Positive allosteric modulators of nicotinic acetylcholine receptor

Abstract

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α7 receptor.

1 - 14 . (canceled) 
     
     
         15 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R1, R2, R3, R4 and R5 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, cyano and halogen, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from chlorine and fluorine. 
       
     
     
         16 . The compound of  claim 15 , of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound of Formula (III): 
       
         
           
           
               
               
           
         
       
       wherein:
 R6 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkoxy, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from hydroxyl, C 1-6 alkoxy, and fluorine; 
 A7 is C—R7 or N; A8 is C—R8 or N; and A9 is C—R9 or N; provided that at least one of A7, A8 and A9 is N, and no more than two of A7, A8 and A9 is N; 
 R7, R8, R9, R10 and R11 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, cyano and NR12R13, C 1-6 alkylsulfonyl, halogen and OR14, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkoxy is optionally substituted with one or more substituents selected from chlorine, fluorine, C 1-6 alkoxy, cyano and NR12R13; 
 R12 and R13 independently represent H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; 
 R14 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the others are C; 
 or R9 and R10 may be linked together to form a moiety of the formula: 
 
       
         
           
           
               
               
           
         
         wherein n is 1, 2 or 3. 
       
     
     
         18 . The compound of  claim 17 , of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 17 , of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 17 , wherein no more than one of A7, A8 and A9 is N. 
     
     
         21 . The compound of  claim 17 , wherein A7 is N, A8 is C—R8 and A9 is C—R9. 
     
     
         22 . The compound of  claim 17 , wherein A8 is N, A7 is C—R7 and A9 is C—R9. 
     
     
         23 . The compound of  claim 17 , wherein R7, R10 and R11 are H. 
     
     
         24 . The compound of  claim 17 , wherein R9 is selected from methyl, C 1-4 alkoxy and cyano, wherein said methyl is optionally substituted with C 1-4 alkoxy, or one or more fluorine. 
     
     
         25 . The compound of  claim 17 , selected from the group consisting of: IM24, IM25, IM26, IM27, IM28, IM29, IM30, IM31, IM32, IM33, IM34, IM35, IM36, IM37, IM38, IM39, IM40, IM41, IM42, IM43, IM44, and IM45. 
     
     
         26 . A method of making a compound of Formula (II) according to  claim 15 , the method comprising:
 (1) reacting a compound of the formula:   
       
         
           
           
               
               
           
         
         wherein R1, R2, R3, R4 and R5 are as defined in claim  1 ; 
         with ethyldiazoacetate, to afford a compound of the formula: 
       
       
         
           
           
               
               
           
         
         (2) hydrolyzing the product of (1) to afford the racemic compound of Formula (II). 
       
     
     
         27 . The method of  claim 26 , further comprising separating the enantiomers of the compound of Formula (II) by supercritical fluid chromatography (SFC). 
     
     
         28 . A method of making a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein A7, A8, A9, R10 and R11 are as defined in claim  3 , the method comprising: 
         (1) coupling an organometallic reactant derived from an aryl bromide of the formula: 
       
       
         
           
           
               
               
           
         
         with a sulfinyl imine of the formula: 
       
       
         
           
           
               
               
           
         
         wherein —SiTBS is tert-butyldimethylsilyl; 
         to afford diastereomers of formulae: 
       
       
         
           
           
               
               
           
         
         (2) separating and deprotecting the diastereomers under acidic conditions to afford the compound of formula: 
       
       
         
           
           
               
               
           
         
       
     
     
         29 . A method of making a compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R1, R2, R3, R4 and R5 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, cyano and halogen, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from chlorine and fluorine; 
         R6 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkoxy, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl is optionally substituted with one or more substituents independently selected from hydroxyl, C 1-6 alkoxy, and fluorine; 
         A7 is C—R7 or N; A8 is C—R8 or N; and A9 is C—R9 or N; provided that at least one of A7, A8 and A9 is N, and no more than two of A7, A8 and A9 is N; 
         R7, R8, R9, R10 and R11 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, cyano and NR12R13, C 1-6 alkylsulfonyl, halogen and OR14, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 alkoxy is optionally substituted with one or more substituents selected from chlorine, fluorine, C 1-6 alkoxy, cyano and NR12R13; 
         R12 and R13 independently represent H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl; 
         R14 represents a monocyclic saturated ring moiety having 4-6 ring atoms wherein one of said ring atoms is O and the others are C; 
         or R9 and R10 may be linked together to form a moiety of the formula: 
       
       
         
           
           
               
               
           
         
         wherein n is 1, 2 or 3; 
         the method comprising condensing a compound of Formula (II) according to  claim 16  with a compound of Formula (III) according  claim 17  to afford the compound of Formula (I), or a pharmaceutically acceptable salt thereof.