IP Library › Patent Application 12201026

Patent Application

App. No. 12/201,026

AMINO-5-[4-(DIFLUOROMETHOXY) PHENYL]-5-PHENYLIMIDAZOLONE COMPOUNDS FOR THE INHIBITION OF BETA-SECRETASE

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App. No.: 12/201,026

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Abstract

The present invention provides a 2-amino-5-[4-(difluoromethoxy)phenyl]-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.

Claims (277)

1 . A compound of formula I

wherein

R 1 and R 2 are each independently H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted or R 1 and R 2 may be taken together with the atom to which they are attached form an optionally substituted 5- to 7-membered ring optionally interrupted by an additional heteroatom selected from O, N or S;

R 3 is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;

R 4 , R 5 and R 6 are each independently H, halogen, NO 2 , CN, COR 7 , NR 10 CO 2 R 11 , NR 15 COR 16 , OR 14 , NR 12 R 13 , SO n R 17 or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R 4 and R 5 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 7 and R 17 are each independently H, NR 8 R 9 or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;

R 8 and R 9 are each independently H or an alkyl, alkenyl, alkynyl or cycloalkyl group each optionally substituted or R 8 and R 9 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 11 , R 14 and R 16 are each independently H or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;

R 10 and R 15 are each independently H or an optionally substituted alkyl group; and

R 12 and R 13 are each independently H or an alkyl or cycloalkyl group each optionally substituted or

R 12 and R 13 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; 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 3 is C 1 -C 4 alkyl.

4 . The compound according to claim 1 wherein R 4 , R 5 and R 6 are each independently H, halogen, COR 7 , OR 14 , or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl group each optionally substituted

5 . The compound according to claim 2 wherein R 3 is methyl.

6 . The compound according to claim 4 wherein R 5 and R 6 are each independently H or halogen.

7 . The compound according to claim 5 wherein R 4 is H, COR 7 , OR 14 or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl group each optionally substituted; and R 4 is at the 3-position of the phenyl ring.

8 . The compound according to claim 7 wherein R 5 and R 6 are each independently H or halogen.

9 . The compound according to claim 1 selected from the group consisting essentially of:

(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-Amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-Amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-Amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[3-(2,2-difluoroethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2,2,2-trifluoroethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3,3,3-trifluoropropyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pentylphenyl)-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(2-methylbutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-(3-but-3-en-1-ylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-Amino-5-[3-(cyclopropyl methyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)propanenitrile;

(5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one;

N-(3-{(4R)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;

N-(3-{(4S)-2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;

(5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(6-fluorohexyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1Z)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxypropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(4,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-N-propylbenzamide;

(1E)-3-chloroprop-1-enyl 2,5-dichlorophenyl sulfone;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-fluoroethoxy)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(3,3,3-trifluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(methoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(butoxymethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-{3-[(cyclopropylmethoxy)methyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(ethoxymethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(propoxymethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-{[2-fluoro-1-(fluoromethyl)ethoxy]methyl}phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,2-trifluoroethoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2,2,3,3-tetrafluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one;

4-[4-(difluoromethoxy)phenyl]-4-[3-(3-methoxyprop-1-yn-1-yl)phenyl]-1-methyl-4,5-dihydro-1H-imidazol-2-amine;

2-amino-5-[3-(1,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

5-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile;

4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)butanenitrile;

2-amino-5-{3-[(1E)-4,4-difluorobut-1-en-1-yl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyhex-4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxyhex-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-methoxypent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(methoxymethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxypent-1-en-1-yl}phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-methoxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-hydroxybut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[2-(2-methoxyethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-fluoropent-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

5-(3-acetylphenyl)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-4-fluorobut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(4,4,4-trifluorobutoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(2,2-difluoroethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-phenoxypropoxy)phenyl]-3,5-dihydro-4H-imidazol-4-one;

4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenoxy)butanenitrile;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(but-2-yn-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-amino-5-[3-(2,2-difluoromethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutanoyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[3-(but-3-en-1-yloxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5S)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-pent-4-en-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-(3-but-3-en-1-yl-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}benzaldehyde;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-hydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1,4-dihydroxybut-2-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

(5R)-2-amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxocyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-oxocyclobutyl)phenyl]-3,5-dihydro-4H-imidazol-4-one;

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;

methyl [3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutyl]acetate;

methyl [3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate;

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 to said patient a therapeutically effective amount of a compound of formula I

wherein

R 3 is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;

n is 0, 1 or 2;

R 7 and R 17 are each independently H, NR 8 R 9 or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;

R 11 , R 14 and R 16 are each independently H or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;

R 10 and R 15 are each independently H or an optionally substituted alkyl group; and

R 12 and R 13 are each independently H or an alkyl or cycloalkyl group each optionally substituted or R 12 and R 13 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; 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 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

R 3 is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;

n is 0, 1 or 2;

R 7 and R 17 are each independently H, NR 8 R 9 or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;

R 11 , R 14 and R 16 are each independently H or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;

R 10 and R 15 are each independently H or an optionally substituted alkyl group; and

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 R 3 is C 1 -C 4 alkyl.

18 . The composition according to claim 17 having a formula I compound wherein R 4 , R 5 and R 6 are each independently H, halogen, COR 7 , OR 14 , or an alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl group each optionally substituted.

19 . The composition according to claim 18 having a formula I compound wherein R 4 is at the 3-position of the phenyl ring; and R 5 and R 6 are each independently H or halogen.

20 . The composition according to claim 15 having a formula I compound selected from the group consisting essentially of: