Quinazoline based EGFR inhibitors containing a zinc binding moiety
The present invention relates to quinazoline containing zinc-binding moiety based derivatives of Formula (I) 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.
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 I:
or a solvate or pharmaceutically acceptable salt thereof, 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 method of claim 1 , wherein B is a straight chain C 5 to C 7 alkylene.
3. The method of claim 2 , wherein B is a straight chain C 6 alkylene and X is O.
4. The method of claim 1 , wherein R 1 is hydrogen or methoxy.
5. The method of claim 1 , wherein each R 2 is independently selected from Br, Cl, F and ethynyl.
6. The method of claim 1 , wherein n is 1 or 2.
7. The method of claim 1 , wherein the compound is represented by formula (II):
or a solvate or pharmaceutically acceptable salt thereof.
8. The method of claim 7 , wherein B is a straight chain C 5 to C 7 alkylene.
9. The method of claim 8 , wherein B is a straight chain C 6 alkylene.
10. The method of claim 1 , wherein n is 1 and R 2 is C 2 to C 4 alkynyl.
11. The method of claim 10 , wherein R 2 is ethynyl.
12. The method of claim 10 , wherein the compound is represented by Formula IV,
or a solvate or pharmaceutically acceptable salt thereof.
13. The method of claim 12 , wherein B is a straight chain C 5 to C 7 alkylene.
14. The method of claim 12 , wherein R 1 is methoxy.
15. The method of claim 12 , wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof.
16. The method of claim 1 , wherein the compound is represented by Formula (III),
or a solvate or pharmaceutically acceptable salt thereof, wherein B is a C 3 to C 9 alkylene.
17. The method of claim 16 , wherein B is a straight chain C 5 to C 7 alkylene.
18. The method of claim 16 , wherein R 1 is methoxy.
19. The method of claim 16 , wherein the compound is
or a solvate or pharmaceutically acceptable salt thereof.