N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide | 1258291-83-6

• 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: N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide
• CAS: 1258291-83-6
• 化学式: C₁₂H₉Cl₂N₃O
• 分子量: 282.129
• InChiKey: LNYGUDBEQCHOAZ-UHFFFAOYSA-N

物化性质

• 沸点：
  399.6±42.0 °C(Predicted)
• 密度：
  1.503±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  68
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide 在 盐酸 、 N,N-二异丙基乙胺 、 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 、 甲醇 为溶剂， 反应 4.0h， 生成 N-(4-(2,6-dichlorobenzamido)pyridin-2-yl)azetidine-3-carboxamide hydrochloride
  参考文献：
  名称：

  Lead identification of novel and selective TYK2 inhibitors

  摘要：

  A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine I as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.070
• 作为产物：
  描述：

  2,6-二氯苯甲酰氯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 sodium hydride 、 lithium hexamethyldisilazane 、 2-二环己膦基-2'-(N,N-二甲胺)-联苯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 17.33h， 生成 N-(2-aminopyridin-4-yl)-2,6-dichlorobenzamide
  参考文献：
  名称：

  Lead identification of novel and selective TYK2 inhibitors

  摘要：

  A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine I as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.070

文献信息

• JANUS KINASE INHIBITOR COMPOUNDS AND METHODS
  申请人：GOODACRE SIMON CHARLES

  公开号：US20100317643A1

  公开（公告）日：2010-12-16

  The invention provides compounds of Formula I, stereoisomers or pharmaceutically acceptable salts thereof, wherein A, B, D, R 1 , R 2 , R 4 and R 5 are defined herein, a pharmaceutical composition that includes a compound of Formula I and methods of use thereof

  这项发明提供了公式I的化合物，其立体异构体或药学上可接受的盐，其中A、B、D、R1、R2、R4和R5在此处被定义，包括公式I化合物的药物组合物以及其使用方法
• Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors
  作者：Jun Liang、Anne van Abbema、Mercedesz Balazs、Kathy Barrett、Leo Berezhkovsky、Wade Blair、Christine Chang、Donnie Delarosa、Jason DeVoss、Jim Driscoll、Charles Eigenbrot、Nico Ghilardi、Paul Gibbons、Jason Halladay、Adam Johnson、Pawan Bir Kohli、Yingjie Lai、Yanzhou Liu、Joseph Lyssikatos、Priscilla Mantik、Kapil Menghrajani、Jeremy Murray、Ivan Peng、Amy Sambrone、Steven Shia、Young Shin、Jan Smith、Sue Sohn、Vickie Tsui、Mark Ultsch、Lawren C. Wu、Yisong Xiao、Wenqian Yang、Judy Young、Birong Zhang、Bing-yan Zhu、Steven Magnuson

  DOI：10.1021/jm400266t

  日期：2013.6.13

  Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound

  在这里，我们从铅分子3开始，报告我们的铅优化工作，以鉴定有效的，选择性的和口服生物利用的TYK2抑制剂。我们使用基于结构的设计来发现2，6-二氯-4-氰基苯基和（1 R，2 R）-2-氟环丙基酰胺的修饰，相对于3，它们各自显示出更高的TYK2效力以及JAK1和JAK2选择性。进一步的优化最终导致化合物37在小鼠中表现出良好的TYK2酶和白介素12（IL-12）细胞效能，以及可接受的细胞JAK1和JAK2选择性以及出色的口服暴露。在小鼠IL-12 PK / PD模型中测试时，化合物37 结果显示，细胞因子干扰素-γ（IFNγ）的抑制作用具有统计学意义，表明对TYK2激酶活性的选择性抑制可能足以阻断IL-12体内途径。
• Janus kinase inhibitor compounds and methods
  申请人：Goodacre Simon Charles

  公开号：US08486950B2

  公开（公告）日：2013-07-16

  The invention provides compounds of Formula I, stereoisomers or pharmaceutically acceptable salts thereof, wherein A, B, D, R1, R2, R4 and R5 are defined herein, a pharmaceutical composition that includes a compound of Formula I and methods of use thereof.

  本发明提供了公式I的化合物、立体异构体或其药学上可接受的盐，其中A、B、D、R1、R2、R4和R5在此定义，以及包括公式I的化合物的药物组合物和使用方法。
• US8486950B2
  申请人：——

  公开号：US8486950B2

  公开（公告）日：2013-07-16
• [EN] JANUS KINASE INHIBITOR COMPOUNDS AND METHODS<br/>[FR] COMPOSÉS INHIBITEURS DES KINASES JANUS ET PROCÉDÉS
  申请人：HOFFMANN LA ROCHE

  公开号：WO2010142752A1

  公开（公告）日：2010-12-16

  The invention provides compounds of Formula (I), stereoisomers or pharmaceutically acceptable salts thereof, wherein A, B, D, R1, R2, R4 and R5 are defined herein, a pharmaceutical composition that includes a compound of Formula (I), methods of making those compounds as well as methods of use thereof