Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof

A compound having the structure of Formula I:

• where:
• n is from 1-12;
• each A is independently selected from the group consisting of:
• O and S;
• X is NH or NR2;
• each R1 is independently selected from the group consisting of:
• hydrogen, C1-C8 alkyl, substituted C1-C8 alkyl, C1-C8 alkenyl, substituted C1-C8 alkenyl, C1-C8 alkynyl, substituted C1-C8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, C1-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, alkylthio, substituted alkylthio, OH, OR2, NH2, NHR2, SR2, substituted sulfonyl, and substituted sulfinyl;
• each R2 is independently selected from the group consisting of:
• hydrogen, C1-C8 alkyl, substituted C1-C8 alkyl, C1-C8 alkenyl, substituted C1-C8 alkenyl, C1-C8 alkynyl, substituted C1-C8 alkynyl, C3-C7 aryl, substituted C3-C7 aryl, cyano, OH, C1-C8 alkoxy, substituted C1-C8 alkoxy, amino, substituted amino, C3-C10 cycloalkyl, substituted C3-C10 cycloalkyl, C3-C9 heterocycloalkyl, substituted C3-C9 heterocycloalkyl, C3-C9 heteroaryl, substituted C3-C9 heteroaryl, and any naturally or non-naturally occurring amino acid side chain, wherein any R2 substituent may be covalently bonded to or share another R2 substituent to form a C3-C12 cyclic, heterocyclic, aryl, heteroaryl, spirocyclic, or bicyclic ring system;
• each W is independently selected from the group consisting of:
• CH2, C(R2)2, CHR2, O, NH, NR2, C(═O), C(═S), S, S(═O), S(═O)2, —C—, —CH—, a C3-C12 spirocyclic group of
• where m is 1-19, sulfonyl, substituted sulfonyl, sulfinyl, and substituted sulfinyl, wherein any two adjacent W atoms may form CR2═CR2 or C≡C;
• L4 is selected from the group consisting of:
• R2, acyl, acylamino, aminocarbonylamino, aminothiocarbonyl, aminoacyl carbonyloxy, aminosulfonyl, amidino, carboxy ester, —CO— ethylene glycol, —CO-polyethylene glycol, substituted sulfonyl, substituted sulfinyl, thioacyl, aminoacyl, phthalimido, and formyl;
• and wherein any two or more W groups can be bonded together to form a C3-C12 cycloalkyl ring structure, a C3-C12 fused cycloalkyl ring structure, a C3-C12 aryl ring structure, a C3-C12 fused aryl ring structure, a C3-C12 heteroaryl ring structure, a C3-C12 fused heteroaryl ring structure, a C3-C12 heterocyclic ring structure, and a C3-C12 fused heterocyclic ring structure;
• or a tautomer and/or a pharmaceutically acceptable salt thereof.