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 - 32 . (canceled)
33 . A method for treating a disorder chosen from a myeloproliferative neoplasm (MPN) or a myelodysplastic syndrome (MDS) in a subject in need thereof, comprising administering to the subject 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.
34 . The method as recited in claim 33 , wherein the disorder is a myeloproliferative neoplasm (MPN).
35 . The method as recited in claim 34 , wherein the myeloproliferative neoplasm (MPN) is chronic myelogenous leukemia (CML).
36 . The method as recited in claim 34 , wherein the myeloproliferative neoplasm (MPN) is acute myeloid leukemia (AML).
37 . The method as recited in claim 33 , wherein the disorder is a myelodysplastic syndrome (MDS).
38 . The method as recited in claim 33 , wherein the compound has structural Formula III:
or a salt thereof, wherein:
L is chosen from a bond, methylene, and ethylene;
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; 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.
39 . The method as recited in claim 38 , 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.
40 . The method as recited in claim 39 , wherein Z is
and R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
41 . The method as recited in claim 38 , wherein R 2d is chosen from null and C 1 -C 4 alkoxy.
42 . The method as recited in claim 41 , wherein R 2d is C 1 -C 4 alkoxy.
43 . The method as recited in claim 42 , 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.
44 . The method as recited in claim 43 , wherein Z is
and R 9 is chosen from halo, amino, and C 1 -C 4 alkoxy.
45 . The method as recited in claim 33 , wherein the 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.
46 . The method as recited in claim 45 , wherein n is 1, forming azetidin-1-yl.
47 . The method as recited in claim 45 , wherein L is a bond.
48 . The method as recited in claim 47 , wherein Y is
49 . A method for treating a disorder chosen from a myeloproliferative neoplasm (MPN) or a myelodysplastic syndrome (MDS) in a subject in need thereof, comprising administering to the subject a compound of structural formula:
or a salt thereof.
50 . The method as recited in claim 49 , wherein the disorder is a myeloproliferative neoplasm (MPN).
51 . The method as recited in claim 50 , wherein the myeloproliferative neoplasm (MPN) is chronic myelogenous leukemia (CML).
52 . The method as recited in claim 50 , wherein the myeloproliferative neoplasm (MPN) is acute myeloid leukemia (AML).
53 . The method as recited in claim 49 , wherein the disorder is a myelodysplastic syndrome (MDS).