Pyridyl dimethylsulphonic derivative

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound of general formula (I): , where Ar1 is a phenyl group substituted with 1-3 halogen atoms; Ar2 is a phenyl group which can be substituted with a halogen, alkoxyalkyl, alkoxyhalogenalkyl, or pyridyl group which can be substituted with halogenalkyl; X is -S-, -SO- or -SO2-; Y is a hydrogen atom, -NR1R2 (where R1 is a hydrogen atom, lower alkyl group or hydroxy group; and R2 is a hydrogen atom, lower alkyl group which can be substituted, lower alkanoyl group, alkoxycarbonyl group which can be substituted, lower alkoxy group which can be substituted, amino group which can be substituted; or R1 and R2 together with a nitrogen atom with which they are bonded form a piperidine, morpholine, azetidine or piperazine ring, which can be substituted wiht a hydroxy group) or -OR1', where R1 is a hydrogen atom); Z is an oxygen atom or sulphur atom; and R is a hydrogen atom or a lower alkyl group; or to salts thereof. The invention also relates to a medicinal agent and a pharmaceutical composition which inhibit production/secretion of β- amyloid protein, to use of said compounds to prepare a medicinal agent and to a method of treating diseases caused by abnormal production or secretion of β- amyloid protein.

EFFECT: novel compounds which can inhibit production/secretion of β- amyloid protein and which can be used in treating Alzheimer disease or Down syndrome are obtained and described.

30 cl, 136 ex, 1 tbl

 

The present invention relates to a new compound which has the effect of inhibiting the production/secretion of β-amyloid protein, and to therapeutic tool for the treatment of various diseases caused by abnormal production and/or secretion of β-amyloid protein such as Alzheimer's disease, down syndrome and other diseases associated with amyloid deposits.

Alzheimer's disease is a neurodegenerative disorder that is pathologically characterized by the formation of senile plaques and neurofibrillary plexus together with degeneration of neurons and their deaths. Alzheimer's disease causes symptoms of dementia, when memory, learning, thinking, judgment, etc. progressively lost, leading, thus, to death. Up to the present time has not been known any method that would be effective for the prevention and treatment of this disease.

Protein plays a major role in the formation of senile plaques, otlichayuschihsya in the brain, is the β-amyloid protein (amyloid β protein, β), which consists of 39-43 amino acids. β-Amyloid protein possesses cytotoxicity, which are believed to cause Alzheimer's disease (non-Patent document 1). β-Amyloid protein, the secretory cells, is a polypeptide composed primarily 40-42 and is of inoculat, and, in particular, it is known that β-amyloid protein, consisting of 42 amino acids, deposits in the brain at an early stage with a high capacity for aggregation and has a strong cytotoxicity (non-Patent document 2). Although β-amyloid protein is produced everywhere in the body, its original function is still not clear.

β-Amyloid protein is produced by processing of amyloid protein precursor (APP)is a transmembrane protein. Among patients suffering from Alzheimer's disease, there are cases recognition mutations in the APP gene. In addition, it is known that in cells transfected with this mutant APP gene, the amount of production/secretion of β-amyloid protein increases. Based on this believe that drug, inhibiting the production/secretion of β-amyloid protein, will be effective for the prevention or treatment of Alzheimer's disease.

As for the method of splitting the RDA to β-amyloid protein, have been reported asparaginase, such as VASA (enzyme cleavage of APP by β-site) (non-Patent document 3) or Asp1 (non-Patent document 4), as β-secretase associated with the N-terminal cleavage of β-amyloid protein. At the same time, with regard to γ-secretase, which is responsible for C-terminal cleavage, there are good reasons for redelegate, that Presenilin is part of it (non-Patent document 5). It was reported about the inhibitors of these β-secretase and γ-secretase (non-Patent document 6), and many of them are peptide compounds.

Smith et al. open the link in Patent document 1, which has sulfonamidnuyu skeleton and regulates the production of β-amyloid protein. Belanger et al. also open the link in Patent document 2, which has bicycloalkanes skeleton and inhibits γ-secretase. In addition, Patent documents 3, 4 and 5 disclose compounds having the activity of inhibiting the production of β-amyloid protein. Patent documents 6, 7 and 8 also reveal diarylamino compounds that inhibit γ-secretase. In addition, Patent documents 9 and 10 also disclose compounds that inhibit the production of β-amyloid protein. At the same time, Patent document 11 discloses tianeptine derivative, which inhibits the aggregation of amyloid proteins.

[Patent document 1] international Publication No. WO 00/50391.

[Patent document 2] international Publication No. WO 01/70677.

[Patent document 3] international Publication No. WO 02/40451.

[Patent document 4] international Publication No. WO 02/40508.

[Patent document 5] international Publication No. WO 02/47671.

[Patent document 6] international Publication No.WO 02/081433.

[Patent document 7] international Publication No. WO 02/081435.

[Patent document 8] international Publication No. WO 03/018543.

[Patent document 9] international Publication No. WO 03/055850.

[Patent document 10] international Publication No. WO 05/000798.

[Patent document 11] Japanese Laid Patent Application No. 9-95444.

[Non-patent document 1] Science, Vol. 259, p. 514 (1993).

[Non-patent document 2] Journal of Biological Chemistry, Vol. 270, p. 7013 (1995).

[Non-patent document 3] Science, Vol. 286, p. 735 (1999).

[Non-patent document 4] Molecular and Cellular Neuroscience, Vol. 16, p. 609 (2000).

[Non-patent document 5] Journal of Medicinal Chemistry, Vol. 44, p. 2039 (2001).

Disclosure of invention

The problems solved by the present invention

The present invention is the provision of compounds, which has a strong effect of inhibiting the production/secretion of β-amyloid protein and, thus, is effective for the prevention and/or treatment of various diseases associated with abnormal production and/or secretion of β-amyloid protein.

Means of solving problems

The authors of the present invention was performed a large amount of research, and as a result, it was found that pyridylmethylamine, pyridylmethylamine connection and pyridylmethylamine connection, all presented to the following General formula (1), inhib the shape of the production/secretion of β-amyloid protein by a strong inhibition of γ-secretase and are therefore useful as therapeutic agents for the treatment of various diseases, caused by abnormal production and/or secretion of β-amyloid protein, thus was established the present invention.

Thus, the present invention provides a compound represented by the following General formula (1):

where Ar1represents a substituted phenyl group;

Ar2represents a phenyl group which may be substituted, or a heterocyclic group which may be substituted;

X represents-S-, -SO - or-SO2-;

Y represents a hydrogen atom, -NR1R2(where R1represents a hydrogen atom, a lower alkyl group or a hydroxy-group; and R2represents a hydrogen atom, a lower alkyl group which may be substituted, lower alkanoyloxy group, alkoxycarbonyl group which may be substituted, lower alkoxygroup, which may be substituted, amino group which may be substituted, phosphonopropyl, phenyl group which may be substituted, or an aromatic heterocyclic group which may be substituted; or R1and R2together with the nitrogen atom to which they are linked, form a saturated heterocyclic group, such saturated heterocyclic group represents a group which may be substituted) or-OR1'(where R 1'represents a hydrogen atom or a lower alkyl group which may be substituted);

Z represents an oxygen atom or a sulfur atom; and

R3represents a hydrogen atom, a lower alkyl group or halogen atom;

or its salt, or MES compounds or salts.

In addition, the present invention provides a drug containing the compound represented by General formula (1), its salt or MES compound or salt as an active ingredient.

The present invention also aims at providing a pharmaceutical composition containing the compound represented by General formula (1), its salt or MES compound or salt and a pharmaceutically acceptable carrier.

In addition, the present invention is directed to the use of compounds represented by General formula (1), its salt or MES compound or salt to obtain the drug.

Moreover, the present invention is directed to providing a method of treating diseases caused by abnormal production and/or secretion of β-amyloid protein, the method includes introducing an effective amount of the compound represented by General formula (1), its salt or MES compounds or salts.

The effects of the invention

The present invention which may provide the means for a pharmaceutical for the prevention and/or treatment of various diseases, for example, Alzheimer's disease, down's syndrome or other diseases associated with amyloid deposits.

The best way of carrying out the invention

Next will be described compounds represented by the General formula (1).

Ar1represents a substituted phenyl group.

In this case, the above phenyl group has as substituents, 1 to 3 atoms or groups selected from the group consisting of a halogen atom and a lower alkyl group which may be substituted by halogen atom, hydroxy-group. Preferably, the number of substituents is 2 or 3. In the case when the deputies should use several of the substituents, these substituents may represent the same atoms or groups, or part of the substituents may represent different atoms and/or groups, or all substituents may represent different atoms and/or groups.

If there are two Deputy, the position of substitution is preferably represent 2-position and 5-position; whereas in the case of three Vice-position substitution preferably represent 2-position, 3-position and 6-position.

In addition, the atom and the Deputy, which are substituted in the phenyl group represented by Ar1will be described below.

The term “halogen atom” OSN which denotes a chlorine atom, fluorine atom, bromine atom or iodine atom. Of these, a chlorine atom and a fluorine atom are preferred, and, in particular, the fluorine atom is preferred.

The term “lower alkyl group which may be substituted by a halogen atom or hydroxy-group” means unsubstituted lower alkyl group and lower alkyl group described above substituted by a halogen atom or hydroxy-group.

The term “lower alkyl group” means a linear, branched or cyclic alkyl group containing 1-6 carbon atoms. Therefore, specific examples of the lower alkyl group include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, 2-methylbutyl group, 2,2-dimethylbutyl group, 2-methylpentyl group, n-hexoloy group, cyclopropyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopropylethyl group, cyclopentyloxy group, tsiklogeksilnogo group, etc.

For the lower alkyl group substituted by a halogen atom or a hydroxy-group, the number of substitutions, a halogen atom or hydroxy-group is not limited, provided that the substitution can take place, but this number is preferably from 1 to 3. Chrome is also when several atoms or groups you want to use as alternates, substitutions you can use the same atoms or groups, or for substitutions you can use different atoms or groups, but preferably, when substitutions have the same atoms. Therefore, a lower alkyl group substituted by a halogen atom or a hydroxy-group, includes chloromethylene group, dichloromethylene group, trichlorethylene group, formeterol group, deformational group, triptorelin group, 2-foretelling group, 2-deperately group, 2-triptorelin group, 1-foretelling group, 1-deperately group, 1,2-deperately group, hydroxymethylene group, 2-hydroxyethyloxy group, 1-hydroxyethylene group, etc.

Thus, specific examples of Ar1include 2-chloraniline group, 3-chloraniline group, 4-chloraniline group, 2-florfenicol group, 3-florfenicol group, 4-florfenicol group, 2,5-dichloraniline group, 2,6-dichloraniline group, 2,3,6-trichlorophenyl group, 2,3-differenly group, 2,4-differenly group, 2,5-differenly group, 2,6-differenly group, 3,5-differenly group, 2,3,5-triptorelin group, 2,3,6-triptorelin group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,5-dimetilfenil the ing group, 3-chloro-2-methylphenyl group, 3-fluoro-2-methylphenyl group, 5-chloro-2-methylphenyl group, 5-fluoro-2-methylphenyl group, 2-chloro-5-methylphenyl group, 2-fluoro-3-methylphenyl group, 2-chloro-5-methylphenyl group, 2-fluoro-5-methylphenyl group, 2-chloromethylpyridine group, 3-chloromethylpyridine group, 2-dichlorodiphenyl group, 3-dichlorodiphenyl group, 2-trichloromethylpyridine group, 3-trichloromethylpyridine group, 2-formatieren group, 3-formatieren group, 4-formatieren group, 2-deformational group, 3-deformational group, 2-triftormetilfullerenov group, 3-triftormetilfullerenov group, 2-chloro-5-chloromethylpyridine group, 2-chloro-5-dichlorodiphenyl group, 2-chloro-5-trichloromethylpyridine group, 2-chloro-5-formatieren group, 2-chloro-5-deformational group, 2-chloro-5-triftormetilfullerenov group, 5-chloro-2-chloromethylpyridine group, 5-chloro-2-formatieren group, 5-chloro-2-deformational group, 5-chloro-2-triftormetilfullerenov group, 2-fluoro-5-chloromethylpyridine group, 2-fluoro-5-formatieren group, 2-fluoro-5-deformational group, 2-fluoro-5-triftormetilfullerenov group, 5-fluoro-2-chloromethylpyridine group, 5-fluoro-2-formatieren group, 5-fluoro-2-deformational group, 5-fluoro-2-triftormetilfullerenov group 2-methyl-5-chlorine is methylphenylene group, 2-methyl-5-formatieren group, 2-methyl-5-deformational group, 2-methyl-5-triftormetilfullerenov group, 2-chloromethyl-5-methylphenyl group, 2-vermeil-5-methylphenyl group, 2-deformity-5-methylphenyl group, 2-trifluoromethyl-5-methylphenylene group, 5-chloro-2-florfenicol group, 2-chloro-5-florfenicol group, 5-chloro-2-hydroxymethylamino group, 5-fluoro-2-hydroxymethylamino group 2-chloro-5-hydroxymethylamino group, 2-fluoro-5-hydroxymethylamino group, 2,3-debtor-5-hydroxymethylamino group, 2,6-debtor-5-hydroxymethylamino group, etc. Of this 2.5-diferencia group and 2,3,6-triptorelin group are preferred.

Next will be described in Ar2.

Ar2represents a phenyl group which may be substituted, or a heterocyclic group which may be substituted.

In this description, the term “phenyl group which may be substituted” means unsubstituted phenyl group and phenyl group which is substituted by one Deputy or two identical or different substituents selected from the group comprising lower alkyl group which may be substituted by a halogen atom, a hydroxy-group, the lower alkoxygroup, which may be substituted, and halogen atom. If there is one Deputy, Paul the position of substitution is preferably a 4-Polozheniye, whereas in the case when there are two substitute, substitution at the 3-position and 4-position or substitution at the 3-position and 5-position are preferred.

Lower alkyl group which may be substituted by a halogen atom, which is a surrogate for the above-mentioned phenyl group, means the same group as the lower alkyl group which may be substituted by a halogen atom described above as the substituent for Ar1.

For low alkoxygroup, which may be substituted, which is used as a substituent for the above-mentioned phenyl groups, the term ”lower alkoxygroup” means alkoxygroup containing the above-described lower alkyl group as a constituent fragment, and these lower alkoxygroup can be optionally substituted by a halogen atom. Thus, the lowest alkoxygroup, which may be substituted, may include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, tert-butoxypropyl, phenoxypropan, hexoloy group, cyclopropylamino, cryptometer, trichlormethiazide, etc. From them, methoxy group and tripterocarpa are preferred.

As examples of the halogen atom as the substituent for the above-mentioned phenyl groups can be applied in the lead the same halogen atoms, described above as the substituents for Ar1and the chlorine atom and a fluorine atom are preferred, and the fluorine atom is particularly preferred.

Heterocyclic group, such as in heterocyclic group which may be substituted, means a monocyclic or bicyclic heterocyclic group, and specifically means pyridine-2-ilen group, pyridine-3-ilen group, thiophene-2-ilen group, benzofuran-6-ilen group, dihydrobenzofuran-6-ilen group, pyrimidine-5-ilen group or the like, These heterocyclic groups may be substituted with one group or atom, or two identical or different groups or atoms selected from the group comprising lower alkyl group which may be substituted by a halogen atom the hydroxy-group, the lower alkoxygroup, which may be substituted, and halogen atom as described in the case when Ar2represents a phenyl group which may be substituted. That is, when the substituents are several groups or atoms, these groups or atoms may be the same or may be different from each other.

When Ar2represents a substituted pyridine-2-ilen group, substituted pyridine-3-ilen group, or pyrimidine-5-ilen group, these groups preferably contain the Deputy position in the research Institute of the pair relative to the connection with the sulfur atom. Namely, when Ar2represents a substituted pyridine-2-ilen group, preferably, when the substitution group or atom is a 5-position, whereas, when Ar2represents a substituted pyridine-3-ilen group, preferably, when the substitution group or atom is in the 6-position. When Ar2represents a substituted pyrimidine-5-ilen group, preferably, when the substitution group or atom is in the 2-position.

Therefore, specific examples of Ar2include phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 4-propylphenyl group, 4-isopropylphenyl group, 4-cyclopropylamino group, 4-butylphenyl group, 4-tert-butylphenyl group, 4-cyclobutylmethyl group, 4-cyclopentylphenol group, 4-cyclohexylaniline group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2-methyl-4-ethylphenyl group, 3-methyl-4-ethylphenyl group, 3-ethyl-4-methylphenyl group, 4-chloromethylpyridine group, 4-dichlorodiphenyl group, 4-trichlorocarbanilide group, 2-formatieren group, 2-deformational group, 2-triftormetilfullerenov group, 3-format fanilow group, 3-deformational group, 3-triftormetilfullerenov group, 4-formatieren group, 4-deformational group, 4-triftormetilfullerenov group, 4-trichloromethyl-3-methylphenyl group, 4-trifluoromethyl-3-methylphenyl group, 5-trichloromethyl-3-methylphenyl group, 5-trifluoromethyl-3-methylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-metoksifenilny group, 3-metoksifenilny group, 4-metoksifenilny group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 4-(triptoreline)phenyl group, 2-chloraniline group, 3-chloraniline group, 4-chloraniline group, 2,3-dichloraniline group, 2,4-dichloraniline group, 3,4-dichloraniline group, 3,5-dichloraniline group, 2-florfenicol group, 3-florfenicol group, 4-florfenicol group, 2,3-differenly group, 2,4-differenly group, 3,4-differenly group, 3,5-differenly group, 4-chloro-3-methylphenyl group, 4-fluoro-3-methylphenyl group, 3-chloro-4-methylphenyl group, 3-fluoro-4-methylphenyl group, 3-fluoro-4-formatieren group, 3-fluoro-4-deformational group, 5-chloro-3-methylphenyl group, 5-fluoro-3-methylphenyl group, 3-fluoro-4-triftormetilfullerenov group, 3-fluoro-5-triftormetilfullerenov group, 3-fluoro-4-metoksifenilny group, 3-the ENT-4-metoksifenilny group, 3-fluoro-4-ethoxyphenyl group, 3-chloro-4-ethoxyphenyl group, 4-fluoro-3-metoksifenilny group, 4-chloro-3-metoksifenilny group, 4-fluoro-3-ethoxyphenyl group, 4-chloro-3-ethoxyphenyl group; pyridine-2-ilen group, 3-methylpyridin-2-ilen group, 4-methylpyridin-2-ilen group, 5-methylpyridin-2-ilen group, 6-methylpyridin-2-ilen group, 5-(chloromethyl)pyridine-2-ilen group, 5-(dichloromethyl)pyridine-2-ilen group, 5-(trichloromethyl)pyridine-2-ilen group, 5-(permitil)pyridine-2-ilen group, 5-(deformity)pyridine-2-ilen group, 5-(trifluoromethyl)pyridine-2-ilen group, 5-hydroxypyridine-2-ilen group, 5-methoxypyridine-2-ilen group, 5-ethoxypyridine-2-ilen group, 3-chloropyridin-2-strong group, 3-herperidin-2-ilen group, 4-chloropyridin-2-ilen group, 4-herperidin-2-ilen group, 5-chloropyridin-2-ilen group, 5-herperidin-2-ilen group, 6-chloropyridin-2-ilen group, 6-herperidin-2-ilen group, 5-chloro-3-methylpyridin-2-ilen group, 5-fluoro-3-methylpyridin-2-ilen group, 5-chloro-4-methylpyridin-2-ilen group, 5-fluoro-4-methylpyridin-2-ilen group, 5-chloro-6-methylpyridin-2-ilen group, 5-fluoro-6-methylpyridin-2-ilen group, 5-trifluoromethyl-4-methylpyridin-2-ilen group; pyridine-3-ilen group, 2-methylpyridin-3-ilen group, 4-methylpyridin-3-ilen group, 5-methylpyridin-3-ilen group, 6-methylpyridin-3-ilen group,6-(chloromethyl)pyridine-3-ilen group, 6-(dichloromethyl)pyridine-3-ilen group, 6-(trichloromethyl)pyridine-3-ilen group, 2-(permitil)pyridine-3-ilen group, 2-(deformity)pyridine-3-ilen group, 2-(trifluoromethyl)pyridine-3-ilen group, 4-(permitil)pyridine-3-ilen group, 4-(deformity)pyridine-3-ilen group, 4-(trifluoromethyl)pyridine-3-ilen group, 5-(permitil)pyridine-3-ilen group, 5-(deformity)pyridine-3-ilen group, 5-(trifluoromethyl)pyridine-3-ilen group, 6-(permitil)pyridine-3-ilen group, 6-(deformity)pyridine-3-ilen group, 6-(trifluoromethyl)pyridine-3-ilen group, 6-methoxypyridine-3-ilen group, 2-chloropyridin-3-ilen group, 2-herperidin-3-ilen group, 4-chloropyridin-3-strong group, 4-herperidin-3-ilen group, 5-chloropyridin-3-ilen group, 5-herperidin-3-ilen group, 6-chloropyridin-3-ilen group, 6-herperidin-3-ilen group, 6-chloro-4-methylpyridin-3-ilen group, 6-fluoro-4-methylpyridin-3-ilen group, 6-chloro-5-methylpyridin-3-ilen group, 6-fluoro-5-methylpyridin-3-ilen group, 5-methyl-6-triptorelin-3-ilen group; thiophene-2-ilen group, 3-methylthiophene-2-ilen group, 4-methylthiophene-2-ilen group, 5-methylthiophene-2-ilen group, 5-trichloromethylthio-2-ilen group, 5-triptorelin-2-ilen group, 5-hydroxythiophene-2-ilen group, 5-chlorothiophene-2-ilen group, 5-fortifed-2-ilen group; benzofuran-6-ilen group, 3-methylbenzofuran the n-6-ilen group, 5-methylbenzofuran-6-ilen group, 2,3-dihydrobenzofuran-6-ilen group, 3-methyl-2,3-dihydrobenzofuran-6-ilen group, 5-methyl-2,3-dihydrobenzofuran-6-ilen group; pyrimidine-5-ilen group, 2-methylpyrimidin-5-ilen group, 2-chloropyrimidine-5-ilen group, 2-ftorpirimidinu-5-ilen group, 2-trichloromethylpyridine-5-ilen group, 2-cryptomaterial-5-ilen group, etc.

Of them, phenyl group, 4-methylphenylene group, 4-chloraniline group, 4-Fortunella group, 4-trichloromethylpyridine group, 4-triftormetilfullerenov group, 4-metoksifenilny group, 4-(triptoreline)phenyl group, 3,4-diferencia group, 3,5-diferencia group, 4-chloro-3-methylphenylene group, 4-fluoro-3-methylphenylene group, 5-chloropyridin-2-ilen group, 5-herperidin-2-ilen group, 5-methylpyridin-2-ilen group, 5-(permitil)pyridine-2-ilen group, 5-(deformity)pyridine-2-ilen group, 5-(trifluoromethyl)pyridine-2-ilen group, 6-chloropyridin-3-ilen group, 6-herperidin-3-ilen group, 6-methylpyridin-3-ilen group, 6-(permitil)pyridine-3-ilen group, 6-(deformity)pyridine-3-ilen group, 6-(trifluoromethyl)pyridine-3-ilen group, 2-(trifluoromethyl)pyrimidine-5-ilen group, 5-chlorothiophene-2-ilen group, 5-fortifed-2-ilen group, benzofuran-6-ilen group, 2,3-dihydrobenzofuran-6-ilen group, etc. are preferred which, and more preferred are a phenyl group, a 4-methylphenylene group, 4-triftormetilfullerenov group, 4-chloraniline group, 4-Fortunella group, 4-metoksifenilny group, 4-(triptoreline)phenyl group, 3,4-diferencia group, 4-chloro-3-methylphenylene group, 4-fluoro-3-methylphenylene group, 3,5-diferencia group, 5-(trifluoromethyl)pyridine-2-ilen group, 6-(trifluoromethyl)pyridine-3-ilen group and benzofuran-6-ilen group.

X represents-S-, -SO - or-SO2-. Compound and a compound represented by the General formula (1), and where X represents-SO - or-SO2-can demonstrate the desired effect, in particular in vivo.

Y represents a hydrogen atom, -NR1R2or1'.

When Y is-NR1R2as a concrete example, R1and R2you can lead the group, described below, but are not specifically limited, provided that these groups may be metabolised in the body with the formation of the-NH2as Y.

R1means a hydrogen atom, a lower alkyl group or a hydroxy-group. As described above, the lower alkyl group means a linear, branched or cyclic alkyl group containing 1-6 carbon atoms, and methyl group and ethyl group are preferred. For R1 a hydrogen atom or a methyl group are especially preferred.

R2represents a hydrogen atom, a lower alkyl group which may be substituted, lower alkanoyloxy group, alkoxycarbonyl group which may be substituted, lower alkoxygroup, which may be substituted, amino group which may be substituted, phosphonopropyl, phenyl group which may be substituted, or an aromatic heterocyclic group which may be substituted.

The term “lower alkyl group which may be substituted” in the case when R2represents a lower alkyl group which may be substituted, means unsubstituted lower alkyl group and a lower alkyl group containing as substituents 1-3 groups selected from the group comprising lower alkanoyloxy group, carboxyl group, lower alkoxycarbonyl group, a hydroxy-group, the lower alkoxygroup, which may be substituted, mercaptopropyl, lower allylthiourea, lower alkylsulfonyl group, lower alkylsulfonyl group, amino group which may be substituted, halogen atom, phenyl group which may be substituted, an aromatic heterocyclic group which may be substituted. When there are several groups as mandated the residents, these groups may be the same, some groups may be the same or all groups can be different.

In this specification, the lower alkyl group such as a lower alkyl group which may be substituted, includes the same groups as those described above, but a methyl group, ethyl group, through the group and tert-bucilina group are preferred, with methyl group or ethyl group is more preferred.

Next will be described substituents for the lower alkyl group in the case when R2represents a lower alkyl group which may be substituted.

The term “lower alcoolica group” means a linear or branched alkanoyloxy group containing 2 to 6 carbon atoms, and examples of such groups include acetyl group, propionyl group, butyryloxy group, valerino group, hexanoyl group, etc.

The term “lower alkoxycarbonyl group” means a lower alkoxycarbonyl group containing the above-described lower alkyl group as a component of the fragment, and means methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group or the like

Lowest alkoxygroup, such as in the lowest alkoxygroup, which may be substituted, means the same group as the lower alcox the group, described as a substituent for Ar1and examples of such groups include a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, phenoxypropan, cyclopropylamino, cyclopentyloxy, cyclopropylmethoxy, etc. From them, methoxy group and ethoxypropan are preferred. These low alkoxygroup can be optionally substituted carboxyl group, alkoxycarbonyl group, a hydroxy-group or heterocyclic group, such as Peregrina group. Therefore, the preferred lower alkoxygroup, which may be substituted, include a methoxy group, ethoxypropan, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2-hydroxyethoxy, pyridine-3-yletoxarap etc., whereas the methoxy group, ethoxypropan, carboxymethoxy, ethoxycarbonylmethoxy, 2-hydroxyethoxy, pyridine-3-yletoxarap, etc. can be mentioned as more preferred group.

The term “lower allylthiourea” shall mean the lower allylthiourea containing the above-described lower alkyl group as a component of the fragment, and examples of such groups include metalcorp, ethylthiourea, PropertyGroup, tert-butylthiourea, cyclopropylamino etc.

The term “nissanaltima group” means a lower alkylsulfonyl group, containing the above-described lower alkyl group as a component of the fragment, and examples of such groups include methylsulfinyl group, ethylsulfinyl group, propylsulfonyl group, tert-butylsulfonyl group, cyclopropylmethyl group, etc.

The term “lower alkylsulfonyl group” means a lower alkylsulfonyl group containing the above-described lower alkyl group as a component of the fragment, and examples of such groups include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, tert-butylsulfonyl group, cyclopropylmethyl group, etc.

The term “amino group which may be substituted” means the unsubstituted amino group, and amino group, substituted by one Deputy, selected from the group comprising lower alkyl group, lower alkanoyloxy group, lower alkoxycarbonyl group and nitrogen-containing heterocyclic group, and examples of such groups include an amino group, methylaminopropyl, dimethylaminopropyl, acetylamino, propionamido, bucillamine, methoxycarbonylamino, ethoxycarbonylmethyl, tert-butoxycarbonylamino, etc. From them dimethylaminopropan is preferred.

The halogen atom means, as described above, acomplia, fluorine atom, bromine atom or iodine atom.

The term “phenyl group which may be substituted” means unsubstituted phenyl group, and phenyl group substituted by one to three hydroxy groups, or lower alkoxygroup. There is no limitation provisions of substitute for deputies. In addition, when the phenyl group contains several deputies, this phenyl group may be substituted by the same substituents, or a part of the substituents may be the same or all substituents may represent a different group. Thus, specific examples of the phenyl group which may be substituted include a phenyl group, 3-hydroxyphenyl group, 3,4-dihydroxyphenyl group, 3-hydroxy-4-metoksifenilny group, 3,5-dihydroxyphenyl group, 3-metoksifenilny group, 3,4-dimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, etc.

The term “aromatic heterocyclic group which may be substituted” means a nitrogen-containing aromatic heterocyclic group which may be substituted by the above lower alkyl group, and means pyridyloxy group, pyridazinyl group, pyrimidinyl group, personilnya group, pyrazolidine group, imidazolidinyl group or triazolyl group, each of which is nezametno is, and methylpyridyl group, methylpyridinium group, methylpyrrolidinyl group, methylpyrazolo group or the like

Moreover, in the case when R2represents a lower alkyl group substituted by a hydroxy-group, the above hydroxy-group can optionally be substituted by the Deputy, which can be either hydrolyzed in the body with the formation of the above hydroxy-group. The type of the substituent is not specifically limited, and you can use those deputies that are known to possess this property. For example, you can specify the Deputy, which ensures the formation of ester bonds, or the like, such as a substituted carbonyl group or phosphonopropyl. As specific examples of the substituted carbonyl group can lead alkanoyloxy group, benzoyloxy group, an aromatic heterocyclic carbonyl group or the like, These groups can be optionally substituted by a hydroxy-group, amino group, carboxypropyl or the like, Therefore, a substitute for a lower alkyl group which may be substituted, may include acetochlor, propionyloxy, butyryloxy, hydroxyacetaldehyde, aminoacetaldehyde, accelerograph, carboxitherapy, carboxyphenoxypropane, carboxymethyloxime, benzoyloxy, ka is oxybenzoates, pyridylcarbonyl, karboksimyetilirovaniye, phosphonooxy etc.

Thus, examples of the lower alkyl group which may be substituted, as in the case of R2include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, 2-methylpentyl group, n-hexoloy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group; acetylamino group, 1-acetylamino group, 2-acetylethyl group, 3-acetylamino group; carboxymethyl group, 2-carboxyaniline group, 3-carboxypropyl group, 2-carboxypropyl group; methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonyl group, butoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylethyl group, 2-propoxycarbonyl group, 2-butoxycarbonylamino group, 2-tert-butoxycarbonylamino group; hydroxymethylene group, 2-hydroxyethyloxy group, 1-hydroxyethylene group, 1,2-dihydroxyethyl group, 1-hydroxymethyl-2-hydroxyethylene group, 1-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxy-1-g is proximodistally group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 2-hydroxyisopropyl group, 2-hydroxyisobutyryl group, 4-hydroxycyclohexyl group; acetoxymethyl group, propionylthiocholine group, butyrylcholine group, hydroxyethoxyethyl group, aminoethoxymethyl group, accelerograph, carboxylatomethyl group, carboxypropylbetaine group, benzoyloxymethyl group, carboxymethyloxyamino group, pyridylcarbonyl group, carboxymethylaminomethyl group, phosphonomethyl group; methoxymethyl group, ethoxymethyl group, karboksimetoksimetilguanina group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-hydroxyethoxymethyl group, (pyridin-3-ylethoxy)methyl group, methoxyamino group, ethoxyethylene group, methoxypropyl group, methoxyisobutyl group, methoxybutyl group; mercaptomethyl group; methylthiomethyl group, ethylthiomethyl group, 2-methylthioethyl group, 2-ethylthioethyl group, 3-methylthiopropionate group, 2-methylthiophenyl group, 3-ethylthiophene group; methylsulfonylamino group, ethylsulfinyl group, 2-methylsulfonylamino group 2-ethylsulfinyl group, 3-methylsulfinylpropyl group, 3-ethylsulfinyl group; methylsulfonylamino group, ethylsulfonyl group, 2-methylsulfonylamino group, 2-ethylsulfonyl group, 3-methylsulfinylpropyl group, 2-methylsulfonylamino group, 3-ethylsulfonyl group; aminomethyl group, dimethylaminomethyl group, acetamidomethyl group, propionylthiocholine group, butyrylthiocholine group, 2-aminoethyl group, 2-acetylaminophenol group, 2-propionylthiocholine group, 2-butyrylthiocholine group, 1-acetylaminophenol group, 1-propionylthiocholine group, 1-butyrylthiocholine group, methoxycarbonylamino group, ethoxycarbonylmethyl group, tert-butoxycarbonylmethylene group, 2-methoxycarbonylethyl group, 2-ethoxycarbonylmethyl group, 2-tert-butoxycarbonylmethyl group; chloromethylene group, formeterol group, 2-chloraniline group, 2-foretelling group; phenylmethylene group, 3-hydroxytrimethylene group, 3,4-dihydroxyphenylethanol group, 3-hydroxy-4-methoxyphenethyl group, 3,5-dihydroxyphenylethanol group, 3-methoxyphenethyl group, 3,4-dimethoxyphenylthio group, 3,4,5-trimethoxybenzylamine group; 2-pyridylmethyl group, 3-iriternational group, 4-pyridylmethyl group, 3-methyl-4-pyridylmethyl group, 2-pyridinylmethyl group, 2-pyrimidinemethanol group, 4-pyrimidinemethanol group, 2-personalityyou group, 1H-imidazol-2-ylmethylene group, 1H-pyrazole-5-ylmethylene group, 1H-triazole-5-ylmethylene group, etc.

The term “lower alcoolica group”, such as in the case when R2represents the lowest alkanoyloxy group means a linear or branched alkanoyloxy group containing 2 to 6 carbon atoms, and examples of such groups include acetyl group, propionyl group, butyryloxy group, valerino group, hexanoyl group, etc.

The term “lower alkoxycarbonyl group which may be substituted”, such as in the case when R2represents the lowest alkoxycarbonyl group which may be substituted, means above the lower alkoxygroup, which may be substituted by a hydroxy-group or aromatic heterocyclic group, and examples of such groups include carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, 2-hydroxyethoxyethyl group, pyridylcarbonyl group, etc.

The term “lower alkoxygroup, which may be substituted”, such as in the case when R2represents a lower alkoxygroup to what I may be substituted, means above the lower alkoxygroup, which may be substituted by a hydroxy-group or aromatic heterocyclic group, and examples of such groups include a methoxy group, ethoxypropan, 2-hydroxyethoxy, 2-pyridyloxy etc.

The term “amino group which may be substituted”, such as in the case when R2represents an amino group which may be substituted, means an unsubstituted amino group, and methylaminopropyl, dimethylaminopropyl, ethylamino, 2-hydroxyethylamino, 2-pyridylamino, acetylamino, etc. in Addition, the amino group which may be substituted, may be a substituted aliphatic heterocyclic group containing as its constituent fragment of the nitrogen atom, which forms the above amino group, and examples of such groups include morpholine-4-ilen group, piperidino, piperazinone, 4-methylpiperazine etc.

The term “phenyl group which may be substituted”, such as in the case when R2represents a phenyl group which may be substituted, means unsubstituted phenyl group and phenyl group which may be substituted by one Deputy, selected from the group comprising lower alkyl group, hydroxy-lower alkyl group is, the hydroxy-group, aminocarbonyl group, methylaminomethyl group and dimethylaminocarbonylmethyl group. Preferably, when such substituents are in the para-position on the relationship between the above phenyl group and an amino group. Thus, examples of the phenyl group which may be substituted include phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-hydroxymethylamino group, 4-hydroxyphenyl group, 4-aminocarbonylmethyl group, 4-methylaminoethanol group, 4-dimethylaminocarbonylmethyl group, etc.

Aromatic heterocyclic group, such as in the case when R2represents a heterocyclic group that may include 5 - or 6-membered nitrogen-containing aromatic heterocyclic group such as 2-pyridyloxy group, 3-pyridyloxy group, 2-pyrimidinyl group, 4-pyrimidinyl group, 2-pyridazinyl group, 1H-imidazol-2-ilen group, 1H-pyrazole-5-ilen group, 1H-triazole-5-ilen group, etc.

Of them, for R2as preferred groups may include hydrogen atom, methyl group, ethyl group, tert-bucilina group, cyclopropyl group, carboxymethyl group, 2-carboxyaniline group, 2-(etoxycarbonyl)ethyl group, hydroxymethylene the group, 2-hydroxyethylene group, 4-hydroxycyclohexyl group, 2-hydroxy-1-hydroxymethylation group, acetoxymethyl group, methylthiopropionate group, methylsulfinylpropyl group, methylsulfonylamino group, methylcarbamoylmethyl group, methoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, 2-chloraniline group, hydroxyethoxyethyl group, dimethylaminomethylene group, karboksimetoksimetilguanina group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 2-hydroxyethoxymethyl group, (pyridin-3-ylethoxy)methyl group, mercaptomethyl group, acetyl group and a methoxy group; and more preferred groups may include hydrogen atom, methyl group, ethyl group, cyclopropyl group, carboxymethyl group, 2-carboxyaniline group, hydroxymethylene group, 2-hydroxyethylene group, acetoxymethyl group, methylsulfinylpropyl group, methylsulfonylamino group, methoxycarbonylmethyl group, hydroxyethoxyethyl group, dimethylaminomethylene group, karboksimetoksimetilguanina group, ethoxycarbonylmethyl group, 2-hydroxyethoxymethyl group, (pyridin-3-ylethoxy)methyl group, mercaptomethyl group, are the strong group and a methoxy group. Even more preferred groups are a hydrogen atom, methyl group, ethyl group, hydroxymethylene group, 2-hydroxyethylene group, dimethylaminomethylene group and a methoxy group.

As a substituent, represented by-NR1R2in a preferred group can be enabled amino group, methylaminopropyl, dimethylaminopropyl, (hydroxymethyl)amino group, N-methyl-N-(hydroxymethyl)amino group, (2-hydroxyethyl)amino group and N-methyl-N-(2-hydroxyethyl)amino group.

In addition, R1and R2together with the nitrogen atom to which these groups are bound, may form a saturated heterocyclic group. Saturated heterocyclic group means a 4-7-membered saturated heterocyclic group which may contain as its components 1 to 3 identical or different atoms selected from nitrogen atom, oxygen atom and sulfur atom, in addition to the above nitrogen atom. Specific examples of such groups include azetidinol group, pyrrolidinyl group, pyrazolidine group, imidazolidinyl group, diazolidinyl group, isothiazolinone group, oxazolidinyl group, isooxazolyl group, piperidinyl group, piperazinilnom group, morpholinyl group, thiomorpholine group, hexahydropyridine group is, tetrahydropyranyloxy group, homopiperazine group, homopiperazine group, homomorpholine group, etc.

Of them azetidinone group, pyrrolidinyl group, pyrazolidinone group, imidazolidinyl group, piperidinyl group, piperazinilnom group, hexahydropyridine group, hexahydropyridine group, morpholinyl group, thiomorpholine group and homopiperazine group are preferred, and more preferred are piperidinyl group, piperazinilnom group, morpholinyl group and thiomorpholine group.

Such a 4-7-membered saturated heterocyclic group may be substituted by one or two or three identical or different groups selected from the group comprising lower alkyl group, hydroxy-lower alkyl group, a hydroxy-group, oxoprop, amino group and halogen atom. Provided that the substitution can take place, these substituents may be substituted on the same atom or may be substituted by different atoms. As specific examples of the lower alkyl group and halogen atom, which can be used for substitution of the above saturated heterocyclic group, can lead to the same groups as those described above.

When a 4-7-membered saturated heterocyclic what group represents thiomorpholine group, preferably, one or two carbonyl group have been substituted by sulfur atom.

So, in the case when R1and R2together with the nitrogen atom to which they are bound, form a 4-7-membered saturated heterocyclic group which may be substituted, and specific examples of such groups include azetidin-1-ilen group, 3-methylaziridine-1-ilen group, 2,2-dimethylamide-1-ilen group, 3,3-dimethylamide-1-ilen group, 3-hydroxyazetidine-1-ilen group, 2-oxoazetidin-1-ilen group, 3-oxoazetidin-1-ilen group, 3-torasemide-1-ilen group, 3,3-diversecity-1-ilen group; pyrrolidin-1-ilen group, 2,2-dimethylpiperidin-1-ilen group, 3,3-dimethylpiperidin-1-ilen group, 2-hydroxypyrrolidine-1-ilen group, 3-hydroxypyrrolidine-1-ilen group, 3,4-dihydroxypyrrolidine-1-ilen group, 2-oxopyrrolidin-1-ilen group, 3-oxopyrrolidin-1-ilen group, 2,5-dioxopiperidin-1-ilen group, 3-aminopyrrolidine-1-ilen group; pyrazolidine-1-ilen group, 2-methylpiperidin-1-ilen group, 2-hydroxypyrrolidine-1-ilen group, 3-oxopyrrolidin-1-ilen group, 3,5-dioxopiperidin-1-ilen group; imidazolidin-1-ilen group, 3-methylimidazolidine-1-ilen group, 2-Oxymetazoline-1-ilen group, 4-Oxymetazoline-1-ilen group, 3-methyl-2-Oxymetazoline-1-ilen group, 3-methyl-4-accomidate the n-1-ilen group, 2.2-dimethylimidazole-1-ilen group; piperidine-1-ilen group, 4-methylpiperidin-1-ilen group, 2,2-dimethylpiperidin-1-ilen group, 3,3-dimethylpiperidin-1-ilen group, 4,4-dimethylpiperidin-1-ilen group, 4-hydroxyethylpiperazine-1-ilen group, 4-hydroxypiperidine-1-ilen group, 2-oxopiperidin-1-ilen group, 3-oxopiperidin-1-ilen group, 4-oxopiperidin-1-ilen group, 4-aminopiperidin-1-ilen group, 4-foreperiod-1-ilen group, 4-chloropyridin-1-ilen group, 3,3-deformability-1-ilen group, 4,4-deformability-1-ilen group, 3,3-dichloropyridine-1-ilen group, 4,4-dichloropyridine-1-ilen group; piperazine-1-ilen group, 4-methylpiperazin-1-ilen group, 4-ethylpiperazin-1-ilen group, 4-isopropylpiperazine-1-ilen group, 2-cyclopropylmethyl-1-ilen group, 3-cyclopropylmethyl-1-ilen group, 4-cyclopropylmethyl-1-ilen group, 4-cyclobutylmethyl-1-ilen group, 2,2-dimethylpiperazine-1-ilen group, 3,3-dimethylpiperazine-1-ilen group, 2,6-dimethylpiperazine-1-ilen group, 2-cyclopropyl-4-methylpiperazin-1-ilen group, 3-cyclopropyl-4-methylpiperazin-1-ilen group, 3,4,5-trimethylpyrazine-1-ilen group, 2,2,4-trimethylpyrazine-1-ilen group, 3,3,4-trimethylpyrazine-1-ilen group, 4-hydroxyethylpiperazine-1-ilen group, 4-hydroxypiperidine-1-ilen group, 2-oxopiperidin-1-Ile is a second group, 3-oxopiperidin-1-ilen group, 2-oxo-4-methylpiperazin-1-ilen group, 3-oxo-4-methylpiperazin-1-ilen group, 2,3-dioxopiperazinyl-1-ilen group, 3,5-dioxopiperazinyl-1-ilen group, 2,6-dioxopiperidin-1-ilen group, 2,3-dioxo-4-methylpiperazin-1-ilen group, 3,5-dioxo-4-methylpiperazin-1-ilen group, 3,3,4-trimethyl-5-oxopiperidin-1-ilen group, 2,2,4-trimethyl-3-oxopiperidin-1-ilen group; hexahydropyridine-1-ilen group, 2-methylhexahydrophthalic-1-ilen group, 3,3-dimethyltetrahydrofuran-1-ilen group, 4,4-dimethyloxazolidine-1-ilen group, 6-hydroxyacetophenone-1-ilen group, 3-oxohexanoate-1-ilen group, 6-oxohexanoate-1-ilen group; hexahydropirimidine series-1-ilen group, 2-methylhexahydrophthalic-1-ilen group, 3-methylhexahydrophthalic-1-ilen group, 2.2-dimethyloxazolidine-1-ilen group, 4,4-dimethyloxazolidine-1-ilen group, 5,5-dimethyloxazolidine-1-ilen group, 6,6-dimethyloxazolidine-1-ilen group, 2-oxohexanoate-1-ilen group, 4-oxohexanoate-1-ilen group, 5-oxohexanoate-1-ilen group, 6-oxohexanoate-1-ilen group; morpholine-4-ilen group, 2,2-dimethylmorpholine-4-ilen group, 3,3-dimethylmorpholine-4-ilen group; thiomorpholine-4-strong group, 2,2-dimethyl morpholin-4-ilen group, 3,3-dimethylmorpholine-4-ilen group, 2-Osotimehin-4-ilen group, 1,1-diocletianopolis-4-ilen group; homopiperazin-1-ilen group, 2-methylhomopiperazine-1-ilen group, 4-methylhomopiperazine-1-ilen group, 4-cyclopropylmethyl-1-ilen group, 2,2-dimethylpiperidin-1-ilen group, 3,3-dimethylpiperidin-1-ilen group, 5,5-dimethylpiperidin-1-ilen group, 6,6-dimethylpiperidine-1-ilen group, 7,7-dimethylpiperidin-1-ilen group, 3,4,5-trimethylpyrazine-1-ilen group, 2-oklahomaepinion-1-ilen group, 3-oklahomaepinion-1-ilen group, 5-oklahomaepinion-1-ilen group, 6-oklahomaepinion-1-ilen group, 7-oklahomaepinion-1-ilen group, 2-oxo-4-methylhomopiperazine-1-ilen group, 3-oxo-4-methylhomopiperazine-1-ilen group, 5-oxo-4-methylhomopiperazine-1-ilen group 6-oxo-4-methylhomopiperazine-1-ilen group, 7-oxo-4-methylhomopiperazine-1-ilen group, 2,3-dioxopiperidin-1-ilen group, 2,3-dioxo-4-methylhomopiperazine-1-ilen group and the like, including 4-hydroxypiperidine-1-ilen group, 3-oxopiperidin-1-ilen group and a morpholine-1-ilen group are preferred.

When Y is-OR1', R1'represents a lower alkyl group which may be substituted by hydrogen atom or hydroxy-group. The lower alkyl group Osnach the em as described above, a linear, branched or cyclic alkyl group containing 1 to 6 carbon atoms. Such groups can be substituted by one or two hydroxy groups. The position of substitution of the hydroxy-group is not specifically limited, provided that the substitution can take place. Therefore, the examples R1'may include hydrogen atom, methyl group, ethyl group, hydroxymethylene group, hydroxyethylene group and the like From them is a hydrogen atom, methyl group and ethyl group are preferred.

Z represents an oxygen atom or a sulfur atom.

R3represents a hydrogen atom, a lower alkyl group or halogen atom. The lower alkyl group means, as described above, a linear, branched or cyclic group containing 1-6 carbon atoms. The halogen atom represents the same groups as those described above. Of them is a hydrogen atom, a methyl group and a chlorine atom are preferred.

The combination of substituents in the General formula (1) is not specifically limited, but an example of a preferred combination of the substituents includes 2.5 differenly group for Ar1; 4-florfenicol group for Ar2; -SO - X; dimethylaminopropyl for Y; the oxygen atom for Z and a methyl group for R3.

Moreover, another example of the combination predpochtite is selected substituents includes 2.5 differenly group or 2,3,6-triptorelin group for Ar 1; phenyl group, 4-florfenicol group or 6-(trifluoromethyl)pyridine-3-ilen group for Ar2; -SO2for X; (hydroxymethyl)amino group or the amino group for Y; the oxygen atom for Z and a methyl group for R3.

As an example of a preferred combination of the substituents you can specify, for example, a combination of 2,5-defterlerini group for Ar1, 4-forfamilies group for Ar2, -SO2- for X (hydroxymethyl)amino group for Y, the oxygen atom for Z and a methyl group for R3; or a combination of 2,3,6-triptorelin group for Ar1, 4-forfamilies group for Ar2, -SO2- for X (hydroxymethyl)amino group for Y, the oxygen atom for Z and a methyl group for R3; the combination of 2,3,6-triptorelin group for Ar1, phenyl groups for Ar2, -SO2- for X (hydroxymethyl)amino group for Y, the oxygen atom for Z and a methyl group for R3; the combination of 2,3,6-triptorelin group for Ar1, 6-(trifluoromethyl)pyridine-3-ilen group for Ar2, -SO2- for X (hydroxymethyl)amino group for Y, the oxygen atom for Z and a methyl group for R3.

The connection represented by the General formula (1) according to the present invention can exist in the form of stereoisomers, or optical isomers derived from asymmetric carbon atoms, and these shall stereoisomer, optical isomers and their mixtures are included in the present invention.

Salt compounds represented by the General formula (1) according to the present invention is not specifically limited, provided that it is pharmaceutically acceptable salt, and specific examples of such salts include salts of mineral acids, such as hydrochloride, hydrobromide, hydroiodide, phosphates, nitrates and sulfates; benzoate; salts of organic sulfonic acids, such as methanesulfonate, 2-hydroxyethanesulfonic and p-toluensulfonate; and salts of organic carboxylic acids, such as acetates, propanoate, oxalates, malonate, succinate, glutarate, adipate, tartratami, maleates, malty and mandelate.

Also, when the compound represented by General formula (1)contains an acid group, the compound may be a salt ion of an alkali metal or alkali earth metal ion. MES such compounds are not specifically limited, provided that it is pharmaceutically acceptable, and, in particular, you can specify hydrates, ethanolate etc.

Next will be described a method of obtaining a compound represented by the General formula (1) according to the present invention.

The connection represented by the General formula (1) according to the present invention, its salt and MES of such compounds or salts can be obtained by combinations of the known method is to obtain, used in General chemistry, and representative methods of synthesis described below.

Next will be described a representative method of obtaining the pyridine compounds of General formula (1) according to the present invention, where Z represents an oxygen atom (1: Z=O).

where Ar1, Ar2, R1, R2, R3, R1'and Y is defined above.

1) a Method of obtaining alcohol derivative (3)

where Ar1and R3defined above.

In a solvent such as toluene or diethyl ether, 2,5-dibromopyridine derivative (2) can be subjected to interaction with the equivalent of the ORGANOMETALLIC reagent (as representatives you can specify an organolithium reagent or a Grignard reagent), to thereby selectively lichirovarc 5-position of the pyridine. By adding an aldehyde represented by Ar1CHO, as the electrophilic reagent to the resulting solution to obtain an alcohol derivative (3).

In another way, when dimethylformamide or ethyl formate is added in as an electrophilic reagent in the reaction described above, it is possible to obtain an aldehyde derivative (4). Alcohol derivative can also be synthesized by adding Ar1-Li, which is obtained with Ar1-Br or Ar1-H, and one or two equival new ORGANOMETALLIC reagent (as a representative, you can specify organolithium reagent) in a solvent, such as tetrahydrofuran or diethyl ether.

In addition, arylcarbamoyl (Ar1-CHO), arylboronic (Ar1-Br) or aryl (Ar1-H), or 2,5-dibromopyridine derivative (2)used in the production method, described above, may be known compounds or they can be obtained through a combination of methods that are well known to specialists in this area with average skills.

2) a method of obtaining a sulfide derivative (6)

where L represents a removable group; and Ar1, Ar2and R3defined above.

The compound (5) can be obtained from the alcohol derivative (3). The sulfide compound (6) can be obtained by reacting the obtained compound (5) with tilenum connection (Ar2-SH) in the presence of a base. In this case tilne compound can be in the form of a salt of an alkali metal salt or alkaline earth metal (e.g. lithium, sodium, potassium).

In the reaction between the compound (5) and thiol (Ar2-SH) temperature is normally in the range from -20 to 200°C and preferably from room temperature to 60°C. depending on the connection type (5) or Colnago connection (Ar2-SH) may be preferable higher the reaction temperature, and may sometimes be preferred as the reaction takes place in a hermetically akritas vitro. The reaction time usually ranges from 0.5 hour to 1 day.

Examples of the base include inorganic bases such as hydrides of alkali metals or alkaline earth metals (e.g. lithium hydride, sodium hydride, potassium hydride, calcium hydride); amides of alkali metals or alkaline earth metals (e.g. lithium amide, sodium amide, diisopropylamide lithium, dicyclohexylamine lithium hexamethyldisilazide lithium hexamethyldisilazide sodium, hexamethyldisilazide potassium); lower alkoxides of alkali metals or alkaline earth metals (e.g. sodium methoxide, ethoxide sodium tert-piperonyl potassium); hydroxides of alkali metals or alkaline earth metals (e.g. sodium hydroxide, potassium hydroxide, hydroxide lithium, barium hydroxide; carbonates of alkali metals or alkaline earth metals or silver (for example, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate; bicarbonates of alkali metals (e.g. sodium bicarbonate, potassium bicarbonate); connection alkylate (for example, n-utility) or alkyl Grignard reagent (for example, methylmagnesium); silver oxide, and organic bases such as amines (e.g. triethylamine, diisopropylethylamine, N-methylmorpholine); and basic heterocyclic compounds (for example, dimethylaminopyridine, pyridine, imidazo is, 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 include alcohol solvents, ether solvents, halogen solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and water, and a mixture of two or more of these solvents can also be used. Of them methylene chloride, tetrahydrofuran, diethyl ether, etc. are preferred.

The compound (5)that contains the deleted group, L, can be obtained from the alcohol derivative (3) by converting the hydroxy-group to remove the group in accordance with the known method. Examples of the deleted group represented by L include a halogen atom (chlorine, bromine, iodine, etc.), C1-6alkylsulfonates, which may be halogenated (methansulfonate, econsultancy, tripterocalyx etc.), C6-10aromatic hydrocarbons, sulfonyloxy, which may be substituted, etc. Deputy for the group of aromatic hydrocarbons, sulfonyloxy may include one to three halogen atom, a C1-6alkyl group which may be halogenated, a C6-10alkoxygroup etc. Preferred examples of the deleted group include benzolsulfonate, p-that is wilsonphillips, 1-naphthalenesulfonate, 2-naphthalenesulfonates etc.

In addition, tilne connection (Ar2-SH)used in the production method, described above, may be a known compound, or can be obtained through a combination of methods that are well known to specialists in this area with average skills.

3) the Method of deriving pyridine-2-carboxylic acid (7)

where Ar1, Ar2and R3defined above.

Derived pyridine-2-carboxylic acid (7) can be obtained by adding an ORGANOMETALLIC reagent to 2-bromopyridine derivative (6), followed by stirring and then adding carbon dioxide as an electrophilic reagent.

As a specific example of the organic solvent can result in a volatile solvent, such as tetrahydrofuran or diethyl ether, a hydrocarbon solvent such as toluene, or hexamethylphosphoramide (HMPA), or a combination thereof. As the ORGANOMETALLIC reagent in the reaction using the equivalent to excess amount of, preferably, an equivalent number alkylate (for example, n-utility, sec-utility, tert-utility, finelite etc). The reaction temperature is usually in the range from -100 to 50°C and preferably about what -78 to 0°C. Mixing time is usually in the range from 0.1 hour to 1 day.

This reaction solution was added carbon dioxide in gaseous or solid form as an electrophilic reagent. The reaction temperature is usually in the range from -100 to 50°C and preferably from -78 to 0°C. the reaction Time is usually in the range from 0.1 hour to 1 day.

4) the Method of deriving pyridine-2-carboxylic acid (9)

where Ar1, Ar2and R3defined above.

Pyridine-2-carbaldehyde derivative (8) can be obtained by adding an ORGANOMETALLIC reagent to 2-bromopyridine derivative (6), followed by stirring and then adding dimethylformamide or ester of formic acid, such as ethyl formate, as electrophilic reagent.

As an example, an organic solvent can result in a volatile solvent, such as tetrahydrofuran or diethyl ether, a hydrocarbon solvent such as toluene, or hexamethylphosphoramide (HMPA), or a combination thereof. As the ORGANOMETALLIC reagent in the reaction using the equivalent to excess amount of, preferably, an equivalent number alkylate (for example, n-utility, sec-utility, tert-utility, finelite etc). The reaction temperature usually is away in the range from -100 to 50°C and preferably from -78 to 0°C. Mixing time is usually in the range from 0.1 hours to 3 days.

This reaction solution was added dimethylformamide or ester of formic acid, such as ethyl formate.

The reaction temperature is usually in the range from -100 to 50°C and preferably from -78 to 0°C. the reaction Time is usually in the range from 0.1 hours to 3 days. The resulting pyridine-2-carbaldehyde derivative (8) can be oxidized using an oxidant in a solvent to obtain a derivative of pyridine-2-carboxylic acid (9).

The reaction temperature usually ranges from -20 to 200°C and preferably from 0 to 100°C, and the reaction time is from 0.5 hours to 3 days. As an example, the solvent can lead to organic acid (e.g. formic acid, acetic acid), an alcohol solvent, ether solvent, a halogen solvent, an aromatic solvent, a nitrile solvent, an amide solvent, a ketone solvent, sulfoxide solvent or water, and you can also use a mixture of two or more such solvents. Of them formic acid, methylene chloride, chloroform, methanol, ethanol, etc. are preferred.

Examples of the oxidizing agent include hydrogen peroxide, organic percolate connection (for example, permorming acid, peracetic acid, meta is Obermenzing acid), metaperiodate (for example, metaperiodate sodium), allniters, diazol the tetroxide,halogen, N-halogen compounds (for example, N-chlorosuccinimide, N-bromosuccinimide), hydroperoxides (such as, tert-butylhydroperoxide), iodobenzaldehyde, iodobenzaldehyde, tert-butylhypochlorite, sulfurylchloride, oxygen, ozone, selenium oxide, selenium acid, etc.

As for specific examples of the reaction conditions, one or two of the equivalent quantity of hydrogen peroxide added to the pyridine-2-carbaldehyde derivative (8) in a solvent, representing formic acid, and the mixture can be processed at room temperature in a period of time from about 1 hour to 2 days of receiving, thus, the derived pyridine-2-carboxylic acid (9).

5) the Method for production of pyridine-2-carboxamide derivatives (1aN) and (1cN)

As for the pyridine derivatives of the present invention, the pyridine-2-carboxamide derived (1aN) or (1cN) can be obtained by combining the derived pyridine-2-carboxylic acid (7) or (9), primary or secondary amine (HNR1R2) or its salt and a condensing agent in a solvent in the following manner.

where Ar1, Ar2, R1, R2and R3defined above.

The reaction temperature usually ranges from -20 to 200°C and p is edocfile from 0 to 50°C. The reaction time usually ranges from 0.5 hour to 3 days. As an example, the solvent can lead ether solvents, halogenated solvents, aromatic solvents, alcohol solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents or water, and you can also use a mixture of two or more such solvents. Of them tetrahydrofuran, methylene chloride, chloroform, etc. are preferred.

As the condensing agent, you can specify 1,3-dicyclohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide, hexaflurophosphate (benzotriazol-1 yloxy)triprolidine, etc. and you can also add a tertiary amine, such as 1-hydroxybenzotriazole and/or N-ethyldiethanolamine.

In another way pyridine-2-carboxamide proizvodnje (1aN) or (1cN) can also be obtained by converting the derivative pyridine-2-carboxylic acid (7) or (9) the acid chloride of the acid with the addition of then primary or secondary amine in a solvent.

As for the specific example of the reaction, thionyl chloride is added in excess to the derived pyridine-2-carboxylic acid (7) or (9) at room temperature. Preferably, at the same time there was a very small amount of dimethylformamide, is, if using solvent, preferably methylene chloride, chloroform or the like, By concentrating the mixture, followed by dilution with a solvent and adding the equivalent to the excess amine can be obtained pyridine-2-carboxamide derived (1aN) or (1cN). The solvent preferably represents tetrahydrofuran, methylene chloride, chloroform, dimethylformamide or the like, and at the same time, the base may be a tertiary amine such as triethylamine, or an aromatic amine such as pyridine.

In addition, amine (HNR1R2used in the production method, described above, may be a known compound, or can be obtained through a combination of methods that are well known to specialists in this area with average skills.

6) the Method for production of pyridine-2-carboxylate derivative (1aO) or (1cO)

As for the pyridine derivatives of the present invention, the pyridine-2-carboxylate derivative (1aO) or (1cO) can be obtained by combining the derived pyridine-2-carboxylic acid (7) or (9), alcohol and condensing agent in a solvent.

where Ar1, Ar2, R1'and R3defined above.

The reaction temperature usually ranges from -20 to 200°C and preferably between 0 and d is 50°C, and the reaction time is usually in the range from 0.5 hours to 3 days. Example of the solvent is an ether solvent, a halogen solvent, an aromatic solvent, a nitrile solvent, an amide solvent, a ketone solvent or sulfoxide solvent, and you can also use a mixture of two or more such solvents. Of them toluene, tetrahydrofuran, methylene chloride, etc. are preferred.

As the condensing agent, you can specify 1,3-dicyclohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and the like, and can simultaneously be present from 0.1 to 2 equivalent amounts of amine, such as 4-dimethylaminopyridine.

In another way pyridine-2-carboxylate derivative (1aO) or (1cO) can also be obtained by converting the derivative pyridine-2-carboxylic acid (7) or (9) the acid chloride of the acid, and then adding the alcohol in the solvent, while the presence of a base.

As for the specific example of the reaction, thionyl chloride is added in excess to the derived pyridine-2-carboxylic acid (7) or (9) at room temperature. Preferably, when at the same time, there is a very small amount of dimethylformamide, and, in the case of using the solvent, methylene chloride, chloroform or the like is prefer the elegance for use. By concentrating the mixture, followed by dilution with a solvent and the addition of an equivalent to excess amount of alcohol and the Foundation can be obtained pyridine-2-carboxylate derivative (1aO) or (1cO). The solvent preferably represents tetrahydrofuran, methylene chloride, chloroform, dimethylformamide or the like, and, at the same time, tertiary amine or aromatic amine, such as triethylamine or pyridine, may be present as a base.

In addition, alcohol (HOR1'used in the production method, described above, may be a known compound or can be obtained through a combination of methods that are well known to specialists in this area with average skills.

7) the Method of obtaining the pyridine derivative (1b) or (1c)

As for the pyridine derivatives of the present invention, alvinlee compound (1b) or sulfonylurea compound (1c) can be obtained by oxidation of the sulfide compound (1a) with an oxidant in a solvent as follows.

where Ar1, Ar2, R3and Y is defined above.

The reaction temperature is usually in the range from -20 to 150°C and preferably from 0 to 50°C, and the reaction time is usually in the range from 0.5 hours to 3 days.

The solvent may be a sleep the postal solvent, the ether solvent, a halogen solvent, an aromatic solvent, carbonisation solvent, a nitrile solvent, an amide solvent, a ketone solvent, sulfoxide solvent or water, you can also use a mixture of two or more such solvents. Of them methylene chloride, chloroform, methanol, ethanol, acetic acid, etc. are preferred.

As oxidizing agent, you can specify the peroxide, organic percolate connection (e.g., peracetic acid, meta-chloroperbenzoic acid), metaperiodate (for example, metaperiodate sodium), acilitate, dinitrophenoxy, halogen, N-halogen compounds (for example, N-chlorosuccinimide, N-bromosuccinimide), hydroperoxides (such as, tert-butylhydroperoxide), iodobenzaldehyde, iodobenzaldehyde, tert-butylhypochlorite, sulfurylchloride, oxygen, ozone, selenium oxide, selenium acid, etc.

As for the specific example reakciei, alvinlee compound (1b) can be obtained by adding a sulfide compound (1a) and 1-2 equivalent amounts of meta-chloroperbenzoic acid or periodate sodium in a solvent such as methylene chloride, tetrahydrofuran-water or methanol, and processing the mixture at a temperature of from 0 to 100°C for about a period of time from 1 hour to 2 days. Alternatively, sulfonyl the e compound (1c) can be obtained by reacting the sulfide compound (1a) with 2-5 equivalent amounts of an oxidant (for example, meta-chloroperbenzoic acid, periodate sodium, hydrogen peroxide, hydrogen peroxide-ammonium molybdate, etc.) in methylene chloride, tetrahydrofuran-water, formic acid or methanol, at temperatures from 0 to 100°C, for a time from about 1 hour to 3 days.

In addition, in the case of obtaining optically active sulfoxide (1b)as an oxidant can be used tetraisopropoxide titanium/optically pure diethyltartrate/tert-butylhydroperoxide, tetraisopropoxide titanium/optically pure diethyltartrate/peracetic acid or the like

With regard to compounds (1) according to the present invention, in the case when Z is a sulfur atom, a pyridine derivative according to the present invention can be obtained as follows.

8) a method of obtaining a pyridyl-2-thioamide derivative (1: Y=NR1R2, Z=S) or pyridyl-2-dicarboxylate derivative (1: Y=OR1', Z=S)

where Ar1, Ar2, R3X and Y are defined above.

Pyridyl-2-carboxamide derivative (1: Y=NR1R2, Z=O) or pyridyl-2-carboxylate derivative (1: Y=OR1', Z=O) can be transformed into pyridyl-2-thioamide derivative (1: Y=NR1R2, Z=S) or pyridyl-2-dicarboxylate derivative (1: Y=OR1', Z=S) by known methods. For example, 1 to 5 equivalent amounts of the reagent is of Losson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide) can be added to the pyridyl-2-carboxamide derivative (1: Y=NR 1R2, Z=O) or pyridyl-2-carboxylate derivative (1: Y=OR1', Z=O) in a solvent. As a solvent, preferred are toluene, xylene, tetrahydrofuran, dioxane, methylene chloride, and the like, the reaction Temperature is from 0°C to 200°C and preferably from room temperature to 130°C, and the reaction time is usually in the range from 0.5 hours to 3 days.

As for ways to get the pyridine derivative (1) compounds of the present invention, illustrated above, are sometimes necessary to protect this Vice, as the nitrogen atom, the hydroxy-group or carboxyl group, and in this case it is possible to use widely known protective group that can be removed in a suitable way. Such protective groups can be removed, when necessary, by the General method known in the chemistry of organic synthesis.

In addition, with regard to Y (-NR1R2) pyridine derivative (1) compounds of the present invention, in the case when R1and/or R2represents a hydrogen atom, a possible further structural modification. For example, in the case carboxamide (R1, R2=H) it can be converted to N-(hydroxymethyl)carboxamid (R1=H, R2=CH2OH) by reacting with an aqueous solution of formaldehyde and aqueous sodium hydroxide in Dima is silt ether of ethylene glycol.

Also, if there is one or more functional groups of the groups for R1and/or R2also possible further structural modification. For example, a compound containing a hydroxy-group of the groups for R1and/or R2can be converted into such a group as an ester, carbamate or halogen, using known methods. In addition, such groups can be converted to groups such as alkoxy, amine, amide, or sulfide. This conversion is also possible for different functional groups other than the hydroxy-group, and this conversion can be accomplished using known methods. Reagents, solvents and reaction conditions used in these methods can be those which are well known to specialists in this area with average skills.

The connection represented by the General formula (1) according to the present invention strongly inhibits the production/secretion of β-amyloid protein in vitro. In addition, the compound represented by General formula (1) according to the present invention, also strongly inhibits the production/secretion of β-amyloid protein in vivo by oral administration. On the basis of these results, consider that the compound represented by General formula (1) according to the present invention is extremely useful in the quality of the ve preventive and therapeutic lekarstvennogo means disease, caused by abnormal production and/or secretion of β-amyloid protein such as Alzheimer's disease, down syndrome and other diseases associated with amyloid deposits.

In particular, it was recognized that the compound represented by the following formula (1-1), where the General formula (1) Ar1is a 2.5 differenly group, Ar2is a 4-florfenicol group, X represents-SO-, Y represents dimethylaminopropyl, Z represents an oxygen atom and R3represents a methyl group:

namely 5-[(2,5-differenl)[(4-forfinal)sulfinil]methyl]-N,N,4-trimethylpyridine-2-carboxamide has a sufficient difference between the dose to effect when administered orally and the dose for the induction of immunosuppressive actions for repeated introduction, and it is considered a compound which has excellent characteristics of the pharmaceutical product.

Also, the effect similar to the compounds (1-1), was observed after oral administration of the following compounds (1-2), (1-3), (1-4), (1-5), which are considered to have excellent properties as pharmaceutical products:

the compound represented by the following formula (1-2), where the General formula (1) Ar1is a 2.5 differenly group, Ar2is a 4-florfenicol g is the SCP, X represents-SO2-, Y represents (hydroxymethyl)amino group, Z represents an oxygen atom and R3represents a methyl group:

namely 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide;

the compound represented by the following formula (1-3), where the General formula (1) Ar1is a 2,3,6-triptorelin group, Ar2is a 4-florfenicol group, X represents-SO2-, Y represents (hydroxymethyl)amino group, Z represents an oxygen atom and R3represents a methyl group:

namely 5-[[(4-forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide;

the compound represented by the following formula (1-4), where the General formula (1) Ar1is a 2,3,6-triptorelin group, Ar2represents a phenyl group, X represents-SO2-, Y represents (hydroxymethyl)amino group, Z represents an oxygen atom and R3represents a methyl group:

namely N-(1-hydroxymethyl)-4-methyl-5-[(phenylsulfonyl)(2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide; and

the connection data is built by the following formula (1-5), where the General formula (1) Ar1is a 2,3,6-triptorelin group, Ar2represents a 6-(trifluoromethyl)pyridine-3-ilen group, X represents-SO2-, Y represents (hydroxymethyl)amino group, Z represents an oxygen atom and R3represents a methyl group:

namely, N-(hydroxymethyl)-4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide.

In the case of using the compounds of the present invention as a drug for humans dose for an adult is in the range from 1 mg to 1 g, preferably from 10 mg to 300 mg, per day. In addition, dose when used for the animal can vary depending on the purpose of the introduction (treatment or prevention), the type and size of animal to be treated, the type of pathogen that infected animal, or the severity of the condition, but at the same daily dose usually ranges from 0.1 mg to 200 mg, preferably from 0.5 mg to 100 mg, per kg of animal body weight. This daily dose is administered once a day or divided into 2 to 4 of the introduction. Also, the daily dose may exceed the above number, if necessary.

Pharmaceutical composition comprising the compound of the present invention, can be obtained by the selection of a suitable composition in accordance with the method of administration, using the method of producing composites that are traditionally used. As the dosage form for the pharmaceutical composition containing the compound of the present invention as the basic substance, for example, you can specify as oral tablets, powders, granules, capsules, liquids, syrups, elixirs, oily or aqueous suspensions, etc.

In the case of drugs for injection of the composition, optionally, you can use stabilizers, preservatives or contribute to a dissolution, and the solution, which may contain such adjuvants can be introduced into the container and then subjected to lyophilization drying or the like to obtain a solid composition, which will be used as "ready to use" composition. One container may contain a single dose, or a single container may contain multiple doses.

You can specify as compositions for external use liquids, suspensions, emulsions, ointments, gels, creams, lotions, sprays, plasters, etc.

Solid compositions can be obtained by combining the compounds of the present invention and selected optional pharmaceutically acceptable additives such as fillers, flowability agents, binders, disintegrating agents, substances that contribute to the dissolution, wetting substances is a, lubricants, etc.

As liquid compositions can specify solutions, suspensions, emulsions and the like, and they contain as additives suspendresume substances, emulsifiers, etc.

EXAMPLES

Hereinafter the present invention will be specifically described using Examples, but the scope of the invention is not limited to the following examples. Moreover, if in the Examples presented here nothing is said about the E-isomer or Z-isomer, the compound obtained is either E-isomer or Z-isomer.

Reference example 1: (6-Bromo-4-methylpyridin-3-yl)(2,5-differenl)methanol

In an argon atmosphere a solution of n-utility in hexane (1,60 M, by 8.22 ml, 13,2 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (3.00 g, 12,0 mmol) in diethyl ether (120 ml) at -78°C. After stirring the reaction mixture for 30 minutes was added 2,5-differentally (1,34 ml of 12.0 mmol). After stirring for 1 hour at the same temperature was added a saturated aqueous solution of ammonium chloride at room temperature. After separation of organic layer, the organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution CME is using hexane:ethyl acetate=4:1, concentrated under reduced pressure to obtain specified in the title compound (1.26 g, 4,01 mmol, 34%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.27 (3H, s), 2,53 (1H, d, J=4, 2 Hz), to 6.22 (1H, d, J=4, 2 Hz), 6,95-7,06 (2H, m), 7,08-7,14 (1H, m), 7,29 (1H, s), at 8.36 (1H, s).

MS m/z: 314, 316 (M++H).

Example 1: 2-Bromo-5-[[(4-chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin

In nitrogen atmosphere thionyl chloride (2,90 ml, 39.8 mmol) and N,N-dimethylformamide (0,20 ml) was added to a solution of (6-bromo-4-methylpyridin-3-yl)(2,5-differenl)methanol (1.25 g, 3,98 mmol) in methylene chloride (20 ml) at 0°C and the resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and to the residue was added methylene chloride. The mixture was washed with a saturated aqueous solution of sodium bicarbonate and then saturated brine and 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 (45 ml) was added a solution of 4-chlorbenzoyl (575 mg, 3,98 mmol) in N,N-dimethylformamide (5 ml) and then potassium carbonate (550 mg, 3,98 mmol) under nitrogen atmosphere at 0°C and the resulting mixture was stirred for 30 minutes at room temperature. To the reaction mixture were added ethyl acetate is water at 0°C, the organic layer was separated and then the organic layer was washed with saturated saline solution. 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 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 (1.48 g, to 3.36 mmol, 84%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), 5,77 (1H, s), 6,92-7,03 (2H, m), 7,19-of 7.25 (4H, m), 7,28-7,34 (1H, m), 7,29 (1H, s), 8,39 (1H, s).

MS m/z: 440, 442 (M++H).

Example 2: 5-[[(4-Chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin-2-carbaldehyde

In an argon atmosphere a solution of n-utility in hexane (1,60 M, 2,52 ml, a 4.03 mmol) was added to a solution of 2-bromo-5-[[(4-chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridine (1.48 g, to 3.36 mmol) in toluene (40 ml) at -78°C. the Reaction mixture was stirred for 1 hour and then was added N,N-dimethylformamide (0,312 ml, a 4.03 mmol) at the same temperature. After stirring the reaction mixture for 30 minutes was added to the water at the same temperature and the mixture was allowed to warm to room temperature. To the reaction mixture were added ethyl acetate and the resulting mixture was washed with a saturated aqueous solution of lorida ammonium, and then saturated saline solution. 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 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 (419 mg, 1.07 mmol, 32%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,43 (3H, s), 5,88 (1H, s), 6,94-7,05 (2H, m), 7,20-7,27 (4H, m), of 7.36-7,42 (1H, m), of 7.75 (1H, s), 8,79 (1H, s), 10,02 (1H, s).

MS m/z: 390 (M++H).

Example 3: 5-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid

31% aqueous hydrogen peroxide (2 ml) was added to a solution of 5-[[(4-chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin-2-carbaldehyde (415 mg, 1.06 mmol) in formic acid (20 ml) and the resulting mixture was stirred for 2 hours at room temperature. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in methylene chloride and washed with 1N. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. Receiving the hydrated residue was washed with diethyl ether and collected by filtration to obtain specified in the title compound (347 mg, 0,79 mmol, 74%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), 5,98 (1H, s), 6,93-7,01 (1H, m), 7.03 is-7,10 (1H, m), 7,44-of 7.48 (2H, m), to 7.61-the 7.65 (2H, m), 7,72 for 7.78 (1H, m), 8,03 (1H, s), which 9.22 (1H, s).

IR (ATR) cm-1: 1739, 1712, 1495, 1417, 1311, 1155, 1092, 727.

TPL: 208-209°C.

Analytically calculated for C20H14ClF2NO4S: C, 54,86; H, 3,22; Cl, 8,10, F, 8,68; N, 3,20; S, 7,32. Found: C, 54,55; H, 3,15; Cl, 8,02; F, At 8.60; N, 3,25; S, 7,44.

MS m/z: 438 (M++H).

Example 4: 5-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[[(4-chlorophenyl)sulfonyl](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid (88 mg, 0.20 mmol) in methylene chloride (2 ml) was added at room temperature, methylamine hydrochloride (15 mg, 0.22 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 4-methylmorpholine (0,048 ml, 0.44 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.22 mmol). After stirring for 5 hours at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 in pengendalian and the obtained residue was washed mixed solvent, consisting of diethyl ether and hexane and then collected by filtration to obtain specified in the title compound (73 mg, 0.16 mmol, 81%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 3.04 from (3H, d, J=5,1 Hz), 5,96 (1H, s), 6,92-was 7.08 (2H, m), the 7.43 (2H, d, J=8.6 Hz), to 7.61 (2H, d, J=8.6 Hz), 7,74-7,81 (1H, m), of 7.97 (1H, s), 8,00 (1H, userd, J=5,1 Hz), 9,13 (1H, s).

IR (ATR) cm-1: 1674, 1533, 1495, 1329, 1151.

TPL: 200-201°C.

Analytically calculated for C21H17ClF2N2O3S: C, 55,94; H, 3,80; Cl, 7,86; F, 8,43; N, 6,21; S, 7,11. Found: C, 55,70; H, 3.72 Points; Cl, To $ 7.91; F, 8,51; N, 6,17; S, 7,26.

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

Example 5: 5-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]-N,N,4-trimethylpyridine-2-carboxamide

To a solution of 5-[[(4-chlorophenyl)sulfonyl](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid (88 mg, 0.20 mmol), poluchennoi in Example 3, in methylene chloride (2 ml)was added at room temperature dimethylaminohydrolase (18 mg, 0.22 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 4-methylmorpholine (0,048 ml, 0.44 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (42 mg, 0.22 mmol). After stirring for 6 hours at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated PR is the reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of diethyl ether and hexane, and collected by filtration to obtain specified in the title compound (83 mg, 0.18 mmol, 89%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,24 (3H, s), 3,14 (6H, s), 5,96 (1H, s), 6,91-6,98 (1H, m), 7,00-7,07 (1H, m), 7,44 (2H, d, J=8.6 Hz), 7,47 (1H, s), the 7.65 (2H, d, J=8.6 Hz), 7,72 for 7.78 (1H, m), 9,16 (1H, s).

IR (ATR) cm-1: 1633, 1493, 1327, 1151, 1084.

TPL: 207-208°C.

Analytically calculated for C22H19ClF2N2O3S: C, 56,84; H, 4,12; Cl, 7,63; F, 8,17; N, 6,03; S 6,90. Found: C, 56,53; H, 4,08; Cl, 7,53; F, Of 8.25; N, 5,93; S 7,00.

MS m/z: 465 (M++H).

Example 6: 5-[[(4-Chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid

To a solution of 2-bromo-5-[[(4-chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridine (5,04 g of 11.4 mmol)obtained in Example 1 in toluene (100 ml)was added a solution of n-utility in hexane (1,54 M, 8,91 ml, 13.7 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C and was barbotirovany in a mixture of carbon dioxide. The reaction mixture was stirred for 30 minutes and then was allowed to warm to room temperature and to the mixture was added saturated aqueous races is the thief of ammonium chloride. The reaction mixture was concentrated under reduced pressure, then was added to the residue chloroform and the mixture was washed for 1H. a solution of hydrochloric acid. 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 flash chromatography on silica gel. The fraction obtained by elution methylene chloride:methanol=10:1 was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the connection header (of 2.06 g, 5.08 mmol, 44%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,46 (3H, s), 5,88 (1H, s), 6,95-7,05 (2H, m), 7,24 (4H, s), of 7.36-7,42 (1H, m), 8,02 (1H, s), 8,61 (1H, s).

MS m/z: 406 (M++H).

Example 7: 5-[[(4-Chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid (406 mg, 1.00 mmol) in N,N-dimethylformamide (10 ml) was added (benzotriazol-1 yloxy)triprolidine hexaflurophosphate (781 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), ammonium chloride (107 mg, 2.00 mmol) and N-ethyldiethanolamine (0,697 ml, 4.00 mmol) in an argon atmosphere at room temperature. After paramasivan what I spent 12 hours at room temperature to the reaction mixture were added ethyl acetate and the mixture washed 0,5h. a solution of hydrochloric acid. 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 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 (398 mg, 0.98 mmol, 98%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,42 (3H, s), of 5.55 (1H, users), 5,88 (1H, s), 6,93? 7.04 baby mortality (2H, m), 7,22 (4H, s), 7,35-7,41 (1H, m), to 7.77 (1H, users), of 8.00 (1H, s), 8,58 (1H, s).

MS m/z: 405 (M++H).

Example 8: 5-[[(4-Chlorophenyl)sulfinil](2.5-differenl)methyl]-4-methylpyridin-2-carboxamide

3-Chloroperbenzoic acid (259 mg, 0.98 mmol) was added to a solution of 5-[[(4-chlorophenyl)thio](2.5-differenl)methyl]-4-methylpyridin-2-carboxamide (395 mg, 0.98 mmol) in methylene chloride (10 ml) at 0°C. After stirring for 14 days at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 in bonigen the m pressure and the obtained residue was washed mixed solvent, consisting of ethanol and diethyl ether, and collected by filtration to obtain, thus, specified the title compound (243 mg, of 0.58 mmol, 59%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,95 (2,1H, C), 2,15 (0,9H, C), 5,35 (0,3H, s), lower than the 5.37 (0,7H, s), 5,51-5,62 (1H, m), 6,88-was 7.08 (2H, m), 7.23 percent-of 7.55 (5H, m), 7,80-of 7.90 (1H, m), 7,94 (0,7H, s), 7,99 (0,3H, s), 8,87 (0,7H, m), 9,05 (0,3H, s).

IR (ATR) cm-1: 3126, 1695, 1595, 1493, 1421, 1053, 823.

Analytically calculated for C20H15ClF2N2O2With: C, 57,08; H, 3,59; Cl, 8,42; F, 9,03; N, 6,66; S, A 7.62. Found: C, 56,75; H, 3,59; Cl, 8,35; F, 9,06; N, 6,65; S, 7,71.

MS m/z: 421 (M++H).

Example 9: 5-[[(4-Chlorophenyl)sulfonyl](2.5-differenl)methyl]-4-methylpyridin-2-carboxamide

3-Chloroperbenzoic acid (66 mg, 0.25 mmol) was added to a solution of 5-[[(4-chlorophenyl)sulfinil](2.5-differenl)methyl]-4-methylpyridin-2-carboxamide (105 mg, 0.25 mmol) in methylene chloride (5 ml) at 0°C. After stirring for 5 days at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to preparative thin-layer chromatography (showed a mixture of methylene chloride:methanol=40:1 and suirable a mixture of methylene chloride:methanol=4:1). The obtained fraction con who was interaval under reduced pressure and the obtained residue was washed mixed solvent, consisting of ethanol and diethyl ether, and collected by filtration to obtain, thus, specified the title compound (56 mg, 0.13 mmol, 51%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (3H, s), to 5.57 (1H, users), 5,97 (1H, s), 6,92-7,00 (1H, m), 7,01-to 7.09 (1H, m), 7,44 (2H, d, J=8.5 Hz), a 7.62 (2H, d, J=8.5 Hz), 7,75-7,81 (1H, m), 7,82 (1H, users), to 7.99 (1H, s), 9,16 (1H, s).

IR (ATR) cm-1: 3442, 3288, 1701, 1493, 1315, 1153, 1088.

TPL: 241-242°C.

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

Reference example 2: 2-Bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridin

To a solution of (6-bromo-4-methylpyridin-3-yl)(2,5-differenl)methanol (9,42 g, 30.0 mmol)obtained in Reference example 1 in methylene chloride (150 ml), was added thionyl chloride (21,9 ml, 300 mmol) and N,N-dimethylformamide (0,232 ml) at 0°C and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, to the residue was added ethyl acetate and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (9,82 g, 29.5 mmol, 98%) as a brown solid.

1H-NMR (400 MHz, CDCl3) δ: at 2.36 (3H, s), 6.42 per (1H, s), 7,01-7,07 (2H, m), 7,26-to 7.32 (1H, m), 7,33 (1H, s), 8,31 (1H, s).

MS m/z: 332, 334 (M+ +H).

Example 10: 2-Bromo-5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin

To a solution of 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (6,44 g, and 19.4 mmol) in N,N-dimethylformamide (100 ml) was added 4-fermentation (of 2.06 ml, and 19.4 mmol) and then potassium carbonate (2,94 g of 21.3 mmol) in an argon atmosphere at 0°C and the mixture was stirred for 1 hour at room temperature. To the reaction mixture were added ethyl acetate and water, the organic layer was separated and then the organic layer was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 obtain specified in the connection header (8,20 g, and 19.3 mmol, 100%) as a light brown solid.

1H-NMR (400 MHz, CDCl3) δ: 2,28 (3H, s)5,72 (1H, s), 6,91-6,98 (4H, m), 7,27-7,34 (3H, m), 7,28 (1H, s), 8,43 (1H, s).

MS m/z: 424, 426 (M++H).

Example 11: 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carbaldehyde

In an argon atmosphere a solution of n-utility in hexane (1,54 M, 22,3 ml, to 34.4 mmol) was added to a solution of 2-bromo-5-[(2,5-di is terphenyl)[(4-forfinal)thio]methyl]-4-methylpyridine (8,10 g, of 19.1 mmol) in toluene (200 ml) at -78°C. the Reaction mixture was stirred for 30 minutes and then was added N,N-dimethylformamide (1,63 ml, or 21.0 mmol) at the same temperature. The reaction mixture was stirred for 30 minutes, then added the water at the same temperature and the mixture was allowed to warm to room temperature. To the reaction mixture were added ethyl acetate and the resulting mixture was washed with a saturated aqueous solution of ammonium chloride and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=10:1 was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of diethyl ether and hexane and then collected by filtration to obtain, thus, specified in the connection header (4,27 grams, or 11.4 mmol, 60%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,39 (3H, s), of 5.83 (1H, s), 6,92-to 7.00 (4H, m), 7,30 and 7.36 (2H, m), 7,37-the 7.43 (1H, m), 7,73 (1H, s), 8,83 (1H, s), there is a 10.03 (1H, s).

MS m/z: 374 (M++H).

Example 12: 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

31% aqueous hydrogen peroxide(10 ml) was added to a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carbaldehyde (4,22 g, 11.3 mmol) in formic acid (100 ml) and the resulting mixture was stirred for 3 hours at room temperature. To the reaction mixture was added water, precipitated thus, the solid was collected by filtration and washed with 0,1N. a solution of hydrochloric acid. The obtained solid substance was dissolved in methylene chloride and the solution washed with 0,1N. a solution of hydrochloric acid. Then the organic layer was dried over anhydrous sodium sulfate and filtered, and then concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the connection header (4,34 g of 10.3 mmol, 91%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,30 (3H, s), 5,97 (1H, s), 6,91-6,99 (1H, m), 7.03 is-7,10 (1H, m), 7,16 (2H, t, J=8,4 Hz), 7.68 per for 7.78 (3H, m), 8,02 (1H, s), 9,23 (1H, s).

IR (ATR) cm-1: 3361, 1763, 1593, 1493, 1402, 1288, 1236, 1149.

Analytically calculated for C20H14F3NO4S: C, 57,01; H, 3,35; F, 13,53; N, 3,32; S, TO 7.61. Found: C, 56,87; H, 3,23; F, 13,54; N, 3,39; S, 7,86.

MS m/z: 422 (M++H).

Example 13: 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (105 mg, 0.25 mmol) in methylene chloride (3 ml) d is balali methylaminopropane (19 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0,061 ml, 0.55 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg, 0.28 mmol) at room temperature. After stirring for 2 hours at room temperature to the reaction mixture were added water and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and hexane and then collected by filtration to obtain specified in the title compound (73 mg, 0,17 mmol, 67%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,20 (3H, s), 3.04 from (3H, d, J=5,1 Hz), 5,95 (1H, s), 6,92-6,99 (1H, m), 7,01-was 7.08 (1H, m), 7,10-7,17 (2H, m), 7,66-7,72 (2H, m), 7,75-7,80 (1H, m), of 7.96 (1H, s), 8,01 (1H, userd, J=5,1 Hz), 9,14 (1H, s).

IR (ATR) cm-1: 1672, 1591, 1533, 1493, 1327, 1294, 1236, 1146, 1082.

TPL: 201-202°C.

Analytically calculated for C21H17F3N2O3S: C, 58,06; H, 3,94; F, 13,12; N, 6,45; S, 7,38. Found: C, 58,05; H, 3,83, F, Of 13.05; N, 6,47; S, 7,51.

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

Example 14: 5-[(2,5-Differenl)[(4-forfinal)sulfone is]methyl]-N,N,4-trimethylpyridine-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (105 mg, 0.25 mmol)obtained in Example 12 in methylene chloride (3 ml), was added dimethylaminohydrolase (23 mg, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0,061 ml, 0.55 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg, 0.28 mmol) at room temperature. After stirring for 3 hours at room temperature to the reaction mixture were added water and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (77 mg, 0,17 mmol, 69%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (3H, s), 3,14 (6H, s), 5,95 (1H, s), 6.90 to-6,97 (1H, m), 7,00-7,07 (1H, m), 7,11-to 7.18 (2H, m), 7,47 (1H, s), 7,70 for 7.78 (3H, m), 9,18 (1H, s).

IR (ATR) cm-1: 1633, 1589, 1493, 1404, 1327, 1294, 1236, 1147, 1084.

TPL: 176-177°C.

Analytical calc is but for C 22H19F3N2O3S: C, 58,92; H, 4,27; F, 12,71; N, 6,25; S, 7,15. Found: C, 58,74; H, 4,18; F, 12,68; N, 6,32; S, 7,26.

MS m/z: 449 (M++H).

Example 15: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (211 mg, 0.50 mmol)obtained in Example 12, N,N-dimethylformamide (5 ml) was added hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (390 mg, 0.75 mmol), 1-hydroxybenzotriazole (101 mg, 0.75 mmol), ammonium chloride (54 mg, 1.00 mmol) and N-ethyldiethanolamine (0,348 ml, 2.00 mmol in an argon atmosphere at room temperature. After stirring for 5 hours at room temperature to the reaction mixture were added ethyl acetate and water and the resulting mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the connection header (154 is g, of 0.37 mmol, 73%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), to 5.58 (1H, users), 5,96 (1H, s), 6,91-6,99 (1H, m), 7,01-was 7.08 (1H, m), 7,11-to 7.18 (2H, m), to 7.67-7,73 (2H, m), 7,76-of 7.82 (1H, m), 7,83 (1H, users), 7,98 (1H, s), 9,17 (1H, s).

IR (ATR) cm-1: 3429, 3168, 1691, 1589, 1491, 1421, 1313, 1234, 1146, 1080.

Analytically calculated for C20H15F3N2O3S: C, 57,14; H, 3,60; F, 13.56MHZ; N, 6,66; S, 7,63. Found: C, 56,96; H, 3,55; F, 13,76; N, 6,67; S Of 7.82.

MS m/z: 421 (M++H).

Example 16: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-ethyl-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (126 mg, 0.30 mmol)obtained in Example 12 in methylene chloride (3 ml), was added etilamingidrokhlorida (27 mg, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (0,073 ml, 0.66 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (63 mg, 0.33 mmol) at room temperature. After stirring for 7 days at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl is Etat=7:3, concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (120 mg, 0.27 mmol, 89%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 1.27 (3H, t, J=7.4 Hz), 2,19 (3H, s), 3,51 (2H, DQC, J=7,4, 6,1 Hz), 5,95 (1H, s), 6,92-6,99 (1H, m), 7,01-was 7.08 (1H, m), 7,11-7,17 (2H, m), 7,66-7,73 (2H, m), 7,75-7,81 (1H, m), of 7.96 (1H, s), 8,00 (1H, ushort, J=6,1 Hz), 9,14 (1H, s).

IR (ATR) cm-1: 1672, 1591, 1520, 1493, 1292, 1240, 1149.

TPL: 191-193°C.

Analytically calculated for C22H19F3N2O3S: C, 58,92; H, 4,27; F, 12,71; N, 6,25; S, 7,15. Found: C, 58,64; H, Or 4.31; F, 12,84; N, 6,22; S, 7,20.

MS m/z: 449 (M++H).

Example 17: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (421 mg, 1.00 mmol)obtained in Example 12 in methylene chloride (10 ml) was added 2-aminoethanol (0,067 ml, 1.10 mmol), 1-hydroxybenzotriazole (149 mg, 1.10 mmol), 4-methylmorpholine (0,12 ml, 1.10 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (211 mg, 1.10 is mmol) at room temperature. After stirring for 7 days at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The PR is anceschi layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (427 mg, of 0.92 mmol, 92%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 2,58 (1H, users), 3,63-3,68 (2H, m), 3,85 (2H, t, J=4.9 Hz), 5,95 (1H, s), 6,92-6,99 (1H, m), 7,01-was 7.08 (1H, m), 7,11-to 7.18 (2H, m), to 7.67-7,73 (2H, m), 7,75-7,80 (1H, m), of 7.96 (1H, s), 8,40 (1H, ushort, J=6,1 Hz), 9,16 (1H, s).

IR (ATR) cm-1: 3554, 3410, 1676, 1589, 1520, 1493, 1279, 1236, 1144.

TPL: 153-154°C.

Analytically calculated for C22H19F3N2O4S: C, 56,89; H, 4,12, F, 12,27; N, 6,03; S 6,90. Found: C, 56,85; H, 4,05; F, 12,56; N, 6,03; S 6,97.

MS m/z: 465 (M++H).

Example 18: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-ethyl-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (126 mg, 0.30 mmol)obtained in Example 12 in methylene chloride (3 ml) was added N-methylethylamine (to 0.060 ml, 0.66 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (63 mg, 0.33 mmol) at room is the temperature. After stirring for 4 hours at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of diethyl ether and hexane, and collected by filtration to obtain specified in the title compound (38 mg, 0.08 mmol, 27%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,19-of 1.30 (3H, m), of 2.23 (3H, s), 3,10 (3H, s), 3,47 (1,2H, q, J=7.4 Hz), 3,60 (0,8H, q, J=7.4 Hz), 5,95 (1H, s), 6.89 in-6,97 (1H, m), 6,99-7,07 (1H, m), 7,14 (2H, t, J=8,3 Hz), 7,44 (0,6H, s), 7,46 (0,4H, C), 7,69-7,79 (3H, m), 9,17 (0,6H, s), 9,18 (0,4H, C).

IR (ATR) cm-1: 1626, 1591, 1493, 1286, 1240, 1147, 1084.

TPL: 165-167°C.

Analytically calculated for C23H21F3N2O3S: C, 59,73; H, 4,58, F, 12,32; N, 6,06; S 6,93. Found: C, 59,31; H, Or 4.31; F, 12,59; N, 6,00; S, 7,05.

MS m/z: 463 (M++H).

Example 19: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-(2-hydroxyethyl)-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carbon is Oh acid (337 mg, 0.80 mmol)obtained in Example 12 in methylene chloride (8 ml) was added 2-(methylamino)ethanol (0,077 ml, 0.96 mmol), 1-hydroxybenzotriazole (130 mg, 0.96 mmol), 4-methylmorpholine (0,194 ml of 1.76 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (184 mg, 0.96 mmol) at room temperature. After stirring for 24 hours at room temperature the reaction mixture was washed for 1H. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with ethyl acetate, concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (328 mg, 0.69 mmol, 85%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,24 (0,3H, s)to 2.29 (2,7H, s), 3,17 (2,7H, s), 3,21 (0,3H, s), 3,47-4,01 (4H, m), 5,95 (1H, s), 6,89-of 6.96 (1H, m), 7,01-was 7.08 (1H, m), to 7.15 (2H, t, J=8.5 Hz), 7,52 (0,1H, C), 7,68 (0,9H, C)7,70 for 7.78 (3H, m), the remaining 9.08 (0,9H, C), 9,19 (0,1H, s).

IR (ATR) cm-1: 3228, 1626, 1591, 1495, 1236, 1149, 833.

TPL: 123-125°C.

Analytically calculated for C23H21F3N2O4S: 0,25H2O: C, 57,20; H, 4,49; F, 11,80; N, 5,80; S 6,64. Found: C, 57,13; H, 4,34; F, 11,92; N, 5,86; S, S,84.

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

Example 20: 5-[(2,5-Differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxylic acid

To a solution of 2-bromo-5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridine (1.39 g, or 3.28 mmol)obtained in Example 10 in toluene (60 ml) was added a solution of n-utility in hexane (1,54 M, 2.55 ml, 3.93 mmol) in an argon atmosphere at -78°C. After stirring for 1 hour at the same temperature the mixture barbotirovany carbon dioxide. The reaction mixture was allowed to warm to room temperature for 2 hours, then to the mixture was added 0,1N. hydrochloric acid solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of methylene chloride:methanol=10:1 was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol, diethyl ether and hexane, and collected by filtration to obtain specified in the title compound (815 mg, of 2.09 mmol, 64%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,41 (3H, s), of 5.83 (1H, s), 6.89 in-7,03 (4H, m), 7,27-7,44 (3H, m), of 8.00 (1H, s), 8,67 (1H, s).

MS m/z: 390 (M++H).

Por the measures 21: 5-[(2,5-Differenl)[(4-forfinal)sulfinil]methyl]-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxylic acid (307 mg, of 0.79 mmol) in methylene chloride (8 ml) was added methylaminopropane (108 mg, was 1.58 mmol), 1-hydroxybenzotriazole (213 mg, was 1.58 mmol), 4-methylmorpholine (0,347 ml of 3.15 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (302 mg, was 1.58 mmol) at room temperature. After stirring for 16 hours at room temperature the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 a solution of the obtained residue in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (110 mg, 0.41 mmol) at 0°C. After stirring for 1 hour at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to preparative thin-layer chromatography (showed a mixture of hexane:atilas is tat=2:1, was suirable a mixture of methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (129 mg, 0.31 mmol, 39%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,94 (1,95H, C), 2,13 (1,05H, s), 3.04 from (1,95H, d, J=5,1 Hz), 3,05 (1,05H, d, J=5,1 Hz), 5,32 (0,35H, (C), 5,35 (0,65H, s), 6.87 in-7,13 (4H, m), 7,27-7,35 (2,35H, m), of 7.48-7,54 (0,65H, m), 7,92 (0,65H, C), 7,97 (0,35H, C)8,00 (0,35H, userd, J=5,1 Hz), 8,03 (0,65H, userd, J=5,1 Hz), 8,84 (0,65H, C), 9,01 (0,35H, C).

IR (ATR) cm-1: 3359, 1664, 1591, 1529, 1491, 1228, 1086, 1051.

Analytically calculated for C21H17F3N2O2S: C, 60,28; H, 4,10, F, 13,62; N, 6,69; S, 7,66. Found: C, 59,86; H, 4.04 The; F, 13,65; N, 6,65; S, To 7.67.

MS m/z: 419 (M++H).

Example 22: 5-[(2,5-Differenl)[(4-forfinal)sulfinil]methyl]-N,N,4-trimethylpyridine-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxylic acid (307 mg, of 0.79 mmol)obtained in Example 20 in methylene chloride (8 ml) was added dimethylaminohydrolase (130 mg, was 1.58 mmol), 1-hydroxybenzotriazole (213 mg, was 1.58 mmol), 4-methylmorpholine (0,347 ml of 3.15 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (302 mg, was 1.58 mmol) at room temperature. After stirring for 17 hours at room themes is the temperature value of the reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 a solution of the obtained residue in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (112 mg, 0.42 mmol) at 0°C. After stirring for 1 hour at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to preparative thin-layer chromatography (showed a mixture of hexane:ethyl acetate=1:2, was suirable a mixture of methylene chloride: methanol=4:1). The obtained fraction was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (78 mg, 0.18 mmol, 23%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,03 (2H, s), 2,11 (1H, s), 3,14 (4H, s)and 3.15 (2H, s), 5,31 (0,33H, C), lower than the 5.37 (0,67H, s), 6.87 in-7,13 (4H, m), 7,30-7,40 (3H, m), 7,43 (0,67H, C), 7,46 (0,33H, C)8,96 (0,67H, C), 9,03 (0,33H, C).

IR (ATR) cm-1: 1631, 1587, 1493, 1408, 1217, 1049.

And Litichevsky calculated for C 22H19F3N2O2S: C, 61,10; H, 4,43, F, OF 13.18; N, 6,48; S, 7,41. Found: C, 60,83; H, 4,36; F, 13,43; N, 6,44; S, 7,42.

MS m/z: 433 (M++H).

Example 23: 5-[(2,5-Differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxylic acid (178 mg, 0.46 mmol)obtained in Example 20 N,N-dimethylformamide (5 ml) was added hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (357 mg, 0.69 mmol), 1-hydroxybenzotriazole (93 mg, 0.69 mmol), ammonium chloride (49 mg, of 0.91 mmol) and N-ethyldiethanolamine (0,319 ml and 1.83 mmol in an argon atmosphere at room temperature. After stirring for 5 hours at room temperature to the reaction mixture were added ethyl acetate and water and the resulting mixture was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 to obtain specified in the title compound (156 mg, 0.40 mmol, 88%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ:of 2.38 (3H, C)to 5.56 (1H, users), of 5.83 (1H, s), 6,91-7,01 (4H, m), 7,28-7,34 (2H, m), of 7.36-7,41 (1H, m), to 7.77 (1H, users), to 7.99 (1H, s), 8,61 (1H, s).

MS m/z: 389 (M++H).

Example 24: 5-[(2,5-Differenl)[(4-forfinal)sulfinil]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxamide (152 mg, 0,39 mmol) in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (104 mg, 0,39 mmol) at 0°C. After stirring for 2 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (91 mg, 0.23 mmol, 58%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,95 (1,9H, C), and 2.14 (1,1H, C), 5,33 (0,37H, C), are 5.36 (0,63H, C), 5,51-5,64 (1H, m), 6.87 in-7,14 (4H, m), 7,27-7,37 (2,37H, m), 7,49-7,56 (0,63H, m), 7,80-of 7.90 (1H, m), 7,94 (0,63H, C), 7,98 (0,37H, C), 8,87 (0,63H, C), 9,05 (0,37H, C).

IR (ATR) cm-1: 3458, 3377, 3155, 1697, 1491, 1421, 1348, 1227, 1082, 1043.

Analytically, the calc is slena for C 20H15F3N2O2S: C, 59,40; H, 3,74; F, 14,09; N, 6,93; S, TO 7.93. Found: C, 59,29; H, 3,76; F, 13,88; N, 6,88; S 7,93.

MS m/z: 405 (M++H).

Example 25: 2-Bromo-5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridin

To a solution of O-ethyl S-[6-(trifluoromethyl)pyridin-3-yl] dithiocarbonate (2.67 g, 10.0 mmol) in ethanol (30 ml) was added 1N. an aqueous solution of sodium hydroxide (30 ml) and the resulting mixture was stirred for 2 hours at 50°C. the Reaction mixture was cooled to room temperature and washed with methylene chloride. Then the aqueous layer was acidified using 1N. a solution of hydrochloric acid and was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure to obtain 6-(trifluoromethyl)pyridine-3-thiol in the form of a crude product.

To a solution of (6-bromo-4-methylpyridin-3-yl)(2,5-differenl)methanol (3,14 g, 10.0 mmol)obtained in Reference example 1 in methylene chloride (50 ml) was added thionyl chloride (7,29 ml, 100 mmol) and N,N-dimethylformamide (0,50 ml) at 0°C and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, then the residue was added ethyl acetate and water, and then was added dropwise at 0°C saturated aqueous solution of hydrocarb the Nata sodium. After separation of organic layer, the organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. To a solution of the obtained residue in N,N-dimethylformamide (45 ml) was added a solution of 6-(trifluoromethyl)pyridine-3-thiol in N,N-dimethylformamide (5 ml) and then potassium carbonate (1.52 g, 11.0 mmol) under nitrogen atmosphere at 0°C and the resulting mixture was stirred for 16 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of diethyl ether and hexane, and collected by filtration to obtain specified in the connection header (3,43 g, 7.22 mmol, 72%) as a pale yellow solid.

1H-NMR (400 MHz, CDCl3) δ: at 2.36 (3H, s), to 5.93 (1H, s), 6,97-to 7.09 (2H, m), 7,25-to 7.32 (1H, m), 7,35 (1H, s), 7,55 (1H, d, J=8,3 Hz), to 7.67 (1H, DD, J=8,3, 2.2 Hz), 8,39 (1H, s), 8,53 (1H, d, J=2.2 Hz).

MS m/z: 475, 477 (M++H).

Example 26: 5-[(2,differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridin-2-carboxylic acid

To a solution of 2-bromo-5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridine (3,43 g, 7.22 mmol) in toluene (70 ml) was added a solution of n-utility in hexane (1,54 M, 5,62 ml, 8,66 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C and the mixture was barbotirovany carbon dioxide. After stirring for 1 hour at the same temperature the reaction mixture was allowed to warm to room temperature and was added saturated aqueous solution of ammonium chloride. The reaction mixture was concentrated under reduced pressure and then the residue was added methylene chloride and water. After separation of the organic layer to the aqueous layer was added 1N. hydrochloric acid solution, and then it was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of methylene chloride:methanol=100:1 was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the header of the compound (862 mg, a 1.96 mmol 27%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,52 (3H, s), 6,04 (1H, s), 7,01-7,11 (2H, m), 7,33-7,39 (1H, m), EUR 7.57 (1H, d, J=8,3 Hz), of 7.70 (1H, DD, J=8,3, 2.2 Hz), 8,08 (1H, s), 8,55 (1H, d, J=2.2 Hz), to 8.62 (1H, s).

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

Example 27: 5-[(2,5-Differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-N,N,4-trimethylpyridine-2-carboxamide

To a solution of 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridin-2-carboxylic acid (352 mg, 0.80 mmol) in methylene chloride (10 ml) was added dimethylaminohydrolase (73 mg, 0.88 mmol), 1-hydroxybenzotriazole (119 mg, 0.88 mmol), 4-methylmorpholine (0,194 ml of 1.76 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (169 mg, 0.88 mmol) at room temperature. After stirring for 13 hours at room temperature the reaction mixture was washed 0,5h. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 (370 mg, 0.79, which mmol, 99%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 2,43 (3H, s), is 3.08 (3H, s), of 3.12 (3H, s), of 6.02 (1H, s), 6,97-was 7.08 (2H, m), 7,31-7,37 (1H, m), 7,49 (1H, s), 7,55 (1H, is, J=8.1 Hz), to 7.68 (1H, DD, J=8,1, 2.0 Hz), 8,54 (1H, d, J=2.0 Hz), to 8.57 (1H, s).

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

Example 28: 5-[(2,5-Differenl)[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl]methyl]-N,N,4-trimethylpyridine-2-carboxamide (compound A) and 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]sulfinil]methyl]-N,N,4-trimethylpyridine-2-carboxamide (compound B)

To a solution of 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-N,N,4-trimethylpyridine-2-carboxamide (365 mg, 0.78 mmol) in methylene chloride (10 ml) was added 3-chloroperbenzoic acid (259 mg, 0.98 mmol) at 0°C. After stirring for 6 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (94 mg, 0,19 mmol, 24%) as a white solid. Then the fraction obtained by elution with a mixture of hexane:ethyl acetate=1:2, was concentrated under reduced giving the situation and the obtained residue was washed mixed solvent, consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the connection header B (114 mg, 0.24 mmol, 30%) as a white solid.

Connection And

1H-NMR (400 MHz, CDCl3) δ: 2,30 (3H, s)and 3.15 (6H, s), 6,01 (1H, s), 6,91-6,99 (1H, m), 7,05 for 7.12 (1H, m), 7,52 (1H, s), 7,65-7,71 (1H, m), 7,80 (1H, d, J=8.1 Hz), to 8.20 (1H, DD, J=8,1, 2.2 Hz), 8,99 (1H, d, J=2.2 Hz), which 9.22 (1H, C).

IR (ATR) cm-1: 1630, 1493, 1333, 1155, 1105, 1076, 723, 625.

Analytically calculated for C22H18F5N3O3S: C, 52,90; H, 3,63; F, 19,02; N, TO 8.41; S, 6.42 PER. Found: C, 52,69; H, To 3.58; F, 19.14 Per; N, 8,42; S, 6,51.

MS m/z: 500 (M++H).

Connection

1H-NMR (400 MHz, CDCl3) δ: 2,10 (2,1H, C), 2,17 (0,9H, C), 3,14 (2,1H, s), 3.15 in (2,1H, C), and 3.16 (0,9H, C), and 3.16 (0,9H, C)5,38 (0,3H, s), 5,51 (0,7H, s), 6,84-7,11 (2H, m), 7,19-to 7.32 (1H, m), 7,47 (0,7H, ), 7,52 (0,3H, s), 7,72 (0,3H, DD, J=8,1, 0.7 Hz), to 7.77 (0,7H, DD, J=8,1, 0.7 Hz), 7,84 (0,3H, DD, J=8,1, 2.0 Hz), 8,04 (0,7H, DD, J=8,1, 2.0 Hz), and 8.50 (0,7H, d, J=2.0 Hz), 8,65 (0,3H, d, J=2,0 Hz), 9,02 (0,7H, s), 9.15, with (0,3H, s).

IR (ATR) cm-1: 1631, 1493, 1331, 1169, 1132, 1068.

Analytically calculated for C22H18F5N3O2S: C, 54,66; H, 3,75; F, 19,65; N, 8,69; S 6,63. Found: C, 54,38; H, 3,66; F, 19,94; N, 8,70; S 6,68.

MS m/z: 484 (M++H).

Example 29: 5-[(2,5-Differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridin-2-carboxylic acid (132 mg, 030 mmol), obtained in Example 26, in methylene chloride (5 ml) was added 2-aminoethanol (0,020 ml, 0.33 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), 4-methylmorpholine (0.036 ml, 0.33 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (63 mg, 0.33 mmol) at room temperature. After stirring for 6 hours at room temperature the reaction mixture was washed 0,5h. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 (143 mg, 0.30 mmol, 99%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 2,46 (3H, s), 2,52 (1H, users), 3,61-to 3.67 (2H, m), a-3.84 (2H, t, J=4.9 Hz), 6,03 (1H, s), 6,98-to 7.09 (2H, m), 7,29-to 7.35 (1H, m), 7,55 (1H, d, J=8,3 Hz), to 7.67 (1H, DD, J=8,3, 2.2 Hz), of 8.04 (1H, s), with 8.33 (1H, ushort, J=6,1 Hz), 8,54 (1H, d, J=2.2 Hz), 8,59 (1H, s).

MS m/z: 484 (M++H).

Example 30: 5-[(2,5-Differenl)[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide (195 mg, 0.40 mmol in methylene chloride (8 ml) was added 3-chloroperbenzoic acid (214 mg, 0.81 mmol) at 0°C. After stirring for 10 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (118 mg, 0.23 mmol, 57%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,30 (3H, s), 2.49 USD (1H, users), 3,64-3,70 (2H, m), 3,86 (2H, t, J=4,7 Hz), of 6.02 (1H, s), 6,92-7,00 (1H, m), 7,05-7,13 (1H, m), of 7.64-7,71 (1H, m), 7,80 (1H, d, J=8,3 Hz), of 8.04 (1H, s), 8,18 (1H, DD, J=8,3, 2.0 Hz), to 8.41 (1H, ushort, J=5.6 Hz), 8,97 (1H, d, J=2.0 Hz), which 9.22 (1H, s).

IR (ATR) cm-1: 3373, 1662, 1533, 1493, 1327, 1238, 1184, 1155, 1138, 1074, 723.

Analytically calculated for C22H18F5N3O4S: C, 51,26; H, 3,52; F, 18,43; N, 8,15; S, 6,22. Found: C, 51,02; H, 3.46 In, F, 18,86; N, 8,14; S, 6,29.

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

Example 31: 5-[(2,5-Differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methyl is iridin-2-carboxylic acid (176 mg, 0.40 mmol)obtained in Example 26, N,N-dimethylformamide (4 ml) was added hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (312 mg, of 0.60 mmol), 1-hydroxybenzotriazole (81 mg, of 0.60 mmol), ammonium chloride (43 mg, 0.80 mmol) and N-ethyldiethanolamine (0,279 ml of 1.60 mmol) in an argon atmosphere at room temperature. After stirring for 5 hours at room temperature to the reaction mixture were added ethyl acetate and water and the resulting mixture was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 (168 mg, 0.38 mmol, 96%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,47 (3H, s)to 5.56 (1H, users), 6,04 (1H, s), 6,98-to 7.09 (2H, m), 7,31-7,37 (1H, m), 7,56 (1H, d, J=8,3 Hz), to 7.67 (1H, DD, J=8,3, 2.2 Hz), of 7.75 (1H, users), of 8.06 (1H, s), 8,54 (1H, d, J=2.2 Hz), 8,59 (1H, s).

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

Example 32: 5-[(2,5-Differenl)[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[[6-(trifluoromethyl)pyridin-3-yl]thio]methyl]-4-methylpyridin-2-carboxamide (164 m is, of 0.37 mmol) in methylene chloride (4 ml) was added 3-chloroperbenzoic acid (215 mg, 0.81 mmol) at 0°C. After stirring for 4 days at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of methylene chloride:methanol=100:1 was concentrated under reduced pressure and the obtained residue was washed with ethanol and collected by filtration to obtain specified in the title compound (109 mg, 0.23 mmol, 62%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s)5,59 (1H, users), 6,03 (1H, s), 6,92-7,00 (1H, m), 7,06-7,13 (1H, m), 7,66-7,72 (1H, m), 7,80 (1H, d, J=8,3 Hz), 7,82 (1H, users), with 8.05 (1H, s), 8,19 (1H, DD, J=8,3, 2.0 Hz), 8,98 (1H, d, J=2,0 Hz), 9,24 (1H, s).

IR (ATR) cm-1: 3410, 1685, 1495, 1331, 1157, 1136, 1103, 1076.

Analytically calculated for C20H14F5N3O3S: C, 50,96; H, 2,99, F, 20,15; N, 8,91;, 6,80. Found: C, 51,06; H, 2,94; F, 20,25; N, 8,94; With, Of 6.96.

MS m/z: 472 (M++H).

Reference example 3: (6-Bromo-4-methylpyridin-3-yl)(2,3,6-tryptophanyl)methanol

A solution of n-utility in hexane (1,54 M, and 12.2 ml, to 18.7 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (4,27 g of 17.0 mmol) in di is tilava ether (200 ml) in an argon atmosphere at -78°C. After stirring the reaction mixture for 30 minutes, to the mixture was added 2,3,6-tripersonality (1,99 ml of 17.0 mmol). After stirring for 30 minutes at the same temperature to the mixture at room temperature was added a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 to obtain specified in the connection header (4,60 g, a 13.9 mmol, 81%) as a pale yellow solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.25 (3H, s), and 2.83 (1H, users), of 6.29 (1H, s), 6,84-6,92 (1H, m), 7,11-7,21 (1H, m), 7,28 (1H, s), 8,53 (1H, s).

MS m/z: 332, 334 (M++H).

Reference example 4: 2-Bromo-5-[chloro(2,3,6-tryptophanyl)methyl]-4-methylpyridin

To a solution of (6-bromo-4-methylpyridin-3-yl)(2,3,6-tryptophanyl)methanol (4,60 g, a 13.9 mmol) in methylene chloride (70 ml) was added thionyl chloride (10.1 ml, 139 mmol) and N,N-dimethylformamide (0,60 ml) at 0°C and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure, the obtained residue was added ethyl acetate, and then to the mixture was added water, and the eating saturated aqueous solution of sodium bicarbonate at 0°C. After separation of organic layer, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (4,65 g, 13.3 mmol, 96%) as a light brown solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.25 (3H, s), of 6.45 (1H, s), 6,86-6,93 (1H, m), 7,14-of 7.23 (1H, m), 7,29 (1H, s), 8,80 (1H, s).

MS m/z: 350, 352 (M++H).

Example 33: 2-Bromo-5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin

To a solution of 2-bromo-5-[chloro(2,3,6-tryptophanyl)methyl]-4-methylpyridine (4,65 g, 13.3 mmol) in N,N-dimethylformamide (70 ml) was added in an argon atmosphere at 0°C 4-fermentation (1,41 ml, 13.3 mmol)and then potassium carbonate (2,02 g, 14.6 mmol) and the resulting mixture was stirred for 4 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue about ivali hexane and then collected by filtration to obtain specified in the connection header (of 5.17 g, 11.7 mmol, 88%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,16 (3H, s), 5,67 (1H, s), 6.75 in-PC 6.82 (1H, m), 6,91-6,99 (2H, m), 7,01-7,11 (1H, m), 7,24 (1H, s), 7,33-7,39 (2H, m), 8,88 (1H, s).

MS m/z: 442, 444 (M++H).

Example 34: 5-[[(4-Forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxylic acid

To a solution of 2-bromo-5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridine (2.65 g, 6,00 mmol) in toluene (60 ml) was added a solution of n-utility in hexane (1,54 M, and 4.68 ml, 7.20 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and was again cooled to -78°C and then the mixture barbotirovany carbon dioxide. After stirring for 30 minutes at the same temperature the reaction mixture was allowed to warm to 0°C was added a saturated aqueous solution of ammonium chloride. The reaction mixture was concentrated under reduced pressure and then the residue was added chloroform and 1N. hydrochloric acid solution. After separation of organic layer, the organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of methylene chloride:methanol=10:1 was concentrated under reduced pressure and the resulting residue washed is whether the mixed solvent, consisting of diethyl ether and hexane, and collected by filtration to obtain specified in the connection header (981 mg, 2,41 mmol, 40%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 3,47 (1H, users), 5,74 (1H, s), 6.73 x-for 6.81 (1H, m), 6.90 to-6,98 (2H, m), 7,00-7,10 (1H, m), 7,29-to 7.35 (2H, m), to 7.93 (1H, s), 9,12 (1H, s).

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

Example 35: 5-[[(4-Forfinal)thio](2,3,6-tryptophanyl)methyl]-N,N,4-trimethylpyridine-2-carboxamide

To a solution of 5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxylic acid (383 mg, of 0.94 mmol) in methylene chloride (10 ml) was added dimethylaminohydrolase (85 mg, of 1.03 mmol), 1-hydroxybenzotriazole (140 mg, of 1.03 mmol), 4-methylmorpholine (0,227 ml, 2,07 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (198 mg, of 1.03 mmol) was added at room temperature. After stirring for 17 hours at room temperature the reaction mixture was washed 0,5h. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 (373 mg, 0.86 mmol, 91%) in the de white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (3H, s), of 3.12 (3H, s), of 3.13 (3H, s), 5,77 (1H, s), 6.75 in-6,83 (1H, m), 6,91-6,99 (2H, m), 7,02-7,11 (1H, m), 7,33-7,39 (2H, m), 7,42 (1H, s), 9,07 (1H, s).

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

Example 36: 5-[[(4-Forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-N,N,4-trimethylpyridine-2-carboxamide (compound A) and 5-[[(4-forfinal)sulfinil](2,3,6-tryptophanyl)methyl]-N,N,4-trimethylpyridine-2-carboxamide (compound B)

To a solution of 5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-N,N,4-trimethylpyridine-2-carboxamide (370 mg, 0.85 mmol) in methylene chloride (10 ml) was added 3-chloroperbenzoic acid (283 mg, 1.07 mmol) at 0°C. After stirring for 18 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (110 mg, 0.24 mmol, 28%) as a white solid. Then the fraction obtained by elution with a mixture of hexane:ethyl acetate=:4, concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the connection header B (157 mg, 0.35 mmol, 41%) as a white solid.

Connection A

1H-NMR (400 MHz, CDCl3) δ: 2,13 (3H, s), of 3.13 (3H, s)and 3.15 (3H, s), 5,90 (1H, s), 6,82-of 6.90 (1H, m), 7,13-7,24 (3H, m), 7,47 (1H, s), 7,75-of 7.82 (2H, m), 9,40 (1H, s).

IR (ATR) cm-1: 1631, 1587, 1491, 1406, 1329, 1234, 1146.

Analytically calculated for C22H18F4N2O3S: C, 56,65; H, TO 3.89; F, 16,29; N, 6,01; S, 6.87 IN. Found: C, 56,63; H, 3,91; F, 16,54; N, 6,01; S,? 7.04 Baby Mortality.

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

Compound B

1H-NMR (400 MHz, CDCl3) δ: 1,88 (0,9H, C)2,36 (2,1H, C), 3,10 (0,9H, C), 3,13 (0,9H, C), 3,14 (2,1H, s), 3.15 in (2,1H, C), 5,41 (0,3H, s), 5,44 (0,7H, s), 6,72-6,80 (0,7H, m), 6,91-6,98 (0,3H, m), 7,02-7.23 percent (3H, m), of 7.36 (0,3H, s), 7,42-7,47 (0,6H, m), 7,51 (0,7H, s), 7,55-to 7.61 (1,4H, m), 9,00 (0,3H, s), 9,12 (0,7H, C).

IR (ATR) cm-1: 1637, 1589, 1491, 1223, 1086, 1066.

Analytically calculated for C22H18F4N2O2S: C, 58,66; H, 4,03; F, 16,87; N, 6,22; S, 7,12. Found: C, 58,51; H, 3,98, F, Of 16.84; N, 6,15; S, 7,22.

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

Example 37: 5-[[(4-Forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxylic acid (407 mg, 1.00 mmol)obtained in Example 34, in N,N-dimethylformamide (10 ml) d is balali hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (781 mg, 1.50 mmol), 1-hydroxybenzotriazole (203 mg, 1.50 mmol), ammonium chloride (107 mg, 2.00 mmol) and N-ethyldiethanolamine (0,697 ml, 4.00 mmol) was added in an argon atmosphere at room temperature. After stirring for 16 hours at room temperature to the reaction mixture were added ethyl acetate and the resulting mixture was washed 0,5h. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 (392 mg, 0.96 mmol, 96%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.25 (3H, s), of 5.55 (1H, users), 5,78 (1H, s), 6.75 in-6,83 (1H, m), 6,92-6,99 (2H, m), 7,02 for 7.12 (1H, m), 7,32-7,38 (2H, m), to 7.84 (1H, users), of 7.96 (1H, s), the remaining 9.08 (1H, s).

MS m/z: 407 (M++H).

Example 38: 5-[[(4-Forfinal)sulfinil](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (389 mg, 0.96 mmol) in methylene chloride (10 ml) was added 3-chloroperbenzoic acid (254 mg, 0.96 mmol) at 0°C. After stirring for 13 days at room temperature the reaction mixture is washed with 1N. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to preparative thin-layer chromatography (showed a mixture of hexane:ethyl acetate=1:2, was suirable a mixture of methylene chloride: methanol=4:1). The obtained fraction was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (78 mg, 0.18 mmol, 19%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: at 2.36 (3H, s), 5,46 (1H, s), ceiling of 5.60 (1H, users), 6,74-PC 6.82 (1H, m),? 7.04 baby mortality-7,16 (3H, m), 7,52-to 7.59 (2H, m), a 7.85 (1H, users), with 8.05 (1H, s), 9,12 (1H, s).

IR (ATR) cm-1: 3446, 3209, 1689, 1587, 1495, 1412, 1342, 1230, 1043.

Analytically calculated for C20H14F4N2O2S: C, 56,87; H, 3,34; F, 17,99; N, 6,63; S, TO 7.59. Found: C, 56,66; H, 3,38; F, 18,12; N, 6,63; S, 7,65.

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

Example 39: 5-[[(4-Forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-forfinal)sulfinil](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (106 mg, 0.25 mmol) in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (66 mg, 0.25 mmol) at 0°C. After stirring for 5 days at the room for the Noah temperature, the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to preparative thin-layer chromatography (showed a mixture of hexane:ethyl acetate=2:3, was suirable a mixture of methylene chloride: methanol=4:1). The obtained fraction was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (67 mg, 0.15 mmol, 61%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,14 (3H, s)5,59 (1H, users), 5,90 (1H, s), 6,82-of 6.90 (1H, m), 7,14-of 7.25 (3H, m), 7,73-7,79 (2H, m), 7,87 (1H, users), 7,98 (1H, s), 9,43 (1H, s).

IR (ATR) cm-1: 3396, 3167, 1687, 1587, 1496, 1419, 1296, 1234, 1144, 1078, 845, 816.

Analytically calculated for C20H14F4N2O3S: C, 54,79; H, 3,22; F, 17,33; N, 6,39; S, 7,31. Found: C, 54,54; H, 3,26; F, 17,17; N, 6,37; S, 7,39.

MS m/z: 439 (M++H).

Example 40: 2-Bromo-5-[(2,5-differenl)[(4-methoxyphenyl)thio]methyl]-4-methylpyridin

To a solution of 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (1,00 g, a 3.01 mmol)obtained in Reference example 2 in N,N-dimethylformamide (15 ml) was added 4-methoxybenzoyl (0,381 ml, a 3.01 mmol)and then potassium carbonate (457 mg, of 3.31 mmol), in the atmosphere and the heat at 0°C and the resulting mixture was stirred for 13 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C and after separation of the organic layer, the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 (1.08 g, 2.48 mmol, 82%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: of 2.26 (3H, s), of 3.77 (3H, s), to 5.66 (1H, s), 6,77 (2H, d, J=8.5 Hz), 6.89 in-6,98 (2H, m), 7,25 (1H, s), 7,29 (2H, d, J=8.5 Hz), 7,31-7,38 (1H, m), 8,43 (1H, s).

MS m/z: 436, 438 (M++H).

Example 41: 5-[(2,5-Differenl)[(4-methoxyphenyl)thio]methyl]-4-methylpyridin-2-carbaldehyde

To a solution of 2-bromo-5-[(2,5-differenl)[(4-methoxyphenyl)thio]methyl]-4-methylpyridine (1.08 g, 2.48 mmol) in toluene (30 ml) was added a solution of n-utility in hexane (1,54 M, 1.77m, of 2.72 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C and to the mixture was added N,N-dimethylformamide (0,221 ml of 2.72 mmol). After stirring the reaction mixture for 2 hours was added to the water at the same temperature and the mixture was allowed to warm to room te is the temperature. To the reaction mixture were added ethyl acetate and the resulting mixture was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 (597 mg, 1.55 mmol, 63%) as a yellow oily substance.

1H-NMR (400 MHz, CDCl3) δ: at 2.36 (3H, s), 3,76 (3H, s), 5,77 (1H, s), 6,77 (2H, d, J=8,8 Hz), 6,93-6,98 (2H, m), 7,29 (2H, d, J=8,8 Hz), 7,42-7,47 (1H, m), 7,71 (1H, s), 8,82 (1H, s), 10,02 (1H, s).

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

Example 42: 5-[(2,5-Differenl)[(4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

31% aqueous hydrogen peroxide (1.50 ml) was added to a solution of 5-[(2,5-differenl)[(4-methoxyphenyl)thio]methyl]-4-methylpyridin-2-carbaldehyde (595 mg, 1.54 mmol) in formic acid (15 ml) and the resulting mixture was stirred for 3 hours at room temperature. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and washed 0,01H. a solution of hydrochloric acid. The obtained solid substance was dissolved in methylene chloride and the solution washed with 0,1N. solution PI is estevadeordal acid. Then the organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (404 mg, of 0.93 mmol, 60%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.25 (3H, s), a 3.87 (3H, s), 5,95 (1H, s)6,91 (2H, d, J=8,8 Hz), 6,93-6,99 (1H, m), 7,01-was 7.08 (1H, m), to 7.59 (2H, d, J=8,8 Hz), 7,80-7,86 (1H, m), 7,98 (1H, s), 9,18 (1H, s).

TPL: 194-195°C.

MS m/z: 434 (M++H).

Example 43: 5-[(2,5-Differenl)[(4-methoxyphenyl)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (108 mg, 0.25 mmol) in methylene chloride (3 ml) was added 2-aminoethanol (0,017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0,030 ml, 0.28 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg, 0.28 mmol) at room temperature. After stirring for 17 hours at room temperature the reaction mixture was washed with water and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the resulting mod is subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:4, concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and then collected by filtration to obtain specified in the title compound (96 mg, 0.20 mmol, 81%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,15 (3H, s), of 2.56 (1H, users), 3,62-3,68 (2H, m), 3,82-3,88 (2H, m), 3,86 (3H, s), to 5.93 (1H, s), make 6.90 (2H, d, J=8,8 Hz), 6,92-7,07 (2H, m), EUR 7.57 (2H, d, J=8,8 Hz), 7,82-7,88 (1H, m), to 7.93 (1H, s), 8,40 (1H, ushort, J=5.6 Hz), 9,11 (1H, s).

IR (ATR) cm-1: 3456, 3367, 1653, 1591, 1535, 1493, 1294, 1265, 1147.

TPL: 134-135°C.

Analytically calculated for C23H22F2N2O5S: C, 57,97; H, 4,65, F, OF 7.97; N, 5,88; S, 6.73 X. Found: C, 57,93; H, 4,39; F, 8,18; N, 5,91; S 6,79.

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

Reference example 5: O-ethyl S-(3-fluoro-4-methoxyphenyl) dithiocarbonate

3-Fluoro-4-methoxyaniline (5.0 g, of 35.4 mmol) was dissolved in methanol (35 ml) and to the mixture was added 1N. hydrochloric acid solution (106 ml) at -5°C. Then, to the mixture was added dropwise a solution of sodium nitrite (2.9 g, 42,5 mmol) in water (20 ml) and the mixture was stirred for 30 minutes at the same temperature. The resulting reaction solution was added dropwise to a solution of O-utilityservice potassium (8.5 g, 53,1 mmol) in water (100 ml) at 65°C. the Reaction mixture was heated to 90°C, peremeshivayu for 30 minutes and then cooled to room temperature. Added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with water (2 times), saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered and then 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=99:1 was concentrated under reduced pressure to obtain specified in the title compound (3.0 g, 12.2 mmol, 34%) as a yellow oily substance.

1H-NMR (400 MHz, CDCl3) l: of 1.33 to 1.37 (3H, m), 3,93 (3H, s), 4,60-4,63 (2H, m), 6,98-7,00 (1H, m), 7.23 percent-of 7.25 (2H, m).

Example 44: 2-Bromo-5-[(2,5-differenl)[(3-fluoro-4-methoxyphenyl)thio]methyl]-4-methylpyridin

To a solution of O-ethyl S-(3-fluoro-4-methoxyphenyl) dithiocarbonate (1,23 g, 5.00 mmol) in ethanol (15 ml) was added 1N. an aqueous solution of sodium hydroxide (15 ml) and the resulting mixture was stirred for 2 hours at 50°C. the Reaction mixture was cooled to room temperature and washed with methylene chloride. Then the aqueous layer was acidified using 1N. a solution of hydrochloric acid and was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then iltram concentrated under reduced pressure. To a solution of the obtained residue and 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (1.66 g, 5.00 mmol)obtained in Reference example 2 in N,N-dimethylformamide (25 ml) was added potassium carbonate (760 mg, of 5.50 mmol) under nitrogen atmosphere and the resulting mixture was stirred for 19 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 (1.85 g, 4.07 mmol, 81%) as an oily material green color.

1H-NMR (400 MHz, CDCl3) δ: to 2.29 (3H, s), 3,85 (3H, s)5,69 (1H, s), 6,79 for 7.12 (5H, m), 7,28 (1H, s), 7,28-7,33 (1H, m), 8,42 (1H, m).

Example 45: 5-[(2,5-Differenl)[(3-fluoro-4-methoxyphenyl)thio]methyl]-4-methylpyridin-2-carbaldehyde

To a solution of 2-bromo-5-[(2,5-differenl)[(3-fluoro-4-methoxyphenyl)thio]methyl]-4-methylpyridine (1.85 g, 4.07 mmol) in toluene (40 ml) was added a solution of n-utility in hexane (1,54 M, 3,17 ml, 4,89 mmol) in an argon atmosphere at -78°C. the Reaction mixture p is remedial for 30 minutes at -40°C and then cooled to -78°C was added N,N-dimethylformamide (0,378 ml, 4,89 mmol). After completion of adding dropwise the reaction mixture was allowed to warm to 0°C and added to water at a specified temperature. To the reaction mixture was added ethyl acetate, the organic layer was separated and the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=12:1 was concentrated under reduced pressure to obtain specified in the title compound (1.20 g, of 2.97 mmol, 73%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 2,40 (3H, s), 3,85 (3H, s)5,80 (1H, s), 6,79-6,85 (1H, m), 6,94-7,01 (2H, m), 7,06-7,13 (2H, m), of 7.36-7,42 (1H, m), 7,73 (1H, s), 8,82 (1H, m), there is a 10.03 (1H, s).

Example 46: 5-[(2,5-Differenl)[(3-fluoro-4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

31% aqueous hydrogen peroxide (3 ml) was added to a solution of 5-[(2,5-differenl)[(3-fluoro-4-methoxyphenyl)thio]methyl]-4-methylpyridin-2-carbaldehyde (1.20 g, of 2.97 mmol) in formic acid (30 ml) and the resulting mixture was stirred for 2 hours at room temperature. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and p is washed 0,01H. a solution of hydrochloric acid. The obtained solid substance was dissolved in methylene chloride and the solution washed with 0,1N. a solution of hydrochloric acid. Then the organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (825 mg and 1.83 mmol, 61%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), of 3.96 (3H, s), 5,97 (1H, s), 6,91-7,10 (3H, m), 7,37 was 7.45 (2H, m), 7,72 for 7.78 (1H, m), 8,02 (1H, s), of 9.21 (1H, s).

TPL: 196-197°C.

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

Example 47: 5-[(2,5-Differenl)[(3-fluoro-4-methoxyphenyl)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(3-fluoro-4-methoxyphenyl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (113 mg, 0.25 mmol) in methylene chloride (3 ml) was added 2-aminoethanol (0,017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0,030 ml, 0.28 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg, 0.28 mmol) at room temperature. After stirring for 19 hours at room temperature the reaction mixture was washed with water and then saturated saline solution. The organization is practical layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with ethyl acetate, concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (99 mg, 0.20 mmol, 80%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s)to 2.55 (1H, users), 3,62-3,68 (2H, m), 3,85 (2H, t, J=4.9 Hz), of 3.95 (3H, s), 5,95 (1H, s), 6,92-was 7.08 (3H, m), 7,37 was 7.45 (2H, m), 7,74-7,80 (1H, m), of 7.96 (1H, s), 8,40 (1H, ushort, J=5.4 Hz), 9,14 (1H, s).

IR (ATR) cm-1: 3460, 3371, 1651, 1599, 1535, 1493, 1281, 1219, 1134.

TPL: 137-138°C.

Analytically calculated for C23H21F3N2O5S: C, 55,87; H, 4,28; F, 11,53; N, 5,67; S, 6.48 IN. Found: C, 55,73; H; 4,00; F, 11,77; N, 5,66; S, 6,58.

MS m/z: 495 (M++H).

Reference example 6: S-(4-ethoxyphenyl) O-utilitiesand

4-Ethoxyaniline (5.0 g, of 36.4 mmol) was dissolved in methanol (20 ml) and to the mixture was added at -10°C for 1H. hydrochloric acid solution (110 ml). Then was added dropwise a solution of sodium nitrite (3.0 g, 43,7 mmol) in water (20 ml) and the resulting mixture was stirred for 30 minutes at the same temperature. The resulting reaction solution was added dropwise to a solution of O-utilityservice feces is I (8.8 g, the 54.6 mmol) in water (100 ml) at 65°C. the Reaction mixture was heated to 90°C, stirred for 30 minutes and then cooled to room temperature. To the mixture was added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with water (2 times), saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered and then 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=99:1 was concentrated under reduced pressure to obtain specified in the connection header (2,08 g, 8,58 mmol, 24%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 1,24 was 1.43 (6H, m), a 4.03-4,07 (2H, m), 4,60 (2H, q, J=7,1 Hz), 6,92-6,93 (2H, m), 7,38-7,40 (2H, m).

Example 48: 2-Bromo-5-[(2,5-differenl)[(4-ethoxyphenyl)thio]methyl]-4-methylpyridin

To a solution of S-(4-ethoxyphenyl) O-utilityservice (1.45 g, 6,00 mmol) in ethanol (15 ml) was added 1N. an aqueous solution of sodium hydroxide (15 ml) and the resulting mixture was stirred for 2 hours at 50°C. the Reaction mixture was cooled to room temperature and washed with methylene chloride. Then the aqueous layer was acidified using 1N. rest the rum hydrochloric acid and was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. To a solution of the obtained residue and 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (1.66 g, 5.00 mmol)obtained in Reference example 2 in N,N-dimethylformamide (25 ml) was added potassium carbonate (760 mg, of 5.50 mmol) under nitrogen atmosphere and the resulting mixture was stirred for 3 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 (1.18 g, 2,62 mmol, 52%) as a solid light green color.

1H-NMR (400 MHz, CDCl3) δ: of 1.39 (3H, t, J=7,1 Hz in), 2.25 (3H, s), 3,98 (2H, q, J=7,1 Hz), the 5.65 (1H, s), of 6.75 (2H, d, J=8,8 Hz), 6.89 in-6,98 (2H, m), 7,25 (1H, m), 7,27 (2H, d, J=8,8 Hz), 7,31-7,37 (1H, m), 8,43 (1H, m).

Example 49: 5-[(2,5-Differenl)[(4-ethoxyphenyl)thio]methyl]-4-methylpyridin-2-carbaldehyde

To a solution of 2-bromo-5-[(2,5-differenl)[(4-ethoxy enyl)thio]methyl]-4-methylpyridine (1.18 g, 2,62 mmol) in toluene (30 ml) was added a solution of n-utility in hexane (1,54 M 2,04 ml, 3.14 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C and to the mixture was added N,N-dimethylformamide (0,243 ml, 3.14 mmol). After completion of adding dropwise the reaction mixture was allowed to warm to -40°C and was added to water at a specified temperature. To the reaction mixture was added ethyl acetate, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 connection header (786 mg, 1.97 mmol, 75%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: to 1.38 (3H, t, J=7,1 Hz), a 2.36 (3H, s), 3,98 (2H, q, J=7,1 Hz), USD 5.76 (1H, s), of 6.75 (2H, d, J=8.6 Hz), 6,92-6,99 (2H, m), 7,27 (2H, d, J=8.6 Hz), 7,41-of 7.48 (1H, m), 7,71 (1H, s), 8,82 (1H, s), 10,02 (1H with).

Example 50: 5-[(2,5-Differenl)[(4-ethoxyphenyl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

31% aqueous hydrogen peroxide (2 ml) was added to a solution of 5-[(2,5-differenl)[(4-ethoxyphenyl)t is o]methyl]-4-methylpyridin-2-carbaldehyde (783 mg, a 1.96 mmol) in formic acid (20 ml) and the resulting mixture was stirred for 2 hours at room temperature. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in methylene chloride and the solution washed with 0,1N. a solution of hydrochloric acid. Then the organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (797 mg, 1.78 mmol, 91%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: the 1.44 (3H, t, J=7,1 Hz), 2,24 (3H, s)4,08 (2H, q, J=7,1 Hz), 5,95 (1H, s), 6.89 in (2H, d, J=8,8 Hz), 6,92-6,99 (1H, m), 7,01-was 7.08 (1H, m), EUR 7.57 (2H, d, J=8,8 Hz), 7,80-7,86 (1H, m), 7,98 (1H, s), 9,17 (1H, s).

MS m/z: 448 (M++H).

Example 51: 5-[(2,5-Differenl)[(4-ethoxyphenyl)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-ethoxyphenyl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (112 mg, 0.25 mmol) in methylene chloride (3 ml) was added 2-aminoethanol (0,017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0,030 ml, 0.28 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethy the aminopropyl)carbodiimide (53 mg, 0.28 mmol) at room temperature. After stirring for 3 hours at room temperature the reaction mixture was washed with water and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:2, was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (97 mg, 0.20 mmol, 79%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: the 1.44 (3H, t, J=7,1 Hz), of 2.15 (3H, s), 2.57 m (1H, ushort, J=5,1 Hz), 3,62-3,68 (2H, m), 3,82-3,88 (2H, m), 4,07 (2H, q, J=7,1 Hz), to 5.93 (1H, s), 6.87 in (2H, d, J=8,8 Hz), 6,92-7,06 (2H, m), 7,56 (2H, d, J=8,8 Hz), 7,82-7,89 (1H, m), 7,92 (1H, s), 8,40 (1H, ushort, J=5.6 Hz), 9,11 (1H, s).

IR (ATR) cm-1: 3381, 1668, 1593, 1527, 1493, 1321, 1269, 1140.

Analytically calculated for C24H24F2N2O5S: C, 58,77; H, 4,93, F, OF 7.75; N, 5,71; S, 6,54. Found: C, 58,41; H, 4,90, F, To $ 7.91; N, 5,73; S, 6,66.

MS m/z: 491 (M++H).

Reference example 7: 5-(Trifluoromethyl)pyridine-2-thiol

The thiourea (684 mg, 8,80 mmol) was added to a solution of 2-chloro-5-(trifluoromethyl)pyridine (1.45 g, 8,00 mmol) in ethane is Le (4 ml) and the resulting mixture was heated to boiling point under reflux for 2 hours. The reaction mixture was cooled to room temperature, and then to the mixture was added a solution of potassium hydroxide (792 mg to 12.0 mmol) in water (4 ml) and the resulting mixture was heated to boiling point under reflux for 2 hours. The reaction mixture was cooled again to room temperature and to the mixture was added 1N. the sodium hydroxide solution and methylene chloride. After separation of the aqueous layer to the water layer was added acetic acid and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of hexane and diethyl ether, and collected by filtration to obtain specified in the title compound (860 mg, 4,80 mmol, 60%) as a solid pale yellow color.

1H-NMR (400 MHz, CDCl3) δ: 7,45 (1H, DD, J=9,0, 2.2 Hz), to 7.59 (1H, d, J=9.0 Hz), 7,81 (1H, m).

MS m/z: 180 (M++H).

Example 52: 2-Bromo-5-[(2,5-differenl)[[5-(trifluoromethyl)pyridin-2-yl]thio]methyl]-4-methylpyridin

To a solution of 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (1,59 g, 4,78 mmol)obtained in Reference example 2 in N,N-dimethylformamide (25 ml) was added 5-(trifluoromethyl)pyridine-2-thiol (857 mg, 4,78 mmol)and then potassium carbonate (992 mg, 7,18 mmol) in the atmosphere Argo is at 0°C and the resulting mixture was stirred for 2 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 (1.97 g, 4,15 mmol, 87%) as an oily material light green color.

1H-NMR (400 MHz, CDCl3) δ: 2,43 (3H, s), 6,72 (1H, s), 6,93-7,07 (2H, m), 7,19-of 7.25 (1H, m), 7,28 (1H, d, J=8,3 Hz), 7,32 (1H, s), of 7.70 (1H, DD, J=8,3, 2.2 Hz), 8,35 (1H, m), 8,58 at 8.60 (1H, m).

MS m/z: 475, 477 (M++H).

Example 53: 5-[(2,5-Differenl)[[5-(trifluoromethyl)pyridin-2-yl]thio]methyl]-4-methylpyridin-2-carbaldehyde

To a solution of 2-bromo-5-[(2,5-differenl)[[5-(trifluoromethyl)pyridin-2-yl]thio]methyl]-4-methylpyridine (1.97 g, 4,15 mmol) in toluene (45 ml) was added a solution of n-utility in hexane (1,54 M, 3,23 ml, equal to 4.97 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C and to the mixture was added N,N-dimethylformamide (0,385 ml, equal to 4.97 mmol). After completion of adding dropwise the reaction mixture was allowed to warm to 0°C and we use the and water at the same temperature. To the reaction mixture was added ethyl acetate, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 specified in the title compound (1.07, and 2,52 mmol, 61%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 2,56 (3H, s), 6,85 (1H, s), 6,95-to 7.09 (2H, m), 7.23 percent-7,29 (1H, m), 7,31 (1H, d, J=8.5 Hz), 7,71 (1H, DD, J=8,5, 2.0 Hz), 7,79 (1H, m), 8,58 at 8.60 (1H, m), 8,79 (1H, s), 10,02 (1H, s).

Example 54: 5-[(2,5-Differenl)[[5-(trifluoromethyl)pyridin-2-yl]sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

31% aqueous hydrogen peroxide (2 ml) was added to a solution of 5-[(2,5-differenl)[[5-(trifluoromethyl)pyridin-2-yl]thio]methyl]-4-methylpyridin-2-carbaldehyde (1.07 g, 2,52 mmol) in formic acid (20 ml) and the resulting mixture was stirred for 2 hours at room temperature. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in methylene chloride and the solution washed with 0,1N. rest the rum hydrochloric acid. Then the organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethanol and hexane, and collected by filtration to obtain specified in the title compound (604 mg, 1.28 mmol, 51%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2.63 in (3H, s), to 6.95 (1H, s), 6,97-7,07 (2H, m), to 7.67-7,73 (1H, m), of 8.09 (1H, s), 8,15-8,17 (2H, m), 8,96 (1H, s), 9,07 (1H, s).

MS m/z: 473 (M++H).

Example 55: 5-[(2,5-Differenl)[[5-(trifluoromethyl)pyridin-2-yl]sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[[5-(trifluoromethyl)pyridin-2-yl]sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (118 mg, 0.25 mmol) in methylene chloride (3 ml) was added 2-aminoethanol (0,017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0,030 ml, 0.28 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (53 mg, 0.28 mmol) at room temperature. After stirring for 5 hours at room temperature the reaction mixture was washed with water and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash XP is matography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure and the obtained residue was washed with hexane and dried under reduced pressure to obtain specified in the title compound (91 mg, 0.18 mmol, 71%) as a colorless foamy substance.

1H-NMR (400 MHz, CDCl3) δ: 2,46 (1H, users), to 2.55 (3H, s), 3,61-3,66 (2H, m), 3,83 (2H, ushort, J=5,1 Hz), make 6.90 (1H, s), 6,97-7,07 (2H, m), 7,66-7,72 (1H, m), 8,02 (1H, s), 8,12-of 8.15 (2H, m), a 8.34 (1H, ushort, J=5.6 Hz), 8,96 (1H, s), 9,03 (1H, s).

IR (ATR) cm-1: 3377, 1664, 1529, 1495, 1325, 1165, 1138, 1099, 1072.

Analytically calculated for C22H18F5N3O4S: C, 51,26; H, 3,52; F, 18,43; N, 8,15; S, 6,22. Found: C, 51,39; H, 3,61; F, 18,36; N, 8,04; S Of 6.31.

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

Example 56: 2-Bromo-5-[(2,5-differenl)(phenylthio)methyl]-4-methylpyridin

2-Bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (2.0 g, 6.0 mmol)obtained in Reference example 2, and sensation (618 μl, 6.0 mmol) was dissolved in N,N-dimethylformamide (30 ml), to the mixture was added at 0°C. potassium carbonate (996 mg, 7.2 mmol) and then the resulting mixture was stirred over night at room temperature. To the reaction mixture were added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and the filtrate concentri is ovali under reduced pressure. The obtained solid is washed with a mixed solution of hexane and ethyl acetate and filtered to obtain specified in the title compound (1.6 g, 3.9 mmol, 66%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), of 5.81 (1H, s), 6,93-7,00 (2H, m), 7,22-7,39 (7H, m), of 8.37 (1H, s).

Example 57: 5-[(2,5-Differenl)(phenylthio)methyl]-4-methylpyridin-2-carbaldehyde

A solution of 2-bromo-5-[(2,5-differenl)(phenylthio)methyl]-4-methylpyridine (1.2 g, 3.0 mmol) in toluene (30 ml) was cooled to -78°C was added n-utility (1.54 M solution in hexane, 2.5 ml, 3.9 mmol) in argon atmosphere. After stirring for 10 minutes at the specified temperature of the mixture was allowed to warm to -40°C, stirred for 30 minutes and again cooled to -78°C and to the mixture was added N,N-dimethylformamide (302 μl, 3.9 mmol). After stirring for 30 minutes at the same temperature to the mixture was added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then 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=93:7, concentrated under reduced pressure with poluchenierazreshenija the title compound (250 mg, 0.70 mmol, 25%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 2,42 (3H, s), 5,91 (1H, s), 6,95-7,01 (2H, m), 7.23 percent-to 7.32 (5H, m), 7,44-7,47 (1H, m), 7,74 (1H, s), 8,78 (1H, s), 10,02 (1H, s).

Example 58: 5-[(2,5-Differenl)(phenylsulfonyl)methyl]-4-methylpyridin-2-carboxylic acid

5-[(2,5-Differenl)(phenylthio)methyl]-4-methylpyridin-2-carbaldehyde (250 mg, 0.70 mmol) was dissolved in formic acid (7 ml) and to the mixture was added a 31% aqueous hydrogen peroxide (0.7 ml) at 0°C. After stirring for 3 hours at room temperature to the reaction solution were added water and the precipitated thus, the solid was collected by filtration. The solid is washed with sufficient amount of water and then dried under reduced pressure to obtain specified in the title compound (90 mg, 0.22 mmol, 32%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (3H, s), of 5.99 (1H, s), 6,91-was 7.08 (2H, m), 7,46-7,52 (2H, m), of 7.64-of 7.70 (3H, m), 7,80-to 7.84 (1H, m), 7,98 (1H, s), 9,20 (1H, s).

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

Example 59: 5-[(2,5-Differenl)(phenylsulfonyl)methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

5-[(2,5-Differenl)(phenylsulfonyl)methyl]-4-methylpyridin-2-carboxylic acid (90 mg, 0.22 mmol), 2-aminoethanol (27 ml, 0.45 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (64 mg, 0.34 mmol), 1-guide oxybisethanol (30 mg, 0.22 mmol) and triethylamine (92 ml, 0.66 mmol) was dissolved in methylene chloride (15 ml) and the resulting solution was stirred overnight at room temperature. To the reaction mixture were added water and the resulting mixture was extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography (showed 5% methanol/methylene chloride, was suirable 30% methanol/methylene chloride) to obtain the specified title compound (30 mg, 0,067 mmol, 30%) as an amorphous substance of white color.

1H-NMR (400 MHz, CDCl3) δ: 2,14 (3H, s), 2,52-of 2.56 (1H, m), 3,62-3,68 (2H, m), 3,82-a 3.87 (2H, m), 5,97 (1H, s), 6.90 to-7,07 (2H, m), 7,43-7,49 (2H, m), 7,62-of 7.69 (3H, m), 7,81-7,87 (1H, m), to 7.93 (1H, s), 8,39 (1H, users), 9,13 (1H, s).

IR (ATR) cm-1: 3413, 2940, 1662, 1650, 1529, 1496, 1307, 1143.

MS m/z: 447 (M++H).

FAB-MS: 447,1194 (calculated for C22H21F2N2O4S: 447,1190).

Example 60: 2-Bromo-5-[(2,5-differenl)[(4-were)thio]methyl]-4-methylpyridin

2-Bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (2.0 g, 6.0 mmol)obtained in Reference example 2 and 4-methylbenzoyl (746 mg, 6.0 mmol) was dissolved in N,N-dimethylformamide (30 ml) and to the mixture was added potassium carbonate (996 mg, 7.2 mmol) at 0°C. the mixture is Then AC is stirred over night at room temperature. To the reaction mixture was added water, the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then 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=95:5, concentrated under reduced pressure to obtain specified in the title compound (2.5 g, 6.0 mmol, quantitative) as an oily material light green color.

1H-NMR (400 MHz, CDCl3) δ: to 2.29 (3H, s), is 2.30 (3H, s), of 5.75 (1H, s), 6.90 to-6,99 (2H, m), 7,05 (2H, d, J=8.1 Hz), 7,21 (2H, d, J=7.8 Hz), 7,26 (1H, s), 7,33-7,39 (1H, m), scored 8.38 (1H, s).

Example 61: 5-[(2,5-Differenl)[(4-were)thio]methyl]-4-methylpyridin-2-carbaldehyde

A solution of 2-bromo-5-[(2,5-differenl)[(4-were)thio]-methyl]-4-methylpyridine (2.5 g, 6.0 mmol) in toluene (60 ml) was cooled to -78°C in an argon atmosphere to the mixture was added n-utility (1.54 M solution in hexane, 4.6 ml, 7.1 mmol). After stirring for 10 minutes at the specified temperature of the mixture was allowed to warm to -40°C and was stirred for 30 minutes. The mixture was again cooled to -78°C and then added N,N-dimethylformamide (720 ml, 7.1 mmol). After stirring for 30 minutes at the specified rate which the temperature was added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then 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=95:5, concentrated under reduced pressure to obtain specified in the title compound (900 mg, 2.4 mmol, 41%) as an oily substance pale yellow color.

1H-NMR (400 MHz, CDCl3) δ: to 2.29 (3H, s)to 2.41 (3H, s), to 5.85 (1H, s), of 6.96-6,98 (2H, m), 7,05 (2H, d, J=8.1 Hz), 7,22 (2H, d, J=8.1 Hz), 7,45-7,47 (1H, m), 7,72 (1H, s), 8,78 (1H, s), 10,02 (1H, s).

Example 62: 5-[(2,5-Differenl)[(4-were)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

5-[(2,5-Differenl)[(4-were)thio]methyl]-4-methylpyridin-2-carbaldehyde (900 mg, 2.4 mmol) was dissolved in formic acid (20 ml) was added in 31% aqueous hydrogen peroxide (2.5 ml) at 0°C. After stirring for 5 hours at room temperature to the reaction solution were added water and the precipitated thus, the solid was collected by filtration. The solid is washed with sufficient amount of water and then dried under reduced pressure to obtain specified in the title compound (520 mg, 1.2 mmol, 51%) as a solid white color is the same.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (3H, s), 2,43 (3H, s), 5,97 (1H, s), 6,92-was 7.08 (2H, m), 7,26 (2H, d, J=8,3 Hz), 7,56 (2H, d, J=8,3 Hz), 7,81-7,86 (1H, m), 7,98 (1H, s), 9,17 (1H, s).

MS m/z: 418 (M++H).

Example 63: 5-[(2,5-Differenl)[(4-were)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

5-[(2,5-Differenl)[(4-were)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (208 mg, 0.5 mmol), 2-aminoethanol (46 ml, 0.75 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (144 mg, 0.75 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol) and triethylamine (209 ml, 1.5 mmol) was dissolved in methylene chloride (35 ml) and the resulting solution was stirred overnight at room temperature. To the reaction mixture were added water and the resulting mixture was extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography (showed 6% methanol/methylene chloride, was suirable 30% methanol/methylene chloride) to obtain the specified title compound (125 mg, 0.27 mmol, 54%) as an amorphous substance of white color.

1H-NMR (400 MHz, CDCl3) δ: 2,14 (3H, s), 2,42 (3H, s), 2,58 (1H, t, J=5,2 Hz), 3,62-to 3.67 (2H, m), 3,85 (2H, q, J=5,2 Hz), 5,95 (1H, s), 6,92-7,07 (2H, m), from 7.24 (2H, d, J=8,3 Hz), 7,54 (2H, d, J=8,3 Hz), 7,8-7,88 (1H, m), 7,92 (1H, s), 8,40 (1H, users), 9,11 (1H, s).

IR (ATR) cm-1: 3388, 1664, 1594, 1527, 1492, 1145.

MS m/z: 461 (M++H).

Analytically calculated for C23H22F2N2O4S: C, 59,99; H, 4,82, F, OF 8.25; N, BETWEEN 6.08; S OF 6.96. Found: C, 59,94; H, 4,81; F, 8,03; N, 5,94; S, For 6.81.

Referential example 8: S-(4-chloro-3-were) O-ethyl dithiocarbonate

4-Chloro-3-methylaniline (4.5 g, of 31.8 mmol) was dissolved in methanol (20 ml) was added 1N. hydrochloric acid solution (95 ml) at -5°C. Then, to the mixture was added dropwise a solution of sodium nitrite (2.6 g, is 38.2 mmol) in water (20 ml) and the mixture was stirred for 30 minutes at the same temperature. The resulting reaction solution was added dropwise to a solution of O-utilityservice potassium (7.6 g, while 47.7 mmol) in water (100 ml) at 65°C. the Reaction mixture was heated to 90°C, stirred for 30 minutes and then cooled to room temperature. Added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with water (2 times), saturated aqueous sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and filtered and then 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 is Etat=99:1, concentrated under reduced pressure to obtain specified in the title compound (3.9 g, 15.8 mmol, 50%) as an oily material light brown color.

1H-NMR (400 MHz, CDCl3) δ: of 1.34 (3H, t, J=7,1 Hz), 2,39 (3H, s), br4.61 (2H, q, J=7, 1 Hz), 7,25-7,40 (3H, m).

Example 64: 2-Bromo-5-[[(4-chloro-3-were)thio](2.5-differenl)methyl]-4-methylpyridin

To a solution of S-(4-chloro-3-were) O-utilityservice (3,9 g, 15.8 mmol) in ethanol (50 ml) and tetrahydrofuran (20 ml) was added 1N. aqueous sodium hydroxide solution (48 ml) and the resulting mixture was stirred for 3 hours at 60°C. the Reaction mixture was cooled to room temperature, added water and the mixture was washed with methylene chloride. The aqueous layer was acidified 5h. a solution of hydrochloric acid and then was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue and 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridin (4.5 g, of 13.8 mmol)obtained in Reference example 2 was dissolved in N,N-dimethylformamide (80 ml) and to the mixture was added potassium carbonate (2.4 g, 18 mmol), then stirred overnight at room temperature. To the reaction mixture were added water and the mixture was extracted twice with ethyl acetate. The combined organic layers Ave is mawali saturated salt solution, then was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The obtained solid is washed with a mixed solution of hexane and ethyl acetate and filtered to obtain specified in the title compound (4.3 g, 9.5 mmol, 60%) as a light brown solid.

1H-NMR (400 MHz, CDCl3) δ: to 2.29 (3H, s), 2,31 (3H, s), 5,78 (1H, s), 6,93-7,33 (7H, m), 8,39 (1H, s).

MS m/z: 454, 456 (M++H).

Example 65: 5-[[(4-Chloro-3-were)thio](2.5-differenl)methyl]-4-methylpyridin-2-carbaldehyde

A solution of 2-bromo-5-[[(4-chloro-3-were)thio](2.5-differenl)methyl]-4-methylpyridine (2.0 g, 4.4 mmol) in toluene (50 ml) was cooled to -78°C in an argon atmosphere to the mixture was added n-utility (1.54 M solution in hexane, 3.4 ml, 5.3 mmol). After stirring for 10 minutes at the specified temperature of the mixture was allowed to warm to -40°C, stirred for 30 minutes and again cooled to -78°C and then added N,N-dimethylformamide (409 μl, 5.3 mmol). After stirring for 30 minutes at the same temperature was added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue which was vergili column flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=95:5, concentrated under reduced pressure to obtain specified in the title compound (700 mg, 1.7 mmol, 40%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: to 2.29 (3H, s), 2,43 (3H, s), 5,88 (1H, s), 6,99-7,05 (3H, m), 7,19-7,21 (2H, m), 7,38-7,41 (1H, m), of 7.75 (1H, s), 8,79 (1H, s), 10,02 (1H, s).

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

Example 66: 5-[[(4-Chloro-3-were)sulfonyl](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid

5-[[(4-Chloro-3-were)thio](2.5-differenl)methyl]-4-methylpyridin-2-carbaldehyde (700 mg, 1.7 mmol) was dissolved in formic acid (15 ml) and added 31% aqueous hydrogen peroxide (1.7 ml) at 0°C. After stirring for 2 hours at room temperature to the reaction mixture were added water and the precipitated thus, the solid was collected by filtration. The solid is washed with sufficient amount of water and dried under reduced pressure to obtain specified in the title compound (600 mg, 1.3 mmol, 78%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), of 2.38 (3H, s), 5,97 (1H, s), 6,93-to 7.09 (2H, m), 7,41-7,44 (2H, m), 7,56-EUR 7.57 (1H, m), 7,73-to 7.77 (1H, m), 8,03 (1H, s), which 9.22 (1H, s).

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

Example 67: 5-[[(4-Chloro-3-were)sulfonyl](2.5-differenl)methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

5-[[(4-Chloro-3-were)sulfonyl](2.5-differenl)methyl]-4-methylpyridin-2-carboxylic acid (300 mg, 0.66 mmol), 2-aminoethanol (60 μl, of 0.99 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (191 mg, 0,99 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol) and triethylamine (275 μl, to 1.98 mmol) was dissolved in methylene chloride (60 ml) and the resulting mixture was stirred over night at room temperature. To the reaction mixture were added water and the mixture was extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography (showed 5% methanol/methylene chloride, was suirable 30% methanol/methylene chloride) to obtain the specified title compound (190 mg, 0.38 mmol, 58%) as a white amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), of 2.38 (3H, s), 2,58 at 2.59 (1H, m), 3,65-3,66 (2H, m), 3,84-3,86 (2H, m), 5,95 (1H, s), 6,92-7,07 (2H, m), 7,37-the 7.43 (2H, m), 7,55 (1H, s), 7,74-7,80 (1H, m), of 7.97 (1H, s), 8,40 (1H, users), 9,14 (1H, s).

IR (ATR) cm-1: 3390, 1664, 1527, 1492, 1147, 1049,

MS m/z: 495 (M++H).

Analytically calculated for C23H21ClF2N2O4S·0,25H2O: C, 55,31; H, 4,34; Cl 7,10; F, To 7.61; N, 5,61; S, 6.42 Per. Found: C, 55,29; H, 4,24; Cl 7,50; F, 7,56; N, 5,64; S, 6,51.

Referential example 9: O-ethyl S-(4-fluoro-3-were) dition rbonate

4-Fluoro-3-methylaniline (5.0 g, 40 mmol) was dissolved in methanol (20 ml) and to the mixture was added 1N. hydrochloric acid solution (120 ml) at -5°C. Then was added dropwise a solution of sodium nitrite (3,3 g, 48 mmol) in water (20 ml) and then the resulting mixture was stirred for 30 minutes at the same temperature. The resulting reaction solution was added dropwise to a solution of O-utilityservice potassium (9.6 g, 60 mmol) in water (100 ml) at 65°C. the Reaction mixture was heated to 90°C, stirred for 30 minutes and then cooled to room temperature. Added water and the mixture was extracted twice with ethyl acetate. The combined layers were washed successively with water (2 times), saturated aqueous sodium hydrogen carbonate and saturated saline, then was dried over anhydrous sodium sulfate and filtered and then 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=99:1 was concentrated under reduced pressure to obtain specified in the title compound (4.0 g, to 17.4 mmol, 43%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 1.30 and 1.35 (3H, m)to 2.29 (3H, s), 4,59-4,63 (2H, m), 7,05 (1H, t, J=8,9 Hz), 7,26-7,37 (2H, m).

Example 68: 2-Bromo-5-[(2,5-differenl)[(4-the tor-3-were)thio]methyl]-4-methylpyridin

To a solution of O-ethyl S-(4-fluoro-3-were) dithiocarbonate (4.0 g, to 17.4 mmol) in ethanol (55 ml) and tetrahydrofuran (10 ml) was added 1N. aqueous sodium hydroxide solution (48 ml) and the mixture was stirred for 3 hours at 60°C. the Reaction mixture was cooled to room temperature, added water and then the mixture was washed with methylene chloride. The aqueous layer was acidified 5h. a solution of hydrochloric acid and then was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue and 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridin (4.8 g, 14.7 mmol)obtained in Reference example 2 was dissolved in N,N-dimethylformamide (80 ml) and to the mixture was added potassium carbonate (2.6 g, 19.2 mmol), then stirred overnight at room temperature. To the reaction mixture were added water and the resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained solid is washed with a mixed solution of hexane and ethyl acetate and then filtered to obtain specified in the title compound (3.1 g, 7.1 mmol, 41%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,19 (3H, s), of 2.28 (3H, s), 5,71 (1H, s), 6,85-7,33 (7H, m), 8,43 (1H, s).

MS m/z: 438, 440 (M++H).

Example 69: 5-[(2,5-Differenl)[(4-fluoro-3-were)thio]methyl]-4-methylpyridin-2-carbaldehyde

A solution of 2-bromo-5-[(2,5-differenl)[(4-fluoro-3-were)thio]methyl]-4-methylpyridine (2.0 g, 4.6 mmol) in toluene (50 ml) was cooled to -78°C in an argon atmosphere to the mixture was added n-utility (1.54 M solution in hexane, 3.6 ml, 5.5 mmol). After stirring for 10 minutes at the specified temperature of the mixture was allowed to warm to -40°C, stirred for 30 minutes and again cooled to -78°C and then added N,N-dimethylformamide (424 ml, 5.5 mmol). After stirring for 30 minutes at the same temperature was added water and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then 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=95:5, concentrated under reduced pressure to obtain specified in the title compound (1.1 g, 2.8 mmol, 63%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 2,18 (3H, s), 2,39 (3H, s) of 5.82 (1H, C), 6,85-of 6.99 (3H, m), 7,09-7,19 (2H, m), 7,37-7,41 (1H, m), 7,73 (1H, s), 8,82 (1H, s), 10,02 (1H, s).

MS m/z: 388 (M++H).

Example 70: 5-[(2,5-Differenl)[(4-fluoro-3-were)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

5-[(2,5-Differenl)[(4-fluoro-3-were)thio]methyl]-4-methylpyridin-2-carbaldehyde (1.1 g, 2.8 mmol) was dissolved in formic acid (20 ml) and to the mixture was added a 31% aqueous hydrogen peroxide (2.8 ml) at 0°C. After stirring for 2 hours at room temperature to the reaction solution were added water and the precipitated thus, the solid was collected by filtration. The solid is washed with sufficient amount of water and dried under reduced pressure to obtain specified in the title compound (1.0 g, 2.3 mmol, 81%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,28 (3H, s), is 2.30 (3H, s), 5,96 (1H, s), 6,93-7,10 (3H, m), of 7.48-7,58 (2H, m), 7,73-to 7.77 (1H, m), 8,02 (1H, s), 9,23 (1H, s).

MS m/z: 436 (M++H).

Example 71: 5-[(2,5-Differenl)[(4-fluoro-3-were)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

5-[(2,5-Differenl)[(4-fluoro-3-were)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (300 mg, 0.69 mmol), 2-aminoethanol (60 ml, 1.0 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (193 mg, 1.0 mmol), 1-hydroxybenzotriazole (93 mg, 0.69 mmol) and triethyl is min (292 μl, 2.1 mmol) was dissolved in methylene chloride (60 ml) and the solution was stirred over night at room temperature. To the reaction mixture were added water and the mixture was extracted twice with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography (showed 5% methanol/methylene chloride, was suirable 30% methanol/methylene chloride) to obtain the specified title compound (190 mg, 0,39 mmol, 58%) as a white amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), and 2.27 (3H, s), to 2.57 (1H, t, J=5,2 Hz), 3,63-to 3.67 (2H, m), 3,85 (2H, q, J=5,2 Hz)5,94 (1H, s), 6,92-was 7.08 (3H, m), 7,44-7,49 (1H, m), 7,54-EUR 7.57 (1H, m), 7,74 for 7.78 (1H, m), of 7.96 (1H, s), to 8.40 (1H, users), to 9.15 (1H, s).

IR (ATR) cm-1: 3388, 1664, 1527, 1490, 1240, 1141.

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

Analytically calculated for C23H21F3N2O4S: C, 57,73; H, 4,42; F, 11,91; N, 5,85; S 6,70. Found: C, 57,57; H, 4,63; F, 11,66; N, The Ceiling Of 5.60; S, 6,59.

Example 72: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methyl-N-[3-(methylthio)propyl]pyridine-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (222 mg, 0,527 mmol)obtained in Example 12 in methylene chloride (5 ml) was added 3-methylthiopropionate (66 mg, 0,632 mmol),1-hydroxybenzotriazole (71 mg, 0,527 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (121 mg, 0,632 mmol) and 4-methylmorpholine (69 ml, 0,632 mmol). The reaction solution was stirred for 3 days at room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of ethyl acetate:methylene chloride=1:20, concentrated under reduced pressure to obtain specified in the title compound (253 mg, 0,497 mmol, 94%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 1,90-2,00 (2H, m)to 2.13 (3H, s), measuring 2.20 (3H, s), 2,60 (2H, t, J=7.2 Hz), 3,55-the 3.65 (2H, m), 5,95 (1H, s), 6.90 to-7,20 (4H, m), 7,66 to 7.75 (2H, m), 7,75-to 7.84 (1H, m), of 7.96 (1H, s), 8,13-to 8.20 (1H, m), 9,14 (1H with).

IR (ATR) cm-1: 3421, 1679, 1589, 1525, 1494, 1295, 1278, 1234, 1143, 850, 825.

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

Example 73: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methyl-N-[3-(methylsulfinyl)propyl]pyridine-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methyl-N-[3-(methylthio)propyl]pyridine-2-carboxamide (149 mg, 0,293 mmol) in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (51 mg, 0,293 mmol) under ice cooling and the mixture was stirred for 30 minutes. Under ice cooling to the reaction solution was added 3-chloroperbenzoic acid (20 mg, 0,116 mmol) and received the ing the mixture was stirred for 15 minutes. To the reaction solution was added 1N. an aqueous solution of sodium hydroxide and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of methanol:methylene chloride=1:30, was concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (122 mg, 0,232 mmol, 79%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,10-of 2.20 (2H, m), of 2.23 (3H, s), 2,58-2,61 (3H, m), was 2.76-and 2.83 (2H, m), 3,60-3,71 (2H, m), 5,96 (1H, s), 6.90 to-to 7.09 (2H, m), 7,11-7,19 (2H, m), 7.68 per-7,74 (2H, m), 7,75-of 7.82 (1H, m), of 7.96 (1H, s), 8,21-8,29 (1H, m)to 9.15 (1H, s).

IR (ATR) cm-1: 3394, 1670, 1590, 1525, 1492, 1319, 1288, 1236, 1149, 1049.

TPL: 170-173°C.

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

Analytically calculated for C24H23F3N2O4S2: C 54,95; H, 4,42; F, 10,87; N, OF 5.34; S, 12,23. Found: C, 54,96; H, 4,34; F, 11,14; N, 5,42; S, 12,20.

Example 74: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methyl-N-[3-(methylsulphonyl)propyl]pyridine-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]ethyl]-4-methyl-N-[3-(methylthio)propyl]pyridine-2-carboxamide (100 mg, 0,197 mmol)obtained in Example 72, in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (68 mg, 0,393 mmol). The reaction solution was stirred for 15 minutes at room temperature and then was added 3-chloroperbenzoic acid (30 mg, 0,174 mmol). The reaction solution was stirred for 15 minutes at room temperature. To the reaction solution was added 1N. an aqueous solution of sodium hydroxide and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of methylene chloride:ethyl acetate=3:2, was concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (79 mg, 0,146 mmol, 74%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,17-of 2.28 (2H, m), of 2.23 (3H, s), with 2.93 (3H, s), 3,09-3,17 (2H, m), 3,62-3,70 (2H, m), 5,96 (1H, s), 6.90 to-to 7.09 (2H, m), 7,10-7,20 (2H, m), to 7.67-of 7.82 (3H, m), 7,95 (1H, s), 8,18-of 8.28 (1H, m)to 9.15 (1H, s).

IR (ATR) cm-1: 3392, 1668, 1590, 1525, 1494, 1317, 1288, 1236, 1151, 1141, 1081.

TPL: 182-185°C.

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

Analytically vechicle what about C 24H23F3N2O5S2: C, 53,32; H, 4,29; F, 10,54; N, 5,18; S UP 11,86. Found: C, 53,38; H, 4,24; F, 10,54; N, 5,19; S, 12,01.

Example 75: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (93 mg, 0,221 mmol)obtained in Example 12 in methylene chloride (3 ml) was added 2-amino-1,3-propandiol (24 mg, 0,265 mmol), 1-hydroxybenzotriazole (30 mg, 0,221 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (51 mg, 0,265 mmol) and 4-methylmorpholine (29 μl, 0,265 mmol) and the resulting mixture was stirred for 17 hours at room temperature. To the reaction solution were added ethyl acetate and the mixture washed sequentially with saturated sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of methanol:methylene chloride=1:20, concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated so hard prophetic the STV was collected by filtration to obtain specified in the title compound (81 mg, 0,164 mmol, 74%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 2,46-to 2.57 (2H, m), a 3.87-a 4.03 (4H, m), 4,10-4,19 (1H, m), 5,96 (1H, s), 6.90 to-to 7.09 (2H, m), 7,11-7,19 (2H, m), to 7.67-7,74 (2H, m), 7,75-of 7.82 (1H, m), of 7.96 (1H, s), 8,63 (1H, userd, J=7,6 Hz), 9,17 (1H, s).

IR (ATR) cm-1: 3421, 3278, 1639, 1590, 1536, 1494, 1319, 1292, 1234, 1143, 1076, 1041.

TPL: 150-152°C.

MS m/z: 495 (M++H).

Analytically calculated for C23H21F3N2O5S: C, 55,87; H, 4,28; F, 11,53; N, 5,67; S, 6.48 IN. Found: C, Is 55.74; H, 4,13; F, 11,74; N, 5,68; S 6,63.

Example 76: 1-[[5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]piperidine-4-ol

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (94 mg, 0,223 mmol)obtained in Example 12 in methylene chloride (3 ml) was added 4-hydroxypiperidine (27 mg, 0,268 mmol), 1-hydroxybenzotriazole (30 mg, 0,223 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (51 mg, 0,268 mmol) and 4-methylmorpholine (29 μl, 0,268 mmol) and the resulting mixture was stirred for 18 hours at room temperature. To the reaction solution were added ethyl acetate and the mixture was washed successively with an aqueous solution of sodium bicarbonate and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. Received in financial p the resulting concentration residue was subjected to column chromatography on silica gel and the fraction, obtained by elution with a mixture of methanol:methylene chloride=1:30, was concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (76 mg, 0,151 mmol, 68%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: 1.60-to 1,72 (2H, m), 1,90-of 2.09 (2H, m), of 2.25 (3H, s), 3,30-3,50 (2H, m), 3,82-4,08 (2H, m), 4,12-to 4.28 (1H, m), 5,95 (1H, s), 6.89 in-6,98 (1H, m), 7,00-was 7.08 (1H, m), 7,10-7,20 (2H, m), 7,46 (1H, s), 7,70-7,80 (3H, m), 9,17 (1H, s).

IR (ATR) cm-1: 3463, 1606, 1589, 1492, 1444, 1326, 1282, 1238, 1147, 1081, 1027.

TPL: 171-173°C.

MS m/z: 505 (M++H).

Analytically calculated for C25H23F3N2O4S: C, 59,52; H, 4,59; F, 11,30; N, 5,55; S, 6,36. Found: C, 59,43; H, 4,68; F, 11,41; N, 5,55; S, 6,53.

Example 77: 4-[[5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]morpholine

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (119 mg, 0,282 mmol)obtained in Example 12 in methylene chloride (3 ml) was added morpholine (30 μl, 0,339 mmol), 1-hydroxybenzotriazole (38 mg, 0,282 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (65 mg, 0,339 mmol) and 4-methylmorpholine (37 μl, 0,339 mmol). The reaction solution was stirred for 5 days at room temperature and conc is listed under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of 65% ethyl acetate/hexane, concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (94 mg, 0,192 mmol, 68%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.26 (3H, s), 3,68-3,86 (8H, m), 5,95 (1H, s), 6.89 in-was 7.08 (2H, m), 7,10-7,20 (2H, m), 7,53 (1H, s), 7,70-7,80 (3H, m), 9,17 (1H, s).

IR (ATR) cm-1: 1629, 1590, 1492, 1461, 1324, 1280, 1226, 1147, 1114, 1083.

TPL: 165-167°C.

MS m/z: 491 (M++H).

Analytically calculated for C24H21F3N2O4S: C, 58,77; H, 4,32; F, ARE 11.62; N, 5,71; S, 6,54. Found: C, 58,81; H, 4,25; F, 11,94; N, 5,78; S Of 6.71.

Example 78: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-methoxy-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (96 mg, 0,228 mmol)obtained in Example 12 in methylene chloride (3 ml) were added hydrochloride O-methylhydroxylamine (23 mg, 0,273 mmol), 1-hydroxybenzotriazole (31 mg, 0,228 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (52 mg, 0,273 mmol) and 4-methylmorpholine (59 ml, 0,546 mmol). The reaction of the races is the thief was stirred for 5 days at room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of 65% ethyl acetate/hexane, concentrated under reduced pressure to obtain white solid. The obtained solid substance was washed with a mixture of ethyl acetate-hexane and then collected by filtration to obtain specified in the title compound (66 mg, 0.147 mmol, 64%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), 3,91 (3H, s)5,94 (1H, s), 6.90 to-7,10 (2H, m), 7,11-7,20 (2H, m), 7,65-7,80 (3H, m), 7,95 (1H, s), 9,11 (1H, s)of 10.21 (1H, users).

IR (ATR) cm-1: 3343, 1689, 1587, 1475, 1295, 1238, 1207, 1172, 1141, 1112, 1079.

TPL: 231-234°C.

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

Analytically calculated for C21H17F3N2O4S: C, 56,00; H, 3,80, F, 12,65; N, 6,22; S, 7,12. Found: C, 56,00; H, 3,80, F, Is 12.85; N, 6,32; S, 7.23 Percent.

Example 79: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-methoxy-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (99 mg, 0,235 mmol)obtained in Example 12 in methylene chloride (3 ml) was added the hydrochloride of N,O-dimethylhydroxylamine (28 mg, 0,282 mmol), 1-hydroxybenzotriazole (32 mg, 0,235 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (54 mg, 0,382 mmol) and 4-methylmorpholine (61 ml, 0,564 mmol). The reaction rastv the R was stirred for 5 days at room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (73 mg, of) 0.157 mmol, 67%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 3,42 (3H, users), 3,81 (3H, s), 5,95 (1H, s), 6.90 to-to 7.09 (2H, m), 7,10-7,19 (2H, m), of 7.48-to 7.59 (1H, m), 7.68 per-7,81 (3H, m), 9,20 (1H, s).

IR (ATR) cm-1: 1631, 1590, 1490, 1425, 1324, 1286, 1232, 1147, 1083, 987, 904.

TPL: 156-158°C.

MS m/z: 465 (M++H).

Analytically calculated for C22H19F3N2O4S: C, 56,89; H, 4,12, F, 12,27; N, 6,03; S 6,90. Found: C, 56,96; H, 4,11, F, 12,53; N, Between 6.08; S 7,02.

Example 80: ethyl ester of N-[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]-β-alanine

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (106 mg, 0,252 mmol)obtained in Example 12 in methylene chloride (3 ml) were added hydrochloride ethyl ester of β-alanine (46 mg, 0,302 mmol), 1-hydroxybenzotriazole (34 mg, 0,252 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (58 mg, 0,302 mmol) and 4-methylmorpholine (6 ml, 0,604 mmol). The reaction solution was stirred for 15 hours at room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and 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 (126 mg, 0,242 mmol, 96%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: of 1.29 (3H, t, J=7,1 Hz), measuring 2.20 (3H, s)of 2.64 (2H, t, J=6,1 Hz), 3,70-with 3.79 (2H, m), 4,20 (2H, q, J=7,1 Hz), 5,95 (1H, s), 6.90 to-to 7.09 (2H, m), 7,14 (2H, t, J=8.6 Hz), 7,65-7,73 (2H, m), 7,76-7,83 (1H, m), to 7.95 (1H, s), 8,40-and 8.50 (1H, m), 9,14 (1H, s).

IR (ATR) cm-1: 3396, 1727, 1671, 1589, 1521, 1492, 1326, 1292, 1236, 1186, 1147, 1081.

MS m/z: 520 (M+).

Example 81: N-[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]-β-alanine

To a solution of ethyl ester of N-[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]-β-alanine (120 mg, 0,231 mmol) in tetrahydrofuran (5 ml) and water (3 ml) was added monohydrate of lithium hydroxide (12 mg, 0,277 mmol) and the mixture was stirred for 2.5 hours at room temperature. To the reaction solution was added 1N. hydrochloric acid solution (0.3 ml) and water and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sulfate NAT the Oia and was filtered and then the filtrate was concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (102 mg, 0,207 mmol, 90%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,20 (3H, s), is 2.74 (2H, t, J=6.3 Hz), of 3.78 (2H, q, J=6.3 Hz), 5,95 (1H, s), 6.90 to-to 7.09 (2H, m), 7,14 (2H, t, J=8.5 Hz), the 7.65 to 7.75 (2H, m), 7,76-of 7.82 (1H, m), of 7.96 (1H, s), of 8.47 (1H, ushort, J=6.3 Hz), 9,17 (1H, s).

IR (ATR) cm-1: 3062, 2969, 1716, 1654, 1589, 1531, 1490, 1326, 1230, 1182, 1145, 1085.

TPL: 223-226°C.

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

Analytically calculated for C23H19F3N2O5S: C, 56,09; H, TO 3.89; F, 11,57; N, 5,69; S, 6,51. Found: C, 56,00; H, 3,91; F, 11,57; N, 5,67; S, 6,60.

Example 82: Tert-butyl [2-[[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (374 mg, 0,888 mmol)obtained in Example 12 in methylene chloride (10 ml) was added tert-butyl (2-amino-ethyl)carbamate (170 μl, 1.07 mmol), 1-hydroxybenzotriazole (120 mg, 0,888 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (206 mg, 1.07 mmol) and 4-methylmorpholin (116 μl, 1.07 mmol) and the mixture was stirred for 19 hours at room temperature. To the reaction solution were added ethyl acetate and the mixture washed posledovatelnostyu aqueous solution of sodium bicarbonate and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and 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 (491 mg, 0,871 mmol, 98%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: USD 1.43 (9H, s), measuring 2.20 (3H, s), 3,32 is-3.45 (2H, m), 3,53-the 3.65 (2H, m), 4,87 is equal to 4.97 (1H, m), 5,95 (1H, s), 6.90 to-to 7.09 (2H, m), 7,14 (2H, t, J=8,4 Hz), to 7.67-of 7.82 (3H, m), 7,95 (1H, s), 8,25-8,35 (1H, m)to 9.15 (1H with).

IR (ATR) cm-1: 3334, 1700, 1670, 1589, 1521, 1492, 1365, 1328, 1236, 1145, 1081.

MS m/z: 564 (M++H).

Example 83 N-[2-(acetylamino)ethyl]-5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide

To a solution of tert-butyl [2-[[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate (90 mg, 0,160 mmol) in methylene chloride (5 ml) was added triperoxonane acid (2 ml) and the resulting mixture was stirred for 2.5 hours at room temperature. The reaction solution was concentrated under reduced pressure and to the mixture were added methylene chloride and 0,5h. an aqueous solution of sodium hydroxide. The organic layer was separated, dried over anhydrous sodium sulfate and filtered is then the filtrate was concentrated under reduced pressure. The resulting concentration residue was dissolved in methylene chloride (5 ml) and to the mixture was added acetic anhydride (23 μl, 0,240 mmol), triethylamine (26 μl, 0,240 mmol) and a catalytic amount of 4-dimethylaminopyridine. The reaction solution was stirred for 20 hours at room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and 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 (79 mg, 0,156 mmol, 98%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: 1,99 (3H, s), of 2.23 (3H, s), 3.46 in-3,54 (2H, m), to 3.58-3,59 (2H, m), 5,96 (1H, s), 6,18-6,28 (1H, m), 6.90 to-to 7.09 (2H, m), to 7.15 (2H, t, J=8.5 Hz), to 7.77-a 7.92 (3H, m), of 7.96 (1H, s), 8,33-8,43 (1H, m), 9,16 (1H with).

IR (ATR) cm-1: 3392, 3361, 1587, 1536, 1490, 1454, 1317, 1276, 1232, 1147.

MS m/z: 505 (M+).

Analytically calculated for C24H22F3N3O4S: C, 57,02; H, 4,39; F, 11,27; N, 8,31; S 6,34. Found: C, A 56.88; H, 4,47, F, Of 11.45; N, 8,25; S, 6,44.

Example 84: Methyl [2-[[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate

To a solution of tert-butyl [2-[[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate (90 mg, 0,160 mm is l), obtained in Example 82, in methylene chloride (5 ml) was added triperoxonane acid (2 ml) and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure and to the mixture were added methylene chloride and 0,5h. an aqueous solution of sodium hydroxide. The organic layer was separated, then dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was dissolved in methylene chloride (5 ml) and to the mixture was added methylchloroform (19 ml, 0,240 mmol) and triethylamine (26 ml, 0,240 mmol). The reaction solution was stirred for 20 hours at room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of 60% ethyl acetate/hexane, concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate-hexane and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (71 mg, 0,136 mmol, 85%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 3,40-of 3.48 (2H, m), to 3.58-the 3.65 (2H, m), 3,68 (3H, s), 5,11-5,22 (1H, m), 5,96 (1H, s), 6.90 to-to 7.09 (2H, m), to 7.15 (2H, t, J=8.5 Hz), 7.68 per-7,73 (2H, m), 7,7-of 7.82 (1H, m), 7,95 (1H, s), 8,28-8,35 (1H, m)to 9.15 (1H, s).

IR (ATR) cm-1: 3396, 3340, 1718, 1670, 1589, 1533, 1490, 1452, 1315, 1270, 1234, 1145.

TPL: 167-169°C.

MS m/z: 521 (M+).

Analytically calculated for C24H22F3N3O5S: C, 55,27; H, 4.25 IN, F, OF 10.93; N, 8,06; S, 6,15. Found: C, 55,23; H, 4,21; F, 11,13; N, Of 7.96; S, 6,20.

Example 85: 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide (744 mg, of 1.84 mmol)obtained in Example 15, the dimethyl ether of ethylene glycol (8 ml)was added an aqueous solution of formaldehyde (37%, 0.4 ml) and 5% aqueous sodium hydroxide solution (1.6 ml) at 0°C and the resulting mixture was stirred for 3 hours at room temperature. To the reaction mixture was added sodium carbonate (80 mg) and the mixture was stirred for 10 minutes at room temperature. The mixture was concentrated under reduced pressure and then the residue was dissolved in chloroform, dried over magnesium sulfate and filtered. Then the filtrate was concentrated under reduced pressure and the obtained residue was washed with diethyl ether and then collected by filtration to obtain specified in the title compound (524 mg, of 1.16 mmol, 63%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), 3,06 (1H, usher.), free 5.01 (2H, t, J=6,8 Hz) 5,96 (1H, C), 6,92-6,98 (1H, m), 7,01-was 7.08 (1H, m), 7,14 (2H, t, J=8,8 Hz), to 7.67-7,73 (2H, m), 7,75-7,80 (1H, m), of 7.96 (1H, s), 8,78 cent to 8.85 (1H, usher.), 9,17 (1H, s).

IR (ATR) cm-1: 3405, 1683, 1589, 1511, 1492, 1236, 1147, 1035, 723, 593, 555, 522.

TPL: 164-166°C.

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

Analytically calculated for C21H17F3N2O4S: C, 56,00; H, 3,80, F, 12,65; N, 6,22; S, 7,12. Found: C, 55,97; H, 3,80, F, 12,83; N, 6,12; S, 7,18.

Example 86: [[[5-[(2,5-Differenl)(4-perpenicular)methyl]-4-methylpyridin-2-yl]carbonyl]amino]acetate

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide (200 mg, 0.44 mmol)obtained in Example 85, in pyridine (2 ml) was added acetic anhydride (2 ml) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and then the residue was dissolved in ethyl acetate and washed with water. The solution was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=10:3 was concentrated under reduced pressure, washed with diethyl ether and collected by filtration to obtain specified in the title compound (86 mg, 0,17 mmol, 39%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.08 (3H, s), of 2.23 (3H, s), vs. 5.47 (2H, d, J=7,3 Hz), 5,96 (1H, s), 6,91-6,97 (1H, m), 7,01-was 7.08 (1H, m), 7,14 (2H, t, J=8,8 Hz), of 7.70 (2H, DD, J=8,8, 5,1 Hz), 7,74-7,80 (1H, m), to 7.99 (1H, s), 8,96 (1H, t, J=7,3 Hz), 9,17 (1H, s).

IR (ATR) cm-1: 3280, 1735, 1677, 1519, 1492, 1234, 1147, 1018, 715, 568, 530.

TPL 111-113°C.

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

Analytically calculated for C23H19F3N2O5S: C, 56,09; H, TO 3.89; F, 11,57; N, 5,69; S, 6,51. Found: C, 55,91; H, Of 3.77; F, 11,68; N, 5,66; S 6,67.

Example 87: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-(TRANS-4-hydroxycyclohexyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (114 mg, 0,271 mmol)obtained in Example 12 in methylene chloride (3 ml)were added hydrochloride, TRANS-4-aminocyclohexanol (49 mg, 0,325 mmol), 1-hydroxybenzotriazole (37 mg, 0,271 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 mg, 0,325 mmol) and 4-methylmorpholine (71 ál, 0,650 mmol) and the mixture was stirred for 17 hours at room temperature. To the reaction solution were added ethyl acetate and the mixture washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. Received in resultsetconcurrency residue was subjected to column chromatography on silica gel and the fraction, obtained by elution with a mixture of methanol:methylene chloride=1:40, was concentrated under reduced pressure to obtain specified in the title compound (129 mg, 0,249 mmol, 92%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: 1.32 to to 1.60 (4H, m), 1,98-to 2.18 (4H, m), of 2.20 (3H, s), 3,64 of 3.75 (1H, m), 3,89-4,00 (1H, m), 5,95 (1H, s), 6.90 to-to 7.09 (2H, m), 7,11-7,19 (2H, m), 7.68 per-7,74 (2H, m), 7,75-of 7.82 (1H, m), 7,88 (1H, userd, J=8,8 Hz), of 7.96 (1H, s), 9,13 (1H, s).

IR (ATR) cm-1: 3380, 2933, 1664, 1589, 1521, 1492, 1326, 1292, 1236, 1145, 1081.

MS m/z: 518 (M+).

Analytically calculated for C26H25F3N2O4S: C, 60,22; H, 4,86; F, 10,99; N, OF 5.40; S, 6,18. Found: C, 60,15; H, 4,86; F, 10,82; N, 5,41; S, 6,21.

Example 88: 1-[[5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]azetidin-3-ol

To a solution of 1-(diphenylmethyl)azetidin-3-ol (230 mg, 0,961 mmol) in ethanol (10 ml) was added palladium on carbon (50 mg) and the mixture was stirred for 1.5 hours in an atmosphere of hydrogen. The reaction suspension was filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was dissolved in methylene chloride (10 ml) was added 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (113 mg, 0,268 mmol)obtained in Example 12, 1-hydroxybenzotriazole (36 mg, 0,268 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 m is, 0,322 mmol) and 4-methylmorpholine (35 ml, 0,322 mmol). The mixture was stirred for 4 days at room temperature. The reaction solution was concentrated under reduced pressure, was added ethyl acetate and the mixture washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of methanol:methylene chloride =1:40, was concentrated under reduced pressure to obtain a solid substance. The obtained solid was washed with ethanol and then collected by filtration to obtain specified in the title compound (72 mg, 0,151 mmol, 56%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,08-and 2.14 (1H, m), 2,17 (1,5H, s), 2,19 (1,5H,), was 4.02-of 4.12 (1H, m), 4,42-to 4.62 (2H, m), 4,70-4,80 (1H, m), 4,95 is 5.07 (1H, m)5,94 (1H, s), 6.90 to-to 7.09 (2H, m), 7,11-7,19 (2H, m), 7,65-7,72 (2H, m), 7,75-of 7.82 (1H, m), 7,89 (0,5H, s), to $ 7.91 (0,5H, s), 9,17 (1H, s).

IR (ATR) cm-1: 3409, 1612, 1587, 1546, 1494, 1461, 1419, 1359, 1324, 1294, 1234, 1216, 1143.

TPL: 219-221°C.

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

Analytically calculated for C23H19F3N2O4S: C, 57,98; H, WAS 4.02; F, 11,96; N, 5,88; S, 6.73 X. Found: C, 57,70; H, 4.04 The; F, 12,21; N, 5,90; S 6,79.

Example 89: 4-[[5-[2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]piperazine-2-he

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (114 mg, 0,271 mmol)obtained in Example 12 in methylene chloride (3 ml) was added piperazine-2-he (33 mg, 0,325 mmol), 1-hydroxybenzotriazole (37 mg, 0,271 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 mg, 0,325 mmol) and 4-methylmorpholine (35 ml, 0,325 mmol). The reaction mixture was stirred for 4 days at room temperature and then concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of methanol:methylene chloride=1:30, was concentrated under reduced pressure. The obtained solid substance was washed with a simple ether and then collected by filtration to obtain specified in the title compound (116 mg, 0,230 mmol, 85%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (1,5H, s), and 2.27 (1,5H, s), 3,49-the 3.65 (2H, m), 3,92-to 4.15 (2H, m), 4,40-a 4.53 (2H, m), 5,96 (1H, s),5,99-6,10 (1H, m), 6.89 in-7,10 (2H, m), 7,11-7,20 (2H, m), 7,58 (0,5H, s), 7,65 (0,5H, s), 7,70-7,83 (3H, m), 9,16 (0,5H, s), 9,18 (0,5H, s).

IR (ATR) cm-1: 1681, 1660, 1619, 1589, 1492, 1471, 1413, 1322, 1297, 1236, 1218.

MS m/z: 504 (M++H).

FAB-MS: 504,1189 (calculated for C24H21O4N3F3S: 504,1205).

Example 90 N-(2-chloroethyl)-5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide (120 mg, 0,258 mmol)obtained in Example 17, in methylene chloride (5 ml) was added thionyl chloride (100 ml) and the mixture was stirred for 4 hours at room temperature. To the reaction solution was added thionyl chloride (100 ml) and the mixture was stirred for 1.5 hours at room temperature. The reaction solution was concentrated under reduced pressure, and then to the mixture was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of 35% ethyl acetate/hexane, concentrated under reduced pressure to obtain specified in sagola the ke of the compound (102 mg, 0,211 mmol, 82%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), 3,69-are 3.90 (4H, m), 5,96 (1H, s), 6.90 to-to 7.09 (2H, m), 7,11-7,20 (2H, m), to 7.67-7,74 (2H, m), to 7.77-7,83 (1H, m), of 7.96 (1H, s)of 8.37-to 8.45 (1H, m), 9,17 (1H, s).

IR (ATR) cm-1: 3369, 1685, 1590, 1525, 1488, 1438, 1328, 1295, 1232, 1147, 1078.

MS m/z: 483 (M++H).

Example 91: Diethyl 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

Ethanolic solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (104 mg, 0,247 mmol)obtained in Example 12, and concentrated hydrochloric acid (50 ml) was heated to the boiling temperature under reflux for 21 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. To the resulting concentration residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of 30% ethyl acetate/hexane, concentrated under reduced giving the situation with obtaining a solid substance. The obtained solid was washed with ethanol and then collected by filtration to obtain specified in the title compound (90 mg, 0,200 mmol, 81%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: of 1.45 (3H, t, J=7,1 Hz), of 2.23 (3H, s), 4,47 (2H, q, J=7,1 Hz), 5,97 (1H, s), 6.90 to-to 7.09 (2H, m), 7,10-to 7.18 (2H, m), 7,69-7,80 (3H, m), of 7.90 (1H, s), 9,36 (1H, s).

IR (ATR) cm-1: 1739, 1589, 1556, 1332, 1317, 1278, 1232, 1216, 1145, 1101, 1081.

TPL: 151-153°C.

MS m/z: 450 (M++H).

FAB-MS: 450,1008 (calculated for C22H19O4NF3S: 450,0987).

Example 92: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N,N,4-trimethylpyridine-2-carbothioamide

A solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N,N,4-trimethylpyridine-2-carboxamide (168 mg, the 0.375 mmol)obtained in Example 14, and the reagent Losson (167 mg, 0,413 mmol) in toluene (10 ml) was heated to boiling point under reflux for 3 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained by elution with a mixture of 40% ethyl acetate/hexane, concentrated under reduced pressure. To the resulting concentration residue was added a simple ether and precipitated so solid FDS is rali by filtration to obtain specified in the title compound (119 mg, 0,256 mmol, 68%) as a powder pale yellow color.

1H-NMR (400 MHz, CDCl3) δ: of 2.26 (3H, s), 3,24 (3H, s), of 3.60 (3H, s)5,94 (1H, s), 6,88-was 7.08 (2H, m), 7,10-7,19 (2H, m), the 7.43 (1H, s), 7,70-7,80 (3H, m), which is 9.09 (1H, s).

IR (ATR) cm-1: 1585, 1527, 1492, 1407, 1315, 1292, 1230, 1139, 1081.

TPL: 161-164°C.

MS m/z: 465 (M++H).

Analytically calculated for C22H19F3N2O2S2: C, A 56.88; H, 4,12, F, 12,27; N, 6,03; S, 13,81. Found: C, 56,60; H, 4,10, F, 12,27; N, 6,06; S, 13,64.

Example 93: 5-[[(4-Forfinal)thio](2,3,6-tryptophanyl)methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxylic acid (163 mg, 0.40 mmol)obtained in Example 34, in methylene chloride (5 ml) was added 2-aminoethanol (0,027 ml, 0.44 mmol), 1-hydroxybenzotriazole (60 mg, 0.44 mmol), 4-methylmorpholine (0,048 ml, 0.44 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (84 mg, 0,44 mmol) at room temperature. After stirring for 3 hours at room temperature the reaction mixture was washed with water and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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, conc is listed under reduced pressure to obtain specified in the title compound (175 mg, 0,39 mmol, 97%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: of 2.25 (3H, s), 2,68 is 2.75 (1H, m), 3,62-3,68 (2H, m), 3,82-to 3.89 (2H, m), 5,78 (1H, s), 6.75 in-6,84 (1H, m), 6,92-7,00 (2H, m), 7,02 for 7.12 (1H, m), 7,32-7,39 (2H, m), 7,94 (1H, s)of 8.37-to 8.45 (1H, m), 9,07 (1H, C).

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

Example 94: 5-[[(4-Forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-forfinal)thio](2,3,6-tryptophanyl)methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide (173 mg, 0.38 mmol) in methylene chloride (5 ml) was added 3-chloroperbenzoic acid (204 mg, 0.77 mmol) at room temperature. After stirring for 3 hours at room temperature again was added 3-chloroperbenzoic acid (102 mg, 0.38 mmol) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was washed for 1H. aqueous solution of sodium hydroxide, the organic layer was dried over anhydrous sodium sulfate and filtered and then 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=1:2, 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 (126 mg, 0.26 mmol, 68%) as the solid substance of white color.

1H-NMR (400 MHz, CDCl3) δ: 2,14 (3H, s), 2,60 (1H, t, J=5.4 Hz), 3,63 at 3.69 (2H, m), 3,83-to 3.89 (2H, m), of 5.89 (1H, s), 6,82-of 6.90 (1H, m), 7,14-of 7.25 (3H, m), 7,73-7,79 (2H, m), of 7.97 (1H, s), to 8.41-8,48 (1H, m), 9,42 (1H, s).

IR (ATR) cm-1: 3379, 1662, 1533, 1493, 1329, 1230, 1146, 1082, 820.

TPL: 164-165°C.

Analytically calculated for C22H18F4N2O4S: C, 54,77; H, 3,76, F, OF 15.75; N, 5,81; S, 6,65. Found: C, 54,76; H, 3,69; F, 15,76; N, Of 5.84; S, 6.75 In.

MS m/z: 483 (M++H).

Example 95: 5-[(2,5-Differenl)[(4-forfinal)thio]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-4-methylpyridin-2-carboxylic acid (483 mg, 1,24 mmol)obtained in Example 20 in methylene chloride (10 ml) was added 2-aminoethanol (0,083 ml of 1.36 mmol), 1-hydroxybenzotriazole (184 mg, of 1.36 mmol), 4-methylmorpholine (0,150 ml of 1.36 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (262 mg, 1,36 mmol) at room temperature. After stirring for 4 hours at room temperature to the reaction mixture were added water and the mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:3, koncentrirane and under reduced pressure to obtain specified in the title compound (481 mg, 1.11 mmol, 90%) as a colorless foamy substance.

1H-NMR (400 MHz, CDCl3) δ: is 2.37 (3H, s), 2.57 m-to 2.65 (1H, m), 3,61-3,66 (2H, m), 3,80-a 3.87 (2H, m), of 5.82 (1H, s), 6,91-to 7.00 (4H, m), 7,28-7,38 (3H, m), of 8.00 (1H, s), 8,31-of 8.37 (1H, m), 8,61 (1H, s).

LC-MS m/z: 433 (M++H).

Example 96: 5-[(2,5-Differenl)[(4-forfinal)sulfinil]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)thio]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide (478 mg, 1.11 mmol) in methylene chloride (15 ml) was added 3-chloroperbenzoic acid (293 mg, 1.11 mmol) at 0°C. After stirring for 3 hours at the same temperature, the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide, the organic layer was dried over anhydrous sodium sulfate and filtered and then 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=1:2, was concentrated under reduced pressure. The obtained residue was washed with hexane and then the residue was dried under reduced pressure to obtain specified in the title compound (238 mg, of 0.53 mmol, 48%) as a colorless foamy substance.

1H-NMR (400 MHz, CDCl3) δ: 1,94 (1,5H, s), 2.13 and (1,5H, C)of 2.51-to 2.65 (1H, m), 3,63-3,70 (2H, m), 3,83-are 3.90 (2H, m), 5,33 (0,5H, s), 5,35 (0,5H, s), 6.87 in-7,14 (4H, m), 7,28-7,37 (2,5H, m), 7,4-7,54 (0,5H, m), 7,92 (0,5H, s), 7,97 (0,5H, C)at 8.36-8,46 (1H, m), cent to 8.85 (0,5H, s), 9,03 (0,5H, s).

IR (ATR) cm-1: 3383, 1660, 1589, 1527, 1489, 1225, 1082, 1049.

Analytically calculated for C22H19F3N2O3S: C, 58,92; H, 4,27; F, 12,71; N, 6,25; S, 7,15. Found: C, 58,53; H, 4,30; F, 12,91; N, 6,16; S 7,08.

MS m/z: 449 (M++H).

Reference example 10: O-ethyl S-(3,5-differenl) dithiocarbonate

3,5-Diptiranjan (7,11 g of 54.0 mmol) was dissolved in methanol (30 ml) was added 1N. hydrochloric acid solution (150 ml) at -10°C. Then at the same temperature to the mixture was added dropwise a solution of sodium nitrite (4,54 g, 64.8 mmol) in water (30 ml) and then the mixture was stirred for 30 minutes at the same temperature. The resulting reaction solution was added dropwise to a solution of O-utilityservice potassium (commercial product) (13,0 g, 81.0 mmol) in water (150 ml) at 65°C. the Reaction mixture was heated to 100°C, stirred for 30 minutes and then cooled to room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with hexane, concentrated at the pony who hinnon pressure obtaining specified in the title compound (1.86 g, 7,94 mmol, 15%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: of 1.36 (3H, t, J=7,1 Hz), 4,63 (2H, q, J=7,1 Hz), 6.87 in-6,94 (1H, m), 7.03 is-7,10 (2H, m).

Example 97: 2-Bromo-5-[(2,5-differenl)[(3,5-differenl)thio]methyl]-4-methylpyridin

To a solution of O-ethyl S-(3,5-differenl) dithiocarbonate (1.86 g, 7,94 mmol) in ethanol (20 ml) was added 1N. an aqueous solution of sodium hydroxide (20 ml) and the mixture was stirred for 2 hours at 65°C. the Reaction mixture was cooled to room temperature and washed with methylene chloride. Then the aqueous layer was acidified using 1N. a solution of hydrochloric acid and was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. To a solution of the obtained residue and 2-bromo-5-[chloro(2,5-differenl)methyl]-4-methylpyridine (2.64 g, 7,94 mmol)obtained in Reference example 2 in N,N-dimethylformamide (40 ml) was added potassium carbonate (1,21 g, 8,73 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 2 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate is filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed with hexane and then collected by filtration to obtain specified in the title compound (2.35 g, 5,31 mmol, 67%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: is 2.37 (3H, s), 5,86 (1H, s), 6,62-6,69 (1H, m), of 6.71-of 6.78 (2H, m), of 6.96-7,07 (2H, m), 7,27-to 7.32 (1H, m), 7,33 (1H, s), 8,32 (1H, m).

MS m/z: 442, 444 (M++H).

Example 98: 5-[(2,5-Differenl)[(3,5-differenl)thio]methyl]-4-methylpyridin-2-carbaldehyde

To a solution of 2-bromo-5-[(2,5-differenl)[(3,5-differenl)thio]methyl]-4-methylpyridine (2.35 g, 5,31 mmol) in toluene (60 ml) was added a solution of n-utility in hexane (1,54 M, 4,14 ml, 6.38 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C was added N,N-dimethylformamide (0,494 ml, 6.38 mmol). After completion of adding dropwise the reaction mixture was allowed to warm to 0°C and added to water at a specified temperature. To the reaction mixture was added ethyl acetate, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sulfa what Ohm sodium and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to 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 connection header (1,36 g, 3,47 mmol, 65%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2.49 USD (3H, s), 5,97 (1H, s), 6,63-6,70 (1H, m), 6.73 x-to 6.80 (2H, m), 6,98-to 7.09 (2H, m), 7,33-7,39 (1H, m), 7,79 (1H, s), a total of 8.74 (1H, m), there is a 10.03 (1H, s).

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

Example 99: 5-[(2,5-Differenl)[(3,5-differenl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid

To a solution of 5-[(2,5-differenl)[(3,5-differenl)thio]methyl]-4-methylpyridin-2-carbaldehyde (1,36 g, 3,47 mmol) in formic acid (40 ml) was added a 31% aqueous hydrogen peroxide (4 ml) and the mixture was stirred for 2 hours at 0°C. After stirring for 2 hours at room temperature to the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in methylene chloride and the solution washed with 0,1N. a solution of hydrochloric acid. Then the organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed etilovym ether and then collected by filtration to obtain specified in the title compound (1.39 g, and 3.16 mmol, 91%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.38 (3H, s), of 6.02 (1H, s), 6,95-7,02 (1H, m), 7,06-to 7.15 (2H, m), 7.23 percent-7,30 (2H, m), of 7.64-of 7.70 (1H, m), 8,07 (1H, s), 9,24 (1H, s).

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

Example 100: 5-[(2,5-Differenl)[(3,5-differenl)sulfonyl]methyl]-N-(2-hydroxyethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(3,5-differenl)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (105 mg, 0.24 mmol) in methylene chloride (5 ml) was added 2-aminoethanol (0,016 ml, 0.26 mmol), 1-hydroxybenzotriazole (36 mg, 0.26 mmol), 4-methylmorpholine (0,029 ml, 0.26 mmol) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (51 mg, 0.26 mmol) at room temperature. After stirring for 4 hours at room temperature the reaction mixture was washed for 1H. a solution of hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and collected by filtration to obtain specified in the title compound (36 mg, 0.07 mmol, 31%) in the de solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,30 (3H, s), 2,47 of $ 2.53 (1H, m), 3,63 at 3.69 (2H, m), 3,82-to 3.89 (2H, m)6,00 (1H, s), 6,93-7,13 (3H, m), 7,22-7,30 (2H, m), 7,65-7,72 (1H, m), 8,01 (1H, s), at 8.36-8,44 (1H, m), 9,17 (1H, s).

IR (ATR) cm-1: 3388, 1660, 1604, 1529, 1493, 1444, 1333, 1298, 1146, 1078, 989.

TPL: 82-84°C.

Analytically calculated for C22H18F4N2O4S: C, 54,77; H, 3,76, F, OF 15.75; N, 5,81; S, 6,65. Found: C, 54,89; H, 3,95, F, 15,46; N, 5,76; S, 6,78.

MS m/z: 483 (M++H).

Example 101: 5-[[(4-Forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (150 mg, 0.34 mmol)obtained in Example 39, dimethyl ether of ethylene glycol (3 ml) was added an aqueous solution of formaldehyde (37%, 0.1 ml) and 5% aqueous sodium hydroxide solution (0.4 ml) at 0°C and the mixture was stirred over night at room temperature. To the reaction mixture was added sodium carbonate (20 mg) and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and then the residue was dissolved in chloroform, dried over magnesium sulfate and filtered. Then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:1, centered at p is low pressure and the obtained residue was washed with diethyl ether and then collected by filtration to obtain specified in the title compound (93 mg, 0.20 mmol, 58%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,15 (3H, s), 3.04 from-to 3.09 (1H, m), free 5.01 (2H, t, J=7.2 Hz), of 5.89 (1H, s), 6,85-to 6.88 (1H, m), 7,15-of 7.23 (3H, m), 7,74 for 7.78 (2H, m), of 7.97 (1H, s), 8,84-8,88 (1H, br), 9,43 (1H, s).

IR (ATR) cm-1: 3332, 1650, 1592, 1521, 1496, 1145, 1054, 817, 582.

MS m/z: 469 (M++H).

Analytically calculated for C21H16F4N2O4SO·5H2O: C, 52,83; H, 3,59; F, 15,92; N, BY 5.87; S, 6,72. Found: C, 52,65; H, 3,56; F, $ 15.87 With; N, 5,81; S, 6,65.

Example 102: 2-Bromo-4-methyl-5-[(phenylthio)(2,3,6-tryptophanyl)methyl]pyridine

To a solution of 2-bromo-5-[chloro(2,3,6-tryptophanyl)methyl]-4-methylpyridine (1.80 g, 5,13 mmol)obtained in Reference example 4 in N,N-dimethylformamide (25 ml) was added potassium carbonate (1,21 g, 8,73 mmol) and sensation (of 0.58 ml, the 5.65 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 24 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and the organic layer was washed with water and then saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate, concentrated under reduced pressure to obtain the specified reception in the e connection (2,05 g, a 4.83 mmol, 94%) as a colorless oily substance.

1H-NMR (400 MHz, CDCl3) δ: 2,17 (3H, s), USD 5.76 (1H, s), 6,76-PC 6.82 (1H, m), 7,02-7,10 (1H, m), 7,24 and 7.36 (6H, m), of 8.90 (1H, s).

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

Example 103: 4-Methyl-5-[(phenylthio)(2,3,6-tryptophanyl)methyl]pyridine-2-carbaldehyde

To a solution of 2-bromo-4-methyl-5-[(phenylthio)(2,3,6-tryptophanyl)methyl]pyridine (2.00 g, 4.40 mmol) in toluene (40 ml) was added a solution of n-utility in hexane (1,58 M, 3.3 ml, 5,28 mmol) in an argon atmosphere at -75°C. the Reaction mixture was stirred for 1 hour at -40°C and then cooled to -75°C and was added N,N-dimethylformamide (0.68 ml, 8,80 mmol). After completion of adding dropwise the reaction mixture was allowed to warm to 0°C and added water at the same temperature. To the reaction mixture was added ethyl acetate, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered and then 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, concentrated under reduced pressure to obtain specified in the connection header (1,03 g, was 2.76 mmol, 63%) as an oily substance pale yellow color.

1H-NMR (400 MHz, CCl 3) δ: 2,28 (3H, s), 5,88 (1H, s), 6,78-6,84 (1H, m),? 7.04 baby mortality for 7.12 (1H, m), 7.24 to 7,38 (5H, m), of 7.70 (1H, s), 9,34 (1H, s)10,06 (1H, s).

MS m/z: 374 (M++H).

Example 104: 4-Methyl-5-[(phenylsulfonyl)(2,3,6-tryptophanyl)methyl]pyridine-2-carboxylic acid

To a solution of 4-methyl-5-[(phenylthio)(2,3,6-tryptophanyl)methyl]pyridine-2-carbaldehyde (1,00 g, 2.68 mmol) in formic acid (10 ml) was added a 31% aqueous hydrogen peroxide (3 ml) and the mixture was stirred for 4 hours at 0°C. To the reaction mixture were added water and the precipitated thus, the solid was collected by filtration and washed with water. The obtained solid substance was dissolved in ethyl acetate and washed with water and then saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethanol and then collected by filtration to obtain specified in the connection header (0,99 g, 2.36 mmol, 88%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,16 (3H, s), 5,91 (1H, s), 6,82-to 6.88 (1H, m), 7,17-of 7.25 (1H, m), 7,50-rate of 7.54 (2H, m), 7,68 (1H, t, J=7.5 Hz), 7,72 (2H, d, J=7,3 Hz), to 7.99 (1H, s), at 9.53 (1H, s).

MS m/z: 422 (M++H).

Example 105: 4-Methyl-5-[(phenylsulfonyl)(2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of 4-methyl-5-[(phenylsulfonyl)(2,3,6-triterpene is)methyl]pyridine-2-carboxylic acid (300 mg, 0.71 mmol) in N,N-dimethylformamide (6 ml) was added hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (556 mg, 1.07 mmol), benzotriazol-1-ol (144 mg, 1.07 mmol), ammonium chloride (76 mg, of 1.42 mmol) and N-ethyldiethanolamine (0.5 ml, to 2.85 mmol) in an argon atmosphere at room temperature. After stirring for 3 hours at room temperature to the reaction mixture were added ethyl acetate and water and the mixture was extracted with ethyl acetate and then washed with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was washed with diethyl ether and then collected by filtration to obtain specified in the title compound (227 mg, 0.54 mmol, 76%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,09 (3H, s), 5,67 (1H, users), of 5.92 (1H, s), 6,82-to 6.88 (1H, m), 7,14-7,24 (1H, m), 7,50 (2H, t, J=7.5 Hz), to 7.67 (1H, t, J=7.5 Hz), 7,74 (2H, d, J=7.5 Hz), 7,88 (1H, Sirs), of 7.96 (1H, s), to 9.45 (1H, s).

MS m/z: 421 (M++H).

Example 106 N-(1-hydroxymethyl)-4-methyl-5-[(phenylsulfonyl)(2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of 4-methyl-5-[(phenylsulfonyl)(2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide (215 mg, 0.51 mmol) in dimethyl ether of ethylene glycol (6 ml) was added an aqueous solution of formaldehyde (37%, 0.2 ml) and 5% water is actor sodium hydroxide (0.8 ml) at 0°C and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added sodium carbonate (40 mg) and the mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and then the residue was dissolved in chloroform, dried over magnesium sulfate and filtered. Then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=1:2, was concentrated under reduced pressure and the obtained residue was washed with diethyl ether and then collected by filtration to obtain specified in the title compound (90 mg, 0.20 mmol, 39%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,11 (3H, s), 3,14-3,18 (1H, m), free 5.01 (2H, t, J=7,1 Hz), 5,91 (1H, s), 6,80-of 6.90 (1H, m), 7,12-7,24 (1H, m), 7,45-7,53 (2H, m), to 7.61 for 7.78 (3H, m), 7,94 (1H, s), 8,88 (1H, usher.), to 9.45 (1H, s).

IR (ATR) cm-1: 3382, 3334, 1654, 1494, 1149, 1054, 987, 723, 595, 555.

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

Example 107: N-acetyl-5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide (150 mg, 0.36 mmol)obtained in Example 15, N,N-dimethylformamide (7 ml) was added sodium hydride (60%, 34 mg of 0.79 mmol) at 0°C and the mixture was stirred for 1 hour at room temperature. Then to the reaction the solution was added acetic anhydride (40 ml) at 0°C and the mixture was stirred for 1 hour at room temperature. To the reaction mixture were added water and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of hexane:ethyl acetate=10:3 was concentrated under reduced pressure and the obtained residue was washed with diethyl ether and n-hexane and then collected by filtration to obtain specified in the title compound (80 mg, 0,17 mmol, 48%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: to 2.29 (3H, s), 2,60 (2H, s), 5,96 (1H, s), 5,97 (1H, s), 6,92-6,98 (1H, m), 7,02-was 7.08 (1H, m), to 7.15 (2H, t, J=8,8 Hz), 7,72 (2H, d, J=8,8 Hz), 7,74-7,79 (1H, m), 8,03 (1H, s), 9,20 (1H, s), 10,38 (1H, Sirs).

IR (ATR) cm-1: 1725, 1706, 1589, 1463, 1259, 1234, 1187, 1143, 1079, 970, 844, 717, 671, 593, 520, 487.

TPL: 182-183°C.

MS m/z: 463 (M++H).

Analytically calculated for C22H17F3N2O4S: C, 57,14; H, 3,71, F, 12,32; N, 6,06; S 6,93. Found: C, 57,33; H, 3,62; F, 12,64; N, 6,09; S 7,00.

Referential example 11: (4 Methoxybenzyloxy)acetate

To a solution of 4-methoxybenzylamine alcohol (1,00 g of 7.24 mmol) in tetrahydrofuran (20 ml) was added sodium hydride (695 mg, of 17.4 mmol) and bromoxynil acid (1,00 g of 7.24 mmol) at 0°C and the mixture was stirred over night at room temperature. To the reaction solution were added water and the mixture ek who was tragically with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution dichloromethane:methanol=10:1 was concentrated under reduced pressure and the obtained residue was washed with diethyl ether and n-hexane and then collected by filtration to obtain specified in the title compound (448 mg, 2.28 mmol, 32%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 3,82 (3H, s), 4,11 (2H, s), 4,58 (2H, m), 6.89 in (2H, d, J=8.5 Hz), 7,29 (2H, d, J=8.5 Hz), 9,50 (1H, Sirs).

Example 108: [[[5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methyl (4-methoxybenzyloxy)acetate

To a solution of (78 mg, 0.40 mmol) 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide (150 mg, 0.33 mmol)obtained in Example 85, N,N-dimethylformamide (3 ml) was added the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (96 mg, 0.50 mmol) and a catalytic amount of dimethylaminopyridine and the mixture was stirred over night at room temperature. To the reaction mixture were added water and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to chromatography on silica gel. The faction is received when the elution by the mixture hexane:ethyl acetate=2:1, concentrated under reduced pressure to obtain specified in the title compound (205 mg, 0.33 mmol, 99%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.23 (3H, s), with 3.79 (3H, s), 4,56 (2H, s)to 5.56 (2H, d, J=7.5 Hz), 5,96 (1H, s)6,86 (2H, d, J=8,8 Hz), 6,91-6,98 (1H, m), 7,01-7,07 (1H, m), 7,14 (2H, t, J=8,8 Hz), 7,28 (2H, d, J=8,8 Hz), of 7.70 (2H,, d, J=8,8 Hz), 7,74-7,79 (1H, m), 7,98 (1H, s), of 9.00 (1H, t, J=7.5 Hz), 9,17 (1H, s).

IR (ATR) cm-1: 3386, 1751, 1691, 1589, 1511, 1492, 1236, 1145, 1105, 1081, 817, 723, 590, 524.

Example 109: [[[5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methyl hydroxyacetate

To a mixed solution of [[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methyl (4-methoxybenzyloxy)acetate (150 mg, 0.24 mmol) in dichloromethane-water (1:1, 10 ml) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (65 mg, 0.29 mmol) and the mixture was stirred over night at room temperature. To the reaction solution were added water and the mixture was extracted with dichloromethane. The extract was washed with saturated saline, dried over anhydrous sodium sulfate, then the solvent was concentrated under reduced pressure and the obtained residue was subjected to column chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=50:3 was concentrated under reduced pressure, washed Dyatlov the m ether and collected by filtration to obtain specified in the title compound (26 mg, 0.05 mmol, 21%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,24 (3H, s), 4,19 (2H, s), ceiling of 5.60 (2H, d, J=7.5 Hz), 5,96 (1H, s), 6,91-6,98 (1H, m), 7,01-was 7.08 (1H, m), to 7.15 (2H, t, J=8,8 Hz), of 7.70 (2H, d, J=8,8 Hz), 7,74 for 7.78 (1H, m), to 7.99 (1H, s), of 9.02 (1H, t, J=7.5 Hz), 9,18 (1H, s).

IR (ATR) cm-1: 3386, 1747, 1687, 1589, 1515, 1492, 1236, 1145, 1081, 590, 526.

TPL: 84°C.

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

Analytically calculated for C23H19F3N2O6S: C, 54,33; H, OF 3.77; F, 11,21; N, 5,51; S OF 6.31. Found: C, 54,61; H, 3,93; F, 11,32; N, 5,59; S, 6,33.

Example 110: 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(dimethylaminomethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide (150 mg, 0.33 mmol)obtained in Example 15, N,N-dimethylformamide (3 ml) was added formaldehyde solution (37%, 54 ml) and dimethylaminohydrolase (136 mg, 1,67 mmol) at 0°C and the mixture was stirred for 2 hours at room temperature. To the reaction mixture were added water and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was subjected to chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=10:1 was concentrated under reduced pressure and the obtained residue was washed with diethyl ether and dihormati the om and dried to obtain specified in the title compound (99 mg, 0.21 mmol, 63%) as a white solid.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), of 2.38 (6H, s)to 4.33 (2H, d, J=5.6 Hz), 5,97 (1H, s), 6,91-6,98 (1H, m), 7,01-was 7.08 (1H, m), to 7.15 (2H, t, J=8,8 Hz), of 7.70 (2H, d, J=8,8 Hz), 7,75-7,81 (1H, m), 7,98 (1H, s), 8,43 (1H, t, J=5.6 Hz), 9,16 (1H, s).

IR (ATR) cm-1: 3340, 1670, 1592, 1521, 1494, 1238, 1145, 1039, 838, 817, 711, 657, 590, 530.

Analytically calculated for C23H22F3N3O3S·0,75H2O: C, 56.26 VERTICAL; H, 4,82, F, OF 11.61; N, 8,56; S, 6,53. Found: C, 55,97; H, 4,56; F, To 12.44; N, 8,46; S, 6,51.

Example 111 N-[[2-(tert-butyldiphenylsilyl)ethoxy]methyl]-5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide

5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide (113 mg, 0,251 mmol)obtained in Example 85, and a solution of 2-(tert-butyldiphenylsilyl)ethanol (136 mg, 0,453 mmol) and p-toluensulfonate acid (10 mg) in benzene (5 ml) was stirred for 3 hours while heating to 60°C. the Reaction solution was cooled to room temperature and then concentrated under reduced pressure. To the resulting concentration residue was added ethyl acetate, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated at igenom pressure. The resulting concentration residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with a mixture of 25% ethyl acetate/hexane, concentrated under reduced pressure to obtain specified in the title compound (93 mg, to 0.127 mmol, 51%) as an amorphous substance.

1H-NMR (400 MHz, CDCl3) δ: 1,04 (9H, s), of 2.21 (3H, s), 3,65-of 3.85 (4H, m), 4.95 points-of 5.05 (2H, m), 5,96 (1H, s), 6.90 to-was 7.08 (4H, m), 7,30-the 7.43 (6H, m), 7,60-7,80 (7H, m), 7,98 (1H, s), 8,65-7,02 (1H, m), 9,14 (1H, s).

MS m/z: 733 (M++H).

Example 112: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-[(2-hydroxyethoxy)methyl]-4-methylpyridin-2-carboxamide

To a solution of N-[[2-(tert-butyldiphenylsilyl)-ethoxy]methyl]-5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxamide (56 mg, 0,076 mmol) and acetic acid (5 ml, 0,091 mmol) in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) (91 μl, 0,091 mmol) and the mixture was stirred for 6 hours at room temperature. To the reaction solution was again added acetic acid (5 μl, 0,091 mmol) and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran) (91 μl, 0,091 mmol) and the mixture was stirred for 16 hours at room temperature. Again added to the reaction solution of acetic acid (5 μl, 0,091 mmol) and tetrabutylammonium fluoride (1 M Rast is the PR in tetrahydrofuran) (91 μl, 0,091 mmol) and the mixture was stirred for 5 hours at room temperature. To the reaction solution was added saturated aqueous solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with a mixture of 70% ethyl acetate/hexane, concentrated under reduced pressure. To the resulting concentration residue was added a simple ether to precipitate a solid substance and ether drove with obtaining specified in the title compound (35 mg, 0,071 mmol, 93%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), 3,68-of 3.80 (4H, m), 4.95 points-of 5.05 (2H, m), 5,96 (1H, s), 6.90 to-was 7.08 (2H, m), 7,10-to 7.18 (2H, m), 7,60-7,80 (3H, m), to 7.99 (1H, s), is 8.75 (1H, ushort, J=7,0 Hz), 9,18 (1H, s).

IR (ATR) cm-1: 3347, 1668, 1589, 1513, 1494, 1309, 1282, 1230, 1147.

TPL: 175-177°C.

MS m/z: 495 (M++H).

Analytically calculated for C23H21F3N2O5S: C, 55,87; H, 4,28; F, 11,53; N, 5,67; S, 6.48 IN. Found: C, 55,63; H, 4,27; F, 11,40; N, 5,54; S, To 6.43.

Example 113: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methyl-N-[(pyridine-3-ylethoxy)methyl]pyridine-2-carboxamide

The benzene solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide (155 mg, 0,344 mmol)obtained in Example 85, 3-pyridinemethanol (40 μl, 0,413 mmol) and dehydrate p-toluensulfonate acid (98 mg, 0,516 mmol) was heated to boiling point under reflux for 2 hours, driving away in this water. The reaction solution was cooled to room temperature, then was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to column flash chromatography on silica gel, and the fraction obtained by elution with a mixture of 70% ethyl acetate/hexane, concentrated under reduced pressure. To the resulting concentration residue was added a simple ether and precipitated thus, the solid was collected by filtration to obtain specified in the title compound (46 mg, of 0.085 mmol, 25%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.25 (3H, s), of 4.66 (2H, s), 5,00-5,10 (2H, m), 5,97 (1H, s), 6.90 to-was 7.08 (2H, m), 7,10-to 7.18 (2H, m), 7,25-7,33 (1H, m), to 7.67-7,80 (4H, m), 8,01 (1H, s), 8,50-8,55 (1H, m), at 8.60 (1H, users), a total of 8.74 (1H, ushort, J=7,1 Hz) 9,18 (1H, C).

IR (ATR) cm-1: 1675, 1590, 1523, 1492, 1309, 1295, 1236, 1147.

TPL: 121-123°C.

MS m/z: 541 (M+).

Analytically calculated for C27H22F3N2O4S: C, 59,88; H, 4.09 TO; F, 10,52; N, 7,79; S OF 5.92. Found: C, 59,80; H, 4,07; F, Of 10.73; N, 7,70; S, 6,13.

Example 114: 2-Bromo-4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]thio](2,3,6-tryptophanyl)methyl]pyridine

To a solution of O-ethyl S-[6-(trifluoromethyl)pyridin-3-yl] dithiocarbonate (3,09 g, 11.6 mmol) in ethanol (30 ml) was added 1N. an aqueous solution of sodium hydroxide (30 ml) and the mixture was stirred in nitrogen atmosphere for 1 hour at 60°C. the Reaction mixture was cooled to room temperature, added water and the mixture was washed with dichloromethane. Then the aqueous layer was acidified using 1N. a solution of hydrochloric acid and was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (50 ml) and under nitrogen atmosphere was added 2-bromo-5-[chloro(2,3,6-tryptophanyl)methyl]-4-methylpyridin (3.94 g, and 11.2 mmol)obtained in Reference example 4, and then potassium carbonate (1,71 g, 12.4 mmol) at 0°C. the Mixture was stirred for 16 hours at room temperature. To the reaction mixture were added ethyl acetate and water at 0°C, the organic layer was separated and then the organic layer PR is mawali saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 connection header (4,76 g, 9,65 mmol, 86%) as an oily substance pale yellow color.

1H-NMR (400 MHz, CDCl3) δ: 2,24 (3H, s), by 5.87 (1H, s), for 6.81-6.90 to (1H, m), 7,08-to 7.18 (1H, m), 7,30 (1H, s), EUR 7.57 (1H, d, J=8,3 Hz), 7,76 (1H, DD, J=8,3, 2.0 Hz), at 8.60 (1H, d, J=2.0 Hz), cent to 8.85 (1H, s).

MS m/z: 493, 495 (M++H).

Example 115: 4-Methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]thio](2,3,6-tryptophanyl)methyl]pyridine-2-carbaldehyde

To a solution of 2-bromo-4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]thio](2,3,6-tryptophanyl)methyl]pyridine (4,76 g, 9,65 mmol) in toluene (100 ml) was added a solution of n-utility in hexane (1,58 M, 6,72 ml, 10.6 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -40°C and then cooled to -78°C was added N,N-dimethylformamide (0,897 ml, 11.6 mmol). After completion of adding dropwise the reaction mixture was allowed to warm to 0°C and to the mixture was added saturated aqueous solution of ammonium chloride at the same temperature. To the reaction mixture were added dichloromethane and water and the organic layer is tdelay. Then the organic layer was dried over anhydrous sodium sulfate and filtered and then 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=5:1 was concentrated under reduced pressure to obtain specified in the connection header (2,52 g, 5,70 mmol, 59%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: 2,35 (3H, s), of 5.99 (1H, s), 6,83-6,91 (1H, m), 7,10-7,20 (1H, m), 7,58 (1H, d, J=8,3 Hz), 7,76 (1H, s), 7,79 (1H, DD, J=8,3, 2.0 Hz), at 8.60 (1H, d, J=2.0 Hz), 9,29 (1H, s)10,06 (1H, s).

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

Example 116: 4-Methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxylic acid

To a solution of 4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]thio](2,3,6-tryptophanyl)methyl]pyridine-2-carbaldehyde (2,52 g, 5,70 mmol) in formic acid (60 ml) was added a 31% aqueous hydrogen peroxide (6 ml) at 0°C. After stirring the reaction mixture for 5 hours at room temperature, to the mixture was added water and then dichloromethane. After separation of organic layer, the organic layer was washed with a saturated aqueous solution of ammonium chloride and then with 10% aqueous sodium thiosulfate solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate con who was interaval under reduced pressure. The obtained residue was washed with ethanol and then collected by filtration to obtain specified in the connection header (2,19 g, 4,47 mmol, 78%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.26 (3H, s), to 5.93 (1H, s), 6,85-6,93 (1H, m), 7.23 percent-7,33 (1H, m), 7,86 (1H, d, J=8,3 Hz), 8,07 (1H, s), compared to 8.26 (1H, DD, J=8,3, 2.2 Hz), 8,99 (1H, d, J=2.2 Hz), 9,50 (1H, s).

MS m/z: 491 (M++H).

Example 117: 4-Methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of 4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxylic acid (392 mg, 0.800 to mmol) in N,N-dimethylformamide (10 ml) was added hexaflurophosphate (benzotriazol-1 yloxy)triprolidine (624 mg, 1.20 mmol), benzotriazol-1-ol (162 mg, 1.20 mmol), ammonium chloride (85,6 mg, to 1.60 mmol) and N-ethyldiethanolamine (0,557 ml, 3,20 mmol) under nitrogen atmosphere at room temperature. After stirring for 2 hours at the same temperature, the reaction mixture was dissolved in ethyl acetate and the solution washed with 1N. the hydrochloric acid solution, 1N. aqueous solution of sodium hydroxide, saturated aqueous ammonium chloride and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and obtained the 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 and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and then collected by filtration to obtain specified in the title compound (229 mg, 0,468 mmol, 58%) as a solid white color. The filtrate was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethanol and diethyl ether, and then collected by filtration to obtain specified in the title compound (66 mg, is 0.135 mmol, 17%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 5,61 (1H, users), 5,96 (1H, s), 6,85-6,93 (1H, m), 7,21-7,31 (1H, m), to 7.84 (1H, d, J=8,3 Hz), the 7.85 (1H, users), of 8.04 (1H, s), 8,24 (1H, DD, J=8,3, 2.2 Hz), 8,99 (1H, d, J=2.2 Hz), 9,39 (1H, s).

IR (ATR) cm-1: 3462, 3159, 1701, 1595, 1495, 1329, 1192, 1163, 1140, 1107, 1078, 1018, 989.

TPL: 237-238°C.

MS m/z: 490 (M++H).

Analytically calculated for C20H13F6N3O3S: C, 49,08; H, 2,68; F, 23,29; N, 8,59; S, 6,55. Found: C, 48,99; H, 2,70; F, 23,14; N, 8,60; S 6,70.

Example 118 N-(1-hydroxymethyl)-4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of 4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide (147 mg, 0.30 mmol) in dimethyl ether of ethylene glycol (0.8 ml) was added an aqueous solution of formaldehyde (37%, 0,200 ml) and 1N. an aqueous solution of sodium hydroxide (0,200 ml) at room temperature and the mixture was stirred for 16 hours. To the reaction mixture were added ethyl acetate and the mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and 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 and the obtained residue was washed mixed solvent consisting of ethyl acetate and diethyl ether, and then collected by filtration to obtain specified in the title compound (113 mg, 0,218 mmol, 73%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,22 (3H, s), 3,10 (1H, t, J=7.8 Hz), 5,02 (2H, DD, J=7,8, 6.4 Hz), 5,95 (1H, s), 6,84-6,93 (1H, m), 7,21-7,31 (1H, m), to 7.84 (1H, d, J=8,3 Hz), 8,02 (1H, s), 8,24 (1H, DD, J=8,3, 2.2 Hz), 8,86 (1H, t, J=6.4 Hz), 8,99 (1H, d, J=2.2 Hz), 9,39 (1H, s).

IR (ATR) cm-1: 3249, 1655, 1541, 1496, 1333, 1186, 1161, 1105, 1078, 1043.

TPL: 181-182°C.

MS m/z: 520 (M++H).

Analytically calculated for C21H15F6N3O4S: C, 48,56; H, 2.91 IN; F, 21,95; N, 8,09; S, 6,17. Found: C, 48,48; H, 2,84; F, 21,67; N, 8,18; S, 6,39.

Reference example 12: 2-Bromo-5-[[[tert-butyl(diphenyl)silyl]oxy](2,3,6-tryptophanyl)methyl]-4-methylpyridin

To a solution of (6-bromo-4-methylpyridin-3-yl)(2,3,6-tryptophanyl)methanol (51,3 g, 154 mmol)obtained in Reference example 3, and tert-butyl chloro(diphenyl)silane (43,0 ml, 162 mmol) in N,N-dimethylformamide (350 ml) was added imidazole (22.1 g, 324 mmol) at room temperature and the mixture was stirred for 8 days at room temperature. To the reaction mixture were added water and ethyl acetate, the organic layer was separated and the organic layer was washed with a saturated aqueous solution of ammonium chloride and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered and then 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=20:1 was concentrated under reduced pressure to obtain specified in the connection header (75,6 g, 133 mmol, 86%) as a colorless foamy substance.

1H-NMR (400 MHz, CDCl3) δ with 1.07 (9H, s), of 1.85 (3H, s), 6,11 (1H, s), 6,58-of 6.65 (1H, m), 6,91-7,01 (1H, m), 7,12 (1H, s), 7,20-rate of 7.54 (10H, m), 9,12 (1H, s).

MS m/z: 570, 572 (M++H).

Reference example 13: 5-[[[Tert-butyl(diphenyl)silyl]oxy](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 2-bromo-5-[[[tert-butyl(diphenyl)silyl]oxy](2,3,6-tryptophanyl)methyl]-4-methylpyridine (75,6 g, 133 mmol) in tol is OLE (1200 ml) was added a solution of n-utility in hexane (1,60 M, 99,4 ml, 159 mmol) in an argon atmosphere at -78°C. the Reaction mixture was stirred for 30 minutes at -50°C and then cooled to -78°C and the mixture barbotirovany carbon dioxide. After stirring for 30 minutes at the same temperature the reaction mixture was allowed to warm to 0°C, to the mixture was added water and then 1N. hydrochloric acid solution and the mixture was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (1000 ml) and to the mixture was added isobutylparaben (25,3 ml, 195 mmol) and then triethylamine (36.2 ml, 260 mmol) at -5°C. After stirring the mixture for 30 minutes at the same temperature was added 7n. a solution of ammonia in methanol (100 ml, 700 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and the obtained residue was added ethyl acetate and water. After separation of organic layer, the organic layer was washed for 1H. a solution of hydrochloric acid, saturated aqueous sodium hydrogen carbonate and then with saturated saline and organic SL the St was dried over anhydrous sodium sulfate and filtered. Then 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=1:1 was concentrated under reduced pressure to obtain specified in the connection header (50.0 g, 93,5 mmol, 70%) as an oily material light brown color.

1H-NMR (400 MHz, CDCl3) δ: 1,09 (9H, s)a 1.96 (3H, s)to 5.56 (1H, users), 6,23 (1H, s), 6,58-of 6.65 (1H, m), 6,92-7,01 (1H, m), 7,20-rate of 7.54 (10H, m), a 7.85 (1H, s), 7,88 (1H, users), was 9.33 (1H, s).

MS m/z: 535 (M++H).

Reference example 14: 5-[Hydroxy(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[[[tert-butyl(diphenyl)silyl]oxy](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (50.0 g, 93,5 mmol) in tetrahydrofuran (500 ml) was added 1 n solution of tetrabutylammonium fluoride in tetrahydrofuran (100 ml, 100 mmol) at 0°C. After stirring the mixture for 2 hours at room temperature was added a saturated aqueous solution of ammonium chloride and the mixture was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and water. After separation of organic layer, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The remainder of the prom is Wali mixed solvent, consisting of ethyl acetate and diethyl ether, and then diethyl ether, and then the residue was dried under reduced pressure to obtain specified in the connection header (20,8 g of 70.2 mmol, 75%) as a solid white color.

1H-NMR (400 MHz, CD3OD) δ: 2,22 (3H, s), 6.35mm (1H, s), 6,93-7,02 (1H, m), 7.24 to 7,34 (1H, m), a 7.85 (1H, s), 8,99 (1H, s).

MS m/z: 297 (M++H).

Reference example 15: [6-Carbarnoyl-4-methylpyridin-3-yl](2,3,6-tryptophanyl)methyl methanesulfonate

To a solution of 5-[hydroxy(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (7,11 g of 24.0 mmol) in N,N-dimethylformamide (150 ml) was added methanesulfonamide (and 3.72 ml, 48,0 mmol) and then triethylamine (13.4 ml, 96,0 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 2 hours at room temperature. To the reaction mixture were added water and ethyl acetate at 0°C, the organic layer was separated and the organic layer was washed sequentially 1H. a solution of hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered and then 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 dichloromethane:methanol=49:1, centered at the pony who hinnon pressure obtaining specified in the title compound (4.71 g, 12.6 mmol, 52%) as a foamy substance light brown color.

1H-NMR (400 MHz, CDCl3) δ: of 2.38 (3H, s), 3.04 from (3H, s), the 5.65 (1H, users), 6,91-6,98 (1H, m), 7,16 (1H, s), 7,21-7,30 (1H, m), to 7.84 (1H, users), 8,02 (1H, s), 8,88 (1H, s).

Example 119: 5-[[(4-Chlorophenyl)sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of [6-carbarnoyl-4-methylpyridin-3-yl](2,3,6-tryptophanyl)methylmethanesulfonate (187 mg, 0,500 mmol)obtained in Reference example 15, N,N-dimethylformamide (5 ml) was added 4-chlorbenzoyl (72,2 mg, 0,500 mmol) and then potassium carbonate (82,9 mg, 0,600 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 3 days at room temperature. To the reaction mixture were added ethyl acetate and water, the organic layer was separated and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (5 ml) and to the mixture was added 3-chloroperbenzoic acid (318 mg, 1.20 mmol) at 0°C. After stirring for 4 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then f is ltrate concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=99:1 was concentrated under reduced pressure to obtain specified in the title compound (190 mg, 0,418 mmol, 84%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,15 (3H, s), 5,62 (1H, users), 5,90 (1H, s), 6,83-6,91 (1H, m), 7,16-7,26 (1H, m), 7,45 is 7.50 (2H, m), 7,65-of 7.70 (2H, m), 7,87 (1H, users), to 7.99 (1H, s), 9,42 (1H, s).

IR (ATR) cm-1: 3396, 3168, 1687, 1496, 1419, 1311, 1238, 1146, 1082.

MS m/z: 455 (M++H).

Example 120: 5-[[(4-Chlorophenyl)sulfonyl](2,3,6-tryptophanyl)methyl]-N-(hydroxymethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[[(4-chlorophenyl)sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (190 mg, 0,418 mmol) in dimethyl ether of ethylene glycol (4 ml) was added an aqueous solution of formaldehyde (37 percent, 94.2 ml) and 1N. an aqueous solution of sodium hydroxide (21,0 μl) at room temperature and the mixture was stirred for 17 hours. To the reaction mixture were added ethyl acetate and the mixture was washed with a saturated aqueous solution of ammonium chloride. Then the organic layer was added 1N. hydrochloric acid solution and the mixture was stirred for 1 hour. After separation of organic layer, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. the received residue was subjected to flash chromatography on silica gel and the fraction, obtained by elution with a mixture of hexane:ethyl acetate=1:1 was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethyl acetate and diethyl ether, and then collected by filtration to obtain specified in the title compound (113 mg, 0,233 mmol, 56%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,16 (3H, s), 3,06 (1H, t, J=7.8 Hz), free 5.01 (2H, DD, J=7,8, and 6.6 Hz), 5,90 (1H, s), 6,83-6,91 (1H, m), 7,16-7,26 (1H, m), 7,45 is 7.50 (2H, m), 7,65-of 7.70 (2H, m), of 7.97 (1H, s), 8,88 (1H, t, J=6.6 Hz), 9,42 (1H, s).

IR (ATR) cm-1: 3251, 1657, 1537, 1493, 1335, 1232, 1149, 1088, 1047.

TPL: 177-178°C.

MS m/z: 485 (M++H).

Analytically calculated for C21H16ClF3N2O4S: C, 52,02; H, 3,33; Cl, 7,31; F, 11,75; N, 5,78; S, 6,61. Found: C, 52,06; H, 3,31; Cl, 7.23 Percent; F, 11,46; N, 5,78; S, 6,69.

Example 121: 5-[[(3,4-Differenl)sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of [6-carbarnoyl-4-methylpyridin-3-yl](2,3,6-tryptophanyl)methylmethanesulfonate (262 mg, 0,700 mmol)obtained in Reference example 15, N,N-dimethylformamide (7 ml) was added 3,4-differentation (80,6 μl, 0,700 mmol) and then potassium carbonate (116 mg, 0,840 mmol) under nitrogen atmosphere at 0°C and the resulting mixture was stirred for 3 days at room temperature. To the reaction mixture were added ethyl acetate and water, the organic layer was separated and the organic with the Oh was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (7 ml) and to the mixture was added 3-chloroperbenzoic acid (446 mg, 1,68 mmol) at 0°C. After stirring for 5 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained from the dichloromethane:methanol=99:1 was concentrated under reduced pressure and the obtained residue was washed with 2-propanol and collected by filtration to obtain, thus, specified the title compound (213 mg, 0,467 mmol, 67%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,18 (3H, s)5,59 (1H, users), 5,90 (1H, s), 6,84-6,92 (1H, m), 7.18 in-to 7.35 (2H, m), 7,49-7,56 (1H, m), 7,58-the 7.65 (1H, m), 7,87 (1H, users), 8,01 (1H, s), 9,42 (1H, s).

IR (ATR) cm-1: 3396, 3165, 1691, 1597, 1498, 1417, 1333, 1279, 1238, 1142.

TPL: 200-201°C.

MS m/z: 457 (M++H).

Analytically calculated for C20H13F5N2O3S: C, 52,63; H, 2,87; F, 20,81; N, 6,14; S, 7,03. Found: C, 52,58; H, 2,77; F, 20,94; N, 6,18; S, 7,14.

Example 122: 5-[[(3,4-Differenl)sulfonyl](2,3,6-tryptophanyl)methyl]-N-(hydroxide who yl)-4-methylpyridin-2-carboxamide

To a solution of 5-[[(3,4-differenl)sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (160 mg, 0,350 mmol) in dimethyl ether of ethylene glycol (3 ml) was added an aqueous solution of formaldehyde (37%, 78,9 ml) and 1N. an aqueous solution of sodium hydroxide (17,5 ml) at room temperature and the mixture was stirred for 18 hours. To the reaction mixture were added ethyl acetate and the resulting mixture was washed with a saturated aqueous solution of ammonium chloride. Then the organic layer was added 1N. hydrochloric acid solution and the mixture was stirred for 1 hour. After separation of organic layer, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and then 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=1:1 was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethyl acetate and diethyl ether, and then collected by filtration to obtain specified in the title compound (100 mg, 0,206 mmol, 59%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,19 (3H, s)and 3.15 (1H, t, J=7,6 Hz), free 5.01 (2H, DD, J=7,6, 6,8 Hz), 5,90 (1H, s), 6,84-6,92 (1H, m), 7,19-to 7.35 (2H, m), 7,50 and 7.6 (1H, m), 7,58-to 7.64 (1H, m), to 7.99 (1H, s), 8,87 (1H, t, J=6.8 Hz), 9,42 (1H, s).

IR (ATR) cm-1: 3394, 3332, 1647, 1522, 1496, 1417, 1335, 1284, 1213, 1141, 1055.

TPL: 119-120°C.

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

Analytically calculated for C21H15F5N2O4S: C, 51,85; H, 3,11; F, 19,53; N, 5,76; S, 6,59. Found: C, To 51.64; H, 3,01; F, 19,45; N, 5,81; S 6,74.

Example 123: 4-Methyl-5-[[[4-(triptoreline)phenyl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of [6-carbarnoyl-4-methylpyridin-3-yl](2,3,6-tryptophanyl)methylmethanesulfonate (262 mg, 0,700 mmol)obtained in Reference example 15, N,N-dimethylformamide (7 ml) was added 4-(triptoreline)sensation (136 mg, 0,700 mmol) and then potassium carbonate (116 mg, 0,840 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 3 days at room temperature. To the reaction mixture were added ethyl acetate and water, the organic layer was separated and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and then saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (7 ml) and to the mixture was added 3-chloroperbenzoic acid (446 mg, 1,68 mmol) at 0°C. After stirring for 3 hours at room temperature the reaction mixture was washed for 1H. aq is m sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution dichloromethane:methanol=99:1 was concentrated under reduced pressure and the obtained residue was washed mixed solvent consisting of ethyl acetate and diethyl ether, and then collected by filtration to obtain specified in the title compound (244 mg, 0,484 mmol, 69%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,15 (3H, s), 5,62 (1H, users), 5,90 (1H, s), 6,83-6,91 (1H, m), 7,16-7,26 (1H, m), 7,45 is 7.50 (2H, m), 7,66-7,71 (2H, m), 7,88 (1H, users), to 7.99 (1H, s), 9,42 (1H, s).

IR (ATR) cm-1: 3438, 3161, 1703, 1597, 1493, 1419, 1323, 1255, 1217, 1151.

TPL: 219-220°C.

MS m/z: 505 (M++H).

Analytically calculated for C21H14F6N2O4S: C, 50,00; H 2,80; F, 22,60; N, 5,55; S, 6,36. Found: C, 49,65; H, 2,74; F, 22,49; N, 5,52; S, To 6.43.

Example 124 N-(hydroxymethyl)-4-methyl-5-[[[4-(triptoreline)phenyl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of 4-methyl-5-[[[4-(triptoreline)phenyl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide (177 mg, 0,350 mmol) in dimethyl ether of ethylene glycol (3 ml) was added an aqueous solution of formaldehyde (37%, 78,9 ml) and 1N. the aqueous hydroxide solution three is (17,5 ml) at room temperature and the mixture was stirred for 2 days. To the reaction mixture were added ethyl acetate and the mixture was washed with a saturated aqueous solution of ammonium chloride. Then the organic layer was added 1N. hydrochloric acid solution and the mixture was stirred for 1 hour. After separation of organic layer, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and then 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=1:1 was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of ethyl acetate and diethyl ether, and then collected by filtration to obtain specified in the connection header (59,4 mg, 0,111 mmol, 32%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,15 (3H, s)to 3.09 (1H, t, J=7,6 Hz), free 5.01 (2H, DD, J=7,6, and 6.6 Hz), of 5.89 (1H, s), 6,82-of 6.90 (1H, m), 7,16 and 7.36 (3H, m), to 7.77-7,83 (2H, m), 7,98 (1H, s), 8,88 (1H, t, J=6.6 Hz), 9,43 (1H, s).

IR (ATR) cm-1: 3236, 1657, 1541, 1495, 1252, 1227, 1151, 1043.

TPL: 140-141°C.

MS m/z: 535 (M++H).

Analytically calculated for C22H16F6N2O5S: C, 49,44; H, 3,02; F, 21,33; N, 5,24; S 6,00. Found: C, 49,44; H, 2,94; F, 21,42; N, From 5.29; S, 6,15.

Reference example 16: S-(benzofuran-6-yl) O-ethyl dithiocarbonate

/p>

To a solution of benzofuran-6-ylamine (574 mg, or 4.31 mmol) in methanol (2 ml) was added dropwise 1N. hydrochloric acid solution (10 ml) and then a solution of sodium nitrite (362 mg, 5.17 mmol) in water (2 ml) at 0°C and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was added to a solution of O-utilityservice potassium (1,38 g, to 8.62 mmol) in water (2 ml)which was heated to 65°C. After stirring for 2 hours at the same temperature, the reaction mixture was cooled to room temperature, added water and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, then 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:ethyl acetate=50:1 was concentrated under reduced pressure to obtain specified in the title compound (351 mg, about 1.47 mmol, 34%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: of 1.33 (3H, t, J=7,1 Hz), to 4.62 (2H, q, J=7,1 Hz), 6,80-6,84 (1H, m), 7,35-7,40 (1H, m), of 7.64 (1H, d, J=8.1 Hz), 7.68 per-of 7.69 (1H, m), 7,71 (1H, d, J=2.2 Hz).

MS m/z: 239 (M++H).

Example 125: 5-[(1-Benzofuran-6-ylthio)(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

S-(benzofuran-6-yl) O-utilitiesand (145 mg, 0,604 mmol)obtained in Reference example 16, was dissolved in ethanol (3 ml), was added 1N. an aqueous solution of sodium hydroxide (3 ml) and the mixture was stirred for 2 hours at 60°C. the Reaction mixture was cooled to room temperature, added water and 1N. an aqueous solution of sodium hydroxide (4 ml) and the mixture is then washed with dichloromethane. The aqueous layer was acidified using 1N. a solution of hydrochloric acid and then was extracted with ethyl acetate. The extract was washed with water and saturated saline, then was dried over magnesium sulfate and concentrated. To the residue in an atmosphere of argon was added N,N-dimethylformamide (4 ml). Was added [6-carbarnoyl-4-methylpyridin-3-yl](2,3,6-tryptophanyl)methylmethanesulfonate (271 mg, 0,725 mmol)obtained in Reference example 15, and then potassium carbonate (100 mg, 0,725 mmol) at 0°C and then the mixture was stirred for 4 hours at room temperature. The reaction mixture was cooled to 0°C and then added ethyl acetate and water. The organic layer was separated and then washed with water and saturated salt solution. After drying over magnesium sulfate the organic layer was concentrated and 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 (226 mg, 0,528 mmol, 87%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.26 (3H, s), 5,48 is 5.54 (1H, m), 5,88 (1H, s), 6,74 (1H, m), 6,76-6,83 (1H, m), 7,06 (1H, DDD, J=18,1, 9,0, a 4.9 Hz), 7,26-7,28 (1H, m), 7,49 (1H, d, J=8.0 Hz), 7,54 (1H, s), 7,63 (1H, d, J=2.2 Hz), 7,84 (1H, s), 7,94 (1H, s), 9,14 (1H, s).

MS m/z: 429 (M++H).

Example 126: 5-[(1-Benzofuran-6-ylsulphonyl)(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of 5-[(1-benzofuran-6-ylthio)(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (93,0 mg, 0,217 mmol) in ethyl acetate (5 ml) and methanol (5 ml) was added 30% aqueous hydrogen peroxide (2.5 ml) and heptamolybdate of hexammine tetrahydrate (10 mg, 0,00809 mmol) and the mixture was stirred for 9 hours at room temperature. To the reaction mixture was added heptamolybdate of hexammine tetrahydrate (10 mg, 0,00809 mmol) and the mixture was stirred for 16 hours at room temperature. In addition, to the reaction mixture were added 30% aqueous hydrogen peroxide (1.0 ml) and the resulting mixture was stirred for 3 hours. To the reaction mixture were added water and an organic solvent drove away under reduced pressure. The obtained residue was extracted with ethyl acetate and washed successively with water, sodium thiosulfate, water and saturated salt solution. The residue was dried over magnesium sulfate and then concentrated. The obtained residue was subjected to column flash chromatography on silica gel and the fraction, p is obtained upon elution with a mixture of hexane:ethyl acetate=2:3, was concentrated. The obtained solid was recrystallized from ethyl acetate to obtain specified in the connection header (35,8 mg, 0,0778 mmol, 36%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.08 (3H, s), of 5.55 (1H, s), 5,98 (1H, s), 6,80-6,87 (1H, m), 6.89 in (1H, DD, J=2,2, 1.0 Hz), 7,19 (1H, DDD, J=18,0, 9,3, a 4.9 Hz), 7,60 (1H, DD, J=8,1) and 1.7 Hz), 7,69 (1H, d, J=8.1 Hz), the 7.85 (1H, d, J=2.2 Hz), 7,86-of 7.90 (1H, users), 7,94 (2H, m), 9,48 (1H, s).

IR (ATR) cm-1: 3456, 3153, 1699, 1597, 1493, 1427, 1313, 1242, 1182, 1149, 1124, 1051, 989, 887, 829, 771, 727, 708, 633, 586, 563, 501, 420.

TPL: 237-240°C.

MS m/z: 461 (M++H).

Analytically calculated for C22H15F3N2O4S: C, 57,39; H, 3,28, F, 12,38; N, BETWEEN 6.08; S OF 6.96. Found: C, 57,25; H, 3,25; F, 12,37; N, 5,91; S 6,97.

Example 127: 5-[(1-Benzofuran-6-ylsulphonyl)(2,3,6-tryptophanyl)methyl]-N-(hydroxymethyl)-4-methylpyridin-2-carboxamide

To 1,2-dimethoxyethane solution (5 ml) of 5-[(1-benzofuran-6-ylsulphonyl)(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (210 mg, 0,457 mmol) was added an aqueous solution of formaldehyde (37%, 0,111 ml) and 1N. an aqueous solution of sodium hydroxide (0,023 ml) and the mixture was stirred for 4 hours at room temperature. To the reaction mixture were added an aqueous solution of formaldehyde (37%, 0,111 ml) and 1N. an aqueous solution of sodium hydroxide (0,023 ml) and the mixture was stirred for 5 hours at room temperature. Again added water dissolve the formaldehyde (37%, 0,111 ml) and then the mixture was stirred for 18 hours at room temperature. To the reaction solution were added water and the mixture was extracted with ethyl acetate and then washed with water and saturated salt solution. The mixture was dried over magnesium sulfate and concentrated and 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. The obtained solid was recrystallized from 2-propanol to obtain specified in the title compound (138 mg, 0,273 mmol, 60%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,09 (3H, s), 3.04 from (1H, t, J=7,3 Hz), free 5.01 (2H, t, J=7,3 Hz), 5,98 (1H, s), 6,80-6,87 (1H, m), 6.89 in (1H, DD, J=2,2, 0.7 Hz), 7,19 (1H, DDD, J=17,8, 9,0, a 4.9 Hz), 7,60 (1H, DD, J=8,0, 1.7 Hz), 7,69 (1H, d, J=8.0 Hz), the 7.85 (1H, d, J=2.2 Hz), to 7.93 (2H, m), cent to 8.85-8,91 (1H, m), 9,48 (1H, s).

IR (ATR) cm-1: 3394, 1670, 1601, 1516, 1496, 1423, 1321, 1302, 1230, 1186, 1144, 1126, 1054, 1036, 822, 729, 714, 633, 586, 552, 532, 496.

TPL: 185-186°C (Dec.).

MS m/z: 491 (M++H).

Analytically calculated for C23H17F3N2O5S·0,25C3H8O: C, 56, 43; H, 3,79; F, 11,28; N, 5,54; S 6,34. Found: C, 56,38; H, 3,76; F, 11,51; N, 5,49; S, To 6.43.

Example 128: 4-Methyl-5-[[[4-(trifluoromethyl)phenyl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide

To a solution of [6-(aminocarbonyl)-4-methylpyridin-3-yl](2,3,6-tryptophanyl)matile unsulfonated (262 mg, 0,700 mmol)obtained in Reference example 15, and 4-(trifluoromethyl)bentolila (129 mg, 0,700 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (116 mg, 0,840 mmol) under nitrogen atmosphere at 0°C and the mixture was stirred for 2 hours at room temperature. To the reaction mixture were added ethyl acetate and water, the organic layer was separated and then the organic layer was washed with saturated saline solution. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (465 mg, about 1.75 mmol) at 0°C. After stirring for 14 hours at room temperature the reaction mixture was washed for 1H. aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure and the obtained residue was subjected to flash chromatography on silica gel. The fraction obtained by elution with a mixture of dichloromethane:methanol=99:1 was concentrated under reduced pressure to obtain specified in the title compound (260 mg, 0,532 mmol, 76%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,14 (3H, s), to 5.58 (1H, users), to 5.93 (1H, s), 6,83-6,91 (1H, m), 7,17-7,26 (1H, m), 7,75-7,81 (2H, m), 7,84-7,94 (3H, m), of 8.00 (1H, s), 9,43 (1H, s).

p> MS m/z: 489 (M++H).

Example 129 N-(hydroxymethyl)-4-methyl-5-[[[4-(trifluoromethyl)phenyl]sulfonyl](2,3,6-tryptophanyl)methyl]-pyridine-2-carboxamide

To a solution of 4-methyl-5-[[[4-(trifluoromethyl)phenyl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide (171 mg, 0,350 mmol) in dimethyl ether of ethylene glycol (5 ml) was added an aqueous solution of formaldehyde (37%, 78,9 μl) and an aqueous solution of sodium hydroxide (17,5 ml) at room temperature and the mixture was stirred for 15 hours. To the reaction mixture were added ethyl acetate and the mixture was washed with a saturated aqueous solution of ammonium chloride. Then the organic layer was added 1N. hydrochloric acid solution and the mixture was stirred for 1 hour. After separation of organic layer, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and then 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=1:1 was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of 2-propanol and hexane and then collected by filtration to obtain specified in the title compound (139 mg, 0,268 mmol, 77%) as a solid substance below the color.

1H-NMR (400 MHz, CDCl3) δ: 2,15 (3H, s), 3,03-is 3.08 (1H, m), 4,98-of 5.05 (2H, m), to 5.93 (1H, s), 6,83-6,91 (1H, m), 7.18 in-7,26 (1H, m), to 7.77 (2H, d, J=8.5 Hz), 7,89 (2H, d, J=8.5 Hz), 7,98 (1H, s), 8,83-8,91 (1H, m), 9,43 (1H, s).

IR (ATR) cm-1: 3479, 3381, 1682, 1520, 1491, 1402, 1321, 1255, 1186, 1171, 1147, 1128, 1055, 1016.

TPL: 190-192°C.

Analytically calculated for C22H16F6N2O4S: C, 50,97; H, 3,11; F, 21,99; N, OF 5.40; S, TO 6.19. Found: C, 50,95; H, 3,06; F, 22,24; N, 5,47; S Of 6.31.

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

Example 130 ethyl[[[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methoxy]acetate

A solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(hydroxymethyl)-4-methylpyridin-2-carboxamide (421 mg, 0,935 mmol)obtained in Example 85, ethylhydroxylamine (106 ml, 1.12 mmol), monohydrate p-toluensulfonate acid (18 mg, 0,094 mmol) in benzene (10 ml) was heated to boiling point under reflux for 30 minutes. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. To the resulting concentration residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with of ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. According to the scientists in the concentration residue was subjected to column flash chromatography on silica gel and the fraction, obtained by elution with a mixture of 35% ethyl acetate/hexane, concentrated under reduced pressure to obtain specified in the title compound (175 mg, 0,326 mmol, 35%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 1.27 (3H, t, J=7.2 Hz), 2,22 (3H, s), 4,15-of 4.25 (4H, m)5,08 (2H, d, J=7,2 Hz), 5,96 (1H, s), 6.90 to-7,20 (4H, m), to 7.67-of 7.82 (3H, m), 7,98 (1H, s), 8,76 (1H, ushort, J=7,2 Hz), 9,18 (1H, s).

IR (ATR) cm-1: 1752, 1683, 1590, 1513, 1494, 1286, 1236, 1203, 1149, 1093.

MS (m/z): 537 (M++H).

Analytically calculated for C25H23F3N2O6S: C, 55,97; H, 4,32; F, TO 10.62; N, 5,22; S, 5,98. Found: C, 55,93; H, 4,24; F, 10,33; N, 5,28; S 6,06.

Example 131: [[[[5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methoxy]acetic acid

To a mixed solution of ethyl[[[[5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methoxy]acetate (167 mg, 0,311 mmol) in tetrahydrofuran (6 ml) and water (3 ml) was added monohydrate of lithium hydroxide (16 mg, 0,373 mmol) and the mixture was stirred for 20 hours at room temperature. To the reaction solution was added 1N. hydrochloric acid solution (0.5 ml) and water and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. Obtained as a result of the concentration residue was subjected to column flash chromatography on silica gel and the fraction, obtained by elution with a mixture of methanol:methylene chloride =1:1,0, concentrated under reduced pressure. To the resulting concentration residue was added a mixed solution of ethyl acetate-hexane and then the residue was collected by filtration to obtain specified in the title compound (38 mg, of 0.075 mmol, 24%) as white powder.

1H-NMR (400 MHz, CDCl3) δ: 2,24 (3H, s), 4,24 (2H, s), 4,98-of 5.05 (2H, m), 5,96 (1H, s), 6.90 to-7,20 (4H, m), to 7.67-7,80 (3H, m), of 8.00 (1H, s), cent to 8.85-8,95 (1H, m), 9,19 (1H, s).

IR (ATR) cm-1: 1762, 1682, 1589, 1521, 1492, 1321, 1292, 1236, 1147.

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

Analytically calculated for C23H19F3N2O6S·0,75H2O: C, 52,92; H, 3.96 POINTS; F, 10,92; N, LOWER THAN THE 5.37; S, 6,14. Found: C, 53,20; H, 3,90, F, 10,69; N, 5,19; S, 6,03.

Example 132: 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-(mercaptomethyl)-4-methylpyridin-2-carboxamide

A solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-N-(hydroxymethyl)-4-methylpyridin-2-carboxamide (170 mg, 0,377 mmol)obtained in Example 85, and reagent Losson (76 mg, 0,377 mmol) in toluene (5 ml) was heated to boiling point under reflux for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting concentration residue was subjected to column flash chromatography on silica gel and is raccio, obtained by elution with a mixture of 30% ethyl acetate/hexane, concentrated under reduced pressure to obtain a solid substance. The obtained solid was washed with ethanol and then collected by filtration to obtain specified in the title compound (71 mg, 0,152 mmol, 40%) as a white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 2.49 USD (1H, t, J=8,8 Hz), 4,55 with 4.65 (2H, m), 5,95 (1H, s), 6.90 to-7,20 (4H, m), to 7.67-7,80 (3H, m), of 7.96 (1H, s), 8,45-8,55 (1H, m), 9,16 (1H, s).

IR (ATR) cm-1: 1673, 1589, 1508, 1492, 1315, 1286, 1238, 1211, 1147.

TPL: 190-193°C.

EI-MS (m/z): 466 (M+).

Analytically calculated for C21H17F3N2O3S2: C 54,07; H, 3,67; F, 12,22; N, 6,01; S OF 13.75. Found: C, 54,05; H, 3,64; F, 12,13; N, 6,07; S, 13,78.

Example 133: 5-[(2,5-Differenl)((4-forfinal)sulfonyl)methyl]-N-(hydroxymethyl)-N,4-dimethylpyridin-2-carboxamide

To a solution of 5-[(2,5-differenl)[(4-forfinal)sulfonyl]methyl]-4-methylpyridin-2-carboxylic acid (405 mg, 0,961 mmol)obtained in Example 12, 1-hydroxybenzotriazole (130 mg, 0,961 mmol), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (277 mg, 1.44 mmol), triethylamine (158 μl, 1.44 mmol) and anhydrous sodium sulfate in tetrahydrofuran (5 ml) was added a solution obtained by mixing of methylamine (2 M solution in tetrahydrofuran:1,4 ml) and 37% aqueous formalin solution (467 mg, USD 5.76 mmol) for 90 minutes at the room for the Noah temperature. The reaction solution was stirred for 90 minutes at room temperature and then subjected to filtration using silica gel. Was suirable with ethyl acetate and the eluate was concentrated under reduced pressure. The resulting concentration residue was subjected to column chromatography on silica gel, and the fraction obtained from the eluate of hexane:ethyl acetate =1:2, was concentrated under reduced pressure to obtain a solid (73 mg). The obtained solid was washed with hexane:ethyl acetate =1:2 and then collected by filtration to obtain specified in the title compound (39 mg, 0,084 mmol, 8.7 per cent) in the form of white powder.

1H-NMR (400 MHz, CDCl3) δ: of 2.27 (3H, s)of 3.25 (3H, s), 4,70-4,84 (2H, m), 5,67 (1H, t, J=8.0 Hz), 5,95 (1H, s), 6.90 to-7,19 (4H, m), 7,69 for 7.78 (4H, m), 9,12 (1H, s).

IR (ATR) cm-1: 1635, 1589, 1490, 1326, 1295, 1230, 1149, 1039.

TPL: 184-186°C.

MS m/z: 465 (M++H).

Analytically calculated for C22H19F3N2O4S: C, 56,89; H, 4,12, F, 12,27; N, 6,03; S 6,90. Found: C, 56,83; H, 4,03; F, 12,18; N, 5,90; S 6,90.

Reference example 17:

5-Bromo-2-(deformity)pyridine

To a solution of 5-bromopyridin-2-carbaldehyde (372 mg, 2.00 mmol) in dichloromethane (5 ml) was added bis(2-methoxyethyl)aminosteroid (0,553 ml, 3.00 mmol) under nitrogen atmosphere at 0°C. the Reaction mixture was stirred for 3 hours at room is temperature and to the mixture was added saturated aqueous solution of sodium bicarbonate. Then added water and dichloromethane to separate the organic layer and the organic layer was dried over anhydrous sodium sulfate and filtered. Then 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=49:1 was concentrated under reduced pressure to obtain specified in the title compound (301 mg, 1,45 mmol, 72%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: is 6.61 (1H, t, J=55,2 Hz), 7,55 (1H, d, J=8,3 Hz), 7,98 (1H, DD, J=8,3, 2.2 Hz), 8,72 (1H, d, J=2.2 Hz).

MS m/z: 208, 210 (M++H).

Reference example 18: Tert-butyl [6-(deformity)pyridine-3-yl]carbamate

To a solution of 5-bromo-2-(deformity)pyridine (250 mg, 1.20 mmol) in diethyl ether (10 ml) was added a solution of n-utility in hexane (1,60 M, 0,825 ml of 1.32 mmol) in an argon atmosphere at -78°C. After stirring the mixture for 30 minutes at the same temperature was added carbon dioxide. The reaction temperature was allowed to rise to 0°C, then the reaction mixture was added water, and then 1H. an aqueous solution of sodium hydroxide (5 ml) and the organic layer was separated. The organic layer was extracted twice 1H. aqueous solution of sodium hydroxide (15 ml) and then the resulting aqueous layer were combined and acidified using 1N. the solution is aristolochioides acid and was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure to obtain solid brown color (148 mg). The obtained solid (145 mg) was dissolved in a mixed solvent consisting of 2-methyl-2-propanol (4 ml) and toluene (4 ml) and under nitrogen atmosphere was added triethylamine (0,233 ml, 1,68 mmol) and azide then diphenylphosphinic acid (0,269 ml of 1.26 mmol) at room temperature. The reaction mixture was heated to boiling point under reflux for 18 hours, then cooled to room temperature and 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= 9:1 was concentrated under reduced pressure to obtain specified in the connection header (82,4 mg of 0.337 mmol, 29%) as a solid pale yellow color.

1H-NMR (400 MHz, CDCl3) δ: 1,53 (9H, s), of 6.66 (1H, t, J=55,6 Hz), 6,62 (1H, users), 7,58 (1H, d, J=8.6 Hz), 8,09-8,16 (1H, m), 8,46 (1H, d, J=2.5 Hz).

MS m/z: 245 (M++H).

Reference example 19: 6-(Deformity)pyridine-3-amine

To a solution of tert-butyl [6-(deformity)pyridine-3-yl]carbamate (1,11 g of 4.54 mmol) in dichloromethane (8 ml) was added triperoxonane acid (8 ml) at room t is mperature. The reaction mixture was stirred for 5 hours at the same temperature and then concentrated under reduced pressure. To the obtained residue were added dichloromethane and a saturated aqueous solution of sodium bicarbonate. The organic layer was isolated and the organic layer was dried over anhydrous sodium sulfate and filtered. Then 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=2:1 was concentrated under reduced pressure to obtain specified in the title compound (540 mg, 3.75 mmol, 82%) as an oily material light green color.

1H-NMR (400 MHz, CDCl3) δ: 3,91 (2H, users), 6,56 (1H, t, J=55,9 Hz),? 7.04 baby mortality (1H, DD, J=8,5, 2.7 Hz), 7,41 (1H, d, J=8.5 Hz), 8,07 (1H, d, J=2.7 Hz).

MS m/z: 145 (M++H).

Reference example 20: S-[6-(deformity)pyridine-3-yl] O-ethyl dithiocarbonate

6-(Deformity)pyridine-3-amine (305 mg, 2,12 mmol) was dissolved in methanol (4 ml) was added 1N. hydrochloric acid solution (4 ml) at -5°C. Then, to the mixture was added dropwise a solution of sodium nitrite (222 mg, 3,17 mmol) in water (2 ml) and the mixture was stirred for 30 minutes at the same temperature. The resulting reaction mixture was added dropwise to a solution of O-utilityservice potassium (678 mg, to 4.23 mmol) input (4 ml) at 60°C, then the reaction temperature was raised to 80°C and the mixture was stirred for 30 minutes. The reaction mixture was cooled to room temperature, then added ethyl acetate and water and the organic layer was collected by separation. The obtained organic layer was washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under reduced pressure. The obtained residue was purified preparative thin-layer chromatography on silica gel (manifesting solvent: hexane:ethyl acetate=19:1) to obtain the specified title compound (156 mg, 0,626 mmol, 30%) as an oily yellow substance.

1H-NMR (400 MHz, CDCl3) δ: of 1.37 (3H, t, J=7,1 Hz), with 4.64 (2H, q, J=7,1 Hz), to 6.67 (1H, t, J=7,1 Hz), 7,72 (1H, d, J=8.1 Hz), 7,98 (1H, DD, J=8,1, 2.2 Hz), 8,71 (1H, d, J=2.2 Hz).

Example 134: 5-[[[6-(Deformity)pyridine-3-yl]thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

To a solution of S-[6-(deformity)pyridine-3-yl] O-ethyl dithiocarbonate (206 mg, 0,826 mmol) in ethanol (3 ml) was added 1N. an aqueous solution of sodium hydroxide (3 ml) and the mixture was stirred for 1 hour at 60°C. the Reaction mixture was cooled to room temperature, was added dichloromethane and water and the aqueous layer was separated. The resulting aqueous layer was acidified using 1N. a solution of hydrochloric acid and extragere the Ali dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and then the filtrate was concentrated under reduced pressure.

To a solution of 5-[hydroxy(2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (355 mg, 1.20 mmol)obtained in Reference example 14, N,N-dimethylformamide (6 ml) was added methanesulfonamide (0,186 ml of 2.40 mmol) and then triethylamine (0,502 ml of 3.60 mmol) under nitrogen atmosphere at room temperature and the mixture was stirred for 1 hour. To the reaction mixture was added ethyl acetate, water and then a saturated aqueous solution of ammonium chloride and the organic layer was separated. The obtained organic layer was washed with saturated saline, then was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N,N-dimethylformamide (12 ml) and to the mixture was added prior thiol and potassium carbonate (199 mg, 1.44 mmol). The mixture was stirred for 2 hours in nitrogen atmosphere at room temperature. To the reaction mixture were added ethyl acetate and water and the organic layer was collected by separation. The organic layer was washed with a saturated aqueous solution of ammonium chloride and then with saturated saline. The obtained organic layer was dried over anhydrous sodium sulfate and filtered and then the filtrate to what has centriole 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=1:1 was concentrated under reduced pressure to obtain specified in the title compound (133 mg, 0,303 mmol, 37%) as a foamy substance light brown color.

1H-NMR (400 MHz, CDCl3) δ: 2,31 (3H, s), of 5.55 (1H, users), to 5.93 (1H, s), 6,59 (1H, t, J=55,4 Hz), for 6.81-to 6.88 (1H, m), 7,07-7,17 (1H, m), 7,54 (1H, d, J=8,3 Hz), to 7.77 (1H, DD, J=8,3, 2.2 Hz), 7,81 (1H, users), of 8.00 (1H, s), 8,55 (1H, d, J=2.2 Hz), the remaining 9.08 (1H, s).

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

Example 135: 5-[[[6-(Deformity)pyridine-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide

5-[[[6-(Deformity)pyridine-3-yl]thio](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (132 mg, 0,300 mmol) was dissolved in ethyl acetate (3 ml) and methanol (2 ml), to the mixture was added a 31% aqueous hydrogen peroxide (3 ml) and heptamolybdate of hexammine tetrahydrate (37,1 mg 0,030 mmol). The mixture was stirred for 17 hours at room temperature. To the reaction mixture was added ethyl acetate, water and then a saturated aqueous solution of sodium bicarbonate and the organic layer was separated. The obtained organic layer is washed with 10% aqueous sodium thiosulfate solution and then with saturated saline, dried over anhydrous sodium sulfate and filtered and then the filtrate was concentrated under pony is hinnon pressure. The obtained residue was subjected to flash chromatography on silica gel, and the fraction obtained by elution with a mixture of dichloromethane:methanol=100:1 was concentrated under reduced pressure to obtain specified in the title compound (118 mg, of 0.250 mmol, 83%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: 2,20 (3H, s)to 5.56 (1H, users), 5,94 (1H, s), of 6.68 (1H, t, J=54.9 Hz), 6,84-6,91 (1H, m), 7,20-7,27 (1H, m), 7,79 (1H, d, J=8,3 Hz), the 7.85 (1H, users), 8,03 (1H, s), 8,19 (1H, DD, J=8,3, 2.2 Hz), 8,93 (1H, d, J=2.2 Hz), 9,40 (1H, s).

MS m/z: 472 (M++H).

Example 136: 5-[[[6-(Deformity)pyridine-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide

To a solution of 5-[[[6-(deformity)pyridine-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]-4-methylpyridin-2-carboxamide (90,0 mg, 0,191 mmol) in dimethyl ether of ethylene glycol (2 ml) was added an aqueous solution of formaldehyde (37%, to 43.0 μl, 0,573 mmol) and 1H. an aqueous solution of sodium hydroxide (9,5 mm) at room temperature and the mixture was stirred for 1 hour. To the reaction mixture were added ethyl acetate and the mixture was washed with a saturated aqueous solution of ammonium chloride. Then the organic layer was added 1N. hydrochloric acid solution (5 ml) and the mixture was stirred for 1 hour. After separation of organic layer, the organic layer was washed with a saturated aqueous solution of hydrocarbon the sodium and then with saturated salt solution, was dried over anhydrous sodium sulfate and filtered and then 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=2:3 was concentrated under reduced pressure. The obtained residue was washed mixed solvent consisting of 2-propanol and hexane and then collected by filtration to obtain specified in the connection header (77.0 mg, 0,154 mmol, 80%) as a solid white color.

1H-NMR (400 MHz, CDCl3) δ: of 2.21 (3H, s), 3,05 (1H, t, J=7.8 Hz), 4,98-of 5.05 (2H, m)5,94 (1H, s), of 6.68 (1H, t, J=54.9 Hz), 6,84-6,92 (1H, m), 7,20-7,27 (1H, m), 7,79 (1H, d, J=8,3 Hz), 8,01 (1H, s), 8,19 (1H, DD, J=8,3, 2,2 Hz), 8,86 (1H, t, J=6.9 Hz), of 8.92 (1H, d, J=2.2 Hz), 9,40 (1H, s).

IR (ATR) cm-1: 3442, 3383, 1676, 1523, 1491, 1338, 1153, 1084, 1055, 1036, 1014.

TPL: 181-183°C.

Analytically calculated for C21H16F5N3O4S: C, 50,30; H, 3,22; F, 18,94; N, SCORED 8.38; S, 6,39. Found: C, 50,07; H, 3,35, F, Of 19.03; N, 8,40; S 6,50.

MS m/z: 502 (M++H).

(Test example 1) screening System using cells for identification of a substance that inhibits the production/secretion of β-amyloid protein

The potency of the compound that inhibits the production of β-amyloid protein, was measured in cell E35 obtained by introducing APP751 gene, gene-protein precursor of β-amyloid protein wild-type person, glue the key human gliomas (cell H4), by determining the amount of β-amyloid protein (Aβ)secreted into the culture medium, using sandiego enzyme-linked immunosorbent assay (ELISA).

Namely, the cells E35 inoculated in 96-well plates, cultured in the incubator at 37°C, maintaining the balance by 5% carbon dioxide, used as a culture medium modified Dulbecco eagle medium containing inactivated 10% fetal bovine serum. 24 hours after inoculation was added a test compound dissolved in DMSO solution. Solution in DMSO of the test compounds were obtained in a concentration of 2000× of the final concentration, so that the concentration of DMSO in culture medium was 0.05 percent. After culturing for 24 hours, the culture supernatant was removed and added to 96-well plates to ELISA, which caused a monoclonal antibody against Aβ, 25-1, in the solid phase. The plates were incubated at 4°C for 16 - 20 hours. The tablets were washed in phosphate-buffer solution (pH of 7.4) and then added biotinylated monoclonal antibody against Aβ, MA32-40. The tablets were left to stand at 4°C for 2 hours. The tablets were washed again with phosphate buffer solution and then added conjugated with alkaline phosphatase streptavidin for conjugation with streptavidin b is a otin. Then the tablets were washed in phosphate-buffer solution. Added Blue Phos (Kirkegaard &Perry Laboratories, Inc.). After incubation tablets over the relevant time period the reaction was stopped with acid and measured the absorbance in each well. The amount of Aβ contained in the culture supernatant was determined using a calibration curve, which was obtained separately, and this number was compared with the number in the control cells, which did not add connection. Thus, the expected concentration which inhibited 50% of the production of Aβ (EC50 value). In addition, 25-1 antibody and MA32-40 antibody used in ELISA, was a mouse monoclonal antibody derived from cloned hybridoma cell lines, each of which was obtained and selected in accordance with the standard method using Aβ25-35 and Aβ-8 as antigens, respectively, and which specifically recognize their target antigens.

The cytotoxic concentration was determined using the following analysis. The H4 cells were cultured in 96-well tablets to their polygonfromtext, to the mixture was added a test compound and continued cultivation. After 72 hours was determined by the number of surviving cells using Alamar Blue (Biosource, Inc.), used for the display of color and opredelenijami dye. The concentration at which the number of surviving cells had reached 80% of the control cells, which did not contain compounds, called cytotoxic concentration. Any connection that demonstrates the difference in cytotoxic concentrations for EC50was identified as the compound having the activity of inhibiting the production of β-amyloid protein.

The results of the evaluation of the compounds (1) according to the present invention in accordance with the above-described method of analysis are presented in Table 1. Used the following estimates: ++++ for the case when EC50was 5 nm or less; +++ for the case when EC50was 5 - 50 nm; ++ for the case when EC50was 50 - 500 nm; and a + for the case when EC50was 500 nm - 5 μm.

The control connection, which is known as having activity of inhibiting the secretion of β-amyloid protein, LY ((N)-((S)-2-hydroxy-3-methylbutyryl)-1-(L-alanine)-(S)-1-amino-3-methyl-4,5,6,7-tetrahydro-2H-3-benzazepin-2-one)was synthesized by the methods described in patent documents 3-5 specified in the present description.

++++
Table 1
The test example No.The activity of inhibiting the production of Aβ (EC50)
4 ++++
5++
9++++
13++++
14++
15++++
16++++
17++++
18++
19+
21+++
22+
24+++
28A+
28VDC+
30++++
32+++
36A+++
36V+
38+++
39++++
43 +++
47+++
55++
59+++
63++++
67++++
71+++
73++++
74++++
75++++
76+
77+
78+++
79++
83++++
84++++
85++++
94++++
101++++
105++++
106++++
117
118++++
120++++
123++++
124+++
Reference compound LY+++

(Test example 2) evaluation of the inhibitory effect against the production of β-amyloid protein and immunosuppressive activity in vivo

(Method of experiment)

As an example of compound (1) compound described in Example 22, Example 85, Example 101, Example 106 or Example 118 (respectively, compounds represented by the above formulas (1-1), (1-2), (1-3), (1-4) or (1-5), which will hereinafter be indicated as the compound (1-1), (1-2), (1-3), (1-4) or (1-5)), or a control compound LY suspended in 0.5% aqueous solution of methylcellulose and oral suspension was administered in a single dose to male rats SD (age about 5 weeks). For the control group treated with the solvent, was introduced only 0.5% aqueous solution of methylcellulose. After 3 hours after the introduction of the brain cut out and abiriliveto brain. The brain substance homogenized using a 42% aqueous solution of formic acid and centrifuged at 100000×g for 60 minutes. The obtained supernatant was neutralized with 1 M Tris and the concentration of Aβ in these samples was measured using a sandwich ELISA as described in test Example 1. In addition, compounds (1-1) to (1-5), or a control compound LY oral was administered to male SD rats continuously for 7 days and rats were subjected to histopathological and serological survey to determine the immunosuppressive effect of the connection.

(The results)

As for the compounds (1-1), (1-2), (1-3), (1-4) and (1-5), observed a significant difference between doses, showing a statistically significant decrease intracerebral number of Aβ, and doses, demonstrating the immunosuppressive effect. On the other hand, for the control connection LY there was no significant difference between the effective dose and the dose that causes toxicity was not observed.

1. The connection represented by the following General formula (I):

where Ar1represents a phenyl group substituted by 1-3 halogen atoms;
Ar2represents a phenyl group which may be substituted with halogen, alkoxyalkyl, alkoxyalkyl, or Peregrina group to whom I can be replaced by halogenation;
X represents-S-, -SO - or-SO2-;
Y represents a hydrogen atom, -NR1R2(where R1represents a hydrogen atom, a lower alkyl group or a hydroxy-group; and R2represents a hydrogen atom, a lower alkyl group which may be substituted, lower alkanoyloxy group, alkoxycarbonyl group which may be substituted, lower alkoxygroup, which may be substituted, amino group which may be substituted; or R1and R2together with the nitrogen atom to which they are bound, form piperidino, morpholino, azetidinone or pieperazinove ring which may be substituted by a hydroxy-group), or1'(where R1'represents a hydrogen atom);
Z represents an oxygen atom or a sulfur atom; and
R represents a hydrogen atom or a lower alkyl group;
or its salt.

2. The compound or its salt according to claim 1, where Ar1is a 2.5 differenly group or 2,3,6-triptorelin group.

3. The compound or its salt according to claim 1, where Ar2represents a phenyl group, a 4-methylphenyl group, 4-chloraniline group, 4-florfenicol group, 4-metoksifenilny group, 4-(triptoreline)phenyl group, 4-triftormetilfullerenov group, 4-chloro-3-methylphenyl group, 4-fluoro-3-methylphenyl group, 3,4-di is tarpenring group or 3,5-differenly group.

4. The compound or its salt according to claim 1, where Ar2it represents the combination of 5-(trifluoromethyl)pyridine-2-ilen group, 6-(trifluoromethyl)pyridine-3-ilen group.

5. The compound or its salt according to claim 1, where R1represents a hydrogen atom.

6. The compound or its salt according to claim 1, where R1represents a methyl group.

7. The compound or its salt according to claim 1, where R2represents a hydrogen atom, methyl group, ethyl group, tert-boutelou group, cyclopropyl group, carboxymethyl group, 2-carboxyaniline group, 2-(etoxycarbonyl)ethyl group, hydroxymethylene group, 2-hydroxyethyloxy group, 4-hydroxycyclohexyl group, 2-hydroxy-1-hydroxymethylamino group, acetoxymethyl group, methylthiopropionate group, methylsulfinylpropyl group, methylsulfonylamino group, methylcarbamoylmethyl group, methoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, 2-chloraniline group, hydroxyethoxyethyl group, dimethylaminomethyl group, karboksimetoksimetilguanina group, ethoxycarbonylmethyl group, mercaptomethyl group, 2-hydroxyethoxymethyl group, (pyridin-3-ylethoxy)methyl group, acetyl group or a methoxy group.

8. The compound or its salt according to claim 1, where R2the present is the focus of a hydrogen atom, methyl group, ethyl group, hydroxymethylene group, 2-hydroxyethyloxy group, dimethylaminomethyl group or a methoxy group.

9. The compound or its salt according to claim 1, where-NR1R2represents an amino group, methylaminopropyl, dimethylaminopropyl, (hydroxymethyl)amino group, N-methyl-N-(hydroxymethyl)amino group, (2-hydroxyethyl)amino group or N-ethyl-N-(2-hydroxyethyl)amino group.

10. The compound or its salt according to claim 1, where Y is a 4-hydroxypiperidine-1-yl group, 3-oxopiperidin-1-yl group or morpholine-4-yl group.

11. The compound or its salt according to claim 1, where Z is an oxygen atom.

12. The compound or its salt according to claim 1, where R3represents a methyl group.

13. The compound or its salt according to claim 1, where Ar1is a 2.5 differenly group; Ar2is a 4-florfenicol group; X represents-SO-; Y represents dimethylaminopropyl; Z represents an oxygen atom; and R3represents a methyl group.

14. 5-[[2,5-Differenl)[(4-forfinal)sulfinil]methyl]-N,N,4-trimethylpyridine-2-carboxamide or its salt.

15. The compound or its salt according to claim 1, where Ar1is a 2.5 differenly group or 2,3,6-triptorelin group; Ar2represents a phenyl group, a 4-florfenicol group or 6(trifluoromethyl)pyridine-3-ilen group; X represents-SO2-; Y represents (hydroxymethyl)amino group or amino group; Z represents an oxygen atom; R3represents a methyl group.

16. The compound, its salt according to clause 15, where Ar1is a 2.5 differenly group; AG2is a 4-florfenicol group; X represents-SO2-; Y represents (hydroxymethyl)amino group; Z represents an oxygen atom; and R3represents a methyl group.

17. 5-[(2,5-Differenl)[(4-forfinal)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide or its salt.

18. The compound or its salt according to clause 15, where Ar1is a 2,3,6-triptorelin group; Ar2is a 4-florfenicol group; X represents-SO2-; Y represents (hydroxymethyl)amino group; Z represents an oxygen atom; and R3represents a methyl group.

19. 5-[[(4-Forfinal)sulfonyl](2,3,6-tryptophanyl)methyl]-N-(1-hydroxymethyl)-4-methylpyridin-2-carboxamide or its salt.

20. The compound or its salt according to clause 15, where Ar1is a 2,3,6-triptorelin group; Ar2represents a phenyl group; X represents-SO2-; Y represents (hydroxymethyl)amino group; Z represents an oxygen atom; and R3

21. N-(1-hydroxymethyl)-4-methyl-5-[(phenylsulfonyl)(2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide or its salt.

22. The compound or its salt according to clause 15, where Ar1is a 2,3,6-triptorelin group; Ar2represents a 6-(trifluoromethyl)pyridine-3-ilen group; X represents-SO2-; Y represents (hydroxymethyl)amino group; Z represents an oxygen atom; and R3represents a methyl group.

23. N-(1-hydroxymethyl)-4-methyl-5-[[[6-(trifluoromethyl)pyridin-3-yl]sulfonyl](2,3,6-tryptophanyl)methyl]pyridine-2-carboxamide or its salt.

24. Drug used for the treatment or prevention of diseases caused by abnormal production and/or secretion of β-amyloid protein, comprising the compound or its salt according to any one of claims 1 to 23 as the active ingredient.

25. Drug at point 24, where the disease is caused by abnormal production and/or secretion of β-amyloid protein, represents Alzheimer's disease or down's syndrome.

26. Pharmaceutical composition for treatment or prevention of diseases caused by abnormal production and/or secretion of β-amyloid protein, comprising the compound or its salt according to any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

27. The use of compounds or salts thereof according to any one of claims 1 to 23 for received what I medicines intended for the treatment or prevention of diseases caused by abnormal production and/or secretion of β-amyloid protein.

28. The application of item 27, where the disease is caused by abnormal production and/or secretion of β-amyloid protein, represents Alzheimer's disease or down's syndrome.

29. A method of treating diseases caused by abnormal production and/or secretion of β-amyloid protein, comprising introducing an effective amount of the compound or its salt according to any one of claims 1 to 23.

30. The method according to clause 29, where the disease is caused by abnormal production and/or secretion of β-amyloid protein, represents Alzheimer's disease or down syndrome.



 

Same patents:

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17 cl, 99 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

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29 cl, 227 ex, 6 tbl

FIELD: chemistry.

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13 cl, 2 tbl, 20 ex

FIELD: chemistry.

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24 cl, 312 tbl, 14 ex

FIELD: chemistry.

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25 cl, 9 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel salt form of 5-[(2R,5S)-5-methyl-4-propylmorpholin-2-yl]piridine-2-amine (I): , and specifically to 5-[2R,5S)-5-methyl-4-propylmorpholin-2-yl]pyridine-2-amine di-(1S)-camphorsulphonate (di-S-camsylate), to a pharmaceutical composition having effect on dopamine D3 receptor, as well use of the given compound in preparing a medicinal agent for treating sexual dysfunction and neuropsychiatric disorders and a method of obtaining the said compound and an intermediate compound.

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11 cl, 9 ex, 2 tbl, 6 dwg

FIELD: chemistry.

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EFFECT: obtainment of compound with excellent inhibition effect on vanilloid receptor type 1 activity, efficiency in treatment of diseases involving vanilloid receptor type 1 activity.

17 cl, 56 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a free base (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)- ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine in crystalline form, having a powder X-ray diffraction pattern with peaks at diffraction angles (2θ) 15.7±0.1, 17.3±0.1 and 19.7±0.1. The invention also relates to a pharmaceutical composition, to methods of treating cancer in mammals, as well as to a method of treating abnormal cell growth in mammals in need of such treatment.

EFFECT: obtaining an novel biologically active compound having the said inhibitory activity.

12 cl, 1 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula : in which R1 represents a hydrogen atom or alkyl optionally substituted with (1) aralkyloxy group, (2) aroyl, (3) isoquinolinyl or (4) aryl, optionally substituted with an alkoxy group; the solid line and the dashed line between A1 and A2 represent a double bond (A1=A2) or a single bond (A1-A2); A1 is a group of formula C(R4), and A2 is a nitrogen atom when the solid line and the dashed line between A1 and A2 represents a double bond (A1=A2); A1 is a group of formula C=O, and A2 is a group of formula N(R5) when the solid line or the dashed line between A1 and A2 represent a single bond (A1-A2); R2 represents alkyl optionally substituted with a cyano group, aryl optionally substituted with an alkoxy group, aralkyl optionally substituted with a halogen atom, a cyano group, an alkoxy group, an alkyl or carbamoyl or alkynyl; R3 represents a hydrogen atom, a halogen atom, cyano, formyl, carboxyl, alkyl optionally substituted with (1) amino group optionally substituted with alkyl, or (2) alkoxy group, aryl optionally substituted with an alkoxy group, tetrazolyl, alkylcarbonyl, cycloalkylcarbonyl, heteroarylcarbonyl, where heteroaryl is a 4-6-member monocyclic radical containing 1-2 heteroatoms selected from a nitrogen atom or oxygen atom, alkoxycarbonyl, carbamoyl optionally substituted with alkyl, cycloalkyl or cycloalkylalkyl, hydroxyl, alkoxy group or a group of formula: -Rd-C(O)O-Re, where Rd represents a single bond, and Re represents a group of formula: -CH(R4a)OC(O)R4b, where R4a represents alkyl or R4b represents cycloalkyloxy or aryloxy; R represents a hydrogen atom, hydroxyl, cyano, alkyl, carbamoyl, carboxyl, aryloxy optionally substituted with an alkoxy group or carbamoyl, alkylsulfonyl, alkylcarbonyl or alkoxycarbonyl; R5 represents a hydrogen atom or alkyl; -Y represents a group of formula (A) given below: in which m1 equals 2, and R6 is absent, or to pharmaceutically acceptable salts of the said compounds. The invention also relates to compounds of formula (VI), to pharmaceutical compositions, to a dipeptidyl peptidase IV inhibitor, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds with dipeptidyl peptidase IV inhibition properties.

20 cl, 76 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula I: ,

to their synthesis method, a pharmaceutical composition based on said compounds and use of said compounds in making medicinal agents. Substitutes R1, R2, R4, R5, as well as values of A, B, D and n are given in the formula of invention.

EFFECT: obtaining novel compounds of formula I: ,

as well as their pharmaceutically acceptable salts which have inhibitory effect on cholesteryl ester transfer protein (CETP).

14 cl, 251 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel anthranilic acid derivatives having inhibitory effect on production of matrix metalloprotease 13 of formula 1 , where R1 is a hydrogen atom or carboxy protective group selected from C1-3alkyl; R2 is phenyl, C3-6cycloalkyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl, which can be optionally substituted with C1-6alkyl, C1-6alkoxy, acetyl, acetoxy, halogen, halogenC1-6alkyl, nitro group, hydroxyl group, CN, amino group, phenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-4 heteroatoms selected from N, O, S, which can be disubstituted with C1-6alkyl; R3 is phenyl, C3-6cycloalkyl, C5cycloalkenyl, saturated or unsaturated 5-6-member heterocyclic group containing 1-3 heteroatoms selected from N, O, S, which can be condensed with phenyl (except benzoxazole), which can be optionally substituted with C1-6alkyl, C1-6alkoxy, phenyl, acetyl, halogen, halogenC1-6alkyl, halogenC1-6alkoxy, nitro group, hydroxyl group, hydroxyC1-6alkyl, CN, acetylamino, ketone, phenoxy, benzoyl, benzyl, amino group, which can be disubstituted with C1-6alkyl, carboxy group, C1-6alkylsufonyl group or pyrrolyl; X1 is a carbonyl group or sulfonyl group; X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl, or a bond; provided that when X1 is a sulfonyl group and X4 is a bond, X2 is a C1-3alkylene, C2-3alkenylene or C2-3alkynylene group which can be optionally substituted with C1-3alkyl; X3 is an oxygen atom or a bond; and X4 is a group with general formula -X5-X6- or -X6-X5-, where the bond on the left side of each formula is bonded to R3; and X5 is an oxygen atom, a sulphur atom, an imino group which can be optionally protected or a bond; X6 is a C1-4alkylene, C2-3alkenylene or C2-3alkynylene group or a bond, as well as to their pharmaceutically acceptable salts. The invention also relates to a matrix metalloprotease 13 production inhibitor and a therapeutic agent for making a medicinal agent for treating rheumatoid arthritis.

EFFECT: possibility of making a medicinal agent for treating rheumatoid arthritis.

8 cl, 7 tbl, 633 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds with formula I: , in which: R1 is R6C(O)-, HC(O)-, R6SO2-, R6OC(O)-, (R6)2NC(O)-, R6-, (R6)2NC(O)C(O)-; R2 is a hydrogen atom, -CF3 or R8; R3 is a hydrogen atom or (C1-C4)aliphatic group-; R4 is -COOH; R5 is -CH2F or -CH2O-2,3,5,6- tetrafluorophenyl; R6 is (C1-C12)aliphatic or (C3-C10)cycloaliphatic group, (C6-C10)aryl-, (C3-C10)heterocyclyl-; and where R6 is substituted with up to 6 substitutes, independently chosen from R; R is a halogen atom, OR7 and -R7; R7 is (C1-C6)aliphatic group-, (C3-C10)cycloaliphatic group; R8 is (C1-C12)aliphatic- or (C3-C10)cycloaliphatic group; to a pharmaceutical composition with caspase-inhibiting activity, based on compound with formula I, to methods of treatment as well as to methods of inhibiting caspase-mediated functions and to a method of reducing production of IGIF or IFN-β. The invention also relates to a method of preserving cells, as well as to a method of producing compound with formula I.

EFFECT: new compounds are obtained and described, which can be used for treating diseases in the development of which caspase activity takes part.

34 cl, 4 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to the cycloalkyl derivative of 3-hydroxy-4-pyridinine with general formula , where R1 represents X with the condition that, R2 is Y; or R1 is T with the condition that, R2 is W; or R1 is X with the condition that, R2R5N taken together, form a heterocyclic ring, formed from morpholinyl or piperazinyl, where the morpholinyl or piperazinyl group is either unsubstituted or substituted with between one to three C1-C6 alkyl groups; X is C3-C6 cycloalkyl; Y is chosen from a group consisting of C3-C6 cycloalkyl, C1-C6 alkyl and C1-C6 alkyl, monosubstituted with C3-C6 cycloalkyl; T represents C1-C6 alkyl; W represents C3-C6 cycloalkyl; R3 represents hydrogen; R4 is chosen from a group consisting of hydrogen and C1-C6 alkyl. The invention also relates to the method of obtaining the derivative as well as to pharmaceutical compositions based on these compounds and use of these compounds in making medicinal preparations.

EFFECT: obtaining new compounds, which can be used in removing surplus iron from patients suffering from diseases related to iron oversaturation.

17 cl, 17 ex, 8 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: described is method of obtaining N-(2-nitroxyethyl)nicotinamide (nicorandyl) of formula by nitrating intermediate N-(2-hydroxyethyl)nicotinamide, which, in its turn, is obtained by interaction of ethylnicotinate with excess of monoethanolamine, differing by the following: reaction is carried out in ethanol and output of N-(2-hydroxyethyl)nicotinamide is brought up to quantitative.

EFFECT: increase of nicorandyl output from 83-84% to 94% and reduction of wastes amount.

1 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to method of obtaining N-(iso) nicotinoyl-γ- aminobutyric acid or its sodium (potassium) salt, which is realized by acidifying γ-aminobutyric acid with mixed anhydride of (iso)nicotinic and aliphatic carboxylic acid or alcoxy-carbonic acid, obtained by interaction of suspension of ammonium salt or alkaline metal salt of (iso)nicotinic acid with chloranhydride of aliphatic carboxylic acid or with chloranhydride of alcoxy-carbonic acid in aprotonic polar solvent medium or in mixture of polar aprotonic and inert solvent, which does not mix with water and forms with it azeotrope. Suspension of sodium (potassium) salt of (iso)nicotinic acid is obtained by interaction of (iso)nicotinic acid with sodium or potassium hydroxide in medium of mixture of polar aprotonic solvent and enert solvent, which does not mix with water and forms azeotrope with it, with further removal of water in form of azeotrope with inert solvent. Sodium (potassium) salt of N-(iso)nicotinoyl-γ-aminobutyric acid is obtained by interaction of N-(iso)nicotinoyl-γ-aminobutyric acid with sodium or potassium hydroxide with its simultaneous or consecutive sedimentation with water-soluble ketone or alcohol, further filtration and drying or by interaction of N-(iso)nicotinoyl-γ-aminobutyric acid with sodium or potassium hydroxide in mixture of polar aprotonic solvent and inert solvent, which does not mix with water and which forms azeotrope with it or, in medium of at least one inert solvent, which does not mix with water and forms azeotrope with it, with further removal of water from reaction mixture in form of azeotrope with inert solvent and product isolation by known methods. Method allows to obtain N-(iso)nicotinoyl-γ-aminobutyric acid and its sodium or potassium salt with 87-94% output in terms of (iso)nicotinic acid.

EFFECT: increase of product output, eliminating organic amins application and simplification of technology of target product obtaining.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to tricyclic derivatives, represented by formula (I) or to their pharmaceutical salts, which have proliferative activity and ability to inhibit angiogenesis, to the method of obtaining them (alternatives), the proliferative agent and an angiogenesis inhibitor on their base. , where R1 represents T1B1; Ti represents -N(R5)C(O)-, where R5 represents H or C1-C5 alkyl group; and B1 is chosen from a group, consisting of the following values (a),(b),(f),(g): , where represents , or ; R6 represents H, halogen or hydroxy group; R7 represents a hydroxy or -ONO2 group, under the condition that R6 represents H, R7 is different from hydroxyl; T2 represents -O-C(O)-; B2 the stated (a) group or -Z1-R7, where Z1 represents a linear C2-C5alkyl group, n2 represents an integer 0-3; and n3 represents an integer 0-5; R2 represents CH3; R3 represents C1-C4 unbranched or branched alkyl, or C3-C7 cycloalkyl, under the condition that, if B1 represents (a), R6 represents H, R7 represents an -ONO2 group and R3 is not CH3; R4 represents SCH3 or OCH3; X represents O.

EFFECT: perfection of the method of obtaining compounds.

7 cl, 6 tbl, 14 dwg, 48 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyridineamides of the general formula (I): wherein one among X or Y means -N= and another means -CR7=; R1, R2, R3, R5, R6 and R7 mean independently hydrogen atom or (C1-C6)-alkyl; R4 means halogen-(C1-C6)-alkyl or unsubstituted phenyl or phenyl substituted with one or some substitutes chosen from group consisting of (C1-C6)-alkyl, halogen atom, halogen-(C1-C6)-alkyl, (C1-C6)-alkoxy-group and cyano-group, and to their pharmaceutically acceptable salts. Indicated compounds possess inhibitory effect with respect to monoaminoxidase B activity and can be used as a medicinal agent in treatment of diseases mediated by monoaminoxidase B inhibitors, in particular, Alzheimer's disease or Parkinson's disease or feeble-mindedness.

EFFECT: valuable medicinal properties of compounds and drug.

12 cl, 1 tbl, 16 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new amide-type carboxamide derivatives of formula [1] , wherein X represents -N= or -CH= group; R1 represents halogen atom, lower alkyl and a like; R1 represents -CO-R21-R22 (meanings of R21 and R22 are as defined in claim 1); Y1 and Y2 are independently halogen atom, lower alkyl, lower alcoxy group, and a like; ring A represents phenyl and a like; or pharmaceutically acceptable salts thereof. Said derivatives are useful as FXa inhibitors. Also disclosed are pharmaceutical composition based on abovementioned compounds and uses thereof.

EFFECT: new amide-type carboxamide derivatives.

7 cl, 105 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) , in which Ar is furanyl, thiophenyl, thiazolyl, pyridinyl; R1 is independently chosen from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen and nitro; R2 is independently chosen from a group consisting of hydrogen and halogen; R4 is hydroxyl or residue of pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid or 1-aminocyclopentane carboxylic acid, bonded through a nitrogen atom of an amino acid residue; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; p is 0, and s is 0, or to their pharmaceutically acceptable salts, under the condition that, the compound is not S-1- [5-(biphenyl-4-yloxymethyl)furan-2-carbonyl]pyrrolidin-2-carboxylic acid, 5-(biphenyl-4-yloxymethyl)furan-2-carboxylic acid, 3-(biphenyl-4-yloxymethyl)benzoic acid, 2-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-4-yloxymethyl)benzoic acid, 5-(biphenyl-4-yloxymethyl)thiophene-2-carboxylic acid. Invention also relates to a pharmaceutical composition based on formula (I) compounds, which stimulates glycogen synthase activity.

EFFECT: wider range of use of the compounds.

27 cl, 34 ex, 8 dwg

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