Dual Modulators Of 5HT2A and D3 Receptors

Abstract

The present invention relates to compounds of the formula (I) wherein R 1 , R 2 , X and n are as defined in the specification as dual modulators of the serotonin 5-HT 2a and dopamine D 3 receptors, their manufacture, pharmaceutical compositions containing them and their use for the treatment of psychotic disorders, as well as other diseases such as depression and anxiety, drug dependence, dementias and memory impairment.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         each X is independently halogen, cyano; C 1-6 -alkyl, C 1-6 -alkoxy or C 1-6 -haloalkyl; 
         n is 0, 1, 2 or 3; 
         R 1  is H or C 1-6 -alkyl; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         R 3  is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 3-10 -cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, each of which is optionally substituted by one to five substituents selected from the group consisting of:
 halo, 
 cyano, 
 —SO 2 —C 1-6 -alkyl, 
 hydroxyl, 
 C 1-6 -alkyl, 
 C 1-6 -haloalkyl, 
 —CO(O)—C 1-6 -alkyl, 
 C 1-6 -alkoxy optionally substituted by one or more R a , 
 C 3-10 -cycloalkyl optionally substituted by one or more R a , 
 4 to 10 membered heterocycloalkyl optionally substituted by one or more R a , 
 aryl optionally substituted by one or more R a , 
 5 to 10 membered heteroaryl optionally substituted by one or more R a , and 
 —NR b R c ,
 wherein R b  is H or C 1-6 -alkyl and wherein R c  is H, C 1-6 -alkyl or aryl optionally substituted by one or more R a ; 
 
 wherein R a  is selected from:
 halo, 
 cyano, 
 oxo, 
 hydroxyl, 
 halobenzenesulfonyl, 
 C 1-6 -alkyl 
 C 1-6 -haloalkyl, 
 —NH(CO)—C 1-6 -alkyl, 
 di(C 1-6 )alkylamino, 
 —O(CO)—C 1-6 -alkyl, 
 C 1-6 -alkylsulfonyl, 
 C 1-6 -alkoxy 
 C 1-6 -haloalkoxy, 
 4 to 10 membered heterocycloalkyl 
 aryl, 
 aryloxy, and 
 5 to 10 membered heteroaryl; 
 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein:
 each X is independently fluorine or chlorine;   n is 0, 1 or 2;   R 1  is hydrogen;   R 2  is   
       
         
           
           
               
               
           
         
       
       and
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . The compound of  claim 1  having formula (Ia): 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently fluorine or chlorine; 
         n is 0, 1 or 2; 
         m is 0, 1, 2 or 3; 
         R 4  is selected from the group consisting of:
 halo, 
 cyano, 
 hydroxy, 
 C 1-6 -alkyl, 
 C 1-6 -haloalkyl, 
 di(C 1-6 )alkylamino, 
 —CO(O)—C 1-6 -alkyl, 
 C 1-6 -alkoxy optionally substituted by one or more R a , 
 C 3-10 -cycloalkyl optionally substituted by one or more R a , 
 4 to 10 membered heterocycloalkyl optionally substituted by one or more R a , 
 aryl optionally substituted by one or more R a , 
 5 to 10 membered heteroaryl optionally substituted by one or more R a , and 
 —NR b R c , 
 
         wherein R a , R b  and R c  are as defined in  claim 1 ; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of  claim 3 , wherein
 each X is independently fluorine or chlorine;   n is 1;   m is 0, 1 or 2;   R 4  is selected from the group consisting of:
 halo, 
 C 1-6 -alkoxy optionally substituted by one or more R a , 
 6 membered heterocycloalkyl optionally substituted by one or more R a , and 
 5 to 6 membered heteroaryl optionally substituted by one or more R a , 
   wherein R a  is selected from
 halo, 
 oxo, 
 hydroxyl and 
 C 1-6 -alkyl 
   or a pharmaceutically acceptable salt thereof.   
     
     
         5 . The compound of  claim 3 , selected from the group consisting of
 3-Fluoro-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,   N-trans-(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzamide   4-tert-Butoxy-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,   4-Chloro-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,   N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-pyrrol-1-yl-benzamide,   Benzo[1,3]dioxole-5-carboxylic acid trans (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide, and   Benzo[1,3]dioxole-5-carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.   
     
     
         6 . The compound of  claim 1  having (Ib): 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently fluorine or chlorine; 
         n is 0, 1 or 2; 
         m and p are each independently 0, 1 or 2; 
         R 4  and R 5  are each independently selected from the group consisting of:
 halo, 
 cyano, 
 hydroxy, 
 C 1-6 -alkyl, 
 C 1-6 -haloalkyl, 
 —CO(O)—C 1-6 -alkyl, 
 C 1-6 -alkoxy optionally substituted by one or more R a , 
 C 3-10 -cycloalkyl optionally substituted by one or more R a , 
 4 to 10 membered heterocycloalkyl optionally substituted by one or more R a , 
 aryl optionally substituted by one or more R a , 
 5 to 10 membered heteroaryl optionally substituted by one or more R a , and 
 —NR b R c , 
 
         Y is oxygen or —SO 2 —; 
         one, two or three of A 1 , A 2 , A 3 , A 4  and A 5  are nitrogen and the others are CR 6 , or A 1 , A 2 , A 3 , A 4  and A 5  are CR 6  wherein 
         each R 6  is independently hydrogen or R 7 ; and 
         each R 7  is independently C 1-6 alkyl, C 1-6 alkyloxy, hydroxyl, amino, C 1-6 alkylamino, N,N-di-(C 1-6 alkyl)-amino, halo, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, hetero-C 1-6 alkyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfanyl, or cyano; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound of  claim 6 , wherein
 X is fluorine;   n and m are each independently 0 or 1;   p is 0;   R 4  is selected from the group consisting of:
 halo, 
 cyano, 
 hydroxy, 
 C 1-6 -alkyl, and 
 C 1-6 -haloalkyl, 
   Y is oxygen or —SO 2 —;   one or two of A 1 , A 2 , A 3 , A 4  and A 5  are nitrogen and the others are CH 2 ;   or a pharmaceutically acceptable salt thereof.   
     
     
         8 . The compound of  claim 6 , selected from the group consisting of
 N-trans-(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,   N-trans (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,   N-Trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-6-morpholin-4-yl-nicotinamide,   5-Morpholin-4-yl-pyrazine-2-carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   6-Morpholin-4-yl-pyridazine-3-carboxylic acid-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   2-Morpholin-4-yl-pyrimidine-5-carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   3-Fluoro-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,   4-(1,1-Dioxo-1,6-thiomorpholin-4-yl)-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,   N-trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-morpholin-4-yl-isonicotinamide,   N-trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide,   N-trans (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-piperidin-1-yl-benzamide,   4-(2,6-Dimethyl-morpholin-4-yl)-N-trans (4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,   4-(2,6-Dimethyl-morpholin-4-yl)-N-trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide, and   4-(1,1-Dioxo-1,6,4-thiomorpholin-4-yl)-N trans-(4-{2-[4-(5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide.   
     
     
         9 . The compound of  claim 1  having formula (Ic): 
       
         
           
           
               
               
           
         
         wherein 
         each X is independently fluorine or chlorine; 
         n is 0, 1 or 2; 
         R 8  and R 9  form a 3-, 4-, 5-, or 6-membered saturated ring, optionally comprising one or two heteroatoms selected from oxygen and nitrogen; 
         R 10  is selected from the group consisting of halogen, cyano, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl and C 1-6 -alkoxy; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . The compound of  claim 1  having formula (Id): 
       
         
           
           
               
               
           
         
         wherein 
         X 1 =H and X 2 =fluoro or chloro; or 
         X 2 =H and X 1 =fluoro or chloro; and 
         R 11  is selected from the group consisting of C 1-6 -alkyl and C 1-6 -alkoxy, each of which is optionally substituted by halogen, hydroxy, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy or C 5-6 -cycloalkyl which is optionally substituted by C 1-6 -alkyl or C 1-6 -alkoxy; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The compound of  claim 10  having formula (Id′): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound of  claim 11 , selected from the group consisting of
 4N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,   Tetrahydro-pyran-4-carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   N-trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,   N-trans (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,   N-trans (4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,   Trans 4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine,   2,3-Dihydro-benzo[1,4]dioxine-2-carboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   N-trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(3-methyl-pyrazol-1-yl)-acetamide, and   3,3,3-Trifluoro-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-propionamide.   
     
     
         13 . The compound of  claim 11 , selected from the group consisting of
 2-(3,5-Dimethoxy-phenyl)-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3,3,3-trifluoro-2-hydroxy-propionamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-pyran-2-yl)-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans (4-methoxy-cyclohexyl)-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(1,4-dioxa-spiro[4.5]dec-8-yl)-acetamide, and   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3,3-dimethoxy-propionamide.   
     
     
         14 . The compound of  claim 1  having formula (Ie): 
       
         
           
           
               
               
           
         
         wherein 
         X 1 =H and X 2 =fluoro or chloro; or 
         X 2 =H and X 1 =fluoro or chloro; and 
         R 12  is selected from the group consisting of halo, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -haloalkyl and C 1-6 -alkoxy; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         15 . The compound of  claim 14  having formula (Ie′): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The compound of  claim 15 , selected from the group consisting of
 1-Hydroxy-cyclopropanecarboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide, and   1-Trifluoromethyl-cyclobutanecarboxylic acid trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.   
     
     
         17 . The compound of  claim 1  having formula (Ig): 
       
         
           
           
               
               
           
         
         wherein 
         X is fluorine or chlorine; 
         n is 0, 1 or 2; 
         R 13  is selected from the group consisting of C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, aryl optionally substituted by one or more R a , and 5 to 10 membered heteroaryl optionally substituted by one or more R a ; 
         R a  halo, C 1-6 -alkyl and C 1-6 -alkoxy; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . The compound of  claim 17 , selected from the group consisting of
 Ethanesulfonic acid (4-trans {2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   4-Chloro-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzenesulfonamide,   N-trans(4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-methoxy-benzenesulfonamide, and   Pyridine-3-sulfonic acid trans(4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide.   
     
     
         19 . The compound of  claim 1 , selected from the group consisting of:
 3-Fluoro-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-4-morpholin-4-yl-benzamide,   N-trans (4-{2-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-isonicotinamide,   4-(2,6-Dimethyl-morpholin-4-yl)-N-trans (4-{2-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-benzamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-pyran-2-yl-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(S)-tetrahydro-pyran-2-yl-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide,   (R)—N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-butyramide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1S,3S)-3-methoxy-cyclopentyl)-acetamide, and   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-4-methyl-cyclohexyl)-acetamide.   
     
     
         20 . The compound of  claim 1 , selected from the group consisting of
 N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-trans-methoxy-4-methyl-cyclohexyl)-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-cis-methoxy-4-methyl-cyclohexyl)-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,   (R)—N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,   (S)—N-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-butyramide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-trans (4-methoxymethyl-cyclohexyl)-acetamide,   N-trans (4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-4-methyl-cyclohexyl)-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-cyano-propionamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyano-acetamide, and   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(R)-tetrahydro-furan-2-yl-acetamide.   
     
     
         21 . The compound of  claim 1 , selected from the group consisting of
 N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-cyclopropyl-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methanesulfonyl-acetamide,   N-trans-(4-{2-[4-(6-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide,   N-trans-(4-{2-[4-(5-Chloro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide,   N-trans-(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-methanesulfonamide,   N-trans-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,   N-trans-(4-{2-[4-(6-Chloro-5-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(tetrahydro-furan-2-yl)-acetamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-methoxy-acetamide, and   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-methoxy-cyclopentyl)-acetamide.   
     
     
         22 . The compound of  claim 1 , selected from the group consisting of
 N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-methoxy-cyclohexyl)-acetamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-methoxy-propionamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-hydroxy-acetamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-3-hydroxy-propionamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-(4-hydroxy-cyclohexyl)-acetamide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-((1R,3R)-3-hydroxy-cyclopentyl)-acetamide,   Tetrahydro-pyran-4-carboxylic acid trans-(4-{2-[4-(5,6-difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-amide,   N-trans-(4-{2-[4-(5,6-Difluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-2-[1,3]dioxan-2-yl-acetamide, and   N-trans-(4-{2-[4-(6-Methyl-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-acetamide.   
     
     
         23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         each X is independently halogen, cyano; C 1-6 -alkyl, C 1-6 -alkoxy or C 1-6 -haloalkyl; 
         n is 0, 1, 2 or 3; 
         R 1  is H or C 1-6 -alkyl; 
         R 2  is 
       
       
         
           
           
               
               
           
         
         R 3  is hydrogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 1-6 -alkoxy, C 3-10 -cycloalkyl, aryl, 4 to 10 membered heterocycloalkyl, or 5 to 10 membered heteroaryl, each of which is optionally substituted by one to five substituents selected from the group consisting of:
 halo, 
 cyano, 
 —SO 2 —C 1-6 -alkyl, 
 hydroxyl, 
 C 1-6 -alkyl, 
 C 1-6 -haloalkyl, 
 —CO(O)—C 1-6 -alkyl, 
 C 1-6 -alkoxy optionally substituted by one or more R a , 
 C 3-10 -cycloalkyl optionally substituted by one or more R a , 
 4 to 10 membered heterocycloalkyl optionally substituted by one or more R a , 
 aryl optionally substituted by one or more R a , 
 5 to 10 membered heteroaryl optionally substituted by one or more R a , and 
 —NR b R c ,
 wherein R b  is H or C 1-6 -alkyl and wherein R c  is H, C 1-6 -alkyl or aryl optionally substituted by one or more R a ; 
 
 wherein R a  is selected from:
 halo, 
 cyano, 
 oxo, 
 hydroxyl, 
 halobenzenesulfonyl, 
 C 1-6 -alkyl 
 C 1-6 -haloalkyl, 
 —NH(CO)—C 1-6 -alkyl, 
 di(C 1-6 )alkylamino, 
 —O(CO)—C 1-6 -alkyl, 
 C 1-6 -alkylsulfonyl, 
 C 1-6 -alkoxy 
 C 1-6 -haloalkoxy, 
 4 to 10 membered heterocycloalkyl 
 aryl, 
 aryloxy, and 
 5 to 10 membered heteroaryl; 
 
 
         or a pharmaceutically acceptable salt thereof 
         and a pharmaceutically acceptable carrier.