RESUMEN
A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.
Asunto(s)
Compuestos de Bencilo/química , Paladio/química , Pirazoles/química , Pirazoles/síntesis química , Piridinas/química , Piridinas/síntesis química , Catálisis , Ésteres , Estructura MolecularRESUMEN
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
Asunto(s)
Acrilamidas/farmacología , Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/genética , Técnicas de Química Sintética , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/genética , Femenino , Humanos , Concentración 50 Inhibidora , Neoplasias Pulmonares/genética , Masculino , Ratones , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Ratas Endogámicas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Silenes, generated through thermolysis of acylpolysilanes, add to alpha,beta-unsaturated esters to form cyclobutanes and silylsubstituted cyclopropanes in moderate yields. Upon Si-C bond oxidation the cyclopropanes are converted directly to 1,4-dicarbonyl compounds, thus demonstrating the formal acyl anion chemistry of acyl polysilanes.