Substituted tricyclic compounds as protein kinase inhibitors
View Patent ↗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 a structure selected from (II) or (III):
or a steroisomer, prodrug or pharmaceutically acceptable salt thereof,
wherein
X is NH, S or O;
Z is CH or N;
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 1 is a direct bond, —NR′—, —OC(═S)NH— or —NHC(═S)O—, wherein R′ is H or alkyl;
Cycl 1 is selected from:
L 2 is —C(═S)NH—, —NHC(═S)—, —NHC(═S)NH—, —C(═O)NH—, —NHC(═O)—, —NHC(═O)NH—, —NH(CH 2 ) n —, —(CH 2 ) n NH—, —NH(CH 2 ) n NH—, —C (═S)NH(CH 2 ) n —, —NHC(═S)(CH 2 ) n —, —(CH 2 ) n C(═S)NH(CH 2 ) n —, —(CH 2 ) n NHC(═S)(CH 2 ) n —, —S(═O) 2 —, —S(═O) 2 NH—, —NHS(═O) 2 —, —NHC(═S)NHCH 2 —, —NH—, or —C(═S)—, wherein n is, at each occurrence the same or different and independently 1, 2, 3 or 4; and
Cycl 2 is selected from:
2. The compound of claim 1 , wherein the compound has structure (II).
3. The compound of claim 2 wherein L 1 is a direct bond.
4. The compound of claim 3 wherein X is NH and Z is CH.
5. The compound of claim 3 wherein R 1 and R 2 are selected from —OCH 3 , —OH, —Cl, —CF 3 or —OC(═O)CH 3 , and R 3 is hydrogen or —NH 2 .
6. The compound of claim 3 wherein L 2 is selected from —C(═S)NH—, —C(═S)NHCH 2 —, —NHC(═S)NH—, or —NHC(═O)NH—.
7. The compound of claim 2 , wherein L 1 is —NH—or —OC(═S)NH—.
8. The compound of claim 7 , wherein X is NH and Z is CH.
9. The compound of claim 7 , wherein R 1 and R 2 are methoxy, and R 3 is hydrogen or —NH 2 .
10. The compound of claim 7 , wherein L 2 is selected from —NHCH 2 —, —NH—, —C(═S)NH—, —NHC(═S)—, —C(═S)NHCH 2 —, —NHC(═S)NH—, —NHC(═O)NH—or —S(═O) 2 .
11. The compound of claim 1 , wherein the compound has structure (III).
12. The compound of claim 11 wherein L 1 is a direct bond.
13. The compound of claim 12 wherein R 1 , R 2 and R 3 are hydrogen.
14. The compound of claim 12 wherein Cycl 1 is:
15. The compound of claim 12 wherein L 2 is selected from —C(═S)NH—, —C(═S)— or —C(═S)NHCH 2 —.
16. The compound of claim 12 wherein Cycl 2 is selected from:
17. The compound of claim 11 wherein L 1 is —NH— or —OC(═S)NH—.
18. The compound of claim 17 wherein R 1 , R 2 and R 3 are hydrogen.
19. The compound of claim 17 wherein Cycl 1 is selected from:
20. The compound of claim 17 wherein L 2 is selected from —NHC(═S)NH—, —NHC(═O)—, —NH— or —NHCH 2 —.
21. The compound of claim 17 wherein Cycl 2 is selected from:
22. A composition comprising a compound of claim 1 in combination with a pharmaceutically acceptable excipient.