Inhibitors of tyrosine kinases and uses thereof
View Patent ↗Disclosed herein are compounds that inhibit the activity of particular tyrosine kinases. Methods for the preparation of such compounds are disclosed. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the compounds disclosed, alone or in combination with other therapeutic agents, for the treatment of tyrosine kinase-mediated diseases or conditions or tyrosine kinase-dependent diseases or conditions are provided.
1. A compound of Formula (III):
wherein:
R a and R b are each independently selected from among H, halogen, CN, NO 2 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
T is 1 ,6-dimethyl-9-oxo-8,9-dihydro- 1H-imidazo[4,5-h]isoquinolin-2,7-ylene, or 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene;
L is —X 250a —Y 250 — or —Y 250 —X 250a —, wherein,
X 250a is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 5 -C 8 cycloalkenyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl;
Y 250 is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NR 45 —, —NH—, —NHC(═O)—, —NR 45 C(═O)—, —NR 45 C(═O)NR 45 —, —C(═O)NH—, —C(═O)NR 45 —, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —NR 45 SO 2 —, —SO 2 NH—, —SO 2 NR 45 —, —C(R 45 )═NO—, —CH═NO—, —ON═CH—, aryl, —NHC(═O)O—, —OC(═O)NH—, —NR 45 C(═O)O—, or —OC(═O)NR 45 —;
where each R 45 is independently selected from among hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 alkynyl;
M is N or CH;
W is
E is oxygen or sulfur;
R 100 is halogen, —OH, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -Cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl), C 1 -C 6 alkoxy, C 1 -C 6 alkenyloxy, C 1 -C 6 alkynyloxy, or —NR 102a R 102b ;
R 102a and R 102b are independently hydrogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, aralkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);
R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl,
R 350a is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, a substituted or unsubstituted C 2 -C 6 alkenyl, a substituted or unsubstituted C 2 -C 6 alkynyl, a substituted or unsubstituted C 1 -C 6 haloalkyl, a substituted or unsubstituted C 2 -C 6 haloalkenyl, or a substituted or unsubstituted C 2 -C 6 haloalkynyl;
n is 1; or a
pharmaceutically acceptable salt or a pharmaceutically acceptable prodrug thereof.
2. The compound of claim 1 , wherein:
T is 1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,7-ylene substituted at the 2 position with
and substituted at the 7 position with
3. The compound of claim 2 , wherein
Y 250 is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —SO 2 NH—, —NHC(═O)O—, or —OC(═O)NH—;
E is O; and
R 350a is hydrogen, a substituted or unsubstituted C 1 -C 6 alkyl, or a substituted or unsubstituted C 1 -C 6 haloalkyl.
4. The compound of claim 3 , wherein
X 250a is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; and
n is 1.
5. The compound of claim 4 , wherein compound has a structure selected from among:
6. The compound of claim 5 , wherein:
R 100 is halogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -Cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalky);
R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.
7. The compound of claim 6 , wherein:
R 350a is hydrogen;
Y 250 is a bond, —C(═O)—, —NHC(═O)—, —C(═O)NH—.
8. The compound of claim 7 , wherein L is selected from among:
9. The compound of claim 8 , wherein the compound has a structure of Formula (IIIc).
10. The compound of claim 9 , wherein:
L is C 1 -C 4 alkyl or
and
R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, aryl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.
11. The compound of claim 1 , wherein: T is 1,7-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-2,6-ylene substituted at the 2 position with
and substituted at the 6 position with
12. The compound of claim 11 , wherein
Y 250 is a bond, —O—, —S(═O)—, —S(═O) 2 —, —C(═O)—, —NH—, —NHC(═O)—, —NHC(═O)NH—, —C(═O)NH—, —OC(═O)—, —C(═O)O—, —NHSO 2 —, —SO 2 NH—, —NHC(═O)O—, or —OC(═O)NH—;
E is O; and
R 350a is hydrogen, or a substituted or unsubstituted C 1 -C 6 alkyl.
13. The compound of claim 12 , wherein
X 250a is a substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 haloalkyl, substituted or unsubstituted C 2 -C 6 alkenyl, substituted or unsubstituted C 2 -C 6 haloalkenyl, substituted or unsubstituted C 2 -C 6 alkynyl, or substituted or unsubstituted C 2 -C 6 haloalkynyl; and
n is 1.
14. The compound of claim 13 , wherein compound has a structure selected from among:
15. The compound of claim 14 , wherein:
R 100 is halogen, or an optionally substituted group selected from among C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, C 1 -C 4 alkyl(phenyl), C 3 -C 8 cycloalkyl, C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), C 2 -C 8 heterocycloalkyl, and C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl);
R 200 is an optionally substituted group selected from among C 2 -C 10 acyl, C 1 -C 6 alkylsulfonyl, C 2 -C 6 alkenylsulfonyl, arylsulfonyl, C 1 -C 10 alkoxycarbonyl, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, and di(C 1 -C 6 alkyl)aminosulfonyl.
16. The compound of claim 15 , wherein:
R 350a is hydrogen;
Y 250 is —C(═O)—; and
X 250a is a substituted or unsubstituted C 1 -C 6 alkyl.
17. The compound of claim 16 , wherein L is
18. The compound of claim 17 , wherein the compound has a structure of Formula (IIIb).
19. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
20. The pharmaceutical composition of claim 19 , wherein the composition is formulated for oral administration.