Anti-parasitic compounds and uses thereof
The present disclosure provides compounds of Formula (I′), Formula (II), and Formula (III). The compounds described herein may useful in treating and/or preventing protozoan infections in a subject in need thereof, treating and/or preventing trypanosomal infections (e.g., Trypanosoma cruzi ( T. cruzi ) or Trypanosoma brucei infections) and/or plasmodial infections in a subject in need thereof, treating and/or preventing diseases in a subject in need thereof (e.g., Chagas disease, malaria, and/or sleeping sickness), and may be useful in treating and/or preventing infectious diseases in a subject in need thereof. Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including a compound described herein.
1. A compound of Formula (I′):
or a pharmaceutically acceptable salt thereof, wherein:
n is 1;
X1 is NR 4 ;
R A1 is hydrogen, halogen, C(═O)R 1 , substituted or unsubstituted carbocyclyl, substituted or unsubstituted heteroaryl, —OR, —N(R A ) 2 , —SR, —CN, —SCN, or —NO 2 ;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —NH 2 ,
b is 0, 1, 2, 3, 4, 5, or 6;
c is 0, 1, 2, 3, 4, or 5;
R a3 is independently substituted or unsubstituted alkyl, halogen, —OR a4 , —N 3 , —N(R a4 ) 2 , —SR a4 , —CN, —SCN, —SO 2 R a4 , —C(═O)R a4 , C(═O)OR a4 , —C(═O)N(R a4 ) 2 , or —NO 2 ;
R a4 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl;
R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or oxygen protecting group;
R 2 is of the formula:
d is 0, 1, 2, 3, 4, or 5;
each instance of R b1 is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted 5-membered monocyclic heteroaryl, substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl, —OR b2 , —N 3 , —N(R b3 ) 2 , —SR b2 , —CN, —SCN, —SO 2 R b2 , C(═O)R b2 , C(═O)OR b2 , —C(═O)N(R b3 ) 2 , or —NO 2 ;
R b2 is hydrogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R b3 is independently hydrogen, or substituted or unsubstituted C 1-6 alkyl;
R 3 is hydrogen, halogen, 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;
R 3A is hydrogen, halogen, 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;
R 4 is halogen, hydrogen, —C(═O)R D2 , —C(═O)OR D , —C(═O)N(R d1 ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
R D2 is hydrogen or substituted or unsubstituted C 2-6 alkyl;
R D is hydrogen or substituted or unsubstituted C 1-6 alkyl;
each instance of R d1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group, or two instances of R d1 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring;
R X is hydrogen, substituted or unsubstituted C 2-10 alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and
each instance of R A is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or nitrogen protecting group, or optionally two R A are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl;
wherein carbocyclyl is non-aromatic;
wherein the compound is not of the formula:
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is hydrogen, —C(═O)R D2 , —C(═O)OR D , —C(═O)N(R d1 ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted imine, substituted or unsubstituted thiocarbonyl group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl,
R D2 is hydrogen or substituted or unsubstituted C 2-6 alkyl;
R D is hydrogen or substituted or unsubstituted C 1-6 alkyl; and
each instance of R d1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group, or two instances of R d1 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A1 is —C(═O)R 1 .
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3A is hydrogen.
5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
n is 1; and
R 1 is —NH 2 ,
6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:
wherein:
d is 0, 1, 2, or 3; and
each instance of R b1 is independently substituted or unsubstituted heterocyclyl, substituted or unsubstituted 5-membered monocyclic heteroaryl, or substituted or unsubstituted 9- to 10-membered bicyclic heteroaryl.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is of the formula:
wherein:
f is 1, 2, 3, 4, 5, or 6;
R C is independently substituted or unsubstituted acyl, 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, —OR c1 , —N(R c2 ) 2 , —NR c2 C(═O)R c1 , or SR c1 ;
R c1 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, or oxygen protecting group; and
each instance of R c2 is independently hydrogen, substituted or unsubstituted acyl, 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, or nitrogen protecting group, or two R c2 are taken together with the intervening atoms to form substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is of the formula:
and R X is substituted or unsubstituted C 2-6 alkyl.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is of the formula: —C(═O)R D2 or —C(═O)OR D ; R D2 is hydrogen or substituted or unsubstituted C 2-6 alkyl; and R D is hydrogen or substituted or unsubstituted C 1-6 alkyl.
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is of the formula: —C(═O)N(R d1 ) 2 , and each instance of R d1 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or nitrogen protecting group, or two instances of R d1 are taken together with the intervening atoms to form a substituted or unsubstituted, heterocyclic ring.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
14. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
16. A method of treating a parasitic infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1 , a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:
18. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 4 is
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
21. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NH 2 .
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:
24. A pharmaceutical composition comprising a compound of claim 21 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is of the formula:
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is:
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X1 is —NR 4 —;
R 4 is hydrogen, —C(═O)N(R d1 ) 2 ,
R X is substituted or unsubstituted C 2-6 alkyl; and
and each instance of R d1 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl.