6,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid | 1557247-72-9

• 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-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
• 英文别名: 6,6-Dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid；6,6-dimethyl-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxylic acid
• CAS: 1557247-72-9
• 化学式: C₁₆H₂₈N₂O₃Si
• 分子量: 324.495
• InChiKey: VHODDVSQSBUIKH-UHFFFAOYSA-N

物化性质

• 沸点：
  434.8±45.0 °C(Predicted)
• 密度：
  1.11±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.41
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  64.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6,6-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid 在 lithium aluminium tetrahydride 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 生成 N-[1-(2-hydroxy-1-phenyl-ethyl)pyrazol-4-yl]-6,6-dimethyl-1-(2-trimethylsilylethoxymethyl)-5,7-dihydro-4H-indazole-3-carboxamide
  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
• 作为产物：
  描述：

  4,4-二甲基环己酮 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-dimethyl-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。
• Discovery of Potent and Highly Selective Interleukin-2-Inducible T-Cell Kinase Degraders with <i>In Vivo</i> Activity
  作者：Danli Zhou、Yingying Zuo、Zhengying Pan

  DOI：10.1021/acs.jmedchem.2c02078

  日期：——

  indicated that compounds 23 and 28 are highly selective ITK degraders. Moreover, compound 28 showed good plasma exposure levels and elicited efficient, rapid, and prolonged ITK degradation in Balb/c mice. Furthermore, it significantly suppressed IL-2 secretion stimulated by anti-CD3 antibody. Compound 28 represents the first effective and highly selective ITK degrader. Thus, 28 is a valuable tool compound

  白细胞介素 2 诱导型 T 细胞激酶 (ITK) 是人类自身免疫性疾病和 T 细胞恶性淋巴瘤的有前途的治疗靶点。本文报告了一系列基于结构设计策略的以嵌合体为目标的大脑招募 ITK 蛋白水解的开发。代表性化合物23和28在 Jurkat 细胞中表现出有效的 ITK 降解和 IL-2 抑制活性。全球蛋白质组学分析表明化合物23和28是高度选择性的 ITK 降解剂。此外，化合物28显示出良好的血浆暴露水平，并在 Balb/c 小鼠中引起有效、快速和长时间的 ITK 降解。此外，它显着抑制了抗 CD3 抗体刺激的 IL-2 分泌。化合物28代表第一个有效和高选择性的 ITK 降解剂。因此，28是一种有价值的工具化合物，可用于进一步的体外和体内研究，探索 ITK 降解在人类疾病中的潜在生物学效应和潜在治疗效用。
• Tetrahydroindazoles as Interleukin-2 Inducible T-Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo
  作者：Jason D. Burch、Kathy Barrett、Yuan Chen、Jason DeVoss、Charles Eigenbrot、Richard Goldsmith、M. Hicham A. Ismaili、Kevin Lau、Zhonghua Lin、Daniel F. Ortwine、Ali A. Zarrin、Paul A. McEwan、John J. Barker、Claire Ellebrandt、Daniel Kordt、Daniel B. Stein、Xiaolu Wang、Yong Chen、Baihua Hu、Xiaofeng Xu、Po-Wai Yuen、Yamin Zhang、Zhonghua Pei

  DOI：10.1021/jm501998m

  日期：2015.5.14

  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.
• [EN] PYRAZOLE CARBOXAMIDE COMPOUNDS, COMPOSITIONS AND METHODS OF USE<br/>[FR] COMPOSÉS PYRAZOLE CARBOXAMIDES, COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：HOFFMANN LA ROCHE

  公开号：WO2014023258A1

  公开（公告）日：2014-02-13

  Provided herein are compounds of formula (AA): N N H HN O N N R R 6 A (R a ) p, (AA) stereoisomers or a pharmaceutically acceptable salt thereof, wherein A, R a, p, R 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。
• 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.