UA76491C2 - Cyclohexyl sulphones - Google Patents

Abstract

Novel sulphones of formula I are disclosed. The compounds modulate the processing of amyloid precursor protein by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease. (I)

Description

Description of the invention

This invention relates to a new class of compounds, their salts, pharmaceutical compositions containing them, 2 methods of their preparation and use in the therapy of the human body. In particular, the invention relates to new sulfones that modulate APP processing under the action of γ-secretase and are therefore useful in the treatment or prevention of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia. Although this disease is primarily a disease of the elderly, affecting up to 1,095 of the population over the age of 65, AO also affects a significant number of 70 younger patients with a genetic predisposition. AI is a neurodegenerative disease clinically characterized by progressive loss of memory and cognitive function and pathologically characterized by the deposition of extracellular protein plaques in the cortical and associative areas of the brain of people suffering from this disease. These plaques mainly include fibrillar aggregates of p-amyloid peptide (Ar). The role of secretases, including the putative y-secretase, in the processing of amyloid precursor protein (APP) with the formation of AD is well described in the literature, a review of the literature about it is given, for example, in UMO 01/70677.

There are relatively few reports in the literature of compounds with inhibitory activity against γ-secretase as measured in a cell-based assay. The review is given in UMO 01/70677. Many of the relevant compounds are peptides or peptide derivatives.

The present invention relates to a new class of non-peptide compounds useful in treatment or prevention

AO by modulating the processing of APP under the influence of the putative γ-secretase, thus suppressing the production of Aр.

This invention relates to the compound of formula I:

AKVO 7 KE ee. ШЬ Б ШЧО "y n « "y Ф 35 y y- where: t is equal to 0 or 1; 7 represents SM, О228, СО2822 or СОМ(В 22)";

B" represents H, C. 4-alkyl or OH; "40 B: represents H or C. 4-alkyl; - c Ag! represents phenyl or pyridyl, each of which has 0-3 substituents, regardless selected from halogen, CM, and MO,, CEz, OH, OSR", Su, 6-alkyl or C-1-alkyl, which, optionally, has a substituent selected from halogen, CM,

MO», SE», OH and C..-alkoxy;

Huh? is phenyl, which is substituted by halogen in positions 2 and 5; -I 75 Va represents H, C 1 -alkyl, C 3 -cycloalkyl, C 6 -cycloalkyl-C. 6-alkyl, 6-6-alkenyl, any of which optionally has a substituent selected from halogen, CM, MO, CEz, ОВ?Р, СОН? MSH(B22)", COM(B2U)", Ag and SOAG, me) or ka represents Ag or two K 72 groups together with the nitrogen atom to which they are mutually attached, they can be closed by an M-heterocyclic group having 0 -4 substituents independently selected from 50, -5, halogen, C..4-alkyl, CM,

MO», SEz, OH, C.i.,-Alkoxy, C.i.-Alkoxycarbonyl, SON, amino, C../-alkylamino, di(C.-.4-alkyl)amino, is) carbamoyl, Ag and SOAG; - M V? is H, C 1 -alkyl, C 3 -cycloalkyl, C 6 -cycloalkyl-C. .beta.-alkyl, C.sub.6-alkenyl, any one of which optionally has a substituent selected from halogen, CM, MO", CE3, OH, C-4-Alkoxy, C--Alkoxycarbonyl, SON, amino, C. 4-alkylamino, di(C-4-alkyl)amino, carbamoyl, Ag or COAg, or K?? is Ag or two B 25 groups, together with the nitrogen atom to which they are mutually attached, can close an M-heterocyclic group having 0-4 substituents independently selected from -0, -5, halogen, C4-alkyl, CM, MO», SEz, OH, C..-Alkoxy, about C..a-Alkoxycarbonyl, SON, amino, C..4-alkylamino, di(C..4-alkyl)amino, carbamoyl, Ar and SOAG; co Ag is phenyl or heteroaryl having 0-3 substituents selected from halogen, C 4.4-alkyl, CM, MO», SEZ,

On, C. ,/-Alkoxy, C. ,-Alkoxycarbonyl, amino, C. -Alkylamino, di(C..4-alkyl)amino, carbamoyl, 60 C.4-alkylcarbamoyl and di(C..4-alkyl ) carbamoyl; or a pharmaceutically acceptable salt thereof.

When a symbol occurs more than once in formula I or its substitute, individual such symbols are independent of each other, unless otherwise specified.

The term "C.Y-alkyl" as used herein, where x is an integer greater than 1, refers to 65 straight and branched chain alkyl groups where the number of carbon atoms that make up said alkyl ranges from 1 to x. Specific alkyl groups include methyl, ethyl, n-propyl,

isopropyl and tert-butyl. Names of derivatives such as "C 5.6-alkenyl", "hydroxy-C.4.6-alkyl", "heteroaryl-C..6-alkyl", "Co-6-alkynyl" and "C; 6-6-alkyl" ", must be interpreted in a similar way.

The term "C3-6-cycloalkyl" as used herein refers to a system of non-aromatic monocyclic or /fused bicyclic hydrocarbon rings containing from C to b carbon atoms. Examples of it include cyclopropyl, cyclobutane, cyclopentyl, cyclohexyl and cyclohexenyl.

The term "C3-5-Cycloalkyl-C1-4-6-alkyl" as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The term "M-heterocyclyl" as used herein refers to a cyclic or polycyclic system containing 7/0 to 10 ring atoms selected from C, M, O, and 5, wherein none of the rings comprising the system is aromatic and where at least one ring atom is nitrogen and the bond is through said ring nitrogen atom.

Preferred M-heterocyclyl groups are 4-6 membered monocyclic systems such as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, oxazolidinyl, and thiazolidinyl.

The term "heteroaryl" as used herein refers to a cyclic or polycyclic system containing up to 10 ring atoms selected from C, M, O, and 5, wherein at least one of the rings comprising the system is aromatic and includes , at least one ring atom that differs from carbon. Preferred heteroaryl groups are monocyclic systems containing 5 or b members, such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, triazolyl and thiadiazolyl groups. Further examples of heteroaryl groups include tetrazole, 1,2,4-triazine and 1,3,5-triazine.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, with fluorine and chlorine being preferred.

For use in medicine, the compounds of formula I may preferably be in the form of pharmaceutically acceptable salts, but other salts may be useful in the preparation of the indicated compounds or their pharmaceutically acceptable tri-salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts, such as salts formed with hydrochloric, sulfuric, methanesulfonic, fumaric, maleic, succinic, and) acetic, benzoic, oxalic, citric, tartaric, carbonic, or phosphoric acid, and when the compounds of the invention have an acidic part, sodium, potassium, calcium or magnesium salts and salts formed with appropriate organic ligands, for example, quaternary ammonium salts or pyridinium salts. When the compounds according to the invention have at least one asymmetric center, they can accordingly exist in the form of enantiomers. When the compounds of the invention have two or more asymmetric centers, they may additionally exist as diastereoisomers. It should be understood that all such isomers and their mixtures in any proportion are included within the scope of this invention.

Regardless of the presence or absence of asymmetric centers, some compounds of the present invention may exist as enantiomers due to the asymmetry of the molecule in general. It should be understood that in such cases both enantiomers and their mixtures in any proportion are included within the scope of the invention and that structural formulas depicting molecules of this type should be represented by both of the possible enantiomers, unless otherwise specified.

In compounds of formula I, Ag! is optionally substituted phenyl or pyridyl, in particular, optionally substituted phenyl or 3-pyridyl. Ag" is preferably selected from phenyl groups substituted in the 4-position by halogen, methyl or trifluoromethyl, and phenyl groups substituted by halogen in the 3- and 4-positions. "Ag" is preferably 2,5-difluorophenyl. " In specific variants of implementation of Ag! is 4-chlorophenyl or 4-trifluoromethylphenyl and Ag? is 2,5-difluorophenyl. in the typical case represents H, methyl or OH, preferably H. them B: in the typical case represents H or methyl, preferably H. (o) When t is equal to 1, all are, preferably, do not represent at the same time C..4-alkyl. Specific values of K 22 include H, phenyl, pyridyl, C3-6-cycloalkyl (such as cyclopropyl, cyclobutyl, and cyclopentyl), C3-6-cycloalkyl-C4-alkyl (such as cyclopropylmethyl), C3-6-alkenyl ( such as allyl) and is unbranched or branched C. v-alkyl, which is optionally substituted by CEz, Ag, OK??, M(К22)», СО? or - SOM)»

Examples of M-heterocyclic groups represented by M(K?2)'' include piperidin-1-yl. (optionally substituted by OH, SON, CO2-C..4-alkyl, Me or Ri), piperazin-1-yl (optionally substituted by Me or RI), 22 morpholin-4-yl, thiomorpholin-4-yl , 1,1-dioxothiomorpholin-4-yl, 2-oxoimidazolidin-1-yl,

Gee! 5,5-dimethyl-2,2-dioxooxazolidin-3-yl, 2,5-dioxoimidazolidin-1-yl, 2-oxooxazolidin-3-yl, 2-oxopyridin-1-yl and 2-oxopyrrolidin-1-yl. where 225 is typically H or C. 4-alkyl.

When 7 is OB. 22, and respectively represents H, Ag (especially pyridyl), alkyl (such as methyl, 60 ethyl, propyl, or butyl) or substituted alkyl (especially CNoAg, such as benzyl or pyridylmethyl).

When 7 is CO 2272 , Ka is respectively H or alkyl (such as methyl, ethyl, propyl or butyl).

When 7 represents COM(K 22 )", the K72 groups independently represent H or optionally substituted alkyl, 65 cycloalkyl, cycloalkylalkyl or alkenyl or together close the M-heterocyclyl group. It is very possible that one

Ba is H and the other is H, alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl,

t-butyl, tert-butyl or 1-ethylpropyl), alkenyl (such as allyl), cycloalkyl (such as cyclopropyl, cyclobutyl or cyclopentyl), cycloalkylalkyl (such as cyclopropylmethyl) or substituted alkyl (such as alkyl, substituted Ag, especially, 2-pyridylethyl, 3-(imidazol-1-yl)upropyl or 2-phenylethyl; or alkyl substituted with CE'

SO"? or СооМ(222)», especially 2,2,2-trifluoroethyl, methoxycarbonylmethyl or carbamoylmethyl). Alternatively, two K72 groups bridge an M-heterocyclic group such as morpholine, thiomorpholine, thiomorpholine-1,1-dioxide, 4-methylpiperazine, 4-phenylpiperazine, piperidine, 4-hydroxypiperidine, or a piperidine that is substituted at 3- or 4 - provisions of the CO? and/or C 4-alkyl, especially 3- or 4-carboxypiperidine, 3- or 4-ethoxycarbonylpiperidine, 3-carboxy-3-methylpiperidine and 3-ethoxycarbonyl-3-methylpiperidine.

Examples of individual compounds according to formula I are given in the examples section appended to the description.

Compounds of formula I have activity as modulators of APP processing under the action of γ-secretase.

The invention also relates to pharmaceutical compositions that include one or more compounds of the formula

It or their pharmaceutically acceptable salts and a pharmaceutically acceptable carrier. Said compositions are preferably in the form of dosage forms, such as tablets, pills, capsules, powders, granules, 72 sterile parenteral solutions or suspensions, dosage aerosols or liquid sprays, drops, ampoules, transdermal patches, autoinjector devices or suppositories , for oral, parenteral, intranasal, sublingual or rectal administration or for administration by inhalation or insufflation. To obtain solid compositions, such as tablets, the main active ingredient is mixed with a pharmaceutical carrier, such as conventional tablet ingredients known to those skilled in the art, for example, as described in MO 0170677, and the mixture is converted into a dosage form. A typical dosage form contains from 0.1 to 500 mg, for example, 1, 2, 5, 10, 25, 50, 100 or 200 mg, of the active ingredient. Tablets or pills of the new composition can be coated or otherwise shaped to form a dosage form that provides the advantage of prolonged action, as described, for example, in UMO 01/70677.

Liquid forms in which the new compositions of this invention can be included for oral or injection administration include aqueous solutions, flavored syrups, aqueous or oily suspensions, and flavored edible g) oils, as described in MO 01/70677.

The present invention also relates to a compound of formula I or its pharmaceutically acceptable salt for use in a method of treating the human body. Treatment is mainly related to the condition associated with D-amyloid deposition. The condition is predominantly a neurological disease associated with β-amyloid deposition, such as Alzheimer's disease. F

This invention further relates to the use of the compound of formula I! or a pharmaceutically acceptable salt thereof in the manufacture of a medicinal product for the treatment or prevention of Alzheimer's disease. WITH

Also described is a method of treating a subject suffering from Alzheimer's disease or susceptible to the disease (Te)

Alzheimer's disease, which includes administering to the indicated subject an effective amount of the compound according to the formula or its pharmaceutically acceptable salt. -

For the treatment or prevention of Alzheimer's disease, a suitable dosage level is from about 0.01 to 25 Ωg/kg per day, preferably from about 0.05 to 10 Ωg/kg per day, and especially from about 0.1 to

BOmg/kg of body weight per day. The compounds can be administered at a regimen of 1 to 4 times per day. In some cases, however, a dose outside these limits may be used. - then Compounds of formula I, in which t is 0 and 7 is СО2Н?2 or СОМ(К 72)", can be obtained by combining with carboxylic acid (1), respectively, with KOH or НМ(В 72)", with ie de Ag

Ф Со,Н 2 АК о 50 - (0 and where Аг, Агг, В Ій and have the above values. Any of the standard ones can be used

HF) coupling methods, including the use of coupling agents such as dimethylaminopyridine,

HF hydroxybenzotriazole, dicyclohexylcarbodiimide, carbonyldiimidazole and the like. In one preferred method, the acid is converted into the corresponding acid chloride (for example, by treatment with oxalyl chloride in a DMF solution) and reacted directly with the desired nucleophile. In another preferred method, the acid is converted into an active ether derivative, such as pentafluorophenol ester (for example, by combining with phenol in the presence of dicyclohexylcarbodiimide) and the specified intermediate is reacted with the desired nucleophile.

Acids (1) can be prepared by hydrolysis of esters (2), typically under alkaline conditions such as treatment

ТСОН in an ethanol solution: б5 with АРВОm 7 І and

A o (» z where B2 is alkyl, such as methyl or ethyl, and Ag", Ag? and B! have the meanings indicated above.

Complex esters (2) can be obtained by reduction of alkylidene derivatives (3) with optional subsequent alkylation of the product (C 4.4-alkyl)-Y, where Y is a leaving group (especially bromide or iodide), where B 712 differs from H: i Same dnnonsody s o "(8) where Ag, Ag? and B? have the same values as above. Reduction can be carried out using sodium borohydride and nickel (II) chloride in ethanol, while optional alkylation can be carried out by treating the ester (2, B'Z-H) with a strong base (for example, sodium bis(trimethylsilyl)amide) in Ge! aprotic solvent at a low temperature with further processing (C../-alkyl)-i and heating to room temperature. "

If necessary, unsaturated complex esters (3) can be hydrolyzed into the corresponding acids and Ge converted into amides by interaction with НМ(К 22)" before the restoration of the olefinic bond. m

Unsaturated complex esters (3) are accessible by condensation of ketone (4) with РНИЗР-СНСО ОВ: with Ag not; with . "Ah VO; -I

Ф 4) е 1 d2:р2 : : : where Аг", Аг- and К- have the values specified above, while ketone (4) is obtained by decarboxylation of enols (5), ис), which, in turn, are obtained by interaction sulfone (6), at least with two equivalents of acrylate (7): -x Z on ss with Ak 5O; ABS. ZO Ag o so, ime) 60 de Ag", Ag? and KE have the values given above. Decarboxylation can be performed by heating at 1502С

DMSO in the presence of sodium chloride and water, while the reaction of (6) with (7) can be carried out at ambient temperature in an inert solvent such as THF in the presence of a strong base such as potassium tert-butoxide. 65 Sulfones (6) are obtained by oxidation of simple thioethers Ag 2-СНо-ЗАг!' (8), which, in turn, are obtained by the interaction of thiols Ag'ZH (9) with benzyl derivatives Ag"CH"-I. (10), where I is a leaving group such as chloride or bromide and where Ag! and Ag ? have the values given above. The reaction between (9) and (10) takes place in an inert solvent such as dichloromethane in the presence of a base such as triethylamine, while the oxidation of (8) in (b) is usually carried out with m-chloroperoxybenzoic acid also in an inert solvent such as dichloromethane.

Compounds of formula I, in which t is 0 and 7 is CM or OB 22, can be obtained by the interaction of sulfonate ether (11), respectively, with cyanide ion or Vg2OH: then and C 2 ; 1) where I" is a sulfonate leaving group (such as a mesylate, tosylate, or triflate) and Ag7, Ag?, Bc, and Ha have the values indicated above. The substitution reaction can be carried out in DMF at an elevated temperature, for example, at about 802C When the nucleophile is B2OH, it is beneficial to generate the appropriate anion by treating Ha with sodium hydride before interaction with (11).

Sulfonates (11) are obtained by reacting alcohols (12) with the corresponding sulfonyl chloride (for example, under anhydrous conditions at low temperature in the presence of a tertiary amine). (22)

Ag o « zi o zv Ag m

It is difficult to obtain alcohols (12) by hydroboration of alkenes (13): t s Y what i nn KTK - and also species". With "a. y na bi pi vkknin i sh» eh yo de Ag", Ag? and VO have the values indicated above. The method in a typical case involves interaction with borane in

THF at room temperature followed by treatment with alkaline hydrogen peroxide and separation of the required 22 cis-isomer by chromatography. Alkenes (13) are available from ketones (4) by condensation with RizRASNE 75, where B": has

Gee! the same values as above.

An alternative route to alcohols (12) in which BC is H involves reduction of ketone (4) (e.g., where using borohydride) to the corresponding secondary alcohol (14), conversion of said alcohol (14) to the corresponding mesylate (or equivalent group), carrying out nucleophilic substitution with a cyanide ion, 60 hydrolysis of the formed nitrile into the corresponding carboxylic acid with further reduction into the primary alcohol.

Hydrolysis is typically carried out under acidic conditions (for example, in a mixture of acetic acid and concentrated HCl at 11022) and reduction is conveniently carried out by sequential treatment with isobutyl chloroformate and borohydride in THF.

Compounds of the formula 1, in which t is 1 and BC 9 is H or C 44-alkyl, can be obtained 69 by oxidizing alcohol (12) into the corresponding aldehyde or ketone and transforming its carbonyl group by the method

described above in connection with the conversion of ketones (4) into compounds of the formula I!, in which t is 0. For example, the oxidation of alcohols (12), in which Kk is H, provides the corresponding cyclohexanecarboxaldehydes, which can be condensed with RA zP-СО2ЕЙ to obtain ethyl ether of 2-cyclohexylpropenoic acids. In turn, they can be hydrogenated into the corresponding ethyl-2-cyclohexylpropionates, which, optionally, can be subjected to alkylation and/or hydrolysis into the corresponding acids and/or converted into various amide or alternative ether derivatives.

When the starting materials and reagents used in the synthetic schemes described above are not themselves commercially available, they can be obtained using standard methods of organic synthesis 70 for commercially available materials.

It should be understood that many of the synthetic schemes described above can give mixtures of stereoisomers.

In particular, some products can be formed as mixtures of cis- and trans-isomers in which the specified ring substituent is on the same or opposite side of the ring as the arylsulfonyl group. Such mixtures can be separated by conventional methods, such as fractional crystallization and preparative chromatography.

Some compounds according to the invention can exist in the form of optical isomers due to the presence of one or more chiral centers or due to the general asymmetry of the molecule. Such compounds can be obtained in racemic form or individual enantiomers can be obtained either by enantiospecific synthesis or by isomerization. New compounds can, for example, be resolved into their constituent enantiomers by standard methods such as preparative HPLC or preparation of the diastereomeric pair by salt formation with an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (g) -di-p-tolusoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. New compounds can also be separated by the formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary compound. Ha

During the performance of any of the synthetic sequences mentioned above, it may be necessary and/or desirable to protect sensitive or reactive groups in any of the participating molecules. This can be achieved by i) using commonly accepted protective groups, such as the groups described in |Rgogesiime sSgotsmrz ip Ogdapis Spetizighu, ey. 9.E.MU. MsOtie, Riepyt Rhevzv, 1973; apa T.MU Sgeepe apa R.O.M. MUtsiv, Rgoiesime Sgotsrv ip Ogdapis

Zupipevziz, Wopp UMieu apa bopz, 1991). Protecting groups may be removed at a suitable subsequent stage using methods known in the art.

Suitable methods for analyzing the level of activity of compounds of this invention relative to G-secretase are described in (MO on 01/70677 and in Viospetivig, 2000, 39(30), 8698-8704). "Her

The compounds of the examples of the present invention all have an EU50 of less than 1 µM, preferably less than 1 µM, and most preferably less than T00nM, in at least one of the above-mentioned assays. at

The following examples illustrate the present invention. -

Examples

Intermediate product 1 "- s ;" -And (22) ve , ! ! 4-Chlorothiophenol (3.bg, 0.025mol) in dichloromethane (100ml) is treated with 2,5-dichlorobenzyl bromide (5.17g, is, 0.025Bmol) and triethylamine (3.Oml, 0.028mol), the reaction mixture is stirred for 2 hours , then diluted with dichloromethane (250 ml) and washed with water (100 ml) and saturated salt solution (100 ml).

The separated organic layer is dried (M950,) and evaporated to dryness. The product is purified by passing through a layer of silicon dioxide, eluting with hexane-ethyl acetate mixtures. "H NMR SOSIZ 7.23 (4H, s), 6.69-6.86 (ZH, m) and vv 404 (2H, s).

The specified simple thioether (5.127, 0.018 mol) is dissolved in dichloromethane (10 Oml) and treated with (F, m-chloroperoxybenzoic acid (14.3 g, 0.042 mol (5Ow/9o)) and stirred for 2 hours. The reaction mixture then washed with Ma»boOB (596 solution, 100ml), saturated salt solution (50ml), dried (MazO,) and evaporated to dryness. The obtained sulfone was purified on silicon dioxide, eluting with hexane-ethyl acetate mixtures, 6o 3.6 g. 7.61 (2H, d, U-8.6Hz), 7.45 (2H, d, 9U-8.6Hz), 7.13-7.08 (1H, m), 7.05-7.01 (1H, m), 7.05-7.00 (1H, m), 6.99-6.87 (1H, m) and 4.36 (2H, s).

Intermediate product 2 b5

Obtained as intermediate 1 using 4-trifluoromethylthiophenol, the product is obtained as a solid. "H NMR (36OMHz, SOSIv) 6 7.85-7.83 (2Н, m), 7.76-7.74 (2Н, m), 7.15-7.10 (1Н, m), 7, 06-7.0 (1H, m), 6.92-6.86 (1H, m) and 4.46 (2H, s).

Example of obtaining 1

J so che an 1 sch

Shi. In the village (8)

Potassium tert-butoxide (3.64 ml of a 1M solution in tetrahydrofuran, 3.b4mol) was added dropwise to intermediate 1 (1g, 3.3mol) and methyl acrylate (0.84ml, 9.27mol) in tetrahydrofuran (30ml). The reaction mixture was stirred for 2 hours, diluted with ethyl acetate (100ml) and washed with water (50ml) and saturated salt solution (50ml). The organic phase is separated, dried (Mo5O4) and evaporated to dryness and the product is purified on silicon dioxide, eluting with mixtures of hexane-ethyl acetate (1.0 g). IN NMR SOSIZ 12.0 (1H, s), 7.41 (4H, s), 7.06-7.0 (2H, m), 6.87-6.81 (1IN, s), 3.81 (ZN, s), 3.38 (IN, dd, 9U-3.2, 15.8Hzsh), 3.02-2.92 (2Н, m), 2.52 (1Н, Z dd, У-5 .7, 18.5 Hz), 2.3-2.2 (1H, m) and 2.2-2.1 (1H, m). Gee)

Example of obtaining 2 35 . - cheers with G | | they are only ШЯ yav y posy y y y y y y y » SCHI Y g, zi btIM Ye zho i-y

The ester from Preparation Example 1 (1.0g, 2.25mol) in dimethylsulfoxide (10ml) was treated with Mass (0.3g, 4.9bmol) and water (0.9ml, 4.9bmol) and heated at 1509 for 2 hours The cooled reaction mixture is diluted with ethyl acetate (100 ml), washed with saturated MHCl (100 ml) and the organic phase is separated, dried (Ma53O)) and evaporated to dryness. The product is purified on silicon dioxide, eluting with mixtures (se) of 50 hexane-ethyl acetate, 0.5 g. "H NMR SOSIZ 7.43-7.37 (4Н, m), 7.22-7.1 (2Н, m) , 6.97-6.9 (1H, m), 3.05-2.98 (2H, more m) and 2.61-2.53 (2H, m).

An example of obtaining З ко и Я as ХО with "Shk is IY because K is also F -" ey b5

Synthesized according to the methods of production examples 1 and 2 using intermediate product 2, obtaining the product in the form of a solid substance (0.3 g). "H NMR (Z6OMHCz, SOSIv) 5 7.71-7.69 (2H, d, 9-7.5Hz), 6.62-6.60 (2H, d, 9-7.4Hz), 7.22 -7.11 (2Н, m), 6.95-6.88 (1Н, m), 3.02-2.99 (2Н, m), 2.63-2.54 (4Н, m) and 2 ,25-2,16 (2N m).

Example of obtaining 4

Ethyl (diethoxyphosphinyl)acetate (5.1 bml, 2 bmol) was added dropwise to a suspension of sodium hydride (60905 dispersion in mineral oil, 988mg, 24.7mol) in tetrahydrofuran (bOml) and the mixture was stirred at room temperature for 1 hour. During 20 min. dropwise add the ketone from Preparation Example 2 (5g, 1Zmol) in tetrahydrofuran (5Oml) and the mixture is stirred at room temperature for 18 hours. Water is added and the mixture is extracted with ethyl acetate. The combined organic fractions are washed with water, dried (Ma5ZO)) and the solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on silica gel eluting with a mixture of isohexane:E(OAc (85:15), obtaining the product in the form of a white solid (5.2 g, 8890). o

TN nMR (360 MHz, SOSIi) 5 7.41-7.36 (4H, m), 7.18-7.13 (1H, m), 7.11-7.05 (1H, m), 6.93 -6.86 (1H, m), 5.64 (1H, s), 4.14-4.10 (2H, m), 3.99-3.96 (1H, m), 2.91-2 .80 (2Н, m), 2.42-2.38 (1Н, m), 2.31-2.04 (ЗН, m), 1.89-1.78 (1Н, m), 1.28 -1.24 (ZH, m).

An example of receiving 5 units

Fo hon on Z "F wo (Se)

There is something m. A vi " and a s shchi s ;" n (a) (B) - Ketone from the example of preparation 2 (0.1g, 0.2bmol) in methanol (2ml) is treated with Mavn, (0.098g, 0.2bmol) and

FD is stirred for 1 hour. The reaction mixture was quenched with NOSI (Tn, 10 ml), diluted with ethyl acetate (20 ml), then the organic phase was separated, dried (Mo95O y) and evaporated to dryness. Cis- and trans-products are purified on silicon dioxide, eluting with hexane-ethyl acetate mixtures.

Ge) 20 (a) (trans) 0.052 g. "H NMR (SOSIS) 7.39-7.33 (4Н, m), 7.11-7.02 (2Н, m), 6.88-6.82 (1Н, m), 3.80-3 .73 (1H, m), 2.80-2.60 (2H, m), 2.22-2.16 (2H, m), 2.08-2.04 (2H, m), 1.53 (1Н, lat.) and 1.27-1.13 (2Н, m). 2H, m), 6.90-6.83 (IN, m), 3.97-3.95 (1H, m), 3.77-3.68 (IN, m), 3.51-3, 49 (1H, m), 2.61-2.53 (2H, m), 1.91-1.83 (2H, m) and 1.50-1.42 (2H, m).

Example of obtaining 6

F) name) 60 b5

Trans-cyclohexanol from Example 5 (2.7 g, b, Umol) and triethylamine (1.bml, 10.Zmol) in 75 dichloromethane (5Homl) are treated with methanesulfonyl chloride (0.645ml, 8.9mol) at -302С. Through ЗОхв. the mixture is washed with water (2Oml), 1095 aqueous citric acid (20ml) and saturated aqueous sodium bicarbonate (5Oml), dried (Ma5O)) and evaporated to dryness. The solid was triturated with ether to give the mesylate (2.6 g). "H NMR (SOSIv) 7.40-7.37 (4Н, m), 7.12-7.07 (2Н, m), 6.92-6.83 (1Н, m), 4.78-4 .65 (1H, m), 2.96 (ZH, s), 2.88-2.52 (2H, m), 2.29-2.21 (AN, m) and 1.59-1.47 (2H, m).

An example of obtaining 7 s o "-

fo

I I (Se)

The trans-mesylate from preparation example b (103 mg, 0.22 mol) is dissolved in toluene (200 ml) and added to

From a sample of tetrabutylammonium cyanide subjected to azeotropic distillation in advance (354 mg, 1.32 mol) and a mixture of heated to 702 for 18 hours and then cooled to room temperature. The solution is diluted with water (1Oml) and washed with ethyl acetate (2x5Oml). The organic phase is washed with a saturated salt solution (1 Oml), dried (Ma5O)) and evaporated. The resulting clear oil is purified by column chromatography on silica gel eluting with 10-2095 ethyl acetate in hexanes, thereby obtaining cyanide. "H NMR (SOSIv) with 70 7.42-7.36 (4Н, s), 7.10-7.05 (2Н, m), 6.89-6.84 (1Н, m), 2.88 -2.86 (IN, m), 2.76-2.72 (2Н, m), 2.52-2.45 (1Н, с m), 2.12-2.07 (1Н, m) and 1.56-1.49 (1H, m). :z» Production example 8 -I (22) sh» at 50 - o Cyanide from production example 7 (14 Мg, 0.3 bmol) is dissolved/suspended in a mixture of glacial acetic acid (1Oml) and conc. HCl (bml) and heated at 1109 for 15 hours. The mixture was cooled, diluted with ethyl acetate and washed with water (x3), dried (Mo5O)) and evaporated to dryness. This crude residue (153 mg) was purified by preparative TLC (595 methanol in a mixture of dichloromethane/196 acetic acid). "H NMR 60 (SOCI,) 7.38-7.35 (AN, s), 7.08-7.06 (2Н, m), 6.90- 6.84 (1Н, m), 2.65-2.58 (2Н, m), 2.38-2.33 (ЗН, m) and 1.76-1.49 (4Н, m).

Example of obtaining 9 b5

Cyanide from preparation example 8 (5O0mg, 0.12mol) is dissolved in a mixture of tetrahydrofuran (4.5ml) and water 759. (0.Bml) and stirred at 202С. The mixture is treated with hydrogen peroxide (2Oml, 0.bmol) and then with lithium hydroxide (bml, O0.25mol) for 2 hours. Hydrogen peroxide (2Oml, 0.bmol) and then lithium hydroxide (bmg, 0.25mol) are added and the mixture is stirred at room temperature for 72 hours. The mixture is cooled, diluted with ethyl acetate and washed with water (x2) and sat. with sodium bisulfite, dried (MosO,) and evaporated to dryness. This crude residue (51 mg) is purified by preparative TLC (2095 ethyl acetate in hexanes). "H NMR (SOSIV) 7.37 (4H, s), 7.10-7.02 (2H, m), 6.90-6.84 (IN, m), 5.57 (2H, shr.s ), 2.54-2.48 (ЗН, m), 2.43-2.39 (1Н, m), 2.19-2.15 (2Н, m) and 1.62-1.50 (ЗН , m).

Example 1

SI " Y Z | y 3o nya S her

In Y and ; se "Her friend -

Sodium borohydride (31mg, 8.233mol) was added to a mixture of the unsaturated ester from Example 4 (3.74g, 8.23mol) and nickel (II) chloride (2.67g, 20.3mol) in ethanol (1000ml). The mixture is stirred at room temperature for 20 minutes, then water (100 ml) is added. The mixture is filtered through Nuyotm, washed with -70% ethanol and ethyl acetate. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer is separated, dried (Ma5O4) and the solvent is evaporated under reduced pressure. The residue is purified by flash column chromatography on silica gel, eluting with a mixture of isohexane-E(Ac (85:15), obtaining the faster-moving cis isomer as an oil (1.36 g, 3695), H NMR (400 MHz,

SOSIZ) 6 7.37-7.30 (4H, m), 7.09-7.00 (2H, m), 6.86-6.79 (IN, m), 4.14 (2H, square, U-7.1Hz), 247 (2H, d, -1 U-7.6Hz), 2.46-2.38 (2H, m), 2.19-2.14 (1H, m), 1, 76-1.71 (2H, m), 1.57-1.48 (4H, m), 1.27 (ZH, t, 9-71); and the slower moving trans isomer as an oil (200mg, 5.396). b» Example 2 about: you (se) 50 | I r. y kl tv di Her ' s t -- t I

And also for Ki that plo. yuyu "Like mine

Lithium hydroxide (350 mg, 14.57 mol) is added to a solution of the complex cis-ester from example 1 (1.33 g, 2.91 mol) in ethanol (40 ml). The mixture is degassed and stirred at room temperature under nitrogen gas for 5 hours. The mixture was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. bo The organic extract is dried (Ma5O,) and the solvent is evaporated under reduced pressure to give a white solid, which is then crystallized from IRA to give the product as a white solid (95Omg, 7695). "YAN NMR (400 MHz, СО53О0) 5 7.51-7.49 (2Н, m), 7.40-7.37 (2Н, m), 7.19-7.10 (2Н, m), 7, 00-6.94 (IN, m), 2.51-2.35 (6Н, m), 2.13-2.10 (1Н, m), 1.78-1.74 (2Н, m), 1.57-1.50 (2H, m).

Example C

Vr and BYY as Shk and "TRAS and V shchi NU STATI t . with e p y

The acid from example 2 (5mg, 0.117mol), morpholine (30mg, 0.351mol), 1-hydroxybenzotriazole (24mg, 0.17bmol) and triethylamine (bbmg, 0.4b68mol) are mixed in tetrahydrofuran at room temperature in an atmosphere of nitrogen gas for 10 minutes. . 1-(3-dimethylaminopropyl)-33-ethylcarbodiimide hydrochloride (45 mg, 0.234 mol) was added to the mixture and the mixture was stirred for 24 hours. The mixture was poured into aqueous sodium hydroxide (1M) and extracted with ethyl acetate. The organic extract was dried (Ma5O,) He ) and the solvent is evaporated under reduced pressure. The residue is purified by flash column chromatography on silica gel eluting with 5 to 1095 methanol in dichloromethane to give the product as a white foam (5Omg, 8695). "H NMR (400MHz, CO53O0) 5 7 .50 (2H, d, U-8.6Hz), 7.37 (2H, d, U-8.6Hz), 7.19-7.09 (2H, m), 7.00-6.93 ( IN, m), 3.69-3.63 (4H, m), 3.59-3.56 (4H, m), 2.55 (2H, d, 9U-7.4Hz), 2.47- 2.39 (4H, m), 2.16-2.07 - (IN, m), 1.78-1.74 (2H, m), 1.58-1.51 (2H, m). t/2 (EbB'") (MY) 498-500. Gee!

Examples 4-15

The following compounds are prepared by the method of example C using the appropriate amine instead of morpholine. From 325 and g gyi t v y you - . I am 5. and. - and what - and cha and I "

And 2 more he mentioned. With - ; with,

F what sh» at 50 -

F) name) 60 b5 rya ryu v shi PON Senasvavomv | and 8 in OV

Examples 16-33 n | AI sho (F) ko bo 65

Z I ok y shchi i I

OO

70 nn: the site goes and ke. p ve I

The compounds of the specified examples are obtained in the following manner using the appropriate free amine base or amine salt with prior neutralization.

Oxalyl chloride (0.05 ml, 0.57 mol) and dimethylformamide (1 drop). After 30 minutes, the solution is evaporated to a small volume, and the required amine (1.75 mol) is added to a solution of the residue in dichloromethane (b5ml). After stirring the solution for 20 minutes, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel, eluting with increasing concentrations of ethyl acetate in isohexane (2595, 50905). Fractions containing the product are evaporated, thereby obtaining the amide. Chromatographic purification is carried out on silica gel using, where necessary, appropriate concentrations of ethyl acetate in isohexane, ethyl acetate or methanol in ethyl acetate. - (o) « (Se) and - - s. and? -I (o) sh» s - ime) 60 b5

I will give an example V. MELE 1 Refinement

M 00000 f|Mbcyclobutyl |cha2doya |195l980 ! things tav vsaakyudai ny Yo kleya t - son nanni nninidechnntoya so och zni ne z nni in fan y z ryasno noya rt iii ii ni-ni nya K z ss sot porti pes 7 s song channya vyt penya 2 niy : Ф 8 0000 fMEbvklepropii Ii468 -

Example 33 c z" CHNI Kk "t: MAO Y : iy z 9 Shchi - NO, A Ve ; Z

And 50 Se koe I (se) SCHE 7: th and sun. (FI i g : o a

Trifluoroacetic anhydride (0.05 ml) is added to a solution of cis-amide from Example 9 (4 mg) and pyridine (0.05 mg/ml) in tetrahydrofuran (ml). The solution is stirred at room temperature for 2 hours with the addition of 0.5M HCl (aqueous) and ethyl acetate. The organic phase is dried (M950O)), evaporated to a small volume and purified by chromatography on silica gel eluting with a mixture of isohexane-ethyl acetate (5:11), thus obtaining the desired product in the form of a colorless solid. "H NMR (Z36OMHz, SOSIv) 5 1.61-1.70 (2Н, m), 1.86-1.94 (2Н, m), 2.03-2.10 (1Н, m), 2, 42-2.45 (4H, m), 2.51 (2H, d, U-8.0HZ), 6.8 (IN, m), 7.02-7.09 (2H, 65 m), 7 .30 (H, d, 4-8.6Hz), 7.36 (2H, d, 9-8.7Hz).

Example 34 and on p

The acid from preparation example 8 (153 mg) is dissolved in anhydrous THF (1 Oml) and cooled to 0 C in a nitrogen atmosphere. Triethylamine (b1 µl, 0.4 mol) and isobutyl chloroformate (57 µl, 4 mol) were added and the mixture was stirred at 02C for one hour. The precipitate that forms is removed by filtration and washed with an additional ml of anhydrous THF. The combined layers of THF are again cooled to 02C and sodium borohydride (7mg, 1.84mol) is added as a solution in water (2ml) (boiling!). After stirring for 30 minutes at 0 C., the reaction mixture is diluted with ethyl acetate, washed with ammonium chloride solution, sodium bicarbonate (5) solution and saturated salt solution, then dried (Ma5ZO)) and evaporated to dryness. The residue is purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:3), thereby obtaining the desired alcohol (75 mg). "NN NMR (SOSIv) 7.39-7.31 (4Н, m), 7.10-7.01 (2Н, m), 6.88-6.81 (1Н, m), 3.71 (2Н , d, 9-7.5Hz), 2.46-2.32 (AN, m), 1.90-1.85 (2H, m), 1.78-1.74 (1H, m) and 1 ,54-1,44 (2H, m). t/2-423 |MMaY". --

Example 35 Ge"! « (Se) " shchi ge) and - - s z - a me) !

Stage (1) t» To a solution of the acid from example 2 (1g) in OCM (5Oml) and ethyl acetate (3Oml) add pentafluorophenol (1.5eq.) with 50 1 ОСС (1.5eq.) and stir at room temperature for 1 hours The reaction mixture is evaporated in vacuo, dissolved in ethyl acetate and filtered. The filtrate is evaporated in a vacuum, thus obtaining complex "6 ether of pentafluorophenol with sufficient purity for use in subsequent reactions.

Stage (2)

Glycine methyl ether hydrochloride (125 mg, 1.0 mol) and triethylamine (0.15 ml) were added to the pentafluorophenol ester obtained in step (1) (155 mg, 0.25 mol) and dissolved in DMF (3 mL) under a nitrogen atmosphere. After about 2 hours, the reaction mixture is diluted with water, extracted with ethyl acetate (x3), washed with water, saturated salt solution, dried (MazO)), filtered and evaporated. Purified by flash column chromatography (from a mixture of 1:1 isohexane/(ethyl acetate to a mixture of 9:11 ethyl acetate/methanol), obtaining a white solid (Bbmg/. "H NMR (SOCI) 5 1.08-1.16 (1H, m), 1.30-1.537 (IN, m), 1.67-1.71 (IN, m), 1.75-1.79 (2H, m), 60 1.94-1, 95 (IN, m), 2.20-2.26 (1Н, m), 2.41 (4Н, d, 9У-7.8ГЦС), 3.77 (ЗН, с), 4.05 (2Н, d, U-51Hz), 6.19 (1H, width), 6.79-6.85 (1H, m), 7.00-7.07 (2H, m), 7.30-7.37 (4H, m).

Example 36 b5 and mn,

The glycine ester obtained in example C5 (5Omg, 0.Tmol), placed in a sealed tube and dissolved in a 2M solution of ammonia in methanol (3ml), is heated to 502 for 3 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by trituration with ether to give a white solid (28 mg). MS(Ei! k): 485 (MN).

Example 37 of Art

I F sy She: sewed r s: i. w : VE and o | SHY ay F ge V y shk .

With Te

Who am I? what-

The alcohol of example 34 (4 g, 1 mol) is dissolved in dichloromethane (280 ml) and treated with periodinan

Desa-Martin (4.66 bg, 11 mol) and the mixture is stirred for 45 min. before adding saturated aqueous sodium bisulfite (10 Oml) and after 5 min. the mixture is separated and the organic phase is washed with saturated aqueous sodium bicarbonate (100 ml), dried (Mo5O)) and evaporated to dryness. The crude residue (4g) was dissolved in anhydrous dichloromethane (100ml) and treated with methyltriphenylphosphinoacetate (4.7g, 14mol), and stirred at room temperature for 16 hours. The solvent is evaporated and the residue is purified by column chromatography on silica gel eluting with 10-2095 ethyl acetate in hexanes, thereby obtaining the product. 02 (ZN, m), 6.78-6.83 (1H, m), 5.91 (1IN, d, 9U-16Hz), 3.77 (ZN, s), 2.55-2.45 ( ЗН, m), 2.40-2.38 (2Н, m), 1.95-1.90 (2Н, m) and 1.65-1.52 (2Н, m). - And Example 38 and, 29 WHAT. i: m - i Sh p y -dh | I

GF 0-0 KA

The alkene from example 37 (3.bg, Umol) is dissolved in ethyl acetate (3500 ml). The flask is degassed and then 1090 60 palladium on charcoal (40Omg) is added and the mixture is stirred under a hydrogen atmosphere for 45 minutes. The solution is filtered through Celite and filtered. The resulting clear oil was purified by preparative TLC, eluting with 595% ethyl acetate in hexanes. The resulting oil is then further purified by column chromatography on silica gel eluting with 5-1096 ethyl acetate in hexane to give the product. "H NMR (SOSIv) 7.37-7.34 (4Н, m), 7.08-7.00 b (2Н, m), 6.85-6.81 (1Н, m), 3.67 ( ЗН, с), 2.45-2.39 (4Н, m), 2.33 (2Н, t, 9U-8.4HzС), 1.81 (2Н, sq, U-84Gu), 1.72- 1.68 (2Н, m) and 1.60-1.43 (ЗН, m).

Example 39

AND THEIR M NN NN o yu re . and Y - "And that's it"

And I what

The ester of example 38 (104 mg, О0.2 mol) is dissolved in a mixture of ethanol (10 ml) and water (3 ml) and stirred at 202С. The flask is degassed and then lithium hydroxide (27 mg, 1.15 mol) is added. The mixture is stirred for 3 hours at room temperature. Then another hydrochloric acid is added and the mixture is washed with ethyl acetate (2x5Oml). The organic phase is washed with a saturated salt solution (50 ml), dried (MazO,) and evaporated. The obtained 2o oil is then further purified by preparative TLC eluting with ethyl acetate, thereby obtaining the acid. "H NMR (SOSIi) 7.37-7.30 (4Н, m), 7.09-6.99 (2Н, m), 6.85-6.79 (IN, m), 2.42-2 .36 (6Н, m), 1.85-1.79 (2Н, m), 1.73-1.69 (2Н, m), 1.63-1.58 (1Н, m) and 1.53 -1.45 (2Н, m).

Example 40 What what "y. In And ch. g that with - SHE her ee R and in -x

Residential complex! The acid from Example 39 (52 mg, 0.118 mol) in dichloromethane (2 ml) is treated with oxalyl chloride (88 μl, 2 M. solution in dichloromethane, 0.17 bmol). A drop of M,M-dimethylformamide is added and the solution is left with stirring for 2 hours. After the specified time, the solvent is removed in vacuo and the residue is redissolved in dichloromethane (ml). This solution is added dropwise to a solution of ammonia in methanol (2M, 2ml). The reaction mixture is evaporated in vacuo and the residue is chromatographed on silicon dioxide, eluting with 8090 -I ethyl acetate in hexanes. The resulting substance is further purified by preparative TLC eluting with 100965 ethyl acetate followed by recrystallization from hot hexane, thereby obtaining the product (7.4 mg, 14905). g» TN NMR (Z360MHz, SOSIv) 1.45-1.53 (2H, m), 1.57-1.65 (IN, wide), 1.70-1.75 (2H, m), 1 ... 3.02 (ZN, s), 6.79-6.86 (IN, m), 7.00-7.09 (2Н, m), 7.31-7.37 (AN, m); MB (E5"), 470 (M"1), 294 (M 7175). - Example 41

F) name) 60 b5

70 not me and

The complex cis-ester from example 1 (6bO9mg, 1.467mol) in tetrahydrofuran (14ml) is cooled to -789C, treated with sodium bis(trimethylsilyl)amide (2.20ml, 1M solution in tetrahydrofuran, 2.20mol) and stirred while heating to room temperature temperature for 2 hours. Then, methyl iodide (457 μl, 7.5 mol) is added to the mixture at -209C and stirring is continued, reheating to room temperature for 2 hours.

The reaction mixture was quenched with glacial acetic acid (132 μl, 2.20 mol), diluted with ammonium chloride (50965, aq., 8 Oml) and extracted with ethyl acetate (3x10 Oml). The combined organic layers were then washed with brine (sat., 200 mL), dried (Mo 5 O ), and evaporated in vacuo to give the crude product (67 mg). This substance from 29 is chromatographed on silicon dioxide, eluting with 895 ethyl acetate in hexanes, obtaining the product (272 mg, 4095). "H NMR (400 MHz, SOSIV) 1.16 (ZN, d, U-6.9 Hz), 1.28 (ZN, t, 9U-7.1Hz), 1.45-1.51 (2Н, m), 1.71-1.77 (2Н, m), 1.89-1.94 (1Н , m), 2.28-2.48 (ZH, width), 2.54-2.60 (1H, width), 2.70-2.74 (1H, m), 4.09-4 ,18 (2Н, m), 6.77-6.84 (1Н, m), 6.99-7.08 (2Н, m), 7.26-7.36 (4Н, m). "-

Example 42 7 RUSH b ay sche che " kvshvschoi tot J

But what Che r. "

Z y - s Also ay :z» t i

It is obtained from the ketone of preparation example C according to the methods of preparation example 4 and examples 1 and 2. "H NMR (36OMHz, СОСИв), 1.52-1.61 (2Н, m), 1.76-1.81 (2Н, m ), 2.20-2.26 (1H, m), 2.39 (2H, d, 9-7.6Hz), 2.40-2.50

Sh- (DAN, m), 5.37 (IN, width), 5.51 (IN, width), 6.75-6.83 (1H, m), 7.01-7.08 (2H , m), 7.51 (2H, d, 9U-8.3Hz) and 7.64

Ф СН, d, У-8.3Hz).

Example 43 of Kiya ge so 50; 'ya I r da Y DY t Shchy Y as FI Shchy Se g. y: te: ; - y (FI 22017 in goes about i vo shchi gi " se sv si

It is obtained from the acid of example 42 according to the method of example 35 using ammonia in the second stage. MS MN 462(463). 65 Example 44 shchi and Sho shi and SHHO - and y. - up to 70 | and and

It is obtained from the ketone of preparation example C according to the methods of preparation examples 5-8 and examples 34, 37, C8 and 39. NMR (Z360MHz, SOSIV) 5 10.1 (1Н, m), 7.64 (2Н, d, U- 8.3Hz), 7.53 (2H, d, 9U-8.3Hz), 7.09-7.00 (2H, m), 6.83-6.76 (1H, m), 2.50- 2.37 (6H, m), 1.85-1.81 (2H, square, 9U-7.4Hz), 1.75-1.70 (2H, m), 1.63-1.59 (1H , m), 1.55-1.45 (2Н, m).

MC (Esh) 477 (MN.ju.

Claims (14)

The formula of the invention 1. The compound of formula I: с ис Е Shchi. o ApvO, E Ag EV "- where: Fo t is equal to 0 or 1; 7 represents SM, OMK78, СО22 or СОМ(В 72)"; in B" is H, C. 4-alkyl or OH; Ge) with B: is H or C. 4-alkyl; M Ag is phenyl or pyridyl, each of which has 0-3 substituents, regardless selected from halogen, CM, MO,, CEz, OH, OSR", Su. 1-6-alkyl or C-1-alkyl, which, optionally, has a substituent selected from halogen, CM, MO", CE", OH and C./-Alkoxy; "Ar" is phenyl, which is substituted by halogen in positions 2 and 5; Ba is H, C 4.6-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C.4 b-alkyl, C b-alkenyl, any of them, t c optionally, has a substituent selected from halogen, CM, MO», CEz, OB??, СОБ25, М(К2)», СОМ(Б2У )", Ag and SOAG, with" or 22 is Ag, or two groups of K 22 together with the nitrogen atom to which they are mutually attached can close an M-heterocyclic group having 0-4 substituents independently selected from 50, -5, halogen, C..4-alkyl, SM, MO», SEz, OH, C.i.,-alkoxy, C.-alkoxycarbonyl, SON, amino, C../-alkylamino, di(C.-. 4-alkyl)amino, carbamoyl, Ag and SOAG; their B is H, C/4-alkyl, C3 6-cyclo alkyl, C3 6-cycloalkyl-C.4 in-alkyl, C3-alkenyl, any of them, He) optionally has a substituent selected from halogen, CM, MO», CEz, OH, C.. 4-Alkoxy, C..-Alkoxycarbonyl, SON, C..4-amino, C..4-alkylamino, di(C..4-alkyl)amino, carbamoyl, Ag or COAGg, or 225 is Ag, or two groups of 5p, together with the nitrogen atom to which they are mutually attached, can close the M-heterocyclyl group having 0-4 se) substituents independently selected from -0, -5, halogen, C.id-alkyl, CM, MO». SEz, OH, cS...-Alkoxy, also C..a-Alkoxycarbonyl, SON, amino, C..4-alkylamino, di(C..4-alkyl)amino, carbamoyl, Ag and SOAG; Ag is a phenyl or heteroaryl having 0-3 substituents selected from halogen, C 4,4-alkyl, C, M, C, C, H, C, /-Alkoxy, C, -Alkoxycarbonyl, amino, C - alkylamino, di(C..4-alkyl)amino, carbamoyl, C..1-alkylcarbamoyl and di(C..4-alkyl)ucarbamoyl; or a pharmaceutically acceptable salt thereof. (F) 2. Compound according to claim 1, where Ag! selected from phenyl groups substituted in the 4-position with halogen, methyl or trifluoromethyl, and phenyl groups substituted with halogen in the 3- and 4-positions. 3. Compound according to claim 1 or claim 2, where Ag! is 4-fluorophenyl or 4-trifluoromethylphenyl and Ag? is 2,5-difluorophenyl. 4. The compound according to any of claims 1-3, where 7 represents CO" 72, and 72 represents H or C. d-alkyl. 5. The compound according to claim 1, where t is equal to 1, Ag is 4-chlorophenyl, Ag 2 is 2,5-difluorophenyl, CT | Ve, both, represent H and 7 represents SON, or a pharmaceutically acceptable salt thereof. b. Compound according to claim 1, where t is equal to 1, Ag! represents 4-trifluoromethylphenyl, Ag 2 represents bo 2,5-difluorophenyl, B" and BC, both, represent H, and 7 represents CO 2H, or its pharmaceutically acceptable salt. 7. The compound according to claim 1, where t is 0, Ag is 4-chlorophenyl, Ag? is 2,5-difluorophenyl, K 1c is H, and 7 is SOMH", or a pharmaceutically acceptable salt thereof. 8. Compound according to claim 1, where t is equal to 0, Ag! represents 4-trifluoromethylphenyl, Ag 2 represents 2,5-difluorophenyl, VK: represents H, and 7 represents СОМН", or its pharmaceutically acceptable salt. 9. The compound according to claim 1, where t is 0, Ag is 4-chlorophenyl, Ag? is 2,5-difluorophenyl, K 1c is H, and 7 is SOMNON»CH» or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, where t is 0, Ag is 4-chlorophenyl, Ag? is 2,5-difluorophenyl, K 1c 70 is H, and 7 is CM, or its pharmaceutically acceptable salt. 11. A compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof for use in a method of treating the human body. 12. A pharmaceutical composition containing a compound specified in any of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 19 13. Use of the compound specified in any of claims 1-10, or its pharmaceutically acceptable salt, in the manufacture of a medicinal product for the treatment or prevention of Alzheimer's disease. 14. A method of treating a subject suffering from Alzheimer's disease or predisposed to Alzheimer's disease, wherein said subject is administered an effective amount of a compound of formula I! according to claim 1 or its pharmaceutically acceptable salt. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2006, M 8, 15.08.2006. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with (8) "- (22) " (Se) m. - with . and? -I (22) sh» o 50 - F) ime) 60 b5