Novel 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments

Abstract

The invention provides novel 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, and related processes and intermediates for preparing these compounds, as well as compositions and methods employing these compounds for the treatment and/or prevention of central nervous system (CNS) disorders, including but not limited to depression and anxiety.

1 - 71 . (canceled) 
     
     
         72 . A method of making a 1-heteroaryl-3-azabicyclo[3.1.0]hexane of the following Formula III, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar is a heterocyclic aryl group selected from furan, methylfuran, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, methoxypyridine, pyridazine, pyrazine, triazine, indole, methylindole, benzofuran, benzothiophene, benzothiazole, isoquinoline, cinnoline, phthalazine, quinazoline, chromane and isochromane, and Ar is either unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, —NO 2 , —CN, —NH 2 , carboxy, C 2-8  alkenyl, C 2-8  alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxyl, C 1-8  alkylamino, and di(C 1-8 )alkylamino, comprising:
 (a) reacting a compound of the following formula (i), 
 
       
         
           
           
               
               
           
         
       
       wherein Ar is defined as above, with epichlorohydrin or an enantiomer thereof, to produce a compound of the following formula (ii), 
       
         
           
           
               
               
           
         
         or an enantiomer or diastereomer thereof, wherein Ar is as defined above; 
         (b) reducing the compound of formula (ii) to produce a compound of the following formula (iii), 
       
       
         
           
           
               
               
           
         
       
       or an enantiomer or diastereomer thereof, wherein Ar is as defined above; and
 (c) causing cyclization of the compound of formula (iii) to produce the 1-heteroaryl-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof. 
 
     
     
         73 . The method according to  claim 72  further comprising:
 (d) alkylating the 1-heteroaryl-3-azabicyclo[3.1.0]hexane produced in (c) to produce a compound of the following Formula I, 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar is as defined in  claim 72  and R 1  is selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-8  cycloalkyl, C 2-10  alkenyl, and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy. 
     
     
         74 . A method of making a 1-heteroaryl-3-azabicyclo[3.1.0]hexane of the following Formula I, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar is a heterocyclic aryl group selected from furan, methylfuran, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, methoxypyridine, pyridazine, pyrazine, triazine, indole, methylindole, benzofuran, benzothiophene, benzothiazole, isoquinoline, cinnoline, phthalazine, quinazoline, chromane and isochromane, and Ar is either unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, —NO 2 , —CN, —NH 2 , carboxy, C 2-8  alkenyl, C 2-8  alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxyl, C 1-8  alkylamino, and di(C 1-8 )alkylamino and R 1  is selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-8  cycloalkyl, C 2-10  alkenyl, and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy, comprising:
 (a) reacting a compound of the following formula (iv), 
 
       
         
           
           
               
               
           
         
         wherein R 1  is as defined above, with 
       
       
         
           
           
               
               
           
         
       
       wherein Ar is as defined above, to produce a compound of the following formula (v), 
       
         
           
           
               
               
           
         
         wherein R 1  and Ar are as defined above; 
         (b) causing cyclopropanation of the compound of formula (v) to produce a compound of the following formula (vi), 
       
       
         
           
           
               
               
           
         
         wherein R 1  and Ar are as defined above; and 
         (c) reducing the compound of formula (vi) to produce the 1-heteroaryl-3-azabicyclo[3.1.0]hexane. 
       
     
     
         75 . A method of making a 1-heteroaryl-3-azabicyclo[3.1.0]hexane of the following Formula III, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar is a heterocyclic aryl group selected from furan, methylfuran, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, methoxypyridine, pyridazine, pyrazine, triazine, indole, methylindole, benzofuran, benzothiophene, benzothiazole, isoquinoline, cinnoline, phthalazine, quinazoline, chromane and isochromane, and Ar is either unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, —NO 2 , —CN, —NH 2 , carboxy, C 2-8  alkenyl, C 2-8  alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxyl, C 1-8  alkylamino, and di(C 1-8 )alkylamino, comprising:
 (a) coupling a compound of the following formula (vii), 
 
       
         
           
           
               
               
           
         
       
       with 
       
         
           
           
               
               
           
         
       
       wherein Ar is as defined above, to produce a compound of the following formula (viii), 
       
         
           
           
               
               
           
         
         wherein Ar is as defined above; 
         (b) causing cyclopropanation of the compound of formula (viii) to produce a compound of the following formula (ix), 
       
       
         
           
           
               
               
           
         
         wherein Ar is as defined above; 
         (c) reducing the compound of formula (ix) to produce a compound of the following formula (x), 
       
       
         
           
           
               
               
           
         
         wherein Ar is as defined above; and 
         (d) deprotecting the compound of formula (x) to produce the 1-heteroaryl-3-azabicyclo[3.1.0]hexane. 
       
     
     
         76 . The method according to  claim 75  further comprising:
 (e) alkylating the 1-heteroaryl-3-azabicyclo[3.1.0]hexane produced in (d) to produce a compound of the following Formula I, 
 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar is as defined in  claim 75  and R 1  is selected from hydrogen, unsubstituted C 1-10  alkyl, C 3-8  cycloalkyl, C 2-10  alkenyl, and C 3-10  alkynyl, and substituted C 1-10  alkyl, C 3-10  alkenyl and C 3-10  alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6  alkoxy, aryl substituted C 1-6  alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6  alkyl, C 1-6  alkyl independently substituted with one or more of cyano and halogen, C 1-4  alkoxy, and C 1-4  haloalkoxy. 
     
     
         77 . A method of making a 1-heteroaryl-3-azabicyclo[3.1.0]hexane of the following Formula III, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Ar is a heterocyclic aryl group selected from furan, methylfuran, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, methoxypyridine, pyridazine, pyrazine, triazine, indole, methylindole, benzofuran, benzothiophene, benzothiazole, isoquinoline, cinnoline, phthalazine, quinazoline, chromane and isochromane, and Ar is either unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, —NO 2 , —CN, —NH 2 , carboxy, C 2-8  alkenyl, C 2-8  alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8  cycloalkyl, C 1-3  alkoxy, C 1-3  alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3  alkanoyl, halo(C 1-3 )alkoxyl, C 1-8  alkylamino, and di(C 1-8 )alkylamino, comprising:
 causing cyclization of a compound of formula (iii) 
 
       
         
           
           
               
               
           
         
       
       wherein Ar is as defined above, to produce the 1-heteroaryl-3-azabicyclo[3.1.0]hexane, or an enantiomer or diastereomer thereof. 
     
     
         78 . The method according to  claim 77 , wherein the compound of formula (iii) is prepared by reducing a compound of formula (ii) 
       
         
           
           
               
               
           
         
       
       wherein Ar is as defined in  claim 77 . 
     
     
         79 . The method according to  claim 72  further comprising isolating the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III or pharmaceutically acceptable salt thereof. 
     
     
         80 . The method according to  claim 73  further comprising isolating the compound of Formula I or pharmaceutically acceptable salt thereof. 
     
     
         81 . The method according to  claim 74  further comprising isolating the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula I or pharmaceutically acceptable salt thereof. 
     
     
         82 . The method according to  claim 75  further comprising isolating the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III or pharmaceutically acceptable salt thereof. 
     
     
         83 . The method according to  claim 76  further comprising isolating the compound of Formula I or pharmaceutically acceptable salt thereof. 
     
     
         84 . The method according to  claim 77  further comprising isolating the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III or pharmaceutically acceptable salt thereof. 
     
     
         85 . The method according to  claim 72 , wherein the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III is:
 1-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.0]hexane;   1-(5-methylfuran-2-yl)-3-azabicyclo[3.1.0]hexane;   1-(benzofuran-3-yl)-3-azabicyclo[3.1.0]hexane;   1-(benzothiazol-2-yl)-3-azabicyclo[3.1.0]hexane;   1-(5-chlorobenzo[b]thiophen-3-yl)-3-azabicyclo[3.1.0]hexane;   (1S,5S)-1-(6-fluoro-benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane; or   (1R, 5R)-1-(6-fluoro-benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane; or   a pharmaceutically acceptable salt thereof.   
     
     
         86 . The method according to  claim 77 , wherein the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III is:
 1-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.0]hexane;   1-(5-methylfuran-2-yl)-3-azabicyclo[3.1.0]hexane;   1-(benzofuran-3-yl)-3-azabicyclo[3.1.0]hexane;   1-(benzothiazol-2-yl)-3-azabicyclo[3.1.0]hexane;   1-(5-chlorobenzo[b]thiophen-3-yl)-3-azabicyclo[3.1.0]hexane;   (1S,5S)-1-(6-fluoro-benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane; or   (1S,5S)-1-(6-fluoro-benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane; or   a pharmaceutically acceptable salt thereof.   
     
     
         87 . The method according to  claim 74 , wherein the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula I is:
 3-methyl-1-(1-methylindol-5-yl)-3-azabicyclo[3.1.0]hexane; or   1-(1-methyl-1H-indol-5-yl)-3-ethyl-3-azabicyclo[3.1.0]hexane; or   a pharmaceutically acceptable salt thereof.   
     
     
         88 . The method according to  claim 75 , wherein the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III is 1-(benzothiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof. 
     
     
         89 . The method according to  claim 77 , wherein the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III is (1S,5S)-1-(6-fluoro-benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof. 
     
     
         90 . The method according to  claim 77 , wherein the 1-heteroaryl-3-azabicyclo[3.1.0]hexane of Formula III is (1R,5R)-1-(6-fluoro-benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.