Taar1 ligands

Abstract

The invention relates to a compound of formula wherein R 1 , R 2 , X, L, W, n, and o are defined herein and to pharmaceutically suitable acid addition salts thereof, with the exception of the following compounds 6-(4-methyl-piperazin-1-yl)-N-phenethyl-nicotinamide (CAS 199478-31-4), N-(3,4-dichloro-benzyl)-3-fluoro-benzamide (CAS 424815-98-5), N-(4-chloro-benzyl)-3-fluoro-benzamide (CAS 544661-83-8), N-(3-chloro-benzyl)-3-fluoro-benzamide (CAS 796051-07-5), and N-phenethyl-6-phenylamino-nicotinamide (CAS 571913-74-1). The compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1 and are useful for the treatment of CNS disorders.

1 . A compound of formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, —O—(CH 2 ) p -aryl or aryl; 
 R 2  is halogen, lower alkyl substituted by halogen, NR′R″, —(CH 2 ) p -heteroaryl or is —O-heterocycloalkyl, wherein the substitution on heteroaryl or heterocycloalkyl is lower alkyl; 
 R′ and R″ are each independently hydrogen, —(CH 2 ) p —O-lower alkyl, —(CH 2 ) p -optionally substituted aryl, —(CH 2 ) p -heteroaryl, —(CH 2 ) p -heterocycloalkyl, or R′ and R″ together with the N atom to which they are attached form a heterocycloalkyl group optionally substituted by lower alkyl, —CH 2 -cycloalkyl, —S(O) 2 CH 3 , —(CH 2 ) p —O-lower alkyl or by substituted aryl wherein the substitution on aryl is lower alkyl or lower alkoxy; 
 W is phenyl, benzo[1,3]dioxolyl, pyridine-2,3- or 4-yl, indolyl or cycloalkyl; 
 L is —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 —, —CH 2 CH(CH 3 )— or —CH 2 CH 2 CH 2 —; 
 X is N or CH; 
 n is 1 or 2; in case n is 2, each R 1  can be the same or different; 
 o is 1 or 2; in case o is 2, each R 2  can be the same or different; and 
 p is 0, 1, 2 or 3; 
 or a pharmaceutically suitable acid addition salt thereof, with the exception of the following compounds 
 6-(4-methyl-piperazin-1-yl)-N-phenethyl-nicotinamide, 
 N-(3,4-dichloro-benzyl)-3-fluoro-benzamide, 
 N-(4-chloro-benzyl)-3-fluoro-benzamide, 
 N-(3-chloro-benzyl)-3-fluoro-benzamide, and 
 N-phenethyl-6-phenylamino-nicotinamide. 
 
     
     
         2 . A compound of  claim 1  wherein X is N. 
     
     
         3 . A compound of  claim 1  having formula IA 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, —O—(CH 2 ) p -aryl or aryl; 
 R′ and R″ are each independently hydrogen, —(CH 2 ) p —O-lower alkyl, —(CH 2 ) p -optionally substituted aryl, —(CH 2 ) p -heteroaryl, —(CH 2 ) p -heterocycloalkyl, or R′ and R″ together with the N atom to which they are attached form a heterocycloalkyl group optionally substituted by lower alkyl, —CH 2 -cycloalkyl, —S(O) 2 CH 3 , —(CH 2 ) p —O-lower alkyl or by substituted aryl wherein the substitution on aryl is lower alkyl or lower alkoxy 
 W is phenyl, benzo[1,3]dioxolyl, pyridine-2,3- or 4-yl, indolyl or cycloalkyl; 
 L is —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 —, —CH 2 CH(CH 3 )—, —CH 2 CH 2 CH 2 —, 
 n is 1 or 2; in case n is 2, R′ may be the same or different; 
 p is 0, 1, 2 or 3, 
 or a pharmaceutically suitable acid addition salt thereof, with the exception of the following compounds 
 6-(4-methyl-piperazin-1-yl)-N-phenethyl-nicotinamide and 
 N-phenethyl-6-phenylamino-nicotinamide. 
 
     
     
         4 . A compound of  claim 2 , wherein R′ and R″ together with the N atom to which they are attached form a heterocycloalkyl group. 
     
     
         5 . A compound of  claim 4 , wherein the heterocyclic group is
 4-methyl-piperazin-1-yl.   
     
     
         6 . A compound of  claim 5 , selected from the group consisting of
 N-benzyl-6-(4-methyl-piperazin-1-yl)-nicotinamide,   (N-(4-chloro-benzyl)-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-[2-(4-chloro-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-[2-(3-chloro-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   6-(4-methyl-piperazin-1-yl)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-nicotinamide,   N-[2-(4-methoxy-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-[2-(3-methoxy-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-(2-benzo[1,3]dioxol-5-yl-ethyl)-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-(2-biphenyl-4-yl-ethyl)-6-(4-methyl-piperazin-1-yl)-nicotinamide,   6-(4-methyl-piperazin-1-yl)-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide,   6-(4-methyl-piperazin-1-yl)-N-[2-(3-phenoxy-phenyl)-ethyl]-nicotinamide,   N-[2-(4-benzyloxy-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-[2-(1-methyl-1H-indol-3-yl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   N-(2-cyclohexyl-ethyl)-6-(4-methyl-piperazin-1-yl)-nicotinamide, and   N-cyclohexyl-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide.   
     
     
         7 . A compound of  claim 4 , wherein the heterocycloalkyl group is piperazin-1-yl. 
     
     
         8 . A compound of  claim 7 , selected from the group consisting of
 N-[2-(4-chloro-phenyl)-ethyl]-6-piperazin-1-yl-nicotinamide,   N-[2-(4-phenoxy-phenyl)-ethyl]-6-piperazin-1-yl-nicotinamide,   N-[2-(3-phenoxy-phenyl)-ethyl]-6-piperazin-1-yl-nicotinamide, and   N-[2-(4-benzyloxy-phenyl)-ethyl]-6-piperazin-1-yl-nicotinamide.   
     
     
         9 . A compound of  claim 1 , wherein R 2  is —O-heterocycloalkyl. 
     
     
         10 . A compound of  claim 9 , wherein the O-heterocycloalkyl group is 1-methyl-piperidin-4-yloxy. 
     
     
         11 . A compound of  claim 10 , wherein the compound is 6-(1-methyl-piperidin-4-yloxy)-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide. 
     
     
         12 . A compound of  claim 1 , wherein o is 2 and one of R 2  is NR′R″ and the other R 2  is halogen. 
     
     
         13 . A compound of  claim 12 , selected from the group consisting of
 5-bromo-N-[2-(4-chloro-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-nicotinamide,   5-bromo-6-(4-methyl-piperazin-1-yl)-N-[2-(4-phenoxy-phenyl)-ethyl]-nicotinamide,   5-bromo-N-[2-(4-chloro-phenyl)-ethyl]-6-piperazin-1-yl-nicotinamide, and   5-bromo-N-[2-(4-phenoxy-phenyl)-ethyl]-6-piperazin-1-yl-nicotinamide.   
     
     
         14 . A compound of  claim 1 , wherein W is Ar. 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, —O—(CH 2 ) p -aryl or aryl; 
 R 2  is halogen, lower alkyl substituted by halogen, NR′R″, —(CH 2 ) p -heteroaryl or is —O-heterocycloalkyl, wherein the substitution on heteroaryl or heterocycloalkyl is lower alkyl; 
 R′ and R″ are each independently hydrogen, —(CH 2 ) p —O-lower alkyl, —(CH 2 ) p -optionally substituted aryl, —(CH 2 ) p -heteroaryl, —(CH 2 ) p -heterocycloalkyl, or R′ and R″ together with the N atom to which they are attached form a heterocycloalkyl group optionally substituted by lower alkyl, —CH 2 -cycloalkyl, —S(O) 2 CH 3 , —(CH 2 ) p —O-lower alkyl or by substituted aryl wherein the substitution on aryl is lower alkyl or lower alkoxy; 
 W is phenyl, benzo[1,3]dioxolyl, pyridine-2,3- or 4-yl, indolyl or cycloalkyl; 
 L is —CH 2 —, —CH(CH 3 )—, —CH 2 CH 2 —, —CH 2 CH(CH 3 )— or —CH 2 CH 2 CH 2 —; 
 X is N or CH; 
 n is 1 or 2; in case n is 2, each R 1  can be the same or different; 
 o is 1 or 2; in case o is 2, each R 2  can be the same or different; and 
 p is 0, 1, 2 or 3; 
 or a pharmaceutically suitable acid addition salt thereof, with the exception of the following compounds 
 6-(4-methyl-piperazin-1-yl)-N-phenethyl-nicotinamide, 
 N-(3,4-dichloro-benzyl)-3-fluoro-benzamide, 
 N-(4-chloro-benzyl)-3-fluoro-benzamide, 
 N-(3-chloro-benzyl)-3-fluoro-benzamide, and 
 N-phenethyl-6-phenylamino-nicotinamide 
 and a pharmaceutically acceptable carrier.