AMINO-IMIDAZOLONES FOR THE INHIBITION OF BETA-SECRETASE
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.