MCT4 inhibitors for treating disease
Disclosed herein are compounds and compositions useful in the treatment of MCT4 mediated diseases, such as proliferative and inflammatory diseases, having the structure of Formula I: Methods of inhibition MCT4 activity in a human or animal subject are also provided.
1. 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;
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. The compound as recited in claim 1 , and/or a salt thereof, wherein
A 1 and A 2 are C; and
A 3 is N.
3. The compound as recited in claim 1 , and/or a salt thereof, wherein W is chosen from
and
R 4 and R 5 are independently chosen from alkyl, with R 4 and R 5 together having no more than 6 carbons.
4. The compound as recited in claim 3 , and/or a salt thereof, 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 alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl.
5. The compound as recited in claim 4 , and/or a salt thereof, wherein Y is chosen from aryl and heteroaryl, any 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.
6. The compound as recited in claim 1 , wherein the compound has structural Formula II:
and/or a salt thereof, wherein:
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;
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;
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 alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl.
7. The compound as recited in claim 6 , and/or a salt thereof, 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 alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl.
8. The compound as recited in claim 7 , and/or a salt thereof, wherein Y is chosen from phenyl, thienyl, and thiazolyl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl.
9. The compound as recited in claim 8 , and/or a salt thereof, wherein R 4 and R 5 are chosen from the following combinations:
R 4 and R 5 are each methyl;
R 4 and R 5 are each ethyl; and
R 4 is methyl and R 5 is ethyl.
10. The compound as recited in claim 1 , wherein the compound has structural Formula III:
and/or a salt thereof, wherein:
L is chosen from a bond and methylene;
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;
R 6 is chosen from H and methyl;
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; and
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 alkenyl, alkoxy, alkyl, alkylamino, aryl, halo, heteroaryl, and haloalkyl.
11. The compound as recited in claim 10 , and/or a salt thereof, 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 alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
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 alkoxy, alkyl, alkylamino, halo, and haloalkyl.
12. The compound as recited in claim 11 , and/or a salt thereof, wherein Y is chosen from phenyl, thienyl, and thiazolyl, any of which may be optionally substituted with one to three R 2 groups each independently chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl.
13. The compound as recited in claim 12 , and/or a salt thereof, wherein R 4 and R 5 are chosen from the following combinations:
R 4 and R 5 are each methyl;
R 4 and R 5 are each ethyl; and
R 4 is methyl and R 5 is ethyl.
14. The compound as recited in claim 13 , and/or a salt thereof, 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 one or two R 3 groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
15. A compound of structural Formula III
and/or a salt thereof, wherein:
L is chosen from a bond and methylene;
R 4 and R 5 are chosen from the following combinations:
R 4 and R 5 are each methyl;
R 4 and R 5 are each ethyl; and
R 4 is methyl and R 5 is ethyl;
R 6 is chosen from H and methyl;
Y is phenyl meta-substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, and haloalkoxy;
Z is phenyl, substituted with one or two R 3 groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
16. The compound as recited in claim 15 , and/or a salt thereof, wherein Y is meta-substituted with an R 2 group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy.
17. The compound as recited in claim 14 , and/or a salt thereof, wherein Z is ortho-substituted with an R 3 group chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
18. The compound as recited in claim 17 , and/or a salt thereof, wherein Z is ortho-substituted with halo.
19. The compound as recited in claim 18 , and/or a salt thereof, wherein Z is ortho-substituted with chloro.
20. The compound as recited in claim 14 , and/or a salt thereof, wherein R 6 is H.
21. The compound as recited in claim 13 , and/or a salt thereof, wherein:
Y is thienyl, substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
Z is phenyl, substituted with one or two R 3 groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
22. The compound as recited in claim 21 , and/or a salt thereof, wherein Y is substituted with an R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, and haloalkoxy.
23. The compound as recited in claim 22 , and/or a salt thereof, wherein Y is meta-substituted with an R 2 group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy.
24. The compound as recited in claim 21 , and/or a salt thereof, wherein Z is ortho-substituted with an R 3 group chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
25. The compound as recited in claim 24 , and/or a salt thereof, wherein Z is ortho-substituted with halo.
26. The compound as recited in claim 25 , and/or a salt thereof, wherein Z is ortho-substituted with chloro.
27. The compound as recited in claim 21 , and/or a salt thereof, wherein R 6 is H.
28. The compound as recited in claim 13 , and/or a salt thereof, wherein:
Y is thiazolyl, substituted with one R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, haloalkoxy, alkyl, halo, and haloalkyl; and
Z is phenyl, substituted with one or two R 3 groups chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
29. The compound as recited in claim 28 , and/or a salt thereof, wherein Y is substituted with one R 2 group chosen from alkoxy, cycloalkoxy, cycloalkylmethoxy, and haloalkoxy.
30. The compound as recited in claim 29 , and/or a salt thereof, wherein Y is meta-substituted with an R 2 group chosen from methoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, isopropoxy, isobutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclopropylmethoxy, cyclobutylmethoxy, and cyclopentylmethoxy.
31. The compound as recited in claim 28 , and/or a salt thereof, wherein Z is ortho-substituted with one R 3 group chosen from alkoxy, alkyl, alkylamino, halo, and haloalkyl.
32. The compound as recited in claim 31 , and/or a salt thereof, wherein Z is ortho-substituted with one halo.
33. The compound as recited in claim 32 , and/or a salt thereof, wherein Z is ortho-substituted with one chloro.
34. The compound as recited in claim 28 , and/or a salt thereof, wherein R 6 is H.
35. The compound as recited in claim 1 , and/or a salt thereof, wherein the compound is chosen from:
36. An isolated enantiomer of a compound as recited in claim 35 .
37. A pharmaceutical composition comprising a compound as recited in claim 1 , and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
38. A compound as recited in claim 1 , and/or a pharmaceutically acceptable salt thereof, for use in human therapy.
39. A compound as recited in claim 1 , and/or a pharmaceutically acceptable salt thereof, for use in treating a monocarboxylate transporter MCT4-mediated disorder.