Claims for Patent: 8,658,643

Summary for Patent: 8,658,643

Title:	Pyrimidinyl pyridazinone derivatives
Abstract:	Compounds selected from the group according to claim 1 are inhibitors of tyrosine kinases, in particular of Met kinase, and can be employed, inter alia, for the treatment of tumours.
Inventor(s):	Schadt; Oliver (Rodenbach, DE), Dorsch; Dieter (Ober-Ramstadt, DE), Stieber; Frank (Heidelberg, DE), Blaukat; Andree (Schriesheim, DE)
Assignee:	Merck Patent GmbH (Darmstadt, DE)
Application Number:	13/565,914
Patent Claims:	1. A method for treating a disease which is influenced by inhibition of Met kinase, wherein treating does not include prevention; comprising administering to a subject having said disease an effective amount of one of the following compounds TABLE-US-00006 No. Name "A1" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, sulfate "A2" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, mesylate "A3" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, besylate "A4" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, p-tosylate "A5" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, fumarate "A6" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, maleate "A7" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride monohydrate "A8" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrobromide "A9" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, mesylate "A10" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, besylate "A11" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, malate "A12" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, fumarate "A13" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, maleate or "A14" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, p- tosylate or a tautomer or stereoisomer thereof. 2. A method according to claim 1, wherein said disease is a solid tumour. 3. A method according to claim 1, wherein said disease is a solid tumour which originates from the group consisting of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the urogenital tract, the lymphatic system, the stomach, the larynx and the lung. 4. A method according to claim 1, wherein said disease is a solid tumour which originates from the group consisting of monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma. 5. A method according to claim 1, wherein said disease is a solid tumour which originates from the group consisting of lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, colon carcinoma and breast carcinoma. 6. A method according to claim 1, wherein said disease is a tumour of the blood and immune system. 7. A method according to claim 1, wherein said disease is a tumour which originates from the group consisting of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and chronic lymphatic leukaemia. 8. A method according to claim 1, further comprising administering a pharmaceutically active compound, which is not a compound of claim 1. 9. A method according to claim 1, wherein one of the following compounds is administered TABLE-US-00007 No. Name "A1" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, sulfate "A2" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, mesylate "A3" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, besylate "A4" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, p-tosylate "A5" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, fumarate "A6" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, maleate "A7" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride monohydrate "A8" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrobromide "A9" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, mesylate "A10" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, besylate "A11" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, malate "A12" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, fumarate "A13" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, maleate or "A14" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, p- tosylate. 10. A method according to claim 1, wherein 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1- ,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride monohydrate is administered. 11. A method for stabilizing or improving the clinical symptoms of a disease which is influenced by inhibition of Met kinase, comprising administering to a subject in need thereof an effective amount of one of the following compounds TABLE-US-00008 No. Name "A1" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, sulfate "A2" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, mesylate "A3" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, besylate "A4" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, p-tosylate "A5" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, fumarate "A6" 6-(1-Methyl-1H-pyrazol-4-yl)-2-{3-[5-(2-morpholin-4- ylethoxy)pyrimidin-2-yl]-benzyl}-2H-pyridazin-3-one, maleate "A7" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride monohydrate "A8" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrobromide "A9" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, mesylate "A10" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, besylate "A11" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, malate "A12" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, fumarate "A13" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, maleate or "A14" 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2- yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, p- tosylate or a tautomer or stereoisomer thereof. 12. A method according to claim 11, wherein 3-(1{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6- -dihydropyridazin-3-yl)-benzonitrile, hydrochloride monohydrate is administered. 13. A method according to claim 11, wherein the disease is a solid tumour. 14. A method according to claim 13, wherein 3-(1{3-[5-(1-Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6- -dihydropyridazin-3-yl)-benzonitrile, hydrochloride monohydrate is administered. 15. A method according to claim 11, wherein the disease is a solid tumour which originates from the group consisting of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the urogenital tract, the lymphatic system, the stomach, the larynx and the lung, or the disease is a solid tumour which originates from the group consisting of monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma, or the disease is a solid tumour which originates from the group consisting of lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, colon carcinoma and breast carcinoma, or the disease is a tumour of the blood and immune system, or the disease is a tumour which originates from the group consisting of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and chronic lymphatic leukaemia. 16. A method according to claim 15, wherein 3-(1{3-[5-(1 -Methylpiperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyri- dazin-3-yl)-benzonitrile, hydrochloride monohydrate is administered. 17. A method according to claim 2, wherein 3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-6-oxo-1- ,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride monohydrate is administered. 18. A method according to claim 1, wherein the disease is a solid tumour which originates from the group consisting of tumors of the squamous epithelium, the bladder, the stomach, the kidneys, of head and neck, the oesophagus, the cervix, the thyroid, the intestine, the liver, the brain, the prostate, the urogenital tract, the lymphatic system, the stomach, the larynx and the lung, or the disease is a solid tumour which originates from the group consisting of monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma, or the disease is a solid tumour which originates from the group consisting of lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, glioblastomas, colon carcinoma and breast carcinoma, or the disease is a tumour of the blood and immune system, or the disease is a tumour which originates from the group consisting of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and chronic lymphatic leukaemia, and wherein 3-(1-{3-[5-(1-Methylpiperidin-4-ylmethoxy) pyrimidin-2-yl]benzyl}-6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile, hydrochloride monohydrate is administered.