MCT4 inhibitors for treating disease
Provided herein is a method for treating a monocarboxylate transporter MCT4-mediated disorder in a subject in need thereof. The method comprises the step of administering to the subject a compound of structural Formula I and/or a salt thereof. The treatment of the monocarboxylate transporter MCT4-mediated disorder may inhibit activity of MCT4, or a mutant thereof, sometimes with at least a 100-fold selectivity for MCT4 over MCT1.
1. A compound of structural Formula I
wherein:
A 1 , A 2 , and A 3 are independently chosen from N and C, wherein at least one of A 1 , A 2 , and A 3 is N;
L is chosen from a bond and methylene;
W is chosen from
R 4 and R 5 are independently chosen from C 1 -C 6 alkyl, wherein R 4 and R 5 together comprise no more than 6 carbons;
X is H;
Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl; and
Z is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.
2. A method for treating a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula I
and/or a salt thereof,
wherein the condition is cancer which has developed resistance to chemotherapeutic drugs and/or ionizing radiation, and
wherein:
A 1 , A 2 , and A 3 are independently chosen from N and C, wherein at least one of A 1 , A 2 , and A 3 is N;
L is chosen from a bond and methylene;
W is chosen from
R 4 and R 5 are independently chosen from C 1 -C 6 alkyl, wherein R 4 and R 5 together comprise no more than 6 carbons;
X is hydrogen;
Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl; and
Z is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.
3. The compound of claim 1 , wherein
A 1 and A 2 are C; and
A 3 is N.
4. The compound of claim 3 , wherein L is a bond.
5. The compound of claim 4 , wherein Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, alkylamino, amino, halo, cycloalkyl, aryl, and heteroaryl.
6. The compound of claim 5 , wherein Y is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 2 groups each independently chosen from alkenyl, alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl.
7. The compound of claim 6 , wherein:
Y is phenyl, substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
Z is phenyl, substituted with an R 3 group chosen from alkyl, alkoxy, haloalkyl, alkylamino, amino, and halo.
8. The compound of claim 7 , wherein R 2 is cycloalkoxy and R 3 is amino.
9. The compound of claim 8 , wherein R 4 and R 5 are methyl.
10. The method of claim 2 , wherein
A 1 and A 2 are C; and
A 3 is N.
11. The method of claim 10 , wherein L is a bond.
12. The method of claim 11 , wherein Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, alkylamino, amino, halo, cycloalkyl, aryl, and heteroaryl.
13. The method of claim 12 , wherein Y is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 2 groups each independently chosen from alkenyl, alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl.
14. The method of claim 13 , wherein:
Y is phenyl, substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
Z is phenyl, substituted with an R 3 group chosen from alkyl, alkoxy, haloalkyl, alkylamino, amino, and halo.
15. The method of claim 14 , wherein R 2 is cycloalkoxy and R 3 is amino.
16. The method of claim 15 , wherein R 4 and R 5 are methyl.
17. A method for treating cardiac hypertrophy, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of structural Formula I
and/or a salt thereof,
wherein:
A 1 , A 2 , and A 3 are independently chosen from N and C, wherein at least one of A 1 , A 2 , and A 3 is N;
L is chosen from a bond and methylene;
W is chosen from
R 4 and R 5 are independently chosen from C 1 -C 6 alkyl, wherein R 4 and R 5 together comprise no more than 6 carbons;
X is hydrogen;
Y is chosen from alkenyl, alkenylamino, alkyl, aminoalkenyl, aminoalkyl, aryl, cycloalkyl, and heteroaryl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, cycloalkoxy, cycloalkylmethoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl; and
Z is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, alkylamino, amino, amido, sulfonamido, halo, cyano, hydroxy, cycloalkyl, aryl, and heteroaryl.
18. The method of claim 17 , wherein
A 1 and A 2 are C; and
A 3 is N.
19. The method of claim 18 , wherein L is a bond.
20. The method of claim 19 , wherein Z is chosen from phenyl and pyridinyl, either of which may be optionally substituted with one to three R 3 groups each independently chosen from alkyl, alkenyl, alkoxy, haloalkyl, alkylamino, amino, halo, cycloalkyl, aryl, and heteroaryl.
21. The method of claim 20 , wherein Y is chosen from aryl and heteroaryl, either of which may be optionally substituted with one to three R 2 groups each independently chosen from alkenyl, alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, aryl, halo, heteroaryl, and haloalkyl.
22. The method of claim 21 , wherein:
Y is phenyl, substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
Z is phenyl, substituted with an R 3 group chosen from alkyl, alkoxy, haloalkyl, alkylamino, amino, and halo.
23. The method of claim 22 , wherein R 4 and R 5 are methyl.