Indol-3-y-carbonyl-piperidin and piperazin-derivatives

Abstract

The present invention relates to indol-3-yl-carbonyl-piperidin and piperazin derivatives which act as V1a receptor antagonists and which are represented by Formula I: wherein the residues R 1 to R 3 are as defined herein. The invention also relates to pharmaceutical compositions containing such compounds, and methods for preparation of the compounds and compositions. The invention further relates to methods for treating dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H,
 C 1-6 -alkyl substituted by CN, C 1-6 -alkoxy, OH, halo, or NR i R ii , 
 C 2-6 -alkyl, 
 aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which is optionally substituted by one or more B, 
 —(CH 2 ) m —R a  wherein R a  is:
 CN, 
 OR i , 
 NR i R ii , or 
 C 3-6 -cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
 or —(CH 2 ) n —(CO)—R b  or —(CH 2 ) n —(SO 2 )—R b , wherein R b  is:
 C 1-6 -alkyl, 
 C 1-6 -alkoxy, 
 C 3-6 -cycloalkyl, 
 —(CH 2 ) m —NR iii R iv , 
 NR i R ii , or 
 C 3-6 -cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
 
         or R 1  and R 3  together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl which is optionally substituted by ═O, C(O)O—C 1-6 -alkyl or C 1-6 -alkyl; 
         there is one or more R 2 , wherein each R 2  is the same or different, 
         R 2  is one or more H, OH, halo, CN, nitro, C 1-6 -alkoxy, —O—CH 2 —C 2-6 -alkenyl, benzyloxy, C 1-6 -haloalkoxy, or C 1-6 -alkyl optionally substituted by —NR iii R iv  or halo,
 or two R 2  together with the indole ring to which they are attached form an oxo or dioxo bridge; 
 
         R 3  is H,
 F, 
 —(CO)—R c , wherein R c  is:
 C 1-6 -alkyl, 
 —(CH 2 ) n —NR i R ii , 
 —(CH 2 ) n —NR iii R iv , or 
 5 or 6 membered heterocycloalkyl optionally substituted by C 1-6 -alkyl, 
 
 or C 1-6 -alkyl which is optionally substituted by
 halo, 
 NR i R ii , 
 NR iii R iv , 
 —O(CO)—C 1-6 -alkyl, 
 or —NH(CO)R d , wherein R d  is C 1-6 -alkyl optionally substituted by halo or nitro, or R d  is aryl or a 5 or 6 membered heteroaryl, each of which is optionally substituted by halo, nitro, C 1-6 -alkyl or C 1-6 -haloalkyl; 
 
 
         A is selected from the group consisting of (a), (a′), (b), (c) and (d): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 4  is —NH(CO)R e , wherein R e  is
 C 1-6 -alkoxy or aryl optionally substituted by halo, 
 C 1-6 -alkoxy, or 
 CN, 
 or aryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclic heteroaryl ring, each of which is optionally substituted by CN, halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, nitro, hydroxyl, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, S(O) 2 —C 1-6 -alkyl, or C 1-6 -haloalkoxy, or by an oxo or dioxo bridge; 
 
         R 6  is C 2-6 -alkyl,
 —C(O)—R f  wherein R f  is an aryl group substituted by halo, C 1-6 -alkoxy, or CN, 
 aryl, 5 or 6 membered heteroaryl, or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, CN, nitro, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, COOH, S(O) 2 —C 1-6 -alkyl, hydroxyl, or C 1-6 -haloalkoxy, or by an oxo or dioxo bridge, 
 or benzyl substituted by halo, C 1-6 -alkyl, or C 1-6 -haloalkyl or by an oxo—or dioxo bridge; 
 
         B is halo,
 CN, 
 NR i R ii , 
 C 1-6 -alkyl optionally substituted by CN, halo or C 1-6 -alkoxy, 
 C 1-6 -haloalkyl, 
 C 1-6 -alkoxy, 
 C 1-6 -haloalkoxy, 
 C 3-6 -cycloalkyl, 
 —C(O)O—C 1-6 -alkyl, 
 C(O)NR i R ii , 
 —C(O)—C 1-6 -alkyl, 
 —S(O) 2 —C 1-6 -alkyl, 
 —S(O) 2 —NR i R ii , or 
 (CR iii R iv ) n -phenyl, or (CR iii R iv ) n -5 or 6 membered heteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety is optionally substituted by one or more substituent(s) selected from the group consisting of:
 halo, CN, NR i R ii , C 1-6 -alkyl optionally substituted by CN or C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 3-6 -cycloalkyl, —C(O)O—C 1-6 -alkyl, —C(O)—NR i R ii , —C(O)—C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl, and —S(O) 2 —NR i R ii ; 
 
 
         R i  and R ii  are each independently H, C 1-6 -alkyl, —(CO)O—C 1-6 -alkyl, —C(O)—NR iii R iv , —C(O)—C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl or —S(O) 2 —NR iii R iv ; 
         R iii  and R iv  are each independently H or C 1-6 -alkyl; 
         m is 1 to 6; and 
         n is 0 to 4; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 ,
 wherein   R i  is H,
 C 1-6 -alkyl optionally substituted by CN or C 1-6 -alkoxy, 
 aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which is optionally substituted by one or more B, 
 —(CH 2 ) n —R a  wherein R a  is:
 CN, 
 OR i , 
 NR i R ii , or 
 C 3-6 -cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
 or —(CH 2 ) n —(CO)—R b  or —(CH 2 ) n —(SO 2 )—R b , wherein R b  is:
 C 1-6 -alkyl, 
 C 1-6 -alkoxy, 
 C 3-6 -cycloalkyl, 
 —(CH 2 ) m —NR iii R iv , 
 NR i R ii , or 
 C 3-6 -cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
   or R 1  and R 3  together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl which is optionally substituted by (CO);   there is one or more R 2 , wherein each R 2  is the same or different,   R 2  is one or more H, OH, halo, CN, nitro, C 1-6 -alkyl optionally substituted by —NR iii R iv , C 1-6 -alkoxy, —O—CH 2 —C 2-6 -alkenyl, or benzyloxy,
 or two R 2  together with the indole ring to which they are attached form an oxo or dioxo bridge; 
   R 3  is H,
 halo, 
 —(CO)—R c , wherein R c  is:
 C 1-6 -alkyl, 
 —(CH 2 ) n —NR i R ii , 
 —(CH 2 ) n —NR iii R iv , or 
 5 or 6 membered heterocycloalkyl optionally substituted by C 1-6 -alkyl, 
 
 or C 1-6 -alkyl or aryl, each of which is optionally substituted by
 halo, 
 —O(CO)—C 1-6 -alkyl, or 
 —NH(CO)R d , wherein R d  is C 1-6 -alkyl optionally substituted by halo or nitro, or R d  is aryl or a 5 or 6 membered heteroaryl, each of which is optionally substituted by halo, nitro, C 1-6 -alkyl or C 1-6 -haloalkyl; 
 
   A is selected from the group consisting of (a), (b), (c) and (d):   
       
         
           
           
               
               
           
         
         wherein 
         R 4  is —NH(CO)R e , wherein R e  is
 C 1-6 -alkoxy or aryl optionally substituted by halo, 
 C 1-6 -alkoxy, or 
 CN, 
 or aryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by CN, halo, C 1-6 -alkyl, C 1-6 -alkoxy, or C 1-6 -haloalkyl, or by a dioxo bridge; 
 
         R 6  is C 1-6 -alkyl,
 —C(O)—R f  wherein R f  is an aryl group optionally substituted by halo, C 1-6 -alkoxy, or CN, 
 or aryl, 5 or 6 membered heteroaryl, benzyl, or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, or CN or by a dioxo bridge; 
 
         B is halo,
 CN, 
 NR i R ii , 
 C 1-6 -alkyl optionally substituted by CN, halo or C 1-6 -alkoxy, 
 C 1-6 -alkoxy, 
 C 1-6 -haloalkoxy, 
 C 3-6 -cycloalkyl, 
 —C(O)O—C 1-6 -alkyl, 
 —C(O)NR i R ii , 
 —C(O)—C 1-6 -alkyl, 
 —S(O) 2 —C 1-6 -alkyl, —S(O) 2 —NR i R ii , or 
 
         (CR iii R iv ) n -phenyl, or (CR iii R iv ) n -5 or 6 membered heteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety is optionally substituted by one or more substituent(s) selected from the group consisting of:
 halo, CN, NR i R ii , C 1-6 -alkyl optionally substituted by CN or C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 3-6 -cycloalkyl, —C(O)O—C 1-6 -alkyl, —C(O)—NR i R ii , —C(O)—C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl, and —S(O) 2 —NR i R ii ; 
 
         R i  and R ii  are each independently H, C 1-6 -alkyl, C 1-6 -alkyl-NR iii R iv , —(CO)O—C 1-6 -alkyl, —C(O)—NR iii R iv , —C(O)—C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl or —S(O) 2 —NR iii R iv ; 
         R iii  and R iv  are each independently H or C 1-6 -alkyl; 
         m is 1 to 6; and 
         n is 0 to 4; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein
 R 1  is H,
 C 1-6 -alkyl optionally substituted by CN or C 1-6 -alkoxy, 
 aryl, 
 5 or 6 membered heteroaryl, 
 sulfonylaryl, 
 —(CH 2 ) m −R a  wherein R a  is C 3-6 -cycloalkyl, 5 or 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more substituents selected from the group consisting of:
 halo, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, —C(O)O—C 1-6 -alkyl, and phenyl optionally substituted by halo, C 1-6 -alkyl, C 1-6 -haloalkyl or C 1-6 -alkoxy, 
 
 (CH 2 ) m —NR i R ii , 
 or —(CH 2 ) n —(CO)—R b , wherein R b  is aryl or 5 or 6 membered-heterocycloalkyl; 
   there is one or more R 2 , wherein each R 2  is the same or different,   R 2  is one or more H, halo, CN, nitro, C 1-6 -alkyl, C 1-6 -alkoxy, —O—CH 2 —C 2-6 -alkenyl, or benzyloxy, or
 two R 2  together with the indole ring to which they are attached form an oxo or dioxo bridge; 
   R 3  is H,
 halo, 
 —(CO)—R c , wherein R c  is C 1-6 -alkyl, 5 or 6 membered heterocycloalkyl optionally substituted by C 1-6 -alkyl, or R c  is —(CH 2 ) n —NR i R ii , 
 or C 1-6 -alkyl or aryl, each of which is optionally substituted by
 —O(CO)—C 1-6 -alkyl, or 
 —NH(CO)R d , wherein R d  is C 1-6 -alkyl optionally substituted by halo or nitro, or R d  is aryl or a 5 or 6 membered heteroaryl, each of which is optionally substituted by halo, nitro, C 1-6 -alkyl or C 1-6 -haloalkyl; 
 
   R i  and R ii  are each independently selected from H, C 1-6 -alkyl and —(CO)O—C 1-6 -alkyl;   m is 1 to 6;   n is 0 to 4;   A is selected from the group consisting of (a), (b), (c) and (d):   
       
         
           
           
               
               
           
         
         wherein 
         R 4  is —NH(CO)R c , wherein R c  is C 1-6 -alkoxy or aryl optionally substituted by halo,
 or aryl, benzyl, aryloxy or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, or C 1-6 -haloalkyl, or by a dioxo bridge; and 
 
         R 6  is C 1-6 -alkyl,
 —C(O)—R f  wherein R f  is an aryl group optionally substituted by halo, 
 or aryl, benzyl, or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, or C 1-6 -haloalkyl, or by a dioxo bridge; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The compound of  claim 1 , wherein:
 R 1  is H,
 C 1-6 -alkyl substituted by NR i R ii , 
 —(CH 2 ) m —R a  wherein R a  is:
 NR i R ii , or 
 5 to 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
 or —(CH 2 ) n —(CO)—R b  or —(CH 2 ) n —(SO 2 )—R b , wherein R b  is:
 C 1-6 -alkyl, 
 C 1-6 -alkoxy, 
 NR i R ii , or 
 5 to 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
   or R 1  and R 3  together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl which is optionally substituted by ═O, C(O)O—C 1-6 -alkyl or C 1-6 -alkyl;   there is one or more R 2 , wherein each R 2  is the same or different,   R 2  is one or more H, halo, or C 1-6 -alkyl;   R 3  is H, or
 C 1-6 -alkyl; 
   A is selected from the group consisting of (a), (a′), (b), (c) and (d):   
       
         
           
           
               
               
           
         
         wherein 
         R 4  is —NH(CO)R e , wherein R e  is C 1-6 -alkoxy, or aryl optionally substituted by halo,
 or aryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclic heteroaryl ring, each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, nitro, hydroxyl, or C 1-6 -haloalkoxy, or by an oxo or dioxo bridge; 
 
         R 6  is aryl, 5 or 6 membered heteroaryl, or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, CN, nitro, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, COOH, or S(O) 2 —C 1-6 -alkyl, or by an oxo or dioxo bridge; 
         B is halo, C 1-6 -alkyl optionally substituted by CN, halo or C 1-6 -alkoxy, or C 1-6 -alkoxy; 
         R i  and R ii  are each independently H, C 1-6 -alkyl, C 1-6 -alkyl-NR iii R iv , —C(O)—C 1-6 -alkyl or —S(O) 2 —C 1-6 -alkyl; 
         R iii  and R iv  are each independently H or C 1-6 -alkyl; 
         m is 1 to 6; and 
         n is 0 to 4; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The compound of  claim 1 ,
 wherein R 1 , R 2  and R 3  are not simultaneously H, or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound of  claim 1 , wherein R 4  is not 
       
         
           
           
               
               
           
         
         optionally substituted by CN, halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, nitro, hydroxyl, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, S(O) 2 —C 1-6 -alkyl, or C 1-6 -haloalkoxy, or by an oxo bridge. 
       
     
     
         7 . The compound of  claim 1 , having formula (1-a) or (I-a′): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         8 . The compound of  claim 7 ,
 wherein   R 1  is H or —(CH 2 ) m R a  wherein R a  is aryl and m is 1 to 6;   there is one or more R 2 , wherein each R 2  is the same or different,   R 2  is one or more H or halo;   R 3  is H or C 1-6 -alkyl; and   R 4  is aryl which is optionally substituted by halo or C 1-6 -alkoxy;   or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The compound of  claim 7 , wherein R 1 , R 2  and R 3  are not simultaneously H, or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound of  claim 7 , which is selected from the group consisting of:
 (1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;   (1-Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;   (1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone; and   (1-Benzyl-2-methyl-1H-indol-3-yl)-(5-methyl-4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-methanone.   
     
     
         11 . The compound of  claim 1 , having formula (I-c) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         12 . The compound of  claim 11 , wherein
 R 1  is H or
 C 1-6 -alkyl substituted by NR i R ii , 
 —(CH 2 ) m —R a  wherein R a  is:
 NR i R ii , or 
 5 to 6 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more C 1-6 -alkyl, 
 
 or —(CH 2 ) n —(CO)—R b , wherein R b  is:
 NR i R ii , or 
 5 to 7 membered-heterocycloalkyl which is optionally substituted by one or more C 1-6 -alkyl; 
 
   there is one or more R 2 , wherein each R 2  is the same or different,   R 2  is one or more H, halo or C 1-6 -alkyl;   R 3  is H or C 1-6 -alkyl;   R 6  is aryl, 5 or 6 membered heteroaryl, or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, CN, nitro, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, COOH, or S(O) 2 —C 1-6 -alkyl, or by an oxo or dioxo bridge;   R i  and R ii  are each independently H, C 1-6 -alkyl, C 1-6 -alkyl-NR iii R iv , —C(O)—C 1-6 -alkyl, or —S(O) 2 —C 1-6 -alkyl;   R iii  and R iv  are each independently H or C 1-6 -alkyl;   m is 1 to 6; and   n is 0 to 4;   or a pharmaceutically acceptable salt thereof.   
     
     
         13 . The compound of  claim 11 , wherein R 1 , R 2  and R 3  are not simultaneously H, or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The compound of  claim 11 , which is selected from the group consisting of:
 (1-Benzyl-2-methyl-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone;   (1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;   (1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;   (1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone;   (1-Benzyl-2-methyl-1H-indol-3-yl)-[4-(4-chloro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-(4-phenyl-piperazin-1-yl)-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(2-chloro-6-nitro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(2,6-dichloro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]-methanone; and   (6-Chloro-1H-indol-3-yl)-[4-(2-nitro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone.   
     
     
         15 . The compound of  claim 11 , which is selected from the group consisting of:
 (6-Chloro-1H-indol-3-yl)-[4-(2-chloro-phenyl)-piperazin-1-yl]-methanone;   [4-(2-Amino-6-chloro-phenyl)-piperazin-1-yl]-(6-chloro-1H-indol-3-yl)-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(4-methoxy-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(3-methoxy-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(2-nitro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(4-fluoro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(3-fluoro-phenyl)-piperazin-1-yl]-methanone;   3-Chloro-4-[4-(6-chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-benzonitrile; and   (6-Chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone.   
     
     
         16 . The compound of  claim 11 , which is selected from the group consisting of:
 2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-5-methyl-indol-1-yl}-N,N-dimethyl-acetamide;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone or hydrochloride salt thereof;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide or hydrochloride salt thereof;   N-(2-Amino-ethyl)-2-{6-chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide or hydrochloride salt thereof;   [1-(2-Amino-ethyl)-6-chloro-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone; and   [6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone.   
     
     
         17 . The compound of  claim 11 , which is selected from the group consisting of:
 [6-Chloro-1-(2-methylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   [1-(2-Amino-ethyl)-6-Chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-methylamino-ethyl)-acetamide;   N-(2-Amino-ethyl)-2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide;   2-{6-Chloro-3-[4-(2-methoxymethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide;   2-{6-Chloro-3-[4-(2-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide; and   2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-(2-dimethylamino-ethyl)-acetamide.   
     
     
         18 . The compound of  claim 11 , which is selected from the group consisting of:
 (6-Chloro-1H-indol-3-yl)-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(3-methyl-pyridin-2-yl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(3,5-dichloro-pyridin-4-yl)-piperazin-1-yl]-methanone;   (6-Chloro-1H-indol-3-yl)-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone;   2-[4-(6-Chloro-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinonitrile;   (6-Chloro-1H-indol-3-yl)-(4-pyridin-2-yl-piperazin-1-yl)-methanone;   (6-Chloro-1H-indol-3-yl)-(4-thiazol-2-yl-piperazin-1-yl)-methanone;   2-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carbonyl)-indol-1-yl]-N-methyl-acetamide;   2-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   2-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide; and   2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide.   
     
     
         19 . The compound of  claim 11 , which is selected from the group consisting of:
 2-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;   2-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   (6-Chloro-1-(S)-1-piperidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1-(RS)-1-pyrrolidin-3-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   [6-Chloro-1-((S)-1-methyl-piperidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   [6-Chloro-1-((RS)-1-methyl-pyrrolidin-3-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   2-[6-Chloro-3-(2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;   2-{6-Chloro-3-[4-(3-methyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;   2-{6-Chloro-3-[4-(3,5-dichloro-pyridin-4-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;   2-[6-Chloro-3-(4-pyridin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide; and   2-[6-Chloro-3-(4-thiazol-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide.   
     
     
         20 . The compound of  claim 11 , which is selected from the group consisting of:
 2-{6-Chloro-3-[4-(3-cyano-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;   2-[6-Chloro-3-(4-pyrimidin-2-yl-piperazine-1-carbonyl)-indol-1-yl]-N,N-dimethyl-acetamide;   (6-Chloro-2-methyl-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;   2-{6-Chloro-3-[4-(6-Chloro-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   2-{6-Chloro-3-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   2-[6-Chloro-3-(4-thieno[2,3-c]pyridin-7-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide;   2-{6-Chloro-3-[4-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   2-[4-(6-Chloro-1-methylcarbamoylmethyl-1H-indole-3-carbonyl)-piperazin-1-yl]-nicotinic acid;   2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-(2-dimethylamino-ethyl)-acetamide; and   2-{6-Chloro-3-[4-(4-fluoro-2-methanesulfonyl-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.   
     
     
         21 . The compound of  claim 11 , which is selected from the group consisting of:
 2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;   2-{6-Chloro-3-[4-(2-ethoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;   2-{6-Chloro-3-[4-(2-methoxy-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone;   [6-Chloro-1-(2-dimethylamino-ethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-(4-methyl-piperazin-1-yl)-ethanone;   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide; and   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetamide.   
     
     
         22 . The compound of  claim 11 , which is selected from the group consisting of:
 2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-1-piperazin-1-yl-ethanone;   2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   2-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide;   [1-((S)-2-Amino-propyl)-6-chloro-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   (6-Chloro-1-(S)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   [6-Chloro-1-((S)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   2-{6-Chloro-3-[4-(2,4-difluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide; and   2-{6-Chloro-3-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N,N-dimethyl-acetamide.   
     
     
         23 . The compound of  claim 11 , which is selected from the group consisting of:
 (6-Chloro-1-(R)-1-pyrrolidin-2-ylmethyl-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   [6-Chloro-1-((R)-1-methyl-pyrrolidin-2-ylmethyl)-1H-indol-3-yl]-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone;   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-acetamide;   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-methanesulfonamide;   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-acetamide;   N-(2-{6-Chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-ethyl)-N-methyl-methanesulfonamide;   2-[6-Chloro-3-(4-thieno[3,2-c]pyridin-4-yl-piperazine-1-carbonyl)-indol-1-yl]-N-methyl-acetamide; and   2-{6-Chloro-3-[4-(3-iodo-pyridin-2-yl)-piperazine-1-carbonyl]-indol-1-yl}-N-methyl-acetamide.   
     
     
         24 . The compound of  claim 1 , having formula (I-d) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . The compound of  claim 24 , wherein R 1 , R 2  and R 3  are not simultaneously H, or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The compound of  claim 24 , wherein:
 R 1  is H;   R 2  is one or more halo;   R 3  is H; and   R 6  is aryl substituted by C 1-6 -alkoxy;   or a pharmaceutically acceptable salt thereof.   
     
     
         27 . The compound of  claim 24 , which is
 (6-Chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-4-oxy-piperazin-1-yl]-methanone.   
     
     
         28 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is H,
 C 1-6 -alkyl substituted by CN, C 1-6 -alkoxy, OH, halo, or NR i R ii , 
 C 2-6 -alkyl, 
 aryl, 5 or 6 membered heteroaryl or sulfonylaryl each of which is optionally substituted by one or more B, 
 —(CH 2 ) m —R a  wherein R a  is:
 CN, 
 OR i , 
 NR i R ii , or 
 C 3-6 -cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
 or —(CH 2 ) n —(CO)—R b  or —(CH 2 ) n —(SO 2 )—R b , wherein R b  is:
 C 1-6 -alkyl, 
 C 1-6 -alkoxy, 
 C 3-6 -cycloalkyl, 
 —(CH 2 ) m —NR iii R iv , 
 NR i R ii , or 
 C 3-6 -cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl each of which is optionally substituted by one or more B, 
 
 
         or R 1  and R 3  together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl which is optionally substituted by ═O, C(O)O—C 1-6 -alkyl or C 1-6 -alkyl; 
         there is one or more R 2 , wherein each R 2  is the same or different, 
         R 2  is one or more H, OH, halo, CN, nitro, C 1-6 -alkoxy, —O—CH 2 —C 2-6 -alkenyl, benzyloxy, C 1-6 -haloalkoxy, or C 1-6 -alkyl optionally substituted by —NR iii R iv  or halo,
 or two R 2  together with the indole ring to which they are attached form an oxo or dioxo bridge; 
 
         R 3  is H,
 F, 
 —(CO)—R c , wherein R c  is:
 C 1-6 -alkyl, 
 —(CH 2 ) n —NR iii R iv , 
 —(CH 2 ) n —NR iii R iv , or 
 5 or 6 membered heterocycloalkyl optionally substituted by C 1-6 -alkyl, 
 
 or C 1-6 -alkyl which is optionally substituted by
 halo, 
 NR i R ii , 
 NR iii R iv , 
 —O(CO)—C 1-6 -alkyl, 
 or —NH(CO)R d , wherein R d  is C 1-6 -alkyl optionally substituted by halo or nitro, or R d  is aryl or a 5 or 6 membered heteroaryl, each of which is optionally substituted by halo, nitro, C 1-6 -alkyl or C 1-6 -haloalkyl; 
 
 
         A is selected from the group consisting of (a), (a′), (b), (c) and (d): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 4  is —NH(CO)R e , wherein R e  is
 C 1-6 -alkoxy or aryl optionally substituted by halo, 
 C 1-6 -alkoxy, or 
 CN, 
 or aryl, 5 or 6 membered heteroaryl, benzyl, aryloxy or a 9 or 10-membered bicyclic heteroaryl ring, each of which is optionally substituted by CN, halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, nitro, hydroxyl, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, S(O) 2 —C 1-6 -alkyl, or C 1-6 -haloalkoxy, or by an oxo or dioxo bridge; 
 
         R 6  is C 2-6 -alkyl,
 —C(O)—R f  wherein R f  is an aryl group substituted by halo, C 1-6 -alkoxy, or CN, 
 aryl, 5 or 6 membered heteroaryl, or a 9 or 10-membered bicyclic heteroaryl ring each of which is optionally substituted by halo, C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -haloalkyl, CN, nitro, NR i R ii , NR iii R iv , C 1-6 -alkoxy-C 1-6 -alkylene, COOH, S(O) 2 —C 1-6 -alkyl, hydroxyl, or C 1-6 -haloalkoxy, or by an oxo or dioxo bridge, 
 or benzyl substituted by halo, C 1-6 -alkyl, or C 1-6 -haloalkyl or by an oxo—or dioxo bridge; 
 
         B is halo,
 CN, 
 NR i R ii , 
 C 1-6 -alkyl optionally substituted by CN, halo or C 1-6 -alkoxy, 
 C 1-6 -haloalkyl, 
 C 1-6 -alkoxy, 
 C 1-6 -haloalkoxy, 
 C 3-6 -cycloalkyl, 
 —C(O)O—C 1-6 -alkyl, 
 —C(O)NR i R ii , 
 —C(O)—C 1-6 -alkyl, 
 —S(O) 2 —C 1-6 -alkyl, 
 —S(O) 2 —NR i R ii , or 
 (CR iii R iv ) n -phenyl, or (CR iii R iv ) n -5 or 6 membered heteroaryl wherein the phenyl or 5 or 6 membered heteroaryl moiety is optionally substituted by one or more substituent(s) selected from the group consisting of:
 halo, CN, NR i R ii , C 1-6 -alkyl optionally substituted by CN or C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -haloalkoxy, C 3-6 -cycloalkyl, —C(O)O—C 1-6 -alkyl, —C(O)—NR i R ii , —C(O)—C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl, and —S(O) 2 —NR i R ii ; 
 
 
         R i  and R ii  are each independently H, C 1-6 -alkyl, C 1-6 -alkyl-NR iii R iv , —(CO)O—C 1-6 -alkyl, —C(O)—NR iii R iv , —C(O)—C 1-6 -alkyl, —S(O) 2 —C 1-6 -alkyl or —S(O) 2 —NR iii R iv ; 
         R iii  and R iv  are each independently H or C 1-6 -alkyl; 
         m is 1 to 6; and 
         n is 0 to 4; 
         or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.