Compounds for inhibiting nlrp3 and uses thereof

Abstract

The present disclosure relates to inhibitors of NLRP3 useful in the treatment of diseases and disorders inhibited by said protein and having the Formula (I):

1 .- 30 . (canceled) 
     
     
         31 . A compound of formula (II-h): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:
 each R 2a  is independently hydrogen, deuterium, or halogen; 
 R 1  is C 1 -C 6  alkyl, —(CH 2 ) n —(C 3 -C 10  cycloalkyl), —(CH 2 ) n —(C 6 -C 10  aryl), —(CH 2 ) n -(3- to 8-membered heterocycloalkyl), or —(CH 2 ) n -(5- to 9-membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more halo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 6 -C 10  aryl , —R 4 OR 5  or —NR 5 R 6 ; and 
 Y is C 6 -C 10  aryl, wherein the aryl is optionally substituted with one or more halo, —CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, cycloalkyl, or —R 4 OR 5 ; 
 R 4  is a bond, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
 each R 5  and R 6  are independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 3 -C 8  cycloalkyl, 3- to 8-membered heterocycloalkyl, C 6 -C 10  aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; and 
 n is an integer from 0 to 4. 
 
     
     
         32 . The compound of  claim 31 , wherein R 1  is C 1 -C 6  alkyl optionally substituted with one or more halo, CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 6 -C 10  aryl, —NR 4 R 5 , or —R 4 OR 5 . 
     
     
         33 . The compound of  claim 32 , wherein R 1  is C 1 -C 6  alkyl optionally substituted with one or more CN, C 1 -C 6  alkyl, or —R 4 OR 5 . 
     
     
         34 . The compound of  claim 31 , wherein each R 2a  is independently hydrogen or deuterium. 
     
     
         35 . The compound of  claim 31 , wherein at least one R 2a  is halogen. 
     
     
         36 . The compound of  claim 31 , wherein R 1  is —(CH 2 ) n -(3- to 8-membered heterocycloalkyl), wherein the 3- to 8-membered heterocycloalkyl is substituted with one or more halo. 
     
     
         37 . The compound of  claim 31 , wherein n is 0. 
     
     
         38 . The compound of  claim 31 , wherein n is 1. 
     
     
         39 . The compound of  claim 31 , wherein R 1  is —(CH 2 ) n —(C 3 -C 10  cycloalkyl) substituted with one or more halo, C 1 -C 6  alkyl, or —R 4 OR 5 . 
     
     
         40 . The compound of  claim 31 , wherein Y is C 6 -C 10  aryl substituted with one or more halo, C 1 -C 6  alkyl, or —R 4 OR 5 . 
     
     
         41 . The compound of  claim 31 , wherein Y is phenyl substituted with one or more halo. 
     
     
         42 . The compound of  claim 31 , selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof. 
     
     
         43 . A pharmaceutical composition comprising a compound of  claim 31 , and a pharmaceutically acceptable carrier. 
     
     
         44 . A pharmaceutical composition comprising a compound of  claim 42 , and a pharmaceutically acceptable carrier. 
     
     
         45 . A method of treating or preventing an NLRP3-related disease or disorder, comprising administering to the subject the compound of  claim 31 . 
     
     
         46 . The method of  claim 45 , wherein the NLRP3-related disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3. 
     
     
         47 . A method of treating or preventing an NLRP3-related disease or disorder, comprising administering to the subject, the compound of  claim 42 . 
     
     
         48 . The method of  claim 47 , wherein the NLRP3-related disease or disorder is inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an ocular disease, a skin disease, a lymphatic disease, a rheumatic disease, a psychological disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that has been determined to carry a germline or somatic non-silent mutation in NLRP3.