2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile
• 英文别名: 2-[3-[4-[6-(1-Methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]pyrazol-1-yl]-1-(2,2,2-trifluoroethyl)azetidin-3-yl]acetonitrile；2-[3-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]pyrazol-1-yl]-1-(2,2,2-trifluoroethyl)azetidin-3-yl]acetonitrile
• 化学式: C₂₀H₁₈F₃N₉
• 分子量: 441.418
• InChiKey: CVWIGSVNTPFWIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.48
• 重原子数：
  32.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  92.86
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为产物：
  描述：

  1-(1-甲基吡唑)乙酮 在 环丁砜 、 potassium phosphate 、 XPhos Pd G2 、 ammonium acetate 、 caesium carbonate 、 pyridinium hydrobromide perbromide 、 N,N-二异丙基乙胺 、 三氟乙酸 、 sodium hydroxide 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 185.5h， 生成 2-(3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)azetidin-3-yl)acetonitrile
  参考文献：
  名称：

  Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases

  摘要：

  Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family that regulates signal transduction downstream of receptors for the IL-23/IL-12 pathways and type I interferon family, where it pairs with JAK2 or JAK1, respectively. On the basis of human genetic and emerging clinical data, a selective TYK2 inhibitor provides an opportunity to treat autoimmune diseases delivering a potentially differentiated clinical profile compared to currently approved JAK inhibitors. The discovery of an ATP-competitive pyrazolopyrazinyl series of TYK2 inhibitors was accomplished through computational and structurally enabled design starting from a known kinase hinge binding motif. With understanding of PK/PD relationships, a target profile balancing TYK2 potency and selectivity over off-target JAK2 was established. Lead optimization involved modulating potency, selectivity, and ADME properties which led to the identification of the clinical candidate PF-06826647 (22).

  DOI：

  10.1021/acs.jmedchem.0c00948