IP Library › Granted Patent US 9,834,539

Granted Patent B2

US 9,834,539 · App. 14/858,167 · Granted Dec 5, 2017

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

Inventors: Jian Lin (Acton, MA); Anna Ericsson (Acton, MA); Ann-Marie Campbell (Monroe, CT); Gary Gustafson (Ridgefield, CT); Zhongguo Wang (Lexington, MA); R. Bruce Diebold (Waltham, MA); Susan Ashwell (Carlisle, MA); David R. Lancia, Jr. (Boston, MA); Justin Andrew Caravella (Cambridge, MA); Wei Lu (Newton, MA)

Assignee: FORMA Therapeutics, Inc.

C07D401/12 C07D401/14 C07D471/04

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,834,539
App. No.: 14/858,167
Granted: Dec 5, 2017
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

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, U, W 1 , W 2 , W 3 , R 1 -R 6 , and R 9 are described herein.

Claims (177)

1. A compound of Formula I:

or pharmaceutical salt, enantiomer, 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:

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;

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-{[(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; or

5-{[(1S)-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:

5-{[(1S)-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;

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; or

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 cell proliferative disease comprising administering to a patient in need thereof a compound of claim 1 , 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).

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

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 method of treating a cancer comprising administering to a patient in need thereof a compound of claim 1 , wherein the cancer 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).

34. The method of claim 33 , wherein the cancer is glioma, glioblastoma multiforme (GBM), acute myeloid leukemia (AML), chondrosarcoma, intrahepatic cholangiocarcinoma (IHCC), myelodysplastic syndrome (MDS), or myeloproliferative disease (MPD).

35. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 20 , 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).

36. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 21 , 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).

37. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 20 , wherein the cancer 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).

38. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 21 , wherein the cancer 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).

39. 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 acute myeloid leukemia (AML).

40. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 1 , wherein the cancer is acute myeloid leukemia (AML).

41. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 20 , wherein the disease is acute myeloid leukemia (AML).

42. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 20 , wherein the cancer is acute myeloid leukemia (AML).

43. A compound of claim 1 selected from: