5-(((1R,2S)-2-aminocyclohexyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡唑并嘧啶类
• 英文名称: 5-(((1R,2S)-2-aminocyclohexyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
• 英文别名: 5-{[(1r,2s)-2-Aminocyclohexyl]amino}-N-[1-Methyl-3-(Trifluoromethyl)-1h-Pyrazol-4-Yl]pyrazolo[1,5-A]pyrimidine-3-Carboxamide；5-[[(1R,2S)-2-aminocyclohexyl]amino]-N-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide
• 化学式: C₁₈H₂₁F₃N₈O
• 分子量: 422.413
• InChiKey: LAXFSYWLDNVHAQ-NWDGAFQWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5-(((1R,2S)-2-aminocyclohexyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 、 二氯乙醚 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-5-(((1R,2S)-2-morpholinocyclohexyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  [EN] PYRAZOLOPYRIMIDINE INHIBITORS OF IRAK4 ACTIVITY
  [FR] INHIBITEURS DE L'ACTIVITÉ D'IRAK4 À BASE DE PYRAZOLOPYRIMIDINE

  摘要：

  本发明涉及式(I)的IRAK4的吡唑吡咯啉抑制剂，并提供包含这种抑制剂的组合物，以及用于治疗IRAK4介导或相关疾病或病症的方法。

  公开号：

  WO2016144846A1
• 作为产物：
  描述：

  5-氯吡唑并[1,5-a]嘧啶-3-羧酸乙酯 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 、 lithium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 、 乙腈 为溶剂， 反应 30.0h， 生成 5-(((1R,2S)-2-aminocyclohexyl)amino)-N-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

  摘要：

  Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

  DOI：

  10.1021/acsmedchemlett.5b00107

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。
• Pyrazolopyrimidine inhibitors of IRAK4 activity
  申请人：MERCK SHARP & DOHME CORP.

  公开号：US10329294B2

  公开（公告）日：2019-06-25

  The present invention relates to pyrazolopyrimidine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

  本发明涉及式（I）的IRAK4吡唑嘧啶抑制剂，并提供了包含这种抑制剂的组合物，以及用其治疗IRAK4介导的或相关的病症或疾病的方法。
• 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。
• PYRAZOLOPYRIMIDINE INHIBITORS OF IRAK4 ACTIVITY
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP3267996B1

  公开（公告）日：2020-11-11
• [EN] PYRAZOLOPYRIMIDINE INHIBITORS OF IRAK4 ACTIVITY<br/>[FR] INHIBITEURS DE L'ACTIVITÉ D'IRAK4 À BASE DE PYRAZOLOPYRIMIDINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2016144846A1

  公开（公告）日：2016-09-15

  The present invention relates to pyrazolopyrimidine inhibitors of IRAK4 of formula (I) and provides compositions comprising such inhibitors, as well as methods therewith for treating IRAK4-mediated or -associated conditions or diseases.

  本发明涉及式(I)的IRAK4的吡唑吡咯啉抑制剂，并提供包含这种抑制剂的组合物，以及用于治疗IRAK4介导或相关疾病或病症的方法。