Prodrugs of peptide epoxy ketone protease inhibitors

A compound having a formula

• or a pharmaceutically acceptable salt thereof;
• wherein m is 2-10, Het is heterocyclyl that includes from 5-6 ring atoms, wherein at least one ring atom is a nitrogen atom selected from —N(H)—, —N(M)-, or —N(C1-C3 alkyl)-, wherein said ring nitrogen atom is optionally further substituted with a group R11, thereby forming a quaternary nitrogen atom and wherein the positive charge associated with the quaternary nitrogen atom is balanced by a pharmaceutically acceptable anion;
• M is C1-C12 alkyl;
• RS1, RS2, RS3, and RS4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyC1-6alkyl, C6-10aryl, and C7-12aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether;
• RN1, RN2, RN3, and RN4 are each independently selected from H and R14;
• R11 is a moiety that is removable at a pH>7 or in the presence of an esterase;
• each R14 is, independently, a moiety that is removable at a pH>7 or in the presence of an esterase;
• R20 is absent or
• R21 is a divalent spacer comprising one or more of the following moieties:
• heteroatom, alkylene chain, heteroalkylene chain, polyheteroalkylene chain, alkenylene chain, arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms (wherein from 1-3 of the ring atoms are independently selected from N, NH, N—C1-C6 alkyl, O, and S), heterocycloalkylene including 3-9 ring atoms (wherein from 1-3 of the ring atoms are independently selected from N, NH, N—C1-C6 alkyl, O, and S), —OC(═O)—, —C(═O)O—, —NHC(═O)—, —C(═O)NH—, —N(C1-6 alkyl)C(═O), —C(═O)N(C1-6 alkyl)-, —C(═O)—, —NHC(═O)NH—, cyclodextrin, human serum albumin, amino acid, and hydrazine, wherein arylene including 6-10 ring atoms, heteroarylene including from 5-10 ring atoms, and heterocycloalkylene including 3-9 ring atoms are each optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxyl, C1-6 alkoxy, heteroalkyl, C6-10 aryloxy, C7-12 aralkoxy, CF3, quaternary ammonium ion, sugar, C1-6 alkyl, —C(═O)(C1-6 alkyl), —SO2(C1-6 alkyl), —C(═O)O(C1-6 alkyl), —C(═O)O(heteroalkyl), —C(═O)NH(C1-6 alkyl), —C(═O)NH(heteroalkyl), —C(═O)(phenyl), —SO2(phenyl), and phosphate;
• and
• RS5 is H, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyC1-6alkyl, C6-10aryl, or C7-12aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether.