Novel heteroaryl derivatives, their preparation and use

Abstract

A heteroaryl derivative having the formula (I). The compounds of the invention are considered useful for the treatment of affective disorders such as general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia and eating disorders, and neurological disorders such as psychosis.

1 .  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents O, NR 16 , S or CR 4 R 5 .  
 Y is —CR 6 R 7 —, —CR 6 R 7 —CR 8 R 9 —, —CR 6 ═CR 7 — or CO—CR 6 R 7 ; or  
 X and Y together form a group —CR 4 ═CR 5 — or —CR 4 ═CR 5 —CR 6 R 7 —;  
 Z represents O or S; 
 n is 2, 3, 4, 5, 6, 7, 8, 9 or 10;  
 m is 2 or 3:  
 A is O or S;  
 W is N, C or CH;  
 Q is N, C or CH;  
 wherein the dotted line means an optional bond;  
 
 R 1 -R 9  are each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl-C 1-6 -alkyl, C 1-6 -alkoxy, C 1-6 -alkylthio, hydroxy, formyl, acyl, amino, C 1-6 -alkylamino, di(C 1-6 -alkyl)amino, acylamino, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C 1-6 -alkylaminocarbonylamino and di(C 1-6 -alkyl)aminocarbonylamino; and  
 R 16  is selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl-C 1-6 -alkyl, formyl, acyl; and R 10  and R 11  are each independently selected from hydrogen and C 1-6 -alkyl or may together form a bridge consisting of two or three methylene groups; and  
 R 12 , R 13 , R 14  and R 15  are each independently selected from hydrogen, halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-8 -cycloalkyl, C 3-8 -cycloalkyl-C 1-6 -alkyl, aryl, heteroaryl, C 1-6 -alkoxy, C 1-6 -alkylthio, C 1-6 -alkylsulphonyl, hydroxy, formyl, acyl, amino, acylamino, aminocarbonyl, C 1-6 -alkoxycarbonylamino, aminocarbonylamino, C 1-6 -alkylaminocarbonylamino, di(C 1-6 -alkyl)aminocarbonylamino, SO 2 NR 20 R 21  and NR 20 R 21  wherein R 20  and R 21  independently represent hydrogen, C 1-6 -alkyl, C 3-8 -cycloalkyl or phenyl; or R 20  and R 21  together with the nitrogen to which they are attached form a 5- or 6-membered ring optionally containing one further heteroatom, which ring may optionally be substituted by C 1-6 -alkyl or acyl;  
 any of its enantiomers or any mixture thereof, or an acid addition salt thereof.  
 
     
     
         2 . A compound of  claim 1 , characterised in that Z is —O—.  
     
     
         3 . A compound of  claim 1 , characterised in that Y is —CR 6 R 7  or Y is —CH 2 CO—.  
     
     
         4 . A compound of  claim 1 , characterised in that X is O or NH.  
     
     
         5 . A compound of  claim 1 , characterised in that W is N.  
     
     
         6 . A compound of  claim 1 , characterised in that n is 2, 3 or 4.  
     
     
         7 . A compound of  claim 6 , characterised in that n is 2.  
     
     
         8 . A compound of  claim 1 , characterised in that R 1 , R 2  and R 3  are independently representing hydrogen, halogen or CN.  
     
     
         9 . A compound of  claim 1 , characterised in that R 12 , R 13 , R 14  and R 15  are independently selected from the group consisting of hydrogen, halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 1-6 -alkoxy, cyano, C 1-6 -alkylsulphonyl, acyl, nitro, trifluoromethyl and trifluoromethoxy.  
     
     
         10 . A compound of  claim 1 , characterised in that R 12 , R 13 , R 14  and R 15  are independently selected from a group consisting of hydrogen, heteroaryl, trifluoromethyl, cyano, C 1-6 -alkyl, C 3-8 -cycloalkyl, halogen, NR 20 R 21 , SO 2 NR 20 R 21 , aryl, C 1-6 -alkylsulfonyl aminocarbonyl and acylamino.  
     
     
         11 . A compound of  claim 10 , characterised in that R 12 , R 13 , R 14  and R 15  are independently selected from the group consisting of hydrogen, thiophen, trifluoromethyl, cyano, methyl, ethyl, cyclopropyl, chloro, bromo, fluoro, piperazinyl, 1-piperidinyl, 1-piperidinyl-sulfonyl, methanesulfonyl, methylsulfidyl, phenyl aminocarbonyl and acylamino.  
     
     
         12 . The compound according to  claim 1  which is 
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile, 1a  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methyl-4-trifluoromethylnicotinonitrile, 1b  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methyl-4-trifluoromethylnicotinonitrile, 1c  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-(thiophen-2-yl)-4-trifluoromethylnicotinonitrile, 1d  
 {2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinonitrile, 1e  
 3-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1f  
 2-Chloro-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl] ethoxy} pyridine, 1g  
 2-Bromo-3-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 1h  
 3-Chloro-5-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl] ethoxy}pyridine, 1i  
 2-Chloro-3-{2-[4-(8-cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 1j  
 2-Bromo-3-{2-[4-(8-Cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 1k  
 3-Chloro-5-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 1l  
 3-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-2-methylpyridine, 1m  
 4-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-3-(piperidin-1-ylsulfonyl)pyridine, 1n  
 4-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-3-(piperidin-1-ylsulfonyl)pyridine, 1o  
 2-{4-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine, 1p  
 2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine 1q  
 2-{4-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-5-trifluoromethylpyridine, 1r  
 2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine, 1s  
 2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulfanyl}-4,6-dimethyl-nicotinonitrile, 1t  
 2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]butylsulfanyl}-4,6-dimethyl-nicotinonitrile, 1u  
 2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulfanyl}-5-trifluoromethylpyridine, 1v  
 2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propylsulfanyl}-4,6-dimethylnicotinonitrile, 1x  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2a  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2b  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2c  
 2-{2-[4-(8-Cyano-2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylnicotinamide, 2d  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin 1-yl]ethylsulfanyl}nicotinonitrile, 2e  
 4-Cyano-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}pyridine, 2f  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-6-methylnicotinamide, 2g  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4-methyl-6-(piperidin-1-yl)nicotinonitrile, 2h  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4-methyl-6-(4-methylpiperazin-1-yl)nicotinonitrile, 2i  
 6-Cyclopropyl-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy)-4-trifluoromethylnicotinonitrile, 2j  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethoxy}-3-methanesulfonyl-4-methyl-6-phenylpyridine, 2k  
 2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethyl-3-phenylsulfonylpyridine, 2l  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}pyridine, 2m  
 2-{3-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile, 2n  
 6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-methylnicotinonitrile, 2o  
 5-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2p  
 6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2q  
 6-Chloro-2-{3-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2r  
 2-{3-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile, 2s  
 6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-methylnicotinonitrile, 2t  
 5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylnicotinonitrile, 2u  
 5-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-S-yl)piperazin-1-yl]ethylsulfanyl} nicotinonitrile, 2v  
 6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}nicotinonitrile, 2x  
 6-Chloro-2-{3-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-S-yl)piperazin-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2y  
 2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile, 2z  
 2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2aa  
 6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2ab  
 4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ac  
 5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2ad  
 5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile, 2ae  
 6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile, 2af  
 6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-3-on-8-yl)piperazin-1-yl]ethylsulfanyl]-5-fluoronicotinonitrile, 2ag  
 2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile, 2ah  
 2-[2-[4-(6-Chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2ai  
 6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-4-methylnicotinonitrile, 2aj  
 4-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-6-methylnicotinonitrile, 2ak  
 5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-4,6-dimethylnicotinonitrile, 2al  
 5-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile, 2am  
 6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]nicotinonitrile, 2an  
 6-Chloro-2-[2-[4-(6-chloro-2,3-dihydro-1,4-benzoxazin-8-yl)piperazin-1-yl]ethylsulfanyl]-5-fluoronicotinonitrile, 2ao  
 5-Cyano-4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2ap  
 5-Cyano-4-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2aq  
 5-Cyano-4-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}pyrimidine, 2ar  
 5-Cyano-4-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylsulfanyl-2-phenylpyrimidine, 2 as  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylpyrimidine, 2 at  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethylpyrimidine, 2au  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-methoxynicotinonitrile, 2av  
 6-Chloro-2-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2ax  
 6-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-5-fluoronicotinonitrile, 2ay  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-5-ethylpyrimidine, 2az  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine, 2ba  
 2-{2-[4-(2,3-Dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4,6-dimethoxypyrimidine, 2bb  
 4-Chloro-2-{2-[4-(8-cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-6-methylpyrimidine, 2bc  
 2-{2-[4-(8-Cyano-2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]ethylsulfanyl}-4-trifluoromethylpyrimidine, 2bd  
 or an acid addition salt thereof.  
 
     
     
         13 . A pharmaceutical composition comprising at least one compound of Formula I according to  claim 1 , or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.  
     
     
         14 . (Cancelled)  
     
     
         15 . (Cancelled)  
     
     
         16 . (Cancelled)  
     
     
         17 . A method for the treatment of a disorder or disease of living animal body, which is responsive to the effect of inhibition of serotonin uptake and antagonism of 5-HT 1A  receptors comprising administering to a living animal body, a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         18 . A method for the treatment of a disorder or disease of living animal body, which is responsive to the effect of 5-HT 1A  and D 4  receptors comprising administering to a living animal body, a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         19 . A method of treatment according to  claim 1  where the disorder or disease is an affective disorder or a neurological disorder.  
     
     
         20 . The method of treatment according to  claim 19 , where the affective disorder is general anxiety disorder, panic disorder, obsessive compulsive disorder, depression, social phobia or an eating disorder.  
     
     
         21 . The method of treatment according to  claim 19 , where the neurological disorder is psychosis.  
     
     
         22 . The method of treatment according to  claim 17 , wherein the living animal is a human.  
     
     
         23 . The method of treatment according to  claim 18 , wherein the living animal is a human.