RESUMO
A novel, previously undescribed 4H-thiazolo[5',4':4,5]pyrano[2,3-c]pyridine tricyclic scaffold has been discovered. The application of this novel chemotype leading to a potent and selective prototype PI3Kα inhibitor with favorable physicochemical and PK-properties is described.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Aminação , Animais , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Ratos , Tiazóis/farmacocinéticaRESUMO
A cyclisation within a 4',5-bisthiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors led to a novel 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole tricyclic sub-series. The synthesis and optimisation of this 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole sub-series and the expansion to a related tricyclic 4,5-dihydrothiazolo[4,5-h]quinazoline sub-series are described. From this work analogues including 11, 12, 19 and 23 were identified as potent and selective PI3Kα inhibitor in vivo tool compounds.