Heterocyclic methylsulfonic derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where R1 represents phenyl group, containing 1-3 substitutes, selected from halogen and cyano group; R2 represents pyridyl group, which has 1-3 substitutes, selected from monocyclic or polycyclic heterocyclic group, which can have 1-3 substitutes, selected from halogen atoms, cyanogroup, as well as other values of R2 radical, given in formula of invention, R3 represents phenyl group or pyridyl group, which has 1-2 substitutes, selected from halogen and trihalogenmethyl group; R4 represents hydrogen atom; and X represents -SO2-; its salt or its solvate. As well as to medication and pharmaceutical composition, inhibiting production or secretion of β-amyloid protein, and containing compound of formula (I), and to application of compound of pt.1 in order to obtain medication.

EFFECT: obtaining novel compounds, inhibiting production or secretion of β-amyloid protein.

14 cl, 1 tbl, 296 ex

 

The present invention relates to new compounds with inhibitory activity against the production and secretion β-amyloid protein; and a drug for the treatment of various diseases caused by abnormal production or secretion β-amyloid protein such as Alzheimer's disease, down's syndrome and other diseases associated with amyloid deposits.

Alzheimer's disease is a neurodegenerative disease with pathological features, such as degeneration or loss of nerve cells, the formation of senile plaques and neurofibrillary plexus. Alzheimer's disease causes symptoms of dementia, such as the gradual loss of memory, ability to recognize, thinking, reasoning, etc. and, ultimately, leads to death. Up to the present time was not known effective method for the treatment or prevention of this disease.

The main protein, forming senile plaques, deposits which occur in the brain, is β-amyloid protein (amyloid βprotein, Aβ), which consists of 39-43 amino acids. β-Amyloid protein shows cytotoxicity, which are believed to cause Alzheimer's disease (non-patent document 1). β-Amyloid protein, the secretory cells, is the second polypeptide, consisting mainly of 40 or 42 amino acids, and, in particular, it is known that in the brain there is a rapid deposition of that protein, which consists of 42 amino acids, due to its high capacity for aggregation and, in addition, he has a strong cytotoxicity (non-patent document 2). β-Amyloid protein is produced everywhere in vivo, but its function remains unknown.

β-Amyloid protein is formed by processing the amyloid protein precursor (APP), which is a membrane protein. The APP gene mutation observed in patients with hereditary Alzheimer's disease. It is known that increasing the number produced or secreted β-amyloid protein occurs in cells, in which was included with this mutated APP gene. This suggests that the drug inhibiting the production or secretion β-amyloid protein, should be effective for prevention or treatment of Alzheimer's disease.

With regard to the stage of processing of the amyloid protein precursor for producing β-amyloid protein, was reported BACE (chip off the enzyme β-APP) (non-patent document 3) or Asp1 (non-patent document 4), each representing asparaginases, as β-secretase for removal of N-end β-amyl is odnogo protein. There are very reasonable assumption that γ-secretase, which it C-terminal site, consists partly presenilin (non-patent document 5). Although there were news about the inhibitors β-secretase and γ-secretase (non-patent document 6), most of them are peptideprophet connections.

In patent document 1, SMITH and others, are disclosed compounds having sulfonamidnuyu structure and able to control production β-amyloid protein. In patent document 2, BELANGER and others, are disclosed compounds having bicycloalkanes structure and inhibiting γ-secretase. Also in patent documents 3, 4 and 5 revealed diarylamino compounds that inhibit γ-secretase. In patent document 6 reveals tianeptine derivatives inhibiting the aggregation of amyloid protein.

Non-patent document 1: Science,259, 514 (1993).

Non-patent document 2: Journal of Biological Chemistry,270, 7013 (1995).

Non-patent document 3: Science,286, 735 (1999).

Non-patent document 4: Molecular and Cellular Neuroscience,16, 609 (2000).

Non-patent document 5: Journal of Medicinal Chemistry,44, 2039 (2001).

Patent document 1: WO00/50391.

Patent document 2: WO01/70677.

Patent document 3: WO02/081433.

Patent document 4: WO02/081435.

Patent document 5: WO03/18543.

Patent document 6: JP-A-1997-5444.

The purpose of this invention is to provide compounds having a different structure from the structure of the above known compounds which have inhibitory activity against the production or secretion β-amyloid protein, and which possess the desired properties as pharmaceuticals.

The authors of this invention have conducted various studies. As a result, it was found that heterocyclic methylthiazolidine, heterocyclic methylsulfonate compounds and heterocyclic methylsulfonate compounds represented by the following formula (1), have excellent inhibitory activity against the production or secretion β-amyloid protein and therefore are useful as medicines for the treatment of various diseases resulting from abnormal production or secretion β-amyloid protein, which led to the creation of the present invention.

Thus, the present invention presents a compound represented by the formula (1):

[Chemical formula 1]

(where R1and R3each independently represents an aromatic hydrocarbon group which may have a Deputy, or an aromatic heterocyclic group which may and the geta Deputy, R2represents a saturated or unsaturated monocyclic heterocyclic group or unsaturated polycyclic heterocyclic group, which may have a Deputy, R4represents a hydrogen atom or a C1-6alkyl group and X represents-S-, -SO - or-SO2-); its N-oxide or S-oxide; its salt or its MES.

The present invention also relates to a pharmaceutical preparation containing as active ingredient a compound represented by the formula (1); its N-oxide or S-oxide; its salt or its MES.

The present invention also relates to pharmaceutical compositions containing the compound represented by formula (1), its N-oxide or S-oxide; its salt or its MES; and a pharmaceutically acceptable carrier.

The present invention also relates to the use of compounds represented by formula (1), its N-oxide or S-oxide, its salts or its MES to obtain drugs.

The present invention also relates to a method of treatment of a disease resulting from abnormal production or secretion β-amyloid protein, comprising introducing an effective amount of the compound represented by formula (1), its N-oxide or S-oxide, its salts or its MES.

The present invention can provide the * connection, having excellent inhibitory activity against the production or secretion β-amyloid protein, and with the desired properties as a drug.

Best mode for carrying out the present invention

The compound represented by formula (1)described below.

Examples of the aromatic hydrocarbon group represented by R1or R3include phenyl and naftalina group, which phenyl group is preferred.

Examples of the aromatic heterocyclic group represented by R1or R3include 5 - or 6-membered aromatic heterocyclic group containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include groups pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyridyl, pyrimidinyl, tetrazolyl, thiadiazolyl, pyrazinyl and pyridazinyl.

Of these groups, preferred groups are thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl and pyridazinyl; more preferred are thienyl, pyridyl, pyrimidinyl and pyridazinyl and especially preferred are thienyl, pyridyl and pyrimidinyl.

Examples of the saturated monocyclic heterocyclic group, presented the military R 2include 3-7-membered heterocyclic group containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include groups pyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrofuryl, piperidinyl, piperazinil, homopiperazine, morpholine, thiomorpholine, aziridinyl, imidazolidinyl, pyrazolidine, tetrahydropyranyl, tetrahydropyranyl, DIOXOLANYL, oxathiolanes and hexahydropyridine.

Of these groups, preferred groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothieno, piperidinyl, piperazinil, homopiperazine, morpholine, thiomorpholine, imidazolidinyl, pyrazolidine, tetrahydropyranyl and tetrahydrothiopyran and more preferred are piperidinyl, tetrahydropyranyl, tetrahydropyranyl and hexahydropyridine.

Examples of the unsaturated monocyclic heterocyclic group represented by R2include 4-7-membered group containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include groups pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, triazinyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazoline is, pyranyl, dihydropyridin, tetrahydropyranyl, dihydropyrimidines, tetrahydropyridine and tetrahydropyrimidines.

Of these groups, preferred groups are pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl, pyrrolyl, imidazolyl, pyrazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, dihydropyrimidines and tetrahydropyridines and more preferred are imidazolyl, pyridyl, pyrimidinyl and thiazolyl.

Examples of unsaturated polycyclic heterocyclic group represented by R2include 8-10-membered group containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include groups benzofuranyl, benzothiazolyl, indolyl, hinely, ethanolic, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophene, benzisothiazole, benzisoxazole, bromanil, bromanil, Isopropenyl, isopropanol, indolinyl, indazoles, indolizinyl, isoindolyl, isoindolines, hemolysins, honokalani, hintline, cinnoline, phthalazine, naphthyridine, purinol, tetrahydrothiopyran, imidazopyridine, triazolopyridine, pyrrolopyridine, carbazolyl, xantener, acridines, phenazines, phenoxazines, phenothiazines and x is nucleinic.

Of these groups, preferred groups are benzofuranyl, benzothiazolyl, indolyl, hinely, ethanolic, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophene, benzisothiazole, benzisoxazole, bromanil, bromanil, Isopropenyl, isopropanol, indolinyl, indazoles, indolizinyl, hemolysins, honokalani, hintline, cinnoline, phthalazine, naphthyridine, imidazopyridine and triazolopyridine; and more preferred are benzimidazolyl, bromanil, imidazopyridine and triazolopyridine.

Aromatic hydrocarbon group or aromatic heterocyclic group represented by R1or R3may be substituted by 1-3 substituents, which are the same or different from each other and selected from halogen atoms, C1-6alkyl groups, trihalomethyl groups, C1-6alkoxygroup, C2-6alkenyl groups, formyl groups, C2-6alkanoyl groups, carboxyl groups, carboxamido C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl group, carbonyl group, nitro group, ceanography, amidinopropane, C2-6alkenylacyl, hydroxy-group, tocography, amino, C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxycarbonyl groups, carbamoyl group, C-6 alkylcarboxylic groups, di(C1-6alkyl)carbamoyl groups, thiocarbamoyl group, C1-6alkyldiethanolamine groups, di(C1-6alkyl)thiocarbamoyl groups, mercaptopropyl, C1-6alkylthio, C1-6alkylsulfonyl groups, C1-6alkylsulfonyl groups and C6-10aromatic hydrocarbons-C1-6alkyl groups.

As the substituent for the aromatic hydrocarbon group or aromatic heterocyclic group represented by R1or R3preferred are halogen atoms, C1-6alkyl group, trihalomethyl group, C1-6alkoxygroup, cyano, amidinopropane, the hydroxy-group, C1-6alkylamino, di(C1-6alkyl)amino group, carnemolla group, C1-6alkylcarboxylic group and di(C1-6alkyl)carbamoyl group; more preferred are halogen atoms, C1-6alkyl group, trihalomethyl group, C1-6alkoxygroup and cyano, and especially preferred are halogen atoms and cyano. Of the halogen atoms chlorine atoms and fluorine are preferred.

Examples of the substituent for the saturated or unsaturated monocyclic heterocyclic group or unsaturated polycyclic heterocyclic group, not only at the authorized R 2include the group-Q101-Q102-Q103-Q104-Q105-Q106-Q107(where Q101represents a simple bond, C1-6alkylenes group, C2-6alkenylamine group or a heterocyclic group; Q102represents a simple bond, -O-, -NH-, -CH=N-, -C(alkyl)=N-, -N (alkyl)- or-S-; Q103represents a simple bond, -CO-, -CS-, -SO-, -SO2- or-CONH-; Q104represents a simple bond, C1-6alkylenes group, C2-6alkynylamino group, C3-8cycloalkenyl group, C4-7cycloalkenyl group, aromatic hydrocarbon group or heterocyclic group; Q105represents a simple bond, -NH - or-N(alkyl)-; Q106represents a simple bond, -O-, -CO-, -CS-, -SO2-, -SO - or-S - and Q107represents a hydrogen atom, a halogen atom, a hydroxy-group, oxoprop, C1-6alkyl group, a C2-6alkenylphenol group, C3-7cycloalkyl group, C1-6alkoxygroup, C2-6alkenylacyl, group, azide, cyano, amino, C1-6alkylamino, di(C1-6alkyl)amino group, a C2-6alkanolamines, di(C2-6alkanoyl)amino group, carboxyhaemoglobin, C1-6alkoxycarbonylmethyl, di(C1-6alkoxycarbonyl)amino group, heterocyclic group, aromatizes the Yu hydrocarbon group, C4-7cycloalkenyl group, a heterocycle-oxygraph or aromatic hydrocarbon-oxygraph, where C1-6Allenova or an alkyl group, a C2-6Alcanena or Alchemilla group, C3-7cycloalkenes or C3-7cycloalkyl group, C4-7cycloalkenyl or C4-7cycloalkenyl group, heterocyclic group, a heterocycle-oxygraph, aromatic hydrocarbon group or aromatic hydrocarbon-oxygraph can be substituted by 1-3 substituents selected from halogen atoms, C1-6alkyl groups, C1-6alkoxygroup, C2-6alkenyl groups, carboxamido C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl group, a formyl group, a C2-6alkanoyl group, carbonyl group, nitro group, ceanography, azide group, amidinopropane, C2-6alkenylacyl, hydroxy-group, carboxyl group, C7-16Uralkalij groups, tocography, C2-6alkanoyl groups, C2-6thioalcohols groups, tiparillos group, an amino group, a C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkoxycarbonyl groups, carbamoyl group, C1-6alkylcarboxylic groups, di(C1-6alkyl)carbamoyl groups, thiocarbamoyl group, C1-6alkyldiethanolamine groups, di(C1-6alkyl)thiocarbamoyl groups, C1-6alkoxycarbonylmethyl, C1-6alkoxycarbonyl (C1-6alkyl)amino, C2-6alkanolamines, C2-6alkanoyl (C1-6alkyl)amino, thio C2-6alkanolamines, thio C2-6alkanoyl (C1-6alkyl)amino group, formylamino, formyl (C1-6alkyl)amino group, coformulating, diformyl (C1-6alkyl)amino, C2-6alkanoyloxy, formyloxy, C1-6alkoxycarbonylmethyl, carbamoyloximes, C1-6alkylcarboxylic, di(C1-6alkyl)carbamoyloximes, aminocarbonylmethyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminocarbonylmethyl, aminocarbonyl (C1-6alkyl)amino, C1-6alkylaminocarbonyl (C1-6alkyl)amino, di(C1-6alkyl)aminocarbonyl (C1-6alkyl)amino group, mercaptopropyl, C1-6alkylthio, C1-6alkylsulfonyl groups, C1-6alkylsulfonyl groups, aminosulfonyl group, C1-6alkylaminocarbonyl groups, di(C1-6alkyl)aminosulfonyl groups, aminosulfonyl, C1-6alkylaminocarbonyl, di(C1-6alkyl)aminosulfonyl, aminosulfonyl (C1-6alkyl)amino, C1-6alkylaminocarbonyl (C1-6alkyl)amino and di(C1-6alkyl)amino is sulfonyl (C 1-6alkyl)amino group.

The substituents for the heterocyclic group represented by R2more specifically described below.

The heterocyclic group represented by R2may be substituted by 1-3 substituents selected from halogen atoms, ceanography, C1-6alkyl groups, hydroxy-group, C1-6alkoxygroup, C2-6alkenylacyl, carboxy C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl group, a heterocycle-carbonyl C1-6alkyl groups, hydroxy, C1-6alkyl groups, C6-10aromatic hydrocarbon-sulfonyl C1-6alkyl groups, N,N-dialkylaminoalkyl C1-6alkyl group, a heterocycle-C1-6alkyl groups, C6-10aromatic hydrocarbons-C1-6alkyl groups, C6-10aromatic hydrocarbon-thio C1-6alkyl groups, azido-C1-6alkyl groups, amino C1-6alkyl groups, C1-6alkylamino C1-6alkyl groups, di(C1-6alkyl)amino, C1-6alkyl groups, hydroxy, C1-6alkylamino C1-6alkyl groups, C1-6alkoxy, C1-6alkylamino1-6alkyl groups, di(C1-6alkoxyl1-6alkyl)amino, C1-6alkyl groups, N-hydroxy C1-6alkyl-N-C1-6alkoxy, C1-6alkylamino C1-6alkyl groups, C2-6alkanolamine C1-6 alkyl groups, di(C2-6alkanoyl)amino, C1-6alkyl groups, carboxamido C1-6alkyl groups, di(C1-6alkylcarboxylic C1-6alkyl)amino, C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl groups, di(C1-6alkoxycarbonyl)amino, C1-6alkyl groups, carbamoylating C1-6alkyl groups, N-C1-6alkylcarboxylic C1-6alkyl groups, (N,N-di(C1-6alkyl)carbarnoyl)amino, C1-6alkyl groups, aminosulfonyl C1-6alkyl groups, N-C1-6alkylsulfonamides C1-6alkyl groups, (di(C1-6alkyl)aminosulfonyl)amino, C1-6alkyl groups, C6-10aromatic hydrocarbon-sulfonylamino-C2-6alkanolamine C1-6alkyl groups, amino C1-6alkylcarboxylic C1-6alkyl groups, N-C1-6alkylamino C1-6alkylcarboxylic C1-6alkyl groups, N,N-di(C1-6alkyl)amino, C1-6alkylcarboxylic C1-6alkyl group, a heterocycle-C1-6alkylcarboxylic C1-6alkyl group, a heterocycle-C2-6alkenylboronic C1-6alkyl groups, C6-10aromatic hydrocarbons-C2-6alkenylboronic C1-6alkyl groups, C6-10aromatic hydrocarbon-carbylamine C1-6alkyl groups, C6-10 1-6alkyl group, a heterocycle-carbylamine C1-6alkyl groups, C1-6alkoxysilane C1-6alkyl groups, N-(C6-10aromatic hydrocarbon-sulfonyl)-N-C1-6alkylamino C1-6alkyl groups, C1-6alkylsulfonamides C1-6alkylamino, carbamoylated C1-6alkyl groups, N-C1-6alkylcarboxylic C1-6alkyl groups, N,N-di(C1-6alkyl)carbamoylated C1-6alkyl groups, C6-10aromatic hydrocarbons-C1-6alkylcarboxylic C1-6alkyl groups, C1-6alkoxycarbonyl-C1-6alkyl groups, C6-10aromatic hydrocarbons, oxycarbonate C1-6alkyl groups, heterocyclic carbohydratecontaining groups, C6-10aromatic hydrocarbon carbohydratecontaining groups, C2-6alkenyl groups, carboxy-C2-6alkenyl groups, C1-6alkoxycarbonyl-C2-6alkenyl groups, carbarnoyl C2-6alkenyl group, a heterocycle-C2-6alkenyl groups, formyl group, carboxyl group, a heterocycle-carbonyl group, a C6-10aromatic hydrocarbon-carbonyl group, a C1-6alkoxycarbonyl groups, carbamoyl group, N-C1-6alkylcarboxylic groups, N,N-di(C1-6alkyl)carbamoyl groups, (C3-7cycloalkyl 1-6alkyl)carbamoyl groups, C1-6alkylthio C1-6alkylcarboxylic groups, C1-6alkylsulfonyl C1-6alkylcarboxylic groups, C1-6alkylsulfonyl C1-6alkylcarboxylic groups, hydroxyaminopyrimidines group, C1-6alkoxycarbonyl groups, hydroxy, C1-6alkylcarboxylic groups, C1-6alkoxy, C1-6alkylcarboxylic groups, amino C1-6alkylcarboxylic groups, amino C1-6alkyldiethanolamine groups, hydroxy, C1-6alkylcarboxylic groups, C1-6alkoxycarbonyl C1-6alkylcarboxylic groups, (C1-6alkoxycarbonyl)C1-6alkylcarboxylic groups, (C1-6alkoxycarbonyl)C1-6alkyldiethanolamine group, a heterocycle-carbamoyl group, a heterocycle-C1-6alkylcarboxylic groups, C6-10aromatic hydrocarbon-carbamoyl groups, hydrazinecarboxamide groups, N-C1-6alkyldiethanolamine groups, N'-C1-6alkyldiethanolamine groups, N',N'-di(C1-6alkyl)hydrazinecarboxamide groups, N,N'-di(C1-6alkyl)hydrazinecarboxamide groups, N,N',N'-three(C1-6alkyl)hydrazinecarboxamide groups, N'-(heterocyclicamines)hydrazinecarboxamide groups, amino groups, C1-6alkoxy, C1-6alkylamino, amino, C1-6alkylamino, (C1-6alnilam is but C 1-6alkyl)amino, N-C1-6alkylamino C1-6alkyl-N-C1-6alkylamino, (C1-6alkoxycarbonyl C1-6alkyl)amino groups, (di(C1-6alkyl)amino, C1-6alkyl)amino group, a heterocycle-amino C1-6alkylamino, carboxyl C1-6alkylamino, N-carboxyl C1-6alkyl-N-C1-6alkylamino, heterocycle-C1-6alkylamino, N-(heterocycle-C1-6alkyl)-N-C1-6alkylamino, hydroxys1-6alkylamino, N-hydroxy C1-6alkyl-N-C1-6alkylamino, (C1-6alkylthio C1-6alkyl)amino groups, (C1-6alkylcarboxylic C1-6alkyl)amino, N-C1-6alkylaminocarbonyl C1-6alkyl-N-C1-6alkylamino, C1-6alkylsulfonyl C1-6alkylamino, C1-6alkylsulfonyl C1-6alkylamino, groups represented by the formula: -N(R12)SO2R11(where R11represents a C1-6alkyl group, heterocyclic group, a C1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl group, hydroxy, C1-6alkyl group, amino (C1-6alkyl group, a C1-6alkylamino C1-6alkyl group, di(C1-6alkyl)amino, C1-6alkyl group, a carboxy C1-6alkyl group, carbarnoyl C1-6alkyl group, triforma the ilen group, deformational group, formeterol group, an amino group, a C1-6alkylamino or di(C1-6alkyl)amino group, and R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group), hydroxy, C1-6alkoxy, C1-6alkylamino, C6-10aromatic hydrocarbons-C1-6alkylamino, heterocycle-carbonylation, C1-6alkoxycarbonylmethyl, heterocycle-C1-6alkylcarboxylic, C6-10aromatic hydrocarbon-carbonylation, heterocycle-amino group, hydroxyisopropyl, C1-6alkoxyimino, carbonyl group, hydroxyimino C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkylamino, (C2-6alkanolamine C1-6alkyl)amino, C6-10aromatic hydrocarbon groups and heterocyclic groups (where C6-10aromatic hydrocarbon group, or a heterocycle or heterocyclic group may be substituted by 1-3 substituents selected from halogen atoms, C1-6alkyl groups, C1-6alkoxygroup, C2-6alkenyl groups, formyl groups, C2-6alkanoyl groups, carboxyl groups, carboxamido C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl group, carbonyl group, nitro group, ceanography, amidinopropane, C 2-6alkenylacyl, hydroxy-group, tocography, amino, C1-6alkylamino, di(C1-6alkyl)amino, amino (C1-6alkyl groups, C1-6alkoxycarbonyl groups, carbamoyl group, C1-6alkylcarboxylic groups, di(C1-6alkyl)carbamoyl groups, thiocarbamoyl group, C1-6alkyldiethanolamine groups, di(C1-6alkyl)thiocarbamoyl groups, C2-6alkanolamines, C2-6alkanoyl (C1-6alkyl)amino, thio C2-6alkanolamines, thio C2-6alkanoyl (C1-6alkyl)amino group, formylamino, formyl (C1-6alkyl)amino group, coformulating, diformyl (C1-6alkyl)amino, C2-6alkanoyloxy, formyloxy, mercaptopropyl, C1-6alkylthio, C1-6alkylsulfonyl groups, C1-6alkylsulfonyl groups, aminosulfonyl groups, C1-6alkylaminocarbonyl groups, di(C1-6alkyl)aminosulfonyl groups, C1-6alkylsulfonamides, C1-6alkylsulfonyl (C1-6alkyl)amino and hydroxy, C1-6alkyl groups).

The heterocyclic group represented by R2preferably substituted 1-3, more preferably 2 substituents selected from halogen atoms, ceanography, C1-6alkyl groups, hydroxy-group, C1-6 alkoxygroup, C2-6alkenylacyl, carboxy C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl groups, hydroxy, C1-6alkyl groups, C6-10aromatic hydrocarbon-sulfonyl C1-6alkyl group, a heterocycle-C1-6alkyl groups, C6-10aromatic hydrocarbons-C1-6alkyl groups, C6-10aromatic hydrocarbon-thio C1-6alkyl groups, azido-C1-6alkyl groups, amino C1-6alkyl groups, di(C1-6alkyl)amino, C1-6alkyl groups, di(C1-6alkoxy, C1-6alkyl)amino, C1-6alkyl groups, C2-6alkanolamine C1-6alkyl groups, di(C2-6alkanoyl)amino, C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl groups, di(C1-6alkoxycarbonyl)amino, C1-6alkyl groups, (N,N-di(C1-6alkyl)carbarnoyl)amino, C1-6alkyl groups, N-C1-6alkylsulfonamides C1-6alkyl groups, (di(C1-6alkyl)aminosulfonyl)amino, C1-6alkyl groups, C6-10aromatic hydrocarbon-sulfonylamino-C2-6alkanolamine C1-6alkyl groups, N,N-di(C1-6alkyl)amino1-6alkylcarboxylic C1-6alkyl group, a heterocycle-C1-6alkylcarboxylic C1-6alkyl group, a heterocycle-C2-6altercare the laminitis C 1-6alkyl groups, C6-10aromatic hydrocarbon-carbylamine C1-6alkyl groups, C6-10aromatic hydrocarbon-thiocarbanilide C1-6alkyl group, a heterocycle-carbylamine C1-6alkyl groups, C1-6alkoxysilane C1-6alkyl groups, N-(C6-10aromatic hydrocarbon-sulfonyl)-N-C1-6alkylamino C1-6alkyl groups, C1-6alkylsulfonamides C1-6alkylamino, N,N-di(C1-6alkyl)carbamoylated C1-6alkyl groups, C6-10aromatic hydrocarbons-C1-6alkylcarboxylic C1-6alkyl groups, C1-6alkoxycarbonyl-C1-6alkyl groups, C6-10aromatic hydrocarbon-oxycarbonate C1-6alkyl groups, carboxy-C2-6alkenyl groups, C1-6alkoxycarbonyl-C2-6alkenyl groups, carbarnoyl C2-6alkenyl group, a heterocycle-C2-6alkenyl groups, formyl group, carboxyl group, a heterocycle-carbonyl group, a C1-6alkoxycarbonyl groups, carbamoyl group, N,N-di(C1-6alkyl)carbamoyl groups, (C3-7cycloalkyl-C1-6alkyl)carbamoyl groups, C1-6alkylthio C1-6alkylcarboxylic groups, C1-6alkylsulfonyl C1-6alkylcarboxylic groups, C1-6alkylsulfonyl C1-6 alkylcarboxylic groups, C1-6alkoxycarbonyl groups, amino C1-6alkylcarboxylic groups, amino C1-6alkyldiethanolamine groups, hydroxy, C1-6alkylcarboxylic groups, C1-6alkoxycarbonyl C1-6alkylcarboxylic groups, (C1-6alkoxycarbonyl)C1-6alkylcarboxylic groups, (C1-6alkoxycarbonyl)C1-6alkyldiethanolamine groups, heterocyclization group, a heterocycle-C1-6alkylcarboxylic groups, N',N'-di(C1-6alkyl)hydrazinecarboxamide groups, N'-(heterocycle-carbonyl)-hydrazinecarboxamide groups, amino groups, C1-6alkoxy, C1-6alkylamino, amino, C1-6alkylamino, C1-6alkylamino C1-6alkylamino, (C1-6alkylamino C1-6alkyl) (C1-6alkyl)amino, C1-6alkoxycarbonyl C1-6alkylamino, di(C1-6alkyl)amino, C1-6alkylamino, heterocycles C1-6alkylamino, carboxyl C1-6alkylamino, (carboxyl C1-6alkyl) (C1-6alkyl)amino group, a heterocycle-C1-6alkylamino (heterocycle-C1-6alkyl) (C1-6alkyl)amino, hydroxy, C1-6alkylamino, (hydroxy, C1-6alkyl) (C1-6alkyl)amino, C1-6alkylthio C1-6alkylamino, C1-6alkylaminocarbonyl C1-6alkylamino is PP, (C1-6alkylaminocarbonyl C1-6alkyl) (C1-6alkyl)amino, C1-6alkylsulfonyl C1-6alkylamino, C1-6alkylsulfonyl C1-6alkylamino, groups represented by the formula: -N(R12)SO2R11(where R11represents a C1-6alkyl group, heterocyclic group, a C1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl group, hydroxy, C1-6alkyl group, amino (C1-6alkyl group, a C1-6alkylamino C1-6alkyl group, di(C1-6alkyl)amino, C1-6alkyl group, a carboxy C1-6alkyl group, carbarnoyl C1-6alkyl group, triptorelin group, deformational group, formeterol group, an amino group, a C1-6alkylamino or di(C1-6alkyl)amino group, and R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group), hydroxy, C1-6alkoxy, C1-6alkylamino, C6-10aromatic hydrocarbons-C1-6alkylamino, heterocycle-carbonylation, C1-6alkoxycarbonylmethyl, heterocycle-alkylcarboxylic, C6-10aromatic hydrocarbon-carbonylation, carbonyl group, hydroxyimino C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkylamino is, (C2-6alkanolamine C1-6alkyl)amino, C6-10aromatic hydrocarbon groups and heterocyclic groups (where C6-10aromatic hydrocarbon group or heterocyclic group may be substituted by 1-3 substituents selected from halogen atoms, C1-6alkyl groups, C1-6alkoxygroup, C2-6alkanoyl group, carbonyl group, nitro group, ceanography, hydroxy-group, amino C1-6alkyl groups, C1-6alkoxycarbonyl groups, formylamino and hydroxy, C1-6alkyl groups).

As R2a more preferred group represented by the formula:

[Chemical formula 2]

(where R10represents a hydrogen atom, a C1-6alkyl group, hydroxy, C1-6alkyl group, a C1-6alkylsulfonyl C1-6alkyl group, a C1-6alkylsulfonyl C1-6alkyl group, a carboxy C1-6alkyl group, a heterocycle-C1-6alkyl group or a group represented by the formula: -SO2-R11(where R11represents a C1-6alkyl group, heterocyclic group, a C1-6alkyl-heterocyclic group, a heterocycle group-C1-6alkyl, hydroxy, C1-6alkyl, amino (C1-6alkyl, C1-6alkylamino C1-6alkyl, di(C1-6alkyl)is Mino C 1-6alkyl, carboxy (C1-6alkyl, carbarnoyl C1-6alkyl, trifluoromethyl, deformity, vermeil, amino, C1-6alkylamino or di(C1-6alkyl)amino), R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group, or R11and R12taken together with the sulfur atom is linked to R11and with the nitrogen atom is linked to R12may form a 5 - or 6-membered aliphatic heterocycle, and R13represents a C1-6alkyl group, halogen atom or cyano).

As R2also preferred group represented by the formula:

[Chemical formula 3]

(where R13represents a C1-6alkyl group, halogen atom or cyano and n is an integer having a value of from 0 to 6).

As R4especially preferred is a hydrogen atom. As X are preferred-SO2- and-SO from the point of view of their pharmacological effect, of which-SO2- is especially preferred from the point of view of its pharmacological effect.

Particular substituents for the aromatic hydrocarbon group or aromatic heterocyclic group represented by R1or R3and substitutes for saturated or Nene is sydeney monocyclic heterocyclic group or unsaturated polycyclic heterocyclic group, presents R2described below.

The term "heterocycle" means a cycle containing 1-4 heteroatoms (N, O, S etc) as a component of its cyclic structure, and may be any of saturated, unsaturated or aromatic cycle or can be either a monocycle or politics. Polycyclic heterocycle covers heterocyclic spiraeoideae and heterocyclic compounds having Poperechnaya a cyclic structure. The term "heterocycle" in the definition of "heterocycle-C1-6alkyl group" and the like means a heterocyclic group selected from the above heterocycle. The term "heterocyclic group" means a monovalent group selected from the "heterocycle".

Examples of the saturated monocyclic heterocyclic group include a 3-7-membered group containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include groups pyrrolidinyl, tetrahydrofuranyl, oxetanyl, tetrahydrofuryl, piperidinyl, piperazinil, homopiperazine, morpholine, thiomorpholine, oxiranyl, tylenol, dioxane, aziridinyl, imidazolidinyl, pyrazolidine, tetrahydropyranyl, tetrahydropyranyl, oxazolidinyl, diazolidinyl, isoxazolidine, isothiazolinones, DIOXOLANYL, oxathiolanes and hexahydropyridine.

Examples Genaside the Noi, or aromatic monocyclic heterocyclic group include a 4-7-membered group, containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, triazinyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidine, oxazolidine, thiazolidine, isoxazolidine, isothiazolinones, pyranyl, dihydropyridin, tetrahydropyranyl, dihydropyridines, dihydropyrimidines, tetrahydropyridine and tetrahydropyrimidines.

Examples of polycyclic heterocyclic groups include 8-14-membered group containing 1-4 atoms selected from nitrogen atoms, oxygen and sulfur. Specific examples include groups benzofuranyl, benzothiazolyl, indolyl, hinely, ethanolic, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothiophene, benzisothiazole, benzisoxazole, bromanil, bromanil, Isopropenyl, isopropanol, indolinyl, indazoles, indolizinyl, isoindolyl, isoindolines, hemolysins, honokalani, hintline, cinnoline, phthalazine, naphthyridine, purinol, tetrahydrothiopyran, imidazopyridine, pyrrolopyridine, carbazolyl, xantener, acridines, phenazines, phenoxazines, phenothiazines and hinokitiol.

The term "halogen atoms" means chlorine atoms, fluorine, the Roma and iodine, of which the chlorine atoms and fluorine are preferred.

The term "C1-6alkyl group" means a linear or branched C1-6alkyl group. Specific examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylpentyl and n-hexyl.

The term "C1-6Allenova group" means a linear or branched C1-6alkylenes group. Specific examples of such alkalinous groups include methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene and hexamethylene.

The term "C2-6Alchemilla group" means a linear or branched C2-6alkenylphenol group. Specific examples of such alkenylphenol groups include vinyl, allyl, propenyl, butenyl and pentenyl.

The term "C2-6alkenylamine group" means a linear or branched C2-6alkenylamine group. Specific examples of such alkenylamine group include vinile, propylen, Butenin and penttinen.

Examples of "C3-7cycloalkyl group" include C3-7cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples of C4-7cycloalkenyl groups include C4-7cycloalkenyl groups, such as cyclopentenyl and cyclohexenyl.

Examples of combinations of cloulkili groups and alkyl groups include cycloalkenyl group, of which C3-7cycloalkyl-C1-6alkyl groups are especially preferred.

The term "C1-7alkoxygroup" means alkoxygroup containing the above-described alkyl or cycloalkyl group. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentox, cyclopentyloxy, cyclohexyloxy, cycloheptylamine.

The term "C2-6alcoolica group" means a linear or branched C2-6alkanoyloxy group, and examples include acetyl, propionyl, butyryl, valeryl and hexanoyl.

As R1especially preferred are 2,5-diferencia or 2-fluoro-5-cyanoaniline group. As R3especially preferred are 4-chloraniline, 4-Fortunella, 2,4-differenly, 3,4-differenly, 3-fluoro-4-chloraniline, 4-triftormetilfullerenov, 5-chloro-2-thienyl, 5-chloro-2-perederina, 6-chloro-3-Peregrina and 6-trifluoromethyl-3-Peregrina group.

Compounds of the present invention, represented by formula (1)can have stereoisomer or enantiomer formed from asymmetric hydrocarbon. The present invention covers all stereoisomers and enantiomers and mixtures thereof. S-oxide compounds of the present invention exists when the heterocyclic group contains a sulfur atom. S-oxide covers monoc the ID, and dioxide.

There are no specific restrictions with respect to the salts of the compounds of the present invention, represented by formula (1), provided that it must be pharmaceutically acceptable salt. Specific examples of salts include salts of mineral acids, such as hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate and sulfate, organic sulfonates, such as methanesulfonate, 2-hydroxyethanesulfonic and p-toluensulfonate, and organic carboxylates such as benzoate, acetate, propanoate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and Mandela.

When the compound represented by formula (1)contains an acid group, such a compound can form a salt with alkali metal ion or alkali earth metal ion. There are no specific limitations as to the MES, provided that he should be pharmaceutically acceptable. Specific examples include hydrates and ethanol solvate.

Methods for obtaining compounds of the present invention, represented by formula (1)described below.

Compounds of the present invention, represented by formula (1), or their salts, or their solvate can be obtained with well-known chemical methods of obtaining, in their combination. Typical synthesis methods described below.

Typical ways received what I sulfide (1a), sulfanilimide (1b) and sulfonylurea (1c) of the compounds of the present invention, represented by formula (1)described below.

1)The method of producing sulfide (1a)

The sulfide compound (1a) of the present invention receives, as described below.

[Chemical formula 4]

(where Y represents a group to delete and R1-R4defined above).

Sulfide derivative (1a) of the present invention can be obtained by conversion of the alcohol derivative (2) in the compound (3) with the subsequent interaction of the compound (3) with a thiol (R3-SH) in the presence of a base. In this case, the thiol compound can be used as a salt of an alkali metal or alkaline earth metal (e.g. lithium salt, sodium salt or potassium salt).

The reaction temperature of the compound (3) and thiol (R3-SH) is usually in the range from -20 to 200°C, preferably from room temperature to 100°C. may Sometimes be preferred reaction temperature is above the specified limits, depending on the compound (3) or thiol compounds (R3-SH). Sometimes preferably the reaction in a sealed tube. The reaction time is usually from 0.5 hours to one day.

Examples of the base are the hydrides of alkali metals or alkaline earth metals (such the AK lithium hydride, sodium hydride, potassium hydride and calcium hydride); amides of alkali metals or alkaline earth metals (such as lithium amide, sodium amide, diisopropylamide lithium, dicyclohexylamine lithium hexamethyldisilazide lithium hexamethyldisilazide sodium and hexamethyldisilazide potassium); lower alkoxides of alkali metals or alkaline earth metals (such as sodium methoxide, ethoxide sodium tert-piperonyl potassium); hydroxides of alkali metals, alkaline earth metals or silver (such as silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide; carbonates of alkali metals, alkaline earth metals or silver carbonate sodium, potassium carbonate, cesium carbonate and silver carbonate; bicarbonates of alkali metals (such as sodium bicarbonate and potassium bicarbonate); connection alkylate (such as n-utility) or alkylated Grignard reagents (such as methylmagnesium); inorganic bases, such as silver oxide, or amines (such as triethylamine, diisopropylethylamine and N-methylmorpholine); and organic bases, for example, cosóate heterocyclic compounds (such as dimethylaminopyridine, pyridine, imidazole, 2,6-lutidine, kallidin, 1,8-diazabicyclo[5,4,0]undec-7-ene, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane).

Examples of the solvent are Speer the new solvents, ether solvents, halogenated solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and water. You can use a mixture of two solvents. Of these solvents, methylene chloride, tetrahydrofuran and dimethylformamide are preferred.

The alcohol derivative (2)used on above the stage, can be obtained in a known manner. There are various ways, and one example of such a method is described below. The alcohol derivative (2) can be obtained by adding an ORGANOMETALLIC reagent (typically, organolithium reagent of formula R2-Li or a Grignard reagent of formula R2-MgCl, R2-MgBr, or the like), in the amount equivalent to the excess, to the aldehyde or ketone of the formula R1(C=O)-R4in a solvent such as tetrahydrofuran or diethyl ether, to interact with them. The above ORGANOMETALLIC reagent can be easily obtained, for example, when R2represents an aromatic hydrocarbon group or aromatic heterocyclic group, adding alkyllithium reagent or alkylatedthe Grignard reagent to arivalagan or heteroarylboronic for exchanging metals as described in the dissertation of H. Gilman, et. al. J. Org. Chem.,16, 1788-1791 (1951), or in the dissertation of F. Trecourt, et al., Tetrahedron,56, 1349-1460 (2000).

The compound (3)containing the deleted group Y can be obtained by converting the hydroxyl group of the alcohol derivative (2) in a group to delete a known manner. Examples of the deleted group represented by Y include halogen atoms (such as chlorine, bromine and iodine), C1-6alkylsulfonates that can be galogenirovannyie (such as methanesulfonate, econsultancy, tripterocalyx), and C6-10aromatic hydrocarbon - sulfonyloxy, which may have a substituent. The substituents for the aromatic hydrocarbon group, sulfonyloxy include 1-3 halogen atom, a C1-6alkyl groups, which may be galogenirovannyie, and C1-6alkoxygroup. Preferred examples of the deleted group include benzosulfimide, p-toluensulfonate, 1 naphthalenesulfonate and 2 naphthalenesulfonate.

As an alternative method for the synthesis of sulfide compound (1a), you can specify the reaction Mitsunobu between alcohol derivative (2) and the thiol compound (R3-H). Specifically, the compound (1a) can be obtained by the interaction of the alcohol derivative (2) with 1-3 equivalents of a thiol (R3-SH) in a solvent in the presence of 1-3 equivalents or triarylphosphine (such as triphenylphosphine), Li is about trialkylphosphine (such as tributylphosphine) and 1-2 equivalents of a compound of azodicarboxylic acid (such as diethylazodicarboxylate, diisopropylsalicylic, bipiperidine azodicarboxylic acid or bidimentional azodicarboxylic acid).

The reaction temperature is usually in the range from -20°C to 150°C, preferably from 0 to 80°C. the reaction Time is usually from 0.5 hours to 5 days. Examples of the solvent include ether solvents, halogenated solvents and aromatic solvents. You can use a mixture of two or more such solvents. Of these solvents, tetrahydrofuran is preferred.

2)The method of obtaining sulfanilimide compounds (1b)

Alvinlee compound (1b) according to the present invention can be obtained, as described below, by oxidation of the sulfide compound (1a) with an oxidizing agent in a solvent.

[Chemical formula 5]

(where each of R1-R4defined above).

The reaction temperature is usually in the range from -20°C to 200°C, preferably from 0 to 100°C. the reaction Time is usually from 0.1 hour up to 7 days, preferably from 0.5 hour to 2 days. Examples of the solvent include alcohol solvents, ether solvents, halogenated solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide R is storytale and water. You can use a mixture of two or more such solvents. Of these solvents are methylene chloride, chloroform, methanol and ethanol are preferred.

Examples of the oxidizing agent include hydrogen peroxide, organic percolate compounds (such as peracetic acid and meta-chloroperbenzoic acid), metaperiodate (such as metaperiodate sodium), acilitate, dinitrophenoxy, halogen, N-halogenated compounds (such as N-chlorosuccinimide and N-bromosuccinimide), hydroperoxides such as tert-butylhydroperoxide), diacetate odensala, dichloride odensala, tert-butylhypochlorite, sulfurylchloride, unbound oxygen, ozone, selenium oxide and Zelenikovo acid.

Specific reaction conditions are as follows. Alvinlee compound (1b) can be obtained by processing sulfide compound (1a) 1-2 equivalents of meta-chloroperbenzoic acid, periodate sodium or hydrogen peroxide, in a solvent such as methylene chloride, tetrahydrofuran, water, methanol or the like at a temperature of 0-100°C for a time from about 1 hour to 2 days.

Optically active sulfoxide (1b) can be obtained by using as the oxidant tetraisopropoxide titanium/optically pure diethyltartrate/tert-butylhydroperoxide, tetraisopropoxide titanium/optically pure diethyltartrate/peracetic acid or the like

3-1)The method of obtaining sulfonylurea compounds (1c)

Sulfonylurea compound (1c) according to the present invention can be obtained, as described below, by oxidation of the sulfide compound (1a) or sulfanilimide compound (1b) with an oxidizing agent in a solvent.

[Chemical formula 6]

(where each of R1-R4defined above).

The reaction temperature is usually in the range from -20°C to 150°C, preferably from 0°C to 100°C, and the reaction time is usually from 0.1 hour up to 7 days, preferably from 1 hour to 5 days.

Examples of the solvent include alcohol solvents, ether solvents, halogenated solvents, aromatic solvents, carbonisation solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and water. You can use a mixture of two or more such solvents. Of these solvents are methylene chloride, chloroform, methanol, ethanol, acetic acid, water, etc. are preferred.

Examples of the oxidizing agent include hydrogen peroxide, hydrogen peroxide - catalyst based on transition metal (such as ammonium molybdate or iron chloride (III), organic percolate compounds (such as peracetic acid is the meta-chloroperbenzoic acid), metaperiodate (such as metaperiodate sodium), peroxosulfates potassium permanganates such as potassium permanganate), perborate sodium, halogen, N-halogenated compounds (such as N-chlorosuccinimide and N-bromosuccinimide), hydroperoxides such as tert-butylhydroperoxide), diacetate odensala, dichloride odensala, hypochlorites such as sodium hypochlorite or tert-butylhypochlorite), unbound oxygen, ozone, selenium oxide and Zelenikovo acid. A preferred example of the reaction conditions includes the interaction of the sulfide compound (1a) with 2-5 equivalents of oxidizing agent (such as meta-chloroperbenzoic acid, periodate sodium, hydrogen peroxide or hydrogen peroxide-ammonium molybdate) in methylene chloride, a mixture of tetrahydrofuran-water or methanol, at a temperature in the range from 0 to 100°C, during the time from about 1 hour to 5 days.

3-2)The method of obtaining sulfonylurea compounds (1c)

Sulfonylurea compound (1c) can also be obtained by the method described below.

[Chemical formula 7]

[where Y1is a deleted group or a hydroxyl group and each of R1-R4defined above].

Each of sulfanilic compounds (1c)containing various groups as R2can be obtained by the interaction of sulfo the ilen compounds (1d), which can be obtained in a known manner or in accordance with the known method, with an electrophilic reagent (R2-Y1in the presence of a base.

Specifically, the compound (1d) is subjected to interaction with the number of R2-Y1from the equivalent to excess, in the presence of a base in the amount equivalent to the excess. The reaction temperature is usually in the range from -78°C to 200°C, and the reaction time is usually from 0.5 hours to 1 day.

The solvent can be used ether solvents, halogenated solvents, aromatic solvents, nitrile solvents, amide solvents and the like, separately or in combination. Of these solvents tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, toluene, etc. are preferred.

Examples of the deleted group represented by Y1include halogen atoms (such as chlorine, bromine and iodine), C1-6alkylsulfonates that can be galogenirovannyie (such as methanesulfonate, econsultancy, tripterocalyx) and C6-10aromatic uglevodorodyonogo, which may have a substituent. Examples of the substituent for the aromatic group uglevodorodyonogo include 1-3 halogen atom, a C1-6alkyl groups to which e can be galogenirovannyie, and C1-6alkoxygroup. Specific examples of groups C1-6aromatic uglevodorodyonogo, which may have a Deputy, include benzosulfimide, p-toluensulfonate, 1 naphthalenesulfonate and 2 naphthalenesulfonate.

Examples of the base include compounds alkylate (such as n-utility, second-utility and tert-utility), hydrides of alkali metals or alkaline earth metals (such as lithium hydride, sodium hydride, potassium hydride and calcium hydride), amides of alkali metals or alkaline earth metals (such as lithium amide, sodium amide, diisopropylamide lithium, dicyclohexylamine lithium hexamethyldisilazide lithium hexamethyldisilazide sodium and hexamethyldisilazide potassium), lower alkoxides of alkali metals or alkaline earth metals (such as sodium methoxide, ethoxide sodium tert-piperonyl potassium), hydroxides of alkali metals, alkaline earth metals or silver (such as silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide), carbonates of alkali metals, alkaline earth metals or silver (sodium carbonate, potassium carbonate, cesium carbonate and silver carbonate), bicarbonates of alkali metals (such as sodium bicarbonate and potassium bicarbonate), and silver oxide.

3-3)The method of obtaining sulfonylurea compounds (1c)

Sulfonylurea compound (1c) in accordance with the present invention can also be obtained, as described below, the interaction of the compound (3) with a salt of an alkali metal, alkaline earth metal or tetrabutylammonium and sulfinol acid of formula R3-SO2-M+(5).

[Chemical formula 8]

(where Y represents a group to delete, M+represents a metal ion and each of R1- R4defined above).

Specifically, the compound (3) is subjected to interaction with an equivalent or excess amount sulfinol acid or its salts (5) in a solvent. The reaction temperature is usually in the range from -20°C to 200°C, preferably from room temperature to 100°C. may Sometimes be preferred reaction temperature is above the specified limits, depending on the compound (3) or sulfinate (5). Sometimes preferably the reaction in a sealed tube. The reaction time is usually from 0.5 hours to 3 days, preferably from 0.5 hours to 1 day.

Examples of the solvent include alcohol solvents, ether solvents, halogenated solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and water. You can use a mixture of such solvents. Of these solvents, butanol, dimethoxy the Tang, N-organic, dimethylformamide and the like are preferred.

In the above-described methods for obtaining compounds (1) according to the present invention are sometimes necessary to protect substituent, such as a nitrogen atom, hydroxyl group or carboxyl group, and in this case you can use the well-known protective group, which can optionally be removed. The protective group, if necessary, you can remove common in the field of organic chemistry method.

One or more substituents in R1-R4sulfide compound (1a), sulfanilimide compounds (1b) and sulfonylurea compounds (1c)obtained by any of the methods described above, can be subjected to further structural change. For example, when the compound contains, in any of the R1-R4Deputy, substituted 1,3-dioxolane-2-ilen group, can be converted to the compound, substituted formyl group, by hydrolysis, carried out in a known manner. When the compound contains, in any of the R1-R4Deputy, replaced by bromine group, can be converted to the compound, substituted formyl group, in a known manner. Formyl group in a known manner to convert the carboxylic acid group, substituted or unsubstituted aminomethyl group, guy is roximately group, 2-(alkoxycarbonyl)atenolol group or the like, in Addition, the hydroxyl portion of hydroxymethylene group can be converted into the group of ester, carbonate, carbamate, halogen, nitrile, sulfonate or the like group in a known manner. Further, these groups may be converted into an alkoxy group, amine, amide, carboxylic acid, sulfide or the like, 2-(Alkoxycarbonyl)atenolol group can be converted to 2-carboxyaniline group or the like in a known manner. Not only the groups described above, but various functional groups other than hydroxyl groups, can also be subjected to such conversion. The conversion can be carried out in a known method. Specifically, when R2represents 2-chloro-4-pyridyloxy group, by reacting this compound with an amine, such as alkylamine, dialkylamino, benzylamino, pyrrolidine, piperidine or morpholine, you can get a pyridine derivative containing the group of chlorine at position 2, which replaced the above amine. In this case, the use of 3,4-dimethoxyphenethylamine gives 3,4-dimethoxybenzaldehyde, and processing of the received connection triperoxonane acid or nitrate of cerium-diammonium gives 2-aminopyridine derived. Moreover, by treating 2-aminopyridine derived by methanesulfonamido in the presence of pyridine floor the compound is converted into 2-methanesulfonylaminoethyl derived. At such stages of the conversion you can use the reagents, solvents and reaction conditions known to the experts in this field.

Compounds (1) according to the present invention obtained as described above can be converted into their salts or solvate using conventional methods.

Compounds (1) according to the present invention are strong inhibitron production or secretion β-amyloid protein and, thus, are useful as drugs for prevention or treatment of diseases resulting from abnormal production or secretion β-amyloid protein such as Alzheimer's disease and down syndrome, or other diseases associated with amyloid deposits.

When the compound of the present invention is used as a drug for humans, the daily dose for an adult is from 1 mg to 1 g, preferably from 10 mg to 300 mg When it is administered to animals, the dose varies depending on the purpose of the introduction (treatment or prevention), or the size of the animal being treated, the type of bacteria, which is an animal infected with, or degree of infection, but the daily dose is usually sostavit from 0.1 mg to 200 mg, preferably from 0.5 mg to 100 mg per kg of animal body weight. The daily dose is administered once a day or on lat into two to four doses for administration throughout the day. If necessary, the daily dose may exceed the above number.

Pharmaceutical composition comprising the compound of the present invention, can be formulated into a desired shape, selectable depending on the route of administration, with the help of various commonly used methods of obtaining. Examples of forms of pharmaceutical composition containing as a main ingredient a compound of the present invention include preparations for oral administration such as tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions.

Preparations for injection may contain a stabilizer, an antiseptic, solubilizers substance or the like is Also possible restructuring immediately before use solid product, which was obtained by filling the vessel with a solution that may contain the substance, and then dried. In one vessel can be included quantity for a single administration or in one vessel may include a number of multiple introductions.

Examples of drugs for external use include liquids, suspensions, emulsions, ointments, gels, creams, lotions, sprays and patches.

Solid preparations together with the compound of the present invention contain a pharmaceutically acceptable additive. They can in order to teach by mixing the compounds of the present invention with additives, selected from fillers, substances that create volume, binders, disintegrating agents, agents that promote dissolution, moisturizers and lubricants, as necessary.

Examples of liquid preparations include solutions, suspensions and emulsions. As the additives they contain suspendisse substance or emulsifier.

Examples

Further, the present invention is described in more detail by means of examples. However, it should be borne in mind that the scope of the present invention is not limited to the following examples. All compounds obtained as described below in the examples are specific to either E-type or Z-type, unless specifically stated otherwise.

Reference Example 1:2-[(4-Chlorophenyl)sulfanilyl]-1,4-differenza

[Chemical formula 9]

Method 1:

1) When 0°C 4-chlorbenzoyl (of 5.45 g of 38.2 mmol), triphenylphosphine (11.1 g, to 41.6 mmol) and diisopropylethylamine (8,16 ml of 41.6 mmol) was sequentially added to a solution of 2,5-differenziava alcohol (5,00 g, to 34.7 mmol) in tetrahydrofuran (150 ml). The reaction mixture was stirred at room temperature for 4 days and then concentrated. The obtained residue was purified column chromatography on silica gel (1% ethyl acetate―hexane) to obtain 2-[(4-chlorophenyl)thiomethyl]-1,4-diferente (2,68 g, 29%) as a colourless m the ultralights.

1H-NMR (400 MHz, CDCl3) δ: Android 4.04 (2H, s), 6,85-to 7.00 (3H, m), 7.23 percent (4H, s).

2) After addition of 3-chloroperbenzoic acid (225 mg, of 1.30 mmol) to a solution of 2-[(4-chlorophenyl)thiomethyl]-1,4-diferente (271 mg, 1.00 mmol) in methylene chloride (5 ml) at 0°C the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with methylene chloride, washed with saturated aqueous solution of potassium bicarbonate and saturated saline solution, dried over MgSO4) and concentrated. The obtained residue was dissolved in methylene chloride (5 ml). After cooling to 0°C was added 3-chloroperbenzoic acid (450 mg, 2,60 mmol) and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with methylene chloride. The diluted solution was washed with a saturated aqueous solution of potassium bicarbonate and saturated saline solution, dried over MgSO4) and concentrated. The obtained residue was purified column chromatography on silica gel (9% ethyl acetate:hexane) to obtain the specified title compound (210 mg, 69%) as a colourless solid.

1H-NMR (400 MHz, CDCl3)δ: 4,36 (2H, s)6,91 (1H, TD, J=9,0, 4,4 Hz), 6,99-7,06 (1H, m), 7,11 (1H, DDD, J=8,3, 5,6, and 3.2 Hz), was 7.45 (2H, d, J=8,8 Hz), a 7.62 (2H, d, J=8,8 Hz).

MS (m/z): 303 (M++H).

Method 2:

1) After adding potassium carbonate (4,00 g, 29,0 mmol) and 2-b is amatil-1,4-diferente (5,00 g, and 24.2 mmol) to a solution of 4-chlorbenzoyl (3,86 g of 26.6 mmol) in N,N-dimethylformamide (120 ml) the resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture were added a saturated solution of ammonium chloride (50 ml) and water (20 ml), then was extracted with diethyl ether. The extracts were combined, washed with water and saturated saline solution, dried over MgSO4) and concentrated. The obtained residue was purified column chromatography on silica gel (1% ethyl acetate:hexane) to obtain 2-[(4-chlorophenyl)thiomethyl]-1,4-diferente (6,41 g, 98%) as a colourless oil.

2) H2O (16.4 ml), 30% H2O2(16.4 ml, 145 mmol) and tetrahydrate hexaminolevulinate (425 mg, 0,344 mmol) was added at 0°C to a solution of 2-[(4-chlorophenyl)thiomethyl]-1,4-diferente (6,54 g, 24,1 mmol) in methanol (100 ml). The resulting mixture was stirred for 1 hour, followed by stirring at room temperature for 15 hours. Besieged thus, the solid was collected by filtration and the filtrate was concentrated to approximately half its quantity. The resulting aqueous solution was extracted with methylene chloride. The obtained solid substance was first dissolved in the extract. The resulting solution was washed successively with water and saturated saline solution, dried over MgSO4) and concentrated. The obtained OST is OK recrystallized from hexane to obtain specified in the connection header (6,34 g, 87%) as colorless needle crystals.

Method 3: To a suspension of 4-chlorobenzenesulfonate sodium (19,0 g, 95.5 mmol) in butanol (200 ml) was added 2-methyl bromide-1,4-differental (12.3 ml, 95.5 mmol). The resulting mixture was heated at the boil under reflux for 5 hours. Besieged thus, the solid was collected by filtration and dissolved in methylene chloride. The resulting solution was washed with saturated saline solution, dried over MgSO4). After concentrating the obtained solid was recrystallized from hexane to obtain specified in the title compound (12.3 g, 43%) as colorless needle crystals.

Reference Example 2:4-(4-Chlorophenylsulfonyl)pyridine

[Chemical formula 10]

A solution of the hydrochloride of 4-chloromethylpyridine (1.26 g, 7,65 mmol), 4-chlorobenzenesulfonate sodium (1.52 g, 7,65 mmol) and potassium acetate (1.50 g, and 15.3 mmol) in 1-propanol (50 ml) was stirred under heating at 70°C for 8 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was passed through a short column (silica gel, ethyl acetate) and the eluate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel, and the fraction obtained when e is funding hexane:ethyl acetate (=2:3), concentrated under reduced pressure to obtain specified in the title compound (1.26 g, 62%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: the 4.29 (2H, s), 7,06 (2H, d, J=6,1 Hz), 7,47 (2H, d, J=8,8 Hz), to 7.59 (2H, d, J=8.5 Hz), to 8.57 (2H, d, J=6,1 Hz).

MS (m/z): 268 (M++H).

Reference Example 3:2-[(2,5-Differenl)-hydroxymethyl]pyridine

[Chemical formula 11]

The solution (1,53M, to 3.92 ml, 0.6 mmol) n-utility in hexane in an argon atmosphere at -78°C was added dropwise to a solution of 2-bromopyridine (572 μl, 6 mmol) in tetrahydrofuran (10 ml) followed by stirring for 30 minutes. To the resulting brown solution was added dropwise 2.5-differentally (655 μl, 6 mmol) and the temperature of the reaction mixture was gradually raised to room temperature. To the reaction mixture were added water. The resulting mixture was then extracted with ethyl acetate. After removal of the solvent by drying the residue obtained by concentration under reduced pressure was purified by chromatography on silica gel with obtaining specified in the title compound (120 mg, 9%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: the 5.45 (1H, W), between 6.08 (1H, s), 6.87 in-to 7.15 (3H, m), 7,2-7,3 (2H, m), the 7.65 (1H, m), 8,56 (1H, m).

TPL: 65-66°C.

Reference Example 4:hydrochloride of 2-[chloro-(2,5-differenl)methyl]-3-methylpyridine

In argon atmosphere, the solution (1.5 ml, 3 mmol) isopropylacrylamide in tetrahydrofuran was added dropwise under ice cooling to a solution of 2-bromo-3-methylpyridine (510 mg, 3 mmol) in tetrahydrofuran (2.0 ml). The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise under ice cooling 2.5-differentally (328 μl, 3 mmol). The temperature of the reaction mixture is then gradually raised to room temperature. After adding a saturated aqueous solution of ammonium chloride the mixture was extracted with ethyl acetate. After removal of the solvent by drying the residue obtained by concentration under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=8:1) to obtain a mixture containing specified in the header connection. To the mixture was added thionyl chloride (2.0 ml) and one drop of dimethylformamide. The resulting mixture was stirred at room temperature for 14 hours. The excess thionyl chloride drove under reduced pressure to obtain a white precipitate. The residue was ground into powder with hexane and diethyl ether to obtain specified in the title compound (101 mg, 12%).

1H-NMR (400 MHz, CDCl3)δ: is 2.37 (3H, s), 6,95-7,10 (2H, m), 7,28 (1H, s), 7,7-7,8 (2H, m), 8,11 (1H, d, J=6.3 Hz), 8,72 (1H, d, J=4,9 Hz).

<> TPL: 118-119°C.

MS m/z: 254 (M++H).

Reference Example 5:2-[(2,5-Differenl)-hydroxymethyl]-5-methylpyridin

[Chemical formula 13]

In argon atmosphere, the solution (1.5 ml, 3 mmol) isopropylacrylamide in tetrahydrofuran was added dropwise under ice cooling to a solution of 2-bromo-5-methylpyridine (510 mg, 3 mmol) in tetrahydrofuran (2 ml). The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise under ice cooling 2.5-differentally (328 μl, 3 mmol) and then the temperature of the reaction mixture was gradually raised to room temperature. To the reaction mixture were added saturated aqueous solution of ammonium chloride and then the mixture was extracted with ethyl acetate. After removal of the solvent by drying the residue obtained by concentration under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (130 mg, 18%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,31 (3H, s)5,38 (1H, W), 6,04 (1H, s), 6,83-to 7.18 (4H, m), 7,44 (1H, DD, J=2,0, 8.0 Hz), of 8.37 (1H, m).

MS m/z: 236 (M++H).

Reference Example 6:2-[(2,5-Differenl)-hydroxymethyl]-4-methylpyridin

[Chemical formula 14]

In argon atmosphere, the solution (1.5 ml,3 mmol) isopropylacrylamide in tetrahydrofuran was added dropwise under ice cooling to a solution of 2-bromo-4-methylpyridine (334 μl, 3 mmol) in tetrahydrofuran (2 ml). The resulting mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise under ice cooling 2.5-differentally (328 μl, 3 mmol). The temperature of the mixture was gradually raised to room temperature. After adding a saturated aqueous solution of ammonium chloride the mixture was extracted with ethyl acetate. Then solvent was removed by drying. The residue obtained by concentration under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (456 mg, 65%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 2,30 (3H, s), of 5.48 (1H, Sirs), of 6.02 (1H, s), 6,83-7,13 (5H, m), scored 8.38 (1H, m).

TPL: 105-106°C.

MS m/z: 236 (M++H).

Reference Example 7:2-Bromo-3-methoxypyridine

[Chemical formula 15]

In nitrogen atmosphere sodium hydride, 60% in oil (605 mg, 15.1 mmol)was added in portions with ice cooling to a methanol (10 ml). Twenty minutes was added a solution of 2-bromo-3-hydroxypyridine (2.5 g, 14.4 mmol) in dimethylformamide (20 ml). The resulting mixture is kept off the methanol under reduced pressure. To the residue was added methyliodide (0,94 ml, 15.1 mmol), followed by stirring at room temperature during the 3 hours. Then the reaction mixture was concentrated to dryness, and the concentrate was added water (50 ml) and a simple ether (50 ml). The organic layer was separated and washed with saturated aqueous sodium bicarbonate and saturated saline solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove solvent. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=8:1) to obtain the specified title compound (1.51 g, 56%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 3,90 (3H, s), 7,12 (1H, m), 7,21 (1H, DD, J=4,8, 8.0 Hz), of 7.97 (1H, m).

TPL: 34°C.

Referential Example 8:3 Allyloxy-2-bromopyridin

[Chemical formula 16]

The synthesis was carried out in the same way that used for the synthesis of 2-bromo-3-methoxypyridine, obtaining specified in the title compound (2.35 g, 76%) as oil.

1H-NMR (400 MHz, CDCl3)δ: to 4.62 (2H, m), 5,33 (1H, DD, J=1,2, 10.4 Hz), vs. 5.47 (1H, DD, J=1,2, 17.6 Hz), the 6.06 (1H, m), 7,11 (1H, DD, J=1.2 Hz, 8.0 Hz), 7,18 (1H, DD, J=4,8, 8.0 Hz), 7,98 (1H, m).

MS m/z: 215 (M++H).

Referential Example 9:2-[(2,5-Differenl)-hydroxymethyl]-3-methoxypyridine

[Chemical formula 17]

In argon atmosphere, the solution (1.5 ml, 3 mmol) isopropylacrylamide in tetrahydrofuran was added dropwise with cooling gap is the situation with ice to a solution of 2-bromo-3-methoxypyridine (564 mg, 3 mmol) in tetrahydrofuran (2 ml). The reaction mixture was then stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise under ice cooling 2.5-differentally (328 μl, 3 mmol). The temperature of the reaction mixture was gradually raised to room temperature. After adding a saturated aqueous solution of ammonium chloride the mixture was extracted with ethyl acetate. After removal of the solvent by drying needle crystals obtained by concentration under reduced pressure, triturated to powder with hexane to obtain specified in the title compound (660 mg, 88%).

1H-NMR (400 MHz, CDCl3)δ: 3,71 (3H, s)to 5.56 (1H, Shir., J=6.0 Hz), 6,16 (1H, d, J=6.0 Hz), 's 6.75 to 7.00 (3H, m), 7,14 (1H, m), 7,26 (1H, m), 8,18 (1H, m).

TPL: 94-95°C.

MS m/z: 252 (M++H).

Reference Example 10:3 Allyloxy-2-[(2,5-differenl)-hydroxymethyl]pyridine

[Chemical formula 18]

In argon atmosphere, the solution (1.5 ml, 3 mmol) isopropylacrylamide in tetrahydrofuran was added dropwise under ice cooling to a solution of 3-allyloxy-2-bromopyridine (642 mg, 3 mmol)obtained in reference example 8, in tetrahydrofuran (2 ml). The mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise under ice cooling is m 2.5-differentally (328 μl, 3 mmol). The temperature of the reaction mixture was gradually raised to room temperature. To the reaction mixture were added saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate. Then solvent was removed by drying and the residue obtained by concentration under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the specified title compound (375 mg, 45%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 4.38 (1H, m), of 4.44 (1H, m), 5,16 (1H, m), is 5.18 (1H, m), 5,61 (1H, Shir., J=6.4 Hz), 5,78 (1H, m), 6,17 (1H, d, J=6.0 Hz), 6.73 x-of 6.96 (3H, m), 7,10 (1H, m), 7,22 (1H, m), 8,19 (1H, m).

MS m/z: 278 (M++H).

Referential Example 11:3-[(2,5-Differenl)-hydroxymethyl]pyridine

[Chemical formula 19]

In argon atmosphere, the solution (1.5 ml, 3 mmol) isopropylacrylamide in tetrahydrofuran was added dropwise under ice cooling to a solution of 3-bromopyridine (286 μl, 3 mmol) in tetrahydrofuran (2 ml). The mixture was stirred at room temperature for 60 minutes. To the resulting brown solution was added dropwise under ice cooling 2.5-differentally (328 μl, 3 mmol). The temperature of the reaction mixture was gradually raised to room temperature. To the reaction mixture were added saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate. Then is alali the solvent by drying. The residue remaining after concentration under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (296 mg, 45%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 3,76 (1H, W), 6,10 (1H, s), 6,88-6,98 (2H, m), 7,20-7,30 (2H, m), of 7.70 (1H, m), 8,42 (1H, d, J=4,8 Hz), 8,53 (1H, m).

TPL: 79-80°C.

Reference Example 12:5-[(2,5-Differenl)-hydroxymethyl]pyrimidine

[Chemical formula 20]

In the same manner as in reference example 11 was obtained is listed in the title compound (117 mg, 18%) in the form of oil, using a 5-bromopyrimidine.

1H-NMR (400 MHz, CDCl3)δ: 6,12 (1H, s), 6.90 to-7,02 (2H, m), 7,26 (1H, m), to 8.70 (2H, s), 9,04 (1H, s).

MS m/z: 205 (M+-OH).

Reference Example 13:2-[(tert-Butoxycarbonylamino)-(2,5-differenl)methyl]-1-methyl-1H-benzimidazole

[Chemical formula 21]

Solution in acetonitrile (3 ml) of 2,5-diferentialglea (164 μl, 1.5 mmol), 1-methylbenzimidazole (132 mg, 1 mmol) and di-tert-BUTYLCARBAMATE (252 μl, 1.1 mmol) was stirred at room temperature for 20 hours. The precipitate was collected by filtration and then was ground into powder with hexane to obtain specified in the title compound (310 mg, 83%) as a white solid.

1H-NMR (400 MHz, CDCl3)4 : to 1.45 (9H, s), 3,86 (3H, s), the 6.9 to 7.0 (2H, m), 7,12 (1H, s), 7,22-to 7.35 (3H, m), 7,45 (1H, m), to 7.77 (1H, d, J=8.0 Hz).

TPL: 163-164°C.

MS m/z: 375 (M++H).

Reference Example 14:2-[(tert-Butoxycarbonylamino)-(2,5-differenl)methyl]-1-methyl-5-chloro-1H-imidazol

[Chemical formula 22]

Solution in acetonitrile (6 ml) of 2,5-diferentialglea (327 μl, 3 mmol), 5-chloro-1-methylimidazole (187 mg, 2 mmol) and di-tert-BUTYLCARBAMATE (504 μl, 2.2 mmol) was stirred at room temperature for 20 hours. The precipitate was collected by filtration, and then was ground into powder with hexane to obtain specified in the title compound (472 mg, 66%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: to 1.48 (9H, s)to 3.67 (3H, s), 6,88 and 7.1 (4H, m), 7,39 (1H, m).

TPL: 125-126°C.

MS m/z: 359 (M++H).

Reference Example 15:2-[(2,5-Differenl)-hydroxymethyl]thiazole

[Chemical formula 23]

To a solution of 2-bromothiazole (180 mg, 2 mmol) in tetrahydrofuran (10 ml) was added dropwise at -78°C a solution of n-utility (1,57M, 1,40 ml, 2.2 mmol) in hexane, followed by stirring for 10 minutes. Then add 2.5-differentally (238 μl, 2.2 mmol) and the temperature of the mixture was gradually raised to 0°C under stirring. For completion of the reaction was added an aqueous solution of chloride of shumilkin) and to the reaction mixture was added a simple ether. The ether layer was washed with water and saturated saline and then dried over anhydrous magnesium sulfate. After filtration the solution was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (358 mg, 79%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.77 (1H, d, J=4.0 Hz), 6,33 (1H, d, J=4.0 Hz), 6,95-7,10 (2H, m), 7,24 (1H, m), 7,34 (1H, d, J=3.6 Hz), of 7.75 (1H, d, J=3.6 Hz).

MS m/z: 228 (M++H).

Reference Example 16:2-[(tert-Butoxycarbonylamino)-(2,5-differenl)methyl]-1-(4-methoxyphenyl)-1H-imidazol

[Chemical formula 24]

A solution of 2,5-diferentialglea (327 μl, 3 mmol), 1-(4-methoxyphenyl)imidazole (348 mg, 2 mmol) and di-tert-BUTYLCARBAMATE (504 μl, 2.2 mmol) in acetonitrile (6 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated and then the residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1 → 1:1) to obtain the specified title compound (774 mg, 93%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.40 (9H, s), 3,86 (3H, s)6,76 (1H, s), 6.90 to-7,00 (4H, m), 7,02 (1H, s), 7,11 (1H, s), 7,26 (2H, m), 7,33 (1H, m).

MS m/z: 417 (M++H).

Reference Example 17:5-Chloro-2-pyridinyl

[Chemical formula 25]

To a solution of 2,5-dichloropyridine (296 mg, 2.0 mmol) in ethanol (4 ml) was added thiourea (152 mg, 2.00 mmol). Then the mixture was heated at the boil under reflux for 18 hours. After cooling the reaction mixture to room temperature, added water (1 ml) solution of potassium hydroxide (198 mg, 3.00 mmol) and the mixture was heated at the boil under reflux for 3 hours. The reaction mixture was cooled to room temperature. Then added water and the mixture was washed with dichloromethane. The aqueous layer was acidified with acetic acid and then was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then filtered. After filtration, the filtrate was concentrated under reduced pressure. The obtained solid is washed with diethyl ether and collected by filtration to obtain specified in the title compound (83 mg, or 0.57 mmol, 29%) as a yellow powder.

1H-NMR (400 MHz, CDCl3)δ: to 7.35 (1H, DD, J=9,3, 2.4 Hz), 7,46 (1H, d, J=9.3 Hz), to 7.64 (1H, d, J=2,4 Hz).

MS m/z: 146 (M++H).

Reference Example 18:2.5-Differenl-4-pyridinemethanol

[Chemical formula 26]

A solution of 1-bromo-2,5-diferente (1.08 ml, 9,60 mmol) in tetrahydrofuran (30 ml) was stirred at -78°C, and then the solution was added n-utility (7,32 ml, 11.5 mmol) in hexane. To the reaction mixture was added at -78°C solution of 4-pyridinecarboxamide (0,764 ml of 8.00 mmol) in tetrahydro is the furan (10 ml). The resulting mixture was stirred at the same temperature for 30 minutes. After the temperature of the reaction mixture was raised to room temperature, was added diethyl ether. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=7:3 was concentrated under reduced pressure. The obtained solid is washed with diisopropyl ether and then collected by filtration to obtain specified in the connection header (1,15 g, 5,20 mmol, 65%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 4.25 (1H, Shir. C)6,09 (1H, s), 6.89 in-7,05 (2H, m), 7,14-of 7.23 (1H, m), 7,34 (2H, d, J=5.4 Hz), 8,44 (2H, d, J=5.4 Hz).

Reference Example 19:Tetrahydrothiopyran-4-ol

[Chemical formula 27]

Tetrahydrothiopyran-4-one (5,00 g, 43,0 mmol) was dissolved in methanol (100 ml). Then to the resulting solution was added under cooling with ice borohydride sodium (1.6 g, of 42.3 mmol) and the resulting mixture was stirred at room temperature for 14 hours. To the residue obtained by concentration of the reaction mixture under reduced pressure, was added to the control (50 ml). Then the liquid resulting mixture was slightly acidified 1 N. a solution of hydrochloric acid and then was extracted with diethyl ether. The extract was sequentially washed with 1 N. a solution of hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain specified in the connection header (4,40 g that 37.2 mmol, 87%) as pale yellow-brown solid.

1H-NMR (400 MHz, CDCl3)δ: 1,47 (1H, Shir. C), 1,64 and 1.80 (2H, m), 2,10-of 2.24 (2H, m), 2,55-2,70 (2H, m), 2,73-is 2.88 (2H, m), 3,60 of 3.75 (1H, m).

MS m/z: 119 (M++H).

Reference Example 20:5-Dibromomethyl-2-(2,5-differentail)pyridine (Compound A) and 5-methyl bromide-2-(2,5-differentail)pyridine (Compound B)

[Chemical formula 28]

When heated and boiled under reflux of n-bromosuccinimide (17.0 g, or 95.7 mmol) and a catalytic amount of 2,2'-azobis(2-methylpropionitrile) was added to a solution of 2-[(2,5-differenl)-hydroxymethyl]-5-methylpyridine (7.50 g, 31.9 per mmol)obtained in reference example 5, in carbon tetrachloride (100 ml). The resulting mixture was stirred at the boiling point under reflux for 24 hours. The reaction mixture was cooled to room is temperature and the formed precipitate was filtered. The precipitate was added to aqueous sodium thiosulfate solution and then was extracted with chloroform. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated saline, then was dried over sodium sulfate. The residue obtained by concentration of the solution under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate =10:1) to obtain specified in the header of the connection A (3,91 g, 31%) and are specified in the connection header B (3,34 g, 34%), each in the form of oil.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 6,70 (1H, s), 7,12 (1H, m), 7,24 (1H, m), 7,39 (1H, m)to 8.12 (1H, d, J=8,4 Hz), 8,19 (1H, DD, J=2.0 a, and 8.4 Hz), 8,77 (1H, d, J=2.0 Hz).

MS m/z: 392 (M++H).

Compound B

1H-NMR (400 MHz, CDCl3)δ: to 4.52 (2H, s), 7,12 (1H, m), 7,21 (1H, m), 7,39 (1H, m), 7,94 (1H, DD, J=2,0, 8.0 Hz), 8,08 (1H, d, J=8.0 Hz), 8,67 (1H, d, J=2.0 Hz).

MS m/z: 313 (M++H).

Reference Example 21:[6-(2,5-Diferenzierbarer)pyridine-3-yl]acetate

[Chemical formula 29]

When heated and boiled under reflux of n-bromosuccinimide (6.0 g, 33.6 mmol) and a catalytic amount of 2,2'-azobis(2-methylpropionitrile) was added to a solution of 2-[(2,5-differenl)-hydroxymethyl]-5-methylpyridine (2.64 g, and 11.2 mmol)obtained in reference example 5, in carbon tetrachloride (60 ml). The resulting mixture was then stirred. After boiling with inverse x is Hladilnika within 7 hours the reaction mixture was cooled to room temperature and was added to aqueous sodium thiosulfate solution. The resulting mixture was extracted with simple ether. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated saline, then was dried over sodium sulfate. The residue obtained by concentration of the solution under reduced pressure, was dissolved in toluene. The resulting solution was again concentrated.

The obtained residue was dissolved in N,N-dimethylformamide (20 ml). To the resulting solution was added sodium acetate (4.59 g, 56 mmol) and the mixture was stirred at 70°C for 17 hours. After cooling, the reaction mixture was dissolved in ethyl acetate (100 ml). The solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (600 mg, 18%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,12 (3H, s), 5,19 (2H, s), 7,10 (1H, m), 7,19 (1H, m), 7,37 (1H, s), 7,88 (1H, DD, J=2,4,8,0 Hz), 8,07 (1H, d, J=8.0 Hz), to 8.62 (1H, d, J=2,4 Hz).

MS m/z: 292 (M++H).

Reference Example 22:2-[(2,5-Differenl)-hydroxymethyl]-5-(1,3-dioxolane-2-yl)pyridine

[Chemical formula 30]

To a solution of pyridine (60 ml) 5-dibromomethyl-2-(2,5-differentail)pyridine (Compound A) (3,91 g, 10 mmol)obtained in reference example 20 was added to the ethyl shall glycol (6.2 g, 100 mmol). The resulting mixture was stirred under heating at 90°C for 17 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in a simple ether (200 ml). The resulting solution was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (60 ml). To the resulting solution was added under cooling with ice borohydride sodium (190 mg, 5 mmol). The resulting mixture was stirred at room temperature for 1 hour. After addition of water the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1 → 1:1) to obtain the specified title compound (1.52 g, 52%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 4,0-4,2 (4H, m), of 5.84 (1H, s), 6,10 (1H, s)6,91 (1H, m), of 6.99 (1H, m), to 7.09 (1H, m), 7,26 (1H, d, J=8.0 Hz), 7,76 (1H, DD, J=2,0, 8.0 Hz), 8,64 (1H, d, J=2.0 Hz).

MS m/z: 294 (M++H).

Reference Example 23:3-Chloro-4-[(2,5-differenl)-hydroxymethyl]pyridine

[Chemical formula 31]

To a solution of Diisopropylamine (1.4 ml, 10 mmol) in t is traditionale (14 ml) at -78° C was added n-utility (6.3 ml, 1,59M solution in hexane). The resulting mixture was stirred for 10 minutes, then added 3-chloropyridin (1.13 g, 10 mmol). Thirty minutes was added 2,5-differentally (of 1.09 ml, 10 mmol) and the temperature of the mixture was gradually raised to 0°C. the Mixture was stirred for another 10 minutes. After adding an aqueous solution of ammonium chloride the mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with saturated saline and then dried. After filtration of the residue obtained by concentration of the solution under reduced pressure, triturated to powder with ethanol to obtain specified in the connection header (1,33 g, 52%).

1H-NMR (400 MHz, CDCl3)δ: 4,87 (1H, W), of 6.26 (1H, s), 6.90 to-7,02 (3H, m), 7,58 (1H, d, J=4,8 Hz), of 8.47 (1H, s), 8,48 (1H, d, J=4,8 Hz).

TPL: 169-170°C.

MS m/z: 255 (M+).

Reference Example 24:2,5-Dichloro-4-[(2,5-differenl)-hydroxymethyl]pyridine

[Chemical formula 32]

To a solution of Diisopropylamine (1.4 ml, 10 mmol) in tetrahydrofuran (14 ml) at -78°C was added n-utility (6.3 ml, 1,59M solution in hexane). After stirring for 10 minutes to the reaction mixture were added 2.5-dichloropyridine (1.48 g, 10 mmol). Thirty minutes was added 2,5-differentally (of 1.09 ml, 10 mmol) and the temperature of the mixture fasting is n raised to the 0° C. Stirring was continued for another 10 minutes. After adding an aqueous solution of ammonium chloride the mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with saturated saline and then dried. After filtration of the residue obtained by concentration of the filtrate under reduced pressure, triturated to powder with ethanol to obtain specified in the connection header (1,93 g, 67%).

1H-NMR (400 MHz, CDCl3)δ: 2,64 (1H, d, J=4.0 Hz), 6,28 (1H, d, J=4.0 Hz), 6.89 in (1H, m), 7,02 (2H, m), of 7.64 (1H, s), 8,30 (1H, s).

TPL: 160-161°C.

MS m/z: 289 (M+).

Reference Example 25:(3,6-Dichloropyridine-2-yl)(pyridin-4-yl)methanol

[Chemical formula 33]

Under stirring at -78°C tert-utility (1,51M solution in pentane: 4,6 ml) was added dropwise to a solution of 2,5-dichloropyridine (1,02 g, 6,89 mmol) in a simple ether (20 ml). After stirring at -78°C within 2 hours to the reaction mixture was added pyridine-4-carbaldehyde (0,65 ml, 6,89 mmol). The resulting mixture was stirred at -78°C for 1 hour. Then to the reaction mixture were added water. The temperature of the mixture was raised to room temperature. The mixture was extracted with methylene chloride. The extract is then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Received the initial residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:50), concentrated under reduced pressure. The obtained solid substance was washed with a simple ether and then collected by filtration to obtain specified in the connection header (819 mg, is 3.21 mmol, 47%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: with 4.64 (1H, sird, J=6.3 Hz), 6,00 (1H, sird, J=6.3 Hz), 7,27 (1H, d, J=8.6 Hz), 7,31 (2H, d, J=5.8 Hz), to 7.67 (1H, d, J=8.6 Hz), to 8.57 (2H, d, J=5.8 Hz).

MS (m/z): 254 (M+).

Reference Example 26:O-ethyl S-(6-chloro-3-pyridyl)dithiocarbonate

[Chemical formula 34]

5-Amino-2-chloropyridine (643 mg, 3.00 mmol) was dissolved in 1 N. hydrochloric acid (10 ml). Was added dropwise at -5°C water (1 ml) solution of sodium nitrite (207 mg, 3.00 mmol). The reaction mixture was stirred at 60°C for 30 minutes and then at the same temperature was added dropwise water (1 ml) solution of O-utilitiesand potassium (481 mg, 3.00 mmol). The reaction mixture was stirred at 80°C for 1 hour, then the reaction mixture was cooled to room temperature. Added ethyl acetate and the resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to Nochnoi flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=49:1 was concentrated under reduced pressure to obtain specified in the title compound (148 mg, 0,63 mmol, 21%) as a yellow oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.37 (3H, t, J=7,1 Hz), 4,63 (2H, t, J=7,1 Hz), 7,41 (1H, d, J=8,3 Hz), 7,76 (1H, DD, J=8,3,2,4 Hz), to 8.45 (1H, d, J=2,4 Hz).

MS m/z: 234(M++H).

Reference Example 27:(2,6-Dichloro-5-herperidin-3-yl)methanol

[Chemical formula 35]

Ethylchloride (1,32 ml of 13.8 mmol) was added under ice cooling to a solution of 2,6-dichloro-5-fornicating acid (2.76 g, 13,1 mmol) and triethylamine (1,92 ml of 13.8 mmol) in toluene (60 ml). After stirring at room temperature for 1 hour the reaction mixture was concentrated under reduced pressure.

The residue was dissolved in tetrahydrofuran (30 ml). The resulting solution was added dropwise, at -78°C, to a suspension of sociallyengaged (524 mg, of 13.8 mmol) in tetrahydrofuran (20 ml). The temperature of the reaction mixture was raised to 0°C. To the mixture was added dropwise 1 N. aqueous sodium hydroxide solution (of 3.25 ml). The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under decreased the pressure obtaining specified in the connection header (1,93 g, 9,85 mmol, 75%) as an orange solid.

1H-NMR (400 MHz, CDCl3)δ: 2,18 (1H, Shir. C)of 4.77 (2H, s), to 7.77 (1H, d, J=7,8 Hz).

TPL: 65-67°C.

Reference Example 28:3-(tert-Butyldiphenylsilyl)-5-herperidin

[Chemical formula 36]

To a solution of (2,6-dichloro-5-herperidin-3-yl)methanol (18,9 g of 96.2 mmol)obtained in reference example 27, and triethylamine (32,2 ml, 231 mmol) in ethanol (650 ml) was added the catalyst, 10% palladium on carbon (3,20 g). The resulting mixture was stirred for 7 hours in an atmosphere of hydrogen. The catalyst was filtered through celite, then the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution and then was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure.

The obtained residue was dissolved in dichloromethane (600 ml). To the resulting solution was sequentially added triethylamine (of 14.8 ml, 106 mmol), tert-butylchloroformate (25,0 ml, 96.3 mmol) and 4-dimethylaminopyridine (1.18 g, 9,63 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over besod the first sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate=19:1 was concentrated under reduced pressure to obtain specified in the title compound (30.0 g, or 81.9 mmol, 85%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 1,10 (9H, s), 4,78 (2H, s), of 7.36-7,49 (7H, m), 7,63-of 7.70 (4H, m), 8,32 (1H, s), at 8.36 (1H, d, J=2,4 Hz).

MS m/z: 366 (M++H).

Reference Example 29:[5-(tert-Butyldiphenylsilyl)-3-herperidin-2-yl] (2.5-differenl)methanol

[Chemical formula 37]

At -78°C a solution of n-utility in hexane (30,0 ml, 46.8 mmol) and N,N,N',N'-tetramethylethylenediamine (7,06 ml, 46.8 mmol) were added sequentially to diethyl ether (250 ml). After stirring at -20°C for 30 minutes, the reaction mixture was cooled to -78°C was added a solution of 3-(tert-butyldiphenylsilyl)-5-herperidin (15.5 g, 42,5 mmol) in diethyl ether (50 ml). The resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added 2.5-differentally (6,04 g, 42,5 mmol). The resulting mixture was stirred for 2 hours. To the reaction mixture was added water, and then saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with diethyl ether. About the organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under reduced pressure to obtain specified in the title compound (17.0 g, a 33.5 mmol, 79%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 1,10 (9H, s), 4,78 (2H, s), 5,12 (1H, d, J=6.6 Hz), to 6.22 (1H, d, J=6.6 Hz), 6.87 in? 7.04 baby mortality (3H, m), 7,33-of 7.48 (7H, m), to 7.61-of 7.70 (4H, m), 8,32 (1H, s).

MS m/z: 508 (M++H).

Reference Example 30:(2.5-Differenl) (3-fluoro-5-hydroxymethyluracil-2-yl)methanol

[Chemical formula 38]

To a solution of [5-(tert-butyldiphenylsilyl)-3-herperidin-2-yl] (2.5-differenl)methanol (853 mg, 1,68 mmol) in tetrahydrofuran (7 ml) solution was added (the 1.04 ml, 1.04 mmol) tetrabutylammonium in tetrahydrofuran. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and then the resulting residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained at lwiro the years with a mixture of hexane:ethyl acetate=1:1, concentrated under reduced pressure to obtain specified in the title compound (413 mg, 1.53 mmol, 91 %) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 1,91 (1H, t, J=5.4 Hz), 4,79 (2H, d, J=5.4 Hz), 5,16 (1H, d, J=6.6 Hz), 6,23 (1H, d, J=6.6 Hz), 6.75 in? 7.04 baby mortality (3H, m), 7,46 (1H, d, J=9.8 Hz), to 8.41 (1H, s).

TPL: 94-96°C.

MS m/z: 270 (M++H).

Reference Example 31:6-(2,5-Differenl)hydroxymethyl-5-fornicating

[Chemical formula 39]

To a solution of (2,5-differenl) (3-fluoro-5-hydroxymethyluracil-2-yl)methanol (406 mg and 1.51 mmol)obtained in reference example 30, in acetone (9 ml) was added water (9 ml) solution of potassium permanganate (795 mg, 7.03 mmol) and the resulting mixture was heated at the boil under reflux for 4 hours. The precipitate was filtered through celite. The filtrate was acidified using 1 N. a solution of hydrochloric acid and then was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of hexane and dichloromethane and then collected by filtration to obtain a white solid (367 mg).

To a solution of the obtained solid (240 mg) in N,N-dimethylformamide (8 ml) was added hexaphosphate 1H-benzotriazol-1-electroparadise one (666 mg, 1.28 mmol), benzotriazol-1-ol (173 mg, 1.28 mmol), N-ethyldiethanolamine (0,595 ml, to 3.41 mmol) and ammonium chloride (91 mg, 1,71 mmol) and the resulting mixture was stirred at room temperature for 9 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed successively with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate=1:4, concentrated under reduced pressure.

The obtained residue was dissolved in ethanol (8 ml). When 0°C to the resulting solution was added borohydride sodium (30 mg, 0.79, which mmol). After stirring at room temperature for 1 hour to the reaction mixture were added water. The resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with ethyl acetate, concentrated under reduced pressure to obtain specified in the title compound (118 mg,0.42 mmol, 42%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: equal to 4.97 (1H, d, J=6.6 Hz), 6,27 (1H, d, J=6.6 Hz), 6,91-7,06 (3H, m), 7,87 (1H, DD, J=9,4, 1,6 Hz), 8,81 (1H, s).

TPL: 162-164°C.

MS m/z: 283 (M++H).

Reference Example 32:2-[(2,5-Differenl)hydroxymethyl]-6-(1,3-dioxolane-2-yl)pyridine

[Chemical formula 40]

The solution isopropylacrylamide (2,0M, and 12.4 ml of 24.8 mmol) in tetrahydrofuran in an argon atmosphere was added dropwise under ice cooling to a solution of 2-bromo-6-(1,3-dioxolane-2-yl)pyridine (2.7 ml of 24.8 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred at room temperature for 3 hours. To the resulting brown solution was added dropwise under ice cooling 2.5-differentally (2.7 ml of 24.8 mmol). The temperature of the reaction mixture was gradually raised to room temperature and then stirring was continued for 16 hours. Was added a saturated aqueous solution of ammonium chloride, and then the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1, centered at p, the lower the pressure receiving specified in the connection header (2,90 g, of 9.89 mmol, 40%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 4.09 to is 4.21 (4H, m), 5,43 (1H, d, J=4.4 Hz), 5,90 (1H, s), 6,11 (1H, d, J=4.4 Hz), 6.87 in-6,95 (1H, m), 6,99-7,05 (1H, m), 7,10-to 7.15 (1H, m), 7.23 percent (1H, d, J=7.8 Hz), of 7.48 (1H, d, J=7.8 Hz), 7,72 (1H, t, J=7,8 Hz).

MS m/z: 294 (M++H).

Reference Example 33:1-[3-(tert-Butyldimethylsilyloxy)propyl]piperidine-2-he

[Chemical formula 41]

Sodium hydride (60% in oil, 2,22 g of 55.6 mmol) was added in portions at 0°C to a solution (200 ml) piperidine-2-it (5,00 g, and 50.5 mmol) in tetrahydrofuran. The reaction mixture was then stirred at room temperature for 3 hours. After adding to the reaction mixture (3 bromopropane)-tert-butyldimethylsilyl (14.1 ml, about 60.6 mmol) and N,N-dimethylformamide (20 ml) the resulting mixture was stirred at room temperature for 4 days. To the reaction mixture were added water and then was extracted with ethyl acetate. The extract was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1, was concentrated to obtain specified in the connection header (6,44 g of 23.8 mmol, 47%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: of 0.05 (6H, s)to 0.89 (9H, s), 1,74-of 1.85 (6H, m), a 2.36 (2H, t, J=6.0 Hz), 3.27 to of 3.32 (2H, m), 3,393,43 (2H, m), the 3.65 (2H, t, J=6.3 Hz).

MS m/z: 272 (M++H).

Reference Example 34:3-Bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]piperidine-2-he

[Chemical formula 42]

tert-Utility (1,50M solution in pentane, 1,40 ml, 2.10 mmol) was added dropwise in an argon atmosphere to a solution (5 ml) of 1-[3-(tert-butyldimethylsilyloxy)propyl]piperidine-2-it (542 mg, 2.00 mmol) in tetrahydrofuran at -78°C. the Reaction mixture was stirred at -78°C for 15 minutes. After adding to the reaction mixture solution tribromide tetrabutylammonium (1,16 g is 2.40 mmol) in tetrahydrofuran (5 ml) the temperature of the mixture was gradually raised to -40°C under stirring. To the reaction mixture at -40°C was added water and then the temperature of the mixture was raised to room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:3, was concentrated to obtain specified in the connection header (for 72.8 mg, 0,208 mmol, 10%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: of 0.05 (6H, s)to 0.89 (9H, s), 1,74-of 1.88 (3H, m), 2,18 of-2.32 (3H, m), 3,28-of 3.48 (4H, m), the 3.65 (2H, t, J=6,1 Hz), 4.53-in-of 4.57 (1H, m).

MS m/z: 350 (M+ +H).

Example 1:2-[[(4-Chlorophenyl)sulfonyl](cyclohexyl)methyl]-1,4-differenza

[Chemical formula 43]

2-[(4-Chlorophenyl)sulfanilyl]-1,4-differental (240 mg, 0,793 mmol)obtained in reference example 1 was dissolved in toluene (20 ml). After addition of cyclohexanol (of 0.11 ml, 1.0 mmol) and cyanomethylene-n-butylphosphine (250 mg, 1.0 mmol) the resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction mixture was allowed to cool and then was added cyclohexanol (to 0.22 ml, 2.1 mmol) and cyanomethylene-n-butylphosphate (500 mg, of 2.08 mmol). The resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction mixture was allowed to cool and was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=30:1) to obtain white solid. White solid was washed with hexane to obtain specified in the title compound (188 mg, 62%) as a white powder.

Melting point: 107-109°C.

1H-NMR (400 MHz, CDCl3)δ: 0,92-1,08 (1H, m), 1,08-1,22 (1H, m), 1,22 of 1.50 (3H, m), 1,60-1,75 (3H, m), 1,75-of 1.88 (1H, m), is 2.37 (1H, sird, J=12,5 Hz), 2,48-2,62 (1H, m), of 4.44 (1H, d, J=7,6 Hz), 6,68-to 6.80 (1H, m), 6,86-to 6.95 (1H, m,), 7,30 (2H, DM, J=8.6 Hz), 7,38-7,52 (1H, m), 7,49 (2H, DM, J=8.6 Hz).

Elemental Analysis for C9 H19ClF2O2S. Calculated: C 59,29; H 4,98; Cl Of 9.21; F 9,87; S 8,33. Found: C 59,11; H 4,93; Cl 9,18; F 9,82; S 8,49.

Example 2:4-[(4-Chlorophenylsulfonyl)(cyclopentyl)methyl]-pyridine

[Chemical formula 44]

Solution in toluene (5 ml) of 4-(4-chlorophenylsulfonyl)pyridine (70 mg, 0,261 mmol)obtained in reference example 2, Cyclopentanol (49 μl, 0,538 mmol) and cyanomethylene-n-butylphosphine (129 mg, 0,538 mol) was heated at the boil under reflux for 3 days in an atmosphere of argon. After cooling to room temperature, to the reaction mixture was added Cyclopentanol (49 μl, 0,538 mmol) and cyanomethylene-n-butylphosphate (129 mg, 0,538 mol). The reaction mixture was heated at the boil under reflux for 22 hours in an argon atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate (=2:1), concentrated under reduced pressure to obtain specified in the title compound (77 mg, 88%) as a white solid. The obtained solid was washed with hexane-simple ether and filtered to obtain specified in the title compound as a white powder.

The rate is temperature melting point: 133-135° C.

1H-NMR (400 MHz, CDCl3)δ: 0,92-1,08 (1H, m), 1,44 of-1.83 (6H, m), 2,33 at 2.45 (1H, m), 2,78-2,90 (1H, m), 3,88 (1H, d, J=10.3 Hz), 7,03 (2H, d, J=5,1 Hz), 7,32 (2H, d, J=8.6 Hz), the 7.43 (2H, d, J=8.6 Hz), 8,46 (2H, d, J=5.6 Hz).

Elemental Analysis for C17H18ClNO2S. Calculated: C 60,80; H Of 5.40; Cl 10,56; N 4,17; S Of 9.55. Found: C 60,76; H 5,44; Cl Is 10.68; N 4,20; S Being 9.61.

Example 3:4-[(4-Chlorophenylsulfonyl)(tetrahydropyran-4-yl)methyl]pyridine

[Chemical formula 45]

Solution in toluene (5 ml) of 4-(4-chlorophenylsulfonyl)pyridine (70 mg, 0,261 mmol)obtained in reference example 2, tetrahydropyran-4-ol (51 μl, 0,538 mmol) and cyanomethylene-n-butylphosphine (129 mg, 0,538 mol) was heated at the boil under reflux for 3 days in an atmosphere of argon. After cooling the reaction mixture to room temperature, to the mixture was added tetrahydropyran-4-ol (51 μl, 0,538 mmol) and cyanomethylene-n-butylphosphate (129 mg, 0,538 mol). The mixture was heated at the boil under reflux in an argon atmosphere for 22 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=1:2)was concentrated under reduced pressure to obtain specified in the title compound (6 mg, 71%) as a white solid. The obtained solid was washed with hexane-simple ether and filtered to obtain specified in the title compound as a white powder.

Melting point: 208-209°C.

1H-NMR (400 MHz, CDCl3)δ: 1,22-of 1.42 (2H, m), 1,60-1,75 (1H, m), 2,30-to 2.40 (1H, m), 2,78-a 3.01 (1H, m)to 3.41 (1H, TD, J=11,7, 2.4 Hz), 3,51 (1H, TD, J=11,9, 2.0 Hz), 3,80-3,93 (1H, m), a 3.87 (1H, d, J=8.6 Hz), 3,98-4,06 (1H, m), 7,00 for 7.12 (2H, m), 7,30 (2H, d, J=8,8 Hz), the 7.43 (2H, d, J=8.6 Hz), of 8.47 (2H, d, J=5.4 Hz).

MS (m/z): 352 (M++H).

Example 4:4-[(1-Benzylpiperidine-4-yl)(4-chlorophenylsulfonyl)methyl]pyridine

[Chemical formula 46]

Solution in toluene (5 ml) of 4-(4-chlorophenylsulfonyl)pyridine (70 mg, 0,261 mmol)obtained in reference example 2, 1-benzylpiperidine-4-ol (103 mg, 0,538 mmol) and cyanomethylene-n-butylphosphine (129 mg, 0,538 mol) was heated at the boil under reflux for 3 days in an atmosphere of argon. After cooling to room temperature, to the reaction mixture were added 1-benzylpiperidine-4-ol (103 mg, 0,538 mmol) and cyanomethylene-n-butylphosphate (129 mg, 0,538 mol). The resulting mixture was heated in an argon atmosphere while boiling under reflux for 22 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash is cromatografia on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:10), concentrated under reduced pressure. The obtained residue was purified by high-performance liquid chromatography (using a mixed solvent system of water/acetonitrile/formic acid), with specified title compound (40 mg, 35%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: to 1.21 to 1.37 (2H, m), 1,49 is 1.70 (1H, m), 1,92 is 2.01 (1H, m), 2,03 with 2.14 (1H, m), of 2.25 to 2.35 (1H, m), 2,52-to 2.65 (1H, m), 2,79-to 2.85 (1H, m), 2,90-of 3.00 (1H, m), 3,47 (2H, s), 3,86 (1H, d, J=8.1 Hz), 7,02-7,12 (2H, m), 7,20-7,38 (7H, m), the 7.43 (2H, d, J=8.5 Hz), to 8.45 (2H, d, J=5.4 Hz).

HRMS (FAB): as C24H26O2N2ClS (M++H).

Calculated: 441,1404. Found: 441,1387.

Example 5:4-[(4-Chlorophenylsulfonyl)(1 methylpiperidin-4-yl)methyl]pyridine

[Chemical formula 47]

A solution of 4-(4-chlorophenylsulfonyl)pyridine (70 mg, 0,261 mmol)obtained in reference example 2, 1-methylpiperidin-4-ol (62 μl, 0,538 mmol) and cyanomethylene-n-butylphosphine (62 μl, 0,538 mol) in toluene (5 ml) was heated at the boil under reflux for 3 days in an atmosphere of argon. After cooling to room temperature, to the reaction mixture were added 1-methylpiperidin-4-ol (62 μl, 0,538 mmol) and cyanomethylene-n-butylphosphate (129 mg, 0,538 mol). The resulting mixture was heated at the boiling reverse holodilniki is for 22 hours in an argon atmosphere. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:50), concentrated under reduced pressure. The obtained residue was purified by high-performance liquid chromatography (used a mixed solvent system of water/acetonitrile/formic acid) to obtain the specified title compound (31 mg, 33%) as a white solid. The obtained solid was washed with hexane-ether and filtered to obtain specified in the title compound as a white powder.

Melting point: 176-177°C.

1H-NMR (400 MHz, CDCl3)δ: 1,22-to 1.38 (2H, m), 1.50 is by 1.68 (1H, m), 1,88 of 1.99 (1H, m), 2,00-2,10 (1H, m), of 2.25 (3H, s), 2,30-to 2.40 (1H, m), 2,50-2,63 (1H, m), 2,74-and 2.83 (1H, m), 2,89-2,95 (1H, m), 3,86 (1H, d, J=8,3 Hz), was 7.08 (2H,, d, J=4.6 Hz), 7,30 (2H, d, J=8.6 Hz), 7,44 (2H, d, J=8.6 Hz), 8,46 (2H, d, J=5.6 Hz).

Elemental Analysis for C18H21ClN2O2S. Calculated: C 59,25; H 5,80; Cl 9,72; N 7,68; S 8,79. Found: C 59,00; H 5,76; Cl 9,75; N To 7.61; S 8,77.

Example 6:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)-methyl]pyridine

[Chemical formula 48]

2-[(2,5-Differenl)-hydroxymethyl]pyridine (88 mg, 0.40 mmol)obtained in reference example 3 was dissolved in thionyl chloride (2,ml). To the resulting solution was added a catalytic amount of dimethylformamide, followed by stirring for 15 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane and the resulting mixture was again concentrated. The residue was dissolved in dimethylformamide (5 ml). To the resulting solution under nitrogen atmosphere was added 4-chlorbenzoyl (79 mg, 0.55 mmol) and potassium carbonate (226 mg, of 1.64 mmol) and the mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (128 mg, 92%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 5.89 (1H, s), 6,80-7,27 (7H, m), 7,38 (1H, d, J=7,6 Hz), of 7.48 (1H, m), the 7.65 (1H, m), 8,63 (1H, m).

MS m/z: 348 (M++H).

Example 7:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-3-methylpyridin

[Chemical formula 49]

To a solution of the hydrochloride of 2-[chloro-(2,5-differenl)methyl]-3-methylpyridine (94 mg, 0.32 mmol)obtained in reference example 4 in dimethylformamide (5 ml) was added under nitrogen atmosphere 4-chlorobenzo the thiol (70 mg, 0.49 mmol) and potassium carbonate (265 mg, 1.92 mmol). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (103 mg, 89%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 2.21 (3H, s), by 5.87 (1H, s), 6,77 (1H, m), 7,00-7,19 (5H, m), of 7.36 (1H, m), 7,45 (1H, m), to 8.45 (1H, DD, J=1,2, 4,8 Hz).

MS m/z: 362 (M++H).

Example 8:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-4-methylpyridin

[Chemical formula 50]

After dissolving 2-[(2,5-differenl)-hydroxymethyl]-4-methylpyridine (235 mg, of 0.53 mmol)obtained in reference example 6, in thionyl chloride (2.0 ml) to the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated. The obtained residue was dissolved in dimethylformamide (10 ml). To the resulting solution under nitrogen atmosphere was added 4-chlorbenzoyl (217 mg, 1.5 mo is ü) and potassium carbonate (828 mg, 6.0 mmol). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (290 mg, 80%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,31 (3H, s), of 5.82 (1H, s), 6,80-7,0 (3H, m), to 7.15 (2H, d, J=8,8 Hz), 7,16 (1H, m), 7,21 (2H, d, J=8,8 Hz), 7,45 (1H, m), to 8.45 (1H, d, J=5.6 Hz).

MS m/z: 362 (M++H).

Example 9:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-3-methoxypyridine

[Chemical formula 51]

After dissolving 2-[(2,5-differenl)-hydroxymethyl]-3-methoxypyridine (251 mg, 1.0 mmol)obtained in reference example 9, in thionyl chloride (2.0 ml) to the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated. The obtained residue was dissolved in dimethylformamide (10 ml). To the resulting solution were added under nitrogen atmosphere 4-chlorbenzoyl (289 mg, 2.0 mmol) and carbon is potassium t (1.10 g, 8.0 mmol). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (256 mg, 58%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.77 (3H, s), and 6.25 (1H, s), PC 6.82 (2H, m), to 7.15 (2H, d, J=8,4 Hz), 7,10-7,20 (2H, m), 7,25 (2H, d, J=8,8 Hz), 7,52 (1H, m), 8,24 (1H, m).

MS m/z: 378 (M++H).

Example 10:3 Allyloxy-2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]pyridine

[Chemical formula 52]

3 Allyloxy-2-[(2,5-differenl)-hydroxymethyl]pyridine (370 mg, of 1.33 mmol)obtained in reference example 10, was dissolved in thionyl chloride (2.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated. The obtained residue was dissolved in dimethylformamide (10 ml). To the resulting solution were added under nitrogen atmosphere 4-chlorbenzoyl (217 mg, 1.5 mmol) and potassium carbonate (828 mg, 6.0 IMO is b). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (256 mg, 68%) as oil.

1H-NMR (400 MHz, CDCl3)δ: to 4.46 (2H, m), of 5.24 (1H, d, J=a 10.6 Hz), 5,28 (1H, d, J=and 17.2 Hz), 5,90 (1H, m), of 6.29 (1H, d, J=1.2 Hz), PC 6.82 (2H, m), to 7.15 (2H, d, J=8,4 Hz), 7,06-7,20 (2H, m), from 7.24 (2H, d, J=8,4 Hz)to 7.50 (1H, m), 8,24 (1H, m).

MS m/z: 404 (M++H).

Example 11:3-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]pyridine

[Chemical formula 53]

3-[(2,5-Differenl)-hydroxymethyl]pyridine (87 mg, 0,39 mmol)obtained in reference example 11, was dissolved in thionyl chloride (1.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide and the resulting mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane and the resulting mixture was again concentrated. The obtained residue was dissolved in dimethylformamide (5 ml)and then added in a nitrogen atmosphere 4-chlorbenzoyl (84 mg, of 0.58 mmol) and potassium carbonate (323 m is, 2.34 mmol). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (131 mg, 96%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 5,73 (1H, s), 6,84-of 6.96 (2H, m), 7,18 (2H, m), 7,19 (2H, m), 7,15-7,22 (2H, m), 7,71 (1H, m), 8,49 (1H, DD, J=1,6,4,8 Hz), 8,58 (1H, d, J=2.0 Hz).

MS m/z: 348 (M++H).

Example 12:5-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]pyrimidine

[Chemical formula 54]

5-[(2,5-Differenl)-hydroxymethyl]pyrimidine (111 mg, 0.5 mmol)obtained in reference example 12, was dissolved in thionyl chloride (1.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide and the resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane and the resulting mixture was again concentrated. The residue was dissolved in dimethylformamide (5 ml)and then added in a nitrogen atmosphere 4-chlorbenzoyl (108 mg, 0.75 mmol) and potassium carbonate (414 mg, 3.0 mmol). Received see what camping was stirred at 50° C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=4:1) mixture (202 mg) in the form of oil specified in the connection header and unidentified compounds.

1H-NMR (400 MHz, CDCl3)δ: to 5.66 (1H, s), of 6.96 (2H, m), 7,17-7,34 (5H, d), to 8.70 (2H, s), which is 9.09 (1H, s).

MS m/z: 349 (M++H).

Example 13:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]pyridine

[Chemical formula 55]

To a solution of 2-[[(4-chlorophenyl)thio]-(2,5-differenl)-methyl]pyridine (120 mg, 0,345 mmol)obtained in example 6 in methanol (12 ml) was added tetrahydrate hexaminolevulinate (80 mg). To the mixture was added 30% aqueous hydrogen peroxide solution (6 ml) followed by stirring for 24 hours. The precipitate was collected by filtration and recrystallized from ethanol to obtain specified in the title compound (96 mg, 73%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: to 5.93 (1H, s), 6.87 in-7,00 (2H, m), 7,28 (1H, m), 7,37 (2H, d, J=8,8 Hz), 7,53 (2H, d, J=8,8 Hz), 7,60 (1H, d, J=8.0 Hz), 7,71 (1H, m), 8,00 (1H, m), 8,59 (1H, m).

TPL 171-172° C.

MS m/z: 380 (M++H).

Elemental Analysis for C18H12ClF2NO2S. Calculated: C, 56,92; H, 3,18; N, 3,69; S, 8,44; Cl, Was 9.33; F, 10,00. Found: C, 56,76; H, 3,19; N, Of 3.77; S, 8,55; Cl, 9,27; F, 10,02.

Example 14:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)-methyl]-3-methylpyridin

[Chemical formula 56]

In the same way as in example 13, was received is indicated in the title compound (35 mg, 35%) as needle crystals by synthesis using 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-3-methylpyridine obtained in example 7, and purification by chromatography on silica gel (hexane:ethyl acetate=5:1).

1H-NMR (400 MHz, CDCl3)δ: a 2.36 (3H, s), 6,18 (1H, s), 6.89 in-7,02 (2H, m), 7,17 (1H, m), 7,37 (2H, d, J=8,4 Hz), 7,46 (1H, d, J=7,2 Hz), 7,53 (2H, d, J=8,4 Hz), of 8.06 (1H, m), 8,53 (1H, d, J=4.0 Hz).

TPL: 142-143°C.

Elemental Analysis for C19H14ClF2NO2S. Calculated: C,57,94; H,To 3.58; N,3,56; S,8,12; Cl,9,00; F,9,65. Found: C,58,03; H,3,66; N,3,78; S,8,12; Cl,9,13; F,9,59.

Example 15:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-5-methylpyridin

[Chemical formula 57]

1)2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-5-methylpyridin

[Chemical formula 58]

2-[(2,5-Differenl)-hydroxymethyl]-5-methylpyridin (125 mg, of 0.53 mmol)obtained in reference example 5 was dissolved in tinerilor the de (1.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated. The residue was dissolved in dimethylformamide (5 ml). To the resulting solution were added under nitrogen atmosphere 4-chlorbenzoyl (115 mg, 0.80 mmol) and potassium carbonate (438 mg, 3,18 mmol). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (120 mg, 66%) as oil.

1H-NMR (400 MHz, CDCl3)δ: to 2.29 (3H, s), of 5.83 (1H, s), 6,80-6,93 (2H, m), 7,16 (2H, m), 7,20 (2H, m), 7,28 (1H, m), the 7.43 (1H, m), to 8.41 (1H, d, J=0.8 Hz).

MS m/z: 362 (M++H).

2)2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-5-methylpyridin

In the same way as in example 13, was received is indicated in the title compound (91 mg, 73%) as needle crystals by synthesis using 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-5-methylpyridine obtained reacts is her above.

1H-NMR (400 MHz, CDCl3)δ: of 2.33 (3H, s), of 5.89 (1H, s), 6,88-7,01 (2H, m), 7,37 (2H, d, J=8,8 Hz), of 7.48-7,56 (2H, m), 7,53 (2H, d, J=8,8 Hz), to 7.99 (1H, m), 8,42 (1H, s).

TPL: 159-160°C.

Elemental Analysis for C19H14ClF2NO2S. Calculated: C,57,94; H,To 3.58; N,3,56; S,8,12; Cl,9,00; F,9,56. Found: C.57,88; H,3,61; N,3,68; S,8,27; Cl,9,11; F,9,70.

Example 16:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-4-methylpyridin

[Chemical formula 59]

In the same way as in example 13, was received is indicated in the title compound (140 mg, 95%) as needle crystals by synthesis using 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-4-methylpyridine obtained in example 8, and purification by chromatography on silica gel (hexane:ethyl acetate=3:1).

1H-NMR (400 MHz, CDCl3)δ: a 2.36 (3H, s), 5,88 (1H, s), 6,88-7,02 (2H, m), to 7.09 (1H, d, J=5,2 Hz), 7,37 (2H, d, J=8,8 Hz), 7,41 (1H, m), 7,52 (2H, d, J=8,8 Hz), of 7.97 (1H, m), 8,43 (1H, d, J=5,2 Hz).

TPL: 116-117°C.

Elemental Analysis for C19H14ClF2NO2S. Calculated: C,57,94; H,To 3.58; N,3,56; S,8,12; Cl,9,00; F,9,65. Found: C,57,80; H,3,66; N,3,72; S,8,29; Cl,9,05; F,9,71%.

Example 17:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-3-methoxypyridine

[Chemical formula 60]

In the same way as in example 13, was received is indicated in the title compound (71 mg, 87%) as colorless columnar cu is growth through synthesis using 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-3-methoxypyridine, obtained in example 9, and recrystallization from ethanol.

1H-NMR (400 MHz, CDCl3)δ: and 3.72 (3H, s), 6,62 (1H, s), 6.90 to? 7.04 baby mortality (2H, m), to 7.09 (1H, m), 7,24 (1H, m), 7,35 (2H, d, J=8,8 Hz), 7,53 (2H, d, J=8,8 Hz), 8,18 (1H, m), 8,30 (1H, m).

TPL: 184-185°C.

Elemental Analysis for C19H14ClF2NO3S. Calculated: C,55,68; H,3,44; N,3,42; S,7,82; Cl,8,65; F,9,27. Found: C,55,68; H,Of 3.45; N,Of 3.60; S,7,98; Cl,Total Of 8.74; F,9,23.

Example 18:3 Allyloxy-2-[[(4-chlorophenyl)sulfonyl]-(2,5-differenl)methyl]pyridine

[Chemical formula 61]

In the same way as in example 13, was received is indicated in the title compound (135 mg, 80%) as needle crystals using synthesis using 3-allyloxy-2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]pyridine obtained in example 10, and crystallization from ethanol.

1H-NMR (400 MHz, CDCl3)δ: of 4.38 (1H, m), 4,46 (1H, m), from 5.29 (1H, DD, J=1,2, 10.4 Hz), to 5.35 (1H, DD, J=1,2,17,2 Hz), to 5.93 (1H, m), of 6.68 (1H, s), 6,91? 7.04 baby mortality (2H, m), was 7.08 (1H, m), 7,22 (1H, DD, J=4,8, and 8.4 Hz), 7,34 (2H, d, J=8,8 Hz), 7,53 (2H, d, J=8,8 Hz), 8,17 (1H, m), 8,31 (1H, m).

TPL: 119-120°C.

Elemental Analysis for C21H16ClF2NO3S. Calculated: C,57,87; H,3,70; N,3,21; S Of 7.36; Cl,8,13; F,8,72. Found: C,57,90; H,Of 3.75; N,3,37; S,7,51; Cl,8,20; F,8,73.

Example 19:3-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]pyridine

[Chemical formula 62]

In the same way as in example 13, has been specified is in the title compound (118 mg, 86%) as needle crystals by synthesis using 3-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]pyridine obtained in example 11, and purification by chromatography on silica gel (hexane:ethyl acetate=4:1).

1H-NMR (400 MHz, CDCl3)δ: of 5.68 (1H, s), 6,91-7,07 (2H, m), 7,34 (1H, m), 7,40 (2H, d, J=8,4 Hz), EUR 7.57 (2H, d, J=8,4 Hz), 7,76 (1H, m), of 8.04 (1H, m), 8,53 (1H, d, J=2.0 Hz), 8,59 (1H, m).

TPL: 130-131°C.

Elemental Analysis for C18H12ClF2NO2S. Calculated: C,56,92; H,3,18; N,3,69; S,8,44; Cl,Was 9.33; F,10,00. Found: C,56,87; H,And 3.16; N,3,74; S,8,51; Cl,9,34; F,10,00.

Example 20:4-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)-methyl]pyridine

[Chemical formula 63]

2.5-Differenl-4-pyridinemethanol (75 mg, 0.34 mmol)obtained in reference example 18, was dissolved in thionyl chloride (1.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide and the mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane. The resulting mixture was again concentrated. The obtained residue was dissolved in dimethylformamide (5 ml)and then added in a nitrogen atmosphere 4-chlorbenzoyl (74 mg, 0.51 mmol) and potassium carbonate (281 mg, 2.04 mmol). The resulting mixture was stirred at 50°C for 1 hour. After cooling the reaction mixture to room temperature, to the mixture was added Dyatlov the th ether (50 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain a mixture containing 4-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]pyridine.

To a solution of the mixture in methanol (12 ml) was added tetrahydrate hexaminolevulinate (60 mg) and 30% aqueous hydrogen peroxide solution (6 ml) successively. The resulting mixture was stirred for 65 hours. To the reaction mixture were added ethyl acetate (80 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove solvent. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1-1:1) to obtain the specified title compound (51 mg, 39%). Recrystallization of the obtained compound from ethanol gave colorless needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 5,64 (1H, s), 6,91-7,06 (2H, m), 7,40 (2H, d, J=8.0 Hz), was 7.45 (2H, d, J=4,8 Hz), 7,58 (2H, d, J=8.0 Hz), of 7.70 (1H, s), 8,61 (2H, d, J=4,8 Hz).

TPL: 126-127°C.

Elemental Analysis for C18H12ClF2NO2S. Calculated: C,56,92; H,3,18; N,3,69; S,8,44; Cl,Was 9.33; F,10,00. Found: C,56,66; H,And 3.16; N,3,83; S,8,58; Cl,To 9.32; F,9,99.

Example 21:5-[[(4-Chlorophenyl)sulfonyl]-(2,5-differeni is)methyl]pyrimidine

[Chemical formula 64]

In the same way as in example 13, was received is indicated in the title compound (71 mg, 87%; output: two stage after receiving 5-[(2,5-differenl)-hydroxymethyl]pyrimidine in reference example 12) as colorless columnar crystals using synthesis using 5-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]pyrimidine obtained in example 12, and purification by chromatography on silica gel (hexane:ethyl acetate=5:1).

1H-NMR (400 MHz, CDCl3)δ: the 5.65 (1H, s), 6,93-7,10 (2H, m), the 7.43 (2H, d, J=8,8 Hz), to 7.61 (2H, d, J=8,8 Hz), 7,73 (1H, m), of 8.90 (2H, s), of 9.21 (1H, s). TPL: 136-137°C.

Elemental Analysis for C17H11ClF2N2O2S. Calculated: C,53,62; H,2.91 In; N,Of 7.36; S,8,42; Cl,9,31; F,9,98. Found: C,53,64; H,And 2.83; N,7,44; S,8,61; Cl,9,34; F,9,96.

Example 22:3-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-4-hydroxypropan-2-he

[Chemical formula 65]

After you have added at room temperature, glacial acetic acid (60 mg, 1 mmol) and pyridine (80,5 μl, 1 mmol) to a solution of 2,5-diferentialglea (109 μl, 1 mmol), 4-hydroxycoumarin (162 mg, 1 mmol) and 4-chlorothiophenol (144,6 mg, 1 mmol) in ethanol (4 ml) the mixture was stirred for 24 hours. The precipitate was collected by filtration and washed with a small amount of ethanol to obtain specified in the header is soedineniya (345 mg, 80%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 6,16 (1H, s), 6,95 for 7.12 (3H, m), 7.24 to 7,27 (1H, m), 7,27 (2H, d, J=8,8 Hz), 7,32 (1H, t, J=7,6 Hz), the 7.43 (2H, d, J=8,8 Hz), 7,56 (1H, m), 7,94 (1H, DD, J=1,6,7,6 Hz).

TPL: 146-147°C.

MS m/z: 431 (M++H).

Example 23:3-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-4-methoxypropan-2-on (compound a) and 3-[[(4-chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-2-methoxypropan-4-one (Compound B)

[Chemical formula 66]

A solution of 2 N. trimethylsilyldiazomethane in hexane (0,41 ml, 0,822 mmol) was added in portions to a solution of 3-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-4-hydroxypropan-2-she (118 mg, 0,274 mmol) in a mixture of benzene-methanol (10:1) at room temperature. The resulting mixture was stirred for 5 minutes. Was added acetic acid until then, until the solution became colorless, and then the reaction mixture was concentrated under reduced pressure.

The residue was dissolved in methanol (12 ml). To the resulting solution was added 30% aqueous hydrogen peroxide solution (6 ml) and tetrahydrate hexaminolevulinate (60 mg). The resulting mixture was stirred for 20 hours. To the reaction mixture were added ethyl acetate (50 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Remainder the eyes of the Ali chromatography on silica gel (hexane:ethyl acetate=5:1-3:1) to obtain the non-polar compound (22 mg, 17%) in the form of needle-shaped crystals and polar compounds (9.0 mg, 7%) as white solids after curing of hexane. The analysis of nonpolar compounds by the method of NOE (nuclear Overhauser effect (nuclear Overhauser effect)) NOE was observed between the methoxy and hydrogen in position 5 chromenone. Analysis of polar compounds, on the other hand, showed no NOE between the methoxy and hydrogen in the aromatic ring chromanone, but this effect was observed between the methoxy and hydrogen in position 6 diferencialniho rings. On the basis of these results, the structure of non-polar compounds identified as 3-[[(4-chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-4-methoxypropan-2-on (compound a)and the structure of polar compounds identified as 3-[[(4-chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-2-methoxypropan-4-one (Compound B).

Connection A

1H-NMR (400 MHz, CDCl3)δ: 4,13 (3H, s), to 6.39 (1H, s), to 6.88 (1H, m), 6,98 (1H, m), 7.3 to 7.4 (2H, m), the 7.43 (2H, d, J=8,8 Hz), 7,58 (1H, m), of 7.70 (2H, d, J=8,8 Hz), 7,73 (1H, m), of 8.09 (1H, m).

TPL: 178-179°C.

Elemental Analysis for C23H15ClF2O3S. Calculated: C,57,93; H,3,17; S 6,72; Cl,7,43; F,7,97. Found: C,57,59; H,3,14; S 6,85; Cl,7,52,F, 8,01.

Compound B

1H-NMR (400 MHz, CDCl3)δ: to 4.23 (3H, s), is 6.54 (1H, s), 6.89 in (1H, m), of 6.96 (1H, m), 7,41 (2H, d, J=8,4 Hz), 7,4-7,46 (2H, m), 7,63 (1H, m), 7,73 (2H, d, J=8,4 Hz), 8,02 (1H, m)to 8.14 (1H, DD, J=1,6, 8.0 Hz).

TPL: 162-163°C.

FAB-MS 477,0366 (Calculated for C 23H16ClF2O5S: 477,0375).

Example 24:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-1-methyl-1H-benzimidazole

[Chemical formula 67]

To 2-[(tert-butoxycarbonylamino)-(2,5-differenl)methyl]-1-methyl-1H-benzimidazole (204 mg, 0,545 mmol)obtained in reference example 13, was added triperoxonane acid (2.0 ml). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated under reduced pressure. The residue was dissolved in thionyl chloride (1.0 ml). To the resulting solution was added one drop of dimethylformamide. The resulting mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane and the resulting mixture was again concentrated under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). After adding 4-chlorbenzoyl (118 mg, 0.82 mmol) and potassium carbonate (451 mg, of 3.27 mmol) the resulting mixture was stirred at 50°C for 2 hours. The reaction mixture was then allowed to stand at room temperature and to the mixture was added ethyl acetate (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous sulfate m is fester and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=10:1 → 5:1) to obtain the specified title compound (195 mg, 89%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: to 3.67 (3H, s), 5,91 (1H, s), 6.87 in-6,93 (2H, m), 7,19 (2H, d, J=8,8 Hz), 7,27 (2H, d, J=8,8 Hz), 7,25-7,33 (3H, m), 7,60 (1H, m), a 7.85 (1H, m).

MS m/z: 401 (M++H).

Example 25:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-1-methyl-5-chloro-1H-imidazol

[Chemical formula 68]

To 2-[(tert-butoxycarbonylamino)-(2,5-differenl)methyl]-1-methyl-5-chloro-1H-imidazole (404 mg, 1.13 mmol)obtained in reference example 14 was added triperoxonane acid (10 ml). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and the resulting solution was added a drop of dimethylformamide. The mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated under reduced pressure. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorbenzoyl (244 mg, was 1.69 mmol) and potassium carbonate (936 mg, of 6.78 mmol) the resulting mixture was stirred at 50° C for 2 hours. The reaction mixture was allowed to stand to reach room temperature. Was added ethyl ether (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=10:1 → 5:1) to obtain the specified title compound (195 mg, 89%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.57 (3H, s), 5,67 (1H, s), 6.89 in-6,95 (2H, m), 6,97 (1H, s), 7,20 (2H, d, J=8,4 Hz), 7,21 (2H, d, J=8,4 Hz), 7,54 (1H, m).

MS m/z: 386 (M++H).

Example 26:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]thiazole

[Chemical formula 69]

2-[(2,5-Differenl)-hydroxymethyl]thiazole (348 mg, 1.53 mmol)obtained in reference example 15, was dissolved in thionyl chloride (1.5 ml). To the resulting solution was added a drop of dimethylformamide. The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated under reduced pressure. The residue was dissolved in dimethylformamide (10.0 ml). To the resulting solution were added 4-chlorbenzoyl (332 mg, 2.3 mmol) and potassium carbonate (845 mg, 6.12 mmol). The resulting mixture was stirred at 50°C for 2 hours. The reaction is ionic mixture was allowed to stand to reach room temperature and then to the mixture was added ethyl acetate (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=10:1 → 6:1) to obtain the specified title compound (130 mg, 24%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 6,04 (1H, s), 6.90 to-7,06 (2H, m), 7,22 (2H, d, J=8,4 Hz), 7,30 (2H, d, J=8,4 Hz), 7,15-to 7.35 (2H, m), 7,76 (1H, d, J=3.2 Hz).

MS m/z: 354 (M++H).

Example 27:2-[[(4-Chlorophenyl)thio]-(2,5-differenl)methyl]-1-(4-methoxyphenyl)-1H-imidazol

[Chemical formula 70]

Triperoxonane acid (10 ml) was added to 2-[(tert-butoxycarbonylamino)-(2,5-differenl)methyl]-1-(4-methoxyphenyl)-1H-imidazole (667 mg, 1.6 mmol)obtained in reference example 16. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated under reduced pressure. The residue was dissolved in thionyl chloride (2.0 ml) and the resulting solution was added a drop of dimethylformamide. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, and then concentrated under reduced pressure is I. The residue was dissolved in dimethylformamide (5.0 ml). To the resulting solution were added 4-chlorbenzoyl (347 mg, 2.4 mmol) and potassium carbonate (1,32 g, 9.6 mmol). The resulting mixture was stirred at 50°C for 2 hours. The reaction mixture was allowed to stand to reach room temperature and then to the mixture was added ethyl ether (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=10:1 → 5:1), and then was led from ethanol to obtain specified in the title compound (535 mg, 75%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 3,86 (3H, s), to 5.57 (1H, s), 6.8 or 6.9 (3H, m)6,91 (2H, d, J=8,4 Hz), 7,00 (2H, d, J=8,4 Hz), 7,06 (2H, d, J=6.8 Hz), 7,11 (2H, d, J=6.8 Hz), 7,16 (1H, s), 7,81 (1H, m).

MS m/z: 443 (M++H).

Example 28:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-1-methyl-1H-benzimidazole (Compound A) and 2-[[(4-chlorophenyl)sulfinil]-(2,5-differenl)methyl]-1-methyl-1H-benzimidazole (Compound B)

[Chemical formula 71]

Tetrahydrate hexaminolevulinate (60 mg) was added to a solution of 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-1-methyl-1H-benzimidazole (190 mg, 0,474 mmol)obtained in example 24, in methanol (12 ml). To the mixture was added 30% in the command hydrogen peroxide solution (6 ml) followed by stirring for 17 hours. To the reaction mixture were added ethyl acetate (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=6:1 → 4:1) to obtain the non-polar connection (Connection A) (48 mg, 23%) and polar compounds (Compound B) (23 mg, 12%), which had the form of needle-shaped crystals and white solids, respectively.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 3,90 (3H, s), 6,14 (1H, s), 6,9-7,1 (2H, m), 7,26-7,42 (3H, m), 7,39 (2H, d, J=8,8 Hz), 7,46 (2H, d, J=8,8 Hz), 7,81 (1H, d, J=8.0 Hz), 8,16 (1H, m).

TPL: 213-214°C.

Elemental Analysis for C21H15ClF2N2OS. Calculated: C,58,27; H,3,49; N,6,47; S,7,41; Cl,8,19; F,8,78. Found: C,58,08; H,3,62; N,6,53; S,7,35; Cl,8,10,F, A Total Of 8.74.

Compound B

1H-NMR (400 MHz, CDCl3)δ: 3,35 (3/2H, s), 3,78 (3/2H, s)5,52 (1/2H, s), 5,57 (1/2H, s), 6,78 and 7.1 (2H, m), 7,2-7,4 (7H, m), 7,76-of 7.95 (2H, m).

TPL: 130-131°C.

FAB-MS: 477,0646 (Calculated for C21H16ClF2N2OS: 477,0640).

Example 29:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-1-methyl-5-chloro-1H-imidazol

[Chemical formula 72]

Tetrahydrate hexaminolevulinate (60 mg) was added to a solution of 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-1-methyl-5-chloro-1H-imidazole (141 mg, and 0.37 mmol)obtained when the ore 25, in methanol (12 ml). To the mixture was added 30% aqueous hydrogen peroxide solution (6 ml) followed by stirring for 64 hours. To the reaction mixture were added ethyl acetate (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was led from ethanol to obtain specified in the title compound (103 mg, 67%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 3,71 (3H, s), 5,88 (1H, s), 6,93-was 7.08 (2H, m), 7,03 (1H, s), the 7.43 (4H, s), 7,98 (1H, m).

TPL: 179-180°C.

Elemental Analysis for C17H12Cl2F2N2O2S. Calculated: C,48,90; H,At 2.93; N,Of 6.71; S,7.68 Per; Cl,16,99; F,9,11. Found: C,48,90; H,At 2.93; N,6,77; S 7,80; Cl,17,02; F,9,19.

Example 30:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]thiazole

[Chemical formula 73]

Tetrahydrate hexaminolevulinate (30 mg) was added to a solution of 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]thiazole (124 mg, 0.35 mmol)obtained in example 26, in methanol (6.0 ml). To the mixture was added 30% aqueous hydrogen peroxide solution (3 ml) and the mixture was stirred for 15 hours. To the reaction mixture were added ethyl acetate (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrate the Wali under reduced pressure. The residue was led from ethanol to obtain specified in the title compound (91 mg, 67%) as colorless columnar crystals.

1H-NMR (400 MHz, CDCl3)δ: 6,21 (1H, s), 6,92-was 7.08 (2H, m), 7,41 (2H, d, J=8,8 Hz), was 7.45 (1H, d, J=3.6 Hz), 7,56 (2H, d, J=8,8 Hz), 7,86 (1H, d, J=3.6 Hz), 7,94 (1H, m).

TPL: 163-164°C.

Elemental Analysis for C16H10ClF2NO2S2. Calculated: C,49,81; H,2,61; N,3,63; S,16,62; Cl,9,19; F,9,85. Found: C,49,98; H,2,61; N,Of 3.77; S,16,60; Cl,9,25; F,9,87.

Example 31:2-[[(4-Chlorophenyl)sulfonyl]-(2,5-differenl)methyl]-1-(4-methoxyphenyl)-1H-imidazol

[Chemical formula 74]

Tetrahydrate hexaminolevulinate (60 mg) was added to a solution of 2-[[(4-chlorophenyl)thio]-(2,5-differenl)methyl]-1-(4-methoxyphenyl)-1H-benzimidazole (118 mg, 0.27 mmol)obtained in example 27, in methanol (12 ml). To the mixture was added 30% aqueous hydrogen peroxide solution (6 ml) followed by stirring for 64 hours. To the reaction mixture were added ethyl acetate (60 ml). The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was led from ethanol to obtain specified in the title compound (76 mg, 60%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: to 3.89 (3H, s), of 5.83 (1H, s), 6,93-7,05 (4H, m), 6,97 (2H, d, J=8,8 Hz), 7,01 (H, d, J=8,8 Hz), 7,38 (2H, d, J=8,8 Hz), 7,41 (2H, d, J=8,8 Hz), 8,15 (1H, m).

TPL: 150-151°C.

Elemental Analysis for C23H17ClF2N2O3S. Calculated: C,58,13; H,3,61; N,5,90; S 6,75; Cl,7,47,F, 8,00. Found: C,58,09; H,3,51; N,Of 5.99; S,6,88; Cl,Of 7.48; F,8,06.

Example 32:5-Chloro-2-[(2,5-differenl-4-pyridylmethyl)thio]pyridine

[Chemical formula 75]

To a solution of 2,5-differenl-4-pyridinemethanol (221 mg, 1.00 mmol)obtained in reference example 18, in dichloromethane (10 ml) at 0°C was added triethylamine (0,279 ml, 2.00 mmol), and then methanesulfonanilide (0,116 ml, 1.50 mmol). The resulting mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (10 ml), was added 5-chloro-2-pyridinethiol (145 mg, 1.00 mmol)obtained in reference example 17, and potassium carbonate (166 mg, 1.20 mmol). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. OS is atok was subjected to flash chromatography on silica gel and the fraction, obtained by elution with a mixture of hexane:ethyl acetate=17:3 was concentrated under reduced pressure to obtain specified in the title compound (267 mg, 0.77 mmol, 77%) as a yellow solid.

1H-NMR (400 MHz, CDCl3)δ: of 6.52 (1H, s), 6,92-6,98 (1H, m), 6,99-7,06 (1H, m), of 7.48 (1H, DD, J=8,5,0,7 Hz), 7,17-of 7.23 (1H, m), 7,34 (2H, d, J=6,1 Hz), 7,47 (1H, DD, J=8,5, 2.4 Hz), with 8.33 (1H, DD, J=2,4,0,7 Hz), 8,54 (2H, d, J=6,1 Hz).

MS m/z: 349 (M++H).

Example 33:5-Chloro-2-[(2,5-differenl-4-pyridylmethyl)-sulfonyl]pyridine

[Chemical formula 76]

To a solution of 5-chloro-2-[(2,5-differenl-4-pyridylmethyl)-thio]pyridine (239 mg, of 0.68 mmol) in methanol (6 ml) was added water (12 ml) solution of oxone (connection peroxomonosulfate potassium, 2KHSO5·KHSO4·K2SO4) (631 mg, 1,03 mmol) at 0°C. the Reaction mixture was stirred at room temperature for 3 days, then to the mixture was added dichloromethane. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified preparative high performance liquid chromatography (using a mixed solvent system of water/acetonitrile/formic acid). The obtained solid was washed with hexane/diisopropyl the ether and then collected by filtration to obtain specified in the title compound (67 mg, 0.18 mmol, 26%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,44 (1H, s), of 6.96-was 7.08 (2H, m), of 7.48 (2H, d, J=6.3 Hz), 7,70-to 7.77 (1H, m), 7,79 (1H, DD, J=8,3,2,2 Hz), to 7.84 (1H, DD, J=8,3,0,7 Hz), 8,61 (2H, d, J=6.3 Hz), 8,67 (1H, DD, J=2,2, 0.7 Hz).

Elemental Analysis for C17H11ClF2N2O2S. Calculated: C,53,62; H,2.91 In; F,9,98; N,Of 7.36; S,8,42. Found: C,53,55; H,2,87; F,10,10, N,7,40; S,8,55.

MS m/z: 381 (M++H).

Example 34:4-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]tetrahydropyran

[Chemical formula 77]

2-[(4-Chlorophenyl)sulfanilyl]-1,4-differental (200 mg, 0,661 mmol)obtained in reference example 1, and tetrahydro-4H-Piran-4-ol (0,13 ml of 1.36 mmol) was dissolved in toluene (10 ml). After adding cyanomethylene-n-butylphosphine (330 mg, 1.37 mmol) the resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction mixture was then allowed to cool. After adding cyanomethylene-n-butylphosphine (200 mg, 0,829 mmol) the resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure p is the torching of a white solid. The obtained white solid was washed with hexane to obtain specified in the title compound (157 mg, 0,406 mmol, 61%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 1.28 to 1.48 (2H, m), 1,71 (1H, DDD, J=25,3, 11,7, a 4.3 Hz), is 2.37 (1H, sird, J=a 12.7 Hz), 2,70-is 2.88 (1H, m), 3,40 (1H, TD, J=11,7,2,5 Hz), 3,50 (1H, TD, J=12,0, 2.2 Hz), 3,91 (1H, DM, J=11.2 Hz), was 4.02 (1H, DM, J=11.7 Hz), to 4.46 (1H, d, J=8,8 Hz), 6,68-to 6.80 (1H, m), 6,88-6,98 (1H, m), 7,31 (2H, d, J=8.5 Hz), of 7.36 was 7.45 (1H, m), 7,49 (2H, d, J=8,5 Hz).

TPL: 150-152°C.

MS m/z: 387 (M++H).

Elemental Analysis for C18H17ClF2O3S. Calculated: C,55,89; H,4,43; Cl,9,16; F,9,82; S,8,29. Found: C,Of 55.64; H,4,27; Cl,9,41; F,9,89; S,8,28.

Example 35:4-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]tetrahydrothiopyran

[Chemical formula 78]

2-[(4-Chlorophenyl)sulfanilyl]-1,4-differental (500 mg, of 1.65 mmol)obtained in reference example 1, and tetrahydrothiopyran-4-ol (400 mg, to 3.38 mmol)obtained in reference example 19 was dissolved in toluene (20 ml). After adding cyanomethylene-n-butylphosphine (800 mg, and 3.31 mmol) the resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction mixture was allowed to cool down and to the mixture was added cyanomethylene-n-butylphosphate (400 mg, of 1.66 mmol). The resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction the mixture was allowed to cool and then concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=15:1 was concentrated under reduced pressure to obtain white solid. The obtained white solid was washed with hexane/diisopropyl ether to obtain specified in the title compound (404 mg, 1.00 mmol, 61%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 1,47 (1H, DDD, J=23,4, 10,0, 3,3 Hz), 1,68 (1H, DDD, J=25,0, 11,4, and 3.3 Hz), 2,13 (1H, DM, J=11,4 Hz), 2,50-2,78 (5H, m), 2,82 (1H, TD, J=12,8, and 2.6 Hz), 4,47 (1H, d, J=7,3 Hz), 6,72-PC 6.82 (1H, m), 6.90 to-7,00 (1H, m), 7,31 (2H, d, J=8,8 Hz), 7,40-of 7.60 (1H, m), 7,49 (2H, d, J=8,8 Hz).

TPL: 150-152°C.

MS m/z: 403 (M++H).

Elemental Analysis for C18H17ClF2O2S2. Calculated: C,53,66; H,4,25; Cl,8,80; F,9,43; S 15,92. Found: C,53,52; H,4,21; Cl,9,00; F,9,54; S 15,88.

Example 36:4-[[(4-Chlorophenyl)sulfonyl] (2.5-differenl)methyl]tetrahydrothiopyran-1,1-dioxide (Compound A) and 4-[[(4-chlorophenyl)sulfonyl](2.5-differenl)methyl]tetrahydrothiopyran-1-oxide (Compound B (Isomer A) and Compound B (Isomer B)

[Chemical formula 79]

After dissolving 4-[[(4-chlorophenyl)sulfonyl](2.5-differenl)methyl]tetrahydrothiopyran (360 mg, 0,893 mmol) in dichloromethane (15 ml) to the resulting solution under ice cooling was added 3-chloroperbenzoic acid (320 mg, of 1.85 mmol). After paramasivan is at room temperature for 14 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel, and the fraction obtained by elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain white solid. The obtained white solid was dissolved in dichloromethane. The resulting solution was washed sequentially 1 N. aqueous sodium hydroxide solution and saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain white solid. The obtained white solid was washed with diethyl ether obtaining specified in the header of the connection A (187 mg, 0,430 mmol, 48%) as a white powder. In addition, the fraction obtained by elution with a mixture of dichloromethane:methanol=50:1 was concentrated under reduced pressure to obtain a mixture specified in the title Compound B (Isomer A) and specified in the title Compound B (Isomer B) as a white solid. The resulting mixture was separated and purified flash chromatography on silica gel (dichloromethane:methanol=80:1). The obtained white solid was washed with diethyl ether obtaining specified in the title compound B (Isomer A) (iskopaemoe) (78 mg, 0,19 mmol, 21%) as a white powder and is specified in the header of Compound B (Isomer B) (vysokopole the (e) (69 mg, 0,17 mmol, 19%) as a white powder.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 1,85 is 2.00 (1H, m), 2,18 to 2.35 (2H, m), 2,68-only 2.91 (2H, m), 2,98-3,10 (2H, m), 3,10-of 3.28 (2H, m), of 4.54 (1H, sird, J=7,1 Hz), 6,74-of 6.90 (1H, m), 6,94-7,06 (1H, m), 7,33 (2H, d, J=8.7 Hz), 7,35-of 7.55 (1H, m,), 7,49 (2H, d, J=8.7 Hz).

TPL: 245-248°C.

Elemental Analysis for C18H17ClF2O4S2. Calculated: C,49,71; H,3,94; Cl,8,15; F,A Total Of 8.74; S,14,75. Found: C,49,38; H,A 3.87; Cl,8,50; F,8,86; S,14,62.

Compound B (Isomer A)

1H-NMR (400 MHz, CDCl3)δ: 1,76 (1H, sird, J=13,4 Hz), 2,18 (1H, DDM, J=25,4, 12,5 Hz), 2,32-2,70 (4H, m), 2,74-2,90 (1H, m), 2,98 (1H, DM, J=14,0 Hz)to 3.09 (1H, DM, J=14.4 Hz), a 4.53 (1H, d, J=7,3 Hz), 6,72-6,86 (1H, m), 6.90 to-7,02 (1H, m), 7,32 (2H, d, J=8.5 Hz), 7,40-of 7.60 (1H, m), 7,49 (2H, d, J=8,5 Hz).

TPL: 255-256°C.

Elemental Analysis for C18H17ClF2O3S2. Calculated: C,51,61; H,4.09 To; Cl,8,46; F,9,07; S,15,31. Found: C,51,51; H,4.04 The; Cl,8,69; F,9,15; S,15,20.

Compound B (Isomer B)

1H-NMR (400 MHz, CDCl3)δ: of 1.42 (1H, DDM, J=22,3, 11.7 Hz), with 1.92 (1H, DDM, J=11,7, and 11.0 Hz), 2,14-of 2.27 (1H, m)to 2.66 (1H, TD, J=12,2, 2.7 Hz), 2,70-2,90 (3H, m), 3,10-3,24 (1H, m), 3,32-3,44 (1H, m), 4,49 (1H, d, J=8.1 Hz), 6,72-6,85 (1H, m), 6.90 to-7,02 (1H, m), 7,32 (2H, d, J=8.5 Hz), 7,34-7,50 (1H, m), of 7.48 (2H, d, J=8,5 Hz).

TPL: 184-187°C.

Elemental Analysis for C18H17ClF2O3S2. Calculated: C,51,61; H,4.09 To; Cl,8,46; F,9,07; S,15,31. Found: C,51,82; H,4,23; Cl,8,42; F,9,12; S,15,07.

Example 37:tert-Butyl 4-[[(4-chlorophenyl)sulfonyl](2.5-differenl)methyl]-1-piperidinecarboxylate

[The chemical form of the as 80]

2-[(4-Chlorophenyl)sulfanilyl]-1,4-differental (1,25 g of 4.13 mmol)obtained in reference example 1, and tert-butyl 4-hydroxy-1-piperidinecarboxylate (1.70 g, 8,44 mmol) was dissolved in toluene (50 ml). To the resulting solution was added cyanomethylene-n-butylphosphate (2.00 g, 8,29 mmol). The resulting mixture was heated at the boil under reflux for 14 hours in an argon atmosphere. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain white solid. The obtained white solid was washed with diethyl ether obtaining specified in the title compound (1.68 g, 3.46 mmol, 84%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 1,10-1,25 (1H, m), 1,40-1,70 (2H, m)of 1.44 (9H, s), 2,30-of 2.50 (1H, m), 2,60-2,95 (3H, m), 4,00-of 4.25 (2H, m), of 4.45 (1H, d, J=7.8 Hz), 6,69-to 6.80 (1H, m), 6,88-6,98 (1H, m), 7,31 (2H, d, J=8.6 Hz), 7,35 is 7.50 (1H, m), 7,49 (2H, d, J=8.6 Hz).

TPL: 193-196°C.

Elemental Analysis for C23H26ClF2NO4S. Calculated: C,56,84; H,5,39; Cl,7,30,F, Of 7.82; N,2,88; S,6,60. Found: C,56,41; H,5,43; Cl,To 7.77; F,To 7.61; N,2,99; S,6,58.

Example 38:hydrochloride 4-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]piperidine

[Chemical formula 1]

tert-Butyl 4-[[(4-chlorophenyl)sulfonyl](2.5-differenl)methyl]-1-piperidinecarboxylate (1.56 g, is 3.21 mmol) was dissolved in dichloromethane (50 ml). To the resulting solution under ice cooling was added dropwise triperoxonane acid (5.0 ml). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. To the obtained residue was added dichloromethane (10 ml) and 1 n hydrochloric acid solution in ethanol (10 ml). The resulting mixture was concentrated under reduced pressure to obtain white solid. The obtained solid was washed with diethyl ether obtaining specified in the connection header (1,36 g of 3.12 mmol, 97%) as a white powder.

1H-NMR (400 MHz, CD3OD)δ: 1,38-of 1.52 (1H, m), 1.70 to of 1.92 (2H, m), 2,73 (1H, sird, J=14,2 Hz), 2,86-of 3.00 (1H, m), 3,05 (1H, TD, J=12,9, 3.1 Hz), 3,13 (1H, TD, J=13,1, 3.1 Hz), 3,30 is 3.40 (1H, m), 3,48 (1H, DM, J=13,0 Hz), 4.72 in (1H, d, J=8.6 Hz), 6,82-6,98 (1H, m),? 7.04 baby mortality for 7.12 (1H, m), 7,40-of 7.55 (1H, m), 7,44 (2H, d, J=8.6 Hz), EUR 7.57 (2H, d, J=8.6 Hz).

TPL: 184-190°C.

Elemental Analysis for C18H18ClF2NO2S·HCl·0,75H2O. Calculated: C,49,61; H,4,74; Cl,16,27; F,8,72; N,3,21; S Of 7.36. Found: C,49,57; H,4.75 V; Cl,15,79; F,9,16; N,3,34; S,7,25.

Example 39:2-[(4-Chlorophenylthio)-(2,5-differenl)methyl]-5-[(4-chlorophenylthio)methyl]pyridine

[Chemical formula 82]

A suspension of sodium borohydride (33 mg, 0.88 mmol) in ethanol (15 ml) was cooled to -78°C. To the suspension was added in portions with stirring, a solution of [6-(2,5-diferenzierbarer)pyridine-3-yl]acetate (510 mg, about 1.75 mmol)obtained in reference example 21, in ethanol (10 ml). The reaction mixture was stirred for 30 minutes. Was added an aqueous solution of ammonium chloride and the mixture was allowed to stand to reach room temperature. The reaction mixture was extracted with ethyl acetate (100 ml). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in methylene chloride (30 ml)and then added with ice cooling, the triethylamine (270 μl) and methanesulfonamide (270 μl). The reaction mixture was stirred at room temperature for 3 days. After addition of water the mixture was extracted with ethyl acetate (60 ml). The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (25 ml). To the resulting solution under nitrogen atmosphere was added 4-chlorbenzoyl (751 mg, 5.3 mmol) and potassium carbonate (718 mg, 5.2 mmol). The reaction mixture was stirred at 60°C for 1 hour. After cooling, the reaction mixture prior to matnog temperature to the mixture was added diethyl ether (80 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel (hexane:ethyl acetate=10:1) to obtain the specified title compound (237 mg, 27%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 3,99 (2H, s), of 5.81 (1H, s), make 6.90 (2H, m), to 7.15 (2H, d, J=8,8 Hz), 7,16 (2H, d, J=8,8 Hz), 7,19 (4H, d, J=8,8 Hz), 7,20 (1H, d, J=7,6 Hz), 7,38 (1H, m), 7,49 (1H, DD, J=2,0,7,6 Hz), scored 8.38 (1H, Shir.).

TPL: 87-88°C.

Example 40:2-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]-5-[(4-chlorophenylsulfonyl)methyl]pyridine

[Chemical formula 83]

Tetrahydrate hexaminolevulinate (30 mg) was added to a solution of 2-[(4-chlorophenylthio)-(2,5-differenl)methyl]-5-[(4-chlorophenylthio)methyl]pyridine (75 mg, 0.15 mmol) in methanol (6.0 ml)and then added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 22 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with water, aqueous sodium thiosulfate solution and saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (2% MeOH/CHCl3) obtaining specified in the title compound (70 mg, 62%) as needle crystals.

1 H-NMR (400 MHz, CDCl3)δ: the 4.29 (2H, s), 5,91 (1H, s), 6.90 to-was 7.08 (2H, m), 7,39 (2H, DD, J=1,6, 6,8 Hz), was 7.45 (2H, DD, J=1,6, 6,8 Hz), 7,51 (2H, d, J=8,8 Hz), 7,55 (2H, d, J=8,8 Hz), 7,60 (1H, d, J=8.0 Hz), the 7.65 (1H, DD, J=to 2.4, 8.0 Hz), to $ 7.91 (1H, m), 8,23 (1H, s).

TPL: 186-187°C.

Elemental Analysis for C25H17Cl2F2NO4S2. Calculated: C,52,82; H,A 3.01; N,2,46; S,11,28; Cl,12,47; F,6,68. Found: C,52,88; H,3,10; N,2,63; S,11,38; Cl,12,40; F,6,83.

Example 41:2-[(4-Chlorophenylthio)-(2,5-differenl)methyl]-5-(1,3-dioxolane-2-yl)pyridine

[Chemical formula 84]

The triethylamine (1.08 ml, 7.8 mmol) and methanesulfonamide (0,52 ml, 6.8 mmol) was added under nitrogen atmosphere under ice cooling to a solution of 2-[(2,5-differenl)-hydroxymethyl]-5-(1,3-dioxolane-2-yl)pyridine (1.52 g, 5.2 mmol)obtained in reference example 22, in methylene chloride (30 ml). The resulting mixture was stirred at room temperature for 3 hours. After adding saturated aqueous sodium bicarbonate solution the mixture was extracted with simple ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (30 ml). To the resulting solution was added chlorbenzoyl (901 mg, 6.2 mmol) and potassium carbonate (1.08 g, 7.8 mmol) followed by stirring at 60°C for 3 hours. After cooled the I to room temperature, the reaction mixture was diluted simple ether. The diluted solution was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (1.56 g, 71%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 4,0-to 4.15 (4H, m), of 5.84 (1H, s), of 5.92 (1H, s), 6,85-of 6.96 (2H, m), 7,19 (2H, d, J=8,8 Hz), 7,25 (2H, d, J=8,8 Hz), the 7.43 (1H, d, J=8.0 Hz), the 7.43 (1H, m), to 7.77 (1H, DD, J=2,0, 8.0 Hz), to 8.70 (1H, d, J=2.0 Hz).

TPL: 70-73°C.

MS m/z: 420 (M++H).

Example 42:2-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]-5-(1,3-dioxolane-2-yl)pyridine

[Chemical formula 85]

Tetrahydrate hexaminolevulinate (150 mg) was added to a solution of 2-[(4-chlorophenylthio)-(2,5-differenl)methyl]-5-(1,3-dioxolane-2-yl)pyridine (1.54 g, to 3.67 mmol) in methanol (30 ml). To the mixture was added 30% aqueous hydrogen peroxide solution (15 ml) followed by stirring for 24 hours. The reaction mixture was diluted with ethyl acetate, and then the diluted solution was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was led from ethanol to obtain specified in the title compound (1.22 g, 74%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: was 4.02-4,10 4H, m)of 5.85 (1H, s), 5,97 (1H, s)6,91 (1H, m), of 6.96 (1H, m), 7,38 (2H, d, J=8,4 Hz), 7,53 (2H, d, J=8,4 Hz), 7,63 (1H, d, J=7,6 Hz), 7,82 (1H, d, J=8.0 Hz), 7,94 (1H, m), 8,67 (1H, Sirs).

TPL: 167-168°C.

FAB-MS: 452,0544 (Calculated for C21H17ClF2NO4S: 452,0535).

Example 43:2-[(4-Chlorophenylsulfonyl)-(2,5-differenl)-methyl]-5-(hydroxymethyl)pyridine

[Chemical formula 86]

To a solution (30 ml) of 2-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-5-(1,3-dioxolane-2-yl)pyridine (295 mg, 0.54 mmol) in 1,4-dioxane was added 1 n hydrochloric acid (30 ml). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue.

The obtained residue was dissolved in ethanol (10 ml). To the resulting solution under ice cooling was added borohydride sodium (10 mg, 0.27 mmol). The resulting mixture was stirred for 1 hour. Added water and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The obtained residue behaviour is whether chromatography on silica gel (3% methanol/chloroform) to obtain the specified title compound (205 mg, 93%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 4,74 (2H, s)5,94 (1H, s)6,91 (1H, m), of 6.99 (1H, m), 7,38 (2H, d, J=8,4 Hz), 7,53 (2H, d, J=8,4 Hz), a 7.62 (1H, d, J=8.0 Hz), 7,76 (1H, DD, J=2,0, 8.0 Hz), 7,98 (1H, m), 8,58 (1H, d, J=2,0 Hz).

TPL: 151-152°C.

FAB-MS: 410,0444 (Calculated for C19H15ClF2NO3S: 410,0429).

Example 44:Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]acrylate

[Chemical formula 87]

To a solution (10 ml) of 2-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-5-(1,3-dioxolane-2-yl)pyridine (212 mg, 0.47 mmol)obtained in example 42, in 1,4-dioxane was added 1 n hydrochloric acid (10 ml). The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue.

The obtained residue was dissolved in tetrahydrofuran (15 ml). In an atmosphere of nitrogen was added methyl(triphenylphosphonium)acetate (188 mg, 0,56 mmol) and the resulting mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by chromatography on silica gel (who exan:ethyl acetate=5:1) to obtain the specified title compound (187 mg, 86%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: of 3.80 (3H, s)5,94 (1H, s), of 6.50 (1H, d, J=16.0 Hz), 6,91 (1H, m), of 6.99 (1H, m), 7,38 (2H, d, J=8,8 Hz), 7,53 (2H, d, J=8,8 Hz), 7,63 (1H, d, J=8.0 Hz), 7,63 (1H, d, J=16.0 Hz), to 7.84 (1H, DD, J=a 2.0, 8.0 Hz), 7,98 (1H, m), to 8.70 (1H, d, J=2.0 Hz).

TPL: 145-146°C.

MS m/z: 464 (M++H).

Example 45:Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]propionate

[Chemical formula 88]

Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]acrylate (160 mg, 0.34 mmol) was dissolved in ethanol (15 ml). To the resulting solution was added palladium on carbon (30 mg). The resulting mixture was intensively stirred in hydrogen atmosphere at a pressure of 1 atmosphere for 24 hours. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (94 mg, 58%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 2,63 (2H, t, J=7,6 Hz), 2,95 (2H, t, J=7,6 Hz), the 3.65 (3H, s), of 5.89 (1H, s), make 6.90 (1H, m), 6,97 (1H, m), of 7.36 (2H, d, J=8,4 Hz), 7,53 (2H, d, J=8,4 Hz), 7,55 (2H, m), 8,00 (1H, m), to 8.45 (1H, d, J=1.6 Hz).

TPL: 121-123°C.

MS m/z: 466 (M++H).

Example 46:3-[6-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]propionic acid

[Chemical formula 89]

Methyl 3-[6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]propionate (92 mg, 0.20 mmol) was dissolved in tetrahydrofuran (5 ml). To the resulting solution was added an aqueous solution (3 ml) of lithium hydroxide (23 mg, 0.5 mmol) and the mixture was stirred for 2 hours. After adding a 10% solution of sodium hydrosulphate the resulting mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The obtained residue was led from ethanol to obtain specified in the title compound (67 mg, 75%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 2,69 (2H, t, J=7,6 Hz), 2,96 (2H, t, J=7,6 Hz), of 5.92 (1H, s), make 6.90 (1H, m), 6,98 (1H, m), of 7.36 (2H, d, J=8,4 Hz), 7,52 (2H, d, J=8,4 Hz), 7,56 (2H, m), to 7.99 (1H, m), of 8.47 (1H, d, J=2.4 Hz).

TPL: 158-160°C.

MS m/z: 452 (M++H).

Elemental Analysis for C21H16ClF2NO4S. Calculated: C,55,82; H,3,57; N,3,10; S,7,10; Cl,A 7.85; F,To 8.41. Found: C,55,70; H,Of 3.75; N,3,19; S,7,12; Cl,8,64; F,8,11.

Example 47:[6-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]carbaldehyde

[Chemical formula 90]

To a solution (30 ml) of 2-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-5-(1,3-dioxolane-2-yl)pyridine (602 mg, 1.3 mmol)obtained in example 42, in 1,4-dioxane was added 1 N. restorelocation acid (30 ml). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (530 mg, 98%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 6,01 (1H, s)6,94 (1H, m), 7,01 (1H, m), 7,40 (2H, d, J=8,4 Hz), 7,54 (2H, d, J=8,4 Hz), 7,81 (1H, d, J=8,4 Hz), of 7.97 (1H, m), to 8.20 (1H, DD, J=2.0 a, and 8.4 Hz), 9,05 (1H, d, J=2.0 Hz), 10,12 (1H, C).

Example 48:2-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]-5-(piperidine-1-ylmethyl)pyridine

[Chemical formula 91]

To a solution (5 ml) of [6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]carbaldehyde (82 mg, 0.2 mmol) and piperidine (40 μl, 0.4 mmol) in methylene chloride was added at room temperature, acetic acid (23 μl, 0.4 mmol) and triacetoxyborohydride sodium (85 mg, 0.4 mmol). The resulting mixture was stirred for 3 hours. The reaction was completed by addition of saturated aqueous sodium bicarbonate solution, after which the reaction mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, prom is Wali water and saturated salt solution, was dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) followed by crystallization from ethanol to obtain specified in the title compound (89 mg, 93%).

1H-NMR (400 MHz, CDCl3)δ: a 1.5-1.6 (6H, m), 2.3 to 2.4 (4H, m), of 3.45 (2H, s), 5,91 (1H, s), make 6.90 (1H, m), 6,98 (1H, m), 7,35 (2H, d, J=8,4 Hz), 7,52 (2H, d, J=8,4 Hz), 7,53 (1H, m), and 7.7 (1H, W), 8,02 (1H, m), 8,49 (1H, d, J=2,4 Hz).

TPL: 113-114°C.

MS m/z: 477 (M++H).

Elemental Analysis for C24H23ClF2N2O2S. Calculated: C,60,44; H,A 4.86; N,By 5.87; S,6,72; Cl,7,43; F,7,97. Found: C,59,87; H,To 4.81; N,Of 5.83; S,6,87; Cl,7,55; F,8,02.

Example 49:4-[[6-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]methyl]morpholine

[Chemical formula 92]

To a solution of [6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]carbaldehyde (82 mg, 0.2 mmol)obtained in example 47, and research (35 μl, 0.4 mmol) in methylene chloride (5 ml) was added at room temperature, acetic acid (23 μl, 0.4 mmol) and triacetoxyborohydride sodium (85 mg, 0.4 mmol). The resulting mixture was stirred for 3 hours. The reaction was completed by addition of saturated aqueous sodium bicarbonate solution, after which the reaction mixture was diluted with ethyl acetate (80 ml). The organic layer was separated, washed with water and saturated saline solution, dried and the eat was concentrated under reduced pressure to obtain a residue. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) followed by crystallization from ethanol to obtain specified in the title compound (90 mg, 94%).

1H-NMR (400 MHz, CDCl3)δ: 2,4 (4H, m), 3,49 (2H, s), and 3.6 (4H, m), of 5.92 (1H, s), make 6.90 (1H, m), 6,98 (1H, m), of 7.36 (2H, d, J=8,4 Hz), 7,53 (2H, d, J=8,4 Hz), EUR 7.57 (1H, d, J=8.0 Hz), 7,71 (1H, Shir.- d, J=8.0 Hz), 8,02 (1H, m), 8,53 (1H, d, J=2.0 Hz).

TPL: 120-121°C.

MS m/z: 479 (M++H).

Elemental Analysis for C22H21ClF2N2O3S. Calculated: C,57,68; H,Was 4.42; N,5,85; S 6,70; Cl,7,40; F,7,93. Found: C,57,41; H,4,43; N,5,90; S 6,82; Cl,7,52,F, To $ 7.91.

Example 50:[6-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]carboxylic acid

[Chemical formula 93]

To a solution of [6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]carbaldehyde (110 mg, 0.27 mmol)obtained in example 47, in tert-butanol (3.0 ml) was added methyl 2-2-butene (143 μl, 1.35 mmol). To the resulting suspension was added an aqueous solution (0.6 ml) of sodium dihydrophosphate (32.4 mg, 0.27 mmol). Then was added sodium chlorite (98 mg, of 1.08 mmol) and the mixture was stirred for 2 hours. To the reaction mixture were added water (30 ml) and acetic acid (1 ml). The resulting mixture was extracted with ethyl acetate (100 ml). The extract was washed with saturated saline solution, dried and person to distil under reduced pressure. The obtained residue which was ritalinbuy from ethanol to obtain specified in the title compound (71 mg, 62%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 6,03 (1H, s), of 6.96 (1H, m), 7,03 (1H, m), 7,42 (2H, d, J=8,4 Hz), 7,56 (2H, d, J=8,4 Hz), 7,73 (1H, d, J=8,4 Hz), of 7.97 (1H, m), 8,35 (1H, DD, J=2.0 a, and 8.4 Hz), 9,20 (1H, d, J=2.0 Hz).

TPL: >230°C.

MS m/z: 424 (M++H).

Elemental Analysis for C19H12ClF2NO4S. Calculated: C,53,84; H,2,85; N,3,30; S,EUR 7.57; Cl,Of 8.37; F,8,97. Found: C,53.47 USD; H,Of 2.81; N,3.46 In; S,7,65; Cl,8,49; F,9,00.

Example 51:3-[(4-Chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-N-oxide

[Chemical formula 94]

To a solution of 3-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine (162 mg, 0,427 mmol)obtained in example 19, in methylene chloride (15 ml) was added 3 chloroperbenzoic acid (81 mg, 0.47 mmol). The resulting mixture was stirred for 24 hours. The reaction mixture was diluted simple ether (60 ml). The diluted mixture was washed with saturated aqueous sodium bicarbonate solution, water and saturated saline solution, dried and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to chromatography on silica gel (ethyl acetate) to obtain the specified title compound (68 mg, 40%). This connection has led from ethanol to obtain colorless needle-like crystals.

1H-NMR (400 MHz, CDCl3)δ: to 5.58 (1H, s), to 6.95 (1H, m), 7,03 (1H, m), 7,29 (1H, DD, J=6,6, 8.0 Hz), 7,2 (2H, d, J=8.6 Hz), EUR 7.57 (1H, d, J=8.0 Hz), a 7.62 (2H, d, J=8,4 Hz), 7,66 (1H, m), 8,10 (1H, d, J=6.6 Hz), 8,29 (1H, s).

TPL: 183-184°C.

Elemental Analysis for C18H12ClF2NO3S. Calculated: C,54,62; H,A 3.06; N,3,54; S,8,10; Cl,8,96; F,9,60. Found: C,To 54.19; H,2,99; N,3,67; S,8,27; Cl,8,92; F,At 9.53.

Example 52:4-[(4-Chlorophenylsulfonyl)-(2,5-differenl)-methyl]pyridine-N-oxide

[Chemical formula 95]

To a solution of 4-[(4-chlorophenylsulfonyl)-(2,5-differenl)-methyl]pyridine (221 mg, of 0.58 mmol)obtained in example 20 in methylene chloride (20 ml) was added 3-chloroperbenzoic acid (100 mg, of 0.58 mmol). The resulting mixture was stirred for 20 hours. The reaction mixture was diluted simple ether (60 ml). The diluted mixture was washed with saturated aqueous sodium bicarbonate solution, water and saturated saline solution, dried and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was subjected to chromatography on silica gel (ethyl acetate) to obtain the specified title compound (183 mg, 80%). This connection has led from ethanol to obtain colorless needle-like crystals.

1H-NMR (400 MHz, CDCl3)δ: 5,62 (1H, s), 6,97 (1H, m), 7,06 (1H, m), 7,42 (2H, d, J=7,2 Hz), 7,44 (2H, d, J=8,8 Hz), 7,60 (2H, d, J=8,8 Hz), 7,68 (1H, m), 8,17 (2H, d, J=7,2 Hz).

TPL: 211-212°C.

Elemental Analysis for C18H12ClF2NO3 S. Calculated: C,54,62; H,A 3.06; N,3,54; S,8,10; Cl,8,96; F,9,60. Found: C,To 54.19; H,2,92; N,3,65; S,Compared To 8.26; Cl,8,99; F,Being 9.61.

Example 53:3-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)-methyl]pyridine

[Chemical formula 96]

3-Chloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (511 mg, 2.0 mmol)obtained in reference example 23 was dissolved in thionyl chloride (3.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide and the mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added toluene, and then concentrated.

The obtained residue was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorbenzoyl (375 mg, 2.6 mmol) and potassium carbonate (414 mg, 3 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 3 hours. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (60 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel (hexane:ethyl acetate=8:1) to obtain the specified title compound (196 mg, 26%) as a solid.

1H-NMR (400 MHz, CDCl3)δ: 6,07 (1H, s), 6,95-was 7.08 (2H, m), 7,18 (1H, m), and 7.3 (2H, d, J=8,8 Hz), 7,26 (2H, d, J=8,8 Hz), 7,58 (1H, d, J=5,2 Hz), 8,51 (1H, d, J=5,2 Hz), 8,58 (1H, s).

TPL: 70-72°C.

MS m/z: 382 (M++1).

Example 54:2,5-Dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)-methyl]pyridine

[Chemical formula 97]

2,5-Dichloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (580 mg, 2.0 mmol)obtained in reference example 24 was dissolved in thionyl chloride (3.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 17 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added toluene, and then concentrated. The residue was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorbenzoyl (375 mg, 2.6 mmol) and potassium carbonate (414 mg, 3 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 17 hours. After cooling the reaction mixture to room temperature, to the mixture was added diethyl ether (60 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel (hexane:simple ether=10:1) to obtain the specified title compound (484 mg, 58%) as a solid.

1H-NMR (400 MHz, CDCl3)δ: 5,96 (1H, C), 6,95? 7.04 baby mortality (2H, m), 7,01 (1H, m), 7.23 percent (2H, d, J=8,8 Hz), 7,26 (2H, d, J=8,8 Hz), 7,54 (1H, s), with 8.33 (1H, s).

TPL: 128-129°C.

MS m/z: 416 (M++1).

Example 55:3-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine

[Chemical formula 98]

To a solution of 3-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (122 mg, 0.32 mmol)obtained in example 53, in methanol (12 ml) was added tetrahydrate hexaminolevulinate (60 mg), and then was added 30% aqueous hydrogen peroxide solution (6 ml). The resulting mixture was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was led from ethanol to obtain specified in the title compound (103 mg, 78%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 6,23 (1H, s)6,94 (1H, m), 7,06 (1H, m), 7,41 (2H, d, J=8.0 Hz), 7,53 (1H, m), to 7.59 (2H, d, J=8.0 Hz), 8,11 (1H, d, J=5,2 Hz), 8,55 (1H, s), at 8.60 (1H, d, J=5,2 Hz).

TPL: 160-161°C.

Elemental Analysis for C18H11Cl2F2NO2S. Calculated: C,52,19; H,2,68; N,3,38; S,7,74; Cl,17,12; F,9,17. Found: C,52,17; H,2,69; N,3,44; S Of 7.96; Cl,17,12; F,9,00.

Example 56:3-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)-methyl]pyridine

[Chemical formula 99]

To a solution of 3-chloro-4-[(4-CHL is rfinity)-(2,5-differenl)methyl]pyridine (75 mg, 0.20 mmol)obtained in example 53, in methylene chloride (10 ml) was added 3-chloroperbenzoic acid (33 mg, 0.20 mmol). The resulting mixture was stirred for 3 hours under ice cooling. After simple dilution with ether (80 ml) of the diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (48 mg, 60%) as a mixture of diastereoisomers (1:1).

1H-NMR (400 MHz, CDCl3)δ: of 5.53 (1/2H, s), 5,66 (1/2H, s), 6,83 (1/2H, s), 6,95-7,08 (3/2H, m), 7.23 percent (1/2H, m), 7,25 (1H, d, J=8,4 Hz), 7,26 (1H, d, J=8,4 Hz), 7,34 (1H, d, J=8,4 Hz), was 7.36 (1H, d, J=8,4 Hz), 7,37 (1/2H, m), 7,76 (1/2H, d, J=5,2 Hz), 7,98 (1/2H, d, J=5,2 Hz), of 8.47 (1/2H, s), 8,56 (1/2H, d, J=5,2 Hz), 8,60 (1/2H, s), 8,61 (1/2H, d, J=5,2 Hz).

FAB-MS: 397,9992 (Calculated for C18H12Cl2F2NOS: 397,9985).

Example 57:2,5-Dichloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine, 0.5 hydrate

[Chemical formula 100]

To a solution of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (60 mg, 0.14 mmol)obtained in example 54, in methylene chloride (3.0 ml) was added 3-chloroperbenzoic acid (62 mg, 0.36 mmol). The resulting mixture was stirred at room temperature for 3 hours. After simple dilution with ether (80 ml) of the diluted mixture was washed with saturated is one solution of sodium bicarbonate and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) and was led from hexane to obtain specified in the title compound (55 mg, 88%).

1H-NMR (400 MHz, CDCl3)δ: x 6.15 (1H, s), 6,93 (1H, m), 7,05 (1H, m), 7,44 (2H, d, J=8,8 Hz)to 7.50 (1H, m), to 7.59 (2H, d, J=8,8 Hz), 8,13 (1H, s), 8,55 (1H, s), with 8.33 (1H, s).

TPL: 147-148°C.

Elemental Analysis for C18H10Cl3F2NO2S,0,5H2O. Calculated: C,47,23; H,2,42; N,A 3.06; S,7,01; Cl,23,24; F,8,30. Found: C,47,25; H,2,24; N,3,21; S,7,19; Cl,23,25; F,8,32.

Example 58:4-[5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]morpholine

[Chemical formula 101]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (100 mg, 0.24 mmol)obtained in example 54, and research (200 μl) in 1,4-dioxane (1.0 ml) was stirred at 100°C for 2 days under nitrogen atmosphere. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and saturated saline solution, dried and then concentrated under reduced pressure to obtain a residue. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (100 mg, 89%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.48 (4H, m), 3,82 (4H, m)6,00 (1H, s)6,94 (1H, s), 6,94? 7.04 baby mortality (2H, m), to 7.09 (1H, m), 723 (2H, d, J=8,4 Hz), 7,24 (2H, d, J=8,4 Hz)to 8.12 (1H, s).

MS m/z: 467 (M++H).

Example 59:4-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]morpholine

[Chemical formula 102]

Tetrahydrate hexaminolevulinate (60 mg) was added to a solution of 4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]the research (90 mg, 0,19 mmol) in methanol (12 ml)and then added 30% aqueous hydrogen peroxide solution (6 ml). The resulting mixture was stirred for 6 hours. The reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel (hexane:ethyl acetate=3:1) and was led from ethanol to obtain specified in the title compound (80 mg, 83%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: of 3.54 (4H, m), a-3.84 (4H, m), 6,12 (1H, s), make 6.90 (1H, m), 7,02 (1H, m), 7,42 (2H, d, J=8,4 Hz), 7,45 (1H, s), 7,46 (1H, m), 7,58 (2H, d, J=8,4 Hz), of 8.06 (1H, s).

TPL: 180-181°C.

Elemental Analysis for C22H18Cl2F2N2O3S. Calculated: C,52,92; H,3,63; N,5,61; S,6.42 Per; Cl,14,20; F,To 7.61. Found: C,52,68; H,Of 3.56; N,5,69; S 6,70; Cl,14,32; F,7,97.

Example 60:4-[2-[5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]aminoethyl]morpholine

[Chemical formula 103]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (100 mg, 0.24 mmol)obtained in example 54 and 4-(2-amino-ethyl)research (200 μl) in 1,4-dioxane (1.0 ml) was stirred at 100°C for 2 days under nitrogen atmosphere. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and saturated saline solution, dried and concentrated under reduced pressure to obtain a residue. The obtained residue was purified by chromatography on silica gel (3% methanol/chloroform) to obtain the specified title compound (12 mg, 10%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,42 (4H, m), of 2.54 (2H, d, J=6.0 Hz), with 3.27 (2H, q, J=6.0 Hz), to 3.67 (4H, m), 5,12 ( width,1H), 5,90 (1H, s), is 6.61 (1H, s), 6,86-7,0 (2H, m), 7,06 (1H, m), to 7.15 (2H, d, J=8,4 Hz), 7,16 (2H, d, J=8,4 Hz), 7,95 (1H, s).

MS m/z: 510 (M++H).

Example 61:4-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]aminoethyl]morpholine-N-oxide

[Chemical formula 104]

Tetrahydrate hexaminolevulinate (10 mg) was added to a solution of 4-[2-[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]aminoethyl]the research (11 mg, to 0.032 mmol) in methanol (12 ml)and then added 30% aqueous hydrogen peroxide solution (1 ml). The resulting mixture was stirred for 8 hours. The reaction mixture was diluted with ethyl acetate. R is sravleniyu the mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (3% methanol, 3% solution of tert-butylamine in chloroform) to obtain the specified title compound (5.0 mg, 42%).

1H-NMR (400 MHz, CDCl3)δ: a 3.2 and 3.4 (4H, m), of 3.54 (2H, m), 3,81 (2H, m), 3,91 (2H, m), of 4.44 (2H, m)6,09 (1H, s), to 6.88 (1H, m), 6,98 (1H, m), 7,22 (1H, s), 7,40 (2H, d, J=8,4 Hz), 7,51 (1H, m), 7,60 (2H, d, J=8,4 Hz), 7,94 (1H, s).

FAB-MS: 558,0837 (Calculated for C24H24Cl2F2N3O4S: 558,0833).

Example 62:5-Azidomethyl-2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine

[Chemical formula 105]

2-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-5-(hydroxymethyl)pyridine (471 mg, 1.15 mmol)obtained in example 43 was dissolved in a mixture of carbon tetrachloride (4 ml) and N,N-dimethylformamide (16 ml). To the resulting solution was added sodium azide (112 mg, 1,72 mmol) and triphenylphosphine (451 mg, 1,72 mmol). The resulting mixture was stirred at 90°C for 3 hours. To the reaction mixture were added water and then was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1, Kon who was interaval under reduced pressure to obtain specified in the title compound (244 mg, 0,561 mmol, 49%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: was 4.42 (2H, s), 5,96 (1H, s)6,94 (1H, m), 6,99-7,05 (1H, m), 7,40 (2H, d, J=8,8 Hz), 7,55 (2H, d, J=8,8 Hz), 7,60 (1H, d, J=8.1 Hz), 7,72 (1H, DD, J=8,1, 2.0 Hz), 8,02 (1H, m), to 8.57 (1H, d, J=2,0 Hz).

MS m/z: 435 (M++H).

Example 63: [6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]pyridine-3-yl]methylamine

[Chemical formula 106]

In an argon atmosphere to ethanol (10 ml) was added 5-azidomethyl-2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine (77 mg, 0,177 mmol), palladium on carbon (14 mg) and ethyl acetate (2 ml). The resulting mixture was stirred for 50 minutes in an atmosphere of hydrogen at a pressure of 1 atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=10:1 was concentrated under reduced pressure to obtain specified in the title compound (28 mg, 0,0685 mmol, 39%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 1.84 (2H, Shir. C)to 3.92 (2H, s)5,94 (1H, s), 6,92 (1H, m), 7.03 is-6,98 (1H, m), 7,39 (2H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), 7,60 (1H, d, J=8.1 Hz), 7,74 (1H, d, J=8.1 Hz), 8,01 (1H, m), to 8.57 (1H, s).

MS m/z: 409 (M++H).

Example 64:tert-Butyl [[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]carbamate

[Chemicas the second formula 107]

5-Azidomethyl-2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine (230 mg, 0,529 mmol)obtained in example 62, and palladium on carbon (46 mg) was added to a mixture of ethyl acetate (15 ml) and ethanol (15 ml). The resulting mixture was stirred for 45 minutes in a hydrogen atmosphere at a pressure of 1 atmosphere. The reaction mixture was filtered. The filtrate is then concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 ml). To the resulting solution were added triethylamine (70 μl, 0,499 mmol) and di-tert-butyl carbonate (174 mg, 0,996 mmol). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (78 mg, 0,153 mmol, 37%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 1.45 (9H, s), 4,34 (2H, d, J=5.6 Hz), 4,91 (1H, Shir. C)to 5.93 (1H, s)6,91 (1H, m), 6,98? 7.04 baby mortality (1H, m), 7,39 (2H, d, J=8,8 Hz), 7,54 (2H, d, J=8,8 Hz), to 7.59 (1H, d, J=7.8 Hz), to 7.67 (1H, DD, J=7,8,2,2 Hz), to 7.99 (1H, m), 8,53 (1H, d, J=2.2 Hz).

MS m/z: 509 (M++H).

Example 65: tert-Butyl [[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-N-(tert-butoxycarbonyl who yl)carbamate

[Chemical formula 108]

Diisopropylsalicylic (128 μl, 0,653 mmol) was added under nitrogen atmosphere to a solution of 2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-(hydroxymethyl)pyridine (178 mg, 0,435 mmol)obtained in example 43, di-tert-butyl of iminodicarboxylate (142 mg, 0,653 mmol) and triphenylphosphine (171 mg, 0,653 mmol) in tetrahydrofuran (5 ml). The resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture were added water and then was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution. The obtained organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (78 mg, 0,128 mmol, 32%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: to 1.48 (18H, s), 4,78 (2H, s)5,94 (1H, s), 6,93 (1H, TD, J=9,0, 4,4 Hz), 6,98? 7.04 baby mortality (1H, m), 7,38 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), 7,58 (1H, d, J=8.1 Hz), 7,71 (1H, DD, J=8,1, 2.4 Hz), of 7.96-8,00 (1H, m), to 8.57 (1H, d, J=2,4 Hz).

MS m/z: 609 (M++H).

Example 66:Hydrochloride [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine

[Chemical is Kai formula 109]

To a solution of tert-butyl[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-N-(tert-butoxycarbonyl)carbamate (70 mg, 0,115 mmol) in ethanol (2 ml) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue were added ethanol. The mixture was concentrated under reduced pressure to obtain specified in the title compound (51 mg, 0,115 mmol, 100%) as a white powder.

1H-NMR (400 MHz, CD3OD)δ: 4,18 (2H, s), from 6.22 (1H, s), 7,03 (1H, TD, J=9,3, 4,4 Hz), 7,11-7,17 (1H, m), 7,52 (2H, d, J=8,8 Hz), to 7.64 (2H, d, J=8,8 Hz), 7,79 (1H, d, J=8,3 Hz), 7,92 (1H, DD, J=8,3, 2.2 Hz), 8,05-of 8.09 (1H, m)8,71 (1H, d, J=2.2 Hz).

Elemental Analysis for C20H15ClF2N2O2S·HCl. Calculated: C,51,25; H,3,62; Cl,15,92; F,8,53; N,6,29. Found: C,51,11; H,3,57; Cl,15,50; F,8,39; N,Of 5.83.

Example 67:N-acetyl-N-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]ndimethylacetamide (Compound A) and N-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]ndimethylacetamide (Compound B)

[Chemical formula 110]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (40 mg, 0,0978 mmol)obtained in example 63, in dichloromethane (3 ml) was added to pereohlajdenia ice N-methylmorpholine (26 μl, 0,234 mmol) and acetylchloride (16 μl, 0,234 mmol). The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture were added water and then was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:3 was concentrated under reduced pressure to obtain specified in the header of the connection A (iskopaemoe connection) (15 mg, 0,0304 mmol, 40%) as a white powder and are specified in the Connection header B (high-polar compound) (12 mg, 0,0266 mmol, 27%) as a white powder.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 2,43 (6H, s), 4,96 (2H, s), to 5.93 (1H, s)6,91 (1H, m), 6,98-7,03 (1H, m), 7,39 (2H, d, J=8.5 Hz), 7,54-to 7.61 (2H, m), 7,55 (2H, d, J=8.5 Hz), 8,02 (1H, m), 8,51 (1H, d, J=1.7 Hz).

TPL: 60-64°C.

MS m/z: 493 (M++H).

Compound B

1H-NMR (400 MHz, CDCl3)δ: 2,03 and 2,04 (3H,rotamer), 4,42-4,50 (2H, m), of 5.89 (1H, Shir. C)to 5.93 (1H, s), 6,92 (1H, TD, J=9,1, 4,4 Hz), 6,97-7,02 (1H, m), 7,41 (2H, d, J=8.1 Hz), EUR 7.57 (2H, d, J=8.1 Hz), to 7.61 (1H, d, J=8.1 Hz), 7,71 (1H, d, J=8.1 Hz), 7,98-8,03 (1H, m), 8,54 (1H, s).

TPL: 177-178°C

MS m/z: 451 (M++H).

Example 68:N-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-the l]methyl]-N',N'-dimethylsulfone

[Chemical formula 111]

To a solution of hydrochloride [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (60 mg, is 0.135 mmol)obtained in example 66, in dichloromethane (5 ml) was added N-methylmorpholine (180 μl, of 1.62 mmol), 4-dimethylaminopyridine (10 mg, 0,0819 mmol) and N,N-dimethylsulphamoyl (66 μl, 0,609 mmol). The resulting mixture was stirred at room temperature for 24 hours. To the reaction mixture were added water and then was extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure to obtain specified in the title compound (48 mg, 0,0930 mmol, 70%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: was 2.76 (6H, s), the 4.29 (2H, d, J=6.4 Hz), 4,43 (1H, t, J=6.4 Hz), 5,94 (1H, s), 6,92 (1H, m), 6,98? 7.04 baby mortality (1H, m), 7,41 (2H, d, J=8.6 Hz), 7,58 (2H, d, J=8.6 Hz), 7,66 (1H, d, J=8.1 Hz), 7,79 (1H, DD, J=8,1, 2,5 Hz), 8,02 (1H, m), 8,61 (1H, d, J=2.5 Hz).

TPL: 177-178 (C.

MS m/z: 516 (M++H).

Example 69:Ethyl 2-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]what ethylamino]-2-oxoacetate

[Chemical formula 112]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (30 mg, 0,0734 mmol)obtained in example 63, in dichloromethane (4 ml) was added under ice cooling, N-methylmorpholine (10 μl, 0,0881 mmol) and ethylchloride (9 μl, 0,0807 mmol). The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and then was extracted with dichloromethane. The organic layer is then washed with saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure to obtain specified in the title compound (28 mg, 0,0550 mmol, 76%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 1.39 (3H, t, J=7,1 Hz), 4,37 (2H, q, J=7,1 Hz), 4,55 (2H, d, J=5,9 Hz), 5,94 (1H, s), 6.89 in-6,94 (1H, m), 6,98-7,05 (1H, m), 7,40 (2H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), 7,53 (1H, Shir. C)a 7.62 (1H, d, J=8.1 Hz), 7,72 (1H, d, J=8.1 Hz), 7,97-8,03 (1H, m), 8,58 (1H, s).

TPL: 193-194°C.

MS m/z: 509 (M++H).

Example 70:N-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-2-(4-methylphen is sulfonylamino)ndimethylacetamide

[Chemical formula 113]

To a solution of hydrochloride [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (40 mg, 0,0898 mmol)obtained in example 66, in dichloromethane (6 ml) was added triethylamine (45 μl, 0,324 mmol), 4-dimethylaminopyridine (5 mg, 0,0449 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (21 mg, to 0.108 mmol) and N-p-tailgatin (25 mg, to 0.108 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was then washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2,3, concentrated under reduced pressure to obtain specified in the title compound (41 mg, 0,0661 mmol, 73%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.44 (3H, s)and 3.59 (2H, d, J=6.4 Hz), of 4.44 (2H, DD, J=6,1, 2,8 Hz), 5,42 (1H, t, J=6,1 Hz), 5,95 (1H, s)6,91 (1H, m), of 6.96-7.03 is (2H, m), 7,33 (2H, d, J=8,3 Hz), 7,41 (2H, d, J=8.6 Hz), EUR 7.57 (2H, d, J=8.6 Hz), 7,58 (1H, d, J=8.1 Hz), 7,66 (1H, DD, J=8,1, 2.4 Hz), 7,74 (2H, d, J=8,3 Hz), 8,01 (1H, m), 8,49 (1H, d, J=2,4 Hz).

TPL: 217-218°C.

MSm/z: 620 (M ++H).

Example 71:N-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-2-dimethylaminoacetyl

[Chemical formula 114]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (30 mg, 0,0734 mmol)obtained in example 63, in dichloromethane (5 ml) was added triethylamine (12 μl, 0,0881 mmol), 4-dimethylaminopyridine (5 mg, 0,0367 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (17 mg, 0,0881 mmol) and N,N-dimethylglycine (9 mg, 0,0881 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:4, concentrated under reduced pressure to obtain specified in the title compound (21 mg, 0,0425 mmol, 58%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.30 (6H, s), 3,01 (2H, s), 4,50 (2H, d, J=6,1 Hz), to 5.93 (1H, s)6,91 (1H, m), 6,98? 7.04 baby mortality (1H, m), 7,40 (2H, d, J=8.6 Hz), 7,55 (2H, d, J=8.6 Hz), 7,60 (1H, d, J=8.1 Hz), a 7.62 (1H, Shir. C)of 7.69 (1H, DD, J=8,1, ,4 Hz), 8,02 (1H, m), 8,56 (1H, d, J=2,4 Hz).

TPL: 177-179°C.

MS m/z: 494 (M++H).

Example 72:N-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-4-(formylmethylene)benzamid

[Chemical formula 115]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (50 mg, 0,122 mmol)obtained in example 63, in dichloromethane (5 ml) was added triethylamine (21 μl, 0.147 mmol), 4-dimethylaminopyridine (7 mg, 0,0610 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (28 mg, 0.147 mmol) and N-formyl-4-(methylamino)benzoic acid (26 mg, 0.147 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:7, was concentrated under reduced pressure to obtain specified in the title compound (60 mg, 0,105 mmol, 87%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: at 3.35 (3H, s), 4,67-4,71 (2H, m)5,94 (1H, s) 6,53 (1H, Shir. C)of 6.90 (1H, m), 6,97-7,03 (1H, m), 7,25 (2H, d, J=8.6 Hz), 7,40 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), 7,63 (1H, d, J=8.1 Hz), 7,78 (1H, DD, J=8,1, 2.2 Hz), 7,86 (2H, d, J=8.6 Hz), 8,03 (1H, m), 8,61 (1H, s)8,64 (1H, d, J=2.2 Hz).

MS m/z: 570 (M++H).

Example 73:N-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-4-(methyldiethanolamine)thiobenzamide

[Chemical formula 116]

In an argon atmosphere to a solution of N-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-4-(formylmethylene)benzamide (46 mg, 0,0807 mmol) in toluene (5 ml) was added a reagent Lawson (69 mg, 0,169 mmol). The resulting mixture was heated at the boil under reflux for 12 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (40 mg, to 0.0664 mmol, 83%) as a yellow amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: and 3.72 (3H, s)5,08 (2H, d, J=4.4 Hz), of 5.92 (1H, s), 6.89 in (1H, TD, J=9,0, 4,4 Hz), 6,98-7,05 (1H, m), 7,25 (2H, d, J=8.6 Hz), 7,40 (2H, d, J=8.6 Hz), 7,55 (2H, d, J=8.6 Hz), 7,60 (1H, d, J=8,1 Hz), 7,81 (1H, d, J=8.1 Hz), 7,87 (2H, d, J=8.6 Hz), 8,02-of 8.06 (1H, m), to 8.20 (1H, Shir. C)to 8.62 (1H, s)to 9.70 (1H, s).

MS m/z: 602 (M++H).

Example 74:N-[[6-[(4-Chlorphenyl Lionel)(2.5-differenl)methyl]pyridine-3-yl]methyl]-2-(pyridin-3-yl)ndimethylacetamide

[Chemical formula 117]

[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (30 mg, 0,073 mmol)obtained in example 63, hydrochloride 3-pyridyloxy acid (16 mg, 0,092 mmol), 4-(dimethylamino)pyridine (5 mg, 0.04 mmol) and triethylamine (of 0.025 ml, 0.18 mmol) was dissolved in dichloromethane (5 ml). To the resulting solution were added at room temperature, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (17 mg, 0,089 mmol). The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were added saturated aqueous solution (0.1 ml) of sodium bicarbonate. The residue obtained by concentration of the reaction mixture under reduced pressure was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=30:1 was concentrated under reduced pressure to obtain white solid. The obtained solid substance was washed with a simple ether to obtain specified in the title compound (35 mg, of 0.066 mmol, 90%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,59 (2H, s), of 4.45 (2H, DD, J=5,9, 1.5 Hz), of 5.92 (1H, s), 5,96-6,10 (1H, m), 6,86-6,98 (1H, m), 6,99-7,05 (1H, m), 7.24 to to 7.35 (1H, m), 7,39 (2H, d, J=8,8 Hz), 7,55-of 7.60 (3H, m), 7,60-7,71 (2H, m), of 7.96-of 8.06 (1H, m), and 8.50 (2H, d, J=1.6 Hz), 8,55 (1H, d, J=4,8, 1,6 Hz).

MS m/z: 528 (M++H).

Example 75:[6-(4-Chlorophenylsulfonyl)(2,5-differeni is)methylpyridin-3-yl]methyldiethylamine

[Chemical formula 118]

To a solution in dichloromethane (0.3 ml) of 2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-(hydroxymethyl)pyridine (20 mg, 0,049 mmol)obtained in example 43 was added sequentially at 0°C N-methylmorpholin (to 0.011 ml, 0.10 mmol) and p-nitrophenylphosphate (15 mg, 0,074 mmol). The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture were then added sequentially at 0°C N-methylmorpholin (0,033 ml, 0.30 mmol) and p-nitrophenylphosphate (15 mg, 0,074 mmol). The resulting mixture was stirred at room temperature for 30 minutes. After adding to the reaction mixture at 0°C dimethylamine hydrochloride (20 mg, 0.25 mmol) and stirring for 13 hours, the reaction mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=7:3 was concentrated under reduced pressure. The obtained solid was washed with hexane and collected by filtration to obtain specified in the title compound (13 mg, or 0.027 mmol, 55%) as a white solid.

1H-NMR (400 MHz, CDCl 3)δ: to 2.94 (6H, s), 5,14 (2H, s)5,94 (1H, s), 6.87 in-7,07 (2H, m), 7,39 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), a 7.62 (1H, d, J=7.8 Hz), of 7.75 (1H, DD, J=7,8, 2.0 Hz), 7,99-8,07 (1H, m), 8,63 (1H, d, J=2.0 Hz).

MS m/z: 481 (M++H).

Example 76:[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl 4-nitrophenylarsonic

[Chemical formula 119]

To a solution of 2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-(hydroxymethyl)pyridine (41 mg, 0.10 mmol)obtained in example 43, in dichloromethane (0.5 ml) were added sequentially at 0°C N-methylmorpholin (0,033 ml, 0.30 mmol) and 4-nitrophenylphosphate (40 mg, 0.20 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure. The obtained solid was washed with hexane and collected by filtration to obtain specified in the title compound (52 mg, 0,090 mmol, 90%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 5,33 (2H, s), 5,97 (1H, s), 6.87 in-6,95 (1H, m), 6,98-7,06 (1H, m), 7,39 (2H, d, J=9.0 Hz), 7,40 (2H, d, J=8.5 Hz), EUR 7.57 (2H, d, J=8.5 Hz), 7,71 (1H, d, J=7,6 Hz), the 7.85 (1H, DD, J=7,6, ,0 Hz), 7,97-with 8.05 (1H, m), 8,29 (2H, d, J=9.0 Hz), 8,72 (1H, d, J=2.0 Hz).

MS m/z: 575 (M++H).

Example 77:[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methylbenzylamine

[Chemical formula 120]

To a solution of [6-(4-chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl 4-nitrophenylarsonic (51 mg, 0,089 mmol) in dichloromethane (1 ml) were added sequentially at 0°C N-methylmorpholin (0,020 ml, 0.18 mmol) and benzylamine (a 0.012 ml, 0.11 mmol). The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure. The obtained solid is washed with diisopropyl ether and collected by filtration to obtain specified in the title compound (33 mg, to 0.060 mmol, 68%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 4.38 (2H, Shir. d, J=5.4 Hz), is 5.06 (1H, Shir. C)5,16 (2H, s)5,94 (1H, s), 6.87 in? 7.04 baby mortality (2H, m), 7,22-7,38 (5H, m), 7,39 (2H, d, J=8,3 Hz), 7,54 (2H, d, J=8,3 Hz), a 7.62 (1H, d, J=8,3 Hz), 7,74 (1H, d, J=8,3 Hz), of 7.96-8,03 (1H, m), 8,61 (1H, s).

MS m/z: 543 (M++H).

Note the p 78: N-[[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonyl

[Chemical formula 121]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (28 mg, 0,068 mmol)obtained in example 63, in dichloromethane (0.5 ml) were added sequentially at 0°C N-methylmorpholin (of 0.015 ml, 0.14 mmol) and 3-cyanobenzenesulfonyl (22 mg, 0.10 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with 1 N. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=7:3 was concentrated under reduced pressure. The obtained solid was washed with hexane and collected by filtration to obtain specified in the title compound (23 mg, 0.040 mmol, 59%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 4.26 deaths (2H, d, J=6.4 Hz), to 5.08 (1H, t, J=6.4 Hz), 5,91 (1H, s), 6,86-7,06 (2H, m), 7,40 (2H, d, J=8.1 Hz), 7,55 (2H, d, J=8.1 Hz), EUR 7.57-of 7.70 (3H, m), 7,81 (1H, d, J=7,4 Hz), 7,94-with 8.05 (2H, m), 8,11 (1H, s), 8,46 (1H, s).

MS m/z 574 (M++H).

Example 79:N-[[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl]-3-C the ANO-N-methylbenzenesulfonamide

[Chemical formula 122]

To a solution of N-[[6-(4-chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl]-3-cyanobenzenesulfonyl (21 mg, 0,037 mmol) in tetrahydrofuran (0.5 ml) were added sequentially at 0°C methanol (0.003 ml, 0,073 mmol), triphenylphosphine (19 mg, 0,073 mmol) and diisopropylethylamine (of 0.014 ml, 0,073 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain specified in the title compound (13 mg, 0,021 mmol, 58%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,70 (3H, s), 4,25 (2H, d, J=6.4 Hz), 5,95 (1H, s), 6.87 in-7,05 (2H, m), 7,40 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8.5 Hz), 7,66 (1H, d, J=8.1 Hz), 7,73 (1H, t, J=7.8 Hz), 7,81 (1H, DD, J=8,1, 2,2 Hz), to $ 7.91 (1H, d, J=7.8 Hz), 7,99-of 8.09 (2H, m)to 8.12 (1H, s), 8,53 (1H, t, J=2.2 Hz).

MS m/z: 588 (M++H).

Example 80:3-[[6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methylpyridin-3-yl]methyl]-1,1-dimethyloxetane

[Chemical formula 123]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (31 mg, 0,076 mmol)obtained in example 63, in dichloromethane (1 ml) was added to the sequentially at 0° C triethylamine (to 0.032 ml, 0.23 mmol) and N,N-dimethylcarbamoyl (of 0.014 ml, 0.15 mmol). The resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture were added successively at 0°C triethylamine (to 0.032 ml, 0.23 mmol) and N,N-dimethylcarbamoyl (of 0.014 ml, 0.15 mmol). The resulting mixture was stirred at room temperature for 29 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with ethyl acetate, concentrated under reduced pressure. The obtained solid was washed with hexane and collected by filtration to obtain specified in the title compound (18 mg, being 0.036 mmol, 48%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 2.93 (6H, s), of 4.44 (2H, d, J=4, 2 Hz), was 4.76 (1H, t, J=4, 2 Hz), to 5.93 (1H, s), 6,85? 7.04 baby mortality (2H, m), 7,39 (2H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), 7,58 (1H, d, J=8.5 Hz), 7,74 (1H, DD, J=8,5, 2,0 Hz), 7,98-of 8.06 (1H, m), to 8.57 (1H, d, J=2.0 Hz).

MS m/z: 480 (M++H).

Example 81:Methyl [6-(4-chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methylcarbamate

[Chemical formula 124]

In the same way as in example 80, has been specified is second in the title compound (16 mg, 0,034 mmol, 42%) as a yellow solid, using [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (34 mg, 0,082 mmol)obtained in example 63, and methylcarbonate is 0.019 ml, 0.25 mmol).

1H-NMR (400 MHz, CDCl3)δ: 3,71 (3H, s), and 4.40 (2H, d, J=6,1 Hz), 5,07 (1H, Shir. C)to 5.93 (1H, s), 6.87 in? 7.04 baby mortality (2H, m), 7,39 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), 7,60 (1H, d, J=7.8 Hz), of 7.70 (1H, d, J=7.8 Hz), 7,97-of 8.04 (1H, m), 8,55 (1H, s).

MS m/z: 467 (M++H).

Example 82:N-[[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl]methanesulfonamide

[Chemical formula 125]

In the same way as in example 80, has been specified in the title compound (20 mg, 0.040 mmol, 49%) as a white solid by using [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (34 mg, 0,082 mmol)obtained in example 63, and methanesulfonanilide is 0.019 ml, 0.25 mmol).

1H-NMR (400 MHz, CDCl3)δ: of 2.97 (3H, s), 4,37 (2H, d, J=6,1 Hz), 4,70 (1H, Shir. C)5,95 (1H, s), 6,88-7,07 (2H, m), 7,40 (2H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), the 7.65 (1H, d, J=8.1 Hz), 7,80 (1H, d, J=8.1 Hz), 7,97-8,07 (1H, m), 8,61 (1H, s).

MS m/z: 487 (M++H).

Example 83:N-[[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl]-1-acetyl-4-piperidinecarboxylic

[Chemical formula 126]

In the same way as in example 80, has been specified in the title compound (24 mg ,043 mmol, 52%) as colorless foamy substance, using [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (34 mg, 0,082 mmol)obtained in example 63, and 1-acetyl-4-piperidinecarboxylate (56 mg, 0.25 mmol).

1H-NMR (400 MHz, CDCl3)δ: 1,58-to 1.79 (2H, m), 1,82-of 1.95 (2H, m), is 2.09 (3H, s), 2,30-to 2.41 (1H, m), 2,59-2,70 (1H, m), 3,03-3,13 (1H, m), 3,82-to 3.92 (1H, m), to 4.41-a 4.53 (2H, m), 4,55-4,63 (1H, m), 5,90 is 5.98 (2H, m), 6,85-6,94 (1H, m), 6,97? 7.04 baby mortality (1H, m), 7,40 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), 7,60 (1H, d, J=8.1 Hz), 7,66 (1H, d, J=8.1 Hz), 7,98-with 8.05 (1H, m), 8,53 (1H, s).

MS m/z: 562 (M++H).

Example 84:[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methylpyridin-3-yl]methyl methylcarbonate

[Chemical formula 127]

To a solution in dichloromethane (2 ml) of 2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-(hydroxymethyl)pyridine (50 mg, 0.12 mmol)obtained in example 43 was added sequentially at 0°C pyridine (0,040 ml, 0.49 mmol) and methylchloroform is 0.019 ml, 0.24 mmol). The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added at 0°C methylchloroform is 0.019 ml, 0.24 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with 1 N. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Receiving the hydrated residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure. The obtained solid was washed with hexane and collected by filtration to obtain specified in the title compound (50 mg, 0.11 mmol, 88%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 3,81 (3H, s), is 5.18 (2H, s), 5,95 (1H, s), 6.89 in? 7.04 baby mortality (2H, m), 7,40 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), the 7.65 (1H, d, J=8.1 Hz), 7,78 (1H, DD, J=8,1, 2.2 Hz), 7,97-8,03 (1H, m)8,64 (1H, d, J=2.2 Hz).

MS m/z: 468 (M++H).

Example 85:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carbaldehyde (Isomer A and Isomer B)

[Chemical formula 128]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carbaldehyde (100 mg, 0.25 mmol)obtained in example 47, in dichloromethane (3 ml) was added N-methylmorpholine (32 μl, 0.29 mmol) and hydroxylamine hydrochloride (26 mg, 0.36 mmol). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with dichloromethane, washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. Faction poluchenno is when elution by the mixture hexane:ethyl acetate=3:2, concentrated under reduced pressure to obtain specified in the title Isomer A (iskopaemoe connection) (79 mg, 0,19 mmol, 72%) as a white powder and is specified in the title Isomer B (high-polar compound) (17 mg, 0.040 mmol, 17%) as a white powder.

Isomer A

1H-NMR (400 MHz, CDCl3)δ: 5,97 (1H, s), 6,91-of 6.96 (1H, m), 6,99-7,05 (1H, m), 7,40 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), 7,66 (1H, d, J=8.1 Hz), 7,78 (1H, s), of 7.96-8,02 (2H, m)to 8.14 (1H, s), is 8.75 (1H, d, J=1.7 Hz).

TPL: 187-188°C.

MS m/z: 423 (M++H).

Isomer B

1H-NMR (400 MHz, CDCl3)δ: 5,98 (1H, s), 6,91-6,97 (1H, m), 7,00-7,06 (1H, m), 7,40 (1H, s), 7,41 (2H, d, J=8.6 Hz), EUR 7.57 (2H, d, J=8.6 Hz), 7,71 (1H, d, J=8,3 Hz), of 7.90-8,02 (2H, m), to 8.41 (1H, DD, J=8,3, 2,1 Hz), 9,00 (1H with).

TPL: 194-196°C.

MS m/z: 423 (M++H).

Example 86:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-N-cyclohexylethylamine

[Chemical formula 129]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (80 mg, 0,19 mmol)obtained in example 50, in dichloromethane (5 ml) was added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0,095 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol) and aminomethylation (30 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with dichloromethane and the industry is Ali successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (58 mg, 0.11 mmol, 59%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 0,95 and 1.80 (11H, m), 3,32 (2H, d, J=6.4 Hz), 5,98 (1H, s), 6,13-6,16 (1H, m), 6.90 to-of 6.96 (1H, m), 7,00-706 (1H, m), 7,40 (2H, d, J=8.6 Hz), 7,55 (2H, d, J=8.6 Hz), 7,69 (1H, d, J=8,3 Hz), 7,97-8,02 (1H, m), 8,13 (1H, DD, J=8,3, 2.2 Hz), to 8.94 (1H, d, J=2.2 Hz).

MS m/z: 519 (M++H).

Example 87:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-N-(5-chloropyridin-2-yl)nicotinamide

[Chemical formula 130]

To a solution in dichloromethane (5 ml) of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (80 mg, 0,19 mmol)obtained in example 50, was added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0,095 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol) and 2-amino-5-chloropyridin (29 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane and washed serial is Ino water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (27 mg, 0,051 mmol, 27%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,04 (1H, s), 6,92-6,97 (1H, m), 7,01-7,07 (1H, m), 7,42 (2H, d, J=8.6 Hz), EUR 7.57 (2H, d, J=8.6 Hz), of 7.75 (1H, DD, J=9,1,2,4 Hz), 7,80 (1H, d, J=8.1 Hz), 7,97 shed 8.01 (1H, m), compared to 8.26 (1H, DD, J=8,1,2,2 Hz), of 8.28 (1H, d, J=2.4 Hz) of 8.33 (1H, d, J=9.1 Hz), 8,51 (1H, s), 9,12 (1H, d, J=2.2 Hz).

MS m/z: 534 (M++H).

Example 88:N',N'-dimethylhydrazide 6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinic acid

[Chemical formula 131]

To a solution in dichloromethane (5 ml) of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (80 mg, 0,19 mmol)obtained in example 50, was added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0,095 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol) and 1,1-dimethylhydrazine (21 μl, 0.23 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane the m The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=50:1 was concentrated under reduced pressure to obtain specified in the title compound (60 mg, 0.13 mmol, 68%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 2.57 m (0,9H, C)2,72 (5,1H, C), 5,98 (1H, s), 6.48 in (0,15H, s), 6.90 to-7,06 (2,85H, m), 7,41 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), to 7.68 (1H, d, J=8.1 Hz), 7,97-of 8.04 (1H, m), 8,13-8,17 (1H, m), 8,94 (0,85H, C), 9,07 (0,15H, s).

MS m/z: 466 (M++H).

Example 89:N'-(Furan-2-carbonyl)hydrazide 6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinic acid

[Chemical formula 132]

To a solution in dichloromethane (5 ml) of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (80 mg, 0,19 mmol)obtained in example 50, was added triethylamine (32 μl, 0.23 mmol), 4-dimethylaminopyridine (12 mg, 0,095 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (44 mg, 0.23 mmol) and 2-orangered (29 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 7.5 hours. Rea is operating, the mixture was diluted with dichloromethane. The diluted mixture was then washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=50:1 was concentrated under reduced pressure. The obtained solid was recrystallized from dichloromethane-hexane to obtain specified in the title compound (58 mg, 0.11 mmol, 58%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,01 (0,7H, s), 6,02 (0,3H, s), 6,55 (0,7H, DD, J=3,4, 1.7 Hz), 6,91-of 6.96 (1H, m), 6,99? 7.04 baby mortality (1H, m), 7,21 (0,7H, d, J=3,4 Hz), 7,41 (2H, d, J=8.6 Hz), 7,53 (0,3H, DD, J=1,7, 0.7 Hz), 7,56-of 7.60 (3H, m), 7,74 (1H, d, J=8,3 Hz), to 7.77 (0,3H, d, J=8,8 Hz), 7.95 is-to 7.99 (1H, m), 8,15-8,19 (1H, m), 8,99 (0,3H, s), 9,03 (1H, d, J=2.2 Hz), 9,14 (0,7H, Shir. C)9,67 (0,7H, Shir. C)9,98 (0,3H, Shir. C).

MS m/z: 532 (M++H).

Example 90:N-[[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]-(E)-3-(pyridin-4-yl)acrylamide

[Chemical formula 133]

To a solution in dichloromethane (1 ml) of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine (41 mg, 0.10 mmol)obtained in example 63, (E)-3-(pyridin-4-yl)acrylic acid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol) and N-metalmorph is on (to 0.011 ml, 0.10 mmol) was added at 0°C hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (19 mg, 0.10 mmol). The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with ethyl acetate, concentrated under reduced pressure. The obtained solid is washed with diethyl ether and collected by filtration to obtain specified in the title compound (35 mg, 0,065 mmol, 65%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 4,53-of 4.66 (2H, m), to 5.93 (1H, s), 6,09-of 6.17 (1H, m), to 6.57 (1H, d, J=15.6 Hz), 6,86-6,93 (1H, m), of 6.96? 7.04 baby mortality (1H, m), 7,34 (2H, d, J=5,9 Hz), 7,40 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8.5 Hz), 7,60 (1H, d, J=15.6 Hz), to 7.61 (1H, d, J=8.1 Hz), 7,74 (1H, DD, J=8,1,2,2 Hz), 7,99-of 8.06 (1H, m), 8,59 (1H, d, J=2.2 Hz), 8,64 (2H, d, J=5,9 Hz).

MS m/z: 540 (M++H).

Example 91:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl] (thiomorpholine-4-yl)methanon

[Chemical formula 134]

In the same manner as in example 90, has been specified in the title compound (240 mg, 0.47 mmol, 94%) as a white solid by using [6-[(4-chlorophenylsulfonyl the)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (212 mg, 0.50 mmol)obtained in example 50, and thiomorpholine (0,047 ml, 0.50 mmol).

1H-NMR (400 MHz, CDCl3)δ: 2,61 (2H, Shir. C)to 2.74 (2H, Shir. C)of 3.69 (2H, Shir. C)of 4.04 (2H, Shir. C)5,97 (1H, s), 6,88-to 6.95 (1H, m), 6,98-7,06 (1H, m), 7,41 (2H, d, J=8.5 Hz), EUR 7.57 (2H, d, J=8.5 Hz), 7,73 (1H, d, J=8.1 Hz), 7,79 (1H, DD, J=8,1, 2.2 Hz), 7.95 is-8,02 (1H, m)8,64 (1H, d, J=2.2 Hz).

MS m/z: 509 (M++H).

Example 92:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl] (1,1-dioxo-1λ6-thiomorpholine-4-yl)methanon (Compound A) and [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl] (1-oxo-1λ4-thiomorpholine-4-yl)methanon (Compound B)

[Chemical formula 135]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl] (thiomorpholine-4-yl)methanone (153 mg, 0.30 mmol) in dichloromethane (3 ml) was added under ice cooling 3-chloroperbenzoic acid (96 mg, 0.36 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and washed sequentially 1 N. aqueous sodium hydroxide solution and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:2, concentrated the Ali under reduced pressure to obtain specified in the header of the connection A (iskopaemoe connection) (81 mg, 0.15 mmol, 50%) as a white powder, whereas the fraction obtained by elution with a mixture of dichloromethane:methanol=10:1 was concentrated under reduced pressure to obtain specified in the connection header B (high-polar link) (73 mg, 0.14 mmol, 46%) as a white powder.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 3,10 (4H, Shir. C)4,13 (4H, Shir. C)of 5.99 (1H, s), 6,88-6,93 (1H, m), 7,00-7,06 (1H, m), 7,42 (2H, d, J=8.5 Hz), 7,58 (2H, d, J=8.5 Hz), 7,79 (1H, d, J=8.1 Hz), 7,86 (1H, DD, J=8,1) and 1.7 Hz), 7,97-8,02 (1H, m), 8,71 (1H, d, J=1.7 Hz).

MS m/z: 541 (M++H).

Compound B

1H-NMR (400 MHz, CDCl3)δ: 2,70-of 3.00 (4H, m), 3,74 (1H, Shir. C)4,10 (2H, Shir. C)4,63 (1H, Shir. C)5,98 (1H, s), 6,88-6,94 (1H, m), 7,00-7,06 (1H, m), 7,42 (2H, d, J=8.6 Hz), 7,58 (2H, d, J=8.6 Hz), to 7.77 (1H, d, J=8.1 Hz), to 7.84 (1H, DD, J=8,1, 2.2 Hz), 7,98-8,02 (1H, m), to 8.70 (1H, d, J=2.2 Hz).

MS m/z: 525 (M++H).

Example 93:N-(3-Metaltipped)-6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinamide

[Chemical formula 136]

In the same manner as in example 90, has been specified in the title compound (238 mg, 0.47 mmol, 93%) as a white solid by using [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (212 mg, 0.50 mmol)obtained in example 50, 3-methylthiopropionate (by 0.055 ml, 0.50 mmol).

1H-NMR (400 MHz, CDCl3)δ: 1,92 is 2.01 (2H, m), and 2.14 (3H, s), 2.63 in (2H, t, J=6.8 Hz), to 3.58-of 3.64 (2H, m), of 5.99 (1H, s), 6,57-only 6.64 (1H, m), 6.90 to-6,97 (1H, m) 6,99-7,06 (1H, m), 7,41 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8.5 Hz), 7,71 (1H, d, J=8.1 Hz), of 7.96-8,03 (1H, m), 8,16 (1H, DD, J=8,1, 2.2 Hz), 8,96 (1H, d, J=2.2 Hz).

MS m/z: 511 (M++H).

Example 94:N-(3-Methylsulfinylpropyl)-6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinamide (Compound A) and N-(3-methylsulfinylpropyl)-6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinamide (Compound B)

[Chemical formula 137]

To a solution of N-(3-metaltipped)-6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinamide (153 mg, 0.30 mmol) in dichloromethane (3 ml) was added at 0°C 3-chloroperbenzoic acid (purity: 65% or higher) (96 mg, 0.36 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 1 N. aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with ethyl acetate, concentrated under reduced pressure. The obtained solid is washed with diethyl ether and collected by filtration to obtain specified in the header of the Connection A (53 mg, 0,098 mmol, 32%) as a white solid. The fraction obtained by elution with a mixture of dichloromethane:methanol=15:1, and then concentrated under pony is hinnon pressure. The obtained solid is washed with diethyl ether and collected by filtration to obtain specified in the connection header B (68 mg, 0.13 mmol, 43%) as a white solid.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 2,20-of 2.30 (2H, m), 2,98 (3H, s), 3,17 (2H, t, J=6.8 Hz), 3,65-and 3.72 (2H, m), of 5.99 (1H, s), 6,82-to 6.88 (1H, m), 6.90 to-6,97 (1H, m), 6,99-7,06 (1H, m), 7,41 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8,5 Hz), 7,72 (1H, d, J=8.1 Hz), of 7.96-8,02 (1H, m), 8,16 (1H, DD, J=8,1, 2.2 Hz), of 9.00 (1H, d, J=2.2 Hz).

MS m/z: 543 (M++H).

Compound B

1H-NMR (400 MHz, CDCl3)δ: 2,11-of 2.23 (1H, m), 2.26 and-is 2.37 (1H, m), 2.63 in (3H, s), 2,78-of 2.86 (1H, m), 2,92-of 3.00 (1H, m), 3,51-3,61 (1H, m), 3,66 of 3.75 (1H, m), of 5.99 (1H, s), 6.90 to-6,98 (1H, m), 6,99-7,06 (1H, m), 7,40 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), 7,69 (1H, d, J=8.1 Hz), 7,88 shed 8.01 (2H, m), by 8.22 (1H, DD, J=8,1, 2.2 Hz), the remaining 9.08 (1H, d, J=2.2 Hz).

MS m/z: 527 (M++H).

Example 95:2-Chloro-5-[(3-chloropyridin-4-yl) (2,5-differenl)methylthio]pyridine

[Chemical formula 138]

To a solution of O-ethyl S-(6-chloro-3-pyridyl)dithiocarbonate (164 mg, 0.70 mmol)obtained in reference example 26, in ethanol (7 ml) was added 1 N. aqueous sodium hydroxide solution (7 ml). The resulting mixture was stirred at 80°C for 3 hours. After cooling the reaction mixture to room temperature, to the mixture was added 1 n hydrochloric acid. The resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and Phi is travali. The filtrate was concentrated under reduced pressure to obtain 6-chloro-3-pyridinol in the form of a yellow solid.

To a solution in dichloromethane (3 ml) of 3-chloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (153 mg, of 0.60 mmol)obtained in reference example 23, were added successively at 0°C triethylamine (0,167 ml, 1.20 mmol) and methanesulfonamide (0,070 ml, 0.90 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (3 ml)consistentlyaddeda solution of 6-chloro-3-pyridinol in N,N-dimethylformamide (2 ml) and potassium carbonate (100 mg, to 0.72 mmol). The resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=17:3 was concentrated under decreased the pressure obtaining specified in the title compound (111 mg, 0.29 mmol, 48%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 6,04 (1H, s), 6,95-7,05 (2H, m), 7,10-7,20 (1H, m), 7,25 (1H, d, J=8.1 Hz), EUR 7.57 (1H, d, J=5,1 Hz), 7,60 (1H, DD, J=8,1, 2,5 Hz), 8,31 (1H, d, J=2.5 Hz), 8,54 (1H, d, J=5,1 Hz), 8,59 (1H, s).

MS m/z: 383 (M++H).

Example 96:2-Chloro-5-[(3-chloropyridin-4-yl)(2,5-differenl)methylsulphonyl]pyridine

[Chemical formula 139]

To a solution of 2-chloro-5-[(3-chloropyridin-4-yl)(2,5-differenl)methylthio]pyridine (109 mg, 0.28 mmol) in methanol (4 ml) was added a 31% aqueous hydrogen peroxide solution (2 ml) and tetrahydrate hexaminolevulinate (30 mg). The resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=17:3 was concentrated under reduced pressure to obtain specified in the title compound (108 mg, 0.26 mmol, 92%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 6.26 (1H, s), 6,94-7,03 (1H, m), 7,06-to 7.15 (1H, m), 7,44 (1H, d, J=8,3 Hz), 7,50-7,56 (1H, m), 7,89 (1H, DD, J=8,3, 2.7 Hz), to 8.12 (1H, d, J=5,1 Hz), 8,59 (1H, d, J=2.7 Hz), 861 (1H, C)8,66 (1H, d, J=5,1 Hz).

MS m/z: 415 (M++H).

Example 97:5-[(3-Chloropyridin-4-yl) (2,5-differenl)-methylsulphonyl]-2-herperidin

[Chemical formula 140]

To a solution of 2-chloro-5-[(3-chloropyridin-4-yl)(2,5-differenl)methylsulphonyl]pyridine (66 mg, 0.16 mmol) in acetonitrile (2 ml) was added potassium fluoride (94 mg, 1,60 mmol) and bromide tetraphenylporphine (134 mg, 0.32 mmol). The resulting mixture was heated at the boil under reflux for 16 hours. After cooling the reaction mixture to room temperature, to the mixture was added dichloromethane. The resulting mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=17:3 was concentrated under reduced pressure to obtain specified in the title compound (4.5 mg, to 0.011 mmol, 7%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 6.26 (1H, s), 6,93-7,13 (3H, m), 7,50-7,56 (1H, m), 8,01-8,08 (1H, m), 8,13 (1H, d, J=5,1 Hz), 8,48 (1H, d, J=2.2 Hz), at 8.60 (1H, s), 8,66 (1H, d, J=5,1 Hz).

MS m/z: 440 (M++H+MeCN).

Example 98:N'-[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-iletiler]-2-thiophenecarboxylate

[Chemical formula 141]

[6-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-3-yl]carbaldehyde (100 mg, 0,245 mmol)obtained in example 47, 2-thiophenecarboxylate (41.7 mg, 0,294 mmol) was dissolved in ethanol (3 ml). The resulting mixture was stirred at room temperature for 3 days. Besieged thus, the solid was collected by filtration and washed with ethanol. The obtained solid was recrystallized from ethanol to obtain specified in the connection header (91,0 mg, 0,171 mmol, 70%) as a white solid.

1H-NMR (400 MHz, CDCl3/DMSO-d6)δ: 5,98 (1H, s), 6,93-7,01 (1H, m), 7,02-to 7.09 (1H, m), 7,14-7,20 (1H, Shir. m), 7,42 (2H, d, J=8.5 Hz), EUR 7.57 (2H, d, J=8.5 Hz), 7,62-7,73 (2H, Shir. m), 8,02-to 8.20 (3H, m), of 8.95 (1H, s), and 11.5 (1H, s).

MS m/z: 532 (M++H).

Example 99:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]nicotinamide

[Chemical formula 142]

To a suspension in dichloromethane (4 ml) of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (100 mg, 0,236 mmol)obtained in example 50, was added thionyl chloride (1,00 ml) and N,N-dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness. The obtained residue was dissolved in dichloromethane (6 ml). To the resulting solution was added 28% aqueous ammonia (2 ml). The mixture displaced ivali at room temperature for 3 hours, and then the reaction mixture was acidified using 1 N. a solution of hydrochloric acid. The mixture was concentrated and the resulting solid was collected by filtration. The obtained solid substance was washed with water and ethanol and then recrystallized from ethanol to obtain specified in the connection header (47,9 mg, 0,113 mmol, 46%) as a white solid.

1H-NMR (400 MHz, CDCl3/DMSO-d6)δis: 6.00 (1H, s)6,38 (1H, Shir. C)6,94-6,99 (1H, m), 7,02-was 7.08 (1H, m), the 7.43 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8.5 Hz), to 7.67 (1H, d, J=7,6 Hz), the 7.65 to 7.75 (1H, Shir. m), 7,99-of 8.04 (1H, m), compared to 8.26 (1H, DD, J=8,1, 2.4 Hz), 9,12 (1H, d, J=1.7 Hz).

MS m/z: 423 (M++H).

Example 100:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-N-(4-methylcyclohexyl)nicotinamide

[Chemical formula 143]

To a suspension of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (100 mg, 0,236 mmol)obtained in example 50, in dichloromethane (4 ml) was added thionyl chloride (1,00 ml) and N,N-dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated to dryness and the obtained residue was dissolved in dichloromethane (6 ml). To the resulting solution was added N-methylmorpholine (51,8 μl, 0,472 mmol) and 4-methylcyclohexylamine time (37.4 μl, 0,283 mmol). The resulting mixture was stirred at room temperature is 18 hours, and then was diluted with dichloromethane. The diluted mixture was washed successively 1 N. a solution of hydrochloric acid, water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1, was concentrated to obtain a white solid. The obtained solid was recrystallized from ethyl acetate-hexane to obtain specified in the connection header (70,3 mg, is 0.135 mmol, 57%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 0,92 (1,8H, d, J=6.6 Hz), 0,96 (1,2H, d, J=6.4 Hz), 1,05-1,30 (3H, m), 1.32 to 1,43 (0,6H, m), 1,55-1,83 (4,4H, m), 2,03-2,12 (1H, m), 3,86-3,97 (0,6H, m), 4,20-4,28 (0,4H, m), 5,88 (0,6H, d, J=7,1 Hz), 5,98 (1H, s), 6,18 (0,4H, d, J=7,3 Hz), 6.90 to-of 6.96 (1H, m), 6,98-7,06 (1H, m), 7,41 (1,2H, d, J=8.1 Hz), 7,41 (0,8H, d, J=8.1 Hz), 7,56 (1,2H, d, J=8.1 Hz), EUR 7.57 (0,8H, d, J=8.1 Hz), to 7.67-7,72 (1H, m), 7,97-with 8.05 (1H, m), 8,10-8,18 (1H, m), 8,93 (0,6H, d, J=2.2 Hz), 8,96 (0,4H, d, J=2.2 Hz).

MS m/z: 519 (M++H).

Example 101:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-N-methoxynicotinate

[Chemical formula 144]

To a suspension in dichloromethane (6 ml) [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (100 mg, 0,236 mmol)obtained in example 50, was added N-methylmorpholine (77,7 μl, 0,708 mmol), hydrochloride of O-methylhydroxylamine (23,6 mg, 0,283 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (to 54.3 mg, 0,283 mmol). The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added tetrahydrofuran (1 ml). After stirring at room temperature for 18 hours the reaction mixture was diluted with dichloromethane. The diluted mixture was washed with water and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1, was concentrated to obtain a white solid. The obtained solid was washed with ethyl acetate to obtain specified in the connection header (55,1 mg, 0,122 mmol, 52%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,90 (2,4H, C), 3,97 (0,6H, s), 5,97 (0,2H, C), 5,98 (0,8H, s), 6.90 to-7,07 (2H, m), 7,39-7,46 (2H, m), 7,54-to 7.59 (2H, m), 7,63 (0,2H, d, J=8,3 Hz), 7,73 (0,8H, d, J=8.1 Hz), 7,94-8,00 (1H, m), 8,10-of 8.15 (1H, m), 8,76 (1H, Shir. C)8,92 (0,8H, d, J=1.7 Hz), 9,01 (0,2H, d, J=1.5 Hz).

MS m/z: 453 (M++H).

Example 102:N,N-Dimethyl-[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methylamine

[Chemical formula 145]

[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carbaldehyde (100 mg, 0245 mmol), obtained in example 47, the solution of dimethylamine in tetrahydrofuran (2,0M, 0.25 ml, 0.50 mmol) and acetic acid (0,029 ml, 0.51 mmol) was dissolved in 1,2-dichloroethane (5 ml)and then added triacetoxyborohydride sodium (115 mg, 0,515 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 days. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The resulting mixture was separated into layers. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=40:1 was concentrated under reduced pressure to obtain white solid. The obtained solid was washed with hexane to obtain specified in the title compound (88 mg, 0.20 mmol, 82%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.23 (6H, s), of 3.43 (2H, s)5,94 (1H, s), 6,88-6,98 (1H, m), 6,98-7,06 (1H, m), 7,38 (2H, d, J=8.6 Hz), 7,52 to 7.62 (3H, m), 7,71 (1H, DD, J=8,1, 2,1 Hz), 7,98-8,08 (1H, m), 8,51 (1H, d, J=2.1 Hz).

MS m/z: 437 (M++H).

Example 103:N-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]methyl]bis(2-what ethoxyethyl)Amin

[Chemical formula 146]

[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carbaldehyde (100 mg, 0,245 mmol)obtained in example 47, bis(2-methoxyethyl)amine (70 mg, of 0.53 mmol) and acetic acid (0,029 ml, 0.51 mmol) was dissolved in 1,2-dichloroethane (5 ml). To the resulting solution were added at room temperature triacetoxyborohydride sodium (115 mg, 0,515 mmol). The resulting mixture was stirred at room temperature for 3 days. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and ethyl acetate. The resulting mixture was separated into layers. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure to obtain white solid. The obtained solid was washed with hexane to obtain specified in the title compound (101 mg, 0,192 mmol, 78%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,73 (4H, t, J=5.8 Hz), and 3.31 (6H, s), 3,47 (4H, d, J=5.8 Hz in), 3.75 (2H, s), to 5.93 (1H, s), 6,88-6,97 (1H, m), 6,97-7,07 (1H, m), 7,38 2H, d, J=8,8 Hz), 7,50-of 7.60 (3H, m), 7,76 (1H, DD, J=8,1, 2.0 Hz), 7,98-8,08 (1H, m), 8,54 (1H, d, J=2.0 Hz).

MS m/z: 525 (M++H).

Example 104:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-N,N-diethylnicotinamide

[Chemical formula 147]

[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (90 mg, 0.21 mmol)obtained in example 50, the solution in tetrahydrofuran dimethylamine(2,0M, of 0.21 ml, 0.42 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (of 0.045 ml, 0.32 mmol) was dissolved in dichloromethane (5 ml). To the resulting solution was added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (61 mg, 0.32 mmol) at room temperature, followed by stirring at room temperature for 14 hours. The residue obtained by concentration of the reaction mixture under reduced pressure was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain specified in the title compound (35 mg, of 0.066 mmol, 90%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: a 3.01 (3H, s), 3,14 (3H, s), 5,97 (1H, s), 6,88-6,99 (1H, m), 6,99-was 7.08 (1H, m), 7,40 (2H, d, J=8.7 Hz), EUR 7.57 (2H, d, J=8.7 Hz), of 7.70 (1H, DD, J=8,0, 0.7 Hz), 7,82 (1H, DD, J=8.0 a, 2,2 Hz), 7,93-8,04 (1H, m), 8,68 (1H, DD, J=2,2, 0.7 Hz).

MS m/z: 451 (M++H).

Example 105:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-ethyl]pyridine-3-yl] (4-methylpiperazin-1-yl)methanon

[Chemical formula 148]

[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (90 mg, 0.21 mmol)obtained in example 50, N-methylpiperazine (0.036 ml, 0.33 mmol), 4-(dimethylamino)pyridine (15 mg, 0.12 mmol) and triethylamine (of 0.045 ml, 0.32 mmol) was dissolved in dichloromethane (5 ml). To the resulting solution were added at room temperature, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (61 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were added N-methylpiperazine (0.036 ml, 0.33 mmol), triethylamine (of 0.045 ml, 0.32 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (61 mg, 0.32 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was then concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=25:1 was concentrated under reduced pressure to obtain specified in the title compound (86 mg, 0,17 mmol, 80%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.33 (3H, s), of 2.38 (2H, Shir. C)of 2.50 (2H, Shir. C)3,44 (2H, Shir. C)3,81 (2H, Shir. C)5,97 (1H, s), 6.87 in-6,98 (1H, m), 6,98-was 7.08 (1H, m), 7,40 (2H, d, J=8,8 Hz), EUR 7.57 (2H, d, J=8,8 Hz), 7,71 (1H, DD, J=8,1, 0.7 Hz), 7,81 (1H, DD, J=8,1, 2.2 Hz), 7,94-of 8.04 (1H, m), 8,66 (1H, DD,J=2,2, 0,7 Hz).

MS m/z: 506 (M++H).

Example 106:4-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]aminoethyl]morpholine

[Chemical formula 149]

4-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]aminoethyl]morpholine-N-oxide (78 mg, 0.14 mmol)obtained in example 61 was dissolved in solvent mixture of acetic acid (2.0 ml) and water (2.0 ml). The resulting solution was heated to 60°C and to the mixture was added iron powder (40 mg, to 0.72 mmol). The resulting mixture was stirred for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous solution of potassium carbonate, and then extracted with ethyl acetate (60 ml). The extract was washed with saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (3% methanol/chloroform solution) to obtain the specified title compound (30 mg, 40%).

1H-NMR (400 MHz, CDCl3)δ: of 2.5-2.8 (6H, m)and 3.59 (2H, W), 3,81 (4H, W), the 5.45 (1H, W), 6,10 (1H, s), to 6.88 (1H, m), 7,01 (1H, m), 7,25 (1H, s), 7,42 (2H, d, J=8,8 Hz), 7,49 (1H, m), 7,60 (2H, d, J=8,4 Hz), of 7.97 (1H, s).

MS m/z: 542 (M++H).

Example 107:tert-Butyl 2-[N-[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]-N-methylamino]ethyl-methylcarbamate

[Chemical formula 150]

A solution of 2,5-dichlo the-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (78 mg, 0,19 mmol)obtained in example 54, in 1,4-dioxane (2.0 ml) and N,N'-dimethylethylenediamine (400 μl) was stirred at 100°C for 2 days under nitrogen atmosphere. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and saturated saline solution, dried and then concentrated under reduced pressure to obtain a residue. The obtained residue was dissolved in tetrahydrofuran (10 ml). To the resulting solution were added at room temperature triethylamine (31 μl, 0.22 mmol) and di-tert-BUTYLCARBAMATE (49 mg, 0.22 mmol). The resulting mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the specified title compound (68 mg, 64%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 1,26 and of 1.32 (9H, Shir.-with, rotamer), 2,75 I2,78 (3H, Shir.-with, rotamer), 2,95 (3H, Sirs), 3,30 (2H, m), the 3.65 (2H, m), of 5.92 (1H, s), 6,6-6,8 (1H, m), 6,84-6,97 (2H, m), 7,05 (1H, m), 7,14 (2H, d, J=8,8 Hz), 7,17 (2H, d, J=8,4 Hz), 7,98 (1H, s).

MS m/z: 568 (M++H).

Example 108:tert-Butyl 2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]-N-methylamino]ethylmethylketone

[Chemical formula 151]

To a solution of tert-butyl 2-[N-[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)IU is Il]pyridine-2-yl]-N-methylamino]ethyl-methylcarbamate (67 mg, 0.12 mmol) in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate, and then the diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (64 mg, 91%).

1H-NMR (400 MHz, CDCl3)δ: of 1.33 and 1.38 (9H, Shir.-with, rotamer), 2,87, and 2,89 (3H, Sirs, rotamer), 3,11 (3H, Sirs), 3,3-3,4 (2H, m), 3,6-3,9 (2H, m), 6,12 (1H, s), 6.89 in (1H, m), 7,00 (1H, m), 7,26 (1H, m), 7,41 (2H, d, J=8,4 Hz), 7,53 (1H, m), to 7.59 (2H, d, J=8,4 Hz), of 8.00 (1H, s).

EI-MS: 599,1204 (Calculated for C27H29Cl2F2N3O4S: 599,1224).

Example 109:5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-2-[N-methyl-N-[2-(methylamino)ethyl]amino]-pyridin

[Chemical formula 152]

tert-Butyl 2-[N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]-N-methylamino]ethylmethylketone (61 mg, 0.10 mmol) was dissolved in methylene chloride (2.0 ml). To the resulting solution were added at room temperature, anisole (40 ml) and triperoxonane acid (200 μl) and the mixture was stirred for 1 hour. The residue obtained by concentration of the reaction is Oh mixture under reduced pressure, was purified by chromatography on silica gel (3% methanol/chloroform 3% → methanol, 3% tert-butylamine/chloroform) to obtain the specified title compound (21 mg, 41%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 2.51 (3H, s), 2,90 (2H, d, J=6.0 Hz), 3,14 (3H, s), and 3.72 (2H, m), 6,13 (1H, s), 6.89 in (1H, m), 7,00 (1H, m), of 7.36 (1H, m), 7,41 (2H, d, J=8,4 Hz), 7,52 (1H, m), 7,60 (2H, d, J=8,4 Hz), 8,00 (1H, s).

FAB-MS: 500,0770 (Calculated for C22H22Cl2F2N3O2S: 500,0778).

Example 110:(2'S)-5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-[2'-(hydroxymethyl)pyrrolidin-1'-yl]pyridine

[Chemical formula 153]

Solution in 1,4-dioxane (1.0 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (60 mg, 0.14 mmol)obtained in example 54, and (S)-2-pyrrolidineethanol (200 μl) was stirred at 100°C for 3 days under nitrogen atmosphere. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 ml). The diluted mixture was washed with water and saturated saline solution, dried and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (40 mg, 58%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.78 (1H, m)to 2.06 (3H, m), 3,29 (1H, m), 3,50 (1H, m), 3,66 (1H, m), and 3.72 (1H, m)to 4.33 (1H, m), 5,97 and 5,98 (1H, s, rotamer), 6.73 x and 6,77 (1H, s, R is tamer), 6,92-to 7.15 (3H, m), 7,25 (4H, m), 7,98 (1H, s).

MS m/z: 481 (M++H).

Example 111:(2'S)-5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl-2-[2'-(hydroxymethyl)pyrrolidin-1'-yl]pyridine

[Chemical formula 154]

Tetrahydrate hexaminolevulinate (30 mg) was added to a solution of (2'S)-5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-[2'-(hydroxymethyl)pyrrolidin-1'-yl]pyridine (39 mg, 0.08 mmol) in methanol (6 ml)and then added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate (60 ml). The diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (33 mg, 79%) as oil.

1H-NMR (400 MHz, CDCl3)δof 1.75 (1H, m), 2,02 (3H, m), 3,3-3,5 (1H, m), 3,52 of 3.75 (3H, m), 4,2-of 4.35 (1H, m), equal to 6.05 (1H, Sirs), at 6.84 (1H, m), of 6.96 (1H, m), of 7.36 (1H, s), of 7.36 and 7,37 (2H, d, J=8,8 Hz, rotamer), the 7.43 (1H, m), 7,53 and rate of 7.54 (2H, d, J=8,8 Hz, rotamer), 7,89 and of 7.90 (1H, s, rotamer).

FAB-MS: 513,0627 (Calculated for C23H21Cl2F2N2O3S: 513,0618).

Example 112:tert-Butyl [4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate

[Chemical formula 155]

A solution of tert-butyl 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (60 mg, 0.14 mmol)obtained in example 54, in 1,4-dioxane (1.0 ml) and tert-butyl (morpholine-2-yl)methylcarbamate (200 mg) was stirred at 100°C for 2 days under nitrogen atmosphere. After cooling to room temperature the reaction mixture was diluted with ethyl acetate (50 ml). The diluted mixture was washed with water and saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:simple ether=5:1) to obtain the specified title compound (45 mg, 52%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.46 (9H, s), of 2.72 (1H, m)of 3.00 (1H, m), up 3.22 (1H, m), 3,44 (1H, m), 3,6-of 3.75 (2H, m), 3,9-4,1 (3H, m), of 4.95 (1H, W), of 5.99 and 6.00 (1H, s, rotamer), of 6.96 and 6,97 (1H, s, rotamer), 6,9-7,1 (3H, m), 7,24 (4H, s), 8,11 (1H, s).

MS m/z 596 (M++H).

Example 113:tert-Butyl [4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate

[Chemical formula 156]

Tetrahydrate hexaminolevulinate (30 mg) was added to a solution of tert-butyl [4-[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate (44 mg, 0,074 mmol) in methanol (6 ml)and then added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 h the owls. The reaction mixture was diluted with ethyl acetate (60 ml)and then diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (31 mg, 67%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.40 (9H, s), 2,69 (1H, m), to 3.02 (1H, m), 3,18 (1H, m)to 3.41 (1H, W), 3,6-of 3.75 (2H, m)to 3.92 (1H, m), was 4.02 (1H, m), 4,13 (1H, m), 4,91 (1H, W), 6,07 (1H, s), 6,85 (1H, m), of 6.99 (1H, m), 7,37 (2H, d, J=8,4 Hz), 7,35-7,45 (2H, m), 7,53 (2H, d, J=8,4 Hz), 8,17 (1H, s).

FAB-MS: 628,1255 (Calculated for C28H30Cl2F2N3O5S: 628,1251).

Example 114:2-Aminomethyl-4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]morpholine

[Chemical formula 157]

tert-Butyl [4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]morpholine-2-yl]methylcarbamate (30 mg, 0.05 mmol) was dissolved in methylene chloride (1.5 ml). To the resulting solution were added at room temperature, anisole (30 ml) and triperoxonane acid (150 μl). The resulting mixture was stirred for 1 hour. The residue obtained by concentration of the reaction mixture under reduced pressure was purified by chromatography on silica gel (3% methanol/chloroform → 3% methanol, 3% tert-butylamine/chloroform) to obtain specified in the header is soedineniya (17 mg, 67%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,77 (1H, m), 2,9-3,3 (2H, m), 3,5-of 3.85 (3H, m), of 3.97 (1H, m), 4.04 the-of 4.25 (2H, m), 6,12 (1H, s), make 6.90 (1H, m), 7,02 (1H, m), 7,42 (2H, d, J=8,4 Hz), 7,4-of 7.55 (2H, m), 7,58 (2H, d, J=8,4 Hz), with 8.05 (1H, s).

FAB-MS: 528,0695 (Calculated for C23H22Cl2F2N3O3S: 528,0727).

Example 115:5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-(4'-hydroxypiperidine-1'-yl)pyridine

[Chemical formula 158]

Solution in 1,4-dioxane (1.0 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (60 mg, 0.14 mmol)obtained in example 54 and 4-hydroxypiperidine (200 mg) was stirred at 100°C for 1 day under nitrogen atmosphere. After cooling to room temperature the reaction mixture was diluted with diethyl ether (50 ml). The diluted mixture was washed with water and saturated saline solution, dried and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (30 mg, 43%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.62 (2H, m), is 2.05 (2H, m), 3,30 (2H, m), 3,98 (3H, m), 5,97 (1H, s), of 6.96 for 7.12 (3H, m), 7.23 percent (4H, m), 7,26 (1H, s), 8,10 (1H, s).

MS m/z: 481 (M++H).

Example 116:5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-2-(4'-hydroxypiperidine-1'-yl)pyridine

[Chemical formula 159]

Tetrahydrate hexaminolevulinate (30 mg) was added to a solution of 5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-(4'-hydroxypiperidine-1'-yl)pyridine (29 mg, 0.06 mmol) in methanol (6 ml)and then added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate (60 ml). The diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=2:1), and then were led out of a simple ester of obtaining specified in the title compound (17 mg, 55%) as a solid.

1H-NMR (400 MHz, CDCl3)δ: of 1.64 (2H, m), 2,02 (2H, m)to 3.33 (2H, m), 3,98 (1H, m), 4,08 (2H, m), 6,11 (1H, s), 6,92 (1H, m), 7,02 (1H, m), 7,42 (2H, d, J=8,8 Hz), 7,45 (1H, m), 7,53 (1H, s), 7,58 (2H, d, J=8,8 Hz), with 8.05 (1H, s).

TPL: 146-148°C.

FAB-MS: 513,0588 (Calculated for C23H21Cl2F2N2O3S: 513,0618).

Example 117:3,6-Dichloro-2-[(4-chlorophenylsulfonyl)(pyridine-4-yl)methyl]pyridine

[Chemical formula 160]

To a solution of (3,6-dichloropyridine-2-yl)(pyridin-4-yl)methanol (161 mg, 0,631 mmol)obtained in reference example 25, in methylene chloride (10 ml) was added triethylamine (208 μl, 1,89 mmol) and thionyl chloride (138 μl, 1,89 mmol). The resulting mixture was stirred PR is room temperature for 4 hours, and then concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (10 ml). To the resulting solution were added 4-chlorbenzoyl (137 mg, 0,947 mmol) and potassium carbonate (131 mg, 0,947 mmol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 days, and then was stirred at 60°C for 4 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate. The resulting mixture was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography. The fraction obtained by elution with a mixture of 40% ethyl acetate/hexane, concentrated under reduced pressure. The obtained residue was dissolved in methanol (10 ml). To the resulting solution was added 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (73 mg). The resulting mixture was stirred at to matnog temperature for 5 hours, and then methanol drove away under reduced pressure. To the thus obtained solution was added a saturated aqueous solution of sodium bicarbonate and then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography. The fraction obtained by elution with a mixture of methanol:methylene chloride=1:80, concentrated under reduced pressure to obtain specified in the title compound (49 mg, 0.118 the mmol, 19%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: between 6.08 (1H, s), 7,31 (1H, d, J=8,3 Hz), 7,41 (2H, d, J=8,8 Hz), was 7.45 (2H, d, J=6.0 Hz), 7,51 (2H, d, J=8,8 Hz), 7,69 (1H, d, J=8,3 Hz), 8,58 (2H, d, J=6.0 Hz).

MS (m/z): 413,415 (M++H).

Example 118:2-[1-(4-Chlorophenylsulfonyl)-1-(2,5-differenl)ethyl]-5-methylpyridin

[Chemical formula 161]

A solution of 2-[[(4-chlorophenyl)sulfonyl] (2.5-differenl)methyl]-5-methylpyridine (52 mg, 0,132 mmol)obtained in example 15, N,N-dimethylformamide (5 ml) was added dropwise under ice cooling to a suspension of sodium hydride (60% in oil) (30 mg, 0.75 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 15 minutes under ice cooling, and then to the mixture was added methyliodide (12 μl, 0,198 mmol). After stirring at room temperature is within 1 hour to the reaction mixture was added water under ice cooling. The resulting mixture was concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=8:1 was concentrated under reduced pressure. The obtained residue was utverjdali with hexane and collected by filtration to obtain specified in the title compound (50 mg, 0,122 mmol,93%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,14 (3H, s), of 2.33 (3H, s), 6,80-7,10 (2H, m), 7.23 percent-7,34 (4H, m), 7,39-7,51 (2H, m), 7,88-8,00 (1H, m), 8,15 (1H, s).

MS (m/z): 408 (M++H).

Example 119:3,6-Dichloro-2-[(6-chloropyridin-3-ylthio)(pyridine-4-yl)methyl]pyridine

[Chemical formula 162]

To a solution in ethanol (7 ml) of O-ethyl S-(6-chloro-3-pyridyl)dithiocarbonate (164 mg, 0.70 mmol)obtained in reference example 26 was added 1 N. aqueous sodium hydroxide solution (7 ml). The resulting mixture was stirred at 80°C for 3 hours. After cooling the reaction mixture to room temperature, to the mixture was added 1 n hydrochloric acid. The resulting mixture was extracted with of dihormati the om. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 6-chloro-3-pyridinol in the form of a yellow solid.

To a solution of (3,6-dichloropyridine-2-yl)(pyridin-4-yl)methanol (153 mg, of 0.60 mmol)obtained in reference example 25, in dichloromethane (3 ml) were added sequentially at 0°C triethylamine (0,167 ml, 1.20 mmol) and methanesulfonamide (0,070 ml, 0.90 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (3 ml) was added a solution of 6-chloro-3-pyridinol in N,N-dimethylformamide (2 ml)and then potassium carbonate (100 mg, to 0.72 mmol). The resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexanitrate=7:3, concentrated under reduced pressure to obtain specified in the title compound (83 mg, 0.22 mmol, 36%) as a yellow oil.

1H-NMR (400 MHz, CDCl3)δ: 5,69 (1H, s), 7,20 (1H, d, J=8,3 Hz), 7,24 (1H, d, J=8,3 Hz), 7,35 (2H, d, J=6,1 Hz), 7,52 (1H, DD, J=8,3, 2.4 Hz), a 7.62 (1H, d, J=8,3 Hz), 8,32 (1H, d, J=2.4 Hz), 8,55 (2H, d, J=6,1 Hz).

MS m/z: 382 (M++H).

Example 120:3,6-Dichloro-2-[(6-chloropyridin-3-ylsulphonyl)(pyridine-4-yl)methyl]pyridine (Compound A) and 3,6-dichloro-2-[(6-chloropyridin-3-ylsulphonyl)(pyridine-4-yl)methyl]pyridine (Compound B (Isomer A) and Compound B (Isomer B)

[Chemical formula 163]

To a solution in methanol (4 ml) of 3,6-dichloro-2-[(6-chloropyridin-3-ylthio)(pyridine-4-yl)methyl]pyridine (82 mg, 0.24 mmol) was added 31% aqueous hydrogen peroxide solution (2 ml) and tetrahydrate hexaminolevulinate (30 mg). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure to get pointed to by the th in the title compound A (41 mg, 0,098 mmol, 46%), whereas the fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain specified in the title compound B (Isomer A) (iskopaemoe connection) (8 mg, 9%) and indicated in the title Compound B (Isomer B) (high-polar compound) (8 mg, 9%), each received in the form of a white solid.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 6,11 (1H, s), 7,35 (1H, d, J=8,3 Hz), was 7.36 (2H, d, J=6,1 Hz), 7,40 (1H, d, J=8,3 Hz), 7,73 (1H, d, J=8,3 Hz), 7,78 (1H, DD, J=8,3, 2.4 Hz), 8,48 (1H, d, J=2.4 Hz), 8,61 (2H, d, J=6,1 Hz).

MS m/z: 414 (M++H).

Compound B (Isomer A)

1H-NMR (400 MHz, CDCl3)δ: 5,54 (1H, s), of 6.99 (2H, d, J=6,1 Hz), 7,27 (1H, d, J=8,3 Hz), 7,37 (1H, d, J=8,3 Hz), 7,55 (1H, DD, J=8,3, 2.2 Hz), 7,73 (1H, d, J=8,3 Hz), of 8.47 (1H, d, J=2.2 Hz), 8,51 (2H, d, J=6,1 Hz).

MS m/z: 398 (M++H).

Compound B (Isomer B)

1H-NMR (400 MHz, CDCl3)δ: of 5.40 (1H, s), 7,26 (1H, d, J=8.5 Hz), 7,42 (1H, d, J=8,3 Hz), 7,53 (2H, d, J=6,1 Hz), EUR 7.57 (1H, d, J=8.5 Hz), of 7.96 (1H, DD, J=8,3, 2.4 Hz), a 8.34 (1H, d, J=2.4 Hz), 8,68 (2H, d, J=6,1 Hz).

MS m/z: 398 (M++H).

Example 121:2-[[(3-Chloropyridin-4-yl)(2,5-differenl)-methyl]sulfonyl]pyrimidine

[Chemical formula 1]

To a solution of 3-chloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (102 mg, 0.40 mmol)obtained in reference example 23, in dichloromethane (4 ml) were added sequentially at 0°C triethylamine (0,112 ml, 0.80 mmol) and methanol villoria (0,046 ml, of 0.60 mmol). The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate is then concentrated under reduced pressure.

To a solution of the obtained residue in N,N-dimethylformamide (4 ml) was added 2-pyrimidinyl (45 mg, 0.40 mmol)and then potassium carbonate (83 mg, of 0.60 mmol). The resulting mixture was stirred at room temperature for 23 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. To a solution of the obtained residue in dichloromethane (4 ml) was added at 0°C 3-chloroperbenzoic acid (purity: 65% or higher) (212 mg, 0.80 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 1 N. aqueous sodium hydroxide solution, then the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:3 was concentrated under reduced pressure to obtain indicated the data in the title compound (19 mg, 0,049 mmol, 12%) as a colorless foamy substance.

1H-NMR (400 MHz, CDCl3)δ: of 6.26 (1H, s), 6,93-7,13 (3H, m), 7,50-7,56 (1H, m), 8,01-8,08 (1H, m), 8,13 (1H, d, J=5,1 Hz), 8,48 (1H, d, J=2.2 Hz), at 8.60 (1H, s), 8,66 (1H, d, J=5,1 Hz).

MS m/z: 382 (M++H).

Example 122:6-(4-Chlorophenylthio) (2.5-differenl)methyl-5-fornicating

[Chemical formula 2]

To a solution of 6-(2,5-differenl)hydroxymethyl-5-fioricetonline (114 mg, 0.40 mmol)obtained in reference example 31, in dichloromethane (4 ml) were added sequentially at 0°C triethylamine (0,113 ml, 0.81 mmol) and methanesulfonamide (0,047 ml, 0.61 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in N,N-dimethylformamide (6 ml) was added 4-chlorbenzoyl (70 mg, 0.49 mmol)and then potassium carbonate (67 mg, 0.49 mmol). The resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under PON the leaders introduce pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain specified in the title compound (120 mg, 0.29 mmol, 73%) as a yellow solid.

1H-NMR (400 MHz, CDCl3)δ: 6,14 (1H, s), 6,88-of 6.96 (2H, m), 7,21 (2H, d, J=8.5 Hz), 7,28 (2H, d, J=8.5 Hz), 7,58-7,74 (1H, m), a 7.85 (1H, DD, J=9,4, 1,6 Hz), 8,80 (1H, s).

MS m/z: 409 (M++H).

Example 123:6-(4-Chlorophenylsulfonyl)(2.5-differenl)methyl-5-fornicating (Compound A) and 6-(4-chlorophenylsulfonyl) (2.5-differenl)methyl-5-fornicating (Compound B)

[Chemical formula 3]

To a solution of 6-(4-chlorophenylthio) (2.5-differenl)methyl-5-fioricetonline (120 mg, 0.29 mmol) in methanol (3 ml) was added 30% aqueous hydrogen peroxide solution (2 ml) and tetrahydrate hexaminolevulinate (73 mg). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dichloromethane. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:this is the acetate=1:1, concentrated under reduced pressure to obtain specified in the header of the connection A (33 mg, of 0.075 mmol, 25%) as a white solid. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:3 was concentrated under reduced pressure to obtain specified in the connection header B (39 mg, 0,092 mmol, 31%) as a white solid.

Connection A

1H-NMR (400 MHz, CDCl3)δ: 6,37 (1H, s), 6.90 to-6,97 (1H, m), 7,01-was 7.08 (1H, m), the 7.43 (2H, d, J=8.5 Hz), 7,58 (2H, d, J=8.5 Hz), 7,94 (1H, DD, J=9,2, 1.8 Hz), 8.17 and is 8.22 (1H, m), 8,91 (1H, s).

TPL: 222-224°C.

MS m/z: 441 (M++H).

Compound B

1H-NMR (400 MHz, CD3OD)δ: 5,86 (1H, s), 6,94-7,02 (1H, m), 7,06-7,14 (1H, m), 7,44 (2H, d, J=8,8 Hz), of 7.48 (2H, d, J=8,8 Hz), 7,66-7,71 (1H, m), 8,07 (1H, DD, J=9,8, 1.7 Hz), which is 9.09 (1H, s).

TPL: 171-173°C.

Elemental analysis for C19H12ClF3N2O2S. Calculated: C,53,72; H,2,85; Cl,8,35; F,13,42; N,6,59; S,At 7.55. Found: C,53,44; H,2,96; Cl,Of 8.37; F,13,34; N,6,66; S,7,54.

Example 124:[6-(4-Chlorophenylthio)(2.5-differenl)methyl-5-herperidin-3-yl]methanol

[Chemical formula 4]

To a solution of [5-(tert-butyldiphenylsilyl)-3-herperidin-2-yl] (2.5-differenl)methanol (17.0 g, a 33.5 mmol)obtained in reference example 29, in dichloromethane (180 ml) was added at room temperature triethylamine (7,00 ml of 50.2 mmol) and methanesulfonamide (3,11 ml, with 40.2 mmol). The resulting mixture peremeci the Ali for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in N,N-dimethylformamide (300 ml) was added sequentially 4-chlorbenzoyl (5,33 g, to 36.8 mmol) and potassium carbonate (5,55 g, with 40.2 mmol). The resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=30:1 was concentrated under reduced pressure.

To a solution of the obtained residue in tetrahydrofuran (200 ml) was added a solution of 42.3 ml, of 42.3 mmol) tetrabutylammonium in tetrahydrofuran. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sulfate is the atrium and filtered. The filtrate is then concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the connection header (9.80 g, 24,8 mmol, 74%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: was 4.76 (2H, s), 6,13 (1H, s), 6,84-of 6.96 (2H, m), 7,20 (2H, d, J=8.7 Hz), 7,27 (2H, d, J=8.7 Hz), the 7.43 (1H, d, J=9.8 Hz), EUR 7.57-to 7.64 (1H, m), 8,43 (1H, s).

Example 125:[6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl-5-herperidin-3-yl]methanol

[Chemical formula 5]

To a solution of [6-(4-chlorophenylthio) (2.5-differenl)methyl-5-herperidin-3-yl]methanol (9.80 g, 24,8 mmol) in methanol (200 ml) was added 30% aqueous hydrogen peroxide solution (14,0 ml) and tetrahydrate hexaminolevulinate (612 mg). The resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture were added 30% aqueous hydrogen peroxide solution (14,0 ml). The resulting mixture was stirred at room temperature for 3 days. To the reaction mixture was again added 30% aqueous hydrogen peroxide solution (14,0 ml). The resulting mixture was stirred at 50°C for 5 hours. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration. The obtained solid substances is the primary objective was washed with water and dried under reduced pressure. The solid was dissolved in ethyl acetate. The resulting solution was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the connection header (6,41 g, 15.0 mmol, 61%) as a white solid. After concentration of the alkaline solution under reduced pressure, the residue was recrystallized from ethanol to obtain specified in the title compound (2.14 g, 5.00 mmol, 20%) as a white solid. After the alkaline solution was again concentrated under reduced pressure, the residue was washed with diethyl ether and collected by filtration to obtain specified in the title compound (780 mg, 1.82 mmol, 7%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 1,90 (1H, t, J=5.6 Hz), 4,80 (2H, d, J=5.6 Hz), 6,32 (1H, s), 6.89 in-6,97 (1H, m), 6,99-7,06 (1H, m), 7,41 (2H, d, J=8,8 Hz), 7,49 (1H, d, J=9.8 Hz), EUR 7.57 (2H, d, J=8,8 Hz), 8,18-8,24 (1H, m), charged 8.52 (1H, s).

TPL: 181-183°C.

MS m/z: 428 (M++H).

Example 126:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-herperidin-3-yl]carbaldehyde

[Chemical formula 6]

To a solution in dichloromethane (100 ml) of [6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]methanol (,46, for 19.8 mmol), triethylamine (13,8 ml, the 98.9 mmol) and dimethyl sulfoxide (7,02 ml, the 98.9 ml) at room temperature was added a complex of a sulfur trioxide-pyridine (9,44 g of 59.3 mmol). The resulting mixture was stirred for 16 hours. The reaction mixture was washed with saturated brine, then the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with dichloromethane, concentrated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to obtain specified in the connection header (6,33 g, 14.9 mmol, 75%) as a yellow solid.

1H-NMR (400 MHz, CDCl3)δ: 6,40 (1H, s), 6,91-6,98 (1H, m), 7,02-to 7.09 (1H, m), the 7.43 (2H, d, J=8.6 Hz), to 7.59 (2H, d, J=8.6 Hz), 7,89 (1H, DD, J=8,6) and 1.7 Hz), 8.17-a 8,23 (1H, m), of 9.02 (1H, s), 10,15 (1H, d, J=2.2 Hz).

Example 127:6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl-5-fornicating acid

[Chemical formula 7]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-3-yl]carbaldehyde (1.28 g, 3.00 mmol) in formic acid (30 ml) was added at room temperature 30% aqueous hydrogen peroxide solution (1,02 ml of 9.00 ml). The resulting mixture was stirred at room temperature for one hour. Then the reaction mixture was stirred at 50°C for 1 hour. After cooling to room temperature, to the mixture was added water. Besieged thus, the solid was collected by filtration, washed with water and dried under reduced pressure. The obtained solid substance was dissolved in ethyl acetate. The solution was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was washed with ethanol and collected by filtration to obtain specified in the title compound (1.19 g, 2,69 mmol, 89%) as a white solid.

1H-NMR (400 MHz,DMSO-d6)δ: 6,37 (1H, s), 7,27-7,42 (2H, m), of 7.64 (2H, d, J=8,8 Hz), to 7.67 (2H, d, J=8,8 Hz), 8,01-8,07 (1H, m), 8,17 (1H, DD, J=9,6, 1.7 Hz), 9,04 (1H, s).

TPL: 249-251°C.

Elemental analysis for C19H11ClF3NO4S. Calculated: C,51,65; H,Of 2.51; Cl,8,02; F,12,90; N,3,17; S,7,26. Found: C,51,70; H,2,73; Cl,Of 7.96; F,12,81; N,3,36; S,7,39.

Example 128:6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl-5-fluoro-N-thiazol-2-iniatiated

[Chemical formula 8]

To a solution in dichloromethane (2 ml) was added 6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-fornicating acid (100 mg, 0.23 mmol)was added at room temperature thiazol-2-ylamine (25 mg, 0.25 mmol), benzotriazol-1-ol (34 mg ,25 mmol), 4 methylmorpholin (0,027 ml, 0.25 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48 mg, 0.25 mmol). The resulting mixture was stirred at room temperature for 14 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure. The residue was washed with ethanol and collected by filtration to obtain specified in the title compound (72 mg, 0.14 mmol, 60%) as a white solid.

1H-NMR (400 MHz,DMSO-d6)δ: 6,38 (1H, s), 7.24 to 7,42 (2H, m), 7,60 (1H, d, J=3,7 Hz), the 7.65 (2H, d, J=9.1 Hz), to 7.68 (2H, d, J=9.1 Hz), 8,03-8,10 (1H, m), scored 8.38 (1H, d, J=9.6 Hz), 9,17 (1H, s)13,00 (1H, s).

TPL: 243-245°C.

Elemental analysis calculated for C22H13ClF3N3O3S2. Calculated: C,50,43; H,2,50; Cl,6,77; F,10,88; N,8,02; S,12,24. Found: C,50,34; H,2,48; Cl,6,93; F,10,82; N,8,11; S,12,29.

Example 129:6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl-5-fluoro-N-isoxazol-3-iniatiated

[Chemical formula 9]

In the same way as in example 128, received the specified reception in the e compound (43 mg, of 0.085 mmol, 37%) as a white solid using 6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-fornicating acid (100 mg, 0.23 mmol)obtained in example 127, and isoxazol-3-ylamine (0,018 ml, 0.25 mmol).

1H-NMR (400 MHz, CDCl3)δ: 6,41 (1H, s), 6,92-7,00 (1H, m), 7.03 is-7,11 (1H, m), 7,25 (1H, d, J=1.7 Hz), 7,44 (2H, d, J=8.6 Hz), 7,60 (2H, d, J=8.6 Hz), with 8.05 (1H, DD, J=9,1, 2.0 Hz), 8,20 compared to 8.26 (1H, m), 8,40 (1H, d, J=1.7 Hz), 9,14 (1H, d, J=1.5 Hz), of 10.25 (1H, s).

TPL: 200-202°C.

Elemental analysis calculated for C22H13ClF3N3O4S. Calculated: C,52,03; H,2,58; Cl,6,98; F,11,22; N,8,27; S Of 6.31. Found: C,51,84; H,2,55; Cl,Of 7.36; F,11,19; N,At 8.36; S,6,46.

Example 130:6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl-5-fluoro-N-pyridine-2-iliternational

[Chemical formula 10]

In the same way as in example 128, received specified in the title compound (86 mg, 0.16 mmol, 72%) as a colorless amorphous substance using 6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-fornicating acid (100 mg, 0.23 mmol)obtained in example 127, and pyridine-2-ylmethylamino (0,026 ml, 0.25 mmol).

1H-NMR (400 MHz, CDCl3)δ: of 4.77 (2H, d, J=4.4 Hz), 6,37 (1H, s), 6,91-to 7.09 (2H, m), 7,25-7,34 (2H, m), the 7.43 (2H, d, J=8,8 Hz), 7,58 (2H, d, J=8,8 Hz), 7,72 (1H,TD, J=7,6, 1.7 Hz), 7,94 (1H, s), of 7.96 (1H, DD, J=9,3, 2,0 Hz), 8,19-of 8.25 (1H, m), 8,59 (1H, d, J=4.4 Hz), 9,03 (1H, s).

Elemental analysis calculated for C25H17ClF3N3O3S. Rasch the Eastern Europe and Caucasus: C,56,45; H,3,22; Cl,6,66; F,10,71; N,Of 7.90; S,6,03. Found: C,56,32; H,3,30; Cl,6,63; F,10,61; N,7,88; S,6,14.

Example 131:Methyl (E)-3-[6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]acrylate

[Chemical formula 11]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-3-yl]carbaldehyde (1.70 g, 4.00 mmol)obtained in example 126, in tetrahydrofuran (15 ml) was added at room temperature methyl (triphenylphosphonium)acetate (1.47 g, 4.40 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with dichloromethane, concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of ethanol and hexane and then collected by filtration to obtain specified in the title compound (1.60 g, and 3.31 mmol, 83%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 3.84 (3H, s), 6,33 (1H, s), 6,53 (1H, d, J=16,7 Hz), 6.89 in-6,97 (1H, m), 6,99-was 7.08 (1H, m), 7,42 (2H, d, J=8,3 Hz), 7,55 (1H, d, J=9,6, 1.5 Hz), 7,58 (2H, d, J=8,3 Hz), the 7.65 (1H, d, J=16,7 Hz), 8,18-8,24 (1H, m), 8,67 (1H, s).

MS m/z: 482 (M++H).

Example 132:Methyl 3-[6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]propionate

[Chemical formula 12]

A suspension of Raney Nickel (R-100", a product from the company Nikko Rica Corporation) (1 ml) was washed successively with water and ethanol to obtain a suspension in ethanol (10 ml). The resulting suspension was added to a solution of methyl 3-[6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]acrylate (1,38 g of 2.86 mmol) in ethanol (40 ml). The resulting mixture was stirred at room temperature in hydrogen atmosphere for 1 hour. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (1,37 g, and 2.83 mmol, 99%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 2.66 (2H, t, J=7,4 Hz)of 3.00 (2H, t, J=7.4 Hz), of 3.69 (3H, s), of 6.29 (1H, s), 6,88-of 6.96 (1H, m), 6,98-7,06 (1H, m), 7,29 (1H, DD, J=10,1, 1.5 Hz), 7,40 (2H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), 8,20 compared to 8.26 (1H, m), 8,42 (1H, s).

MS m/z: 484 (M++H).

Example 133:3-[6-(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl-5-herperidin-3-yl]propionic acid

[Chemical formula 13]

To a solution of methyl 3-[6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]propionate (387 mg, 0.80 mmol) in ethanol (8 ml) was added 1 N. aqueous sodium hydroxide solution (4 ml). Poluchenno the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified using 1 N. a solution of hydrochloric acid and then was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of diethyl ether and hexane and then collected by filtration to obtain specified in the title compound (349 mg, of 0.74 mmol, 93%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,73 (2H, t, J=7.4 Hz), a 3.01 (2H, t, J=7.4 Hz), of 6.29 (1H, s), 6,89-of 6.96 (1H, m), 6,99-7,06 (1H, m), 7,30 (1H, DD, J=9,8, 1.7 Hz), 7,40 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), 8,19 compared to 8.26 (1H, m,), 8,44 (1H, s).

TPL: 174-176°C.

MS m/z: 470 (M++H).

Elemental analysis for C21H15ClF3NO4S. Calculated: C,53,68; H,3,22; Cl,7,55; F,12,13; N,2,98; S 6,82. Found: C,53,68; H,3,35; Cl,7,42; F,12,09; N,3,16; S,6,92.

Example 134:Hydrochloride 3-[6-(4-Chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]-1-(4-methylpiperazin-1-yl)propane-1-it

[Chemical formula 14]

To a solution of 3-[6-(4-chlorophenylsulfonyl)(2.5-differenl)methyl-5-herperidin-3-yl]propionic acid (100 mg, 0.21 mmol) in dichloromethane (3 ml) was added at room temperature 1-methylpiperazine (0,026 ml, 0.23 mmol), benzotriazol-1-ol (32 mg, 0.23 mmol), 4-methylmorpholine (0,026 ml, 0.23 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodies is Yes (45 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, then the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=19:1 was concentrated under reduced pressure. The residue was dissolved in ethanol (3 ml)and then added 1 n solution of hydrochloric acid (0,224 ml). After stirring at room temperature for 30 minutes the reaction mixture was concentrated under reduced pressure. The obtained residue was washed with ethanol and collected by filtration to obtain specified in the title compound (111 mg, 0,19 mmol, 89%) as a white solid.

1H-NMR (400 MHz,DMSO-d6)δ: 2,40-is 3.08 (6H, m)of 2.75 (3H, s), 2,90 (2H, t, J=7,1 Hz), 3,19-3,50 (2H, m), 3,92-4,17 (1H, m), 4,29-to 4.52 (1H, m), 6,23 (1H, s), 7.24 to 7,39 (2H, m), to 7.61 (2H, d, J=8,8 Hz), 7,66 (2H, d, J=8,8 Hz), of 7.75 (1H, DD, J=10,8, 1.5 Hz), 8,10-8,16 (1H, m), 8,53 (1H, s), 10,70 (1H, s).

TPL: 243-245°C.

Elemental analysis for C26H25ClF3N3O3S·HCl: Calculated: C,53,07; H,4,45; Cl,12,05,F, RS 9.69; N,7,14; S,the 5.45. Found: C,52,81; H,4,51; Cl,11,74; F,9,48; N,7,09; S 5,50.

Example 135:(E)-3-[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-the l]acrylic acid

[Chemical formula 15]

To a solution of methyl (E)-3-[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]acrylate (460 mg, 0,991 mmol)obtained in example 44, in tetrahydrofuran (5 ml) was added 1 n sodium hydroxide solution (3.0 ml). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was acidified using 1 N. a solution of hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. Untreated specified in the title compound was obtained in stoichiometric quantity. Part of the obtained solid substance was recrystallized from ethyl acetate-hexane to obtain specified in the connection header (to 29.4 mg, 0,0653 mmol) as a colourless solid.

1H-NMR (400 MHz, CDCl3)δ: 5,96 (1H, s), of 6.52 (1H, d, J=16.1 Hz), 6,94 (1H,TD, J=9,0, 4.6 Hz), 6,99-7,06 (1H, m), 7,41 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), to 7.64 (1H, d, J=16.1 Hz), to 7.64 (1H, d, J=8.1 Hz), 7,88 (1H, DD, J=8,1, 2.2 Hz), 8,01 (1H, DDD, J=9,0, 5,6, 3,4 Hz), 8,72 (1H, d, J=2.2 Hz).

TPL: 236-238°C.

Elemental analysis for C21H14ClF2NO4S. Calculated: C,56,07; H,3,14; Cl,7,88; F,To 8.45; N,3,11; S,7,13. Found: C,55,98; H,3,21; Cl,Of 7.90; F,To 8.45; N,3,21; S,7,12.

Example 136:(E)-3-[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]acrylamide

[Chemical Faure the ula 16]

(E)-3-[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]acrylic acid (370 mg, 0,822 mmol) was dissolved in dichloromethane (6 ml). To the resulting solution was added thionyl chloride (2.00 ml) and N,N-dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness. The obtained residue was dissolved in dichloromethane (6 ml)and then added concentrated aqueous ammonia solution (2.00 ml). After stirring at room temperature for 2 hours, the reaction mixture was diluted with dichloromethane. The diluted mixture was washed with water, 0.1 G. of the solution of hydrochloric acid and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained solid was recrystallized from ethanol to obtain specified in the title compound (250 mg, 0,558 mmol, 68%) as a white solid.

1H-NMR (400 MHz, CDCl3/DMSO-d6)δ: 5,79 (1H, Shir. C)5,95 (1H, s), 6.42 per (1H, Shir. C)6,63 (1H, d, J=15,9 Hz)6,94 (1H,t of d, J=9,0, 4,4 Hz), 7,00-7,07 (1H, m), 7,41 (2H, d, J=8.5 Hz), 7,56 (2H, d, J=8.5 Hz), a 7.62 (1H, d, J=15,9 Hz), to 7.64 (1H, d, J=8.1 Hz), the 7.85 (1H, DD, J=8,1, 2,2 Hz), 8,02 (1H, DDD, J=9,0, 5,4, 3,2 Hz), a total of 8.74 (1H, d, J=2.2 Hz).

TPL: 219-220°C.

Elemental analysis for C21H15ClF2N2O3S. Calculated: C,56,19; H,3,37; Cl,Of 7.90; F,8,46; N,6,24; S,7,14. Found: C,55,9; H,3,34; Cl,8,03; F,To 8.45; N,6,39; S,7.23 Percent.

Example 137:Ethyl N-[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinoyl]glycine

[Chemical formula 17]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (100 mg, 0,236 mmol)obtained in example 50, in dichloromethane (5 ml) was added triethylamine (80 μl, 0,566 mmol), 4-dimethylaminopyridine (14 mg, amount of 0.118 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54 mg, 0,283 mmol) and ethylpyrimidine (40 mg, 0,283 mmol). The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain specified in the title compound (95 mg, 0,187 mmol, 79%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 1.33 (3H, t, J=7,1 Hz), 4,25 (2H, d, J=5,1 Hz), 4,28 (2H, q, J=7,1 Hz), 6,00 (1H, s), of 6.99 (1H, Shir. C)6,91-6,97 (1H, m), 7,00-7,06 (1H, m), 7,42 (2H, d, J=8.5 Hz), 7,56 (2H, the, J=8.5 Hz), 7,73 (1H, d, J=8,3 Hz), of 7.96-8,00 (1H, m), 8,18 (1H, DD, J=8,3, 2.2 Hz), 9,01 (1H, d, J=2.2 Hz).

MS m/z: 509 (M++H).

Example 138:tert-Butyl [2-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate

[Chemical formula 18]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (100 mg, 0,236 mmol)obtained in example 50, in dichloromethane (5 ml) was added triethylamine (40 μl, 0,283 mmol), 4-dimethylaminopyridine (14 mg, amount of 0.118 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54 mg, 0,283 mmol) and tert-butyl N-(2-amino-ethyl)carbamate (45 ál, 0,283 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain specified in the title compound (57 mg, 0,101 mmol, 43%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 1.44 (9H, s), 3,37-of 3.43 (2H, m), 3,55-,59 (2H, m), equal to 4.97 (1H, Shir. C)to 6.00 (1H, s), 6,92-7,05 (2H, m), 7,40 (2H, d, J=8.6 Hz), 7,55 (2H, d, J=8.6 Hz), 7,60 (1H, Shir. C)of 7.70 (1H, d, J=8,3 Hz), 7,92-of 7.97 (1H, m), 8,17 (1H, DD, J=8,3, 2.4 Hz), 9,03 (1H, d, J=2,4 Hz).

MS m/z: 566 (M++H).

Example 139:N-(2-amino-ethyl)-6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]nicotinamide

[Chemical formula 19]

To a solution of tert-butyl [2-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate (50 mg, 0,0880 mmol) in ethanol (2 ml) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. The obtained solid was washed with diethyl ether obtaining specified in the title compound (44 mg, 0,0880 mmol, Quant.) as 1,5 hydrochloride (white powder).

1H-NMR (400 MHz, CD3OD)δ: 3,19 (2H, t, J=5,9 Hz), of 3.69 (2H, d, J=5,9 Hz), 6,27 (1H, s), 7.03 is-to 7.09 (1H, m), 7,12-to 7.18 (1H, m), 7,54 (2H, d, J=8.6 Hz), 7,66 (2H, d, J=8.6 Hz), 7,83 (1H, d, J=8,3 Hz), 8,06-8,10 (1H, m), of 8.27 (1H, DD, J=8,3, 2.4 Hz), the remaining 9.08 (1H, d, J=2,4 Hz).

TPL: >250°C (decomp.).

Elemental analysis for C21H18ClF2N3O3S·1,5H2O·1,5HCl. Calculated: C,Of 46.06; H,4,14; Cl,16,18; F,6,94; N,To 7.67; S,5,86. Found: C,46,39; H,3,93; Cl,16,58; F,At 6.84; N,7,74; S 5,94.

Example 140:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-N-(2-hydroxyethyl)nicotinamide

[Chemical is a mini-formula 20]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-yl]carboxylic acid (100 mg, 0,236 mmol)obtained in example 50, in dichloromethane (5 ml) was added triethylamine (80 μl, 0,566 mmol), 4-dimethylaminopyridine (15 mg, the amount of 0.118 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54 mg, 0,283 mmol) and ethnologically (28 mg, 0,283 mmol). The resulting mixture was stirred at room temperature for 17.5 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=30:1 was concentrated under reduced pressure to obtain specified in the title compound (69 mg, 0,148 mmol, 63%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.38 (1H, t, J=4.9 Hz), the 3.65 (2H, TD, J=5,4, a 4.9 Hz), 3,85 (2H, q, J=4.6 Hz), of 5.99 (1H, s), 6,77 (1H, Shir. C)6,90-of 6.96 (1H, m), 7,00-7,06 (1H, m), 7,42 (2H, d, J=8.6 Hz), 7,56 (2H, d, J=8.6 Hz), of 7.70 (1H, d, J=8.1 Hz), 7,97 shed 8.01 (1H, m), 8,15 (1H, DD, J=8,1, 2.2 Hz), 8,99 (1H, d, J=2.2 Hz)H, m).

TPL: 179-181°C.

Elemental analysis for C21H17ClF2N O4S. Calculated: C,54,02; H,3,67; Cl,To 7.59; F,8,14; N,6,00; S,6.87 In. Found: C,53,83; H,3,63; Cl,7,72; F,8,14; N,6,06; S 7,02.

Example 141:tert-Butyl [2-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-carbothioic]amino]ethyl]carbamate

[Chemical formula 21]

To a solution of tert-butyl [2-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-carbonyl]amino]ethyl]carbamate (120 mg, 0,212 mmol)obtained in example 138, in toluene (8 ml) was added in argon atmosphere reagent Lawson (94 mg, 0,233 mmol). The resulting mixture was stirred for 1.5 hours while boiling under reflux. After cooling, the solvent was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1, was concentrated to obtain specified in the title compound (84 mg, 0.144 mmol, 68%) as a yellow amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 1.46 (9H, s), 3,52 is 3.57 (2H, m), 3,82-3,86 (2H, m), 5,09 (1H, Shir. C)of 5.99 (1H, s), 6,92-6,98 (1H, m), 6,99-7,05 (1H, m), 7,41 (2H, d, J=8.6 Hz), 7,55 (2H, d, J=8.6 Hz), 7,63 (1H, d, J=8,3 Hz), 7,89-7,94 (1H, m), 8,21 (1H, DD, J=8,3, 2.2 Hz), 9,06 (1H, d, J=2.2 Hz), being 9.61 (1H, Shir. C).

MS m/z: 582 (M++H).

Example 142:N-(2-amino-ethyl)-6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]thionicotinamide

[Chemical formula 22]

To a solution of tert-butyl [2-[[6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-3-carbothioic]amino]ethyl]carbamate (80 mg, 0,137 mmol) in ethanol (3 ml) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethanol, and then concentrated. This procedure was repeated three times to obtain specified in the title compound (76 mg, 0,137 mmol, Quant.) as 1.75 hydrochloride (yellow powder).

1H-NMR (400 MHz, DMSO-d6)δ: 3,07-of 3.12 (2H, m), 3,93-of 3.97 (2H, m), 6,46 (1H, s), 7,20-7,26 (1H, m), 7,28-7,34 (1H, m), 7,66 (2H, d, J=9.0 Hz), 7,69 (2H, d, J=9.0 Hz), 7,88 (1H, d, J=8,3 Hz), 8,05-to 8.12 (1H, m), 8,14 (2H, Shir. C), 8,24 (1H, DD 8,3, 2,4), 9,05 (1H, d, J=2.4 Hz), a 10.74 (1H, Shir. C).

TPL: 164-166°C.

Elemental analysis for C21H18ClF2N3O2S2·0,5H2O·1,75HCl: Calculated: C,45,46; H,of 3.77; Cl,17,57; F,6,85; N,EUR 7.57; S,to 11.56. Found: C,45,02; H,3,83; Cl,17,37; F,6,36; N,7,54; S,11,36.

Example 143:2-[(4-Chlorophenylthio) (2.5-differenl)methyl]-6-(1,3-dioxolane-2-yl)pyridine

[Chemical formula 23]

The triethylamine (1.77 ml, 12.7 mmol) and methanesulfonamide (851 μl, 11.0 mmol) was added in an argon atmosphere under ice cooling to a solution of 2-[(2,5-differenl)hydroxymethyl]-6-(1,3-dioxolane-2-yl)pyridine (2,48 g, 8,46 mmol)obtained in reference example 32, in dichloromethane (30 ml). The resulting mixture was stirred at room temperature T. the value of 3.5 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and then was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

To a solution of the obtained residue (2.14 g, USD 5.76 mmol) in dimethylformamide (20 ml) was added 4-chlorbenzoyl (1.0 g, 6,91 mmol) and potassium carbonate (1.19 g, 8,64 mmol). The resulting mixture was stirred at 50°C for 2 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether. The diluted solution was washed successively with water and saturated salt solution. The obtained organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=5:1 was concentrated under reduced pressure to obtain specified in the connection header (2,12 g of 5.05 mmol, 88%) as a pale yellow oil.

1H-NMR (400 MHz, CDCl3)δ: 4,06-4,20 (4H, m), of 5.84 (1H, s), of 5.89 (1H, s), 6,86-of 6.96 (2H, m), 7,17 (2H, d, J=8,8 Hz), 7.23 percent (2H, d, J=8,8 Hz), 7,38 (1H, d, J=7.8 Hz), the 7.43 (1H, d, J=7.8 Hz), 7,44-of 7.48 (1H, m), of 7.69 (1H, t, J=7,8 Hz).

MS m/z: 420 (M++H).

Example 144:2-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-6-(1,3-dioxolane-2-yl)pyridine

[Henichesk the I formula 24]

To a solution of 2-[(4-chlorophenylthio) (2.5-differenl)methyl]-6-(1,3-dioxolane-2-yl)pyridine (2,40 g, 5,72 mmol) in methanol (40 ml) was added tetrahydrate hexaminolevulinate (200 mg) and 30% aqueous hydrogen peroxide solution (20 ml). The resulting mixture was stirred for 5 days. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration. The residue was washed with water. The residue was dissolved in ethyl acetate. The resulting solution was washed successively with water and saturated salt solution. The organic layer was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain specified in the connection header (2,09 g, 4,63 mmol, 81%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 4,05-4,17 (4H, m), 5,73 (1H, s), 5,98 (1H, s), 6,93-7,05 (2H, m), 7,41 (2H, d, J=8,8 Hz), 7,52 (2H, d, J=8,8 Hz), 7,50-7,53 (1H, m), of 7.64 (1H, DD, J=7,6, 1.0 Hz), 7,80 (1H, t, J=7,6 Hz), to $ 7.91-7.95 is (1H, m).

MS m/z: 452 (M++H).

Example 145:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]pyridine-2-yl]carbaldehyde

[Chemical formula 25]

To a solution of 2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-6-(1,3-dioxolane-2-yl)pyridine (2,05 g of 4.54 mmol) in 1,4-dioxane (40 ml) was added concentrated hydrochloric acid (10 ml). The resulting mixture was stirred at room temperature T. the value of 20 hours. The solvent was concentrated under reduced pressure. To the residue was added ethyl acetate. The resulting mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (1.85 g, of 4.54 mmol, Quant.) in the form of a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,05 (1H, s), 6,92-6,98 (1H, m), 7,02-was 7.08 (1H, m), the 7.43 (2H, d, J=8,8 Hz), 7,58 (2H, d, J=8,8 Hz), of 7.90 (1H, DD, J=7,1, 2.0 Hz), 7,93-to 7.99 (2H, m), 8,04-of 8.09 (1H, m), 10,00 (1H, s).

MS m/z: 408 (M++H).

Example 146:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]picolina acid

[Chemical formula 26]

To a solution of [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde (390 mg, 0,956 mmol) in formic acid (5 ml) was added 30% aqueous hydrogen peroxide solution (325 μl, 2,87 mmol). The resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture were added water and then the mixture was filtered. The residue was washed with water. The obtained residue was dissolved in ethyl acetate. The resulting solution was washed sequentially with a saturated aqueous solution of ammonium chloride, water and saturated salt solution. The obtained organic layer was dried over Sul is an atom of magnesium and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to obtain specified in the title compound (310 mg, 0,731 mmol, 77%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,01 (1H, s), 6,93-6,99 (1H, m),? 7.04 baby mortality-7,10 (1H, m), 7,44 (2H, d, J=8.6 Hz), to 7.61 (2H, d, J=8.6 Hz), 7,78-of 7.82 (1H, m), to 7.99 (1H, d, J=7.8 Hz), of 8.06 (1H, t, J=7.8 Hz), compared to 8.26 (1H, d, J=7,8 Hz).

TPL: 200-201°C.

Elemental analysis for C19H12ClF2NO4S: Calculated: C,53,84; H,2,85; Cl,Of 8.37; F,8,97; N,3,30; S,EUR 7.57. Found: C,53,55; H 2,80; Cl,8,23; F,9,00; N,3,55; S,7.68 Per.

Example 147:[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]pyridine-2-yl] (4-methylpiperazin-1-yl)methanon

[Chemical formula 27]

To a solution of 6-[(4-chlorophenylsulfonyl)(2.5-differenl)-methyl]pikolinos acid (130 mg, 0,307 mmol) in dichloromethane (5 ml) was added N-methylmorpholine (41 μl, 0,368 mmol), 1-hydroxybenzotriazole (13 mg, 0,368 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (71 mg, 0,368 mmol) and 1-methylpiperazine (40 μl, 0,368 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue p who has Dorgali column flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=30:1 was concentrated under reduced pressure to obtain specified in the title compound (40 mg, 0,0791 mmol, 26%) as a white amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: a 2.36 (3H, s), 2,44-to 2.65 (4H, m), 3,48-4,00 (4H, m), 5,91 (1H, s), 6.87 in-6,94 (1H, m), 6,98-7,05 (1H, m), 7,41 (2H, d, J=7.8 Hz), 7,55-of 7.60 (3H, m), 7,74 (1H, d, J=7,3 Hz), the 7.85 (1H, t, J=7,6 Hz), 8,06-8,13 (1H, m).

FAB-MS: 506,1085 (Calculated for C24H23ClF2N3O3S: 506,1117).

Example 148:tert-Butyl [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbamate

[Chemical formula 28]

Diphenylphosphinite (428 μl, 2.00 mmol) and triethylamine (394 μl, and 2.83 mmol) was added in an argon atmosphere to a solution of 6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pikolinos acid (600 mg, of 1.42 mmol)obtained in example 146, in a mixture of butanol (2 ml) and toluene (10 ml). The resulting mixture was stirred for 23 hours under heating and boiling under reflux. The reaction mixture was washed with saturated saline solution. The obtained organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1, was concentrated at the shorter the scale the pressure to get specified the title compound (380 mg, 0,768 mmol, 54%) as a pale yellow amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: and 1.54 (9H, s), USD 5.76 (1H, s), 6.90 to-6,95 (1H, m), 6,99-7,05 (1H, m), 7,14 (1H, d, J=7,3 Hz), 7,19 (1H, Shir. C), 7,40 (2H, d, J=8,8 Hz), 7,55 (2H, d, J=8,8 Hz), the 7.65 (1H, DD, J=8,3, 7,3 Hz), 7,95 (1H, d, J=8,3 Hz), 8,01-with 8.05 (1H, m).

MS m/z: 495 (M++H).

Example 149:6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]pyridine-2-ylamine

[Chemical formula 29]

To a solution of tert-butyl [6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbamate (370 mg, 0,748 mmol) in ethanol (5 ml) was added concentrated hydrochloric acid (5 ml). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with saturated sodium bicarbonate solution and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (210 mg, 0,537 mmol, 71%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: to 4.46 (2H, Shir. C)5,72 (1H, s), of 6.45 (1H, d, J=8.1 Hz), to 6.88 (1H, d, J=7,3 Hz), 6,91-7,03 (2H, m), 7,39 (2H, d, J=8.6 Hz), 7,39-the 7.43 (1H, m), 7,56 (2H, d, J=8.6 Hz), 7,98-8,03 (1H, m).

TPL: 183-184°C.

Elemental analysis for C18H13ClF2N2 2S. Calculated: C,54,76; H,3,32; Cl,8,98; F,9,62; N,7,10; S,8,12. Found: C,54,46; H,3,22; Cl,8,82; F,Of 9.55; N,7,07; S,8,11.

Example 150:N-[6-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]pyridine-2-yl]-2-(pyridin-2-yl)ndimethylacetamide

[Chemical formula 30]

To a solution of 6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-ylamine (74 mg, 0,187 mmol) in dichloromethane (5 ml) was added N-methylmorpholine (90 μl, 0,818 mmol), 1-hydroxybenzotriazole (11 mg, 0,313 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (60 mg, 0,312 mmol) and the hydrochloride of 2-pyridyloxy acid (54 mg, 0,312 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane. The diluted solution was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (48 mg, 0,0934 mmol, 50%) as a white amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 3,86 (1H, d, J=15,9 Hz), 3,95 (1H, d, J=15,9 Hz), of 5.82 (1H, s), 6,92-of 6.96 (1H, m), 6,98-was 7.08 (1H, m), 7,21 (1H, d, J=7,6 Hz), 7,25-7,33 (3H, m), 7,39 (2H, d, J=8.5 Hz), 7,54 (2H, d, J=8.5 Hz), 7,66-7,73 (2H, m), 8.07-a 8,11 (1H, m), to 8.20 (1H, d, J=8.6 Hz), 8,69 (1H, d, J=4.4 Hz).

FAB-MS: 514,0800 (Calculated for C25H19ClF2N3O3S: 514,0804).

Example 151:(E)-2-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-6-(2-pyridin-2-elwenil)pyridine

[Chemical formula 31]

To a solution of 6-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde (100 mg, 0,245 mmol)obtained in example 145, in 1,4-dioxane (5 ml) were added hydrochloride triphenyl (2-pyridylmethyl)phosphorylated (336 mg, 0,773 mmol) and triethylamine (215 μl, 1.55 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and then to the obtained concentrate was added ethyl acetate. The resulting mixture was washed successively with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (202 mg, 0,418 mmol, 81%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 5.99 (1H, s), 6,98-was 7.08 (2H, m), 7,21-of 7.25 (1H, m), 7,37-of 7.48 (6H, m), 7,54(2H, d, J=8.1 Hz), to 7.64 (1H, d, J=15,4 Hz), 7,69 to 7.75 (2H, m), 8,04-of 8.09 (1H, m), 8,65 (1H, d, J=4.4 Hz).

FAB-MS: 483,0739 (Calculated for C25H18ClF2N2O2S: 483,0746).

Example 152:2-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-6-(2-pyridin-2-retil)pyridine

[Chemical formula 32]

To a solution of (E)-2-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-6-(2-pyridin-2-elwenil)pyridine (180 mg, 0,373 mmol) in ethanol (5 ml) and 1,4-dioxane (2 ml) was added a suspension (1 ml) of Raney Nickel in ethanol. In an atmosphere of hydrogen at a pressure of 1 atmosphere, the resulting mixture was intensively stirred for 1.5 hours. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure, and then recrystallized from hexane:ethyl acetate to obtain specified in the title compound (110 mg, 0,227 mmol, 61%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,13 is 3.23 (4H, m), of 5.92 (1H, s), 6,93-7,06 (2H, m), 7,07 for 7.12 (3H, m), 7,37-7,40 (3H, m), 7,52-of 7.60 (4H, m), 8,05-of 8.09 (1H, m), charged 8.52 (1H, d, J=3,7 Hz).

TPL: 88-89°C.

Elemental analysis for C25H19ClF2N2O2S: Calculated: C,61,92; H,3,95; Cl,7,31; F,To 7.84; N,5,78; S,6,61. Found: C,61,84; H,4,08; Cl,7,26; F,Of 7.69; N,5,90; S,6.75 In.

Example 153:3-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-1-(3-hydroxypropyl)piperidine-2-he

[Chemical formula 33]

n-Utility (1,56M solution in hexane, 0,140 ml, 0,218 mmol) was added in an argon atmosphere at -78°C to a solution of 2-[(4-chlorophenyl)sulfanilyl]-1,4-diferente (63,0 mg, 0,208 mmol)obtained in reference example 1, 1,2-dimethoxyethane (2 ml). The resulting mixture was stirred at -78°C for 5 minutes. After addition of 3-bromo-1-[3-(tert-butyldimethylsilyloxy)propyl]piperidine-2-she (for 72.8 mg, 0,208 mmol)obtained in reference example 34, the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was cooled to 0°C. After addition of water the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was column purified flash chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain nizkoposhibnogo silyl-protected compound (30.0 mg) and highly polar silyl-protected compound (30.0 mg), both compounds were obtained as colorless oils. Received a highly polar silyl-protected compound (30.0 mg) was dissolved in tetrahydrofuran (3 ml)and then was added hydrogen fluoride-pyridine (0.5 ml). The mixture p is remedial at room temperature for 3 hours. After dilution with ethyl acetate, the diluted mixture was washed with water, saturated salt solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:3, was concentrated to obtain a white solid. The obtained solid substance was recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the title compound (11.8 mg, 0,0258 mmol, 12%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 1,50-1,60 (2H, m), 1,88-of 2.08 (3H, m), 2,70-2,77 (1H, m), 2,86-of 2.93 (1H, m), 3,20-to 3.36 (5H, m), 3,62 (1H, DDD, J=13,7, 9,0, 4.6 Hz), 3,70-of 3.78 (1H, m), 5,71-5,73 (1H, m)6,86 (1H, TD, J=9,0, 4.6 Hz), of 6.96-7,02 (1H, m), 7,37 (2H, d, J=8,8 Hz), 7,55 to 7.62 (3H, m).

TPL: 120-121°C.

FAB-MS: 458,0966 (Calculated for C21H23ClF2NO4S: 458,1004).

Example 154:tert-Butyl 3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]propionate

[Chemical formula 34]

In a small amount of a saturated aqueous solution of potassium carbonate was dissolved hydrochloride tert-butyl ether β-alanine (1.5 g), and then were extracted with methylene chloride. The extract was dried and concentrated to obtain 720 mg of tert-butyl methyl ether β-alanine in free form. The obtained ester and a solution of 2,5-dichloro-4-[(4-CHL is rfinity)-(2,5-differenl)methyl]pyridine (300 mg, to 0.72 mmol)obtained in example 54 in 1,4-dioxane (2.0 ml), was stirred at 120°C for 4 days in an argon atmosphere. After cooling to room temperature the reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and saturated saline solution, dried and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the specified title compound (79 mg, 16%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.46 (9H, s), 2,52 (2H, t, J=6.0 Hz), to 3.58 (2H, q, J=6.0 Hz), of 4.95 (1H, W), 5,96 (1H, s), of 6.68 (1H, s), 6,9-7,05 (2H, m), 7,11 (1H, m), 7,22 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, J=8,4 Hz), 8,02 (1H, s).

MS: 525 (M++H).

Example 155:3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]propionic acid

[Chemical formula 35]

To a solution of tert-butyl 3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]propionate (79 mg) in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg). To the mixture was added 30% aqueous hydrogen peroxide solution (3 ml) and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (60 ml). The diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. To the obtained residue, EXT is ulali triperoxonane acid (1.0 ml). The resulting mixture was stirred for 1 hour. From the reaction mixture drove triperoxonane acid under reduced pressure. The residue was dissolved in water-ethanol mixture (1:1). The resulting solution was podslushivaet by adding saturated aqueous solution (0.2 ml) of sodium bicarbonate. Was added an aqueous solution of sodium bisulfate and the resulting mixture was extracted with ethyl acetate (80 ml). The extract was washed with saturated saline solution, dried and concentrated under reduced pressure. The residue was led in a simple ether to obtain specified in the title compound (61 mg, 81%) as a 0.5 hydrate.

1H-NMR (400 MHz, CDCl3)δ: was 2.76 (2H, m), and 3.72 (2H, m), 6,11 (1H, s), 6,92 (1H, m),? 7.04 baby mortality (1H, m), 7,44 (2H, d, J=8,8 Hz), 7,46 (1H, s)of 7.48 (1H, m), to 7.61 (2H, d, J=8,8 Hz), 7,94 (1H, s).

TPL: 200-205°C.

Elemental analysis for C21H16Cl2F2N2O4S·0,5H2O: Calculated: C,49,42; H,To 3.36; N,5,49; S,6,28; Cl,13,89; F,7,44. Found: C,49,51; H,Or 3.28; N,5,52; S,6.35mm; Cl,Of 13.75; F,To 7.77.

Example 156:2-[[5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl] (methyl)amino]ethanol

[Chemical formula 36]

Solution in 1,4-dioxane (2.0 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (200 mg, 0.48 mmol)obtained in example 54, and methylaminoethanol (200 μl) was stirred at 110°C for 3 days in an atmosphere of argon. After ohla the Denia to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (164 mg, 75%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.07 (3H, s), of 3.73 (2H, d, J=4,8 Hz), 3,85 (2H, d, J=4,8 Hz), of 5.99 (1H, s)6,86 (1H, s), 6,91 for 7.12 (3H, m), 7.23 percent (2H, d, J=8,8 Hz), 7,25 (2H, d, J=8,8 Hz), 8,00 (1H, s).

MS m/z: 455 (M++H).

Example 157:5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-[2-(pyridin-2-yl)ethylamino]pyridine

[Chemical formula 37]

Solution in 1,4-dioxane (1.5 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (150 mg, 0.36 mmol)obtained in example 54, and 2-pyridine-2-ylethylamine (400 μl) was stirred at 120°C for 5 days in an atmosphere of argon. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (126 mg, 70%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.07 (2H, d, J=6.4 Hz), 3,71 (2H, q, J=6.4 Hz), 5,24 (1H, W), 5,96 (1H, s), 6,69 (1H, s), 6,93-7,30 (9H, m), to 7.61 (1H, dt, J=2.0 a, 7,6 Hz), 8,01 (1H, s), 8,56 (1H, m).

MS m/z: 502 (M++H).

Example 158:5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)-methyl]-2-[3-(imidazol-1-yl)propylamino]pyridine

[Chemical formula 38]

Solution in 1,4-dioxane (1.5 m is) 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (200 mg, 0.48 mmol)obtained in example 54, and 3-(imidazol-1-yl)Propylamine (400 μl) was stirred at 120°C for 5 days in an atmosphere of argon. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (94 mg, 39%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,11 (2H, m)to 3.35 (2H, m), 4,11 (2H, d, J=6.8 Hz), a 4.86 (1H, m)5,94 (1H, s), 6,69 (1H, s), of 6.96 (1H, s), 6,95-7,26 (3H, m), 7,12 (1H, s), 7,21 (2H, d, J=8,8 Hz), 7.23 percent (2H, d, J=8,8 Hz), a 7.92 (1H, m), 8,02 (1H, s).

MS m/z: 505 (M++H).

Example 159:2-[[5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethanol

[Chemical formula 39]

Solution in 1,4-dioxane (1.5 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (180 mg, 0.43 mmol)obtained in example 54, and 2-aminoethanol (300 μl) was stirred at 120°C for 64 hours in an argon atmosphere. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (106 mg, 56%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 3,00 (1H, W), 3,51 (2H, W), 3,81 (2H, d, J=4,8 Hz), of 5.05 (1H, W), 5,95 (1H, s), 6,74 (1H, s), 6,92-7,06 (2H, m, 7,13 (1H, m), 7.23 percent (4H, s), to 7.99 (1H, s).

MS m/z: 441 (M++H).

Example 160:1-[3-[[5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]propyl]pyrrolidin-2-he

[Chemical formula 40]

Solution in 1,4-dioxane (1.5 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (200 mg, 0.48 mmol)obtained in example 54, and 1-(3-aminopropyl)pyrrolidin-2-she (400 μl) was stirred at 120°C for 17 hours in an argon atmosphere. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (68 mg, 27%) as oil.

1H-NMR (400 MHz, CDCl3)δ: or 1.77 (2H, m), 2,04 (2H, m), is 2.41 (2H, m), 3,30 is 3.40 (6H, m), of 5.53 (1H, W), 5,94 (1H, s), 6,72 (1H, s), 6.90 to-7,03 (2H, m), 7,13 (1H, m), 7,22 (2H, d, J=8.0 Hz), 7,25 (2H, d, J=8.0 Hz), to 7.99 (1H, s).

MS m/z: 522 (M++H).

Example 161:tert-Butyl 4-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]piperidine-1-carboxylate

[Chemical formula 41]

Solution in 1,4-dioxane (2.2 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (300 mg, 0.48 mmol)obtained in example 54, and tert-butyl 4-aminopiperidine-1-carboxylate (600 mg) was stirred at 120°C for 5 days in an atmosphere of argon. Polioksidony to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (36 mg, 9%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.34 (2H, m)of 1.47 (9H, s)to 1.98 (2H, m)to 2.94 (2H, m), with 3.79 (1H, m), 4,11 (2H, m), 4,58 (1H, W), 5,95 (1H, s), 6,63 (1H, s), 6,93? 7.04 baby mortality (2H, m), 7,12 (1H, m), 7,22 (4H, s), 8,01 (1H, s).

MS m/z: 580 (M++H).

Example 162:tert-Butyl 3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]propellernet

[Chemical formula 42]

Solution in 1,4-dioxane (1.5 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (300 mg, 0.48 mmol)obtained in example 54, and tert-butyl (3-aminopropyl)carbamate (400 μl) was stirred at 120°C for 2 days in an atmosphere of argon. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (71 mg, 27%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.45 (9H, s)of 1.73 (2H, m), 3,21 (2H, m)to 3.38 (2H, m), is 4.85 (1H, W), 5,10 (1H, W), 5,95 (1H, s), of 6.96? 7.04 baby mortality (2H, m), 7,12 (1H, m), 7,22 (2H, d, J=8,8 Hz), 7,24 (2H, d, J=8,8 Hz), 8,00 (1H, s).

MS m/z: 554 (M++H).

Example 163:5-Chloro-4-[(4-chlorophenylthio)-(2,5-differenl)-methyl]-2-[(2-methylthioethyl)amino]pyridine

[Chemical formula 43]

Solution in 1,4-dioxane (1.5 ml) of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (200 mg, 0.48 mmol)obtained in example 54, and 2-methyldiethylamine (200 μl) was stirred at 120°C for 2 days in an atmosphere of argon. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (29 mg, 13%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 2,12 (3H, s), is 2.74 (2H, d, J=6.4 Hz), 3,52 (2H, m), to 4.98 (1H, W), 5,96 (1H, s), 6,69 (1H, s), 6,92-7,05 (2H, m), 7,13 (1H, m), 7.23 percent (4H, m), 8,02 (1H, s).

MS m/z: 471 (M++H).

Example 164:2-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl](methyl)amino]ethanol

[Chemical formula 44]

To a solution of 2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl](methyl)amino]ethanol (160 mg, 0.35 mmol)obtained in example 156, in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate (60 ml). The diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified chromium is cografya on silica gel (hexane:ethyl acetate=2:1) followed by crystallization from hexane-ethanol to obtain specified in the title compound (162 mg, 95%) in the form of needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 3,20 (3H, s), 3,7-of 3.85 (2H, m)to 3.89 (2H, m), 6,14 (1H, s)6,94 (1H, m),? 7.04 baby mortality (1H, m), 7,42 (1H, W), 7,44 (2H, d, J=8,8 Hz), 7,52 (1H, m), a 7.62 (2H, d, J=8,8 Hz), to 7.99 (1H, s).

TPL: 88-89°C.

Elemental analysis for C21H18Cl2F2N2O3S·0,5H2O. Calculated: C,50,82; H,3,86; N,5,64; S,6,46; Cl,14,29; F,7,66. Found: C,51,16; H,3,66; N,5,78; S 6,62; Cl,14,32; F,7,73.

Example 165:2-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl](methyl)amino]ethyl ethylcarbamate

[Chemical formula 45]

To a solution of 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl](methyl)amino]ethanol (73 mg, 0.15 mmol) in methylene chloride (1.0 ml) was added pyridine (0.5 ml)and then added utilizationa (100 μl). The resulting mixture was stirred for 19 hours. The mixture was concentrated under reduced pressure and then the resulting residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (65 mg, 74%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.06 (3H, t, J=7.2 Hz), 3,19 (3H, s), 3,20 (2H, m), 3,68 (1H, m), 3,91 (1H, m), 4,25 (1H, m), and 4.40 (1H, m), 5,15 (1H, W), 6,16 (1H, s), 6,92 (1H, m), 7,03 (1H, m), 7,45 (2H, d, J=8,4 Hz), 7,49 (1H, s), 7,55 (1H, m), 7,60 (2H, d, J=8,4 Hz), 8,03 (1H, s).

EI-MS: 557,0714 (Calculated for C24H23Cl2F2N3O4S: 557,0754).

Example 166:5-Chloro--[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-2-[2-(pyridin-2-yl)ethylamino]pyridine

[Chemical formula 46]

To a solution of 5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-[2-(pyridin-2-yl)ethylamino]pyridine (120 mg, 0.35 mmol)obtained in example 157, in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate (80 ml). The diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (43 mg, 33%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 3,19 (2H, t, J=5,2 Hz), 3,81 (2H, m), the 5.51 (1H, W), 6,13 (1H, s)6,91 (1H, m), 7,03 (1H, m), 7,20-7,30 (3H, m), the 7.43 (2H, d, J=8,8 Hz)to 7.50 (1H, m), a 7.62 (2H, d, J=8,8 Hz), 7,68 (1H, s), 7,98 (1H, s), at 8.60 (1H, m).

FAB-MS: 534,0651 (Calculated for C25H20Cl2F2N3O2S: 534,0621).

Example 167:5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-2-[3-(imidazol-1-yl)propylamino]pyridine

[Chemical formula 47]

To a solution of 5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-[3-(imidazol-1-yl)propylamino]pyridine (94 mg, 0,19 mmol)obtained in example 158, in methanol (6 ml) was added tetrahydro hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate (80 ml), then diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (7% methanol-chloroform) to obtain the specified title compound (5 mg, 5%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 2.20 (2H, m), 3,44 (2H, m), 4,32 (2H, m), 5,77 (1H, W), 6,13 (1H, s)6,91 (1H, m), 7,02 (1H, m), 7,10 (1H, s), 7,30 (1H, s), 7,40 (1H, s), 7,44 (2H, d, J=8,4 Hz), 7,54 (1H, m), the 7.65 (2H, d, J=8,4 Hz), of 7.97 (s,1H), with 8.05 (1H, s)8,89 (1H, s).

FAB-MS: 537,0737 (Calculated for C24H21Cl2F2N4O2S: 537,0730).

Example 168:2-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethanol

[Chemical formula 48]

To a solution of 2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethanol (143 mg, 0.33 mmol)obtained in example 159, in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate (60 ml), then diluted solution was washed with water and saturated saline and koncentrirane and under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) and was led from ethanol to obtain specified in the title compound (98 mg, 63%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: of 3.60 (2H, m), a 3.87 (2H, m), of 5.53 (1H, W), 6,11 (1H, s), 6,92 (1H, m), 7,03 (1H, m), 7,40 (1H, s), was 7.45 (2H, d, J=8,8 Hz), of 7.48 (1H, m), to 7.61 (2H, d, J=8,8 Hz), of 7.96 (1H, s). TPL: 168-169°C.

Elemental analysis for C20H16Cl2F2N2O3S. Calculated: C,50,75; H,3,41; N,Of 5.92; S,6,77; Cl,14,98; F,8,03. Found: C,50,33; H,3,40; N,5,95; S 6,90; Cl,14,93,F, 8,04.

Example 169:1-[3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]propyl]pyrrolidin-2-he

[Chemical formula 49]

To a solution of 1-[3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]propyl]pyrrolidin-2-she (143 mg, 0.33 mmol)obtained in example 160, in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 17 hours. The reaction mixture was diluted with ethyl acetate (60 ml), then diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (2% methanol-ethyl acetate) and was led from simple broadcast receiving the receiving specified in the title compound (42 mg, 60%) in the form of needle crystals.

1H-NMR (400 MHz, CDCl3)δ: is 1.82 (2H, m), is 2.05 (2H, m), 2,43 (2H, m), 3,35-3,50 (6H, m), of 5.53 (1H, W), 6,12 (1H, s), 6,92 (1H, m), 7,02 (1H, m), 7.23 percent (1H, s), 7,42 (2H, d, J=8,4 Hz), 7,53 (1H, m), a 7.62 (2H, d, J=8,4 Hz), of 7.96 (1H, s).

TPL: 78-80°C.

Elemental analysis for C25H23Cl2F2N3O3S. Calculated: C,54.16 Per; H,4,18; N,7,58; S 5,78; Cl,12,79; F,6,85. Found: C,EUR 54.15; H,4,37; N,7,39; S,The Ceiling Of 5.60; Cl,12,20; F,6,64.

Example 170:tert-Butyl 4-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]piperidine-1-carboxylate

[Chemical formula 50]

To a solution of tert-butyl 4-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]piperidine-1-carboxylate (41 mg, 0,070 mmol)obtained in example 161, in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 20 hours. After dilution with ethyl acetate (80 ml) of the diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the specified title compound (41 mg, 95%) as oil.

1H-NMR (400 MHz, CDCl3)δ: 1,43 (2H, m)of 1.47 (9H, s)2,04 (2H, m), of 2.97 (2H, m), 3,88 (1H, m), 4,08 (2H, m), between 6.08 (1H, s), 6.89 in (1H, m), 7,02 (1H, m), 7,25 (1H, s), and 7.4 (2H, d, J=8.0 Hz), 7,46 (1H, m), 7,58 (2H, d, J=8.0 Hz), of 7.96 (1H, s).

MS m/z: 612 (M++H).

Example 171:The dihydrochloride of 4-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]piperidine

[Chemical formula 51]

To tert-butyl 4-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]piperidine-1-carboxylate (41 mg, 0,067 mmol) was added a 20% solution of hydrochloric acid in methanol. The resulting mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in chloroform, and then concentrated. The obtained amorphous substance was dried under reduced pressure to obtain specified in the title compound (34 mg, 84%).

1H-NMR (400 MHz, CD3OD)δ: 1,90 (2H, m), 2,33 (2H, m), up 3.22 (2H, m), 3,52 (2H, m), 4,10 (1H, m), 6,28 (1H, s), to 7.09 (1H, m), 7.23 percent (1H, m), 7,53 (1H, m), to 7.61 (2H, d, J=6.4 Hz), of 7.75 (2H, d, J=6.4 Hz), 7,89 (1H, s), with 8.05 (1H, s).

Elemental analysis for C23H21Cl2F2N3O2S·2HCl·H2O. Calculated: C,45,79; H,4,18; N,Of 6.96; S,5,31; Cl,23,50; F,6,30. Found: C,45,48; H,To 4.17; N,7,2; S,5,24; Cl,22,82,F, Of 6.02.

Example 172:tert-Butyl 3-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]propellernet

[Chemical formula 52]

To a solution of tert-butyl 3-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-debtor enyl)methyl]pyridine-2-yl]amino]propylgallate (70 mg, 0.13 mmol)obtained in example 162, in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 20 hours. After dilution with ethyl acetate (80 ml), diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (61 mg, 82%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.45 (9H, s), is 1.77 (2H, m), 3,23 (2H, m), 3,42 (2H, m), 4,89 (1H, W), are 5.36 (1H, W), 6,10 (1H, s), make 6.90 (1H, m), 7,02 (1H, m), 7,24 (1H, s), 7,42 (2H, d, J=8,8 Hz), 7,49 (1H, m), to 7.59 (2H, d, J=8,8 Hz), 7,95 (1H, s).

MS m/z: 586 (M++H).

Example 173:the dihydrochloride of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]propane-1,3-diamine

[Chemical formula 53]

To tert-butyl 3-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]propylgallate (70 mg, 0.13 mmol) was added a 20% solution of hydrochloric acid in methanol (2 ml). The resulting mixture was stirred for 2 hours. The residue obtained by concentration of the reaction mixture under reduced pressure, was led from ethanol to obtain specified in the title compound as a white solid(42 mg, 83%).

1H-NMR (400 MHz,DMSO-d6)δ: to 1.83 (2H, m), 2,87 (2H, m)to 3.33 (2H, m), 6,16 (1H, s), 7,28 (1H, m), of 7.36 (1H, s), 7,38 (1H, m), 7,52 (1H, m), of 7.69 (2H, d, J=8,4 Hz), 7,74 (2H, d, J=8,4 Hz), with 8.05 (1H, s).

TPL: 193-195°C.

Elemental analysis for C21H19Cl2F2N3O2S·2HCl. Calculated: C,45,10; H,Of 3.78; N,7,51; S 5,73; Cl,25,36; F,6,79. Found: C,44,55; H,3,74; N,7,52; S 5,73; Cl,25,09; F,6.73 X.

Example 174:N-[3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]propyl]ndimethylacetamide

[Chemical formula 54]

To a solution of dihydrochloride of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]propane-1,3-diamine (47 mg, 0,084 mmol) in methylene chloride (5.0 ml) was added pyridine (17 μl, 0.34 mmol) and acetic anhydride (9,5 μl, 0.10 mmol). The resulting mixture was stirred for 1 hour. The residue obtained by concentration of the reaction mixture was purified by chromatography on silica gel (ethyl acetate:methanol=10:1) to obtain the specified title compound (35 mg, 79%). The compound obtained was led in a simple ether to obtain a white solid (27 mg).

1H-NMR (400 MHz, CDCl3)δ: of 1.80 (2H, m), 2,02 (3H, s)to 3.36 (2H, m), of 3.45 (2H, m), 5.25-inch (1H, W), 6,12 (1H, s), x 6.15 (1H, m), 6,93 (1H, m),? 7.04 baby mortality (1H, m), 7,44 (2H, d, J=8,8 Hz)to 7.50 (1H, m), a 7.62 (2H, d, J=8,8 Hz), of 7.97 (1H, s).

TPL: 103-105°C.

FAB-MS: 528,0740 (Calculated for C23H22Cl2F2N3O3S: 58,0727).

Example 175:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]-N'-(pyrimidine-2-yl)propane-1,3-diamine

[Chemical formula 55]

To a solution of dihydrochloride of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]propane-1,3-diamine (76 mg, 0,136 mmol)obtained in example 173, in 1,4-dioxane (1.0 ml) was added triethylamine (76 μl, 0.54 mmol) and 2-chloropyrimidine (23 mg, 0.20 mmol). The resulting mixture was stirred at 80°C for 19 hours. The reaction mixture was allowed to cool to room temperature and then was diluted with ethyl acetate. The diluted mixture was washed with water and saturated saline solution, dried and concentrated. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1: 2) to obtain the specified title compound (50 mg, 65%). This connection has led in ethanol to obtain a white solid (36 mg).

1H-NMR (400 MHz, CDCl3)δ: of 1.94 (2H, m), of 3.48 (2H, m)and 3.59 (2H, m), 5,33 (1H, W), the ceiling of 5.60 (1H, W), 6,12 (1H, s), 6,56 (1H, t, J=4,8 Hz), 6,92 (1H, m), 7,03 (1H, m), 7,24 (1H, s), 7,44 (2H, d, J=8.0 Hz), 7,51 (1H, m), to 7.61 (2H, d, J=8.0 Hz), 8,00 (1H, s), 8,32 (1H, d, J=4,8 Hz).

TPL: 176-178°C.

FAB-MS: 564,0811 (Calculated for C25H22Cl2F2N5O2S: 564,0839).

Example 176:5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]-2-[(2-methylsulfonylmethyl)amino]pyridine

[Chemical formula 56]

To a solution of 5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]-2-[(2-methylthioethyl)amino]pyridine (29 mg, 0.061 mmol)obtained in example 163, in methanol (3 ml) was added tetrahydrate hexaminolevulinate (15 mg), and then was added 30% aqueous hydrogen peroxide solution (1.5 ml). The resulting mixture was stirred for 20 hours. After dilution with ethyl acetate (80 ml) of the diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) followed by crystallization from a simple broadcast receiving specified in the title compound (24 mg, 73%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,98 (3H, s), 3,37 (2H, t, J=6.0 Hz), of 3.94 (2H, m), 5,38 (1H, m), 6,10 (1H, s), make 6.90 (1H, m), 7,01 (1H, m), 7,32 (1H, s), 7,42 (2H, d, J=8,8 Hz), 7,45 (1H, m), to 7.59 (2H, d, J=8,8 Hz), 8,00 (1H, s).

TPL: 134-136°C.

Elemental analysis for C21H18Cl2F2N2O4S. Calculated: C, 47,11; H, 3,39; N,5,23; S 11,98. Found: C, 46,80; H, 3,35; N, 5,30; S, 11,84.

Example 177:2,5-Dichloro-4-[(2,5-differenl)-(4-forfinally)methyl]pyridine

[Chemical formula 57]

2,5-Dichloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (1.22 g, 4.8 mmol)obtained in reference example 24, restore and in thionyl chloride (5.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide. The resulting mixture was stirred for 4 hours.

The reaction mixture was concentrated under reduced pressure. To the obtained residue was added 1,4-dioxane, and then concentrated. The residue was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-fermentation (730 mg, 5.7 mmol) and potassium carbonate (2,07 g, 15 mmol). The resulting solution was stirred at room temperature for 24 hours under nitrogen atmosphere. To the reaction mixture were added diethyl ether (120 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was led in ethanol to obtain specified in the title compound (950 mg, 49%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: of 5.92 (1H, s), 6,94? 7.04 baby mortality (4H, m), 7,19 (1H, m), 7,33 to 7.4 (2H, m), EUR 7.57 (1H, s), with 8.33 (1H, s).

TPL: 95-97°C.

MS m/z: 400 (M++1)

Example 178:2-[[5-Chloro-4-[(2,5-differenl)-(4-forfinally)methyl]pyridine-2-yl]amino]ethanol

[Chemical formula 58]

Solution in 1,4-dioxane (1.5 ml) of 2,5-dichloro-4-[(2,5-differenl)-(4-forfinally)methyl]pyridine (200 mg, 0.50 mmol) and 2-aminoethanol (300 μl) was stirred at 120°C for 2 days in an atmosphere arg is on. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) to obtain the specified title compound (120 mg, 56%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 3.53 (2H, m), 3,82 (2H, m), of 4.95 (1H, W), of 5.89 (1H, s), 6,74 (1H, s), 6.90 to-7,00 (4H, m), 7,16 (1H, m), 7,31 and 7.36 (2H, m), to 7.99 (1H, s).

MS m/z: 425 (M++H).

Example 179:2-[[5-Chloro-4-[(2,5-differenl)-(4-perpenicular)methyl]pyridine-2-yl]amino]ethanol

[Chemical formula 59]

To a solution of 2-[[5-chloro-4-[(2,5-differenl)-(4-forfinally)methyl]pyridine-2-yl]amino]ethanol (119 mg, 0.27 mmol) in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 19 hours. After dilution with ethyl acetate (80 ml) of the diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:1) and was led from ethanol to obtain specified in the title compound (65 mg, 56%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 3,61 (2H, m), 3,88 (2H, d, J=4,8 Hz)6,09 (1H, s), make 6.90 (1H, m),? 7.04 baby mortality (1H, m), 7,10-to 7.18 (2H, m), 7,42 (1H, s), 7,49 (1H, m), 7,66-7,71 (2H, m), 7,95 (1H, s)./p>

TPL: 157-158°C.

Elemental analysis for C20H16ClF3N2O3S. Calculated: C,52,58; H,Of 3.53; N,6,13; S 7,02; Cl,7,76; F,12,48. Found: C,52,18; H,3,51; N,To 6.19; S,7,10; Cl,7,82; F,12,38.

Example 180:5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-2-[2-(pyridin-4-yl)ethylamino]pyridine

[Chemical formula 60]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio) (2.5-differenl)-methyl]pyridine (220 mg, 0,528 mmol)obtained in example 54 and 4-(2-amino-ethyl)pyridine (400 μl) in dioxane (1.5 ml) was heated at 120°C for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the obtained residue was added water, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride=1:30, was concentrated under reduced pressure to obtain specified in the title compound (114 mg, 0,227 mmol, 43%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 2,90 (2H, t, J=7,1 Hz), 3,54-the 3.65 (2H, m), 4,70-to 4.81 (1H, m), 5,96 (1H, s), only 6.64 (1H, s), 6.90 to-7,03 (2H, m), 7,05-7,16 (3H, m), 7,22 (4H, s), 8,03 (1H, s), 8,53 (2, d, J=6,1 Hz).

MS m/z: 501 (M+).

Example 181:5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-[2-(pyridin-4-yl)ethylamino]pyridine

[Chemical formula 61]

To a solution of 5-chloro-4-[(4-chlorophenylthio) (2.5-differenl)-methyl]-2-[2-(pyridin-4-yl)ethylamino]pyridine (110 mg, 0,219 mmol) in methanol (6 ml) was added under ice cooling 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (34 mg). The reaction mixture was stirred at room temperature for 22 hours, then the methanol drove away under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with a saturated solution of sodium bicarbonate, aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:3 was concentrated under reduced pressure to obtain specified in the title compound (102 mg, 0,191 mmol, 87%) as a pale yellowish white solid. The obtained solid is washed with diisopropyl ether-hexane and collected by filtration to obtain specified in the header is soedineniya (87 mg) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,96 (2H, t, J=7,1 Hz), 3,68 (2H, q, J=6.8 Hz), 4.72 in (1H, t, J=6,1 Hz), 6,12 (1H, s), 6,89-of 6.96 (1H, m), 6,98-was 7.08 (1H, m), 7,20 (2H, d, J=5,9 Hz), 7,24 (1H, s), 7,40-to 7.50 (3H, m), 7,60 (2H, d, J=8.6 Hz), 8,03 (1H, s), 8,56 (2H, d, J=5,9 Hz).

TPL: 148-150°C.

Elemental analysis for C25H19N3O2Cl2F2S. Calculated: C,56,19; H,To 3.58; N,7,86; Cl,Of 13.27; F,7,11; S 6,00. Found: C,56,01; H,3,57; N,7,93; Cl,Of 13.27; F,? 7.04 Baby Mortality; S,6,16.

Example 182:2-[2-[5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-ylamino]ethoxy]ethanol

[Chemical formula 62]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine (210 mg, 0,504 mmol)obtained in example 54, and 2-(2-aminoethoxy)ethanol (400 μl) in dioxane (1.5 ml) was heated at 120°C for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the obtained residue was added water, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of 30% methanol/methylene chloride, concentrated under reduced pressure to obtain specified in the header is VCE compound (85 mg, 0,175 mmol, 35%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 2,11 (1H, Shir. C)of 3.53 (2H, q, J=5.3 Hz), 3,61 (2H, t, J=4.4 Hz), 3,70 (2H, t, J=5,1 Hz), 3.72 points-of 3.80 (2H, m), of 4.95 (1H, t, J=5.6 Hz), 5,97 (1H, s)of 6.71 (1H, s), 6,80-7,03 (2H, s), 7,08-7,17 (1H, m), 7.18 in-7,30 (4H, m), 8,03 (1H, s).

MS (m/z): 484 (M+).

Example 183:2-[2-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-ylamino]ethoxy]ethanol

[Chemical formula 63]

To a solution of 2-[2-[5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-ylamino]ethoxy]ethanol (80 mg, 0,155 mmol) in methanol (6 ml) was added under ice cooling 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (32 mg). The resulting mixture was stirred at room temperature for 24 hours, then the methanol drove away under reduced pressure. To the residue was added ethyl acetate. The resulting mixture was washed successively with a saturated solution of sodium bicarbonate, aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:3 was concentrated under reduced pressure to obtain specified in the title compound (70 mg, is 0.135 the mol, 87%) as an amorphous substance. The obtained amorphous substance was utverjdali using a mixture of simple ether-hexane, followed by filtration to obtain specified in the title compound (55 mg) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,11 (1H, Shir. C), 3,55-3,63 (2H, m), 3,66 (2H, t, J=4.5 Hz), 3,74 (2H, t, J=5,1 Hz), 3,78-of 3.85 (2H, m), 5,03-5,13 (1H, m), 6,13 (1H, s), 6.89 in-6,97 (1H, m), 6,98-was 7.08 (1H, m), 7,30 (1H, s), was 7.45 (2H, d, J=8.5 Hz), of 7.48-7,56 (1H, m), a 7.62 (2H, d, J=8.5 Hz), 8,00 (1H, s). TPL: 113-115°C.

Elemental analysis for C22H20N2O4Cl2F2S. Calculated: C,51,07; H,3,90; N,5,41; Cl,13,70; F,7,34; S,6,20. Found: C,50,81; H,A 3.83; N,5,49; Cl,13,64; F,7,46; S 6,34.

Example 184:5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-2-[(3-methoxypropyl)amino]pyridine

[Chemical formula 64]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine (216 mg, 0,518 mmol)obtained in example 54, and 3-methoxypropylamine (200 μl) in dioxane (1.5 ml) was heated at 120°C for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated under reduced pressure to obtain a pale yellow oil (101 mg).

To the R. is the target of the obtained pale-yellow oil (101 mg) in methanol (6 ml) was added under ice cooling 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (41 mg). The reaction mixture was stirred at room temperature for 16 hours, then the methanol drove away under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with a saturated solution of sodium bicarbonate, aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (90 mg, 0,180 mmol, 35%) as a white solid. The obtained solid substance was washed with a simple ether-hexane and collected by filtration to obtain specified in the title compound (64 mg) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 1,87-to 1.98 (2H, m), 3,39 (3H, s), of 3.46 (2H, q, J=6,1 Hz), 3,55 (2H, t, J=5.8 Hz), 5,09 (1H, Shir. t, J=5.3 Hz), 6,13 (1H, s), 6,88-of 6.96 (1H, m), 6,98-was 7.08 (1H, m), 7,20 (1H, s), the 7.43 (2H, d, J=8.7 Hz), 7,50-EUR 7.57 (1H, m), a 7.62 (2H, d, J=8.7 Hz), 7,98 (1H, s).

TPL: 146-148°C.

Elemental analysis for C22H20N2O3Cl2F2S. Calculated: C,52,70; H,Was 4.02; N,5,59; Cl,14,14; F,7,58; S,6,40. Found: C,52,72; H,Of 3.95; N,5,78; Cl,14,14; F,7,75; S,6,54.

Example 185:5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-2-(3,4-is methoxybenzylamine)pyridine

[Chemical formula 65]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]pyridine (218 mg, 0,523 mmol)obtained in example 54, and 3,4-dimethoxyaniline (400 μl) in dioxane (1.5 ml) was heated at 120°C for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (140 mg, 0,256 mmol, 49%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 3,86 (3H, s), 3,88 (3H, s), 4,42 (2H, d, J=5.6 Hz), 4,99 (1H, t, J=5.6 Hz), 5,95 (1H, s), of 6.68 (1H, s), 6,80-7,02 (6H, m), 7,12-7,21 (4H, m), with 8.05 (1H, s).

MS m/z: 547 (M++H).

Example 186:5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(3,4-dimethoxyphenethylamine)pyridine

[Chemical formula 66]

To a solution of 5-chloro-4-[(4-chlorophenylthio) (2.5-differenl)methyl]-2-(3,4-dimethoxyphenethylamine)pyridine (131 mg, 0,239 mmol) in methanol (6 ml) was added under ice cooling 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (31 mg). The reaction mixture was stirred at room temperature for 1 hours, then methanol drove away under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with a saturated solution of sodium bicarbonate, aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of 35% ethyl acetate/hexane, concentrated under reduced pressure to obtain specified in the title compound (75 mg, 0,129 mmol, 54%) as a white solid. The obtained white solid was washed with simple ether-hexane and filtered to obtain specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3)δ: to 3.89 (6H, s), 4,48-4,51 (2H, m), 5.08 to further 5.15 (1H, m), 6,12 (1H, s), 6,85-7,05 (5H, m), 7,24 (1H, s), 7,28-to 7.35 (1H, m), 7,40 (2H, d, J=8.5 Hz), 7,55 (2H, d, J=8.5 Hz), 8,01 (1H, s).

TPL: 204-206°C.

Elemental analysis for C27H22N2O4Cl2F2S. Calculated: C,55,97; H,A 3.83; N,A 4.83; Cl,12,24; F,6,56; S Of 5.53. Found: C,56,05; H,3,82; N,4,87; Cl,12,30; F,6,60; S 5,73.

Example 187:5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]-2-[(pyridine-4-ylmethyl)amino]pyridine

[Chemical formula 67]

A solution of 2,5-dichloro-4-[(4-chlorphenyl what about) (2.5-differenl)methyl]pyridine (229 mg, 0,550 mmol)obtained in example 54 and 4-aminomethylpyridine (200 μl) in dioxane (1.5 ml) was heated at 120°C for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:3 was concentrated under reduced pressure to obtain specified in the title compound (37 mg, 0,076 mmol, 14%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 4,55 (2H, d, J=6,1 Hz), is 5.06 (1H, t, J=6.0 Hz), 5,94 (1H, s), is 6.61 (1H, s), 6.90 to-to 7.09 (3H, m), 7,13-7,30 (6H, m), with 8.05 (1H, s), 8,55 (2H, d, J=6,1 Hz).

MS m/z: 488 (M++H).

Example 188:5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-[(pyridine-4-ylmethyl)amino]pyridine

[Chemical formula 68]

To a solution of 5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-2-[(pyridine-4-ylmethyl)amino]pyridine (35 mg, 0,072 mmol) in methanol (2 ml) was added under ice cooling 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (23 mg). The reaction mixture was stirred at room temperature for 22 hours, then the methanol drove away under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively asystem solution of sodium bicarbonate, aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride=1:30, was concentrated under reduced pressure to obtain a pale yellow solid. The obtained pale yellow solid was washed by a simple ether-hexane and filtered to obtain specified in the title compound (16 mg, 0,031 mmol, 43%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 4,63 (2H, DD, J=6,1, 2,9 Hz), 5,20 (1H, t, J=6.4 Hz), 6,11 (1H, s), 6.87 in-6,95 (1H, m), 6,99-was 7.08 (1H, m), 7,25 (1H, s), 7,30 (2H, d, J=6.0 Hz), 7,35-7,40 (1H, m), 7,42 (2H, d, J=8,9 Hz), 7,56 (2H,, d, J=8,9 Hz), 8,02 (1H, s), 8,59 (2H, d, J=6.0 Hz).

TPL: 141-142°C.

FAB-MS: 520,0465 (Calculated for C24H18O2N3Cl2F2S: 520,0461).

Example 189:N-[3-[[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]propyl]methanesulfonamide

[Chemical formula 69]

To a solution of dihydrochloride of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]propane-1,3-diamine (60 mg, 0,107 mmol)obtained in example 173, in methylene chloride (5.0 ml) was added triethylamine (70 μl, 0.05 mmol) and methanesulfonamide (10 μl, ,13 mmol). The resulting mixture was stirred for 20 minutes. To the reaction mixture was added ether (50 ml). The resulting mixture was washed with water and saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=2:1) to obtain the specified title compound (60 mg, 99%). This connection has led in ethanol to obtain a white solid (46 mg).

1H-NMR (400 MHz, CDCl3)δ: to 1.86 (2H, quintet, J=6.0 Hz), 2,95 (3H, s), 3,21 (2H, q, J=6.0 Hz), 3,55 (2H, q, J=6.0 Hz), 4,99 (1H, W), the 5.65 (1H, W), 6,11 (1H, s)6,91 (1H, m), 7,03 (1H, m), 7,29 (1H, s), 7,44 (2H, d, J=8,8 Hz), 7,49 (1H, m), 7,60 (2H, d, J=8,8 Hz), 8,00 (1H, s).

TPL: 138-139°C.

Elemental analysis for C22H21Cl2F2N3O4S2. Calculated: C,46.81 / Bbl; H,Of 3.75; N,7,44; S,11,36.; F,6.73 X; Cl,12,56; Found: C,46.81 / Bbl; H,And 3.72; N,7,43; S,Is 11.39; F,6,80; Cl,12,41.

Example 190:1-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]tetrahydropyrimidin-2-he

[Chemical formula 70]

To a solution of dihydrochloride of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]propane-1,3-diamine (51 mg, 0,091 mmol)obtained in example 173, in methylene chloride (5.0 ml) was added triethylamine (51 μl, 0.36 mmol) and 1,1'-carbonyldiimidazole (16.2 mg, 0.10 mmol). The resulting mixture was stirred for 17 hours. To the reaction is MESI was added ethyl acetate (80 ml). The resulting mixture was washed with water and saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was dissolved in dimethylformamide (1.0 ml). To the resulting solution was added potassium carbonate (to 27.2 mg, 0.2 mol), followed by stirring under heating at 50°C within 24 hours. After cooling to room temperature, to the reaction mixture were added water. The resulting mixture was diluted with ethyl acetate (60 ml). The organic layer obtained by separation was washed with a saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:2) to obtain the specified title compound (15 mg, 99%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,12 (2H, m), of 3.46 (2H, m)to 3.99 (2H, m), with 5.22 (1H, W), of 6.26 (1H, s), of 6.96 (1H, m), 7,03 (1H, m), the 7.43 (2H, d, J=8,8 Hz), 7,68 (1H, m), 7,76 (2H, d, J=8,8 Hz), 8,23 (1H, s), 8,93 (1H, s).

MS m/z: 512 (M++H).

TPL: >230°C.

Example 191:tert-Butyl 2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethylcarbamate

[Chemical formula 71]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine (610 mg, of 1.46 mmol)obtained in example 54, and tert-butyl (2-amino-ethyl)carbamate (700 mg, of 4.38 mmol) in 1,4-dioxane (6.0 ml) was stirred PR is 120° C for 4 days in an argon atmosphere. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to obtain the specified title compound (176 mg, 22%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.43 (9H, s)to 3.36 (2H, m), 3,42 (2H, m), free 5.01 (1H, W), 5,12 (1H, W), 5,95 (1H, s), 6.90 to? 7.04 baby mortality (2H, m), 7,13 (1H, m), 7,21 (2H, d, J=8,4 Hz), 7.23 percent (2H, d, J=8,4 Hz), 8,00 (1H, s).

MS m/z: 540 (M++H).

Example 192:tert-Butyl 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethylcarbamate

[Chemical formula 72]

To a solution of tert-butyl 2-[[5-chloro-4-[(4-chlorophenylthio)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethylcarbamate (176 mg, 0.32 mmol) in methanol (6 ml) was added tetrahydrate hexaminolevulinate (30 mg), and then was added 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 20 hours. The reaction mixture was diluted with ethyl acetate (80 ml), then diluted mixture was washed with water and saturated saline and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (148 mg, 81%) as oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.45 (9H, s), 3,39 (2H, m), 3,49 (2, m)of 5.03 (1H, W), of 5.29 (1H, W), 6,12 (1H, s)6,91 (1H, m), 7,03 (1H, m), 7,24 (1H, s), the 7.43 (2H, d, J=8,8 Hz), 7,52 (1H, m), to 7.61 (2H, d, J=8,8 Hz), 7,98 (1H, s).

MS m/z: 572 (M++H).

Example 193:The dihydrochloride of N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]ethane-1,2-diamine

[Chemical formula 73]

To tert-butyl 2-[[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amino]ethylcarbamate (146 mg, 0.25 mmol) was added a solution of 20% hydrochloric acid in methanol (1 ml). The resulting mixture was stirred for 1 hour. The residue obtained by concentration of the reaction mixture under reduced pressure, was led from ethanol to obtain specified in the title compound (106 mg, 76%).

1H-NMR (400 MHz,DMSO-d6)δ: 2,99 (2H, m), 3,51 (2H, m), 6,17 (1H, s), 7,28 (1H, m), 7,38 (1H, m), 7,39 (1H, s), 7,52 (1H, m), of 7.69 (2H, d, J=8,8 Hz), of 7.75 (2H, d, J=8,8 Hz), of 8.04 (1H, s).

TPL: 163-166°C.

Elemental analysis for C20H17Cl2F2N3O2S·2HCl·0,5H2O. Calculated: C,43,34; H,To 3.64; N,7,58; S 5,78; Cl,25,59,F, 6,86. Found: C,43,32; H,3,55; N,To 7.67; S Of 5.83; Cl,25,84; F,6,87.

Example 194:3-[5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-ylamino]-2,2-DIMETHYLPROPANE-1-ol

[Chemical formula 74]

A solution of 2,5-dichloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine (191 mg, 0,458 mmol)obtained in example 54, and 3-and the Ino-2,2-DIMETHYLPROPANE-1-ol (515 mg, 5.00 mmol) in dioxane (1.5 ml) was heated at 120°C for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (199 mg, 0,412 mmol, 90%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 0.91 (6H, s), 3,12 of 3.28 (4H, m), to 4.73 (1H, t, J=6.4 Hz), to 4.87 (1H, Shir. C)of 5.92 (1H, s), 6,62 (1H, s), 6,92-7,07 (2H, m), 7,16-to 7.32 (5H, m), of 7.96 (1H, m).

MS m/z: 483 (M++H).

Example 195:3-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-ylamino]-2,2-DIMETHYLPROPANE-1-ol

[Chemical formula 75]

To a solution of 3-[5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-ylamino]-2,2-DIMETHYLPROPANE-1-ol (188 mg, 0,389 mmol) in methanol (6 ml) was added under ice cooling 30% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (35 mg). The resulting mixture AC is stirred at room temperature for 13 hours, then methanol drove away under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with a saturated solution of sodium bicarbonate, aqueous sodium thiosulfate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain white solid. The obtained white solid was utverjdali using a simple ether-hexane, washed and collected by filtration to obtain specified in the title compound (156 mg, 0,303 mmol, 78%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 0.94 (3H, s)of 0.95 (3H, s), 3,20 (2H, d, J=6.6 Hz), with 3.27 (2H, d, J=7,1 Hz), and 4.68 (1H, Shir. C)4,94 (1H, t, J=6.9 Hz), 6,09 (1H, s), 6,86-to 6.95 (1H, m), 7,00-to 7.09 (1H, m), 7,29 (1H, s), 7,40-7,52 (3H, m), 7,60 (2H, d, J=8.6 Hz), 7,94 (1H, s).

TPL: 176-178°C

Elemental Analysis for C23H22N2O3Cl2F2S. Calculated: C,53,60; H,4,30; N,5,44; Cl,13,76; F,7,37; S,6,22. Found: C,53,50; H,4.26 Deaths; N,5,44; Cl,13,78; F,7,31; S,6,30.

Example 196:[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 76]

To a solution of 5-chloro-4[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(3,4-dimethoxyphenethylamine)pyridine (43 mg, 0,074 mmol)obtained in example 186, in a mixture of acetonitrile (4 ml)/water (1 ml) was added under ice cooling giammarinaro (100 mg) of cerium (IV). The resulting mixture was stirred for 1.5 hours. To the reaction mixture were added a saturated solution of sodium bicarbonate, then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by thin-layer chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (12 mg, 0,028 mmol, 38%) as pale yellowish white powder.

1H-NMR (400 MHz, CDCl3)δ: the 4.65 (2H, Shir. C), 6,13 (1H, s), 6.89 in-6,98 (1H, m), 7,00-to 7.09 (1H, m), 7,33 (1H, s), 7,44 (2H, d, J=8,8 Hz), 7,49-EUR 7.57 (1H, m), a 7.62 (2H, d, J=8,8 Hz), to 7.99 (1H, s).

TPL: 147-150°C.

MS m/z: 429 (M++H).

Elemental Analysis for C18H12N2O2Cl2F2S. Calculated: C,50,36; H,2,82; N,6,53; Cl,16,52; F,Cent To 8.85; S,7,47. Found: C,50,46; H,2,68; N,6,63; Cl,16,42; F,9,00; S,7,66.

Example 197:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 77]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (106 mg, 0,247 mmol)obtained in example 196, in pyridine (2 ml) was added under cooling with ice methanesulfonyl arid (29 μl, 0,370 mmol). The mixture was stirred at room temperature for 3 days and then concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (58 mg, 0,114 mmol, 46%) as a white solid. The obtained white solid was washed with hexane - simple ether and collected by filtration to obtain specified in the title compound (28 mg) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: at 3.35 (3H, s), to 6.19 (1H, s), 6.90 to-6,99 (1H, m), 7,01-7,10 (1H, m), 7,42-7,53 (3H, m), 7,60-of 7.70 (3H, m), of 7.97 (1H, s), 8,32 (1H, s).

TPL: 220-222°C.

MS m/z: 507 (M++H).

FAB-MS: 506,9824 (calculated for C19H15O4N2Cl2F2S2: 506,9818).

Elemental Analysis for C19H14N2O4Cl2F2S2. Calculated: C,44,98; H,2,78; N,5,52; Cl,13,98; F,7,49; S 12,64. Found: C,45,35; H,2,85; N,5,63; Cl,13,49; F,7,34; S 12,69.

Reference Example 35:5-Perperi the Jn-2-carbonitril

[Chemical formula 78]

To a mixture of hydrogen fluoride-pyridine (100 ml) was added under ice cooling 5-amino-2-cyanopyridine (24.5 g, 0,206 mol). The resulting mixture was stirred for 10 minutes. To the reaction mixture was added sodium nitrite (15.6 g, 0,226 mol). The resulting mixture was stirred at room temperature for 10 minutes and then stirred at 50°C for 2 hours. To the reaction mixture was added 20% aqueous sodium hydroxide solution. The mixture was extracted with diethyl ether. The obtained organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (16.0 g, 0,131 mmol, 64%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: EUR 7.57 (1H, DDD, J=8,6, 8,6, 3.1 Hz), to 7.77 (1H, DD, J=8,6, 4,4 Hz), at 8.60 (1H, d, J=3.1 Hz).

IR (ATR) cm-1: 3095, 2237, 1577, 1467, 1409, 1375, 1272, 1240, 1197, 1120, 1010.

MS m/z: 122 (M+).

EI-MS: 122,0293 (Calculated for C6H3FN2: 122,0280).

Reference Example 36:2-(1,3-dioxolane-2-yl)-5-herperidin

[Chemical formula 79]

Hydride diisobutylaluminum (1,01M solution in hexane, 58 ml of 58.9 mmol)was added dropwise to a solution of 5-herperidin-2-carbonitrile (6,54 g, 53.8 mmol) in dichloromethane (150 ml) at -75°C in argon atmosphere. The reaction mixture was stirred for 3 hours. At the same temperature was added a solution of hydrochloric acid (80 ml), concentrated hydrochloric acid:water=1:3), and then the mixture was heated to room temperature. From the reaction mixture were separated dichloromethane layer. To the aqueous layer was then added sodium bicarbonate. The mixture was extracted with diethyl ether. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The dichloromethane layer obtained above was washed with water, dried over magnesium sulfate and concentrated under reduced pressure.

To a solution of the combined residue in benzene (150 ml) was added monohydrate p-toluensulfonate acid (1,02 g, are 5.36 mmol) and ethylene glycol (30 ml, 0,536 mol). The resulting mixture was stirred for 2 hours under heating and boiling under reflux. After cooling, was added saturated aqueous sodium bicarbonate solution and the mixture was extracted with diethyl ether. The extract was washed with saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:is tracecut=4:1, concentrated under reduced pressure to obtain specified in the title compound (3.33 g, of 19.7 mmol, 37%) as a reddish brown oil.

1H-NMR (400 MHz, CDCl3)δ: was 4.02-is 4.21 (4H, m), of 5.85 (1H, s), 7,45 (1H, DDD, J=8,3,8,3,2,9 Hz), EUR 7.57 (1H, DD, J=8,3,4,5 Hz), 8,48 (1H, d, J=2,9 Hz).

MS m/z: 170 (M++H).

Reference Example 37:4-[(2,5-Differenl)hydroxymethyl]-2-(1,3-dioxolane-2-yl)-5-herperidin

[Chemical formula 80]

Diisopropylamide lithium (1,8M solution in heptane, 12 ml, 21.5 mmol) was added at -75°C in an argon atmosphere to a solution of 2-(1,3-dioxolane-2-yl)-5-herperidin (690 mg, 4,08 mmol) in tetrahydrofuran (100 ml). The resulting mixture was stirred for 2 hours. To the reaction mixture was added dropwise 2.5-differentally (2,1 ml of 19.5 mmol) followed by stirring for 2.5 hours. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with diethyl ether. The extract was washed with saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated under reduced pressure to obtain specified in the connection header(2,53 g, 8,03 mmol, 73%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: to 2.65 (1H, d, J=4.6 Hz), 4,05-is 4.21 (4H, m), of 5.84 (1H, s), 6.35mm (1H, d, J=4.6 Hz), of 6.96-7,05 (2H, m), 7,09-7,26 (1H, m), 7,76 (1H, d, J=5,9 Hz), 8,40 (1H, d, J=1.5 Hz).

MS m/z: 312 (M++H).

Example 198:4-[(4-Chlorophenylthio)(2.5-differenl)methyl]-2-(1,3-dioxolane-2-yl)-5-herperidin

[Chemical formula 81]

The triethylamine (1.7 ml, of 12.0 mmol) and methanesulfonamide (850 μl, 10.4 mmol) in an argon atmosphere was added under ice cooling to a solution of 4-[(2,5-differenl)hydroxymethyl]-2-(1,3-dioxolane-2-yl)-5-herperidin (2.5 g, 8,03 mmol) in dichloromethane (30 ml). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and then was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

To a solution of the residue in dimethylformamide (20 ml) was added 4-chlorbenzoyl (1.39 g, for 9.64 mmol) and potassium carbonate (1.66 g, 12,0 mmol). The resulting mixture was stirred at 50°C for 3 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether. The diluted solution was washed successively with water and saturated salt solution. The obtained organic layer is dried is over sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=4:1), concentrated under reduced pressure to obtain specified in the title compound (2.86 g, of 5.85 mmol, 81%) as a yellow oil.

1H-NMR (400 MHz, CDCl3)δ: 4,06-4,18 (4H, m), of 5.82 (1H, s)5,94 (1H, s), of 6.96-7.03 is (2H, m), 7,20-7,28 (5H, m), 7,71 (1H, d, J=5,9 Hz), scored 8.38 (1H, d, J=1.2 Hz).

MS m/z: 438 (M++H).

Example 199:4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-2-(1,3-dioxolane-2-yl)-5-herperidin

[Chemical formula 82]

To a solution of 4-[(4-chlorophenylthio)(2.5-differenl)methyl]-2-(1,3-dioxolane-2-yl)-5-herperidin (2,80 g, to 6.39 mmol) in methanol (50 ml) was added tetrahydrate hexaminolevulinate (200 mg) and 30% aqueous hydrogen peroxide solution (30 ml). The resulting mixture was stirred for 3 hours. To the reaction mixture were added water. Besieged thus, the solid was collected by filtration and then washed with water. The obtained solid substance was dissolved in ethyl acetate. The solution was washed with water and saturated salt solution. The organic layer was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated at the pony who hinnon pressure obtaining specified in the title compound (1.39 g, 2,96 mmol, 46%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 4,08-to 4.28 (4H, m), 4,08-to 4.28 (4H, m), 5,88 (1H, s), 6,10 (1H, s), 6,94-7,00 (1H, m), 7.03 is-7,10 (1H, m), the 7.43 (2H, d, J=8,3 Hz), a 7.62 (2H, d, J=8,3 Hz), 7,66-of 7.70 (1H, m), 8,17 (1H, d, J=5,9 Hz), to 8.41 (1H, s).

MS m/z: 470 (M++H).

Example 200:[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-herperidin-2-yl]carbaldehyde

[Chemical formula 83]

To a solution of 4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(1,3-dioxolane-2-yl)-5-herperidin (2,60 g of 5.53 mmol) in 1,4-dioxane (40 ml) was added concentrated hydrochloric acid (20 ml). The resulting mixture was stirred at room temperature for 5 hours. The solvent was concentrated under reduced pressure. To the residue was added ethyl acetate. The resulting mixture was washed successively with water, saturated aqueous sodium bicarbonate and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated under reduced pressure to obtain specified in the title compound (1.86 g, 4,37 mmol, 79%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,13 (1H, s), 6,93-6,99 (1H, m), 7,05-7,10 (1H, m), 7,45 (2H, d, J=7.8 for the TS) the 7.65 (2H, d, J=7.8 Hz), 7,70 to 7.75 (1H, m), 8,59 (1H, s), at 8.60 (1H, s)10,06 (1H, s).

MS m/z: 426 (M++H).

Example 201:4-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-5-foreconomy acid

[Chemical formula 84]

To a solution of [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]carbaldehyde (700 mg, of 1.64 mmol) in formic acid (10 ml) was added 30% aqueous hydrogen peroxide solution (562 μl, is 4.93 mmol). The resulting mixture was stirred at room temperature for 2.5 hours. To the reaction mixture were added water. Besieged thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in ethyl acetate. The solution was washed successively with a saturated aqueous solution of ammonium chloride, water and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compound (656 mg, 1.48 mmol, 91%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,14 (1H, s), 6,93-7,00 (1H, m), 7,05-7,11 (1H, m), 7,46 (2H, d, J=8.6 Hz), to 7.67 (2H, d, J=8.6 Hz), 7,75-7,79 (1H, m), of 8.47 (1H, s), cent to 8.85 (1H, d, J=5.6 Hz).

IR (ATR) cm-1: 3288, 2942, 1751, 1722, 1693, 1608, 1575, 1492, 1398, 1326, 1290, 1241, 1182, 1147, 1089, 1043, 1014.

TPL: 208-209°C.

MS m/z: 442 (M++H).

Elemental Analysis the C 19H11ClF3NO4S·0,75H2O. Calculated: C,50,12; H,2,77; Cl,7,79; F,To 12.52; N Is 3.08; S,? 7.04 Baby Mortality. Found: C,50,49; H,2,97; Cl,7,53; F,12,02; N,3,11, S,6,89.

Example 202:tert-Butyl [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]carbamate

[Chemical formula 85]

Diphenylphosphinite (162 μl, 0,762 mmol) and triethylamine (151 μl, of 1.09 mmol) in an argon atmosphere was added to a solution of 4-[-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-foreconomy acid (240 mg, 0,543 mmol) in a mixture of tert-butanol (2 ml) and toluene (5 ml). The reaction mixture was heated at the boil under reflux for 15 hours. After cooling, to the reaction mixture were added ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=4:1), concentrated under reduced pressure to obtain specified in the title compound (181 mg, 0,353 mmol, 65%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 1.57 (9H, s), 6,07 (1H, s), 6,93-6,99 (1H, m), 7,02-was 7.08 (1H, m), the 7.43 (2H, d, J=8.6 Hz), 7,49 (1H, Shir. C)of 7.70 (2H, d, J=8.6 Hz), 7,71 to 7.75 (1H, m), of 8.04 (1H, s), and 8.6 (1H, d, J=4,9 Hz).

MS m/z: 442 (M+-tBu+2H).

Example 203:[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]amine

[Chemical formula 86]

To a solution of tert-butyl [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]carbamate (170 mg, 0,331 mmol) in ethanol (5 ml) was added concentrated hydrochloric acid (5 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution and then was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane:ethyl acetate to obtain specified in the title compound (110 mg, 0,266 mmol, 81%) as a pale purple powder.

1H-NMR (400 MHz, CDCl3)δ: 4,51 (2H, s), of 5.99 (1H, s), 6,92-6,97 (1H, m), 7,02-was 7.08 (1H, m), 7,16 (1H, d, J=4.6 Hz), 7,44 (2H, d, J=8.6 Hz), to 7.61-the 7.65 (1H, m), 7,63 (2H, d, J=8.6 Hz), 7,86 (1H, s).

IR (ATR) cm-1: 3645, 3174, 1631, 583, 1565, 1496, 1427, 1396, 1330, 1278, 1236, 1178, 1151, 1085, 1014.

TPL: 181-183°C.

MS m/z: 413 (M++H).

Elemental Analysis for C18H12ClF3N2O2S. Calculated: C,52,37; H,2,93; Cl,8,59; F,13,81; N,6,79; S,To 7.77. Found: C,52,09; H,2,88; Cl,To 8.57; F,13,4; N 6,90; S,7,81.

Example 204:N-[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-herperidin-2-yl]methanesulfonamide

[Chemical formula 87]

Methanesulfonanilide (12 μl, of) 0.157 mmol) was added under ice cooling to a solution of [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]amine (54 mg, 0,131 mmol) and pyridine (16 μl, 0,197 mmol) in methylene chloride (5 ml). The resulting mixture was stirred at room temperature for 7 hours, and then was added pyridine (16 μl, 0,197 mmol) and methanesulfonamide (12 μl, of) 0.157 mmol). The reaction mixture was stirred at room temperature for 17 hours, then to the mixture was added pyridine (16 μl, 0,197 mmol) and methanesulfonamide (12 μl, of) 0.157 mmol). The resulting mixture was stirred at room temperature for 2 hours and then to the mixture was added pyridine (16 μl, 0,197 mmol) and methanesulfonamide (12 μl, of) 0.157 mmol). The resulting mixture was stirred at room temperature for 21 hours, then to the mixture was added pyridine (16 μl, 0,197 mmol) and methanesulfonamide (12 μl, of) 0.157 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sulphate of soda is I and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=2:1), concentrated under reduced pressure to obtain specified in the title compound (54 mg, 0,110 mmol, 84%) as a white solid. The obtained white solid was washed with hexane-simple ether and collected by filtration to obtain specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,30 (3H, s), the 6.06 (1H, s), 6.90 to-6,99 (1H, m), 7,02-7,10 (1H, m), 7,46 (2H, d,8,8 Hz), 7,58-of 7.69 (3H, m), 7,83-to $ 7.91 (2H, m), 8,21 (1H, s).

TPL: 217-219°C.

MS m/z: 490 (M+).

EI-MS: 490,0008 (calculated for C19H14O4N2ClF3S2: 490,0036).

Elemental Analysis for C19H14N2O4ClF3S2. Calculated: C,46,49; H,2,87; N,5,71; Cl,7,22; F,Of 11.61; S 13,06. Found: C,46,90; H,2,95; N,5,78; Cl,7,33; F,To 11.56; S 13,04.

Reference Example 38:(4-Bromo-5-methylpyridin-2-yl)methanol

[Chemical formula 88]

Triperoxonane anhydride (20,6 ml, 0,146 mol) was added in an argon atmosphere to a solution of 4-bromo-2,5-dimethylpyridine 1-oxide (9,8 g of 48.5 mmol) in dichloromethane (100 ml) under cooling with ice. The resulting mixture was stirred for 20 minutes and then stirred at room temperature for the of 7.5 hours. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in dichloromethane (50 ml) was added a saturated aqueous solution (100 ml) of sodium bicarbonate. The resulting mixture was stirred for 14 hours. The reaction mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=1:1), concentrated under reduced pressure to obtain specified in the connection header (8,17 g of 40.4 mmol, 83%) as a yellow powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.38 (3H, s), 3,42 (1H, s), 4,71 (2H, s), of 7.48 (1H, s), 8,35 (1H, s).

MS m/z: 202 (M++H).

Reference Example 39:4-Bromo-2-[(tert-butyldimethylsilyloxy)methyl]-5-methylpyridin

[Chemical formula 89]

The imidazole (2,95 g, a 43.3 mmol), 4-dimethylaminopyridine (481 mg, of 3.94 mmol) and tert-BUTYLCARBAMATE (6,53 g, a 43.3 mmol) under nitrogen atmosphere was added to a solution of (4-bromo-5-methylpyridin-2-yl)methanol (of 7.96 g, to 39.4 mmol) in dichloromethane (100 ml) under cooling with ice. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, then was extracted with dichloromethane. The extract was dried over anhydrous sulfate NAT the Oia and concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (12.4 g, to 39.4 mmol, Quant.) in the form of a light yellow oil.

1H-NMR (400 MHz, CDCl3)δ: of 0.12 (6H, s)to 0.96 (9H, s), a 2.36 (3H, s), 4,78 (2H, s), to 7.67 (1H, s), 8,29 (1H, s).

MS m/z: 316 (M++H).

Reference Example 40:2-[(tert-Butyldimethylsilyloxy)methyl]-4-[(2,5-differenl)-hydroxymethyl]-5-methylpyridin

[Chemical formula 90]

n-Utility (solution 1,58M in hexane, 400 ál, 0,632 mmol) in an argon atmosphere was added to a solution of 4-bromo-2-[(tert-butyldimethylsilyloxy)methyl]-5-methylpyridine (200 mg, 0,632 mmol) in diethyl ether (3 ml) at -78°C. the resulting mixture was stirred for 1 hour. Was added dropwise 2.5-differentally (69 μl, 0,632 mmol), then the reaction mixture was stirred for 1 hour. To the reaction mixture were added water and saturated aqueous sodium bicarbonate solution and then was extracted with diethyl ether. The extract was washed with saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained PR is the elution by the mixture hexane:ethyl acetate=2:1, concentrated under reduced pressure to obtain specified in the title compound (178 mg, 0,469 mmol, 74%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 0,06 (3H, s), and 0.09 (3H, s)of 0.91 (9H, s), and 2.26 (3H, s), 2,52 (1H, Shir. C)rate 4.79 (2H, s), 6,24 (1H, s), 6,95-7,10 (3H, m), 7,58 (1H, s), of 8.27 (1H, s).

MS m/z: 380 (M++H).

Example 205:2-[(tert-Butyldimethylsilyloxy)methyl]-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-5-methylpyridin

[Chemical formula 91]

The triethylamine (to 4.41 ml, and 31.7 mmol) and methanesulfonamide (2.2 ml, a 27.4 mmol) in an argon atmosphere was added under ice cooling to a solution of 2-[(tert-butyldimethylsilyloxy)methyl]-4-[(2,5-differenl)-hydroxymethyl]-5-methylpyridine (8.0 g, 21.1 mmol) in dichloromethane (100 ml). The resulting mixture was stirred at room temperature for 50 minutes. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and then was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

To a solution of the residue in dimethylformamide (100 ml) was added 4-chlorbenzoyl (3,66 g, to 25.3 mmol) and potassium carbonate (of 4.38 g, and 31.7 mmol). The resulting mixture was stirred at 50°C for 1.5 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether is. The diluted solution was washed successively with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=5:1 was concentrated under reduced pressure to obtain specified in the title compound (9.3 g, 18.4 mmol, 87%) as a pale yellow oil.

1H-NMR (400 MHz, CDCl3)δ: 0,04 (3H, s), and 0.08 (3H, s)of 0.91 (9H, s), of 2.33 (3H, s), of 4.77 (2H, d, J=4, 2 Hz), of 5.83 (1H, s), 6,92-7,00 (2H, m), 7,20 (4H, s), 7,33-7,38 (1H, m), 7,56 (1H, s), 8,29 (1H, s).

MS m/z: 506 (M++H).

Example 206:[4-[(4-Chlorophenylthio)(2.5-differenl)methyl]-5-methylpyridin-2-yl]methanol

[Chemical formula 92]

To a solution of 2-[(tert-butyldimethylsilyloxy)methyl]-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-5-methylpyridine (200 mg, 0,395 mmol) in tetrahydrofuran (3 ml) was added tetrabutylammonium (a 1.0 M solution in tetrahydrofuran, 593 μl, 0,593 mmol). The resulting mixture was stirred for 20 minutes. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to flash column chromium is ographie on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (150 mg, 0.384 mmol, 97%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 2,31 (3H, s), of 3.54 (1H, Shir. C)4,72 (2H, s), of 5.81 (1H, s), 6,94-7,03 (2H, m), 7,20 (4H, s), 7,22-7,28 (1H, m), 7,33 (1H, s), 8,35 (1H, s).

MS m/z: 392 (M++H).

Example 207:[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-5-methylpyridin-2-yl]methanol

[Chemical formula 93]

To a solution of [4-[(4-chlorophenylthio)(2.5-differenl)methyl]-5-methylpyridin-2-yl]methanol (6.5 g, of 16.6 mmol) in methanol (150 ml) was added tetrahydrate hexaminolevulinate (500 mg) and 30% aqueous hydrogen peroxide solution (150 ml). The resulting mixture was stirred for 23 hours. To the reaction mixture were added water. Besieged thus, the solid was collected by filtration and then washed with water. The solid was dissolved in ethyl acetate. The resulting solution was washed with water and saturated salt solution. The organic layer was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure to obtain specified in the title compound (4.0 g, 9,44 mmol, 57%) as a white p the Rosca.

1H-NMR (400 MHz, CDCl3)δ: 2,13 (3H, s), 3,53 (1H, Shir. C)4,80 (1H, d, J=14.4 Hz), is 4.85 (1H, d, J=14.4 Hz), 5,88 (1H, s), 6.90 to-of 6.96 (1H, m), 7,01-7,07 (1H, m), the 7.43 (2H, d, J=8,8 Hz), 7,60 (2H, d, J=8,8 Hz), 7,60 (2H, d, J=8,8 Hz), 7,63-to 7.67 (1H, m), to 7.93 (1H with), at 8.36 (1H, s).

IR (ATR) cm-1: 3179, 1604, 1573, 1492, 1427, 1394, 1349, 1322, 1280, 1234, 1151, 1085, 039, 1010.

TPL: 196-198°C.

MS m/z: 424 (M++H).

Elemental Analysis for C20H16ClF2NO3S. Calculated: C,56,67; H,3,80; Cl,At 8.36; F,8,96; N,3,30; S,7,56. Found: C,56,41; H,3,83; Cl,8,28; F,8,89; N,And 3.31; S,To 7.67.

Example 208:[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-methylpyridin-2-yl]carbaldehyde

[Chemical formula 94]

Dimethyl sulfoxide (164 μl, 2.36 mmol), triethylamine (329 μl, 2.36 mmol) and a complex of a sulfur trioxide-pyridine (255 mg, of 1.42 mmol) under nitrogen atmosphere was added to a solution of [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-methylpyridin-2-yl]methanol (200 mg, 0,472 mmol) in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (160 mg, 0,379 mmol, 80%) as a white powder.

1H-NMR (400 MHz, CDCl3δ : to 2.29 (3H, s)5,94 (1H, s), 6,92-6,97 (1H, m), 7,02-was 7.08 (1H, m), the 7.43 (2H, d, J=8,8 Hz), a 7.62 (2H, d, J=8,8 Hz), 7,70 to 7.75 (1H, m), to 8.57 (1H, s), 8,59 (1H, s), 10,08 (1H, s).

MS m/z: 422 (M++H).

Example 209:4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-metilpikolinovaya acid

[Chemical formula 95]

To a solution of [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-methylpyridin-2-yl]carbaldehyde (150 mg, 0,356 mmol) in formic acid (3 ml) was added 30% aqueous hydrogen peroxide solution (121 μl, 1.07 mmol). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water. Besieged thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in ethyl acetate. The solution was washed successively with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compound (140 mg, 0,320 mmol, 90%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.33 (3H, s), 5,96 (1H, s), 6,92-6,98 (1H, m), 7,02-was 7.08 (1H, s), 7,44 (2H, d, J=8.6 Hz), to 7.64 (2H, d, J=8,6), 7,74 for 7.78 (1H, m), to 8.45 (1H, s), 8,81 (1H, s).

IR (ATR) cm-1: 1922, 1683, 1598, 1488, 1450, 1428, 1396, 1375, 1326, 1290, 1236, 1174, 47, 1085, 1047, 1014.

TPL: 105-107°C.

MS m/z: 438 (M++H).

Elemental Analysis for C20 H14ClF2NO4S·0,75H2O. Calculated: C,53,22; H,3.46 In; Cl,A 7.85; F,8,42; N,3,10; S,7,10. Found: C,53,44; H,3,90; Cl,7,47; F,Of 8.06; N,3,07; S 6,95.

Example 210: tert-Butyl [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-methylpyridin-2-yl]carbamate

[Chemical formula 96]

Diphenylphosphinite (2,9 ml of 13.6 mmol) and triethylamine (2.7 ml, and 19.4 mmol) in an argon atmosphere was added to a solution of 4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-metilakrilovoe acid (2.8 mg, 6,40 mmol) in a mixture of tert-butanol (20 ml) and toluene (40 ml). The resulting mixture was stirred for 16 hours under heating and boiling under reflux. After cooling, to the reaction mixture were added ethyl acetate. The mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was washed successively with hexane and ethyl acetate to obtain specified in the connection header (2,60 g, 5,11 mmol, 80%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: was 1.58 (9H, s)2,07 (3H, s), 5,88 (1H, s), 6,92-6,98 (1H, m), 7,00-7,06 (1H, m), 7,42 (2H, d, J=8,8 Hz), 7,42 (2H, d, J=8,8 Hz), EUR 7.57 (1H, Shir. C)to 7.67-7,72 (1H, m), 7,71 (2H, d, J=8,8 Hz), 8,02 (1H, s), 8,67 (1H, s).

MS m/z: 509 (M++H).

Example 211:[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-ethylpyridine-2-yl]amine

[Chemical formula 97]

To a solution of tert-butyl [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-methylpyridin-2-yl]carbamate (200 mg, 0,393 mmol) in ethanol (5 ml) was added concentrated hydrochloric acid (6 ml). The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline solution, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from hexane:ethyl acetate to obtain specified in the title compound (125 mg, 0,306 mmol, 78%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 1,89 (3H, s), 5,95-5,96 (3H, m), 7,12 (1H, s), 7,22-7,34 (2H, m), 7,51-of 7.55 (1H, m), the 7.65 (2H, d, J=8,8 Hz), 7,69 (1H, s), 7,78 (2H, d, J=8,8 Hz).

IR (ATR) cm-1: 3424, 1637, 1554, 1492, 1457, 1411, 1309, 1276, 1230, 1151, 1089, 1039, 1008.

TPL: 188-189 °C.

Elemental Analysis for C19H15ClF2N2O2S. Calculated: C,55,82; H,3,70; Cl,8,67; F,9,29; N,6,85; S 7,84. Found: C,55,58; H,3,95; Cl,8,61; F,9,13; N,6,91; S,7,89.

Example 212 N-[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)-methyl]-5-methylpyridin-2-yl]methanesulfonamide

[Chemical formula 98

To a solution in methylene chloride (5 ml) of [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-methylpyridin-2-yl]amine (133 mg, 0,325 mmol) and pyridine (39 μl, 0,488 mmol) was added under ice cooling methanesulfonanilide (28 μl, 0,358 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added pyridine (26 μl, 0,325 mmol) and methanesulfonamide (25 μl, 0,325 mmol). The resulting mixture was stirred at room temperature for 16 hours, then to the mixture was added pyridine (26 μl, 0,325 mmol) and methanesulfonamide (25 μl, 0,325 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure to obtain specified in the title compound (108 mg, 0,222 mmol, 68%) as a white solid. The obtained white solid was washed with hexane-simple ether and collected Phi is trevanian obtaining specified in the title compound (67 mg) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,13 (3H, s), 3,29 (3H, s), to 5.85 (1H, s), 6.89 in-6,99 (1H, m), 7,01-7,10 (1H, m), 7,45 (2H, d, J=8,3 Hz), to 7.59-of 7.69 (3H, m), of 7.90 (1H, s)to 8.12 (1H, s).

TPL: 214-217°C.

MS m/z: 486 (M+).

Elemental Analysis for C20H17N2O4ClF2S2. Calculated: C,49,33; H,To 3.52; N,5,75; Cl,7,28; F,7,80; S,13,17. Found: C,49,18; H,Of 3.45; N,Of 5.82; Cl,7,18; F,7,98; S,13,14.

Example 213:2,5-Dichloro-4-[(2,5-differenl)-(4-forfinally)methyl]pyridine

[Chemical formula 99]

2,5-Dichloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (1.22 g, 4.8 mmol)obtained in reference example 24 was dissolved in thionyl chloride (5.0 ml). To the resulting solution was added a catalytic amount of dimethylformamide and the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added 1,4-dioxane, and then concentrated.

The obtained residue was dissolved in dimethylformamide (10 ml). To the resulting solution under nitrogen atmosphere was added 4-fermentation (730 mg, 5.7 mmol) and potassium carbonate (2,07 g, 15 mmol). The mixture was stirred at room temperature for 24 hours. To the reaction mixture were added diethyl ether (120 ml). The resulting mixture was washed with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The remainder of crystalliza the Ali in ethanol to obtain specified in the title compound (95 mg, 49%) as needle crystals.

1H-NMR (400 MHz, CDCl3)δ: of 5.92 (1H, s), 6,94? 7.04 baby mortality (4H, m), 7,19 (1H, m), 7,33 to 7.4 (2H, m), EUR 7.57 (1H, s), with 8.33 (1H, s).

IR (ATR) cm-1: 1571, 1489, 1329, 1222, 1157, 1109, 835.

TPL: 95-97°C.

MS m/z: 400 (M++H).

Example 214:[5-Chloro-4-[(2,5-differenl)-(4-perpenicular)methyl]pyridine-2-yl] (3,4-dimethoxybenzyl)Amin

[Chemical formula 100]

A solution of 2,5-dichloro-4-[(2,5-differenl)-(4-forfinally)methyl]pyridine (740 mg, of 1.85 mmol) and 3,4-dimethoxyaniline (836 μl, 5,55 mmol) in 1,4-dioxane (3.0 ml) was stirred at 120°C for 3 days in an atmosphere of argon in a sealed tube. After cooling to room temperature, to the reaction mixture were added ethyl acetate (80 ml). The resulting mixture was washed with saturated saline solution, dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain compound amine (235 mg) as oil.

The compound obtained was dissolved in methanol (9.0 ml). To the solution was added tetrahydrate hexaminolevulinate (30 mg) and 30% aqueous hydrogen peroxide solution (3.0 ml). The resulting mixture was stirred at room temperature for 20 hours. After dilution with ethyl acetate (80 ml) of the diluted solution was washed with water and saturated saline solution, dried and the concentration of Aravali under reduced pressure. To the obtained residue were added ethanol and after crystallization has been specified in the title compound (159 mg, 15%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: to 3.89 (6H, s), 4,50 (2H, m), 6,10 (1H, s), 6,85-7,05 (5H, m), 7,11 (2H, t, J=8,4 Hz), 7,25-to 7.35 (1H, m), 7,29 (1H, s), to 7.61 (2H, DD, J=5,2, 8,4), to 7.99 (1H, s).

IR (ATR) cm-1: 3249, 1589, 1490, 1236, 1147, 817.

TPL: 158-159°C.

MS m/z: 563 (M++H).

Example 215:[5-Chloro-4-[(2,5-differenl)-(4-perpenicular)methyl]pyridine-2-yl]amine

[Chemical formula 101]

[5-Chloro-4-[(2,5-differenl)-(4-perpenicular)-methyl]pyridine-2-yl] (3,4-dimethoxybenzyl)amine (157 mg, 0.28 mmol) was dissolved in triperoxonane acid (5.0 ml). The resulting solution was stirred at 65°C for 17 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, dried and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain the specified title compound (114 mg, 99%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: was 4.76 (2H, W), 6,12 (1H, s)6,91 (1H, m), 7,06 (1H, m), 7,14 (2H, t, J=8,4), 7,37 (1H, s), 7,53 (1H, m), 7,69 (2H, DD, J=48, and 8.4 Hz), 7,98 (1H, s).

IR (ATR) cm-1: 3456, 3167, 1639, 1591, 1491, 1417, 1327, 1238, 1140, 1084.

TPL: 157-159°C.

MS m/z: 413 (M++H).

Elemental Analysis for C18H12ClF3N2O2S. Calculated: C,52,37; H,2,93; Cl,8,59; F,13,81; N,6,79; S,To 7.77. Found: C,52,45; H,2,96; Cl,8,62; F,13,69; N,PC 6.82; S,7,83.

Example 216:N-[5-Chloro-4-[(2,5-differenl)-(4-perpenicular)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 102]

To a solution of [5-chloro-4-[(2,5-differenl)-(4-perpenicular)methyl]pyridine-2-yl]amine (114 mg, 0.276 mmol) in methylene chloride (10.0 ml) was added pyridine (440 μl, 5.5 mmol). To the mixture was added methanesulfonamide (adding 77 μl times a day for 3 days, 230 μl, 3.0 mmol). The resulting mixture was stirred in total for 4 days. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (hexane:ethyl acetate=2:1) and after crystallization in a simple broadcast received is listed in the title compound (51 mg, 38%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: at 3.35 (3H, s), to 6.19 (1H, s), 6,92 (1H, m), was 7.08 (1H, m), to 7.15 (2H, t, J=8,8 Hz)to 7.50 (1H, m), 7,73 (2H, m), of 8.00 (1H, s), 8,32 (1H, s).

MS m/z: 491 (M++H).

IR (ATR) cm-1: 1590, 1490, 1330, 1149, 968, 852. TPL: 178-179°C.

Elemental Analysis for C19H14ClF3N2O4S2. Calculated: C,46,49; H,2,87; N,5,71; S 13,06; Cl,7,22; F,Of 11.61. Found: C,46,55; H,2,96; N,5,73; S 13,02; Cl,7,13; F,Is 11.39.

Example 217:Optical separation of N-[5-chloro-4-[(2,5-differenl)(4-perpenicular)methyl]pyridine-2-yl]methanesulfonamide (optical isomer A; optical isomer B)

[Chemical formula 103]

N-[5-Chloro-4-[(2,5-differenl)(4-perpenicular)-methyl]pyridine-2-yl]methanesulfonamide obtained in example 216, subjected to optical separation under the conditions described below, using supercritical chromatography (Gilson) on a chiral column.

Column: CHIRALPAK AD, 2.0 cm × 25 cm, product of Daicel Chemical Industries, Ltd.

Mobile phase: 2-propanol:carbon dioxide=1:99 → 50:50 (three minutes, and then 50:50).

Flow rate: 6.0 ml/min

Pressure: 14 MPa.

Temperature: 35°C.

Detection: UV (254 nm).

The retention times and the data obtained for each optical isomer is shown below.

Optical isomer A: 16.3 minutes.

1H-NMR (400 MHz, CDCl3)δ: at 3.35 (3H, s), 6,18 (1H, s), 6.89 in-6,97 (1H, m), 7,02-7,10 (1H, m), 7,12-7,20 (2H, m), 7,47-rate of 7.54 (1H, m), 7,69-7,76 (2H, m), 7,83 (1H, Shir. C)7,98 (1H, s), 8,32 (1H, s).

Optical isomer B: 18.4 minutes.

1H-NMR (400 MHz, CDCl3)δ: to 3.36 (3H, s), 6,18 (1H, s), 6,89-of 6.96 (1H, m), 7,02-7,10 (1H, m), 7,12-7,20 (2H, m), 7,46-rate of 7.54 (1H, m), 7,69-7,76 (2H, m), to 7.99 (1H, s), 8,32 (1H, s).

[α]D25: +102,6 (c=0.5, CHCl3).

Example 218:Natrii what I salt of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 104]

To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanesulfonamide (15,1 g, to 29.8 mmol)obtained in example 197, in ethanol (100 ml) was added 1 N. aqueous sodium hydroxide solution (32,8 ml). The resulting mixture was concentrated under reduced pressure. To the obtained residue was added 2-propanol to dissolve therein residue when heated. The resulting solution was allowed to stand at room temperature. Besieged thus, the solid was collected by filtration to obtain specified in the connection header (9,10 g of 16.6 mmol, 56%).

1H-NMR (400 MHz,DMSO-d6)δ: and 2.79 (3H, s), 6,10 (1H, s), 7,14 (1H, s), 7.23 percent-7,40 (2H, m), of 7.48-EUR 7.57 (1H, m), to 7.68 (2H, d, J=8,8 Hz), of 7.75 (2H, d, J=8,8 Hz), 7,89 (1H, s).

IR (ATR) cm-1: 1583, 1494, 1463, 1384, 1326, 1230, 1151, 1108, 1089, 1012, 813, 755.

Elemental Analysis for C19H13N2O4Cl2F2S2Na·1,0H2O. Calculated: C,41,69; H,Was 2.76; N,5,12; Cl,12,95; F,6,94; S,11,72. Found: C,41,77; H,2,66; N,5,18; Cl,13,02; F,7,03; S,11,78.

Example 219:[5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 105]

A solution of 5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]-2-(3,4-dimethoxyphenethylamine)pyridine (1.89 g, of 3.45 mmol)obtained in example 185, triperoxonane acid (5 ml) was stirred the ri 65° C for 2 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution, then extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=2:1), concentrated under reduced pressure to obtain white solid. The obtained white solid was washed with hexane - simple ether and collected by filtration to obtain specified in the title compound (1.06 g, to 2.67 mmol, 77%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 4,50 (2H, s), 5,96 (1H, s)6,76 (1H, s), 6.90 to-7,10 (2H, m), 7,12-to 7.35 (5H, m), 8,02 (1H, s).

IR (ATR)cm-1: 3129, 1635, 1602, 1540, 1490, 1469, 1415, 1093, 1012, 819, 728.

MS m/z: 397 (M++H).

Example 220:N-[5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]-N-(methylsulphonyl)-methanesulfonamide (Compound A) and N-[5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]methanesulfonamide (Compound B)

[Chemical formula 106]

To a solution of [5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]pyridine-2-yl]amine (575 mg, 1,45 mmol) in pyridine (5 ml) was added at 0°C is ethanolgasoline (0,123 ml, to 1.59 mmol). The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture were added at 0°C methanesulfonanilide (0,123 ml of 1.59 mmol). The resulting mixture was stirred at room temperature for 22 hours. To the reaction mixture was added pyridine (3 ml), and then added methanesulfonamide (0,123 ml of 1.59 mmol) at 0°C. After stirring at room temperature for 25 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The diluted solution was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=4:1), concentrated under reduced pressure to obtain specified in the header of the connection A (iskopaemoe connection)(334 mg, 0,603 mmol, 42%) as an amorphous substance and are specified in the connection header B (high-polar compound)(269 mg, 0,566 mmol, 39%) as a white solid.

Connection A

1H-NMR (400 MHz, CDCl3)δ: of 3.56 (6H, s), 5,97 (1H, s), 6,95-to 7.09 (3H, m), 7,20-7,31 (4H, m), 7,76 (1H, s), to 8.45 (1H, s).

IR (ATR) cm-1: 1583, 1492, 1367, 1321, 1159, 1093, 1006, 962, 931, 821, 59.

MS m/z: 552 (M+).

Compound B

1H-NMR (400 MHz, CDCl3)δ: 3.15 in (3H, s), of 6.02 (1H, s), 6,94-7,13 (3H, m), 7,20-to 7.35 (4H, m), to 7.59 (1H, s), 8,07 (1H, Shir. C)8,30 (1H, s).

TPL: 149-151°C

IR (ATR) cm-1: 1590, 1556, 1488, 1475, 1380, 1348, 1149, 993, 962, 831, 784.

MS m/z: 475 (M++H).

FAB-MS: 474,9925 (Calculated for C19H15O2N2Cl2F2S2: 474,9920).

Elemental Analysis for C19H14N2O2Cl2F2S2. Calculated: C,48,01; H,2,97; N,Of 5.89; Cl,14,92; F,7,99; S,13,49. Found: C,48,27; H,2,95; N,5,91; Cl,14,79; F,Of 7.96; S,13,61.

Example 221:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 107]

To a solution of N-[5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]methanesulfonamide (331 mg, 0,696 mmol) in methylene chloride (10 ml) was added at 0°C 3-chloroperbenzoic acid (120 mg, 0,696 mmol). The resulting mixture was stirred at 0°C for 50 minutes. At the same temperature to the reaction mixture were added 3-chloroperbenzoic acid (60 mg, 0,348 mmol). After stirring at 0°C for 10 minutes to the reaction mixture were added saturated aqueous solution of sodium thiosulfate. The resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under decreased the pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=2:1), concentrated under reduced pressure. To the obtained residue was added a simple ether and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (281 mg, 0,572 mmol, 82%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: to 3.36 (3H, s), 5,48 (0,5H, s), 5,66 (0,5H, s), 6,79-6,88 (0,5H, m), 6,95-7,09 (1,5H, m), 7.18 in-7,44 (5H, m), of 7.64 (0,5H, s), 7,83 (0,5H, C)8,23 (0,5H, C)at 8.36 (0,5H, s), 8,70 (1H, Shir. C).

IR (ATR) cm-1: 3124, 3081, 1594, 1492, 1463, 1334, 1143, 964, 871, 821, 742.

MS m/z: 491 (M++H).

FAB-MS: 490,9853 (Calculated for C19H15O3N2Cl2F2S2: 490,9869).

Elemental Analysis for C19H14N2O3Cl2F2S2. Calculated: C,46,44; H,2,87; N,5,70; Cl,14,43; F,7,73; S Of 13.05. Found: C,46,64; H,To 3.02; N,5,64; Cl,14,31; F,7,74; S 13,02.

Example 222:[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]hydrazine

[Chemical formula 108]

To a solution of 2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine (524 mg, at 1.17 mmol)obtained in example 57, in ethanol (10 ml) was added hydrazine monohydrate (2 ml). The resulting mixture was heated at the boil under reflux for 3 hours. After cooling on the room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=1:1), concentrated under reduced pressure to obtain light yellow oil. To the obtained oil was added hexane - simple ether and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (95 mg, 0,214 mmol, 18%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: to 3.89 (2H, s), 6,03 (1H, s), 6,16 (1H, s), 6.89 in-6,97 (1H, m), 7,00-to 7.09 (1H, m), 7,44 (2H, d, J=8,8 Hz), 7,50-7,58 (1H, m), 7,60-to 7.68 (3H, m), 8,03 (1H, s).

IR (ATR) cm-1: 3249, 1590, 1550, 1492, 1413, 1315, 1174, 1149, 1083, 811, 754.

MS m/z: 443 (M+).

Elemental Analysis for C18H13N3O2Cl2F2S. Calculated: C,48,66; H,2,95; N,9,46; Cl,15,96; F,8,55; S,7,22. Found: C,48,48; H,Of 2.81; N,9,40; Cl,15,80,F, 8,59; S,7.23 Percent.

Example 223:tert-Butyl N'-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]hydrazinecarboxamide

[Chemical formula 109]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]hydrazine (166 mg, 0,374 mmol) in methylene chloride (5 ml) was added di-tert-BUTYLCARBAMATE (122 mg, 0,560 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to the Lee column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated under reduced pressure to obtain specified in the title compound (166 mg, 0,305 mmol, 82%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: is 1.51 (9H, s), to 6.19 (1H, s), 6.42 per (1H, s), 6,59 (1H, Shir. C)6,91-to 7.09 (2H, m), the 7.43 (2H, d, J=8,8 Hz), 7,50-7,56 (1H, m), EUR 7.57 (1H, s), 7,63 (2H, d, J=8,8 Hz), of 8.06 (1H, s).

IR (ATR) cm-1: 3336, 3295, 1681, 1596, 1558, 1496, 1477, 1321, 1151, 1091, 809.

MS m/z: 544 (M++H).

Example 224:tert-Butyl N'-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-N'-methylsulfonylbenzoyl

[Chemical formula 110]

To a solution in methylene chloride (5 ml) of tert-butyl N'-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]hydrazinecarboxamide (178 mg, 0,327 mmol) and triethylamine (43 μl, 0,392 mmol) was added methanesulfonamide (30 μl, 0,392 mmol) at 0°C. the resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture were added triethylamine (43 μl, 0,392 mmol) and methanesulfonamide (30 μl, 0,392 mmol). After stirring at room temperature for 3 hours the reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The diluted solution was washed successively with a saturated aqueous solution of bicarbonate n the sodium and saturated saline solution, was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=4:1), concentrated under reduced pressure to obtain specified in the title compound (174 mg, 0,280 mmol, 85%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 1.52 (9H, s), of 3.56 (3H, s), 6,21 (1H, s), 6,92-7,10 (2H, m), 7,31 (1H, Shir. C), 7,44 (2H, d, J=8.7 Hz), 7,47-rate of 7.54 (1H, m), 7,63 (2H, d, J=8.7 Hz), with 8.05 (1H, s), of 8.28 (1H, s).

IR (ATR) cm-1: 3320, 1731, 1583, 1494, 1353, 1326, 1236, 1149, 1091, 958, 754, 728.

MS m/z: 622 (M++H).

Example 225:1-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-1-methylsulfonylmethane

[Chemical formula 111]

To a solution of tert-butyl N'-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-N'-methylsulfonylbenzoyl (167 mg, 0,268 mmol) in methylene chloride (5 ml) was added triperoxonane acid (2.5 ml). The resulting mixture was stirred at room temperature for 21 hours, then concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with methylene chloride. The organic layer obtained by separation from the sewed over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=2:1), concentrated under reduced pressure to obtain specified in the title compound (91 mg, 0,174 mmol, 65%) as a white solid. The solid is washed with a simple ether and collected by filtration to obtain specified in the title compound (60 mg) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 3.25 (3H, s), 4,80 (2H, Shir. C), and 6.25 (1H, s), 6.90 to-7,10 (2H, m), 7,44 (2H, d, J=8.6 Hz), 7,53-to 7.61 (1H, m), to 7.68 (2H, d, J=8.6 Hz), 8,32 (1H, s), 8,44 (1H, s).

TPL: 152-154°C

IR (ATR) cm-1: 1583, 1490, 1361, 1319, 1149, 1079, 958, 833, 754.

MS m/z: 522 (M++H).

Elemental Analysis for C19H15N3O4Cl2F2S2. Calculated: C,43,69; H,2,89; N,8,04; Cl,13,57; F,7,27; S,To 12.28. Found: C,43,86; H,At 2.93; N,To $ 7.91; Cl,13,19; F,7,31; S,To 12.28.

Reference Example 41:2,5-Dibromo-4-[(2,5-differenl)-hydroxymethyl]pyridine

[Chemical formula 112]

n-Utility (1,59M solution in hexane, 76 ml, 121 mmol) was added in an argon atmosphere at -70°C to a solution of Diisopropylamine (17 ml, 121 mmol) in tetrahydrofuran (400 ml). The reaction mixture was stirred for 1 hour. To the reaction mixture was added dropwise a solution of 2,5-dibromopyridine in tetrahydrofuro the e (100 ml) and the resulting mixture was stirred for 2 hours. To the reaction mixture was added dropwise 2.5-differentally (15 ml, 139 mmol) and the mixture was stirred for 1 hour. After adding water, the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with dichloromethane:hexane to obtain pale yellow powder. The filtrate was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=6:1 was concentrated under reduced pressure. The obtained residue and the above light yellow powder was combined with obtaining specified in the connection header (18,4 g, to 48.6 mmol, 52%) as a pale yellow powder.

1H-NMR (400 MHz, CDCl3)δ: 2,62 (1H, s), 6,24 (1H, s), 6,85-6,89 (1H, m), 7,00-7,10 (2H, m), 7,79 (1H, s), 8,43 (1H, s).

MS m/z: 378 (M++H).

Example 226:2,5-Dibromo-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine

[Chemical formula 113]

The triethylamine (5.1 ml, to 36.8 mmol) and methanesulfonamide (2,6 ml, 31.9 per mmol) was added in an argon atmosphere under ice cooling to a solution of 2,5-dibromo-4-[(2,5-differenl)hydroxymethyl]pyridine (9.3 g, 24.5 mmol) in dichloromethane (200 ml). The reaction mixture was stirred at room temperature for 30 minutes. After the adding the water the resulting mixture was concentrated under reduced pressure. The obtained residue was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

To a solution of the obtained residue in dimethylformamide (200 ml) was added 4-chlorbenzoyl (4.3 g, 29.4 mmol) and potassium carbonate (5.1 g, to 36.8 mmol). The resulting mixture was stirred at room temperature for 17 hours. After addition of water the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was washed with hexane to obtain a white powder. The filtrate was subjected to column flash chromatography on silica gel. The fraction obtained by elution with dichloromethane, concentrated under reduced pressure. The obtained residue and the above white powder was combined with obtaining specified in the title compound (9.1 g, 18.0 mmol, 73%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 5,94 (1H, s), 7,00-7,05 (2H, m), 7,15-7,20 (1H, m), 7,25 (2H, d, J=8.6 Hz), 7,29 (2H, d, J=8.6 Hz), 7,68 (1H, s), to 8.45 (1H, s).

MS m/z: 504 (M++H).

Example 227:[5-Bromo-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]methanol

[Chemical formula 114]

n-Utility (1,59M R is the target in hexane, with 0.27 ml, 0,435 mmol) was added in an argon atmosphere to a solution of 2,5-dibromo-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine (200 mg, 0,396 mmol) in toluene (10 ml) at -78°C. the Reaction mixture was stirred for 2 hours. To the reaction mixture was added dropwise dimethylformamide (40 μl, 0,514 mmol) followed by stirring for 1 hour. To the reaction mixture were added methanol (10 ml) and borohydride sodium (30 mg, 0,791 mmol). The temperature of the mixture was raised to room temperature. The reaction mixture was stirred for 1 hour. After addition of water the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (160 mg, 0,350 mmol, 89%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 3,18 (1H, t, J=5,2 Hz), 4.72 in (2H, d, J=5,2 Hz), 6,04 (1H, s), 6,95-7,05 (2H, m), 7,16-7,21 (1H, m), 7,22 (2H, d, J=7.8 Hz), 7,25 (2H, d, J=7.8 Hz), 7,51 (1H, s)8,64 (1H, s).

MS m/z: 456 (M++H).

Example 228:[5-Bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanol

[Chemical formula 115]

img src="https://img.russianpatents.com/871/8718390-s.jpg" height="30" width="25" >

To a solution of [5-bromo-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]methanol (550 mg, 1.20 mmol) in a mixture of methanol (10 ml) and ethyl acetate (10 ml) was added tetrahydrate hexaminolevulinate (100 mg) and 30% aqueous hydrogen peroxide solution (10 ml). The resulting mixture was stirred for 19 hours. After addition of water the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium thiosulfate and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure, and then recrystallized from hexane:ethyl acetate to obtain specified in the title compound (506 mg, 1.04 mmol, 86%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,18 (1H, t, J=5.0 Hz), 4,79-4,88 (2H, m), 6,24 (1H, s), 6,92-6,97 (1H, m), 7.03 is-to 7.09 (1H, m), 7,45 (2H, d, J=8.6 Hz), 7,51-of 7.55 (1H, m), to 7.61 (2H, d, J=8.6 Hz), 8,11 (1H, s), 8,65 (1H, s).

IR (ATR) cm-1: 3262, 1583, 1492, 1427, 1392, 1330, 1280, 1236, 1157, 1083, 1033.

TPL: 172-173°C.

MS m/z: 488 (M++H).

Elemental Analysis for C19H13BrClF2NO3S. Calculated: C,46,69; H,2,68; Br,16,35; Cl,7,25; F,To 7.77; N,287; S,6,56. Found: C,46,59; H,2,55; Br,To 16.31; Cl,7,05; F,7,78; N,2,89; S 6,70.

Example 229:[5-Bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde

[Chemical formula 116]

Dimethyl sulfoxide (218 μl, of 3.07 mmol), triethylamine (428 μl, of 3.07 mmol) and a complex of a sulfur trioxide-pyridine (293 mg, of 1.84 mmol) was added under nitrogen atmosphere to a solution of [5-bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanol (300 mg, 0,614 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (227 mg, 0,466 mmol, 76%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 6.29 (1H, s), 6,93-7,00 (1H, m),? 7.04 baby mortality-7,10 (1H, m), 7,44 (2H, d, J=8,8 Hz), EUR 7.57 to 7.62 (1H, m), a 7.62 (2H, d, J=8,8 Hz), 8,68 (1H, s), 8,88 (1H, s), of 10.09 (1H, s).

MS m/z: 486 (M++H).

Example 230:5-Bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]picolina acid

[Chemical formula 117]

To a solution of [5-bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde (225 mg, 0.42 mmol) in formic acid (5 ml) was added 30% aqueous hydrogen peroxide solution (157 μl, of 1.39 mmol). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture were added water and the precipitated thus, the solid was filtered. The obtained solid substance was washed with water. The solid was dissolved in ethyl acetate. The resulting solution was washed successively with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (226 mg, 0,461 mmol, 97%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,30 (1H, s), 6,94-6,99 (1H, m), 7,05-7,11 (1H, m), 7,46 (2H, d, J=8,8 Hz), to 7.61-7,66 (1H, m), the 7.65 (2H, d, J=8,8 Hz), the rate of 8.75 (1H, s), to 8.94 (1H, s).

MS m/z: 502 (M++H).

Example 231:tert-Butyl [5-bromo-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]carbamate

[Chemical formula 118]

Diphenylphosphinite (131 μl, 0,613 mmol) and triethylamine (122 μl, 0,875 mmol) was added in an argon atmosphere to a solution of 5-bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pikolinos acid (220 mg, 0,438 mmol) in a mixture of tert-butanol (5 ml) and toluene (5 ml). The reaction mixture was stirred for 14 hours under heating and boiling under reflux. After cooling, to the resulting residue were added ethyl acetate. The resulting mixture was washed successively nassen the m aqueous solution of sodium bicarbonate and saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (128 mg, 0,223 mmol, 51%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 1.59 (9H, s), 6,23 (1H, s), 6,92-7,00 (1H, m), 7,02-was 7.08 (1H, m), 7,33 (1H, Shir. C)the 7.43 (2H, d, J=8,4 Hz), EUR 7.57 to 7.62 (1H, m), 7,71 (2H, d, J=8,4 Hz), of 8.28 (1H, s), 8,86 (1H, s).

MS m/z: 573 (M++H).

Example 232:[5-Bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 119]

To a solution of tert-butyl [5-bromo-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbamate (130 mg, 0,227 mmol) in ethanol (2 ml) was added concentrated hydrochloric acid (2 ml). The resulting mixture was stirred at room temperature for 63 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added a saturated solution of sodium bicarbonate, then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from hexane:ethyl acetate with what rucenim specified in the title compound (72 mg, 0,152 mmol, 67%) as a pale yellow powder.

1H-NMR (400 MHz, CDCl3)δ: of 4.67 (2H, s), 6,12 (1H, s), 6,91-6,97 (1H, m), 7,02-was 7.08 (1H, m), of 7.36 (1H, s), was 7.45 (2H, d, J=8.6 Hz), of 7.48-rate of 7.54 (1H, m), a 7.62 (2H, d, J=8.6 Hz), 8,11 (1H, s).

IR (ATR) cm-1: 3467, 3372, 1617, 1585, 1540, 1492, 1475, 1413, 1330, 1311, 1280, 1238, 1178, 1151, 1081, 1033, 1012.

TPL: 204-206°C.

MS m/z: 473 (M++H).

Elemental Analysis for C18H12BrClF2N2O2S. Calculated: C,45,64; H,2,55; Br,16,87; Cl,Of 7.48; F,8,02; N,5,91; S 6,77. Found: C,45,87; H,2,58; Br,16,61; Cl,7,56; F,With 8.05; N,5,90; S 6,90.

Reference Example 42:5-Cyano-2-forbindelse

[Chemical formula 120]

Diisopropylamine (2,80 ml of 19.8 mmol) was dissolved in tetrahydrofuran (20 ml). To the resulting solution was added dropwise at -78°C a solution of n-utility in hexane (1,60M, 11,4 ml, 18.2 mmol). The reaction mixture was stirred at the same temperature for 30 minutes and then was added dropwise a solution of 4-perbenzoate (2.00 g, 16.5 mmol) in tetrahydrofuran (20 ml). After stirring at the same temperature for another 30 minutes to the reaction mixture was added dropwise N,N-dimethylformamide (1.7 ml, 21.5 mmol). The reaction mixture was stirred at the same temperature for 10 minutes. To the reaction mixture was added acetic acid and saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate. The organic layers were combined, with the sewed over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=10:2, concentrated under reduced pressure to obtain specified in the connection header (1,83 g, 12.3 mmol, 74%) as a light yellowish-brown oil.

1H-NMR (400 MHz, CD3OD)δ: 7,37 (1H, t, J=9.0 Hz), 7,92 (1H, DDD, J=9,0,6,4,2,2 Hz), 8,21 (1H, DD, J=6,4,2,2 Hz), 10,4 (1H, s).

IR (ATR) cm-1: 1953, 1695, 1600, 1482, 1236, 1105, 846, 624, 580.

MS m/z: 150 (M++H).

Reference Example 43:3-[(2,5-Dichloropyridine-4-yl)hydroxymethyl]-4-perbenzoate

[Chemical formula 121]

Diisopropylamine (0,52 ml, 3,70 mmol) was dissolved in tetrahydrofuran (5 ml). To the resulting solution was added dropwise at -78°C a solution of n-utility in hexane (1,54M, 2,20 ml, 3,39 mmol). The reaction mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 2,5-dichloropyridine (0,46 g is 3.08 mmol) in tetrahydrofuran (20 ml). After stirring at the same temperature for another 1 hour to the reaction mixture was added dropwise a solution of 5-cyano-2-forventelige (0,46 g is 3.08 mmol) in tetrahydrofuran (5 ml). The resulting mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added us is on an aqueous solution of ammonium chloride, then was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=10:2, concentrated under reduced pressure to obtain specified in the title compound (0.68 g, 2.28 mmol, 74%) as a light yellowish-brown oil.

1H-NMR (400 MHz, CDCl3)δinstance: 6.33 (1H, s), 7,22 (1H, t, J=8,3 Hz), 7,60 (1H, DD, J=6,6 and 2.2 Hz), 7,66 (1H, s), 7,66-of 7.69 (1H, m), a 8.34 (1H, s).

IR (ATR) cm-1: 3413, 1577, 1492, 1334, 1247, 1110, 829, 534.

MS m/z: 297 (M++H).

Example 233:3-[(4-Chlorophenylsulfonyl)(2.5-dichloropyridine-4-yl)methyl]-4-perbenzoate

[Chemical formula 122]

Thionyl chloride (3 ml) and a catalytic amount of N,N-dimethylformamide was added under ice cooling to a solution of 3-[(2,5-dichloropyridine-4-yl)hydroxymethyl]-4-perbenzoate (677 mg, 2.28 mmol) in dichloromethane (5 ml). The resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture was added water, then was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

The obtained residue was dissolved in NN-dimethylformamide (5 ml). To the resulting solution were added 4-chlorobenzenesulfonate sodium (905 mg, 4,56 mmol). The mixture was stirred at room temperature for 20 hours. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=10:2, concentrated under reduced pressure to obtain specified in the title compound (170 mg, of 0.37 mmol, 16%) as a light tan solid.

1H-NMR (400 MHz, CDCl3)δ: to 6.19 (1H, s), to 7.15 (1H, t, J=8.5 Hz), of 7.48 (2H, d, J=8.5 Hz), a 7.62 (2H, d, J=8.5 Hz), 7,72 (1H, DDD, J=8,5, 5,4, 2,4 Hz)to 8.12 (1H, DD, J=5,4, 2.4 Hz), 8,13 (1H, s), at 8.36 (1H, s).

IR (ATR) cm-1: 1569, 1494, 1315, 1257, 1120, 1081, 752, 617, 570, 536.

MS m/z: 456 (M+).

Example 234:3-[(2-Amino-5-chloropyridin-4-yl)(4-chlorophenylsulfonyl)methyl]-4-perbenzoate

[Chemical formula 123]

3-[(4-Chlorobenzenesulfonyl)(2.5-dichloropyridine-4-yl)methyl]-4-perbenzoate (559 mg, of 1.23 mmol) was dissolved in N-organic (12 ml)and then was added 3,4-dimethoxyphenethylamine (of 0.91 ml, 6,13 mmol). The resulting mixture was stirred under heating at 140°C for 4 hours. To the reaction mixture add the Yali water, then was extracted with ethyl acetate. The extract was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=2:1 was concentrated under reduced pressure.

The obtained residue was dissolved in triperoxonane acid (5 ml) and the resulting solution was stirred under heating at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain specified in the title compound (50 mg, 0.11 mmol, 9%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 4,74 (2H, s), 6,16 (1H, s), 7,12 (1H, t, J=8,8 Hz), 7,32 (1H, s)of 7.48 (2H, d, J=8.5 Hz), a 7.62 (2H, d, J=8.5 Hz), 7,98 (1H, s), 8,15 (1H, DD, J=8,8, 2.0 Hz), 8,55 (1H, d, J=2.0 Hz).

IR (ATR) cm-1: 1614, 1475, 1411, 1311, 1259, 1145, 1091, 755, 642, 620, 561, 543, 460.

TPL: >220°C.

MS m/z: 436 (M++H).

Elemental Analysis for C19H12Cl2FN3O2S. Calculated: C,52,31; H,2,77; Cl,16,25; F,Of 4.35; N,9,63; S,7,35. Found: C,52,17; H,2,85; Cl,16,50; F,4,32; N,9,40; S,7,30.

Example 235:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-forfinal)methyl]pyridi the-2-yl]-N-(methylsulphonyl)-methanesulfonamide

[Chemical formula 124]

3-[(2-Amino-5-chloropyridin-4-yl)(4-chlorophenylsulfonyl)-methyl]-4-perbenzoate (50 mg, 0.11 mmol) was dissolved in dichloromethane (5 ml), and then to the resulting solution were added at 0°C acanaloniidae (27 μl, 0,39 mmol), triethylamine (48 μl, 0,39 mmol) and a catalytic amount of 4-dimethylaminopyridine. The resulting mixture was stirred at the same temperature for 30 minutes. Added water and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=10:3 was concentrated under reduced pressure to obtain specified in the title compound (80 mg, 0.11 mmol, 99%) as a white powder.

1H-NMR (400 MHz, CDCl4)δ: the 3.65 (6H, s), and 6.25 (1H, s), from 7.24 (1H, t, J=8,8 Hz), was 7.45 (2H, d, J=8.5 Hz), 7,66 (2H, d, J=8.5 Hz), of 7.75 (1H, DDD, J=8,8, 6,6, 2.0 Hz), 8,16 (1H, s), 8,19 (1H, DD, J=6,6, 2.0 Hz), 8,43 (1H, s).

IR (ATR) cm-1: 1725, 1583, 1492, 1369, 1326, 1164, 931, 835, 757, 628, 551, 505, 460.

MS m/z: 592 (M++H).

Example 236:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-forfinal)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 125]

N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(5-cyano-2-forfinal)methyl]pyridine-2-yl]-N-(methylsulphonyl)-methanesulfonamide (80 mg, 0.11 mmol) was dissolved in tetrahydrofuran (3 ml), and then to the resulting solution at 0°C was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1,0M, 0.15 ml, 0.15 mmol). The resulting mixture was stirred at room temperature for 1 hour. The residue obtained by concentration of the reaction mixture under reduced pressure was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of n-hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain white solid. The obtained white solid was washed with simple ether to obtain specified in the title compound (32 mg, 0.06 mmol, 46%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,37 (3H, s), of 6.20 (1H, s), 7,14 (1H, d, J=8,8 Hz), of 7.48 (2H, d, J=8.5 Hz), a 7.62 (2H, d, J=8.5 Hz), 7.68 per-7,72 (1H, m), 7,92 (1H, s), 8,11 (1H, DD, J=6,6, 2.0 Hz), a 8.34 (1H, s).

IR (ATR) cm-1: 1596, 1494, 1473, 1328, 1151, 1089, 755, 636, 541, 516.

TPL: 118-120°C.

MS m/z: 514 (M++H).

Elemental Analysis for C20H14Cl2FN3O4S2. Calculated: C,46,70; H,2,74; Cl,13,78; F,Of 3.69; N,8,17; S,12,47. Found: C,47,00; H,2,94; Cl,13,64; F,To 3.58; N,8,15; S,To 12.44.

Reference Example 44:5-Chloro-2-(of 2.2.5.5-tetramethyl-1,2,5-azodivaleric-1-yl)pyridine

[Chemical formula 126]

To a solution of 5-chloropyridin-2-ylamine (10,28 g, 80,0 mmol) in tetrahydrofuran (350 ml) was added at -78°C a solution of n-utility in hexane (1,58M, and 50.6 ml, 80,0 mmol). The resulting mixture was stirred for 1 hour. At the same temperature to the reaction mixture solution was added 1,2-bis(chlorodimethylsilyl)ethane (17,22 g, 80,0 mmol) in tetrahydrofuran (50 ml) followed by stirring for 1 hour. At the same temperature was added a solution of n-utility in hexane (1,58M, and 50.6 ml, 80,0 mmol) and the resulting mixture was stirred for 30 minutes. At room temperature, to the reaction mixture were added saturated aqueous solution of sodium chloride. To the mixture was added diethyl ether to separate the mixture into layers. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to distillation under reduced pressure (120°C/3,0 MND) obtaining specified in the connection header (12,97 g of 47.9 mmol, 60%) as a colourless substance in the form of needle crystals.

1H-NMR (400 MHz, CDCl3)δ: 0,29 (12H, s)of 0.82 (4H, s), of 6.50 (1H, d, J=8,8 Hz), 7,34 (1H, DD, J=8,8, 2.7 GHz), with 8.05 (1H, d, J=2.7 Hz).

Reference Example 45:(2-Amino-5-chloropyridin-4-yl)(2,5-differenl)methanol

[Chemical formula 127]

To a mixture solution of n-utility in hexane (1,5M, to 8.41 ml, 13.3 mmol) and tetrahydrofuran (40 ml) was added Diisopropylamine (of 1.86 ml, 13.3 mmol) at -78°C. the resulting mixture was stirred at 0°C for 1 hour, then the reaction mixture was cooled to -78°C. To the reaction mixture was added a solution of 5-chloro-2-(of 2.2.5.5-tetramethyl-1,2,5-azodivaleric-1-yl)pyridine (3,27 g, 12.1 mmol) in tetrahydrofuran (10 ml). The resulting mixture was stirred at the same temperature for 1 hour. Then to the reaction mixture was added a solution of 2,5-diferentialglea (1.89 g, 13.3 mmol) in tetrahydrofuran (10 ml). After stirring at the same temperature for 30 minutes was added at 0°C 1 n hydrochloric acid (50 ml). To the reaction mixture were added 1 N. aqueous solution (100 ml) of sodium hydroxide. The resulting product was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixture of solvents dichloromethane/hexane and collected by filtration to obtain specified in the connection header (1,76 g of 6.50 mmol, 54%) as a white solid.

1H-NMR (400 MHz,DMSO-d6)δ: 5,96 (1H, d, J=4.9 Hz), 6,17 (2H, s), of 6.31 (1H, d, J=4.9 Hz), of 6.68 (1H, s), 6,97? 7.04 baby mortality (1H, m), 7,15-7,29 (2H, m), 7,82 (1H, s).

MS m/z: 271 (M++H).

Reference Example 46:(2-Amino-5-chloropyridin-4-yl)(2,5-differenl)methyl Tr is t-BUTYLCARBAMATE

[Chemical formula 128]

Di-tert-BUTYLCARBAMATE (3,63 g of 16.6 mmol) and 4-dimethylaminopyridine (203 mg, of 1.66 mmol) was added under nitrogen atmosphere at room temperature to a solution of (2-amino-5-chloropyridin-4-yl)(2,5-differenl)methanol (4,50 g of 16.6 mmol) in dichloromethane (150 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=50:1 was concentrated under reduced pressure to obtain specified in the connection header (5,70 g of 15.4 mmol, 92%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: for 1.49 (9H, s), a 4.53 (2H, s), of 6.66 (1H, s), 6.89 in-6,95 (1H, m), 6,99-to 7.09 (2H, m), 7,00 (1H, s), 8,01 (1H, s).

MS m/z: 371 (M++H).

Reference Example 47:tert-Butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate

[Chemical formula 129]

A solution of bis(trimethylsilyl)amide sodium in tetrahydrofuran (1M, to 33.8 ml, 33.8 mmol) was added under nitrogen atmosphere at 0°C to a solution of (2-amino-5-chloropyridin-4-yl)(2,5-differenl)methyl tert-BUTYLCARBAMATE (5,70 g of 15.4 mmol) in tetrahydrofuran (80 ml) followed by a solution of di-tert-BUTYLCARBAMATE (of 3.69 g of 16.9 mmol in tetrahydrofuran (20 ml). After stirring at room temperature for 30 minutes to the reaction mixture were added saturated aqueous solution of ammonium chloride. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

The obtained residue was dissolved in a mixture solvent of tetrahydrofuran (50 ml) and methanol (50 ml). To the resulting solution were added at room temperature and 1 n sodium hydroxide solution (50 ml). The resulting mixture was stirred at 50°C for 2 hours and concentrated under reduced pressure. The resulting product was extracted with dichloromethane. The residue was washed with a mixture solvent of ethanol/hexane and collected by filtration to obtain specified in the connection header (3,49 g, 9,41 mmol, 61%) as a white solid. The filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of ethanol/diethyl ether/hexane and collected by filtration to obtain specified in the connection header (828 mg, of 2.23 mmol, 15%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: and 1.54 (9H, s), 2,69 (1H, d, J=4.9 Hz), 6,32 (1H, d, J=4.9 Hz), 6,88-was 7.08 (3H, m), 7,81 (1H, s), 8,17 (1H, s), with 8.33 (1H, s).

MS m/z: 371 (M++H).

Reference Example 48:O-Ethyl S-(4-chloro-3-methoxyphenyl) dithiocarbonate

[Chemical formula 130]

1 N. hydrochloric acid(80 ml) was dissolved 4-chloro-3-methoxyaniline (2,77 g, 17.6 mmol). To the resulting solution was added dropwise at 0°C aqueous solution (10 ml) of sodium nitrite (1,33 g, and 19.3 mmol), then the reaction mixture was stirred at the same temperature for 30 minutes. The temperature of the reaction mixture was raised to 60°C. At the same temperature to the reaction mixture was added dropwise an aqueous solution (30 ml) O-utilityservice potassium (3,10 g, and 19.3 mmol). The temperature of the reaction mixture was raised to 90°C. After stirring for 1 hour the reaction mixture was cooled to room temperature. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:dichloromethane=9:1 was concentrated under reduced pressure to obtain specified in the connection header (of 1.05 g, 4.00 mmol, 23%) as a yellow oil.

1H-NMR (400 MHz, CDCl3)δ: of 1.35 (3H, t, J=7,1 Hz), 3,91 (3H, s), to 4.62 (2H, square, J=7,1 Hz), 7.03 is-was 7.08 (2H, m), 7,41 (1H, d, J=8,1 Hz).

MS m/z: 263 (M++H).

Example 237:t is et-Butyl [5-chloro-4-[(4-chloro-3-methoxybenzylthio)(2.5-differenl)methyl]pyridine-2-yl]carbamate

[Chemical formula 131]

To a solution of O-ethyl S-(4-chloro-3-methoxyphenyl)dithiocarbonate (394 mg, 1.50 mmol) in ethanol (5 ml) was added 1 N. aqueous sodium hydroxide solution (5 ml). The resulting mixture was heated at the boil under reflux for 1 hour. After cooling the reaction mixture to room temperature, the ethanol drove away under reduced pressure. The residue was washed with dichloromethane. The aqueous layer was acidified with acetic acid. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 4-chloro-3-methoxybenzoyl in the form of a colorless oil.

To a solution of tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (371 mg, 1.00 mmol)obtained in reference example 47, in dichloromethane was added at 0°C methanesulfonanilide (0,155 ml, 2.00 mmol)and then triethylamine (0,418 ml, 3.00 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the residue in N,N-dimethylformamide (10 ml) successively add the Yali in the atmosphere of nitrogen a solution of N,N-dimethylformamide (5 ml) of 4-chloro-3-methoxybenzoyl, obtained as above, and potassium carbonate (207 mg, 1.50 mmol). The resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=19:1 was concentrated under reduced pressure to obtain specified in the title compound (354 mg, 0.67 mmol, 67%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 1.55 (9H, s), 3,81 (3H, s), 6,07 (1H, s), 6,91-was 7.08 (3H, m), 6,97 (1H, DD, J=7,8, 2.0 Hz), 7,00 (1H, d, J=2.0 Hz), 7.23 percent (1H, d, J=7.8 Hz), 7,86 (1H, s), 8,18 (1H, s), 8,55 (1H, s).

MS m/z: 527 (M++H).

Example 238:tert-Butyl [5-chloro-4-[(4-chloro-3-methoxybenzenesulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbamate

[Chemical formula 132]

To a solution of tert-butyl [5-chloro-4-[(4-chloro-3-methoxybenzylthio)(2.5-differenl)methyl]pyridine-2-yl]carbamate (354 mg, 0.67 mmol) in ethyl acetate (8 ml) was added methanol (8 ml), 31% aqueous hydrogen peroxide solution (8 ml) and tetrahydrate hexaminolevulinate (166 mg, 0.13 mmol). The resulting mixture was stirred at room Tempe is the atur for 20 hours. To the reaction mixture were added water and ethyl acetate and methanol drove away under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under reduced pressure. The obtained residue was washed with a mixture of solvents diethyl ether/hexane and collected by filtration to obtain specified in the title compound (308 mg, 0.55 mmol, 82%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: was 1.58 (9H, s), 3,82 (3H, s), 6,27 (1H, s), 6,94-to 7.09 (2H, m), 7,24 (1H, d, J=2.0 Hz), was 7.36 (1H, DD, J=8,3, 2.0 Hz), 7,46 (1H, d, J=8,3 Hz), 7,56 to 7.62 (2H, s), 8,18 (1H, s)8,89 (1H, s).

MS m/z: 559 (M++H).

Example 239:[5-Chloro-4-[(4-chloro-3-methoxybenzenesulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 133]

To a solution of tert-butyl [5-chloro-4-[(4-chloro-3-methoxybenzenesulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbamate (300 mg, 0.54 mmol) in dichloromethane (5 ml) was added at 0°C triperoxonane acid (5 ml). The resulting mixture was stirred at room temperature for the of 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with 1 N. aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether and then collected by filtration to obtain specified in the title compound (208 mg, 0.45 mmol, 84%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: is 3.82 (3H, s), of 4.66 (2H, s), 6,14 (1H, s), 6,91-6,98 (1H, m), 7,02-to 7.09 (1H, m), to 7.09 (1H, d, J=2.0 Hz), 7,25 (1H, DD, J=8,3, 2.0 Hz), 7,34 (1H, s), 7,46 (1H, d, J=8,3 Hz), 7,51-EUR 7.57 (1H, s), 7,99 (1H, s).

IR (ATR) cm-1: 3151, 1645, 1595, 1481, 1414, 1390, 1325, 1254, 1140, 1055, 1026.

TPL: 198-200°C.

Elemental Analysis for C19H14Cl2F2N2O3S. Calculated: C,49,69; H,3,07; Cl,15,44,F, Of 8.27; N,6,10; S 6,98. Found: C,49,56; H,3,03; Cl,15,29; F,8,58; N,Between 6.08; S,7,07.

MS m/z: 459 (M++H).

Example 240:[5-Chloro-4-[(2,5-differenl)(4-methoxybenzenesulfonyl)methyl]pyridine-2-yl]amine

[Chemical formula 134]

To a solution of tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (148 mg, 0.40 mmol)obtained in reference example 47, in dichloromethane was added methanesulfonamide (0,046 ml of 0.60 mmol)and then triethylamine (0,167 ml, 1.20 mmol) at 0°C. the resulting mixture is PE is amasyali at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in N,N-dimethylformamide (4 ml) was added under nitrogen atmosphere 4-methoxybenzoyl (56 mg, 0.40 mmol)and then potassium carbonate (66 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 19 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in ethyl acetate (8 ml) was added methanol (8 ml), 31% aqueous hydrogen peroxide solution (4 ml) and tetrahydrate hexaminolevulinate (99 mg, 0.08 mmol). The resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture were added water. The ethyl acetate and methanol drove away under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in chlormethine (3 ml) was added at 0° C triperoxonane acid (3 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:2, was concentrated under reduced pressure. The residue was washed with a mixture of solvents diethyl ether/hexane and then collected by filtration to obtain specified in the title compound (67 mg, 0.16 mmol, 40%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: a 3.87 (3H, s), 4,63 (2H, s), 6,10 (1H, s), 6.87 in-6,94 (1H, m), of 6.90 (2H, d, J=8,8 Hz), 6,98-7,06 (1H, m), 7,31 (1H, s), 7,51-EUR 7.57 (1H, m), to 7.59 (2H, d, J=8,8 Hz), of 7.97 (1H, s).

IR (ATR) cm-1: 3469, 3294, 3172, 1630, 1593, 1491, 1419, 1327, 1261, 1244, 1230, 1142, 1092.

TPL: 153 to 155°C.

Elemental Analysis for C19H15ClF2N2O3S. Calculated: C,53,71; H,3,56; Cl,8.34 Per; F,To 8.94; N,6,59; S,At 7.55. Found: C,53,53; H,3,55; Cl,8.34 Per; F,9,06; N,Of 6.31; S,7,79.

MS m/z: 425 (M++H).

Example 241:[5-Chloro-4-[(5-chloropyridin-2-ylsulphonyl)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 135]

In the same manner as in example 240, the received specified in the title compound (74 mg, 0,17 mmol, 43%) as a white solid, using tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (148 mg, 0.40 mmol)obtained in reference example 47, 5-chloro-2-pyridinethiol (58 mg, 0.40 mmol)obtained in reference example 17.

1H-NMR (400 MHz, CDCl3)δ: to 4.62 (2H, s), 6,77 (1H, s), 6,95-was 7.08 (2H, m), 7,28 (1H, s), 7,40-7,47 (1H, m), 7,82-to 7.84 (2H, m), of 8.00 (1H, s), 8,68-to 8.70 (1H, m).

IR (ATR) cm-1: 3427, 3317, 3199, 1635, 1491, 1477, 1327, 1238, 1163, 1113, 1018.

TPL: 187-189°C.

Elemental Analysis for C17H11Cl2F2N3O2S. Calculated: C,To 47.46; H,2,58; Cl,16,48; F,8,83; N,9,77; S,7,45. Found: C,47,43; H,2,64; Cl,16,52; F,8,98; N,RS 9.69; S,7,71.

MS m/z: 430 (M++H).

Example 242:N-[5-Chloro-4-[(5-chloropyridin-2-ylsulphonyl)-(2,5-differenl)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 136]

A solution of bis(trimethylsilyl)amide, sodium (1M, 0,705 ml, 0.71 mmol) in tetrahydrofuran was added in an argon atmosphere at 0°C to a solution of [5-chloro-4-[(5-chloropyridin-2-ylsulphonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (92 mg, 0.21 mmol) in tetrahydrofuran (4 ml). The resulting mixture was stirred for 30 minutes. To the reaction mixture was added methanesulfonamide (by 0.055 ml, 0.71 mmol). The resulting mixture was stirred at the given temperature T. the value of 2 hours. The temperature of the reaction mixture was then raised to room temperature. To the reaction mixture were added saturated aqueous solution of ammonium chloride. The resulting product was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:ethyl acetate=19:1 was concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of ethanol/hexane and then collected by filtration to obtain specified in the title compound (27 mg, 0,053 mmol, 25%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 3.32 (3H, s)6,86 (1H, s), 6,98-to 7.09 (2H, m), of 7.36-the 7.43 (1H, m), of 7.75 (1H, s), a 7.85 (1H, DD, J=8,3, 2.2 Hz), of 7.90 (1H, d, J=8,3 Hz), to 7.93 (1H, s), 8,32 (1H, s), 8,67 (1H, d, J=2.2 Hz).

IR (ATR) cm-1: 1603, 1568, 1493, 1389, 1329, 1240, 1144, 1109.

TPL: 214-216°C.

Elemental Analysis for C18H13Cl2F2N3O4S2. Calculated: C,42,53; H,2,58; Cl,13,95; F,7,47; N,8,27; S Br12.62. Found: C,42,56; H,2,56; Cl,14,03; F,Rate Of 7.54; N,8,23; S,12,58.

MS m/z: 508 (M++H).

Reference Example 49:5-Chlorothiophene-2-thiol

[Chemical formula 137]

To a solution of 5-chlorothiophene-2-sulphonylchloride (0,557 ml, 4.00 mmol) in acetic acid (1 ml) was added a solution of tin chloride (II) 1 N. hydrochloric acid (3 ml) (3.03 g, 16.0 mmol) at 75°C. the Reaction mixture was cooled to room temperature, and then to the mixture was added water. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. To the obtained residue was added toluene, and then concentrated under reduced pressure. The obtained residue was washed with diethyl ether and collected by filtration to obtain specified in the title compound (98 mg, of 0.65 mmol, 16%) as a yellow solid. The filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixture of solvents diethyl ether/hexane and collected by filtration to obtain specified in the title compound (118 mg, 0.78 mmol, 20%) as a yellow solid.

1H-NMR (400 MHz, CDCl3)δ: for 6.81 (1H, d, J=3,9 Hz), 6,85 (1H, d, J=3,9 Hz).

Example 243:[5-Chloro-4-[(5-chlorothiophene-2-ylsulphonyl)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 138]

In the same manner as in example 240, the received specified in the title compound (96 mg, 0.22 mmol, 55%) as a white solid, using tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (148 mg, 0.40 mmol)obtained in sulochna example 47, and 5-chlorothiophene-2-thiol (90 mg, of 0.60 mmol).

1H-NMR (400 MHz, CDCl3)δ: of 4.66 (2H, s), and 6.25 (1H, s), 6,93 (1H, d, J=4, 2 Hz), 6,97-7,11 (2H, m), 7,28 (1H, s), 7,29 (1H, d, J=4, 2 Hz), 7,47-7,53 (1H, m), 8,02 (1H, s).

IR (ATR)cm-1: 3438, 3180, 1643, 1595, 1543, 1485, 1404, 1315, 1242, 1138, 993.

TPL: 170-171°C.

Elemental Analysis for C16H10Cl2F2N2O2S2. Calculated: C,44,15; H,2,32; Cl,16,29; F,8,73; N,6,44; S,14,73. Found: C,44,22; H,2,41; Cl,16,00; F,8,77; N,6,46; S,14,81.

MS m/z: 435 (M++H).

Example 244:tert-Butyl [5-chloro-4-[(6-chloropyridin-3-ylthio)(2.5-differenl)methyl]pyridine-2-yl]carbamate

[Chemical formula 139]

In the same manner as in example 237, got mentioned in the title compound (190 mg, 0.38 mmol, 94%) as a white solid using O-ethyl S-(6-chloropyridin-3-yl)dithiocarbonate (187 mg, 0.80 mmol)obtained in reference example 26, and tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (151 mg, 0.41 mmol)obtained in reference example 47.

1H-NMR (400 MHz, CDCl3)δ: of 1.56 (9H, s), 6,01 (1H, s), 6,93-was 7.08 (3H, m), 7,22 (1H, d, J=8,3 Hz), 7,42 (1H, s), 7,71 (1H, DD, J=8,3, 2,5 Hz), 8,16 (1H, s)of 8.37 (1H, d, J=2,5 Hz)and 8.50 (1H, s).

MS m/z: 498 (M++H).

Example 245:[5-Chloro-4-[(6-chloropyridin-3-ylsulphonyl)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 140]

To a solution of tert-butyl [5-chloro-4-[(6-chloropyridin-ylthio)(2.5-differenl)methyl]pyridine-2-yl]carbamate (187 mg, 0.38 mmol) in dichloromethane (5 ml) was added at room temperature 3-chloroperbenzoic acid (199 mg, 0.75 mmol). The resulting mixture was stirred for 2 hours. The reaction mixture was washed with 1 N. aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

The obtained residue was dissolved in dichloromethane (3 ml). When 0°C was added triperoxonane acid (3 ml) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was washed with 1 N. aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of ethanol/hexane and collected by filtration to obtain specified in the title compound (90 mg, 0.21 mmol, 55%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: and 4.68 (2H, s), x 6.15 (1H, s), 6,93-7,00 (1H, m), 7,05 for 7.12 (1H, m), 7,29 (1H, s), 7,44 (1H, d, J=8,3 Hz), of 7.48-rate of 7.54 (1H, m)and 7.1 (1H, DD, J=8,3, 2.4 Hz), 8,01 (1H, s), 8,58 (1H, d, J=2,4 Hz).

IR (ATR) cm-1: 3342, 3167, 1495, 1479, 1331, 1240, 1161, 1115.

TPL: 157-158°C.

Elemental Analysis for C17H11Cl2F2N3O2S. Calculated: C,To 47.46; H,2,58; Cl,16,48; F,8,83; N,9,77; S,7,45. Found: C,Is 47.24; H,2,59; Cl,16,50; F,8,80; N,9,82; S,To 7.61.

MS m/z: 430 (M++H).

Example 246:4-[(2-Amino-5-chloropyridin-4-yl)(2,5-differenl)methylsulphonyl]benzonitrile

[Chemical formula 141]

In the same manner as in example 240, the received specified in the title compound (99 mg, 0.24 mmol, 59%) as a white solid, using tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (148 mg, 0.40 mmol)obtained in reference example 47, 4-mercaptobenzoic (56 mg, 0.41 mmol).

1H-NMR (400 MHz, CDCl3)δ: and 4.68 (2H, s), x 6.15 (1H, s), 6,89-of 6.96 (1H, m), 7.03 is-7,10 (1H, m), 7,31 (1H, s), 7,49-of 7.55 (1H, m), 7,76 (2H, d, J=8.5 Hz), 7,81 (2H, d, J=8.5 Hz), to 7.99 (1H, s).

IR (ATR) cm-1: 3388, 1618, 1495, 1415, 1331, 1149.

TPL: 233-235°C.

Elemental Analysis for C19H12ClF2N3O2S. Calculated: C,54,36; H,2,88; Cl,8,44; F,9,05; N,10,01; S Of 7.64. Found: C,54,41; H,2,93; Cl,To 8.41; F,Of 8.92; N,9,92; S,7,69.

MS m/z: 420 (M++H).

Example 247:[5-Chloro-4-[(2,5-differenl)(3,4-differentiality)methyl]pyridine-2-yl]amine

[Chemical formula 142]

In the same manner as in example 240, received the decree of the TES in the title compound (59 mg, 0.14 mmol, 27%) as a white solid, using tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (185 mg, 0.50 mmol)obtained in reference example 47, and 3,4-differentation (84 mg, 0.55 mmol).

1H-NMR (400 MHz, CDCl3)δ: of 4.67 (2H, s), 6,13 (1H, s), 6,91-6,98 (1H, m), 7.03 is-7,10 (1H, m), 7.23 percent-7,31 (1H, m), 7,31 (1H, s), 7,45-of 7.55 (3H, m), of 8.00 (1H, s).

IR (ATR) cm-1: 3452, 3168, 1635, 1599, 1493, 1415, 1325, 1281, 1244, 1144, 1120.

TPL: 140-141°C.

Elemental Analysis for C18H11ClF4N2O2S. Calculated: C,50,18; H,2.57 M; Cl,8,23; F,17,64; N,6,50; S,7,44. Found: C,50,12; H,2,60; Cl,8,25; F,Of 17.35; N,6,51; S,7,58.

MS m/z: 431 (M++H).

Example 248:N-[5-Chloro-4-[(2,5-differenl)(3,4-differentiality)methyl]pyridine-2-yl]-N-(methylsulphonyl)methanesulfonamide

[Chemical formula 143]

Methanesulfonanilide (0,034 ml, 0.44 mmol), triethylamine (holding 0.062 ml, 0.44 mmol) and 4-dimethylaminopyridine (4 mg, 0.03 mmol) under nitrogen atmosphere was added to a solution of [5-chloro-4-[(2,5-differenl)(3,4-differentiality)methyl]pyridine-2-yl]amine (63 mg, 0.15 mmol) in dichloromethane (3 ml) at 0°C. the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with 1 N. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Receiving the hydrated residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=3:1 was concentrated under reduced pressure to obtain specified in the title compound (73 mg, 0.12 mmol, 85%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 3,63 (6H, s), from 6.22 (1H, s), 7,02-7,16 (2H, m), 7,22-7,31 (1H, m), 7,45-7,51 (2H, m), 7,56 to 7.62 (1H, m), 8,17 (1H, s), to 8.45 (1H, s).

MS m/z: 587 (M++H).

Example 249:N-[5-Chloro-4-[(2,5-differenl)(3,4-differentiality)methyl]pyridine-2-yl]methanesulfonamide

[Chemical formula 144]

Solution (1M, 0,ml, 0.15 mmol) tetrabutylammonium in tetrahydrofuran was added under nitrogen atmosphere to a solution of N-[5-chloro-4-[(2,5-differenl)(3,4-differentiality)methyl]pyridine-2-yl]-N-(methylsulphonyl)methanesulfonamide (72 mg, 0.12 mmol) in tetrahydrofuran (2 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then the obtained residue was dissolved in ethyl acetate. The resulting solution was washed sequentially 1 N. a solution of hydrochloric acid and a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained when e is iravani a mixture of hexane:ethyl acetate=3:1, concentrated under reduced pressure. The obtained residue was washed with a mixture of solvents diethyl ether/hexane and collected by filtration to obtain specified in the title compound (53 mg, 0.10 mmol, 84%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: at 3.35 (3H, s), to 6.19 (1H, s), 6,92-6,99 (1H, m),? 7.04 baby mortality for 7.12 (1H, m), 7,25-to 7.32 (1H, m), 7,44-of 7.60 (3H, m), 7,98 (1H, s), to 7.99 (1H, s), a 8.34 (1H, s).

IR (ATR) cm-1: 1599, 1495, 1468, 1333, 1281, 1146, 1003, 970.

TPL: 118-120°C.

MS m/z: 509 (M++H).

FAB-MS: 509,0044 (Calculated for C19H14ClF4N2O4S2: 509,0020).

Reference Example 50:O-Ethyl S-(6-triptorelin-3-yl)dithiocarbonate

[Chemical formula 145]

After dissolving 6-triptorelin-3-ylamine (1,00 g of 6.02 mmol) in 1 N. hydrochloric acid (15 ml) and methanol (3 ml) to the resulting solution was added dropwise at -10°C aqueous solution (3 ml) of sodium nitrite (506 mg, 7.22 mmol). The reaction mixture was added dropwise to aqueous solution (15 ml) o-utilityservice potassium (1,93 g, 12,0 mmol), heatedup to 65°C. the Reaction mixture was stirred at the same temperature for 30 minutes. After cooling the reaction mixture to room temperature the product was extracted with ethyl acetate. The extract was washed with saturated saline solution. The organic layer was dried the hell anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=100:1 was concentrated under reduced pressure to obtain specified in the title compound (895 mg, 3.35 mmol, 56%) as a yellow oil.

1H-NMR (400 MHz, CDCl3)δ: to 1.38 (3H, t, J=7,1 Hz)and 4.65 (2H,q, J=7,1 Hz), 7,76 (1H, d, J=8.1 Hz), 8,01 (1H, DD, J=8,1, 2.0 Hz), 8,79 (1H, d, J=2.0 Hz).

MS m/z: 268 (M++H).

Example 250:[5-Chloro-4-[(2,5-differenl)(6-triptorelin-3-ylsulphonyl)methyl]pyridine-2-yl]amine

[Chemical formula 146]

To a solution of O-ethyl S-(6-triptorelin-3-yl) dithiocarbonate (160 mg, of 0.60 mmol) in ethanol (2 ml) was added 1 N. aqueous sodium hydroxide solution (2 ml). The resulting mixture was stirred at 65°C for 2 hours. After cooling the reaction mixture to room temperature, to the mixture was added water. The resulting mixture was washed with dichloromethane. The aqueous layer was acidified using 1 N. a solution of hydrochloric acid and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 6-triptorelin-3-thiol in the form of a colorless oil.

To a solution of tert-butyl [5-chloro-4-[(2,5-debtor enil)(hydroxy)methyl]pyridine-2-yl]carbamate (185 mg, 0.50 mmol)obtained in reference example 47, in dichloromethane at room temperature was sequentially added methanesulfonamide (0,077 ml, 1.00 mmol) and triethylamine (0,279 ml, 2.00 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in N,N-dimethylformamide (5 ml) was sequentially added under nitrogen atmosphere a solution of 6-triptorelin-3-thiol obtained as described above, in N,N-dimethylformamide (5 ml) and potassium carbonate (104 mg, 0.75 mmol). The resulting mixture was stirred at room temperature for 15 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in ethyl acetate (10 ml) was added methanol (10 ml), 31% aqueous hydrogen peroxide solution (5 ml) and tetrahydrate hexaminolevulinate (99 mg, 0.08 mmol). The resulting mixture was stirred at 50°C for 4 hours. To react the Onna mixture were added water and ethyl acetate and methanol drove away under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under reduced pressure.

To a solution of the obtained residue in dichloromethane (5 ml) was added at 0°C triperoxonane acid (5 ml). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, then the residue was dissolved in dichloromethane. The resulting solution was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure. The obtained residue was washed with a mixture solvent of ethanol/hexane and collected by filtration to obtain specified in the title compound (75 mg, 0.16 mmol, 32%) as a white solid.

1H-NMR (400 MHz,CDCl 3)δ: 4,71 (2H, s), 6,18 (1H, s), 6,91-6,99 (1H, m), 7,06-7,14 (1H, m), 7,30 (1H, s), 7,50-7,56 (1H, m), 7,81 (1H, d, J=8.1 Hz), 8,01 (1H, s), to 8.20 (1H, DD, J=8,1, 2.0 Hz), of 8.90 (1H, d, J=2.0 Hz).

IR (ATR) cm-1: 3446, 3157, 1649, 1601, 1485, 1419, 1325, 1147, 1101, 1076.

TPL: 201-202°C.

Elemental Analysis for C18H11ClF5N3O2S·0,25H2O. Calculated: C,46,16; H,2,48; Cl,EUR 7.57; F,To 20.28; N,8,97; S 6,85. Found: C,46,30; H,2,36; Cl,To 7.61; F,19,96; N,8,93; S,7,12.

MS m/z: 464 (M++H).

Reference Example 51:O-Ethyl S-(4-chloro-3-forfinal) dithiocarbonate

[Chemical formula 147]

In the same manner as in reference example 50, has been specified in the title compound (379 mg and 1.51 mmol, 38%) as a yellow oil using 4-chloro-3-ftoranila (582 mg, 4.00 mmol).

1H-NMR (400 MHz, CDCl3)δ: of 1.36 (3H, t, J=7,1 Hz), 4,63 (2H, square, J=7,1 Hz), 7,22-of 7.25 (1H, m), 7,30-to 7.35 (1H, m), 7,43-7,49 (1H, m).

Example 251:[5-Chloro-4-[(4-chloro-3-perpenicular)(2.5-differenl)methyl]pyridine-2-yl]amine

[Chemical formula 148]

In the same way as in example 250, has been specified in the title compound (78 mg, 0,17 mmol, 35%) as a white solid using O-ethyl S-(4-chloro-3-forfinal)dithiocarbonate (150 mg, of 0.60 mmol) and tert-butyl [5-chloro-4-[(2,5-differenl)(hydroxy)methyl]pyridine-2-yl]carbamate (185 mg, 0.50 mmol)obtained in reference example 47.

1H-NMR (400 MHz, CDCl3 )δ: and 4.68 (2H, s), 6,14 (1H, s), 6,92-6,99 (1H, m), 7.03 is-7,10 (1H, m), 7,31 (1H, s), 7,40-of 7.55 (4H, m), of 8.00 (1H, s).

IR (ATR) cm-1: 3159, 1628, 1543, 1495, 1473, 1408, 1335, 1238, 1149, 1055.

TPL: 159-160°C.

Elemental Analysis for C18H11Cl2F3N2O2S. Calculated: C,48,34; H,2,48; Cl,15,85; F,12,74; N,6,26; S,7,17. Found: C,48,22; H,2,47; Cl,15,89; F,Was 12.75; N,6,24; S,7,34.

MS m/z: 447 (M++H).

Example 252:Methyl (E)-3-[4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]acrylate

[Chemical formula 149]

Methyl (triphenylphosphonium)acetate (259 mg, 0,775 mmol) was added in an argon atmosphere to a solution of [4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]carbaldehyde (300 mg, 0,705 mmol)obtained in example 200, in tetrahydrofuran (5 ml). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (303 mg, 0,629 mmol, 89%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 3.84 (3H, s), 6,07 (1H, s), 6,92 (1H, d, J=15.6 Hz), 6,94-6,99 (1H, m), 7,05-7,11 (1H, m), 7,45 (2H, d, J=8,3 Hz), 7,63 (2H, d, J=8,3 Hz), 7,65-of 7.69 (1H, m), 7,73 (1H, d, J=15.6 Hz), 8,05 (1, d, J=5.6 Hz), 8,44 (1H, s).

MS m/z: 482 (M++H).

Example 253:Methyl 3-[4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]propionate

[Chemical formula 150]

A suspension of Raney Nickel (R-100", product of Nikko Rika Corporation) was washed successively with water and ethanol to obtain, respectively, of a suspension in ethanol. The obtained suspension in ethanol (1 ml) was added to a solution of methyl (E)-3-[4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]acrylate (290 mg, 0,602 mmol) in a mixture of ethanol (6 ml) and 1,4-dioxane (4 ml). The resulting mixture was intensively stirred for 30 minutes in a hydrogen atmosphere at a pressure of 1 atmosphere. The reaction mixture was filtered, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane. The resulting solution was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was washed with hexane to obtain specified in the title compound (252 mg, 0,521 mmol, 87%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: and 2.83 (2H, t, J=7,1 Hz), 3,19 (2H, t, J=7,1 Hz), 3,71 (3H, s), the 6.06 (1H, s), 6,93-6,99 (1H, m), 7.03 is-to 7.09 (1H, m), 7,44 (2H, d, J=8.6 Hz), 7,63 (2H, d, J=8.6 Hz), of 7.64-of 7.69 (1H, m), 7,88 (1H, d, J=5.4 Hz), 8,31 (1H, s).

MS m/z: 484 (M++H).

Example 254:3-[4-[(4-Chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]propionic acid

[The chemical form of the and 151]

To a solution of methyl 3-[4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-5-herperidin-2-yl]propionate (150 mg, 0,310 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added 1 N. aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was slightly acidified 1 N. a solution of hydrochloric acid, then was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (145 mg, 0,310 mmol, Quant.) in the form of a white powder.

1H-NMR (400 MHz, CDCl3)δ: is 2.88 (2H, t, J=6.6 Hz), 3,21-of 3.25 (2H, m), 6,07 (1H, s), 6,93-6,99 (1H, m),? 7.04 baby mortality-7,10 (1H, m), 7,45 (2H, d, J=8.6 Hz), a 7.62 (2H, d, J=8.6 Hz), 7,63-to 7.67 (1H, m), 7,92 (1H, d, J=5.4 Hz), with 8.33 (1H with).

IR (ATR) cm-1: 3453, 1716, 1664, 1614, 1571, 1496, 1430, 1394, 1330, 1284, 1238, 1187, 1151, 1089, 1010.

TPL: 89-91°C.

MS m/z: 470 (M++H).

Elemental Analysis for C21H15ClF3NO4S·0,75H2O. Calculated: C,52,18; H,3,44; Cl,7,33; F,To 11.79; N,2,90; S 6,63. Found: C,52,20; H,3,65; Cl,7,11; F,11,43; N,2,99; S,6,58.

Reference Example 52:2-Bromo-5-chloro-4-[(2,5-differenl)hydroxymethyl]pyridine

[Chemical formula 152]

n-Utility (solution 1,58M in hexane, 88 ml, 138 mmol) was added in an argon atmosphere at -78°C to a solution of Diisopropylamine is (21 ml, 150 mmol) in tetrahydrofuran (200 ml). The resulting mixture was stirred for 1 hour. To the reaction mixture was added dropwise a solution of 2-bromo-5-chloropyridine (19 g, by 98.7 mmol) in tetrahydrofuran (100 ml). The resulting mixture was stirred for 1.5 hours. To the reaction mixture was added dropwise 2.5-differentally (16 ml, 148 mmol) followed by stirring for 2 hours. After adding water, the mixture was concentrated under reduced pressure. The residue was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=6:1 was concentrated under reduced pressure to obtain specified in the title compound (24.8 g, 74,1 mmol, 75%) as a pale yellow powder.

1H-NMR (400 MHz, CDCl3)δ: to 2.65 (1H, d, J=4, 2 Hz), of 6.20 (1H, d, J=4, 2 Hz), 6,88-6,92 (1H, m), 7,01-7,27 (2H, m), 7,81 (1H, s), 8,30 (1H, s).

MS m/z: 334 (M++H).

Example 255:2-Bromo-5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine

[Chemical formula 153]

The triethylamine (2.6 ml, 18.5 mmol) and methanesulfonamide (1.3 ml, 16.0 mmol) was added in an argon atmosphere under ice cooling to a solution (80 ml) of 2-bromo-5-chloro-4-[(2,5-differenl)hydroxymethyl]-pyrid is to (4.12 g, 12.3 mmol) in dichloromethane. The resulting mixture was stirred at room temperature for 1.5 hours. To the reaction mixture were added saturated aqueous sodium bicarbonate solution and then was extracted with diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

To a solution of the obtained residue in dimethylformamide (40 ml) was added 4-chlorbenzoyl (2.1 g, of 14.8 mmol) and potassium carbonate (2.6 g, 18.5 mmol). The resulting mixture was stirred at 50°C for 4 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether. The diluted mixture was washed successively with water and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=10:1 was concentrated under reduced pressure to obtain specified in the title compound (3.3 g, 7,16 mmol, 58%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 5,96 (1H, s), 6,99-7,06 (2H, m), 7,15-7,20 (1H, m), 7,25 (2H, d, J=8,8 Hz), 7,28 (2H, d, J=8,8 Hz), 7,69 (1H, s), 8,32 (1H, s).

MS m/z: 460 (M++H).

Example 256:[5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]pyridine-2-yl]methanol

[Chemical formula 154]

n-Utility (solution 1,58M in hexane, 0.33 ml, 0,520 mmol) was added in an argon atmosphere to a solution of 2-bromo-5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine (200 mg, 0,434 mmol) in toluene (5 ml) at -78°C. the resulting mixture was stirred for 2 hours. To the reaction mixture was added dropwise dimethylformamide (44 μl, 0,564 mmol). The reaction mixture was stirred for 1 hour. To the reaction mixture were added methanol (5 ml) and borohydride sodium (33 mg, 0,868 mmol). The temperature of the mixture was raised to room temperature, followed by stirring for 2 hours. To the reaction mixture were added water and then the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain specified in the title compound (142 mg, 0,344 mmol, 80%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 3,19 (1H, t, J=5.4 Hz), and 4.75 (2H, d, J=5.4 Hz), the 6.06 (1H, s), of 6.96? 7.04 baby mortality (2H, m), 7,16-7,21 (1H, m), 7,22 (2H, d, J=8,8 Hz), 7,25 (2H, d, J=8,8 Hz), 7,52 (1H, s), 8,51 (1H, s).

MS m/z: 412 ( ++H).

Example 257:[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanol

[Chemical formula 155]

To a solution of [5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]pyridine-2-yl]methanol (130 mg, 0,315 mmol) in methanol (5 ml) was added tetrahydrate hexaminolevulinate (20 mg) and 30% aqueous hydrogen peroxide solution (3 ml). The resulting mixture was stirred for 6 hours. To the reaction mixture was added water, then the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium bicarbonate, saturated aqueous sodium thiosulfate and saturated salt solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure. The residue was recrystallized from hexane:ethyl acetate to obtain specified in the title compound (101 mg, 0,227 mmol, 72%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 3,22 (1H, t, J=5.4 Hz), a 4.86 (2H, DD, J=5,4, 2.0 Hz), 6,24 (1H, s), 6,91-6,97 (1H, m), 7,02-to 7.09 (1H, m), 7,45 (2H, d, J=8,8 Hz), 7,52-EUR 7.57 (1H, m), to 7.61 (2H, d, J=8,8 Hz), 8,10 (1H, s), charged 8.52 (1H with).

IR (ATR) cm-1: 3255, 1583, 1492, 1428,1394, 1330, 1280, 1236, 1159, 1085, 1035.

TPL: 164-165°C.

MS m/z: 444 (M++H).

Elemental Analysis for C19H13Cl2F2NO3S. Calculated: C,51,36; H,2,95; Cl,15,96; F,8,55; N,3,15; S,7,22. Found: C,51,26; H,2.91 In; Cl,15,97; F,8,72; N,3,11; S,7,45.

Example 258:[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde

[Chemical formula 156]

Dimethyl sulfoxide (880 μl, 11.3 mmol), triethylamine (1,14 ml, 11.3 mmol) and a complex of a sulfur trioxide-pyridine (1.07 g, of 6.75 mmol) was added under nitrogen atmosphere to a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]methanol (1.0 g, 2.25 mmol) in dichloromethane (25 ml). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain specified in the title compound (770 mg, of 1.74 mmol, 77%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 6,23 (1H, s), 6,93-6,99 (1H, m),? 7.04 baby mortality-7,10 (1H, m), 7,44 (2H, d, J=8,8 Hz), to 7.59-to 7.64 (1H, m), a 7.62 (2H, d, J=8,8 Hz), 8,69 (1H, s), 8,73 (1H, s), of 10.09 (1H, s).

MS m/z: 442 (M++H).

Example 259:Methyl (E)-3-[5-Chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]Smoot is at

[Chemical formula 157]

Methyl (triphenylphosphonium)acetate (632 mg, 1,89 mmol) was added in an argon atmosphere to a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde (760 mg, 1,72 mmol) in tetrahydrofuran (15 ml). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (776 mg, 1.56 mmol, 91%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 3.85 (3H, s), from 6.22 (1H, s), 6,93-6,98 (1H, m), of 6.99 (1H, d, J=15.6 Hz), 7.03 is-7,10 (1H, m), 7,44 (2H, d, J=8.6 Hz), 7,54-7,58 (1H, m), 7,60 (2H, d, J=8.6 Hz), 7,73 (1H, d, J=15.6 Hz), 8,17 (1H, ), 8,56 (1H, s).

MS m/z: 498 (M++H).

Example 260:Methyl 3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]propionate

[Chemical formula 158]

A suspension of Raney Nickel (R-100", product of Nikko Rika Corporation) was washed successively with water and ethanol to obtain, respectively, of a suspension in ethanol. The obtained suspension in ethanol (2 ml) was added to a solution of methyl (E)-3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)m is Teal]-pyridine-2-yl]acrylate (770 mg, 1.55 mmol) in a mixture of ethanol (10 ml) and 1,4-dioxane (5 ml). In an atmosphere of hydrogen at a pressure of 1 atmosphere the mixture was intensively stirred for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 ml). The resulting solution was dried over magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (720 mg, 1.44 mmol, 93%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,84 (2H, t, J=7,1 Hz), 3,20 (2H, t, J=7,1 Hz), 3,70 (3H, s), from 6.22 (1H, s), 6,92-6,97 (1H, m), 7,02-was 7.08 (1H, m), the 7.43 (2H, d, J=8.6 Hz), 7,53-7,58 (1H, m), to 7.61 (2H, d, J=8.6 Hz), 8,03 (1H, ), 8,44 (1H, s).

MS m/z: 500 (M++H).

Example 261:3-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]propionic acid

[Chemical formula 159]

To a solution of methyl 3-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]propionate (200 mg, 0.400 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added 1 N. aqueous sodium hydroxide solution (2 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was slightly acidified by adding 1 n hydrochloric acid, then was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced is the making. The obtained residue was recrystallized from hexane:ethyl acetate to obtain specified in the title compound (161 mg, 0,331 mmol, 83%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,90 (2H, t, J=6,7 Hz), 3,24 (2H, t, J=6,7 Hz), 6,21 (1H, s), 6,92-6,97 (1H, m), 7.03 is-was 7.08 (1H, m), 7,44 (2H, d, J=8.6 Hz), 7,51-7,56 (1H, m), to 7.61 (2H, d, J=8.6 Hz), of 8.06 (1H, s), of 8.47 (1H, ).

IR (ATR) cm-1: 1718, 1587, 1496, 1423, 1396, 1365, 1321, 1280, 1240, 1205, 1174, 1083, 1054, 1014.

TPL: 194-196°C.

MS m/z: 486 (M++H).

Elemental Analysis for C21H15Cl2F2NO4S. Calculated: C,51,86; H,3,11; Cl,14,58; F,7,81; N,2,88; S,6,59. Found: C,51,87; H,3,07; Cl,14,37; F,To 7.77; N,2,95; S,6.75 In.

Example 262:5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]picolina acid

[Chemical formula 160]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]carbaldehyde (150 mg, 0,339 mmol)obtained in example 258, in formic acid (3 ml) was added 30% aqueous hydrogen peroxide solution (115 μl, of 1.02 mmol). The resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture were added water and the precipitated thus, the solid was filtered. The solid is washed with water. The obtained solid substance was dissolved in ethyl acetate. The resulting solution was washed successively with water and saturated salt solution. The organic layer is left the house taking over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane:ethyl acetate to obtain specified in the title compound (88 mg, 0,192 mmol, 57%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,30 (1H, s), 6,93-7,00 (1H, m), 7,05-7,11 (1H, m), 7,45 (2H, d, J=8,8 Hz), 7,62-7,66 (1H, m), of 7.64 (2H, d, J=8,8 Hz), of 8.95 (1H, s), 9,24 (1H, s).

IR (ATR) cm-1: 1758, 1712, 1583, 1542, 1494, 1425, 1396, 1328, 1280, 1228, 1153, 1085, 1054, 1014.

TPL: 94-96°C.

MS m/z: 458 (M++H).

Elemental Analysis for C19H11Cl2F2NO4S. Calculated: C,49, 80mm; H,2,42; Cl,15,47; F,8,29; N,A 3.06; S,7,00. Found: C,50,05; H,2,58; Cl,15,17; F,Of 8.28; N,A 3.06; S,7,05.

Example 263:2-Bromo-5-chloro-4-[(2,5-differenl)(4 cryptosecurity)methyl]pyridine

[Chemical formula 161]

To a solution of 2-bromo-5-chloro-4-[(2,5-differenl)-hydroxymethyl]pyridine (1,34 g, 4.00 mmol)obtained in reference example 52, in dichloromethane was sequentially added methanesulfonamide (0,619 ml of 8.00 mmol) and triethylamine (2,23 ml, 16.0 mmol) in a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with water and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in N,N-dimethylformamide (60 ml) under nitrogen atmosphere consistently doba is Lyali 4-triptorelin (784 mg, 4.40 mmol) and potassium carbonate (663 mg, 4,80 mmol). The resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture were added ethyl acetate and the mixture washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=50:1 was concentrated under reduced pressure to obtain specified in the connection header (1,33 g, 2,69 mmol, 67%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 6,10 (1H, s), 6,99-7,11 (2H, m), 7,14-7,20 (1H, m), of 7.36 (2H, d, J=8.1 Hz), 7,52 (2H, d, J=8.1 Hz), 7,69 (1H, s), at 8.36 (1H, s).

MS m/z: 494,496 (M++H).

Example 264:Methyl (E)-3-[5-chloro-4-[(2,5-differenl)(4 cryptosecurity)methyl]pyridine-2-yl]acrylate

[Chemical formula 162]

To a solution of 2-bromo-5-chloro-4-[(2,5-differenl)(4 cryptosecurity)methyl]pyridine (396 mg, 0.80 mmol) in toluene (12 ml) at -78°C in argon atmosphere was added a solution (1,59M, 0,604 ml, 0.96 mmol) n-utility in hexane. The resulting mixture was stirred for 30 minutes. At the same temperature was added N,N-dimethylformamide (of 0.081 ml, 1.04 mmol) and the resulting mixture was stirred for 30 minutes. To the PE klonoa mixture was added saturated aqueous solution of ammonium chloride, and then the water. After the temperature of the mixture was raised to room temperature, the resulting product was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under reduced pressure to obtain the aldehyde compound (186 mg).

The connection of the aldehyde (133 mg) was dissolved in tetrahydrofuran (2 ml). To the resulting solution at room temperature was added methyl (triphenylphosphonium)acetate (120 mg, 0.36 mmol). The resulting mixture was stirred at the same temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and then the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=19:1 was concentrated under reduced pressure to obtain specified in the title compound (132 mg, 0.26 mmol, 46%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: is 3.82 (3H, s), 6,17 (1H, s), 6,92 (1H, d, J=15.7 Hz), 6,99-to 7.09 (2H, m), 7,13-to 7.18 (1H, m), 7,35 (2H, d, J=8.1 Hz), to 7.50 (2H, d, J=8.1 Hz), to 7.61 (1H, s), to 7.61 (1H, d, J=15.7 Hz), 8,59 (1H, s).

MS m/z: 500 (M++H).

Example 265:Methyl (E)-3-[5-chloro-4-[(2,5-differeni is)(4-triftormetilfullerenov)methyl]pyridine-2-yl]acrylate

[Chemical formula 163]

To a solution of methyl (E)-3-[5-chloro-4-[(2,5-differenl)(4 cryptosecurity)methyl]pyridine-2-yl]acrylate (118 mg, 0.24 mmol) in ethyl acetate (6 ml) was added methanol (6 ml), 31% aqueous hydrogen peroxide solution (6 ml) and tetrahydrate hexaminolevulinate (58 mg, 0.05 mmol). The resulting mixture was stirred at room temperature for 11 hours. To the reaction mixture were added water. The ethyl acetate and methanol drove away under reduced pressure, then the residue was added a saturated salt solution. The product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under reduced pressure to obtain specified in the title compound (111 mg, 0.21 mmol, 88%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 3,86 (3H, s), and 6.25 (1H, s), 6,91-6,98 (1H, m), 7,01 (1H, d, J=15.7 Hz),? 7.04 baby mortality-7,11 (1H, m), 7,53-to 7.59 (1H, m), 7,74 (1H, d, J=15.7 Hz), 7,74 (2H, d, J=8,3 Hz), 7,83 (2H, d, J=8,3 Hz), 8,18 (1H, ), 8,56 (1H, s).

MS m/z: 532 (M++H).

Example 266:Methyl 3-[5-chloro-4-[(2,5-differenl)(4-triftormetilfullerenov)methyl]pyridine-2-yl]propionate

[Himicheskaya 164]

In a solvent mixture of ethyl acetate (3 ml) and methanol (3 ml) was dissolved methyl (E)-3-[5-chloro-4-[(2,5-differenl)(4-triftormetilfullerenov)methyl]pyridine-2-yl]acrylate (110 mg, 0.21 mmol). To the resulting solution was added the catalyst, 10% palladium on carbon (60 mg). The resulting mixture was stirred in hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration through celite, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain specified in the title compound (94 mg, 0.18 mmol, 85%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,82-2,89 (2H, m), 3,21 (2H, t, J=7,1 Hz), 3,70 (3H, s), and 6.25 (1H, s), 6.90 to-6,97 (1H, m), 7.03 is-7,10 (1H, m), 7,54-of 7.60 (1H, m), 7,73 (2H, d, J=8,3 Hz), to 7.84 (2H, d, J=8,3 Hz), of 8.04 (1H, s), 8,44 (1H, s).

MS m/z: 534 (M++H).

Example 267:3-[5-Chloro-4-[(2,5-differenl)(4-triftormetilfullerenov)methyl]pyridine-2-yl]propionic acid

[Chemical formula 165]

To a solution of methyl 3-[5-chloro-4-[(2,5-differenl)(4-triftormetilfullerenov)methyl]pyridine-2-yl]propionate (92 mg, 0,17 mmol) in tetrahydrofuran (2 ml) was added at 0°C methanol (2 ml) and 1 N. waters of the initial sodium hydroxide solution (2 ml). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1 n hydrochloric acid and the product was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed with ethanol and collected by filtration to obtain specified in the title compound (61 mg, 0.12 mmol, 68%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,90 (2H, t, J=6,7 Hz), 3,18-and 3.31 (2H, m), and 6.25 (1H, s), 6.90 to-6,97 (1H, m), 7.03 is-7,10 (1H, m), 7,51-EUR 7.57 (1H, m), 7,74 (2H, d, J=8,3 Hz), 7,82 (2H, d, J=8,3 Hz), 8,07 (1H, s), of 8.47 (1H, s).

IR (ATR) cm-1: 1707, 1495, 1408, 1321, 1244, 1174, 1159, 1124, 1063.

TPL: 166-167°C.

Elemental Analysis for C22H15ClF5NO4S. Calculated: C,50,83; H,2.91 In; Cl,6,82; F,18,27; N,2,69; S,6,17. Found: C,50,66; H,2,93; Cl,6,87; F,17,83; N,2,75; S,6,28.

MS m/z: 520 (M++H).

Example 268:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-1-methyl-1H-imidazole-4-sulfonamide

[Chemical formula 166]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (93 mg, 0,217 mmol)obtained in example 196, and pyridine (21 μl, is 0.260 mmol) in methylene chloride (5 ml) was added 1-methyl-1H-imidazol-4-sulphonylchloride (47 mg, is 0.260 mmol). The resulting mixture AC is stirred at room temperature for 18 hours. After adding to the reaction mixture of pyridine (1 ml) the resulting mixture was stirred at room temperature for 7 hours and the reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:50), concentrated under reduced pressure to obtain white solid. The obtained white solid was washed with ethanol and collected by filtration to obtain specified in the title compound (68 mg, 0,119 mmol, 55%) as a white powder.

1H-NMR (400 MHz,DMSO-d6)δ: of 3.69 (3H, s), and 6.25 (1H, s), 7.29 trend was 7.45 (2H, m), 7,47-rate of 7.54 (1H, m), to 7.68 (2H, d, J=8,8 Hz), of 7.75 (2H, d, J=8,8 Hz), to 7.77 (1H, s), 7,94 (1H, s), 8,10 (1H, s), compared to 8.26 (1H, s), 11,40 (1H, Shir. C).

TPL: 294-296°C

IR (ATR) cm-1: 1594, 1562, 1494, 1382, 1332, 1159, 1118, 993, 817, 755, 723.

MS m/z: 572 (M+).

EI-MS: 571,9962 (Calculated for C22H16O4N4Cl2F2S2: 571,9958).

Elemental Analysis for C22H16N4O4Cl2F2S2. Calculated: C,46,08; H,Of 2.81; N,9,77; Cl,12,37; F6,63; S,11,18. Found: C,46,04; H,2,77; N,9,74; Cl,12,46; F,6,90; S,11,21.

Example 269:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-1-pyridin-4-ylmethanone

[Chemical formula 167]

To a solution in methylene chloride (2 ml) of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (104 mg, 0,242 mmol)obtained in example 196, and pyridine (74 μl, of 0.533 mmol) was added (4-pyridylmethyl)sulphonylchloride (91 mg, 0,266 mmol). The resulting mixture was stirred at room temperature for 17 hours. To the reaction mixture was added pyridine (74 μl, of 0.533 mmol) and (4-pyridylmethyl)sulphonylchloride (91 mg, 0,266 mmol). The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:40), concentrated under reduced pressure to obtain specified in the title compound (66 mg, 0,113 mmol, 47%) as a white solid.

1H-NMR (400 MHz,DMSO-d6)δ: 4,88 (2H, s), 6,30 (1H, s), 7,27 (2H, d, J=6.0 Hz), 7,29-7,49 (3H, m, of 7.70 (2H, d, J=8,8 Hz), 7,74 (1H, s), 7,79 (2H, d, J=8,8 Hz), to 8.45 (1H, s), 8,53 (2H, d, J=6.0 Hz), 11,00 (1H, Shir. C).

TPL: 257°C (decomp.)

IR (ATR) cm-1: 1592, 1490, 1467, 1340, 1326, 1280, 1238, 1186, 1155, 1128, 1085, 1004, 966, 902, 869, 823.

MS m/z: 584 (M++H).

Elemental Analysis for C24H17N3O4Cl2F2S2. Calculated: C,49,32; H,At 2.93; N,7,19; Cl,12,13; F,6,50; S,10,97. Found: C,49,35; H,3,12; N,7,17; Cl,12,05,F, To 6.43; S,Of 10.93.

Example 270:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]piperidine-1-sulfonamide

[Chemical formula 168]

A solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (101 mg, 0,235 mmol)obtained in example 196, and piperidine-1-sulphonylchloride (48 mg, 0,259 mmol) in pyridine (2 ml) was stirred at 70°C for 19 hours. To the reaction mixture was added piperidine-1-sulphonylchloride (48 mg, 0,259 mmol) and the resulting mixture was stirred at 70°C for 4 days. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The diluted solution was washed with water and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. Faction poluchennymi the elution by the mixture hexane:ethyl acetate (=4:1), concentrated under reduced pressure to obtain white solid. The obtained solid was washed with hexane-simple ether and collected by filtration to obtain specified in the title compound (63 mg, 0,109 mmol, 47%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 1,51-to 1.61 (2H, m)of 1.65 and 1.75 (4H, m)to 3.38 (4H, t, J=4.6 Hz), 6,21 (1H, s), 6,94-7,10 (2H, m), 7,41-7,52 (3H, m), of 7.70 (2H, d, J=8.6 Hz), 8,24 (1H, s), 8,29 (1H, s)8,71 (1H, Shir. C).

TPL: 192-194°C

IR (ATR) cm-1: 1598, 1563, 1492, 1396, 1346, 1322, 1234, 1145, 1083, 998, 923, 900, 833.

MS m/z: 576 (M++H).

Elemental Analysis for C23H21N3O4Cl2F2S2. Calculated: C,47,92; H,To 3.67; N,7,29; Cl,12,30; F,6,59; S,11,12. Found: C,47,87; H,3,66; N,7,33; Cl,12,12; F,6,66; S,11,25.

Example 271:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-4-methylpiperidin-1-sulfonamide

[Chemical formula 169]

Solution in acetonitrile (5 ml) of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (101 mg, 0,235 mmol)obtained in example 196, hydrochloride 4-methylpiperazin-1-sulphonylchloride (126 mg, 0,534 mmol) and triethylamine (150 μl, 1.07 mmol) was heated at the boil under reflux for 23 hours. To the reaction mixture were added hydrochloride 4-methylpiperazin-1-sulphonylchloride (126 mg, 0,534 mmol) and triethylamine (150 μl, 1.07 mmol). The resulting mixture is agrawala boiling under reflux for 22 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:20), concentrated under reduced pressure to obtain specified in the title compound (34 mg, 0,057 mmol, 16%) as a pale yellow solid.

1H-NMR (400 MHz, CDCl3)δ: 2,31 (3H, s), 2,45-2,60 (4H, m), 3,38-to 3.52 (4H, m), of 6.20 (1H, s), 6,95-7,10 (2H, m), 7,41-to 7.50 (3H, m), of 7.69 (2H, d, J=8,8 Hz), 8,24 (1H, s), compared to 8.26 (1H, s).

TPL: 215-218°C.

IR (ATR) cm-1: 1600, 1565, 1496, 1392, 1348, 1330, 1157, 1093, 935, 835, 819.

MS m/z: 591 (M++H).

Elemental Analysis for C23H22N4O4Cl2F2S2. Calculated: C,46,70; H,Of 3.75; N,For 9.47; Cl,11,99; F,6.42 Per; S,10,84. Found: C,46,89; H,3,76; N,9,40; Cl,11,78; F,6.42 Per; S Of 10.72.

Example 272:3-Chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]-N-(3-chloropropanesulfonyl)propane-1-sulfonamide

[Chemical formula 170]

To a solution in methylene chloride (5 ml) of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-debtor the Nile)methyl]pyridine-2-yl]amine (130 mg, 0,303 mmol)obtained in example 196, and triethylamine (42 μl, 0,303 mmol) at 0°C was added 3-chloropropanesulfonyl (37 μl, 0,303 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. When 0°C was sequentially added triethylamine (42 μl, 0,303 mmol) and 3-chloropropanesulfonyl (37 μl, 0,303 mmol). The resulting mixture was stirred at room temperature for 7 hours. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=5:1), concentrated under reduced pressure. To the obtained residue was added ether and precipitated thus, the solid was collected by filtration to obtain specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,47-to 2.57 (4H, m), 3,74 (4H, t, J=6,1 Hz), 3.96 points-of 4.05 (4H, m), of 6.20 (1H, s), 6,98-to 7.15 (2H, m), 7,40-7,53 (3H, m), a 7.62 (2H, d, J=8,3 Hz), by 8.22 (1H, s)8,64 (1H, s).

MS m/z: 709,711 (M++H).

Example 273:3-Chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-differenl)methyl]pyridine-2-yl]propane-1-sulfonamide

[Chemical formula 171]

1H-NMR (400 MHz, CDCl3)δ: 2,35 is 2.44 (2H, m), 3,61-to 3.67 (2H, m), 3,70 (2H, t, J=6,1 Hz), to 6.19 (1H, s), 6.90 to-6,99 (1H, m), 7,02-7,10 (1H, m), 7,42-7,53 (3H, m), of 7.64 (2H, d, J=8,3 Hz), to 7.84 (1H, Shir. C)8,01 (1H, s), 8,31 (1H, s).

IR (ATR) cm-1: 1596, 1560, 1488, 1384, 1336, 1234, 1145, 1083, 997, 925, 844.

MS m/z: 568,570 (M+).

Example 274:5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(1,1-dioxo-1λ6-isothiazolin-2-yl)pyridine

[Chemical formula 172]

A solution of 3-chloro-N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]propane-1-sulfonamida (83 mg, 0,146 mmol) and 1,8-databits the CLO[5,4,0]-7-undecene (26 μl, 0,175 mmol) in acetonitrile (5 ml) was stirred at 70°C for 4.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate. The diluted solution was washed successively 1 N. a solution of hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=1:1), concentrated under reduced pressure to obtain specified in the title compound (75 mg, 0,141 mmol, 96%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,52-2,62 (2H, m), 3,47 (2H, t, J=7,6 Hz), was 4.02 (2H, t, J=6.6 Hz), 6,24 (1H, s), 6,95-7,10 (2H, m), 7,44 (2H, d, J=8.6 Hz), 7,49-7,56 (1H, m), 7,74 (2H, d, J=8.6 Hz), 8,13 (1H, s), 8,24 (1H, ).

TPL: 219-221°C.

IR (ATR) cm-1: 1587, 1496, 1467, 1386, 1346, 1315, 1278, 1238, 1137, 1089, 998, 831.

MS m/z: 532 (M+).

Elemental Analysis for C21H16N2O4Cl2F2S2. Calculated: C,47,29; H,To 3.02; N,5,25; Cl,To 13.29; F,7,12; S 12,02. Found: C,47,39; H,To 3.02; N,Lower Than The 5.37; Cl,13,32; F,7,24; S 11,95.

Example 275 N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-N-(cryptomelane the l-triftormetilfullerenov

[Chemical formula 173]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (103 mg, 0,240 mmol)obtained in example 196, and pyridine (19 μl, 0,240 mmol) in methylene chloride (5 ml) at 0°C was added triftormetilfullerenov anhydride (39 μl, 0,240 mmol). The resulting mixture was stirred at room temperature for 3 hours, then was added at 0°C pyridine (19 μl, 0,240 mmol) and triftormetilfullerenov anhydride (39 μl, 0,240 mmol). The resulting mixture was stirred at room temperature for 15 hours, then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=5:1), concentrated under reduced pressure to obtain specified in the title compound (84 mg, 0,120 mmol, 50%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 6,23 (1H, s), 6,99-to 7.15 (2H, m), 7,38-of 7.48 (3H, m), a 7.62 (2H, d, J=8,8 Hz), at 8.36 (1H, s), 8,53 (1H, s).

IR (ATR) cm-1: 1581, 1498, 1442, 1332, 1214, 1159, 1122, 1085, 997, 944, 923, 865, 755.

MS m/z: 693 (M++H).

Example 276:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]triftormetilfullerenov

[Chemical formula 174]

To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-gift henyl)methyl]pyridine-2-yl]-N-(trifloromethyl)triftoratsetofenona (77 mg, 0,111 mmol) in a mixture of tetrahydrofuran (5 ml) and water (1 ml) was added monohydrate of lithium hydroxide (5.0 mg, 0,111 mmol). The resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane: ethyl acetate (=2:1) containing 0.5% triperoxonane acid, concentrated under reduced pressure. To the obtained residue was added ether and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (39 mg, 0,069 mmol, 63%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 6,21 (1H, s), 6,95-7,03 (1H, m), 7,06-to 7.15 (1H, m), 7,42-7,52 (3H, m), 7,71 (2H, d, J=8,8 Hz), 8,23 (1H, s)8,71 (1H, s).

TPL: 221-223°C

IR (ATR) cm-1: 1637, 1496, 1382, 1336, 1195, 1157, 1130, 1085, 1010, 923, 779, 754.

MS m/z: 560 (M+).

Elemental Analysis for C19H11N2O4Cl2F5S2. Calculated: C,40,65; H,To 1.98; N,4,99; Cl,12,63,F, 16,92; S,11,42. Found: C,40,68; H,1,94; N,5,06; Cl,12,46; F,16,91; S,11,47.

Example 277:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-debtor enyl)methyl]pyridine-2-yl]etranslate

[Chemical formula 175]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (982 mg, to 2.29 mmol)obtained in example 196, and 2-chloroethanesulfonate (0,29 ml, is 2.74 mmol) in methylene chloride (10 ml) was added pyridine (of 0.44 ml, 5,49 mmol). The resulting mixture was stirred at room temperature for 3.5 hours. To the reaction mixture were added 2-chloroethanesulfonate (143 μl, 1.37 mmol) and pyridine (222 μl, of 2.75 mmol). The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added ethyl acetate. The resulting mixture was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated under reduced pressure to obtain specified in the header of the compound (573 mg, 1.10 mmol, 48%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 6,17 and 6.25 (2H, m), 6,65-6,70 (2H, m), 6,91-7,10 (2H, m), 7,41-7,49 (3H, m), 7,66 (2H, d, J=8.6 Hz), 8,16 (1H, s), with 8.33 (1H, s).

IR (ATR) cm-1: 1600, 1565, 1492, 1388, 1349, 1322, 1147, 1081, 998, 916, 821, 757.

MS m/z: 519 (M++H).

Example 278:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)is ethyl]pyridine-2-yl]-2-piperidine-1-retensioned

[Chemical formula 176]

To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]atlantogenata (34 mg, 0,065 mmol) in ethanol (5 ml) was added piperidine (10 μl, 0,098 mmol). The resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:30), concentrated under reduced pressure to obtain specified in the title compound (35 mg, 0,058 mmol, 89%) as an amorphous substance. The obtained amorphous substance was utverjdali by adding ethanol and collected by filtration to obtain specified in the title compound as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 1,45 to 1.76 (6H, m), 2,50-to 2.65 (4H, m), of 2.97 (2H, t, J=5,9 Hz), 3,30-to 3.38 (2H, m), 6,21 (1H, s), 6,92-7,10 (2H, m), 7,44 (2H, d, J=8.6 Hz), 7,52-to 7.59 (1H, m), of 7.69 (2H, d, J=8.6 Hz), of 8.06 (1H, s), by 8.22 (1H, s).

TPL: 200-203°C

IR (ATR) cm-1: 1600, 1571, 1492, 1390, 1332, 1141, 1083, 1002, 962, 919, 811, 754.

MS m/z: 604 (M++H).

Elemental Analysis for C25H25N3O4Cl2F2S2. Calculated: C,49,67; H,To 4.17; N,6,95; Cl,11,73; F,6,29; S,10,61. Found: C,49,90; H,4,13; N,6,88; Cl,11,64; F,6,17; S,10,52.

Example 279:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methylpyridin-2-yl]-2-(dimethylamino)econsultant

[Chemical formula 177]

To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]atlantogenata (64 mg, 0,123 mmol)obtained in example 277, in tetrahydrofuran (3 ml) was added a solution of tetrahydrofuran (THF) in dimethylamine (2M, of 0.18 ml, 0.36 mmol). The resulting mixture was stirred at room temperature for 3 days, then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:20), concentrated under reduced pressure to obtain specified in the title compound (67 mg, 0,117 mmol, 97%) as a white solid. The obtained solid was washed with ethanol and collected by filtration to obtain specified in the title compound (43 mg) as a white powder.

1H-NMR (400 MHz, CD3OD)δ: 2,73 (6H, s), 3,37 (2H, t, J=7.0 Hz), 3,82 (2H, t, J=7.0 Hz), of 6.31 (1H, s), 7,16-7,26 (2H, m), 7,53-the 7.65 (3H, m), of 7.75 (2H, d, J=8,8 Hz), to 7.84 (1H, s), 8,24 (1H, s).

IR (ATR) cm-1: 1587, 1494, 1455, 1321, 1151, 1087, 998, 757.

MS m/z: 564 (M++H).

FAB-MS: 564,0399 (Calculated for C22H22O4N3Cl2F2S2: 564,0397).

Example 280 N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-2-morpholine-4-retensioned

[Chemical formula 178]

To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]atlantogenata (53 mg, is 0.102 mmol)obtained in example 277, in ethanol (3 ml) was added morpholine (18 μl, 0,204 mmol). The resulting mixture was stirred at room temperature for 3 days, then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:40), concentrated under reduced pressure. To the obtained residue was added a simple ether. Besieged thus, the solid was collected by filtration to obtain specified in the title compound (45 mg, 0,074 mmol, 73%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: of 2.51-2,60 (4H, m), 2,96 (2H, t, J=6,1 Hz), 3,36 is-3.45 (2H, m), 3,70-of 3.80 (4H, m), from 6.22 (1H, s), 6.90 to-7,10 (2H, m), 7,45 (2H, d, J=8,8 Hz), 7,50-to 7.59 (1H, m), to 7.68 (2H, d, J=8,8 Hz), 8,19 (1H, s), 8,24 (1H, s).

TPL: 219-221°C.

IR (ATR) cm-1: 1602, 1565, 1492, 1388, 1321, 1286, 1238, 1147, 1116, 1083, 998.

MS m/z: 606 (M++H).

FAB-MS: 606,0499 (Calculated for C24H24O5N3Cl2F2S2: 606,0503).

Elemental Analysis for C24H23N3O5Cl2F2S2. Calculated: C,47,53; H,3,82; N,6,93; Cl,Of 11.69; F,6,27; S,10,57. Found: C,47,73; H,A-3.84; N,6,97; Cl,11,72; F,6,25; S Of 10.72.

Example 281: tert-Butyl 4-[2-[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-differeni is)methyl]pyridine-2-yl]amino]sulfonyl]ethyl]piperazine-1-carboxylate

[Chemical formula 179]

To a solution of N-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]atlantogenata (59 mg, 0,114 mmol)obtained in example 277, in ethanol (3 ml) was added 1-(tert-butoxycarbonyl)piperazine (32 mg, 0,170 mmol). The resulting mixture was stirred at room temperature for 3 days, then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:40), concentrated under reduced pressure to obtain specified in the title compound (75 mg, 0,106 mmol, 93%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: of 1.46 (9H, s)of 2.50 (4H, t, J=5.0 Hz), of 2.97 (2H, t, J=6.0 Hz), 3,35-of 3.42 (2H, m), 3,44-of 3.54 (4H, m), from 6.22 (1H, s), 6.90 to-7,10 (2H, m), 7,45 (2H, d, J=8,8 Hz), 7,50-7,58 (1H, m), to 7.68 (2H, d, J=8,8 Hz), 8,19 (1H, s), 8,24 (1H, s).

IR (ATR) cm-1: 1691, 1592, 1494, 1330, 1240, 1147, 1083, 998, 755.

MS m/z: 705 (M++H).

Example 282:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-2-piperazine-1-retensioned

[Chemical formula 180]

To a solution of tert-butyl 4-[2-[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]ethyl]piperazine-1-carboxylate (72 mg, is 0.102 mmol) in ethanol (5 ml) was added concentrated hloristovodorodnykh acid (1 ml). The resulting mixture was stirred at room temperature for 2 days, then concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed by a simple ether to obtain specified in the title compound (23 mg, of 0.038 mmol, 37%) as a white powder.

1H-NMR (400 MHz, DMSO-d6)δ: 2,40-2,47 (4H, m), 2,62-2,70 (2H, m), 2,83-2,90 (4H, m), x 6.15 (1H, s), 7,25-7,42 (3H, m), 7,47-of 7.55 (1H, m), to 7.68 (2H, d, J=8.7 Hz), to 7.77 (2H, d, J=8.7 Hz), 8,03 (1H, s).

MS m/z: 605 (M++H).

Example 283:Ethyl [[[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]acetate

[Chemical formula 181]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amine (331 mg, 0,771 mmol)obtained in example 196, and pyridine (94 μl, of 1.16 mmol) in methylene chloride (10 ml) at 0°C solution was added ethylchlorothioformate (216 mg, of 1.16 mmol) in methylene chloride (2 ml). The resulting mixture was stirred at room temperature for 12 hours, then added sequentially at 0°C pyridine (94 μl, of 1.16 mmol) and the solution ethylchlorothioformate (216 mg, 1,16 IMO the ü) in methylene chloride (2 ml). The resulting mixture was stirred at room temperature for 9 hours, then the reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=3:1), concentrated under reduced pressure to obtain specified in the title compound (239 mg, 0,412 mmol, 53%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 1.29 (3H, t, J=7.2 Hz), 4,25 (2H, q, J=7.2 Hz), 4,37 (2H, s), 6,21 (1H, s), 6,91-7,10 (2H, m), 7,45 (2H, d, J=8.6 Hz), 7,50-7,58 (1H, m), 7,66 (2H, d, J=8.6 Hz), of 8.09 (1H, s), 8,30 (1H, s).

IR (ATR) cm-1: 1745, 1600, 1567, 1496, 1386, 1355, 1317, 1280, 1232, 1147, 1081.

MS m/z: 579 (M++H).

Example 284:N-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]-2-hydroxyethanesulfonic

[Chemical formula 182]

To a solution of ethyl [[[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]acetate (67 mg, 0,116 mmol) in tetrahydrofuran (5 ml) at 0°C was added a 1M solution of sociallyengaged simple ether (0,18 ml)Poluchennuyu the mixture was stirred at 0° C. After completion of the reaction was confirmed by TLC analysis, the reaction mixture was added saturated aqueous solution of ammonium chloride. The resulting mixture was filtered through celite. The filtrate was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate (=2:1), concentrated under reduced pressure to obtain specified in the title compound (39 mg, 0,073 mmol, 63%) as a white solid.

1H-NMR (400 MHz, DMSO-d6)δ: 3,63 (2H, t, J=6.3 Hz), 3.75 to of 3.85 (2H, m), 4,94 (1H, Shir. C)6,28 (1H, s), 7,28-of 7.55 (3H, m), of 7.70 (2H, d, J=8.7 Hz), 7,80 (2H, d, J=8.7 Hz), 7,81 (1H, s)of 8.37 (1H, s), 10,91 (1H, Shir. C).

TPL: 155-158 °C

IR (ATR) cm-1: 3093, 2867, 1600, 1565, 1492, 1392, 1322, 1139, 1083, 813, 754.

MS m/z: 536 (M+).

EI-MS: 535,9835 (Calculated for C20H16O5N2Cl2F2S2: 535,9846).

Elemental Analysis for C20H16N2O5Cl2F2S2·0,5H2O. Calculated: C,43,96; H,3,14; N,5,13; Cl,12,98,F, Of 6.95; S,11,74. Found: C,44,22; H,Of 3.07; N,5,13; Cl,12,89; F,7,10; S,11,65.

Example 285:2-[[[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]ndimethylacetamide

[Chemical formula 183]

7 N. the solution of AMIA is and in methanol (5 ml) was added ethyl [[[5-chloro-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]acetate (78 mg, is 0.135 mmol)obtained in example 283. The resulting mixture was stirred at room temperature for 3 days, then concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:25), concentrated under reduced pressure to obtain specified in the title compound (66 mg, 0,120 mmol, 89%) as a white solid.

1H-NMR (400 MHz, DMSO-d6)δ: 4,33 (2H, s), of 6.29 (1H, s), 7,29-7,56 (4H, m), of 7.64-7,72 (3H, m), 7,76-to 7.84 (3H, m), 8,35 (1H, s), 11,16 (1H, Shir. C).

IR (ATR) cm-1: 1691, 1596, 1565, 1492, 1382, 1322, 1238, 1149, 1083, 995, 966, 811.

MS m/z: 550 (M++H).

Elemental Analysis for C20H15N3O5Cl2F2S2·0,5H2O. Calculated: C,42,94; H,Is 2.88; N,7,51; Cl,12,68,F, 6,79; S,11,46. Found: C,42,64; H,2,73; N,7,46; Cl,12,57,F, 6,97; S,11,48.

Example 286:[[[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]acetic acid

[Chemical formula 184]

To a solution of ethyl [[[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]amino]sulfonyl]acetate (60 mg, 0.104 g mmol)obtained in example 283, in a mixture of tetrahydrofuran (5 ml) and water (1 ml) was added monohydrate of lithium hydroxide (9.1 mg, 0,218 mmol). The resulting mixture was stirred at room temperature over their 2 hours. To the reaction mixture was added 1 n hydrochloric acid. The resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of methanol:methylene chloride (=1:30) containing 0.5% triperoxonane acid, concentrated under reduced pressure to obtain specified in the title compound (54 mg, 0,098 mmol, 94%) as a white solid.

1H-NMR (400 MHz, DMSO-d6)δ: 4,45-4,60 (2H, m), of 6.29 (1H, s), 7,29-of 7.55 (3H, m), of 7.69 (2H, d, J=8,9 Hz), 7,80 (2H, d, J=8,9 Hz), 7,81 (1H, s), scored 8.38 (1H, s).

MS m/z: 551 (M++H).

Example 287:(Z)-5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(3-[1,3]dioxolane-2-ylpropyl)pyridine (Isomer 287-A) and (E)-5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(3-[1,3]dioxolane-2-ylpropyl)pyridine (Isomer 287-B)

[Chemical formula 185]

n-Utility (1,59M solution in hexane, 1.3 ml, 1,99 mmol) in an argon atmosphere at -78° (C) was added to a solution of 2-(1,3-dioxolane-2-yl)ethyltriphenylphosphonium (738 mg, 1,99 mmol) in tetrahydrofuran (30 ml). The resulting mixture was stirred for 1 hour. To the reaction mixture was added [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)met the l]pyridine-2-yl]carbaldehyde (400 mg, 0,904 mmol)obtained in example 258. The temperature of the mixture was raised to room temperature, followed by stirring for 4 hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride. The mixture then was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain Isomer 287-A (iskopaemoe connection)(140 mg, 0,266 mmol, 29%) as a colorless amorphous substance and Isomer 287-B (high-polar compound)(170 mg, 0,323 mmol, 36%) as a colorless amorphous substance.

Isomer 287-A

1H-NMR (400 MHz, CDCl3)δ: 3,03-3,17 (2H, m), 3,88-4,10 (4H, m), 5,11 (1H, t, J=4.3 Hz), 6,10 (1H,dt, J=12,0, 7,6 Hz), and 6.25 (1H, s), of 6.65 (1H, d, J=12.0 Hz), 6,93-6,99 (1H, m), 7.03 is-to 7.09 (1H, m), 7,44 (2H, d, J=8.6 Hz), to 7.61 (2H, d, J=8.6 Hz), to 7.67-7,71 (1H, m), 8,10 (1H, s), 8,49 (1H, s).

MS m/z: 526 (M++H).

Isomer 287-B

1H-NMR (400 MHz, CDCl3)δ: 2,67-a 2.71 (2H, m), 3,88-4,08 (4H, m), 5,07 (1H, t, J=4.6 Hz), of 6.20 (1H, s), of 6.68 (1H, d, J=15,9 Hz), 6,85-7,00 (2H, m), 7,02-was 7.08 (1H, m), 7,44 (2H, d, J=8.1 Hz), 7,55 to 7.62 (1H, m), to 7.61 (2H, d, J=8.1 Hz), of 7.96 (1H, s), 8,43 (1H, s).

MS m/z: 526 (M++H).

Example 288:4-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]butylaldehyde

[Himicheskaya 186]

Aqueous suspension of Raney Nickel (R-100", product of Nikko Rica Corporation) was washed successively with water and ethanol, and then to the mixture was added ethanol to obtain, respectively, of a suspension in ethanol. The obtained ethanol suspension (1 ml) was added to a solution of (Z) and (E)-5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]-2-(3-[1,3]dioxolane-2-ylpropyl)pyridine (80 mg, 0,152 mmol) in ethanol (5 ml) and 1,4-dioxane (3 ml). In an atmosphere of hydrogen at a pressure of 1 atmosphere the mixture was intensively stirred for 30 minutes. The reaction mixture was filtered, then the filtrate was concentrated under reduced pressure.

To a solution of the obtained residue in 1,4-dioxane (4 ml) was added concentrated hydrochloric acid (1 ml) and the resulting mixture was stirred at room temperature for 1 hour. The solvent was then concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The organic layer was washed with saturated saline solution. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 concentrated p and reduced pressure to obtain specified in the title compound (44 mg, 0,0908 mmol, 59%) as a colorless amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: 2,09-2,17 (2H, m), of 2.56 (2H,TD, J=7,3, 1.5 Hz), of 2.92 (2H, t, J=7,7 Hz), 6,21 (1H, s), 6,92-6,97 (1H, m), 7.03 is-was 7.08 (1H, m), 7,45 (2H, d, J=8.6 Hz), 7,51-of 7.55 (1H, m), to 7.61 (2H, d, J=8.6 Hz), 7.95 is (1H, s), of 8.47 (1H, s), 9,81 (1H, t, J=1.5 Hz).

MS m/z: 484 (M++H).

Example 289:4-[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]butyric acid

[Chemical formula 187]

To a solution of 4-[5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]butylaldehyde (40 mg, 0,0828 mmol) in formic acid (1 ml) was added 30% aqueous hydrogen peroxide solution (84 μl, 0,745 mmol). The resulting mixture was stirred at room temperature for 9 hours. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed successively with water and saturated salt solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from hexane:ethyl acetate to obtain specified in the title compound (13 mg, 0,0260 mmol, 32%) as a white powder.

1H-NMR (400 MHz, CDCl3)δ: 2,16-to 2.18 (2H, m), 2,46 (2H, t, J=7.2 Hz), 2,99 (2H, t, J=7.5 Hz), to 6.22 (1H, s), 6,92-6,98 (1H, m), 7.03 is-was 7.08 (1H, m), 7,45 (2H, d, J=8.6 Hz), 7,51-7,56 (1H, m), to 7.61 (2H, d, J=8.6 Hz), 8,00 (1H with), 8,49 (1H, s).

TPL: 147-148°C.

MS m/z: 500 (M++).

Example 290:2-methyl bromide-5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine

[Chemical formula 188]

To a solution of [5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]pyridine-2-yl]methanol (582 mg, of 1.41 mmol)obtained in example 256, in dichloromethane (15 ml) at 0°C was sequentially added tetrabromide carbon (936 mg, 2.82 mmol) and triphenylphosphine (407 mg, 1.55 mmol). The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=20:1 was concentrated under reduced pressure to obtain specified in the title compound (518 mg, of 1.09 mmol, 77%) as a colourless oil.

1H-NMR (400 MHz, CDCl3)δ: 4,51 (1H, d, J=10.5 Hz), of 4.54 (1H, d, J=10.5 Hz), 6,03 (1H, s), 6,94-7,06 (2H, m), 7,10-7,16 (1H, m), 7.23 percent (2H, d, J=8.5 Hz), 7,28 (2H, d, J=8.5 Hz), 7,73 (1H, s), 8,49 (1H, s).

MS m/z: 474,476 (M++H).

Example 291:[5-Chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine-2-yl]acetonitrile

[Chemical formula 189]

Trimethylsilylmethyl (0,226 ml of 1.63 mmol) and the solution tetrabutylammonium (1M, and 1.63 ml, and 1.63 mmol) in tetrahydrofuran was sequentially added in an argon atmosphere at room themes is the temperature value to a solution of 2-methyl bromide-5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)methyl]pyridine (516 mg, of 1.09 mmol) in acetonitrile (10 ml). The resulting mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=9:1 was concentrated under reduced pressure to obtain specified in the title compound (390 mg, of 0.93 mmol, 85%) as a brown oil.

1H-NMR (400 MHz, CDCl3)δ: 3,90 (1H, d, J=19,0 Hz), 3,95 (1H, d, J=19,0 Hz), 6,04 (1H, s), of 6.96-7,07 (2H, m), 7,12-to 7.18 (1H, m), from 7.24 (2H, d, J=8,8 Hz), 7,29 (2H, d, J=8,8 Hz), to 7.67 (1H, s), charged 8.52 (1H, s).

MS m/z: 421 (M++H).

Example 292:[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]acetonitrile

[Chemical formula 190]

To a solution of [5-chloro-4-[(4-chlorophenylthio)(2.5-differenl)-methyl]pyridine-2-yl]acetonitrile (387 mg, of 0.92 mmol) in ethyl acetate (5 ml) was added methanol (5 ml), 31% aqueous hydrogen peroxide solution (3 ml) and tetrahydrate hexaminolevulinate (227 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water. The ethyl acetate and methanol drove away under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate solution. The resulting product was extracted with dichloromethane. The organic layer was dried over anhydrous sulfate is the atrium and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=17:3 was concentrated under reduced pressure to obtain specified in the title compound (364 mg, 0.80 mmol, 87%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: was 4.02 (2H, s), from 6.22 (1H, s), 6,92-6,99 (1H, m),? 7.04 baby mortality-7,11 (1H, m), 7,46 (2H, d, J=8.6 Hz), of 7.48-rate of 7.54 (1H, m), a 7.62 (2H, d, J=8.6 Hz), 8,15 (1H, s), 8,56 (1H, s).

MS m/z: 453 (M++H).

Example 293:[5-Chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]acetic acid

[Chemical formula 191]

To a solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2.5-differenl)methyl]pyridine-2-yl]acetonitrile (113 mg, 0.25 mmol) in acetic acid (2 ml) was added at room temperature a mixture of water (2 ml) and concentrated sulfuric acid (2 ml). The resulting mixture was stirred at 100°C for 2 hours. After cooling the reaction mixture to room temperature, to the mixture was added water. The resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was washed with a mixture of solvents diethyl ether/hexane and then collected by filtration to obtain a decree of the tion in the title compound (101 mg, 0.21 mmol, 86%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 1,74 (1H, Shir. C)4,00 (1H, d, J=17,9 Hz), of 4.05 (1H, d, J=17,9 Hz), 6,23 (1H, s), 6,92-6,99 (1H, m),? 7.04 baby mortality-7,11 (1H, m), 7,45 (2H, d, J=8.6 Hz), of 7.48-rate of 7.54 (1H, m), a 7.62 (2H, d, J=8.6 Hz), to 8.12 (1H, s), charged 8.52 (1H, s).

MS m/z: 472 (M++H).

Reference Example 53:(2,5-Dichloro-4-pyridyl)(2,6-differenl)methanol

[Chemical formula 192]

n-Utility (1,60M solution in hexane, of 2.33 ml, 3.72 mmol) was added in an argon atmosphere at -78°C to a solution of Diisopropylamine (0,520 ml, 3.72 mmol) in tetrahydrofuran (12 ml). The resulting mixture was then stirred at -78°C for 30 minutes. To the reaction mixture were added a solution (2 ml) of 2,5-dichloropyridine (500 mg, to 3.38 mmol) in tetrahydrofuran. The resulting mixture was stirred at -78°C for 1 hour. Then to the reaction mixture solution was added 2,6-diferentialglea (395 mg, 3.72 mmol) in tetrahydrofuran (2 ml) followed by stirring at -78°C for 2 hours. To the reaction mixture was added 1 n hydrochloric acid (7 ml) and then the temperature of the reaction mixture was raised to room temperature. The reaction mixture was diluted with ethyl acetate. The diluted mixture was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained solid was washed with dichloromethane to obtain a decree of the tion in the title compound (746 mg, 2.57 mmol, 76%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: 2,62 (1H, Shir. d, J=3,7 Hz), 6,30 (1H, Shir. C)6,87-6,93 (2H, m), 7,28-7,37 (1H, m), to $ 7.91 (1H, s), of 8.25 (1H, s).

MS m/z: 290 (M++H).

Example 294:2,5-Dichloro-4-[(4-chlorophenylsulfonyl)(2,6-differenl)methyl]pyridine

[Chemical formula 193]

(2,5-Dichloro-4-pyridyl)(2,6-differenl)methanol (744 mg, 2.57 mmol)obtained in reference example 53, suspended in dichloromethane (6 ml), then was added thionyl chloride (0.5 ml) and dimethylformamide (one drop). The resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture was again added thionyl chloride (1.0 ml). The resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated. The obtained residue was neutralized with saturated sodium bicarbonate solution and then was extracted with dichloromethane. The extract was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was dissolved in dimethylformamide (10 ml). After adding 4-chlorobenzenesulfonate sodium (613 mg, is 3.08 mmol) the resulting mixture was heated at 50°C for 5 hours and then at 80°C for 3 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated salt solution is m, was dried over magnesium sulfate and concentrated. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=4:1 concentrated. The obtained solid substance was recrystallized from a mixture of diethyl ether-hexane to obtain specified in the header of the compound (761 mg, 1,69 mmol, 66%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: of 6.02 (1H, s), 6,84-of 6.90 (2H, m), 7,32-7,40 (1H, m), 7,46 (2H, d, J=8.5 Hz), the 7.65 (2H, d, J=8.5 Hz), 8,35 (1H, s), 8,43-8,46 (1H, m).

MS m/z: 448 (M++H).

Example 295:5-Chloro-4-[(4-chlorophenylsulfonyl)(2,6-differenl)methyl]-2-(3,4-dimethoxyphenethylamine)pyridine

[Chemical formula 194]

To a solution (20 ml) of 2,5-dichloro-4-[(4-chlorophenylsulfonyl)(2,6-differenl)methyl]pyridine (755 mg, by 1.68 mmol)obtained in example 294, N-methyl-2-pyrrolidone in an atmosphere of argon was added 3,4-dimethoxyphenethylamine (0,745 ml, 5,04 mmol). The resulting mixture was heated at 150°C for 5 hours. The reaction mixture was cooled to room temperature and then was diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate, water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to colon is the offered by flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1, was concentrated to obtain specified in the title compound (295 mg, 0,509 mmol, 30%) as a white amorphous substance.

1H-NMR (400 MHz, CDCl3)δ: to 3.89 (3H, s), 3,90 (3H, s), 4,48 (2H, d, J=5.6 Hz), is 5.06 (1H, t, J=5.6 Hz), of 6.02 (1H, s), for 6.81-to 6.88 (3H, m), 6,93-7,00 (2H, m), 7,28 and 7.36 (1H, m), 7,40 (2H, d, J=8,3 Hz), 7,51 (1H, s), 7,56 (2, d, J=8,3 Hz), 8,00 (1H, s).

MS m/z: 579 (M++H).

Example 296:5-Chloro-4-[(4-chlorophenylsulfonyl)(2,6-differenl)methyl]pyridine-2-ylamine

[Chemical formula 195]

5-Chloro-4-[(4-chlorophenylsulfonyl)(2,6-differenl)methyl]-2-(3,4-dimethoxyphenethylamine)pyridine (293 mg, 0,506 mmol)obtained in example 295, was dissolved in triperoxonane acid (4 ml). The resulting solution was heated at 65°C for 2 hours. The reaction mixture was concentrated. The residue was podslushivaet saturated aqueous sodium bicarbonate, then extracted with ethyl acetate. The extract was washed with water and saturated saline solution, dried over magnesium sulfate and concentrated. The obtained residue was subjected to column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=2:1, was concentrated. The obtained solid substance was recrystallized from a mixture of ethyl acetate-hexane to obtain specified in the title compound (147 mg, 0,343 mmol, 8%) as a white solid.

1H-NMR (400 MHz, CDCl3)δ: to 4.62 (2H, s), 6,01 (1H, s), 6,82-6,89 (2H, m), 7,29-7,38 (1H, m), 7,44 (2H, d, J=8.5 Hz), to 7.59 (1H, Shir. C)the 7.65 (2H, d, J=8.5 Hz), to 7.99 (1H, s).

IR (ATR) cm-1: 3502, 3400, 1620, 1603, 1545, 1471, 1412, 1333, 1279, 1230, 1151, 1084, 993, 928, 891, 829, 795, 756, 623, 559, 513, 459.

TPL: 179-181°C.

MS m/z: 429 (M++H).

Elemental Analysis for C18H12Cl2F2N2O2S. Calculated: C,50,36; H,2,82; Cl,16,52; F,Cent To 8.85; N,6,53; S,7,47. Found: C,50,36; H,2,83; Cl,16,39; F,8,88; N,6,48; S,7,56.

Example test

The method for determining the activity of inhibitor production or secretion β-amyloid protein

Inhibitory activity of the compounds obtained in examples directed against education β-amyloid protein, was tested by the method described below.

Cells E35 was obtained by transfection of the gene APP751, representing the predecessor of man β-amyloid protein of wild-type glioma person (H4 cells).

Cells E35 were sown in 96-well plates and cultured in the incubator at 37°C, using the modified Dulbecco Wednesday Needle containing 10% inactivated fetal bovine serum (10% FBS-DMEM). Twenty-four hours after vysielanie test compound dissolved in DMSO so as to obtain its concentration 2,000 times the final concentration, was added to the medium in the amount of 1/2000 volume ku is turalei environment. Cells were cultured for twenty-four hours and then collected the supernatant. Number β-amyloid protein (Aβ), secreted in the supernatant was measured using a solid-phase sandwich immunofermentnogo assay (ELISA). Namely, monoclonal antibody 25-1, recognizing Aβ25-35, was immobilized on 96-well tablet ELISA, and then incubated at 4°C for 16-20 hours. After washing with phosphate buffer (pH of 7.4)(PBS) was added biotinylated monoclonal antibody MA32-40, recognizing Aβ1-8, and the plate is kept at 4°C for 2 hours. The supernatant was removed and the wells were thoroughly washed in PBS, and then the tablet was added conjugated with alkaline phosphatase streptavidin. The absorbance was measured in the process of adding BlouPhos (manufacturer KPL) as substrate. The number of Aβcontained in the supernatant was calculated using a calibration curve constructed separately, using the known concentration of Aβ. IR50the test compound was represented as the concentration at which an observed 50% inhibition of the production of Aβ compared with the number of Aβ in the control cells, to which was added DMSO only.

On the other hand, the cytotoxicity of the test compounds was determined in the following way. Experience the e connection dissolved in DMSO, was added to the cells H4, cultured in 10% FBS-DMEM. After incubation for 72 hours, viable cells were counted using Alamar Blue (manufactured by BIOSOURCE). The concentration of the test compounds, in which the number of viable cells was 80% or less of the number of control cells, to which was added DMSO only, was defined as the concentration at which cytotoxicity occurs.

If the difference is at least 10 times between IR50and the concentration at which cytotoxicity occurs, it was considered that the compound has inhibitory activity against the production or secretion β-amyloid protein.

The results of the evaluation of the compounds of the present invention using the above analysis are presented in Table 1. Compounds demonstrating IR50not more than 5 nm, was estimated as +++, connections, showing IR50in the range from 5 nm to 50 nm, were evaluated as ++, and connections, showing IR50in the range from 50 to 500 nm, was estimated as +.

Table 1
ConnectionActivityConnectionActivity
1+220 (B)+
19+21 +++
20+222++
23 (Compound A)++225++
42+234+++
43+236+++
46+239+
55++240++
56++241++
57++242+
59++243++
61+++245++
82+246++
84+247+++
106+++249+++
109++250++
111++251+++
114++254+
115+++261++
116++267++
164+++268 +++
168+++269+++
176+++270++
196+++271+++
197+++274++
203++276++
211+++278+++
215+++279+++
216+++280+++

1. The compound represented by formula (1):

[Chemical formula 1]

where R1represents a phenyl group that contains 1-3 substituent selected from halogen and cyanopropyl;

R2represents pyridyloxy group, which has 1-3 substituents selected from monocyclic or polycyclic heterocyclic group, which may have 1-3 substituent selected from halogen atoms, ceanography, C1-6alkyl groups, hydroxy-group, C1-6alkoxygroup,2-6alkenylacyl, carboxy alkyl groups, With2-6alkoxycarbonyl alkyl group, a heterocycle-carbonyl C1-6alkyl groups, hydroxy, C1-6alkyl groups, sub> 6-10aromatic hydrocarbon-sulfonyl C1-6alkyl groups, N,N-dialkylaminoalkyl C1-6alkyl group, a heterocycle-C1-6alkyl groups With6-10aromatic hydrocarbons-From1-6alkyl groups With6-10aromatic hydrocarbon-thio C1-6alkyl groups, azido-C1-6alkyl groups, amino C1-6alkyl groups, C1-6alkylamino C1-6alkyl groups, di(C1-6alkyl)amino, C1-6alkyl groups, hydroxy, C1-6alkylamino C1-8alkyl groups, C1-6alkoxy alkylamino1-6alkyl groups, bis (C1-6alkoxy, C1-6alkyl)amino, C1-6alkyl groups (hydroxy, C1-6alkyl) (C1-6alkoxy, C1-6alkyl) amino, C1-6alkyl groups, C1-6alkanolamine alkyl groups, di(C2-6alkanoyl) amino alkyl groups, carboxamido C1-6alkyl groups, di(C1-6alkylcarboxylic C1-6alkyl) amino, C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl groups, di(C1-6alkoxycarbonyl)amino, C1-6alkyl groups, carbamoylating C1-6alkyl groups, N-C1-6alkylcarboxylic C1-6alkyl groups, (N,N-di(C1-6alkyl)carbarnoyl)amino, C1-6alkyl groups, aminosulfonyl C1-6alkyl groups, N-C1-6alkylsulfonamides C1-6alkyl groups, di(C1-6alkyl) aminosulfonyl alkyl groups, C6-10aromatic hydrocarbon-sulfonyl amino - C1-6alkanolamine C1-6alkyl groups, amino C1-6alkylcarboxylic C1-6alkyl groups, N-C1-6alkylamino C1-6alkylcarboxylic C1-6alkyl groups, N,N-di(C1-6alkyl) amino, C1-6alkylcarboxylic C1-6alkyl group, a heterocycle-C1-6alkylcarboxylic C1-6alkyl group, a heterocycle-C2-6alkenylboronic C1-6alkyl groups With6-10aromatic hydrocarbon-alkenylboronic C1-6alkyl groups With6-10aromatic hydrocarbon-carbylamine C1-6alkyl groups With6-10aromatic hydrocarbon-thiocarbanilide C1-6alkyl group, a heterocycle-carbylamine C1-6alkyl groups, C1-6alkoxysilane C1-6alkyl groups, (C6-10aromatic hydrocarbon-sulfonyl) (C1-6alkyl) amino, C1-6alkyl groups, C1-6alkylsulfonamides C1-6alkyl groups, carbamoylated C1-6alkyl groups, N-C1-6alkylcarboxylic C1-6alkyl groups, N,N-di(C1-6alkyl) carbamoylated C1-6alkyl groups With6-10aromatic hydrocarbons - C1-6alkylcarboxylic C1-6alkyl groups, C1-6 alkoxycarbonyl-C1-6alkyl groups With6-10aromatic hydrocarbon-oxycarbonate C1-6alkyl groups, heterocyclic carbohydratecontaining groups6-10aromatic hydrocarbon-carbohydratecontaining groups2-6alkenyl groups, carboxy-C2-6alkenyl groups, C1-6alkoxycarbonyl-C2-6alkenyl groups, carbarnoyl2-6alkenyl group, a heterocycle-alkenyl groups, formyl group, carboxyl group, a heterocycle-carbonyl group, a C6-10aromatic hydrocarbon-carbonyl group, a C1-6alkoxycarbonyl groups, carbamoyl group, N-C1-6alkylcarboxylic groups, N,N-di(C1-6alkyl)carbamoyl groups3-8cycloalkyl-C1-6alkylcarboxylic groups, alkylthio C1-6alkylcarboxylic groups, C1-6alkylsulfonyl C1-6alkylcarboxylic groups, C1-6alkylsulfonyl C1-6alkylcarboxylic groups, hydroxyaminopyrimidines group, C1-6alkoxycarbonyl groups, hydroxy alkylcarboxylic groups, C1-6alkoxy, C1-6alkylcarboxylic groups, amino C1-6alkylcarboxylic groups, amino C1-6alkyldiethanolamine groups, hydroxy, C1-6alkylcarboxylic groups, C1-6alkoxycarbonyl C1-6alkylcarboxylic groups C 1-6alkoxycarbonyl C1-6alkylcarboxylic groups, C1-6alkoxycarbonyl C1-6alkyldiethanolamine group, a heterocycle-carbamoyl group, a heterocycle-C1-6alkylcarboxylic groups6-10aromatic hydrocarbon-carbamoyl groups, hydrazinecarboxamide group, N-C1-6alkyldiethanolamine groups, N'-C1-6alkyldiethanolamine groups, N',N'-di(C1-6alkyl) hydrazinecarboxamide groups, N,N'(C1-6alkyl)hydrazinecarboxamide groups, N,N',N'-three(C1-6alkyl)hydrazinecarboxamide groups, N'-(heterocycle-carbonyl)-hydrazinecarboxamide groups, amino groups, C1-6alkoxy, C1-6alkylamino, amino, C1-6alkylamino, C1-6alkyl amino of alkylamino, (C1-6alkylamino C1-6alkyl) (C1-6alkyl) amino groups, (C1-6alkylcarboxylic C1-6alkyl) amino groups, (C1-6alkylsulfonyl alkyl) amino, C1-6alkoxycarbonyl C1-6alkylamino, di(C1-6alkyl) amino, C1-6alkilani-nogroup, heterocycle-amino C1-6alkylamino, carboxyl C1-6alkylamino, (carboxyl C1-6alkyl) (C1-6alkyl) amino group, a heterocycle-C1-6alkylamino, (heterocycle - C1-6alkyl) (C1-6alkyl) amino, hydroxy, C1-6alkylamino, (hydroxy, C 1-6alkyl) (C1-6alkyl) amino, C1-6alkylthio C1-6alkylamino, C1-6alkylaminocarbonyl C1-6alkylamino, (C1-6alkylaminocarbonyl C1-6alkyl) (C1-6alkyl) amino, C1-6alkylsulfonyl C1-6alkylamino, C1-6alkylsulfonyl C1-6alkylamino, groups represented by the formula: -N(R12)SO2R11(where, R11represents a C1-6alkyl group, heterocyclic group, a C1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl group, hydroxy, C1-6alkyl group, amino (C1-6alkyl group, a C1-6alkylamino C1-6alkyl group, di(C1-6alkyl) amino, C1-6alkyl group, a carboxy C1-6alkyl group, carbarnoyl C1-6alkyl group, triptorelin group, deformational group, formeterol group, an amino group, a C1-6alkylamino or di(C1-6alkyl)amino group, and R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group, hydroxy, C1-6alkoxy, C1-6alkylamino,6-10aromatic hydrocarbons-C1-6alkylamino, heterocycle-carbonylation, C1-6alkoxycarbonylmethyl, heterocycle-C1-6alkylcarboxylic, 6-10aromatic hydrocarbon-carbonylation, heterocycle-amino group, hydroxyisopropyl, C1-6alkoxyimino, carbonyl group, hydroxyimino C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkylamino, (C2-6alkanolamine C1-6alkyl) amino, C1-6aromatic hydrocarbon groups and heterocyclic groups (where C6-10aromatic hydrocarbon group or a heterocycle or heterocyclic group may be substituted by 1-3 substituents selected from halogen atoms, C1-6alkyl groups, C1-6alkoxygroup,2-6alkenyl groups, formyl groups, With2-6alkanoyl groups, carboxyl groups, carboxamido C1-6alkyl groups, C1-6alkoxycarbonyl C1-6alkyl group, carbonyl group, nitro group, ceanography, amidinopropane,2-6alkenylacyl, hydroxy-group, tocography, amino, C1-6alkylamino, di(C1-6alkyl) amino, amino (C1-6alkyl groups, C1-6alkoxycarbonyl groups, carbamoyl group, C1-6alkylcarboxylic groups, di(C1-6alkyl)carbamoyl groups, thiocarbamoyl group, C1-6alkyldiethanolamine groups, di(C1-6alkyl) thiocarbamoyl groups2-6alkanolamines,2-6alkanoyl (C1-6and the keel) amino groups, tio2-6alkanolamines, tio2-6alkanoyl (C1-6alkyl) amino group, formylamino group, formyl (C1-6alkyl) amino group, coformulating, diformyl (C1-6alkyl)amino, C2-6alkanoyloxy, formyloxy, mercaptopropyl, C1-6alkylthio, C1-6alkylsulfonyl groups, C1-6alkyl sulfanilic groups, aminosulfonyl group, C1-6alkylaminocarbonyl groups, di(C1-6alkyl)aminosulfonyl groups, C1-6alkylsulfonamides and C1-6alkyl sulfonyl (C1-6alkyl)amino;

R3represents a phenyl group or pyridyloxy group which has 1 to 2 substituent selected from halogen and trihalomethanes group;

R4represents a hydrogen atom; and X represents-SO2-;

its salt or its MES.

2. The compound according to claim 1, where R2represents a group of the formula:

[Chemical formula 2]

where R10represents a hydrogen atom, a C1-6alkyl group, hydroxy, C1-6alkyl group, a C1-6alkyl sulfinil C1-6alkyl group, a C1-6alkylsulfonyl C1-6alkyl group, a carboxy C1-6alkyl group, a heterocycle-C1-6alkyl GRU is PU or group, represented by the formula: -SO2-R11(where R11represents a C1-6alkyl, heterocyclic group, With1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl, hydroxy1-6alkyl, amino1-6alkyl, C1-6alkylamino alkyl, di(C1-6alkyl) amino With1-6alkyl, carboxy1-6alkyl, carbarnoyl1-6alkyl, trifluoromethyl, deformity, vermeil, amino, C1-6alkylamino or di(C1-6alkyl) amino), R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group, or R11and R12taken together with the sulfur atom is linked to R11and with the nitrogen atom is linked to R12may form a 5 - or 6-membered aliphatic heterocycle, and R13represents a C1-6alkyl group, halogen atom or cyano; its salt or its MES.

3. The compound according to claim 1, where R2represents a group of the formula:

[Chemical formula 3]

where R10represents a group of the formula: -SO2-R11(where R11represents a C1-6alkyl, heterocyclic group, With1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl, hydroxy1-6alkyl, amino1-6alkyl, C1-6alkylamino the 1-6alkyl, di(C1-6alkyl) amino With1-6alkyl, carboxy1-6alkyl, carbarnoyl1-6alkyl, trifluoromethyl, deformity, vermeil, amino, C1-6alkylamino or di(C1-6alkyl) amino), R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group, or R11and R12taken together with the sulfur atom is linked to R11and with the nitrogen atom is linked to R12may form a 5 - or 6-membered aliphatic heterocycle, and R13represents a C1-6alkyl group, halogen atom or cyano;

its salt or its MES.

4. The compound according to claim 1, where R2is a compound of the formula:

[Chemical formula 4]

where R13represents a C1-6alkyl group, halogen atom or cyano, and n is an integer having a value of 0-6; its salt or its MES.

5. The compound according to claim 1, where R1is a 2.5 differenly or 2-fluoro-5-cyanophenyl group, R3is a 4-chloraniline, 4-florfenicol, 2,4-differenly, 3,4-differenly, 3-fluoro-4-chloraniline, 4-triftormetilfullerenov, 5-chloro-2-pyridinol, 6-chloro-3-pyridinol or 6-trifluoromethyl-3-pyridyloxy group; R2represents the t of a group represented by the formula:

[Chemical formula 5]

where R10represents a hydrogen atom, a C1-6alkyl group, hydroxy1-6alkyl group, alkylsulfonyl1-6alkyl group, a C1-6alkylsulfonyl1-6alkyl group, carboxy1-6alkyl group, a heterocycle-C1-6alkyl group, or a group of the formula: -SO2-R11(where R11represents a C1-6alkyl, heterocyclic group, With1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl, hydroxy1-6alkyl, amino1-6alkyl, C1-6alkylamino1-6alkyl, di(C1-6alkyl) amino With1-6alkyl, carboxy1-6alkyl, carbarnoyl1-6alkyl, trifluoromethyl, deformity, vermeil, amino, C1-6alkylamino or di(C1-6alkyl) amino), R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group, or amino group, or R11and R12taken together with the sulfur atom is linked to R11and with the nitrogen atom is linked to R12may form a 5 - or 6-membered aliphatic heterocycle, and R13represents a C1-6alkyl group, halogen atom or cyano; salt; or MES.

6. The compound according to claim 1, where R1is a 2.5 ditto is phenyl or 2-fluoro-5-cyanophenyl group, R3is a 4-chloraniline, 4-florfenicol, 2,4-differenly, 3,4-differenly, 3-fluoro-4-chloraniline, 4-triftormetilfullerenov, 5-chloro-2-pyridinol, 6-chloro-3-pyridinol or 6-trifluoromethyl-3-pyridyloxy group;

R2represents a group of the formula:

[Chemical formula 6]

where R10represents a group of the formula: -SO2-R11(where R11represents a

With1-6alkyl, heterocyclic group, With1-6alkyl-heterocyclic group, a heterocycle-C1-6alkyl, hydroxy1-6alkyl, amino1-6alkyl, C1-6alkylamino1-6alkyl, di(C1-6alkyl)amino With1-6alkyl, trifluoromethyl, deformity, fluorine-methyl, amino, C1-6alkyl amino or di(C1-6alkyl) amino), R12represents a hydrogen atom, a C1-6alkyl group, a hydroxy-group or amino group, or R11and R12taken together with the sulfur atom is linked to R11and with the nitrogen atom is linked to R12may form a 5 - or 6-membered aliphatic heterocycle, and R13represents a C1-6alkyl group, halogen atom or cyano; its salt or its MES.

7. The compound according to claim 1, where R1is a 2.5 differenly or 2-fluoro--cyanophenyl group, R3represents a

4-chloraniline, 4-florfenicol, 2,4-differenly, 3,4-differenly, 3-fluoro-4-chloraniline, 4-triftormetilfullerenov, 5-chloro-2-pyridinol, 6-chloro-3-pyridinol or 6-trifluoromethyl-3-pyridyloxy group;

R2represents a group of the formula:

[Chemical formula 7]

where R13represents a C1-6alkyl group, halogen atom or cyano and n is an integer having a value of 0-6; its salt or their MES.

8. Drug, inhibiting the production or secretion β-amyloid protein, containing as active ingredient a compound according to any one of claims 1 to 13;

its salt; or MES.

9. The drug of claim 8, used for prevention or treatment of diseases resulting from abnormal production or secretion β-amyloid protein.

10. The drug according to claim 9, where the disease resulting from abnormal production or secretion β-amyloid protein, represents Alzheimer's disease or down's syndrome.

11. The pharmaceutical composition inhibiting the production or secretion β-amyloid protein, comprising the compound according to any one of claims 1 to 13, its salt or its MES and pharmaceutically when memy media.

12. The use of compounds according to claim 1, its salt or its MES to obtain a drug that inhibits the production or secretion β-amyloid protein.

13. The application indicated in paragraph 12, where the drug is an agent for the prevention or treatment of diseases resulting from abnormal production or secretion β-amyloid protein.

14. Use item 13, where the disease resulting from abnormal production or secretion β-amyloid protein, represents Alzheimer's disease or down's syndrome.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns applications of compositions formulated as follows or its salt, solvate or prodrug of medical agent for treatment or prevention of disease state mediated by glucokinase (GLK). Besides, given invention concerns new group of composition formulated as (I) and to method of specified compositions production. The invention enables to widen range of agents used for treatment or prevention of disease conditions mediated by glucokinase (GLK) where each of R1, R2, R3, n and m has values specified in the description.

EFFECT: increased efficiency.

19 cl, 51 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is related to the compounds of general formula (I) and their pharmaceutically acceptable salts with properties β2-adrenoreceptor agonists, to the method of their production and based on them pharmaceutical composition. The compounds can be used for treatment of conditions when the symptomatic severity can be reduced by β2- adrenoreceptor activation, e.g., obstructive or inflammatory respiratory diseases. In the general formula (I) , X means -R1-Ar-R2 or -Ra-Y; Ar means phenylen, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, phenyl, C1-C10 alcoxy, substituted by phenyl group or phenyl, substituted by C1-C10 alcoxy group; R1 and R2 are bound to the adjacent carbon atoms within Ar group, and either R1 means C1-C10alkylen, and R2 means hydrogen, C1-C10alkyl or halogen, Ra means the bond or C1-C10 alkylen optionally substituted by group of the row: hydroxy, C1-C10 alcoxy, C6-C10aryl or C7-C14aralkyl; Y means C1-C10alkyl, or C2-C10alkynil, optionally substituted by hydroxyl group, C3-C10cycloalkyl, optionally condensed with one or more benzene rings and optionally substituted by group of the row: C1-C10alkyl, C1-C10alcoxy, C3-C10cycloalkyl, C7-C14aralkyl, C7-C14aralkyloxy or C6-C10aryl, where groups C7-C14aralkyl, C7-C14aralkyloxy or C6-C10 aryl are optionally substituted by group of the row: halogen, C1-C10alkyl, C1-C10alcoxy; C6-C10aryl, optionally substituted by group of the row: halogen, hydroxy, C1-C10alkyl, C1-C10alcoxy, C1-C10halogenalkyl, phenoxy, C1-C10alkylthio, C6-C10aryl, 5-6-term saturated heterocyclic ring, containing one nitrogen atom in cycle; phenoxy, optionally substituted by C1-C10alcoxy group; 5-6-term heterocyclic ring, containing one or two nitrogen or oxygen atoms in cycle, and the described heterocyclic ring is optionally substituted by group of the row: C1-C10alkyl, C6-C10aryl, C7-C14aralkyl, C1-C10alcoxycarbonil or 5-7-term heterocyclil (C1-C10)alkyl, containing one nitrogen atom in cycle; -NRdRe, where Rd means hydrogen or C1-C10alkyl, and Re means C1-C10alkyl, or Re means C6-C10aryl, or Re means 5-6-term heterocyclic ring, containing one nitrogen or sulfur atom in cycle, and the ring is optionally substituted by halogen-substituted phenyl group or Re means C6-C10arylsypfonil, optionally substituted by groups C1-C10alkylamino or di(C1-C10alkyl)amino; -SRf, where Rf means C6-C10aryl or C7-C14aralkyl, optionally substituted by group of row: halogen or C1-C10halogenalkyl; or -CONHRg, where Rg means C6-C10aryl, provided, if Ra means the bond, then Y doesn't mean C1-C5alkyl.

EFFECT: compound can prevent or reduce symptom's intensity.

15 cl, 4 tbl, 157 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention relates to the novel compounds with formula (I) and their pharmaceutically acceptable salts. The compounds of this invention has the properties of the NPY receptor antagonists and can be used fortreatment of such diseases as arthritis, diabetes, malnutrition, obesity. In general formula (I) , R1 means phenyl or 6-term nitrogen-containing heteroaryl, where in at least one of two meta-positions each phenyl group or 6-term nitrogen-containing heteroaryl group is substituted by group R5; R2 means hydrogen; R3 means C3-C6cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, where in at least one of two ortho-positions each group of C3-C6 cycloalkyl, naphthyl, phenyl or 5-6-term heteroaryl, containing N or S as heteroatoms, substituted by group R6; R4 means hydrogen, C1-C6alkyl; R5 means hydrogen, cyano, trifluoromethyl, C1-C6alkyl-SO2-, amino-SO2-, halogen, C1-C6alcoxy, C1-C6alkylcarbonil or aminocarbonil; R6 means hydrogen, halogen, cyano, nitro, trifluoromethyl, C1-C6 alkyl, C1-C6 alcoxy or hydroxy, provided, one R5 group, and R6 doesn't mean hydrogen.

EFFECT: described compounds and based on them pharmaceutical agents are efficient in treatment and prevention of above listed diseases.

19 cl, 2 tbl, 2 dwg, 130 ex

FIELD: organic chemistry, medicine, pharmacy, cosmetology.

SUBSTANCE: invention relates to novel biphenylmethylthiazolidinedions of the general formula (I): , their salts, and to their optical and geometrical isomers possessing agonistic activity with respect to PPARγ receptors, to pharmaceutical and cosmetic compositions based on thereof, and to their using for preparing composition used in treatment of different cutaneous diseases. In compound of the formula (I) R1 means radical of the following formula (a): or (b): ; R2 and R3 mean hydrogen atom; X means binding groups showing the following structures: -CH2-N(R8)-CO-, -N(R8)-CO-N(R9)- that can be read from left to right or vice versa; R4 means phenyl substituted with group R10, pyrrolyl, naphthyl, biphenyl, indenyl, benzothienyl and all these groups can be mono- or di-substituted with group R11 and/or R12, group -(CH2)n-(CO)qR13, adamantyl, cyclopentylethyl, group -(CH2)n-O-R13; R5 means hydroxyl or alkoxyl with 1-19 carbon atoms; R6 means group -OR14. Values R8, R9, R10, R11, R12, R13, n and q are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

25 cl, 2 dwg, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl, naphthyl, 5-6-membered heterocyclyl comprising oxygen (O), nitrogen (N) or sulfur atom (S) as heteroatoms and wherein phenyl, naphthyl and heterocyclyl are optionally substituted with 1-3 substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy, nitro; di-(C1-C6)-alkylamino or (C1-C6)-alkoxy groups; R2 means hydrogen atom; R3 means (C1-C6)-alkyl or trifluoromethyl; A1 means C-R3 or nitrogen atom; A2 means piperidine or pyrrolidine wherein nitrogen atom in piperidine or pyrrolidine ring is added to A3 wherein A3 means -S(O)2- or -C(O)-; n = 0, 1 or 2. Also, invention relates to a pharmaceutical composition based on compounds proposed by the invention. Proposed compounds possess properties of NPY receptors antagonists and can be used in treatment arthritis, diabetes mellitus, nutrition disorders, obesity and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 1 dwg, 26 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. The compounds claimed by the invention have inhibition effect on VR1 receptor activation and can be applied in pain prevention or treatment. In the general formula (I) , or , L is a low alkylene, E cycle is benzene or 5-membered heteroaromatic ring containing sulfur atom as a heteroatom, D cycle is a monocyclic or bicyclic hydrocarbon cycle optionally condensed with C5-7 cycloalkyl, 6-membered monocyclic heteroaromatic cycle containing nitrogen atom as heteroatom or 9-11-membered bicyclic heteroaromatic cycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O, G cycle is a 5-7-membered monocyclic saturated or partially saturated heterocycle or 10-membered bicyclic heterocycle containing 1 to 3 equal or different heteroatoms selected out of the group including N, S and O. The invention also concerns pharmaceutical composition based on the said compounds, and application thereof in obtaining pain prevention or treatment medication, and a method of pain prevention or treatment.

EFFECT: obtaining prevention or treatment medium against pain.

24 cl, 470 ex, 41 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: derivatives possess antiproliferative activity and stimulate an apoptosis in cells where absence of normal regulation of development of a cell and its destruction is observed. The derivatives are applied as a part of pharmaceutical compositions in combination with pharmaceutically acceptable mediums. The pharmaceutical compositions can be applied for treatment of diseases caused by hyperproliferation, including tumour growth, lymphoproliterative diseases and angiogenesis. Invention compounds pertain to the group of replaced pyrazoles and Pyrazolinums characterised by the formula of the invention.

EFFECT: derivatives possess useful biological properties.

56 cl, 115 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a compound of the formula (I) where A ring is (C3-C8)-cycloalkyl or (C3-C8)-cycloalkenyl where two carbon atoms in the cycloalkyl ring can be substituted by oxygen atoms; R1, R2 are H, F, Cl, Br, OH, CF3, OCF3, (C1-C6)-alkyl or O-(C1-C6)-alkyl independently from each other; R3 is H or (C1-C6)-alkyl; R4, R5 are H, (C1-C6)-alkyl independently from each other; X is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; Y is (C1-C6)-alkyl where one carbon atom in the alkyl group can be substituted by oxygen atom; and its pharmaceutically acceptable salts. The invention also concerns such compounds as (+)-cis-2-(3-(2-(4-fluorphenyl)oxazole-4-ylmethoxy)cyclohexyloxymethyl)-6-methylbenzoic acid of the formula 6b , 2-{3-[2-(3-methoxyphenyl)-5-methyloxazole-4-ylmethoxy]cyclohexyl-oxymethyl}-6-methylbenzoic acid of the formula 53 and 2-methyl-6-[3-(5-methyl-2-n-tolyloxazole-4-ylmethoxy)cyclohexylomethyl]benzoic acid of the formula 70 , or their enantiomers. The invention also concerns pharmaceutical composition exhibiting PPARα agonist effect, including one or more compounds of the formula (I) as an active component together with a pharmaceutically acceptable carrier. The pharmaceutical composition is obtained by mixing of active compound of the formula (I) with a pharmaceutically acceptable carrier and rendering it a form viable for introduction.

EFFECT: obtaining of diarylcycloalkyl derivatives applicable as PPAR-activators.

9 cl, 2 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compounds of the formula (I) where: X is O; Y represents a bond, CH2, NR35, CH2NH, CH2NHC(O), CH(OH), CH(NHC(O)R33), CH(NHS(O)2R34), CH2O or CH2S; Z is C(O), or if Y is a bond, then Z can also be S(O)2; R1 could be substituted with phenyl; R4 is hydrogen, C1-6-alkyl (substituted possibly by C3-6-pilkoalkyl) or C3-6-cycloalkyl; R2, R3, R5, R6, R7 and R8 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; type independently indicate 0 or 1; R9 could possibly be substituted with an aryl or heterocycle; R10, R32 and R35 are independently hydrogen, C1-6-alkyl or C3-6-cycloalkyl; R33 and R34 are C1-6-alkyl or C3-6-cycloalkyl; where the aforesaid aryl and heterocyclic groups, when possible, can be substitute with: halogen cyanogens, nitro, hydroxyl, oxo, S(O)Kr12, OC(O)NR13R14, NR15R16, NR17C(O)R18, NR19C(O)NR20R21, S(O)2NR22R23, NR24S(O)2R25, C(O)NR26R27, C(O)R28, CO2R29, NR30CO2R31, by C1-6-alkyl (which itself can be monosubstituted with NHC(O)phenyl), C1-6-halogenalkyl, C1-6-alkoxy(C1-6)alkyl, C1-6-alkoxy, C1-6-halogenaloxy, C1-6-alkoxy(C1-6)-alkoxy, C1-6-alkylthio, C2-6-alkenyl, C2-6-alkinil, C3-10-cycloalkyl, methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkyl, morpholinyl, heteroaryl, heteroaryl(C1-4)alkyl, heteroarylhydroxy of heteroaryl(C1-4)alkoxy, where any of the said phenyl and heteroaryl groups can be substituted by halogen, hydroxyl, nitro, S(O)r(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-.4-alkyl)2, cyanogens, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), CO2H, CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3; k and r independently mean 0, 1 or 2; R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R26, R27, R29 and R30 independently represent hydrogen, C1-6-alkyl (probably replaced by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), C3-6-cycloalkyl, phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), NH(C1-4-alkyl)2, S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, S(O)2)(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2, cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4-alkyl), C(O)N(C1-4-alkyl)2, CO2H5 CO2(C1-4-alkyl), NHC(O)( C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)( C1-4-alkyl), CF3 or OCF3); alternatively, NR13R14, NR15R16, NR20R21, NR22R23, NR26R27 can independently form 4-7-member heterocyclic ring, selected from the group, which includes: azetidine (which can be substituted by hydroxyl or C1-4-alkyl), pyrrolidine, piperidine, azepine, 1,4-morpholine or 1,4-piperazine, the latter is probably substituted by C1-4-alkyl on the peripheral nitrogen; R12, R25, R28 and R31 are independently C1-6-alkyl (possibly substituted by halogen, hydroxyl or C3-10-cycloalkyl), CH2(C2-6-alkenyl), phenyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4- alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connec to form a ring as described hereabove for R13 and R14), cyanogen, C1-4- alkyl, C1-4- alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), NHC(O)(C1-4-alkyl), CF3 or OCF3) or heterocyclyl (itself probably replaced by halogen, hydroxyl, nitro, NH2, NH(C1-4-alkyl), N(C1-4-alkyl)2, (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), S(O)2(C1-4-alkyl), S(O)2NH2, S(O)2NH(C1-4-alkyl), S(O)2N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), cyanogen, C1-4-alkyl, C1-4-alkoxy, C(O)NH2, C(O)NH(C1-4- alkyl), C(O)N(C1-4-alkyl)2 (and these alkyl groups can connect to form a ring as described hereabove for R13 and R14), CO2H, CO2(C1-4-alkyl), NHC(O)(C1-4-alkyl), NHS(O)2(C1-4-alkyl), C(O)(C1-4-alkyl), CF3 or OCF3); or its N-oxide; or its pharmaceutically acceptable salt, solvate or solvate of its salt, which are modulators of activity of chemokines (especially CCR3); also described is the pharmaceutical composition on their basis and the method of treating the chemokines mediated painful condition.

EFFECT: obtaining new compounds possessing useful biological properties.

13 cl, 238 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazole derivatives of general formula I and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and based medicinal product. Compounds can be applied for treatment and prevention of diseases mediated by adenosine receptors, e.g., epilepsy, depressions, narcomania, Parkinson's disease. In general formula I R denotes phenyl unsubstituted or substituted with halogen or -SN2N(CH3) (CH2)nOCH3, or denotes benzyl, lower alkyl, lower alkoxy-group, - (CH2)nOCH3, or denotes pyridine-3- or -4-yl unsubstituted or substituted with lower alkyl, halogen, morpholinyl, - (CH2)n-halogen, - (CH2)nOCH3, - (CH2)n-diethylene-imide oxide-4-yl, or (CH2)n-tetrahydropyrrole-1-yl; R1 denotes phenyl unsubstituted or substituted with halogen tetrahydropyran-4-yl, 3,6-2H-2n-pyran-4-yl or morpholine-4-yl; n denotes mutually independent 1 or 2.

EFFECT: production of benzothiazole derivatives which can be applied for treatment and prevention of diseases mediated by adenosine receptors.

9 cl, 4 dwg, 27 ex

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