Calpain modulators and therapeutic uses thereof

A compound having the structure selected from the group consisting of:

• or a pharmaceutically acceptable salt thereof, wherein:
• A2 is selected from the group consisting of optionally substituted 3-10 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted C3-10 carbocyclyl, —CR2—, —S—, —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;
• A4 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, —CR2—, —S—, —O—, —NR—, optionally substituted C2-C6 alkenyl, and single bond;
• As 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, —CR2—, —S—, —O—, —NR—, optionally substituted C2-C6 alkenyl, 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, —CR2—, —S—, —O—, —NR—, optionally substituted C2-C6 alkenyl, and single bond;
• 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, —CR2—, —S—, —O—, —NR—, optionally substituted C2-C6 alkenyl, and single bond;
• y is an integer from 1 to 4;
• z is an integer from 0 to 4;
• R6 is independently selected from —H and, optionally substituted C1-4 alkyl;
• R1 is selected from the group consisting of H, —CH2F, —CH2Cl, —COOH, —C(═O)N(R)OR, —CONR2R3, —CH(CH3)═CH2, —CH(CF3)NR2R3, —C(F)═CHCH2CH3,
• and
• each R, R2, and R3 are independently selected from —H, optionally substituted
• C1-4 alkyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-6 alkoxy, optionally substituted 2- to 5-membered polyethylene glycol, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10 aryl, and optionally substituted 5-10 membered heteroaryl;
• J, L, M, M1 and M2 are each independently selected from the group consisting of C(R4) and N;
• Y is selected from the group consisting of NR5, O, and S, or Y is a nitrogen atom bonded to the A4 group, wherein the A4 group is —CH2—;
• X and Z are each independently selected from the group consisting of C(R4) and N;
• X1 is selected from the group consisting of C(R4) and N, or X1 is a carbon atom bonded to the A4 group;
• each R4 is independently selected from the group consisting of —H, C1-4 alkyl, C3-7 carbocyclyl, halo, hydroxy, and C1-C6 alkoxy;
• and
• R5 is selected from the group consisting of —H, C1-4 alkyl, and C3-7 carbocyclyl.