1-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea | 1009622-76-7

• 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-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea
• 英文别名: 1-[4-[4-(Hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methyl-urea
• CAS: 1009622-76-7
• 化学式: C₁₈H₂₃N₅O₃
• 分子量: 357.412
• InChiKey: GFKSGOJBUYBTKM-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  99.6
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 生成 3-methyl-1-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(pyridin-4-ylsulfanylmethyl)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
• 作为产物：
  描述：

  1-甲基-3-(4-溴苯基)脲 在 bis-triphenylphosphine-palladium(II) chloride 、 potassium acetate 、 sodium carbonate 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 19.0h， 生成 1-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]-3-methylurea
  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

• 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：EP2057140B1

  公开（公告）日：2012-08-08
• US7750003B2
  申请人：——

  公开号：US7750003B2

  公开（公告）日：2010-07-06
• [EN] MORPHOLINO PYRIMIDINE DERIVATIVES USEFUL IN THE TREATMENT OF PROLIFERATIVE DISORDERS<br/>[FR] DÉRIVÉS DE LA MORPHOLINO PYRIMIDINE UTILES DANS LE TRAITEMENT DE MALADIES PROLIFÉRATIVES
  申请人：ASTRAZENECA AB

  公开号：WO2008023159A1

  公开（公告）日：2008-02-28

  [EN] 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.
  [FR] La présente invention concerne un composé de formule (I) ou un sel de celui-ci pharmaceutiquement acceptable, des procédés pour les préparer, des compositions pharmaceutiques les contenant ainsi que leur utilisation thérapeutique, par exemple dans le traitement d'une maladie proliférative telle que le cancer et en particulier une maladie médiée par une mTOR kinase et/ou par une ou plusieurs enzymes PI3K.