Heterocyclic Carboxylate Compounds as Glycolate Oxidase Inhibitors

1 . A method of inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting glycolate oxidase (GO) in a patient comprising administering to the patient in need thereof, a therapeutically effective amount of a compound of formula III:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein:

R 2 is hydrogen, —(CH 2 CH 2 O) 1-9 CH 2 CH 2 OCH 3 , C 1-6 alkyl optionally substituted with one to three R 4 , cycloalkyl, or heteroaryl optionally substituted with one to three R 5 ;

each R 3 is independently aryl, heteroaryl, or heterocyclyl, wherein each R 3 is optionally substituted with one to three R 6 ;

each R 4 is independently halo, hydroxy, —OC 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —OC(O)R a , —OC(O)OR a , —OP(O)(OR b ) 2 , or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R 5 ; provided only one R 4 is heterocyclyl;

each R 5 is independently cyano, halo, C 1-4 alkyl, hydroxy, —OC 1-4 alkyl, C 1-4 haloalkyl, or —OC 1-4 haloalkyl;

each R 6 is independently cyano, halo, —C(O)R 7 , —C(O)OR 7 , —C(O)NR 7 R 8 , —S(O) 2 NR 7 R 8 , —NR 7 C(O)R 8 , —OR 7 , C 1-4 alkyl, —OC 1-4 alkyl, C 1-4 haloalkyl, —OC 1-4 haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein each is optionally substituted with one to three C 1-4 alkyl, —C(O)OH or C 1-4 haloalkyl;

R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclyl;

each R a is independently C 1-6 alkyl optionally substituted with —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , or —OP(O)(OR b ) 2 ; and

each R b is independently hydrogen or C 1-4 alkyl.

2 . The method of claim 1 , comprising administering to the patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising the compound of formula III and a pharmaceutically acceptable excipient.

3 . A method of inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting glycolate oxidase (GO) in a patient comprising administering to the patient in need thereof, a therapeutically effective amount of a compound of formula IV:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein:

R 2 is hydrogen, —(CH 2 CH 2 O) 1-9 CH 2 CH 2 OCH 3 , C 1-6 alkyl optionally substituted with one to three R 4 , cycloalkyl, or heteroaryl optionally substituted with one to three R 5 ;

each R 4 is independently halo, hydroxy, —OC 1-6 alkyl, —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —OC(O)R a , —OC(O)OR a , —OP(O)(OR b ) 2 , or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R 5 ; provided only one R 4 is heterocyclyl;

each R 5 is independently cyano, halo, C 1-4 alkyl, hydroxy, —OC 1-4 alkyl, C 1-4 haloalkyl, or —OC 1-4 haloalkyl;

each R a is independently C 1-6 alkyl optionally substituted with —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , or —OP(O)(OR b ) 2 ; and

each R b is independently hydrogen or C 1-4 alkyl.

4 . The method of claim 3 , comprising administering to the patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising the compound of formula IV and a pharmaceutically acceptable excipient.

5 . The method of claim 3 wherein:

R 2 is hydrogen, C 1-6 alkyl optionally substituted with one to three R 4 , or cycloalkyl;

each R 4 is independently —OC 1-6 alkyl, —OC(O)R a , —OC(O)OR a , —OP(O)(OR b ) 2 , or monocyclic heterocyclyl;

each R a is independently C 1-6 alkyl optionally substituted with —NH 2 or —OP(O)(OR b ) 2 ; and

R b is hydrogen.

6 . The method of claim 4 , wherein:

R 2 is hydrogen, C 1-6 alkyl optionally substituted with one to three R 4 , or cycloalkyl;

each R 4 is independently —OC 1-6 alkyl, —OC(O)R a , —OC(O)OR a , —OP(O)(OR b ) 2 , or monocyclic heterocyclyl;

each R a is independently C 1-6 alkyl optionally substituted with —NH 2 or —OP(O)(OR b ) 2 ; and

R b is hydrogen.

7 . A method of inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting glycolate oxidase (GO) in a patient comprising administering to the patient in need thereof, a therapeutically effective amount of a compound selected from:

8 . The method of claim 7 , comprising administering to the patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable excipient.

9 . A method of inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting glycolate oxidase (GO) in a patient comprising administering to the patient in need thereof, a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

10 . The method of claim 9 , comprising administering to the patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.

11 . A method of inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting glycolate oxidase (GO) in a patient administering to the patient in need thereof, a therapeutically effective amount of a compound having the structure:

or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

12 . The method of claim 11 , comprising administering to the patient in need thereof, a therapeutically effective amount of a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient.