Novel modulators of nrf2 and uses thereof

Abstract

There is provided modulators of Nrf2 protein which comprises a compound which binds at least one of the BTB domain, IVR domain and Kelch domain of Keap1 protein, activating or inhibiting Nrf2. There is also provided pharmaceutical compositions containing the modulators, as well as uses and method of use of the modulators for the treatment of conditions.

1 . A modulator of a Nrf2 protein comprising a compound which binds at least one of a BTB domain, an IVR domain and a Kelch domain of a Keap1 protein,
 wherein
 said BTB domain has an amino acid sequence as set forth in SEQ ID NO:2, 
 said IVR domain has an amino acid sequence as set forth in SEQ ID NO:3, and 
 said Kelch domain has an amino acid sequence as set forth in SEQ ID NO:4, and 
   wherein said modulator restores, enhances, reduces or impairs protein-protein interactions among said Keap1 protein and at least one of said Nrf2 protein and a Cul3 protein, for inhibiting or activating the activity of Nrf2; and   wherein said compound is a compound of formula:   
       
         
           
           
               
               
           
         
         wherein
 R 17 , R 18 , R 19 , and R 20  are independently chosen or identical, and are chosen from hydrogen, halide, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, alkyloxide, substituted alkyloxide, halogenated alkyl, halogenated alkenyl, halogenated alkyloxide, halogenated substituted alkyloxide, amine, substituted amine, cycloalkyl, substituted cycloalkyl, 
 heterocyclic aromatic or non-aromatic 5- to 10-membered ring containing 1-4 heteroatoms selected from N, O or S, wherein N and S can be oxidized and N can be quaternized, 
 ═O, CH 3 , OCH 3 , OC 2 H 5 , NO 2 , CN, F, Cl, Br, SH, CF 3 , OCF 3 , O(CF 2 ) 2 H, NH 2 , N (CH 3 ) 2 , N (C 2 H 4 OH) 2 , CH(OC 2 H 5 ) 2 , 
 
       
       
         
           
           
               
               
           
         
         wherein   indicates an attachment point, and 
         R′ is chosen from hydrogen, halide, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, alkyloxide, substituted alkyloxide, halogenated alkyl, halogenated alkenyl, halogenated alkyloxide, halogenated substituted alkyloxide, amine, substituted amine, cycloalkyl, substituted cycloalkyl, 
         heterocyclic aromatic or non-aromatic 5- to 10-membered ring containing 1-4 heteroatoms selected from N, O or S, wherein N and S can be oxidized and N can be quaternized, 
         ═O, CH 3 , OCH 3 , OC 2 H 5 , NO 2 , CN, F, Cl, Br, SH, CF 3 , OCF 3 , O(CF 2 ) 2 H, NH 2 , N (CH 3 ) 2 , N(C 2 H 4 OH) 2 , CH(OC 2 H 5 ) 2 , 
       
       
         
           
           
               
               
           
         
         wherein   is a single bond or a double bond; 
       
       with the proviso that
 R 17  is different than O, S, NYZ, wherein Y and Z is H, a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl, 
 R 19  is different than 
 
       
         
           
           
               
               
           
         
       
       wherein X is O, N, or S, and Y is H, a C 1 -C 10  alkyl group, alkenyl, vinyl, aryl, or heteroaryl, 
       and 
       pharmaceutically acceptable salt, racemic mixture, enantiomer, diastereoisomer, isomer, and tautomer thereof. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The modulator according to  claim 1 , wherein said compound of formula (III) is: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The modulator according to  claim 1 , wherein said compound of formula (III) is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The modulator according to  claim 1 , wherein said compound of formula (III) is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The modulator according to  claim 1 , wherein said compound of formula (III) are: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (III) according to  claim 1 , in association with a pharmaceutically acceptable carrier. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 .- 26 . (canceled) 
     
     
         27 . A method for preventing or treating a disease which involves the abnormal activation and or expression level of a Nrf2 protein in a patient in need thereof, and/or the abnormal inhibition of a Nrf2 protein, the method comprising administering a therapeutically effective amount of a compound of formula as defined in  claim 1 . 
     
     
         28 . (canceled) 
     
     
         29 . The method according to  claim 27 , wherein said disease is an oxidative stress associated disease chosen from Parkinson's disease, Parkinson's disease with dementia with Lewy body, Huntington's disease, multiple system atrophy (MSA), progressive supranuclear palsy (PSA), corticobasal degeneration (CBD), frontotemporal lobe degeneration, atherosclerosis, heart failure, myocardial infarction, Alzheimer's disease, Fragile X syndrome, and chronic fatigue. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 27 , wherein said disease is a cancer. 
     
     
         32 . (canceled) 
     
     
         33 . The method as claimed in  claim 31 , wherein said cancer is liver cancer, lung cancer, breast cancer, prostate cancer, colon cancer, neuroblastoma or leukemia. 
     
     
         34 . The method of  claim 27 , wherein said administering is for effecting neuroprotection.