Seven Member Ring of Nucleosides as inhibitors of viral Replication, Methods for their Synthesis, Pharmaceutical compositions containing them and their use in the treatment of infections with viruses of the Flaviviridae Family

摘要

Nucleoside analog compounds that inhibit replication of RNA-dependent viral RNA, compositions comprising these compounds and the use of these compounds for the treatment of viral infection, especially hepatitis C, in an infected host. Claim 1: A compound of the general structural formula (1) wherein X is O, S, SO2, N-R, CH-R, or C-RR; R is H; C1-4 alkyl, C2-4 alkenyl, or C2-4 alkynyl, each of which could be optionally substituted; CN, N3, halo, OH, CONH2, NH2, or amidino; R1 is OH, monophosphate, diphosphate, triphosphate, phosphonate, phosphoryl, a derivative of phosphonate, acyl, hydrogen, alkyl, O-acyl, O-alkyl, O-aryl,O-alcoxialquilo O-ariloxialquilo O- alquilo substituido O-alquenilo substituido O-alquinilo substituido alquilsulfonilo arilsulfonilo alquenilsulfonilo aralquilsulfonilo un residuo amino cido o cualquier substituto divisible que proporcione OH in vivo R2 R3 R4 y R5 cada uno independientemente es H OH SH NH2 halo alquilcarbonilo 1. Halohydrazide, haloalkyl, cyclopentadiene, o-asphalt, o-alkylsulfonyl; o-tar; o-aculo; s-tar; s-alquenilo; s-acilo; NH tar; n (TAR) 2; NH (alquenilo);N (alquenilo) 2; NH (TAR);N (asphalt) 2; NH (ACIO);N (acyl) 2; CONH2; COOH; CONH-alkyl; CON (alkyl) 2; COSH2; COSH-alkyl; COS (alkyl) 2; C1-6-O-C1-6 alkyl; C1-6-O-alkenyl alkyl; C1-6-O-alkynyl alkyl; C1-6-S-alkyl; C1-6-S-alkenyl alkyl; C1-6-S-alkynyl alkyl; CH2CN; or CH2N3; and each of R1 ',R2',R3',R4',R5 'and W independently is H, OH, C1-10 alkylcarbonyl, phosphoryl, phosphonate, phosphinate, phosphonoamidate, Cl, F, Br, I, CN, NO2, N3, NH2, acylamino, amide, amidine, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbonyl, thiocarbonyl, acyl, haloalkyl, haloalkenyl, haloalkynyl, cyclopropyl, sulfonyl, sulfoxide, sulfate, sulphonate, sulfamoyl, sulfonamide, C1-6-O-C1-6 alkyl, C1 alkyl -6-O-alkenyl, C1-6-O-alkynyl alkyl, C1-6-S-alkyl, C1-6-S-alkenyl alkyl, C1-6-S-alkynyl alkyl, CONH2, COOR, CH2CN, or CH2N3; and each R2, R3, R4 and R5 and their corresponding R 'can form a half spiro; each R2 + R3, R3 + R4,Or R4 + R5 can be combined into a ring composed of 3-6 members, among which 1-3 non atoms can be selected; each R2 '+ R3',R3'+R4',O R4 '+ R5' can be independently combined into a ring composed of 3-6 members, and the ring can optionally be composed of 1-3 heteroatoms; it is expected that at least two R2, R3, R4, R5 and W should be oh; it is further predicted that w will be oh only when x is ch-r or c-r-r; and any additional preview of R1, R2 and R3, R4 or R5 is Oh or NH2 followed by R1R2',R3',The corresponding r4'o R5 'cannot be Oh or NH2 at the same time; the reference is selected from the group (2),characterized in that, each occurrence of A, L and T independently is CH, N, C-alkyl, O or S depending on the correct valence; or C-halo, C-C1-6 alkyl, C-C2-6 alkenyl, C-C2-6 alkynyl, C2-6 alkylamino, C-CF3, C-OH, C-NH2, C-NO2, C-CN , C-N3, C-COOR, or C-CONH2; D is CH, C-CN, C-NO2, N, C-C1-6 alkyl, C-CONH2, C-CONH-C1-6 alkyl, C-CON (C1-6 alkyl) (C1-6 alkyl),C-NH2, C-alkoxy, C-OH, C-alkylamino, CC (= NH) NH2, C-COOH, C-COO-alkyl, C-CSNH2, C-CSNH-alkyl, C-CSN (alkyl) 2 , C- di (C1-6 alkyl) amino, C-halo, C-heterocycle, wherein any alkyl is optionally substituted by one to three substitutes selected from the group consisting of alkoxy, hydroxyl, carboxy, halo and amino, and in where the heterocycle is a 5- to 6- membered ring that has one to three heteroatoms; E is N or C-halo, C-C1-6 alkyl, C-C2-6 alkenyl, C-C2-6 alkynyl, C1-6 alkylamino, C-CF3, C-OH, C-NH2, C-NO2, C-CN, C-N3, C-COOR, or C-CONH2; Z is O or S; R6, R7, R8 and R9, each independently is H, OH, SH, NH2, NO2, CN, N3, C1-6 alkyl, C2-6 alkenyl,C2-6 alkynyl, C1-6 alkylamino, di (C1-6 alkyl) amino, C3-6 cycloalkylamino, C3-6 cycloalkyl, halo, C1-6 alkoxy, carboxy, C1-6 alkoxycarbonyl, C1-6 alkylthio, C1 alkylsulfonyl -6, (C1-6 alkyl) 0-2 aminomethyl, or CF3; R10 and R11 each independently is H, OH, SH, NH2, halo, C1-10 alkylcarbonyl, monophosphate, diphosphate, triphosphate, phosphoryl such as phosphate, phosphonate, phosphinate, phosphonoamidate, carbamate, phosphorothioate, phosphorodithioate, carbonyl, thiocarbonyl, aminoacyl , amidine, NO2, CN, N3, sulfonyl, sulfoxide, sulfate, sulfonate, sulfamoyl, sulfonamide, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, acyl, haloalkyl, haloalkenyl, haloalkynyl, cyclopropyl, CONH2,One person or each person or each person or each person or each person or each person or each person - R-R Depending on the appropriate Valencia required, dotted lines indicate the presence of a simple or double-sided link; or a pharmaceutically acceptable salt or salt made, or a stereoscopic / isomerized salt or Taurus form therein.