6,6-dimethyl-N-[1-(2-methylsulfonyl-1-phenyl-ethyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxamide | 1557250-07-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 6,6-dimethyl-N-[1-(2-methylsulfonyl-1-phenyl-ethyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxamide
• 英文别名: 6,6-dimethyl-N-[1-(2-methylsulfonyl-1-phenylethyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxamide
• CAS: 1557250-07-3
• 化学式: C₂₈H₄₁N₅O₄SSi
• 分子量: 571.816
• InChiKey: MVHGVDALQNQVJF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.79
• 重原子数：
  39
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  117
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6,6-dimethyl-N-[1-(2-methylsulfonyl-1-phenyl-ethyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxamide 在 三异丙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 6,6-dimethyl-N-(1-((1R)-2-(methylsulfonyl)-1-phenylethyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
  参考文献：
  名称：

  Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo

  摘要：

  The Medicinal chemistry community has directed considerable efforts toward the discovery Of selective inhibitors of interleukin-2 inducible T-cell kinase (ITK) given its role in T-cell signaling downstream of the T-cell receptor (TCR) and the implications of this target for inflammatory disorders such as asthma. We have previously disclosed a structure-and property-guided lead optimization effort which resulted in the discovery of a new series of tetrahydroindazole-containing selective ITK inhibitors. Herein we disclose further optimization of this series that resulted in further potency improvements, reduced off-target receptor binding liabilities, and reduced cytotoxicity. Specifically, we have identified a correlation between the basicity of solubilizing elements in the ITK inhibitors and off-target antiprolifetative effects, Which was exploited to reduce cytotoxicity while maintaining kinase selectivity. Optimized analogues were shown to reduce IL-2 and IL-13 production in vivo following oral or intraperitoneal dosing in mice.

  DOI：

  10.1021/jm501998m
• 作为产物：
  描述：

  6,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid 在 N,N-二异丙基乙胺 、 间氯过氧苯甲酸 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 6,6-dimethyl-N-[1-(2-methylsulfonyl-1-phenyl-ethyl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxamide
  参考文献：
  名称：

  [EN] PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
  [FR] COMPOSÉS PYRAZOLE CARBOXAMIDES, COMPOSITIONS ET PROCÉDÉS D'UTILISATION

  摘要：

  本文提供了以下式（AA）的化合物：N N H HN O N N R R 6 A（R a）p，（AA）立体异构体或其药学上可接受的盐，其中A、R a、p、R和R 6在此处有定义，包括这些化合物的组合物以及用于治疗疾病的制备和使用这些化合物的方法。

  公开号：

  WO2014023258A1