Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of PHEX

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein

A is

B is

R is hydrogen or lower alkyl;

R 1 is hydrogen or lower alkyl;

R 2 is hydrogen, or lower alkyl;

R 3 is hydrogen or lower alkyl;

R 4 is lower alkyl, substituted lower alkyl, cycloalkyl-(CH 2 ) w —, aryl-(CH 2 ) w —, substituted aryl —(CH 2 ) w — or heteroaryl-(CH 2 ) w —;

R 5 is hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl-(CH 2 ) x —, aryl-(CH 2 ) x —, substituted aryl-(CH 2 ) x —, or heteroaryl-(CH 2 ) x —;

R 6 is hydrogen or R 7 —CO—;

R 7 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) y , aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y — or heteroaryl-(CH 2 ) y —;

R 11 is hydrogen or lower alkyl;

D is —COOH;

E is hydrogen, —COOH, —CONH 2 , —CONH(lower alkyl), —CON(lower alkyl) 2 , —CONH—(CH 2 ) 2 -aryl, —CON(—(CH 2 ) 2 -aryl) 2 , —CO-amino acid, —CH 2 COOH, CH 2 OH, —CH 2 CH 2 OH, or —COOR 16 ;

R 16 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y —, heteroaryl-(CH 2 ) y —,

R 13 is hydrogen, lower alkyl, cycloalkyl or phenyl;

R 14 is hydrogen, lower alkyl, lower alkoxy or phenyl;

R 15 is lower alkyl or aryl-(CH 2 ) y —;

C is carbon;

H is hydrogen;

O is oxygen;

N is nitrogen;

S is sulfur;

P is phosphorus;

v is zero or one;

w is zero or an integer ranging from 1 to 4;

x is an integer ranging from 0 to 4;

y is zero or an integer ranging from 1 to 6; and

z is zero, one, two, or three.

2. The compound of claim 1 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-acetylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-methyl-pentanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-methyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-hexanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-phenyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid, 3-(3-Biphenyl-4-yl-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, 3-(3-(4-Benzyloxy-phenyl)-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(4-fluoro-phenyl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[2-mercapto-3-(4-methoxy-phenyl)-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-cyclohexyl-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(1H-indol-3-yl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-naphthalen-2-yl-propionylamino]-succinamic acid, N-(1-Carboxy-2-naphthalen-2-yl-ethyl)-3-(2-mercapto-3-phenyl propionylamino)-succinamic acid, N-(1-Carboxy-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[1-Carboxy-2-phenyl-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(2-Biphenyl-4-yl-1-Carboxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(1-Benzyl-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, 4-[1-Carboxy-2-(1H-indol-3-yl)-ethylcarbamoyl]-4-(2-mercapto-3-phenyl-propionylamino)-ethyl]-butyric acid, N-[2-(1H-indol-3-yl)-methylcarbamoyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, N-[1-(1-Carboxy-2-hydroxy-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[2-(1H-indol-3-yl)-methoxycarbonyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, or N-[2-(1H-indol-3-yl)1-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.

3. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a physiologically acceptable carrier or excipient.

5. The pharmaceutical composition of claim 4 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-acetylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-methyl-pentanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-methyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-hexanoylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-phenyl-butyrylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid, 3-(3-Biphenyl-4-yl-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, 3-(3-(4-Benzyloxy-phenyl)-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(4-fluoro-phenyl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[2-mercapto-3-(4-methoxy-phenyl)-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-cyclohexyl-2-mercapto-propionylamino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(1H-indol-3-yl)-2-mercapto-propionylamino]-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-naphthalen-2-yl-propionylamino]-succinamic acid, N-(1-Carboxy-2-naphthalen-2-yl-ethyl)-3-(2-mercapto-3-phenyl propionylamino)-succinamic acid, N-(1-Carboxy-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[1-Carboxy-2-phenyl-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(2-Biphenyl-4-yl-1-Carboxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-(1-Benzyl-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid, N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, 4-[1-Carboxy-2-(1H-indol-3-yl)-ethylcarbamoyl]-4-(2-mercapto-3-phenyl-propionylamino)-ethyl]-butyric acid, N-[2-(1H-indol-3-yl)-methylcarbamoyl -ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, N-[1-(1-Carboxy-2-hydroxy-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid, N-[2-(1H-indol-3-yl)-methoxycarbonyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid, or N-[2-(1H-indol-3-yl)1-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.

6. The pharmaceutical composition of claim 5 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-2-phenyl-acetylamino)-succinamic acid.

7. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-acetylamino)-succinamic acid.

8. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid.

9. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-propionylamino)-succinamic acid.

10. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-methyl-pentanoylamino)-succinamic acid.

11. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-methyl-butyrylamino)-succinamic acid.

12. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-hydroxy-2-mercapto-propionylamino)-succinamic acid.

13. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl)-3-(3-hydroxy-2-mercapto-butyrylamino)-succinamic acid.

14. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-hexanoylamino)-succinamic acid.

15. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-4-phenyl-butyrylamino)-succinamic acid.

16. The compound of claim 2 , wherein the compound is further defined as 3-(3-Biphenyl-4-yl-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid.

17. The compound of claim 2 , wherein the compound is further defined as 3-(3-(4-Benzyloxy-phenyl)-2-mercapto-propionylamino)-N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-succinamic acid.

18. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(4-fluoro-phenyl)-2-mercapto-propionylamino]-succinamic acid.

19. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[2-mercapto-3-(4-methoxy-phenyl)-propionylamino]-succinamic acid.

20. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-cyclohexyl-2-mercapto-propionylamino)-succinamic acid.

21. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-[3-(1H-indol-3-yl)-2-mercapto-propionylamino]-succinamic acid.

22. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-naphthalen-2-yl-propionylamino]-succinamic acid.

23. The compound of claim 2 , wherein the compound is further defined as N-(1-Carboxy-2-naphthalen-2-yl-ethyl)-3-(2-mercapto-3-phenyl propionylamino)-succinamic acid.

24. The compound of claim 2 , wherein the compound is further defined as N-(1-Carboxy-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid.

25. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(4-hydroxy-phenyl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.

26. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-phenyl-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid.

27. The compound of claim 2 , wherein the compound is further defined as N-(2-Biphenyl-4-yl-1-Carboxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid.

28. The compound of claim 2 , wherein the compound is further defined as N-(1-Benzyl-2-hydroxy-ethyl)-3-(2-mercapto-3-phenyl-propionyl amino)-succinamic acid.

29. The compound of claim 2 , wherein the compound is further defined as N-[1-Carboxy-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.

30. The compound of claim 2 , wherein the compound is further defined as 4-[1-Carboxy-2-(1H-indol-3-yl)-ethylcarbamoyl]-4-(2-mercapto-3-phenyl-propionylamino)-ethyl]-butyric acid.

31. The compound of claim 2 , wherein the compound is further defined as N-[2-(1H-indol-3-yl)-methylcarbamoyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid.

32. The compound of claim 2 , wherein the compound is further defined as N-[1-(1-Carboxy-2-hydroxy-ethylcarbamoyl)-2-(1H-indol-3-yl)-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.

33. The compound of claim 2 , wherein the compound is further defined as N-[2-(1H-indol-3-yl)-methoxycarbonyl-ethyl]-3-(2-mercapto-acetyl amino)-succinamic acid.

34. The compound of claim 2 , wherein the compound is further defined as N-[2-(1H-indol-3-yl)1-ethyl]-3-(2-mercapto-3-phenyl-propionylamino)-succinamic acid.