTORC1和mTORC2的有效选择性双重抑制剂中（29b）。
• MORPHOLINO PYRIMIDINE DERIVATIVES USEFUL IN THE TREATMENT OF PROLIFERATIVE DISORDERS
  申请人：Finlay Maurice Raymond Verschoyle

  公开号：US20090325957A1

  公开（公告）日：2009-12-31

  A compound of formula (I) or a pharmaceutically 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.

  化合物式(I)或其药学上可接受的盐，其制备方法，包含它们的制药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中，特别是在由mTOR激酶和/或一个或多个PI3K酶介导的疾病中。
• Transcutaneous immunostimulation
  申请人：Finlay Maurice Raymond Verschoyle

  公开号：US20080171743A1

  公开（公告）日：2008-07-17

  A compound of formula (I) or a pharmaceutically 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.

  公式为（I）的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用途，例如在治疗增生性疾病如癌症和特别是由mTOR激酶和/或一个或多个PI3K酶介导的疾病中的用途。