Compounds and methods for inhibiting the interaction of BCL proteins with binding partners

A compound represented by formula 10:

• or an unsaturated form thereof or a pharmaceutically acceptable salt thereof;
• wherein
• m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or 6;
• A is —C(A1)(A2)-;
• each of A1 and A2 is independently H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, or —S(O)2R10;
• or has the formula 10a:
• wherein independently for each occurrence of 10a;
• n is 1, 2, 3, 4, 5, or 6;
• and
• R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2;
• or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
• or A1 and A2 taken together form ═O or ═S;
• or A1 and A2 taken together with the carbon to which they are attached form a 5 to 8 heterocyclyl, of which one or two ring atoms are independently S, O or N
• B is S or has the formula 10b:
• wherein
• D is N or CR10;
• p is 0, 1, 2, 3, 4, or 5;
• each of R7 and R8 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heterocyclyl, cycloalkenyl, or heteroaryl;
• or R7 and R8 taken together form a 3-8 membered ring;
• or R7 and R8 taken together form a 4-8 membered ring;
• R9 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
• R1 has the formula 10c or 10d:
• wherein
• q is 0, 1, 2, 3, 4, or 5;
• r is 0, 1, 2, 3, 4, or 5;
• W is a bond;
• or alkyl diradical, alkenyl diradical, or alkynyl diradical;
• Z is H, —SR10, —S(O)2R11, —NR10S(O)2R11, —S(O)R10, —N(R10)(R11), —C(O)R11, —CO2R11, —C(O)N(R10)(R11), —C(S)N(R10)(R11), —CH2C(O)heterocyclyl, —NR10C(O)R11, —NR10CO2R11, —OC(O)N(R10)(R11), —NC(O)CH(R10)(R11), —C(═NR10)N(R10)(R11), —C(═NR10)R11, hydroxyalkyl, monocyclic aryl, bicyclic aryl, heteroaryl, or heterocyclyl;
• Ar1 is represented by formula 10e:
• Wherein
• s is 0, 1, 2, 3, or 4;
• each of X2 and X3 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, OR11, —C(O)N(R10)(R11), —C(O)R11, —CO2R11, —S(O)2N(R10)(R11), SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11);
• or has the formula 10a;
• Ar2 represent independently for each occurrence are monocyclic or bicyclic aryl with 6-14 ring atoms;
• or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N;
• X1 is a bond, —C(R10)2—, —S—, —N(R10)— or —O—;
• R2 is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl;
• or has the formula 10a:
• R3 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
• each of R4, R5 and R10 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl;
• or has the formula 10a;
• or any two instances of R10 taken together form a 3-8 membered ring;
• or R4 and R5 taken together form a 3-8 membered ring;
• R6 is H or alkyl;
• R11 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
• wherein
• t is 0, 1, 2, 3, 4, or 5;
• each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
• and
• R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.

A compound represented by formula 14:

• or an unsaturated form thereof or a pharmaceutically acceptable salt thereof;
• wherein
• Y is —C(R10)2—, —(C═O)—, —(C═S)—, or —C(═NR10)—;
• X is —N(R10)—, or a bond;
• m represents independently for each occurrence 0, 1, 2, 3, 4, 5, or 6;
• A is —C(A1)(A2)-;
• each of A1 and A2 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, heteroaralkyl, —C(O)N(R10)2, —C(O)R10, —CO2R10, —S(O)2N(R10)2, —S(O)R10, —S(O)2OR10, —S(O)2R10;
• or has the formula 14a:
• wherein independently for each occurrence of 14a;
• n is 1, 2, 3, 4, 5, or 6;
• and
• R15 is aryl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, or —C(O)N(R10)2;
• or is a polycyclic ring containing 8-14 carbon atoms, of which one, two or three ring atoms are independently S, O or N;
• or A1 and A2 taken together form ═O or ═S;
• or A1 and A2 taken together with the carbon to which they are attached form a 5 to 8 heterocyclyl, of which one or two ring atoms are independently S, O or N;
• B is —(C(R)2X)—, —(XC(R)2)—, or —(C(R2)2—;
• X independently for each occurrence is S or —(NR10)—;
• R independently for each occurrence is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, aralkyl, heterocyclyl, heteroaryl, or heteroaralkyl;
• or has formula 14a;
• R1 has the formula 14b:
• wherein
• q is 0, 1, 2, 3, 4, or 5;
• r is 0, 1, 2, 3, 4, or 5;
• Ar1 is represented by formula 14c:
• Wherein
• s is 0, 1, 2, 3, or 4;
• X2 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, —OR11, —C(O)N(R10)(R11), —C(O)R11, —CO2R11, —S(O)2N(R10)(R11), —SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11);
• or has the formula 14a;
• X3 is independently for each occurrence H, alkyl, alkynyl, aryl, cycloalkyl, heterocyclyl, aralkyl, heteroaryl, heteroaralkyl, hydroxyl, acyloxy, nitrile, nitro, halide, —OR11, —C(O)N(R10)(R11), —C(O)R11, —S(O)2N(R10)(R11), —SR11, —S(O)R11, —S(O)2OR11, —S(O)2R11, —C(═NR10)N(R10)(R11), or —C(═NR10)(R11);
• or has the formula 14a;
• Ar2 represent independently for each occurrence are monocyclic or bicyclic aryl with 6-14 ring atoms;
• or a monocyclic or bicyclic heteroaryl with 5-14 ring atoms, of which one, two or three ring atoms are independently S, O or N;
• X1 is a bond, —(C(R10)2)—, —S—, —(NR10)—, or —O—;
• R2 is H, a branched or unbranched alkyl or alkenyl, cycloalkyl, heterocyclyl, or bicycloalkyl;
• or has the formula 14a:
• R3 is H, heterocyclyl, heteroaryl, —OR10, —SR10, —N(R10)2, —N(R10)CO2R10, —N(R10)C(O)N(R10)2, —CO2R10, —OCO2R10, —OC(O)N(R10)2, —C(O)N(R10)2, halide, nitrile, nitro, or acylthio;
• each of R4, R5 and R10 is independently for each occurrence H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, or heteroaryl;
• or has the formula 14a;
• or any two instances of R10 taken together form a 3-8 membered ring;
• or R4 and R5 taken together form a 3-8 membered ring;
• R6 is H or alkyl;
• R11 independently for each occurrence is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, cycloalkenyl, bicycloalkyl, heterocyclyl, heteroaryl, or —[C(R12)(R13)]t—R14;
• wherein
• t is 0, 1, 2, 3, 4, or 5;
• each of R12 and R13 is independently for each occurrence H, alkyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
• and
• R14 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclylalkyl, alkoxy, amino, amido, or carboxyl.