Claims for Patent: 9,834,539

Summary for Patent: 9,834,539

Title:	Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
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, W1, W2, W3, R1-R6, and R9 are described herein.
Inventor(s):	Jian Lin, Anna Ericsson, Ann-Marie Campbell, Gary Gustafson, Zhongguo Wang, R. Bruce Diebold, Susan Ashwell, David R. Lancia, Jr., Justin Andrew Caravella, Wei Lu
Assignee:	Forma Therapeutics Inc
Application Number:	US14/858,167
Patent Claims:	1. A compound of Formula I: or pharmaceutical salt, enantiomer, isomer, or tautomer thereof, wherein: each W1 and W2 is independently CH, CF or N; W3 is independently, CR2 or N; U is N or CR6; A is selected from the group consisting of H, D, halogen, CN, —CHO, —COOH, —COOR, —C(O)NH2, —C(O)NHR, R′S(O)2—, —O(CH2)nC(O)R′, R′S(O)—, heteroaryl, —SOMe, —SO2Me, 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, —CH2CN, halogen, —NR7R8, CHCF2, CF3, C1-C6 alkyl, R7S(O)2—, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 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, C1-C6 alkoxy, NH2, R7S(O)2—, CN, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, and R7S(O)—; R1 is independently OH, CN, halogen, CHCF2, CF3, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkenyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 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, NH2, CN, C1-C6 alkyl, and C1-C6 alkoxy; each R2 is independently H, OH, CN, halogen, CF3, CHF2, benzyl, C1-C6 alkyl, C1-C6 alkoxy, NH2, —O(CH2)nR′, —O(CH2)nC(O)NHR′, —O(CH2)nC(O)R′, NHR7, —N(R7)(R8), NHC(O)R7, NHS(O)R7, NHS(O)2R7, NHC(O)OR7, NHC(O)NHR7, —S(O)2NHR7, NHC(O)N(R8)R7, OCH2R7, CHRR′ or OCHR′R7, wherein C1-C6 alkyl, C1-C6 alkoxy is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more halogen, 3- to 8-membered heterocyclyl, aryl, -heteroaryl-C(O)NH2, and heteroaryl; or R1 and R2 can combine to form a C4-C6 cycloalkyl or a 3- to 8-membered heterocyclyl containing at least one atom selected from the group consisting of N, O, and S; R3 is H, C1-C6 alkyl, or —OH; R4 and R5 are independently H, halogen, CH2OH, C1-C3 alkyl, or C1-C3 alkyl substituted with halogen, or R4 and R5 when combined can form a C3-C6 cycloalkyl or C3-C6 heterocyclyl; each R6 is H, halogen, C1-C6 alkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkoxy, C1-C6 alkoxy substituted with one or more halogen, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, or heteroaryl; R7 and R8 are independently H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, and heteroaryl; or when combined R7 and R8 can form a 3- to 8-membered heterocyclyl or heteroaryl ring; R9 is independently H, D, CD3, CF3, C1-C6 alkyl, C2-6 alkenyl, C3-6 alkynyl, C3-C8 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 R1 is not C1-C6 alkyl or C1-C6 alkoxy and R1 and R2 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 R9 is H, C1-C6 alkyl or C3-C6 cycloalkyl. 5. The compound of claim 4, wherein R9 is methyl. 6. The compound of claim 1, wherein A is H or F. 7. The compound of claim 1, wherein R3 is H, methyl or ethyl. 8. The compound of claim 1, wherein R4 and R5 are H. 9. The compound of claim 1, wherein R4 is H and R5 is methyl. 10. The compound of claim 1, wherein R4 is H and R5 is (S)-methyl. 11. The compound of claim 1, wherein R4 and R5 are halogen. 12. The compound of claim 1, wherein R4 is F and R5 is methyl. 13. The compound of claim 1, wherein R4 and R5 can combine to form a C3-C5 cycloalkyl. 14. The compound of claim 1, wherein W1, W2, and W3 are CH, or CF. 15. The compound of claim 1, wherein W1 or W3 is N. 16. The compound of claim 1, wherein R1 is halogen. 17. The compound of claim 16, wherein R1 is chloro. 18. The compound of claim 1, wherein R2 is H, halogen, or C1-C6 alkoxy. 19. The compound of claim 1, wherein R2 is C1-C6 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: 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-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-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-{[(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-{[(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; or 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. 44. A compound of claim 43, wherein the compound is 6-chloro-7-methoxy-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one. 45. A compound of claim 43, wherein the compound is 6-chloro-3-{[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino]methyl}-7-(pyridin-2-ylmethoxy)-1,2-dihydroquinolin-2-one. 46. A compound of claim 43, wherein the compound is 5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile. 47. A compound of claim 43, wherein the compound is 5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1,6-dihydropyridine-2-carbonitrile. 48. A compound of claim 43, wherein the compound is 5-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile. 49. A compound of claim 43, wherein the compound is 5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyrazine-2-carbonitrile. 50. A compound of claim 43, wherein the compound is 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. 51. A compound of claim 43, wherein the compound is 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. 52. A compound of claim 43, wherein the compound is 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. 53. A compound of claim 43, wherein the compound is 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. 54. A pharmaceutical composition comprising the compound according to claim 43 and pharmaceutically acceptable carrier. 55. A pharmaceutical composition comprising the compound according to claim 44 and pharmaceutically acceptable carrier. 56. A pharmaceutical composition comprising the compound according to claim 45 and pharmaceutically acceptable carrier. 57. A pharmaceutical composition comprising the compound according to claim 46 and pharmaceutically acceptable carrier. 58. A pharmaceutical composition comprising the compound according to claim 47 and pharmaceutically acceptable carrier. 59. A pharmaceutical composition comprising the compound according to claim 48 and pharmaceutically acceptable carrier. 60. A pharmaceutical composition comprising the compound according to claim 49 and pharmaceutically acceptable carrier. 61. A pharmaceutical composition comprising the compound according to claim 50 and pharmaceutically acceptable carrier. 62. A pharmaceutical composition comprising the compound according to claim 51 and pharmaceutically acceptable carrier. 63. A pharmaceutical composition comprising the compound according to claim 52 and pharmaceutically acceptable carrier. 64. A pharmaceutical composition comprising the compound according to claim 53 and pharmaceutically acceptable carrier. 65. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 43, 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). 66. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 44, 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). 67. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 45, 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). 68. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 46, 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). 69. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 47, 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). 70. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 48, 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 cell proliferative disease comprising administering to a patient in need thereof a compound of claim 49, 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). 72. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 50, 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). 73. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 51, 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). 74. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 52, 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). 75. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 53, 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). 76. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 43, wherein the disease is acute myeloid leukemia (AML). 77. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 44, wherein the disease is acute myeloid leukemia (AML). 78. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 45, wherein the disease is acute myeloid leukemia (AML). 79. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 46, wherein the disease is acute myeloid leukemia (AML). 80. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 47, wherein the disease is acute myeloid leukemia (AML). 81. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 48, wherein the disease is acute myeloid leukemia (AML). 82. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 49, wherein the disease is acute myeloid leukemia (AML). 83. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 50, wherein the disease is acute myeloid leukemia (AML). 84. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 51, wherein the disease is acute myeloid leukemia (AML). 85. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 52, wherein the disease is acute myeloid leukemia (AML). 86. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound of claim 53, wherein the disease is acute myeloid leukemia (AML). 87. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 43, 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). 88. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 44, 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). 89. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 45, 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). 90. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 46, 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). 91. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 47, 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). 92. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 48, 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). 93. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 49, 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). 94. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 50, 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). 95. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 51, 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). 96. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 52, 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). 97. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 53, 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). 98. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 43, wherein the cancer is acute myeloid leukemia (AML). 99. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 44, wherein the cancer is acute myeloid leukemia (AML). 100. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 45, wherein the cancer is acute myeloid leukemia (AML). 101. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 46, wherein the cancer is acute myeloid leukemia (AML). 102. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 47, wherein the cancer is acute myeloid leukemia (AML). 103. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 48, wherein the cancer is acute myeloid leukemia (AML). 104. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 49, wherein the cancer is acute myeloid leukemia (AML). 105. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 50, wherein the cancer is acute myeloid leukemia (AML). 106. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 51, wherein the cancer is acute myeloid leukemia (AML). 107. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 52, wherein the cancer is acute myeloid leukemia (AML). 108. A method of treating a cancer comprising administering to a patient in need thereof a compound of claim 53, wherein the cancer is acute myeloid leukemia (AML).