tert-butyl 2-chloro-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate | 1207370-38-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: tert-butyl 2-chloro-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate
• 英文别名: tert-butyl 2-chloro-4-morpholino-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate；tert-butyl 2-chloro-4-morpholin-4-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate
• CAS: 1207370-38-4
• 化学式: C₁₆H₂₃ClN₄O₃
• 分子量: 354.837
• InChiKey: MEFNJVJFIIWTRO-UHFFFAOYSA-N

物化性质

• 沸点：
  554.5±50.0 °C(Predicted)
• 密度：
  1.284±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  67.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-chloro-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate 在 四(三苯基膦)钯 、 potassium acetate 、 sodium carbonate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 水 、 乙腈 为溶剂， 生成 tert-butyl 2-[4-(ethoxycarbonylamino)phenyl]-4-morpholin-4-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate
  参考文献：
  名称：

  Potent, Selective, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin Kinase Domain Exhibiting Single Agent Antiproliferative Activity

  摘要：

  Selective inhibitors of mammalian target of rapamycin (mTOR) kinase based upon saturated heterocycles fused to a pyrimidine core were designed and synthesized. Each series produced compounds with K-i < 10 nM for the mTOR kinase and >500-fold selectivity over closely related PI3 kinases. This potency translated into strong pathway inhibition, as measured by phosphorylation of mTOR substrate proteins and antiproliferative activity in cell lines with a constitutively active PI3K pathway. Two compounds exhibiting suitable mouse PK were profiled in in vivo tumor models and were shown to suppress mTORC1 and mTORC2 signaling for over 12 h when dosed orally. Both compounds were additionally shown to suppress tumor growth in vivo in a PC3 prostate cancer model over a 14 day study.

  DOI：

  10.1021/jm301389h
• 作为产物：
  描述：

  吗啉 、 2,4-二氯-5,6-二氢吡啶并[3,4-d]嘧啶-7-甲酸叔丁酯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 6.0h， 以98.7%的产率得到tert-butyl 2-chloro-4-morpholino-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate
  参考文献：
  名称：

  [EN] 5,6,7,8-TETRAHYDROPYRIDO[3,4-D]PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
  [FR] COMPOSÉS DE 5,6,7,8-TÉTRAHYDROPYRIDO[3,4-D]PYRIMIDINE, LEUR UTILISATION COMME INHIBITEURS DE LA MTOR KINASE ET DE LA PI3 KINASE, ET LEURS SYNTHÈSES

  摘要：

  公式I的化合物：或其药用可接受的盐，其中组成变量如本文所述，包含该化合物的组合物，以及制造和使用该化合物的方法。

  公开号：

  WO2010120996A1

文献信息

• [EN] PYRIMIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE<br/>[FR] COMPOSÉS DE PYRIMIDINE, COMPOSITIONS ET PROCÉDÉS D'UTILISATION
  申请人：GENENTECH INC

  公开号：WO2010014939A1

  公开（公告）日：2010-02-04

  Disclosed are compounds of Formula I, including steroisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, that are useful in modulating PIKK related kinase signaling, e.g., mTOR, and for the treatment of diseases (e.g., cancer) that are mediated at least in part by the dysregulation of the PIKK signaling pathway (e.g., mTOR).

  揭示了公式I的化合物，包括立体异构体、几何异构体、互变异构体、溶剂合物、代谢物和其药学上可接受的盐，这些化合物在调节PIKK相关激酶信号传导方面很有用，例如mTOR，并用于治疗至少部分由PIKK信号传导途径失调引起的疾病（例如癌症）。
• [EN] COMPOUNDS AND THERAPEUTIC USES THEREOF<br/>[FR] COMPOSÉS ET LEURS UTILISATIONS THÉRAPEUTIQUES
  申请人：VIOGEN BIOSCIENCES LLC

  公开号：WO2020243457A1

  公开（公告）日：2020-12-03

  The invention relates to compounds, pharmaceutical compositions and methods useful for treating cancer, systemic or chronic inflammation, rheumatoid arthritis, diabetes, obesity, T-cell mediated autoimmune disease, diseases associated with over production of IL12/IL23, lysosomal storage disorders, filovirus infections, ischemia, neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, viral infection including SARS-CoV-2, and other complications associated with the foregoing diseases and disorders.

  这项发明涉及化合物、药物组合物和方法，用于治疗癌症、全身性或慢性炎症、类风湿关节炎、糖尿病、肥胖症、T细胞介导的自身免疫疾病、与IL12/IL23过度产生相关的疾病、溶酶体贮积疾病、丝状病毒感染、缺血、包括阿尔茨海默病、肌萎缩侧索硬化和额颞叶痴呆症在内的神经退行性疾病、包括SARS-CoV-2的病毒感染，以及与上述疾病和疾病相关并发症。
• A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen)
  作者：Martyn Frederickson、Irwin R. Selvam、Dimitrios Evangelopoulos、Kirsty J. McLean、Mona M. Katariya、Richard B. Tunnicliffe、Bethany Campbell、Madeline E. Kavanagh、Sitthivut Charoensutthivarakul、Richard T. Blankley、Colin W. Levy、Luiz Pedro S. de Carvalho、David Leys、Andrew W. Munro、Anthony G. Coyne、Chris Abell

  DOI：10.1016/j.ejmech.2022.114105

  日期：2022.2

  such means, with several members of the set showing promising activity against Mtb strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity). Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign to design a limited number of analogues (less

  迫切需要抗结核病 (TB) 的新药来对抗对当前抗结核药物日益增长的耐药性。本文描述了一种针对有希望的 TB 目标的命中生成的新策略，涉及 X 射线晶体学筛选与表型筛选相结合。这种组合方法（XP 筛选）既可以验证目标参与度，也可以确定细胞活性。这种方法的实用性通过针对 CYP121A1 的 XP 筛选来说明，CYP121A1 是一种来自结核分枝杆菌( Mtb ) 的细胞色素 P450 酶，被认为是经过验证的药物发现目标。通过这种方式合成和测试了一个集中筛选集，该集的几个成员显示出有希望的针对Mtb菌株 H37Rv。一种化合物被观察为对 CYP121A1 的 X 射线照射，并在多种测定条件下显示出对Mtb菌株 H37Rv 的改进活性（泛测定活性）。在 X 射线晶体学筛选期间获得的数据用于基于结构的活动以设计数量有限的类似物（少于 20 个），其中许多还显示出针对Mtb菌株 H37Rv 的泛分析活性。其中包括苯并[
• PYRIMIDINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
  申请人：Bergeron Philippe

  公开号：US20100069357A1

  公开（公告）日：2010-03-18

  Disclosed are compounds of Formula I, including steroisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, that are useful in modulating PIKK related kinase signaling, e.g., mTOR, and for the treatment of diseases (e.g., cancer) that are mediated at least in part by the dysregulation of the PIKK signaling pathway (e.g., mTOR).

  本发明涉及I式化合物，包括其立体异构体、几何异构体、互变异构体、溶剂化物、代谢物和药学上可接受的盐，其对调节PIKK相关激酶信号传导，例如mTOR，并用于治疗至少部分由PIKK信号通路失调介导的疾病（例如癌症）具有用处。
• Pyrimidine compounds, compositions and methods of use
  申请人：Genentech, Inc.

  公开号：US08163763B2

  公开（公告）日：2012-04-24

  Disclosed are compounds of Formula I, including stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, that are useful in modulating PIKK related kinase signaling, e.g., mTOR, and for the treatment of diseases (e.g., cancer) that are mediated at least in part by the dysregulation of the PIKK signaling pathway (e.g., mTOR).

  本发明涉及公式I的化合物，包括立体异构体、几何异构体、互变异构体、溶剂化物、代谢物和药学上可接受的盐，其在调节PIKK相关激酶信号传导方面具有用途，例如mTOR，并用于治疗至少部分由PIKK信号通路失调引起的疾病（例如癌症）。