5-[5-((2S)-1-tert-butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methylindazole-1-carboxylic acid tert-butyl ester | 552332-03-3

• 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: 5-[5-((2S)-1-tert-butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methylindazole-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 3-methyl-5-[5-[[(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]aziridin-2-yl]methoxy]pyridin-3-yl]indazole-1-carboxylate
• CAS: 552332-03-3
• 化学式: C₂₆H₃₂N₄O₅
• 分子量: 480.564
• InChiKey: LEXAJYMAFFADSX-KCHZNAQISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  95.6
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  5-[5-((2S)-1-tert-butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methylindazole-1-carboxylic acid tert-butyl ester 在 copper(I) bromide dimethylsulfide complex 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.67h， 生成 (1S)-1-(2,6-difluorobenzyl)-2-[5-(3-methyl-1H-indazol-5-yl)pyridin-3-yloxy]ethylamine tristrifluoroacetate
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019
• 作为产物：
  描述：

  tert-butyl N-[(2R)-1-(5-bromopyridin-3-yl)oxy-3-[tert-butyl(dimethyl)silyl]oxypropan-2-yl]carbamate 在 tris(dibenzylideneacetone)dipalladium (0) 、 三(邻甲基苯基)磷 四丁基氟化铵 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 5-[5-((2S)-1-tert-butoxycarbonyl-aziridin-2-ylmethoxy)-pyridin-3-yl]-3-methylindazole-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Syntheses of Potent, Selective, and Orally Bioavailable Indazole-Pyridine Series of Protein Kinase B/Akt Inhibitors with Reduced Hypotension

  摘要：

  Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.

  DOI：

  10.1021/jm0701019

文献信息

• Kinase inhibitors
  申请人：——

  公开号：US20030187026A1

  公开（公告）日：2003-10-02

  Compounds having the formula 1 are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.

  具有以下化学式的化合物对抑制蛋白激酶很有用。还公开了抑制蛋白激酶的组合物以及在患者中抑制蛋白激酶的方法。
• US6831175B2
  申请人：——

  公开号：US6831175B2

  公开（公告）日：2004-12-14