[2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl][5-(piperidin-1-yl)pyrazin-2-yl]methanone | 1421502-62-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并吡啶类
• 英文名称: [2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl][5-(piperidin-1-yl)pyrazin-2-yl]methanone
• 英文别名: PF-06263276；[2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl]-3,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl]-(5-piperidin-1-ylpyrazin-2-yl)methanone
• CAS: 1421502-62-6
• 化学式: C₃₁H₃₁FN₈O₂
• 分子量: 566.638
• InChiKey: XDJGNPSZQSWJCV-UHFFFAOYSA-N

物化性质

• 沸点：
  921.1±65.0 °C(Predicted)
• 密度：
  1.394±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  42
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  8

安全信息

• WGK Germany：
  3

反应信息

• 作为产物：
  描述：

  6-溴-1H-吲唑-3-甲醛 在 盐酸 、 potassium phosphate 、 四(三苯基膦)钯 、 盐酸羟胺 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸酐 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 99.0h， 生成 [2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl]-1 ,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl][5-(piperidin-1-yl)pyrazin-2-yl]methanone
  参考文献：
  名称：

  Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin

  摘要：

  By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization; of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.

  DOI：

  10.1021/acs.jmedchem.6b01634

文献信息

• [EN] INDAZOLES<br/>[FR] INDAZOLES
  申请人：PFIZER LTD

  公开号：WO2013014567A1

  公开（公告）日：2013-01-31

  The present invention relates to compounds of formula (I) to pharmaceutically acceptable salts therefore and to pharmaceutically acceptable solvates of said compounds and salts, wherein the substituents are defined herein; to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly asthma and COPD.

  本发明涉及式(I)化合物及其药学上可接受的盐和该化合物及盐的药学上可接受的溶剂，其中取代基在此定义；含有这种化合物的组合物；以及这种化合物在治疗各种疾病，特别是哮喘和慢性阻塞性肺疾病中的用途。
• Development of a Scalable Synthesis for an Inhaled pan-JAK Inhibitor
  作者：Alexander Gontcharov、Javier Magano、Lacey Samp、Tim L. Houck、Peter R. Rose、Anil Rane、Jotham W. Coe、Steven W. Kortum、SeungWon Chung、Peter Jones、David Pattavina

  DOI：10.1021/acs.oprd.9b00253

  日期：2019.9.20

  A scalable synthesis of a pan-JAK inhibitor is described. The original synthesis by the Medicinal Chemistry group has been modified to develop a new protecting group strategy, a 3-step telescoped synthesis to generate an imidazole ring from a nitrile, and a telescoped borylation/Suzuki coupling sequence as well as to replace HATU with process-friendly CDI in the final amidation step. Efficient API

  描述了泛JAK抑制剂的可扩展合成。药物化学小组对原始合成方法进行了修改，以开发新的保护基策略，通过三步伸缩式合成法从腈基生成咪唑环，并采用伸缩式硼酸化/铃木偶联序列，并用工艺取代了HATU最终酰胺化步骤中友好的CDI。已实施有效的API纯化和多晶型物互变方案，以获得具有所需纯度和可吸入制剂物理性能的API。
• [EN] 4,5,6,7-TETRAHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE AND 1,4,5,6,7,8-HEXAHYDROIMIDAZO[4,5-D]AZEPINE DERIVATIVES AS JANUS KINASE INHIBITORS<br/>[FR] DÉRIVÉS 4,5,6,7-TÉTRAHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE ET 1,4,5,6,7,8-HÉXAHYDROIMIDAZO[4,5-D]AZÉPINE EN TANT QU'INHIBITEURS DE JANUS KINASE
  申请人：TOPIVERT PHARMA LTD

  公开号：WO2017077283A1

  公开（公告）日：2017-05-11

  There are provided compounds of formula (I), wherein X, Ak, s, L, Q, R1 and R2 have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of the JAK family) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

  提供了化合物的公式（I），其中X，Ak，s，L，Q，R1和R2具有在描述中给出的含义，这些化合物具有抗炎活性（例如通过抑制JAK家族的一个或多个成员）并可用于治疗，包括在制药组合中，特别是用于治疗炎症性疾病，包括肺部，眼部和肠道的炎症性疾病。
• [EN] 4,5,6,7-TETRAHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE AND 1,4,5,6,7,8-HEXAHYDROIMIDAZO[4,5-D]AZEPINE DERIVATIVES AS JANUS KINASE INHIBITORS<br/>[FR] DÉRIVÉS DE 4,5,6,7-TÉTRAHYDRO-1H-IMIDAZO[4,5-C]PYRIDINE ET 1,4,5,6,7,8-HEXAHYDROIMIDAZO[4,5-D]AZÉPINE À UTILISER EN TANT QU'INHIBITEURS DE JANUS KINASE
  申请人：TOPIVERT PHARMA LTD

  公开号：WO2017077288A1

  公开（公告）日：2017-05-11

  There are provided compounds of formula I, wherein X, Ak, s, A, R1 and R2 have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of the JAK family) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

  提供了式I的化合物，其中X，Ak，s，A，R1和R2具有描述中给出的含义，这些化合物具有抗炎活性（例如通过抑制JAK家族成员之一）并用于治疗，包括在药物组合中，特别是用于治疗炎症性疾病，包括肺部，眼部和肠道的炎症性疾病。
• INDAZOLES
  申请人：Coe Jotham Wadsworth

  公开号：US20130029968A1

  公开（公告）日：2013-01-31

  The present invention relates to compounds of formula (I): to pharmaceutically acceptable salts therefore and to pharmaceutically acceptable solvates of said compounds and salts, wherein the substituents are defined herein; to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly asthma and COPD.

  本发明涉及化合物公式（I）：其药学上可接受的盐和该化合物及其盐的药学上可接受的溶剂，其中所述取代基在此定义；含有这种化合物的组合物；以及在治疗各种疾病，尤其是哮喘和COPD方面使用这种化合物的用途。