ethyl trans-1-benzyl-3-((tert-butyldiphenylsilyl)oxy)piperidine-4-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: ethyl trans-1-benzyl-3-((tert-butyldiphenylsilyl)oxy)piperidine-4-carboxylate
• 英文别名: Ethyl 1-benzyl-3-[tert-butyl(diphenyl)silyl]oxypiperidine-4-carboxylate；ethyl 1-benzyl-3-[tert-butyl(diphenyl)silyl]oxypiperidine-4-carboxylate
• 化学式: C₃₁H₃₉NO₃Si
• 分子量: 501.741
• InChiKey: MHYABFCGECSILQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.02
• 重原子数：
  36
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  38.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl trans-1-benzyl-3-((tert-butyldiphenylsilyl)oxy)piperidine-4-carboxylate 在 盐酸 、 4-二甲氨基吡啶 、 palladium on activated charcoal 、 四丁基氟化铵 、 氢气 、 caesium carbonate 、 溶剂黄146 、 N,N-二异丙基乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 89.0h， 生成 3R,4S or (3S,4R)-1-(1-(2-chloro-6-cyclopropylbenzoyl)-4-fluoro-1H-indazol-3-yl)-3-hydroxypiperidine-4-carboxylic acid
  参考文献：
  名称：

  Discovery of N-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases

  摘要：

  The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor ROR gamma t is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL -22, IL-26, and GMCSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for ROR gamma t inhibition. A variety of ROR gamma t inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.

  DOI：

  10.1021/acsmedchemlett.9b00431
• 作为产物：
  描述：

  N-苄基-3-氧代哌啶-4-羧酸乙酯盐酸盐 在 咪唑 、 sodium tetrahydroborate 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 68.25h， 生成 ethyl trans-1-benzyl-3-((tert-butyldiphenylsilyl)oxy)piperidine-4-carboxylate
  参考文献：
  名称：

  [EN] 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
  [FR] COMPOSÉS 3-AMINOCYCLOALKYL UTILISÉS EN TANT QU'INHIBITEURS DE RORGAMMAT ET UTILISATIONS DE CEUX-CI

  摘要：

  公开号：

  WO2014028600A3

文献信息

• Discovery of <i>N</i>-(Indazol-3-yl)piperidine-4-carboxylic Acids as RORγt Allosteric Inhibitors for Autoimmune Diseases
  作者：Hongjun Zhang、Blair T. Lapointe、Neville Anthony、Rita Azevedo、Jos Cals、Craig C. Correll、Matthew Daniels、Sujal Deshmukh、Hans van Eenenaam、Heidi Ferguson、Laxminarayan G. Hegde、Willem Jan Karstens、John Maclean、J. Richard Miller、Lily Y. Moy、Vladimir Simov、Sunil Nagpal、Arthur Oubrie、Rachel L. Palte、Gopal Parthasarathy、Nunzio Sciammetta、Mario van der Stelt、Janice D. Woodhouse、B. Wesley Trotter、Kenneth Barr

  DOI：10.1021/acsmedchemlett.9b00431

  日期：2020.2.13

  The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor ROR gamma t is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL -22, IL-26, and GMCSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for ROR gamma t inhibition. A variety of ROR gamma t inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit 1, a tool compound 14 was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in 14 to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of 25, which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.
• [EN] 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF<br/>[FR] COMPOSÉS 3-AMINOCYCLOALKYL UTILISÉS EN TANT QU'INHIBITEURS DE RORGAMMAT ET UTILISATIONS DE CEUX-CI
  申请人：MERCK SHARP & DOHME

  公开号：WO2014028600A3

  公开（公告）日：2014-04-24