DIPHENYLIMIDAZOLYL COMPOUNDS 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 β-amyloid deposits or β-amyloid levels in a patient.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein X is N, NO or CR 19 ;
 Y is N, NO or CR 11 ; 
 Z is N, NO or CR 20  with the proviso that no more than two of X, Y or Z may be N or NO; 
 R 1  and R 2  are each independently H, CN 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 3- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S or R 3  may be taken together with the atom to which it is attached and an adjacent carbon atom to form a double bond; 
 R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15  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 or when attached to adjacent carbon atoms R 5  and R 6  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 7 , R 8 , R 9 , R 10 , R 11 , R 19  and R 20  are each independently H, halogen, NO 2 , CN, OR 16 , 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 or C 3 -C 8  cycloalkyl group each optionally substituted; 
 m is 0 or 1; 
 n is 0, 2 or 3;   is a single bond or a double bond with the proviso that when m is 0 then   must be a single bond; 
 R 12 , R 13  and R 16  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 or aryl group each optionally substituted; and 
 R 14 , R 15 , R 17  and R 18  are each independently H or C 1 -C 4 alkyl; 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 m and n are 1. 
     
     
         4 . The compound according to  claim 1  having the structure Ia 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 4  having the structure Ib 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound according to  claim 5  wherein R 1  and R 2  are H. 
     
     
         7 . The compound according to  claim 6  wherein X is N. 
     
     
         8 . The compound according to  claim 7  wherein n is 0 or 2. 
     
     
         9 . The compound according to  claim 1  selected from the group consisting of:
 7-[(3-(Pyrimidin-5-yl)phenyl]-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine;   7-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-7-(4-trifluoromethoxy-phenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;   9-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-9-(4-trifluoromethoxy-phenyl)-2,4,5,9-tetrahydro-3H-imidazo[1,5-a][1,3]diazepin-7-ylamine;   1-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-1-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-2,3a,9-triaza-cyclopentacycloocten-3-ylamine; and   7-[3-(2-Fluoropyridin-3-yl)phenyl]-2,2-dimethyl-7-(4-trifluoromethoxyphenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;   a tautomer thereof; or   a pharmaceutically acceptable salt thereof   
     
     
         10 . A method for the treatment, prevention or amelioration of a disease or disorder characterized by elevated β-amyloid deposits or β-amyloid levels in a patient which comprises providing said patient with a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein X is N, NO or CR 19 ;
 Y is N, NO or CR 11 ; 
 Z is N, NO or CR 20  with the proviso that no more than two of X, Y or Z may be N or NO; 
 R 1  and R 2  are each independently H, CN 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 3- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S or R 3  may be taken together with the atom to which it is attached and an adjacent carbon atom to form a double bond; 
 R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15  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 or when attached to adjacent carbon atoms R 5  and R 6  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 7 , R 8 , R 9 , R 10 , R 11 , R 19  and R 20  are each independently H, halogen, NO 2 , CN, OR 16 , 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 or C 3 -C 8  cycloalkyl group each optionally substituted; 
 m is 0 or 1; 
 n is 0, 2 or 3; 
    is a single bond or a double bond with the proviso that when m is 0 then   must be a single bonds 
 R 12 , R 13  and R 16  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 or aryl group each optionally substituted; and 
 R 14 , R 15 , R 17  and R 18  are each independently H or C 1 -C 4  alkyl; or 
 
       a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 10  having a formula I compound wherein the structure is Ia 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 11  having a formula I compound wherein the structure is Ib 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method according to  claim 12  wherein said disease or disorder is selected from the group consisting of Alzheimer's disease; mild cognitive impairment; Down's syndrome; hereditary cerebral hemorrhage with amyloidosis of the Dutch type; cerebral amyloid angiopathy; and degenerative dementia. 
     
     
         14 . The method according to  claim 13  wherein said disease is Alzheimer's disease. 
     
     
         15 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein X is N, NO or CR 19 ;
 Y is N, NO or CR 11 ; 
 Z is N, NO or CR 20  with the proviso that no more than two of X, Y or Z may be N or NO; 
 R 1  and R 2  are each independently H, CN 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 3- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S or R 3  may be taken together with the atom to which it is attached and an adjacent carbon atom to form a double bond; 
 R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15  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 or when attached to adjacent carbon atoms R 5  and R 6  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 7 , R 8 , R 9 , R 10 , R 11 , R 19  and R 20  are each independently H, halogen, NO 2 , CN, OR 16 , 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 or C 3 -C 8  cycloalkyl group each optionally substituted; 
 m is 0 or 1; 
 n is 0, 2 or 3; 
    is a single bond or a double bond with the proviso that when m is 0 then   must be a single bond, 
 R 12 , R 13  and R 16  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 or aryl group each optionally substituted; and 
 R 14 , R 15 , R 17  and R 18  are each independently H or C 1 -C 4 alkyl; 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 the structure is Ia 
       
         
           
           
               
               
           
         
       
     
     
         17 . The composition according to  claim 16  having a formula I compound wherein the structure is Ib 
       
         
           
           
               
               
           
         
       
     
     
         18 . The composition according to  claim 17  wherein R 1  and R 2  are H and Y is CR 11 . 
     
     
         19 . The composition according to  claim 15  having a formula I compound selected from the group consisting of:
 7-[(3-(Pyrimidin-5-yl)phenyl]-7-[4-(trifluoromethoxy)phenyl]-7H-imidazo[1,5-a]imidazol-5-ylamine;   7-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-7-(4-trifluoromethoxy-phenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;   9-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-9-(4-trifluoromethoxy-phenyl)-2,4,5,9-tetrahydro-3H-imidazo[1,5-a][1,3]diazepin-7-ylamine;   1-[3-(2-Fluoro-pyridin-3-yl)-phenyl]-1-(4-trifluoromethoxy-phenyl)-1,4,5,6,7,8-hexahydro-2,3a,9-triaza-cyclopentacycloocten-3-ylamine; and   7-[3-(2-Fluoropyridin-3-yl)phenyl]-2,2-dimethyl-7-(4-trifluoromethoxyphenyl)-2,7-dihydro-3H-imidazo[1,5-a]imidazol-5-ylamine;   a tautomer thereof; or   a pharmaceutically acceptable salt thereof.   
     
     
         20 . A process for the preparation of a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein X is N, NO or CR 19 ;
 Y is N, NO or CR 11 ; 
 Z is N, NO or CR 20  with the proviso that no more than two of X, Y or Z may be N or NO; 
 R 1  and R 2  are each independently H, CN 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 3- to 7-membered ring optionally containing one or two heteroatoms selected from O, N or S or R 3  may be taken together with the atom to which it is attached and an adjacent carbon atom to form a double bond; 
 R 5  and R 6  are each independently H, halogen, NO 2 , CN, OR 13 , NR 14 R 15  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 or when attached to adjacent carbon atoms R 5  and R 6  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 7 , R 8 , R 9 , R 10 , R 11 , R 19  and R 20  are each independently H, halogen, NO 2 , CN, OR 16 , 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 or C 3 -C 8  cycloalkyl group each optionally substituted; 
 m is 0 or 1; 
 n is 0, 2 or 3; 
    is a single bond or a double bond with the proviso that when m is 0 then   must be a single bond; 
 R 12 , R 13  and R 16  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 or aryl group each optionally substituted; and 
 R 14 , R 15 , R 17  and R 18  are each independently H or C 1 -C 4  alkyl; 
 
       which process comprises reacting a compound of formula II 
       
         
           
           
               
               
           
         
       
       wherein Hal is Cl or Br. 
       
         
           
           
               
               
           
         
       
       wherein W is B(OH) 2 , Sn(n Bu) 3  or Sn(CH 3 ) 3  and X, Y, Z, R 8 , R 9  and m are as described for formula I hereinabove in the presence of a palladium catalyst optionally in the presence of a solvent.