Fused-bicyclic aryl 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 (I) 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:
each W 1 and W 2 is independently CH;
W 3 is CR 2 ;
U is N;
V is N;
Z is C;
indicates a single or double bond but never two double bonds adjacent to one another in the ring in which the occurs;
A and B, are taken together with the atoms to which they are attached and form a 5 to 7-membered heterocyclyl or heteroaryl ring system which can be further substituted with one or more R 10 substituents;
R 1 is halogen;
R 2 is H;
R 3 is H;
R 4 and R 5 are independently H or C 1 -C 3 alkyl;
R 6 is H; and
each R 10 is independently C 1 -C 6 alkyl, ═O, or —C(O)R 11 ;
R 11 is C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein R 4 is H and R 5 is methyl.
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 1 is chloro.
5. The compound of claim 4 , wherein R 10 is methyl.
6. The compound of claim 1 having a Formula Ia:
wherein:
the C ring is oxazolonyl or dihydrooxazinonyl.
7. The compound of claim 6 , wherein R 4 is H and R 5 is methyl.
8. The compound of claim 7 , wherein R 4 is H and R 5 is (S)-methyl.
9. The compound of claim 8 , wherein R 1 is chloro.
10. The compound of claim 9 , wherein R 10 is methyl.
11. A pharmaceutical composition comprising 6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
12. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 7-chloro-1-methyl-1H-pyrimido[4,5-d][1,3]oxazin-2(4H)-one.
13. The mixture of claim 12 further comprising 6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is 6-chloro-3-[(1S)-1-({1-methyl-2-oxo-1H,2H,4H-pyrimido[4,5-d][1,3]oxazin-7-yl}amino)ethyl]-1,2-dihydroquinolin-2-one, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is (S)-5-((1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)oxazolo[4,5-d]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition comprising the compound of claim 15 and pharmaceutically acceptable carrier.