Bridged bicyclic amine derivatives useful as CCR-3 receptor antagonists

Abstract

Compounds having the formula (1), are useful as CCR-3 receptor antagonists, wherein T is a bridged heterocyclyl group having one N atom and a bridge of one to two bridgehead carbon atoms; Ar and Ar 1 are aryl or heteroaryl; F is alkylene, alkenylene, or a bond; E is —C(═O)N(R 10 )—, —SO 2 N(R 10 )—, —N(R 11 )C(═O)N(R 10 )—, —N(R 11 )SO 2 N(R 10 )—, —N(R 11 )C(═S)N(R 10 )—, —N(R 11 )C(═O)—, —N(R 11 )SO 2 —, —N(R 12 )C(═O)CH(R 13 )—, or CH(R 13 )C(═O)N(R 12 )—; Q is —C(═O)— or C 1-2 alkylene; and R 3 , R 4 , R 5 , R 9 , R 10 , R 11 , R 12 , and R 13 are defined as set forth in the specification.

1 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
     wherein 
 T is  
                     
 where R 6  is taken together with one of R 7  and R 8  to form a bridge of one to two carbon atoms, and the other of R 7  and R 8  is selected from hydrogen and R 9 ;  
 Ar and Ar 1  are, independently of each other, aryl or heteroaryl, with the proviso that Ar and Ar 1  are not simultaneously phenyl;  
 F is alkylene, alkenylene, or a bond;  
 E is selected from —C(═O)N(R 10 )—, —SO 2 N(R 10 )—, —N(R 11 )C(═O)N(R 10 )—, —N(R 11 )SO 2 N(R 10 )—, —N(R 11 )C(═S)N(R 10 )—, —N(R 11 )C(═O)—, —N(R 11 )SO 2 —, —N(R 12 )C(═O)CH(R 13 )—, and CH(R 13 )C(═O)N(R 12 )—, where: 
 R 10 , R 11 , R 12 , and R 13  are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(═O)-Z, where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;  
 or alternatively, R 12  and R 13  may be taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form a heterocyclyl or heteroaryl ring optionally substituted with up to two groups selected from R 14 ;  
 
 R 3  and R 4  are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, -(alkylene)-C(═O)-Z 1 , or -(alkylene)-C(O) 2 Z 1 , where Z 1  is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;  
 R 5  is hydrogen or alkyl;  
 Q is —C(═O)— or C 1-2 alkylene;  
 R 9  is attached to any available carbon atom of ring T and is selected from lower alkyl, hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, or a lower alkyl substituted with one of hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy;  
 R 14  is selected from lower alkyl, hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, trifluoromethoxy, and a lower alkyl substituted with one of hydroxy, lower alkoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy;  
 m is 0 or 1; and  
 n is 0 to 4; and 
 or a pharmaceutically acceptable salt thereof.  
 
 
   
   
       2 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 Ar or Ar 1  is optionally substituted phenyl;    F is a bond;    E is selected from —C(═O)N(R 10 )—, —N(R 11 )C(═O)N(R 10 )—, —N(R 11 )C(═O)—, —N(R 12 )C(═O)CH(R 13 )—, and CH(R 13 )C(═O)N(R 12 )—, where: 
 R 10 , R 11 , R 12 , and R 13  are, independently of each other, hydrogen or alkyl;  
 or alternatively, R 12  and R 13  may be taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form a heterocyclyl or heteroaryl ring optionally substituted with up to two groups selected from R 14 ;  
   R 3  and R 4  are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, heteroalkyl, or -(alkylene)-C(═O)-Z 1 , where Z 1  is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;    Q is —CH 2 —;    R 9  and R 14  are independently selected from methyl, ethyl, hydroxy, methoxy, halo, cyano, trifluoromethyl, or trifluoromethoxy; and    n is 0 to 2.    
   
   
       3 . A compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     and R 9  is attached to any available carbon atom of ring T and is selected from lower alkyl and hydroxy, and n is 0 to 2.  
   
   
       4 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 Ar is a phenyl ring optionally substituted with one, two or three substituents selected from alkyl, heteroalkyl, alkoxy, —COR 15 , —SO 2 R 17 , methylenedioxy, hydroxy, halo, acylamino, amino, mono- or disubstituted amino, —CONR 15 R 16 , -(alkylene)-CONR 15 R 16 , —COOR 15 , -(alkylene)-COOR 15  and —NR 16 SO 2 R 17 ;    R 15  and R 16  are each independently hydrogen or alkyl; and    R 17  is alkyl, amino or mono or disubstituted amino.    
   
   
       5 . A compound of  claim 4 , or a pharmaceutically acceptable salt thereof, wherein 
 Ar is selected from phenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methylsulfonylphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, and 3,4,5-trimethoxyphenyl.    
   
   
       6 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein F is a bond.  
   
   
       7 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
 E is —C(═O)N(R 10 )—, —N(R 10 )C(═O)N(R 11 )—, or N(R 12 )C(═O)CH(R 13 )—, where R 10  and R 11  are hydrogen or lower alkyl, and R 12  and R 13  are taken together with the nitrogen and carbon atoms to which they are attached, respectively, to form                          where R 18  and R 19  are selected from hydrogen and lower alkyl.    
   
   
       8 . A compound of  claim 7 , or a pharmaceutically acceptable salt thereof, wherein 
 E is                          and m is 0.    
   
   
       9 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
 R 3  is hydrogen; and    R 4  is hydrogen, methyl, ethyl, 1-methylethyl, isopropyl, 1-hydroxyethyl or 2-hydroxyethyl.    
   
   
       10 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
 R 3  is hydrogen; and R 4  is 1-methylethyl.    
   
   
       11 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein T is  
     
       
         
         
             
             
         
       
     
   
   
       12 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is —CH 2 —.  
   
   
       13 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 Ar 1  is a phenyl ring optionally substituted with one, two or three substituent selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono- or disubstituted amino.    
   
   
       14 . A compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein: 
 Ar 1  is 4-chlorophenyl or 3,4-dichlorophenyl.    
   
   
       15 - 17 . (canceled)  
   
   
       18 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable excipient.  
   
   
       19 - 20 . (canceled)