2-[2-(2,2-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one | 1535209-40-5

• 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: 2-[2-(2,2-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one
• 英文别名: 2-[2-(2,2-dimethyl-3H-indol-1-yl)-2-oxoethyl]-4-morpholin-4-yl-1H-pyrimidin-6-one
• CAS: 1535209-40-5
• 化学式: C₂₀H₂₄N₄O₃
• 分子量: 368.436
• InChiKey: XKPMADVSFJYDPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  74.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2,2-dimethyl-2,3-dihydro-1H-indole 、 ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate 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25%的产率得到2-[2-(2,2-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)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

• 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.