rel-Ethyl (3R,4S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-1-(4-fluoro-1H-indazol-3-yl)-4-piperidinecarboxylate | 1561772-51-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: rel-Ethyl (3R,4S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-1-(4-fluoro-1H-indazol-3-yl)-4-piperidinecarboxylate
• CAS: 1561772-51-7
• 化学式: C₃₁H₃₆FN₃O₃Si
• 分子量: 545.72
• InChiKey: MZOIPKHWHZBPGY-RJKANMQXNA-N

物化性质

• 沸点：
  625.8±55.0 °C (Predicted,Press: 760 Torr)
• 密度：
  1.21±0.1 g/cm³ (Predicted,Temp: 20 °C; Press: 760 Torr)
• pKa：
  14.82±0.40 (Predicted,Most Acidic Temp: 25 °C)

反应信息

• 作为反应物：
  描述：

  2-chloro-6-cyclopropylbenzoyl chloride 、 rel-Ethyl (3R,4S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-1-(4-fluoro-1H-indazol-3-yl)-4-piperidinecarboxylate 在 4-二甲氨基吡啶 N,N-二异丙基乙胺 、 四丁基氟化铵 、 lithium hydroxide 、 盐酸 作用下， 以 二氯甲烷 、 四氢呋喃 、 水 为溶剂， 以57 %的产率得到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

文献信息

• [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