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 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 C 2 to C 4 alkynyl; and
n is 1.
2. The compound of claim 1 wherein R 2 is ethynyl.
3. The compound according to claim 1 represented by Formula III,
or a solvate or pharmaceutically acceptable salt thereof, wherein B is a C 3 to C 9 alkylene.
4. The compound of claim 3 or a solvate or pharmaceutically acceptable salt thereof wherein B is a straight chain C 5 to C 7 alkylene.
5. The compound of claim 4 wherein R 1 is methoxy.
6. The compound of claim 3 , wherein the compound is in a crystalline form.
7. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 or a solvate or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. A compound of the formula
or a solvate or pharmaceutically acceptable salt thereof.
9. The compound of claim 8 , wherein the compound is in a crystalline form or a mixture of two or more crystalline forms.
10. A pharmaceutical composition comprising as an active ingredient a compound of claim 8 or a solvate or pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier.