Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone Compounds For The Inhibition Of Beta-secretase

A compound of formula I

• wherein
• R1 and R2 are each independently H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted or R1 and R2 may be taken together with the atom to which they are attached form an optionally substituted 5- to 7-membered ring optionally containing an additional heteroatom selected from O, N or S;
• R3 is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
• R4, R5 and R6 are each independently H, halogen, NO2, CN, COR7, NR10CO2R11, NR15COR16, OR14, NR12R13, SOnR17 or an alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, cycloalkyl or cycloheteroalkyl group each optionally substituted or when attached to adjacent carbon atoms R4 and R5 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;
• R7 and R17 are each independently H, NR8R9 or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl group each optionally substituted;
• R8 and R9 are each independently H or an alkyl, alkenyl, alkynyl or cycloalkyl group each optionally substituted or R8 and R9 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;
• R11 R14 and R16 are each independently H or an alkyl, haloalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl or an aryl group each optionally substituted;
• R10 and R15 are each independently H or an optionally substituted alkyl group;
• and
• R12 and R13 are each independently H or an alkyl, alkenyl, aryl or cycloalkyl group each optionally substituted or R12 and R13 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;
• provided that the compound is not selected from the group consisting of:
• 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;
• (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;
• 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;
• 2-Amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-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;
• (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-(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-(cyclopropylmethyl)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;
• 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;
• N-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide;
• 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-(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-[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-(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-(3-methoxyprop-1-yn-1-yl)-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-[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-(6-fluorohexyl)-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;
• 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-[(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;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-6-methoxy-hex-1-en-1-A-phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-5-hydroxy-pent-1-en-1-A-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-[2-(2-methoxyethyl)-cyclopropyl]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-[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-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(3hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-hydroxy-phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• (5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• (5S)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropox-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• (5R)-2-Amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenyl]-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;
• 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
• 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-A-3-methyl-3,5-dihydro-4H-imidazol-4-one
• 2-Amino-5-(3-but-3-en-1-yl-4fluorophenyl-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 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;
• 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-hydroxy-cyclobutyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• ethyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate;
• methyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate;
• methyl[3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutyl]acetate;
• 2-Amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoromethoxy)-phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one
• (5S)-2-Amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoro-methoxy)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-[(1R)-1-fluoropent-4-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1R)-1-fluorobut-3-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• N-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)ethanesulfonamide;
• 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-hydroxypent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• 2-Amino-5-{3-[(E)-2-cyclopropylvinyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one;
• and provided that the compound is not as shown in any one of the following tables (A-H):
• A
• R
• CH2CH2CF3
• CH3
• CH2CH2CH2CH3
• CH2CH3
• CH2CH2CH3
• CH(CH2F)CH2F
• B
• R
• R5
• CH2CH2OCH3
• H
• OCH3
• H
• CH2OCH3
• H
• CH2OH
• H
• CH2F
• H
• CH2CH2F
• H
• CH2F
• F
• CHF2
• H
• C
• R4
• CH2CH2F
• COCH2CH2CH2CH2F
• COCH2CH2CH2F
• D
• R
• R5
• H
• CH2CH2CH2CF3
• H
• CH2CHF2
• H
• CH2CH2CH2CH2F
• H
• CH2CH2CH2OC6H5
• H
• CH2CH2CH2CN
• H
• CH2CH2CHF2
• F
• F
• CH2CH2CH2CH2F
• F
• CH2CHF2
• F
• CH2CH2CH═CH2
• H
• CH2CH2CH═CH2
• F
• CH2CH2CH2CH═CH2
• H
• (R)-CH2(CH3)CH2CH═CH2
• H
• (S)—CH2(CH3)CH2CH═CH2
• H
• CH2═CHCH2(CH3)CH2
• H
• CH3C(═CH2)CH2CH2
• H
• CH2═CHCH2
• H
• E
• R
• 3,4-difluorophenyl
• 3-methoxyphenyl
• 3-chlorophenyl
• n-propyl
• 3-cyanophenyl
• 3-(trilfuoromethoxy)phenyl
• 3-pyridyl
• 4-cyanophenyl
• 2-thienyl
• benzyl
• 3,5-difluorophenyl
• F
• Chiral
• R
• R′
• —
• CH2OCH3
• H
• —
• CH2OCH3
• CH3
• 4-R
• CH2OCH3
• H
• 4-S
• CH2OCH3
• H
• G
• Chiral
• R
• R5
• —
• CH2CH2CH2F
• H
• —
• CH2CH2CH2Cl
• H
• —
• CH2CH2CH3
• H
• —
• CH2CH2OH
• H
• —
• CH2CH2CH2CH2OH
• H
• —
• CH2CH2CH2CH2F
• H
• —
• CH2CH2Cl
• H
• 5-R
• CH2CH3
• H
• 5-S
• CH2CH3
• H
• 5-S
• CH2CH2CH2OH
• H
• 5-R
• CH2CH2CH2CH2OH
• H
• 5-S
• CH2CH2CH2CH2OH
• H
• 5-R
• CH2CH2OH
• H
• 5-S
• CH2CH2OH
• H
• 5-S
• CH2CH2CH2F
• H
• 5-R
• CH2CH2CH2F
• H
• 5-S
• CH2CH2CH2OH
• F
• 5-R
• CH2CH2CH2OH
• F
• 5-S
• CH2CH2CH2F
• F
• 5-R
• CH2CH2CH2F
• F
• —
• CH2CH2OCH3
• H
• —
• CH2OCH3
• H
• 5-S
• CH2CH2OCH3
• H
• 5-R
• CH2CH2OCH3
• H
• —
• CH2CH2F
• H
• —
• CH2CH(CH3)2
• H
• —
• CH(OH)CH2CH3
• H
• —
• CH2CH(OH)CH3
• H
• —
• CH(CH3)2
• H
• —
• CH2CH3
• H
• —
• CH2CH2CH2CH3
• H
• —
• cyclopropyl
• H
• —
• cyclohexyl
• H
• —
• cyclopentylmethyl
• H
• —
• cyclohexylmethyl
• H
• 5-S
• CH2OCH3
• H
• 5-R
• CH2OCH3
• H
• —
• CH2OCH3
• F
• —
• CH2CH2OCH3
• F
• —
• CH2OH
• H
• —
• (S)—CH(OH)CH3
• H
• —
• (R)-CH(OH)CH3
• H
• —
• CH(OH)CH(CH3)2
• H
• —
• 1-
• H
• hydroxycyclopentyl
• —
• 1-
• H
• hydroxycyclohexyl
• —
• C(OH)(CH3)2
• H
• —
• C(OH)(CH3)CH2CH3
• H
• —
• H
• H
• —
• (S)—CH(OH)C6H5
• H
• 5-S
• CH2CH2OCH3
• H
• 5-R
• CH2CH2OCH3
• H
• 5-S
• CH2OCH3
• H
• 5-R
• CH2OCH3
• H
• —
• CH3
• F
• —
• CH3
• H
• 5-R
• (S)—CH(OH)CH3
• H
• 5-S
• (S)—CH(OH)CH3
• H
• 5-R
• CH3
• H
• 5-S
• CH3
• H
• 5-R
• CH2CH2CH2OH
• H
• or
• H
• R
• R′
• R″
• R5
• CH3
• H
• H
• H
• CH3
• H
• H
• F
• H
• H
• H
• H
• CH3
• CH3
• H
• F
• H
• H
• CH3
• H
• CH2CH2CH3
• H
• H
• H
• CH2CH2CH2CH2CH3
• H
• H
• H
• CH2CH2CH2Cl
• H
• H
• H
• C6H5
• H
• H
• H
• 2,4-difluorophenyl
• H
• H
• H
• CH2CH2CH2CH2CH2CH3
• H
• H
• H
• H
• H
• C6H5
• H
• CH2CH2CH2CH3
• H
• H
• H.