Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies

Abstract

The present application discloses compounds which are activators of autophagic flux and pharmaceutical compositions comprising said activators. It further discloses use of said compounds and pharmaceutical compositions in the treatment of neurodegenerative diseases, particularly proteinopathies and tauopathies such as Alzheimer's disease. It further discloses methods of enhancing autophagic flux.

What is claimed is: 
     
         1 . A compound having the formula (II): 
       
         
           
           
               
               
           
         
         wherein Y 1  and Y 2  are, independently selected from the group consisting of CH and wherein X is selected from the group consisting of H, halide, and aryl; 
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         3 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         4 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         5 . A compound having the formula (III): 
       
         
           
           
               
               
           
         
         wherein Y 1  is CH; 
         wherein Y 2  is N; 
         wherein X is halide; 
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         6 . The compound of  claim 5 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         7 . A compound having the formula (IV): 
       
         
           
           
               
               
           
         
         wherein X is halide; 
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         8 . The compound of  claim 7 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         9 . A compound having the formula (V): 
       
         
           
           
               
               
           
         
         wherein X is H; 
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         10 . The compound of  claim 9 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         11 . A compound having the formula (VI): 
       
         
           
           
               
               
           
         
         wherein X is H; 
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         12 . The compound of  claim 11 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         13 . A compound having the formula (VII): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         14 . The compound of  claim 13 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         15 . A compound having the formula (VIII): 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         16 . The compound of  claim 15 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         17 . A compound having the formula (IX): 
       
         
           
           
               
               
           
         
         wherein Y 3  is CH or N; 
         wherein R 2  is optionally substituted (2-aminoethyl)aryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         18 . The compound of  claim 17 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         19 . A compound having the formula (X): 
       
         
           
           
               
               
           
         
         wherein Y 3  is CH; 
         wherein R 2  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         20 . The compound of  claim 19 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         21 . A compound having the formula (XI): 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         22 . The compound of  claim 21 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         23 . A compound having the formula (XII): 
       
         
           
           
               
               
           
         
         wherein Y 4  is CH or N; 
         wherein R 3  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         24 . The compound of  claim 23 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         25 . A compound having the formula (XIII): 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         26 . The compound of  claim 25 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         27 . A compound having the formula (XIV): 
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, 
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         28 . The compound of  claim 27 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         29 . A compound having the formula (XV): 
       
         
           
           
               
               
           
         
         wherein X is H or halide; 
         wherein Z 1  is O; 
         wherein R 4  is selected from the group consisting of H, optionally substituted alkyl, Et, CF 3 , optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and 
       
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 29 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         31 . The compound of  claim 29  wherein the compound is: 
       
         
           
           
               
               
           
         
         or a salt, enantiomer, racemate, mixture thereof, or combination thereof. 
       
     
     
         32 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 31  or a pharmaceutically acceptable salt thereof. 
     
     
         33 . A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 31  or pharmaceutical composition of  claim 32 . 
     
     
         34 . The method of  claim 33 , wherein the neurodegenerative disease is a proteinopathy. 
     
     
         35 . The method of  claim 34 , wherein the proteinopathy is a tauopathy. 
     
     
         36 . The method of  claim 33 , wherein the neurodegenerative disease is Alzheimer's disease. 
     
     
         37 . A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of a compound of any one of  claims 1 - 31  or pharmaceutical composition of  claim 32 .