Inhibitors of the ICE/ced-3 family of cysteine proteases

A compound of the following formula:

• 26
• wherein:
• n is 0, 1 or 2;
• q is 1 or 2;
• r is 1 or 2;
• R is lower alkyl, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)alkyl, substituted (heteroaryl)alkyl, NRa(Rb) or ORc;
• R1 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, or substituted heteroaryl;
• R2 is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, (CH2)pCO2R3, (CH2)mNH2, (CH2)mNHCOR10, (CH2)mN(C═NH)NH2, (CH2)pOR11, (CH2)pSR2, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), or (CH2)mheteroaryl;
• X is CH2, C═O, O, S, NH, C═ONH or CH2OC═ONH;
• A is a natural or unnatural amino acid of Formula IIa-i:
• 27 28
• B is a hydrogen atom, a deuterium atom, C1-10 so straight chain or branched alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, 2-benzoxazolyl, substituted 2-oxazolyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), (CH2)mheteroaryl, halomethyl, CO2R13, CONR14R15, CH2ZR16, CH2OCO(aryl), CH2OCO(substituted aryl), CH2OCO(heteroaryl), CH2OCO(substituted heteroaryl), or CH2OPO(R17)R18, where Z is an oxygen or a sulfur atom, or B is a group of the Formula IIIa-c:
• 29
• and wherein
• Ra and Rb are the same or different and independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)alkyl, or substituted (heteroaryl)alkyl, with the proviso that Ra and Rb cannot both be hydrogen;
• Rc is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, naphthyl, substituted naphthyl, (1 or 2 naphthyl)alkyl, substituted (1 or 2 naphthyl)alkyl, heteroaryl, substituted heteroaryl, (heteroaryl)alkyl, or substituted (heteroaryl)alkyl;
• R3 is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or substituted phenylalkyl;
• R4 is alkyl, cycloalkyl, phenyl, substituted phenyl, (CH2)nNH2, (CH2)mNHCOR10, (CH2)mN(C═NH)NH2, (CH2)pCO2R3,(CH2)pOR11, (CH2)pSR12, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), or (CH2)mheteroaryl;
• R4a is hydrogen, or methyl;
• or
• R4 and R4a taken together are —(CH2)d— where d is an integer from 2 to 6;
• R5 is phenyl, substituted phenyl, (CH2)pphenyl, (CH2)p(substituted phenyl), cycloalkyl, or benzofused cycloalkyl;
• R6 is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), or (CH2)m(1 or 2-naphthyl);
• R7 is hydrogen, fluorine, oxo, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), OR11, SR12, or NHCOR10;
• R8 is hydrogen, oxo, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), or (CH2)m(1 or 2-naphthyl);
• R9 is alkyl, cycloalkyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), or COR10;
• R10 is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), OR13, or NR4R15;
• R11 is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), or (CH2)m(1 or 2-naphthyl);
• R12 is alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), or (CH2)n(1 or 2-naphthyl);
• R13 is alkyl, cycloalkyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)m(substituted phenyl), or (CH2)m(1 or 2-naphthyl);
• R14 is hydrogen, alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, (CH2)mcycloalkyl, (CH2)mphenyl, (CH2)1(substituted phenyl), or (CH2)m(1 or 2-naphthyl);
• R15 is hydrogen or alkyl;
• or R14 and R15 taken together form a five, six or seven membered carbocyclic or heterocyclic ring, such as morpholine or N-substituted piperazine;
• R16 is phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, (CH2)mphenyl, (CH2)m(substituted phenyl), (CH2)m(1 or 2-naphthyl), or (CH2),heteroaryl;
• R17 and R18 are independently alkyl, cycloalkyl, phenyl, substituted phenyl, naphthyl, or phenylalkyl, substituted phenylalkyl, or (cycloalkyl)alkyl;
• R19 and R20 are independently hydrogen, alkyl, phenyl, substituted phenyl, (CH2)mphenyl, or (CH2)m(substituted phenyl), or R19 and R20 taken together are —(CH═CH)2—;
• R21 is hydrogen, alkyl, phenyl, substituted phenyl, (CH2)mphenyl, (CH2)m(substituted phenyl);
• R22, R23 and R24 are independently hydrogen or alkyl;
• Y1 is CH2, (CH2)2, (CH2)3, or S;
• Y2 is O or NR24;
• Y3 is CH2, O, or NR24;
• a is 0 or 1 and b is 1 or 2, provided that when a is 1 then b is 1;
• c is 1 or 2, provided that when c is 1 then a is 0 and b is 1;
• m is 1, 2, 3 or 4;
• and
• p is 1 or 2;
• or a pharmaceutically acceptable salt thereof.