Heterocyclic carboxylate compounds as glycolate oxidase inhibitors
The present disclosure relates generally to modulators of human glycolate oxidase enzyme and methods of use and manufacture thereof.
1. 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 ;
each R b is independently hydrogen or C 1-4 alkyl.
2. 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 ;
each R b is independently hydrogen or C 1-4 alkyl.
3. The compound of claim 2 , 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.
4. A compound selected from:
5. A compound having the structure:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.
6. A compound having the structure:
or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.
7. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable excipient.
9. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable excipient.
10. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable excipient.
11. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable excipient.
12. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable excipient.