Compounds for enzyme inhibition

1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,

wherein

each A is independently selected from C═O, C═S, and SO 2 ; or

A is optionally a covalent bond when adjacent to an occurrence of Z;

B is absent or is N(R 9 )R 10 ;

L is absent or is selected from C═O, C═S, and SO 2 ;

M is C 1-12 alkyl;

Q is absent or is selected from O, NH, and N—C 1-6 alkyl;

X is selected from O, S, NH, and N—C 1-6 alkyl;

each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or

Z is optionally a covalent bond when adjacent to an occurrence of A;

R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl;

R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;

R 4 is N(R 5 )L-Q-R 6 ;

R 5 is selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl;

R 6 is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM;

R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;

R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and

R 10 is an N-terminal protecting group; and

R 15 is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl;

provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.

2. The compound of claim 1 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 aralkyl.

3. The compound of claim 2 , wherein R 7 and R 8 are both hydrogen.

4. The compound of claim 3 , wherein R 15 is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.

5. The compound of claim 1 , wherein R 5 is hydrogen.

6. The compound of claim 1 , wherein L and Q are absent.

7. The compound of claim 1 , wherein R 6 is an N-terminal protecting group.

8. The compound of claim 7 , wherein R 6 is selected from t-butoxycarbonyl and benzyloxycarbonyl.

9. The compound of claim 1 , wherein the carbon bearing R 1 has a D stereochemical configuration.

10. The compound of claim 9 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.

11. The compound of claim 1 , wherein R 2 is selected from C 1-6 alkyl-phenyl, C 1-6 alkyl-indolyl, C 1-6 alkyl-thienyl, C 1-6 alkyl-thiazolyl, and C 1-6 alkyl-isothiazolyl.

12. The compound of claim 1 , wherein R 2 is selected from

wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 alkyl, wherein C 1-4 alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and

R is hydrogen or a suitable protecting group.

13. The compound of claim 1 , wherein R 3 is selected from C 1-6 alkyl-phenyl and C 1-6 alkyl-indolyl.

14. The compound of claim 13 , wherein R 3 is selected from

wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and

R is hydrogen or a suitable protecting group.

15. The compound of claim 1 , wherein R 6 is selected from heterocyclylMZAZ-C 1-8 alkyl-, heterocyclylM-, and carbocyclylM-.

16. The compound of claim 15 , wherein R 6 is heterocyclylMZAZ-C 1-8 alkyl-, and heterocyclylM-.

17. The compound of claim 1 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.

18. The compound of claim 17 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.

19. The compound of claim 1 , wherein an EC 50 ratio of the compound in an assay of constitutive proteasome activity as compared to the EC 50 of the compound in an assay of immunoproteasome activity is greater than 1.0.

20. The compound of claim 19 , wherein the EC 50 ratio is greater than 3.0.

21. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

22. The pharmaceutical composition of claim 21 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.