1'-((2-(trimethylsilyl)ethoxy)methyl)-1',4,4',5,5',7'-hexahydro-2H-spiro[furan-3,6'-indazole]-3'-carboxylic acid | 1557248-08-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1'-((2-(trimethylsilyl)ethoxy)methyl)-1',4,4',5,5',7'-hexahydro-2H-spiro[furan-3,6'-indazole]-3'-carboxylic acid
• 英文别名: 1'-((2-(trimethylsilyl)ethoxy)methyl)-1,4,4',5,5',7'-hexahydro-2H-spiro[furan-3,6-indazole]-3'-carboxylic acid；1-(2-trimethylsilylethoxymethyl)spiro[5,7-dihydro-4H-indazole-6,3'-oxolane]-3-carboxylic acid
• CAS: 1557248-08-4
• 化学式: C₁₇H₂₈N₂O₄Si
• 分子量: 352.506
• InChiKey: YPKLEUSQTYZHDC-UHFFFAOYSA-N

物化性质

• 沸点：
  498.0±45.0 °C(Predicted)
• 密度：
  1.23±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.79
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.76
• 拓扑面积：
  73.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1'-((2-(trimethylsilyl)ethoxy)methyl)-1',4,4',5,5',7'-hexahydro-2H-spiro[furan-3,6'-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 N-(1-benzyl-1H-pyrazol-4-yl)-1'-((2-(trimethylsilyl)ethoxy)methyl)-1',4,4',5,5',7'-hexahydro-2H-spiro[furan-3,6'-indazole]-3'-carboxamide
  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：

  1,4,10-trioxadispiro[4.2.4⁸.2⁵]tetradecan-9-one 在 吡啶 、 lithium aluminium tetrahydride 、 正丁基锂 、 lithium hydroxide monohydrate 、 sodium hydride 、 溶剂黄146 、 二异丙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 、 三氯氧磷 作用下， 以 四氢呋喃 、 正己烷 、 水 、 乙腈 为溶剂， 反应 74.0h， 生成 1'-((2-(trimethylsilyl)ethoxy)methyl)-1',4,4',5,5',7'-hexahydro-2H-spiro[furan-3,6'-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。
• Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin-2 Inducible T-Cell Kinase Inhibitors
  作者：Jason D. Burch、Kevin Lau、John J. Barker、Fred Brookfield、Yong Chen、Yuan Chen、Charles Eigenbrot、Claire Ellebrandt、M. Hicham A. Ismaili、Adam Johnson、Daniel Kordt、Colin H. MacKinnon、Paul A. McEwan、Daniel F. Ortwine、Daniel B. Stein、Xiaolu Wang、Dirk Winkler、Po-Wai Yuen、Yamin Zhang、Ali A. Zarrin、Zhonghua Pei

  DOI：10.1021/jm500550e

  日期：2014.7.10

  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.