Oxopyridine derivatives useful as aminocarboxymuconate semialdehyde decarboxylase (ACMSD) inhibitors

1. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is —H, —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN;

R 2 is -halo, (C 2 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, monocyclic heteroaryl, —CN, —NO 2 , —OR c , —NR a R b , S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R b , wherein:

the (C 2 -C 5 )alkyl group represented by R 2 is optionally substituted with —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , —C(═O)R a , (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl, or phenyl, wherein the (C 3 -C 6 )cycloalkyl, monocyclic heteroaryl and phenyl substituents on the (C 2 -C 5 )alkyl group represented by R 2 are optionally and independently substituted with —CH 3 , halomethyl, halo, methoxy or halomethoxy;

the (C 3 -C 6 )cycloalkyl, phenyl and monocyclic heteroaryl groups represented by R 2 are optionally and independently substituted with (C 1 -C 5 )alkyl, halo(C 1 -C 5 )alkyl, halo, —CN, —NO 2 , —OR c , —NR a R b , —S(O) i R a , —NR a S(O) i R b , —S(O) i NR a R b , —C(═O)OR a , —OC(═O)OR a , —C(═S)OR a , —O(C═S)R a , —C(═O)NR a R b , —NR a C(═O)R b , —C(═S)NR a R b , —NR a C(═S)R b , —NR a (C═O)OR b , —O(C═O)NR a R b , —NR a (C═S)OR b , —O(C═S)NR a R b , —NR a (C═O)NR a R b , —NR a (C═S)NR a R b , —C(═S)R a , or —C(═O)R a ;

each R a and each R b are independently selected from —H and (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R a or R b is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

R c is —H, halo(C 1 -C 5 )alkyl, or (C 1 -C 5 )alkyl, wherein the (C 1 -C 5 )alkyl group represented by R c is optionally substituted with hydroxyl or (C 1 -C 3 )alkoxy;

each i is independently 0, 1, or 2;

each R 3 is independently —H, —CH 3 , or —F;

A is absent, —CH 2 —, a phenylene group or a pyridylene group, wherein the phenylene group and the pyridylene group represented by A are optionally and independently substituted with 1 or 2 groups represented by R 4 ;

each R 4 is independently —CH 3 , —OCH 3 , halomethyl, halomethoxy, halo, or —CN; and

B is —COOH or tetrazolyl;

provided that the compound is other than

or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound of claim 1 , wherein the compound is represented by the following structural formula:

3. The compound of claim 1 , wherein the compound is represented by the following structural formula:

4. The compound of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

5. The compound of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

6. The compound of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

7. The compound of claim 1 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

8. The compound of claim 1 , wherein R 2 is (C 2 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 —, wherein i) the (C 2 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy, or —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .

9. The compound of claim 1 , wherein:

R 1 is —H, —CH 3 , —OCH 3 , —F, —Cl, or —CN;

R 2 is (C 2 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl, or benzyl, wherein the (C 2 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 ;

R 3 is —H, —F, or —CH 3 ; and

R 4 is —F, —CH 3 , or methoxy.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1 .

11. The pharmaceutical composition of claim 10 , wherein the compound is represented by the following structural formula:

12. The pharmaceutical composition of claim 10 , wherein the compound is represented by the following structural formula:

13. The pharmaceutical composition of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

14. The pharmaceutical composition of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1, X 1 and X 2 are each independently CH or N, and at least one of X 1 and X 2 is CH.

15. The pharmaceutical composition of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

16. The pharmaceutical composition of claim 10 , wherein the compound is represented by the following structural formula:

wherein n is 0 or 1.

17. The pharmaceutical composition of claim 10 , wherein R 2 is (C 2 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, furanyl, pyrimidyl, pyridyl, benzyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 —, wherein i) the (C 2 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; ii) the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 , halomethyl, —OCH 3 , halomethoxy, or —CN; and iii) the thienyl, furanyl, pyridyl, pyrimidyl, thienyl-CH 2 —, furanyl-CH 2 —, pyridyl-CH 2 —, or pyrimidyl-CH 2 — group represented by R 2 is optionally and independently substituted with —CH 3 .

18. The pharmaceutical composition of claim 10 , wherein:

R 1 is —H, —CH 3 , —OCH 3 , —F, —Cl, or —CN;

R 2 is (C 2 -C 5 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, thienyl, pyridyl, or benzyl, wherein the (C 2 -C 5 )alkyl represented by R 2 is optionally substituted with halo, (C 1 -C 5 )alkoxy, or (C 3 -C 6 )cycloalkyl; the phenyl or benzyl group represented by R 2 is optionally and independently substituted with —CH 3 ;

R 3 is —H, —F, or —CH 3 ; and

R 4 is —F, —Cl, —CH 3 , or methoxy.