trans-N,N-dimethyl-N'-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,4-cyclohexanediamine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并三嗪类
• 英文名称: trans-N,N-dimethyl-N'-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,4-cyclohexanediamine
• 化学式: C₁₄H₂₁N₅
• 分子量: 259.354
• InChiKey: BGFQLVAKOOLCDZ-HAQNSBGRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.01
• 重原子数：
  19.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  45.46
• 氢给体数：
  1.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  4-氯吡咯并[1,2-F][1,2,4]三嗪 、 trans-dimethylcyclohexane-1,4-diamine 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 2.0h， 以54%的产率得到trans-N,N-dimethyl-N'-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,4-cyclohexanediamine
  参考文献：
  名称：

  Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4

  摘要：

  We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2018.01.008

文献信息

• Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4
  作者：Sébastien L. Degorce、Rana Anjum、Keith S. Dillman、Lisa Drew、Sam D. Groombridge、Christopher T. Halsall、Eva M. Lenz、Nicola A. Lindsay、Michele F. Mayo、Jennifer H. Pink、Graeme R. Robb、James S. Scott、Stephen Stokes、Yafeng Xue

  DOI：10.1016/j.bmc.2018.01.008

  日期：2018.2

  We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib. (C) 2018 Elsevier Ltd. All rights reserved.