8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-N-(1-propanoylazetidin-3-yl)-9H-purin-6-amine | 1610704-72-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-N-(1-propanoylazetidin-3-yl)-9H-purin-6-amine
• 英文别名: 1-[3-[[8-(1-Ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]amino]azetidin-1-yl]propan-1-one；1-[3-[[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]amino]azetidin-1-yl]propan-1-one
• CAS: 1610704-72-7
• 化学式: C₁₈H₂₄N₈O
• 分子量: 368.442
• InChiKey: BGLCMAMMMFHRFS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  93.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  6-氯-4-甲基嘧啶-4,5-二胺,6-氯-4-甲基-4,5-二氨基嘧啶 在 盐酸 、 iron(III) chloride hexahydrate 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 150.0h， 生成 8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-N-(1-propanoylazetidin-3-yl)-9H-purin-6-amine
  参考文献：
  名称：

  Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability

  摘要：

  PI3K delta catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3K delta inhibitor bearing a benzimidazolonepiperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolonepiperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.

  DOI：

  10.1021/acs.jmedchem.8b01818

文献信息

• [EN] PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA<br/>[FR] INHIBITEURS PURIQUES DE LA PHOSPHATIDYLINOSITOL 3-KINASE DELTA HUMAINE
  申请人：MERCK SHARP & DOHME

  公开号：WO2014075393A1

  公开（公告）日：2014-05-22

  The instant invention provides compounds of formula I which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.

  该即时发明提供了式I的化合物，这些化合物是PI3K-δ抑制剂，因此可用于治疗PI3K-δ介导的疾病，如炎症、哮喘、慢性阻塞性肺病和癌症。
• PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
  申请人：Merck Sharp & Dohme Corp.

  公开号：US20160207926A1

  公开（公告）日：2016-07-21

  The instant invention provides compounds of formula I which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.

  本发明提供了I式化合物，它们是PI3K-delta抑制剂，因此可用于治疗PI3K-delta介导的疾病，如炎症、哮喘、COPD和癌症。
• US9938281B2
  申请人：——

  公开号：US9938281B2

  公开（公告）日：2018-04-10
• Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability
  作者：Joey L. Methot、Hua Zhou、Sam D. Kattar、Meredeth A. McGowan、Kevin Wilson、Yudith Garcia、Yongi Deng、Michael Altman、Xavier Fradera、Charles Lesburg、Thierry Fischmann、Chaomin Li、Steve Alves、Sanjiv Shah、Rafael Fernandez、Peter Goldenblatt、Armetta Hill、Lynsey Shaffer、Dapeng Chen、Vince Tong、Robbie L. McLeod、Hongshi Yu、Alan Bass、Ray Kemper、Nicholas T. Gatto、Lisa LaFranco-Scheuch、Benjamin Wesley Trotter、Timothy Guzi、Jason D. Katz

  DOI：10.1021/acs.jmedchem.8b01818

  日期：2019.5.9

  PI3K delta catalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3K delta inhibitor bearing a benzimidazolonepiperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolonepiperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.