Aminopyrimidine compound

Abstract

The present invention provides a compound having a CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like.The present invention relates to a compound represented by the formula (I):wherein each symbol is as defined in the specification, or a salt thereof.

1 - 8 . (canceled) 
     
     
         9 . A method of inhibiting calcium/calmodulin-dependent protein kinase II in a mammal, which comprises administering an effective amount of a compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is CH or N; 
         R 1  is a C 1-3  alkyl group; 
         R 2  is 
         (1) a group represented by the formula: —O—X 1 -X 2 —O—(CH 2 —CH 2 —O) p —Y:
 wherein 
 X 1  is a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, 
 X 2  is 
 (i) a bond, or 
 (ii) a group represented by the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein n is an integer of 1 to 4, 
           
           p is an integer of 0 to 7, and 
           Y is 
           (i) a hydrogen atom, or 
           (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, 
         
         (2) a group represented by the formula: —O—X 3 —Z 1 :
 wherein 
 X 3  is a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, and 
 Z 1  is 
 (i) a cyano group, 
 (ii) a C 1-6  alkylsulfonyl group, or 
 (iii) a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, 
 
         (3) a group represented by the formula: —O—X 4 —Z 2 :
 wherein 
 X 4  is a bond or a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, and 
 Z 2  is a 5- or 6-membered monocyclic nitrogen containing aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6  alkyl groups, or 
 
         (4) a hydroxy group; 
         R 3  is a cyano group or a halogen atom; and 
         R 4  is a morpholinyl group or a bridged morpholinyl group, each optionally substituted by 1 to 3 C 1-6  alkyl groups; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The method according to  claim 9 , wherein the compound is selected from
 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride,   2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol,   5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and   5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,   or a pharmaceutically acceptable salt thereof.   
     
     
         11 . A method for the prophylaxis or treatment of cardiac diseases in a mammal, which comprises administering an effective amount of a compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is CH or N; 
         R 1  is a C 1-3  alkyl group; 
         R 2  is 
         (1) a group represented by the formula: —O—X 1 -X 2 —O—(CH 2 —CH 2 —O) p —Y:
 wherein 
 X 1  is a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, 
 X 2  is 
 (i) a bond, or 
 (ii) a group represented by the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein n is an integer of 1 to 4, 
           
           p is an integer of 0 to 7, and 
           Y is 
           (i) a hydrogen atom, or 
           (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, 
         
         (2) a group represented by the formula: —O—X 3 —Z 1 :
 wherein 
 X 3  is a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, and 
 Z 1  is 
 (i) a cyano group, 
 (ii) a C 1-6  alkylsulfonyl group, or 
 (iii) a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, 
 
         (3) a group represented by the formula: —O—X 4 —Z 2 :
 wherein 
 X 4  is a bond or a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, and 
 Z 2  is a 5- or 6-membered monocyclic nitrogen containing aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6  alkyl groups, or 
 
         (4) a hydroxy group; 
         R 3  is a cyano group or a halogen atom; and 
         R 4  is a morpholinyl group or a bridged morpholinyl group, each optionally substituted by 1 to 3 C 1-6  alkyl groups; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The method according to  claim 11 , wherein the compound is selected from
 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride,   2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol,   5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and   5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,   or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The method according to  claim 11 , wherein the cardiac disease is selected from catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia. 
     
     
         14 . The method according to  claim 13 , wherein the cardiac disease is postoperative atrial fibrillation. 
     
     
         15 . The method according to  claim 13 , wherein the cardiac disease is catecholaminergic polymorphic ventricular tachycardia. 
     
     
         16 . The method according to  claim 13 , wherein the cardiac disease is heart failure. 
     
     
         17 . The method according to  claim 13 , wherein the cardiac disease is fatal arrhythmia. 
     
     
         18 . The method according to  claim 11 , wherein the mammal is a human. 
     
     
         19 . A pharmaceutical composition comprising a compound represented by the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         A is CH or N; 
         R 1  is a C 1-3  alkyl group; 
         R 2  is 
         (1) a group represented by the formula: —O—X 1 -X 2 —O—(CH 2 —CH 2 —O) p —Y:
 wherein 
 X 1  is a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, 
 X 2  is 
 (i) a bond, or 
 (ii) a group represented by the formula: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein n is an integer of 1 to 4, 
           
           p is an integer of 0 to 7, and 
           Y is 
           (i) a hydrogen atom, or 
           (ii) a C 1-6  alkyl group optionally substituted by 1 to 3 halogen atoms, 
         
         (2) a group represented by the formula: —O—X 3 —Z 1 :
 wherein 
 X 3  is a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, and 
 Z 1  is 
 (i) a cyano group, 
 (ii) a C 1-6  alkylsulfonyl group, or 
 (iii) a 3- to 8-membered monocyclic oxygen-containing non-aromatic heterocyclic group, 
 
         (3) a group represented by the formula: —O—X 4 —Z 2 :
 wherein 
 X 4  is a bond or a C 1-6  alkylene group optionally substituted by 1 to 4 halogen atoms, and 
 Z 2  is a 5- or 6-membered monocyclic nitrogen containing aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6  alkyl groups, or 
 
         (4) a hydroxy group; 
         R 3  is a cyano group or a halogen atom; and 
         R 4  is a morpholinyl group or a bridged morpholinyl group, each optionally substituted by 1 to 3 C 1-6  alkyl groups; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the compound is selected from
 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(2-ethoxyethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-methoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((3-(3-ethoxypropoxy)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclohexyl)-3-(3-ethoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(2-methoxyethoxy)ethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile hydrochloride,   2-(3-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)propoxy)ethan-1-ol,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(2-(oxetan-3-yl)ethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(oxetan-3-ylmethoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-hydroxy-3-methylbutoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile,   4-((4-((5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)pyrimidin-2-yl)amino)-1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-3-yl)oxy)-2-methylbutan-2-ol,   5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,   2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-(2-((1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-(2-methoxyethoxy)propoxy)-1H-pyrazol-4-yl)amino)pyrimidin-5-yl)benzonitrile, and   5-(3-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy)-4-chlorophenyl)-N-(1-((1r,4r)-4-((2S,6R)-2,6-dimethylmorpholino)cyclohexyl)-3-(3-methoxypropoxy)-1H-pyrazol-4-yl)pyrimidin-2-amine,   or a pharmaceutically acceptable salt thereof.