6,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid | 1557247-90-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 6,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
• 英文别名: 6,6-difluoro-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxylic acid
• CAS: 1557247-90-1
• 化学式: C₁₄H₂₂F₂N₂O₃Si
• 分子量: 332.423
• InChiKey: UPBYCTSJWVYVSI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.02
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  64.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  6,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid 、 1-苄基-1H-吡唑-4-胺 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase Inhibitors

  摘要：

  Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.

  DOI：

  10.1021/jm500550e
• 作为产物：
  描述：

  4,4-二氟环已酮 在 吡啶 、 正丁基锂 、 lithium hydroxide monohydrate 、 sodium hydride 、 二异丙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 正己烷 、 水 、 乙腈 为溶剂， 反应 2.0h， 生成 6,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
  参考文献：
  名称：

  Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase Inhibitors

  摘要：

  Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.

  DOI：

  10.1021/jm500550e

文献信息

• PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
  申请人：Genentech, Inc.

  公开号：US20150158851A1

  公开（公告）日：2015-06-11

  Provided herein are compounds of formula (AA): stereoisomers or a pharmaceutically acceptable salt thereof, wherein A, R a , p, R 5 and R 6 are defined herein, compositions including the compounds and methods of manufacturing and using the compounds for the treatment of diseases.

  本文提供了式（AA）的化合物：其立体异构体或其药学上可接受的盐，其中A、Ra、p、R5和R6在此定义，包括该化合物的组合物以及制造和使用该化合物治疗疾病的方法。