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:
Inventor(s):	Lin Jian, Ericsson Anna, Campbell Ann-Marie, Gustafson Gary, Wang Zhongguo, Diebold R. Bruce, Ashwell Susan, Lancia, Jr. David R., Caravella Justin Andrew, Lu Wei
Assignee:	FORMA Therapeutics, Inc.
Application Number:	US14858167
Patent Claims:	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 Ris H claim 1 , C-Calkyl or C-Ccycloalkyl.5. The compound of claim 4 , wherein Ris methyl.6. The compound of claim 1 , wherein A is H or F.7. The compound of claim 1 , wherein Ris H claim 1 , methyl or ethyl.8. The compound of claim 1 , wherein Rand Rare H.9. The compound of claim 1 , wherein Ris H and Ris methyl.10. The compound of claim 1 , wherein Ris H and Ris (S)-methyl.11. The compound of claim 1 , wherein Rand Rare halogen.12. The compound of claim 1 , wherein Ris F and Ris methyl.13. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.14. The compound of claim 1 , wherein W claim 1 , W claim 1 , and Ware CH claim 1 , or CF.15. The compound of claim 1 , wherein Wor Wis N.16. The compound of claim 1 , wherein Ris halogen.17. The compound of claim 16 , wherein Ris chloro.18. The compound of claim 1 , wherein Ris H claim 1 , halogen claim 1 , or C-Calkoxy.19. The compound of claim 1 , wherein Ris C-Calkoxy substituted with heteroaryl or 3- to 8-membered heterocyclyl.20. The compound of 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; or5-{[(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 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; or5-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide.27. A pharmaceutical composition comprising the compound according to 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 claim 1 , glioblastoma multiforme claim 1 , paraganglioma claim 1 , acute myeloid leukemia (AML) claim 1 , prostate cancer claim 1 , thyroid cancer claim 1 , colon cancer claim 1 , chondrosarcoma claim 1 , cholangiocarcinoma claim 1 , peripheral T-cell lymphoma claim 1 , melanoma claim 1 , intrahepatic cholangiocarcinoma (IHCC) claim 1 , myelodysplastic syndrome (MDS) claim 1 , or myeloproliferative disease (MPD).29. The method of claim 28 , wherein the cell proliferative disease is glioma claim 28 , glioblastoma multiforme (GBM) claim 28 , acute myeloid leukemia (AML) claim 28 , chondrosarcoma claim 28 , intrahepatic cholangiocarcinoma (IHCC) claim 28 , myelodysplastic syndrome (MDS) claim 28 , or myeloproliferative disease (MPD).30. The method of claim 28 , wherein administering is performed orally claim 28 , parentally claim 28 , subcutaneously claim 28 , by injection claim 28 , or by infusion.31. A method of inhibiting mutant isocitrate dehydrogenase comprising administering to a patient in need thereof a compound of .32. A method of reducing 2-hydroxyglutarate comprising administering to a patient in need thereof a compound of .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 claim 1 , glioblastoma multiforme claim 1 , paraganglioma claim 1 , acute myeloid leukemia (AML) claim 1 , prostate cancer claim 1 , thyroid cancer claim 1 , colon cancer claim 1 , chondrosarcoma claim 1 , cholangiocarcinoma claim 1 , peripheral T-cell lymphoma claim 1 , melanoma claim 1 , intrahepatic cholangiocarcinoma (IHCC) claim 1 , myelodysplastic syndrome (MDS) claim 1 , or myeloproliferative disease (MPD).34. The method of claim 33 , wherein the cancer is glioma claim 33 , glioblastoma multiforme (GBM) claim 33 , acute myeloid leukemia (AML) claim 33 , chondrosarcoma claim 33 , intrahepatic cholangiocarcinoma (IHCC) claim 33 , myelodysplastic syndrome (MDS) claim 33 , 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 claim 20 , glioblastoma multiforme claim 20 , paraganglioma claim 20 , acute myeloid leukemia (AML) claim 20 , prostate cancer claim 20 , thyroid cancer claim 20 , colon cancer claim 20 , chondrosarcoma claim 20 , cholangiocarcinoma claim 20 , peripheral T-cell lymphoma claim 20 , melanoma claim 20 , intrahepatic cholangiocarcinoma (IHCC) claim 20 , myelodysplastic syndrome (MDS) claim 20 , 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 claim 21 , glioblastoma multiforme claim 21 , paraganglioma claim 21 , acute myeloid leukemia (AML) claim 21 , prostate cancer claim 21 , thyroid cancer claim 21 , colon cancer claim 21 , chondrosarcoma claim 21 , cholangiocarcinoma claim 21 , peripheral T-cell lymphoma claim 21 , melanoma claim 21 , intrahepatic cholangiocarcinoma (IHCC) claim 21 , myelodysplastic syndrome (MDS) claim 21 , 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 claim 20 , glioblastoma multiforme claim 20 , paraganglioma claim 20 , acute myeloid leukemia (AML) claim 20 , prostate cancer claim 20 , thyroid cancer claim 20 , colon cancer claim 20 , chondrosarcoma claim 20 , cholangiocarcinoma claim 20 , peripheral T-cell lymphoma claim 20 , melanoma claim 20 , intrahepatic cholangiocarcinoma (IHCC) claim 20 , myelodysplastic syndrome (MDS) claim 20 , 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 claim 21 , glioblastoma multiforme claim 21 , paraganglioma claim 21 , acute myeloid leukemia (AML) claim 21 , prostate cancer claim 21 , thyroid cancer claim 21 , colon cancer claim 21 , chondrosarcoma claim 21 , cholangiocarcinoma claim 21 , peripheral T-cell lymphoma claim 21 , melanoma claim 21 , intrahepatic cholangiocarcinoma (IHCC) claim 21 , myelodysplastic syndrome (MDS) claim 21 , 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 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; or5-{[(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 claim 43 ,2-dihydropyridin-3-yl)amino]methyl}-1 claim 43 ,2-dihydroquinolin-2-one.45. A compound of claim 43 , wherein the compound is 6-chloro-3-{[(1-methyl-2-oxo-1 claim 43 ,2-dihydropyridin-3-yl)amino]methyl}-7-(pyridin-2-ylmethoxy)-1 claim 43 ,2-dihydroquinolin-2-one.46. A compound of claim 43 , wherein the compound is 5-{[(1S)-1-(6-chloro-2-oxo-1 claim 43 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,6-dihydropyridine-2-carbonitrile.47. A compound of claim 43 , wherein the compound is 5-{[(1S)-1-(6-chloro-2-oxo-1 claim 43 ,2-dihydroquinolin-3-yl)ethyl]amino}-6-oxo-1 claim 43 ,6-dihydropyridine-2-carbonitrile.48. A compound of claim 43 , wherein the compound is 5-{[(1R)-1-(6-chloro-2-oxo-1 claim 43 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,6-dihydropyridine-2-carbonitrile.49. A compound of claim 43 , wherein the compound is 5-{[(1S)-1-(6-chloro-2-oxo-1 claim 43 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,6-dihydropyrazine-2-carbonitrile.50. A compound of claim 43 , wherein the compound is 5-{[(1S)-1-(6-chloro-7-methoxy-2-oxo-1 claim 43 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,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 claim 43 ,2-dihydroquinolin-3-yl]ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,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 claim 43 ,2-dihydroquinolin-3-yl}ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,6-dihydropyridine-2-carbonitrile.53. A compound of claim 43 , wherein the compound is 5-{[(1S)-1-(6-chloro-8-fluoro-2-oxo-1 claim 43 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 43 ,6-dihydropyridine-2-carbonitrile.54. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.55. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.56. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.57. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.58. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.59. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.60. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.61. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.62. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.63. A pharmaceutical composition comprising the compound according to and pharmaceutically acceptable carrier.64. A pharmaceutical composition comprising the compound according to 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 claim 43 , glioblastoma multiforme claim 43 , paraganglioma claim 43 , acute myeloid leukemia (AML) claim 43 , prostate cancer claim 43 , thyroid cancer claim 43 , colon cancer claim 43 , chondrosarcoma claim 43 , cholangiocarcinoma claim 43 , peripheral T-cell lymphoma claim 43 , melanoma claim 43 , intrahepatic cholangiocarcinoma (IHCC) claim 43 , myelodysplastic syndrome (MDS) claim 43 , 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 claim 44 , glioblastoma multiforme claim 44 , paraganglioma claim 44 , acute myeloid leukemia (AML) claim 44 , prostate cancer claim 44 , thyroid cancer claim 44 , colon cancer claim 44 , chondrosarcoma claim 44 , cholangiocarcinoma claim 44 , peripheral T-cell lymphoma claim 44 , melanoma claim 44 , intrahepatic cholangiocarcinoma (IHCC) claim 44 , myelodysplastic syndrome (MDS) claim 44 , 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 claim 45 , glioblastoma multiforme claim 45 , paraganglioma claim 45 , acute myeloid leukemia (AML) claim 45 , prostate cancer claim 45 , thyroid cancer claim 45 , colon cancer claim 45 , chondrosarcoma claim 45 , cholangiocarcinoma claim 45 , peripheral T-cell lymphoma claim 45 , melanoma claim 45 , intrahepatic cholangiocarcinoma (IHCC) claim 45 , myelodysplastic syndrome (MDS) claim 45 , 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 claim 46 , glioblastoma multiforme claim 46 , paraganglioma claim 46 , acute myeloid leukemia (AML) claim 46 , prostate cancer claim 46 , thyroid cancer claim 46 , colon cancer claim 46 , chondrosarcoma claim 46 , cholangiocarcinoma claim 46 , peripheral T-cell lymphoma claim 46 , melanoma claim 46 , intrahepatic cholangiocarcinoma (IHCC) claim 46 , myelodysplastic syndrome (MDS) claim 46 , 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 claim 47 , glioblastoma multiforme claim 47 , paraganglioma claim 47 , acute myeloid leukemia (AML) claim 47 , prostate cancer claim 47 , thyroid cancer claim 47 , colon cancer claim 47 , chondrosarcoma claim 47 , cholangiocarcinoma claim 47 , peripheral T-cell lymphoma claim 47 , melanoma claim 47 , intrahepatic cholangiocarcinoma (IHCC) claim 47 , myelodysplastic syndrome (MDS) claim 47 , 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 claim 48 , glioblastoma multiforme claim 48 , paraganglioma claim 48 , acute myeloid leukemia (AML) claim 48 , prostate cancer claim 48 , thyroid cancer claim 48 , colon cancer claim 48 , chondrosarcoma claim 48 , cholangiocarcinoma claim 48 , peripheral T-cell lymphoma claim 48 , melanoma claim 48 , intrahepatic cholangiocarcinoma (IHCC) claim 48 , myelodysplastic syndrome (MDS) claim 48 , 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 claim 49 , glioblastoma multiforme claim 49 , paraganglioma claim 49 , acute myeloid leukemia (AML) claim 49 , prostate cancer claim 49 , thyroid cancer claim 49 , colon cancer claim 49 , chondrosarcoma claim 49 , cholangiocarcinoma claim 49 , peripheral T-cell lymphoma claim 49 , melanoma claim 49 , intrahepatic cholangiocarcinoma (IHCC) claim 49 , myelodysplastic syndrome (MDS) claim 49 , 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 claim 50 , glioblastoma multiforme claim 50 , paraganglioma claim 50 , acute myeloid leukemia (AML) claim 50 , prostate cancer claim 50 , thyroid cancer claim 50 , colon cancer claim 50 , chondrosarcoma claim 50 , cholangiocarcinoma claim 50 , peripheral T-cell lymphoma claim 50 , melanoma claim 50 , intrahepatic cholangiocarcinoma (IHCC) claim 50 , myelodysplastic syndrome (MDS) claim 50 , 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 claim 51 , glioblastoma multiforme claim 51 , paraganglioma claim 51 , acute myeloid leukemia (AML) claim 51 , prostate cancer claim 51 , thyroid cancer claim 51 , colon cancer claim 51 , chondrosarcoma claim 51 , cholangiocarcinoma claim 51 , peripheral T-cell lymphoma claim 51 , melanoma claim 51 , intrahepatic cholangiocarcinoma (IHCC) claim 51 , myelodysplastic syndrome (MDS) claim 51 , 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 claim 52 , glioblastoma multiforme claim 52 , paraganglioma claim 52 , acute myeloid leukemia (AML) claim 52 , prostate cancer claim 52 , thyroid cancer claim 52 , colon cancer claim 52 , chondrosarcoma claim 52 , cholangiocarcinoma claim 52 , peripheral T-cell lymphoma claim 52 , melanoma claim 52 , intrahepatic cholangiocarcinoma (IHCC) claim 52 , myelodysplastic syndrome (MDS) claim 52 , 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 claim 53 , glioblastoma multiforme claim 53 , paraganglioma claim 53 , acute myeloid leukemia (AML) claim 53 , prostate cancer claim 53 , thyroid cancer claim 53 , colon cancer claim 53 , chondrosarcoma claim 53 , cholangiocarcinoma claim 53 , peripheral T-cell lymphoma claim 53 , melanoma claim 53 , intrahepatic cholangiocarcinoma (IHCC) claim 53 , myelodysplastic syndrome (MDS) claim 53 , 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 claim 43 , glioblastoma multiforme claim 43 , paraganglioma claim 43 , acute myeloid leukemia (AML) claim 43 , prostate cancer claim 43 , thyroid cancer claim 43 , colon cancer claim 43 , chondrosarcoma claim 43 , cholangiocarcinoma claim 43 , peripheral T-cell lymphoma claim 43 , melanoma claim 43 , intrahepatic cholangiocarcinoma (IHCC) claim 43 , myelodysplastic syndrome (MDS) claim 43 , 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 claim 44 , glioblastoma multiforme claim 44 , paraganglioma claim 44 , acute myeloid leukemia (AML) claim 44 , prostate cancer claim 44 , thyroid cancer claim 44 , colon cancer claim 44 , chondrosarcoma claim 44 , cholangiocarcinoma claim 44 , peripheral T-cell lymphoma claim 44 , melanoma claim 44 , intrahepatic cholangiocarcinoma (IHCC) claim 44 , myelodysplastic syndrome (MDS) claim 44 , 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 claim 45 , glioblastoma multiforme claim 45 , paraganglioma claim 45 , acute myeloid leukemia (AML) claim 45 , prostate cancer claim 45 , thyroid cancer claim 45 , colon cancer claim 45 , chondrosarcoma claim 45 , cholangiocarcinoma claim 45 , peripheral T-cell lymphoma claim 45 , melanoma claim 45 , intrahepatic cholangiocarcinoma (IHCC) claim 45 , myelodysplastic syndrome (MDS) claim 45 , 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 claim 46 , glioblastoma multiforme claim 46 , paraganglioma claim 46 , acute myeloid leukemia (AML) claim 46 , prostate cancer claim 46 , thyroid cancer claim 46 , colon cancer claim 46 , chondrosarcoma claim 46 , cholangiocarcinoma claim 46 , peripheral T-cell lymphoma claim 46 , melanoma claim 46 , intrahepatic cholangiocarcinoma (IHCC) claim 46 , myelodysplastic syndrome (MDS) claim 46 , 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 claim 47 , glioblastoma multiforme claim 47 , paraganglioma claim 47 , acute myeloid leukemia (AML) claim 47 , prostate cancer claim 47 , thyroid cancer claim 47 , colon cancer claim 47 , chondrosarcoma claim 47 , cholangiocarcinoma claim 47 , peripheral T-cell lymphoma claim 47 , melanoma claim 47 , intrahepatic cholangiocarcinoma (IHCC) claim 47 , myelodysplastic syndrome (MDS) claim 47 , 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 claim 48 , glioblastoma multiforme claim 48 , paraganglioma claim 48 , acute myeloid leukemia (AML) claim 48 , prostate cancer claim 48 , thyroid cancer claim 48 , colon cancer claim 48 , chondrosarcoma claim 48 , cholangiocarcinoma claim 48 , peripheral T-cell lymphoma claim 48 , melanoma claim 48 , intrahepatic cholangiocarcinoma (IHCC) claim 48 , myelodysplastic syndrome (MDS) claim 48 , 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 claim 49 , glioblastoma multiforme claim 49 , paraganglioma claim 49 , acute myeloid leukemia (AML) claim 49 , prostate cancer claim 49 , thyroid cancer claim 49 , colon cancer claim 49 , chondrosarcoma claim 49 , cholangiocarcinoma claim 49 , peripheral T-cell lymphoma claim 49 , melanoma claim 49 , intrahepatic cholangiocarcinoma (IHCC) claim 49 , myelodysplastic syndrome (MDS) claim 49 , 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 claim 50 , glioblastoma multiforme claim 50 , paraganglioma claim 50 , acute myeloid leukemia (AML) claim 50 , prostate cancer claim 50 , thyroid cancer claim 50 , colon cancer claim 50 , chondrosarcoma claim 50 , cholangiocarcinoma claim 50 , peripheral T-cell lymphoma claim 50 , melanoma claim 50 , intrahepatic cholangiocarcinoma (IHCC) claim 50 , myelodysplastic syndrome (MDS) claim 50 , 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 claim 51 , glioblastoma multiforme claim 51 , paraganglioma claim 51 , acute myeloid leukemia (AML) claim 51 , prostate cancer claim 51 , thyroid cancer claim 51 , colon cancer claim 51 , chondrosarcoma claim 51 , cholangiocarcinoma claim 51 , peripheral T-cell lymphoma claim 51 , melanoma claim 51 , intrahepatic cholangiocarcinoma (IHCC) claim 51 , myelodysplastic syndrome (MDS) claim 51 , 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 claim 52 , glioblastoma multiforme claim 52 , paraganglioma claim 52 , acute myeloid leukemia (AML) claim 52 , prostate cancer claim 52 , thyroid cancer claim 52 , colon cancer claim 52 , chondrosarcoma claim 52 , cholangiocarcinoma claim 52 , peripheral T-cell lymphoma claim 52 , melanoma claim 52 , intrahepatic cholangiocarcinoma (IHCC) claim 52 , myelodysplastic syndrome (MDS) claim 52 , 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 claim 53 , glioblastoma multiforme claim 53 , paraganglioma claim 53 , acute myeloid leukemia (AML) claim 53 , prostate cancer claim 53 , thyroid cancer claim 53 , colon cancer claim 53 , chondrosarcoma claim 53 , cholangiocarcinoma claim 53 , peripheral T-cell lymphoma claim 53 , melanoma claim 53 , intrahepatic cholangiocarcinoma (IHCC) claim 53 , myelodysplastic syndrome (MDS) claim 53 , 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).