1-(4-(3-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepan-1-yl)ethanone | 1421693-18-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-(3-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepan-1-yl)ethanone
• CAS: 1421693-18-6
• 化学式: C₂₂H₂₆FN₇OS
• 分子量: 455.559
• InChiKey: RDYPRIMFGSVNPH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.89
• 重原子数：
  32.0
• 可旋转键数：
  5.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  86.28
• 氢给体数：
  2.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  1-(4-(3-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepan-1-yl)ethanone 在 盐酸 、 水 作用下， 以 甲醇 为溶剂， 反应 3.0h， 以37%的产率得到5-(2-((5-(1,4-diazepan-1-yl)-2-fluorophenyl)amino)pyrimidin-4-yl)-N,4-dimethylthiazol-2-amine
  参考文献：
  名称：

  Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

  摘要：

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.

  DOI：

  10.1021/jm301475f
• 作为产物：
  描述：

  1-(4-甲基-2-(甲基氨基)噻唑-5-基)乙酮 在 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) 作用下， 以 甲醇 、 乙二醇甲醚 为溶剂， 反应 1.0h， 生成 1-(4-(3-((5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepan-1-yl)ethanone
  参考文献：
  名称：

  Substituted 4-(Thiazol-5-yl)-2-(phenylamino)pyrimidines Are Highly Active CDK9 Inhibitors: Synthesis, X-ray Crystal Structures, Structure–Activity Relationship, and Anticancer Activities

  摘要：

  Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the CS-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC50 = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper,(34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B-and T-cells.

  DOI：

  10.1021/jm301475f