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

文献信息

• Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases
  作者：Brian S. Gerstenberger、Catherine Ambler、Eric P. Arnold、Mary-Ellen Banker、Matthew F. Brown、James D. Clark、Alpay Dermenci、Martin E. Dowty、Andrew Fensome、Susan Fish、Matthew M. Hayward、Martin Hegen、Brett D. Hollingshead、John D. Knafels、David W. Lin、Tsung H. Lin、Dafydd R. Owen、Eddine Saiah、Raman Sharma、Felix F. Vajdos、Li Xing、Xiaojing Yang、Xin Yang、Stephen W. Wright

  DOI：10.1021/acs.jmedchem.0c00948

  日期：2020.11.25

  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).