PYRIDIN-2(1H)-ONE QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

1 . A compound of Formula I:

or pharmaceutical 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;

U is N or CR 6 ;

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

wherein X and Y are independently in each occurrence C, N, NR′, 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 and R′ at each occurrence are independently selected from the group consisting of H, OH, CN, —CH 2 CN, halogen, —NR 7 R 8 , CHCF 2 , CF 3 , C 1 -C 6 alkyl, R 7 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 R is optionally substituted with one or more substituents selected from the group consisting of OH, halogen, C 1 -C 6 alkoxy, NH 2 , R 7 S(O) 2 —, CN, C 3 -C 8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, and R 7 S(O)—;

R 1 is independently OH, CN, halogen, CHCF 2 , CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkenyl, 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;

each 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′, —O(CH 2 ) n C(O)NHR′, —O(CH 2 ) n C(O)R′, NHR 7 , —N(R 7 )(R 8 ), NHC(O)R 7 , NHS(O)R 7 , NHS(O) 2 R 7 , NHC(O)OR 7 , NHC(O)NHR 7 , —S(O) 2 NHR 7 , NHC(O)N(R 8 )R 7 , OCH 2 R 7 , CHRR′ or OCHR′R 7 , wherein C 1 -C 6 alkyl, C 1 -C 6 alkoxy 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;

or R 1 and R 2 can combine to form a C 4 -C 6 cycloalkyl or a 3- to 8-membered heterocyclyl containing at least one atom selected from the group consisting of N, O, and S;

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 6 cycloalkyl or C 3 -C 6 heterocyclyl;

each R 6 is 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, or heteroaryl;

R 7 and R 8 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 7 and R 8 can form a 3- to 8-membered heterocyclyl or heteroaryl ring;

R 9 is independently H, D, CD3, CF 3 , C 1 -C 6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3 -C 8 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with amino, OH, halo, or alkoxy;

n is 0, 1, or 2; and

r is 0, 1, or 2;

with the proviso that when A is H, then R 1 is not C 1 -C 6 alkyl or C 1 -C 6 alkoxy and R 1 and R 2 cannot combine to form a 3- to 8-membered heterocyclyl.

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

3 . The compound of claim 2 , wherein U is N.

4 . The compound of claim 1 , wherein A is CN and R 9 is H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl.

5 . The compound of claim 4 , wherein R 9 is methyl.

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

7 . The compound of claim 1 , wherein R 3 is H, methyl or ethyl.

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

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

10 . The compound of claim 1 , wherein R 4 is H and R 5 is (S)-methyl

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

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

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

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

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

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

17 . The compound of claim 16 , wherein R 1 is chloro.

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

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

20 . The compound of claim 1 selected from the group consisting of:

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

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

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

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

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

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

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

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

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

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

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

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

5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile;

5-{[(1R)-1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[1-(6-chloro-7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1R)-1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[1-(6-chloro-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1R)-1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-({1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-3-yl]ethyl}amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-{6-chloro-2-oxo-7-[(1R)-1-(pyridin-2-yl)ethoxy]-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[6-chloro-7-(cyclopropylmethoxy)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-[(1-{6-chloro-7-[(3,3-difluorocyclobutyl)methoxy]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl) amino]-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[6-chloro-2-oxo-7-(propan-2-yloxy)-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1R)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile; and

5-{[(1 S)-1-(7-chloro-3-oxo-3,4-dihydroquinoxalin-2-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile.

21 . The compound of claim 1 selected from the group consisting of:

5-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1-(trifluoromethyl)-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[6-chloro-7-(2-hydroxypropan-2-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-7-cyclopropyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-(6-chloro-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-{6-chloro-7-[(2-hydroxy-2-methylpropyl)amino]-2-oxo-1,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[7-(azetidin-1-yl)-6-chloro-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[7-(azetidin-1-yl)-6-chloro-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

5-{[(1S)-1-[6-chloro-7-(3,3-difluoroazetidin-1-yl)-2-oxo-1,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile;

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

5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide.

22 . The compound of claim 1 having the Formula Ia:

23 . The compound of claim 22 having the Formula Ia-1:

24 . The compound of claim 22 having the Formula Ia-2:

25 . The compound of claim 1 having the Formula Ib:

26 . The compound of claim 25 having the Formula Ib-1:

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

28 . A method of treating a disease or disorder associated with mutant isocitrate dehydrogenase comprising administering to a patient in need thereof a compound of claim 1 .

29 . The method of claim 28 , wherein the disease is glioma, glioblastoma multiforme (GBM), acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD) or a solid tumor.

30 . The method of claim 28 , wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion.

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

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

33 . A compound of any one of claims 1 - 26 for use in the manufacture of a medicament for treating a disease mediated by mutant isocitrate dehydrogenase.

34 . Use of a compound of any one of claims 1 - 26 for treating a disease mediated by mutant isocitrate dehydrogenase.