Small molecule modulators of the btb domain of keap1

Abstract

The present application relates to compounds of formula (I′) or formula (I), such as formula (Ia), and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington disease (HD) and other CAG-triplet repeat (or polyglutamine) diseases, amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), diffuse Lewy body disease, chorea-acanthocytosis, primary lateral sclerosis, multiple sclerosis (MS), frontotemporal dementia, Friedreich's ataxia, acute head injury, and epilepsy (repression of microglia activation).

1 .- 77 . (canceled) 
     
     
         78 . A method of treating an inflammatory disorder in a subject, comprising administering to a subject in need thereof an effective amount of at least one compound of formula (I′) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is selected from —C(O)— and —S(O) 2 —; 
 R 1  and R 2  each independently is selected from H and C 1-6  alkyl; or R 1  and R 2  taken together with the carbon to which they are attached form a spirocycloalkyl ring; 
 R 3  is selected from hydroxyl and optionally substituted alkoxy; 
 R 4  is selected from phenyl, pyridinyl, isoquinolinyl, pyrazinyl, thiophenyl, and thiazolyl; and 
 wherein R 4  is optionally substituted with one or more R 5 ; and 
 R 5 , independently for each occurrence, is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted pyrimidinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, and optionally substituted triazolopyridinyl, wherein the inflammatory disorder is chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis. 
 
     
     
         79 . The method of  claim 78 , wherein X is —C(O)—. 
     
     
         80 . The method of  claim 78 , wherein R 4  is pyridinyl optionally substituted with one or more R 5 . 
     
     
         81 . The method of  claim 78 , wherein:
 R 4  is substituted with one or more R 5 ;   R 5 , independently for each occurrence, is optionally substituted with one or more R 6 ; and   R 6 , independently for each occurrence, is selected from halogen, CN, oxo, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl.   
     
     
         82 . The method of  claim 78 , wherein R 6 , independently for each occurrence, is selected from halogen, CN, oxo, alkyl, alkoxy, alkylsulfonyl, and cycloalkyl. 
     
     
         83 . The method of  claim 78 , wherein the compound of formula (I′), or a pharmaceutically acceptable salt thereof, is a compound of formula (Ia) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  and R 2  each independently is selected from C 1-6  alkyl; or R 1  and R 2  taken together with the carbon to which they are attached form a spirocycloalkyl ring; 
 R 3  is selected from hydroxyl and optionally substituted alkoxy; 
 R 5 , independently for each occurrence, is selected from halogen, CN, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkylsulfonyl, optionally substituted alkoxyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted aryl, and optionally substituted heteroaryl; and 
 p is selected from 0, 1, 2, 3, and 4. 
 
     
     
         84 . The method of  claim 83 , wherein p is selected from 1 and 2. 
     
     
         85 . The method of  claim 83 , wherein R 5 , independently for each occurrence, is selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkenyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally substituted thiazolyl, optionally substituted imidazolyl, optionally substituted pyrimidinyl, optionally substituted isoxazolyl, optionally substituted isothiazolyl, and optionally substituted triazolopyridinyl. 
     
     
         86 . The method of  claim 83 , wherein p is 2, and wherein one occurrence of R 5  is —F and the other occurrence of R 5  is —CH(F) 2 . 
     
     
         87 . The method of  claim 78 , wherein the compound of formula (I′), or a pharmaceutically acceptable salt thereof, is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         88 . The method of  claim 78 , wherein the compound of formula (I′), or a pharmaceutically acceptable salt thereof, is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         89 . The method of  claim 78 , wherein the compound of formula (I′), or a pharmaceutically acceptable salt thereof, is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         90 . The method of  claim 78 , wherein the compound of formula (I′), or a pharmaceutically acceptable salt thereof, is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         91 . The method of  claim 78 , wherein the inflammatory disorder is chronic obstructive pulmonary disease (COPD). 
     
     
         92 . The method of  claim 78 , wherein the inflammatory disorder is idiopathic pulmonary fibrosis.