Tricyclic proteasome activity enhancing compounds

Abstract

Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.

1 . A method of treating cancer or a prion disease in a subject in need thereof comprising administering to the subject an effective amount of a compound represented by formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof; wherein, independently for each occurrence, 
         W is 
       
       
         
           
           
               
               
           
         
       
       or N-heterocyclyl;
 Z 1  is 
 
       
         
           
           
               
               
           
         
         Z 2  is 
       
       
         
           
           
               
               
           
         
         Z 3  is 
       
       
         
           
           
               
               
           
         
         Y is 
       
       
         
           
           
               
               
           
         
         X is 
       
       
         
           
           
               
               
           
         
         R 1  is alkyl, substituted alkyl, cycloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, sulfonyl, sulfinyl or —(CH 2 ) m R 6 ; 
         R 2  is alkyl, substituted alkyl, cycloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, sulfonyl, sulfinyl or —(CH 2 ) m R 6 ; 
         each R 3  is independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, sulfhydryl, alkylthio, haloalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, alkenyl sulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy or —(CH 2 ) m R 7 ; 
         R 4  is cycloalkylalkyl, heterocyclylalkyl, aralkyl or heteroaralkyl; 
         each R 5a  is independently hydrogen, halo, lower alkyl or lower haloalkyl; 
         each R 5b  is independently hydrogen, halo, lower alkyl or lower haloalkyl; 
         R 6  is alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, sulfonyl or sulfinyl; 
         R 7  is alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, sulfhydryl, alkylthio, haloalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, alkenyl sulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl or silyloxy; 
         n is 0, 1 or 2; and 
         each m is independently 1, 2, 3 or 4. 
       
     
     
         2 . The method of  claim 1 , wherein W is 
       
         
           
           
               
               
           
         
       
     
     
         3 . The method of  claim 2 , wherein R 1  is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl or alkylcarbonyl. 
     
     
         4 . The method of  claim 2 , wherein R 1  is alkyl. 
     
     
         5 .- 7 . (canceled) 
     
     
         8 . The method of  claim 2 , wherein R 2  is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, aralkyl or heteroaralkyl. 
     
     
         9 .- 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein W is N-heterocyclyl. 
     
     
         13 .- 14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein Z 1  is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein Z 2  is 
       
         
           
           
               
               
           
         
       
     
     
         17 .- 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein Z 3  is 
       
         
           
           
               
               
           
         
       
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein each R 3  is independently hydrogen, halo, lower alkyl, lower haloalkyl, cyano, lower alkyloxy, lower haloalkoxy or amino. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
       
     
     
         24 .- 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
         and R 4  is cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroaralkyl. 
       
     
     
         27 .- 29 . (canceled) 
     
     
         30 . The method of  claim 1 , wherein Y is 
       
         
           
           
               
               
           
         
         and R 4  is benzyl substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, hydroxy, alkoxy, alkenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, sulfhydryl, alkylthio, haloalkylthio, alkenylthio, alkynylthio, sulfonic acid, alkylsulfonyl, haloalkylsulfonyl, alkenyl sulfonyl, alkynylsulfonyl, alkoxysulfonyl, haloalkoxysulfonyl, alkenyloxysulfonyl, alkynyloxysulfonyl, aminosulfonyl, sulfinic acid, alkylsulfinyl, haloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny, aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy, haloalkoxysulfonyloxy, alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy, haloalkylsulfinyloxy, alkenylsulfinyloxy, alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy, alkenyloxysulfinyloxy, alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido, aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl, phosphoryl, silyl, silyloxy or —(CH 2 ) m R 7 . 
       
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 1 , wherein n is 1. 
     
     
         36 . A method of treating cancer or a prion disease in a subject in need thereof comprising administering to the subject an effective amount of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof. 
       
     
     
         37 .- 40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the method is a method of treating a prion disease; and the prion disease is selected from the group consisting of bovine spongiform encephalopathy, kuru, Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. 
     
     
         42 .- 46 . (canceled) 
     
     
         47 . The method of  claim 1 , wherein said subject is human. 
     
     
         48 . The method of  claim 1 , wherein the method is a method of treating cancer; and the cancer is medullary thyroid carcinoma. 
     
     
         49 . The method of  claim 36 , wherein the method is a method of treating a prion disease; and the prion disease is selected from the group consisting of bovine spongiform encephalopathy, kuru, Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia. 
     
     
         50 . The method of  claim 36 , wherein the method is a method of treating cancer; and the cancer is medullary thyroid carcinoma. 
     
     
         51 . The method of  claim 36 , wherein said subject is human.