2′,4′-substituted nucleosides as antiviral agents

摘要

Embodiments of the invention are to compounds, methods, and compositions for use in the treatment of viral infections. More specifically embodiments of the invention are 2′,4′-substituted nucleoside compounds useful for the treatment of viral infections, such as HIV, HCV, and HBV infections.

主权项

1. A compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein:
(a) R2 is CH3, CH2F, CHF2, CF3, F, CN, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms;(b) R is H, phosphate, H-phosphonate, acyl, alkyl, 0-substituted carboxyalkylamino, sulfonate ester, or benzyl, wherein the phenyl group of the benzyl is optionally substituted, a lipid, an L or D-amino acid, a carbohydrate, a peptide, or a cholesterol;(c) R3 is OH, H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, vinyl, N3, CN, Cl, Br, F, I, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-10 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C1-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, or N(C1-18 acyl)2,wherein alkyl, alkynyl, alkenyl and vinyl are optionally substituted by N3, CN, one to three halogens, NO2, C(O)O(C1-4 alkyl), C(O)O(C1-4 alkyl), C(O)O(C2-4 alkynyl), C(O)O(C2-4 alkenyl), O(C1-4 acyl), O(C1-4 alkyl), O(C2-4 alkenyl), SH, S(C1-4 acyl), S(C1-4 alkyl), S(C2-4 alkynyl), S(C2-4 alkenyl), SO(C1-4 acyl), SO(C1-4 alkyl), SO(C2-4 alkynyl), SO(C2-4 alkenyl), SO2(C1-4 acyl), SO2(C1-4 alkyl), SO2(C2-4 alkynyl), SO2(C2-4 alkenyl), OS(O)2(C1-4 acyl), OS(O)2(C1-4 alkyl), OS(O)2(C2-4 alkenyl), NH2, NH(C1-4 alkyl), NH(C2-4 alkenyl), NH(C2-4 alkynyl), NH(C1-4 acyl), N(C1-4 alkyl)2, or N(C1-4 acyl)2;(d) R4 is a lower alkyl, CN, vinyl, O-(lower alkyl), hydroxyl lower alkyl, CH2F, N3, CH2CN, CH2NH2, CH2NHCH3, CH2N(CH3)2, an optionally substituted ethynyl, halogen, alkenyl, alkynyl, Br-vinyl, hydroxy, O-alkenyl, NO2, amino, lower alkylamino, or di(C1-8 alkyl)amino;(e) R and R3 can together form 5′,3′-cyclic phosphate;(f) Base is a naturally occurring or modified pyrimidine base represented by the following structure: wherein;R5 and R6, are independently H, F, Cl, Br, I, OH, OR′, SH, SR′, NH2, NHR′, NR′2, alkyl of C1-C6, halogenated alkyl of C1-C6, lower alkenyl of C2-C6, halogenated lower alkenyl of C2-C6, lower alkynyl of C2-C6, halogenated lower alkynyl of C2-C6, lower alkoxy of C1-C6, halogenated lower alkoxy of C1-C6, CO2H, CO2R′, CONH2, CONHR′, CONR′2, CH═CHCO2H, or CH═CHCO2R′,wherein R′ is an optionally substituted alkyl; an optionally substituted cycloalkyl; an optionally substituted alkynyl of C2-C6, an optionally substituted lower alkenyl of C2-C6, or optionally substituted acyl, optionally substituted aryl, optionally substituted C1-C4 alkylaryloxy, heteroaryl, optionally substituted C1-C4 alkylheteroaryl, an optionally substituted alkoxy C1-20 alkyl, an optionally substituted amino C1-20 alkyl, or an optionally substituted fluoro C1-20 alkyl.