FLUORINATED EPOXYKETONE-BASED COMPOUNDS AND USES THEREOF AS PROTEASOME INHIBITORS

摘要

The present application relates to novel fluorinated epoxyketone-based compounds, compositions comprising these compounds and their use, in particular for the treatment of diseases, disorders or conditions mediated by proteasome inhibition, in particular, the present application includes compounds of Formula I, and compositions and uses thereof:;

主权项

1. A compound of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof: wherein:
R1 is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C1-10cyanoalkyl, C1-10alkoxy, C2-10alkenyloxy, C2-10alkynyloxy, C3-10 cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6alkylene-O—C1-6haloalkyl, C1-6haloalkyl-C3-8cycloalkyl, C1-6alkynylene-heterocycle, C1-6alkylene-aryl, C1-6alkylene-heteroaryl, C(O)R7, OC(O)R7, C(O)OR7, C1-6alkylene-O—R7, C1-6alkylene-C(O)R7, C1-6alkylene-O—C(O)R7, C1-6alkylene-C(O)OR7, C1-6alkylene-O—C(O)R7, C1-6alkylene-NR7R8, C1-6alkylene-C(O)NR7R8, C1-6alkylene-NR7C(O)OR8, C1-6alkylene-C(O)NR7R8, C1-6alkylene-S—R7, C1-6alkylene-S(O)R7, C1-6alkylene-SO2R7, C1-6alkylene-SO2NR7R8, C1-6alkylene-NR7SO2R8, C1-6alkylene-NR7SO2NR7R8, C(O)NR7R8 and C1-6alkylene-NR7C(O)OR8, wherein any cyclic moiety is optionally substituted with C1-4alkyl and/or is optionally fused to a further cyclic moiety;X is absent or is selected from the group consisting of O, NH, NC1-6alkyl, S, S(O), SO2, C(O), C1-6alkylene, C2-6alkenylene, C2-6alkynylene, C1-6haloalkylene, C3-8cycloalkylene, heterocycloalkylene, arylene and heteroarylene, or X is a combination of two or three of O, NH, NC1-6alkyl, S, S(O), SO2, C1-6alkylene, C2-6alkenylene, C2-6 alkynylene, C1-6haloalkylene, C3-8cycloalkylene, heterocycloalkylene, arylene or heteroarylene, bonded together in a linear fashion, provided that two or three of O, NH, NC1-6alkyl, S, S(O) and SO2 and not bonded directly to each other;R2, R3 and R4 are each independently selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C1-10haloalkyl, C1-10cyanoalkyl, C1-10alkoxy, C2-10alkenyloxy, C2-10alkynyloxy, C3-10cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6alkylene-O—C1-6alkyl, C1-6alkylene-O—C1-6haloalkyl, C2-6alkenylene-O—C1-6haloalkyl, C2-6alkynylene-O—C1-6haloalkyl, C1-6alkylene-C3-8cycloalkyl, C1-6alkylene-heterocycloalkyl, C1-6alkylene-aryl, C1-6alkylene-heteroaryl, C(O)R7, OC(O)R7, C(O)OR7, C1-6alkylene-O—R7, C1-6alkylene-C(O)R7, C1-6alkylene-O—C(O)R7, C1-6alkylene-C(O)OR7, C1-6alkylene-O—C(O)OR7, C1-6alkylene-NR7R5, C1-6alkylene-C(O)NR7R8, C1-6alkylene-NR7C(O)R8, C1-6alkylene-NR7C(O)NR7R8, C1-6alkylene-S—R7, C1-6alkylene-S(O)R7, C1-6alkylene-SO2R7, C1-6alkylene-SO2NR7R8, C1-6alkylene-NR7SO2R8, C1-6alkylene-NR7SO2NR7R8, C(O)NR7R8 and C1-6alkylene-NR7C(O)OR8, wherein any cyclic moiety is optionally fused to a further 5- to 7-membered cyclic moiety, wherein at least one of R2, R3 and R4 is C1-6-alkylene-O—C1-6haloalkyl, and wherein R2, R3 and R4 are optionally substituted with one or more independently-selected R6 groups;R5 is selected from the group consisting of H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, C1-6alkylene-C3-8cycloalkyl, aryl, heteroaryl, and heterocycloalkyl;R6 is selected from the group consisting of C1-6alkyl, OH, halo, O—(C2-3alkylene)-O, C1-6alkoxy, aryloxy, —NH—C1-6alkyl, —N(C1-6alkyl)2, C1-6alkylene-N(C1-6alkyl)2, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; andR7 and R8 are each independently selected from the group consisting of H, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C1-6alkylene-C3-10cycloalkyl, heterocycloalkyl, aryl, C1-6alkylene-aryl, C1-6alkylene-heterocycloalkyl, heteroaryl, and C1-6alkylene-heteroaryl, wherein any cyclic moiety is optionally fused to a further cyclic moiety.