UA78050C2 - Ortho-benzoic acid derivatives for treating insulin resistance - Google Patents

Abstract

The present invention provides a compound of formula (I), wherein n is 0, 1 or 2 and R1 represents halo, a C1-4alkyl group which is optionally substituted by one or more fluoro, a C1-4alkoxy group which is optionally substituted by one or more fluoro and wherein when n is 2 the substituents R1 may be the same or different; R2 represents a C2-8alkyl group which is optionally interrupted by oxygen; Y is absent or represents methylene; and X is O or S; and pharmaceutically acceptable salts and prodrugs thereof, to processes for preparing such compounds, to their utility in treating clinical conditions associated with insulin resistance, to methods for their therapeutic use and to pharmaceuticalcompositions containing them.

Description

Description of the invention

The present invention relates to some new derivatives of benzoic acid, methods of obtaining such 2 compounds, their usefulness in the treatment of clinical conditions associated with insulin resistance, methods of their therapeutic use and pharmaceutical compositions containing them.

Insulin resistance syndrome (IRS), involving type 2 diabetes, which refers to a set of findings involving insulin resistance with accompanying hyperinsulinemia, possibly type 2 diabetes, hypertension, central (visceral) obesity, dyslipidemia, manifested as abnormal levels of 70 lipoprotein, usually characterized by elevated LDL (very low density lipoprotein), particles

Low-density lipoprotein (LDL) and by reducing LDL (high-density lipoprotein) concentrations and reducing fibrinolysis.

A recent epidemiologic study documented that individuals with insulin resistance have a significantly increased risk of cardiovascular morbidity and mortality, particularly myocardial infarction and stroke. In type 2 diabetes, atherosclerosis-related conditions account for up to 8,095 of all deaths. 12 Clinical medicine recognizes the need to increase insulin sensitivity in patients suffering from SRI and, therefore, to correct dyslipidemia, which is believed to cause an accelerated progression of atherosclerosis.

However, it is not now a comprehensively well-defined disease.

Modulators of peroxisome proliferator-activated receptors (APPR, for an overview of APPR, see T.

M. MUyvop ey a, U Mei Spet 2000, Mo! 43, 527| are effective in the treatment of conditions associated with insulin resistance. (5,575,783) discloses that certain benzyloxy-substituted phenylglycinolamides having a cycloalkyl substituent are antiatherosclerotic drugs. This document does not disclose or contemplate the compounds of the present invention.

Unexpectedly, a series of compounds that are selective APPR modulators was discovered. with

The presented invention relates to the compound of the formula I (he)! tA m o o. : where "c) c and - where n is equal to 0, 1 or 2, and c represents halogen, C. 4alkyl, which is optionally substituted by one or more fluorine, C. daloxyl, which is optionally substituted by one or more by fluorine, and if n equals 2, the K 4 substituents can be the same or different; "2" represents C" in-alkyl, which, as an option, is interrupted by oxygen; o c Y is absent or represents methylene; and

X represents O or 5; and" and its pharmaceutically acceptable salts and prodrugs.

Further values of B", B, Y, and X in the compounds of formula | are as follows. It is understood that such values may be USED from any of the definitions, claims, or embodiments defined above or below. - and According to one aspect, X represents 0.

According to a second aspect, X represents 5. co According to a third aspect, Y represents methylene. o According to the fourth aspect, U is absent. sl 50 According to the fifth aspect of B! represents halogen, C. alkyl or C. alkyloxyl, and n is 0.1 or 2.

In particular, B represents fluoro, methoxy, or isopropyl when n is 1 or 2. In particular, n is 0. According to a sixth aspect, 2 represents C 1-7 alkyl.

Term C". alkyl means a linear or branched chain saturated aliphatic hydrocarbon having from 2 to 8 carbon atoms. Examples of said alkyl include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, and straight and branched-chain pentyl, hexyl, heptyl, and octyl.

GF! Those skilled in the art will appreciate that the term interrupted as used above means that the oxygen atom is located within the alkyl chain and is not a terminal atom. The term "prodrugs" as used herein includes derivatives of a carboxyl group that are converted in a mammal, especially a human, to a carboxyl group or a salt or conjugate thereof. It is clear that, without recourse to theory, it is believed that most of the activity associated with the prodrugs is due to the activity of the compound of formula I into which the prodrugs are converted. Prodrugs can be obtained by conventional methods available to specialists. A variety of carboxy group-based prodrugs are known in the art. For example, look at the following derivatives of prodrugs: a) Oevidp Rgodgidv, eayey ru N. Vypaddaaga, (Eivemieg, 1985) and Meijodz ip EpgutoYodu. 42: 309-396, edited by Bu KU/aaeg, ei a. (Asadetis Rgezv, 1985); bo B) A Tehirook oi Ogyd YuOevidp apa OemeIyuortepi, edyea ru Kgodzdaaga-aggep and N. Vypdaaga, Spariieeg 5 "Oezidp apa Arriisayop oi Rgodgodvg", Bu N. Vypadaaga r, 113-191 (1991);

c) N. Vypddaaga, Admapsey Ogyd Oeiimegu Kemiemuv, 8:1-38 (1992); 4) N. Vypaddaago, ey ai, doshigpai! oh Rnagtaseciisa!| Zsiepsev, 77: 285 (1988); and f) M. Kakkeua, ei ai., Spet RIagt Vii, 32: 692 (1984).

The above documents a - e are incorporated by reference.

Cleavage of ip by esters is just one type of prodrug of the parent molecule.

Compounds of the formula | have activity as drugs, in particular, compounds of formula I are selective agonists

APPR", their ECo for APPR, are at least four times lower, and preferably at least 10 or 50 times lower than their respective ECo for APPR ut where ECbvo is measured and calculated as described in studies later in this 70 document. Compounds of the formula | are powerful and selective.

Specific compounds of the invention are one or more of the following: 2-(К4-13-(benzyl(hexyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-((4-2-(2,4-difluorobenzyl)( heptyl)amino|-2-oxoethylphenyl)thio|methylibenzoic acid; 2-(4-2-Ibenzyl(hexyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; 2-(4-2-(2,4-difluorobenzyl) )(heptyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; 2-((4-13-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-4( 4-(3-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenyl)thio|methyl)ibenzoic acid; 2-K4-13-I(butyl(2,3-dimethoxybenzyl)amino|-3- oxopropyl.phenoxy)methyl|benzoic acid; 2-(4-13-(2,3-dimethoxybenzyl)(heptyl)-amino|-3-oxopropylphenoxy)methyl|-benzoic acid; 2-K4-13-(3-ethoxypropyl )(4-isopropylbenzyl)amino|-3-oxopropylphenoxy)methyl|-benzoic acid; 2-(4-13-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoic acid; 2-(4-2-(ethyl(2-fluorobenzyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid ; 2-K4-13-ethyl(2-fluorobenzyl)amino|-3-oxopropyl.phenoxy)methyl|benzoic acid; 2-(14-(2-ethyl4-(trifluoromethyl)benzylamino)-2-oxoethyl)phenylthio)umethyl)benzoic acid; He 2-(4(3-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylphenyl)thiomethyl]ibenzoic acid; and 2-((4-2-(4-chlorobenzyl)(ethyl)amino|- 2-oxoethyl)phenyl)thio)methyl)ibenzoic acid and their pharmaceutically acceptable salts.

The second group of specific compounds of the invention contains a compound selected from the group: 2-((4-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylphenyl)thio|methylibenzoic acid; av) 2-4(4- (3-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenyl)thio|methyl)ibenzoic acid; 2-C4-(2--ethyl14-"(trifluoromethyl)benzylamino)-2-oxoethyl)phenylthio)methyl)benzoic acid; o 2-(4(3-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylphenyl)thiomethyl benzoic acid; and av) 2-((4-2-(4-chlorobenzyl)(ethyl)amino |-2-oxoethyl)phenyl)thio)methyl)ibenzoic acid and their pharmaceutically acceptable salts. 09

The third group of specific compounds of the invention contains a compound selected from the group: - 2-(К4-13-(benzyl(hexyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-(4-2-Ibenzyl(hexyl)amino|- 2-oxoethylphenoxy)methyl|benzoic acid; 2-(4-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; « 2-((4-13-(2, - c 2-К4-13-(2,3-dimethoxybenzyl)(heptyl)-amino|-3-oxopropyl.phenoxy)methyl|benzoic acid; 2-К4-13-(3-ethoxypropyl)(4-isopropylbenzyl)amino| -3-oxopropylphenoxy)methyl|-benzoic acid; and» 2-(4-13-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoic acid; 2-(4-2-(ethyl(2-fluorobenzyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; 2-K4-13--ethyl(2-fluorobenzyl)amino|-3-oxopropyl.phenoxy)methyl| benzoic acid; - I and their pharmaceutically acceptable salts.

Some compounds of the present invention may be tautomers. It is clear that the present invention applies to all such tautomeries. (a) In the description and appended claims, the chemical formula or name includes all stereo and optical isomers and their racemates, as well as mixtures of individual enantiomers in various proportions, when such isomers and enantiomers exist, as well as their pharmaceutically acceptable salts. Isomers can be separated using conventional methods, such as chromatography or fractional crystallization. Enantiomers can be isolated by resolution of the racemate, for example, fractional crystallization, separation or HPLC. Diastereomers can be separated by separation of isomeric mixtures, for example, by fractional crystallization, HPLC, or flash chromatography. Alternatively, stereoisomers can be obtained by chiral synthesis from chiral starting materials under conditions that will not cause racemization or epimerization, or by derivatization with a chiral reagent. All stereoisomers of o are included in the scope of the invention. Name) Methods of obtaining

The compounds of the invention can be prepared as follows. However, the invention is not limited to these methods, compounds 60 can also be obtained as described for structurally related compounds in the prior art. Reactions can be carried out by standard methods, or as described in the experimental section.

Compounds of formula I can be obtained by reaction of compounds of formula II b5

HER

(in that I m

What and in which B", 2, X and XU are defined earlier, and PO represents the protecting group for the carboxyl hydroxyl, which is described in the handbook "Rgoyesiime Sgotsr ip Ogdapis Zupipeviv", 2 Edyop (1991) ru OSgeepe and UUtsiv), with a means deprotection The protecting group may also be a resin such as Wang's resin or 2-chlorotrityl chloride resin.

Protecting groups can be removed by methods well known in the art. One such is a protecting group, where PO/5 represents a alkyl or arylalkyl, for example, benzyl, so that SOPO represents an ester. Such esters can react with a hydrolyzing agent, for example, lithium hydroxide in the presence of a solvent, for example, a mixture of THF and water, or potassium hydroxide in an alcohol, for example, methanol, at a temperature in the range of 0-2002C or microwave irradiation, with the formation of a compound of formula I.

Compounds of formula II can be obtained by the reaction of compounds of formula II

PI

E c or its salts, for example hydrochloride, c, of which B, B2 and p are defined earlier, with the compound of the formula IM o

IM but | (rea s Shcheo, "c) s s : : : and - or its chloride anhydride, in which X, U and PO were previously determined in an inert solvent, for example, dichloromethane, as an option, in the presence of a coupling agent, for example, 4-dimethylaminopyridine or 1 -ethyl-3-(3-dimethylaminoprolyl)carbodiimide hydrochloride, at a temperature ranging from -259C to 150260.

Compounds of the formula II can also be obtained by the reaction of the compound of the formula M « m - - (8 i» t c "ih t hi -I so in which B", n, B2, X and U are defined earlier with the compound of the formula MI ("c) Orea M!c 50 o E 29 in which PO is defined earlier and | represents a leaving group, for example halogen, for example bromine, as

GF! alternatively, in the presence of a solvent, for example, acetonitrile, and, alternatively, in the presence of a base, for example, potassium carbonate, at a temperature ranging from 0 to 1502C. o Compounds of the formula I, M, M and MI can be obtained by the methods described in the examples or similar methods known to specialists. 60 Compounds of formula II, II, M and M are useful intermediates in the preparation of compounds of formula I. Some of these compounds can be considered new. Novel compounds of formula II, or formula I, or formula IM, or formula U are claimed herein as a further aspect of the present invention.

The compounds of the invention can be isolated from their reaction mixtures using conventional methods.

It is clear to those skilled in the art that in order to obtain a compound of the invention in an alternative, and in some cases, a more convenient way, specific steps of the method mentioned hereinbefore can be carried out in a different sequence, and/or specific reactions can be carried out at different stages of the general pathway (i.e. chemical transformations can be carried out with intermediates other than those associated with the above specific reactions).

In any of the previous methods of preparation, where necessary, the hydroxide, amino or other reactive groups can be protected by using the KR protecting group, (as described in the handbook "Rgoiesime Sgopr ip Ogdapis

Zupipevziv", 2 Ediyop (1991) ru Sgeepe and MUtsiv). The protecting group can also be a resin such as Wang's resin or 2-chlorotrityl chloride resin. Protection and deprotection of functional groups can be carried out before or after any of the reaction steps , previously described herein. Protecting groups can be removed by methods well known in the art. 70 The term "inert solvent" refers to a solvent that does not react with starting materials, reagents, intermediates, or products in a manner that adversely affects the yield of the desired product.

Pharmaceutical drugs

The compounds of the invention will typically be administered orally, parenterally, intravenously, intramuscularly, subcutaneously or by other suitable injectable routes, buccally, rectally, vaginally, transdermally and/or nasally, and/or by inhalation, in the form of pharmaceutical preparations containing the active ingredient as a free acid or a pharmaceutically acceptable salt in a pharmaceutically acceptable dosage form.

Depending on the disorder and the patient being treated, and the route of administration, the compositions may be administered at various dosages.

Suitable daily doses of the compounds of the invention in the therapeutic treatment of humans are approximately 0.0001-10mg/kg of body weight, preferably 0.001-10mg/kg of body weight.

Oral compositions are preferred, especially tablets or capsules, which can be formulated by methods known to those skilled in the art to provide a dose of the active compound in the range of 0.5 mg to 50 mg, for example mg, Zmg, 5mg, 1Omg, 25Bmg, Bomg, 100Omg and 250mg.

According to the following aspect of the invention, a pharmaceutical composition containing any compound of the invention, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable adjuvants, diluents and/or carriers is provided. i9)

Pharmacological properties

The present compounds of formula (I) are useful for the prevention and/or treatment of clinical conditions associated with inherent or induced reduced sensitivity to insulin (insulin resistance) and associated metabolic disorders (also known as metabolic syndrome). These clinical conditions include, but are not limited to, general obesity, abdominal obesity, hypertension, hyperinsulinemia, hyperglycemia, type 2 diabetes, and dyslipidemia characterized by insulin resistance. This av! dyslipidemia, also known as the atherogenic lipoprotein profile, is characterized by moderately elevated non-esterified fatty acids, elevated triglyceride-enriched very low density lipoprotein (LDL) particles, high Apo B levels, low high density lipoprotein (HDL) levels, - associated with low particle levels aroAi and high levels of AroB in the presence of small, dense particles of low-density lipoproteins (LDL), phenotype B.

The compounds of the present invention are expected to be useful in the treatment of patients with combined or mixed hyperlipidemias or varying degrees of hypertriglyceridemia and afternoon dyslipidemia with or without other manifestations of the metabolic syndrome. - sh

Treatment with the present compounds is expected to reduce cardiovascular morbidity and mortality associated with atherosclerosis due to their anti-dyslipidemic as well as anti-inflammatory properties. Cardiovascular disease states involve macroangiopathies of various internal organs, causing myocardial infarction, congestive heart failure, cerebrovascular disease, and peripheral arterial insufficiency of the lower extremities. As a result of their insulin sensitizing effect, compounds -I of formula I are also expected to prevent and delay the development of type 2 diabetes from metabolic syndrome and gestational diabetes. Therefore, the development of long-term complications associated with chronic hyperglycemia in diabetes, such as micro-angiopathies that cause kidney disease, damage to av! retina and is expected to delay lower extremity peripheral vascular disease. In addition, compounds

May be useful in the treatment of a variety of non-cardiovascular conditions, whether or not associated with insulin resistance, such as polycystic ovary syndrome, obesity, cancer, and inflammatory disease states, including neurodegenerative disorders such as mild cognitive impairment, disease Alzheimer's disease

Parkinson's disease and multiple sclerosis.

The compounds of the present invention are expected to be useful in regulating glucose levels in type 2 diabetic patients.

The present invention relates to a method of treating or preventing dyslipidemias, insulin resistance syndrome and/or metabolic disorders (as defined above) involving the administration of a compound of the formula to a mammal (especially a human) in need thereof.

The present invention relates to a method of treating or preventing type 2 diabetes, which involves administering an effective amount of a compound of formula I to a mammal (especially a human) in need thereof.

According to the following aspect, the present invention relates to the use of a compound of formula I as a medicament.

According to the following aspect, the present invention relates to the use of a compound of formula I in the manufacture of a medicament for the treatment of insulin resistance and/or metabolic disorders. 65 Combination therapy

The compounds of the invention may be combined with another therapeutic agent useful in the treatment of disorders,

associated with the development and progression of atherosclerosis, such as hypertension, hyperlipidemia, dyslipidemia, diabetes, and obesity. The compounds of the invention can be combined with another therapeutic agent that reduces the ratio

LNG:LVH or an agent that causes a decrease in circulating levels of LNG-cholesterol. In patients with diabetes, the compounds of the invention can also be combined with therapeutic agents used to treat complications related to micro-angiopathies.

The compounds of the invention can be used in conjunction with other therapies for the treatment of metabolic syndrome or type 2 diabetes and associated complications involving biguanide drugs, such as metformin, phenformin and buformin, insulin (synthetic insulin analogues, amylin) and oral antihyperglycemic agents 7/0 (which are divided into food glucose regulators and alpha-glucosidase inhibitors). An example of an alpha-glucostdase inhibitor is acarbose or voglibose or miglitol. An example of a dietary glucose regulator is repaglinide or nateglinide.

According to another aspect of the invention, the compound of formula I or its pharmaceutically acceptable salt, solvate, solvate of such a salt or its prodrug, can be used in association with another APPR-modulating agent.

APPR-modulating agents include, but are not limited to, an agonist of APPR-alpha and/or gamma and/or delta, or its pharmaceutically acceptable salts, solvates, solvates of such salts, or prodrugs. Suitable alpha and/or gamma agonists of APPR, their pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs are known in the art. These include compounds (described in MO 01/12187, MO 01/12612, MO 99/62870, MO 99/62872, MO 99/62871, MO 98/57941, MO 01/40170, U Mei Spet, 1996,39, 665, Ekhregi Oripiop op Tnegaretsiis Raiyepiv, 10 (5), 523-634 (in particular, the compounds described in the patent application on page 634) and U Mei Speth, 2000, 43, 527), which are incorporated by reference. Especially the agonist APPR alpha and/or gamma refers to VM5 298585, clofibrate, fenofibrate, bezafibrate, gemfibrozil and ciprofibrate; SUU9578, pioglitazone , rosiglitazone, rivoglitazone, balaglitazone,

KAR-297, TT-501, 5B 213068, MUuU1929, SMUU 7845, MU 0207, I -796449, I -165041 and SUMU 2433. Especially an agonist

APPR alpha and/or gamma refers to (5)-2-ethoxy-3-I4-(-2--4-methanesulfontoxy-phenyl)ethoxy)phenyl|propane sc

Db Acid and its pharmaceutically acceptable salts.

In addition, the combination of the invention can be used in combination with a sulfonylurea, such as glimepiride, o); glibenclamide (glimidine), gliclazide, glipizide, glihidone, chlorpropamide, tolbutamide, acetohexamide, glysopyramide, carbutamide, glibonuride, glisoxepid, glibutiazole, glibuzol, glighexamide, glimidine, glipinamide, fenbutamide, tolcylamide, and tolazamide. Preferably, the sulfonylurea is glimepiride or glibenclamide (glimidine). glimepiride is more preferably a sulfonylurea. Thus, the present invention relates to the use of a compound of the present invention in combination with one, two or more existing therapies described in this section. Doses of other existing therapies for the treatment of type 2 diabetes and associated complications are known to those skilled in the art and have been approved for use by regulatory bodies such as the EOA and can be found in the EBA-published Ogapde VsokK. Alternatively, lower doses may be used as a result of the benefit of the combination. The present invention also relates to compounds of the present invention in combination with a cholesterol-lowering agent. Cholesterol-lowering agents of this application include, but are not limited to, NMO-CoA (3-hydroxy-3-methylglutaryl coenzyme A reductase A) reductase inhibitors. Accordingly, the NMO-CoA reductase inhibitor is a statin selected from the group consisting of atorvastatin, bervastatin, cerivastatin, dalvastatin, fluvastatin, itavastatin, lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and simvastatin, or a pharmaceutically acceptable salt thereof, especially sodium or of calcium, or a schwc solvate, or a solvate of such a salt. A particular statin is atorvastatin, or a pharmaceutically acceptable salt, solvate, solvate of such a salt, or prodrug thereof. An even more special statin is the salt of atorvastatin and calcium. )» Especially the best statin is, however, the compound Kk! chemical name (E)-7-(4--4-fluorophenyl)-6-isopropyl-2-I(methyl(imitylsulfonyl)-amino|-pyrimidin-5-yl|(ZK,55)-3,5-dihydroxyhept - b-enoic acid, (also known as -I (E)-7-(4--4-fluorophenyl)-6-isopropyl-2-N-methyl-M-(methylsulfonyl)-amino|-pyrimidine-5- il|(ZK,55)-3,5-dihydroxy hept-b-enoic acid| or its pharmaceutically acceptable salt or solvate, or a solvate of such a salt Compound co (E)-7-(4--4-fluorophenyl)-6 -isopropyl-2-I(methyl-(methylsulfonyl)-amino)|-pyrimidin-5-yl)(ZK,55)-3,5-dihydroxyhept o -6-enoic acid and its calcium and sodium salts were disclosed (In the European patent application publication 5r MeER-A-0521471, and in Viogdapis and Measipa! Spetizig, (1997), 5(2), 437-444). This latter statin is now known generically as rosuvastatin. o In the present application, the term "cholesterol-lowering agent" also involves chemical modifications of inhibitors

NMO-CoA reductases, such as esters, prodrugs, and metabolites, are active or inactive.

The present invention also relates to compounds of the present invention in combination with a complexing 5b bile acid compound, for example, cholestipol or cholestyramine or cholestagel.

The present invention also relates to a compound of the present invention in combination with an inhibitor of the ileo-intestinal bile acid transport system (IF inhibitor). ka Suitable compounds exhibiting inhibitory activity against TKKJK, (described, see, for example, compounds described in MO 93/16055, UMO 94/18183, UMO 94/18184, UMO 94/24087, MO 96/05188, MO 96/ 08484, MO in 96/16051, UUO 97/33882, MO 98/07749, UMO 98/38182, UMO 98/40375, UMO 98/56757, UMO 99/32478, MO 99/35135, UMO 99/64409, MO 99 /64410, MO 00/01687, MO 00/20392, UMO 00/20393, UMO 00/20410, UMO 00/20437, UMO 01/34570, MO 00/35889, MO 00/47568, UMO 00/61568, UMO 01 /68637, UMO 01/68096, UMO 02/08211, UMO 00/38725, UMO 00/38726, MO 00/38727, MO 00/38728, MO 00/38729, OV 19825804, OR. 10072371, 05 5070253 315, EP 417 725, EP 489 423, EP 549 967, EP 573 848, EP 624 593, EP 624 594, EP 624 595, EP 869 121, EP 864 582, and EP 1 070 703), 65 Contents of these patent applications especially the compounds described in clause 1 and the named examples are incorporated by reference.

Special classes of TKKJK inhibitors, suitable for use according to the present invention, are benzothiepines and compounds (described in the formulas of the inventions, especially item 17 MUO 00/01687, MUO 96/08484 and MO 97/33882|, introduced as a reference, by others suitable classes of TCC inhibitors are 1,2-benzothiazepines, 1,4-benzothiazepines and 1,5-benzothiazepines.The next suitable class of TCC inhibitors are 1,2,5-benzothiadiazepines.

One particularly suitable compound that exhibits inhibitory activity against TCCFA is (ZK,5K)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4- benzothiazepin-8-yl-D-O-glucopyranosiduronic acid (EP 864 5821. Other suitable inhibitors of TKKJK involve one of the group: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M -(K)-1"-phenyl-1'-IM'"carboxymethyl)carbamoyl|methylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3- dibutyl-5-phenyl-7-methylthio-8-(M-(K)-o,-I(M'«Ecarboxymethyl)carbamot|-4-hydroxybenzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5 -benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)-1"-phenyl-1-(M'2-sulfoethyl)carbamoyl|methyl) Icarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(M-(K)-1"-phenyl-1'-IM'EE2-sulfoethyl)carbamoyl|methylcarba 75 Mmoylmethoxy )-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, - (M-(2-sulfoethyl)carbamot|-4-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5- phenyl-7-methylthio-8-(M-(K)-o; -(ME2-sulfoethyl)carbamoyl-1H-4-hydroxybenzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1, 1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(M-(K)-o; -(M'2-carboxyethyl)carbamoyl|benzylcarbamoylmethoxy)-2,3,4, 5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(M'2-carboxyethyl)carbamoyl |-4-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-( M-(K)- o; c -(M'E5-carboxypentyl)carbamoyllibsenyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; he) 1,1-dioxo-3,3- dibutyl-5-phenyl-7-methylthio-8-(M-(K) - o, -(M'2-carboxyethyl)carbamoyl|benzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(o,ozo -(ME2-sulfoethyl)carbamoyl|-2-fluorobenzylcarbamoylmethoxy)-2,3, 4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(M-(K)- o; t) -(IM "K)-(2-hydroxy-1-carboxyethyl)carbamoylbenzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; o 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM'«K)-(2-hydroxy-1-carboxyethyl)carbamoyl |benzyl)carbamoyl|methoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; so 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, cha -DM'Ya(K)-1-(M"-(K) -(2-hydroxy-1-carboxyethyl)carbamoyl-2-hydroxyethylcarbamoyl)benzyl|carbamoylmethoxy)-2,3 4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl- 5-phenyl-7-methylthio-8-(M-(K)-o; " -(M'"K)-(carboxymethyl)carbamoyl|benzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1, 5-benzothiazepine; 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(M-(K)- o, - c -(M'«K)-(ethoxy) Xmethyl)phosphoryl-methyl)carbamoyl(benzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; )» 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7- methylthio-8-7M-((K)-o; -(M'EK)-2-Khydroxymethyl)phosphoryl|ethylcarbamoyl)benzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)-o,

Ge | -(ME2-methylthio-1-carboxyethyl)carbamoylIbsenyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, o -(ME:-Kmethyluethyl)phosphoryl|ethyl)carbamoyl)-4- hydroxybenzyl|carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzo 1 20 thiazepine; o 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(MK)- o; -(M'E2:-Kmethyl)u(hydroxy)phosphoryl|ethylcarbamoyl)- 4-hydroxybenzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-6 enzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(ME2-methylsulfinyl-1-carboxyethyl)carbamoyl ibsensyl)carbamoylmethoxy)-2, 3,4,5-tetrahydro-1,5-benzothiazepine; (F) 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-(M-(K)-o, ka -(ME2-sulfoethyl)carbamoyl)|-4-hydroxybenzyl )icarbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, vo 0 -ІМЄ1-carboxy-2-methylthio-ethyl)carbamoyl|-4 -hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothi adiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(M-((5)-1-carboxy-2-(K)- hydroxypropyl)carbamoyl(4-hydroxybenzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,

B-benzothiadiazepine; 65 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM-((5)-1-carboxy-2-methylpropyl)carbamot /-4-hydroxybenzyl)carbamomethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM-((5)-1-carboxybutyl)carbamoyl1-4-hydroxybenzyl) carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM-((5)-1-carboxypropyl)carbamoylIbenzyl)carbamoylmethoxy)-2 ,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM-((5)-1-carboxyethyl)carbamoyl|benzyl)carbamoylmethoxy) -2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, 10. -Im-((5)-1-carboxy-2-(K) -hydroxypropyl)carbamoyl|benzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiade iazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -I(M-(2-sulfoethyl)carbamoylI-4-hydroxybenzylcarbamoylmethoxy)-2, 3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, 12 -( M-((5)-1-carboxyethyl)carbamot|c-4-hydroxybenzylcarbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl- 5-phenyl-7-methylthio-8-(M-(K)-o,-I(M-(K)-1-carboxy-2-methylthioethyl)carbamoyl|benzylcarbamoylmethoxy)-2,3,4,5-tetrahydro -1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(M-((5)-1 -(M-((5)-2-Hydroxy-1-carboxyethyl)carbamoyl|propyl)iocarbamoyl Ibsenyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo -3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)-o, -(IM-((5)-1-carboxy-2-methylpropyl)carbamoyl|benzylcarbamoylmethoxy)-2, 3,4,5-tetrahydro-1,2,5-benzothiadiazepine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)-o, sc two 7IM -(5)-1-carboxypropyl)carbamoyl-1-4-hydroxybenzylcarbamoylmetho xy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiase o pin; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K,5)-o; -9M-(1-(25)-2-(5)-1 -hydroxy-1-(3,4-dihydroxyphenyl)prop-2-ylylcarbamoyl)-4-hydroxybenzyl)carbamoylmethoxy!)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; av 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM-(2-(5)-3-(2)-4 -(K)-5-(K)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl|-4-hydroxybenzyl)carbamoylmethoxy)-2,3,4 o,o-tetrahydro-1,2,5- benzothiadiazepine; and av 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(M-(K)- o, -(IM-(2-(5)-3-(2)- 4-(K)-5-(K)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl|benzylcarbamoylmethoxy)-2,3,4,5-tetrahydroiso-1,2,5-benzothiadiazepine; - or its pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug.

According to an additional aspect of the present invention, there is provided a combination therapy involving the administration of an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous, sequential or separate by using one or more of the following means selected from group C c inhibitor of BPHE (cholesteryl ester transfer protein), for example, |described in UMO 00/38725 p.7 p.22 - p.10, p.17)|, which is introduced as a reference; )" cholesterol absorption antagonist, for example, azetidinones such as CH 58235 and described in O5 5 767 115), which are incorporated by reference; an inhibitor of BMP (microsomal transport protein), for example, described in Zsiepse, 282, 751-54, 1998), which is incorporated by reference; with a nicotinic acid derivative, involving sustained-release products and combinations such as nicotinic acid (niacin), acipimox, and niceritrol; (а) a phytosterol compound, for example, ethanols; sl 50 probukol; an anti-obesity compound, for example, orlistat (EP 129,748) and sibutramine (SV 2 184 122 and 05 4 929 629); (42) omega-3 fatty acid, such as Otasogtm; antihypertensive compound, eg, angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor antagonist, adrenergic blocker, alpha adrenergic blocker, beta adrenergic blocker, 2o eg metoprolol, mixed alpha/beta adrenergic blocker, adrenergic stimulant, calcium channel blocker, AT-1 blocker, saluretic, diuretic or vasodilator; an antagonist or inverse agonist of SVI, for example, which is described in UMO 01/70700 and EP 656351; where is aspirin; antagonist of melanin-concentrating hormone (MCH); 60 ROK inhibitor, or modulators of nuclear receptors, for example, I HC, EHC, EHE, and COoOK-alpha; or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs, optionally together with a pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as a human, in need of such therapeutic treatment. 65 Specific ACE inhibitors or pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs involving active metabolites that can be used in combination with a compound of formula I include, but are not limited to, the following compounds: alazepril, alatriopril, altiopril calcium, ancovenin, benazepril, benazepril hydrochloride, benazeprilat, benzoylcaptopril, captopril, captopril-cysteine, captopril-glutathione, ceranapril, ceranopril, ceronapril, cilazapril, cilazaprilat, delapril, delapril diacid, enalapril, enalaprilat, vnapril, epicaptopril, furoximitin, fosphenopril, fosenopril, fosenopril sodium, fosinopril, fosinopril sodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril, lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, movelitipril, muracein A, muracein B, muracein C, pentopril, perindopril, periadoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride, quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride, 7/0 spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocapril hydrochloride, teprotide, trandolapril, trandolaprilat, utibapril, zabicipril, zabiciprilat, zofenopril, and zofenoprilat. Preferred ACE inhibitors for use in accordance with the present invention are ramipril, ramiprilat, lisinopril, enalapril and enalaprilat. Even better ACE inhibitors for use according to the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, their pharmaceutically acceptable salts, solvates, solvates of such salts or prodrugs for use in combination with a compound of formula | include, but are not limited to, the compounds: candesartan, candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan, selmisartan, and eproartan.

Particularly preferred angiotensin II antagonists or their pharmaceutically acceptable derivatives for use according to the present invention are candesartan and candesartan cilexetil.

Therefore, according to an additional feature of the invention, a method of treating type 2 diabetes and its associated complications in warm-blooded animals, such as humans, requiring such therapeutic treatment is proposed, which involves the application to the specified animal of an effective amount of the compound of formula I, or its pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug when administered simultaneously, sequentially or separately with an effective amount of one other compound described herein or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug.

Therefore, according to an additional feature of the invention, a method of treating hyperlipidemic conditions (io) in warm-blooded animals, such as humans, requiring such therapeutic treatment is proposed, which involves the application to said animal of an effective amount of a compound of the formula !, or a pharmaceutically acceptable salt, solvate, solvate thereof such a salt or prodrug with simultaneous, sequential or separate use with an effective o

With an amount of one other compound described herein, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug thereof. at

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate thereof, or a prodrug thereof, and one other compound described herein, or a pharmaceutically acceptable salt, solvate, solvate thereof, or a prodrug thereof , in association with a pharmaceutically acceptable diluent or carrier. uh-

According to a further aspect of the present invention, there is provided a kit comprising a compound of the formula or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof, and one other compound described herein or a pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug thereof.

According to the following aspect of the presented invention, a kit containing: "a) a compound of the formula | or its pharmaceutically acceptable salt, solvate, solvate of such salt or prodrug, in the first unit dosage form;

B) one other compound described herein, or a pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof; in the second unit dosage form; and c) a container containing said first and second dosage forms.

According to the following aspect of the presented invention, a kit containing: -I a) a compound of formula I or its pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug, together with a pharmaceutically acceptable diluent or carrier, in the first unit dosage form; co B) one other compound described herein, or a pharmaceutically acceptable salt, solvate, solvate of such a salt, or a prodrug thereof; in the second unit dosage form; and c) a container containing said first and second dosage forms. According to another feature of the invention, it is proposed to use a compound of formula I, or its pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug, and one of the other compounds described here, or its pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug, in the production of a medication for use in the treatment of metabolic syndrome or type 2 diabetes and associated complications in warm-blooded animals such as humans.

According to another feature of the invention, the use of the compound of formula I, or its pharmaceutical use, is proposed

F) an acceptable salt, solvate, solvate of such a salt or prodrug, and one of the other compounds described here, or its ka pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug, in the production of a medication for use in the treatment of hyperlipidemic conditions in warm-blooded animals, like a person 60 According to a further aspect of the present invention there is provided a combination treatment involving the administration of an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, solvate, solvate of such a salt or prodrug thereof, optionally together with a pharmaceutically acceptable diluent or carrier, with simultaneous, sequential or by separately administering an effective amount of one of the other compounds described herein, or a pharmaceutically acceptable salt, solvate, solvate of such salt, or prodrug, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as a human, in need of such therapeutic treatment

Examples

"H NMR" and "ZS NMR" measurements are carried out on spectrometers Magiap Megsigu 300 or Magiap OMITU riiz 400, 500 or 600, working at frequencies of TN 300, 400, 500 and bOMHz, respectively, and at frequencies of 130, 75, 100, 125 and 150OMHz, in accordance. Measurements are made on the delta scale (5).

Unless otherwise stated, chemical shifts are presented in ppm with solvent as internal standard.

Abbreviation

SRI syndrome of insulin resistance

TLC thin-layer chromatography

NEW 1-hydroxybenzotriazole hydrate

OIV AN diisobutylaluminum hydride

DMSO dimethylsulfoxide

EUAs ethyl acetate

OME M,M-dimethylformamide

THF tetrahydrofuran

HPLC high-performance liquid chromatography

Mesm acetonitrile

TFOC trifluoroacetic acid

Ra/C of palladium on coal

NATY O-(7-azabenzotriazolyl-1-yl)-M,M,M'M'-tetramethyluronium hexafluorophosphate

DCM dichloromethane

TVTY O-(benzotriazol-1-yl)-M,M,M' M'-tetramethyluronium tetrafluoroborate

PBIREA M,M-diisopropylethylamine

LOBSTER 4-dimethylaminopyridine p

Trisamine Tris(hydroxymethyl)aminomethane Ge)

ISOGOTE 9 RIG ABZN 5i - column with silicon oxide, suitable for chromatography

Borohydride on a polymer substrate - borohydride on Atregiye IKA-400 from AiIagisp

LC-MS liquid chromatography - mass spectroscopy

A triplet is a singlet and a doublet

Z quartet o d hippy quintet so t multiplet

Zo rg is wide -

B5 is a wide singlet and doublet of a multiplet

B wide triplet « da doublet of doublets

Example 1 no) c a) M-benzyl-M-hexyl-3-(4-hydroxyphenyl)propane amide)» M-hexylbenzylamine (0.bg, 3.133 mmol) and 3-(4-hydroxyphenyl)propionic acid (0 .52g 3.13bmmol) are mixed in DMF (1Oml) and the mixture is cooled. NOVT (0.424g, 3.13bmmol) and reagent TVTIi (1g, 3.13bmmol) are added, followed by OIREA (1.216g, 9409mmol). The mixture was stirred at room temperature overnight and then evaporated. The resulting mixture is distributed between ethyl acetate and an aqueous solution of sodium bicarbonate - (saturated). The aqueous portions were extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and then evaporated. Chromatography of the residue on a column (ISOI OTEF 51, 5g/25ml) using ethyl acetate/heptane (10:90, then 25:75) as eluent gives 7b6Omg of the desired product, yield 7195. o TN NMR (rotamers, 5X00MHz, SOCI3): 5 0.84 (, ЗН), 1.16-1.27 (t, 6Н), 1.41-1.51 (t, 2Н), 2.55, 2.63 (и, и, 1 50 2Н ), 2.88, 2.94 (B B 2H), 3.09, 3.31 6 2H), 4.404.57 (c, 85, 2H), 6.69, 6.73 (a, a, 2 ), 6.98 (a, 2n), 7.05, 7.07 (a, 9, 2H), 7.14 (a, 1H) and 7.21-7.31 (t, 5H) with B) Methyl 2-(4-13-I(benzyl (hexyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoate

M-benzyl-M-hexyl-3-(4-hydroxyphenyl)propanamide (183mg, 0.54mmol), methyl 2-(bromomethyl)benzoate (13bmg,

0.59 mmol) and potassium carbonate (112 mg, 0.81 mmol) were mixed in acetonitrile. The mixture is stirred at 662 overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic phase (gF) is washed (water x2, brine x1), dried (M25O)) and evaporated. Further purification by preparative HPLC (using a gradient SNUSM/1096SNUSM-water phase containing 0.1 M MOH.OAc as eluent) gave 91 mg (yield 3490) of the desired product. IN nMR (rotamers, 400 MHz, SOSIz,): 5 0.84-0.88 (t, ЗН), 1.19-1.29 (t, 6Н), 1.42-1.53 bo (t, 2Н ), 2.57, 2.65 (5 B 2), 2.92, 2.99 (B 2H), 3.10, 3.34 (B i, 2H), 3.89, 3.90 (8 , 8, ЗН), 4.42, 4.60 (5, 8, 2Н), 5.47, 5.48 (85, 85, 2Н), 6.86-6.93 (t, 2Н), 7 .07 (5 2H), 7.14-7.19 (t, 2H), 7.21-7.38 (t, 4H), 7.52-7.56 (t, 1H), 7.75 ( i, 1H), 8.00-8.03 (t, 1H). c) 2-K4-(3-(benzyl(hexyl)amino)|-3-oxopropyl)uphenoxy)methyl|benzoic acid

Methyl 2-(4-13-(benzyl(hexyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoate (bimg, 0.1 mmol) and lithium hydroxide 65 (7 mg, 0.29 mmol) are dissolved in 3 ml of a 1:1 mixture THF and water in a microwave ampoule. The resulting reaction mixture is irradiated in a microwave oven at 1202C for 4 minutes.

Add water and THF, evaporate under reduced pressure. The residue is acidified with 1M hydrochloric acid and extracted with ethyl acetate (x3). The organic phases are combined, washed (with water, brine), dried (sodium sulfate) and evaporated. The crude material of the product is further purified by preparative HPLC (using a gradient

CH3CM/1096CH3CM-water phase containing 0.1M MH.OAc as eluent). ZVmg (yield 6490) of the pure product is obtained after drying by sublimation. "H NMR (rotamers, 400MHz, SOSIz): 5 0.86 (i, 3H), 1.19-1.28 (t, 6H), 1.43-1.55 (t, 2H), 2.60 , 2.69 (5 6 2H), 2.92, 2.99 (B 6 2H), 3.11, 3.936 (5 5 2H), 4.43, 4.61 (85, 8, 2H), 5 .52, 5.53 (8, 85, 2H), 6.87-6.93 (t, 2H), 7.05-7.09 (t, 2H), 7.14-7.33 (t, 5H), 7.36-7.40 (t, 1H), 7.55-7.59 (t, 1H), 7.77 (Y, 1H) and 8.12-8.15 (t, 1H) . 26, 31,61, 31,82, 35,39, 35,68, 46,84, 47,48, 48,72, 51,35, 68,42, 115,16, 115,22, 126,39, 127.15, 127.42, 127.49, 127.72, 128.23, 128.70, 129.10, 129.72, 131.31, 133.45, 133.81, 133.84, 137, 10, 137.82, 140.88, 157.33, 157.40, 171.20, 173.10, 173.39.

Example 2 a) M-(2,4-difluorobenzyl)-M-heptylamine

Heptylamine (345.6 mg, 3 mmol) was added to 2,4-difluorobenzaldehyde (440.5 mg, 3.1 mmol) in Meon (3 mL) and trimethylorthoformate (2 mL), followed by acetic acid (0.05 mL). The mixture is kept in a microwave cabinet (synthesizer

Smith) at 15023 for 10 minutes. Then add DCM (3 ml) and then add borohydride on a polymer support (1.2 g, "Zmmol). The mixture is shaken overnight, and more borohydride on a polymer support (1.2 g) is added. The mixture is shaken for a week, then filtered and evaporated. The residue added to a column (ISOI OTEYARNB, 10 Hg) and eluted with MesMm, Meon, and then MeOnH (sat. Mnz) to give 53 bmg of an oily product, yield 72905.

TN NMR (400 MHz, SOSIz): 85 0.87 (B ZN), 1.23-1.32 (t, 8H), 1.45-1.52 (t, 2H), 2.59 (i, 2H ), 3.78 (v, 2H), 6.75-6.85 (t, 2H) and 7.27-7.33 (t, 1H)

b) (4-(2-(Methoxycarbonyl)benzylhio)phenyl)acetic acid 4-Mercaptophenylacetic acid (995mg, 5.915mmol) in THF (15ml) is cooled in an ice bath and sodium hydride (55-6595, 520mg, 1 Zmmol). The mixture was stirred for 30 minutes and then 2-bromomethyl-benzoic acid methyl ester (1.49g, 6.507mmol) in THF (5ml) was added. The resulting mixture is stirred overnight and the temperature is allowed to reach room temperature. Water is introduced drop by drop and the mixture is stirred for about 20 minutes. Then evaporate to remove THF. The residue is acidified with 195 hydrochloric acid, pH-3, and then extracted with ethyl acetate. The organic extracts are combined, dried with magnesium sulfate and evaporated. M)

Chromatography of the residue on a column (ISOI OTEO5I, 20g/7Oml), using as an eluent DCM, then MEON/DCM at (1:99), gives 224 mg of the desired product, yield 65905.

TN NMR (500MGu, SOSIz): 5 3.62 (5, 2H), 3.90 (v, ЗН), 4.52 (v, 2H), 7.17 (d, 2H), 7.23-7 .40 (t, 5H) and 7.94 (4, 1H)). so c) Methyl 2-1(4-(2-(2,4-difluorobenzyl)(heptyl)amino)|-2-oxoethylphenyl)thio|-methyl)benzoate cha (4-42-(methoxycarbonyl)benzyl|thio) phenyl)acetic acid (581mg, 1.83bmmol) and

IM-(2,4-difluorobenzyl)-M-heptylamine (465 mg, 1.968 mmol) was combined in DMF and the mixture was cooled in an ice bath. NOVT (260.bmg, 1.928mmol) and TVTIi (619mg, 1.92v8mmol) are added, followed by OIREA (747.7mg, 5.785mmol).

The mixture was stirred at room temperature overnight and then evaporated. The resulting mixture is distributed between ethyl acetate and an aqueous solution of sodium bicarbonate (saturated). The aqueous portion is extracted with ethyl acetate (3

The extracts and combined organic extracts are dried over magnesium sulfate and then evaporated. Chromatography of the residue on a column (ISOI YUSHTEOA5I, 20g/7Oml) using ethyl acetate/heptane (5:95, then 10:90) as eluent gave 767mg) of the desired product, yield 7795.

TN NMR (rotamers, 5ХО0MHz, СОСИ8): 5 0.88-0.93 (t, ЗН), 1.23-1.34 (t, 8Н), 1.48-1.57 (t, 2Н), 3.19-3.24, 3.30 - 3.37 (t, t, 2H), 3.67-3.74 (t, 2H), 3.92 (v, ЗН), 4.50, 4 .63 (85, 8, 2H), 4.53 (in, 2H), 6.78-6.89 (t, -i 2H), 7.00-7.40 (pt, 8H) and 7.95 (49, 2H). so a) 2-(4-2-(2,4-Difluorobenzyl(heptyl)amino|-2-oxoethyl)phenyl)thio|methyl|benzoic acid

Methyl 2-1(4-2-((2,4-difluorobenzyl)(heptyl)amino)|-2-oxoethylphenyl)thio|methyl)-benzoate (Zimg, 0.057 mmol) (α) was dissolved in THF (ml) and cool in an ice bath. Add lithium hydroxide (2 mg, 0.075 mmol) in 50 mL water. After addition, the cooling bath is removed and the mixture is stirred overnight. LC-MS shows the presence of a very small amount of product. More lithium hydroxide (LiH) is added and the mixture is stirred for more than 6 days and HPLC shows about 3095 product. Another (Zmg) of lithium hydroxide is added and the mixture is stirred for another 13 days, evaporated in a vacuum to remove THF. The residue is acidified with 1095 hydrochloric acid, pH-3, and extracted with ethyl acetate (x2). The organic phases are combined, dried with magnesium sulfate and evaporated. Chromatography of the residue on a column (IZOH ShTEO5I, 500 g/ml) using DCM, MeOon/DCM

GF! (0.5:99.5) as eluent gives 17 mg of desired product, yield 56905.

TN NMR (rotamers, X00 MHz, SOSIz): 5 0.89-0.93 (t, ЗН), 1.25-1.34 (t, 8Н), 1.52-1.60 (t, 2Н), 3.27, 3.37 o (B 6 2H), 3.71, 3.76 (in, 85, 2H), 4.55, 4.65 (8, 85, 2H), 6.80-6, 92 (t, 2H), 7.07-7.17 (t, 2H), 7.28-7.37 (t,

BN), 7.42-7.47 (t, 1H) and 7.95-7.98 (t, 1H). for 13C NMR (rotamers, 125 MHz, SOSIz): 5 14.01, 22.51, 26.78, 26.85, 27.28, 28.56, 28.85, 28.93, 31.65, 31, 70, 38.22, 39.94, 40.25, 41.57, 41.60, 45.16, 4648, 47.94, 103.53 (0, 104.26(O, 111.50(Bg) , 111.71(y), 119.65(4), 120.37(a4), 127.05, 128.95 (B), 129.61, 129.68, 131.15, 131.66(4 ), 131.76(4), 132.41, 132.80, 132.88, 133.85, 134.03, 140.43, 160.58 (da), 160.91(4a4), 162.21 (da), 162.53 (a9), 170.46, 171.44 and 171.54. 65 Example C a) (4-42-(Methoxycarbonyl)benzyl|oxyphenyl)acetic acid

4-Hydroxyphenylacetic acid (7 mg, 4.995 mmol) is dissolved in ethanol (99.595, 20 ml). Add potassium hydroxide (560.5 mg, 9.99 mmol). The mixture is stirred at room temperature for 30 minutes. Then methyl ester of 2-bromomethylbenzoic acid (1144.2 mg, 4.p995 mmol) is introduced dropwise. The resulting mixture is heated to

Reflux for 2 hours and then evaporate to dryness in vacuo. Water and ethyl acetate are added to the residue and the phases are separated. The aqueous phase is acidified with 1095 hydrochloric acid, pH-5, and then extracted with ethyl acetate. The organic phase is dried with magnesium sulfate and evaporated to dryness under vacuum.

Chromatography of the residue on a column (ISOI OTEO5I, 5g/bml) using DCM, Meonudhm (1:99) as eluent gives the desired product (262mg), yield 17:595.

TN NMR (BOOMHCc, SOCIz): 5 3.61 (in, 2H), 3.91 (in, 3H), 5.50 (in, 2H), 6.97 (4, 2H), 7.22 ia, 2H), 7.39 (i, 1H), 7.57 (I, 1H), 7.76 (d, 1H) and 8.04 (a, 1H).

B) Methyl 2-H(4-2-(benzyl(hexyl)amino)|-2-oxoethylphenoxy)methyl|benzoate (4-42-(Methoxycarbonyl)benzyl|oxy)phenyl)acetic acid (5Omg, 0.16bmmol) dissolve in DCM (2ml), add M-hexylbenzylamine (38.2mg, O0.2mmol), then add EOS (38.Zmg, O0.2mmol), and then add DMAP 75 (244mg, O0.2mmol). The mixture is stirred at room temperature overnight. 1956 NSI (Iml) and water (ml) are added to the mixture. The two phases are separated using a Whatman filter. The resulting organic solution is evaporated in vacuo and the oily product (71 mg) is left, and then used directly in the next step.

TN NMR (rotamers, 5HO0MHz, SOSI8): 5 0.86-0.91 (t, 3H), 1.22-1.32 (t, 6H), 1.47-1.58 (t, 2H), 3.21, 3.39 (5 5 2H), 3.65, 3.75 (85, 85, 2H), 3.93 (in, ЗН), 4.53, 4.64 (in, 8, 2H ), 5.51, 5.52 (c, 8, 2H), 6.96, 6.99 (a, a, 2H), 7.16 (a, 2H), 7.23-7.42 (t , 6H), 7.59 (i, 1H), 7.78 (d, 1H) and 8.06 (a, 1H). c) 2-K4-2-(Benzyl(hexyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid

Methyl 2-(4-(2-I(benzyl(hexyl)amino|-2-oxoethylphenoxy)methyl|benzoate (7Omg, 0.148mmol) in THF (2mL) was cooled in an ice bath. Lithium hydroxide (7.08mg, 0, 29bmmol) in water (11ml) is added dropwise. c The cooling bath is then removed and the mixture is stirred overnight. HPLC shows that the reaction is not complete, more lithium hydroxide (0.2M, 00.5ml) is added. The reaction mixture is stirred for more than 4 days, then evaporated in vacuo to remove THF. The residue was acidified with 195 hydrochloric acid, pH-3-4, and extracted with ethyl acetate. The organic phase was dried with magnesium sulfate and evaporated. Chromatography of the residue on a column (ISOH OTEO5I, 2g/bml) using DCM, Meonudhm (1:99 and then 2:98) as eluent gives 24 mg of desired product, yield 3595.

TN NMR (rotamers, X00 MHz, SOSIz): 5 0.86-0.90 (t, 3H), 1.21-1.30 (t, 6H), 1.46-1.58 (171, 2H), 3.21, 3.39 (6 6 2H), 3.68, 3.77 (8, 8, 2H), 4.53, 4.65 (85, 8, 2H), 5.53, 5.54 (5, c, H), 6.95, 6.98 (y, a, 2H), o 7.14-7.17 (t, 2H), 7.22-7.33 (t, AN), 7.35-7.43 (t, 2H), 7.60 (i, 1H), 7.80 (a, 1H) and 8.164, 1H). ee) 13C NMR (rotamers, 125 MHz, SOSIz): 5 13.94, 13.97, 22.49, 22.53, 26.47, 26.57, 27.29, 28.36, 31.40, m 31.50, 39.82, 40.12, 46.50, 47.43, 48.28, 51.31, 68.21, 115.15, 126.25, 126.85, 127.20, 127, 24, 127,36, 127,48, 127,54, 127,97,128,49, 128,87, 129,76, 129,89, 131,52, 133,18, 136,80, 137,57, 140, 40, 157.59, 170.60, 171.76 and 172.03.

Example 4 « 20 a) Methyl 2-(4-2-((2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylufenoxy)methyl|-benzoate shv c a) M-(2,4-Difluorobenzyl)- M-heptylamine (1 mg, 0.44 mmol) was added to (4-42-(methoxycarbonyl)benzyl|oxy)phenyl)acetic acid (120 mg, 0.4 mmol) in DCM (1 mL), followed by EOS (84 mg, 1 » 0O.44mmol), and then DMAR (54mg, 0.44mmol). The mixture was stirred at room temperature overnight and then washed with 195% hydrochloric acid, water and brine and dried over magnesium sulfate and evaporated.

Chromatography of the residue on a column (ISOI OTEF5I, 5g/15ml) using DCM and Meon/UDHM (0.5:99.5) as eluent gives 155mg of the desired product, yield 7495.

TN NMR (rotamers, 5X00MHz, SOSIz): 5 0.88-0.92 (t, ЗН), 1.23-1.33 (t, 8Н), 1.49-1.57 (t, 2Н), 3.24, 3.34 so (6 6 2H), 3.66, 3.72 (8, 8, 2H), 3.92 (in, ЗН), 4.53, 4.62 (in, 8, 2H), 5.50, 5.51 (85, 8, 2H), 6.77-6.89 (t, av) 2H), 6.95, 6.98 (a, a, 2H), 6, 99-7.04, 7.29-7.33 (t, t, 1), 7.17, 7.20 (a, a, 2H), 7.39(, 1), 7.57 (i, tn), 50.7.75-1.19 (t, 1H) and 8.05 (4, 1H). and b) 2-K(4-22-12,4-Difluorobenzyl)(heptyl)amino|-2-oxoethylphenoxy|methyl|benzoic acid o Lithium hydroxide (13.3 mg, 0.554 mmol) in water (1, 5ml) add methyl 2-(4-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethyl)phenoxy)methyl|benzoate (145mg, 0.277mmol) dissolved in THF (3ml) to 70335. The mixture is then microwaved (Smith synthesizer) at 15023 for 7 minutes and then evaporated to remove THF. The residue is acidified with 1905 hydrochloric acid, pH-4, and then extracted with ethyl acetate (x2). The organic portions are combined, washed with brine, dried with magnesium sulfate, and then evaporated. Chromatography of the residue on a column (ISOI OTEF5I, 2g/bml) using DCM and meon/udhXmM (0.5:99.5, then 1:99) as eluent gave 94 mg of the desired product, yield 6795.

TN NMR (rotamers, X00MHz, SOSIz): 5 0.86-0.91 (t, ЗН), 1.22-1.32 (t, 8Н), 1.48-1.56 (t, 2Н), 3.23, 3.34 60 (B B 2H), 3.68, 3.73 (8, 85, 2H), 4.52, 4.63 (in, 8, 2H), 5.53 (in, B, 2H), 6.77-6.87 (t, 2H), 6.93-6.97 (t, 2H), 6.99-7.04, 7.27-7.33 (t, t , 1H), 7.16-7.20 (t, 2H), 7.41 (i, 1H), 7.58-7.62 (t, 1H), 7.78 (i, 1H) and 8, 15(9, 1H). 13C NMR (rotamers, 125MHz, SOSIz): 5 14.00, 22.51, 26.75, 26.84, 27.26, 28.54, 28.86, 28.94, 31.64, 31.70 , 39.75, 40.08, 41.39, 45.05, 46.30,47.98, 68.21, 103.67 (0, 104.12 (0, 111.52 (a), 115, 17, 119.80 (4), 120.52 (4), 126.97, 127.04, 127.21, 128.81 (ri), 129.78, 129.85, 131.52, 133.16 , 140.33, 157.65, 160.48 65 (da), 160.85 (aa), 162.13 (aa), 162.46 (aa), 171.01, 171.93 and 171.99,

Example 5 a) M-(2,4-difluorobenzyl)-M-heptyl-3-(4-hydroxyphenyl)propane amide 3-(4-Hydroxyphenyl)propionic acid (108mg, 0.6b5O0mmol) is dissolved in DMF. They add

IM-(2,4-difluorobenzyl)-M-heptylamine (164.7 mg, O0.682 mmol). The mixture is cooled in an ice bath. Add TVTO (219mg, 0.682mmol) and then SIREA (0.238ml, 1.365mmol). The mixture is stirred overnight and the temperature is allowed to reach room temperature. Ethyl acetate and an aqueous solution of sodium bicarbonate (saturated) are added, and then the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic phases are combined and dried over magnesium sulfate and evaporated. Chromatography of the residue on a column (ISOI OTEO5I, 5g/15ml) using 7/0. DXM and then Meon/DXM (1:99). as eluent, gives 223 mg of desired product, yield 8895.

TN NMR (rotamers, X00MHz, SOSIz): 5 0.86-0.90 (t, ЗН), 1.21-1.31 (t, 8Н), 1.47-1.53 (t, 2Н), 2.60, 2.67 (6 OB 2), 2.85-2.96 (t, 2H), 3.15, 3.32 (5 B 2H), 4.41, 4.60 (85, 8 , 2H), 6.75-6.85 (t, 4H), 6.90-6.96, 7.12-7.18 (t, t, 1H) and 7.00, 7.04 (ad, a, 2H).

B) Methyl 2-(4-13-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenoxy)methyl|-benzoate

IM-(2,4-difluorobenzyl)-M-heptyl-3-(4-hydroxyphenyl)upropanamide (195 mg, 0.50 mmol), 2-bromomethylbenzoic acid methyl ester (120.4 mg, 0.52 mmol) and anhydrous potassium carbonate ( 10 mg, 0.751 mmol) is mixed in acetonitrile (15 ml). The mixture is refluxed overnight and then evaporated to dryness. Water and ethyl acetate are added and the two phases are separated. The organic phase is dried with magnesium sulfate and evaporated. Chromatography of the residue on a column (ISOI OTEO5I, 2 g/bml) using heptane/dhm (50:50), then DCM, then Meon/dhm (0.5:99.5) as eluent gave 187 mg of the desired product, output 69.59.

TN NMR (rotamers, 5HO0MHz, SOSI8): δ 0.87-0.91 (t, ЗН), 1.21-1.31 (t, 8Н), 1.44-1.56 (t, 2Н), 2.56-2.69 (t, 2H), 2.91-3.01 (t, 2H), 3.14, 3.32 (5 6 2H), 3.92 (v, ZN), 443, 4.59 (85, 8, 2H), 549 (in, 2H), 6.75-6.97 (t, 4H), 7.08-7.28 (t, ЗН), 7.38 (, 1H ), 7.56 (i, 1H), 7.76 (d, 1H) and 8.04 (i, 1H), c c) 2-К4-13-(2,4-Difluorobenzyl)(heptyl)amino| -3-oxopropyl)uphenoxy)methyl|benzoic acid o

Lithium hydroxide (13.3 mg, 0.554 mmol) in water (Iml) is added to methyl 2-K4-13-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropyl)phenoxy|methyl|benzoate (14Omg, 0.277 mmol), dissolved in THF (2 ml). The mixture is then microwaved (Smith synthesizer) at 15022 for 7 minutes and then evaporated to remove THF. The residue is acidified with 1905 hydrochloric acid, pH-4, and extracted with ethyl acetate (x2). The organic extracts were combined and washed with brine and dried over magnesium sulfate and then evaporated. Chromatography of the residue on a column (ISOI OTEPHO5I, 2 g/bml) using DCM, then mMeon/dcm (1:99) as eluent, gives 121 mg of the desired product, yield 83905. o "IN NMR (rotamers, X00MHz, SOCIz): 5 0.89-0.93 (t, ZN), 1.24-1.33 (t, 8H), 1.49-1.58 (t, 2H), 2.64-2.74 00 (t , 2H), 2.97-3.03 (t, 2H), 3.17, 3.37 (5 5 2H), 446, 4.65 (85, 85, 2H), 5.58, 5.59 (in, in, 2H), 6.78-6.87 them (t, 2H), 6.94-6.97 (t, 2H), 6.99-7.04, 7.27-7.31 (t, t, 1), 7.14, 7.17 (a, a, 2H), 742-745 (t, 1H), 7.61-7.64 (t, 1H), 7.82-7 .85 (t, 1H) and 8.19-8.22 (y, 1H), 13C NMR (rotamers, 125MHz, SOCIz): 5 13.96, 22.46, 22.49, 26.67, 26, 85, 27,38, 28,57, 28,80, 28,94, 30,69, 30,84, 31,58, 31,67, 35,01, 3526, 41,63, 44,76, 44, 78, 4643, 47.78, 68.15, 10360009, 104.07(O, « 400 111.41(a9), 111.49 (da), 114.91, 119.74 (4), 120.45 (4), 126.86, 127.72, 128.53 (rg), 129.40, 131.49, 131.58, DC U)

Ghani 133.15, 133.32, 140.54, 157.12, 160.33 (da), 160.81 (ad), 162.07 (aa), 162.33 (aa), 171.07, 173.04 and 173.11.

Example 6)» a) 3--4-Mercaptophenyl)propanoic acid (2.0 g, 10.97 mmol) is dissolved in dry THF (bOml) and cooled to 09. Sodium hydride (0.64 g, 24.1 mmol) is added. The mixture is stirred for 30 minutes, methyl 2-(bromomethyl)benzoate (2.77g, 12.07mmol) dissolved in dry THF (100ml) is added dropwise. The solution is allowed to warm to room temperature and stirred overnight. By adding water (1 Oml) drop by drop, the remains of sodium hydride are deactivated. The solvent is removed by evaporation, and the residue is acidified to pH (NSI 195). Aqueous phase

Co is washed with E(OAc (3xX10ml). The organic phases are combined, dried with magnesium sulfate and evaporated. The crude material (c) is purified by preparative HPLC (starting with a mixture of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 50 mL to 10095, buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KK-100-7-C8, 50 Ωm x 25 Ωm, flow 4 Ωml/min). The fractions containing the product are combined and the acetonitrile is removed by evaporation. m) E is added (OAc (10 ml) and the organic phase are washed with two portions of brine and dried with magnesium sulfate.

Removal of the solvent by evaporation gives 2.26 g of 3-(4-12-(methoxycarbonyl)benzyl/hydro)phenyl)propanoic acid (yield 62.390). 52 TN nMR (BO0MHZc, SOSIv): 5 2.66 (B 2H), 2.92 ( 2H), 3.90 (v, 3H), 4.51 (8, 2H), 7.10 (y, 2H ), 7.19 (49,

HF) 1H)U, 7.25 (a, 2H), 7.29 (, 1H), 7.36 (i, 1H) and 7.94 (a, 1H).

B) Methyl 2-1(4-(3-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenyl)thio|-methyl)benzoate o IM-(2,4-difluorobenzyl)-M-heptylamine ( 0.64g, 2.65mmol) is dissolved in DMF (10ml), 3-(4-C2-(methoxycarbonyl)benzyl/hyo)phenyl)propanoic acid (0.80g, 2.41mmol) is added and the mixture is cooled to 020. Add /-M-KIN-1,2,3-benzotriazole-1-thoxy)-(dimethylamino)methylene|-M-methylmethanammonium tetrafluoroborate (0.85g, 2.6bmmol) and diisopropylethylamine (0.65g, 5.05mmol) . The mixtures are allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) is added and the organic phase is washed with two portions of sodium bicarbonate (aq., 1 Oml). EtOAc is removed by evaporation and the crude product is purified by preparative

HPLC (starting with acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KK-100-7-С8, 500 mm x 25 O mm, flow 4 Oml/minute).

The product-containing fractions were combined and the acetonitrile was removed by evaporation. EtOAc (1 Oml) is added and the organic phase is washed with two portions of brine and dried with magnesium sulfate. The solvent is removed by evaporation to obtain 1.10 g of methyl 8:00 2-X4-13-(2,4-difluorobenzyl)(heptyl)amino)|-33-oxopropylphenyl)thio|methyl)-benzoate (yield 82.2905).

TN NMR (rotamers, BOHMhz, SOSIz): 5 0.89 (Hii, ZN), 1.22-1.32 (t, 8H), 1.47-1.55 (t, 2H), 2.55, 2.66 (and,

BO 2H), 2.95-3.01 (t, 2H), 3.16, 3.33 (her, 2H), 3.89, 3.90 (8, 8, ЗН), 4.44, 4 .60 (85, 8, 2H), 4.50, 4.51 (v, 8, 2H), 6.76-6.85 (t, 2H), 6.92-6.96, 7.20- 7.25 (t, t, 4H), 7.07, 7 12 (a, a, 2H), 7.27-7.31 (t, 1H), 7.32-7.34 (t, 1H) and 7.91-7.92 (t, 1H). c) 2-1(4-13-(2,4-Difluorobenzyl)(heptyl)amino|-3-oxopropylphenyl)thio|-methyl)benzoic acid

Methyl 2-(I(4-(3-(2,4-difluorobenzyl)(heptyl)amino|-33-oxopropylphenyl)thio|-methyl)benzoate (1.05g, 1.89mmol) is dissolved in EN (9595, 5ml) ), potassium hydroxide is added. (0.21g, 3.77mmol). The reaction is carried out in a unit microwave oven (7 minutes, 15023). It is finished by adding EtOAc (5ml) and washing with 75.HC (2xB5ml, 1M). The organic layer is dried with magnesium sulfate and the solvent is removed by evaporation with the formation of 0.96 g of 2-1(4-13-(2,4-difluorobenzyl)u(heptyl)amino)|-3-oxopropylphenyl)thio|methylubenzoic acid (yield 94.3905).

TN NMR (rotamers, 5X00MHz, SOSIz): 5 0.88-0.92 (t, ЗН), 1.24-1.33 (t, 8Н), 1.50-1.57 (t, 2Н), 2.64, 2.69 (6 6 2), 2.95-3.00 (t, 2H), 3.20, 3.34 (B KB 2H), 448.4.62 (8, 85, 2H ), 4.55, 4.56 (v, v, 2H), 6.79-6.87 (t, 2H), 6.98-7.03, 7.27-7.30 (t, t, 2H), 7.06-7.10 (t, 2H), 7.22-7.24 (t, 2H), 7.31-7.36b(t, 1H), 7.41-7.46 ( t, 1Hn) and 8.03 (a, 1H). 13C NMR (rotamers, 125 MHz, SOSIz): 5 14.01, 22.51, 22.54, 26.74, 26.90, 27.42, 28.63, 28.86, 28.98, 30.92 , 31.18, 31.64, 31.72, 34.65, 38.23, 38.28, 41.58, 44.82, 46.44, 47.77, 103.46(O, 104.14 (O. 111.52(a4), 111.58(a94), 119.74(a9), 120.51(da4), 127.09, 128.55, 128.63, 129.03, 131.16, 131 ... 160.88(da), 162.16(a49), 162.44(a9), 170.88(lg), 172.56 and 172.59. (o,

Example 7 a) M-(2,3-dimethoxybenzyl)butan-1-amine (0.59g, 2.6bMmol) is dissolved in DMF (10ml), 3-(4-hydroxyphenyl)propanoic acid (04g, 2.41mmol) is added ) and the mixture is cooled to 09Sb. Add ozo M-KIN-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene)|-M-methylmethanammonium tetrafluoroborate (0.85g, 2.65mmol) and diisopropylethylamine (0.65g, 5.05mmol). The mixture is allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) is added and the organic phase is washed with two portions of sodium bicarbonate (aq., 10 ml). E(Ac) is removed by evaporation and the crude product is purified by preparative HPLC (starting with acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK- 100-7-S8, 50 mm x 25 Ohm, flow 4 Ohm/min).

The product-containing fractions were combined and the acetonitrile was removed by evaporation. EtOAc (1 Oml) is added and the organic phase is washed with two portions of brine and dried with magnesium sulfate. The solvent is removed by evaporation to obtain 1.08 g of M-butyl-M-(2,3-dimethoxybenzyl)-3-(4-hydroxyphenyl)propanamide (yield 82.390). "

TN NMR (rotamers, X00 MHz, SOSIz): 5 0.85-0.89 (t, ЗН), 1.20-1.30 (t, 2H), 1.44-1.53 (t, 2H), 2.60, 2.65 (5 65 2H), 2.88, 2.94 (B B 2H), 3.13, 3.33 (B her, 2H), 3.78, 3.80 3.83 , 3.85 (85, 5, 5, 8, 6H), 4.43, 4.68 - s (85, 8, 2H), 6.57, 6.67 (y, 9, 1H), 6, 74-6.86 (pt, ZN) and 6.95-7.05 (t, ZN).

B) M-butyl-M-(2,3-dimethoxybenzyl)-3-(4-hydroxyphenyl)propanamide (5mg, 0.13mmol) and methyl )»2-(bromomethyl)benzoate (0.034g, 0.15mmol) are dissolved in acetonitrile (1 Oml) and potassium carbonate (37 mgHg, 0.27 mmol) is added. The mixture is stirred at 6°C for three hours. Add trisamine on a polymer substrate (0.Seq.) and stir overnight. The polymer is filtered off and the solvent is removed by evaporation. - Add EtOAc (10 ml) and wash the organic phase with portions of water. After drying the crude product (magnesium sulfate), the solvent is removed by evaporation. The residue is purified by preparative HPLC (starting with acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100-7-С8, 50mm x25Ωm, flow 4Oml/min). s 20 The fractions containing the product were combined and the acetonitrile was removed by evaporation. EtOAc (10 mL) was added and the organic phase was washed with two portions of brine and dried over magnesium sulfate. Removal of the solvent by evaporation gave 15 mg of methyl 2-( (4-3-I(butyl(2,3-dimethoxybenzyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoate (21,496).

TN NMR (rotamers, 5X00 MHz, SOSIz): 5 0.89-0.95 (t, 3H), 1.24-1.35 (t, 2H), 1.48-1.57 (t, 2H), 2.62, 2.69 (6 6 2), 2.95, 3.01 (B B 2H), 3.17, 3.36 (B her 2H), 3.83, 3.86, 3.89 , 3.90, 3.93, 3.94 (8, 8, 8, 8, 8, gF) 8, 9H), 4.48, 4.71 (in, 85, 2H), 5.50, 5 .52 (8, 8, 2H), 6.62, 6.75 (a, a, 1nH), 6.84-6.97 (t, ZH), 7.00-7.04 (t, t 1NU , 7.11, 7.19 (a, a, 2H), 7.38-7.42 (t, 1H), 7.56-7.60 (t, 1H), 7.78 (i, 1H) and 8.04-8.07 (t, 1H). c) Methyl 2-K4-13-(butyl(2,3-dimethoxybenzyl)amino|-3-oxopropyl)phenoxy)methyl|-benzoate (15 mg, 0.029 mmol ) is dissolved in a THF/water mixture (2/1, 2 ml) and GION (1.4 mg, 0.058 mmol) is added. The reaction is carried out in a single block of a microwave oven (1502C, 7 minutes). EtOAc (1 Oml) is added and the organic phase is washed with two portions of HCl (2 hbml, 1M). The organic phase is dried with magnesium sulfate and the solvent is removed by evaporation, with the formation of 1 mg of 2-(4-3-butyl(2,3-dimethoxybenzyl)amino|-3-oxopropyl)uphenoxy)methyl|-benzoic acid (yield 8990). 65 TN NMR (rotamers, X00MHz, SOSIz): 5 0.89-0.95 (t, ЗН), 1.24-1.35 (t, 2H), 1.48-1.57 (t, 2H) , 2.62, 2.69 (6 6 2), 2.95, 3.01 (5 B 2H), 3.17, 3.36 (5 2H), 3.83, 3.85, 3, 88, 3.89 (8, 85, 8, 85, 6H), 4.48, 4.71

(5, 8, 2H), 5.50, 5.52 (8, 8, 2H), 6.62, 6.75 (y, a, yin), 6.84-6.97 (t, ЗН) , 7.00-7.04 (t, 1H), 7.11, 7.19 (a, a, 2H), 7.38-7.42 (t, 1H), 7.56-7.60 ( t, 1H), 7.78 (Her, 1H) and 8.04-8.07 (t, 1H). 13C NMR (rotamers, 125 MHz, SOSIz): 5 13.76, 13.85, 20.02, 20.21, 29.55, 30.30, 30.69, 30.84, 30.96,

C35,13,35,34, 42,60, 46,17, 46,37, 47,20, 55,69, 55,75, 60,35, 61,74, 68,20, 111,23, 111, 79, 114.88, 114.96, 118.79, 120.88, 124.15, 124.21, 126.81, 127.18, 127.26, 129.46, 130.51, 131.25, 131.52, 133.23, 133.65, 140.59, 146.50, 147.17, 152.48, 152.61, 157.02, 157.10, 170.79, 172.93 and 173, 25.

Example 8 a) Mm-(2,3-Dimethoxybenzyl)-M-heptylamine (0.70g, 2.6bmmol) is dissolved in DMF (10ml), 70g of 3-(4-hydroxyphenyl)propanoic acid (04g, 2.41mmol) is added ) and the mixture is cooled to 09Sb. They add

M-KIN-1,2,3-benzotriazol-1-yloxy)Xdimethylamino)methylene)|-M-methylmethanammonium tetrafluoroborate (0.85g, 2.65mmol) and diisopropylethylamine (0.65g, 5.05mmol). The mixtures are allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) is added and the organic phase is washed with two portions of sodium bicarbonate (aq., 10 ml). E(As is removed by evaporation and the crude product is purified by preparative HPLC 75 (starting with a mixture of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, KK column -100-7-S8, 5O0mm x25Omm, flow 4Oml/min).

The product-containing fractions were combined and the acetonitrile was removed by evaporation. EtOAc (1 Oml) is added and the organic phase is washed with two portions of brine and dried with magnesium sulfate. The solvent is removed by evaporation to obtain 0.98 g of M-(2,3-dimethoxybenzyl)-heptyl-3-(4-hydroxyphenyl)propanamide (yield 70905).

TN NMR (rotamers, 5X00MHz, SOSIz): 5 0.85-0.89 (t, ЗН), 1.20-1.30 (t, 8Н), 1.47-1.56 (t, 2Н), 2.62, 2.67 (6 6 2), 2.89, 2.95 (5 B 2H), 3.14, 3.33 (B B 2H), 3.79, 3.80, 3.84 , 3.85 (5, 85, 85, 8, 6H), 4.45, 4.69 (5, 5, 2H), 6.58, 6.68 (y, 49, 1H), 6.74- 6.88 (pt, ZN) and 6.96-7.05 (t, ZN).

M-(2,3-dimethoxybenzyl)-M-heptyl-3-(4-hydroxyphenyl)propanamide 0.196g, 0.47mmol) and methyl 2-(bromomethyl)benzoate (0.12g, 0.52mmol) are dissolved in acetonitrile (1 Oml) and add potassium carbonate (131 mg, sch 29 0.95 mmol). The mixture is stirred at 6°C for three hours. Add trisamine on a polymer substrate (ge) (0.Seq.) and stir overnight. The polymer is filtered off, the solvent is removed by evaporation, and added

EtOAc (1 Oml) and the organic phase is washed with water. After drying (magnesium sulfate) the crude product and removing the solvent by evaporation, the crude product is purified by preparative HPLC (starting with a mixture of acetonitrile/buffer 60/40, then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of 3% acetonitrile/water 10/90 and acetate ammonium (0.1 M, column KK-100-7-C8, 50 mm x 25 Ω, flow 4 Oml/min). The fractions containing the product are combined and the acetonitrile is removed by evaporation. E(Ac (1 Oml) is added and the organic phase is washed with two portions of brine and dried over magnesium sulfate Removal of the solvent by evaporation gave 30 mg of methyl 2-((4-(3-(2,3-dimethoxybenzyl)(heptyl)amino|-3-oxopropylphenoxy)methylibenzoate (yield 14.6905). (ee)

TN NMR (rotamers, X00MHz, SOSIz): δ 0.86-0.89 (t, ЗН), 1.19-1.30 (t, 8Н); 1.46-1.55 (t, 2H), 2.60, 2.66 im- (6 6 2), 2.93, 2.98 (i KB 2H), 3.14, 3.33 (B 5 2H), 3.80, 3.83, 3.86, 3.87, 3.90, 3.91 (8, 8, 8, 8, 8, 8, 9H), 4.45, 4.68 (c, 85, 2H), 5.48, 549 (c, 8, 2H), 6.59, 6.73 (a, a, 1), 6.81-7.01 (t, 4H) 7, 08, 7.16 (a, a, 2H) 7.35-7.39 (t, 1H), 7.53-7.57 (t, 1H), 7.76 (i, 1H) and 8.01 -8.04 (t, 1H). c) Methyl 2-K4-13-(2,3-dimethoxybenzyl)(heptyl)amino|-3-oxopropyl)uphenoxy)methyl|-benzoate (ZOmg, « 9.069 mmol) is dissolved in a mixture of THF/water (2/1, 2 ml) and add GION (Z, Zmg, 0.14 mmol). The reaction is carried out in a single block of a microwave cabinet (1502C, 7 minutes). Remove EtOAc (10 ml) and wash the organic phase with two portions of CARRIER (2 x 5 ml, 1 M). The organic phase is dried with magnesium sulfate and the solvent is removed by evaporation, with the formation of ZOmg 2-K4-13-(2,3-dimethoxybenzyl) (heptyl)-amino|-3-oxopropyl-phenoxy)methyl|benzoic acid (yield 78.9).

TN NMR (rotamers, X00MHz, SOSIv): 5 0.84-0.87 (t, ЗН), 1.20-1.28 (t, 8Н), 1.45-1.55 (t, 2Н), 2.63, 2.69 - (6 6 2), 2.93, 2.99 (B B 2H), 3.13, 3.33 (B 6 2H), 3.79, 3.81, 3, 84, 3.85 (5, 85, 85, 8, 6H), 4.45, 4.69 o (5, 8, 2H), 5.52, 5.53 (in, 8, 2H), 6, 60, 6.72 (a, a, yin), 6.79-7.01 (t, 4H) 7.08, 7.16 (a, a, 2H) 7.36-7.41 (t, 1H ), 7.55-7.60 (t, 1H), 7.79 (i, 1H) and 8.13-8.16 (t, 1H) by 13C NMR (rotamers. 125MHz. SOCIz): 5 14, 04, 22.52, 22.56, 26.77, 26.96, 27.45, 28.60, 28.92, 29.03, 1 50 30.83, 30.97, 31.66, 31, 75, 35,16, 35,36, 42,61, 46424646, 4745, 55,69, 55,75, 60,35, 60,73, o 68,19,111,26,111,83, 114,88, 114,95 , 118,84,120,91, 124,14, 124,20, 126,85, 127,15, 127,22, 129,46, 130,52, 131,26, 131,51, 133,19, 133,66 , 140.61, 146.59 147.19, 152.48,152.60,157.02, 157.11,170.77, 172.92 and 173.23.

Example 9 a) M-(3-ethoxypropyl)-M-(4-isopropylbenzyl)amine 59 p-isopropylbenzaldehyde (1.007g, 6.798mmol) is dissolved in methanol (5ml). Trimethyl orthoformate (5 ml) gF) is added. 3-Ethoxypropylamine (681mg, 6.bmmol) was then added followed by acetic acid (0.2ml). After standing at 7 room temperature overnight, DCM (5 mL) was added, followed by polymer-supported borohydride (5.28 g, 13.2 mmol). The mixture is shaken at room temperature for 4 days, and then filtered. The filtrate is evaporated.

The residue is dissolved in acetonitrile, then divided into two portions and loaded into 2 columns (ISOI OTEYARNIB, bo 10g/7O0ml, moistened with acetonitrile), eluted with acetonitrile, then methanol, and then methanol (MNuz sat.).

The product fractions are combined and evaporated. An oily product of 1.283 g is obtained, yield 83905.

TN NMR (ZO0MHCz, SOCIz): 8 1.19 (6 ЗН), 1.25 (4, 6Н), 1.75-1.84 (t, 2Н), 2.73 (5 2Н), 2.85 -2.94 (t, 1H), 3.43-3.52 (t, 4H), 3.75 (c, 2H), 7.18 (y, 2H) and 7.24 (a, 2H). 65 B). M-(3-ethoxypropyl)-M-(4-1isopropylbenzyl)amine (0.62g, 2.65mmol) is dissolved in DMF (10ml), 3-(4-hydroxyphenyl)upropanoic acid (0.4g, 2.41mmol) is added ) and the mixture is cooled to 09C. They add

M-(IN-1,2,3-benzotriazol-1-yloxy)Xdimethylamino)-methylene|-M-methylmethanesulfonyl tetrafluoroborate (0.85g, 2.65mmol) and diisopropylethylamine (0.65g, 5.05mmol). The mixtures are allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) is added and the organic phase is washed with two portions of sodium bicarbonate (aq., 10 ml). E(Ac) is removed by evaporation and the crude product is purified by preparative HPLC (starting with acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100 -7-C8, 50 mm x 25 Ω, flow 4 Oml/min). The fractions containing the product were combined and the acetonitrile was removed by evaporation. EtOAc (1 Oml) was added and the organic phase was washed with two portions of brine and dried over magnesium sulfate. The solvent was removed by evaporation and 70 obtained 1 .0 g of M-(3-ethoxypropyl)-3-(4-hydroxyphenyl)-M-(4-isopropylbenzyl)propanamide (yield 75.8905).

TN NMR (rotamers, 5ХО0MHz, СОСИв8): 5 1.16-1.21 (t, ЗН), 1.26, 1.27 (а, а, 6Н), 1.75-1.80, 1.84 -1.90 (t, t, 2H), 2.64, 2.74 (5 B 2H), 2.86-3.00 (t, ЗН), 3.33, 3.37 (0 6 2H) , 34 1 -3.50 (t, 4H). 4.43, 4.62 (v, v, 2H), 6.80-6.84 (pt, 2H) and 6.97-7.22 (t, 6H). a) M-(3-ethoxypropyl)-3-(4-hydroxyphenyl)-M-(4-isopropylbenzyl)ipropanamide (0.18g, 0.47mmol) and methyl 75 2-(bromomethyl)benzoate (0.12g, O0 .52 mmol) is dissolved in acetonitrile (1 Oml) and potassium carbonate (131 mg, 0.95 mmol) is added. The mixture is stirred at 6°C for three hours. Add trisamine on a polymer substrate (0.Seq.) and stir overnight. The polymer is filtered off, the solvent is removed by evaporation, and added

EtOAc (10 ml) and the organic phase are washed with portions of water. After drying with magnesium sulfate, the solvent is removed by evaporation, the crude product is purified by preparative HPLC (starting with a mixture of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100-7-C8, 5O0mm x 25Ωmm, flow 4Oml/min). The fractions containing the product are combined and the acetonitrile is removed by evaporation. E(Ac (1Oml) is added and the organic phase is washed with two portions of brine and dried with magnesium sulfate. Removal of the solvent by evaporation gives 0.1 bg of methyl 2-(4-3-((3-ethoxypropyl)(4-isopropylbenzyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoate (yield 63.5905). c 29 e) "H NMR ( rotamers, CHO0OMHz, SOSI8): 5 1.17, 1.21 (6 6 Z), 1.27, 1.28 (48, a, 6H), 1.75-1.80, 1.84-1, 89 ge) (t, t, 2H), 2.63, 2.73 (6, 2H), 2.89-3.04 (t, ЗН), 3.32, 3.37 (B 5 2H), 3.4 1 -3.50 (t, 4H), 3.93, 3.94 (5, 8, ЗН), 4.46, 4.61 (v, 8, 2H), 5.51, 5, 53 (c, c, 2H), 6.92, 6.95 (a, a, 2H), 7.04-7.22 (t, 6H), 7.40 (5 1H), 7.58 (i , 1H), 7.78 -7.80 (t, 1H) and 8.05-8.07 (t, 1H). a) Methyl 2-(K4-13-(3-ethoxypropyl)(4-isopropylbenzyl)amino|-3-oxopropyl)uphenoxy)-methyl|benzoate (0.16 g, about 300.00 mmol) is dissolved in a mixture of THF/water (2/1, 2ml) and add GION (14.4mg, 0.bOmmol). The reaction is carried out in IS o) a unit block of a microwave oven (1502C, 7 minutes). Remove EtOAc (10 ml) and wash the organic phase with two portions of NOSI (2 x 5 ml, 1 M). The organic phase is dried with magnesium sulfate and the solvent is removed by evaporation with the formation of 0.108 g of 2-(4-3-((3-ethoxypropyl) (4-isopropylbenzyl)amino|-3-oxopropylphenoxy)-methyl|benzoic acid (yield 69.390).

TN NMR (rotamers, 5ЧО0MHz, СОСИз): 5 1.15, 1.19 (B 6, ЗН), 1.23-1.25 (t, 6Н), 1.74-1.79, 1.84- 1.89 (t, t, 2H), 2.66, 2.76 (5 5 2H), 2.86-3.03 (t, ZN), 3.30, 3.36 (Her KB 2H), 3.40-3.50 (t, 4H), 4.44, 4.61 (in, in, 2H), 5.55, 5.56 (8, 8, 2H), 6.90-6.94 (t, 2H), 7.02-7.20 (t, 6H), 7.40 (f 1), 1.57-1.60 (t, 1H), 7.79-7.82 « (t , 1H) and 8.15-8.18 (t, 1H). 13C NMR (rotamers, 125 MHz, SOSIz): 5 15.15, 23.98, 27.78, 28.61, 30.93, 31.01, 33.73, 35.07, 35.38, - s 43 .86, 44.13, 47.96, 51.26, 66.06, 66.22, 66.82, 67.98, 68.13, 114.77, 126.03, 126.38, 126.72 , 126.97, in» 127.90, 129.31, 131.31, 132.88, 133.23, 133.39, 133.84, 134.56, 140.30, 140.38, 147.71 , 148.05, 156.90, 170.48, 173.02 and 173.26.

Example 10 a) M-(2,4-difluorobenzyl)-M-propylamine - 2,4-Difluorobenzaldehyde (1.003g, 7.055mmol) is dissolved in methanol (bml). Trimethyl orthoformate (ml) is added. Propylamine (401 mg, 6.784 mmol) is then added, followed by acetic acid (0.2 mL). After 1 hour, add

DCM (5ml) and then polymer-supported borohydride (2.5mmol/g, 5.42g, 13.55mmol). The mixture is shaken at room temperature for 4 days, and then filtered. The filtrate is evaporated. The residue is dissolved in 20 ml of acetonitrile, then divided into two portions and loaded into 2 columns (ISOI TER, 10g/7Oml, moistened with acetonitrile), elute with acetonitrile, then methanol, and then methanol (MNuz Sainen.). Product fractions are combined m) and evaporated. An oily product (892 mgH), yield 71905 was obtained. .79 (in, 2H), 6.75-6.85 (t, 2H) and 7.27-7.33 (t, 1H).

B). M-(2-(4-difluorobenzyl)-3-(4-hydroxyphenyl)-M-propylpropanamide

HF) 3-(4-Hydroxyphenyl)propionic acid (245mg, 1.474mmol) in DMF (bml) was cooled in an ice bath.

IM-(2,4-Difluorobenzyl)-M-prolylamine (300.4 mg, 1.622 mmol) was added, followed by TVTO (521 mg, 1.622 mmol), followed by PSIREA (40 mg, 3.09 mmol). Sumi and her and and. В Я , З, - The mixture is stirred at room temperature during the night. An aqueous solution of sodium bicarbonate (saturated) is added. The mixture is extracted with ethyl acetate (x2). The extracts are combined and dried with magnesium sulfate and evaporated. Chromatography of the residue on a column (150 OTEO5I, 5g/25ml) using

DxM/heptane (50:50), DxM, then Meon/dxm (1:99, then 2:98) as eluent gave ZZbmg of the desired product, yield 68.

TN NMR (rotamers, ZOOMHz, SOSIz): 5 0.82-0.88 (t, ЗН), 1.45-1.58 (t, 2Н), 2.59, 2.65 (5 6 2Н), v5 2.88-2.98 (t, 2H), 3.11, 3.27 (5 2H), 4.40, 4.59 (v, 8, 2H), 6.71-7.03 (t , 6H), 7.07-7.16 (t, 1)Ta?,79 (v, Bg, 1H). c) Methyl 2-(4-(3-12,4-difluorobenzyl)(propyl)amino|-3-oxopropylphenoxy)methyl|-benzoate

M-(2,4-Difluorobenzyl)-3-(4-hydroxyphenyl)-M-propylpropanamide (290mg, 0.87mmol) was dissolved in acetonitrile (10ml). 2-Bromomethyl-benzoic acid methyl ester (209mg, 0.913mmol) is added, and then potassium carbonate, anhydrous. (18Omg, 1.305mmol). The mixture is heated to boiling under reflux overnight, and then

Evaporate to dryness. Water and ethyl acetate are added and the two phases are separated. The organic phase is dried with magnesium sulfate and evaporated. Chromatography of the residue on a column (ISOY UTEF5I, 20g/7Oml) using DCM, and then

Meon/dhm (1:99) as eluent gave 184 mg of desired product, yield 4490.

TN NMR (rotamers, 500 MHz, SOSIz): 5 0.85-0.92 (t, ЗН), 1.52-1.60 (t, 2Н), 2.61, 2.68 (5 6 2Н), 2.95-3.01 (t, 2H), 3.15, 3.32 (i Kf 2H), 3.92, 3.93 (v, 8, ZN), 445, 4.62 (8, 8 , 2H), 5.51, 5.52 (8, in, 70. 2H), 6.77-6.86 (t, 2H), 6.92-6.99, 7.23-7.27 ( t, t, ЗН), 7.12, 7.16 (a, a, 2H), 7 38-7.42 (t, 1H), 7.57 (6 1H) 7.78 (d, 1H) and 8.04-8.07 (t, 1H). a) 2-K4-33-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid

A mixture of methyl 2-(4-13-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropyl)uphenoxy)-methyl|benzoate /(0.184g, 0.382mmol) and lithium hydroxide (0.018g, 0.7bmmol) ) in THF (2ml) and water (2ml) are heated at 1502C for 7 minutes. 75 The mixture is diluted with water, acidified with hydrochloric acid and extracted with methylene chloride. The combined extracts are dried with magnesium sulfate and evaporated, Kk! formation of 2-(4-13-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid.

TN nMR (400 MHz, SOSI): 5 0.85 (5 3), 1.4-1.6 (t, 2), 2.6-2.7 (t, 2), 2.9-3.0 (t, 2), 3.05-3.15 and 3.25-3.35 (multiplets, rotamers, 2), 4.4 and 4.6 (singlets, rotamers, 2), 5.5 (t, 2), 6.7-6.8 (t, 2), 6.9-7.0 (t, 2), 7.05-7.2 (t, 23, 7.4 (B, 1), 7.6 (B 1), 7.8 (d, 1), 8.15 (4, 1).

Example 11 a) Methyl 2-(14-(2--ethyl4-(trifluoromethyl)benzyl|amino)-2-oxoethyl)phenyl/)thio| methyl) benzoate

Ethyl 4-(trifluoromethyl)benzylamine (284 mg, 1.4 mmol) and (4-(2-(methoxycarbonyl)benzylhio)phenyl)acetic acid (443 mg, 1.4 mmol, See Example 25) were mixed in DMF (15 mL). TVT (472mg, 1.47mmol) is added, and at 29, then OIREA (190mg, 1.47mmol) is added. The mixture is stirred at room temperature for 1 hour. E6YUDAs Ge) (20 ml) is added. The mixture is then washed with an aqueous solution of sodium bicarbonate (sat.), 195 NCI, water (x2) and brine, dried over magnesium sulfate and evaporated. The named compound (66Zmg) remains, yield 94965.

TN NMR (rotamers, X00MHz, SOSIz): 5 1.08-1.15 (t, ZN), 3.31, 3.45 (d, 4, 2H), 3.63 -3.76 (v, 8 . a, 2H) and 7.94 (y, 2H).

b) 2-(C4-(2-Ethyl4-trifluoromethyl)benzylamino)-2-oxo)phenylthio)methyl)benzoic acid and)

Methyl 2-(14-(2--ethyl)-4-(trifluoromethyl)benzyl|amino)-2-oxoethyl)phenyl)hyo)methyl)-benzoate (64Omg, about 1.276bmmol) was dissolved in THF (2Oml). Lithium hydroxide (b1mg, 2.552mmol) in water (1Oml) was added. The mixture is stirred at room temperature and the reaction is checked by LC-MOS. After 24 hours, add lithium d) hydroxide (ZOmg) and water (1Oml). After only 70 hours, LC-MS shows the completion of the reaction. The mixture is evaporated to remove THF. The residue is washed with diethyl ether, then acidified with 1095 HCl, pH-2, and extracted with EtOAc (x2). The extracts are combined and washed with brine, dried over magnesium sulfate and evaporated. Chromatography of the residue on a column (ZOI STE 51, 5 g/25 ml) using DCM and then Meon/dXM (0.5:99.5, then 1:99) as eluent gives the title compound (510 mg), yield 82905. "

TN NMR (rotamers, ZOOMGhz, SOSIz): 5 1.07-1.15 (t, ZN), 3.31, 3.45 (d, 4, 2H), 3.64, 3.77 (v, 8 , 23), IZ with 4.54 (5, 2H), 4.55, 4.66 (in, 8, 2H), 7.05-7.40 (t, 8H), 7.55, 7.60 (y, d, 2H) and 7.97 (ad, 2H). y» 13C NMR (rotamers, 75 MHz, SOSIz): 5 12.60, 13.80, 38.17, 38.25, 40.00, 40.44, 41.63, 42.40, 47.94, 50 ,61, 118-134 (complex multiplet), 140.32, 140.70, 141.50, 170.48 and 171.20

Example 12 2-K4-2-(Ethyl(2-fluorobenzyl)amino|-2-oxoethyl)uphenoxy)methylbenzoic acid and a) M-(2-Fluorobenzyl)ethanamine (0.554g, 3.615mmol) are dissolved in DMF (10ml ). (4-Hydroxyphenyl)acetic acid (0.500 g, 3.286) was added and the mixture was cooled to 026.

M-(IN-1,2,3-Benzotriazol-1-yloxy)Hudimethylamino)methylene|-M-methylmethanammonium tetrafluoroborate (1.161g, about 3.615mmol) and M-ethyl-M,M-diisopropylamine (0.892g , 6.901 mmol) are added. The solution is stirred overnight at 20°C room temperature. EtOAc (20 ml) is added and the organic phase is washed with two portions of sodium carbonate (2 x 20 ml, aq.). The organic layer is dried over magnesium sulfate and the solvent is removed by evaporation. Raw

Shk The material is purified by preparative HPLC (starting with an isocratic mixture of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100-7-С8 , 5Ommx25Omm, flow 4Oml/min). The fractions containing the product are combined and the acetonitrile is removed by evaporation. E(OAc (1Oml) is added and the organic phase is washed with two portions of brine and (F) is dried with magnesium sulfate and the solvent is removed by evaporation to give 0.6b9g

He M-ethyl-M-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide (yield 73.19). "YAN NMR (rotamers, B0OMHz, SOSIz): 5 1.12 (t, ЗН), 3.35-3.5 (t, 2Н), 3.62-3.72 (t, 2Н), 4.57 -4.78 (t, in 2H), 6.7 (5 2H), 6.98-7.38 (t, 6H).

B) M-Ethyl-M-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide (0.381 g, 1.327 mmol) and methyl 2-(bromomethyl)benzoate (0.334 g, 1.46 mmol) are dissolved in acetonitrile (1 mL ) and add potassium carbonate (0.367 tg, 2.654 mmol). The mixture is stirred at 6530 for three hours. When

M-ethyl-M-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide is spent, Rho-trisamine (0.Eq.) is added and solution 65 is stirred overnight at room temperature. The polymer is filtered off and the acetonitrile is removed by evaporation. E(Ac (1 Oml) is added and the organic phase is washed with two portions of water, dried with magnesium sulfate and the solvent is removed by evaporation, with the formation of 0.545 g of methyl 2-(4-2-(ethyl(2-fluorobenzyl)amino|-2-oxoethylphenoxy)methyl | of benzoate (yield 94.390). "YAN NMR (rotamers, ZOOMHz, SOSI8): 5 1.12 (t, ЗН), 3.23-3.35 (t, 2Н), 3.6-3.75 (t , 2H), 3.88 (z, ЗН), 4.45-4.70 (t, 2H), 5.45 (v, 2H), 6.84-7.35 (t, 9H), 7, 5 (Her, 1H), 7.72 (a, 1n), 8.0 (a, 1H). c) Methyl 2-(4-2-(ethyl(2-fluorobenzyl)amino|-2-oxoethyl)phenoxy )methyl|-benzoate (0.545g, 1.251mmol) was dissolved in EN (5ml) and potassium hydroxide (0.105g, 1.877mmol) was added. The reaction was carried out in a microwave unit (7 minutes, 15022). The solvent was removed by evaporation, and NH (20ml, 1M) and the aqueous phase is washed with two portions of EtOAc (20ml). The organic phases are combined and the solvent is removed by evaporation at 70. The crude material is purified by preparative HPLC (starting with isocratic acetonitrile/buffer 60/40 and then increasing the concentration of acetonitrile up to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KK-100-7-С8, 5 mmx2500 mm, flow rate 4 Oml/min). Fractions containing the product are combined and the acetonitrile is removed by evaporation. EtOAc (1 mL) and the organic phase were added (washed with two portions of brine and dried with magnesium sulfate. The solvent was removed by evaporation to give 0.124 g of 2-(4-(2-(ethyl(2-fluorobenzyl)amino)|-2-oxoethyl) uphenoxy)methyl|benzoic acid (23.59).

TN NMR (rotamers, X00MHz, SOSIz): 5 1.12 (t, ZN), 3.25-3. 5 (t, 2H), 3.65-3.8 (t, 2H), 4.5-4.75 (t, 2H), 5.52 (t, 2H), 6.84-7.45 ( t, 9H), 7.55 (I, 1H), 7.78 (y, 1H), 8.13 (y, 1H).

Example 13 2-(4-3-(Ethyl(2-fluorobenzyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid,

M-(2-Fluorobenzyl)ethanamt (0.554g, 3.615mmol) was dissolved in DMF (10ml), 3-(4-hydroxyphenyl)propanoic acid (0.546g, 3.28bmmol) was added and the mixture was cooled to 02.

M-(IN-1,2,3-benzotriazole-1-thoxy)dimethylamino)-methylene|-M-methylmethanammonium tetrafluoroborate (1.161g, 3.615mmol) and M-ethyl-M,M-diisopropalamine (0.892g, 6.901 mmol) are added. The solution is stirred overnight at room temperature. EOAc (20 ml) is added and the organic phase is washed with two portions of sodium carbonate (2 x 20 ml, aq.). The organic layer is dried over magnesium sulfate and the solvent is removed by evaporation. The crude (Fo) material is purified by preparative HPLC (starting with an isocratic mixture of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100- 7-C8, 5Ωmx25Ωm, flow 4Oml/min). Fractions containing the product were combined and the acetonitrile was removed by evaporation. EtOAc (1Oml) was added and the organic phase was washed with two portions of brine and dried over magnesium sulfate, and then the solvent was evaporated to give 0.803 Mr. O

M-ethyl-M-(2-fluorobenzyl)-3-(4-hydroxyphenyl)propanamide (yield 81.1905). at

TN NMR (rotamers, 5HO0MHz, SOSI8): 5 1.1 (t, 3H), 2.58-2.72 (t, 2H), 2.83-3.0 (t, 2H), 3.2- 3.5 (t, 2H), 4.45-4.7 (y, 2H), 6.78 (I, 2H), 6.95-7.35 (t, 6H). co

B) M-Ethyl-M-(2-fluorobenzyl)-3-(4-hydroxyphenyl)propanamide (0.400 g, 1.327 mmol) and methyl 2-(bromomethyl)benzoate (0.334 g, 1.46 mmol) are dissolved in acetonitrile ( 1Oml) and add potassium carbonate (0.367tg, 2.654mMmol). The mixture is stirred at 6550 for three hours. When

M-ethyl-M-(2-fluorobenzyl)-2-(4-hydroxyphenyl)acetamide is spent, Rho-trisamine (0.Eq.) is added and the solution is stirred overnight at room temperature. The polymer is filtered off and the acetonitrile is removed by evaporation. E(Ac (1 Oml) is added and the organic phase is washed with two portions of water, dried over magnesium sulfate and the solvent is removed by evaporation. E(Ac (1 Oml) is added and the organic phase is washed with two portions of water, dried over magnesium sulfate and the solvent is removed by evaporation. The crude material is purified by preparative HPLC (starting with an isocratic mixture of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100-7-С8 , 5Hommx25Omm, flow 4Oml/min). Fractions containing the product are combined and acetonitrile is removed - by evaporation. EtOAc (1Oml) is added and the organic phase is washed with two portions of brine and dried over magnesium sulfate. The solvent is removed by evaporation with the formation of 0.454 g of methyl 2-(4 -3-(ethyl(2-fluorobenzyl)amino|-3-oxopropyl)uphenoxy)methyl|-benzoate (yield 76.1905). o TN NMR (rotamers, 400 MHz, SOCI3): δ 1.08 (t, ЗН) . ,4 5-4.7 (t, 2H), 5.45 (v, 2H), 6.82-7.28 (t, 8H), 7.36 (i, 1H,!, 7.53 (B, 1 .H), 7.73 (a, 1H), 8.0 (a, 1Hn). o c) Methyl 2-(4-(3--ethyl(2-fluorobenzyl)amino|-3-oxopropyl)uphenoxy)methyl|-benzoate (0.454g, 1.001mmol) is dissolved in EN (5ml) and potassium hydroxide ( 0.085g, 1.514mmol). The reaction is carried out in a unit block of a microwave cabinet (7 minutes, 15022). Remove the solvent by evaporation, add HC (200ml, 1M) and wash the aqueous phase with two portions of EtOAc (20ml). The organic phases are combined and the solvent is removed by evaporation. The crude material is purified by preparative HPLC (starting with an isocratic mixture (F) of acetonitrile/buffer 60/40, and then the concentration of acetonitrile is increased to 10095, the buffer is a mixture of

GI acetonitrile/water 10/90 and ammonium acetate (0.1M, column KK-100-7-C8, 500mmx25Omm, flow 4Oml/min.). The product-containing fractions are combined and the acetonitrile is removed by evaporation. E(Ac) (1 Oml) is added and the organic phase is washed with two portions of brine and dried with magnesium sulfate. The solvent is removed by evaporation, with the formation of 0.079 g of 2-(4-(3-(ethyl(2-fluorobenzyl)amino|-3-oxopropyl- phenoxy)methyl|benzoic acid (18.09). "IN NMR (rotamers, X00MHz, SOCI8): 85 1.12 (t, 3H), 2.60-2.75 (t, 2H), 3.03 ( t, 2H), 3.23-3.50 (t, 2H), 4.45-4.73 (t, 2H), 5.57 (v, 2H), 6.88-7.35 (t, 8H), 7.41 (i, 1H), 7.60 (i. 1H), 7.80 (a, 1h), 8.18 (a, 1H).

The following examples are obtained in a similar way. 65 Example 14 2-4(3-2-(2,4-Difluorobenzyl)(heptyl)amino|-2-oxoethylphenyl)thio|methylibenzoic acid.

Example 15 2-((4-2-(4-Chlorobenzyl)(ethyl)amino|-2-oxoethylphenyl)thio|methylibenzoic acid.

Biological activity

Compositions

The compounds are dissolved in DMSO to obtain 16mM stock solutions. For research, the original solutions are further diluted with DMSO and cultivation media.

General chemicals and reagents

The luciferase assay reagent was obtained from RasKag, O5A. Restriction enzymes were obtained from Woengipdeg /o and Mepi-polymerase from Mem/Epoiapa Wioiarv.

Cell lines and cell culture conditions 02-05, (Human osteogenic sarcoma) were obtained from ATCC, OBA. Cells are grown and re-frozen in batches from transfer number 6. Cells are cultured in Dulbecco's medium, modified with Needle (OMEM) with 25 mM glucose, 2 mM glutamine or 4 mM I -alanyl-I -glutamine, 1096 fetal calf serum, at 595 CO". 7/5 Use phosphate buffered saline (PBS) without adding calcium or magnesium. All cell culture reagents were obtained from Sibso (Sh5A) and 96-well cell culture plates were obtained from UMass.

Plasmid constructs for heterologous expression

Standard recombinant DNA methods are carried out as described by A!yzibei! (7). Reporter luciferase vector, ro! BA (clone consists of Kk! 5 copies of the SAI4 DNA binding sequence,

Z-"ССАСОБАСТОТССТОСОАССТ-У, cloned into Zasi/Khpo! promoter roI Z sites (Rgoteda). Fragment

Zassi/Chnoi carrying OA5 sites are created using hybridized overlapping oligonucleotides.

The expression vectors used are based on reo5 (Zigaiadepe). All vectors contain an EsokI/MNei fragment encoding the DNA binding domain of BAI 4 (encoding amino acid positions 1-145, database entry number PO4386) and then fused in frame with a fragment encoding the nuclear localization sequence from the T-antigen of the virus sch ov polyoma. The sequence of nuclear localization is created using hybridized overlapping oligonucleotides created by MpeiKrp! sticky ends (5-STAOSOSToSTASAASAAAASASOSAADOOsTTTOOTAS-3). at);

Ligand-binding domains from APPR o; human and mouse and human and mouse APPRUuU were PCR-amplified as Krpi/Watni fragments and cloned in frame to the SAIH4 DNA binding domain and nuclear localization sequence. The sequences of all used plasmid constructs were confirmed by sequencing. The following av expression vectors are used for temporary transfections: oyu o so zv - refers to the position of the nucleotide from the database entry used to express the ligand-binding domain.

Transient transfections - with Frozen stock solutions of cells from passage 6 are thawed and grown to passage 8 for transfection. Confluent cells are trypsinized, washed and pelleted by centrifugation at 270 x ) for 2 minutes. The cell pellet is resuspended in cold BFFR to a cell concentration of approximately 18x10 cells/ml. After adding DNA, the cell suspension is incubated on ice for approximately 5 minutes before electroporation at 230M, 960μF in Viogaa'e Sepe Riivegtm in batches of 0.5 ml. A total of 50 μg of DNA is added to each batch of 0.5 ml of cells, involving 2.5 μg of expression vector, 25 μg of reporter vector and 22.5 μg of

Ge | non-specific DNA (rVishevzstiri, 5igagadepe).

After electroporation, cells are diluted to a concentration of approximately 3200O cells/ml in OMEM without phenol red, and approximately 2500 cells/cell are seeded into 96-well plates. For the reverse step 20 of obtaining cells, the seeded tablets are incubated at 37 °C for 3-4 hours before the addition of test compounds. In studies of APPR hu, the cellular medium is supplemented with desorbed resin-charcoal fetal calf serum (FVC) to prevent reverse activation by fatty acid components of the FVC. Desorbed tar-coal NWT is produced as follows; 10 g of charcoal and 25 g of Vio-Kai 200-400 mesh anion exchange resin are added to 500 ml of heat-activated NWT, and the solution is stirred on a magnetic stirrer at room temperature overnight. The NWT is centrifuged the next day and desorption is repeated for 4-6 hours. After the second treatment, the NWT is centrifuged and filter sterilized to remove carbon and resin residues.

The method of research in the initial solutions of compounds in DMSO is diluted to an acceptable concentration in reference tablets. From reference tablets, compounds are diluted in cultivation media to obtain solutions of test compounds for final doses.

After bringing the amount of cell medium to 7bmcl in each cell, add BbBOmcl of the test compound solution. Transiently transfected cells are exposed to the compound for approximately 24 hours prior to the luciferase assay. For the luciferase assay, 100 µl of the assay reagent is added manually to each cell and the plates are left for approximately 20 minutes to lyse the cells. After lysis, luciferase activity was measured in a multicell counter 1420, Misiog, from UMayasn.

Control compounds

TAO-pioglitazone is used as a control substance for activation of APIPR in humans and mice. 2,8,11,14-Eicosatetrayonic acid (ETIK) is used as a control substance for APPR.o in humans.

Calculations and analysis

A concentration-effect curve is constructed to calculate EC 5o values. The values used are derived from the average of two or three independent measurements (after subtraction of the background average) and are expressed as a percentage of the maximum activation obtained from the control compound. Values are plotted against 70 logarithms of test compound concentrations. Values of EKoo are established by linear interpolation between the given points and the calculated concentrations required to achieve 5095 maximal activation obtained from the control compound.

Compounds of formula I have an ECo of less than 50 μmol/L for APPRO, and preferred compounds have an ECo of less than 5 μmol/L, for example, the ECo of some examples for human APPR-Apifa are as follows:

Example 5 0.163 μmol/l;

Example 10 0.168 μmol/l;

Example 11 0.02 bmcmol/l; and

Example 15 0.027μmol/l.

Claims (12)

The formula of the invention 1. The compound of the formula o c 25 dk o She "y S nei M o 30 | i o, ho 7 IS Kk | "c) 1 so 35 where p is equal to 0, 1 or 2, and v represents a halogen, Su .lalkil, which is optionally substituted by one or more fluorine, C1.daloxyl which is optionally substituted by one or more fluorine, and if n is 2, the substituents in may be the same or different; 2 represents C" dalalkyl which, as variant interrupted by oxygen; " 20 Y is absent or represents methylene; and sho! X represents O or 5; c and its pharmaceutically acceptable salts and prodrugs. 1" 2. The compound according to claim 1, in which X represents 0. 3. The compound according to claim 1, in which X represents 5. 4. The compound according to any of the preceding clauses, in which U represents methylene. -1 5. A compound according to any one of claims 1, 2 or 3, in which M is absent. 6. A compound according to any of the previous clauses, in which in! represents halogen, C. alkyl, or C. alkyloxyl, and n co is 0, 1, or 2. at 7. The compound according to any of the previous items, in which B represents fluorine, methoxy or isopropyl, when n is equal to 1 or 2. 8. A compound according to any of the previous clauses, in which n is equal to 0. 2 9. A compound according to any of the preceding clauses, in which 2 represents St. talkil. 10. The compound according to claim 1, selected from the group: 2-(К4-13-(benzyl(hexyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-((4-2-(2,4-difluorobenzyl) (heptyl)amino|-2-oxoethylphenyl)thio|methylibenzoic acid; 2-(4-2-Ibenzyl(hexyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; o 2-(4-2-(2,4 -difluorobenzyl)(heptyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; ko 2-((4-13-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2 -4(4-(3-(2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenyl)thio|methyl)ibenzoic acid; 60 2-K4-13-I(butyl(2,3-dimethoxybenzyl)amino |-3-oxopropyl.phenoxy)methyl|benzoic acid; 2-К4-13-(2,3-dimethoxybenzyl)(heptyl)-amino|-3-oxopropyl.phenoxy)methyl|benzoic acid; 2-К4-13- (3-ethoxypropyl)(4-isopropylbenzyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-(4-13-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropyl)uphenoxy)methyl| benzoic acid; 2-(4-2-(ethyl(2-fluorobenzyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; 65 2-K4-13--ethyl(2-fluorobenzyl)amino|-3-oxopropyl.phenoxy)methyl |benzoic acid; 2-(14-(2-ethyl4-(trifluoromethyl)benzylamino)-2-oxoethyl)phenylthiomethyl)benzoic acid; 2-41(3-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylIfenyl)thio|methylibenzoic acid and 2-((4-2-(4-chlorobenzyl)(ethyl)amino|-2 -oxoethylphenyl)thio|methyl)benzoic acid; and pharmaceutically acceptable salts thereof. 11. The compound according to claim 2, selected from the group: 2-(К4-13-(benzyl(hexyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-(4-2-Ibenzyl(hexyl)amino|-2 -oxoethylphenoxy)methyl|benzoic acid; 2-(4-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylphenoxy)methyl|benzoic acid; 2-((4-13-(2,4- difluorobenzyl)(heptyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 70 2-K4-13-I(butyl(2,3-dimethoxybenzyl)amino|-3-oxopropyl.phenoxy)methyl|benzoic acid; 2- K4-13-(2,3-dimethoxybenzyl)(heptyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoic acid; 2-K4-13-(3-ethoxypropyl)(4-isopropylbenzyl)amino|-3-oxopropylphenoxy)methyl|benzoic acid; 2-(4-13-(2,4-difluorobenzyl)(propyl)amino|-3-oxopropyl)uphenoxy)methyl|benzoic acid; 2-(4-2-(ethyl(2-fluorobenzyl)amino|-2-oxoethylufenoxy)methyl|benzoic acid; 2-K4-13--ethyl(2-fluorobenzyl)amino|-3-oxopropyl)ufenoxy)methyl| benzoic acid; and pharmaceutically acceptable salts thereof. 12. The compound according to claim 3, selected from the group: 2-((4-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylphenyl)thio|methylibenzoic acid; 2-4(4-(3- (2,4-difluorobenzyl)(heptyl)amino|-3-oxopropylphenyl)thio|methyl)ibenzoic acid; 2-C4-(2--ethylI4-"trifluoromethyl)benzyl|amino)-2-oxoethyl)phenylthio)methyl) benzoic acid; 2-41(3-2-(2,4-difluorobenzyl)(heptyl)amino|-2-oxoethylIfenyl)thio|methylibenzoic acid and 2-4(4-2-(4-chlorobenzyl)(ethyl)amino|-2 -oxoethylphenyl)uthiomethyl)ibenzoic acid and its pharmaceutically acceptable salts. 0 И И 0. c Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 2, 15.02.2007. State Department of Intellectual Property of the Ministry of Education and o); of Sciences of Ukraine. "c) and "c) s m. "no s i" -I (ee) («c) s 50 (42) Ф) ime) 60 b5