N-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-3-carboxamide | 1422982-56-6

• 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: N-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-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]-6-[1-(oxan-2-yl)pyrazol-4-yl]-1-(2-trimethylsilylethoxymethyl)indazole-3-carboxamide
• CAS: 1422982-56-6
• 化学式: C₃₃H₃₈N₈O₃Si
• 分子量: 622.802
• InChiKey: KIUPDKPCNRUQFL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.28
• 重原子数：
  45.0
• 可旋转键数：
  11.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  124.81
• 氢给体数：
  1.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  N-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-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6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxylic acid [1-(3-cyanobenzyl)-1H-pyrazol-4-yl]amide
  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：

  6-bromo-1-(2-trimethylsilanylethoxymethyl)-1H-indazole-3-carboxylic acid [1-(3-cyanobenzyl)-1H-pyrazol-4-yl]amide 、 potassium 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-trifluoroborate 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 sodium carbonate 作用下， 以 水 、 乙腈 为溶剂， 反应 0.17h， 以102 mg的产率得到N-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-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

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

  公开号：WO2013024011A1

  公开（公告）日：2013-02-21

  A compound of formula I: stereoisomers or a pharmaceutically acceptable salt thereof, wherein X, X1, X2, X3, R1, R2, R3, R4, R5 and R6 are described herein, compositions including the compounds and methods of making and using the compounds for the treatment of diseases.

  公式I的化合物：其立体异构体或其药学上可接受的盐，其中X、X1、X2、X3、R1、R2、R3、R4、R5和R6如本文所述，包括该化合物的组合物以及用于治疗疾病的制备和使用该化合物的方法。
• INDAZOLE COMPOUNDS, COMPOSITIONS AND METHODS OF USE THEREOF
  申请人：Genentech, Inc.

  公开号：US20140309210A1

  公开（公告）日：2014-10-16

  A compound of formula I: stereoisomers or a pharmaceutically acceptable salt thereof, wherein X, X 1 , X 2 , X 3 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are described herein, compositions including the compounds and methods of making and using the compounds for the treatment of diseases.

  化合物I的公式：立体异构体或其药学上可接受的盐，其中X，X1，X2，X3，R1，R2，R3，R4，R5和R6如本文所述，包括该化合物的组合物以及使用该化合物治疗疾病的方法和制备方法。
• 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.