1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidine-4-carboxylic acid | 1561769-84-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidine-4-carboxylic acid
• 英文别名: 1-[1-[2-chloro-6-(trifluoromethyl)benzoyl]pyrazolo[4,3-b]pyridin-3-yl]piperidine-4-carboxylic acid
• CAS: 1561769-84-3
• 化学式: C₂₀H₁₆ClF₃N₄O₃
• 分子量: 452.82
• InChiKey: CDTBRAGUFMYFOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  88.3
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-哌啶甲酸 、 (3-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)(2-chloro-6-(trifluoromethyl)phenyl)methanone 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 1-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidine-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-AMINOCYCLOALKYLES EN TANT QU'INHIBITEURS DE RORGAMMAT ET LEURS UTILISATIONS
  申请人：MERCK SHARP & DOHME

  公开号：WO2014026330A1

  公开（公告）日：2014-02-20

  The present invention relates to compounds according to Formula (I) or a pharmaceutically acceptable salt or solvate thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.

  本发明涉及公式（I）或其药学上可接受的盐或溶剂的化合物。这些化合物可用于治疗RORgammaT介导的疾病或症状。
• 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20150218169A1

  公开（公告）日：2015-08-06

  The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts or solvates thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.

  本发明涉及公式I的化合物及其药学上可接受的盐或溶剂。这些化合物可用于治疗RORgammaT介导的疾病或病症。
• 3-AMINOCYCLOALKYL COMPOUNDS AS ROR-GAMMA-T INHIBITORS AND USES THEREOF
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2920149B1

  公开（公告）日：2019-03-20
• US9663522B2
  申请人：——

  公开号：US9663522B2

  公开（公告）日：2017-05-30
• [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：WO2014028600A2

  公开（公告）日：2014-02-20

  The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts or solvates thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.