Triazole compounds that modulate Hsp90 activity
View Patent ↗The present invention relates to substituted triazole compounds and compositions comprising substituted triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a substituted triazole compound of the invention, or a pharmaceutical composition comprising such a compound.
1. A compound of Formula (VI), or a pharmaceutically acceptable salt thereof:
R 1 is H, OR 12 or C 1 -C 3 alkyl;
R 2 is OR 12 or halo;
R 3 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
R 5 and R 6 are individually hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, benzyl, 5-7 membered heteroaryl, —N(R 12 ) 2 , —C(O)R 12 , —C(O)OR 12 , —S(O) p R 12 , or —S(O) p N(R 12 ) 2 , wherein each R 5 and R 6 that is not hydrogen is optionally and independently substituted with one or more R 20 ; or R 5 and R 6 , taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl which is optionally substituted with 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 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, C 3 -C 7 cycloalkyl, phenyl, or benzyl, wherein each R 12 with at least one hydrogen atom is optionally substituted with one or more R 20 ; or two R 12 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 C 3 -C 7 cycloalkyl which are each optionally and independently substituted with one or more R 20 ;
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 heterocyclyl-(C 1 -C 3 )alkyl, C 6 -C 20 aryl-(C 1 -C 3 )alkyl, 5-14 membered heteroaryl-(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 , and —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 37 and R 38 are individually hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, benzyl, 5-7 membered heteroaryl, —N(R 12 ) 2 , —C(O)R 12 , —C(O)OR 12 , —S(O) p R 12 , or —S(O) p N(R 12 ) 2 , wherein each R 37 and R 38 that is not hydrogen is optionally and independently substituted with one or more R 20 ; or R 37 and R 38 , taken together with the nitrogen to which they are attached, form a 5-7 membered heterocyclyl which is optionally substituted with one or more R 20 ; and
p is 0, 1, or 2.
2. The compound of claim 1 , wherein R 1 is H, OH or methoxy.
3. The compound of claim 1 , wherein R 2 is F, OH, methoxy, ethoxy, propoxy, or isopropoxy.
4. The compound of claim 1 , wherein R 3 is H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl or C 5 -C 6 cycloalkyl.
5. The compound of claim 1 , wherein R 5 and R 6 are independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, phenyl, benzyl, —C(O)R 12 , —S(O) p R 12 or —S(O) p N(R 12 ) 2 .
6. The compound of claim 1 , wherein R 37 and R 38 are individually C 1 -C 4 alkyl optionally substituted with one or more R 20 ; or are taken together with the N atom to which they are attached to form a 5- or 6-membered heterocyclyl which is optionally substituted with one or more R 20 .
7. The compound of claim 1 , wherein R 1 is H, OH or methoxy; R 2 is F, OH, methoxy, ethoxy, propoxy, or isopropoxy; R 3 is H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl or C 5 -C 6 cycloalkyl; and R 37 and R 38 are individually C 1 -C 4 alkyl optionally substituted with one or more R 20 ; or are taken together with the N atom to which they are attached to form a 5- or 6-membered heterocyclyl which is optionally substituted with one or more R 20 .
8. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 .
9. The pharmaceutical composition of claim 8 , further comprising one or more additional anticancer agents.
10. The compound of claim 1 , wherein:
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, C 6 -C 20 aryl, C 3 -C 7 cycloalkyl-(C 1 -C 3 )alkyl, C 6 -C 20 aryl-(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* , —R 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 , and —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* ).