Chromenone inhibitors of monocarboxylate transporters

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 (IA)

wherein

R 1 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 1 -C 6 )fluoroalkyl;

R 2 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (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, or 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;

Z is O, CH 2 , CH(CH 3 ), S, NH, N((C 1 -C 6 )alkyl), OCH 2 , OCH(CH 3 ), CH 2 S, CH(CH 3 )S, CH 2 NH, CH(CH 3 )NH, CH 2 N(CH 3 ), or CH(CH 3 )N(CH 3 );

R 3 is monocyclic or bicylic (C6-C10)aryl or a monocyclic or bicyclic (5- to 10-membered)heteroaryl, wherein the aryl or heteroaryl can be substituted or unsubstituted;

L is O, (CH 2 ) m wherein m=1 or 2, CH((C 1 -C 6 )alkyl), CH((C 3 -C 7 )cycloalkyl), CH((C 1 -C 6 )alkyl)CH 2 , S, NH, N((C 1 -C 8 )alkyl), OCH 2 , OCH((C 1 -C 6 )alkyl), SCH 2 , SCH((C 1 -C 6 )alkyl), CH 2 NH, CH 2 N((C 1 -C 6 )alkyl), CH(CH 3 )NH, CH(CH 3 )N((C 1 -C 6 )alkyl), or a bond;

R 4 is a group of formula (IIA)

wherein a wavy line indicates a point of bonding, n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 1 -C 6 )fluoroalkyl; R 6 is H, methyl, or OH;

or, R 4 is a group of formula (IIB)

wherein a wavy line indicates a point of bonding, n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 1 -C 6 )fluoroalkyl;

or, R 4 is a group of formula (IIC)

wherein a wavy line indicates a point of bonding, n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, (C 8 -C 10 )aryl, or (4- to 7-membered)heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of NH, N(C1-C6)alkyl, O, and S; R 6 is halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )fluoroalkyl, or (C 1 -C 6 )fluoroalkoxy; wherein the ring is a (C 6 -C 10 )aryl or a (5- to 9-membered)heteroaryl comprising a carbon atom at the position of bonding of group L, and 0-3 independently selected R 6 groups are present as substituents on the ring; or, wherein the ring is a non-aromatic cycloalkyl or heterocyclyl ring comprising a carbon atom at the position of bonding of group L,

wherein the carbon atom of the ring bonded to L can be bonded directly to L, or can be bonded to L via a tether of an alkylene linker comprising 3 to 7 carbon atoms, wherein one of two of said 3 to 7 carbon atoms can be replaced by an independently selected heteroatom selected from the group consisting of O, NH, N(C 1 -C 6 )alkyl, or N(C 1 C 6 )fluoroalkyl;

or, R 4 is a group of formula (IID)

wherein a wavy line Indicates a point of bonding; n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, (C 6 -C 10 )aryl, or (4- to 7-membered)heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of NH, N(C1-C6)alkyl, O, and S; R 6 is halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 C 6 )fluoroalkyl, or (C 1 -C 6 )fluoroalkoxy; wherein the ring is a (5- to 9-membered)heterocyclyl or a (5- to 9-membered)heteroaryl comprising a nitrogen atom at the position of bonding of group L, wherein the nitrogen atom of the ring bonded to L can be bonded directly to L, or can be bonded to L via a tether of an alkylene linker comprising 3 to 7 carbon atoms, wherein one of two of said 3 to 7 carbon atoms can be replaced by an independently selected heteroatom selected from the group consisting of O, NH, N(C 1 -C 6 )alkyl, or N(C 1 -C 6 )fluoroalkyl; and 0-3 independently selected R 6 groups are present as substituents on the ring;

or a pharmaceutically acceptable salt thereof.

2. 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 characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4, comprising administering an effective amount of a compound of formula (IA)

wherein

R 1 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 1 -C 6 )fluoroalkyl;

R 2 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (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, or 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;

Z is O, CH 2 , CH(CH 3 ), S, NH, N((C 1 -C 6 )alkyl), OCH 2 , OCH(CH 3 ), CH 2 S, CH(CH 3 )S, CH 2 NH, CH(CH 3 )NH, CH 2 N(CH 3 ), or CH(CH 3 )N(CH 3 );

R 3 is monocyclic or bicylic (C6-C10)aryl or a monocyclic or bicyclic (5- to 10-membered)heteroaryl, wherein the aryl or heteroaryl can be substituted or unsubstituted;

L is O, (CH 2 ) m wherein m=1 or 2, CH((C 1 -C 6 )alkyl), CH((C3-C7)cycloalkyl), CH((C 1 -C 6 )alkyl)CH 2 , S, NH, N((C 1 -C 6 )alkyl), OCH 2 , OCH((C 1 -C 6 )alkyl), SCH 2 , SCH((C 1 -C 6 )alkyl), CH 2 NH, CH 2 N((C 1 -C 6 )alkyl), CH(CH 3 )NH, CH(CH 3 )N((C 1 -C 6 )alkyl), or a bond;

R 4 is a group of formula (IIA)

wherein a wavy line indicates a point of bonding, n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 1 -C 6 )fluoroalkyl; R 6 is H, methyl, or OH;

or, R 4 is a group of formula (IIB)

wherein a wavy line indicates a point of bonding, n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, or (C 1 -C 6 )fluoroalkyl;

or, R 4 is a group of formula (IIC)

wherein a wavy line indicates a point of bonding, n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, (C 6 -C 10 )aryl, or (4- to 7-membered)heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of NH, N(C1-C6)alkyl, O, and S; R 6 is halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )fluoroalkyl, or (C 1 -C 6 )fluoroalkoxy; wherein the ring is a (C 6 -C 10 )aryl or a (5- to 9-membered)heteroaryl comprising a carbon atom at the position of bonding of group L, and 0-3 independently selected R 6 groups are present as substituents on the ring; or, wherein the ring is a non-aromatic cycloalkyl or heterocyclyl ring comprising a carbon atom at the position of bonding of group L,

wherein the carbon atom of the ring bonded to L can be bonded directly to L, or can be bonded to L via a tether of an alkylene linker comprising 3 to 7 carbon atoms, wherein one of two of said 3 to 7 carbon atoms can be replaced by an independently selected heteroatom selected from the group consisting of O, NH, N(C 1 -C 6 )alkyl, or N(C 1 -C 6 )fluoroalkyl;

or, R 4 is a group of formula (IID)

wherein a wavy line Indicates a point of bonding; n=0, 1, or 2; R 5 is H, straight chain (C 1 -C 6 )alkyl, branched chain (C 3 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 6 )fluoroalkyl, (C 6 -C 10 )aryl, or (4- to 7-membered)heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of NH, N(C1-C8)alkyl, O, and S; R 6 is halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )fluoroalkyl, or (C 1 -C 6 )fluoroalkoxy; wherein the ring is a (5- to 9-membered)heterocyclyl or a (5- to 9-membered)heteroaryl comprising a nitrogen atom at the position of bonding of group L, wherein the nitrogen atom of the ring bonded to L can be bonded directly to L, or can be bonded to L via a tether of an alkylene linker comprising 3 to 7 carbon atoms, wherein one of two of said 3 to 7 carbon atoms can be replaced by an independently selected heteroatom selected from the group consisting of O, NH, N(C 1 -C 6 )alkyl, or N(C 1 -C 6 )fluoroalkyl; and 0-3 independently selected R 6 groups are present as substituents on the ring;

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the compound shows an antitumor, antidiabetes, anti-inflammatory, or immunosuppressive pharmacological effect.

4. The method of claim 2 , wherein the mammal is a human.

5. The method of claim 2 , further comprising administering an effective amount of a biguanide to the mammal.

6. The method of claim 5 , wherein the biguanide is metformin.

7. The method of claim 2 , further comprising administering an effective amount of a standard-of-care therapeutic agent to the mammal.

8. The method of claim 2 , wherein administration is carried out by an oral, intravenous, intranasal or transdermal method.

9. The method of claim 2 , wherein the condition is characterized by the heightened activity or by the high prevalence of MCT1 and/or MCT4.

10. The method of claim 9 , wherein the condition is cancer or type II diabetes.

11. The method of claim 9 , wherein the condition is cancer and the treatment follows a determination of elevated MCT1 and/or MCT4 expression levels in the tumor or tumors.