Quinazoline based EGFR inhibitors
The present invention relates to quinazoline containing zinc-binding moiety based derivatives of formula I 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.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein
X is O, S, CH 2 , or —CONH—;
B is an unsubstituted C 5 to C 7 alkylene;
R 1 is selected from hydrogen, hydroxy or C 1 to C 4 alkoxy;
R 2 is each independently selected from halogen, hydroxy, 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 or ester thereof wherein B is an unsubstituted straight chain C 6 alkylene.
3. The compound of claim 1 or a pharmaceutically acceptable salt or ester thereof wherein R 1 is selected from hydrogen, hydroxy and methoxy.
4. The compound of claim 1 or a pharmaceutically acceptable salt or ester thereof wherein each R 2 is independently selected from Br, Cl, F, hydroxy and ethynyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt or ester thereof wherein n is 1 or 2.
6. A pharmaceutical composition comprising as an active ingrdient a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof and a pharmaceutical acceptable carrier.
7. A compound represented by formula (II):
or a pharmaceutically acceptable salt or ester thereof,
wherein:
B is an unsubstituted C 3 to C 9 alkylene;
R 1 is selected from hydrogen, hydroxy or C 1 to C 4 alkoxy;
R2 is each independently selected from halogen, hydroxy, C 1 to C 4 alkyl, C 2 to C 4 alkenyl, and C 2 to C 4 alkenyl; and
n is 1, 2 or 3.
8. The compound of claim 7 or a pharmaceutically acceptable salt or ester thereof wherein B is an unsubstituted straight chain C 5 to C 7 alkylene.
9. The compound of claim 8 or a pharmaceutically acceptable salt or ester thereof wherein B is an unsubstituted straight chain C 6 alkylene.
10. A compound according to claim 7 or a pharmaceutically acceptable salt or ester thereof represented by formula (III):
11. The compound of claim 10 or a pharmaceutically acceptable salt or ester thereof wherein B is an unsubstituted straight chain C 5 to C 7 alkylene.
12. The compound of claim 11 or a pharmaceutically acceptable salt or ester thereof wherein R 1 is hydroxy or methoxy and B is an unsubstituted straight chain C 6 alkylene.
13. A compound according to claim 7 or a pharmaceutically acceptable salt or ester thereof represented by formula (IV):
14. The compound of claim 13 or a pharmaceutically acceptable salt or ester thereof wherein B is an unsubstituted straight chain C 5 to C 7 alkylene.
15. The compound of claim 14 or a pharmaceutically acceptable salt or ester thereof wherein R 1 is hydroxy or methoxy and B is an unsubstituted straight chain C 6 alkylene.
16. A pharmaceutical composition comprising as an active ingredient a compound of claim 7 or a pharmaceutically acceptable salt or ester thereof and a pharmaceutical acceptable carrier.
17. A compound according to claim 7 or a pharmaceutically acceptable salt or ester thereof represented by formula (V):
18. The compound of claim 17 or a pharmaceutically acceptable salt or ester thereof wherein B is an unsubstituted straight chain C 5 to C 7 alkylene.
19. The compound of claim 18 or a pharmaceutically acceptable salt or ester thereof wherein R 1 is hydroxy or methoxy and B is an unsubstituted straight chain C 6 alkylene.