Inhibitors of microbially induced amyloid

Abstract

The present disclosure provides compounds useful for the prevention of amyloid formation and the treatment of amyloid related disorders, including synucleopathics such as Parkinson's Disease.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 L 1  is a bond or —N(R 5 )(C═O)—; 
 L 2  is —(C═O)— or —(C═O)O—; 
 G 1  is —N(R 5 ) 2  or R 6 ; 
 G 2  is —H, —N(R 5 ) 2  or —N(R 5 )(R 6 ); 
 R 5  is independently, for each occurrence, —H or C 1-6  alkyl; 
 R 6  is aryl substituted with n instances of R 7 ; 
 R 7  is independently, for each occurrence, —F, —OH or —O(C 1-6  alkyl); and 
 n is 0, 1, 2, or 3; 
 provided that the compound does not have the structure: 
 
       
         
           
           
               
               
           
         
       
     
     
         2 . The compound of  claim 1 , wherein Formula (I) is of Formula (I-a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
 G 1  is R 6 ;   G 2  is —NH 2  or —N(R 5 )(R 6 );   R 5  is —H or —CH 3 ;   R 6  is phenyl substituted with n instances of R 7 ;   R 7  is independently, for each occurrence, —F, —OH or —OCH 3 ;   n is 0, 1, 2, or 3;   provided that:
 (a) the compound comprises at least one instance of R 6 ; and/or 
 (b) the compound comprises at least three instances of R 7 . 
   
     
     
         4 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein R 5  is —CH 3 . 
     
     
         5 . The compound of  claim 1 , wherein Formula (I) is of Formula (I-b): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein G 1  is R 6 . 
     
     
         7 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein G 2  is —NH 2 . 
     
     
         8 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein G 2  is —N(R 5 )(R 6 ). 
     
     
         9 . The compound of  claim 5 , wherein Formula (I-b) is of Formula (I-b-1) or Formula (I-b-2): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein each R 7  is independently selected from —OH and —OCH 3 . 
     
     
         11 . The compound or pharmaceutically acceptable salt of  claim 1 , having 3-5 instances of R 7 . 
     
     
         12 . The compound or pharmaceutically acceptable salt of  claim 1 , wherein each R 6  is independently selected from: 
       
         
           
           
               
               
           
         
       
       wherein each R 6  is independently selected from: 
       
         
           
           
               
               
           
         
       
     
     
         13 - 14 . (canceled) 
     
     
         15 . The compound  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         16 - 35 . (canceled) 
     
     
         36 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         37 - 43 . (canceled) 
     
     
         44 . A method for inhibiting amyloid formation in a subject in need thereof, comprising administering to the subject a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method for preventing or treating an amyloid disorder in a subject in need thereof, comprising administering to the subject a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The method of  claim 45 , wherein the amyloid disorder is a neurological disorder, intestinal dysbiosis, intestinal hyperpermeability, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis or Crohn's disease. 
     
     
         47 . The method of  claim 45 , wherein the amyloid disorder is Parkinson's disease (PD), Lewy body dementia, multiple system atrophy, α-synucleinopathy, PD-associated constipation, PD-associated hyposmia, Huntington's Disease, Alexander's Disease, amyotrophic lateral sclerosis (ALS), or Alzheimer's Disease. 
     
     
         48 - 56 . (canceled) 
     
     
         57 . A method of disrupting and/or inhibiting the formation of amyloid aggregates comprising contacting amyloid or a precursor of amyloid with a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         58 . A method of disrupting the formation of amyloid aggregates in a subject in need thereof, comprising:
 administering to said subject a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof.   
     
     
         59 - 77 . (canceled)