Pyridinyl quinolinone derivatives 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 A, B, U, V, Z, W 1 , W 2 , W 3 , and R 1 -R 6 are described herein.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
W 1 and W 2 are CH;
W 3 is CR 2 ;
U and V are independently N or CH, provided that U and V are not both N;
Z is C;
A is CN;
B is H or C 1 -C 6 alkoxy;
R 1 is halogen;
R 2 is H;
R 3 is H or D;
R 4 and R 5 are independently H or C 1 -C 3 alkyl; and
R 6 is H or C 1 -C 6 alkoxy.
2. The compound of claim 1 , wherein B is methoxy.
3. The compound of claim 2 , wherein R 4 is H and R 5 is methyl.
4. The compound of claim 3 , wherein R 4 is H and R 5 is (S)-methyl.
5. The compound of claim 4 , wherein R 1 is chloro.
6. The compound of claim 1 having the Formula Ia:
7. The compound of claim 1 having the Formula Ia-1:
8. The compound of claim 1 having the Formula Ib:
9. The compound of claim 8 having the Formula Ib-1:
10. A pharmaceutical composition comprising 6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
11. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 6-chloro-4-methoxynicotinonitrile.
12. The mixture of claim 11 , further comprising 6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile, or a pharmaceutically acceptable salt thereof.