Amino-5-(6-membered)heteroarylimidazolone compounds and the use thereof for beta-secretase modulation

Abstract

The present invention provides a 2-amino-5-heteroaryl-5-phenylimidazolone compound of formula I The present invention also provides methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles

1 - 9 . (canceled) 
     
     
         10 . A method for the treatment of a disease or disorder associated with excessive BACE activity in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein W is CO, CS or CH 2 ;
 X is N, NO, or CR; 
 Y is N, NO, or CR 10 ; 
 Z is N, NO, or CR 11  with the proviso that at least one of X, Y or Z must be N or NO; 
 R 1  and R 2  are each independently H, COR 34 , CO 2 R 12  or an optionally substituted C 1 -C 4 alkyl group; 
 R 3  is H, OR 13  or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl or aryl(C 1 -C 6 )alkyl group each optionally substituted; 
 R 4  and R 5  are each independently H, halogen, NO 2 , CN, OR 14 , CO 2 R 15 , COR 16 , NR 17 R 18 , SO p NR 19 R 20  or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted; 
 R 6  is H, halogen, NO 2 , CN, OR 21 , NR 22 R 23  or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted; 
 R 7  is H, halogen, NO 2 , CN, OR 24 , NR 25 R 26  or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, aryl or heteroaryl group each optionally substituted; 
 R, R 8 , R 9  and R 10  are each independently H, halogen, NO 2 , CN, OR 27 , CO 2 R 28 , COR 29 , NR 3 OR 31 , SO p NR 32 R 33  or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 8 cycloalkyl group each optionally substituted; 
 R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 21 , R 24 , R 27 , R 28  and R 29  are each independently H or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, cycloheteroalkyl or aryl group each optionally substituted; 
 R 17 , R 18 , R 19 , R 20 , R 22 , R 23 , R 25 , R 26 , R 30 , R 31 , R 32  and R 33  are each independently H, COR 34 , SO p R 35  or a C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8  cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted or R 17 , R 18 ; or R 19 , R 20 , or R 22 , R 23 , or R 25 , R 26 , or R 30 , R 31 , or R 32 , R 33  may be taken together with the atom to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; 
 R 34  is H, or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; and 
 R 35  is a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted; or 
 
       a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 10  wherein said disease or disorder is selected from the group consisting of: Alzheimer's disease; cognitive impairment; Down's Syndrome; HCHWA-D; cognitive decline; senile dementia; cerebral amyloid angiopathy; and a neurodegenerative disorder. 
     
     
         12 . The method according to  claim 10  wherein said disease or disorder is characterized by the production of β-amyloid deposits or neurofibrillary tangles. 
     
     
         13 . A method for modulating the activity of BACE which comprises contacting a receptor thereof with an effective amount of a compound of formula I of  claim 10 . 
     
     
         14 . A method for the treatment of Alzheimer's disease in a patient in need thereof which comprises providing to said patient an effective amount of a compound of formula I of  claim 10 . 
     
     
         15 - 20 . (canceled)