Compounds

Abstract

A compound having the general formula and methods of using such compounds for the treatment of diseases and pharmaceutical composition comprising such compounds.

1 . A method of treating major depressive disorder or emesis comprising administering a therapeutically-effective amount of a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1a  is H, NR 9 R 10 , —OR 9 ,  
                     
 R 1b  and R 1c  are independently H or —OR 9 , or R 1b  and R 1c  together are ═O, ═CH 2  or —OCH 2 CH 2 O—;  
 R 2  is H, oxo, —OR 9  or —CH 3 ;  
 R 3 , R 4 , R 5  and R 6  are each independently selected from H, cyano, nitro, trifluoromethoxy, trifluoromethyl, C 1-6 alkylsulfonyl, halo, —OR 9 , —OCH 2 O—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)OR 9 , —C(═O)NR 9 R 10 , —OC(═O)R 9 , —NR 9 C(═O)R 10 , aminosulfonyl, and C 1-6 alkyl substituted by cyano, nitro, trifluoromethoxy, trifluoromethyl, C 1-6 alkylsulfonyl, halo, —OR 9 , —OCH 2 O—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)OR 9 , —C(═O)NR 9 R 10 , —OC(═O)R 9 , —NR 9 C(═O)R 10 , or aminosulfonyl; wherein at least one of R 3 , R 4 , R 5  and R 6  is H;  
 R 9  and R 10  are each independently H or C 1-6 alkyl;  
 R 11  is phenyl, substituted in at least the ortho position by C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, C 1-6 alkanesulfonamido, C 1-6 alkanoyl, C 1-6 alkoxy-carbonyl, succinamido, carbamoyl, C 1-6 alkylcarbamoyl, di-C 1-6 alkylcarbamoyl, C 1-6 alkoxy-C 1-6 alkylcarbamoyl, N-methylcarbamoyl, C 1-6 alkanoylamino, ureido, C 1-6 ureido, di-C 1-6 alkylureido, amino, C 1-6 alkylamino, or di-C 1-6 alkylamino;  
 R 12  is selected from hydrogen, hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkanoylamino, C 1-6 alkyl, carbamoyl, C 1-6 alkylcarbamoyl and bis(C 1-6 alkyl)carbamoyl;  
 R 13  is —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;  
 R 14  is hydrogen, hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkanoylamino, C 1-6 alkyl, carbamoyl, C 1-6 alkylcarbamoyl or di-C 1-6  alkylcarbamoyl;  
 M is —C(═O)— or —S(═O) 2 —;  
 L is —NH— or —CH 2 —;  
 X 1  and X 2  are independently H or halogen, wherein at least one of X 1  and X 2  is halogen;  
 Y and Z are CH 2  or O, wherein Y does not equal Z; and  
 n is 0 or 1;  
 or any pharmaceutically-acceptable salt thereof, or any composition comprising the same.  
 
     
     
         2 . A method according to  claim 1  wherein R 3 , R 4 , R 5  and R 6  are selected from H, cyano, nitro, —S(═O)C 1-6 alkyl, halo, —OR 9 , —OCH 2 O—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)OR 9 , —C(═O)NR 9 R 10 , —OC(═O)R 9 , —NR 9 C(═O)R 10 , aminosulfonyl and —C 1-6 alkylcyano; wherein at least two of R 3 , R 4 , R 5  and R 6  are H.  
     
     
         3 . A method according to  claim 1  wherein R 3 , R 4 , R 5  and R 6  are selected from H, cyano, methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro, cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl, dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyl and acetylamino; wherein at least two of R 3 , R 4 , R 5  and R 6  are H.  
     
     
         4 . A method according to  claim 1  wherein R 3 , R 4 , R 5  and R 6  are selected from H, cyano, methoxy, ethyl, fluoro and nitro; wherein at least two of R 3 , R 4 , R 5  and R 6  are H.  
     
     
         5 . A method according to  claim 1  wherein: 
 R 1a  is                          R 1b  is H; and    R 1c  is H.    
     
     
         6 . A method according to  claim 1  wherein: 
 R 1a  is                          R 1b  is H; and    R 1c  is H.    
     
     
         7 . A method according to  claim 1  wherein R 1a  is H, NR 9 R 10  or —OR 9 .  
     
     
         8 . A method according to  claim 1  wherein R 2  is —OR 5  or —CH 3 .  
     
     
         9 . A method of treating severe anxiety disorders, stress disorders, major depressive disorder with anxiety, eating disorders, bipolar disorders, substance abuse disorder, schizophrenic disorders, psychotic disorders, movement disorders, cognitive disorders, depression, anxiety, mania or hypomania, aggressive behaviour, obesity, rheumatoid arthritis, Alzheimer's disease, cancer, oedema, allergic rhinitis, inflammation, pain, gastrointestinal-hypermotility, Huntington's disease, COPD, hypertension, migraine, bladder hypermotility, or urticaria comprising administering a therapeutically-effective amount of a compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1a  is H, NR 9 R 10 , —OR 9 ,  
                     
 R 1b  and R 1c  are independently H or —OR 9 , or R 1b  and R 1c  together are ═O, ═CH 2  or —OCH 2 CH 2 O—;  
 R 2  is H, oxo, —OR 9  or —CH 3 ;  
 R 3 , R 4 , R 5  and R 6  are each independently selected from H, cyano, nitro, trifluoromethoxy, trifluoromethyl, C 1-6 alkylsulfonyl, halo, —OR 9 , —OCH 2 O—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)OR 9 , —C(═O)NR 9 R 10 , —OC(═O)R 9 , —NR 9 C(═O)R 10 , aminosulfonyl, and C 1-6 alkyl substituted by cyano, nitro, trifluoromethoxy, trifluoromethyl, C 1-6 alkylsulfonyl, halo, —OR 9 , —OCH 2 O—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)OR 9 , —C(═O)NR 9 R 10 , —OC(═O)R 9 , —NR 9 C(═O)R 10 , or aminosulfonyl; wherein at least one of R 3 , R 4 ,R 5  and R 6  is H;  
 R 9  and R 10  are each independently H or C 1-6 alkyl;  
 R 11  is phenyl, substituted in at least the ortho position by C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, C 1-6 alkanesulfonamido, C 1-6 alkanoyl, C 1-6 alkoxy-carbonyl, succinamido, carbamoyl, C 1-6 alkylcarbamoyl, di-C 1-6 alkylcarbamoyl, C 1-6 alkoxy-C 1-6 alkylcarbamoyl, N-methylcarbamoyl, C 1-6 alkanoylamino, ureido, C 1-6 ureido, di-C 1-6 alkylureido, amino, C 1-6 alkylamino, or di-C 1-6 alkylamino;  
 R 12  is selected from hydrogen, hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkanoylamino, C 1-6 alkyl, carbamoyl, C 1-6 alkylcarbamoyl and bis(C 1-6 alkyl)carbamoyl;  
 R 13  is —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;  
 R 14  is hydrogen, hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, C 1-6 alkanoyl, C 1-6 alkoxycarbonyl, C 1-6 alkanoylamino, C 1-6 alkyl, carbamoyl, C 1-6 alkylcarbamoyl or di-C 1-6  alkylcarbamoyl;  
 M is —C(═O)— or —S(═O) 2 —;  
 L is —NH— or —CH 2 —;  
 X 1  and X 2  are independently H or halogen, wherein at least one of X 1  and X 2  is halogen;  
 Y and Z are CH 2  or O, wherein Y does not equal Z; and  
 n is 0 or 1;  
 or any pharmaceutically-acceptable salt thereof, or any composition comprising the same.  
 
     
     
         10 . A method according to  claim 9  wherein R 3 , R 4 , R 5  and R 6  are selected from H, cyano, nitro, —S(═O)C 1-6 alkyl, halo, —OR 9 , —OCH 2 O—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —C(═O)OR 9 , —C(═O)NR 9 R 10 , —OC(═O)R 9 , —NR 9 C(═O)R 10 , aminosulfonyl and —C 1-6 alkylcyano; wherein at least two of R 3 , R 4 , R 5  and R 6  are H.  
     
     
         11 . A method according to  claim 9  wherein R 3 , R 4 , R 5  and R 6  are selected from H, cyano, methoxy, ethoxy, isopropoxy, fluoro, bromo, chloro, iodo, nitro, cyanomethyl, carboxy, carbamoyl, ethynyl, methyl, ethyl, dimethylcarbamoyl, methylsulfonyl, aminosulfonyl, prop-2-enyl, acetyl and acetylamino; wherein at least two of R 3 , R 4 , R 5  and R 6  are H.  
     
     
         12 . A method according to  claim 9  wherein R 3 , R 4 , R 5  and R 6  are selected from H, cyano, methoxy, ethyl, fluoro and nitro; wherein at least two of R 3 , R 4 , R 5  and R 6  are H.  
     
     
         13 . A method according to  claim 9  wherein: 
 R 1a  is                          R 1b  is H; and    R 1c  is H.    
     
     
         14 . A method according to  claim 9  wherein: 
 R 1a  is                          R 1b  is H; and    R 1c  is H.    
     
     
         15 . A method according to  claim 9  wherein R 1a  is H, NR 9 R 10  or —OR 9 .  
     
     
         16 . A method according to  claim 9  wherein R 2  is —OR 5  or —CH 3 .