tert-butyl 2-[4-(ethylcarbamoyloxy)phenyl]-4-morpholin-4-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate | 1416274-59-3

• 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-[4-(ethylcarbamoyloxy)phenyl]-4-morpholin-4-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate
• CAS: 1416274-59-3
• 化学式: C₂₅H₃₃N₅O₅
• 分子量: 483.568
• InChiKey: FCGKCXWBDFRSGQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  106
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl 2-[4-(ethylcarbamoyloxy)phenyl]-4-morpholin-4-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidine-7-carboxylate 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 [4-(7-benzoyl-4-morpholin-4-yl-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-2-yl)phenyl] N-ethylcarbamate
  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：

  2,4-二氯-5,6-二氢吡啶并[3,4-d]嘧啶-7-甲酸叔丁酯 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 、 异丙醇 、 乙腈 为溶剂， 反应 26.0h， 生成 tert-butyl 2-[4-(ethylcarbamoyloxy)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

文献信息

• Potent, Selective, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin Kinase Domain Exhibiting Single Agent Antiproliferative Activity
  作者：Michael F. T. Koehler、Philippe Bergeron、Elizabeth Blackwood、Krista K. Bowman、Yung-Hsiang Chen、Gauri Deshmukh、Xiao Ding、Jennifer Epler、Kevin Lau、Leslie Lee、Lichuan Liu、Cuong Ly、Shiva Malek、Jim Nonomiya、Jason Oeh、Daniel F. Ortwine、Deepak Sampath、Steve Sideris、Lan Trinh、Tom Truong、Jiansheng Wu、Zhonghua Pei、Joseph P. Lyssikatos

  DOI：10.1021/jm301389h

  日期：2012.12.27

  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.