Heterocyclic inhibitors of monocarboxylate transporters
The invention provides compounds of formulae A, B, and C as described herein that inhibit monocarboxylate transporters, such as MCT1 and MCT4. Compounds of the invention can be used for treatment of a condition in a patient, wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4, such as cancer or type II diabetes.
1. A compound of formula A
wherein:
R 1 is selected from the group consisting of, (C 1 -C 6 )alkyl, (C 3 -C 6 )branched alkyl, and (C 3 -C 7 )cycloalkyl;
R 2 is selected from the group consisting of, (C 1 -C 6 )alkyl, and (C 3 -C 6 )branched alkyl;
R 3 is a monocyclic aryl or a monocyclic or bicyclic heteroaryl group, wherein the aryl or heteroaryl can be substituted or unsubstituted;
R 4 is hydrogen, CF 3 , (C 1 -C 6 )alkyl, or (C 3 -C 6 )branched alkyl;
Z is CH 2 ;
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, and 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 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 .
4. 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:
5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.