US2010168194A1PendingUtilityA1
Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone Compounds For The Inhibition Of Beta-secretase
Est. expiryMar 23, 2027(~0.7 yrs left)· nominal 20-yr term from priority
Inventors:Michael S. MalamasAlbert Jean RobichaudAlexander Michael PorteKoi Michele MorrisWilliam Ronald SolvibileJi-In KimSchuyler A. Antane
A61P 43/00A61P 25/28C07D 233/70C07D 413/12C07D 405/12C07D 403/12C07D 409/12
42
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Claims
Abstract
The present invention provides compounds and methods for the use thereof to inhibit β-secretase (BACE) and treat β-amyloid deposits and neurofibrillary tangles.
Claims
exact text as granted — not AI-modified1 . 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 containing 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, heteroaryl or an 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, alkenyl, aryl 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;
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
CH 2 CH 2 CF 3
CH 3
CH 2 CH 2 CH 2 CH 3
CH 2 CH 3
CH 2 CH 2 CH 3
CH(CH 2 F)CH 2 F
B
R
R5
CH 2 CH 2 OCH 3
H
OCH 3
H
CH 2 OCH 3
H
CH 2 OH
H
CH 2 F
H
CH 2 CH 2 F
H
CH 2 F
F
CHF 2
H
C
R4
CH 2 CH 2 F
COCH 2 CH 2 CH 2 CH 2 F
COCH 2 CH 2 CH 2 F
D
R
R5
H
CH 2 CH 2 CH 2 CF 3
H
CH 2 CHF 2
H
CH 2 CH 2 CH 2 CH 2 F
H
CH 2 CH 2 CH 2 OC 6 H 5
H
CH 2 CH 2 CH 2 CN
H
CH 2 CH 2 CHF 2
F
F
CH 2 CH 2 CH 2 CH 2 F
F
CH 2 CHF 2
F
CH 2 CH 2 CH═CH 2
H
CH 2 CH 2 CH═CH 2
F
CH 2 CH 2 CH 2 CH═CH 2
H
(R)-CH 2 (CH 3 )CH 2 CH═CH 2
H
(S)—CH 2 (CH 3 )CH 2 CH═CH 2
H
CH 2 ═CHCH 2 (CH 3 )CH 2
H
CH 3 C(═CH 2 )CH 2 CH 2
H
CH 2 ═CHCH 2
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′
—
CH 2 OCH 3
H
—
CH 2 OCH 3
CH 3
4-R
CH 2 OCH 3
H
4-S
CH 2 OCH 3
H
G
Chiral
R
R5
—
CH 2 CH 2 CH 2 F
H
—
CH 2 CH 2 CH 2 Cl
H
—
CH 2 CH 2 CH 3
H
—
CH 2 CH 2 OH
H
—
CH 2 CH 2 CH 2 CH 2 OH
H
—
CH 2 CH 2 CH 2 CH 2 F
H
—
CH 2 CH 2 Cl
H
5-R
CH 2 CH 3
H
5-S
CH 2 CH 3
H
5-S
CH 2 CH 2 CH 2 OH
H
5-R
CH 2 CH 2 CH 2 CH 2 OH
H
5-S
CH 2 CH 2 CH 2 CH 2 OH
H
5-R
CH 2 CH 2 OH
H
5-S
CH 2 CH 2 OH
H
5-S
CH 2 CH 2 CH 2 F
H
5-R
CH 2 CH 2 CH 2 F
H
5-S
CH 2 CH 2 CH 2 OH
F
5-R
CH 2 CH 2 CH 2 OH
F
5-S
CH 2 CH 2 CH 2 F
F
5-R
CH 2 CH 2 CH 2 F
F
—
CH 2 CH 2 OCH 3
H
—
CH 2 OCH 3
H
5-S
CH 2 CH 2 OCH 3
H
5-R
CH 2 CH 2 OCH 3
H
—
CH 2 CH 2 F
H
—
CH 2 CH(CH 3 ) 2
H
—
CH(OH)CH 2 CH 3
H
—
CH 2 CH(OH)CH 3
H
—
CH(CH 3 ) 2
H
—
CH 2 CH 3
H
—
CH 2 CH 2 CH 2 CH 3
H
—
cyclopropyl
H
—
cyclohexyl
H
—
cyclopentylmethyl
H
—
cyclohexylmethyl
H
5-S
CH 2 OCH 3
H
5-R
CH 2 OCH 3
H
—
CH 2 OCH 3
F
—
CH 2 CH 2 OCH 3
F
—
CH 2 OH
H
—
(S)—CH(OH)CH 3
H
—
(R)-CH(OH)CH 3
H
—
CH(OH)CH(CH 3 ) 2
H
—
1-
H
hydroxycyclopentyl
—
1-
H
hydroxycyclohexyl
—
C(OH)(CH 3 ) 2
H
—
C(OH)(CH 3 )CH 2 CH 3
H
—
H
H
—
(S)—CH(OH)C 6 H 5
H
5-S
CH 2 CH 2 OCH 3
H
5-R
CH 2 CH 2 OCH 3
H
5-S
CH 2 OCH 3
H
5-R
CH 2 OCH 3
H
—
CH 3
F
—
CH 3
H
5-R
(S)—CH(OH)CH 3
H
5-S
(S)—CH(OH)CH 3
H
5-R
CH 3
H
5-S
CH 3
H
5-R
CH 2 CH 2 CH 2 OH
H
or
H
R
R′
R″
R5
CH 3
H
H
H
CH 3
H
H
F
H
H
H
H
CH 3
CH 3
H
F
H
H
CH 3
H
CH 2 CH 2 CH 3
H
H
H
CH 2 CH 2 CH 2 CH 2 CH 3
H
H
H
CH 2 CH 2 CH 2Cl
H
H
H
C 6 H 5
H
H
H
2,4-difluorophenyl
H
H
H
CH 2 CH 2 CH 2 CH 2 CH 2 CH 3
H
H
H
H
H
C 6 H 5
H
CH 2 CH 2 CH 2 CH 3
H
H
H.
2 . A compound as claimed in claim 1 , having the structure of formula II
wherein, only one of R 4 and R 5 can be hydrogen.
3 . A compound as claimed in claim 2 , having the structure of formula IIA
4 . A compound as claimed in claim 2 , having the structure of formula IIB
5 . A compound as claimed in claim 1 , having the structure of formula III
wherein, only one of R 4 and R 5 can be hydrogen.
6 . A compound as claimed in claim 5 , having the structure of formula IIIA
7 . A compound as claimed in claim 5 , having the structure of formula IIIB
8 . A compound as claimed in claim 1 , wherein:
R 4 is H or fluorine and R 5 is OR 18 where R 18 is an alkyl, haloalkyl, alkenyl or haloalkenyl group each optionally substituted; or R 4 is H and R 5 is OR 18 where R 18 is an alkyl group substituted with a cycloalkyl group; or R 4 is H and R 5 is OR 18 where R 18 is an alkyl group substituted with a cyclopropyl group; or R 4 is H and R 5 is OR 18 where R 18 is an optionally substituted alkenyl group; or R 4 is H and R 5 is OR 18 where R 18 is an optionally substituted haloalkyl group; or R 4 is fluorine and R 5 is OR 18 where R 18 is an optionally substituted haloalkyl group; or R 4 is H and R 5 is OR 18 where R 18 is an optionally substituted haloalkenyl group; or R 4 is H and R 5 is NHR 19 where R 19 is H or an alkyl, cycloalkyl, alkenyl or aryl group each optionally substituted; or R 4 is H and R 5 is NHR 19 where R 19 is an alkyl group substituted with a heteroaryl group; or R 4 is H and R 5 is NHCOR 20 where R 20 is an alkyl, haloalkyl, cycloalkyl, alkoxyalkyl, alkenyl, aryl or heteroaryl group each optionally substituted; or R 4 is H and R 5 is NHCOR 20 where R 20 is an optionally substituted alkyl group; or R 4 is H and R 5 is NHCOR 20 where R 20 is an optionally substituted haloalkyl group; or R 4 is H and R 5 is NHCOR 20 where R 20 is an optionally substituted cycloalkyl group; or R 4 is H and R 5 is NHCOR 20 where R 20 is an optionally substituted heteroaryl group; or R 4 is H and R 5 is NHCOR 20 where R 20 is an optionally substituted heteroaryl group containing one O heteroatom; or R 4 is H and R 5 is NHCOR 20 where R 20 is an optionally substituted heteroaryl group containing one S heteroatom; or R 4 is H and R 5 is NHCOR 20 where R 20 is a heteroaryl group fused to an aryl group; or R 4 is H and R 5 is CH 2 NR 21 R 22 where R 21 and R 22 are independently H or an optionally substituted alkyl group or R 21 and R 22 may be taken together with the N atom to which they are attached to form an optionally substituted 5-membered ring; or R 4 is H or fluorine and R 5 is an alkenyl or haloalkenyl group each optionally substituted; or R 4 is fluorine and R 5 is an optionally substituted alkenyl group; or R 4 is H and R 5 is an optionally substituted haloalkenyl group; or R 4 is H and R 5 is a haloalkenyl group substituted with a cycloalkyl group; or R 4 is H and R 5 is a haloalkenyl group substituted with a cyclopropyl group; or R 4 is H and R 5 is a haloalkenyl group substituted with a cyclopropyl group where the haloalkenyl group contains one fluorine atom; or R 4 is H and R 5 is an optionally substituted group of formula IV
where the dashed line denotes an optional double bond and R 23 is a haloalkyl or alkoxyalkyl group each optionally substituted or CO 2 R 24 where R 24 is an alkyl group; or
R 4 is H and R 5 is an optionally substituted group of formula IVA
where R 23 is a haloalkyl group; or
R 4 is H and R 5 is an optionally substituted group of formula V
where the double bond can be in a cis or trans configuration; or
R 4 and R 5 are attached to adjacent carbon atoms and are taken together with the atoms to which they are attached to form an optionally substituted 5- to 7-membered ring containing one O heteroatom; or
R 4 and R 5 are attached to adjacent carbon atoms and are taken together with the atoms to which they are attached to form an optionally substituted 5-membered ring containing one O heteroatom; or
R 4 is H and R 5 is an optionally substituted cycloalkyl group; or
R 4 is OR 25 where R 25 is an optionally substituted haloalkyl group and R 5 is H;
R 4 is H or fluorine and R 5 is an alkyl, haloalkyl, alkoxyalkyl, alkenyl, haloalkenyl or alkynyl group each optionally substituted; or
R 4 is H or fluorine and R 5 is an optionally substituted group of formula VI
where n is an integer of 1-4; or
R 4 is H or fluorine and R 5 is a group of formula VII
where R 26 is an optionally substituted cycloalkyl group; or
R 4 is H or fluorine and R 5 is a group of formula VII
where R 26 is an optionally substituted cyclopropyl group; or
R 4 is H or fluorine and R 5 is a group of formula VIII
where R 27 is an alkyl, haloalkyl or alkoxyalkyl group each optionally substituted; or
R 4 is H or fluorine and R 5 is a group of formula VIII
where R 27 is an optionally substituted alkyl group; or
R 4 is H or fluorine and R 5 is a group of formula VIII
where R 27 is an optionally substituted haloalkyl group; or
R 4 is H or fluorine and R 5 is a group of formula VIII
where R 27 is an optionally substituted alkoxyalkyl group; or
R 4 is an optionally substituted alkoxyalkyl group and R 5 is CN.
9 . A compound of formula IXA, IXB or a mixture thereof
wherein
R 28 is H or halogen;
R 29 is an alkyl, haloalkyl, alkoxyalkyl or cycloalkyl group each optionally substituted;
R 30 and R 31 are each independently H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted or R 30 and R 31 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; and
R 32 is H or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted.
10 . A compound as claimed in claim 9 , wherein R 28 is halogen and R 29 is an optionally substituted cycloalkyl group.
11 . A compound as claimed in claim 9 , wherein R 28 is fluorine.
12 . A compound as claimed in claims 9 , wherein the cycloalkyl group is a monocyclic moiety of 3-5 carbon atoms.
13 . A compound as claimed in claim 9 , wherein R 30 , R 31 and R 32 are each independently H or an alkyl group.
14 . A compound as claimed in claim 13 , wherein R 30 and R 31 are both H and R 32 is an alkyl group.
15 . A compound as claimed in claim 9 , wherein R 28 is H and R 29 is an optionally substituted cycloalkyl group,
16 . A compound as claimed in claim 1 , wherein R 1 and R 2 are H.
17 . A compound as claimed in claim 1 , wherein R 3 is C 1 -C 4 alkyl.
18 . A compound as claimed in 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.
19 . A compound as claimed in claim 1 , wherein R 3 is methyl.20. A compound as claimed in any one of claims 1 - 8 and 16 - 19 wherein R 5 and R 6 are each independently H or halogen.
20 . A compound as claimed in claim 1 , wherein R 1 and R 2 are H and R 3 is methyl.
21 . A compound as claimed in claim 1 , 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.
22 . A compound as claimed in claim 1 , wherein R 5 and R 6 are each independently H or halogen.
23 . A compound as claimed in claim 1 , selected from the group consisting of:
(E)-2-amino-5-[3-(2-cyclopropyl-1-fluorovinyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (Z)-2-amino-5-[3-(2-cyclopropyl-1-fluorovinyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-prop-1-en-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-ethylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; (E)-2-amino-4-(4-(difluoromethoxy)phenyl)-4-(3-(4-methoxybut-2-en-2-yl)phenyl)-1-methyl-1H-imidazol-5(4H)-one; 2-amino-4-(3-cyclopropylphenyl)-4-(4-(difluoromethoxy)phenyl)-1-methyl-1H-imidazol-5(4H)-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-{[(2-furylmethyl)-amino]methyl}phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(propylamino)-methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(ethylamino)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(dimethylamino)-methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-Amino-5-(4-difluoromethoxy-phenyl)-5-[3-(isopropylamino-methyl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one; methyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-1-methoxycyclobutyl]acetate; methyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate; 2-amino-5-[3-(5-chloropent-1-yn-1-yl)-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-(5-fluoropent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-Amino-5-(4-difluoromethoxy-phenyl)-3-methyl-5-o-tolyl-3,5-dihydro-imidazol-4-one; 2-Amino-5-(4-difluoromethoxy-phenyl)-5-(4-fluoro-3-fluoromethyl-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one; 5-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-methoxy-benzonitrile; 4-{5-[2-Amino-4-(4-difluoromethoxy-phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-2-fluoro-phenyl}-butyronitrile; 2-Amino-5-(4-difluoromethoxy-phenyl)-5-[4-fluoro-3-(1-fluoro-pent-4-enyl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one; 2-Amino-5-(4-difluoromethoxy-phenyl)-5-[3-(1-fluoro-pent-4-enyl)-phenyl]-3-methyl-3,5-dihydro-imidazol-4-one; 5-(3-{(4S)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile; 5-(3-{(4R)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile; (R)-2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-4-(3-(pent-4-enyloxy)phenyl)-1H-imidazol-5(4H)-one; (R)-2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-4-(3-((R)-pent-4-en-2-yloxy)phenyl)-1H-imidazol-5(4H)-one; (R)-2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-4-(3-((S)-pent-4-en-2-yloxy)phenyl)-1H-imidazol-5(4H)-one; (4R)-2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-4-(3-(2-methylbut-3-enyloxy)phenyl)-1H-imidazol-5(4H)-one; (R)-2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-4-(3-(3-methylbut-3-enyloxy)phenyl)-1H-imidazol-5(4H)-one; (R)-4-(3-(allyloxy)phenyl)-2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-1H-imidazol-5(4H)-one; 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-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-prop-1-yn-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-prop-1-yn-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-prop-1-yn-1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one; (5S)-2-Amino-5-[3-(cyclopropylethynyl)phenyl]-5-[4 (difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-Amino-5-[3-(cyclopropylethynyl)phenyl]-5-[4 (difluoromethoxy)-phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-Amino-5-[3-(cyclopropylethynyl)-4-fluorophenyl]-5-[4(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-Amino-5-[3-(cyclopropylethynyl)-4-fluorophenyl]-5-[4(difluoromethoxy)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-4yl}phenyl)cyclobutylidene]acetate; ethyl[3-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro1H-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-dihydro1H-imidazol-4-yl}phenyl)-1-methoxycyclobutyl]acetate; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[3-(2-hydroxyethylidene)cyclobutyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-fluorobut-3-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[3-(2-fluoroethyl)cyclobutyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[3-(2-methoxyethyl)cyclobutyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-(3-anilinophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(isopropylamino)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(dimethylamino)methyl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(ethylamino)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(propylamino)methyl]phenyl}-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-{3-[(butylamino)methyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(pyrrolidin-1-ylmethyl)phenyl]-3,5-dihydro-4H-imidazol-4-one; 2-amino-5,5-bis[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-{[(2-furylmethyl)amino]methyl}phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-(3-cyclopropylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxy-1-methylprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-ethoxy-1-methylprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(1S)-1-methylbut-3-en-1-yl]phenyl}-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-methoxy-1-methylpropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-ethoxy-1-methylpropyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(1R)-1-methylbut-3-en-1-yl]phenyl}-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(2-methyl-1-benzofuran-5-yl)-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(2-methyl-1-benzofuran-5-yl)-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-(3-aminophenyl)-5-[4-(difluoromethoxy)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)acetamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)propanamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)butanamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-3-chloropropanamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2,2,2-trifluoroacetamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-3-methylbutanamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methylpropanamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclopropanecarboxamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutanecarboxamide; (2E)-N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)but-2-enamide; N-(3-(2-amino-4-(4-(difluoromethoxy)phenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl)phenyl)-3-methylbut-2-enamide; (2E)-N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-3-phenylacrylamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-furamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-(benzyloxy)acetamide; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(propylamino)phenyl]-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(butylamino)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(isobutylamino)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(isopropylamino)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(cyclopentylamino)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(cyclohexylamino)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-{3-[(2E)-but-2-en-1-ylamino]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(cyclobutylamino)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(2-furylmethyl)amino]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)benzamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2,2,2-trichloroacetamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-3-bromothiophene-2-carboxamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-1-benzofuran-3-carboxamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2,3-dihydro-1-benzofuran-5-carboxamide; N-(3-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)thiophene-2-carboxamide; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(3-methylbut-1-yn-1-yl)phenyl]-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(cyclopropylethynyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[3-(cyclopropylethynyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[3-(cyclopropylethynyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(cyclopropylethynyl)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[3-(cyclopropylethynyl)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[3-(cyclopropylethynyl)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[3-(cyclopropylethynyl)-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-[(1E)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-prop-1-yn-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-prop-1-yn-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-prop-1-yn-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1Z)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1Z)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1E)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1Z)-prop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-{3-[(Z)-2-cyclopropyl-1-fluorovinyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-{3-[(E)-2-cyclopropyl-1-fluorovinyl]phenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 5-(3-{(4S)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile; 5-(3-{(4R)-2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)pentanenitrile; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(1-fluoropent-4-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(1-fluoropent-4-en-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 4-(5-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-2-fluorophenyl)butanenitrile; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-methylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 5-{2-amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-2-methoxybenzonitrile; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(fluoromethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(2-methylphenyl)-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(5-fluoropent-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[3-(5-chloropent-1-yn-1-yl)-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-methylphenyl)-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-ethoxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxypent-4-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hex-5-en-1-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-4-fluoro-1-methylbut-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3,3-difluoroprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-fluoroprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hex-5-en-I-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hexylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-ethylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-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-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-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; (5R)-2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[3-(cyclopropylmethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (R,E)-2-amino-4-(4-(difluoromethoxy)phenyl)-4-(3-(6-methoxyhex-1-enyl)phenyl)-1-methyl-1H-imidazol-5(4H)-one; (5S)-2-amino-5-[3-(2,2-difluoroethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[3-(2,2-difluoroethoxy)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-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; (5R)-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; (5S)-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; (5R)-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; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3-(pent-4-en-1-yloxy)phenyl]-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-{[(1S)-1-methylbut-3-en-1-yl]oxy}phenyl)-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-{[(1R)-1-methylbut-3-en-1-yl]oxy}phenyl)-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(2-methylbut-3-en-1-yl)oxy]phenyl}-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-{3-[(3-methylbut-3-en-1-yl)oxy]phenyl}-3,5-dihydro-4H-imidazol-4-one; (5R)-543-(allyloxy)phenyl]-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-isopropoxyphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(2-fluoroethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-methylbut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-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; (5R)-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; and (5S)-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; or
a tautomer thereof; or
a pharmaceutically acceptable salt thereof.
24 . A compound as claimed in claim 1 , selected from the group consisting of:
2-amino-5-[4-(difluoromethoxy)phenyl]-5-(4-fluoro-3-morpholin-4-ylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-(3-but-3-en-1-yn-1-yl-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2-furylmethyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropoxy)-4-fluorophenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropoxy)-4-fluorophenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3,3-difluoropropoxy)-4-fluorophenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-methylphenyl)-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-ethoxybut-1-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-[3-(4-fluorobut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-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-[4-fluoro-3-(4-fluorobut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-fluorobut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(4-fluorobut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; and (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoroprop-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one; or
a tautomer thereof; or
a pharmaceutically acceptable salt thereof.
25 . A compound as claimed in claim 1 , wherein the compound is as shown in one of the following tables (X or Y):
X
Chiral
R
R′
—
CH2CH3
H
—
CH2CH2CH3
H
—
CH2CH2CH2CH3
H
—
CH2CH2Cl
H
—
CF3
H
—
CH2CH(CH3)2
H
—
CH2CH2CH2CH3
H
—
CH(CH3)2
H
—
cyclopropyl
H
—
cyclobutyl
H
—
CH3CH═CH
H
—
(CH3)2C═CH
H
—
PhCH═CH
H
—
Furan-2-yl
H
—
PhCH2OCH2
H
—
Ph
H
—
Cl3C
H
—
1-Ph-5-CF3-
H
pyrazole-4-yl
—
1-(4-Cl-Ph)-5-
H
CF3-pyrazole-4-yl
—
3-bromo-thiophen-
H
2-yl
—
Benzofuran-3-yl
H
—
Benzofuran-5-yl
H
—
Thiophene-2-yl
H
Y
Chiral
R
R′
—
CH2CH2CH3
H
—
CH2CH2CH2CH3
H
—
(CH3)2CHCH2
H
—
Isopropyl
H
—
Cyclopentyl
H
—
cyclohexyl
H
—
CH3CH═CH
H
—
cycobutyl
H
—
Furan-2-yl-CH2
H
or
a tautomer thereof; or
a pharmaceutically acceptable salt thereof.
26 . A compound of claim 1 , selected from the group consisting of:
a tautomer thereof; or
a pharmaceutically acceptable salt thereof.
27 . 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 according to claim 1 .
28 . The method according to claim 27 , 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.
29 . The method according to claim 27 , wherein said disease or disorder is characterized by the production of β-amyloid deposits or neurofibrillary tangles.
30 . A method for modulating the activity of BACE which comprises contacting a receptor thereof with an effective amount of a compound according to claim 1 .
31 . 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 according to claim 1 .
32 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 1 .
33 . A compound as claimed in claim 1 , for the treatment of a disorder associated with excess BACE activity.
34 . A compound as claimed in claim 33 , 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.
35 . A compound as claimed in claim 33 , wherein said disease or disorder is characterized by the production of 6-amyloid deposits or neurofibrillary tangles.
36 . A compound as claimed in claim 1 , for modulating the activity of BACE which comprises contacting a receptor thereof with an effective amount of a compound according to claim 1 .
37 . A compound as claimed in claim 1 , for the treatment of Alzheimer's disease.
38 . Use of a compound as claimed in claim 1 , in the manufacture of a medicament for the treatment of a disorder associated with excess BACE activity.Cited by (0)
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