Quinazoline based EGFR inhibitors containing a zinc binding moiety
The present invention relates to quinazoline containing zinc-binding moiety based derivatives that have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt, wherein
X is O, S, CH 2, or-CONH-;
B is a C 3 to C 9 alkylene;
R 1 is selected from hydrogen, C 1 to C 4 alkoxy or substituted C 1 to C 4 alkoxy;
R 2 is each independently selected from halogen, C 1 to C 4 alkyl, C 2 to C 4 alkenyl, and C 2 to C 4 alkynyl; and
n is 1,2 or 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 5 to C 7 alkylene.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 6 alkylene and X is O.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is independently selected from hydrogen or methoxy.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is each independently selected from Br, Cl, F and ethynyl.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein n is 1 or 2.
7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof represented by formula (II):
8. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 5 to C 7 alkylene.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein B is a straight chain C 6 alkylene.