Amino-imidazolones for the inhibition of beta-secretase

Abstract

The present invention provides an amino-imidazolone compound of formula I Also provided are compositions and methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         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 , R 6  and R 7  are each independently H, halogen, NO 2 , CN, OR 11 , NR 12 R 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, cycloheteroalkyl, aryl or aryl(C 1 -C 4 )alkyl 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 8 , R 9  and R 10  are each independently H, halogen, NO 2 , CN, OR 14 , NR 15 R 16  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 6 cycloalkyl, cycloheteroalkyl, aryl or aryl(C 1 -C 4 )alkyl group each optionally substituted or when attached to adjacent carbon atoms R 5  and R 9  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; 
         n is 0, 1 or 2; 
         R 11  and R 14  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 12 , R 13 , R 15  and R 16  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 12  and R 13  or R 15  or R 16  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; 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 n is 1. 
     
     
         4 . The compound according to  claim 1  wherein n is 0. 
     
     
         5 . The compound according to  claim 1  wherein R 5  and R 8  are each independently a C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1-6 haloalkyl or benzyl group each optionally substituted and R 6 , R 7 , R 9  and R 10  are H. 
     
     
         6 . The compound according to  claim 1  wherein R 1  and R 2  are H and n is 0 or 1. 
     
     
         7 . The compound according to  claim 6  wherein R 3  and R 4  are H and R 5  is t-butyl, CF 3 , C 1 -C 3 alkoxy or an optionally substituted benzyl group 
     
     
         8 . The compound according to  claim 7  wherein R 3  is H or C 1 -C 3 alkoxy; R 9  is H or C 1 -C 3 alkyl; and R 6 , R 7 , R 9  and R 10  are H. 
     
     
         9 . The compound according to  claim 1  selected from the group consisting of: 
       8-(4-tert-butylphenyl)-8-phenyl-2,3,4,8-tetrahydroimidazol[1,5-a]pyrimidin-6-amine; 
       8-(3-benzylphenyl)-8-phenyl-2,3,4,8-tetrahydroimidazol[1,5-a]pyrimidin-6-amine; 
       8-[3-(4-fluorophenoxy)phenyl]-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-[3-(4-methoxybenzyl)phenyl]-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-[3-(4-fluorobenzyl)phenyl]-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-phenyl-8-[3-(trifluoromethyl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-(3-methoxyphenyl)-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       7-(4-methoxy-3-methylphenyl)-7-(3-propoxyphenyl)-2,7-dihydro-3h-imidazo[1,5-a]imidazol-5-amine; 
       8-(4-methoxy-3-methylphenyl)-8-(3-propoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-(4-methoxy-3-methylphenyl)-3,3-dimethyl-8-(3-propoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8,8-diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-[3-(2-cyclopropyl-ethyl)-phenyl]-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine; 
       8-(3-allylphenyl)-8-(4-trifluoromethoxyphenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine; 
       8-(3-propyl-phenyl)-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine; 
       3-[6-amino-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-8-yl]-N-ethyl-benzamide; 
       N-{3-[6-amino-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-8-yl]-phenyl}-propionamide hydrochloride; 
       a tautomer thereof; 
       a stereoisomer thereof; and 
       a pharmaceutically acceptable salt thereof. 
     
     
         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 said patient an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         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 , R 6  and R 7  are each independently H, halogen, NO 2 , CN, OR 11 , NR 12 R 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, cycloheteroalkyl, aryl or aryl(C 1 -C 4 )alkyl 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 8 , R 9  and R 10  are each independently H, halogen, NO 2 , CN, OR 14 , NR 15 R 16  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 aryl(C 1 -C 4 )alkyl group each optionally substituted or when attached to adjacent carbon atoms R 8  and R 9  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; 
         n is 0, 1 or 2; 
         R 11  and R 14  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 12 , R 13 , R 15  and R 16  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 12  and R 13  or R 15  or R 16  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; 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 essentially of: Alzheimer's disease; cognitive impairment; Down's Syndrome; HCHWA-D; cognitive decline; senile dementia; cerebral amyloid angiopathy; degenerative dementia; and a neurodegenerative disorder. 
     
     
         12 . The method according to  claim 10 , wherein the disease is characterized by production of β-amyloid deposits or neurofibrillary tangles. 
     
     
         13 . The method according to  claim 10  wherein the disease is Alzheimer's Disease. 
     
     
         14 . A method for modulating the activity of BACE which comprises contacting a receptor thereof with an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         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 , R 6  and R 7  are each independently H, halogen, NO 2 , CN, OR 11 , NR 12 R 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, cycloheteroalkyl, aryl or aryl(C 1 -C 4 )alkyl 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 8 , R 9  and R 10  are each independently H, halogen, NO 2 , CN, OR 14 , NR 15 R 16  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 aryl(C 1 -C 4 )alkyl group each optionally substituted or when attached to adjacent carbon atoms R 8  and R 9  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; 
         n is 0, 1 or 2; 
         R 11  and R 14  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 12 , R 13 , R 15  and R 16  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 12  and R 13  or R 15  or R 16  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; or 
       
       a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         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 , R 6  and R 7  are each independently H, halogen, NO 2 , CN, OR 11 , NR 12 R 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, cycloheteroalkyl, aryl or aryl(C 1 -C 4 )alkyl 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 8 , R 9  and R 10  are each independently H, halogen, NO 2 , CN, OR 14 , NR 15 R 16  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 aryl(C 1 -C 4 )alkyl group each optionally substituted or when attached to adjacent carbon atoms R 8  and R 9  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; 
         n is 0, 1 or 2; 
         R 11  and R 14  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 12 , R 13 , R 15  and R 16  are each independently H, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl or R 12  and R 13  or R 15  or R 16  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; or 
       
       a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The pharmaceutical composition according to  claim 15  having a compound of formula I wherein R 1  and R 2  are H. 
     
     
         17 . The pharmaceutical composition according to  claim 16  having a compound of formula I wherein n is 0 or 1. 
     
     
         18 . The pharmaceutical composition according to  claim 17  having a compound of formula I wherein R 3 , R 4 , R 6 , R 7  and R 10  are H and R 5  is t-butyl, CF 3 , C 1 -C 3 alkoxy or an optionally substituted benzyl group. 
     
     
         19 . The pharmaceutical composition according to  claim 18  having a compound of formula I wherein R 8  is H or C 1 -C 3 alkoxy and R 9  is H or C 1 -C 3 alkyl. 
     
     
         20 . The pharmaceutical composition according to  claim 15  having a compound of formula I selected from the group consisting essentially of: 
       8-(4-tert-butylphenyl)-8-phenyl-2,3,4,8-tetrahydroimidazol[1,5-a]pyrimidin-6-amine; 
       8-(3-benzylphenyl)-8-phenyl-2,3,4,8-tetrahydroimidazol[1,5-a]pyrimidin-6-amine; 
       8-[3-(4-fluorophenoxy)phenyl]-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-[3-(4-methoxybenzyl)phenyl]-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-[3-(4-fluorobenzyl)phenyl]-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-phenyl-8-[3-(trifluoromethyl)phenyl]-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-(3-methoxyphenyl)-8-phenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       7-(4-methoxy-3-methylphenyl)-7-(3-propoxyphenyl)-2,7-dihydro-3h-imidazo[1,5-a]imidazol-5-amine; 
       8-(4-methoxy-3-methylphenyl)-8-(3-propoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-(4-methoxy-3-methylphenyl)-3,3-dimethyl-8-(3-propoxyphenyl)-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8,8-diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine; 
       8-[3-(2-cyclopropyl-ethyl)-phenyl]-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine; 
       8-(3-allylphenyl)-8-(4-trifluoromethoxyphenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-6-ylamine; 
       8-(3-propyl-phenyl)-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[5,5-a]pyrimidin-6-ylamine; 
       3-[6-amino-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-8-yl]-N-ethyl-benzamide; 
       N-{3-[6-amino-8-(4-trifluoromethoxy-phenyl)-2,3,4,8-tetrahydro-imidazo[1,5-a]pyrimidin-8-yl]-phenyl}-propionamide hydrochloride; 
       a tautomer thereof; 
       a stereoisomer thereof; and 
       a pharmaceutically acceptable salt thereof.