Tubulysin compounds, methods of making and use

摘要

Tubulysin compounds of the formula (I);
where R1, R2, R3a, R3b, R4, R5, W, and n are as defined herein, are anti-mitotic agents that can be used in the treatment of cancer, especially when conjugated to a targeting moiety.

主权项

1. A compound having a structure represented by formula (I)wherein
R1 is H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH2)1-2O(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkynyl), (CH2)1-2OC(═O)(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkynyl), unsubstituted or substituted C(═O)(C1-C10 alkyl), unsubstituted or substituted C(═O)(C2-C10 alkenyl), unsubstituted or substituted C(═O)(C2-C10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, or unsubstituted or substituted alkylaryl; R2 is H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted (CH2)1-2O(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2O(C2-C10 alkynyl), (CH2)1-2OC(═O)(C1-C10 alkyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkenyl), unsubstituted or substituted (CH2)1-2OC(═O)(C2-C10 alkynyl), unsubstituted or substituted C(═O)(C1-C10 alkyl), unsubstituted or substituted C(═O)(C2-C10 alkenyl), unsubstituted or substituted C(═O)(C2-C10 alkynyl), unsubstituted or substituted cycloaliphatic, unsubstituted or substituted heterocycloaliphatic, unsubstituted or substituted arylalkyl, unsubstituted or substituted alkylaryl, or wherein each R2a is independently H, NH2, NHMe, Cl, F, Me, Et, or CN; R3a and R3b are independently H, C1-C5 alkyl, CH2(C5-C6 cycloalkyl), CH2C6H5, C6H5, or CH2CH2OH; R4 is wherein R4a is H or C1-C3 alkyl; and Y is H, OH, Cl, F, CN, Me, Et, NO2, or NH2; R5 is H, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, CO(C1-C5 alkyl), CO(C2-C5 alkenyl), or CO(C2-C5 alkynyl); W is O or S; and n is 0, 1, or 2;or a pharmaceutically acceptable salt thereof.