methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(pyridin-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate | 1485470-01-6

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(pyridin-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate
• CAS: 1485470-01-6
• 化学式: C₃₁H₄₀N₂O₄S
• 分子量: 536.736
• InChiKey: DEJMNCRGPAIWFM-DJEOUUAESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.88
• 重原子数：
  38.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  68.73
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(pyridin-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate 在 甲醇 、 lithium hydroxide 作用下， 以 水 为溶剂， 反应 1.0h， 以20%的产率得到methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(pyridin-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate
  参考文献：
  名称：

  Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection

  摘要：

  Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

  DOI：

  10.1021/jm401420j
• 作为产物：
  描述：

  1,4-环己二酮单乙二醇缩酮 在 吡啶 、 盐酸 、 tris(dibenzylideneacetone)dipalladium(0) chloroform complex 、 sodium tetrahydroborate 、 copper(l) iodide 、 正丁基锂 、 偶氮二甲酸二异丙酯 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 三乙胺 、 二异丙胺 、 三苯基膦 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 83.0h， 生成 methyl 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4R)-4-methyl-N-((1s,4S)-4-(pyridin-3-yloxy)cyclohexyl)cyclohexanecarboxamido)thiophene-2-carboxylate
  参考文献：
  名称：

  Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection

  摘要：

  Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.

  DOI：

  10.1021/jm401420j