RESUMEN
Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Paladio/química , Sulfonamidas/farmacología , Uracilo/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , 2-Naftilamina , Antivirales/síntesis química , Antivirales/química , Catálisis , Desarrollo de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Sulfonamidas/síntesis química , Sulfonamidas/química , Uracilo/síntesis química , Uracilo/química , Uracilo/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
A general method for Pd-catalyzed sulfonamidation of aryl nonafluorobutanesulfonates (aryl nonaflates) is described. A biaryl phosphine ligand, t-BuXPhos, formed the most active catalyst, and K(3)PO(4) in tert-amyl alcohol was found to be the optimal base-solvent combination for the reaction. The reaction conditions were tolerant of various functional groups such as cyano, nitro, ester, aldehyde, ketone, chloride, carbamate, and phenol. Heterocyclic aryl nonaflates were found to be suitable coupling partners. High yields of the coupled products were obtained from the reactions between inherently disfavored substrates such as electron-rich nonaflates and electron-poor sulfonamides. Kinetic data suggest reductive elimination to be the rate-limiting step for the reaction. The only limitation of this methodology that we have identified is the inability of 2,6-disubstituted aryl nonaflates to efficiently participate in the reaction.
Asunto(s)
Paladio/química , Sulfonamidas/química , Ácidos Sulfónicos/química , Catálisis , Hidrólisis , Cinética , Ligandos , Fosfinas/químicaRESUMEN
A novel series of non-ATP-competitive MK2 inhibitors based on a furan-2-carboxyamide scaffold was discovered through high-throughput screening using the affinity selection-mass spectrometry-based Automated Ligand Identification System platform. Medicinal chemistry efforts optimized the initial screening hit to leadlike compounds with significant improvements in biochemical and cellular potencies, while maintaining excellent kinase selectivity and in vitro pharmacokinetic properties. Biophysical and biochemical studies confirmed the unique non-ATP-competitive binding mode of this series and suggested that highly selective inhibitors of MK2 should be feasible by targeting the outside ATP pocket.