6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one | 1383974-00-2

• 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: 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one
• 英文别名: 4-morpholin-4-yl-2-[2-oxo-2-(4-pyridin-3-yl-2,3-dihydroindol-1-yl)ethyl]-1H-pyrimidin-6-one
• CAS: 1383974-00-2
• 化学式: C₂₃H₂₃N₅O₃
• 分子量: 417.467
• InChiKey: GXZTVBBVCJUSKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  87.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one 、 sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate 、 水 在 magnesium sulfate 、 silica 、 methanol-dichloromethane 作用下， 以 N,N-二甲基甲酰胺 、 吡啶 、 二氯甲烷 为溶剂， 反应 18.0h， 以gradient: dichloromethane/methanol from 100/0 to 95/05, so as to give 456 mg of 2-[2-((+)-2-hydroxymethyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one的产率得到2-{2-[2-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one
  参考文献：
  名称：

  NOVEL PYRIMIDINE DERIVATIVES, PREPARATION THEREOF, AND PHARMACEUTICAL USE THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS

  摘要：

  本发明涉及从嘧啶衍生的新化合物，制备该化合物的方法，获得的新中间体，将其用作药物的用途，含有该化合物的制药组合物，以及将其作为AKT抑制剂的治疗用途。

  公开号：

  US20130274253A1
• 作为产物：
  描述：

  ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate 、 4-pyridin-3-yl-2,3-dihydro-1H-indole 在 sodium hydroxide 、 吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 64.0h， 以78%的产率得到6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one
  参考文献：
  名称：

  Discovery and Optimization of Pyrimidone Indoline Amide PI3Kβ Inhibitors for the Treatment of Phosphatase and Tensin Homologue (PTEN)-Deficient Cancers

  摘要：

  Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3K beta in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3K beta-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3K beta inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110 beta with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.

  DOI：

  10.1021/jm401642q

文献信息

• NOVEL PYRIMIDINE DERIVATIVES, PREPARATION THEREOF, AND PHARMACEUTICAL USE THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS
  申请人：Brollo Maurice

  公开号：US20130274253A1

  公开（公告）日：2013-10-17

  The present invention relates to novel chemical compounds derived from pyrimidines, to the method for preparing same, to the novel intermediates obtained, to the use thereof as drugs, to the pharmaceutical compositions containing same, and to the therapeutic use thereof as AKT inhibitors.

  本发明涉及从嘧啶衍生的新化合物，以及制备该化合物的方法，获得的新中间体，将其用作药物的用途，含有该化合物的药物组合物，以及将其作为AKT抑制剂的治疗用途。
• NOUVEAUX DERIVES DE PYRIMIDINES, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE COMME INHIBITEURS DE PHOSPHORYLATION D'AKT(PKB)
  申请人：SANOFI

  公开号：EP2658844B1

  公开（公告）日：2016-10-26
• US9133168B2
  申请人：——

  公开号：US9133168B2

  公开（公告）日：2015-09-15
• [EN] NOVEL PYRIMIDINE DERIVATIVES, PREPARATION THEREOF, AND PHARMACEUTICAL USE THEREOF AS AKT(PKB) PHOSPHORYLATION INHIBITORS<br/>[FR] NOUVEAUX DERIVES DE PYRIMIDINES, LEUR PREPARATION ET LEUR UTILISATION PHARMACEUTIQUE COMME INHIBITEURS DE PHOSPHORYLATION D'AKT(PKB)
  申请人：SANOFI SA

  公开号：WO2012089633A9

  公开（公告）日：2012-08-23

  [EN] The present invention relates to novel chemical compounds derived from pyrimidines, to the method for preparing same, to the novel intermediates obtained, to the use thereof as drugs, to the pharmaceutical compositions containing same, and to the therapeutic use thereof as AKT inhibitors.
  [FR] La présente invention concerne de nouveaux composés chimiques dérivés de pyrimidines, leur procédé de préparation, les nouveaux intermédiaires obtenus, leur application à titre de médicaments, les compositions pharmaceutiques les renfermant et leur utilisation thérapeutique en tant qu'inhibiteurs d'AKT.
• Discovery and Optimization of Pyrimidone Indoline Amide PI3Kβ Inhibitors for the Treatment of Phosphatase and Tensin Homologue (PTEN)-Deficient Cancers
  作者：Victor Certal、Jean-Christophe Carry、Frank Halley、Angela Virone-Oddos、Fabienne Thompson、Bruno Filoche-Rommé、Youssef El-Ahmad、Andreas Karlsson、Véronique Charrier、Cécile Delorme、Alexey Rak、Pierre-Yves Abecassis、Céline Amara、Loïc Vincent、Hélène Bonnevaux、Jean-Paul Nicolas、Magali Mathieu、Thomas Bertrand、Jean-Pierre Marquette、Nadine Michot、Tsiala Benard、Marc-Antoine Perrin、Olivier Lemaitre、Stephane Guerif、Sébastien Perron、Sylvie Monget、Florence Gruss-Leleu、Gilles Doerflinger、Houlfa Guizani、Maurice Brollo、Laurence Delbarre、Luc Bertin、Patrick Richepin、Véronique Loyau、Carlos Garcia-Echeverria、Christoph Lengauer、Laurent Schio

  DOI：10.1021/jm401642q

  日期：2014.2.13

  Compelling molecular biology publications have reported the implication of phosphoinositide kinase PI3K beta in PTEN-deficient cell line growth and proliferation. These findings supported a scientific rationale for the development of PI3K beta-specific inhibitors for the treatment of PTEN-deficient cancers. This paper describes the discovery of 2-[2-(2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (7) and the optimization of this new series of active and selective pyrimidone indoline amide PI3K beta inhibitors. 2-[2-(2-Methyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one (28), identified following a carefully designed methyl scan, displayed improved physicochemical and in vitro pharmacokinetic properties. Structural biology efforts enabled the acquisition of the first X-ray cocrystal structure of p110 beta with the selective inhibitor compound 28 bound to the ATP site. The nonplanar binding mode described herein is consistent with observed structure-activity relationship for the series. Compound 28 demonstrated significant in vivo activity in a UACC-62 xenograft model in mice, warranting further preclinical investigation. Following successful development, compound 28 entered phase I/Ib clinical trial in patients with advanced cancer.