(6S,9R)-2,2,2-trichloroethyl 2-(4-(3-ethylureido)phenyl)-4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxylate | 1428902-80-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (6S,9R)-2,2,2-trichloroethyl 2-(4-(3-ethylureido)phenyl)-4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxylate
• CAS: 1428902-80-0
• 化学式: C₂₆H₃₁Cl₃N₆O₄
• 分子量: 597.929
• InChiKey: BRNAROFEKUJHQE-ZAAXVRCTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.08
• 重原子数：
  39.0
• 可旋转键数：
  5.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  108.92
• 氢给体数：
  2.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (6S,9R)-2,2,2-trichloroethyl 2-(4-(3-ethylureido)phenyl)-4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxylate 在 ammonium acetate 、 锌 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 48.0h， 以49%的产率得到1-ethyl-3-(4-((6S,9R)-4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-6,9-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
• 作为产物：
  描述：

  (1R,5S)-8-苄基-8-氮杂双环[3.2.1]辛烷-2-酮 在 2-氯吡啶 、 titanium(IV) tetraethanolate 、 三氟甲磺酸酐 、 铁粉 、 氯化铵 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 49.85h， 生成 (6S,9R)-2,2,2-trichloroethyl 2-(4-(3-ethylureido)phenyl)-4-((S)-3-methylmorpholino)-6,7,8,9-tetrahydro-5H-6,9-epiminocyclohepta[d]pyrimidine-10-carboxylate
  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