Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1-substituent

A series of pyrazolopyrimidine mammalian Target Of Rapamycin (mTOR) inhibitors with various substituents at the 1-position have been prepared, resulting in compounds with excellent potency, selectivity and microsomal stability. Combination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8 h following iv administration and showed excellent oral activity in a xenograft tumor model.

Graphical abstractCombination of a 1-cyclohexyl ketal group with a 2,6-ethylene bridged morpholine in the 4-position and a ureidophenyl group in the 6-positon of the pyrazolopyrimidine resulted in compound 8a, that selectively suppressed key mTOR biomarkers in vivo for at least 8 h following oral administration and showed excellent activity in a tumor xenograft model.Figure optionsDownload full-size imageDownload as PowerPoint slide