(R)-6-(5-cyano-1H-indol-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (R)-6-(5-cyano-1H-indol-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide
• 英文别名: 6-(5-cyanoindol-1-yl)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]-4-(propan-2-ylamino)pyridine-3-carboxamide
• 化学式: C₂₃H₂₆FN₅O₂
• 分子量: 423.49
• InChiKey: HPVVUVJYKCRNCV-HXUWFJFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4,6-二氯烟酸乙酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 水 、 caesium carbonate 、 N,N-二异丙基乙胺 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 lithium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基乙酰胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 87.0h， 生成 (R)-6-(5-cyano-1H-indol-1-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)nicotinamide
  参考文献：
  名称：

  HETEROARYL SUBSTITUTED NICOTINAMIDE COMPOUNDS

  摘要：

  公开的是Formula (I)的化合物或其盐，其中：HET是从吡唑基、吲哚基、吡咯并[2,3-b]吡啶基、吡咯并[2,3-d]嘧啶基、吡唑并[3,4-b]吡啶基、吡唑并[3,4-d]嘧啶基、2,3-二氢-1H-吡咯并[2,3-b]吡啶基、咪唑并[4,5-b]吡啶基和嘌呤基中选择的杂环芳基，其中所述杂环芳基被R a 和R b 取代；以及R 1 和R 2 在此处定义。还公开了使用这些化合物作为IRAK4调节剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓炎症性和自身免疫性疾病方面是有用的。

  公开号：

  US20150191464A1

文献信息

• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20190151295A1

  公开（公告）日：2019-05-23

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为白细胞介素-1受体相关激酶4（IRAK-4；目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合E3泛素连接酶的Von Hppel-Lindau、cereblon配体的双功能化合物，另一端结合目标蛋白的部分，使得目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。
• Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
  申请人：Arvinas Operations, Inc.

  公开号：US11065231B2

  公开（公告）日：2021-07-20

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，这些化合物可作为白细胞介素-1受体相关激酶4（IRAK-4）（靶蛋白）的调节剂。特别是，本公开涉及双功能化合物，其一端含有与 E3 泛素连接酶结合的 Von Hppel-Lindau（脑龙）配体，另一端含有与靶蛋白结合的分子，从而使靶蛋白靠近泛素连接酶，以实现对靶蛋白的降解（和抑制）。本公开物具有与降解/抑制靶蛋白相关的广泛药理活性。本公开的化合物和组合物可以治疗或预防因目标蛋白聚集或积聚而导致的疾病或失调。
• US9169252B2
  申请人：——

  公开号：US9169252B2

  公开（公告）日：2015-10-27
• [EN] HETEROARYL SUBSTITUTED NICOTINAMIDE COMPOUNDS<br/>[FR] COMPOSÉS NICOTINAMIDE SUBSTITUÉS PAR UN HÉTÉROARYLE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2015103453A1

  公开（公告）日：2015-07-09

  Disclosed are compounds of Formula (I) or salts thereof, wherein: HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b] pyridinyl, and purinyl, wherein said heteroaryl is substituted with Ra and Rb; and R1 and R2 are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.
• HETEROARYL SUBSTITUTED NICOTINAMIDE COMPOUNDS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20150191464A1

  公开（公告）日：2015-07-09

  Disclosed are compounds of Formula (I) or salts thereof, wherein: HET is a heteroaryl selected from pyrazolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl, and purinyl, wherein said heteroaryl is substituted with R a and R b ; and R 1 and R 2 are define herein. Also disclosed are methods of using such compounds as modulators of IRAK4, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

  公开的是Formula (I)的化合物或其盐，其中：HET是从吡唑基、吲哚基、吡咯并[2,3-b]吡啶基、吡咯并[2,3-d]嘧啶基、吡唑并[3,4-b]吡啶基、吡唑并[3,4-d]嘧啶基、2,3-二氢-1H-吡咯并[2,3-b]吡啶基、咪唑并[4,5-b]吡啶基和嘌呤基中选择的杂环芳基，其中所述杂环芳基被R a 和R b 取代；以及R 1 和R 2 在此处定义。还公开了使用这些化合物作为IRAK4调节剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓炎症性和自身免疫性疾病方面是有用的。