Substituted tricyclic compounds as protein kinase inhibitors
Protein kinase inhibitors are disclosed having utility in the treatment of protein kinase-mediated diseases and conditions, such as cancer. The compounds of this invention have the following structure: including steroisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein A is a ring moiety selected from: and wherein R1, R2, R3, X, Z, L1, Cycl1, L2 and Cycl2 are as defined herein. Also disclosed are compositions containing a compound of this invention, as well as methods relating to the use thereof.
1. A compound having the following structure:
or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
X is NH, S or O;
Z is CH or N, with the proviso when X=NH then Z=CH;
R 1 and R 2 are the same or different and are independently hydrogen, hydroxyl, halo, —CN, —NO 2 , —NH 2 , —R, —OR, —SCH 3 , —CF 3 , —C(═O)OR or —OC(═O)R, where R is alkyl or substituted alkyl;
R 3 is hydrogen, —NH 2 , alkyl, —CN, or —NO 2 ;
L 2 is selected from —NHCH 2 —, —NH—, —C(═S)NH—, —NHC(═S)—, —C(═S)NHCH 2 —, —NHC(═S)NH—, —NHC(═O)—, —NHC(═O)NH—; —S(═O) 2 —; and
Cycl 2 is:
where w is
2. The compound of claim 1 , wherein L 2 is —C(═S)NH—.
3. The compound of claim 1 , wherein R 1 and R 2 are selected from —R or —OR where R is alkyl or substituted alkyl, hydroxyl, halo, —CF 3 , or —OC(═O)CH 3 is selected from hydrogen or —NH 2 .
4. The compound of claim 1 , wherein R 1 and R 2 are selected from —OCH 3 , —Cl, or —CF 3 , and R 3 is hydrogen.
5. A compound having the following structure:
or a stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are the same or different and are independently hydrogen, hydroxyl, halo, —CN, —NO 2 , —NH 2 , —R, —OR, —SCH 3 , —CF 3 , —C(═O)OR or —OC(═O)R, where R is alkyl or substituted alkyl; and
R 3 is hydrogen, —NH 2 , alkyl, —CN, or —NO 2 .
6. The compound of claim 5 , wherein R 1 and R 2 are selected from —R or —OR where R is alkyl or substituted alkyl, hydroxyl, halo, —CF 3 , or —OC(═O)CH 3 , and R 3 is hydrogen.
7. The compound of claim 5 , wherein R 1 and R 2 are selected from —OCH 3 , —CF 3 , or —CI, and R 3 is hydrogen.
8. A compound having the following structure:
9. A compound having the following structure:
10. A composition comprising a compound of any one of claims 1 , 5 , 8 and 9 in combination with a pharmaceutically acceptable excipient.