Compounds of 3H - and 3h tiazolo oxazolo 4, 5 - d pyrimidine ona3 disubstituted 2 -, 5 - and 3, 5, 7 - potency of the Tri substituted compounds with immunomodulatory activity, their prodrugs and Pharmaceutical compositions containing them and their use in the treatment of Viral Diseases

摘要

Compounds of 3H-oxazolo and 3H-thiazolo [4,5-d] pyrimidin-2-one 3,5-disubstituted and 3,5,7-trisubstituted and their prodrugs having immunomodulatory activity, therapeutic or preventive use of such compounds and pharmaceutical compositions containing them and used in the treatment of disease of viral origin. Claim 1: A compound of the formula (1),wherein: X is O or S, Y is O or S, R1 is H, alkyl, aryl, cycloalkyl or heterocyclyl; R2 is NH2, -NHC (O) R4, -NHR5, - N = CHNR6R7, R3 is H, Cl, Br, or OR8, R4 is -C1-7alkyl or -C1-7alkyl, R5 is -C1-7alkyl; R6 and R7 are, independently, -C1-7 alkyl or together with nitrogen form a 5- or 6-membered heterocyclic ring; R8 is -CHR9R10; R9 is H, -C1-7 alkyl, cycloalkyl, aryl, heterocyclyl, -NR11R12, or OR5; R10 is -C1-7 alkyl, cycloalkyl, aryl, heterocyclyl, -NR11R12, or OR5; R11 and R12 are, independently, H, -C1-7 alkyl or -C (O) R4; wherein, when X is O, Y is S, and R3 is H, Cl, Br, or OR8, R1 is not H or beta-D-ribose or its esters;wherein the above alkyl, aryl, cycloalkyl or heterocyclyl moieties are optionally substituted with 1-4 substituents selected from hydrogen; alkanoyl; alkylamine; Not me; aryl, cycloalkyl, heterocyclyl; azido; C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylamine, C1-6 dialkylamine, C2-6 alkenyl or C2-6 alkynyl, wherein each of which may be interrupted by one or several heteroatoms; carboxyl; cyano; halo; hydroxy; mercapto; nitro; thioalkyl; -N = N-NH2; -C (O) 2-C 1-6 alkyl, -C (O) 2-aryl, -C (O) 2-cycloalkyl, -C (O) 2-heterocyclyl, -O-halo-C 1-6 alkyl, -O- (alkyl C1-6l) aryl, -O- (C1-6 alkyl) cycloalkyl,-O- (C1-6 alkyl) heterocyclyl, -O- (C1-6 alkyl) amino, -O- (C1-6 alkyl) alkylamino, -O- (C1-6 alkyl) dialkylamino, -O-C1-6 alkyl -C (O) -amino, -O-C 1-6 alkyl-C (O) -alkylamino, -O-C 1-6 alkyl-S (O) 2-amino, -O-C 1-6 alkyl-S (O) 2- alkylamino, -O-C 1-6 alkyl-S (O) 2- dialkylamino, -O-C 1-6 alkyl-C (O) -dialkylamino, -O-aryl, -O-heterocyclyl, -NHC (O) -C 1-6 alkyl , -NHC (O) -C 1-6 alkenyl, -NHC (O) -aryl, -NHC (O) -cycloalkyl, -NHC (O) -heterocyclyl, -NHC (O) - (C 1-6 alkyl) aryl, - NHC (O) - (C1-6 alkyl) cycloalkyl, - NHC (O) - (C1-6 alkyl) heterocyclyl, -NHC (O) - (C1-6 alkyl) amino, -NHC (O) - (C1 alkyl -6) alkylamine, -NHC (O) - (C1-6 alkyl) dialkylamine, -NHC (O) -C1-6C (O) amino, -NHC (O) -C1-6C (O) alkylamine,-NHC (O) -C 1-6 alkyl (O) dialkylamine, -NHC (O) - C 1-6 alkyl (H) -C 1-6 alkyl (O) 2-C 1-6 alkyl, -NH-C 1-6 alkyl (O) -amino, -NH-C1-6-C (O) -alkylamino, -NH-C1-6-C-alkyl (O) -dialkylamino, -NHC (O) -C1-6S alkyl (O) 2C1-6 alkyl, -NHC ( O) -C 1-6 alkyl-S-heterocyclyl, -NHS (O) 2-C 1-6 alkyl, -NHS (O) 2-aryl, - NH-C 1-6 alkyl-S (O) 2-amino, -NH-C 1 alkyl -6-S (O) 2-alkylamino, -NH-C 1-6 alkyl-S (O) 2-dialkylamino, -NHS (O) 2-cycloalkyl, -NHS (O) 2-heterocyclyl, -NHS (O) C 1 alkyl -6, -NHS (O) aryl, -NHS (O) cycloalkyl, -NHS (O) heterocyclyl, -NHSalkylC1-6, -NHSaryl, -NHScycloalkyl, and -NH-S-heterocyclyl;wherein each of the above substituents may also be optionally substituted with 1-5 substituents selected from: amino; C1-6 alkylamine, C1-6 dialkylamine; C1-6 alkyl, C1-6 alkoxy, C1-6 alkenyl, C1-6 hydroxyl, and C1-6 hydroxyalkyl, each optionally substituted with: cyano; halo; and nitro; or one of its pharmaceutically acceptable salts or hydrates. Claim 8: A compound of the formula (2),where: X is O or S, Y is O or S, Z is O or CH2; R2 is -NH2, -NHC (O) R4, -NHR5, -N = CHNR6R7, R4 is -C1-7 alkyl or -C1-7 alkyl, R5 is -C1-7 alkyl; R6 and R7 are, independently, -C1-7 alkyl or together with nitrogen form a 5- or 6-membered heterocyclic ring; R13 is OH or SH; R14 is H, -CH2OH or -CH2-O-C (O) C1-18 alkyl; R15 is OH, alkenyl, -OC (O) C1-18 alkyl, -OC (O) aryl or -OC (O) heterocyclyl; R16, 17, R18, and R19 are, independently, H, halo, N3, alkyl, - (CH2) mOR20, - (CH2) mOC (O) C1-18 alkyl, - OC (O) aryl, -OS ( O) 2aryl or R16 and R17 are an alkenyl or R17 and R19 combine to form a dioxol ring; R20 is H or alkyl; m is 0 or 1; n is 1 or 2; where when R2 is NH2,then one of the following must be present: Z is CH2; n is 2 or m is 1; at least R16, R17, R18, and R19 is halo, N3, alkyl or - (CH2) mOR20, where m is 1, and where when R17 is N3, then R18 and R19 are not H, and where when R17 is OH and R16 and R19 are H, R18 is not F; or R16 and R17 are an alkenyl; wherein the alkyl, aryl, cycloalkyl or heterocyclyl moieties are optionally substituted with 1-4 substituents selected from hydrogen; alkanoyl; alkylamine; Not me; aryl, cycloalkyl, heterocyclyl; azido; C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkylamine, C 1-6 dialkylamine, C 2-6 alkenyl or C 2-6 alkynyl,wherein each of which may be interrupted by one or more heteroatoms; carboxyl; cyano; halo; hydroxy; mercapto; nitro; thioalkyl; -N = N-NH2; -C (O) 2-C 1-6 alkyl, -C (O) 2-aryl, -C (O) 2-cycloalkyl, -C (O) 2-heterocyclyl, -O-halo-C 1-6 alkyl, -O- (alkyl C1-6l) aryl, -O- (C1-6 alkyl) cycloalkyl, -O- (C1-6 alkyl) heterocyclyl, -O- (C1-6 alkyl) amino, -O- (C1-6 alkyl) alkylamino, -O- (C1-6 alkyl) dialkylamino, -O-C1-6-C-alkyl (O) -amino, -O-C1-6-C-alkyl (O) -alkylamino, -O-C1-6-S-alkyl (O) 2-amino, -O-C 1-6 alkyl-S (O) 2-alkylamino, -O-C 1-6 alkyl-S (O) 2-dialkylamino, -O-C 1-6 alkyl-C (O) -dialkylamino, -O -aryl, -O- heterocyclyl, -NHC (O) -C1-6 alkyl, -NHC (O) -C1-6 alkenyl,-NHC (O) -aryl, -NHC (O) -cycloalkyl, -NHC (O) -heterocyclyl, -NHC (O) - (C1-6 alkyl) aryl, -NHC (O) - (C1-6 alkyl) cycloalkyl, -NHC (O) - (C1-6 alkyl) heterocyclyl, -NHC (O) - (C1-6 alkyl) amino, - NHC (O) - (C1-6 alkyl) alkylamine, -NHC (O) - (C1-6 alkyl) dialkylamine, -NHC (O) -C1-6C alkyl (O) amino, -NHC (O) -C1-6C alkyl (O) alkylamine, -NHC (O) -C1-6C alkyl (O) dialkylamine, -NHC (O) -C 1-6 alkyl (H) -C 1-6 alkyl (O) 2-C 1-6 alkyl, -NH-C 1-6 alkyl (O) -amino, - NH-C 1-6 alkyl-C (O) -alkylamino, -NH-C1-6-C (O) -dialkylamino, -NHC (O) -C1-6S (O) 2C1-6 alkyl, -NHC (O) -C1-6-S-heterocyclyl, -NHS ( O) 2-C 1-6 alkyl, -NHS (O) 2-aryl, -NH-C 1-6 alkyl-S (O) 2-amino, -NH-C 1-6 alkyl-S (O) 2-alkylamino,-NH- C1-6-S (O) 2-dialkylamino, -NHS (O) 2-cycloalkyl, -NHS (O) 2-heterocyclyl, -NHS (O) C1-6 alkyl, -NHS (O) aryl, - NHS (O) cycloalkyl, -NHS (O) heterocyclyl, -NHSalkylC1-6, -NHSaryl, -NHScycloalkyl, and -NH-S-heterocyclyl; wherein each of the above substituents may also be optionally substituted with 1-5 substituents selected from: amino; C1-6 alkylamine, C1-6 dialkylamine; C1-6 alkyl, C1-6 alkoxy, C1-6 alkenyl, C1-6 hydroxyl, and C1-6 hydroxyalkyl, each optionally substituted with: cyano; halo; and nitro; or one of its pharmaceutically acceptable salts, hydrates or tautomers.