Hydantoins that modulate bace-mediated app processing

Abstract

In certain embodiments hydantoin compounds are provided herein that are effective to inhibit BACE activity against APP. Without being bound to a particular theory, it is believed the activity of the hydantoins identified herein appears to be associated with binding to BACE and/or to APP particularly when these moieties form a BACE/APP complex. Accordingly, it is believed the compounds described herein represent a new class of compounds designated herein as APP-Binding-BACE Inhibitors (ABBIs) and provide a new mechanism to modulate APP processing. The hydantoins described herein appear to show improved brain permeability and functional BACE inhibition.

1 . A compound according to the formula: 
       
         
           
           
               
               
           
         
         wherein 
         M is 
       
       
         
           
           
               
               
           
         
         R 7  is selected from the group consisting of C═O, C═S, C—NH 2 , and C═NH, and the bond represented by the wavy line is a single bond when R 7  is C═O, C═S, or C═NH, and a double bond when R 7  is C—NH 2 ; 
         R 8  and R 9  are independently selected from the group consisting of H, alkyl, cycloalkyl, and aryl, provided that when the bond represented by the wavy line is a double bond, then R 9  is absent; 
         R 0  is selected from the group consisting of aryl, substituted aryl, disubstituted aryl, heteroaryl, substituted heteroaryl, disubstituted heteroaryl, alkyl, haloalkyl, cycloalkyl, alkenyl, and alkynyl; 
         X 1  is selected from the group consisting of C-halogen, CH, and N; 
         A is methyl or H; 
         R 5  and R 6  are independently selected from halogen, H, alkyl, aryl, trichloromethyl, and trifluoromethyl; 
         R 3  and R 4  are independently absent or selected from the group consisting of alkyl, cycloalkyl, alkoxy, thioalky; and 
         when X 1  is C, then R 0  is not phenyl monosubstituted at the para position with —OCHF 2 , 
         or a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of a tautomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt of an enantiomer thereof. 
       
     
     
         2 .- 126 . (canceled)