Methods and compositions of treating a
Briefly described, embodiments of this disclosure include compounds, pharmaceutical compositions, methods of treating a host infected with a virus from the Flaviviridae family of viruses, methods of inhibiting HCV replication in a host, methods of inhibiting the binding of NS4B polypeptide to the 3′UTR of HCV negative strand RNA in a host, methods of treating liver fibrosis in a host, and the like.
1. A compound having the structure shown in Formula II-a, or a pharmaceutically acceptable salt or a stereoisomer thereof:
wherein R 1 is
wherein V is selected from the group consisting of alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl, and m is 0, 1 or 2;
R 3 is —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is selected from the group consisting of: —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O-alkyl, —O-aryl, —SO 2 (alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), NHSO 2 (alkyl),
each of R 4 -R 7 are independently selected from the group consisting of: —H, —Br, —Cl, —F, —I, —CH 3 , —CN, —OH, —OCH 3 , —NO 2 , —NH 2 , —NHCO(alkyl), —NHCO(aryl),
or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together with a bond to form a 5, 6, or 7-membered ring; or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together to form a 1,2-(methylenedioxy)benzene ring system; provided that the compound of Formula II-a is not
2. The compound of claim 1 , wherein R 1 is
and V is aryl.
3. The compound of claim 1 , wherein R 3 is —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is —NH 2 , —NH(alkyl), —N(alkyl) 2 , or —OH.
4. The compound of claim 1 , wherein R 3 is selected from the group consisting of: —O(CH 2 ) 2 NMe 2 , —O(CH 2 ) 2 NEt 2 , —O(CH 2 ) 3 NEt 2 ,
5. The compound of claim 1 , wherein R 1 is —CH 2 V, wherein V is selected from cycloalkyl, heterocyclo, or heteroaryl.
6. The compound of claim 1 , wherein R 4 and R 7 are both hydrogen, and R 5 and R 6 are both a substituent other than hydrogen.
7. A pharmaceutical composition comprising a compound as shown in Formula II-a, or a pharmaceutically acceptable salt, a stereoisomer a tautomer, or a prodrug thereof:
wherein R 1 is
wherein V is selected from the group consisting of: alkyl, cycloalkyl, heterocyclo, aryl, and heteroaryl, and m is 0, 1 or 2;
R 3 is —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is selected from the group consisting of: —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O-alkyl, —O-aryl, —SO 2 (alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), NHSO 2 (alkyl)
each of R 4 -R 7 are independently selected from the group consisting of: —H, —Br, —Cl, —F, —I, —CH 3 , —CN, —OH, —OCH 3 , —NO 2 , —NH 2 , —NHCO(alkyl), —NHCO(aryl),
or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together with a bond to form a 5, 6, or 7 -membered ring; or optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together to form a 1,2-(methylenedioxy)benzene ring system; provided that the compound of Formula II-a is not
8. A compound having the structure shown in Formula III
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or a prodrug thereof, wherein
m is 1 or 2;
V is an unsubstituted or a monosubstituted phenyl, cyclohexyl, or a 6-membered heterocyclo group, where the heterocyclo group contains 1 nitrogen atom;
R 3 is —O-L-X;
L is an unsubstituted or a monosubstituted C 1 -C 5 alkylene;
X is selected from the group consisting of: —N(R 20 ) 2 , 4-substituted phenyl;
R 5 is hydrogen, alkyl, halo, a substituted or an unsubstituted 5, 6, 7 membered heterocyclo, or —NR 21 R 22 ;
each R 20 is independently selected from a substituted or an unsubstituted C 1 -C 3 alkyl;
R 21 and R 22 are each independently selected from hydrogen, a substituted or an unsubstituted C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl group, —COR 16 , or —SO 2 R 16 , or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5-7 membered substituted or unsubstituted heterocyclo group; and
R 16 is substituted or unsubstituted C 1 -C 3 alkyl.
9. The compound of claim 8 , wherein m is 1.
10. The compound of claim 8 , wherein
X is selected from the group consisting of: a 5, 6, or 7 membered non aromatic heterocyclo that is unsubstituted or is substituted with 1 or 2 —OH, C 1 -C 3 alkoxy, —CO 2 R 17 , or —CON(R 18 ) 2 , a substituted or an unsubstituted 5 or 6 membered aryl or heteroaryl group, a C 1 -C 3 alkyl, and a C 1 -C 3 alkyl substituted with —OH, C 1 -C 3 alkoxy, —CO 2 R 17 , —NR 23 R 24 , or —CO 2 H;
R 17 is a substituted or an unsubstituted C 1 -C 6 alkyl;
each R 18 is independently selected from hydrogen or a substituted or an unsubstituted C 1 -C 3 alkyl; and
R 23 and R 24 are each independently selected from hydrogen, a substituted or an unsubstituted aryl, heteroaryl, or C 1 -C 3 alkyl, or R 23 and R 24 together with the nitrogen atom they are attached form a substituted or an unsubstituted 5-7 membered non aromatic heterocycle.
11. The compound of claim 10 , wherein X is 1-pyrrolidinyl that is unsubstituted or substituted with 1 or 2 —OH, C 1 -C 3 alkoxy, a substituted or an unsubstituted 6 membered aryl, a C 1 -C 3 alkyl, or a C 1 -C 3 alkyl substituted with —OH, C 1 -C 3 alkoxy, or —NR 23 R 24 .
12. The compound of claim 10 , wherein X is a substituted or an unsubstituted piperidinyl or a 7-membered non aromatic heterocyclo group where the 7-membered non aromatic heterocyclo group contains 1 nitrogen atom.
13. The compound of claim 8 , wherein L is —(CH 2 ) n — and n is 1, 2, 3, or 4.
14. The compound of claim 13 , wherein V is 4-chlorophenyl or 4-isopropylphenyl.
15. The compound of claim 13 , wherein V is 4-chlorophenyl.
16. The compound of claim 13 , wherein R 5 is hydrogen, halo, a substituted or an unsubstituted 5, 6, 7 membered heterocyclo, or —NR 21 R 22 .
17. A pharmaceutical composition comprising the compound as shown in formula III and a pharmaceutically acceptable carrier, excipient, or diluent:
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or a prodrug thereof, wherein m is 1 or 2;
V is an unsubstituted or a monosubstituted phenyl, cyclohexyl, or a 6-membered heterocyclo group, where the heterocyclo group contains 1 nitrogen atom;
R 3 is —O-L-X;
L is an unsubstituted or a monosubstituted C 1 -C 5 alkylene;
X is selected from the group consisting of: —N(R 20 ) 2 , 4-substituted phenyl,
R 5 is hydrogen, alkyl, halo, a substituted or an unsubstituted 5, 6, 7 membered heterocyclo, or —NR 21 R 22 ;
each R 20 is independently selected from a substituted or an unsubstituted C 1 -C 3 alkyl;
R 21 and R 22 are each independently selected from hydrogen, a substituted or an unsubstituted C 1 -C 3 alkyl, C 3 -C 8 cycloalkyl, aryl, heteroaryl group, —COR 16 , or —SO 2 R 16 , or R 21 and R 22 together with the nitrogen atom to which they are attached form a 5-7 membered substituted or unsubstituted heterocyclo group; and
R 16 is substituted or unsubstituted C 1 -C 3 alkyl.
18. A compound having the structure shown in Formula II-a, or a pharmaceutically acceptable salt or a stereoisomer thereof:
wherein R 1 is —H;
R 3 is selected from the group consisting of: —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O-alkyl, —O-aryl, —SO 2 (alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), NHSO 2 (alkyl),
each of R 4 -R 7 are independently selected from the group consisting of: —H, —Br, —CI, —F, —I, —CH 3 , —CN, -OH, -OCH 3 , —NO 2 , —NH 2 , —NHCO(alkyl), —NHCO(aryl),
or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together with a bond to form a 5, 6, or 7-membered ring; or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together to form a 1,2-(methylenedioxy)benzene ring system; provided that the compound of Formula II-a is not
19. A pharmaceutical composition comprising a compound as shown in Formula II-a, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a prodrug thereof:
wherein R 1 is selected from the group consisting of: —H;
R 3 is selected from the group consisting of: —OH, —O(CH 2 ) n X, or —(CH 2 ) n X, wherein n is 1, 2, 3, or 4, and X is —NH 2 , —NH(alkyl), —N(alkyl) 2 , —OH, —O-alkyl, —O-aryl, —SO 2 (alkyl), —SO 2 NH 2 , —SO 2 NH(alkyl), NHSO 2 (alkyl),
each of R 4 -R 7 are independently selected from the group consisting of: —H, —Br, —CI, —F, —I, —CH 3 , —CN, —OH, —OCH 3 , —NO 2 , —NH 2 , —NHCO(alkyl), —NHCO(aryl),
or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together with a bond to form a 5, 6, or 7-membered ring; or, optionally, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are joined together to form a 1,2-(methylenedioxy)benzene ring system; provided that the compound of Formula II-a is not
20. The composition of claim 19 , further comprising an NS3 protease inhibitor.
21. The composition of claim 19 , further comprising an NS5A inhibitor.
22. The composition of claim 19 , further comprising an NS3 helicase inhibitor.
23. The composition of claim 19 , further comprising a therapeutic agent that is selected from the group consisting of: an HCV NS5B RNA-dependent RNA polymerase inhibitor and a nucleoside analog.
24. The composition of claim 19 , further comprising a therapeutic agent that is selected from the group consisting of: a thiazolide and a sustained release thiazolide.
25. The composition of claim 19 , further comprising a therapeutic agent that is selected from the group consisting of: an interferon-alpha and a pegylated interferon.
26. The composition of claim 19 , further comprising a therapeutic agent that is selected from the group consisting of: ribavirin, levovirin, and viramidine.
27. The composition of claim 19 , further comprising a TLR7 agonist.
28. The composition of claim 19 , further comprising a TLR9 agonist.
29. The composition of claim 19 , further comprising a cyclophilin inhibitor.
30. The composition of claim 19 , further comprising an alpha-glucosidase inhibitor.
31. The composition of claim 7 , further comprising an NS3 protease inhibitor.
32. The composition of claim 7 , further comprising an NS5A inhibitor.
33. The composition of claim 7 , further comprising an NS3 helicase inhibitor.
34. The composition of claim 7 , further comprising a therapeutic agent that is selected from the group consisting of: an HCV NS5B RNA-dependent RNA polymerase inhibitor and a nucleoside analog.
35. The composition of claim 7 , further comprising a therapeutic agent that is selected from the group consisting of: a thiazolide and a sustained release thiazolide.
36. The composition of claim 7 , further comprising a therapeutic agent that is selected from the group consisting of: an interferon-alpha and a pegylated interferon.
37. The composition of claim 7 , further comprising a therapeutic agent that is selected from the group consisting of: ribavirin, levovirin, and viramidine.
38. The composition of claim 7 , further comprising a TLR7 agonist.
39. The composition of claim 7 , further comprising a TLR9 agonist.
40. The composition of claim 7 , further comprising a cyclophilin inhibitor.
41. The composition of claim 7 , further comprising an alpha-glucosidase inhibitor.
42. The composition of claim 17 , further comprising an NS3 protease inhibitor.
43. The composition of claim 17 , further comprising an NS5A inhibitor.
44. The composition of claim 17 , further comprising an NS3 helicase inhibitor.
45. The composition of claim 17 , further comprising a therapeutic agent that is selected from the group consisting of: an HCV NS5B RNA-dependent RNA polymerase inhibitor and a nucleoside analog.
46. The composition of claim 17 , further comprising a therapeutic agent that is selected from the group consisting of: a thiazolide and a sustained release thiazolide.
47. The composition of claim 17 , further comprising a therapeutic agent that is selected from the group consisting of: an interferon-alpha and a pegylated interferon.
48. The composition of claim 17 , further comprising a therapeutic agent that is selected from the group consisting of: ribavirin, levovirin, and viramidine.
49. The composition of claim 17 , further comprising a TLR7 agonist.
50. The composition of claim 17 , further comprising a TLR9 agonist.
51. The composition of claim 17 , further comprising a cyclophilin inhibitor.
52. The composition of claim 17 , further comprising an alpha-glucosidase inhibitor.
53. A compound having the structure shown below, or a pharmaceutically acceptable salt or a stereoisomer thereof:
54. A compound having the structure shown below, or a pharmaceutically acceptable salt or a stereoisomer thereof:
55. A pharmaceutical composition comprising a compound as shown below, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a prodrug thereof:
56. A compound having the structure shown below, or a pharmaceutically acceptable salt or a stereoisomer thereof:
57. A pharmaceutical composition comprising a compound as shown below, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a prodrug thereof:
58. A compound having the structure shown below, or a pharmaceutically acceptable salt or a stereoisomer thereof:
59. A pharmaceutical composition comprising a compound as shown below, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or a prodrug thereof: