2-[(1R,9S)-4-[4-(ethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]-3,5,12-triazatricyclo[7.2.1.02,7]dodeca-2(7),3,5-trien-12-yl]-N,2-dimethylpropanamide | 1428902-75-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-[(1R,9S)-4-[4-(ethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]-3,5,12-triazatricyclo[7.2.1.02,7]dodeca-2(7),3,5-trien-12-yl]-N,2-dimethylpropanamide
• CAS: 1428902-75-3
• 化学式: C₂₈H₃₉N₇O₃
• 分子量: 521.663
• InChiKey: OTOIKFVTBJUTPZ-RBDMOPTHSA-N

物化性质

• 沸点：
  656.2±55.0 °C(Predicted)
• 密度：
  1.224±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  112
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-溴-N,2-二甲基-丙酰胺 、 1-ethyl-3-(4-(4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidin-2-yl)phenyl)urea 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 反应 18.0h， 以6%的产率得到2-[(1R,9S)-4-[4-(ethylcarbamoylamino)phenyl]-6-[(3S)-3-methylmorpholin-4-yl]-3,5,12-triazatricyclo[7.2.1.02,7]dodeca-2(7),3,5-trien-12-yl]-N,2-dimethylpropanamide
  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

• 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.