5-(3,3-dimethylbut-1-ynyl)-3-((1r,4r)-N-isopropyl-4-methylcyclohexanecarboxamido)thiophene-2-carboxylic acid | 896740-67-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4r)-N-isopropyl-4-methylcyclohexanecarboxamido)thiophene-2-carboxylic acid
• CAS: 896740-67-3
• 化学式: C₂₂H₃₁NO₃S
• 分子量: 389.559
• InChiKey: QZGDCCMKSRXDDS-WKILWMFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.41
• 重原子数：
  27.0
• 可旋转键数：
  4.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  57.61
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  4-Methylcyclohexanecarboxylic Acid 在 吡啶 、 甲醇 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 101.0h， 生成 5-(3,3-dimethylbut-1-ynyl)-3-((1r,4r)-N-isopropyl-4-methylcyclohexanecarboxamido)thiophene-2-carboxylic acid
  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

文献信息

• INHIBITORS OF FLAVIVIRIDAE VIRUSES
  申请人：Watkins William J.

  公开号：US20130052161A1

  公开（公告）日：2013-02-28

  Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections (e.g. hepatitis C infections), particularly drug resistant Flaviviridae virus infections.

  提供的是式子I的化合物及其药学上可接受的盐和酯。所提供的化合物、组合物和方法对于治疗黄病毒科病毒感染（例如丙型肝炎感染）特别是耐药性黄病毒科病毒感染是有用的。
• COMPOUNDS AND METHODS FOR THE TREATMENT OR PREVENTION OF FLAVIVIRIDAE VIRAL INFECTIONS
  申请人：VERTEX PHARMACEUTICALS INCORPORATED

  公开号：US20140065103A1

  公开（公告）日：2014-03-06

  A compound is selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprises a compound selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier of excipient. A method of treating a HCV infection in a subject comprises administering to the subject a therapeutically effective amount of selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof. A method of inhibiting or reducing the activity of HCV polymerase in a subject or in a biological in vitro sample comprises administering to the subject or to the sample a therapeutically effective amount of selected from the structural formulae depicted in FIG. 1 or a pharmaceutically acceptable salt thereof.

  从图1所示的结构式中选择一个化合物或其药学上可接受的盐。一种制药组合物包括从图1所示的结构式中选择的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。一种治疗HCV感染的方法包括向受试者施用从图1所示的结构式中选择的化合物或其药学上可接受的盐的治疗有效量。一种抑制或减少受试者或体外生物样品中HCV聚合酶活性的方法包括向受试者或样品施用从图1所示的结构式中选择的化合物或其药学上可接受的盐的治疗有效量。
• US8741946B2
  申请人：——

  公开号：US8741946B2

  公开（公告）日：2014-06-03
• US9296719B2
  申请人：——

  公开号：US9296719B2

  公开（公告）日：2016-03-29
• Discovery of GS-9669, a Thumb Site II Non-Nucleoside Inhibitor of NS5B for the Treatment of Genotype 1 Chronic Hepatitis C Infection
  作者：Scott E. Lazerwith、Willard Lew、Jennifer Zhang、Philip Morganelli、Qi Liu、Eda Canales、Michael O. Clarke、Edward Doerffler、Daniel Byun、Michael Mertzman、Hong Ye、Lee Chong、Lianhong Xu、Todd Appleby、Xiaowu Chen、Martijn Fenaux、Ahmad Hashash、Stephanie A. Leavitt、Eric Mabery、Mike Matles、Judy W. Mwangi、Yang Tian、Yu-Jen Lee、Jingyu Zhang、Christine Zhu、Bernard P. Murray、William J. Watkins

  DOI：10.1021/jm401420j

  日期：2014.3.13

  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.