4-((3-bromopyridin-2-yl)oxy)benzonitrile

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-((3-bromopyridin-2-yl)oxy)benzonitrile
• 英文别名: 4-(3-Bromopyridin-2-yl)oxybenzonitrile
• 化学式: C₁₂H₇BrN₂O
• 分子量: 275.104
• InChiKey: QOVXWYKCZHJVQN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  16
• 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：
  45.9
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-((3-bromopyridin-2-yl)oxy)benzonitrile 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 叔丁基二甲硅基三氟甲磺酸酯 、 碳酸氢钠 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 为溶剂， 反应 31.0h， 生成 2-amino-N-(4-(2-(4-cyanophenoxy)pyridin-3-yl)thiophen-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide
  参考文献：
  名称：

  Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design

  摘要：

  Retinoic acid receptor related orphan receptor gamma t (ROR gamma t), has been identified as the master regulator of T(H)17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T(H)17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.

  DOI：

  10.1021/acs.jmedchem.8b00783
• 作为产物：
  描述：

  3-溴-2-氯吡啶 在 potassium tert-butylate 、 L-脯氨酸 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.5h， 生成 4-((3-bromopyridin-2-yl)oxy)benzonitrile
  参考文献：
  名称：

  Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design

  摘要：

  Retinoic acid receptor related orphan receptor gamma t (ROR gamma t), has been identified as the master regulator of T(H)17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T(H)17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.

  DOI：

  10.1021/acs.jmedchem.8b00783

文献信息

• BIARYL DERIVATIVE AND MEDICINE CONTAINING SAME
  申请人：Kaken Pharmaceutical Co., Ltd.

  公开号：EP3351533A1

  公开（公告）日：2018-07-25

  Provided is a compound showing excellent antifungal activity against Trichophyton fungus, which is a major causative microorganism of superficial mycosis, and high effectiveness on diseases caused by Trichophyton fungi. A biaryl derivative represented by the formula (I) or a salt thereof: wherein ring A is an optionally substituted phenyl, or an optionally substituted 5- or 6-membered ring heteroaryl (ring A may be further condensed to form an optionally substituted fused ring); Q is CH2, C=O, NH, O, S or the like; X1, X2 and X3 are CR1 or N; Y is CH or N; Z is CR2b or N; R2a and R2b are each a hydrogen atom, a halogen atom, an optionally substituted C1-C6 alkyl group, a C1-C6 haloalkyl group or the like; R2a and R2b may form, together with carbon atoms bonded thereto, an optionally substituted carbocycle, or an optionally substituted heterocycle.

  本发明提供了一种化合物，该化合物对毛癣菌具有极佳的抗真菌活性，而毛癣菌是表皮真菌病的主要致病微生物，该化合物对毛癣菌引起的疾病具有极高的疗效。一种由式（I）代表的双芳基衍生物或其盐： 其中环 A 是任选取代的苯基，或任选取代的 5 或 6 元环杂芳基（环 A 可进一步缩合形成任选取代的融合环）；Q 是 CH2、C=O、NH、O、S 或类似物；X1、X2 和 X3 是 CR1 或 N；Y 是 CH 或 N；Z 是 CR2b 或 N；R2a 和 R2b 各为氢原子、卤素原子、任选取代的 C1-C6 烷基、C1-C6 卤代烷基或类似基团；R2a 和 R2b 可与其键合的碳原子一起形成任选取代的碳环或任选取代的杂环。
• Potent and Orally Bioavailable Inverse Agonists of RORγt Resulting from Structure-Based Design
  作者：Frank Narjes、Yafeng Xue、Stefan von Berg、Jesper Malmberg、Antonio Llinas、Roine I. Olsson、Johan Jirholt、Hanna Grindebacke、Agnes Leffler、Nafizal Hossain、Matti Lepistö、Linda Thunberg、Hanna Leek、Anna Aagaard、Jane McPheat、Eva L. Hansson、Elisabeth Bäck、Stefan Tångefjord、Rongfeng Chen、Yao Xiong、Ge Hongbin、Thomas G. Hansson

  DOI：10.1021/acs.jmedchem.8b00783

  日期：2018.9.13

  Retinoic acid receptor related orphan receptor gamma t (ROR gamma t), has been identified as the master regulator of T(H)17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T(H)17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.