Substituted azoles, antiviral active component, pharmaceutical composition, synthesis and application method

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

 

The present invention relates to new azoles, to the new antiviral active component of the pharmaceutical composition, antiviral drug, method of prevention and treatment of viral diseases, especially caused by hepatitis C (HCV).

Viral infection can cause many diseases, which poses a serious threat to the health and life of mankind. Over the last 20 years found at least 30 new infectious diseases: AIDS, viral hepatitis, acute and chronic diarrhoea, haemorrhagic fevers (Ebola, Venezuelan, Brazilian, rift valley) [(a) Lednicky J.A., Rayner J.O. Uncommon respiratory pathogens. Curr. Opin. Pulm. Med. 2006, 12(3), 235-239. b) F.G. Hayden Respiratory viral threats. Curr. Opin. Infect. Dis. 2006, 19(2), 169-178]. In particular, special concern is the possibility of human infection with the so-called "bird flu" [a) Liu J.P. Avian influenza--a pandemic waiting to happen? J. Environ. Immunol. Infect. 2006, 39(1), 4-10. b) Henter J.I.; Chow C.B.; Leung C.W., Lau Y.L. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet. 2006 367(9513), 870-873. Review]. According to statistics 60-65% of epidemic infections are of viral etiology. Because of the complexity of interactions in the triad "virus - host organism - drug" most modern antiviral drugs during therapy are the side effects and form a resistant viral strains [R. Jain, N.M. Clark, Diaz-Linares M, Grim S.A. Limitations of current antiretroviral agents and opportunities for development. Curr. Pharm. Des. 2006, 12(9), 1065-1074]. Currently, the number of antiviral drugs that can be used in clinical practice, is extremely limited - only 43 low molecular weight substances [http://integrity.prous.com/integrity]that not meets the needs of the prevention and treatment of viral diseases. In addition, there are a significant number of viral infections that cause disease, for which treatment does not currently exist chemotherapeutic agents. This applies, for example, diseases caused by papilloma viruses, adenoviruses, herpes 6, smallpox, syndrome SARS, haemorrhagic fevers, West Nile fever, avian influenza, etc. [De Clercq E. Recent highlights in the development of new antiviral drugs. Curr Opin Environ. 2005, 8(5), 552-560].

Hepatitis C virus belongs to Flaviviruses (genus Flaviviridae) along with other important human pathogens such as yellow fever virus, West Nile virus, the virus Dengue (Dengue) and hepatitis a virus (GBV-C). Flavivirus have a similar genome organization, including the presence of the gene encoding non-structural protein NS5A. NS5A plays an important role in the replication of the viral RNA genome as a structural component of the viral replication complex. Because this protein is currently validated in clinical trials the AK target for drug development against chronic hepatitis C, NS5A is a promising target for other clinically important flaviviruses listed above.

Thus, great importance is finding new protivovirusnyh drugs, particularly with high activity and low toxicity.

In the patent literature contains publications on various derivatives of 2-pyrrolidin-2-yl-1H-imidazoles, which are ligands of non-structural protein NS5A and inhibit the hepatitis C virus (HCV) [WO 2008021927 A2, WO 2009020825 A1, WO 2009020828 A1, WO 2010065668 A1, WO 2010065681 A1, WO 2010096302 A1, WO 2010096462 A1, WO 2010096777 A1, WO 2010111534 A1, WO 2010111673 A1, WO 2010117635 A1, WO 2010117977 A1].

However, the search for new high-performance protivovirusnyh drugs currently still is one of the main directions of development of new pharmacological agents for the treatment of a wide and diverse range of viral infections, including HCV.

In this regard, the actual is the synthesis of new compounds and their use as antiviral active ingredients for pharmaceutical compositions and medicaments, including HCV.

Below are definitions of terms used in the description of this invention.

"Aliphatic" radical, means the radical obtained by removing a hydrogen atom from a non-aromatic C-H connection. Aliphatic radical outdoornature contain substituents - aliphatic or aromatic radicals, as defined in this section. Representatives of aliphatic radicals include alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, aralkyl, aralkylamines, uralelectromontrage, aralkyl, aralkyl, aralkylamines, heteroalkyl, heteroalkyl, heteroalicyclic, heteroalicyclic, heteroaryl, kannelirovannye aristically, kannelirovannye heteroalicyclic, kannelirovannye arylchloroalkanes, kannelirovannye heteroarylboronic, kannelirovannye arylheteroacetic, kannelirovannye heteroalicyclic, kannelirovannye arylheteroacetic, kannelirovannye heterooligomerization.

"Aliphatic" biradical means biradical obtained by removing a hydrogen atom from C-H communication aliphatic radical, as defined above.

"Alkenyl" means aliphatic linear or branched hydrocarbon group containing 2 to 7 carbon atoms and containing at least one carbon-carbon double bond. Branched means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl. The alkyl group may have one or more substituents, such as halogen, alkenylacyl, C is cloaker, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroarylboronic, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, arelaxation, heteroarylboronic or,,whereandindependently from each other represent "amino substituents of the group", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, orandtogether with the N atom to which they are bound, form throughand4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-enyl, n-pentenyl and cyclohexylmethanol.

"Alkenylacyl" means alkenyl-O-group in which alkenyl defined in this section. Prefer the elegance of alkenylamine groups are allyloxy and 3 butenyloxy.

"Alkenylacyl" means alkenyl-O-alkyl group in which the alkyl and alkenyl defined in this section.

"Alkyl" means an aliphatic hydrocarbon of linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more "lower alkyl" substituents. The alkyl may have one or more identical or different substituents ("alkyl substituents including halogen, alkenylacyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroaromatic, Uralkali, arylsulfonyl, alkylsulfonates, annelirovannymi heteroarylboronic, annelirovannymi heteroalicyclic, annelirovannymi heterooligomerization, annelirovannymi heteroalicyclic, annelirovannymi arylchloroalkanes, annelirovannymi aristically, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic, alkoxycarbonyl, arelaxation,

heteroarylboronic or,,,whereandindependently from each other represent "amino substituents of the group", value is defined in this section, for example, a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, orandtogether with the N atom to which they are bound, form throughand4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylation, methoxycarbonylmethyl and pyridinedicarboxylate. Preferred "alkyl substituents" are cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkoxy, alkoxycarbonyl, Alcoxy, aryloxy, alkylthio, heteroaromatic, Uralkali, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, arelaxation, heteroarylboronic or,, annelirovannymi arylheteroacetic, annelirovannymi arylheteroacetic.

"Quinil" means aliphatic linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and containing at least one carbon-carbon triple bond.

Branched means that linear alkenylphenol chain connected inany one or more lower alkyl groups, such as methyl, ethyl or propyl. The alkyl group may have one or more substituents, such as halogen, alkenylacyl, cycloalkyl, cyano, hydroxy, alkoxy, alkyloxy, Alcoxy, aryloxy, aryloxyalkyl, alkylthio, heteroarylboronic, heterocyclyl, geterotsiklicheskikh, alkoxycarbonyl, arelaxation, heteroarylboronic or,,whereandindependently from each other represent "amino substituents of the group", which is defined in this section, for example a hydrogen atom, alkyl, aryl, aralkyl, heteroalkyl, heterocyclyl or heteroaryl, orandtogether with the N atom to which they are bound, form throughand4-7-membered heterocyclyl or heterocyclyl. Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, benzyloxycarbonylation and pyridinedicarboxylate. Preferred alkenylamine groups are ethynyl, propenyl, n-butenyl, ISO-butenyl, 3-methylbut-2-e is Il, n-pentenyl, buta-1,3-Dien and hexa-1,3,5-Triin.

"Alkyloxyalkyl" means quinil-O-alkyl group in which the alkyl and quinil defined in this section.

"Alkoxy" means alkyl-O-group in which alkyl is defined in this section. The preferred acyloxy groups are methoxy, ethoxy, n-propoxy, ISO-propoxy and n-butoxy.

"Alkyloxyalkyl" means alkyl-O-alkyl group in which the alkyl groups are independent of each other and defined in this section.

"Alkyloxyalkyl" means alkyl-O-(CHR)n-O-alkyl group, in which R represents a hydrogen atom or alkyl, and n>2, preferably 2, 3 or 4.

"Alkyloxyaryl" means alkyl-O-aryl group in which the alkyl and aryl is defined in this section.

"Altenroxel" means alkenyl-O-aryl group in which alkenyl and aryl is defined in this section.

"Alkyloxyaryl" means quinil-O-aryl group in which quinil and aryl is defined in this section.

"Alkylthio" means alkyl-S-group in which the alkyl group defined in this section.

"Alkylthiomethyl" means alkyl-S-alkyl group in which the alkyl groups are independent of each other and defined in this section.

"Alkylaryl" means alkyl-S-aryl group in which the alkyl and aryl is defined in this section.

"Alkenylsilanes" means lceil-S-aryl group, in which alkenyl and aryl is defined in this section.

"Alkynylaryl" means quinil-S-aryl group in which quinil and aryl is defined in this section.

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, predominantly from 6 to 10 carbon atoms. Aryl can contain one or more "cyclic system substituents"which may be the same or different. Representatives of aryl groups are phenyl or naphthyl, substituted phenyl or substituted naphthyl. The aryl may be annylirovan with non-aromatic cyclic system or heterocycle.

"Aryloxy" means aryl-O-group, where aryl is defined in this section. Representatives of aryloxy groups are phenoxy and 2 naphthyloxy.

"Aristeo" means an aryl-S-group, where aryl is defined in this section.

Representatives of aaltio groups are phenylthio and 2 naphthylthio.

"Biradical" means the radical obtained by removing two hydrogen atoms from two C-H linkages of a molecule.

"Hydrate" means the MES, in which water is a molecule or molecules of solvent.

"Deputy" means a chemical moiety that is attached to scaffold (fragment), for example, Deputy alkyl", "Deputy amino group", "will replace the l carbamoyl", "Deputy cyclic system.

"Active component" (drug substance, drug substance, drug-substance) means a physiologically active substance is synthetic or other (biotechnology, plant, animal, microbial or other origin, possessing pharmacological activity and which is the active beginning of the pharmaceutical composition used for the production and manufacture of the medicinal product (tools).

"The drug (the drug), a substance (or mixture of substances in the form of pharmaceutical compositions in the form of tablets, capsules, injections, ointments and other fabricated forms intended for restoring, correcting or modifying physiological functions in humans and animals, as well as for treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and others.

"Lower alkyl" means a linear or branched alkyl with 1-4 carbon atoms.

"Therapeutic cocktail" is simultaneously SKOLKOVO initiative combination of two or more drugs with different mechanisms of pharmacological action and aimed at different biological target involved in the pathogenesis of the disease.

"Pharmaceutical composition" means a composition comprising a compound of formula 1 and, on rainy least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, distributing and perceiving means, means of delivery, such as preservatives, stabilizers, fillers, shredders, moisturizers, emulsifiers, suspendresume agents, thickeners, sweeteners, flavors, fragrances, antibacterial agents, fungicides, lubricants, regulators prolonged delivery, the choice and the value of which depends on the nature and mode of appointment and dosage. Examples suspendida agents are ethoxylated isostearoyl alcohol, polyoxyethylene, sorbitol and sorbitol ester, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, as well as mixtures of these substances. Protection from the action of microorganisms can be ensured by various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid and similar compounds. The composition may also include isotonic agents such as sugars, sodium chloride and the like. Prolonged action of the composition can be achieved with agents that slow the absorption of the active principle, for example, aluminum monostearate and VC is tin. Examples of suitable carriers, solvents, diluents and delivery vehicles include water, ethanol, polyalcohol, and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as etiloleat). Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like. Examples of shredders and distributes funds are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulphate, talc, and polyethylene with high molecular weight. Pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal injection of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal the e or intraocular forms of administration and rectal forms of administration.

"Pharmaceutically acceptable salt" refers to the relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, separation, or purification of compounds or prepared. In particular, salts of bases can be obtained specifically on the basis of the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of the thus obtained salts are hydrochloride, hydrobromide, sulphates, bisulfate, phosphates, nitrates, acetates, oxalates, valeriote, oleates, palmitate, stearates, laurate, borate, benzoate, lactates, tozilaty, citrates, maleate, fumarate, succinate, tartratami, mesylates, malonate, salicylates, propionate, econsultancy, bansilalpet, sulfamate and the like (for a Detailed description of the properties of such assistance is given in S.M. Berge et al., "Pharmaceutical Salts" J.Pharm. Sci. 1977, 66: 1-19). Salts of the stated acids can also be specially obtained by the reaction of purified acid with a suitable base, can be synthesized metal salts and amines. The metal include sodium, potassium, calcium, barium, zinc, magnesium, lithium and aluminum, the most desirable of which are sodium and potassium salts.

Suitable inorganic bases, from which may be obtained metal salts, are the hydroxide, carbonate, bicarbonate and sodium hydride, hydroxide and bicarbonate of potassium, potash, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide. As organic bases, of which can be obtained salts of the stated acids, selected amines and amino acids with sufficient basicity to form a stable salt, and suitable for use in medical purposes (in particular, they should have a low toxicity). Such amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, Tris(hydroxymethyl)aminomethane and the like. In addition, for the salt formation can be used tetraalkylammonium hydroxide, such as choline, Tetramethylammonium, tetraethylammonium and the like. As amino acids can be used basic amino acids such as lysine, ornithine and arginine.

The subject of this invention are new substituted azoles of the General formulas 1A and 1B and their pharmaceutically acceptable salts.

where: the solid lines with accompanying dashed linesrepresents a single or double bond, and if one of them a single is the link, the other double bond;

X and Y do not necessarily accept different values and represent a nitrogen atom, oxygen, sulfur or an NH group;

R1and R2are not necessarily identical radicals selected from 2.1-2.20, where the asterisk (*) indicates the point of attachment to azole fragments;

And represents:

- aliphatic C2-C8biradical selected from diradicals 3.1-3.36, where the asterisk (*) indicates the point of attachment azole fragments;

- dioxane, cyclo - and bicycloheptene biradical selected from diradicals 3.37-3.47, in which the asterisk (*) indicates the point of attachment azole fragments;

- alkyloxyalkyl, altneratively, alkyloxyalkyl diradicals and their thioanalogues, preferably of the formula 3.48-3.56, in which the asterisk (*) indicates the point of attachment azole fragments;

- aryl and titanovyi diradicals selected from diradicals 3.57-3.71, in which the asterisk (*) indicates the point of attachment azole fragments;

/tr>

- alkylcyclohexanes, alkynylamino, alkynylaryl, alkylthiophenes, alkenylphenol and alkylthiophenes biradical selected from diradicals 3.72-3.129, in which the asterisk (*) indicates the point of attachment azole fragments;

- alkyloxyalkyl, altneratively, alkyloxyalkyl biradical selected from diradicals 3.130-3.136, in which the asterisk (*) indicates the point of attachment azole fragments;

- cycloalkylcarbonyl, origianaly and typedarray biradical selected from diradicals 3.137-3.154, in which the asterisk (*) indicates the point of attachment azole fragments,

and

provided that in one of the azole rings Y=NH, and the other Y=O, R1=R2=2.3.

In represents:

- alifaticheskii the C 2-C8radical selected from the radicals 4.1-4.12, in which the asterisk (*) indicate the place of attachment of azole fragment;

- aryl and tofinally radical selected from the radicals 4.13-4.30, where the asterisk (*) indicate the place of attachment of azole fragment;

- alkylcyclohexanes, alkynylaryl, alkylthiophenes and alkylthiophenes radical 4.31-4.47, in which the asterisk (*) indicate the place of attachment of azole fragment;

- cycloalkylcarbonyl, 4-cycloalkenyl, (bicicleta)benzene, 4-(bicicleta)biphenylyl, origianaly and typedarray radical selected from the radicals 4.48-4.72, in which the asterisk (*) indicate the place of attachment of azole fragment.

Ex:

((R)-1-{(R)-2-[5-(4-{2-[(R)-1-((R)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-buta-1,3-dienyl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl]-karamanova acid methyl ester;

((S)-1-{(S)-2-[5-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-karamanova acid methyl ester dihydrochloride;

((S)-1-{(S)-2-[5-(6-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalene-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-karamanova acid methyl ester dihydrochloride;

[(S)-1-((S)-2-{5-[5-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-karamanova acid methyl ether;

dimethyl (2S,2'S)-1,1'-((2R,2'R)-2,2'-(5,5'-(4,4'-(thiophene-2,5-diyl)bis(4,1-phenylene))bis(1H-imidazole-5,2-diyl))bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-oxobutyl-2.1-diyl)dicarbamate.

Preferred substituted azoles are compounds of General formula 5.1-5.70, in which X, Y, R1, R2and solid lines, with their accompanying dashed lineshave the above value.

Preferred substituted azoles are compounds of General formula 6.1-6.70, in which A, X, Y, and solid lines with accompanying dashed lineshave the above value.

Substituted azoles of the General formulas 1A and 1B according to this invention were obtained by use of known chemical reactions and commercial reagents. The structure of the obtained compounds is confirmed by LCMS and NMR spectroscopy. Compounds were named using chemdraw (Chembridge Soft Inc.) program.

In schemes IP is alsomany following abbreviations: DIPEA - diisopropylethylamine, EDAC - N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, HOBt is 1-hydroxybenzotriazole, N-Boc-L-Pro-OH N-(tert-butoxycarbonyl)-L-Proline, N-Moc-L-Val-OH = N-(methoxycarbonyl)-L-valine, RP HPLC - Reversed-phase high-performance liquid chromatography, HPLC - high performance liquid chromatography, DSM=DCM - dichloromethane, DMF IS N,N-dimethylformamide, PdCl2dppf - [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, DBU is 1,8-Diazabicyclo[5.4.0]undec-7-ene, HCV hepatitis C virus, DMEM (DMEM) - Dulbecco''s Modified Eagle Medium Nutrient medium, DMEM.

Thus, methyl ester [(1S)-1-[[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid 14 receive the following scheme:

v

Dimethyl ether [[1,1'-TRANS,TRANS-bicyclohexyl]-4,4'-diylbis[4,2-oxazolidinyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid 20 get from dimethyl ether, diphenyl-4,4'-dicarboxylic acid 20.1 on the following schema.

Methyl ester [(S)-1-((S)-2-{5-[5-(6-{2-[(S)-1-((S)-2-methods is starsonline-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalene-2-yl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 24 obtained by the following schema.

Methyl ester [(S)-1-((S)-2-{5-[5-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyral)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 25 obtained by the following schema.

Methyl ester ((S)-1-{(S)-2-[5-(5'-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[2,2']bithiophene-5-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-carbamino acid 30 obtained by the following schema.

Methyl ester {(S)-1-[(S)-2-(5-{5-[4-(5-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-thiophene-2-yl)-phenyl]-thiophene-2-yl}-1H-imidazol-2-yl)-pyrrolidin-1-the carbonyl]-2-methyl-propyl}-carbamino acid 35 obtained by the following schema.

1,4-Bis-{5-[5-{(R)-1-[(R)-2-(cyclopropanecarbonyl-amino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl]-thiophene-2-yl}-benzene 36 obtained by the following schema.

Methyl ester [(S)-1-((S)-2-{5-[5-(5-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalene-1-yl)-thiophene-2-yl]-1H-shall midazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 37 obtained by the following schema.

Methyl ester [(S)-1-((R)-2-{4-[4-(4-{2-[(S)-1-((R)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-oxazol-4-yl}-TRANS-cyclohexyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 38 received based on dimethyl ether diphenyl-4,4'-dicarboxylic acid 20.1 according to the scheme presented below.

Methyl ester {(S)-2-methyl-1-[(S)-2-(5-phenyl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acid 42 receive the scheme shown below.

Methyl ester {(S)-2-methyl-1-[(S)-2-(5-naphthalene-1-yl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acid 43 receive the scheme shown below.

Methyl ester {(S)-2-methyl-1-[(S)-2-(5-naphthalene-2-yl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acid 44 receive the scheme shown below.

Methyl ester {(S)-2-methyl-1-[(S)-2-(5-thiophene-2-yl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acids 58 and methyl ester {(S)-2-methyl-1-[(S)-2-[5-(2,2'-dateopen-5-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbolin]-propyl}-carbamino acid 59 receive under the scheme presents the oops below.

The biological activity of azoles of the General formulas 1A and 1B.

Antiviral activity of substituted azoles of the General formulas 1A and 1B were determined in cell line human hepatoma Huh7 containing subgenomic RNA replicon HCV (genotype 1b, clone Con1). As the experimental method was used option immune test ELISA for virus NS5A protein in 96-well format. The cytotoxicity of the compounds was evaluated in parallel.

The Huh7 cells were inoculated in 96-well plates (7.5×103cells per well in 100 μl medium). Solutions of test compounds in the environment DMEM {(DMEM) 1X; Source: Cellgro; Directory: 10-013-CV} were prepared directly before use. Just preparing eleven serial three-fold dilutions with concentrations ranging from 20 nm to 0.2 PM. 4 hours after sowing cells serial cultivation of drugs were added to the cells (100 μl per well). The final concentration of test compounds ranged from 10 nm to 0.1 PM, and DMSO - 0.5%. If necessary, we investigated higher concentrations the claimed azoles. Each drug dilution was tested on two identical holes. Next, cells were incubated for three days at 37°C/5% CO2. The cells were fixed by addition of 250 µl/well of a mixture of acetone/methanol (1:1). After 1 minute, the cells washed three times RA is tworoom PBS (Phosphate Buffered Saline). After that, the cells were blocked by adding 150 μl/well of 10% fetal calf serum in PBS solution for 1 hour at room temperature. Next, cells were incubated with mouse monoclonal antibodies to core-HCV antigen, clone C7-50 (Source: Affinity BioReagents; Directory: MA-080) (100 µl/well, working dilution is 1:500 in 10% fetal calf serum in PBS solution) for two hours at 37°C. Cells were washed 6 times with a solution of PBS/0.05% tween-20, then incubated for 1 hour with antibodies goat to mouse IgG (conjugated with horseradish peroxidase, 100 µl/well, working dilution is 1:2500 10% fetal calf serum in PBS solution). Cells were washed 6 times with a solution of PBS/0.05% tween-20, once with a solution of PBS, after which was added 100 μl/well of substrate (1 tablet PDX+12 ml citrate/phosphate buffer+5 μl of 30% H2O2). The tablet was kept for 30 min in the dark at room temperature. The reaction was stopped by adding 100 μl/well of 2n. H2SO2and measured the optical density (wavelength 490 nm) using a multichannel spectrophotometer Victor3 V 1420 (Perkin Elmer). Values IR50(concentration of asola, lowering the level of viral RNA replicon 50%) for each test Azola was calculated using XLfit 4.

Cytotoxicity test of azoles were studied in experiments on the culture of the cell line g is patami human Huh7. The number of living cells was determined using the ATPLite kit (Perkin Elmer, Boston, USA) according to manufacturer's instructions. Cytotoxic effects were assessed, waseela cells in black microplate with a transparent bottom (96 wells, 104cells per well). For each bis-azole used three independent repeat. Test bis-azoles were added after 18 hours, after which cells were incubated with the substances within 96 hours. Washed twice each well of phosphate-saline buffer (0.2 ml/well) and then literally cells by adding cell buffer (50 μl/well) (all these reagents included in the kit ATPLite). Microplate were incubated for 5 minutes on a rotating platform at 600 Rev/min, then was added to each well 50 µl of substrate solution (part of the ATPLite kit). Incubated for another 5 minutes on a rotating platform at 600 Rev/min, kept for 10 minutes in the dark and then measured the luminescence of the device TopCount NXT (Packard, Perkin Elmer).

As a quantitative parameter for the assessment of cytotoxicity used the value of CC50that corresponds to the concentration of bis-azole that will kill 50% of cells.

The calculation of the parameter CC50: to calculate the efficiency of inhibition (% Ing) used the formula: % Ing=[(LPOS-Lex)/(LPOS-LOTP)]·100%, where LPOSpositive is the control, luminescence in cells with cells without substance; LOTP- negative control, luminescence in cells with medium without cells; Lex- luminescence in cells with a substance in a certain concentration. Values of CC50then considered using XLfit 4. The results of the testing of new azoles of the General formulas 1A and 1B show a high (nanomolar) or very high (picomolar) activity. Inhibitory activity against genotype gT1b, gT1a and gT2a HCV new azoles of the General formulas 1A and 1B are presented in the table below and are indicated as: *>1000 nm, ** 999 nm to 10 nm, *** from 9.9 nm to 1 nm and****<1 nm.

No. Conn.gT1bgT2agT1a
14·2HCl************
18·2HCl************
30***********
25**********
35**********
42******
36**********
38·2HCl*****
20·2HCl*****
43****
59*****
44****
37·2HCl***********
58*******
37·2HCl***********
17·2HCl****

The object of the present invention are new compounds, the spectrum of biological activity which includes viral protein NS5A, representing the azoles of the General formulas 1A and 1B and their pharmaceutically acceptable salts.

The object of this invention is the active ingredient of pharmaceutical compositions and medicines intended for the treatment and prevention flavivirus (genus Flaviviridae) diseases, such as diseases caused by the hepatitis C virus and hepatitis GBV-C, representing the azoles of the General formulas 1A and 1B and their pharmaceutically acceptable salts.

The subject of this invention is a pharmaceutical composition containing as an active ingredient pharmaceutically effective amount of a ligand of General formula 1A and 1B and their pharmaceutically acceptable salts.

Pharmaceutical compositions can include pharmaceutically acceptable excipients. Under the pharmaceutically acceptable excipients are meant to be applied in the field of pharmaceutical diluents, auxiliary agents and/or carriers. The pharmaceutical composition along with the active component of the General formulas 1A and 1B according to the present invention may include other active ingredi the options provided that they do not cause unwanted effects, such as allergic reactions.

If you want to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed to produce different forms, however, they can contain conventional pharmaceutical carriers, for example: oral forms such as tablets, gelatin capsules, pills, solutions or suspensions); forms for injection (such as solutions or suspensions for injection or dry powder for injection, which requires only the addition of water for injection before use); local forms such as ointments or solutions).

The media used in the pharmaceutical compositions of the present invention, are media that are used in the pharmaceutical industry to obtain common forms, including: oral forms are used binders, lubricating agents, disintegrators, solvents, diluents, stabilizers, suspendresume agents, colorless agents, korrigentami taste; in forms for injection are used antiseptic agents, solubilization, stabilizers; local forms are used bases, diluents, lubricating agents, antiseptic agents.

The object of the present invention is also with the persons receiving the pharmaceutical composition, which consists in mixing at least one active ingredient of General formula 1A and 1B or its pharmaceutically acceptable salt with an inert filler and/or diluent.

The subject of this invention is also a pharmaceutical composition in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable packing, for the treatment and prevention flavivirus (genus Flaviviridae) disease due to hepatitis C virus and hepatitis GBV-C, containing as an active ingredient pharmaceutically effective amount of a ligand of General formula 1A and 1B and their pharmaceutically acceptable salts.

The object of the present invention is also a method of treating flavivirus diseases by introducing a pharmacologically effective amount of substituted azole General formulas 1A and 1B, or its pharmaceutically acceptable salts, or pharmaceutical compositions containing the above azole.

The clinical dosage of the pharmaceutical composition containing as an active ingredient an azole of the General formulas 1A and 1B, patients can be corrected depending on: therapeutic efficiency and bio-availability of active ingredients in the body, the speed of their metabolism and excretion from the body, and depending on age, gender and stage of disease of the patient, the ri this daily dose in adults is usually 10~500 mg. Therefore, during the preparation of pharmaceutical compositions of the present invention in the form of dosage units it is necessary to consider the above-mentioned effective dosages, each unit dosage of the drug should contain 10~500 mg Azola General formulas 1A and 1B. In accordance with the instructions of the doctor or pharmacist these medications can be taken several times during a defined time period (preferably from one to six times).

The object of the present invention is also a therapeutic cocktail for the prevention and treatment flavivirus diseases, including diseases caused by hepatitis C, including as one of the components of substituted azole of the General formulas 1A and 1B, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing the above azole.

Therapeutic cocktails for the prevention and treatment of the above flavivirus diseases, including hepatitis C, along with drugs in this invention may include: inhibitors of inosine-5-monophosphate dehydrogenase, such as Ribavirin (allowed) and Ribamidil; inhibitors of the NS3 protease of hepatitis C, for example, Telaprevir and boceprevir; inhibitors of RNA polymerase NS5B, e.g VX222, R7128, PF-868554, ANA598; alpha-glucosidase inhibitors, such as aminoplast Celgosivir is; as well as agonists of TLR receptors, hepatoprotectors, cyclosporine, various proteins (e.g., interferons), antibodies, vaccines, etc.

For combination therapy any classes of agents that can be useful when combined with substituted azoles of the present invention, can include, for example, nucleoside and non-nucleoside inhibitors of HCV polymerase, protease inhibitors, inhibitors of helicase, NS4B inhibitors and medical agents that are functionally inhibit internal ribosomal site of entry (IRES) and other drugs that inhibit attachment or entry of the virus into cells, the transcription of HCV RNA, replication, maturation or attenuation of the virus. Specific compounds in these classes and useful in this invention include, but are not limited macrocyclic, heterocyclic and linear HCV protease inhibitors such as telaprevir (VX-950), boceprevir (SCH-503034), narlaprevir (SCH-900518), ITMN-191 (R-7227), TMC-435350 (a.k.a. TMC-435), MK-7009, BI-201335, BI-2061 (ciluprevir), BMS-650032, ACH-1625, ACH-1095 (HCV NS4A inhibitor connecting factor protease), VX-500, VX-813, PHX-1766, PHX2054, IDX-136, IDX-316, ABT-450 EP-013420 (and related) and VBY-376; nucleoside inhibitors of HCV polymerase (replicase), useful in this invention include, but are not limited to the following: R7128, PSI-7851, IDX-184, IDX-102, R1479, UNX-08189, PSI-6130, PSI-938 and PSI-879 and various other nucleoside and nucleotide analogues and the HCV inhibi the ora, including (but not limiting) derived from 2'-C-methyl modified nucleosides and nucleotides; and 7'-deaza modified nucleosides and nucleotides. Inhibitors non-nucleoside HCV polymerase (replicase), useful in this invention include, but are not limited to: HCV-796, HCV-371, VCH-759, VCH-916, VCH-222, ANA-598, MK-3281, ABT-333, ABT-072, PF-00868554, BI-207127, GS-9190, A-837093, JKT-109, GL-59728 and GL-60667.

In addition, NS5A inhibitors of the present invention can be used in combination with antagonists cyclophilin and immunophilin (for example, without limitation DEBIO connections, NM-811, as well as cyclosporine and its derivatives), inhibitors of kinases, inhibitors of heat shock proteins (e.g., HSP90, HSP70), other immune modulating agents, which may include, without limitation, the interferons (alpha, beta, omega, gamma, lambda or synthetic), such as Intron A™, Roferon-A™, Canferon-A300™, Advaferon™, Infergen™, Humoferon™, Sumiferon MP™, Alfaferon™, IFN-β™, Feron™ and similar interferon compounds, derivateservlet polyethylene glycol (pegylated), such as PEG interferon-α-2a (Pegasys™), PEG interferon-α-2b (PEGIntron™), pegylated IFN-α-con 1 and the like; prolonged formulas and derivatives of interferon compounds such as the albumin-condensed interferon, Albuferon™, Locteron™, and the like; interferons with different types of controlled delivery (e.g., ITCA-638, omega-interferon delivered DUROS subcutaneous system of the first delivery); compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of the response of cells of type 1 helper T, such as SCV-07 and the like; TOLL-like receptor agonists such as CpG-10101 (action), isotorabine, ANA773 and the like; thymosin α-1, ANA-245 and ANA-246, histamine dihydrochloride, propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and such a prophylactic and therapeutic vaccines such as: Inno Vac, HCV E1E2/MF59 and the like. In addition any of the above methods, including the introduction of a NS5A inhibitor, an agonist of the receptor interferon type I (e.g., IFN-α) and the agonist receptor interferon type II (e.g., IFN-γ), can be strengthened by the introduction of an effective amount of TNF-α antagonist. Typical non-limiting TNF-α antagonists, which are suitable for use in such combination therapy, - ENBREL™ and HUMIRA™.

In addition, NS5A inhibitors of the present invention can be used in combination with Antiprotozoal, and other anti-viruses are considered to be effective in the treatment of HCV infection, such as a prodrug nitazoxanide. Nitazoxanide can be used as an agent in combination with the compounds disclosed in this invention, as well as in combination with other agents useful in the treatment of HCV infection, such as peginterferon alfa-2a and ribavarin (e.g., Rossignol, JF and'keeffe, EB, Future Environ. 3: 539-545, 008).

NS5A inhibitors of the present invention can also be used with alternative forms of interferons and pegylated interferons, ribavirin or its analogs (e.g., Tarabavarin, levovirion), microRNA, malorealnymi RNA compounds (e.g., SIRPLEX-140-N and the like), analogues of nucleotides or nucleosides, immunoglobulins, hepatic, anti-inflammatory agents and other NS5A inhibitors. Inhibitors of other targets in the HCV life cycle include inhibitors of NS3 helicase; inhibitors NS4A co-factor inhibitors, antisense oligonucleotides, such as: ISIS-14803, AVI-4065 and the like; the vector-encoded short hairpin RNA (shRNA); HCV specific ribozymes, such as heptazyme, RPI, 139199 and the like; entry inhibitors such as: Nareh, HuMax-nurse and the like; alpha-glucosidase inhibitors, such as celgosivir, UT-231B and the like; BAP 02003002 and BIVN 401 and IMPDH inhibitors. Other illustrative compounds inhibitors of HCV include inhibitors disclosed in the known scientific and patent publications.

Additionally, the combination of, for example, ribavirin and interferon can be entered as combination therapy with at least one azole of the present invention. The present invention is not limited to the above classes or compounds and considers known and new compounds and combinations of biologically active agents. meets in mind, that combined therapy of the present invention include any chemically compatible combination of bis-azoles this patentable group with other compounds patentable group or other connections outside patentable group, and the combination does not eliminate the antiviral activity of the compounds of this patentable group or antiviral activity of the pharmaceutical compositions.

Combination therapy can be sequential, i.e. the first treatment with one agent, and then another (for example, when each stage of treatment involves another connection of the present invention or when one stage of treatment involves the connection of the present invention, and the other involves one or more biologically active agents), or may be treated with both agents simultaneously. Sequential therapy may involve substantial time after the completion of the first stage of therapy before the second stage. Treatment with both agents at the same time can be carried out in a single daily dose or in multiple doses. Combination therapy does not require the restriction of the two agents, and may include three or more agents. Doses for simultaneous and sequential combination therapy will depend on the absorption, distribution, speeds metabolism and excretion is komponentov combination therapy, as well as other factors well known to the specialist. The size of the dose will also vary depending on the severity of the condition, which should be eased. For each particular patient specific regimen of doses and schedule can be adjusted over time in accordance with the needs of the individual and the professional judgment of the person who treats or supervises the treatment method of combination therapy.

Although the above invention has been described in some detail with illustrations and examples to facilitate the understanding, for the specialist in this area it is obvious that with this invention, there may be some changes and modifications not departing from the spirit and scope of the invention as defined in the attached claims.

The following examples illustrate, but not limit the invention.

Example 1. Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid 14.

To a solution of 8.15 g (42 mmol) of 1,4-bis-(trimethylsilyl)-1,3-butadiene in 50 ml of dry ether under argon added 31 ml (46.5 mmol) of a 1.5 M solution of MeLi×LiBr in the air. The mixture is peremeshivayte 6 h at room temperature. To the mixture is added slowly to 50 ml of a saturated solution of NH2Cl, extracted with pentane, dried over Na2SO4and remove the solvents in a weak vacuum. The liquid residue is dissolved in 70 ml of THF, add 20 ml of triethylamine, 8.8 g (20 mmol) of the compound 14.1, 458 mg (0.5 mmol) Pd2(dba)3, 524 mg (2 mmol) of triphenylphosphine, 190 mg (1 mmol) CuI and the mixture is stirred under argon for 12 h at 40°C. the Mixture is filtered through celite, applied to silica gel and isolated compound 2 flash chromatography (eluent CHCl3: EtOAc=10:1). Output 7,56 g (87%). LCMS (M+H)+434.

To a solution of 7.36 g (17 mmol) of the compound 14.2 in 120 ml of THF and 120 ml of methanol add? 7.04 baby mortality g (51 mmol) of potash, and the mixture is stirred for 2 hours the Solvent is removed in vacuum, the residue is treated with 150 ml of THF and filtered. To the resulting solution connection 14.3 add to 5.56 g (15,3 mmol) of the compound 13-1 (5-iodine-2-[(2S)-1-BOC-pyrrolidin-2-yl]-1H-imidazole), 366 mg (0.4 mmol) Pd2(dba)3, 630 mg (2.4 mmol) of triphenylphosphine, 152 mg (0.8 mmol) CuI and the mixture is stirred under argon for 12 h at 40°C. the Mixture is filtered through celite, applied to silica gel and separated with a 14.4 connection from the main part of the impurities flash chromatography (eluent CHCl3: Meon=80:1). After evaporation of the solvent the residue is treated with 60 ml of acetonitrile, kept in ultrasonic bath until the onset of crystallization and leave for 3 hours. The precipitation is filtered off, washed with what reconition, ether and dried in vacuum. Output vs. 5.47 g (54%). LCMS (M+H)+597. To connect 14.4 (0.695 g) add 15 ml of 3M HCl solution in dioxane and stirred for 12 hours the Mixture is evaporated in vacuum, get a connection with 14.5 yield 55%. LCMS (ESI): LCMS (M+H)+397.1H NMR (DMSO-d6, 400 MHz) δ 2.02 (USS, 8H), 2.99 (m, 4H), 3.40 (USS, 2H), 6.22 (m, 4H), 6.75 (s, 1H), 7.22 (s, 1H), 7.77 (m, 2H), 7.83 (d, 2H). A mixture of 50 mg (0.283 mmol, 2.4 EQ.) N-methoxycarbonyl-L-valine, 40 mg (0.295 mmol, 2.5 EQ.) 1-hydroxybenzotriazole and 53 mg (0.277 mmol, 2.35 equiv.) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 1 ml of acetonitrile is stirred for 1 h, add 64 mg (0.118 mmol, 1 EQ.) connections 14.5 and 82 μl (61 mg, 0.472 mmol, 4 equiv.) diisopropylethylamine. The reaction mass was stirred for 12 h at room temperature. Completeness of the reaction control method LCMS. After completion of the reaction the solvent is completely distilled off on a rotary evaporator, the residue is dissolved in dichloromethane. The extract was washed with 10% sodium carbonate solution, dried over Na2SO4and evaporated on a rotary evaporator. Further purification carried out by HPLC. The dihydrochloride 14·2HCl produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 14 in CH2Cl2and planting ether. Get 56 mg (67%) of compound 14·2HCl. LCMS (M+1)+711.1H NMR (DMSO-d6, 400 MHz) δ 0.87 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J 1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.99 (m, 4H), 2.06 (m, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.02 (d, J=0.42, 2H), 4.73 (m, 2H), 6.86 (s, 1H), 7.33 (s, 1H), 7.76 (d, J=8.26, 2H), 7.90 (m, 2H), 8.80 (m, 4H).

Example 2. Dimethyl ether [[1,1'-TRANS,TRANS-bicyclohexyl]-4,4'-diylbis[4,2-oxazolidinyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid 20.

4,4'-Dimethyl diphenyl-4,4'-in primary forms 20.1 (9 g, 33 mmol) hydronaut in CH3COOH (100 ml) in the presence of 10% Pd/C (3 g) and Rh2O3(0.15 g) at 250°C for 16 hours and the pressure 60-20 ATM N2. The mixture otfiltrovat, evaporated under reduced pressure, to the residue add an excess of 10% solution To2CO3in water and the mixture extracted with CHCl3. The organic layer pariwat that gives 9 g (96%) of compound 20.2.1H NMR (CDCl3): 3.67 (s); 3.65 (s) (total 6N, me) 2.56 (1H, USS) 2.20 (Ust, 1H) 2.0 (m, 4H) 1.80 (Ust, 2H) 1.5-1.0 (m, N). Connection 20.2 (9 g, 31 mmol) is boiled in EtOH (100 ml) and N2O (20 ml) in the presence of 50% KOH solution (9 g, 80 mmol) for 30 minutes. The solution is evaporated, the residue is dissolved in H2O (0.5 l) and add an excess of HCl. The residue is filtered off, giving 7.2 g (91%) di-acid 20.3.1H NMR (DMSO-d6): 2.44 (1H, USS) 2.05 (Ust, 1H) 1.88 (m, 4H) 1.68 (m, 2H) 1.43 (m, 4H) 1.18 (m, 4H) 0.98 (m, 4H). Acid 20.3 7.2 g (28 mmol) is heated at 300°C for 0.5 hour with stirring, then the e Ar. Sublimat and the residue is dissolved in hot 20% solution of KOH (50 ml) and stirred with 1 g of activated charcoal. The solution is filtered, diluted with water (0.5 l) and treated with excess HCl. The precipitate is filtered off, giving 5 g (69%) of TRANS,TRANS-dicarboxylic acid 20.4.1H NMR 12.0 (USS, 2HE) 2.50 (t, 2H,3J 1.8 Hz), 2.07 (dt, 2H,3J 12 Hz,3J 1.8 Hz), 1.95-1.85 (m, 4H) 1.75-1.65 (m, 4H) 1.30-1.20 (m, 4H) 1.00-0.90 (m, 4H). TRANS,TRANS-dicarboxylic acid 20.4 (4.3 g, 17 mmol) is heated with SOCl2(50 ml) in the presence of DMF (0.5 ml) for 2 hours. The solution is evaporated, giving the crude solid dichlorohydrin 20.5 (NMR LDA-2450), which is used in the next stage without additional purification. A solution of the obtained compound 20.5 in ether is added slowly to a solution of diazomethane (136 mmol) in Et2O at a temperature of 0-10°C. the Mixture is stirred for 10 hours, the precipitation is filtered off and dried in air. NMR LDA-2260, yield 5.4 g (42%) of pure TRANS,TRANS-link 20.6.1H NMR LDA-2260 (CDCl3) 5.24 (USS, 2H) 2.16 (USM 2H), 1.92-1.80 (m, 8H) 1.40 (m, 4H) 1.05 (m, 6N). Bis-diazoketone 20.6 (1.3 g, 4.3 mmol) dissolved in DCM (50 ml) and add 40% solution of HBr in acetic acid (1 ml). After cessation of gas evolution, the solution further stirred for 30 minutes, then add crushed To2CO3(10 g) and the mixture is stirred for another 30 minutes; excess To2CO3filtered off, iltram evaporated, the residue is recrystallized from heptane. Output connections 20.7 1.5 g (85%).1H NMR (CDCl3) LDA-2459. 3.97 (s, 4H, 2CH2 Br), 2.65 (TT, 2H,3J 12 Hz3J 3 Hz), 2.0-1.8 (m, 8H) 1.3-1.4 (m, 4H) 1.1-1.0 (m, 6N). N-BOC-(S)-Proline-HE (765 mg, 3.6 mmol) dissolved in MeCN (30 ml), added with stirring DIPEA (460 mg, 3.6 mmol) and after 5 minutes add the connection 20.7 (1.8 mmol). The solution is boiled overnight, cooled, the solvent evaporated, the residue is dissolved in DCM (50 ml) and washed sequentially with 0.1 N. HCl solution (2×20 ml) and a saturated solution of NaHCO3/NaCl (20 ml). The output connection is 20.8 1.4 g (95%). Connection 20.8 (1.7 mmol) dissolved in toluene (50 ml) and add NH4OAc (10 g). The mixture is boiled under stirring for 24 hours, then the organic layer is evaporated, giving 1.08 g (95%) of compound 20.9. LCMS M+1 639. Connection 20.9 (1.6 mmol) dissolved in 5 M HCl solution in dioxane (50 ml) and stirred at 40°C for 1 hour. Then the solution is evaporated to dryness, the residue is extracted with CHCl3(50 ml), the extracts washed successively with a 10% solution To2CO3(50 ml), the solution is dried over K2CO3and again evaporated to dryness. The residue is dissolved in DCM (50 ml) and to it add sequentially DIPEA (1.02 g, 7.9 mmol), N-methoxycarbonyl-(S)-valine-HE (1.04 g, 5.9 mmol) and TBTU (1.92 g, 5.9 mmol). The mixture is stirred for 16 hours, then washed with 0.1 N. HCl solution (2×50ml), a 10% solution of K2CO3(2×50 ml), the organic layer evaporated and subjected to RP HPLC. Get the connection 20. The dihydrochloride 20·2HCl produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 20 in CH2Cl2and planting ether. LCMS (M+1) 753.1H NMR (CDCl3) 0.73 (d, 3H, Me), 0.87 (d, 6N, me), 1.06 (d, 3H, Me), 1.4-2.7 (m, N), 3.64 (m, 1H), 3.69 (s, 3H, OMe), 3.75 (s, 3H, OMe), 3.80 (m, 3H), 4.34 (m, 1H), 5.24 (m, 1H), 5.42 (m, 1H), 7.12 (s, 1H), 7.30 (, 1H).

Example 3. Methyl ester [(S)-1-((S)-2-{5-[5-(6-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalene-2-yl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 24.

To a mixture of 6.87 g (24.2 mmol) of the compound 24.1 and 5.47 g (25.4 mmol) of N-Boc-L-Proline in 40 ml of acetonitrile added 4.3 ml (24.8 mmol) of diisopropylethylamine. The mixture is stirred for 3 h at room temperature, the acetonitrile is distilled off in vacuum, the residue is diluted with 100 ml of toluene, washed with saturated saline solution, a 5% solution of NaHCO3, dried over Na2SO4and evaporated in vacuum. The obtained ether 24.2 dissolved in 75 ml of toluene, added 18.5 g (0.24 mol) of ammonium acetate and stirred at 100°C for 18 hours the Mixture was washed with water, dried over Na2SO4, put on SiO2and produce product 24.3 column of chromatography the th (eluent hexane-ethyl acetate=4:1). Output connections 24.3 4.76 g (49%). LCMS (ESI): m/z 398.1, 400.0 (M+N)+.1H NMR (CDCl3, 400 MHz) δ 10.80 (USS, N), 10.52 (USS, N), 7.09 (d, J=1.2 Hz, 1H), 6.96 (m, 2H), 4.93 (m, 1H), 3.40 (USM, 2H), 3.00 (USM, 1H), 2.13 (m, 2H), 1.96 (m, 1H), 1.50 (s, N). The mixture 0.613 mmol (1.1 EQ.) broowaha ether 18.1 and 1.40 mmol (2.5 EQ.) sodium carbonate in 6 ml of ethanol and 1.4 ml of water purge with argon, add 203 mg (0.56 mmol, 1 EQ.) connection 24.3 and 20 mg (0.028 mmol, 0.05 EQ.) Pd(PPh3)2Cl2and stirred for 12 h at 85°C in argon atmosphere. Completeness of the reaction control method LCMS. After completion of the reaction the reaction mass is filtered through celite and evaporated on a rotary evaporator. The residue is dissolved in dichloromethane, washed with water, dried over Na2SO4and evaporated on a rotary evaporator. Connection 24.4 allocate the method of column chromatography (eluent - toluene:ethyl acetate=2:1) with a purity of 85%. Further purification carried out by HPLC. Obtain 174 mg (41%) of compound 24.4 LCMS (ESI): m/z 681.4 (M+N)+that debaucherous 3M HCl solution in dioxane. Get the connection 24.5 as tetrahydrochloride with yield 68%. LCMS (ESI): m/z 481.4 (M+N)+.1H NMR (DMSO-d6, 400 MHz) δ 10.40 (USS, 1H), 10.30 (USS, 1H), 9.96 (USS, N), 9.49 (USS, N), 8.53 (c, 1H), 8.23 (d, J=13.6 Hz, 2H), 8.07 (m, 2H), 7.95 (m, 2H), 7.83 (s, 1H), 7.69 (s, 1H), 7.56 (s, 1H), 5.07 (USM, 1H), 4.86 (USM, 1H), 3.76 (USM, 1H), 3.48 (USM, 1H), 3.38 (USM, 2H), 2.41 (USM, 2H), 2.34 (USM, 2H), 2.21 (USM, 2H) 2.02 (USM, 2H). The resulting product 24.5 turn with the release of 53% in the product 24 by analogy with the synthesis of compound 14 from compound 14.5. The dihydrochloride 24·2HCl produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 24 in CH2Cl2and planting ether. LCMS (ESI): m/z 795.8 (M+N)+.1H NMR (DMSO-d6, 400 MHz) δ 15.29 (USS, 1H), 14.76 (USS, N), 8.49 (s, 1H), 8.21 (d, J=16.0 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 7.99 (m, 2H), 7.93 (d, J=8.8 Hz, 1H), 7.88 (USS, 1H), 7.74 (s, 1H), 7.71 (USS, 1H), 5.22 (t, J=6.4 Hz, 1H), 5.13 (t, J=6.4 Hz, 1H), 4.13 (m, 2H), 3.97 (m, 2H), 3.84 (USM, 2H), 3.54 (s, 6N), 2.36 (m, 2H), 2.19 (m, 4H), 2.06 (m, 4H), 0.92 (m, N), 0.86 (d, J=6.8 Hz, M), 0.79 (d, J=6.8 Hz, N).

Example 4. Methyl ester [(S)-1-((S)-2-{5-[5-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyral)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 25.

To a mixture of 348 mg (1 mmol) of the compound 24.3, 295 mg (0.87 mmol) of the compound 25.1 and 17 mg (0.09 mmol) of CuI in 3 ml of DMF added 0.15 ml (0.87 mmol) of diisopropylethylamine and 31 mg (0.09 mmol) of PD(PPh3)Cl2under argon and the mixture was stirred at 80°C for 12 hours after the reaction mixture is diluted with chloroform, washed with water, dried over Na2SO4and evaporated in vacuum. Allocate product 25.2 by HPLC. Yield 173 mg (30%). LCMS (ESI): m/z 655.3 (M+N)+. Product 25.2 debaucherous M HCl solution in dioxane with quantitative output connection 25.3 (LC-MS (ESI): m/z 455.6 (M+N) +), which in turn connection 25 with the release of 41% by analogy with the transformation of compounds 14.5 in connection 14. LCMS (ESI): m/z 769.7 (M+N)+. The dihydrochloride 25 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 25 in CH2Cl2and planting ether.1H NMR (DMSO-d6, 400 MHz) δ 15.11 (USS, N), 14.69 (USS, N), 8.15 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.87 (USS, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.58 (USS, 1H), 7.45 (d, J=2.8 Hz, 1H), 7.27 (m, 2H), 5.16 (t, J=6.8 Hz, 1H), 5.10 (t, J=6.6 Hz, 1H), 4.11 (m, 2H), 3.92 (m, 2H), 3.83 (m, 2H), 3.56 (s, N), 3.54 (s, N), 2.34 (m, 2H), 2.16 (m, 4H), 2.03 (m, 4H), 0.90 (m, N), 0.84 (t, J=7.2 Hz, N), 0.77 (t, J=7.2 Hz, N).

Example 5. Methyl ester ((S)-1-{(S)-2-[5-(5'-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-[2,2']bithiophene-5-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-carbamino acid 30.

To the mixture 1.194 g (3 mmol) of the compound 24.3, 840 mg (3.3 mmol) of bis(pinacolato)Debora and 882 mg (9 mmol) of COAs in 9 ml DMF added 75 mg (0.09 mmol) of Pd(dppf)Cl2·CH2Cl2under argon and the mixture was stirred at 90°C for 12 hours after the reaction mixture is diluted with chloroform, washed with water, dried over Na2SO4, put on SiO2and produce product 29.1 column chromatography (eluent hexane-ethyl acetate = 1:2). The output 324 mg (34%). LCMS (ESI): m/z 637.5 (M+N)+. The resulting product 30.1 debaucherous 3M dissolve the om HCl in dioxane with quantitative output connection 30.2. LCMS (ESI): m/z 437.3 (M+N)+.1H NMR (DMSO-d6, 400 MHz) δ 10.31 (USS, 2H), 9.50 (USS, 2H), 7.81 (s, 2H), 7.47 (d, J=3.2 Hz, 2H), 7.31 (DD, J1=4.0 Hz, J2=0.8 Hz, 2H), 4.85 (USM, 2H), 3.35 (m, 4H), 2.41 (m, 2H), 2.33 (m, 2H), 2.15 (m, 2H), 2.00 (m, 2H). The last turn in the connection 30 by analogy with the transformation of compounds 14.5 in connection 14. The connection 30 is obtained in yield of 77%. LCMS (ESI): m/z 751.8 (M+N)+. The dihydrochloride 30 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 30 in CH2Cl2and planting ether.1H NMR (DMSO-d6, 400 MHz) δ 14.42 (USS, N), 7.91 (s, 2H), 7.91 (s, 2H), 7.63 (s, 2H), 7.41 (d, J=3.6 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 5.10 (t, J=7.0 Hz, 2H), 4.10 (t, J=7.8 Hz, 2H), 3.92 (m, 2H), 3.83 (m, 2H), 3.53 (s, 6N), 2.34 (m, 2H), 2.15 (m, 4H), 2.02 (m, 4H), 0.89 (m, 1.2H), 0.83 (d, J=6.8 Hz, M), 0.77 (d, J=6.8 Hz, N).

Example 6. Methyl ester {(S)-1-[(S)-2-(5-{5-[4-(5-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-thiophene-2-yl)-phenyl]-thiophene-2-yl}-1H-imidazol-2-yl)-pyrrolidin-1-the carbonyl]-2-methyl-propyl}-carbamino acid 35.

A mixture of 598 mg (1.5 mmol) of the compound 24.3, 124 mg (0.75 mmol) of benzene-1,4-ziborovoy acid and 320 mg (3 mmol) of Na2CO3in 4 ml of ethanol and 0.35 ml of water is blown with argon. Added 105 mg (0.15 mmol) of Pd(PPh3)2Cl2and the mixture is stirred under argon in a sealed tube at 80°C for 12 h okonchan and the reaction mixture is diluted with chloroform, washed with water, dried over Na2SO4, put on SiO2and produce product 35.1 column chromatography (eluent hexane-ethyl acetate=1:2). The output 318 mg (59%). LC-MS (ESI): m/z 713.7 (M+H)+. To 310 mg of compound 35.1 add 3 ml of 3M HCl solution in dioxane and stirred for 12 hours the Mixture is evaporated in vacuum, get the connection 35.2. The quantitative output. LC-MS (ESI): m/z 513.5 (M+N)+.1H NMR (DMSO-d6, 400 MHz) δ 10.32 (USS, 2H), 9.56 (USS, 2H), 7.83 (s, 2H), 7.72 (s, 4H), 7.58 (USM, 2H), 7.55 (USM, 2H), 4.88 (USM, 2H), 3.37 (m, 4H), 2.40 (m, 4H), 2.17 (m, 2H), 2.01 (m, 2H). A mixture of 46 mg (0.26 mmol) of N-(methoxycarbonyl)-L-valine, 37 mg (0.27 mmol) of 1-hydroxybenzotriazole and 49 mg (0.26 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in 1 ml of acetonitrile is stirred for 1 h, add 70 mg (0.11 mmol) of the compound 35.2 and 76 μl (0.44 mmol) of diisopropylethylamine. The mixture was stirred for 12 h at room temperature, evaporated to dryness in a vacuum and release the connection 35 by HPLC. The yield 59 mg (67%). LC-MS (ESI): m/z 827.8 (M+N)+. The dihydrochloride 35 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 6 in CH2Cl2and planting ether.1H NMR (DMSO-d6, 400 MHz) δ 14.40 (USS, N), 7.75 (s, 4H), 7.65 (USM, 4H), 7.28 (d, J=8.0 Hz, 2H), 5.11 (t, J=6.8 Hz, 2H), 4.11 (t, J=7.8 Hz, 2H), 3.92 (m, 2H), 3.83 (USM, 2H), 3.54 (s, 6N), 2.34 (m, 2H), 2.15 (m, 4H), 2.03 (m, 4H), 0.90 (m, N), 0.84 (d, J=6.4 Hz, D), 0.78 (d, J=6.4 Hz, N).

Example 7. 1,4-Bis-{5-[5-{(S)-1-(S)-2-(cyclopropanecarbonyl-amino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl]-thiophene-2-yl}-benzene 36.

The connection 36 receive by analogy with the transformation of compounds 14.5 in compound 14, but as the acid using N-cyclopropyl-L-phenylglycine. LCMS (ESI): m/z 915.7 (M+N)+. The dihydrochloride 36 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 36 in CH2Cl2and planting ether.

Example 8. Methyl ester [(S)-1-((S)-2-{5-[5-(5-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalene-1-yl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-carbamino acid 37.

A mixture of 442 mg (1 mmol) of the compound 37.1, 279 mg (1.1 mmol) of bis(pinacolato)of DIBORANE and 294 mg (3 mmol) of potassium acetate in 4 ml of dioxane rinsed with argon, added 24 mg (0.03 mmol) of Pd(dppf)Cl2·CH2Cl2and the mixture is stirred under argon at 85°C for 24 h after the reaction mixture is diluted with chloroform, washed with water, dried over Na2SO4and evaporated in vacuum. Allocate product 37.2 by HPLC. Yield 250 mg (51%). LC-MS (ESI): m/z 490.8. (M+N)+. A mixture of 225 mg (0.46 mmol) of the compound 37.2, 182 mg (0.46 mmol) of the compound 24.3 and 98 mg (0.92 mmol) of Na2CO3in 4 ml of ethanol and 0.35 ml of water is blown with argon. Added 32 mg (0.05 mmol) of Pd(PPh3)2Cl2and the mixture is stirred under argon in a closed the tube at 80°C for 12 hours Upon termination of the reaction mixture is diluted with chloroform, washed with water, dried over Na2SO4, put on SiO2and produce product 37.3 column chromatography (eluent hexane-ethyl acetate-Et3N=1:1:0.05). The product yield 37.3 257 mg (82%, LC-MS (ESI): m/z 681.5 (M+H)+), which debaucherous 3M HCl solution in dioxane with quantitative output connection 37.4 (LC-MS (ESI): m/z 481.3 (M+N)+), which in turn compound 37 (LC-MS (ESI): m/z 795.7 (M+N)+) by analogy with the transformation of compounds 14.5 in connection 14. The dihydrochloride 37 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 37 in CH2Cl2and planting ether.

Example 9. Synthesis of methyl ester [(1S)-1-[[(2S)-2-[4-[4-[4-[2-[(2S)-1-[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]phenyl]cyclohexyl]-2-oxazolyl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid 38.

4,4'-Dimethyl diphenyl-4,4'-in primary forms 20.1 (9 g, 33 mmol) hydronaut in CH3COOH (70 ml) in the presence of 10% Pd/C (3 g) and Rh2O3(0.05 g) at 150°C for 16 h under pressure 60-20 ATM N2. The mixture is filtered, evaporated under reduced pressure, to the residue add excess 10% aqueous solution of K2CO3and the mixture is extracted with CHCl3. The organic extracts upriv the Ute and subjected to column chromatography, eluent 10% EtOAc-hexane. The output connection is 38.1 6 g (65%). Compound 27 (6 g, 22 mmol) is boiled in EtOH (100 ml) and H2O (20 ml) in the presence of 50% KOH solution (9 g, 80 mmol) for 30 minutes. The solution is evaporated, the residue is dissolved in water (0.5 l) and add an excess of HCl. The precipitate is filtered off, giving 5 g (92%) of a mixture of CIS+TRANS-dicarboxylic acids 38.2. A mixture of dicarboxylic acids 38.2 5 g (20 mmol) is heated at 300°C under stirring in a stream of Ar for 30 min (at this temperature the compound is melted). Sublimat and the residue is dissolved in hot 20% solution of KOH (50 ml) and stirred with 1 g of activated charcoal. The solution is filtered, diluted with water (0.5 l) and treated with excess HCl. The precipitate is filtered off, giving 3 g (60%) of dicarboxylic acid 38.3 (TRANS-isomer 90%, CIS-isomer (10%).1H NMR (DMSO-d6) 12.5 (USS, 2H) 7.88 (d, 2H, J 8 Hz), 7.34 (d, 2H, J 8 Hz), 2.56 (USM, 1H) 2.26 (USM, 1H) 2.0 (m, 2H) 1.82 (m, 2H) 1.50-1.40 (m, 4H). Connection 38.5 get the same connection 20.6, the yield is 50%.1H NMR LDA-2488 (CDCl3) 7.70 (d, 2H) 7.28 (d, 2H) 5.88 (s, 1H) 5.31 (USS, 1H) 2.60 (dt, 1H,3J 12 Hz,3J 2 Hz), 2.33 (USM, 1H) 2.05-2.00 (m, 4H) 1.65-1.45 (m, 4H). Connection 38.6 get the same connection 20.7, dibromide purified column chromatography, yield 42%.1H NMR (CDCl3): 7.94 (d, 2H) 7.33 (d, 2H) 4.44 (s, 2H, ArCOCH2Br) 4.00 (s, 2H, CyCOCH2Br) 2.84 (m, 1H) 2.63 (m, 1H) 2.15-2.05 (m, 4H) 1.60 (m, 4H). Connect the out 38.7 get the same connection 20.8, output 100%. Connection 38.8 get the same connection 20.9, yield 100%, LCMS 632 (M+1). Compound 38 (free base, LCMS 746 (M+1)) are obtained similarly to the connection 20. The dihydrochloride 38·2HCl produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 38 in CH2Cl2and planting ether.1H NMR (CDCl3) 0.87 (d, 6N, me), 0.93 (d, 3H, Me), 1.03 (d, 3H, Me), 1.5-2.5 (m, 22N), 3.59 (m, 1H), 3.68 (s, 3H, OMe), 3.71 (s, 3H, OMe), 3.80 (m, 3H), 4.34 (m, 1H), 5.24 (m, 1H), 5.42 (m, 1H), 7.16 (s, 1H), 7.24 (, 1H), 7.22 (USD, 2H), 7.68 (USM, 2H).

Similarly, using the corresponding starting compound and a suitable chiral building blocks, were obtained the following compounds:

Dimethyl [1,4-dioxane-2,5-diylbis[1H-imidazole-5,2-diyl(1S)ethylidene(methylimino)[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 649.

Methyl ester [(1S)-1-[[[(1S)-1-[5-[2-[4-[2-[(1S)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]cyclohexyl]-1,3-dioxane-5-yl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 729.

Methyl ester [(1S)-1-[[[(1S)-1-[5-[5-[4-[2-[(1S)-1-[[(2S)--[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]cyclohexyl]-1,3-dioxane-2-yl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 729.

Methyl ester [(1S)-1-[[[(1R)-1-[5-[5-[4-[2-[(1R-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]cyclohexyl]-1,4-dioxane-2-yl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 729.

Methyl ester [(1S)-1-[[[(1R)-1-[5-[5-[4-[2-[(1R)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]cyclohexyl]-1,4-dioxane-2-yl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 731.

Dimethyl [1,4-cyclohexanebis[1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, dihydrochloride, compound 11, LCMS (M+1) 669,1H NMR (DMSO-D6, 400 MHz) δ 0.87 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 6N), 1.86 (m, 6N), 1.97 (m, 4H), 2.10 (m, 2H), 2.51 (m, 2H), 3.56 (m, 2H), 3.61 (d, J=9.40, 6N), 3.63 (m, 2H), 4.02 (m, 2H), 4.75 (d, J=0.42, 2H), 6.42 (s, 2H), 9.06 (m, 4H).

Dimethyl ether [[1,1'-TRANS-bicyclohexyl]-4,4'-diylbis[1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, compound 21, LCMS (M+1) 751,1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.46 (m, 8H), 1.56 (m, 8H), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 2.15 (m, 2H), 2.42 (m, 2H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.01 (d, J=0.42, 2H), 4.75 (m, 2H), 6.37 (s, 2H), 9.06 (m, 4H).

Dimethyl ether [bicyclo[2.2.]octane-1,4-diylbis[1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 695.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]bicyclo[2.2.2]Oct-1-yl]-TRANS-cyclohexyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 778.

Methyl ester [(1R)-1-[[(2R)-2-[5-[2-[2-[5-[(1R)-2-[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]cyclopentyl]-1H-imidazol-2-yl]ethoxy]ethyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid (compound 7). LCMS (M+1) 659.1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.45, J2=0.93, 6N), 0.97 (t, J1=6.45, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 4H), 2.10 (m, 2H), 2.46 (t, J1=14.76, J2=8.00, 4H), 3.31 (t, J1=9.55, J2=0.81, 4H), 3.56 (m, 2H), 3.61 (m, 8H), 3.96 (d, J=0.42, 2H), 4.76 (m, 2H), 6.95 (s, 2H), 8.91 (m, 4H).

Dimethyl ether [THIOBIS[2,1-ethandiyl-1H-imidazole-5,2-diyl(1S)ethylidene(methylimino)[(1R)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 651.

Methyl ester [(1R)-1-[[[(1S)-1-[5-[2-[[(E)-2-[2-[(1S)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]ethynyl]oxy]ethyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 633.

Dimethyl [1,2-atanderson[hydroxy-2,1-ethandiyl-1H-imidazole-5,2-diyl(1S)ethylidene(methylimino)[(1R)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, dihydrochloride, LCMS (M+1) 679.

Dimethyl ether [xibis[(1E)-1-propen-3,1-diyl-1H-imidazole-5,2-diyl(1S)ethylidene(methylimino)[(1R)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 659.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[3-[2-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]ethoxy]-1-PROPYNYL]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]carbamino acid, LCMS (M+1) 645.

Dimethyl ether [oxybis[1-propyne-3,1-diyl-1H-imidazole-5,2-diyl(1R)ethylidene(methylimino)[(1R)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 645.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[3-[[(2E)-3-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-yl]-2-propenyl]oxy]-1-propenyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 657.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[3-[2-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-yl]ethoxy]-1-PROPYNYL]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 645.

2,2'-[1,4-Naftalindisul(1H-imidazole-5,2-diyl)]bis[1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-,(2S,2'S)-pyrrolidin, LCMS (M+1) 802.

2,2'-[1,5-Naftalindisul(1H-imidazole-5,2-diyl)]bis[1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-,(2S,2'S)-pyrrolidin, LCMS (M+1) 802.

2,2'-[2,5-Teenville(1H-imidazole-5,2-diyl)]bis[1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-,(2S',2'S)-pyrrolidin, LCMS (M+1) 758.

Dimethyl ether [[2,2'-dateopen]-5,5'-diylbis[1H-imidazole-5,2-diyl(1S)ethylidene(methylimino)[(1R)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-CT the amine acid, the connection 29, LCMS (M+1) 727,1H NMR (DMSO-D6, 400 MHz) δ 0.87 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.40 (t, J1=7.12, J2=6.78, 6N), 1.95 (d, J=8.50, 2H), 3.02 (t, J1=14.23, J2=1.50, 6N), 3.61 (d, J=9.40, 6N), (m, 2H), 4.03 (d, J=8.50, 2H), 4.89 (m, 2H), 6.51 (d, J=4.00, 2H), 6.86 (d, J=0.25, 2H), 7.24 (d, J=0.25, 2H), 8.79 (m, 4H).

N,N'-[[2,2'-dateopen]-5,5'-diylbis[1H-imidazole-5,2-diyl(1S)ethylidene]]bis[N'-methyl-α-phenyl-, (αR)-1-piperidineacetate, the connection 32, LCMS (M+1) 816,1H NMR (DMSO-D6, 400 MHz) δ 1.39 (t, J1=7.12, J2=6.97, 6N), 1.54 (m, 2H), 1.67 (m, 6N), 1.75 (m, 4H), 2.63 (m, 4H), 2.71 (m, 4H), 2.97 (t, J1=14.23, J2=1.50, 6N), 3.94 (m, 2H), 5.37 (d, J=0.30, 2H), 6.52 (d, J=4.00, 2H), 6.87 (d, J=0.25, 2H), 7.22 (m, 6N), 7.39 (m, 4H), 7.46 (t, J1=7.32, J2=2.10, 2H), 11.18 (m, 2H).

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[5'-[2-[(2S)-1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-yl]-1H-imidazol-2-yl]-, (2R)-pyrrolidin, the connection 33, LCMS (M+1) 840,1H NMR (DMSO-D6, 400 MHz) δ 1.51 (m, 2H), 1.70 (m, 10H), 1.84 (m, 2H), 1.99 (m, 2H), 2.10 (m, 2H), 2.65 (m, 4H), 2.72 (m, 4H), 3.45 (m, 2H), 3.53 (m, 2H), 3.96 (d, J=0.42, 2H), 4.58 (m, 2H), 4.64 (m, 2H), 6.51 (d, J=4,00, 2H), 6.92 (d, J=0.25, 2H), 7.25 (USD, 6N), 7.38 (m, 4H), 7.44 (t, J1=7.32, J2=2.10, 2H), 11.18 (m, 2H).

N,N'-[[2,2'-dateopen]-5,5'-diylbis[1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-2-oxo-1-phenyl-2,1-ethandiyl]]]bis-cyclopropanecarboxamide the dihydrochloride, compound 34, LCMS (M+1) 840,1H NMR (DMSO-D6, 400 MHz) δ 0.83 (m, 4H), 0.91 (m, 4H), 1.64 (m, 2H), 1.76 (m, 2H), 1.84 (m, 2H), 1.99 (m, 2H), 2.10 m, 2H), 3.43 (d, J=4.78, 2H), 3.50 (m, 2H), 4.60 (m, 2H), 5.17 (d, J=0.42, 2H), 6.51 (d, J=4.00, 2H), 6.92 (d, J=0.25, 2H), 7.19 (m, 4H), 7.27 (m, 8H), 9.72 (m, 4H).

1-[(2S)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[5-[4'-[2-[(2S)-1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][1,1'-diphenyl]-4-yl]-2-thienyl]-1H-imidazol-2-yl]-, (2S)-pyrrolidin, LCMS (M+1) 910.

2,2'-[2,5-Teenville(4,1-phenylene-1H-imidazole-5,2-diyl)]bis[1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-, (2S,2'S)-pyrrolidin, LCMS (M+1) 910.

1-[(2S)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[4-[5'-[2-[(2R)-1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-yl]phenyl]-1H-imidazol-2-yl]-, (2R)-pyrrolidin, LCMS (M+1) 916.

2,2'-[2,6-Naftalindisul(5,2-Tandil-1H-imidazole-5,2-diyl)]bis[1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-,(2R,2'R)-pyrrolidin, LCMS (M+1) 966.

1-[(2S)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[4-[5-[6-[2-[(2R)-1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-2-naphthalenyl]-2-thienyl]phenyl]-1H-imidazol-2-yl]-, (2R,2'R)-pyrrolidin, LCMS (M+1) 966.

1-[(2S)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[[4-[4-[2-[(2R)-1-[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-TRANS-cyclohexyl]ethinyl]-1H-imidazol-2-yl]-, (2R)-pyrrolidin, LCMS (M+1) 830.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[4-[4-[2-[(2S)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-TRANS-cyclohexyl]-1H-imidazol-2-yl]-, (2S)-pyrrolidin, LCMS (M+1) 806.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[4[4-[2-[(2S)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]cyclohexyl]-1H-imidazol-2-yl]-, (2S)-pyrrolidine, dihydrochloride, LCMS (M+1) 806.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[6-[4-[2-[(2S)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]cyclohexyl]-1,3,5-hexatriene]-1H-imidazol-2-yl]-, (2S)-pyrrolidin, LCMS (M+1) 830.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[[4-[4-[2-[(2S)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]cyclohexyl]ethinyl]-1H-imidazol-2-yl]-, (2S)-pyrrolidin, LCMS (M+1) 830.

2,2'-[1,4-Cyclohexadiene(1,3-butadien-4,1-diyl-1H-imidazole-5,2-diyl)]bis[1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-, (2R,2'R)-pyrrolidin, LCMS (M+1) 854.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[4-[4-[2-[(2R)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]bicyclo[2.2.2]Oct-1-yl]-1,3-butadienyl]-1H-imidazol-2-yl]-, (2R)-pyrrolidin, LCMS (M+1) 832.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[6-[4-[2-[(2R)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]bicyclo[2.2.2]Oct-1-yl]-1,3,5-hexatriene]-1H-imidazol-2-yl]-, (2R)-pyrrolidin, LCMS (M+1) 856.

1-[(2R)-2-Phenyl-2-(1-piperidinyl)acetyl]-2-[5-[[4-[4-[2-[(2R)-1-[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]bicyclo[2.2.2]Oct-1-yl]ethinyl]-1H-imidazol-2-yl]-, (2R)-pyrrolidin, LCMS (M+1) 856.

N-[(1S)-2-[(2S)-2-[5-[[5-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-dioxane-2-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropane is the oksamid, LCMS (M+1) 785.

N-[(1S)-2-[(2S)-2-[5-[[2-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-dioxane-5-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 785.

N-[(1S)-2-[(2S)-2-[5-[2-[4-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,3-dioxane-5-yl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 809.

N-[(1S)-2-[(2S)-2-[5-[5-[4-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,3-dioxane-2-yl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 809.

N-[(1S)-2-[(2S)-2-[5-[6-[5-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-dioxane-2-yl]-1,3,5-hexatriene]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 833.

N-[(1S)-2-[(2S)-2-[5-[[5-[4-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,3-dioxane-2-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 833.

N-[(1S)-2-[(2S)-2-[5-[[2-[4-[2-[(2S)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,3-dioxane-5-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 833.

N-[(1S)-2-[(2R)-2-[5-[[5-[4-[2-[(2R)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,3-dioxane-2-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 833.

N-[(1S)-2-[(2R)-2-[5-[[5-[2-[(2R)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,4-dioxane-2-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 785.

N-[(1S)-2-[(2R)-2-[5-[5-[4-[2-[(2R)-1-[(2S)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,4-dioxane-2-yl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 809.

N,N'-[1,4-Dioxane-2,5-diylbis[2,1-ethandiyl-1H-imidazole-5,2-diyl(2R)of-2.1-pyrrolidinyl[(1S)-2-oxo-1-phenyl-2,1-ethandiyl]]]bis-cyclopropanecarboxamide, LCMS (M+1) 809.

N-[(1R)-2-[(2S)-2-[5-[[5-[4-[2-[(2S)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1,4-dioxane-2-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 833.

N-[(1R)-2-[(2S)-2-[5-[6-[5-[2-[(2S)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,4-dioxane-2-yl]-1,3,5-hexatriene]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 833.

N-[(1R)-2-[(2S)-2-[5-[6-[5-[[2-[(2S)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidin the yl]-1H-imidazol-5-yl]ethinyl]-1,4-dioxane-2-yl]-1,3,5-hexatriene]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 857.

N,N-[1,4-Dioxane-2,5-diylbis[1,3-butadien-4,1-diyl-1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1R)-2-oxo-1-phenyl-2,1-ethandiyl]]]bis-cyclopropanecarboxamide, LCMS (M+1) 857.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[6-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3,5-hexatriene]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, compound 16, LCMS (M+1) 735 401H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.01 (d, J=0.42, 2H), 4.75 (m, 2H), 6.86 (s, 1H), 7.28 (s, 1H), 7.72 (d, J=8.26, 2N), 7.90 (d, J=1.95, 2H), 8.80 (m, 4H).

Methyl ester [(1S)-1-[[(2S)-2-[5-[[4-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]phenyl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, compound 15, LCMS (M+1) 735 401H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.01 (d, J=0.42, 2H), 4.75 (m, 2H), 6.82 (d, J=0.93, 1H), 7.33 (s, 1H), 7.88 (t, J1=2.02, J2=0.71, 2H), 7.93 (m, 2H), 8.80 (m, 4H).

Dimethyl [1,4-phenylenebis[1,3-butadien-4,1-diyl-1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, compound 17, LCMS (M+1) 759 40 1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.01 (d, J=0.42, 2H), 4.75 (m, 2H), 7.33 (s, 2H), 7.81 (s, 4H), 8.80 (m, 4H).

Methyl ester [(1S)-1-[[(2S)-2-[5-[6-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-2-naphthalenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, compound 19, LCMS (M+1) 761 401H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.01 (d, J=0.42, 2H), 4.75 (m, 2H), 6.94 (s, 1H), 7.33 (s, 1H), 7.65 (d, J=8.56, 1H), 7.85 (m, 1H), 7.91 (m, 1H), 8.05 (USD, 2H), 8.61 (t, J1=1.65, J2=0.33, 1H), 8.79 (m, 4H).

N-[(1R)-2-[(2R)-2-[5-[5-[6-[2-[(2R)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3,5-hexatriene]-1-naphthalenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 874.

N-[(1R)-2-[(2R)-2-[5-[[4-[4-[2-[(2R)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1-naphthalenyl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 874.

N-[(1R)-2-[(2R)-2-[5-[[5-[4-[2-[(2R)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-1-naphthalenyl]ethinyl]-1H-imide is evil-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 874.

N-[(1R)-2-[(2R)-2-[5-[5-[2-[2-[(2R)-1-[(2R)-2-[(Cyclopropanecarbonyl)amino]-2-phenylacetyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]ethyl]-2-thienyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-cyclopropanecarboxamide, LCMS (M+1) 785.

N,N'-[2,5-Teenville[2,1-ethandiyl-1H-imidazole-5,2-diyl(1S)ethylidene]]bis[N'-methyl-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 790.

N-Methyl-N-[(1S)-1-[5-[(E)-2-[5-[2-[(1S)-1-[methyl[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-2-thienyl]ethynyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 760.

N-Methyl-N-[(1S)-1-[5-[(E)-2-[5-[2-[2-[(1S)-1-[methyl[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]ethyl]-2-thienyl]ethynyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 788.

N,N'-[2,5-Teenville[(E)of-2.1-ethandiyl-1H-imidazole-5,2-diyl(1S)ethylidene]]bis[N'-methyl-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 786.

N-Methyl-N-[(1R)-1-[5-[[5-[2-[2-[(1R)-1-[methyl[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]ethyl]-2-thienyl]ethinyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 786.

N-Methyl-N-[(1R)-1-[5-[(E)-2-[5-[[2-[(1R)-1-[methyl[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]ethinyl]-2-thienyl]ethynyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 784.

N-Methyl-N-[(1R)-1-[5-[[5-[2-[(1R)-1-[methyl[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-2-thienyl]ethinyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αS)-1-piperidino the Tamid, LCMS (M+1) 758.

N-Methyl-N-[(1R)-1-[5-[4-[5-[2-[(1R)-1-[methyl[(2S)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-2-thienyl]-1,3-butadienyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αS)-1-piperidineacetate, LCMS (M+1) 782.

N-Methyl-N-[(1S)-1-[5-[5-[6-[2-[(1S)-1-[methyl[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-1,3,5-hexatriene]-2-thienyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 806.

N-Methyl-N-[(1S)-1-[5-[[5-[4-[2-[(1S)-1-[methyl[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-1,3-butadienyl]-2-thienyl]ethinyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 806.

N,N'-[2,5-Teenville[1,3-butadien-4,1-diyl-1H-imidazole-5,2-diyl(1S)ethylidene]]bis[N'-methyl-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 830.

N-Methyl-N-[(1S)-1-[5-[[5-[4-[2-[(1S)-1-[methyl[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-1,3-butadienyl]-2-thienyl]methyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 796.

N-Methyl-N-[(1R)-1-[5-[2-[5-[4-[2-[(1R)-1-[methyl[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-1,3-butadienyl]-2-thienyl]ethyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 810.

N-Methyl-N-[(1R)-1-[5-[(E)-2-[5-[4-[2-[(1R)-1-[methyl[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]-1,3-butadienyl]-2-thienyl]ethynyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 808.

Methyl ester [(1S)-1-[[(2S)-2-[5-[5-[[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-ethyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]phenyl]ethinyl]-2-thienyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 769.

Dimethyl [1,2-ethandiyl[5,2-Tandil-1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, dihydrochloride, compound 26, LCMS (M+1) 775,1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 4H), 2.10 (m, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.03 (m, 2H), 4.74 (m, 2H), 6.61 (d, J=3.50, 2H), 7.00 (d, J=0.25, 2H), 7.17 (d, J=3.50, 2H), 8.79 (m, 4H).

Dimethyl [1,3-butadien-1,4-diylbis[5,2-Tandil-1H-imidazole-5,2-diyl(2S)of-2.1-pyrrolidinyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, dihydrochloride, compound 27, LCMS (M+1) 799,1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 4H), 2.10 (m, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.03 (m, 2H), 4.74 (m, 2H), 6.54 (d, J=3.50, 2H), 7.00 (d, J=0.25, 2H), 7.67 (d, J=3.50, 2H), 8.79 (m, 4H).

Methyl ester [(1S)-1-[[(2S)-2-[5-[5-[4-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]phenyl]-1,3-butadienyl]-2-thienyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]the carbonyl]-2-methylpropyl]-carbamino acid, dihydrochloride, compound 28, LCMS (M+1) 793,1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 4H), 2.10 (m, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.03 (m, 2H), 4.74 (m, 2H), 6.54 (d, J=3.50, 1H), 6.86 (s, 1H), 7.00 (d, J=0.25, 1H), 7.67 (s, 1H), 7.76 (m, 2H), 7.91 (d, J=8.26, 2H), 8.79 (m, 4H).

Meth is lovy ether [(1S)-1-[[(2S)-2-[5-[[5'-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-yl]ethinyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]the carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 775.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[5'-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-yl]-1,3-butadienyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 799.

Methyl ester [(1S)-1-[[(2S)-2-[5-[5-[4-[[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]ethinyl]phenyl]-2-thienyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 769.

Methyl ester [(1S)-1-[[(2S)-2-[5-[5-[4-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]phenyl]-2-thienyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]the carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 793.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[5-[[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]ethinyl]-2-thienyl]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 769.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[5-[4-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-butadienyl]-2-thienyl]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]the carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 793.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]methoxy]phenyl]-1H-imidazol-2-the l]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, hydrochloride, compound 10, LCMS (M+1) 693;1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 4H), 2.10 (m, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 4.01 (d, J=0.42, 2H), 4.75 (m, 2H), 5.12 (s, 2H), 6.71 (d, J=0.93, 1H), 6.87 (s, 1H), 7.07 (d, J=0,7 .89, 2H), 7.89 (d, J=0.7.89, 2H), 8.98 (m, 4H).

N-Methyl-N-[(1R)-1-[5-[2-[4-[2-[(1R)-1-[methyl[(2R)-2-phenyl-2-(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]phenoxy]ethyl]-1H-imidazol-2-yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 772.

N-Methyl-N-[(1R)-1-[5-[3-[4-[2-[(1R)-1-[methyl[(2R)-2-phenyl-2(1-piperidinyl)acetyl]amino]ethyl]-1H-imidazol-5-yl]phenoxy]propyl]-1H-imidazol-2-}yl]ethyl]-α-phenyl-, (αR)-1-piperidineacetate, LCMS (M+1) 786.

Methyl ester [(1S)-1-[[[(1S)-1-[5-[(1E)-3-[4-[2-[(1S)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]phenoxy]-1-propenyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 695.

Methyl ester [(1S)-1-[[[(1S)-1-[5-[3-[4-[2-[(1S)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]phenoxy]-1-PROPYNYL]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]carbamino acid, LCMS (M+1) 693.

Dimethyl [1,4-phenylenebis[hydroxy-2,1-ethandiyl-1H-imidazole-5,2-diyl(1S)ethylidene(methylimino)[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 727.

Dimethyl [1,4-phenylenebis[hydroxy-1-propyne-3,1-diyl-1H-imidazole-5,2-diyl(1S)of atili the Yong(methylimino)[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethandiyl]]]bis-carbamino acid, LCMS (M+1) 747.

Methyl ester [(1S)-1-[[[(1R)-1-[5-[5-[4-[2-[(1R)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]cyclohexyl]-2-thienyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]carbamino acid, LCMS (M+1) 747.

Methyl ester [(1S)-1-[[[(1R)-1-[5-[5-[4-[2-[(1R)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-TRANS-cyclohexyl]-2-thienyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 747.

Methyl ester [(1S)-1-[[[(1R)-1-[5-[5-[4-[2-[(1R)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]bicyclo[2.2.2]Oct-1-yl]-2-thienyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 753.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[5-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,3-dioxane-2-yl]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, compound 22, LCMS (M+1) 749,1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6H), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 3.22 (m, 1H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 3.84 (m, 2H), 4.01 (d, J=0.42, 2H), 4.08 (m, 2H), 4.75 (m, 2H), 5.48 (m, 1H), 6.75 (s, 1H), 6.86 (s, 1H), 7.68 (d, J=8.06, 2H), 7.92 (d, J=1.99, 2H), 8.92 (m, 4H).

Methyl ester [(1S)-1-[[[(1R)-1-[5-[4-[2-[2-[(1R)-1-[[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamine is]ethyl]-1H-imidazol-5-yl]-1,3-dioxane-5-yl]phenyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 725.

Methyl ester [(1S)-1-[[(2S)-2-[5-[4-[5-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl]-1,4-dioxane-2-yl]phenyl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, compound 23, LCMS (M+1) 749,1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 6N), 0.97 (t, J1=6.50, J2=0.93, 6N), 1.64 (m, 2H), 1.84 (m, 2H), 1.97 (m, 2H), 2.10 (m, 2H), 3.45 (d, J=14.76, 2H), 3.56 (m, 2H), 3.63 (m, 8H), 3.73 (m, 2H), 3.90 (m, 2H), 4.03 (m, 2H), 4.47 (m, 1H), 4.64 (m, 1H), 4.75 (m, 2H), 6.82 (s, 1H), 6.86 (s, 1H), 7.68 (d, J=8.06, 2H), 7.92 (m, 2H), 8.92 (m, 4H).

Methyl ester [(1R)-1-[[[(1S)-1-[5-[6-[5-[2-[(1S)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-1,3-dioxane-2-yl]-2-naphthalenyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 775.

Methyl ester [(1R)-1-[[[(1S)-1-[5-[6-[2-[2-[(1S)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-1,3-dioxane-5-yl]-2-naphthalenyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 775.

Methyl ester [(1R)-1-[[[(1S)-1-[5-[6-[5-[2-[(1S)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-1,4-dioxane-2-yl]-2-naphthalenyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 775.

Methyl ester [(1R)-1-[[[(1S)-1-[5-[2-[4'-[2-[(1S)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]metelli what about]ethyl]-1H-imidazol-5-yl][1,1'-diphenyl]-4-yl]-1,3-dioxane-5-yl]-1H-imidazole-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 801.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[5-[4'-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl][1,1'-diphenyl]-4-yl]-1,3-dioxane-2-yl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 801.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[5-[4'-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl][1,1-diphenyl]-4-yl]-1,4-dioxane-2-yl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 801.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[5-[5-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-1,3-dioxane-2-yl]-2-thienyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 731.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[5-[2-[2-[(1R)-1-[[(2R)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-1,3-dioxane-5-yl]-2-thienyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 731.

Methyl ester [(1R)-1-[[[(1R)-1-[5-[5-[5-[2-[(1R)-1-[[(2H)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]methylamino]ethyl]-1H-imidazol-5-yl]-1,4-dioxane-2-yl]-2-thienyl]-1H-imidazol-2-yl]ethyl]methylamino]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 731.

Methyl ester [(1S)-1-[[(2S)-2-[5-[2-[5'-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-and the]-1,3-dioxane-5-yl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 838.

Methyl ester [(1S)-1-[[(2S)-2-[5-[5-[5'-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-yl]-1,3-dioxane-2-yl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 838.

Methyl ester [(1S)-1-[[(2S)-2-[5-[5-[5'-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-2-pyrrolidinyl]-1H-imidazol-5-yl][2,2'-dateopen]-5-yl]-1,4-dioxane-2-yl]-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 838.

Example 10. Methyl ester {(S)-2-methyl-1-[(S)-2-(5-phenyl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acid 42.

To a solution of 196 mg (0.5 mmol) of the compound 42.1 in 10 ml of methanol is added 10 mg of 10% Pd/C and the mixture is stirred in a stream of hydrogen for 12 hours the Mixture is filtered through celite and evaporated in vacuum. Output connections 42.2 153 mg (98%). LC-MS (ESI): m/z 314 (M+H)+. Connection 42.2 debaucherous 3M HCl solution in dioxane with quantitative output connection 42.3 (LCMS (ESI): m/z 214 (M+H)+), which in turn connection 42 (LCMS (ESI): m/z 371 (M+H)+) by analogy with the transformation connection 18.5 in connection 18. The dihydrochloride 42 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 42 in CH2Cl2and planting ether.1H NMR (DMSO-d6, 400 MHz) δ 14.85 (USM, 2H), 8.05 (s, 1H), 7.86 (m, 2H), .50 (m, 2H), 7.41 (m, 1H), 7.27 (d, J=8.8 Hz, 1H), 5.17 (t, J=6.8 Hz, 1H), 4.11 (t, J=7.8 Hz, 1H), 4.00 (m, 1H), 3.83 (USM, 1H), 3.56 (s, N), 3.53 (s, 2.75H), 2.36 (m, 1H), 2.16 (m, 2H), 2.06 (m, 1H), 2.00 (m, 1H), 0.90 (m, N), 0.84 (d, J=6.4 Hz, M), 0.77 (d, J=6.4 Hz, N).

Example 11. Methyl ester {(S)-2-methyl-1-[(S)-2-(5-naphthalene-1-yl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acid 43.

Connection 43.1 receive according to the method described for compound 42.2. Yield 92%. LCMS (ESI): m/z 364 (M+N)+. Connection 43.1 debaucherous 3M HCl solution in dioxane with quantitative output connection 43.2 (LCMS (ESI): m/z 264 (M+H)+), which in turn compound 43 (LCMS (ESI): m/z 421 (M+N)+) by analogy with the transformation of compounds 14.5 in connection 14. The dihydrochloride 43 is produced by adding an excess of 3M HCl solution in dioxane to a solution of the base 42 in CH2Cl2and planting ether.

Example 12. Methyl ester {(S)-2-methyl-1-[(S)-2-(5-naphthalene-2-yl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acid 44.

Synthesis of ligand 44 carried out by analogy with the synthesis of the ligand 43. Connection 44.1 obtained with a yield of 97%. LCMS (ESI): m/z 364,4 (M+N)+. NMR (DMSO-d6, 400 MHz) δ 14.6 (USS, 1,5H), 8.36 (s, 1H), 8.22 (d, J=21.6 Hz, 1H), 8.09 (d, J=18.8 Hz, 1H), 7.97 (m, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.60 (m, 2H), 5.07 (m, 1H), 7.20 (m, 1H), 3.44 (m, 1H), 2.43, (USM, 1H), 2.08 (m, 1H), 1.98 (m, 2H),1.41 (s, N), 1.18 (s, N). Connection 44.2 obtained with a yield of 94%. LCMS (ESI): m/z 264,3 (M+N)+. NMR (DMSO-d6, 400 MHz) δ 10.09 (USS, 1H), 9.58 (USS, N), 8.43 (s, 1H), 8.11 (s, 1H), 8.00 (USS, 2H), 7.93 (USM, 2H), 7.54 (m, 2H), 4.97 (USM, 1H), 3.40 (USM, 1H), 2.42 (m, 1H), 2.20 (USM, 1H), 2.03 (m, 2H). Ligand 44 obtained with the yield of 33%. The dihydrochloride 44·2HCl produced by adding an excess of 3M HCl solution in dioxane to a solution of the base in 1144 CH2Cl2and planting ether. LCMS (ESI): m/z UAH 421,2 (M+N)+. NMR (DMSO-d6, 400 MHz) δ 15.02 (USS, 1H), 14.67 (USS, 1H), 8.43 (s, 1H), 8.18 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.94 (m, 3H), 7.59 (m, 2H), 7.29 (d, J=8,4 Hz, 1H), 5.19 (t, J=6.6 Hz, 1H), 4.13 (t, J=7.6 Hz, 1H), 3.96 (USM, 1H), 3.86, (USM, 1H), 3.56 (s, N), 3.54 (s, N), 2.40 (m, 1H), 2.18 (USM, 2H), 2.05 (m, 2H), 0.91 (m, N), 0.81 (DD, J1=27.2 Hz, J2=6.4 Hz, N).

Example 13. Methyl ester {(S)-2-methyl-1-[(S)-2-(5-thiophene-2-yl-1H-imidazol-2-yl)-pyrrolidin-1-carbolin]-propyl}-carbamino acids 58 and methyl ester {(S)-2-Methyl-1-[(S)-2-[5-(2,2'-dateopen-5-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbolin]-propyl}-carbamino acid 59.

Suspended 256 mg (0,762 mmol, 1 EQ.) broowaha ether and 404 mg (3,81 mmol, 5 EQ.) sodium carbonate in a mixture of 7.5 ml of ethanol and 1.8 ml of water. After the mixture was bubbled argon for 40 minutes at 90°C. the mixture is Then cooled to 80°C, add 667 mg (1,68 mmol, 2.2 EQ.) connection 24.3 and bubbled argon for another 10 minutes. Then added 53 mg (0,0762 mmol,0.1 EQ.) [PD(h 3)2]Cl2and bubbled argon for 5 minutes. In the end, to the reaction mixture of 2.9 mg (0,0762 mmol, 0.1 EQ.) sodium borohydride. The reaction mass is stirred for 15 h at 85°C in argon atmosphere. Completeness of the reaction control method LCMS. After completion of the reaction the reaction mass is filtered through a layer of Celite, the filtrate evaporated on a rotary evaporator. The residue is dissolved in dichloromethane, the extract washed with water, dried with anhydrous sodium sulfate, evaporated on a rotary evaporator. Compound 7 is cleaned by the method of column chromatography (eluent a gradient of hexane:THF: triethylamine= 12:1:0.1 to 8:1:0,1). The connection 6 is cleaned by the method of HPLC. Get the connection 58.1 - 71 mg, yield 29%, the connection 59.1 120 mg, yield 39%.

Connection 58.1 - LCMS (ESI): m/z 320.0 (M+N)+. NMR (CDCl3-d3, 400 MHz) δ 10.5 (USS, N), 7.21 (USM, 1H), 7.17 (d, J=4.0 Hz, 1H), 7.12 (s, 1H), 7.02 (t, J=4.0 Hz, 1H), 4.96 (m, 1H), 3.50 (USM, 1H), 3.41 (USM, 1H), 3.00 (USM, 1H), 2.15 (USM, 2H), 1.96 (m, 1H), 1.50 (s, N). Connection 59.1 - LCMS (ESI): m/z 402,1 (M+N)+. Synthesis of ligands 58 and 59 are carried out by analogy with the synthesis of compounds 14 of 14.5. Dihydrochloride 58 and 59 is produced by adding an excess of 3M HCl solution in dioxane to solutions of bases 58 and 59 in CH2Cl2and planting ether. Connection 58.2: LCMS (ESI): m/z to 220.1 (M+N)+. Ligand 58: LCMS (ESI): m/z 377,2 (M+H)+. Connection 59.2: LCMS (ESI): m/z 302,3 (M+H)+. NMR (DMSO-d6400 M is C) δ 10.3 (USS, 1H), 9.48 (USS, 1H), 7.80 (s, 1H), 7.52 (d, J=4.8 Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 7,32 (d, J=4.8 Hz, 1H), 7.29 (t, J=3.6 Hz, 1H), 7.10 (DD, J1=4.8 Hz, J2=4.0 Hz, 1H), 4,84 (USM, 1H), 3.34 (USM, 2H), 2.41 (m, 1H), 2.33 (m, 1H), 2.15 (m, 1H), 1.99 (m, 1H). Ligand 59: LC-MS (ESI): m/z 459,5 (M+N)+. NMR (DMSO-d6, 400 MHz) δ 14.45 (USS, 1H), 7.90 (s, 1H), 7.58 (m, 2H), 7.37 (s, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.13 (m, 1H), 5.09 (t, J=6.4 Hz, 1H), 4.10 (t, J=7.2 Hz, 1H), 3.90 (USM, 1H), 3.84 (USM, 1H), 3.56 (s, N), 3.54 (, N), 2.35 (m, 1H), 2.15 (USM, 2H), 2.02 (m, 2H), 0.88 (m, N), 0.80 (DD, J1=23.0 Hz, J2=6.6 Hz, N).

Methyl ester [(1S)-1-[[(2R)-2-(5-ethinyl-1H-imidazol-2-yl)-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 319.

Methyl ester [(1S)-2-methyl-1-[[(2R)-2-[5-(2-PROPYNYL)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]propyl]-carbamino acid, LCMS (M+1) 333.

Methyl ester [(1S)-1-[[(2R)-2-[5-(3-butenyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 347.

Methyl ester [(1S)-1-[[(2R)-2-[5-(2-butynyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 347.

Methyl ester [(1S)-1-[[(2S)-2-[5-(1,3-butadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, compound 39, LCMS (M+1) 343.1H NMR (DMSO-D6, 400 MHz) δ 0.88 (t, J1=6.50, J2=0.93, 3H), 0.95 (t, J1=6.75, J2=0.93, 3H), 1.64 (m, 1H), 1.85 (m, 1H), 1.92 (s, 1H), 1.99 (m, 2H), 2.10 (m, 1H), 3.56 (m, 1H), 3.61 (d, J=9.40, 3H), 3.68 (m, 1H), 4.03 (d, J=0.42, 1H), 4.73 (m, 1H), 7.25 (s, 1H), 8.80 (m, 2H).

Methyl e is Il [(1S)-2-methyl-1-[[(2S)-2-[5-(2,4-pentadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]propyl]-carbamino acid, LCMS (M+1) 357.

Methyl ester [(1S)-2-methyl-1-[[(2S)-2-[5-(1,3-pentadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]propyl]-carbamino acid, LCMS (M+1) 357.

Methyl ester [(1R)-2-methyl-1-[[(2R)-2-[5-(1,4-pentadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]propyl]-carbamino acid, LCMS (M+1) 357.

Methyl ester [(1R)-1-[[(2R)-2-[5-(3,5-hexadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 371.

Methyl ester [(1S)-1-[[(2S)-2-[5-(1,3-hexadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 371.

Methyl ester [(1S)-1-[[(2S)-2-[5-(1,5-hexadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 371.

Methyl ester [(1S)-1-[[(2S)-2-[5-(4-cyclohexyl-1,3-butadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carbamino acid, LCMS (M+1) 425.

Methyl ester [(1S)-1-[[(2S)-2-[5-(4-bicyclo[2.2.2]Oct-1-yl-1,3-butadienyl)-1H-imidazol-2-yl]-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-carb is mirovoi acid, LCMS (M+1) 451.

Example 14. Obtaining a pharmaceutical composition in tablet form. Mix 1600 mg of starch, 1600 mg of powdered lactose, 400 mg of talc and 1000 mg of bis-azole 14. The resulting block is crushed into granules and sieved through a sieve, collecting the granules with a size 14-16 mesh. The obtained granules tabletirujut in a suitable form tablets weighing 560 mg each.

Example 15. Obtaining a pharmaceutical composition in capsule form. Thoroughly mixed with the bis-azole 14 with lactose powder in a 2:1 ratio. The obtained powder mixture is Packed 300 mg in gelatin capsules of suitable size.

Example 16. Obtaining pharmaceutical compositions in the form of injectable compositions for intramuscular, intraperitoneal or subcutaneous injection. Mix 500 mg bis-azole 14 with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injectable water. The resulting solution is filtered and placed in 1 ml ampoules which are sealed.

1. Substituted azoles of the General formulas 1A and 1B and their pharmaceutically acceptable salts

where solid lines with accompanying dashed linesrepresents a single or double bond, provided that when one of them is single bond, the other double bond;
X and Y do not necessarily accept different values and represent the atoms is nitrogen, oxygen, sulfur or an NH group;
R1and R2are not necessarily the same radicals 2.1-2.20, where the asterisk (*) are joining azole fragments;


And is a:
- aliphatic C2-C8biradical selected from the diradicals of the formula 3.1-3.36, where the asterisk (*) indicates the point of attachment azole fragments;

- dioxane, cyclo - and bicycloheptene biradical selected from the diradicals of the formula 3.37-3.47, in which the asterisk (*) indicates the point of attachment azole fragments;


- alkyloxyalkyl, altneratively, alkyloxyalkyl biradical and their thio analogue selected from the diradicals of the formula 3.48-3.56, in which the asterisk (*) indicates the point of attachment azole fragments;

aryl and titanovyi biradical, selected from the diradicals of the formula 3.57-3.71, in which the asterisk (*) indicates the point of attachment azole fragments;


- alkylcyclohexanes, alkynylamino, alkynylaryl, alkylthiophenes, alkenylphenol and alkylthiophenes of biradical is, selected from the diradicals of the formula 3.72-3.129, in which the asterisk (*) indicates the point of attachment azole fragments;



- alkyloxyalkyl, altneratively, alkyloxyalkyl biradical selected from the diradicals of the formula 3.130 - 3.136, in which the asterisk (*) indicates the point of attachment azole fragments;

- cycloalkylcarbonyl, origianaly and typedarray biradical selected from the diradicals of the formula 3.137-3.154, in which the asterisk (*) indicates the point of attachment azole fragments,


and

provided that in one of the azole rings Y=NH, and the other Y=O, R1=R2=2.3;
In is:
- aliphatic C2-C8radical selected from the radicals of formulae 4.1-4.12, in which the asterisk (*) indicate the place of attachment of azole fragment;

- aryl and tofinally radical selected from radicals of the formula 4.13-4.30, where the asterisk (*) in asana the place of attachment of azole fragment;


- alkylcyclohexanes, alkynylaryl, al is ultiately and alkylthiophenes radical, selected from formulas 4.31-4.47, in which the asterisk (*) indicate the place of attachment of azole fragment;


- cycloalkylcarbonyl, 4-cycloalkenyl, (bicicleta)benzene, 4-(bicicleta)biphenyloxy, origianaly and typedarray adikal, selected from the radicals 4.48-4.72, in which the asterisk (*) are joining azole fragments;


excluding
((R)-1-{(R)-2-[5-(4-{2-[(R)-1-((R)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-buta-1,3-dienyl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-karamanova acid methyl ester;
((S)-1-{(S)-2-[5-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-karamanova acid methyl ester dihydrochloride;
((S)-1-{(S)-2-[5-(6-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalene-2-yl)-1H-imidazol-2-yl]-pyrrolidin-1-carbonyl}-2-methyl-propyl)-karamanova acid methyl ester dihydrochloride;
[(S)-1-((S)-2-{5-[5-(4-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-thiophene-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-carbonyl)-2-methyl-propyl]-karamanova acid methyl ether;
dimethyl (2S,2'S)-1,1'-((2R,2'R)-2,2'-(5,5'-(4,4'-(thiophene-2,5-diyl)bis(4,1-phenylene))bis(1 H-imidazole-5,2-diyl))bis(pyrrolidin-2.1-diyl))bis(3-methyl-1-exabot the n-2,1-diyl)dicarbamate.

2. Compounds according to claim 1, which represents a substituted azoles of the General formula 5.1-5.70, in which X, Y, R1, R2and solid lines, with their accompanying dashed lineshave the above






3. Compounds according to claim 1, which represents a substituted azoles of the General formula 6.1-6.70, in which A, X, Y, and solid lines with accompanying dashed lineshave the above


































4. Compounds according to claims 1 to 3, a represents a substituted azoles of the formula 6, 7, 9-12, 14-17, 19-30, 32-49, 51, 54, 56-62

















































5. The ligands, the spectrum of biological activity which includes viral protein NS5A, which represents a substituted azoles of the General formulas 1A and 1B according to any one of claims 1 to 4, and their pharmaceutically acceptable salts.

6. Active ingredient of pharmaceutical compositions and medicines intended for the treatment and prevention of diseases caused by hepatitis C virus and hepatitis GBV-C represents a substituted azoles of the General formulas 1A and 1B according to any one of claims 1 to 4, and their pharmaceutically acceptable salts.

7. Pharmaceutical composition for the treatment and prevention of diseases caused by hepatitis C virus and hepatitis GBV-C, containing the active ingredient according to claim 6 in a pharmaceutically effective amount.

8. The pharmaceutical composition according to claim 7 in the form of tablets, capsules, or injections, placed in pharmaceutically acceptable UE is forging.

9. A method of obtaining a pharmaceutical composition by mixing at least one active ingredient of General formula 1A and 1B or its pharmaceutically acceptable salt with an inert filler and/or diluent.

10. A method of treating diseases caused by hepatitis C virus and hepatitis GBV-C, by introducing a pharmacologically effective amount of the active component according to claim 6 or a pharmaceutical composition according to claim 7 or 8.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

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

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds specified in cl. 1, and also to a pharmaceutical composition possessing binding activity with respect to Bcl proteins, to applying the declared compounds for preparing a drug for treating cancer and for treating a bcl-mediated disorder.

EFFECT: use of the compounds as Bcl protein inhibitors.

18 cl, 2 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (IB) or to their pharmaceutically acceptable salts:

, wherein R means formula: R1 means -C(O)NR3R4, -C(O)R3 and -C(O)OR3; each R3 and R4 independently means H, C1-10 alkyl, wherein alkyl is optionally substituted by one -OH; R3 and R4 are bound together with N atoms to form a 5-6-member heterocyclic ring which additionally contains one O heteroatom; R5 means H; R6 means CN; R7 means H; W means C. What is described is a method for producing both them and intermediate compounds of formula (1-1c): , wherein: R1 means -C(O)NR3R4; R3 and R4 are specified above.

EFFECT: compounds (IB) shows DPP-IV inhibitory activity that allows them being used in a pharmaceutical composition.

9 cl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula (I) or its pharmaceutically acceptable salts which have action of mTOR inhibitors. What is also declared is preparing a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I) and a pharmaceutically acceptable carrier or diluent; besides, what is declared is the use of the compound of formula (I) or its pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

EFFECT: preparing the pharmaceutically acceptable salts for preparing the drug for ensuring anticancer action.

11 cl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

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

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula in which: X denotes S, N-R5 or O; R denotes H; alkyl; heteroaryl, which is a thienyl optionally substituted with alkyl; R1 denotes alkyl; aryl, optionally substituted with a halogen; heteroaryl which is a thienyl optionally substituted with an alkyl, a a halogen, a methoxy group; R2 denotes heteroaryl which is 2-, 3- or 4-pyridyl; R3 denotes H; aryl, optionally substituted with a halogen, a methoxy group; heteroaryl, which is a thienyl optionally substituted with a halogen; alkyl, optionally substituted with oxytetrahydropyranyl; R4 denotes H; R5 denotes H; alkyl; or salt thereof.

EFFECT: invention also relates to a method of producing said compounds, which can be used as antifungal agents for crops, as well as agents against other pests, such as insects or mites and weeds which can harm crops.

10 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I): or pharmaceutically acceptable salt thereof, or stereoisomer, in which: n equals 0 or 1; X denotes CH2, C=O; R1 denotes a) -(CH2)mR3 or -CO(CH2)mR3, where m equals 0, 1; and R3 denotes a 5-10-member aryl or heteroaryl, where the heteroaryl denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected oxygen, nitrogen or sulphur, optionally substituted with one or more halogens; b) -C=YR4, where Y denotes O; and R4 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; (C0-C10)alkyl-(5-10-member heteroaryl), where "heteroaryl" denotes a mono- or bicyclic aromatic ring containing 5-10 ring atoms, from which at least one or two atoms are heteroatoms selected from oxygen, nitrogen or sulphur, said heteroaryl is optionally substituted with one or more substitutes selected from halogen, oxo or 2-(C1-C6)alkyl, where Z denotes S; (C0-C10)alkyl-(5-10-member aryl), said aryl is optionally substituted with one or more substitutes selected from halogen; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; or -Z-(C1-C6)alkyl, where Z denotes S or SO2, and where said (C1-C6)alkyl can be optionally substituted with one or more halogens; or (C1-C6)alkyl-CO-O-R12, where R12 denotes H or (C1-C6)alkyl; or c) -C=ZNHR6, where Z denotes O or S; and R6 denotes: (C1-C10)alkyl; (C1-C10)alkoxy; 5-10-member aryl or heteroaryl, where "heteroaryl" denotes a bicyclic aromatic ring containing 9 ring atoms, from which at least one or two atoms are oxygen atoms; optionally substituted with one or more substitutes selected from halogen; cyano; (C1-C6)alkoxy, which itself is optionally substituted with one or more halogens; (C1-C6)alkyl, which itself is optionally substituted with one or more halogens; and R2 denotes H or (C1-C6)alkyl. Also described is a pharmaceutical composition for inhibiting TNFα, based on the compound of formula I.

EFFECT: novel compounds which can regulate production of certain cytokines, including TNF-α, are obtained and described.

27 cl, 81 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

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