Pteridine dione monocarboxylate transporter inhibitors

1. A MCT-inhibitory compound of formula A or of formula B

wherein

R 1 and R 2 are each independently 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;

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

J is O, S, S(O), S(O) 2 , NH, N(C 1 -C 6 )alkyl, or NC(═O)(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, (C 3 -C 6 )branched alkyl, (C 1 -C 6 )fluoroalkyl, (C 3 -C 7 )cycloalkyl, a (4- to 7-membered)heteroaryl, or 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;

Z is a bond, or is —O—, —CH 2 —, —CH(Me)-, —S—, —NH—, or —N(C 1 -C 6 )alkyl;

n=1, 2, 3, or 4;

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

wherein wavy lines indicate points of bonding, and wherein each M is an independently selected CH or N, provided that M group is a nitrogen atom in one or two instances;

G is S, O, NH, NMe, or NCF 3 ;

T is independently at each occurrence CH or N;

wherein R 5 is optionally present, R 5 being 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;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein a monocyclic R 3 is any one of

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

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

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

wherein a wavy line indicates a point of bonding.

3. The compound of claim 1 , wherein a bicyclic R 3 is any one of

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

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

wherein j=2-6, and wherein 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 R 1 =Me, R 2 =i-Bu, R 4 =H, Z=CH 2 , and other groups are as specified in claim 1 .

5. The compound of claim 1 of formula A wherein n=3.

6. The compound of claim 1 , wherein the compound 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:

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