Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors
The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: where Y 1 , X 1 , X 2 , Y 2 , W 1 , W 2 , W 3 , and R 1 -R 5 are described herein.
1. A compound of Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
W 1 and W 2 are CH;
W 3 is CR 2 ;
R 1 is halogen;
each R 2 is H or C 1 -C 6 alkoxy;
R 3 is H or C 1 -C 6 alkyl;
R 4 is H;
R 5 is methyl;
R 6 is —CN, —C(O)NH 2 , or —NHCOR 7 ,
R 6 ′ is H, methyl, or ethyl; and
R 7 is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl.
2. The compound of claim 1 , wherein R 1 is chloro.
3. The compound of claim 2 , wherein R 4 is H and R 5 is (S)-methyl.
4. The compound of claim 3 , wherein R 3 is H.
5. The compound of claim 4 , wherein R 6 is CN.
6. The compound of claim 5 , wherein R 6 ′ is H.
7. The compound of claim 5 , wherein R 6 ′ is methyl.
8. The compound of claim 4 , wherein R 6 is —C(O)NH 2 .
9. The compound of claim 8 , wherein R 6 ′ is methyl.
10. The compound of claim 1 , wherein the compound is 2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1,3-thiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and a compound selected from:
2-bromo(chloro)-4-methylthiazole-5-carboxamide;
2-chloro(bromo)-4-methylthiazole-5-carbonitrile; and
2-chlorothiazole-5-carbonitrile.
13. The mixture of claim 12 , wherein the mixture comprises (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 2-bromo(chloro)-4-methylthiazole-5-carboxamide.
14. The mixture of claim 13 , further comprising 2-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1,3-thiazole-5-carboxamide, or a pharmaceutically acceptable salt thereof.
15. The mixture of claim 12 , wherein the mixture comprises (S)-3(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 2-chloro(bromo)-4-methylthiazole-5-carbonitrile.
16. The mixture of claim 15 , further comprising 2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1,3-thiazole-5-carbonitrile, or a pharmaceutically acceptable salt thereof.
17. The mixture of claim 12 , wherein the mixture comprises (S)-3(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 2-chlorothiazole-5-carbonitrile.
18. The mixture of claim 17 , further comprising 2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1,3-thiazole-5-carbonitrile, or a pharmaceutically acceptable salt thereof.