Heteroaryl-substituted piperidines

Abstract

The invention relates to novel heteroaryl-substituted piperidines, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular of cardiovascular diseases and tumour diseases.

1 . A method of prevention of a thromboembolic disorder, comprising administering to a human or animal in need thereof an anticoagulatory amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         in which 
         A represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           # is the point of attachment to the piperidine ring, 
           and 
           * is the point of attachment to R 2 , 
         
         R 1  represents phenyl,
 where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl and C 3 -C 6 -cycloalkyl,
 where C 2 -C 4 -alkoxy may be substituted by a substituent selected from the group consisting of methoxy and ethoxy, 
 
 and
 where cycloalkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen and C 1 -C 4 -alkyl, 
 
 
         R 2  represents hydrogen, trifluoromethyl, aminomethyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl, cyclopentenyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl, 5- or 6-membered heteroaryl or pyridylaminocarbonyl,
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
 where alkylamino may be substituted by a substituent selected from the group consisting of C 1 -C 4 -alkoxy and C 1 -C 6 -alkylamino, 
 
 
         and
 where C 1 -C 4 -alkyl may be substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylcarbonyloxy, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylamino, 4- to 6-membered heterocyclyl, phenyl, phenoxy, 5- or 6-membered heteroaryl and 5- or 6-membered heteroarylthio, where cycloalkyl, heterocyclyl, phenyl, phenoxy, heteroaryl and heteroarylthio may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, 
 
         R 3  represents C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
 where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by a substituent selected from the group consisting of hydroxyl, amino, cyano and C 1 -C 4 -alkoxy, 
 and 
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, oxo, hydroxyl, amino, aminomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl, 
 
         or one of its salts, its solvates or the solvates of its salts. 
       
     
     
         2 . The method according to  claim 1 , wherein in the compound of formula (I),
 A represents a group of the formula   
       
         
           
           
               
               
           
         
         
           where 
           # is the point of attachment to the piperidine ring, 
           and 
           * is the point of attachment to R 2 , 
         
         R 1  represents phenyl,
 where phenyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, trifluoromethoxy, methyl, ethyl, isopropyl and methoxy, 
 
         R 2  represents methyl, ethyl, isopropyl, n-propyl, tert-butyl, methoxycarbonyl, ethoxycarbonyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyridinyl, phenyl, 1,3-benzodioxolyl, thienyl, furanyl, pyrrolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl or pyrazinyl,
 where azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyridinyl, phenyl, thienyl, furanyl, pyrrolyl, thiazolyl, isoxazolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl and pyrazinyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy and ethylamino,
 where ethylamino may be substituted by a substituent selected from the group consisting of methoxy and dimethylamino, 
 
 
         and
 where methyl and ethyl may be substituted by a substituent selected from the group consisting of hydroxyl, amino, methoxy, ethoxy, isopropoxy, dialkylamino, methylsulphonyl, cyclopropylamino, morpholinyl, phenyl and phenoxy,
 where phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, hydroxymethyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy and ethoxy, 
 
 
         R 3  represents tert-butyl, N-methyl-N-ethylamino, methoxyalkylamino, cyclopropyl, cyclopentyl, azetidinyl, 3,3-difluoroazetidinyl, 3-hydroxyazetidinyl, 3-methylazetidinyl, 3-methoxyazetidinyl, 3-dimethylaminoazetidinyl, pyrroldinyl, 3,3-difluoropyrroldin-1-yl, 3-hydroxypyrroldin-1-yl, 3-aminopyrroldin-1-yl, 4,4-difluoropiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-aminopiperidin-1-yl, 4-cyanopiperidin-1-yl, 3-methoxypiperidin-1-yl, thiazolidinyl, morpholin-4-yl, 2,2-dimethylmorpholin-4-yl, 2-oxopiperazin-1-yl or 3-oxo-4-methylpiperazin-1-yl, 
         or one of its salts, its solvates or the solvates of its salts. 
       
     
     
         3 . The method of  claim 1 , wherein in the compound of formula (I):
 A represents a group of the formula   
       
         
           
           
               
               
           
         
         
           where 
           # is the point of attachment to the piperidine ring, 
           and 
           * is the point of attachment to R 2 , 
         
         R 1  represents phenyl,
 where phenyl is substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, trifluoromethoxy, methyl and ethyl, 
 
         R 2  represents methyl, ethyl or isopropyl,
 where methyl and ethyl may be substituted by a substituent methoxy, 
 
         R 3  represents 3-hydroxyazetidinyl, 3-hydroxypyrroldin-1-yl, 4-hydroxypiperidin-1-yl, 4-cyanopiperidin-1-yl or morpholin-4-yl, 
         or one of its salts. 
       
     
     
         4 . The method of  claim 1 , wherein the substituents —R 1  and -A-R 2  of the compound of formula (I) are in the cis-position to one another. 
     
     
         5 - 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the thromboembolic disorder is selected from the group consisting of: ST-segment elevation myocardial infarction (STEMI); non-ST-segment elevation myocardial infarction (non-STEMI); stable angina pectoris; unstable angina pectoris; reocclusions and restenoses after coronary interventions, angioplasty, stent implantations or aortocoronary bypass; a peripheral arterial occlusion disease; pulmonary embolisms; deep venous thrombosis; renal vein thrombosis; a transitory ischaemic attack; and thrombotic and thromboembolic stroke. 
     
     
         16 . A method for the treatment and/or prophylaxis of cardiogenic thromboembolisms in a patient with acute, intermittent or persistent cardiac arrhythmia or atrial fibrillation, in a patient undergoing cardioversion, or in a patient with a heart valve disorder, intravasal object, artificial heart valve, catheter, intraaortic balloon counterpulsation, or pacemaker probe, comprising administering to the patient an anticoagulatory amount of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         in which 
         A represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           # is the point of attachment to the piperidine ring, 
           and 
           * is the point of attachment to R 2 , 
         
         R 1  represents phenyl,
 where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl and C 3 -C 6 -cycloalkyl,
 where C 2 -C 4 -alkoxy may be substituted by a substituent selected from the group consisting of methoxy and ethoxy, 
 
 and
 where cycloalkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen and C 1 -C 4 -alkyl, 
 
 
         R 2  represents hydrogen, trifluoromethyl, aminomethyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl, cyclopentenyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl, 5- or 6-membered heteroaryl or pyridylaminocarbonyl,
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
 where alkylamino may be substituted by a substituent selected from the group consisting of C 1 -C 4 -alkoxy and C 1 -C 6 -alkylamino, 
 
 
         and
 where C 1 -C 4 -alkyl may be substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylcarbonyloxy, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylamino, 4- to 6-membered heterocyclyl, phenyl, phenoxy, 5- or 6-membered heteroaryl and 5- or 6-membered heteroarylthio,
 where cycloalkyl, heterocyclyl, phenyl, phenoxy, heteroaryl and heteroarylthio may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, 
 
 
         R 3  represents C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
 where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by a substituent selected from the group consisting of hydroxyl, amino, cyano and C 1 -C 4 -alkoxy, 
 
         and
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, oxo, hydroxyl, amino, aminomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl, 
 
         or one of its salts. 
       
     
     
         17 . The method according to  claim 16 , wherein the cardiogenic thromboembolisms are selected from brain ischaemias, stroke, and systemic thromboembolisms and ischaemias. 
     
     
         18 . A method for the treatment and/or prophylaxis of thromboembolic complications in connection with microangiopathic haemolytic anaemias, extracorporeal circulation, haemodialysis, haemofiltration, ventricular assist devices, artificial hearts, or heart valve prostheses, comprising administering to a human or animal in need thereof an anticoagulatory amount of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         in which 
         A represents a group of the formula 
       
       
         
           
           
               
               
           
         
         
           where 
           # is the point of attachment to the piperidine ring, 
           and 
           * is the point of attachment to R 2 , 
         
         R 1  represents phenyl,
 where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, methylsulphonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl and C 3 -C 6 -cycloalkyl,
 where C 2 -C 4 -alkoxy may be substituted by a substituent selected from the group consisting of methoxy and ethoxy, 
 
 and
 where cycloalkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen and C 1 -C 4 -alkyl, 
 
 
         R 2  represents hydrogen, trifluoromethyl, aminomethyl, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 1 -C 4 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl, cyclopentenyl, 4- to 6-membered heterocyclyl, phenyl, 1,3-benzodioxolyl, 5- or 6-membered heteroaryl or pyridylaminocarbonyl,
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, amino, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, monofluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl,
 where alkylamino may be substituted by a substituent selected from the group consisting of C 1 -C 4 -alkoxy and C 1 -C 6 -alkylamino, 
 
 
         and
 where C 1 -C 4 -alkyl may be substituted by a substituent selected from the group consisting of halogen, hydroxyl, amino, aminocarbonyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkylthio, C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkylcarbonyloxy, C 1 -C 4 -alkylsulphonyl, C 1 -C 4 -alkoxycarbonyl, C 1 -C 4 -alkoxycarbonylamino, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylamino, 4- to 6-membered heterocyclyl, phenyl, phenoxy, 5- or 6-membered heteroaryl and 5- or 6-membered heteroarylthio,
 where cycloalkyl, heterocyclyl, phenyl, phenoxy, heteroaryl and heteroarylthio may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, 
 
 
         R 3  represents C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylamino, C 3 -C 7 -cycloalkyl, 4- to 6-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,
 where alkyl, C 2 -C 6 -alkoxy and alkylamino may be substituted by a substituent selected from the group consisting of hydroxyl, amino, cyano and C 1 -C 4 -alkoxy, 
 and 
 where cycloalkyl, heterocyclyl, phenyl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, oxo, hydroxyl, amino, aminomethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, mono fluoromethoxy, difluoromethoxy, trifluoromethoxy, mono fluoromethylsulphanyl, difluoromethylsulphanyl, trifluoromethylsulphanyl, hydroxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -alkylaminocarbonyl, 
 
         or one of its salts.