HK1181755A - 5-amino-3,6-dihydro-1h-pyrazin-2-one derivatives useful as inhibitors of beta-secretase (bace) - Google Patents

Description

5-amino-3, 6-dihydro-1 as inhibitors of beta-secretase (BACE)H-Pyrazin-2-one derivatives

Technical Field

The present invention relates to novel 5-amino-3, 6-dihydro-1H-pyrazin-2-one derivatives as inhibitors of β -secretase (also known as β -site amyloid cleaving enzyme, BACE1, Asp2 or memapsin 2). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions in the prevention and treatment of diseases in which beta-secretase is involved, such as Alzheimer's Disease (AD), mild cognitive impairment, senility, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.

Background

Alzheimer's Disease (AD) is an age-related neurodegenerative disease. AD patients suffer from cognitive impairment and memory loss as well as behavioral problems such as anxiety. More than 90% of people with AD are sporadic cases, while less than 10% are familial or hereditary. About 1 in every 10 persons in the united states at age 65 has AD, and 1 in every 2 persons at age 85. The average life expectancy after initial identification is 7-10 years, and AD patients require expensive ancillary living facilities or close care of their families. AD is an increasingly serious medical problem as the population ages. Current therapies for AD only treat the symptoms of the disease and include acetylcholinesterase inhibitors to improve cognition and anxiolytics and antipsychotics to control behavioral problems associated with the disease.

The standard pathological features in the brain of AD patients are neurofibrillary tangles resulting from hyperphosphorylation of tau (tau) protein and amyloid plaques formed by aggregation of beta-amyloid 1-42 (A.beta.1-42) peptide. A β 1-42 forms oligomers, then fibers, and finally amyloid plaques. Oligomers and fibers are believed to be particularly neurotoxic and may cause most of the neurological damage associated with AD. Drugs that prevent the formation of a β 1-42 have the potential to be disease-modifying drugs for the treatment of AD. A β 1-42 is produced by Amyloid Precursor Protein (APP), which consists of 770 amino acids. The N-terminus of A.beta.1-42 is cleaved by beta-secretase (BACE), and then gamma-secretase cleaves the C-terminus. In addition to A.beta.1-42, gamma-secretase also releases A.beta.1-40 as well as A.beta.1-38 and A.beta.1-43 as the main cleavage products. These a β forms can also aggregate to form oligomers and fibers. Therefore, BACE inhibitors are expected to prevent the formation of A β 1-42 and A β 1-40, A β 1-38, and A β 1-43 and would be potential therapeutic agents for the treatment of AD.

Brief description of the invention

The invention relates to 5-amino-3, 6-dihydro-1H-pyrazin-2-ones of formula (I)

And stereoisomeric forms thereof, wherein

R¹、R²Independently selected from hydrogen, fluoro, cyano, C_1-3Alkyl, mono-and polyhalo-C_1-3Alkyl and C_3-6A cycloalkyl group; or

R¹And R²Taken together with the carbon atoms to which they are attached, may form C_3-6A cycloalkyl-bicyclic ring;

R³、R⁴independently selected from hydrogen, C_1-3Alkyl radical, C_3-6Cycloalkyl, mono-and polyhalo-C_1-3Alkyl, homoaryl (homoaryl) and heteroaryl;

X¹、X²、X³、X⁴independently is C (R)⁵) Or N, with the proviso that no more than two of them represent N; each R⁵Selected from hydrogen, halo, C_1-3Alkyl, mono-and polyhalo-C_1-3Alkyl, cyano, C_1-3Alkoxy, mono-and polyhalo-C_1-3An alkoxy group;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen or C_1-3An alkyl group;

ar is a homoaryl or heteroaryl group;

wherein homoaryl is phenyl or phenyl substituted with one, two or three substituents selected from: halo, cyano, C_1-3Alkyl radical, C_1-3Alkoxy, mono-and polyhalo-C_1-3An alkyl group;

heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, each optionally substituted with one, two, or three substituents selected from: halo, cyano, C_1-3Alkyl radical, C_1-3Alkoxy, mono-and polyhalo-C_1-3An alkyl group;

and addition salts and solvates thereof.

The description of the present invention is exemplified by pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any of the above compounds. The description of the present invention exemplifies a pharmaceutical composition prepared by mixing any of the above compounds with a pharmaceutically acceptable carrier. Illustrative of the invention is a process for preparing a pharmaceutical composition comprising a mixture of any of the above compounds and a pharmaceutically acceptable carrier.

Exemplified herein are methods of treating a disorder mediated by beta-secretase, comprising administering to a subject in need thereof a therapeutically effective amount of any of the above compounds or pharmaceutical compositions.

As another illustration of the invention is a method of inhibiting beta-secretase, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

An example of the invention is a method of treating a condition selected from the group consisting of: alzheimer's disease, mild cognitive impairment, senility, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, preferably Alzheimer's disease, comprising administering to a subject in need thereof a therapeutically effective amount of any of the above compounds or pharmaceutical compositions.

Another example of the invention is any of the above compounds for use in treating the following diseases in a subject in need thereof: (a) alzheimer's disease, (b) mild cognitive impairment, (c) aging, (d) dementia, (e) dementia with Lewy bodies, (f) Down's syndrome, (g) dementia associated with stroke, (h) dementia associated with Parkinson's disease and (i) dementia associated with beta-amyloid.

Detailed Description

The present invention relates to compounds of formula (I) as defined hereinbefore and pharmaceutically acceptable salts thereof. The compounds of formula (I) are inhibitors of beta-secretase, also known as beta-site amyloid cleaving enzyme, BACE1, Asp2 or memapsin2, and are useful in the treatment of alzheimer's disease, mild cognitive impairment, senility, dementia associated with stroke, dementia with lewy bodies, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, preferably alzheimer's disease, mild cognitive impairment or dementia, more preferably alzheimer's disease.

In one embodiment of the invention, R¹And R²Independently selected from hydrogen, fluoro, cyano, and polyhaloC_1-3An alkyl group; or

R¹And R²Taken together with the carbon atoms to which they are attached, may form C_3-6A cycloalkyl-bicyclic ring;

R³is C_1-3An alkyl group;

R⁴is C_1-3An alkyl group;

X¹、X²、X³、X⁴independently is C (R)⁵) Wherein each R⁵Selected from hydrogen and halo;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen;

ar is a homoaryl or heteroaryl group;

wherein the homoaryl is phenyl or phenyl substituted with one or two substituents selected from: halo, cyano, C_1-3Alkyl and C_1-3An alkoxy group;

heteroaryl is selected from pyridyl, pyrimidinyl and pyrazinyl, each optionally substituted with one or two substituents selected from: halo, cyano, C_1-3Alkyl and C_1-3An alkoxy group; or

Addition salts or solvates thereof.

In another embodiment of the invention, R¹And R²Independently selected from hydrogen, fluoro, cyano, and trifluoromethyl; or

R¹And R²Taken together with the carbon atoms to which they are attached, may form C_3-6A cyclopropyl ring;

R³is methyl;

R⁴is methyl;

X¹、X²、X³、X⁴is CH;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen;

ar is a homoaryl or heteroaryl group;

wherein the homoaryl is phenyl or phenyl substituted with one or two substituents selected from: halo and cyano;

heteroaryl is selected from pyridyl, pyrimidinyl and pyrazinyl, each optionally substituted with one or two substituents selected from: chloro, fluoro, cyano, methyl and methoxy; or

Addition salts or solvates thereof.

In another embodiment, R¹、R²Is hydrogen; r³、R⁴Independently methyl or ethyl; x¹And X³Is CH or CF; x²And X⁴Is CH; l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen; ar is heteroaryl; heteroaryl is selected from pyridyl, pyrimidinyl and pyrazinyl, each optionally substituted with chloro, cyano, methyl, methoxy or trifluoromethyl.

In another embodiment, R¹、R²Is hydrogen; r³、R⁴Is methyl; x¹、X²、X³、X⁴Is CH; l is-N (R)⁶) CO-, wherein R⁶Is hydrogen; ar is heteroaryl; heteroaryl being substituted by chloro, cyano, methoxy or trifluoromethylA pyridyl group; pyrimidinyl and pyrazinyl substituted with methyl.

Definition of

"halo" shall mean fluoro, chloro and bromo; "C_1-3Alkyl "shall mean a straight or branched chain saturated alkyl group having 1,2 or 3 carbon atoms, such as methyl, ethyl, 1-propyl and 2-propyl; "C_1-3Alkoxy "shall mean where C is_1-3An ether group whose alkyl group is as defined above; "Mono-and polyhalogenated C_1-3Alkyl "shall mean C as defined above substituted by 1,2, 3 or, if possible, by a plurality of halogen atoms as defined above_1-3An alkyl group; "Mono-and polyhalogenated C_1-3Alkoxy "shall mean in which mono-and polyhalogenated C_1-3An ether group whose alkyl group is as defined above; "C_3-6Cycloalkyl shall mean cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; "C_3-6Cycloalkanediyl "shall mean divalent radicals such as cyclopropanediyl, cyclobutanediyl, cyclopentanediyl and cyclohexanediyl.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder sought to be treated.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

It will be appreciated that certain compounds according to formula (I) and addition salts, hydrates and solvates thereof may contain one or more chiral centres and exist as stereoisomeric forms.

Hereinabove and hereinafter, the term "compound of formula (I)" is intended to include addition salts, solvates and stereoisomers thereof.

The terms "stereoisomer" or "stereochemically isomeric form" are used interchangeably hereinabove and hereinbelow.

The present invention includes all stereoisomers of the compounds of formula (I) as pure stereoisomers or as mixtures of two or more stereoisomers.

Enantiomers are stereoisomers that are mirror images of each other that do not overlap. The 1:1 mixture of the enantiomers in pairs is a racemate or a racemic mixture. Diastereomers (or diastereomers) are stereoisomers of diastereomers, that is, they are not in relative enantiomeric relationship. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Thus, the present invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration of the asymmetric atom is designated as R or S. A resolved compound whose absolute configuration is unknown, depending on the direction in which it rotates plane-polarized light, can be designated (+) or (-).

When a particular stereoisomer is identified, this means that the stereoisomer is essentially free, i.e. has less than 50%, preferably less than 20%, more effectively less than 10%, even more effectively less than 5%, especially less than 2%, and most preferably less than 1% of other isomers. Thus, when a compound of formula (I) is for example designated (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated e.g. as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is designated, for example, as cis, this means that the compound is substantially free of trans isomer.

Furthermore, certain crystalline forms of the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, certain compounds of the present invention may form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are intended to be included within the scope of the present invention.

For pharmaceutical use, salts of the compounds of the present invention refer to non-toxic "pharmaceutically acceptable salts". However, other salts may be useful in preparing the compounds according to the invention or pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts, which may be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands, such as quaternary ammonium salts.

Representative acids that may be used to prepare pharmaceutically acceptable salts include (but are not limited to) the following: acetic acid, 2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+) -camphoric acid, camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, beta-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+) -L-lactic acid, (±) -DL-lactic acid, lactobionic acid, maleic acid, (-) -L-malic acid, Malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (pamoic acid), phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and undeceneAnd (4) acid. Representative bases that may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: ammonia, L-arginine, benzphetamine (benethamine), benzathine (benzathine), calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylenediamine, glycine, alanine, glycine, lysine,N-methyl-glucosamine, hydrabamine, 1HImidazole, L-lysine, magnesium hydroxide, 4- (2-hydroxyethyl) -morpholine, piperazine, potassium hydroxide, 1- (2-hydroxyethyl) -pyrrolidine, secondary amines, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

The chemical names of the compounds of the present invention are generated according to the nomenclature accepted by chemical abstracts.

Certain compounds according to formula (I) may also exist in their tautomeric form. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

Preparation of the Compounds

Experimental procedure 1

The final compound according to formula (I) may be prepared by reacting the intermediate compound of formula (II) with a suitable source of ammonia, such as ammonium chloride or aqueous ammonia, according to reaction scheme (1), in a suitable reaction-inert solvent, such as water or methanol, under thermal conditions, such as heating the reaction mixture at 60 ℃, for example for 6 hours. In reaction scheme (1), all variables are as defined in formula (I):

reaction scheme 1

Experimental procedure 2

Wherein L is-N (R)⁶) The final compound of formula (I-a) of CO-can be obtained by reacting the intermediate compound of formula (III-a) with the compound of formula (IV) according to the reaction scheme (A)2) In a suitable reaction-inert solvent such asN,NIn dimethylformamide, in a suitable base such as K₃PO₄Copper catalysts such as CuI and diamines such as (1)R,2R) - (-) -1, 2-diaminocyclohexane is heated under thermal conditions, for example at 180 ℃ for, for example, 140 minutes under microwave irradiation. In reaction scheme (2), all variables are as defined in formula (I) and W is halo:

reaction scheme 2

Experimental procedure 3

Alternatively, the final compound according to formula (I-a) may be prepared by reacting the intermediate compound of formula (III-b) with the compound of formula (V) according to reaction scheme (3) in a suitable reaction-inert solvent such as dichloromethane in the presence of a suitable base such as triethylamine in the presence of a condensing agent such asO- (7-Azobenzotriazol-1-yl-) -N,N,N ’,N ’Tetramethyluronium hexafluorophosphate [ HATU, CAS 148893-10-1]In the presence of (a) is performed by heating the reaction mixture under thermal conditions, for example at 25 ℃, for example for 2 hours. In reaction scheme (3), all variables are as defined in formula (I):

reaction scheme 3

Experimental procedure 4

Alternatively, the final compound according to formula (I-a) may be prepared by reacting the intermediate compound of formula (III-b) with a compound of formula (VI) according to reaction scheme (4) by heating the reaction mixture under thermal conditions, e.g. at 25 ℃ for e.g. 2 hours in a suitable reaction inert solvent, e.g. dichloromethane, in the presence of a suitable base, e.g. pyridine. In reaction scheme (4), all variables are as defined in formula (I) and Y is halo:

reaction scheme 4

Experimental procedure 5

The final compounds according to formula (I-b) wherein L is a bond can be prepared by reacting the intermediate compound of formula (III-a) with the compound of formula (VII) according to reaction scheme (5) in a suitable reaction-inert solvent such as ethanol or a mixture of reaction-inert solvents such as 1, 2-dimethoxyethane/water/ethanol in a suitable base such as K₃PO₄Or Cs₂CO₃Aqueous solution, Pd-complex catalysts such as [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride [ CAS 72287-26-4 ]]Or trans-bis-dicyclohexyl) palladium diacetate [ DAPCy, CAS 628339-96-8]In the presence of (a) heating the reaction mixture under thermal conditions, for example at 80 ℃ for, for example, 48 hours, or at 130 ℃ for, for example, 10 minutes under microwave irradiation. In reaction scheme (5), all variables are as defined for formula (I) and W is halo. R⁷And R⁸May be hydrogen or alkyl, or may be combined together to form, for example, a group of the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂-a divalent group of:

reaction scheme 5

Many of the intermediates and starting materials in the foregoing preparations are known compounds which can be prepared according to methods known in the art for the preparation of the compounds or analogous compounds, while certain intermediates are novel compounds. Many such methods of preparation are described in more detail below.

Experimental procedure 6

Intermediates according to formula (II) can be prepared according to reaction scheme (6) by reacting an intermediate compound of formula (VIII) with a sulfur donating agent (e.g. phosphorus pentasulfide or 2, 4-bis- (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane (diphosphetane) 2, 4-disulfide [ Lawesson's reagent, CAS 19172-47-5] for the synthesis of thioamides in a reaction inert solvent such as tetrahydrofuran or toluene in the presence of a suitable base such as pyridine under thermal conditions such as heating the reaction mixture at 90 ℃ for e.g. 18 hours. In reaction scheme (6), all variables are as defined in formula (I):

reaction scheme 6

Experimental procedure 7

Intermediates according to formula (VIII) wherein L is a bond can be prepared according to reaction scheme (7) by reacting an intermediate compound of formula (IX-a) with a compound of formula (VII) according to reaction scheme (7) in a suitable mixture of a suitable inert solvent such as 1, 4-dioxane/water, in a suitable base such as Na₂CO₃Aqueous solution, Pd-complex catalyst such as tetrakis- (triphenylphosphine) palladium (0) [ CAS 14221-01-3]In the presence of (a), under thermal conditions, for example at 80 ℃ for, for example, 20 hours, or, for example, at 150 ℃ for, for example, 15 minutes under microwave irradiation. In reaction scheme (7), all variables are as defined for formula (I) and W is halo. R⁷And R⁸May be hydrogen or alkyl, or may be combined together to form, for example, a group of the formula-CH₂CH₂-、-CH₂CH₂CH₂-or-C (CH)₃)₂C(CH₃)₂-a divalent group of:

reaction scheme 7

Experimental procedure 8

The intermediate compounds of formulae (III-a), (III-b) and (III-c) can be prepared generally according to the reaction procedures shown in the following reaction schemes (8) and (9):

reaction scheme 8

A: methoxyimine-to-amidine conversion

B: thioamide-to-amidine conversion

C: amide-to-methoxyimine conversion

D: amide-to-thioamide conversion (sulfurization)

E: nitro-to-amino reduction

The intermediate compounds of formulae (III-a), (III-B), and (III-c) in reaction scheme (8) above can be prepared from the corresponding intermediate compounds of formulae (XI-a), (XI-B), and (XI-c) according to thioamide-to-amidine conversion procedures known in the art (reaction step B), or alternatively, for the intermediate compounds of formulae (III-a) and (III-c), from the corresponding intermediate compounds of formulae (X-a) and (X-c) according to methoxyimine-to-amidine conversion procedures known in the art (reaction step A). The conversion is conveniently carried out by treating the corresponding intermediate compounds of formulae (XI-a), (XI-b) and (XI-c) or (X-a) and (X-c) with an ammonia source, for example ammonium chloride or aqueous ammonia, in a suitable reaction-inert solvent, for example water or methanol and the like, and heating the reaction mixture under thermal conditions, for example at 70 ℃ to 85 ℃ for, for example, 6 to 18 hours.

Further, the intermediate compound of the formula (III-b) in the above reaction scheme (8), wherein R⁶= H, may be prepared from the corresponding intermediate compound of formula (III-c) according to nitro-to-amino reduction procedure known in the art (reaction step E). The reduction may conveniently be carried out according to catalytic hydrogenation procedures known in the art. For example, the reduction may be carried out by stirring the reactants under a hydrogen atmosphere in the presence of a suitable catalyst, such as palladium on carbon, platinum on carbon, raney nickel, and the like. Suitable solvents are, for example, water, alkanols (e.g. methanol, ethanol, etc.), esters (e.g. ethyl acetate, etc.). In order to increase the rate of the reduction reaction, it may be advantageous to increase the temperature and/or the pressure of the reaction mixture. Undesirable further hydrogenation of certain functional groups in the reactants and reaction products can be prevented by adding catalyst poisons, such as thiophenes and the like, to the reaction mixture.

In the above reaction scheme (8), the intermediate compounds of formulae (X-a) and (X-C) can be prepared from the corresponding intermediate compounds of formulae (IX-a) and (IX-C) according to amide-to-methoxyimine conversion procedures known in the art (reaction step C). The conversion may conveniently be carried out by treating the corresponding intermediate compounds of the formulae (IX-a) and (IX-c) in a suitable reaction-inert solvent, such as dichloromethane, at an appropriate elevated temperature, such as 25 ℃, for example for 60 hours.

The thioamide derivatives of formulae (XI-a), (XI-b) and (XI-c) in the above reaction scheme (8) can be prepared from the amide derivatives of formulae (IX-a), (IX-b) and (IX-c) according to a sulfurization procedure known in the art (reaction step D). The conversion may conveniently be carried out by treating the amide with a sulfurizing agent such as phosphorus pentasulfide or 2, 4-bis- (4-methoxyphenyl) -1, 3-dithia-2, 4-diphosphetane 2, 4-disulfide [ Lawesson's reagent, CAS 19172-47-5] in the presence of a suitable base such as pyridine in a reaction-inert solvent such as tetrahydrofuran or toluene, heating the reaction mixture under thermal conditions, for example at 90 ℃ for, for example, 18 hours:

reaction scheme 9

F: NDeprotection of

G: Cyclization of

H: NAcylation of

In the above reaction scheme (9), the intermediate according to formula (IX-b) may be prepared by reacting an intermediate compound of formula (IX-d) wherein Z is a protecting group for an amide such asTo pair-methoxybenzyl, according to amines known in the artN-reaction of the deprotection procedure (reaction step F). The above-mentionedNDeprotection may conveniently be carried out by treating the corresponding intermediate compound of formula (IX-d) with a suitable amine functional group deprotecting agent such as ammonium cerium (IV) nitrate in an inert solvent such as a mixture of acetonitrile/water at an appropriate elevated temperature such as 25 ℃ for e.g. 4 hours.

In the above reaction scheme (9), intermediates according to formulae (IX-a), (IX-c) and (IX-d) can be prepared by reaction of intermediate compounds of formulae (XII-a), (XII-c) and (XII-d) according to a cyclization procedure known in the art (reaction step G). The cyclisation is conveniently carried out by treating the corresponding intermediate compounds of formulae (XII-a), (XII-c) and (XII-d) with an intermediate compound of formula (XIII). The reaction is carried out in a suitable reaction-inert solvent, such as ethanol, under thermal conditions, such as at 70 ℃, with the reaction mixture being heated, for example, for 3 hours. In reaction scheme (9), all variables are as defined in formula (I), halo is chloro or bromo and C of Alk_1-3An alkyl group.

In the above reaction scheme (9), according to the formulae (XII-a), (XII-c) and (XII-d)Intermediates can be prepared by reacting intermediate compounds of formula (XIV-a), (XIV-c) and (XIV-d) according to methods known in the artNThe acylation procedure (reaction step H). The above-mentionedNAcylation may conveniently be carried out by treating the corresponding intermediate compounds of formula (XIV-a), (XIV-c) and (XIV-d) with an intermediate compound of formula (XV). The reaction is carried out in a suitable reaction-inert solvent such as dichloromethane in the presence of a suitable base such as triethylamine at low temperature such as 0 ℃ for e.g. 1 hour. In reaction scheme (9), all variables are as defined in formula (I), halo is chloro or bromo and C of Alk_1-3An alkyl group.

Intermediate compounds of formula (XIV-a), (XIV-c) and (XIV-d), wherein Z is suitableNProtecting groups such asTo pair-methoxybenzyl, which can be prepared generally according to the Strecker-type procedure known in the art.

Pharmaceutical composition

The invention also provides compositions for preventing or treating diseases in which inhibition of beta-secretase is beneficial, such as Alzheimer's Disease (AD), mild cognitive impairment, senility, dementia with Lewy bodies, Down's syndrome, dementia associated with stroke, dementia associated with Parkinson's disease and dementia associated with beta-amyloid. The composition comprises a therapeutically effective amount of a compound according to formula (I) and a pharmaceutically acceptable carrier or diluent.

When the active ingredient may be administered alone, it is preferably presented as a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier or diluent. A carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The pharmaceutical compositions of the present invention may be prepared by any method well known in the art of pharmacy. A therapeutically effective amount of a particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably administered in a form suitable (preferably) for systemic administration, e.g., oral, transdermal or parenteral administration; or topical administration, e.g., via inhalation, nasal spray, eye drops, or via a single dosage form of cream, gel, shampoo, etc. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, for example, water, glycerol, oils, alcohols and the like; or in the case of powders, tablets, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed. Because of their ease of administration, tablets and capsules represent the most advantageous oral unit dosage form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients may be included, for example to aid solubility. Injectable solutions may be prepared, for example, where the carrier comprises saline solution, glucose solution, or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally comprises penetration enhancers and/or suitable wetting agents, optionally in combination with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect on the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. These compositions may be administered in a variety of ways, such as transdermal patches, spot-ons or ointments.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. As used herein the specification and claims, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, sachets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, and segregated multiples thereof.

The precise dose and frequency of administration will depend, as is well known to those skilled in the art, on the particular compound of formula (I) used, the particular condition being treated, the severity of the particular condition being treated, the age, weight, sex, range of conditions and general physical condition of the particular patient and other medical treatments which the individual may be carrying out. Furthermore, it is apparent that the effective daily dose may be reduced or increased as assessed by the response of the subject being treated and/or by the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, effectively from 0.1 to 70% by weight, more effectively from 0.1 to 50% by weight of the active ingredient, and from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more effectively from 50 to 99.9% by weight of the pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The compounds of the invention may be used for systemic administration, e.g. oral, transdermal or parenteral administration; or topically, e.g., via inhalation, nasal spray, eye drops, or via cream, gel, shampoo, etc. The compounds are preferably administered orally. As is well known to those skilled in the art, the precise dose and frequency of administration will depend upon the particular compound according to formula (I) being used, the particular condition being treated, the severity of the particular condition being treated, the age, weight, sex, extent and general physical condition of the particular patient and other medical treatments which the individual may be subjected to. Furthermore, it is apparent that the effective daily dose may be reduced or increased as assessed by the response of the subject being treated and/or by the physician prescribing the compounds of the instant invention.

The amount of a compound of formula (I) that can be combined with a carrier material to produce a single dosage form will vary depending upon the disease being treated, the species of mammal, and the particular mode of administration. In general, however, a suitable unit dose of a compound of the invention may, for example (preferably), contain between 0.1 mg and about 1000 mg of active compound. Preferred unit doses are between 1 mg to about 500 mg. More preferred unit doses are between 1 mg to about 300 mg. Even more preferred unit doses are between 1 mg to about 100 mg. The unit dose may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times a day, so that the total dose for a 70 kg adult is in the range of 0.001 to about 15 mg per administration per kg body weight of the patient. The preferred dose per administration is 0.01 to about 1.5 mg per kg body weight of the patient, and such therapy may last for weeks or months, and in some cases years. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed; the age, weight, general health, sex, and diet of the individual being treated; the number and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the particular disease being treated.

Typical doses may be in the form of a1 mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day or multiple times a day, or a time-release capsule or tablet taken once a day and containing a relatively high proportion of the active ingredient. The time-release effect can be achieved by a capsule substance that dissolves at different pH values, a capsule that slowly releases using osmotic pressure, or by any other known controlled release method.

As will be appreciated by those skilled in the art, dosages outside of these ranges may be required in some instances. Further, note that in connection with the individual patient's response, the clinician or attending physician will know how and when to initiate, discontinue, adjust or terminate therapy.

With respect to the compositions, methods, and kits provided above, those skilled in the art will appreciate that the preferred compounds for individual use are those indicated as being preferred above. Further preferred compounds for use in the compositions, methods and kits are those provided in the non-limiting examples below.

Experimental part

Hereinafter, the term "m.p." means melting point, "THF" means tetrahydrofuran, "DMF" means dimethylformamide, "DCM" means dichloromethane, "AcOEt" means ethyl acetate, "AcOH" means acetic acid, "MeOH" means methanol, "rac" means racemic.

A. Preparation of intermediates

Example A1

Preparation ofIntermediates 1: rac-2-amino-2- (3-bromo-phenyl) -propionitrile

Trimethylcyanosilane (25.+ -2 mL, 201 mmol) was added to stirred 3-bromoacetophenone (25 g, 125.6 mmol) and NH₄NH of Cl (13.4 g, 251.2 mmol)₃In MeOH (500 mL). The mixture was stirred at room temperature for 4 days. The solvent was then evaporated in vacuo and the residue taken up in AcOEt. The solid was filtered off and the solvent was evaporated in vacuo to yieldIntermediates 1(26 g, 92% yield) was used in the next step without further purification.

Example A2

Preparation ofIntermediates 2: rac-2-amino-2- (3-bromo-phenyl) -propionic acid

Will be provided withIntermediates 1(26 g, 115.5 mmol) was dissolved in 6N HCl (139 mL) and the mixture was refluxed for 18 h. Cooling to room temperatureThereafter, the solvent was evaporated in vacuo to giveIntermediates 2(24 g, 85% yield) was used in the next step without further purification.

Example A3

Preparation ofIntermediates 3: rac-2-amino-2- (3-bromo-phenyl) -propionic acid methyl ester

Thionyl chloride (8.97 mL, 122.9 mmol) was added dropwise to the stirred solution at 0 deg.CIntermediates 2(10 g, 41 mmol) in MeOH (125 mL). The mixture was then refluxed for 18 hours. The solvent was evaporated in vacuo and the residue partitioned with Na₂CO₃Saturated aqueous solution and DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt 0/100-30/70 in DCM). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 3(4.1 g, 39% yield) as a colorless oil.

Examples A4

IntermediatesPreparation of 4 : 2-(3- Bromination - Phenyl radical )-2-(2- Chloro-substituted phenyl ether - Acetylamino group )- Propionic acid methyl ester

At 0 ℃. Chloroacetyl chloride (0.34 mL, 4.26 mmol) was added dropwise under nitrogenIntermediates 3(1 g, 3.87 mmol) and Et₃N (0.74 mL, 5.81 mmol) in DCM (35 mL) was stirred. The mixture was stirred at 0 ℃ for 1 hour. The mixture was then diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtering and vacuum evaporating the solvent to obtainIntermediates 4(1.3 g, 89% yield). It was used in the next step without further purification.

Examples A5

IntermediatesPreparation of 5 : racemic modification -3-(3- Bromination - Phenyl radical )-1,3- Dimethyl group - Piperazine derivatives -2,5- Diketones

A33% solution of methylamine in EtOH (5.36 mL, 43.04 mmol) was added to a sealed tube at room temperatureIntermediates 4(2.4 g, 7.17 mmol) in EtOH (53 mL) was stirred. Then, the mixture was stirred at 70 ℃ for 3 hours. Evaporating the solvent in vacuo to yieldIntermediates 5(1.95 g, 88% yield). It was used in the next step without further purification.

Examples A6

IntermediatesPreparation of 6 : racemic modification -1,3- Dimethyl group -3-(3- Pyrimidines -5- Base of - Phenyl radical )- Piperazine derivatives -2,5- Diketones

Tetrakis (triphenylphosphine) palladium (0) (0.023 g, 0.020 mmol) was added at room temperatureIntermediates 51, 4-dioxane (18 mL) (0.3 g, 1.01 mmol) and pyrimidine-5-boronic acid (0.25 g, 2.02 mmol) and Na₂CO₃(saturated aqueous solution) (4 mL) in a stirred suspension. The mixture was stirred for 15 minutes at 150 ℃ under microwave irradiation. The mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-3/97). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 6(0.26 g, 87% yield) as an off-white solid.

Examples A7

IntermediatesPreparation of 7 : racemic modification -1,3- Dimethyl group -3-(3- Pyrimidines -5- Base of - Phenyl radical )-5- Thio group - Piperazine derivatives -2- Ketones

Lawesson's reagent (0.27 g, 0.66 mmol) was added to the reaction mixture at room temperatureIntermediates 6(0.26 g, 0.60 mmol) and pyridine (0.053 mL, 0.66 mmol) in toluene (9 mL). The mixture was stirred at 90 ℃ for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-6/94). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 7(0.17 g, 91% yield) as a white solid.

Examples A8

IntermediatesPreparation of 8 : racemic modification -3-(3- Bromination - Phenyl radical )-5- Methoxy radical -1,3- Dimethyl group -3,6- Dihydro H--1 Pyrazine esters -2- Ketones

Trimethyloxonium tetrafluoroborate (0.87 g, 5.89 mmol) was added to the mixture at room temperatureIntermediates 5(0.5 g, 1.68 mmol) in DCM (10 mL) and the mixture stirred at room temperature for 60 h. The mixture was then cooled to 0 ℃ with ice cold NaHCO₃Diluted (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtering and vacuum evaporating the solvent to obtainIntermediates 8(0.51 g, 71% yield). It was used in the next step without further purification.

Examples A9

IntermediatesPreparation of 9 : racemic modification -5- Amino group -3-(3- Bromination - Phenyl radical )-1,3- Dimethyl group -3,6- Dihydro H--1 Pyrazine esters -2- Ketones

Method A

Ammonium chloride (0.47 g, 8.77 mmol) was added to the contents of a sealed tube at room temperature under nitrogenIntermediates 8(0.45 g, 1.46 mmol) in MeOH (15 mL). The mixture was stirred at 85 ℃ for 18 hours. The solvent was removed in vacuo and the residue Na₂CO₃Diluted (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by ion chromatography using ISOLUTE ^® SCX2 column (eluting first with MeOH and then 7M ammonia in methanol). Collecting the desired fraction eluted with 7M ammonia in methanol and concentrating in vacuo to giveIntermediates 9(0.16 g, 24% yield) as a light brown oil.

Method B

32% aqueous ammonia (15 mL) was addedIntermediates 10(0.48 g, 1.53 mmol) and the mixture was stirred in a sealed tube at 50 ℃ for 18 hours. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtering and vacuum evaporating the solvent to obtainIntermediates 9(0.45 g, quantitative yield). It is used in the next step without further processingAnd (5) purifying.

Examples A10

IntermediatesPreparation of 10 : racemic modification -3-(3- Bromination - Phenyl radical )-1,3- Dimethyl group -5- Thio group - Piperazine derivatives -2- Ketones

Lawesson's reagent (1.63 g, 4.04 mmol) was added to the reaction mixture at room temperatureIntermediates 5(1.04 g, 3.36 mmol) and pyridine (0.30 mL, 3.70 mmol) in toluene (33 mL). The mixture was stirred at 90 ℃ for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (silica gel; MeOH 0/100-4/96 in DCM). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 10(0.5 g, 47% yield) as a colorless oil.

Examples A11

IntermediatesPreparation of 11 : racemic modification -2- Amino group -2-(3- Nitro radical - Phenyl radical )- Propionitrile

Intermediates 11Synthesized following the same method as described in example a 1. Starting from 1- (3-nitro-phenyl) -ethanone (10 g, 60.55 mmol), obtainedIntermediates 11As a yellow solid (10.2 g, 88% yield).

Examples A12

IntermediatesPreparation of 12 : racemic modification -2- Amino group -2-(3- Nitro radical - Phenyl radical )- Propionic acid

At room temperature, mixingIntermediates 11(10.2 g, 53.07 mmol) was added to a 6N HCl solution (79 mL). The mixture was stirred at reflux for 24 hours. After cooling, water (300 mL) and AcOEt (300 mL) were added. The aqueous layer was separated, partially evaporated in vacuo and neutralized by addition of 25% aqueous NaOH. The mixture was cooled in an ice-water bath and the precipitate was filtered off, washed with cold water and then Et₂O washing and drying in vacuum to obtainIntermediates 12(7 g, 63% yield) as a white solid.

Examples A13

IntermediatesPreparation of 13 : racemic modification -2- Amino group -2-(3- Nitro radical - Phenyl radical )- Propionic acid methyl ester

Intermediates 13Synthesized following the same method as described in example a 3. ByIntermediates 12(6 g, 28.55 mmol) to yieldIntermediates 13As a colorless oil (4 g, 63% yield).

Examples A14

IntermediatesPreparation of 14 : 2-(2- Chloro-substituted phenyl ether - Acetylamino group )-2-(3- Nitro radical - Phenyl radical )- Propionic acid methyl ester

Intermediates 14Synthesized following the same method as described in example a 4. ByIntermediates 13(1.65 g, 7.36 mmol) to yieldIntermediates 14 (2.2 g, 99% yield).

Examples A15

IntermediatesPreparation of 15 : racemic modification -1,3- Dimethyl group -3-(3- Nitro radical - Phenyl radical )- Piperazine derivatives -2,5- Diketones

Intermediates 15Synthesized following the same method as described in example a 5. ByIntermediates 14(2.2 g, 7.32 mmol) to yieldIntermediates 15 (1.92 g, quantitative yield).

Examples A16

IntermediatesPreparation of 16 : racemic modification -1,3- Dimethyl group -3-(3- Nitro radical - Phenyl radical )-5- Thio group - Piperazine derivatives -2- Ketones

Intermediates 16Synthesized following the same method as described in example a 10. ByIntermediates 15(1.92 g, 7 mmol) to yieldIntermediates 16As a colorless oil (0.315 g, 16% yield).

Examples A17

IntermediatesPreparation of 17 : racemic modification -5- Amino group -1,3- Dimethyl group -3-(3- Nitro radical - Phenyl radical )-3,6- Dihydro H--1 Pyrazine esters -2- Ketones

32% aqueous ammonia (3 mL) was addedIntermediates 16 (0.315 g, 1.13 mmol) in a 7M solution of ammonia in methanol (3 mL) and the mixture stirred in a sealed tube at 67 ℃ for 4 h. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The residue was purified by flash column chromatography (silica gel; MeOH in DCM 1/99-7/93). The desired fractions were collected and concentrated in vacuo. The residue was again purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 7/93-10/90). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 17(0.11 g, 37% yield).

Examples A18

IntermediatesPreparation of 18 : racemic modification -5- Amino group -3-(3- Amino group - Phenyl radical )-1,3- Dimethyl group -3,6- Dihydro H--1 Pyrazine esters -2- Ketones

Will be provided withIntermediates 17(0.46 g, 1.75 mmol) of EtOH (20 mL) and AcOEt (10 mL) in an H-Cube reactor (1 mL/min, 30 mm Pd/C5% column, all H₂Mode, at room temperature, 1 cycle) hydrogenation. Then, the solvent was evaporated in vacuo to giveIntermediates 18(0.41 g, quantitative yield) as a white solid.

Examples A19

IntermediatesPreparation of 19 : 1-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )- Ethanones

Mixing AlCl₃A mixture of (200 g, 1515.1 mmol) in 1-bromo-2, 4-difluoro-benzene (120 g, 621.79 mmol) was stirred at 60 ℃ for 10 min. Acetyl chloride (73 g, 929.9 mmol) was then added dropwise over 4 hours and the mixture was stirred at 95 ℃ for 6 hours. The mixture was cooled at-10 ℃ and ice (300 g) was added over 1 hour. AcOEt (500 mL) was then added and the separated organic layer was washed with water and dried (Na)₂SO₄) Filtration and concentration in vacuo. The residue was purified by flash column chromatography (silica gel; AcOEt 1/50 in heptane). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 19(60 g, 41% yield).

Examples A20

IntermediatesPreparation of 20 : racemic modification -2- Amino group -2-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )- Propionitrile

Intermediates 20Synthesized following the same method as described in example a 1. ByIntermediates 19(60 g, 255.31 mmol) to obtainIntermediates 20(31 g, 47% yield).

Examples A21

IntermediatesPreparation of 21 Racemic modification -2- Amino group -2-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )- Propionic acid

Will be provided withIntermediates 20A mixture of (28 g, 107.65 mmol) and 6N HCl (300 mL) in AcOH (300 mL) was heated to reflux for 72 h. After cooling to room temperature, the solvent was evaporated in vacuo. AcOEt (400 mL) and water (300 mL) were added. The separated aqueous layer was washed with AcOEt (200 mL). The aqueous layer was separated and adjusted to pH = 7. AcOEt (250 mL) was then added, the organic layer separated and dried (Na)₂SO₄) Filtering and vacuum evaporating the solvent to obtainIntermediate (II)Body 21(22 g, 72% yield).

Examples A22

IntermediatesPreparation of 22 : racemic modification -2- Amino group -2-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )- Propionic acid methyl ester

Will be provided withIntermediates 21A mixture of (22 g, 78.55 mmol) of 4N HCl in MeOH (400 mL) was heated to reflux for 72 h. After cooling to room temperature, the solvent was evaporated in vacuo. AcOEt (400 mL) and water (300 mL) were added. The separated aqueous layer was washed with AcOEt (200 mL). The aqueous layer was separated and adjusted to pH = 7. AcOEt (250 mL) was then added. The organic layer was separated and dried (Na)₂SO₄) Filtering and vacuum evaporating the solvent to obtainIntermediates 22(20 g, 87% yield).

Examples A23

IntermediatesPreparation of 23 : racemic modification -2-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )-2-(2- Chloro-substituted phenyl ether - Acetylamino group )- Propionic acid methyl ester

Intermediates 23Synthesized following the same method as described in example a 4. ByIntermediates 22(4 g, 13.60 mmol) to yieldIntermediates 23 (5 g, 99% yield).

Examples A24

IntermediatesPreparation of 24 : racemic modification -2-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )-2-(2- Ethylamino group - Acetylamino group )- Propionic acid methyl ester

A solution of ethylamine 2M in THF (4.05 mL, 8.1 mmol) was added to the reaction mixture in a sealed tube at room temperatureIntermediates 23(1 g, 2.7 mmol) in EtOH (12 mL) was stirred. Then, the mixture was stirred at 70 ℃ for 3 hours. Evaporating the solvent in vacuo to yieldIntermediates 24(0.55 g, 54% yield). It was used in the next step without further purification.

Examples A25

IntermediatesPreparation of 25 : racemic modification -3-(5- Bromination -2,4- Difluoro (F) - Phenyl radical )-1- Ethyl radical -3- Methyl radical - Piperazine derivatives -2,5- Diketones

AcOH (0.5 mL) was added to the reaction mixture in a sealed tube at room temperatureIntermediates 24(0.55 g, 1.45 mmol) in EtOH (25 mL) in a stirred solution. The mixture was stirred at 95 ℃ for 16 hours. Then, with Na₂CO₃The mixture was diluted (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-2/98). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 25(0.33 g, 66% yield).

Examples A26

IntermediatesPreparation of 26 : racemic modification -3-[2,4- Difluoro (F) -5-(5- Methoxy radical - Pyridine compound -3- Base of )- Phenyl radical ]-1- Ethyl radical -3- Methyl radical - Piperazine derivatives -2,5- Diketones

Tetrakis (triphenylphosphine) palladium (0) (0.022 g, 0.019mmol) was added at room temperatureIntermediates 25(0.33 g, 0.95 mmol) and 3-methoxy-5-pyridineboronic acid (0.19 g, 1.24 mmol) in 1, 4-dioxane (12 mL) and Na₂CO₃(saturated aqueous solution) (4 mL). The mixture was stirred for 15 minutes at 150 ℃ under microwave irradiation. With NaHCO₃The mixture was diluted (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; MeOH in DCM 0/100-11/89). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 26(0.26 g, 73% yield) as a colorless oil.

Examples A27

IntermediatesPreparation of 27 : racemic modification -3-[2,4- Difluoro (F) -5-(5- Methoxy radical - Pyridine compound -3- Base of )- Phenyl radical ]-1- Ethyl radical -3- Methyl radical -5- Thio group - Piperazine derivatives -2- Ketones

Lawesson's reagent (0.23 g, 0.57 mmol) was added to the reaction mixture at room temperatureIntermediates 26(0.26 g, 0.47 mmol) and pyridine (0.046 mL, 0.57 mmol) in toluene (9 mL). The mixture was stirred at 90 ℃ for 18 hours. Then, more Lawesson's reagent (0.23 g,0.57 mmol) and the resulting mixture is heated at 85 ℃ for 8 hours. Then, more Lawesson's reagent (0.30 g, 0.75 mmol) was added and the resulting mixture was heated at 85 ℃ for 16 h. With Na₂CO₃The mixture was diluted (saturated aqueous solution) and extracted with AcOEt. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; MeOH in DCM 0/100-6/94). Collecting the desired fractions and concentrating in vacuo to obtainIntermediates 27(0.14 g, 76% yield).

B. Preparation of the final Compound

Examples B1

Compound (I)Preparation of 1 : racemic modification -5- Amino group -1,3- Dimethyl group -3-(3- Pyrimidines -5- Base of - Phenyl radical )-3,6- Dihydro H--1 Pyrazine esters -2- Ketones

32% aqueous ammonia (2 mL) was addedIntermediates 7(0.17 g, 0.54 mmol) and stirred in a sealed tube at 65 ℃ for 2 hours and then at 70 ℃ for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-6/94). Collecting the desired fraction and subjecting it to vacuumConcentrating to obtainCompound (I) 1(0.09 g, 56% yield) as a white solid.

Examples B2

Compound (I)Preparation of 2 : racemic modification -5- Amino group -3-[3-(5- Methoxy radical - Pyridine compound -3- Base of )- Phenyl radical ]-1,3- Dimethyl group -3,6- Dihydro H--1 Pyrazine esters -2- Ketones

EtOH (3 mL) was added toIntermediates 9 (0.16 g, 0.35 mmol), trans-bis (dicyclohexylamine) palladium diacetate [ DAPCy, CAS 628339-96-8](0.021 g, 0.035 mmol), potassium phosphate (0.22 g, 1.05 mmol) and 3-methoxy-5-pyridine-boronic acid pinacol ester (0.12 g, 0.53 mmol). The mixture was stirred at 80 ℃ for 48 hours. After cooling, water and Na₂CO₃The mixture was diluted (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-7/93). The desired fractions were collected and concentrated in vacuo and the crude product purified again by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-7/93). Collecting the desired fractions and concentrating in vacuo to obtainCompound (I) 2(0.013 g, 11% yield).

Examples B3

Compound (I)Preparation of 3 : racemic modification -5- Chloro-substituted phenyl ether - Pyridine compound -2- Formic acid [3-(6- Amino group -2,4- Dimethyl group -3- Oxo radical -2,3,4,5- Tetrahydro-alkanes - Pyrazine esters -2- Base of )- Phenyl radical ]- Amides of carboxylic acids

Method A

Trans-1, 2-diaminocyclohexane (0.002 g, 0.018 mmol) was added to a sealed tube at room temperature under nitrogenIntermediates 9 (0.052 g, 0.176 mmol), copper (I) iodide (0.002 g, 0.009 mmol), 5-chloro-2-pyridinecarboxamide (0.028 g, 0.176 mmol) and tripotassium phosphate (0.075 g, 0.351 mmol) in DMF (1 mL) in a stirred suspension. The mixture was stirred for 140 minutes under microwave irradiation at 180 ℃. By NH₄The mixture was diluted with Cl (saturated aqueous solution) and extracted with DCM. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica gel; 7M ammonia in methanol in DCM 0/100-1/99). Collecting the desired fractions and concentrating in vacuo to obtainCompound (I) 3(0.004 g, 6% yield).

Method B

At room temperature, 5-chloro-2-pyridinecarboxylic acid (0.234 g, 1.485 mmol) was addedIntermediates 18(0.3 g, 1.292 mmol) in DCM (13 mL). Then, add inN,N-dimethylaniline (0.21 mL, 1.679 mmol), stirred at room temperature for 5 min, and HATU (0.54 g, 1.421 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product was purified by flash column chromatography (silica; methanol in DCM 0/100-10/90). Collecting the desired fractions and concentrating in vacuo to obtainCompound (I) 3(0.294 g, 61% yield).

Examples B4

Compound (I)Preparation of 4 : (S*)-5- Chloro-substituted phenyl ether - Pyridine compound -2- Formic acid [3-(6- Amino group -2,4- Dimethyl group -3- Oxo radical -2,3,4,5- Tetrahydro-alkanes - Pyrazine esters -2- Base of )- Phenyl radical ]- Compound (I)Amides and 5 (R*)-5- chloro-substituted phenyl ether - Pyridine compound -2- Formic acid [3-(6- Amino group -2,4- Dimethyl group -3- Oxo radical -2,3,4,5- Tetrahydro-alkanes - Pyrazine esters -2- Base of )- Phenyl radical ]- Amides of carboxylic acids

By using in Chiralcel^®OD-H (5 μm 250X 20 mm) by preparative SFCCompound (I) 3A sample (294 mg) was separated into the corresponding enantiomer, the mobile phase (0.3% isopropyl-amine, 60% CO)₂40% EtOH/iPrOH 50/50 v/v mixture) to giveCompound (I) 4(0.11 g) andcompound (I) 5(0.15 g). This final derivative was purified again by flash column chromatography (silica; 0.5% NH)₄OH, 95% DCM, 5% EtOH) to give pure productCompound (I) 5 (0.09 g)。

Examples B5

Compound (I)Preparation of 6 : racemic modification -5- Methyl radical - Pyrazine esters -2- Formic acid [3-(6- Amino group -2,4- Dimethyl group -3- Oxo radical -2,3,4,5- Tetrahydro-alkanes - Pyrazine esters -2- Base of )- Phenyl radical ]- Amides of carboxylic acids

5-methylpyrazine-2-carboxylic acid (0.014 g, 0.104 mmol) was added at room temperatureIntermediates 18(0.021 g, 0.09 mmol) in DCM (1.5 mL). Then, pyridine (0.01 mL, 0.118 mmol) was added, and after stirring at room temperature for 5 minutes, HATU (0.038 g, 0.099 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo. The crude product is purified by fast column chromatographyAnd reacted (silica gel; MeOH in DCM 0/100-10/90). The desired fractions were collected and concentrated in vacuo. The residue was again purified by flash column chromatography (silica gel; solid injection; 7M ammonia in methanol in DCM 0/100-2/98). Collecting the desired fractions and concentrating in vacuo to obtainCompound (I) 6(0.009 g, 28% yield).

Examples B6

Compound (I)Preparation of 9 : racemic modification -5- Amino group -3-[2,4- Difluoro (F) -5-(5- Methoxy radical - Pyridine compound -3- Base of )- Phenyl radical ]-1- Ethyl radical -3- Methyl radical -3,6- Dihydro H--1 Pyrazine esters -2- Ketones

32% aqueous ammonia (8 mL) was addedIntermediates 27(0.14 g, 0.36 mmol) in a solution of 7M ammonia in methanol (4 mL) and the mixture stirred in a sealed tube at 65 ℃ for 3 h. After cooling to room temperature, the mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtration and evaporation of the solvent in vacuo gave compound 9 (0.12 g, 90% yield) as a white solid.

Watch (A) 1

C. Analysis section

LCMS

For (LC) MS-profiling of the compounds of the invention, the following procedure was used.

General procedure A

UPLC (ultra performance liquid chromatography) measurements were performed using an Acquity UPLC (Waters) system comprising a sample manager, a binary pump with degasser, a four-column oven, a Diode Array Detector (DAD) and the columns specified in each method. The MS detector was configured with an ESCI dual ionization source (electrospray coupled with atmospheric pressure chemical ionization). Nitrogen was used as the atomizing gas. The source temperature was maintained at 140 ℃. Data acquisition was performed with MassLynx-Openlynx software.

Method of producing a composite material 1:

In addition to general procedure a: reverse phase UPLC was performed at 50 ℃ on a BEH-C18 column (1.7 μm, 2.1X 50 mm) from Waters at a flow rate of 1.0 ml/min without split flow to the MS detector. The gradient conditions used were: 95% A (0.5 g/l ammonium acetate solution +5% acetonitrile), 5% B (acetonitrile) to 40% A, 60% B in 3.8 min, to 5% A, 95% B in 4.6 min, held for 5.0 min. The injection amount was 2. mu.l. Low resolution mass spectra (single quadrupole, SQD detector) were acquired using an interchannel delay time of 0.08 seconds, scanning from 100 to 1000 in 0.1 seconds. The capillary needle voltage was 3 kV. The cone voltages for the positive and negative ionization modes were 25V and 30V, respectively.

General procedure B:

LC measurements were performed using a UPLC (ultra performance liquid chromatography) acquity (waters) system comprising a binary pump with degasser, an autosampler, a Diode Array Detector (DAD) and a column specified in each of the following methods, the column being maintained at a temperature of 40 ℃. The flow is carried from the column to the MS detector. The MS detector was configured with an electrospray ionization source. The capillary needle voltage was 3 kV and the source temperature was maintained at 130 ℃ on a Quattro (Waters triple quadrupole mass spectrometer). Nitrogen was used as the atomizing gas. Data acquisition was performed with MassLynx-Openlynx software (Waters).

Method of producing a composite material 2:

Except for general procedure B: reverse phase UPLC was performed on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) Phenyl-Hexyl column (1.7 μm, 2.1 x 100 mm) at a flow rate of 0.343 ml/min. Gradient conditions were carried out using two mobile phases (mobile phase A: 95% 7mM ammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile): from 84.2% a and 15.8% B (hold 0.49 min) to 10.5% a and 89.5% B in 2.18 min, hold 1.94 min, and return to the initial condition in 0.73 min, hold 0.73 min. A2 ml injection volume was used. The cone voltage for both the positive and negative ionization modes was 20V. Mass spectra were acquired using an intermediate scan delay time of 0.1 seconds, scanning from 100 to 1000 in 0.2 seconds.

Melting Point

The values are either peak or melting ranges, and the resulting values have experimental uncertainties, which are typically associated with analytical methods.

Mettler FP 81HT/FP90 device (as indicated by FP90 in Table 2)

For many compounds, melting points were determined on an open capillary on a Mettler FP 81HT/FP90 apparatus. Melting points are measured with a temperature gradient of 1,3, 5 or 10 ℃/min. The maximum temperature was 300 ℃. Melting points were read from a digital display.

Watch (A) 2 : analytical data-R_tMeaning the retention time (in minutes), [ M + H]⁺Refers to the protonated mass of the compound, and the method refers to the method used for (LC) MS;

n.d. means not determined

SFCMS

General procedure

SFC measurements were performed using the Berger Instruments Inc. (Newark, DE, USA) analytical SFC system, which includes delivery of carbon dioxide (CO)₂) FCM-1200 binary pump fluid control module) and regulator, CTC analytical automatic liquid sampler, TCM-20000 thermal control module for heating the column from room temperature to 80 ℃. An Agilent 1100 UV diode array detector equipped with a high pressure flow cell withstanding up to 400 bar was used. The liquid flow was split by the column to the MS spectrometer. The MS detector was equipped with an atmospheric pressure ionizing ionization source. The ionization parameters for the Waters ZQ mass spectra were: corona current: 9 mua, source temperature: 140 ℃, taper hole: 30V, probe temperature 450 ℃, extractor 3V, desolventizing gas 400L/hr, and taper hole gas 70L/hr. Nitrogen was used as the atomizing gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data System.

Method of producing a composite material 1:

In addition to the general procedure: chiral separation of SFC from Chiralcel^®OD DAICEL column (10 μm, 4.6X 250 mm) was performed at 35 ℃ at a flow rate of 3.0 ml/min. The mobile phase is CO₂40% ethanol/isopropanol (1/1) (containing 0.3% iPrNH)₂) Hold for 7 minutes.

Watch (A) 3 : analysis of SFC Data-R_tMeaning the retention time (in minutes), [ M + H]⁺Refers to the protonation mass of the compound and the method refers to the method used for (SFC) MS analysis of enantiomerically pure compounds.

Optical rotation :

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with a sodium lamp and are reported as follows: [ alpha ] to]_λ ^tdeg.C (c g/100 mL, solvent).

Watch (A) 4 : analytical data-optical rotation of enantiomerically pure Compound

D. Pharmacological examples

The compounds provided by the present invention are inhibitors of beta-site APP-cleaving enzyme 1(BACE 1). Inhibition of BACE1, an aspartic protease, is believed to be involved in the treatment of Alzheimer's Disease (AD). The production and accumulation of β -amyloid peptide (a β) from β -Amyloid Precursor Protein (APP) is believed to play an important role in the development and progression of AD. A β is produced by the sequential cleavage of Amyloid Precursor Protein (APP) at the N-and C-termini of the A β domain by β -secretase and γ -secretase, respectively.

It is expected that compounds of formula (I) will have substantial utility for BACE1 by virtue of their ability to inhibit enzymatic activity. Inhibitors were tested using biochemical Fluorescence Resonance Energy Transfer (FRET) based assays and the cellular alpha Lisa assay in SKNBE2 cells described below, and the results are shown in tables 5 and 6.

Biochemical engineering FRETAnalysis of

This assay is a Fluorescence Resonance Energy Transfer (FRET) based assay. The substrate for this assay is APP derived from a 13 amino acid peptide containing the "Swedish" Lys-Met/Asn-Leu mutation at the β -secretase cleavage site of the Amyloid Precursor Protein (APP). This material also contains two fluorophores: (7-methoxycoumarin-4-yl) acetic acid (Mca) is a fluorescence donor with an excitation wavelength at 320 nm and an emission wavelength at 405 nm, and 2, 4-dinitrophenyl (Dnp) is a proprietary quencher acceptor. The distance between these two groups is chosen so that the donor fluorescence energy is significantly quenched by the acceptor by resonance energy transfer, depending on the excitation light. Once cleaved by BACE1, the fluorophore Mca is separated from the quencher group Dnp, allowing recovery of the full fluorescent production of the donor. The increase in fluorescence is linearly related to the rate of proteolysis.

Briefly, recombinant BACE1 protein at a final concentration of 1. mu.g/ml 384-well format plates was incubated at room temperature for 120 min in the presence or absence of compound in a10 μm matrix of incubation buffer (40 mM citrate buffer pH 5.0, 0.04% PEG, 4% DMSO). The amount of proteolysis (excitation at 320 nm and emission at 405 nm) was then measured directly by fluorescence measurement at T =0 and T = 120. The results are expressed as RFU (relative fluorescence units) as the difference between T120 and T0.

The best curve was fitted as a plot of% Controlmin versus compound concentration by the least squares sum method. Thus, an IC can be obtained₅₀Value (inhibitory concentration causing 50% inhibitory activity).

LC = median of low control values

= low control: enzyme-free reactions

HC = median of high control values

= high control: reactions containing enzymes

% effect =100- [ (sample-LC)/(HC-LC) × 100]

% control = (sample/HC) × 100

% Controlmin = (sample-LC)/(HC-LC) × 100

The following exemplified compounds were tested essentially as described above and had the following activities:

watch (A) 5

SKNBE2 Cell alpha of a cell Lisa Analysis of

Two α Lisa assays were used to quantify the amount of total a β and a β 1-42 produced and secreted in the culture medium of human neuroblastoma SKNBE2 cells. This assay is based on the human neuroblastoma SKNBE2 expressing the wild-type amyloid precursor protein (hAPP 695). Compounds were diluted and added to these cells, cultured for 18 hours, and then a β 1-42 and total a β were measured. Total A β and A β 1-42 were measured as a sandwich α Lisa. α Lisa is a sandwich assay using biotinylated antibody AbN/25 attached to streptavidin coated beads and antibody Ab4G8 or cAb42/26 attached to acceptor beads for detection of total A β and A β 1-42, respectively. In the presence of total A β and A β 1-42, the beads will be in close proximity. Excitation of the donor beads initiates release of singlet oxygen molecules that initiate an energy transfer cascade in the acceptor beads, resulting in light emission. Light emission (excitation at 650 nm and emission at 615 nm) was measured after 1 hour of incubation.

The best curve was fitted as a plot of the sum of the squares least squares and% Controlmin versus compound concentration. Thus, an IC can be obtained₅₀Value (inhibitory concentration causing 50% inhibition of activity).

LC = median of low control values

= low control: cells were pre-cultured in compound-free, biotinylated Ab-free alpha Lisa

HC = median of high control values

= high control: cells were precultured in the absence of compound

% effect =100- [ (sample-LC)/(HC-LC) × 100]

% control = (sample/HC) × 100

% Controlmin = (sample-LC)/(HC-LC) × 100

The following exemplified compounds were tested essentially as described above and showed the following activities:

watch (A) 6

。

Claims (9)

1. A compound of formula (I)

And stereoisomeric forms thereof, wherein

R¹、R²Independently selected from hydrogen, fluoro, cyano, C_1-3Alkyl, mono-and polyhalo-C_1-3Alkyl and C_3-6A cycloalkyl group; or

R¹And R²Taken together with the carbon atoms to which they are attached, may form C_3-6A cycloalkyl-bicyclic ring;

R³、R⁴independently selected from hydrogen, C_1-3Alkyl radical, C_3-6Cycloalkyl, mono-and polyhalo-C_1-3Alkyl, homoaryl and heteroaryl;

X¹、X²、X³、X⁴independently is C (R)⁵) Or N, with the proviso that no more than two of them represent N; each R⁵Selected from hydrogen, halo, C_1-3Alkyl, mono-and polyhalo-C_1-3Alkyl, cyano, C_1-3Alkoxy, mono-and polyhalo-C_1-3An alkoxy group;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen or C_1-3An alkyl group;

ar is a homoaryl or heteroaryl group;

wherein homoaryl is phenyl or phenyl substituted with one, two or three substituents selected from: halo, cyano, C_1-3Alkyl radical, C_1-3Alkoxy, mono-and polyhalo-C_1-3An alkyl group;

heteroaryl is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl, each optionally substituted with one, two, or three substituents selected from: halo, cyano, C_1-3Alkyl radical, C_1-3Alkoxy, mono-and polyhalo-C_1-3An alkyl group; or

Addition salts or solvates thereof.

2. The compound according to claim 1, wherein

R¹And R²Independently selected from hydrogen, fluoro, cyano, and polyhaloC_1-3An alkyl group; or

R¹And R²Taken together with the carbon atoms to which they are attached, may form C_3-6A cycloalkyl-bicyclic ring;

R³is C_1-3An alkyl group;

R⁴is C_1-3An alkyl group;

X¹、X²、X³、X⁴independently is C (R)⁵) Wherein each R⁵Selected from hydrogen and halo;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen;

ar is a homoaryl or heteroaryl group;

wherein the homoaryl is phenyl or phenyl substituted with one or two substituents selected from: halo, cyano, C_1-3Alkyl and C_1-3An alkoxy group;

heteroaryl is selected from pyridyl, pyrimidinyl and pyrazinyl, each optionally substituted with one or two substituents selected from: halo, cyano, C_1-3Alkyl and C_1-3An alkoxy group; or

Addition salts or solvates thereof.

3. The compound according to claim 1, wherein

R¹And R²Independently selected from hydrogen, fluoro, cyano, and trifluoromethyl; or R¹And R²Taken together with the carbon atoms to which they are attached, may form C_3-6A cyclopropyl ring;

R³is methyl;

R⁴is methyl;

X¹、X²、X³、X⁴is CH;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen;

ar is a homoaryl or heteroaryl group;

wherein the homoaryl is phenyl or phenyl substituted with one or two substituents selected from: halo and cyano;

heteroaryl is selected from pyridyl, pyrimidinyl and pyrazinyl, each optionally substituted with one or two substituents selected from: chloro, fluoro, cyano, methyl and methoxy; or

Addition salts or solvates thereof.

4. The compound according to claim 1, wherein

R¹、R²Is hydrogen;

R³、R⁴independently methyl or ethyl;

X¹and X³Is CH or CF;

X²and X⁴Is CH;

l is a bond or-N (R)⁶) CO-, wherein R⁶Is hydrogen;

ar is heteroaryl;

heteroaryl is selected from pyridyl, pyrimidinyl and pyrazinyl, each optionally substituted with chloro, cyano, methyl, methoxy or trifluoromethyl.

5. The compound according to claim 1, wherein

R¹、R²Is hydrogen;

R³、R⁴is methyl;

X¹、X²、X³、X⁴is CH;

l is-N (R)⁶) CO-, wherein R⁶Is hydrogen;

ar is heteroaryl;

heteroaryl is pyridyl substituted with chloro, cyano, methoxy or trifluoromethyl; pyrimidinyl and pyrazinyl substituted with methyl.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 5 and a pharmaceutically acceptable carrier.

7. A process for the preparation of a pharmaceutical composition as defined in claim 6, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in any one of claims 1 to 5.

8. A compound as defined in any one of claims 1 to 5 for use in the treatment, prevention or prophylaxis of Alzheimer's Disease (AD), mild cognitive impairment, senility, dementia with lewy bodies, down's syndrome, dementia associated with stroke, dementia associated with parkinson's disease or dementia associated with beta-amyloid.

9. A method of treatment selected from alzheimer's disease, mild cognitive impairment, senility, dementia with lewy bodies, down's syndrome, dementia associated with stroke, dementia associated with parkinson's disease and dementia associated with beta amyloid, which comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 5 or a pharmaceutical composition as defined in claim 6.