N-(1-benzyl-1H-pyrazol-4-yl)-1',4',5',7'-tetrahydrospiro[cyclopropane-1,6'-indazole]-3'-carboxamide | 1557232-34-4

• 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: N-(1-benzyl-1H-pyrazol-4-yl)-1',4',5',7'-tetrahydrospiro[cyclopropane-1,6'-indazole]-3'-carboxamide
• 英文别名: N-(1-benzylpyrazol-4-yl)spiro[1,4,5,7-tetrahydroindazole-6,1'-cyclopropane]-3-carboxamide
• CAS: 1557232-34-4
• 化学式: C₂₀H₂₁N₅O
• 分子量: 347.42
• InChiKey: STCNDRXGYAQSKS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  螺[2.5]-6-辛酮 在 吡啶 、 盐酸 、 正丁基锂 、 lithium hydroxide monohydrate 、 sodium hydride 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 二异丙胺 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 4.0h， 生成 N-(1-benzyl-1H-pyrazol-4-yl)-1',4',5',7'-tetrahydrospiro[cyclopropane-1,6'-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

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.