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 R 1 , R 2 , R 3 , X, Z, L 1 , Cycl 1 , L 2 and Cycl 2 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 stereoisomet, or pharmaceutically acceptable salt thereof, wherein:
X is S, O or NH;
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:
2. The compound of claim 1 , wherein L 2 is —C(═S)NHCH 2 —.
3. The compound of claim 1 , wherein R 1 and R 2 are selected from hydrogen, —OCH 3 , —OH, —Cl, —CF 3 , or —OC(═O)CH 3 , and R 3 is selected from hydrogen or —NH 2 .
4. The compound of claim 1 , wherein R 1 , R 2 , and R 3 are hydrogen.
5. A compound having the following structure:
or 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 K 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:
6. The compound of claim 5 , wherein L 2 is —C(═S)NHCH 2 —.
7. The compound of claim 5 , wherein R 1 and R 2 are selected from hydrogen, —OCH 3 , —OH, —Cl, —CF 3 , or —OC(═O)CH 3 , and R 3 is selected from hydrogen or —NH 2 .
8. The compound of claim 5 , wherein R 1 , R 2 , and R 3 are hydrogen.
9. A compound having the following structure:
10. A composition comprising a compound of any one of claims 1 , 5 and 9 in combination with a pharmaceutically acceptable excipient.
11. The compound of any one of claims 1 to 9 , wherein the compound is a hydrochloride salt.