Compounds for the treatment and prevention of infections
Provided herein are compounds of Formula (I) or (II): (I) (II) pharmaceutically acceptable salts, tautomers, prodrugs, and stereoisomers thereof, and pharmaceutical compositions thereof, wherein X, R N , R 1 , R 3 , R 4 , p, and m are as defined herein. Such compounds and compositions have been found useful in the treatment or prevention of viral infections, e.g., polyomaviral infections, and are further envisioned useful in treatment or prevention of other pathogenic conditions associated with endosomal trafficking. Methods of treating or preventing an infection by a pathogen secreting an AB 5 toxin is also contemplated.
1. A method of treating a viral infection, the method comprising administering to a subject suffering from or likely to suffer from a viral infection an effective amount of a compound of Formula (II):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;
wherein:
X is O, S, or NH;
each instance of R 1 is independently halo, —NO 2 , —CN, —SCN, —OR A1 , —SR A1 , —N(R A1 ) 2 , —C(═O)R A1 , —OC(═O)R A1 , —SC(═O)R A1 , —NR A1 C(C)R A1 , —S(═O) 2 R A1 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
or two R 1 groups are joined to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
R N is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R 3 is independently halo, —NO 2 , —CN, —SCN, —OR A3 , —SR A3 , —N(R A3 ) 2 , —C(═O)R A3 , —OC(═O)R A3 , —SC(═O)R A3 , —NR A3 C(═O)R A3 , —S(═O) 2 R A3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
each instance of R A3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A3 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
or two R 3 groups are joined to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
R 4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;
p is 0, 1, or 2; and
m is 0, 1, 2, 3, or 4.
2. The method of claim 1 , wherein the viral infection is an infection caused by human papillomavirus, human immunodeficiency virus, influenza virus, or polyomavirus.
3. The method of claim 1 , wherein X is S.
4. The method of claim 1 , wherein R 1 is halo or substituted or unsubstituted C 1-6 alkyl.
5. The method of claim 4 , wherein R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl, or n-hexyl.
6. The method of claim 1 , wherein R N is a group of formula:
wherein:
L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
each instance of R 2 is independently halo, —NO 2 , —CN, —SCN, —OR A2 , —SR A2 , —N(R A2 ) 2 , —C(═O)R A2 , —OC(═O)R A2 , —SC(═O)R A2 , —NR A2 C(═O)R A2 , —S(═O) 2 R A2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
each instance of R A2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A2 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
or two R 2 groups are joined to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring; and
n is 0, 1, 2, 3, 4 or 5.
7. The method of claim 6 , wherein n is 1, 2, 3, 4, or 5, and each instance of R 2 is independently halo, —NO 2 , or —OR A2 .
8. The method of claim 6 , wherein L 1 is a bond.
9. The method of claim 6 , wherein L 1 is substituted or unsubstituted C 1 alkylene, substituted or unsubstituted C 2 alkylene, or substituted or unsubstituted C 3 alkylene.
10. The method of claim 1 , wherein m is 0.
11. The method of claim 1 , wherein m is 1, 2, 3, or 4, and each instance of R 3 is independently halo or substituted or unsubstituted alkyl.
12. The method of claim 1 , wherein R 4 is hydrogen.
13. The method of claim 1 , wherein the compound of Formula (II) is selected from the group consisting of:
and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
14. A method of treating an infection by a bacteria that secretes an AB 5 toxin, the method comprising administering to a subject suffering from or likely to suffer from the infection an effective amount of a compound of Formula (II-a):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;
wherein:
X is S;
R 1 is halo, —NO 2 , —CN, —SCN, —OR A1 , —SR A1 , —N(R A1 ) 2 , —C(═O)R A1 , —OC(═O)R A1 , —SC(═O)R A1 , —NR A1 C(═O)R A1 , —S(═O) 2 R A1 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R N is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R 3 is independently halo, —NO 2 , —CN, —SCN, —OR A3 , —SR A3 , —N(R A3 ) 2 , —C(═O)R A3 , —OC(═O)R A3 , —SC(═O)R A3 , —NR A3 C(═O)R A3 , —S(═O) 2 R A3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
each instance of R A3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A3 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
or two R 3 groups are joined to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
R 4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;
and
m is 0, 1, 2, 3, or 4;
provided the compound is not:
15. The method of claim 14 , wherein the bacteria secreting an AB 5 toxin is E. coli bacteria.
16. The method of claim 14 , wherein the AB 5 toxin is selected from the group consisting of ricin, Shiga toxin, Shiga-like toxins, cholera toxin, heat-labile enterotoxin, pertussis toxin, and subtilase cytotoxin.
17. A compound of Formula (II-a):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof;
wherein:
X is S;
R 1 is halo, —NO 2 , —CN, —SCN, —OR A1 , —SR A1 , —N(R A1 ) 2 , —C(═O)R A1 , —OC(═O)R A1 , —SC(═O)R A1 , —NR A1 C(═O)R A1 , —S(═O) 2 R A1 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R N is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R 3 is independently halo, —NO 2 , —CN, —SCN, —OR A3 , —SR A3 , —N(R A3 ) 2 , —C(═O)R A3 , —OC(═O)R A3 , —SC(═O)R A3 , —NR A3 C(═O)R A3 , —S(═O) 2 R A3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
each instance of R A3 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A3 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
or two R 3 groups are joined to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring;
R 4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;
and
m is 0, 1, 2, 3, or 4;
provided the compound is not:
18. The compound of claim 17 , wherein the compound is:
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.
19. A pharmaceutical composition comprising a compound of claim 17 , or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
20. The compound of claim 17 , wherein R 1 is halo or substituted or unsubstituted C 1-6 alkyl.
21. The compound of claim 17 , wherein R 1 is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl, or n-hexyl.
22. The compound of claim 21 , wherein R 1 is ethyl.
23. The compound of claim 17 , wherein R N is a group of formula:
wherein:
L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene;
each instance of R 2 is independently halo, —NO 2 , —CN, —SCN, —OR A2 , —SR A2 , —N(R A2 ) 2 , —C(═O)R A2 , —OC(═O)R A2 , —SC(═O)R A2 , —NR A2 C(═O)R A2 , —S(═O) 2 R A2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,
each instance of R A2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted thiol, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom, or two R A2 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
or two R 2 groups are joined to form a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, or substituted or unsubstituted heterocyclic ring; and
n is 0, 1, 2, 3, 4 or 5.
24. The compound of claim 23 , wherein n is 1, 2, 3, 4, or 5, and each instance of R 2 is independently halo, —NO 2 , or —OR A2 .
25. The compound of claim 24 , wherein n is 1, and R 2 is halo.
26. The compound of claim 23 , wherein L 1 is a bond.
27. The compound of claim 23 , wherein L 1 is substituted or unsubstituted C 1 alkylene, substituted or unsubstituted C 2 alkylene, or substituted or unsubstituted C 3 alkylene.
28. The compound of claim 27 , wherein L 1 is substituted or unsubstituted C 1 alkylene.
29. The compound of claim 17 , wherein m is 0.
30. The compound of claim 17 , wherein m is 1.
31. The compound of claim 17 , wherein m is 1, 2, 3, or 4, and each instance of R 3 is independently halo or substituted or unsubstituted alkyl.
32. The compound of claim 17 , wherein R 4 is hydrogen.
33. The method of claim 7 , wherein n is 1, and R 2 is halo.
34. The method of claim 9 , wherein L 1 is substituted or unsubstituted C 1 alkylene.
35. The method of claim 1 , wherein m is 1.
36. The method of claim 1 , wherein the compound is of Formula (II-a):
or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein X is S.
37. The method of claim 5 , wherein R 1 is ethyl.