Caspase inhibitors and methods of use thereof

A compound having formula I:

• or an enantiomer or a mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, wherein
• X and Y are selected as follows:
• i) X is C═O;
• and Y is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —RaORb, or —RaN(Rc)(Rd);
• or
• ii) X is —O—, or —N(Ro)—;
• Y is hydrogen, —C(O)Rd, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
• Y is optionally substituted with one to three groups Q1;
• R3, Y1, Y2 and Y3 are selected as follows:
• i) Y1 together with R3 forms an optionally substituted saturated or unsaturated bicyclic ring B, where substituents on ring B, when present, are selected from one to three groups Q1;
• Y2 is absent, hydrogen or alkyl;
• and
• Y3 is absent, hydrogen or alkyl;
• or
• ii) R3 is hydrogen or alkyl;
• Y1 and Y2 together are ═O;
• and Y3 is —N(Z1)(Z2);
• X, Y, R3 and Y1 are selected such that when X is O, then Y1 and R3 cannot form ring B;
• each Q1 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• each Q1 is optionally substituted with one to three groups Q2 each Q2 is independently alkyl, halo, haloalkyl, aryl or haloaryl;
• each Ra is independently alkylene or a direct bond;
• Rb is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• each Rc is independently hydrogen or alkyl;
• each Rd is independently alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl or —RaORb;
• each Rd is optionally substituted with one to three groups Q1;
• R1 and R2 are selected as follows:
• i) R1 and R2 are each independently hydrogen, alkyl or cycloalkyl;
• or
• ii) R1 and R2 together with the carbon atom on which they are substituted form an optionally substituted saturated or unsaturated ring A, where the substituents on ring A, when present, are selected from one to three groups Q1;
• R4, R5, R6, R7 and R8 are each independently hydrogen or alkyl;
• R9 is aryl or heteroaryl, each optionally substituted with one to four substituents Q1;
• R10 is alkylene;
• Z1 and Z2 are selected as follows:
• i) Z1 is hydrogen or alkyl;
• and Z2 is aryl, cycloalkyl, heteroaryl or heterocyclyl, each optionally substituted with one to four substituents Q3;
• or
• ii) Z1 and Z2 together with the nitrogen atom on which they are substituted form an optionally substituted saturated or unsaturated ring C, where the substituents on ring C, when present, are selected from one to three groups Q3;
• each Q3 is independently selected from alkyl, halo, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —R11OR12, —R11OR11OR12, —R11N(R13)(R14), —R11SR12, —R11OR11N(R13)(R14), —R11C(J)N(R13)(R14), —R11OR11C(J)N(R13)(R14), —C(J)R15 and R11S(O)tR16;
• where each Q3 is optionally substituted with one to three groups Q4, where each Q4 is independently alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;
• each R11 is independently alkylene, alkenylene or a direct bond;
• each R12 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• R13 and R14 are selected as follows:
• i) R13 and R14 are each independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• or
• ii) R13 and R14 together with the nitrogen atom on which they are substituted form a 5 or 6-membered heterocyclyl or heteroaryl ring, optionally substituted with one or two alkyl, halo, haloalkyl, hydroxyl, alkoxy or cycloalkyl;
• each R15 is independently hydroxy, alkyl, haloalkyl, alkoxy, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclyl;
• each R16 is independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl;
• J is O or S;
• and
• t is 0-2.