NOVEL VIRAL REPLICATION INHIBITORS

摘要

The present invention relates to a series of novel compounds, methods to prevent or treat viral infections in animals by using the novel compounds and to said novel compounds for use as a medicine, more preferably for use as a medicine to treat or prevent viral infections, particularly infections with RNA viruses, more particularly infections with viruses belonging to the family of the Flaviviridae, and yet more particularly infections with the Dengue virus. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of viral infections. The invention also relates to processes for preparation of the compounds.;

主权项

1. A compound of formula (A),wherein,
cycle A is selected from the group consisting of cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; and heterocycle; wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and heterocycle, can be unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH, —NH2, NH(alkyl), or N(alkyl)2; cycle C is a monocycle selected fromwherein the wavy line () indicates the point of attachment to the carbonyl of the main formula (A) and the hashed line () indicates the point of attachment to the cycle A of the main formula (A);
X1 is selected from C; and N; X2 is selected from CR12; NR13; N; O; and S; X3 is selected from CR14, NR15; N; O; and S; X4 is selected from CR16, NR17; N; O; and S; each R9 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; ═O; and ═S; wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH or NH2; W1 is selected from CR32R32a; NR33; O; S; and SO2; each p and q is independently selected from 1 and 2, whereby p+q is selected from 2 and 3; cycle B is selected from aryl; and heterocycle; wherein said aryl and heterocycle can be unsubstituted or substituted with one or more Z1a; R1 is selected from cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; heterocycle-heteroalkynyl;
and wherein said cycloalkyl; cycloalkenyl; cycloalkynyl; aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl and heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more Z1b; R2 is selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl;
and wherein said alkyl, cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl, heteroalkenyl, and heteroalkynyl, can be unsubstituted or substituted with one or more Z1c; each R12, R14, and R16 is independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; trifluoromethyl; trifluoromethoxy; nitro; amino; cyano; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl;
wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, and heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH or NH2; R13, R15, and R17 is independently selected from hydrogen; hydroxyl; sulfhydryl; —S(O)Z2; —S(O)2Z3; —S(O)2NZ4Z5; trifluoromethyl; —C(O)Z3; —C(O)OZ2; —C(O)NZ4Z5; —C(O)H; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl;
wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH or NH2; each R32 and R32a is independently selected from hydrogen; halogen; hydroxyl; sulfhydryl; ═O; ═S; trifluoromethyl; trifluoromethoxy; cyano; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, can be unsubstituted or substituted with one or more substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH or NH2; each R33 is independently selected from hydrogen; alkyl; alkenyl; alkynyl; heteroalkyl; heteroalkenyl; and heteroalkynyl; and wherein said alkyl, alkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, can be unsubstituted or substituted with one or more substituents selected from hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH or NH2; each Z1a, Z1b, and Z1c is independently selected from the group consisting of halogen; hydroxyl; sulfhydryl; —OZ2; ═O; —SZ2; ═S; —S(O)Z2; —S(O)2Z3; —S(O)2NZ4Z5; trifluoromethyl; trifluoromethoxy; nitro; —NZ4Z5; —NZ4S(O)2Z2; —NZ4C(O)Z2; —NZ4C(O)NZ4Z5; cyano; —C(O)Z3; —C(O)OZ2; —C(O)NZ4Z5; —C(O)H; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl, heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
and wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —OCF3, cyano, nitro, —C(O)OH or NH2; each Z2 is independently selected from alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —C(O)OH or NH2; each Z3 is independently selected from hydroxyl; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —C(O)OH or NH2; each Z4 and Z5 is independently selected from hydrogen; alkyl; cycloalkyl; alkenyl; cycloalkenyl; alkynyl; cycloalkynyl; heteroalkyl; heteroalkenyl; heteroalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl; arylheteroalkyl; arylheteroalkenyl; arylheteroalkynyl; heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; heterocycle-heteroalkyl; heterocycle-heteroalkenyl; or heterocycle-heteroalkynyl;
wherein said alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, heterocycle-alkyl, heterocycle-alkenyl, heterocycle-alkynyl, heterocycle-heteroalkyl, heterocycle-heteroalkenyl, or heterocycle-heteroalkynyl can be unsubstituted or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, hydroxyl, ═O, halogen, —SH, ═S, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —C(O)OH or NH2; and wherein Z4 and Z5 can be taken together in order to form a (5-, 6-, or 7-membered) heterocycle which can be unsubstituted or substituted with alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF3, cyano, nitro, —C(O)OH or —NH2; and isomers (in particular stereo-isomers or tautomers), solvates, salts (in particular pharmaceutically acceptable salts) or prodrugs thereof,
with the proviso that said compound is not2-anilino-2-(4-tert-butylphenyl)-1-(2-phenyl-1-piperidyl)ethanone;2-anilino-1-(2-phenyl-1-piperidyl)-2-[4-(trifluoromethyl)phenyl]ethanone;2-anilino-2-(4-tert-butylphenyl)-1-(2-phenylazepan-1-yl)ethanone.