MX2008001436A - Cycloalkyl amino-hydantoin compounds and use thereof forî²-secretase modulation - Google Patents

Abstract

The present invention provides a 2-amino-5-cycloalkyl-hydantoin compound of formula (I) The present invention also provides methods and compositions for the inhibition ofÃ-secretase (BACE) and the treatment ofÃ-amyloid deposits and neurofibrillary tangles.

Description

COMPOUNDS OF AMINO-HYDANTOINE CYCLE MINISTER AND USE OF THESE FOR THE MODULATION OF ß-SECRETASE FIELD OF THE INVENTION The present invention relates to cycloalkyl amino-hydantoin compounds and methods for using them to modulate (and, preferably, inhibit) β-secretase (BACE) and to treat β-amyloid deposits and neurofibrillary tangles.

BACKGROUND OF THE INVENTION Β-amyloid deposits and neurofibrillary tangles are two of the major major pathological characterizations associated with Alzheimer's disease (AD). Clinically, AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. It also affects, as the disease progresses, the motor, sensory and linguistic abilities until a global damage of multiple cognitive functions occurs. These cognitive losses take place gradually, but typically lead to severe damage and death in 4 -12 years.

Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brain of patients with Trisomy 21 (Down syndrome), hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D), and other neurodegenerative disorders. Neurofibrillary tangles also occur in other neurodegenerative disorders that include disorders that induce dementia (Varghese, J., et al, Journal of Medicinal Chemistry, 2003, 46, 4625-4630). Β-amyloid deposits are predominantly an aggregate of a peptide Aß, which in turn is a product of the Proteolysis of amyloid precursor protein (APP). More specifically, the Aβ peptide results from the cleavage of APP at the C-terminal by one or more? -secretases, and at the N-terminus by the enzyme? -secretase (BACE), also known as aspartyl protease, as part of the β-pathway? -amiloidogenic.

The activity of BACE is directly correlated with the generation of the Aβ peptide from the APP (Sinha, et al, Nature, 1999, 402, 537-540), and studies increasingly indicate that BACE inhibition inhibits BACE production. Aβ peptide (Roberds, SL, et al, Human Molecular Genetics, 2001, 10, 1317-1324) Therefore, it is an object of the present invention to provide compounds that are inhibitors of β-secretase and are useful as therapeutic agents in the treatment, prevention or amelioration of a disease or disorder characterized by β-amyloid deposits or levels of β-amyloid elevated 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 β-amyloid deposits or elevated β-amyloid levels in a patient.

It is another feature of this invention that the compounds provided may also be useful for further studies and to elucidate the β-secretase enzyme.

These and other objects and features of the invention will be more apparent in the detailed description set forth below.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of formula I Wherein A is cycloalkyl; W is CO, CS or CH2; Ri, R2, and 3 are each independently H, or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each group is optionally substituted, or R1 and R2 can be taken together with the atom to which they are attached to form a ring of 5-7 members optionally substituted interrupted by an additional heteroatom selected from O, N or S.

R, R5, and Re are each independently H, halogen, NO2) CN, OR7, COR7, CO2R7, CONR8R9I NR8R9, NR8COR7, NR8SO2R10, SO2NR8R9 or SO "R? O or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl group , aryl, heteroaryl, each group optionally substituted or when attached to the adjacent carbon atoms R4 and R5 or R5 and R6 can be taken together with the atoms to which they are attached to form a 5-7 membered ring optionally interrupted by one, two or three heteroatoms selected from O, N or S; n is O, 1, or 2; R is independently in each occurrence H, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group, each group optionally substituted R8 and R9 are each independently at each occurrence H, OR7, COR7, CO2R, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group, each optionally substituted group, or R8 and R9 can be taken together with the atom to which they are attached to form a ring of optionally substituted 5 to 7 members interrupted by an additional heteroatom selected from O, N or S; Y R10 is independently in each occurrence an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted group; or a tautomer of these, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

The present invention also relates to the use of cycloalkyl amino-hydantoin compounds for the treatment of β-amyloid deposits and neurofibrillary tangles. These compounds are particularly useful for treating Alzheimer's disease, cognitive impairment, Down 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 the largest neurodegenerative disease of the brain that presents clinically by the progressive loss of memory, knowledge, reasoning, judgment and emotional stability and gradually leads to profound mental deterioration and death . The exact cause of AD is unknown, but growing 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. Seikoe, Phisiology Review, 2001. 81, 741). Patients with AD exhibit characteristic neuropathological markers such as neuritic plaques (and in a-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 brains with Ad. In addition, β-amyloid deposits and vascular β-amyloid angiopathy also characterize individuals with Down Syndrome, Hereditary Cerebral Hemorrhage with Dutch-type Amyloidosis and other neurodegenerative and dementia-inducing disorders. Overexpression of the amyloid precursor protein (APP), altered cleavage of the APP to A-beta or a decrease in the separation of A-beta from patients' brains may increase the levels of soluble or fibrillar forms of A-beta in the brain. The cleavage enzyme of APP in the β site, BACE1, also called memapsin-2 or Asp-2, was identified in 1999 (R. Vassar, B. D. Bennett, et al, Nature, 1999. 402, 537). The BACE1 is an aspartic protease bound to the membrane with all the known functional properties and characteristics of the β-secretase. The inhibitors of low molecular weight, non-peptides, not related to substrate of BACE1 or β-secretase are seriously sought both as an aid in the study of the β-secretase enzyme and as potential therapeutic agents.

Surprisingly, it has now been found that the 2-amino-5-cycloalkyl-hydantoin compounds of formula I demonstrate the inhibition of β-secretase and the selective inhibition of BACE1. Advantageously, said cycloalkyl hydantoin compounds can be used as effective therapeutic agents for the treatment, prevention or amelioration of a disease or disorder characterized by deposits of β-amyloid or by elevated β-amyloid levels in a patient. Accordingly, the present invention provides a 2-amino-5-cycloalkyl-hydantoin compound of formula I.

Wherein A is cycloalkyl; W is CO, CS or CH2; Ri. R2, and R3 are each independently H, or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each group is optionally substituted, or RT and R2 can be taken together with the atom to which they are attached to form an optionally substituted 5-7 membered ring interrupted by an additional heteroatom selected from O, N or S.

R l Rs, and Re are each independently H, halogen, NO2, CN, OR7, COR7, CO2R7, CONR8R9 > NR8R9, NR8COR7, NR8SO2R10, SO2NR8R9 or SOnR10 or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group, each group optionally substituted or when attached to the adjacent carbon atoms R4 and R5 or R5 and R6 may be taken together with the atoms to which they are attached to form a 5- to 7-membered ring optionally substituted and optionally interrupted by one, two or three heteroatoms selected from O, N or S; n is O, 1, 6 2; R7 is independently at each occurrence H, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group, each group optionally substituted; R8 and R9 are each independently at each occurrence H, OR7, COR7, CO2R7, or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group, each group optionally substituted, or R8 and R9 can be taken together with the atom to which they are attached to form a ring of optionally substituted 5 to 7 members interrupted by an additional heteroatom selected from O, N or S; Y R10 is independently in each occurrence an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted group; or a tautomer of these, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. It is understood that the claims cover all possible steroisomers, tautomers and prodigies. Moreover, unless stated otherwise, each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is contemplated as being optionally substituted.

In one embodiment, R5 is alkyl, alkoxy, or haloalkoxy. Preferred haloalkoxy groups are OCF3 and OCHF2 A can be monocyclic cycloalkyl or polycyclic cycloalkyl.

In one modality, A is polycyclic.

In a preferred embodiment, A is a bridged polycyclic cycloalkyl group, such as norbornyl or adamantyl. Thus, the preferred constituents A are those of formula II or III: II III Where m is 1 or 2. More preferably, A is adamantyl.

In other embodiments, A is a monocyclic cycloalkyl group.

In certain embodiments R5 is phenyl optionally substituted with CN, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy or cycloalkyl, preferably trifluoromethyl.

The term "cycloalkyl" as used in the specifications and claims designates cyclic alkylated chains having the specified number of carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, up to 20 carbon atoms, for example 3 to 12 carbon atoms, which can be a simple ring (monocyclic) or multiple rings (polycyclic, including spiro, fused and bridged rings, up to three rings) fused together or covalently linked.

The term "cycloheteroalkyl" denotes a cycloalkyl ring with five to seven members that contains one or two heteroatoms, which may be the same or different, selected from N, O, or S and optionally containing a double bond. Exemplary cycloheteroalkyl ring systems are the following rings wherein Xi is NR, O or S; and R is H or an optional substituent as described below: As used herein, the term "alkyl" includes both saturated straight or branched chain aliphatic hydrocarbon groups having the specified number of carbon atoms, for example, methyl, ethyl, propyl, isopropyl, isobutyl, secondary butyl, tertiary butyl. , isopentyl, neopentyl, isohexyl, or the like. The term "alkyl" further includes both unsubstituted and mono-, di- and tri-substituted hydrocarbon groups with particularly preferred halogen substitution.

The term "alkenyl" refers to an unsaturated or partially unsaturated aliphatic hydrocarbon group having the specific number of carbon atoms, for example 2 to 6 carbon atoms, for example, ethenyl, 1-propenyl, 2, butenyl, etc. . The term "alkenyl" further includes both unsubstituted and mono-, di-, and tri-substituted hydrocarbon groups, with particularly preferred halogen substitution.

The term "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. The 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 below.

The term "halogen" designates fluorine, chlorine, iodine and bromine.

The term "aryl" designates an aromatic carbocyclic portion of up to 20 carbon atoms, for example 6 to 20 carbon atoms, which may be a single ring (monocyclic) or multiple rings (polycyclic, up to three rings) fused together or bound covalently Examples of aryl portions include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, or the like.

The term "heteroaryl" denotes a ring containing 5 to 7 aromatic carbon members incorporating at least one nitrogen atom, oxygen or sulfur atom.

Such heteroaryl ring systems include pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, primidinyl, pyrazinyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, or the like.

An optionally substituted portion may be substituted with one or more substituents. The substituent groups that are optionally present may be one or more of those customarily employed in the development of the pharmaceutical compounds or of the modification of such compounds to influence their structure / activity, persistence, absorption, stability or other beneficial properties. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanate, cyanate, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsufinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl (for example cycloheteroalkyl or heteroaryl) or cycloalkyl.

Optional substituents may be, for example, alkyl, for example methyl or ethyl, alkoxy, for example, methoxy halolcoxy, for example trifluoromethoxy, difluoromethoxy, halogen, aryloxy, for example phenoxy halalkyl, for example trifluoromethyl, heteroaryl, for example furyl, cycloalkyl, for example cyclopentyl or cyclohexyl, carbamoyl, carboxyl, alkoxycarbonyl or the like, halogen atoms or lower alkyl, lower alkoxy or haloalkyl groups are preferred , where "lower" denotes 1 to 4 carbon atoms. Typically, substituents with 0 to 4 may be present.

When any of the above substituents represents or contains an alkyl substituent group, it may be linear or branched and may contain up to 12 carbon atoms, preferably up to 6 carbon atoms, more preferably up to 4 carbon atoms.

The compounds of the present invention can be converted to salts, in particular pharmaceutically acceptable salts using procedures recognized in the art. Suitable salts with bases are, for example, metal salts, such as alkali metal salts or alkaline earth metal salts, for example, sodium, potassium or magnesium salts, or salts with ammonium or an organic amine, such as morpholino, thiomorpholino, piperidine, pyrrolidine, a mono-, di- or tri-alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono- , di-, or tri-hydroxyalkylamine lower, for example mono-, di- or triethanolamine. Internal salts can be additionally formed. Salts which are unsuitable for pharmaceutical uses but which can be used, for example, for the isolation or purification of the free compounds or their pharmaceutically acceptable salts, are also included. The term "pharmaceutically acceptable salt", as used herein, refers to salts derived from organic and inorganic acids such as, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic acids. , phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, naphthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and acceptable acids similarly known when a compound of this invention contains a basic portion. The salts may also be formed of organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium or potassium, when a compound of this invention contains a carboxylate or phenolic portion, or a similar portion, layers of forming addition salts of base.

The compounds of the invention can exist as one or more tautomers. One skilled in the art will recognize that the compounds of formula I may also exist as the tautomer It as shown below.

(Item) Tautomers often exist in balance with one another. As these tautomers interconvert under ambient and physiological conditions, they provide the same useful biological effects. The present invention includes mixtures of such tautomers as well as also individual tautomers of the formula I and formula Item.

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 deastereomers. Although shown without taking into account the stereochemistry of formula I, the present invention includes such optical isomers and diastereomers; as well as endemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the stereoisomers R and S and pharmaceutically acceptable salts thereof. Where a stereoisomer is preferred, it may in some embodiments be delivered substantially free of the corresponding enantiomer. Thus, a substantially free enantiomer of the corresponding enantiomer refers to a compound that is isolated or separated by separation techniques or free preparation of the corresponding enantiomer. "Substantially free" as used herein, means that the compound is made up of a significantly greater proportion of a stereoisomer, preferably less than about 50%, more preferably less than about 75%, and even more preferably less than about 99%.

Preferred compounds of the invention are those compounds of formula I wherein W is CO. Also preferred are those compounds of formula I wherein Ri and R2 are each independently H or alkyl. Another group of preferred compounds are those compounds of formula I wherein R5 is or R7 or heteroaryl. An additional group of preferred compounds are those compounds of formula I wherein R3 is alkyl.

The most preferred compounds of the invention are those compounds of formula I wherein W is CO and A is adamantyl. Another group of more preferred compounds are those compounds of formula I wherein W is CO, A is adamantyl and Ri and R2 are H. An additional group of more preferred compounds are those compounds of formula I in W is CO; A is adamantyl and R5 is difluoromethoxy.

Preferred compounds of formula I include: (5S) -5- (1-adamantyl) -2-amino-5- [4- (difluoromethoxy) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-bicyclo [2.2.1] hept-1-yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-ethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-butoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (3-ethyl-4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxy-3,5-dimethylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S) -5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R) -5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; - (1-adamantyl) -2-amino-5- (3,4-dimethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxy-2,3-dimethylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-bicyclo [2.2.1] hept-2-yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-hexahydro-2,5-methanopentalene-3a (1 H) -yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazole-4- ona; 5- (1-adamantyl) -2-amino-3-methyl-5- (4'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4'-methoxy-1,1'-biphenyl-3-yl) -3-methyl-3,5-dihydro-4 H -amidazole-4- ona; 5- (1-adamantyl) -2-amino-3-methyl-5- (3'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (3'-methoxy-1,1 '-biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; S-1-adamanti -amino-d-IS '^' - dimethyl-l. 1'-biphenyl-S-i -S-methyl-S.S-dihydro-H-imidazoM-one; 3 '- [4- (1-adamantyl) -2-amino-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] -1, 1'-biphenyl-3-carbonitrile; 5- (1-adamantyl) -2-amino-5- [3- (3-furyl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one; S'-^ -Il-adamantyl-amino-l-methyl-d-oxo ^. S-dihydro-I H-imidazoM-ylj-l .l'-biphenyi-carbonitrile; 3 '- [4- (1-adamantyl) -2-amino-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] -1, 1'-biphenyl-4- carbonitrile; S-1-adamantyl-amino-S-1S'-2-difluoro-1, 1'-biphenyl-S-i -S-methyl-S-dihydro-H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (1, 1'-biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-3-methyl-5- (2'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (3,5-difluorobenzyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 5-cyclohexyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cyclohexyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cyclohexyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 2-amino-5-cyclohexyl-3- (2,2-diethoxyethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (2-phenylethyl) -3,5-dihydro-4H-imidazol-4-one; 5-cyclohexyl-2-imino-3-methyl-5-phenylimidazolidin-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (tetrahydrofuran-2-ylmethyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (2-fluoroethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- [2- (difluoromethoxy) benzyl] -5-phenyl-3,5-dihydro-4H-imidazol-4-one; N - [(2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) acetyl] -L-aspartic acid; N - [(2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) acetyl] -D-aspartic acid; Trans-4 - [(2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) methyl] cyclohexanecarboxylic acid; 6- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) hexanoic acid; 5- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) pentanoic acid; 4- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) butanoic acid; 2-amino-5-cyclohexyl-3- (5-hydroxypentyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 3- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) propanoic acid; 3- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) -2-methylpropanoic acid; 2-amino-3-benzyl-5-cyclohexyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3-isobutyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3-hexyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-3,5-dicyclohexyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (4-hydroxybutyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; Acid (2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) acetic acid; 2-amino-5-cyclohexyl-3- (cyclohexylmethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (2-furylmethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (4-hydroxyphenyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (3-hydroxyphenyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (thien-2-ylmethyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (4-methoxyphenyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (2-thien-2-ylethyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- [2- (4-hydroxy-phenyl) -ethyl] -5-phenyl-3,5-dihydro-4H-imidazol-4-one; [4- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl74,5-dihydro-1 H-imidazol-1-yl) phenyl] acetic acid; 4 - [(2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) methyl] benzoic acid; - (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) -2-hydroxybenzoic acid; Ethyl 3- (2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) benzoate; -cyclobutyl-2-imino-3-methyl-5-phenylimidazolidin-4-one; 5- (2-adamantyl) -2-imino-3-methyl-5-phenylimidazolidin-4-one; 5-cyclopentyl-2-imino-3-methyl-5-phenylimidazolidin-4-one; 5-cyclobutyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cycloheptyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5- (2-adamantyl) -3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cyclopentyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cyclobutyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cycloheptyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5- (2-adamantyl) -2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cyclopentyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cyclobutyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5-cycloheptyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5- (2-adamantyl) -3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5-cyclopentyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (2-methylphenyl) imidazolidin-4-one; 5- (3-benzylphenyl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (3-methylphenyl) imidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (4-methylphenyl) imidazolidin-4-one; 5-cyclohexyl-5- (4-fluorophenyl) -2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-5- (3-methoxyphenyl) -3-methylimidazolidin-4-one; 5-cyclohexyl-5- (3,4-dichlorophenyl) -2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (4-phenoxyphenyl) imidazolidin-4-one; 5- (3-chlorophenyl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-5- (3,5-dichlorophenyl) -2-imino-3-methylimidazolidin-4-one; 5- (1,1'-biphenyl-2-yl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5- (1, 1 '-biphenyl-4-yl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-5- (2,5-dimethylphenyl) -2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- [4- (trifluoromethyl) phenyl] imidazolidin-4-one; 5-cyclohexyl-2-imino-5- (2-methoxyphenyl) -3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-5- (4-methoxyphenyl) -3-methylimidazolidin-4-one; 5- (4-chlorophenyl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 2-amino-5-cyclohexyl-5- (3-cyclopentyl-phenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5- (3-cyclohexylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; - [3- (benzyloxy) phenyl] -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; N-. { 3- [2-amino-4- (4-methoxy-3-methylphenyl) -1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] phenyl} -2- (4-chlorophenoxy) -2-methylpropanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3-methoxybenzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3-methoxypropanamide; (2R) -N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2-methoxy- 2- phenylacetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3-methyl-2-furamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (2-methoxyethoxy) acetamide; N ~ 1 ~ - [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] - N ~ 2 ~, N ~ 2-dimethylglycinamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -3- (dimethylamino) benzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -4- (dimethylamino) butanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -1-methylpiperidine-4-carboxamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2-cyclopropylacetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- phenoxypropanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3- (thluoromethyl) benzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (2-methoxyphenyl) acetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -1-methyl-1 H-pyrrole-2 -carboxamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2-methoxyacetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2-furamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2- (benzyloxy) acetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2-methoxybenzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3,4-dimethoxybenzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (2,5-dimethoxyphenyl) acetamide; (2E) -N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] but-2-enamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] butanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (3-methoxyphenyl) acetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -1, 3-benzodioxol-5-carboxamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (4-chlorophenoxy) -2- methylpropanamide; or a tautomer thereof or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

The compounds of the invention can be prepared using conventional methods using reagents and readily available starting materials. The reagents used in the preparation of the compounds of this invention can be commercially obtained or can be prepared by standard procedures described in the literature. Representative compounds of the present invention can be prepared using the following synthetic schemes. In the skilled practitioner will know how to make use of the variants of these reaction sequences, which in themselves are well known in the art. For example, the compounds of formula I wherein W is CO and Ri, and R2 are H (la) can be prepared according to the following synthetic scheme illustrated in flow chart I.

FLOW DIAGRAM I 1 In flow diagram I, benzyl bromide or benzyl chloride 1 is converted to a phosphonium salt 2 after treatment with triphenylphosphine and a non-polar solvent, that is toluene. The phosphonium salt 2 is first treated with a base, ie, alkyl lithium, sodium hydride, potassium perorthoxide, in a solvent that does not adversely affect the subsequent addition of acid chloride 3, ie, toluene, ether, tetrahydrofuran , and subsequently the generated anion is treated with carboxylic acid chloride 3 to produce the corresponding halide 4. The acid chloride 3 is obtained commercially or prepared from the corresponding carboxylic acid after treatment with a chlorinating agent such as oxalyl chloride or thionyl chloride . The halide 4 is oxidized with potassium permanganate in the presence of magnesium sulfate in a polar or non-polar solvent, ie, toluene, tetrahydrofuran, acetone to supply diketone 5. The condensation of the substituted guanidine 8 with diketone 5 in the presence of an inorganic base, i.e., sodium carbonate, in a polar solvent, i.e., ethyl alcohol, dioxane, N, N-dimethylformamide achieve the desired compound of formula la.

Alternatively, the compounds of formula la can be prepared as shown in Flow Chart II where Et represents ethyl and Me represents methyl.

FLOW DIAGRAM II 11 12 NH A / R3 (the) In flow diagram II, benzaldehyde 9 is treated with triethylphosphite and chlorotrimethylsilane in an aprotic solvent, ie, toluene, to produce silyl ether 10. Compound 10 is treated sequentially with a base, i.e., lithium disopropylamide, and an acid chloride 3 to give silyloxy ether 11. The hydrolysis of said silyloxy ether in a aqueous inorganic base, i.e., sodium bicarbonate, provides alcohol 12. Compound 12 is oxidized with manganese dioxide to produce diketone 5. The condensation of said diketone with the substituted guanidine 8 in the presence of an inorganic base, i.e. Sodium carbonate, in a polar solvent, ie, ethyl alcohol, dioxane or N, N-dimethylformamide achieve the desired compound of formula la.

Alternatively, compounds of formula la can be prepared according to the synthetic scheme shown in flow diagram III.

FLOW DIAGRAM III In flow diagram III, the Grignard reagent 20 is generated in situ and reacts with the glycolic acid chloride 13 to give the diketone 5. Said diketone is condensed with the guanidine substituted to 8, as described above in the flow I and II, to supply the desired compound of formula la.

The compounds of formula I wherein W is CO, Rt, and R2, are H and R5 is aryl or heteroaryl (Ib) can be prepared according to the following synthetic system illustrated in flow diagram IV where Hal represents Cl, Br or I FLOW DIAGRAM IV fifteen ('«>) In flow diagram IV, diketone 15 is used in a palladium-catalyzed cross-coupling reaction (Suzuki, Stille) with a heteroaryl or aryl boronic acid or a heteroaryl or trialkyl / thallyl stearate 6 in the presence of a variety of catalysts Pd (0) or Pd (II), such as dichlorobis (tri-o-tolifosphine) palladium (ll), Pd (OAc) 2 / tri-o-tolifosphine, tetrakis (thphenylphosphine) palladium (0) or the like in a non-polar or polar solvent, i.e., toluene, diethoxyethyl ether, dioxane, or for Suzuki reactions in the presence of inorganic bases, i.e. potassium carbonate to provide the diketone 7 wherein R 5 is a heteroaryl or aryl group. Condensation of substituted guanidine 8 with diketone 7 as described in flow chart I provides the desired compound of formula Ib.

The substituted guanidine 8 can be prepared using conventional methods, such as the reaction of 1-H-pyrazole-1-carboxamidine hydrochloride with a primary amine, R 3 NH 2.

The compounds of formula I wherein A is adamantyl; Ri and R2 are H; and R 5 is a substituted phenyl group (le) can be prepared as shown in flow diagram V wherein R represents one or more optional substituents.

FLOW DIAGRAM V In flow diagram V, bromobenzyl bromide 13 is treated with magnesium chips to give the corresponding Gringnard reagent, which is treated in situ with 1-adamantyloyl chloride to give the ketone 17. The Suzuki 17 coupling with boronic acid 18 produces the biphenyl compound 19. The biphenyl 19 is oxidized with selenium dioxide to give the corresponding diketone 20. The condensation of the diketone 20 with the substituted guanidine 8 as described above in the flow diagram I produces the desired compound of formula you.

The compounds of formula I wherein W is CO, R ^ R2, R and R6 are H and R5 is cyclohexyl or cyclopentyl (Id) can be prepared as shown in flow diagram VI where m is 1 or 2.

FLOW DIAGRAM VI 22 24 25 (ItJ) In flow diagram VI, bromophenylacetyl chloride 22 reacts with a Grignard reagent generated in situ 23 to give ketone 24. Heck coupling of said ketone with cyclopentene or cyclohexene supplies compound 25. Hydrogenation of compound 25, followed by oxidation with selenium dioxide gives the diketone 26. The condensation of compound 26 with the substituted guanidine 8 produces the desired compound of formula Id.

The compounds of formula I wherein W is CO and Ri and R2 are H (la) can also be prepared according to the synthetic scheme shown in the flow diagram VII.

FLOW DIAGRAM Vil Cul, Pd (PPh3) 4 27 28 30 (the) In flow diagram VI, a cycloalkyl aldehyde 27 reacts with dimethyl (1-diazo-2-oxopropyl) phosphonate in the presence of K2CO3 and methanol to give the alkyne 28. Compound 28 is coupled with a substituted halobenzene 29 to give Compound 30. Compound 30 reacts with NaHCO3 and aqueous MgSO4, followed by treatment with KMnO4 to give the diketone 5. The diketone is then condensed with guanidine 8, as described above, to give the desired compound of formula la.

The compounds of the formula I wherein W is CS (le) can be readily prepared using conventional procedures, such as reacting a compound of the formula la with CS2 in the presence of a solvent to obtain the desired compound of the formula le. Similarly, compounds of formula I wherein W is CH2 (If) can be prepared by reacting a compound of formula I with a suitable reducing agent such as SnCl2 to obtain the desired compound of formula If. The reactions are shown in flow diagram VIII.

FLOW DIAGRAM VIII Compounds of formula I wherein R and R2 are different from H can be readily prepared using conventional procedures such as reacting a compound of formula la, le or If with an alkylating agent, such as an alkyl halide, to give the compound of formula I wherein Ri and R2 are different from H. by using either an equivalent, or two or more equivalents, of the alkylating agent, the compounds of formula I wherein R-es is different from H and R2 is H or where Ri and R2 are different from H can be obtained.

Advantageously, the compounds of formula I act as BACE inhibitors for the treatment or prevention of ß-amyloid deposits and the neurofibrillary tangles associated with such diseases as Alzheimer's disease, Trisomy 21 (Down Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type (HCHWA-D), and other neurodegenerative disorders. According to the above the present invention provides methods to modulate BACE and to treat, prevent, or improve β-amyloid deposits and neurofibrillary tangles associated with such diseases as Alzheimer's disease, Trisomy 21 (Down Syndrome), Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type (HCHWA-D), and other neurodegenerative disorders. Such methods generally involve administering to a patient suffering or suspected to be susceptible to the disease or injury an effective amount of a compound of formula I. Also according to the present invention a method is provided for treating Alzheimer's disease and Senile Dementia related in humans or others mammals w 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, w comprises administering to a patient and / or contacting a receptor thereof with an effective amount of at least one compound of formula I. Certain methods also include determining the activity BACE, before or after said contact stage.

The present invention also provides methods for improving β-amyloid deposits in a mammal, comprising administering to said mammal an effective amount of at least one compound of formula I. Additional methods improve neurofibrillary tangles in a mammal, and comprise administering to said mammal an effective amount of at least one compound of formula I.

Methods to improve the symptoms of Alzheimer's disease, cognitive impairment, Down syndrome, HCHWA-D, cognitive decline, senile dementia, cerebral amyloid angiopathy, degenerative dementia, or other neurodegenerative disorders in a mammal are also provided. 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 "supply", with respect to supplying a compound or substance covered by this invention, means directly administering such a compound or substance, or administering a prodrug, derivative, or analog that will form the effective amount of the compound or the substance inside the body. This invention also covers providing the compounds of this invention for treating the disease states described herein, wherein the compounds are useful for treating.

The terms "administering", "administering", or "administration", as used herein, refer to directly administering a compound or composition to a patient, or administering a prodrug or analog derivative of the compound to the patient, which will form an amount equivalent 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 dose" as used herein, refers to the amount of a compound that, when administered to a patient, is effective to at least partially improve (and, in the preferred modalities, cure) a condition of which the patient is suspected to suffer. It is understood that the effective dose of the active compounds of this invention may vary depending on the particular compound used, the mode of administration, the condition, and the severity thereof, the condition to be treated, as well as the various physical factors. related to the individual that is being treated. For treating Alzheimer's disease and other related senile dementias, generally, satisfactory results can be obtained when the compounds of this invention are administered to an individual in need of a daily dose of 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 animals, the total daily dose 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 can be adjusted to provide the optimal therapeutic result. This regimen can be adjusted to provide the optimal therapeutic response.

The present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula I and a pharmaceutically acceptable carrier.

The term "carrier", as used herein, will include carriers, excipients, and diluents. Examples of carriers are well known to those skilled in the art and are prepared according to acceptable pharmaceutical methods, 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 here as a reference in its entirety. The pharmaceutically carriers acceptable are those that are compatible with the other ingredients in the formulation and biologically acceptable.

The compounds of this invention can be administered orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers may 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 a conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and β-blocking agents. Oral formulations containing the active compounds of this invention may comprise any oral form conventionally used, which include tablets, capsules, oral forms, pills, pills and oral liquids, suspensions or solutions. In powders, the carrier is a finely divided solid, which is a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in the proper proportions and compacted in the desired shape and size. The powders and tablets preferably contain up to 99% of the active ingredient.

The capsules may contain the mixtures of the active compounds with the inert fillers and / or diluents such as pharmaceutically acceptable starches, (for example corn starch, potato or tapioca), sugars, artificial sweetening agents, powdered celluloses, such as crystalline celluloses. and microcrystalline, flours, jellies, gums, etc.

Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and use pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents , which include, but are not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose , polyvinyl pyrrolidine, alginic acid, acacia gum, gum xanthan, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, waxes with low melt and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of the surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, ketostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate. , magnesium aluminum silica, and triethanolamine. The oral formulations here can use formulations with standard delay or release in time to alter the absorption of the compounds. The oral formulation may also consist of administering the active ingredient in water or fruit juice containing the appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, molasses 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 pharmaceutically acceptable oils or fats. The liquid carrier may 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 such as the above, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example , glycols) and their derivatives, and oils (for example fractionated coconut oil and arachis oil). For parenteral administration the vehicle can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions with sterile liquid form for parenteral administration. The liquid vehicle for pressurized compositions may be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compositions for oral administration may be in liquid or solid form.

Preferably the pharmaceutical composition is in a unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is subdivided into unit dose containing the unit amounts of the active ingredient; the unit dosage forms can be packaged compositions, for example, packaged powders, flasks, ampoules, pre-filled syringes or bags containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or this may be the appropriate number of any such compositions in package form. Such a unit dose form may contain from about 1 mg / kg to about 250 mg / kg, and may be given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful for directing the active compounds present in the bloodstream of the recipient, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous), rectally, vaginally and transdermally. Such administrations can 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 dose may vary depending on the particular compound used, the mode of administration, the condition, and the severity thereof, of the condition be treated, as well as the various physical factors related to the individual to be treated. In the therapeutic application, the compounds of the present invention were delivered to a patient who already suffers from a disease in an amount sufficient to cure or at least partially improve the symptoms of the disease and its complications. An adequate amount to achieve this is defined as "therapeutically effective amount". The dose to be used in the treatment of a specific case must be subjectively determined by the attending physician. The The variables involved include the specific condition, and the patient's size, age, and response pattern.

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 intrabronchial inhalation, the compounds of this invention can be formulated in an aqueous or partially aqueous solution.

The compounds of this invention can be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or a pharmaceutically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxylpropylcellulose. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures of these in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid in one. proportion in which there is easy syringability. This must be stable under the conditions of processing 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 (for example, glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of this invention can be administered transdermally through the use of a transdermal patch. For the purposes of this disclosure, transdermal administrations are understood to include all administrations throughout the body surface and the interior coatings of body passages that include epithelial and mucosal tissues. Such administrations can be carried out using the present compounds or pharmaceutically salts acceptable of these, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration can be achieved through the use of a transdermal patch containing the active compound and the vehicle that is inert to the active compound, is not toxic to the skin, and allows the delivery of the agent for systemic absorption into the bloodstream. through the skin. The vehicle can take any number of forms such as creams and ointments, pastes, gels and occlusive devices. The creams and ointments can be liquid and semi-solid viscous emulsions of any of the types of oil in water or water in oil. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient, may also be suitable. A variety of occlusive devices can be used to release the active ingredient into the bloodstream, such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known 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.), Desing of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol 4 Academic Press (1985); Krogsgaard-Larsen, et al. (ed.), "Desing 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), each of which is incorporated herein by reference in its entirety.

It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the condition and the individual being treated will be submitted to the judgment of the medical practitioner involved. It is preferred that the administration of one or more compounds present here begin at a low dose and increase until the desired effects are achieved.

For a clearer understanding, and in order to illustrate the invention more clearly, specific examples of these are set forth below. The following examples are merely illustrative and should not be understood as limiting the scope of the principles underlying the invention in any way. Various modifications of the invention, in addition to that described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fit within the scope of the appended claims.

Unless otherwise stated, all parts are parts by weight. The following abbreviations are used: Ph represents phenyl, TEA is triethylamine, DMSO is dimethisulfoxide, DMF is NN-dimethylformamide, NMR is proton nuclear magnetic resonance, and MS is mass spectroscopy with (+) referring to the positive mode that generally gives a absorption M + 1 (or M + H) where M is equal to the molecular mass. All compounds are analyzed at least by MS and NMR.

EXAMPLE 1 Preparation of 2-Amino-5-bicichlor.2.2.11hept-1 -yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Step a) Preparation of bicyclo [2.2.1] heptane-1-carboxylic acid The compound is synthesized according to the procedure described in Reike, R.D .; Bales, S.E .; Hundnall, P.M .; Burns, T.P .; Poindexter, G.S .; Org Syn, 1988 (VI) 845.

Step b) Preparation of Bicyclo [2.2.1] heptane-1-carbonyl chloride A solution of bicyclo [2.2.1] heptane-1-carboxylic acid (0.3 g, 2.1 mmol) in thionyl chloride plus one drop of DMF is heated at a reflux temperature for 3 h and concentrated to dryness under reduced pressure. The residue is used without any additional purification.

Step c) Preparation of 4-methoxy-benzyl triphenylphosphine 3-methyl chloride, A solution of triphenylphosphine (3 g, 11.4 mmol) in toluene is treated with 3-methyl-4-methoxybenzyl chloride (1.9 g, 11.4 mmol), heated at reflux temperature for 3 h and filtered. The filter cake is washed with a small amount of ether, and dried to obtain a white solid, 1.9 g (33% yield), MS m / e (M) +397; 1 H NMR (300 MHz DMSOd6) d1.9 (s, 3 H), 3.72 (s, 3 H), 5.3 (d, 2 H), 6.55 (s, 1 H), 6.82 (m, 2 H), 7.65 (t, 6 H) ), 7.75 (m, 6H), 7.92 (t, 3H).

Step d) Preparation of 1-Bicyclo [2.2.1] hept-1-yl-2- (4-methoxy-3-methyl-phenyl) -ethane-1,2-dione A solution of 3-methyl-4-methoxybenzyl triphenylphosphonium chloride (1.8 g, 4.2 mmol) in toluene is treated with n-BuLi 2.5 N (4.2 mmol), stirred for 15 min at room temperature, treated in a portion with a toluene solution of bicyclo [2.2.1] heptane-1-carbonyl chloride (0.33 g, 2.1 mmol), stir at room temperature for 3 h and filter. The filtrate is diluted with water, treated with KMnO (0.5 g, 4.2 mmol) and MgSO (1 g, 8.4 mmol) is heated at 60 ° C for 16 h, cooled to room temperature and filtered. The filter cake is washed with ether and water. The washings were combined with the filtrate and the phases were separated. The organic phase is dried over MgSO and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel in ethyl acetate / exan 20: 1 to achieve the title diketone as a yellow oil, 0.04 g, MS m / e (M) + 272; 1 H NMR (300 MHz DMSOd6) d1.3 (m, 2H), 1.6 (m, 6H), 2.1 (s, 3H), 2.3 (m, 1H), 3.8 (s, 3H), 7.1 (d, 1 H) ), 7.6 (m, 2H).

Step e) Preparation of 2-amino-5-bicyclo [2.2.1] hept-1-yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazole -4-one A solution of 1-bicyclo [2.2.1] hept-1-yl-2- (4-methoxy-3-methylphenyl) ethane-1,2-dione (0.40 g, 0.14 mmol) in ethanol (3 mL) and water (1 mL) is treated with 1-methylguanidine hydrochloride (0.05 g, 0.44 mmol) followed by K2CO3 (0.06 g, 0.44 mmol), heated at reflux temperature for 3 h, and cooled to room temperature and concentrated to Remove the ethanol. The remaining aqueous mixture is diluted with water and extracted with CHCl3. The organic extracts were combined, dried over MgSO and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel in 10% methanol / ethyl acetate to give the title product as a white solid, 0.01 g (24% yield); 1HRMN (DMSO-d6 300 MHz) d 1.2 (m, 7H), 1.6 (m, 1 H), 2.05 (m, 1 H), 2.1 (s, 3H), 2.95 (s, 3H), 3.8 (s, 3H), 6.4 (b, 2H), 6.8 (d, 2H), 7.4 (m, 3H), MS m / e 328 (M) +.

EXAMPLE 2 Preparation of 5- (1-AdamantM) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Step a) Preparation of 1- (1-Adamantyl) -2- (4-methoxyphenyl) ethane-1,2-dione A solution of 4-methoxybenzyl triphenylphosphonium chloride (4.19 g, 10 mmol) in toluene is treated with n-BuLi 2.5 N (10 mmol), stirred for 15 min at room temperature, treated with toluene chloride solution. 1-adamantanecarbonyl (1 g, 5 m mol) in one portion, stirred at room temperature for 3 h and concentrated to dryness in vacuo. The residue is dissolved in a mixture of water and toluene, treated with KMnO, (1.58 g, 10 mmol) and MgSO, (4.8 g, 40 mmol), heated at 60 ° C for 16 h, cooled to room temperature and it filters. The filter cake is washed with ether and water. The washings were combined with the filtrate and the phases were separated. The organic phase is dried over MgSO 4 and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel in ethyl acetate / hexane 20: 1 to achieve the title diketone as a yellow oil, 0.15 g, MS m / e 298 (M) +; 1 HNRM (DMSO-d6 300 MHz) d 1.7 (m, 6H), 1.8 (m, 6H), 2.0 (m, 3H), 2.4 (s, 1H), 3.8 (s, 3H), 7.1 (d, 2H) 7.7 (d, 2H).

Step b) Preparation of 5- (1-Adamantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Using essentially the same procedure described in Example 1, step e, and employing 1- (1-adamantyl) -2- (4-methoxyphenyl) ethane-1,2-dione and 1-methylguanidine hydrochloride, the title product is obtained as a white solid, 0.04 g (26% yield), MS m / e 352 (M) +; HRMN (DMSO-d6 300 MHz) d 1.4 (m, 6H), 1.5 (m, 3H), 1.6 (m, 3H), 1.9 (m, 3H), 2.95 (s, 3H), 3.7 (s, 3H) , 6.4 (b, 2H), 6.8 (d, 2H), 7.5 (d, 2H).

EXAMPLE 3 Preparation of 5-I1 -Adamantl) -2-amino-5- (4-ethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Using essentially the same procedures described in Example 2, step a and Example 1, step e, and employing 1- (1-adamantyl) -2- (4-ethoxyphenyl) ethane-1, 2- dione and 1-methylguanidine hydrochloride, the title product is obtained as a white solid, MS m / e 368 (M) +; 1 H NMR (DMSO-d 6, 300 MHz) d 1.2 (t, 3 H), 1.3 (m, 6 H), 1.5 (m, 3 H), 1.6 (m, 3 H), 1.8 (m, 3 H), 2.8 (s, 3H), 4.0 (t, 2H), 6.4 (b, 2H), 6.8 (d, 2H), 7.5 (d, 2H).

EXAMPLE 4 Preparation of 5- (1 -Anymantyl) -2-amino-5- (4-butoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazolone Using essentially the same procedures described in Example 2, step a and Example 1, step e, and employing 1- (1-adamantyl) -2- (4-butoxyphenyl) ethane-1,2-dione and 1-methylguanidine hydrochloride, the title product is obtained as a white solid, MS m / e 396 (M) +; 1 H NMR (DMSO-d 6, 300 MHz) d 0.9 (t, 3 H), 1.4 (m, 8 H), 1.6 (m, 3 H), 1.7 (m, 5 H), 1.9 (m, 3 H), 2.9 (s, 3H), 3.9 (t, 2H), 6.4 (b, 2H), 6.8 (d, 2H), 7.5 (d, 2H).

EXAMPLE 5 Preparation of 5- (1 -Anymantyl) -2-amino-5- (3-ethyl-4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazole-one Using essentially the same procedures described in Example 2, step a and Example 1, step e, and employing 1- (1-adamantyl) -2- (3-ethyl-4-methoxyphenyl) ethane-1,2-dione and hydrochloride 1-methylguanidine, the title product is obtained as a white solid, MS m / e 382 (M) +; 1 H NMR (DMSO-d 6, 300 MHz) d 1.0 (t, 3 H), 1.4 (m, 7 H), 1.5 (m, 3 H), 1.6 (m, 3 H), 1.8 (m, 3 H), 2.4 (q, 2H), 2.8 (t, 2H), 3.7 (s, 3H), 6.4 (b, 2H), 6.8 (d, 1 H), 7.4 (m, 2H).

EXAMPLE 6 Preparation of 5- (1 -Adamantl) -2-amino-5- (4-methoxy-3,5-dimethylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Stage a) Preparation of 5-Chloromethyl-2-methoxy-1,3-dimethylbenzene A solution of 2-methoxy-1,3-dimethylbenzene (10 g, 73 mmol) in glacial acetic acid is treated with paraformaldehyde (12 g, 142 mmol), heated at 60 ° C with HCl (gas) bubbled for 4 h It is cooled to room temperature. The reaction is poured in water and extracted with ether. The extracts are combined, washed sequentially with water, saturated aqueous sodium bicarbonate and saline, dried over MgSO 4 and concentrated in vacuo. The resulting residue is distilled (100 ° C and 0.2 mmHg) to give the chloromethylbenzene compound as a clear oil, 2.3 9 (17% yield), 1 H NMR (DMSO-d6.300 MHz) d 2.2 (s, 6H) , 3.6 (s, 3H), 4.6 (s, 2H), 7.0 (s, 2H).

Step b) Preparation of (4-Methoxy-3,5-dimethyl-benzyl) -triphenyl-phosphonium chloride Using essentially the same procedure described in Example 1, step e, and using 5-chloromethyl-2-methoxy-1,3-dimethyl-benzene and triphenylphosphine, the title phosphonium chloride is obtained as a white solid, MS m / e 411 (M) +; 1 H NMR (DMSO-d 6 300 MHz) d 1.9 (s, 6H), 3.3 (s, 3H), 5.0 (d, 2H), 7.6 (m, 6H), 7.7 (m, 6H), 7.9 (m, 3H) ).

Step c) Preparation of 1-Adamantan-1-yl-2- (4-methoxy-3,5-dimethyl-phenyl) -ethane-1,2-dione Using essentially the same procedure described in Example 2, step a, and using (4-methoxy-3,5-dimethyl-benzyl) -triphenyl-phosphonium chloride and 1-adamantanecarbonyl chloride, the diketone is obtained. of the title as a yellow oil, MS m / e 327 (M) +; 1 H NMR (DMSO-d 6 300 MHz) d 1.6 (m, 6H), 1.8 (m, 6H), 2.0 (m, 3H), 2.3 (s, 6H), 3.7 (s, 3H), 7.4 (s, 2H).

Step d) Preparation of 5- (1-Adamantyl) -2-amino-5- (4-methoxy-3,5-dimethyl-phenyl) -3-methyl-3,5-dihydro-4H-imidazole-4 -one Using essentially the same procedure described in Example 1, step e, and employing 1-adamantan-1-yl-2- (4-methoxy-3,5-dimethylphenyl) ethane-1,2-dione and 1-methylguanidine, obtain the title product as a white solid, MS m / e 382 (M) +; 1 H NMR (DMSO-d 6 300 MHz) d 1.4 (m, 6H), 1.5 (m, 3H), 1.7 (m, 3H), 1.8 (m, 3H), 2.1 (s, 6H), 2.8 (s, 3H) ), 3.6 (s, 3H), 6.4 (b, 2H), 7.2 (s, 2H).

EXAMPLE 7 Preparation of 5- (1-Adamantyl) -2-amino-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one Step a) Preparation of diethyl 1-phenyl-1- (trimethylsiloxy) methane phosphonate Under a nitrogen atmosphere, in a cold (0 ° C) solution of benzaldehyde (10.15 mL, 0.1 mmol) and triethylphosphite (19.1 mL, 0.1 mol), chlorotrimethylsilane (12.6 mL, 0.1 mol) is added dropwise over 10 minutes. After the addition is complete, the ice bath is removed and the reaction mixture is heated to 120 ° C (oil bath) for 8 hours and distilled (180 ° C, 10.0 mmHg) to achieve the title compound as a colorless oil (25 g, 79% yield); MS m / e (M + H) +317; 1 H NMR (400 MHz, CDCl 3) d 0.08 (s, 9 H), 1.22 (m, 6 H), 4.01 (m, 4 H), 4.97 (d, 1 H), 7.32 (m, 3 H), 7.44 (m, 2 H) ).

Step b) Preparation of diethyl ester of (2-Adamantan-1-yl-2-oxo-1-phenyl-1-trimethylsilanyloxy-ethyl) -phosphonic acid Under a nitrogen atmosphere, in a cold solution (-78 ° C) of 1-phenyl) [(trimethylsilyl) oxy] methyl} diethyl phosphonate (3.16 g, 10 mmol) in THF is added dropwise lithium diisopropylamide (2M, 5.25 mL) for 10 minutes. The reaction mixture is stirred for another 30 minutes, treated with adamantane-1-carboxylic acid chloride (2099, 10 mmol) in THF, heated slowly to room temperature overnight. Under cooling the reaction mixture is poured into saturated NH 4 Cl solution and extracted with ether. The extracts are combined, dried over MgSO 4 and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel (hexanes / EtOAc 95/5)) to achieve the title diester as an oil colorless (2.1 g, 43% yield); MS m / e (M + H) +479.1; 1 H NMR (400 MHZ, DMSOd 6) d 0.21 (s, 9H), 1.13 (t, 6H), 1.45-1.82 (m, 15H), 3.91 (dq, 4H), 7.30-7.43 (m, 5H).

Step c) 1 -Adamantan-1 -yl-2-phenyl-ethane-1,2-dione A mixture of diethyl ester of (2-adamantan-1-yl-2-oxo-1-phenyl-1-trimethylsilanyloxyethyl) -phosphonic acid (2.1 g, 4.38 mmol), a mixture of H2O / saturated NaHCO3 solution (1: 1) in methanol is heated at reflux temperature for 2 hours, cooled, acidified with 2N HCl and extracted with ether. The ether extracts are combined, dried over MgSO 4 and concentrated in vacuo. Purification of this residue by flash chromatography on silica gel (hexane / EtOAc 95/5) gives the title diketone as a yellow oil (0.21 g, 18% yield); MS m / e (M +) + 268.15; 1 H NMR (400 MHz, DMSO-d 6) d 1.70 (m, 6H), 1.90 (bs, 6H), 2.02 (m, 3H), 7.62 (m, 2H,), 7.79 (m, 3H).

Step d) Preparation of 5- (1-Adamantyl) -2-amino-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one A mixture of 1-adamantan-1-yl-2-phenylethane-1,2-dione (0.21 g, 0.78 mmol), Na 2 CO 3 (0.25 g, 2.34 mmol), N-methylguanidine hydrochloride (0.12 g, 1.01 mmol), and H 2 O (0.70 mL) in dioxane and EtOH are stirred at 80 ° C for 18 hours and concentrated in vacuo. The resulting residue is dissolved in CHCl3, washed with water, dried over K2CO3 and evaporated to dryness. Purification of this residue by flash chromatography on silica gel (EtOAc / CH 2 Cl 2 / Et 3 N 7.5 / 2 / 0.5) gives the title product as a white solid (0.11 g, 43% yield, mp 250 ° C); MS m / e (M + H) +324; 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6H), 1.50 (m, 3H), 1.70 (m, 3H), 1.85 (bs, 3H), 2.85 (s, 3H), 6.40 (bs, 2H), 722 (m, 3H), 7.62 (m, 2H).

EXAMPLE 8 Preparation of 5- (1-Adenamant) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Stage a) Preparation of. { (4-methoxy-3-methylphenyl) [(trimethylsilyl) oxy] methyl} diethyl phosphonate Under a nitrogen atmosphere, in a cold (0 ° C) solution of 3-methyl-4-methoxy-benzaldehyde (15 g, 0.1 mol) and triethylphosphite (19.1 mL, 0.1 mol), chlorotrimethylsilane is added dropwise (12.6 mL). , 0.1 mol) for 10 minutes, heated at 120 ° C (oil bath) for 8 hours and distilled (180 ° C, 10.0 mmHg). The distillate is further purified by flash chromatography on silica gel (hexanes / ethyl acetate / isopropyl alcohol, 7 / 2.5 / 0.5) to give the title phosphonate compound as a white solid (16 g, 44% yield, mp 37). ° C); MS m / e (M + H) +361; 1 H NMR (400 MHz, DMSO 6) d 0.1 (s, 9 H), 1.18 (d t, 6 H), 2.1 (s, 3 H), 3.68 (s, 3 H), 3.85 (m, 4 H), 4.97 (d, 1 H ), 6.87 (m, 1H), 7.20 (m, 2H).

Step b) Preparation of diethyl ester of 2-Adamantan-1-yl-1- (4-methoxy-3-methyl-phenyl) -2-oxo-1-trimethylsilanyloxy-ethyl] -phosphonic acid Using substantially the same procedure described in Example 7, step b, and employing. { (4-methoxy-3-methylphenyl) [(trimethylsilyl) oxy] methyl} diethyl phosphonate (3.6 g, 10 mmol) and adamantane-1-carboxylic acid chloride (2.09 g, 10 mmol), the title diester compound is obtained as a yellow oil (0.98 g, 22% yield); MS m / e (M + H) +523.2; 1 H NMR (400 MHZ, DMSO-d 6) d 0.21 (s, 9H), 1.15 (t, 6H), 1.45-1.82 (m, 15H), 2.17 (s, 3H), 3.78 (s, 3H), 3.91 ( dq, 4H), 6.90 (d, 1 H), 7.20 (m, 2H).

Step c) Preparation of 1-Adamantan-1-yl-2- (4-methoxy-3-methyl-phenyl) -ethane-1,2-dione Using substantially the same procedure described in Example 7, step c, and using diethyl ester of 2-adamantan-1-yl-1- (4-methoxy-3-methyl-phenyl) -2-oxo-1-trimethylsilanyloxy- ethyl] -phosphonic acid (0.98 g, 1.87 mmol), the title diketone is obtained as a yellow oil (0.21 g, 53% yield); MS m / e (M + H) +313.14; 1 H NMR (400 MHz, CDCl 3) d 1.69 (m, 6 H), 1.93 (bs, 6 H), 2.01 (bs, 3 H), 2.21 (s, 3 H), 3.87 (s, 3 H), 6.85 (d, 1 H). ,), 7.60 (m, 2H).

Step d) Preparation of 5- (1-Adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Using substantially the same procedure described in Example 7, step d, and employing 1-adamantan-1-yl-2- (4-methoxy-3-methyl-phenyl) -ethane-1,2-dione (0.21 g, 0.67 mmol), the title product is obtained as a white solid (0.105 g, 42% yield, mp 255 ° C); MS m / e (M + H) +368; 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6 H), 1.55 (m, 3 H), 1.70 (m, 3 H), 1.85 (bs, 3 H) 2.10 (s, 3 H), 2.85 (s, 3 H) ), 3.78 (s, 3H), 6.30 (bs, 2H), 6.80 (d, 1 H), 7.42 (m, 2H).

EXAMPLE 9 Preparation of (5S) - (1--Anymantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-d -hydro-4H-imidazol-4-one The racemate 5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one is separated by technical HPLC about Chiralcel AD, 046 x 25 cm using the mobile phase EtOH: H2O (6: 4 with 0.1% DEA) at a flow rate of 1.0 mL / min. The S-isomer of the title is obtained after evaporation as a white solid; mp 376 ° C: MS m / e (M + H) +368: 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6 H), 1.55 (m, 3 H), 1.70 (m, 3 H), 1.85 (bs, 3H), 2.10 (s, 3H), 2.85 (s, 3H), 3.70 (s, 3H), 6.40 (bs, 2H), 6.80 (d, 1H), 7.42 (m, 2H).

EXAMPLE 10 Preparation of (5R) -f 1 -Adamantil) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one The racemate 5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one is separated by HPLC technique on Chiralcel AD, 046 x 25 cm using the mobile phase EtOH: H2O (6: 4 with 0.1% DEA) at a flow rate of 1.0 mL min. The R-isomer of the title is obtained, after evaporation, as a white solid; mp 376 ° C; MS m / e (M + H) +368; 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6 H), 1.50 (m, 3 H), 1.70 (m, 3 H), 1.85 (bs, 3 H), 2.10 (s 3 H), 2.85 (s. 3H), 3.70 (s, 3H), 6.40 (bs, 2H). 6.80 (d, 1 H), 7.42 (m, 2H).

EXAMPLE 11 Preparation of 5- (1-Adamantyl) -2-amino-5- (3,4-dimethoxyphenyl-3,5-dihydro-4H-imidazol-4-one) Using essentially the same procedures described in Example 7, steps a-d and employing. { (3,4-dimethoxyphenyl) [(trimethylsilyl) oxy] methyl} diethyl phosphonate as the starting material, the title product is obtained as a white solid, 0.08 g, mp 130 ° C; MS m / e (M + H) +384; 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6H), 1.50 (m, 3H), 1.70 (m.3H), 1.85 (bs, 3H), 2.85 (s, 3H), 3.65 (ds, 6H), 6.30 (bs, 2H), 6.80 (d, 1 H), 7.20 (m, 2H).

EXAMPLE 12 Preparation of 5- (1-Adamantyl) -2-amino-5- (4-methoxy-2,3-dimethylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Step a) Preparation of 1-Chloromethyl-4-methoxy-2,3-dimethyl-benzene.

In a stirred solution cooled (0 ° C) (4-methoxy-2,3-dimethyl-phenyl) -methanol (5 g, 30.08 mmol) in dioxane anhydrous ZnCl 2 (0.1 g) is added, then SOCI 2 (4.4 ml, 60.16). mmol) in dioxane (6 ml) for one hour. The reaction mixture is allowed to come to room temperature and is stirred for another hour. The volatiles were removed in vacuo and the residue was dissolved in ether and washed with saturated aqueous NaHCO3 then dried over MgSO4. Evaporation and purification by distillation gives the title chloromethylbenzene compound as a white solid (1.2 g, 22% yield). MS m / e (M) +184; 1 H NMR (400 MHz, DMSO-d 6) d 2.01 (s, 3 H), 2.41 (s, 3 H), 76 (s 3 H), 4.78 (s, 2 H), 6.77 (d, 1 H), 7.19 (d , 1 HOUR).

Step b) Preparation of 4-methoxy-2,3-dimethylbenzyltriphenylphosphonium chloride.

A solution of 1-chloromethyl-4-methoxy-2,3-dimethyl-benzene (1.02 g, 5.20 mmol) and triphenylphosphine (1.46 g, 5.57 mmol) in toluene is heated at reflux temperature for 18 hours. The resulting white suspension is diluted with hexane and filtered. The filter cake is washed with hexane to give the title phosphonium chloride as a white solid (1.93 g, 80% yield); MS m / e (M) +411; 1 H NMR (400 MHz, DMSO-d 6) d 1.38 (s, 3 H), 1.88 (s, 3 H), 3.67 (s, 3 H), 4.99 (d, 2 H), 6.66 (d, 1 H), 6.77 (d , 1 H), 7.58 (m, 6H), 7.68 (m, 6H), 7.86 (m, 3H).

Step C) Preparation of 1-Adamantan-1-yl-2- (4-methoxy-2,3, dimethylphenyl) -ethane-1,2-dione.

Under a nitrogen atmosphere, a cold (0 ° C) suspension of 4-methoxy-2,3-dimethyl-benzyl-triphenyl-phosphonium chloride (1.90 g, 4.3 mmol) in toluene is treated dropwise with n-BuLi (2.5 M in hexane, 1.8 mL) over a period of 10 minutes, warmed to room temperature, stirred for 80 minutes, cooled to 0 ° C treated with a solution of adamantane-1-carboxylic acid chloride (0.427). g, 2.15 mmol) in toluene, warmed to room temperature, stirred for 18 hours and concentrated in vacuo. The resulting residue is dissolved in a mixture of H2O and acetone, treated with MgSO4 (2.0 g) and KmNO »(1.3 g), stirred at 50 ° C for 18 hours with ether and H2O and filtered through solka floc. . The filtrate is separated; The organic phase is dried over MgSO and evaporated to dryness. This residue is purified by flash chromatography on silica gel (hexane / EtOAc 95/5), to give the title diketone compound as an off white solid (0.21 g, 30% yield, mp 140 ° C); MS m / e (M + H) +327.1; 1 HOUR NMR (400 MHZ, CDCl 3) d 1.70 (m, 6H), 1.95 (m, 6H), 2.02 (m, 3H), 2.17 (s, 3H), 2.57 (s, 3H), 3.85 (s, 3H), 6.72 (d, 1 H), 7.29 (d, 1H).

Step d) Preparation of 5- (1-Adamantyl) -2-amino-5- (4-methoxy-2,3-dimethyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one.

Using substantially the same procedure described in Example 7, step d, and employing 1-adamantan-1-yl-2- (4-methoxy-2,3, dimethylphenyl) ethane-1,2-dione (0.19 g, 0.582 mmol ) and methylguanidine hydrochloride, the title product is obtained as a white solid (0.12 g, 54% yield, mp 295 ° C); MS m / e (MH) "380; 1H NMR (400 MHZ, DMSO-d6) d 1.40 (m, 6H), 1.50 (m, 3H), 1.70 (m.3H), 1.80 (bs, 3H), 2.00 (s, 3H), 2.60 (s, 3H), 2.80 (s, 3H), 3.65 (s, 3H), 6.20 (bs, 2H), 6.60 (d, 1H), 7.85 (d, 1 H).

EXAMPLE 13 Preparation of 2-Amino-5-biccof2.2.1lhept-2-yl-5- (4-methoxy-3-methylphen-3-methyl-3,5-dihydro-4H-imidazol-4-one.

Using essentially the same procedure described in Example 7, step d, and employing 1-bicyclo [2.2.1] hept-2-yl-2- (4-methoxy-3-methylphenyl) ethane-1,2-dione and hydrochloride of methylguanidine, the title product is obtained as a white solid (0.175 g, 34% yield, mp 121 ° C); MS m / e (M + H) +326; 1 H NMR (400 MHz, DMSO-d 6) d 0.85-1.40 (m, 8H), 1.60 (m, 1H), 1.70 (m.1 H), 2.01 (bs, 1 H), 2.10 (s, 3H), 2.90 (s, 3H), 3.78 (s, 3H), 6.40 (bs, 2H), 6.81 (d, 1 H), 7.30 (m, 2H).

EXAMPLE 14 Preparation of 2-Amino-5-hexahydro-2,5-methanopentalen-3a (1 H) -yl-5- (4-methoxy-3-methylphen-D-3-methyl-3,5-dihydro-4H-imidazol-4-one) Step a) Preparation of diethyl ester of [2- (Hexahydro-2,5-methano-pentalen-3a-yl) -1 - (4-methoxy-3-methyl-phenyl) -2-oxo-1-trimethylsilanyloxy- ethyl] - phosphonic.

Using substantially the same procedure described in Example 7, step b, and employing. { (4-methoxy-3-methylphenyl) [(trimethylsilyl) oxy] methyl} diethylphosphonate (3.61 g, 10 mmol), and bicyclo [3.3.1] nonane-3-carboxylic acid chloride (10 mmol), the title diester is obtained as a yellow oil (2.2 g, 42% yield) ) MS m / e (M + H) +509.2; 1 H NMR (400 MHZ, DMSO-d 6) d 0.25 (s, 9 H), 1.15 (t, 3 H), 1.22 (t, 3 H), 1.36- 2.03 (m, 13 H), 2.18 (s, 3 H), 3.80 ( s, 3H), 4.04 (m, 4H), 6.76 (d, 1 H), 7.29 (m, 2H).

Step b) Preparation of 1- (Hexahydro-2,5-methano-pentalen-3a-yl) -2- (4-methoxy-3-methyl-phenyl) -ethane-1,2-dione.

Using substantially the same procedure described in Example 7, step c, and employing [2- (hexahydro-2,5-methano-pentalen-3a-yl) -1- (4-methoxy-3-methyl-) diethyl ester. phenyl) -2-oxo-1-trimethylsilanyloxy-ethyl] -phosphonic acid (1.1 g, 2.17 mmol) and replacing the methanol with dioxane, the diketone title compound is obtained as a yellow oil (0.125 g, 20% yield); MS m / e (M + H) +299.4; 1 H NMR (400 MHZ, CDCl 3) d 1.59-1.61 (m, 5H), 1.80 (m, 4H), 2.18 (m, 2H), 2.20 (s, 3H), 2.37 (m, 2H), 3.95 (s, 3H), 6.84 (d, 1 H), 7.65 (m, 2H).

Step c) Preparation of 2-Amino-5-hexahydro-2,5-methanopentalene-3a (1H) -yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro- 4H-imidazol-4-one.

Using essentially the same procedure described in Example 7, step d, and employing 1- (hexahydro-2,5-methano-pentalen-3a-yl) -2- (4-methoxy-3-methyl-phenyl) ethane-1 , 2-dione (0.11 g, 0.36 mmol) and methylguanidine hydrochloride, the title product is obtained as a white solid (0.07 g, yield 54, mp 160 ° C); MS m / e (M + H) +354; 1 H NMR (400 MHz, DMSO-d 6) d 1.10-1.40 (m, 11 H), 1.80 (m, 1 H), 2.00 (m, 1 H), 2.10 (s, 3 H), 2.81 (s, 3 H), 3.70 (s, 3H), 6.30 (bs, 2H), 6.78 (d, 1 H), 7.42 (m, 2H).

EXAMPLE 15 Preparation of 5- (1--Anymantyl) -2-amino-3-methyl-5- (4'-methyl-1,1-b-phenyl-3-yl) -3,5-dihydro-4H-imidazole-4- ona Step a) Preparation of 1- (1-Adamantyl) -2- (3-bromophenyl) ethanone 3-Bromobenzyl bromide 1 (7.50 g) is dissolved in diethyl ether. The solution is cooled to 0-30 ° C and magnesium (0.72 g) is added. The reaction mixture is stirred for 2 hours, copper bromide (1) (4.32 g) and anhydrous lithium bromide (5.22 g) are dissolved in tetrahydrofuran. The solution is cooled to -78 ° O The Grignard solution is slowly added and maintained at -78 ° O. A solution of adamantane-1-carbonyl chloride (5.94 g) in tetrahydrofuran is added and the reaction is stirred for 10 minutes. at -78 ° C and 10 minutes at 0 ° O The reaction solution is diluted with diethyl ether and washed with 1 M hydrochloric acid and 1 M sodium hydroxide. The organic phase is dried over sodium sulfate.

Anhydrous magnesium and evaporates. The residue is purified by flash chromatography (hexanes: ethyl acetate 9: 1) to obtain the title ethanone compound as a colorless oil (5.70 g). 1 H NMR 7.40-7.00 (m, 4H), 3.70 (s, 2H), 2.05 (m, 2H), 1.85 (s, 6H), 2.00-1.60 (m, 6H).

Step b) Preparation of 5- (1-Adamantyl) -2-amino-3-methyl-5- (4'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazole-4 -one A solution of 1- (1-adamantyl) -2- (3-bromophenyl) -ethanone (121 mg) in DMF is treated with 4-methylphenylboronic acid (122 mg) followed by anhydrous potassium carbonate (250 mg) and tetrakis ( triphenylphosphine) palladium (0) (35 mg). The reaction mixture is sealed, degassed and heated in a microwave oven at 150 ° C for 30 h. The reaction is cooled and filtered. The filtrate is evaporated in vacuo. The resulting residue is dissolved in diethyl ether, washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting oil is dissolved in 1,4-dioxane, treated with selenium (IV) oxide (60 mg), heated at 95 ° C overnight, cooled to room temperature, diluted with hexane and filtered . The filtrate is concentrated to a yellow oil residue. This oil is dissolved in ethyl alcohol, treated with 1-methylguanidine hydrochloride (42 mg) followed by a solution of sodium carbonate (119 mg) in water, heated at 70 ° C overnight and concentrated in vacuo. . The resulting residue is dissolved in DMSO and filtered. The filtrate is purified by Gilson preparative reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% NH4OH / water; Solvent B: 0.02% NH 4 OH / acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL / min; Detection: 254 nm DAD, to achieve the title product as a white amorphous solid, characterized by LCMS analysis. LCMS conditions: HPLC system HP 1100; Waters Xterra MS C18, 2 mm (i.d.) x 50 mm (length), column 3.5 um, set at 50 ° C; Flow rate 1.0 mL / min; Solvent A: 0.02% NH 4 OH in water; Solvent B 0.02% NH 4 OH in ACN; Gradient: Time 0: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ~ 2.0 mM; Injection volume: 5uL; Detection: 220 nm, 254 nm DAD.

EXAMPLES 16-26 Preparation of the compounds 5- (1-Adamantyl) -2-amino-3-methyl-5- (substituted phenyl) -3,5-dihydro-4H-imidazol-4-one Using essentially the same procedure described in Example 15 above, the compounds shown in Table I are obtained and identified by HRMN and mass spectral analysis. LCMS Conditions: HP 1100 HPLC System; Waters Xterra MS C18, 2 mm (i.d.) x 50 mm (length), column 3.5 um, set at 50 ° C; Flow rate 1.0 mUmin; Solvent A: 0.02% NH 4 OH in water; Solvent B 0.02% NH 4 OH in ACN; Gradient: Time 0: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ~ 2.0 mM; Injection volume: 5uL; Detection: 220 nm, 254 nm DAD. In Table 1, RT designates retention time.

TABLE I Ex. RT No. R5 [M + H] (min) 16 4-methoxyphenyl 430 2.75 17 3-methylphenyl 414 2.87 18 3-methoxyphenyl 430 2.74 19 3,4-dimethylphenyl 428 3.06 20 3-cyanophenyl 425 2.66 21 3-furylphenyl 390 2.52 22 4-cyanophenyl 425 2.67 23 3- (trifluoromethyl) phenyl 468 3.01 24 3,4-difluorophenyl 436 2.83 25 phenyl 400 2.77 26 2-methylphenyl 414 2.82 EXAMPLE 27 Preparation of 5- (1-Adamantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Step a) Preparation of compound 2 A 1.0 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (52.3 mL, 52.3 mmol) is added to a stirred suspension of (4-methoxy-benzyl) -triphenyl-phosphonium chloride (21.9 g, 52.3 mmol) in tetrahydrofuran. . The mixture is stirred at 15 min at room temperature, cooled to -5 ° C, treated with a solution of 1-admantanecarboxylic acid chloride 1 (9.44 g, 47.5 mmol) in THF and stirred for an additional 2 h although heating slowly to room temperature. The mixture is treated with water and sodium periodate (11.18 g, 52.3 mmol), stirred at 50 ° C for 17 h, cooled to room temperature and diluted with ethyl acetate. The organic phase is separated and washed sequentially with water and saline, dried over sodium sulfate, filtered and concentrated. Purification of the resulting residue by flash chromatography (silica, 5:95 to 10:90 ethyl acetate / hexanes) achieves 2 (6.85 g, 48%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 7.78 (d , J = 8.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 2.05-1.55 (m, 15H); ESI MS m / z 299 [C19H2203 + H] +.

Step b) Preparation of the compound 5- (1-adamantyl) -2-amino-5- (4-methoxy-phenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one A mixture of 2 (6.71 g, 22.5 mmol) and 1-methylguanidine hydrochloride (11.1 g, 101 mmol) in dioxane and ethanol is stirred at room temperature for 5 min, treated with an aqueous solution of sodium carbonate (10.7 g, 101 mmol), heated at 85 ° C with stirring for 3.25 h, cooled to room temperature environment and concentrates in a vacuum. Purification of the resulting residue by flash chromatography (silica, 95: 5: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide) achieves the title product as a white solid, 3.41 g (43% yield), mp 150-155 ° C; 1 H NMR (300 MHz, CDCl 3) d 7.55 (d, J = 6.9 Hz, 2 H), 6.86 (d, J = 6.9 Hz, 2 H), 3.78 (s, 3 H), 3.02 (s, 3 H), 1.93-1.44. (m, 15H); IR (ATR) 3358, 2903, 1663, 1508, 1459, 1308, 1248, 1177, 1102, 1033, 998, 837, 804, 729 cm "; ESI MS m / z 354 [C 21 H 27 N 3 O 2 + H] +.

EXAMPLE 28 Preparation of (5S) -5- (1 -Anymantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one TAI and (5R) -5- ( 1-Adamantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one fBl B A racemic mixture of 5- (1-adamantyl) -2-amino-5- (4-methoxy-phenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one is separated by HPLC on Chiralcel AD , 0.46 x 25 cm using the mobile phase EtOH: hexane (1: 9 with 0.1% DEA) and a flow rate of 1.0 mL / min to achieve the S'isomer of the title (A), mp 215 ° C; [a] 25 = -17.4 (C = 1% in MeOH); 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6 H), 1.55 (m, 3 H), 1.70 (m, 3 H), 1.85 (bs, 3 H), 2.10 (s, 3 H), 2.85 (s, 3H), 3.70 (s, 3H), 6.40 (bs, 2H), 6.80 (d, 1H), 7.42 (d, 2H); MS m / e (M-H) '352; and the R-isomer of the title (B), mp 215 ° C; [a] 25 = -17.6 (C = 1% in MeOH); 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (m, 6H), 1.50 (m, 3H), 1.70 (m, 3H), 1.85 (bs, 3H), 2.10 (s, 3H), 2.85 (s, 3H), 3.70 (s, 3H), 6.40 (bs, 2H), 6.80 (d, 2H), 7.42 (2, 2H); MS m / e (M-HV 352; EXAMPLE 29 Preparation of 5- (1 -Anymantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one T PPhjBr T F3cs J 4. Na2C03 (aq) Using essentially the same procedure described in Example 27 and using [4- (trifluoromethoxy) benzyl] triphenylphosphonium bromide in Step 1, the title compound is obtained as a white solid, mp 125 ° C, identified by NMR and analysis spectral mass.

EXAMPLE 30 Preparation of 5-r3- (benzyloxy) phenan-5-cyclohexyl-2-imino-3-methylimidazolidinone Step a) Preparation of compound 2 A mixture of 1 (11.84 g) and magnesium (1.62 g) in tetrahydrofuran (60 mL) is treated with 1,2-dibromoethane (100 μL), stirred at room temperature for 1 hour at reflux temperature for 1 h and Allows cooling to room temperature. In a separate vessel dissolve copper bromide (1) (6.84 g) and lithium bromide (7.83 g) in tetrahydrofuran (50 mL). This solution is cooled to 0 ° C and treated with the previous Grignard solution. The reaction solution is added slowly, at -78 ° C, in oxalyl chloride (19.6 mL) in tetrahydrofuran (100 mL), kept at -78 ° C for 10 minutes, allowed to warm to room temperature over a period of time.

After 1 h, pour carefully (warm evolution) into a vessel containing saline solution (200 mL) and extract with diethyl ether (300 mL). The organic phase is separated, washed with 1 M hydrochloric acid (200 mL) and extracted with a 5M sodium hydroxide solution. The basic aqueous extracts are combined, filtered through Celite pad, acidified to pH 1 with concentrated hydrochloric acid, and extracted with diethyl ether. The ether extracts are combined, dried over magnesium sulfate and concentrated in vacuo to achieve 2 as a yellow oil (6.67 g), by LCMS analysis (retention time 1.60 min, 255 [M-H]). LCMS Conditions: HP 1100 HPLC System; Waters Xterra MS C18, 2 mm (i.d.) x 50 mm (length), column 3.5 um, set at 50 ° C; Flow rate 1.0 mlJmin; Solvent A: 0.02% NH 4 OH in water; Solvent B 0.02% NH 4 OH in ACN; Gradient: Time 0: 10% B; 2.5 min 50 90% B; 3 min 90% B; Sample concentration: ~ 2.0 mM; Injection volume: 5uL; Detection: 220 nm. 254 nm DAD.

Step b) Preparation of compound 3 The compound (2) (6.67 g) is dissolved in dichloromethane treated with DMF (500 μL), treated slowly with oxalyl chloride (26 mL) (evolution of gas) and stirred for 3 h and concentrated in vacuo. The resulting residue is dissolved in diethyl ether and filtered through Celite. The filtrate is evaporated to dryness to obtain 3 as a yellow liquid (5.94 g).

Step c) Preparation of compound 4 At 0 ° C, phenylmagnesium bromide (0.5 mL, 0.5 M solution in THF) is added to a solution of copper (I) bromide (111 mg) and lithium bromide (134 mg) in THF. This mixture is treated with a solution of acid chloride (3) (212 mg) in THF, allowed to warm to room temperature and diluted with diethyl ether, washed sequentially with 1 M hydrochloric acid and 1 M sodium hydroxide, Dry over anhydrous magnesium sulfate and evaporate to dryness to give 4 as a yellow oil (200 mg).

Step c) Preparation of 5- [3- (benzyloxy) phenyl] -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one A solution of 4 (200 mg) and 1-N-methylguanidine hydrochloride (85 mg) in ethanol is treated with sodium carbonate (245 mg) in water, heated at 70 ° C for 3 h and concentrated in vacuo. The resulting residue is purified using preparative reverse phase HPLC to give the title product as a white amorphous solid (18 mg), characterized by LCMS analysis, 348 [M + H]; Retention time 2.82 min. Gilson preparative reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% NH OH / water; Solvent B: 0.02% NH 4 OH / acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A. 16 min: 95% A; Flow rate 22.5 mL / min; Detection: 254 nm DAD.

LCMS Conditions: HP 1100 HPLC System; Waters Xterra MS C18, 2 mm (i.d.) x 50 mm (length), column 3.5 um, set at 50 ° C; Flow rate 1.0 mL / min; Solvent A: 0.02% NH 4 OH in water; Solvent B 0.02% NH OH in ACN; Gradient: Time 0: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ~ 2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD.

EXAMPLE 31 Preparation of Adamantane-1-carbaldehyde To a suspension of pyridinium chlorochromate (3.88 g, 18 mmol) in methylene chloride (100 mL) is added a solution of 1-adamantanemethanol (2.0 g, 12 mmol) in methylene chloride (30 mL) in one portion. After stirring for 2 h at room temperature, the reaction mixture is diluted with ether (50 ml). The mixture is filtered through a funnel packed with silica gel (20 g) and washed with ether. The filtrate is concentrate to obtain the title compound 1.7 g (85%) as a white solid, mp: 132-135 ° C. MS (+) ES: 165 (M + H) +.

EXAMPLE 32 Preparation of 1-Etynyldamantane To a stirred mixture of adamantane-1-carbaldehyde (2.0 g, 12.2 mmol) and K2CO3 (3.36 g, 24.4 mmol) in methanol (200 mL) was added (dimethyl-1-diazo-2-oxopropyl) phosphonate (2.8 g, 14.6 mmol) dropwise After stirring for 4 h at room temperature, the reaction mixture is diluted with ether (100 ml) The mixture is washed with a solution of NaHCO 3 (5% in water, 300 ml). The organic layer is separated, dried (MgSO4) and concentrated The crude material is purified by chromatography (silica gel, 100% hexane) to give the title compound 1.5 g (75%) as a white solid, mp: 80-82 ° O MS (+) ES: 161 (M + H) +.

EXAMPLE 33 Preparation of 1- (f4- (Difluoromethoxy) phenylethynyl) adamantine A mixture of 1-ethynylamdamantane (320 mg, 2 mmol), 4-difluoromethoxy-4-iodobenzene (540 mg, 2 mmol), Cul (19 mg, 0.1 mmol) and Pd (PPh3) (92 mg, 0.08 mmol) in triethylamine (6 ml) and acetonitrile (3 ml) is placed under reflux for 3 h. After removal of the solvent, the crude mixture is purified by flash chromatography (silica gel, hexane / ethyl acetate: 95/5) to give the title compound 470 mg (78%) as a clear oil. MS (+) ES: 303 (M + H) +.

EXAMPLE 34 Preparation of 1- (1-Adamantyl) -2-r4- (difluoromethoxy) phenylethane-1,2-dione To a solution of 1- (4-difluoromethoxyphenylethynyl) adamantine (460 mg, 1.5 mmol) in acetone (20 mL) was added a solution of NaHCO3 (77 mg, 0.91 mmol) and MgSO4 (270 mg, 2.25 mmol) in water ( 10 mL), followed by the addition of KMnO 4 (711 mg, 4.5 mmol) in one portion. After stirring for 24 h at room temperature, the reaction mixture is extracted with hexane (2x20 ml). The combined organic extracts are dried (MgSO). Removal of the solvent affords the title compound 480 mg (94%) as a white solid, mp: 118-120 ° C. MS (+) ES: 335 (M + H) +.

EXAMPLE 35 Preparation of 5- (1 -Anymantyl) -2-amino-5-f4- (difluoromethoxy) phenin-3-methyl-3,5-dihydro-4H-imidazol-4-one A mixture of 1-adamantan-1-yl-2- (4-difluoromethoxyphenylethynyl) ethane-1,2-dione (480 mg, 1.44 mmol), methylguanidine hydrochloride (313 mg, 2.88 mmol) and Na2CO3 (453 mg, 4.32 mmol) in ethanol and water was put under reflux for 3 h and concentrated in vacuo. The resulting residue is purified by flash chromatography (silica gel, EtOAc / 2.0 M ethanolic NH 3: 95/5) to give the title compound 108 mg (20%) as a white solid, mp: 216-218 ° O Identified by NMR and spectral mass analysis. MS (+) ES: 390 (M + H) +.

EXAMPLE 36 Preparation of 2-Amino-5-cyclohexyl-5-f4- (difluoromethoxy) phenin-3-methyl-3,5-dihydro-4H-imidazol-4-one Using essentially the same procedure described in Example 35 and employing 1-cyclohexyl-2 - (- 4-difluoromethoxyphenylethynyl) ethane-1,2-dione and methylguanidine, the titled compound was obtained as a solid, mp 178-180 ° C. identified by NMR and mass spectral analysis. MS (+) APPI: 338 (M + H) EXAMPLE 37 Preparation of the compound 2-Amino-5-cyclohexyl-3- (3,5-difluorobenzyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one Phenyl glycolic acid (2) (10.8 g) is dissolved in dichloromethane (200 mL). Added N, N-Dimethylformamide (100 μL) followed by the slow addition of oxalyl chloride (72 mL, 2.0 M in dichloromethane) after 12 h the solvent is removed, and the residue is re-dissolved in diethyl ether (100 mL) . The insoluble particles are filtered (Celite) and the solvent is removed leaving a brown liquid (11.80 g). 13C NMR: 181.1, 166.7, 135.9, 130.5, 129.4, 129.3 Copper bromide (I) (7.20 g) and lithium bromide (8.70 g) are dissolved in tetrahydrofuran (300 mL). The solution is cooled to -78 ° C and cyclohexylmagnesium chloride (25 mL, 2.0 M in diethyl ether) is added. The solution is kept at this temperature for 10 minutes, phenylglycolic acid chloride 2 (8.40 g) in tetrahydrofuran (10 mL) is added. The solution is stirred for 15 minutes and then heated to room temperature for 30 min. Diethyl ether (500 mL) is added and the solution is washed with 1 M hydrochloric acid (2 x 200 mL) and 1 M sodium hydroxide (200 mL). Drying with magnesium sulfate and removal of the solvent produced the crude product. Purification by flash chromatography (hexane: ethyl acetate 25: 1) gives yellow oil (5.51 g). 1 H NMR: 8.00-8.90 (m, 2H), 7.70-58 (m, 1 H), 7.56-7.40 (m, 2H), 3.18-3-00 (m, 1 H), 2.00-1.05 (m, 10H) ). 13c NMR: 206.1, 194.2, 134.5, 132.5, 129.9, 128.8, 45.8, 27.1, 25.7, 25.3. 3,5-Difluorobenzylamine (72 mg) and 1-H-pyrazole-1-carboxamidine hydrochloride (73 mg) are dissolved in N.N-dimethylformamide. Diisopropylethylamine (0.74 mL) is added and the solution is heated at 40 ° C overnight. The solvent is evaporated and the crude product is used without further purification.

Compound 3 (107.5 mg) and crude compound 5 are dissolved in ethanol (5 mL). Sodium carbonate (79 mg) in water (1 ml) is added and the solution is heated at 70 ° C overnight. The solvent is evaporated and the crude product is purified using preparative reverse phase HPLC (Gilson preparative reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID, 5 μM 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, 15 min: 10% A, 16 min: 95% A; flow 22.5 mL / min; Detection: 254 nm DAD) providing a white amorphous solid (32 mg). The compound is characterized by LCMS analysis (LCMS conditions: HP 1100 HPLC system, Waters Xterra MS C18, 2 mm (id) x 50 mm (length), column 3.5 μm, set at 50 ° C, flow rate 1.0 mL / min; Solvent A: 0.02% NH4OH in water, Solvent B 0.02% NH OH in ACN, Gradient: Time 0: 10% B, 2.5 min 90% B, 3 min 90% B, Sample concentration: ~ 2.0 mM; injection: 5 μL; Detection: 220 nm, 254 nm DAD.) EXAMPLES 38 TO 73 Preparation of the compounds 2-Amino-5-cyclohexyl-5-phenyl-3-substituted-3,5-dihydro-4H-imidazol-4-one Using essentially the same procedure described in Example 37 and employing the appropriately substituted guanidine, the compounds shown in Table II were obtained and identified by HRMN and mass spectral analysis. The LCMS conditions were the same as those used in Example 37. TABLE Ex RT No. R3 [M + H] [min] 38 Ethyl 286 2.58 39 Propyl 300 2.65 40 3-hydroxypropyl 316 2.3 41 2.2, -dietoxyethyl 374 2.64 42 2-phenylethyl 362 2.50 43 Methyl 272 2.30 44 tetrahydrofuran-2-ylmethyl 342 2.59 TABLE II, continued Ex. RT No. R3 [M + H] [min] 45 2-fluoroethyl 304 2.45 46 2-difluoromethyloxybenzyl 414 2.57 47 N-acetyl-L-aspartyl 431 2.32 48 N-acetyl-D-aspartyl 431 2.32 49 4-methylenecyclohexyl carboxylic acid 398 1.95 50 hexanoic acid 372 2.46 51 pentanoic acid 358 1.89 52 butanoine acid 345] 2.40 53 5-hydroxypropyl 344 1.90 54 propanic acid 330 2.40 55 1-methyl-3-propanoic acid 344 1.88 56 Benzilo 348 2.66 57 2-methylpropyl 314 2.63 58 Hexilo 342 2.93 59 cyclohexyl 340 2.71 60 2-hydroxybutyl 330 2.36 61 ethanecarboxylic acid 316 2.37 62 Methylcyclohexyl 354 2.31 63 2-furylmethyl 338 2.40 64 4-hydroxyphenyl 350 2.30 65 3-hydroxyphenyl 350 2.30 TABLE II, continued Ex. RT [min] No. R3 [M + H] 66 thien-2-ylmethyl 354 2.40 67 4-methoxyphenyl 364 3.30 68 2-thien-2-ylethyl 368 3.30 69 2- (4-hydroxyphenyl) ethyl 378 3.00 70 4-phenylacetic acid 392 2.20 71 4-methylbenzoic acid 392 2.40 72 5- (2-hydroxybenzoic acid) 392 2.50 73 ethyl-3-benzoate 406 2.80 JEMPLOS 74-88 Preparation of 2-Amino-5-cycloalkyl-5-phenyl-3-substituted-3,5-dihydro-4H-imidazol-4-one compounds Using essentially the same procedure described in Example 37 and employing the appropriate cycloalkylmagnesium chloride and the desired substituted guanidine, the compounds shown in Table III are obtained and identified by HRMN and mass spectral analysis. The LCMS conditions used are the same as those described in Example 35. RT designates retention time.

TABLE Ex. RT No. R3 A [M + H] (min) 74 Methyl cyclobutyl 244 2.21 75 Methyl 2-adamantyl 324 2.83 76 Methyl cyclopentyl 258 2.34 77 Ethyl cyclobutyl 258 2.31 78 Ethyl cycloheptyl 300 2.63 79 Ethyl 2-adamantyl 338 2.55 80 Ethyl cyclopentyl 272 2.43 81 Propyl cyclobutyl 272 2.41 82 Propyl cycloheptyl 314 2.73 83 Propyl 2-adamantyl 352 3.01 84 Propyl cyclopentyl 286 2.51 85 3-hydroxypropyl cyclobutyl 288 2.08 86 3-hydroxypropyl cycloheptyl 330 2.42 87 3-hydroxypropyl 2-adamantyl 368 2.64 88 3-hydroxypropyl cyclopentyl 302 2.21 I EXAMPLE 89 Preparation of 2-Amino-5-cyclohexyl-5- (2-methylphenyl) -3-methyl-3,5-dihydro-4H-midazol-4-one A solution of copper bromide (I) (72 mg) and lithium bromide (87 mg) in THF is cooled to 0 ° C, treated with 2-toluylmagnesium bromide (1 mL, 0.5 M in tetrahydrofuran), maintained at 0 ° C for 10 minutes, treated with a solution of cyclohexylglycolic acid chloride (85 mg) in THF, stirred for 15 minutes, diluted with diethyl ether, washed sequentially with 1 M hydrochloric acid and 1 M sodium hydroxide. , dried over magnesium sulfate and concentrated in vacuo to achieve diketone 2 as a yellow oil (73 mg).

A solution of ethanol of 2 (73 mg) and 1-N-methylguanidine hydrochloride (55 mg) is treated with sodium carbonate (159 mg) in water, heated at 70 ° C overnight and evaporated to dryness . The resulting residue is purified by preparative HPLC (Gilson preparative reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID, 5 μM column, 2 mL injection, Solvent A: 0.02% NH OH / water, Solvent B: 0.02 % NH4OH / acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 20 10% A. 16 min: 95% A; Flow rate 22.5 mL / min; Detection: 254 nm DAD) to give the title product as an amorphous solid (7 mg), [M + H] 286, retention time 1.73 min using the LCMS Conditions: HPLC system HP 1100; Waters Xterra MS C18, 2 mm (i.d) x 50 mm (length), column 3.5 μm adjusted to 50 ° C; Flow rate 1.0 mL / min; Solvent A: 0.02% NH 4 OH in water; Solvent B 0.02% NH 4 OH in ACN; Gradient: Time 0: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ~ 2.0mM; Injection volume: 5 μL; Detection: 220 nm. 254 nm DAD).

EXAMPLES 90-107 Preparation of the compounds of 2-Amino-5-aryl-5-cyclohexyl-3-methyl-3,5-dihydro-4H-imidazol-4-one Using essentially the same procedure described in Example 89 and employing the appropriate phenylmagnesium bromide, the compounds shown in Table IV are obtained and identified by HRMN and mass spectral analysis. The LCMS conditions are the same as those used in Example 89. RT designates the retention time.

TABLE IV Ex. RT No. R4 R5 [M + H] [min] 90 3-benzyl H 362 2.88 91 3-methyl H 286 1.83 92 4-methyl H 286 1.75 93 4-fluoro H 290 1.71 94 3-methoxy H 302 1.74 TABLE IV. continuation Ex. RT No. R4 R5 [M + H] [min] 95 3-chloro 4-chloro 341 1.86 96 4-phenoxy H 364 1.93 97 3-chloro H 306 2.55 98 3-chloro 5-chloro 341 1.85 99 2-phenyl H 348 1.9 100 4-phenyl H 348 1.99 101 2-methyl 5-methyl 300 1.81 102 4-trifluoromethyl H 340 1.86 103 2-methoxy H 302 1.78 104 4-methoxy H 302 1.74 105 4-chloro H 306 1.86 106 2-CH = CH-CH = = CH-3 322 1.82 107 3-CH = CH-CH = = CH-4 322 1.85 EXAMPLE 108 Preparation of 2-Amino-5-cyclohexyl-5- (3-cyclopentylphenyl) 3-methyl-3,5-dihydro-4H-imidazol-4-one A solution of copper bromide (I) (2.47 g) and anhydrous lithium bromide (2.99 g) in THF at -78 ° C is treated with cyclohexylmagnesium chloride (8.59 mL, 2.0 M solution in diethyl ether) followed by a solution of 3-bromophenylacetyl chloride (4.00 g) in THF, stirred for 10 minutes, allowed to come to room temperature, diluted with diethyl ether, washed sequentially with 1 M hydrochloric acid and 1 M sodium hydroxide, dried over magnesium sulfate anhydrous and evaporated. The resulting residue is taken up in hexane: ethyl acetate 4: 1 and filtered through a pad of silica gel to give 2 as a colorless oil (4.61 g); H NMR: 7.40-7.05 (m, 4H), 3.70 (s, 2H), 2.40 (m, 1 H), 1.90-1.60 (m, 5H), 1.40-1.05 (m, 5H): 13C NMR: 210.2, 136.5, 132.4, 129.9, 129.8, 128.1, 122.4, 50.4, 46.9, 28.4, 25.7.25.5.

A solution of 2 (280 mg) in DMF (1.0 mL) is treated with diisopropylethylamine (1.0 mL) followed by palladium (II) acetate (23 mg), tri (o-tolyl) phosphine (61 mg) and cyclopentene (0.5 mL). The reaction mixture is heated in a microwave oven for 300 seconds at 150 ° C and evaporated to dryness. The residue is taken up in diethyl ether, washed with water, dried over magnesium sulfate and concentrated in vacuo to give a dark oil residue. The oil is purified by preparative reverse phase HPLC system to give compound 3.

A solution 3 in methanol is treated with palladium hydroxide (20 mg, 10% on carbon) and hydrogenated at atmospheric pressure for 6 h. The resulting reaction mixture is filtered and the filtrate is evaporated to dryness to give a brown residue. This residue is dissolved in dioxane, treated with selenium dioxide (IV) (100 mg), heated at 95 ° C overnight, cooled to room temperature, diluted with hexanes and filtered. The filtrate is concentrated in vacuo to give the diketone 4 as a brown oil (ca 70 mg).

The diketone 4 reacts with methyl guanidine in essentially the same manner described in Example 27, Step b, to give the title product, after purification by Gilson preparative reverse phase HPLC1 as a white amorphous solid (93 mg), characterized by analysis2 LCMS, 340 [M + H], retention time 2. 65 minutes. 1 Gilson preparative reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% NH4OH / water; Solvent B: 0.02% NH 4 OH / acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mUrnin; Detection: 254 nm DAD) system and solvent removal provided. 2 LCMS Conditions: HP 1100 HPLC System; Waters Xterra MS C18, 2 mm (i.d) x 50 mm (length), column 3.5 um, set at 50 ° C; Flow rate 1.0 mL / min; Solvent A: 0.02% NH 4 OH in water; Solvent B 0.02% NH 4 OH in ACN; Gradient: Time 0: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: -2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD) EXAMPLE 109 Preparation of 2-Amino-5-cyclohexyl-5- (3-cyclohexyl-phenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Using essentially the same procedure described in Example 108 and employing cyclohexene in the Heck coupling reaction, the title product is obtained, LCMS * 2.65 min., [M + H] 340.

The conditions are the same as that used in Example 108.

EXAMPLE 110 Preparation of N-r3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl-3-methoxybenzamide Using essentially the same procedures described in Examples 34 and 35 and using 3-methoxybenzoyl chloride, the title product is obtained, and is identified using a Gilson preparative reverse phase HPLC system: YMC Pro C18, 20 mm x 50 mm ID, column 5 μM; 2 mL injection; Solvent A: 0.02% NH OH / water; Solvent B: 0.02% NH 4 OH / acetonitrile; Gradient: Time 0: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL / min; Detection: 254 nm DAD, retention time 2.6 min., 420 [M + H]. 15 EXAMPLES 111-135 Preparation of N-r3- (2-Amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazole-4-M) phenol-benzamide derivatives Using essentially the same procedure described in Example 110 and employing a suitable acid chloride, the compounds shown in Table V are obtained and identified by LC and mass spectral analysis. (The LCMS conditions are the same as those used in Example 110).

TABLE V Ex. RT [min] No. [M + H] 111 3-methoxyphenyl 421 2.6 112 2-methoxyethyl 373 2.29 113 methoxyphenylmethyl 435 2.63 114 3-methyl-2-furyl 395 2.63 115 (2-methoxyethoxy) methyl 403 2.36 116 (N, N-dimethylamino) methyl 117 3- (N, N-dimethylamino) phenyl 434 2.74 118 3- (N, N-dimethylamino) propyl 400 1.47 119 4- (1-methylpiperidyl) 412 1.47 120 methylcyclopropyl 369 2.44 121 (1-phenoxy-1-methyl) methyl 435 1.99 122 3- (trifluoromethyl) -phenyl 459 2.03 123 2-methoxybenzyl 435 2.61 124 2-N-methylpyrroyl 394 2.58 125 methoxymethyl 359 2.28 126 2-furanyl 381 2.43 127 benzyloxymethyl 435 2.68 128 2-methoxyphenyl 421 2.75 129 3,4-dimethoxyphenyl 451 2.56 130 2,5-dimethoxyphenyl 465 2.61 TABLE V. continued Ex. RT [min] No. R [M + H] 131 1-E-propenyl 355 2.42 132 propyl 357 2.44 133 3-methoxybenzyl 435 2.57 134 5- (1,3-benzo [1.3] dioxoyl) 435 2.57 135 2- (2- (chlorophenoxy) propane) 484 2.13 EXAMPLE 136 Preparation of (5S) -5- (1-Adamantyl) -2-amino-5- (4-difluoromethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one trifluoroacetic acid salt TAI and acid salt (5R) -5- (1-Adamantyl) -2-amino-5- (4-difluoromethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one Trifluoroacetic fBl A racemic mixture of 5- (1-adamantyl) -2-amino-5- (4-difluoromethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one was separated by HPLC on Quiracel AD-H , 25 x 2 cm using mobile phase (20% ethanol in hexane / TFA) in hexane / TFA and a flow rate of 21 mL / min to provide the isomer S titrated (A), mp 225-226 ° C; [a] 25 = + 10.4 (C = 1% in DMSO); 1 H NMR (400 MHz, DMSO-d 6) d 1.40 (t, 6H), 1.55 (q, 6H), 1.92 (s, 3H), 3.06 (s, 3H), 7.22 (d, 2H), 7.22 (t, 1 H), 7.58 (d, 2H); MS m / e (MH) "388; i the R isomer titrated (B), mp 225-226 ° C; [a] 25 = -12.8 (C = 1% in DMSO); 1H NMR (400 MHZ, DMSO- d6) d 1.40 (t, 6H), 1.55 (q, 6H), 1.92 (s, 3H), 3.06 (s, 3H), 7.22 (d, 2H), 7.22 (t, 1 H), 7.58 (d, 2H); MS m / e (MH) "388.

EXAMPLE 137 Bonding Affinity Evaluation of BACE-1 Test Compounds Fluorescent kinetic tests Final Test Conditions: 10 nM human BACE1 (or 10 nM Murine BACE1), 25 μm substrate (WABC-6, MW 1549.6, AnaSpec), Shock absorber: 50 mM in Na-Acetate, pH 4.5, 0.05% CHAPS, 25% PBS, room temperature. Na-Acetate is from Aldrich, Cat. # 24,124-5, CHAPS is from Research Organics, Cat. # 1304C 1 X, PBS is from Mediatech (Cellgro), Cat # 21-031-CV, peptide substrate AbzSEVNLDAEFRDpa is from AnaSpec , Peptide Name: WABC-6 Determination of storage substrate concentration (AbzSEVNLDAEFRDpa) -25 mM storage solution is made in DMSO using the weight of the peptide and MW, and diluted -25 μM (1: 1000) in 1X PBS. The concentration is determined by absorbance at 354 nm using an extinction coefficient e of 18172 M "1 cm'1, the concentration of storage substrate is corrected, and storage of substrate stored in small aliquots at -800 O [Substrate Storage ] = ABS 354nm * 106/18172 (in mM).

The e354 nm extinction coefficient is adapted from the TACE peptide substrate, which has the same payer-fluorophore pair.

Determination of the Storage Enzyme Concentration: the storage concentration of each enzyme is determined by absorbance 280 nm using e of 64150 M "1 cm" 1 for hBACEl and MuBACEl in 6 M Guanidine Hydrochloride (from Research Organics, Cat. # 5134G-2), pH -6. The extinction coefficient e280 nm for each enzyme is calculated based on a known amino acid composition and the published extinction coefficients for the Trp residues (5.69 M "1 cm" 1) and Tyr (1.28 M "1 cm" 1) ( Anal Biochem 182,319-326).

Stages of Dilution and Mixing: total reaction volume: 100 μL Solutions of 2X inhibitor are prepared in buffer A (66.7 mM Na-Acetate, pH 4.5, 0.0667% CHAPS), 4X enzyme dilution is prepared in buffer A (66.7 mM Na -Acetate, pH 4.5, 0.0667% CHAPS), Prepare substrate dilution of 100 μM in .1X PBS, and Inhibitor 2X 50 μL Inhibitor, substrate 25 μL 100 μM is added to each well of 96 well plate (from DYNEX Technologies, VWR #: 11311-046), immediately followed by 25 μL of 4X enzyme (added to the inhibitor and the substrate mixture), and the fluorescence readings are started.

Fluorescence readings: Readings at 320 nm and? Em at 420 nm are taken each 40 sec for 30 min at room temperature and the linear slope for the proportion of cleavage from the substrate (v) is determined.

Calculation of% Inhibition:% Inhibition = 100 * (1- v / v0) v: ratio of substrate cleavage in the presence of inhibitor v0: proportion of substrate cleavage in the absence of the inhibitor Determination of ICgn:% of Inhibition = ((B * IC50n) + (100 * l0n)) / (IC50n + l0n) (Model # 39 of the LSW Toolbar in Excel where B is the% inhibition of enzyme control, which should be close to 0)% Inhibition is plotted against the inhibitor concentration (l0) and the data is adjusted to the previous equation to obtain the IC50 value and the Hill number (n) for each compound. It is preferred to test at least 10 different concentrations of inhibitor. The data obtained are shown in Table VI below. < CD m o o CN CN ro Table VI, continued BACE 1 Ex. No. IC50 μM 64 A 67 A 72 A 90 B 92 B 108 A 107 A 114 A 124 A 125 A 126 A 135 A 136A C 136B C

Claims (16)

1. A compound of formula wherein A is cycloalkyl; W is CO, CS or CH2, Ri, R2. and R3 are each independently H, or an alkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted group or R1 and R2 can be taken together with the atom to which they are attached to form a 5-7 membered ring optionally interrupted by an additional heteroatom selected from O, N or S. R5, and R6 are each independently H, halogen, NO2, CN, OR, COR7, CO2R7, CONR8R9, NR8R9, NR8COR7, NR8SO2R10, SO2NR8R9 or SOnR10 or an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, each optionally substituted group or when attached to the adjacent carbon atoms R4 and R5 or R5 and R6 can be taken together with the atoms to which they are attached to form an optionally substituted 5 to 7 membered ring optionally interrupted by one, two or three heteroatoms selected from O, N or S; n is O, 1, or 2; R7 is independently at each occurrence H, or an alkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group, each group optionally substituted; R8 and R9 are each independently in each occurrence H, OR7, COR7, CO2R7, or an alkyl, alkenyl alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl group, each optionally substituted group or R8 and R9 can 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; Y R10 is independently in each occurrence an alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group, each group optionally substituted; or a tautomer of these, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein W is CO.
3. The compound according to claim 1 or claim 2 wherein A is adamantyl.
4. The compound according to any one of claims 1 to 3 wherein R ^ and R2 are H.
5. The compound according to any one of claims 1 to 4 wherein R 3 is C 1 -C 4 alkyl.
6. The compound according to any one of claims 1 to 5 wherein R5 is OR7.
7. 7. The compound according to any one of claims 1 to 6 wherein A is adamantyl and Ri and R2 are H.
8. 8. The compound according to claim 2 wherein R 3 is C 1 C alkyl, and R 5 is OR 7.
9. 9. The compound according to claims 6 or 8 wherein R7 is CHF2.
10. 10. The compound according to claim 1 selected from the group consisting essentially of: (5S) -5- (1-adamantyl) -2-amino-5- [4- (difluoromethoxy) phenyl] -3-methyl-3,5-dihydro-4H-midazol-4-one; 2-amino-5-bicyclo [2.2.1] hept-1-yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-ethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-butoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (3-ethyl-4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxy-3,5-dimethylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-3-methyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; (5S) -5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; (5R) -5- (1-adamantyl) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (3,4-dimethoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4-methoxy-2,3-dimethylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-bicyclo [2.2.1] hept-2-yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-hexahydro-2,5-methanopentalene-3a (1H) -yl-5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-3-methyl-5- (4'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (4'-methoxy-1,1'-biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-3-methyl-5- (3'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (3'-methoxy-1,1 '-biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-5- (3 ', 4'-dimethyl-1,1'-biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazole-4 -one; 3 '- [4- (1-adamantyl) -2-amino-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] -1, 1'-biphenyl-3-carbonitrile; 5- (1-adamantyl) -2-amino-5- [3- (3-furyl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one; 3 '- [4- (1-adamantyl) -2-amino-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] -1, 1'-biphenyl-4-carbonitrile; 3 '- [4- (1-adamantyl) -2-amino-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] -1, 1' -biphenyl-4-carbonitrile; 5- (1-adamantyl) -2-amino-5- (3 ', 4'-difluoro-1,1' -biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazole-4 -one; 5- (1-adamantyl) -2-amino-5- (1, 1'-biphenyl-3-yl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- (1-adamantyl) -2-amino-3-methyl-5- (2'-methyl-1,1'-biphenyl-3-yl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (3,5-difluorobenzyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 5-cyclohexyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cyclohexyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cyclohexyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 2-amino-5-cyclohexyl-3- (2,2-diethoxyethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (2-phenylethyl) -3,5-dihydro-4H-imidazol-4-one; 5-cyclohexyl-2-imino-3-methyl-5-phenylimidazolidin-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (tetrahydrofuran-2-ylmethyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (2-fluoroethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- [2- (difluoromethoxy) benzyl] -5-phenyl-3,5-dihydro-4H-imidazol-4-one; N - [(2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) acetyl] -L-aspartic acid; N - [(2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) acetyl] -D-aspartic acid; Trans-4 - [(2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) methyl] cyclohexanecarboxylic acid; 6- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) hexanoic acid; 5- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) pentanoic acid; 4- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H -imidazol-1-yl) butanoic acid; 2-amino-5-cyclohexyl-3- (5-hydroxypentyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 3- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) propanoic acid; 3- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) -2-methylpropanoic acid; 2-amino-3-benzyl-5-cyclohexyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3-isobutyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3-hexyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-3,5-dicyclohexyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (4-hydroxybutyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; Acid (2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) acetic acid; 2-amino-5-cyclohexyl-3- (cyclohexylmethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (2-furylmethyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (4-hydroxyphenyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (3-hydroxyphenyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (thien-2-ylmethyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- (4-methoxyphenyl) -5-phenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5-phenyl-3- (2-thien-2-ylethyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-3- [2- (4-hydroxyphenyl) ethyl] -5-phenyl-3,5-dihydro-4H-imidazol-4-one; [4- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) phenyl] acetic acid; 4 - [(2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) methyl] benzoic acid; 5- (2-Amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) -2-hydroxybenzoic acid; Ethyl 3- (2-amino-4-cyclohexyl-5-oxo-4-phenyl-4,5-dihydro-1 H-imidazol-1-yl) benzoate; 5-cyclobutyl-2-imino-3-methyl-5-phenylimidazolidin-4-one; 5- (2-adamantyl) -2-imino-3-methyl-5-phenylimidazolidin-4-one; 5-cyclopentyl-2-imino-3-methyl-5-phenylimidazolidin-4-one; 5-cyclobutyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cycloheptyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5- (2-adamantyl) -3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cyclopentyl-3-ethyl-2-imino-5-phenylimidazolidin-4-one; 5-cyclobutyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cycloheptyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5- (2-adamantyl) -2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cyclopentyl-2-imino-5-phenyl-3-propylimidazolidin-4-one; 5-cyclobutyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5-cycloheptyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5- (2-adamantyl) -3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5-cyclopentyl-3- (3-hydroxypropyl) -2-imino-5-phenylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (2-methylphenyl) imidazolidin-4-one; 5- (3-benzylphenyl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (3-methylphenyl) imidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (4-methylphenyl) imidazolidin-4-one; 5-cyclohexyl-5- (4-fluorophenyl) -2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-5- (3-methoxyphenyl) -3-methylimidazolidin-4-one; 5-cyclohexyl-5- (3,4-dichlorophenyl) -2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- (4-phenoxyphenyl) imidazolidin-4-one; 5- (3-chlorophenyl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-5- (3,5-dichlorophenyl) -2-imino-3-methylimidazolidin-4-one; 5- (1, 1 '-biphenyl-2-yl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5- (1, 1 '-biphenyl-4-yl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-5- (2,5-dimethylphenyl) -2-imino-3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-3-methyl-5- [4- (trifluoromethyl) phenyl] imidazolidin-4-one; 5-cyclohexyl-2-imino-5- (2-methoxyphenyl) -3-methylimidazolidin-4-one; 5-cyclohexyl-2-imino-5- (4-methoxyphenyl) -3-methylimidazolidin-4-one; 5- (4-chlorophenyl) -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; 2-amino-5-cyclohexyl-5- (3-cyclopentyl-phenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-cyclohexyl-5- (3-cyclohexylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one; 5- [3- (benzyloxy) phenyl] -5-cyclohexyl-2-imino-3-methylimidazolidin-4-one; N-. { 3- [2-amino-4- (4-methoxy-3-methylphenyl) -1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl] phenyl} -2- (4-chlorophenoxy) -2-methylpropanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3-methoxybenzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3-methoxypropanamide; (2R) -N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2-methoxy-2- phenylacetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3-methyl-2-furamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (2-methoxyethoxy) acetamide; N-1 - [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] - N-2-, N ~ 2-dimethylglycinamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3- (dimethylamino) benzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -4- (dimethylamino) butanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -1-methylpiperidine-4-carboxamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2-cyclopropylacetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- phenoxypropanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3- (trifluoromethyl) benzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2- (2-methoxyphenyl) acetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -1-methyl-1 H-pyrrole-2 -carboxamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2-methoxyacetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2-furamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (benzyloxy) acetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2-methoxybenzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -3,4-dimethoxybenzamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (2,5-dimethoxyphenyl) acetamide; (2E) -N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] but-2-enamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] butanamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1 H-imidazol-4-yl) phenyl] -2- (3-methoxyphenyl) acetamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -1,3-benzodioxole-5-carboxamide; N- [3- (2-amino-4-cyclohexyl-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl) phenyl] -2- (4-chlorophenoxy) -2-methylpropanamide; or a tautomer of these; or a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.
11. 11. A method for the treatment of a disease or disorder associated with excessive BACE activity in a patient in need thereof comprising supplying said patient with a therapeutically effective amount of a compound according to any one of claims 1 to 10.
12. 12. The method according to claim 10 wherein said disease or disorder is selected from the group consisting essentially of: Alzheimer's disease; cognitive damage; Down's Syndrome; HCHW A-D; cognitive decline; senile dementia; cerebral amyloid angiopathy; and neurodegenerative disorder.
13. 13. The method according to claims 11 or 12 wherein said disease or disorder is characterized by the production of ß-amyloid deposits or neurofibrillary tangles.
14. 14. The method according to claim 11 wherein said disease or disorder is Alzheimer's disease.
15. 15. A method for modulating BACE activity comprising contacting a receptor thereof with an effective amount of a compound according to any one of claims 1 to 10.
16. 16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 10.