Pyrazole And Mtor [3, 4 - D] Pyrimidine Class/pi3k Inhibitors Synthesis

The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Herein, we report the design and synthesis of a series of1H-pyrazolo[3,4-d]pyrimidines as potent and selective inhibitors of the mammalian target of rapamycin (mTOR). Modification by the4-ureidophenyl and6-amino substituent is proved to be capable of improving the inhibition, selectivity and stability.In this thesis, we firstly described the synthesis of1H-pyrazolo[3,4-d]pyrimidine analogs by the parallel synthetic methods. Firstly, the starting material of barbituric acid was formylated by Vilsmeier-Haack reaction, then chlorided, and cyclized with (tetrahydro-2H-pyran-4-yl)hydrazine, which was synthesized by reductive amination of dihydro-2H-pyran-4(3H)-one and tert-butyl hydrazinecarboxylate and deprotection, to give the key intermediate of4,6-dichloro-l-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-d]pyrimidine3. At the same time, we synthesized the analogs of aromatic pinacolatoboron4by coupling of bromoaromatics with bis(pinacolato)diboron. Finally, we successfully accomplished the synthesis of the target compounds by sequential Suzuki cross-coupling and nucleophilic substitution reaction with a series of amines. All of the involved intermediates and target compounds were characterized by LC-MS,1H NMR,13C NMR, NOE.