Heterocyclic inhibitors of monocarboxylate transporters

1. A compound of formula B

wherein:

R 1 is selected from the group consisting of hydrogen and C 1 -C 6 )alkyl;

R 2 is selected from the group consisting of hydrogen and (C 1 -C 6 )alkyl;

R 3 is a monocyclic or bicyclic (C 6 -C 10 ) aryl or a monocyclic or bicyclic (5- to 10-membered) heteroaryl group, wherein the aryl or heteroaryl can be substituted or unsubstituted;

R 4 is hydrogen, (C 1 -C 6 )alkyl, CF 3 , (C 3 -C 6 )branched alkyl, (C 3 -C 7 )cycloalkyl, (C 6 -C 10 )aryl, (5- to 7-membered)heteroaryl, or (4- to 7-membered) saturated heterocyclyl with 1-2 instances of heteroatoms selected from the group consisting of NH, NMe, O, and S;

Z is CH 2 , CH((C 1 -C 6 )alkyl), CH((C 3 -C 7 )cycloalkyl), or O;

n=1, 2, or 3;

the cyclic group indicated as “ring” is an aryl or heteroaryl group of any one of the following:

wherein wavy lines indicate points of bonding, and wherein M is independently selected CH or N, provided that M group can be a nitrogen atom in 0, 1, or 2, instances;

L is S, O, NH, N(C 1 -C 6 )alkyl, or NCF 3 ;

each Q is independently CH or N;

wherein R 5 is optionally present, when present, R 5 is one to four instances of independently selected F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, OCF 3 , O(C 1 -C 6 )alkyl, or CO—(C 1 -C 6 )alkyl

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the R 3 group is monocyclic, and is of one of the following formulas

wherein X is H, (C 1 -C 6 )alkyl, or CF 3 ; and

Y is optionally present and, when Y is present, Y is 1-3 instances of a substituent selected from the group consisting of F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N((C 1 -C 6 )alkyl) 2 , NH—(CH 2 ) j —CH 2 -Q, and

wherein j=2-6 and Q is one of the following groups

wherein a wavy line indicates a point of bonding.

3. The compound of claim 1 , wherein the R 3 group is bicyclic, and is of one of the following formulas:

wherein the group X is H, (C 1 -C 6 )alkyl, or CF 3 ; and

Y is optionally present and, when Y is present, Y is 1-3 instances of a substituent selected from the group consisting of F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N((C 1 -C 6 )alkyl) 2 , NH—(CH 2 ) j —CH 2 -Q, and

wherein j=2-6 and Q is one of the following groups

wherein a wavy line indicates a point of bonding, and wherein Y can be disposed on any ring of a multi-ring system.

4. The compound of claim 1 , wherein the R 3 group is bicyclic and is of one of the following formulas:

wherein the group X is H, (C 1 -C 6 )alkyl, or CF 3 ; and

Y is optionally present and, when Y is present, Y is 1-3 instances of a substituent selected from the group consisting of F, Cl, Br, CF 3 , (C 1 -C 6 )alkyl, O(C 1 -C 6 )alkyl, NH 2 , NH(C 1 -C 6 )alkyl, N((C 1 -C 6 )alkyl) 2 , NH—(CH 2 ) j —CH 2 -Q, and

wherein j=2-6 and Q is one of the following groups

wherein a wavy line indicates a point of bonding, and wherein Y can he disposed on any ring of a multi-ring system.

5. The compound of claim 1 , of formula B, wherein R 1 is Me, R 2 is alkyl, Z is CH 2 or CH(Me), R 4 is H, Me, or CF 3 , the cyclic group indicated as “ring” is aryl or heteroaryl, and all other groups are as specified in claim 1 .

6. The compound of claim 1 , wherein the compound is any one of the following including all stereoisomeric forms, all isotopic forms, and all pharmaceutically acceptable salt forms thereof:

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

8. A method of inhibiting monocarboxylate transporter MCT1, monocarboxylate transporter MCT4, or both, comprising contacting the monocarboxylate transporter with an effective amount or concentration of a compound of claim 1 .

9. A method of treatment of a condition in a mammal wherein treatment of the condition with a compound having an inhibitor effect on MCT1, MCT4, or both is medically indicated, comprising administering an effective amount of a compound of claim 1 .

10. The method of claim 9 wherein the compound shows an antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effect.

11. The method of claim 9 wherein the mammal is a human.

12. The method of claim 9 further comprising administering an effective amount of a biguanide to the mammal.

13. The method of claim 12 wherein the biguanide is metformin.

14. The method of claim 9 further comprising administering an effective amount of a standard-of-care therapeutic agent to the mammal.

15. The method of claim 9 wherein administration is carried out by an oral, intravenous, intranasal or transdermal method.

16. The method of claim 9 wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4.

17. The method of claim 16 wherein the condition is lymphoma or type II diabetes.

18. The method of claim 17 wherein the condition is lymphoma and the treatment follows a determination of elevated MCT1 and/or MCT4 expression levels in the lymphoma.