Inhibitors of viral replication, their process of preparation and their therapeutical uses
The present invention relates to aromatic carbocycle or heterocycle compounds comprising an acid function and being of formula (5), wherein W, Q 1 , Q 2 , Q 3 , Q 4 , R 1 , R 3 , R 4 , R 7 , R 9 , R 11 , a, c, e, and g are as described in the description; and the use of such compounds in the treatment or the prevention of viral disorders, including HIV.
1. A compound of formula (5A)
wherein:
(a) W is a substituted aromatic carbocycle;
(b) R 1 , R 9 , and R 11 are each independently hydrogen, —CN, —OH, —O-cycloalkyl, —O-cycloalkenyl, —O-cycloalkynyl, —NH 2 , —NR 13 -cycloalkyl, —NR 13 -cycloalkenyl, —NR 13 -cycloalkynyl, —S-cycloalkyl, —S-cycloalkenyl, —S-cycloalkynyl, —COOH, —C(O)NH 2 , —CF 3 , —SO 2 NH 2 , —NHSO 2 NH 2 , —NHC(O)NH 2 , —OC(O)NH 2 , halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, —O-aryl, —NR 13 -aryl, —S-aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, —O-heterocycle, —NR 13 -heterocycle, —S-heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl, and are non-substituted or substituted by at least one T 1 ;
wherein a carbon atom or a heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl can be oxidized to form CO═O, C═S, N═O, N═S, S═O or S(O) 2 ;
wherein the aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl group can be fused with at least one carbocycle or heterocycle; and
wherein the alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, or heterocyclyl-alkynyl group can include one or more heteroatoms, selected from O, S and N, in the alkyl, alkenyl, or alkynyl moiety;
(c) R 3 is C 4 -C 20 alkyl, C 4 -C 20 alkenyl, C 4 -C 20 alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl, and is non-substituted or substituted by at least one T 1 ;
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ;
wherein the aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl can be fused with at least one carbocycle or heterocycle; and
wherein the alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, or heterocyclyl-alkynyl group can include one or more heteroatoms, selected from O, S and N, in the alkyl, alkenyl, or alkynyl moiety;
(d) R 4 is —O-alkyl;
(e) R 7 is —CN, —OH, —O-cycloalkyl, —O-cycloalkenyl, —O-cycloalkynyl, —NH 2 , —NR 13 -cycloalkyl, —NR 13 -cycloalkenyl, —NR 13 -cycloalkynyl, —S-cycloalkyl, —S-cycloalkenyl, —S-cycloalkynyl, —COON, —C(O)NH 2 , —CF 3 , —SO 2 NH 2 , —NHSO 2 NH 2 , —NHC(O)NH 2 , —OC(O)NH 2 , halogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, —O-aryl, —NR 13 -aryl, —S-aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, —O-heterocycle, —NR 13 -heterocycle, —S-heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl, and is non-substituted or substituted by at least one T 1 ;
wherein a carbon atom or a heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ;
wherein the aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl group can be fused with at least one carbocycle or heterocycle; and
wherein the alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl-alkyl, heterocyclyl-alkenyl, or heterocyclyl-alkynyl group can include one or more heteroatoms, selected from O, S and N, in the alkyl, alkenyl, or alkynyl moiety;
(f) R 13 is hydrogen, alkyl, aryl or arylalkyl,
wherein a carbon atom of said alkyl or aryl can be oxidized to form C═O or C═S;
each T 1 is independently hydrogen, halogen, —OT 3 , —OCF 3 , ═O, —ST 3 , ═S, —S(O)T 4 , —S(O) 2 T 4 , —S(O) 2 NT 5 T 6 , —CF 3 , —NO 2 , —NT 5 T 6 , —NT 3 S(O) 2 T 4 , CN, —NT 3 C(O)T 4 , —NT 3 C(O)NT 5 T 6 , —C(O)OT 3 , —C(O)NT 5 T 6 , —C(O)T 4 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl is non-substituted or substituted with at least one T 7 ;
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ;
(g) each T 2 is independently hydrogen, halogen, —OT 8 , —OCF 3 , ═O, —ST 8 , ═S, —S(O)T 8 , —S(O) 2 T 9 , —S(O) 2 NT 10 T 11 , —CF 3 , —NO 2 , —NT 10 T 11 , —NT 8 S(O) 2 T 9 , —CN, —NT 8 C(O)T 9 , —NT 8 C(O)NT 10 T 11 , —C(O)OT 8 , —C(O)NT 10 T 11 , —C(O)T 9 , alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl is non-substituted or substituted with at least one T 7 ; and
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylheteroalkyl, arylheteroalkenyl, arylheteroalkynyl, cycloalkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycle, heterocyclyl-alkyl, heterocyclyl-alkenyl, heterocyclyl-alkynyl, heterocyclyl-heteroalkyl, heterocyclyl-heteroalkenyl, or heterocyclyl-heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ;
(h) T 3 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle is non-substituted or substituted with at least one substituent independently selected from —OH, ═O, halogen, —SH, ═S, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 and —C(O)NH 2 ; and
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ;
(i) T 4 is —OH, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle is non-substituted or substituted with at least one substituent independently selected from —OH, ═O, halogen, —SH, ═S, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 and —C(O)NH 2 ; and
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl aryl, or heterocycle can be oxidized to form CO═O, C═S, N═O, N═S, S═O or S(O) 2 ;
(j) T 5 and T 6 :
are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, or heterocycle is non-substituted or substituted with at least one substituent independently selected from —OH, ═O, halogen, —SH, ═S, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 and —C(O)NH 2 ; and
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl aryl, or heterocycle can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ; or
together form a 4, 5, 6 or 7 membered heterocycle that is non-substituted or substituted with an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, —OH, halogen, —SH, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 or —C(O)NH 2 ;
(k) each T 7 is independently an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, —OH, ═O, halogen, —SH, ═S, —CF 3 , —CN, —NO 2 , —COOH, —NH 2 , or —C(O)NH 2 ;
(l) T 8 is hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl is non-substituted or substituted with at least one substitutent independently selected from —OH, ═O, halogen, —SH, ═S, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 and —C(O)NH 2 ; and
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ;
(m) T 9 is —OH, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl can be substituted or non substituted with one or more —OH, ═O, halogen, —SH, ═S, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 or —C(O)NH 2 ,
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ; and
(n) T 10 and T 11 :
are each independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl;
wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl is non-substituted or substituted with at least one substitutent independently selected from —OH, ═O, halogen, —SH, ═S, —CF 3 , —O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 and —C(O)NH 2 ; and
wherein a carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl can be oxidized to form C═O, C═S, N═O, N═S, S═O or S(O) 2 ; or
together form a 4, 5, 6 or 7 membered heterocycle that is non-substituted or substituted with an alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, —OH, halogen, —SH, —CF 3 , O-alkyl, —OCF 3 , —CN, —NO 2 , —C(O)OH, —NH 2 or —C(O)NH 2 .
2. A compound of claim 1 , wherein: R 1 is hydrogen, halogen, —O-aryl, or alkyl; R 3 is 3,4-hydro-2H-1-benopyran, aryl, or cycloalkenyl, non-substituted or substituted by at least one T 1 ; and R 11 is hydrogen or non-substituted or substituted by at least one T 1 .
3. A compound of claim 1 , wherein: R 1 is hydrogen; R 3 is 3,4-hydro-2H-1-benopyran; and R 11 is hydrogen.
4. A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient and at least a pharmaceutically acceptable carrier.
5. A pharmaceutical composition according to claim 4 further comprising a further antiviral agent.
6. A method of treatment of a viral infection comprising administering a compound according to claim 1 to a patient in need thereof.
7. The method according to claim 6 wherein said viral infection is a retroviral infection.
8. The method according to claim 7 wherein said retroviral infection is HIV.
9. A method for the treatment of an HIV infection in a mammal being infected or having a risk to be infected by the HIV comprising administering the pharmaceutical composition according to claim 4 .
10. A method of inhibiting the replication of HIV comprising exposing said HIV to an effective amount of a compound according to claim 1 under conditions where replication of HIV is inhibited.