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

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: 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)-methyl11. 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 CF15. 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 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-{[( ...

QUINOLINONE FIVE-MEMBERED HETEROCYCLIC COMPOUNDS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 147-. (canceled)49. The compound of claim 48 , wherein Ris chloro.50. The compound of claim 49 , wherein Ris H and Ris (S)-methyl.51. The compound of claim 50 , wherein Ris H.52. The compound of claim 51 , wherein Ris —CN.53. The compound of claim 52 , wherein R′ is —H.54. The compound of claim 52 , wherein R′ is methyl.55. The compound of claim 51 , wherein Ris —C(O)NH.56. The compound of claim 55 , wherein R′ is methyl.57. The compound of claim 48 , wherein the compound is 2-{[(1S)-1-(6-chloro-2-oxo-1 claim 48 ,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1 claim 48 ,3-thiazole-5-carboxamide claim 48 , or a pharmaceutically acceptable salt thereof.58. A pharmaceutical composition comprising the compound of claim 48 , or a pharmaceutically acceptable salt thereof claim 48 , and a pharmaceutically acceptable carrier.59. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and a compound selected from:2-bromo(chloro)-4-methylthiazole-5-carboxamide;2-chloro(bromo)-4-methylthiazole-5-carbonitrile; and2-chlorothiazole-5-carbonitrile.60. The mixture of claim 59 , wherein the mixture comprises (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 2-bromo(chloro)-4-methylthiazole-5-carboxamide.61. The mixture of claim 60 , further comprising 2-{[(1S)-1-(6-chloro-2-oxo-1 claim 60 ,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1 claim 60 ,3-thiazole-5-carboxamide claim 60 , or a pharmaceutically acceptable salt thereof.62. The mixture of claim 59 , wherein the mixture comprises (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 2-chloro(bromo)-4-methylthiazole-5-carbonitrile.63. The mixture of claim 62 , further comprising 2-{[(1S)-1-(6-chloro-2-oxo-1 claim 62 ,2-dihydroquinolin-3-yl)ethyl]amino}-4-methyl-1 claim 62 ,3- ...

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

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: 134-. (canceled)46. The composition of claim 40 , wherein the suitable base is KCO.47. The composition of claim 42 , wherein the suitable oxidizing agent is m-CPBA.48. The composition of claim 43 , wherein the suitable acid is HCl. This application claims the benefit of priority of U.S. Provisional Application No. 62/053,006, filed Sep. 19, 2014 and U.S. Provisional Application No. 62/128,089, filed Mar. 4, 2015, and U.S. Provisional Application No. 62/150,812, filed Apr. 21, 2015, all of which are incorporated herein by reference in their entireties.The present invention is directed to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of diseases or disorders associated with such mutant IDH proteins including cell-proliferation disorders and cancers. Specifically, the invention is concerned with compounds and compositions inhibiting mt-IDH, methods of treating diseases or disorders associated with mt-IDH, and methods of synthesis of these compounds.Isocitrate dehydrogenases (IDHs) are enzymes that participate in the citric acid cycle (cellular metabolism). They catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate, α-KG). There are three isoforms within the IDH family. IDH-1, expressed in the cytoplasm and peroxisome, IDH-2, localized in the mitochondria, both utilize NADP+ as the cofactor and exist as homodimers. IDH-3 is localized in mitochondrial matrix and utilizes NAD+ as a cofactor and exists as tetramer. Mutations in IDH-1 (cytosolic) and IDH-2 (mitochondrial) have been identified in various diseases or disorders including glioma, glioblastoma multiforme, paraganglioma, supratentorial primordial neuroectodermal tumors, acute myeloid leukemia (AML), prostate ...

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

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: 2. The compound of claim 1 , wherein A is CN.3. The compound of claim 2 , wherein B is C-Calkoxy or C-Calkyl.4. The compound of claim 3 , wherein B is methoxy.5. The compound of claim 3 , wherein B is C-Calkyl.6. The compound of claim 5 , wherein B is methyl.7. The compound of claim 1 , wherein A is H or F.13. The compound of claim 1 , claim 1 , claim 1 , claim 1 , or claim 1 , wherein Ris Me claim 1 , Et claim 1 , and cyclopropyl.15. The compound of claim 14 , wherein B is C-Calkoxy.16. The compound of claim 15 , wherein B is methoxy17. The compound of claim 1 , wherein Rand Rare H.18. The compound of claim 1 , wherein Ris H and Ris methyl.19. The compound of claim 1 , wherein Ris H and Ris (S)-methyl20. The compound of claim 1 , wherein Rand Rare halogen.21. The compound of claim 1 , wherein Ris F and Ris methyl.22. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.23. The compound of claim 1 , wherein W claim 1 , W claim 1 , and Ware CH claim 1 , or CF.24. The compound of claim 1 , wherein Wor Wis N.25. The compound of claim 1 , wherein Ris halogen.26. The compound of claim 23 , wherein Ris chloro.27. The compound of claim 1 , wherein Ris H claim 1 , halogen claim 1 , or C-Calkoxy.28. The compound of claim 1 , wherein Ris C-Calkoxy substituted with heteroaryl or 3-to 8-membered heterocyclyl.35. The compound of selected from the group consisting of:4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;4-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;4-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-3-methanesulfonylbenzonitrile;4-{[1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxybenzonitrile;4-({1-[6-chloro-2-oxo-7-(pyridin-2-ylmethoxy)-1 ...

QUINOLINONE PYRIMIDINES COMPOSITIONS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 2. The compound of claim 1 , wherein A is CN.3. The compound of claim 2 , wherein B is C-Calkoxy or C-Calkyl.4. The compound of claim 3 , wherein B is methoxy.5. The compound of claim 1 , wherein A is H or F.7. The compound of claim 6 , wherein R′ is methyl claim 6 , ethyl claim 6 , isopropyl claim 6 , or isobutyl.8. The compound of claim 6 , wherein R′ is phenyl claim 6 , aryl claim 6 , or heteroaryl.11. The compound of claim 10 , wherein R is methyl claim 10 , ethyl claim 10 , or cyclopropyl.16. The compound of claim 1 , wherein Rand Rare H.17. The compound of claim 1 , wherein Ris H and Ris methyl.18. The compound of claim 1 , wherein Ris H and Ris (S)-methyl.19. The compound of claim 1 , wherein Rand Rare halogen.20. The compound of claim 1 , wherein Ris F and Ris methyl.21. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.22. The compound of claim 1 , wherein W claim 1 , W claim 1 , and Ware CH23. The compound of claim 1 , wherein W claim 1 , W claim 1 , or Wis N.24. The compound of claim 1 , wherein W claim 1 , W claim 1 , or Wis CF25. The compound of claim 1 , wherein Ris halogen.26. The compound of claim 25 , wherein Ris chloro.27. The compound of claim 1 , wherein Ris H claim 1 , halogen claim 1 , or C-Calkoxy.28. The compound of claim 1 , wherein Ris C-Calkoxy substituted with heteroaryl or C-Cheterocyclyl.29. The compound of selected from the group consisting of:N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(2,2-dimethylpropyl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(cyclopropylmethyl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(oxan-3-yl)methanesulfonamide;N-(2-{[(1S)- ...

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

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: 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)-methyl11. 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 CF15. 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 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-{[( ...

PYRIDINYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 2. The compound of claim 1 , wherein A is CN.3. The compound of claim 2 , wherein B is C-Calkoxy or C-Calkyl.4. The compound of claim 3 , wherein B is methoxy.5. The compound of claim 3 , wherein B is methyl.6. The compound of claim 2 , wherein U is N or V is N.7. The compound of claim 1 , wherein A is H or F.10. The compound of claim 9 , wherein R is methyl claim 9 , ethyl claim 9 , and cyclopropyl.15. The compound of claim 1 , wherein Rand Rare H.16. The compound of claim 1 , wherein Ris H and Ris methyl.17. The compound of claim 1 , wherein Ris H and Ris (S)-methyl18. The compound of claim 1 , wherein Rand Rare halogen.19. The compound of claim 1 , wherein Ris F and Ris methyl.20. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.21. The compound of claim 1 , wherein W claim 1 , W claim 1 , and Ware CH claim 1 , or CF22. The compound of claim 1 , wherein Wor Wis N.23. The compound of claim 1 , wherein Ris halogen.24. The compound of claim 26 , wherein Ris chloro.25. The compound of claim 1 , wherein Ris H claim 1 , halogen claim 1 , or C-Calkoxy.26. The compound of claim 1 , wherein Ris C-Calkoxy substituted with heteroaryl or 3- to 8-membered heterocyclyl.27. The compound of selected from the group consisting of:6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile;6-{[(1S)-1-(6-chloro-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile;6-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methylpyridine-3-carbonitrile;6-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methylpyridine-3-carbonitrile;6-{[(1S)-1-(6-chloro-2-oxo-1,2- ...

Treating patients harboring an isocitrate dehydrogenase 1 (idh-1) mutation

Methods of treating patients diagnosed with AML or MDS harboring mutant IDH-1 include detecting an IDH1 mutation and the therapeutic administration of an inhibitor of a mutant IDH-1 as a single agent, or in combination with azacitidine (AZA) or cytarabine.

PYRIDINYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 142-. (canceled)43. A method of treating a cell proliferative disease comprising administering to a patient in need thereof a compound selected from the group consisting of:6-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile;6-{[(1 S)-1-(6-chloro-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile;6-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile;6-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methylpyridine-3-carbonitrile;6-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methylpyridine-3-carbonitrile;6-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methoxypyridine-3-carbonitrile;5-{[(1 S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-6-methoxypyridine-2-carbonitrile;6-{[(1R)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methylpyridine-3-carbonitrile;6-{[1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-2-methylpyridine-3-carbonitrile;6-chloro-3-[(1 S)-1-{[4-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1 S)-1-{[6-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1 S)-1-[6-methyl-4-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino)ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1 S)-1-{[4-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1 S)-1-{[3-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1 S)-1-{[3-methyl-4-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;6-chloro-3-[(1 S)-1-{[4-fluoro-6-(2-oxo-1,3-oxazolidin-3-yl)pyridin-2-yl]amino} ...

INHIBITING MUTANT IDH-1

Methods of treating patients diagnosed with cancer harboring an IDH-1 mutation are provided, including the therapeutic administration of a certain inhibitor of a mutant IDH-1 as a single agent, or in combination with azacitidine (AZA). 113-. (canceled)15. The method of claim 14 , wherein the patient is diagnosed with histologically or cytologically confirmed IDH1 gene-mutated advanced glioma or glioblastoma multiforme with confirmed IDH1 gene-mutated disease with first or second recurrence claim 14 , prior to the administration of the compound of Formula (1).16. The method of claim 14 , wherein the compound of Formula (1) is administered to the patient as a single agent for the treatment of the glioma.17. The method of claim 14 , wherein the pharmaceutical composition is administered to the patient in need thereof in a tablet or capsule oral unit dosage form on consecutive days throughout a course of treatment of at least 15 consecutive days.18. The method of claim 14 , wherein150 mg of the compound of Formula (1) is administered to the patient twice per day on consecutive days throughout a course of treatment of between 15 days and 6 months.19. The method of claim 14 , wherein the patient is diagnosed as having a low grade glioma or secondary glioblastoma multiforme (GBM).20. The method of claim 14 , where the patient is diagnosed with a glioma having a R132 IDH1 mutation.21. The method of claim 14 , wherein the compound of Formula (I) is administered as a Type A solid form.22. A method of treating a patient diagnosed with a brain cancer characterized by an IDH1 mutation claim 14 , comprising administering a total of 150 mg twice per day of olutasidenib to the patient in need thereof.23. The method of claim 22 , wherein the patient is diagnosed with histologically or cytologically confirmed IDH1 gene-mutated advanced glioma or glioblastoma multiforme with confirmed IDH1 gene-mutated disease with first or second recurrence claim 22 , prior to the administration of ...

QUINOLINONE FIVE-MEMBERED HETEROCYCLIC COMPOUNDS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: (I) where Y, X, X, Y, W, W, W, and R-Rare described herein. 2. The compound of claim 1 , wherein two adjacent Rand/or R′ combine to form pyrrolidinyl claim 1 , piperidinyl claim 1 , phenyl claim 1 , oxazolyl claim 1 , thiazolyl claim 1 , isoxazolyl claim 1 , isothiazolyl claim 1 , pyrrolyl claim 1 , pyrazolyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , furyl claim 1 , imidazolyl claim 1 , pyridyl claim 1 , pyrimidinyl claim 1 , pyrrolyl claim 1 , furyl claim 1 , thienyl claim 1 , oxazolyl claim 1 , thiazolyl claim 1 , isoxazolyl claim 1 , isothiazolyl claim 1 , imidazolyl claim 1 , pyrazolyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , triazolyl claim 1 , tetrazolyl claim 1 , pyrazinyl claim 1 , pyridazinyl claim 1 , triazinyl claim 1 , pyridinyl claim 1 , pyrimidinyl claim 1 , morpholinyl claim 1 , thiomorpholinyl claim 1 , oxazolonyl claim 1 , oxazinonyl claim 1 , dihydrooxazinonyl claim 1 , imidazolonyl claim 1 , pyrrolonyl claim 1 , thiazolonyl claim 1 , dihydropyridinonyl claim 1 , dihydrothiazinedioxide claim 1 , dihydrodioxinyl claim 1 , dihydropyranonyl claim 1 , dihydrothiophenedioxide claim 1 , piperidinonyl claim 1 , pyrrolidinonyl or dihydrooxazinonyl claim 1 ,3. The compound of claim 1 , wherein Ris CN claim 1 , C(O)NH claim 1 , —NHCOR claim 1 ,4. The compound of claim 1 , wherein R′ is H claim 1 , methyl claim 1 , or ethyl.5. The compound of claim 1 , wherein Rand Rare H.6. The compound of claim 1 , wherein Ris H and Ris methyl.7. The compound of claim 1 , wherein Ris H and Ris (S)-methyl.8. The compound of claim 1 , wherein Rand Rare halogen.9. The compound of claim 1 , wherein Ris F and Ris methyl.10. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.11. The compound of any of the forgoing claims claim 1 ...

FUSED-BICYCLIC ARYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 127-. (canceled)28. A pharmaceutical composition comprising a compound , or a pharmaceutically acceptable salt thereof , selected from:3-{[(1,3-benzoxazol-4-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(isoquinolin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}naphthalene-1-carbonitrile;6-chloro-3-{[(quinolin-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2,3-dihydro-1-benzofuran-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one;7-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}-3,4-dihydro-2H-1,4-benzoxazin-3-one;3-{[2-(1H-1,3-benzodiazol-5-yl)-1H-1,3-benzodiazol-5-yl]amino}methyl)-6,7-dimethoxy-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1H-indol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(isoquinolin-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3,4-dihydro-2H-1-benzopyran-8-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(6-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-1H-indazol-6-yl)amino]methyl}-1,2- ...

QUINOLINONE PYRIMIDINES COMPOSITIONS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 150-. (canceled)51. A compound selected from the group consisting of:N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(2,2-dimethylpropyl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(cyclopropylmethyl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(oxan-3-yl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(propan-2-yl)pyridine-3-sulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-2-methyl-N-(propan-2-yl)propane-1-sulfonamide;N-[(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)methyl]-N-cyclopropylmethanesulfonamide;3-[(1S)-1-{[4-(tert-butylamino)pyrimidin-2-yl]amino}ethyl]-6-chloro-1,2-dihydroquinolin-2-one;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(2-methylpropyl)methanesulfonamide;6-chloro-3-[(1S)-1-{[4-(cyclopropylamino)pyrimidin-2-yl]amino}ethyl]-1,2-dihydroquinolin-2-one;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(propan-2-yl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-1-cyclopropyl-N-(propan-2-yl)methanesulfonamide;(S)-6-Chloro-3-(1-((4-(1,1-dioxidoisothiazolidin-2-yl)pyrimidin-2-yl)amino)ethyl)quinolin-2(1H)-one;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)methanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N-cyclopropylmethanesulfonamide;N-(2-{[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}pyrimidin-4-yl)-N,2- ...

PYRIDINYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

The invention relates to methods of reducing the level of -hydroxyglutarate in cells by administration of an inhibitor of mutant isocitrate dehydrogenase- 1. A method of reducing the production of 2-hydroxyglutarate (2-HG) in a cell producing 2-HG (“2-HG producing cell”) ,wherein the method comprises the step of contacting the 2-HG producing cell with an inhibitor of mutant isocitrate dehydrogenase-1 protein (mt-IDH1),{'sub': '50', 'wherein the inhibitor of mt-IDH1 has an ICvalue of 1 micromolar or less against HCT116 cells harboring mt-IDH1 (“HCT116 mt-IDH1 cells”) selected from the group consisting of HCT116 isogenic IDH1-R132H cells and HCT116 isogenic IDH1-R132C cells;'} [{'sub': '2', "a. culturing the HCT116 mt-IDH1 cells in a growth media comprising McCoy's 5A, 10% fetal bovine serum, 1× antibiotic-antimycotic solution, and 0.3 mg/mL G418 in 5% COin an incubator at 37° C.;"}, "b. trypsinizing and resuspending the HCT116 mt-IDH1 cells in an assay media comprising McCoy's 5A with no L-glutamine, 10% fetal bovine serum, 1× antibiotic-antimycotic solution, and 0.3 mg/mL G418;", 'c. obtaining an aliquot of 10,000 cells/100 μL and transferring the aliquot to each well of a clear 96-well tissue culture plate;', {'sub': '2', 'd. incubating the cells in the culture plate in 5% COat 37° C. in an incubator overnight;'}, {'sub': '2', 'e. obtaining an aliquot of 50 μL of an assay media comprising the inhibitor of mt-IDH1, and adding the aliquot to each well of the clear 96-well tissue culture plate and maintaining the culture plate in 5% COat 37° C. in an incubator for 24 hours;'}, 'f. removing the media from each well of the clear 96-well tissue culture plate and adding 150 μL of a methanol/water mixture (80/20 v/v) to each well;', 'g. maintaining the plate at −80° C. freezer for 12 hours;', 'h. obtaining an aliquot of 125 μL of extracted methanol/water mixture and analyzing the aliquot by a high-throughput-mass spectrometry to determine the cellular 2-HG level; and', {' ...

FUSED-BICYCLIC ARYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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 (I) where A, B, U, V, Z, W, W, W, and R-Rare described herein. 3. The compound of claim 2 , wherein Ris methyl claim 2 , ethyl claim 2 , isopropyl claim 2 , or isobutyl.5. The compound of claim 4 , wherein Ris methyl claim 4 , ethyl claim 4 , isopropyl claim 4 , or isobutyl.6. The compound of claim 1 , wherein Rand Rare H.7. The compound of claim 1 , wherein Ris H and Ris methyl.8. The compound of claim 1 , wherein Ris H and Ris (S)-methyl.9. The compound of claim 1 , wherein Rand Rare halogen.10. The compound of claim 1 , wherein Ris F and Ris methyl.11. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.12. The compound of any of the foregoing claims claim 1 , wherein W claim 1 , Wand Ware CH or CF.13. The compound of any of the foregoing claims claim 1 , wherein W claim 1 , W claim 1 , or Wis N.14. The compound of any of the foregoing claims claim 1 , wherein Ris halogen.15. The compound of claim 14 , wherein Ris chloro.16. The compound of any of the foregoing claims claim 14 , wherein Ris H or C-Calkoxy.17. The compound of any of the foregoing claims claim 14 , wherein Ris C-Calkoxy substituted with heteroaryl or C-Cheterocyclyl.18. The compound of selected from the group consisting of:3-{[(1,3-benzoxazol-4-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(isoquinolin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl) ...

INHIBITING MUTANT IDH-1

Methods of treating patients diagnosed with cancer harboring an IDH-1 mutation are provided, including the therapeutic administration of a certain inhibitor of a mutant IDH-1 as a single agent, or in combination with azacitidine (AZA). 2. The use of claim 1 , wherein a 150 mg amount of Compound 1 (or a corresponding amount in the form of a pharmaceutically acceptable salt thereof) is administered to the patient twice per day (BID) throughout the course of treatment.3. The use of claim 1 , wherein the cancer is a mIDH-1 form of acute myeloid leukemia.4. The use of claim 3 , wherein the acute myeloid leukemia is relapsed or refractory or is drug-resistant.5. The use of claim 1 , wherein the cancer is a mIDH-1 solid tumor.6. The use of claim 1 , wherein the cancer is of a mIDH-1 glioma.7. The use of claim 6 , wherein the mIDH-1 glioma is an advanced glioma that has recurred or progressed prior to the administration of Compound 1.8. The use of any one of the preceding claims claim 6 , wherein the mIDH1 is a R132X mutation.9. The use of claim 8 , wherein the R132X mIDH-1 mutation is selected from R132L claim 8 , R132G and R132S.10. The use of any one of the preceding claims claim 8 , wherein the pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof is orally administered to the patient.11. The use of any one of the preceding claims claim 8 , wherein Compound 1 claim 8 , (or a corresponding amount in the form of a pharmaceutically acceptable salt thereof) is administered as a single agent for the treatment of the cancer harboring the IDH-1 mutation.12. The use of any of the preceding claims claim 8 , wherein the course of treatment is at least 15 consecutive days to reach a steady state blood concentration of Compound 1 (or a corresponding amount in the form of a pharmaceutically acceptable salt thereof) in the patient.13. The use of any one of the preceding claims claim 8 , wherein the course of treatment is at least 6 months.14. ...

FUSED-BICYCLIC ARYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 2. The compound of claim 1 , wherein Ris H and Ris methyl.3. The compound of claim 2 , wherein Ris H and Ris (S)-methyl.4. The compound of claim 3 , wherein Ris chloro.5. The compound of claim 4 , wherein Ris methyl.7. The compound of claim 6 , wherein the C ring is pyrrolidinyl.8. The compound of claim 7 , wherein Ris H and Ris methyl.9. The compound of claim 7 , wherein Ris H and Ris (S)-methyl.10. The compound of claim 8 , wherein Ris chloro.11. The compound of claim 9 , wherein Ris methyl.12. The compound of claim 1 , wherein the compound is (S)-3-(1-(1-acetyl-2 claim 1 ,3-dihydro-1H-pyrrolo[3 claim 1 ,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one claim 1 , or a pharmaceutically acceptable salt thereof.13. A pharmaceutical composition comprising the compound of and pharmaceutically acceptable carrier.14. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 1-(4-chloro-2 claim 11 ,3-dihydro-1H-pyrrolo[3 claim 11 ,2-c]pyridin-1-yl)ethanone.15. The mixture of further comprising (S)-3-(1-(1-acetyl-2 claim 13 ,3-dihydro-1H-pyrrolo [3 claim 13 ,2-c]pyridin-4-ylamino)ethyl)-6-chloroquinolin-2(1H)-one or a pharmaceutically acceptable salt thereof.17. The compound of claim 16 , wherein B and Rare taken together with the atoms to which they are attached to form a 5-membered heterocyclyl ring system which can be further substituted with one or more Rsubstituents.18. The compound of claim 17 , wherein the 5-membered heterocyclyl ring system is pyrrolidinyl.19. The compound of claim 16 , wherein Ris chloro.20. The compound of claim 17 , wherein Ris chloro. This application claims the benefit of priority of U.S. Provisional Application No. 62/150,815, filed Apr. 21, 2015, all of which is incorporated herein by reference in its ...

INHIBITING MUTANT ISOCITRATE DEHYDROGENASE 1 (mIDH-1)

Patients diagnosed with a cancer harboring an IDH-1 mutation can be treated by the administration of a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, a selective inhibitor of 2-HG production from mIDH-1 enzymes including the R132 mutations R132C, R132H, R132L, R132G, and R132S. 120-. (canceled)22. The method of claim 21 , wherein the patient is diagnosed with a susceptible IDH1 mutation selected from the group consisting R132G claim 21 , R132S and R132L.23. The method of claim 21 , wherein the patient is diagnosed with a susceptible IDH1 mutation selected from the group consisting R132H and R132C.24. The method of claim 21 , wherein the patient is diagnosed with a co-mutation selected from the group consisting of DNMT3A claim 21 , NPM1 claim 21 , SRSF2 claim 21 , NRAS claim 21 , RUNX1 claim 21 , ASXL1 claim 21 , STAG2 claim 21 , TET2 claim 21 , SMC1A claim 21 , SF3B1 claim 21 , U2AF1 claim 21 , PHF6 claim 21 , JAK2 claim 21 , MPL claim 21 , NF1 claim 21 , ASXL2 claim 21 , BCOR claim 21 , EED claim 21 , WT1 claim 21 , CBL claim 21 , CSF3R claim 21 , ETNK1 claim 21 , PTPN11 claim 21 , ATM and TP53.25. The method of claim 21 , wherein the patient is diagnosed with a co-mutation selected from the group consisting of FLT3 claim 21 , NPM1 claim 21 , CEBPA and TP53.26. The method of claim 21 , wherein the patient is diagnosed with a co-mutation selected from the group consisting of FLT3 claim 21 , NPM1 claim 21 , CEBPA claim 21 , TP53 and IDH2.27. The method of claim 22 , wherein the patient is diagnosed with a co-mutation selected from the group consisting of DNMT3A claim 22 , NPM1 claim 22 , SRSF2 claim 22 , NRAS claim 22 , RUNX1 claim 22 , ASXL1 claim 22 , STAG2 claim 22 , TET2 claim 22 , SMC1A claim 22 , SF3B1 claim 22 , U2AF1 claim 22 , PHF6 claim 22 , JAK2 claim 22 , MPL claim 22 , NF1 claim 22 , ASXL2 claim 22 , BCOR claim 22 , EED claim 22 , WT1 claim 22 , CBL claim 22 , CSF3R claim 22 , ETNK1 claim 22 , PTPN11 claim 22 , ...

PHENYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

The invention relates to methods of reducing the level of 2-hydroxyglutarate in cells by administration of an inhibitor of mutant isocitrate dehydrogenase-1. 1. A method of reducing the production of 2-hydroxyglutarate (2-HG) in a cell producing 2-HG (“2-HG producing cell”) ,wherein the method comprises the step of contacting the 2-HG producing cell with an inhibitor of mutant isocitrate dehydrogenase-1 protein (mt-IDH1),{'sub': '50', 'wherein the inhibitor of mt-IDH1 has an ICvalue of 0.1 micromolar or less against HCT116 cells harboring mt-IDH1 (“HCT116 mt-IDH1 cells”) selected from the group consisting of HCT116 isogenic IDH1-R132H cells and HCT116 isogenic IDH1-R132C cells;'}{'sub': '50', 'claim-text': [{'sub': '2', "a. culturing the HCT116 mt-IDH1 cells in a growth media comprising McCoy's 5A, 10% fetal bovine serum, 1× antibiotic-antimycotic solution, and 0.3 mg/mL G418 in 5% COin an incubator at 37° C.;"}, "b. trypsinizing and resuspending the HCT116 mt-IDH1 cells in an assay media comprising McCoy's 5A with no L-glutamine, 10% fetal bovine serum, 1× antibiotic-antimycotic solution, and 0.3 mg/mL G418;", 'c. obtaining an aliquot of 10,000 cells/100 μL and transferring the aliquot to each well of a clear 96-well tissue culture plate;', {'sub': '2', 'd. incubating the cells in the culture plate in 5% COat 37° C. in an incubator overnight;'}, {'sub': '2', 'e. obtaining an aliquot of 50 μL of an assay media comprising the inhibitor of mt-IDH1, and adding the aliquot to each well of the clear 96-well tissue culture plate and maintaining the culture plate in 5% COat 37° C. in an incubator for 24 hours;'}, 'f. removing the media from each well of the clear 96-well tissue culture plate and adding 150 μL of a methanol/water mixture (80/20 v/v) to each well;', 'g. maintaining the plate at −80° C. freezer for 12 hours;', 'h. obtaining an aliquot of 125 μL of extracted methanol/water mixture and analyzing the aliquot by a high-throughput-mass spectrometry to determine ...

QUINOLINONE PYRIMIDINES COMPOSITIONS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

The invention relates to methods of reducing the level of 2-hydroxyglutarate in cells by administration of an inhibitor of mutant isocitrate dehydrogenase-1. 1. A method of reducing the production of 2-hydroxyglutarate (2-HG) in a cell producing 2-HG (“2-HG producing cell”) ,wherein the method comprises the step of contacting the 2-HG producing cell with an inhibitor of mutant isocitrate dehydrogenase-1 protein (mt-IDH1),{'sub': '50', 'wherein the inhibitor of mt-IDH1 has an ICvalue of less than 1 micromolar against HCT116 cells harboring mt-IDH1 (“HCT116 mt-IDH1 cells”) selected from the group consisting of HCT116 isogenic IDH1-R132H cells and HCT116 isogenic IDH1-R132C cells;'}{'sub': '50', 'claim-text': [{'sub': '2', "a. culturing the HCT116 mt-IDH1 cells in a growth media comprising McCoy's 5A, 10% fetal bovine serum, 1× antibiotic-antimycotic solution, and 0.3 mg/mL G418 in 5% COin an incubator at 37° C.;"}, "b. trypsinizing and resuspending the HCT116 mt-IDH1 cells in an assay media comprising McCoy's 5A with no L-glutamine, 10% fetal bovine serum, 1× antibiotic-antimycotic solution, and 0.3 mg/mL G418;", 'c. obtaining an aliquot of 10,000 cells/100 μL and transferring the aliquot to each well of a clear 96-well tissue culture plate;', {'sub': '2', 'd. incubating the cells in the culture plate in 5% COat 37° C. in an incubator overnight;'}, {'sub': '2', 'e. obtaining an aliquot of 50 μL of an assay media comprising the inhibitor of mt-IDH1, and adding the aliquot to each well of the clear 96-well tissue culture plate and maintaining the culture plate in 5% COat 37° C. in an incubator for 24 hours;'}, 'f. removing the media from each well of the clear 96-well tissue culture plate and adding 150 μL of a methanol/water mixture (80/20 v/v) to each well;', 'g. maintaining the plate at −80° C. freezer for 12 hours;', 'h. obtaining an aliquot of 125 μL of extracted methanol/water mixture and analyzing the aliquot by a high-throughput-mass spectrometry to determine ...

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

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: 134-. (canceled)43. The method of claim 35 , wherein the suitable acid is HCl.44. The method of claim 36 , wherein the suitable reducing agent is NaBH.45. The method of claim 39 , wherein the suitable methylating agent is MeI.46. The method of claim 40 , wherein the suitable base is KCO.47. The method of claim 42 , wherein the suitable oxidizing agent is m-CPBA.52. The composition of claim 48 , wherein the process further comprises obtaining Intermediate III-1 from 5-fluoro-6-oxo-1 claim 48 ,6-dihydropyridine-2-carbonitrile.53. The composition of claim 52 , wherein the process further comprises obtaining 5-fluoro-6-oxo-1 claim 52 ,6-dihydropyridine-2-carbonitrile from 6-cyano-3-fluoropyridin-2-yl acetate.54. The composition of claim 53 , wherein the process further comprises obtaining 6-cyano-3-fluoropyridin-2-yl acetate from 2-cyano-5-fluoropyridine-1-oxide.55. The composition of claim 54 , wherein the process further comprises obtaining 2-cyano-5-fluoropyridine-1-oxide from 5-fluoropicolinonitrile. This application is a continuation of U.S. patent application Ser. No. 16/290,240, filed Mar. 1, 2019, which is a continuation of U.S. patent application Ser. No. 15/964,844, now U.S. Pat. No. 10,414,752, filed Apr. 27, 2018, which is a continuation of U.S. patent application Ser. No. 15/452,256, filed Mar. 7, 2017, which is a continuation of U.S. patent application Ser. No. 14/858,167, filed Sep. 18, 2015, which issued as U.S. Pat. No. 9,834,539, which claims the benefit of priority of U.S. Provisional Application No. 62/053,006, filed Sep. 19, 2014 and U.S. Provisional Application No. 62/128,089, filed Mar. 4, 2015, and U.S. Provisional Application No. 62/150,812, filed Apr. 21, 2015, all of which are incorporated herein by reference in their entireties.The present ...

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

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: 2. The composition of claim 1 , wherein the process further comprises obtaining Compound III-1 from 5-fluoro-6-oxo-1 claim 1 ,6-dihydropyridine-2-carbonitrile.3. The composition of claim 2 , wherein the process further comprises obtaining 5-fluoro-6-oxo-1 claim 2 ,6-dihydropyridine-2-carbonitrile from 6-cyano-3-fluoropyridin-2-yl.4. The composition of claim 3 , wherein the process further comprises obtaining 6-cyano-3-fluoropyridin-2-yl acetate from 2-cyano-5-fluoropyridine-1-oxide.5. The composition of claim 4 , wherein the process further comprises obtaining 2-cyano-5-fluoropyridine 1-oxide from 5-fluoropicolinonitrile.6. The composition of claim 1 , wherein the process further comprises obtaining Compound II-1 from (R)—N—((S)-1-(2 claim 1 ,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide.7. The composition of claim 6 , wherein the process further comprises obtaining (R)—N—((S)-1-(2 claim 6 ,6-dichloroquinolin-3-yl)ethyl)-2-methylpropane-2-sulfinamide from (R claim 6 ,E)-N-((2 claim 6 ,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide.8. The composition of claim 7 , wherein the process further comprises obtaining (R claim 7 ,E)-N-((2 claim 7 ,6-dichloroquinolin-3-yl)methylene)-2-methylpropane-2-sulfinamide from 2 claim 7 ,6-dichloroquinoline-3-carbaldehyde.17. The method of claim 10 , wherein the methylating agent is MeI.18. The method of claim 11 , wherein the base is KCO.19. The method of claim 13 , wherein the oxidizing agent is m-CPBA.20. The method of claim 14 , wherein the acid is HCl. This application is a continuation application of U.S. patent application Ser. No. 15/964,844, filed Apr. 27, 2019, which is a continuation application of U.S. patent application Ser. No. 15/452,256, filed Mar. 7, 2017, which is a continuation ...

QUINOLINONE PYRIMIDINES COMPOSITIONS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 2. The method of claim 1 , wherein the mutant isocitrate dehydrogenase is in a cell claim 1 , and the method further comprises reducing 2-HG produced by the cell.3. The method of claim 1 , wherein the neomorphic activity is R-2-HG neomorphic activity.4. The method of claim 1 , wherein the mutant isocitrate dehydrogenase is mutant IDH1.5. The method of claim 1 , wherein the mutant isocitrate dehydrogenase is mutant IDH1 having (R)-2-HG neomorphic activity.6. The method of claim 1 , wherein the compound is contacted with a mutant IDH1 protein claim 1 , NADPH and alpha-ketoglutarate under conditions effective to inhibit NADPH consumption.7. The method of claim 2 , wherein the cell is a colon cancer cell.8. The method of claim 2 , wherein the cell is a HCT116 cell.9. The method of claim 2 , in an assay for identifying the presence of a R132 mutant IDH1 in a sample comprising the cell claim 2 , the method comprising the steps of:(a) contacting the sample comprising cells that produce cellular 2-HG, with the compound;{'sub': '50', '(b) measuring an inhibition of cellular 2-HG production in the sample with an ICvalue of about 1 micromolar or less, to identify the sample as containing a cell having a R132 IDH1 mutation.'}10. The method of claim 9 , wherein the method is a cellular 2-HG assay using a sample comprising R132 mutant IDH1 cells.11. The method of claim 9 , wherein the sample is obtained from a patient diagnosed with cancer.12. The method of claim 9 , wherein the sample is contacted with the compound for about 24 hours prior to detecting the cellular 2-HG level in the sample.13. The method of claim 9 , wherein the sample comprises R132 mutant IDH1 cells that catalyze the NADPH-dependent reduction of alpha-ketoglutarate R-2-HG.14. The method of claim 11 , wherein ...

FUSED-BICYCLIC ARYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 3. The compound of claim 2 , wherein Ris methyl claim 2 , ethyl claim 2 , isopropyl claim 2 , or isobutyl.5. The compound of claim 4 , wherein Ris methyl claim 4 , ethyl claim 4 , isopropyl claim 4 , or isobutyl.6. The compound of claim 1 , wherein Rand Rare H.7. The compound of claim 1 , wherein Ris H and Ris methyl.8. The compound of claim 1 , wherein Ris H and Ris (S)-methyl.9. The compound of claim 1 , wherein Rand Rare halogen.10. The compound of claim 1 , wherein Ris F and Ris methyl.11. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.12. The compound of any of the foregoing claims claim 1 , wherein W claim 1 , Wand Ware CH or CF.13. The compound of any of the foregoing claims claim 1 , wherein W claim 1 , W claim 1 , or Wis N.14. The compound of any of the foregoing claims claim 1 , wherein Ris halogen.15. The compound of claim 14 , wherein Ris chloro.16. The compound of any of the foregoing claims claim 14 , wherein Ris H or C-Calkoxy.17. The compound of any of the foregoing claims claim 14 , wherein Ris C-Calkoxy substituted with heteroaryl or C-Cheterocyclyl.18. The compound of selected from the group consisting of:3-{[(1,3-benzoxazol-4-yl)amino]methyl}-6-chloro-1,2-dihydroquinolin-2-one;6-chloro-3-{[(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(2-oxo-2H-chromen-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]methyl}-1,2-dihydroquinolin-2-one;6-chloro-3-{[(isoquinolin-3-yl)amino]methyl}-1,2-dihydroquinolin-2-one;4-{[(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}naphthalene-1-carbonitrile;6-chloro-3-{[(quinolin-8- ...

QUINOLINONE FIVE-MEMBERED HETEROCYCLIC COMPOUNDS AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 2. The compound of claim 1 , wherein two adjacent Rand/or R′ combine to form pyrrolidinyl claim 1 , piperidinyl claim 1 , phenyl claim 1 , oxazolyl claim 1 , thiazolyl claim 1 , isoxazolyl claim 1 , isothiazolyl claim 1 , pyrrolyl claim 1 , pyrazolyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , furyl claim 1 , imidazolyl claim 1 , pyridyl claim 1 , pyrimidinyl claim 1 , pyrrolyl claim 1 , furyl claim 1 , thienyl claim 1 , oxazolyl claim 1 , thiazolyl claim 1 , isoxazolyl claim 1 , isothiazolyl claim 1 , imidazolyl claim 1 , pyrazolyl claim 1 , oxadiazolyl claim 1 , thiadiazolyl claim 1 , triazolyl claim 1 , tetrazolyl claim 1 , pyrazinyl claim 1 , pyridazinyl claim 1 , triazinyl claim 1 , pyridinyl claim 1 , pyrimidinyl claim 1 , morpholinyl claim 1 , thiomorpholinyl claim 1 , oxazolonyl claim 1 , oxazinonyl claim 1 , dihydrooxazinonyl claim 1 , imidazolonyl claim 1 , pyrrolonyl claim 1 , thiazolonyl claim 1 , dihydropyridinonyl claim 1 , dihydrothiazinedioxide claim 1 , dihydrodioxinyl claim 1 , dihydropyranonyl claim 1 , dihydrothiophenedioxide claim 1 , piperidinonyl claim 1 , pyrrolidinonyl or dihydrooxazinonyl claim 1 ,3. The compound of claim 1 , wherein Ris CN claim 1 , C(O)NH claim 1 , —NHCOR claim 1 ,4. The compound of claim 1 , wherein R′ is H claim 1 , methyl claim 1 , or ethyl.5. The compound of claim 1 , wherein Rand Rare H.6. The compound of claim 1 , wherein Ris H and Ris methyl.7. The compound of claim 1 , wherein Ris H and Ris (S)-methyl.8. The compound of claim 1 , wherein Rand Rare halogen.9. The compound of claim 1 , wherein Ris F and Ris methyl.10. The compound of claim 1 , wherein Rand Rcan combine to form a C-Ccycloalkyl.11. The compound of any of the forgoing claims claim 1 , wherein W claim 1 , W claim 1 , and Ware CH.12. The ...

INHIBITING MUTANT ISOCITRATE DEHYDROGENASE 1 (mIDH-1)

Patients diagnosed with a cancer harboring an IDH-1 mutation can be treated by the administration of a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, a selective inhibitor of 2-HG production from mIDH-1 enzymes including the R132 mutations R132C, R132H, R132L, R132G, and R132S. 1. A method of treating a patient diagnosed with a solid tumor characterized by an IDH1 mutation , the method comprising orally administering to the patient in need thereof a pharmaceutical composition comprising a total of 150 mg of olutasidenib twice per day (BID).2. The method of claim 1 , wherein the olutasidenib is administered as a single agent.3. The method of claim 1 , wherein the solid tumor is selected from glioma claim 1 , hepatobiliary carcinoma claim 1 , chondrosarcoma claim 1 , and intrahepatic cholangiocarcinoma.4. The method of claim 1 , wherein the olutasidenib is administered to the patient in need thereof in a tablet or capsule oral unit dosage form on consecutive days throughout a course of treatment.5. The method of claim 4 , wherein the course of treatment is at least 15 consecutive days.6. The method of claim 4 , wherein the course of treatment is at least 6 months.7. The method of claim 1 , wherein the solid tumor is characterized by an R132 IDH1 mutation.8. A method of treating a patient diagnosed with a glioma characterized by an IDH1 mutation claim 1 , the method comprising orally administering to the patient in need thereof a pharmaceutical composition comprising a total of 150 mg of olutasidenib twice per day (BID).9. The method of claim 8 , wherein the olutasidenib is administered as a single agent.10. The method of claim 8 , wherein the glioma is characterized by an R132 IDH1 mutation.11. The method of claim 10 , wherein the R132 IDH1 mutation is selected from R132C claim 10 , R132H claim 10 , R132G claim 10 , R132S claim 10 , and R132L.12. The method of claim 10 , wherein the glioma is further characterized by at least ...

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

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: 134-. (canceled)44. The pharmaceutical composition of claim 43 , formulated in a dosage form for oral administration.45. The pharmaceutical composition of claim 44 , formulated in a solid dosage form for oral administration.46. The pharmaceutical composition of claim 43 , formulated as a tablet or capsule dosage form.47. The pharmaceutical composition of claim 45 , comprising a total of about 50 mg of a compound of formula (I-13).48. The pharmaceutical composition of claim 45 , comprising a total of about 150 mg of a compound of formula (I-13).53. A pharmaceutical composition for inhibiting mutant IDH1 claim 45 , comprising a pharmaceutically acceptable carrier and from about 5% to about 90% by weight of a mutant IDH1 inhibitor consisting of the compound 5-{[(1S)-1-(6-chloro-2-oxo-1 claim 45 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 45 ,6-dihydropyridine-2-carbonitrile.54. The composition of claim 53 , formulated as a solid dosage form for oral administration claim 53 , and comprising about 50-150 mg of the compound 5-{[(1S)-1-(6-chloro-2-oxo-1 claim 53 ,2-dihydroquinolin-3-yl)ethyl]amino}-1-methyl-6-oxo-1 claim 53 ,6-dihydropyridine-2-carbonitrile in an enatiomeric purity (e.e. %) of at least 98% as determined by chiral HPLC analysis. This application is a divisional application of U.S. patent application Ser. No. 15/452,256, filed Mar. 7, 2018, which is a continuation application of U.S. patent application Ser. No. 14/858,167, filed Sep. 18, 2015, which issued as U.S. Pat. No. 9,834,539, which claims the benefit of priority of U.S. Provisional Application No. 62/053,006, filed Sep. 19, 2014 and U.S. Provisional Application No. 62/128,089, filed Mar. 4, 2015, and U.S. Provisional Application No. 62/150,812, filed Apr. 21, 2015, all of which are ...

PHENYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 155-. (canceled)57. The compound of claim 56 , wherein B is methoxy.58. The compound of claim 57 , wherein Ris H and Ris methyl.59. The compound of claim 58 , wherein Ris H and Ris (S)-methyl.60. The compound of claim 59 , wherein Ris chloro.63. A pharmaceutical composition comprising (S)-4-((1-(6-chloro-2-oxo-1 claim 59 ,2-dihydroquinolin-3-yl)ethyl)amino)-2-methoxybenzonitrile claim 59 , or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.64. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 4-fluoro-2-methoxybenzonitrile.65. The mixture of claim 64 , further comprising (S)-4-((1-(6-chloro-2-oxo-1 claim 64 ,2-dihydroquinolin-3-yl)ethyl)amino)-2-methoxybenzonitrile claim 64 , or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier claim 64 , or a pharmaceutically acceptable salt thereof. This application is a continuation of U.S. application Ser. No. 14/858,174, filed Sep. 18, 2015, now U.S. patent Ser. No. 10/005,734, which claims the benefit of priority of U.S. Provisional Application No. 62/053,006, filed Sep. 19, 2014 and U.S. Provisional Application No. 62/128,089, filed Mar. 4, 2015, and U.S. Provisional Application No. 62/206,631, filed Aug. 18, 2015, all of which are incorporated herein by reference in their entireties.The present invention is directed to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of diseases or disorders associated with such mutant IDH proteins including cell-proliferation disorders and cancers. Specifically, the invention is concerned with compounds and compositions inhibiting mt-IDH, methods of treating diseases or disorders associated with mt-IDH, and methods of ...

PYRIDINYL QUINOLINONE DERIVATIVES AS MUTANT-ISOCITRATE DEHYDROGENASE INHIBITORS

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: 142-. (canceled)44. The compound of claim 43 , wherein B is methoxy.45. The compound of claim 44 , wherein Ris H and Ris methyl.46. The compound of claim 45 , wherein Ris H and Ris (S)-methyl.47. The compound of claim 46 , wherein Ris chloro.52. A pharmaceutical composition comprising 6-{[(1S)-1-(6-chloro-2-oxo-1 claim 46 ,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile claim 46 , or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.53. A mixture comprising (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride and 6-chloro-4-methoxynicotinonitrile.54. The mixture of claim 53 , further comprising 6 {[(1S)-1-(6-chloro-2-oxo-1 claim 53 ,2-dihydroquinolin-3-yl)ethyl]amino}-4-methoxypyridine-3-carbonitrile claim 53 , or a pharmaceutically acceptable salt thereof. This application is a U.S. Continuation Application of Ser. No. 15/677,748, filed Aug. 15, 2017, which is a U.S. Continuation Application of Ser. No. 14/858,170, filed Sep. 18, 2015, issued as U.S. Pat. No. 9,771,349, on Sep. 26, 2017, which claims the benefit of priority of U.S. Provisional Application No. 62/053,006, filed Sep. 19, 2014 and U.S. Provisional Application No. 62/128,089, filed Mar. 4, 2015, and U.S. Provisional Application No. 62/150,819, filed Apr. 21, 2015, all of which are incorporated herein by reference in their entireties.The present invention is directed to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of diseases or disorders associated with such mutant IDH proteins including cell-proliferation disorders and cancers. Specifically, the invention is concerned with compounds and compositions inhibiting mt-IDH, methods of treating diseases or disorders associated ...

Inhibiting mutant idh-1

Methods of treating patients diagnosed with cancer harboring an IDH-1 mutation are provided, including the therapeutic administration of a certain inhibitor of a mutant IDH-1 as a single agent, or in combination with azacitidine (AZA).

INHIBITING MUTANT ISOCITRATE DEHYDROGENASE 1 (mIDH-1)

Patients diagnosed with a cancer harboring an IDH-1 mutation can be treated by the administration of a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, a selective inhibitor of 2-HG production from mIDH-1 enzymes including the R132 mutations R132C, R132H, R132L, R132G, and R132S. 120-. (canceled)22. The method of claim 21 , wherein the patient is diagnosed with a cancer characterized by a concurrent mutation selected from the group consisting of FLT3 claim 21 , NPM1 claim 21 , CEBPA and TP53.23. The method of claim 21 , wherein the patient is diagnosed with a cancer that is not characterized by an IDH2 mutation.24. The method of claim 21 , wherein the patient is diagnosed with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) characterized by the IDH1 mutation prior to the administration of Compound 1.25. The method of claim 24 , wherein the patient is diagnosed with MDS or AML further characterized by a concurrent mutation selected from the group consisting of FLT3 claim 24 , NPM1 claim 24 , CEBPA and TP53.26. The method of claim 21 , wherein the patient is diagnosed with a cancer characterized by a concurrent mutation selected from the group consisting of DNMT3A claim 21 , NPM1 claim 21 , SRSF2 claim 21 , NRAS claim 21 , RUNX1 claim 21 , ASXL1 claim 21 , FLT3 claim 21 , STAG2 claim 21 , TET2 claim 21 , SMC1A claim 21 , SF3B1 claim 21 , U2AF1 claim 21 , PHF6 claim 21 , JAK2 claim 21 , MPL claim 21 , NF1 claim 21 , ASXL2 claim 21 , BCOR claim 21 , EED claim 21 , WT1 claim 21 , CBL claim 21 , CSF3R claim 21 , ETNK1 claim 21 , PTPN11 claim 21 , ATM and TP53.28. The method of claim 27 , wherein the patient is diagnosed with a hematological malignancy characterized by a co-mutation selected from the group consisting of DNMT3A claim 27 , NPM1 claim 27 , SRSF2 claim 27 , NRAS claim 27 , RUNX1 claim 27 , ASXL1 claim 27 , STAG2 claim 27 , TET2 claim 27 , SMC1A claim 27 , SF3B1 claim 27 , U2AF1 claim 27 , PHF6 claim 27 , ...

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

Alpha amino acid derivatives--inhibitors of leukocyte adhesion mediated by VLA-4

Disclosed are certain alpha amino acid compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by vla-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g, human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

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

Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by vla-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds are also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors

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 Y 1 , X 1 , X 2 , Y 2 , W 1 , W 2 , W 3 , and R 1 -R 5 are described herein.

Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors.

La presente invención se refiere a inhibidores de proteínas de isocitrato deshidrogenasa mutante (mt-IDH) con actividad neomórfica útiles en el tratamiento de trastornos de proliferación celular y cánceres, que tiene la Fórmula: (ver fórmula), donde A, B, U, V, Z, W1, W2, W3 y R1-R6 se describen en la presente.

Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4

Complement modulators and related methods

The present disclosure presents compounds and compositions that interact with complement components. Some compounds inhibit complement activity. Included are small molecule compounds and compositions that function as C5 inhibitor compounds. Methods for inhibiting complement activity and methods of treating complement-related indications with the C5 inhibitor compounds and compositions are provided.

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

Cette invention concerne des inhibiteurs de protéines d'isocitrate déshydrogénase mutantes (mt-idh) ayant une activité néomorphe, utiles pour traiter les troubles liés à la prolifération cellulaire et les cancers, de formule : (i) où a, u, w1, w2, w3, r1-r6, et r9 sont tels que décrits dans la présente.

Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors

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, B, W1, W2, W3, and R1-R6 are described herein.

Alpha amino acid derivatives-inhibitors of leukocyte adhesion mediated by VLA-4

Disclosed are certain alpha amino acid compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Phenylalanine derivatives as alpha 4 integrin inhibitors

Disclosed are a series of phenylalanine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.

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

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: (I) where A, U, W1, W2, W3, R1-R6, and R9 are described herein.

Inhibiting mutant IDH-1

Methods of treating patients diagnosed with cancer harboring an IDH-1 mutation are provided, including the therapeutic administration of a certain inhibitor of a mutant IDH-1 as a single agent, or in combination with azacitidine (AZA).

Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4.

CARBAMYLOXY COMPOUNDS FOR INHIBITING VLA-4-MEDIATED LEUKOCYTE ADHESION

Compounds which inhibit leukocyte adhesion mediated by VLA-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

ABSTRACT The invention relates to inhibitors of mutant isocitrate dehydrogenase (nt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: R6 1 1 A R4 R6 u ' I 1 R1 W2W12( N /N v-- Z , B 1 - H R2 W3 N ---......"0 FI3 (I). Date Recue/Date Received 2020-04-22

Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Compounds which inhibit leukocyte adhesion mediated by VLA-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Phenyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

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, B, W 1 , W 2 , W 3 , and R 1 -R 8 are described herein.

Phenyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

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, B, W1, W2, W3, and R1-R8 are described herein.

Complement Modulators and Related Methods

The present disclosure presents compounds and compositions that interact with complement components. Some compounds inhibit complement activity. Included are small molecule compounds and compositions that function as C5 inhibitor compounds. Methods for inhibiting complement activity and methods of treating complement-related indications with the C5 inhibitor compounds and compositions are provided.

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

La presente invención se refiere a inhibidores de proteínas de isocitrato deshidrogenasa mutante (mt-IDH) con actividad neomórfica útiles en el tratamiento de trastornos de proliferación celular y cánceres, que tienen la Fórmula: (ver Fórmula) donde A, U, W1, W2, W3, R1-R6, y R9 se describen en la presente.

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

The application relates to an inhibitor of mutant isocitrate dehydrogenase (mt-IDH) proteins with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula (I-13):

Thiophene derivatives as CHK 1 inhibitors

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

Acyl derivatives that treat VLA-4-related disorders

4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by vla-4, pharmaceutical compositions comprising thereof and their use

A találmány tárgyát leukociták adhézióját gátló, különösen VLA-4kötésére képes (I) általános képletű vegyületek és (IA) általánosképletű gyógyszer előhatóanyagai, valamint a fenti vegyületekgyógyászatilag elfogadható sói képezik. A képletekben R1 jelentése adott esetben helyettesített alkil-, aril-, cikloalkil-,heterogyűrűs vagy heteroarilcsoport; R2 jelentése hidrogénatom vagy adott esetben helyettesített alkil-,cikloalkil-, cikloalkenil-, heterogyűrűs, aril-, heteroarilcsoport,vagy R1 és R2 az R2 helyettesítőhöz kötődő nitrogénatommal és az R1helyettesítőhöz kötődő -SO2- csoporttal együtt adott esetbenhelyettesített heterogyűrűs csoportot alkothatnak; R3 jelentése hidrogénatom vagy adott esetben helyettesített alkil-,cikloalkil-, aril-, heteroaril- vagy heterogyűrűs csoport, és ha R2nem alkot gyűrűt az R1 helyettesítővel, akkor R2 és R3 az R2helyettesítővel kapcsolódó nitrogénatommal és az R3 helyettesítővelkapcsolódó szénatommal adott esetben helyettesített heterogyűrűscsoportot alkothatnak; R5 jelentése -(CH2)x-Ar-R5' általános képletű csoport, ahol R5'jelentése -NR12-C(Z)-NR8R8' vagy -NR12C(Z)-R13; Ar jelentése aril-, heteroaril-, helyettesített aril- vagyhelyettesített heteroarilcsoport; x jelentése 1-4 értékű egész szám; és Q jelentése -C(X)NR7-, ahol R7 jelentése hidrogénatom vagyalkilcsoport; és X jelentése oxigén- vagy kénatom. A találmány tárgyátképezik a fenti hatóanyagokat tartalmazó gyógyászati készítmények,valamint ezek alkalmazása VLA-4 megkötésére biológiai mintában. Ó FIELD OF THE INVENTION The present invention relates to compounds of formula (I) and prodrugs of general formula (IA) which inhibit leukocyte adhesion, in particular VLA-4 binding, and pharmaceutically acceptable salts thereof. In the formulas, R1 is optionally substituted alkyl, aryl, cycloalkyl, heterocyclic or heteroaryl; R 2 is hydrogen or optionally substituted alkyl, cycloalkyl, cycloalkenyl, heterocyclic, aryl, heteroaryl, or R 1 and R 2 may be taken together with ...

Inhibiting mutant isocitrate dehydrogenase 1 (mlDH-1)

Patients diagnosed with a cancer harboring an IDH-1 mutation can be treated by the administration of a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, a selective inhibitor of 2-HG production from mIDH-1 enzymes including the R132 mutations R132C, R132H, R132L, R132G, and R132S.

REPLACED THIOPHENS AND USES OF THE SAME

Compuestos derivados del tiofeno, y sus sales farmacéuticas, composiciones y métodos de uso. Estos compuestos proveen un tratamiento o profilaxis del cáncer. Reivindicación 1: Un compuesto caracterizado porque responde a la fórmula (1) o una sal aceptable para uso farmacéutico o éster hidrolizable in vivo del mismo, en donde: R1 y R2 se seleccionan en forma independiente en cada caso entre H, C1-6 alquilo opcionalmente sustituido, o heterociclilo opcionalmente sustituido; con la salvedad de que R1 yR2 no sean ambos H; o R1 y R2 y el N al cual están unidos forman en combinación un heterociclilo opcionalmente sustituido; R4 se selecciona entre H, OH, carbociclilo opcionalmente sustituido, heterociclilo opcionalmente sustituido, o C1-6 alquilo opcionalmente sustituido; R5 se selecciona entre H, carbociclilo opcionalmente sustituido, o C1-6 alquilo opcionalmente sustituido. Compounds derived from thiophene, and their pharmaceutical salts, compositions and methods of use. These compounds provide a cancer treatment or prophylaxis. Claim 1: A compound characterized in that it responds to formula (1) or a salt acceptable for pharmaceutical use or in vivo hydrolysable ester thereof, wherein: R1 and R2 are independently selected in each case from H, C1-6 alkyl optionally substituted, or optionally substituted heterocyclyl; with the proviso that R1 and R2 are not both H; or R1 and R2 and the N to which they are attached form in combination an optionally substituted heterocyclyl; R4 is selected from H, OH, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted C1-6 alkyl; R5 is selected from H, optionally substituted carbocyclyl, or optionally substituted C1-6 alkyl.

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

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: [Formula] where A, U, w1, w2, w3, R1-R6, And R9 are described herein.

Thiophene derivatives as CHK 1 inihibitors

Substituted thiphenes and uses thereof

INHIBITING MUTANT ISOCITRATE DEHYDROGENASE 1 (mIDH-1)

Patients diagnosed with a cancer harboring an IDH-1 mutation can be treated by the administration of a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, a selective inhibitor of 2-HG production from mIDH-1 enzymes including the R132 mutations R132C, R132H, R132L, R132G, and R132S.

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

R6 R4 R5 U A R W2 W N'R Ho Ri W3 N 0 R3 (I) The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) protein with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: )I) where A, U, WI, W2, W3, R1-R6, and R9 are described herein.

Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors

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: (I) where A, B, U, V, Z, W 1 , W 2 , W 3 , and R 1 -R 6 are described herein.

Carbamyloxy compounds that inhibit leukocyte adhesion mediated by VLA-4

Det er beskrevet forbindelser som binder VLA-4. Noen av disse forbindelsene inhiberer også leukocyttadhesjonen og spesielt leukocyttadhesjon mediert av VLA-4. Slike forbindelser er nyttige for behandling av betennelses- sykdommer i en pattedyrpasient, for eksempel menneske, så som astma, Alzheimer's sykdom, aterosklerose, AIDS-demens, diabetes, inflammatorisk magesykdom, leddgikt, vevstransplantasjon, tumormetastase og hjerteischemi. Forbindelsene kan også bli administrert for behandling av inflammatoriske hjerne- sykdommer så som multippel sklerose.

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

Compounds which inhibit leukocyte adhesion mediated by VLA-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemiia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Carbamyloxy compounds which inhibit leukocyte adhesion mediated by vla-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4

Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

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

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: (I) where A, U, W1, W2, W3, R1-R6, and R9 are described herein.

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

R6 R4 R5 U A R W2 W N'R Ho Ri W3 N 0 R3 (I) The invention relates to inhibitors of mutant isocitrate dehydrogenase (mt-IDH) protein with neomorphic activity useful in the treatment of cell-proliferation disorders and cancers, having the Formula: )I) where A, U, WI, W2, W3, R1-R6, and R9 are described herein.

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

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: (I) where A, U, W1, W2, W3, R1-R6, and R9 are described herein.

Chinolinonowe pochodne pirydyn-2(1H)-onu jako inhibitory zmutowanej dehydrogenazy izocytrynianowej

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

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 (I), where A, U, W1, W2, W3, R1-R6, and R9 are described herein.

Derivados de piridin-2(1H)-ona quinolinona como inhibidores de isocitrato deshidrogenasa mutante

La invención se refiere a inhibidores de proteínas isocitrato deshidrogenasa (mt-IDH) mutantes con actividad neomórfica útiles en el tratamiento de trastornos de proliferación celular y cánceres, que tienen la Fórmula: (I) donde A, U, W1, W2, W3, R1- R6 y R9 se describen en el presente documento. (Traducción automática con Google Translate, sin valor legal)

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

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: (I) where A, U, W1, W2, W3, R1-R6, and R9 are described herein.

Inhibicija mutiranog idh-1

Thiophenderivate als chk-1-inhibitoren

3-(heteroaryl)alanine derivatives-inhibitors of leukocyte adhesion mediated by vla-4

Disclosed are certain 3-(heteroaryl)alanine derivatives which bind VLA-4 and inhibit leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Beta-amino acid derivatives-inhibitors of leukocyte adhesion mediated by vla-4

3-(Heteroaryal) alanine derivatives-inhibitors of leukocyte adhesion mediated by VLA-4

Disclosed are certain 3-(heteroaryl)alanine derivatives which bind VLA-4 and inhibit leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis.

Verbindungen mit einer 4-amino-phenylalaningruppe,die die vla-4 vermittelte adhäsion von leukozyten inhibieren

Verbindungen die die vla-4 vermittelte adhäsion von leukozyten inhibieren

Acyl derivate zur behandlung von krankheiten die in zusammenhang mit vla-4 stehen

Inhibiting mutant isocitrate dehydrogenase 1 (mIDH-1)

Patients diagnosed with a cancer harboring an IDH-1 mutation can be treated by the administration of a therapeutically effective amount of a pharmaceutical composition comprising Compound 1, a selective inhibitor of 2-HG production from mIDH-1 enzymes including the R132 mutations R132C, R132H, R132L, R132G, and R132S.

Substituierte thiophene und deren verwendungen

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

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.

Carbamyloxy-verbindungen zur hemmung der durch vla-4 vermittelten leukozytenadhäsion

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

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: (I) where A, U, W1, W2, W3, R1-R6, and R9 are described herein.

Inhibare de IDH-1 mutant

Sunt furnizate metode de tratare a pacienţilor diagnosticaţi cu cancer care poartă o mutaţie IDH-1, inclusiv administrarea terapeutică a unui anumit inhibitor al unui IDH-1 mutant ca agent unic sau în combinaţie cu azacitidină (AZA).

Tiofenos sustituidos y sus usos

Esta invención se refiere a compuestos novedosos que tienen la fórmula estructural (I) y sus sales farmacéuticamente aceptables, composiciones y métodos de uso. Estos nuevos compuestos proporcionan un tratamiento o profilaxis del cáncer.

Παραγωγα πυριδιν-2(1η)-ονο κινολινονης ως αναστολεις μεταλλακτικης-αφυδρογονασης ισοκιτρικου

Η εφεύρεση αφορά σε αναστολείς πρωτεϊνών μεταλλακτικής αφυδρογονάσης ισοκιτρικού (mt-IDH) με νεομορφική δραστικότητα χρήσιμους στη θεραπεία διαταραχών πολλαπλασιασμού κυττάρων και καρκίνων, που έχουν τον Τύπο: (Ι) όπου A, U, W1, W2, W3, R1-R6, και R9 περιγράφονται στο παρόν.

Hamowanie mutanta idh-1