(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide | 1609649-58-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: (1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide
• 英文别名: N-[1-[(3-cyanophenyl)methyl]pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)indazole-3-carboxamide
• CAS: 1609649-58-2
• 化学式: C₂₅H₂₈N₆O₂Si
• 分子量: 472.622
• InChiKey: XFPYTYBNBTTXOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.72
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  97.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以70%的产率得到N-(1-(3-氰基苄基)-1H-吡唑-4-基)-1H-吲唑-3-甲酰胺
  参考文献：
  名称：

  Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors

  摘要：

  There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.023
• 作为产物：
  描述：

  3-羟甲基苯甲腈 在 偶氮二甲酸二异丙酯 、 铁粉 、 氯化铵 、 三苯基膦 、 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 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.17h， 生成 (1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide
  参考文献：
  名称：

  Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors

  摘要：

  There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.04.023

文献信息

• Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors
  作者：Richard M. Pastor、Jason D. Burch、Steven Magnuson、Daniel F. Ortwine、Yuan Chen、Kelly De La Torre、Xiao Ding、Charles Eigenbrot、Adam Johnson、Marya Liimatta、Yichin Liu、Steven Shia、Xiaolu Wang、Lawren C. Wu、Zhonghua Pei

  DOI：10.1016/j.bmcl.2014.04.023

  日期：2014.6

  There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes. (C) 2014 Elsevier Ltd. All rights reserved.