Peptide compounds

FIELD: chemistry of peptides, medicine, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents benzofuranyl substituted with halogen atom or styryl substituted with halogen atom; R2 represents substituted hydroxyl substituted with mercapto-group or substituted sulfonyl, or its pharmaceutically acceptable salts. Compound of the formula (I) and its pharmaceutically acceptable salts possess the strong inhibitory effect on production of nitrogen oxide (NO) and can be useful in prophylaxis and/or treatment of NO-mediated diseases in humans and animals.

EFFECT: valuable medicinal and biochemical properties of compounds.

 

The technical FIELD

This invention relates to new peptide compounds and their pharmaceutically acceptable salts, applicable as a medicine.

BACKGROUND of the INVENTION

Some well-known peptide compounds described, for example, in EP 0394989 A2, W96/16981 and JP-A-10-81671.

The INVENTION

This invention relates to new peptide compounds.

One of the objectives of this invention to provide new and useful peptide compounds, and their pharmaceutically acceptable salts, having a strong inhibitory effect on the production of nitric oxide (NO).

Another objective of this invention is to develop a method of obtaining a peptide compounds and their salts.

The next task of this invention to provide pharmaceutical compositions containing the specified peptide compound or its pharmaceutically acceptable salt.

Another objective of the invention is the use of these peptide compounds or their pharmaceutically acceptable salts as a drug for the prophylactic and therapeutic treatment of NO-mediated diseases, including respiratory diseases such as respiratory distress syndrome in adults (ARDS) and asthma; cardiovascular diseases, such as cardio-the vascular ischemia, myocarditis, heart failure, hypotension, and atherosclerosis; endocrine diseases such as diabetes (for example, insulin-dependent diabetes mellitus and so on), complications of diabetes (e.g. diabetic nephropathy, diabetic retinopathy, diabetic neuropathy etc) and gout; renal diseases such as glomerulonephritis and renal failure; gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (e.g. ulcerative colitis, chronic colitis, etc.); diseases of the pancreas, such as pancreatitis; liver disease such as hepatitis and cirrhosis of the liver; diseases bones or joints, such as synovitis, arthritis, osteoarthritis, osteoporosis; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis; skin diseases such as dermatitis and eczema; cancer, such as solid tumors and metastases; rejection of organ transplants; shock (e.g., septic shock, etc.); caused by sepsis syndrome, systemic inflammatory response; and sexual dysfunction, such as sexual dysfunction in men (e.g., erectile dysfunction and sexual disorders in women (e.g., disorders of orgasm-related damage of the clitoris), in humans and animals.

Described is administered the peptide compounds of the present invention are new and can be represented by the following General formula (I):

in which

R1is benzofuranyl, substituted with halogen, or styryl, substituted with halogen;

R2is substituted by hydroxyl, substituted mercapto or substituted sulfonyl; and

X represents

Suitable pharmaceutically acceptable salts of the described compounds (I) are conventional non-toxic salts and include, for example, a salt with a base or an acid additive salt such as a salt with an inorganic base, such as alkali metal salt (e.g. sodium salt, potassium salt etc), salt, alkaline earth metal (e.g. calcium salt, magnesium salt etc), ammonium salt, salt with organic base, for example salt of organic amine (for example, salt of triethylamine salt of pyridine, picoline salt, ethanolamine salt, triethanolamine salt, salt dicyclohexylamine, salt N,N'-dibenziletilendiaminom etc.); additive salt with inorganic acid (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); additive salts with organic carboxylic or sulfonic acid (e.g., formate, acetate, triptorelin, maleate, tartrate, citrate, fumarate, methanesulfonate, bansilalpet, toluensulfonate etc); and salts with basic or acidic amino acid (e.g. arginine, asparagine the second acid, glutamic acid and so on).

In above - and below part of this specification, suitable examples and illustrations of the various definitions included in the scope of the present invention, is explained in detail as follows.

Unless otherwise specified, the term "lower" means a group containing from 1 to 6, preferably from 1 to 4 carbon atoms.

Suitable "halogen" includes, for example, fluorine, bromine, chlorine and iodine.

"Styryl, substituted with halogen" means still having a halogen atom as a substituent in the benzene ring. Suitable examples of styrene, substituted with halogen" include 2-(2-chlorophenyl)ethynyl, 2-(3-chlorophenyl)ethynyl, 2-(4-chlorophenyl)-ethynyl, 2-(2-bromophenyl)ethynyl, 2-(3-bromophenyl)ethynyl, 2-(4-bromophenyl)ethynyl, 2-(2-forfinal)ethynyl, 2-(3-forfinal)ethynyl, 2-(4-forfinal)ethynyl etc.

"Substituted hydroxyl" means a group of the formula: -Y-R3in which Y represents-O-, a R3provides a suitable organic group.

"Substituted mercapto" means a group of the formula: -Y-R3in which Y represents-S-, a R3provides a suitable organic group.

"Substituted sulfonyl" means a group of the formula: -Y-R3in which Y represents-SO2-, a R3provides a suitable organic group.

Examples of the aforementioned "suitable organic groups include lower and the keel, halo(lower)alkyl, optionally substituted heterocyclic group and optionally substituted aryl. Each of the specified heterocyclic group and aryl optionally substituted by one or more, preferably one to three, substituents such as lower alkyl, lower alkoxy, halogen, halo(lower)alkyl, etc.

In the formula: -Y-R3Y preferably represents-O-.

"Heterocyclic group" includes saturated or unsaturated heterogenities or condensed heterocyclic group containing a heteroatom(s)selected from the group comprising a nitrogen atom, a sulfur atom and an oxygen atom.

Suitable examples of the "heterocyclic group" include:

unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing 1-4 nitrogen atom, for example pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridin, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl), tetrazolyl (for example, 1H-tetrazolyl 2N-tetrazolyl) etc.;

- saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing 1-4 nitrogen atom, such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinil etc.;

unsaturated condensed heterocyclic groups which, containing 1-4 nitrogen atom, for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl etc.;

unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing 1 or 2 oxygen atoms and 1-3 nitrogen atom, for example oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl) etc.;

- saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing 1 or 2 oxygen atoms and 1-3 nitrogen atom, such as morpholinyl, Sydney etc.;

unsaturated condensed heterocyclic group containing 1 or 2 oxygen atoms and 1-3 nitrogen atom, for example benzoxazolyl, benzoxadiazole etc.;

unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atom, for example thiazolyl, isothiazolin, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), dihydrothiazine etc.;

- saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atom, such as diazolidinyl etc.;

unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities the th group, containing 1 or 2 sulfur atom, such as thienyl, dehydrodidemnin etc.;

unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atom, for example benzothiazolyl, benzothiadiazoles, imidazothiazoles etc.;

unsaturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing an oxygen atom, such as furyl, etc.;

- saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing an oxygen atom, such as tetrahydrofuranyl, tetrahydropyranyl etc.;

- saturated 3 to 8-membered (more preferably 5 - or 6-membered) heterogenities group containing an oxygen atom and 1 or 2 sulfur atom, such as dihydroartemisinin etc.;

unsaturated condensed heterocyclic group containing 1 or 2 sulfur atom, for example benzothiazyl, benzodithiol etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1 or 2 sulfur atom, such as benzoxanthenes etc; etc.

Preferred examples of the heterocyclic group include unsaturated 5 - or 6-membered heterogenities group containing 1-4 nitrogen atom; and unsaturated 5 - or 6-membered heterogenities group containing 1 or 2 sulfur atom and 1 to 3 nitrogen atom.

More prepact the positive examples of the heterocyclic group include pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl, and particularly preferred examples of the heterocyclic group include pyridyl, pyrazinyl and thiazolyl.

Suitable "aryl" includes6-C12aryl, such as phenyl and naphthyl, of which more preferred is phenyl.

Suitable "lower alkyl" and the rest "lower alkyl" in the term "halo(lower)alkyl" include linear or branched alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl, which is preferred With1-C4alkyl.

Suitable "lower alkoxy" includes straight or branched alkoxy containing 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy, of which more is preferred To1-C4alkoxy.

Suitable "halo(lower)alkyl" includes lower alkyl, substituted by one or more, preferably one to three, halogen atoms, such as trifluoromethyl, trichloromethyl, tribromoethyl, 2,2,2-triptorelin and 3,3,3-cryptochromes, of which it is preferable to have trihalo(lower)alkyl.

Suitable examples of the optionally substituted heterocyclic gr is PPI include 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methoxy-2-pyridyl, 6-methyl-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl, 3-chloro-2-pyridyl, 3,5-dichloro-2-pyridyl, 3-(trifluoromethyl)-2-pyridyl, 5-(trifluoromethyl)-2-pyridyl, 2-pyrazinyl, 5-chloro-2-pyrazinyl, 6-chloro-2-pyrazinyl, 1,3-thiazole-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 5-methyl-1,3-thiazol-2-yl, 5-chloro-1,3-thiazol-2-yl, 3-pyridazinyl, 4-pyridazinyl, 6-chloro-3-pyridazinyl, 6-methoxy-3-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-chloro-4-pyrimidinyl, 6-(trifluoromethyl)-4-pyrimidinyl, 2-(trifluoromethyl)-4-pyrimidinyl etc.

Suitable examples of the optionally substituted aryl include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-forfinal, 3-forfinal, 4-forfinal, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, etc.

In the formula (I), the group of the formula:

,

preferably represents

more preferably

and particularly preferably

Suitable "aminosidine group" includes, for example, acyl and a conventional protective group such as mono(or di-or tri-)aryl(lower)alkyl such as mono(or di-or tri-)phenyl (lower)alkyl (e.g. benzyl, trityl etc). Suitable examples of the specified acyl include aliphatic acyl such as lower alkanoyl, to the which may be substituted by one to three halogen atoms (for example, formyl, acetyl, propanol, butanol, 2-methylpropanol, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, trichloroacetyl, TRIFLUOROACETYL and so on), low alkoxycarbonyl (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxybenzoyl etc), aryl(lower)alkoxycarbonyl [for example, phenyl(lower)-alkoxycarbonyl (for example, benzyloxycarbonyl etc) and so on] and so on

Suitable "carboxyamide group" includes, for example, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl and so on), optionally substituted phenyl(lower)alkyl such as mono(or di-or tri-)phenyl(lower)alkyl which may be substituted by nitro (for example, benzyl, 4-nitrobenzyl, benzhydryl, trityl etc), etc.

The described compound (I) of the present invention can be obtained in the following ways :

Method (1)

Method (2)

where each of R1, R2and X has the above values.

Starting compound can be obtained in the following ways :

Method (A)

How (In)

Method (C)

Method (D)

Method (E)

Method (F)

Method (G)

Way (N)

Method (I)

Method (J)

The way (To)

where each of R1, R2and X have the above values,

each of R4and R5is aminosidine group, and

each of R6and R7is carboxyamide group.

Below is a detailed description of how to obtain the claimed compound.

Method (1)

The compound (I) or its salt can be prepared by the interaction of the compound (II) or its reactive derivative at carboxypropyl, or its salt with the compound (III) or its reactive derivative at the amino group or its salt.

A suitable reactive derivative of compound (III) includes imino-type Schiff's base or its tautomeric isomer type of enamine obtained by the interaction of the compound (III) with the compound carbonyl, such as aldehyde, ketone or the like; a derivative silila obtained by the interaction of the compound (III) with the compound silila, such as N,O-bis(trimethylsilyl)acetamide", she N-trimethylsilylacetamide or the like; a derivative obtained by the interaction with the organisations (III) trichloride phosphorus or phosgene.

A suitable reactive derivative of compound (II) includes gelegenheid, the anhydride of the acid and the activated ester. A suitable example is the acid chloride acid; acid azide, mixed acid anhydride, such as substituted phosphoric acid (e.g., dialkylphosphorous acid, phenylphosphine acid, diphenylphosphoryl acid, dibenzylamine acid, halogenated phosphoric acid, etc), dialkylphosphorous acid, sulfurous acid, tisera acid, alkanesulfonyl (for example, methanesulfonate, econsultation etc), sulfuric acid, alkaluria acid, aliphatic carboxylic acid (e.g., pavlikova acid, pentane acid, isopentane acid, 2-ethylmalonate acid, trichloroethane acid, etc.); aromatic carboxylic acid (e.g. benzoic acid and so on); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; activated ester (for example, a complex cinematology ether complex methoxymethyl ether complex dimethylaminomethylene [(CH3)2N+=CH-] ether complex vinyl ether complex propargilovyh ether complex p-nitrophenyloctyl ether complex of 2,4-dinitrophenolate ether complex trichloranisole ether complex Penta is lohenry ether, complex methylphenylene ether complex phenylazophenyl ether, phenyl complex tiefer, complex p-nitrophenyloctyl tiefer, complex p-crazily tiefer, complex carboxymethylchitin, complex pyranyloxy ether complex pyridyloxy ether complex piperidinyl ether complex 8-finalities etc); or an ester of N-hydroxidealuminum (for example, N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole and etc). The desired reactive derivative can be optionally selected from them according to the type of compound (II).

Communication is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not render harmful influence on the interaction, or their mixtures.

If the compound (II) used for interaction in the form of the free acid or in the form of its salt, the interaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinobutyrophenone; N-cyclohexyl-N'-(4-diethylaminoethoxy)carbody the ID; N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonyl-bis(2-Mei); pentamethylene-N-cyclohexylamine; diphenylethan-N-cyclohexylamine; ethoxyacetylene; 1-alkoxy-1-chlorethylene; trialkylphosphine; isopropylpalmitate; phosphorous oxychloride (phosphorylchloride); phosphor trichloride; thionyl chloride; oxacillin; triphenylphosphine; salt of 2-ethyl-7-hydroxybenzotriazole; intramolecular salt hydroxide 2-ethyl-5-(m-sulfophenyl)isoxazole; 1-(p-chlorobenzenesulfonate)-6-chloro-1H-benzotriazole; so-called Vilsmeier reagent generated by the interaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like

The interaction can also be carried out in the presence of organic or inorganic bases such as bicarbonate of an alkali metal, three(lower)alkylamine, pyridine, N-(lower)alkalifying, N,N-di(lower)alkylbenzenes or similar

Temperature interaction does not matter, and the interaction is usually carried out both during cooling and during heating.

Method (2)

The compound (I) or its salt can be prepared by the interaction of the compound (IV) or its reactive derivative at carboxypropyl, or its salt with the compound (V) or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), therefore, the applied reagents and reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Method (A)

The compound (VII) or its salt can be prepared by the interaction of the compound (VI) or its reactive derivative at carboxypropyl, or its salt with the compound (V) or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Method (B)

The compound (VIII) or its salt can be obtained by the reaction of removal aminosidine group from compound (VII) or its salt.

Suitable method such reactions removal includes conventional method such as hydrolysis, recovery, etc.

(i) For hydrolysis:

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable bases include inorganic base and organic base, such as alkali metal (e.g. sodium, potassium etc), alkaline earth metal (e.g. magnesium, calcium and so on), the hydroxide or carbonate or bicarbonate, trialkylamine (for example, trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo the[4.3.0]non-5-ene or the like

Suitable acids include organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid etc) and inorganic acid (e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and so on).

Remove using a Lewis acid such as trigalogenmetany acid (e.g., trichloroacetic acid, triperoxonane acid, etc. or the like, is preferably carried out in the presence of the agent, exciting cations (e.g. anisole, phenol, etc). This reaction is usually carried out without the use of solvent.

The reaction can be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, telengard, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents, not acting adversely on the reaction, or a mixture thereof.

The reaction temperature does not matter, and the reaction is usually carried out both during cooling and during heating.

(ii) recovery:

The restoration carried out in the usual way, including chemical reduction and catalytic reduction.

Suitable barrel is Ivanushki reagents, which can be used for chemical recovery, are hydrides (e.g., hydrogen iodide, hydrogen sulfide, sociallyengaged, sodium borohydride, cyanoborohydride sodium, etc. or a combination of metal (e.g. tin, zinc, iron etc) or metallic compound (e.g. chromium chloride, chromium acetate, etc. and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluensulfonate, hydrochloric acid, Hydrobromic acid, etc.).

Suitable catalysts which can be used in catalytic reduction are conventional catalysts such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), Nickel catalysts (e.g., the recovered Nickel, Nickel oxide, Raney Nickel, etc.), cobalt catalysts (for example, the recovered cobalt, Raney cobalt, etc.), iron catalysts (e.g., restoring the fixed iron the Raney iron, iron Ullman (Ullman), etc. and so on

Recovery is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, telengard, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide or any other organic solvents that do not have a negative effect on the reaction, or a mixture thereof.

In addition, if the above acids that can be used in chemical reduction are in the liquid state, they can also be used as a solvent.

The reaction temperature of such recovery does not matter, and the reaction is usually carried out both during cooling and during heating.

Method (C)

The compound (X) or its salt can be prepared by the interaction of the compound (IX) or its reactive derivative at carboxypropyl, or its salt with the compound (VIII) or its reactive derivative at the amino group or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Method (D)

The compound (II) or its salt can be obtained by removal aminosidine group from compound (X) or its salt.

This interaction can be carried out in the same way as the interaction in the above method (C), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (B).

Method (E)

The compound (XII) or its salt can be prepared by the interaction of the compound (II) or its reactive derivative at carboxypropyl, or its salt with the compound (XI) or its reactive derivative at the amino group or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Method (F)

The compound (XIII) or its salt can be obtained by removal carboxyamide group from compound (XII) or its salt.

This interaction can be carried out in the same way as the interaction in the above method (C), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (B).

Method (G)

The compound (XV) or its salt can be prepared by the interaction of the compound (XIII) or its reactive derivative is about carboxypropyl, or its salt with the compound (XIV) or its reactive derivative at the amino group or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Method (H)

The compound (IV) or its salt can be obtained by removal carboxyamide group from compound (XV) or its salt.

This interaction can be carried out in the same way as the interaction in the above method (C), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (B).

Method (I)

The compound (XVI) or its salt can be prepared by the interaction of the compound (IX) or its reactive derivative at carboxypropyl, or its salt with the compound (XIV) or its reactive derivative at the amino group or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Method (J)

The compound (XVII) or the ol can be obtained by removal aminosidine group of the compound (XVI) or its salt.

This interaction can be carried out in the same way as the interaction in the above method (C), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (B).

Method (K)

The compound (XV) or its salt can be prepared by the interaction of the compound (II) or its reactive derivative at carboxypropyl, or its salt with the compound (XVII) or its reactive derivative at the amino group or its salt.

This interaction can be carried out in the same way as the interaction in the above method (1), so that the reagents and the reaction conditions (e.g. solvent, reaction temperature and so on) are the same as in method (1).

Suitable salts of the parent compounds and their reactive derivatives in the methods (1) and (2) and methods (a)to(K) can be attributed to the compounds illustrated for the compound (I).

The compound obtained in the above manner can be isolated and purified in the usual way, such as sputtering, recrystallization, column chromatography, pereosazhdeniya or similar

It should be noted that the compound (I) and other compounds can include one or more stereoisomers such as optical isomers (optical isomers) is the geometric isomers (geometric isomers), due to asymmetric atom (atoms) of carbon double bonds (double bonds), all such isomers and mixtures thereof are included in the scope of this invention.

The described compounds (I) and their pharmaceutically acceptable salts include the solvate [for example, the compounds of inclusion (e.g., hydrate etc)].

The described compounds (I) and their pharmaceutically acceptable salts have a strong inhibitory effect on the production of nitric oxide (NO).

Accordingly, it is expected that the described compounds (I) and their pharmaceutically acceptable salts have an inhibitory synthase nitric oxide (NOS) activity, or the activity of inhibiting the production of NOS.

Accordingly, the described compounds (I) and their pharmaceutically acceptable salts are useful for the prevention and/or treatment of NO-mediated diseases in humans and animals, including respiratory diseases such as respiratory distress syndrome in adults (ARDS) and asthma; cardiovascular diseases, such as cardiovascular ischemia, myocarditis, heart failure, hypotension, and atherosclerosis; endocrine diseases such as diabetes (for example, insulin-dependent diabetes mellitus and so on), complications of diabetes (e.g. diabetic nephropathy, diabetic retinopathy, diabetic neuropathy etc) and gout; renal ill the tion, such as glomerulonephritis and renal failure; gastrointestinal diseases such as peptic ulcer and inflammatory bowel disease (e.g. ulcerative colitis, chronic colitis, etc.); diseases of the pancreas, such as pancreatitis; liver disease such as hepatitis and cirrhosis of the liver; diseases of the bones or joints, such as synovitis, arthritis, osteoarthritis, osteoporosis; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis; skin diseases such as dermatitis and eczema; cancer, such as solid tumors and metastases; rejection when organ transplantation; shock (e.g., septic shock, etc.); caused by sepsis syndrome, systemic inflammatory response.

The described compounds (I) and their pharmaceutically acceptable salts are also useful for prophylaxis and/or treatment of NO-mediated nerve diseases, including diseases of the Central nervous system, such as Central nervous system disorders, cerebral vascular diseases (for example, cerebral infarction, cerebral ischemia, intracerebral hemorrhage, and so on), migraine, Alzheimer's disease; diseases of the peripheral nervous system, such as neuritis, pain (e.g. post herpetic neuralgia, reflex sympathetic dystrophy (RSD), causalgia, painful is th syndrome deafferentation, neuropathic pain etc), allodynia, hyperalgesia, neurological disorders and neuroprotection; Parkinson's disease; amyotrophic lateral sclerosis.

Moreover, the described compounds (I) and their pharmaceutically acceptable salts are useful for the treatment of sexual disorders such as sexual dysfunction in men, including erectile dysfunction and sexual disorders in women, including violations of orgasm associated with damage to the clitoris.

Further, the described compounds (I) and their pharmaceutically acceptable salts are useful for the prevention and/or treatment of NO-mediated ophthalmologic diseases, including conjunctive, such as conjunctivitis (e.g., allergic conjunctivitis, vernal conjunctivitis, keratoconjunctivitis sicca, viral conjunctivitis, bacterial conjunctivitis, etc.); uveal diseases such as uveitis (e.g., Behcet's disease, a disease Harada (Harada), sympathetic ophthalmia, sarcoidosis, diabetic iritis, etc.); scleral diseases, such as scleritis; diseases of the cornea, such as corneal neovascularization, keratitis, corneal edema, corneal opacity, corneal dystrophy, keratoconus and neuroparalytic keratitis; diseases of the retina and vitreous body, such as diabetic retinopathy, occlusion of the retinal artery, occlusion of retinal vein, the Central with Morococha horioretinopatia, Central hemorrhagic chorioretinal, macular degeneration (e.g., age-related macular degeneration (AMD), retinal detachment, pigmentary retinal degeneration, neovascularization yellow spots, the gap yellow spots, proliferative vitreoretinopathy, hemorrhage into the vitreous body vitreous opacity; diseases of the lens, such as cataract (e.g., senile cataract, traumatic cataract, diabetic cataract, atopic cataract, etc.); glaucoma, such as primary open-angle glaucoma, primary angle-closure glaucoma, glaucoma under normal pressure and neovascular glaucoma; ocular hypertension; vision disorders such as amblyopia, impaired color vision and night blindness; refractive problems such as astigmatism, hyperopia, myopia and presbyopia; and diseases of the lacrimal apparatus, such as dry eye syndromes, obstruction of the lacrimal ducts and dacryocystitis.

To illustrate the usefulness of the described compound (I) is the result of the pharmacological test compounds (I) are presented in the following.

The analyzed connection:

Connection (a): 5-chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(1,3-thiazol-2-yloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

The compound (b): (2E)-3-(4-chlorophenyl)-N - [(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyrazinone)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]acrylamide

Connection (s): 5-chloro-N-[(1S)-2-[(2-{4-[(6-methoxy-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

The compound (d): 5-chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridyloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Connection (e): (2E)-3-(4-chlorophenyl)-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-phenoxy-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)ethyl]acrylamide

Connection (f): 5-chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2,2,2-triptoreline)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Compound (g): (2E)-3-(4-chlorophenyl)-N-[(1S)-2-{[2-(4-isopropoxy-1-piperidinyl)-2-oxoethyl]amino}-2-oxo-1-(2-pyridylmethyl)ethyl]acrylamide

Test 1: the Research activity, inhibiting the production of nitric oxide

This study used cell macrophage line RAW264.7 (culture Collection of the American type, No. TIB71). The RAW264.7 cells grown in plastic flasks for culturing F75 at 37°C, 5% in modified according to the method of Dulbecco environment Needle (DMEM), supplemented with L-glutamine, penicillin, streptomycin and 10% thermoactivation fetal calf serum. They were removed from the flasks for culturing rubber scraper for cells, centrifuged and re-suspended in DMEM without phenol red. Cells are placed in 96-well microtiter plates (105to etoc per well) and give them the opportunity to adhere for 2 hours. Add the analyzed samples and cells subjected to pre-incubation for 1 hour. Then activate cells by lipopolysaccharide (LPS) (1 μg/ml) and interferon - γ (INF γ) (3 μm/ml) for 18-24 hours. Add an equal amount of Griess reagent (1% sulfanilamide/0.1% of N-naphthylethylenediamine/a 2.5% N3RHO4), and the cells incubated at room temperature for 10 minutes. Determine the absorbance at 570 nm, using the device for reading tablets, and measure the NO2-using NaNO2as a standard.

Test results:

Table 1
The analyzed compound (10-6M)Inhibition (%)
(a)100
(b)97,6
(c)100
(d)100
(e)100
(f)100
(g)100

Test 2: Protective effect of compound (I) in combination with FK506 on cardiac allograft in rats

Method:

In experiments using rats-males Lewis and ACI weighing 175-200 g Rats anesthetist pentobarbital sodium (50 mg/kg, I.P. Pavlova.) and subjected to allogeneic (donor Lewis for the recipient ACI), geerat the microscopic heart transplant. The experimental group divided into a group receiving one drug and the group receiving combined drug. Dose of one drug FK506 obtained in a manner similar to the method described in EP-0184162, 0.32 mg/kg Dose combination medicinal product includes FK506 (0,32 mg/kg) + compound (I) (10 mg/kg). Transplanted hearts examined daily by palpation, with full exclusion is defined as the cessation of palpable contractility. Every drug is suspended in a solution of 0.5% methylcellulose and daily administered using a gastric probe in a volume of 5 ml/kg body weight for 14 days.

The combination of the compounds (I) and FK506 significantly extends the life of the transplant.

The above experimental results show that the activity and/or efficacy of immunosuppressant for transplant rejection can be significantly and synergistically increased due to the introduction of the compound (I) in combination with another drug, which have a strong inhibitory effect on the production of nitric oxide.

When therapeutic introduction of the described compound (I) in accordance with the present invention and its pharmaceutically acceptable salts is used in the form of conventional pharmaceutical preparations mixed with the conventional pharmaceutically acceptable carrier, such as organic or inorganic solid or liquid excipient, suitable for oral, parenteral or topical use. The pharmaceutical preparation may be obtained in solid form such as granules, capsules, tablets, pills, suppositories, or ointments, or in liquid form such as solution, suspension or emulsion for injection, intravenous drip infusion, ingestion, eye drops, etc. If necessary in the above preparation may be included excipient, such as a stabilizing agent, a moisturizing or emulsifying agent, oil, or any other commonly used additives.

Effective ingredient is usually administered in the form of single doses of from 0.001 to 500 mg/kg, preferably from 0.01 to 10 mg/kg, 1 to 4 times a day. However, the above dose may be raised or lowered in accordance with the age, body weight and condition of the patient or by way of introduction.

In accordance with the present invention the pharmaceutical composition comprising FK506 and the compound (I) or its pharmaceutically acceptable salt. Pharmaceutical composition containing FK506 and the compound (I) or its pharmaceutically acceptable salt, useful as an immunosuppressant. For example, the pharmaceutical composition of the present invention is useful as Lekarstvo the th means to prevent or treat rejection in organ transplantation.

When using compounds (I) in combination with FK506 mass ratio of compound (I) or its pharmaceutically acceptable salt to FK506 is in the range of 0.1/1 to 1,000/1, preferably in the range of 1/1-100/1.

Preferred variants of the compounds of the present invention represented by the General formula (I), following.

(1) Compound of formula (I)in which R2represents a group of the formula: -Y-R3where R3represents lower alkyl, halo(lower)alkyl, optionally substituted heterocyclic group or optionally substituted aryl, and Y is-O-, -S - or-SO2or its pharmaceutically acceptable salt.

(2) the Above compound (1)in which R3is lower alkyl; halo(lower)alkyl; heterocyclic group, optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl; or aryl, optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

(3) the Above compound (2)in which R3is lower alkyl; halo(lower)alkyl; heterocyclic group selected from the group comprising a pyridyl, pyrazinyl, thiazolyl, pyridazin the l and pyrimidinyl, while specified heterocyclic group optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl; or phenyl, optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

(4) the Compound of formula (I)in which X represents

or its pharmaceutically acceptable salt.

(5) the Above compound (4)in which R2is substituted by hydroxyl, or its pharmaceutically acceptable salt.

(6) the Above compound (5)in which R2represents a group of formula: -O-R3where R3represents lower alkyl, halo(lower)alkyl, optionally substituted heterocyclic group or optionally substituted aryl, or its pharmaceutically acceptable salt.

(7) the Above compound (6)in which R3represents lower alkyl, halo(lower)alkyl, pyridyl, pyrazinyl, thiazolyl or phenyl, where each of the specified pyridyl, pyrazinyl, thiazolyl and phenyl optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and galonsky)alkyl, or its pharmaceutically acceptable salt.

(8) the Above compound (7)in which R3represents lower alkyl, halo(lower)alkyl, pyridyl, pyrazinyl, thiazolyl or phenyl, with the specified pyridyl optionally substituted by a Deputy selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

(9) the Compound of formula (I)in which R1is benzofuranyl substituted by chlorine, or styryl substituted by chlorine, or its pharmaceutically acceptable salt.

(10) the Compound of formula (I)in which R1represents 5-chloro-1-benzofuran-2-yl or 2-(4-chlorophenyl)ethynyl, or its pharmaceutically acceptable salt.

Following receipt and detailed examples are intended to illustrate the present invention.

Getting 1

Benzyl({(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)-propanol}amino)acetate

To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)propanoic acid (55,0 g), tosilata complex pillbonivae ether (69.7 g) and diphenylphosphinite them (46.7 ml) in N,N-dimethylformamide (550 ml) dropwise at 4°add N,N-diisopropylethylamine (75,6 ml). The mixture is heated at room temperature and stirred for 3 hours. The resulting mixture was poured into ice-cold saturated aqueous solution of bicarbonate is the atrium (700 ml). The mixture is extracted twice with ethyl acetate (generally 1.3 l) and sequentially washed with water (400 ml × 2), saturated aqueous ammonium chloride (200 ml), aqueous sodium hydrogen carbonate solution (300 ml × 2) and brine (40 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated, obtaining specified in the header connection (77,4 g) as light brown crystals.

ESI-MS: 414,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,48 (DD, J=5,2 Hz, 1H), 7,82 (width, 1H), 7,60 (TD, J=8,2 Hz, 1H), 7,40-7,29 (m, 5H), 7,21 (d, J=8 Hz, 1H), 7,14 (DD, J=8.5 Hz, 1H), 6,33 (width, 1H), further 5.15 (s, 2H), 4,62 (width, 1H), Android 4.04 (d, J=6 Hz, 2H), 3,36-3,18 (m, 2H), USD 1.43 (s, 9H).

Getting 2

Benzyl{[(2S)-2-amino-3-(2-pyridyl)propanol]amino}-acetyldigitoxin

To a solution of benzyl({(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-pyridyl)propanol}amino)acetate (73,8 g) in ethyl acetate (150 ml) was added dropwise 4 N. hydrogen chloride in ethyl acetate (669 ml) at 10°C for 30 minutes. The mixture is heated to room temperature and stirred for 3 hours. The mixture is diluted with ethyl acetate (300 ml). The precipitate is collected by filtration, washed with ethyl acetate (700 ml) and dried in vacuum, obtaining specified in the header of the connection.

1H-NMR (300 MHz, DMSO-d6) δ 9,31 (t, J=6 Hz, 1H), 8,83 (d, J=5 Hz, 1H), 8,70 (width, 3H), 8,40 (t, J=8 Hz, 1H), of 7.96 (d, J=8 Hz, 1H), 7,87 (t, J=5 Hz, 1H), 7,41-7,30 (m, 5H), 5,14 (s, 2H), 4.53-in (lat., 1H), of 4.05 (DD, J=18.6 Hz, 1H), 3,99 (l is, J=18.6 Hz, 1H), 3,64 (DD, J=15,5 Hz, 1H), 3,54 (DD, J=15,8 Hz, 1H).

Getting 3

Benzyl{[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetate

To a solution of 4-harkerite acid (49.2 g) in dichloromethane (400 ml) add oxalicacid (30,5 ml) and 1 drop of N,N-dimethylformamide and the mixture is stirred at room temperature for 6 hours. The reaction mixture is evaporated to dryness, and the residual acid chloride acid dissolved in dichloromethane (900 ml). To the resulting solution was added benzyl{[(2S)-2-amino-3-(2-pyridyl)propanol]amino}acetyldigitoxin (104 g) in 10°C, followed by addition of triethylamine (116 ml) for 40 minutes. The mixture allow to warm to room temperature and stirred for 2 hours. The reaction mixture is evaporated to dryness and the residue is washed sequentially with water (500 ml × 5) and tetrahydrofuran-n-hexane (1:2), 500 ml × 10) and dried in vacuum, obtaining mentioned in the title compound (115 g) as a white solid.

ESI-MS: 478,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,51 (DD, J=5,2 Hz, 1H), 8,27 (t, J=5 Hz, 1H), 7,83 (d, J=6 Hz, 1H), to 7.64 (TD, J=8,2 Hz, 1H), EUR 7.57 (d, J=16 Hz, 1H), 7,44 (d, J=9 Hz, 2H), 7,39-7,28 (m, 8H), 7,19 (DD, J=8.5 Hz, 1H), 6,47 (d, J=16 Hz, 1H), 5,14 (s, 2H), 4,98 (seemingly kV, J=6 Hz, 1H), 4,07 (d, J=5 Hz, 2H), 3,36 (DD, J=15,5 Hz, 1H), 3,26 (DD, J=15.6 Hz, 1H).

Getting 4

{[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}of uksosn the I acid

To a suspension of benzyl{[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetate (10.8 g) in methanol (200 ml) was added 1 N. aqueous sodium hydroxide solution (22,6 ml) and the mixture is stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo and the residue treated with an aqueous solution of citric acid (10%, 100 ml). The obtained white precipitate is collected by filtration, washed with tetrahydrofuran-hexane (1:1, 150 ml) and dried in vacuum, obtaining specified in the header connection (8,25 g) as a white solid.

ESI-MS: 388,2 (M+N)

1H-NMR (300 MHz, DMSO-d6) δ 12,6 (width, 1H), 8,50-at 8.36 (m, 3H), 7,68 (TD, J=8,2 Hz, 1H), 7,56 (d, J=9 Hz, 2H), 7,47 (d, J=9 Hz, 2H), 7,34 (d, J=16 Hz, 1H), 7,30 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), of 6.68 (d, J=16 Hz, 1H), 4,96-4,86 (m, 1H), 3,78 (DD, J=18.6 Hz, 1H), 3,74 (DD, J=18.6 Hz, 1H), 3,24 (DD, J=14,5 Hz, 1H), 2,99 (DD, J=14,10 Hz, 1H).

Getting 5

Benzyl{[(2S)-2-{[5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetate

Specified in the title compound is obtained from {[(2S)-2-amino-3-(2-pyridyl)propanol]amino}acetyldihydrocodeine and 5-chloro-1-benzofuran-2-carboxylic acid in the same manner as in obtaining 3.

ESI-MS: 492,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,70-8,49 (m, 3H), 7,71 to 7.62 (m, 2H), 7,52-to 7.18 (m, 10H), 5,16 (s, 2H), 5,11-5,02 (m, 1H), 4,19-a 4.03 (m, 2H), 3,44 (DD, J=to 15.4 Hz, 1H), 3,35 (DD, J=15.7 Hz, 1H).

Getting 6

{[(2S)-2-{[(5-Chloro-1-benzofuran-2-yl)Carboni is]amino}-3-(2-pyridyl)propanol]amino}acetic acid

Specified in the title compound is obtained from benzyl{[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetate in the same manner as in obtaining 4.

ESI-MS: 402,2 (M+N)

1H-NMR (300 MHz, DMSO-d6) δ 12,6 (width, 1H), 9,00 (d, J=8 Hz, 1H), 8,49 (DD, J=5,2 Hz, 1H), 8,46 (t, J=6 Hz, 1H), 7,88 (d, J=2 Hz, 1H), 7,72 (d, J=9 Hz, 1H), to 7.67 (TD, J=8,2 Hz, 1H), 7,53 (d, J=1 Hz, 1H), of 7.48 (DD, J=9,2 Hz, 1H), 7,33 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 5,04-4,94 (m, 1H), 3,80 (DD, J=18.6 Hz, 1H), 3,74 (DD, J=18.6 Hz, 1H), 3,32 (DD, J=14,4 Hz, 1H), up 3.22 (DD, J=14,10 Hz, 1H).

Getting 7

tert-Butyl 4-(1,3-thiazol-2-yloxy)-1-piperidinecarboxylate

To a suspension of sodium hydride (about 60%oil suspension, 5,67 g) dimethoxyethane (40 ml) add a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (23.9 g) in dimethoxyethane (60 ml) for 30 minutes and the mixture is stirred for a further 1 hour. To this mixture 2-bromothiazole (15.0 g) and the mixture refluxed for 4 hours. After cooling, the obtained pale-brown suspension was diluted with simple ether (300 ml) and the mixture is filtered through a layer of celite. The filtrate is washed with saline, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil is purified column chromatography on silica gel (eluent; 15% ethyl acetate in n-hexane), getting mentioned in the title compound (22.1 g) as a yellow oil.

ESI-MS: RUB 285.2 (M+N)

1NAMR (300 MHz, CDCl3) δ 7,11 (d, J=4 Hz, 1H), to 6.67 (d, J=4 Hz, 1H), 5,13 (Sept., J=4 Hz, 1H), of 3.73 (DDD, J=14,7,4 Hz, 2H), 3,32 (DDD, J=14,8,4 Hz, 2H), 2,08 is 1.96 (m, 2H), 1,88-of 1.74 (m, 2H), 1,47 (s, 9H).

Example 1

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(1,3-thiazol-2-yloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]acrylamide

To a solution of tert-butyl 4-(1,3-thiazol-2-yloxy)-1-piperidinecarboxylate (with 2.93 g) in ethyl acetate (12 ml) was added dropwise 4 N. hydrogen chloride in ethyl acetate (15 ml) at 10°C. the Mixture is heated to room temperature and stirred for one hour. The mixture is concentrated and dried in vacuum. The residual yellow solid substance is added to ice-cold mixture of {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid (4.0 g), 1-hydroxybenzotriazole (1,53 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.17 g) in N,N-dimethylformamide (40 ml). To the mixture are added dropwise N,N-diisopropylethylamine (3,9 ml). The mixture is heated to room temperature and stirred for 2 hours. The resulting mixture was poured into ice-cold saturated aqueous solution of sodium bicarbonate (200 ml). The mixture is extracted three times with ethyl acetate (total 400 ml) and sequentially washed with saturated aqueous ammonium chloride (100 ml), water (70 ml × 3) and brine (20 ml). The organic layer is dried over anhydrous magnesium sulfate and concentrated. Statomat column chromatography on silica gel (eluent; 1% methanol in chloroform)to give specified in the header of the connection (of 4.57 g) as a pale yellow solid, recrystallized from ethyl acetate.

ESI-MS: 554,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (DD, J=5,2 Hz, 1H), 8,04-of 7.97 (m, 1H), of 7.96-7,88 (m, 1H), 7,63 (TD, J=8,2 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=9 Hz, 2H), 7,34 (d, J=9 Hz, 2H), 7,25 (d, J=8 Hz, 1H), 7,18 (DD, J=8,5 Hz, 1H), 7,10 (d, J=4 Hz, 1H), of 6.68 (d, J=4 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5.25-in, 5,15 (SIRM, 1H), 5,06-4,99 (m, 1H), a 4.03 (d, J=4 Hz, 2H), 3,83-to 3.52 (m, 3H), of 3.43 (DD, J=15,5 Hz, 1H), 3,37-of 3.31 (m, 1H), 3,26 (DD, J=15.6 Hz, 1H), 2,08-of 1.81 (m, 4H).

Example 2

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(1,3-thiazol-2-yloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(1,3-thiazol-2-yloxy)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]-amino}acetic acid in the same manner as in example 1.

ESI-MS: 568,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,80-8,72 (m, 1H), to 8.62 (d, J=5,2 Hz, 1H), 8,19-8,11 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 7,10 (d, J=4 Hz, 1H), of 6.68 (d, J=4 Hz, 1H), 5.25-in, 5,16 (m, 1H), 5,15 is 5.07 (m, 1H), 4,07 (d, J=4 Hz, 2H), 3,83-of 3.53 (m, 3H), of 3.48 (DD, J=15,5 Hz, 1H), 3,40 be 3.29 (m, 2H), 2,08-is 1.81 (m, 4H).

Getting 8

tert-Butyl 4-(2-pyrazinone)-1-piperidinecarboxylate

To a suspension of sodium hydride (about 60%oil suspension, 114 mg) in dimetilan is xide (5 ml) added dropwise a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (576 mg). There is a substantial foaming and the solution becomes pale orange color. To the resulting solution add chloropyrazine (377 mg) and the mixture is stirred at room temperature for 12 hours. The resulting mixture is divided between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residual oil triturated with a mixture of ethyl acetate and n-hexane, obtaining mentioned in the title compound (472 mg) as white crystals.

ESI-MS: 280,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ to 8.20 (d, J=1 Hz, 1H), 8,10 (d, J=3 Hz, 1H), with 8.05 (DD, J=3.1 Hz, 1H), 5,20 (Sept., J=4 Hz, 1H), 3,84-and 3.72 (m, 2H), 3,30 (DDD, J=14,8,4 Hz, 2H), 2.05 is-of 1.93 (m, 2H), 1,81 by 1.68 (m, 2H), to 1.48 (s, 9H).

Example 3

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyrazinone)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-(2-pyrazinone)-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 549,4 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), they were 8.22-to 8.20 (m, 1H), 8,13 (d, J=3 Hz, 1H), with 8.05 (DD, J=3.1 Hz, 1H), 8,03-7,88 (m, 2H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,27 (d, J=8 Hz, 1H), 7,19 (DD, J=8.5 Hz, 1H), 6,50 (q, j =16 Hz, 1H), 5,33-5,22 (m, 1H), 5,07-4,99 (m, 1H), 4,05 (apparent d, J=4 Hz, 2H), 3,92-of 3.78 (m, 1H), 3,68-to 3.52 (m, 2H), 3,48-up 3.22 (m, 3H), 2,07-of 1.92 (m, 2H), 1,88-of 1.78 (m, 2H)Primer 4

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyrazinone)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(2-pyrazinone)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 563,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81-8,71 (m, 1H), to 8.62 (DD,J=5,2 Hz, 1H), they were 8.22-to 8.14 (m, 2H), 8,13 (d, J=3 Hz, 1H), with 8.05 (DD, J=3.1 Hz, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (DD, J=9.1 Hz, 1H), 7,43 (d, J=1 Hz, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 5,32-to 5.21 (m, 1H), 5,16-of 5.06 (m, 1H), 4,15-4,00 (m, 2H), 3,92 is 3.76 (m, 1H), 3,69-of 3.54 (m, 2H), 3,49 (DD, J=15,5 Hz, 1H), 3,40 of 3.28 (m, 2H), 2,07-1,90 (m, 2H), 1,89-of 1.74 (m, 2H).

9

tert-Butyl 4-(4-pyridyloxy)-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 4-glacialinterglacial in the same way as in obtaining 8.

ESI-MS: 279,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,42 (d, J=6 Hz, 2H), 6,80 (d, J=6 Hz, 2H), 4,58 (Sept., J=4 Hz, 1H), 3,69 (DDD, J=14,8,4 Hz, 2H), 3,37 (DDD, J=14,8,4 Hz, 2H), 2,01-of 1.88 (m, 2H), 1,84 was 1.69 (m, 2H), 1,47 (s, 9H).

Example 5

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(4-pyridyloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-this is]acrylamide

Specified in the title compound is obtained from tert-butyl 4-(4-pyridyloxy)-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 548,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (DD, J=5,2 Hz, 1H), 8,43 (DD, J=5,2 Hz, 2H), 8,04-7,86 (m, 2H), to 7.64 (TD, J=8,2 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,26 (d, J=8 Hz, 1H), 7,18 (DD, J=8.5 Hz, 1H), 6,79 (DD, J=5,2 Hz, 2H), 6,50 (d, J=16 Hz, 1H), 5,06-to 4.98 (m, 1H), 4,70-to 4.62 (m, 1H), 4,12-of 3.96 (m, 2H), 3,84-up 3.22 (m, 6H), 1,98-to 1.79 (m, 4H).

Example 6

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(4-pyridyloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(4-pyridyloxy)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 562,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,83-8,71 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,43 (d, J=6 Hz, 2H), by 8.22-to 8.12 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 6,79 (d, J=6 Hz, 2H), 5,15 is 5.07 (m, 1H), 4,71-to 4.62 (m, 1H), 4,16-to 3.99 (m, 2H), 3,83 be 3.29 (m, 6H), 2.00 in to 1.77 (m, 4H).

Receive 10

tert-Butyl 4-(3-pyridyloxy)-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 3-herperidin the mayor the same way, both get 8.

ESI-MS: 279,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,33-8,30 (m, 1H), they were 8.22 (DD, J=4.3 Hz, 1H), 7.23 percent-7,20 (m, 2H), 4,51 (Sept., J=4 Hz, 1H), 3,71 (DDD, J=14,7,4 Hz, 2H), 3,35 (DDD, J=14,8,4 Hz, 2H), 2.00 in a 1.88 (m, 2H), 1,83 is 1.70 (m, 2H), 1,47 (s, 9H).

Example 7

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(3-pyridyloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-(3-pyridyloxy)-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 548,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), 8,33-8,30 (m, 1H), 8,24 (DD, J=4,1 Hz, 1H), 8,06-7,87 (m, 2H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,29-7,16 (m, 5H), of 6.50 (d, J=16 Hz, 1H), 5,06-4,99 (m, 1H), 4,63-of 4.57 (m, 1H), 4,13-of 3.97 (m, 2H), 3,81 is 3.23 (m, 6H), 1,99-of 1.81 (m, 4H).

Example 8

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(3-pyridyloxy)-1-piperidinyl]ethyl}amino]-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(3-pyridyloxy)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 562,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,83-to 8.70 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,33-8,29 (m, 1H), 8,25 is 8.22 (m, 1H), 8,21-8,10 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 is C, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,30-7,16 (m, 4H), 5,16 is 5.07 (m, 1H), with 4.64-4,55 (m, 1H), 4,15-3,98 (m, 2H), 3,80 of 3.28 (m, 6H), 1,98 and 1.80 (m, 4H).

Receipt 11

tert-Butyl 4-[(6-methoxy-2-pyridyl)oxy)-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 2-chloro-6-methoxypyridine in the same way as in obtaining 8.

ESI-MS: 309,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 7,49 (t, J=8 Hz, 1H), 6,29 (d, J=8 Hz, 2H), 5,17 (Sept., J=4 Hz, 1H), 3,88 (s, 3H), 3,81-3,70 (m, 2H), and 3.31 (DDD, J=14,8,4 Hz, 2H), 2,04-of 1.92 (m, 2H), 1,82-to 1.67 (m, 2H), 1,47 (s, 9H).

Example 9

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(6-methoxy-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-[(6-methoxy-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 578,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), 8,04-7,86 (m, 2H), 7,63 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,53-7,42 (m, 3H), 7,35 (d, J=8 Hz, 2H), 7,26 (d, J=8 Hz, 1H), 7,18 (DD, J=8.5 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 6,29 (d, J=8 Hz, 2H), 5,32-5,20 (m, 1H), 5,06-to 4.98 (m, 1H), 4,03 (apparent d, J=4 Hz, 2H), 3,86 (s, 3H), 3,82-is 3.21 (m, 6H), 2,02-of 1.74 (m, 4H).

Example 10

5-Chloro-N-[(1S)-2-[(2-{4-[(6-methoxy-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the header is VCE compound is obtained from tert-butyl 4-[(6-methoxy-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same way, as in example 1.

ESI-MS: 592,4 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,82-8,71 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,19-of 8.09 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,52 was 7.45 (m, 2H), 7,42 (s, 1H), 7,38 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 6,29 (d, J=8 Hz, 2H), 5,31-to 5.21 (m, 1H), 5,16-5,08 (m, 1H), 4,07 (apparent d, J=4 Hz, 2H), 3,86 (s, 3H), 3,82-3,44 (m, 4H), 3,40 of 3.28 (m, 2H), 2,03 is 1.70 (m, 4H).

Getting 12

tert-Butyl 3-[(5-[chloro-2-pyridyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl 3-hydroxy-1-piperidinecarboxylate and 2.5-dichloropyridine in the same way as in obtaining 8.

ESI-MS: 313,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,07 (d, J=3 Hz, 1H), 7,52 (DD, J=9,3 Hz, 1H), 6,66 (d, J=9 Hz, 1H), 4,99 (Sirs, 1H), 3,90-3,10 (SIRM, 4H), 2,10-1,70 (SIRM, 3H), 1.60-to 1,50 (m, 1H), 1,34 (Sirs, 9H).

Example 11

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{3-[(5-chloro-2-pyridyl)-oxy]-1-piperidinyl}-2-oxoethyl}amino]-2-oxo-1-(2-pyridylmethyl)ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 3-[(5-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 582,3 (M+H).

1H-NMR (300 MHz, CDCl3) δ 8,58-8,51 (m, 1H), 8,10-7,81 (m, 3H), 7,66-7,41 (m, 5H), 7,34 (d, J=8 Hz, 2H), 7,25 (d, J=8 Hz, 1H), 7,20-7,14 (m, 1H), 6,69-6,60 (m, 1H), 6,53-6,44 (m, 1H), 5,10-4,96 (m, 2H), 4,16-of 3.80 (m, 2H), of 3.77-3,20 (m, 6H), 2,10-1,50 (m, 4H).

Example 12

5-Chloro-N-[(1S)-2-[(2-{3-[(5-chloro-2-pyridyl)) - Rev. XI]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 3-[(5-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 596,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,84-8,69 (m, 1H), 8,65-8,58 (m, 1H), 8.17-a of 7.97 (m, 2H), 7.68 per-of 7.60 (m, 2H), 7,56-7,46 (m, 2H), 7,43 and 7.36 (m, 2H), 7,29-7,24 (m, 1H), 7.23 percent-7,16 (m, 1H), 6,70-6,60 (m, 1H), 5,15-to 4.98 (m, 2H), 4,20-of 3.85 (m, 2H), 3,76-of 3.27 (m, 6H), 2,09 of 1.50 (m, 4H).

13

tert-Butyl 4-(2-pyridyloxy]-1-piperidinecarboxylate

To a solution of 2-hydroxypyridine (2.0 g), tert-butyl-4-hydroxy-1-piperidinecarboxylate (5.3g) and triphenylphosphine (8,3 g) in tetrahydrofuran (63 ml) at 8°slowly add diethylazodicarboxylate (5.5 g), and the mixture is stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, obtaining the crude product is specified in the connection header, and the resulting crude product is purified by chromatography on silica gel.

1H-NMR (300 MHz, CDCl3) δ 8,16-8,10 (m, 1H), 7,60-7,52 (m, 1H), 6,88-for 6.81 (m, 1H), of 6.71 (d, J=8 Hz, 1H), 5,27-5,17 (m, 1H), 3,85-3,70 (m, 2H), 3,35 is 3.23 (m, 2H), 2.05 is-1,90 (m, 2H), 1,80-of 1.65 (m, 2H), 1,47 (s, 9H).

Example 13

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridyloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-(2-pyridyl) - Rev. XI)-1 piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same way, as in example 1.

ESI-MS: m/z 548 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,01 (d, J=5 Hz, 1H), 8,04-a 7.85 (m, 2H), to 7.67-7,53 (m, 3H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,28-to 7.15 (m, 2H), 6,85 (DD, J=8,8 Hz, 1H), 6,70 (d, J=8 Hz,, 1H), 6,50 (d, J=16 Hz, 1H), 5,34-a 5.25 (m, 1H), 5,06-to 4.98 (m, 1H), 4,06-4,01 (m, 2H), 3,91-of 3.77 (m, 1H), 3,66-to 3.50 (m, 2H), 3,48-3,20 (m, 3H), 2.05 is-1,90 (m, 2H), 1,86-1,71 (m, 2H).

Example 14

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridyloxy)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(2-pyridyloxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 562 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,80-8,71 (m, 1H), to 8.62 (d, J=5 Hz, 1H), 8,16-8,07 (m, 2H), 7.68 per-7,52 (m, 3H), of 7.48 (d, J=8 Hz, 1H), 7,40 (d, J=8 Hz, 1H), 7,37 (DD, J=2,8 Hz, 1H), 7,30-to 7.15 (m, 2H), 6,85 (DD, J=8,8 Hz, 1H), 6,70 (d, J=8 Hz, 1H), 5,35-5,24 (m, 1H), 5,15 is 5.07 (m, 1H), 4.09 to as 4.02 (m, 2H), 3,90-3,71 (m, 1H), 3,67-3,44 (m, 3H), 3,39-3,26 (m, 2H), 2.05 is is 1.70 (m, 4H).

Getting 14

tert-Butyl 4-[(6-methyl-2-pyridyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 2-hydroxy-6-methylpyridine in the same way as in obtaining 13.

1H-NMR (300 MHz, CDCl3) δ 7,44 (DD, J=8,8 Hz, 1H), of 6.68 (d, J=8 Hz, 1H), of 6.49 (d, J=8 Hz, 1H), 5,26-5,16 (m, 1H), 3,82-3,68 (m, 2H), 3,35-3,24 (m, 2H), 2,42 (s, 3H), 2,02-1,90 (m, 2H), 1,79-of 1.64 (m, 2H), 1,47 (s, 9H).

Example 15

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(6-methyl-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-1-oxo-1-(2-pyridylmethyl)ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-[(6-methyl-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 562 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,04-of 7.85 (m, 2H), 7,63 (DD, J=2,16 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,50-7,40 (m, 3H), 7,35 (d, J=8 Hz, 2H), 7,30-to 7.15 (m, 2H), 6,70 (d, J=8 Hz, 1H), 6,55-of 6.45 (m, 2H,), 5,35-a 5.25 (m, 1H), 5,07-to 4.98 (m, 1H), 4,07-4,00 (m, 2H), 3,86-and 3.72 (m, 1H), 3,70-to 3.52 (m, 2H), 3,48-3,20 (m, 3H), 2,41 (s, 3H), 2,01-1,71 (m, 4H).

Example 16

5-Chloro-N-[(1S)-2-[(2-{4-[(6-methyl-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(6-methyl-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 576 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,80-to 8.70 (m, 1H), to 8.62 (d, J=5 Hz, 1H), 8,16-8,07 (m, 1H), 7,69-of 7.60 (m, 2H), 7,51-7,35 (m, 4H), 7,30-7,16 (m, 2H), 6,70 (d, J=8 Hz, 1H), of 6.49 (d, J=8 Hz, 1H), 5,35-a 5.25 (m, 1H), 5,16-of 5.06 (m, 1H), 4,10-was 4.02 (m, 2H), 3,85-of 3.27 (m, 6H), is 2.41 (s, 3H), 2,02 is 1.70 (m, 4H).

Receive 15

tert-Butyl 4-[(6-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate

Specified in the agolove compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 6-chloro-2-hydroxypyridine in the same way, as in getting 13.

1H-NMR (300 MHz, CDCl3) δ to 7.50 (DD, J=8,8 Hz, 1H), 6.87 in (d, J=8 Hz, 1H), is 6.61 (d, J=8 Hz, 1H), 5,26-of 5.15 (m, 1H), 3,80-3,68 (m, 2H), 3,35-of 3.25 (m, 2H), 2,03-1,90 (m, 2H), 1,78-of 1.65 (m, 2H), 1,47 (s, 9H).

Example 17

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(6-chloro-2-pyridyl)-oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 582 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,56 (d, J=5 Hz, 1H), 8,04-7,87 (m, 2H), 7,69-7,49 (m, 3H), 7,46 (d, J=8 Hz, 2H), was 7.36 (d, J=8 Hz, 2H), 7,30-to 7.15 (m, 2H), make 6.90 (d, J=8 Hz, 1H), only 6.64 (DD, J=2,8 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,35-a 5.25 (m, 1H), 5,07-4,99 (m, 1H), 4,08-4,00 (m, 2H), 3,90 of 3.75 (m, 1H), 3,67-to 3.50 (m, 2H), 3,49-3,20 (m, 3H), 2.06 to 1,90 (m, 2H), 1,87-of 1.73 (m, 2H).

Example 18

5-Chloro-N-[(1S)-2-[(2-{4-[(6-chloro-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 596 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,80-8,71 (m, 1H), to 8.62 (d, J=5 Hz, 1H), 8,14 (d, J=2 Hz, 1H), 7,69-of 7.60 (m, 2H), 7,56 was 7.45 (m, 2H), 7,41 (d, J=8 Hz, 1H), 7,34 (DD, J=2,8 Hz,1H), 7,30-7,16 (m, 2H), make 6.90 (d, J=8 Hz, 1H), to 6.67 (DD, J=2,8 Hz, 1H), 5,35-5,24 (m, 1H), 5,15 is 5.07 (m, 1H), 4,10-a 4.03 (m, 2H), 3,89 of 3.75 (m, 1H), 3,66-3,44 (m, 3H), 3,40 of 3.28 (m, 2H), 2.05 is-1,89 (m, 2H), 1,86-1,69 (m, 2H).

Getting 16

tert-Butyl 4-{[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 5-trifluoromethyl-2-hydroxypyridine in the same way as in obtaining 13.

1H-NMR (300 MHz, CDCl3) δ 8,40 (Sirs, 1H), 7,76 (DD, J=2,8 Hz, 1H), 6,69 (d, J=8 Hz, 1H), 5,33-5,23 (m, 1H), 3,84-3,70 (m, 2H), 3,35 is 3.23 (m, 2H), 2.05 is-of 1.92 (m, 2H), 1,80-of 1.66 (m, 2H), to 1.48 (s, 9H).

Example 19

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-{[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 616 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,40 (Sirs, 1H), 8,04-to 7.95 (m, 1H), to $ 7.91 (d, J=8 Hz, 1H), to 7.77 (DD, J=2,8 Hz, 1H), 7,63 (DD, J=2,16 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,29-to 7.15 (m, 2H), 6,80 (DD, J=2,8 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,41-and 5.30 (m, 1H), 5,06 is equal to 4.97 (m, 1H), 4,08-4,00 (m, 2H), 3,92-3,20 (m, 6H), 2.06 to of 1.92 (m, 2H), 1,86-1,71 (m, 2H).

Example 20

5-Chloro-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyrid lmutil)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-{[5-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 630 (M+1)

1H-NMR (300 MHz, CDCl3) δ is 8.75 (d, J=8 Hz, 1H), to 8.62 (d, J=5 Hz, 1H), 8,40 (Sirs, 1H), 8,18-8,10 (m, 1H), to 7.77 (DD, J=2,8 Hz, 1H), 7,69-of 7.60 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,41 (d, J=8 Hz, 1H), 7,39 (DD, J=2,8 Hz, 1H), 7,30-to 7.15 (m, 2H), 6,80 (DD, J=2,8 Hz, 1H), 5,41-and 5.30 (m, 1H), 5,15 is 5.07 (m, 1H), 4,10-a 4.03 (m, 2H), 3,90-of 3.80 (m, 1H), 3,70-of 3.27 (m, 5H), 2,07 is 1.91 (m, 2H), 1,87-1,72 (m, 2H).

Getting 17

tert-Butyl 4-[(5-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 5-chloro-2-hydroxypyridine in the same way as in obtaining 13.

1H-NMR (300 MHz, CDCl3) δ of 8.06 (d, J=2 Hz, 1H), 7,51 (DD, J=2,8 Hz, 1H), to 6.67 (d, J=8 Hz, 1H), 5,20-5,10 (m, 1H), 3,83-3,70 (m, 2H), 3.33 and-3,20 (m, 2H), 2,02-1,90 (m, 2H), 1.77 in-of 1.64 (m, 2H), 1,47 (s, 9H).

Example 21

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(5-chloro-2-pyridyl)-oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 582 (M+1)

1H-NMR (300 M is C, CDCl3) δ 8,55 (d, J=5 Hz, 1H), with 8.05 (d, J=2 Hz, 1H), 7,98 (Sirs, 1H), of 7.90 (d, J=8 Hz, 1H), 7,63 (DD, J=2,16 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,52 (DD, J=2,8 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,28-7,14 (m, 2H), 6,66 (DD, J=2,8 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,27-5,17 (m, 1H), 5,06 is equal to 4.97 (m, 1H), 4,06-3,98 (m, 2H), 3,90 of 3.75 (m, 1H), 3,70-3,20 (m, 5H), 2,03 is 1.70 (m, 4H).

Example 22

5-Chloro-N-[(1S)-2-[(2-{4-[(5-chloro-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 596 (M+1)

1H-NMR (300 MHz, CDCl3) δ is 8.75 (d, J=8 Hz, 1H), to 8.62 (d, J=5 Hz, 1H), 8.17-a of 8.09 (m, 1H), with 8.05 (d, J=2 Hz, 1H), 7,69-of 7.60 (m, 2H), 7,52 (DD, J=2,8 Hz, 1H), 7,49 (d, J=8 Hz, 1H), 7,41 (d, J=8 Hz, 1H), 7,39 (DD, J=2,8 Hz, 1H), 7,30-7,17 (m, 2H), to 6.67 (DD, J=2,8 Hz, 1H), 5,27-5,17 (m, 1H), 5,16 is 5.07 (m, 1H), 4,10-was 4.02 (m, 2H), 3,90 is 3.76 (m, 1H), 3,65-of 3.43 (m, 3H), 3,39-3,26 (m, 2H), 2.05 is-to 1.87 (m, 2H), 1.85 to to 1.70 (m, 2H).

Getting 18

tert-Butyl-4-phenoxy-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and phenol in the same manner as in obtaining 13.

1H-NMR (300 MHz, CDCl3) δ 7,32-7,20 (m, 2H), 6,98-to 6.80 (m, 3H), 4,50-to 4.41 (m, 1H), 3.75 to to 3.64 (m, 2H), 3,39-of 3.27 (m, 2H), 1,99-of 1.66 (m, 4H), of 1.47 (s, 9H).

Example 23

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-phenoxy-1-piperid the Nile)ethyl]amino}-1-(2-pyridylmethyl)ethyl]-acrylamide

Specified in the title compound is obtained from tert-butyl 4-phenoxy-1 piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 547 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,05-of 7.82 (m, 2H), 7.62mm (DD, J=2,16 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,12-7,38 (m, 6H), of 6.96 (DD, J=8,8 Hz, 1H), make 6.90 (d, J=8 Hz, 2H), of 6.49 (DD, J=2,16 Hz, 1H), 5,06 is equal to 4.97 (m, 1H), 4,60-4,50 (m, 1H), 4,06-to 3.99 (m, 2H), 3,81-to 3.52 (m, 3H), 3,48-3,20 (m, 3H), 1,90-to 1.79 (m, 4H)Primer 24

5-Chloro-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-phenoxy-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-phenoxy-1 piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 561 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,84-8,69 (m, 1H), 8,61 (d, J=5 Hz, 1H), 8,19-8,08 (m, 1H), to 7.67-of 7.60 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,41 (d, J=8 Hz, 1H), 7,38 (DD, J=2,8 Hz, 1H), 7,32-to 7.15 (m, 4H), of 6.96 (dd, J=8,8 Hz, 1H), make 6.90 (d, J=8 Hz, 2H), 5,15-of 5.06 (m, 1H), br4.61-4,51 (m, 1H), 4.09 to as 4.02 (m, 2H), 3,80-3,44 (m, 4H), 3,40 of 3.28 (m, 2H), 1,92 and 1.80 (m, 4H).

Getting 19

tert-Butyl-4-(2,2,2-triptoreline)-1-piperidinecarboxylate

To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (30.0 g), 2,2,2-triptoreline (149 g) and triphenylphosphine (58,6 g) in tetrahydrofuran (450 ml) slowly at 8°add diet azodicarboxylate (38,9 g). The mixture is stirred at room temperature for 2 hours and at 60°C for 8 hours. The reaction mixture was concentrated in vacuo, receiving the raw product specified in the connection header. The raw product is purified by chromatography on silica gel.

1H-NMR (300 MHz, CDCl3) δ 3,90-to 3.58 (m, 5H), 3,20-3,10 (m, 2H), 1,90-of 1.78 (m, 2H), 1,65 of 1.50 (m, 2H), of 1.46 (s, 9H)Primer 25

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2,2,2-triptoreline)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]acrylamide

Specified in the title compound is obtained from tert-butyl 4-(2,2,2-trithorax)-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]-amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 553 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,05-of 7.82 (m, 2H), 7.62mm (DD, J=2,16 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,34 (d, J=8 Hz, 2H), 7,28-7,13 (m, 2H), of 6.49 (DD, J=2,16 Hz, 1H), of 5.05-4.95 points (m, 1H), 4,10-to 3.92 (m, 2H), 3,90-3,63 (m, 4H), 3,60-to 3.35 (m, 3H), 3,30-and 3.16 (m, 2H), 1,88-of 1.56 (m, 4H).

Example 26

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2,2,2-triptoreline)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(2,2,2-triptoreline)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]-amino}acetic acid in the same manner as in PR is as 1.

ESI-MS: m/z 567 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,83-8,67 (m, 1H), 8,61 (d, J=5 Hz, 1H), 8,19-with 8.05 (m, 1H), 7,69-to 7.59 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,40 (d, J=8 Hz, 1H), 7,39 (DD, J=2,8 Hz, 1H), 7,30-7,16 (m, 2H), 5,15-of 5.05 (m, 1H), 4,12-of 3.94 (m, 2H), 3,90-to 3.64 (m, 4H), 3,60-of 3.42 (m, 3H), 3,39-3,17 (m, 2H), 1,90 is 1.58 (m, 4H).

20

tert-Butyl-4-isopropoxy-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 2-jumprope in the same way as in obtaining 7.

1H-NMR (300 MHz, CDCl3) δ a 3.87-to 3.73 (m, 2H), 3.75 to the 3.65 (m, 1H), 3,55 is-3.45 (m, 1H), 3,10-2,47 (m, 2H), 1.85 to of 1.40 (m, 4H), of 1.26 (s, 9H)and 1.15 (d, J=7 Hz, 6H).

Example 27

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-{[2-(4-isopropoxy-1-piperidinyl)-2-oxoethyl]amino}2-oxo-1-(2-pyridylmethyl)ethyl]-acrylamide

Specified in the title compound is obtained from tert-butyl 4-isopropoxy-1 piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 513 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,01-7,81 (m, 2H), 7,66-of 7.55 (m, 2H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,14-7,27 (m, 2H), of 6.49 (DD, J=2,16 Hz, 1H), of 5.05-equal to 4.97 (m, 1H), 4.04 the-of 3.96 (m, 2H), 3,90-of 3.31 (m, 6H), 3,29-3,10 (m, 2H), 1,82-of 1.45 (m, 4H), to 1.14 (d, J=7 Hz, 6H).

Example 28

5-Chloro-N-[(1S)-2-{[2-(4-isopropoxy-1-piperidinyl)-2-oxoethyl]amino}-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-and is propoxy-1 piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same way, as in example 1.

ESI-MS: m/z 527 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,83-8,68 (m, 1H), 8,61 (d, J=5 Hz, 1H), 8,15-with 8.05 (m, 1H), 7.68 per-of 7.60 (m, 2H), of 7.48 (d, J=8 Hz, 1H), 7,44-7,35 (m, 2H), 7,30-to 7.15 (m, 2H), 5,15-of 5.05 (m, 1H), 4,06-4,00 (m, 2H), 3,89 of 3.75 (m, 1H), 3,78 of 3.28 (m, 6H), 3,23-3,10 (m, 1H), 1,82-of 1.45 (m, 4H), to 1.14 (d, J=7 Hz, 6H).

Getting 21

tert-Butyl-4-butoxy-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 1-iodobutane in the same way as in obtaining 7.

1H-NMR (300 MHz, CDCl3) δ 3,82-3,70 (m, 2H), 3,48-to 3.36 (m, 3H), 3,12-3,00 (m, 2H), 1,87 to 1.76 (m, 2H), of 1.46 (s, 9H), 1.60-to of 1.30 (m, 4H), 0,98-0,80 (m, 5H).

Example 29

(2E)-N-[(1S)-2-{[2-(4-Butoxy-1-piperidinyl)-2-oxoethyl]-amino}-2-oxo-1-(2-pyridylmethyl)ethyl]-3-(4-chlorophenyl)acrylamide

Specified in the title compound is obtained from tert-butyl 4-butoxy-1 piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 527 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,55 (d, J=5 Hz, 1H), 8,01-of 7.82 (m, 2H), 7.62mm (DD, J=2,16 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,32-7,14 (m, 2H), of 6.49 (DD, J=2,16 Hz, 1H), of 5.05-4.95 points (m, 1H), 4,05-3,95 (m, 2H), 3,84 at 3.69 (m, 1H), 3,59-3,11 (m, 8H), 1,84 is 1.70 (m, 2H), 1,44-of 1.29 (m, 4H), of 0.91 (t, J=7 Hz, 3H).

Example 30

N-[(1S)-2-{[2-(4-Butoxy-1-piperidinyl)-2-oxoethyl]amino}-2-oxo-1-(2-pyridylmethyl)ethyl]-5-chloro-1-benzofuran-2-carboxamide

Specified in the header connection on ucaut of tert-butyl-4-butoxy-1 piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same way, as in example 1.

ESI-MS: m/z 541 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,87-8,55 (m, 2H), 8.17-a of 8.04 (m, 1H), 7,71-to 7.59 (m, 2H), 7,51-to 7.15 (m, 5H), 5,15-5,04 (m, 1H), 4,07-to 3.99 (m, 2H), 3,83 at 3.69 (m, 1H), 3,60-of 3.27 (m, 7H), 3,24-3,11 (m, 1H), 1.85 to about 1.47 (m, 6H), 1,44-1,29 (m, 2H), of 0.91 (t, J=7 Hz, 3H).

Getting 22

tert-Butyl 4-[(6-[chloro-2-pyrazinyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 2,6-dichloropyrazine in the same way as in obtaining 8.

ESI-MS: 314,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,13 (s, 1H), 8,10 (s, 1H), total of 5.21 (Sept., J=4 Hz, 1H), 3,82-3,70 (m, 2H), 3,32 (DDD, J=14,9,4 Hz, 2H), 2.05 is-of 1.93 (m, 2H), 1,82 by 1.68 (m, 2H), to 1.48 (s, 9H).

Example 31

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(6-chloro-2-pyrazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-2-pyrazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 583,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), 8,16 (s, 1H), 8,11 (d, J=1.5 Hz, 1H), 8,02 (s, 1H), of 7.96-7,89 (m, 1H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=9 Hz, 2H), 7,35 (d, J=9 Hz, 2H), 7,26 (d, J=8 Hz, 1H), 7,19 (DD, J=8.5 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,33-5,22 (m, 1H), 5,07-4,99 (m, 1H), 4,05 (apparent d, J=4 Hz, 2H), 3,92 is 3.76 (m, 1H), 3,67-3,51 (m, 2H), 3,48-is 3.21 (m, 3H), 2.06 to of 1.92 (m, 2H), 1,88-of 1.73 (m, 2H)Primer 32

5-Chloro-N-[(1S)-2-[(2-{4-[(6-the ENT-2-pyrazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-2-pyrazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 597,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81 is 8.75 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,20-of 8.09 (m, 3H), of 7.65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,43 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 5,33-5,23 (m, 1H), 5,16 is 5.07 (m, 1H), 4,07 (apparent d, J=4 Hz, 2H), 3,91 is 3.76 (m, 1H), 3,67 of 3.28 (m, 5H), 2,07 is 1.91 (m, 2H), 1,89-1,72 (m, 2H).

23

tert-Butyl 4-[(6-chloro-3-pyridazinyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 3.6-dichloropyridazine in the same way as in obtaining 8.

ESI-MS: 314,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 7,38 (d, J=9 Hz, 1H), 6,94 (d, J=9 Hz, 1H), 5,44 (Sept., J=4 Hz, 1H), a 3.87-to 3.73 (SIRM, 2H), 3,26 (DDD, J=14,9,4 Hz, 2H), 2,13-2,02 (m, 2H), 1,83-to 1.67 (m, 2H), to 1.48 (s, 9H).

Example 33

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(6-chloro-3-pyridazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-3-pyridazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 583,2 (M+is)

1H-NMR (300 MHz, CDCl3) δ 8,51-8,46 (m, 2H), 8,15-8,08 (m, 1H), 7,82 for 7.78 (m, 1H), 7,69 (TD, J=8,2 Hz, 1H), 7,56 (d, J=9 Hz, 2H), 7,47 (d, J=9 Hz, 2H), 7,39-7,29 (m, 3H), 7,20 (DD, J=8.5 Hz, 1H), of 6.68 (d, J=16 Hz, 1H), 5,43-5,32 (m, 1H), 5,00-of 4.90 (m, 1H), 4.04 the-of 3.97 (m, 2H), 3.95 to a-3.84 (m, 1H), of 3.73-3,62 (m, 1H), 3,41-up 3.22 (m, 3H), 3,07-2,96 (m, 1H), 2,14-of 1.95 (m, 2H), 1,80-of 1.53 (m, 2H).

Example 34

5-Chloro-N-[(1S)-2-[(2-{4-[(6-chloro-3-pyridazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-3-pyridazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 597,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,84-to 8.70 (m, 1H), 8,65 at 8.60 (m, 1H), 7,69-to 7.61 (m, 2H), 7,52-7,46 (m, 1H), 7,44 and 7.36 (m, 3H), 7,30-7,25 (m, 1H), 7.23 percent-to 7.18 (m, 1H), 6,97-6,91 (m, 1H), 5,54-5,43 (m, 1H), 5,16 is 5.07 (m, 1H), 4,11-a 4.03 (m, 2H), was 4.02-to 3.89 (m, 1H), 3,68 of 3.56 (m, 1H), 3,53-3,26 (m, 4H), 2,17-2,00 (m, 2H), 1,89-of 1.73 (m, 2H).

Getting 24

tert-Butyl 4-[(6-methoxy-3-pyridazinyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 3-chloro-6-methoxypyridazine in the same way as in obtaining 7.

ESI-MS: 310,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ of 6.96-to 6.88 (m, 2H), 5,31 (TT, J=8,4 Hz, 1H), Android 4.04 (s, 3H), 3,89-3,75 (SIRM, 2H), up 3.22 (DDD, J=14,8,4 Hz, 2H), 2.13 and is 2.01 (m, 2H), 1,81-of 1.66 (m, 2H), 1,47 (s, 9H).

Example 35

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2[(2-{4-[(6-methoxy-3-pyridazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(6-methoxy-3-pyridazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 579,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), 8,06-to 7.84 (m, 2H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,26 (d, J=8 Hz, 1H), 7,18 (DD, J=8.5 Hz, 1H), 6,97-6,86 (m, 2H), 6,50 (d, J=16 Hz, 1H), 5,42-5,31 (m, 1H), 5,06-to 4.98 (m, 1H), 4,06-to 3.89 (m, 3H), Android 4.04 (s, 3H), 3,66 of 3.56 (m, 1H), 3,51-to 3.36 (m, 2H), 3,35-3,20 (m, 2H), 2,16 is 2.00 (m, 2H), 1,87-1,72 (m, 2H).

Example 36

5-Chloro-N-[(1S)-2-[(2-{4-[(6-methoxy-3-pyridazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(6-methoxy-3-pyridazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 593,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81-8,71 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,20-8,10 (m, 2H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 6,97-6,87 (m, 2H), 5,42-5,32 (m, 1H), 5,16-5,08 (m, 1H), 4,07 (apparent d, J=4 Hz, 2H), Android 4.04 (s, 3H), 4,01-3,90 (m, 1H), 3,67 is 3.57 (m, 1H), 3,53 is 3.25 (m, 4H), 2,17-2,00 (m, 2H), 1,87-1,73 (m, 2H).

Receive 25

tert-Butyl 4-[(3-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 2,3-dichloropyridine in the same way, both get 7.

ESI-MS: 313,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,02 (DD, J=5,2 Hz, 1H), 7,63 (DD, J=8,2 Hz, 1H), 6,83 (DD, J=8.5 Hz, 1H), 5,32 (TT, J=8,4 Hz, 1H), 3,71 (DDD, J=14,8,4 Hz, 2H), 3,41 (DDD, J=14,8,4 Hz, 2H), 2,02-1,89 (m, 2H), 1,87-of 1.74 (m, 2H), to 1.48 (s, 9H).

Example 37

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(3-chloro-2-pyridyl)-oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(3-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 582,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), 8,06-7,86 (m, 3H), 7.68 per-EUR 7.57 (m, 3H), 7,46 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,29-of 7.23 (m, 1H), 7,18 (DD, J=8.5 Hz, 1H), 6,85 (DD, J=8.5 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,44-of 5.34 (m, 1H), 5.08 to 4,99 (m, 1H), 4,14-3,95 (m, 2H), 3,85-of 3.54 (m, 3H), 3,49-3,20 (m, 3H), 2,01 and 1.80 (m, 4H).

Example 38

5-Chloro-N-[(1S)-2-[(2-{4-[(3-chloro-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(3-chloro-2-pyridyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 596,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,86-8,71 (m, 1H), 8,63 (DD, J=5,2 Hz, 1H), 8,21-of 8.09 (m, 1H), 8,02 (DD, J=5,2 Hz, 1H), 7,70-7,60 (who, 3H), 7,50 (d, J=9 Hz, 1H), 7,43 (s, 1H), 7,40 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 6,86 (DD, J=8.5 Hz, 1H), 5,44 and 5.36 (m, 1H), 5,17-5,08 (m, 1H), 4,15-4,00 (m, 2H), 3,85-3,56 (m, 3H), 3,55 of 3.28 (m, 3H), 2.00 in is 1.81 (m, 2H), 1,65-of 1.56 (m, 2H).

Getting 26

tert-Butyl 4-[(6-chloro-4-pyrimidinyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 4.6-dichloropyrimidine in the same way as in obtaining 7.

ESI-MS: 314,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (s, 1H), 6,76 (s, 1H), 5,31 (TT, J=8,4 Hz, 1H), 3,84-3,70 (m, 2H), 3,29 (DDD, J=14,8,4 Hz, 2H), 2.05 is-of 1.93 (m, 2H), 1,81-of 1.66 (m, 2H), 1,47 (s, 9H).

Example 39

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(6-chloro-4-pyrimidinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-4-pyrimidinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 583,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,57-8,56 (m, 1H), 8,55 (s, 1H), 8,05-to 7.99 (m, 1H), of 7.96-7,89 (m, 1H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=9 Hz, 2H), of 7.96-7,89 (m, 1H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=9 Hz, 2H), 7,35 (d, J=9 Hz, 2H), 7,26 (d, J=8 Hz, 1H), 7,19 (DD, J=8.5 Hz, 1H), 6,76 (apparent d, J=2 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,42-5,32 (m, 1H), 5,07-to 4.98 (m, 1H), 4,05 (d, J=4 Hz, 2H), 3,93-of 3.77 (m, 1H), 3,65-3,47 (m, 2H), 3,47-is 3.21 (m, 3H), 2,07 is 1.91 (m, 2H), 1,87-1,71 (m, 2H).

Example 40

-Chloro-N-[(1S)-2-[(2-{4-[(6-chloro-4-pyrimidinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(6-chloro-4-pyrimidinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 597,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81-a total of 8.74 (m, 1H), 8,63 (DD, J=5,2 Hz, 1H), 8,56 (s, 1H), 8,17 (Sirs, 1H), 7,66 (TD, J=8,2 Hz, 1H), 7,66 (d, J=2 Hz, 1H), 7,50 (d, J=9 Hz, 1H), 7,43 (s, 1H), 7,40 (DD, J=9,2 Hz, 1H), 7,29 (d, J=8 Hz, 1H), 7,22 (DD, J=8.5 Hz, 1H), 6,77 (apparent d, J=2 Hz, 1H), 5,44-5,33 (m, 1H), 5,16-5,08 (m, 1H), 4.09 to (apparent d, 2H), 3,92-of 3.78 (m, 1H), 3,67-3,44 (m, 3H), 3,41-3,29 (m, 2H), 2,08-of 1.92 (m, 2H), 1,88-1,72 (m, 2H).

Getting 27

tert-Butyl 4-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 6-(trifluoromethyl)-4-pyrimidinone in the same way as in obtaining 13.

ESI-MS: 348,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,86 (s, 1H), 7,06 (s, 1H), 5,39 (TT, J=8,4 Hz, 1H), 3,85-and 3.72 (m, 2H), 3,30 (DDD, J=14,8,4 Hz, 2H), 2,08-of 1.95 (m, 2H), 1,84 by 1.68 (m, 2H), to 1.48 (s, 9H).

Example 41

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}of the criminal code is usnei acid in the same way, as in example 1.

ESI-MS: 617,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,86 (s, 1H), to 8.57 (DD, J=5,2 Hz, 1H), 8,08 shed 8.01 (m, 1H), 7,98-7,89 (m, 1H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=9 Hz, 2H), 7,35 (d, J=9 Hz, 2H), 7,27 (d, J=8 Hz, 1H), 7,19 (DD, J=8.5 Hz, 1H), 7,07 (s, 1H), 6,50 (d, J=16 Hz, 1H), 5,51-5,41, (m, 1H), 5,06-to 4.98 (m, 1H), 4,05 (d, J=4 Hz, 2H), 3.96 points-of 3.80 (m, 1H), 3,68-to 3.50 (m, 2H), 3,50-is 3.21 (m, 3H), 2,10-of 1.95 (m, 2H), 1,90-of 1.74 (m, 2H).

Example 42

5-Chloro-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)-ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 631,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,86 (s, 1H), 8,84 is 8.75 (m, 1H), 8,63 (DD, J=5,2 Hz, 1H), 8,20 (Sirs, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (DD, J=9.1 Hz, 1H), 7,43 (d, J=1 Hz, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 7,07 (s, 1H), 5,52-5,41 (m, 1H), 5,16 is 5.07 (m, 1H), 4.09 to (apparent d, J=4 Hz, 2H), 3.95 to of 3.80 (m, 1H), 3,69 is-3.45 (m, 3H), 3,42-3,30 (m, 2H), 2,11-of 1.95 (m, 2H), 1,90-of 1.75 (m, 2H).

Getting 28

tert-Butyl 4-{[2-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 4-hydroxy-2-(trifluoromethyl)-pyrimidine in the same way as in obtaining 13.

ESI-is From: 348,3 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (d, J=6 Hz, 1H), 6,86 (d, J=6 Hz, 1H), 5,39 (TT, J=8,4 Hz, 1H), 3,83-3,71 (m, 2H), 3.33 and (DDD, J=14,8,4 Hz, 2H), 2,08 is 1.96 (m, 2H), 1,84 by 1.68 (m, 2H), to 1.48 (s, 9H).

Example 43

5-Chloro-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[2-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)-ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-{[2-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 631,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,84-a total of 8.74 (m, 1H), 8,63 (DD, J=5,2 Hz, 1H), 8,58 (d, J=6 Hz, 1H), 8,24-to 8.14 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,43 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 6.87 in (d, J=6 Hz, 1H), 5,51-5,41 (m, 1H), 5,16-5,08 (m, 1H), 4,08 (apparent d, 2H), 3,94-of 3.80 (m, 1H), 3,68-3,44 (m, 3H), 3,44 be 3.29 (m, 2H), 2,11-of 1.95 (m, 2H), 1,90-of 1.74 (m, 2H).

Getting 29

tert-Butyl 4-[(5-chloro-2-pyrazinyl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 5-chloro-2-pyrazinone in the same way as in 13. 5-chloro-2-pyrazino receive in accordance with the method described in J. Org. Chem. 29, 2491-2492 (1964).

ESI-MS: 314,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,07 (d, J=1 Hz, 1H), to 7.99 (d, J=1 Hz, 1H), 5,14 (TT, J=8,4 Hz, 1H), 3,83-3,70 (m, 2H), 3,29 (DDD, J=14,8,4 Hz, 2H), 2,031,91 (m, 2H), 1,66 and 1.80 (m, 2H), to 1.48 (s, 9H).

Example 44

5-Chloro-N-[(1S)-2-[(2-{4-[(5-chloro-2-pyrazinyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-2-pyrazinyl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 597,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,82-8,72 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,21-8,13 (m, 1H), of 8.06 (s, 1H), to 7.99 (s, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 5,26-5,16 (m, 1H), 5,15 is 5.07 (m, 1H), 4,08 (apparent d, 2H), 3,90 of 3.75 (m, 1H), 3,67-of 3.43 (m, 3H), 3,40 of 3.28 (m, 2H), 2.06 to 1,90 (m, 2H), 1,87-1,71 (m, 2H).

30

2-Bromo-5-methyl-1,3-thiazole

To a solution of 2-amino-5-methyl-1,3-thiazole (11,7 g) in acetonitrile (200 ml) dropwise at 0°add tert-butylnitrite (8,33 ml) followed by the addition of copper bromide(II) (5 g) for 5 minutes. After stirring at 0°C for 3 hours the mixture is concentrated and separated between 1 N. hydrochloric acid and ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered through a layer of celite and concentrated in vacuo, obtaining specified in the header link is (3,24 g) in the form of oil.

ESI-MS: OF 177.8 (M+N)

1H-NMR (300 MHz, CDCl3) δ to 7.25 (s, 1H), 2,44 (s, 3H).

Getting 31

tert-Butyl 4-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 2-bromo-5-methyl-1,3-thiazole in the same manner as in obtaining 7.

ESI-MS: 299,3 (M+N)1H-NMR (300 MHz, CDCl3) δ 6,74 (s, 1H), 5,06 (TT, J=8,4 Hz, 1H), 3,78-3,66 (m, 2H), 3,30 (DDD, J=14,8,4 Hz, 2H), 2,31 (s, 3H), 2.06 to 1,95 (m, 2H), 1.85 to 1,72 (m, 2H), 1,47 (s, 9H).

Example 45

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 568,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (DD, J=5,2 Hz, 1H), 8,04-of 7.97 (m, 1H), of 7.96-7,87 (m, 1H), 7,63 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,34 (d, J=8 Hz, 2H), 7,25 (d, J=8 Hz, 1H), 7,18 (DD, J=8,5 Hz, 1H), 6.73 x (apparent s, 1H), 6,50 (d, J=16 Hz, 1H), 5,13 (Sirs, 1H), 5,06-to 4.98 (m, 1H), 4,03 (apparent d, J=4 Hz, 2H), 3,83-to 3.49 (m, 3H), of 3.43 (DD, J=15,5 Hz, 1H), 3,37-3,20 (m, 2H), 2,31 (d, J=1 Hz, 3H), 2.05 is-to 1.79 (m, 4H).

Example 46

5-Chloro-N-[(1S)-2-[(2-{4-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

The criminal code is mentioned in the title compound is obtained from tert-butyl 4-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same way, as in example 1.

ESI-MS: 582,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81-8,73 (m, 1H), 8,63 (DD, J=5,2 Hz, 1H), 8,19-8,11 (m, 1H), 7,66 (TD, J=8,2 Hz, 1H), 7,66 (d, J=2 Hz, 1H), 7,50 (d, J=9 Hz, 1H), 7,43 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 7,43 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 6.75 in-of 6.71 (m, 1H), 5,19 is 5.07 (m, 2H), 4,07 (apparent d, J=4 Hz, 2H), 3,81-3,44 (m, 4H), 3,39-3,27 (m, 2H), 2,31 (d, J=1 Hz, 3H), 2,07-of 1.78 (m, 4H).

Getting 32

tert-Butyl 4-[(5-chloro-1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate

To a solution of tert-butyl 4-[(1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate (8.0 g) in acetic acid (80 ml) was added dropwise N-chlorosuccinimide (4.5 g). The mixture is heated to 60-70°C and stirred for 5 hours. The resulting mixture was poured into a mixture of ice (80 g) and water (80 ml) and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue is dissolved in ethyl acetate. The solution turned into basically, applying a solution of 1 n sodium hydroxide. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified column chromatography on silica gel (eluent; 9% ethyl acetate in n-hexane), receiving specified in the header connection (5,56 g) as white crystals.

ESI-MS: spreads for about 319.2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 6,93 (s, 1H), 5,11 (TT, J=8,4 Hz, 1H), 3,79-3,63 (m, 2H), and 3.31 (DDD, J=14,8,4 Hz, 2H), 2,07-of 1.94 (m, 2H), 1,87-1,72 (m, 2H), 1,47 (s, 9H).

Example 47

2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(5-chloro-1,3-thiazol-2-yl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 588,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (DD, J=5,2 Hz, 1H), 8,06-7,98 (m, 1H), 7.95 is-7,88 (m, 1H), 7,63 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,46 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,25 (d, J=8 Hz, 1H), 7,18 (DD, J=8,5 Hz, 1H), 6,92 (s, 1H), 6,50 (d, J=16 Hz, 1H), 5,23-5,13 (m, 1H), of 5.05-equal to 4.97 (m, 1H), 4,03 (apparent d, J=4 Hz, 2H), 3,83-to 3.49 (m, 3H), 3,48-3,20 (m, 3H), 2.06 to of 1.78 (m, 4H).

Example 48

5-Chloro-N-[(1S)-2-[(2-{4-[(5-chloro-1,3-thiazol-2-yl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-1,3-thiazol-2-yl)oxy]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 602,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81-8,73 (m, 1H), 8,63 (DD, J=5,2 Hz, 1H), 8,21-8,13 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 6,92 (s, 1H), 5,23-of 5.06 (m, 2H), 4,06 (apparent d, J=4 Hz, 2H), 3,81-of 3.43 (m, 4H), 3,40-of 3.27 (m, 2H), 2.06 to of 1.78 (m, 4H).

Receive 33

tert-Butyl(3R)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinecarboxylic

Specified in the title compound is obtained from tert-butyl(3R)3-hydroxy-1-pyrrolidinecarboxylic and 2,4-dichloropyridine in the same way, both get 7.

ESI-MS: 299,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,08 (s, 1H), 7,53 (d, J=9 Hz, 1H), 6,69 (d, J=9 Hz, 1H), 5,49 (Sirs, 1H), 3,71 is 3.40 (m, 4H), 2,14 (Sirs, 2H), 1,47 (s, 9H).

Example 49

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{(3R)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl(3R)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 568,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,58 are 8.53 (m, 1H), 8,08-with 8.05 (m, 1H), 8,03-7,98 (m, 1H), of 7.90-7,83 (m, 1H), 7,66 is 7.50 (m, 3H), 7,45 (d, J=8 Hz, 2H), 7,34 (d, J=8 Hz, 2H), 7,28-7,22 (m, 1H), 7,21-7,14 (m, 1H), 6,69-of 6.61 (m, 1H), of 6.49 (d, J=16 Hz, 1H), 5,58-5,49 (m, 1H), 5,06 is equal to 4.97 (m, 1H), 3,99 (d, J=4 Hz, 1H), 3,91 (d, J=4 Hz, 1H), 3,83-3,51 (m, 4H), 3.46 in-3,37 (m, 1H), 3,30-is 3.21 (m, 1H), 2,34-to 2.06 (m, 2H).

Example 50

5-Chloro-N-[(1S)-2-[(2-{(3R)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl(3R)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 582,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,75-8,69 (m, 1H), 8,69-8,65 (m, 1H), 8,21-to 8.14 (m, 1H), 8,08-of 8.04 (m, 1H), 7.68 per-of 7.60 (m, 2H), EUR 7.57 was 7.45 (m, 2), 7,43-7,35 (m, 2H), 7,30-7,16 (m, 2H), 6,69-6,62 (m, 1H), 5,58-5,49 (m, 1H), 5,15-of 5.06 (m, 1H), was 4.02 (d, J=4 Hz, 1H), 3,94 (d, J=4 Hz, 1H), 3,84 of 3.28 (m, 6H), 2,35-2,07 (m, 2H).

Getting 34

tert-Butyl(3S)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinecarboxylic

Specified in the title compound is obtained from tert-butyl(3S)-3-hydroxy-1-pyrrolidinecarboxylic and 5-chloro-2-pyridinol in the same way as in obtaining 13.

ESI-MS: 299,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,08 (s, 1H), 7,53, J=9 Hz, 1H), of 6.68 (d, J=9 Hz, 1H), 5,48 (Sirs, 1H), 3,69-of 3.42 (m, 4H), 2,14 (Sirs, 2H), of 1.46 (s, 9H).

Example 51

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{(3S)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl(3S)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 568,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,60-8,51 (m, 1H), 8,11-to 7.95 (m, 2H), 7,93-to 7.84 (m, 1H), 7.68 per-7,40 (m, 5H), 7,39 for 7.12 (m, 4H), 6,70-of 6.61 (m, 1H), 6,55-to 6.43 (m, 1H), 5,59-vs. 5.47 (m, 1H), 5,07-of 4.95 (m, 1H), 4.04 the-3,88 (m, 1H), 3,86-3,18 (m, 6H), 2,38-2,02 (m, 2H).

Example 52

5-Chloro-N-[(1S)-2-[(2-{(3S)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl(3S)-3-[(5-chloro-2-pyridyl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(5-chloro-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same way, as in example 1.

ESI-MS: 582,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,77-8,71 (m, 1H), 8,64-8,59 (m, 1H), 8,21-to 8.12 (m, 1H), 8,08-of 8.04 (m, 1H), 7.68 per-of 7.60 (m, 2H), 7,56 was 7.45 (m, 2H), 7,41 (s, 1H), 7,38 (DD, J=9,2 Hz, 1H), 7,30-of 7.23 (m, 1H), 7,22-7,16 (m, 1H), 6,65 (d, J=9 Hz, 1H), 5,58-5,49 (m, 1H), 5,15 is 5.07 (m, 1H), was 4.02 (d, J=4 Hz, 1H), 3,94 (d, J=4 Hz, 1H), 3,84-of 3.42 (m, 5H), to 3.33 (DD, J=15.6 Hz, 1H), 2,36-2,07 (m, 2H).

Receive 35

tert-Butyl(3R)-3-[(6-chloro-2-pyrazinyl)oxy]-1-pyrrolidinecarboxylic

Specified in the title compound is obtained from tert-butyl(3R)-3-hydroxy-1-pyrrolidinecarboxylic and 2,6-dichloropyrazine in the same way as in obtaining 7.

1H-NMR (300 MHz, CDCl3) δ 8,17 (s, 1H), 7,12 (s, 1H), 5,54 (Sirs, 1H), of 3.73-of 3.43 (m, 4H), 2.26 and-a 2.12 (m, 2H), to 1.48 (s, 9H)Primer 53

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{(3R)-3-[(6-chloro-2-pyrazinyl)oxy]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl(3R)-3-[(6-chloro-2-pyrazinyl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 569,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,59 are 8.53 (m, 1H), they were 8.22-of 8.00 (m, 3H), to $ 7.91-to 7.84 (m, 1H), to 7.67-7,56 (m, 2H), 7,46 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,29-7,24 (m, 1H), 7,22-7,14 (m, 1H), of 6.49 (d, J=16 Hz, 1H), 5,65-of 5.53 (m, 1H), 5,07 is equal to 4.97 (m, 1H), was 4.02 (d, J=4 Hz, 1H), 3,94 (d, J=4 Hz, 1H), 3,88-of 3.54 (m, 4H), 3,47-to 3.36 (m, 1H), 3,31-is 3.21 (m, 1H), 2,39-2,12 (m, 2H).

Example 54

5-Chloro-N-[(1S)-2-[(2-{(3R)-3-[(6-chloro-2-pyrazinyl)is XI]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl(3R)-3-[(6-chloro-2-pyrazinyl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 583,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,68 at 8.60 (m, 2H), at 8.36-of 8.28 (m, 1H), 8,21-8,10 (m, 2H), to 7.77-of 7.69 (m, 1H), 7,65-7,63 (m, 1H), 7,50 was 7.45 (m, 1H), 7,42-7,24 (m, 4H), 5,65 is 5.54 (m, 1H), 5,20-5,11 (m, 1H), 4.09 to as 4.02 (m, 1H), 4,01-3,95, (m, 1H), 3,88-to 3.58 (m, 4H), 3,51-3,44 (m, 2H), 2,38 is 2.10 (m, 2H).

Getting 36

tert-Butyl(3R)-3-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-pyrrolidinecarboxylic

Specified in the title compound is obtained from tert-butyl(3R)-3-hydroxy-1-pyrrolidinecarboxylic and 2-bromo-5-methyl-1,3-thiazole in the same manner as in obtaining 7.

ESI-MS: 285,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ to 6.75 (s, 1H), 5,46-of 5.40 (m, 1H), of 3.77-to 3.38 (m, 4H), 2,31 (s, 3H), 2.40 a is 2.00 (m, 2H), 1,47 (s, 9H).

Example 55

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{(3R)-3-[(5-methyl-1,3-thiazol-2-yl]oxy}-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl(3R)-3-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 554,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,58-charged 8.52 (m, 1H), 8,06-to 7.95 (m, 1H), 7,93-7,80 (m, 1H), to 7.67-of 7.55 (m, 2H), 7,45 (d, J=8 Hz, 2H, 7,34 (d, J=8 Hz, 2H), 7,28-7,22 (m, 1H), 7,21-7,14 (m, 1H), 6,74 (s, 1H), of 6.49 (d, J=16 Hz, 1H), of 5.53-5,43 (m, 1H), 5,06 is equal to 4.97 (m, 1H), 4,01-3,90 (m, 2H), 3,79-3,19 (m, 6H), 2,33-2,03 (m, 5H).

Example 56

5-Chloro-N-[(1S)-2-[(2-{(3R)-3-[(5-methyl-1,3-thiazol-2-yl)-oxy]-1-pyrrolidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl(3R)-3-[(5-methyl-1,3-thiazol-2-yl)oxy]-1-pyrrolidinecarboxylic and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 568,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,77-8,67 (m, 1H), 8,64-8,59 (m, 1H), 8,23-8,13 (m, 1H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.64 (d, J=2 Hz, 1H), of 7.48 (d, J=9 Hz, 1H), 7,41 (s, 1H), 7,38 (DD, J=9,2 Hz, 1H), 7,30-7,24 (m, 1H), 7.23 percent-7,16 (m, 1H), 6,76-of 6.71 (m, 1H), of 5.53-5,43 (m, 1H), 5,15 is 5.07 (m, 1H), 4,05-to 3.99 (m, 1H), 3,98-3,93 (m, 1H), 3,79 of 3.28 (m, 6H), 2,33-2,05 (m, 5H).

Getting 37

tert-Butyl 3-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-azetidinone

Specified in the title compound is obtained from tert-butyl 3-hydroxy-1-apatitenephelite and 6-(trifluoromethyl)-4-pyrimidinone in the same way as in obtaining 13.

ESI-MS: 320,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,87 (s, 1H), 7,14 (s, 1H), 5,44 (TT, J=7,4 Hz, 1H), 4,37 (DD, J=10,7 Hz, 2H), 4,01 (DD, J=10.4 Hz, 2H), 1,45 (s, 9H).

Example 57

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-{[2-oxo-2-(3-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-azetidine)ethyl]amino}-1-(2-pyridylmethyl)ethyl]-2-propenamide

Ukazannoi the title compound is obtained from tert-butyl 3-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-apatitenephelite and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same way, as in example 1.

ESI-MS: 589,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,88 (s, 1H), 8,55 (DD, J=5,2 Hz, 1H), 8,06 (Sirs, 1H), to $ 7.91-to 7.84 (m, 1H), to 7.64 (TD, J=8,2 Hz, 1H), to 7.59 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,26 (d, J=8 Hz, 1H), 7,19 (DD, J=8.5 Hz, 1H), 7,15 (s, 1H), 6.48 in (d, J=16 Hz, 1H), 5,57-vs. 5.47 (m, 1H), of 5.05-4,96 (m, 1H), with 4.64 was 4.42 (m, 2H), 4,24-4,06 (m, 2H), 3,89 (apparent d, J=4 Hz, 2H), 3,41 (DD, J=15,5 Hz, 1H), 3,26 (DD, J=15.6 Hz, 1H).

Example 58

5-Chloro-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-azetidine)ethyl]amino}-1-(2-pyridylmethyl)-ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 3-{[6-(trifluoromethyl)-4-pyrimidinyl]oxy}-1-apatitenephelite and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 603,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,88 (s, 1H), total of 8.74-8,67 (m, 1H), 8,61 (DD, J=5,2 Hz, 1H), compared to 8.26 (Sirs, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,41 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,28 (d, J=8 Hz, 1H), 7,21 (DD, J=8.5 Hz, 1H), 7,15 (s, 1H), 5,58-of 5.48 (m, 1H), 5,14-of 5.05 (m, 1H), 4,65-4,55, (m, 1H), to 4.52-4,43 (m, 1H), 4,25-4,06 (m, 2H), 3,89 (apparent d, J=4 Hz, 2H), 3,47 (DD, J=to 15.4 Hz, 1H), 3.33 and (DD, J=15.7 Hz, 1H).

Getting 38

3,5-Dichloro-2-(4-piperidinyloxy)pyridinedimethanol

To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (0.5 g), 3,5-dichloro-2-pyridone (0,41 g) and triphenylphosphine (0,98 g) in tetrahydrofuran at 8°slowly add diethylazodicarboxylate is at (0.65 g), and the mixture is stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, obtaining the crude product.

To a solution of the crude product in methanol (5 ml) at 8°add 4 N. hydrogen chloride in ethyl acetate (6.2 ml). The mixture is stirred at room temperature for 1 hour and concentrated in vacuo. The residual solid is washed with ethyl acetate, getting mentioned in the title compound (585 g).

1H-NMR (300 MHz, CDCl3) δ to 7.99 (d, J=2 Hz, 1H), 7,68 (d, J=2 Hz, 1H), 5,45 lower than the 5.37 (m, 1H), 3.45 was to be 3.29 (m, 4H), 2,44 and 2.13 (m, 4H).

Example 59

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(3,5-dichloro-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

To a mixture of {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]-amino}-3-(2-pyridyl)propanol]amino}acetic acid (0,19 g), 3,5-dichloro-2-(4-piperidinyloxy)pyridinecarboxamide (0.16 g), 1-hydroxybenzotriazole (0,084 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.11 g) in N,N-dimethylformamide (2.5 ml) dropwise with 8°add N,N-diisopropylethylamine (0,27 ml). The mixture is heated to room temperature and stirred for 6 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous surfacematerial and concentrated in vacuo. The residue is purified column chromatography on silica gel, getting mentioned in the title compound (231 mg).

1H-NMR (300 MHz, CDCl3) δ 8,61 are 8.53 (m, 1H), 8.07-a a 7.85 (m, 3H), 7,70-EUR 7.57 (m, 3H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,30-to 7.15 (m, 2H), 6,51 (DD, J=2,15 Hz, 1H), 5,38 is 5.28 (m, 1H), 5,07-to 4.98 (m, 1H), 4,13-3,95 (m, 2H), 3,85-3,20 (m, 6H), 2.00 in to 1.79 (m, 4H).

ESI-MS: m/z 616 (M+1)Example 60

5-Chloro-N-[(1S)-2-[(2-{4-[(3,5-dichloro-2-pyridyl)oxy]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from 3,5-dichloro-2-(4-piperidinyloxy)pyridinecarboxamide and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 59.

ESI-MS: m/z 630 (M+1)

1H-NMR (300 MHz, CDCl3) δ cent to 8.85-to 8.70 (m, 1H), 8,67-8,59 (m, 1H), they were 8.22-8,10 (m, 1H), of 7.96 (d, J=2 Hz, 1H), 7,70-of 7.60 (m, 3H), 7,49 (d, J=8 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=8,2 Hz, 1H), 7,32-7,16 (m, 2H), 5,39 is 5.28 (m, 1H), 5,17-of 5.06 (m, 1H), 4,15-3,98 (m, 2H), 3,83 of 3.28 (m, 6H), 2,01-to 1.79 (m, 4H).

Getting 39

tert-Butyl 4-{[3-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 3-(trifluoromethyl)-2-hydroxypyridine in the same way as in obtaining 13.

1H-NMR (300 MHz, CDCl3) δ 8,33-8,24 (m, 1H), of 7.90-7,81 (m, 1H), 6,99-of 6.90 (m, 1H), 5,48-5,33 (m, 1H), 3,63-3,44 (m, 4H), 1,99-to 1.77 (m, 4H), of 1.47 (s, 9H).

Example 61

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-[2-oxo-2-(4-{[3-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-{[3-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 616 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,59 are 8.53 (m, 1H), 8,30 is 8.25 (m, 1H), 8,06-7,83 (m, 3H), 7,66-of 7.55 (m, 2H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,29-7,14 (m, 2H), 7,00-6,93 (m, 1H), 6,50 (DD, J=15.3 Hz, 1H), 5,55-of 5.45 (m, 1H), 5,06-to 4.98 (m, 1H), 4,14-3,90 (m, 3H), 3,60-to 3.35 (m, 4H), 3,30-3,20 (m, 1H), 2.00 in to 1.79 (m, 4H).

Example 62

5-Chloro-N-[(1S)-2-oxo-2-{[2-oxo-2-(4-{[3-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinyl)ethyl]amino}-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-{[3-(trifluoromethyl)-2-pyridyl]oxy}-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: m/z 630 (M+1)

1H-NMR (300 MHz, CDCl3) δ cent to 8.85-8,67 (m, 1H), to 8.62 (d, J=5 Hz, 1H), 8,28 (d, J=5 Hz, 1H), 8,20-8,07 (m, 1H), 7,86 (d, J=8 Hz, 1H), 7,69-to 7.59 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,42 (s, 1H), 7,38 (DD, J=8,2 Hz, 1H), 7,30-to 7.15 (m, 2H), 7,00-6,92 (m, 1H), 5,50 (Sirs, 1H), 5,16-of 5.05 (m, 1H), 4,16-to 3.89 (m, 3H), 3,61-of 3.27 (m, 5H), 2.00 in to 1.79 (m, 4H).

Receive 40

4-(4-Pertenece)piperidine

To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylate (2.0 g), 4-terfenol (1.1 g) and triphenylphosphine (3.9 g) in tetrahydrofuran at 8°slowly DOB is given in diethylazodicarboxylate (2.6 g) and the mixture is stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, obtaining the crude product.

To a solution of the crude product in ethyl acetate (5 ml) and methanol (5 ml) at 8°add 4 N. hydrogen chloride in ethyl acetate (25 ml). The mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo, obtaining mentioned in the title compound (1.08 g).

Example 63

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-({2-[4-(4-pertenece)-1-piperidinyl]-2-oxoethyl}amino)-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from 4-(4-pertenece)of piperidine and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same manner as in example 59.

ESI-MS: m/z 565 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,60 are 8.53 (m, 1H), 8.07-a a 7.85 (2H, m), 7.68 per-7,56 (m, 2H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,31-to 7.15 (m, 2H),? 7.04 baby mortality-6,93 (m, 2H), 6.90 to-to 6.80 (m, 2H), 6,50 (DD, J=15.2 Hz, 1H), 5,06 is equal to 4.97 (m, 1H), 4,50-and 4.40 (m, 1H), 4,11-3,95 (m, 2H), 3,79-3,20 (m, 6H), 1,94 is 1.75 (m, 4H).

Example 64

5-Chloro-N-[(1S)-2-({2-[4-(4-pertenece)-1-piperidinyl]-2-oxoethyl}amino)-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from 4-(4-pertenece)of piperidine and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)Carboni is]amino}-3-(2-pyridyl)propanol]amino}acetic acid in the same way, as in example 59.

ESI-MS: m/z 579 (M+1)

1H-NMR (300 MHz, CDCl3) δ cent to 8.85-to 8.70 (m, 1H), 8,67 at 8.60 (m, 1H), they were 8.22-of 8.09 (m, 1H), 7,70-of 7.60 (m, 2H), 7,49 (d, J=8 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=2,8 Hz, 1H), 7,32-7,16 (m, 2H),? 7.04 baby mortality-6,92 (m, 2H), 6.90 to-to 6.80 (m, 2H), 5,16-is 5.06 (m, 1H), 4,51-and 4.40 (m, 1H), 4,15-of 3.96 (m, 2H), 3.75 to 3,44 (m, 4H), 3,40-3,26 (m, 2H), 1,95-of 1.73 (m, 4H).

Getting 41

4-[4-(Trifluoromethyl)phenoxy]piperidineacetic

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 4-(trifluoromethyl)phenol in the same manner as in obtaining 38.

1H-NMR (300 MHz, DMSO-d6) δ to 7.67 (d, J=8 Hz, 2H), 7,19 (d, J=8 Hz, 2H), 4,85-4,737 (m, 1H), 3,29-3,00 (m, 4H), 2,20-2,05 (m, 2H), 1,98-of 1.78 (m, 2H).

Example 65

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-[(2-oxo-2-{4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl}ethyl)amino]-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from 4-[4-(trifluoromethyl)phenoxy]piperidinedione and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 59.

ESI-MS: m/z 615 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,60 are 8.53 (m, 1H), 8,10-a 7.85 (m, 2H), 7.68 per-7,51 (m, 4H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,30-to 7.15 (m, 2H), 6,95 (d, J=8 Hz, 2H), 6,50 (DD, J=15.2 Hz, 1H), 5,07 is equal to 4.97 (m, 1H), 4,68-4,58 (m, 1H), 4.09 to of 3.97 (m, 2H), 3,86-3,20 (m, 6H), 1,99-of 1.78 (m, 4H).

Example 66

5-Chloro-N-[(1S)-2-oxo-2-[(2-oxo-2-{4-[4-(trifluoromethyl)-phenoxy]-1-piperidinyl}ethyl)amino]-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamid the

Specified in the title compound is obtained from 4-[4-(trifluoromethyl)phenoxy]piperidinedione and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]-amino}acetic acid in the same manner as in example 59.

ESI-MS: m/z 629 (M+1)

1H-NMR (300 MHz, CDCl3) δ cent to 8.85-8,71 (m, 1H), 8,66-8,59 (m, 1H), 8,24-8,10 (m, 1H), 7,70-of 7.60 (m, 2H), 7,55 (d, J=8 Hz, 2H), 7,50 (d, J=8 Hz, 1H), 7,43 (s, 1H), 7,39 (DD, J=8,2 Hz, 1H), 7,33-7,16 (m, 2H), 6,95 (d, J=8 Hz, 2H), 5,16-of 5.06 (m, 1H), 4,69-4,59 (m, 1H), 4,15-of 3.97 (m, 2H), a 3.87-3,29 (m, 6H), 2.00 in to 1.77 (m, 4H).

Getting 42

tert-Butyl 4-(4-chlorophenoxy)-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-hydroxy-1-piperidinecarboxylate and 4-chlorophenol in the same way as in obtaining 13.

1H-NMR (300 MHz, CDCl3) δ 7,31-7,14 (m, 2H), 6,74-6,60 (m, 2H), 4,47 is 4.36 (m, 1H), 3.75 to 3,61 (m, 2H), 3,40-3,26 (m, 2H), 1,97-of 1.84 (m, 2H), 1,80-of 1.66 (m, 2H), 1,47 (s, 9H).

Example 67

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-{(2-[4-(4-chlorophenoxy)-1-piperidinyl]-2-oxoethyl}amino)-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-(4-chlorphenoxy)-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 581 (M+1)

1H-NMR (300 MHz, CDCl3) δ 8,60-8,51 (m, 1H), 8,09-to 7.84 (m, 2H), 7.68 per-of 7.55 (m, 2H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,30-7,14 (m, 4H), 6,83 (d, J=8 Hz, 2H), 6,50 (d, J=15 Hz, 1H), ,05-4,97 (m, 1H), 4,55 is 4.45 (m, 1H), 4,11-of 3.94 (m, 2H), 3,80-3,20 (m, 6H), 1,91-of 1.73 (m, 4H).

Example 68

5-Chloro-N-[(1S)-2-({2-[4-(4-chlorophenoxy)-1-piperidinyl]-2-oxoethyl}amino)-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(4-chlorophenoxy)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: m/z 595 (M+1)

1H-NMR (300 MHz, CDCl3) δ cent to 8.85-to 8.70 (m, 1H), 8,65 at 8.60 (m, 1H), 8,23-8,10 (m, 1H), 7,70-of 7.60 (m, 2H), 7,50 (d, J=8 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=8,2 Hz, 1H), 7,17-7,31 (m, 4H), to 6.88 (d, J=8 Hz, 2H), 5,15-of 5.06 (m, 1H), 4,55-to 4.46 (m, 1H), 4,15-of 3.97 (m, 2H), 3,29 of 3.28 (m, 6H), 1,95-of 1.74 (m, 4H).

Getting 43

tert-Butyl 4-(2-pyridylthio)-1-piperidinecarboxylate

To a suspension of sodium hydride (about 60%oil suspension, 397 mg) in dimethoxyethane (4 ml) at 0°add a solution of 2-pyridinethiol (1,05 g) dimethoxyethane (6 ml) and the mixture is stirred at room temperature for 1 hour. To the mixture of tert-butyl 4-bromo-1-piperidinecarboxylate (2,74 g) and the mixture refluxed for 2 hours. After cooling, the resulting suspension is diluted with simple ether and filtered through a layer of celite. The filtrate is washed with saline, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified column chromatography on silica gel(eluent; 14% ethyl acetate in n-hexane), getting mentioned in the title compound (2.2 g) as a white solid.

ESI-MS: 295,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,42 (DD, J=5,2 Hz, 1H), 7,47 (TD, J=8,2 Hz, 1H), 7,16 (d, J=8 Hz, 1H), 6,99 (DD, J=8.5 Hz, 1H), 4,06-a 3.83 (m, 3H), 3,16-to 3.02 (m, 2H), 2,12-2,00 (m, 2H), 1,71-of 1.56 (m, 2H), of 1.46 (s, 9H).

Example 69

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridylthio)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-(2-pyridylthio)-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 564,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (DD, J=5,2 Hz, 1H), to 8.41 (DD, J=5,2 Hz, 1H), 8,02-of 7.96 (m, 1H), 7.95 is-7,88 (m, 1H), 7,63 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,52-7,42 (m, 3H), 7,35 (d, J=8 Hz, 2H), 7,28-of 7.23 (m, 1H), to 7.18 (DD, J=8.5 Hz, 1H), 7,15 (d, J=8 Hz, 1H), 7,00 (DD, J=8.5 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,06 is equal to 4.97 (m, 1H), 4.26 deaths-Android 4.04 (m, 2H), was 4.02 (apparent d, J=4 Hz, 2H), 3,70-3,59 (m, 1H), 3,43 (DD, J=15,5 Hz, 1H), 3,30-3,10 (m, 3H), 2,19-2,02 (m, 2H), 1,73-and 1.54 (m, 2H).

Example 70

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridylthio)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-(2-pyridylthio)-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same ways the Ohm, as in example 1.

ESI-MS: 578,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,80-8,73 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), to 8.41 (DD, J=5,2 Hz, 1H), 8,18-8,10 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,51-7,44 (m, 2H), 7,42 (s, 1H), 7,38 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 7,15 (d, J=8 Hz, 1H), 6,99 (DD, J=8.5 Hz, 1H), 5,15-of 5.06 (m, 1H), 4,25-4,00 (m, 4H), 3,71-3,59 (m, 1H), 3,49 (DD, J=15,5 Hz, 1H), 3,38-to 3.09 (m, 3H), 2,19 is 2.01 (m, 2H), 1,73-of 1.52 (m, 2H).

Example 71

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridylsulfonyl)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)-ethyl]-2-propenamide

Specified in the title compound is obtained from 2-(4-piperidinophenyl)pyridinecarboxamide and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 59.

ESI-MS: 596,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,75-8,80 (m, 1H), 8,58-charged 8.52 (m, 1H), 8,12-of 7.82 (m, 4H), 7.68 per-of 7.55 (m, 3H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,28-to 7.15 (m, 2H), 6,54-6,44 (m, 1H), 5,04-4,96 (m, 1H), 4,68-4,56 (m, 1H), 3,99 (apparent d, J=4 Hz, 2H), 3,88-to 3.67 (m, 2H), 3,47-to 3.35 (m, 1H), 3,29-3,19 (m, 1H), 3,11-of 2.97 (m, 1H), 2,74-2,61 (m, 1H), 2,12-1,90 (m, 2H), 1,86 by 1.68 (m, 2H).

Example 72

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(2-pyridylsulfonyl)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from 2-(4-piperidinylcarbonyl)pyridinecarboxamide and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in PR is as 59.

ESI-MS: 578,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ cent to 8.85-to 8.57 (m, 3H), 8,23-to 7.95 (m, 3H), 7,69-of 7.55 (m, 3H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,38 (DD, J=9,2 Hz, 1H), 7,29-7,16 (m, 2H), 3,52-of 3.42 (m, 1H), 3,37-3,26 (m, 1H), 3,12-2,99 (m, 1H), 2,74-2,61 (m, 1H), 2.13 and is 1.91 (m, 2H), 1,88-of 1.65 (m, 2H).

Getting 44

tert-Butyl 4-[(5-chloro-2-pyridyl)thio]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl-4-mercapto-1-piperidinecarboxylate and 2.5-dichloropyridine in the same way as in obtaining 7.

1H-NMR (300 MHz, CDCl3) δ scored 8.38 (DD, J=2.1 Hz, 1H), 7,45 (DD, J=8,2 Hz, 1H), 7,10 (DD, J=8,1 Hz, 1H), 4,01-of 3.85 (m, 3H), 3,14-3,00 (m, 2H), 2,10-to 1.98 (m, 2H), 1.70 to was 1.58 (m, 2H), of 1.46 (s, 9H).

Example 73

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(5-chloro-2-pyridyl)-thio]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)-ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-2-pyridyl)thio]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)-propanol]amino}acetic acid in the same manner as in example 1.

ESI-MS: 598,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), of 8.37 (d, J=2 Hz, 1H), 8,03-of 7.97 (m, 1H), 7.95 is-7,89 (m, 1H), 7,63 (TD, J=8,2 Hz, 1H), to 7.61 (d, J=16 Hz, 1H), 7,49-7,42 (m, 3H), 7,35 (d, J=8 Hz, 2H), 7,28-of 7.23 (m, 1H), to 7.18 (DD, J=8.5 Hz, 1H), to 7.09 (d, J=8 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,06 is equal to 4.97 (m, 1H), 4,27-to 4.14 (m, 1H), 4,10-of 3.97 (m, 3H), 3,70-to 3.58 (m, 1H), 3,43 (DD, J=15,5 Hz, 1H), 3,30-of 3.07 (m, 3H), 2,17-2,00 (m, 2H), 1,72-and 1.54 (m, 2H).

Example 74

5-Chloro-N-[(1S)-2-[(2-{4-[(5-chloro-2-pyridyl)thio]-1-Piperi inyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(5-chloro-2-pyridyl)thio]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]-amino}acetic acid in the same manner as in example 1.

ESI-MS: 612,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,81-8,73 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), of 8.37 (d, J=2 Hz, 1H), 8,19-to 8.12 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,52-7,35 (m, 4H), 7,30-7,24 (m, 1H), 7,20 (DD, J=8.5 Hz, 1H), to 7.09 (d, J=8 Hz, 1H), 5,15 is 5.07 (m, 1H), 4.26 deaths-to 4.14 (m, 1H), 4,10-of 3.97 (m, 3H), 3,71-of 3.60 (m, 1H), 3,49 (DD, J=to 15.4 Hz, 1H), 3,38-of 3.07 (m, 3H), 2,18 is 2.01 (m, 2H), 1,72-of 1.53 (m, 2H).

Example 75

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(4-pyridylthio)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from 4-(4-piperidinyl)pyridinecarboxamide and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 59.

ESI-MS: 564,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,56 (DD, J=5,2 Hz, 1H), 8,45 (d, J=6 Hz, 2H), 8,08-7,88 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7.62mm (d, J=16 Hz, 1H), 7,47 (d, J=8 Hz, 2H), was 7.36 (d, J=8 Hz, 2H), 7,29-7,24 (m, 1H), 7,20 (DD, J=8,5 Hz, 1H), 7,15 (d, J=6 Hz, 1H), 6,50 (d, J=16 Hz, 1H), 5,06 is equal to 4.97 (m, 1H), 4,27-4,13 (m, 1H), 4,03 (apparent d, J=4 Hz, 2H), 3.75 to to 3.52 (m, 2H), 3,49-3,39 (m, 1H), 3,31-3,11 (m, 3H), 2,14 is 2.01 (m, 2H), 1,72-of 1.55 (m, 2H).

Example 76

5-Chloro-N-[(1S)-2-oxo-2-({2-oxo-2-[4-(4-pyridylthio)-1-piperidinyl]ethyl}amino)-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

The decree is Noah in the title compound is obtained from 4-(4-piperidinyl)pyridinecarboxamide and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same way, as in example 59.

ESI-MS: 578,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,82-8,72 (m, 1H), to 8.62 (DD, J=5,2 Hz, 1H), 8,44 (d, J=6 Hz, 2H), by 8.22-to 8.12 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), 7,49 (d, J=9 Hz, 1H), 7,42 (s, 1H), 7,39 (DD, J=9,2 Hz, 1H), 7,27 (d, J=8 Hz, 1H), 7,20 (DD, J=8.5 Hz, 1H), 7,14 (d, J=6 Hz, 1H), 5,14-of 5.06 (m, 1H), 4,25-4,12 (m, 1H), 4,05 (apparent d, J=4 Hz, 2H), 3.75 to 3,43 (m, 3H), 3,38-3,10 (m, 3H), 2,14 is 2.01 (m, 2H), 1,73-1.55V (m, 2H).

45

tert-Butyl 4-[(4-chlorophenyl)thio]-1-piperidinecarboxylate

Specified in the title compound is obtained from tert-butyl 4-bromo-1-piperidinecarboxylate and 4-chlorbenzoyl in the same way as in obtaining 7.

1H-NMR (300 MHz, CDCl3) δ 7,39-7,24 (m, 4H), 4,07-a-3.84 (m, 2H), 3,23-3,10 (m, 1H), 3.00 and is 2.80 (m, 2H), from 2.00 and 1.80 (m, 2H), 1,61-of 1.30 (m, 11H)Primer 77

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(4-chlorophenyl)thio]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from tert-butyl 4-[(4-chlorophenyl)thio]-1-piperidinecarboxylate and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 597,2 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,55 (DD, J=5,2 Hz, 1H), 8,03-a 7.85 (m, 2H), 7,63 (TD, J=8,2 Hz, 1H), 7,60 (d, J=16 Hz, 1H), 7,45 (d, J=8 Hz, 2H), 7,37-7,22 (m, 7H), 7,18 (DD, J=8.5 Hz, 1H), of 6.49 (d, J=16 Hz, 1H), 5,04-4,96 (m, 1H), 4,30-4,16 (m, 1H), 3,99 (apparent d, J=4 Hz, 2H), 3,71-3,59 (m, 1H), 3,47-3,37 (m, 1H), 3,29-and 3.16 (m, 2H), 3,15-only 2.91 (m, 2H), 2.00 in a 1.88 (m, 2H), 1,59-of 1.42 (m, 2H).

Example 78

5-Chloro-N-[1S)-2-[(2-{4-[(4-chlorophenyl)thio]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the title compound is obtained from tert-butyl 4-[(4-chlorophenyl)thio]-1-piperidinecarboxylate and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 1.

ESI-MS: 611,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,80-8,71 (m, 1H), 8,61 (DD, J=5,2 Hz, 1H), 8,18-8,08 (m, 1H), 7,65 (TD, J=8,2 Hz, 1H), 7,65 (d, J=2 Hz, 1H), of 7.48 (d, J=9 Hz, 1H), 7,41 (s, 1H), 7,40-to 7.15 (m, 7H), 5,13-5,04 (m, 1H), 4,29-4,17 (m, 1H), was 4.02 (apparent d, J=4 Hz, 2H), 3,71-of 3.60 (m, 1H), 3,48 (DD, J=to 15.4 Hz, 1H), 3,38-and 3.16 (m, 2H), 3,16 of 2.92 (m, 2H), 2,01-to 1.87 (m, 2H), 1,63-of 1.41 (m, 2H).

Example 79

(2E)-3-(4-Chlorophenyl)-N-[(1S)-2-[(2-{4-[(4-chlorophenyl)-sulfonyl]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-2-propenamide

Specified in the title compound is obtained from 4-[(4-chlorophenyl)sulfonyl]piperidinedione and {[(2S)-2-{[(2E)-3-(4-chlorophenyl)-2-propenyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same manner as in example 59.

ESI-MS: 629,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,57-8,51 (m, 1H), 8,05-7,83 (m, 2H), 7,82-7,74 (m, 2H), to 7.67-7,52 (m, 4H), 7,45 (d, J=8 Hz, 2H), 7,35 (d, J=8 Hz, 2H), 7,28-7,13 (m, 2H), 6,53-to 6.43 (m, 1H), 5,03-is 4.93 (m, 1H), 4,71-of 4.57 (m, 1H), 3,98 (apparent d, J=4 Hz, 2H), 3,86 of 3.75 (m, 1H), 3.46 in-to 3.34 (m, 1H), 3,29-3,19 (m, 1H), 3,16-2,90, (m, 2H), 2,65-of 2.50 (m, 1H), 2,15-of 1.95 (m, 2H), 1,69-1,49 (m, 2H).

Example 80

5-Chloro-N-[(1S)-2-[(2-{4-[(4-chlorophenyl)sulfonyl]-1-piperidinyl}-2-oxoethyl)amino]-2-oxo-1-(2-pyridylmethyl)ethyl]-1-benzofuran-2-carboxamide

Specified in the header connect the tion obtained from 4-[(4-chlorophenyl)sulfonyl]piperidinedione and {[(2S)-2-{[(5-chloro-1-benzofuran-2-yl)carbonyl]amino}-3-(2-pyridyl)propanol]amino}-acetic acid in the same way, as in example 59.

ESI-MS: 643,1 (M+N)

1H-NMR (300 MHz, CDCl3) δ 8,83-8,67 (m, 1H), 8,63-8,56 (m, 1H), they were 8.22-of 8.09 (m, 1H), 7,82-7,74 (m, 2H), 7,69-7,34 (m, 7H), 7,29-to 7.15 (m, 2H), 5,13-to 5.03 (m, 1H), 4,70-4,58 (m, 1H), 4.09 to 3,91 (m, 2H), 3,88 of 3.75 (m, 1H), 3,52 is 3.40 (m, 1H), 3,37-of 3.25 (m, 1H), 3,17-only 2.91 (m, 2H), 2,65-of 2.50 (m, 1H), 2,15 is 1.96 (m, 2H), 1,68 to 1.47 (m, 2H).

1. The compound of formula (I)

in which R1is benzofuranyl, substituted with halogen, or styryl, substituted with halogen;

R2is substituted by hydroxyl, substituted mercapto or substituted sulfonyl, where the substituents are selected from the group comprising lower alkyl, halo(lower)alkyl, optionally substituted heterocyclic group, selected from the group comprising a pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl; or optionally substituted aryl;

X represents

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R2represents a group of the formula: -Y-R3where R3represents lower alkyl, halo(lower)alkyl, optionally substituted heterocyclic group, selected from the group comprising a pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl; or optionally substituted aryl, and Y is-O-, -S - or-SO2-or his farmaci is almost acceptable salt.

3. The compound according to claim 2, in which R3is lower alkyl;

halo(lower)alkyl; heterocyclic group selected from the group comprising a pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl, optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl; or aryl, optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

4. The compound according to claim 3 in which R3is lower alkyl;

halo(lower)alkyl; heterocyclic group selected from the group comprising a pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl, with specified heterocyclic group optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl; or phenyl, optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

5. The compound according to claim 1, in which X represents

or in pharmaceutical preparations is automatic acceptable salt.

6. The compound according to claim 5, in which R2is substituted by hydroxyl, where the substituents have the meanings indicated in claim 1, or its pharmaceutically acceptable salt.

7. The connection according to claim 6, in which R represents a group of formula: -O-R3where R3represents lower alkyl, halo(lower)alkyl, optionally substituted heterocyclic group, selected from the group comprising a pyridyl, pyrazinyl, thiazolyl, pyridazinyl and pyrimidinyl; or optionally substituted aryl, or its pharmaceutically acceptable salt.

8. The connection according to claim 7, in which R3represents lower alkyl, halo(lower)alkyl, pyridyl, pyrazinyl, thiazolyl or phenyl, where each of the specified pyridyl, pyrazinyl, thiazolyl and phenyl optionally substituted by one or more substituents selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

9. The connection of claim 8, in which R3represents lower alkyl, halo(lower)alkyl, pyridyl, pyrazinyl, thiazolyl or phenyl, with the specified pyridyl optionally substituted by a Deputy selected from the group comprising lower alkyl, lower alkoxy, halogen and halo(lower)alkyl, or its pharmaceutically acceptable salt.

10. The compound according to claim 1, in which R1is benzofuranyl, for ewenny chlorine, or styryl substituted by chlorine, or its pharmaceutically acceptable salt.

11. The compound according to claim 1, in which R1represents 5-chloro-1-benzofuran-2-yl or 2-(4-chlorophenyl)ethynyl, or its pharmaceutically acceptable salt.

12. Pharmaceutical composition having inhibitory effect on the production of nitric oxide (NO)containing the compound according to claim 1 or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable carrier.

13. The use of compounds according to claim 1 or its pharmaceutically acceptable salts for the preparation of drugs having inhibitory action on the production of nitric oxide (NO).

14. Pharmaceutical composition having inhibitory effect on the production of nitric oxide (NO), containing FK506 and connection according to claim 1 or its pharmaceutically acceptable salt.

15. The use of pharmaceutical compositions containing FK506 and connection according to claim 1 or its pharmaceutically acceptable salt, as an immunosuppressant.

16. The use of pharmaceutical compositions containing FK506 and connection according to claim 1 or its pharmaceutically acceptable salt, for the preparation of a medicinal product for preventing or treating rejection in the transplantation of organs.

Priority items:

05.09.2001 - claims 1-5,10-16;

02.01.2001 - PP-9.



 

Same patents:

The invention relates to a group of compounds of General formula (I) high degree of purification

The invention relates to a derivative of D-Proline General formula

< / BR>
or

< / BR>
where R is SH, benzyl or phenyl, optionally substituted by a hydroxy-group or a lower alkoxygroup, or a group of the formula

< / BR>
R1is hydrogen or halogen; X represents -(CH2)n-; -CH(R2)(CH2)n-; -CH2O(CH2)n-; CH2NH-; benzyl, -C(R2)=CH-; CH2CH (OH)- or thiazol-2,5-diyl; Y represents-S -; (CH2)n; -O-; -NH-; -N (R2)-; -CH=CH-; -NHC(O)NH-; -N(R2)C(O)N(R2)-; -N[CH2WITH6H3(OCH3)2]-; -N(CH2WITH6H5)-; -N(CH2WITH6H5)C(O)N(CH2WITH6H5)-; -N(alkoxyalkyl)-; -N(cyclooctylmethyl)-; 2,6-pyridyl; 2,5-furanyl; 2,5-thienyl; 1,2-cyclohexyl; 1,3-cyclohexyl; 1,4-cyclohexyl; 1,2-naphthyl; 1,4-naphthyl; 1,5-naphthyl; 1,6-naphthyl or diphenylene; 1,2-phenylene; 1,3-phenylene or 1,4-phenylene, where phenylenebis group optionally substituted by 1-4 substituents selected from the group comprising halogen, lower alkyl, lower alkoxygroup, the hydroxy-group, carboxypropyl, -COO-lower thiazolyl, 2-oxo[1,2,3,5] oxadiazolyl, 5-thioxo[1,2,4]oxadiazolyl and 5-tert-butylsulfonyl[1,2,4] oxadiazolyl; X' represents -(CH2)n-; (CH2)nCH(R2)-; -(CH2)nOCH2-; -NHCH2-; benzyl, -CH= C(R2)-; -CH(OH)CH2or thiazol-2,5-diyl; R2denotes lower alkyl, lower alkoxygroup or benzyl and n = 0-3, their pharmaceutically acceptable salts, mono - and diesters, except (R)-1-[(R)- and (R)-1-[(S)-3-mercapto-2-methylpropionyl] pyrrolidin-2-carboxylic acid; medicinal product with amyloidoses activity, and the method of obtaining these derivatives

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

FIELD: chemistry of peptides, microbiology, biotechnology.

SUBSTANCE: L-alanyl-L-glutamine is prepared by incubation of a mixture containing a microorganism able to produce L-alanyl-L-glutamine from L-alanine ester and L-glutamine, L-alanine ester and L-glutamine, and isolation of the end product. Using the invention allows simplifying the process for preparing L-alanyl-L-glutamine. Invention can be used in pharmacy and food processing industry.

EFFECT: improved preparing method of dipeptide.

3 cl, 3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

23 cl, 61 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to method for production of acetylamidiniophenylalanylcyclohexylglycilpypidinioalanin amides of formula I , wherein X anions are physiologically acceptable anions, and analogous thereof. Said compounds are effective inhibitors of fibrillation factor Xa and are useful, for example, in prevention of thrombosis. Claimed method includes coupling of 2-[2-acetylamino-3-(4-amidinophenyl)-propionylamino]-2-cyclohexylacetic acid, obtained from 2-[2-acetylamino-3-(4-cyanophenyl)acryloylamino]-2-cyclohexylacetic acid by assimetric hydration and converting of cyano group to amidine, or salt thereof with 3-(2-amino-2-carbamoylethyl)-1-methylpyridinic acid or salt thereof. Also are disclosed starting materials and intermediated used in this method, process for production the same and acetyl-(S)-4-amidiniophenylalanyl-(S)- cyclohexylglycil-(S)-(1-methyl-3-pypidinio)alanin amide in form of ditosylate.

EFFECT: simplified method; increased commercial availability of compounds with applicable anion.

14 cl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to the substituted pyrazoles, pharmaceutical compositions comprising these compounds and methods for their using in treatment of autoimmune diseases wherein cathepsin S is their mediating agent. Described substituted pyrazoles represent compounds of the formula (I): wherein a dotted line is placed near the group -C-R6 or absent, or it represents a bond; Y represents nitrogen atom or -CR20; Z represents nitrogen atom or -CR21; T represents nitrogen atom or -CR2; S represents nitrogen atom or -CR3 under condition that from 0 to 3 among S, T, Y and Z represent nitrogen atom, and additionally under condition that one among S, T, Y and Z can represent the group =N+-O- if other three are not nitrogen atom; R20 is chosen from hydrogen, halogen atom, hydroxy-, cyano-group, 4-7-membered heterocycle comprising nitrogen and oxygen atom; R21 represents hydrogen atom; R2 is chosen from hydrogen, halogen atom and hydroxy-group; R3 is chosen from hydrogen, halogen atom, (C1-C5)-alkoxy-group, (C1-C5)-alkyl, cyano-group, -RgRhN, 4-7-membered heterocyclyl comprising nitrogen and oxygen atom and -R17OC=O; R5 and R6 represent hydrogen atom; R7 and R8 can be combined in common and form optionally substituted 5-7-membered carbocylic or heterocyclic ring comprising nitrogen atom and wherein the indicated ring can be unsaturated or aromatic and this ring is substituted optionally with -Rt(C=O)- or -RtSO2; Rt represents (C1-C6)-alkyl; Rg, Rh and R17 represent (C1-C5)-alkyl; G represents (C3-C6)-alkanediyl; Ar represents monocyclic aryl ring optionally substituted from 1 to 3 substitutes chosen independently from halogen atom, (C1-C5)-alkyl and (C1-C5)-halogenalkyl; R32 represents hydrogen atom, (C1-C5)-alkyl, cyano-group, C1-C5)-hydroxyalkyl, -(C=O)NRvRx, -CHO or (C1-C6)-alkoxycarbonyl wherein each from Rv and Rx is chosen independently from hydrogen atom (H), (C1-C5)-alkyl, (C1-C5)-hydroxyalkyl, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom, (C1-C5)-heterocyclyl comprising nitrogen and oxygen atom-(C1-C5)-alkylene, (C1-C5)-aminoalkylene; Q represents -NR33, sulfur (S) or oxygen (O) atom; R33 represents hydrogen atom, (C1-C5)-alkyl, (C2-C5)-heterocyclyl comprising oxygen atom-(C1-C5)-alkylene, -R35OC=O and -R35OC=O; R35 represents (C1-C5)-alkyl, or their pharmaceutically acceptable salts, amides and esters, or their stereoisomeric forms.

EFFECT: improved for inhibition, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

25 cl, 3 tbl, 135 ex

FIELD: medicine, immunology.

SUBSTANCE: invention relates to compositions and method for immunosuppression achievement. Claimed compositions contain two main agents: namely the first agent targeted to interleukin-15 receptor (IL-15R), and the second agent which inhibits costimulating signal transferred between T-cell and antigen-presenting cell (APC).

EFFECT: diagnosis and therapy of immune deceases, in particular autoimmune deceases with improved effectiveness.

45 cl, 3 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention relates to a new crystalline nonsolvated form of 40-O-(2-hydroxy)-ethylrapamycin that shows crystalline lattice with the following parameters: a = 14.37Å; b = 11.24Å; c = 18.31 Å, and volume value is 2805Å. Also, invention relates to a method for preparing this crystalline form that involves crystallization of 40-O-(2-hydroxy)ethylrapamycin from a solvent with mixture with aliphatic hydrocarbon of the formula CnH2n+2 wherein n = 5, 6 or 7. Also, invention relates to a pharmaceutical composition based on thereof and its using in preparing medicinal agents used in treatment or prophylaxis of organ or tissue transplant rejection, autoimmune, inflammatory states, asthma, proliferative disorders, tumor or hyperproliferative vascular diseases. Invention provides preparing the novel crystalline nonsolvated form of 40-O-(2-hydroxy)ethylrapamycin possessing immunosuppressive properties.

EFFECT: improved preparing method, improved and valuable medicinal properties of compound and composition.

7 cl, 2 ex

FIELD: transplantology.

SUBSTANCE: invention discloses pharmaceutical compositions containing substance effective as modulators of biological activity "induced by activation of lymphocytic immunomodulating molecule (AILIM)" (known also as "induced common stimulator (ICOS)"), in particular modulating transduction of AILIM-mediated signal.

EFFECT: achieved suppression, treatment, or prevention of rejection of transplant arising in case of transplantation of organ, a part thereof or tissue.

11 cl, 7 dwg

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