5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid | 1557248-38-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid
• 英文别名: 5,5-Difluoro-5a-methyl-1H,4H,4aH,5H,5aH,6H-cyclopropa[f]indazole-3-carboxylic acid；5,5-difluoro-5a-methyl-1,4,4a,6-tetrahydrocyclopropa[f]indazole-3-carboxylic acid
• CAS: 1557248-38-0
• 化学式: C₁₀H₁₀F₂N₂O₂
• 分子量: 228.198
• InChiKey: UPJCUIBKJREYLW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  66
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid 、 1-苄基-1H-吡唑-4-胺 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-(1-benzylpyrazol-4-yl)-5,5-difluoro-5a-methyl-1,4,4a,6-tetrahydrocyclopropa[f]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：

  7,7-difluoro-1-methylbicyclo[4.1.0]heptan-3-one 在 potassium tert-butylate 、 水 、 一水合肼 、 溶剂黄146 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 26.0h， 生成 5,5-difluoro-5a-methyl-1,4,4a,5,5a,6-hexahydrocyclopropa[f]indazole-3-carboxylic acid
  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

文献信息

• [EN] ALKYNYL ALCOHOLS AND METHODS OF USE<br/>[FR] ALCOOLS D'ALCYNYLE ET PROCÉDÉS D'UTILISATION CORRESPONDANTS
  申请人：HOFFMANN LA ROCHE

  公开号：WO2015025025A1

  公开（公告）日：2015-02-26

  The invention relates to compounds of Formula (0): wherein Q, A1-A8, R4 and R5 and each has the meaning as described herein. Compounds of Formula (0) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over- activation of NF-kB signaling is observed.

  这项发明涉及以下式的化合物（0）：其中Q，A1-A8，R4和R5分别具有如本文所述的含义。式（0）的化合物及其药物组成物在治疗观察到NF-kB信号通路的不良或过度活化的疾病和紊乱中是有用的。
• 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。
• ALKYNYL ALCOHOLS AND METHODS OF USE
  申请人：F.Hoffmann-La Roche AG

  公开号：EP3036230A1

  公开（公告）日：2016-06-29