RESUMO
High throughput screening to identify inhibitors of the mTOR kinase revealed sulfonyl-morpholino-pyrimidine 1 as an attractive start point. The compound displayed good physicochemical properties and selectivity over related kinases such as PI3Kα. Library preparation of related analogs allowed the establishment of additional SAR understanding and in particular the requirement for a key hydrogen bond donor motif at the 4-position of the phenyl ring in compounds such as indole 19. Isosteric replacement of the indole functionality led to the identification of urea compounds such as 32 that show good levels of mTOR inhibition in both enzyme and cellular assays.
Assuntos
Antineoplásicos/síntese química , Morfolinas/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/síntese química , Sulfonas/síntese química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Ligação de Hidrogênio , Indóis/química , Concentração Inibidora 50 , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacologia , Serina-Treonina Quinases TOR/química , Ureia/análogos & derivados , Ureia/químicaRESUMO
A novel method for the synthesis of a wide range of 1,5-disubstituted 1,2-dihydro-1,2,4-triazol-3-ones is described. The key step involves a reaction between a dilithiated BOC-hydrazine and a N-alkoxycarbonylcarboximidothioate. A broad range of aryl and alkyl functional groups are tolerated, providing a versatile route for the synthesis of triazolones.