Triazole compounds that modulate HSP90 activity

1. A compound represented by the following structure:

or a tautomer, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

X 41 is O, S, or NR 42 ;

X 42 is CR 44 or N;

Y 40 is N or CR 43 ;

Y 41 is N or CR 45 ;

Y 42 , for each occurrence, is independently N, C or CR 46 ;

R′ 40 is NHR 7 ;

R 41 is —H, —OH, —SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 8 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 8 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 8 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —OC(NR 8 )NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 8 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 8 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —SR 7 , —S(O) p R 7 , —OS(O) p R 7 , —OS(O) p OR 7 , —OS(O) p NR 10 R 11 , —S(O) p OR 7 , —NR 8 S(O) p R 7 , —NR 7 S(O) p NR 10 R 11 , —NR 7 S(O) p OR 7 , —S(O) p NR 10 R 11 , —SS(O) p R 7 , —SS(O) p OR 7 , —SS(O) p NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ;

R 42 is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R 7 , —(CH 2 ) m C(O)OR 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —S(O) p R 7 , —S(O) p OR 7 , or —S(O) p NR 10 R 11 ;

R 43 and R 44 are, independently, —H, —OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —SR 7 , —S(O) p R 7 , —OS(O) p R 7 , —S(O) p OR 7 , —NR 8 S(O) p R 7 , —S(O) p NR 10 R 11 , or R 43 and R 44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;

R 45 is —H, —OH, —SH, —NR 7 H, —OR 26 , —SR 26 , —NHR 26 , —O(CH 2 ) m OH, —O(CH 2 ) m SH, —O(CH 2 ) m NR 7 H, —S(CH 2 ) m OH, —S(CH 2 ) m SH, —S(CH 2 ) m NR 7 H, —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —NR 7 C(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —NR 7 C(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —NR 7 C(O)OR 7 , —OCH 2 C(O)R 7 , —SCH 2 C(O)R 7 , —NR 7 CH 2 C(O)R 7 , —OCH 2 C(O)OR 7 , —SCH 2 C(O)OR 7 , —NR 7 CH 2 C(O)OR 7 , —OCH 2 C(O)NR 10 R 11 , —SCH 2 C(O)NR 10 R 11 , —NR 7 CH 2 C(O)NR 10 R 11 , —OS(O) p R 7 , —SS(O) p R 7 , —NR 7 S(O) p R 7 , —OS(O) p NR 10 R 11 , —SS(O) p NR 10 R 11 , —NR 7 S(O) p NR 10 R 11 , —OS(O) p OR 7 , —SS(O) p OR 7 , —NR 7 S(O) p OR 7 , —OC(S)R 7 , —SC(S)R 7 , —NR 7 C(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —NR 7 C(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —NR 7 C(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —NR 7 C(NR 8 )OR 7 , —OC(NR 8 )NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , or —NR 7 C(NR 8 )NR 10 R 11 ; and

R 46 , for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanidino, a haloalkyl, a heteroalkyl, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —SR 7 , —S(O) p R 7 , —OS(O) p R 7 , —S(O) p OR 7 , —NR 8 S(O) p R 7 , or —S(O) p NR 10 R 11 ;

R 7 and R 8 , for each occurrence, is independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;

R 10 and R 11 , for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;

R 26 is a lower alkyl;

p, for each occurrence, is independently, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3 or 4.

2. The compound of claim 1 , wherein R 41 is selected from the group consisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.

3. The compound of claim 1 , wherein X 41 is NR 42 , and R 42 is selected from the group consisting of —H, a lower alkyl, a lower cycloalkyl, —C(O)N(R 27 ) 2 , and —C(O)OH, wherein each R 27 is independently —H or a lower alkyl.

4. The compound of claim 1 , wherein R 43 and R 44 are, independently, selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

5. The compound of claim 1 , wherein X 42 is CR 44 ; Y 40 is CR 43 ; and R 43 and R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.

6. The compound of claim 1 , wherein the compound is represented by the following structural formula:

or a tautomer, a pharmaceutically acceptable salt, or a prodrug thereof.

7. The compound of claim 6 , wherein X 42 is CR 44 , and R 43 and R 44 are, independently, selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

8. The compound of claim 6 , wherein X 42 is CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.

9. The compound of claim 6 , wherein X 42 is CR 44 .

10. The compound of claim 6 , wherein X 42 is N.

11. The compound of claim 6 , wherein the compound is represented by the following structural formula:

or a tautomer, a pharmaceutically acceptable salt, or a prodrug thereof, wherein:

X 45 is CR 54 or N;

R 56 is selected from the group consisting of —H, methyl, ethyl, isopropyl, and cyclopropyl;

R 52 is selected from the group consisting of —H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, —(CH 2 ) 2 OCH 3 , —CH 2 C(O)OH, and —C(O)N(CH 3 ) 2 ;

R 53 and R 54 are each, independently, —H, methyl, ethyl, or isopropyl; or

R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and

R 55 is selected from the group consisting of —H, —OH, —OCH 3 , and OCH 2 CH 3 .

12. The compound of claim 1 , wherein the compound is represented by the following structural formula:

or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 60 is —H, an optionally substituted alkyl, or an optionally substituted aryl.

13. The compound of claim 12 , wherein R 41 is selected from the group consisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.

14. The compound of claim 13 , wherein R 41 is selected from the group consisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

15. The compound of claim 14 , wherein R 42 is —H or an optionally substituted lower alkyl.

16. The compound of claim 1 , wherein the compound is selected from the group consisting of

4-Isopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-phenylamino-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol;

4-Isopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-methyl amino-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol;

4-Isopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-benzylamino-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol;

4-(5-amino-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol;

4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol;

4-(5-(3-aminophenylamino)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol;

4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(3-(trifluoromethyl)phenylamino)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol;

4-isopropyl-6-(5-(3-methoxyphenylamino)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-5-methylisoxazole-3-carboxamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)butyramide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-methoxyacetamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)isobutyramide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)furan-2-carboxamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2-phenylacetamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-3,4-difluorobenzamide;

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-2,2,2-trifluoroacetamide;

2-(4-chlorophenoxy)-N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide; and

N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)cyclopentanecarboxamide;

or a tautomer, a pharmaceutically acceptable salt, or a prodrug thereof.

17. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound according to claim 1 .

18. The pharmaceutical composition of claim 17 , further comprising one or more therapeutic agents.

19. A method of treating cancer in a mammal, comprising administering to the mammal an effective amount of a compound of claim 1 .