1-[(2,4-Difluorophenyl)methyl]-7-fluoro-6-[[3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one | 1276034-22-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[(2,4-Difluorophenyl)methyl]-7-fluoro-6-[[3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one
• 英文别名: 1-[(2,4-difluorophenyl)methyl]-7-fluoro-6-[3-(trifluoromethyl)pyridin-2-yl]oxyquinazolin-4-one
• CAS: 1276034-22-0
• 化学式: C₂₁H₁₁F₆N₃O₂
• 分子量: 451.328
• InChiKey: IPLBJRILNUWLQL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  32
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  54.8
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  1-[(2,4-Difluorophenyl)methyl]-7-fluoro-6-[[3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one 、 二甲胺 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 以11%的产率得到1-[(2,4-Difluorophenyl)methyl]-7-(dimethylamino)-6-[[3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one
  参考文献：
  名称：

  Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype

  摘要：

  We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.037
• 作为产物：
  描述：

  4,5-二氟-2-硝基苯甲酸 在 硫酸 、 sodium hydride 、 sodium cyanoborohydride 、 caesium carbonate 、 溶剂黄146 、 三氟乙酸 、 sodium hydroxide 作用下， 以 二甲基亚砜 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0~80.0 ℃ 、101.33 kPa 条件下， 生成 1-[(2,4-Difluorophenyl)methyl]-7-fluoro-6-[[3-(trifluoromethyl)-2-pyridyl]oxy]quinazolin-4-one
  参考文献：
  名称：

  Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype

  摘要：

  We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.037

文献信息

• [EN] QUINAZOLINONE DERIVATIVES AS VIRAL POLYMERASE INHIBITORS<br/>[FR] DÉRIVÉS DE QUINAZOLINONE COMME INHIBITEURS DE POLYMÉRASE VIRALE
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2011032277A1

  公开（公告）日：2011-03-24

  Compounds of formula I: (I) wherein X, R2, R3, R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.

  式I中的化合物：(I)其中X，R2，R3，R5和R6的定义如下，在抑制乙型肝炎病毒NS5B聚合酶方面是有用的。
• VIRAL POLYMERASE INHIBITORS
  申请人：STAMMERS Timothy

  公开号：US20110230465A1

  公开（公告）日：2011-09-22

  Compounds of formula I: wherein X, R 2 , R 3 , R 5 and R 6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.

  式I的化合物：其中X、R2、R3、R5和R6的定义如本文所述，可用作丙型肝炎病毒NS5B聚合酶的抑制剂。
• Structure-based design of novel HCV NS5B thumb pocket 2 allosteric inhibitors with submicromolar gt1 replicon potency: Discovery of a quinazolinone chemotype
  作者：Pierre L. Beaulieu、René Coulombe、Jianmin Duan、Gulrez Fazal、Cédrickx Godbout、Oliver Hucke、Araz Jakalian、Marc-André Joly、Olivier Lepage、Montse Llinàs-Brunet、Julie Naud、Martin Poirier、Nathalie Rioux、Bounkham Thavonekham、George Kukolj、Timothy A. Stammers

  DOI：10.1016/j.bmcl.2013.05.037

  日期：2013.7

  We describe the structure-based design of a novel lead chemotype that binds to thumb pocket 2 of HCV NS5B polymerase and inhibits cell-based gt1 subgenomic reporter replicons at sub-micromolar concentrations (EC50 <200 nM). This new class of potent thumb pocket 2 inhibitors features a 1H-quinazolin-4-one scaffold derived from hybridization of a previously reported, low affinity thiazolone chemotype with our recently described anthranilic acid series. Guided by X-ray structural information, a key NS5B-ligand interaction involving the carboxylate group of anthranilic acid based inhibitors was replaced by a neutral two-point hydrogen bonding interaction between the quinazolinone scaffold and the protein backbone. The in vitro ADME and in vivo rat PK profile of representative analogs are also presented and provide areas for future optimization of this new class of HCV polymerase inhibitors. (C) 2013 Elsevier Ltd. All rights reserved.