(3S,6R)-4-(5-(4-fluorophenyl)isoxazole-3-carbonyl)-6-(hydroxymethyl)-3-isobutylpiperazin-2-one | 1552272-87-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (3S,6R)-4-(5-(4-fluorophenyl)isoxazole-3-carbonyl)-6-(hydroxymethyl)-3-isobutylpiperazin-2-one
• 英文别名: (3S,6R)-4-[5-(4-fluorophenyl)isoxazole-3-carbonyl]-6-(hydroxymethyl)-3-isobutyl-piperazin-2-one；(3S,6R)-4-[5-(4-fluorophenyl)-1,2-oxazole-3-carbonyl]-6-(hydroxymethyl)-3-(2-methylpropyl)piperazin-2-one
• CAS: 1552272-87-3
• 化学式: C₁₉H₂₂FN₃O₄
• 分子量: 375.4
• InChiKey: QGDCTXDVKYKJHI-ZBFHGGJFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  95.7
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (3S,6R)-4-(5-(4-fluorophenyl)isoxazole-3-carbonyl)-6-(hydroxymethyl)-3-isobutylpiperazin-2-one 在 manganese(IV) oxide 、 potassium acetate 、 戴斯-马丁氧化剂 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 14.0h， 生成 (3S,6R)-4-(5-(4-fluorophenyl)isoxazole-3-carbonyl)-3-isobutyl-6-(thiazol-2-yl)piperazin-2-one
  参考文献：
  名称：

  Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives

  摘要：

  HTS screening identified compound 2a (piper-azinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and la potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

  DOI：

  10.1021/jm4012643
• 作为产物：
  描述：

  (3S,6R)-6-(tert-butoxymethyl)-3-isobutylpiperazin-2-one 在 盐酸 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 1.5h， 生成 (3S,6R)-4-(5-(4-fluorophenyl)isoxazole-3-carbonyl)-6-(hydroxymethyl)-3-isobutylpiperazin-2-one
  参考文献：
  名称：

  Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives

  摘要：

  HTS screening identified compound 2a (piper-azinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and la potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

  DOI：

  10.1021/jm4012643

文献信息

• Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives
  作者：Ramesh Kakarla、Jian Liu、Devan Naduthambi、Wonsuk Chang、Ralph T. Mosley、Donghui Bao、Holly M. Micolochick Steuer、Meg Keilman、Shalini Bansal、Angela M. Lam、William Seibel、Sandra Neilson、Phillip A. Furman、Michael J. Sofia

  DOI：10.1021/jm4012643

  日期：2014.3.13

  HTS screening identified compound 2a (piper-azinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and la potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.