(S)-(3-((8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl)oxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone | 1610715-29-1

• 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: (S)-(3-((8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl)oxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone
• 英文别名: [(3S)-3-{[8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl]oxy}pyrrolidin-1-yl](oxan-4-yl)methanone；[(3S)-3-[8-(1-ethyl-5-methylpyrazol-4-yl)-9-methylpurin-6-yl]oxypyrrolidin-1-yl]-(oxan-4-yl)methanone
• CAS: 1610715-29-1
• 化学式: C₂₂H₂₉N₇O₃
• 分子量: 439.517
• InChiKey: FHKPLLOSJHHKNU-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  100
• 氢给体数：
  0
• 氢受体数：
  7

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 iron(III) chloride hexahydrate 、 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 16.0h， 生成 (S)-(3-((8-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-yl)oxy)pyrrolidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone
  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

• PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
  申请人：ACHAB Abdelghani Abe

  公开号：US20150353552A1

  公开（公告）日：2015-12-10

  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 inflammation, asthma, COPD and cancer.

  本发明提供了式I的化合物，它们是PI3K-delta抑制剂，因此可用于治疗由PI3K-delta介导的疾病，如炎症、哮喘、COPD和癌症。
• Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators
  作者：Joey L. Methot、Hua Zhou、Meredeth A. McGowan、Neville John Anthony、Matthew Christopher、Yudith Garcia、Abdelghani Achab、Kathryn Lipford、Benjamin Wesley Trotter、Michael D. Altman、Xavier Fradera、Charles A. Lesburg、Chaomin Li、Stephen Alves、Craig P. Chappell、Renu Jain、Ruban Mangado、Elaine Pinheiro、Sybill M. G. Williams、Peter Goldenblatt、Armetta Hill、Lynsey Shaffer、Dapeng Chen、Vincent Tong、Robbie L. McLeod、Hyun-Hee Lee、Hongshi Yu、Sanjiv Shah、Jason D. Katz

  DOI：10.1021/acs.jmedchem.1c00237

  日期：2021.4.22
• US9730940B2
  申请人：——

  公开号：US9730940B2

  公开（公告）日：2017-08-15