6,6-dimethyl-N-(1-((S)-phenyl(piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide | 1557234-07-7

• 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-((S)-phenyl(piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
• 英文别名: (S)-6,6-dimethyl-N-(1-(phenyl(piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide；6,6-dimethyl-N-[1-[(S)-phenyl(piperidin-4-yl)methyl]pyrazol-4-yl]-1,4,5,7-tetrahydroindazole-3-carboxamide
• CAS: 1557234-07-7
• 化学式: C₂₅H₃₂N₆O
• 分子量: 432.569
• InChiKey: ILYQIAVPXLQYSF-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  87.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6,6-二甲基-4,5,6,7-四氢-2H-吲唑-3-羧酸乙酯 在 盐酸 、 lithium hydroxide monohydrate 、 sodium hydride 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 3.0h， 生成 6,6-dimethyl-N-(1-((R)-phenyl(piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide 、 6,6-dimethyl-N-(1-((S)-phenyl(piperidin-4-yl)methyl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-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

• 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.