Prodrugs of peptide epoxy ketone protease inhibitors

摘要

Provided herein are compounds of formula (I):;
which are pro-drugs of epoxy ketone protease inhibitors. The compounds disclosed herein include one or more moieties that (i) confer enhanced solubility, permeability, pharmacokinetics, and/or pharmacodynamics properties to epoxy ketone protease inhibitors, and (ii) can be released in vivo. Also provided herein are pharmaceutical compositions of the compounds of formula (I), and methods of using the compounds of formula (I) to treat diseases and conditions.

主权项

1. A compound having a formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 has formula (II):  wherein 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 further optionally 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; R2 is R12 , R3 is hydroxyl or activated hydroxyl; R4 and R5, together with the carbon atom to which both are attached, form a carbonyl group; or R4 and R5, together with the carbon atom to which both are attached, form R13, 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; R12 is: —OSO2—R19—R20-PEG; R13 is a masked carbonyl group that is removable at a pH<6.5 or in the presence of an enzyme selected from esterase, amidase, phosphodiesterase or phosphoamidase and CYP P450, or any combination thereof; each R14 is, independently, a moiety that is removable at a pH>7 or in the presence of an esterase; R19 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, heterocycloalkylene including 3-9 ring atoms, —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, amino acid mimetic, or 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 or a salt thereof; R20 is  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.