Compounds for enzyme inhibition

A method of inhibiting an N-terminal nucleophile hydrolase;

• inhibiting or reducing HIV infection;
• affecting the level of viral gene expression in a subject;
• altering the variety of antigenic peptides produced by the proteasome in an organism;
• or treating inflammation, a neurodegenerative disease, a muscle-wasting disease, cancer, a chronic infectious disease, fever, an immune-related condition, denervation, or nerve injury, comprising administering 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 SO2;
• or
• A is optionally a covalent bond when adjacent to an occurrence of Z;
• L is absent or is selected from C═O, C═S, and SO2;
• M is absent or is C1-12alkyl;
• Q is absent or is selected from O, NH, and N-C1-6alkyl;
• X is selected from O, NH, and N-C1-6alkyl;
• Y is absent or is selected from O, NH, N-C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10;
• each Z is independently selected from O, S, NH, and N-C1-6alkyl;
• or
• Z is optionally a covalent bond when adjacent to an occurrence of A;
• R1, R2, R3, and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents;
• R5 is N(R6)LQR7;
• R6 is selected from hydrogen, OH, and C1-6alkyl;
• R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZAZ-C1-8alkyl-, R11Z-C1-8alkyl-, (R8O)(R9O)P(═O)O-C1-8alkyl-ZAZ-C1-8alkyl-, R8ZAZ-C1-8alkyl-ZAZ-C1-8alkyl, heterocyclylMZAZ-C1-8alkyl-, (R8O)(R9O)P(═O)O-C1-8alkyl-, (R10)2N-C1-12alkyl-, (R10)3N+-C1-12alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH;
• or
• R6 and R7 together are C1-6alkyl-Y-C1-6alkyl, C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ-C1-6alkyl, ZAZ-C1-6alkyl-ZAZ, or C1-6alkyl-A, thereby forming a ring;
• R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring;
• each R10 is independently selected from hydrogen and C1-6alkyl;
• and
• R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl,
• provided that when R6 is H or CH3 and Q is absent, LR7 is not hydrogen, unsubstituted C1-6alkylC═O, a further chain of amino acids, t-butoxycarbonyl (Boc), benzoyl (Bz), fluoren-9-ylmethoxycarbonyl (Fmoc), triphenylmethyl(trityl), benzyloxycarbonyl (Cbz), trichloroethoxycarbonyl (Troc);
• or substituted or unsubstituted aryl or heteroaryl;
• and
• in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.