Potent poxvirus inhibitor
View Patent ↗This invention provides compounds of formulas (I), (II), (III), and (IV) as defined in the specification, and pharmaceutical compositions comprising the same, and methods of inhibiting, treating, or abrogating a poxvirus infection in a subject using the compounds or compositions.
1. A compound of formula (I)
wherein
R 4 , R 5 , R 6 , R 7 , R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ are independently selected from the group consisting of H, C 1 -C 6 alkyl, halo, cyano, nitro, C 1 -C 6 haloalkyl, OR a , SR a , NR m R n , NR a COR b , SOR b , SO 2 R b , COR b , COOR a , aryl, heteroaryl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;
R a and R b are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;
R m and R n are independently selected from the group consisting of H, C 1 -C 6 alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl; or R m and R n , together with the nitrogen atom to which they are attached, form a 3-7 membered heterocycloalkyl group; and
n is 1, 2, 3, 4, or 5;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein n is 1, 2, or 3.
3. The compound of any one of claims 1 and 2 , wherein R 4 , R 5 , R 6 , R 7 , R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ each independently are H, C 1 -C 6 alkyl, or halo.
4. The compound of any one of claims 1 and 2 , wherein R 4 , R 5 , R 6 , and R 7 each independently are H or CH 3 .
5. The compound of any one of claims 1 and 2 , wherein R 6 is CH 3 .
6. The compound of any one of claims 1 and 2 , wherein R 4 , R 5 , and R 7 are H, and R 6 is CH 3 .
7. The compound of any one of claims 1 and 2 , wherein R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ each independently are H or halo.
8. The compound of any one of claims 1 and 2 , wherein R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ each independently are H or chloro.
9. The compound of any one of claims 1 and 2 , wherein R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ are H.
10. The compound of any one of claims 1 and 2 , wherein R 3′ and R 5′ are halo.
11. The compound of any one of claims 1 and 2 , wherein R 3′ and R 5′ are chloro.
12. The compound of any one of claims 1 and 2 , wherein R 2′ , R 4′ , and R 6′ are H, and R 3′ and R 5′ are chloro.
13. The compound of claim 1 , wherein the compound is
3-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)propanamide;
2-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)acetamide; or
4-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)butanamide.
14. The compound of any one of claims 1 and 2 , wherein the compound is
2-(6-methyl-3-(phenylthio)-1H-indol-2-yl)acetamide;
3-(6-methyl-3-(phenylthio)-1H-indol-2-yl)propanamide; or
4-(6-methyl-3-(phenylthio)-1H-indol-2-yl)butanamide.
15. The compound of any one of claims 1 and 2 , wherein the compound is
2-(3-((4-chlorophenyl)thio)-6-methyl-1H-indol-2-yl)acetamide;
3-(3-((4-chlorophenyl)thio)-6-methyl-1H-indol-2-yl)propanamide; or
4-(3-((4-chlorophenyl)thio)-6-methyl-1H-indol-2-yl)butanamide.
16. A composition comprising a compound of formula (I) according to any one of claims 1 and 2 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
17. A method of inhibiting, treating, or abrogating a poxvirus infection in a subject, the method comprising administering to said subject a compound of formula (II),
wherein
R 4 , R 5 , R 6 , R 7 , R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ are independently selected from the group consisting of H, C 1 -C 6 alkyl, halo, cyano, nitro, C 1 -C 6 haloalkyl, OR a , SR a , NR m R n , NR a COR b , SOR b , SO 2 R b , COR b , COOR a , aryl, heteroaryl, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl;
R a and R b are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl;
R m and R n are independently selected from the group consisting of H, C 1 -C 6 alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl; or R m and R n , together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl group; and
n is 0, 1, 2, 3, 4, or 5;
or a composition thereof, or a pharmaceutically acceptable salt thereof,
wherein said compound reduces, inhibits, or abrogates activity of a DNA polymerase of said poxvirus.
18. The method of claim 17 , wherein n is 1, 2, or 3.
19. The method of any one of claims 17 and 18 , wherein R 4 , R 5 , R 6 , R 7 , R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ each independently are H, C 1 -C 6 alkyl, or halo.
20. The method of any one of claims 17 and 18 , wherein R 4 , R 5 , R 6 , and R 7 each independently are H or CH 3 .
21. The method of any one of claims 17 and 18 , wherein R 4 , R 5 , and R 7 are H, and R 6 is CH 3 .
22. The method of any one of claims 17 and 18 , wherein R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ each independently are H or halo.
23. The method of any one of claims 17 and 18 , wherein R 2′ , R 3′ , R 4′ , R 5′ , and R 6′ are H.
24. The method of any one of claims 17 and 18 , wherein R 2′ , R 4′ , and R 6′ are H, and R 3′ and R 5′ are chloro.
25. The method of any one of claims 17 and 18 , wherein the compound is
3-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)propanamide;
2-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)acetamide; or
4-(3-((3,5-dichlorophenyl)thio)-6-methyl-1H-indol-2-yl)butanamide.
26. The method of any one of claims 17 and 18 , wherein the compound is
2-(6-methyl-3-(phenylthio)-1H-indol-2-yl)acetamide;
3-(6-methyl-3-(phenylthio)-1H-indol-2-yl)propanamide; or
4-(6-methyl-3-(phenylthio)-1H-indol-2-yl)butanamide.
27. The method of any one of claims 17 and 18 , wherein the compound is
2-(3-((4-chlorophenyl)thio)-6-methyl-1H-indol-2-yl)acetamide;
3-(3-((4-chlorophenyl)thio)-6-methyl-1H-indol-2-yl)propanamide; or
4-(3-((4-chlorophenyl)thio)-6-methyl-1H-indol-2-yl)butanamide.
28. The method of any one of claims 17 and 18 , wherein said poxvirus is a vaccinia virus.
29. The method of any one of claims 17 and 18 , wherein said poxvirus is a variola.
30. The method of any one of claims 17 and 18 , wherein said poxvirus is a molluscum contagiosum virus.
31. The method of any one of claims 17 and 18 , wherein said inhibiting a poxvirus infection in a subject comprises the step of inhibiting DNA synthesis of said poxvirus.
32. The method of any one of claims 17 and 18 , wherein said DNA polymerase is an E9 DNA polymerase or a homologue thereof from a different species.
33. The method of any one of claims 17 and 18 , wherein said compound reduces, inhibits, or abrogates interaction of said DNA polymerase with a processivity factor.
34. The method of claim 33 , wherein said processivity factor is an A20 or D4R processivity factor or a homologue thereof from a different species.
35. The method of any one of claims 17 and 18 , wherein said subject is a human.