(3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid
• 英文别名: (3S,4S)-2-(4-tert-butyl-3-chlorophenyl)-3-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-oxo-3,4-dihydroisoquinoline-4-carboxylic acid
• 化学式: C₂₈H₂₆ClNO₅
• 分子量: 491.971
• InChiKey: XGDKZTMGSABEJP-LOSJGSFVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid 在 O-(四氢-2H-吡喃-2-基)羟基胺 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide
  参考文献：
  名称：

  [EN] OXO-TETRAHYDRO-ISOQUINOLINE CARBOXYLIC ACIDS AS STING INHIBITORS
  [FR] ACIDES OXO-TÉTRAHYDRO-ISOQUINOLINE CARBOXYLIQUES EN TANT QU'INHIBITEURS DE LA PROTÉINE STING

  摘要：

  本发明提供了一种式I的化合物，这些化合物是STING抑制剂，因此可用于治疗STING介导的疾病，如炎症、哮喘、慢性阻塞性肺病（COPD）和癌症。

  公开号：

  WO2019182886A1
• 作为产物：
  描述：

  1-叔丁基-2-氯-4-硝基苯 在 二氧化铂 、 indium(III) chloride 、 氢气 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 19.5h， 生成 (3S,4S)-2-(4-(tert-butyl)-3-chlorophenyl)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid
  参考文献：
  名称：

  Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING

  摘要：

  Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein ligand as well as ligand ligand interactions. Successful implementation of this strategy led to the identification of 18, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release.

  DOI：

  10.1021/acsmedchemlett.8b00466

文献信息

• Oxo-tetrahydro-isoquinoline carboxylic acids as STING inhibitors
  申请人：Merck Sharp & Dohme Corp.

  公开号：US11311528B2

  公开（公告）日：2022-04-26

  The instant invention provides compounds of formula I which are STING inhibitors, and as such are useful for the treatment of STING-mediated diseases such as inflammation, asthma, COPD and cancer.

  本发明提供的式 I 化合物是 STING 抑制剂，因此可用于治疗 STING 介导的疾病，如炎症、哮喘、慢性阻塞性肺病和癌症。
• OXO-TETRAHYDRO-ISOQUINOLINE CARBOXYLIC ACIDS AS STING INHIBITORS
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP3768266A1

  公开（公告）日：2021-01-27
• Discovery of a Novel cGAMP Competitive Ligand of the Inactive Form of STING
  作者：Tony Siu、Michael D. Altman、Gretchen A. Baltus、Matthew Childers、J. Michael Ellis、Hakan Gunaydin、Harold Hatch、Thu Ho、James Jewell、Brian M. Lacey、Charles A. Lesburg、Bo-Sheng Pan、Berengere Sauvagnat、Gottfried K. Schroeder、Serena Xu

  DOI：10.1021/acsmedchemlett.8b00466

  日期：2019.1.10

  Drugging large protein pockets is a challenge due to the need for higher molecular weight ligands, which generally possess undesirable physicochemical properties. In this communication, we highlight a strategy leveraging small molecule active site dimers to inhibit the large symmetric binding pocket in the STING protein. By taking advantage of the 2:1 binding stoichiometry, maximal buried interaction with STING protein can be achieved while maintaining the ligand physicochemical properties necessary for oral exposure. This mode of binding requires unique considerations for potency optimization including simultaneous optimization of protein ligand as well as ligand ligand interactions. Successful implementation of this strategy led to the identification of 18, which exhibits good oral exposure, slow binding kinetics, and functional inhibition of STING-mediated cytokine release.
• [EN] OXO-TETRAHYDRO-ISOQUINOLINE CARBOXYLIC ACIDS AS STING INHIBITORS<br/>[FR] ACIDES OXO-TÉTRAHYDRO-ISOQUINOLINE CARBOXYLIQUES EN TANT QU'INHIBITEURS DE LA PROTÉINE STING
  申请人：MERCK SHARP & DOHME

  公开号：WO2019182886A1

  公开（公告）日：2019-09-26

  The instant invention provides compounds of formula I which are STING inhibitors, and as such are useful for the treatment of STING-mediated diseases such as inflammation, asthma, COPD and cancer.

  本发明提供了一种式I的化合物，这些化合物是STING抑制剂，因此可用于治疗STING介导的疾病，如炎症、哮喘、慢性阻塞性肺病（COPD）和癌症。