7-(4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one | 1095647-89-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: 7-(4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
• 英文别名: 7-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1,3,4,5-tetrahydro-1-benzazepin-2-one
• CAS: 1095647-89-4
• 化学式: C₁₉H₂₀F₃N₅O
• 分子量: 391.396
• InChiKey: YGXQGDCKKNZRJA-UHFFFAOYSA-N

物化性质

• 密度：
  1.402±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  78.9
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  7-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one 、 环丁基胺 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 7-(4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
  参考文献：
  名称：

  Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): Structure–activity relationships and strategies for the elimination of reactive metabolite formation

  摘要：

  The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.

  DOI：

  10.1016/j.bmcl.2008.10.030

文献信息

• Trifluoromethylpyrimidine-based inhibitors of proline-rich tyrosine kinase 2 (PYK2): Structure–activity relationships and strategies for the elimination of reactive metabolite formation
  作者：Daniel P. Walker、F. Christopher Bi、Amit S. Kalgutkar、Jonathan N. Bauman、Sabrina X. Zhao、John R. Soglia、Gary E. Aspnes、Daniel W. Kung、Jacquelyn Klug-McLeod、Michael P. Zawistoski、Molly A. McGlynn、Robert Oliver、Matthew Dunn、Jian-Cheng Li、Daniel T. Richter、Beth A. Cooper、John C. Kath、Catherine A. Hulford、Christopher L. Autry、Michael J. Luzzio、Ethan J. Ung、W. Gregory Roberts、Peter C. Bonnette、Leonard Buckbinder、Anil Mistry、Matthew C. Griffor、Seungil Han、Angel Guzman-Perez

  DOI：10.1016/j.bmcl.2008.10.030

  日期：2008.12

  The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.