This invention relates to 2-amino-5-piperidinylimidazolone compounds and
Use thereof for p-secretase modulation
FIELD OF THE INVENTION
The present invention relates to 2-amino-5-piperidinylimidazolone compounds
and to methods for using them to modulate (and, preferably, inhibit) p-secretase
(BACE) and to reduce P-amyloid deposits and neurofibrillary tangles.
BACKGROUND OF THE INVENTION
P-Amyloid deposits and neurofibrillary tangles are two major pathologic
characterizations associated with Alzheimer's disease (AD). Clinically, AD is
characterized by the of loss of memory, cognition, reasoning, judgment, and
orientation. Also affected, as the disease progresses, are motor, sensory, and
linguistic abilities until global impairment of multiple cognitive functions occurs. These
cognitive losses take place gradually, but typically lead to severe impairment and
eventual death in 4-12 years.
Amyloidogenic plaques and vascular amyloid angiopathy also characterize the
brains of patients with Trisomy 21 (Down's Syndrome), Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other
neurodegenerative disorders. Neurofibrillary tangles also occur in other
neurodegenerative disorders including dementia-inducing disorders (Varghese, J., et
al, Journal of Medicinal Chemistry, 2003. 46, 4625-4630).
P-Amyloid deposits are predominately an aggregate of Aß peptide, which in
turn is a product of the proteolysis of amyloid precursor protein (APP). More
specifically, Aß peptide results from the cleavage of APP at the C-terminus by one or
more γ-secretases, and at the N-terminus by P-secretase enzyme (BACE), also known
as aspartyl protease, as part of the p-amyloidogenic pathway.
BACE activity is correlated directly to the generation of Aß peptide from APP
(Sinha, et al, Nature, 1999. 402, 537-540), and studies indicate that the inhibition of
BACE inhibits the production of Aß peptide (Roberds, S. L, et al, Human Molecular
Genetics, 2001. 10, 1317-1324).
Therefore, it is an object of this invention to provide compounds which are
inhibitors of B-secretase and are useful as therapeutic agents in the treatment,
prevention or amelioration of a disease or disorder characterized by elevated B-
amyloid deposits or B-amyloid levels in a patient.
It is another object of this invention to provide therapeutic methods and
pharmaceutical compositions useful for the treatment, prevention or amelioration of a
disease or disorder characterized by elevated B-amyloid deposits or B-amyloid levels
in a patient.
It is a feature of this invention that the compounds provided may also be useful
to further study and elucidate the activity of the B-secretase enzyme.
These and other objects and features of the invention will become more
apparent by the detailed description set forth hereinbelow.
SUMMARY OF THE INVENTION
The present invention provides a compound of formula I
(Formula Removed)
wherein
R is H, COR7, C02R7, CONR8R9, S02NR8R9, SOmR10, or an alkyl, alkenyl, alkynyl,
cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted;
R1, R2, and R3 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 interrupted by an additional
heteroatom selected from O, N or S;
R4, R5, and R6 are each independently H, halogen, N02, CN, OR11, COR11,
C02Rn, CONR12R13, NR12R13, NR12COR14, NR12S02R14, S02NR12R13, SOnR14
or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted or when attached to adjacent carbon atoms
R4 and R5 or R5 and R6 may be taken together with the atoms to which they
are attached to form an optionally substituted 5- to7-membered ring optionally
interrupted by one, two or three heteroatoms selected from O, N or S;
m and n are each independently 0,1 or 2;
R7 and Rn are each independently H or an alkyl, alkenyl, alkynyl, cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R8, R9, R12 and R13 are each independently H, OR15, COR15, C02R15 or an alkyl,
alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each
optionally substituted or R8 and R9 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 interrupted by an additional heteroatom selected
from O, N or S;
Rio and R14 are each independently an alkyl, alkenyl, alkynyl, cycloalkyl,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R15 is H or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R16, R17 and R18 are each independently H, halogen, CN, OR19 or an alkyl,
cycloalkyl, cyclohetereoalkyl, aryl or heteroaryl group each optionally
substituted; and
R19 is H or an alkyl, cycloalkyl, cyclohetereoalkyl, aryl or heteroaryl group each
optionally substituted; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt
thereof.
The present invention also relates to the use of 2-amino-5-piperidinyl-
imidazolone compounds for the treatment of p-amyloid deposits and neurofibrillary
tangles. These compounds are particularly useful in treating Alzheimer's disease,
cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile
dementia, cerebral amyloid angiopathy, degenerative dementia, or other
neurodegenerative disorders.
DETAILED DESCRIPTION OF THE INVENTION
Alzheimer's disease (AD) is a major degenerative disease of the brain which
presents clinically by progressive loss of memory, cognition, reasoning, judgement and
emotional stability and gradually leads to profound mental deterioration and death.
The exact cause of AD is unknown, but increasing evidence indicates that amyloid
beta peptide (A-beta) plays a central role in the pathogenesis of the disease. (D. B.
Schenk; R. E. Rydel et al, Journal of Medicinal Chemistry, 1995, 21, 4141 and D. J.
Selkoe, Physiology Review, 2001, 81, 741). Patients with AD exhibit characteristic
neuropathological markers such as neuritic plaques (and in p-amyloid angiopathy,
deposits in cerebral blood vessels) as well as neurofibrillary tangles detected in the
brain at autopsy. A-beta is a major component of neuritic plaques in AD brains. In
addition, p-amyloid deposits and vascular p-amyloid angiopathy also characterize
individuals with Downs Syndrome, Hereditary Cerebral Hemmorhage with Amyloidosis
of the Dutch type and other neurodegenreative and dementia-inducing disorders.
Over expression of the amyloid precursor protein (APP), altered cleavage of APP to A-
beta or a decrease in the clearance of A-beta from a patient's brain may increase the
levels of soluble or fibruilar forms of A-beta in the brain. The p-site APP cleaving
enzyme, BACE1, also called memapsin-2 or Asp-2, was identified in 1999 (R. Vassar,
B. D. Bennett, et al, Nature, 1999, 402, 537). BACE1 is a membrane-bound aspartic
protease with all the known functional properties and characteristics of p-secretase.
Low molecular weight, non-peptide, non-substrate-related inhibitors of BACE1 or p-
secretase are earnestly sought both as an aid in the study of the p-secretase enzyme
and as potential therapeutic agents.
Surprisingly, it has now been found that 2-amino-5-piperidinylimidazolone
compounds of formula I demonstrate inhibition of p-secretase and the selective
inhibition of BACE1. Advantageously, said piperidinylimidazolone compounds may be
used as effective therapeutic agents for the treatment, prevention or amelioration of a
disease or disorder characterized by elevated p-amyloid deposits or p-amyloid levels
in a patient. Accordingly, the present invention provides a 2-amino-5-piperidinyl-
imidazolone compound of formula I
(Formula Removed)
wherein
R is H, COR7, C02R7, CONR8R9, SO2NR8R9,SOmR10, or an alkyl, alkenyl, alkynyl,
cycloalkyi, cycloheteroalkyl, aryl or heteroaryl group each optionally
substituted;
RL R2, and R3 are each independently H or an alkyl, cycloalkyi, 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 interrupted by an additional
heteroatom selected from O, N or S;
R4, R5, and R6 are each independently H, halogen, N02, CN, ORn, CORn,
C02Rn, CONR12R13, NR12R13, NR12COR14, NR12S02R14, S02NR12R13, SOnR14
or an alkyl, alkenyl, alkynyl, cycloalkyi, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted or when attached to adjacent carbon atoms
R4 and R5 or R5 and R6 may be taken together with the atoms to which they
are attached to form an optionally substituted 5- to7-membered ring optionally
interrupted by one, two or three heteroatoms selected from O, N or S;
m and n are each independently 0,1 or 2;
R7 and R11 are each independently H or an alkyl, alkenyl, alkynyl, cycloalkyi,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R8 ,R9, R12 and R13 are each independently H, OR15, COR15, C02R15 or an alkyl,
alkenyl, alkynyl, cycloalkyi, cycloheteroalkyl, aryl or heteroaryl group each
optionally substituted or R8 and R9 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 interrupted by an additional heteroatom selected
from O, N or S;
R10 and R14 are each independently an alkyl, alkenyl, alkynyl, cycloalkyi,
cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R15 is H or an alkyl, alkenyl, alkynyl, cycloalkyi, cycloheteroalkyl, aryl or heteroaryl
group each optionally substituted;
R16, R17 and R18 are each independently H, halogen, CN, OR19 or an alkyl,
cycloalkyi, cyclohetereoalkyi, aryl or heteroaryl group each optionally
substituted; and
R19 is H or an alkyl, cycloalkyi, cyclohetereoalkyi, aryl or heteroaryl group each
optionally substituted; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt
thereof.
In one embodiment, R5 is an optionally substituted heteroaryl group.
Representative heteroaryl groups include pyridine, thiophene, thiazole, thiadiazole,
furan, oxazole, oxadiazole, pyrrole, pyrazole, imidazole, triazole, oxathiole, isoxazole,
oxazole, oxatriazole, dioxazole, oxathiazole, tetrazole, pyridazine, pyrimidine,
pyrazine, triazine, oxazine, oxathiazine, or oxadiazine. The heteroaryl group may be
unsubstituted or substituted with alkyl, alkoxy, trifluordalkyl, trifluoroalkoxy, amino,
halogen, hydroxyl, or CN, or forms an N-oxide. For example R5 may be an optionally
substituted pyridine or pyrimidine group.
In another embodiment, R5 is a phenyl group optionally substituted with CN,
OCF3 or halogen.
As used herein, the term "alkyl" includes both straight chain and branched-
chain (unless defined otherwise) monovalent saturated hydrocarbon moieties of 1-12
carbon atoms, preferably 1-6 carbon atoms, more preferably 'lower' alkyl of 1-4 carbon
atoms. Examples of saturated hydrocarbon alkyl moieties include, but are not limited
to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, fert-butyl,
isobutyl, seobutyl; higher homologs such as n-pentyl, n-hexyl, and the like. Alkyl
groups can be optionally substituted. Suitable alkyl substitutions include, but are not
limited to, CN, OH, halogen, alkenyl, alkynyl, cycloalkyl, phenyl, carbamoyl, carbonyl,
alkoxy or aryloxy.
The term "haloalkyl" as used herein designates a CnH2n+1 group having from
one to 2n+1 halogen atoms which may be the same or different and the term
haloalkoxy as used herein designates an OCnH2n+1group having from one to 2n+1
halogen atoms which may be the same or different. Preferably the term haloalkyl
designates CF3 and the term haloalkoxy designates OCF3.
The term "alkenyl", as used herein, refers to either a straight chain or
branched-chain hydrocarbon moiety containing at least one double bond and having
from 2-12 carbon atoms, preferably 2-6 carbon atoms, more preferably 2-4 carbon
atoms. Such hydrocarbon alkenyl moieties may be mono or polyunsaturated, and may
exist in the E or Z configurations. The compounds of this invention are meant to
include all possible E and Z configurations. Examples of mono or polyunsaturated
hydrocarbon alkenyl moieties include, but are not limited to, chemical groups such as
vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl, butadienyl, 2-(butadienyl), 2,4-
pentadienyl, 3-(1,4-pentadienyl), and higher homologs, isomers, or the like.
The term "alkynyl", as used herein, refers to an alkyl group having one or more
triple carbon-carbon bonds. Alkynyl groups preferably contain 2 to 6 carbon atoms.
Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl,
pentynyl, and the like. In some embodiments, alkynyl groups can be substituted with
up to four substituent groups, as described hereinabove.
The term "cycloalkyl", as used herein, refers to a monocyclic, bicyclic, tricyclic,
fused, bridged, or spiro saturated carbocyclic moiety of 3-10 carbon atoms. Any
suitable ring position of the cycloalkyl moiety may be covalently linked to the defined
chemical structure. Examples of cycloalkyl moieties include, but are not limited to,
chemical groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyt,
norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, or the like.
The term "cycloheteroalkyl", as used herein, designates a five- to seven-
membered cycloalkyl ring system containing 1 or 2 heteroatoms, which may be the
same or different, selected from N, O or S and optionally containing one double bond.
Exemplary of the cycloheteroalkyl ring systems included in the term as designated
herein are the following rings wherein X is NR', O or S; and R' is H or an optional
substituent as described hereinbelow:

(Formula Removed)
The term "aryl", as used herein, designates an aromatic carbocyclic moiety of
up to 20 carbon atoms, e.g. 6-20 carbon atoms, which may be a single ring
(monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked
covalently. Examples of aryl moieties include, but are not limited to, chemical groups
such as phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl,
anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl,
and the like. In some embodiments "aryl" groups can be substituted with from 1-5
substituents.
The term "heteroaryl" as used herein designates an aromatic heterocyclic ring
system, e.g. having from 5-20 ring atoms, which may be a single ring (monocyclic) or
multiple rings (bicyclic, up to three rings) fused together or linked covalently.
Preferably, heteroaryl is a 5- to 6-membered ring. The rings may contain from one to
four hetero atoms selected from nitrogen, oxygen, or sulfur, wherein the nitrogen or
sulfur atom(s) are optionally oxidized, or the nitrogen atom(s) are optionally
quatemized. Examples of heteroaryl moieties include, but are not limited to,
heterocycles such as furan, thiophene, pyrrole, pyrazole, imidazole, oxazole,
isoxazole, thiazole, isothiazole, 1 H-tetrazole, 1,3,4-oxadiazole, 1H-1,2,4-triazole, 1,3,4-
triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoxazole, benzisoxazole,
benzothiazole, benzofuran, benzothiophene, thianthrene, , benzimidazole, indole,
indazole, quinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, 9H-
carbazole, a-carboline, or the like.
The term "halogen", as used herein, designates fluorine, chlorine, bromine, or
iodine.
In the specification and claims, when the terms alkyl, alkenyl,
alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl are designated as being
optionally substituted, the substituent groups which are optionally present may be one
or more of those customarily employed in the development of pharmaceutical
compounds or the modification of such compounds to influence their structure/activity,
persistence, absorption, stability or other beneficial property. Specific examples of
such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl,
alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,
alkoxycarbonyl, carboxyl, carboxyalkoxy, carboxyalkyl, alkanoyl, alkylthio,
alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,
benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms or lower alkyl
or lower alkoxy groups. A substituent may be divalent, for instance, oxo,
oxymethyleneoxy or oxyethyleneoxy. Typically, 0-3 substituents may be present.
When any of the foregoing substituents represents or contains an alkyl substituent
group, this may be linear or branched and may contain up to 12, preferably up to 6,
more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt formed by a
compound of formula I and a pharmaceutically acceptable acid such as phosphoric,
sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric,
acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Where the compound of formula I contains an acidic function such as a carboxyl
group, the pharmaceutically acceptable salts may be derived from a base, for instance
a sodium salt.
Compounds of the invention include esters, carbamates or other conventional
prodrug forms, which in general, are functional derivatives of the compounds of the
invention and which are readily converted to the inventive active moiety in vivo.
Correspondingly, the method of the invention embraces the treatment of the various
conditions described hereinabove with a compound of formula I or with a compound
which is not specifically disclosed but which, upon administration, converts to a
compound of formula I in vivo. Also included are metabolites of the compounds of the
present invention defined as active species produced upon introduction of these
compounds into a biological system.
Compounds of the invention may exist as one or more tautomers. One skilled
in the art will recognize that compounds of formula I may also exist as the tautomer (It)
as shown below. °
(Formula Removed)
Tautomers often exist in equilibrium with each other. As these tautomers
interconvert under environmental and physiological conditions, they provide the same
useful biological effects. The present invention includes mixtures of such tautomers as
well as the individual tautomers of Formula I and Formula It.
The compounds of this invention may contain an asymmetric carbon atom and
some of the compounds of this invention may contain one or more asymmetric centers
and may thus give rise to optical isomers and diastereomers. While shown without
respect to stereochemistry in Formula I, the present invention includes such optical
isomers and diastereomers; as well as the racemic and resolved, enantiomerically
pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers
and pharmaceutically acceptable salts thereof. Where a stereoisomer is preferred, it
may in some embodiments be provided substantially free of the corresponding
enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer
refers to a compound that is isolated or separated via separation techniques or
prepared free of the corresponding enantiomer. "Substantially free", as used herein,
means that the compound is made up of a significantly greater proportion of one
stereoisomer, preferably less than about 50%, more preferably less than about 75%,
and even more preferably less than about 90%.
Preferred compounds of the invention are those compounds of formula I
wherein R16, R17 and R18 are H. Another group of preferred compounds are those
compounds of formula I wherein R6 is NR12COR14 or an optionally substituted aryl or
heteroaryl group. A further group of preferred compounds are those formula I
compounds wherein R3 is alkyl, preferably a C1-C4 alkyl group, more preferably methyl.
More preferred compounds of the invention are those compounds of formula I
wherein the pipendinyl ring is attached in the 3- or 4-position. Another group of more
preferred compounds is those compounds of formula I wherein the piperidinyl ring is
attached in the 3- or 4-position; R is COR7; and R1 and R2 are H. A further group of
more preferred compounds are those compounds of formula I wherein the piperidinyl
ring is attached in the 3- or 4-position; R is COR7; R6 is NR12COR14 or an optionally
substituted phenyl or heteroaryl group; and R16, R17 and R18 are H.
Preferred compounds of the invention include:
2-amino-5-(1,1 '-biphenyl-3-yl)-5-(1 -isobutyrylpiperidin-4-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(1,1'-biphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(3-methoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(2-f uroyl)piperidin-4-yl]-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(2-methoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(4-methoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(3,4-dimethoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-[1 -(1,3-benzodioxol-5-ylcarbonyl)piperidin-4-yl]-5-(1,1 '-biphenyl-3-yl)-3-
methyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(1 -naphthoyl)piperidin-4-yl]-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(4-propylbenzoyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(4-propoxybenzoyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-({4-[2-amino-4-(1,1 '-biphenyl-3-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]piperidin-1-yl}carbonyl)benzonitrile;
3-({4-[2-amino-4-(1,1 '-biphenyl-3-yl)-1 -methyl-5-oxo-4,5-dihydro-1H- imidazol-4-
yl]piperidin-1-yl}carbonyl)benzonitrile;
4-({4-[2-amino-4-(1,1 '-biphenyl-3-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]piperidin-1-yl}carbonyl)benzonitrile;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(2-chloro-6-methylisonicotinoyl)piperidin-4-yl]-3-
methyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(3-furoyl)piperidin-4-yl]-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(thien-2-ylcarbonyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(thien-3-ylcarbonyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(phenylsulfonyl)piperidin-4-yl]-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-{1-[(benzyloxy)acetyl]piperidin-4-yl}-5-(1,1'-biphenyl-3-yl)-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-(1 -prop-2-ynylpiperidin-4-yl)-3,5-dihydro-4H-
imidazol-4-one;
5-(1 -acetylpiperidin-4-yl)-2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-(1 -propionylpiperidin-4-yl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-(1 -butyrylpiperidin-4-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3-cyclohexylphenyl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
5-(1-acetylpiperidin-4-yl)-2-amino-5-(3-cyclohexylphenyl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-
4/+imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(2',5,-difluoro-1,1'-biphenyl-3-yl)-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-propoxyphenyl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3-isobutoxyphenyl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(but-3-ynyloxy)phenyl]-3-methyl-3,5-dihydro-
4H-im idazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(cyclopropylmethoxy)phenyl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
A/-{3-[2-amino-4-(1 -benzoylpiperidin-4-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]phenyl}-2-methoxyacetamide;
3-[2-amino-4-(1 -benzoylpiperidin-4-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl]-A/-
isobutylbenzamide;
ethyl 3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidine-1 -
carboxylate;
2-amino-5-[1-(2-furoyl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-
one;
2-amino-5-[1-(isoxazol-5-yl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-
4-one;
2-amino-3-methyl-5-phenyl-5-[1-(trifluoroacetyl)piperidin-3-yl]-3,5-dihydro-4H-imidazol-
4-one;
2-amino-5-[1-(cyclopentylcarbonyl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
5-[1-(1-adamantylcarbonyl)piperidin-3-yl]-2-amino-3-methyl-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-3-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-methyl-5-phenyl-5-[1-(thien-2-ylcarbonyl)piperidin-3-yl]-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-[1-(3-methoxybenzoyl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-3-methyl-5-[1-(3-methylbutanoyl)piperidin-3-yl]-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
4-[3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidin-1 -yl]-4-
oxobutanoic acid;
{2-[3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidin-1 -yl]-2-
oxoethoxy}acetic acid;
5-[3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidin-1 -yl]-5-
oxopentanoic acid;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(5-methoxypyridin-3-yl)phenyl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3'-methoxybiphenyl-3-yl)-3-methyl-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3'-fluorobiphenyi-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3'-chlorobiphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(2',5'-difluorobiphenyl-3-yl)-3-methyl-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3',5'-difluorobiphenyl-3-yl)-3-methyl-3,5-dihydro-
4H-imidazol-4-one; or
a tautomer thereof or a stereoisomer thereof or a pharmaceutically acceptable salt
thereof.
Compounds of the invention may be conveniently prepared using conventional
synthetic methods and, if required, standard separation and isolation techniques. For
example, compounds of formula I wherein R is H (la) may be prepared by reducing a
compound of formula II using standard reduction techniques such as catalytic
hydrogenation. Compounds of formula I wherein R is other than H (lb) may be
prepared by coupling a compound of formula la with a reagent, such as an alkyl- aryl-
or acylhaiide (R-Hal) in the presence of a base. The reactions are shown in Flow
Diagram I wherein Hal represents CI, Br or I.
FLOW DIAGRAM I
(Formula Removed)
Reagents suitable for converting compounds of formula la to compounds of
formula lb include alkyl- or arylhalides, alkyl or aryl acid chlorides, anhydrides,
carboxyiic acids or the like. Compounds of formula II and their preparation are
described in copending US Patent Application Number 60/695305 and International
Application No. PCT/US/2006/024912, which applications are incorporated herein by
reference thereto.
The compounds having formula II can be prepared by reacting a diketone
having formula VII shown below with an aminoguanidine derivative of formula A

(Formula Removed)

wherein Ri and R2 are preferably H, in the presence of a base, such as a metal
carbonate, to give the desired compound having formula II. For example, compounds
of formula II wherein R1 and R2 are H (lla) may be prepared by reacting a
bromobenzene compound of formula III with trifluoromethylsilylacetylene to give the
arylalkyne of formula IV; reacting the formula IV alkyne with a bromopyridine
compound of formula V to give the alkyne compound of formula VI; oxidizing the
formula VI alkyne with an oxidizing agent such as Pd(ll)CI/DMSO, N-
bromosuccinimide/DMSO, ozone, sodium periodate with ruthenium (IV) oxide hydrate,
sulfur trioxide, KMn04, l2/DMSO, or combinations thereof, preferably KMn04, to give
the diketone of formula VII; and reacting said formula VII diketone with an
aminoguanidine derivative of formula VIII in the presence of a base, such as a metal
carbonate, to give the desired formula lla compound. The reaction is shown in flow
diagram II.
FLOW DIAGRAM II
(Formula Removed)

Advantageously, the compounds of formula I act as BACE inhibitors for the
treatment or prevention of p-amyloid deposits and neurofibrillary tangles associated
with such diseases as Alzheimer's disease, Trisomy 21 (Down's Syndrome),
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and
other neurodegenerative disorders. Accordingly, the present invention provides
methods for modulating BACE and treating, preventing, or ameliorating ß -amyloid
deposits and neurofibrillary tangles associated with diseases and disorders such as
Alzheimer's disease, Trisomy 21 (Down's Syndrome), Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other
neurodegenerative disorders. Such methods generally involve administering to a
patient suspected of suffering from or being susceptible to the disease or injury an
effective amount of a compound of formula I. Also according to the present invention
there is provided a method of treating Alzheimer's disease and related senile
dementia's in humans or other mammals which comprises administering to a human or
other mammal an effective amount of a compound of the present invention.
The present invention also provides methods for modulating (and, preferably,
inhibiting) the activity of BACE, comprising administering to a patient and/or contacting
a receptor thereof with an effective amount of at least one compound of Formula I.
Certain methods further comprise determining BACE activity, either before or after said
contacting step.
The present invention also provides methods of ameliorating P-amyloid
deposits in a mammal, comprising administering to said mammal an effective amount
of at least one compound of Formula I. Further methods ameliorate neurofibrillary
tangles in a mammal, and comprise administering to said mammal an effective amount
of at least one compound of Formula I.
Also provided are methods of ameliorating symptoms of Alzheimer's disease,
cognitive impairment, Down's Syndrome, HCHWA-D, cognitive decline, senile
dementia, cerebral amyloid angiopathy, degenerative dementia, or other
neurodegenerative disorders in a mammal, comprising administering to said mammal
an effective amount of at least one compound of Formula I.
As used in accordance with this invention, the term "providing," with respect to
providing a compound or substance covered by this invention, means either directly
administering such a compound or substance, or administering a prodrug, derivative,
or analog which will form the effective amount of the compound or substance within
the body. This invention also covers providing the compounds of this invention to treat
the disease states disclosed herein that the compounds are useful for treating.
The terms "administer", "administering", or "administration", as used herein,
refer to either directly administering a compound or composition to a patient, or
administering a prodrug derivative or analog of the compound to the patient, which will
form an equivalent amount of the active compound or substance within the patient's
body.
The term "patient", as used herein, refers to a mammal, preferably a human.
The terms "effective amount", "therapeutically effective amount" and "effective
dosage" as used herein, refer to the amount of a compound that, when administered to
a patient, is effective to at least partially ameliorate (and, in preferred embodiments,
cure) a condition from which the patient is suspected to suffer. It is understood that
the effective dosage of the active compounds of this invention may vary depending
upon the particular compound utilized, the mode of administration, the condition, and
severity thereof, of the condition being treated, as well as the various physical factors
related to the individual being treated. For treating Alzheimer's disease and other
related senile dementia's, generally, satisfactory results may be obtained when the
compounds of this invention are administered to the individual in need at a daily
dosage of from about 0.1 mg to about 1 mg per kilogram of body weight, preferably
administered in divided doses two to six times per day, or in a sustained release form.
For most large mammals, the total daily dosage is from about 3.5 mg to about 140 mg
preferably from about 3.5 to about 5 mg. In the case of a 70 kg human adult, the total
daily dose will generally be from about 7 mg to about 70 mg and may be adjusted to
provide the optimal therapeutic result. This regimen may be adjusted to provide the
optimal therapeutic response.
The present invention also provides a pharmaceutical composition which
comprises an effective amount of a compound of formula I and a pharmaceutically
acceptable carrier.
The term "carrier", as used herein, shall encompass carriers, excipients, and
diluents. Examples of carriers are well known to those skilled in the art and are
prepared in accordance with acceptable pharmaceutical procedures, such as, for
example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed.
Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), which is
incorporated herein by reference in its entirety. Pharmaceutically acceptable carriers
are those that are compatible with the other ingredients in the formulation and
biologically acceptable.
The compounds of this invention may be administered orally or parenterally,
neat or in combination with conventional pharmaceutical carriers. Applicable solid
carriers can include one or more substances which may also act as flavoring agents,
lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders
or tablet-disintegrating agents or encapsulating materials. They are formulated in
conventional manner, for example, in a manner similar to that used for known
antihypertensive agents, diuretics and 0-blocking agents. Oral formulations containing
the active compounds of this invention may comprise any conventionally used oral
forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids,
suspensions or solutions. In powders, the carrier is a finely divided solid, which is an
admixture with the finely divided active ingredient. In tablets, the active ingredient is
mixed with a carrier having the necessary compression properties in suitable
proportions and compacted in the shape and size desired. The powders and tablets
preferably contain up to 99% of the active ingredient.
Capsules may contain mixtures of the active compound(s) with inert fillers
and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or
tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as
crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
Useful tablet formulations may be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically acceptable
diluents, binding agents, lubricants, disintegrants, surface modifying agents (including
surfactants), suspending or stabilizing agents, including, but not limited to, magnesium
stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch,
gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl
cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia
gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine,
sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol,
sodium chloride, low melting waxes and ion exchange resins. Preferred surface
modifying agents include nonionic and anionic surface modifying agents.
Representative examples of surface modifying agents include, but are not limited to,
poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, colliodol silicon dioxide, phosphates,
sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral
formulations herein may utilize standard delay or time release formulations to alter the
absorption of the active compound(s). The oral formulation may also consist of
administering the active ingredient in water or fruit juice, containing appropriate
solubilizers or emulisifiers as needed.
Liquid carriers may be used in preparing solutions, suspensions, emulsions,
syrups and elixirs. The active ingredient of this invention can be dissolved or
suspended in a pharmaceutically acceptable liquid carrier such as water, an organic
solvent, a mixture of both or pharmaceutical^ acceptable oils or fat. The liquid carrier
can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening
agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples
of liquid carriers for oral and parenteral administration include water (particularly
containing additives as above, e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric alcohols and
polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated
coconut oil and arachis oil). For parenteral administration the carrier can also be an
oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used
in sterile liquid form compositions for parenteral administration. The liquid carrier for
pressurized compositions can be halogenated hydrocarbon or other pharmaceutically
acceptable propellant.
Liquid pharmaceutical compositions, which are sterile solutions or suspensions,
can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous
injection. Sterile solutions can also be administered intravenously. Compositions for
oral administration may be in either liquid or solid form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as
tablets, capsules, powders, solutions, suspensions, emulsions, granules, or
suppositories. In such form, the composition is sub-divided in unit dose containing
appropriate quantities of the active ingredient; the unit dosage forms can be packaged
compositions, for example, packeted powders, vials, ampoules, prefilled syringes or
sachets containing liquids. The unit dosage form can be, for example, a capsule or
tablet itself, or it can be the appropriate number of any such compositions in package
form. Such unit dosage form may contain from about 1 mg/kg to about 250 mg/kg,
and may given in a single dose or in two or more divided doses. Such doses may be
administered in any manner useful in directing the active compounds herein to the
recipient's bloodstream, including orally, via implants, parenterally (including
intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and
transdermally. Such administrations may be carried out using the present compounds,
or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches,
suspensions, solutions, and suppositories (rectal and vaginal).
When administered for the treatment or inhibition of a particular disease state
or disorder, it is understood that the effective dosage may vary depending upon the
particular compound utilized, the mode of administration, the condition, and severity
thereof, of the condition being treated, as well as the various physical factors related to
the individual being treated. In therapeutic application, compounds of the present
invention are provided to a patient already suffering from a disease in an amount
sufficient to cure or at least partially ameliorate the symptoms of the disease and its
complications. An amount adequate to accomplish this is defined as a "therapeutically
effective amount". The dosage to be used in the treatment of a specific case must be
subjectively determined by the attending physician. The variables involved include the
specific condition and the size, age and response pattern of the patient.
In some cases it may be desirable to administer the compounds directly to the
airways in the form of an aerosol. For administration by intranasal or intrabrochial
inhalation, the compounds of this invention may be formulated into an aqueous or
partially aqueous solution.
The compounds of this invention may be administered parenterally or
intraperitoneally. Solutions or suspensions of these active compounds as a free base
or pharmaceutically acceptable salt may be prepared in water suitably mixed with a
surfactant such as hydroxyl-propylcellulose. Dispersions may also be prepared in
glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary
conditions of storage and use, these preparations contain a preservative to inhibit the
growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous
solutions or dispersions and sterile powders for the extemporaneous preparation of
sterile injectable solutions or dispersions. In all cases, the form must be sterile and
must be fluid to the extent that easy syringability exists. It must be stable under the
conditions of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi. The carrier can
be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof,
and vegetable oils.
The compounds of this invention can be administered transdermal^ through
the use of a transdermal patch. For the purposes of this disclosure, thransdermal
administrations are understood to include all administrations across the surface of the
body and the inner linings of bodily passages including epithelial and mucosal tissues.
Such administrations may be carried out using the present compounds, or
pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches,
suspensions, solutions, and suppositories (rectal and vaginal).
Transdermal administration may be accomplished through the use of a
transdermal patch containing the active compound and a carrier that is inert to the
active compound, is non-toxic to the skin, and allows delivery of the agent for systemic
absorption into the blood stream via the skin. The carrier may take any number of
forms such as creams and ointments, pastes, gels and occlusive devices. The creams
and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or
water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or
hydrophilic petroleum containing the active ingredient may also be suitable. A variety
of occlusive devices may be used to release the active ingredient into the blood
stream, such as a semi-permeable membrane covering a reservoir containing the
active ingredient with or without a carrier, or a matrix containing the active ingredient.
Other occlusive devices are known in the literature.
In certain embodiments, the present invention is directed to prodrugs. Various
forms of prodrugs are known in the art, for example, as discussed in, for example,
Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in
Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), "Design
and Application of Prodrugs", Textbook of Drug Design and Development, Chapter 5,
113-191 (1991), Bundgaard, et al., Journal of Drug Deliver reviews, 8:1-38 (1992),
Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and
Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society
(1975).
It is understood that the dosage, regimen and mode of administration of these
compounds will vary according to the malady and the individual being treated and will
be subject to the judgment of the medical practitioner involved. It is preferred that the
administration of one or more of the compounds herein begin at a low dose and be
increased until the desired effects are achieved.
For a more clear understanding, and in order to illustrate the invention more
clearly, specific examples thereof are set forth hereinbelow. The following examples
are merely illustrative and are not to be understood as limiting the scope and
underlying principles of the invention in any way. Various modifications of the
invention, in addition to those described herein, will be apparent to those skilled in the
art from the foregoing description. Such modifications are also intended to fall within
the scope of the appended claims.
Unless otherwise stated, all parts are parts by weight. The following
abbreviations are used: DIPEA is N,N-diisopropylethylamine; DMF is N,N-dimethyl
formamide; DMSO is dimethylsulfoxide; EDCI is 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride; EtOAc is ethyl acetate; TEA is triethylamine; THF is
tetrahydrofuran; HNMR is proton nuclear magnetic resonance, and MS is mass
spectroscopy with (+) referring to the positive mode which generally gives a M+1 (or
M+H) absorption where M = the molecular mass.

EXAMPLE 1
Preparation of 2-Amino-5-(1.1 '-biphenvl-3-vl)-3-methvl-5-piperidin-4-vl-3.5-
dihvdro-4H-imidazol-4-onedihvdrochloride
(Formula Removed)
A suspension of 2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-5-pyridin-4-yl-3,5-
dihydro-4H-imidazol-4-one (1.3 g, 3.8 mmol) in ethanol is treated with cone. HCI (0.47
ml_, 5.7 mmol) followed by Pt02 (84 mg). The reaction mixture is placed on a Parr
shaker under hydrogen (50 psi) and hydrogenated for 18 h. Additional cone. HCI (0.16
mL, 1.9 mmol) is added and the hydrogenation is continued for 2 h. The precipitated
solid is collected by filtration. This solid (with the catalyst) is dissolved in methanol and
filtered to remove the catalyst. The filtrate is concentrated to dryness to give the title
compound (0.95 g, 59%) as a solid, mp 223-226°C, MS(+) ES: 349 (M+H)+.
EXAMPLE 2
Preparation of 2-Amino-5-(1.1 '-biphenvl-3-yl)-5-(1-isobutvrvlpiperidin-4-vl>-3-
methvl-3,5-dihydro-4H-imidazol-4-one

(Formula Removed)
A solution of 2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-5-piperidin-4-yl-3,5-
dihydro-4H-imidazol-4-one (69 mg, 0.2 mmol) in DMF is treated with 2-methyl-
propanoyl chloride (21 mg, 0.2 mmol) and DIPEA (38 mg, 0.3 mmol) at room
temperature. After stirring for 3 h, the reaction is quenched with water and extracted
with ethyl acetate. The combined extracts are washed with water, brine, dried
(MgS04) and concentrated. The resultant residue is purified by chromatography (silica
gel, CH2CI2/2M NH3 in MeOH: 95/5) to afford the title compound (60 mg, 72%) as a
white solid, mp 131-134°C, MS (+) ES: 419 (M+H)+.
EXAMPLE 3
Preparation of 2-Amino-5-(1.1'-biphenvl-3-yl)-3-methvl-5-ri-(thien-2-v»carbonvn-
piperidin-4-vl]-3.5-dihydro-4H-imidazol-4-one

(Formula Removed)

To a suspension of 2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-5-piperidin-4-yl-3,5-
dihydro-4H-imidazol-4-one (obtained by dissolving the corresponding hydrochloride
salt in methanol, neutralizing with 2M NHa/MeOH and evaporation of the mixture to
dryness) (80 mg, 0.18 mmol, assuming 2 equiv of remaining NH4CI in the mixture) in
CHCI3 is added 2-thiophenecarboxylic acid (23 mg, 0.18 mmol) at room temperature.
The mixture is stirred for 5 minutes and 1 -(3-dimethylaminopro- pyl)-3-
ethylcarbodimide hydrochloride (51 mg, 0.26 mmol) is added. After stirring for 2 h, the
reaction is quenched with saturated aqueous Na2C03 and extracted with ethyl acetate.
The combined extracts are washed sequentially with saturated aqueous Na2C03 and
brine, then dried (MgS04) and concentrated. The crude material is purified by
chromatography (silica gel, CH2CI2/2M NH3 in MeOH: 92/8) to afford the title
compound (51 mg, 63%) as a white solid, mp: 135-137°C, MS (+) ES: 459 (M+H)+.
EXAMPLES 4-22
Preparation of 2-Amino-5-(1.1 '-biphenyl-3-vlV5-n-substituted-piperidin-4-vn-3-
methvl-3.5-dihvdro-4H-imidazol-4-one

(Formula Removed)

Using essentially the same procedures described in Examples 2 and 3 and
employing the appropriate reagent, i.e. acid, acid chloride, sulfonyl chloride or alkyl
chloride, the compounds shown in Table I are obtained and identified by NMR and
mass spectral analyses.
TABLE I
(Table Removed)
EXAMPLE 23
Preparation of 2-Amino-5-(3-cvclohexvlphenvl)-3-methvl-5-piperidin-4-yl-3.5-
dihvdro-4H-imidazol-4-one hydrochloride

(Formula Removed)

To a suspension of 2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-5-pyridin-4-yl-3,5-
dihydro-4H-imidazol-4-one (0.71 g, 2.08 mmol) in ethanol is added cone. HCI (0.26
mL, 3.12 mmol) followed by Pt02 (91 mg). The reaction mixture is placed on a Parr
shaker under hydrogen (50 psi) and hydrogenated for 48 h. The catalyst is removed
by filtration and the filtrate is concentrated to dryness to give the title compound (0.87
g, 96%) as a solid, mp 212-215°C, MS(+) ES: 355 (M+H)+.
EXAMPLES 24 and 25
Preparation of 2-Amino-5-(1-substitutedpiperidin-4-vl)-5-(3-cvclohexylphenvh-3-
methvl-3,5-dihydro-4H-imidazol-4-one
(Formula Removed)
Using essentially the same procedures described in Example 2 and employing
the appropriate acid chloride, the compounds shown in Table II are obtained and
identified by NMR and mass spectral analyses.
TABLE II
(Table Removed)

EXAMPLE 26
Preparation of 2-Amino-3-methvl-5-phenvl-5-piperidin-3-vl-3,5-dihvdro-4H
-imidazol-4-one
(Formula Removed)
A mixture of 2-amino-3-methyl-5-phenyl-5-pyridin-3-yl-3,5-dihydro-4H-imidazol-
4-one (4.9 g, 18.05 mmol), Pt02 (0.24 g) and 4 M HCI (9 ml) ethanol is placed on a
Parr shaker under hydrogen (48 psi) and hydrogenated overnight. After filtrating off
the catalyst, the filtrate is neutralized with saturated aqueous Na2C03to pH -10 and
concentrated to dryness to give the title compound as a white solid (contained a
mixture of Na2C03 and NaCI salts) (6.7 g). MS(+) ES: 273 (M+H)+.
EXAMPLE 27
Preparation of 2-Amino-3-methvl-5-phenvl-5-piperidin-4-vi-3.5-dihydro-4H-
imidazol-4-one
(Formula Removed)
A mixture of 2-amino-3-methyl-5-phenyl-5-pyridin-4-yl-3,5-dihydro-4H-imidazol-
4-one (533 mg, 2.00 mmol), Pt02 (0.57 mg) and acetic acid (3 ml) in ethanol is placed
on a Parr shaker under hydrogen (50 psi) and hydrogenated for 24 h. The reaction
mixture is treated with cone. HCI (pH = ~3) and Pt02 (227 mg). The hydrogenation is
continued for 48 h. The catalyst is removed by filtration and the filtrate is neutralized
with cone. NH4OH. The EtOH is removed and the residue is extracted with 4/1
CH2Cl2/'PrOH. The combined extracts are washed with H2O, brine, dried (MgS04),
filtered and concentrated to dryness to give the title compound (122 mg, 22%) as a
white solid, mp 269-271 °C, MS(-) ES: 271 (M+H)EXAMPLE 28
Preparation of N-(3-Ethynvlphenyl)-2-methoxvace :amide
(Formula Removed)
A cooled solution of 3-ethynylphenylamine (7.02 g, 60 mmol) and TEA (7.28 g,
72 mmol) in methylene chloride is treated dropwise with a solution of methoxyacetyl
chloride (7.8 g, 72 mmol) in methylene chloride over a period of 30 min at 0 °C,
allowed to warm to room temperature, stirred overnight and concentrated in vacuo.
The resultant residue is partitioned between water and ethyl acetate. The organic
phase is separated, washed sequentially with saturated NaHC03 and H20, dried over
MgS04 and evaporated to dryness to afford the title compound as a colorless oil, 10.2
g (90% yield), 1HNMR (CDCI3): 5 (ppm) 3.04 (s, 1H,), 3.48 (s, 3H), 3.98 (s, 2H), 7.24
(m, 2H), 7.61 (d, 1H), 7.66 (s, 1H), 8.21 (s, b, 1H).
EXAMPLE 29
Preparation of 2-Methoxv-N-(3-pyridin-4-vlethvnvlphenvDacetamide

(Formula Removed)

A mixture of 4-bromopyridine hydrochloride (10.40 g, 54 mmol), Cul (201 mg),
Pd(PPh3)2CI2(1.13 g, 1.62 mmol) and triethyl amine (38 mL) is stirred for 30 minutes at
room temperature, treated with a solution of N-(3-ethynylphenyl)-2-methoxyacetamide
(10.2 g, 54 mmol) in DMF, heated at 65-70 °C for 12 h, cooled to room temperature
and partitioned between water and EtOAc. The organic layer is separated, dried over
MgS04 and concentrated in vacuo. The resultant residue is purified by flash
chromatography (silica gel, EtOAc: 100%) to afford the title compound as a solid, 8.0 g
(57% yield), 1HNMR (CDCI3): 5 (ppm) 3.50 (s, 3H), 4.02 (s, 2H), 7.31-7.33 (m, 4H),
7.45 (b, 2H), 7.56 (d, 1H), 7.85 (s, 1H), 8.30 (s, 1H).
EXAMPLE 30
Preparation of 2-Methoxv-N-r-3-;2-oxo-2-pvridin-4-vl-acetvlV-phenvnacetamide
(Formula Removed)
A solution of 2-methoxy-N-(3-pyridin-4-ylethynyl-phenyl)-acetamide (8.0 g, 30
mmol) in acetone is treated, with stirring, with a solution of MgS04 (5.51 g, 46 mmol)
and NaHC03 (1.51 g, 18 mmol) in water, followed by treatment, in one portion, with
KMn04 (10.43 g, 66 mmol). After stirring for 5 minute, the reaction mixture is extracted
with ether. The combined extracts are dried over MgS04 and concentrated to dryness
to afford the title compound as a solid, 2.7g (30% yield), 1HNMR (CDCI3): 5 (ppm)
3.50 (s, 3H), 4.02 (s, 2H), 7.51 (t, 1H) 7.71 (d, 2H), 7.76 (d, 2H) 8.06 (d, 1H), 8.08 (s,
1H), 8.43 (s,1H), 8.86 (d,2H).
EXAMPLE 31
Preparation of N-r3-(2-Amino-1 -methvl-5-oxo-4-pvridin-4-vl-4.5-dihvdro-1 H-
imidazol-4-vl)phenvn-2-methoxyacetamide

(Formula Removed)
A mixture of 2-methoxy-N-[-3-(2-oxo-2-pyridin-4-yl-acetyl)-phenyl]acetamide
(2.7 g, 9 mmol), methylguanidine (1.98 g, 18 mmol) and Na2C03 (2.86 g, 27.2 mmol)
in ethanol and water is heated at reflux temperature for 3 h and concentrated in vacuo.
The resultant residue is purified by flash chromatography (silica gel, EtOAc/2.0M
ethanolic NH3: 90/10 to 80/20) to afford the title compound as a solid, 1.5 g (47%
yield), mp 92-93 °C; MS (+) ES: 394 [M+H]+.
EXAMPLE 32
Preparation of N-r3-(2-Amino-1 -methyl-5-oxo-4-piperidin-4-vl-4.5-dihvdro-1 H
imidazol-4-vl)phenvn-2-methoxvacetamide

(Formula Removed)
A mixture of N-[3-(2-amino-1-methyl-5-oxo-4-pyridin-4-yl-4,5-dihydro-1H-
imidazol-4-yl)phenyl]-2-methoxyacetamide (353 mg, 1.0 mmol), Pt02 (40 mg) and
concentrated hydrochloride acid (0.17 ml_, 2.0 mmol) is hydrogenated at 45 psi for 24
h at ambient temperature. The reaction mixture is filtered and the filtrate is
concentrated to dryness. The resultant residue is dissolved in ethanol and stirred with
Amberlyst A-26(OH) ion exchange resin (1.0 g) for 24 h and filtered. The filtrate is
concentrated to dryness to afford the title compound as a solid, 340 mg (95% yield),
mp 170-174°C, MS (+) ES: 360 [M+H]+.
EXAMPLE 33
Preparation of M-[3-(2-Amino-4-(1 -r4-(benzvloxv)benzovnpiperidin-4-vl}-1 -methvl-
5-oxo-4.5-dihvdro-1W-imidazol-4-yl)phenvn-2-methoxvacetamide

(Formula Removed)

A cooled solution of N-[3-(2-amino-1-methyl-5-oxo-4-piperidin-4-yl-4,5-dihydro-
1Himidazol-4-yl)phenyl]-2-methoxyacetamide (180 mg, 0.5 mmol) and
p-benzyloxybenzoic acid (114 mg, 0.5 mmol) in methylene chloride and DMF is treated
portionwise with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (105
mg, 0.55 mmol) at 0°C, stirred for 2 h at 0°C and for 12 h at room temperature and
concentrated in vacuo. The resultant residue is purified by flash chromatography
(silica gel, EtOAc/2.0M ethanolic NH3: 80/20) to afford the title compound as a white
solid, (80% yield), mp 149-152°C, MS (+) ES: 570 [M+H]+.
EXAMPLE 34
Preparation of N-(3-(2-Amino-4-[ 1 -(4-hvdroxvbenzovnpiperidin-4-vn-1 -methvl-5-
oxo-4,5-dihydro-4H-imidazol-4-vl)phenvl)-2-methoxvacetamide

(Formula Removed)

A mixture of N-(3-{2-amino-4-[1-(benzyloxybenzoyl)-piperidin-4-yl]-1-methyl-5-
oxo-4,5-dihydro-1 H imidazol-4-yl}phenyl)-2-methoxyacetamide (50 mg, 0.088 mmol)
and Pd/C (5 mg) in ethanol is hydrogenated at 45 psi for 2 h and filtered. The filtrate is
concentrated to dryness to afford the title compound as a solid, 40 mg (95% yield), mp
184-187°C, MS (+) ES: 480 [M+Hf.
EXAMPLE 35
Preparation of Methyl 4-{r4-(2-amino-4-[3-r(methoxvacetyl)aminolphenvl}-1-
methvl-5-oxo-4.5-dihvdro-4H-imidazol-4-vl}piperidin-1-vncarbonvl}benzoate

(Formula Removed)
Using the essentially same procedure described in Example 33 and employing
terephthalic acid monomethyl ester, the title compound is obtained as a solid, mp 1 Sl-
1630, MS (+) ES: 521 [M+H]+.
EXAMPLE 36
Preparation of Sodium 4-{(4-(2-Amino-4-[3-r(rnethoxvacetvl)aminolphenvl)-1-
methvl-5-oxo-4.5-dihvdro-1Wmidazol-4-vhpiperidin-1-vncarbonyl}benzoate

(Formula Removed)

A solution of NaOH (7.06 mg, 0.177 mmol) in ethanol is treated with 4-(4-{2-
amino-4-[3-(2-methoxyacetylamino)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-
yl}piperidine-1-carbonyl)benzoic acid methyl ester (92 mg, 0.177 mmol), stirred for 48
h at room temperature and concentrated in vacuo. The resultant residue is dissolved
in a small amount of CH2CI2, treated with ether and filtered. The filtercake is dried to
afford the title compound as a solid, 70 mg (75% yield), mp >250°C, MS (+) ES: 507
[M+H]+.
EXAMPLES 37-58
Preparation of AH3-12-Amino-4-H-acvlpiperidin-4-vn-1 -methvl-5-oxo-4.5-dihvdro-
-4H-imidazol-4-vl}phenyl)-2-methoxvacetamide

(Formula Removed)

Using essentially the same procedure described in Example 33 and employing
the appropriate acid, the compounds shown in Table III are obtained and identified by
NMR and mass spectral analyses.
(Table Removed)
EXAMPLE 59
Preparation of N-{3-[2-Amino-4-(1 -benzvlpiperidin-4-vl)-1 -methyl-5-oxo-4.5-
dihvdro-4H-imidazol-4-vnphenyi}-2-methoxvacetamide
(Formula Removed)
A mixture of N-[3-(2-amino-1-methyl-5-oxo-4-pyperidin-4-yl-4,5-dihydro-1/-/
imidazol-4-yl)phenyl]-2-methoxyacetamide (180 mg, 0.5 mmol), benzylbromide (85
mg, 0.5 mmol) and K2C03 (138 mg, 1.0 mmol) in acetonitrile and ethanol is stirred at
room temperature for 24 h and concentrated in vacuo. The resultant residue is purified
by flash chromatography (silica gel, EtOAc/2.0M ethanolic NH3: 80/20) to afford the
title compound as a white solid, 102 mg (46% yield), mp 120-123 °C, MS (+) ES: 450
[M+H]+.
EXAMPLE 60
Preparation of Ethyl 3-(2-Amino-1-methvl-5-oxo-4-phenvl-4.5-dihydro-1K-
imidazol-4-vl)piperidine-1-carboxvlate
(Formula Removed)
A solution of 2-amino-3-methyl-5-phenyl-5-(piperidin-3-yl)-3,5-dihydroimidazol-
4-one (0.096 g, 0.35 mmol) in DMSO is treated sequentially with a solution of
diisopropylethylamine (DIPEA) (0.5 mL) in THF and ethyl chloroformate (0.32 mmol),
shaken for 16 h and concentrated in vacuo under a nitrogen stream. The resultant
residue is dissolved in DMSO and purified by preparative reverse phase HPLC1 and
characterized by LCMS2 analysis, M+H 345, retention time 2.07 min.
Gilson preparataive reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID,
5uM column; 2 mL injection; Solvent A: 0.02% NH4OH/water; Solvent B: 0.02%
NH4OH/acetonitrile; Gradient: Time 0: 95%A; 2 min: 95% A; 14 min: 10% A; 16 min:
95%A; Flow rate 22.5 mL/min; Detection: 254 nm DAD
2LCMS Conditions: Hewlett Packard 1100 HPLC system; Waters Xterra MS C18, 2 mm
(i.d.) x 50 mm (length), 3.5 urn column, set at 50°C; Flow rate 1.0 mL/min; Solvent A:
0.02% NH4OH/water; Solvent B: 0.02% NH4OH/acetonitrile; Gradient: Time 0: 10% B; 2.5
min: 90% B; 3 min: 90% B; Sample concentration: -2.0 mM; Injection volume: 5 u.L;
Detection: 220 nm, 254nm DAD.
EXAMPLES 61-73
Preparation of 2-Amino-5-(phenvl)-5-(1 -substituted-piperidin-3-yl)-3-methvl-3,5-
dihydro-4H-imidazol-4-one

(Formula Removed)
Using essentially the same procedure described in Example 60 and employing
the appropriate reagent, i.e. acid, anhydride or acid chloride, the compounds shown in
Table IV are obtained, and identified by LCMS analysis. HPLC and LCMS conditions
are the same as those used in Example 60. The column heading RT designates
retention time.
(Table Removed)
*diastereomer, 2nd diastereomer rt is 1.31 min
"diastereomer, 2nd diastereomer rt is 1.68 min
EXAMPLE 74
Preparation of (1-Benzovlpiperidin-4-yl)methanol

(Formula Removed)
A cooled solution of piperidin-4-ylmethanol (2.6 g, 22.6 mmol) and triethyl
amine (4.6 g, 45.2 mmol) in methelene chloride was treated dropwise with stirring with
a solution of benzoyl chloride (3.16 g, 22.6 mmol) in methelene chloride over a period
of 30 min. After addition is complete, the reaction mixture is allowed to warm to room
temperature, stirred for 4 h at room temperature and concentrated under vacuum. The
resultant residue is purified by flash chromatography (silica gel, EtOAc: 100%) to
afford the title compound as an oil, 3.0 g (60% yield), which solidified upon standing.
MS (+) ES: 220.1 (M+H)+, 1HNMR (CDCI3) 8 (ppm) 1.23 (b, 2H), 1.76 (b, 3H), 2.88 (d,
2H), 3.51 (d, 2H), 3.81 (b, 1H), 4.72 (s, 1H), 7.39 (m, 5H).
EXAMPLE 75
Preparation of 1-Benzovlpiperidine-4-carbaldehvde
(Formula Removed)

To a suspension of pyridinium chlorochromate (4.4 g, 20.5 mmol) in methylene
chloride is added in one portion a solution of (1-benzoylpiperidin-4-yl)methanol (3.0 g,
13.7 mmol) in methylene chloride. The reaction mixture is stirred under nitrogen at
room temperature for 90 min, diluted with ether and filtered through a pack of silica gel.
The filtercake is washed with ethyl acetate. The filtrates are combined and
concentrated to dryness to afford the title compound as an oil, 1.5 g (50% yield). MS
(+) ES: 218 (M+H)+, 1HNMR (DMSO-d6) 5 (ppm) 1.42 (b, 2H), 1.84 (b, 2H), 2.58 (m,
1H), 3.03 (b, 2H), 3.46 (b, 1H), 4.19 (s, 1H), 7.31-7.43 (m, 5H), 9.56 (s, 1H).
EXAMPLE 76
Preparation of 1-Benzovl-4-ethynvlpiperidine
(Formula Removed)
Astirred mixture of 1-benzoylpiperidine-4-carbaldehyde (1.3 g, 6 mmol) and
K2C03 (1.65 g, 12 mmol) in methanol is treated dropwise with dimethyl (1-diazo-2-
oxopropyl)phosphonate (1.38 g, 7.2 mmol) over a 10 min. period, stirred for 4 h,
diluted with ether and washed sequentially with 5% sodium bicarbonate and water.
The organic phase is dried over MgS04 and concentrated in vacuo. The resultant
residue is purified by flash chromatography using ethyl acetate/hexane (30/70) as
eluent to afford the title compound as a white solid, 1.2 g (94% yield), mp 101-103°C.
MS (+) ES: 214.1 (M+H)+, 1HNMR (DMSO-d6): 8(ppm) 1.45 (b, 2H), 1.74 (b, 2H), 2.62
(m, 1H), 3.17 (b, 2H), 3.40 (b, 1H), 3.91 (b, 1H), 7.30-7.42 (m, 5H).
EXAMPLE 77
Preparation of 1-Benzovl-4-[(3-bromophenvl)ethynvnpiperidine

(Formula Removed)
A mixture of 1 -benzoyl-4-ethynylpiperidine (852 mg, 4 mmol) and 1 -bromo-3-
iodobenzene (1.13 g, 4 mmol), Cul (38 mg, 0.2 mmol), Pd(PPh3)2CI2(184 mg,
0.16 mmol) in a mixture of triethyl amine (12 mL) and acetomlrile (6 mL) is heated at
reflux temperature for 3 h, cooled to room temperature and evaporated under reduced
pressure. The resultant residue is partitioned between water and EtOAc. The organic
phase is separated, dried over MgS04 and concentrated in vacuo. This residue is
purified by flash chromatography (silica gel, EtOAc/hexane: 20/80 to 50/50) to afford
the title compound as a colorless oil, 1.1 g (75% yield). MS (+) ES: 368.0(M+H)+,
1HNMR (DMSO-d6): 8 (ppm) 1.57 (b, 2H), 1.83 (b, 2H), 2.95 (m, 1H), 3.21 (b, 1H),
3.38 (b, 1H), 3.44 (b, 1H), 3.96 (b, 1H), 7.27 (t, 1H), 7.34-7.42 (m, 6H), 7.50 (d, 1H),
7.57(s, 1H).
EXAMPLE 78
Preparation of 1-(1-Benzovlpiperidin-4-vl)-2-(3-bromophenyl)ethane-1,2-dione

(Formula Removed)
A solution of 1-benzoyl-4-[(3-bromophenyl)ethynyl]piperidine (1.1 g, 3 mmol) in
acetone is treated with stirring with a solution of MgS04 (540 mg, 4.5 mmol) and
NaHC03 (150 mg, 1.8 mmol) in water, treated in one portion with solid KMn04 (1.42 g,
9 mmol), stirred for 10 min and extracted with ether. The extracts are combined, dried
over MgS04 and concentrated in vacuo to afford the title compound as a yellow oil 900
mg (76% yield). MS (+) ES: 400(M+H)+, 1HNMR (DMSO-d6): 8 (ppm) 1.55 (b, 2H),
1.81 (b, 2H), 2.95 (b, 1H), 3.09 (b, 1H), 3.40 (m, 1H), 3.65 (b, 1H), 4.42(b, 1H), 7.30-
7.45 (m, 5H), 7.51 (t, 1H), 7.90 (m, 1H), 8.00 (s, 1H).
EXAMPLE 79
Preparation of 2-Amino-5-n-benzovlpiperidin-4-vl)-5-(3-bromophenvl)-3-methvl-
3.5-dihydro-4H-imidazol-4-one

A mixture of 1-(1-benzoylpiperidin-4-yl)-2-(3-bromophenyl)ethane-1,2-dione
(900 mg, 2.25 mmol), methylguanidine (493 mg, 4.5 mmol) and Na2C03 (567 mg, 5.4
mmol) in ethanol is heated at reflux temperature for 3 h, cooled to room temperature
and concentrated in vacuo. The resultant residue is purified by flash chromatography
(silica gel, EtOAc/2.0M ethanolic NH3: 95/5) to afford the title compound as a white
solid, 700 mg (68% yield), mp >250°C. MS (+) ES: 455.1 (M+H)+, 1HNMR (DMSO-d6):
5 (ppm) 1.02-1.04 (b, 4H), 2.20 (b, 1H), 2.48-2.58 (b, 2H), 2.88 (s, 3H), 3.00(b, 1H),
3.55 (b, 1H), 4.33 (b, 1H), 6.70 (s, 2H), 7.27 (m, 2H), 7.41 (m, 3H), 7.61 (d, 1H), 7.74
(s, 1H).
EXAMPLES 80-87
Preparation of 2-amino-5-(1-benzovlpiperidin-4-yl)-5-(3-substituted-phenvl}-3-
methyl-3.5-dihvdro-4H-imidazol-4-one Compounds
(Formula Removed)
A mixture of an appropriately substituted boronic acid (R4-B(OH)2) (0.528
mmol), dichloro(triphenylphosphine)palladium (18.5 mg, 0.0264 mmol),
triphenylphosphine (3.5 mg (0.0132 mmol) and sodium carbonate (83 mg, 0.8 mmol) is
treated with a solution of 2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3-bromophenyl)-3-
methyl-3,5-dihydro-4H-imidazol-4-one in toluene/ethanol (1/1), heated to reflux
temperature for 3 h, cooled to room temperature and concentrated in vacuo. The
resultant residue is purified by chromatography (silica gel, EtOAc/2M ethanolic NH3:
90/10) to afford the compounds shown in Table V. The compounds shown in Table V
were identified by NMR and mass spectral analyses.
(Table Removed)
EXAMPLE 88
Evaluation of BACE-1 Binding Affinity of Test Compounds
Fluorescent Kinetic Assay
Final Assay Conditions: 10 nM human BACE1 (or 10 nM Murine BACE1), 25 \M
substrate (WABC-6, MW 1549.6, from AnaSpec), Buffer: 50 mM Na-Acetate, pH 4.5,
0.05% CHAPS, 25% PBS, room temperature. Na-Acetate was from Aldrich, Cat.#
24,124-5, CHAPS was from Research Organics, Cat. # 1304C 1X, PBS was from
Mediatech (Cellgro), Cat# 21-031-CV, peptide substrate AbzSEVNLDAEFRDpa was
from AnaSpec, Peptide Name: WABC-6
Determination of stock substrate (AbzSEVNLDAEFRDpa) concentration: ~ 25 mM
stock solution is made in DMSO using the peptide weight and MW, and diluted to -25
u.M (1:1000) in 1X PBS. Concentration is determined by absorbance at 354 nm using
an extinction coefficient e of 18172 M'1cm"\ the concentration of stock substrate is
corrected, and the substrate stock stored in small aliquots in -80° C.
[Substrate Stock] = ABS 354nm * 106 /18172 (in mM)
The extinction coefficient e354nm was adapted from TACE peptide substrate, which had
the same quencher-fluorophore pair.
Determination of Stock Enzyme Concentration: the stock concentration of each
enzyme is determined by absorbance at 280 nm using e of 64150 M'1cm"1 for hBACEl
and MuBACEl in 6 M Guanidinium Hydrochloride (from Research Organics, Cat. #
5134G-2), pH ~ 6. The extinction coefficient e280nm for each enzyme was calculated
based on known amino acid composition and published extinction coefficients for Trp
(5.69 M"1 cm'1) and Tyr (1.28 M"1 cm"1) residues (Anal. Biochem. 182, 319-326).
Dilution and mixing steps: total reaction volume: 100 uL
2X inhibitor dilutions in buffer A(66.7 mM Na-Acetate, pH 4.5, 0.0667%
CHAPS) were prepared,
4X enzyme dilution in buffer A(66.7 mM Na-Acetate, pH 4.5, 0.0667% CHAPS)
were prepared,
100 uM substrate dilution in 1X PBS was prepared, and
50 uL 2X Inhibitor, 25 uL 100 uM substrate are added to each well of 96-well
plate (from DYNEX Technologies, VWR #: 11311-046), immediately followed by 25 u.L
4X enzyme (added to the inhibitor and substrate mix), and the fluorescence readings
are initiated.
Fluorescence Readings: Readings at λex 320 nm and λem 420 nm are taken every 40
sec for 30 min at room temperature and the linear slope for substrate cleavage rate (Vj)
determined.
Calculation of % Inhibition:
% Inhibition = 100 * (1 - Vi / v0)
V;: substrate cleavage rate in the presence of inhibitor
v0: substrate cleavage rate in the absence of inhibitor
IC^n Determination:
% Inhibition = ((B * IC50n) + (100 * l0n)) / (IC50" + lon)
(Model # 39 from LSW Tool Bar in Excel where B is the % inhibition from the enzyme
control, which should be close to 0.) % Inhibition is plotted vs. Inhibitor Concentration
(l0) and the data fit to the above equation to obtain IC50 value and Hill number (n) for
each compound. Testing at least 10 different inhibitor concentrations is preferred.
The data obtained are shown in Table VI below.
For Table VI
A = 0.01uM-1.00uM
B = 1.01uM-3.00uM
C = >3.00µM
(Table Removed)

WE CLAIM:
1.

A 2-amino-5-piperidinylimidazolone compounds of formula

(Formula Removed)
wherein
R is H, COR7, C02R7, CONRsRg, S02NR8Rg, SOmR10, or an alkyl, alkenyl, alkynyl,
cycloalkyi, cycloheteroalkyi, aryl or heteroaryl group each optionally
substituted;
R1, R2, and R3 are each independently H or an alkyl, cycloalkyi, cycloheteroalkyi,
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 interrupted by an additional
heteroatom selected from O, N or S;
R4, R5, and R6 are each independently H, halogen, N02, CN, ORn, CORn,
CO2R11, CONR12R13, NR12R13, NR12COR14, NR12S02R14, S02NR12R13, SOnR14
or an alkyl, alkenyl, alkynyl, cycloalkyi, cycloheteroalkyi, aryl or heteroaryl
group each optionally substituted or when attached to adjacent carbon atoms
R4 and R5 or R5 and R6 may be taken together with the atoms to which they
are attached to form an optionally substituted 5- to7-membered ring optionally
interrupted by one, two or three heteroatoms selected from O, N or S;
m and n are each independently 0,1 or 2;
R7 and R11 are each independently H or an alkyl, alkenyl, alkynyl, cycloalkyi,
cycloheteroalkyi, aryl or heteroaryl group each optionally substituted;
R8, R9, R12 and R13 are each independently H, OR15, COR15, CO2R15 or an alkyl,
alkenyl, alkynyl, cycloalkyi, cycloheteroalkyi, aryl or heteroaryl group each
optionally substituted or R8 and R9 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 interrupted by an additional heteroatom selected
from O, N or S;
R10 and R14 are each independently an alkyl, alkenyl, alkynyl, cycloalkyi,
cycloheteroalkyi, aryl or heteroaryl group each optionally substituted;
R15 is H or an alkyl, alkenyl, alkynyl, cycloalkyi, cycloheteroalkyi, aryl or heteroaryl
group each optionally substituted;
R16, R17 and R18 are each independently H, halogen, CN, OR19 or an alkyl,
cycloalkyi, cyclohetereoalkyl, aryl or heteroaryl group each optionally
substituted; and
R19 is H or an alkyl, cycloalkyi, cyclohetereoalkyl, aryl or heteroaryl group each
optionally substituted; or
a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt
thereof.
2. The compound according to claim 1 wherein R16, R17 and R18 are H.
3. The compound according to claim 1 wherein Ri and R2 are H.
4. The compound according to claim 1 wherein R3 is a C1-C4 alkyl group.
5. The compound according to claim 1 wherein R6 is NR12COR14 or an
optionally substituted aryl or heteroaryl group.
6. The compound according to claim 2 wherein the piperidinyl ring is
attached in the 3- or 4-position.
7. The compound according to claim 2 wherein R3 is C1-C4 alkyl and R6 is
NR12CORi4 or an optionally substituted phenyl or heteroaryl group.
8. The compound according to claim 6 wherein R is COR7 and R1 and R2
are H.
9. The compound according to claim 1 selected from the group consisting
essentially of:
2-amino-5-(1,1 '-biphenyl-3-yl)-5-(1 -isobutyrylpiperidin-4-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1 -benzoylpiperidin-4-yl)-5-(1,1 '-biphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(3-methoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(2-furoyl)piperidin-4-yl]-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1'-biphenyl-3-yl)-5-[1-(2-methoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(4-methoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(3,4-dimethoxybenzoyl)piperidin-4-yl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-[1 -(1,3-benzodioxol-5-ylcarbonyl)piperidin-4-yl]-5-(1,1 '-biphenyl-3-yl)-3-
methyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(1 -naphthoyl)piperidin-4-yl]-3,5-dihydro-
4/-Aim idazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(4-propylbenzoyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(4-propoxyberizoyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-({4-[2-amino-4-(1,1 '-biphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]piperidin-1-yl}carbonyl)benzonitrile;
3-({4-[2-amino-4-(1,1 '-biphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]piperidin-1-yl}carbonyl)benzon'rtrile;
4-({4-[2-amino-4-(1,1'-biphenyl-3-yl)-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]piperidin-1-yl}carbonyl)benzonitrile;
2-amino-5-(1,1'-biphenyl-3-yl)-5-[1-(2-chloro-6-methylisonicotinoyl)piperidin-4-yl]-3-
methyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-5-[1 -(3-furoyl)piperidin-4-yl]-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-5-[1-(thien-2-ylcarbonyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(thien-3-ylcarbonyl)piperidin-4-yl]-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-[1 -(phenylsulfonyl)piperidin-4-yl]-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-{1-[(benzyloxy)acetyl]piperidin-4-yl}-5-(1,1'-biphenyl-3-yl)-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1,1 '-biphenyl-3-yl)-3-methyl-5-(1 -prop-2-ynylpiperidin-4-yl)-3,5-dihydro-4H-
imidazol-4-one;
5-(1-acetylpiperidin-4-yl)-2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1'-biphenyl-3-yl)-3-methyl-5-(l'-propionylpiperidin-4-yl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1,1'-biphenyl-3-yl)-5-(1-butyrylpiperidin-4-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3-cyclohexylphenyl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
5-(1-acetylpiperidin-4-yl)-2-amino-5-(3-cyclohexylphenyl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyridin-3-ylphenyl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyrazin-2-ylphenyl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(2',5'-difluoro-1,1'-biphenyl-3-yl)-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-propoxyphenyl)-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3-isobutoxyphenyl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(but-3-ynyloxy)phenyl]-3-methyl-3,5-dihydro-
4W-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(cyclopropylmethoxy)phenyl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
N-{3-[2-amino-4-(1 -benzoylpiperidin-4-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-
yl]phenyl}-2-methoxyacetamide;
3-[2-amino-4-(1 -benzoylpiperidin-4-yl)-1 -methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl]-A/-
isobutylbenzamide;
ethyl 3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidine-1 -
carboxylate;
2-amino-5-[1-(2-furoyl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-
one;
2-amino-5-[1-(isoxazol-5-yl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-
4-one;
2-amino-3-methyl-5-phenyl-5-[1-(trifluoroacetyl)piperidin-3-yl]-3,5-dihydro-4H-imidazol-
4-one;
2-amino-5-[1-(cyclopentylcarbonyl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
5-[1-(1-adamantylcarbonyl)piperidin-3-yl]-2-amino-3-methyl-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-3-yl)-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one;
2-amino-3-methyl-5-phenyl-5-[1-(thien-2-ylcarbonyl)piperidin-3-yl]-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-[1-(3-methoxybenzoyl)piperidin-3-yl]-3-methyl-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-3-methyl-5-[1-(3-methylbutanoyl)piperidin-3-yl]-5-phenyl-3,5-dihydro-4H-
imidazol-4-one;
4-[3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidin-1 -yl]-4-
oxobutanoic acid;
{2-[3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidin-1 -yl]-2-
oxoethoxyjacetic acid;
5-[3-(2-amino-1 -methyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-4-yl)piperidin-1 -yl]-5-
oxopentanoic acid;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(2-fluoropyridin-3-yl)phenyl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-3-methyl-5-(3-pyrimidin-5-ylphenyl)-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-[3-(5-methoxypyridin-3-yl)phenyl]-3-methyl-3,5-
dihydro-4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3'-methoxybiphenyl-3-yl)-3-methyl-3,5-dihydro-
4H-imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3'-fiuorobiphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3'-chlorobiphenyl-3-yl)-3-methyl-3,5-dihydro-4H-
imidazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(2',5'-difluorobiphenyl-3-yl)-3-methyl-3,5-dihydro-
4H-im idazol-4-one;
2-amino-5-(1-benzoylpiperidin-4-yl)-5-(3',5'-difluorobiphenyl-3-yl)-3-methyl-3,5-dihydro-
4H-imidazol-4-one;
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 as claimed in any one of
claima 1 to 9.
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; and a neurodegenerative disorder.
12. The method according to claim 10 wherein said disease or disorder is
characterized by the production of ß-amyloid deposits or neurofibrillary tangles.
13. The method according to claim 11 wherein said disease or disorder 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 as claimed in
any one of claims 1 to 9.
15. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and an effective amount of a compound as claimed in any one of
claims 1 to 9.
16. Use of a compound as claimed in any one of claima 1 to 9 for the
preparation of a medicament for the treatment of a disease or disorder associated with
excessive BACE activity.
17. 2-amino-5-piperidinylimidazolone compounds of Formula 1 as claimed
herein before, and to methods for using them to modulate (and, preferably, inhibit) B-
secretase (BACE) and to reduce p-amyloid deposits and neurofibrillary tangles
substantially such as herein described.