New thyroid hormone beta-receptor agonist

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

 

The technical FIELD TO WHICH the PRESENT INVENTION

The present invention relates to new heterocyclic compound and a new agonist β receptor thyroid hormone containing compound as an active ingredient, which is suitable for hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism and/or latent hypothyroidism and the like.

The level of technology

Thyroid hormone is synthesizedin vivoin the form of thyroxine (T4), which is an inactive form, is released into the blood, is converted into triiodothyronine (T3), which represents the active form, in each of the target tissue, binds to α-receptors (TRα) and β receptor (TRβ) receptor, thyroid hormone (TR), classified as a nuclear receptor that functions as a transcription factor in the nucleus of cells and is provided physiological effect, characteristic for each target organ. T3 undergoes metabolism in the target organ and is mainly excreted in the bile. Physiological action of thyroid hormone in mammals plays a very important role in the growth and differentiation, as well as in the maintenance of vital functions, such as control of heart rate, the concentration of cholesterol and triglyce the Idov in the blood, the velocity of the General metabolism and body weight and the like. From the point of view of pathological physiology, tachycardia, arrhythmia, heart failure, and fatigue, shortness of breath and rapid heartbeat, reducing the tone of skeletal muscles, osteoporosis and the like are observed in hyperthyroidism, such as disease greivsa (non-patent document 1, non-patent document 2). On the other hand, is also observed beneficial effect for the treatment of metabolic diseases, such as reduced concentration of cholesterol in the blood, elevated levels of primary metabolism and the like. Back, low frequency heartbeat, increased concentration of cholesterol in the blood and increased body weight observed in hypothyroidism (deficiency of thyroid hormone), caused by disease of the pituitary gland, congenital dysfunction and the like.

Allowing specific manifestation of the useful aspects of thyroid hormone, such as reduced concentration of cholesterol in the blood or increased basal metabolic rate, while avoiding harmful results, such as increased heart rate and the like, and specific accumulation in the liver connection was made on the development of several types of analogs of thyroid hormone (non-patent document 3, non-patent document 4). As a result, however, the e could avoid the influence primarily on the circulatory system, and their development has not led to any progress (non-patent document 5).

It was reported that the receptors of thyroid hormone include subtypes of receptors TRα and TRβ (5 species TRα1, TRα2, TRβ1, and TRβ2 TRβ3, including splice variants), and each receptor has a different tissue distribution. Namely, it was found that both TRα and TRβ together are present in the liver, where 70-80% come TRβ involved in the metabolism of fats and heart TRα receptor involved in increased heart rate and increased cardiac output (non-patent document 6, non-patent document 7).

As TRβ agonist (traminette)reported diphenylmethanone derived and diarylethene derivative (patent documents 1-13), pyridazinone derivative (patent document 14), the pyridine derivative (patent document 15) and indole derivative (patent document 16). However, they are different from the compounds of the present invention structure.

[List documents]

[patent documents]

patent document 1: WO97/21993

patent document 2: WO2004/066929

patent document 3: WO2004/093799

patent document 4: WO2000/039077

patent document 5: WO2001/098256

patent document 6: WO2003/018515

patent document 7: WO2003/084915

patent document 8: WO2002/094319

patent document 9: WO2003/064369

patent document 10: JP-A-2002-053564

patent document 12: JP-A-2000-256190

patent document 13: WO2007/132475

patent document 14: WO2007/009913

patent document 15: WO2003/094845

patent document 16: WO2002/051805

[patent documents]

non-patent document 1: Physiol. Rev., 81, 1097, 2001.

non-patent document 2: J. Steroid. Biochem. Mol. Biol., 76, 31, 2001.

non-patent document 3: Curr. Top Med. Chem., 3, 1601, 2003.

non-patent document 4: Nature, 324, 425, any document 5: Cardiovascular Drug Reviews, 23, 133, 2005.

non-patent document 6: Endocrinology, 142, 544, 2001.

non-patent document 7: J. Biol. Chem., 267, 11794, 1992.

The ESSENCE of the PRESENT INVENTION

Problems that will be solved by the present invention

The present invention relates to new heterocyclic compound and a new agonist β receptor thyroid hormone containing compound as an active ingredient, which is suitable for the treatment of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism and/or latent hypothyroidism and the like.

Solutions to these problems

The inventors of the present invention conducted intensive studies in an attempt to solve the aforementioned problems and found that a specific heterocyclic derivative can achieve our purpose, which has resulted in the completion n of the present invention.

The present invention relates to the next heterocyclic derivative or its pharmacologically acceptable salts, and their use.

The present invention includes the following specific options for implementation.

(1) a Compound represented by the formula [I]:

where

A represents an optionally substituted alkyl, optionally substituted carbocyclic group, optionally substituted aryl, optionally substituted heterocyclic group, optionally substituted heteroaryl, optionally substituted amino or optionally substituted carbarnoyl,

X represents an optionally substituted methylene, -O - or-S-,

Q represents N or C-R4,

L1represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11-, -CH2nR11- or-S-,

L2represents a single bond, -CR6R7- or divalent heterocyclic group,

R1and R2are the same or different and each represents hydrogen, alkyl, alkenyl or halogen,

R3and R4are the same or different and each represents hydrogen, alkyl, alkoxy, cyano or halogen,

R1and R3not necessarily connected, forming carbocycle or heteros is CL,

R5represents a carboxyl group, alkoxycarbonyl group or bioisostere group, carboxyl group,

R6and R7are the same or different and each represents hydrogen, optionally substituted alkyl or halogen, or

R6and R7connected to become cycloalkyl or heterocycle,

R8represents hydroxy, alkanolamine or alkylsulfonamides,

R9and R10are the same or different and each represents hydrogen, alkyl or halogen, and

R11represents hydrogen or alkyl,

or its pharmacologically acceptable salt.

(2) Compound (1)where the Deputy optionally substituted alkyl for A represents the same or different 1-3 groups selected from the

aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano;

heterocyclic group, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano;

heteroaryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano;

cycloalkyl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano;

hydroxy;

alkoxy;

halogen;

AMI is gruppy, optionally substituted 1 or 2 alkilani; and

oxo,

Deputy optionally substituted aryl, optionally substituted carbocyclic group, optionally substituted heterocyclic group and optionally substituted heteroaryl for A represents the same or different 1-3 groups selected from the

the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;

alkenyl, optionally substituted alkoxy or cycloalkyl;

cycloalkyl, optionally substituted by alkyl, alkoxy or cycloalkyl;

alkoxy, optionally substituted alkoxy, cycloalkyl or halogen;

cycloalkane, optionally substituted by alkyl, alkoxy or cycloalkyl;

halogen;

cyano;

hydroxy;

oxo;

heterocycle;

alkylsulfonyl; and

mono - or dialkylamino,

Deputy optionally substituted amino for A represents the same or different 1 or 2 alkyl, optionally substituted alkoxy, cycloalkyl or halogen;

alkenyl, optionally substituted alkoxy or cycloalkyl;

cycloalkyl, optionally substituted by alkyl, alkoxy or cycloalkyl;

alkanoyl, optionally substituted alkoxy, cycloalkyl or halogen; or

aryl, optionally substituted by alkyl, alkoxy or cyclea the kilometres,

Deputy optionally substituted of carbamoyl for A represents the same or different 1 or 2 alkyl, optionally substituted aryl,

Deputy optionally substituted alkyl for R6or R7represents alkoxy, hydroxy or halogen, and

Deputy optionally substituted methylene X represents an alkoxy or hydroxy, or its pharmacologically acceptable salt.

(3) Compound (1) or (2), where A represents an optionally substituted alkyl, optionally substituted carbocyclic group, optionally substituted aryl, optionally substituted heterocyclic group or optionally substituted heteroaryl,

Q represents C-R4,

R1and R2are the same or different, and each represents alkyl or halogen,

R3and R4are the same or different and each represents hydrogen, alkyl or halogen,

X represents a methylene, -O - or-S-,

R5represents a carboxyl group, alkoxycarbonyl group or bioisostere group, carboxyl group,

L1represents a single bond, methylene, -CH=CH-, -O-, -NH-, -NHCO -, or-S-,

L2represents a single bond, -CR6R7- or divalent heterocyclic group is,

R6and R7are the same or different and each represents hydrogen, alkyl or halogen, or R6and R7form cycloalkyl or heterocycle together with the adjacent carbon atom,

R8represents hydroxy and

R9and R10represent hydrogen, or its pharmacologically acceptable salt.

(4) the Compound of any of (1)to(3), where A represents an optionally substituted carbocyclic group, or its pharmacologically acceptable salt.

(5) the Compound of any of (1)to(3), where A represents an optionally substituted aryl, or its pharmacologically acceptable salt.

(6) the Compound (4), where optionally substituted carbocyclic group is an optionally substituted cycloalkyl, or its pharmacologically acceptable salt.

(7) the Compound of any of (1)to(3), where A represents an optionally substituted alkyl, or its pharmacologically acceptable salt.

(8) the Compound of any of (1)to(3), where A represents an optionally substituted heterocyclic group, or its pharmacologically acceptable salt.

(9) the Compound of any of (1)to(3), where A represents an optionally substituted heteroaryl, or its pharmacologically acceptable salt.

(10) the Compound of any of (1)to(9), where X represents methylene, or his farm is ecologicheski acceptable salt.

(11) the Compound of any of (1)to(10), where R1and R2are the same groups, or its pharmacologically acceptable salt.

(12) the Compound of any of (1)to(11), where R1and R2are the same or different, and each represents alkyl, or its pharmacologically acceptable salt.

(13) the Compound of any of (1)to(12), where R1and R3connected, forming carbocycle or a heterocycle, or its pharmacologically acceptable salt.

(14) the Compound of any of (1)to(13), where R8represents hydroxy, or its pharmacologically acceptable salt.

(15) (4-{[5-Hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)acetic acid (example 3);

{4-[(6-cyclopentyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (example 5);

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (example 7);

{2-bromo-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid (example 13);

3-({4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid (example 22);

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid (example 23);

3-[(4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (example 29);

3-[(4-{[5-hydroxy-6-(5,6,7,8-tetrahydronaphthalen the-2-yl)pyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (example 30);

({5-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-3,4,6-trimethylpyridine-2-yl}oxy)acetic acid (example 45);

3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid (example 52);

N-[2-chloro-4-(6-cyclohexyl-5-hydroxypyridine-2-ylmethyl)for 3,5-dimetilfenil]amino-3-oxopropanoic acid (example 54);

3-[(2-fluoro-4-{[6-(2-fluoro-3-were)-5-hydroxypyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (example 60);

{4-[(6-cyclohexyl-4-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (example 65);

{4-[(6-cyclohexyl-3-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (example 73);

{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (example 92);

3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3, 5dimethylphenyl}amino)-3-oxopropanoic acid (example 131);

{4-[6-(3-forfinal)-5-hydroxypyridine-2-ylmethyl]-2,3,5-trimethylpentane}acetic acid (example 171);

(4-{[6-(3-chlorophenyl)-5-hydroxypyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid (example 173);

3-{2-fluoro-4-[5-hydroxy-6-(2,3,4-tryptophanyl)pyridine-2-ylmethyl]for 3,5-dimethylphenoxy}-1,2,4-oxadiazol-5(4H)-he (example 191);

3-[(2-fluoro-4-{[5-hydroxy-6-(3-pyrrolidin-1-ylphenyl)pyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (example 206);

2-{4-[(5-what hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (example 216);

3-{2-fluoro-4-[5-hydroxy-6-(3-propoxyphenyl)pyridine-2-ylmethyl]for 3,5-dimethylphenoxy}-1,2,4-oxadiazol-5(4H)-he (example 236);

[3,5-dibromo-2-fluoro-4-(5-hydroxy-6-vinylpyridin-2-ylmethyl)phenoxy]acetic acid (example 256);

(5-ethyl-4-{[6-(3-forfinal)-5-hydroxypyridine-2-yl]methyl}-2,3-dimethylphenoxy)acetic acid (example 269), or its pharmacologically acceptable salt.

(16) a Drug containing the compound of any of (1)to(15), or its pharmacologically acceptable salt as an active ingredient.

(17) the Drug (16), which is an agonist β receptor thyroid hormone.

(18) the Drug (16), which is used for treatment or prevention of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism and/or latent hypothyroidism.

(19) the Use of compounds of any one of (1)to(15) for drugs for treatment or prevention of disease, which is facilitated by the activation of β receptor thyroid hormone.

(20) a Method for the treatment or prevention of disease, which is facilitated by the activation of β receptor thyroid hormone, which includes the introduction of compounds of any of(1)-(15).

(21) the Compound represented by the formula [II]:

where Z1and Z 2are the same or different, and each represents-O-PG (PG represents a protective group),

Z3represents A or halogen,

Xarepresents oxygen, sulfur or a group represented by

where RXrepresents hydroxyl, optionally protected by a protective group, and other symbols are as mentioned above, or its salt.

The effect of the present invention

Heterocyclic derivative of the formula [I] of the present invention has an agonistic effect on β receptor, thyroid hormone, and it can be a drug, is effective for prevention or treatment of diseases associated with this action, for example, a drug for the prevention, reduction and/or treatment of hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, hypothyroidism, latent hypothyroidism, atherosclerosis, metabolic syndrome, obesity, diabetes, cardiovascular disease, coronary artery disease, myocardial infarction, ventricular failure, congestive heart failure, fatty liver, cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver (NAFLD), depression, de is enzie, osteoporosis, alopecia, nail disease, skin diseases, kidney disease, chronic renal failure and/or cancer and the like, in particular, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism and/or latent hypothyroidism and the like.

The compound of the formula [II] of the present invention are suitable as intermediate compounds for heterocyclic derivative of the formula [I] of the present invention.

Description of embodiments of the present invention

Group represented by each term and each character in the present description, are explained next.

Examples of “alkyl” include C1-6preferably C1-4, alkyl with normal chain or branched chain, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, pentyl, hexyl and the like.

Alkoxy “alkoxycarbonyl” and “alkoxy” includes C1-6preferably C1-4, alkoxy with normal chain or branched chain, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentyloxy, hexyloxy and the like.

“Halogen” includes fluorine atom, chlorine atom, bromine atom and iodine atom.

“Alkanoyl includes C1-6preferably C1-4al is anoil with a normal chain or branched chain, in particular, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl and the like.

“Alkenyl includes C2-6preferably C2-4alkenyl with a normal chain or branched chain, in particular vinyl, allyl, 1-methyl-2-propenyl, 3-butenyl, 2-pentenyl, 3-hexenyl and the like.

Cycloalkyl “cycloalkane and cycloalkyl includes C3-8preferably C3-6cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

“Cycloalkane includes C3-8preferably C3-6cycloalkane, in particular, cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane and the like.

“Cycloalken includes C3-8preferably C3-6, cycloalkene, in particular, cyclopropene, cyclobutene, cyclopentene, cyclohexene and the like.

“Carbocycle includes C6-14preferably C6-10, monocyclic, bicyclic or tricyclic nonaromatic carbocycle, which is optionally partially or fully saturated.

“Carbocyclic group” includes C3-14preferably C5-10, monocyclic, bicyclic or tricyclic non-aromatic carbocyclic group which optionally is partially or fully saturated.

“Aromatic ring” includes C6-14monocyclic, bicyclic or tricycle the mini-aromatic ring, preferably C6-10monocyclic or bicyclic aromatic ring, particularly a benzene, naphthalene, phenanthrene, anthracene and the like.

Aryl “arylcarbamoyl” and “aryl” includes C6-14monocyclic, bicyclic or tricyclic aryl, preferably C6-10monocyclic or bicyclic aryl. In particular may be mentioned phenyl, naphthyl, tenantry, antracol and the like.

“Heterocycle” includes a result 5-12-membered monocyclic or bicyclic nonaromatic a heterocycle containing 1-4 heteroatoms selected from a phosphorus atom, nitrogen atom, oxygen atom and sulfur atom (particularly, nitrogen atom, oxygen atom and sulfur atom, which optionally is partially or fully saturated.

Preferred monocyclic heterocycle is a result of 5-7-membered heterocycle containing 1-4 heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom, which optionally is partially or fully saturated. A preferred example of the monocyclic heterocycle is a result of 5-7-membered heterocycle containing 1-4 heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom, which optionally is partially or fully saturated. Its specific examples include oxazoline, Pyrrhus is lidin, piperidine, piperazine, morpholine, tetrahydropyran, tetrahydrofuran, imidazolidine, oxazolidine and the like.

The bicyclic heterocycle includes the bicyclic heterocycle, where the condensed same or different above-mentioned monocyclic heterocycles, the bicyclic heterocycle, where the above-mentioned monocyclic heterocycle condensed with a benzene ring, monocyclic heteroaromatic ring or cycloalkanes, and the bicyclic heterocycle, where the monocyclic heteroaromatic ring condensed with cycloalkanes. Specific examples of bicyclic heterocycle include indolin, isoindoline, tetrahydroquinoline, tetrahydrofuran, tetrahydrobiopterin and the like.

“Heterocyclic group” includes the resulting 5-12-membered monocyclic or bicyclic nonaromatic heterocyclic group containing 1-4 heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom, which optionally is partially or fully saturated.

Monocyclic heterocyclic group includes the resulting 5-7-membered heterocyclic group containing 1-4 heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom, which optionally is partially or fully saturated. Specific examples include oxazolyl, pyrrolidin the sludge, piperidyl, piperazinil, morpholyl, tetrahydropyranyl, tetrahydrofuryl, imidazolidinyl, oxazolidinyl and the like.

Bicyclic heterocyclic group contains 8-12-membered bicyclic heterocyclic group condensed same or different above-mentioned monocyclic heterocycles, 8-12 membered bicyclic heterocyclic group condensed the above-mentioned monocyclic heterocycle and a benzene ring, monocyclic heteroaromatic ring or cycloalkane, and 8-12-membered bicyclic heterocyclic group condensed monocyclic heteroaromatic ring and cycloalkane. Specific examples of the bicyclic heterocyclic groups include indolyl, isoindolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

“Heteroaromatic ring” represents an aromatic ring containing at least one heteroatom (nitrogen, oxygen or sulfur and the carbon atom, which includes 5 - or 6-membered monocyclic heteroaromatic ring, an 8-10 membered bicyclic heteroaromatic ring, where the condensed same or different monocyclic heteroaromatic ring, an 8-10 membered bicyclic heteroaromatic ring, where the monocyclic heteroaromatic ring con is inspirowana with benzene.

Particular examples of heteroaromatic rings include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, thiazole, isoxazol, isothiazol, oxadiazole, thiadiazole, furazan, pyridine, pyrazin, pyrimidine, pyridazine, triazine, indole, indazole, benzimidazole, purine, quinoline, isoquinoline, phthalazine, cinoxacin, hinzelin, cinnolin, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzothiazole and the like.

“Heteroaryl” represents an aromatic cyclic group containing at least one heteroatom (nitrogen, oxygen or sulfur and the carbon atom, which comprises a 5 - or 6-membered monocyclic group, an 8-10 membered bicyclic group condensed same or different monocyclic heteroaromatic ring and 8-10-membered bicyclic group, monocyclic heteroaromatic ring condensed with the benzene.

Specific examples of heteroaryl groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, furutani, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, indolyl, indazoles, benzimidazoles, purinol, hinely, ethanolic, phthalazine, honokalani, hintline, cinnoline, benzofuranyl, benzothiazol, benzoxazolyl benzothiazolyl, benzisoxazole, benzothiazole and the like.

“Bioisostere group, carboxyl group” includes phosphoric acid, phosphate ester, and a group represented by the following formula

where R51and R52are the same or different, and each represents alkanoyloxy, alkyl, optionally substituted by alkoxycarbonyl or hydrogen, R51and R52can be combined to form a heterocycle, optionally substituted aryl, optionally substituted with halogen, and R53and R54are the same or different, and each represents alkyl or hydrogen, preferably hydrogen).

A preferred form of each group follows.

“Optionally substituted alkyl” for A can be substituted by 1-5, preferably 1-3, substituents, and the substituents include (1) aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (2) heterocyclic group optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (3) heteroaryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (4) cycloalkyl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (5) Hydra is XI, (6) alkoxy, (7) halogen, (8) amino group, optionally substituted 1 or 2 alkilani and (9) oxo.

“Alkyl” for A is, for example, preferably 2-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-butyl, 3-pentyl, 2-methyl-2-butyl and the like, more preferably 2-propyl, 2-methyl-2-propyl, 2-butyl and 3-pentyl, and alkyl “substituted alkyl” for A is, for example, preferably methyl, ethyl, 1-propyl, 2-methyl-1-propyl and similar.

The preferred substitute optionally substituted alkyl” for A consists of (1) aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano (in particular, 4-ftoheia), (2) heterocyclic group optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (3) heteroaryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (4) cycloalkyl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, and (5) hydroxy, where alkyl may be substituted by the same or different, 1-3, preferably 1-2, groups.

“Substituted alkyl” for A is, for example, preferably a group represented by the formula:

where A1represents any group selected from (a) aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano (in particular, 4-ftoheia), (2) heterocyclic group optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (3) heteroaryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, (4) cycloalkyl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy, alkanoyl and cyano, and (5) alkyl groups,

particularly preferably the group represented

Preferred examples of carbocyclic group “optionally substituted carbocyclic group” to include A bicyclic group condensed aromatic ring and cycloalkyl (in particular, tetrahydronaphthyl), and cycloalkyl, particularly preferably cycloalkyl. Among others, C5-C7 cycloalkyl is preferred, and cyclohexyl and cycloheptyl is especially preferred.

Preferred aryl “optionally substituted aryl” and “optionally substituted arylcarbamoyl” for A include naphthyl and phenyl.

Preferred heterocyclic group “optionally substituted heterocyclic group” includes A 5 - or 6-membered monocyclic heterocyclic group optionally partially or fully saturated, and 9-12-membered bicyclic heterocyclic group, optionally partially or fully saturated, each of which contains 1-3 heteroatoms (nitrogen, oxygen or sulfur) and a carbon atom.

Its specific examples include pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, dioxane, dioxolane and condensed ring group this group with a monocyclic heteroaromatic ring or an aromatic ring and the like.

Preferred heteroaryl “optionally substituted heteroaryl” includes A 5 - or 6-membered aromatic monocyclic group and a 9 - or 10-membered bicyclic aromatic group, each of which contains 1-3 heteroatoms (oxygen or sulfur) and a carbon atom. Its specific examples include furanyl, thienyl, benzofuranyl, benzothiazol and the like.

“Optionally substituted aryl”, “optionally substituted arylcarbamoyl”, “optionally substituted carbocyclic group”, “optionally substituted heterocyclic group” and “optionally substituted heteroaryl” can contain the same or different, 1-3 Deputy, and Deputy includes (1) alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen, (2) alkenyl, optionally substituted alkoxy or cycloalkyl, (3) cycloalkyl, neo is Astelin substituted by alkyl, alkoxy or cycloalkyl, (4) alkoxy, optionally substituted alkoxy, cycloalkyl or halogen, (5) cycloalkane, optionally substituted by alkyl, alkoxy or cycloalkyl, (6) halogen, (7) cyano, (8) hydroxy, (9) oxo, (10) heterocyclic group, (11) alkylsulfonyl, (12) mono - or dialkylamino and the like.

The preferred substitute optionally substituted aryl”, “optionally substituted arylcarbamoyl” and “optionally substituted heteroaryl” for A include alkyl, optionally substituted alkoxy or halogen, alkoxy, optionally substituted with halogen, heterocyclic group, mono or dialkylamino, alkylsulfonyl, cyano and halogen, in particular methyl, ethyl, isopropyl, trifluoromethyl, methoxymethyl, methoxy, ethoxy, n-propoxy, isopropoxy, triptoreline, pyrrolidinyl, dimethylcarbamoyl, methanesulfonyl, cyano and halogen and the like, and preferably halogen, methyl, ethyl, methoxy, ethoxy and cyano. Aryl and heteroaryl may be substituted by the same or different, 1-3, preferably 1-2, groups.

The preferred substitute optionally substituted carbocyclic group” and “optionally substituted heterocyclic group” includes A halogen; alkyl, optionally substituted by hydroxy, alkoxy or halogen; alkoxy; cyano; hydroxy, in particular halogen, hydroxy, methyl, ethyl, hydroxymethyl, methoxymethyl, methoxy, ethoxy and cyano. Carbocyclic group and heterocyclic group may be substituted by the same or different, 1-3, preferably 1-2, groups.

The preferred substitute optionally substituted amino” for A consists of (1) alkyl, optionally substituted alkoxy, cycloalkyl or halogen, (2) alkenyl, optionally substituted alkoxy or cycloalkyl, (3) cycloalkyl, optionally substituted by alkyl, alkoxy or cycloalkyl, (4) alkanoyl, optionally substituted alkoxy, cycloalkyl or halogen, (5) aryl, optionally substituted by alkyl, alkoxy or cycloalkyl, preferably alkyl, cycloalkyl and aryl. In particular, one can mention methyl, cyclohexyl and phenyl. Amino optionally substituted by the same or different 1 or 2 groups.

Deputy “optionally substituted of carbamoyl” for A include alkyl, optionally substituted aryl, in particular 2-phenylethyl and 2-phenyl-1-propyl. Carbarnoyl may be substituted by same or different 1 or 2 groups.

“Alkyl” for R1or R2represents, for example, particularly preferably methyl or ethyl.

“Alkenyl for R1or R2represents, for example, particularly preferably vinyl.

“Alkyl” for R3or R4pre is is, for example, particularly preferably methyl or ethyl.

“Alkoxy” for R3or R4represents, for example, particularly preferably methoxy.

R1and R2are preferably the same.

Preferably, one of R3and R4represents hydrogen, and the second represents alkyl or halogen.

Carbocycle formed R1and R3interconnected, includes nonaromatic carbocycle, preferably 5 - or 6-membered cycloalkyl or 5 - or 6-membered cycloalkyl, particularly preferably cyclopentane.

The heterocycle formed by R1and R3connected between each other includes a 5 - or 6-membered nonaromatic a heterocycle containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur, preferably 5-membered nonaromatic a heterocycle containing one heteroatom selected from oxygen, nitrogen and sulfur, particularly preferably tetrahydrofuran.

Specific examples of the formula:

where R1and R3connected, forming carbocycle or heterocycle include formula:

where X13represents methylene, oxygen or sulfur, and other symbol represents, as mentioned above.

R5represents preferably carboxyl groups is or 5-oxo-4,5-di-[1,2,4]oxadiazol-3-yl.

Alkyl “optionally substituted alkyl” for R6or R7is particularly preferably methyl, and examples of the substituent include alkoxy, hydroxy and halogen.

Cycloalkane formed R6and R7connected with each other, is particularly preferably C3-5cycloalkane (especially cyclopropane).

The heterocycle formed by R6and R7connected to each other, preferably represents C3-7particularly preferably C3-5a heterocycle. Its examples include tetrahydropyran, tetrahydrofuran and the like.

Alkanolamine for R8represents, for example, acetylamino, formylamino and the like.

Alkylsulfonamides for R8represents, for example, methanesulfonamido, ethanolamine, isopropanolamine, n-propylsulfonyl and the like.

R8represents preferably hydroxy.

R9represents preferably a hydrogen or halogen (especially fluorine), particularly preferably hydrogen.

R10represents preferably a hydrogen or halogen (especially fluorine), particularly preferably hydrogen.

Alkyl for R11includes methyl and ethyl.

L1represents preferably-O-.

“Divalent heterocyclic group is for L 2include divalent monocyclic heterocyclic group, preferably containing one or more nitrogen atoms, and its examples include pyrrolidinyl, morpholinyl, piperidinyl and the like.

-L1-L2-R5represents preferably R5(each of L1and L2represents a single bond or a group selected from groups represented by the following formula:

More preferably the group represented by the formula:

X preferably represents optionally substituted methylene, particularly preferably methylene.

Deputy “optionally substituted methylene” for X include alkoxy and hydroxy.

Q preferably represents C-R4.

The compound of the formula [I] or its pharmacologically acceptable salt include the compounds described in the examples and their pharmaceutically acceptable salts, preferably

(4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)acetic acid (Example 3);

{4-[(6-cyclopentyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (Example 5);

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (Example 7);

{2-bromo-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-is immiltenali}acetic acid (Example 13);

3-({4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid (Example 22);

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid (Example 23);

3-[(4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 29);

3-[(4-{[5-hydroxy-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 30);

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}acetic acid (Example 41);

({5-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-3,4,6-trimethylpyridine-2-yl}oxy)acetic acid (Example 45);

3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid (Example 52);

3-[(2-fluoro-4-{[6-(2-fluoro-3-were)-5-hydroxypyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 60);

N-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}glycine (Example 62);

{4-[(6-cyclohexyl-4-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (Example 65);

3-[(4-{[6-(3-ethoxyphenyl)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 66);

3-({5-ethyl-2-fluoro-4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl]-3-methylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he (Example 72);

{4-[(6-cyclohexyl-3-fluoro-5-GI is oxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (Example 73);

6-[4-(3-hydroxyethoxy-5-yl)-2,3,6-trimethylbenzyl]-2-isopropylpyridine-3-ol (Example 81);

{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}acetic acid (Example 83);

3-[(2-fluoro-4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 87);

{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid (Example 92);

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3, 5dimethylphenyl}amino)-3-oxopropanoic acid (Example 98);

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-methoxy-3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he (Example 107);

3-[({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-5-methyl-2,3-dihydro-1-benzofuran-7-yl}oxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 117);

3-({2-fluoro-4-[(5-hydroxy-6-piperidine-1-espiridion-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he (Example 118);

(4-{[6-(3,4-differenl)-5-hydroxypyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid (Example 120);

(4-{[5-hydroxy-6-(3-were)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid (Example 122);

3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3, 5dimethylphenyl}amino)-3-oxopropanoic acid (Example 131);

3-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}-2-forproposal acid (Example 136);

3-{[2-fluoro-4-({5-hydrox the-6-[2-(trifluoromethyl)phenyl]pyridine-2-yl}methyl) - for 3,5-dimethylphenoxy]methyl}-1,2,4-oxadiazol-5(4H)-he (Example 148);

({7-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-6-methyl-2,3-dihydro-1H-inden-4-yl}oxy)acetic acid (Example 152);

(4-{[6-(3-chlorophenyl)-5-hydroxypyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid (Example 173);

(4-{[6-(3-ethylphenyl)-5-hydroxypyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid (Example 176);

3-{[2-fluoro-4-({6-[4-fluoro-3-(trifluoromethyl)phenyl]-5-hydroxypyridine-2-yl}methyl) - for 3,5-dimethylphenoxy]methyl}-1,2,4-oxadiazol-5(4H)-he (Example 189);

3-[(2-fluoro-4-{[5-hydroxy-6-(3-pyrrolidin-1-ylphenyl)pyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 206);

2-{4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (Example 216);

3-[(4-{[6-(3-ethyl-2-forfinal)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 249);

3-[(4-{[6-(3-ethyl-4-forfinal)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he (Example 250);

3-{[2-fluoro-4-({5-hydroxy-6-[1-(methoxymethyl)cyclohexyl]pyridin-2-yl}methyl) - for 3,5-dimethylphenoxy]methyl}-1,2,4-oxadiazol-5(4H)-he (Example 268);

(5-ethyl-4-{[6-(3-forfinal)-5-hydroxypyridine-2-yl]methyl}-2,3-dimethylphenoxy)acetic acid (Example 269);

(5-ethyl-4-{[5-hydroxy-6-(3-were)pyridine-2-yl]methyl}-2,3-dimethylphenoxy)acetic acid (Example 270); and

(4-{[6-(3-chlorophenyl)-5-hydroxypyridine-2-yl]methyl}-5-ethyl-23 dimethylphenoxy)acetic acid (Example 271), and their pharmacologically acceptable salts.

In the compound represented by the formula [II], the preferred values of A and R1-R4are takimi the same as the values of A and R1-R4in the formula [I].

Xarepresents preferably a group represented by the formula:

where the symbols are as mentioned above.

Hydroxy-protective group for RXincludes protective group commonly used for the protection of hydroxy, for example, hydroxy-protective group described in Protective Groups in Organic Synthesis Third Edition (Theodora W. Green and Peter G. Wuts). Its specific examples include alkanoyl, trialkylsilyl, alkyl and the like.

PG-O-PG for Z1or Z2includes protective group commonly used for phenolic hydroxy group, for example, hydroxy-protective group described in Protective Groups in Organic Synthesis Third Edition (Theodora W. Green and Peter G. Wuts). Their specific examples include methoxymethyl, ethoxymethyl, ethoxyethyl, benzyl, allyl, triisopropylsilyl and the like. In-O-PG for Z1or Z2, PG for Z1and Z2preferably represent different protective groups.

As salts of the compounds of formula [I] in the above, you can apply salt accession acid or salt attaching the base, where the type of salt is not specifically limited, provided that it is physiologically pickup the problem.

Examples of pharmacologically acceptable salts include, when the compound has a basic group, salt accession inorganic acids such as hydrochloride, sulfate, phosphate, hydrobromide and the like, and salts of accession of organic acids such as acetate, fumarate, oxalate, citrate, methanesulfonate, bansilalpet, tosylate, maleate and the like. In addition, when the compound contains an acid group, examples of the salt include a salt with a base, such as alkali metal salts (sodium salt, potassium etc), salts of alkaline earth metals (calcium salt etc) and the like.

When the compound of the formula [I] or its salt contains optically active form, it can be divided into each optical isomer standard methods of separation of optical isomers. Alternatively, optically active form of compounds of formula [I] or its salt can be obtained by using optically pure source connection or whose spatial configuration is known.

One or more species of the compounds of formula [I] of the present invention or their salts can be administered to patients. Preferably, the active ingredient and a pharmacologically and pharmaceutically acceptable additive are mixed and provide in the form of the drug in the form of well-known specialists in this field of technology.

Connected to the e of the present invention receive in a suitable form for injection (powder, injection, tablet, capsule or drug product for external use, and the like) together with is usually applied with a suitable diluent and other additives, and can enter the human or animal a suitable way of introduction depending on its dosage form (for example, intravenous administration, oral administration, transdermal administration or local injection and the like).

As pharmacologically and pharmaceutically acceptable additives can be applied excipient, baking powder, a binder, a lubricating substance, a substance for coating, dye, solvent, base, isotonic agent and the like.

Examples of the preparation suitable for oral administration include tablet, capsule, powder, fine granules, granules, liquid, syrup and the like. Examples of the preparation suitable for parenteral administration include injection, drip infusion, suppository and the like.

With regard to the preparation suitable for oral administration, can be used as additives and excipients, baking powder, a binder, a lubricating substance, a substance for coating base and the like. In addition, when the compound of the present invention is administered to patients for the treatment, other agents suitable for treatment of the target disease, and the unity of the present invention can be used in combination.

Route of administration of the medicinal product of the present invention is not specifically limited, and can be administered orally or parenterally. The dose varies depending on age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the disease being treated, the patient, taking into account their or other factors. The compound of the present invention, its optical isomers and its pharmaceutically acceptable salt are non-lethal and can safely be applied. Their daily dose varies depending on the disease and body weight of patients, type of connection, the method of administration and the like. Parenterally, for example, approximately of 0.0001-1000 mg/individual/day, preferably about 0.001 to 1000 mg/person/day, particularly preferably 0.01 to 500 mg/person/day, preferably administered subcutaneously, intravenously, intramuscularly, or intrarectal, and approximately of 0.0001-1000 mg/individual/day, preferably 0.01 to 500 mg/person/day, preferably administered orally.

Compounds represented by formulas [I] and [II]can be obtained as follows.

Unless specified otherwise, the following symbols in the methods of preparation, the examples and reference examples have the following meanings.

APCI: chemical ionization at atmospheric Yes the relocation

Ac: acetyl

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

Bn: benzyl

Boc:tert-butoxycarbonyl

Bu: butyl

ESI: electrospray ionization

Et: ethyl

Me: methyl

MOM: methoxymethyl

Ms: methanesulfonyl

Ph: phenyl

Tf: trifloromethyl

TMS: trimethylsilyl

Ts:p-toluensulfonyl

The compound of the formula [II] can be obtained according to the following method.

The method of obtaining 1

where PG1and PG2represent different protective groups, Aarepresents aryl or heteroaryl, optionally condensed with cycloalkanes, RX1represents acetoxy, or halogen, Hal represents halogen, and other symbols are as mentioned above.

The compound (3) can be obtained by reaction of the compound (2), for example, with an organic metal reagent, such asn-utilitiy reagent for the exchange of halogen to metal, and adding the compound (1)obtained on the basis Angew. Chem. Int. Ed. 2002, 41, 1062. This reaction is preferably conducted in a solvent inert to the reaction (for example, ether solvents such as tetrahydrofuran, diethyl ether and the like, or hydrocarbon solvents such as toluene and the like) at from -78°C to room temperature.

As each of PGsup> 1and PG2you can choose a protective group, allowing selective release. As PG1is the preferred methoxymethyl group, and as PG2are the preferred 1-ethoxy-1-ethyl group, benzyl group and the like.

In addition, the compound (3) can respond, without isolation, with a reagent for introducing a protective group, such as acetic anhydride and the like.

[stage 2]

The compound (5) can be obtained by reaction of the compound (3) with compound (4) in the presence of a base and a palladium catalyst. As the palladium catalyst can preferably be used palladium catalysts with zero valence or divalent catalysts such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II), palladium (II) acetate and the like. As a basis it is possible it is preferable to use inorganic bases, such as carbonate of an alkali metal, a hydroxide of an alkali metal, a phosphate of an alkali metal, fluoride of an alkali metal and the like, organic bases such as triethylamine, etc. and the like.

This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited, provided that it has no adverse influence on the reaction, and m is should accordingly apply for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially 80-120°C.

In addition, boric acid, such as Aa-B(OH)2and its ether containing tin reagent, such as Aa-SnBu4containing magnesium reagent, such as Aa-MgBr, - and zinc-containing reagent, such as Aa-ZnBr, can be used instead of the compound (4).

[stage 3]

The compound (6), where RX1represents acetoxy, can be obtained by acetylation of compound (5) and restore this connection. Acetylation can be performed commonly used method, for example, by reaction of the compound with acetic anhydride in pyridine at room temperature.

The compound (6), where RX1is a halogen, can be obtained by halogenoalkanes connection (5). Halogenoalkane not specifically limited, provided that it is a commonly used method, and, for example, the chlorination is preferably proceeds at room temperature in the presence of a base such as triethylamine and N,N-dimethylaminopyridine, and applying gloriouse agent, such as methanesulfonate and thionyl chloride, and optionally applying a salt such as lithium chloride, in a solvent inert to Yes the Noi responses (e.g., ethereal solvents such as ethyl acetate, halogenated solvents such as dichloromethane, hydrocarbon solvents such as toluene and the like). [stage 4]

Compound (7) can be obtained by reduction of compound (6). Restoring flows well when using the reaction of catalytic hydrogenation in a hydrogen atmosphere in the presence of a palladium catalyst, or restoration, applying trialkylsilyl in the presence of an acidic catalyst. The catalytic hydrogenation reaction preferably proceeds in a solvent inert to the reaction (for example, ether solvents such as ethyl acetate, alcohol solvents such as ethanol, ether solvents such as tetrahydrofuran and the like)at room temperature in hydrogen atmosphere (1-3 ATM). Recovery using trialkylsilyl, preferably proceeds in a solvent inert to the reaction (for example, methylene chloride)in the presence of an acidic catalyst such as BF3-Et2O, triperoxonane acid and triftorbyenzola silver, while cooling on ice.

Method recovery, applying trialkylsilyl, stage 3, can be performed before stage 2 can be performed after stage 2.

The method of obtaining 2

where each symbol represents the FDS is th, as was mentioned above.

[stage 1]

The compound (10) can be obtained by treating compound (8) alkyllithium reagent or alkalinity reagent for the reaction of the exchange of the halogen-metal, and the reaction of the compound with compound (9). This reaction can be carried out in a suitable solvent. The solvent is not specifically limited, provided that it has no adverse influence on the reaction and can accordingly be used, for example, ether solvents such as tetrahydrofuran, hydrocarbon solvents such as toluene, etc. and the like. This reaction can preferably be carried out at from -78°C to room temperature.

Connection, where Rxis a protected hydroxyl, can also be obtained by reaction with compound (9) and, without isolation, by reaction with a reagent for introducing a protective group, such as acetic anhydride and the like.

The method of obtaining 3

where X1Hrepresents OH or SH, X1represents O or S, and other symbols are as mentioned above.

[stage 1]

The compound (12) can be obtained by reaction of the compound (8) with compound (11) in the presence of a catalyst containing a transition metal, such as copper iodide (I) and the like, and base. As a basis you can prepact the tion to apply inorganic salts, such as potassium carbonate, cesium carbonate and the like. This reaction can be carried out in a suitable solvent. The solvent is not specifically limited, provided that it has no adverse influence on the reaction, and can accordingly be used, for example, dimethyl sulfoxide and the like. This reaction preferably proceeds at 60-150°C, especially at 80-120°C.

The method of obtaining 4

where Ra-Rdare the same or different and represent substituents such as hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino and the like, Rdand Rccan be combined to form optionally substituted cyclic group (for example, a heterocycle and carbocycle), and other symbols are as mentioned above.

[stage 1a]

Compound (16) can be obtained from compound (15), which can be obtained from compound (13) and compound (14) in the same way as in the method of obtaining 1, stage 2, by the reaction of catalytic hydrogenation, including recovery in hydrogen atmosphere in the presence of palladium catalyst. The catalytic hydrogenation reaction preferably proceeds in a solvent inert to the reaction (for example, ether solvents such as etilize is at, alcohol solvents such as ethanol, ether solvents such as tetrahydrofuran and the like)at room temperature in hydrogen atmosphere (1-3 ATM).

Using the following connection (19) instead of compound (14)can be obtained compound represented by the formula [1], where A represents cycloalkyl, optionally condensed with an aromatic ring, or heterocyclic group.

where Z represents cycloalkenyl, optionally condensed with an optionally substituted aromatic ring, or heterocyclic group.

Compound (16) can also be obtained by applying the reagent on the basis of boric acid, a borate, a reagent containing tin, the reagent containing magnesium, and a reagent containing zinc, the respective compounds (14) and compound (19).

[stage 1b]

The compound (17) can be obtained by reaction of the compound (13) in the presence of carbon monoxide, amine (othercRd), the base and palladium catalyst. As the palladium catalyst can preferably be applied palladium catalyst with a zero valence or divalent catalysts such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II), palladium (II) acetate and the like. As the base can preferably approx shall take inorganic base, such as a carbonate of an alkali metal, a hydroxide of an alkali metal, a phosphate of an alkali metal, fluoride of an alkali metal and the like, an organic base such as triethylamine, etc. and the like. As alcohol is possible, it is preferable to use methanol, ethanol and the like. Hexacarbonyl molybdenum and the like can be used instead of carbon monoxide.

This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially at 80-120°C.

[stage 1c]

The compound (18) can be obtained by reaction of the compound (13) with the amine (othercRd). You can also apply a palladium catalyst and base. For the reaction using a palladium catalyst, Tris(benzylideneacetone)dipalladium(0), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene,tert-piperonyl sodium and the like can be used in combination. As the base can preferably be used an inorganic base such as a carbonate of an alkali metal, a hydroxide of alkaline metal, alkaline phosphate is atalla, the fluoride of the alkali metal and the like, an organic base such as triethylamine, etc. and the like. This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, dimethoxyethane, tetrahydrofuran, dimethyl sulfoxide and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially at 80-120°C.

The method of obtaining 5

where Rfand Reare the same or different, and each represents an alkyl or alkenyl, or Rfand Recan be combined to form optionally substituted carbocycle or a heterocycle, and the other symbols are as mentioned above.

[stage 1]

The compound (20) can be obtained by treating compound (13) alkyllithium reagent, or mixed halide reagent alkylate and alkaline for the reaction of the exchange of the halogen-metal, and the reaction of the compound with an electrophile (e.g., a ketone: RfC(=O)Reand the like).

The exchange reaction of the halogen-metal can be carried out in a solvent inert to the reaction (for example, ether solvents such as tetrahydrofuran and the like). This reaction can be applied in doctitle be carried out at from -78°C to room temperature.

The method of obtaining 6

where Rhand Rgare the same or different, and each represents an alkyl or alkenyl, Rhand Rgcan be combined to form carbocycle or a heterocycle, and the other symbols are as mentioned above.

[stage 1]

Compound (22) can be obtained dehalogenation connection (21) accepted way, and alkanolammonium connection accepted way. This reaction can be carried out in a suitable solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can be applied, for example, ether solvents such as tetrahydrofuran, an amide solvents such as N,N-dimethylformamide, and their mixed solvents.

[stage 2]

The compound (23) can be obtained by heating compound (22) in the presence of a base. As a basis it is possible it is preferable to use sodium acetate and the solvent can preferably be applied acetic anhydride. This reaction preferably proceeds at 160°C to 240°C, and preferably runs under microwave irradiation.

The compound represented by the formula [I]can be obtained from compounds represented by the formula [II], in the following way.

The method of obtaining 7

where R5arepresents a carboxyl group optionally protected by a protective group, or its bioisostere group, optionally protected by a protective group, LG is a leaving group (e.g. halogen, arylsulfonate, such as tosyloxy, alkylsulfonate and the like), and other symbols are as mentioned above.

[stage 1]

The compound (26) can be obtained by reaction of the compound (24) with compound (25) in the presence of a base. This reaction can be carried out in a solvent inert to the reaction (for example, acetonitrile, ether solvents such as ethyl acetate, ether solvents such as tetrahydrofuran, an amide solvents such as dimethylformamide and the like). As the base can preferably be used an inorganic base such as cesium carbonate, potassium carbonate, etc. and the like. This reaction preferably proceeds at 0°C-80°C, especially at room temperature to 60°C.

[stage 2]

Compound (27) can be obtained by releasing the connection (26) accepted way.

The way to obtain 8

where the characters are, as mentioned above.

[stage 1]

Compound (29) can be obtained from compound (24) and compound (28) in the same way as in the method of obtaining 7, the study is 1.

[stage 2]

The compound (30) can be obtained by reaction of the compound (29) with sodium bicarbonate and hydroxylamine hydrochloride, and the reaction of the obtained compound with 1,1-carbonyl diimidazol (CDI).

The reaction with hydroxylamine can be carried out in a solvent inert to the reaction (for example, alcohol solvents such as methanol and the like), and preferably it takes place at 60°C-100°C.

Reaction with CDI can be carried out in a solvent inert to the reaction (for example, ether solvents such as 1,4-dioxane and the like), and preferably it is at 80°C-120°C

[stage 3]

The compound (31) can be obtained by releasing PG1connection (30) accepted way.

The method of obtaining 9

where R represents alkyl, and other symbols are as mentioned above.

[stage 1]

Compound (32) can be obtained by reaction of the compound (24) with triftormetilfullerenov in the presence of a base. This step is preferably proceeds in a solvent inert to the reaction (for example, methylene chloride), in the presence of a base, such as 2,6-lutidine, diisopropylethylamine and the like, under cooling on ice.

[stage 2]

The compound (33) can be obtained by reaction of the compound (32) with trimethylsilylacetamide in the presence of base is, iodide copper (I) and palladium catalyst (reaction Sonogashira). As the palladium catalyst can preferably be applied palladium catalyst with a zero valence or divalent catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II), palladium(II) acetate and the like. As the base can preferably be used an inorganic base such as a carbonate of an alkali metal, a hydroxide of an alkali metal, a phosphate of an alkali metal, fluoride of an alkali metal and the like, an organic base such as triethylamine, etc. and the like.

This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially at 80-120°C.

[stage 3]

Compound (34) can be obtained by treating compound (33) with a base (e.g. an inorganic base such as potassium carbonate) in a suitable solvent. This reaction can be carried out in a suitable solvent. The solvent is not specifically about what reichen provided that it has no adverse influence on the reaction and can be applied, for example, alcohol solvents such as methanol and the like. This reaction preferably proceeds at 0°C to room temperature.

[stage 4]

Compound (35) can be obtained by treating compound (34) base (for example, inorganic salts of metal such as diisopropylamide lithium hexamethyldisilazide lithium and the like alkylbetaine, such as utility and the like) in a suitable solvent, and the process of joining alkylhalogenide. This reaction can be carried out in a suitable solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can be applied, for example, ether solvents such as tetrahydrofuran. This reaction preferably takes place at from -78°C to room temperature.

[stage 5]

Compound (36) can be obtained by reaction of the compound (35) with hydroxylamine hydrochloride. This reaction can be carried out in a suitable solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can be applied, for example, 10% aqueous sodium hydroxide solution, alcohol solvents such as ethanol, and aprotic solvents such as methylene chloride or mixed dissolve the ü. This reaction preferably proceeds at 0°C-80°C, especially at 0°C-60°C.

[stage 6]

The compound (37) can be obtained by releasing PG1compound (36) accepted way.

The method of obtaining 10

where the characters are, as mentioned above.

Compound (39) can be obtained by reaction of the compound (32) with compound (38) in the presence of palladium catalyst. As the palladium catalyst can preferably be applied palladium catalyst with a zero valence or divalent catalyst, such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II), palladium(II) acetate and the like. As additives can be added, for example, lithium chloride, chloride of triethylamine, cesium fluoride, iodide copper (I) and the like.

This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially at 80-120°C.

[stage 3]

The compound (40) can be obtained by releasing PG1 compound (39) the generally accepted method.

The method of obtaining 11

where the characters are, as mentioned above.

[stage 1]

Compound (41) can be obtained by reaction of the compound (32) with benzophenone in the presence of palladium catalyst. As the palladium catalyst, palladium acetate(II), BINAP and cesium carbonate can be used in combination. As the base can preferably be used an inorganic base such as a carbonate of an alkali metal, a hydroxide of an alkali metal, a phosphate of an alkali metal, fluoride of an alkali metal and the like, an organic base such as triethylamine, etc. and the like. This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, dimethoxyethane, tetrahydrofuran, and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially at 80-120°C.

[stage 2]

Compound (42) can be obtained by removing benzophenone compounds (41) accepted way. Remove benzophenone can be, for example, by reaction of the compound (41) with hydroxylamine hydrochloride in a suitable solvent, in the presence of sodium acetate is ri room temperature. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, an alcohol solvent.

[stage 3]

Compound (44) can be obtained by acylation of the compound (42) (43) the conventional way, with subsequent hydrolysis.

[stage 4]

The compound (45) can be obtained by releasing PG1compound (44) accepted way.

The method of obtaining 12

where the characters are, as mentioned above.

Compound (46) can be obtained by reaction of the compound (32) in the presence of carbon monoxide, alcohol (ROH: R represents alkyl), base and palladium catalyst. As the palladium catalyst can preferably be used palladium catalysts with zero valence or divalent catalysts such as tetrakis(triphenylphosphine)palladium(0), dichloride, bis(triphenylphosphine)palladium(II), palladium(II) acetate and the like. As a basis it is possible it is preferable to use inorganic bases, such as carbonate of an alkali metal, a hydroxide of an alkali metal, a phosphate of an alkali metal, fluoride of an alkali metal and the like, organic bases such as triethylamine and the like, and the like. As alcohol can predpochtite the flax to use methanol, ethanol and the like. Hexacarbonyl molybdenum and the like can be used instead of carbon monoxide.

This reaction can be carried out in a suitable solvent or without solvent. The solvent is not specifically limited provided that it has no adverse influence on the reaction and can accordingly be used, for example, dimethoxyethane, tetrahydrofuran, dimethylformamide, methanol, ethanol, toluene, benzene, chloroform, and their mixed solvent. This reaction preferably proceeds at 60-150°C, especially 80-120°C.

[stage 2]

The compound (47) can be obtained by releasing PG1compound (46) accepted way.

The method of obtaining 13

where R8ais alkanoyl or alkylsulfonyl, and other symbols are as mentioned above.

[stage 1]

Compound (49) can be obtained by the selective release PG1compound (48) accepted way, and the reaction of the compound with the anhydride of triftoratsetata in the presence of a base. The reaction with the anhydride of triftoratsetata preferably proceeds in a solvent inert to the reaction (for example, methylene chloride) in the presence of a base, such as 2,6-lutidine, while cooling on ice.

[stage 2]

Connection (50) can be obtained to those who e way, as in the method of obtaining 11, stage 1 and stage 2.

[stage 3]

The compound (51) can be obtained by alkanolamines or alkylsulfonamides connection (50) commonly used method.

The method of obtaining 14

Functional group, usually contained in the compound of the present invention, synthetic intermediate connection and the source connection, you can turn the commonly used methods, for example, the following methods and the like.

(1) When the compound of the present invention, synthetic intermediate connection or source compound contains functional groups (hydroxy, amino, carboxy and the like), the reaction can be performed after the protection of a functional group with a protective group commonly used in organic synthetic chemistry (for example, the method described in Protective Groups in Organic Synthesis Third Edition (Theodora W. Green and Peter G. Wuts)). The target compound can be obtained by removing the protective group after the reaction. Examples of hydroxy-protective group include tetrahydropyranyl, TMS, alkanoyl, benzoyl and the like, examples of the amino-protective groups include Boc, benzyloxycarbonyl and the like, and examples of the carboxy-protective group include alkyl, such as methyl, ethyl and the like, benzyl and the like.

(2) When the compound of the present invention, synthetic intermediate connection or the source from which the Association contains amino, connection, where optionally substituted alkyl contains mono - or di-substituted amino, you can get protected amino, optionally, (i) by reaction with alkylhalogenide in the presence of a base (sodium hydride, triethylamine, sodium carbonate, potassium carbonate and the like), or (ii) the reaction of Mitsunobu alcohol, applying dialkyldithiocarbamate and triphenylphosphine, and releasing amino, if necessary.

(3) When the compound of the present invention, synthetic intermediate connection or source compound contains amino, amide, you can get the conventional method, usually applied to produce the amide peptide synthesis, and the like. Its examples include a process involving the reaction with carboxylic acid in the presence of a condensing reagent, and method including a reaction with galogenangidridy carboxylic acid or acid anhydride. In the method using condensing agent, any of N-ethyl-N'-(3-diethylaminopropyl)carbodiimide, N,N'-dicyclohexylcarbodiimide, iodide, 1-methyl-2-bromopyridine, N,N'-carbonyldiimidazole, diphenylphosphinite, hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine, hexaflurophosphate fluoro-N,N,N',N'-tetramethylguanidine and the like can preferably be used in as the condensing reagent is. As the solvent, any one of water, methanol, isopropanol, ethanol, methylene chloride, THF, dioxane, DMF, dimethylacetamide, chloroform and the like can preferably be applied separately or as a mixed solvent. This reaction preferably proceeds at -78°C - 100°C, more preferably -25°C - 25°C. the Course of this reaction can be facilitated by adding, as the base, inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate and the like, or organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, N,N-dimethylaminopyridine, picoline, lutidine and the like, and, as an additive, N-hydroxysuccinimide, 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, N,N-dimethylaminopyridine or N-hydroxybenzotriazole and the like. In the method, applying gelegenheid carboxylic acid or anhydride of carboxylic acid can preferably be applied methylene chloride, chloroform, THF, DMF and the like as a solvent alone or as a mixed solvent. This reaction preferably proceeds at -78°C - 100°C, more preferably at -25°C - 25°C. This reaction proceeds in the presence of a base, such as pyridine, triethylamine, N,N-dimethylaminopyridine, diisopropylethylamine and the like, preferably at -78°C - 100°C, more p is edocfile -25°C - 25°C and the solvent can preferably be used to implement any methylene chloride, chloroform, THF, DMF and the like separately or as a mixed solvent.

(4) When the compound of the present invention, synthetic intermediate connection or source compound containing a double bond, it can be converted into the corresponding single bond by catalytic regeneration, using a catalyst based on transition metal (platinum, palladium, rhodium, ruthenium, Nickel).

(5) When the compound of the present invention, synthetic intermediate connection or the original connection contains an ester group, it can be converted to the corresponding carboxy group by hydrolysis using an alkali (sodium hydroxide, potassium hydroxide and the like).

(6) When the compound of the present invention, synthetic intermediate connection or source compound contains carbarnoyl, it can be converted to the corresponding nitrile by reaction with triperoxonane anhydride.

(7) When the compound of the present invention, synthetic intermediate connection or the original compound contains a carboxy group, can be converted into the corresponding 4,5-dihydrooxazolo-2-yl reaction with 2-halogenation in the presence of a condensing agent.

(8) When the compound of the present invention, synthetic grass is e intermediate connection or the original connection contains a hydroxy group, it can be converted into the corresponding halogen treatment halogenation agent. In addition, when the compound of the present invention or the original compound contains halogen, it can be converted into alkoxy processing alcohol.

(9) When the compound of the present invention, synthetic intermediate connection or source compound contains an ether, it can be converted to the corresponding hydroxy group recovery regenerating agent (metal regenerating reagent, such as alumalite lithium, sodium borohydride, lithium borohydride and the like, DIBORANE and the like).

(10) When the compound of the present invention, synthetic intermediate connection or the original connection contains a hydroxy group, it can be converted into aldehyde, ketone or carboxy group by oxidation with an oxidizing agent.

(11) When the compound of the present invention, synthetic intermediate connection or source compound contains a carbonyl or aldehyde, it can be converted into optionally mono - or di-substituted aminomethyl the reaction of reductive amination in the presence of the amine compound and the reducing agent (sodium borohydride, cyanoborohydride sodium and the like).

(12) When the compound of the present invention, synthetic intermediate compound Il is the source compound contains a carbonyl or aldehyde, it can be converted into a double bond, using the Wittig reaction.

(13) When the compound of the present invention, synthetic intermediate connection or source compound contains a sulfonamide, it can be converted into the corresponding salt sulfonamida (sodium salt, potassium salt and the like) by treatment with alkali (sodium hydroxide, potassium hydroxide and the like) in alcohol (methanol, ethanol and the like).

(14) When the compound of the present invention, synthetic intermediate connection or source compound contains aldehyde, it can be converted to the corresponding oxime by reaction with hydroxylamine or O-alkylhydroxylamines in alcohol (methanol, ethanol and the like), in the presence of a base (sodium hydrogen carbonate and the like).

(15) When the compound of the present invention, synthetic intermediate connection or source compound contains halogen, it can be converted to the corresponding cyano group processing tianyoude agent.

(16) When the compound of the present invention, synthetic intermediate connection or source compound contains halogen, it can be converted into the corresponding amine by reaction according to the method described in Tetrahedron, 2041-2075, 2002.

(17) When the compound of the present invention, synthetic intermediate connection or source connect the ie contains the cyano group, it can be converted into aldehyde group using a reducing agent (diisobutylaluminum and the like).

(18) When the compound of the present invention, synthetic intermediate connection or the original connection contains a vinyl group, it can be converted into a formyl group by oxidation with ozone or by oxidation with osmium subsequent controllable periodic destruction by oxidation.

(19) the Amino group of compound (38) the method of obtaining 8 can be converted into 6-cyano-3,5-dioxo-1,2,4-triazine-2-ilen group in a manner analogous to the method described in J. Med. Chem., 1983, 26, 96.

(20) When the compound of the present invention, synthetic intermediate connection or source compound contains phenolic hydroxy group, it can be turned in phosphonomethoxy group in a manner analogous to the method described in Tetrahedron Lett., 1986, 27, 1477.

(21) When the compound of the present invention, synthetic intermediate connection or the original connection contains an aldehyde group, it can be converted into 1,3-oxazolidin-2,4-Dion-5-ilen group in a manner analogous to the method described in J. Med. Chem., 2002, 45, 1518.

(22) When the compound of the present invention, synthetic intermediate connection or the original connection contains an aldehyde group, it can be converted into 1,2,4-oxadiazolidine-3,5-Dion-2-ilen group in a manner analogous to FPIC is Boo, described in Eur. J. Med. Chem., 2001, 36, 31.

(23) When the compound of the present invention, synthetic intermediate connection or the original connection contains an aldehyde group, it can be turned into semicarbazone, using the formation, and semicarbazone can be converted into 1,2,4-triazole-3-one-5-ilen group in a manner analogous to the method described in J. Heterocyclic. Chem., 1986, 23, 881.

(24) When the compound of the present invention, synthetic intermediate connection or the original connection contains an aldehyde group, it can be converted into 1,3-imidazolidin-2,4-Dion-5-ilen group, applying and as reducing agent.

(25) When the compound of the present invention, synthetic intermediate connection or source compound contains an amino group, it can be converted into 1,3-imidazolidin-2,4-Dion-1-ilen group, applying characaterization.

(26) When the compound of the present invention, synthetic intermediate connection or the original connection contains a cyano group, it can be turned into tetrazolyl group using sodium azide.

(27) When the compound of the present invention, synthetic intermediate connection or source compound contains phosphono group, it can be turned into dialkylphosphate group by reaction with alkylhalogenide.

(28) When the connection of this izaberete the Oia, synthetic intermediate connection or source compound contains phosphono group, phosphate ester or hostname can be obtained by transformation of the group in dehalogenating group processing halogenation agent (for example, trichloride phosphorus, pentachloride phosphorus, thionyl chloride, oxalylamino etc), and by reaction with the desired alcohol or desired amine.

(29) When the compound of the present invention, synthetic intermediate connection or source compound contains phosphono group, it can be transformed into a phosphonate ester or phosphoamide reaction with the alcohol or amine in the presence of a condensing agent. As examples of the condensing agent can preferably be used to implement any N-ethyl-N'-(3-diethylaminopropyl)carbodiimide, N,N'-dicyclohexylcarbodiimide, iodide, 1-methyl-2-bromopyridine, N,N'-carbonyldiimidazole, diphenylphosphinite, hexaflurophosphate benzotriazol-1-yloxytris(dimethylamino)phosphonium chloride 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholine, hexaflurophosphate fluoro-N,N,N',N'-tetramethylguanidine and the like.

Compounds of formulas [I] and [II]obtained above, and each synthetic intermediate compound is isolated and purified accepted in chemistry methods, such as extraction, crystallization, recrystallization, various chromatography and the such.

Pharmacologically acceptable salts of the compounds of formulas [I] and [II]obtained above, can be obtained by using prior art, and salt cleanse is common in chemistry methods, such as recrystallization and the like.

The compounds [I] and [II] of the present invention include a mixture of stereoisomers, or each stereoisomer, which is pure or almost pure. For example, when the compound of the present invention contains one or more asymmetric centers at any carbon atom, the compounds [I] and [II] may contain an enantiomer or a diastereoisomer or a mixture thereof. The compound of the present invention includes these isomers and their mixtures. In addition, when the compound [I] and [II] of the present invention contain a double bond, they may represent a geometric isomer (CIS form, TRANS form) and when the compound [I] and [II] of the present invention contains an unsaturated bond such as carbonyl and the like, they can be tautomer. The compound of the present invention includes all of these isomers and mixtures thereof.

EXAMPLES

The present invention is explained in more detail hereinafter with reference to examples; however, the scope of the present invention is not limited to the following examples.

Example 1

{4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic KIS the PTA

Compound 2 (CAS No. 848442-41-1, 3.58 g, of 13.1 mmol) was dissolved in tetrahydrofuran (15 ml)and the mixture was cooled to -78°C. was Slowly added dropwise n-utility (a 1.6 M hexane solution of 8.8 ml, 14.1 mmol)and the mixture was stirred for 1 hour. Connection 1 (CAS No. 939430-71-4, 2,03 g, 10.0 mmol) was dissolved in tetrahydrofuran (17 ml)and the mixture was cooled to -78°C. was Added dropwise within 30 minutes lithium reagent obtained previously. After stirring for 80 minutes, the mixture was heated to room temperature. After 1 hour was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sulfation sodium, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (2,07 g, 52%).

MS m/z 396/398 [M+H]+, APCI(+)

Connection 3 (508 mg, 1.28 mmol) was dissolved in dimethoxyethane (5 ml), was added water (0.5 ml), cesium carbonate (1.25 g, of 3.85 mmol) and pinacolone ether of isopropylmalonic acid (539 mg, 3,20 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (44 mg, of 0.038 mmol)and the mixture was heated to 90°C. After stirring for 11 hours the mixture was cooled to room temperature. Was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous self the volume of sodium was filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (449 mg, 87%).

MS m/z 402 [M+H]+, APCI(+)

Compound 4 (444 mg, 1.10 mmol) was dissolved in pyridine (0.54 ml)was added acetic anhydride (0.31 in ml, 9.3 mmol) and dimethylaminopyridine (13.5 mg, 0,111 mmol). After stirring for 6.5 hours was added 0,5h chloroethanol acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (454 mg, 93%).

MS m/z 444 [M+H]+, APCI(+)

Compound 5 (450 mg, 1.01 mmol) was dissolved in ethyl acetate (5 ml) was added acetic acid (1 ml)and 10% Pd/C (200 mg). After purging with hydrogen, the mixture was stirred for 14 hours. The mixture was filtered through radiolite and well washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 6 (225 mg, 57%).

MS m/z 388 [M+H]+, APCI(+)

Compound 6 (450 mg, 1.01 mmol) was dissolved in ethanol (4.5 ml) and acetic acid (0.9 ml)and the mixture was stirred at room temperature for 14 hours. Was added acetic acid (3.6 ml), and the mixture was heated is up to 50°C. After 1 hour the mixture was cooled to room temperature, and neutralized 2n aqueous solution of sodium hydroxide. The filtrate was extracted with ethyl acetate, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 7 (213 mg, 67%).

MS m/z 316 [M+H]+, APCI(+)

Compound 7 (20 mg, 0,063 mmol) was dissolved in acetonitrile (0.54 ml), and added methylbromide (29.0 mg, 0,190 mmol) and cesium carbonate (124 mg, 0,380 mmol). After stirring for 1 hour was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel, and the resulting compound 8 (23,8 mg) was dissolved in methanol (0.7 ml) and tetrahydrofuran (0.7 ml). Added 6N chloroethanol acid (0.7 ml)and the mixture was stirred at room temperature for 1 hour, and heated to 60°C. After 2.5 hours the mixture was cooled to room temperature, was added 4n aqueous sodium hydroxide solution (2 ml), and the mixture was heated to 60°C. After 3 hours the mixture was cooled to room temperature, and neutralized 2n chloroethanol acid. The mixture was extracted with tetrahydrofuran, dried over anhydrous sodium sulfate, filtered, Cohn who was entrirely, and the suspension is washed with diethyl ether to obtain compound 9 (20 mg, 97%).

MS m/z 328 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 2

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid

Connection 1 (1.20 g, 3.04 from mmol) was dissolved in ethanol (12 ml) and acetic acid (2.4 ml), and the mixture was heated to 50°C. After 7 hours the mixture was cooled to room temperature, and the precipitation was collected by filtration, dissolved in ethyl acetate, and neutralized 2n aqueous solution of sodium hydroxide. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and neutralized 2n aqueous solution of sodium hydroxide. The organic layers were combined, washed with saturated salt solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 2 (874 mg, 89%).

MS m/z 324/326 [M+H]+, APCI(+)

Compound 2 (872 mg, 2,69 mmol) was dissolved in acetonitrile (16 ml) was added in tetrahydrofuran (8 ml), benzylbromide (552 mg, 3,23 mmol) and cesium carbonate (2,63 g, 8,08 mmol). After stirring for 4 hours was added water, and the mixture was extracted with chlorine is formom. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (971 mg, 87%).

MS m/z 414/416 [M+H]+, APCI(+)

Connection 3 (969 mg, 2.34 mmol) was dissolved in pyridine (1.5 ml), was added acetic anhydride (0,88 ml, 9.3 mmol) and dimethylaminopyridine (28,6 mg, 0,234 mmol). After stirring for 18 hours was added 1H chloroethanol acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (1,03 g, 97%).

MS m/z 428/430 [M-OCOCH3+CH3OH]+, APCI(+)

Compound 4 (190 mg, 0,418 mmol) was dissolved in methylene chloride (6 ml), was added triethylsilane (72,8 mg, 0,627 mmol)and the mixture was cooled on ice. Was slowly added dropwise a complex of boron TRIFLUORIDE and diethyl ether (88.9 mg, 0,627 mmol). After stirring for 10 minutes was added saturated aqueous sodium bicarbonate, and the mixture was neutralized 2n chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified of colonos the second chromatography on silica gel, to obtain compound 5 (119 mg, 72%).

MS m/z 398/400 [M+H]+, APCI(+)

Compound 5 (497 mg, 1,24 mmol) was dissolved in dimethoxyethane (10 ml), was added water (1 ml), cesium carbonate (1.22 g, 3,74 mmol), pinacolyl ether of cyclohexanemethanol acid (649 mg, of 3.12 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (72 mg, holding 0.062 mmol)and the mixture was heated to 90°C. After stirring for one day, the mixture was cooled to room temperature. Was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (480 mg, 87%).

MS m/z 444 [M+H]+, ESI(+)

Compound 6 (477 mg, 1.07 mmol) was dissolved in ethanol (14 ml) and, after purging with argon, was added 10% Pd/C (250 mg). After purging with hydrogen, the mixture was stirred for 9 hours, filtered through radiolite and washed with ethyl acetate. The filtrate was concentrated to obtain compound 7 (369 mg, 1,03 mmol, 97%). Part (248 mg, 0,700 mmol) of the obtained compound 7 was dissolved in acetonitrile (0.54 ml) was added methylbromide (160 mg, 1.04 mmol) and cesium carbonate (683 mg, of 2.09 mmol). After stirring for 2 hours was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sulfate on the matter, was filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 8 (242 mg, 81%).

MS m/z 428 [M+H]+, APCI(+)

Compound 8 (239 mg, 0,559 mmol) was dissolved in methanol (2.4 ml) and tetrahydrofuran (2.4 ml). Added 6N chloroethanol acid (2.4 ml)and the mixture was stirred for 5.5 hours at room temperature and was heated to 60°C. After 1 hour the mixture was cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (5 ml) and tetrahydrofuran (4 ml), was added 1N sodium hydroxide (1.5 ml). The mixture was heated to 50°C and, after 1 hour, cooled to room temperature and neutralized 1H chloroethanol acid. The mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran, and the extract was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 9 (204 mg, 99%).

MS m/z 368 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using andartes stage of obtaining salts.

Example 3

(4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)acetic acid

Connection 1 (416 mg, 1.05 mmol) was dissolved in dioxane (7 ml) was added water (2 ml), potassium carbonate (435 mg, 3,15 mmol) and 2-naphthaleneboronic acid (271 mg, 1.57 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (36 mg, to 0.032 mmol)and the mixture was heated to 90°C. After stirring for 7.5 hours the mixture was cooled to room temperature. Was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (515 mg, 99%).

MS m/z 488 [M+H]+, APCI(+)

Compound 2 (510 mg, 1.04 mmol) was dissolved in pyridine (0,50 ml) was added acetic anhydride (0,29 ml, 3.1 mmol) and dimethylaminopyridine (12,8 mg, 0,105 mmol). After stirring for 3 hours was added 0,5h chloroethanol acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (492 mg, 89%).

MS m/z 530 [M+H]+, APCI(+)

With the Association 3 (497 mg, 1.01 mmol) was dissolved in methylene chloride (5 ml), was added triethylsilane (0.17 g, 1.5 mmol)and the mixture was cooled on ice. Was slowly added dropwise a complex of boron TRIFLUORIDE and diethyl ether (0.21 mg, 1.5 mmol). After 20 minutes was slowly added dropwise triethylsilane (0,087 g, 0.95 mmol) and a complex of boron TRIFLUORIDE and diethyl ether (0.11 g, 0.79, which mmol). After 10 minutes, was slowly added dropwise triethylsilane (0.17 g, 1.9 mmol) and a complex of boron TRIFLUORIDE and diethyl ether (0,22 g, 1.6 mmol). After stirring for 10 minutes was added water and saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (189 mg, 47%).

MS m/z 400 [M+H]+, APCI(+)

Compound 4 (86,0 mg, 0,215 mmol) was dissolved in acetonitrile (4 ml) was added methylbromide (65.9 mg, 0,431 mmol) and cesium carbonate (280 mg, 0,861 mmol). After stirring for 14 hours was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (79 mg). To the obtained connection dobavlyali solution 2n chloromethane acid-methanol (2 ml), and the mixture was stirred at room temperature for 5.5 hours. The mixture was heated to 60°C and, after 1.5 hours, cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (of 57.5 mg, 63%).

MS m/z 428 [M+H]+, APCI(+)

Compound 6 (57 mg, is 0.135 mmol) was dissolved in methanol (6 ml), was added 1N sodium hydroxide (1 ml). After 12.5 hours, and the mixture was heated to 60°C and after 1 hour the mixture was cooled to room temperature and neutralized 1H chloroethanol acid. The mixture was extracted with ethyl acetate, and the extract was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with water and diethyl ether to obtain compound 7 (41.3 mg, 74%).

MS m/z 412 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 4

{4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid

2,3,5-Tr is METHYLPHENOL (3,23 g, of 23.7 mmol) was dissolved in methylene chloride (48 ml) and methanol (32 ml) was added tribromide Tetra-n-butylamine (11.5g, of 23.9 mmol). After 20 minutes the mixture was concentrated, added water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was washed with hexane to obtain compound 2 (4,87 g, 95%).

MS m/z 213/215 [M-H]-, ESI(-)

Compound 2 (4,87 g, and 22.6 mmol) was dissolved in methylene chloride (48 ml), and added ethylenically ether (8,16 g, 113 mmol) andp-toluensulfonate pyridinium (569 mg, and 2.26 mmol). After 4 hours was added triethylamine (11.4 g, 113 mmol)and the mixture was concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (to 6.43 g, 99%).

MS m/z 304/306 [M+NH4]+, APCI(+)

Connection 3 (3,39 g of 11.8 mmol) was dissolved in tetrahydrofuran (15 ml)and the mixture was cooled to -78°C. was Slowly added dropwise n-utility (a 1.6 M hexane solution, 8.0 ml, 12.8 mmol)and the mixture was stirred for 1 hour. Compound 4 (CAS No. 939430-71-4, 2,07 g, 10.2 mmol) was dissolved in tetrahydrofuran (16 ml)and the mixture was cooled to -78°C. Lithium reagent obtained above was added dropwise within 30 minutes, and the mixture was stirred for 45 minutes and was heated to room temperature. After 1 hour was added water,and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (1.73 g, 41%).

MS m/z 410/412 [M+H]+, APCI(+)

Compound 5 (2,02 g, 4,94 mmol) was dissolved in ethanol (20 ml), was added acetic acid (4 ml). After stirring at room temperature for one day the mixture was stirred at 60°C for 1 hour and cooled to room temperature. After concentration the residue was purified column chromatography on silica gel to obtain compound 6 (1.19 g, 71%).

MS m/z 338/340 [M+H]+, APCI(+)

Compound 6 (1.19 g, to 3.52 mmol) was dissolved in acetonitrile (23 ml) was added benzylbromide (663 mg, a 3.87 mmol) and cesium carbonate (3,44 g, 10.5 mmol). After stirring at room temperature for 2.5 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 7 (1.39 g, 93%).

MS m/z 428/430 [M+H]+, APCI(+)

To compound 7 (1.39 g, 3.25 mmol) was added pyridine (1,05 ml), acetic anhydride (0,613 ml) and dimethylaminopyridine (and 39.7 mg). After 15 hours was added water and 1N chlorine is vodorodnoy acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 8 (1.40 g, 92%).

MS m/z 442/444 [M-CH3COO+CH3OH]+, APCI(+)

Compound 8 (1.40 g, 2,99 mmol) was dissolved in methylene chloride (28 ml) was added triethylsilane (0,521 g, 4,48 mmol). Was added at 0°C the complex of boron TRIFLUORIDE and diethyl ether (0,636 g, 4,48 mmol). After 10 minutes, was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 9 (996 mg, 81%).

MS m/z 412/414 [M+H]+, APCI(+)

Compound 9 (505 mg, of 1.23 mmol) was dissolved in dimethoxyethane (12 ml), was added water (1.2 ml), cesium carbonate (1.20 g, 3,68 mmol) and pinacolone ether of isopropylmalonic acid (515 mg, a 3.06 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (142 mg, 0,123 mmol)and the mixture was heated to 90°C. After stirring for 17 hours the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate is, was filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 10 (503 mg, 98%).

MS m/z 418 [M+H]+, APCI(+)

Compound 10 (500 mg, 1.20 mmol) was dissolved in tetrahydrofuran (12 ml) and, after purging with argon, was added 10% Pd/C (255 mg). After purging with hydrogen, the mixture was stirred for 8 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated and the resulting residue was dissolved in tetrahydrofuran (12 ml). After purging with argon was added 10% Pd/C (255 mg). After purging with hydrogen, the mixture was stirred for 17 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated and the resulting residue was dissolved in tetrahydrofuran (12 ml) and, after purging with argon, was added 10% Pd/C (255 mg). After purging with hydrogen, the mixture was stirred for 5 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 11 (375 mg, 95%).

MS m/z 330 [M+H]+, APCI(+)

Compound 11 (157 mg, 0,477 mmol) was dissolved in acetonitrile (5 ml), was added methylbromide (109 mg, 0,715 mmol) and cesium carbonate (465 mg, 1,43 mmol). After stirring for 20 hours was added water, and the mixture was extracted with ethyl acetate. Organic SL the St was washed with saturated salt solution, was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 12 (180 mg, 94%).

MS m/z 402 [M+H]+, APCI(+)

Compound 12 (178 mg, 0,443 mmol) was dissolved in methanol (2.5 ml) and tetrahydrofuran (2.5 ml). Added 6N chloroethanol acid (2.5 ml)and the mixture was stirred for 20 hours at room temperature, and was heated to 60°C. After 2 hours the mixture was cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate, the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (5 ml) was added 2n sodium hydroxide (to 0.67 ml)and the mixture was heated at 60°C. After 2.5 hours the mixture was cooled to room temperature, neutralized 2n chloroethanol acid and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 13 (145 mg, 95%).

MS m/z 342 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can receive the te using the standard process of getting salt.

Example 5

{4-[(6-cyclopentyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid

Connection 1 (539 mg, 1,31 mmol) was dissolved in 1,4-dioxane (8 ml), was added water (2 ml), potassium carbonate (543 mg, 3.93 mmol) and 1-cyclopentadecanone acid (220 mg, a 1.96 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (45 mg, 0,039 mmol)and the mixture was heated to 90°C. After stirring for 4 hours the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (449 mg, 77%).

MS m/z 444 [M+H]+, APCI(+)

Compound 2 (446 mg, 1.01 mmol) was dissolved in tetrahydrofuran (10 ml) and, after purging with argon, was added 10% Pd/C (214 mg). After purging with hydrogen, the mixture was stirred for 7 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 3 (349 mg, 98%).

MS m/z 356 [M+H]+, APCI(+)

Connection 3 (140 mg, 0,394 mmol) was dissolved in acetonitrile (4 ml) was added methylbromide (90 mg, 0,591 mmol) and carbonate price is s (385 mg, 1.18 mmol). After stirring for 20 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (155 mg, 92%).

MS m/z 428 [M+H]+, APCI(+)

Compound 4 (153 mg, 0,358 mmol) was dissolved in methanol (2 ml) and tetrahydrofuran (2 ml). Added 6N chloroethanol acid (2 ml)and the mixture was stirred for 18 hours at room temperature and was heated to 60°C. After 2 hours the mixture was cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (4 ml), was added 2n sodium hydroxide (0.5 ml), and the mixture was heated to 60°C. After 2.5 hours the mixture was cooled to room temperature and neutralized 2n chloroethanol acid. Added water and saturated salt solution, and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl EF the R, to obtain compound 5 (132 mg, 100%).

MS m/z 368 [M-H]-, ESI(-)

The hydrobromide, hydrochloride, para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 6

(4-{[5-hydroxy-6-(tetrahydrofuran-2-yl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

Connection 1 (522 mg, of 1.27 mmol) was dissolved in 1,4-dioxane (8 ml), was added water (2 ml), potassium carbonate (525 mg, of 3.80 mmol) and 2-Farnborough acid (213 mg, 1,90 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (44 mg, of 0.038 mmol)and the mixture was heated to 90°C. After stirring for 2.5 hours the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (441 mg, 78%).

MS m/z 444 [M+H]+, APCI(+)

Compound 2 (330 mg, 0,744 mmol) was dissolved in tetrahydrofuran (10 ml) and, after purging with argon, was added 10% Pd/C (158 mg). After purging with hydrogen, the mixture was stirred for 19 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate is concentrated is Ali, and the residue was purified column chromatography on silica gel to obtain compound 3 (238 mg, 89%).

MS m/z 358 [M+H]+, APCI(+)

Connection 3 (124 mg, 0,347 mmol) was dissolved in acetonitrile (4 ml) was added methylbromide (80 mg, 0,520 mmol) and cesium carbonate (339 mg, 1.04 mmol). After stirring for 5 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (139 mg, 93%).

MS m/z 430 [M+H]+, APCI(+)

Compound 4 (116 mg, 0,270 mmol) was dissolved in methanol (1.5 ml) and tetrahydrofuran (1.5 ml). Added 6N chloroethanol acid (1.5 ml), and the mixture was heated to 40°C. After stirring for 2.5 hours the mixture was stirred for 16 hours at room temperature and again heated to 40°C. After 3 hours the mixture was cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate, the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (3 ml) was added 2n sodium hydroxide (0.4 ml). The mixture was heated to 40°C, and after 5 hours was cooled to room the first temperature and neutralized 1H chloroethanol acid. Added water and a saturated saline solution, and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 5 (73 mg, 73%).

MS m/z 370 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 7

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid

Connection 1 (313 mg, 0,762 mmol) was dissolved in dimethoxyethane (6 ml), was added cesium carbonate (744 mg, 2.28 mmol), pinacolyl ether of cyclohexanemethanol acid (396 mg, 1,90 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (44,0 mg, 0,0380 mmol)and the mixture was heated to 90°C. After stirring for 7 hours, the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (331 mg, 9%).

MS m/z 474 [M+NH4]+, APCI(+)

Compound 2 (331 mg, 0,725 mmol) was dissolved in ethanol (10 ml) and, after purging with argon, was added 10% Pd/C (165 mg). After purging with hydrogen, the mixture was stirred for 7 hours, filtered through radiolite and washed with ethyl acetate. The filtrate was concentrated to obtain compound 3.

MS m/z 370 [M+H]+, APCI(+)

Compound 3 was dissolved in acetonitrile (3 ml), was added methylbromide (94,4 mg, 0,617 mmol) and cesium carbonate (402 mg, of 1.23 mmol). After stirring for 30 minutes was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (134 mg, 76%).

MS m/z 442 [M+H]+, APCI(+)

Compound 4 (131 mg, 0,297 mmol) was dissolved in methanol (1 ml) and tetrahydrofuran (1 ml). Added 6N chloroethanol acid (1 ml)and the mixture was stirred for 15 hours at room temperature. The mixture was heated to 60°C and, after 1 hour, cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in m is canola (5 ml), and was added 2n sodium hydroxide (0.5 ml). The mixture was heated to 60°C, and after 2 hours, cooled to room temperature and neutralized 2n chloroethanol acid. The mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran, and the extract was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed with diethyl ether to obtain compound 5 (85,1 mg, 75%).

MS m/z 382 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 8

(4-{[5-hydroxy-6-(tetrahydro-2H-Piran-2-yl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

Connection 1 (564 mg, 1.37 mmol) was dissolved in dimethoxyethane (14 ml), was added water (1.4 ml), cesium carbonate (1,34 g, 4,11 mmol) and pinacolone ether of digidropiridinovmi acid (719 mg, of 3.42 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (158 mg, 0,137 mmol)and the mixture was heated to 90°C. After stirring for 5.5 hours, the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and conc the Wali. The residue was purified column chromatography on silica gel to obtain compound 2 (375 mg, 60%).

MS m/z 460 [M+H]+, APCI(+)

Compound 2 (372 mg, 0,809 mmol) was dissolved in tetrahydrofuran (8 ml) and, after purging with argon, was added 10% Pd/C (172 mg). After purging with hydrogen, the mixture was stirred for 7 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated and the resulting residue was dissolved in tetrahydrofuran (8 ml). After purging with argon was added 10% Pd/C (172 mg). After purging with hydrogen, the mixture was stirred for 15 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 3 (254 mg, 84%).

MS m/z 372 [M+H]+, APCI(+)

Connection 3 (104 mg, 0,280 mmol) was dissolved in acetonitrile (3 ml) was added methylbromide (64 mg, 0,420 mmol) and cesium carbonate (274 mg, 0,840 mmol). After stirring for 20 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (125 mg, 100%).

MS m/z 444 [M+H]+, APCI(+)

Compound 4 (123 mg, 0,277 mmol) was dissolved in methane is Le (1.5 ml) and tetrahydrofuran (1.5 ml). Added 6N chloroethanol acid (1.5 ml), and the mixture was heated to 40°C. After stirring for 2.5 hours the mixture was stirred for 16 hours at room temperature and again heated to 40°C. After 3 hours the mixture was cooled to room temperature, and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (3 ml) was added 2n sodium hydroxide (0.4 ml). The mixture was heated to 40°C. and, after 5 hours, cooled to room temperature, and neutralized 1H chloroethanol acid. Added water and saturated salt solution, and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 5 (106 mg, 99%).

MS m/z 384 [M-H]-, ESI(-)

The hydrobromide, hydrochloride, para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 9

{4-[(5-hydroxy-6-isopropylpyridine-2-yl)oxy]-2,3,5-trimethylpentane}acetic acid

Connection 1 (CAS No. 199168-10-0, 3,41 g of 11.4 mmol) and compound 2 (CAS No. 36592-80-0, 2.76 grams, or 11.4 mmol) was dissolved in dimethyl sulfoxide (17 ml). Was added potassium carbonate (3.15 g, of 22.8 mmol)and the mixture was purged with argon. Added copper iodide (1.08 g, 5.7 mmol)and the mixture was heated to 90°C. After 1 day, the mixture was cooled to room temperature and added water and ethyl acetate. Was added ammonium chloride, and the mixture was thoroughly stirred, filtered through radiolite and were extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (3,23 g, 68%).

MS m/z 414/416 [M+H]+, APCI(+)

Connection 3 (1,14 g, was 2.76 mmol) was dissolved in dimethoxyethane (11 ml), was added water (1 ml), cesium carbonate (2.70 g, 8,29 mmol) and pinacolone ether of isopropylmalonic acid (1,16 g, 6,91 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (95,9 mg, 0,0829 mmol)and the mixture is boiled under reflux. After 21.5 hours, the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica compound is barely for to obtain compound 4 (616 mg, 53%).

MS m/z 420 [M+H]+, APCI(+)

Compound 4 (370 mg, 0,913 mmol) was dissolved in ethanol (4 ml) and, after purging with argon, was added 10% Pd/C (185 mg). After purging with hydrogen, the mixture was stirred for 17.5 hours, filtered through radiolite and thoroughly washed with ethyl acetate. The filtrate was concentrated to obtain compound 5. The obtained compound 5 was dissolved in acetonitrile (6 ml) was added methylbromide (209 mg, of 1.36 mmol) and cesium carbonate (890 mg, 2,73 mmol). After stirring for a period of 15.5 hours was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (292 mg, 79%).

MS m/z 404 [M+H]+, APCI(+)

Compound 6 (290 mg, 0,719 mmol) was dissolved in methanol (3 ml) and tetrahydrofuran (3 ml). Added 6N chloroethanol acid (3 ml) and, after 1 day was added 4n aqueous sodium hydroxide solution (5 ml), and the mixture was heated to 60°C. After 6 hours the mixture was cooled to room temperature and neutralized 2n chloroethanol acid. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed with diethyl ether. The obtained residue was dissolved settled in methanol (3 ml) and tetrahydrofuran (3 ml) was added 6N chloroethanol acid (3 ml). The mixture was heated to 60°C and, after 2 hours, cooled to room temperature and neutralized 4n aqueous solution of sodium hydroxide. The mixture was extracted with ethyl acetate, and the extract was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed with diethyl ether to obtain compound 7 (180 mg, 73%).

MS m/z 344 [M-H]-, ESI(-)

The hydrobromide, hydrochloride, para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 10

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)oxy]-2,3,5-trimethylpentane}acetic acid

The compound was obtained in a manner analogous to the method in example 9.

MS m/z 384 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 11

{2-fluoro-4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid

Compound 1 (500 mg, of 1.59 mmol) was dissolved in acetonitrile (10 ml) was added benzylbromide (299 mg, about 1.75 mmol) and cesium carbonate (777 mg, of 2.38 mmol). After stirring for 2 hours the mixture was filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (642 mg, 100%).

MS m/z 406 [M+H]+, APCI(+)

Compound 2 (300 mg, 0,740 mmol), silver acetate (207 mg, 0,815 mmol) and iodine (207 mg, 0,816 mmol) was dissolved in methylene chloride (6 ml). The mixture was stirred for 3 hours in the dark conditions at room temperature, was added silver acetate (25 mg, 0,150 mmol) and iodine (38 mg, 0,150 mmol)and the mixture was stirred protected from light conditions again for 2 hours at room temperature. The mixture was filtered, added chloroform, and the mixture was washed successively with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate, water and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (355 mg, 90%).

MS m/z 532 [M+H]+, APCI(+)

Connection 3 (354 mg, 0,666 mmol) and N-forbindelseshastighed (845 mg, 2.68 mmol) was dissolved in tetrahydrofuran (7 ml)and the mixture was cooled to -78°C. was Slowly added dropwisen-utility (1.59 M hexane solution, 1.7 ml, 2,70 mmol)and the mixture was stirred for 1 hour. Was added at -78°C saturated aqueous solution of ammonium chloride, and the mixture was heated to room temperature. The mixture was extracted with ethyl acetate, the extract washed with water and saturated salt solution, was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (158 mg, 56%).

MS m/z 424 [M+H]+, APCI(+)

Compound 4 (158 mg, 0,374 mmol) was dissolved in ethanol (10 ml) and, after purging with argon, was added 5% Pd/C (100 mg). After purging with hydrogen, the mixture was stirred for 8 hours, filtered through radiolite and thoroughly washed with ethyl acetate. The filtrate was concentrated to obtain 5. The obtained compound 5 was dissolved in acetonitrile (4 ml), was added methylbromide (100 mg, 0,977 mmol) and cesium carbonate (210 mg, to 0.645 mmol). After stirring for 3 hours was added water, and the mixture was extracted with ethyl acetate and washed with saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (122 mg, 80%).

MS m/z 406 [M+H]+, APCI(+)

Compound 6 (122 mg, 0,300 mmol) was dissolved in methanol (1.4 ml) and tetrahydrofuran (1.4 ml). Added 6N chloroethanol acid (1.4 ml)and the mixture was stirred at 50°C for 1 hour. The mixture was cooled to room temperature and neutralized 1N aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic layer was washed with saturated Sol is tax solution, was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (1.4 ml) and tetrahydrofuran (1.4 ml) was added 1N sodium hydroxide (1.4 ml)and the mixture was stirred at 50°C for 1 hour. The mixture was cooled to room temperature, neutralized 1H chloroethanol acid and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was recrystallized from methanol to obtain compound 7 (51 mg, 42%).

MS m/z 346 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 12

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}acetic acid

2-Fluoro-4-NITROPHENOL (25.4 g, 162 mmol) was dissolved in methylene chloride (270 ml), was added triethylamine (17,2 g, 170 mmol)and the mixture was cooled on ice. Was added dropwise within 10 minutes methanesulfonanilide (19,4 g, 170 mmol). After stirring for 20 minutes was added chloroform. The organic layer was washed 1H chloroethanol acid, saturated aqueous sodium bicarbonate and saturated saline solution, sushi is over anhydrous magnesium sulfate, was filtered and concentrated. The obtained residue was recrystallized from a mixture of ethyl acetate-hexane to obtain compound 2 (28,7 g, 76%). The filtrate was concentrated, and the obtained residue was purified column chromatography on silica gel to obtain compound 2 (8,80 g, 23%).

MS m/z 253 [M+NH4]+, APCI(+)

Compound 2 (33,2 g, 141 mmol) was dissolved in methylene chloride (280 ml), was added powdered zinc (92,3 g of 1.41 mol)and the mixture was cooled on ice. Was added dropwise for 2 hours, acetic acid (59.3 g, 0,988 mol). The mixture was stirred for 5 minutes, filtered through celite and thoroughly washed with chloroform, and ethyl acetate. The filtrate was neutralized with saturated aqueous sodium bicarbonate, and the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of chloroform-hexane to obtain compound 3 (12.4 g, 43%). The filtrate was concentrated to obtain compound 3 (15,8 g, 54%).

MS m/z 206 [M+H]+, APCI(+)

Connection 3 (14.6 g, a 71.1 mmol) was dissolved in methylene chloride (120 ml) and methanol (120 ml) was added calcium carbonate (15.7 g, 157 mmol), and the mixture was cooled on ice. Dissolved bromine (22,7 g, 142 mmol) in methylene chloride (30 ml) and added dropwise within 20 minutes. After re is eshiwani within 5 minutes the mixture was heated to room temperature. After 15 hours the mixture was filtered through celite. To the filtrate was added saturated aqueous sodium thiosulfate solution, and the mixture was neutralized with saturated aqueous sodium bicarbonate. After concentration, the residue was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was recrystallized from a mixture of ethyl acetate-hexane to obtain compound 4 (19.7 g, 76%). The filtrate was concentrated, and the obtained residue was purified column chromatography on silica gel to obtain compound 4 (of 4.66 g, 18%).

MS m/z 360/362/364 [M-H]-, ESI(-)

Compound 4 (12.4 g, a 34.2 mmol) was dissolved in 1,4-dioxane (170 ml) was added potassium carbonate (11.8 g of 85.4 mmol) and trimethylboroxine (3,22 g, 25.6 mmol)and the mixture was purged with argon. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (1.39 g, 1,71 mmol)and the mixture was heated to 110°C. After stirring for 1 hour was added trimethylboroxine (3,22 g, 25.6 mmol)and the mixture was additionally stirred for 1 hour and added trimethylboroxine (3,22 g, 25.6 mmol). After stirring for 16 hours was added trimethylboroxine (3,22 g, 25.6 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) with methylene chloride (1.39 g, 1,71 mmol). P is after stirring for 3 hours was added trimethylboroxine (4,29 g, by 34.2 mmol). The mixture was additionally stirred for 3 hours and added trimethylboroxine (4,29 g, a 34.2 mmol). After stirring for 2 hours the mixture was cooled to room temperature, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 5 (5.30 g, 66%).

MS m/z 234 [M+H]+, APCI(+)

Compound 5 (of 6.95 g, to 29.8 mmol) was dissolved in acetonitrile (150 ml)was added sulfuric acid (7,31 g, to 74.5 mmol)and the mixture was cooled on ice. Sodium nitrite (4.11 g, to 59.6 mmol) was dissolved in water (15 ml) and, after cooling with ice, the mixture was added dropwise within 10 minutes. After stirring for 30 minutes was added dropwise a cooled on an ice water solution of potassium iodide (19,8 g, 119 mmol) (15 ml). After stirring for 5 minutes was added cold water (75 ml)and the mixture was heated to room temperature. After stirring for 40 minutes was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (8,96 g, 87%).

M M/z 362 [M+NH 4]+, APCI(+)

Compound 6 (11.8 g, to 34.3 mmol) was dissolved in methylene chloride (170 ml) was added potassium hydroxide (5,77 g, 103 mmol), suspended in methanol (40 ml). After 1 hour, the mixture was neutralized 1H chloroethanol acid and was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 7 (7.98 g, 88%).

MS m/z 265 [M-H]-, ESI(-)

Compound 7 (7.98 g, 30.0 mmol) was dissolved in acetonitrile (150 ml) was added benzylbromide (5,13 g, 30.0 mmol) and cesium carbonate (11.7 g, 36,0 mmol). After stirring for 15 hours the mixture was filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 8 (10.4 g, 97%).

MS m/z 357 [M+H]+, APCI(+)

Compound 8 (10.4 g, 29.2 mmol) was dissolved in tetrahydrofuran (100 ml)was cooled to -78°C, was added dropwise within 15 minutesn-utility (1.3 M hexane solution, or 33.7 ml, while 43.8 mmol)and the mixture was stirred for 25 minutes. Was added dropwise over 5 minutes dimethylformamide (10.7 g, 146 mmol). After stirring for 5 minutes the mixture was heated to room temperature is. After 1 hour was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 9 (6,24 g, 83%).

MS m/z 259 [M+H]+, APCI(+)

Compound 10 (7,60 g, and 25.4 mmol) was dissolved in toluene (180 ml)and the mixture was cooled to -78°C, was added dropwise within 10 minutes n-utility (of 1.65 M hexane solution of 15.4 ml, and 25.4 mmol)and the mixture was stirred for 1 hour. Compound 9 (6,24 g, and 24.2 mmol) was dissolved in toluene (70 ml)and the mixture was added dropwise over 35 minutes. After 15 minutes was added a saturated aqueous solution of ammonium chloride, and the mixture was heated to room temperature. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 11 (8,78 g, 84%).

MS m/z 432/434 [M+H]+, APCI(+)

Compound 11 (8,78 g, 20.3 mmol) was dissolved in pyridine (35 ml) was added acetic anhydride (35 ml). After stirring for 14 hours, the reaction mixture was concentrated, and the residue was dried azeotrope with toluene. The remainder of the PTS is looking in column chromatography on silica gel, to obtain compound 12 (9.60 g, 100%).

MS m/z 414/416 [M+H-CH3CO2H]+, ESI(+)

Compound 12 (9.60 g, 20.3 mmol) was dissolved in methylene chloride (130 ml), was added triethylsilane (of 5.89 g, and 50.6 mmol) and the mixture was cooled on ice. Was added dropwise during 5 minutes to a complex of boron TRIFLUORIDE and diethyl ether (7,19 g, and 50.6 mmol). After stirring for 20 minutes was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile (100 ml), and added chloromethylation ether (1,30 g, 16.2 mmol) and cesium carbonate (13,2 g, a 40.5 mmol). After stirring for 16 hours the mixture was filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 13 (to 7.67 g, 91%).

MS m/z 416/418 [M+H]+, APCI(+)

Compound 13 (296 mg, 0,712 mmol) was dissolved in 1,4-dioxane (4 ml), was added water (1 ml), potassium carbonate (295 mg, 2.14 mmol) and 1-cyclohexadienone acid (134 mg, 1.07 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (25 mg, 0,021 mmol)and the mixture was heated to 90°C. After stirring for 40 minutes, the mixture was cooled to room temperature the s, was filtered through celite and thoroughly washed with ethyl acetate. To the filtrate was added a saturated saline solution, and the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 14 (329 mg, 100%).

MS m/z 462 [M+H]+, APCI(+)

Compound 14 (326 mg, 0,706 mmol) was dissolved in tetrahydrofuran (8 ml) and, after purging with argon, was added 5% Pd/C (301 mg). After purging with hydrogen, the mixture was stirred for 1 hour, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was dissolved in acetonitrile (4 ml) was added methylbromide (156 mg, of 1.02 mmol) and cesium carbonate (665 mg, 2.04 mmol). After stirring for 18 hours the mixture was filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 15 (282 mg, 90%).

MS m/z 446 [M+H]+, APCI(+)

Compound 15 (280 mg, 0,628 mmol) was dissolved in methanol (3 ml) and tetrahydrofuran (3 ml). Added 6N chloroethanol acid (3 ml), and the mixture was heated to 60°C. After 2 hours the mixture was cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic layer is washed with saturated salt solution, was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (6 ml) was added 2n sodium hydroxide (0.9 ml). The mixture was heated to 60°C and after 2 hours, cooled to room temperature and neutralized 1H chloroethanol acid. Added water and saturated salt solution, and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran, and the extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 16 (232 mg, 95%).

MS m/z 386 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 13

{2-bromo-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid

Compound 1 (200 mg, 0,563 mmol) was dissolved in methylene chloride (4.0 ml)and the mixture was cooled to -50°C. was Added in small portions 1,3-dibromo-5,5-dimethylhydantoin (82,1 mg, 0,281 mmol). After stirring for 3 hours was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over without the one sodium sulfate, was filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (144 mg, 59%).

MS m/z 434/436 [M+H]+, APCI(+)

Compound 2 (260 mg, 0,598 mmol) was dissolved in acetonitrile (5.2 ml) was added cesium carbonate (584 mg, to 1.79 mmol) and methylbromide (137 mg, 0,897 mmol). After stirring for 4 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (252 mg). The obtained compound 3 was dissolved in methanol (4.0 ml) and tetrahydrofuran (4.0 ml). Added 6N chloroethanol acid (4.0 ml), and the mixture was heated to 60°C. After stirring for 1.5 hours the mixture was cooled to room temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in methanol (5.0 ml). Added 2n sodium hydroxide (1.0 ml), and the mixture was heated to 60°C and was stirred for 2 hours. After heating to room temperature the mixture was neutralized 2n chloroethanol sour is Oh and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 4 (206 mg, 88%).

MS m/z 446/448 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 14

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}propanoic acid

Compound 1 (200 mg, 0,563 mmol) was dissolved in acetonitrile (4.0 ml) was added cesium carbonate (275 mg, services, 0.844 mmol) and ethyl 2-bromopropionate (250 mg, 0,995 mmol). After stirring for 4 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (213 mg, 83%).

MS m/z 456 [M+H]+, APCI(+)

Compound 2 (213 mg, 0,468 mmol) was dissolved in methanol (2.0 ml) and tetrahydrofuran (2.0 ml). Added 6N chloroethanol acid (2.0 ml), and the mixture was heated to 60°C. After stirring for 1.5 hours the mixture was cooled up to matnog temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in methanol (4.3 ml). Added 2n sodium hydroxide (1.0 ml), and the mixture was heated to 60°C, and was stirred for 2 hours. The mixture was cooled to room temperature and neutralized 2n chloroethanol acid and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension in diethyl ether to obtain compound 3 (173 mg, 97%).

MS m/z 382 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 15

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}propanoic acid

The compound was obtained from compound 3 of example 7 in a manner analogous to the method in example 14.

MS m/z 396 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate podobnie the present compounds can be obtained using standard stage of obtaining salts.

Example 16

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}-2-methylpropanoate acid

Compound 1 (200 mg, 0,563 mmol) was dissolved in acetonitrile (4.0 ml) was added cesium carbonate (275 mg, services, 0.844 mmol) and ethyl 2-bromoisobutyrate (158 mg, 0,788 mmol). The mixture was boiled under reflux and, after stirring for 4 hours, cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (264 mg, 62%).

MS m/z 470 [M+H]+, APCI(+)

Compound 2 (163 mg, 0,348 mmol) was dissolved in methanol (2.0 ml) and tetrahydrofuran (2.0 ml). Added 6N chloroethanol acid (2.0 ml), and the mixture was heated to 60°C. After stirring for 1.5 hours the mixture was cooled to room temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide, and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in methanol (3.3 ml). Added 2n sodium hydroxide (1.0 ml), and the mixture was heated to 60° C and was stirred techeneenii. The mixture was cooled to room temperature, neutralized 2n chloroethanol acid and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension in diethyl ether to obtain compound 3 (128 mg, 93%).

MS m/z 396 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 17

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}-2-methylpropanoate acid

The compound was obtained from compound 3 of example 7 in a manner analogous to the method in example 16.

MS m/z 410 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 18

1-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}cyclopropanecarbonyl acid

Compound 1 (400 mg, 1.13 mmol) was dissolved in acetonitrile (8.0 ml) was added cesium carbonate (550 mg, was 1.69 mmol) and ethyl 2,4-dibro is butyrate (462 mg, 1,69 mmol). After stirring overnight was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (414 mg, 67%).

MS m/z 548/550 [M+H]+, APCI(+)

Compound 2 (414 mg, 0,755 mmol) was dissolved in tetrahydrofuran (8,3 ml) and addedtert-piperonyl potassium (127 mg, 1.13 mmol). The mixture was heated under reflux and stirred overnight. The mixture was cooled to room temperature and was added cesium carbonate (738 mg, and 2.26 mmol) and ethyliodide (177 mg, 1.13 mmol). After stirring overnight was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (211 mg, 60%).

MS m/z 468 [M+H]+, APCI(+)

Connection 3 (207 mg, 0,443 mmol) was dissolved in methanol (4.0 ml) and tetrahydrofuran (4.0 ml). Added 6N chloroethanol acid (4.0 ml), and the mixture was heated to 60°C. After stirring for 2 hours the mixture was cooled to room temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide and extras is listed with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in methanol (5.0 ml). Added 2n sodium hydroxide (1.0 ml), and the mixture was heated to 60° C and was stirred overnight. The mixture was cooled to room temperature and neutralized 2n chloroethanol acid and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-diethyl ether to obtain compound 4 (125 mg, 71%).

MS m/z 394 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 19

({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)(oxo)acetic acid

Connection 1 (of 4.00 g, 11.3 mmol) was dissolved in methylene chloride (80 ml) and cooled on ice. Added diisopropylethylamine (4,36 g, 33.8 mmol) and triftormetilfullerenov (4,76 g of 16.9 mmol). After stirring for 4 hours the mixture was stirred overnight, during which it was heated. obavljale water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (4,76 g, 87%).

MS m/z 488 [M+H]+, APCI(+)

Compound 2 and 4.75 g, 9.73 mmol) was dissolved in tetrahydrofuran (95 ml) was added cesium carbonate (4,76 g, 14.6 mmol), benzophenone (2,12 g, 11.7 mmol), (R)-BINAP (937 mg, of 1.46 mmol) and palladium acetate (219 mg, 0,973 mmol). The mixture was purged with argon, was heated under reflux and stirred overnight. The mixture was cooled to room temperature, added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (2,08 g, 40%).

MS m/z 519 [M+H]+, APCI(+)

Connection 3 (2,08 g, 4,01 mmol) was dissolved in methanol (20 ml) and dimethylformamide (20 ml). Added hydroxylamine hydrochloride (557 mg, 8,02 mmol) and sodium acetate (987 mg to 12.0 mmol). After stirring overnight was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and conc is listed. The residue was purified column chromatography on silica gel to obtain compound 4 (1,14 g, 80%).

MS m/z 355 [M+H]+, APCI(+)

Compound 4 (300 mg, 0,846 mmol) was dissolved in methylene chloride (6.0 ml) and cooled on ice. Was added triethylamine (103 mg, of 1.02 mmol) and ethylchloride (142 mg, of 1.02 mmol). After stirring overnight, during which it was heated to room temperature, added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (359 mg, 93%).

MS m/z 455 [M+H]+, APCI(+)

Compound 5 (359 mg, 0,789 mmol) was dissolved in methylene chloride (3.5 ml). Added thioanisole (980 mg, 7,89 mmol) and triftormetilfullerenov (3.5 ml). After stirring for 4 hours the mixture was heated to 40°C and was stirred for 30 minutes. The mixture was cooled to room temperature and concentrated. Was added water, and the mixture was neutralized with saturated aqueous sodium bicarbonate and was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to the floor of the IC connection 6 (330 mg, 100%).

MS m/z 411 [M+H]+, APCI(+)

Compound 6 (330 mg, 0,804 mmol) was dissolved in methanol (6.6 ml) and tetrahydrofuran (4.0 ml). Added 1N sodium hydroxide (2.0 ml)and the mixture was stirred overnight, neutralized 1H chloroethanol acid, and was extracted with a mixture of ethyl acetate-diethyl ether-acetone-methanol. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of methylene chloride-hexane to obtain compound 7 (258 mg, 84%).

MS m/z 381 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 20

({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}amino)(oxo)acetic acid

The compound was obtained from compound 3 of example 7 in a manner analogous to the method in example 19.

MS m/z 395 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 21

3-({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanal the I acid

Connection 1 (919 mg, of 2.92 mmol) was dissolved in methylene chloride (18,4 ml) and cooled on ice. Added diisopropylethylamine (1.13 g, a total of 8.74 mmol) and the anhydride of triftoratsetata (863 mg, a 3.06 mmol). After stirring overnight, during which it was heated to room temperature, added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (1,00 g, 77%).

MS m/z 448 [M+H]+, APCI(+)

Compound 2 (1,00 g, 2,24 mmol) was dissolved in tetrahydrofuran (20 ml) was added cesium carbonate (1.10 g, to 3.36 mmol), benzophenone (488 mg, 2,69 mmol), (R)-BINAP (216 mg, 0,336 mmol) and palladium acetate (50,3 mg, 0,224 mmol)and the mixture was purged with argon. The mixture was heated under reflux and stirred overnight. The mixture was cooled to room temperature, added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (488 mg, 46%).

MS m/z 479 [M+H]+, APCI(+)

Connection 3 (482 mg, 1.01 mmol) dissolve the Yali in methanol (4.8 ml) and tetrahydrofuran (4.8 ml). Added 6N chloroethanol acid (5.5 ml), and the mixture was heated to 60°C. After stirring for 2 hours the mixture was cooled to room temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in tetrahydrofuran (9.6 ml) and cooled on ice. Added 1N sodium hydroxide (6.0 ml) was added in small portions ethyl 3-chloro-3-oxopropionate (910 mg, 6,04 mmol). After stirring for 2 hours the mixture was stirred overnight, during which it was heated to room temperature. After cooling, ice was added 10h sodium hydroxide (3.0 ml)and the mixture was stirred for 2 hours. Was added water, and the aqueous layer washed with ethyl acetate, neutralized 2n chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of diethyl ether-hexane to obtain compound 6 (188 mg, 61%).

MS m/z 355 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like us who Otsego compounds can be obtained using standard stage of obtaining salts.

Example 22

3-({4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid

Compound 3 was obtained in a manner analogous to the method of compound 7 of example 2.

Compound 8 was obtained from compound 3 in a manner analogous to the method in example 21.

MS m/z 389 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 23

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid

The compound was obtained from compound 7 of example 2 in a manner analogous to the method in example 21.

MS m/z 395 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 24

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}amino)-3-oxopropanoic acid

The compound was obtained from compound 3 of example 7 in a manner analogous to the method in example 21.

MS m/z 409 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, mA who eat this and similar compounds can be obtained using standard stage of obtaining salts.

Example 25

(2E)-3-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}acrylic acid

In argon atmosphere, the compound 1 (295 mg, 0,588 mmol) was dissolved in dimethylformamide (2 ml), was added triethylamine (65 mg, 0,647 mmol) and methyl acrylate (253 mg, to 2.94 mmol) and 1,3-bis(diphenylphosphino)propane (27 mg, 0,065 mmol) and palladium acetate (13 mg, 0,059 mmol). The mixture tightly closed and stirred overnight at 100°C. was Added methyl acrylate (127 mg, about 1.47 mmol) and 1,3-bis(diphenylphosphino)propane (27 mg, 0,065 mmol) and palladium acetate (13 mg, 0,059 mmol). The mixture tightly closed and stirred overnight at 100°C. the Mixture was cooled to room temperature, was added chloroform and 5% chloroethanol acid, and the mixture was stirred and filtered through celite. The organic layer was washed successively with 5% chloroethanol acid and water and a saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (127 mg, 49%).

MS m/z 438 [M+H]+, APCI(+)

Compound 2 (42 mg, 0,096 mmol) was dissolved in methanol (0.2 ml) and tetrahydrofuran (0.6 ml). Added 6N chloroethanol acid (0.2 ml), and the mixture was heated to 50°C. After 2 hours the mixture was cooled to room temperature and neutralized with saturated aqueous g is drocarbons sodium. After extraction with ethyl acetate the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (1 ml) and tetrahydrofuran (0.6 ml) was added 1N sodium hydroxide (0.2 ml). The mixture was heated to 50°C. After stirring over night the mixture was cooled to room temperature and neutralized with a saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate and washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 3 (28 mg, 77%).

MS m/z 378 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 26

3-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}propanoic acid

Connection 1 (125 mg, 0,286 mmol) was dissolved in ethanol (3 ml) and acetic acid (0.8 ml), was added 10% Pd/C (63 mg), and the mixture was purged with hydrogen. The mixture was stirred at room temperature overnight, filtered through celite and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (102 mg, 81%).

MS /z 440 [M+H]+, APCI(+)

Compound 2 (100 mg, 0,227 mmol) was dissolved in tetrahydrofuran (2 ml)was added 6N chloroethanol acid (0.45 ml)and the mixture was stirred at 50°C for 3 hours. Added 6N chloroethanol acid (0,23 ml)and the mixture was further stirred at 50°C for 2 hours. The mixture was cooled to room temperature, was added saturated aqueous sodium bicarbonate and ethyl acetate, and the mixture was stirred. After extraction with ethyl acetate was added a saturated aqueous solution of ammonium chloride, and the mixture was stirred. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (63 mg, 73%).

MS m/z 380 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 273-({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he

Connection 1 (93,0 mg, 0,295 mmol) was dissolved in acetonitrile (3 ml) was added bromoacetonitrile (53,1 mg, 0,442 mmol) and cesium carbonate (192 mg, 0,590 mmol). After stirring at to the room temperature for 4 hours was added water, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (84,3 mg, 81%).

MS m/z 355 [M+H]+, APCI(+)

Compound 2 (80.0 mg, 0,226 mmol) was dissolved in methanol (2 ml) was added hydroxylamine hydrochloride (23,5 mg, 0,339 mmol) and sodium bicarbonate (to 47.4 mg, 0,564 mmol). After boiling under reflux for 1.5 hours the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated and was added 1,4-dioxane (2 ml). Added 1,1'-Carbonyldiimidazole (43,9 mg, 0,271 mmol). After boiling under reflux for 4 hours the mixture was cooled to room temperature, added water, and the mixture was neutralized 0,5h chloroethanol acid. The mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (80,8 mg, 86%).

MS m/z 412 [M-H]-, ESI(-)

Connection 3 (77.0 mg, 0,186 mmol) was dissolved in isopropanol (1 ml) and tetrahydrofuran (1 ml). Added 6N chloroethanol acid (1 ml)and the mixture was stirred for 12 hours is at room temperature. The mixture was heated to 60°C and, after 30 minutes, cooled to room temperature and neutralized 2n sodium hydroxide. The mixture was extracted with ethyl acetate, and the extract was concentrated, and the obtained residue was washed with diethyl ether to obtain compound 4 (35,3 mg, 51%).

MS m/z 368 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 28

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 7 of example 2 in a manner analogous to the method in example 27.

MS m/z 408 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 29

3-[(4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 4 of example 3 in a manner analogous to the method in example 27.

MS m/z 452 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present is to be placed can be obtained using the standard process of getting salt.

Example 30

3-[(4-{[5-hydroxy-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (425 mg, 0,873 mmol) was dissolved in ethanol (9 ml) and acetic acid (1 ml). Was added 5% Pd/C (510 mg)and the mixture was purged with hydrogen. After 16 hours the mixture was filtered through radiolite and washed with ethyl acetate. After concentration was added to the obtained residue, acetic anhydride (0,71 ml) and pyridine (0,41 ml). After stirring for 21 hours was added ethyl acetate, and the mixture is washed with 1N chloroethanol acid and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was dissolved in ethanol (10 ml) and acetic acid (1 ml). Was added 20% Pd(OH)2/C (403 mg), and the mixture was purged with hydrogen. After 5 hours the mixture was filtered through radiolite, washed with ethanol and concentrated. This catalytic reduction was repeated twice. The obtained residue was purified column chromatography on silica gel to obtain compound 2 (185 mg, 48%).

MS m/z 446 [M+H]+, APCI(+)

Compound 2 (174 mg, 0,392 mmol) was dissolved in methanol (6 ml), was added potassium carbonate (108 mg, 0,785 mmol). After 2.5 hours, the added water and 1N chloroethanol acid, and the mixture was extracted with chloroform. Organic leisurely over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (151 mg, 96%).

MS m/z 404 [M+H]+, APCI(+)

Compound 6 was obtained from compound 3 in a manner analogous to the method in example 27.

MS m/z 456 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 31

3-({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 11 of example 4 in a manner analogous to the method in example 27.

MS m/z 382 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 32

3-({4-[(6-cyclopentyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 3 of example 5 in a manner analogous to the method in example 27.

MS m/z 408 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using the standard process of getting from the it.

Example 33

3-[(4-{[5-hydroxy-6-(tetrahydrofuran-2-yl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)methyl]-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 3 of example 6 in a manner analogous to the method in example 27.

MS m/z 410 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 34

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 3 of example 7 in a manner analogous to the method in example 27.

MS m/z 422 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 35

3-[(4-{[5-hydroxy-6-(tetrahydro-2H-Piran-2-yl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)methyl]-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 3 of example 8 in a manner analogous to the method in example 27.

MS m/z 424 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can in order to teach using the standard process of getting salt.

Example 36

3-({4-[(5-hydroxy-6-isopropylpyridine-2-yl)oxy]-2,3,5-trimethylpentane}methyl)-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 5 of example 9 in a manner analogous to the method in example 27.

MS m/z 384 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 37

3-({2-fluoro-4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he

The compound was obtained from compound 5 of example 11 in a manner analogous to the method in example 27.

MS m/z 386 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 38

(4-{[5-hydroxy-6-({[(2R)-2-phenylpropyl]amino}carbonyl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

Connection 1 (309 mg, 0.75 mmol), hexacarbonyl molybdenum (396 mg, 1.5 mmol), palladium (II) acetate (34 mg, 0.15 mmol), BINAP (93 mg, 0.15 mmol), cesium carbonate (269 mg, 0,825 mmol) suspended in toluene (7.5 ml) and, after purging with argon, was added (R)-β-methylphenethylamine (132 mg, 0,975 mmol and acetonitrile (3.75 ml), and the mixture was stirred at 80°C for 1 hour. The mixture was cooled to room temperature and was added iodine (381 mg, 1.5 mmol). The mixture was stirred for 1 hour and filtered through celite. Added ethyl acetate and an aqueous solution of sodium sulfite, and the mixture was stirred for 30 minutes and filtered through celite. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (241 mg, 60%).

MS m/z 539 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 449 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 521 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 461 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 39

2-cyclohexyl-6-[4-(3-hydroxyethoxy-5-yl)-2,3,6-trimethylbenzyl]pyridine-3-ol

Connection 1 (355 mg, 0,708 mmol) was dissolved in N,N-dimethylformamide is (5 ml), was added triethylamine (1.5 ml), trimethylsilylacetamide (104 mg, 1.06 mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg, 0.035 mmol), copper iodide (20 mg, 0,106 mmol) and tetrabutylammonium iodide (392 mg, 1.06 mmol)and the mixture was purged with argon. The mixture was stirred at 70°C for 4 hours and heated to 80°C. After stirring for 1 hour the mixture was cooled to room temperature, was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (299 mg, 94%).

MS m/z 450 [M+H]+, APCI(+)

Compound 2 (295 mg, 0,656 mmol) was dissolved in methanol (6 ml) and dichloromethane (3 ml) and cooled on ice. Was added potassium carbonate (136 mg, 0,984 mmol)and the mixture was heated to room temperature. After stirring for 1 hour was added potassium carbonate (136 mg, 0,984 mmol). After stirring for 2.5 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column is cromatografia on silica gel, to obtain compound 3 (237 mg, 96%).

MS m/z 378 [M+H]+, APCI(+)

Connection 3 (233 mg, 0,617 mmol) was dissolved in tetrahydrofuran (6 ml)and the mixture was cooled to -78°C. was Added dropwise hexamethyldisilazide lithium (1M tertrahydrofuran ring solution of 0.741 ml, of 0.741 mmol). After stirring for 2 hours was added dropwise ethylchloride (134 mg, of 1.23 mmol)and the mixture was heated to room temperature. After 1.5 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (210 mg, 76%).

MS m/z 450 [M+H]+, APCI(+)

Compound 4 (207 mg, 0,460 mmol) was dissolved in ethanol (5 ml) and dichloromethane (0.5 ml)and added dropwise to the mixture chilled on ice hydroxylamine hydrochloride (96 mg, 1.38 mmol) and 10% aqueous sodium hydroxide solution (of 1.84 ml, 4,60 mmol) for 5 minutes. After stirring for 10 minutes the mixture was heated to 40°C. After stirring for 16 hours the mixture was cooled to room temperature and neutralized 2n chloroethanol acid. Was added a saturated salt solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous su is hatom magnesium, was filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (171 mg, 85%).

MS m/z 435 [M-H]-, ESI(-)

Compound 5 (169 mg, 0,387 mmol) was dissolved in methanol (1.5 ml) and tetrahydrofuran (1.5 ml)was added 6N chloroethanol acid (1.5 ml), and the mixture was heated to 50°C. After stirring for 6.5 hours the mixture was cooled to room temperature and neutralized 2n aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with chloroform to obtain compound 6 (122 mg, 80%).

MS m/z 391 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 40

{4-[(5-hydroxy-6-pyrrolidin-1-espiridion-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid

Connection 1 (206 mg, 0,500 mmol) was dissolved in dimethyl sulfoxide (1 ml), was added pyrrolidine (356 mg, 5 mmol)and the mixture was subjected to reaction in a microwave oven at 160°C for 2 hours. The mixture was cooled to room temperature, was added ethyl acetate and adny solution of sodium bicarbonate, and the mixture was stirred. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (95,5 mg, 43%).

MS m/z 447 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 357 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 429 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 371 [M+H]+, APCI(+)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 41

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}acetic acid

The complex borohydride and tetrahydrofuran (1M tertrahydrofuran ring solution of 1.55 ml) was purged with argon, cooled on ice and added dropwise to cyclohexen (256 mg, 3.10 mmol). Compound 1 (200 mg, 0,445 mmol) was dissolved in tetrahydrofuran (1.5 ml)was added dropwise to the above solution, and the mixture was stirred at 0°C for 2 hours were Combined and added dropwise 1N aqueous sodium hydroxide solution (1,26 ml) and methanol (1.5 ml), was added dropwise 33% aqueous hydrogen peroxide solution (0.75 ml)and the mixture was stirred at 0°C for 1 hour. The mixture was concentrated, added 1H chloroethanol acid and ethyl acetate, and the mixture was stirred. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (149 mg, 81%).

MS m/z 410 [M-H]-, ESI(-)

Compound 3 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 366 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 42

4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylbenzoic acid

Connection 1 (251 mg, 0.50 mmol), hexacarbonyl molybdenum (264 mg, 1.0 mmol), palladium acetate (22 mg, 0.10 mmol), BINAP (62 mg, 0.10 mmol) and cesium carbonate (179 mg, 0.55 mmol) suspended in toluene (5 ml) and, after purging with argon, was added methanol (320 mg, 10 mmol) and acetonitrile (2.5 ml)and the mixture was stirred at 90°C during the night. The mixture was cooled to room temperature, was added iodine (254 mg, 1.0 mmol)and the mixture was stirred for 1 hour and filtered through purpose is. Added ethyl acetate and an aqueous solution of sodium sulfite, and the mixture was stirred for 30 minutes and filtered through celite. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (27 mg, 14%) and the corresponding shape in the form of methyl ester (88 mg, 42%).

MS m/z 396 [M-H]-, ESI(-)

Compound 2 (26 mg, of 0.066 mmol) was dissolved in tetrahydrofuran (0.8 ml). Added 6N chloroethanol acid (0.2 ml), and the mixture was heated to 50°C. After 3 hours the mixture was cooled to room temperature, was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was washed with a mixture of ether-hexane to obtain compound 3 (17 mg, 76%).

MS m/z 352 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 43

{2-chloro-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid

Connection 1 (1,00 g, of 2.81 mmol) was dissolved in carbon tetrachloride (20 ml)and the mixture was cooled to 0°C. was Slowly added dropwisetert-butylhypochlorite (336 mg, to 3.09 mmol)and the mixture was stirred for 2 hours. Was added water, and the mixture was extracted with ethyl acetate, and the extract was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (312 mg, 28%).

MS m/z 390/392 [M+H]+, APCI(+)

Compound 2 (220 mg, 0,56 mmol) was dissolved in acetonitrile (3 ml) was added methylbromide (130 mg, 0,850 mmol) and cesium carbonate (276 mg, 0,847 mmol). After stirring for 4 hours was added water, and the mixture was extracted with ethyl acetate and washed with saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (211 mg, 81%).

MS m/z 462/464 [M+H]+, APCI(+)

Connection 3 (211 mg, 0,457 mmol) was dissolved in methanol (2 ml) and tetrahydrofuran (2 ml). Added 6N chloroethanol acid (2 ml)and the mixture was stirred at 60°C for 4 hours. The mixture was cooled to room temperature and neutralized 1N aqueous solution of sodium hydroxide. After extraction with ethyl acetate the organic with the Oh was washed with saturated salt solution, was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (2 ml) and tetrahydrofuran (2 ml), was added 1N sodium hydroxide (2 ml)and the mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature, neutralized 1H chloroethanol acid and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was washed in suspension with ether and the resulting powder was dried by filtration under reduced pressure to obtain compound 4 (141 mg, 77%).

MS m/z 402/404 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 44

{2-cyano-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid

Connection 1 (3.80 g, is 10.7 mmol) was dissolved in acetonitrile (40 ml), was added benzylbromide (1,4 ml, 11.0 mmol) and cesium carbonate (5,23 g, 16.0 mmol). After stirring overnight the mixture was filtered through radiolite and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (4,55 g, 90%).

MS m/z 471 [M+H]+ , APCI(+)

Compound 2 (4,55 g, 10.2 mmol) was dissolved in dichloromethane (90 ml) was added iodine (3,37 g, 13,2 mmol) and silver acetate (2,21 g, 13,2 mmol). In the dark conditions, the mixture was stirred overnight and filtered through radiolite. The filtrate was washed successively with an aqueous solution of sodium thiosulfate, saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (5,43 g, 93%).

MS m/z 572 [M+H]+, APCI(+)

Connection 3 (1,00 g of 1.75 mmol) was dissolved in degassed N,N'-dimethylformamide (20 ml), was added copper iodide (I) (33 mg, 0,173 mmol) and cyanide zinc (411 mg, 3.50 mmol)and the mixture was purged with argon. Added tetrakis(triphenylphosphine)palladium (0) (102 mg, 0,0883 mmol)and the mixture was stirred at 90°C during the night. The mixture was cooled to room temperature, was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was filtered through radiolite. After extraction with ethyl acetate, the organic layer was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (158 mg, 19%).

<> MS m/z 471 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 8 of example 2.

MS m/z 453 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 393 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 45

({5-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-3,4,6-trimethylpyridine-2-yl}oxy)acetic acid

Connection 1 (3,30 g, 11.0 mmol) was dissolved in toluene (66 ml) and, after cooling to -78°C, was added n-utility (2,6 M hexane solution of 4.45 ml, 11.6 mmol)and the mixture was stirred. After 30 minutes, was added dropwise in small portions a solution of compound 2 (2,92 g, 12.1 mmol) in toluene, and the mixture was stirred for 1 hour and warmed up to room temperature. After stirring for 2 hours was added a saturated aqueous solution of ammonium chloride, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (3.03 g, 66%).

MS m/z 415/417 [M+H]+, APCI+)

Connection 3 (3,02 g, 7,28 mmol) was dissolved in pyridine (2.30 g, of 29.1 mmol) was added acetic anhydride (2,23 g and 21.8 mmol). After stirring over night the reaction mixture was concentrated, and the residue was dried azeotrope with toluene. The residue was purified column chromatography on silica gel to obtain compound 4 (3,17 g, 95%).

MS m/z 457/459 [M+H]+, APCI(+)

Compound 4 (3,17 g, 6,94 mmol) was dissolved in methylene chloride (63 ml)was added triethylsilane (968 mg, 8,32 mmol) and the mixture was cooled on ice. Was added dropwise over 1 hour a complex of boron TRIFLUORIDE and diethyl ether (3,54 g 25,0 mmol). After stirring for 30 minutes was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile (63 ml)was added chloromethylation ether (558 mg, 6,94 mmol) and cesium carbonate (of 2.26 g, 6,94 mmol). After stirring overnight was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (637 mg, 23%).

MS m/z 399/401 [M+H]+, APCI(+)

Compound 5 (610 mg, 1.53 mmol) was dissolved in 1,4-dioxane (12 ml) was added cesium carbonate (1,49 g, 4,59 mmol) and 1-cyclohexadienone acid (304 mg, to 2.29 mmol)and the mixture was purged with argon. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane (125 mg, 0.15 mmol)and the mixture is boiled under reflux. After stirring over night the mixture was cooled to room temperature, filtered through celite and thoroughly washed with ethyl acetate. After concentration the residue was purified column chromatography on silica gel to obtain compound 6 (586 mg, 86%).

MS m/z 445 [M+H]+, APCI(+)

Compound 6 (584 mg, 1,31 mmol) was dissolved in ethanol (58 ml) and, after purging with argon, was added 10% Pd/C (292 mg). After purging with hydrogen, the mixture was stirred for 1 day. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated to obtain compound 7 (464 mg, 99%).

MS m/z 357 [M+H]+, APCI(+)

Compound 7 (460 mg, 1,29 mmol) was dissolved in chloroform (9 ml) and, after cooling on ice, was added N-bromosuccinimide (290 mg, and 1.63 mmol). After stirring for 3 hours was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered has concentrically. The residue was purified column chromatography on silica gel to obtain compound 8 (546 mg, 97%).

MS m/z 435/437 [M+H]+, APCI(+)

Compound 8 (387 mg, 0,888 mmol) was dissolved in N,N'-dimethylformamide (8 ml) was added methylbromide (215 mg, of 1.33 mmol) and silver carbonate (735 mg, of 2.66 mmol)and the mixture was heated to 80°C. the Mixture was stirred overnight and filtered through celite. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 9 (360 mg, 80%).

MS m/z 507/509 [M+H]+, APCI(+)

Compound 9 (359 mg, 0,708 mmol) was dissolved in 1,4-dioxane (12 ml), was added potassium carbonate (293 mg, 2,12 mmol) and trimethylboroxine (234 mg, 1.77 mmol)and the mixture was purged with argon. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (29.0 mg, 0,0354 mmol)and the mixture is boiled under reflux. After stirring over night the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to the CSOs, to obtain compound 10 (302 mg, 96%).

MS m/z 443 [M+H]+, APCI(+)

Compound 10 (294 mg, 0,665 mmol) was dissolved in methanol (2.0 ml) and tetrahydrofuran (2.0 ml). Added 6N chloroethanol acid (2.0 ml), and the mixture was heated to 60°C. After stirring for 2 hours the mixture was cooled to room temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in methanol (6 ml). Added 2n sodium hydroxide (1.0 ml), and the mixture was heated to 60°C and was stirred for 2 hours. After heating to room temperature, the mixture was neutralized 1H chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with hexane to obtain compound 11 (223 mg, 87%).

MS m/z 383 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 46

3-[({5-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-3,4,6-timetype the one-2-yl}oxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (154 mg, 0,354 mmol) was dissolved in N,N'-dimethylformamide (3 ml), was added bromoacetonitrile (65,6 mg, mean HDI of 0.531 mmol) and silver carbonate (293 mg, 1.06 mmol)and the mixture was heated to 80°C. the Mixture was stirred overnight and filtered through celite. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (80 mg, 48%).

MS m/z 474/476 [M+H]+, APCI(+)

Compound 2 (80 mg, has 0.168 mmol) was dissolved in 1,4-dioxane (2 ml), was added potassium carbonate (70 mg, 0,504 mmol) and trimethylboroxine (55,6 mg, 0,420 mmol)and the mixture was purged with argon. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane (6,90 mg, 0,00845 mmol)and the mixture is boiled under reflux. After stirring over night the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (61 mg, 89%).

MS m/z 410 [M+H]+, APCI(+)

Connection 3 (59,0 mg, 0.144 mmol who) was dissolved in methanol (1 ml) was added hydroxylamine hydrochloride (15.8 mg, 0,216 mmol) and sodium bicarbonate (36,3 mg, 0,432 mmol). After boiling under reflux overnight, the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in 1,4-dioxane (1 ml) was added 1,1'-carbonyldiimidazole (35,0 mg, 0,216 mmol). After stirring for 1 hour the mixture was boiled under reflux. After stirring for 5 hours the mixture was cooled to room temperature, added water, added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (14,2 mg, 21%). Compound 4 (14,2 mg, 0,0303 mmol) was dissolved in methanol (1 ml) and tetrahydrofuran (1 ml). Added 6N chloroethanol acid (0.5 ml), and the mixture was heated to 60°C. After 3 hours the mixture was cooled to room temperature and neutralized 2n sodium hydroxide. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chronochromie on silica gel, to obtain compound 5 (9.8 mg, 76%).

MS m/z 423 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 47

(4-{[6-cyclohexyl-5-(formylamino)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

Connection 1 (1,94 g's, 5.25 mmol) was dissolved in acetonitrile (39 ml) was added ethylbromoacetate (1,38 mg, 7.87 mmol) and cesium carbonate (5,13 g, 15.7 mmol). After stirring overnight was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (1.65 g, 69%).

MS m/z 456 [M+H]+, APCI(+)

Compound 2 (1.64 g, of 3.60 mmol) and thioanisole (4,47 g, 36,0 mmol) was dissolved in dichloromethane (16 ml), was added triftormetilfullerenov (16 ml), and the mixture was heated to 40°C. After stirring for 3 hours the mixture was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate. After extraction with ethyl acetate the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (1.12 g, 76%).

MS m/z 412 [M+H]+, APCI(+)

Connection 3 (1.12 g, of 2.72 mmol) and diisopropylethylamine (1.06 g, 8.17 mmol) was dissolved in methylene chloride (22 ml) and, after cooling on ice, was added to the anhydride of triftoratsetata (1,15 g, 4.09 to mmol). After stirring for 4 hours the mixture was stirred overnight, during which it was heated to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (876 mg, 59%).

MS m/z 544 [M+H]+, APCI(+)

Compound 4 (875 mg, of 1.61 mmol) was dissolved in tetrahydrofuran (18 ml), was added cesium carbonate (1.57 in g, a 4.83 mmol), benzophenone (583 mg, up 3.22 mmol), (R)-BINAP (155 mg, 0,241 mmol), and palladium acetate (36,1 mg, 0,161 mmol)and the mixture was purged with argon. The mixture was heated under reflux and stirred overnight. The mixture was cooled to room temperature, added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified kolonen the th chromatography on silica gel, to obtain compound 5 (705 mg, 76%). Compound 5 (703 mg, 1,22 mmol) was dissolved in methanol (7 ml) was added N,N'-dimethylformamide (7 ml), hydroxylamine hydrochloride (170 mg, 2.45 mmol) and sodium acetate (301 mg, to 3.67 mmol). After stirring overnight was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (445 mg, 89%).

MS m/z 411 [M+H]+, APCI(+)

A mixed solution of formic acid (122 mg, 2,60 mmol) and acetic anhydride (216 mg, 2,12 mmol) was heated to 60°C. After 2 hours the mixture was cooled on ice and added to the solution of compound 6 (100 mg, 0,244 mmol) in tetrahydrofuran (2 ml). After stirring for 1 hour the mixture was heated to room temperature and was stirred overnight. Was added a saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 7 (103 mg, 96%).

MS m/z 439 [M+H]+, APCI(+)

Compound 7 (100 mg, 0,228 mmol) was dissolved in methane is e (2.0 ml) and after cooling on ice, was added 1N sodium hydroxide (0.3 ml). After stirring for 8 hours, the mixture was neutralized 1H chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of diethyl ether-hexane to obtain compound 8 (82 mg, 87%).

MS m/z 409 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 48

[4-({6-cyclohexyl-5-[(methylsulphonyl)amino]pyridine-2-yl}methyl)-2,3,5-trimethylphenol]acetic acid

Compound 1 (100 mg, 0,244 mmol) and triethylamine (37,1 mg, 0,365 mmol) was dissolved in dichloromethane (2 ml) and, after cooling on ice, was added methanesulfonamide (of 31.4 mg, 0,268 mmol). After stirring for 3 hours was added triethylamine (36,5 mg, 0,361 mmol) and methanesulfonamide (14,8 mg, 0,132 mmol). After stirring for 3 hours was added water to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filter the Lee and concentrated. The residue was purified column chromatography on silica gel, and the resulting residue was dissolved in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) and, after cooling on ice, was added 1N sodium hydroxide (0.5 ml). After stirring over night, the respective reaction solutions were mixed together and the mixture is neutralized 1H chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was washed in suspension with a mixture of diethyl ether-hexane to obtain compound 2 (87,6 mg, 78%).

MS m/z 459 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 49

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-ethyl-3,5-dimethylphenoxy}acetic acid

Connection 1 (1,00 g of 1.75 mmol) was dissolved in degassed 1,4-dioxane (20 ml), was added potassium carbonate (1.45 g, 10.5 mmol), and ethylboronic acid (647 mg, 8,76 mmol)and the mixture was purged with argon. Was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (256 mg, 0,350 mmol)and the mixture is boiled under reflux during the night. The mixture is cooled to room temperature and filtered through radiolite. Added ethyl acetate, and the mixture was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (326 mg, 39%).

MS m/z 474 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 8 of example 2.

MS m/z 456 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 396 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 50

3-[{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}(methyl)amino]-3-oxopropanoic acid

Connection 1 (108 mg, 0,305 mmol) and triethylamine (93,0 mg, 0,914 mmol) was dissolved in tetrahydrofuran (2 ml) and, after cooling on ice, was added to the anhydride triperoxonane acid (70,4 mg, 0,335 mmol). After stirring for 3 hours was added to the reaction solution, water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified colonoscopy because it allows the Noah chromatography on silica gel, to obtain compound 2 (137 mg, 99%).

MS m/z 451 [M+H]+, APCI(+)

Compound 2 (130 mg, 0,289 mmol) and cesium carbonate (376 mg, 1,154 mmol) was dissolved in acetonitrile (3 ml) was added logmean (123 mg, 0,866 mmol). After stirring over night to the reaction solution was added water, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (127 mg, 95%).

MS m/z 465 [M+H]+, APCI(+)

Connection 3 (125 mg, 0,269 mmol) was dissolved in a mixture of methanol (2.0 ml) and tetrahydrofuran (3 ml) and, after cooling on ice, was added 1N sodium hydroxide (0,32 ml). After stirring for 3 hours the reaction solution was neutralized 1H chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (99 mg, 99%).

MS m/z 369 [M+H]+, APCI(+)

Compound 4 (a 99.0 mg, 0,269 mmol) and triethylamine (81,6 mg, 0,806 mmol) was dissolved in dichloromethane (2 ml) and, after cooling on ice, was added ethyl 3-chloro-3-oxopropionate (910 mg, 6,04 mmol). The mixture was stirred for but and, in the process what she was heated, and was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (71 mg, 55%).

MS m/z 483 [M+H]+, APCI(+)

Compound 5 (88,3 mg, 0,183 mmol) was dissolved in dichloromethane (1.0 ml), was added triftormetilfullerenov (1.0 ml), and the mixture was heated to 40°C. After stirring for 3 hours the mixture was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate. After extraction with chloroform, the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (39,4 mg, 49%). Compound 6 (39,0 mg, 0,0889 mmol) was dissolved in methanol (0,80 ml) and, after cooling on ice, was added 1N sodium hydroxide (0,40 ml). After stirring for 8 hours the mixture was concentrated. The residue was washed with ethyl acetate, neutralized 1H chloroethanol acid and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the connection is out 7 (37.5 mg, 98%).

MS m/z 409 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 51

{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-methoxy-3,5-dimethylphenoxy}acetic acid

Connection 1 (1,00 g of 1.75 mmol) was dissolved in degassed 1,4-dioxane (18 ml), was added water (18 ml), potassium hydroxide (216 mg, of 3.85 mmol)and 2-di-tert-butylphosphino-2',4',6'-triisopropylphenyl (60,0 mg, 0,141 mmol)and the mixture was purged with argon. Added Tris(dibenzylideneacetone)dipalladium (0) (32,0 mg, 0,0350 mmol)and the mixture is boiled under reflux during the night. The mixture was cooled to room temperature, added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (469 mg, 58%).

MS m/z 462 [M+H]+, APCI(+)

Compound 2 (469 mg, of 1.02 mmol) was dissolved in acetonitrile (10 ml), was added methyliodide (296 mg, of 2.09 mmol) and cesium carbonate (500 mg, 1.53 mmol). After stirring at room temperature for 2 hours was added methyl shall Oded Hagai (296 mg, of 2.09 mmol)and the mixture was stirred for 2 hours. Was added water, and the mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (445 mg, 92%).

MS m/z 476 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 8 of example 2.

MS m/z 458 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 398 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 52

3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid

Compound 2 was obtained in a manner analogous to the method for compound 2 of example 5.

MS m/z 458 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 370 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 2 of example 21.

MS m/z 502 [M+H]+, APCI(+)

Compound 4 (2,22 g, 4,43 mmol) races shall varali in dioxane (22 ml), was added potassium phosphate (5,64 g of 26.6 mmol), 2-di-tert-butylphosphine (844 mg, 1.77 mmol) and benzylamine (1,90 g of 17.7 mmol)and the mixture was purged with argon. Added Tris(dibenzylideneacetone)dipalladium (0) (810 mg, 0,885 mmol)and the mixture was stirred at 100°C during the night. The mixture was cooled to room temperature, was added ethyl acetate and water, and the mixture was filtered through radiolite. After extraction with ethyl acetate, the extract was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (1.63 g, 81%).

MS m/z 459 [M+H]+, APCI(+)

Compound 5 (1,71 g, 3.72 mmol) was dissolved in ethanol (34 ml) and acetic acid (8.5 ml) and, after purging with argon, was added the catalyst, which represents 20% palladium hydroxide on coal (854 mg). After purging with hydrogen, the mixture was stirred for 7 hours, filtered through radiolite and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (1.08 g, 79%).

MS m/z 369 [M+H]+, APCI(+)

Compound 7 was obtained in a manner analogous to the method for compound 5 of example 21.

MS m/z 483 [M+H]+, APCI(+)

Compound 7 (1,23 g, 2.56 mmol) and thioanisole (3,01 ml, 25.6 mmol) was dissolved in dichloromethane (12 ml) and, polioksidony on ice, added triperoxonane acid (12 ml). After stirring at 40°C for 2 hours was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The extract was washed successively with water and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 8 (0,92 g, 82%).

MS m/z 439 [M+H]+, APCI(+)

Compound 8 (196 mg, 0,447 mmol) was dissolved in methanol (3.9 ml) and, after cooling on ice, was added 1N sodium hydroxide (0,89 ml). The mixture was heated to room temperature and was stirred overnight, neutralized with a saturated aqueous solution of ammonium chloride and was extracted with a mixture of ethyl acetate-methanol. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained solid residue was washed with ether and dried under reduced pressure to obtain compound 9 (187 mg, 100%).

MS m/z 409 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 53

3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,6-debtor-3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he

Connection 1 (1,00 g, 2.68 mmol) was dissolved in chloroform (10 ml) and cooled on ice. Was added N-bromosuccinimide (501 mg, of 2.81 mmol)and the mixture was stirred at room temperature for 4 hours. Was added water, and the mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (925 mg, 76%).

MS m/z 452/454 [M+H]+, APCI(+)

Compound 2 (324 mg, 0,716 mmol) was dissolved in acetonitrile (7 ml) was added diethylcarbamoyl (147 mg, of 1.08 mmol) and potassium carbonate (300 mg, 2,17 mmol). The mixture was heated under reflux overnight and cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate, and the extract was washed successively with water and saturated salt solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (302 mg, 76%).

MS m/z 551/553 [M+H]+, APCI(+)

Connection 3 (301 mg, 0,546 mmol) was dissolved in tetrahydrofuran (4 ml)was cooled to -78°C and slowly added dropwise n-utility (hexane solution, 397 μl, 0,655 mmol). The mixture was stirred those which begins 30 minutes. Was slowly added dropwise N-forbindelseshastighed (517 mg, 0,610 mmol)dissolved in THF (2 ml)and the mixture was stirred for 3 hours, heated to room temperature and was stirred overnight. Was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (172 mg, 65%).

MS m/z 491 [M+H]+, APCI(+)

Compound 4 (172 mg, 0.351 mmol) was dissolved in ethanol (3.5 ml), was added potassium hydroxide (140 mg, of 2.50 mmol), the mixture was boiled under reflux for 2 days. The mixture was cooled to room temperature and neutralized with a saturated aqueous solution of ammonium chloride. After extraction with ethyl acetate the organic layer was washed successively with water and saturated saline solution, dried over anhydrous magnesium sulfate and filtered. The residue was purified column chromatography on silica gel to obtain compound 5 (84 mg, 61%).

MS m/z 392 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 2 of example 27.

MS m/z 431 [M+H]+, APCI(+)

Compound 7 was obtained in a manner analogous to the method for having soedineniya 3 of example 27.

MS m/z 488 [M-H]-, ESI(-)

Compound 8 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 444 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 54

3-({2-chloro-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid

Connection 1 (3.50 g, 9,87 mmol) was dissolved in carbon tetrachloride (20 ml)and the mixture was cooled on ice. Was added N-chlorosuccinimide (1.45 g, 10.9 mmol)and the mixture was stirred at room temperature for 3 hours. Added chloroform, and the mixture was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (2,32 g, 60%).

MS m/z 389/391 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 5 of example 21.

MS m/z 503/505 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 8 of example 52.

MS m/z 459/461 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 9 of example 52.

MS m/z 429/431 [M-H]-, ESI(-)

Hydrobro the ID, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 55

3-({2-bromo-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid

Compound 1 (500 mg, of 1.41 mmol) was dissolved in N,N'-dimethylformamide (10 ml)and the mixture was cooled on ice. Was added N-bromosuccinimide (251 mg, of 1.41 mmol)and the mixture was stirred at 0°C for 4 hours. Added ethyl acetate, and the mixture was washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (555 mg, 91%).

MS m/z 433/435 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 5 of example 21.

MS m/z 547/549 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 8 of example 52.

MS m/z 503/505 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 9 of example 52.

MS m/z 473/475 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard is Tadei obtain salt.

Example 56

3-({4-[(6-Deut-butyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he

Connection 1 (508 mg, 1,22 mmol), copper iodide (I) with (58.2 mg, 0,305 mmol), potassium iodide (121 mg, 0,733 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane (to 49.9 mg, 0,0611 mmol) was purged with argon was added N,N-dimethylacetamide (10 ml). AddedDeut-butylzinc bromide (0.5 M tertrahydrofuran ring solution, 4,88 ml of 2.44 mmol)and the mixture was heated to 60°C. After one day, the mixture was cooled to room temperature. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (333 mg, 62%).

MS m/z 438 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4 and the compound 2 of example 27.

MS m/z 387 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 444 [M-H]-, ESI(-)

Compound 5 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 400 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, Malea what this and similar compounds can be obtained using standard stage of obtaining salts.

Example 57

3-{[2-fluoro-4-({5-hydroxy-6-[methyl(phenyl)amino]pyridine-2-yl}methyl) - for 3,5-dimethylphenoxy]methyl}-1,2,4-oxadiazol-5(4H)-he

Connection 1 (208 mg, 0,500 mmol), N-methylaniline (80 mg, 0.75 mmol), Tris(benzylideneacetone)dipalladium (0) (23 mg, of 0.025 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43 mg, of 0.075 mmol) andtert-piperonyl sodium (72 mg, 0. 75 mmol) was purged with argon, was added toluene (5 ml)and the mixture is boiled under reflux during the night. The mixture was cooled to room temperature, was added ethyl acetate and water, and the mixture was stirred and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (223 mg, 91%).

MS m/z 487 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 397 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 2 of example 27.

MS m/z 436 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 493 [M-H]-, ESI(-)

Compound 6 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 449 [-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 58

3-({3,5-dichloro-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)oxy]phenyl}amino)-3-oxopropanoic acid

Connection 1 (395 mg, 1.15 mmol) was dissolved in dimethyl sulfoxide (2 ml) was added compound 2 (297 mg, 1.15 mmol), copper iodide (110 mg, 0,575 mmol) and potassium carbonate (318 mg, 2,30 mmol)and the mixture was heated to 90°C. After stirring for 3 hours the mixture was cooled to room temperature, was added ethyl acetate, water and ammonium chloride, and the mixture is vigorously stirred. After 30 minutes the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3.

MS m/z 473/475 [M+H]+, APCI(+)

Compound 3 was dissolved in dichloromethane (10 ml)was added N,N'-dimethylbarbituric acid (1.20 g, to 7.68 mmol) and tetranitropentaerithrite (0) (148 mg, 0,128 mmol)and the mixture was heated to 40°C. After stirring for 6 hours was added tetranitropentaerithrite (0) (148 mg, 0,128 the mol). After stirring for 17 hours was added tetranitropentaerithrite (0) (148 mg, 0,128 mmol). After stirring for 4 hours the mixture was cooled to room temperature and was diluted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (201 mg, 49%, stage 2).

MS m/z 353/355 [M+H]+, APCI(+)

Compound 4 (198 mg, 0,561 mmol) was dissolved in dichloromethane (3 ml) and tetrahydrofuran (3 ml) was added pyridine (67 mg, 0,841 mmol)and the mixture was cooled on ice. Was added dropwise ethylmalonate (93 mg, 0,617 mmol)and the mixture was stirred for 1 hour. Was added a saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (217 mg, 83%).

MS m/z 467/469 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 9 of example 52.

MS m/z 437/439 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, baselslt is at, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 59

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile

To compound 1 (300 mg, services, 0.844 mmol) was added water (3 ml) and concentrated chloroethanol acid (3 ml)and the mixture was cooled on ice. Was added dropwise an aqueous solution (1 ml) of sodium nitrite (for 72.8 mg, 1.05 mmol) and, after 30 minutes, was added a chilled on ice water solution (3 ml) of N-cyanoacetylurea (145 mg, 0,928 mmol) and pyridine (3.0 ml, 38 mmol). After 2 hours, the precipitation was filtered, washed with water and dried. To the resulting solid residue was added sodium acetate (350 mg, 4,27 mmol) and acetic acid (8 ml), and the mixture was heated to 120°C. After 3 hours the mixture was cooled to room temperature, was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel. The obtained solid residue was washed in suspension with a mixture of ether-ethanol and dried to obtain compound 2 (78 mg, 21%).

MS m/z 432 [M+H]+, APCI(+)

The hydrobromide, hydrochloride,pair/i> -toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 60

3-[(2-fluoro-4-{[6-(2-fluoro-3-were)-5-hydroxypyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (208 mg, 0.50 mmol), 2-fluoro-3-methylphenylimino acid (115 mg, 0.75 mmol), tetranitropentaerithrite (0) (58 mg, 0.05 mmol) and potassium carbonate (207 mg, 1.50 mmol) was purged with argon, suspended in water (0.7 ml) and 1,4-dioxane (2.8 ml), and the mixture was stirred at 90°C for 1 hour. The mixture was cooled to room temperature, was added ethyl acetate and water, and the mixture was stirred and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated salt solution, filtered through ChemElute and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (233 mg, 95%).

MS m/z 490 [M+H]+, APCI(+)

Compound 2 (232 mg, 0.47 mmol) was dissolved in ethanol (4 ml) and acetic acid (1 ml) was added 5% Pd/C (90 mg). After purging with hydrogen, the mixture was stirred for 4 hours, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (153 mg, 81%).

MS m/z 400 [M+H] , APCI(+)

Connection 3 (152 mg, 0.38 mmol) was dissolved in acetonitrile (4.5 ml) was added bromoacetonitrile (81 mg, of 0.68 mmol) and cesium carbonate (440 mg, 1.35 mmol)and the mixture was stirred at room temperature for 1 hour. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated salt solution, filtered through ChemElute and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (160 mg, 96%).

MS m/z 439 [M+H]+, APCI(+)

Compound 4 (158 mg, 0.36 mmol) was dissolved in methanol (1.5 ml) was added in tetrahydrofuran (0.5 ml), hydroxylamine hydrochloride (38 mg, 0.54 mmol) and sodium hydrogen carbonate (91 mg, of 1.08 mmol). After boiling under reflux for 1.5 hours the mixture was cooled to room temperature, was added an aqueous solution of ammonium chloride and ethyl acetate, and the mixture was stirred. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. Added 1,4-dioxane (3 ml), and then 1,1'-carbonyldiimidazole (88 mg, 0.54 mmol). After stirring at room temperature for 1 hour the mixture was boiled under reflux for 2.5 hours. The mixture was cooled to room temperature, was added ethyl acetate and water, and see what camping was neutralized with 5% chloroethanol acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (163 mg, 91%).

MS m/z 496 [M-H]-, ESI(-)

Compound 5 (161 mg, 0.32 mmol) was dissolved in tetrahydrofuran (3.5 ml)was added 6N chloroethanol acid (0.75 ml)and the mixture was stirred at 60°C for 2 hours. The mixture was cooled to room temperature, was added 2n sodium hydroxide (2.25 ml) and the mixture was stirred. Was added an aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (135 mg, 92%).

MS m/z 452 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 61

3-[(4-{[6-(4,4-debtor-1-hydroxycyclohexyl)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

To compound 1 (508 mg, 1,22 mmol) was added yo the ID of sodium (366 mg, of 2.44 mmol) and copper iodide (I) (46,5 mg, 0,244 mmol) and (1R,2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine (69,5 mg, 0,489 mmol)and the mixture is suspended in dioxane (2.5 ml). After purging with argon, the mixture was heated to 120°C. After 5 days the mixture was cooled to room temperature, was added sodium iodide (366 mg, 2,44 mmol) and copper iodide (I) (46,5 mg, 0,244 mmol) and (1R, 2R)-(-)-N,N'-dimethylcyclohexane-1,2-diamine (69,5 mg, 0,489 mmol)and the mixture was heated to 120°C. After 1 day, the mixture was cooled to room temperature, was added a saturated aqueous solution of ammonium chloride and ethyl acetate, and the mixture was stirred vigorously. The resulting suspension was filtered through radiolite, and the residue was washed with ethyl acetate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (331 mg, 53%).

MS m/z 508 [M+H]+, APCI(+)

Compound 2 (330 mg, 0,650 mmol) was dissolved in tetrahydrofuran (3 ml)was cooled to -78°C, was slowly added dropwisen-utility (a 1.6 M hexane solution of 0.49 ml, 0.78 mmol)and the mixture was stirred for 1 hour. Was slowly added dropwise a solution (3 ml) 4,4-diverticulectomy (122 mg, 0,911 mmol) in tetrahydrofuran, and the mixture was stirred for 1 hour, and warmed up to room te is the temperature. After 1 hour was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (261 mg, 78%).

MS m/z 516 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 11 of example 4 and the compound 2 of example 27.

MS m/z 465 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 522 [M-H]-, ESI(-)

Compound 6 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 478 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 62

N-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}glycine

Compound 1 (2.00 g, 3,99 mmol) was dissolved in tetrahydrofuran (18 ml), was added cesium carbonate (1,95 g, 5,98 mmol), benzophenone (867 mg, 4,79 mmol), (R)-BINAP (384 mg, 0,598 mmol) and palladium acetate (89,5 mg, 0,399 mmol)and the mixture was purged with argon. The mixture was heated under reflux and stirred overnight. The mixture was cooled to room temp the atmospheric temperature, was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (967 mg, 46%).

MS m/z 533 [M+H]+, APCI(+)

Compound 2 (1.78 g, 3.35 mmol) was dissolved in methanol (18 ml) and N,N'-dimethylformamide (18 ml). Added hydroxylamine hydrochloride (466 mg, of 6.71 mmol) and sodium acetate (826 mg, 10.1 mmol). After stirring overnight was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (1.18 g, 95%).

MS m/z 369 [M+H]+, APCI(+)

Compound 3 (200 mg, 0,542 mmol) was dissolved in acetonitrile (4 ml), was added ethylbromoacetate (104 mg, 0,675 mmol) and cesium carbonate (550 mg, was 1.69 mmol). After stirring for 7 hours was added ethylbromoacetate (104 mg, 0,675 mmol) and cesium carbonate (550 mg, was 1.69 mmol). After stirring overnight was added ethylbromoacetate (104 mg, 0,675 mmol)and the mixture is boiled under reflux. After stirring for 7 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer PR is mawali saturated salt solution, was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (147 mg, 59%).

MS m/z 441 [M+H]+, APCI(+)

Compound 4 (141 mg, 0,319 mmol) was dissolved in methanol (0.6 ml) and tetrahydrofuran (0.6 ml). Added 6N chloroethanol acid (1.0 ml), and the mixture was heated to 60°C. After stirring for 2 hours the mixture was cooled to room temperature. The mixture was neutralized 4n aqueous solution of sodium hydroxide and was extracted with ethyl acetate. The organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was dissolved in methanol (2.8 ml). Added 2n sodium hydroxide (0.5 ml), and the mixture was heated to 60°C and was stirred overnight. The mixture was cooled to room temperature, was added 4n aqueous sodium hydroxide solution (3.0 ml), and the mixture was concentrated. The residue was washed with ethyl acetate, neutralized 1H chloroethanol acid, and the precipitated precipitate was collected by filtration to obtain compound 5 (from 91.5 mg, 75%).

MS m/z 381 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 63

Compound 1 (300 mg, services, 0.844 mmol) was dissolved in N,N'-dimethylformamide (3 ml) was added sodium hydride (60% dispersion in mineral oil, 40.5 mg, 1.01 mmol). After stirring for 30 minutes was added diethylphosphonoacetate (104 mg, 0,675 mmol). After stirring for 3 hours, during which it was cooled, added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (364 mg, 85%).

MS m/z 506 [M+H]+, APCI(+)

Compound 2 (363 mg, 0,718 mmol) was dissolved in dichloromethane (7.3 ml) was added trimethylsilylpropyne (1,16 g 7,180 mmol). After stirring overnight was added water (4.0 ml) and acetonitrile (4.0 ml). After stirring over night the mixture was made basic 1N aqueous solution of sodium hydroxide, and the aqueous layer washed with ethyl acetate and neutralized 1H chloroethanol acid. The precipitation was collected by filtration and washed with ice water. The filtrate was cooled on ice, was kept for 2 hours, and the precipitation was collected by filtration and washed with ice water. The obtained solids were mixed, was added 6N chloroethanol acid (9.7 ml)and the mixture boil gently for about the and under reflux. After stirring for 30 minutes the mixture was made basic 4n aqueous solution of sodium hydroxide, and the aqueous layer washed with ethyl acetate, neutralized 1H chloroethanol acid and cooled on ice. After keeping for 30 minutes, the precipitated precipitate was collected by filtration and washed with ice water to obtain compound 3 (32,5 mg, 11%).

MS m/z 404 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 64

N-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylbenzoyl}glycine

Connection 1 (4.26 deaths / g, a total of 8.74 mmol) was dissolved in toluene (90 ml) and acetonitrile (45 ml) and purged with argon. Added hexacarbonyl molybdenum (4.61 in g, 17.5 mmol), palladium acetate (0,392 g of 1.75 mmol), BINAP (1,09 g of 1.75 mmol), cesium carbonate (3.13 g, being 9.61 mmol) and methanol (ceiling of 5.60 g, 175 mmol)and the mixture was heated to 90°C. After stirring for 16 hours the mixture was cooled to room temperature, was added iodine (4.44 g, 17.5 mmol)and the mixture vigorously stirred. After 2 hours the mixture was filtered through celite, and was added to the filtrate ethyl acetate and saturated aqueous sodium thiosulfate solution, and the mixture is vigorously stirred. After 30 minutes the mixture was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (3.13 g, 90%).

MS m/z 398 [M+H]+, APCI(+)

Compound 2 (1.12 g, 2.82 mmol) was dissolved in methanol (15 ml) and tetrahydrofuran (15 ml)was added 6N chloroethanol acid (15 ml), and the mixture was heated to 50°C. After stirring for 22.5 hours the mixture was heated to 60°C. After stirring for 2 hours the mixture was cooled to room temperature and filtered through celite. The filtrate was neutralized 2n aqueous sodium hydroxide solution and concentrated. The residue was extracted with ethyl acetate, and the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue was dissolved in methanol (30 ml), was added 2n sodium hydroxide (14.1 ml of 28.2 mmol)and the mixture was heated to 60°C. After stirring for 1.5 hours the mixture was cooled to room temperature, neutralized 6N chloroethanol acid and concentrated. The residue was extracted with a mixture of ethyl acetate-tetrahydrofuran-methanol, and the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated to the CSOs, to obtain compound 3 (0,969 g, 100%).

MS m/z 338 [M-H]-, ESI(-)

Connection 3 (227 mg, 0,669 mmol) was dissolved in dichloromethane (7 ml) and N,N'-dimethylformamide (0.7 ml), and added the hydrochloride of the methyl ester of glycine (126 mg, 1.00 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (192 mg, 1.00 mmol) and 1-hydroxy-7-asobancaria (137 mg, 1.00 mmol)and the mixture was cooled on ice. Was added N-methylmorpholine (135 mg, of 1.34 mmol)and the mixture was stirred for 10 minutes and warmed up to room temperature. After stirring for 18 hours the mixture was concentrated. To the residue was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (183 mg, 67%).

MS m/z 411 [M+H]+, APCI(+)

Compound 4 (180 mg, 0,438 mmol) was dissolved in methanol (4 ml), was added 1N sodium hydroxide (0,877 ml, 0,877 mmol). After stirring for 24 hours the mixture was neutralized 2n chloroethanol acid and concentrated. To the residue was added a saturated salt solution, and the mixture was extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was dried over besttranslator magnesium, was filtered and concentrated. The obtained residue was washed in suspension with a mixture of hexane-ether to obtain compound 5 (176 mg, 100%).

MS m/z 395 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 65

{4-[(6-cyclohexyl-4-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid

Connection 1 (439 mg, 1.06 mmol) was dissolved in tetrahydrofuran (8 ml)and the mixture was cooled to -78°C. was Slowly added dropwise n-utility (a 1.6 M hexane solution, 0.75 ml, 1.1 mmol)and the mixture was stirred for 1 hour. Was added N-forbindelseshastighed (504 mg, 1,60 mmol)and the mixture was stirred for 1 hour and warmed up to room temperature. After 1 hour was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (375 mg, 82%).

MS m/z 430/432 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 2 of example 5.

MS m/z 476 [M+H]+, APCI(+)

Compound 4 was obtained by the method, and is similar to the method for compound 8 of example 2.

MS m/z 460 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 400 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 66

3-[(4-{[6-(3-ethoxyphenyl)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (6,24 g, 15.0 mmol) was dissolved in tetrahydrofuran (150 ml), was added 5% Pd/C (1,36 g), and the mixture was purged with hydrogen and stirred for 4 hours, filtered and concentrated. The obtained residue was dissolved in acetonitrile (170 ml). Added cesium carbonate (8,48 g, 26 mmol) and bromoacetonitrile (2,71 g, 23 mmol)and the mixture was stirred at room temperature for 1.5 hours. Added ethyl acetate and water, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (4,65 g, 85%).

MS m/z 365/367 [M+H]+, APCI(+)

Compound 2 (128 mg, 0.35 mmol), 3-ethoxyphenylurea acid (88 mg, of 0.53 mmol), the complex [1,1'-bis(diphenylphosphino)f is frozen]dichloropalladium(II) dichloromethane (29 mg, 0.04 mmol) and cesium carbonate (342 mg, 1.05 mmol) was weighed and was purged with argon, suspended in dioxane (3.5 ml) and boiled under reflux during the night. The mixture was cooled to room temperature, filtered through celite, washed with an aqueous solution of ammonium chloride and saturated salt solution, filtered through ChemElute and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (132 mg, 82%).

MS m/z 451 [M+H]+, APCI(+)

Connection 3 (129 mg, 0.29 mmol) was dissolved in methanol (1.5 ml) was added in tetrahydrofuran (0.5 ml), hydroxylamine hydrochloride (30 mg, 0.43 mmol) and sodium hydrogen carbonate (227 mg, 0.86 mmol). After boiling under reflux for 1.5 hours the mixture was cooled to room temperature, was added an aqueous solution of ammonium chloride and ethyl acetate, and the mixture was stirred. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. Added 1,4-dioxane (3 ml) and then 1,1'-carbonyldiimidazole (70 mg, 0.43 mmol). After stirring at room temperature for 1 hour the mixture was boiled under reflux for 2.5 hours. The mixture was cooled to room temperature, was added ethyl acetate and water, and the mixture was neutralized with 5% khorovod the native acid. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (124 mg, 85%).

MS m/z 508 [M-H]-, ESI(-)

Compound 4 (123 mg, 0.24 mmol) was dissolved in ethanol (3.5 ml)was added 6N chloroethanol acid (0.6 ml)and the mixture was stirred at 50°C for 5 hours. The mixture was cooled to room temperature and neutralized 2n sodium hydroxide (1.8 ml). Added ethyl acetate and an aqueous solution of ammonium chloride, and the mixture was stirred. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (75 mg, 67%).

MS m/z 464 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 67

N-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylbenzyl}glycine

In argon atmosphere, the compound 1 (700 mg, 1.8 mmol) was dissolved in toluene (4 ml), and the mixture is cooled on ice. bis(2-Methoxyethoxy)alumoweld sodium (3.6 M toluene solution, 1.0 ml, 3.6 mmol) and 1-methylpiperidin (of 0.44 ml, 4.0 mmol) were mixed and added to the toluene solution of the compound 1. The mixture was stirred for 1 hour, during which it was heated to room temperature, added water and the mixture was filtered through radiolite. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (379 mg, 57%).

MS m/z 368 [M+H]+, APCI(+)

Compound 2 (100 mg, 0.27 mmol) was dissolved in ethanol (1 ml). Was added sodium acetate (90 mg, 1.1 mmol), hydrochloride of the ethyl ester of glycine (175 mg, 1.3 mmol) and Lamborghini sodium (27 mg, 0.43 mmol)and the mixture was stirred over night. Was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (61 mg, 50%).

MS m/z 455 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 381 [M-H]+, APC(+)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 68

3-[({4-[(5-hydroxy-6-vinylpyridin-2-yl)(methoxy)methyl]-5-methyl-2,3-dihydro-1-benzofuran-7-yl}oxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (3,22 g of 10.75 mmol) was dried azeotrope with toluene and, after purging with argon, was dissolved in toluene (90 ml)and the mixture was cooled to -78°C. was Slowly added dropwise n-utility (of 1.57 M hexane solution, 6.85 ml of 10.7 mmol)and the mixture was stirred for 30 minutes. Was added dropwise a solution of compound 2 (2,62 g, 9,77 mmol) in toluene (10 ml)and the mixture was stirred for 1 hour, during which it was heated to room temperature. Was added an aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (3.75 g, 87%).

MS m/z 442/444 [M+H]+, APCI(+)

Connection 3 (221 mg, 0,500 mmol), phenylboronic acid (91 mg, 0.75 mmol), tetranitropentaerithrite (0) (58 mg, 0.05 mmol) and potassium carbonate (207 mg, 1.5 mmol) was blown argon is, added dioxane (2.8 ml) and water (0.7 ml)and the mixture was stirred at 90°C during the night. The mixture was cooled to room temperature, was added ethyl acetate and water, and the mixture was stirred and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (231 mg, 96%).

MS m/z 484 [M+H]+, APCI(+)

Compound 4 (85 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2 ml)and the mixture was cooled on ice. Was added sodium hydride (60% dispersion in mineral oil, 7.7 mg, 0,19 mmol)and the mixture was stirred for 10 minutes. Added methyliodide (37 mg, 0.27 mmol)and the mixture was stirred for 2 hours, during which it was heated to room temperature. Added methyliodide (19 mg, 0.13 mmol) and sodium hydride (60% dispersion in mineral oil, 3 mg, 0.07 mmol)and the mixture was additionally stirred for 1 hour. Added ethyl acetate and water, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain the soybean is inania 5 (76 mg, 86%).

MS m/z 498 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 408 [M+H]+, APCI(+)

Compound 7 was obtained in a manner analogous to the method for compound 2 of example 27.

MS m/z 447 [M+H]+, APCI(+)

Compound 8 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 504 [M-H]-, ESI(-)

Compound 9 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 460 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 69

3-[({4-[[6-(2-fluoro-3-were)-5-hydroxypyridine-2-yl](hydroxy)methyl]-5-methyl-2,3-dihydro-1-benzofuran-7-yl}oxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (221 mg, 0,500 mmol), 2-fluoro-3-methylphenylimino acid (115 mg, 0.75 mmol), tetranitropentaerithrite (0) (58 mg, 0.05 mmol) and potassium carbonate (207 mg, 1.5 mmol) was purged with argon, was added 1,4-dioxane (2.8 ml) and water (0.7 ml)and the mixture was stirred at 90°C during the night. The mixture was cooled to room temperature, was added ethyl acetate and water, and the mixture was stirred and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated Sol is the first solution, was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (246 mg, 95%).

MS m/z 516 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 426 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 2 of example 27.

MS m/z 465 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 522 [M-H]-, ESI(-)

Compound 6 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 478 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 70

{3-bromo-2-fluoro-4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl]-5-methylphenoxy}acetic acid

Connection 1 (571 mg, 1,67 mmol) was dissolved in tetrahydrofuran (1.7 ml) and, after cooling on ice, was added dropwise isopropylaniline-lithium chloride (1.3 M tertrahydrofuran ring solution of 1.29 ml, a rate of 1.67 mmol). After stirring for 1 hour was added dropwise isopropylaniline-lithium chloride (1.3 M tertrahydrofuran ring solution of 0.64 ml, 0,835 mmol). After AC is shivani for 1 hour was added compound 2 (457 mg, to 1.67 mmol). After stirring for 45 minutes the mixture was heated to room temperature. After stirring for 14 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3.

MS m/z 488/490 [M+H]+, APCI(+)

Compound 3 was dissolved in dichloromethane (15 ml), was added triethylamine (292 mg, is 2.88 mmol)and the mixture was cooled on ice. Was added dropwise methanesulfonanilide (247 mg, of 2.16 mmol)and the mixture was heated to room temperature. After stirring for 1 hour was added triethylamine (146 mg, 1.44 mmol) and methanesulfonamide (124 mg, of 1.08 mmol). After stirring for 30 minutes was added triethylamine (146 mg, 1.44 mmol) and methanesulfonamide (124 mg, of 1.08 mmol). After stirring for 30 minutes was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in dichloromethane (15 ml), was added triethylsilane (201 mg, at 1.73 mmol)and the mixture was cooled on ice. Added triternata the sulfonate silver (444 mg, of 1.73 mmol) and after stirring for 45 minutes, was added saturated aqueous sodium bicarbonate and saturated salt solution, and the mixture is vigorously stirred. After 15 minutes the mixture was filtered through celite, and the filtrate was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (389 mg, 49%, stage 2).

MS m/z 472/474 [M+H]+, APCI(+)

Compound 4 (386 mg, 0,817 mmol) was dissolved in tetrahydrofuran (8 ml), was added N-methylmorpholine (107 mg, of 1.23 mmol) and tetranitropentaerithrite (0) (47 mg, 0,0409 mmol). After stirring for 30 minutes was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (317 mg, 90%).

MS m/z 432/434 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 504/506 [M+H]+, APCI(+)

Compound 7 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 444/446 [M-H]-, ESI(-)

Hydrobromic is, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 71

3-[(4-{[6-(3,3-diverticulosis)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

To compound 1 (497 mg, 0,980 mmol) was added 4,4-dipertikaikan (314 mg, 2.34 mmol),tert-piperonyl sodium (225 mg, 2.34 mmol), palladium acetate (26 mg, 0.12 mmol) and 2-(dicyclohexylphosphino)-2'-methylbiphenyl (85 mg, 0.23 mmol). Was added toluene (12 ml)and the mixture was purged with argon and was heated to 80°C. After 18 hours the mixture was cooled to room temperature, added water and 6N chloroethanol acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (165 mg, 32%).

MS m/z 514 [M+H]+, APCI(+)

Compound 2 (165 mg, 0,322 mmol) was dissolved in methanol (3 ml), was added sodium borohydride (24,4 mg, 0,644 mmol). After 5 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated the Ali and dried. To the obtained residue was added dichloromethane (3 ml), was added triethylamine (0,27 ml of 1.93 mmol), trimethylamine hydrochloride (3 mg, 0.03 mmol) and methanesulfonamide (0,074 ml, 0.96 mmol). After 15 hours was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain diastereomers (61 mg, 32%, 36 mg, 19%) of compound 3.

MS m/z 594 [M+H]+, APCI(+)

Connection 3 (59 mg, 0,099 mmol) was dissolved in N,N'-dimethylformamide (1.2 ml) was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0,030 ml, 0.20 mmol). The mixture was heated to 60°C and, after 3 hours, heated to 100°C. After one day, the mixture was cooled to room temperature, was added 1N chloroethanol acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (31 mg, 63%).

MS m/z 498 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 11 of example 4 and the compound 2 of example 27.

MS m/z 449 [M+H]+, ESI(+)

Compound 6 was obtained in a manner analogous to the method for compound 3 example is 27.

MS m/z 506 [M-H]-, ESI(-)

Compound 7 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 462 [M-H]-, ESI(-)

The hydrobromide, hydrochloride, para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 72

3-({5-ethyl-2-fluoro-4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl]-3-methylphenoxy}methyl)-1,2,4-oxadiazol-5(4H)-he

Connection 1 (1.6 g, 3.4 mmol) was dissolved in dichloromethane (33 ml), and the mixture was cooled on ice. Added methanesulfonamide (0,78 ml, 10 mmol) and triethylamine (1.9 ml, 14 mmol)and the mixture was heated to room temperature. Next, added methanesulfonamide (and 0.40 ml, 5.2 mmol) and triethylamine (0.95 ml, 6.8 mmol) and, after stirring overnight, was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel. The obtained residue (1.7 g) was dissolved in dichloromethane (34 ml)and the mixture was cooled on ice. In an atmosphere of argon was added triethylsilane (0,81 ml, 5.1 mmol) and triftorbyenzola silver (1.3 g, 5.1 mmol)and the mixture was stirred for 1 hour. Added the feast upon the aqueous solution of sodium bicarbonate, and the mixture was filtered through radiolite. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (970 mg, 60%).

MS m/z 472/474 [M+H]+, APCI(+)

In argon atmosphere, the compound 2 (970 mg, 2.10 mmol) was dissolved in tetrahydrofuran (21 ml) was added morpholine (of 0.28 ml, 3.2 mmol) and tetranitropentaerithrite (0) (119 mg, 0.11 mmol). After stirring for 6 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified short column chromatography on silica gel to obtain compound 3 (745 mg, 82%).

MS m/z 432/434 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 3 of example 2.

MS m/z 522/524 [M+H]+, APCI(+)

In argon atmosphere, the compound 4 (630 mg, 1.2 mmol) was dissolved in dimethoxyethane (13 ml) and water (1.3 ml). Added tetranitroaniline (0) (139 mg, 0.12 mmol) and pinacolone ether of vinylboronic acid (462 mg, 3.0 mmol) and cesium carbonate (1.1 g, 3.6 mmol)and the mixture was heated to 90°C and peremeshivayu throughout the night. Was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified short column chromatography on silica gel to obtain compound 5 (457 mg, 81%).

MS m/z 470 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 382 [M+H]+, APCI(+)

Compound 7 was obtained in a manner analogous to the method for compound 2 of example 27.

MS m/z 421 [M+H]+, APCI(+)

Compound 8 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 478 [M-H]+, APCI(+)

Compound 9 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 434 [M+H]+, APCI(+)

The hydrobromide, hydrochloride,para-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 73

{4-[(6-cyclohexyl-3-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid

Connection 1 (880 mg, 7,78 mmol) suspended in water (13 ml)and the suspension was cooled on ice. Was added sodium hydroxide (560 mg, 14.0 mmol) to obtain the solution, was added the dropwise within 5 minutes, 5% aqueous sodium hypochlorite solution (to 11.6 ml, for 7.78 mmol). After stirring for 10 minutes the mixture was heated to room temperature. After stirring for 20 hours the mixture was cooled on ice and added dropwise 5% aqueous sodium hypochlorite solution (2,32 ml, 1.56 mmol). After stirring for 10 minutes the mixture was heated to room temperature. After stirring for 72 hours was added 6N chloroethanol acid to bring the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain compound 2.

MS m/z 148/150 [M+H]+, APCI(+)

Connection 2 suspended in water (7 ml) was added potassium carbonate (2,01 g, 14.6 mmol) to obtain the solution. Was added iodine (1.06 g, 4,16 mmol)and the mixture was stirred for 18 hours. Was added a saturated aqueous solution of sodium thiosulfate. Added 6N chloroethanol acid to bring the pH to 2, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain compound 3.

MS m/z 272/274 [M-H]-, ESI(-)

Compound 3 was dissolved in acetonitrile (20 ml) and tetrahydrofuran (20 ml), was added cesium carbonate (vs. 5.47 g, a 16.8 mmol) and chloromethylation ether (676 mg, 8,39 mmol). After stirring for 14 hours the mixture was filtered through a whole is so The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 4.

MS m/z 318/320 [M+H]+, APCI(+)

Compound 4 was dissolved in toluene (40 ml)and the mixture was cooled to -78°C. was Added dropwise within 5 minutes n-utility (1,67M hexane solution of 2.23 ml, 3.72 mmol)and the mixture was stirred for 25 minutes. Compound 5 (0,945 g, 3.72 mmol) was dissolved in toluene (5 ml)and the mixture was added dropwise within 5 minutes. After stirring for 25 minutes, the mixture was heated to room temperature. After stirring for 1 hour was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (1,57 g, 45%, stage 4).

MS m/z428/430 [M+H-H2O]+, APCI(+)

Compound 6 (1,03 g, 2,31 mmol) was dissolved in 1,4-dioxane (16 ml) was added water (4 ml), potassium carbonate (958 mg, 6,93 mmol) and 1-cyclohexadienone acid (440 mg, 3.46 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (80 mg, 0,0693 mmol)and the mixture was heated to 90°C. After stirring for 2 hours was added 1-cyclohexadienone acid (440 mg, 3.46 in IMO is b) and tetranitropentaerithrite (0) (160 mg, 0,139 mmol). After stirring for 1.5 hours the mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 7 (963 mg, 84%).

MS m/z 492 [M+H]+, APCI(+)

Compound 7 (960 mg, of 1.95 mmol) was dissolved in pyridine (3 ml), was added acetic anhydride (3 ml), and the mixture was heated to 80°C. After stirring for 3 hours the mixture was heated to 100°C. After stirring for 1 hour the reaction mixture was concentrated and dried azeotrope with toluene. The residue was dissolved in acetic acid (20 ml) and, after purging with argon, was added 20% palladium hydroxide on coal (312 mg). After purging with hydrogen, the mixture was stirred for 16 hours and was added 20% palladium hydroxide on coal (312 mg). After purging with hydrogen, the mixture was stirred for 9 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and dried azeotrope with toluene. The residue was purified column chromatography on silica gel to obtain compound 8 (537 mg, 71%).

MS m/z 388 [M+H]+, APCI(+)

Compound 9 was obtained by a method similar is th way to connect 12 example 4.

MS m/z 460 [M+H]+, APCI(+)

Compound 10 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 400 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 74

3-[(5-ethyl-4-{[6-(3-ethylphenyl)-5-hydroxypyridine-2-yl]methyl}-2-fluoro-3-methylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he

Connection 1 (206 mg, 0,464 mmol) was dissolved in 1,4-dioxane (4 ml), was added water (1 ml), potassium carbonate (192 mg, of 1.39 mmol) and 3-ethylvinylbenzene acid (104 mg, 0,696 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (54 mg, 0.046 mmol)and the mixture was heated to 90°C. After stirring for 14 hours the mixture was cooled to room temperature. Was added a saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (88 mg, 37%).

MS m/z 514 [M+H]+, APCI(+)

Compound 2 (86 mg, 0,167 mmol) was dissolved in pyridine (1.5 ml), was added acetic anhydride (1.5 ml), and the mixture was heated to 100°C. After re is eshiwani within 2 hours the reaction mixture was concentrated and dried azeotrope with toluene. The residue was dissolved in acetic acid (3 ml) and, after purging with argon, was added 20% palladium hydroxide on coal (28 mg). After purging with hydrogen, the mixture was stirred for 5 hours and was added 20% palladium hydroxide on coal (28 mg). After purging with hydrogen, the mixture was stirred for 20 hours, filtered through celite and thoroughly washed with ethyl acetate and methanol. The filtrate was concentrated and dried azeotrope with toluene. The residue was purified column chromatography on silica gel to obtain compound 3 (53 mg, 78%).

MS m/z 410 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 2 of example 27.

MS m/z 449 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 3 of example 27.

MS m/z 506 [M-H]-, ESI(-)

Compound 6 was obtained in a manner analogous to the method for compound 4 of example 27.

MS m/z 462 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 75

[2-fluoro-4-({5-hydroxy-6-[1-(methoxymethyl)cyclohexyl]pyridin-2-yl}methyl) - for 3,5-dimethylphenoxy]acetic acid

Connection 1 (3,30 g of 7.93 mmol) was dissolved in tetrahydrofuran (50 ml) was added [1,1'-bis(diphenylprop the but)ferrocene]dichloropalladium (II) (581 mg, 0,793 mmol). After cooling, ice was added dropwise within 10 minutestert-butylaniline (1,02 M tertrahydrofuran ring solution, with 23.3 ml of 23.8 mmol). After stirring for 5 minutes the mixture was heated to room temperature. After stirring for 20 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (2,33 g, 77%).

MS m/z 382 [M+H]+, APCI(+)

Compound 2 (2,33 g, 6,11 mmol) was dissolved in methanol (30 ml) and tetrahydrofuran (30 ml) was added 6N chloroethanol acid (30 ml). After stirring for 20 hours the mixture was neutralized 4n aqueous solution of sodium hydroxide. Was added sodium chloride, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain compound 3 (2,02 g, 98%).

MS m/z 338 [M+H]+, APCI(+)

Connection 3 (of 2.06 g, 6,11 mmol) was dissolved in N,N'-dimethylformamide (30 ml) and, after cooling, ice was added sodium hydride (60% dispersion in mineral oil, 366 mg, 9,16 mmol). After stirring for 2 hours the mixture was heated to room the second temperature. After stirring for 2 hours was added dropwise (2-bromation)cyclohexane (purity 80%, 2.16 g, 9,16 mmol). After stirring for 18 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (2,40 g, 88%).

MS m/z 446 [M+H]+, APCI(+)

Compound 4 (850 mg, 1.92 mmol) was dissolved in acetic anhydride (4 ml) was added potassium acetate (567 mg, 5,77 mmol)and the mixture was heated up to 200°C in a microwave oven. After stirring for 2 hours the mixture was cooled to room temperature. Was added water, and the mixture was dried azeotrope with toluene. To the residue was added ethyl acetate, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (531 mg, 57%).

MS m/z 484 [M+H]+, APCI(+)

Compound 5 (1,58 g, 3,24 mmol) was dissolved in methanol (16 ml)and the mixture was cooled on ice. Added carbonate is Aliya (1,34 g, 9,72 mmol)and the mixture was heated to room temperature. After stirring for 2 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (1,15 g, 80%).

MS m/z 446 [M+H]+, APCI(+)

Compound 6 (1,15 g, 2.58 mmol) was dissolved in acetonitrile (13 ml), was added cesium carbonate (2,52 g, 7,74 mmol) and chloromethylation ester (312 mg, a 3.87 mmol). The mixture was stirred for 30 minutes and filtered through celite. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 7 (1.18 g, 94%).

MS m/z 490 [M+H]+, APCI(+)

Compound 7 (200 mg, 0,408 mmol) was dissolved in acetone (4 ml), was added water (1 ml) and N-methylmorpholin-N-oxide (96 mg, 0,817 mmol)and the mixture was cooled on ice. Added osmium tetroxide (2.5% solution intert-butyl alcohol, 42 mg, 0,00408 mmol)and the mixture was heated to room temperature. After stirring for 1.5 hours was added osmium tetroxide (2.5% solution intert-butyl alcohol, 42 mg, 0,00408 mmol). After stirring for 3.5 hours was added N-methylmorpholine-N-oxide (144 mg, of 1.23 mmol). After p is remesiana for 15 hours was added pyridine (65 mg, 0,817 mmol) and osmium tetroxide (2.5% solution intert-butyl alcohol, 42 mg, 0,00408 mmol). After stirring for 1.5 hours was added N-methylmorpholine-N-oxide (144 mg, of 1.23 mmol). After stirring for 3.5 hours was added osmium tetroxide (2.5% solution intert-butyl alcohol, 42 mg, 0,00408 mmol). After stirring for 2.5 hours was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (4 ml) was added water (0.8 ml). After cooling on ice, was added periodate sodium (131 mg, 0,613 mmol). After stirring for 3.5 hours added periodate sodium (44 mg, 0,204 mmol). After stirring for 30 minutes the mixture was heated to room temperature. After stirring for 2 hours the mixture was filtered through celite and diluted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 8 (181 mg, 90%).

MS m/z 492 [M+H]+, APCI(+)

Compound 8 (179 mg, 0,364 mmol) was dissolved in methanol (4 ml) and tetrahydrofuran (1 ml) and, after about the ladenia on ice, was added sodium borohydride (21 mg, 0,546 mmol). After stirring for 15 minutes the mixture was heated to room temperature, was stirred for 30 minutes and was added saturated aqueous solution of ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 9 (171 mg, 95%).

MS m/z 494 [M+H]+, APCI(+)

Compound 9 (169 g, 0,342 mmol) was dissolved in tetrahydrofuran (4 ml) and, after cooling on ice, was added sodium hydride (60% dispersion in mineral oil, 27 mg, 0,685 mmol). After stirring for 30 minutes was added dropwise logmean (146 mg, of 1.03 mmol)and the mixture was heated to room temperature. After stirring for 2.5 hours was added sodium hydride (60% dispersion in mineral oil, 68 mg, 1,71 mmol) and jodean (292 mg, 2.05 mmol). After stirring for 20 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 10 (157 mg, 90%).

MS m/z 508 [M+H]+, APCI(+)

Compound 11 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 418 [M+H]+, APCI(+)

Compound 12 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 490 [M+H]+, APCI(+)

Compound 13 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 430 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 76

(4-{[6-(4,4-diverticulosis)-5-hydroxypyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

Connection 1 (460 mg, 0,902 mmol) was dissolved in tetrahydrofuran (4 ml)was cooled to -78°C, was slowly added dropwise n-utility (a 1.6 M hexane solution of 0.79 ml, 1.2 mmol)and the mixture was stirred for 30 minutes. Was slowly added dropwise a solution (2 ml) 4,4-diverticulectomy (193 mg, 1.44 mmol) in tetrahydrofuran. After stirring for 30 minutes the mixture was heated to room temperature. After 1 hour was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. OST the current was purified column chromatography on silica gel, to obtain compound 2.

MS m/z 512 [M+H]+, APCI(+)

Compound 2 was dissolved in toluene (2.6 ml) was added monohydratep-toluenesulfonic acid (164 mg, 0,864 mmol) and molecular sieves 4A (500 mg)and the mixture is boiled under reflux. After 1 day, the mixture was cooled to room temperature and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate and saturated saline solution, dried over anhydrous sodium sulfate, filtered, concentrated and dried. To the obtained residue was added acetonitrile (2.6 ml) and chloromethylation ether (0,096 ml, 1.2 mmol). Added cesium carbonate (413 mg, of 1.27 mmol)and the mixture was stirred for 5 hours. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3.

MS m/z 494 [M+H]+, APCI(+)

Compound 3 was dissolved in ethanol (2 ml) and acetic acid (1 ml)was added 20% palladium hydroxide on coal (120 mg). After purging with hydrogen, the mixture was stirred for 15 hours, filtered through radiolite and washed with ethyl acetate. The filtrate was concentrated, and the obtained residue was purified column chromatography on silica gel to get the ü compound 4 (40 mg, 11%, stage 3).

MS m/z 406[M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 478 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 418 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 77

(2-fluoro-4-{[5-hydroxy-6-(1-hydroxyethyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)acetic acid

Connection 1 (4.15 g, 10 mmol), cyanide zinc (705 mg, 6 mmol), powdered zinc (392 mg, 6 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.1 g, 2 mmol) and bis(benzylideneacetone)palladium (0) (575 mg, 1 mmol) was weighed and, after purging with argon, was added N,N-dimethylacetamide (25 ml)and the mixture was stirred at 120°C for 4 hours. The mixture was cooled to room temperature, was added ethyl acetate and an aqueous solution of ammonium chloride. The mixture was stirred and filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (2.24 g, 55%)

MS m/z 407 [M+H]+, APCI(+)

Compound 2 (250 mg, of 0.62 mmol) was dissolved in tetrahydrofuran (2.5 ml) and, after purging with argon, cooled on ice. Was added dropwise methylmagnesium (3 M ether solution, 0.7 ml, 2.1 mmol)and the mixture was heated to room temperature and was stirred for 3 hours. Was added an aqueous solution of ammonium chloride and ethyl acetate, and the mixture was stirred and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (156 mg, 60%).

MS m/z 424 [M+H]+, APCI(+)

Connection 3 (144 mg, 0.34 mmol) was dissolved in ethanol (2.8 ml) and acetic acid (0.7 ml) was added 5% Pd/C (30 mg). After purging with hydrogen, the mixture was stirred for 3 hours, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (103 mg, 90%).

MS m/z 336 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 408 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 348 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and n is such the present compounds can be obtained using standard stage of obtaining salts.

Example 78

(4-{[5-hydroxy-6-(3-methylcyclohexyl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

In argon atmosphere, the compound 1 (226 mg, 0.45 mmol) was dissolved in tetrahydrofuran (0.5 ml) and cooled on ice. Was added a mixture of isopropylacrylamide and lithium chloride (1.3 M tertrahydrofuran ring solution of 0.52 ml of 0.68 mmol)and the mixture was stirred for 1 hour. Solution was added 3-ethoxy-2-cyclohexenone (95 mg, of 0.68 mmol) in tetrahydrofuran (0.5 ml). The mixture was stirred for 2 hours, during which it was heated to room temperature. Added 1H chloroethanol acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (190 mg, 90%).

MS m/z 472 [M+H]+, APCI(+)

Compound 3 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 384 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 3 of example 2.

MS m/z 474 [M+H]+, APCI(+)

Methyltriphenylphosphonium (759 mg, 2.1 mmol) andtert-piperonyl potassium (238 mg, 2.1 mmol) suspended in toluene (12 ml)and the mixture was stirred with heating in an argon atmosphere at 100°C. the donkey warming to room temperature, 6 ml of the mixture was added to a solution of compound 4 (100 mg, 0.21 mmol) in toluene (3 ml)and the mixture was stirred for 30 minutes. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (89 mg, 90%).

MS m/z 472 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 384 [M+H]+, APCI(+)

Compound 7 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 456 [M+H]+, APCI(+)

Compound 8 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 396 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

Example 79

(4-{[5-hydroxy-6-(3-methoxycyclohexyl)pyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid

In argon atmosphere, the compound 1 (133 mg, 0.28 mmol) was dissolved in tetrahydrofuran (1 ml)and the mixture was cooled to -78°C. was Added three(second-butyl)borohydride potassium (1 M tertrahydrofuran ring solution, 0.4 ml, 0.40 mmol)and the mixture was stirred for 30 minutes and warmed up to room so the temperature. Was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (82 mg, 62%).

MS m/z 476 [M+H]+, APCI(+)

Compound 2 (74 mg, 0.15 mmol) was dissolved in tetrahydrofuran (1.5 ml). Added logmean (0,087 ml of 0.93 mmol) and sodium hydride (60% dispersion in mineral oil, 12 mg, 0.30 mmol)and the mixture was stirred over night. Was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (73 mg, 99%).

MS m/z 490 [M+H]+, APCI(+)

Compound 4 was obtained in a manner analogous to the method for compound 11 of example 4.

MS m/z 400 [M+H]+, APCI(+)

Compound 5 was obtained in a manner analogous to the method for compound 12 example 4.

MS m/z 472 [M+H]+, APCI(+)

Compound 6 was obtained in a manner analogous to the method for compound 13 in example 4.

MS m/z 412 [M-H]-, ESI(-)

The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, Benz is sulfonate, maleate and the like of the present compounds can be obtained using standard stage of obtaining salts.

The compound of example 80 a sample of 300 was obtained according to the methods of obtaining 1-14 and the above examples and reference examples. The hydrobromide, hydrochloride,pair-toluensulfonate, methanesulfonate, bansilalpet, maleate and the like of the compounds of example 80 example 300 can be obtained by using the conventional stage of the formation of salts.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23
Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

These compounds included in the compound represented by the formula [I], and can be obtained according to methods of obtaining 1-14, the above examples and reference examples.

di[(2,2-dimethylpropanoate)methyl]({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({2-fluoro-4-[(5-what hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}methyl)phosphonate;

di[(2,2-dimethylpropanoate)methyl]({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}methyl)phosphonate;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({2-fluoro-4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}methyl)phosphonic acid;

diamid N,N'-bis[(etoxycarbonyl)methyl]({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}methyl)phosphonic acid;

diamide ,N'-bis[(etoxycarbonyl)methyl]({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3,5-dimethylphenoxy}methyl)phosphonic acid;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-2,6-dimethylbenzyl)-2-isopropylpyridine-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-2,6-dimethylbenzyl)-2-cyclohexylpiperidine-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-2,6-dimethylbenzyl)-2-cycloheptatrien-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-2,3,6-trimethylbenzyl)-2-isopropylpyridine-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-2,3,6-trimethylbenzyl)-2-cyclohexylpiperidine-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-2,3,6-trimethylbenzyl)-2-cycloheptatrien-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-3-fluoro-2,6-dimethylbenzyl)-2-isopropylpyridine-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-3-fluoro-2,6-dimethylbenzyl)-2-cyclohexylpiperidine-3-ol;

6-(4-{[4-(3-chlorophenyl)-2-oxido-1,3,2-dioxaphosphinan-2-yl]methoxy}-3-fluoro-2,6-dimethylbenzyl)-2-cycloheptatrien-3-ol;

3-{[4-({6-[(4-forfinal)(hydroxy)methyl]-5-hydroxypyridine-2-yl}methyl) - for 3,5-dimetilfenil]amino}-3-oxopropanoic acid;

3-{[4-({6-[(4-forfinal)(hydroxy)methyl]-5-hydroxypyridine-2-yl}methyl)-2,3,5-trimetilfenil]amino}-3-oxopropanoic acid;

3-{[2-fluoro-4-({6-[(4-forfinal)(hydroxy)methyl]-5-hydroxypyridine-2-yl}methyl) - for 3,5-dimetilfenil]amino}-3-oxopropanoic KIS the PTA;

{[4-({6-[(4-forfinal)(hydroxy)methyl]-5-hydroxypyridine-2-yl}methyl) - for 3,5-dimetilfenil]amino}(oxo)acetic acid;

{[4-({6-[(4-forfinal)(hydroxy)methyl]-5-hydroxypyridine-2-yl}methyl)-2,3,5-trimetilfenil]amino}(oxo)acetic acid;

{[2-fluoro-4-({6-[(4-forfinal)(hydroxy)methyl]-5-hydroxypyridine-2-yl}methyl) - for 3,5-dimetilfenil]amino}(oxo)acetic acid;

2-{4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl]-2,3,5-trimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{2-fluoro-4-[(5-hydroxy-6-isopropylpyridine-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3, 5dimethylphenyl}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

2-{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3, 5dimethylphenyl}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

Connect the texts of example 2-1 - example 2-17 received according to the methods of obtaining 1-14 and the above examples and reference examples.

Table 2-1

Table 2-2

Reference example 1

6-[(4-benzyloxy-2,6-dimethyl(phenylhydroxylamine]-2-chloro-3-methoxypiperidine

Connection 1 (CAS No. 199168-10-0, 344 mg, 1.15 mmol) was dissolved in toluene (8 ml)and the mixture was cooled to -78°C. was Slowly added dropwise n-utility (of 1.65 M hexane solution, 0.7 ml, 1.15 mmol)and the mixture was stirred for 30 minutes. Compound 2 (CAS No. 28924-92-7, 251 mg, 1.04 mmol) was dissolved in toluene (2 ml)and the mixture was added dropwise within 5 minutes. After stirring for 30 minutes the mixture was heated to room temperature. After 2 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. OST is OK purified column chromatography on silica gel, to obtain compound 3 (308 mg, 71%).

MS m/z 414/416 [M+H]+, APCI(+)

Reference example 2

4-benzyloxy-3-fluoro-2,6-dimethylbenzaldehyde

2-Fluoro-5-methylanisole (1,00 g, 7,14 mmol) and N,N,N',N”,N”-pentamethyldiethylenetriamine (1,36 g, 7.85 mmol) was dissolved in tetrahydrofuran (20 ml)and the mixture was cooled to -78°C. was Slowly added dropwisen-utility (1,20 M hexane solution, 6,55 ml, 7,86 mmol)and the mixture was stirred for 2 hours. Was slowly added dropwise iodine (3,63 g of 14.3 mmol)dissolved in tetrahydrofuran (4 ml)and the mixture was stirred for 30 minutes and warmed up to room temperature. Was added a saturated aqueous solution of sodium thiosulfate, and the mixture was extracted with ethyl acetate, the extract was washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (1.68 g, 88%). Compound 2 (1.68 g, of 6.31 mmol), potassium carbonate (2.20 g, 15.9 mmol) and trimethylboroxine (1.98 g, 15.8 mmol) was dissolved in dioxane (32 ml)and the mixture was purged with argon. Added complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (258 mg, 0,316 mmol)and the mixture is boiled under reflux. After stirring for 15 hours the mixture was cooled to room temperature, Phi is trevali through radiolite, and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (715 mg, 74%).

MS m/z 155 [M+H]+, APCI(+)

Connection 3 (714 mg, 4,63 mmol) was dissolved in methylene chloride, and the mixture was stirred, cooled to 0°C was added dropwise tribromide boron (a 1.0 M solution in methylene chloride, of 9.30 ml of 9.30 mmol). After stirring for 1 hour the mixture was heated to room temperature. Was added water, and the mixture was extracted twice with chloroform. The extract was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (434 mg, 69%).

MS m/z 139 [M-H]-, ESI(-)

Compound 4 (433 g, to 3.09 mmol) was dissolved in methylene chloride (6.5 ml) and methanol (4.3 ml) was added tribromide Tetra-n-butylamine (1.56 g, 3,24 mmol). After stirring for 2 hours was added water, and the mixture was extracted with diethyl ether. The extract was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (573 mg, 85%).

MS m/z 217/219 [M-H]-, ESI(-)

Compound 5 (571 mg, 2,61 mmol) was dissolved in acetonitrile (6.5 ml) was added benzylbromide (491 mg, 2,87 mmol) carbonate cesium (1.28 g, 3.93 mmol). After stirring for 2 hours was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (783 mg, 97%).

MS m/z 326/328 [M+NH4]+, APCI(+)

Compound 6 (782 mg, of 2.53 mmol) was dissolved in tetrahydrofuran (13 ml)and the mixture was cooled to -78°C. was Slowly added dropwise n-utility (1,2 M hexane solution of 3.16 ml, with 3.79 mmol)and the mixture was stirred for 10 minutes. Was slowly added dropwise N,N-dimethylformamide (555 mg, to 7.59 mmol)and the mixture was stirred for 10 minutes and warmed up to room temperature. Was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 7 (464 mg, 71%).

MS m/z 259 [M+H]+, APCI(+)

Reference example 3

6-(benzyloxy)-2,4-diethylnicotinamide

Compound 1 (10.0 g, a 49.5 mmol) and silver carbonate (27,3 g, a 99.0 mmol) was dissolved in N,N'-dimethylformamide (100 ml)was added benzylbromide (8,89 g, 52,0 mm is l), and the mixture was heated to 80°C. After stirring overnight the mixture was filtered through celite. Was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (12.5 g, 87%).

MS m/z 292/294 [M+H]+, APCI(+)

Compound 2 (5,00 g of 17.1 mmol) was dissolved in tetrahydrofuran (100 ml)and the mixture was cooled to -78°C. was Added dropwise within 10 minutes n-utility (2,6 M hexane solution of 7.24 ml, of 18.8 mmol)and the mixture was stirred for 15 minutes. Was added dropwise in small portions N,N'-dimethylformamide (6.25 g, 85.6 mmol)and the mixture was stirred for 1 hour and warmed up to room temperature. After stirring for 2 hours was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (of 3.06 g, 74%).

MS m/z 242 [M+H]+, APCI(+)

Reference example 4

2,6-dichloro-4-(diarylamino)phenol

Connection 1 (3,14 g, 17.6 mmol) suspended in dihormati is e (60 ml), and the suspension was cooled on ice. Was added triethylamine (2,68 g of 26.5 mmol) to obtain the solution to which was added p-toluensulfonate (3,36 g, 17.6 mmol). After stirring for 30 minutes was added saturated aqueous sodium bicarbonate, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (5.53 g, 94%).

MS m/z 332/334 [M+H]+, APCI(+)

Compound 2 (5.53 g, of 16.6 mmol) was dissolved in N,N'-dimethylformamide (30 ml), was added potassium carbonate (6.90 to g, to 49.9 mmol), sodium iodide (2.50 g, of 16.6 mmol) and allylbromide (4,84 g, 40.0 mmol)and the mixture was heated to 50°C. After stirring for 6.5 hours added allylbromide (2,42 g, 20.0 mmol). After stirring for 16.5 hours added allylbromide (2,42 g, 20.0 mmol)and the mixture was heated to 70°C. After stirring for 16.5 hours was added potassium carbonate (6.90 to g, to 49.9 mmol) and allylbromide (4,84 g, 40.0 mmol). After stirring for 22 hours the mixture was cooled to room temperature, filtered through celite and diluted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The remainder of the PTS is looking in column chromatography on silica gel, to obtain compound 3 (4.71 g, 69%).

MS m/z 412/414 [M+H]+, APCI(+)

Connection 3 (1.08 g, 2,62 mmol) was dissolved in methanol (9 ml), was added potassium hydroxide (1.47 g, to 26.2 mmol), and the mixture was heated to 70°C. After stirring for 20 minutes the mixture was cooled to room temperature and neutralized 6N chloroethanol acid. After extraction with ethyl acetate, the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 4 (575 mg, 85%).

MS m/z 258/260 [M+H]+, APCI(+)

Reference example 5

4-(allyloxy)-2,6-dibromo-3-forbindelse

Connection 1 (of 5.00 g of 13.8 mmol) was dissolved in acetonitrile (25 ml) and was added dropwise a cooled on ice, mixed solution of sulfuric acid (25 ml) and water (25 ml) for 15 minutes. After stirring for 20 minutes was added dropwise over 7 minutes, chilled on ice, mix a solution of sodium nitrite (1,71 g of 24.8 mmol) and water (15 ml). After stirring for 15 minutes the mixture was added to a mixed solution of potassium iodide (8.00 g, 48.2 mmol) and water (25 ml). After stirring for 50 minutes was added water, and the mixture was extracted with chloroform. The organic layer was washed saturated the aqueous solution of sodium carbonate, saturated aqueous sodium thiosulfate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (ceiling of 5.60 g, 86%).

MS m/z 490/492/494 [M+NH4]+, APCI(+)

Compound 2 (5,08 g of 10.7 mmol) was dissolved in methanol (40 ml) and, after cooling on ice, was added 5N aqueous sodium hydroxide solution (to 6.43 ml, to 32.2 mmol)and the mixture was heated to room temperature. After stirring for 1 hour the mixture was concentrated. The residue was acidified using 1N chloroethanol acid. After extraction with ethyl acetate the organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (Android 4.04 g, 95%).

MS m/z 393/395/397 [M-H]-, ESI(-)

Connection 3 (Android 4.04 g, 10.2 mmol) was dissolved in acetonitrile (50 ml) was added cesium carbonate (6,65 g of 20.4 mmol) and allylbromide (1.85 g, and 15.3 mmol). After stirring for 4 hours the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 4 (to 3.92 g, 88%).

Compound 4 (to 3.92 g, 8,99 mmol) was dissolved in N,N'-dimethylformamide (30 ml)was added CYANOGEN is on copper (1,61 g, 18.0 mmol) and L-Proline (1.04 g, 8,99 mmol)and the mixture was heated to 80°C. After stirring for 24 hours the mixture was cooled to room temperature. Added ethyl acetate and aqueous ammonia, and the mixture is vigorously stirred. After 30 minutes was added a saturated salt solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (2,43 g, 81%).

Compound 5 (1.18 g, of 3.53 mmol) was dissolved in toluene (20 ml) and, after cooling on ice, was added dropwise within 5 minutes diisobutylaluminum (1M toluene solution, 5,28 ml, 5,28 mmol). After stirring for 50 minutes, was added dropwise methanol, and the mixture was cooled to room temperature. Added a 1M sulfuric acid (50 ml) and ethyl acetate (100 ml)and the mixture vigorously stirred. After 1 hour the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (1.04 g, 87%).

MS m/z 351/353/355 [M+H+MeOH-H2O]+, APCI(+)

Reference example 6

2-cyclohexyl-6-iodine-3-(metaxiotis and)pyridine

Connection 1 (charged 8.52 g, 48.1 mmol) suspended in acetonitrile (160 ml) and water (30 ml), was added sodium iodide (8.65 g, 57,7 mmol)and the mixture was cooled on ice. Was added sodium hydroxide (1.92 g, 48.1 mmol) to obtain the solution to which was added dropwise within 15 minutes with 5% aqueous sodium hypochlorite solution (71,6 ml, 48.1 mmol). After stirring for 10 minutes the mixture was heated to room temperature. After stirring for 50 minutes, was added dropwise over 5 minutes with 5% aqueous sodium hypochlorite solution (21,5 ml, 14.4 mmol). After stirring for 15 minutes was added dropwise over 5 minutes with 5% aqueous sodium hypochlorite solution (21,5 ml, 14.4 mmol). After stirring for 20 minutes was added dropwise within 5 minutes sodium iodide (2.16 g, 14.4 mmol) was added 5% aqueous sodium hypochlorite solution (21,5 ml, 14.4 mmol). After stirring for 20 minutes was added dropwise over 5 minutes with 5% aqueous sodium hypochlorite solution (14,3 ml, being 9.61 mmol). After stirring for 15 minutes, the mixture was neutralized 6N chloroethanol acid, concentrated and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. About who headed the remainder of the purified column chromatography on silica gel, to obtain compound 2 (9,46 g, 65%).

MS m/z 304 [M+H]+, APCI(+)

Compound 2 (9,46 g, and 31.2 mmol) was dissolved in acetonitrile (80 ml) and tetrahydrofuran (80 ml), was added cesium carbonate (15.3 g, 46.8 mmol) and chloromethylation ether (3,01 g, or 37.4 mmol). After stirring for a period of 14.5 hours added chloromethylation ether (1,00 g, 12.5 mmol). After stirring for 1.5 hours the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 3 (10.2 g, 94%).

MS m/z 348 [M+H]+, APCI(+)

Reference example 7

4-(allyloxy)-2,6-dichloro-3-forbindelse

Connection 1 (431 mg, 2.10 mmol) was dissolved in dichloromethane (11 ml) and, after cooling on ice, was added dropwisetert-butylhypochlorite (456 mg, 4.20 mmol). After stirring for 30 minutes was added dropwisetert-butylhypochlorite (46 mg, 0,420 mmol). After stirring for 20 minutes was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 2 (475 mg, 82%).

MS m/z 274/276/278 [M+H]+, APCI(+)

Compound 2 (472 mg, 1,72 mmol) was dissolved in acetonitrile (3 ml)and the mixture was added dropwise during 5 minutes to a cooled on ice, mixed solution of sulfuric acid (3 ml) and water (3 ml). After stirring for 10 minutes was added dropwise over 2 minutes, chilled on ice, mix a solution of sodium nitrite (214 mg, 3.10 mmol) and water (1.5 ml). After stirring for 20 minutes, the mixture was added directly to cooled on ice to a solution of potassium iodide (1,00 g, 6,03 mmol) and water (3 ml). After stirring for 5 minutes the mixture was heated to room temperature. After stirring for 45 minutes was added water, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium carbonate, saturated aqueous sodium thiosulfate and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (563 mg, 85%).

Connection 3 (560 mg, 1,45 mmol) was dissolved in methanol (7 ml)was added 5N aqueous sodium hydroxide solution (1,45 ml, 7,27 mmol). After stirring for 1 hour the mixture was concentrated. The residue was dissolved in water and brought the pH to 2 6N chloroethanol acid. The resulting residue was collected by filtration, washed Ho is one with water and dried to to obtain compound 4 (434 mg, 97%).

MS m/z 305/307 [M-H]-, ESI(-)

Compound 4 (432 mg, of 1.41 mmol) was dissolved in acetonitrile (10 ml) was added cesium carbonate (1,38 g, 4,22 mmol) and allylbromide (255 mg, 2,11 mmol). After stirring for 6 hours the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 5 (458 mg, 94%).

Compound 5 (455 mg, 1,31 mmol) was dissolved in toluene (13 ml)and the mixture was cooled to -78°C. was Added dropwise over 3 minutes n-utility (of 1.65 M hexane solution, 0,874 ml, 1.44 mmol). After stirring for 15 minutes, was added dropwise N,N'-dimethylformamide (0,479 g, 6,56 mmol). After stirring for 10 minutes the mixture was heated to room temperature. After stirring for 1 hour was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 6 (167 mg, 51%).

MS m/z 263/265 [M+H+MeOH-H2O]+, APCI(+)

Reference example 8

4-(benzyloxy)-2,6-diethyl-3-forbindelse

Connection 1 (640 mg, at 1.91 mmol) was dissolved in tetrahydrof the wound (20 ml) was added N-methylmorpholine (250 mg, 2,87 mmol) and tetranitropentaerithrite (0) (110 mg, 0,0955 mmol). After stirring for 20 minutes the mixture was concentrated. The residue was dissolved in ethyl acetate. The organic layer was washed 1H chloroethanol acid and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in acetonitrile (20 ml) was added cesium carbonate (1,87 g, 5,73 mmol) and benzylbromide (490 mg, 2,87 mmol). After stirring for 16 hours the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 2 (601 mg, 82%).

Compound 2 (299 mg, 0,777 mmol) was dissolved in dimethoxyethane (8 ml) was added water (0.8 ml), cesium carbonate (1.52 g, of 4.66 mmol) and pinacolone ether of vinylboronic acid (598 mg, 3.88 mmol)and the mixture was purged with argon. Added tetranitropentaerithrite (0) (179 mg, 0,155 mmol)and the mixture was heated to 90°C. After stirring for 16 hours was added water (0.8 ml), pinacolyl ether of vinylboronic acid (299 mg, 1.94 mmol) and tetranitropentaerithrite (0) (90 mg, 0,0777 mmol). After stirring for 8 hours the mixture was cooled to room temperature, was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed nasionalisme solution was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 3 (129 mg, 59%).

MS m/z 280 [M+H]+, APCI(+)

Connection 3 (126 mg, 0,451 mmol) was dissolved in tetrahydrofuran (5 ml) and, after purging with argon, was added to the complex of palladium on coal and Ethylenediamine (13 mg). After purging with hydrogen, the mixture was stirred for 6 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was dissolved in tetrahydrofuran (5 ml) and, after purging with argon was added palladium complex on the corner and ethylene diamine (40 mg). After purging with hydrogen, the mixture was stirred for 14 hours, filtered through celite and thoroughly washed with ethyl acetate. The filtrate was concentrated, and the residue was dissolved in acetonitrile (5 ml) was added cesium carbonate (441 mg, 1.35 mmol) and benzylbromide (77 mg, 0,451 mmol). After stirring for 4 hours the mixture was filtered through celite. The filtrate was concentrated, and the residue was purified column chromatography on silica gel to obtain compound 4 (113 mg, 88%).

MS m/z 284 [M+H]+, APCI(+)

Compound 4 (214 mg, 0,755 mmol) was dissolved in toluene (4 ml) and, after cooling on ice, was added dropwise over 3 minutes diisobutylaluminum (1 M toluene solution of 1.13 ml, 1,13 the mol). After stirring for 1 hour was added dropwise over 3 minutes diisobutylaluminum (1 M toluene solution of 1.13 ml, 1.13 mmol). After stirring for 25 minutes, was added dropwise diisobutylaluminum (1 M toluene solution, 0,755 ml, 0,755 mmol). After stirring for 20 minutes was added dropwise methanol, and the mixture was cooled to room temperature. Added a 1M sulfuric acid and ethyl acetate, and the mixture is vigorously stirred. After 1 hour, was added 50% sulfuric acid and 6N chloroethanol acid, and the mixture is vigorously stirred. After standing for one night, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified column chromatography on silica gel to obtain compound 5 (54 mg, 25%).

MS m/z 287 [M+H]+, APCI(+)

Compounds of reference example 9 and reference example 27 was obtained according to the methods of obtaining 1-14 and the above examples and reference examples.

Table 3-1

Experimental example

Test to activate transcription of receptors in human thyroid hormone α1 (TRα1) and β1 (TRβ1)

pcDNA3.1 vector (obtained from Invitrogen), which expresses TRα1 or β1, cloned from human liver cells, and the expression vector luciferase Firefly pDR4-LuC (obtained from Stratagene), containing a signal sequence for thyroid hormone, which is a reporter, was transferrable in 293T cells grown in modified according to the method of Dulbecco environment Needle (DMEM)containing a mixture of 10% charcoal treated with dextran fetal bovine serum (FBS), the use of lipofectamine 2000 (obtained from Invitrogen). After 16 hours the cells were again placed in a 96-well plate, and the medium was replaced with DMEM containing a mixture of 0.1% activated charcoal treated with dextran FBS. After 3 hours was added compound, diluted dimethylsulfoxide solution, and measured after 24 hours, luciferase activity.

As a positive control was used 3,3',5-triiodothyronine-L-Tronin (T3), which is a biological ligand. Activating the transcription of the effect of compounds on TRα1 and TRβ1 was reflected each EC50value and the maximum mn is the increase in luciferase activity relative to the minimum value of luciferase activity T 3in the form of 100. The results are shown in the following tables.

Table 4-1
ExampleTRβ (µm)Selectivity
10,003B
20,002B
30,02A
40,0005B
50,0005A
60,05B
70,001A
80,05A
90,007C
100,03B
110,001B
2 0,0007B
130,0003A
140,01B
150,009B
160,02B
170,02B
182C
190,005B
200,004C
210,03B
220,2A
230,01A
240,03B
250,001C
260,006 C
270,0003C
28is 0.0002C
290,002A
300,002A

Table 4-2
ExampleTRβ (µm)Selectivity
31is 0.0002B
320,0004B
330,008B
340,0004B
350,009B
360,003C
370,0001B
41 0,004B
420,3B
440,2B
450,005A
520,006A
540,006A
600,0006A
620,004B
640,08B
650,01A
73is 0.0002A
800,1B
810,0001B
920,001A
1070,01 C
1170,002B
1180,02B
1310,004A
1360,001C
1520,005B
1710,002A
1730,0004A
1910,006A
2060,003A

Table 4-3
ExampleTRβ (µm)Selectivity
2160,004A
2360,003A
2560,003 A
2680,001B
2690,0007A

selectivity (TRα/TRβ):

A: 5<(TRα/TRβ)

B: 2<(TRα/TRβ)<5

C: 2>(TRα/TRβ)

Industrial applicability

Heterocyclic derivative of the present invention has an agonistic effect in relation to β receptor, thyroid hormone, and it can be a drug, is effective for prevention or treatment of diseases associated with this action.

This application is based on patent application No. 2009-102259 entered in the register in Japan, the content of which is inserted fully in the present invention.

1. The compound represented by the formula [I]:

where
A represents a
optionally substituted alkyl, where the Deputy optionally substituted alkyl for A represents the same or different 1-3 groups selected from
aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy and alkanoyl;
cycloalkyl, optionally substituted by 1-3 groups selected from alkyl and halogen;
hydroxy;
alkoxy;
halogen;
the amino and
oxo;
optional substituted the th carbocyclic group, selected from a monocyclic group and a bicyclic group condensed aromatic ring and cycloalkyl,
optionally substituted aryl,
optionally substituted heterocyclic group, which is a 5 - or 6-membered monocyclic heterocyclic group, fully saturated, each of which contains 1 heteroatom selected from nitrogen and oxygen,
where the Deputy optionally substituted aryl, optionally substituted carbocyclic group and optionally substituted heterocyclic group for A is the same or different 1-3 groups selected from
the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;
cycloalkyl, optionally substituted by alkyl or alkoxy;
alkoxy, optionally substituted with halogen;
halogen;
hydroxy;
oxo;
heterocycle;
alkylsulfonyl and
mono - or dialkylamino,
optionally substituted amino, where the Deputy optionally substituted amine to A represents the same or different 1 or 2 alkyl or aryl, or
optionally substituted carbarnoyl, where Deputy optionally substituted of carbamoyl for A represents the same or different 1 or 2 alkyl, optionally substituted aryl,
X is an optional what about the substituted methylene or-O-, where the Deputy optionally substituted methylene X represents an alkoxy or hydroxy,
Q represents N or C-R4,
L1represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or-CH2NR11-,
L2represents a single bond, -CR6R7- or divalent heterocyclic group, where the heterocyclic group is a 5 - or 6-membered monocyclic heterocyclic group, fully saturated, each of which contains 1 heteroatom selected from nitrogen and oxygen,
R1and R2are the same or different and each represents hydrogen, alkyl or halogen,
R3and R4are the same or different and each represents hydrogen, alkyl, alkoxy, cyano or halogen,
R1and R3not necessarily connected, forming carbocycle, which represents a 5 - or 6-membered cycloalkyl, or heterocycle, which is a 5 - or 6-membered aliphatic heterocycle containing an oxygen atom,
R5represents a carboxyl group, alkoxycarbonyl group or bioisostere group, carboxyl group,
R6and R7are the same or different and each represents hydrogen or alkyl, or
R6The R 7connected to become cycloalkane,
R8represents hydroxy, alkanolamine or alkylsulfonamides,
R9and R10represent hydrogen or halogen, and
R11represents hydrogen or alkyl,
or its pharmacologically acceptable salt.

2. The compound according to claim 1, where A is a
optionally substituted alkyl, where the Deputy optionally substituted alkyl for A represents the same or different 1-3 groups selected from
aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy and alkanoyl;
cycloalkyl, optionally substituted by 1-3 groups selected from alkyl and halogen;
hydroxy;
alkoxy;
halogen;
the amino and
oxo,
optionally substituted carbocyclic group selected from a monocyclic group and a bicyclic group condensed aromatic ring and cycloalkyl,
optionally substituted aryl, or
optionally substituted heterocyclic group, which is a 5 - or 6-membered monocyclic heterocyclic group, fully saturated, each of which contains 1 heteroatom selected from nitrogen and oxygen,
where the Deputy optionally substituted aryl, optionally substituted carbocyclic group and optional samisen the th heterocyclic group for A is the same or different 1-3 groups selected from
the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;
cycloalkyl, optionally substituted by alkyl or alkoxy;
alkoxy, optionally substituted with halogen;
halogen;
hydroxy;
oxo;
heterocycle;
alkylsulfonyl and
mono - or dialkylamino,
Q represents C-R4,
R1and R2are the same or different, and each represents alkyl or halogen,
R3and R4are the same or different and each represents hydrogen, alkyl or halogen,
X represents a methylene or-O-,
R5represents a carboxyl group, alkoxycarbonyl group or bioisostere group, carboxyl group,
L1represents a single bond, methylene, -CH=CH-, -O-, -NH -, or-NHCO-,
L2represents a single bond, -CR6R7- or divalent heterocyclic group, where the heterocyclic group is a 5 - or 6-membered monocyclic heterocyclic group, fully saturated, each of which contains 1 heteroatom selected from nitrogen and oxygen,
R6and R7are the same or different and each represents hydrogen or alkyl, or R6and R7form cycloalkane together with the neighboring carbon atom,br/> R8represents hydroxy, and
R9and R10represent hydrogen, or its pharmacologically acceptable salt.

3. The compound according to claim 1 or 2, where A represents an optionally substituted carbocyclic group selected from a monocyclic group and a bicyclic group condensed aromatic ring and cycloalkyl where the Deputy optionally substituted carbocyclic group for A is the same or different 1-3 groups selected from
the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;
cycloalkyl, optionally substituted by alkyl or alkoxy;
alkoxy, optionally substituted with halogen;
halogen;
hydroxy;
oxo;
heterocycle;
alkylsulfonyl and
mono - or dialkylamino, or its pharmacologically acceptable salt.

4. The compound according to claim 1 or 2, where A represents an optionally substituted aryl, where the Deputy optionally substituted aryl for A represents the same or different 1-3 groups selected from
the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;
cycloalkyl, optionally substituted by alkyl or alkoxy;
alkoxy, optionally substituted with halogen;
halogen;
hydroxy;
oxo;
heterocycle;
alkylsulfonic is and
mono - or dialkylamino, or its pharmacologically acceptable salt.

5. The compound according to claim 3, where the optionally substituted carbocyclic group is cycloalkyl, which may be substituted by same or different 1 to 3 groups selected from
the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;
cycloalkyl, optionally substituted by alkyl or alkoxy;
alkoxy, optionally substituted with halogen;
halogen;
hydroxy;
oxo;
heterocycle;
alkylsulfonyl and
mono - or dialkylamino, or its pharmacologically acceptable salt.

6. The compound according to claim 1 or 2, where A represents an optionally substituted alkyl, where the Deputy optionally substituted alkyl for A represents the same or different 1-3 groups selected from
aryl, optionally substituted by 1-3 groups selected from alkyl, halogen, alkoxy and alkanoyl;
cycloalkyl, optionally substituted by 1-3 groups selected from alkyl and halogen;
hydroxy;
alkoxy;
halogen;
the amino and
oxo, or its pharmacologically acceptable salt.

7. The compound according to claim 1 or 2, where A represents an optionally substituted heterocyclic group, which is a 5 - or 6-membered monocyclic heterocyclic group, completely is a rich, each of which contains 1 heteroatom selected from nitrogen and oxygen,
where the Deputy optionally substituted carbocyclic group for A is the same or different 1-3 groups selected from
the alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen;
cycloalkyl, optionally substituted by alkyl or alkoxy;
alkoxy, optionally substituted with halogen;
halogen;
hydroxy;
oxo;
heterocycle;
alkylsulfonyl and
mono - or dialkylamino, or its pharmacologically acceptable salt.

8. The compound according to claim 1, where X represents methylene, or its pharmacologically acceptable salt.

9. The compound according to claim 1, where R1and R2are the same groups, or its pharmacologically acceptable salt.

10. The compound according to claim 1, where R1and R2are the same or different, and each represents alkyl, or its pharmacologically acceptable salt.

11. The compound according to claim 1, where R1and R3connected, forming carbocycle, which represents a 5 - or 6-membered cycloalkyl, or heterocycle, which is a 5 - or 6-membered aliphatic heterocycle containing an oxygen atom, or its pharmacologically acceptable salt.

12. The compound according to claim 1, where R8represents hydroxy, or pharmacolo the automatic acceptable salt.

13. (4-{[5-Hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)acetic acid;
{4-[(6-cyclopentyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid;
{4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid;
{2-bromo-4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimethylphenoxy}acetic acid;
3-({4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid;
3-({4-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid;
3-[(4-{[5-hydroxy-6-(2-naphthyl)pyridin-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he;
3-[(4-{[5-hydroxy-6-(5,6,7,8-tetrahydronaphthalen-2-yl)pyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he;
({5-[(6-cyclohexyl-5-hydroxypyridine-2-yl)methyl]-3,4,6-trimethylpyridine-2-yl}oxy)acetic acid;
3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl] - for 3,5-dimetilfenil}amino)-3-oxopropanoic acid;
N-[2-chloro-4-(6-cyclohexyl-5-hydroxypyridine-2-ylmethyl)for 3,5-dimetilfenil]amino-3-oxopropanoic acid;
3-[(2-fluoro-4-{[6-(2-fluoro-3-were)-5-hydroxypyridine-2-yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he;
{4-[(6-cyclohexyl-4-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid;
{4-[(6-cyclohexyl-3-fluoro-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}of uksosn the I acid;
{4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2,3,5-trimethylpentane}acetic acid;
3-({4-[(6-cycloheptyl-5-hydroxypyridine-2-yl)methyl]-2-fluoro-3, 5dimethylphenyl}amino)-3-oxopropanoic acid;
{4-[6-(3-forfinal)-5-hydroxypyridine-2-ylmethyl]-2,3,5-trimethylpentane}acetic acid;
(4-{[6-(3-chlorophenyl)-5-hydroxypyridine-2-yl]methyl}-2,3,5-trimethylpentane)acetic acid;
3-{2-fluoro-4-[5-hydroxy-6-(2,3,4-tryptophanyl)pyridine-2-ylmethyl]for 3,5-dimethylphenoxy}-1,2,4-oxadiazol-5(4H)-he;
3-[(2-fluoro-4-{[5-hydroxy-6-(3-pyrrolidin-1-ylphenyl)pyridine-2 - yl]methyl} - for 3,5-dimethylphenoxy)methyl]-1,2,4-oxadiazol-5(4H)-he;
2-{4-[(5-hydroxy-6-vinylpyridin-2-yl)methyl] - for 3,5-dimetilfenil}is 3.5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;
3-{2-fluoro-4-[5-hydroxy-6-(3-propoxyphenyl)pyridine-2-ylmethyl]for 3,5-dimethylphenoxy}-1,2,4-oxadiazol-5(4H)-he;
[3,5-dibromo-2-fluoro-4-(5-hydroxy-6-vinylpyridin-2-ylmethyl)phenoxy]acetic acid;
(5-ethyl-4-{[6-(3-forfinal)-5-hydroxypyridine-2-yl]methyl}-2,3-dimethylphenoxy)acetic acid, or a pharmacologically acceptable salt.

14. Drug with agonistic action on the β receptor thyroid hormone containing compound according to any one of claims 1 to 13, or its pharmacologically acceptable salt as an active ingredient.

15. Drug for 14 for the treatment or prevention hyperbole is teinemia, hyperlipidemia, hypertriglyceridemia, familial hypercholesterolemia, dyslipidemia, atherosclerosis, hypothyroidism and/or latent hypothyroidism.

16. The use of compounds according to any one of claims 1 to 13 for obtaining a medicinal product for the treatment or prevention of disease, which is facilitated by the activation of β receptor thyroid hormone.

17. Method for the treatment or prevention of disease, which is facilitated by the activation of β receptor thyroid hormone, which comprises introducing the compound according to any one of claims 1 to 13.

18. The compound represented by the formula [II]:

where Z1and Z2are the same or different, and each represents-O-PG (PG represents a protective group),
Z3represents A or halogen,
Xarepresents oxygen or a group represented by

where RXrepresents hydroxyl, optionally protected by a protective group, and other symbols are the same as in claim 1, or its salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula its stereoisomers, including R and S isomers, wherein: 'A' represents N; Y and Y' represent O; '---' is absent; R1 and R2 are identical or different, and independently represent hydrogen or C1-12 alkyl; R3 represents hydrogen; R4 represents heteroaryl which can be optionally substituted in any acceptable position by one or more substitutes Ra; Z represents -(CH2)n-heteroaryl which can be optionally substituted in any acceptable position by one or more substitutes Ra; T, U, V and W are identical or different, and independently represent hydrogen or halogen; Ra is independently specified in hydrogen, halogen, C1-12 alkyl, C1-12 haloalkyl, -C(=Y)OR7, -(CH2)nYR7, each of which can be optionally substituted in any acceptable position by halogen; R7 represents hydrogen or C1-12 alkyl; m represents 1; m′ represents 0; n represents 1; wherein: the above heteroaryl is specified in 1,2,3-triazolyl, pyridinyl, 1-oxypyridinyl (pyridinyl-N-oxide), pyrazinyl, isoxazolyl, imidazo[1,2-α]pyrimidinyl, imidazo[1,2-α]pyrazinyl. The compounds of the given invention are applicable to prevent, relieve and/or treat bacterial infections in an individual. The bacterial infection is caused by the drug-resistant species Staphylococcus, Streptococcus, Enterococcus, Bacterioides, Clostridia, H. influenza, Moraxella, acid-resistant species like Mycobacterium tuberculosis, as well as linezolid-resistant species Staphylococcus and Enterococcus.

EFFECT: phenyloxazolidinone compounds as antimicrobial agents.

12 cl, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel indole and benzomorpholine derivatives of a formula (I) or its pharmaceutically acceptable salt, where R1 represents C1-6-alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 represents halogeno; R3 represents hydrogen; n equals 2, X represents -CH2CH2-O or -CH=CH-; Y represents -O- or -CR4(OH)-; R4 represents hydrogen or C1-3 alkyl. Invention also relates to a pharmaceutical composition based on formula (I) compound and a method of treatment or prevention of the said pathological states.

EFFECT: obtained are novel compounds, which are positive allosteric modulators of matabotropic subtype 2 receptors (mGluR2), which are useful for treatment or prevention of neurological and psychiatric disorders, associated with glutamate dysfunction, and diseases, involving metabotropic subtype 2 receptors GluR2.

22 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: biotechnologies.

SUBSTANCE: in a compound of formula ,

X means N or CH, R1 means hydrogen or cyano, R2 means saturated 4-7-membered residue of heterocyclyl, which is bound through a nitrogen atom that contains 1 to 2 heteroatoms chosen from N and O. Besides, heterocyclyl residue can be replaced with one substituent chosen from a group consisting of C3-C6-cycloalkyl, or with 1-4 fluorine atoms. The invention also refers to a method for obtaining compounds and to a medicine on their basis.

EFFECT: compounds can be used for production of a medicine suitable for being used in a method of treatment or prophylaxis of cardiovascular diseases, cardiac insufficiency, anemia, chronic diseases of kidneys and kidney failure.

16 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to methods of treating or relieving severity of disease in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease. Methods include introduction of effective amount of N-(5-hydroxy-2,4-di-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide or pharmaceutical composition, containing said compound, to patient.

EFFECT: treatment of relief of disease severity in patient, where disease is selected from mucoviscidosis, hereditary emphysema, chronic obstructive pulmonary disease (COPD), "dry eye" disease.

16 cl, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of organic chemistry, namely to compounds of the general formula I , and its pharmaceutically acceptable salts, where R1, R2 and R3 represent hydrogen, D, E, G, J and L represent CH; n equals to an integer number 1 or 2; W represents oxygen; R4 represents C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkenyl, where the said C1-6alkyl is possibly substituted with one substituent, independently selected from a group, consisting of hydrogen, C1-4alkyl, C3-6cycloalkyl and C3-6cycloalkenyl; Y represents carbonyl; R5 represents C1-6alkyl, C1-6alkoxy or C3-4heteroaryl, which represents a heterocyclic aromatic ring, containing 1-2 heteroatoms, selected from nitrogen and oxygen. The invention also relates to a pharmaceutical composition based on a formula I compound, application of the formula I compound and a method of prevention, treatment of alleviation of a disease, associated with abnormal angiogenesis.

EFFECT: obtained are novel compounds useful in treatment of diseases associated with unregulated angiogenesis, such as cancer, as well as skin and eye diseases.

13 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel fungicidally active 5-fluoropyrimidines of general formula I. In compounds of formula , R1 is -N(R3)R4; R2 is -OR21; R3 is: H; C1-C6-alkyl, optionally substituted with 1-3 groups R5; C2-C6-alkenyl, optionally substituted with 1-3 groups R5; a 5- or 6-member heteroaromatic cycle, selected from a group consisting of furanyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, triazolyl; wherein each heteroaromatic cycle is optionally substituted with 1-3 R29 groups; 3H-isobenzofuran-1-oyl; -C(=O)R6; -C(=S)R6; -C(=S)NHR8; -(=O)N(R8)R10; -OR7; -P(O)(OR15)2; -S(O)2R8;-SR8; -Si(R8)3; -N(R9)R10; -(CHR24)mOR29 or -C(=NR16)SR16; where m equals an integer from 1 to 3; R4 is: H; C1-C6-alkyl, optionally substituted with 1-3 R5 groups; or -C(=O)R6; alternatively, R3 and R4 together can form: a 5- or 6-member saturated or unsaturated cycle containing 1-2 heteroatoms selected from N and O, where each cycle can be optionally substituted with 1-3 R11 groups; =C(R12)N(R13)R14 or =C(R15)OR15. The rest of the radicals are given in the claim.

EFFECT: obtaining novel fungicidally active 5-fluoropyrimidines of general formula I.

4 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using an oxadiazolyl compound of the formula I

,

wherein R1 and R2 mean hydrogen; X means a methylene group; Y represents an oxygen atom; n represents an integer of 0, 1, 2 or 3, and m represents an integer of 0 or 1; R3 means a group of N-oxide pyridine according to the formula B which is attached as shown by an unmarked bond: ,

wherein R4, R5, R6 and R7 are the same or different and mean hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl; the term "alkyl" means carbon chains, unbranched or branched, containing one to six carbon atoms; the term "halogen" means fluorine, chlorine, bromine or iodine; or its pharmacologically acceptable salt for preparing a drug for preventing or treating diseases related to the central and peripheral nervous system, wherein the above drug is administered according to a dosage regimen characterised by a dosage rate within approximately twice a day to approximately once every two days.

EFFECT: optimising the dosage regimen.

84 cl, 3 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

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