RESUMEN
Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity.
Asunto(s)
Isoquinolinas , Proteínas Proto-Oncogénicas p21(ras) , Isoquinolinas/farmacología , Diseño de Fármacos , MutaciónRESUMEN
An efficient and straightforward approach for the synthesis of C7 site-selective BINOL derivatives has been achieved via cost-effective Co(III)-catalyzed C-H cascade alkenylation/intramolecular Friedel-Crafts alkylation of BINOL units and propargyl cycloalkanols. Under the advantage of the pyrazole directing group, the protocol allows the rapid synthesis of various BINOL-tethered spiro[cyclobutane-1,1'-indenes].
RESUMEN
Intramolecular C-H activation/C-O coupling, dearomatization, and [4+2] cycloaddition of BINOL units have been well developed in a one-pot approach with maleimide derivatives as the dienophiles. This tandem catalytic system generates a variety of functionalized bridged polycyclic products in a step-economical manner, which greatly enriches the modification methods and strategies for the BINOL skeletons.