3-(4-((4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl)-3-oxopropanenitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 3-(4-((4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl)-3-oxopropanenitrile
• 英文别名: 3-[4-[[4-Amino-3-(1-methylpyrazol-4-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]piperidin-1-yl]-3-oxopropanenitrile；3-[4-[[4-amino-3-(1-methylpyrazol-4-yl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]piperidin-1-yl]-3-oxopropanenitrile
• 化学式: C₁₈H₂₁N₉O
• 分子量: 379.424
• InChiKey: UMCRCQRCEJRTSJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  132
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-氨基吡唑并[3,4-d]嘧啶 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 四(三苯基膦)钯 、 偶氮二甲酸二异丙酯 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三苯基膦 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 49.5h， 生成 3-(4-((4-amino-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidin-1-yl)-3-oxopropanenitrile
  参考文献：
  名称：

  Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors

  摘要：

  Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 ttM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors. (C) 2018 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmc.2018.04.005

文献信息

• Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors
  作者：Yuan Yin、Cheng-Juan Chen、Ru-Nan Yu、Zhi-Jian Wang、Tian-Tai Zhang、Da-Yong Zhang

  DOI：10.1016/j.bmc.2018.04.005

  日期：2018.9

  Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 ttM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors. (C) 2018 Published by Elsevier Ltd.