Heterocyclic inhibitors of MCT4
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 II:
or a salt thereof, wherein:
L is chosen from a bond, methylene, and ethylene;
W is chosen from
Y is chosen from
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy;
R 2d is chosen from null and C 1 -C 4 alkoxy;
R 2e is C 1 -C 4 alkyl;
Z is chosen from
n is 1 or 2;
R 4 and R 5 are independently chosen from H and C 1 -C 6 alkyl, wherein R 4 and R 5 together comprise no more than 6 carbons and wherein at least one of R 4 and R 5 is C 1 -C 6 alkyl, or
R 4 and R 5 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R 6 is chosen from H and C 1 -C 4 alkyl; and
R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
2. The compound as recited in claim 1 , having the structural Formula III:
or salt thereof, wherein:
L is chosen from a bond, methylene, and ethylene;
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy;
R 2d is chosen from null and C 1 -C 4 alkoxy;
Z is chosen from
n is 1 or 2;
R 4 and R 5 are independently chosen from H and C 1 -C 6 alkyl, wherein R 4 and R 5 together comprise no more than 6 carbons and wherein at least one of R 4 and R 5 is C 1 -C 6 alkyl, or
R 4 and R 5 , together with the atoms to which they are attached, form a 3-7 membered cycloakyl or heterocycloalkyl ring; and
R 6 is chosen from H and C 1 -C 4 alkyl; and
R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
3. The compound as recited in claim 1 , wherein
W is chosen from
R 4 and R 5 are independently chosen from H, methyl, and ethyl, and wherein at most one of R 4 and R 5 is H; and
R 6 is chosen from H and C 1 -C 4 alkyl.
4. The compound as recited in claim 3 , wherein Z is
and R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
5. The compound as recited in claim 2 , wherein R 2c is chosen from H and C 1 -C 4 alkoxy.
6. The compound as recited in claim 5 , wherein R 2c is C 1 -C 4 alkoxy.
7. The compound as recited in claim 6 , wherein R 4 and R 5 are independently chosen from H, methyl, and ethyl, and wherein at most one of R 4 and R 5 is H.
8. The compound as recited in claim 7 , wherein Z is
and R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
9. The compound as recited in claim 1 , wherein the compound has structural Formula VII:
or a salt thereof, wherein:
L is chosen from a bond and methylene;
W is chosen from
Y is chosen from
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy;
R 2d is chosen from null and C 1 -C 4 alkoxy;
R 2e is C 1 -C 4 alkyl;
n is 1 or 2;
R 4 and R 5 are independently chosen from C 1 -C 3 alkyl; and
R 6 is chosen from H and C 1 -C 4 alkyl.
10. The compound as recited in claim 9 , wherein W is
R 4 and R 5 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and R 6 is chosen from H and C 1 -C 4 alkyl.
11. The compound as recited in claim 10 , wherein n is 1, forming azetidin-1-yl.
12. The compound as recited in claim 11 , wherein L is a bond.
13. The compound as recited in claim 1 , wherein compound has structural Formula VIII:
or a salt thereof, wherein:
L is chosen from a bond and methylene;
Y is chosen from
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy;
R 2d is chosen from null and C 1 -C 4 alkoxy;
R 2e is C 1 -C 4 alkyl;
n is 1 or 2;
R 4 and R 5 are independently chosen from C 1 -C 3 alkyl; and
R 6 is chosen from H and C 1 -C 4 alkyl.
14. The compound as recited in claim 13 , wherein Y is
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy; and R 2d is chosen from null and C 1 -C 4 alkoxy.
15. The compound as recited in claim 13 , wherein n is 1, forming azetidin-1-yl.
16. The compound as recited in claim 15 , wherein L is a bond.
17. The compound as recited in claim 16 , wherein Y is
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy; and R 2d is chosen from null and C 1 -C 4 alkoxy.
18. A compound of structural Formula XI:
or a salt thereof, wherein:
W is chosen from
m is 1, 2, or 3;
L is chosen from a bond and methylene;
Z is chosen from
n is 1 or 2;
R 4 and R 5 are independently chosen from C 1 -C 3 alkyl;
R 6 is chosen from H and C 1 -C 4 alkyl; and
R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
19. The compound as recited in claim 18 , wherein W is
R 4 and R 5 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and R 6 is chosen from H and C 1 -C 4 alkyl.
20. The compound as recited in claim 19 , wherein L is a bond.
21. The compound as recited in claim 18 , wherein R 9 is chosen from chloro, dimethylamino, and ethoxy.
22. The compound as recited in claim 21 , wherein R 9 is chosen from chloro and ethoxy.
23. The compound as recited in claim 18 , wherein n is 1, forming azetidin-1-yl.
24. The compound as recited in claim 1 , wherein W is
R 4 and R 5 , together with the atoms to which they are attached, form a 3-7 membered cycloalkyl or heterocycloalkyl ring; and R 6 is chosen from H and C 1 -C 4 alkyl.
25. The compound as recited in claim 24 , wherein R 9 is chosen from chloro and ethoxy.
26. The compound as recited in claim 25 , wherein L is a bond.
27. The compound as recited in claim 26 , wherein:
Y is
R 2c is chosen from H, C 1 -C 4 alkoxy and C 1 -C 4 cycloalkoxy; and
R 2d is chosen from null and C 1 -C 4 alkoxy.
28. The compound as recited in claim 27 , wherein:
R 2c is chosen from methoxy, methylpropoxy, cyclopropoxy, and cyclobutoxy; and
R 2d is chosen from null and methoxy.
29. A compound chosen from:
or a salt thereof.
30. An isolated enantiomer of a compound as recited in claim 29 .
31. A pharmaceutical composition comprising a compound as recited in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.