Quinazoline based EGFR inhibitors containing a zinc binding moiety

摘要

The present invention relates to quinazoline containing zinc-binding moiety based derivatives of Formula (IV) below.;;These compounds have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and are useful in the treatment of EGFR-TK related diseases and disorders such as cancer. These compounds may further act as HDAC inhibitors.

主权项

1. A method of treating a cancer selected from breast cancer, hepatocellular carcinoma, colon cancer, head and neck cancer, renal carcinoma, lung cancer, prostate cancer, gastric carcinoma, leukemia and pancreatic cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound represented by formula (IV):or a pharmaceutically acceptable salt or solvate thereof, wherein B1 is absent, O, S, aryl, heteroaryl, heterocylic, NH or alkylamino; B2 is absent, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, heterocyclic, C(O), S(O), or S(O)2; B3 is absent, O, NH, alkylamino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyl, aryl, heteroaryl, or heterocyclic; B4 is absent, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkenyl, heterocyclic, heteroaryl or aryl; R20, R21, and R22 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, CF3, CN, N3, NO2, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; Q is absent or substituted or unsubstituted alkyl: Y is absent, N, or CH; R′is hydrogen or acyl; R4 is independently selected from hydrogen, hydroxy, amino, halogen, CF3, CN, N3, NO2, sulfonyl, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylheterocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, or alkynylheterocyclylalkynyl, which one or more methylenes can be interrupted or terminated by O, S, S(O), S(O)2, N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; R7 is hydrogen, —OH, —O-aliphatic, —O-substituted aliphatic, O-acyl or aliphatic, provided that when Y is absent, R7 is absent; and R8 is hydrogen, acyl, aliphatic or substituted aliphatic.