1-heterocyclylsulphonyl, 2-aminomethyl, 5-(hetero)aryl substituted 1-h-pyrrole derivatives as acid secretion inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compound described by formula where R1 represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle with the monocyclic nitrogen-containing heterocyclic group optionally condensed with heterocycle, optionally having 1 to 5 substitutes chosen from a group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (5) amino, (6) mono- C1-6 alkylamino, (7) C1-6 alkoxycarbonyl and (8) C1-6 alkyl optionally having 1 to 3 halogen atoms, R2 represents (i) C6-14 aryl group optionally substituted by 1 to 5 substitutes chosen of a group consisting of (1) halogen atom, (2) cyano, (3) C1-6 alkoxy optionally having 1 to 3 halogen atoms, (4) C1-6 alkylthio optionally having 1 to 3 halogen atoms, (5) C1-6alkylcarbonyl, (6) C1-6 alkylsulphonyl, (7) C1-6 alkylthionyl, (8) C3-7 cycloalkyl, (9) C1-6 alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6 alkyl group substituted by 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) cyano and (2) C1-6 alkyl group optionally having 1 to 3 halogen atoms, (iii) a pyridyl group optionally substituted by 1 to 4 substitutes chosen from a group consisting of (1) halogen atom, (2) 5-10-members aromatic heterocyclic group containing carbon atom, and 1 or 2 presentations of 1-4 heteroatoms chosen from nitrogen atom, sulphur atom and oxygen atom, and (3) C1-6 alkyl group optionally having 1 to 3 halogen atoms, or (iv) a bipyridyl group optionally substituted by 1 to 3 halogen atoms, each R3 and R4 represents hydrogen atom, or one of R3 and R4 represents hydrogen atom, and another represent a lower alkyl group, halogen atom or a cyanogroup, and R5 represents an alkyl group, or to its salt. Also, the invention refers to a pharmaceutical composition showing an acid secretion inhibitory effect enabled by the compound of formula I, to a method for treatment or prevention, besides, to application of the compound of formula I for preparing a pharmaceutical composition for treatment or prevention of a number of diseases presented in the patent claim.

EFFECT: preparation of the new compounds showing the acid secretion inhibitory effect and exhibiting antiulcerant action.

20 cl, 92 ex, 24 tbl

 

The technical field

The present invention relates to compounds of pyrrole with suppressive activity against the secretion of acid.

The level of technology

Proton pump inhibitors, represented by omeprazole, which inhibits the secretion of gastric acid, for the treatment of peptic ulcer, reflux esophagitis and the like, are widely used in clinical practice. However, the existing proton pump inhibitor are problematic in the sense of action and side effects. In particular, since the proton pump inhibitor is unstable in acidic conditions, they are often given as an intestinal drugs until the effect will take a few hours. In addition, because the existing proton pump inhibitor show unstable effects of treatment due to metabolic enzyme polymorphism and interaction of the drug with pharmaceutical substances such as diazepam and the like, the improvement is needed.

As pyrrole compounds having inhibitory activity against proton pump, in EP-A-0259085 described compound represented by the formula:

and the like.

As the compounds having antagonistic action of the m in the ratio of thromboxane A2 (TXA2) and inhibitory activity against TXA2 synthase, in JP-A-8-119936 described compound represented by the formula:

where r1 represents a carboxy, protected carboxy, carboxy(lower)alkyl, protected carboxy(lower)alkyl, carboxy(lower)alkenyl or protected carboxy(lower)alkenyl, r2 represents hydrogen; lower alkyl; heterocyclyl (lower)alkyl, optionally having amidoamine or protected aminoamide; heterocyclyl (lower)alkenyl; or heterocyclyl carbonyl, r3 represents hydrogen or lower alkyl, r4 represents an acyl, r5 is a hydrogen, A0represents the lowest alkylene, and Z0represents S or NH, provided that when r1 represents carboxy or protected carboxy, then Z0represents NH.

In addition, as a drug for the treatment of tumors or autoimmune diseases, in WO2004/103968 described compound represented by the formula:

where r6 represents aryl, aralkyl or heteroaryl, r7 is an aryl or heteroaryl, and r8 represents an aryl, heteroaryl or optionally substituted aminomethyl.

Disclosure of the invention

Objectives of the invention

Drug, effectively overwhelming the secretion of gastric acid, as known in hibitory proton pump superior in the sense of stability in acidic conditions, the dispersion effects due to metabolic enzyme polymorphism and drug interactions, which are disadvantages of the known proton pump inhibitor is expected to show a higher effect in the treatment of peptic ulcer, reflux esophagitis and the like. Until now, however, the proton pump inhibitor, is able adequately to meet these requirements, not found. Thus, the aim of the present invention is a compound which has an excellent suppressive effect on the secretion of acid (in particular, inhibitory action on the proton pump), which is superior in the sense of addressing these shortcomings.

Ways of solving problems

The authors of this invention have conducted various studies and found that the compound represented by formula (I):

(I)

where R1represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, optionally having substituent(s)

R2predstavljaet an optionally substituted C 6-14aryl group, optionally substituted thienyl group or optionally substituted pyridyloxy group,

R3and R4represent each a hydrogen atom, or one of R3and R4represents a hydrogen atom and the other represents an optionally substituted lower alkyl group, acyl group, halogen atom, cyano or nitro-group, and

R5represents an alkyl group,

or its salt [hereinafter abbreviated refers to as compound (I)] unexpectedly has a very strong suppressive action on the secretion of acid (inhibitory activity against proton pump) and is fully acceptable as a drug carrying out the present invention.

Accordingly, the present invention relates to the next.

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

(I)

where R1represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, optionally having substituent(s), R2represents an optionally substituted C6-14 aryl group, optionally substituted thienyl group or optionally substituted pyridyloxy group, R3and R4represent each a hydrogen atom, or one of R3and R4represents a hydrogen atom and the other represents an optionally substituted lower alkyl group, acyl group, halogen atom, cyano or nitro-group, and R5represents an alkyl group, or its salt.

[2] the Compound represented by formula (I):

(I)

where R1represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, a monocyclic nitrogen-containing heterocyclic group optionally condensed with a benzene ring or a heterocycle, optionally having substituent(s), R2represents an optionally substituted C6-14aryl group or optionally substituted thienyl group, R3and R4represent each a hydrogen atom, or one of R3and R4represents a hydrogen atom and the other represents an optionally substituted lower alkyl group, acyl group, halogen atom, cyano or nitro-group, and R5represents an alkyl group, or the th Sol.

[3] the Above compound [1] or [2], where R1represents a monocyclic nitrogen-containing heterocyclic group.

[4] the Above compound [1] or [2], where the monocyclic nitrogen-containing heterocyclic group is pyridyloxy group.

[5] the Above compound [1] or [2], where R2represents a phenyl group, optionally substituted by 1-5 substituents selected from (i) halogen atom and (ii) C1-6the alkyl, optionally substituted by 1-5 halogen atoms.

[6] the Above compound [1], where R2represents pyridyloxy group, optionally substituted with 1-4 substituent(s)selected from C1-6of alkyl, halogen atom, alkoxy, cyano, acyl, nitro and amino.

[7] the Above compound [1] or [2], where R3and R4represent each a hydrogen atom.

[8] the Above compound [1] or [2], where R5represents a methyl group.

[9] 1-{5-(2-Forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine or its salt.

[10] 1-[4-Fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

[11] N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine or its salt.

[12] 1-[5-(2-Herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

[13] -[5-(2-Forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

[14] N-Methyl-1-[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine or its salt.

[15] the Prodrug of the above compound [1] or [2].

[16] the Pharmaceutical composition containing the above compound [1] or [2] or its prodrug.

[17] the Above pharmaceutical composition [16], which is an inhibitor of gastric secretion.

[18] the Above pharmaceutical composition [16], which is a potassium-competitive acid blocker.

[19] the Above pharmaceutical composition [16], which is an agent for the treatment or prophylaxis of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, lymphoma of the mucosa of the stomach or the acidity of the stomach; or the inhibitor of bleeding in the upper section of the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress.

[20] the Method of treatment or prophylaxis of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatics what I GERD), functional dyspepsia, gastric cancer, lymphoma of the mucosa of the stomach or the acidity of the stomach; or the method of inhibiting the hemorrhage of the upper section of the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress, which includes the introduction of an effective amount of the above compound [1] or [2] or its prodrug to the mammal.

[21] the use of the above compound [1] or [2] or its prodrug to obtain a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, lymphoma of the mucosa of the stomach or the acidity of the stomach; or inhibitor bleeding of the upper section of the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress.

The effect of the invention

Since the compound (I) shows excellent inhibitory activity against proton pump (whereas regular proton pump inhibitor such as omeprazole, lansoprazole, etc. form a covalent bond with C is steenoven the remainder of H +/K+-ATPase and irreversibly inhibit the enzymatic activity, and as the compound (I) reversibly inhibits the activity of the proton pump (H+/K+-Atrata) and by inhibiting K+ antagonist, respectively, suppresses the secretion of acid, it is sometimes called potassium-competitive acid blocker: P-CAB or antagonist of acid pump (ACPA or APA)), it can be applied in the form of a pharmaceutical composition for prevention and/or treatment of peptic ulcer (e.g. gastric ulcer, stomach ulcer due to postoperative stress, duodenal ulcer, anastomoticheskih ulcer, caused by the use of nonsteroidal anti-inflammatory drugs, ulcer due to postoperative stress, etc.); syndrome Zollinger-Ellison; gastritis; erosive and ulcerative esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (symptomatic GERD), for example neurosignal reflux disease or gastroesophageal reflux disease without esophagitis and the like; functional dyspepsia; gastric cancer (including gastric cancer associated with activated secretion of interleukin-1β due to gene polymorphism of interleukin-1); lymphomas of the mucosa of the stomach; the acidity of the stomach; or as an inhibitor of bravoteen the I upper division the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress (for example, stress caused by major surgery requiring postoperative intensive care, and cerebral-vascular disorders, traumatic brain injury, multiple organ failure and extensive burn, each of which needs intensive therapy) and the like. In addition, compound (I) used for the prevention and/or treatment of respiratory diseases, asthma and the like, before the introduction of the anesthetic, the eradication ofHelicobacter pylorior aid in the eradication and the like. As the compound (I) shows low toxicity and excellent solubility, in vivo kinetics and efficiency, it is used in the form of pharmaceutical compositions. In addition, since the compound (I) is stable even in acidic environments, the connection may be administered orally in the form of conventional tablets and the like, uncoated drug intersolubility shell. Resulting product in the form of tablets and the like can be obtained with smaller dimensions, which is preferable for easier swallowing patients who have difficulty swallowing, particularly for the elderly and children. In addition, because of the drugs covered intersolubility shell is unavailable or is there an effect of slow-release, the inhibitory effect in regard to the secretion of gastric acid is manifested quickly and alleviate symptoms such as pain and things happen quickly.

The best variant implementation of the invention

In the formula (I) as “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle” for values of R1may be specified

(1) nitrogen-containing monocyclic heterocyclic group, and

(2) a condensed ring group represented by the formula:

where ring A is a nitrogen-containing monocyclic heterocyclic group, ring B represents a benzene ring or a heterocycle, a and b are, each forming a ring bridging atom (for example, carbon atom, nitrogen atom and the like), andshows a single bond or double bond, provided that communication with the group-SO2in the formula (I) is located on the forming ring A atom (ring atom), other than form a ring bridging atoms a and b.

As used herein, the ring A can contain only as forming a ring A atom (ring atom), at least one (preferably 1-4, more preferably 1 or 2) atom is zhota, and one or both of the bridge forming a ring of atoms a and b can be nitrogen atoms.

“Nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle”, does not necessarily have a substituent(s), and the substituent(s) may be in any of the rings A or B.

As the “nitrogen-containing monocyclic heterocyclic group” of the “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle” and the above-mentioned ring A can be mentioned, for example, aromatic nitrogen-containing monocyclic heterocyclic group, saturated or unsaturated non-aromatic nitrogen-containing monocyclic heterocyclic group (aliphatic nitrogen-containing monocyclic heterocyclic group) and the like, containing, as forming a ring atom (ring atom), at least one (preferably 1-4, more preferably 1 or 2) nitrogen atom.

As the “aromatic nitrogen-containing monocyclic heterocyclic group” can be mentioned, for example, nitrogen-containing aromatic monocyclic heterocyclic groups such as pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl (1H-imidazol-1-yl, 1H-imidazol-4-yl and is like what), pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazole-1-yl, 1,2,4-triazole-4-yl and the like), tetrazolyl, pyridyl (2-, 3 - or 4-pyridyl and the like), pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and their N-oxide forms, and the like. Of them 5 - or 6-membered aromatic nitrogen-containing monocyclic heterocyclic group is preferred, and thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridazinyl are preferred, and pyridyl is especially preferred.

As a “saturated or unsaturated non-aromatic nitrogen-containing monocyclic heterocyclic group” can be specified partially reduced forms (e.g., imidazolyl, tetrahydropyrimidines and the like) of the above “aromatic nitrogen-containing monocyclic heterocyclic group”, for example, azetidine, pyrrolidine, piperidyl (2-, 3 - or 4-piperidyl), morpholinyl, thiomorpholine, piperazinil (1-piperazinil and the like), homopiperazine and the like. Of them 5 - or 6-membered non-aromatic nitrogen-containing monocyclic heterocyclic group is preferred.

As the “heterocycle”, optional condenser the data with a nitrogen-containing monocyclic heterocyclic group, can be specified, for example, aromatic heterocycle or nonaromatic a heterocycle.

As the “aromatic heterocycle” can be specified, for example, 5 - or 6-membered aromatic heterogenities rings, such as furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazol ring, imidazole ring, pyrazole nucleus ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,3,4-oxadiazoline ring, furazane ring, 1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring, 1,3,4-thiadiazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazinone ring, triazine ring and the like and, for example, 8-12-membered aromatic condensed heterocyclic compounds, such as benzofuranol ring, isobenzofuran ring, benzo[b]thiophene ring, indole ring, isoindole ring, 1H-indazol ring, benzidazole ring, benzoxazole ring, 1,2-benzisoxazole ring, benzothiazoline ring, benzopyrene ring, 1,2-benzothiazoline ring, 1H-benzotryazolyl ring, quinoline ring, isoquinoline ring, cinnoline ring, hintline ring, hinoksolinov ring, phthalazine the second ring, naphthyridine ring, purine ring, pteridine ring, carbazole ring, α-carolynowoe ring, β-carolynowoe ring, γ-carolynowoe ring, acridine ring, phenoxazine ring, phenothiazine ring, phenazine ring, phenoxathiin ring, thianthrene ring, phenanthridinium ring, phenanthrene ring, indolizine ring, pyrrolo[1,2-b]pyridazinone ring, pyrazolo[1,5-a]pyridine ring, imidazo[1,2-a]pyridine ring, imidazo[1,5-a]pyridine ring, imidazo[1,2-b]pyridazinone ring, imidazo[1,2-a]pyrimidine ring, a 1,2,4-triazolo[4,3-a]pyridine ring, a 1,2,4-triazolo[4,3-b]pyridazinone ring and the like (preferably, a heterocycle, where the above-mentioned 5 - or 6-membered aromatic heterophilically ring condensed with a benzene ring or a heterocycle, where two identical or different heterocycle above stated 5 - or 6-membered aromatic heterogenities condensed ring, more preferably a heterocycle, where the above-mentioned 5 - or 6-membered aromatic monocyclic heterocyclic group condensed with a benzene ring, preferably imidazopyrimidines and the like) and the like.

As a “non-aromatic heterocycle can be mentioned, for example, 3-8-membered us is on or unsaturated non-aromatic heterocycles, such as oxirane ring, azetidine ring, oxetane ring, titanoboa ring, pyrolidine ring, tertrahydrofuran ring ring, Tirnovo ring, piperidine ring, tetrahydropyran ring, morpholine ring, thiomorpholine ring, pieperazinove ring, 3-hexahydrotriazine[c]pyrrole ring, homopiperazine ring, homopiperazine ring and the like, or non-aromatic heterocycles, where the double bonds of the aforementioned aromatic heterophilically ring or condensed aromatic heterocycle, partially or fully saturated, such as dihydropyridine ring, dihydropyrimidine ring, 1,2,3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring and the like.

The preferred nitrogen-containing monocyclic heterocyclic group condensed with a benzene ring or a heterocycle, can be specified, for example, nitrogen-containing condensed aromatic heterocyclic group such as 8-to 16-membered (preferably 8-12-membered) nitrogen-containing aromatic bicyclic condensed heterocyclic groups such as 2 - or 3-indolyl, 1 - or 3-isoindolyl, 1H-indazol-3-yl, 2-benzimidazolyl, 2-benzoxazolyl, 3-benzisoxazole, 2-benzothiazolyl, 3-benzothiazolyl, 2-, 3 - or 4-henol the l, 1-, 3 - or 4-ethanolic, 3 - or 4-indolinyl, 2 - or 4-hintline, 2 - or 3-honokalani, 1 - or 4-phthalazine, naphthyridine, purinol, pteridinyl, 1,7-phenanthrolin-2-, 3 - or 4-yl, 1-, 2 - or 3-indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,2-b]pyrazolyl, imidazo[1,5-a]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-c]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5-b]pyridazinyl, pyrazolo[3,4-b]pyridyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridinyl, [1,2,4]triazolo[1,2-a]pyridazinyl, [1,2,3]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-c]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, pyrazolo[5,1-b]thiazolyl, pyrrolo[2,1-f][1,2,4]triazinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridyl, thieno[3,2-b]pyrimidinyl, thieno[2,3-b]pyridyl, thieno[2,3-c]pyridyl, thieno[3,2-b]pyridyl, thieno[3,2-c]pyridyl, pyrido[2,3-b]Persil, pyrido[3,4-b]Persil, pyrido[2,3-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl and the like, and the like. As the nitrogen-containing condensed aromatic heterocycle preferred are condensed pyridine, where the pyridine ring condensed with one or two (preferably one) of the above 5 - or 6-membered nitrogen-containing aromatic monocycles the x heterocycles, or one or two (preferably one) of the benzene ring (when condensed with a benzene ring, a pyridine ring has a connection), condensed pyrimidine, where the pyrimidine ring condensed with one or two (preferably one) of the above 5 - or 6-membered nitrogen-containing aromatic monocyclic heterocycles, or one or two (preferably one) of the benzene ring (when condensed with a benzene ring, pyrimidine ring is connected) and the like.

As a “non-aromatic nitrogen-containing heterocycle“ can be specified, for example, 3-8-membered (preferably 5 - or 6-membered) nitrogen-containing saturated or unsaturated (preferably saturated) non-aromatic a heterocycle (aliphatic nitrogen-containing heterocycle, such as azetidin, pyrrolidin, imidazolidin, thiazolidin, oxazolidine, piperidine, morpholine, thiomorpholine, piperazine and the like, or nitrogen-containing the non-aromatic heterocycle, where the double bond in the above-mentioned nitrogen-containing aromatic monocyclic heterocycle or nitrogen-containing condensed aromatic heterocycle, partially or fully saturated, such as 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and so similar.

As the “nitrogen-containing monocyclic heterocyclic g is uppy, optionally condensed with a benzene ring or a heterocycle”, 5 - or 6-membered aromatic nitrogen-containing monocyclic heterocyclic group, mentioned above, is preferred. Among them 6-membered nitrogen-containing aromatic heterocyclic group such as pyridyl (e.g. 2-, 3 - or 4-pyridyl and the like), pyrimidinyl (for example, 2-, 4 - or 5-pyrimidinyl and the like), pyridazinyl (for example, 3 - or 4-pyridazinyl and the like) and the like is preferred, and pyridyl is especially preferred.

As a Deputy, who may be “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle”may be specified (1) halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom and the like), (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, formatosi and the like)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (6) C6-14aryloxy (for example, phenyloxy, naphthyloxy and the like), (7) C7-16Arakelots (for example, benzyloxy, penetrate, diphenylmethoxy, 1 naphthalenyloxy, 2-naphthalenyloxy, 2,diphenylethylene, 3 phenylpropoxy, 4-phenylbutyrate, 5-phenylpentane and the like), (8) mercapto, (9) C1-6alkylthio (for example, methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia, pentylthio, hexylthio and the like)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (10) C6-14aaltio (for example, phenylthio, naphthylthio and the like), (11) C7-16Uralkali (for example, benzylthio, penetito, diphenylmethyl, 1 naphthylmethyl, 2-naphthylmethyl, 2,2-definietely, 3 phenylpropyl, 4-phenylbutyl, 5-phenylpentane and the like), (12) amino, (13) mono-C1-6alkylamino (for example, methylamino, ethylamino and the like), (14) mono-C6-14arylamino (for example, phenylamino, 1 naphthylamine, 2-naphthylamine and the like), (15) mono-C7-16aralkylamines (for example, benzylamino and the like), (16) di-C1-6alkylamino (for example, dimethylamino, diethylamino and the like), (17) di-C6-14arylamino (for example, diphenylamino and the like), (18) di-C7-16aralkylamines (for example, dibenzylamine and the like), (19) formyl, (20) C1-6alkyl-carbonyl (e.g. acetyl, propionyl and the like), (21) C6-14aryl-carbonyl (e.g. benzoyl, 1-naphtol, 2-naphtol and the like), (22) carboxyl, (23) C1-6alkoxy-carbonyl (for example, meloxicam is of IMT, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like), (24) C6-14aryloxy-carbonyl (for example, phenoxycarbonyl and the like), (25) carbarnoyl, (26) thiocarbamoyl, (27) mono-C1-6alkyl-carbarnoyl (for example, methylcarbamoyl, ethylcarbitol and the like), (28) di-C1-6alkyl-carbarnoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino and the like), (29) C6-14aryl-carbarnoyl (for example, phenylcarbamoyl, 1-afterburner, 2-afterburner and the like), (30) C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and the like), (31) C6-14arylsulfonyl (for example, phenylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl and the like), (32) C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl and the like), (33) C6-14arylsulfonyl (for example, phenylsulfinyl, 1-naphthylmethyl, 2-naphthylmethyl and the like), (34) formylamino, (35) C1-6alkyl-carbylamine (for example, acetylamino and the like), (36) C6-14aryl-carbylamine (for example, benzoylamine, naphthylamine and the like), (37) C1-6alkoxy-carbylamine (for example, methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, butoxycarbonylamino and the like), (38) C1-6alkylsulfonyl (for example, methylsulfonylamino, ethylsulfonyl and that is such), (39) C6-14arylsulfonyl (for example, phenylcarbonylamino, 2-naphthylamine, 1 naphthylamine and the like), (40) C1-6alkyl-carbonyloxy (for example, acetoxy, propionyloxy and the like), (41) C6-14aryl-carbonyloxy (for example, benzoyloxy, niftycorners and the like), (42) C1-6alkoxy-carbonyloxy (for example, methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), (43) mono-C1-6alkyl-carbamoylated (for example, methylcarbamoyl, ethylcarbamate and the like), (44) di-C1-6alkyl-carbamoylated (for example, dimethylcarbamoyl, diethylcarbamoyl and the like), (45) C6-14aryl-carbamoylated (for example, phenylcarbamoyloxy, afterburners and the like), (46) a 5-7 membered saturated cyclic amino (for example, pyrrolidin-1-yl, piperidino, piperazine-1-yl, morpholino, thiomorpholine, hexahydroazepin-1-yl and the like) optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, (47) 5-10-membered aromatic heterocyclic group (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 8-chinolin, 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 1-indolyl, 2-ind is poured, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like)containing, besides carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, (48) C1-3alkylenedioxy (for example, methylenedioxy, Ethylenedioxy and the like), (49) C3-7cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like), (50) C1-6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (51) C2-6Alchemilla group (e.g. allyl, Isopropenyl, Isobutanol, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (52) C2-6Alchemilla group (for example, propargyl, 2-butynyl, 3-butynyl, 3-pentenyl, 3-hexenyl and the like), (53) C1-6an alkyl group (for example, hydroxymethyl, hydroxyethyl and the like), substituted from 1 to 3 hydroxy, and the like.

The Deputy may be able to replace the position and number of substituents is 1-5, preferably 1-3.

As “C6-14aryl groups is” as “is optional substituted C 6-14aryl group” for R2can be specified, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-antral and the like.

As Deputy, which necessarily has a “C6-14aryl group”may include groups similar to the substituents that do not have a “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle” of the above R1.

The number of substituents is 1-5, preferably 1-3.

As a thienyl group as the “optionally substituted thienyl group” for R2can be used 2 - or 3-thienyl.

As Deputy, which not necessarily has “thienyl group, can be specified groups similar to the substituents that do not have a “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle” of the above R1.

The number of substituents is 1-4, preferably 1-3.

As peredelnoj group” as the “optionally substituted peredelnoj group” for R2may be mentioned 2-, 3 - or 4-pyridyl, or bipyridyl (for example, 2,3'-bipyridine-5-yl).

As Deputy, which not necessarily has “pyridi the other group”, can be specified groups similar to the substituents that do not have a “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle” of the above R1.

The number of substituents is 1-4, preferably 1-3.

As the “lower alkyl group” as the “optionally substituted lower alkyl group” for R3or R4can be specified, for example, C1-4alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

As Deputy, which necessarily has a “lower alkyl group”can be mentioned (1) a halogen atom (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom and the like), (2) nitro, (3) cyano, (4) hydroxy, (5) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, formatosi and the like)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (6) C6-14aryloxy (for example, phenyloxy, naphthyloxy and the like), (7) C7-16Arakelots (for example, benzyloxy, penetrate, diphenylmethoxy, 1 naphthalenyloxy, 2-naphthylmethyl, 2,2-diphenylethylamine, 3 phenylpropoxy, 4-phenylbutyrate, 5-phenylpentane and that p is such), (8) mercapto, (9) C1-6alkylthio (for example, methylthio, deformality, triptoreline, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-cryptosporidia, pentylthio, hexylthio and the like)optionally having 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (10) C6-14aaltio (for example, phenylthio, naphthylthio and the like), (11) C7-16Uralkali (for example, benzylthio, penetito, diphenylmethyl, 1 naphthylmethyl, 2-naphthylmethyl, 2,2-definietely, 3 phenylpropyl, 4-phenylbutyl, 5-phenylpentane and the like) (12) amino, (13) mono-C1-6alkylamino (for example, methylamino, ethylamino and the like), (14) mono-C6-14arylamino (for example, phenylamino, 1 naphthylamine, 2-naphthylamine and the like), (15) mono-C7-16aralkylamines (for example, benzylamino and the like), (16) di-C1-6alkylamino (for example, dimethylamino, diethylamino and the like), (17) di-C6-14arylamino (for example, diphenylamino and the like), (18) di-C7-16aralkylamines (for example, dibenzylamine and the like), (19) formyl, (20) C1-6alkyl-carbonyl (e.g. acetyl, propionyl and the like), (21) C6-14aryl-carbonyl (e.g. benzoyl, 1-naphtol, 2-naphtol and the like), (22) carboxyl, (23) C1-6alkoxy-carbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and that p is such), (24) C6-14aryloxy-carbonyl (for example, phenoxycarbonyl and the like), (25) carbarnoyl, (26) thiocarbamoyl, (27) mono-C1-6alkyl-carbarnoyl (for example, methylcarbamoyl, ethylcarbitol and the like), (28) di-C1-6alkyl-carbarnoyl (for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylamino and the like), (29) C6-14aryl-carbarnoyl (for example, phenylcarbamoyl, 1-afterburner, 2-afterburner and the like), (30) C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and the like), (31) C6-14arylsulfonyl (for example, phenylsulfonyl, 1-naphthylmethyl, 2-naphthylmethyl and the like), (32) C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl and the like), (33) C6-14arylsulfonyl (for example, phenylsulfinyl, 1-naphthylmethyl, 2-naphthylmethyl and the like), (34) formylamino, (35) C1-6alkyl-carbylamine (for example, acetylamino and the like), (36) C6-14aryl-carbylamine (for example, benzoylamine, naphthylamine and the like), (37) C1-6alkoxy-carbylamine (for example, methoxycarbonylamino, ethoxycarbonylethyl, propoxycarbonyl, butoxycarbonylamino and the like), (38) C1-6alkylsulfonyl (for example, methylsulfonylamino, ethylsulfonyl and the like), (39) C6-14arylsulfonyl (for example, phenylsulfonyl is, 2 naphthylamine, 1 naphthylamine and the like), (40) C1-6alkyl-carbonyloxy (for example, acetoxy, propionyloxy and the like), (41) C6-14aryl-carbonyloxy (for example, benzoyloxy, niftycorners and the like), (42) C1-6alkoxy-carbonyloxy (for example, methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like), (43) mono-C1-6alkyl-carbamoylated (for example, methylcarbamoyl, ethylcarbamate and the like), (44) di-C1-6alkyl-carbamoylated (for example, dimethylcarbamoyl, diethylcarbamoyl and the like), (45) C6-14aryl-carbamoylated (for example, phenylcarbamoyloxy, afterburners and the like), (46) a 5-7 membered saturated cyclic amino, optionally containing, besides one nitrogen atom and carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom (for example, pyrrolidin-1-yl, piperidino, piperazine-1-yl, morpholino, thiomorpholine, hexahydroazepin-1-yl and the like), (47) 5-10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom (for example, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 8-chinolin, 1-ethanolic, 3-thenail, 4-ethanolic, 5-ethanolic, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl and the like), (48) C1-3alkylenedioxy (for example, methylenedioxy, Ethylenedioxy and the like), (49) C3-7cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like) and the like.

The number of substituents is 1 to 3.

As the “acyl group” for R3or R4it may be mentioned acyl group having 1-20 carbon atoms, which is derived from organic carboxylic acids. Can be used, for example, C1-7alcoholnye group (e.g., formyl; C1-6alkyl-carbonyl such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like), C6-14aryl-carbonyl group (e.g., benzoyl, naphthaleneboronic and the like), C1-6alkoxy-carbonyl group (e.g., methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl and the like), C6-14aryloxy-carbonyl group (for example, phenoxycarbonyl group), C7-19aralkyl-carbonyl group (for example, phenyl-C1-4alkylsulphonyl, such as benzylcarbamoyl, ventilkappen, uniprofessional and the like, naphthyl-C1-4alkylsulphonyl, such as benzylaminocarbonyl, naphthylethylene and the like), C7-19Arakelov-carbonyl group (for example, phenyl-C1-4allyloxycarbonyl, such as benzyloxycarbonyl and the like), 5 - or 6-membered heterocycle-carbonyl group or a condensed heterocycle-carbonyl group (e.g., pyrrolidinones, such as 2 - or 3-pyrrolidinone and the like; pyrazolidinone, such as 3-, 4 - or 5-pyrazolidinone and the like; imidazolinones, such as 2-, 4 - or 5-imidazolidinyl and the like; triazolylmethyl, such as 1,2,3-triazole-4-ylcarbonyl, 1,2,4-triazole-3-ylcarbonyl and the like; tetrachlorocarbon, such as 1H - or 2H-tetrazol-5-ylcarbonyl and the like; fullcarbon, such as 2 - or 3-fullcarbon and the like; thienylboronic, such as 2 - or 3-thienylboronic and the like; oxazolidinones, such as 2-, 4 - or 5-oxazolidinone and the like; isoxazolidinone, such as 3-, 4 - or 5-isoxazolidinone and the like; oxadiazolidine, such as 1,2,3-oxadiazol-4 - or 5-ylcarbonyl, 1,2,4-oxadiazol-3 - or 5-ylcarbonyl, 1,2,5-oxadiazol-3 - or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl and the like; thiazolidinones, such as 2-, 4 - or 5-thiazolidinones and the like; isothiazolinones, such as 3-, 4 - or 5-from thiazolidinones and the like; thiadiazolidine, such as 1,2,3-thiadiazole-4 - or 5-ylcarbonyl, 1,2,4-thiadiazole-3 - or 5-ylcarbonyl, 1,2,5-thiadiazole-3 - or 4-ylcarbonyl, 1,3,4-thiadiazole-2-ylcarbonyl and the like; pyrrolidinylcarbonyl, such as 2 - or 3-pyrrolidinylcarbonyl and the like; pyridylcarbonyl, such as 2-, 3 - or 4-pyridylcarbonyl and the like; pyridylcarbonyl, where the nitrogen atom is oxidized, such as 2-, 3 - or 4-pyridyl-N-oxycarbonyl and the like; pyridinylmethyl, such as 3 - or 4-pyridinylmethyl and the like; pyridinylmethyl, where one or both of the nitrogen atom is oxidized, such as 3-, 4-, 5 - or 6-pyridazinyl-N-oxycarbonyl and the like; pyrimidinecarbonitrile, such as 2-, 4 - or 5-pyrimidinecarbonitrile and the like; pyrimidinecarbonitrile, where one or both of the nitrogen atom is oxidized, such as 2-, 4-, 5 - or 6-pyrimidinyl-N-oxycarbonyl and the like; PersonalCabinet; piperidinylcarbonyl, such as 2-, 3 - or 4-piperidinylcarbonyl and the like; piperazinylcarbonyl; indolocarbazole, such as 3H-indol-2 - or 3-ylcarbonyl and the like; paramiltary, such as 2-, 3 - or 4-paramiltary and the like; tipirneni, such as 2-, 3 - or 4-copernicans and the like; hinolincarbonova, such as 3-, 4-, 5-, 6-, 7 - or 8-hinolincarbonova and the like; athinaikon; pyrido[2,3-d]pyrimidinedione (e.g., pyrido[2,3-d-2-ylcarbonyl); naphthyridinone (for example, 1.5-naphthiridine-2 - or 3-ylcarbonyl), such as 1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridinone and the like; thieno[2,3-d]pyridylcarbonyl (e.g., thieno[2,3-d]pyridine-3-ylcarbonyl); pyrazinopyrinidine (e.g., pyrazino[2,3-b]quinoline-2-ylcarbonyl); 5 - or 6-membered heterocycle-carbonyl group (e.g., chromenickel (for example, 2H-chromen-2 - or 3-ylcarbonyl and the like) and the like), containing 1-4 heteroatoms such as a nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono - or dicyclanil), and the like), 5 - or 6-membered heterocycle-acetyl group (for example, 5 - or 6-membered heterocycle-acetyl group containing 1-4 heteroatom such as nitrogen atom (optionally oxidized), an oxygen atom, a sulfur atom (optionally mono - or dicyclanil), and the like), such as 2-pyrrolidinyl, 3-imidazolidinyl, 5-isoxazolyl and the like.

The Deputy acyl group, for example when the above-mentioned acyl group is alkanoyloxy group or alkoxy-carbonyl group, acyl group optionally substituted by 1-3 alkylthio groups (for example, C1-4alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio and the like), halogen (e.g. fluorine, chlorine, bromine, iodine), alkoxy groups (EmOC is emer, C1-6alkoxy, such as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like), a nitro-group, alkoxy-carbonyl groups (for example, C1-6alkoxy-carbonyl, such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl and the like), alkylamino group (for example, mono - or di-C1-6alkylamino, such as methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n-pentylamine, n-hexylamino, dimethylamino, diethylamino, methylethylamine, di-(n-propyl)amino, di(n-butyl)amino and the like), alkoxyimino groups (for example, C1-6alkoxyimino, such as methoxyimino, amoxiillin, n-propoxyimino, tert-butoxysilane, n-hexylamino and the like) or hydroxyimino.

When the above-mentioned acyl group is an aryl-carbonyl group, aryloxy-carbonyl group, aralkyl-carbonyl group, aracelikarsaalyna group, 5 - or 6-membered heterocycle-carbonyl group or a 5 - or 6-membered heterocycle-acetyl group, it is optionally substituted by 1-5 (preferably 1-3) alkyl groups (for example, C1-6alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopen is l, neopentyl, n-hexyl, isohexyl and the like, C3-6cycloalkyl, such as cyclohexyl and the like), alkenylamine groups (for example, C2-6alkenyl, such as allyl, Isopropenyl, Isobutanol, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like), alkenylamine groups (for example, C2-6quinil, such as propargyl, 2-butynyl, 3-butynyl, 3-pentenyl, 3-hexenyl and the like), alkoxy groups (for example, C1-6alkoxy, such as methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy and the like), acyl groups (for example, C1-7alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like; C6-14aryl-carbonyl such as benzoyl, naphthaleneboronic and the like; C1-6alkoxy-carbonyl, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl and the like; C6-14aryloxy-carbonyl, such as phenoxycarbonyl and the like; C7-19aralkyl-carbonyl such as phenyl-C1-4alkyl-carbonyl (for example, benzylcarbamoyl, ventilkappen, phenylpropionyl and the like) and the like; C7-19Arakelov-carbonyl such as phenyl-C1-4alkyloxy-carbonyl (for example, benzyloxycarbonyl and that is such) and the like], nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (e.g. fluorine, chlorine, bromine, iodine) or alkylthio groups (C1-4alkylthio, such as methylthio, ethylthio, n-propylthio, isobutyric and the like).

As the “halogen atom” for R3or R4may be mentioned fluorine, chlorine, bromine and iodine.

As the “alkyl group” for R5can be specified, for example, C1-6alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) and the like.

As R1preferred is the “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle (for example, 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like), optionally substituted by 1-3 substituents selected from (i) halogen (e.g. fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) C1-6alkoxy (e.g. methoxy, e is hydroxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (vi) amino, optionally substituted C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), (vii) oxo, and (viii) C1-6alkoxy-carbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like).

As R1especially preferred is the “nitrogen-containing monocyclic heterocyclic group optionally condensed with a benzene ring or a heterocycle (for example, 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like), which optionally is substituted by 1-3 substituents selected from (i) halogen (e.g. fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) C1-6alkoxy (e.g. methoxy, this is C, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (vi) amino, optionally substituted C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), (vii) oxo.

As R1in particular, preferred is a 6-membered nitrogen-containing aromatic heterocyclic group (for example, perigrine group (for example, 2-, 3 - or 4-pyridyl and the like), pyrimidinyl group (for example, 2-, 4 - or 5-pyrimidinyl and the like), pyridazinyl group (for example, 3 - or 4-pyridazinyl and the like) and the like), optionally substituted by 1-3 substituents selected from (i) halogen (e.g. fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (n is an example, fluorine, chlorine, bromine, iodine), (vi) amino, optionally substituted C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), and particularly preferred is Peregrina group, optionally substituted by 1-3 substituents selected from (i) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (ii) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine).

As R2preferred are

[1] C6-14aryl group (e.g. phenyl group)optionally substituted by 1-5 (preferably 1-3) substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, this is C, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3-7cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like), (vii) C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and the like), (viii) C1-6alkyl group substituted by 1-3 hydroxy (e.g. hydroxymethyl, hydroxyethyl and the like), (ix) C1-6alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, pentylthio, hexylthio and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (x) C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl and the like),

[2] thienyl group, optionally substituted by 1-3 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, Butoh is si, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acetyl, or

[3] Peregrina group, optionally substituted by 1-4 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (in particular, C1-6) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acyl (e.g. acetyl), (vi) nitro and (vii) amino.

Of them, as R2preferred are

[1] C6-14aryl group (e.g. phenyl group)optionally substituted by 1-5 (preferably 1-3) substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) and the ohms of halogen (e.g., fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and (v) acetyl,

[2] thienyl group, optionally substituted by 1-3 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acetyl, or

[3] Peregrina group, optionally substituted by 1-4 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) lower (in particular, C1-6) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) Csub> 1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acyl (e.g. acetyl), (vi) nitro and (vii) amino.

In particular, preferred are

[1] a phenyl group optionally substituted by 1-5 (preferably 1-3) substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine),

[2] thienyl group, optionally substituted by 1-3 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), or

[3] Peregrina group, optionally substituted by 1-4 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine) and (ii) lowest (in particular, C1-6) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, Isobe is Il, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine).

From the above preferred variant implementation of R2includes [1] a phenyl group optionally substituted by 1-5 substituents selected from (i) halogen atom and (ii) C1-6the alkyl, optionally substituted by 1-5 halogen atoms, [2] pyridyloxy group, optionally substituted by 1-4 substituents selected from lower (C1-6) alkyl, halogen atom, alkoxy (C1-6alkoxy), cyano, acyl (e.g. acetyl), nitro and amino, and the like.

As R2preferred are, in particular, phenyl group, 2-Fortunella group, 2-methylphenylene group, 2-herperidin-3-ilen group, 3-herperidin-4-ilen group, 2-chloropyridin-3-ilen group, 6-chloropyridin-3-ilen group, 4-methylpyridin-3-ilen group, 2-methylpyridin-3-ilen group, 3-methylpyridin-2-ilen group, 2-triptorelin-3-ilen group and 6'-chloro-2,3'-bipyridine-5-ilen group.

Preferably, R3and R4represent each a hydrogen atom, or one of R3and R4represents a hydrogen atom and the other represents C1-6alkyl group (e.g. methyl, ethyl, n-propyl, isobutyl and the like), C1-6alkyl-CT is onilne group (for example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like), halogen atom (e.g. fluorine, chlorine, bromine, iodine), a cyano or a nitro-group. Connection, where both R3and R4represent hydrogen atoms is particularly preferred.

As R5, methyl or ethyl are preferred, and methyl is particularly preferred.

The above preferred embodiments of substituents for R1- R5can be optionally combined to implement the preferred alternative implementation of the compounds (I).

Of the compounds (I), preferred is a compound where

R1is a 5-6-membered aromatic nitrogen-containing monocyclic heterocyclic group (for example, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like) or imidazo[1,2-a]pyrimidinyl group, which optionally is substituted by 1-3 substituents selected from (i) halogen (e.g. fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) C1-6alkoxy (for example the EP, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (vi) amino, optionally substituted C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), (vii) C1-6alkoxy-carbonyl (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like);

R2represents [1] C6-14aryl group (e.g. phenyl group)optionally substituted by 1-5 (preferably 1-3) substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acetyl, (vi) C3-7cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, the CEC shall hexil, cycloheptyl and the like), (vii) C1-6alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl and the like), (viii) C1-6alkyl group substituted by 1-3 hydroxy (e.g. hydroxymethyl, hydroxyethyl and the like), (ix) C1-6alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, pentylthio, hexylthio and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (x) C1-6alkylsulfonyl (for example, methylsulfinyl, ethylsulfinyl and the like),

[2] thienyl group, optionally substituted by 1-3 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine), (ii) cyano, (iii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine) and (v) acetyl,

[3] pyridyloxy group, optionally substituted by 1-4 substituents selected from (i) halogen atom (for example, f the PR, chlorine, bromine, iodine), (ii) cyano, (iii) lower (in particular, C1-6) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (iv) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (v) acyl (e.g. acetyl), (vi) nitro and (vii) amino, or

[4] piperidinol group optionally substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

R3and R4represent each a hydrogen atom, or one of R3and R4represents a hydrogen atom and the other represents C1-6alkyl group (e.g. methyl, ethyl, n-propyl, isobutyl and the like), C1-6alkyl-carbonyl group (e.g. acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl and the like), halogen atom (e.g. fluorine, chlorine, bromine, iodine), a cyano or a nitro-group;

R5represents methyl or ethyl,

especially preferred is the compound where, for example,

R1represents pyridyloxy group, optional the tion substituted by 1-3 substituents, selected from (i) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), (ii) C1-6alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine),

R2represents [1] phenyl group, optionally substituted by 1-5 (preferably 1-3) substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine) and (ii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine),

[2] thienyl group, optionally substituted by 1-3 substituents selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine) and (ii) C1-6the alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), or

[3] pyridyloxy group, neobyazatel is substituted by 1-4 substituents, selected from (i) halogen atom (e.g. fluorine, chlorine, bromine, iodine) and (ii) lowest (in particular, C1-6) alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like), optionally substituted by 1-5 (preferably 1-3) halogen atoms (e.g. fluorine, chlorine, bromine, iodine),

R3and R4represent each a hydrogen atom, R5represents methyl.

As the compound (I) are particularly preferred N-methyl-1-[5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine, 1-[5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, N-methyl-1-[4-methyl-1-(pyridine-3-ylsulphonyl)-5-phenyl-1H-pyrrol-3-yl]methanamine, N-methyl-1-[1-(pyridine-3-ylsulphonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine, N-methyl-1-[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine, 1-[5-(2,4-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, 1-{5-(2-forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine, 1-[4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine, N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine, 1-[5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

As the salt of compound (I) can be specified metal salt, ammonium salt, salt with organic base is there, salts of inorganic bases, salts with organic acids, salts of basic or acidic amino acid and the like. Preferred examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; salts of alkaline earth metals such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. Preferred examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenziletilendiaminom and the like. Preferred examples of salts of inorganic acid include a salt with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of the salt with organic acid include a salt of formic acid, acetic acid, triperoxonane acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid and the like. Preferred examples of the salt of the basic amino acid include a salt with arginine, lysine, ornithine and the like. Preferred n is emery salt of acidic amino acid include a salt with aspartic acid, glutamic acid and the like.

Of these pharmaceutically acceptable salts are preferred. For example, when the compound contains a functional group of the acid, may be mentioned inorganic salts such as alkali metal salt (e.g. sodium salt, potassium salt and the like), alkali earth metal salt (e.g. calcium salt, magnesium salt, barium salt and the like) and the like, ammonium salt and the like; and when the compound contains a functional group of the base, can be specified, for example, salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or salts of organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonate acid, p-toluensulfonate acid and the like.

The compound (I) can be obtained, for example, by methods described in the application of Japan No. 2005-044740,Eur.J. Org. Chem.p. 2283 (2001),J. Med. Chem.vol. 43, p. 1886 (2000),J. Pharm. Pharmacol.vol. 46, p. 740 (1994), WO92/04025,J. Heterocycl. Chem.vol. 25, p. 635 (1988),J. Med. Chem.vol. 14, p. 328 (1971),J. Med. Chem.vol. 35, p. 4195 (1992) orTetrahedron Lett.vol. 26, p. 4047 (1985), or a similar method.

The present invention describes what are the methods of obtaining the compound (I).

Compounds (II)-(XXIV) in the formula may form a salt and can be specified in the form of such salts, for example, similar to the salts of compound (I).

Although the compounds obtained in the respective stages can be used in the next reaction as the reaction mixture or crude product, they can also be easily isolated and purified from the reaction mixture by known methods of separation and purification such as recrystallization, distillation, chromatography and the like.

The compound (II), where R2, R3and R4are as defined above, and R6represents a C1-4alkyl group such as methyl, ethyl, propyl, isopropyl, butyl and the like, can be obtained by a method known per se, such as the method described inChem. Pharm. Bull.vol. 49, p. 1406 (2001),Tetrahedron Lettersvol. 35, p. 5989 (1994), and the like, or a similar method.

The compound (IV) can be obtained by interaction of the compound (II) with the compound represented by the formula (IIIa):

(IIIa)

where R11is the same as defined for R1, (each symbol in the formula is the same as defined above) or a protective group described inProtective Groups in Organic Synthesis, 3rdEd. Theodora W. Greene, Peter G. M. Wuts, pp. 615-617, Wiley-Interscience (1999) (for example the EP, phenyl, 4-were and the like).

This interaction is successfully performed using a reaction-inert solvent. Although within the reaction requirements for the solvent are not specifically stated, are the preferred hydrocarbons, such as benzene, toluene and the like, and ethers such as tetrahydrofuran and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, or a mixture of these solvents, and the like.

Use Foundation now for the reaction. As the base can be specified, for example, inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide and the like, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, and the like, of base metal, such as ataxic potassium tert-piperonyl potassium, sodium methoxide, ethoxide sodium and the like, aromatic amines such as pyridine, lutidine and the like, tertiary amines such as triethylamine, Tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like. The amount of base is from about 1 to 10 mol, preferably from about 1 to about 5 mol, per 1 mol of compound (II).

Although the reaction time varies depending on the reagents and solvent used, it is usually from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 8 hours.

The reaction temperature is usually from about 0 to about 100°C, preferably from about 10 to about 50°C.

The compound (V) (each symbol in the formula is the same as defined above) can be obtained by a method known per se, for example, by the methods described inTetrahedron Lettersvol. 13, p. 5337 (1972),Heterocyclesvol. 7, p. 77 (1977),Chem. Pharm. Bull.vol. 27, p. 2857 (1979),J. Org. Chem.vol. 62, p. 2649 (1997), and so forth, or a similar method.

The compound (VI) (each symbol in the formula is the same as defined above) can be obtained by the interaction of the compound (V) with N-bromosuccinimide (NBS).

N-Bromosuccinimide (NBS) is preferably used in an amount of about one equivalent relative to the compound (V), the interaction is preferably carried out in an atmosphere of inert gas, such as nitrogen, argon and the like.

This interaction is successfully carried out using the reaction-nerty solvent. Although within the reaction requirements for the solvent are not specifically exempted, are preferred solvents, such as ethers (e.g. tetrahydrofuran, diethyl ether, and the like), amides (e.g. N,N-dimethylformamide, N,N-dimethylacetamide and the like) and the like, the solvent consisting of a mixture of these solvents, and the like.

Although the reaction time varies depending on the reagents and solvent, it is usually from about 30 minutes to about 24 hours, preferably about 5-12 hours.

The reaction temperature is usually from about -78 to about 25°C., preferably about -78 to about 0°C.

Adding the base, sometimes, is effective for communication. Although within the reaction substrate requirements are not specified, there may be mentioned organic base, such as pyridine, picoline, lutidine and the like. The number of used organic osnovaniya is from about 0.001 to about 10 equivalents, preferably from about 0.001 to about 0.1 equivalent, per 1 mol of compound (V).

The compound (VII) (each symbol in the formula is the same as defined above) can be obtained from compound (VI) in a manner analogous to the method of producing compound (IV) from compound (II).

The compound (IV (each symbol in the formula is the same as defined above) can also be obtained by the interaction of the compound (VII) with the compound represented by the formula (VIIIa):

(VIIIa)

or the formula (VIIIb):

(VIIIb)

where R2is the same as defined above, the method described inSynthetic Communicationsvol. 11, p. 513 (1981), or a similar method.

The compound (IX) (each symbol in the formula is the same as defined above) can be obtained by reduction of the compound (IV) with a regenerating agent, such as alumalite lithium, Diisobutyl aluminum hydride, sodium borohydride, calcium borohydride, and the like. As the reducing agent, Diisobutyl aluminum hydride is particularly preferred. The amount of the reducing agent is from about 0.75 to about 10 equivalents, preferably from about 1 to about 5 equivalents, per 1 mol of compound (IV).

This interaction is successfully performed using a reaction-inert solvent. Although within the reaction requirements for the solvent are not specifically exempted, solvents, such as hydrocarbons (e.g. benzene, toluene and the like) and ethers (e.g. tetrahydrofuran, diethyl ether, and the like) and the like, the solvent consisting of a mixture of these rest is ritala, and the like, are preferred.

Although the reaction time varies depending on the reagents and solvent, it is usually from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 8 hours.

The reaction temperature is usually from about -78 to about 100°C, preferably from about -78 to about 25°C.

The compound (X) (each symbol in the formula is the same as defined above) can be sitesyoung interaction of the compound (IX) with an oxidising agent, such as a complex of chromic acid-pyridine, chlorochromate pyridinium, manganese dioxide, a complex of a sulfur trioxide-pyridine or perruthenate Tetra-n-Propylamine and the like. As oxidant is preferred manganese dioxide, sulfur trioxide-pyridine complex or perruthenate Tetra-n-propylammonium. The oxidation reaction can be performed, for example, by the method described inSynthesisp. 639 (1994).

The compound (Ia) (each symbol in the formula is the same as defined above) can be obtained by subjecting the compound (X) and the compound represented by formula (XI):

where R5is the same as defined above, the reaction of reductive amination methods, described inShin Jikken Called KozaVol. 14-III, pp. 1380-1385 (Maruzen Press).

In addition, the compound (Ia) can also b is to be obtained in the following way.

The compound (XII) (each symbol in the formula is the same as defined above) can be obtained from compound (VII) in a manner analogous to the method of producing compound (IX) from compound (IV).

The compound (XIII) (each symbol in the formula is the same as defined above) can be obtained from compound (XII) in a manner analogous to the method of obtaining the compound (X) from the compound (IX).

The compound (XIV) (each symbol in the formula is the same as defined above) can be obtained from compound (XIII) in a manner analogous to the method of producing compound (Ia) from compound (X).

The compound (XV) (each symbol in the formula is the same as defined above and R7represents an amino-protective group) can be obtained by introducing a protective group into the amino group of compound (XIV). As the amino-protective group can be a group is specified tert-BUTYLCARBAMATE (BOC group), a group of benzylcarbamoyl (Cbz group), and the like. The reaction of introducing the protective group can be performed by a method known per se, for example, by the method described inProtective Groups in Organic Synthesis, 3rdEd., Theodora W. Greene, Peter G. M. Wuts, pp. 494-653, Wiley-Interscience (1999) and the like.

The compound (XVI) (each symbol in the formula is the same as defined above) can be obtained from compounds which s (XV), similar to the production method of compound (IV) from compound (VII).

The compound (Ia) (each symbol in the formula is the same as defined above) can be obtained by removing the amino-protective group from the compound (XVI) in a manner known per se, for example, by the method described inProtective Groups in Organic Synthesis, 3rdEd., Theodora W. Greene, Peter G. M. Wuts, pp. 494-653, Wiley-Interscience (1999) and so on.

In addition, compound (XVI) and (Ia) can also be obtained in the following ways :

The compound (XVII) (each symbol in the formula is the same as defined above) can be obtained from compound (II) in a manner analogous to the method of producing compound (IX)from compound (IV).

The compound (XVIII) (each symbol in the formula is the same as defined above) can be obtained from compound (XVII) in a manner analogous to the method of obtaining the compound (X)from the compound (IX).

The compound (XIX) (each symbol in the formula is the same as defined above) can be obtained from compound (XVIII) in a manner analogous to the method of producing compound (Ia)from compound (X).

The compound (XX) (each symbol in the formula is the same as defined above) can be obtained from compound (XIX) in a manner analogous to the method of obtaining the compound (XV)from compound (XIV).

The compound (XVI) (each about the value in the formula is the same as defined above) can be obtained from compound (XX) in a manner analogous to the method of producing compound (IV)from compound (II). In addition, the compound (Ia) can be obtained in a manner analogous to the above.

In addition, the compounds (XIII), (X) and (Ia) can also be obtained in the following ways :

The compound (XXI) (each symbol in the formula is the same as defined above) can be obtained from compound (V) in a manner analogous to the method of producing compound (IV)from compound (II).

The compound (XXII) (each symbol in the formula is the same as defined above) can be obtained from compound (XXI) in a manner analogous to the method of producing compound (IX)from compound (IV).

The compound (XXIII) (each symbol in the formula is the same as defined above) can be obtained from compound (XXII) in a manner analogous to the method of obtaining the compound (X)from the compound (IX).

The compound (XIII) (each symbol in the formula is the same as defined above) can be obtained from compound (XXIII) in a manner analogous to the method of producing compound (VI)from compound (V).

The compound (X) (each symbol in the formula is the same as defined above) can be obtained from compound (XIII) in a manner analogous to the method of producing compound (IV), from the who surveillance (VII), or from compound (XVIII) in a manner analogous to the method of producing compound (IV) from compound (II). In addition, the compound (Ia) can be obtained in a manner analogous to the above.

Moreover, the compound (XIII) and compound (XVIII) can also be synthesized by the following method, the compound (Ia) can be obtained in a manner analogous to the above.

The compound (XXIV) (each symbol in the formula is the same as defined above) can be obtained by a method known per se, for example by the method described inJ. Org. Chem.vol. 55, p. 6317 (1990), and so forth, or a similar method.

The compound (XIII) (each symbol in the formula is the same as defined above) can be obtained from compound (XXIV) in a manner analogous to the method of producing compound (IV)from compound (II).

The compound (XVIII) (each symbol in the formula is the same as defined above) can be obtained from compound (XXIV) in a manner analogous to the method of producing compound (IV)from compound (VII).

When R11represents a group other than the group represented by R1in each connection, the connection can be converted to compound (I) after removal of the protective group by a method known per se, for example by the method described inProtective Groups in Oranic Synthesis , 3rdEd., Theodora W. Greene, Peter G. M. Wuts, pp. 615-617, Wiley-Interscience (1999) and so on, using the formula (III)

(III)

where each symbol in the formula is the same as defined above, in a manner analogous to the method of producing compound (IV) from compound (II).

In each of the aforementioned reactions, when the original connection has amino group, carboxyl group or a hydroxy-group as a substituent, a protective group commonly used in the chemistry of peptides, and the like, may be introduced into these groups. In this case, the desired compound can be obtained by removing the protective group as necessary after the reaction. Introduction and removal of these protective groups can be performed by a method known per se, for example, by the method described inProtective Groups in Organic Synthesis, 3rdEd., Theodora W. Greene, Peter G. M. Wuts, Wiley-Interscience (1999) and so on.

The compound (I) can be isolated and purified well-known methods, such as phase transfer, concentration, solvent extraction, separation into fractions, transition liquids, crystallization, recrystallization, chromatography and so on.

When compound (I) are obtained in the form of a free compound, it can be converted into a desired salt by a method known per se or a similar method; conversely, when soy is inania (I) are obtained in the form of a salt, it can be converted into a free form or another desired salt by a method known per se or a similar method.

The compound (I) can be used as prodrugs. The prodrug of compound (I) is a compound which is converted to compound (I) under physiological conditions in the body by interacting with the enzyme, gastric acid or so on, that is, a compound which is converted to compound (I) by enzymatic oxidation, recovery, hydrolysis and the like; a compound which is converted to compound (I) by hydrolysis with gastric acid, and the like.

The prodrug of compound (I) includes the compound, where the amino group of compound (I) is modified with acyl, alkyl or phosphoryla (for example, the connection, where the amino group of compound (I) is modified with the help of eicosanol, Alanya, intramyocardial, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidinyl, pivaloyloxymethyl or tert-butyl, and the like); a compound where the hydroxy-group of the compound (I) is modified with acyl, alkyl, phosphoric acid or boric acid (for example, connection where the hydroxy-group of the compound (I) is modified with acetyl, Palmitoyl, propanol, pivaloyl, succinyl, fumaryl, al the Nile or dimethylaminomethylene, and the like); a compound, where the carboxyl group of compound (I) is modified to ester or amide (e.g., compound, where the carboxyl group of compound (I) is modified in a complex ethyl ester, complex phenyl ether complex carboxymethylate ether complex dimethylaminomethylene ether complex pivaloyloxymethyl ether complex ethoxycarbonylmethylene ether complex Caligraphy ether complex (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl ester, complex cyclohexyloxycarbonyloxy ether or methylamide, and the like); and the like. These prodrugs can be obtained from compound (I) in a manner known in itself.

In addition, the prodrug of compound (I) may be a compound which is converted to compound (I) under physiological conditions as described inPharmaceutical Research and DevelopmentVol. 7 (Molecule Design), pp. 163-198 (1990), published by Hirokawa Publishing Co.

When the compound (I) contains an optical isomer, a stereoisomer, regioisomer or rotamer, any isomers and their mixtures are also covered by the definition of compound (I). For example, when compound (I) has an optical isomer, an optical isomer separated from a racemate, is also covered by the compound (I). These isomers can be obtained as single products in accordance with the methods of synthesis and separation, are known with the company code (concentration, by solvent extraction, column chromatography, recrystallization and the like).

The compound (I) can be crystalline, and as a separate crystalline compound, and a mixture of crystalline compounds covered by the compound (I). Crystalline materials can be obtained by crystallization in accordance with the methods of crystallization, known by themselves.

The compound (I) can be a MES (e.g., hydrate etc.) or may not be a MES, both covered by the compound (I).

A compound labeled with an isotope (for example,3H,14C,35S125I and the like), is also covered by the compound (I).

The compound (I) and its prodrugs of the present invention (hereinafter sometimes abbreviated specified as the connection according to the present invention have inhibitory activity against proton pump and effectively inhibit the secretion of gastric acid. In addition, because they show low toxicity (such as acute toxicity, chronic toxicos, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenesis, and the like) and high solubility in water and possess excellent stability, in vivo kinetics (absorption, distribution, metabolism, clean the m excretion and the like) and high efficiency, their use as pharmaceuticals.

The compound of the present invention is used for the treatment or prophylaxis of peptic ulcer (e.g. gastric ulcer, stomach ulcer due to postoperative stress, duodenal ulcer, anastomoticheskih ulcer, ulcer caused by a nonsteroidal anti-inflammatory drugs, and the like); syndrome Zollinger-Ellison; gastritis; erosive and ulcerative esophagitis; reflux esophagitis such as erosive reflux esophagitis and the like; symptomatic gastroesophageal reflux disease (symptomatic GERD), for example neurosignal reflux disease or gastroesophageal reflux disease without esophagitis and the like; functional dyspepsia; gastric cancer (including cancer stomach associated with activated secretion of interleukin-1β due to gene polymorphism of interleukin-1); lymphomas of the mucosa of the stomach; the acidity of the stomach; hemorrhage of the upper section of the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress (for example, stress caused by major surgery requiring postoperative intensive therapy, and cerebral-vascular disorders, traumatic brain injury, multiple organ failure and extensive burn, each of which needs intensive therapy) and the like; disorders of the respiratory tract, asthma and the like, before the introduction of the usual means, the eradication ofHelicobacter pylorior aid in the eradication and the like, in mammals (e.g. human, monkey, sheep, cattle, horses, dogs, cats, rabbits, rats, mice and so on).

As used herein, the above-mentioned reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD) sometimes referred to simply GERD.

The content of compounds of the present invention in the pharmaceutical composition of the present invention is about 0.01-100% by weight relative to the entire composition. Although it varies depending on the purpose of administration, method of administration, target disease and the fact podobnie, its dose is about 0.5 to 1,500 mg/day, preferably about 5-150 mg/day based on based on the active ingredient, for example, when the compound is administered orally as antiulcer means an adult (60 kg). The compound of the present invention may be administered once a day or 2 or 3 times a day in divided portions.

Connection n the present invention shows low toxicity and can be appropriately administered orally or parenterally (for example, local, rectal, intravenous, and so on) alone or in the form of a preparation containing a pharmaceutical composition comprising a pharmacologically acceptable carrier, in a mixed way, known per se, such as tablets (including covered sugar tablets and film-coated tablets), powders, granules, capsules (including soft capsules), oral disintegrating tablet, orally disintegrating film, liquid, injections, suppositories, drugs with a slow release of the active component, plasters and so on. In particular, the compound of the present invention is preferably introduced in the form of a preparation for oral administration in the form of tablets, granules, capsules and the like.

Used to obtain pharmaceutical compositions pharmacologically acceptable carrier according to the present invention include various organic or inorganic substances carriers commonly used as pharmaceutical ingredients, including excipients, lubricants, binders, dezintegriruetsja substances, water-soluble polymers and basic inorganic salts for solid preparations; and solvents, tools, contributing to the dissolution suspendresume substances, isotonic substances, buffer and softeners for liquid Preparata and the like. Other commonly used pharmaceutical additives such as preservatives, antioxidants, colorants, sweeteners, acidifying substances, bubbling fluidised bed means and flavors, can also be used as needed.

Such fillers include, for example, lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light silicic anhydride, titanium oxide and the like.

Such lubricants include, for example, magnesium stearate, sucrose esters of fatty acids, polyethylene glycol, talc, stearic acid and the like.

Such binders include, for example, hydroxypropylcellulose, hypromellose, crystalline cellulose, starch, polyvinylpyrrolidone, gum Arabic powder, gelatin, pullulan, nitrosamino hydroxypropylcellulose and the like.

Such “dezintegriruetsja substances” include (1) crospovidon, (2) what is called superdisintegrants substances, for example sodium, croscarmellose (FMC-Asahi Chemical) and calcium, carmellose (Gotoku Yakuhin), and the like, (3) sodium carboxymethyl starch (e.g., production of Matsutani Chemical), (4) nizkozameshhennoj hydroxypropyl cellulose (e.g., manufacture of Shin-Etsu Chemical), (5) corn starch and so on. Specified “crospovidone” can transform the conduct any cross-linked polymer, having the chemical name 1-ethynyl-2-pyrrolidinone a homopolymer, including polyvinylpyrrolidone (PVPP) and 1-vinyl-2-pyrrolidinone a homopolymer, and presents Colidon CL (manufactured by BASF), Polyplasdon XL (produced by ISP), Polyplasdon XL-10 (produced by ISP), Polyplasdon INF-10 (produced by ISP), and the like.

Such water-soluble polymers include, for example, ethnosectarian water-soluble polymers [e.g., derivatives of cellulose, such as hydroxypropylcellulose (hereinafter also referred to as HPC), polyvinylpyrrolidone, and so forth], ethnonational water-soluble polymers [e.g., cellulose derivatives, such as hypromellose (hereinafter also referred to as HPMC), and the like, methylcellulose, sodium carboxymethylcellulose and the like, sodium polyacrylate, polyvinyl alcohol, sodium alginate, guar gum and the like] and the like.

Such basic inorganic salts include, for example, basic inorganic salts of sodium, potassium, magnesium and/or calcium. Preferred are the basic inorganic salt of magnesium and/or calcium. More preferred are the basic inorganic salt of magnesium. Such basic inorganic salts of sodium include, for example, sodium carbonate, sodium bicarbonate, disodium hydrogen phosphate and the like. Such core the main inorganic salts include potassium, for example, potassium carbonate, potassium bicarbonate and the like. Such basic inorganic salts of magnesium include, for example, heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide, magnesium alumosilicate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6Al2(OH)16·CO3·4H2O] and alumohydrogen magnesium. Preferred are heavy magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide and the like. Such basic inorganic salts of calcium include, for example, precipitated calcium carbonate, calcium hydroxide and the like

Such solvents include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

Such a means of facilitating dissolution include, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Such “suspendresume substances” include, for example, surfactants such as steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, benzalconi chloride, benzethonium chloride, glyceryl the monostearate and the like; hydrophilic polymers such as polyvinyl is a new spirit, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.

Such “isotonic means” include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

Such “buffer funds” include, for example, buffer solutions of phosphates, acetates, carbonates, citrates and so forth, and the like.

Such softeners include, for example, benzyl alcohol and the like.

Such preservatives include, for example, esters of p-oksibenzoynoy acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid and the like.

Such antioxidants include, for example, sulfites, ascorbic acid, α-tocopherol, and the like.

Such dyes include, for example, food colors such as yellow food dye No. 5, red food dye No. 2, blue food dye No. 2 and the like; food colorful lacquer, red iron oxide and the like.

Such sweeteners include, for example, saccharin sodium, zikali the glycyrrhizinate, aspartame, stevia, thaumatin and the like.

Such “acidifying substances” include, for example, citric acid (citric anhydride), tartaric acid, abloc the second acid and the like.

Such “bubbling fluidised bed substances” include, for example, sodium bicarbonate, and the like.

These “flavors” can be synthetic or naturally occurring substances and include, for example, lemon, lime, orange, menthol, strawberry and the like.

The compound of the present invention can be obtained in the form of a preparation for oral administration are well known methods, such as extrusion-molding with a carrier, such as a filler, dezintegriruetsja substance, binder, grease or the like, and then applying a covering layer on the drug, as necessary, a well-known way to correct taste, dissolve in the intestine or slow release of the active component. For enteric-soluble drug intermediate layer can be obtained well-known way between the enteric-soluble coating layer containing the drug with the aim of separating the two layers.

To obtain the compounds of the present invention in the form of orally disintegrating tablets of existing methods include, for example, a method in which a core containing crystalline cellulose and lactose, cover with a compound of the present invention and, if necessary, a basic inorganic salt and then for obtaining compo is icii additionally coated with a layer, containing water-soluble polymer, which cover the enteric-soluble layer containing polyethylene glycol, additionally coated enteric-soluble layer containing triethylcitrate, then cover enteric-soluble layer containing polyethylene glycol, and, finally, cover with mannitol to obtain pellets, which are mixed with additives and mold.

The above “enteric-soluble layer includes, for example, a layer consisting of a mixture of one or more sets of intestinal water-soluble polymeric substances, such as cellulose acetate phthalate (CAP), hypromellose phthalate, hydroxymethylcellulose acetate succinate, methacrylic acid (e.g., Eudragit L30D-55 (trade name; manufacture of Rohm), Colicoat MAE30DP (trade name; production BASF), Polyquid PA30 (trade name; production San-yo Chemical) and the like), karboksimetiltselljuloza, shellac and the like; substances with a slow release such as copolymers of methacrylic acid (e.g., Eudragit NE30D (trade name), Eudragit RL30D (trade name), Eudragit RS30D (trade name) and the like) and the like; water soluble polymers; plasticizers, such as triethylcitrate, polyethylene glycol, acetylated monoglycerides, triacetin, castor oil and the like; and the like.

asukadera “additive” includes, for example, water-soluble sugar alcohols (e.g. sorbitol, mannitol, ▫ maltitol, recovered starch sugars, xylitol, restored palatinose, aritra and the like), crystalline cellulose (e.g., Ceolas KG 801, Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302, Avicel RC-591 (crystalline cellulose, carmellose sodium) and the like), nizkozameshhennoj hydroxypropylcellulose (e.g., LH-22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical), mixtures thereof, and so the like) and the like. In addition, also use binding substances, acidifying substances, bubbling fluidised bed substances, sweeteners, flavoring agents, lubricants, colorants, stabilizers, fillers, dezintegriruetsja substances and the like.

The compound of the present invention can be used in combination with 1-3 other active ingredients.

Such “other active ingredients” include, for example, anti-Helicobacter pylorithe active substance, imidazole compounds, salts of bismuth compounds chinolone and so on.

Such “anti-Helicobacter pyloriactive substances” include, for example, the antibiotic penicillin (eg, amoxicillin, benzylpenicillin, piperacillin, mecillinam, ampicillin, temocillin, bacampicillin, aspoxicillin, sultamicillin, inanition and the like), antibiotic caremy (e.g., cefixime, cefaclor, and that is such), antibiotic macrolides (eg, erythromycin, clarithromycin, roxithromycin, rokitamycin, flurithromycin, telithromycin and the like), antibiotic tetracyclines (eg, tetracycline, minocycline, streptomycin and the like)antibiotic aminoglycosides (e.g. gentamicin, amikacin, and the like), imipenem, and so on. Of these substances are preferred antibiotic penicillin, antibiotic macrolides and the like.

These imidazole compounds include, for example, metronidazole, miconazole, and the like.

Such “salt of bismuth include, for example, bismuth acetate, bismuth citrate, bismuth subsalicylate, and the like.

Such “ quinolone compounds include, for example, ofloxacin, ciplactin and the like.

For the eradication ofHelicobacter pyloripreferably used is a compound (I) or its salt of the present invention with the antibiotic penicillin (eg, amoxicillin, and the like) and the antibiotic erythromycin (e.g., clarithromycin, and the like).

With the aim of eradication ofHelicobacter pyloriwhen the compound of the present invention has anti-H.pyloriaction (bacteriostatic action or the action of eradication) in itself, it can enhance the antibacterial action of other antibiotics on the basis of the research Institute pH controlling steps in the stomach and the like, and also provides an auxiliary action, such as the effect of eradication on the basis of the steps used in combination with antibiotics.

Such “other active ingredients” and the compound (I) or its salt of the present invention can be mixed, obtained in the form of pharmaceutical compositions for a single admission [for example, tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, drugs with a slow release, and the like] a well-known method and used in combination, and can also be obtained as separate preparations and administered to the same patient simultaneously or separately over a period of time.

In addition, the compound of the present invention can be used in combination with the amplifier peristalsis of the stomach, the drug acting on the lower sphincter of the esophagus (e.g., suppressor, temporarily relaxing the sphincter of the lower esophagus, and the like), the discoverer of the channel ClC-2 (amplifier secretion of intestinal juice), a receptor antagonist of histamine H2, antacid, a sedative agent, a tool for stimulating digestion in the stomach, or nonsteroidal anti-inflammatory drug (NSAID).

As an “amplifier peristalsis of the stomach can be specified, for example, domperidone, metoclopramide, mozafari is, itopride, Tegaserod and the like.

As a drug that activates the lower sphincter of the esophagus can be specified, for example, agonists of the GABA receptor-B, such as baclofen, its optically active form, and the like, and so on.

As the discoverer of the channel ClC-2 (amplifier secretion of intestinal juice)can be specified lubiprostone and the like.

As a receptor antagonist of histamine H2” can be specified cimetidine, ranitidine, famotidine, roksatidina, nizatidine, lafutidine and the like.

As antacid” can be specified sodium bicarbonate, aluminum hydroxide, and the like.

As “sedatives” can be specified diazepam, chlordiazepoxide and the like.

As a stomachic, stimulating digestion can be specified hertziana, svertsiya Japanese, diastasis, and the like.

As a non-steroidal anti-inflammatory drug” can be specified, for example, aspirin, indomethacin, ibuprofen, mefenamovaya acid, diclofenac, etodolac, piroxicam, celecoxib, and the like.

The amplifier peristalsis of the stomach, the drug acting on the lower sphincter of the esophagus, the discoverer of the channel ClC-2 (amplifier secretion of intestinal juice), the antagonist of the histamine H2 receptor, antacid, sedative, medium, is, stimulating digestion in the stomach, or nonsteroidal anti-inflammatory drug and the compound (I) or its salt of the present invention can be mixed, obtained in the form of pharmaceutical compositions for a single admission [for example, tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, drugs with a slow release, and the like] manner known in itself to be used together, or can also be obtained as separate preparations and administered to the same patient simultaneously or separately over a period of time.

The compound of the present invention can be used in combination with the following drugs:

(i) a proton pump inhibitor such as omeprazole, esomeprazole, pantoprazole, rabeprazole, tenatoprazole, ilaprazole and lanzoprazol;

(ii) antacid mixtures for oral administration, such as Maalox®, Aludrox®, Gaviscon®;

(iii) protective means of the mucous membranes, such as polaprezinc, ecabet sodium, ribamidil, teprenone, cetraxate, sukralfat, chlorophyllin-copper and plaunotol;

(iv) stomachic, for example gastric vaccine triglyme and Z-360;

(v) antagonists of 5-HT3for example dolasetron, palonosetron, alosetron, azasetron, ramosetron, mitrazapine, granisetron, tropisetron, E-3620, ondansetron and Hieron;

(vi) agonists 5-HT4for example Tegaserod, mosapride, cinitapride and oxitriptan;

(vii) laxatives, such as Trifyba®, Fybogel®, Konsyl®, Isogel®, Regulan®, Celevac® and Normacol®;

(viii) agonists GABABfor example baclofen and AZD-3355;

(ix) antagonists GABABsuch as GAS-360 and SGS-742;

(x) blockers, calcium channel, for example aranidipine, lacidipine, felodipin, azelnidipine, Clinician, lomerizine, diltiazem, gallopamil, efonidipine, nisoldipine, amlodipine, lercanidipine, bevantolol, nicardipine, isradipine, benidipine, verapamil, nitrendipin, barnidipine, propafenone, manidipine, bepridil, nifedipine, nilvadipine, nimodipine and fasudil;

(xi) dopamine antagonists such as metoclopramide, domperidone and levosulpiride;

(xii) tachykinin (NK) antagonists, particularly NK-3, NK-2 and NK-1 antagonists, such as nepadutant, saredutant, talnetant, (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-were)-7H-[1,4]thiazocine[2,1-g][1,7]naftalin-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-forfinal)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazole-3-one (MK-869), lapitan, dapitan and 3-[[2-methoxy-5-(triptoreline)phenyl]methylamino]-2-phenyl-piperidine (2S,3S);

(xiii) inhibitors of nitric oxide synthase, such as GW-274150, tilarginine, P54, guanidinoacetate and nitroprussiate;

(xiv) antagonists vanilloideae receptor 1, such as AMG-517 W-705498;

(xv) ghrelin agonists, for example capromorelin and TZP-101;

(xvi) stimulants release AchE, for example, Z-338 and KW-5092.

These drugs (i)-(xvi) and compound (I) or its salt of the present invention can be mixed, obtained in the form of pharmaceutical compositions for a single admission [for example, tablets, powders, granules, capsules (including soft capsules), liquids, injections, suppositories, drugs with a slow release, and the like] manner known in itself to be used together, or can also be obtained as separate preparations and administered to the same patient simultaneously or separately over a period of time.

Examples

Further, the present invention is described in more detail with reference examples, examples and experimental examples, which are not restrictive.

In the following reference examples and examples, the term “room temperature” generally refers to a temperature equal to from about 10 to about 35°C, but it is not very specifically limited. The ratio of mixtures of liquids shows volumetric ratio. If not stated otherwise, “%” means mass %. The output is presented in mol./mol.%. Column chromatography with silica gel was performed using silica gel 60 (0,063-0,200 mm) production of MERCK or Fuji Silysia Chemical Ltd. Chromatorex (name ol the product) NH (represented as the main column chromatography with silica gel). The melting point was measured using the instrument Yanagimoto, recording the measurement of the melting point or the device Buechi, recording measurements of the melting point B-545), and it is presented without modification. For1H-NMR spectrum as an internal standard tetramethylsilane was used for the measurements used a Varian Gemini-200 (200 MHz)spectrometer Mercury-300 (300 MHz), Bruker AVANCE AV300 (300 MHz) and JNM-AL400 (400 MHz) apparatus based on nuclear magnetic resonance JEOL DATUM (JEOL DATUM LTD.). To illustrate the measurement results used the following abbreviations:

s: singlet, d: doublet, DD: double doublet, dt: double triplet, t: triplet, square: Quartet, m: multiplet, usher.: broadened, users: broadened singlet, J: binding constant, Hz: Hertz.

Reference example 1

2-bromo-1-(2-forfinal)propane-1-he

To a solution of 2'-forpromotion (25,0 g) in acetic acid (250 ml) was slowly added bromine (8,4 ml). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. To the residue was added water (200 ml) and the mixture was extracted with diisopropyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain specified in the connection header in the form of altago oil (yield to 36.8 g, 97%).

1H-NMR (CDCl3) δ: 1,89 is 1.91 (3H, m), 5,27-of 5.34 (1H, m), 7,12-7,19 (1H, m), 7.24 to 7,30 (1H, m), 7,52-to 7.59 (1H, m), 7,88-to 7.93 (1H, m).

Reference example 2

ethyl 2-cyano-4-oxo-4-phenylbutanoate

To ethylcyanoacrylate (37 ml) was added potassium carbonate (13,82 g) and the mixture was stirred at 40-45°C for 45 minutes. Dropwise within 30 minutes was added a solution (100 ml) pencilvania (10.0 g) in acetone. After completion of adding dropwise, the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Excessive ethylcyanoacrylate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=8:1→1:1) to obtain the specified title compound as a pale yellow oil (yield 10,41 g, 90%).

1H-NMR (CDCl3) δ: of 1.35 (3H, t, J=7.2 Hz), 3,55 (1H, DD, J=16,0, 5.6 Hz), 3,80 (1H, DD, J=16,0, 7,0 Hz)to 4.16 (1H, DD, J=7,0, 5.6 Hz), or 4.31 (2H, square, J=7,2 Hz), 7,40-of 7.70 (3H, m), of 7.90-of 8.00 (2H, m).

Reference example 3

methyl 2-cyano-4-(2-forfinal)-3-methyl-4-oxobutanoate

To a solution of medicinehat.ca (15,5 ml) and diisopropyl the ethylamine (64 ml) in tetrahydrofuran (110 ml) was added a solution of 2-bromo-1-(2-forfinal)propane-1-she (to 36.8 g) in tetrahydrofuran (160 ml) and the mixture was stirred at 70°C for 20 hours. The reaction mixture was left to cool to room temperature, insoluble matter was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=5:1) to obtain the specified title compound as a brown oil (yield to 31.9 g, 80%).

1H-NMR (CDCl3) δ: 1,42 of 1.46 (3H, m), 3,82-of 3.85 (4H, m), 3,99-4,17 (1H, m), 7,14-7,22 (1H, m), 7,25-7,31 (1H, m), 7,55-7,63 (1H, m), a 7.85 to $ 7.91 (1H, m).

Reference example 4

ethyl 2-cyano-4-(2-forfinal)-4-oxobutanoate

To a solution of 2'-fortetienne (28.6 g) in ethyl acetate (400 ml) was added copper bromide (II) (92,6 g) and the mixture was heated under reflux for 4 hours. The reaction mixture was left to cool to room temperature and the insoluble substance was filtered. The filtrate was concentrated under reduced pressure to obtain crude 2-bromo-1-(2-forfinal)ethanone (output 90,5 g) as oil. To ethylcyanoacrylate (168 g) was added potassium carbonate (88 g) and the mixture was stirred at 45°C for 1 hour. Dropwise within 20 minutes was added to the solution (360 ml) of the crude 2-bromo-1-(2-forfinal)ethanone (90,5 g) in acetone. After completion of adding dropwise, the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added water (300 ml) and ethyl acetate (300 ml) and the mixture was extracted with ethyl acetate. Extract amywali 10%aqueous solution of sodium dihydrophosphate and saturated saline solution, was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Excessive ethylcyanoacrylate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=20:1→4:1) to obtain the specified title compound as oil (yield 64,0 g, 100%).

1H-NMR (CDCl3) δ: of 1.35 (3H, t, J=7.2 Hz), 3,55-of 3.80 (2H, m), 4,11 (1H, t, J=6.0 Hz), 4,24-4,34 (2H, m), 7,15-7,29 (2H, m), 7,55 to 7.62 (1H, m), 7,94 (1H, dt, J=7,5, 1.8 Hz).

Reference example 5

ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate

2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 ml) and diethyl ether (30 ml)was added dropwise a solution of bromine (of 8.50 g) in chloroform (20 ml) while maintaining the reaction temperature not higher than 25°C. After adding dropwise, the mixture was stirred at room temperature for 1 hour, the reaction mixture was added water and the mixture was extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain crude 2-bromo-1-(2-triptoreline)ethanone. To ethylcyanoacrylate (44,44 g) was added potassium carbonate (13,82 g) and the mixture was stirred at 45°C for 1 hour. Was added dropwise a solution of crude 2-bromo-1-(2-triptoreline)ethanone in acetone (10 ml). After completion of adding dropwise, the mixture was stirred at the same temperature for 1 hour and was stirred over night at room temperature. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Excessive ethylcyanoacrylate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→7:1) to obtain the specified title compound as oil (yield 10,43 g, based on 2'-(trifluoromethyl)acetophenone, yield 66%).

1H-NMR (CDCl3) δ: of 1.36 (3H, t, J=7.2 Hz), 3,34-of 3.46 (1H, m), 3,59-3,70 (1H, m), 4,08-4,22 (1H, m), 4,32 (2H, square, J=7,2 Hz), EUR 7.57-7,80 (4H, m).

Reference example 6

ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate

In solution (60 ml), ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g) in tetrahydrofuran was breathed hydrogen chloride (28 g) under cooling on ice and the mixture was stirred at room temperature for 3 hours. Then to remove excess hydrogen chloride was breathed nitrogen. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on columns is e silica gel (eluent: hexane-ethyl acetate=6:1) to obtain the specified title compound as a pale yellow solid (yield 4,24 g, 79%).

1H-NMR (CDCl3) δ: of 1.37 (3H, t, J=6,8 Hz)to 4.33 (2H, square, J=6,8 Hz), 6.87 in (1H, d, J=3.2 Hz), 7,20-of 7.60 (5H, m), 8,79 (1H, usher.).

Reference example 7

ethyl 2-chloro-5-(2-forfinal)-1H-pyrrole-3-carboxylate

A mixture of ethyl 2-cyano-4-(2-forfinal)-4-oxobutanoate (19.3 g) and 4 mol/l solution of hydrogen chloride in ethyl acetate (100 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=10:1→3:1) to obtain specified in the connection header in a solid brown color (output 8,76 g, 53%).

1H-NMR (CDCl3) δ: 1,36-of 1.41 (3H, m)to 4.33 (2H, square, J=7,2 Hz), 6,99-7,00 (1H, m), 7,09-7,26 (3H, m), 7,55-to 7.61 (1H, m), the remaining 9.08 (1H, users).

Reference example 8

methyl 2-chloro-5-(2-forfinal)-4-methyl-1H-pyrrole-3-carboxylate

To a solution of methyl 2-cyano-4-(2-forfinal)-3-methyl-4-oxobutanoate (31.0 g) in ethyl acetate (30 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (150 ml) and the mixture was stirred at room temperature for 2 days. To the reaction mixture were added water (200 ml) and the mixture was extracted with ethyl acetate. The extract was washed twice with water and then washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The balance per crystallizable from ethyl acetate to obtain specified in the title compound as a crystalline substance of white color (yield 19.3 g, 58%).

1H-NMR (CDCl3) δ: of 2.33 (3H, s), 3,86 (3H, s), 7,12-7,42 (4H, m), 8,53 (1H, users).

Reference example 9

ethyl 5-phenyl-1H-pyrrole-3-carboxylate

To a solution (50 ml) of ethyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (8.5 g) in ethanol was added 10% palladium on coal (50% water content, 0.5 g) and the mixture was stirred in hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→1:1) to obtain specified in the title compounds as a colorless solid (yield 4,50 g, 62%).

1H-NMR (CDCl3) δ: of 1.36 (3H, t, J=7.2 Hz), or 4.31 (2H, square, J=7,2 Hz), 6,91 (1H, m), 7,20-of 7.70 (6H, m), 8,77 (1H, usher.).

Reference example 10

ethyl 5-(2-forfinal)-1H-pyrrole-3-carboxylate

To a solution (80 ml) of ethyl 2-chloro-5-(2-forfinal)-1H-pyrrole-3-carboxylate (8.6 g) in ethanol was added 10% palladium on coal (50% water content, 0,86 g) and the mixture was stirred in hydrogen atmosphere at room temperature for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (70 ml), was added 10% palladium on coal (50% water content, of 0.90 g) and the mixture was stirred in hydrogen atmosphere at room temperature for 60 hours. The reaction mixture is shown is ovale and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=10:1→5:1) to obtain specified in the connection header in a solid brown color (yield of 1.37 g, 18%).

1H-NMR (CDCl3) δ: rate of 1.67 (3H, t, J=7.2 Hz), or 4.31 (2H, square, J=7,2 Hz), 7.03 is-7,05 (1H, m), 7,08-of 7.25 (3H, m), 7,49-7,50 (1H, m), 7,58-7,66 (1H, m), which 9.22 (1H, users).

Reference example 11

methyl 5-(2-forfinal)-4-methyl-1H-pyrrole-3-carboxylate

To a solution of methyl 2-chloro-5-(2-forfinal)-4-methyl-1H-pyrrole-3-carboxylate (10.2 g) in methanol (200 ml) was added 10% palladium on coal (50% water content, 1.28 g) and the mixture was stirred in hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (100 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave specified in the title compound in the form of a crystalline substance of white color (output 6,70 g, 76%).

1H-NMR (CDCl3) δ: 2,40 (3H, c), 3,82 (3H, c), 7,12-7,33 (3H, m), 7,42-7,49 (2H, m), 8,67 (1H, users).

Reference example 12

ethyl 5-[(trifloromethyl)phenyl]-1H-pyrrole-3-carboxylate

A similar method described in reference examples 7 and 9, and using ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate got mentioned in the title compound as a colourless crystalline substance. More specifically, a mixture of ethyl 2-cyano-4-[(2-trifluoromethyl)phenyl]-4-oxobutanoate (10.2 g) and 4 mol/l solution of hydrogen chloride in ethyl acetate (100 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=10:1→3:1) to obtain ethyl 2-chloro-5-[(2-trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate in the form of a solid brown color (output 6,37 g, 59%). This substance was dissolved in ethanol (120 ml)was added 10% palladium on coal (50% water content, 0.5 g) and the mixture was stirred in hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→1:1) to obtain specified in the title compounds as a colorless solid (yield 2,89 g, 51%).

1H-NMR (CDCl3) δ: of 1.36 (3H, t, J=7.2 Hz), or 4.31 (2H, square, J=7,2 Hz), for 6.81 (1H, c), 7,42-to 7.61 (5H, m), 8,69 (1H, usher.).

Reference example 13

(5-phenyl-1H-pyrrol-3-yl)methanol

RA is solution (100 ml) of ethyl 5-phenyl-1H-pyrrole-3-carboxylate (2.16 g) in tetrahydrofuran was cooled to -78°C and added dropwise within 10 minutes was added to 1.5 mol/l solution (24 ml) hydride diisobutylaluminum in toluene. The mixture was additionally stirred at -78°C for 1 hour was added dropwise water (2 ml) for 2 minutes and the mixture was additionally stirred at room temperature for 1 hour. The reaction mixture was filtered using celite and anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain specified in the connection header in the form of powder light red (yield 1.51 g, 87%).

1H-NMR (DMSO-d6) δ: 4,34 (2H, d, J=5.4 Hz), 4,60 (1H, t, J=5.4 Hz), 6,45-6,46 (1H, m), 6,74 (1H, usher.), 7,11-to 7.15 (1H, m), 7,31-to 7.35 (2H, m), EUR 7.57-to 7.59 (2H, m)11,05 (1H, c).

Reference example 14

[5-(2-forfinal)-4-methyl-1H-pyrrol-3-yl]methanol

A similar method described in reference example 13 and using methyl 5-(2-forfinal)-4-methyl-1H-pyrrole-3-carboxylate (1.63 g) and the solution (15 ml) of 1.5 mol/l diisobutylaluminum hydride in toluene, has been specified in the title compound in the form of a crystalline substance of white color (yield 1.18 g, 82%).

1H-NMR (CDCl3) δ: 1,30 (1H, t, J=4,8 Hz in), 2.25 (3H, c), br4.61 (2H, d, J=4,8 Hz), 6.87 in (1H, d, J=3.3 Hz), 7,10-7,28 (3H, m), 7,44 is 7.50 (1H, m), 8,40 (1H, users).

Reference example 15

5-phenyl-1H-pyrrole-3-carbaldehyde

To a solution (45 ml) (5-phenyl-1H-pyrrol-3-yl)methanol (1.51 g) in acetonitrile was added perruthenate Tetra-n-Propylamine (0,46 g), N-methylmorpholine N-oxide (2,36 g) and powdered molecular sieves 4Å (4.5 g) and the mixture was stirred at room temperature is for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→1:1) to obtain the specified title compound as light yellow colour powder (yield of 0.92 g, 62%).

1H-NMR (CDCl3)δ: 6,95 (1H, m), 7,29-to 7.32 (1H, m), 7,40-7,44 (2H, m), 7,50-7,52 (3H, m), of 9.02 (1H, usher.), 9,84 (1H, c).

Reference example 16

5-(2-forfinal)-4-methyl-1H-pyrrole-3-carbaldehyde

A similar method described in reference example 15, and using [5-(2-forfinal)-4-methyl-1H-pyrrol-3-yl]methanol (1,17 g), perruthenate Tetra-n-Propylamine (101 mg), N-methylmorpholine N-oxide (1.01 g) and powdered molecular sieves 4Å (572 mg)were specified in the title compound in the form of a crystalline substance light pink color (yield of 0.67 g, 58%).

1H-NMR (CDCl3)δ: of 2.45 (3H, c), 7,14 and 7.36 (3H, m), 7,44 is 7.50 (2H, m), 8,82 (1H, users), 9,92 (1H, c).

Reference example 17

5-(2-forfinal)-1H-pyrrole-3-carbaldehyde

Solution (220 ml) of ethyl 5-(2-forfinal)-1H-pyrrole-3-carboxylate (11.6 g) in tetrahydrofuran was cooled to -78°C and added dropwise within 10 minutes was added to 1.5 mol/l solution (100 ml) hydride diisobutylaluminum in toluene. The mixture was stirred at -78°C for 1 hour and added dropwise over 2 minutes was added water (10 ml). The mixture was left to warm to room temperature and the mixture peremeci the Ali for 2 hours. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate and concentrated under reduced pressure to obtain light yellow oil (yield of 8.3 g). To a solution (220 ml) of the obtained oil is light yellow in color (8,30 g) in acetonitrile was added perruthenate Tetra-n-Propylamine (1,75 g), N-methylmorpholine N-oxide (13.5 g) and powdered molecular sieves 4Å (5 g) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:3→1:1) to obtain the specified title compound as a crystalline substance yellow (yield 5.6 g, 60%).

1H-NMR (CDCl3) δ: 7,07-7,28 (4H, m), 7,52-rate of 7.54 (1H, m), to 7.61-to 7.67 (1H, m), 9,49 (1H, users), 9,86 (1H, c).

Reference example 18

5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

Solution (28 ml) of ethyl 5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1,38 g) in tetrahydrofuran was cooled to -78°C and added dropwise within 10 minutes was added to 1.5 mol/l solution (13 ml) hydride diisobutylaluminum in toluene. The mixture was additionally stirred at -78°C for 1 hour and added dropwise over 2 minutes was added water (3 ml). The mixture was left to warm to room temperature and the mixture was additionally stirred for 1 cha is and. The reaction mixture was filtered by adding celite and anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure to obtain light yellow oil (yield of 1.14 g). The oil obtained (1,14 g) was dissolved in acetonitrile (50 ml) and to this solution was added perruthenate Tetra-n-Propylamine (0.26 g), N-methylmorpholine N-oxide (1,32 g) and powdered molecular sieves 4Å (5 g). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→1:1) to obtain specified in the title compounds as a colorless crystalline substance (yield 0.71 g, 61%).

1H-NMR (CDCl3) δ: 6,79-for 6.81 (1H, m), 7,46 for 7.78 (5H, m), 9,13 (1H, usher.), 9,82 (1H, c).

Reference example 19

methyl 1H-pyrrole-3-carboxylate

To a suspension of tert-butoxide potassium (17.9 g) in tetrahydrofuran (200 ml) was added dropwise a solution of p-toluensulfonyl of isocyanide of 25.2 g) and methyl acrylate (11.8 ml) in tetrahydrofuran (200 ml) for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated salt solution, dried on the anhydrous magnesium sulfate, was filtered and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1) to obtain specified in the connection header in the form of a solid white color (output 6,56 g, 41%).

1H-NMR (CDCl3) δ: 3,82 (3H, c), x 6.15 (1H, m), of 6.75 (1H, m), the 7.43 (1H, m), and 8.50 (1H, users).

Reference example 20

methyl 4-methyl-1H-pyrrole-3-carboxylate

A similar method described in reference example 19 and using p-toluensulfonate isocyanide (94,6 g), methyl crotonate (48,5 g) and tert-piperonyl potassium (76,7 g)were specified in the title compound in the form of solid light yellow (output of 16.8 g, 25%).

1H-NMR (CDCl3) δ: to 2.29 (3H, c), of 3.80 (3H, c), 6,53-is 6.54 (1H, m), of 7.36-7,38 (1H, m), of 8.25 (1H, users).

Reference example 21

ethyl 2-methyl-1H-pyrrole-3-carboxylate

To the bromide (25 g) under cooling on ice with stirring was added dropwise within 2 hours of the vinyl acetate (13,4 g). The reaction mixture was additionally stirred at the same temperature for 1 hour. Was added ethyl 3-oxobutanoate (18.5 g) and added dropwise over 1 hour was added 25%aqueous ammonia solution (44 ml). The reaction mixture was additionally stirred at room temperature for 30 minutes, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline solution, sushi is over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→3:1) and recrystallized from hexane to obtain specified in the title compounds as a colorless solid (yield 7,56 g, 35%).

1H-NMR (CDCl3) δ: of 1.32 to 1.37 (3H, m), 2,53 (3H, c), 4,24-or 4.31 (2H, m), 6,55 return of 6.58 (2H, m), 8,13 (1H, usher.).

Reference example 22

methyl 5-bromo-1H-pyrrole-3-carboxylate

Solution (30 ml) of methyl 1H-pyrrole-3-carboxylate (a 3.06 g) in tetrahydrofuran was cooled to -78°C, N-bromosuccinimide (of 4.38 g) and then was added pyridine (3 drops) and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=5:1) to obtain the specified title compound as a pale yellow solid (yield is 3.08 g, 62%).

1H-NMR (CDCl3) δ: 3,81 (3H, c), to 6.58 (1H, m), of 7.36 (1H, m), at 8.60 (1H, users).

Reference example 23

methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate

A similar method described in reference example 22, and using methyl 4-methyl-1H-pyrrole-3-carboxylate (1.0 g) and N-bromakin the MFA (1.28 g), got mentioned in the title compound in the form of solid light yellow (output 489 mg, 31%).

1H-NMR (CDCl3) δ: 2,23 (3H, c), of 3.80 (3H, c), 7,37 (1H, d, J=3.0 Hz), 8,40 (1H, users).

Reference example 24

ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1,53 g) in tetrahydrofuran (20 ml) was added N-bromosuccinimide (1.78 g) at -78°C and the mixture was stirred at the same temperature for 30 minutes. For the extraction of the reaction mixture were added water and diethyl ether. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure at 5°C or below. The residue was washed with hexane to obtain specified in the title compounds as a colorless solid (yield of 2.26 g, 97%).

1H-NMR (CDCl3) δ: 1.30 and 1.35 (3H, m), of 2.51 (3H, c), 4,22-the 4.29 (2H, m), 6,50 (1H, c), 8,01 (1H, usher.).

Reference example 25

2-hydroxy-5-pyrimidinemethanol acid

Fuming sulfuric acid (containing 25% of sulfur dioxide, 100 ml) was cooled to 0°C and 2-aminopyrimidine (25 g) was gradually added over 1 hour. The mixture was heated to 180°C and was stirred for 40 hours. After cooling to room temperature the mixture was poured onto ice (1 kg). The precipitate was collected by filtration and recrystallized from water to obtain specified in the header soy is inane (yield of 25.6 g, 55%).

1H-NMR (DMSO-d6) δ: 6,20-7,20 (2H, m), 8,71 (2H, c).

Reference example 26

2-chloro-5-pyrimidinemethanol chloride

A mixture of 2-hydroxy-5-pyrimidinemethanol acid (12.8 g) and pentachloride phosphorus (37,8 g) was stirred at 180°C for 4 hours. After cooling to room temperature was added toluene (200 ml) and the insoluble substance was filtered. The filtrate was washed with water, with ice, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was left in the refrigerator for one day with obtaining specified in the title compound as a pale yellow solid (yield 14.8 g, 96%).

1H-NMR (CDCl3) δ: 9,19 (2H, c).

Reference example 27

6-chloropyridazine-3-thiol

To a suspension of (88 ml) of sodium hydrosulfide (of 3.78 g) in ethanol was added 3,6-dichloropyridazine (5.0 g) and the mixture was heated under reflux for 1 hour. The solvent was evaporated under reduced pressure and added water (12.5 ml). The mixture was brought to pH equal to about 9, using a 2 mol/l sodium hydroxide solution and the precipitate was filtered. The filtrate is brought to pH equal to about 2, with 6 mol/l hydrochloric acid and the precipitate was collected by filtration to obtain specified in the connection header in the form of a solid yellow (output 4,74 g, 96%).

1H-NMR (CDCl 3) δ: 6,99 (1H, d, J=9.6 Hz), 7,60 (1H, d, J=9.6 Hz).

Reference example 28

6-chloropyridazine-3-sulfonyl fluoride

To a mixture of methanol (10 ml) and water (10 ml), cooled to -20°C, was added hydrofloric potassium (16 g) and 6-chloropyridazine-3-thiol (2.37 g). After stirring at the same temperature for 20 minutes, within 30 minutes was breathed chlorine. Added ice water (20 ml) and the precipitate was collected by filtration. The residue was extracted with ethyl acetate and water. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. For the occurrence of crystallization, the solvent was evaporated under reduced pressure and the crystalline substance was washed with hexane to obtain specified in the connection header in the form of a solid gray color (yield 1.68 g, 53%).

1H-NMR (CDCl3) δ: 7,86-7,89 (1H, m), 8.17-a 8,19 (1H, m).

Reference example 29

hydrochloride pyridine-3-ylsulphonyl chloride

A mixture of 3-pyridine sulfonic acid (50.0 g), pentachloride phosphorus (80,0 g) and phosphorus oxychloride (100 ml) was stirred at 120°C for 8 hours. In nitrogen atmosphere, the mixture was cooled to room temperature and was added chloroform (digidrirovanny, 330 ml). Was breathed hydrogen chloride and the precipitated crystalline substance was collected by filtration and washed with chloroform (digidrirovanny) obtaining specified in the title compound as a solid white color (output 54,7 g, 81%).

1H-NMR (DMSO-d6) δ: 8,03-8,07 (1H, m), 8,68 (1H, d, J=8.1 Hz), 8,87 (1H, d, J=5.7 Hz), 9,01 (1H, c).

Reference example 30

6-methoxypyridine-3-ylsulphonyl chloride

5-Amino-2-methoxypyridine (1.24 g) was dissolved in acetic acid (8,3 ml) and the mixture was stirred under cooling on ice. Added concentrated hydrochloric acid (8,3 ml) and added dropwise over 15 minutes while maintaining the internal temperature not higher than 10°C was added an aqueous solution (5 ml) of sodium nitrite (689 mg). The reaction mixture was stirred for 10 minutes and gradually at 5°C was added to a mixture of copper chloride (280 mg) and acetic acid (17 ml), pre-saturated with gaseous sulfur dioxide. The mixture was left to slowly warm to room temperature before the termination of the generation of gas. The reaction mixture was concentrated to about 5 ml under reduced pressure and the precipitate was collected by filtration to obtain specified in the title compound (yield 1.0 g, 51%) as a crude crystalline substance. This compound was used for next reaction without purification.

Reference example 31

6-chloropyridin-3-ylsulphonyl chloride

While cooling on ice, to water (70 ml) dropwise over 1 hour was added thionyl chloride (12 ml) and the mixture was stirred at room temperature for 12 hours to obtain dioxide-containing solution of sulfur. Separately, the OHL is a discussion on ice, 5-amino-2-chloropyridine (5.0 g) was added to concentrated hydrochloric acid (40 ml) and the mixture was stirred. While maintaining the internal temperature not higher than 5°C was added dropwise an aqueous solution (12.5 ml) of sodium nitrite (2,88 g) and the mixture was additionally stirred for 15 minutes. To the above dioxide-containing solution with the addition of sulfur chloride copper (70 mg), slowly at 5°C was added to the reaction mixture. While cooling on ice, the mixture was additionally stirred for 30 minutes. The precipitate was collected by filtration and washed with water and ethanol to obtain specified in the connection header (exit rate 4.79 g, 58%).

1H-NMR (CDCl3) δ: 7,60-7,63 (1H, m), 8,24-of 8.27 (1H, m), 9,03-9,04 (1H, m).

Reference example 32

2-chloro-3-pyridine sulfonyl chloride

While cooling on ice, to water (140 ml) for 1 hour was added dropwise thionyl chloride (24 ml) and the mixture was stirred at room temperature for 12 hours to obtain dioxide-containing solution of sulfur. Separately, while cooling on ice, concentrated hydrochloric acid (80 ml) was added 3-amino-2-chloropyridine (10 g) and the mixture was stirred. Dropwise while maintaining the internal temperature not higher than 5°C was added an aqueous solution (25 ml) of sodium nitrite (5.75 g) and the mixture was additionally stirred for 15 minutes. To the above dioxide-containing sulphur solution with the addition of the chloride of copper (140 mg) slowly at 5°C was added to the reaction mixture. While cooling on ice, the mixture was additionally stirred for 30 minutes and the precipitate was collected by filtration and washed with water and ethanol to obtain specified in the title compound (yield of 6.99 g, 42%).

1H-NMR (CDCl3) δ: 7,54-7,56 (1H, m), 8,46-8,48 (1H, m), 8,71-8,73 (1H, m).

Reference example 33

6-chloro-5-methylpyridin-3-amine

To aqueous solution (25 ml) of ammonium chloride (1.27 g) was added reduced iron (793 mg) and the mixture was stirred at room temperature for 5 minutes. Dropwise within 10 minutes was added a solution (10 ml) of 2-chloro-3-methyl-5-nitropyridine (816 mg) in methanol. The reaction mixture was stirred at 40°C for 20 minutes and at 50°C for 1.5 hours and was further heated under reflux for 1 hour. The reaction mixture was filtered through celite and the celite was washed with methanol. A large part of the methanol was removed by concentration under reduced pressure was added concentrated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→7:3) to obtain the specified title compound as a solid (yield 280 mg, 42%).

1H-YAM who (CDCl 3) δ: 3,62 (2H, usher.), to 6.88-6.89 in (1H, m), 7,70-7,71 (1H, m).

Reference example 34

6-chloro-5-methylpyridin-3-sulfonyl chloride

To water (3.4 ml) under cooling on ice for 30 minutes was added dropwise thionyl chloride (0.6 ml). The mixture was stirred at room temperature for 12 hours to obtain dioxide-containing solution of sulfur. Separately to concentrated hydrochloric acid (6 ml) cooled on ice was added 6-chloro-5-methylpyridin-3-amine (278 mg) and the mixture was stirred. While maintaining the internal temperature not higher than 5°C was added dropwise an aqueous solution (2 ml) of sodium nitrite (148 mg) and the mixture was additionally stirred for 15 minutes. To the above dioxide-containing sulphur solution with the addition of copper chloride (5 mg) slowly at 5°C was added to the reaction mixture. While cooling on ice, the mixture was additionally stirred for 30 minutes and the precipitate was collected by filtration and washed with water to obtain specified in the title compound as a pale yellow solid (yield 271 mg, 62%).

1H-NMR (CDCl3) δ: 2,54 (3H, c), of 8.15 (1H, c), 8,86 (1H, c).

Reference example 35

2-pyridinesulfonamide

To sulfuric acid (50 ml) cooled on ice was added 2-mercaptopyridine (2.0 g) and the mixture was stirred. Dropwise within 1.5 hours was added a solution of sodium hypochlorite (chlorine content of 5%, 126 ml) and mesdemoiselles was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with water (100 ml) and was extracted with dichloromethane. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compounds as colorless oil (yield of 2.45 g, 77%).

1H-NMR (CDCl3) δ: 7,69-7,71 (1H, m), 8,06-to 8.14 (2H, m), 8,83 cent to 8.85 (1H, m).

Reference example 36

ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.60 g) was dissolved in tetrahydrofuran (50 ml), was added sodium hydride (60% in oil, 446 mg) and the mixture was stirred at room temperature for 15 minutes. Added 15-crown-5 (2,24 ml) and the mixture was further stirred at the same temperature for 15 minutes. Was added 2-chloro-5-pyrimidinemethanol chloride (2.06 to g) and the reaction mixture was stirred at room temperature for 1 hour. Added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→7:3) to obtain the specified title compound as a yellow oil (yield 2,03 g, 70%).

1H-NMR (CDCl3) δ: of 1.35-1.39 (3H, m), 4,30-4,37 (2H, m), only 6.64 (1H, c), 7,22-7,26 (2, m), 7,37-7,51 (3H, m), of 8.04 (1H, c), of 8.37 (2H, c).

Reference example 37

ethyl 1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Under stirring in nitrogen atmosphere to a solution of ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (588 mg) in tetrahydrofuran (20 ml) was added tetrakis(triphenylphosphine)palladium (87 mg) and 2 mol/l solution of trimethylaluminum-hexane (1.5 ml). The mixture was stirred at room temperature for 15 minutes and was added 2 mol/l solution of trimethylaluminum-hexane (1 ml). After stirring at the same temperature for 20 minutes, was added ice water (100 ml) and ammonium chloride (2.0 g) and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound as a pale yellow oil (yield 350 mg, 63%).

1H-NMR (CDCl3) δ: 1,34-of 1.39 (3H, m), 2,77 (3H, c), 4,29 is 4.36 (2H, m), is 6.61 (1H, c), 7,21-7,26 (2H, m), 7,37-7,49 (3H, m), of 8.06 (1H, c), to 8.41 (2H, c).

Reference example 38

ethyl 1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Under stirring, to a solution of ethyl 1-[(2-chloro-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (392 mg) in tetrahydrofuran (10 ml) was added to the 7 mol/l solution of ammonia-methanol (1.0 ml). The mixture was stirred at room temperature for 20 minutes, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compounds as a colorless solid (yield 373 mg, 100%).

1H-NMR (CDCl3) δ: 1,34-of 1.39 (3H, m), 4,28 is 4.36 (2H, m), the ceiling of 5.60 (2H, usher.), 6,59 (1H, c), 7,26-7,46 (5H, m), 8,02-8,03 (3H, m).

Reference example 39

ethyl 1-(imidazo[1,2-a]pyrimidine-6-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carboxylate

A mixture of ethyl 1-[(2-amino-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (373 mg), 2-bromo-1,1-diethoxyethane (394 mg) and acetic acid (20 ml) was stirred in a microwave reaction apparatus at 130°C for 30 minutes. After cooling to room temperature the solvent was evaporated under reduced pressure. To the residue was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→ethyl acetate) to obtain specified in the header joint is in the form of a solid brown color (exit 157 mg, 40%).

1H-NMR (CDCl3) δ: 1,35-1,40 (3H, m), 4,30-4,37 (2H, m), is 6.61 (1H, c), 7,17-7,49 (2H, m), 7,26-7,49 (4H, m), 7,94 (1H, c), to 7.99 (1H, c), 8,11 (1H, c), scored 8.38 (1H, c).

Reference example 40

ethyl 5-phenyl-1-(pyridazin-3-ylsulphonyl)-1H-pyrrole-3-carboxylate

Ethyl 5-phenyl-1H-pyrrole-3-carboxylate (1.06 g) was dissolved in tetrahydrofuran (30 ml), was added sodium hydride (60% in oil, 300 mg) and the mixture was stirred at room temperature for 15 minutes. Added 15-crown-5 (1,52 ml) and the mixture was further stirred at the same temperature for 15 minutes. Added 6-chloropyridazine-3-sulfonyl fluoride (1.28 g) and the reaction mixture was stirred at room temperature for 30 minutes. Added hydrazine (1.60 g) and the reaction mixture was stirred at room temperature for 15 minutes. Added a concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml)was added manganese dioxide (75% chemically processed product, 5.0 g) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified chromate what graphy on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound (yield 613 mg, exit 24% (containing impurities)).

1H-NMR (CDCl3) δ: 1,34-of 1.39 (3H, m), 4,29 is 4.36 (2H, m), is 6.61 (1H, c), 7,11-7,22 (2H, m), 7.24 to 7,51 (5H, m), to 8.20 (1H, c), 9.28 are-of 9.30 (1H, c).

Reference example 41

methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 1.1 g) was washed with hexane and suspended in N,N-dimethylformamide (50 ml). To the suspension at 0°C was added a solution (10 ml) of methyl 5-bromo-1H-pyrrole-3-carboxylate (5.0 g) in N,N-dimethylformamide. After stirring at 0°C for 30 minutes, the solution was added benzosulfimide (3.3 ml) in N,N-dimethylformamide (5 ml) and the reaction mixture was stirred at room temperature for 1 hour. Added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=5:1) to obtain specified in the title compounds as a colorless solid (yield 8.5 g, 99%).

1H-NMR (CDCl3) δ: a 3.83 (3H, c), of 6.68 (1H, d, J=2.1 Hz), 7,55-of 7.60 (2H, m), to 7.67-7,72 (1H, m), of 7.96-to 7.99 (2H, m), 8,08 (1H, d, J=2.1 Hz).

Reference example 42

methyl 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

Sodium hydride (60% in oil, 202 mg) was washed with hexane and suspendido the Ali in N,N-dimethylformamide (10 ml). Dropwise at -78°C was added a solution (10 ml) of methyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (1.0 g) in N,N-dimethylformamide. After completion of adding dropwise, the reaction mixture was stirred at room temperature for 30 minutes and was added dropwise to a cooled on ice to a solution (10 ml) benzosulfimide (of 0.71 ml) in N,N-dimethylformamide. After completion of adding dropwise, the reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain specified in the connection header in a solid brown color (yield : 1.13 g, 69%).

1H-NMR (CDCl3) δ: 2,11 (3H, c), with 3.79 (3H, c), 7,45-of 7.70 (3H, m), a 7.85-of 7.95 (2H, m), of 8.06 (1H, c).

Reference example 43

ethyl 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate

A similar method described in reference example 41, using ethyl 2-methyl-1H-pyrrole-3-carboxylate (8,81 g), sodium hydride (60% in oil, 2.58 g) and benzazolyl chloride (7.8 ml)were specified in the title compound in the form of a crystalline substance of white color (yield 14.3 g, 85%).

1H-NMR (CDCl3) δ: is 1.31 (3H, t, J=7.2 Hz), 2,62 (3H, c), 4,24 (2H, square, J=7,2 Hz), 6,63 (1H, d, J=3.3 Hz), 7,30 (1H, d, J=3.3 Hz), 7,51-EUR 7.57 (2H, m), 7,62-to 7.68 (1H, m), 7,81-to 7.84 (2H, m).

Reference example 44

ethyl 5-bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-Pirro is-3-carboxylate

Ethyl 5-bromo-2-methyl-1H-pyrrole-3-carboxylate (of 2.26 g) was dissolved in tetrahydrofuran (100 ml)was added sodium hydride (60% in oil, of 1.16 g) and the mixture was stirred at room temperature for 15 minutes. Added 15-crown-5 (5,90 ml) and the mixture was further stirred at the same temperature for 15 minutes. Was added 3-pyridine sulphonylchloride hydrochloride (3.13 g) and the reaction mixture was stirred at room temperature for 1 hour. Added a concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→7:3) to obtain the specified title compound as a yellow oil (yield 2,31 g, 64%).

1H-NMR (CDCl3) δ: 1,24 is 1.34 (3H, m)to 2.94 (3H, c), 4,23-4,30 (2H, m), 6,69 (1H, c), 7,51-of 7.55 (1H, m), 8.17-a 8,21 (1H, m), 8,88-8,91 (1H, m), 9,14 (1H, m).

Reference example 45

ethyl 2-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carboxylate

A suspension of ethyl 5-bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carboxylate (of 2.26 g), phenylboric acid (1.54 g), dichloro[bis(triphenylphosphine)]palladium (211 mg) and sodium carbonate (1,91 g) in a mixture of 1,2-dimethoxyethane (20 ml)-water (10 ml) was stirred at 80°C for 40 minutes. On the Les cooling, the reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→6:4) to obtain the specified title compound as a colourless oil (yield 2,39 g, 100%).

1H-NMR (CDCl3) δ: of 1.30 to 1.34 (3H, m), of 2.92 (3H, c), 4,23-4,30 (2H, m), 6,59 (1H, c), 7.23 percent-7,39 (4H, m), 7,50-to 7.68 (2H, m), by 8.22-of 8.25 (1H, m), 8,61-to 8.62 (1H, m), 8,75-8,77 (1H, m).

Reference example 46

[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

Solution (80 ml) of methyl 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (7,1 g) in tetrahydrofuran was cooled to -78°C is added dropwise within 30 minutes was added to 1.5 mol/l solution (42 ml) hydride diisobutylaluminum in toluene and the mixture was further stirred at -78°C for 1 hour. To the reaction mixture was added 1 mol/l hydrochloric acid (20 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain specified in the title compound as a brown oil (yield of 7.1 g, 100%).

1H-NMR (CDCl3) δ: 1,62 (1H, users), 4,51 (2H, c), 6,33-6,34 (1H, m), 7,44 was 7.45 (1H, m), 7,51-EUR 7.57 (2H, m), 7,62-to 7.68 (1H, m), 7,937,97 (2H, m).

Reference example 47

[2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol

A similar method described in reference example 13 and using ethyl 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (8,05 g) and 1.5 mol/l solution diisobutylaluminium hydride in toluene (55 ml)were specified in the title compound in the form of a crystalline substance of white color (yield of 6.61 g, 96%).

1H-NMR (CDCl3) δ: 1,37 (1H, users), to 2.29 (3H, c), 4,42 (2H, users), of 6.29 (1H, d, J=3.6 Hz), 7,30 (1H, d, J=3.6 Hz), 7,49-of 7.55 (2H, m), 7,58-to 7.64 (1H, m), 7,78-7,81 (2H, m).

Reference example 48

5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a solution (80 ml) of [5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (7,1 g) in acetonitrile was added perruthenate Tetra-n-Propylamine (0,63 g), N-methylmorpholine N-oxide hydrate (4,2 g) and powdered molecular sieves 4Å (3.5 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1) to obtain specified in the title compounds as colorless solids yield 4.6 g, 71%).

1H-NMR (CDCl3) δ: was 6.73 (1H, d, J=2.1 Hz), EUR 7.57-7,63 (2H, m), 7,70 to 7.75 (1H, m), 7,98-8,02 (2H, m), 8,10 (1H, d, J=2.1 Hz), 9,77 (1H, c).

Reference example 49

5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 17 and using methyl 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate was obtained is listed in the title compound as a colourless solid (1.78 g, 54%).

1H-NMR (CDCl3) δ: 2,14 (3H, c), 7,50 to 7.62 (3H, m), to $ 7.91-of 7.96 (2H, m), of 8.04 (1H, c), 9,77 (1H, c).

Reference example 50

4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

A suspension of 5-bromo-4-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (1.78 g), phenylboric acid (1,37 g), dichloro[bis(triphenylphosphine)]palladium (0,19 g) and sodium carbonate (1,72 g) in a mixture of 1,2-dimethoxyethane (30 ml) - water (10 ml) was stirred at 100°C for 1 hour. Added 8 mol/l aqueous sodium hydroxide solution (15 ml) and the mixture was stirred at 90°C for 3 hours. After cooling, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→1:1) and the obtained solid was washed with hexane to obtain specified in the title compounds as pale as the addition of a solid substance (yield 815 mg, 69%).

1H-NMR (CDCl3) δ: 2,47 (3H, c), 7,34-of 7.48 (6H, m), 8,58 (1H, usher.), to 9.91 (1H, c).

Reference example 51

2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (6,35 g), dimethyl sulfoxide (50 ml) and triethylamine (25 ml) was added to the complex of sulfur trioxide-pyridine (of 4.57 g) and the mixture was stirred at room temperature for 12 hours. To the reaction mixture was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain specified in the title compound, white (output at 5.27 g, 84%).

1H-NMR (CDCl3) δ: 2,62 (3H, c), of 6.65 (1H, d, J=3.6 Hz), 7,35 (1H, d, J=3.6 Hz), 7,55-to 7.61 (2H, m), 7,66-7,71 (1H, m), a 7.85-7,88 (2H, m), of 9.89 (1H, c).

Reference example 52

2-methyl-1H-pyrrole-3-carbaldehyde

To a solution of 2-methyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (4.59 g) in tetrahydrofuran (20 ml) and methanol (5 ml) was added 8 mol/l aqueous sodium hydroxide solution (2.5 ml) at 0°C and the reaction mixture was stirred at the same temperature for 30 minutes. To the reaction the mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain specified in the connection header in the form of a solid white color (yield 1.06 g, 54%).

1H-NMR (CDCl3) δ: 2,56 (3H, c), 6,58-6,59 (1H, m), 6,65 is 6.67 (1H, m), charged 8.52 (1H, users), of 9.89 (1H, c).

Reference example 53

2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 44 and using 2-methyl-1H-pyrrole-3-carbaldehyde (1.10 g), sodium hydride (60% in oil, 1.20 g), 15-crown-5 (6,0 ml) and pyridine hydrochloride-3-ylsulphonyl chloride (3,22 g)were specified in the title compound in the form of a crystalline substance of white color (yield 1.10 g, 44%).

1H-NMR (CDCl3) δ: 2,66 (3H, c), of 6.68 (1H, d, J=3,9 Hz), 7,34 (1H, d, J=3,9 Hz), 7,51-of 7.55 (1H, m), 8,09-8,13 (1H, m), 8,89-8,91 (1H, m), 9,10-9,11 (1H, m), for 9.90 (1H, c).

Reference example 54

5-bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (974 mg) in N,N-dimethylformamide (10 ml) at 0°C was added N-bromosuccinimide (1,17 g) and the mixture was stirred at room temperature for 1 hour. To reaction the th mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain the specified title compound as a crystalline substance of white color (exit 675 mg, 53%).

1H-NMR (CDCl3) δ: 2,89 (3H, c), 6,18 (1H, c), 7,53-EUR 7.57 (1H, m), 8,21 compared to 8.26 (1H, m), 8,91-8,93 (1H, m), 9,17-9,18 (1H, m), 9,92 (1H, c).

Reference example 55

5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

In argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg) was dissolved in absolute tetrahydrofuran (20 ml) was added sodium hydride (60% in oil, 240 mg) with stirring at room temperature. After stirring at the same temperature for 15 minutes was added 15-crown-5 (1,21 ml) and the mixture was further stirred at the same temperature for 15 minutes. Added hydrochloride pyridine-3-ylsulphonyl (642 mg) and the mixture was further stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated p. and reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain specified in the connection header in a solid brown color (yield 470 mg, 75%).

1H-NMR (CDCl3) δ: 6,60 (1H, d, J=1,8 Hz), 7,15-7,19 (2H, m), 7,25-7,37 (3H, m), 7,42-of 7.48 (1H, m), 7,53-EUR 7.57 (1H, m), 8,13 (1H, d, J=1,8 Hz), 8,49-and 8.50 (1H, m), a total of 8.74-8,76 (1H, m), for 9.90 (1H, c).

Reference example 56

1-[(6-methoxypyridine-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

In argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in absolute tetrahydrofuran (20 ml) was added sodium hydride (60% in oil, 200 mg) at room temperature with stirring. After stirring at the same temperature for 15 minutes was added 15-crown-5 (1,01 ml) and the mixture was further stirred at the same temperature for 15 minutes. Added 6-methoxypyridine-3-ylsulphonyl (623 mg) and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound as oil (yield 59 mg, 17%).

1H-NMR (CDCl3) δ: 3,95 (3H, c), 6,59-6,62 (2H, m), 7,19-7,44 (6H, m), 8,08-8,10 (2H, m), 9,88 (1H, c).

Reference example 57

1-(6-chloropyridin-3-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

In almost the re argon, 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg) was dissolved in absolute tetrahydrofuran (15 ml) was added sodium hydride (60% in oil, 180 mg) at room temperature with stirring. After stirring at the same temperature for 15 minutes was added 15-crown-5 (0,90 ml) and the mixture was further stirred at the same temperature for 15 minutes. Added 6-chloropyridin-3-ylsulphonyl (827 mg) and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→7:3) to obtain the specified title compound as oil (yield 762 mg, 73%).

1H-NMR (CDCl3) δ: 6,62 (1H, c), 7,19-7,49 (7H, m), of 8.09 (1H, c), 8,24 compared to 8.26 (1H, m), of 8.90 (1H, c).

Reference example 58

1-(2-chloropyridin-3-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60% in oil, 180 mg), 15-crown-5 (0,90 ml) and 2-chloro-3-pyridinesulfonamide (716 mg)were specified in the header connection in amorf the Oh form (exit 716 mg, 69%).

1H-NMR (CDCl3) δ: only 6.64 (1H, c), 6,70-of 6.90 (1H, m), 7,05-was 7.08 (2H, m), 7,15-to 7.18 (2H, m), 7,26-to 7.32 (1H, m), 7,55-to 7.59 (1H, m), compared to 8.26 (1H, c), 8,44-8,46 (1H, m), 9,94 (1H, c).

Reference example 59

1-(2-chloropyrimidine-5-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (342 mg), sodium hydride (60% in oil, 120 mg), 15-crown-5 (0,60 ml) and 2-chloro-5-pyrimidinemethanol (554 mg)were specified in the title compound in the form of solid yellow (yield 390 mg, 56%).

1H-NMR (CDCl3) δ: of 6.68 (1H, c), 7,22-7,26 (2H, m), 7,39-7,52 (3H, m), of 8.09 (1H, c), 8,35 (2H, c), to 9.91 (1H, c).

Reference example 60

1-[(6-chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0,30 ml) and 6-chloro-5-methylpyridin-3-sulfonyl chloride (270 mg)were specified in the title compound in the form of a solid substance (yield 244 mg, 68%).

1H-NMR (CDCl3) δ: of 2.27 (3H, c), 6,62 (1H, c), 7,20-7,26 (3H, m), 7,35-7,49 (3H, m), of 8.09 (1H, c), 8,13 (1H, m), for 9.90 (1H, c).

Reference example 61

2-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

Solution (15 ml) of ethyl 2-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carboxylate (980 mg) in tetrahydrofuran about what was ladli to -78°C, dropwise within 10 minutes was added to 1.5 mol/l solution (5.3 ml) hydride diisobutylaluminum in toluene and the mixture was heated to 0°C within 2 hours. Was added water (100 ml) and ethyl acetate (20 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite and the organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a solution of acetonitrile (25 ml), was added perruthenate Tetra-n-Propylamine (93 mg), N-methylmorpholine N-oxide hydrate (466 mg) and powdered molecular sieves 4Å (500 mg) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added ethyl acetate (30 ml). The mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound as a yellow oil (yield 235 mg, 27%).

1H-NMR (CDCl3) δ: at 2.93 (3H, c), 6,51 (1H, c), 7,18-7,42 (6H, m), to 7.59-to 7.64 (1H, m), at 8.60 (1H, c), 8,77-8,79 (1H, m), there is a 10.03 (1H, c).

Reference example 62

1-[(2-methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

In nitrogen atmosphere, a solution of ethyl 1-[(2-methyl-5-Piri is one)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (280 mg) in tetrahydrofuran (20 ml) was cooled to -78°C, under stirring was added 1.5 mol/l solution (3.0 ml) hydride diisobutylaluminum in toluene. After stirring at the same temperature for 15 minutes, the mixture was left to warm to -40°C within 30 minutes. Was added water (50 ml) and after stirring at the same temperature for 5 minutes, the mixture was left to warm to 0°C for 10 minutes. Added ethyl acetate (30 ml) and after stirring at the same temperature for 15 minutes, the mixture was stirred at room temperature for 20 minutes. The gel mixture was filtered through celite and the celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml)was added manganese dioxide (75% chemically processed product, 3.0 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through goals and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound as a pale yellow solid (yield 150 mg, 61%).

1H-NMR (CDCl3) δ: 2,78 (3H, c), only 6.64 (1H, c), 7,21-7,26 (2H, m), of 7.36-7,51 (3H, m) 8,10 (1H, c)to 8.40 (2H, c), for 9.90 (1H, c).

Reference example 63

5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution (96 ml) of 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (475 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 503 mg) at room temperature and the mixture was stirred for 30 minutes. Was added dropwise 15-crown-5 (2,77 g) and the mixture was stirred for 30 minutes. Added pyridine-3-sulphonylchloride hydrochloride (1.35 g) and the mixture was additionally stirred for 3 hours. The reaction mixture was diluted with saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:3→2:3) and vykristallizovyvalas from a mixture of diisopropyl ether-ethyl acetate (4:1) to obtain specified in the title compounds as a colorless crystalline substance (yield 680 mg, 82%).

1H-NMR (CDCl3) δ: of 6.68 (1H, d, J=1,8 Hz), 6,99-7,05 (1H, m), 7,16-7,19 (2H, m), 7,35-7,39 (1H, m), 7,45-7,51 (1H, m), 7,69-7,73 (1H, m)to 8.14 (1H, d, J=1,8 Hz), 8,58-8,59 (1H, m), 8,81-8,83 (1H, m), to 9.91 (1H, c).

Reference example 64

1-(pyridine-3-ylsulphonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde

To the solution (36 ml) of 5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (240 mg) in those who rageragerage was added sodium hydride (60% in oil, 201 mg) at room temperature and the mixture was stirred for 30 minutes. Was added dropwise 15-crown-5 (1,11 g) and the mixture was stirred for 30 minutes. Added pyridine-3-sulphonylchloride hydrochloride (537 mg) and the mixture was additionally stirred for 3 hours. The reaction mixture was diluted with saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→2:3) and vykristallizovyvalas from diisopropyl ether to obtain specified in the title compounds as a colorless crystalline substance (yield 380 mg, 100%).

1H-NMR (CDCl3) δ: 6,69 (1H, d, J=1,8 Hz), 7,34-7,38 (1H, m), 7,44-of 7.48 (1H, m), to 7.61-of 7.69 (4H, m), 8,16 (1H, d, J=1,8 Hz), to 8.45 (1H, d, J=2.4 Hz), 8,81 (1H, m), to 9.91 (1H, c).

Reference example 65

4-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

4-Methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg) was dissolved in tetrahydrofuran (10 ml), was added sodium hydride (60% in oil, 60 mg) and the mixture was stirred at room temperature for 15 minutes. Added 15-crown-5 (0,30 ml) and the mixture was further stirred at the same temperature for 15 minutes. Added 3-pyridinesulfonamide (231 mg) and actionnow the mixture was stirred at room temperature for 1 hour. Added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain specified in the title compounds as a colorless solid (yield 172 mg, 53%).

1H-NMR (CDCl3) δ: 2,03 (3H, c), 7,01? 7.04 baby mortality (2H, m), 7,26-of 7.55 (5H, m), 8,07 (1H, c), of 8.47 (1H, m), 8,75-8,78 (1H, m), becomes 9.97 (1H, c).

Reference example 66

4-methyl-5-phenyl-1-(pyridine-2-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0,30 ml) and 2-pyridinesulfonamide (231 mg) instead of 3-pyridinesulfonamide got mentioned in the title compound in amorphous form (exit 262 mg, 80%).

1H-NMR (CDCl3) δ: 2,03 (3H, c), 6,92-to 6.95 (2H, m), 7,21-7,49 (5H, m), 7,65-of 7.69 (1H, m), 8,14 (1H, c), 8,64-8,65 (1H, m), 9,98 (1H, c).

Reference example 67

1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0,30 ml) and (1,2-dimethyl-1H-imides the l-4-yl)sulfonyl chloride (253 mg), got mentioned in the title compound as a colourless solid (exit 294 mg, 86%).

1H-NMR (CDCl3) δ: 2,05 (3H, c), of 2.33 (3H, c), 3,40 (3H, c), 6,48 (1H, c), 7,11-7,14 (2H, m), 7,26-7,41 (3H, m), 8,08 (1H, c), to 9.93 (1H, c).

Reference example 68

1-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0,30 ml) and (5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl chloride (298 mg)were specified in the title compound as oil (yield 379 mg, 100%).

1H-NMR (CDCl3) δ: 1,74 (3H, c), 2,04 (3H, c), of 3.69 (3H, c),? 7.04 baby mortality-7,07 (2H, m), 7,28-7,38 (3H, m), of 8.09 (1H, c), 9,96 (1H, c).

Reference example 69

1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde

By the reaction in the same conditions described in reference example 65 and using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0,30 ml) and (2,4-dimethyl-1,3-thiazol-5-yl)sulphonylchloride (275 mg)were specified in the title compound as oil (yield of 27.8 mg, 8%).

1H-NMR (CDCl3) δ: 2,05 (3H, c), 2,10 (3H, c)at 2.59 (3H, c), 7,07-7,10 (2H, m), 7,31-7,40 (3H, m), 8,02 (1H, c), 9,96 (1H, c).

Reference example 70

5-(2-forfinal)-4-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

analogichnym way described in reference example 65 and using 5-(2-forfinal)-4-methyl-1H-pyrrole-3-carbaldehyde (301 mg), sodium hydride (60% in oil, 179 mg), 15-crown-5 (0,88 ml) and pyridine-3-ylsulphonyl hydrochloride (476 mg)were specified in the title compound in the form of a crystalline substance of white color (yield 440 mg, 87%).

1H-NMR (CDCl3)δ: 2,02 (3H, c), 6,98? 7.04 baby mortality (1H, m), 7,13-7,24 (2H, m), 7,33-7,38 (1H, m), 7,43-7,51 (1H, m), 7,65-of 7.69 (1H, m), of 8.09 (1H, c), 8,54-8,55 (1H, m), 8,80-8,82 (1H, m), 9,98 (1H, c).

Reference example 71

1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

To a solution (60 ml) of 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.5 g) in methanol was added to chloride of methylamine (7.5 g) and cyanoborohydride sodium (2.4 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain specified in the title compound as a brown oil (yield 4.4 g, 100%).

1H-NMR (CDCl3) δ: 2,47 (3H, c), 2,98 (1H, users), 3,66 (2H, c), 6.35mm (1H, d, J=2.4 Hz), 7,51-EUR 7.57 (3H, m), to 7.61-to 7.68 (1H, m), 7,93-of 7.97 (2H, m).

Seloc the first example 72

tert-butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution of 1-[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (4.4 g) in ethyl acetate (60 ml) was added di-tert-butyl bicarbonate (2.8 ml) and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1) to obtain the specified title compound as a colourless oil (yield 3.4 g, 73%).

1H-NMR (CDCl3) δ: to 1.48 (9H, c), and 2.79 (3H, users), 4,17 (2H, users), 6,24 (1H, users), 7,35 (1H, users), 7,51-EUR 7.57 (2H, m), 7,62-to 7.68 (1H, m), of 7.90-7,94 (2H, m).

Reference example 73

tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate

tert-Butyl {[5-bromo-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0 g) was dissolved in a mixed solvent consisting of tetrahydrofuran (15 ml) and methanol (5 ml)and added dropwise at a temperature not higher than 10°C was added 8 mol/l aqueous sodium hydroxide solution (1.5 ml). After stirring at the same temperature for 4 hours to the residue was added to the ode and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=9:1→4:1) to obtain the specified title compound as a pale yellow oil (yield 410 mg, 61%).

1H-NMR (CDCl3) δ: to 1.48 (9H, c), and 2.79 (3H, c), 4,17 (2H, c)6,09 (1H, users), only 6.64 (1H, users), 8,07 (1H, usher.).

Reference example 74

tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a suspension (10 ml) of sodium hydride (60% in oil, 204 mg) in tetrahydrofuran was added a solution (3 ml) of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (410 mg) in N,N-dimethylformamide at 0°C and at the same temperature was added 15-crown-5 (938 mg) and pyridine-3-ylsulphonyl hydrochloride (456 mg). After stirring at room temperature for 2 hours to the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=8:1→3:1) to obtain specified in the connection header in the form of powder light yellow(output 522 mg, 85%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)2,80 (3H, users), 4,18 (2H, users), 6,28 (1H, users), 7,35 (1H, users), of 7.48-7,52 (1H, m), 8,18 is 8.22 (1H, m), cent to 8.85-8,88 (1H, m), 9,12-9,13 (1H, m).

Reference example 75

tert-butyl {[1-(2-chloro-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

1-(2-Chloro-3-pyridine sulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (443 mg) was dissolved in absolute tetrahydrofuran (5 ml), was added 2 mol/l solution of 0.74 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 30 minutes. To a solution of sodium borohydride (97 mg) in methanol (2.5 ml) was added to the reaction mixture and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml), was added di-tert-butyl bicarbonate (1.40 g), sodium hydrogen carbonate (0.54 g) and water (13 ml) and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate and the solvent UPrev is whether under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→3:1) to obtain specified in the connection header in the form of a solid substance (yield 361 mg, 61%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,87 (3H, c), the 4.29 (2H, c), 6,30-6,32 (1H, m), 6,95-7,00 (1H, m), 7,06-7,33 (5H, m), 7,51-7,56 (2H, m), scored 8.38-to 8.41 (1H, m).

Reference example 76

tert-butyl {[1-(6-chloro-5-methyl-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate

1-[(6-Chloro-5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (244 mg) was dissolved in absolute tetrahydrofuran (6.8 ml)was added 2 mol/l solution (0,34 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to a solution of sodium borohydride (51 mg) in methanol (3 ml) and the mixture was stirred at the same temperature for 3 minutes. Was added di-tert-butyl bicarbonate (654 mg) and 3 minutes later was added water (5 ml) and sodium bicarbonate (420 mg). The mixture was additionally stirred at room temperature for 30 minutes, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→3:1) obtained with the eat stated in the title compound as oil (yield 247 mg, 77%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), of 2.28 (3H, c), 2,82 (3H, c), 4,24-to 4.28 (2H, m), x 6.15 (1H, c), 7.23 percent-7,42 (7H, m), 8,15 (1H, c).

Reference example 77

tert-butyl ({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate

1-[(6-Chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (1.27 g) was dissolved in absolute tetrahydrofuran (20 ml), was added 2 mol/l solution (2.1 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a solution of sodium borohydride (277 mg) in methanol (10 ml) and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate. Was added di-tert-butyl bicarbonate (3,99 g) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml)was added sodium bicarbonate (1,53 g) and water (36 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→3:1) to obtain specified in the connection header in the form of a solid substance (yield 544 mg, 32%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,82 (3H, c)to 4.23 (2H, c), 6,16 (1H, c), 7.23 percent-7,49 (8H, m), of 8.28 (1H, c).

Reference example 78

tert-butyl methyl({[1-(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)carbamate

In argon atmosphere, a mixture of tert-butyl ({[1-(6-chloropyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (100 mg), methylboronic acid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassium carbonate (90 mg) and dioxane (3 ml) was stirred at 80°C for 24 hours. Added melborne acid (14 mg) and tetrakis(triphenylphosphine)palladium (25 mg) and the mixture was stirred at 90°C for 24 hours. Added melborne acid (14 mg), tetrakis(triphenylphosphine)palladium (25 mg), potassium carbonate (90 mg) and dioxane (2 ml) and the mixture was stirred at 90°C for 24 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound as oil (yield to 85.8 mg, 36%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,58 (3H, c), of 2.81 (3H, c), 4,20-to 4.23 (2H, m), 6,13 (1H, c), 7,07-7,10 (1H, m), 7.24 to 7,42 (7H, m), 8,39 (1H, c).

Reference example 79

tert-b is Teal methyl{[1-(pyridine-3-ylsulphonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}carbamate

In an argon atmosphere a suspension of tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (232 mg), 3-tienerporno acid (138 mg), tetrakis(triphenylphosphine)palladium (31,3 mg) and sodium carbonate (175 mg) in 1,2-dimethoxyethane (10 ml) and water (5 ml) was stirred at 105°C for 1 hour. The reaction mixture was left to cool to room temperature, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a pale yellow oil (yield 189 mg, 81%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,82 (3H, users), 4,22 (2H, users), 6,17 (1H, users),? 7.04 baby mortality-7,06 (1H, m), 7,16-7,17 (1H, m), 7,25-to 7.32 (3H, m), EUR 7.57-to 7.61 (1H, m), 8,56 (1H, d, J=2.4 Hz), 8,71-8,73 (1H, m).

Reference example 80

tert-butyl {[5-(4-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-forfinal)boric acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), n who were given indicated in the title compound as a pale yellow oil (yield 293 mg, 94%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), of 2.81 (3H, users), 4,22 (2H, users), 6,12 (1H, users), 7,00-7,06 (2H, m), 7.18 in-7,31 (4H, m), 7,56-of 7.60 (1H, m), 8,54-8,55 (1H, m), 8,73 is 8.75 (1H, m).

Reference example 81

tert-butyl methyl{[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-were)boric acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound as a pale yellow oil (yield 210 mg, 68%). More specifically, a suspension of tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-were)boric acid (190 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 ml) and water (7.5 ml) was stirred at 105°C for 18 hours. The reaction mixture was left to cool to room temperature, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:1→3:1) with the receipt of the m specified in the title compound as a pale yellow oil (yield 210 mg, 68%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)of 1.92 (3H, c), 2,84 (3H, users), 4.26 deaths (2H, users), 6,07 (1H, d, J=1.2 Hz), 6.87 in-6,89 (1H, m), 7,09-7,19 (2H, m), 7,26-to 7.35 (3H, m), 7,58 to 7.62 (1H, m), 8,54-8,55 (1H, m), 8,75-8,77 (1H, m).

Reference example 82

tert-butyl {[5-(4-fluoro-2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-fluoro-2-were)boric acid (215 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound as a pale yellow oil (yield 216 mg, 67%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)of 1.92 (3H, c), 2,84 (3H, users), 4,25 (2H, users), equal to 6.05 (1H, usher.), 6,79-6,91 (3H, m), 7,30-to 7.35 (2H, m), to 7.61-the 7.65 (1H, m), 8,58-8,59 (1H, m), 8,77-8,79 (1H, m).

Reference example 83

tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boric acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound as a pale yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}m is tinkerballa (300 mg), (4-methyl-3-thienyl)boric acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 ml) and water (7.5 ml) was stirred at 105°C for 18 hours. The reaction mixture was left to cool to room temperature, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=6:1→3:1) to obtain the specified title compound as a pale yellow oil (yield 200 mg, 64%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), is 1.81 (3H, c), and 2.83 (3H, users), 4.26 deaths (2H, users), 6,10 (1H, usher.), make 6.90 (1H, usher.), 7,02-7,03 (1H, m), 7,26-to 7.35 (2H, m), to 7.61-the 7.65 (1H, m), 8,58-8,59 (1H, m), 8,75-8,77 (1H, m).

Reference example 84

tert-butyl {[5-(3-cyanophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-cyanophenyl)boric acid (205 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound as a pale yellow oil (yield 298 mg, 94%).

1 3) δ: of 1.47 (9H, c), of 2.81 (3H, users), 4,22 (2H, users), 6,21 (1H, usher.), 7,31-to 7.35 (2H, m), 7,46-of 7.69 (6H, m), 8,56 (1H, d, J=1,8 Hz), 8,76-8,78 (1H, m).

Reference example 85

tert-butyl {[5-(2-chlorophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-chlorophenyl)boronic acid (218 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound in the form of oil-light blue color (exit 171 mg, 53%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)2,84 (3H, users), 4.26 deaths (2H, users), of 6.20 (1H, d, J=1,8 Hz), 7,26 and 7.36 (6H, m), 7,65-7,71 (1H, m), 8,58-8,59 (1H, m), 8,75-8,79 (1H, m).

Reference example 86

tert-butyl {[5-(2,4-differenl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-differenl)boric acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg)were specified in the title compound as a colourless oil (yield 113 mg, 50%).

1H-NMR (CDCl3) δ: 1.50 in (9H, c)2,84 (3H, users), 4,30 (2H, users), of 6.49 (1H, usher.), 6,78-6,92 (3H, m), of 7.48-7,58 (1H, m), 8,78 (1H, usher.).

Reference example 87

tert-butyl {[5-(2,5-differenl)-1H-pyrrol-3-yl]methyl}metalk Ramat

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2.5-differenl)boric acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg)were specified in the title compound as a colourless oil (yield 135 mg, 60%).

1H-NMR (CDCl3) δ: 1.50 in (9H, c)2,84 (3H, users), 4,30 (2H, users), 6,56 (1H, usher.), 6,77-6,85 (2H, m), 7,00-was 7.08 (1H, m), 7,20-7,26 (1H, m), of 8.90 (1H, usher.).

Reference example 88

tert-butyl {[5-(4-chloro-2-forfinal)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-chloro-2-forfinal)boric acid (243 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg)were specified in the title compound as a colourless oil (yield 127 mg, 54%).

1H-NMR (CDCl3) δ: 1.50 in (9H, c)2,84 (3H, c), 4,30 (2H, c), 6,55 (1H, usher.), to 6.80 (1H, usher.), 7,11-to 7.15 (2H, m), 7,46-7,52 (1H, m), 8,82 (1H, usher.).

Reference example 89

tert-butyl {[5-(2,4-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 44 and using tert-butyl {[5-(2,4-differenl)-1H-pyrrol-3-yl]methyl}methylcarbamate (113 mg), sodium hydride (60% in oil, 51 mg), 15-crown-5 (0.21 m is) hydrochloride and pyridine-3-ylsulphonyl (113 mg), got mentioned in the title compound as a pale yellow oil (yield 110 mg, 68%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,82 (3H, users), 4,24 (2H, users), to 6.19 (1H, usher.), 6,77-6,92 (2H, m), 7,11-7,19 (1H, m), 7,33-7,37 (2H, m), 7.68 per-7,72 (1H, m), to 8.62 (1H, d, J=2.4 Hz), 8,77-8,79 (1H, m).

Reference example 90

tert-butyl {[5-(2,5-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 44 and using tert-butyl {[5-(2,5-differenl)-1H-pyrrol-3-yl]methyl}methylcarbamate (135 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.25 ml) and pyridine-3-ylsulphonyl hydrochloride (135 mg)were specified in the title compound as a colourless oil (yield 105 mg, 54%).

1H-NMR (CDCl3)δ: 1.50 in (9H, c), 2,82 (3H, c)to 4.23 (2H, users), 6,24 (1H, usher.), 6,89-7,13 (4H, m), 7,33-7,39 (2H, m), 7,71 to 7.75 (1H, m), 8,67 (1H, d, J=2.4 Hz), 8,78-8,80 (1H, m).

Reference example 91

tert-butyl {[5-(4-chloro-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 44 and using tert-butyl {[5-(4-chloro-2-forfinal)-1H-pyrrol-3-yl]methyl}methylcarbamate (127 mg), sodium hydride (60% in oil, 54 mg), 15-crown-5 (0,22 ml) and pyridine-3-ylsulphonyl hydrochloride (120 mg)were specified in the title compound as a colourless oil (yield 103 mg, 57%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), of 2.81 (3H, c)to 4.23 (2H, users), 6,21 (1H, users) 7,08-to 7.15 (4H, m), 7,32-7,38 (2H, m), 7,69-7,73 (1H, m)8,64 (1H, d, J=2.4 Hz), 8,77-8,79 (1H, m).

Reference example 92

tert-butyl {[5-(3-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (3-forfinal)boric acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound as a pale yellow oil (yield 280 mg, 90%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), of 2.81 (3H, users), 4,22 (2H, users), 6,16 (1H, users), 6,93-7,11 (3H, m), 7,27-to 7.32 (3H, m), to 7.59-7,63 (1H, m), 8,58 (1H, d, J=2.1 Hz), 8,73 is 8.75 (1H, m).

Reference example 93

tert-butyl {[5-bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

5-Bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (565 mg) was dissolved in tetrahydrofuran (2 ml) and methanol (2 ml)at room temperature was added a 40%solution (1.5 ml) of methylamine in methanol and the mixture was stirred for 30 minutes. To the reaction mixture at room temperature was added sodium borohydride (130 mg) and the mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure, to the residue was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract is washed with the saturated aqueous solution of sodium bicarbonate, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (6 ml), was added di-tert-butyl bicarbonate (0.45 ml) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/l hydrochloric acid (10 ml) and the mixture was additionally stirred for 15 minutes. The reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→1:1) to obtain a mixture specified in the title compound and 5-bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde. The mixture was dissolved in tetrahydrofuran (5 ml), was added 2 mol/l solution (4 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 12 hours. To the reaction mixture solution was added sodium borohydride (131 mg) in methanol (1 ml) and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added concentrated aqueous RA is solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (6 ml), was added di-tert-butyl bicarbonate (0.45 ml) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain the specified title compound as a yellow oil (yield 384 mg, 50%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,49 (3H, c), a 2.71 (3H, users), is 4.15 (2H, users), 6,24 (1H, users), 7,47-7,52 (1H, m), 8,13-8,17 (1H, m), 8,84-8,86 (1H, m), 9,07-remaining 9.08 (1H, m).

Reference example 94

2-bromo-1-(2,6-differenl)alanon

To a solution of 1-(2,6-differenl)ethanone (10.0 g) in diethyl ether (50 ml) was added anhydrous aluminium chloride (86 mg) and the mixture was stirred for 5 minutes. Was added dropwise bromine (3.3 ml) at 10-15°C. After stirring at room temperature for 2 hours the mixture was poured into water icmes were extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain specified in the title compound as a pale yellow oil (yield 15.2 g, 100%).

1H-NMR (CDCl3) δ: 4,37 (2H, c), 6,97? 7.04 baby mortality (2H, m), 7,43-7,53 (1H, m).

Reference example 95

ethyl 2-cyano-4-(2,6-differenl)-4-oxobutanoate

To a solution of ethylcyanoacrylate (7,24 g) and diisopropylethylamine (19.9 g) in tetrahydrofuran (30 ml) was added dropwise a solution of 2-bromo-1-(2,6-differenl)ethanone (15,16 g) in tetrahydrofuran (15 ml) at 10-15°C. the Mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, 1 mol/l hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→3:2) to obtain specified in the connection header in the form of oil light green color (yield 13.8 g, 81%).

1H-NMR (CDCl3) δ: of 1.35 (3H, t, J=7,1 Hz), 3,44-of 3.53 (1H, m), 3,63-and 3.72 (1H, m), 4,13-4,18 (1H, m), or 4.31 (2H, square, J=7,1 Hz), 6,95-7,05 (2H, m), 7,44-rate of 7.54 (1H, m).

Reference example 96

methyl 2-cyano-4-(4-cyclohex is phenyl)-4-oxobutanoate

4-Cyclohexylacetophenone (10.0 g) was dissolved in chloroform (30 ml) and diethyl ether (30 ml) slowly dropwise added bromine (8,70 d). After completion of adding dropwise, the reaction mixture was stirred at room temperature for 1 hour, diluted with water and was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain crude 2-bromo-1-(5-cyclohexylidene-2-yl)ethanone (15,8 g) as oil. This substance was dissolved in tetrahydrofuran (20 ml) and added dropwise to a mixture of methyl cyanoacetate (4,95 g), diisopropylethylamine (16.2 g) and tetrahydrofuran (50 ml). The reaction mixture was stirred at room temperature for 20 hours, the insoluble substance was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→3:1) to obtain the specified title compound as oil (yield 12.1 g, 82%).

1H-NMR (CDCl3) δ: 1,20-is 1.51 (5H, m), 1,70-1,90 (5H, m), of 2.51-of 2.64 (1H, m), 3,47-to 3.73 (1H, m), to 3.58-3,88 (1H, m), 3,85 (3H, c), 4.09 to 4,19 (1H, m), 7,32 (2H, d, J=8.1 Hz), 7,89 (2H, d, J=8,1 Hz).

Reference example 97

ethyl 2-chloro-5-(6-differenl)-1H-pyrrole-3-carboxylate

The solution (14 ml) of ethyl 2-cyano-4-(2,6-differenl)-4-oxobutanoate (13,83 g) in ethyl acetate was added dropwise to 4 mol/l solution of a mixture of hydrogen chloride-ethyl acetate (100 ml) at 10-15°C. the Mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→8:2) to obtain the specified title compound as a crystalline substance yellow (yield 10.0 g, 68%).

1H-NMR (CDCl3) δ: to 1.38 (3H, t, J=7.2 Hz), 4,34 (2H, square, J=7,2 Hz), 6,95? 7.04 baby mortality (2H, m), 7,14-of 7.23 (2H, m), 9,20 (1H, usher.).

Reference example 98

methyl 2-chloro-5-(4-cyclohexylphenol)-1H-pyrrole-3-carboxylate

A solution of 14% hydrogen chloride - 1,4-dioxane (50 ml) was added to methyl 2-cyano-4-(4-cyclohexylphenol)-4-oxobutanoate (12.1 g) and the mixture was stirred at room temperature for 8 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was vykristallizovyvalas of diisopropyl ether and collected by filtration to obtain a mixture of approximately 1:1 (3,41 g) specified in the title compound and methyl 2-amino-5-(4-cyclohexylphenol)-3-furoate. The filtrate was concentrated under reduced pressure and the residue is ciali chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:2) to obtain the specified title compound as a crystalline substance (yield 0.64 g, 5%).

1H-NMR (CDCl3) δ: 1,22 is 1.48 (5H, m), 1,71 is 1.91 (5H, m), 2,46-of 2.58 (1H, m), 3,86 (3H, c), for 6.81 (1H, d, J=3.2 Hz), 7.23 percent (2H, d, J=8,3 Hz), was 7.36 (2H, d, J=8,3 Hz), 8,67 (1H, users).

Reference example 99

methyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (of 4.66 g), synthesized from methyl cyanoacetate and penacerrada, in a way similar to that described in reference example 95 and reference example 97, in acetonitrile (200 ml) was added triflate 2,6-dichloro-N-torpedine (6,26 g) for 10 minutes while cooling on ice. The reaction mixture was stirred at the same temperature for 2 hours and at room temperature for 2 hours and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→7:3) to obtain the specified title compound as a pale yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 ml) was added dropwise a solution of pencilvania (75 g) in tetrahydrofuran (370 ml). The mixture was stirred at room temperature for 12 the aces. The reaction mixture was filtered and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/l hydrochloric acid, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with diethyl ether to obtain methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77,4 g, 95%). To a solution (125 ml) of ethyl 2-cyano-4-(2,6-differenl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/l solution of hydrogen chloride-ethyl acetate (25 ml). The mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was washed 6%aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is washed with diisopropyl ether to obtain methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate in the form of a colorless crystalline substance (yield 10.0 g, 37%). Specified in the title compound was synthesized from the thus obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.

1H-NMR (CDCl3) δ: 3,90 (3H, c), 7,26-to 7.32 (1H, m), 7,40-of 7.60 (4H, m), 8,29 (1H, usher.).

Reference p. the emer 100

ethyl 5-(2,6-differenl)-1H-pyrrole-3-carboxylate

To a solution of ethyl 2-chloro-5-(2,6-differenl)-1H-pyrrole-3-carboxylate (9,82 g) in ethanol (200 ml) was added 10% palladium on coal (50% water content, 4,91 g) and the mixture was stirred in hydrogen atmosphere at 40°C for 72 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1) to obtain specified in the title compounds as a colorless crystalline substance (yield 3.80 g, 24%).

1H-NMR (CDCl3) δ: of 1.37 (3H, t, J=7.2 Hz), 4,32 (2H, square, J=7,2 Hz), 6,94? 7.04 baby mortality (2H, m), 7,11-7,21 (1H, m), 7.24 to 7,27 (1H, m), 7,54-of 7.55 (1H, m), 9,37 (1H, usher.).

Reference example 101

methyl 5-(4-cyclohexylphenol)-1H-pyrrole-3-carboxylate

To a solution of a mixture of approximately 1:1 (3,41 g) of methyl 2-chloro-5-(4-cyclohexylphenol)-1H-pyrrole-3-carboxylate and methyl 2-amino-5-(4-cyclohexylphenol)-3-furoate in methanol (30 ml) and ethyl acetate (10 ml) was added 10% palladium on coal (50% water content, 0.34 g) and the mixture was stirred in hydrogen atmosphere at 50°C for 14 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:1→2:1) to obtain the specified title compound as a crystalline substance (yield of 1.25 is, 41%).

1H-NMR (CDCl3) δ: 1,19 of 1.50 (5H, m), 1,73-of 1.93 (5H, m), 2,43-to 2.57 (1H, m), of 3.84 (3H, c)6,86 (1H, c), from 7.24 (2H, d, J=8,3 Hz), 7,41 (2H, d, J=8,3 Hz), was 7.45 (1H, DD, J=3,0, 1.7 Hz), 8,73 (1H, users).

Reference example 102

methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate

Methyl 2-chloro-4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (0,92 mg), 10% palladium on coal (50% water content, 0.20 g) and triethylamine (0,56 ml) suspended in methanol (30 ml) and the mixture was stirred in hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through celite and the insoluble substance was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain specified in the title compounds as a colorless solid (yield 0,69 g, 87%).

1H-NMR (CDCl3) δ: a 3.87 (3H, c), 7,24-7,31 (2H, m), 7,39-7,46 (2H, m), 7,51-rate of 7.54 (2H, m), 8,32 (1H, usher.).

Reference example 103

[5-(2,6-differenl)-1H-pyrrol-3-yl]methanol

Solution (35 ml) of ethyl 5-(2,6-differenl)-1H-pyrrole-3-carboxylate (at 3.35 g) in tetrahydrofuran was cooled to -50°C and added dropwise in small portions was added 1.5 mol/l solution (30 ml) hydride diisobutylaluminum in toluene. The mixture was stirred at the same temperature for 1 hour, the reaction mixture was added water and the mixture was stirred at room temperature in those which begins 1 hour. The reaction mixture was diluted with ethyl acetate, was added celite and anhydrous magnesium sulfate and the mixture was additionally stirred for 15 minutes. The suspension was filtered and the obtained filtrate was concentrated under reduced pressure to obtain specified in the title compound as a crystalline substance of a light red colour (yield 2.70 g, 97%).

1H-NMR (CDCl3) δ: 1,46 (1H, usher.), with 4.64 (2H, c), 6,88-7,02 (4H, m), 7,06-7,16 (1H, m), 9,07 (1H, usher.).

Reference example 104

[5-(4-cyclohexylphenol)-1H-pyrrol-3-yl]methanol

To a solution of methyl 5-(4-cyclohexylphenol)-1H-pyrrole-3-carboxylate (3.0 g) in absolute tetrahydrofuran (40 ml) was added dropwise to 1.5 mol/l solution (21,0 ml) hydride diisobutylaluminum in toluene at -78°C. the Mixture was further stirred at the same temperature for 2 hours. To the reaction mixture was added 1 mol/l hydrochloric acid and the mixture was diluted with ethyl acetate. The insoluble substance was filtered through celite and the filtrate was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a crystalline substance (yield 1.07 g, 40%).

1H-NMR (CDCl3) is: 1,16-1,50 (5H, m), 1,69-of 1.93 (5H, m), 2,45 is 2.55 (1H, m), 4,60 (2H, c), 6,45-6,51 (1H, m), for 6.81-6,86 (1H, m), 7,21 (2H, d, J=8,3 Hz), 7,39 (2H, d, J=8,3 Hz), 8,30 (1H, usher.), 1H not detected.

Reference example 105

5-(2,6-differenl)-1H-pyrrole-3-carbaldehyde

To the solution (26 ml) [5-(2,6-differenl)-1H-pyrrol-3-yl]methanol (2,56 g) in acetonitrile was added perruthenate Tetra-n-Propylamine (430 mg), N-methylmorpholine N-oxide (2.15 g) and powdered molecular sieves 4Å (5 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a crystalline substance of a light red colour (yield of 1.94 g, 77%).

1H-NMR (CDCl3) δ: 6,97-7,06 (2H, m), 7,16-7,24 (1H, m), 7,28-7,31 (1H, m), 7,56-7,58 (1H, m), of 9.55 (1H, usher.), 9,88 (1H, c).

Reference example 106

5-(4-cyclohexylphenol)-1H-pyrrole-3-carbaldehyde

To a solution (35 ml) [5-(4-cyclohexylphenol)-1H-pyrrol-3-yl]methanol (1,00 g) in acetonitrile was added perruthenate Tetra-n-Propylamine (115 mg), N-methylmorpholine N-oxide (0,60 g) and powdered molecular sieves 4Å (1,15 g) under cooling on ice. The mixture was stirred at room temperature for 1.5 hours and the reaction mixture was suspended in ethyl acetate and filtered through a whole is so The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain the specified title compound as a crystalline substance (yield of 0.53 g, 53%).

1H-NMR (CDCl3) δ: 1,17-1,49 (5H, m), 1.70 to 1,95 (5H, m), 2,45-of 2.58 (1H, m), 6.89 in (1H, c), 7,25 (2H, d, J=8.1 Hz), the 7.43 (2H, d, J=8.1 Hz), 7,47 (1H, c), 8,99 (1H, users), 9,82 (1H, c).

Reference example 107

1H-pyrrole-3-carbaldehyde

To a suspension of sodium hydride (13,7 g) in tetrahydrofuran (450 ml) was added dropwise pyrrole (17,4 g) under cooling on ice. The reaction mixture was stirred at the same temperature for 1.5 hours and added dropwise at the same temperature was added chloride triisopropylsilyl (50.0 g). The mixture was additionally stirred at a temperature below 10°C for 1.5 hours, was added ice water and the mixture was extracted with diethyl ether. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Simultaneously to the suspension chloride (chlormethine)dimethylammonio (36.5 g) in dichloromethane (500 ml) at 0°C was added a solution of the residue (57,7 g) in dichloromethane (30 ml). The reaction mixture was heated under reflux for 30 minutes and cooled to 0°C. the Obtained solid substance was collected by filtration and washed with diethyl ether. The obtained solid substance of restore and in water (50 ml), was added at room temperature, 1 mol/l aqueous sodium hydroxide solution (500 ml) and the mixture was stirred for 2 hours. The reaction mixture was extracted with chloroform, and ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is washed with diisopropyl ether to obtain specified in the connection header in the form of a crystalline substance in a light brown colour (yield 9.4 g, 38%).

1H-NMR (CDCl3) δ: 6,68-6,70 (1H, m), 6,83-6,86 (1H, m), 7,45-7,47 (1H, m), 9,00-9,20 (1H, m), 9,82 (1H, c).

Reference example 108

2-chloro-2,2-debtor-1-(2-were)alanon

Magnesium (turnings, 6.2 g) suspended in diethyl ether (10 ml) was added iodine (small amount) and slowly was added dropwise a solution of 2-bromthymol (43,26 g) in diethyl ether (100 ml). After stirring at room temperature for 1 hour, the reaction mixture was added dropwise to a solution of Hortiflorexpo acid (10.0 g) in diethyl ether (100 ml) at -10°C and the mixture was stirred at 0°C for 1 hour. To the reaction mixture was added concentrated aqueous solution of ammonium chloride and the mixture was extracted with diethyl ether. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue is kept under reduced pressure (temperature to the singing: 81-82°C/12-13 mm RT. Art.) obtaining specified in the title compound as a pale yellow oil (yield 4.9 g, 31%).

1H-NMR (CDCl3) δ: 2,54 (3H, c), 7,29 was 7.36 (2H, m), 7,47-7,53 (1H, m), 7,89-a 7.92 (1H, m).

Reference example 109

2.2-debtor-2-iodine-1-(2-were)alanon

To a suspension of zinc (1.6 g) in acetonitrile (40 ml) was added to chloride of trimethylsilyl (3.1 ml) and 2-chloro-2,2-debtor-1-(2-were)alanon (4.0 g) and the mixture was stirred at 55°C for 3 hours. The reaction mixture was left to cool to room temperature, was added iodine (3.5 g) and the mixture was additionally stirred for 2 hours. To the reaction mixture were added water and the mixture was extracted with diethyl ether. The extract was washed hydrogen sulfite solution sodium, aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane) to obtain the specified title compound as a yellow oil (yield 2.6 g, 46%).

1H-NMR (CDCl3) δ: of 2.51 (3H, c), 7,26-to 7.35 (2H, m), 7,46-7,51 (1H, m), to $ 7.91-7,94 (1H, m).

Reference example 110

2.2-debtor-4-iodine-1-(2-were)-4-trimethylsilyloxy-1-he

In a nitrogen atmosphere to a mixture of tetrakis(triphenylphosphine)palladium (0.52 g) and vinyltrimethylsilane (1.9 ml) was added 2,2-debtor-2-iodine-1-(2-were)etano is (2.6 g) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added diethyl ether, the insoluble substance was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane) to obtain the specified title compound as a colourless oil (yield 2.6 g, 74%).

1H-NMR (CDCl3) δ: 0,21 (9H, c)of 2.50 (3H, c), 2,70-2,89 (2H, m), 3,19-3,24 (1H, m), 7,27-to 7.32 (2H, m), 7,42-of 7.48 (1H, m), 7,89-a 7.92 (1H, m).

Reference example 111

3-fluoro-2-(2-were)-1H-pyrrol

To a solution (20 ml), 2,2-debtor-4-iodine-1-(2-were)-4-trimethylsilyloxy-1-she (2.5 g) in tetrahydrofuran was added 28%aqueous ammonia solution (6 ml) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (15 ml) and water (8 ml) was added potassium fluoride (0.75 g). The reaction mixture was stirred at 60°C for 3 hours and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified chromatograph is she on a column of silica gel (eluent: hexane-ethyl acetate=20:1) to obtain the specified title compound as a pale yellow oil (yield 0.87 g, 78%).

1H-NMR (CDCl3) δ: 2,39 (3H, d, J=1.5 Hz), 6,06-between 6.08 (1H, m), 6,60-6,63 (1H, m), 7,19-7,33 (4H, m), 7,71 (1H, users).

Reference example 112

5-bromo-1H-pyrrole-3-carbaldehyde

A solution of 1H-pyrrole-3-carbaldehyde (19.1 g) in tetrahydrofuran (300 ml) was cooled to -70°C was added dropwise a solution of N-bromosuccinimide (35,8 g) in N,N-dimethylformamide (100 ml). After stirring at the same temperature for 1 hour, the mixture was heated to -10°C for 2 hours and was further stirred for 30 minutes. To the reaction mixture were added ice water at 0°C and the mixture was left to warm to room temperature and was extracted with ethyl acetate. The extract was washed with 10%aqueous citric acid solution, 6%aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crystalline substance obtained as a residue, washed with diisopropyl ether to obtain specified in the title compounds as a colorless crystalline substance (yield of 17.7 g, 51%).

1H-NMR (CDCl3) δ: 6,65 of 6.66 (1H, m), 7,37-7,38 (1H, m), 8,80 (1H, usher.), to 9.70 (1H, c).

Reference example 113

5-(2-were)-1H-pyrrole-3-carbaldehyde

5-Bromo-1H-pyrrole-3-carbaldehyde (100 mg), 2-methylphenylimino acid (94 mg) and sodium carbonate (146 mg) suspended in a mixed dissolve the Le, consisting of 1,2-dimethoxyethane (5 ml) and water (2 ml) and the mixture was enough degirolami in nitrogen atmosphere. Added tetrakis(triphenylphosphine)palladium (33 mg) and the mixture was additionally degirolami and heated under reflux at 105°C for 24 hours. The reaction mixture was left to cool to room temperature and the mixture was extracted with water and ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=8:1→3:1) to obtain specified in the title compounds as a colorless crystalline substance (yield 72 mg, 68%).

1H-NMR (CDCl3) δ: 2,44 (3H, c), 6,75-6,77 (1H, m), 7.23 percent and 7.36 (4H, m), 7,50-7,51 (1H, m), is 8.75 (1H, usher.), 9,85 (1H, c).

Reference example 114

4-chloro-5-(2-forfinal)-1H-pyrrole-3-carbaldehyde

To a solution (15 ml) of 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (0.71 g) at 0°C and the mixture was stirred at 60°C for 2 hours. The mixture was cooled to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of the silica gel (eluent: hexane-ethyl acetate=8:1→3:1) to obtain the specified title compound as yellow powder (yield 0.55 g, 46%).

1H-NMR (CDCl3) δ: 7,15-7,40 (3H, m), 7,52 (1H, d, J=3.6 Hz), 7,97-8,03 (1H, m), 9,24 (1H, usher.), 9,96 (1H, c).

Reference example 115

4-fluoro-5-(2-forfinal)-1H-pyrrole-3-carbaldehyde

To a solution (60 ml) of 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (3.1 g) in tetrahydrofuran was added triflate 2,6-dichloro-N-torpedine (5.6 g) at 0°C and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain the specified title compound as a crystalline substance of white color (yield of 0.43 g, 13%).

1H-NMR (CDCl3) δ: 7,11-7,30 (4H, m), 7,80-7,87 (1H, m), 9,14 (1H, users), 9,88 (1H, c).

Reference example 116

4-fluoro-5-(2-were)-1H-pyrrole-3-carbaldehyde

Sodium hydride (0.40 g) was washed twice with hexane and suspended in tetrahydrofuran (10 ml). Solution was added 3-fluoro-2-(2-were)-1H-pyrrole (0,86 g) in tetrahydrofuran (3 ml) at 0°C and the mixture was stirred at the same temperature for 30 minutes. Solution was added (2 ml) of treetop pelsall of triptoreline (2.7 ml) in tetrahydrofuran at 0°C and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture were added ice water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml) and acetonitrile (2 ml), was added chloride (chlormethine)dimethylammonio (1.6 g) and the mixture was heated under reflux for 2 hours and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 ml), was added 1 mol/l aqueous sodium hydroxide solution (20 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain the specified title compound as a yellow oil (yield of 0.48 g, 48%).

1H-NMR (CDCl3) δ: of 2.38 (3H, c), 7.23 percent-to 7.32 (5H, m), scored 8.38 (1H, users), 9,87 (1H, c).

Reference example 117

5-nitro-3-(trifluoromethyl)pyridin-2-ol

To concentrated sulfuric acid (18 ml) cooled on ice was added 2-hydroxy-3-(thrift rmutil)pyridine (3.0 g) and the mixture was stirred at the same temperature for 5 minutes. Dropwise within 5 minutes was added fuming nitric acid (90-95%, 7 ml) and the mixture was left to warm to room temperature for 2 hours, heated to 50°C and was stirred for 3 hours. After cooling to room temperature the reaction mixture was poured into ice (200 g) and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate washed with diisopropyl ether to obtain specified in the connection header in the form of a solid substance (yield 2.7 g, 69%).

1H-NMR (CDCl3) δ: 8,65-8,67 (1H, m), 8,80-8,81 (1H, m), 1H not detected.

Reference example 118

2-chloro-5-nitro-3-(trifluoromethyl)pyridine

A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.65 g), pentachloride phosphorus (3,17 g) and phosphorus oxychloride (1.5 ml) was stirred at 90°C for 3 hours. After cooling to room temperature the reaction mixture was poured into ice and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→3:1) to obtain the specified title compound as a yellow oil (yield of 2.21 g, 77%).

1H-NMR (CDCl3)δ: 8,79-8,81 (1H, m), 9,40-9,41 (1H, m).

Reference example 119

6-chloro-5-(trifluoromethyl)pyridine-3-amine

Water (40 ml) was added reduced iron (1.3 g) and ammonium chloride (2.1 g) and the mixture was stirred at room temperature for 5 minutes. Solution was added 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (1.8 g) in methanol (40 ml) and the mixture was stirred at room temperature for 1 hour. Added reduced iron (2.3 g) and the mixture was further stirred at the same temperature for 3 hours. The reaction mixture was filtered through goals and celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain specified in the connection header in the form of a solid substance (yield 1.0 g, 65%).

1H-NMR (CDCl3) δ: 7,29 (1H, m), to 7.99 (1H, m), 2H not detected.

Reference example 120

6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride

To water (27 ml) under cooling on ice dropwise within 20 minutes was added thionyl chloride (4 ml). The mixture was stirred at room temperature for 12 hours to obtain toxicodynamic solution of sulfur. Separately, concentrated hydrochloric acid 9 ml) with stirring under cooling in ice, was added 6-chloro-5-(trifluoromethyl)pyridine-3-amine (1,14 g) and further added concentrated hydrochloric acid (9 ml). Dropwise within 10 minutes in water (6 ml) was added a solution of sodium nitrite (0,44 g). To the above toxicoderma the sulphur solution with the addition of copper chloride (15 mg) slowly at 5°C was added to the reaction mixture. While cooling on ice, the mixture was additionally stirred for 30 minutes and the precipitate was collected by filtration and washed with water. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→9:1) to obtain specified in the connection header in the form of a solid orange color (exit 437 mg, 27%).

1H-NMR (CDCl3) δ: 8,58 (1H, m), 9,18 (1H, m).

Reference example 121

6-chloro-2-methylpyridin-3-sulfonyl chloride

To water (24 ml) for 20 minutes while cooling on ice, was added dropwise thionyl chloride (4 ml). The mixture was stirred at room temperature for 12 hours to obtain toxicodynamic solution of sulfur. Separately, concentrated hydrochloric acid (6 ml) was added 5-amino-2-chloro-6-methylpyridine (1.0 g) under stirring while cooling on ice and added dropwise within 10 minutes the solution was added sodium nitrite (0.5 g) in water (2 ml). To the above toxicoderma the sulphur solution with the addition of copper chloride (10 mg) at 5°C was gradually added to the reaction mixture. While cooling on ice, the mixture was additionally stirred for 30 minutes and the precipitate of I and by filtration and washed with water to obtain specified in the title compound as a pale yellow solid (yield 1.1 g, 67%).

1H-NMR (CDCl3) δ: 2,99 (3H, c), 7,41 (1H, DD, J=8,7, and 0.9 Hz), compared to 8.26 (1H, d, J=8,4 Hz).

Reference example 122

ethyl 1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Using a similar reaction to that described in reference example 40 and using 5-bromo-6-chloropyridin-3-sulfonyl chloride (3,49 g)were specified in the title compound in the form of solid yellow (yield 1.63 g, 38%).

1H-NMR (CDCl3) δ: of 1.35-1.39 (3H, m), 4,29-4,37 (2H, m), 6,60 (1H, c), 7,18-7,20 (2H, m), 7,35-7,51 (4H, m), of 8.06 (1H, c), to 8.45 (1H, c), 8,78 (1H, c).

Reference example 123

ethyl 5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carboxylate

Using a similar reaction to that described in reference example 40 and using 6-chloro-5-(trifluoromethyl)pyridine-3-sulphonylchloride (413 mg)were specified in the title compound as a colorless solid (yield 191 mg, 35%).

1H-NMR (CDCl3) δ: of 1.37 (3H, t, J=7.2 Hz), 4,33 (2H, DD, J=14,4, 7,2 Hz), is 6.61 (1H, c), 7,16-to 7.18 (2H, m), 7,33 was 7.45 (3H, m), the 7.65 (1H, c), of 8.09 (1H, c), is 8.75 (1H, c), 8,98 (1H, c).

Reference example 124

ethyl 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate

Using a similar reaction to that described in reference example 40 and using 6-chloro-2-methylpyridin-3-sulphonylchloride (543 mg)were specified in the title compound as a red oil (yield 135 mg, 18%).

1H-NMR (CDCl3) δ: 1,35-1,40 (3H, m), 2,4 (3H, c)to 4.33 (2H, DD, J=14,1, 6.9 Hz), 6,59 (1H, d, J=1,8 Hz), 6,82-7,49 (7H, m), 8,21 (1H, d, J=2.1 Hz), 8,51 (1H, DD, J=4,8, 1.8 Hz).

Reference example 125

methyl 4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carboxylate

Using a similar reaction to that described in reference example 36 and using methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg)were specified in the title compound as a colorless solid (yield 206 mg, 73%). More specifically, to a solution of methyl 4-fluoro-5-phenyl-1H-pyrrole-3-carboxylate (172 mg) in tetrahydrofuran (10 ml) was added sodium hydride (60% in oil, 94 mg) and the mixture was stirred for 15 minutes. Added 15-crown-5 (0,48 ml) and the mixture was additionally stirred for 15 minutes. Added hydrochloride pyridine-3-sulphonylchloride (219 mg) and the mixture was stirred for 30 minutes. Added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain specified in the title compounds as a colorless solid (yield 206 mg, 73%).

1H-NMR (CDCl3) δ: the 3.89 (3H, c), 7,17-7,20 (2H, m), 7,26-of 7.55 (5H, m), 7,95 (1H, d, J=4,8 Hz), 8,50-8,51 (1H, m), 8,76-8,78 (1H, m).

Reference example 126

1-[(5-bromopyridin-3-yl)sulfo the yl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 62 and using ethyl 1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (1.63 g)were specified in the title compound in the form of solid light yellow (yield 1.18 g, 80%).

1H-NMR (CDCl3) δ: 6,63 (1H, c), 7,17-7,20 (2H, m), of 7.36-7,39 (2H, m), 7,50-7,52 (2H, m), 8,10 (1H, c), 8,46 (1H, c), 8,79-8,80 (1H, m), to 9.91 (1H, c).

Reference example 127

5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 62 and using ethyl 5-phenyl-1-{[(5-trifluoromethyl)pyridine-3-yl]sulfonyl}-1H-pyrrole-3-carboxylate (190 mg)were specified in the title compound as a colorless solid (yield 138 mg, 83%).

1H-NMR (CDCl3) δ: only 6.64 (1H, d, J=1.5 Hz), 7,15-to 7.18 (2H, m), 7,33-7,38 (2H, m), 7,44-7,47 (1H, m), 7,63-to 7.64 (1H, m)to 8.14 (1H, d, J=1.5 Hz), 8,76 (1H, d, J=2.1 Hz), of 9.00 (1H, d, J=1.5 Hz), 9,92 (1H, c).

Reference example 128

1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 62 and using ethyl 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (364 mg)were specified in the title compound in the form of solid orange (exit 182 mg, 57%).

1H-NMR (CDCl3) δ: 2,47 (3H, c), 6,62 (1H, d, J=1,8 Hz), 6,83-of 6.90 (1H, m), 7,02? 7.04 baby mortality (2H, m), 7,16-7,31 (3H, m), 7,39-7,42 (1H, m), 8,24 1H, c)charged 8.52-8,54 (1H, m), to 9.93 (1H, c).

Reference example 129

4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

Under nitrogen atmosphere a solution of methyl 4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carboxylate (200 mg) in tetrahydrofuran (10 ml) was cooled to -78°C and under stirring was added 1.5 mol/l solution of 1.85 ml) hydride diisobutylaluminum in toluene. After stirring at the same temperature for 15 minutes the mixture was heated to 0°C for 1.5 hours. Was added water (20 ml) and the mixture was stirred at the same temperature for 5 minutes. After stirring was added ethyl acetate (20 ml) and the mixture was stirred for 15 minutes and then stirred at room temperature for 20 minutes. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml)was added manganese dioxide (75% chemically processed product, 1.0 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (Elya is NT: hexane-ethyl acetate=19:1→1:2) to obtain specified in the title compounds as a colorless solid (yield 123 mg, 67%).

1H-NMR (CDCl3) δ: 7,17-7,20 (2H, m), 7,26-EUR 7.57 (5H, m), of 7.96 (1H, d, J=4,8 Hz), 8,50-8,51 (1H, m), 8,76-8,80 (1H, m), 9,92 (1H, c).

Reference example 130

5-(2,6-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-(2,6-differenl)-1H-pyrrole-3-carbaldehyde (420 mg) in tetrahydrofuran (42 ml) at room temperature was added sodium hydride (60% in oil, 244 mg) and the mixture was stirred for 30 minutes. Was added dropwise 15-crown-5 (1,34 g) and the mixture was stirred for 30 minutes. Added hydrochloride 3-pyridinesulfonamide (565 mg) and the mixture was additionally stirred for 1 hour. The reaction mixture was diluted with saturated salt solution and the mixture was extracted with ethyl acetate. The extract obtained was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:3→1:1) and vykristallizovyvalas from diisopropyl ether to obtain specified in the title compounds as a colorless crystalline substance (yield 590 mg, 84%).

1H-NMR (CDCl3) δ: 6,76 (1H, d, J=1.9 Hz), 6.90 to-6,95 (2H, m), 7,40-7,52 (2H, m), to 7.77-7,81 (1H, m), 8,18 (1H, d, J=1.9 Hz), 8,65-8,66 (1H, m), cent to 8.85-8,87 (1H, m), to 9.91 (1H, c).

Reference example 131

5-(4-cyclohexylphenol)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To dissolve the 5-(4-cyclohexylphenol)-1H-pyrrole-3-carbaldehyde (0.17 g) in tetrahydrofuran (12 ml) at room temperature was added sodium hydride (60% in oil, 68 mg). The mixture was stirred for 20 minutes, was added 3-pyridinesulfonamide (0,19 g) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:2→2:1) to obtain the specified title compound as a crystalline substance (yield 0.26 g, 97%).

1H-NMR (CDCl3) δ: 1,21-of 1.53 (5H, m), 1,73-to 1.98 (5H, m), 2,50-2,60 (1H, m), to 6.57 (1H, d, J=1.9 Hz), 7.03 is-to 7.09 (2H, m), 7,13-7,29 (3H, m), of 7.48 (1H, DDD, J=8,3, 2,0, 1.9 Hz), 8,11 (1H, d, J=1.9 Hz), 8,49 (1H, d, J=2.3 Hz), 8,73 (1H, DD, J=4,8, and 1.6 Hz), of 9.89 (1H, c).

Reference example 132

1-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-forfinal)-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 65 and using 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (893 mg) and 6-chloropyridin-3-sulphonylchloride (1.30 grams)were specified in the title compound in the form of solid light red (output 1,14 g, 66%). More specifically, 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (893 mg) was dissolved in tetrahydrofuran (10 ml), was added sodium hydride (60% in oil, 226 mg) and the mixture was stirred at room temperature for 15 minutes. Added the 15-crown-5 (1.1 ml) and the mixture was further stirred at the same temperature for 15 minutes. Added 6-chloropyridin-3-sulphonylchloride (1.30 grams). The reaction mixture was stirred at room temperature for 15 minutes. Added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→3:2) to obtain specified in the connection header in the form of a solid light red (output 1,14 g, 66%).

1H-NMR (CDCl3) δ: of 6.71 (1H, d, J=9.0 Hz), 7,05 (1H, t, J=9.0 Hz), 7,19-of 7.23 (2H, m), 7,38 (1H, d, J=8,4 Hz), 7,45-7,53 (1H, m), 7,63-to 7.67 (1H, m), 8,11 (1H, d, J=1,8 Hz), with 8.33 (1H, d, J=2.7 Hz), to 9.91 (1H, c).

Reference example 133

5-(2-forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

In argon atmosphere, a mixture of 1-[(6-chloropyridin-3-yl)sulfonyl]-5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (365 mg), methylboronic acid (90 mg), tetrakis(triphenylphosphine)palladium (116 mg), potassium carbonate (691 mg) and 1,4-dioxane (25 ml) was stirred at 80°C for 3 days. The reaction mixture was poured into concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with what likehell (eluent: hexane-ethyl acetate=19:1→1:1) to obtain specified in the connection header in the form of a solid yellow (yield 134 mg, 39%).

1H-NMR (CDCl3) δ: 2,64 (3H, c), to 6.67 (1H, d, J=1,8 Hz),? 7.04 baby mortality (1H, t, J=8,4 Hz), 7,17-7,21 (3H, m), 7,45 is 7.50 (1H, m), 7,58 (1H, DD, J=8,7, 3.6 Hz), to 8.12 (1H, d, J=1,8 Hz), to 8.45 (1H, d, J=2.4 Hz), of 9.89 (1H, c).

Reference example 134

5-(2-forfinal)-1-(pyridine-2-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

Using a similar reaction to that described in reference example 65 and using 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (190 mg) and pyridine-2-sulfonyl chloride (231 mg)were specified in the title compound in the form of solid light red (exit 183 mg, 55%).

1H-NMR (CDCl3) δ: to 6.67 (1H, d, J=1,8 Hz), 6,97 (1H, t, J=8.7 Hz), 7,07-7,10 (2H, m), of 7.36-7,42 (1H, m), 7,52-of 7.55 (2H, m), 7,76-of 7.82 (1H, m), 8,23 (1H, d, J=1.5 Hz), 8,67 (1H, d, J=4.5 Hz), 9,92 (1H, c).

Reference example 135

5-(2-forfinal)-1-[(1-methyl-1H-pyrazole-4-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde

A similar method described in reference example 65 and using 5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (189 mg) and 1-methyl-1H-pyrazole-4-sulphonylchloride (217 mg)were specified in the title compound in the form of a crystalline substance yellow (yield 217 mg, 65%).

1H-NMR (CDCl3) δ: of 3.85 (3H, c), to 6.67 (1H, d, J=1,8 Hz),? 7.04 baby mortality-7,11 (1H, m), 7,17-7,22 (1H, m), 7,25-to 7.35 (3H, m), 7,43-7,50 (1H, m), of 8.06 (1H, d, J=1.5 Hz), 9,86 (1H, c).

Reference example 136

5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-(2-were)-1H-pyrrole-3-carbaldehyde (371 mg) in tetrahydrofuran is (10 ml) was added sodium hydride (60% in oil, 288 mg) and 15-crown-5 (1,32 g) at room temperature. After stirring for 5 minutes at the same temperature was added a suspension of the hydrochloride pyridine-3-sulphonylchloride (642 mg) in N,N-dimethylformamide (5 ml). After stirring for 15 minutes was added ice water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=6:1→3:1) to obtain specified in the connection header in the form of oil red (output 521 mg, 80%).

1H-NMR (CDCl3) δ: 1,82 (3H, c), 6,56 (1H, d, J=1.5 Hz), 6.87 in-6,90 (1H, m), 7,11-7,19 (2H, m), 7,30-7,39 (2H, m), 7,56-of 7.60 (1H, m), 8,15 (1H, d, J=1.5 Hz), charged 8.52-8,53 (1H, m), 8,80-8,82 (1H, m), 9,92 (1H, c).

Reference example 137

4-chloro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

A suspension of sodium hydride (60% in oil, 216 mg) in tetrahydrofuran (5 ml) was cooled to 0°C, was added a solution of 4-chloro-5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (335 mg) in tetrahydrofuran (5 ml), 15-crown-5 (991 mg) and pyridine-3-sulphonylchloride hydrochloride (482 mg) at 10°C or below. After stirring for 15 minutes was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and the concentration of Aravali under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→2:1) to obtain the specified title compound as yellow powder (yield 429 mg, 78%).

1H-NMR (CDCl3) δ: 7,02-was 7.08 (1H, m), 7,19-7,29 (2H, m), 7,37-7,41 (1H, m), 7,50-EUR 7.57 (1H, m), 7.68 per-7,72 (1H, m), 8,15 (1H, c), 8,54-8,55 (1H, m), 8,83-8,86 (1H, m), becomes 9.97 (1H, c).

Reference example 138

4-fluoro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

Sodium hydride (60% in oil, 0.25 g) was washed twice with hexane and suspended in tetrahydrofuran (10 ml). At 0°C was added a solution (5 ml) of 4-fluoro-5-(2-forfinal)-1H-pyrrole-3-carbaldehyde (0,43 g) in tetrahydrofuran and the mixture was stirred at the same temperature for 30 minutes. At 0°C was added 15-crown-5 (1.3 ml) and 3-pyridinesulfonamide hydrochloride (0.68 g) and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a crystalline substance light yellow (yield 0.55 g, 76%).

1H-NMR (CDCl3) δ: 7,02-was 7.08 (1H, m), 7,20-7,31 (2H, m), of 7.36-7,41 (1H, m), of 7.48-of 7.55 (1H, m), to 7.67-7,71 (1H, m), of 8.00 (1H, d, J=5,1 Hz), 8,55-8,56 (1H, m), 8,83 cent to 8.85 (1H, m), to 9.93 (1H, c).

Reference example 139

4-fluoro-5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

Sodium hydride (60% in oil, 0.11 g) was washed twice with hexane and suspended in tetrahydrofuran (10 ml). At 0°C was added a solution (5 ml) of 4-fluoro-5-(2-were)-1H-pyrrole-3-carbaldehyde (0.45 g) in tetrahydrofuran and the mixture was stirred at the same temperature for 15 minutes. At 0°C was added a solution (2 ml), 15-crown-5 high (0.56 ml) and 3-pyridinesulfonamide (0,44 g) in tetrahydrofuran and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a crystalline substance light yellow (yield of 0.59 g, 77%).

1H-NMR (CDCl3) δ: 1.77 in (3H, c), 7,02? 7.04 baby mortality (1H, m), 7,17-of 7.23 (2H, m), 7,29-7,34 (1H, m), 7,37-7,42 (1H, m), 7,54-7,58 (1H, m), of 8.00 (1H, d, J=4.5 Hz), 8,49-and 8.50 (1H, m), 8,81-8,83 (1H, m), 9,92 (1H, c).

Reference example 140

2-chloro-5-(2,6-differenl)-1-(pyridine-3-ylsulphonyl-1H-pyrrole-3-carbaldehyde

To a solution of 5-(2,6-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (250 mg) in tetrahydrofuran (10 ml) and N,N-dimethylformamide (10 ml) was added N-chlorosuccinimide (1.06 g) and the mixture was stirred for 15 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:3→1:1) to obtain the specified title compound as a pale yellow oil (yield 160 mg, 58%).

1H-NMR (CDCl3) δ: 6,74 (1H, s), 7,00-7,05 (2H, m), 7,42-7,56 (2H, m), 8,10-to 8.14 (1H, m), 8,91 (1H, DD, J=4,9, 1.5 Hz), 9,07 (1H, d, J=2.1 Hz), 9,92 (1H, s).

Reference example 141

2-chloro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (331 mg) in N,N-dimethylformamide (33 ml) was added N-chlorosuccinimide (268 mg) and the mixture was stirred at 60°C for 1 hour. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. OS is atok was purified by chromatography on a column of silica gel (eluent : hexane-ethyl acetate =7:3→1:1) to obtain the specified title compound as a colourless oil (yield 250 mg, 68%).

1H-NMR (COCl3) δ: of 6.65 (1H, s), 7,13-to 7.35 (3H, m), 7,45-of 7.55 (2H, m), 8,09-8,13 (1H, m), 8,90-9,03 (2H, m), 9,92 (1H, s).

Reference example 142

tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate

1-[(5-Bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (1.18 g) was dissolved in absolute tetrahydrofuran (15 ml), was added 2 mol/l solution (4.6 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 16 hours. To a solution of sodium borohydride (341 mg) in methanol (6 ml) was added to the reaction mixture and the mixture was stirred at the same temperature for 5 minutes. Was added di-tert-butyl bicarbonate (a 3.87 g) and after 5 minutes was added water (15 ml) and sodium bicarbonate (1.26 g). The mixture was additionally stirred at room temperature for 30 minutes, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) and fractions showing Rf values equal to 0.63, 0.30 0,075 (eluent: hexane-ethyl acetate=3:1) examination of the TLC were collected and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml), was added dioxi the manganese (75% chemically processed product, 3.0 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the specified title compound as a colourless oil (yield 733 mg, 48%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,82 (3H, c)to 4.23 (2H, m), 6,16 (1H, c), 7,21-7,56 (7H, m), 8,44 (1H, c), 8,76 (1H, c).

Reference example 143

tert-butyl{[5-{2,4-dimetilfenil)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 19 and using tert-butyl{[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,4-dimetilfenil)boric acid (209 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg)were specified in the title compound as a pale yellow oil (yield 177 mg, 56%).

1H-NMR (COCl3) δ: 1,46 (N, C)1,89 (3H, s), a 2.36 (3H, s), and 2.83 (3H, s), 4,25 (2H, users), 6,03-6,04 (1H, m), 6,76 (1H, d, J=8,l Hz), 6,92-to 6.95 (1H, m), 7,00 (1H, users), 7,26-7,33 (2H, m), to 7.61-the 7.65 (1H, m), 8,56-to 8.57 (1H, m), 8,75-8,77 (1H, m).

Referential example 144

tert-butyl{[5-(2-formylphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl{[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg) RA is tarali in toluene (10 ml) and the mixture was enough degirolami. At room temperature was added DICYCLOHEXYL(2',6'-dimethoxybiphenyl-2-yl)phosphine (66 mg) and Tris(dibenzylideneacetone)dipalladium (0) (37 mg). The mixture was stirred for 30 minutes at the degassing and added 2 mol/l aqueous solution of sodium carbonate (1.2 ml) and 2-formylphenyl)boric acid (180 mg). After additional stirring at room temperature for 15 minutes the mixture was heated to 120°C for 1 hour and was stirred for 16 hours. The reaction mixture was cooled to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→1:1) to obtain the specified title compound as a yellow oil (yield 218 mg, 48%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)of 2.86 (3H, c), 4,27 (2H, users), 6,23 (1H, users), 7,09-7,11 (1H, m), 7,28-7,33 (1H, m), the 7.43 (1H, d, J=1.2 Hz), 7,53-to 7.61 (3H, m), of 7.96-to 7.99 (1H, m), 8,49-and 8.50 (1H, m), 8,75-8,77 (1H, m), being 9.61-9,62 (1H, m).

Reference example 145

tert-butyl methyl{[5-[4-(methylsulphonyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate

A mixture of tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 4-(methanesulfonyl)phenylboric acid (300 mg), tetrakis(triphenyl ospin)palladium (115 mg), sodium carbonate (320 mg), 1,2-dimethoxyethane (10 ml) and water (10 ml) was stirred under nitrogen atmosphere at 80°C for 14 hours. The reaction mixture was left to cool to room temperature, filtered through celite and the filtrate was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1→1:2) to obtain the specified title compound as oil (yield 275 mg, 64%).

1H-NMR (CDCl3) δ: 1.26 in (9H, c), and 2.79 (3H, c), of 3.13 (3H, c), 4,22 (2H, c), of 6.26 (1H, c), 7,26-7,37 (2H, m), 7,44-7,71 (3H, m), to 7.93 (2H, d, J=8,3 Hz), 8,58 (1H, d, J=2.1 Hz), 8,76 (1H, DD, J=4,9, 1.5 Hz).

Reference example 146

tert-butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

tert-Butyl {[5-(2-formylphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (218 mg) was dissolved in tetrahydrofuran (2 ml) and at 0°C was added sodium borohydride (24 mg) and methanol (1 ml). After stirring at the same temperature for 30 minutes, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1→1:3) to obtain the specified title compound as a colourless oil (yield 132 mg, 60%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,10-to 2.15 (1H, m), 2,85 (3H, c), 4,25 (2H, users), 4,30-to 4.38 (2H, m), 6,12 (1H, d, J=1.5 Hz), 6,69-6,72 (1H, m), 7,13-to 7.18 (1H, m), 7,30-to 7.35 (2H, m), 7,44-7,49 (1H, m), to 7.59 to 7.62 (2H, m), 8,50 (1H, d, J=2.4 Hz), 8,76-8,78 (1H, m).

Reference example 147

5-mesityl-1H-pyrrole-3-carbaldehyde

A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g), 2,4,6-trimethylaniline acid (3.28 g), cesium carbonate (13,0 g), tri-tert-butylphosphine (0.10 g), Tris(dibenzylideneacetone)diplegia (0) (0,23 g) and mesitylene (200 ml) was stirred at reflux for 5 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:1) to obtain the specified title compound as amorphous forms brown (output 0,30 g, 28%).

1H-NMR (CDCl3) δ: 2,11 (6H, c), 2,32 (3H, c), 6,51-of 6.52 (1H, m), 6,93 (2H, c), 7,47-7,49 (1H, m), 9,82 (1H, c), 1H not detected.

Reference example 148

5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde

5-Bromo-1H-pyrrole-3-carbaldehyde (174 mg), [2-(methylthio)phenyl]boric acid (202 mg) and sodium carbonate (254 mg) suspended in a mixed solvent consisting of 1,2-dimethoxyethane (5 ml) and water (2 ml) and the mixture enough Gerasimova and in nitrogen atmosphere. Added tetrakis(triphenylphosphine)palladium (58 mg) and the mixture was additionally degirolami and stirred at 105°C for 16 hours. The reaction mixture was left to cool to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=9:1→4:1) to obtain the specified title compound as a crystalline substance light yellow (yield 150 mg, 69%).

1H-NMR (CDCl3) δ: of 2.38 (3H, c), 6,94-to 6.95 (1H, m), 7,21-7,31 (2H, m), 7,39-7,42 (1H, m), of 7.48-7,53 (2H, m), 9,85 (1H, c), for 9.95 (1H, usher.).

Reference example 149

5-(2-bromophenyl)-1H-pyrrole-3-carbaldehyde

A similar method described in reference example 148, and using 5-bromo-1H-pyrrole-3-carbaldehyde (870 mg), (2-bromophenyl)boric acid (1.20 g), sodium carbonate (1.27 g) and tetrakis(triphenylphosphine)palladium (289 mg)were specified in the title compound in the form of a colorless crystalline substance (exit 396 mg, 32%).

1H-NMR (CDCl3) δ: 6,94-to 6.95 (1H, m), 7,16-7,22 (1H, m), 7,34-7,39 (1H, m), 7,49-rate of 7.54 (2H, m), 7,63-7,66 (1H, m), 9.28 are (1H, usher.), 9,85 (1H, c).

Reference example 150

5-[2-(methylsulfinyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrol-3-kerbal is Devida (200 mg) in ethyl acetate (10 ml) was added 3-chloroperbenzoic acid (238 mg) under cooling on ice. After stirring at room temperature for 1 hour to the reaction mixture were added saturated aqueous sodium thiosulfate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate) to obtain specified in the connection header in the form of powder light pink color (exit 160 mg, 75%).

1H-NMR (CDCl3) δ: 2,64 (3H, c),? 7.04 baby mortality-7,06 (1H, m), 7,35-7,41 (1H, m), EUR 7.57-to 7.64 (2H, m), 7,72-of 7.82 (2H, m), 9,86 (1H, c), 12,35 (1H, usher.).

Reference example 151

5-[2-(methylsulphonyl)phenyl]-1H-pyrrole-3-carbaldehyde

To a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (100 mg) in ethyl acetate (5 ml) cooled on ice was added 3-chloroperbenzoic acid (318 mg). After stirring at room temperature for 3 hours to the reaction mixture were added saturated aqueous sodium thiosulfate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1→1:3) to obtain the specified title compound as a crystalline substance SV is to yellow (output 88.9 mg, 78%).

1H-NMR (CDCl3) δ: 2,77 (3H, c), 6,94-of 6.96 (1H, m), 7,54-of 7.60 (2H, m), to 7.67-7,73 (2H, m), 8,20-8,24 (1H, m), 9,88 (1H, c), or 10.60 (1H, c).

Reference example 152

5-(2-forfinal)-4-iodine-1H-pyrrole-3-carbaldehyde

5-(2-Forfinal)-1H-pyrrole-3-carbaldehyde (2.0 g) was dissolved in N,N-dimethylformamide (60 ml), was added N-jodatime (2.38 g) and the mixture was stirred for 12 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, 3%aqueous solution of potassium hydrosulfate and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:3→1:1) to obtain specified in the connection header in the form of a powder, light brown (yield 450 mg, 14%).

1H-NMR (CDCl3) δ: 7,16-7,30 (2H, m), 7,37-7,44 (1H, m), 7,63 (1H, d, J=3,4 Hz), 7,81-7,86 (1H, m), 9,24 (1H, usher.), 9,81 (1H, c).

Reference example 153

5-mesityl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution of 5-mesityl-1H-pyrrole-3-carbaldehyde (0.36 g) in tetrahydrofuran (20 ml) was added sodium hydride (60% in oil, 0.14 g) under cooling on ice and the mixture was stirred at room temperature for 0.5 hours. Solution was added 15-crown-5 (0.75 g) in tetrahydrofuran (3 ml) and after which remesiana for 5 minutes while cooling on ice, was added pyridine-3-ylsulphonyl (0.45 g). The reaction mixture was stirred at room temperature for 0.5 hours, the reaction mixture was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=10:1→2:1) to obtain specified in the connection header amorphous form of a light brown colour (yield of 0.38 g, 62%).

1H-NMR (CDCl3) δ: 1,63 (6H, c)to 2.35 (3H, c), 6,48 (1H, d, J=1.5 Hz), 6,83 (2H, c), 7,26-to 7.35 (1H, m), 7,60-to 7.64 (1H, m), 8,17 (1H, DD, J=1.5 and 0.9 Hz), 8,56 (1H, d, J=2.1 Hz), 8,83 (1H, DD, J=4,5, 1.5 Hz), for 9.90 (1H, c).

Reference example 154

5-[2-(methylthio)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a suspension of sodium hydride (60% in oil, 40 mg) in tetrahydrofuran (3 ml) was added a solution of 5-[2-(methylthio)phenyl]-1H-pyrrole-3-carbaldehyde (150 mg) in tetrahydrofuran (5 ml), 15-crown-5 (182 mg) and pyridine-3-ylsulphonyl (135 mg) under cooling on ice. After stirring at room temperature for 2 hours, was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on columns is e silica gel (eluent: hexane-ethyl acetate=4:1→2:1) to obtain specified in the title compounds as a colorless crystalline substance (yield 170 mg, 69%).

1H-NMR (CDCl3) δ: 2,05 (3H, c), of 6.68 (1H, d, J=2.1 Hz), 6,97-6,99 (1H, m), 7,17-7,31 (3H, m), 7,40 was 7.45 (1H, m), 7,65-of 7.70 (1H, m), 8,16 (1H, d, J=2.1 Hz), 8,45-8,46 (1H, m), 8,75-8,77 (1H, m), for 9.90 (1H, c).

Reference example 155

5-(2-bromophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

A similar method described in reference example 154, using sodium hydride (60% in oil, 91,0 mg), 5-(2-bromophenyl)-1H-pyrrole-3-carbaldehyde (396 mg), 15-crown-5 (418 mg) and pyridine-3-ylsulphonyl (309 mg)were specified in the title compound in the form of solid light yellow (yield 560 mg, 91%).

1H-NMR (CDCl3) δ: 6,66 (1H, d, J=1.5 Hz), 7,31-7,40 (4H, m), of 7.48-7,52 (1H, m), 7,66-7,71 (1H, m), 8,15 (1H, d, J=1,8 Hz), 8,55 (1H, d, J=2.7 Hz), 8,82-8,84 (1H, m), 9,92 (1H, c).

Reference example 156

5-[2-(methylsulphonyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

A similar method described in reference example 154, using sodium hydride (60% in oil, 40 mg), 5-[2-(methylsulphonyl)phenyl]-1H-pyrrole-3-carbaldehyde (88.9 mg), 15-crown-5 (94,4 mg) and pyridine-3-ylsulphonyl (69,7 mg)were specified in the title compound, colorless amorphous form (output 72,0 mg, 52%).

1H-NMR (CDCl3) δ: 2,87 (3H, c), to 6.67 (1H, d, J=1,8 Hz), 7,37-of 7.48 (2H, m), 7,72-7,76 (3H, m), 8,02-with 8.05 (1H, m)to 8.14 (1H, d, J=1,8 Hz)and 8.50 (1H, d, J=2.7 Hz), 8,81-8,83 (1H, m), of 9.89 (1H, c).

Reference example 157

2-[4-formyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl]benzonitrile

Suspense is 5-(2-bromophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (102 mg), cyanide zinc (61,0 mg) and tetrakis(triphenylphosphine)palladium (60,0 mg) in N,N-dimethylformamide (2 ml) was heated (100 W, 4 minutes, 30 seconds), using a focused microwave reactor for chemical synthesis, production of CEM, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→2:1) to obtain the specified title compound as a pale yellow oil (yield of 97.4 mg, 63%).

1H-NMR (CDCl3) δ: 6,79 (1H, d, J=1,8 Hz), 7,41-7,51 (2H, m), 7,58 for 7.78 (4H, m), 8,17 (1H, d, J=1.5 Hz), to 8.45 (1H, d, J=2.7 Hz), 8,84-8,86 (1H, m), to 9.91 (1H, c).

Reference example 158

5-(2-forfinal)-4-iodine-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To the solution (42 ml) of 5-(2-forfinal)-4-iodine-1H-pyrrole-3-carbaldehyde (400 mg) in tetrahydrofuran was added sodium hydride (60% in oil, 102 mg) at room temperature and the mixture was stirred for 30 minutes. Was added dropwise 15-crown-5 (560 mg) and the mixture was stirred for 30 minutes. Added pyridine-3-ylsulphonyl (340 mg) and the mixture was additionally stirred for 1 hour. The reaction mixture was diluted with saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed saturated the output saline, was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:2→1:1) and vykristallizovyvalas from diisopropyl ether to obtain specified in the title compounds as a colorless crystalline substance (yield 540 mg, 93%).

1H-NMR (CDCl3) δ: 7,01-7,07 (1H, m), 7,12-7,17 (1H, m), 7.23 percent-7,28 (1H, m), 7,37-7,41 (1H, m), 7,50-7,58 (1H, m), 7,69-7,73 (1H, m), 8,21 (1H, c), 8,54-8,54 (1H, m), cent to 8.85 (1H, DD, J=4,9, 1.5 Hz), 9,85 (1H, c).

Reference example 159

5-(2,6-dimetilfenil)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g), 2,6-dimethylphenylimino acid (4,50 g), cesium carbonate (13,0 g), tri-tert-butylphosphine (0.10 g), Tris(dibenzylideneacetone)diplegia (0) (0,23 g) and mesitylene (200 ml) was stirred at reflux for 5 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:1) obtaining oil brown (0,48 g). To a solution of the oil in tetrahydrofuran (20 ml) cooled on ice was added sodium hydride (60% in oil, 0,19 g) and the mixture was stirred at to the room temperature for 0.5 hours. Solution was added 15-crown-5 (1.06 g) in tetrahydrofuran (3 ml) and the mixture was stirred for 5 minutes. When cooled on ice was added pyridine-3-ylsulphonyl (0.64 g). The reaction mixture was stirred at room temperature for 0.5 hours, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:1) to obtain specified in the connection header in the form of butter, light brown (yield of 0.42 g, 25%).

1H-NMR (CDCl3) δ: of 1.66 (6H, c)of 6.52 (1H, d, J=2.1 Hz), 6,70 (2H, d, J=7.5 Hz), 7,25-7,34 (2H, m), 7,56-of 7.60 (1H, m), 8,19 (1H, d, J=1.5 Hz), 8,53 (1H, d, J=1,8 Hz), 8,81-8,83 (1H, m), to 9.91 (1H, c).

Reference example 160

2-bromo-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

5-(2-Forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (330 mg) was dissolved in N,N-dimethylformamide (30 ml), was added N-bromosuccinimide (356 mg) and the mixture was stirred at 80°C for 2 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over betwo the major sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=7:3) and vykristallizovyvalas from diisopropyl ether to obtain specified in the title compounds as a colorless crystalline substance (yield 270 mg, 66%).

1H-NMR (CDCl3) δ: 6,70 (1H, c), 7,12-7,26 (2H, m), 7,29-to 7.35 (1H, m), 7,44-7,52 (2H, m), 8.07-a 8,11 (1H, m), 8,89 (1H, DD, J=4,9, 1.5 Hz), 9,01-of 9.02 (1H, m), 9,86 (1H, c).

Reference example 161

2-(2-forfinal)-4-formyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-carbonitril

5-(2-Forfinal)-4-iodine-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (489 mg), copper cyanide (I) (480 mg), Tris(dibenzylideneacetone)dipalladium (0) (49 mg) and 1,1'-bis(diphenylphosphino)ferrocene (89 mg) were mixed in 1,4-dioxane (20 ml) and the mixture was heated under reflux for 3 hours. The reaction mixture was left to cool, was diluted with ethyl acetate and filtered. The obtained filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=2:3→3:7) to obtain the specified title compound as a colourless oil (yield 380 mg, 100%).

1H-NMR (CDCl3) δ: 7,06 for 7.12 (1H, m), 7.24 to to 7.32 (2H, m), 7,40 was 7.45 (1H, m), 7,55-7,63 (1H, m), 7,70-7,74 (1H, m), 8,19 (1H, c), to 8.57 (1H, d, J=1.9 Hz), 888 (1H, DD, J=4,8, and 1.6 Hz), becomes 9.97 (1H, c).

Reference example 162

5-(2-forfinal)-3-formyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-carbonitril

2-Bromo-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (340 mg), copper cyanide (I) (400 mg), Tris(dibenzylideneacetone)dipalladium (0) (40 mg), 1,1'-bis(diphenylphosphino)ferrocene (70 mg) were mixed in 1,4-dioxane (30 ml) and the mixture was heated under reflux for 24 hours. The reaction mixture was left to cool, was diluted with ethyl acetate and filtered. The obtained filtrate was washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:2) and vykristallizovyvalas from diisopropyl ether to obtain specified in the title compounds as a colorless crystalline substance (yield 169 mg, 57%).

1H-NMR (CDCl3) δ: 6,72 (1H, c), 7,12-to 7.18 (1H, m), 7.24 to 7,28 (2H, m), 7,50-of 7.60 (2H, m), 8,10-to 8.14 (1H, m), 8,82 (1H, d, J=2.4 Hz), of 8.92 (1H, DD, J=4,9, 1.5 Hz), to 10.09 (1H, c).

Reference example 163

tert-butyl ({5-bromo-1-[(6-methoxypyridine-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

Sodium hydride (60% in oil, 433 mg) was washed twice with hexane and suspended in tetrahydrofuran (20 ml). To the suspension at 0°C was added a solution of tert-BU is Il [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (2.66 g) in tetrahydrofuran (10 ml), and at the same temperature was added a solution of 15-crown-5 (2,20 ml) and 6-methoxypyridine-3-ylsulphonyl (to 2.29 g) in tetrahydrofuran (5 ml). After stirring at room temperature for 30 minutes to the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=6:1) to obtain the specified title compound as a brown oil (yield was 4.02 g, 95%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), and 2.79 (3H, users), to 4.01 (3H, c), 4,17 (2H, users), and 6.25 (1H, users), PC 6.82 (1H, d, J=9.0 Hz), 7,32 (1H, users), 7,94-7,98 (1H, m), 8,77-8,78 (1H, m).

Reference example 164

tert-butyl {[5-(4-cyanophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-cyanophenyl)boric acid (176 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57,8 mg)were specified in the title compound as a pale yellow oil (yield 382 mg, 84%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), and 2.79 (3H, c), is 4.21 (2H, users), 6,23 (1H, users), 7,28-7,34 (2H, m), 7,39-the 7.43 (2H, m), to 7.59-7,66 (3H, m), 8,55 (1H, d, J=2.1 Hz), a total of 8.74-8,76 (1H, m).

Reference example 165

tert-butyl {[5-(5-cyano-2-forfinal)-1-(pyridine--ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (5-cyano-2-forfinal)boric acid (198 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57,8 mg)were specified in the title compound as a pale yellow oil (yield of 28.9 mg, 6%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,82 (3H, c), 4,24 (2H, users), 6,28 (1H, users), 7,21 (1H, t, J=8.7 Hz), 7,35-7,42 (2H, m), 7,49-7,52 (1H, m), 7,69-7,73 (2H, m), 8,66 (1H, d, J=2.4 Hz), 8,81-8,83 (1H, m).

Reference example 166

tert-butyl {[5-(2-fluoro-5-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-5-methoxyphenyl)boronic acid (256 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) was added to a degassed mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 90°C for 1 hour. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:) with obtaining specified in the title compounds as colorless oil (yield 475 mg, about 100%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), and 2.83 (3H, c), of 3.78 (3H, c), 4,24 (2H, c), from 6.22 (1H, d, J=1.1 Hz), 6,69-of 6.71 (1H, m), 6.90 to-6,98 (2H, m), 7,72 and 7.36 (2H, m), 7,69-7,73 (1H, m), 8,65 (1H, d, J=2.3 Hz), 8,77 (1H, DD, J=4,9 and 1.5 Hz).

Reference example 167

tert-butyl {[5-(2-fluoro-3-formylphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-fluoro-3-formylphenyl)boric acid (252 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg)were specified in the title compound as a pale yellow oil (yield 250 mg, 53%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), and 2.83 (3H, c), 4,25 (2H, users), 6,28 (1H, users), 7,26-7,46 (4H, m), 7.68 per-7,72 (1H, m), 7,92-of 7.97 (1H, m), 8,61 (1H, d, J=2.1 Hz), 8,77-8,79 (1H, m), 10,30 (1H, c).

Reference example 168

tert-butyl {[5-(3-acetyl-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (3-acetyl-2-forfinal)boric acid (273 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg)were specified in the title compound as a pale yellow oil (yield 443 mg, 91%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)at 2.59 (3H, d, J=5.4 Hz), and 2.83 (3H, c), 4,25 (2H, IRS), 6,24 (1H, users), 7,19 and 7.36 (4H, m), 7,66-of 7.70 (1H, m), of 7.90-of 7.96 (1H, m), at 8.60 (1H, d, J=2.4 Hz), 8,76-8,78 (1H, m).

Reference example 169

tert-butyl {[5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A suspension of tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (2-herperidin-3-yl)boronic acid (221 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (173 mg) in 1,2-dimethoxyethane (10 ml) and water (5 ml) was stirred at 105oC for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=6:1→1:1) to obtain the specified title compound as a pale yellow oil (yield 310 mg, 69%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,82 (3H, c)to 4.23 (2H, users), of 6.29 (1H, users), 7.23 percent-7,27 (1H, m), 7,34-7,39 (2H, m), 7,66-7,73 (2H, m), 8,25-of 8.27 (1H, m), 8,66 (1H, d, J=2.4 Hz), 8,78-8,80 (1H, m).

Reference example 170

tert-butyl {[5-(3-herperidin-4-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (215 mg), hydrate (3-herperidin-4-yl)boronic acid (mg), sodium bicarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) was added to a degassed mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 80°C for 3 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a pale yellow oil (yield 60 mg, 27%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,61 (3H, c), 4,24 (2H, c), 6.35mm (1H, c), 7,22-7,26 (1H, m), 7,35-7,40 (2H, m), 7,71 to 7.75 (1H, m), of 8.47 (1H, d, J=4,8 Hz)and 8.50 (1H, d, J=1.3 Hz), to 8.70 (1H, d, J=2.1 Hz), 8,81 (1H, DD, J=4,8, 1,6 Hz).

Reference example 171

tert-butyl {[5-(2-chloropyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-chloropyridin-3-yl)boronic acid (237 mg), sodium bicarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) was added to a degassed mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 100°C for 3 hours. The reaction mixture was left ohla shall be given, added a concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1→1:4) to obtain the specified title compound as a colourless oil (yield 280 mg, 60%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)2,84 (3H, c), 4,27 (2H, c), 6,30 (1H, c), 7,30-7,39 (3H, m), 7,65-7,73 (2H, m), 8,43-to 8.45 (1H, m), 8,67 (1H, d, J=2.3 Hz), 8,80 (1H, DD, J=4,9, 1.5 Hz).

Reference example 172

tert-butyl {[5-(6-chloropyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

Reference example 173

tert-butyl {[5-(6'-chloro-2,3'-bipyridine-5-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (6-chloropyridin-3-yl)boronic acid (237 mg), sodium hydrogen carbonate (252 mg) and tetrakis(triphenylphosphine)palladium (87 mg) was added to a degassed mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 90°C for 3 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline R is the target, was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1→3:7) and the fractions showing Rf value, equal to 0.6 (eluent: hexane-ethyl acetate=1:1), collected with obtaining specified in the header of the compound of reference example 172 in the form of a colorless oil (yield 100 mg, 22%). Then, the fractions showing Rf value equal to 0.4 (eluent: hexane-ethyl acetate=1:1), collected with obtaining specified in the header of the compound of reference example 173 in the form of a light yellow colour powder (yield 100 mg, 19%).

Reference example 172:1H-NMR (CDCl3) δ: of 1.47 (9H, c), of 2.81 (3H, c)to 4.23 (2H, c), 6,24 (1H, c), 7.23 percent-7,38 (3H, m), to 7.59-7,63 (1H, m), 7,72 (1H, DD, J=8,3, 2,3 Hz)to 8.14 (1H, d, J=2.3 Hz), 8,64 (1H, d, J=2.3 Hz), 8,78 (1H, DD, J=4,7) and 1.7 Hz).

Reference example 173:1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,82 (3H, c), 4,24 (2H, c), of 6.29 (1H, c), 7,31-7,37 (2H, m), 7,47 (1H, d, J=8,3 Hz), of 7.64-7.68 per (1H, m), 7,76-7,86 (2H, m), scored 8.38 (1H, DD, J=8,5, 2,5 Hz), 8,51 (1H, d, J=1.9 Hz), 8,63 (1H, d, J=2.3 Hz), 8,77 (1H, DD, J=4,9, 1.5 Hz), 9,04 (1H, d, J=2.3 Hz).

Reference example 174

tert-butyl ({5-(2-herperidin-3-yl)-1-[(6-methoxypyridine-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

A similar method described in reference example 79 and using tert-butyl ({5-bromo-1-[(6-methoxypyridine-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (463 mg), (2-herperidin-3-yl)boronic acid (172 mg), sodium carbonate (260 is g) and tetrakis(triphenylphosphine)palladium (176 mg), got mentioned in the title compound as a pale yellow oil (yield 293 mg, 45%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), and 2.83 (3H, users), of 3.97 (3H, c)to 4.23 (2H, users), 6,28 (1H, c), 6,69-6,72 (1H, m), 7,26 and 7.36 (2H, m), 7,49-7,53 (1H, m), 7,75-7,80 (1H, m), by 8.22-8,23 (1H, m), compared to 8.26-of 8.27 (1H, m).

Reference example 175

tert-butyl ({5-[2-fluoro-3-(hydroxymethyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution of tert-butyl {[5-(2-fluoro-3-formylphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (388 mg) in tetrahydrofuran (8 ml) was added while cooling on ice, sodium borohydride (41.3 mg) and methanol (3 ml). After stirring at the same temperature for 30 minutes, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=2:1→1:2) to obtain specified in the title compounds as colorless oil (yield 238 mg, 61%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), and 2.83 (3H, c), 4,24 (2H, users)and 4.65 (2H, users), to 6.19 (1H, users), 7,15-7,19 (2H, m), 7,34-7,38 (2H, m), 7,51-of 7.55 (1H, m), 7,73-7,76 (1H, m), 8,40-to 8.41 (1H, m), 8,75-8,77 (1H, m), 1H not detected.

Reference example 176

tert-butyl ({5-[2-fluoro-3-(1-hydroxyethyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}ethyl)methylcarbamate

A similar method described in reference example 175, and using tert-butyl {[5-(3-acetyl-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (443 mg)were specified in the header connection amorphous form of light-yellow color (exit 318 mg, 71%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)a 1.50 (3H, d, J=6.3 Hz), and 2.83 (3H, c), 4,25 (2H, users), is 5.06 (1H, square, J=6.3 Hz), of 6.20 (1H, users), 7,09-7,22 (2H, m), 7,34-7,38 (2H, m), to 7.59-to 7.64 (1H, m), 7,72-7,76 (1H, m), 8,40 (1H, d, J=2,4 Hz), 8,75-8,78 (1H, m), 1H not detected.

Reference example 177

tert-butyl {[5-(2-fluoro-3-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-3-methoxyphenyl)boronic acid (256 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (88 mg) was added to a mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 100°C for 2 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain specified in the connection header in the de colorless oil (yield 475 mg, about 100%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,82 (3H, c), 3,90 (3H, c), 4,24 (2H, c), 6,21 (1H, d, J=1.5 Hz), 6,72-6,79 (1H, m), 7,00-to 7.09 (2H, m), to 7.32 and 7.36 (2H, m), 7,69-7,73 (1H, m), 8,63 (1H, d, J=2.3 Hz), 8,76 (1H, DD, J=4,9 and 1.5 Hz).

Reference example 178

tert-butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-6-methoxyphenyl)boronic acid (256 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (176 mg) was added to a mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 100°C for 20 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a colourless oil (yield 100 mg, 21%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,85 (3H, c)to 3.58 (3H, c), 4.26 deaths (2H, c), 6,17 (1H, d, J=1.9 Hz), 6,64-6,70 (2H, m), 7,31-7,39 (3H, m), 7,71 to 7.75 (1H, m), at 8.60 (1H, d, J=1.9 Hz), 8,76 (1H, DD, J=4,9, 1.5 Hz).

Reference example 179

2-[4-(deformedarse)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

Solution (10 m is) 1-bromo-4-(deformedarse)benzene (500 mg), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (654 mg), potassium acetate (660 mg) and 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (and 73.2 mg) in dimethylformamide was stirred at 80°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→8:1) to obtain the specified title compound as a pale yellow oil (yield 348 mg, 58%).

1H-NMR (CDCl3) δ: of 1.35 (12H, c), is 6.54 (1H, t, J=73,5 Hz), to 7.09 (2H, d, J=7.8 Hz), 7,81 (2H, d, J=7,8 Hz).

Reference example 180

tert-butyl ({5-[4-(deformedarse)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 2-[4-(deformedarse)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) suspended in dimethoxyethane (10 ml) and water (4 ml) and the mixture was stirred in nitrogen atmosphere at 105°C for 1 hour. The reaction mixture was left to cool to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated with is the combat solution, was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→2:1) to obtain the specified title compound as a pale yellow oil (yield 550 mg, quantitative yield).

1H-NMR (CDCl3) δ: of 1.46 (9H, c)2,80 (3H, c), is 4.21 (2H, users), 6,13 (1H, users), to 6.57 (1H, t, J=73,2 Hz), 7,06-to 7.09 (2H, m), 7,21-7,31 (4H, m), 7,55-to 7.59 (1H, m), 8,54 (1H, d, J=2.4 Hz), 8,71-8,73 (1H, m).

Reference example 181

tert-butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate

tert-Butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (4-methylpyridin-3-yl)boronic acid (206 mg), sodium hydrogen carbonate (253 mg) and tetrakis(triphenylphosphine)palladium (87 mg) was added to a degassed mixture of 1,2-dimethoxyethane (8 ml) and water (2 ml) and the mixture was stirred in nitrogen atmosphere at 80°C for 6 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1→0:1) to obtain specified in the connection header in the form best is to maintain oil (yield 230 mg, 52%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), 2,11 (3H, c), 2,85 (3H, c), 4,27 (2H, c), x 6.15 (1H, c), 7,18 (1H, d, J=4.9 Hz), 7,34-7,39 (2H, m), 7,58 to 7.62 (1H, m), 7,94 (1H, c), 8,49 (1H, d, J=5.3 Hz), 8,64 (1H, d, J=2.3 Hz), 8,80 (1H, DD, J=4,9, 1.5 Hz).

Reference example 182

3-bromo-2-methylpyridin

The aluminum chloride (200 g) was added dropwise 2-methylpyridin (46.6 g) and the mixture was stirred at 100°C. To the mixture at the same temperature for 1 hour was added dropwise bromine (40,0 g) and the mixture was additionally stirred for 30 minutes. After cooling, the reaction mixture was poured into ice water, was added concentrated hydrochloric acid to acidification of the mixture. The resulting solution was washed with ethyl acetate and the aqueous layer was podslushivaet 8 mol/l aqueous solution of sodium hydroxide. After extraction with diethyl ether, the extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-diethyl ether=10:1) to obtain the specified title compound as a colourless oil (yield 5,09 g, 12%).

1H-NMR (CDCl3) δ: to 2.67 (3H, c), 6,98-7,03 (1H, m), 7,78-of 7.82 (1H, m), 8,40-8,44 (1H, m).

Reference example 183

tert-butyl methyl{[5-(2-methylpyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate

To a solution of 3-bromo-2-methylpyridine (504 mg) in diethyl ether (15 m is) was added 1,62 mol/l solution (2 ml) of n-butyl lithium in hexane at -78°C and the mixture was stirred at the same temperature for 15 minutes. Added triisopropoxide (1,22 ml) at the same temperature and the resulting mixture was stirred at 0°C for 1 hour. To the reaction mixture were added methanol (2 ml) and the mixture was concentrated under reduced pressure. To the residue was added tert-butyl ({5-bromo-1-[(pyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (432 mg), sodium carbonate (1,15 g), tetrakis(triphenylphosphine)palladium (174 mg), 1,2-dimethoxyethane (20 ml) and water (10 ml) and the mixture was stirred in nitrogen atmosphere at 105°C for 1 hour. The reaction mixture was left to cool to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a brown oil (yield 282 mg, 22%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), is 2.09 (3H, c), 2,85 (3H, c), 4,27 (2H, users), 6,14 (1H, users), 7,10-7,14 (1H, m), 7,26-7,38 (3H, m), 7,56-of 7.60 (1H, m), 8,54-8,56 (1H, m), 8,60-8,61 (1H, m), 8,78-8,80 (1H, m).

Reference example 184

6-nicotine amide

A mixture of methyl 6-methylnicotinate (13,9 g) and 28%aqueous ammonia solution (140 ml) was stirred at room temperature for 4 hours. actionnow the mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the connection header in the form of a solid white color (output 8,98 g, 72%).

1H-NMR (CDCl3) δ: 2.63 in (3H, c), the ceiling of 5.60-of 6.20 (2H, osirm), 7,25-7,28 (1H, m), 8,04-8,07 (1H, m), of 8.90 (1H, d, J=2.1 Hz).

Reference example 185

6-methylpyridin-3-amine

To 4 mol/l aqueous solution of sodium hydroxide (60 ml) at 0°C was added bromine (1.0 ml) and the mixture was stirred at the same temperature for 15 minutes. To the resulting solution for 10 minutes was added 6-nicotine amide (2.4 g) and the mixture was stirred at room temperature for 30 minutes and was further stirred at 75°C for 4 hours. The reaction mixture was left to cool to room temperature and was extracted with ethyl acetate:THF=2:1. The extract was washed with a small amount of a saturated salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. recrystallization of the residue from ethyl acetate-hexane gave specified in the title compound as a pale yellow solid (yield of 0.93 g, 49%).

1H-NMR (CDCl3) δ: 2,43 (3H, c), of 3.54 (2H, users), 6,89-to 6.95 (2H, m), 7,99 shed 8.01 (1H, m).

Reference example 186

6-methylpyridin-3-ylsulphonyl

To a mixture of 6-methylpyridin-3-amine (449 mg) and conc. hydrochloric acid (5 ml) was added a solution of sodium nitrite (857 mg) in water (2 ml) at 0°C and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added a solution of concentrated hydrochloric acid (2.5 m is), copper sulphate (69 mg) and hydrosulfite sodium (5,08 g) in water (8 ml) at 0°C and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=10:1) to obtain the specified title compound as a pale yellow solid (yield 0.12 g, 15%).

1H-NMR (CDCl3) δ: 2,73 (3H, c), 7,40-the 7.43 (1H, m), 8,16-to 8.20 (1H, m), 9,11-9,12 (1H, m).

Reference example 187

tert-butyl ({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

To a solution of tert-butyl [(5-bromo-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in tetrahydrofuran (30 ml) was added sodium hydride (60% in oil, 31 mg) at 0°C and the mixture was stirred at the same temperature for 10 minutes. Solution (3 ml), 15-crown-5 (0.16 ml) and 6-methylpyridin-3-ylsulphonyl (117 mg) in tetrahydrofuran was added at the same temperature. After stirring at room temperature for 30 minutes to the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sulfate on the rija and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1) to obtain the specified title compound as a brown oil (yield 213 mg, 79%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)to 2.66 (3H, c), and 2.79 (3H, c), 4,17 (2H, users), of 6.26 (1H, users), 7,26-7,33 (2H, m), 8,03-8,07 (1H, m), 9,01-of 9.02 (1H, m).

Reference example 188

tert-butyl ({5-(2-herperidin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate

A suspension of tert-butyl ({5-bromo-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (206 mg), (2-herperidin-3-yl)boronic acid (80 mg), sodium carbonate (119 mg) and tetrakis(triphenylphosphine)palladium (80 mg) in 1,2-dimethoxyethane (5 ml) and water (2.5 ml) was stirred in nitrogen atmosphere at 105°C for 1 hour. The reaction mixture was left to cool to room temperature, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1) to obtain the specified title compound as a pale yellow oil (yield 87 mg, 41%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,62 (3H, m), 2,82 (3H, c)to 4.23 (2H, users), of 6.29 (1H, c), 7,18-7,27 2H, m), 7,33 (1H, c), 7,54-EUR 7.57 (1H, m), 7,72 to 7.75 (1H, m), compared to 8.26-of 8.27 (1H, m), 8,53 (1H, c).

Reference example 189

5-(2-herperidin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde

To a degassed mixture of 1,2-dimethoxyethane (80 ml) and water (20 ml) was added 5-bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.15), (2-herperidin-3-yl)boronic acid (2.83 g), sodium bicarbonate (2,53 g) and tetrakis(triphenylphosphine)palladium (870 mg) and the mixture was stirred in nitrogen atmosphere at 80°C for 5 hours. The reaction mixture was left to cool, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→2:3) to obtain the specified title compound as a colourless oil (yield 2.25 g, 68%).

1H-NMR (CDCl3) δ: of 6.71 (1H, d, J=1.7 Hz), 7.24 to 7,28 (1H, m), 7,42-of 7.48 (4H, m), 7,62-to 7.68 (1H, m), 7,70-7,76 (1H, m)to 8.14 (1H, d, J=1.9 Hz), 8,28-8,31 (1H, m), for 9.90 (1H, c).

Reference example 190

5-(2-herperidin-3-yl)-1H-pyrrole-3-carbaldehyde

5-(2-Herperidin-3-yl)-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.25 g) was dissolved in methanol (20 ml) and added dropwise at room temperature was added tetrahydrofuran (20 ml), 8 mol/l aqueous solution of hydroxide n is Tria (20 ml) and the mixture was stirred for 1 hour. The reaction mixture was diluted with saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added ethyl acetate and the insoluble substance was collected by filtration to obtain specified in the connection header in the form of a crystalline substance in a light brown colour (yield of 1.03 g, 79%).

1H-NMR (DMSO-d6) δ: 6,99 (1H, d, J=1.5 Hz), 7,43-of 7.48 (1H, m), 7,88 (1H, c), 8,12-of 8.15 (1H, m), 8,27-to 8.34 (1H, m), 9,77 (1H, c), to 12.28 (1H, users).

Reference example 191

4-chloro-5-(2-herperidin-3-yl)-1H-pyrrole-3-carbaldehyde

5-(2-Herperidin-3-yl)-1H-pyrrole-3-carbaldehyde (610 mg) was dissolved in N,N-dimethylformamide (20 ml), was added N-chlorosuccinimide (641 mg) and the mixture was stirred at 80°C for 40 minutes. After cooling, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=3:2→1:1) to obtain the specified title compound as colorless powder (yield 320 mg, 44%).

1H-NMR (DMSO-d6) δ: 7,49-rate of 7.54 (1H, m), 7,86 (1H, d, J=2.3 Hz), 8,12-8,19 (1H, m), 8.30 to-8,32 (1H, m), 9,80 (1H, c), 12,48 (1H users).

Reference example 192

4-chloro-5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde

To a solution (20 ml) of 4-chloro-5-(2-herperidin-3-yl)-1H-pyrrole-3-carbaldehyde (270 mg) in tetrahydrofuran at room temperature was added sodium hydride (60% in oil, 100 mg) and the mixture was stirred for 30 minutes. Was added dropwise 15-crown-5 (530 mg) and the mixture was stirred for 30 minutes. Added 3-pyridylsulfonyl (321 mg) and the mixture was additionally stirred for 1 hour. The reaction mixture was diluted with saturated salt solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:1→1:4) and vykristallizovyvalas from diethyl ether to obtain specified in the title compounds as a colorless crystalline substance (exit 358 mg, 81%).

1H-NMR (CDCl3) δ: 7,35-7,39 (1H, m), 7,42-7,46 (1H, m), 7,69-7,73 (1H, m), 7,76-of 7.82 (1H, m), 8,14 (1H, c), 8,39-to 8.41 (1H, m)8,64 (1H, DD, J=2,5 Hz, 0.6 Hz), 8,89 (1H, DD, J=4,8 Hz, 1.6 Hz), becomes 9.97 (1H, c).

Reference example 193

tributyl(2-thienyl)stannane

A solution (10 ml) of 2-bromothiophene (1.0 g) in tetrahydrofuran was cooled to -70°C was added dropwise a 1.6 mol/l solution of 4.2 ml) n-utility in hexane. After paramesh the cation at the same temperature for 30 minutes was added dropwise to the presence of TBT chloride (2.1 g). After additional stirring for 1 hour, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining oil (2.4 g), containing specified in the title compound, used in the next stage without additional purification.

Reference example 194

tert-butyl methyl{[1-(pyridine-3-ylsulphonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methyl}carbamate

To a solution of crude tributyl(2-thienyl)stannane (1.1 g) and tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg) in toluene was added tetrakis(triphenylphosphine)palladium (116 mg) and the mixture was stirred in nitrogen atmosphere at 120°C for 1 hour. The reaction mixture was left to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=4:1) to obtain the specified title compound as a pale yellow oil (yield 315 mg, 73%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), and 2.83 (3H, c), 4,22 (2H, users), and 6.25 (1H, users),? 7.04 baby mortality-7,07 (1H, m), 7,16-7,17 (1H, m), 7,27-7,31 (2H, m), of 7.36-7,37 (1H, m), 7,62-7,66 (1H, m), 8,58-8,59 (1H, m), 8,71-8,73 (1H, m).

Reference example 195

3-methyl-2-(tributylstannyl)pyridine

A solution (10 ml) of 2-bromo-3-is ethylpyridine (1.0 g) in tetrahydrofuran was cooled to -70°C was added dropwise a 1.6 mol/l solution (4.0 ml), n-utility in hexane. After stirring at the same temperature for 15 minutes was added dropwise to the presence of TBT chloride (2.2 g). After additional stirring for 1 hour, the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1) to obtain the specified title compound as a colourless oil (yield of 1.75 g, 79%).

1H-NMR (CDCl3) δ: 0,85-0,95 (9H, m), 1,11-1,17 (6H, m)of 1.29 to 1.37 (6H, m), 1,49-of 1.57 (6H, m), a 2.36 (3H, c), 6,99-7,03 (1H, m), 7,31-7,34 (1H, m), charged 8.52-8,54 (1H, m).

Reference example 196

tert-butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate

A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0 g), tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluene was stirred in nitrogen atmosphere at 120°C for 30 hours. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=4:1) to obtain the specified title compound as a colourless oil (yield 129 mg, 22%).

1H-NMR (CDCl3) δ: of 1.45 (9H, c)2,80 (3H, users), 4,25 (2H, users), of 6.26 (1H, users), 7.23 percent-7,27 (2H, m), 7,39-7,44 (1H, m), 7,60 (1H, d, J=6.9 Hz), 7,99-8,03 (1H, m), at 8.36 (1H, d, J=4.5 Hz), 8,78-8,80 (1H, m), 8,86-8,87 (1H, m).

Reference example 197

tert-butyl {[5-{2-fluoro-3-[(hydroxyimino)methyl]phenyl}-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution (3 ml) of tert-butyl {[5-(2-fluoro-3-formylphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (182 mg) in 2-propanol was added hydroxylamine hydrochloride (40 mg) and sodium acetate (47 mg). After stirring at room temperature for 3 hours to the reaction mixture was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=8:1→3:1) to obtain the specified title compound as a pale yellow oil (yield 150 mg, 80%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,82 (3H, c), 4,24 (2H, c), from 6.22 (1H, c), 7,15-7,19 (2H, m), 7,31-to 7.35 (2H, m), to 7.67-7,71 (1H, m), 7,76-a 7.85 (1H, m), of 8.27 (1H, c), 8,63 (1H, d, J=2.1 Hz), 8,76-8,78 (1H, m), 1H not detected.

Reference example 198

tert-butyl {[5-(3-cyano-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

To a solution (5 ml) of tert-butyl {[5-{2-fluoro--[(hydroxyimino)methyl]phenyl}-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (150 mg) in tetrahydrofuran was added triethylamine (93 mg) and methanesulfonyl chloride (84 mg) at room temperature. The reaction mixture was stirred at 70oC for 8 hours and cooled to room temperature. Added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=8:1→3:1) to obtain the specified title compound as a pale yellow oil (yield 106 mg, 73%).

1H-NMR (CDCl3) δ: of 1.46 (9H, c), 2,82 (3H, c), 4,24 (2H, c), 6,28 (1H, users), 7,25-7,40 (3H, m), of 7.48-7,53 (1H, m), 7,66-of 7.70 (2H, m), to 8.62 (1H, d, J=2.7 Hz), 8,80-8,82 (1H, m).

Reference example 199

tert-butyl {[5-(4-bromo-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

A similar method described in reference example 79 and using tert-butyl {[5-bromo-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-bromo-3-thienyl)boric acid (248 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (116 mg)were specified in the title compound as a pale yellow oil (yield 470 mg, 92%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c)2,84 (3H, users), 4.26 deaths (2H, users), 6,21-to 6.22 (1H, m), 7.18 in-7,19 (1H, m), 7,30-7,39 (3H, m), 7,63-to 7.67 (1H, m), 8,57-8,58 (1H, m), a total of 8.74-8,76 (1H, m).

Reference example 200

tert-butyl {[5-(4-cyano-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate

RA is Toro (5 ml) of tert-butyl {[5-(4-bromo-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (470 mg) in N,N-dimethylformamide was added cyanide zinc (215 mg) and tetrakis(triphenylphosphine)palladium (212 mg) and the mixture was enough degirolami. The mixture was stirred with heating at 120oC for 18 hours and cooled to room temperature. Added water and ethyl acetate and the mixture filtered through celite. The filtrate was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=4:1→2:1) to obtain the specified title compound as a pale yellow oil (yield 297 mg, 71%).

1H-NMR (CDCl3) δ: of 1.47 (9H, c), and 2.83 (3H, users), 4,25 (2H, users), 6,34 to 6.35 (1H, m), 7,35-7,39 (2H, m), of 7.48 (1H, usher.), the 7.65 to 7.68 (1H, m), 7,87 (1H, d, J=3.0 Hz), 8,53-8,54 (1H, m), 8,78-8,79 (1H, m).

Example 1

N-methyl-1-[5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine the dihydrochloride

5-Phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (230 mg) was dissolved in absolute tetrahydrofuran (10 ml), was added 2 mol/l solution (1 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 2 hours. To a solution of sodium borohydride (76 mg) in methanol (5 ml) was added to the reaction mixture and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with a saturated aqueous solution of hydrocar is onata sodium, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate-methanol=1:0→1:1) and further HPLC (ODS, 0.1% of triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile=97:3→0,1% triperoxonane acid-containing acetonitrile) to produce trifenatate specified in the connection header. The resulting triptorelin neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and ethanol (5 ml) and the mixture was concentrated under reduced pressure and vykristallizovyvalas from ethyl acetate-ethanol to obtain specified in the title compound (yield 85 mg, 29%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 3,97-4,00 (2H, c), of 6.50 (1H, c), 7,14-7,16 (2H, m), 7,35-7,45 (3H, m), 7,62-of 7.70 (1H, m), 7,78-7,83 (2H, m), of 8.47-8,48 (1H, m), 8,84-8,86 (1H, m), the remaining 9.08 (2H, usher.), 1H not detected.

Example 2

1-{1-[(6-methoxypyridine-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

1-[(6-Methoxypyridine-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (59 mg) was dissolved in absolute tetrahydrofuran (5 ml), was added 2 mol/l solution (0.25 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to a solution of sodium borohydride (19 mg) in methanol (2 ml) and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate-methanol=1:0→1:1) to give a free salt (48 mg) specified in the connection header. The obtained free salt was dissolved in ethyl acetate (2 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (3 ml) and the mixture was left to stand at room temperature for 30 minutes. The precipitated crystalline substance was collected by filtration, washed with ethyl acetate to obtain specified in the title compound (yield 39 mg, 58%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 3,90 (3H, c), 3,98 (2H, c), of 6.45 (1H, c), 6,91-6,94 (1H, m), 7,16-to 7.18 (2H, m), of 7.36 was 7.45 (3H, m), to 7.59-7,63 (1H, m), 7,72 (1H, c), 8,09-8,10 (1H, m), 8,91 (2H, usher.).

Example 3

N-methyl-1-{1-[6-(methylamino)pyridine-3-ylsulphonyl]-5-FeNi what-1H-pyrrol-3-yl}methanamine the dihydrochloride

Using the same reaction described in example 2 and using 1-(6-chloro-3-pyridine sulfonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg)were specified in the title compound (yield 58 mg, 47%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 2,78 (3H, c), 3.95 to 3,99 (2H, m), to 6.39-6.42 per (2H, m), 7,20-of 7.23 (3H, m), 7,35-the 7.43 (3H, m), 7,63 (1H, c), 7,82-a 7.85 (2H, m), 9,00 (2H, usher.), 1H not detected.

Example 4

N-methyl-1-{1-[2-(methylamino)pyridine-3-ylsulphonyl]-5-phenyl-

1H-pyrrol-3-yl}methanamine the dihydrochloride

1-(2-Chloropyridin-3-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (173 mg) was dissolved in tetrahydrofuran (10 ml), was added 2 mol/l solution (1/25 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 12 hours. To a solution (2 ml), sodium borohydride (76 mg) in methanol was added to the reaction mixture and the mixture was stirred at room temperature for 20 minutes. Was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent : ethyl acetate → ethyl acetate-methanol =1:4) to give a free salt specified in the connection header. To a solution (3 ml) of the obtained free salt in ethanol was added 4 mol/l solution of CHL is reed hydrogen-ethyl acetate (1 ml). The solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the connection header (exit 126 mg, 59%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, s), 2,77 (3H, d, J=4.5 Hz), 3.95 to 3,99 (2H, m), 4,80 (1H, usher.), 6,28-6,30 (1H, m), 6,41-6,47 (2H, m), 7,10-7,19 (3H, m), 7,32-7,44 (3H, m), 7,88 (1H, s), 8,25-of 8.27 (1H, m), 9,19 (2H, usher.).

Example 5

N-methyl-1-{1-[2-(methylamino)pyrimidine-5-ylsulphonyl]-5-phenyl-1H-pyrrol-3-yl}methanamine hydrochloride

By a similar reaction as described in example 2 and ispolzovalsya 1-(2-chloropyrimidine-5-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carbaldehyde (100 mg)were specified in the title compound (yield 64 mg, 57%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 2,80-2,82 (3H, c), 3,98 (2H, c), 6,47 (1H, c), 7.23 percent-7,26 (2H, m), 7,39-the 7.43 (3H, m), 7,66-to 7.67 (1H, m), of 7.96-of 7.97 (1H, m), 8,11-to 8.12 (1H, m), 8,48-charged 8.52 (1H, m), 8,97 (2H, usher.).

Example 6

N-methyl-1-[2-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine the dihydrochloride

By a similar reaction as described in example 2 and using 2-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (235 mg), obtained adduct with ethanol (1 equivalent)specified in the title compound, as a solid substance (yield 110 mg, 39%).

1H-NMR (DMSO-d6) δ: of 1.06 (3H, t, J=7.2 Hz), 2,43-of 2.50 (6H, m), 3,44 (2H, DD, J=14,1, 7,2 Hz), 3,91-of 3.94 (2H, m), 6,47 (1H, c), 7,21-the 7.43 (2H, m), of 7.36-7,41 (3H, m), 7,56-7,63 (1H, m), 7,82-7,88 (1H, m), 8,53 (1H, c), 8,87-8,93 (3H, m), 2H not detected.

the example 7

N-methyl-1-[1-(2-methylpyrimidin-5-ylsulphonyl)-5-phenyl-1H-pyrrol-3-yl]-methanamine the dihydrochloride

1-[(2-Methyl-5-pyrimidine)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (148 mg) was dissolved in absolute tetrahydrofuran (10 ml), was added 2 mol/l solution (1.25 ml) of methylamine in tetrahydrofuran and the mixture was stirred over night at room temperature. The reaction mixture was added to a solution of sodium borohydride (95 mg) in methanol (3.0 ml) and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml), was added di-tert-butyl bicarbonate (0.55 g), sodium bicarbonate (0.25 g) and water (10 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml)was added manganese dioxide (75% chemically processed product, 1.5 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered cher the C celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the oil. The resulting oil was dissolved in ethanol (1 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure to obtain a solid (67 mg). Recrystallization from ethanol gave specified in the title compound as a colorless solid (yield 34 mg, 18%).

1H-NMR (DMSO-d6) δ: 2,53 (3H, c), 2,70 (3H, c), 3,98 (2H, c), of 6.50 (1H, c), 7,18-7,20 (2H, m), 7,38-7,47 (3H, m), 7,76-to 7.77 (1H, m), 8,59 (2H, c), 8,88 (2H, usher.), 1H not detected.

Example 8

1-[5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

5-(2-Forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (1.52 g) was dissolved in methanol (30 ml)at room temperature was added a 40%solution of methylamine methanol (3.57 g) and the mixture was stirred for 30 minutes. At room temperature was added sodium borohydride (523 mg) and the mixture was stirred for 10 minutes. Added 1 mol/l hydrochloric acid (50 ml) and the mixture was stirred for 5 minutes. The reaction mixture was podslushivaet saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was washed asystem salt solution, was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate-methanol=1:0→7:3) to give a free salt specified in the title compound as a pale yellow oil (yield of 1.30 g). The obtained free salt (750 mg) was dissolved in ethyl acetate (30 ml)dropwise at room temperature was added a solution of fumaric acid (278 mg) in methanol (3 ml). After stirring for 30 minutes the resulting crystalline substance was collected by filtration and washed with ethyl acetate to obtain specified in the title compounds as a colorless crystalline substance (yield 912 mg, 74%).

1H-NMR (DMSO-d6) δ: 2,43 (3H, c), a 3.87 (2H, c), 6,47 (2H, c), of 6.49 (1H, d, J=1,8 Hz), 7,07-7,13 (1H, m), 7,19-7,26 (2H, m), 7,49-7,56 (1H, m), to 7.59-to 7.64 (1H, m), 7,74 (1H, d, J=1,8 Hz), 7,86-of 7.90 (1H, m), 8,56-to 8.57 (1H, m,), 8,87-8,89 (1H, m), 3H not detected.

The melting point 201-203°C.

Example 9

N-methyl-1-{1-(pyridine-3-ylsulphonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanamine the dihydrochloride

1-(Pyridine-3-ylsulphonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde (340 mg) was dissolved in ethanol (34 ml)at room temperature was added a 40%solution of methylamine methanol (695 mg) and the mixture was stirred for 30 minutes. At room temperature was added sodium borohydride (102 mg) and the mixture was stirred in ECENA 10 minutes. Added 1 mol/l hydrochloric acid (10 ml) and the mixture was stirred for 5 minutes. The reaction mixture was podslushivaet saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate-methanol=1:0→7:3) and was dissolved in ethyl acetate (5 ml). Added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was concentrated under reduced pressure. The residue was vykristallizovyvalas from ethyl acetate to obtain specified in the title compound as a crystalline substance of a light red color (exit 288 mg, 69%).

1H-NMR (DMSO-d6) δ: 2,47 (3H, t, J=5.5 Hz), of 4.00 (2H, t, J=5.5 Hz), 6,60 (1H, d, J=1,8 Hz), 7.18 in-7,21 (1H, m), 7,63-7,81 (4H, m), to $ 7.91-of 8.00 (2H, m), 8,58 (1H, d, J=1,8 Hz), 8,90-of 8.92 (1H, m), 9,48-to 9.57 (2H, m), 1H not detected.

Example 10

N-methyl-1-[4-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine the dihydrochloride

By a similar reaction as described in example 2 and using 4-methyl-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (171 mg)were specified in the title compound (yield 110 mg, 50%).

1H-NMR (DMSO-d6) δ: 1,79 (3H, c), to 2.57 (3H, c), 3,96-4,00 (2H, m), 6,98-7,01 (2H, m), of 7.36-the 7.43 (3H, m), 7,55-of 7.60 (1H, m), 7,79-of 7.82 (2H, m), 8,43-8,44 (1, m), 8,84-8,86 (1H, m), 9,13 (2H, usher.), 1H not detected.

Example 11

N-methyl-1-[4-methyl-5-phenyl-1-(pyridine-2-ylsulphonyl)-1H-pyrrol-3-yl]methanamine hydrochloride

4-Methyl-5-phenyl-1-(pyridine-2-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (262 mg) was dissolved in tetrahydrofuran (10 ml), was added 2 mol/l solution (1.0 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added to a solution (5 ml), sodium borohydride (76 mg) in methanol and the mixture was stirred at room temperature for 20 minutes. Added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate-methanol=1:0→1:1) and further HPLC (ODS, 0.1% of triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile=9:1→0,1% triperoxonane acid-containing acetonitrile) to produce trifenatate specified in the connection header. The resulting triptorelin neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and was dried to the anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (3 ml)was added 4 mol/l solution (2 ml) of hydrogen chloride in ethyl acetate. After sedimentation at room temperature for 30 minutes the precipitate was collected by filtration and washed with ethyl acetate to obtain specified in the connection header (exit 141 mg, 47%).

1H-NMR (DMSO-d6) δ: 1,79 (3H, c)at 2.59 (3H, c)to 4.01 (2H, c), 6,88-of 6.90 (2H, m), 7,27 was 7.45 (4H, m), 7,71-7,74 (2H, m), 7.95 is-to 7.99 (1H, m), 8,68-to 8.70 (1H, m), 8,88 (2H, usher.).

Example 12

1-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine the dihydrochloride

1-[(1,2-Dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (294 mg) was dissolved in tetrahydrofuran (5 ml), was added 2 mol/l solution (1.0 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 1 hour. The mixture was heated to 40°C and the mixture was additionally stirred for 4 hours. The reaction mixture was added to a solution (5 ml), sodium borohydride (76 mg) in methanol and the mixture was stirred at room temperature for 1 hour. Added water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=9:1→0:1) to obtain the free of salt specified in the connection header. To a solution (3 ml) of the obtained free salt in ethyl acetate solution was added 4 mol/l hydrogen chloride-ethyl acetate (1 ml). After sedimentation at room temperature for 30 minutes the precipitate was collected by filtration and washed with ethyl acetate to obtain specified in the connection header (exit 196 mg, 53%).

1H-NMR (DMSO-d6) δ: 1,79 (3H, c in), 2.25 (3H, c), 2,60 (3H, m), of 3.45 (3H, c), 3.95 to 3,99 (2H, m), a 4.86 (1H, usher.), 6,99-7,01 (2H, m), 7,13 (1H, c), 7,32-7,39 (3H, m), to 7.59 (1H, c), 8,96 (2H, usher.).

Example 13

1-{1-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

By a similar reaction as described in example 12, and using 1-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (378 mg)were specified in the title compound in the form of a solid substance (yield 238 mg, 55%).

1H-NMR (DMSO-d6) δ: rate of 1.67 (3H, c)to 1.79 (3H, c), 2,58 (3H, c)to 3.67 (3H, c)to 3.99 (2H, c), 6,97-6,99 (2H, m), 7,33-7,41 (3H, m), 7,73 (1H, c), of 8.90 (2H, usher.).

Example 14

1-{1-[(1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

Using 1-[(5-chloro-1,3-dimethyl-1H-pyrazole-4-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (295 mg)was obtained free salt (297 mg) of the compound of example 13 in the form of oil. The oil obtained was dissolved in toluene (10 ml) and methanol (10 ml), was added 10% palladium on coal (50% water content, 30 mg) and 20%RA is the creative ethoxide sodium-ethanol (309 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate solution (5 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After sedimentation at room temperature for 30 minutes the precipitate was collected by filtration and washed with ethyl acetate to obtain specified in the connection header (exit 221 mg, 72%).

1H-NMR (DMSO-d6) δ: 1,80 (3H, c), 1,90 (3H, c), 2,59 (3H, m), 3,63 (3H, c)to 3.99 (2H, c), 6,99-7,02 (2H, m), 7,35-7,40 (3H, m), 7,51 (1H, c), 7,66 (1H, c), 8,87 (2H, usher.).

Example 15

1-{1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine triptorelin

To a solution (1 ml) of 1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (27.7 mg) in tetrahydrofuran was added 2 mol/l solution (0.1 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to solution (1 ml), sodium borohydride (7,6 mg) in methanol and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified using VAG is (ODS, 0,1% triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile (97:3)→0,1% triperoxonane acid-containing acetonitrile only) and was ground into powder with diisopropyl ether to obtain specified in the connection header in the form of a solid substance (yield of 12.1 mg, 33%).

1H-NMR (DMSO-d6) δ: 1,80 (3H, c), of 2.06 (3H, c), 2,58 (3H, c), 2,62 (3H, c), a 4.03 (2H, c), 7,05-7,07 (2H, m), 7,37-7,44 (3H, m), to 7.67 (1H, c), to 8.62 (2H, usher.).

Example 16

[5-(2-forfinal)-4-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride

To a solution of 5-(2-forfinal)-4-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (382 mg) in methanol (5 ml) and tetrahydrofuran (2 ml) was added a 40%solution of methylamine methanol (1.1 ml) and the mixture was stirred at room temperature for 4 hours. To the reaction mixture was added sodium borohydride (51 mg) and the mixture was additionally stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution (50 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of basic silicagel the m (eluent: ethyl acetate) to obtain the free of salt specified in the connection header (exit 342 mg). To a solution of the obtained free salt (336 mg) in ethanol (5 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (5.0 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compound as a crystalline substance of white color (exit 197 mg, 46%).

1H-NMR (DMSO-d6) δ: 1,76 (3H, c)at 2.59 (3H, t, J=5.4 Hz), to 4.01 (2H, t, J=5.4 Hz), 7.03 is-was 7.08 (1H, m), 7,21-7,28 (2H, m), 7,51-to 7.64 (2H, m), 7,82-7,86 (2H, m), 8,53 (1H, d, J=2.4 Hz), 8,80-8,89 (3H, m).

Example 17

1-[1-(2-chloropyridin-3-ylsulphonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride

To a solution (3 ml) of tert-butyl {[1-(2-chloro-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (70 mg) in ethyl acetate was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and the residue was led from a mixture of ethanol-ethyl acetate to obtain specified in the title compound (29 mg, 49%).

1H-NMR (DMSO-d6) δ: 2,56 (3H, c), Android 4.04 (2H, c), 6,48 (1H, c), 6,99-7,02 (2H, m), 7,25 was 7.36 (4H, m), 7,66-of 7.69 (1H, m), 7,83 (1H, c), at 8.60-to 8.62 (1H, m), 8,79 (2H, usher.).

Example 18

5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyrimidine-2-amine

To a solution (4 ml) of 1-(2-chloropyrimidine-5-insul who were radioactive)-5-phenyl-1H-pyrrole-3-carbaldehyde (139 mg) in tetrahydrofuran was added 0.5 mol/l solution of ammonia-dioxane (4 ml). After stirring at room temperature for 1 hour was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml), was added 2 mol/l solution (0.75 ml) of methylamine in tetrahydrofuran and the mixture was stirred over night at room temperature. The reaction mixture was added to a solution (2 ml), sodium borohydride (38 mg) in methanol and the mixture was stirred at room temperature for 5 minutes. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% of triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile=9:1→0,1% triperoxonane acid-containing acetonitrile) to produce trifenatate specified in the connection header. The resulting triptorelin neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed sequentially with a saturated aqueous solution of hydrocar is onata sodium, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting crystalline substance washed with diisopropyl ether to obtain specified in the title compounds as a colorless solid (yield 23 mg, 17%).

1H-NMR (DMSO-d6) δ: of 2.27 (3H, c), 3,52 (2H, c), of 6.31 (1H, c), 7,26-7,40 (6H, m), 7,94 (2H, usher.), of 8.00 (2H, c), 1H not detected.

Example 19

1-[(imidazo[1,2-a]pyrimidine-6-ylsulphonyl)-5-phenyl-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

Under nitrogen atmosphere a solution of ethyl 1-(imidazo[1,2-a]pyrimidine-6-ylsulphonyl)-5-phenyl-1H-pyrrole-3-carboxylate (242 mg) in tetrahydrofuran (10 ml) was cooled to -78°C, under stirring was added 1.5 mol/l solution (2.0 ml) hydride diisobutylaluminum in toluene. After stirring at the same temperature for 1 hour the mixture was heated to -20°C for 1 hour. Was added water (30 ml) and after stirring at the same temperature for 5 minutes and the mixture was left to warm to 0°C for 10 minutes. Added ethyl acetate (20 ml) and after stirring at the same temperature for 15 minutes, the mixture was stirred at room temperature for 20 minutes. The reaction mixture is in the gel state was filtered through celite and the celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with the saturated salt solution, was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml)was added manganese dioxide (75% chemically processed product, 2.0 g) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, the residue was dissolved in absolute tetrahydrofuran (5 ml), was added 2 mol/l solution (0.6 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to a solution of sodium borohydride (45 mg) in methanol (2 ml) and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 ml), was added di-tert-butyl bicarbonate (0,22 g), sodium bicarbonate (84 mg) and water (5 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml), add the Yali manganese dioxide (75% chemically processed product, 1.0 g) and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→0:1) obtaining oil. The resulting oil was dissolved in ethanol (1 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After stirring at room temperature for 2 hours the solvent was evaporated under reduced pressure and the residue triturated in a mixture of ethyl acetate-ethanol to obtain specified in the connection header in a solid brown color (output 8.5 mg, 3%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), as 4.02-of 4.05 (2H, m), of 6.49 (1H, c), 7,16-7,19 (2H, m), 7,32-7,44 (3H, m), 7,79 (1H, c), 7,92-to 7.99 (2H, m), 8,29-8,30 (1H, m), 8,97 (2H, usher.), 9,23-9,24 (1H, m), 1H not detected.

Example 20

N-methyl-1-[5-phenyl-1-(pyridazin-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine fumarate

Under nitrogen atmosphere a solution of ethyl 5-phenyl-1-(pyridazin-3-ylsulphonyl)-1H-pyrrole-3-carboxylate (567 mg) in tetrahydrofuran (16 ml) was cooled to -78°C, under stirring was added 1.5 mol/l solution (6.4 ml) hydride diisobutylaluminum in toluene. The reaction mixture was heated to -20°C for 1 hour. Was added water (75 ml) and after stirring at the same temperature for 5 minutes and the mixture was left is to agrevate to 0°C for 10 minutes. Added ethyl acetate (75 ml) and after stirring at the same temperature for 15 minutes, the mixture was stirred at room temperature for 20 minutes. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml)was added manganese dioxide (75% chemically processed product, 5.0 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was dissolved in absolute tetrahydrofuran (15 ml). Added 2 mol/l solution (1.5 ml) of methylamine in tetrahydrofuran and the mixture was stirred over night at room temperature. The reaction mixture was added to a solution of sodium borohydride (66 mg) in methanol (5 ml) and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified with the aid of the d HPLC (ODS, 0,1% triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile=9:1→0,1% triperoxonane acid-containing acetonitrile) to produce trifenatate specified in the connection header. The resulting triptorelin neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to get a free salt (59 mg) specified in the connection header. The obtained free salt (59 mg) was dissolved in methanol (2 ml) and ethyl acetate (2 ml) was added fumaric acid (21 mg). The solvent was evaporated under reduced pressure, and recrystallization from a mixture of ethyl acetate-methanol gave specified in the title compound as a pale yellow solid (yield 41 mg, 6%).

1H-NMR (DMSO-d6) δ: 2,42 (3H, c), 3,82 (2H, c), 6,41 (1H, c), 6,47 (2H, c), 7,09 for 7.12 (2H, m), 7,29-7,38 (3H, m), 7,63 (1H, c), 7,80-7,83 (1H, m), to $ 7.91-of 7.96 (1H, m), 9,48-9,50 (1H, m), 3H not detected.

Example 21

N-methyl-1-[1-(5-methyl-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methanamine fumarate

To a solution (5 ml) of tert-butyl {[1-(6-chloro-5-methyl-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (237 mg) in tetrahydrofuran in the room for the Noah temperature with stirring was added hydrazine (160 mg). After stirring at the same temperature for 3 hours was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml)was added manganese dioxide (75% chemically processed product, 1.0 g) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the oil. The resulting oil was dissolved in ethanol (2 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After stirring at room temperature for 2 hours the solvent was evaporated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue (93 mg) was dissolved in ethanol (3 ml) was added fumaric acid (29 mg). After settling at room temperature the re within 30 minutes the precipitated crystalline substance was collected by filtration and washed with methanol to obtain specified in the title compounds as a colorless solid (yield 91 mg, 40%).

1H-NMR (DMSO-d6) δ: of 2.27 (3H, c), of 2.38 (3H, c in), 3.75 (2H, c), 6,37 (1H, c), 6,47 (2H, c), 7,15-7,17 (2H, m), of 7.36 was 7.45 (4H, m), 7,58 (1H, c), of 8.28 (1H, c), 8,68 (1H, c), 3H not detected.

Example 22

5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridine-2-ol hydrochloride

tert-Butyl {[1-(6-chloro-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (175 mg) was dissolved in tetrahydrofuran (10 ml), was added 8 mol/l aqueous sodium hydroxide solution (3.8 ml) and the mixture was stirred at 50°C for 2 days. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→0:1) to obtain the free of salt specified in the connection header. To a solution (1 ml) of the obtained free salt in ethanol was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml). After stirring at room temperature for 4 hours the solvent was evaporated under reduced pressure and the residue was led from a mixture of ethanol-ethyl acetate to obtain specified in the title compound (yield 40 mg, 27%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 3,97-4,01 (2H, m), 6,32-6,36 (1H, m), 6,47 (1H, c), 7,20-of 7.23 (4H, m), 7,37-of 7.48 (3H, m), 7,66 (1H, c), to 8.94 (2H, usher.), to 12.35 (1H, usher.).

Example 23

5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)pyridine-2-carbonitrile hydrochloride

In an argon atmosphere a mixture of tert-butyl {[1-(6-chloro-3-pyridine sulfonyl)-5-phenyl-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg), cyanide zinc (II) (51 mg), tetrakis(triphenylphosphine)palladium (50 mg) and N,N-dimethylformamide (4 ml) was stirred at 100°C for 2 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→7:3) to obtain the oil. The resulting oil was dissolved in ethyl acetate (2 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml). After stirring at room temperature for 1 hour the solvent was evaporated under reduced pressure and the residue was vykristallizovyvalas from ethanol to obtain specified in the title compound (yield 57 mg, 68%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 3,98 (2H, c), of 6.52 (1H, c), 7,15-7,17 (2H, m), 7,37-7,47 (3H, m), 7,79 (1H, c), 8,04-8,07 (1H, m), by 8.22-8,24 (1H, m), 8,61-to 8.62 (1H, m), 9,03 (2H, usher.).

Example 24

N-methyl-1-{1-[(6-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanamine the dihydrochloride

tert-Butyl ({[1-(6-methylpyridin-3-yl)sulfonyl-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (113 mg) was dissolved in ethanol (2 ml), added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compound (yield 40 mg, 38%).

1H-NMR (DMSO-d6) δ: 2,50-of 2.53 (6H, m), 3,97-3,99 (2H, m), 6,46 (1H, c), 7,16-to 7.18 (2H, m), 7,38-7,44 (4H, m), the 7.65 to 7.75 (2H, m), a 8.34 (1H, c), 8,98 (2H, usher.), 1H not detected.

Example 25

N-methyl-1-[1-(pyridine-3-ylsulphonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methanamine hydrochloride

By the way, is similar to that described in example 24 and using tert-butyl {[1-(pyridine-3-ylsulphonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (182 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 64 mg, 41%).

1H-NMR (CDCl3) δ: 2,60 (3H, c), 3,98 (2H, users), to 6.57 (1H, users), 7,00 (1H, userd, J=4.5 Hz), 7,16 (1H, users), 7,26-7,31 (2H, m), of 7.70 (2H, users), 8,61 (1H, users), 8,73 (1H, users), 9,86 (2H, users).

Example 26

1-[5-(4-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

tert-Butyl {[5-(4-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (293 mg) was dissolved in dichloromethane (1 ml), at 0°C was added triperoxonane acid (1 ml) and the mixture was stirred at room temperature for 3 hours. The reaction solution was podslushivaet to what t dropwise 6% aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate (5 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate-ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 110 mg, 40%).

1H-NMR (DMSO-d6) δ: 2,47 is 2.51 (3H, m), of 3.97 (2H, t, J=6.0 Hz), 6,52-6,53 (1H, m), 7,15-7,26 (4H, m), EUR 7.57-to 7.61 (1H, m), 7,79-a 7.85 (2H, m), of 8.00 (1H, d, J=2.4 Hz), cent to 8.85-8,87 (1H, m), which 9.22 (2H, usher.), 1H not detected.

Example 27

N-methyl-1-[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine the dihydrochloride

By the way, is similar to that described in example 26 and using tert-butyl methyl{[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (210 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 67 mg, 34%). More specifically, tert-butyl methyl{[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (210 mg) was dissolved in chlormethine (2 ml), at 0°C was added triperoxonane acid (1 ml) and the mixture was stirred at room temperature for 2 hours. The reaction solution was podslushivaet added dropwise 6% aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate (5 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate-ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 67 mg, 34%).

1H-NMR (DMSO-d6) δ: 1,80 (3H, c), 2,49 of $ 2.53 (3H, m)4,00 (2H, t, J=5.4 Hz), 6,46 (1H, d, J=2.4 Hz), 6,83 (1H, d, J=7.8 Hz), 7,13-7,22 (2H, m), 7,33-7,39 (1H, m), to 7.59-7,63 (1H, m), 7,80-a 7.85 (2H, m), 8,46 (1H, d, J=2,4 Hz), 8,88-of 8.90 (1H, m), 9,27 (2H, usher.), 1H not detected.

The melting point 196-200°C.

Example 28

1-[5-(4-fluoro-2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

By the way, is similar to that described in example 26, and use the Zuya tert-butyl {[5-(4-fluoro-2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (216 mg), got mentioned in the title compound as a colorless crystalline substance (yield 81 mg, 40%).

1H-NMR (DMSO-d6) δ: 1,80 (3H, c), 2,49 is 2.51 (3H, m)4,00 (2H, t, J=6.0 Hz), 6,47 (1H, d, J=2.1 Hz), 6,85-of 6.90 (1H, m), 6,98 for 7.12 (2H, m), to 7.61-the 7.65 (1H, m), 7,81-7,88 (2H, m), 8,51 (1H, d, J=2.7 Hz), 8,89-8,91 (1H, m), 9,29 (2H, usher.), 1H not detected.

Example 29

N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine the dihydrochloride

By the way, is similar to that described in example 26 and using tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (200 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 125 mg, 67%). More specifically, tert-butyl methyl{[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (200 mg) was dissolved in dichloromethane (1 ml), at 0°C was added triperoxonane acid (1 ml) and the mixture was stirred at room temperature for 1 hour. The reaction solution was podslushivaet added dropwise 6% aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give the free with the and indicated in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate (5 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethyl acetate-ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 125 mg, 67%).

1H-NMR (DMSO-d6) δ: 1,71 (3H, c), 2,49 is 2.51 (3H, m), 3,98 (2H, t, J=5.7 Hz), of 6.49 (1H, d, J=2.1 Hz), 7,16-of 7.23 (2H, m), 7,58 to 7.62 (1H, m), 7,79-7,86 (2H, m), 8,50-8,51 (1H, m), 8,87-8,89 (1H, m), of 9.30 (2H, usher.), 1H not detected.

The melting point 178-181°C.

Example 30

3-[4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl]benzonitrile hydrochloride

By the way, is similar to that described in example 26 and using tert-butyl {[5-(3-cyanophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (298 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 132 mg, 52%).

1H-NMR (DMSO-d6) δ: 2,48 is 2.51 (3H, m), 3,98 (2H, users), of 6.65 (1H, d, J=1,8 Hz), 7,51-the 7.65 (4H, m), a 7.85-of 7.95 (3H, m), 8,55 (1H, d, J=2.4 Hz), 8,88-of 8.90 (1H, m), 9,25 (2H, usher.).

Example 31

1-[5-(2-chlorophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

By the way, is similar to that described in example 26 and using tert-butyl {[5-(2-chlorophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (171 mg)were specified in the header is Obedinenie in the form of a colorless crystalline substance (yield 74 mg, 46%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, usher.), to 4.01 (2H, t, J=6.0 Hz), of 5.40 (1H, usher.), 6,55 (1H, d, J=2.1 Hz), 7,13-7,16 (1H, m), 7,35-7,40 (1H, m), 7,47-7,51 (2H, m), to 7.61-the 7.65 (1H, m), 7,84-to 7.93 (2H, m), to 8.57 (1H, d, J=2.1 Hz), 8,89-8,91 (1H, m), 9,23 (2H, usher.).

Example 32

1-[5-(2,4-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

By the way, is similar to that described in example 26 and using tert-butyl {[5-(2,4-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (110 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 58 mg, 56%).

1H-NMR (DMSO-d6) δ: 2,48 is 2.51 (3H, m), 3,98 (2H, t, J=5.7 Hz), 6,62 (1H, d, J=1,8 Hz), 7,13-7,17 (2H, m), 7,28 and 7.36 (1H, m), 7,62-7,66 (1H, m), 7,86-of 7.95 (2H, m), 8,61 (1H, d, J=2.4 Hz), 8,89-8,91 (1H, m), 9,31 (2H, user.), 1H not detected.

Example 33

1-[5-(2,5-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride

By the way, is similar to that described in example 26 and using tert-butyl {[5-(2,5-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (105 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 39 mg, 43%).

1H-NMR (DMSO-d6) δ: 2,50 is 2.51 (3H, m)to 3.99 (2H, users), 6,62 (1H, d, J=1,8 Hz), 7,00-7,06 (1H, m), 7,27-7,44 (2H, m), 7,63-to 7.67 (1H, m), 7,86 (1H, usher.), 7,94-of 7.97 (1H, m), 8,65 (1H, d, J=2.7 Hz), 8,90-of 8.92 (1H, m), the remaining 9.08 (2H, m).

Example 34

1-[5-(4-chloro-2-forfinal)-1-(pyridine-3-alsultan the l)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

By the way, is similar to that described in example 26 and using tert-butyl {[5-(4-chloro-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (103 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 32 mg, 33%).

1H-NMR (DMSO-d6) δ: 2,47-2,52 (3H, m), of 3.97 (2H, t, J=6.0 Hz), 5,10 (1H, usher.), only 6.64 (1H, users), to 7.15 (1H, t, J=7.8 Hz), 7,34 and 7.36 (1H, m), 7,50-7,53 (1H, m), 7,62-to 7.67 (1H, m), 7,88 (1H, users), 7,95-7,98 (1H, m)8,64 (1H, d, J=2.4 Hz), of 8.90 (1H, d, J=4,8 Hz), was 9.33 (2H, usher.).

Example 35

1-[5-(3-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride

Tert-butyl {[5-(3-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved in ethyl acetate (3 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (6 ml) and the mixture was stirred at room temperature for 16 hours. The reaction solution was podslushivaet added dropwise 6% aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate-hexane=1:1→9:1) to obtain the free of salt specified in the title compound as a pale yellow oil. The obtained free salt RA is tarali in ethyl acetate, added 4 mol/l solution of hydrogen chloride-ethyl acetate and the mixture was concentrated under reduced pressure. The residue was vykristallizovyvalas of ethyl acetate and hexane, and recrystallized from a mixture of ethyl acetate-ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 84 mg, 35%).

1H-NMR (DMSO-d6) δ: 2.49 USD is 2.51 (3H, m), of 3.97 (2H, c), to 6.57 (1H, d, J=1,8 Hz), 6,98-7,02 (2H, m), 7,27-7,33 (1H, m), 7,40-7,47 (1H, m), 7,58 to 7.62 (1H, m), 7,80-7,87 (2H, m), 8,54 (1H, d, J=2.7 Hz), 8,86-8,88 (1H, m), 9,06 (2H,user.).

Example 36

1-[5-(2-forfinal)-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

A suspension of tert-butyl {[5-bromo-2-methyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (369 mg), (2-forfinal)boric acid (234 mg), sodium carbonate (265 mg) and tetrakis(triphenylphosphine)palladium (48,9 mg) in 1,2-dimethoxyethane (15 ml) and water (7.5 ml) was stirred at 105°C for 12 hours. The reaction mixture was left to cool to room temperature, added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=1:4) to obtain the oil. Polucen the e oil was dissolved in ethanol (5 ml), added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was neutralized by adding saturated aqueous sodium hydrogen carbonate solution (50 ml). The mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate) and further HPLC (ODS, 0.1% of triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile=9:1→0,1% triperoxonane acid-containing acetonitrile) to produce trifenatate specified in the connection header. The resulting triptorelin neutralized with a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to get a free salt specified in the title compound (yield 65 mg). Free salt (62 mg) was dissolved in ethyl is cetate (2 ml), solution was added fumaric acid (17 mg) in methanol (2 ml) and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compound as a crystalline substance of white color (yield 25 mg, 7%).

1H-NMR (DMSO-d6) δ: 2,35 (3H, c), is 2.40 (3H, c in), 3.75 (2H, c), 6,46 (3H, c), 7,20-7,28 (3H, c), 7,44-7,52 (1H, m), 7,63-to 7.67 (1H, m), 7,88-a 7.92 (1H, m), 8,61 (1H, d, J=2.4 Hz), 8,88-of 8.90 (1H, m), 3H not detected.

Example 37

N-methyl-1-(5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrol-3-yl)methanamine hydrochloride

To a solution of 5-phenyl-1-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (137 mg) in absolute tetrahydrofuran (5 ml) was added at room temperature, 2 mol/l solution of 0.36 ml) of methylamine in tetrahydrofuran and the mixture was stirred for 16 hours. Was added sodium borohydride (27 mg) and methanol (2 ml) and the mixture was stirred at the same temperature for 2 minutes. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml), was added di-tert-butyl bicarbonate (218 mg), water (2 ml) and hydrogen is the atrium (84 mg) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml)was added manganese dioxide (75% chemically processed product, 1.0 g) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1), the fractions containing the substance showing an Rf value equal 0,46 (eluent:hexane-ethyl acetate=3:1) using research TLC were collected and concentrated under reduced pressure. The residue was dissolved in ethanol (1 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After stirring at room temperature for 2 hours the solvent was evaporated under reduced pressure. The residue was purified by HPLC (ODS, 0.1% of triperoxonane acid-containing water-0.1% of triperoxonane acid-containing acetonitrile=97:3→0,1% triperoxonane acid-containing acetonitrile) to produce trifenatate specified in the connection header. The resulting triptorelin neutralized with a saturated aqueous solution of the m sodium bicarbonate, were extracted with ethyl acetate, washed sequentially with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml) and the mixture was concentrated under reduced pressure. Recrystallization from ethanol gave specified in the title compound (yield 23 mg, 15%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), of 3.97 (2H, c), of 6.49 (1H, c), 7,13-to 7.15 (2H, m), 7,37-of 7.48 (3H, m), 7,80-7,87 (2H, m), 8,72 (2H, usher.), 8,86 (1H, c), was 9.33 (1H, c).

Example 38

N-methyl-1-{1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanamine the dihydrochloride

By a similar reaction as described in example 12, and using 1-[(2-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrole-3-carbaldehyde (180 mg)were specified in the title compound in the form of a solid substance (yield 110 mg, 48%).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, c), 2,53-to 2.57 (3H, m), as 4.02-4,10 (2H, m), 6,51 (1H, d, J=1,8 Hz), 7,01 (2H, d, J=6.9 Hz), 7,11-to 7.35 (4H, m), 7,44-7,46 (1H, m), to 7.84 (1H, d, J=2.1 Hz), 8,61-to 8.62 (1H, m), 9,07 (2H, usher.), 1H not detected.

Example 39

1-[5-(2,6-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a mixture of 40%aqueous solution of methylamine methanol (560 mg) and methanol (5 ml) at room temperature was added 5-(2,6-differenl)-1-(pyridin-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (250 mg) and the mixture was stirred for 30 minutes. To the reaction mixture was added sodium borohydride (41 mg) and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure at 30°C. the Residue was extracted with saturated aqueous sodium bicarbonate and ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate) and was dissolved in ethanol (5 ml) and to implement the crystallization solution was added fumaric acid (84 mg) in ethanol (5 ml) to obtain specified in the title compounds as a colorless crystalline substance (exit 229 mg, 67%).

1H-NMR (DMSO-d6) δ: 2,43 (3H, c), 3,85 (2H, c), 6,48 (2H, c), to 6.57 (1H, d, J=1.7 Hz), 7,12-to 7.18 (2H, m), 7,55-7,66 (2H, m), 7,81 (1H, d, J=1.7 Hz), 7,93-of 7.97 (1H, m), 8,61 (1H, d, J=2.1 Hz), of 8.90 (1H, DD, J=4,7, 1.5 Hz), 3H not detected.

Example 40

1-[5-(4-cyclohexylphenol)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

To a solution of 5-(4-cyclohexylphenol)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (0,78 g) in methanol (20 ml) was added to chloride of methylamine (1,61 g) and cyanoborohydride sodium (0,49 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, to the residue was added to the concentration of the new aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=3:2→0:1) obtaining oil (0.39 g). The oil was dissolved in ethyl acetate (3 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1.5 ml) and the mixture was concentrated under reduced pressure. Crystallization from methanol-ethyl acetate gave specified in the title compound in the form of a crystalline substance (yield of 0.41 g, 43%).

1H-NMR (DMSO-d6) δ: 1,20-of 1.46 (5H, m), 1,68-of 1.88 (5H, m), 2,45 at 2.59 (1H, m), 2,48 (3H, c), of 3.97 (2H, d, J=5.3 Hz), 6.48 in (1H, c),? 7.04 baby mortality (2H, d, J=8.1 Hz), 7,20 (2H, d, J=8.1 Hz), 7,51-EUR 7.57 (1H, m), 7,73-7,79 (2H, m), 8,43 (1H, c), 8,83 (1H, d, J=4,7 Hz), 9,17 (2H, c), 1H not detected.

Example 41

1-[4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine the dihydrochloride

By a similar reaction as described in example 12, and using 4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (121 mg)were specified in the title compound as a colorless solid (yield of 30.7 mg, 20%). More specifically, 4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (121 mg) was dissolved in tetrahydrofuran (5 ml), was added 2 mol/l solution (0,22 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 4 hours the century To the reaction mixture were added a solution (2 ml), sodium borohydride (28 mg) in methanol and the mixture was stirred at room temperature for 20 minutes. Was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate→ethyl acetate-methanol=1:4) to give a free salt specified in the connection header. To a solution (2 ml) of the obtained free salt in ethanol was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After sedimentation at room temperature for 30 minutes, the mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless solid (yield of 30.7 mg, 20%).

1H-NMR (DMSO-d6) δ: 2,56 at 2.59 (3H, m), a 4.03-of 4.05 (2H, m), 7,14-7,16 (2H, m), 7,41-of 7.48 (3H, m), 7,53 to 7.62 (1H, m), 7,80-a 7.85 (2H, m), and 8.50 (1H, d, J=2.4 Hz), 8,88-8,89 (1H, m), 9,07 (2H, usher.), 1H not detected.

The melting point 201-203°C.

Example 42

1-[4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

4-Fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (0.27 g) was dissolved in tetrahydrofuran (10 ml), was added 2 mol/l solution (0.8 ml) m is tiramina in tetrahydrofuran and the mixture was stirred at room temperature for 2 hours. Was added sodium borohydride (91 mg) and methanol (7 ml) and the mixture was stirred at the same temperature for another 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (hexane-ethyl acetate=19:1→0:1). The above action is performed again to obtain specified in the connection header (0,22 g, yield 39%) as a colourless solid.

1H-NMR (CDCl3) δ: 2,48 (3H, c), 3,63 (2H, c), 7,22-7,42 (7H, m), 7,56-of 7.60 (1H, m), 8,55 (1H, d, J=2.1 Hz), 8,73 (1H, DD, J=4,8, 1.8 Hz), 1H not detected.

The melting point of 98-99°C.

Example 43

1-[4-fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine 0.5 fumarate

1-[4-Fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine (32 mg) was dissolved in ethanol (2 ml)was added fumaric acid (10 mg) and the mixture was defended at room temperature for 1 hour. The precipitate was collected by filtration to obtain specified in the title compounds as a colorless solid (yield 16 mg, 42%).

1H-NMR (DMSO-d6) δ: 2,30 (3H, c), of 3.60 (2H, c), of 6.50 (1H, c), 7,18-7,21 (2H, m), 7,39-to 7.50 (4H, m), EUR 7.57-to 7.61 (1H, m), 7,79-7,83 (1H, m), and 8.50 (1H, d, J=2.1 Hz), 8,87 (1H, DD, J=5,1, 1.8 G is), 2H not detected.

The melting point 163-166°C.

Example 44

the dihydrochloride of 1-{5-(2-forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine

By a similar reaction as described in example 12, using 5-(2-forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde (134 mg)were specified in the title compound as a colorless solid (yield 96,1 mg, 57%). More specifically, 5-(2-forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde (134 mg) was dissolved in tetrahydrofuran (10 ml), was added 2 mol/l solution (0.6 ml) of methylamine in tetrahydrofuran and the mixture was stirred at room temperature for 4 hours. To the reaction mixture were added a solution (5 ml), sodium borohydride (76 mg) in methanol and the mixture was stirred at room temperature for 20 minutes. Was added an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate→ethyl acetate : methanol=1:4) to give a free salt specified in the connection header. To a solution (2 ml) obtained by Svobodniy salt in ethanol was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After otst the air traffic management at room temperature for 30 minutes, the mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compound as a colourless solid substances (output for 96.1 mg, 57%).

1H-NMR (DMSO-d6) δ: 2,50-of 2.56 (6H, m), 3,97-was 4.02 (2H, m), 6,55 (1H, d, J=1,8 Hz), 7,08-7,11 (1H, m), 7,22-7,26 (2H, m), 7,47-of 7.60 (2H, m), 7,76-of 7.82 (2H, m), 8,44 (1H, d, J=2.4 Hz), 9,04 (2H, usher.), 1H not detected.

The melting point 212-213°C.

Example 45

1-[5-(2-forfinal)-1-(pyridine-2-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine hydrochloride

By a similar reaction as described in example 12, using 5-(2-forfinal)-1-(pyridine-2-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (183 mg)were specified in the title compound as a colorless solid (yield to 78.3 mg, 37%).

1H-NMR (DMSO-d6) δ: 2,54 (3H, c), was 4.02 (2H, c), of 6.52 (1H, d, J=2.1 Hz), 7,00? 7.04 baby mortality (1H, m), 7,11-7,19 (2H, m), 7,46-7,51 (1H, m), EUR 7.57-of 7.60 (1H, m), 7,74 for 7.78 (2H, m), 8,03-8,08 (1H, m), 8,70 cent to 8.85 (3H, m).

Example 46

1-{5-(2-forfinal)-1-[(1-methyl-1H-pyrazole-4-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine fumarate

To a solution (3 ml) of 5-(2-forfinal)-1-[(1-methyl-1H-pyrazole-4-yl)sulfonyl]-1H-pyrrole-3-carbaldehyde (217 mg) in tetrahydrofuran was added a 40%solution of methylamine methanol (152 mg) and methanol (1 ml) at room temperature. After stirring at room temperature for 1 hour at 0°C was added sodium borohydride (82 mg). After stirring at room temperature for 30 minutes was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sulfate intothree and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compound as a pale yellow oil (yield 152 mg). A solution of the obtained free salt in ethyl acetate (5 ml) was added to a solution of fumaric acid (50,6 mg) in methanol (1 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol/water=95/5 obtaining specified in the title compounds as a colorless crystalline substance (yield 143 mg, 48%).

1H-NMR (DMSO-d6) δ: 2,46 (3H, c), 3,82 (3H, c), 3,85 (2H, c), 6,41 (1H, d, J=1,8 Hz), 6,46 (2H, c), 7,15-7,26 (3H, m), 7,46-7,56 (3H, m), 8,11 (1H, c), 3H not detected.

Example 47

N-methyl-1-[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine fumarate

To a solution of 5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (521 mg) in tetrahydrofuran (5 ml) and methanol (5 ml) was added a 40%solution of methylamine methanol (373 mg). After stirring at room temperature for 1 hour was added sodium borohydride (202 mg). After stirring at the same temperature for 30 minutes was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on to the column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compound as a yellow oil (yield 422 mg). A solution of the obtained free salt in ethanol (5 ml) was added to a solution (15 ml), fumaric acid (144 mg) in ethanol and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (exit 414 mg, 56%).

1H-NMR (DMSO-d6) δ: is 1.81 (3H, c), a 2.45 (3H, c), 3,88 (2H, c), 6,33 (1H, d, J=1,8 Hz), 6,46 (2H, c), 6,83-6,85 (1H, m), 7,12-7,22 (2H, m), 7,32-7,37 (1H, m), EUR 7.57-to 7.61 (1H, m), of 7.69 (1H, d, J=1,8 Hz), 7,78-of 7.82 (1H, m), 8,44-to 8.45 (1H, m), 8,87-8,89 (1H, m), 3H not detected.

The melting point 207-210°C.

Example 48

1-[4-chloro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of 4-chloro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (429 mg) in tetrahydrofuran (5 ml) and methanol (3 ml) was added at room temperature to 40%solution of methylamine methanol (275 mg). After stirring for 30 minutes was added sodium borohydride (99 mg). After stirring at the same temperature for 1 hour was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the header with the unity in the form of a yellow oil (yield 257 mg). To a solution (10 ml), fumaric acid (79 mg) in methanol was added a solution of the obtained free salt in ethyl acetate (5 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 216 mg, 36%).

1H-NMR (DMSO-d6) δ: 2,43 (3H, c in), 3.75 (2H, c), is 6.54 (2H, c), 7,13-7,19 (1H, m), 7.24 to to 7.32 (2H, m), 7,55-7,66 (2H, m), 7,81 (1H, c), 7,88-a 7.92 (1H, m), 8,56-to 8.57 (1H, m), 8,90-of 8.92 (1H, m), 3H not detected.

Example 49

1-[4-fluoro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of 4-fluoro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)pyrrole-3-carbaldehyde (0,60 g) in tetrahydrofuran (6 ml) and methanol (6 ml) was added a 40%solution of methylamine methanol (1.8 ml) and the mixture was stirred at room temperature for 30 minutes. Was added at room temperature, sodium borohydride (84 mg) and the mixture was stirred for 5 minutes and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a primary si is imaginem (eluent: ethyl acetate) to obtain the free of salt specified in the title compound as a pale yellow oil (yield 0.36 g). The obtained free salt (0.36 g) was dissolved in ethanol (10 ml) was added at room temperature a solution of fumaric acid (0.12 g) in ethanol (10 ml). The reaction mixture was stirred for 14 hours and then concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 0.73 g, 43%).

1H-NMR (DMSO-d6) δ: at 2.36 (3H, c), of 3.69 (2H, c), is 6.54 (2H, c), 7,21-to 7.32 (3H, m), 7,54-the 7.65 (3H, m), 7,86-of 7.90 (1H, m), to 8.57 (1H, d, J=2.4 Hz), 8,89-8,91 (1H, m), 3H not detected.

Example 50

1-[4-fluoro-5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution (5 ml) of 4-fluoro-5-(2-were)-1-(pyridine-3-ylsulphonyl)pyrrole-3-carbaldehyde (0.45 g) in tetrahydrofuran was added a 40%solution of methylamine methanol (1.5 ml) and methanol (5 ml) and the mixture was stirred at room temperature for 30 minutes. Was added at room temperature, sodium borohydride (76 mg) and the mixture was stirred for 30 minutes and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure the AI. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate) to obtain the free of salt specified in the title compound as a pale yellow oil (yield 0.33 g). The obtained free salt (0.33 g) was dissolved in ethanol (4 ml) was added at room temperature a solution of fumaric acid (0.10 g) in ethanol (10 ml). After stirring for 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 0.32 g, 54%).

1H-NMR (DMSO-d6) δ: 1,76 (3H, c), 2,43 (3H, c), of 3.80 (2H, c), of 6.52 (2H, c), 6,97-6,99 (1H, m), 7,19-7,26 (2H, m), 7,37-7,42 (1H, m), 7,58-the 7.65 (2H, m), 7,80-to 7.84 (1H, m), 7,46 (1H, d, J=2.4 Hz), 8,89-8,91 (1H, m), 3H not detected.

Example 51

1-[2-chloro-5-(2,6-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

2-chloro-5-(2,6-differenl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (160 mg) at room temperature was added to a mixture of 40%aqueous solution of methylamine methanol (325 mg) and methanol (20 ml). After stirring for 30 minutes, was added sodium borohydride (48 mg) and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure at 30°C. the Residue was extracted with saturated aqueous sodium bicarbonate and ethyl acetate. The former is ract washed with saturated salt solution, was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate-methanol=1:0→7:3) and was dissolved in ethanol (2 ml) was added a solution of fumaric acid (48 mg) in ethanol (2 ml). Crystallization of the mixture gave specified in the title compound in the form of a colorless crystalline substance (yield 29 mg, 14%).

1H-NMR (DMSO-d6) δ: 2,28 (3H, c), the 3.65 (2H, c), 6,51 (2H, c), of 6.73 (1H, c), 7,21-7,28 (2H, m), 7,55-the 7.65 (1H, m), 7,73-to 7.77 (1H, m), 8,08-to 8.12 (1H, m), 8,82 (1H, d, J=2.4 Hz), 8,96 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 52

1-[2-chloro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of methylamine hydrochloride (232 mg) in methanol (10 ml) was added 2-chloro-5-(2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (250 mg) and the mixture was stirred for 30 minutes. Added triacetoxyborohydride sodium (218 mg) and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure at 30°C and was extracted with saturated aqueous sodium bicarbonate and ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate-methanol=1:0→17:3) and was dissolved in the tracedata (10 ml) was added a solution of fumaric acid (80 mg) in methanol (2 ml). Crystallization of the mixture gave specified in the title compound in the form of a colorless crystalline substance (yield 97 mg, 29%).

1H-NMR (DMSO-d6) δ: 2,23 (3H, c), 3,61 (2H, c), 6,51 (2H, c), is 6.61 (1H, c), 7,27-7,33 (2H, m), 7,43-7,56 (2H, m), 7,69-7,74 (1H, m), 8,02-of 8.06 (1H, m), 8,80 (1H, users), to 8.94 (1H, DD, J=4,8, and 1.4 Hz), 3H not detected.

Example 53

1-{1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

tert-Butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (120 mg) was dissolved in ethanol (3 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After stirring at room temperature for 4 hours the mixture was concentrated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the connection header in the form of a solid substance (yield 51.3 mg, 49%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, s), of 3.96 (2H, m), 6,51 (1H, s), 7,15-7,17 (2H, m), 7,39-to 7.50 (3H, m), to 7.77 (1H, s), to 7.84 (1H, s), 8,48 (1H, s)8,89 (2H, usher.), 9,03 (1H, s).

Example 54

hydrochlorid-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)nicotinanilide

A mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), cyanide zinc (50 mg) and N,N-dimethylformamide (4 ml) was degirolami argon gas. Added tetrakis(triphenylphosphine)palladium (46 mg) and the mixture was stirred at 100°C during the 1.5 hours. After cooling the reaction mixture to room temperature was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent : hexane-ethyl acetate =19:1→3:2) to give a colorless oil. The resulting oil was dissolved in ethanol (2 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml). After stirring at room temperature for 1 hour the mixture was concentrated under reduced pressure and recrystallized from ethanol to obtain specified in the connection header in the form of a solid substance (yield to 32.7 mg, 42%).

1H-NMR (DMSO-d6) δ: 2,50-2,52 (3H, m), 3,98 (2H, s), 6,50 (1H, s), 7,13-7,16 (2H, m), 7,37 is 7.50 (3H, m), 7,76 (1H, d, J=1,8 Hz), of 8.28 (1H, d, J=2.1 Hz), 8,66 (1H, d, J=2.4 Hz), 8,82 (2H, usher.), 9,31 (1H, d, J=2.1 Hz).

Example 55

the hydrochloride of methyl 5-({4-[(methylamino)methyl]-2-phenyl-1H-pyrrol-1-yl}sulfonyl)nicotinate

A mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), dichloro[bis(triphenylphosphine)]palladium (28 mg), triethylamine (0.25 ml) and methanol (15 ml) was stirred in an atmosphere of carbon monoxide (3 ATM) at 100°C for 12 hours. After cooling to the room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent : hexane-ethyl acetate =19:1→3:2) to give a colorless oil. The resulting oil was dissolved in ethanol (2 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml). After stirring at room temperature for 1 hour the mixture was concentrated under reduced pressure and recrystallized from ethanol to obtain specified in the connection header in the form of a solid substance (yield 47.0 mg, 56%).

1H-NMR (DMSO-d6) δ: 2.49 USD is 2.51 (3H, m), 3,91 (3H, s), 3,98 (2H, s), of 6.50 (1H, d, J=1,8 Hz), 7,15-7,17 (2H, m), 7,37 is 7.50 (3H, m), 7,80 (1H, s), 7,93-7,94 (1H, m), 8,81 (1H, d, J=2.1 Hz), 8,91 (2H, usher.), 9,29 (1H, d, J=2.1 Hz).

Example 56

the dihydrochloride of N-methyl-1-{1-[(5-methylpyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methanamine

In an argon atmosphere a mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), methylboronic acid (18 mg), tetrakis(triphenylphosphine)palladium (23 mg), potassium carbonate (138 mg) and 1,4-dioxane (5 ml) was stirred at 80°C for one day. The reaction mixture was poured into a saturated aqueous solution of hydroc is rbonate sodium and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: hexane-ethyl acetate=19:1→1:1) to obtain the oil. The oil was dissolved in ethanol (1 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1 ml). After stirring at room temperature for 1 hour the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol-ethyl acetate to obtain specified in the title compounds as a colorless solid (yield of 32.6 mg, 39%).

1H-NMR (DMSO-d6) δ: 2,28 (3H, c), 2,50 of $ 2.53 (3H, m), 3,94-4,00 (2H, m), 6.48 in (1H, d, J=1,8 Hz), 7,12-to 7.15 (2H, m), 7,37-7,52 (4H, m), of 7.75 (1H, c), 8,29 (1H, d, J=2.1 Hz), to 8.70 (1H, d, J=1.5 Hz), remaining 9.08 (2H, usher.), 1H not detected.

Example 57

hydrochloride of 1-[5-(2,4-dimetilfenil)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine

By the way, is similar to that described in example 33 and using tert-butyl {[5-(2,4-dimetilfenil)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (177 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 68 mg, 45%).

1H-NMR (DMSO-d6) δ: 1,76 (3H, c), 2,32 (3H, c), 2,49 (3H, c)to 3.99 (2H, c), 6,38 (1H, d, J=1,8 Hz), of 6.71 (1H, d, J=8.1 Hz), 6,95-7,03 (2H, m), to 7.59-7,63 (1H, m), to 7.77-a 7.85 (2H, m), 8,48 (1H, d, J=2.7 Hz), 8,88-of 8.90 (1H, m), 9,07 (2H, usher.).

Example 58/b>

N-methyl-1-{5-[4-(methylsulphonyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methanamine the dihydrochloride

To a solution of tert-butyl methyl{[5-[4-(methylsulphonyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (275 mg) in ethyl acetate (2 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at room temperature for 4 hours. The precipitated crystalline substance was collected by filtration, washed with ethyl acetate and recrystallized from ethanol to obtain specified in the title compound as a crystalline substance of white color (exit 157 mg, 33%).

1H-NMR (DMSO-d6) δ: 2,50 (3H, c), 3,29 (3H, c), 3,98 (2H, t, J=5.6 Hz), to 6.67 (1H, d, J=1.9 Hz), of 7.48 (2H, d, J=8.7 Hz), 7,60 (1H, DD, J=8,6, 4,4 Hz), 7,86-of 7.97 (4H, m), 8,59 (1H, d, J=1.9 Hz), 8,88 (1H, DD, J=4,8, 1,4 Hz), 9,20 (2H, c), 1H not detected.

Example 59

(2-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}phenyl)methanol fumarate

tert-Butyl ({5-[2-(hydroxymethyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (132 mg) was dissolved in triperoxonane acid (1 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was podslushivaet saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate-methanol=1:0→9:1) to obtain the free of salt specified in the title compounds as colorless oil (yield of 60.3 mg). A solution of the obtained free salt in ethyl acetate (5 ml) was added to a solution of fumaric acid (19.6 mg) in methanol (2 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 48 mg, 35%).

1H-NMR (DMSO-d6) δ: 2,42 (3H, c), 3,83 (2H, c), of 4.00 (2H, c), 6.35mm (1H, d, J=1.5 Hz), 6,46 (2H, c), for 6.81-6,83 (1H, m), 7,17-7,22 (1H, m), 7,41-to 7.50 (2H, m), 7,55-of 7.60 (1H, m), the 7.65 (1H, c), 7,75 for 7.78 (1H, m), 8,46 (1H, d, J=2.4 Hz), 8,86 (1H, d, J=4,8 Hz), 4H not found.

Example 60

N-methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine fumarate

By a similar reaction as described in example 59, using tert-butyl {[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (943 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 553 mg, 57%). More specifically, tert-butyl {[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (943 mg) was dissolved in triperoxonane acid (3 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is onselaciune saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:9) to give a free salt specified in the title compounds as colorless oil (yield 631 mg). A solution of the obtained free salt in ethyl acetate (5 ml) was added to a solution of fumaric acid (211 mg) in methanol (2 ml) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol-water to obtain specified in the title compounds as a colorless crystalline substance (yield 553 mg, 57%).

1H-NMR (DMSO-d6) δ: 1,71 (3H, c), 2,42 (3H, c), 3,83 (2H, c), 6,34 (1H, d, J=1,8 Hz), 6,45 (2H, c), 7,15-7,16 (1H, m), 7,21-7,22 (1H, m), 7,56-of 7.60 (1H, m), of 7.64-the 7.65 (1H, m), 7,78-of 7.82 (1H, m), 8,48 (1H, d, J=2.4 Hz), 8,84-8,86 (1H, m), 3H not detected.

The melting point 182-183°C.

Example 61

N-methyl-1-(5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl)methanamine fumarate

5-Phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (650 mg) was dissolved in a mixture of 40%aqueous solution of methylamine methanol (808 mg) and methanol (30 ml) at room temperature and the mixture was stirred for 10 minutes. Was added sodium borohydride (118 mg) and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure at 30°C and about who's headed the remainder was extracted with saturated aqueous sodium hydrogen carbonate (40 ml) and ethyl acetate (80 ml). The extract was washed with saturated brine (40 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate) was added a solution of fumaric acid (242 mg) in ethanol (24 ml). The resulting crystalline substance was collected by filtration and recrystallized from a mixture of ethanol-water (85:15) to obtain the specified title compound as a colorless crystalline substance (yield 480 mg, 52%).

1H-NMR (DMSO-d6) δ: 2,42 (3H, c), 3,86 (2H, c), 6.42 per (1H, d, J=1.9 Hz), 6,47 (2H, c), 7,14-to 7.18 (2H, m), 7,34-7,46 (3H, m), 7,54-7,58 (1H, m), to 7.67 (1H, d, J=1.9 Hz), 7,76-7,80 (1H, m), 8,46 (1H, DD, J=2.5 and 0.8 Hz), 8,84 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 62

1-[5-mesityl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of 5-mesityl-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (0,37 g) in tetrahydrofuran (15 ml) was added dropwise a solution of 40%solution of methylamine methanol (0,41 g) in tetrahydrofuran (1 ml) under cooling on ice and the mixture was stirred at room temperature for 2 hours. Was added methanol (10 ml) and the mixture was additionally stirred at room temperature for 2 hours. Gradually when cooled on ice was added sodium borohydride (0.06 g) and the mixture was stirred at room temperature for 1 hour. React the mixture was concentrated under reduced pressure, to the residue was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→ethyl acetate : methanol=5:1) to obtain the free of salt specified in the connection header in the form of butter, light brown. To a solution of the obtained free salt in ethyl acetate (5 ml) was added dropwise a solution of fumaric acid (0.14 g) in methanol (2.5 ml) under cooling on ice and the mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and recrystallized from ethanol-water to obtain specified in the title compound as a crystalline substance of white color (yield 0.32 g, 61%).

1H-NMR (DMSO-d6) δ: 1,58 (6H, c), of 2.28 (3H, c), is 2.44 (3H, c), a 3.87 (2H, c), 6,21 (1H, c), of 6.45 (2H, c), 6,83 (2H, c), 7,60 (1H, DD, J=8,1, 1.8 Hz), of 7.70 (1H, c), to 7.84 (1H, DD, J=8,4, 1.8 Hz), 8,46 (1H, c), 8,88 (1H, d, J=3,9 Hz), 3H not detected.

Example 63

N-methyl-1-{5-[2-(methylthio)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methanamine fumarate

To a solution (3 ml) of 5-[2-(methylthio)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (170 mg) in tetrahydrofuran was added a 40%solution of methylamine methanol (110 mg) and methane is La (1 ml) at room temperature and the mixture was stirred for 1 hour. Was added sodium borohydride (59,8 mg) under cooling on ice. After stirring at room temperature for 2 hours was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compounds as colorless oils. The obtained free salt was dissolved in ethyl acetate and was added to solution (1 ml), fumaric acid (33,2 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 89,3 mg, 38%).

1H-NMR (DMSO-d6) δ: 2,11 (3H, c), 2,43 (3H, c), 3,86 (2H, c), 6,38 (1H, d, J=1,8 Hz), 6,46 (2H, c), 7,07-7,20 (3H, m), 7,41-7,46 (1H, m), 7,53-7,58 (1H, m), 7,68 (1H, d, J=1,8 Hz), 7,79-7,83 (1H, m), 8,43 (1H, d, J=2,4 Hz), 8,82-8,84 (1H, m), 3H not detected.

Example 64

N-methyl-1-{5-[2-(methylsulphonyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methanamine 0.5 fumarate

By the way, is similar to that described in example 63 and using 5-[2-(methylsulphonyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (72,0 mg)were specified in the title compound as colorless is a crystalline substance (yield of 56.4 mg, 66%).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, c)of 3.00 (3H, c), 3,71 (2H, c), 6,41 (1H, c), 6,48 (1H, d, J=1.5 Hz), 7,14-7,17 (1H, m), to 7.61-the 7.65 (2H, m), 7,70-7,80 (2H, m), 7,93-of 7.97 (1H, m), 8,02-with 8.05 (1H, m), 8,66 (1H, d, J=2.1 Hz), 8,87-8,89 (1H, m), 2H not detected.

Example 65

2-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}benzonitrile fumarate

By the way, is similar to that described in example 63 and using 2-[4-formyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl]benzonitrile (129 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 69 mg, 38%).

1H-NMR (DMSO-d6) δ: 2,39 (3H, c), 3,82 (2H, c), 6,47 (2H, c), to 6.58 (1H, d, J=1,8 Hz), 7,34 and 7.36 (1H, m), to 7.59-7,76 (4H, m), 7,84-7,89 (2H, m), 8,53 (1H, d, J=2.4 Hz), 8,87-8,89 (1H, m), 3H not detected.

Example 66

1-[5-(2,6-dimetilfenil)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of 5-(2,6-dimetilfenil)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (0,42 g) in tetrahydrofuran (15 ml) was added dropwise a solution of 40%aqueous solution of methylamine methanol (0,48 g) in tetrahydrofuran (1 ml) under cooling on ice and the mixture was stirred at room temperature for 2 hours. Was added methanol (10 ml) and the mixture was additionally stirred at room temperature for 2 hours. Gradually when cooled on ice was added sodium borohydride (0.07 g) and the mixture was stirred at room temperature for 1 hour. The reaction mixture to which has centriole under reduced pressure, to the residue was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→ethyl acetate : methanol=5:1) to obtain the free of salt specified in the connection header in the form of butter, light brown. To a solution of the obtained free salt in ethyl acetate (5 ml) was added dropwise a solution of fumaric acid (0.12 g) in methanol (2 ml) under cooling on ice and the mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and recrystallized from a mixture of ethanol-water to obtain specified in the title compound as a crystalline substance of white color (yield 0.18 g, 50%).

1H-NMR (DMSO-d6) δ: of 1.62 (6H, c), a 2.45 (3H, c), 3,88 (2H, c), and 6.25 (1H, d, J=1.5 Hz), 6,45 (2H, c), 7,02 (2H, d, J=7.5 Hz), 7,24 (1H, d, J=7.5 Hz), 7,58 to 7.62 (1H, m), 7,71 (1H, c), 7,81-a 7.85 (1H, m), 8,44 (1H, d, J=2.7 Hz), 8,89 (1H, DD, J=4,8, 1.5 Hz), 3H not detected.

Example 67

N-methyl-1-{5-[2-(methylsulfinyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methanamine fumarate

To a suspension (5 ml) of sodium hydride (60% in oil, to 39.5 mg) in tetrahydrofuran was added a solution (3 ml) of 5-[2-(methylsulfinyl)phenyl]-1H-pyrrol-3-carbamide is Yes (160 mg) in N,N-dimethylformamide, 15-crown-5 (181 mg) and pyridine-3-ylsulphonyl chloride (134 mg) under cooling on ice. After stirring at room temperature for 1 hour was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is suspended in tetrahydrofuran (5 ml)at room temperature was added a 40%solution of methylamine methanol (160 mg) and the mixture was stirred for 1 hour. Was added sodium borohydride (86,5 mg) under cooling on ice. After stirring at room temperature for 2 hours, was added water and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→ethyl acetate) to obtain the free of salt specified in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate and was added to solution (1 ml), fumaric acid (28,1 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (you are the od of 83.9 mg, 24%).

1H-NMR (DMSO-d6) δ: 2,41 (3H, c), 2,49 is 2.51 (3H, m), 3,81 (2H, c), 6,46 (2H, c), of 6.50 (1H, d, J=1.5 Hz), 7,00 (1H, usher.), 7,50-8,00 (6H, m), to 8.57 (1H, usher.), 8,87-8,89 (1H, m), 3H not detected.

Example 68

2-(2-forfinal)-4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-carbonitrile fumarate

2-(2-Forfinal)-4-formyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-carbonitrile (295 mg) was dissolved in a solution of methylamine hydrochloride (1.12 g) in methanol (20 ml) and the mixture was stirred for 30 minutes. Added triacetoxyborohydride sodium (1.06 g) and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure at 30°C, to the residue was added concentrated aqueous solution of sodium bicarbonate (40 ml) and the mixture was extracted with ethyl acetate (80 ml). The extract was washed with saturated brine (40 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluent: ethyl acetate : methanol=85:15→75:25) and then by chromatography on a column with a basic silica gel (eluent: ethyl acetate) was added a solution of fumaric acid (96 mg) in ethanol (5 ml). Crystallization of the mixture gave specified in the title compound in the form of a colorless crystalline substance (yield 120 mg, 30%).

1H-NMR (DMSO-d6) δ: 2,40 (3H, c), 3,76 (2H, c), to 6.57 (2H, c), 7,28-7,37 (3H, m), 7,63-7,71 (2H, m), 7,87 (1H, c), 7,95-to 7.99 (1H, is), 8,64 (1H, DD, J=2.5 and 0.6 Hz), to 8.94 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 69

5-(2-forfinal)-3-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-carbonitrile fumarate

5-(2-Forfinal)-3-formyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-carbonitrile (650 mg) was dissolved in a mixture of 40%aqueous solution of methylamine methanol (808 mg) and methanol (30 ml) at room temperature and the mixture was stirred for 10 minutes. Was added sodium borohydride (118 mg) and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure at 30°C, to the residue was added concentrated aqueous solution of sodium bicarbonate (40 ml) and the mixture was extracted with ethyl acetate (80 ml). The extract was washed with saturated brine (40 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent : ethyl acetate) was added a solution of fumaric acid (242 mg) in ethanol (24 ml). The resulting crystalline substance was collected by filtration and recrystallized from ethanol-water (85:15) to obtain the specified title compound as a colorless crystalline substance (yield 480 mg, 52%).

1H-NMR (DMSO-d6) δ: of 2.27 (3H, s), 3,74 (2H, s), to 6.57 (2H, s)of 6.71 (1H, s), 7,29-7,38 (3H, m), 7,58-to 7.64 (1H, m), 7,71 to 7.75 (1H, m), of 7.96-8,00 (1H, m), 8,66 (1H, d, J=2.3 Hz), 8,97 (1H, DD, J=4,9, 1.5 Hz), 3H not about naruhina.

Example 70

4-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}benzonitrile fumarate

To a solution (2 ml) of tert-butyl {[5-(4-cyanophenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (382 mg) in ethyl acetate was added 4 mol/l solution of hydrogen chloride-ethyl acetate (3 ml) at room temperature. The mixture was stirred for 3 hours and was podslushivaet saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate and added to a solution (2 ml), fumaric acid (77,1 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixed solvent consisting of ethanol and water, to obtain specified in the title compounds as a colorless crystalline substance (yield 218 mg, 55%).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, c), with 3.79 (2H, c), 6,47 (2H, c), 6,55 (1H, d, J=1,8 Hz), 7,40-7,44 (2H, m), 7,55-of 7.60 (1H, m), 7,70-7,71 (1H, m), 7,81-7,87 (3H, m), 8,55-8,56 (1H, m), 8,84-8,86 (1H, m), 3H not detected.

Primer

4-fluoro-3-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}benzonitrile 0.5 fumarate

By the way, is similar to that described in example 70, using tert-butyl {[5-(5-cyano-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg)were specified in the title compound in the form of a colorless crystalline substance (yield of 37.1 mg, 40%).

1H-NMR (DMSO-d6) δ: 2,34 (3H, c), 3,71 (2H, c), 6,44 (1H, c), 6,55 (1H, users), 7,52 (1H, t, J=9.0 Hz), 7,60-to 7.68 (2H, m), 7,73 to 7.75 (1H, m), to $ 7.91-to 7.93 (1H, m), 8,03-8,08 (1H, m)8,64 (1H, d, J=2.4 Hz), 8,88-of 8.90 (1H, m), 2H not detected.

Example 72

1-[5-(2-fluoro-5-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

tert-Butyl {[5-(2-fluoro-5-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (475 mg) was dissolved in ethanol (10 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, was added to the solution (13 ml), fumaric acid (116 mg) in methanol and the resulting crystalline substance sobi is Ali by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 385 mg, 78%).

1H-NMR (DMSO-d6) δ: 2,41 (3H, c), 3,71 (3H, c), 3,82 (2H, c), 6,47 (1H, d, J=1.9 Hz), 6.48 in (2H, c), 6,57-6,60 (1H, m), 7,02-7,07 (1H, m), 7,12-to 7.18 (1H, m), 7,60-to 7.64 (1H, m), of 7.70 (1H, d, J=1.5 Hz), 7,89-to 7.93 (1H, m), at 8.60 (1H, d, J=2.3 Hz), 8,88 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 73

1-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}phenyl)Etalon fumarate

By the way, is similar to that described in example 70, using tert-butyl {[5-(3-acetyl-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (118 mg)were specified in the title compound in the form of a colorless crystalline substance (yield of 44.7 mg, 37%).

1H-NMR (DMSO-d6) δ: 2,40 (3H, c), 2,49 of $ 2.53 (3H, m), 3,80 (2H, m), 6,47 (2H, c), of 6.52 (1H, d, J=1,8 Hz), 7,32-7,40 (2H, m), to 7.59-to 7.64 (1H, m), 7,73 (1H, d, J=1,8 Hz), 7,86-to 7.93 (2H, m), at 8.60 (1H, d, J=2.7 Hz), 8,87-8,89 (1H, m), 3H not detected.

Example 74

1-[5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

To a solution of tert-butyl {[5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (2,48 g) in ethyl acetate (10 ml) and methanol (10 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (20 ml) at room temperature. After stirring for 5 hours the mixture was concentrated under reduced pressure. The residue was podslushivaet saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The extract was washed with saturated is olivem solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt specified in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate (10 ml) was added to a solution (10 ml), fumaric acid (350 mg) in methanol. The solvent was evaporated under reduced pressure and the residue was recrystallized from a mixed solvent consisting of ethanol and water, to obtain specified in the title compounds as a colorless crystalline substance (yield 793 mg, 29%).

1H-NMR (DMSO-d6) δ: 2,39 (3H, c), of 3.78 (2H, c), 6,48 (2H, c), 6,56 (1H, d, J=1,8 Hz), 7,40-7,44 (1H, m), to 7.61-the 7.65 (1H, m), 7,72-7,79 (2H, m), 7,89-to 7.93 (1H, m), 8,32-to 8.34 (1H, m), to 8.62 (1H, d, J=1,8 Hz), 8,88-of 8.90 (1H, m,), 3H not detected.

The melting point 183-184°C.

Example 75

1-[5-(3-herperidin-4-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

tert-Butyl {[5-(3-herperidin-4-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (60 mg) was dissolved in methanol (5 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (1.5 ml) and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated under reduced pressure and added a saturated aqueous solution of sodium bicarbonate. The mixture uh what was strayaway with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8 ml), was added a solution of fumaric acid (58 mg) in methanol (2 ml) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 45 mg, 72%).

1H-NMR (DMSO-d6) δ: is 2.37 (3H, c), of 3.78 (2H, c), of 6.49 (2H, c), only 6.64 (1H, d, J=1.5 Hz), 7,30-7,33 (1H, m), 7,62-7,66 (1H, m), to 7.77 (1H, d, J=1.5 Hz), 7,94-7,98 (1H, m), 8,49-8,51 (1H, m)8,64 (1H, d, J=1.5 Hz), 8,69 (1H, d, J=2.3 Hz), of 8.90 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 76

1-[5-(2-chloropyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

tert-Butyl {[5-(2-chloropyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (280 mg) was dissolved in ethanol (10 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 ml), was added a solution of fumaric acid (116 mg) in methanol (3 ml) and the resulting Cree is a metallic substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 197 mg, 68%).

1H-NMR (DMSO-d6) δ: 2,40 (3H, c), 3,81 (2H, c), of 6.49 (2H, c), of 6.52 (1H, d, J=1.9 Hz), 7,47-7,52 (1H, m), to 7.61-7,73 (3H, m), of 7.90-7,94 (1H, m), and 8.50 (1H, DD, J=4,9, 1.9 Hz), 8,63-8,64 (1H, m), of 8.90 (1H, DD, J=4,5, 1.5 Hz), 3H not detected.

Example 77

1-[5-(6-chloropyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine 1.5 fumarate

tert-Butyl {[5-(6-chloropyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in methanol (8 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate : methanol=99:1→19:1) to obtain the free of salt specified in the connection header. The obtained free salt was dissolved in ethyl acetate (8 ml), was added a solution of fumaric acid (116 mg) in methanol (2 ml) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 60 mg, 52%).

1H-NMR (DMSO-d6) δ: 2,41 (3H, c), 3,83 (2H, c), 6,52 (3H, c), to 6.58 (1H, d, J=1.5 Hz), EUR 7.57-7,63 (2H, m), 7,75-,78 (2H, m), the 7.85-7,89 (1H, m), to 8.20 (1H, d, J=2.3 Hz), 8,61 (1H, d, J=2.6 Hz), 8,88 (1H, DD, J=4,9, 1.5 Hz), 4H not found.

Example 78

1-[5-(6'-chloro-2,3'-bipyridine-5-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine 0.5 fumarate

tert-Butyl {[5-(6'-chloro-2,3'-bipyridine-5-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in ethanol (8 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at 70°C for 30 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate : methanol=99:1→19:1) to obtain the free of salt specified in the connection header. The obtained free salt was dissolved in ethyl acetate (8 ml), was added a solution of fumaric acid (116 mg) in methanol (2 ml) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 61 mg, 66%).

1H-NMR (DMSO-d6) δ: 2,33 (3H, c), of 3.69 (2H, c), 6,46 (1H, c), 6,58-6,59 (1H, m), EUR 7.57 to 7.62 (1H, m), 7,66-of 7.70 (2H, m), 7,83-7,88 (2H, m), 8,15 (1H, d, J=8,3 Hz), charged 8.52 (1H, d, J=1.9 Hz), to 8.57 (1H, d, J=2.3 Hz), 8,60-8,61 (1H, m), 8,86 (1H, d, J=4,Hz), 9,18 (1H, d, J=2.3 Hz), 2H not detected.

Example 79

1-{5-(2-herperidin-3-yl)-1-[(6-methoxypyridine-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine hydrochloride

By the way, is similar to that described in example 24 and using tert-butyl ({5-(2-herperidin-3-yl)-1-[(6-methoxypyridine-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (289 mg)were specified in the title compound in the form of a colorless crystalline substance (yield to 74.2 mg, 29%).

1H-NMR (DMSO-d6) δ: 2,52 (3H, c), of 3.94 (3H, c)to 3.99 (2H, c), of 6.65 (1H, d, J=1,8 Hz), 6,99-7,02 (1H, m), 7,42-7,47 (1H, m), 7,73-7,80 (2H, m), to 7.84 (1H, d, J=1,8 Hz), 8,27-of 8.28 (1H, m), 8.34 per-at 8.36 (1H, m), 9,10 (2H, users).

Example 80

(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}phenyl)methanol fumarate

By the way, is similar to that described in example 70, using tert-butyl ({5-[2-fluoro-3-(hydroxymethyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (238 mg)were specified in the title compound in the form of a colorless crystalline substance (yield of 55.3 mg, 22%).

1H-NMR (DMSO-d6) δ: 2,40 (3H, c), of 3.80 (2H, c), of 4.49 (2H, c), to 6.43 (1H, d, J=1,8 Hz), 6,47 (2H, c), 6,97-7,02 (1H, m), 7,17-7,22 (1H, m), 7,54 to 7.62 (2H, m), 7,68 (1H, d, J=1.2 Hz), 7,84-7,88 (1H, m), 8,56 (1H, d, J=2.1 and Hz), 8,86-8,88 (1H, m), 4H not found.

Example 81

1-(2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}phenyl)ethanol fumarate

By the way, is similar to that described in example 70, using t the et-butyl ({5-[2-fluoro-3-(1-hydroxyethyl)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (318 mg), got mentioned in the title compound as a colorless crystalline substance (yield to 69.7 mg, 21%).

1H-NMR (DMSO-d6) δ: 1,31 (3H, d, J=6.3 Hz), is 2.40 (3H, c), 3,81 (2H, c), the 4.90 (1H, square, J=6.3 Hz), to 6.43 (1H, d, J=1,8 Hz), 6,47 (2H, c), 6,94-7,00 (1H, m), 7,16-7,22 (1H, m), 7,58-to 7.68 (3H, m), 7,84-7,87 (1H, m), 8,55 (1H, d, J=2.7 Hz), 8,86-8,88 (1H, m), 4H not found.

Example 82

1-[5-(2-fluoro-3-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

In methanol (20 ml) was dissolved tert-butyl {[5-(2-fluoro-3-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (475 mg), was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at 70°C for 20 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (13 ml)was added fumaric acid (116 mg) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 310 mg, 63%).

1H-NMR (DMSO-d6) δ: 2,41 (3H, c), 3,82 (2H, c), 3,86 (3H, c), of 6.45 (1H, d, J=1.7 Hz), 6.48 in (2H, c), 6,58-6,63 (1H, m), 7,10-7,16 (1H, m), 7.24 to 7,30 (1H, m), to 7.59-7,63 (1H, m), of 7.70 (1H, q, j =1.5 Hz), 7,86-of 7.90 (1H, m), 8,58 (1H, DD, J=2,3, 0.7 Hz), 8,87-8,89 (1H, m), 3H not detected.

Example 83

1-[5-(2-fluoro-6-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

tert-Butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in methanol (20 ml), 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) was added and the mixture was stirred at 70°C for 20 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (6 ml)was added fumaric acid (49 mg) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 53 mg, 51%).

1H-NMR (DMSO-d6) δ: of 2.45 (3H, c), 3,44 (3H, c), 3,83 (2H, c), 6,36 (1H, d, J=1.5 Hz), 6.48 in (2H, c), 6,79-6,86 (2H, m), 7,44-7,52 (1H, m), 7,60-the 7.65 (1H, m), of 7.70 (1H, d, J=1.5 Hz), 7,88-a 7.92 (1H, m), 8,56 (1H, d, J=1,9 Hz), 8,88 (1H, DD, J=4,7) and 1.7 Hz), 3H not detected.

Example 84

1-{5-[4-(deformedarse)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}-N-methylmethanamine fumarate

By the way, is similar to that described in example 0, and using tert-butyl ({5-[4-(deformedarse)phenyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl}methyl)methylcarbamate (550 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 313 mg, 62% in stage 2).

1H-NMR (DMSO-d6) δ: of 2.38 (3H, c), of 3.78 (2H, c), 6,40 (1H, c), 6,47 (2H, c), 7,15-7,24 (4H, m), 7,32 (1H, t, J=73,5 Hz), 7,54-7,58 (1H, m), a 7.62 (1H, c), to 7.77-7,80 (1H, m), and 8.50 (1H, d, J=2.4 Hz), 8,84 (1H, d, J=4.5 Hz), 3H not detected.

Example 85

N-methyl-1-[5-(4-methylpyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine fumarate

tert-Butyl methyl{[5-(4-methylpyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (230 mg) was dissolved in methanol (20 ml)was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) and the mixture was stirred at 70°C for 20 minutes. The reaction mixture was concentrated under reduced pressure, was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate-methanol (99:1→95:5) to give a free salt specified in the connection header. It was dissolved in ethyl acetate (8 ml), was added a solution of fumaric acid (90 mg) in methanol (2 m is) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 115 mg, 48%).

1H-NMR (DMSO-d6) δ: 1,89 (3H, c), 2,43 (3H, c), a-3.84 (2H, c), of 6.45 (1H, d, J=1.9 Hz), 6.48 in (2H, c), 7,29 (1H, d, J=4.9 Hz), 7,60-the 7.65 (1H, m), 7,73 (1H, d, J=1.9 Hz), 7,81-a 7.85 (1H, m), 7,98 (1H, c), of 8.47 (1H, d, J=a 4.9 Hz), 8,51 (1H, d, J=1.9 Hz), of 8.90 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 86

N-methyl-1-[5-(2-methylpyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine fumarate

By the way, is similar to that described in example 70, using tert-butyl methyl{[5-(2-methylpyridin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}carbamate (278 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 93 mg, 32%).

1H-NMR (DMSO-d6) δ: 2,00 (3H, c), 2,43 (3H, c), 3,83 (2H, c), 6.42 per (1H, c), 6,47 (2H, c), 7,20-7,24 (1H, m), 7,28-7,31 (1H, m), to 7.59-7,63 (1H, m), of 7.70 (1H, c), 7,80-to 7.84 (1H, m), 8,49-8,51 (2H, m), 8,88-of 8.90 (1H, m), 3H not found.

Example 87

1-{5-(2-herperidin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine 0.5 fumarate

To a solution of tert-butyl ({5-(2-herperidin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (86 mg) in ethanol (2 ml) was added 4 mol/l solution of hydrogen chloride-ethyl acetate (2 ml) at room temperature. The mixture was stirred for 2 hours and concentrated under reduced pressure. The residue was podslushivaet saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was washed successively saturated the aqueous solution of sodium bicarbonate, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get a free salt specified in the title compound as a pale yellow oil. The obtained free salt was dissolved in ethyl acetate (2 ml) was added to a solution (2 ml), fumaric acid (11.3 mg) in ethanol and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to obtain specified in the title compounds as a colorless crystalline substance (yield 14 mg, 18%).

1H-NMR (DMSO-d6) δ: 2,33 (3H, c), of 2.56 (3H, c), 3,68 (2H, c), 6,44 (1H, c), 6,53 (1H, c), 7,41-to 7.50 (2H, m), of 7.64 (1H, c), 7,74-7,81 (2H, m), a 8.34 (1H, c), 8,48 (1H, c), 2H not detected.

Example 88

1-[4-chloro-5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate

4-Chloro-5-(2-herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrole-3-carbaldehyde (320 mg) was dissolved in a solution of methylamine hydrochloride (591 mg) in methanol (32 ml) and the mixture was stirred for 30 minutes. Added triacetoxyborohydride sodium (557 mg) and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure at 30°C, to the residue was added concentrated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous with what LifeCam magnesium and concentrated under reduced pressure. The residue was purified by chromatography on a column with a basic silica gel (eluent: ethyl acetate : methanol=99:1→95:5) to give a free salt specified in the connection header. It was dissolved in ethyl acetate (8 ml), was added a solution of fumaric acid (102 mg) in methanol (2 ml) and the resulting crystalline substance was collected by filtration to obtain specified in the title compounds as a colorless crystalline substance (yield 52 mg, 12%).

1H-NMR (DMSO-d6) δ: 2,39 (3H, c), 3,70 (2H, c), of 6.65 (2H, c), of 7.48-7,53 (1H, m), 7,63-to 7.68 (1H, m), 7,81 (1H, c), 7,84-of 7.96 (2H, m), 8,40-8,42 (1H, m), 8,65 (1H, d, J=1.9 Hz), 8,93 (1H, DD, J=4,9, 1.5 Hz), 3H not detected.

Example 89

N-methyl-1-[1-(pyridine-3-ylsulphonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methanamine fumarate

By the way, is similar to that described in example 70, using tert-butyl methyl{[1-(pyridine-3-ylsulphonyl)-5-(2-thienyl)-1H-pyrrol-3-yl]methyl}carbamate (315 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 165 mg, 51%).

1H-NMR (DMSO-d6) δ: 2,43 (3H, c), 3,83 (2H, c), 6,47 (2H, c), of 6.52 (1H, d, J=1,8 Hz), 7,07 for 7.12 (2H, m), 7,55 to 7.62 (2H, m), of 7.70 (1H, d, J=1,8 Hz), 7,84-7,88 (1H, m), 8,53-8,54 (1H, m), 8,83 cent to 8.85 (1H, m), 3H not detected.

Example 90

N-methyl-1-[5-(3-methylpyridin-2-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine fumarate

By the way, is similar to that described in example 70, using tert-butyl methyl{[5-(3-methylpyridin-2-yl)-1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (229 mg), got mentioned in the title compound as a colorless crystalline substance (yield 124 mg, 53%).

1H-NMR (DMSO-d6) δ: 2,18 (3H, c), is 2.44 (3H, c), 3,86 (2H, c), 6,46 (2H, c), of 6.52 (1H, d, J=1,8 Hz), to 7.32 and 7.36 (1H, m), 7,66-7,74 (3H, m), 8.17-a 8,21 (1H, m), 8,28-8,30 (1H, m), 8,87-of 8.90 (2H, m), 3H not detected.

Example 91

2-fluoro-3-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}benzonitrile fumarate

By the way, is similar to that described in example 70, using tert-butyl {[5-(3-cyano-2-forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (170 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 96 mg, 74%).

1H-NMR (DMSO-d6) δ: 2,39 (3H, c), of 3.80 (2H, c), 6,47 (2H, c), 6,59 (1H, d, J=1.5 Hz), 7,43-of 7.48 (1H, m), 7,52-EUR 7.57 (1H, m), 7,60-the 7.65 (1H, m), 7,76 (1H, d, J=1,8 Hz), 7,89-to 7.93 (1H, m), 8,02-8,07 (1H, m), 8,59 at 8.60 (1H, m,), 8,89-8,91 (1H, m), 3H not detected.

Example 92

4-{4-[(methylamino)methyl]-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-2-yl}thiophene-3-carbonitrile fumarate

By the way, is similar to that described in example 70, using tert-butyl {[5-(4-cyano-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (297 mg)were specified in the title compound in the form of a colorless crystalline substance (yield 155 mg, 50%).

1H-NMR (DMSO-d6) δ: 2,41 (3H, c), a-3.84 (2H, c), 6,47 (2H, c), 6,56 (1H, d, J=2.1 Hz), to 7.59-7,74 (1H, m), to 7.67 (1H, d, J=3.0 Hz), 7,73-7,74 (1H, m), 7,86-of 7.90 (1H, m), 8,57-8,59 (2H, m), 8,87-8,89 (1H, m), 3h is not found.

Structures of the compounds described in reference examples are shown in tables 1-14.

Table 1
Table 2
Table 3
Table 4
Table 5
Table 6
Table 7
Table 8
Table 9
Table 10
Table 11
Table 12
Table 13
Table 14

Structures of the compounds described in the examples presented in tables 15-23.

Table 15
Table 16
Table 17
Table 18
Table 19
Table 20
Table 21
Table 22
Table 23

The experimental the initial example 1

Study of the inhibitory activity of proton potassium - adenosinetriphosphatase (H+,K+-ATPase)

In accordance with the method of [Biochim. Biophys. Acta, 728, 31 (1983)] Wallmark et al., microsomal membrane fraction of the gastric mucosa were obtained from the stomach of pigs. First I removed the stomach, washed with tap water, immersed in 3 mol/l salt solution and the surface of the mucous membrane was wiped with a paper towel. The membrane of the gastric mucosa was separated, crushed and homogenized in 0.25 mol/l sucrose solution (pH of 6.8)containing 1 mmol/l EDTA and 10 mmol/l Tris-hydrochloric acid, using Polytron (Kinematica). The obtained homogenate was centrifuged at 20,000×g for 30 minutes, and the supernatant was centrifuged at 100,000×g for 90 minutes. Sediment suspended in 0.25 mol/l sucrose solution, was transferred to a 0.25 mol/l sucrose solution containing 7.5% ficoll, and centrifuged at 100,000×g for 5 hours. The fraction containing the surface between the two layers was removed and washed, centrifuger with 0.25 mol/l sucrose solution.

Received microsomal fraction was used as the standard product proton potassium - adenosinetriphosphatase.

To 40 μl of 50 mmol/l HEPES-Tris buffer (5 mmol/l magnesium chloride, 10 mmol/l potassium chloride, 10 mmol/l of valinomycin, pH 6.5)containing 2.5 µg/ml (on on the basis of protein concentration) of the enzyme standard product, added investigated the connection (5 ml) and was dissolved in 10%aqueous solution of dimethyl sulfoxide and the mixture is incubated at 37°C for 30 minutes. The enzymatic reaction was started by adding 5 μl of 2 mmol/l of a solution of adenosine triphosphate Tris salt (50 mmol/l HEPES-Tris buffer (5 mmol/l of magnesium chloride, pH 6.5)). The enzymatic reaction was performed at 37°C for 20 minutes to extinguish the reaction was added 15 μl of the solution of malachite green (0,12%solution of malachite green in sulfuric acid (2.5 mol/l), 7.5% ammonium molybdate and 11% of Tween 20 was mixed in a ratio of 100:25:2). After sedimentation at room temperature for 15 minutes, the resulting reaction product of inorganic phosphorus with malachite green colorimetrically was determined at a wavelength of equal to 610 nm. In addition, the same method was determined by the amount of inorganic phosphoric acid in the reaction solution, free from potassium chloride, which is for determining the activity of proton potassium - adenosinetriphosphatase, subtracted from the amount of inorganic phosphoric acid in the presence of potassium chloride. The degree of inhibition (%) was determined from the value of the control activity and the activity values at various concentrations of the studied compounds and determined the concentration of 50% inhibition (IC50) proton potassium - adenosinetriphosphatase. The results represent deny in table 24.

Experimental example 2

Cell line HepG2 liver cancer man (ATCC No. HB-8065) were perceivable, using a medium Needle, modified by way of Dulbecco (DMEM; Invitrogen)containing 10%fetal bovine serum (FBS; TRACE SCIENTIFIC LTD.), 1 mmol/l sodium pyruvate (Invitrogen), 2 mmol/l L-glutamine (Invitrogen), 50 IU/ml penicillin (Invitrogen) and 50 kg/ml streptomycin (Invitrogen) in 5% CO2, 37°C. the Analyzed reagent were obtained using DMSO to 10 mm and was further diluted with DMEM containing 0.5% FBS, 1 mmol/l sodium pyruvate, 2 mmol/l L-glutamine, 50 IU/ml penicillin and 50 μg/ml streptomycin to a final DMSO concentration 0.1%. HepG2 (2×104cells/well) were cultured on 96 hole white Cup (Costar) with a test reagent with 5% CO2, 37°C. After culturing for one day, using the ATPLite™ (PerkinElmer Life Sciences), determined the intracellular content of ATP. The results are presented in table 24 (n≥3, average ±SD) relative value (%) control (without addition of drug) at 30 μm.

Table 24
Example No.Inhibitory activity of N+/K+-ATPase (IC50nm)The ATP content (%, 30 μm)
2 1345,2
56573,9
243476,5
82287,9
294171,5
348,853,6
414386,7
444878,5
475881,8
74210for 95.2

From the results of table 24 it is obvious that the compound (I) of the present invention has excellent inhibitory activity of H+/K+-ATPase, and also shows low cytotoxicity.

Industrial applicability

As the compound (I) of the present invention shows excellent inhibitory activity against proton pump (whereas normally applied to the proton pump inhibitor, is as omeprazole, lanzoprazol and the like, to form a covalent bond with a cysteine residue in the H+/K+-ATPase and irreversibly inhibit the enzymatic activity, and as the compound (I) reversibly inhibits the activity of the proton pump (H+/K+-ATPase) and the inhibition of K+antagonist, respectively, suppresses the secretion of acid, it is sometimes called potassium-competitive acid blocker: P-CAB or antagonist of acid pump (ACPA or APA)), it can be used clinically used in the pharmaceutical composition for prevention and/or treatment of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, lymphoma of the mucosa of the stomach or the acidity of the stomach; or inhibitor bleeding of the upper section of the gastrointestinal tract due to peptic ulcers, ulcers in the acute stress, hemorrhagic gastritis or invasive stress. As the compound (I) shows low toxicity and has excellent water-solubility, in vivo kinetics and efficiency, it is applicable in the form of pharmaceutical compositions. In addition, since the compound (I) is stable even in acidic environments, it is possible PE the oral introduction of the compound in the form of conventional tablets and the like and getting drugs without intersolubility shell. Resulting product in the form of tablets and the like can be obtained with smaller dimensions, which is preferable for easier swallowing patients who have difficulty swallowing, particularly for the elderly and children. In addition, because of the drugs covered intersolubility shell no effect slow-release, the inhibitory effect in regard to the secretion of gastric acid appears quickly, and withdrawal symptoms, such as pain and things happen quickly.

This application is based on patent applications No. 2005-250356 and 2006-100626 registered in Japan, the contents of which are incorporated herein fully by reference.

1. The compound represented by formula (I):

where R1represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with a heterocycle, and monocyclic nitrogen-containing heterocyclic group optionally condensed with a heterocycle, optionally having from 1 to 5 substituents selected from the group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4)1-6alkoxy, optionally having 1 to 3 halogen atoms, (5) amino, (6) mono-C1-6alkylamino, (7) C1-6alkoxy-carbonyl and (8)1-6the alkyl, the optional ima is the future of 1 to 3 atoms of halogen,
R2represents (i)6-14aryl group, optionally substituted from 1 to 5 substituents selected from the group consisting of (1) halogen atom, (2) cyano, (3) C1-6alkoxy, optionally having 1 to 3 halogen atoms, (4)1-6alkylthio, optionally having 1 to 3 halogen atoms, (5) C1-6alkyl-carbonyl, (6) C1-6alkylsulfonyl, (7) C1-6alkylsulfonyl, (8)3-7cycloalkyl, (9) C1-6alkyl group optionally having 1 to 3 halogen atoms, and (10) C1-6alkyl groups, substituted from 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substituents selected from the group consisting of (1) cyano, and (2) C1-6alkyl group optionally having 1 to 3 halogen atoms, (iii) pyridyloxy group, optionally substituted from 1 to 4 substituents selected from the group consisting of (1) halogen atom, (2) 5-10-membered aromatic heterocyclic group containing, besides carbon atom, 1 or 2 kinds of 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, and (3)1-6alkyl group, optionally having from 1-3 atoms, halogen, or (iv) piperidinol group, optionally substituted from 1 to 3 atoms of halogen,
R3and R4represent each a hydrogen atom, or one of R3and R4before the hat is a hydrogen atom, and the other represents a lower alkyl group, halogen atom or cyano, and
R5represents an alkyl group, or its salt.

2. The compound represented by formula (I):

where R1represents a monocyclic nitrogen-containing heterocyclic group optionally condensed with a heterocycle, and monocyclic nitrogen-containing heterocyclic group optionally condensed with a heterocycle, optionally having from 1 to 5 substituents selected from the group consisting of (1) halogen atom, (2) cyano, (3) hydroxy, (4)1-6alkoxy, optionally having 1 to 3 halogen atoms, (5) amino, (6) mono-C1-6alkylamino, (7) C1-6alkoxy-carbonyl and (8)1-6the alkyl, optionally having 1 to 3 halogen atoms,
R2represents (1)6-14aryl group, optionally substituted from 1 to 5 substituents selected from the group consisting of (1) halogen atom, (2) cyano, (3) C1-6alkoxy, optionally having 1 to 3 halogen atoms, (4)1-6alkylthio, optionally having 1 to 3 halogen atoms, (5) C1-6alkylsulphonyl, (6) With1-6alkylsulfonyl, (7) C1-6alkylsulfonyl, (8)3-7cycloalkyl, (9) C1-6alkyl group optionally having 1 to 3 halogen atoms is, and (10) C1-6alkyl groups, substituted from 1 to 3 hydroxy, (ii) a thienyl group optionally substituted by 1 to 4 substituents selected from the group consisting of (1) cyano, and (2) C1-6alkyl group optionally having 1 to 3 halogen atoms,
R3and R4represent each a hydrogen atom, or one of R3and R4represents a hydrogen atom and the other represents a lower alkyl group, halogen atom or cyano, and
R5represents an alkyl group, or its salt.

3. The compound according to claim 1 or 2, where R1represents a monocyclic nitrogen-containing heterocyclic group.

4. The compound according to claim 1 or 2, where the monocyclic nitrogen-containing heterocyclic group is pyridyloxy group.

5. The compound according to claim 1 or 2, where R2represents a phenyl group, optionally substituted by 1-5 substituents selected from (i) halogen atom and (ii) C1-6the alkyl, optionally substituted by 1-3 halogen atoms.

6. The compound according to claim 1, where R2represents pyridyloxy group, optionally substituted with 1-4 substituent(s)selected from C1-6of alkyl, halogen atom and cyano.

7. The compound according to claim 1 or 2, where R3and R4represent each a hydrogen atom.

8. The compound according to claim 1 or 2, R 5represents a methyl group.

9. 1-{5-(2-Forfinal)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}-N-methylmethanamine or its salt.

10. 1-[4-Fluoro-5-phenyl-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

11. N-Methyl-1-[5-(4-methyl-3-thienyl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine or its salt.

12. 1-[5-(2-Herperidin-3-yl)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

13. 1-[5-(2-Forfinal)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]-N-methylmethanamine or its salt.

14. N-Methyl-1-[5-(2-were)-1-(pyridine-3-ylsulphonyl)-1H-pyrrol-3-yl]methanamine or its salt.

15. Pharmaceutical composition having inhibitory effect on the secretion of acid containing an effective amount of a compound according to claim 1 or 2.

16. The pharmaceutical composition according to item 15, which is an inhibitor of gastric secretion.

17. The pharmaceutical composition according to item 15, which is a potassium-competitive acid blocker.

18. The pharmaceutical composition according to item 15, which is an agent for the treatment or prophylaxis of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, lymph what we mucosa of the stomach or the acidity of the stomach; or inhibitor bleeding of the upper section of the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress.

19. The method of treatment or prophylaxis of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, lymphoma of the mucosa of the stomach or the acidity of the stomach; or the method of inhibiting the hemorrhage of the upper section of the gastrointestinal tract due to peptic ulcers, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress, which comprises introducing an effective amount of a compound according to claim 1 or 2 to the mammal.

20. The use of compounds according to claim 1 or 2 to obtain a pharmaceutical composition for the treatment or prophylaxis of peptic ulcer syndrome Zollinger-Ellison, gastritis, erosive and ulcerative esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, lymphoma of the mucosa of the stomach or the acidity of the stomach; or inhibitor bleeding of the upper section of the gastrointestinal tract due to peptic who Zvi, ulcers caused by acute stress, hemorrhagic gastritis or invasive stress.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel 4-(1H-indol-3-yl)-but-3-en-2-one derivatives of general formula 3: , : which can be used in synthesis of novel preparations for pharmaceutical and agricultural purposes. The method involves mixing 2-alkyl-5-(2-amino-4-alkylphenyl)-furans 1 with aromatic and heteroaromatic aldehydes 2 in acetic acid in equimola ratio at temperature 35°C for 40 minutes in the presence of 0.01 ml hydrochloric acid.

EFFECT: improved method.

2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to its pharmaceutically acceptable additive salts, optionally in the form of stereochemical isomer and exhibiting anti-HIV antiviral activity, particularly having HIV inhibitor properties and applied as a drug. In formula , -a1=a2-a3=a4- represents a bivalent radical of formula -CH=CH-CH=CH-(a-1); -b1=b2-b3-b4 - represents a bivalent radical of formula -CH=CH-CH=CH- (b-1); n is equal to 0, 1, 2, 3, 4; m is equal to 0, 1, 2; each R1 independently represents hydrogen; each R2 represents hydrogen; R2a represents cyano; X1 represents -NR1-; R3 represents C1-6alkyl, substituted cyano; C2-6alkrnyl, substituted cyano; R4 represents halogen; C1-6alkyl; R5 represents 5 or 6-member completely unsaturated cyclic system where one, two or three members of the cycle represent heteroatoms, each independently specified from the group consisting of nitrogen, oxygen and sulphur and where the rest members of the cycle represent carbon atoms; and where 6-member cyclic system can be optionally annelated with a benzene cycle; and where any carbon atom in the cycle can be independently optionally substituted with a substitute specified from C1-6alkyl, amino, mono- and diC1-4alkylamino, aminocarbonyl, mono-and diC1-4alkylcarbonylamino, phenyl and Het; where Het represents pyridyl, thienyl, furanyl; Q represents hydrogen The invention also concerns a pharmaceutical composition.

EFFECT: preparation of the new anti-HIV antiviral compounds.

4 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel thiophene derivatives of formula (I): ,

where the ring system A is characterised by formula ,

R1 denotes hydrogen, C1-C5alkyl or C1-C5alkoxy, R2 denotes hydrogen, C1-C5alkyl, C1-C5alkoxy or trifluoromethyl, R3 denotes hydrogen, hydroxy(C1-C5)alkyl, 2,3-dihydroxypropyl, di(hydroxy(C1-C5)alkyl)(C1-C5)alkyl, -CH2-(CH2)n-COOH, -CH2-(CH2)n-CONR31R32, hydroxy, C1-C5alkoxy, hydroxy(C2-C5)alkoxy, di(hydroxy(C1-C5)alkyl)(C1-C5)alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxypropoxy, -OCH2-(CH2)m-NR31R32, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy, 3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy, 2-morpholin-4-ylethoxy, 3-morpholin-4-ylpropoxy, 3-[(pyrrolidin-3-carboxylic acid)-1-yl]propoxy, 3-[(pyrrolidin-2-carboxylic acid)-1-yl]propoxy or 2-amino-3-hydroxy-2-hydroxymethylpropoxy; R31 denotes hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethylethyl, 2-(C1-C5)alkoxyethyl, 3-(C1-C5)alkoxypropyl, 2-aminoethyl, 2-(C1-C5alkylamino)ethyl or 2-(di-(C1-C5alkyl)amino)ethyl; R32 denotes hydrogen, methyl, ethyl, m equals 1 or 2; n equals 1; and R4 denotes hydrogen, (C1-C5)alkyl or halogen, and configuration isomers thereof, such as optically pure enantiomers, mixtures of enantiomers, such as racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates, as well as salts of said compounds of formula (I), synthesis thereof and use as therapeutically active compounds.

EFFECT: compounds have the effect of immunosuppressive agents.

20 cl, 2 tbl, 46 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4(5)-(2-hetaryl) and 4(5)-(2-hetaryl)-2-(2'-hetaryl)-imidazoles of general formula R=2-furyl, 2-thienyl; R'H; and R=2-furyl, 2-thienyl; R'=2-furyl is obtained using 2-bromoacetylfuran (thiophene) of general formula 2-thienyl and aldehydes in the presence of copper acetate, synthesis of a 2-bromoacetylfuran (thiophene) precursor is carried out by reacting 2-acetylfuran (thiophene) with copper (II) bromide.

EFFECT: increased safety of the process.

2 tbl, 1 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: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a new pharmaceutically acceptable salt, 2-hydroxy-3-[5-(morpholine-4-ylmethyl) pyridine-2-yl]-1H-indole-5-carbonitrilcitrate, to a method for making thereof, pharmaceutical compositions containing said salt, and administration of said active salt within a therapy, and particularly in GSK3-related conditions and disorders.

EFFECT: preparation of the new pharmaceutically acceptable salt.

11 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to application in an effective amount and to new nicotine receptor agonists described by general formula (i) or (ii) for treating inflammatory diseases chosen from a group including asthma, chronic obstructive pulmonary disease (COPD), interstitial pulmonary tissue fibrosis (IPF), sarcoidosis, hypersensitivity pneumonitis (HP), chronic hypersensitivity pneumonitis and bronchiolitis obliterans organising pneumonia (BOOP). The compounds (i) and compounds (ii) relate to formulae (i) (ii) where in formula (i) R1 and R2 independently mean alkyl with 1-10 carbon atoms; Xa means CH or N; Ya means one or more substitutes chosen from hydrogen, halogen, cyano, hydroxyl, alkyl with 1-10 carbon atoms optionally substituted with one or more halogen atoms, and alkoxy with 1-10 carbon atoms; n means an integer 0 or 2; J means a counterion representing a compound for maintaining electric neutrality, e.g., halogen, sulphate, sulphonate; in formula (ii) R3 is chosen from or Xb means N or N+-R10; R4 means one or more substitutes chosen from hydrogen, halogen; each R10, R11 and R12 independently means alkyl with 1-10 carbon atoms; provided the presence of the counterion when Xb means N+-R10.

EFFECT: use of nicotine receptor agonists in the effective amount for treating inflammatory diseases.

26 cl, 40 dwg, 3 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein R means dihydrosubstituted C2-C6alkyl group, and Cy represents spiro[4.5]dec-6-yl, spiro[2.5]oct-4-yl, spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl or 1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl-group. Said compounds act as nociceptive receptor antagonists, and are applied e.g. as agents improving acceptability of narcotic analgesics, relieving narcotic analgesic dependence or narcomania; as an analgesic intensifier; antiobesity agents or appetite suppressants; agents for treating decreasing cognition and senile dementia /amnesia; agents for treating developing cognition disorder; therapeutic agents in schizophrenia; agents for treating neurodegenerative diseases; antidepressants or therapeutic agents in affective disorder; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents in polyuria; and therapeutic agents in hypotension and similar.

EFFECT: preparation of the compounds acting as nociceptive receptor antagonists.

11 cl, 5 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I: where Y1 and Y2 are independently selected from N and CR10, where R10 is selected from group, including hydrogen, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, R1 is selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino, C1-C6alkylsulfanyl, dimethylaminoethoxy and pyperasinyl, substituted up to 2 radicals C1-C6alkyl, R2 and R5 are independently selected from group, including hydrogen, cyano, halogen, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy and dimethylamino, R3 and R4 are independently selected from group, including hydrogen, halogen, cyano, C1-C6alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, or R1 and R5 with phenyl, to which they are bound, form C5-C10heteroaryl, R6 and R7 are independently selected from group, including hydrogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl, on condition that R6 and R7 both do not represent hydrogen, R8 is selected from group, including hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkoxy, R9 is selected from -S(O)2R11, -C(O)R11, -NR12aR12b and -R11, where R11 is selected from group, including aryl, cycloalkyl and heterocycloalkyl, R12a and R12b are independently selected from (C1-C6)alkyl and hydroxy(C1-C6)alkyl, and said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in composition of R9 optionally contain as substituents from 1 to 3 radicals, independently selected from group, including (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, C6-C10aryl(C0-C4)alkyl, C5-C10heteroaryl(C0-C4)alkyl, C3-C12cycloalkyl and C3-C8heterocycloalkyl, where said arylalkyl substituent in composition of R9 optionally contains as substituents from 1 to 3 radicals, independently selected from group, including halogen, cyano, (C1-C6)alkyl, halogen(C1-C6)alkyl, C1-C6alkoxy, halogen(C1-C6)alkoxy, dimethylamino and methyl-pyperasinyl, as well as to its pharmaceutically acceptable salts, hydrates, solvates and isomers. In addition, invention relates to method of inhibiting hedgehog pathway in cell and to method of inhibiting undesirable cell proliferation, when cell contacts with compound described above.

EFFECT: obtained and described are novel compounds, which can be applied in medicine.

13 cl, 153 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: described is an improved method for synthesis of 3(5)-pyridyl-substituted 5(3)-amino-1,2,4-triazoles of general formula (I)

, where R denotes 2-pyridyl, 3-pyridyl or 4-pyridyl, involving reaction of pyridine carboxylic acid of general formula (II)

, where R assumes said values, with an aminoguanidine hydrocarbonate in the presence of hydrochloric acid in molar ratio acid (II): aminoguanidine hydrocarbonate: hydrochloric acid = 1.0:1.0:1.3-1.5, while boiling the reaction mixture with gradual distillation of water at atmospheric pressure until temperature of the reaction mixture equals 165-180°C and then holding the reaction mixture at this temperature for 3-5 hours and then adding an alkali solution in water, boiling alkaline solution and extraction of the end product by filtering after neutralisation of the reaction mixture and cooling.

EFFECT: method enables to obtain said compounds from cheaper material, increases output of end products and shortens duration of the synthesis process.

1 cl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula 1a, where X denotes a halogen or C1-C4halogenalkyl; Z denotes N or CR9; each R5 independently denotes halogen or C1-C4halogenalkyl; R9 denotes H, halogen or C1-C4halogenalkyl; R10 denotes H or C1-C4alkyl; and n is an integer from 0 to 3, involving bringing 2-pyrazoline of formula 2a, where X, Z, R5, R9, R10 and n assume values given above, into contact with bromine in a medium of a suitable inert organic solvent at temperature 80-180°C.

EFFECT: obtaining pyrazoles of formula 1a with high output and purity.

7 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (III): , in which D is a benzene ring, 2-pyridone ring, pyridine ring, benzoxalone ring, benzoxadinone ring or benzimidazole ring; R1 denotes carboxy or hydroxy; R2 independently denotes a halogen atom; alkyl optionally substituted with a halogen atom, aryl or alkylamine; alkynyl, optionally substituted alkoxy; hydroxy; carboxy; alkoxy optionally substituted with phenyl, aromatic heterocyclic ring which denotes a 5-6-member aromatic monocyclic carbocyclic ring containing one or two heteroatoms, independently selected from oxygen and nitrogen atoms; alkylsulphonyl; aryloxy; amino optionally substituted with alkyl; acyl optionally substituted with alkyl or alkyloxy; alkyloxycarbonyl; alkanesulphonyl; arylsulphonyl or alkylcarbamoyl; carbamoyl optionally substituted with alkyl, phenyl, cycloalkyl, acetyl, alkanesulphonyl, heteroarylalkyl, cycloalkylalkyl, heteroaryl which denotes a 5-6-member aromatic monocyclic ring containing one or three heteroatoms independently selected from oxygen and nitrogen atoms, and which is optionally substituted with alkyl or cycloalkyl; acylcyano; nitro, aryl; heteroaryl which denotes a 5-6-member aromatic ring containing one or more heteroatoms independently selected from oxygen, sulphur and nitrogen atoms, and which is optionally substituted with alkyl; alkylsulphonyl; morpholinylsulphonyl; non-aromatic heterocyclic group which denotes a 5-6-member non-aromatic heterocyclic ring containing one or more nitrogen atoms and optionally an oxygen and/or sulphur atom; R3 denotes C1-C6alkyloxy, C1-C6alkylthio; R4 denotes a halogen atom or alkyloxy; R5 denotes alkyl; M denotes sulphonyl; L3 independently denotes alkylene optionally containing one oxygen or nitrogen atom, alkenylene, or -N(R7)-; R7 independently denotes a hydrogen atom, alkyl; Y denotes a single bond or CO; Z denotes CH or N; n equals 0 or 1; p equals 0, 1, or 2; q equals 0 or 1; provided that R1 does not denote carboxy when ring D is a benzene ring, -L3- denotes -(O-alkylene)- and the substitution position of L3 and Y is an ortho-position in ring D; to pharmaceutically acceptable salts thereof. The invention also relates to compounds of formula (IV), a pharmaceutical composition, a method of treating diseases associated with the DP receptor, use of compounds in any of the claims 1-17, as well as compounds of general formula (V).

EFFECT: obtaining novel biologically active compounds having DP receptor antagonist activity.

30 cl, 8 ex, 62 tbl

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