α-ketoamide multicatalytic protease inhibitors

A compound having the Formula I:

• wherein:
• R1 is selected from the group consisting of —C—N, —C(═O)OR8, phthalimido, —NHSO2R8, and —NH—J;
• R2 is selected from the group consisting of H, hydroxyl, alkyl having from one to ten carbons and cycloalkyl having from three to seven carbons;
• R3 is selected from the group consisting of —(CH2)m—NHC(═N—R5)—NH2, —R6—H, —R6—J, —R12—(J)2, —R6—NO, —R—CN, —(CH2)m—NH2, and —(CH2)—NH—J;
• R4 is —CH(CH2R7)—Q;
• R5 is selected from the group consisting of -NO2, —CN, and —J;
• R6 is —(CH2)m—NH—C(═NH)—NH—;
• R12 is —(CH2)m—NH—C(═NH)—N—;
• Q is —C(═O)C(═O)NH—X—A—Y;
• R7 is selected from the group consisting of phenyl, and alkyl having from one to eight carbons, said alkyl group being optionally substituted with one or more halogen atoms, aryl, or heteroaryl groups;
• R8 is selected from the group consisting of hydrogen and alkyl having from one to six carbons, said alkyl group being optionally substituted with one or more halogen atoms, aryl or heteroaryl groups;
• X is a bond or —O—;
• A is an alkylene group of 1 to 8 carbons, said alkylene group being optionally substituted with one or more halogen atoms, aryl, or heteroaryl groups;
• Y is N(R13)—G;
• G is selected from the group consisting of H, a blocking group, SO2R9, —C(═O)NHR10, —C(═S)NHR10, and —CO2R9;
• or the moiety —A—Y forms a 5-, 6-, or 7-membered lactam ring;
• R9 is selected from the group consisting of alkyl, aryl, and heteroaryl, said alkyl, aryl, or heteroaryl groups being optionally substituted with K;
• R10 is selected from the group consisting of H, alkyl, aryl, and heteroaryl, said alkyl, aryl, or heteroaryl groups being optionally substituted with K;
• R13 is selected from the group consisting of H and lower alkyl;
• J is a blocking group;
• K is selected from the group consisting of halogen, CO2R10, R10OC(═O), R10OC(═O)NH, OH, CN, NO2, NR10R11, N═C(NR10R11)2, SR10, OR10, phenyl, naphthyl, heteroaryl, and a cycloalkyl group having from 3 to 8 carbon atoms;
• R11 is the same as R10;
• n is an integer from 5 to 10;
• m is an integer from 2 to 5;
• or a pharmaceutically acceptable salt thereof;
• with the proviso that when X is a bond and R3 is —R6—H or —(CH2)m—NH2, then G is SO2R9.