Substituted dihydropyrazolones and their use

Abstract

The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and haematological diseases and kidney diseases, and for promoting wound healing.

1 . A method of prophylaxis of cardiac insufficiency, coronary heart disease, myocardial infarction, or stroke in a subject comprising administering a therapeutically effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
         in which 
         X represents N or CH; 
         R 1  represents hydrogen or cyano; and 
         R 2  represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom, 
         where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl, 
         or 
         where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, 
       
       or a salt thereof. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A method of prophylaxis of acute renal failure or for promoting wound healing in a subject comprising administering a therapeutically effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
         in which 
         X represents N or CH; 
         R 1  represents hydrogen or cyano; and 
         R 2  represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom, 
         where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl, 
         or 
         where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, 
       
       or a salt thereof. 
     
     
         6 . A method of prophylaxis of retinopathy in premature babies (retinopathia prematurorum) in a subject comprising administering a therapeutically effective amount of a compound of the formula 
       
         
           
           
               
               
           
         
         in which 
         X represents N or CH; 
         R 1  represents hydrogen or cyano; and 
         R 2  represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom, 
         where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C1-C3-alkyl, C1-C3-alkylamino and C3-C6-cycloalkyl, 
         or 
         where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, 
       
       or a salt thereof. 
     
     
         7 . The method of  claim 1 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         8 . The method of  claim 1 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 1 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         10 . The method of  claim 1 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 1 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         12 . The method of  claim 1 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 1 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         14 . The method of  claim 1 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 2 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         16 . The method of  claim 2 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 2 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         18 . The method of  claim 2 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 2 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         20 . The method of  claim 2 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         21 . The method of  claim 2 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         22 . The method of  claim 5 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 5 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         24 . The method of  claim 5 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         25 . The method of  claim 5 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         26 . The method of  claim 5 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 5 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         28 . The method of  claim 5 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 5 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         30 . The method of  claim 5 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method of  claim 6 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         32 . The method of  claim 6 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 6 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         34 . The method of  claim 6 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 6 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         36 . The method of  claim 6 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula 
       
         
           
           
               
               
           
         
       
     
     
         37 . The method of  claim 6 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         38 . The method of  claim 6 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: