Imidazole Amines As Inhibitors Of Beta-secretase

Abstract

The present invention provides a compound of formula I and the use thereof for the therapeutic treatment, prevention or amelioration of a disease or disorder characterized by elevated 3-amyloid deposits or 3-amyloid levels in a patient.

1 . A compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       Q is O, S or CH 2 ; 
       W is O, S or CH 2 ; 
       X is N, NO, SO m , O or CH; 
       Y is N, NO, SO m , O or CR 10 ; 
       Z is N, NO, SO m , O or CR 11  with the proviso that when X is CH, Y is CR 10  and Z is CR 11  then one of Q or W must be O or S; 
       m is 0, 1 or 2; 
       n is 0 or 1; 
       R 1  and R 2  are each independently H or an optionally substituted C 1 -C 4 alkyl group; 
       R 3  and R 4  are each independently H, or an optionally substituted C 1 -C 4  alkyl group or R 3  and R 4  may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 12 , CO 2 R 13 , COR 14 , 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 7  and R 8  are each independently H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  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 cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R 7  and R 8  may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 9  is H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  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; 
       R 10  and R 11  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 12 , R 13 , R 14  and R 15  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, aryl or heteroaryl group each optionally substituted; 
       R 17 , R 18 , R 19  and R 20  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 17  and R 18  or R 19  and R 20  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and 
       p is 0, 1 or 2; or 
     
     a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
   
   
       2 . The compound according to  claim 1  wherein R 1  and R 2  are H. 
   
   
       3 . The compound according to  claim 1  wherein R 9  is an optionally substituted heteroaryl group. 
   
   
       4 . The compound according to  claim 1  wherein X is N. 
   
   
       5 . The compound according to  claim 1  wherein R 3  and R 4  are H. 
   
   
       6 . The compound according to  claim 2  wherein R 9  is an optionally substituted heteroaryl group and R 9  is attached to the phenyl ring in the 3-position of the phenyl ring. 
   
   
       7 . The compound according to  claim 6  wherein X is N. 
   
   
       8 . The compound according to  claim 7  wherein R 3  and R 4  are H. 
   
   
       9 . The compound according to  claim 1  selected from the group consisting essentially of:
 8-[3-(2-fluoropyridin-3-yl)-phenyl]-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-(2,6-diethylpyridin-4-yl)-8-[3-(2-fluoropyridin-3-yl)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-(1-ethyl-1H-pyrazol-4-yl)-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;   8-[3-(5-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;   a tautomer thereof;   a stereoisomer thereof; and   a pharmaceutically acceptable salt thereof.   
   
   
       10 . A method for the treatment, prevention or amelioration of a disease or disorder characterized by elevated [3-amyloid deposits or [3-amyloid levels in a patient which comprises providing said patient with a therapeutically effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       Q is O, S or CH 2 ; 
       W is O, S or CH 2 ; 
       X is N, NO, SO m , O or CH; 
       Y is N, NO, SO m , O or CR 10 ; 
       Z is N, NO, SO m , O or CR 11  with the proviso that when X is CH, Y is CR 10  and Z is CR 11  then one of Q or W must be O or S; 
       m is 0, 1 or 2; 
       n is 0 or 1; 
       R 1  and R 2  are each independently H or an optionally substituted C 1 -C 4 alkyl group; 
       R 3  and R 4  are each independently H, or an optionally substituted C 1 -C 4  alkyl group or R 3  and R 4  may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 12 , CO 2 R 13 , COR 14 , 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 7  and R 8  are each independently H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  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 cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R 7  and R 8  may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 9  is H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  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; 
       R 10  and R 11  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 12 , R 13 , R 14  and R 15  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, aryl or heteroaryl group each optionally substituted; 
       R 17 , R 18 , R 19  and R 20  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 17  and R 18  or R 19  and R 20  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and 
       p is 0, 1 or 2; 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 [3-amyloid deposits or neurofibrillary tangles. 
   
   
       13 . A method for inhibiting the activity of BACE which comprises contacting a receptor thereof with an effective amount of a compound of  claim 1 . 
   
   
       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  claim 1 . 
   
   
       15 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I 
     
       
         
         
             
             
         
       
       wherein 
       Q is O, S or CH 2 ; 
       W is O, S or CH 2 ; 
       X is N, NO, SO m , O or CH; 
       Y is N, NO, SO m , O or CR 10 ; 
       Z is N, NO, SO m , O or CR 11  with the proviso that when X is CH, Y is CR 10  and Z is CR 11  then one of Q or W must be O or S; 
       m is 0, 1 or 2; 
       n is 0 or 1; 
       R 1  and R 2  are each independently H or an optionally substituted C 1 -C 4 alkyl group; 
       R 3  and R 4  are each independently H, or an optionally substituted C 1 -C 4  alkyl group or R 3  and R 4  may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 12 , CO 2 R 13 , COR 14 , 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 7  and R 8  are each independently H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  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 cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R 7  and R 8  may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 9  is H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  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; 
       R 10  and R 11  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 12 , R 13 , R 14  and R 15  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, aryl or heteroaryl group each optionally substituted; 
       R 17 , R 18 , R 19  and R 20  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 17  and R 18  or R 19  and R 20  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and 
       p is 0, 1 or 2; or 
     
     a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
   
   
       16 . The composition according to  claim 15  having a formula I compound wherein R 1  and R 2  are H. 
   
   
       17 . The composition according to  claim 16  having a formula I compound wherein X is N and R 3  and R 4  are H. 
   
   
       18 . The composition according to  claim 17  having a formula I compound wherein R 9  is an optionally substituted heteroaryl group and is attached to the phenyl ring in the 3-position of the phenyl ring. 
   
   
       19 . The composition according to  claim 15  having a formula I compound selected from the group consisting essentially of:
 8-[3-(2-fluoropyridin-3-yl)-phenyl]-8-pyridin-4-yl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-(2,6-diethylpyridin-4-yl)-8-[3-(2-fluoropyridin-3-yl)-phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-(1-ethyl-1H-pyrazol-4-yl)-8-[3-(2-fluoropyridin-3-yl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine;   8-[3-(2-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;   8-[3-(5-fluoropyridin-3-yl)phenyl]-8-[4-(trifluoromethoxy)phenyl]-3,4-dihydro-8H-imidazo[5,1-c][1,2,4]oxadiazin-6-amine;   a tautomer thereof;   a stereoisomer thereof; and   a pharmaceutically acceptable salt thereof.   
   
   
       20 . A process for the preparation of a compound of formula Ia 
     
       
         
         
             
             
         
       
       wherein 
       Q is O, S or CH 2 ; 
       W is O, S or CH 2 ; 
       X is N, NO, SO m , O or CH; 
       Y is N, NO, SO m , O or CR 10 ; 
       Z is N, NO, SO m , O or CR 11  with the proviso that when X is CH, Y is CR 10  and Z is CR 11  then one of Q or W must be O or S; 
       m is 0, 1 or 2; 
       n is 0 or 1; 
       R 1  and R 2  are each independently H or an optionally substituted C 1 -C 4 alkyl group; 
       R 3  and R 4  are each independently H, or an optionally substituted C 1 -C 4  alkyl group or R 3  and R 4  may be taken together to form a 4- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 12 , CO 2 R 13 , COR 14 , 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 7  and R 8  are each independently H, halogen, NO 2 , CN, OR 15 , NR 17 R 18  or a C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, 0 2 -0 6 alkynyl, C 3 -C 8 cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R 7  and R 8  may be taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S; 
       R 9  is an optionally substituted aryl or heteroaryl group; 
       R 10  and R 11  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 12 , R 13 , R 14  and R 15  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, aryl or heteroaryl group each optionally substituted; 
       R 17 , R 18 , R 19  and R 20  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 17  and R 18  or R 19  and R 20  may be taken together with the atom to which they are attached to form a 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S; and 
       p is 0, 1 or 2 
     
     which process comprises reacting a compound of formula II 
     
       
         
         
             
             
         
       
     
     wherein Hal is Cl or Br and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n, O, W, X, Y and Z are as described for formula la hereinabove with an optionally substituted aryl or heteroaryl group having a leaving group selected from B(OH) 2 , Sn(nBu) 3  or Sn(CH 3 ) 3  in the presence of a palladium catalyst optionally in the presence of a solvent.