Compounds for degrading tau protein aggregates and uses thereof

Abstract

Disclosed herein are novel compounds for degrading Tau protein aggregates, pharmaceutical acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof. Also disclosed herein are uses of the compounds, pharmaceutical acceptable salts, enantiomers, non-enantiomers, tautomers, racemates, solvates, metabolic precursors, or prodrugs thereof in manufacture a medicament for treating a tauopathy, as well as method for aiding in the treatment of a tauopathy or treating a tauopathy in a subject.

1 .- 57 . (canceled) 
     
     
         58 . A method of aiding in the treatment of tauopathy or treating tauopathy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of Formula I to Formula VI, 
       
         
           
           
               
               
           
         
       
       or, a pharmaceutical acceptable salt, an enantiomer, a tautomer, a racemate thereof; wherein,
 L 1  is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; 
 L 2  is a substituted or unsubstituted C 1-50  hydrocarbon chain, wherein one or more chain atoms of the C 1-50  hydrocarbon chain are independently replaced with —C(═O)—, —O—, —NR a1 — —S— or a cyclic moiety, wherein R a1  is independently hydrogen, substituted or unsubstituted C 1-6  alkyl or a nitrogen protecting group; 
 Z is C or N; U is O, S or CH; 
 K is CH or N; Q is CH or N; where K and Q are not N at the same time; 
 each occurrence of R′″ is independently selected from the group consisting of H, OH, NH 2 , C 1-6  alkyl, C 1-6  alkylamino, C 1-6  alkoxy and halogen; k is 0, 1, 2 or 3; 
 each occurrence of R′ is independently selected from the group consisting of H, halogen, OH, C 1-6  alkyl, C 1-6  haloalkyl and C 1-6  alkoxy; m is 0, 1, 2, 3 or 4; 
 each occurrence of R″ is independently selected from the group consisting of H, halo, OH, NH 2 , C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  alkylamino, C 3-6  cycloalkylamino, C 3-6  cycloalkyl and C 3-6  heterocycloalkyl; n is 0, 1 or 2; 
 J is CR 6  or N; X is CR 6  or N; Y is CR 6  or N; where at least one of J, X and Y is N, but J and Y are not N at the same time, X and Y are not N at the same time; 
 R 6  is independently selected from the group consisting of H, NH 2 , C 1-6  alkyl and C 1-6  alkoxy, wherein NH 2 , C 1-6  alkyl or C 1-6  alkoxy is optionally substituted by 1 to 3 of C 1-3  alkyl, C 3-6  cycloalkyl and/or halo; 
 in Formula I, L 3  is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3′  is H or C 1-6  alkyl; Y 1  is CH 2  or 
 
       
         
           
           
               
               
           
         
       
       V is N, where Z and U are not heteratoms at the same time; 
       in Formula II, each occurrence of R 2′  is independently selected from the group consisting of H, OH, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1  is CH 2  or 
       
         
           
           
               
               
           
         
       
       V is N, where Z and U are not heteratoms at the same time; 
       in Formula III, V is N, where Z and U are not heteratoms at the same time; 
       in Formula IV, L 3  is a bond, —NR—, —O—, or —S—, wherein R is hydrogen, optionally substituted acyl, optionally substituted alkyl or a nitrogen protecting group; R 3′  is H or C 1-6  alkyl; Y 1  is CH 2  or 
       
         
           
           
               
               
           
         
       
       V is N or NH; T is CH or N; where up to two of U, Z, V and T contain heteroatoms; 
       in Formula V, each occurrence of R 2′  is independently selected from the group consisting of H, OH, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylamino and NH 2 ; m6 is 0, 1, 2, 3 or 4; Y 1  is CH 2  or 
       
         
           
           
               
               
           
         
       
       V is N or NH; T is CH or N; where up to two of U, Z, V and T contain heteroatoms; in Formula VI, V is N; T is CH or N; where up to two of U, Z, V and T contain heteroatoms. 
     
     
         59 . The method of  claim 58 , wherein L 2  is an optionally substituted C 1-45  hydrocarbon chain. 
     
     
         60 . The method of  claim 58 , wherein L 2  is selected from the group consisting of substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, or substituted or unsubstituted heteroalkylene, and combinations thereof, wherein one or more chain atoms of the substituted groups are independently replaced with —C(═O)—, —O—, —NR a1 —, —S— or a cyclic moiety, wherein R a1  is independently hydrogen, substituted or unsubstituted C 1-6  alkyl or a nitrogen protecting group. 
     
     
         61 . The method of  claim 58 , wherein L 2  comprises at least one instance selected from the group consisting of substituted or unsubstituted C 1-6  alkylene, substituted or unsubstituted C 2-6  alkenylene, substituted or unsubstituted C 2-6  alkynylene, substituted or unsubstituted heteroC 1-6 alkylene, substituted or unsubstituted heteroC 2-6 alkenylene, substituted or unsubstituted heteroC 2-6 alkynylene, substituted or unsubstituted C 3-6 carbocyclylene, substituted or unsubstituted 3-6 membered heterocyclylene, substituted or unsubstituted phenylene, and substituted or unsubstituted 5- to 6-membered heteroarylene, wherein one or more chain atoms of the substituted groups are independently replaced with —C(═O)—, —O—, —NR a1 —, —S— or a cyclic moiety, wherein R a1  is independently hydrogen, substituted or unsubstituted C 1-6  alkyl or a nitrogen protecting group. 
     
     
         62 . The method of  claim 58 , wherein L 2  comprises at least one instance selected from the group consisting of substituted or unsubstituted methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, —(CH 2 ) 2 —O(CH 2 ) 2 —, —OCH 2 —, —O(CH 2 ) 2 —, —O(CH 2 ) 3 —, —O(CH 2 ) 4 —, —O(CH 2 ) 5 —, —O(CH 2 ) 6 —, and —NH—C(═O)—. 
     
     
         63 . The method of  claim 60 , wherein at least one chain atom of the hydrocarbon chain of L 2  is independently replaced with a 6-membered heterocyclyl group with 1-3 ring heteroatoms selected from the group consisting of nitrogen and oxygen. 
     
     
         64 . The method of  claim 58 , wherein L 2  is 
       
         
           
           
               
               
           
         
       
       wherein g is 1, 2, 3, 4, 5, or 6. 
     
     
         65 . The method of  claim 58 , wherein L 2  includes the moiety —O—, 
       
         
           
           
               
               
           
         
       
       —NHC(═O)— or —NH—. 
     
     
         66 . The method of  claim 58 , wherein L 2  is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein g is 1, 2, 3, 4, 5, or 6; f is 1, 2, 3, 4, 5, or 6, and h is 1, 2, 3, 4, 5, or 6. 
     
     
         67 . The method of  claim 58 , wherein the compound of Formula I is of Formula I-1; 
       
         
           
           
               
               
           
         
       
     
     
         68 . The method of  claim 58 , wherein the compound of Formula II is of Formula II-1; 
       
         
           
           
               
               
           
         
       
     
     
         69 . The method of  claim 58 , wherein the compound of Formula III is of Formula III-1; 
       
         
           
           
               
               
           
         
       
     
     
         70 . The method of  claim 58 , wherein the compound of Formula IV is of Formula IV-1; 
       
         
           
           
               
               
           
         
       
     
     
         71 . The method of  claim 58 , wherein the compound of Formula V is of Formula V-1; 
       
         
           
           
               
               
           
         
       
     
     
         72 . The method of  claim 58 , wherein the compound of Formula VI is of Formula VI-1; 
       
         
           
           
               
               
           
         
       
     
     
         73 . The method of  claim 70 , wherein the compound is of Formula 2, 7, 9, 11, 12 or 14; 
       
         
           
           
               
               
           
         
       
     
     
         74 . The method of  claim 73 , wherein the compound is of Formula 2, and wherein R 3′  is H or C 1-3  alkyl; and/or, A is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1′  is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, R″ is H, halo, OH, NH 2 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  alkylamino, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 3-5  heterocycloalkyl; and/or, R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R′″ is H, OH, NH 2 , C 1-3  alkyl, C 1-3  alkylamino, C 1-3  alkoxy or halogen. 
     
     
         75 . The method of  claim 73 , wherein the compound is of Formula 7, and wherein R 3′  is H or C 1-3  alkyl; and/or, A is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1′  is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, R″ is H, halo, OH, NH 2 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  alkylamino, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 3-5  heterocycloalkyl; and/or, R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; and/or, m is 0, 1, 2 or 3. 
     
     
         76 . The method of  claim 73 , wherein the compound is of Formula 9, and wherein R 3′  is H or C 1-3  alkyl; and/or, A is O, 
       
         
           
           
               
               
           
         
       
       and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1′  is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, R″ is H, halo, OH, NH 2 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  alkylamino, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 3-5  heterocycloalkyl; and/or, R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R′″ is H, OH, NH 2 , C 1-3  alkyl, C 1-3  alkylamino, C 1-3  alkoxy or halogen. 
     
     
         77 . The method of  claim 73 , wherein the compound is of Formula 11, and wherein R 3′  is H or C 1-3  alkyl; and/or, A is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, m2 is 2, 3, 4, 5 or 6; and/or, R 1′  is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, R″ is H, halo, OH, NH 2 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  alkylamino, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 3-5  heterocycloalkyl; and/or, R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; and/or, m is 0, 1, 2 or 3; and/or, R′″ is H, OH, NH 2 , C 1-3  alkyl, C 1-3  alkylamino, C 1-3  alkoxy or halogen. 
     
     
         78 . The method of  claim 73 , wherein the compound is of Formula 12, and wherein R 3′  is H or C 1-3  alkyl; A is O, NH, 
       
         
           
           
               
               
           
         
       
       m3 is 1, 2, 3, 4, 5 or 6; m4 is 0 or 1, 2 or 3; m5 is 0 or 1, 2 or 3; R 1′  is O, NH, 
       
         
           
           
               
               
           
         
       
       R″ is H, halo, OH, NH 2 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  alkylamino, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 3-5  heterocycloalkyl; R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; m is 0, 1, 2 or 3; R′″ is H, OH, NH 2 , C 1-3  alkyl, C 1-3  alkylamino, C 1-3  alkoxy or halogen. 
     
     
         79 . The method of  claim 73 , wherein the compound is of Formula 14, and wherein R 3′  is H or C 1-3  alkyl; and/or, A is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, m3 is 1, 2, 3, 4, 5 or 6; and/or, m4 is 0, 1, 2, 3 or 4; and/or, m5 is 0 or 1, 2 or 3; and/or, R′″ is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, R″ is H, halo, OH, NH 2 , C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  alkylamino, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 3-5  heterocycloalkyl; and/or, R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; m is 0, 1, 2 or 3; and/or, R′″ is H, OH, NH 2 , C 1-3  alkyl, C 1-3  alkylamino, C 1-3  alkoxy or halogen. 
     
     
         80 . The method of  claim 71 , wherein the compound is of Formula 4; 
       
         
           
           
               
               
           
         
       
     
     
         81 . The method of  claim 80 , wherein R 2′  is H, OH, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  alkylamino or NH 2 ; and/or, m6 is 0, 1, 2 or 3; and/or, R′ is O, NH, 
       
         
           
           
               
               
           
         
       
       and/or, R′ is H, halogen, OH, C 1-3  alkyl, C 1-3  haloalkyl or C 1-3  alkoxy; R″ is H, halo, OH, NH 2 , C 1-3  alkoxy, C 3-5  cycloalkyl, C 3-5  cycloalkylamino or C 1-3  alkylamino; and/or, R′″ is H, OH, NH 2 , C 1-3  alkyl, C 1-3  alkylamino, C 1-3  alkoxy or halogen. 
     
     
         82 . The method of  claim 80 , wherein the compound is of Formula 4-1; 
       
         
           
           
               
               
           
         
       
     
     
         83 . The method of  claim 72 , wherein the compound is of Formula 16 or 17; 
       
         
           
           
               
               
           
         
       
     
     
         84 . The method of  claim 83 , wherein the compound is of Formula 16, and wherein Z is C, U is O or S and T is CH; or, Z is N, U is CH and T is CH; Z is C, T is N and U is CH. 
     
     
         85 . The method of  claim 83 , wherein the compound is of Formula 17, and wherein Z is C, U is O or S and T is CH; or, Z is N, U is CH and T is CH; Z is C, T is N and U is CH. 
     
     
         86 . The method of  claim 58 , wherein the compound is selected from a group consisting of: