2-[(5-fluoro-1H-benzimidazol-2-yl)methyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one | 1374772-35-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2-[(5-fluoro-1H-benzimidazol-2-yl)methyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one
• 英文别名: 2-[(6-fluoro-1H-benzimidazol-2-yl)methyl]-3-methyl-6-morpholin-4-ylpyrimidin-4-one
• CAS: 1374772-35-6
• 化学式: C₁₇H₁₈FN₅O₂
• 分子量: 343.361
• InChiKey: NMLASYCUCSTTHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  73.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate 在 吡啶 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 80.0h， 生成 2-[(5-fluoro-1H-benzimidazol-2-yl)methyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one
  参考文献：
  名称：

  Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kβ Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

  摘要：

  Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.

  DOI：

  10.1021/jm300241b

文献信息

• Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3Kβ Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers
  作者：Victor Certal、Frank Halley、Angela Virone-Oddos、Cécile Delorme、Andreas Karlsson、Alexey Rak、Fabienne Thompson、Bruno Filoche-Rommé、Youssef El-Ahmad、Jean-Christophe Carry、Pierre-Yves Abecassis、Pascale Lejeune、Loic Vincent、Hélène Bonnevaux、Jean-Paul Nicolas、Thomas Bertrand、Jean-Pierre Marquette、Nadine Michot、Tsiala Benard、Peter Below、Isabelle Vade、Fabienne Chatreaux、Gilles Lebourg、Fabienne Pilorge、Odile Angouillant-Boniface、Audrey Louboutin、Christoph Lengauer、Laurent Schio

  DOI：10.1021/jm300241b

  日期：2012.5.24

  Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3Kβ has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3Kβ-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3Kβ and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3Kδ showed key interactions and structural features supporting the observed PI3Kβ isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.