2-(1-ethyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)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-(1-ethyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile
• 英文别名: 2-[1-Ethyl-3-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]pyrazol-1-yl]azetidin-3-yl]acetonitrile；2-[1-ethyl-3-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]pyrazol-1-yl]azetidin-3-yl]acetonitrile
• 化学式: C₂₀H₂₁N₉
• 分子量: 387.447
• InChiKey: LSEHWUWQKGKULM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  92.9
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-(1-甲基吡唑)乙酮 在 环丁砜 、 盐酸 、 potassium phosphate 、 XPhos Pd G2 、 ammonium acetate 、 三乙酰氧基硼氢化钠 、 caesium carbonate 、 pyridinium hydrobromide perbromide 、 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 188.0h， 生成 2-(1-ethyl-3-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1H-pyrazol-1-yl)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

• [EN] PYRAZOLO[1,5-A]PYRAZIN-4-YL DERIVATIVES AS JAK-INHIBITORS<br/>[FR] DÉRIVÉS PYRAZOLO[1,5-A]PYRAZIN-4-YLE COMME INHIBITEURS JAC
  申请人：PFIZER

  公开号：WO2017144995A1

  公开（公告）日：2017-08-31

  A compound compound having the structure (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein A, A' and A" are independently O, C=O, C-R' or N-R", where R' and R" may independently be H, amino, -NR7COR6, COR6, -CONR7R8, C1-C6 alkyl, or hydroxy(C1-C6 alkyl), and R" may be present or absent, and is present where the rules of valency permit, and where not more than one of A, A' and A" is O or C=0; R0 and R are independently H, Br, CI, F, or C1-C6 alkyl; R1 is H, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R2 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-C6 alkyl), phenyl(C1-C6 alkyl), formyl, heteroaryl, heterocyclic, -COR6, -OCOR6, -COOR6, -NR7COR6, -CONR7R8, and -(CH2)n-W, where W is cyano, hydroxy, C3-C8 cycloalkyl, -SO2NR7R8, and -SO2-R9, where R9 is C1-C6 alkyl, C3-C8 cycloalkyl, heteroaryl, or heterocyclic; wherein each of said alkyl, cycloalkyl, heterocyclic, or heteroaryl may be unsubstituted or substituted by halo, cyano, hydroxy, or C1-C6 alkyl; X is C-R3 or N, where R3 may be H or C1-C6 alkyl; R4 and R5 are independently H, amino, C1-C6 alkyl, or hydroxy(C1-C6 alkyl); R6, R7 and R8 are each independently H, C1-C6 alkyl, C1-C4 alkoxy(C1-C6 alkyl), or C3-C8 cycloalkyl, said C1- C6 alkyl is optionally substituted by halo, CN or hydroxy; or, R7 and R8 together with the atom bonded thereto form a 5- or 6-membered ring, said ring being optionally substituted by halo, hydroxy, CN, or C1-C6 alkyl; and, n is 0, 1, 2 or 3. Also provided are methods of treatment as Janus Kinase inhibitors and pharmaceutical compositions containing the compounds of the invention and combinations thereof with other therapeutic agents.