IAP BIR domain binding compounds

A method of enhancing apoptosis in a cell comprising contacting the cell with a compound of Formula IA:

• including any enantiomer, diastereoisomer or tautomer thereof,
• wherein:
• n is 0 or 1;
• m is 0, 1 or 2;
• Y is NH, O or S;
• X and X1 are each a C1-C3 alkyl which forms part of a ring, the ring being optionally substituted with one or more R11 substituents;
• Q and Q1 are, independently:
• 1) —CH2—,
• 2) —CH2CH2—,
• 3) —CH(C1-C6 alkyl)-,
• 4) —CH(C3-C7 cycloalkyl)-,
• 5) —C3-C7 cycloalkyl)-,
• 6) —CH(C1-C6 alkyl-C3-C7 cycloalkyl)-;
• or
• 7) —C(O)—;
• A and A1 are, independently:
• 1) NR6, or
• 2) NR600;
• 2) NR600;
• BG is
• 1) Y1-L-Y100—;
• or
• 2) -L-;
• or BG is —Y1-L1-Z-L100-Y100—, wherein L1 and L100 are equal or L1 and L100 are different;
• Y1 and Y100 are, independently:
• 1) —C(O)—,
• 2) —S(O)2—, or
• 3) —C(O)N(R8)—;
• L, L1 and L100 are, independently:
• 1) —C1-C12 alkyl-,
• 2) —C2-C12 alkenyl-,
• 3) —C2-C12 alkynyl-,
• 4) —C3-C7 cycloalkyl-,
• 5) —C3-C7 cycloalkenyl-,
• 5) -aryl-,
• 6) -biphenyl-,
• 7) -heteroaryl-,
• 8) -heterocycyl-,
• 9) —C1-C6 alkyl-(C2-C6 alkenyl)-C1-C6 alkyl-,
• 10) —C1-C6 alkyl-(C2-C4 alkynyl)-C1-C6 alkyl,
• 11) —C1-C6 alkyl-(C3-C7 cycloalkyl)-C1-C6 alkyl,
• 12) —C1-C6 alkyl-aryl-C1-C6 alkyl,
• 13) —C1-C6 alkyl-biphenyl-C1-C6 alkyl,
• 14) —C1-C6 alkyl-heteroaryl-C1-C6 alkyl,
• 15) —C1-C6 alkyl heterocycyl-C1-C6 alkyl, or
• 16) —C1-C6 alkyl-O—C1-C6 alkyl;
• 17) —N(R8)C(O)N(R8)—, or
• 18) —C1-C6 alkyl-Z—C1-C6 alkyl-;
• wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyenyl and the cycloalkyl are optionally substituted with one or more R7 substituents;
• and the aryl, the heteroaryl, the biphenyl and the heterocyclyl are optionally substituted with one or more R11 substituents;
• Z is selected from:
• 1) —N(R8)CON(R8)—,
• 2) —N(R8)C(O)-aryl-C(O)N(R8)—,
• 3) —N(R8)C(O)-heteroaryl-C(O)N(R8)—,
• 4) —C(O)—,
• 5) —S(O)2—,
• 6) —N(R8)C(O)—,
• 7) —C(O)N(R8)—,
• 8) —OC(O)N(R8)—,
• 9) —S(O)2N(R8)—,
• 10) —N(R8)—C1-C12-alkyl-N(R8)—,
• 11) —N(R8)—C(O)C(O)—N(R8)—,
• 12) —N(R8)—C(O)—C1-C12-alkyl-C(O)—N(R8)—,
• 13) —N(R8)—C(O)-aryl-O-aryl-C(O)—N(R8)—,
• 14) —N(R8)—C(O)-biphenyl-C(O)—N(R8)—,
• 15) —N(R8)—S(O)2—C1-C12-alkyl-S(O)2—N(R8)—,
• 16) —N(R8)—S(O)2-aryl-S(O)2—N(R8)—,
• 17) —N(R8)—S(O)2-heteroaryl-S(O)2—N(R8)—,
• 18) —N(R8)—S(O)2-biphenyl-S(O)2—N(R8)—,
• 19) —N(R8)-aryl-N(R8)—,
• 20) —N(R8)-heteroaryl-N(R8)—, or
• 21) —N(R8)-biphenyl-N(R8)—;
• wherein the alkyl and the cycloalkyl are optionally substituted with one or more R7 substituents, and the aryl, heteroaryl and heterocyclyl are optionally substituted with one or more R11 substituents;
• R1, R1a R100, and R100a are, independently:
• 1) H, or
• 2) C1-C6 alkyl optionally substituted with one or more R7 substituents;
• R2, R3, R4, R5, R5a, R200, R300, R400, R500 and R500a are each independently H or C1-C6 alkyl optionally substituted with one or more R7 substituents;
• R6 and R600 are each, independently:
• 1) H,
• 2) haloalkyl,
• 3) C1-C6 alkyl,
• 4) C2-C6 alkenyl,
• 5) C2-C4 alkynyl,
• 6) C3-C7 cycloalkyl,
• 7) C3-C7 cycloalkenyl,
• 8) aryl,
• 9) heteroaryl,
• 10) heterocyclyl,
• 11) heterobicyclyl,
• 12) —C(O)(O)n—R12,
• 13) —C(═Y)NR9R10, or
• 14) —S(O)2—R12,
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R7 substitutents;
• and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R11 substituents;
• R7 is
• 1) halogen,
• 2) NO2,
• 3) CN,
• 4) haloalkyl,
• 5) C1-C6 alkyl,
• 6) C2-C6 alkenyl,
• 7) C2-C4 alkynyl,
• 8) C3-C7 cycloalkyl,
• 9) C3-C7 cycloalkenyl,
• 10) aryl,
• 11) heteroaryl,
• 12) heterocyclyl,
• 13) heterobicyclyl,
• 14) —OR8,
• 15) —S(O)mR8,
• 16) —NR9R10,
• 17) —NR9S(O)2R12,
• 18) —COR8,
• 19) —C(O)OR8,
• 20) —CONR9R10,
• 21) —S(O)2NR9R10,
• 22) —OC(O)R8,
• 23) —OC(O)Y—R12,
• 24) —SC(O)R8, or
• 25) —NC(Y)R9R10,
• wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R11 substituents;
• R8 is
• 1) H,
• 2) haloalkyl,
• 3) C1-C6 alkyl,
• 4) C2-C6 alkenyl,
• 5) C2-C4 alkynyl,
• 6) C3-C7 cycloalkyl,
• 7) C3-C7 cycloalkenyl,
• 8) aryl,
• 9) heteroaryl,
• 10) heterocyclyl,
• 11) heterobicyclyl,
• 12) —NC(═Y)R9R10, or
• 13) C1-C6 alkyl-C2-C4 alkenyl, or
• 14) C1-C6 alkyl-C2-C4 alkynyl,
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R7 substituents;
• and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R11 substituents;
• R9 and R10 are each, independently:
• 1) H,
• 2) haloalkyl,
• 3) C1-C6 alkyl,
• 4) C2-C6 alkenyl,
• 5) C2-C4 alkynyl,
• 6) C3-C7 cycloalkyl,
• 7) C3-C7 cycloalkenyl,
• 8) aryl,
• 9) heteroaryl,
• 10) heterocyclyl,
• 11) heterobicyclyl,
• 12) —C(O)R12,
• 13) —C(O)Y—R12, or
• 14) —S(O)2—R12,
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R7 substituents;
• and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R11 substituents;
• or R9 and R10 together with the nitrogen atom to which they are bonded form a five, six or seven membered heterocyclic ring optionally substituted with one or more R7 substituents;
• R11 is
• 1) halogen,
• 2) NO2,
• 3) CN,
• 4) —B(OR13)(OR14),
• 5) C1-C6 alkyl,
• 6) C2-C6 alkenyl,
• 7) C2-C4 alkynyl,
• 8) C3-C7 cycloalkyl,
• 9) C3-C7 cycloalkenyl,
• 10) haloalkyl,
• 11) —OR8,
• 12) —NR9R10,
• 13) —SR8,
• 14) —COR8,
• 15) —C(O)OR8,
• 16) —S(O),R8,
• 17) —CONR9R10,
• 18) —S(O)2NR9R10,
• 19) aryl,
• 20) heteroaryl,
• 21) heterocyclyl, or
• 22) heterobicyclyl,
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R7 substituents;
• R12 is
• 1) haloalkyl,
• 2) C1-C6 alkyl,
• 3) C2-C6 alkenyl,
• 4) C2-C4 alkynyl,
• 5) C3-C7 cycloalkyl,
• 6) C3-C7 cycloalkenyl,
• 7) aryl,
• 8) heteroaryl,
• 9) heterocyclyl, or
• 10) heterobicyclyl,
• wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more R7 substituents;
• and wherein the aryl, heteroaryl, heterocyclyl, and heterobicyclyl are optionally substituted with one or more R11 substituents;
• R13 and R14 are each, independently:
• 1) H, or
• 2) C1-C6 alkyl;
• or R13 and R14 are combined to form a ring system;
• or a pharmaceutically acceptable salt thereof;
• whereby apoptosis in the cell is enhanced.