Deubiquitinase Inhibitors and Methods for Use of the Same

Abstract

Disclosed herein are methods of inhibiting a deubiquitinase (DUB), methods of treating pathogenic infections (e.g., viral, bacterial, and/or parasitic), methods of inhibiting cell proliferation, methods of treating a neurodegenerative disease, methods of treating one or more symptoms of a neurodegenerative disease or a genetic disorder, and compounds.

1 . A compound having a formula (II), (IIa) or (III): 
       
         
           
           
               
               
           
         
         each R 1  is selected from the group consisting of H, amido, substituted amido, halide, —(CH 2 ) m R 9 , 
         —NH(CH 2 ) m R 9 , —NHC(O)(CH 2 ) m R 9 , —C(O)NH(CH 2 ) m R 9  and —O(CH 2 ) m R 9  and cannot each be hydrogen for the compound of formula (II);
 X is fluoro or chloro; 
 R 2  is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, 
 Het is heteroaryl or substituted heteroaryl excluding 2-pyridyl; 
 R 9  is amino, substituted amino, hydroxy, alkoxy, substituted alkoxy, cycloheteroalkyl, or substituted cycloheteroalkyl; and 
 m is 2, 3, or 4, 
 
         or salt thereof; 
         wherein the compound excludes a compound having a structure of 
       
       
         
           
           
               
               
           
         
       
     
     
         2 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein Het is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a substituted moiety thereof. 
     
     
         7 - 14 . (canceled) 
     
     
         15 . A method of inhibiting proliferation in a cell comprising contacting the cell with a compound of  claim 1  in an amount to inhibit proliferation. 
     
     
         16 - 20 . (canceled) 
     
     
         21 . A method of inhibiting a deubiquitinase (Dub) comprising contacting a DUB with a compound of formula (I) or salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 the dashed line indicates an optional double bond; 
 R 3  is aminoalkylenearyl or substituted aminoalkylenearyl; 
 R 4  is selected from the group consisting of CN, amino, substituted amino, amido, substituted amido, alkylenethioether, substituted alkylenethioether, alkyl, substituted alkyl, azide, alkyleneazide, or substituted alkyleneazide; 
 R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylenearyl, substituted alkylenearyl, thioether, substituted thioether, amino, substituted amino, halide, hydroxy, nitro, and SH; and 
 R 6  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkenyl, substituted heterocycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenearyl, substituted alkylenearyl, alkyleneheteroaryl, substituted alkyleneheteroaryl, alkylenheterocycloalkenyl, substituted alkyleneheterocycloalkenyl, alkyleneheterocycloalkyl, and substituted alkyleneheterocycloalkyl. 
 
     
     
         22 . A method of inhibiting a pathogenic infection in a cell comprising contacting a pathogen or the cell with a compound of formula (I) or salt thereof; 
       
         
           
           
               
               
           
         
       
       wherein
 the dashed line indicates an optional double bond; 
 R 3  is aminoalkylenearyl or substituted aminoalkylenearyl; 
 R 4  is selected from the group consisting of CN, amino, substituted amino, amido, substituted amido, alkylenethioether, substituted alkylenethioether, alkyl, substituted alkyl, azide, alkyleneazide, or substituted alkyleneazide; 
 R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylenearyl, substituted alkylenearyl, thioether, substituted thioether, amino, substituted amino, halide, hydroxy, nitro, and SH; and 
 R 6  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkenyl, substituted heterocycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenearyl, substituted alkylenearyl, alkyleneheteroaryl, substituted alkyleneheteroaryl, alkylenheterocycloalkenyl, substituted alkyleneheterocycloalkenyl, alkyleneheterocycloalkyl, and substituted alkyleneheterocycloalkyl. 
 
     
     
         23 - 60 . (canceled) 
     
     
         61 . A method of treating one or more symptoms associated with a neurodegenerative disease comprising administering a compound to a subject in need thereof, the compound having a structure: 
       
         
           
           
               
               
           
         
       
       wherein
 the dashed line indicates an optional double bond; 
 R 3  is aminoalkylenearyl or substituted aminoalkylenearyl; 
 R 4  is selected from the group consisting of CN, amino, substituted amino, amido, substituted amido, alkylenethioether, substituted alkylenethioether, alkyl, substituted alkyl, azide, alkyleneazide, or substituted alkyleneazide; 
 R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylenearyl, substituted alkylenearyl, thioether, substituted thioether, amino, substituted amino, halide, hydroxy, nitro, and SH; and 
 R 6  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkenyl, substituted heterocycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenearyl, substituted alkylenearyl, alkyleneheteroaryl, substituted alkyleneheteroaryl, alkylenheterocycloalkenyl, substituted alkyleneheterocycloalkenyl, alkyleneheterocycloalkyl, and substituted alkyleneheterocycloalkyl. 
 
     
     
         62 . A method of treating one or more symptoms associated with a genetic disease comprising administering a compound to a subject in need thereof, the compound having a structure: 
       
         
           
           
               
               
           
         
       
       wherein
 the dashed line indicates an optional double bond; 
 R 3  is aminoalkylenearyl or substituted aminoalkylenearyl; 
 R 4  is selected from the group consisting of CN, amino, substituted amino, amido, substituted amido, alkylenethioether, substituted alkylenethioether, alkyl, substituted alkyl, azide, alkyleneazide, or substituted alkyleneazide; 
 R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, alkylenearyl, substituted alkylenearyl, thioether, substituted thioether, amino, substituted amino, halide, hydroxy, nitro, and SH; and 
 R 6  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkenyl, substituted heterocycloalkenyl, heterocycloalkyl, substituted heterocycloalkyl, alkylenearyl, substituted alkylenearyl, alkyleneheteroaryl, substituted alkyleneheteroaryl, alkylenheterocycloalkenyl, substituted alkyleneheterocycloalkenyl, alkyleneheterocycloalkyl, and substituted alkyleneheterocycloalkyl. 
 
     
     
         63 - 79 . (canceled)