Chemical Compounds

Abstract

The present invention provides compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof wherein R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 5 , nitro, —NR 6 R 7 , cyano, and a group R 8 ; R 1 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7 or cyano; R 2 is hydrogen, C3-C7 cycloalkyl, or a group R 9 ; R 3 is C3-C7 cycloalkyl, or a group R 9 ; or R 2 and R 3 together with N form a 5-14 membered heterocycle, which may be substituted by 1 to 3 R 10 groups; R 4 is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl; R 5 is a C1-C4 alkyl, —OR 6 or —NR 6 R 7 ; R 6 is hydrogen or C1-C6 alkyl; R 7 is hydrogen or C1-C6 alkyl; R 8 is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11 groups; R 9 is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl; R 10 is a group R 8 , C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 6 R 7 , phenyl which may be substituted by 1 to 4 R 11 groups; R 11 is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ; X is carbon or nitrogen; n is 1 or 2; to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of conditions mediated by corticotropin-releasing factor (CRF).

1 . Compounds of formula (I) including stereoisomers, prodrugs and pharmaceutically acceptable salts or solvates thereof  
     
       
         
         
             
             
         
       
       R is aryl or heteroaryl, each of which may be substituted by 1 to 4 groups selected from: 
 halogen, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, —C(O)R 5 , nitro, —NR 6 R 7 , cyano, and a group R 8 ;  
 
       R 1  is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkyl, halo C1-C6 alkoxy, halogen, NR 6 R 7  or cyano;  
       R 2  is hydrogen, C3-C7 cycloalkyl, or a group R 9 ;  
       R 3  is C3-C7 cycloalkyl, or a group R 9 ; or  
       R 2  and R 3  together with N form a 5-14 membered heterocycle, which may be substituted by 1 to 3 R 10  groups;  
       R 4  is hydrogen, C1-C6 alkyl, halogen or halo C1-C6 alkyl;  
       R 5  is a C1-C4 alkyl, —OR 6  or —NR 6 R 7 ;  
       R 6  is hydrogen or C1-C6 alkyl;  
       R 7  is hydrogen or C1-C6 alkyl;  
       R 8  is a 5-6 membered heterocycle, which may be saturated or may contain one to three double bonds, and which may be substituted by 1 or more R 11  groups;  
       R 0  is a C1-C6 alkyl that may be substituted by one or more groups selected from: C3-C7 cycloalkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, hydroxy, haloC1-C6 alkyl;  
       R 10  is a group R 8 , C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, C(O)NR 6 R 7 , phenyl which may be substituted by 1 to 4 R 11  groups;  
       R 11  is C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo C1-C6 alkoxy, hydroxy, halogen, nitro, cyano, or C(O)NR 6 R 7 ;  
       X is carbon or nitrogen;  
       n is 1 or 2.  
     
   
   
       2 . Compounds, according to  claim 1 , in which 
 R 2  and R 3  together with N form a 5-14 membered heterocyclic group, which may be substituted by 1 to 3 R 10  groups.    
   
   
       3 . Compounds, according to  claim 1 , of general formula (Ia)  
     
       
         
         
             
             
         
       
       in which R, R 1 , R 2 , R 3  R 4  and X are defined as in  claim 1 .  
     
   
   
       4 . Compounds, according to  claim 3 , of general formula (IIa)  
     
       
         
         
             
             
         
       
       in which R, R 1 , R 2 , R 4  and R 3  are defined as in  claim 1 .  
     
   
   
       5 . Compounds, according to  claim 4 , in which the group NR 2 R 3  represents a 5-6 membered heterocyclic group, which may be substituted by 1 to 3 R 8  groups.  
   
   
       6 . Compounds, according to  claim 5 , of general formula (IIIa)  
     
       
         
         
             
             
         
       
       wherein R, R 1 , R 4  and R 9  are defined as in  claim 1 .  
     
   
   
       7 . Compounds, according to  claim 1 , of general formula (Ib)  
     
       
         
         
             
             
         
       
       in which R, R 1 , R 2 , R 3  R 4  and X are defined as in  claim 1 .  
     
   
   
       8 . Compounds, according to  claim 7 , of general formula (IIIb)  
     
       
         
         
             
             
         
       
       in which R, R 1 , R 2 , R 4  and R 3  are defined as in  claim 1 .  
     
   
   
       9 . Compounds, according to  claim 1  wherein 
 R 1  is C1-C3 alkyl group or halo C1-C3 alkyl group and R 4  is hydrogen.    
   
   
       10 . Compounds, according  claim 1  wherein 
 R is an aryl group selected from: 2,4-dichlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-4-trifluoromethyl, 2-chloro-4-methoxyphenyl, 2,4,5-trimethylphenyl, 2,4-dimethylphenyl, 2-methyl-4-methoxyphenyl, 2-methyl4-chlorophenyl, 2-methyl-4-trifluoromethyl, 2,4-dimethoxyphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-chlorophenyl, 3-methoxy-4-chlorophenyl, 2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-trifluoromethylphenyl, 2-methoxy-4-isopropylphenyl, 2-methoxy-4-methylphenyl, 2-trifluoromethyl-4-chlorophenyl, 2,4-trifluoromethylphenyl, 2-trifluoromethyl-4-methylphenyl, 2-trifluoromethyl-4-methoxyphenyl, 2-bromo-4-isopropylphenyl, 2-methyl4-cyanophenyl, 2-chloro-4-cyanophenyl, 4-methyl-6-dimethylaminopyridin-3-yl, 3,5-dichloro-pyridin-2-yl, 2,6-bismethoxy-pyridin-3-yl and 3-chloro-5-tricloromethyl-pyridin-2-yl.    
   
   
       11 . A compound, according  claim 1  selected in a group consisting from: 
 1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;    1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;    3-methyl-4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-benzonitrile;    4-[6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl]-3-trifluoromethyl-benzonitrile;    6-methyl-1-(2-methyl-4-trifluoromethoxy-phenyl)-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine;    1-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-5-(3-thiazol-2-yl-pyrazol-1-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine;    1-(4-methoxy-2-methyl-phenyl)-6-methyl-4-(3-thiazol-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine    1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-morpholin-4-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine    1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-4-(3-pyridin-2-yl-pyrazol-1-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine    4-[1,3′]bipyrazolyl-1′-yl-1-(2,4-bis-trifluoromethyl-phenyl)-6-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.    
   
   
       12 . A pharmaceutical composition comprising a compound according to  claim 1  in admixture with one or more physiologically acceptable carriers or excipients.  
   
   
       13 . A method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by CRF (corticotropin-releasing factor), comprising administration of an effective amount of a compound according to  claim 1 .  
   
   
       14 . A method, according to  claim 13 , in the treatment of depression and anxiety, comprising administration of an effective amount of a compound according to  claim 1 .  
   
   
       15 . A method, according to  claim 14 , in the treatment of IBS (irritable bowel disease) and IBD (inflammatory bowel disease), comprising administration of an effective amount of a compound according to  claim 1.