(4R,5S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate | 2417554-92-6

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: (4R,5S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate
• CAS: 2417554-92-6
• 化学式: C₃₀H₂₆F₁₁NO₆S₂
• 分子量: 769.654
• InChiKey: ZZIUULPVCBPCDX-FAEWZGQZSA-N

物化性质

• 沸点：
  694.0±55.0 °C (Predicted,Press: 760 Torr)
• 密度：
  1.59±0.1 g/cm³ (Predicted,Temp: 20 °C; Press: 760 Torr)
• pKa：
  -3.08±0.40 (Predicted,Most Basic Temp: 25 °C)

计算性质

• 辛醇/水分配系数(LogP)：
  7.13
• 重原子数：
  50.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  97.82
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  甲醇 、 一氧化碳 、 (4R,5S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate 、 (3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohex-1-en-1-yl trifluoromethanesulfonate 在 palladium diacetate 、 1,1'-双(二苯基膦)二茂铁 、 Crabtree's catalyst 三正丁胺 、 氢气 、 lithium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 二氯甲烷 、 四氢呋喃 、 水 为溶剂， 以65 %的产率得到(1R,3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-1-carboxylic acid
  参考文献：
  名称：

  Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

  摘要：

  Novel tricyclic analogues were designed, synthesized, and evaluated as ROR gamma t inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

  DOI：

  10.1021/acsmedchemlett.0c00063
• 作为产物：
  描述：

  (3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole 在 N-甲基吗啉 、 双(三甲基硅烷基)氨基钾 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 (4R,5S)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-5-methylcyclohex-1-en-1-yl trifluoromethanesulfonate 、 (3S,4R)-4-((3aR,9bR)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole-3-carbonyl)-3-methylcyclohex-1-en-1-yl trifluoromethanesulfonate
  参考文献：
  名称：

  Discovery of BMS-986251: A Clinically Viable, Potent, and Selective RORγt Inverse Agonist

  摘要：

  Novel tricyclic analogues were designed, synthesized, and evaluated as ROR gamma t inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound 5, which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound 5 was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound 5 (BMS-986251) was selected as a clinically viable developmental candidate.

  DOI：

  10.1021/acsmedchemlett.0c00063