Triazole compounds that modulate HSP90 activity

A method of treating cancer in a subject in need thereof, wherein the cancer is selected the group consisting of myeloid leukemia, T cell leukemia, B cell leukemia, chronic myeloid leukemia, acute myelocytic leukemia, non-Hodgkin's lymphoma, multiple myeloma, non-small cell lung cancer, small cell lung cancer, melanoma, gastrointestinal stromal tumors, gastric cancer, breast cancer, renal cell carcinoma, prostate cancer, colon carcinoma, mesothelioma, pancreatic cancer and ovarian cancer, comprising administering to the subject an effective amount of a compound according to the structural formula:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• m is 0 or 1;
• r is 0, 1 or 2;
• R8 is C1-C3 alkyl or C1-C3 haloalkyl;
• R3 is H, C1-C4 alkyl or C3-C6 cycloalkyl;
• R7 is phenyl, S(O)pR31, OR31, N(R31)2 or ═NN(R31)2;
• R13 and R14 are individually hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, benzyl, 5-7 membered heteroaryl, —N(R32)2, —C(O)R32, —C(O)OR32, —S(O)pR32, or —S(O)pN(R32)2, wherein each R13 and R14 that is not hydrogen is optionally and independently substituted with one or more R21;
• or R13 and R14, taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl which is optionally substituted with one or more R21;
• each R31 is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 5-14 membered heterocyclyl, C6-C20 aryl, 5-14 membered heteroaryl, —OR32, —C(O)R32, —C(O)OR32, —C(S)R32, —C(O)SR32, —C(O)N(R32)2, —C(S)N(R32)2, —C(NR32)OR32, —C(NR32)R32, —C(NR32)N(R32)2, —C(NR32)SR32, —S(O)pR32, —S(O)pOR32 or —S(O)pN(R32)2, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl represented by R31 are independently and optionally substituted by one or more R21;
• or two R31 moieties attached to the same nitrogen atom are taken together to form a 5-14 membered heterocyclyl or a 5-14 membered heteroaryl, each of which are optionally and independently substituted with one or more R21;
• each R32 is independently H, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C3-C7 cycloalkyl, phenyl, or benzyl, wherein each R32 with at least one hydrogen atom is optionally substituted with one or more R21;
• or two R32 substituents that are attached to the same atom or adjacent atoms, taken together with the atom(s) to which they are attached, form a 5-7 membered heterocyclyl or C3-C7 cycloalkyl which are each optionally and independently substituted with one or more R21;
• and
• each R21 is independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, 5-14 membered heterocyclyl, C6-C20 aryl, 5-14 membered heteroaryl, C3-C7 cycloalkyl-(C1-C3)alkyl, 5-14 membered heterocyclyl-(C1-C3)alkyl, C6-C20 aryl-(C1-C3)alkyl, 5-14 membered heteroaryl-(C1-C3)alkyl, halo, cyano, nitro, azido, —N(R32)2, —OR32, —C(O)R32, —C(O)OR32, —C(S)R32, —C(O)SR32, —C(S)SR32, —C(S)OR32, —C(O)N(R32)2, —C(S)N(R32)2, —C(NR32)OR32, —C(NR32)R32, —C(NR32)N(R32)2, —C(NR32)SR32, —OC(O)N(R32)2, —OC(O)R32, —OC(O)OR32, —OC(S)OR32, —OC(NR12)OR32, —SC(O)R32, —SC(O)OR32, —SC(NR32)OR32, —OC(S)R32, —SC(S)R32, —SC(S)OR32, —OC(O)N(R32)2, —OC(S)N(R32)2, —OC(NR32)N(R32)2, —SC(O)N(R32)2, —SC(NR32)N(R32)2, —SC(S)N(R32)2, —OC(NR32)R32, —SC(NR32)R32, —NR32C(O)R32, —NR32C(S)R32, —NR32C(S)OR32, —NR32C(NR32)R32, —NR32C(O)OR32, —NR32C(NR32)OR32, —NR32C(O)N(R32)2, —NR32C(S)N(R32)2, —NR32C(NR32)N(R32)2, —S(O)pR32, —OS(O)pR32, —OS(O)pOR32, —OS(O)pN(R32)2, —S(O)pOR32, —NR32S(O)pR32, —NR32S(O)pN(R32)2, —NR32S(O)pOR32, —S(O)pN(R32)2, —SS(O)pR32, —SS(O)pOR32, —SS(O)pN(R32)2, —OP(O)(OR32)2, or —SP(O)(OR32)2, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl represented by R21 are each optionally and independently substituted with one to three groups from halo, C1-C3 alkyl, phenyl, benzyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, nitro, cyano, azido, amino and C1—O5 carbamoyl;
• or two R21 moieties attached to the same atom form an oxo (═O), thioxo (═S) or imino (═NR32).

A method of treating cancer in a subject in need thereof, wherein the cancer is selected the group consisting of myeloid leukemia, T cell leukemia, B cell leukemia, chronic myeloid leukemia, acute myelocytic leukemia, non-Hodgkin's lymphoma, multiple myeloma, non-small cell lung cancer, small cell lung cancer, melanoma, gastrointestinal stromal tumors, gastric cancer, breast cancer, renal cell carcinoma, prostate cancer, colon carcinoma, mesothelioma, pancreatic cancer and ovarian cancer, comprising administering to the subject an effective amount of a compound according to the structural formula:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• R15 is C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, benzyl, —C(O)R42, —N(R42)2, —C(NR42)R42, C(NR42)N(R42)2, —S(O)pR42 or —S(O)pN(R42)2, wherein each alkyl, alkenyl, cycloalkyl, phenyl and benzyl, represented by R15 is optionally substituted with one or more R22;
• each R42 is independently H or C1-C4 alkyl;
• or two R42 moieties attached to the same nitrogen atom are taken together to form a 5-7 membered heterocyclyl;
• and
• each R22 is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxyl, C3-C6 cycloalkyl, 5-7 membered heterocycle, —C(O)R42, —C(O)OR42, —C(O)N(R42)2, —N(R42)2, or —NR42C(O)R42;
• or two R21 moieties attached to the same atom, taken together, form an oxo (═O), thiooxo (═S), or imino (═N);
• each R25 is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxyl, C3-C6 cycloalkyl, 5-7 membered heterocycle, —C(O)R42, —C(O)OR42, —C(O)N(R42)2, —N(R42)2, or —NR42C(O)R42;
• or two R25 moieties attached to the same atom, taken together, form an oxo (═O), thiooxo (═S), or imino (═N);
• and
• u is 0, 1 or 2;
• provided that R15 is other than isopropyl or —(CH2)2N(CH3)2.

A method of treating cancer in a subject in need thereof, wherein the cancer is selected the group consisting of myeloid leukemia, T cell leukemia, B cell leukemia, chronic myeloid leukemia, acute myelocytic leukemia, non-Hodgkin's lymphoma, multiple myeloma, non-small cell lung cancer, small cell lung cancer, melanoma, gastrointestinal stromal tumors, gastric cancer, breast cancer, renal cell carcinoma, prostate cancer, colon carcinoma, mesothelioma, pancreatic cancer and ovarian cancer, comprising administering to the subject an effective amount of a compound according to the structural formula:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• N-Het is piperidine, piperazine, morpholine, pyrrolidine, imidazolidine, hexahydropyrimidine or pyrazolidine, each optionally and independently substituted with one or two R23;
• R16 is H, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, phenyl, benzyl, —C(O)R52, —N(R52)2, —C(NR52)R52, —C(NR52)N(R52)2, —S(O)pR52 or —S(O)pN(R52)2, wherein each alkyl, alkenyl, cycloalkyl, phenyl and benzyl, represented by R16 is optionally substituted with one or more R23;
• each R52 is independently H or C1-C4 alkyl;
• or two R52 moieties attached to the same nitrogen atom are taken together to form a 5-7 membered heterocyclyl;
• and
• each R23 is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxyl, C3-C6 cycloalkyl, 5-7 membered heterocycle, —C(O)R52, —C(O)OR52, —C(O)N(R52)2, —N(R52)2, or —NR52C(O)R52;
• or two R23 moieties attached to the same atom, taken together, form an oxo (═O), thiooxo (═S), or imino (═N);
• s is 0, 1 or 2;
• provided that when N-Het is morpholine and s is 0, then R16 is other than H, ethyl, isopropyl, isobutyl, propyl, cyclohexyl, or an ethylene substituted with hydroxyl, methoxy, dimethylamine, diethylamine, pyrrolidine, 4-methylpiperazine or morpholine;
• when N-Het is 4-methylpiperidinyl and s is 0, then R16 is other than H;
• when N-Het is pyrrolidinyl and s is 0, then R16 is other than an ethylene substituted with a pyrrolidine, morpholine, or 4-methyl-piperazine;
• and
• when N-Het is 4-methylpiperazinyl or 4-ethylpiperazinyl and s is 0, then R16 is other than isopropyl.