Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists

Abstract

The invention relates to novel benzothiophene-, benzofuran-, and indole ureas and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning, and/or memory.

1 - 15 . (canceled) 
     
     
         16 . A process for preparing a compound of formula (I), comprising: 
       
         
           
           
               
               
           
         
         reacting a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         with a compound of formula (III) 
       
       
         
           
           
               
               
           
         
         and reacting the resulting compound, where appropriate, with an appropriate acid or base to give the compound of formula (I) or a salt thereof; 
         wherein:
 R 1  is 1-azabicyclo[2.2.2]oct-3-yl; 
 R 2  is hydrogen; 
 R 3  is hydrogen; 
 R 4  is hydrogen; 
 R 5  is hydrogen; 
 R 6  is (i) hydrogen, (ii) C 1 -C 6 -alkyl, (iii) C 3 -C 8 -cycloalkyl, (iv) C 6 -C 10 -aryl, (v) 5- to 10-membered heteroaryl, or (vi) C 6 -C 10 -arylcarbonyl,
 wherein (ii) is optionally substituted by phenyl, C 1 -C 6 -alkoxycarbonyl or C 1 -C 6 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkylamino, or C 1 -C 6 -acylamino; 
 
 A is sulfur; 
 X is oxygen, and 
 the ring B is benzo. 
 
       
     
     
         17 . The process of  claim 16 , wherein:
 R 1  is 1-azabicyclo[2.2.2]oct-3-yl;   R 2  is hydrogen;   R 3  is hydrogen;   R 4  is hydrogen;   R 5  is hydrogen;   R 6  is (i) hydrogen, (ii) C 1 -C 6 -alkyl, (iii) C 3 -C 8 -cycloalkyl, (iv) C 6 -C 10 -aryl, or (v) 5- to 10-membered heteroaryl,
 wherein (ii) is optionally substituted by phenyl, or C 1 -C 6 -alkoxy, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 6 -alkyl, C 1 -C 6 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 6 -alkylamino, or C 1 -C 6 -acylamino; 
   A is sulfur;   X is oxygen, and   the ring B is benzo.   
     
     
         18 . The process of  claim 16 , wherein:
 R 1  is 1-aza-bicyclo[2.2.2]oct-3-yl;   R 2  is hydrogen;   R 3  is hydrogen;   R 4  is hydrogen;   R 5  is hydrogen;   R 6  is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, or (vi) C 6 -C 10 -arylcarbonyl,
 wherein (ii) is optionally substituted by phenyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 3 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, 3- to 8-membered heterocyclyl C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino; 
   A is sulfur;   X is oxygen, and   the ring B is benzo.   
     
     
         19 . The process of  claim 16 , wherein:
 R 1  is 1-azabicyclo[2.2.2]oct-3-yl;   R 2  is hydrogen;   R 3  is hydrogen;   R 4  is hydrogen;   R 5  is hydrogen;   R 6  is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, or (v) 5- to 6-membered heteroaryl,
 wherein (ii) is optionally substituted by phenyl, and (iv) and (v) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, hydroxy, chlorine, fluorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 6 -acyl, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino; 
   A is sulfur;   X is oxygen, and   the ring B is benzo.   
     
     
         20 . The process of  claim 16 , wherein:
 R 1  is 1-azabicyclo[2.2.2]oct-3-yl;   R 2 , R 3  and R 4  are hydrogen;   R 5  is hydrogen;   R 6  is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) C 5 -C 6 -cycloalkyl, (iv) phenyl, (v) pyridyl, or (vi) C 6 -C 10 -arylcarbonyl,
 wherein (ii) is optionally substituted by phenyl, C 1 -C 4 -alkoxycarbonyl or C 1 -C 3 -alkoxy, and (iv), (v) and (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -aryl, 5- to 10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano, C 1 -C 3 -alkoxy, C 1 -C 3 -acyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C 1 -C 3 -alkylamino, or C 1 -C 3 -acylamino; 
   A is sulfur;   X is oxygen, and   the ring B is benzo.   
     
     
         21 . The process of  claim 16 , wherein:
 R 1  is 1-azabicyclo[2.2.2]oct-3-yl;   R 2  is hydrogen;   R 3  is hydrogen;   R 4  is hydrogen;   R 5  is hydrogen;   R 6  is (i) hydrogen, (ii) C 1 -C 4 -alkyl, (iii) cyclopentyl, cyclohexyl, (iv) phenyl, (v) benzyl, or (vi) phenethyl,
 wherein (iv) to (vi) are optionally substituted by up to 3 radicals selected independently of one another from the group of hydroxy, chlorine, fluorine, cyano, methoxy, ethoxy, C 1 -C 4 -acyl, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 3 -alkylamino; 
   A is sulfur;   X is oxygen, and   the ring B is benzo.   
     
     
         22 . The process of  claim 16 , wherein the compound or salt thereof of formula (I) is a compound of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein
 R 1  to R 6 , A and X have the meanings indicated in  claim 16 . 
 
       
     
     
         23 . The process of  claim 16 , wherein the compound or salt thereof of formula (I) is a compound of formula (Ib) 
       
         
           
           
               
               
           
         
         wherein
 R 1  to R 6 , A and X have the meanings indicated in  claim 16 . 
 
       
     
     
         24 . The process of  claim 16 , wherein the compound or salt thereof of formula (I) is selected from the group consisting of:
 6-[(Aminocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-chlorophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-phenylethyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride:   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-bromophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-ethoxyphenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-(dimethylamino)phenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-nitrophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,6-difluorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,4-dichlorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-(trifluoromethyl)phenyl]amino}-carbonyl)amino]-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4,5-trimethoxyphenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[{([4-methoxy-3-(trifluoromethyl)phenyl]-amino}carbonyl)amino]-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-methoxyphenyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[{[3-trifluoromethoxyphenyl]amino}-carbonyl)amino]-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclohexylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[(1S)-1-phenylethyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide hydrochloride; and   7-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[22.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride.   
     
     
         25 . The process of  claim 16 , wherein the compound or salt thereof of formula (I) is selected from the group consisting of:
 N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-phenylethyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,6-difluorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide hydrochloride;   N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-methoxyphenyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide hydrochloride; and   7-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide hydrochloride.