Treatment of infectious diseases with glucose uptake inhibitors

1. A method of treating infectious diseases in a mammal comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of glucose uptake having the formula I:

wherein:

A is selected from the group consisting of:

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 method of claim 1 wherein Ring B is a five-membered ring containing 1 or 2 heteroatoms selected from the group consisting of N, O and S.

3. The method 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.

4. A method of treating infectious diseases in a mammal comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound or prodrug thereof, or pharmaceutically acceptable salt or ester of said compound or prodrug, wherein the compound is an inhibitor of glucose uptake having the formula II:

wherein:

A is selected from the group consisting of:

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′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.

5. A method of treating infectious diseases in a mammal comprising administering to a mammalian subject in need thereof a therapeutically effective amount of a compound, or pharmaceutically acceptable salt or ester of said compound, wherein the compound is an inhibitor of glucose uptake having the formula III a :

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′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.

6. The method of any one of claims 1 - 5 wherein the mammal is a human.

7. The method of claim 6 wherein the infectious disease is a parasitic or viral infection.

8. The method of claim 7 wherein the parasitic or viral infection is malaria, leishmaniasis, African trypanosomiasis, tuberculosis, HIV, HCMV or herpes virus.

9. The method of claim 8 wherein the parasitic or viral infection is malaria.