Inhibitors of interleukin-1β converting enzyme

A compound represented by formula (III):

• wherein Y is:
• m is 0 or 1;
• Z is —CH2, —, [—O—, —S—, —S(O)—, —S(O)2—,] —C(O)—, or —C (═N—OR21)—;
• C is benzo, wherein the ring is optionally singly or multiply substituted with —R4;
• R1 is -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, wherein each -aryl or -heteroaryl is optionally singly or multiply substituted with R17;
• R2 is a bond, —C(O)—, —C(O)C(O)—, —S(O)2—, —OC(O)—, —N(H)C(O)—, —N(H)S(O)2—, —N(H)C(O)C(O)—, —CH═CHC(O)—, —OCH2C(O)—, —N(H)CH2C(O)—, —N(R19)C(O)—, —N(R19)S(O)2—, —N(R19)C(O)C(O)—, or —N(R19)CH2C(O)—;
• R4 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —C(O)N(H)alkyl, —CON(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S(O)2alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2;
• R6 is —H, —CH2OR9, —CH2SR10, —CH2N(H)R9, —CH2N(R9)R12, —CHN2, —CH2F, —CH2Cl, —C(O)N(R11)R12, —R13, or —R14;
• R7 is —C(O)alkyl, —C(O)cycloalkyl, —C(O)alkyenyl, —C(O)alkylaryl, —C(O)alkylheteroaryl, —C(O)heterocycle, or —C(O)alkylheterocycle;
• R8 is -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, -alkylheteroaryl, or -alkylheterocycle;
• R9 is —H, —C(O)aryl, —C(O)heteroaryl, —C(O)alkylaryl, —C(O)alkylheteroaryl, -alkylaryl, -alkylheteroaryl, -aryl, -heteroaryl, or —P(O)R15R16;
• R10 is -alkylaryl or -alkylheteroaryl;
• R11 and R12 are independently —H, -alkyl, -aryl, -heteroaryl, -cycloalkyl, -alkylaryl, or -alkylheteroaryl;
• R13 is -alkylaryl or -alkylheteroaryl;
• R14 is
• wherein (i) is optionally substituted with one or more —R17 and (ii) is optionally substituted with one or more —R17, —R18 or —R20;
• X is O or S;
• R15 and R16 are independently —H, —OH, -alkyl, -aryl, -heteroaryl, -cycloalkyl, -alkylaryl, -alkylheteroaryl, —Oalkyl, —Oaryl, —Oheteroaryl, —Oalkylaryl, or —Oalkylheteroaryl;
• R17 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, —S(O)2NH2, —C(O)H, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —CO2alkyl, —C(O)N(H)alkyl, —C(O)N(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S(O)2N(H)alkyl, —S(O)2N(alkyl)2, —S-alkyl, —S(O)2alkyl, or —C(O)alkyl;
• R18 is -aryl, -heteroaryl, -alkylaryl, -alkylheteroaryl, —O-aryl, —O-heteroaryl, —O-alkylaryl, —O-alkylheteroaryl, —N(H)aryl, —N(aryl)2, —N(H)heteroaryl, —N(heteroaryl)2, —N(H)alkylaryl, —N(alkylaryl)2, —N(H)alkylheteroaryl, —N(alkylheteroaryl)2, —S-aryl, —S-heteroaryl, —S-alkylaryl, —S-alkylheteroaryl, —C(O)aryl, —C(O)heteroaryl, —C(O)alkylaryl, —C(O)alkylheteroaryl, —CO2aryl, —CO2heteroaryl, —CO2alkylaryl, —CO2alkylheteroaryl, —C(O)N(H)aryl, —C(O)N(aryl)2, —C(O)N(H)heteroaryl, —C(O)N(heteroaryl)2, —C(O)N(H)alkylaryl, —C(O)N(alkylaryl)2, —C(O)N(H)alkylheteroaryl, —C(O)N(alkylheteroaryl)2, —S(O)2-aryl, —S(O)2-heteroaryl, —S(O)2-alkylaryl, —S(O)2-alkylheteroaryl, —S(O)2N(H)-aryl, —S(O)2N(H)-heteroaryl, —S(O)2N(H)-alkylaryl, —S(O)2N(H)-alkylheteroaryl, —SO2N(aryl)2, —SO2N(heteroaryl)2, —SO2N(alkylaryl)2, —SO2N(alkylheteroaryl)2, —N(H)C(O)N(H)aryl, —N(H)C(O)N(H)heteroaryl, —N(H)C(O)N(H)alkylaryl, —N(H)C(O)N(H)alkylheteroaryl, —N(H)C(O)N(aryl)2, —N(H)C(O)N(heteroaryl)2, N(H)C(O)N(alkylaryl)2, or —N(H)C(O)N(alkylheteroaryl)2;
• R19 is —H, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle;
• R20 is -alkyl-R18;
• and
• R21 is H, alkyl, alkylaryl, or -alkylheteroaryl.

A process for preparing a compound represented by formula (V):

• wherein:
• R22 is:
• R23 is:
• m is 1 or 2;
• Z is —CH2—, [—O—, —S—, —S(O)—, —S(O)2—,] —C(O)—, or —C (═N—OR21)—;
• C is benzo, wherein the ring is optionally singly or multiply substituted with —R4;
• R1 is -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, wherein each -aryl or -heteroaryl is optionally singly or multiply substituted with R17;
• R2 is a bond, —C(O)—, —C(O)C(O)—, —S(O)2—, —OC(O)—, —N(H)C(O)—, —N(H)S(O)2—, —N(H)C(O)C(O)—, —CH═CHC(O)—, —OCH2C(O)—, —N(H)CH2C(O)—, —N(R19)C(O)—, —N(R19)S(O)2—, —N(R19)C(O)C(O)—, or —N(R19)CH2C(O)—;
• R4 is —OH, —F, —Cl, —Br, —I, —NO2, —CN, —NH2, —CO2H, —C(O)NH2, —N(H)C(O)H, —N(H)C(O)NH2, -alkyl, -cycloalkyl, -perfluoroalkyl, —O-alkyl, —N(H)alkyl, —N(alkyl)2, —C(O)N(H)alkyl, —CON(alkyl)2, —N(H)C(O)alkyl, —N(H)C(O)N(H)alkyl, —N(H)C(O)N(alkyl)2, —S-alkyl, —S(O)2alkyl, —C(O)alkyl, —CH2NH2, —CH2N(H)alkyl, or —CH2N(alkyl)2;
• R19 is —H, -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle;
• R21 is H, alkyl, alkylaryl, or alkylheteroaryl;
• and
• R24 -alkyl, -cycloalkyl, -aryl, -heteroaryl, -alkylaryl, or -alkylheteroaryl, or -alkylheterocycle;
• comprising the steps of:
• a) reacting a compound represented by formula (VI):
• (VI) R22—OH, wherein R22 is as defined above, with a compound represented by formula (VII):
• wherein R24 is as defined above, in the presence of an inert solvent, triphenylphoshine, a nucleophilic scavenger, and tetrakis-triphenyl phosphine palladium(0) at ambient temperature under an inert atmosphere;
• and
• b) adding to the mixture formed in step a), HOBT and EDC.