Calpain modulators and therapeutic uses thereof

A compound having the structure of formula:

• or a pharmaceutically acceptable salt thereof, wherein:
• A2 is a single bond;
• A4 is a single bond;
• A3 is directly attached to the ring-atom to which A2 is attached;
• A3 is selected from the group consisting of optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted C3-10 carbocyclyl;
• A5 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-10 carbocyclyl, optionally substituted C1-8 alkyl, —S—, —S(═O)—, —SO2—, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond;
• A6 is selected from the group consisting of optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3-10 carbocyclyl, optionally substituted C1-8 alkyl, optionally substituted C2-8 alkenyl, optionally substituted —O—C1-6 alkyl, optionally substituted —OC2-6 alkenyl, —OSO2CF3, and any natural or non-natural amino acid side chain;
• A7 is selected from the group consisting of optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 3-10 membered heterocyclyl, optionally substituted C3-10 carbocyclyl, optionally substituted C1-8 alkyl, —S—, S(═O)—, —SO2—, —O—, —C(═S)—, —C(═O)—, —NR—, —CH═CH—, —OC(O)NH—, —NHC(O)NH—, —NHC(O)O—, —NHC(O)—, —NHC(S)NH—, —NHC(S)O—, —NHC(S)—, and single bond;
• when A5 and A7 are single bond, A6 is directly attached to the carbon to which —COR1 is attached;
• R1 is selected from the group consisting of H, —COOH, —CH2NO2, —C(═O)NOR, —CONR2R3, —CH(CH3)═CH2, —CH(CF3)NR2R3, —C(F)═CHCH2CH3,
• R14 is halo;
• each R, R2, and R3 are independently selected from —H, optionally substituted C1-4 alkyl, optionally substituted C1-8 alkoxyalkyl, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted C6-10 aryl(C1-C6)alkyl, and optionally substituted 5-10 membered heteroaryl;
• R6 is independently selected from —H and optionally substituted C1-4 alkyl;
• X and Z are each independently selected from the group consisting of C(R4) and N;
• each R4 is independently selected from the group consisting of —H, C1-4 alkyl, C1-4 haloalkyl, C3-7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, hydroxy, and C1-C6 alkoxy;
• Y is selected from the group consisting of NR5, O, S, and SO2;
• and
• R5 is selected from the group consisting of —H, C1-4 alkyl, C1-4 haloalkyl, and C3-7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy).