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: 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 is N;
V is CR 9 ;
Z is C;
A is H;
B and R 9 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;
R 10 is —C(O)R 11 ; and
each R 11 is independently 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 11 is methyl.
6. The compound of claim 1 having a Formula Ib:
wherein:
the C ring is pyrrolidinyl, piperidinyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, furyl, imidazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, morpholinyl, thiomorpholinyl dihydrothiazinedioxide, dihydropyranonyl, or dihydrothiophenedioxide.
7. The compound of claim 6 , wherein the C ring is pyrrolidinyl.
8. The compound of claim 7 , wherein R 4 is H and R 5 is methyl.
9. The compound of claim 7 , wherein R 4 is H and R 5 is (S)—methyl.
10. The compound of claim 8 , wherein R 1 is chloro.
11. The compound of claim 9 , wherein R 11 is methyl.
12. The compound of claim 1 , wherein the compound is (S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one, or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising the compound of claim 12 and pharmaceutically acceptable carrier.
14. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 1-(4-chloro-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)ethanone.
15. The mixture of claim 14 further comprising (S)-3-(1-(1-acetyl-2,3-dihydro-1H-pyrrolo [3,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one or a pharmaceutically acceptable salt thereof.
16. 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 is N;
V is CR 9 ;
Z is C;
A is H;
B and R 9 are taken together with the atoms to which they are attached to form a 5 to 7-membered heterocyclyl 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 is H;
R 5 is (S)—methyl;
R 6 is H;
R 10 is —C(O)R 11 ; and
R 11 is methyl.
17. The compound of claim 16 , wherein B and R 9 are taken together with the atoms to which they are attached to form a 5-membered heterocyclyl ring system which can be further substituted with one or more R 10 substituents.
18. The compound of claim 17 , wherein the 5-membered heterocyclyl ring system is pyrrolidinyl.
19. The compound of claim 16 , wherein R 1 is chloro.
20. The compound of claim 17 , wherein R 1 is chloro.