Alpha-7 NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AND USES THEROF-I

Abstract

The present invention relates to chemical compounds of formula (I), with the substituents as described in the specification, useful in the positive modulation of the alpha 7 nicotinic acetylcholine receptor (α7 nAChR). The invention also relates to the use of these compounds in the treatment or prevention of a broad range of diseases in which the positive modulation of α7 nAChR is advantageous, including neurodegenerative and neuropsychiatric diseases and also neuropathic pain and inflammatory diseases.

1 ) A compound of formula (I) or salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from optionally substituted aryl, optionally substituted benzyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; 
 R 2  is selected from hydrogen, C 1 -C 4  alkyl, F, Cl, CN, phenyl or C 1 -C 4  haloalkyl; 
 R 3  is selected from hydrogen, C 1 -C 4  alkyl, F, Cl, CN, or C 1 -C 4  haloalkyl; or 
 R 2  and R 3  together form C 4 -C 9  cycloalkyl or C 4 -C 9  cycloalkenyl; 
 R 4  is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; 
 R 5  is selected from hydrogen or C 1 -C 4  alkyl; 
 R 6 -R 8  are independently selected from halogen or hydrogen; and 
 n is 1-3, 
 wherein when R 2  and R 3  are hydrogen, and n is 1, R 1  is not (1) phenyl or phenyl substituted with cyclohexyl, heterocyclyl, F or OCH 3 ; or (2) optionally substituted heteroaryl. 
 
     
     
         2 ) A compound according to  claim 1  or a salt thereof wherein R 1  is selected from: optionally substituted benzyl; a optionally substituted aryl; optionally substituted heteroaryl; or optionally substituted heterocyclyl. 
     
     
         3 . (canceled) 
     
     
         4 ) A compound according to  claim 1  represented by formula (Ia) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1a  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH 2 ), —C(O)NR′R′, —NR′S(O) 2 NR′R′, —NR′—S(O) 2 R′, —NR′C(O)R′, —S(O) 2 —NR′R′ and —NR′R′ (where each R′ is independently selected from hydrogen, lower alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, heteroaryl, —OH, or NH 2 ), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl), and —S(O) 2 R′″ (where R′″ is lower alkyl, or cycloalkyl); 
 each R 1b  is independently —H, cyano, halo, nitro, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted C 3-7  cycloalkyl, —P═O(OH)(NH 2 ), —OR, —C(O)R, —C(O)OR, —OC(O)R (where R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, and optionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″, —S(O) 2 —NR′R″ and —NR′R″ (where R′ and R″ are independently selected from hydrogen or lower alkyl), —S(O)R′″ (where R′″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH), or any two adjacent R 1b  or R 1a  and R 1b  together form heterocyclyl or heteroaryl; 
 z is 4; 
 R 2  is selected from hydrogen, C 1-4  alkyl, F, Cl, CN, phenyl or C 1 -C 4  haloalkyl; 
 R 3  is selected from hydrogen, C 1 -C 4  alkyl, F, Cl, CN, or C 1 -C 4  haloalkyl; or 
 R 2  and R 3  together form C 4 -C 9  cycloalkyl or C 4 -C 9  cycloalkenyl; 
 R 4  is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; 
 R 5  is selected from hydrogen or C 1 -C 4  alkyl; 
 R 6 -R 8  are independently selected from halogen or hydrogen; and 
 n is 1-3. 
 
     
     
         5 - 8 . (canceled) 
     
     
         9 ) A compound according to  claim 1  represented by formula (Ib) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from optionally substituted aryl, optionally substituted benzyl, optionally substituted heteroaryl or optionally substituted heterocyclyl; 
 R 2  and R 3  together form C 4 -C 9  cycloalkyl; 
 R 4  is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; 
 R 5  is selected from hydrogen or C 1 -C 4  alkyl; 
 R 6 -R 8  are independently selected from halogen or hydrogen; and 
 n is 1-3. 
 
     
     
         10 . (canceled) 
     
     
         11 ) A compound according to  claim 9  or a salt thereof wherein R 1  is a phenyl group substituted with R 1a , wherein R 1a  is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH 2 ), —C(O)NR′R′, —NR′S(O) 2 NR′R′, —NR′—S(O) 2 R′, —NR′C(O)R′, —S(O) 2 —NR′R′ and —NR′R′ (where each R′ is independently selected from hydrogen, lower alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, heteroaryl, —OH, or NH 2 ), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl), and —S(O) 2 R′″ (where R′″ is lower alkyl, or cycloalkyl). 
     
     
         12 . (canceled) 
     
     
         13 ) A compound according to  claim 1  represented by formula (Ic) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from optionally substituted aryl, optionally substituted benzyl, optionally substituted heteroaryl or optionally substituted heterocyclyl; 
 R 2  and R 3  each independently represent C 1 -C 3  alkyl; 
 R 4  is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; 
 R 5  is selected from hydrogen or C 1 -C 4  alkyl; 
 R 6 -R 8  are independently selected from halogen or hydrogen; and 
 n is 1-3. 
 
     
     
         14 - 16 . (canceled) 
     
     
         17 ) A compound according to  claim 1  represented by formula (I′), or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from optionally substituted aryl, optionally substituted benzyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; 
 R 2  is selected from C 1 -C 4  alkyl, F, Cl, phenyl or C 1 -C 4  haloalkyl; 
 R 3  is selected from hydrogen, C 1 -C 4  alkyl, F, Cl, CN, or C 1 -C 4  haloalkyl; or 
 R 2  and R 3  together form C 4 -C 8  cycloalkyl or C 4 -C 9  cycloalkenyl; 
 R 4  is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; 
 R 5  is selected from hydrogen or C 1 -C 4  alkyl; and 
 n is 1-3. 
 
     
     
         18 - 21 . (canceled) 
     
     
         22 ) A compound according to  claim 1  wherein R 4  is an optionally substituted heteroaryl or optionally substituted aryl and R 5  is —H or —CH 3 . 
     
     
         23 . (canceled) 
     
     
         24 ) A compound according to  claim 22  wherein R 4  is selected from: 
       
         
           
           
               
               
           
         
       
       (a) 
       wherein Hal is a halogen;
 p is 0, 1 or 2; and 
 each R 9  is independently selected from halogen, CN, NO 2 , haloalkyl, aryl, heteroaryl, C 1-3  alkoxy, C 1-3  haloalkoxy, C 1-3  alkyl, or CO 2 R′ (where R′ is a lower alkyl or H); 
 
       or 
       
         
           
           
               
               
           
         
       
       (b) 
       wherein Hal is a halogen;
 p is 0, 1 or 2; and 
 each R 9  is independently selected from halogen, CN, NO 2 , haloalkyl, aryl, heteroaryl, C 1-3  alkoxy, C 1-3  haloalkoxy, C 1-3  alkyl, or CO 2 R′ (where R′ is a lower alkyl or H); 
 
       or 
       (c) a heteroaryl substituted from 1 to 3 times from a group selected from C 1 -C 3  alkyl, C 1-6  alkoxy, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-3  haloalkoxy, —OH, phenyl, benzyl, phenoxy, benzyloxy, benzoyl, —NH 2 , —NHC 1-4  alkyl, —N(C 1-4  alkyl) 2 , —CN, —NO 2 , mercapto, C 1-6  alkylcarbonyl, C 1-6  alkoxycarbonyl, CO 2 H, —S(O)R′″ (where R′″ is lower alkyl or cycloalkyl) and —S(O) 2 R′″ (where R′″ is lower alkyl, cycloalkyl or OH). 
     
     
         25 ) A compound according to  claim 1  represented by formula (Ia′), or a salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each R 1a  is independently selected from the group consisting of optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, optionally substituted heterocyclyl, —P═O(OH)(NH 2 ), —C(O)NR′R′, —NR′S(O) 2 NR′R′, —NR′—S(O) 2 R′, —NR′C(O)R′, —S(O) 2 —NR′R′ and —NR′R′ (where each R′ is independently selected from hydrogen, lower alkyl, C 3 -C 7 cycloalkyl, heterocyclyl, heteroaryl, —OH, or NH 2 ), —S(O)R″ (where R″ is lower alkyl, or cycloalkyl), —S(O) 2 R′″ (where R′″ is lower alkyl, or cycloalkyl), or any two adjacent R 1a  together form heterocyclyl or heteroaryl; 
 m is 0-5; 
 R 2  is selected from C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, phenyl, F, or Cl; 
 R 3  is selected from hydrogen, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, F, Cl, or CN; or 
 R 2  and R 3  together form C 4-9  cycloalkyl or C 4-9  cycloalkenyl; 
 R 4  is selected from optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted aryl; 
 R 5  is independently selected from hydrogen, or C 1 -C 4  alkyl; and 
 n is 1-3. 
 
     
     
         26 - 28 . (canceled) 
     
     
         29 ) A compound according to  claim 25  or a salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
       wherein one of Hal is —H and the other is a halogen;
 p is 0, 1, 2, or 3; and 
 each R 9  is independently selected from halogen, CN, NO 2 , haloalkyl, aryl, heteroaryl, C 1-6  alkoxy, C 1-3  haloalkoxy, C 1-3  alkyl, or CO 2 R′ (where R′ is a lower alkyl or H). 
 
     
     
         30 . (canceled) 
     
     
         31 ) A compound according to  claim 25  or a salt thereof, wherein m is 1 and R 1a  is selected from:
 —S(O) 2 R′″ (where R′″ is lower alkyl, or cycloalkyl), 
 —S(O) 2 NR′R″ (where R′ is hydrogen and R″ is selected from hydrogen, lower alkyl, —OH, or NH 2 ), 
 lower alkyl, substituted 1 or 2 times with a substituent group selected from CF 3  and NH 2 , 
 lower haloalkyl, 
 optionally substituted heterocyclyl (preferably 4 or 5-membered heterocyclyl), 
 —NR′S(O) 2 NR′R′ (where each R′ is independently selected from hydrogen or lower alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, or heteroaryl), or 
 —NR′—S(O) 2 R′ (where each R′ is independently selected from hydrogen or lower alkyl, C 3 -C 7  cycloalkyl, heterocyclyl, or heteroaryl). 
 
     
     
         32 ) A compound according to  claim 31  or a salt thereof, wherein R 1a  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         33 - 34 . (canceled) 
     
     
         35 ) A compound according to  claim 25  or 
       a salt thereof, wherein 
       
         
           
           
               
               
           
         
       
     
     
         36 ) (canceled) 
     
     
         37 ) A compound according to  claim 1  or a salt thereof, represented by the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       an enantiomerically pure single trans-enantiomer or a mixture of trans-isomers of any thereof. 
     
     
         38 - 40 . (canceled) 
     
     
         41 ) A compound according to  claim 1  or a salt thereof, wherein the compound is present as: (i) a mixture of cis-isomers; (ii) a mixture of trans-isomers; or (iii) an enantiomerically pure single trans-enantiomer. 
     
     
         42 . (canceled) 
     
     
         43 ) A pharmaceutical composition that comprises a therapeutically effective amount of one or more compound of  claim 1  or pharmaceutically acceptable salts or pharmaceutically acceptable derivatives thereof, and optionally a pharmaceutically acceptable carrier or diluent. 
     
     
         44 ) A method for: (i) ameliorating treating or preventing cognitive deficits associated with neurodegenerative and neuropsychiatric diseases; (ii) preventing or treating neurodegenerative or neuropsychiatric disorders; (iii) treatment or prevention of inflammatory diseases; or (iv) treatment or prevention of neuropathic pain, said method comprising administering a therapeutically effective amount of one or more positive allosteric modulators of α7 nAChRs compounds of  claim 1 , or a salt or pharmaceutically acceptable derivative thereof. 
     
     
         45 - 49 . (canceled) 
     
     
         50 ) A process for preparing a compound of formula (I) or salt thereof 
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 6  are as defined in  claim 1 , R 7  and R 8  are H, and n is 1, said process comprising the step of reducing a compound of formula (II) 
       
         
           
           
               
               
           
         
       
     
     
         51 . (canceled) 
     
     
         52 ) A process according to  claim 50  wherein said compound of Formula II is reduced by contact with a borane tetrahydrofuran complex. 
     
     
         53 ) A process for preparing a compound of formula (I) or salt thereof 
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 6  are as defined in  claim 1 , R 7  and R 8  are H, and n is 1 or 2, said process comprising the step of reacting a compound of formula (III), (IV) or (V) 
       
         
           
           
               
               
           
         
       
       with an amine of formula NHR 5 R 4 .