1-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea | 1009621-99-1

• 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: 1-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea
• 英文别名: 3-ethyl-1-{4-[4-(methanesulfonylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl}urea；3-ethyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea
• CAS: 1009621-99-1
• 化学式: C₂₀H₂₇N₅O₄S
• 分子量: 433.531
• InChiKey: DVQJAIOBMGYWCL-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  122
• 氢给体数：
  2
• 氢受体数：
  7

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 、 sodium carbonate 、 三乙胺 、 sodium iodide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙二醇二甲醚 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 55.75h， 生成 1-ethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]phenyl]urea
  参考文献：
  名称：

  Discovery of AZD3147: A Potent, Selective Dual Inhibitor of mTORC1 and mTORC2

  摘要：

  High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC(50)-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.

  DOI：

  10.1021/jm501778s

文献信息

• 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）。
• 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。
• Compounds-943
  申请人：AstraZeneca AB

  公开号：US07750003B2

  公开（公告）日：2010-07-06

  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，其制备过程，包含它们的制药组合物以及它们在治疗中的应用，例如在治疗增生性疾病如癌症中，特别是在由mTOR激酶和/或一个或多个PI3K酶介导的疾病中。
• MORPHOLINO PYRIMIDINE DERIVATIVES USEFUL IN THE TREATMENT OF PROLIFERATIVE DISORDERS
  申请人：AstraZeneca AB

  公开号：EP2057140A1

  公开（公告）日：2009-05-13
• US7750003B2
  申请人：——

  公开号：US7750003B2

  公开（公告）日：2010-07-06