Heteroaryl compounds and uses thereof

Abstract

Described herein are compounds of formula (I), and pharmaceutically acceptable salts, solvates, hydrates, isotopically labeled derivatives and radiolabeled derivative thereof, and pharmaceutical compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for detecting and imaging Tau aggregates in the brain for detection of Alzheimer's disease (AD) in a subject.

1 .- 15 . (canceled) 
     
     
         16 . A method of Tau imaging, the method comprising the steps of:
 (a) administering to a subject an effective amount of a heteroaryl compound having a structure of formula (I),   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative or a radiolabeled derivative thereof; and 
         (b) imaging the brain of the subject; 
         wherein, 
         the structural unit 
       
       
         
           
           
               
               
           
         
          is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         
           wherein in Formula I-(c), U is O and Z is N; or U is S and Z is CH; 
           R a  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
            H, OH, halogen, C 1-3  alkyl, C 1-3  alkoxy, NH 2 , C 1-3  alkylamino and C 1-6  alkoxycarbonyl; wherein said C 1-3  alkyl, said C 1-3  alkoxy, said C 1-3  alkylamino, and said C 1-6  alkoxycarbonyl are optionally substituted by OH, halogen, C 2-6  heterocycloalkyloxy or toluenesulfonyloxy; and 
           R b  is selected from the group consisting of 
         
       
       
         
           
           
               
               
           
         
         
            H, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 1-3  alkylcarbonyl, benzyl, and benzoyl; wherein said C 1-6  alkyl, said C 1-6  alkoxycarbonyl, and said C 1-3  alkylcarbonyl are optionally substituted by halogen, OH, C 1-3  alkoxy, C 2-6  heterocycloalkyloxy or toluenesulfonyloxy; 
         
         Q is CH or N; 
         X is CH or N; 
         Y is CR 6  or N; 
         R 6  is selected from the group consisting of H, NH 2  and C 1-6  alkoxy; wherein said NH 2  and said C 1-6  alkoxy are optionally mono-substituted by C 1-3  alkyl and/or halogen; 
         J is CH or N; 
         K is CH or N; and 
         provided that X and Y are not N simultaneously, and J and Y are not N simultaneously; 
         R′ is halogen, OH, C 1-6  alkyl, or C 1-6  alkoxy; 
         R″ is Br, I, OH, NH 2 , 
       
       
         
           
           
               
               
           
         
         ethoxy, 
       
       
         
           
           
               
               
           
         
          C 1-6  alkylamino or C 3-6  heterocycloalkyl; wherein said C 1-6  alkylamino and said C 3-6  heterocycloalkyl are optionally substituted by a substituent selected from the group consisting of oxo, OH, halogen, C 3-6  cycloalkyl, C 1-4  alkoxy carbonyl, C 3-6  heterocycloalkyloxy, toluenesulfonyloxy and phenyl optionally substituted by OH and/or C 1-3  alkoxy; 
         m is 0, 1, 2; and 
         n is 0, 1, or 2; 
         provided that: 
         when Y is N or CH, then n is 1 or 2; and 
         when Y is CR 6 , wherein R 6  is NH 2  or C 1-6  alkoxy; and NH 2  and C 1-6  alkoxy is optionally mono-substituted by C 1-3  alkyl and/or halogen, then n is 0. 
       
     
     
         17 . The method according to  claim 16 , wherein the moiety of 
       
         
           
           
               
               
           
         
       
       is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein R′ is H or F. 
     
     
         18 . The method according to  claim 16 , wherein the compound is of the structure of formula (II), 
       
         
           
           
               
               
           
         
         wherein X is CH or N; and Y is CH or N, provided that X and Y are not N simultaneously; 
         R a  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          H, halogen, C 1-3  alkyl, C 1-3  alkoxy, NH 2 , C 1-3  alkylamino and C 1-6  alkoxycarbonyl; wherein said C 1-3  alkyl, said C 1-3  alkoxy, said C 1-3  alkylamino and said C 1-6  alkoxycarbonyl are optionally substituted by OH, halogen, C 3-6  heterocycloalkyloxy or toluenesulfonyloxy; and 
         R b  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
          H, C 1-6  alkyl, C 1-6  alkoxycarbonyl, C 1-3  alkylcarbonyl, benzyl, and benzoyl; wherein said C 1-6  alkyl, said C 1-6  alkoxycarbonyl, and said C 1-3  alkylcarbonyl are optionally substituted by halogen, OH, C 1-3  alkoxy, C 3-6  heterocycloalkyloxy or toluenesulfonyloxy. 
       
     
     
         19 . The method according to  claim 18 , wherein:
 (i) in formula I-(a):
 R b  is 
   
       
         
           
           
               
               
           
         
         
            H, C 1-3  alkyl, C 1-4  alkoxycarbonyl, C 1-3  alkylcarbonyl, benzyl or benzoyl; wherein said C 1-3  alkyl, said C 1-4  alkoxycarbonyl, and said C 1-3  alkylcarbonyl are optionally substituted by F, Cl, OH, C 1-3  alkoxy, C 3-5  heterocycloalkyloxy or toluenesulfonyloxy; and 
         
         (ii) in formula I-(c):
 Z is CH, and U is S; and/or 
 R a  is selected from the group consisting of 
 
       
       
         
           
           
               
               
           
         
         
            H, OH, F, Cl, methyl, ethyl, methoxy, ethoxy, n-propoxy, NH 2 , N-methylamino, N-ethylamino, N-n-propylamino, N,N-dimethylamino, methylethylamino, methoxycarbonyl and tert-butoxy carbonyl; wherein said methyl, said ethyl, said methoxy, said ethoxy, said n-propoxy, said N-methylamino, said N-ethylamino, said N-n-propylamino, said N,N-dimethylamino, said methylethylamino, said methoxycarbonyl and said tert-butoxy carbonyl are optionally substituted by OH, F, Cl, C 3-5  heterocycloalkyloxy or toluenesulfonyloxy. 
         
       
     
     
         20 . The method according to  claim 18 , wherein,
 R a  is H, F, OH, NH 2 , methoxy, ethoxy,   
       
         
           
           
               
               
           
         
          and 
         R b  is H, methyl, 
       
       
         
           
           
               
               
           
         
       
     
     
         21 . The method according to  claim 16 , wherein:
 R′ is F, OH, methyl or methoxy;   and/or, R″ is OH, NH 2 , methyl,   
       
         
           
           
               
               
           
         
          ethoxy, 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The method according to  claim 16 , wherein the structural unit 
       
         
           
           
               
               
           
         
       
       is of Formula I-(e); and R a  is 
       
         
           
           
               
               
           
         
       
     
     
         23 . A method of Tau imaging, the method comprising the steps of:
 (a) administering to a subject an effective amount of a heteroaryl compound; and   (b) imaging the brain of the subject;   wherein the heteroaryl compound is selected from the group consisting of   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotopically labeled derivative, or a radiolabeled derivative thereof.