Bicyclic amides as kinase inhibitors

Abstract

The invention relates to compounds of formula (I) and their use in the treatment of the animal or human body, to pharmaceutical compositions comprising a compound of formula I and to the use of a compound of formula I for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as in particular tumour diseases.

1 - 13 . (canceled) 
     
     
         14 . 5-(2-Amino-pyrimidin-4-yloxy)-4-fluoro-2-methyl-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide,
 5-(6-Chloro-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   5-(6-Amino-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   7-(6-Amino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide,   7-(6-Amino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,   7-(6-Amino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   7-(6-Methylamino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide,   7-(6-Methylamino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   7-(2-Amino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide, or   7-(2-Amino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (4-morpholin-4-ylmethyl-3-trifluoromethyl-phenyl)-amide,
 or a tautomer thereof, or a salt thereof. 
   
     
     
         15 . A compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         is a group selected from: 
       
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a salt thereof. 
       
     
     
         16 . 6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide or
 6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (2-trifluoromethyl-pyridin-4-yl)-amide,   or a tautomer thereof, or a salt thereof.   
     
     
         17 . A compound selected of the following formula: 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         is selected from: 
       
       
         
           
           
               
               
           
         
         or a tautomer thereof, or a salt thereof. 
       
     
     
         18 . 6-(2-Acetylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide,
 6-(2-Methoxycarbonylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   7-(2-Acetylamino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide,   7-(2-Methoxycarbonylamino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid (4-methyl-3-trifluoromethyl-phenyl)-amide,   7-(2-Amino-pyrimidin-4-yloxy)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid [4-(4-methyl-piperazin-1-yl methyl)-3-trifluoromethyl-phenyl]-amide,   6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-morpholin-4-yl-3-trifluoromethyl-phenyl)-amide,   6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid cis/trans-(4-isopropyl-cyclohexyl)-amide,   6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,   6-(6-Chloro-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   6-(6-Amino-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   6-(6-Methylamino-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   6-(2-Amino-6-chloro-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   6-(2-Amino-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide,   6-(6-Chloro-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,   6-(6-Amino-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide, or   6-(2-Amino-6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-4-chloro-phenyl)-amide,   or a tautomer thereof, or a salt thereof.   
     
     
         19 . 6-(2-Amino-6-chloro-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,
 6-(2-Amino-pyrimidin-4-yloxy)-benzooxazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,   6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-4-chloro-phenyl)-amide,   
       
         
           
           
               
               
           
         
         6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [4-(4-methyl-piperazin-1-yl-methyl)-3-trifluoromethyl-phenyl]-amide, or 
         6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [3,4-bis(trifluoromethyl)-phenyl]-amide, 
         a compound of the following formula: 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-cyclopropyl-4-fluoro-phenyl)-amide, 
         a compound selected from the following formula: 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-morpholin-4-yl-3-trifluoromethyl-phenyl)-amide, 
         a compound selected from the formula: 
       
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
         is selected from 
       
       
         
           
           
               
               
           
         
         6-(6-Chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Cyano-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Aminomethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         {6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidin-4-ylmethyl}-carbamic acid methylester, 
         6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-4-carboxylic acid ethyl ester, 
         6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-4-carboxylic acid, 
         6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-4-carboxylic acid dimethylamide, 
         6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-4-carboxylic acid amide, 
         6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-4-carboxylic acid methylamide, 
         6-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyrimidine-4-carboxylic acid isopropylamide, 
         6-(6-Chloromethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Methylaminomethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Dimethylaminomethyl-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         {6-[5-(4-Fluoro-3-trifluoromethyl-phenylcarbamoyl)-naphthalen-2-ylsulfanyl]-pyrimidin-4-yl}-carbamic acid tert-butyl ester, 
         6-(6-Amino-pyrimidin-4-ylsulfanyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-ylsulfanyl)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidine-4-sulfinyl)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidine-4-sulfonyl)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-ylsulfanyl)-naphthalene-1-carboxylic acid (3-trifluoromethoxy-phenyl)-amide, 
         6-(Pyridin-4-yl-methyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide, 
         6-(2-Methyl-pyridin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         4-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyridine-2-carboxylic acid butyl ester, 
         4-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyridine-2-carboxylic acid amide, 
         4-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyridine-2-carboxylic acid (2-dimethylamino-ethyl)-amide, 
         6-(2-Amino-pyridin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         {4-[5-(3-Trifluoromethyl-phenylcarbamoyl)-naphthalen-2-yloxy]-pyridin-2-yl}-carbamic acid methyl ester, 
         6-[2-(2-Amino-pyrimidin-4-yl)-ethyl]-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-ylethynyl)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-1H-indole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-1H-indole-3-carboxylic acid (3-methoxy-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-1H-indole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide, 
         a compound of the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R is selected from 
       
       
         
           
           
               
               
           
         
         6-(6-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-3-carboxylic acid (3-trifluoro-methyl-phenyl)-amide, 
         a compound of the following formula 
       
       
         
           
           
               
               
           
         
         wherein R is selected from 
       
       
         
           
           
               
               
           
         
         6-(6-Amino-pyrimidin-4-yloxy)-1-ethyl-1H-indole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-1-ethyl-1H-indole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-1-iso-propyl-1H-indole-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Acetylaminopyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-piperazin-1-ylmethyl-3-trifluoromethylphenyl)amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-piperazin-1-ylmethyl-3-trifluoromethylphenyl)amide, 
         {6-[5-(4-piperazin-1-ylmethyl-3-trifluoromethylphenylcarbamoyl)naphthalene-2-yloxy]pyrimidin-4-yl}carbamic acid methyl ester, 
         6-(6-Acetylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide, 
         6-(6-Aminopyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide, 
         (6-{5-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylcarbamoyl]-naphthalen-2-yloxy}-pyrimidin-4-yl)-carbamic acid methyl ester, 
         6-(6-Acetylamino-pyrimidin-4-yloxy)naphthalene-1-carboxylic acid [4-(4-isopropylpiperazin-1-ylmethyl)-3-trifluoromethylphenyl]amide, 
         6-(6-Aminopyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethylphenyl]amide, 
         (6-{5-[4-(4-Isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylcarbamoyl]-naphthalen-2-yloxy}-pyrimidin-4-yl)-carbamic acid methyl ester, 
         7-(6-Acetylamino-pyrimidin-4-yloxy)-isoquinoline-4-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide, 
         (6-{4-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylcarbamoyl]-isoquinolin-7-yloxy}-pyrimidin-4-yl)-carbamic acid methyl ester, 
         7-(6-Amino-pyrimidin-4-yloxy)-isoquinoline-4-carboxylic acid [4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-amide, 
         7-(6-Amino-pyrimidin-4-yloxy)-isoquinoline-4-carboxylic acid [5-tert-butyl-2-(4-isopropyl-phenyl)-2H-pyrazol-3-yl]-amide, 
         7-(6-Amino-pyrimidin-4-yloxy)-isoquinoline-4-carboxylic acid [5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-amide, 
         7-(6-Methylamino-pyrimidin-4-yloxy)-isoquinoline-4-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide, 
         7-(6-Methylamino-pyrimidin-4-yloxy)-isoquinoline-4-carboxylic acid (3-trifluoromethyl-phenyl)-amide, 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(4-dimethylaminomethyl-phenyl)-2H-pyrazole-3-yl]-amide, 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid {5-tert-butyl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid {5-tert-butyl-2-[4-(morpholin-4-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-amide, 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid {5-tert-butyl-2-[4-(morpholin-4-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-amide, 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(3-methyl-phenyl)-2H-pyrazol-3-yl]-amide, 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid {5-tert-butyl-2-[3-(morpholin-4-ylmethyl)-phenyl]-2H-pyrazol-3-yl}-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(3-dimethylaminomethyl-phenyl)-2H-pyrazol-3-yl]-amide, 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(3-dimethylaminomethyl-phenyl)-2H-pyrazol-3-yl]-amide, 
         6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(3-dimethylcarbamoyl-phenyl)-2H-pyrazol-3-yl]-amide, or 
         6-(6-Methylamino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(3-dimethylcarbamoyl-phenyl)-2H-pyrazol-3-yl]-amide, 
         or a tautomer thereof, or a salt thereof. 
       
     
     
         20 . 6-(2-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, or a tautomer thereof, or a salt thereof. 
     
     
         21 . 6-(6-Amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, or a tautomer thereof, or a salt thereof. 
     
     
         22 . 5-(2-Amino-6-chloro-pyrimidin-4-yloxy)-4-fluoro-2-methyl-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, or a tautomer thereof, or a salt thereof. 
     
     
         23 . 6-(2-Amino-6-chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, or a tautomer thereof, or a salt thereof. 
     
     
         24 . A pharmaceutical composition comprising a compound or salt thereof according to  claim 14 , and a pharmaceutically acceptable carrier. 
     
     
         25 . A compound or salt thereof according to  claim 14 , for use in the treatment of the animal or human body, especially in the treatment of a protein kinase dependent disease. 
     
     
         26 . A compound according to  claim 25 , wherein the protein kinase dependent disease to be treated is a protein kinase dependent disease, especially a proliferative disease, depending on any one or more of the following protein kinases: EphB4, c-Abl, Bcr-Abl, c-Kit, Raf, RET, PDGF-R and/or VEGF-R, especially VEGF-R. 
     
     
         27 . Use of a compound according to  claim 14  or a salt thereof, for the preparation of a pharmaceutical composition for use in the treatment of a protein kinase dependent disease. 
     
     
         28 . The use according to  claim 27  wherein the protein kinase dependent disease is a protein kinase dependent disease, especially a proliferative disease, depending on any one or more of the following protein kinases: EphB4, c-Abl, Bcr-Abl, c-Kit, Raf, RET, PDGF-R and/or VEGF-R, especially VEGF-R. 
     
     
         29 . A compound as claimed in  claim 25 , wherein the protein kinase dependent disease is selected from ocular neovascularisation, diabetic retinopathy, age-related macular degeneration, psoriasis, Von Hippel Lindau disease, hemangioblastoma, angioma, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, glomerulonephritis, mesangioproliferative glomerulonephritis, haemolytic-uraemic syndrome, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune disease, acute inflammation, hepatic cirrhosis, diabetes, endometriosis, chronic asthma, arterial or post-transplantational atherosclerosis, neurodegenerative disorders, leukemias, breast cancer, adenocarcinoma, colorectal cancer, lung cancer, renal cancer, liver cancer, pancreatic cancer, ovarian cancer, cancer of the prostate, myeloma, multiple myeloma, myelodysplastic syndrome, AML (acute myeloid leukemia), AMM (agnogenic myeloid metaplasia), mesothelioma, glioma and/or glioblastoma. 
     
     
         30 . A compound as claimed in  claim 26 , wherein the protein kinase dependent disease is selected from ocular neovascularisation, diabetic retinopathy, age-related macular degeneration, psoriasis, Von Hippel Lindau disease, hemangioblastoma, angioma, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, glomerulonephritis, mesangioproliferative glomerulonephritis, haemolytic-uraemic syndrome, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune disease, acute inflammation, hepatic cirrhosis, diabetes, endometriosis, chronic asthma, arterial or post-transplantational atherosclerosis, neurodegenerative disorders, leukemias, breast cancer, adenocarcinoma, colorectal cancer, lung cancer, renal cancer, liver cancer, pancreatic cancer, ovarian cancer, cancer of the prostate, myeloma, multiple myeloma, myelodysplastic syndrome, AML (acute myeloid leukemia), AMM (agnogenic myeloid metaplasia), mesothelioma, glioma and/or glioblastoma.