Caspase inhibitors and the use thereof

A compound having the Formula II:

• 37
• or pharmaceutically acceptable salts or prodrugs thereof wherein:
• R1 is an optionally substituted alkyl or hydrogen;
• R2 is hydrogen or optionally substituted alkyl;
• X is O, S, NR4 or (CR4R5)n, wherein R4 and R5 are, at each occurrence, independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, and n is 0, 1, 2 or 3;
• Y is a residue of a natural or non-natural amino acid;
• A is CR6 or nitrogen;
• B is CR7 or nitrogen;
• C is CR8 or nitrogen;
• D is CR9 or nitrogen;
• E is CR10 or nitrogen;
• provided that not more than three of A, B, C, D and E are nitrogen;
• and R6-R10 independently are hydrogen, halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6)alkynyl, C1-C6 hydroxyalkyl, nitro, amino, cyano, C1-C6 acylamino, hydroxy, C1-C6 acyloxy, C1-C6 alkoxy, alkylthio, or carboxy;
• or
• one of R6 and R7, or R7 and R8, or R8 and R9, or R9 and R10 are taken together with the carbon atoms to which they are attached to form a carbocycle or heterocycle, selected from the group consisting of —OCH2O—, —OCF2O—, —(CH2)3—, —(CH2)4—, —OCH2CH2O—, —CH2N(R13)CH2—, —CH2CH2N(R13)CH2—, —CH2N(R13)CH2CH2—, —N(R13)—CH═CH—, —CH═CH—N(R13)—, —O—CH═CH—, —CH═CH—O—, —S—CH═CH—, —CH═CH—S—, —N═CH—CH═CH—, —CH═N—CH═CH—, —CH═CH—N═CH—, —CH═CH—CH═N—, —N═CH—CH═N—, and —CH═CH—CH═CH—;
• wherein R13 is hydrogen, alkyl or cycloalkyl;
• provided that when X is O, A is CR6, B is CR7, C is CR8, D is CR9 and E is CR10, then at least one of the R6-R10 is not hydrogen.

A compound having the Formula III:

• 38
• or pharmaceutically acceptable salts or prodrugs thereof, wherein:
• R1 is an optionally substituted alkyl or hydrogen;
• R2 is hydrogen or optionally substituted alkyl;
• R3 is an alkyl, saturated carbocyclic, partially saturated carbocyclic, aryl, saturated heterocyclic, partially saturated heterocyclic or heteroaryl group, wherein said group is optionally substituted;
• and
• Y is a residue of a natural or non-natural amino acid.