Glucose uptake inhibitors
Provided herein are compounds that modulate glucose uptake activity and are useful for treating cancer, autoimmune diseases, inflammation, infectious diseases, and metabolic diseases. In certain embodiments, the compounds modulate glucose uptake activity by modulating cellular components, including, but not limited to those related to glycolysis and the known transporters/co-transporters of glucose such as GLUT1 and other GLUT family members/alternative hexose transporters. In certain embodiments, the compounds have the structure of formula I: wherein the variables have the values disclosed herein.
1. A compound having the formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
A is a group having the formula:
Ring B is a five- or six-membered ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S;
Ring C is a five- or six-membered aryl or heteroaryl ring containing from 0 to 2 heteroatoms selected from the group consisting of N, O and S;
each R 1 is independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
n is selected from 0, 1, or 2;
each R 2 is independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
m is selected from 0, 1, or 2;
R 3 and R 4 are H;
D is selected from the group consisting of —O—(CH 2 ) y —C(═O)NR 5 R 6 , —O—C(═O)—(CH 2 ) y —NR 5 R 6 , —O—(CH 2 ) y —NR 5 R 6 , —NH—C(═O)—(CH 2 ) y —NR 5 R 6 , —NH—C(═O)—(CH 2 ) y —R 7 , and —NH—(CH 2 ) y —NR 5 R 6 ;
y is selected from 1, 2, or 3;
R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, and C 3 -C 6 cycloalkyl,
or R 5 and R 6 may be taken together with the nitrogen to which they are attached to form a 5- to 6-membered heterocyclic ring having up to 3 heteroatoms selected from N, O, and S, and which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl; and
R 7 is selected from the group consisting of aryl, heteroaryl, and a hetercyclic group.
2. The compound of claim 1 , wherein the sub-structure
is selected from the group consisting of:
wherein X is selected from O and S, and R 11 is selected from H and C 1 to C 6 alkyl,
wherein R is selected from C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl.
3. The compound of claim 1 , having the formula III a :
or a pharmaceutically acceptable salt thereof,
wherein:
Ring B is a five- or six-membered ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S;
each R 1 is independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
n is selected from 0, 1, or 2;
each R 2 is independently selected from the group consisting of halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
m is selected from 0, 1, or 2;
R 3 and R 4 are H;
D is selected from the group consisting of —O—(CH 2 ) y —C(═O)NR 5 R 6 , —O—C(═O)—(CH 2 ) y —NR 5 R 6 , —O—(CH 2 ) y —NR 5 R 6 , —NH—C(═O)—(CH 2 ) y —NR 5 R 6 , —NH—C(═O)—(CH 2 ) y —R 7 , and —NH—(CH 2 ) y —NR 5 R 6 ;
y is selected from 1, 2, or 3;
R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, and C 3 -C 6 cycloalkyl,
or R 5 and R 6 may be taken together with the nitrogen to which they are attached to form a 5- to 6-membered heterocyclic ring having up to 3 heteroatoms selected from N, O, and S, and which is optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl; and
R 7 is selected from the group consisting of aryl, heteroaryl, and a hetercyclic group.
4. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
5. A method of inhibiting tumor growth or metastasis comprising administering to a patient in need thereof a therapeutically effect amount of the pharmaceutical composition of claim 4 .
6. A method of inhibiting angiogenesis comprising administering to a patient in need thereof a therapeutically effect amount of the pharmaceutical composition of claim 4 .
7. A method of inhibiting inflammation comprising administering to a patient in need thereof a therapeutically effect amount of the pharmaceutical composition of claim 4 .