Pyrrolidine inhibitors of IAP

A method of sensitizing a cell to an apoptotic signal comprising introducing into said cell a compound of Formula I:

• wherein
• A is thiazole;
• ring A and Q together are selected from the group consisting of:
• Q is (a) alkyl, wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, or —NR8—C(NH)—;
• and the alkyl is optionally substituted with one or more halogen, cyano, nitro, optionally substituted carbocycle, or optionally substituted heterocycle;
• or
• (b) a carbocycle or heterocycle optionally substituted with one or more halogen, nitro, cyano, oxo, alkyl, carbocycle, or heterocycle;
• wherein one or more CH2 groups of the alkyl substituent on Q is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—, and the alkyl is optionally substituted with one or more halogen, cyano, nitro, an optionally substituted carbocycle, or an optionally substituted heterocycle;
• and
• wherein the carbocycle or heterocycle substituents on Q are optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, carbocycle, or heterocycle;
• X1 and X2 are each independently O or S;
• Y is CH2;
• R1 is H, or R1 and R2 together form a 5-8 member ring;
• R2 is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle, or heterocyclylalkyl, each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino, or nitro;
• R3 is H or alkyl optionally substituted with halogen or hydroxyl;
• or R3 and R4 together form a 3-6 member heterocycle;
• R3′ is H, or R3 and R3′ together form a 3-6 member carbocycle;
• R4 is H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl;
• wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy, and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino, or nitro;
• or R4 and R4′ together form a heterocycle;
• R4′ is H;
• R5 is H or alkyl;
• R6 and R6′ are each independently H, alkyl, aryl or aralkyl;
• R7 in each instance is independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heterocycle, or —U—V;
• wherein U is —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—;
• and
• V is alkyl, a carbocycle, or a heterocycle;
• and wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—;
• and an alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
• R8 is H, alkyl, a carbocycle, or a heterocycle;
• wherein one or more CH2 groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, or —C(O)—;
• and said alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
• wherein each alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon group, having up to 12 carbon atoms;
• or a salt thereof.

A method for inhibiting the binding of an IAP protein to a caspase protein comprising contacting said IAP protein with a compound of Formula I:

• wherein
• A is thiazole;
• ring A and Q together are selected from the group consisting of:
• Q is (a) alkyl, wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, or —NR8—C(NH)—;
• and the alkyl is optionally substituted with one or more halogen, cyano, nitro, optionally substituted carbocycle, or optionally substituted heterocycle;
• or
• (b) a carbocycle or heterocycle optionally substituted with one or more halogen, nitro, cyano, oxo, alkyl, carbocycle, or heterocycle;
• wherein one or more CH2 groups of the alkyl substituent on Q is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—, and the alkyl is optionally substituted with one or more halogen, cyano, nitro, an optionally substituted carbocycle, or an optionally substituted heterocycle;
• and
• wherein the carbocycle or heterocycle substituents on Q are optionally substituted with one or more hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, carbocycle, or heterocycle;
• X1 and X2 are each independently O or S;
• Y is CH2;
• R1 is H, or R1 and R2 together form a 5-8 member ring;
• R2 is alkyl, a carbocycle, carbocyclylalkyl, a heterocycle, or heterocyclylalkyl, each optionally substituted with halogen, hydroxyl, oxo, thione, mercapto, carboxyl, alkyl, haloalkyl, alkoxy, alkylthio, sulfonyl, amino, or nitro;
• R3 is H or alkyl optionally substituted with halogen or hydroxyl;
• or R3 and R4 together form a 3-6 member heterocycle;
• R3′ is H, or R3 and R3′ together form a 3-6 member carbocycle;
• R4 is H, hydroxyl, amino, alkyl, carbocycle, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy or heterocycloalkyloxycarbonyl;
• wherein each alkyl, carbocycloalkyl, carbocycloalkyloxy, carbocycloalkyloxycarbonyl, heterocycle, heterocycloalkyl, heterocycloalkyloxy, and heterocycloalkyloxycarbonyl is optionally substituted with halogen, hydroxyl, mercapto, carboxyl, alkyl, alkoxy, amino, imino, or nitro;
• or R4 and R4′ together form a heterocycle;
• R4′ is H;
• R5 is H or alkyl;
• R6 and R6′ are each independently H, alkyl, aryl, or aralkyl;
• R7 in each instance is independently H, cyano, hydroxyl, mercapto, halogen, nitro, carboxyl, amidino, guanidino, alkyl, a carbocycle, a heterocycle, or —U—V;
• wherein U is —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—;
• and
• V is alkyl, a carbocycle, or a heterocycle;
• and wherein one or more CH2 groups of an alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, —N(R8)—, —C(O)—, —C(O)—NR8—, —NR8—C(O)—, —SO2—NR8—, —NR8—SO2—, —NR8—C(O)—NR8—, —NR8—C(NH)NR8—, —NR8—C(NH)—, —C(O)—O—, or —O—C(O)—;
• and an alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
• R8 is H, alkyl, a carbocycle, or a heterocycle;
• wherein one or more CH2 groups of said alkyl is optionally replaced with —O—, —S—, —S(O)—, —S(O)2—, or —C(O)—;
• and said alkyl, carbocycle, and heterocycle is optionally substituted with hydroxyl, alkoxy, acyl, halogen, mercapto, oxo (═O), carboxyl, acyl, halo-substituted alkyl, amino, cyano, nitro, amidino, guanidino, an optionally substituted carbocycle, or an optionally substituted heterocycle;
• wherein each alkyl is independently a branched or unbranched, saturated or unsaturated aliphatic hydrocarbon group, having up to 12 carbon atoms;
• or a salt thereof.