1-ethyl-3-(4-(4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-yl)phenyl)urea | 1207365-77-2

• 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: 1-ethyl-3-(4-(4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-yl)phenyl)urea
• 英文别名: 1-ethyl-3-[4-[3-[(3S)-3-methylmorpholin-4-yl]-4,6,12-triazatricyclo[7.2.1.02,7]dodeca-2(7),3,5-trien-5-yl]phenyl]urea
• CAS: 1207365-77-2
• 化学式: C₂₃H₃₀N₆O₂
• 分子量: 422.53
• InChiKey: WTHUAGSLQPUTKZ-NNGSBXSVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  91.4
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-ethyl-3-(4-(4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-yl)phenyl)urea 、 乙醛 在 sodium cyanoborohydride 作用下， 以 乙腈 为溶剂， 反应 5.5h， 以7.5 mg的产率得到1-ethyl-3-[4-[(1R,9S)-12-ethyl-3-[(3S)-3-methylmorpholin-4-yl]-4,6,12-triazatricyclo[7.2.1.02,7]dodeca-2(7),3,5-trien-5-yl]phenyl]urea
  参考文献：
  名称：

  Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)

  摘要：

  We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.

  DOI：

  10.1021/jm400194n
• 作为产物：
  描述：

  在 吗啉 、 2-氯吡啶 、 四(三苯基膦)钯 、 tin(II) chloride dihdyrate 、 三氟甲磺酸酐 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 8.76h， 生成 1-ethyl-3-(4-(4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-5,8-epiminocyclohepta[d]pyrimidin-2-yl)phenyl)urea
  参考文献：
  名称：

  Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)

  摘要：

  We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.

  DOI：

  10.1021/jm400194n

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）。
• 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。
• US8163763B2
  申请人：——

  公开号：US8163763B2

  公开（公告）日：2012-04-24
• Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)
  作者：Anthony A. Estrada、Daniel G. Shore、Elizabeth Blackwood、Yung-Hsiang Chen、Gauri Deshmukh、Xiao Ding、Antonio G. DiPasquale、Jennifer A. Epler、Lori S. Friedman、Michael F. T. Koehler、Lichuan Liu、Shiva Malek、Jim Nonomiya、Daniel F. Ortwine、Zhonghua Pei、Steve Sideris、Frederic St-Jean、Lan Trinh、Tom Truong、Joseph P. Lyssikatos

  DOI：10.1021/jm400194n

  日期：2013.4.11

  We have recently reported a series of tetrahydroquinazoline (THQ) mTOR inhibitors that produced a clinical candidate 1 (GDC-0349). Through insightful design, we hoped to discover and synthesize a new series of small molecule inhibitors that could attenuate CYP3A4 time-dependent inhibition commonly observed with the THQ scaffold, maintain or improve aqueous solubility and oral absorption, reduce free drug clearance, and selectively increase mTOR potency. Through key in vitro and in vivo studies, we demonstrate that a pyrimidoaminotropane based core was able to address each of these goals. This effort culminated in the discovery of 20 (GNE-555), a highly potent, selective, metabolically stable, and efficacious mTOR inhibitor.