5,5-fused arylene or heteroarylene hepatitis C virus inhibitors
Provided herein are 5,5-fused heteroarylene hepatitis C virus inhibitor compounds, for example, of Formula I, IA, or IB, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.
1. A compound of Formula IIIB:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein:
U 1 , W 2 , X 1 , and X 2 are each C;
U 2 and W 1 are each S;
V 1 and V 2 are each independently CR 3a ;
R 1 and R 2 are each independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)CH(NR 1b R 1c )R 1a , —C(O)CH(N(R 1c )C(O)R 1b )R 1a , —C(O)CH(N(R 1c )C(O)OR 1b )R 1a , —C(O)CH(N(R 1c )C(O)NR 1b R 1d )R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —P(O)(OR 1a )R 1d , —CH 2 P(O)(OR 1a )R 1d , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
each R 3a is independently hydrogen or R 3 ;
each R 3 , R 5 , and R 6 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or
two R 5 or two R 6 that are attached to the same ring are linked together to form a bond, —O—, —NR 7 —, —S—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
L 1 and L 2 are each independently selected from:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 ; the star (*) on each moiety represents the point of attachment thought which the moiety is connected to U 1 or W 2 of
and the zigzag line on each moiety represents the point of attachment through which the moiety is connected to
and wherein T 3 is a bond, C, N, O, S, CR 3a , or NR 3a ; U 3 , V 3 , W 3 , and X 3 are each independently C, N, O, S, CR 3a , or NR 3a ; and Y 3 is C or N;
Z 1 and Z 2 are each a bond;
each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;
n is an integer of 2, 3, 4, 5, 6, or 7;
p is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;
q and r are each independently an integer of 1, 2, 3, or 4; and
s, t, and u are each an integer of 1; and
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.
2. The compound of claim 1 , having the structure of Formula IIIBa:
3. The compound of claim 2 , having the structure of Formula IIIBd:
wherein each R 1e is independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (c) —C(O)R 1b , C(O)OR 1b , or —C(O)NR 1b R 1d .
4. The compound of claim 1 , having the structure of Formula IC:
5. The compound of claim 4 , having the structure of Formula ICa:
6. The compound of claim 5 , having the structure of Formula ICd:
wherein each R 1e is independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (c) —C(O)R 1b , —C(O)OR 1b , or —C(O)NR 1b R 1d .
7. The compound of claim 1 , wherein L 1 and L 2 are each independently selected from the group consisting of:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 ; the star (*) on each moiety represents the point of attachment through which the moiety is connected to U 1 or W 2 of
and the zigzag line on each moiety represents the point of attachment through which the moiety is connected to
8. The compound of claim 7 , wherein L 1 and L 2 are each independently selected from the group consisting of:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 .
9. A compound of Formula IIC:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein:
R 1 and R 2 are each independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)CH(NR 1b R 1c )R 1a , —C(O)CH(N(R 1c )C(O)R 1b )R 1a , —C(O)CH(N(R 1c )C(O)OR 1b )R 1a , —C(O)CH(N(R 1c )C(O)NR 1b R 1d )R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —P(O)(OR 1a )R 1d , —CH 2 P(O)(OR 1a )R 1d , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
each R 3 , R 5 , and R 6 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or
two R 5 or two R 6 that are attached to the same ring are linked together to form a bond, —O—, —NR 7 —, —S—C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
L 1 is independently selected from:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 ; the star (*) on each moiety represents the point of attachment thought which the moiety is connected to the thieno[3,2-b]thienyl moiety; and the zigzag line on each moiety represents the point of attachment through which the moiety is connected to
and wherein T 3 is a bond, C, N, O, S, CR 3a , or NR 3a ; U 3 , V 3 , W 3 , and X 3 are each independently C, N, O, S, CR 3a , or NR 3a ; and Y 3 is C or N;
Z 1 and Z 2 are each a bond;
each R 1a , R 1b R 1c , and R 1d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;
n and p are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7;
q and r are each independently an integer of 1, 2, 3, or 4; and
s and t are each an integer of 1;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.
10. The compound of claim 9 , having the structure of Formula IICa:
11. The compound of claim 9 , having the structure of Formula IICd:
wherein each R 1e is independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (c) —C(O)R 1b , —C(O)OR 1b , or —C(O)NR 1b R 1d .
12. The compound of claim 9 , wherein R 1 is —C(O)R 1a , —C(O)CH(NR 1b R 1c )R 1a , —C(O)CH[N(C(O)R 1b )R 1c ]R 1a , —C(O)CH[N(C(O)OR 1b )R 1c ]R 1a , or —C(O)CH[N(C(O)NR 1d R 1b )R 1c ]R 1a .
13. The compound of claim 12 , wherein R 1 is —C(O)CH[N(C(O)OR 1b )R 1c ]R 1a .
14. The compound of claim 9 , wherein R 2 is —C(O)R 1a , —C(O)CH(NR 1b R 1c )R 1a , —C(O)CH[N(C(O)R 1b )R 1c ]R 1a , —C(O)CH[N(C(O)OR 1b )R 1c ]R 1a , or —C(O)CH[N(C(O)NR 1d R 1b )R 1c ]R 1a .
15. The compound of claim 14 , wherein R 2 is —C(O)CH[N(C(O)OR 1b )R 1c ]R 1a .
16. The compound of claim 11 , wherein each R 1e is independently hydrogen or —C(O)OR 1b .
17. The compound of claim 11 , wherein each R 1a is independently hydrogen, methyl, isopropyl, 2-methylpropyl, 1-methylpropyl, 2-methylthioethyl, phenyl, benzyl, 3-indolylmethyl, hydroxymethyl, 1-hydroxyethyl, sulfhydrylmethyl, 4-hydroxybenzyl, aminocarbonylmethyl, 2-(aminocarbonyl)ethyl, carboxymethyl, 2-carboxyethyl, 4-aminobutyl, 3-guanidinopropyl, or 5-imidazolylmethyl.
18. The compound of claim 16 , wherein R 1b is methyl, ethyl, propyl, or butyl.
19. The compound of claim 11 , wherein R 1c is hydrogen.
20. The compound of claim 1 , wherein each R 3a is independently hydrogen, oxo, chloro, fluoro, nitro, amino, hydroxy, methyl, trifluoromethyl, cyclohexyl, phenyl, methoxy, or methoxycarbonyl.
21. The compound of claim 1 , wherein each R 3 is independently oxo, chloro, fluoro, nitro, amino, hydroxy, methyl, trifluoromethyl, cyclohexyl, phenyl, methoxy, or methoxycarbonyl.
22. The compound of claim 9 , wherein n is 0.
23. The compound of claim 1 , wherein two R 5 groups are linked together to form C 1-6 alkylene, optionally substituted with one or more substituents Q.
24. The compound of claim 1 , wherein two R 5 groups are linked together to form methylene or ethylene.
25. The compound of claim 1 , wherein q is 1 or 2.
26. The compound of claim 9 , wherein the moiety
has the structure of:
27. The compound of claim 9 , wherein p is 0.
28. A compound of Formula IIIB:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein:
U 1 , W 2 , X 1 , and X 2 are each C;
U 2 and W 1 are each S;
V 1 and V 2 are each independently CR 3a ;
R 1 and R 2 are each independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)CH(NR 1b R 1c )R 1a , —C(O)CH(N(R 1c )C(O)R 1b )R 1a , —C(O)CH(N(R 1c )C(O)OR 1b )R 1a , —C(O)CH(N(R 1c )C(O)NR 1b R 1d )R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —P(O)(OR 1a )R 1d , —CH 2 P(O)(OR 1a )R 1d , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
each R 3a is independently hydrogen or R 3 ;
each R 3 , R 5 , and R 6 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —N 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or
two R 5 or two R 6 that are attached to the same ring are linked together to form a bond, —O—, —NR 7 —, —S—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
L 1 and L 2 are each independently selected from:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 ; the star (*) on each moiety represents the point of attachment thought which the moiety is connected to U 1 or W 2 of
and the zigzag line on each moiety represents the point of attachment through which the moiety is connected to
and wherein T 3 is a bond, C, N, O, S, CR 3a , or NR 3a ; U 3 , V 3 , W 3 , and X 3 are each independently C, N, O, S, CR 3a , or NR 3a ; and Y 3 is C or N;
Z 1 and Z 2 are each a bond;
each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;
n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;
p is an integer of 2, 3, 4, 5, 6, or 7;
q and r are each independently an integer of 1, 2, 3, or 4; and
s, t, and u are each an integer of 1;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or in R f and R g to ether with the N atom to which they are attached form heterocyclyl.
29. The compound of claim 28 , wherein two R 6 groups are linked together to form C 1-6 alkylene, optionally substituted with one or more substituents Q.
30. The compound of claim 29 , wherein two R 6 groups are linked together to form methylene or ethylene.
31. The compound of claim 28 , wherein r is 1 or 2.
32. The compound of claim 9 , wherein the moiety
has the structure of:
33. The compound of claim 9 , selected from the group consisting of:
and isotopic variants thereof; and pharmaceutically acceptable salts, and prodrugs thereof.
34. A pharmaceutical composition comprising the compound of claim 9 and one or more pharmaceutically acceptable carriers.
35. The pharmaceutical composition of claim 34 , further comprising an antiviral agent.
36. The pharmaceutical composition of claim 35 , wherein the antiviral agent is selected from the group consisting of an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, and a ribozyme.
37. The pharmaceutical composition of claim 36 , wherein the antiviral agent is an interferon.
38. The pharmaceutical composition of claim 37 , wherein the interferon is selected from the group consisting of pegylated interferon alpha 2a, interferon alfahcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, and interferon gamma-1b.
39. The pharmaceutical composition of claim 34 , wherein the composition is formulated for single dose administration.
40. The pharmaceutical composition of claim 34 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
41. The pharmaceutical composition of claim 40 , wherein the oral dosage form is a tablet or capsule.
42. The pharmaceutical composition of claim 34 , wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.
43. The compound of claim 9 , wherein L 1 is independently selected from the group consisting of:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 ; the star (*) on each moiety represents the point of attachment through which the moiety is connected to U 1 or W 2 of
and the zigzag line on each moiety represents the point of attachment through which the moiety is connected to
44. The compound of claim 9 , wherein L 1 is independently selected from the group consisting of:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 .
45. The compound of claim 9 , wherein n is an integer of 2 or more.
46. The compound of claim 45 , wherein two R 5 groups are linked together to form C 1-6 alkylene, optionally substituted with one or more substituents Q.
47. The compound of claim 45 , wherein two R 5 groups are linked together to form methylene or ethylene.
48. The compound of claim 9 , wherein q is 1 or 2.
49. The compound of claim 9 , wherein p is an integer of 2 or more.
50. The compound of claim 49 , wherein two R 6 groups are linked together to form C 1-6 alkylene, optionally substituted with one or more substituents Q.
51. The compound of claim 49 , wherein two R 6 groups are linked together to form methylene or ethylene.
52. The compound of claim 9 , wherein r is 1 or 2.
53. A compound of Formula IIIB:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein:
U 1 , W 2 , X 1 , and X 2 are each C;
U 2 and W 1 are each S;
V 1 and V 2 are each independently CR 3a ;
R 1 and R 2 are each independently (a) hydrogen; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)CH(NR 1b R 1c )R 1a , —C(O)CH(N(R 1c )C(O)R 1b )R 1a , —C(O)CH(N(R 1c )C(O)OR 1b )R 1a , —C(O)CH(N(R 1c )C(O)NR 1b R 1d )R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —P(O)(OR 1a )R 1d , —CH 2 P(O)OR 1a )R 1d , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
each R 3a is independently hydrogen or R 3 ;
each R 3 , R 5 , and R 6 is independently (a) cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(NR 1a )NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(═NR 1a )NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or
two R 5 or two R 6 that are attached to the same ring are linked together to form a bond, —O—, —NR 7 —, —S—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 heteroalkenylene;
L 1 and L 2 are each independently selected from:
a bond,
wherein each moiety is optionally substituted with one, two, three, or four R 3 ; the star (*) on each moiety represents the point of attachment thought which the moiety is connected to U 1 or W 2 of
and the zigzag line on each moiety represents the point of attachment through which the moiety is connected to
and wherein T 3 is a bond, C, N, O, S, CR 3a , or NR 3a ; U 3 , V 3 , W 3 , and X 3 are each independently C, N, O, S, CR 3a , or NR 3a ; and Y 3 is C or N;
Z 1 and Z 2 are each a bond;
R 1a and R 1c together with the C and N atoms to which they are attached form pyrrolidinyl;
each R 1b and R 1d is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;
n and p are each independently an integer of 0, 1, 2, 3, 4, 5, 6, or 7;
q and r are each independently an integer of 1, 2, 3, or 4; and
s, t, and u are each an integer of 1;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(NR a )NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(═NR a )NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(═NR d )NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR b R c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(NR e )NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(═NR e )NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(═NR h )NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.