Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

1. A compound of formula I:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer, or tautomer thereof,

wherein:

each W 1 and W 2 is independently CH, CF or N;

W 3 is independently CR 2 or N;

A is selected from the group consisting of H, D, halogen, CN, —CHO, —COOH, —COOR 9 , —C(O)NH 2 , —C(O)NHR 9 , R 10 S(O) 2 —, —O(CH 2 ) n C(O)R 10 , —O(CH 2 ) n C(O)NR 10 R 9 , R 10 S(O)—, heteroaryl, —S(O)Me, S(O) 2 Me,

B is selected from the group consisting of:

H, D, OH, NO 2 , NH 2 , —NR 11 R 12 , CN, —(CH 2 ) n CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, heteroaryl, —O(CH 2 )R 10 , —(CH 2 ) n C(O)NHR 9 , —C(O)NH 2 , —SR 9 , OR 9 , —(CHR 10 ) n S(O)R 9 , —(CHR 10 ) n S(O) 2 R 9 , —S(O) 2 NR 9 R 10 , —COOR 9 ,

wherein X and Y are independently in each occurrence C, N, NR 10 , S, and O, provided that the ring containing X and Y cannot have more than 4 N or NH atoms or more than one S or O atoms, and wherein the S and O are not contiguous;

R 1 is independently H, OH, CN, halogen, CHF 2 , CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl is optionally substituted one or more times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

R 2 is independently H, OH, CN, halogen, CF 3 , CHF 2 , benzyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , —O(CH 2 ) n R 10 , —O(CHR 9 )R 10 , —O(CH 2 ) n —O—(CH 2 ) m R 10 , —O(CH 2 ) n C(O)NHR 10 , —O(CH 2 )—C(O)R 10 , NHR 11 , —N(R 11 )(R 12 ), —NHC(O)R 11 , —NHS(O)R 11 , —NHS(O) 2 R 11 , —NHC(O)OR 11 , —NHC(O)NHR 11 , —S(O) 2 NHR 11 , —NHC(O)N(R 12 )R 11 , OCH 2 R 11 , CHR 9 R 10 , or OCHR 10 R 11 , wherein C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or benzyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted with one or more halogen, 3- to 8-membered heterocyclyl, aryl, -heteroaryl-C(O)NH 2 , and heteroaryl;

R 3 is H, C 1 -C 6 alkyl, or —OH,

R 4 and R 5 are independently H, halogen, CH 2 OH, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with halogen, or R 4 and R 5 when combined can form a C 3 -C 5 cycloalkyl or C 3 -C 5 heterocyclyl;

R 6 , R 7 , and R 8 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more halogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, —(CHR 11 ) n S(O) 2 R 12 , OR 11 —NR 11 C(O)R 12 , S(O) 2 NR 11 R 12 , or —C(O)NR 11 R 12 ;

R 9 and R 10 at each occurrence are independently selected from the group consisting of H, CN, —CH 2 CN, halogen, —NR 11 R 12 , —C(O)NR 11 R 12 , —NR 11 C(O)R 12 , CHCF 2 , CF 3 , C 1 -C 6 alkyl, R 11 S(O) 2 —, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl, wherein each C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl, is optionally substituted with one or more substituents selected from the group consisting of OH, oxo, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , CN, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, and R 13 S(O) 2 —;

R 11 and R 12 are independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl; or when combined R 11 and R 12 can form a 3- to 8-membered heterocyclyl or heteroaryl ring;

R 13 is independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl;

m is 0, 1, or 2;

n is 0, 1, or 2; and

r is 0, 1, or 2;

provided that:

(1) when R 1 is H, then A is CN or tetrazole;

(2) when R 1 is H and A is tetrazole, then R 2 is not hydrogen, methyl or ethoxy, or (ii) R 2 , B, and R 6 are H;

(3) when R 1 is H and R 2 is methyl, then neither B nor R 6 is methyl;

(4) when R 1 is H and A is CN, then either B or R 6 is not H;

(5) when R 1 is C 1 -C 6 alkoxy, then A is CN or imidazole;

(6) when R 1 is C 1 -C 6 alkyl, then (i) A is CN, tetrazole, or imidazole, or (ii) A is H and B is —S(O) 2 NR 9 R 10 ;

(7) when R 1 is methyl and A is tetrazole, then B and R 6 are H;

(8) when R 1 is tert-butyl, then A is CN; and

(9) when R 2 is C 1 -C 6 alkyl, then A is not H, halogen, or benzimidazole.

2. The compound of claim 1 , wherein A is CN.

3. The compound of claim 2 , wherein B is C 1 -C 6 alkoxy or C 1 -C 6 alkyl.

4. The compound of claim 3 , wherein B is methoxy.

5. The compound of claim 3 , wherein B is C 1 -C 6 alkyl.

6. The compound of claim 5 , wherein B is methyl.

7. The compound of claim 1 , wherein A is H or F.

8. The compound of claim 7 , wherein B is

9. The compound of claim 7 , wherein B is

10. The compound of claim 7 , wherein B is

11. The compound of claim 7 , wherein B is

12. The compound of claim 7 wherein B is

13. The compound of claim 1 , wherein R 9 is Me, Et, and cyclopropyl.

14. The compound of claim 1 , wherein A is

15. The compound of claim 14 , wherein B is C 1 -C 6 alkoxy.

16. The compound of claim 15 , wherein B is methoxy.

17. The compound of claim 1 , wherein R 4 and R 5 are H.

18. The compound of claim 1 , wherein R 4 is H and R 5 is methyl.

19. The compound of claim 1 , wherein R 4 is H and R 5 is (9-methyl.

20. The compound of claim 1 , wherein R 4 and R 5 are halogen.

21. The compound of claim 1 , wherein R 4 is F and R 5 is methyl.

22. The compound of claim 1 , wherein R 4 and R 5 can combine to form a C 3 -C 5 cycloalkyl.

23. The compound of claim 1 , wherein W 1 , W 2 , and W 3 are CH, or CF.

24. The compound of claim 1 , wherein W 1 or W 3 is N.

25. The compound of claim 1 , wherein R 1 is halogen.

26. The compound of claim 23 , wherein R 1 is chloro.

27. The compound of claim 1 , wherein R 2 is H, halogen, or C 1 -C 6 alkoxy.

28. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkoxy substituted with heteroaryl or 3- to 8-membered heterocyclyl.

29. The compound of claim 1 having the formula Ia:

30. The compound of claim 1 having the formula Ib:

31. The compound of claim 1 having the formula Ic:

32. The compound of claim 1 having the formula Id:

33. The compound of claim 1 having the formula Ie:

34. The compound of claim 1 having the formula If:

35. The compound of claim 1 , wherein the compound is

4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-3-methanesulfonylbenzonitrile;

4-{[1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-({1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl}amino)-2-methoxybenzonitrile;

6-chloro-3-[(1S)-1-[(4-methanesulfonyl-3-methoxyphenyl)amino]ethyl]-1,2-dihydroquinolin-2-one;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-hydroxybenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,6-dimethoxybenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(trifluoromethoxy)benzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(2-hydroxyethoxy)benzonitrile;

6-chloro-3-({[4-(1H-imidazol-1-yl)-3-methoxyphenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-ethoxybenzonitrile;

2-(5-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-cyanophenoxy)acetamide;

6-chloro-3-{[(4-methanesulfonyl-3-methoxyphenyl)amino]methyl}-1,2-dihydroquinolin-2-one;

6-chloro-3-({[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3-methoxybenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(trifluoromethyl)benzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methylbenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-fluorobenzonitrile;

6-chloro-3-({[4-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

6-chloro-3-({[4-(1H-imidazol-1-yl)phenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

2-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzamide;

6-chloro-3-{[(4-fluoro-3-methoxyphenyl)amino]methyl}-1,2-dihydroquinolin-2-one;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-N-methylbenzamide;

2-(4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}phenoxy)acetamide;

6-chloro-3-{[(4-chloro-3-methoxyphenyl)amino]methyl}-1,2-dihydroquinolin-2-one;

2-(3-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}phenyl)acetonitrile;

6-chloro-3-{[(2-fluorophenyl)amino]methyl}-1,2-dihydroquinolin-2-one;

3-({[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-6-methyl-1,2-dihydroquinolin-2-one;

2-methoxy-4-{[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzonitrile;

3-({[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

3-({[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

2-methoxy-4-{[(6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzonitrile;

4-{[(6,7-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

3-({[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}methyl)-6-methyl-1,2-dihydroquinolin-2-one;

6,7-dimethyl-3-({[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-1,2-dihydroquinolin-2-one;

N-(3,4-dihydro-2H-pyrrol-5-yl)-3-{[(6,7-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzene-1-sulfonamide;

3-({[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-6,7-dimethyl-1,2-dihydroquinolin-2-one;

2-methoxy-4-{[(6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzonitrile;

3-({[4-(1H-imidazol-1-yl)phenyl]amino}methyl)-6-methoxy-1,2-dihydroquinolin-2-one;

4-{[(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

2-methoxy-4-{[(7-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzonitrile;

3-({[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}methyl)-7-methyl-1,2-dihydroquinolin-2-one;

4-{[(6-bromo-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(6-tert-butyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

2-methoxy-4-({[2-oxo-6-(trifluoromethyl)-1,2-dihydroquinolin-3-yl]methyl}amino)benzonitrile;

4-{[(6-fluoro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(6-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(6-iodo-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(6-ethoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(7-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[(7-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

2-methoxy-4-{[(7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}benzonitrile;

4-{[(6-chloro-7-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-({[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-{[(6-chloro-7-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-hydroxy-3-(morpholin-4-yl)propoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(morpholin-4-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-({[6-chloro-2-oxo-7-(pyridin-3-ylmethoxy)-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-({[6-chloro-7-(oxan-4-ylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(dimethylamino)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(4-methanesulfonylpiperazin-1-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-({[6-chloro-2-oxo-7-(oxolan-3-ylmethoxy)-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-[({6-chloro-7-[(1-methylpiperidin-4-yl)oxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

2-[(6-chloro-3-{[(4-cyano-3-methoxyphenyl)amino]methyl}-2-oxo-1,2-dihydroquinolin-7-yl)oxy]-N,N-dimethylacetamide;

2-[(6-chloro-3-{[(4-cyano-3-methoxyphenyl)amino]methyl}-2-oxo-1,2-dihydroquinolin-7-yl)oxy]acetamide;

4-[({6-chloro-7-[2-(morpholin-4-yl)-2-oxoethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[(1,5-dimethyl-1H-pyrazol-3-yl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-({[7-(benzyloxy)-6-chloro-2-oxo-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-[({6-chloro-7-[(1-methylpiperidin-2-yl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[(2-methylpyridin-4-yl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-({[6-chloro-2-oxo-7-(pyridin-4-ylmethoxy)-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-[({6-chloro-7-[(1,1-dioxo-1λ 6 -thian-4-yl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-({[6-chloro-2-oxo-7-(pyrazin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-[({6-chloro-7-[(1-methyl-1H-imidazol-5-yl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[(1-methyl-1H-imidazol-2-yl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

5-{[(6-chloro-3-{[(4-cyano-3-methoxyphenyl)amino]methyl}-2-oxo-1,2-dihydroquinolin-7-yl)oxy]methyl}-1,2,4-oxadiazole-3-carboxamide;

4-[({6-chloro-2-oxo-7-[2-(pyridin-2-yl)ethoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-7-[2-(pyridin-4-yl)ethoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[3-(dimethylamino)propoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-7-[3-(pyrrolidin-1-yl)propoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-7-[3-(piperidin-1-yl)propoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-7-[2-(pyrrolidin-1-yl)ethoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-7-[2-(2-oxopyrrolidin-1-yl)ethoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-7-[2-(piperidin-1-yl)ethoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(4-methylpiperazin-1-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(1H-imidazol-1-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(2-methyl-1H-imidazol-1-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(1,1-dioxo-1λ 6 -thiomorpholin-4-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-7-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-({[6-chloro-7-(2-ethoxyethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-1 [(6-chloro-8-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino-2-methoxybenzonitrile;

4-[(6-chloro-8-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino-2-methoxybenzonitrile;

4-1 [(6-chloro-8-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino-2-methoxybenzonitrile;

4-({[6-chloro-2-oxo-8-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]methyl}amino)-2-methoxybenzonitrile;

4-[({6-chloro-8-[2-(morpholin-4-yl)ethoxy]-2-oxo-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile;

4-[({6-chloro-2-oxo-8-[2-(pyrrolidin-1-yl)ethoxy]-1,2-dihydroquinolin-3-yl}methyl)amino]-2-methoxybenzonitrile; or

2-methoxy-4-{[(2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)methyl]amino}benzonitrile.

36. The compound of claim 1 , wherein the compound is

4-{[(1S)-1-{6-chloro-2-oxo-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

6-chloro-3-[(1S)-1-{[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

4-{[(1S)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-2-methoxybenzonitrile;

methyl N-(3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)carbamate 3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}benzamide;

6-chloro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)acetamide;

6-chloro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

3-[(1S)-1-{[3-(1-benzyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-6-chloro-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(1-methyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(3-methylpyridin-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)-N-(2-methylpropyl)methanesulfonamide;

methyl N-(3-{[(1S)-1-{6-chloro-2-oxo-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-{6-chloro-2-oxo-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}benzamide;

6-chloro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1-oxazolidin-3-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-{6-chloro-2-oxo-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}phenyl)acetamide;

6-chloro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(4-methylthiophen-3-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-2-one;

3-[(1S)-1-{[3-(1-benzyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-6-chloro-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(1-methyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(3-methylpyridin-4-yl)phenyl]amino}ethyl]-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-{6-chloro-2-oxo-7-[(pyridin-2-yl)methoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}phenyl)-N-(2-methylpropyl)methanesulfonamide;

4-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methylbenzonitrile;

methyl N-(3-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}benzamide;

6-chloro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-7-methoxy-1,2-dihydroquinolin-2-one;

6-chloro-7-methoxy-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)acetamide;

6-chloro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-7-methoxy-1,2-dihydroquinolin-2-one;

6-chloro-7-methoxy-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-methoxy-3-[(1S)-1-{[3-(4-methylthiophen-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

3-[(1S)-1-{[3-(1-benzyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-6-chloro-7-methoxy-1,2-dihydroquinolin-2-one;

6-chloro-7-methoxy-3-[(1S)-1-{[3-(1-methyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-methoxy-3-[(1S)-1-{[3-(3-methylpyridin-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)-N-(2-methylpropyl)methanesulfonamide;

methyl N-(3-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}benzamide;

6-chloro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-7-(propan-2-yloxy)-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-7-(propan-2-yloxy)-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}phenyl)acetamide;

3-[(1S)-1-{[3-(1-benzyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-6-chloro-7-(propan-2-yloxy)-1,2-dihydroquinolin-2-one;

6-chloro-3-[(1S)-1-{[3-(1-methyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-7-(propan-2-yloxy)-1,2-dihydroquinolin-2-one;

methyl N-(3-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}benzamide;

6-chloro-7-(cyclopropylmethoxy)-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-(cyclopropylmethoxy)-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}phenyl)acetamide;

6-chloro-7-(cyclopropylmethoxy)-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}phenyl)-N-(2-methylpropyl)methanesulfonamide;

6-chloro-7-fluoro-3-[(1S)-1-{[3-methoxy-4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

methyl N-(3-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}benzamide;

6-chloro-7-fluoro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-fluoro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)acetamide;

6-chloro-7-fluoro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-fluoro-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-fluoro-3-[(1S)-1-{[3-(4-methylthiophen-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

3-[(1S)-1-{[3-(1-benzyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-6-chloro-7-fluoro-1,2-dihydroquinolin-2-one;

6-chloro-7-fluoro-3-[(1S)-1-{[3-(1-methyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-7-fluoro-3-[(1S)-1-{[3-(3-methylpyridin-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)-N-(2-methylpropyl)methanesulfonamide;

methyl N-(3-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}benzamide;

6-chloro-8-fluoro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-8-fluoro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

N-(3-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}phenyl)acetamide;

6-chloro-8-fluoro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-8-fluoro-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

6-chloro-8-fluoro-3-[(1S)-1-{[3-(4-methylthiophen-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinolin-2-one;

methyl N-(3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}phenyl)carbamate;

3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}benzamide;

6-chloro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

6-chloro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

N-(3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}phenyl)acetamide;

6-chloro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

6-chloro-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

6-chloro-3-[(1S)-1-{[3-(4-methylthiophen-3-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

3-[(1S)-1-{[3-(1-benzyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-6-chloro-1,2-dihydro-1,8-naphthyridin-2-one;

6-chloro-3-[(1S)-1-{[3-(1-methyl-1H-imidazol-5-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

6-chloro-3-[(1S)-1-{[3-(3-methylpyridin-4-yl)phenyl]amino}ethyl]-1,2-dihydro-1,8-naphthyridin-2-one;

N-(3-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}phenyl)-N-(2-methylpropyl)methanesulfonamide;

methyl N-(3-{[(1S)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}phenyl)carbamate;

6-chloro-3-[(1S)-1-{[2-fluoro-3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethyl]-1,2-dihydroquinoxalin-2-one;

6-chloro-3-[(1S)-1-{[3-(5-methyl-1H-1,2,3,4-tetrazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinoxalin-2-one;

N-(3-{[(1S)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}phenyl)acetamide;

6-chloro-3-[(1S)-1-{[3-(1H-imidazol-1-yl)phenyl]amino}ethyl]-1,2-dihydroquinoxalin-2-one; or

6-chloro-3-[(1S)-1-{[3-(1,2-oxazol-4-yl)phenyl]amino}ethyl]-1,2-dihydroquinoxalin-2-one.

37. A pharmaceutical composition comprising the compound according to claim 1 and pharmaceutically acceptable carrier.

38. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 1 wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

39. The method of claim 38 , wherein the disease is glioma, glioblastoma multiforme (GBM), acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

40. The method of claim 38 , wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion.

41. A method of inhibiting mutant isocitrate dehydrogenase comprising administering to a patient in need thereof a compound of claim 1 .

42. A method of reducing 2-hydroxyglutarate comprising administering to a patient in need thereof a compound of claim 1 .

43. A pharmaceutical composition comprising a compound of Formula I′

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, or tautomer thereof,

wherein:

each W 1 and W 2 is independently CH, CF or N;

W 3 is independently CR 2 or N;

A is selected from the group consisting of H, D, halogen, CN, —CHO, —COOH, —COOR 9 , —C(O)NH 2 , —C(O)NHR 9 , R 10 S(O) 2 —, —O(CH 2 )—C(O)R 10 , —O(CH 2 )—C(O)NR 10 R 9 , R 10 S(O)—, heteroaryl, —S(O)Me, —S(O) 2 Me,

B is selected from the group consisting of:

H, D, OH, NO 2 , NH 2 , —NR 11 R 12 , CN, —(CH 2 ) n CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, heteroaryl, —O(CH 2 ) n R 10 , —(CH 2 ) n C(O)NHR 9 , —C(O)NH 2 , —SR 9 , OR 9 , —(CHR 10 ) n S(O)R 9 , —(CHR 10 ) n S(O) 2 R 9 , —S(O) 2 NR 9 R 10 , —COOR 9 ,

wherein X and Y are independently in each occurrence C, N, NR 10 , S, and O, provided that the ring containing X and Y cannot have more than 4 N or NH atoms or more than one S or O atoms, and wherein the S and O are not contiguous;

R 1 is independently H, OH, CN, halogen, CHF 2 , CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl is optionally substituted one or more times with substituents selected from the group consisting of halogen, OH, NH 2 , CN, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

R 2 is independently H, OH, CN, halogen, CF 3 , CHF 2 , benzyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , —O(CH 2 ) n R 10 , —O(CHR 9 ) n R 10 , —O(CH 2 ) n —O—(CH 2 ) m R 10 , —O(CH 2 ) n C(O)NHR 10 , —O(CH 2 ) n C(O)R 10 , NHR 11 , —N(R 11 )(R 12 ), NHC(O)R 11 , NHS(O)R 11 , NHS(O) 2 R 11 , NHC(O)OR 11 , NHC(O)NHR 11 , —S(O) 2 NHR 11 , NHC(O)N(R 12 )R 11 , OCH 2 R 11 , CHR 9 R 10 , or OCHR 10 R 11 , wherein C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or benzyl is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted with one or more halogen, 3- to 8-membered heterocyclyl, aryl, -heteroaryl-C(O)NH 2 , and heteroaryl;

R 3 is H, C 1 -C 6 alkyl, or —OH,

R 4 and R 5 are independently H, halogen, CH 2 OH, C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with halogen, or R 4 and R 5 when combined can form a C 3 -C 5 cycloalkyl or C 3 -C 5 heterocyclyl;

R 6 , R 7 , and R 8 are independently H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy substituted with one or more halogen, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, —(CHR 11 )—S(O) 2 R 12 , —NR 11 C(O)R 12 , S(O) 2 NR 11 R 12 , or —C(O)NR 11 R 12 ;

R 9 and R 10 at each occurrence are independently selected from the group consisting of H, CN, —CH 2 CN, halogen, —NR 11 R 12 , —NR 11 C(O)R 12 , CHCF 2 , CF 3 , C 1 -C 6 alkyl, R 11 S(O) 2 —, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl, wherein each C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl, is optionally substituted with one or more substituents selected from the group consisting of OH, oxo, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH 2 , R 13 S(O) 2 —, CN, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, and R 13 S(O) 2 —;

R 11 and R 12 are independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl; or when combined R 11 and R 12 can form a 3- to 8-membered heterocyclyl or heteroaryl ring;

R 13 is independently H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl;

m is 0, 1, or 2;

n is 0, 1, or 2; and

r is 0, 1, or 2; and

a pharmaceutically acceptable carrier.

44. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a composition of claim 43 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

45. The method of claim 44 , wherein the disease is glioma, glioblastoma multiforme (GBM), acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

46. The method of claim 44 , wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion.

47. A method of inhibiting mutant isocitrate dehydrogenase comprising administering to a patient in need thereof a composition of claim 43 .

48. A method of reducing 2-hydroxyglutarate comprising administering to a patient in need thereof a composition of claim 43 .

49. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 29 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

50. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 30 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

51. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 31 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

52. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 32 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

53. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 33 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

54. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 34 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

55. A compound of claim 1 wherein the compound is:

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,6-dimethoxybenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile;

4-{[1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;

4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(trifluoromethoxy)benzonitrile; or

4-{[(6,7-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile.

56. A compound of claim 55 , wherein the compound is 4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2,6-dimethoxybenzonitrile.

57. A compound of claim 55 , wherein the compound is 4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile.

58. A compound of claim 55 , wherein the compound is 4-{[1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile.

59. A compound of claim 55 , wherein the compound is 4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-(trifluoromethoxy)benzonitrile.

60. A compound of claim 55 , wherein the compound is 4-{[(6,7-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-2-methoxybenzonitrile.

61. A pharmaceutical composition comprising the compound according to claim 56 and pharmaceutically acceptable carrier.

62. A pharmaceutical composition comprising the compound according to claim 57 and pharmaceutically acceptable carrier.

63. A pharmaceutical composition comprising the compound according to claim 58 and pharmaceutically acceptable carrier.

64. A pharmaceutical composition comprising the compound according to claim 59 and pharmaceutically acceptable carrier.

65. A pharmaceutical composition comprising the compound according to claim 60 and pharmaceutically acceptable carrier.

66. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 56 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

67. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 57 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

68. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 58 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

69. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 59 , wherein the disease is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

70. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 60 , wherein the disease is glioma, glioblastoma multiforme, paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

71. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 56 , wherein the cancer is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

72. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 57 , wherein the cancer is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

73. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 58 , wherein the cancer is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

74. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 59 , wherein the cancer is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

75. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 60 , wherein the cancer is glioma, glioblastoma multiforme (GBM), paraganglioma, acute myeloid leukemia (AML), prostate cancer, thyroid cancer, colon cancer, chondrosarcoma, cholangiocarcinoma, peripheral T-cell lymphoma, melanoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).