Pyrrole compounds that modulate HSP90 activity

摘要

The present invention relates to substituted pyrrole compounds and compositions comprising substituted pyrrole 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 pyrrole compound of the invention, or a pharmaceutical composition comprising such a compound.

主权项

1. A method of treating a proliferative disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by the following structural formula: or a pharmaceutically acceptable salt thereof, wherein:
each R1 and R2 is independently —NR10R11, —OR7, or —SR7;R3 is hydrogen, —X50R50, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R3 is optionally and independently substituted;each R4 and R5 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R4 or R5 is optionally and independently substituted;each R7 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R7 is optionally and independently substituted;each R10 and R11 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, or heteraralkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl represented by R10 or R11 is optionally and independently substituted; orR10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;R50 is an optionally substituted aryl or an optionally substituted heteroaryl;X50 is a divalent group selected from a C1-C4 alkylene, NR7, C(O), C(S), C(NR7), and S(O)p;Y is O or S;each Z is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, halo, cyano, nitro, guanadino, or alkoxy, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl represented by Z are optionally and independently substituted;each optional substituent for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl is independently an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteraralkyl, heteroalkyl, alkoxy, halo, cyano, nitro, or guanadino;each p is independently 0, 1 or 2; andn is 0, 1, 2, or 3.