(S)-4-(1-(2,2-dimethyl-propionyl)-pyrrolidine-3-yl)amino-6-(2-methoxypyridine-5-yl)quinazoline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (S)-4-(1-(2,2-dimethyl-propionyl)-pyrrolidine-3-yl)amino-6-(2-methoxypyridine-5-yl)quinazoline
• 英文别名: (S)-1-(3-((6-(6-methoxypyridin-3-yl)quinazolin-4-yl)amino)pyrrolidin-1-yl)-2,2-dimethylpropan-1-one；1-[(3S)-3-[[6-(6-methoxypyridin-3-yl)quinazolin-4-yl]amino]pyrrolidin-1-yl]-2,2-dimethylpropan-1-one
• 化学式: C₂₃H₂₇N₅O₂
• 分子量: 405.5
• InChiKey: QTUNKAAWQJVGKH-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  80.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-溴-4-氯喹唑啉 在 palladium bis[bis(diphenylphosphino)ferrocene] dichloride 、 sodium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 23.0h， 生成 (S)-4-(1-(2,2-dimethyl-propionyl)-pyrrolidine-3-yl)amino-6-(2-methoxypyridine-5-yl)quinazoline
  参考文献：
  名称：

  Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors

  摘要：

  In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3K delta inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3K delta inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3K delta isoform selectivity over PI3K alpha, PI3K beta, and PI3K gamma, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kd pocket, which might explain their potent PI3K delta inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3K delta inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.03.002

文献信息

• Novel 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives as potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitors
  作者：Minhang Xin、Weiming Duan、Yifan Feng、Yuan-Yuan Hei、Hao Zhang、Ying Shen、Hong-Yi Zhao、Shuai Mao、San-Qi Zhang

  DOI：10.1016/j.bmc.2018.03.002

  日期：2018.5

  In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3K delta inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3K delta inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50 = 2.7 nM). Moreover, these three compounds showed favorable PI3K delta isoform selectivity over PI3K alpha, PI3K beta, and PI3K gamma, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6. In addition, molecular docking simulation showed that several key hydrogen bonding interactions were formed for compounds 12d, 20a and 20c in the PI3Kd pocket, which might explain their potent PI3K delta inhibition. These results indicate the 6-aryl substituted 4-pyrrolidineaminoquinazolines were potent PI3K delta inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.