Triazole compounds that modulate HSP90 activity

1. A compound according to the formula:

or a pharmaceutically acceptable salt thereof; wherein:

Y is O or S;

R 1 is H or C 1 -C 4 alkyl;

R 2 and R 3 are each independently H;

R 4 is H or C 1 -C 8 alkyl

or R 2 and R 3 , taken together with the atoms to which they are attached, form a C 4 -C 7 cycloalkyl, C 6 -aryl, 5-7 membered heterocyclyl or 5-7 membered heteroaryl, each of which is optionally substituted with one or more C 1 -C 6 alkyl;

or R 3 and R 4 , taken together with the atoms to which they are attached, form a C 4 -C 7 cycloalkyl, C 6 -aryl, 5-7 membered heterocyclyl, or 5-7 membered heteroaryl, each of which is optionally substituted with one or more C 1 -C 6 alkyl;

or R 4 and R 2′ , taken together with the atoms to which they are attached, form a C 4 -C 7 cycloalkyl, C 6 -aryl, 5-7 membered heterocyclyl, or 5-7 membered heteroaryl, each of which is optionally substituted with one or more C 1 -C 6 alkyl;

R 5 is ZR*, C 3 -C 7 cycloalkyl, 5-14 membered heterocyclyl, C 6 -C 15 aryl, 5-14 membered heteroaryl, C 6 -C 15 aryl-substituted C 1 -C 6 alkylene, 5-14 membered heteraralkyl, each of which may be optionally substituted with one or more R 20 ;

R 6 and R 7 are independently H, C 1 -C 6 alkyl, wherein each alkyl represented by R 6 or R 7 is optionally and independently substituted with one or more R 20 ;

each R 10 is independently selected from H, C 1 -C 6 alkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-14 membered heterocyclyl, C 6 -C 20 aryl, 5-14 membered heteroaryl, C 7 -C 24 aralkyl, 5-14 membered heteraralkyl, —OR 12 , —N(R 12 ) 2 , —C(O)R 12 , —C(O)OR 12 , —C(S)R 12 , —C(O)SR 12 , —C(O)N(R 12 ) 2 , —C(S)N(R 12 ) 2 , —C(NR 12 )OR 12 , —C(NR 12 )R 11 , —C(NR 12 )N(R 12 ) 2 , —C(NR 12 )SR 12 , —S(O) p R 12 , —S(O) p OR 12 or —S(O) p N(R 12 ) 2 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteroaralkyl represented by R 10 are each independently and optionally substituted by one or more R 20 ;

each R 12 is independently H, C 1 -C 3 alkyl, C 2 -C 3 alkenyl, C 1 -C 3 haloalkyl, C 3 -C 7 cycloalkyl, phenyl, or benzyl;

or two R 12 substituents that are attached to the same atom, taken together with the atom to which they are attached, form a 5-7 membered heterocyclyl or C 3 -C 7 with are each optionally and independently substituted with one to three groups selected from halo, C 1 -C 3 alkyl, phenyl, benzyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitrOCyano, azido, amino and C 1 -C 5 carbamoyl;

each R 20 is independently selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-14 membered heterocyclyl, C 6 -C 20 aryl, 5-14 membered heteroaryl, C 3 -C 7 cycloalkyl-(C 1 -C 3 )alkyl, 5-14 membered hetercyclyl-(C 1 -C 3 )alkyl, C 6 -C 20 aryl-(C 1 - 3 )alkyl, 5-14 membered heteraryl-(C 1 -C 3 )alkyl, halo, cyano, nitro, azido, —N(R 12 ) 2 , —OR 12 , —C(O)R 12 , —C(O)OR 12 , —C(S)R 12 , —C(O)SR 12 , —C(S)SR 12 , —C(S)OR 12 , —C(O)N(R 12 ) 2 , —C(S)N(R 12 ) 2 , —C(NR 12 )or 12 , —C(NR 12 )r 12 , —C(NR 12 )N(R 12 ) 2 , —C(NR 12 )SR 12 , —OC(O)N(R 12 ) 2 , —OC(O)R 12 , —OC(O)OR 12 , —OC(S)OR 12 , —OC(NR 12 )or 12 , —SC(O)R 12 , —SC(O)OR 12 , —SC(NR 12 )OR 12 , —OC(S)R 12 , —SC(S)R 12 , —SC(S)OR 12 , —OC(O)N(R 12 ) 2 , —OC(S)N(R 12 ) 2 , —OC(NR 12 )N(R 12 ) 2 , —SC(O)N(R 12 ) 2 , —SC(NR 12 )N(R 12 ) 2 , —SC(S)N(R 12 ) 2 , —OC(NR 12 )r 12 , —SC(NR 12 )R 12 , —NR 12 C(O)R 12 , —NR 12 C(S)R 12 , —NR 12 C(S)OR 12 , —NR 12 C(NR 12 )R 12 , —NR 12 C(O)OR 12 , —NR 12 C(NR 12 )or 12 , —NR 12 C(O)N(R 12 ) 2 , —NR 12 C(S)N(R 12 ) 2 , —NR 12 C(NR 12 )N(R 12 ) 2 , —S(O) p R 12 , —OS—(O) p R 12 , —OS(O) p OR 12 , —OS(O) p N(R 12 ) 2 , —S(O) p OR 12 , —NR 12 S(O) p R 12 , —NR 12 S(O) p N(R 12 ) 2 , —NR 12 S(O) p OR 12 , —S(O) p N(R 12 ) 2 , —SS(O) p R 12 , —SS(O) p OR 12 , —SS(O) p N(R 12 ) 2 , —OP(O)(OR 12 ) 2 , or —SP(O)(OR 12 ) 2 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteroaralkyl represented by R 20 are each optionally and independently substituted with one to three groups from halo, C 1 -C 3 alkyl, phenyl, benzyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, nitro, cyano, azido, amino and C 1 -C 5 carbamoyl;

or two R 20 moieties attached to the same atom form an oxo (═O), thioxo (═S) or imino (═NR 12 );

R* is aryl or heteroaryl, each of which is optionally substituted with one or more R 20 ;

Z is NR 10 , C(O), C(S),C(═NR 10 , or S(O) p ; and

p is 0, 1 or 2;

provided that one of R 2 and R 3 , R 3 and R 4 , or R 4 and R 2′ are taken together to form a cycloalkyl, aryl, heterocyclyl or heteroaryl, as defined above.

2. The compound of claim 1 , represented by the structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

m is 0, 1, or 2;

W and X are independently N, O, C(R 11 ) or C(R 11 ) 2 ;

each R 11 is independently H or C 1 -C 6 alkyl;

R 20 is C 1 -C 6 alkyl; and

n is 1 or 2.

3. The compound of claim 2 , wherein X is O and W is C(R 11 ) or C(R 11 ) 2 .

4. The compound of claim 1 , wherein R 6 and R 7 are independently H or a C 1 -C 6 alkyl, wherein each alkyl represented by R 6 or R 7 is optionally and independently substituted with one or more R20.

5. 5-(6-Hydroxybenzo[d][1,3]-dioxol-5-yl)-4-(4-morpholinophenyl)-4H-1,2,4-triazole-3-carboxamide;

4-(benzo[d][1,3]dioxol-5-yl)-5-(7-hydroxychroman-6-yl)-4H-1,2,4-triazole-3-carboxamide;

5-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-carboxamide;

5-(7-hydroxychroman-6-yl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-carboxamide;

5-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-carboxamide;

5-(2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-carboxamide;

5-(2-hydroxynaphthalen-1-yl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-carboxamide; and

5-(1-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-4-(4-methoxyphenyl)-4H-1,2,4-triazole-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

6. A method of treating cancer in a subject, wherein the cancer is selected from a group consisting of breast cancer, lung cancer, and leukemia; the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 such that the cancer is treated.

7. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .

8. The pharmaceutical composition of claim 7 , further comprising one or more additional therapeutic agents.