Thiophenyl and pyrrolyl azepines as serotonin 5-ht2c receptor ligands and uses thereof

Abstract

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are thiophenyl and pyrrolyl azepine compounds. These compounds are serotonin receptor (5-HT 2c ) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT 2c ) is desired (e.g. addiction, anxiety, depression, obesity, and others).

What is claimed is: 
     
         1 . A compound of the formula 
       
         
           
           
               
               
           
         
         X is NR 11 ; 
         R 1  and R 2  are independently selected from the group consisting of H, halogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, perhaloalkyl, C 1-8  alkylperhalo alkyl, —CN, OR 8 , SR 8 , —SO 2 R 10 , —C(═O)R 10 , —C(═O)NR 8 R 9 , —NR 8 CO 2 R 10 , —SO 2 NR 8 R 9 , —NR 8 SO 2 R 10 , aryl, heteroaryl, C 1-8  alkylaryl, C 1-8  alkylheteroaryl, —C 1-8  alkyl-O—C 1-8  alkyl, —C 1-8  alkyl-O-aryl and —C 1-8  alkyl-O-heteroaryl; 
         R 1  and R 2  taken together with the atoms to which they are attached can form a 5-7-member carbocycle or heterocycle optionally substituted with up to two substituents selected from alkyl, CF 3 , and —OR 8 ; 
         R 3  is selected from the group consisting of H, C 1-8  alkyl, OR 8 , aryl and heteroaryl; 
         R 3a  is H or C 1-8  alkyl; or R 3  and R 3a  taken together are —CH 2 CH 2 —; 
         R 2  and R 3  taken together with the atoms to which they are attached form a 5-7-member carbocycle or heterocycle optionally substituted with up to two substituents selected from alkyl, CF 3 , and —OR 8 ; 
         R 4  is H, C 1-8  alkyl, or OR 8 ; 
         R 4a  is H, C 1-8  alkyl; or R 4  and R 4a  taken together are —CH 2 CH 2 —; 
         R 5  is selected from the group consisting of H, —C 1-8  alkyl, —C 1-8  alkyl-O—C 1-8  alkyl, C 1-8  alkylaryl, —C 1-8  alkylheteroaryl, —C 1-8  alkyl-O-aryl and C 1-8  alkyl-O-heteroaryl; 
         R 5a  is H or —C 1-8  alkyl; 
         R 6  is selected from the group consisting of H, —C 1-8  alkyl, C 1-8  alkyl-O—C 1-8  alkyl, C 1-9  alkylaryl, C 1-9  alkylheteroaryl, —C 1-8  alkyl-O-aryl and —C 1-8  alkyl-O-heteroaryl; 
         R 6a  is H or —C 1-8  alkyl; 
         R 7  is selected from the group consisting of H, —C 1-8  alkyl, —C 1-8 alkylaryl and —C 1-8  alkylheteroaryl; 
         R 8  and R 9  are independently selected from the group consisting of H, —C 1-8  alkyl, —C 2-8  alkenyl, —C 2-8  alkynyl, aryl, heteroaryl, —C 1-8  alkylaryl, —C 1-8  alkyl heteroaryl, —C 1-8  alkyl-O—C 1-8  alkyl, —C 1-8  alkyl-O-aryl and —C 1-8  alkyl-O-heteroaryl; or 
         R 8  and R 9  taken together with the atom to which they are attached form a 5-7-member heterocycle; 
         R 10  is selected from the group consisting of —C 1-8  alkyl, —C 2-8  alkenyl, —C 2-8  alkynyl, aryl, heteroaryl, —C 1-8  alkylaryl, —C 1-8  alkylheteroaryl, —C 1-8  alkyl-O—C 1-8  alkyl, —C 1-8  alkyl-O-aryl and —C 1-8  alkyl-O-heteroaryl; 
         R 11  is selected from the group consisting of H, —C 1-8  alkyl, —C 1-8  alkyl-O—C 1-8  alkyl, —SO 2 R 10 , —C(═O)R 10 , —C(═O)OR 10 , aryl, heteroaryl, C 1-8  alkylaryl and C 1-8  alkylheteroaryl; 
         R 11  and R 1  together with the atoms to which they are attached may form a 5-7-membered heterocycle optionally substituted with up to two substituents selected from —C 1-8  alkyl, CF3, and —OR 8 ; and 
         R 11  and R 4  together with the atoms to which they are attached may form a 5-7-membered heterocycle optionally substituted with up to two substituents selected from —C 1-8  alkyl, CF 3 , and —OR 8 ; 
         wherein aryl and heteroaryl are optionally substituted with up to two substituents selected from —C 1-8  alkyl, halogen, CN, and alkoxy, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . (R,S)-2-Bromo-3,3-dimethyl-4,4a,5,6,7,8-hexahydro-3H-1-thia-6-aza-cyclopenta[cd]azulene, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . A pharmaceutical composition comprising at least one compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         4 . A method of treating a disease, disorder and/or condition in a patient wherein modulation of a 5-HT 2C  function is desired comprising administering an effective amount of at least one compound of  claim 1 .