Heterocyclic inhibitors of monocarboxylate transporter

1. 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 formula A

wherein:

R 1 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 3 -C 7 )cycloalkyl, and (C 1 -C 6 )fluoroalkyl;

R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, a (C 6 -C 10 )aryl ring system, a 5- to 9-membered heteroaryl ring system, a (C 1 -C 6 )alkyl-(C 6 -C 10 )aryl ring system, and a (C 1 -C 6 )alkyl-(5- to 9-membered)heteroaryl ring system;

provided that when R 2 comprises an aryl or heteroaryl ring system, the ring system bears 0-2 independently selected substituents from the group consisting of fluoro, chloro, trifluoromethyl, (C 1 -C 6 )alkoxy, and (C 1 -C 6 )fluoroalkoxy;

R 3 is a monocyclic or bicyclic (C6-C10) 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, (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), O, N, S, S(O), or SO 2 ;

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,

the cyclic group indicated as “ring” is a (C 3 -C 7 )cycloalkyl or a saturated (3- to 7-membered)heterocyclyl comprising 1-2 heteroatoms selected from the group consisting of O, NH, N(C1-C6)alkyl, and N(C1-C6)fluoroalkyl; wherein the points of bonding may be cis or trans; 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 method of claim 1 , wherein for the compound of formula A 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 method of claim 1 , wherein for the compound of formula A 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 method of claim 1 , wherein for the compound of formula A 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.

5. The method of claim 1 , wherein R 1 is Me or cycloalkyl, R 2 is alkyl or branched 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 method of claim 1 , wherein the compound of formula A is any one of the following, including all stereoisomeric forms, all isotopic forms, all crystalline and amorphous forms, and all pharmaceutically acceptable salt forms thereof: