KR20070032015A - Amino-5,5-diphenylimidazolone derivatives for the inhibition of beta-secretase - Google Patents

Abstract

The present invention provides the use of a compound of formula I, for the treatment, prevention or amelioration of a disease or condition characterized by increased β-amyloid accumulation or increased β-amyloid levels in the patient's body.

Description

Amino-5,5-diphenylimidazolone derivatives for inhibiting beta-secretase {AMINO-5,5-DIPHENYLIMIDAZOLONE DERIVATIVES FOR THE INHIBITION OF BETA-SECRETASE}

Alzheimer's disease (AD), a progressive degenerative disease of the brain, mainly associated with aging, is a serious health problem. Clinically, AD is characterized by memory, cognition, reasoning, judgment, and disorientation. In addition, as the disease progresses, motor, sensory, and speech skills are impaired until a number of cognitive functions are impaired overall. The loss of cognition occurs slowly, but serious damage usually occurs within four to twelve years, ultimately leading to death. AD patients show characteristic β-amyloid accumulation in the brain and cerebral vessels (β-amyloid angiopathy) as well as neurofibrillary tangles. Amyloid plaques and vascular amyloid angiopathy also have 21 trisomy (down syndrome), hereditary cerebral hemorrhage with Amyloidosis of the Dutch-type (HCHWA-D), and other neurodegenerative diseases. Characteristic of the patient's brain. Neurofibrillary tangles also occur in other dementia-induced diseases.

The group of proteins known as β-amyloid is thought to be responsible for the onset of Alzheimer's disease and subsequent cognitive decline. Proteolytic processing of amyloid proprotein (APP) produces amyloid β (A-beta) peptides; Specifically, A-beta is produced by cleaving the N-terminus of APP by β-secretase and cleaving the C-terminus of APP by one or more γ-secretases. Aspartyl protease, or β-secretase enzyme (BACE) activity is directly linked to A-beta peptide production from APP (Sinha, et al, Nature , 1999, 402 , 537-540). Increasing research suggests that inhibition of β-secretase enzymes inhibits the production of A-beta peptides. Inhibition of β-secretase and the resulting decrease in A-beta peptides resulted in the reduction of β-amyloid deposits in the brain, the reduction of β-amyloid levels in the cerebral vessels, and the effective treatment of diseases or conditions caused by β-amyloid Can lead to.

Therefore, it is an object of the present invention to provide compounds which are inhibitors of β-secretase and which are useful as therapeutic agents in the treatment, prevention or amelioration of diseases or disorders characterized by increased β-amyloid accumulation or β-amyloid levels in the patient's body. It is.

Another object of the present invention is to provide therapeutic methods and pharmaceutical compositions useful for the treatment, prevention or amelioration of diseases or disorders characterized by increased β-amyloid accumulation or β-amyloid levels in the patient's body.

One feature of the present invention is that the compounds of the present invention may also be useful for studying and identifying β-secretase enzymes in the future.

These and other objects and features of the present invention will become more apparent from the following detailed description.

Summary of the Invention

The present invention provides a compound of formula (I), or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Where

W is CO, CS or CH ₂ ;

X is N, NO or CR ₁₀ ;

Y is N, NO or CR ₁₁ ;

Z may be N, NO or CR ₁₉ , provided that two or less of X, Y or Z may be N or NO;

R ₁ and R ₂ are each independently H, COR ₂₀ , CO ₂ R ₂₁ or an optionally substituted C ₁ -C ₄ alkyl group;

R ₃ is H, OR ₁₂ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl Or an aryl (C ₁ -C ₆ ) alkyl group;

R ₄ and R ₅ are each independently H, halogen, NO ₂ , CN, OR ₁₃ , NR ₁₄ R ₁₅ or optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C _{When a 6} alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl group, or bonded to an adjacent carbon atom, R ₄ and R ₅ together with the atoms to which they are attached are selected from O, N or S May form an optionally substituted 5-7 membered ring optionally containing one or two heteroatoms;

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₉ are each independently H, halogen, NO ₂ , CN, OR ₁₆ , NR ₁₇ R ₁₈ or each optionally substituted C ₁ -C ₆ An alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl group;

n is 0 or 1;

는 n이 0일 때에는 단일 결합이고, 또는 n이 1일 때에는 이중 결합이고;

Is a single bond when n is 0, or is a double bond when n is 1;

R ₁₂ , R ₁₃ , R ₁₆ , R ₂₀ and R ₂₁ are each independently H or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C _2- A C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl group;

R ₁₄ , R ₁₅ , R ₁₇ and R ₁₈ are each independently H or C ₁ -C ₄ alkyl.

The present invention also provides therapeutic methods and pharmaceutical compositions useful for the treatment, prevention or amelioration of a disease or condition characterized by increased β-amyloid accumulation or increased β-amyloid levels in the patient's body.

Alzheimer's disease (AD) is a major degenerative disorder of the brain that is clinically manifested by gradual loss of memory, cognition, reasoning, judgment, and emotional stability, which slowly leads to severe intelligence decline and death. The exact cause of AD is unknown, but there is increasing evidence indicating that amyloid beta peptides (A-beta) play a key role in the development of AD (DB Schenk; RE Rydel et al, Journal of Medicinal Chemistry, 1995, 21). , 4141 and DJ Selkoe, Physiology Review, 2001, 81, 741. AD patients exhibit characteristic neuropathological markers such as neuronal fiber entanglements detected in the brain at necropsy as well as neuritic plaques (accumulation in β-amyloid angiopathy, cerebral vessels). A-beta is a major component of neuroinflammatory plaques in the AD brain. In addition, β-amyloid accumulation and vascular β-amyloid angiopathy are characteristic of individuals with Down syndrome, hereditary cerebral hemorrhage associated with Dutch type amyloidosis, and other neurodegenerative and dementia-induced diseases. Overexpression of amyloid proprotein (APP) from the patient's brain, changes in degradation of APP to A-beta or reduction of A-beta clearance can increase levels of soluble, or fibrous, A-beta in the brain. Β-site APP degrading enzyme, BACE1, also called memapsin-2 or Asp-2, was identified in 1999 (R. Vassar, B. D. Bennett, et al, Nature, 1999, 402, 537). BACE1 is a membrane bound aspartic protease that has all the known functional properties and characteristics of β-secretase. Like BACE1, a second homologous aspartyl protease called BACE2 was found to have β-secretase activity in vitro. Low molecular weight, non-peptidic, non-substrate-related inhibitors of BACE1 or β-secretase are highly desired as an adjunct and also a potential therapeutic in the study of β-secretase enzymes.

Surprisingly, the inventors have found that amino-5,5-diphenylimidazolone, amino-5,5-imidazothione and amino-5,5-imidazole compounds of the formula (I) are shown to inhibit B-secretase and It was found that it indicates selective inhibition. Advantageously, the compounds can be used as therapeutic agents effective in the treatment, prevention or amelioration of diseases or disorders characterized by increased β-amyloid accumulation or β-amyloid levels in the patient's body. Accordingly, the present invention provides a compound of formula (I), or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Where

W is CO, CS or CH ₂ ;

X is N, NO or CR ₁₀ ;

Y is N, NO or CR ₁₁ ;

Z may be N, NO or CR ₁₉ , provided that two or less of X, Y or Z may be N or NO;

R ₁ and R ₂ are each independently H, COR ₂₀ , CO ₂ R ₂₁ or an optionally substituted C ₁ -C ₄ alkyl group;

R ₃ is H, OR ₁₂ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl Or an aryl (C ₁ -C ₆ ) alkyl group;

R ₄ and R ₅ are each independently H, halogen, NO ₂ , CN, OR ₁₃ , NR ₁₄ R ₁₅ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ When they are alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl groups, or are bonded to adjacent carbon atoms, R ₄ and R ₅ together with the atoms to which they are attached are selected from O, N or S; Or an optionally substituted 5-7 membered ring optionally containing two heteroatoms;

R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₉ are each independently H, halogen, NO ₂ , CN, OR ₁₆ , NR ₁₇ R ₁₈ or each optionally substituted C ₁ -C ₆ An alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl group;

n is 0 or 1;

는 n이 0일 때에는 단일 결합이고, 또는 n이 1일 때에는 이중 결합이고;

Is a single bond when n is 0, or is a double bond when n is 1;

R ₁₂ , R ₁₃ , R ₁₆ , R ₂₀ and R ₂₁ are each independently H or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C _2- A C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl group;

R ₁₄ , R ₁₅ , R ₁₇ and R ₁₈ are each independently H or C ₁ -C ₄ alkyl.

X is N, NO or CR ₁₀ ; Preferably N or CR ₁₀ . Y is N, NO or CR ₁₁ ; Preferably CR ₁₁ . Z is N, NO or CR ₁₉ ; Preferably CR ₁₉ . The symbol n is 0 or 1, preferably 1. R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₉ are each independently H, halogen, NO ₂ , CN, OR ₁₆ , NR ₁₇ R ₁₈ or each optionally substituted C ₁ -C ₆ An alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl group; Preferably H, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy. The ring comprising X, Y and Z substitutes a phenyl group, preferably at position 3. Ring members of the ring comprising X, Y and Z linked to a phenyl group are preferably carbon atoms linked to Y and Z.

R ₁ and R ₂ are each independently H, COR ₂₀ , CO ₂ R ₂₁ or an optionally substituted C ₁ -C ₄ alkyl group; Preferably H or an optionally substituted C ₁ -C ₄ alkyl group; More preferably is a H, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl group; Advantageously H.

W is preferably CO.

R ₄ and R ₅ are each independently H, halogen, NO ₂ , CN, OR ₁₃ , NR ₁₄ R ₁₅ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ When they are alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl groups, or are bonded to adjacent carbon atoms, R ₄ and R ₅ together with the atoms to which they are attached are selected from O, N or S; Or optionally substituted 5-7 membered rings, optionally comprising two heteroatoms. Preferably R ₄ and R ₅ are each independently H, halogen, CN, OR ₁₃ , or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₈ cycloalkyl group Or when bonded to an adjacent carbon atom, R ₄ and R ₅ together with said adjacent carbon atom form an optionally substituted 5-7 membered ring optionally containing one or two heteroatoms selected from O, N or S; Which may be formed, the ring preferably comprising two oxygen atoms as hetero atoms. More preferably R ₄ and R ₅ are each independently H, halogen, CN, OR ₁₃ , or C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₈ cycloalkyl group, or , When bonded to an adjacent carbon atom, R ₄ and R ₅ together with the adjacent carbon atom may form a 5 to 7 membered ring optionally containing one or two heteroatoms selected from O, N or S, wherein The ring may be optionally substituted by 1, 2 or 3 halogen atoms. Advantageously at least one of R ₄ and R ₅ is OR ₁₃ , or R ₄ and R ₅ together represent a divalent radical which is a methylenedioxy or ethylenedioxy radical optionally substituted by one or more halogen atoms. R ₁₃ is H or an optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl group ego; Preferably halogen atom, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carbon From carboxyl, alkoxycarbonyl, alkanoyl, alkanoyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl and cycloalkyl groups C ₁ -C ₆ alkyl group substituted by 0, 1, 2 or 3 substituents independently selected.

As used herein and in the claims, the term halogen refers to F, Cl, Br or I, and the term cycloheteroalkyl includes one or two heteroatoms, which may be the same or different, selected from N, O or S. And optionally a 5-7 membered cycloalkyl ring system containing one double bond. Typical examples of the cycloheteroalkyl ring system included in the term as specified herein are the following rings.

Wherein X ₁ is NR, O or S; R is H or any substituent as described below.

Similarly, as used herein and in the claims, the term heteroaryl refers to a 5-10 membered aromatic ring system comprising 1, 2 or 3 heteroatoms which may be the same or different, selected from N, O or S. Point. The heteroaryl ring system may be pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl And the like. The term aryl refers to carbocyclic aromatic ring systems such as phenyl, naphthyl, anthracenyl and the like. The term aryl (C ₁ -C ₄ ) alkyl refers to an aryl group, as defined above, attached to a C ₁ -C ₄ alkyl group which may be straight or branched. The aryl (C ₁ -C ₄ ) alkyl group includes benzyl, phenethyl, naphthylmethyl and the like. As used herein, the term haloalkyl refers to a C _n H _{2n + 1} group having 1 to 2n + 1 halogen atoms, which may be the same or different, and the term haloalkoxy as used herein is 1 to 2n, which may be the same or different. It refers to an OC _n H _{2n + 1} group having +1 halogen atom. Preferably the term haloalkyl refers to CF ₃ and the term haloalkoxy refers to OCF ₃ .

In the description and claims of the present invention, the terms C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ C ₇ cycloalkyl, cycloheteroalkyl, aryl, aryl When it is specified that (C ₁ -C ₄ ) alkyl or heteroaryl is optionally substituted, optionally present substituents affect the development of a pharmaceutical compound or the structure / activity, persistence, absorbency, stability or other beneficial properties of the compound. It may be one or more substituents conventionally used to modify such compounds. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycar Carbonyl, carboxyl, alkanoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms Or lower alkyl or lower alkoxy groups. Typically, 0-3 substituents may be present. When any of the substituents described above represent or include alkyl substituents, they may be straight or branched, and may contain up to 12 carbon atoms, preferably up to 6, more preferably up to 4 carbon atoms.

Pharmaceutically acceptable salts include compounds of formula (I) with phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluene sulfonic acid And any acid addition salt formed by a pharmaceutically acceptable acid such as methane sulfonic acid.

Compounds of the present invention are generally functional derivatives of the compounds of the present invention and include amide, ester, carbamate or other conventional prodrug forms that can be readily converted to the active ingredients of the present invention in vivo. Thus, the methods of the present invention include methods of treating various conditions as described above using a compound of Formula I or a compound that is not specifically described, but which is converted to a compound of Formula I in vivo upon administration. Also included are metabolites of the compounds of the invention which are defined as active species produced upon introduction of the compounds into the biological system.

Compounds of the invention may exist as one or more tautomers. Those skilled in the art will also appreciate that compounds of formula I may exist as tautomers of formula It, as shown below.

Tautomers often exist in equilibrium with one another. Since the tautomers interconvert under environmental and physical conditions, they provide the same, useful biological effect. The present invention includes tautomers of each of Formula I and Formula It as well as mixtures of such tautomers.

Compounds of the present invention may comprise one or more asymmetric carbon atoms or one or more asymmetric (chiral) centers, and thus may generate optical isomers and diastereomers. Accordingly, the present invention provides the above optical isomers and diastereomers; As well as racemic compounds and resolved, enantiomerically pure stereoisomers; As well as other mixtures of R and S stereoisomers. Those skilled in the art will appreciate that when one stereoisomer is concentrated compared to other stereoisomers or when separated from other stereoisomers, the activity may increase or have a beneficial effect. In addition, those skilled in the art know how to isolate, concentrate, or selectively prepare such stereoisomers. Thus, the present invention includes compounds of formula I, stereoisomers thereof, tautomers thereof and pharmaceutically acceptable salts thereof. The compounds of the present invention may exist as mixtures of stereoisomers, as stereoisomers of each, or as optically active or enantiomerically pure forms.

Preferred compounds of the invention are compounds of formula I, wherein W is CO. Another group of preferred compounds of the invention are compounds of formula I, wherein R ₁ and R ₂ are H and R ₃ is C ₁ -C ₄ alkyl. Also preferred are compounds of formula I, wherein n is 1. Another group of preferred compounds of the invention are compounds of formula I, wherein a 5- or 6-membered heteroaryl ring comprising nitrogen is linked to the phenyl ring at position 3 of the phenyl ring; Preferred groups of the compounds of formula (I) are shown in the present specification and claims as formula (Ia). Compounds of formula (Ia) are shown below.

More preferred compounds of the invention are compounds of formula (Ia) wherein the heteroaryl ring comprising nitrogen is a 6 membered ring and is linked to the phenyl ring at position 3 of the heteroaryl ring; A more preferred group of compounds of formula (I) are shown in the present specification and claims as formula (Ib). Formula Ib is shown below.

Another group of more preferred compounds of the invention is a compound of Formula Ib, wherein R ₃ is methyl. Another group of more preferred compounds of the invention is that Y is CR ₁₁ ; R ₁ and R ₂ are H; And R ₃ is methyl.

Examples of preferred compounds of formula (I)

2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-already Dazol-4-one;

(5S) -2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro -4H-imidazol-4-one;

2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazol-4-one ;

(5S) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole -4-one;

(5R) -2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-5- [4- (trifluoromethoxy) phenyl] -3,5-di Hydro-4H-imidazol-4-one;

4- [2-amino-4- (4-methoxy-3-methylphenyl) -1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl] -2-pyridine-3 -Ylbenzonitrile;

2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (4-methyl-3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole- 4-on;

2-amino-5- [4-methoxy-3- (trifluoromethyl) phenyl] -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-already Dazol-4-one;

2-amino-3-ethyl-5- (4-methoxy-3-methylphenyl) -5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrazin-2-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-3-methyl-5- (3-pyrimidin-2-ylphenyl) -5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro-4H-imidazole-4- On;

2-amino-5- (4-hydroxy-3-methylphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-5- [4-methoxy-3- (trifluoromethyl) phenyl] -3-methyl-5- (3-pyrazin-2-ylphenyl) -3,5-dihydro-4H-imide Dazol-4-one;

(5R) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole -4-one;

2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-5- (3,4-diethoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-5- (3,4-dimethoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-cyclopentyl-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On;

2-amino-5- (4-methoxy-3-propoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On;

2-amino-5- (3-butoxy-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On;

2-amino-5- (3-isopropoxy-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4 -On;

2-amino-5- (1,3-benzodioxol-5-yl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4 -On;

2-amino-5- (2,3-dihydro-1-benzofuran-5-yl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H- Imidazol-4-one;

2-amino-5- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole -4-one;

5- [2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4,5-dihydro-1H-imidazol-4-yl] -2-methoxybenzo Nitrile;

2-amino-5- (3-fluoro-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On;

2-amino-5- (2,3-dihydro-1,4-benzodioxin-6-yl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro -4H-imidazol-4-one;

2-amino-5- (3-chloro-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one ;

2-amino-3-methyl-5- (3-pyridin-3-ylphenyl) -5- (3,4,5-trimethoxyphenyl) -3,5-dihydro-4H-imidazole-4- On;

2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyridin-4-ylphenyl) -3,5-dihydro-4H-imidazol-4-one;

2-amino-5- (3-ethoxy-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On;

2-amino-3-methyl-5- (3-pyridin-3-ylphenyl) -5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro-4H-imidazol-4-one ;

2-amino-3-methyl-5- (3-pyridin-3-ylphenyl) -5-[(4-trifluoromethoxy-3-trifluoromethyl) phenyl] -3,5-dihydro-4H Imidazol-4-one;

2-amino-5- (3,4-diethoxyphenyl) -5- (4-fluoro-3-pyridin-3-ylphenyl) -3-methyl-3,5-dihydro-4H-imidazole- 4-on;

2-amino-5- (3-chloro-4-trifluoromethoxyphenyl) -5- (4-fluoro-3-pyridin-3-ylphenyl) -3-methyl-3,5-dihydro-4H Imidazol-4-one;

Tautomers thereof; Stereoisomers thereof; Or pharmaceutically acceptable salts thereof.

Advantageously, the present invention optionally provides compounds of formula II wherein halogen is Cl or Br in the presence of a palladium catalyst and an inorganic base and Q is B (OH) ₂ , Sn (Bu) ₃ or Sn (CH), optionally in the presence of a palladium catalyst and an inorganic base. ₃₎ it provides a process for the preparation of a compound of formula ⅰ which comprises reacting a compound of formula ₃ or ⅲ. The method is shown in flow chart I.

Wherein Hal and Q are as defined above.

Suitable palladium catalysts for use in the process of the invention include dichlorobis (tri-o-tolylphosphine) palladium (II), Pd (OCOCH ₃ ) ₂ / tri-o-tolylphosphine, tetrakis (triphenylphosph) Pd (0) or Pd (II) catalysts such as pin) palladium (0), tris (dibenzylideneacetone) dipalladium (0) triphenylphosphine and the like.

Suitable inorganic bases for use in the process of the invention include Na or K hydroxides, carbonates or bicarbonates, preferably Na ₂ CO ₃ or K ₂ CO ₃ .

Suitable solvents for use in the process of the invention may be of the same polarity as toluene, diethoxy ethyl ether, dioxane, ethylene glycol dimethyl ether or any non-reactive organic solvent capable of solubilizing the compound of formula II or III. Non-polar organic solvents.

Compounds of formula (II) can be prepared using conventional synthetic methods and optionally standard separation or isolation techniques. For example, Compound (IIa), wherein W is CO and R ₁ and R ₂ is H, reacts the substituted guanidine of Formula V with the diketone of Formula IV in the presence of a base such as Na ₂ CO ₃ It can be prepared by obtaining the desired compound of formula IIa. The reaction is shown in flow chart II where Hal is Cl or Br.

The compound of formula (IV) is reacted with the triphenylphosphonium salt of formula (VI) and benzoyl chloride of formula (VII) in the presence of a base such as Na ₂ CO ₃ to obtain the corresponding triphenylphosphine lide, which is substituted with MgSO ₄ It can be prepared by oxidation with KMnO ₄ in the presence to give the desired diketone of formula IV. The reaction is shown in flow chart III.

(Hal and Hal 'are each independently Cl or Br, and Ph represents a phenyl group.)

Alternatively, compound (Ic) of formula (I), wherein W is CO and R ₁ and R ₂ is H, reacts the diketone of formula (IV) with the compound of formula (III) in the presence of a palladium catalyst and an inorganic base. The diketone of formula (VII) can be reacted with a substituted guanidine of formula (V) (as shown in flow chart II above) to afford the desired compound of formula (Ic). Compounds of formula (I), wherein R ₁ is not H (Id), use standard alkylation techniques such as reacting a compound of formula (Ic) with an alkyl halide, R ₁ -Hal, wherein R ₁ is not H and R ₂ is H It can be prepared by obtaining compound (Id) of formula (I). The reaction is shown in flow chart IV where Q is B (OH) ₂ , Sn (Bu) ₃ or Sn (CH ₃ ) ₃ and Hal is Cl or Br.

The compound of formula (I), wherein W is CO and R ₁ and R ₂ are not H, reacts the compound of formula (Id) with the second alkyl halide, R ₂ -Hal to give the desired formula (I) wherein R ₁ and R ₂ are not H. It can manufacture by obtaining.

Advantageously, the compounds of the present invention have increased β-amyloid accumulation or β-amyloid levels in the patient's body, including Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage due to Dutch type amyloidosis and other neurodegenerative and dementia-induced diseases. Useful for the treatment, prevention or amelioration of a disease or condition characterized. Thus, the invention is a disease or condition characterized by increased β-amyloid accumulation or β-amyloid levels in the patient's body, comprising providing the patient with a therapeutically effective amount of a compound of Formula I as described herein. It provides a method of treating, preventing or improving. The compound may be provided by any conventional method known for oral or parenteral administration or effective administration of therapeutic agents to a patient in need thereof.

As used herein in connection with providing a compound or substance encompassed by the present invention, the term "providing" refers to either directly administering the compound or substance or to forming an equivalent amount of the compound or substance in the body. It refers to any of administering a drug, derivative, or analog.

As described herein, an amount useful for treating or preventing a compound of the present invention is an amount of a compound that alleviates the symptoms of a disease, such as, for example, AD, or prevents the development of symptoms or more severe symptoms. Useful amounts of the compounds may vary depending on the formulation and route of administration. For example, in oral administration, higher amounts may be administered to deliver a biologically equivalent amount of the agent than when the compound is formulated as an injection or inhalant. Suitably, the single dose (ie, per unit) of the compound of the invention ranges from about 1 μg / kg to about 10 g / kg. Preferably, the amount is provided on a daily basis. However, the dosage used in the treatment or prevention of certain cognitive deficits or other conditions can be determined subjectively by the attending physician. Relevant variables include the patient's specific cognitive deficits and physique, age, and response patterns. For example, based on the activity profile and efficacy of the compounds of the present invention, the initial daily dose is about 375-500 mg per day, gradually increasing to about 1000 mg per day, thereby achieving the desired dosage level in humans. Can provide.

In practical use, the compounds of the present invention are provided by administering the compounds or their precursors in solid or liquid form, either purely or with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described above.

Solid carriers suitable for use in the compositions of the present invention include one or more materials that may act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, lubricants, compression aids, binders, tablet disintegrating agents or encapsulating materials. In the case of powders, the carrier may be a finely divided solid in the form of a mixture of finely divided compounds of formula (I). In the case of tablets, the compound of formula (I) may be mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powder and tablets may contain up to 99% by weight of the compound of formula (I). Solid carriers suitable for use in the compositions of the present invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting point. Having waxes and ion exchange resins.

In the compositions of the present invention, any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs can be used. The compounds of formula (I) may be dissolved or suspended in pharmaceutically acceptable liquid carriers such as water, organic solvents, or pharmaceutically acceptable oils or fats, or mixtures thereof. The liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity regulators, stabilizers, osmotic agents and the like. Examples of liquid carriers suitable for oral and parenteral administration include water (especially water comprising the aforementioned additives, for example cellulose derivatives, preferably sodium carboxymethyl cellulose solutions), alcohols (monohydric and polyhydric alcohols, Alcohols including, for example, glycols) or derivatives thereof, or oils (eg, fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.

Compositions of the invention that are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered by intravenous injection. Compositions of the invention suitable for oral administration may be in either liquid or solid composition form.

Alternatively, the use of a sustained delivery device may be desirable to alleviate the need for the patient to take medication on a daily basis. "Sustained delivery" is defined as the release of the active agent, ie the compound of the invention, is delayed until it is placed in the delivery environment, after which the drug is released continuously. One skilled in the art knows suitable sustained delivery devices. Examples of suitable sustained delivery devices include, for example, hydrogels (see, eg, US Pat. Nos. 5,266,325; 4,959,217; and 5,292,515), Alza (US Pat. Nos. 4,295,987 and 5,273,752) or Osmotic pumps as described by Merck (European Patent No. 314,206); Hydrophobic membrane materials such as ethylene methacrylate (EMA) and ethylene vinyl acetate (EVA); Bioabsorbable polymer systems (see, eg, WO 98/44964, Bioxid and Cellomeda; see US Pat. Nos. 5,756,127 and 5,854,388); Other bioabsorbable implant devices are described as being composed of, for example, polyester, polyanhydride, or lactic acid / glycolic acid copolymers (see, eg, US Pat. No. 5,817,343 to Alkermes Inc.). In the use of such sustained delivery devices, the compounds of the present invention may be formulated as described herein.

In another aspect, the present invention provides a pharmaceutical kit for delivery of a product. Suitably, the kit comprises a packaging or container with the compound formulated for the desired delivery route. For example, if the kit is designed for inhalation administration, it may comprise a suspension comprising a compound of the invention formulated for delivery of a predetermined dose of aerosol or spray by inhalation. Suitably, the kit includes instructions on how to take it and an insert about the active agent. In some cases, the kit may further comprise instructions on how to monitor the circulating concentration of the medicament and the materials used to perform such an assay, including, for example, reagents, well plates, containers, markers or labels, and the like. have. The kit is readily packaged in an appropriate manner for the treatment of the desired indication. For example, the kit may also include instructions for using a spray pump or other delivery device.

Other suitable components of the kit will be readily apparent to those skilled in the art in view of the desired indications and route of delivery. The dosage may be repeated daily, weekly, or monthly for a predetermined period or as prescribed.

In order to more clearly understand, to illustrate the present invention more clearly, specific embodiments thereof are described below. The following examples are for illustrative purposes only and should be understood not to limit the spirit and basic principles of the invention in any way. Indeed, those skilled in the art will clearly appreciate that various modifications of the present invention are possible in light of the embodiments described below and the above detailed description, in addition to the contents shown and described herein. Moreover, such modifications also fall within the appended claims.

Unless stated otherwise, all fractions are parts by weight. The terms HNMR and HPLC refer to protonocyte magnetic resonance and high performance liquid chromatography, respectively. The terms EtOAc and THF refer to ethyl acetate and tetrahydrofuran, respectively. In the structural formula, the term Ph refers to a phenyl group.

Example 1

Preparation of Ethyl 4-amino-3-bromobenzoate

A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane was added dropwise to a cooled (-10 ° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture was allowed to reach room temperature, stirred for 18 hours and diluted with water. The organic phase was separated, washed twice with brine, dried over MgSO ₄ and concentrated in vacuo. The resulting residue was purified by flash chromatography (SiO ₂ , 8/1 hexanes / EtOAc as eluent) to give 28.6 g (88% yield, MS m / e 242 (M−H) ⁺ ) as a white solid. The title compound was obtained and confirmed by HNMR and mass spectral analysis .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.28 (t, J = 7.01 Hz, 3 H), 4.22 (q, J = 7.16 Hz, 2 H), 6.18 (brs, 2 H), 6.81 ( d, J = 7.91 Hz, 1H), 7.65 (dd, J = 8.54, 1.98 Hz, 1H), 7.89 (d, J = 1.83 Hz, 1H).

Example 2

Preparation of 3-bromo-4-cyanobenzoic acid

A solution of ethyl 4-amino-3-bromobenzoate (23.5 g, 96.3 mmol) in methylene chloride at −10 ° C. was added dropwise with tert-butyl nitrite (14.0 mL, 118.4 mmol), followed by boron trifluoride Treated dropwise with diethyl etherate (18.4 mL, 146.5 mmol). The reaction mixture was allowed to reach room temperature, stirred for 4 hours, diluted with ethyl ether and filtered. The filtercake was dried, dispersed in toluene, cooled to 0 ° C. and treated with a solution of copper (I) cyanide (11.5 g, 129.2 mmol) and sodium cyanide (15.8 g, 323.1 mmol) in water, 30 Stirred at 0 ° C. for min, warmed to 60 ° C., then stirred for 1 h, cooled to rt, diluted with EtOAc and water. The organic phase was separated, dried over MgSO ₄ and concentrated in vacuo. The resulting residue was crystallized from ethyl ether / hexanes to give ethyl ester of the title compound as 18.6 g (76% yield) of off-white solid. The solution of ester (8.5 g, 33.6 mmol) in THF was treated with a solution of NaOH (30 mL, 2.5 N) and ethanol, stirred for 20 h, acidified with 2 N HCl and extracted with ethyl ether. The ether extracts were combined, dried over MgSO ₄ and concentrated in vacuo. The resulting residue was crystallized from ethyl ether / hexanes to give the title compound as 6.81 g (90% yield, MS m / e 223 (MH) ⁺ ) as a beige solid, by HNMR and mass spectral analysis. Confirmed; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (dd, J = 9.76, 1.37 Hz, 1 H), 8.09 (d, J = 8.08 Hz, 1H), 8.29 (d, J = 1.37 Hz, 1H ).

Example 3

Preparation of 2-bromo-4-[(4-methoxy-3-methylphenyl) (oxo) acetyl] benzonitrile

Suspension of 3-bromo-4-cyanobenzoic acid (1.65 g, 7.28 mmol) in thionyl chloride (10 mL) was treated with 3 drops of N, N-dimethylformamide, heated at reflux for 1 hour and vacuum Concentrated in the state. The acid chloride residue was re-evaporated three times with toluene to remove any residual thionyl chloride. A mixture of 3-methyl-4-methoxybenzyl triphenylphosphonium chloride (6.3 g, 14.55 mmol) in toluene at 0 ° C. was treated dropwise with n-butyllithium (6.1 mL, 2.5 M in hexanes) and allowed to reach room temperature. It was stirred for 2 hours, cooled to 0 ° C. and then treated dropwise with the above obtained acid chloride solution in toluene, reached to room temperature, stirred for 2 hours, quenched with water and concentrated in vacuo. The resulting residue was dispersed in acetone and water, treated with MgSO ₄ (7.5 g, 62.5 mmol) and KMnO ₄ (2.18 g, 13.8 mmol), stirred vigorously at 45 ° C. for 18 hours, filtered It was. The filtrate was diluted with EtOAc, washed sequentially with water and brine, dried over MgSO ₄ and evaporated to dryness. The residue was purified by flash chromatography (SiO ₂ , 2/1 hexanes / EtOAc as eluent) to afford the title compound as 1.8 g (69% yield, MS m / e 357 (M + H) ⁺ ) as a yellow solid. And confirmed by HNMR and mass spectral analysis .; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.21 (s, 3H), 3.93 (s, 3H), 7.15 (d, J = 8.54 Hz, 1H), 7.81 (d, J = 1.38 Hz, 1H) , 7.85 (dd, J = 8.54, 2.14 Hz, 1H), 8.03 (dd, J = 8.08, 1.52 Hz, 1H), 8.18 (d, J = 8.08 Hz, 1H), 8.30 (d, J = 1.38 Hz , 1H).

Example 4

Preparation of 4-[(4-methoxy-3-methylphenyl) (oxo) acetyl] -2-pyridin-3-ylbenzonitrile

2-bromo-4-[(4-methoxy-3-methylphenyl) (oxo) acetyl] benzonitrile (200 mg, 0.56 mmol) and 3- (tributylstannyl) pyridine in 1,2-diethoxyethane (268 mg, 0.73 mmol) was treated with dichlorobis (tri-O-tolylphosphine) palladium (II) (39.6 mg, 0.05 mmol), heated at 145 ° C., stirred for 30 minutes, filtered The catalyst was removed. The filtrate was evaporated to dryness. The resulting residue was purified by flash chromatography (SiO ₂ , 2/1 hexanes / EtOAc as eluent) and crystallized from ethyl ether / hexanes to give 181 mg (91% yield, MS m / e 357) as a yellow solid. The title compound was obtained as (M + H) ⁺ ) and confirmed by HNMR and mass spectral analysis. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.21 (s, 3H), 3.93 (s, 3H), 7.18 (d, J = 8.69 Hz, 1H), 7.61 (m, 1H), 7.82 (d, J = 8.54, 1H), 7.84 (dd, J = 8.54, 1.99 Hz 1 H), 8.07 (dd, J = 7.76, 1.67 Hz, 1H), 8.12 (m, J = 1.38 Hz, 2H), 8.25 (d , J = 8.08 Hz, 1H), 8.74 (m, 1H), 8.85 (d, 1.68 Hz, 1H).

Example 5

4- [2-amino-4- (4-methoxy-3-methylphenyl) -1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl] -2-pyridine-3 Preparation of -Benzonitrile

4-[(4-methoxy-3-methylphenyl) (oxo) acetyl] -2-pyridin-3-ylbenzonitrile (160 mg, 0.45 mmol) and 1-methylguanidine hydrochloride in dioxane and ethyl alcohol (222 mg, 2.02 mmol) was treated with Na ₂ CO ₃ (214 mg, 2.02 mmol) in water, stirred at 85 ° C. for 3 hours, and concentrated in vacuo. The resulting residue was partitioned between chloroform and water. The phases were separated and the organic phase was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (SiO ₂ , 15/1 EtOAc / methanol as eluent) and crystallized from CHCl ₃ / hexanes to give the title compound as 138 mg (75% yield) of a white solid. It was confirmed by mass spectral analysis. MS m / e 412 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.09 (s, 3H), 2.98 (s, 3H), 3.74 (s, 3H), 6.74 (brs, 2H), 6.86 (d, J = 8.69 Hz, 1H), 7.22 (s, 1H), 7.26 (d, J = 8.54 Hz, 1H), 7.58 (m, 1H), 7.69 (s, 1H), 7.70 (s, 1H), 7.9-8.0 (m, 2H ), 8.7 (m, 2 H).

Examples 6-33

Preparation of amino-5,5-diphenylimidazolone derivatives

Using the same procedure as described in Examples 4 and 5 above and using the appropriate dione substrate, tributylstannyl-pyridine or tributylstannyl-pyrimidine intermediate and the desired guanidine reagent, Obtained and confirmed by HNMR and mass spectral analysis.

Example 34

2-amino-3-difluoromethyl-5- [4-fluoro-3- (pyrimidin-5-yl) phenyl] -5- [4- (trifluoromethoxy) phenyl] -3,5- Preparation of Dihydro-4H-imidazol-4-one

2-amino-5- [4-fluoro-3- (pyrimidin-5-yl) phenyl] -5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro- in dimethylformamide 4H-imidazol-4-one (0.398 g, 0.92 mmol) solution was treated with KOH (0.057 g, 1.01 mmol), cooled to -45 ° C, boiled with chlorodifluoromethane (1.40 g, 17.6 mmol) To rise. The reaction vessel was sealed and heated at 70 ° C. for 18 hours. The reaction was cooled to room temperature, carefully quenched by pouring water, extracted with ethyl acetate, diluted with brine and extracted again with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The resulting residue was subjected to flash chromatography (silica, 95: 5: 0.5 to 90: 10: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide and 100: 0 to 98: 2 methylene chloride / methanol as eluent). Purification twice with white solid afforded the title compound as a 0.064 g (14% yield, mp 82-94 ° C.) and confirmed by HNMR, infrared and mass spectral analysis. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.21 (s, 1H), 8.89 (s, 2H), 7.64-7.60 (m, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.23-7.18 ( m, 3H), 6.95 (t, J = 58 Hz, 1H), 4.92 (br s, 2H); IR (ATR) 3497, 3309, 3149, 1761, 1678, 1497, 1449, 1416, 1252, 1212, 1162 cm ⁻¹ ; ESI MS m / z 482 [C ₂₁ H ₁₃ F ₆ N ₅ O ₂ + H] ⁺ ;

Example 35

Preparation of 1- (4-methoxy-3-methylphenyl) -2- (3-pyridin-4-ylphenyl) ethane-1,2-dione

Tri-o-tolylphosph in sequential order with a solution of 1- (3-bromo-phenyl) -2- (4-methoxy-3-methylphenyl) ethane-1,2-dione (0.25 g, 0.75 mmol) in dioxane Treated with pin (57 mg, 0.187 mmol), palladium (II) acetate (21 mg, 0.093 mmol), pyridine-4-boronic acid (139 mg, 1.125 mmol) and H ₂ O and stirred at 100 ° C. for 4 h And cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (hexane / EtOAc 3/7 as eluent) to give a yellow solid, 0.145 g (58% yield, MS m / e (M + H) ⁺ 332). The title compound was obtained and confirmed by HNMR and mass spectral analysis. ¹ H NMR (400 MHZ, CDCl ₃ ) δ 2.28 (s, 3H) 3.95 (s, 3H) 6.94 (d, 1H) 7.68 (m, 3H) 7.84 (m, 2H) 7.88 (m, 1H) 8.08 (m , 1H) 8.30 (m, 1 H) 8.75 (m, 2 H).

Example 36

2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyridin-4-ylphenyl) -3,5-dihydro-4H-imidazol-4-one Produce

Using substantially the same procedure as described in Example 5 above, 1- (4-methoxy-3-methylphenyl) -2- (3-pyridin-4-ylphenyl) ethane-1,2-dione and 1 as reactants Using -methylguanidine hydrochloride, the title compound was obtained as a white solid, 0.15 g (90% yield, mp 175 ° C, MS m / e (M) ⁺ 387) and confirmed by HNMR and mass spectral analysis. .; ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.05 (s, 3H) 3.00 (s, 3H) 3.75 (s, 3H) 6.60 (bs, 2H) 6.82 (d, 1H) 7.20 (m, 1H) 7.25 (m, 1 H) 7.40 (m, 1 H) 7.50 (m, 3 H) 7.62 (m, 1 H) 7.8 (m, 1 H) 8.6 (m, 2 H).

Example 37

2-amino-3-methyl-5- (3-pyrimidin-2-ylphenyl) -5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro-4H-imidazole-4- Manufacture of

Using substantially the same procedure as described in Example 36 above, 1- (3-pyrimidin-2-ylphenyl) -2- [4- (trifluoromethoxy) phenyl] ethane-1,2- as reactant Using dione and methylguanidine hydrochloride, the title compound was obtained as a white solid and confirmed by HNMR and mass spectral analysis. MS m / e 428 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.01 (s, 1H), 6.79 (brs, 2H), 7.33-7.49 (m, 2H), 7.58-7.66 (m, 3H), 8.27 (m, 2H ), 7.59 (d, J = 7.77 Hz, 1H), 7.98 (d, J = 7.47 Hz, 1H), 8.26 (s, 1H), 8.61 (t, J = 1.67 Hz, 1H), 8.90 (d, J = 4.88 Hz, 2H).

Example 38

(5R) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole 4-one (A) and (5S) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5 Preparation of -dihydro-4H-imidazol-4-one (B)

Racemate 2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole- The 4-one was digested using chiral HPLC techniques on Chiralcel AD (2 × 25 cm) and using 50% IPA / DEA in 7200 / DEA as the mobile phase at a flow rate of 10 mL / min. The R-isomer, title compound A, was crystallized from chloroform / hexanes and then obtained as a white solid (98% ee), which was confirmed by HNMR and mass spectral analysis. MS m / e 388 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.07 (s, 3H), 2.97 (s, 3H), 3.72 (s, 3H), 6.63 (brs, 2H), 6.85 (d, J = 8.39 Hz, 1H), 7.21 (s, 1H), 7.25 (dd, J = 7.88, 1.01, 1H), 7.46 (t, J = 7.55 Hz, 1H), 7.52 (d, J = 7.89 Hz, 1H), 7.63 (dd , J = 7.54, 0.84 Hz, 1H), 7.75 (s, 1H), 8.99 (s, 2H), 9.18 (s, 1H).

[α] _D ²⁵ = +40.2 (c = 1% in CH ₃ OH)

The S-isomer, title compound B, was crystallized from chloroform / hexanes and then obtained as a white solid (95% ee) which was confirmed by HNMR and mass spectral analysis. MS m / e 388 (M + H) ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.07 (s, 3H), 2.97 (s, 3H), 3.72 (s, 3H), 6.63 (brs, 2H), 6.85 (d, J = 8.39 Hz, 1H), 7.21 (s, 1H), 7.25 (dd, J = 7.88, 1.01, 1H), 7.46 (t, J = 7.55 Hz, 1H), 7.52 (d, J = 7.89 Hz, 1H), 7.63 (dd , J = 7.54, 0.84 Hz, 1H), 7.75 (s, 1H), 8.99 (s, 2H), 9.18 (s, 1H).

[α] _D ²⁵ = -79.6 (c = 0.67% in CH ₃ OH)

The absolute configuration for each of the title compounds A and B is determined by X-ray crystallography.

Example 39

2-amino-5- (3-bromo-4-fluorophenyl) -5- [3-fluoro-4- (trifluoromethoxy) phenyl] -3-methyl-3,5-dihydroimidazole Preparation of 4-one

1- (3-bromo-4-fluorophenyl) -2- [3-fluoro-4- (trifluoromethoxy) -phenyl] ethane-1,2-dione in dioxane and ethanol (0.594 g, 1.45 mmol) and 1-methylguanidine hydrochloride (0.716 g, 6.53 mmol) were stirred for 5 minutes at room temperature, treated with a solution of sodium carbonate (0.692 g, 6.53 mmol) in water (5 mL), and for 45 minutes. Heated at 85 ° C. with stirring, cooled to room temperature and concentrated in vacuo. The resulting residue was partitioned between methylene chloride and water. The organic phase was separated, washed sequentially with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica, 95: 5: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide as eluent) to give a viscous oil. The oil was dissolved in a minimal amount of methylene chloride, treated with hexanes and concentrated to yield the title product as an off-white solid, 0.30 g (45% yield), confirmed by HNMR and mass spectral analysis. ¹ H NMR (500 MHz, CD ₃ OD) δ 7.64 (dd, J = 6.6, 2.2 Hz, 1H), 7.43-7.37 (m, 2H), 7.33 (dd, J = 11.5, 2.1 Hz, 1H), 7.30 (m, 1 H), 7.18 (t, J = 8.6 Hz, 1 H), 3.11 (s, 3 H); ESI MS m / z 464 [C ₁₇ H ₁₁ BrF ₅ N ₃ O ₂ + H] ⁺ .

Example 40

2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- [3-fluoro-4- (trifluoromethoxy) phenyl] -3-methyl-3,5- Preparation of Dihydro-Imidazol-4-ones

Under nitrogen, a mixture of ethylene glycol dimethyl ether, tris (dibenzylideneacetone) -dipalladium (0) (0.015 g, 16.5 μmol) and triphenylphosphine (0.008 g, 32.0 μmol) was stirred for 5 minutes, 2- Amino-5- (3-bromo-4-fluorophenyl) -5- [3-fluoro-4- (trifluoromethoxy) phenyl] -3-methyl-3,5-dihydroimidazole-4 Treated with -one (0.154 g, 0.33 mmol), 5-pyrimidine boronic acid (0.046 g, 0.37 mmol), sodium carbonate (0.105 g, 0.99 mmol) and water, heated at reflux for 1.25 h, cooled to room temperature , Concentrated in vacuo. The resulting residue was purified by flash chromatography (silica, 95: 5: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide as eluent) to give a viscous oil. The oil was suspended in a methylene chloride / hexane mixture and concentrated to yield the title compound as an off-white solid, 0.045 g (29% yield, mp 102-110 ° C.), confirmed by HNMR and mass spectral analysis. ¹ H NMR (500 MHz, CD ₃ OD) δ 9.15 (s, 1H), 8.95 (s, 2H), 7.62-7.56 (m, 2H), 7.39-7.27 (m, 4H), 3.12 (s, 3H) ; IR 3353, 3061, 2956, 1732, 1668, 1498, 1470, 1416, 1251, 1216, 1170 cm ⁻¹ ; ESI MS m / z 464 [C ₂₁ H ₁₄ F ₅ N ₅ O ₂ + H] ⁺ ; HPLC (method 2) 95.0% (AUC) t _R = 13.78 min.

Example 41

2-amino-5- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] -5- [3-fluoro-4- (trifluoromethoxy) phenyl] -3-methyl Preparation of -3,5-dihydro-imidazol-4-one

2-amino-5- (3-bromo-4-fluorophenyl) -5- [3-fluoro-4- (trifluoromethoxy) phenyl] -3-methyl-3,5- in dimethyl formamide Dihydroimidazol-4-one (0.17 g, 0.366 mmol), 5-fluoropyridin-3-yl-tri (n-butyl) stanate (0.212 g, 0.55 mmol) and bis (triphenylphosphino) palladium ( II) Chloride (0.013 g, 0.018 mmol) was degassed, heated at 150 ° C. for 1 hour, cooled to room temperature and diluted with ethyl acetate and 2% aqueous lithium chloride solution. The organic phase was separated, washed with 2% aqueous lithium chloride solution, dried over sodium sulphate and concentrated in vacuo. Purification of the resulting residue by flash chromatography (silica, 97: 3: 0.25 methylene chloride / methanol / condensed ammonium hydroxide as eluent), a white solid, 0.130 g (74% yield, mp 91-97 ° C.) The title compound was obtained and confirmed by HNMR and mass spectral analysis. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.55 (m, 1H), 8.49 (d, J = 3.0 Hz, 1H), 7.83 (d, J = 9.6 Hz, 1H), 7.60-7.21 (m, 6H ), 3.13 (s, 3 H); IR (ATR) 3352, 3070, 1732, 1669, 1598, 2502, 1479, 1421, 1252, 1217, 1171, 883, 817, 794, 703 cm ⁻¹ ; ESI MS m / z 481

Examples 42-99

Preparation of 2-amino-5,5-diphenylimidazolone derivatives

Using substantially the same procedure as described in Examples 40 and 41 above, a suitable 2-amino-5- (3-bromophenyl) -5- (substituted-phenyl) imidazolone substrate and pyridinyl or pyrimidy Using a Neil reagent, the compound shown in Table 2 was obtained and confirmed by HNMR and mass spectral analysis.

Example 100

2-amino-5- [4-fluoro-3- (1-methyl-1H-pyrazol-4-yl) phenyl] 3-methyl-5- [4- (trifluoromethoxy) phenyl] -3, Preparation of 5-dihydro-4H-imidazol-4-one

Using substantially the same procedure as described in Example 41 above, 2-amino-5- (3-bromo-4-fluorophenyl) -3-methyl-5- [4- (trifluoromethoxy as reactant ) Phenyl-3,5-dihydro-4H-imidazol-4-one and 1-methyl-4- (tributylstannyl) -1H-pyrazole gave the title compound as a white solid, Confirmed by HNMR and mass spectral analysis. ¹ H NMR (300 MHz, DMSOd ₆ ) d 2.95 (s, 3H), 3.92 (s, 3H), 6.7 (brs, 2H), 7.15 (t, 1H), 7.28 (m, 3H), 7.5 (m, 2H), 7.65 (m, 2H), 8.0 (d, 1H) MS m / e (M + H) ⁺ 448

Example 101

(5S) -2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-5- [4- (trifluoromethoxy) phenyl] -3,5-di Hydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-5- [4- Preparation of (trifluoromethoxy) phenyl] -3,5-dihydro-4H-imidazol-4-one (B)

Racemate 2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro -4H-imidazol-4-one was digested using chiral HPLC techniques on Chiralcel AD (2 x 25 cm) and using EtOH as mobile phase at a flow rate of 11 mL / min. The S-isomer, title compound A, was crystallized from chloroform / hexanes and then obtained as a white solid (98.8% yield) and confirmed by HNMR and mass spectral analysis. ¹ H NMR (300 MHz, DMSOd ₆ ) δ 2.95 (s, 3H), 3.95 (m, 4H), 6.72 (brs, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 7.55-7.6 ( m, 3H), 7.65 (dd, 1H), 8.9 (s, 2H), 9.2 (s, 1H) MS m / e (M + H) ⁺ 446

The R-isomer, title compound B, was crystallized from chloroform / hexanes and then obtained as a white solid (98.4% yield) and confirmed by HNMR and mass spectral analysis. ¹ H NMR (300 MHz, DMSOd ₆ ) δ 2.95 (s, 3H), 3.95 (m, 4H), 6.72 (brs, 2H), 7.25 (d, 2H), 7.32 (t, 1H), 7.55-7.6 ( m, 3H), 7.65 (dd, 1H), 8.9 (s, 2H), 9.2 (s, 1H) MS m / e (M + H) ⁺ 446

Example 102

(5R) -2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3-methylphenyl] -3-methyl-3,5-dihydro -4H-imidazol-4-one (A) and (5S) -2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3- Preparation of Methylphenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

Racemate 2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3-methylphenyl] -3-methyl-3,5-dihydro- 4H-imidazol-4-one was digested using chiral HPLC techniques on Chiralcel AD (2 × 25 cm) and using 9% EtOH / DEA in hexanes / DEA as mobile phase at a flow rate of 25 mL / min. The isomer, title compound A, was crystallized from chloroform / hexanes and then obtained as a white solid (100% yield) and confirmed by HNMR and mass spectrometry analysis ¹ H NMR (300 MHz, DMSOd ₆ ) δ 2.05 ( s, 3H), 2.96 (s, 3H), 3.67 (s, 3H), 6.62 (brs, 2H), 6.6 (d, 1H), 7.25-7.35 (m, 2H), 7.35-7.5 (m, 2H) , 7.65 (m, 1H), 7.95 (m, 2H), 8.4 (dd, 1H) MS m / e (M + H) ⁺ 405 [α] _D ²⁵ = +22 (c = 1% in CH ₃ OH)

S-isomer, title compound B, was obtained and crystallized from chloroform / hexanes, then obtained as a white solid (98% yield) and confirmed by HNMR and mass spectral analysis. ¹ H NMR (300 MHz, DMSOd ₆ ) δ 2.05 (s, 3H), 2.96 (s, 3H), 3.67 (s, 3H), 6.62 (brs, 2H), 6.6 (d, 1H), 7.25-7.35 ( m, 2H), 7.35-7.5 (m, 2H), 7.65 (m, 1H), 7.95 (m, 2H), 8.4 (dd, 1H), MS m / e (M + H) ⁺ 405, [α] _D ²⁵ = -9.5 (c = 0.4% in CH ₃ OH)

Example 103

(5R) -2-Amino-5- (3,4-diethoxyphenyl) -5- [3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro- 4H-imidazol-4-one (A) and (5S) -2-amino-5- (3,4-diethoxyphenyl) -5- [3- (2-fluoropyridin-3-yl) phenyl] Preparation of 3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

Racemate 2-amino-5- (3,4-diethoxyphenyl) -5- [3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro-4H -Imidazol-4-one was digested using chiral HPLC techniques on a Chiralcel AD (0.46 x 25 cm) column and 25% EtOH in hexanes / DEA as mobile phase. R-isomer, title compound A was obtained and confirmed by HNMR and mass spectral analysis. ¹ H NMR (DMSOd ₆ 300 MHz) δ 1.22 (m, 6H), 2.95 (s, 3H), 3.95 (m, 4H), 6.6 (brs, 2H), 6.85 (d, 1H), 7.0 (m, 2H ), 7.37-7.45 (m, 3H), 7.48 (d, 1H), 7.63 (s, 1H), 7.96 (m, 1H), 8.2 (d, 1H) MS m / e (M + H) ⁺ 449 [ α] _D ²⁵ = +7.4 (c = 1% in CH ₃ OH)

S-isomer, title compound B was obtained and confirmed by HNMR and mass spectral analysis. ¹ H NMR (DMSOd ₆ 300 MHz) δ 1.22 (m, 6H), 2.95 (s, 3H), 3.95 (m, 4H), 6.6 (brs, 2H), 6.85 (d, 1H), 7.0 (m, 2H ), 7.37-7.45 (m, 3H), 7.48 (d, 1H), 7.63 (s, 1H), 7.96 (m, 1H), 8.2 (d, 1H) MS m / e (M + H) ⁺ 449 [ α] _D ²⁵ = -9.8 (c = 1% in CH ₃ OH)

Example 104

2-Amino-5- [3,4-bis- (2-fluoro-ethoxy) -phenyl] -5- [4-fluoro-3- (2-fluoro-pyridin-3-yl) -phenyl ] -3-Methyl-3,5-dihydro-imidazol-4-one

Step a) Preparation of Compound 2

Sodium hydride (1.82 g of 60% dispersion in oil, 45.5 mmol) was washed with hexanes, suspended in DMF (5 mL) and compound 1 (2.0 g, 13.0 mmol) in DMF (15 mL) for 10 min at room temperature. Was added dropwise. After stirring for an additional 1.5 h at rt, the mixture was treated with a 1-bromo-2-fluoro ethane solution in DMF (15 mL), and the mixture was stirred at rt for 18 h, then further Heated at 60 ° C. for 4 hours. The mixture was cooled to rt and diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, washed with 1N NaOH (100 mL), 5% aqueous lithium chloride solution (2 × 100 mL), brine (100 mL), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (silica, 1: 3 ethyl acetate / hexanes) gave compound 2 (1.00 g, 26%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.84 (m, 2H), 4.75 (m, 3H), 4.67 (m, 1H), 4.58 (m, 1H), 4.52 (m, 1H), 4.36 (m, 2H), 4.30 (m, 2H); ESI MS m / z 293 [C ₁₃ H ₁₅ F ₃ O ₄ + H] ⁺ .

Step b) Preparation of Compound 3

A mixture of compound 2 (1.00 g, 3.42 mmol) in ethanol (10 mL) and 1 N NaOH (10 mL) was heated at 75 ° C. for 1 h. The mixture was cooled to rt, concentrated, diluted with water (10 mL) and acidified with 6N HCl. The solid obtained was collected by filtration and dried to give compound 3 (0.76 g, 90%) as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.8 (br s, 1H), 7.58 (dd, J = 8.4, 1.5 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.11 (d , J = 8.5 Hz, 1H), 4.84 (m, 2H). 4.67 (m, 2 H), 4.39-4.22 (m, 4 H).

Step c) Preparation of Compound 4

A mixture of compound 3 (0.76 g, 3.09 mmol), thionyl chloride (8 mL) and DMF (1 drop) was heated to reflux for 4 hours. The mixture was then cooled to room temperature and concentrated. The residue was dissolved in toluene and concentrated again to give compound 4 (0.82 g, 100%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (dd, J = 8.4, 1.8 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 4.89 (m, 2 H). 4.75 (m, 2 H), 4.43-4.26 (m, 4H); IR (ATR) 1734, 1582, 1513, 1417 cm ^-1 .

Step d) Preparation of Compound 6

A 1.0 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (3.25 mL, 3.25 mmol) was added (3-bromo-4-fluorobenzyl) triphenylphosphonium bromide (1.72) in tetrahydrofuran (6 mL). g, 3.25 mmol) to a stirred suspension. The mixture was stirred at room temperature for 25 minutes, then cooled to -40 ° C., treated with compound 4 (0.82 g, 3.10 mmol) in tetrahydrofuran (3 mL) and further heated for 2 hours while slowly heating to room temperature. Stirred. The reaction was then treated with water (5 mL) and sodium periodate (0.69 g, 3.25 mmol) and then heated at 50 ° C. for 19 h. Then the mixture was cooled to rt and diluted with ethyl acetate (25 mL). The organic layer was separated, washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (silica, 1: 3 ethyl acetate / hexanes) gave compound 6 (0.27 g, 20%) as a pale yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (dd, J = 6.5, 2.1 Hz, 1H), 7.92 (m, 1H), 7.63 (d, J = 2.0 Hz), 7.51 (dd, J = 8.4, 2.9 Hz, 1H), 7.23 (m, 1H), 7.96 ( d, J = 8.5 Hz, 1H) 4.85 (m, 2H), 4.76 (m, 2H), 4.39-4.31 (m, 4H).

Step e) Preparation of Compound 7

A mixture of compound 6 (0.26 g, 0.603 mmol) and 1-methylguanidine hydrochloride (0.30 g, 2.71 mmol) in dioxane (8 mL) and ethanol (5.3 mL) was stirred at room temperature for 5 minutes. Then a solution of sodium carbonate (0.29 g, 2.71 mmol) in water (2.3 mL) was added and the mixture was immersed in an 85 ° C. oil bath and stirred for 30 minutes. The reaction mixture was cooled to rt and concentrated, and the residue was partitioned between methylene chloride (50 mL) and water (20 mL). The organic layer was separated, washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (silica, 95: 5: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide) yielded compound 7 (0.154 g, 53%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃₎ ) δ 7.68 (m, 1H), 7.33 (m, 1H), 7.07 (m, 3H), 6.89 (m, 1H), 4.80 (m, 2H), 4.66 (m, 2H), 4.28 (m, 2H) , 4.18 (m, 2 H); ESI MS m / z 486 [C ₂₀ H ₁₉ BrF ₃ N ₃ O ₃ + H] ⁺ .

Step f) 2-amino-5- [3,4-bis- (2-fluoro-ethoxy) -phenyl] -5- [4-fluoro-3- (2-fluoro-pyridin-3-yl Preparation of) -phenyl] -3-methyl-3,5-dihydro-imidazol-4-one

Compound 7 (0.140 g, 0.288 mmol), 2-fluoropyridine-3-boronic acid (0.061 g, 0.430 mmol) in 1: 1 toluene / ethanol (8 mL), sodium carbonate (0.092 g, 0.860 mmol), bis ( A mixture of triphenylphosphino) palladium (II) chloride (0.010 g, 0.014 mmol) and triphenylphosphine (0.008 g, 0.028 mmol) was degassed and heated at 110 ° C. for 1.5 h. The mixture was cooled to rt, concentrated and purified by flash chromatography (silica, 97: 3: 0.25 methylene chloride / methanol / concentrated ammonium hydroxide) to give compound 8 (0.055 g, 39%, mp 85-85) as a white solid. 95 ° C.) was obtained; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.23 (m, 1H), 7.93 (m, 1H), 7.51-7.38 (m, 3H), 7.21 (t, J = 9.0 Hz, 1H), 6.98 (m , 3H), 4.78 (m, 2H), 4.68 (m, 2H), 4.62-4.58 (m, 4H), 3.11 (s, 3H); IR (ATR) 1733, 1666, 1502, 1260 cm ⁻¹ ; ESI MS m / z 503 [C ₂₅ H ₂₄ F ₄ N ₄ O ₃ + H] ⁺ . Anal. Calcd for C ₂₅ H ₂₄ F ₄ N ₄ O ₃ .0.25H ₂ O, calcd. C, 59.28; H, 4. 45; N, 10.73. Found: C, 59.23; H, 4. 47; N, 11.05.

Example 105

(5S) -2-amino-5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3-methylphenyl) -3-methyl-3 , 5-dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl]- Preparation of 5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

Racemate 2-amino-5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3-methylphenyl) -3-methyl-3, 5-Dihydro-4H-imidazol-4-one was separated by HPLC using 15% EtOH / DEA in hexane as mobile phase at Chiralcel OJ, (2 × 25 cm), flow rate 21 mL / min to give the title S isomer (A) ( ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.0 (s, 3H), 2.95 (s, 3H), 3.7 (s, 3H), 6.6 (b, 2H), 6.8 (d, 1H), 7.3 (m, 3H), 7.5 (m, 3H), 8.0 (m, 1H), 8.3 (m, 1H); MS m / e (M) ⁺ 423; [a] ₂₅ = +76.4 (C = 1 in MeOH %); mp 103-105 ° C.) and the title R isomer (B) ( ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.0 (s, 3H), 2.95 (s, 3H), 3.7 (s, 3H), 6.6 ( b, 2H), 6.8 (d, 1H), 7.3 (m, 3H), 7.5 (m, 3H), 8.0 (m, 1H), 8.3 (m, 1H); MS m / e (M) ⁺ 423; [α] ₂₅ = -40.8 (C = 1% in MeOH); mp 103-105 ° C).

Example 106

(5S) 2-Amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro- 4H-imidazol-4-one (A) and (5R) -2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- (4-methoxy-3-methylphenyl ) -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

Racemate 2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro- 4H-imidazol-4-one using Chiralcel OD (2 × 25 cm, mobile phase cm), MeOH (30% with 0.1% DEA) in CO ₂ (100 bar) as mobile phase, and flow rate 50 mL / min Separation by HPLC using the title S isomer (A) ( ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.04 (s, 3H), 2.93 (s, 3H), 3.69 (s, 3H), 6.61 (bs, 2H), 6.81 (m, 1H), 7.22 (m, 1H), 7.27 (m, 1H), 7.29 (m, 1H), 7.60 (m, 1H), 7.61 (m, 1H), 8.89 ( d, 2H), 9.18 (d, 1H); MS m / e (M + H) ⁺ 406; mp 115 ° C; [α] ₂₅ = 48 (C = 1% in MeOH)) and the title R isomer (B) ( ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.04 (s, 3H), 2.93 (s, 3H), 3.69 (s, 3H), 6.60 (bs, 2H), 6.81 (m, 1H), 7.22 (m, 1H), 7.27 (m, 1H), 7.29 (m, 1H), 7.60 (m, 1H), 7.61 (m, 1H), 8.89 (d, 2H), 9.18 (d, 1H); MS m / e (M + H) ⁺ 406; mp 115 ° C; [a] ₂₅ = -39.2 (C = 1% in MeOH).

Example 107

(5S) -2-Amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- [4-methoxy-3- (trifluoromethyl) phenyl] -3-methyl- 3,5-dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- [4 Preparation of -methoxy-3- (trifluoromethyl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- [4-methoxy-3- (trifluoromethyl) phenyl] -3-methyl-3,5- Racemic mixture of dihydro-4H-imidazol-4-one using Chiralcel OD (2 × 25 cm, mobile phase cm) using EtOH / hexane (15/85), flow rate 20 mL / min as mobile phase Separation by HPLC gave the title S isomer (A) ( ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.94 (s, 3H), 3.81 (s, 3H), 6.76 (bs, 2H), 7.19 (m, 1H), 7.32 (m, 1H), 7.32 (m, 1H), 7.50 (m, 1H), 7.70 (m, 2H), 8.89 (d, 2H), 9.18 (d, 1H); MS m / e ( M + H) ⁺ 460.1; mp 100 ° C; [a] ₂₅ = 1.6 (C = 1% in MeOH) and the title R isomer (B) ( ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.94 (s , 3H), 3.81 (s, 3H), 6.76 (bs, 2H), 6.82 (m, 1H), 7.22 (m, 1H), 7.32 (m, 1H), 7.50 (m, 1H), 7.59 (m, 1H), 7.70 (m, 1H ), 8.89 (d, 2H), 9.18 (d, 1H); MS m / e (MH) - 458; mp 100 ℃; [α] 25 = -1.8 (C = MeOH of 1%)).

Example 108

2-amino-5- [4- (2-fluoroethoxy) phenyl] -5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-3, Preparation of 5-dihydro-4H-imidazol-4-one

Step a) Preparation of Methyl 4- (2-fluoroethoxy) benzoate

To a chilled (5 ° C.) solution of 4-hydroxy-benzoic acid methyl ester (7 g, 46 mmol) in DMF (30 mL) under nitrogen atmosphere was added NaH (60%; 2.2 g) in portions for 20 minutes. After the addition was completed, the ice bath was removed and the resulting white suspension was heated to room temperature and stirred for 3 hours. A solution of 1-bromo-2-fluoro-ethane (6.42 g, 50.56 mmol) prepared in DMF (20 mL) was added and the fresh mixture was stirred at 50 ° C. for 18 h. After cooling to room temperature, the mixture was poured into a mixture of ice and 1N HCl (1: 1) and extracted with ethyl acetate. The organic extract was washed with brine and dried over MgSO ₄ . Evaporation and purification by flash chromatography (hexane / ethyl acetate 9/1) gave a white solid (7.75 g, 85% yield). ¹ H NMR (400 MHZ, CDCl ₃ ) δ 3.86 (s, 3H), 4.20 (m, 1H), 4.21 (m, 1H), 4.27 (m, 1H), 4.28 (m, 1H), 6.93 (d, 2H), 7.98 (d, 2H); MS m / e (M + H) ⁺ 198; mp 77 ° C.

Step b) Preparation of 4- (2-fluoroethoxy) benzoic Acid

To a solution of methyl 4- (2-fluoroethoxy) benzoate (7.7 g, 38.85 mmol) in dioxane (100 mL) was added lithium hydroxide (2 M, 39 mL). The reaction mixture was stirred for 18 hours at room temperature and then concentrated in vacuo. The residue was dissolved in H ₂ O (30 ml) and extracted with ether. Under cooling, the aqueous material was acidified with HCl (6N) and extracted with CHCl ₃ . The organic extract was dried over MgSO ₄ . Evaporation and recrystallization from ethyl acetate and methylene chloride gave the title compound as a white solid (5 g, 71% yield). ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 4.28 (m, 1H), 4.35 (m, 1H,) 4.68 (m, 1H), 4.80 (m, 1H), 7.04 (d, 2H), 7.89 ( d, 2H); ^{MS m / e (MH) -} 183.1; mp 203 ° C.

Step c) Preparation of 1- (3-bromo-4-fluorophenyl) -2- [4- (2-fluoroethoxy) -phenyl] ethane-1,2-dione

1.0 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (20 mL, 20 mmol) was added to (3-bromo-4-fluoro-benzyl) triphenylphosphonium bromide in tetrahydrofuran (40 mL). 10.6 g, 20 mmol) was added to the stirred suspension at room temperature. The mixture was stirred for 40 minutes, then cooled to −20 ° C. and treated with 4- (2-fluoroethoxy) benzoyl chloride (4.1 g, 20 mmol) in tetrahydrofuran (40 mL), The mixture was further stirred for 2 hours while heating slowly to room temperature. The mixture was treated with water (20 mL) and sodium periodate (4.3 g, 20 mmol) and then stirred at 50 ° C. for 18 h. After cooling to room temperature, the mixture was extracted with ethyl acetate. The organic extract was washed with brine and dried over MgSO ₄ . Evaporation and purification by flash chromatography (hexane / ethyl acetate 9/1) gave a yellow solid (3 g, 41% yield). ¹ H NMR (400 MHZ, CDCl ₃ ) δ 4.25 (m, 1H), 4.32 (m, 1H,) 4.70 (m, 1H), 4.82 (m, 1H), 7.01 (d, 2H), 7.23 (m, 1H), 7.94 (m, 3H), 8.22 (m, 1H); MS m / e (M + CH 3 COO) - 427; mp 107 ° C.

Step d) 2-amino-5- [4- (2-fluoroethoxy) phenyl] -5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -3-methyl Preparation of -3,5-dihydro-4H-imidazol-4-one

Using the same procedure as described in Examples 39 and 40 and using methylaminoguanidine and 2-fluoropyridine-3-boronic acid respectively, the title product was obtained as a white solid (mp 135 ° C.) ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.93 (s, 3H), 4.09 (m, 1H), 4.11 (m, 1H,) 4.59 (m, 1H), 4.61 (m, 1H), 6.84 , (bs, 2H), 6.86 (m, 2H), 7.30 (m, 3H), 7.44 (m, 1H), 7.52 (m, 2H), 7.95 (m, 1H), 8.26 (m, 1H); ^{MS m / e (MH) -} 439.2.

Examples 109-124

Preparation of 2-amino-5-alkoxyphenyl-5- (3-heteroaryl) phenyl-3-methyl-3,5-dihydro-4H-imidazol-4-one compound

Using the procedure substantially the same as that described in Example 108, using an appropriate boronic acid and 5- (3-bromophenyl) hydantoin substrate, the compounds shown in Table 3 were obtained, by NMR and mass spectral analysis Confirmed.

Example 125

2-amino-5- (3-bromo-4-fluorophenyl) -3- (2-fluoroethyl) -5- (4-trifluoromethoxy-phenyl) -3,5-dihydro-imi Preparation of Dazol-4-one

To a stirring mixture of 2-fluoroethylamine hydrochloride (1.50 g; 15.1 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (1.77 g; 12.1 mmol) in DMF was added diisopropylethylamine (3.58 g; 27.7 mmol) was added. The mixture was stirred under nitrogen atmosphere for 3 hours. Diethyl ether (35 mL) was added, the mixture was stirred, and the oil was precipitated at the bottom of the flask to decanter the ether. This was repeated and the clear oil was dried under high vacuum for 24 hours at ambient temperature. The N- (2-fluoroethyl) -guanidine product (1.6 g) was used without further purification.

1- (3-Bromo-4-fluoro-phenyl) -2- (4-trifluoromethoxy-phenyl) -ethane-1,2-dione (0.181 g; 0.46) in a mixture of dioxane, water and ethanol mmol) and N- (2-fluoroethyl) -guanidine (0.105 g; 0.74 mmol) were treated with solid sodium carbonate heated at 90 ° C. for 5 hours, and evaporated to dryness. The resulting residue was dissolved in chloroform, washed with water, dried over sodium sulfate and evaporated to a pale green solid, 116 mg (52% yield, MS (API-ES) 480.3 [M + H] ⁺ ). The compound was obtained.

Examples 126-128

Preparation of 2-amino-3-substituted-5- (3-heteroaryl) phenyl-5- (4-trifluoromethoxy-phenyl) -3,5-dihydro-imidazol-4-one compound

Using the substantially same procedure as described in Example 108 and using the appropriate boronic acid and 3-alkyl-2-amino-5- (3-bromophenyl) hydantoin substrate, the compounds shown in Table 4 were obtained. It was confirmed by NMR and mass spectral analysis.

Example 129

3-methyl-5- (3-methyl-4-rooxyphenyl) -2- (propylamino) -5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole Preparation of 4-one

2-amino-5- (4-hydroxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro- in N, N-dimethylformamide The 4H-imidazol-4-one (74.6 mg, 0.2 mmol) solution was treated with 2-iodopropane (31.2 mg, 0.4 mmol) and Cs ₂ CO ₃ (130 mg, 0.4 mmol) at room temperature overnight at room temperature. Stirred and quenched with H ₂ O. The phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was combined with the extract, sequentially washed with H ₂ O and brine, dried over MgSO ₄ and evaporated to dryness. The resulting residue was purified by flash chromatography using ethyl acetate / ethanol (2M ammonia) (90/10) as eluent to give a white solid, 60 mg (65% yield, mp 64-66 ° C .; MS (+) ES: 458 (M + H) ⁺ ) to afford the title compound.

Example 130

Preparation of 4-iodo-2-methyl-1-[(1R) -1-phenylethoxy] benzene

A cooled solution of PPh ₃ (262 mg, 10 mmol) in THF was treated with diethyl azodicarboxylate (1.74 g, 10 mmol) at 0 ° C., stirred for 5 minutes, heated to room temperature, 4- Treated with iodo-2-methylphenol (1.17 g, 5 mmol) and R (+)-1-phenylethanol (1.22 g, 10 mmol), stirred at rt for 24 h and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 100% hexa) to afford the title compound as a clear oil, 2.5 g (50%, MS (+): EI 338 M ⁺ ).

Example 131

2-amino-3-methyl-5- {3-methyl-4-[(1R) -1-phenylethoxy] phenyl} -5- (3-pyrimidin-5-ylphenyl) -3,5-di Preparation of Hydro-4H-imidazol-4-one

A solution of 4-iodo-2-methyl-1-[(1R) -1-phenylethoxy] benzene (10 mmol) in triethylamine was added to tetrakis (triphenylphosphine) Pd (0.69 mmol) in acetonitrile, Treatment with copper iodide (0.97 mmol) and 3- (pyrimidin-5-yl) ethynylbenzene (10 mmol) solution at room temperature. The reaction mixture was treated at 80 ° C. for 1 h, cooled and concentrated in vacuo. The resulting residue was purified by chromatography to give 5- [3-({3-methyl-4-[(1R) -1-phenyl} ethynyl) phenyl] pyrimidine (MS (+) as oil). ES: 391 (M + H) ⁺ ) was obtained. A solution of 5- [3-({3-methyl-4-[(1R) -1-phenyl]} ethynyl) phenyl] pyrimidine (8.3 mmol) in acetone was dissolved in NaHCO ₃ (4.98 mmol) in water (80 mmol). Was treated with a warm (˜40 ° C.) solution of MgSO ₄ (12.45 mmol), and then a batch of solid KMnO ₄ (8.3 mmol) was added and stirred at room temperature for 40 minutes, extracted with 1: 1 ether: hexane It was. The extract was combined, dried over MgSO ₄ and concentrated to dryness to give 1- {3-methyl-4-[(1R) -1-phenylethoxy] phenyl} -2- (3-pyrimidine-5- as foam. Ilphenyl) ethane-1,2-dione (MS (+) ES: 423 (M + H) ⁺ ) was obtained. A solution of 1- {3-methyl-4-[(1R) -1-phenylethoxy] phenyl} -2- (3-pyrimidin-5-ylphenyl) ethane-1,2-dione (5.0 mmol) in ethanol Was treated with an aqueous solution of N-methylguanidine hydrochloride (5.5 mmol) and Na ₂ CO ₃ (10.0 mmol), heated at reflux for 1 h and concentrated in vacuo. The resulting residue was purified by chromatography to give the title product as a white solid (mp 112-114 ° C., MS (+) ES: 478 (M + H) ⁺ ).

Example 132

(5R) -2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-5- [4- (trifluoromethoxy) phenyl] -3,5-di Preparation of Hydro-4H-imidazol-4-one

2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro-4H- The racemate mixture of imidazol-4-one was separated by chiral HPLC using 9% EtOH in hexane (0.1% diethylamine) as mobile phase and using Chiralcel AD (2 × 25 cm) (column) The title R-isomer was obtained: [α] ₂₅ = -13.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.95 (s, 3H), 6.65 (brs, 2H), 7.28 (d, 2H), 7.4-7.45 (m, 3H), 7.5 (m, 1H), 7.55 (d , 2H), 7.65 (d, 1 H), 7.95-8.0 (m, 1 H), 8.2 (m, 1 H); MS m / e (M + H) ⁺ 445.

Example 133

(5S) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -3-methyl- 3,5-dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [4-fluoro-3 Preparation of-(2-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4- (difluoromethoxy) phenyl] -5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-3,5- The racemate mixture of dihydro-4H-imidazol-4-one was separated by chiral HPLC using 9% EtOH in hexanes / TFA as mobile phase and using Chiralcel AD (2 × 25 cm) (column), Title product A ([α] ₂₅ = +11.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 3.12 (s, 3H), 7.25 (m, 3H), 7.4-7.5 (m, 4H) , 7.5 (m, 2H), 8.0 (m, 1H), 8.6 (m, 1H), 9.5-9.7 (br, 2H); MS m / e (M + H) ⁺ 445) and the title product B ([α ₂₅ = -10.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 3.12 (s, 3H), 7.25 (m, 3H), 7.4-7.5 (m, 4H), 7.5 (m, 2H ), 8.0 (m, 1H), 8.6 (m, 1H), 9.5-9.7 (br, 2H); MS m / e (M + H) ⁺ 445).

Example 134

(5S) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [4-fluoro-3- (6-fluoropyridin-3-yl) phenyl] -3-methyl- 3,5-dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [4-fluoro-3 Preparation of-(6-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4- (difluoromethoxy) phenyl] -5- [4-fluoro-3- (6-fluoropyridin-3-yl) phenyl] -3-methyl-3,5- The racemic mixture of dihydro-4H-imidazol-4-one was separated by chiral HPLC using 15% EtOH in hexanes as mobile phase and using Chiralcel OJ (0.46 x 10 cm) (column), titled S-isomer (A) ([a] ₂₅ = +6 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.94 (s, 3H), 6.8 (brs, 2H), 7.08 (d, 2H ), 7.12 (t, 1H), 7.28 (m, 2H), 7.4-7.5 (m, 3H), 7.6 (dd, 1H), 8.05 (m, 1H), 8.3 (s, 1H); MS m / e (M + H) ⁺ 445) and the title R-isomer (B) ([α] ₂₅ = -7.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.94 (s, 3H), 6.8 ( brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.28 (m, 2H), 7.45 (d, 2H), 7.4-7.5 (m, 1H), 7.6 (dd, 1H), 8.05 (m, 1H), 8.3 (s, 1H); MS m / e (M + H) ⁺ 445).

Example 135

(5S) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [3- (6-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-di Hydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [3- (6-fluoropyridine-3- Yl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4- (difluoromethoxy) phenyl] -5- [3- (6-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro-4H- The racemate mixture of imidazol-4-one was separated by chiral HPLC using 15% EtOH in hexanes as mobile phase and using Chiralcel OJ (0.46 x 10 cm) (column) to give the title S-isomer (A) ([α] ₂₅ = -7.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.95 (s, 3H), 6.7 (brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.25 (dd, 1H), 7.4 (t, 1H), 7.5-7.55 (m, 4H), 7.7 (s, 1H), 8.2 (m, 1H), 8.37 (s, 1H); MS m / e (M + H) ⁺ 427) and the title R-isomer (B) ([a] ₂₅ = +8.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.95 (s, 3H), 6.7 (brs, 2H), 7.08 (d, 2H), 7.12 (t, 1H), 7.25 (dd, 1H), 7.4 (t, 1H), 7.5-7.55 (m, 4H), 7.7 (s, 1H), 8.2 (m, 1H), 8.37 (s, 1H); MS m / e (M + H) ⁺ 427) were obtained.

Example 136

(5S) -2-amino-5- (3,4-diethoxyphenyl) -5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-3, 5-dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- (3,4-diethoxyphenyl) -5- [4-fluoro-3- (2- Preparation of Fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- (3,4-diethoxyphenyl) -5- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro The racemic mixture of -4H-imidazol-4-one is separated using 20% EtOH in heptanes containing 1% triethylamine as eluent and using WhelkO, (2 x 25 cm) chiral HPLC column. Titled S-Isomer (A) ([α] ₂₅ = -22.2, 1% in methanol; ¹ H NMR (DMSOd ₆ 300 MHz) δ 1.3 (t, 6H), 2.9 (s, 3H), 3.9 (dxq, 4H), 6.6 (b, 2H), 6.8 (d, 1H) 7.0 (m, 2H), 7.3 (t, 1H), 7.5 (m, 3H), 7.9 (s, 1H), 8.3 (m MS m / e (M) ⁺ 467) and the title R-isomer (B) ([α] ₂₅ = +26.0, 1% in methanol; ¹ H NMR (DMSOd ₆ 300 MHz) δ 1.3 as white solid (t, 6H), 2.9 (s, 3H), 3.9 (dxq, 4H), 6.6 (b, 2H), 6.8 (d, 1H) 7.0 (m, 2H), 7.3 (t, 1H), 7.5 (m , 3H), 7.9 (s, 1H), 8.3 (m, 1H); MS m / e (M) ⁺ 467).

Example 137

(5S) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [3- (2,5-difluoropyridin-3-yl) phenyl] -3-methyl-3, 5-dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4- (difluoromethoxy) phenyl] -5- [3- (2,5-di Preparation of Fluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4- (difluoromethoxy) phenyl] -5- [3- (2,5-difluoropyridin-3-yl) phenyl] -3-methyl-3,5-dihydro The racemic mixture of -4H-imidazol-4-one was separated by chiral HPLC using 35% EtOH in hexanes / DEA as mobile phase and using Chiralcel OJ (2 x 25 cm) (column), titled S Isomer (A) ([a] ₂₅ = +2.8 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.94 (s, 3H), 6.7 (brs, 2H), 7.08 (d, 2H) , 7.12 (t, 1 H), 7.4-7.5 (m, 5 H), 7.7 (s, 1 H), 8.0 (m, 1 H), 8.2 (m, 1 H); MS m / e (M + H) ⁺ 445) And the title R-isomer (B) ([α] ₂₅ = +2.8 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.94 (s, 3H), 6.7 (brs, 2H), 7.08 (d , 2H), 7.12 (t, 1H), 7.4-7.5 (m, 5H), 7.7 (s, 1H), 8.0 (m, 1H), 8.2 (m, 1H); MS m / e (M + H) ⁺ 445).

Example 138

(5S) -2-amino-5- [4- (2-fluoroethoxy) -3-methylphenyl] -3-methyl-5- (3-pyrimidin-5 ylphenyl) -3,5-di Hydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4- (2-fluoroethoxy) -3-methylphenyl] -3-methyl-5- (3- Preparation of pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4- (2-fluoroethoxy) -3-methylphenyl] -3-methyl-5- (3-pyrimidine) using substantially the same procedure as described in Examples 133-137 Using the racemate mixture of -5-ylphenyl) -3,5-dihydro-4H-imidazol-4-one, the title S-isomer (A) was prepared as a white solid (mp 116-118 ° C.) ( [a] ₂₅ = -31.46 (1% in DMSO); MS (+) ES: 438 (M + H) ⁺ ), and the title R-isomer (B) was also white solid (mp 112-114 ° C.) ( [α] ₂₅ = +35 (1% in DMSO); MS (+) ES: 438 (M + H) ⁺ ).

Example 139

(5S) -2-amino-5- [4- (2-fluoroethoxy) phenyl] -5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-3,5 -Dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4- (2-fluoroethoxy) phenyl] -5- (4-fluoro-3- Preparation of pyrimidin-5-ylphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4- (2-fluoroethoxy) phenyl] -5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-3,5-dihydro- Chiral HPLC with Chiralcel AD (2 x 25 cm) using racemic mixture of 4H-imidazol-4-one using EtOH: hexanes (15:85) as mobile phase and flow rate 20 mL / min Separated by, the title S-isomer (A) was separated into a white solid (mp 120 ° C.) ([α] ₂₅ = -35.09 (0.53% in MeOH); ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 2.97 ( s, 3H), 4.14-4.15 (m, 1H), 4.20-4.21 (m, 1H,) 4.65-4.66 (m, 1H), 4.74-4.75 (m, 1H), 6.67 (bs, 2H), 6.88- 6.89 (d, 2H), 7.34 (m, 1H), 7.35-7.37 (d, 2H), 7.57, (m, 1H), 7.65 (m, 1H), 8.92 (s, 2H), 9.22 (s, 1H ) .; MS m / e (MH ) - 422.1 a), also a white solid (mp 120 ℃) the title R- isomer _{([α] 25 = +31.2 (} 1% in ^{MeOH); 1 H NMR (400} MHZ, DMSO-d ₆ ) δ 2.97 (s, 3H), 4.15-4.16 (m, 1H,), 4.20-4.21 (m, 1H), 4.65-4.66 (m, 1H), 4.74-4.75 (m, 1H), 6.67 (bs, 2H), 6.88-6.89 (d, 2H), 7.34 (m, 1H), 7.35-7.37 (d, 2H), 7.55, (m, 1H), 7.65 (m, Was obtained as ^{422.1) - MS m / e (} MH); 1H), 8.92 (s, 2H), 9.22 (s, 1H).

Examples 140 and 141

(5S) -2-Amino-5- [4- (2-fluoroethoxy) phenyl] -3-methyl-5- (3-heteroarylphenyl) -3,5-dihydro-4H-imidazole- Preparation of 4-one compound

(5S) -2-amino-5- (3-bromophenyl) -5- [4- (2-fluoroethoxy) phenyl] -3- using substantially the same procedure as described in Example 40 Using methyl-3,5-dihydro-4H-imidazol-4-one and the appropriate heteroarylboronic acid, the compounds shown in Table 5 were obtained and confirmed by HNMR and mass spectral analysis.

Example 142

(5S) -2-amino-5- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] -5- (4-methoxy phenyl) -3-methyl-3,5- Dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] -5- ( Preparation of 4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4-fluoro-3- (5-fluoropyridin-3-yl) phenyl] -5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H The racemate mixture of -imidazol-4-one is separated by chiral HPLC using 30% EtOH in hexanes (0.1% diethylamine) as mobile phase and using Chiralcel OJ (2 x 25 cm) (column) Title S-isomer (A) ([a] ₂₅ = -37.6 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.93 (s 3H), 3.63 (s 3H), 6.6 (brs, 2H), 6.8 (d, 2H), 7.22-7.35 (m, 3H), 7.5 (m, 1H), 7.6 (dd, 1H), 7.8 (m, 1H), 8.5 (d, 1H), 8.6 (d MS m / e (M + H) ⁺ 409) and the title R-isomer (B) ([a] ₂₅ = +35.4 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.93 (s 3H), 3.63 (s 3H), 6.6 (brs, 2H), 6.8 (d, 2H), 7.22-7.35 (m, 3H), 7.5 (m, 1H), 7.6 (dd, 1H), 7.8 ( m, 1H), 8.5 (d, 1H), 8.6 (d, 1H); MS m / e (M + H) ⁺ 409).

Example 143

(5S) -2-amino-5- [4-fluoro-3- (4-fluoropyridin-3-yl) phenyl] -5- (4-methoxyphenyl) -3-methyl-3,5- Dihydro-4H-imidazol-4-one (A) and (5R) -2-amino-5- [4-fluoro-3- (4-fluoropyridin-3-yl) phenyl] -5- ( Preparation of 4-methoxyphenyl) -3-methyl-3,5-dihydro-4H-imidazol-4-one (B)

2-amino-5- [4-fluoro-3- (4-fluoropyridin-3-yl) phenyl] -5- (4-methoxyphenyl) -3-methyl-3,5-dihydro-4H The racemate mixture of imidazol-4-one is separated by chiral HPLC using 80% EtOH in hexanes (0.1% diethylamine) as mobile phase and using Chiralcel OJ (0.46 × 25 cm) (column) Title S-isomer (A) ([a] ₂₅ = -40 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.93 (s, 3H), 3.66 (s, 3H), 6.65 ( brs, 2H), 6.8 (d, 2H), 7.3 (m, 3H), 7.43 (m, 1H), 7.52 (m, 2H), 8.55 (d, 1H), 8.63 (t, 1H); MS m / e (M + H) ⁺ 409) and the title R-isomer (B) ([a] ₂₅ = +38.8 (1% in MeOH); ¹ H NMR (DMSOd ₆ 300 MHz) δ 2.93 (s, 3H), 3.66 (s, 3H), 6.65 (brs, 2H), 6.8 (d, 2H), 7.3 (m, 3H), 7.43 (m, 1H), 7.52 (m, 2H), 8.55 (d, 1H), 8.63 ( t, 1H), MS m / e (M + H) ⁺ 409).

Example 144

4- [4-fluoro-3- (2-fluoropyridin-3-yl) phenyl] -1-methyl-4- (4-trifluoromethoxyphenyl) -4,5-dihydro-1H-already Preparation of Dazol-2-ylamine

Step a) Preparation of Compound 2

A mixture of compound 1 (2.00 g, 5.1 mmol) and 1-methyl-2-thiourea (2.07 g, 23.0 mmol) in ethanol (50 mL) and dioxane (50 mL) was stirred at room temperature for 5 minutes. A solution of sodium carbonate (2.44 g, 23.0 mmol) in water (20 mL) was added and the reaction stirred at 85 ° C. for 15 minutes. The reaction was then cooled to rt, concentrated and diluted with ethyl acetate (100 mL) and brine (20 mL). The organic layer was separated, washed with brine (10 mL), dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography (silica, 1: 9 ethyl acetate / hexanes) gave Compound 2 (2.30 g, 97%) as a yellow solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.61 (dd, J = 6.3, 2.4 Hz, 1H), 7.46-7.27 (m, 6H), 3.27 (s, 3H).

Step b) Preparation of Compound 3

A mixture of Compound 2 (2.20 g, 4.75 mmol) and 1.0 M borane tetrahydrofuran complex in tetrahydrofuran (47.5 mL, 47.5 mmol) was heated to reflux overnight in tetrahydrofuran (66 mL), then 6 N HCl (24 mL, 143 mmol) and heated at 80 ° C. for 1 h. The reaction was cooled to rt, neutralized with sodium bicarbonate solid (12.0 g, 143 mmol) and diluted with ethyl acetate (200 mL). The organic layer was separated, washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography (silica, 1: 9 to 2: 8 ethyl acetate / hexanes) gave compound 3 (0.73 g, 34%) as colorless oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.42 (m, 1H), 7.31-7.05 (m, 6H), 4.18 (s, 2H), 3.19 (s, 3H); ESI MS m / z 450 [C ₁₇ H ₁₃ BrF ₄ N ₂ OS + H] ⁺ .

Step c) Preparation of Compound 4

A mixture of compound 3 (0.73 g, 1.63 mmol) and methyl iodide (0.25 g, 1.79 mmol) in isopropanol (10 mL) was heated at 80 ° C. for 1 h, concentrated and redissolved in isopropanol (20 mL). , Cooled to 0 ° C. and charged with ammonia gas (2.0 g). The reaction vessel was sealed and heated at 80 ° C. for 48 hours. The reaction was cooled to room temperature, concentrated and purified by flash chromatography (100: 0: 0 to 80: 20: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide) to give Compound 4 (0.62 g, 88%) was obtained: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.62 (dd, J = 6.3, 2.4 Hz, 1H), 7.61-7.20 (m, 6H), 4.35 (s, 2H), 3.08 (s, 3H); ESI MS m / z 432 [C ₁₇ H ₁₄ BrF ₄ N ₃ O + H] ⁺ .

Step d) Preparation of Compound 5

A mixture of compound 4 (0.52 g, 1.20 mmol), 4-dimethylaminopyridine (0.77 g, 6.32 mmol) and di-tert-butyldicarbonate (1.38 g, 6.32 mmol) in tetrahydrofuran (5 mL) was added. It was stirred for rt at rt and concentrated. Purification by flash chromatography (silica, 1: 9-2: 8 ethyl acetate / hexanes) gave compound 5 (0.49 g, 65%) as a white solid: ¹ H NMR (300 MHz, CD ₃ OD) δ 7.67 (dd, J = 6.6, 2.1 Hz, 1H), 7.44-7.03 (m, 6H), 4.05 (d, J = 9.9 Hz, 1H), 3.86 (d, J = 9.9 Hz, 1H), 2.79 (s , 3H), 1.39 (s, 18H); ESI MS m / z 632 [C ₂₇ H ₃₀ BrF ₄ N ₃ O ₅ + H] ⁺ .

Step e) Preparation of Compound 6

Compound 5 (0.19 g, 0.300 mmol), 2-fluoropyridine-3-boronic acid (0.064 g, 0.451 mmol) in 1: 1 toluene / EtOH (10 mL), sodium carbonate (0.096 g, 0.900 mmol), bis ( A mixture of triphenylphosphino) palladium (II) dichloride (0.021 g, 0.030 mmol) and triphenylphosphine (0.016 g, 0.060 mmol) was degassed and heated at 110 ° C. for 20 minutes. The mixture was cooled to rt and concentrated. Purification by flash chromatography (silica, 1: 9-4: 6 ethyl acetate / hexanes) gave compound 6 (0.055 g, 28%) as a white solid: ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.24 (m, 1H), 7.82 (m, 1H), 7.48-7.11 (m, 8H), 4.03 (d, J = 9.5 Hz, 1H), 3.95 (d, J = 9.5 Hz, 1H), 2.78 (s, 3H), 1.31 (s, 18 H); ESI MS m / z 649 [C ₃₂ H ₃₃ F ₅ N ₄ O ₅ + H] ⁺ .

Step f) 4- [4-Fluoro-3- (2-fluoro-pyridin-3-yl) -phenyl] -1-methyl-4- (4-trifluoromethoxy-phenyl) -4,5- Preparation of Dihydro-1H-imidazol-2-ylamine

A mixture of compound 6 (0.055 g, 0.085 mmol) and 4 M hydrogen chloride in dioxane (5 mL) was heated at 50 ° C. for 1 h, cooled to rt and concentrated. The reaction mixture was then diluted with chloroform (50 mL) and sodium bicarbonate (10 mL). The organic layer was separated, washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated. Purification by preparative HPLC gave the title product as a white solid, 0.031 g (82% yield, mp 65-70 ° C.); ¹ H NMR (500 MHz, CD ₃ OD) δ 8.22 (m, 1H), 7.95 (m, 1H), 7.35-7.23 (m, 8H), 4.10 (t, J = 7.5 Hz, 2H), 2.93 (t , J = 7.5 Hz, 3H); IR (ATR) 3059, 2926, 1670, 1641, 1570, 1503, 1427, 1253, 1201, 1161, 829, 804, 765, 718 cm ⁻¹ ; ESI MS m / z 449 [C ₂₂ H ₁₇ F ₅ N ₄ O + H] ⁺ .

Example 145

2-amino-5- [3- (2-fluoro-pyridin-3-yl) -phenyl] -3-methyl-5- (4-trifluoromethoxy-phenyl) -3,5-dihydro-imi Preparation of Dazol-4-Thion

Step a) Preparation of Compound 2

A mixture of methylamine hydrochloride (0.210 g, 3.18 mmol), triethylamine (0.320 g, 3.18 mmol) and compound 1 (0.470 g, 1.06 mmol) in ethanol was stirred at 70 ° C. for 1 hour. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was separated, washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated to give compound 2 (0.460 g, 99%) as a yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.71 (br s, 1H), 7.58-7.49 (m, 2H), 7.37 (d, J = 8.9 Hz, 2H), 7.30-7.19 (m, 3H), 3.68 (s, 3H).

Step b) Preparation of Compound 3

A mixture of compound 2 (0.458 g, 1.05 mmol) and t-butyl hydroperoxide (1.88 g of 70% aqueous solution, 21.0 mmol) in methanol (50 mL) and concentrated aqueous ammonium hydroxide solution (10 mL) was stirred overnight at room temperature It was. Then 10% sodium thiosulfate aqueous solution (30 mL) was added; The mixture was concentrated to remove most of the methanol, after which the aqueous mixture was diluted with methylene chloride. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate, filtered and concentrated. Purification of the resulting residue by flash chromatography (silica, 95: 5 methylene chloride / methanol) gave Compound 3 (0.250 g, 57%) as a white solid: ¹ H NMR (300 MHz, CDCl ₃₎ ) δ 7.88 (t, J = 1.7 Hz, 1H), 7.81 (d, J = 8.9 Hz, 2H), 7.72-7.65 (m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 6.98 (d , J = 8.9 Hz, 2H), 3.90 (s, 3H); ESI MS m / z 444 [C ₁₇ H ₁₃ BrF ₃ N ₃ OS + H] ⁺ .

Step c) 2-amino-5- [3- (2-fluoro-pyridin-3-yl) -phenyl] -3-methyl-5- (4-trifluoromethoxy-phenyl) -3,5-di Preparation of Hydro-imidazole-4-thione

Compound 3 (0.16 g, 0.38 mmol), 2-fluoropyridine-3-boronic acid (0.075 g, 0.530 mmol), bis (triphenylphosphino) palladium (II) in 3: 1 DME / water (6.0 mL) A mixture of chloride (0.013 g, 0.019 mmol), triphenylphosphine (0.010 g, 0.038 mmol) and sodium carbonate (0.121 g, 1.14 mmol) was heated at 80 ° C. for 1 hour. The mixture was cooled to rt and concentrated in vacuo. The resulting residue was diluted with ethyl acetate and water. The organic layer was separated, washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated. Purification by flash chromatography of the residue (silica, 97: 2.5: 0.5 methylene chloride / methanol / concentrated ammonium hydroxide) gave 0.087 g of a pale yellow solid. The material was lyophilized from 1: 1 acetonitrile / water (6 mL) to give the title product as a pale yellow solid, 0.069 g (39% yield, mp 89-99 ° C.); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.17 (dt, J = 4.8, 1.5 Hz, 1H), 7.86-7.79 (m, 1H), 7.65 (br s, 1H), 7.55-7.48 (m, 4H) , 7.44-7.38 (m, 1H), 7.27-7.25 (m, 1H), 7.14 (d, J = 8.9 Hz, 2H), 3.48 (s, 3H); ESI MS m / z 461 [C ₂₂ H ₁₆ F ₄ N ₄ OS + H] ⁺ ;

Example 146

Evaluation of hBACE1, MuBACE1 and hBACE2 Inhibition by Test Compounds

Assay conditions : 10 nM human BACE1 (or 10 nM mouse BACE1, 1.5 nM human BACE2) 25 μM substrate (WABC-6, MW 1549.6, manufactured by AnaSpec); Final buffer conditions: 50 mM Na-acetate, pH 4.5, 0.05% CHAPS, 25% PBS; Temperature: room temperature; Reagent Information: Na-Acetate: Aldrich, Cat. # 24,124-5 CHAPS: Research Organics, Cat. # 1304C 1X PBS: Mediatech (Cellgro), Cat # 21-031-CV; Peptide substrate AbzSEVNLDAEFRDpa: AnaSpec, peptide name: WABC-6;

Determination of Storage Substrate (AbzSEVNLDAEFRDpa) Concentration : A 25 mM stock solution in dimethyl sulfoxide (DMSO) was prepared using peptide weight and MW and diluted to 25 μΜ. The concentration is determined by absorbance at 354 nm using an absorption coefficient ε of 18172 M ⁻¹ cm ⁻¹ , and the substrate stock is aliquoted and stored at −80 ° C. [Substrate stock ^{solution] = ABS 354 nm × 10 6} /18172 ( unit: mM)

Determining the stored enzyme concentration: 6 M guanidinium hydrochloride (. Organics Research Products, Cat # 5134G-2), at pH 6 In the hBACE1 and MuBACE1 64150 M ^-1 cm ^-1, in the hBACE2 62870 M ^-1 cm The storage concentration of each enzyme is determined by ABS of 280 nm using ε of ^-1 .

(The extinction coefficient ε ^{280 nm} for each enzyme is known amino acid for Trp (5.69 M ^-1 cm ^-1 ) and Tyr (1.28 M ^-1 cm ^-1 ) residues (Anal. Biochem. 182, 319-326) Calculated based on the composition and published extinction coefficients.)

Dilution and Mixing Steps : Total Reaction Volume: 100 μL

1. Prepare 2 × inhibitor dilutions in Buffer A (66.7 mM Na-acetate, pH 4.5, 0.0667% CHAPS),

2. Prepare 4 × enzyme dilutions in Buffer A (66.7 mM Na-acetate, pH 4.5, 0.0667% CHAPS),

3. Prepare 100 μM substrate dilution in 1 × PBS,

4. Add 50 μL of 2 × inhibitor and 25 μL of 100 μM substrate to each well of a 96-well plate (DYNEX Technologies, VWR #: 11311-046) and immediately add 25 μL of 4 × enzyme to the inhibitor and substrate mixture. Was added and fluorescence reading was started.

Fluorescence readings : Fluorescence values at λ _ex 320 nm and λ _em 420 nm were read every 40 seconds for 30 minutes at room temperature to determine the slope of the straight line to substrate degradation rate (v _i ).

Calculation of% inhibition:% inhibition = 100 × (1- v _i / v ₀ )

(v _i = substrate degradation rate in the presence of inhibitor,

v ₀ = substrate degradation rate in the absence of inhibitor)

IC ₅₀ crystals:% inhibition = [(B × IC ₅₀ ⁿ ) + (100 × I ₀ ⁿ )] / (IC ₅₀ ⁿ + I ₀ ⁿ ).

Fluorescence Response Rate Analysis of Human Recombinant BACE2

This assay is used to determine kinetic and selectivity parameters for the assay of the tested compounds.

Materials and Methods : Final assay conditions: 10 nM human BACE1 (or 10 nM mouse BACE1, 1.5 nM human BACE2) 25 μM substrate (WABC-6, MW 1549.6, manufactured by AnaSpec). Final buffer conditions: 50 mM Na-acetate, pH 4.5, 0.05% CHAPS, 25% PBS. Temperature: room temperature. Reagent Information: Na-Acetate: Aldrich, Cat. # 24,124-5 CHAPS: Research Organics, Cat. # 1304C 1 × PBS: Mediatech (Cellgro), Cat # 21-031-CV peptide substrate AbzSEVNLDAEFRDpa: AnaSpec, peptide name: WABC-6

Determination of Storage Substrate (AbzSEVNLDAEFRDpa) Concentration : A 25 mM stock solution in dimethyl sulfoxide (DMSO) was prepared using peptide weight and MW and diluted to 25 μΜ. The concentration was determined by absorbance at 354 nm using an absorbance coefficient ε of 18172 M ⁻¹ cm ⁻¹ . The substrate stock solution is aliquoted in small amounts and stored at -80 ° C. [Substrate stock ^{solution] = ABS 354 nm × 10 6} /18172 ( unit: mM)

Determining the stored enzyme concentration: 6 M guanidinium hydrochloride (. Organics Research Products, Cat # 5134G-2), at pH 6 In the hBACE1 and MuBACE1 64150 M ^-1 cm ^-1, in the hBACE2 62870 M ^-1 cm The storage concentration of each enzyme is determined by ABS of 280 nm using ε of ^-1 . (The extinction coefficient ε ^{280 nm} for each enzyme is known amino acid for Trp (5.69 M ^-1 cm ^-1 ) and Tyr (1.28 M ^-1 cm ^-1 ) residues (Anal. Biochem. 182, 319-326) Calculated based on the composition and published extinction coefficients.)

Dilution and Mixing Steps : Total Reaction Volume: 100 μL

1. Prepare 2 × inhibitor dilutions in Buffer A (66.7 mM Na-acetate, pH 4.5, 0.0667% CHAPS),

2. Prepare 4 × enzyme dilutions in Buffer A (66.7 mM Na-acetate, pH 4.5, 0.0667% CHAPS),

3. Add 100 μM substrate dilution in 1 × PBS, 50 μL of 2 × inhibitors and 25 μL of 100 μM substrate to each well of a 96-well plate (DYNEX Technologies, VWR #: 11311-046) and immediately 4 × 25 μL of enzyme was added to the inhibitor and substrate mixture and fluorescence reading was started.

Fluorescence readings : Fluorescence values at λ _ex 320 nm and λ _em 420 nm were read every 40 seconds for 30 minutes at room temperature to determine the slope of the straight line to substrate degradation rate (v _i ).

Calculation of% inhibition:% inhibition = 100 × (1- v _i / v ₀ )

(v _i = substrate degradation rate in the presence of inhibitor,

v ₀ = substrate degradation rate in the absence of inhibitor)

IC ₅₀ crystals:% inhibition = [(B × IC ₅₀ ⁿ ) + (100 × I ₀ ⁿ )] / (IC ₅₀ ⁿ + I ₀ ⁿ ).

The data obtained are shown in Table 6.

Description of Table 6

A = 0.01 μM to 0.10 μM

B = 0.11 μM to 1.00 μM

C => 1.00 μM

Ⅰ => 100 times selectivity

Ⅱ = 10 to 100 times selectivity

III = <10-fold selectivity

Results and Discussion :

As can be seen from the data shown in Table 6 above, the compounds of the present invention are potent and selective inhibitors of BACE1.

Claims (15)

A compound of formula (I), or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Where W is CO, CS or CH ₂ ; X is N, NO or CR ₁₀ ; Y is N, NO or CR ₁₁ ; Z may be N, NO or CR ₁₉ , provided that two or less of X, Y or Z may be N or NO; R ₁ and R ₂ are each independently H, COR ₂₀ , CO ₂ R ₂₁ or an optionally substituted C ₁ -C ₄ alkyl group; R ₃ is H, OR ₁₂ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl Or an aryl (C ₁ -C ₆ ) alkyl group; R ₄ and R ₅ are each independently H, halogen, NO ₂ , CN, OR ₁₃ , NR ₁₄ R ₁₅ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ When they are alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl groups, or are bonded to adjacent carbon atoms, R ₄ and R ₅ together with the atoms to which they are attached are selected from O, N or S; Or an optionally substituted 5-7 membered ring optionally containing two heteroatoms; R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₉ are each independently H, halogen, NO ₂ , CN, OR ₁₆ , NR ₁₇ R ₁₈ or each optionally substituted C ₁ -C ₆ An alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl group; n is 0 or 1;

Is a single bond when n is 0, or is a double bond when n is 1; R ₁₂ , R ₁₃ , R ₁₆ , R ₂₀ and R ₂₁ are each independently H or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C _2- A C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl group; R ₁₄ , R ₁₅ , R ₁₇ and R ₁₈ are each independently H or C ₁ -C ₄ alkyl. The compound of claim 1, wherein W is CO. The compound of claim 1 or 2, wherein R ₁ and R ₂ are H and R ₃ is C ₁ -C ₄ alkyl. The compound of any one of claims 1-3, wherein n is 1. 5. The compound according to any one of claims 1 to 4, wherein formula (I) is represented by formula (Ia).

The compound according to any one of claims 1 to 4, wherein formula (I) is represented by formula (Ib).

The compound of claim 6, wherein R ₃ is methyl. 8. The compound of claim 7, wherein Y is CR ₁₁ and R ₁ and R ₂ are H. The method of claim 1, 2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro-4H-already Dazol-4-one; (5S) -2-amino-5- [3- (2-fluoropyridin-3-yl) phenyl] -5- (4-methoxy-3-methylphenyl) -3-methyl-3,5-dihydro -4H-imidazol-4-one; 2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazol-4-one ; (5S) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole -4-one; (5R) -2-amino-5- (4-fluoro-3-pyrimidin-5-ylphenyl) -3-methyl-5- [4- (trifluoromethoxy) phenyl] -3,5-di Hydro-4H-imidazol-4-one; 4- [2-amino-4- (4-methoxy-3-methylphenyl) -1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl] -2-pyridine-3 -Ylbenzonitrile; 2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (4-methyl-3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole- 4-on; 2-amino-5- [4-methoxy-3- (trifluoromethyl) phenyl] -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-already Dazol-4-one; 2-amino-3-ethyl-5- (4-methoxy-3-methylphenyl) -5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrazin-2-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-3-methyl-5- (3-pyrimidin-2-ylphenyl) -5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro-4H-imidazole-4- On; 2-amino-5- (4-hydroxy-3-methylphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5- [4-methoxy-3- (trifluoromethyl) phenyl] -3-methyl-5- (3-pyrazin-2-ylphenyl) -3,5-dihydro-4H-imide Dazol-4-one; (5R) -2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyrimidin-5-ylphenyl) -3,5-dihydro-4H-imidazole -4-one; 2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5- (3,4-diethoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5- (3,4-dimethoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5- (3-cyclopentyl-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On; 2-amino-5- (4-methoxy-3-propoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On; 2-amino-5- (3-butoxy-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On; 2-amino-5- (3-isopropoxy-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4 -On; 2-amino-5- (1,3-benzodioxol-5-yl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4 -On; 2-amino-5- (2,3-dihydro-1-benzofuran-5-yl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H- Imidazol-4-one; 2-amino-5- [3- (cyclopentyloxy) -4-methoxyphenyl] -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole -4-one; 5- [2-amino-1-methyl-5-oxo-4- (3-pyridin-3-ylphenyl) -4,5-dihydro-1H-imidazol-4-yl] -2-methoxybenzo Nitrile; 2-amino-5- (3-fluoro-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On; 2-amino-5- (2,3-dihydro-1,4-benzodioxin-6-yl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro -4H-imidazol-4-one; 2-amino-5- (3-chloro-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazol-4-one ; 2-amino-3-methyl-5- (3-pyridin-3-ylphenyl) -5- (3,4,5-trimethoxyphenyl) -3,5-dihydro-4H-imidazole-4- On; 2-amino-5- (4-methoxy-3-methylphenyl) -3-methyl-5- (3-pyridin-4-ylphenyl) -3,5-dihydro-4H-imidazol-4-one; 2-amino-5- (3-ethoxy-4-methoxyphenyl) -3-methyl-5- (3-pyridin-3-ylphenyl) -3,5-dihydro-4H-imidazole-4- On; 2-amino-3-methyl-5- (3-pyridin-3-ylphenyl) -5- [4- (trifluoromethoxy) phenyl] -3,5-dihydro-4H-imidazol-4-one ; 2-amino-3-methyl-5- (3-pyridin-3-ylphenyl) -5-[(4-trifluoromethoxy-3-trifluoromethyl) phenyl] -3,5-dihydro-4H Imidazol-4-one; 2-amino-5- (3,4-diethoxyphenyl) -5- (4-fluoro-3-pyridin-3-ylphenyl) -3-methyl-3,5-dihydro-4H-imidazole- 4-on; And 2-amino-5- (3-chloro-4-trifluoromethoxyphenyl) -5- (4-fluoro-3-pyridin-3-ylphenyl) -3-methyl-3,5-dihydro-4H A compound selected from the group consisting of imidazol-4-ones, tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof. 10. Treating or preventing a disease or condition characterized by increased β-amyloid deposits or β-amyloid levels in the patient's body, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-9. Or how to improve. The method of claim 10, wherein the disease or condition is Alzheimer's disease; Mild cognitive impairment; Down syndrome; Hereditary cerebral hemorrhage associated with Dutch type amyloidosis; Cerebral amyloid angiopathy; And degenerative dementia. The method of claim 11, wherein the disease is Alzheimer's disease. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 9 and a pharmaceutically acceptable carrier. A process for preparing a compound of formula I, comprising reacting a compound of formula II with a compound of formula III: optionally in the presence of a solvent and in the presence of a palladium catalyst.

(Wherein W is CO, CS or CH ₂ ; X is N, NO or CR ₁₀ ; Y is N, NO or CR ₁₁ ; Z may be N, NO or CR ₁₉ , provided that two or less of X, Y or Z may be N or NO; R ₁ and R ₂ are each independently H, COR ₂₀ , CO ₂ R ₂₁ or an optionally substituted C ₁ -C ₄ alkyl group; R ₃ is H, OR ₁₂ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl Or an aryl (C ₁ -C ₆ ) alkyl group; R ₄ and R ₅ are each independently H, halogen, NO ₂ , CN, OR ₁₃ , NR ₁₄ R ₁₅ or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ When they are alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl groups, or are bonded to adjacent carbon atoms, R ₄ and R ₅ together with the atoms to which they are attached are selected from O, N or S; Or an optionally substituted 5-7 membered ring optionally containing two heteroatoms; R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R ₁₉ are each independently H, halogen, NO ₂ , CN, OR ₁₆ , NR ₁₇ R ₁₈ or each optionally substituted C ₁ -C ₆ An alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl group; n is 0 or 1;

Is a single bond when n is 0, or is a double bond when n is 1; R ₁₂ , R ₁₃ , R ₁₆ , R ₂₀ and R ₂₁ are each independently H or each optionally substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₂ -C ₆ alkenyl, C _2- A C ₆ alkynyl, C ₃ -C ₈ cycloalkyl or aryl group; R ₁₄ , R ₁₅ , R ₁₇ and R ₁₈ are each independently H or C ₁ -C ₄ alkyl.)

(Wherein Hal is Cl or Br and R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as described for Formula I above.)

(Wherein, Q is _{B (OH) 2, Sn (} n. Bu) 3 or _{Sn (CH 3) 3, X} , Y, Z, and R _8, R ₉ and n are as described for Formula Ⅰ .) Use of a compound of any one of claims 1 to 9 in the manufacture of a medicament for treating, preventing or ameliorating a disease or condition characterized by increased β-amyloid deposits or β-amyloid levels in a patient's body.