Substituted methylphenyl ketones suitable for use as pde4 inhibitors

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula I , in which X1, X2, X3, X4 and X5 independently denote -CH- or N; or X3, X4 and X5 independently denote -CH- or N, and X1 and X2 independently denote C and are part of an additional 6-member aromatic ring; in which R1 denotes methyl or ethyl, or R1 denotes hydrogen; R2 denotes methyl, ethyl, propyl, tert-butoxy carbonylmethyl, allyl, difluoromethyl, ethylbenzene, methylbenzene, butenyl, hydroxyethyl, tolyl, pentenyl, methoxyethyl, butynyl, propynyl, methylcarbonyloxy, cyclopentyl, each of which can be substituted with one or more identical or different substitutes selected from R5; or R2 denotes hydrogen; R3 denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, halogenalkyl, hydroxyalkyl, heterocycloalkenyl, alkylaryl, arylalkyl, alkylalkoxycarbonyl, alkylcarbonyloxy or alkoxyalkyl, each of which can be substituted with one or more identical or different substitutes selected from R6; or R3 denotes hydrogen, -CH2-C(O)-heterocycloalkyl or -CH2-C(O)NR9-R12; R11 denotes one or more identical or different substitutes selected from hydrogen, halogen, cyano, amino, alkyl, methylthionyl, methylsulphonyl, amino, cyano or alkoxy; where R5, R6, R9, R12 are as indicated in claim 1, under the condition that R1, R2 and R3 cannot be methyl at the same time; under the condition that when R2 and R3 both denote hydrogen, R1 cannot be methyl or hydrogen; under the condition that when R1 denotes methyl or hydrogen, R2 denotes methyl and R3 denotes hydrogen when ring B cannot be phenyl; and pharmaceutically acceptable salts and N oxides thereof. The invention also describes a pharmaceutical composition for use in case of skin diseases, said composition containing a compound of formula I, and use of said compound in preparing a medicinal agent for preventing conditions associated with skin wounds.

EFFECT: novel compounds which can be useful in treating skin diseases are obtained and described.

19 cl, 304 ex

 

The SCOPE of the INVENTION

This invention relates to new substituted methylvinylketone and their derivatives, to processes for their preparation, to said compounds for use in therapy, to pharmaceutical compositions comprising these compounds, to methods of treating diseases using the compounds and to the use of these compounds to obtain drugs.

The LEVEL of TECHNOLOGY

Phosphodiesterase are enzymes that catalyze the hydrolysis of cyclic AMP and/or cyclic GMP in cells to 5-AMP and 5-HMF, respectively, and they are critical towards the cellular regulation of the levels of camp or cGMP. 11 phosphodiesterase identified to date, phosphodiesterase (PDE) 4, PDE7 and PDE8 are selective about their camp. PDE4 is the most important modulator of camp, expressed in immune and inflammatory cells such as neutrophils, macrophages and T-lymphocytes (Z. Huang and J. A. Mancini, Current Med. Chem. 13, 2006, pp. 3253-3262). Because camp is a second key mediator in the modulation of inflammatory reactions, it was found that PDE4 regulates the inflammatory response inflammatory cells, modulating Pro-inflammatory cytokines, such as TNFα, IL-2, IFN-γ, GM-CSF and LTB4. Inhibition of PDE4 has therefore become an attractive target for therapy of inflammatory the diseases, such as asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, atopic dermatitis, Crohn's disease, etc. (M. D. Houslay et al., Drug Discovery Today 10 (22), 2005, pp. 1503-1519). Because patients suffering from atopic dermatitis (AD), have an increased PDE activity, PDE4-inhibition also appears to be a viable approach to the treatment of AD (Journal of Investigative Dermatology (1986), 87(3), 372-6). The family of PDE4 genes consists of at least four genes, A, B, C and D, which have a high degree of homology (V. Boswell Smith and D. Spina, Curr. Opinion Investig. Drugs 6(11), 2006, pp. 1136-1141). Four PDE4 isoforms are differentially expressed in various tissues and cell types. Thus, PDE4B predominantly expressed in monocytes and neutrophils, but not expressed in the cortex and epithelial cells, while PDE4D is expressed in the lung, cortex, cerebellum and T-lymphocytes (C. Kroegel and M. Foerster, Exp. Opinion Investig. Drugs 16(1), 2007, pp. 109-124). It was reported that inhibition of PDE4D in the brain is associated with side effects observed in clinical introduction of PDE4 inhibitors, especially with nausea and vomiting, whereas inhibition of PDE4B is associated with anti-inflammatory effects (Lipworth B., Lancet 365, 2005, pp. 167-175). However, it is believed that the PDE inhibitors developed to date are specific in respect of any of the four isoforms of PDE4. Numerous PDE4 inhibitors have been studied in which Oseni their therapeutic effect on inflammatory diseases, first of all, asthma and COPD.

The first of them, theophylline is a weak, non-selective inhibitor of phosphodiesterase used in the treatment of respiratory diseases such as asthma and COPD. Treatment with theophylline may, however, lead to moderate and severe side effects such as arrhythmias and convulsions, limiting the clinical usefulness of theophylline (Kroegel and Foerster, above). As phosphodiesterase remains an attractive target for anti-inflammatory therapy, several other, more selective PDE4 inhibitors have been developed and studied in clinical conditions. Clinical development of many of the first generation of PDE4 inhibitors, such as rolipram was terminated due to DLT (dose limiting side effects, primarily nausea and vomiting. The second generation PDE4 inhibitors with obviously less pronounced side effects is currently undergoing clinical trials (Houslay, above). Inhibitors of PDE-4, for example, disclosed in EP 0771794 and EP 0943613. In WO95/20578 and WO96/31476 disclosed structurally different 4-substituted-3,5-dichloropyridine, which are inhibitors of camp-phosphodiesterase. There is a continuing need to develop new inhibitors of PDE4, which have a more favorable therapeutic window, i.e. fewer side effects, while maintaining their therapeutic Ave is tivovospalitiona effect. A brief review of preclinical and clinical trials using selective PDE4 inhibitors, including inhibitors used for the treatment of psoriasis, has recently been shown in Inflammation & Allergy: Drug Targets, 2007, 6(1), 17-26.

The INVENTION

The inventors have unexpectedly found that the new compounds according to the present invention show selective PDE4-inhibitory activity (with >10-fold reduced activity against PDE 1, 2, 3, 5, 7, 8, 9, 10 or 11) and that they can be used as therapeutic agents for the treatment of inflammatory and allergic diseases such as bronchial asthma, allergic rhinitis and nephritis; autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, Crohn's disease and systemic lupus erythematosus, diseases of the Central nervous system, such as depression, amnesia and dementia; organomation associated with ischemic reflux caused by heart failure, stroke and cerebrovascular diseases, etc.; resistant to insulin diabetes; wounds; AIDS, etc.

Compounds according to the present invention can also be used to prevent, treat or alleviate various diseases such as skin diseases or conditions, such as proliferative and inflammatory disorders of the skin, in particular, psoriasis, inflammation of the epidermis, alopecia, skin atrophy induced by steroids skin atrophy, skin ageing, photo-induced skin aging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

Compounds according to the present invention may also have such advantageous properties as low cytotoxicity, reduced inhibition of HERG, low genotoxicity, reduced skin irritation, improved properties of metabolic stability and properties of metabolic excretion, properties of the skin delivery system characteristics after exposure dermal delivery, all of which can make them particularly suitable for use as active pharmaceutical ingredients in the formulations of medicines for the treatment of skin diseases.

Accordingly, the present invention relates to a compound according to formula I

in which X1,X2,X3,X4and X5independently from each other represent CH or N;

or X3X4and X5independently of one another denote-CH - or N, andX1andX2independently of one another denote C and are part of an additional 6-membered aromatic ring;

in what toroi R 1denotes alkyl, alkenyl, quinil, halogenated, hydroxyalkyl or alkylsulphonyl, each of which may be substituted by one or more identical or different substituents selected from R4or R1denotes hydrogen;

R2denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, halogenated, hydroxyalkyl, geteroseksualen, alkylaryl, arylalkyl, alkylalkoxysilane, alkylcarboxylic or alkoxyalkyl, each of which may be substituted by one or more identical or different substituents selected from R5; or R2denotes hydrogen or-CH2-C(O)NR9-R12;

R3denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, halogenated, hydroxyalkyl, geteroseksualen, alkylaryl, arylalkyl, alkylalkoxysilane, alkylcarboxylic or alkoxyalkyl, each of which may be substituted by one or more identical or different substituents selected from R6; or R3denotes hydrogen, -CH2-C(O)-heteroseksualci or-CH2-C(O)NR9-R12;

R4denotes hydrogen, alkyl, alkenyl, quinil, halogen, oxo, alkoxy, hydroxy or halogenated;

R5denotes alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, Ari is hydroxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, hydroxy, alkylsulphonyl, arylcarbamoyl, alkylcarboxylic or amino, each of which may be substituted by one or more identical or different substituents selected from R7; or R5denotes hydrogen, oxo, halogen, cyano or nitro;

R6denotes alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, aryloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, arylcarbamoyl, hydroxy, alkylsulphonyl, alkylcarboxylic or amino, each of which may be substituted by one or more identical or different substituents selected from R8; or R6denotes hydrogen, oxo, halogen, cyano or nitro;

R7denotes alkyl, alkenyl, cycloalkyl, cycloalkenyl, quinil, alkoxy, halogenated, alkylthio, geteroseksualen, heteroseksualci, aryl, alkylaryl, heteroaryl, aryloxy, alkoxycarbonyl, hydroxyalkyl, amino, hydroxy or carboxy; each of which may be substituted by one or more identical or different substituents selected from R10; or Rsub> 7denotes hydrogen, halogen or oxo;

R8denotes alkyl, alkenyl, cycloalkyl, cycloalkenyl, quinil, alkoxy, halogenated, alkylthio, alkylsulfonyl, alkylsulfanyl, geteroseksualen, heteroseksualci, aryl, alkylaryl, heteroaryl, aryloxy, alkoxycarbonyl, hydroxyalkyl, amino, hydroxy or carboxy; each of which may be substituted by one or more identical or different substituents selected from R10; or R8denotes hydrogen, halogen or oxo;

R9denotes hydrogen, alkyl, halogenated or hydroxyalkyl;

R10denotes hydrogen, alkyl, oxo, hydroxy, halogen, carboxy, amino, alkoxy, halogenated or hydroxyalkyl;

R11represents one or more identical or different substituents selected from hydrogen, halogen, cyano, amino, alkyl, methylsulfinyl, methylsulfonyl, amino, cyano, or alkoxy;

R12denotes alkylaryl, arylalkyl, carboxy, alkyl, alkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, aryloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, hydroxy, alkylsulphonyl, arylcarbamoyl, alkylcarboxylic or amino, each of which may be substituted by one or more of the same is whether different substituents, selected from R8; or R12denotes hydrogen;

provided that R1,R2and R3can not be the stands;

provided that when R2and R3both denote hydrogen, R1may not be the stands or hydrogen;

provided that when R1denotes methyl or hydrogen,R2denotes methyl andR3denotes hydrogen, then ring B cannot be phenyl;

and its pharmaceutically acceptable and physiologically split esters, pharmaceutically acceptable salts, hydrates, N-oxides or solvate.

In another aspect the invention relates to pharmaceutical compositions containing a compound of General formula I, as defined here, along with a pharmaceutically acceptable carrier or excipient or pharmaceutically acceptable basis (bases), if necessary together with one or more other therapeutically active compounds.

In another aspect the invention relates to the use of compounds according to formula I, as defined here, and its pharmaceutically acceptable and physiologically split esters, pharmaceutically acceptable salt, hydrate, N-oxide or solvate, to obtain drugs for prevention, cure or relief of skin diseases or with the States, or acute or chronic disorders associated with skin wounds.

In another aspect the invention relates to a method of preventing, treating or alleviating skin diseases or conditions, or acute or chronic disorders associated with skin wounds, including the introduction of a person suffering from at least one of these conditions, an effective amount of one or more compounds of formula I, as defined here, and its pharmaceutically acceptable and physiologically split esters, pharmaceutically acceptable salts, hydrates, N-oxides or the solvate; if necessary together with a pharmaceutically acceptable carrier or one or more excipients, if necessary in combination with other therapeutically active connections.

In another aspect the present invention relates to a method of obtaining compounds of General formula I, including the method described in any place of this application, such as method a), b), c), (d), or such as any of the common methods or procedures described in the examples or the examples of the preparation, and if necessary additional processing of the obtained compound to obtain the compound of General formula I as defined in any place of the present description.

DETAILED description of the INVENTION

The term "hydrocarbon radical" about the means radical, containing only atoms of hydrogen and carbon, it may contain one or more double and/or triple carbon-carbon bonds, and it may include a cyclic group in combination with a branched or linear groups. The specified hydrocarbon comprises 1-20 carbon atoms, and preferably includes 1-12, for example, 1-6, for example, 1-4, for example, 1-3, for example, 1-2 carbon atoms. The term includes alkyl, alkenyl, cycloalkyl, cycloalkenyl, quinil and aryl, as defined below.

The term "aryl" means a radical of an aromatic carbocyclic rings comprising 6-20 carbon atoms, for example, 6-14 carbon atoms, preferably 6-10 carbon atoms, in particular 5 - or 6-membered rings, including condensed carbocyclic rings, at least one aromatic ring, such as phenyl, naphthyl, indenyl and indanyl.

The term "heteroaryl" means radicals of heterocyclic aromatic rings containing 1-6 heteroatoms (selected from O, S and N) and 1-20 carbon atoms, for example, 1-5 heteroatoms and 1-10 carbon atoms, for example, 1-5 heteroatoms and 1-6 carbon atoms, for example, 1-5 heteroatoms and 1 to 3 carbon atoms, in particular 5 - or 6-membered rings with 1-4 heteroatoms, selected from O, S and N, including condensed bicyclic rings with 1-4 heteroatoms, and where at least one ring is aromatic, for example pyridyl, chenail, ethanolic, indolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, furanyl, pyridyl, thiazolyl, benzoxazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolin, benzimidazolyl and benzofuranyl.

In this context, the term "alkyl" means the radical obtained by removing one hydrogen atom of the hydrocarbon. The specified alkyl includes 1-20, preferably 1-12, for example, 1-6, e.g., 1-4 or 1-3 carbon atoms. The term includes the subclasses of normal alkyl (n-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "cycloalkyl" means a saturated cycloalkenyl moiety comprising 3-20 carbon atoms, preferably 3-10 carbon atoms, in particular 3 to 8 carbon atoms, for example, 3-6 carbon atoms, including condensed bicyclic ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term "heteroseksualci" means cycloalkenyl radical, as described above, in which one or more carbon atoms are replaced by heteroatoms, comprising 1-20 carbon atoms, for example, 2-5 or 2-4 carbon atoms, also comprising 1-6 heteroatoms, preferably 1, 2 or 3 heteroatoms selected from O, N or S, for example, PIP is reinel, pyrrolidinyl, morpholinyl, [1,3]DIOXOLANYL and [1,3]dioxole, or including condensed bicyclic rings with 1-4 heteroatoms, and at least one ring includes a heteroatom, and the other ring may be carbocyclic ring, for example, isoindolyl.

The term "alkenyl" means mono-, di-, tri-, Tetra - or pentanediamine hydrocarbon radical, containing 2-10 carbon atoms, in particular 2 to 6 carbon atoms, for example of 2-4 carbon atoms, for example, ethynyl, propenyl (allyl), methylbutanal, butenyl, pentenyl or hexenyl.

The term "cycloalkenyl" means mono-, di-, tri - or tetradentate non-aromatic cyclic hydrocarbon radicals containing 3-20 carbon atoms, including condensed bicyclic ring, usually consisting of 3-10 carbon atoms, for example, 3, 4 or 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl.

The term "geteroseksualen" means cycloalkenyl radical, as described above, in which one or more carbon atoms are replaced by heteroatoms, comprising 1-20 carbon atoms, for example of 2-4 carbon atoms, also comprising 1-6 heteroatoms, preferably 1, 2 or 3 heteroatoms selected from O, N or S, including condensed bicyclic rings with 1-4 heteroatoms, and at the ore one ring includes a heteroatom, and the other ring may be carbocyclic ring, for example, dihydrofuran or 2,5-dihydro-1H-pyrrolyl.

The term "quinil" means a hydrocarbon radical comprising 1-5 triple relations of C-C and 2-20 carbon atoms, usually consisting of 2-10 carbon atoms, in particular 2 to 6 carbon atoms, for example of 2-4 carbon atoms, for example, ethinyl, PROPYNYL, butynyl, pentenyl or hexenyl.

The term "halogen" means a Deputy from the 7th main group of the periodic table, such as fluorine, chlorine and bromine.

The term "halogenated" means an alkyl group as defined above, substituted by one or more halogen atoms, as defined above, for example, fluorine or chlorine, such as deformity or trifluoromethyl.

The term "alkoxy" means a radical of the formula-OR', where R' denotes an alkyl, as defined above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy etc.

The term "hydroxyalkyl" means an alkyl group as defined above, substituted by one or more hydroxy, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl.

The term "amino" means a radical of the formula-NR2in which each R" independently represents hydrogen or a hydrocarbon radical as described above, for example, -NH2, dimethylamino, -NHMe, -NHEt, tert-butylamino.

The term "alkylthio" means a radical of the formula-S-R', the cat is Roy R' denotes alkyl, as defined above, for example, -SMe.

The term "alkoxycarbonyl" means a radical of the formula-C(O)-O-R'in which R' denotes an alkyl, as defined above, for example, methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl etc.

The term "aminocarbonyl" means a radical of the formula-C(O)-NR2in which each R" has the meaning given above.

The term "alkylcarboxylic" means a radical of the formula-NR"-C(O)-R'in which R' denotes an alkyl, as defined above, and each R" has the meaning given above.

The term "alkylaryl" means a radical of the formula-C(O)-R'in which R' denotes an alkyl, as defined above, for example, acetyl.

The term "alkylcarboxylic" means a radical of the formula-O-C(O)-R'in which R' denotes an alkyl, as defined above.

The term "alkoxycarbonyl" means a radical of the formula-O-C(O)-O-R'in which R' denotes an alkyl, as defined above.

The term "heterocyclic ring" includes definitions of heteroaryl, heteroseksualci and geteroseksualen, as defined above, including kannelirovannye ring system with one another or with cyclic hydrocarbons, for example, 2,5-dihydrobenzo(b)dioxazine, 2,3,5,8-tetrahydro[1,4]dioxin, 5,8-dihydro[1,4]dioxin, 2,3-dihydro-1H-isoindole.

The term "alkylaryl" means aryl radical, as defined above, to the verge substituted alkyl radical, as defined above, for example, tolyl (=tolol), ethylbenzene, etc.

The term "arylalkyl" means an alkyl radical as defined above which is substituted by an aryl radical as defined above, for example, benzyl, phenylethyl, naphthylmethyl etc.

The term "alkoxyalkyl" means an alkyl radical as defined above which is substituted by an alkoxy radical, as defined above, that is,- R'-O-R', each R' denotes alkali, equal or different, as described above, for example, methoxymethyl, ethoxymethyl.

The term "aryloxy" means-O-R'"where R'" is aryl as indicated above, for example, phenoxy.

The term "arylcarbamoyl" means-C(O)-R ' " where R ' " is an aryl radical, as defined above, for example, benzoyl, niftycorners.

The term "alkylaminocarbonyl" means-R'-C(O)-O-R'where each R' denotes alkali, equal or different, as described above, for example, tert-butoxycarbonylmethyl, methoxycarbonylmethyl.

The term "pharmaceutically acceptable salt" means a salt, polychemie reaction of compounds of formula I with a suitable inorganic or organic acid, such as hydrochloric, Hydrobromic, uudistoodetena, sulphuric, nitric, phosphoric, formic, acetic, 2,2-dichloracetic, adipic, ascorbic, L-aspartic, L-glutamic, galactosemia, lactic, maleic, L, phthalic, citric, propionic, benzoic, glutaric, gluconic, D-glucuronic methansulfonate, salicylic, succinic, malonic, tartaric, benzolsulfonat, ethane-1,2-disulfonate, 2-hydroxyethanesulfonic acid, toluensulfonate, Sultanova or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I can also be obtained by the interaction with a suitable base, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia and the like, or suitable non-toxic amines, such as (lower) alkylamines followed, for example, triethylamine, hydroxy(lower)alkylamines followed, for example, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, cyclooctylamine, for example, dicyclohexylamine, or benzylamines, for example, N,N'-dibenziletilendiaminom and dibenzylamine, or L-arginine or L-lysine. Salt, obtained by the interaction with a suitable base include, but are not limited to, salts of sodium, salts of choline, salts of 2-(dimethylamino)ethanol, salts of 4-(2-hydroxyethyl)the research, salt, L-lysine salt of N-(2-hydroxyethyl)pyrrolidine, ethanolamine salt, potassium salt, tetrabutylammonium salt, salt designed, salt cetyltrimethylammonium, salts of Tetramethylammonium, salts of tetrapropylammonium, salt, Tris(hydroxymethyl)aminomethane, salts of N-methyl-D-glucamine, salt, silver salt benzene and salt is Retinalamin.

The term "MES" means a molecule formed by the interaction between the connection, for example, a compound of formula I and a solvent, such as alcohol, glycerine or water, and these molecules are in solid form. If the solvent is water, the indicated molecule is called a hydrate.

Compounds according to the invention, which comprise free hydroxyl group or a free carboxylic acid group, may also exist in the form of pharmaceutically acceptable, physiologically split esters and are also included in the scope of the present invention. Such pharmaceutically acceptable esters are preferably represent derivatives of ester prodrugs, such as becoming a result of solvolysis or cleavage under physiological conditions in the compounds according to the invention, which comprise free hydroxyl group or a free carboxylic acid group, respectively, for example, hydrolyzable in vivo.

Embodiments of the present invention

In one or more embodiments of implementation of the present invention ring B is pyridyl, pyrazinyl, hinely, pyrimidinyl or pyridazinyl, if necessary substituted by one or more identical or different substituents selected from fluorine, PI is RA, bromine, cyano, methoxy, -NH2or C1-4amino.

In one or more embodiments of implementation of the present invention ring B, if necessary substituted R11represents a 2-(6-chloropyrazine), 2-pyrazinyl, 4-(3-bromopyridin), 4-(3,5-dibromopyridin), 4-(6-chloropyrimidine), 2-(4-chloropyridin), 3-(2-chloropyridin), 4-(2-methoxyphenyl), 4-(2-cyanopyridyl), 3-pyridazinyl, 4-(2-tert-butylamino-3,5-dichloropyridine), 4-(2-amino-3,5-dichloropyridine), 4-(3,5-dichloropyridine), 2-(3-bromopyrazine), 4-pyridyl, 4-chinolin or 4-(3,5-dichloro-1-oxypyridine).

In one or more embodiments, the implementation of this invention, formula I represents a General formula Iz,

whereX3represents-CH - or N, in which R1,R2and R3have the meanings given in any place of the present description.

In one or more preferred embodiments, the implementation of thisthe invention R1denotes alkyl, alkenyl, quinil, halogenated, hydroxyalkyl or alkylsulphonyl, each of which may be substituted by one or more identical or different substituents selected from R4and/or

R2denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, halogenated, hydroxyalkyl, geteroseksualen, alkylaryl, alkylalkoxysilane, arylalkyl, Alki is carbonyloxy or alkoxyalkyl, each of which may be substituted by one or more identical or different substituents selected from R5; or R2denotes-CH2-C(O)NR9-R12.

In one or more preferred embodiments of implementation of the present invention R1denotes methyl or ethyl.

In one or more embodiments of implementation of the present invention R2indicatesC1-C6alkyl, C1-C6alkenyl, C1-C6alkoxyl1-C6alkyl, hydroxys1-C6alkyl, Halogens1-C6alkyl, C1-C6quinil, C1-C6cycloalkyl, C1-C6alkyls6-C10aryl, C1-C6alkyls1-C6alkoxycarbonyl or C1-C6alkylcarboxylic, each of which may be substituted by one or more identical or different substituents selected from R5.

In one or more embodiments of implementation of the present invention R2denotes methyl, ethyl, propyl, tert-butoxycarbonylmethyl, allyl, deformity, ethylbenzene, methylbenzol, butenyl, hydroxyethyl, ethylphenyl, tolyl, pentenyl, methoxyethyl, butynyl, PROPYNYL, cyclopentyl, each of which may be substituted by one or more identical or different substituents selected from R5.

In one or more embodiments implement N. the present invention R 2denotes cyclopropyl, methylcyclopropyl, cyclopentyl, methyl, ethyl, propyl or allyl, each of which may be substituted by one or more identical or different substituents selected from hydroxy, fluorine or alkoxy.

In one or more embodiments of implementation of the present invention R3denotes methyl, ethyl, propyl, butyl, pentyl, hydroxyethyl, hexyl, butenyl, pentenyl, allyl, butenyl, methylbenzol, ethylbenzene, tolyl, toluoyl, propylbenzoyl, Meilahti, eternity, methylcarbonate, methylcarbonate, methoxyethyl, methoxypropyl, each of which may be substituted by one or more identical or different substituents selected from R6, each of which may be substituted by one or more identical or different substituents selected from R8or R3denotes hydrogen, -CH2-C(O)-heteroseksualci or-CH2-C(O)NR9-R12.

In one or more embodiments of implementation of the present invention R3denotes methyl, ethyl, propyl or allyl, each of which may be substituted by one or more identical or different substituents selected from hydroxy, fluorine or alkoxy.

In one or more embodiments of implementation of the present invention R5denotes methyl, tert-butoxy, ethynyl, cyclopropyl, propenyl, phenyl, butenyl, propyne is l, acylhydrolase, ethinyl, allyl, ethyl or methoxy, each of which may be substituted by one or more identical or different substituents selected from R7or R5denotes hydrogen, oxo, chloro, fluoro, or hydroxy.

In one or more embodiments of implementation of the present invention R6means ethynyl, methyl, tert-butoxy, isoxazolyl, methoxy, PROPYNYL, butenyl, phenyl, pyridyl, benzoxazolyl, thiazolyl, [1,3,4]thiadiazolyl, [1,2,4]oxadiazolyl, 2,3-dihydro-1H-isoindolyl, ethoxy, thiophenyl, propyl, ethyl, butyl, pentyl, allyl, isopropoxy, isopropyl, naphthyl, cyclohexyl, hydroxy, cyclopentyl, phenoxy, tolyl, toluoyl, benzoyl, carbonylation, ethylbenzene, chinoline, -NH2, etoxycarbonyl, methoxycarbonyl, carbarnoyl, isoindole, methylamine, pyrrolidyl, morpholinyl, methylsulphonyl, methylsulfinyl, butylamine, Propylamine, ethylamine, cycloheptyl, hydroxyethyl, hydroxypropyl, indanyl or ethoxyethyl, each of which may be substituted by one or more identical or different substituents selected from R8or R6denotes hydrogen, oxo, fluorine, chlorine or cyano.

In one or more embodiments of implementation of the present invention R8denotes methyl, ethyl, propyl, butyl, phenyl, cyclopropyl, ethoxy, methoxy, allyl, ethynyl, etoxycarbonyl, hydroxy, naphthyl, cyclohexyl, metaxia boil, phenoxy, isopropoxy, -NH2, methylamine, pyrrolidinyl, morpholinyl, methylsulphonyl, methylsulfinyl, cycloheptyl, cyclopentyl, hydroxymethyl, hydroxyethyl, dimethylamino, furanyl, pyridyl, tolyl, piperidinyl, acetyl, thiophenyl, cycloheptyl, each of which may be substituted by one or more identical or different substituents selected from R10or R8denotes hydrogen, oxo, chlorine, bromine, fluorine, cyano or trifluoromethyl.

In one or more embodiments of implementation of the present invention R9denotes hydrogen, methyl or ethyl.

In one or more embodiments of implementation of the present invention R10denotes hydrogen, oxo, methyl, hydroxy, fluorine, cyano, chlorine or methoxy.

In one or more embodiments of implementation of the present invention R2denotes methyl.

In one or more embodiments of implementation of the present invention R1and R2both represent methyl.

In one or more embodiments of implementation of the present invention R1and R3denote methyl and/or deformity.

In one or more embodiments of implementation of the present invention R3denotes-CH2-C(O)NH-R12, -CH2-C(O)NH-heteroseksualci, -CH2CH2-phenyl-R6or-CH2-phenyl-R6.

In one or more embodiments, the implementation of this image is etenia R 2and/or R3denotes-CH2COOH, methyl, hydrogen, allyl, ethyl, tert-butoxycarbonylmethyl, deformity, 3-methyl-5-methylisoxazole, 2-methoxyethane, 2-butyn, 2-methyl-2-butene, 2-Penilaian, benzyl, 2-methyl-1,3-benzoxazole, 4-methyl-2-methylthiazole, 2-methyl-5-cyclopropyl[1,3,4]thiadiazole, 3-methyl[1,2,4]oxadiazol, ethyl acetate, 4-Chlorobenzyl, 5-chloro-2-methylthiophene, tenoxicam, (4-were)ethane, 3-phenylpropane, (3-methoxyphenyl)ethane, (4-methoxyphenyl)ethane, (3-bromophenyl)ethane, (2-methoxyphenyl)ethane, (4-forfinal)ethane, (2-forfinal)ethane, (3,4-acid)ethane, benzoylacetate, isopropylacetate, methyl ester 3-methylbenzoic acid, 3-methylbutane, 1-hexyl, buta-1-ene, Penta-1-ene, 1-propyl, 1-butyl, 2-methylpropan, ethyl ester butyric acid, 4-methylbenzyl, 3-Chlorobenzyl, propoxyphenol, 1-(4-methoxyphenyl)Etalon, 4-methylbenzonitrile, 2-methylnaphthalene, 1-pentyl, methylcyclohexane, 3-methylbenzonitrile, 1 ethoxy-4-chlorobenzene, 2-ethylbutane, 2-hydroxyethane, methyl ester 4-methylbenzoic acid, 1-naphthalene-2-ylatason, 2.5-dimethoxypyridine, 1-p-tolylamino, 4-tormentil, 2-tormentil, 5-trifloromethyl, 5-cryptomaterial, 3-fluoro-5-trifloromethyl, 1-(2-methoxyphenyl)Etalon, 1-(2,4-dimetilfenil)Etalon, 4-Chlorobenzyl, 2-deformational, 4-isopropylbenzyl, 2-fluoro-6-trifloromethyl, 2,3-debtor-4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl, Penta-2-ene, 6-methyl-2-Metelkin the Lin, 2 Chlorobenzyl, 3-methoxybenzyl, 4-methoxybenzyl, (3-chlorophenyl)ethane, 5-methylhexan, ethylcyclohexane, ethyl ether of pentanol acid (propoxymethyl)benzene, ndimethylacetamide, 2-utilizando-1,3-dione, 2-propertindo-1,3-dione, N-methylacetamide, methylcyclopropane, buta-1-ene, 4-albut-1-ene, 2-methylpent-2-ene, ethanol, benzyl, Penta-2-ene, 2-methoxyethane, but-2-ine, propyne, acetate, 1-pyrrolidin-1-ylatason, N-benzylacetone, 1-morpholine-4-ylatason, N-phenylacetamide, N-methyl-N-phenylacetamide, N-(3-hydroxy-3-methylbutyl)ndimethylacetamide, N-n-propylacetamide, N-ethylacetamide, N-isopropylacrylamide, N-butylacetamide, N-cyclopentylacetic, N-(3-methylbutyl)ndimethylacetamide, N-(4-methoxybenzyl)ndimethylacetamide, N-(2,2-dimethylpropyl)ndimethylacetamide, N-cyclohexylacetate, N-(3-methoxybenzyl)ndimethylacetamide, N-cycloheptylamine, N-(2-methoxybenzyl)ndimethylacetamide, N-cyclohexylmaleimide, N-(2-hydroxyethyl)ndimethylacetamide, N-(1-phenylethyl)ndimethylacetamide, N-(3-hydroxypropyl)ndimethylacetamide, N-(2-methoxyethyl)ndimethylacetamide, N-(2-dimethylaminoethyl)ndimethylacetamide, N-(3-dimethylaminopropyl)ndimethylacetamide, N-(1-phenylethyl)ndimethylacetamide, N-(3-isopropoxyphenyl)ndimethylacetamide N-furan-2-ylmethylene, N-pyridine-2-ylmethylene, N-pyridine-3-ylmethylene, N-(2-phenoxyethyl)ndimethylacetamide, N-pyridine-4-ylmethylene, N-(4-active compounds)ndimethylacetamide, N-(3,5-diferensial)ndimethylacetamide, N-(2,3-diferensial)ndimethylacetamide, N-(2-pyridin-2-retil)ndimethylacetamide, N-(2-methylbenzyl)ndimethylacetamide, N-(3-terbisil)ndimethylacetamide, N-(3-methylbenzyl)AC the Tamid, N-(4-methylbenzyl)ndimethylacetamide, N-ventilated, N-(2-pyridin-4-retil)ndimethylacetamide, N-(3-phenylpropyl)ndimethylacetamide, N-(2-Chlorobenzyl)ndimethylacetamide, N-(2-piperidine-1-retil)ndimethylacetamide, N-(3-Chlorobenzyl)ndimethylacetamide, N-(2-morpholine-4-retil)ndimethylacetamide, N-(4-chlorbenzyl)ndimethylacetamide, N-(2-pyridin-3-retil)ndimethylacetamide N-(2-pyrrolidin-1-retil)ndimethylacetamide, N-(2-acetylamino)ndimethylacetamide, (R)-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide, (S)-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide, N-thiophene-2-ylmethylene, N-[3-(2-oxopyrrolidin-1-yl)propyl]ndimethylacetamide, N-(2-hydroxyine-1-yl)ndimethylacetamide, N-cycloheptylmethyl, N-[2-(2-hydroxyethoxy)ethyl]ndimethylacetamide, N-(4-dimethylaminomethyl)ndimethylacetamide, cyclopentane, cyclopropylmethyl, ethyl, Penilaian, benzyl ester acetic acid, 2-methylbenzonitrile, (1-oxypyridine-4-yl)ethane, (4-pyridyl)ethane, (3-pyridyl)ethane, (2-pyridyl)ethane, (4-benzonitrile)ethane, (4-ethylsulfinyl)ethane, (4-methylsulfinylphenyl)ethane, 1-phenylpropane, 2-phenylpropane or 1-methyl-2-Penilaian.

In one or more embodiments of implementation of the present invention R12denotes alkyl, cycloalkyl, hydroxyalkyl, aryl, arylalkyl, alkylcarboxylic, each of which may be substituted by one or more identical or different substituents selected from alkyl, cycloalkyl, alkoxy, geterotsiklicheskie, heteroaryl, aryloxy, amino, hydroxy, halogen, hydroxy, each of which may be substituted by oxo or hydrox the scrap, or R12denotes hydrogen;

In one or more embodiments of implementation of the present invention R12denotes methyl, ethyl, 1-propyl or 2-propyl, if necessary substituted by one or more identical or different substituents selected from fluorine, chlorine, bromine or methyl; or R12denotes hydrogen.

In yet another embodiment, the present invention relates to a compound of General formula Iz, where X3denotes CH; R1and R2both denote methyl, and R3has the meaning described in any place of the present description.

In one or more embodiments of implementation of the present invention R1and R2can't both be hydrogen.

In one or more embodiments of implementation of the present invention R2and/or R3have the meanings as described regarding any one of the compounds illustrated in the following examples.

The present invention includes all embodiments of, and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11and R12combined in any combination as described in any place in the present description.

In one or more embodiments of implementation of the present invention compounds of General structure I have a molecular weight below 800 daltons, in the example, below 750 daltons, for example, below 700 daltons or below 650, 600, 550 or 500 daltons.

In particular, the compounds of formula I may be selected from the following compounds:

2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon (compound 101),

2-(3,5-dichloropyridine-4-yl)-1-(3-hydroxy-2,4-acid), Etalon (compound 102),

1-(2-allyloxy-3-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 103),

2-(3,5-dichloropyridine-4-yl)-1-(2,3-diethoxy-4-methoxyphenyl)alanon (compound 104),

tert-butyl ether {2-tert-butoxycarbonylamino-6-[2-(3,5-dichloropyridine-4-yl)acetyl]-3-methoxyphenoxy}acetic acid (compound 105),

1-(2,3-bis-allyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 106),

1-(2,3-bis-deformedarse-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 107),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(5-methylisoxazol-3-ylethoxy)phenyl]alanon (compound 108),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methoxyethoxy)phenyl]alanon (compound 109),

1-(2-but-2-ynyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 110),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbut-2-enyloxy)phenyl]alanon (compound 111),

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)alanon (compound 112),

1-(2-benzyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 13),

1-(2-allyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 114),

1-[2-(benzoxazol-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 115),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylthiazole-4-ylethoxy)phenyl]alanon (compound 116),

1-[2-(5-cyclopropyl[1,3,4]thiadiazole-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 117),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-([1,2,4]oxadiazol-3-ylethoxy)phenyl]alanon (compound 118),

ethyl ester {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 119),

1-{2-[2-(4-chlorophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (compound 120),

1-[2-(5-chlorothiophene-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 121),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-phenoxyethoxy)phenyl]alanon (compound 122),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-p-thailatex)phenyl]alanon (compound 123),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-phenylpropoxy)phenyl]alanon (compound 124),

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(3-methoxyphenyl)ethoxy]phenyl}Etalon (compound 125),

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(4-methoxyphenyl)ethoxy]phenyl}Etalon (compound 126),

1-{2-[2-(3-bromophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (soedinenii),

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(2-methoxyphenyl)ethoxy]phenyl}Etalon (compound 128),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 129),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2-forfinal)ethoxy]-3,4-acid}Etalon (compound 130),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(3,4-acid), ethoxy]-3,4-acid}Etalon (compound 131),

benzyl ether of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 132),

isopropyl ether {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 133),

methyl ester of 3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzoic acid (compound 134),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbutoxy)phenyl]alanon (compound 135),

2-(3,5-dichloropyridine-4-yl)-1-(2-hexyloxy-3,4-acid), Etalon (compound 136),

1-(2-but-3-enyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 137),

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-Penta-4-tyloxapol)alanon (compound 138),

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-propoxyphenyl)alanon (compound 139),

1-(2-butoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 140),

2-(3,5-dichloropyridine-4-yl)-1-(2-isobutoxy-3,4-acid), Etalon (compound 141),

ethyl ester of 4-{6-[2-(3,5-Dich herperidin-4-yl)acetyl]-2,3-dimethoxyphenoxy}butyric acid (compound 142),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(4-methylbenzylamino)phenyl]alanon (compound 143),

1-[2-(3-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 144),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-phenoxypropane)phenyl]alanon (compound 145),

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(4-methoxyphenyl)-2-oksidoksi]phenyl}Etalon (compound 146),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile (compound 147),

4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile (compound 148),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(naphthalene-2-ylethoxy)phenyl]alanon (compound 149),

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-pentyloxide)alanon (compound 150),

1-(2-cyclohexylmethoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 151),

3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile (compound 152),

1-{2-[2-(4-chlorphenoxy)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (compound 153),

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-ethylbutane)-3,4-acid]alanon (compound 154),

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-hydroxyethoxy)-3,4-acid]alanon (compound 155),

methyl ester of 4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzoic acid (compound 156),

2-(3,5-dichloropyridine-4-is)-1-[3,4-dimethoxy-2-(2-naphthalene-2-yl-2-oksidoksi)phenyl]alanon (compound 157),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2,5-acid)-2-oksidoksi]-3,4-acid}Etalon (compound 158),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-oxo-2-p-thailatex)phenyl]alanon (compound 159),

2-(3,5-dichloropyridine-4-yl)-1-[2-(4-forbindelse)-3,4-acid]alanon (compound 160),

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-forbindelse)-3,4-acid]alanon (compound 161),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-triftormetilfosfinov)phenyl]alanon (compound 162),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-cryptomaterial)phenyl]alanon (compound 163),

2-(3,5-dichloropyridine-4-yl)-1-[2-(3-fluoro-5-triftormetilfosfinov)-3,4-acid]alanon (compound 164),

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(2-methoxyphenyl)-2-oksidoksi]phenyl}Etalon (compound 165),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2,4-dimetilfenil)-2-oksidoksi]-3,4-acid}Etalon (compound 166),

1-[2-(4-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 167),

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-differentoccasions)-3,4-acid]alanon (compound 168),

2-(3,5-dichloropyridine-4-yl)-1-[2-(4-isopropylbenzylamine)-3,4-acid]alanon (compound 169),

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-fluoro-6-triftormetilfosfinov)-3,4-acid]alanon (compound 170),

2-(3,5-dichloropyridine-4-yl)-1-[2-(2,3-debtor-4-methylbenz is lexi)-3,4-acid]alanon (compound 171),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylbenzylamino)phenyl]alanon (compound 172),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbenzylamino)phenyl]alanon (compound 173),

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-Penta-2-tyloxapol)alanon (compound 174),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylinosine-6-ylethoxy)phenyl]alanon (compound 175),

1-[2-(2-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 176),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methoxybenzyloxy)phenyl]alanon (compound 177),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(4-methoxybenzyloxy)phenyl]alanon (compound 178),

1-{2-[2-(3-chlorophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (compound 179),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(5-methylhexanoic)phenyl]alanon (compound 180),

1-[2-(2-cyclohexylmethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 181),

ethyl ester 5-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}pentanol acid (compound 182),

1-[2-(3-benzyloxypropionic)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 183),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 184),

2-(2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)isoindole-1,3-dione (compound 185),

2-(3-{6-[2-(3,5-dichloropurine the-4-yl)acetyl]-2,3-dimethoxyphenoxy}propyl)isoindole-1,3-dione (compound 186),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-methylacetamide (compound 187),

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2,4-acid), Etalon (compound 188),

1-(3-cyclopropylmethoxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 189),

1-(2-allyloxy-3-but-3-enyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 190),

1-(3-but-3-enyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 191),

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-propoxyphenyl)alanon (compound 192),

1-(3-allyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 193),

2-(3,5-dichloropyridine-4-yl)-1-[2,4-dimethoxy-3-(4-methylpent-3-enyloxy)phenyl]alanon (compound 194),

2-(3,5-dichloropyridine-4-yl)-1-[3-(2-hydroxyethoxy)-2,4-acid]alanon (compound 195),

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-penetrometer)alanon (compound 196),

1-(3-benzyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 197),

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-Penta-2-tyloxapol)alanon (compound 198),

2-(3,5-dichloropyridine-4-yl)-1-[2,4-dimethoxy-3-(2-methoxyethoxy)phenyl]alanon (compound 199),

1-(3-but-2-ynyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 200),

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-prop-2-injectively)alanon (compound 201),

2-(3,5-dichloropyridine-4-yl-1-[3,4-dimethoxy-2-(2-oxo-2-pyrrolidin-1 ylethoxy)phenyl]alanon (compound 202),

N-benzyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 203),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-morpholine-4-yl-2-oksidoksi)phenyl]alanon (compound 204),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-phenylacetamide (compound 205),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-methyl-N-phenylacetamide (compound 206),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-hydroxy-3-methylbutyl)ndimethylacetamide (compound 207),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 208),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-isopropylacetate (compound 209),

N-butyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 210),

N-cyclopentyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 211),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methylbutyl)ndimethylacetamide (compound 212),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-methoxybenzyl)ndimethylacetamide (compound 213),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2,2-dimethylpropyl)ndimethylacetamide (compound 214),

N-cyclohexyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 215),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-IU is oxybenzyl)ndimethylacetamide (compound 216),

N-cycloheptyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 217),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methoxybenzyl)ndimethylacetamide (compound 218),

N-cyclohexylmethyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 219),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxyethyl)ndimethylacetamide (compound 220),

(R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(1-phenylethyl)ndimethylacetamide (compound 221),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-hydroxypropyl)ndimethylacetamide (compound 222),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methoxyethyl)ndimethylacetamide (compound 223),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-dimethylaminoethyl)ndimethylacetamide (compound 224),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-dimethylaminopropyl)ndimethylacetamide (compound 225),

(S)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(1-phenylethyl)ndimethylacetamide (compound 226),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-isopropoxyphenyl)ndimethylacetamide (compound 227),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-furan-2-ylmethylene (compound 228),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-2-ylmethylene (compound 229),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-3-ylmethylene (compound 230),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-phenoxyethyl)ndimethylacetamide (compound 231),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-4-ylmethylene (compound 232),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-active compounds)ndimethylacetamide (compound 233),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3,5-diferensial)ndimethylacetamide (compound 234),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2,3-diferensial)ndimethylacetamide (compound 235),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-2-retil)ndimethylacetamide (compound 236),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methylbenzyl)ndimethylacetamide (compound 237),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-terbisil)ndimethylacetamide (compound 238),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methylbenzyl)ndimethylacetamide (compound 239),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-methylbenzyl)ndimethylacetamide (compound 240),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-ventilated (compound 241),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-4-retil)ndimethylacetamide (compound 242),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-phenylpropyl)ndimethylacetamide (compound 243),

N-(2-Chlorobenzyl)-2-{6-[2-(3,5-di is lipiridy-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 244),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-piperidine-1-retil)ndimethylacetamide (compound 245),

N-(3-Chlorobenzyl)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 246),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-morpholine-4-retil)ndimethylacetamide (compound 247),

N-(4-Chlorobenzyl)-2-(6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 248),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-3-retil)ndimethylacetamide (compound 249),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyrrolidin-1-retil)ndimethylacetamide (compound 250),

N-(2-acetylamino)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 251),

(R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide (compound 252),

(S)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide (compound 253),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-thiophene-2-ylmethylene (compound 254),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-[3-(2-oxopyrrolidin-1-yl)propyl]ndimethylacetamide (compound 255),

(2R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxyine-1-yl)ndimethylacetamide (compound 256),

N-cycloheptylmethyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-di is ethoxyphenoxy}ndimethylacetamide (compound 257),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-[2-(2-hydroxyethoxy)ethyl]ndimethylacetamide (compound 258),

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-dimethylaminomethyl)ndimethylacetamide (compound 259),

1-(3-cyclopentyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 260),

1-(3-cyclopropylmethoxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 261),

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2-hydroxy-4-methoxyphenyl)alanon (compound 262),

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-4-methoxy-2-penetrometer)alanon (compound 263),

1-[2-(5-cyclopropyl[1,3,4]thiadiazole-2-ylethoxy)-3-ethoxy-4-methoxyphenyl]-2-(3,5-dichloropyridine-4-yl)alanon (compound 264),

benzyl ether of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2-ethoxy-3-methoxyphenoxy}acetic acid (compound 265),

1-(3-allyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 266),

2-{2-allyloxy-6-[2-(3,5-dichloropyridine-4-yl)acetyl]-3-methoxyphenoxy}benzonitrile (compound 267),

1-(3-allyloxy-4-methoxy-2-penetrometer)-2-(3,5-dichloropyridine-4-yl)alanon (compound 268),

1-{3-allyloxy-2-[2-(4-forfinal)ethoxy]-4-methoxyphenyl}-2-(3,5-dichloropyridine-4-yl)alanon (compound 269),

N-benzyl-2-{6-[2-(3,5-dichloro-1-oxypyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 270),

2-(3,5-dichloro-1-oxypyridine-4-yl)--(3,4-dimethoxy-2-penetrometer)alanon (compound 271),

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 272),

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(1-oxypyridine-4-yl)ethoxy]phenyl}Etalon (compound 274),

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon (compound 275),

4-(2-{6-[2-(3,5-dichloro-1-oxypyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)benzonitrile (compound 276),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-4-ylethoxy)phenyl]alanon (compound 277),

4-(2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)benzonitrile (compound 278),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-2-ylethoxy)phenyl]alanon (compound 279),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-3-ylethoxy)phenyl]alanon (compound 280),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-methanesulfonyl)ethoxy]-3,4-acid}Etalon (compound 281),

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-methanesulfonyl)ethoxy]-3,4-acid}Etalon (compound 282),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(1-phenylpropoxy)phenyl]alanon (compound 283),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-phenylpropoxy)phenyl]alanon (compound 284),

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(1-methyl-2-phenylethane)phenyl]alanon (compound 285),

2-{6-[2-(6-chloropyrazine-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 286),

2-{6-[2-(3-bromopyrazine-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 287),

2-{6-[2-(2,6-dichlorophenyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 288),

2-[2,3-dimethoxy-6-(2-pyridin-4-ylacetic)phenoxy]-N-propylacetamide (compound 289),

2-[2,3-dimethoxy-6-(2-quinoline-4-ylacetic)phenoxy]-N-propylacetamide (compound 290),

2-[2,3-dimethoxy-6-(2-pyrazin-2-ylacetic)phenoxy]-N-propylacetamide (compound 291),

2-{6-[2-(3-bromopyridin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 292),

2-{6-[2-(3,5-dibromopyridin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 293),

2-{6-[2-(6-chloropyrimidine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 294),

2-{6-[2-(4-chloropyridin-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 295),

2-{6-[2-(2-chloropyridin-3-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 296),

2-{2,3-dimethoxy-6-[2-(2-methoxypyridine-4-yl)acetyl]phenoxy}-N-propylacetamide (compound 297),

2-{6-[2-(2-cyano-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 298),

2-[2,3-dimethoxy-6-(2-pyridazin-3-ylacetic)phenoxy]-N-propylacetamide (compound 299),

2-(2-tert-butylamino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 300),

2-(2-amino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (with the Association 301),

2-(3,5-dichloropyridine-4-yl)-1-(4-ethoxy-3-methoxy-2-penetrometer)alanon (compound 302),

{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 504),

methyl ester 2-tert-butoxycarbonylamino-3,4-dimethoxybenzoic acid (compound 506a),

methyl ester 2-carboxymethoxy-3,4-dimethoxybenzoic acid (compound 506b),

methyl ester of 3,4-dimethoxy-2-propylbromoacetate acid (compound 506c) or

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-ethylacetamide (compound 305),

and their pharmaceutically acceptable and physiologically split esters, pharmaceutically acceptable salt, hydrate, N-oxide or solvate.

In one preferred embodiment of the present invention X3denotes N, and X1X2X4and X5denote-CH-. In another embodiment, X1denotes N, and X2X3X4and X5denote-CH-. In another embodiment, X2denotes N, and X1X3X4and X5denote-CH-. In another embodiment, aX4denotes N, and X1X2X3and X5represent-CH-, orX5denotes N, and X1X2X3and X4denote-CH-. In another preferred embodiment, about what westline X 1X2X3X4and X5denote-CH-. In yet another embodiment, X1and X4denote N, and X2X3and X5represent-CH-, or X2and X5denote N and X1X3and X4represent-CH-, or X3and X5denote N and X1X2and X4denote-CH-. In another embodiment, X1and X2denote N, and X3X4and X5represent-CH-, or X4and X5denote N and X1X2and X3denote-CH-.

Suitable substituents R11ring B include halogen, such as chlorine, bromine or fluorine, cyano, methoxy, ethoxy, propoxy or bonds alkylamines, such as tert-butylamine.

The substituents R11ring B may preferably be attached in the ortho- (position 2 and 6) and/or meta (regulations 3 and 5) position relative to the position in which the ring B is attached to methylvinylketone.

In another embodiment, when R3denotes hydrogen, then one of X1X2X3X4or X5denotes nitrogen.

In one or more embodiments of implementation of the present invention the compounds of formula I, as defined above, can be used in therapy and in particular for the treatment of skin diseases.

In one or more embodiments, the implementation of this is part II of the invention, a skin disease or condition selected from a proliferative and inflammatory skin disorders, psoriasis, cancer, inflammation of the skin, alopecia, skin atrophy induced by steroids skin atrophy, skin ageing, photo-induced skin aging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

The compounds of formula I can be obtained in crystalline form or directly by the concentration of the organic solvent or by crystallization or recrystallization from an organic solvent or a mixture of the solvent and co-solvent, which may be organic or inorganic, such as water. The crystals can be separated into essentially free of solvent form or in the form of MES, such as a hydrate. The invention covers all crystalline forms, such as polymorphs and pseudopolymorphs, and mixtures thereof.

The compounds of formula I can include or not to include asymmetrically substituted (chiral) carbon atoms, which give rise to the existence of isomeric forms, e.g., enantiomers and possible diastereomers. The present invention relates to all such isomers both in pure form and in the form of their mixtures (for example, racemates). Pure stereoisomeric forms of the compounds and intermediates of the invention can be obtained by procedures known in the anti-shudder performance techniques. The different isomeric forms may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active amines, such as l-ephedrine. Alternatively, the enantiomers can be separated by chromatographic methods using chiral stationary phases. These pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction proceeds stereoselective or stereospecific. Preferably, if desired specific stereoisomer, the specified connection synthesize stereoselective or stereospecific methods of getting. In these methods, it is preferable to use pure chiral starting materials.

Compounds according to the present invention, if necessary in combination with other active compounds may also be used for the treatment of skin diseases or conditions, or acute or chronic disorders associated with skin wounds, in particular for the treatment of proliferative and FOTS is extreme disorders of the skin, psoriasis, cancer, inflammation of the skin, alopecia, skin atrophy induced by steroids skin atrophy, skin ageing, photo-induced skin aging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

In addition to the treatment of humans, the compounds according to the present invention can also be used in veterinary medicine for treatment of animals, including mammals, such as horses, cattle, sheep, pigs, dogs and cats.

For use in therapy, the compounds according to the present invention are usually in the form of pharmaceutical compositions. The invention therefore relates to pharmaceutical compositions comprising a compound of formula I, if necessary together with one or more other therapeutically active compounds together with pharmaceutically acceptable excipients, the base or carrier (carriers). Excipient must be "acceptable" in the sense that it must be compatible with other ingredients of the composition and not to be harmful to the recipient.

Preferably, the active ingredient is from 0.05 to 99.9 wt.% by weight of the composition.

In a standard dosage form, the compound may be administered one or more times a day with suitable intervals, which always depend, however, on the condition of the patient, and in accordance with the prescription made by a physician. Preferably, the dosage form of the composition contains from 0.1 mg to 1000 mg, preferably 1 mg to 100 mg, for example, 5-50 mg of the compounds of formula I.

A suitable dose of a compound according to the invention will depend, inter alia, on the age and condition of the patient, the severity of the exposed treatment of disease and other factors known to the practitioner. The connection may be administered orally, parenterally or tapicerki under various schemes introduction, for example, daily or every week. In General, single dose is in the range from 0.01 to 400 mg/kg of body weight. The connection may be in the form of a bolus (i.e. all the daily dose is given immediately), or in separate doses two or more times a day.

In the context of topical treatment may be preferable to refer to "unit of use", which indicates a single dose that can be administered to the patient, and which may be readily handled and Packed, remaining physically and chemically stable dose comprising either the active material as such or a mixture with a solid or liquid pharmaceutical diluents or carriers.

The term "unit of use" in connection with the topical use of means single, that is, a single dose, which can be the t to be tapicerki put the patient in the number per square centimeter infected area from 0.1 mg to 10 mg, and preferably from 0.2 mg to 1 mg considered an active ingredient.

It is also envisaged that in some modes of treatment may be useful to introduce at longer intervals, such as every other day, once a week or even longer intervals.

If the treatment involves the introduction of another therapeutically active compounds, it is recommended to consult with Goodman & Gilman''s The Pharmacological Basis of Therapeutics, 9thEd., J. G. Hardman and L. E. Limbird (Eds.), McGraw-Hill 1995, the ratio of useful dosages of these compounds.

Introduction compounds according to the present invention with one or more other active compounds may be simultaneous or sequential.

The compositions include, for example, the compositions in a form suitable for oral (including slow or intended release), rectal, parenteral (including subcutaneous, intraperitoneal, intramuscular, intra-articular and intravenous), transdermal, ocular, topical, nasal or buccal administration.

The formulations may be presented in a standard dosage forms and may be obtained by any method known in the field of pharmacy, for example, as disclosed in Remington, The Science and Practice of Pharmacy, 21ed ed., 2005.

All methods include the stage of introduction of the active ingredient in combination with a carrier which constitutes one or more accessory ingredients. In General, the compositions get odero the but and closely combining the active ingredient with liquid carriers or finely dispersed solid carrier, or with both, and then, if necessary, shaping the product into the desired formulation.

The compositions according to the present invention suitable for oral administration may be in the form of separate units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of powder or granules; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of emulsions of the type oil-in-water or emulsion of the type water-in-oil". Such oils can be edible oils, such as cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspendresume agents for aqueous suspensions include synthetic and natural gums, such as tragakant, alginate, gum Arabic, dextran, carboxymethylcellulose sodium, gelatin, methylcellulose, hypromellose, hydroxypropylcellulose, carbomer and polyvinylpyrrolidone. The active ingredients can also be administered in the form of a bolus, electuary or ointment.

The tablet can be obtained by molding or forming of the active ingredient, if necessary, with one or more auxiliary ingredients. Molded tablets may be the particular pressing, in a suitable mechanism, the active ingredient (ingredient) in granular form, such as powder or granules, if necessary, in a mixture with a binder, such as, for example, lactose, glucose, starch, gelatin, gum Arabic, tragakant, sodium alginate, carboxymethylcellulose, methylcellulose, hypromellose, polyethylene glycol, waxes and the like; a lubricant, such as, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like; a disintegrator such as starch, methylcellulose, agar-agar, bentonite, croscarmellose sodium, glycolate, starch sodium, crosspovidone, etc. or dispersing agent such as Polysorbate 80. Molded tablets can be obtained by molding, in a suitable mechanism, the mixture parascandolo active ingredient and a suitable carrier, moistened with an inert liquid diluent.

Compositions for rectal injection can be in the form of suppositories in which the compound according to the present invention is mixed with low-melting water-soluble or insoluble solids such as cocoa butter, hydrogenated vegetable oil, polyethylene glycol or ethers of fatty acids and glycols, while elixirs can be obtained using myristoleate.

The compositions according to the walking for parenteral administration, preferably include sterile oil or aqueous preparation of the active ingredients, which is preferably isotonic with the blood of a recipient, for example, isotonic saline, isotonic glucose solution or buffer solution. The composition may preferably be sterilized, for example, by filtration through inhibiting bacteria filter, by adding to the composition of the sterilizing agent, by irradiation or by heating the composition. Liposomal compositions, as disclosed, for example, in Encyclopedia of Pharmaceutical Technology, vol.9, 1994, are also suitable for parenteral administration.

Alternatively, the compounds of formula I can be represented in the form of sterile solid preparation, for example, dried by sublimation powder which is easily dissolved in sterile solvent immediately prior to use.

Transdermal formulations may be in the form of a plaster or bandage.

The right eye the introduction of the compositions can be carried out in the form of a sterile aqueous preparation of the active ingredients that can be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems, for example, as disclosed in Encyclopedia of Pharmaceutical Technology, vol.2, 1989, may also be used for eye introduction as the active ingredient.

Formulations suitable for topical or ocular administration, include liquid or semi-liquid preparations such as liniments, lotions, gels, wraps, emulsions of the type oil-in-water or water-in-oil, such as creams, ointments or pastes; or solutions or suspensions such as drops. Compositions for ophthalmic treatment may preferably further comprise a cyclodextrin.

For topical administration the compound of formula I may generally be present in amounts of from 0.01 to 20 wt.% by weight of the composition, for example, from 0.1% to about 10%, but may also be present in an amount up to about 50% by weight of the composition.

Formulations suitable for nasal or buccal administration, include powder, samovytaskivaniya and sprayable formulations, such as aerosols and spray guns. Such compositions are disclosed in more detail, for example, in Modern Pharmaceutics, 2nded., G. S. Banker and CT. Rhodes (Eds.), page 427-432, Marcel Dekker, New York; Modern Pharmaceutics, 3thed., G. S. Banker and CT. Rhodes (Eds.), page 618-619 and 718-721, Marcel Dekker, New York and Encyclopedia of Pharmaceutical Technology, vol. 10, J. Swarbrick and J. C Boylan (Eds), page 191-221, Marcel Dekker, New York.

In addition to the aforementioned ingredients, the formulations of the compounds of formula I can contain one or more additional ingredients such as diluents, buffers, flavouring agents, dyes, surfactants, thickening agents, preservatives, nab is emer, methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like,

When the active ingredient is administered in the form of salts with pharmaceutically acceptable non-toxic acids or bases, preferred salts are, for example, easily water-soluble or partially soluble in water to obtain a special and suitable speed of absorption.

The pharmaceutical composition may further include one or more other active ingredients traditionally used in the treatment of skin diseases or conditions, for example, selected from the group consisting of proliferative and inflammatory skin disorders, psoriasis, cancer, inflammation of the skin, alopecia, skin atrophy induced by steroids skin atrophy, skin ageing, photo-induced skin aging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.

Examples of such additional active ingredients can, for example, be selected from the group consisting of glucocorticoids, vitamin D and analogues of vitamin D, antihistamines, antagonists thrombocytapheresis factor (PAF), anticholinergics, methylxanthines, β-adrenergic agents, inhibitors SOH-2, salicylates, indomethacin, flufenamic, naproxen, cimegidine, gold salts, penitsillamin, lower lobby of Turin serum funds retinoids, zinc salts and salicylazosulfapyridine.

WAYS to GET

Compounds according to the present invention can be obtained by many methods known to the expert in the field of synthesis. The compounds of formula I can, for example, be obtained by using the reactions and techniques described below, together with the methods known from the prior art in the field of synthetic organic chemistry, or variations thereof that will be apparent to the expert. Preferred methods include, but are not limited to, those described below. The reaction is carried out in solvents corresponding to the used reagents and materials and suitable for the on-going transformations. In addition, it should be understood that in the methods of synthesis described below, all proposed reaction conditions, including choice of solvent, the atmosphere of the reaction, the reaction temperature, duration of the experiment and the research procedures chosen so that they were standard for this reaction, as will be readily obvious to the specialist. Not all connections belonging to a given class may be compatible with some of the reaction conditions required in some of the above methods. Such restrictions to the substituents that are compatible with the reaction conditions will be apparent to the person skilled in the art, and can use is to use alternative methods. Compounds according to the present invention or any of the intermediate compound can be purified, if required, using standard methods known to the expert in the field of organic synthesis, for example, methods described in "Purification of Laboratory Chemicals", 5thed. 2003. Starting materials are known or commercially available compounds, or they can be obtained by conventional synthesis methods known to the expert.

GENERAL PROCEDURES, EXAMPLES of OBTAINING AND EXAMPLES

Spectra1H nuclear magnetic resonance (NMR) is usually recorded at 300 MHz. The values of chemical shift (δ, ppm) specified in the specified solvent relative to internal standards tetramethylsilane (δ=0,00) or chloroform (δ=7,25). Values multiplet, as defined (doublet (d), triplet (t), Quartet (q))and not defined (m) are listed in the approximate mid-point, is given, if the range is not specified. (users) indicates broadened singlet. Used organic solvents were usually waterless. Chromatography was performed on silica gel Merck 60 (0,040-0,063 mm). Marked relationship solvent are concerning about:about, unless otherwise noted.

Use the following abbreviations:

ADDP1,-(azodicarbon)piperidin
AIBNazobisisobutyronitrile
Ar-Mearyl-methyl
DCEdichloroethane
DCMdichloromethane
DMFN,N'-dimethylformamide
DMSOthe sulfoxide
Etethyl
hwatch
HATUO-(7-asobancaria-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate
HetAr-Meheteroaryl-methyl
lliter
LDAdiisopropylamide lithium
LiHMDShexamethyldisilazide lithium
mMilli
MCPBAm-chloroperoxybenzoic acid
Memethyl
NBSN-bromosuccinimide
NMP1-methyl-2-pyrrolidinone
NMRnuclear magnetic resonance
rtambient temperature
RTretention time
TBADdi-tert-utilisationbased
TNtriperoxonane acid
THFtetrahydrofuran
TIStriethylsilane
aboutvolume

Preparative HPLC/MS

Preparative HPLC/MS was performed on a Dionex APS system with two preparative pump Shimadzu PP150 and mass spectrometer Thermo MSQ Plus. Column: Waters XTerra C-18, 150×19 mm, 5 μm; solvent system: A=water with 0.1% formic acid) and B=acetonitrile with 0.1% formic acid); volumetric flow rate=18 ml/min; method (10 minutes): Method a linear gradient from 10% B to 100% B in 6 minutes and maintaining 100% B for a further 2 minutes. Fractions were collected based on the ion traces of the relevant ions and with whom drove PDA (240-400 nm).

Analytical HPLC/MS

The way A:

Analytical HPLC/MS was performed on a Dionex APS system with analytical pump P680A and mass spectrometer Thermo MSQ Plus. Column: Waters XTerra C-18, 150×4.6 mm, 5 μm; solvent system: A=water with 0.1% formic acid) and B=acetonitrile with 0.1% formic acid); volumetric flow rate=1.0 ml/min; method (10 minutes): Method a linear gradient from 10% B to 100% B over 6.6 minutes and maintaining 100% B for another 1.5 minutes.

The way B:

Analytical HPLC/MS was performed on a system consisting of a HPLC Waters 2795 mass spectrometer Micromass ZQ, Waters 996 PDA. Column: Waters XTerra C-18, 50×3.0 mm, 5 μm; solvent system: A=water:acetonitrile 95:5 (0.05% of formic acid) and B=acetonitrile (0.05% of formic acid); volumetric flow rate=1.0 ml/min; method (8 minutes): Method a linear gradient from 10% B to 100% B over 6.0 minutes, and maintaining at 100% B for 1 minute.

General methods and examples

Compounds according to the invention can, for example, be obtained according to the following non-limiting General methods and examples:

Method (a)

Mono - or dialkylamino compounds with formula Ia

in which R1has described here is suitable alkyl - or alkenyl-chlorides, bromides, iodides, mesylates or tozilaty in basic conditions (Protective Groups in Organic Chemistry, John Wiley & sons, Ed: T. Greene and P. G Wuts, 3rdedition (1999), p 249-72), or suitable alcohols, for example, alkylmercury, using Mitsunobu reaction conditions (see Synthesis (1981), 1; Tet. Lett. (1993), 34, 1639-42 and Eur. J. Org. Chem. (2004), 2763-72), in a suitable solvent, such as THF, benzene or DMF. The reaction can be carried out in one stage or in two successive stages.

Method b)

The alkylation of compounds of formula Ic,

in which R1and R3(R3≠H) are described here, values, alkyl-, alkenyl or quinil-chlorides, bromides, iodides, mesylates or tozilaty in basic conditions or alkylmercury using Mitsunobu reaction conditions in a suitable solvent, such as THF, acetone, benzene, toluene or DMF.

Method c)

The alkylation of compounds of formula Id (I, where R3=hydrogen),

in which R1and R2(R2≠H) are described here, values, alkyl-, alkenyl or quinil-chlorides, bromides, iodides, mesylates or tozilaty in basic conditions or alkylmercury using Mitsunobu reaction conditions in a suitable solvent, such as THF, acetone, benzene, toluene or DMF.

Method d)

The formation of the amide compounds of formula Ie,

in which R1and R2have the values described here, with the primary or topicname amines using, for example, reagent combinations, such as HATU (Carpino, L. A. J.. Chem. Soc. (1993), 115, 4397), or any other standard chemical peptide combination (Larry Yet, Albany Molecular Research, Technical Reports VoI 4, number 1, p 1-7).

Starting materials of the formulae Ia-Ie can be obtained according to standard procedures known to the specialist. For example, commercially available 2,3,4-methoxybenzoic acid (Aldrich) etherification with MeI in the presence of a suitable base, such as K2CO3orEt3N, in a suitable solvent, such as DMF, THF or DCM at temperatures from ambient temperature to 100°C. the Obtained ester is then condensed with 3,5-dichloro-4-methylpyridine (for example, obtained according to J. Org. Chem. (1961), 26, 789-92, Heterocycles (2001), 55, 2075-84 or PCT9414742) in the presence of a suitable base, such as LDA or LiHMDS, in a suitable solvent, such as THF, at temperatures from minus 78°C to ambient temperature. The resulting ketone is subjected to the reaction of removing the protective group or:

A) In the presence of a suitable acid, such as HI or HBr, in a suitable solvent such as AcOH, at temperatures from 50 to 120°C, obtaining the compounds of formula Ia.

B) In the presence of a suitable Lewis acid, such asBCl3,BBr3orAlCl3, in a suitable solvent, such as dichloromethane, at temperatures from 0° to tamper the tours of the environment, obtaining the compounds of formula Id.

Dialkylamino compounds of formula Ia by alkenylamine, bromides, iodides, mesylates or tozilaty in the presence of a suitable base, such as K2CO3orEt3N, in a suitable solvent, such as DMF, NMP, THF or DCM at temperatures from ambient temperature to 100°C, which ensures the formation of compounds of formula Ib. Subsequent removal of the protective group of compounds with the formula Ib in the presence of a suitable Lewis acid, such asBCl3,BBr3orAlCl3, in a suitable solvent, such as dichloromethane, at temperatures from 0° to ambient temperature, followed by parallelogram alkenylamine, bromides, iodides, mesylates or tozilaty in the presence of a suitable base, such asK2CO3orEt3N, in a suitable solvent, such as DMF, NMP, THF or DCM at temperatures from ambient temperature to 100°C provide unsymmetrical compounds of formula Ib.

Selective monoalkylamines compounds with formula Ia alkyl-, alkenyl or quinil-bromides or iodides in the presence of a suitable base, such asK2CO3, in a suitable solvent, such as DMF or NMP, at a temperature from ambient temperature is about 100°C, which ensures the formation of compounds of formula Ic or Id.

The alkylation of compounds of formula Id alcolhol or bromoacetate in the presence of a suitable base, such asK2CO3, in a suitable solvent, such as DMF or NMP, at a temperature from ambient temperature to 100°C, followed by hydrolysis of the ether carboxylic acids under normal conditions (Protective Groups in Organic Chemistry, John Wiley & sons, Ed: T. Greene and P. G. Wuts, 3rdedition (1999), p 384-86), provide compounds of formula Ie.

Example obtain 1 (compound 501)

2,3,4-trimethoxybenzoate

2,3,4-trimethoxybenzoic acid (Aldrich) (20 g, 94 mmol) was dissolved in dry DMF (250 ml). Added K2CO3(13 g, 94 mmol) and MeI (6.5 ml, 103,4 mmol)and the reaction mixture was heated at 50°C for 5 h, the Reaction mixture was cooled to ambient temperature and added to water (250 ml). Added EtOAc (1 l) and the organic phase washed with water (3×500 ml) and finally NaCl (feast upon.). The organic phase is washed, dried overMgSO4, filtered and concentrated in vacuum. Was re-dissolved in toluene and evaporated. 2,3,4-trimethoxybenzoate received in the form of a yellowish oil.

1H-NMR(CDCl3) δ=7,60 (1H, d), 6,70 (1H, d), to 3.99 (3H, s), 3,91 (3H, s)to 3.89 (3H, s), 3,88 (3H, s). Yield 21 g (99%).

Example obtain 2 (compound 502)

2-(3,5-dichloropyridine-4-yl)-1-(2,3,4-trimethoxyphenyl)e is anon

2,3,4-trimethoxybenzoate example, obtaining 1 (2.7 g, 10 mmol) and 3,5-dichloro-4-methylpyridine (obtained as described in the literature procedures) was dissolved in dry THF (40 ml). The reaction mixture was cooled on ice and treated by adding dropwise (over 5 minutes) 1 M bis(trimethylsilyl)amide lithium (12 ml, 12 mmol). After 1.5 hours at 0°C the reaction was stoppedNH4Cl (feast upon., 100 ml). Organic products were extracted with EtOAc (2×100 ml)and the combined organic phases are washed with NaCl (feast upon., 100 ml). The organic phase was dried overNa2SO4was evaporated in vacuo, and purified flash chromatography using a gradient of EtOAc in heptane as eluent. 2-(3,5-dichloropyridine-4-yl)-1-(2,3,4-trimethoxyphenyl)Etalon received in the form of a solid white color.

1H-NMR(CDCl3) δ=8,43 (2H, s), 7,55 (1H, d), 6,69 (1H, d), br4.61 (2H, s), was 4.02 (3H, s), a 3.87 (3H, s), of 3.84 (3H, s). Yield 2.3 g (65%).

Example 1 (compound 101)

2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-acid), alanon

2-(3,5-dichloropyridine-4-yl)-1-(2,3,4-trimethoxyphenyl)Etalon example, obtaining 2 (20 g, 56 mmol) was dissolved in DCM (75 ml) in an argon atmosphere.BCl3(95 ml of 1 M solution in DCM) was slowly added at ambient temperature for 2 hours. Was slowly added water (50 ml) and then add the group of EtOH (200 ml). The white precipitate was filtered and recrystallized from EtOH. 2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon received in the form of a solid white color.

1H-NMR(CDCl3) δ=11,92 (1H, s), 8,54 (2H, s), to 7.68 (1H, d), 6,60 (1H, d), of 4.67 (2H, s), 3,98 (3H, s), 3,90 (3H, s). The output of 14.2 g (74%)

Example for the preparation of 3 (compound 503)

2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon

2-(3,5-dichloropyridine-4-yl)-1-(2,3,4-trimethoxyphenyl)Etalon example, obtaining 2 (1.25 g, 3.5 mmol) was dissolved in AcOH (100%, 9,25 ml) in an argon atmosphere. Added HI (55-58%, 4,55 ml)and the reaction mixture was heated at 80°C for 18 hours. The reaction mixture was cooled to ambient temperature and evaporated in vacuo.Was slowly added NaHCO3(feast upon., 150 ml), then NaCl (feast upon., 50 ml). Organic products were extracted with EtOAc (4×100 ml). The combined organic phases were washed twice with NaCl (feast upon., 100 ml)Na2S2O3(10%, 100 ml), dried overNa2SO4and evaporated in vacuum. 2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)Etalon received in the form of a solid brown color.

1H-NMR(CDCl3) δ=11,88 (1H, s), 8,54 (2H, s), 7,51 (1H, d), 6,60 (1H, d), 5,62 (1H, users), of 4.67 (2H, s), of 4.00 (3H, s). The output of 0.935 g (81%).

The General procedure for obtaining compounds of formula If, in which R3/sub> has a certain value (R3≠hydrogen):

2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon (0.1 mmol) of example for the preparation of 3 was dissolved in dry DMF (0.75 ml). Added K2CO3(0.1 mmol), then 0.1 mmol of allylbromide or iodide. The reaction mixture was heated at 70°C for 18 hours. After cooling to ambient temperature was added water (1 ml)and the organic products were extracted with EtOAc (3×1 ml). The combined organic phases are washed with NaCl (feast upon., 1 ml) and then dried overNa2SO4. Pure compounds were obtained, re-dissolving the reaction mixture in DMSO, followed by purification standard preparative HPLC.

Using this procedure, received the following connections:

Example 2 (compound 102)

2-(3,5-dichloropyridine-4-yl)-1-(3-hydroxy-2,4-acid), alanon

LC/MS (METHOD B): (m/z) 342,1 (MH+); RT=3,34 min; purity (UV)=100%

Alkylhalogenide: methyliodide

Example 3 (compound 103)

1-(2-allyloxy-3-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 368,2 (MH+); RT=3,81 min; purity (UV)=100%

Alkylhalogenide: allylbromide

The General procedure for obtaining compounds of formula Ig, in which R2=R3and they have a certain value (R3≠hydrogen):

p> 2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon (0.1 mmol) of example for the preparation of 3 was dissolved in dry DMF (0.75 ml). Added K2CO3(0.2 mmol), then 0.2 mmol of alkylchloride, bromide or iodide. In the case of alkylchloride was added KI (0.05 mmol). The reaction mixture was heated at 70°C for 18 hours. After cooling to ambient temperature, added water (1 ml)and the organic products were extracted with EtOAc (3×1 ml). The combined organic phases are washed with NaCl (feast upon., 1 ml) and then dried overNa2SO4. Pure compounds were obtained, re-dissolving the reaction mixture in DMSO, followed by purification standard preparative HPLC.

Using this procedure, received the following connections:

Example 4 (compound 104)

2-(3,5-dichloropyridine-4-yl)-1-(2,3-diethoxy-4-methoxyphenyl)alanon

LC/MS (METHOD B): (m/z) 384,1 (MH+); RT=4,69 min; purity (UV)=100%

Alkylhalogenide: ethyliodide

Example 5 (compound 105)

tert-butyl ether {2-tert-butoxycarbonylamino-6-[2-(3,5-dichloropyridine-4-yl)acetyl]-3-methoxyphenoxy}acetic acid

LC/MS (METHOD B): (m/z) 554,3 (MN-); RT=5,39 min; purity (UV)=100%

Alkylhalogenide: tert-butylbromide

Example 6 (compound 106)

1-(2,3-bis-allyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 408,2 (MH+); RT=4,94 min; purity (UV)=10%

Alkylhalogenide: allylbromide

Example 107 (compound 107)

1-(2,3-bis-deformedarse-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 428,1 (MH+); RT=4,23 min; purity (UV)=100%

Alkylhalogenide: sodium chlorodifluoroacetate. Heated to 100°C for 30 minutes.

The General procedure for obtaining compounds of formula Ih, in which R3(R3≠hydrogen) has the above specified values:

2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-methoxyphenyl)alanon (0.035 mmol) of example 1 was dissolved in dry DMSO (0.25 ml). Was added an aqueous solution of K2CO3(0,025 ml of 2 M), then 0,053 mmol of alkylchloride, bromide or iodide, dissolved in a 0,025 ml of DMSO. The reaction mixture was left at ambient temperature for 48 hours. The pure compound was obtained by purification of the standard preparative HPLC.

Using this procedure, received the following connections:

Example 108 (compound 108)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(5-methylisoxazol-3-ylethoxy)phenyl]alanon

LC/MS (METHOD B): (m/z) 437,1 (MH+); RT=4,01 min; purity (UV)=100%

Alkylhalogenide: 3-chloromethyl-5-methylisoxazol

Example 109 (compound 109)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methoxyethoxy)phenyl]alanon

LC/MS (METHOD B): (m/z) 400,1 (MH+); RT=3,90 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-methoxyethane

Note the R 110 (connection 110)

1-(2-But-2-ynyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 394,1 (MH+); RT=4,30 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-buten

Example 111 (compound 111)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbut-2-enyloxy)phenyl]alanon

LC/MS (METHOD B): (m/z) 410,1 (MH+); RT=a 4.83 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-methyl-2-butene

Example 112 (compound 112)

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)alanon

1H-NMR(CDCl3) δ=8,48 (2H, s), to 7.61 (1H, d), 7,31-was 7.08 (5H, m), of 6.75 (1H, d), 4,50-to 4.46 (4H, m)to 3.92 (3H, s), of 3.77 (3H, s)3,18 (2H, t).

Alkylhalogenide: 1-bromo-2-Penilaian

Example 113 (compound 113)

1-(2-benzyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 432,1 (MH+); RT=4,70 min; purity (UV)=100%

Alkylhalogenide: benzylbromide

Example 114 (compound 114)

1-(2-allyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z 382 (MH+); RT=4,34 min; purity (UV)=100%

Alkylhalogenide: allylbromide

Example 115 (compound 115)

1-[2-(benzoxazol-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z 473 (MH+); RT=4,36 min; purity (UV)=100%

Alkylhalogenide: 2-(chloromethyl)-1,3-benzoxazol

Example 116 (compound 116)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylthiazole-4-ylethoxy)phenyl]alanon

LC/MS (METHOD B): (m/z) 53 (MH+); RT=as 4.02 min; purity (UV)=100%

Alkylhalogenide: 4-(chloromethyl)-2-methylthiazole

Example 117 (compound 117)

1-[2-(5-cyclopropyl[1,3,4]thiadiazole-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 480,1 (MH+); RT=3,86 min; purity (UV)=100%

Alkylhalogenide: 2-(chloromethyl)-5-cyclopropyl[1,3,4]thiadiazole

Example 118 (compound 118)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-([1,2,4]oxadiazol-3-ylethoxy)phenyl]alanon

LC/MS (METHOD B): (m/z 424 (MH+); RT=the 3.65 min; purity (UV)=100%

Alkylhalogenide: 3-(chloromethyl)-[1,2,4]oxadiazol

Example 119 (compound 119)

ethyl ester {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid

1H-NMR(CDCl3) δ=8,48 (2H, s), to 7.61 (1H, d), 6,76 (1H, d), to 4.92 (1H, s), rate 4.79 (2H, s), 4,25 (2H, square), 3,93 (3H, s), 3,88 (3H, s)of 1.27 (3H, t).

Alkylhalogenide: ethylbromoacetate

Example 120 (compound 120)

1-{2-[2-(4-chlorophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon

1H-NMR(CDCl3) δ=8,49 (2H, s), to 7.61 (1H, d), 7.23 percent-to 7.18 (4H, m), of 6.75 (1H, d), of 4.45 (2H, t), 4,37 (2H, s), 3,93 (3H, s), of 3.77 (3H, s), 3,14 (2H, t).

Alkylhalogenide: 4-chlorobenzylchloride

Example 121 (compound 121)

1-[2-(5-chlorothiophene-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z 474 (MH+); RT=5,01 min; purity (UV)=100%

Alkylhalogenide: 5-chloro-2-(chloromethyl)thiophene

Example 122 (compound 122)

2-(3,5-dichloropyridine--yl)-1-[3,4-dimethoxy-2-(2-phenoxyethoxy)phenyl]alanon

1H-NMR(CDCl3) δ=8,48 (2H, s), the 7.65 (1H, d), 7.23 percent (2H, t), 6,92 (1H, t), 6,85 (2H, d), 6,76 (1H, d), 4,78 (2H, s), 4,69-4,63 (2H, m), 4,39-to 4.33 (2H, m), of 3.94 (3H, s)to 3.92 (3H, s).

Alkylhalogenide: 1-bromo-2-phenoxyethane

Example 123 (compound 123)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-p-thailatex)phenyl]alanon

LC/MS (METHOD B): (m/z) 460 (MH+); RT=from 5.29 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(4-were)ethane

Example 124 (compound 124)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-phenylpropoxy)phenyl]alanon

1H-NMR(CDCl3) δ=8,49 (2H, s), to 7.59 (1H, d), 7,22 (5H, m), of 6.75 (1H, d), 4,69 (2H, s), 4,28 (2H, t), 3,93 (3H, s), 3,88 (3H, s), 2,85 (2H, t), of 2.21 (2H, m).

Alkylhalogenide: 1-bromo-3-phenylpropane

Example 125 (compound 125)

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(3-methoxyphenyl)ethoxy]phenyl}alanon

LC/MS (METHOD B): (m/z) 476,2 (MH+); RT=4,86 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(3-methoxyphenyl)ethane

Example 126 (compound 126)

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(4-methoxyphenyl)ethoxy]phenyl}alanon

LC/MS (METHOD B): (m/z) 476,2 (MH+); RT=4,84 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(4-methoxyphenyl)ethane

Example 127 (compound 127)

1-{2-[2-(3-bromophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon

1H-NMR(DMSO-d6) δ=8,62 (2H, s), 7,54 (2H, m), 7,26 (3H, m), 6,97 (1H, d), 4,43 (2H, t), 4,36 (2H, s), 3,88 (3H, s), 3,70 (3H, s), 3,14 (2H, t).

Alkylhalogenide: 1-bromo-2-(3-brave who yl)ethane

Example 128 (compound 128)

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(2-methoxyphenyl)ethoxy]phenyl}alanon

LC/MS (METHOD B): (m/z) 476,2 (MH+); RT=5,08 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(2-methoxyphenyl)ethane

Example 129 (compound 129)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}alanon

LC/MS (METHOD B): (m/z) rub464.3 (MH+); RT=a 4.83 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(4-forfinal)ethane

Example 130 (compound 130)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2-forfinal)ethoxy]-3,4-acid}alanon

LC/MS (METHOD B): (m/z) 464,2 (MH+); RT=4,99 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(2-forfinal)ethane

Example 131 (compound 131)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(3,4-acid), ethoxy]-3,4-acid}alanon

1H-NMR (DMSO-d6) δ=at 8.60 (2H, s), 7,52 (1H, d), to 6.95 (1H, d), 6.89 in (1H, d), for 6.81 (1H, d), of 6.73 (1H, d), 4,43 (2H, t), 4.26 deaths (2H, s), 3,88 (3H, s), 3,76 (3H, s), 3,68 (3H, s), 3,55 (3H, s), 3,06 (2H, t).

Alkylhalogenide: 1-bromo-2-(3,4-acid)ethane

Example 132 (compound 132)

benzyl ether of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid

LC/MS (METHOD B): (m/z) 490,2 (MH+); RT=4,66 min; purity (UV)=100%

Alkylhalogenide: benzylbromide

Example 133 (compound 133)

isopropyl ether {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid

LC/MS (METHOD B): (m/z) 442,2 (MH+); RT=of 4.44 min; purity (is)=100%

Alkylhalogenide: isopropylpalmitate

Example 134 (compound 134)

methyl ester of 3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzoic acid

LC/MS (METHOD A): (m/z) 489,9 (MH+); RT=8,14 min; purity (UV)=100%

Alkylhalogenide: methyl ether 3-chloromethylbenzene acid

Example 135 (compound 135)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbutoxy)phenyl]alanon

LC/MS (METHOD A): (m/z) 412 (MH+); RT=8,99 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-3-methylbutane

Example 136 (compound 136)

2-(3,5-dichloropyridine-4-yl)-1-(2-hexyloxy-3,4-acid), alanon

LC/MS (METHOD A): (m/z) 395,9 (MH+); RT=9,42 min; purity (UV)=100%

Alkylhalogenide: 1 bromhexin

Example 137 (compound 137)

1-(2-but-3-enyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 395,9 (MH+); RT=8,27 min; purity (UV)=100%

Alkylhalogenide: 4-brombach-1-ene

Example 138 (compound 138)

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-Penta-4-tyloxapol)alanon

LC/MS (METHOD A): m/z 410 (MH+); RT=8,62 min; purity (UV)=100%

Alkylhalogenide: 5-bronet-1-ene

Example 139 (compound 139)

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-propoxyphenyl)alanon

LC/MS (METHOD A): (m/z) 383,9 (MH+); RT=8.34 per min; purity (UV)=100%

Alkylhalogenide: 1-jumprope

Example 140 (compound 140)

1-(2-butoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 397,9 (MH+); RT=8,72 min; purity (UV)=100%

Alkylhalogenide: 1-idbutton

Example 141 (compound 141)

2-(3,5-dichloropyridine-4-yl)-1-(2-isobutoxy-3,4-acid), alanon

LC/MS (METHOD A): (m/z) 397,9 (MH+); RT=8,72 min; purity (UV)=100%

Alkylhalogenide: 1-iodine-2-methylpropan

Example 142 (compound 142)

ethyl ester of 4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}butyric acid

LC/MS (METHOD A): m/z 456 (MH+); RT=7,89 min; purity (UV)=100%

Alkylhalogenide: ethyl ester of 4-pamakani acid

Example 143 (compound 143)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(4-methylbenzylamino)phenyl]alanon

LC/MS (METHOD A): (m/z) 445,9 (MH+); RT=8,69 min; purity (UV)=97.1%of

Alkylhalogenide: 4-methylbenzylidene

Example 144 (compound 144)

1-[2-(3-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 465,9 (MH+); RT=8,69 min; purity (UV)=100%

Alkylhalogenide: 3-chlorobenzylchloride

Example 145 (connection 145)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-phenoxypropane)phenyl]alanon

LC/MS (METHOD A): m/z 476 (MH+); RT=8,59 min; purity (UV)=98.2%of

Alkylhalogenide: (3 bromopropane)benzene

Example 146 (compound 146)

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(4-methoxyphenyl)-2-oksidoksi]phenyl}alanon

LC/MS (METHOD A): m/z 490 (MH+); RT=7,74 min; purity (UV)=97.1%of

Alkylhalogenide: 2-bromo-1-(4-methoxyphenyl)is the Thanon

Example 147 (compound 147)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile

LC/MS (METHOD A): (m/z) 456,9 (MH+); RT=7,81 min; purity (UV)=97.1 per cent.

1H-NMR(DMSO-d6) δ=at 8.60 (2H, s), to $ 7.91 (1H, d), 7,81 (1H, d), 7,78 (1H, t), to 7.59 (1H, t), of 7.55 (1H, d), 7,02 (1H, d), 5,43 (2H, s), 4,50 (2H, s)to 3.92 (3H, s), 3,81 (3H, s).

Alkylhalogenide: 2-chloromethylbenzene

Example 148 (compound 148)

4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile

LC/MS (METHOD A): (m/z) 456,9 (MH+); RT=7,82 min; purity (UV)=98,5%

Alkylhalogenide: 4-chloromethylbenzene

Example 149 (compound 149)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(naphthalene-2-ylethoxy)phenyl]alanon

LC/MS (METHOD A): (m/z) 481,9 (MH+); RT=8,86 min; purity (UV)=77,3%

Alkylhalogenide: 2-bromethalin

Example 150 (compound 150)

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-pentyloxide)alanon

LC/MS (METHOD A): (m/z) 411,9 (MH+); RT=9,06 min; purity (UV)=100%

Alkylhalogenide: 1-identin

Example 151 (compound 151)

1-(2-cyclohexylmethoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): m/z 438 (MH+); RT=9,59 min; purity (UV)=100%

Alkylhalogenide: bromeilles

Example 152 (compound 152)

3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile

LC/MS (METHOD A): (m/z) 456,9 (MH+); RT=7,81 min; purity (UV)=96,5%

Alkylhalogenide: 3-CHL is methylbenzonitrile

Example 153 (compound 153)

1-{2-[2-(4-chlorphenoxy)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 495,9 (MH+); RT=8,56 min; purity (UV)=100%

Alkylhalogenide: 1-(2-bromoethoxy)-4-chlorobenzene

Example 154 (compound 154)

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-ethylbutane)-3,4-acid]alanon

LC/MS (METHOD A): m/z 426 (MH+); RT=9,39 min; purity (UV)=92,5%

Alkylhalogenide: 1-iodine-2-ethylbutane

Example 155 (compound 155)

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-hydroxyethoxy)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 385,9 (MH+); RT=6,22 minutes; (UV) purity=88,0%

Alkylhalogenide: 1-iodine-2-hydroxyethane

Example 156 (compound 156)

methyl ester of 4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzoic acid

LC/MS (METHOD A): (m/z) 489,9 (MH+); RT=8,17 min; purity (UV)=89,6%

Alkylhalogenide: methyl ester of 4-chloromethylbenzene acid

Example 157 (compound 157)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-naphthalene-2-yl-2-oksidoksi)phenyl]alanon

LC/MS (METHOD A): (m/z) 509,9 (MH+); RT=to 8.41 min; purity (UV)=89,9%

Alkylhalogenide: 2-bromo-1-naphthalene-2-ylatason

Example 158 (compound 158)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2,5-acid)-2-oksidoksi]-3,4-acid}alanon

LC/MS (METHOD A): (m/z) 519,9 (MH+); RT=7,99 min; purity (UV)=95,7%

Alkylhalogenide: 2-bromo-2,5-dimethoxyphenylacetone

Example 159 (compound 159)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-oxo-2-p-thailatex)phenyl]alanon

LC/MS (METHOD A): (m/z) 473,9 (MH+); RT=8,11 min; purity (UV)=88,1%

Alkylhalogenide: 2-bromo-1-p-tolylamino

Example 160 (compound 160)

2-(3,5-dichloropyridine-4-yl)-1-[2-(4-forbindelse)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 449,9 (MH+); RT=8,32 min; purity (UV)=100%

Alkylhalogenide: 4-tormentilla

Example 161 (compound 161)

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-forbindelse)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 449,9 (MH+); RT=8.34 per min; purity (UV)=95,7%

Alkylhalogenide: 2-tormentilla

Example 162 (compound 162)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-triftormetilfosfinov)phenyl]alanon

LC/MS (METHOD A): (m/z) 499,9 (MH+); RT=8,61 min; purity (UV)=98,9%

Alkylhalogenide: 5-cryptomaterial

Example 163 (compound 163)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-cryptomaterial)phenyl]alanon

LC/MS (METHOD A): (m/z) 515,9 (MH+); RT=8,72 min; purity (UV)=98,9%

Alkylhalogenide: 5-cryptomaterial

Example 164 (compound 164)

2-(3,5-dichloropyridine-4-yl)-1-[2-(3-fluoro-5-triftormetilfosfinov)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 558,9 (MH+); RT=8,71 min; purity (UV)=98,9%

Alkylhalogenide: 3-fluoro-5-cryptomaterial

Example 165 (compound 165)

2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(2-methoxyp the Nile)-2-oksidoksi]phenyl}alanon

LC/MS (METHOD A): m/z 490 (MH+); RT=of 7.96 min; purity (UV)=95,8%

Alkylhalogenide: 2-bromo-1-(2-methoxyphenyl)alanon

Example 166 (compound 166)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2,4-dimetilfenil)-2-oksidoksi]-3,4-acid}alanon

LC/MS (METHOD A): (m/z) 487,9 (MH+); RT=8,49 min; purity (UV)=99,1%

Alkylhalogenide: 2-bromo-1-(2,4-dimetilfenil)alanon

Example 167 (compound 167)

1-[2-(4-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 465,9 (MH+); RT=8,72 min; purity (UV)=98,5%

Alkylhalogenide: 4-chlorobenzylchloride

Example 168 (compound 168)

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-differentoccasions)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 497,8 (MH+); RT=8,19 min; purity (UV)=98,5%

Alkylhalogenide: 2-deformatiessailing

Example 169 (compound 169)

2-(3,5-dichloropyridine-4-yl)-1-[2-(4-isopropylbenzylamine)-3,4-acid]alanon

LC/MS (METHOD A): m/z 474 (MH+); RT=of 9.21 min; purity (UV)=100%

Alkylhalogenide: 4-isopropylbenzylamine

Example 170 (compound 170)

2-(3,5-dichloropyridine-4-yl)-1-[2-(2-fluoro-6-triftormetilfosfinov)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 517,9 (MH+); RT=charged 8.52 min; purity (UV)=98,9%

Alkylhalogenide: 2-fluoro-6-cryptomaterial

Example 171 (compound 171)

2-(3,5-dichloropyridine-4-yl)-1-[2-(2,3-debtor-4-methylbenzoate)-3,4-acid]alanon

LC/MS (METHOD A): (m/z) 481,9 MH+); RT=8,71 min; purity (UV)=98.6%of the

Alkylhalogenide: 2,3-debtor-4-methylbenzylidene

Example 172 (compound 172)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylbenzylamino)phenyl]alanon

LC/MS (METHOD A): (m/z) 445,9 (MH+); RT=8,67 min; purity (UV)=98,5%

Alkylhalogenide: 2-methylbenzylidene

Example 173 (compound 173)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbenzylamino)phenyl]alanon

LC/MS (METHOD A): m/z 446 (MH+); RT=8,69 min; purity (UV)=98.4%of

Alkylhalogenide: 3-methylbenzylidene

Example 174 (compound 174)

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-Penta-2-tyloxapol)alanon

LC/MS (METHOD A): (m/z) 409,9 (MH+); RT=8,67 min; purity (UV)=98,3%

Alkylhalogenide: 1-bronet-2-EN

Example 175 (compound 175)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylinosine-6-ylethoxy)phenyl]alanon

LC/MS (METHOD A): m/z 497 (MH+); RT=5,27 min; purity (UV)=98,1%

Alkylhalogenide: 6-methyl bromide-2-methylinosine

Example 176 (compound 176)

1-[2-(2-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 465,9 (MH+); RT=8,71 min; purity (UV)=96,3%

Alkylhalogenide: 2-chlorobenzylchloride

Example 177 (compound 177)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methoxybenzyloxy)phenyl]alanon

LC/MS (METHOD A): (m/z) 461,9 (MH+); RT=compared to 8.26 min; purity (UV)=96,3%

Alkylhalogenide: 3-methoxybenzylidene

Example 178 (compound 178)

2-(35-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(4-methoxybenzyloxy)phenyl]alanon

LC/MS (METHOD A): (m/z) 461,9 (MH+); RT=by 8.22 min; purity (UV)=77,9%

Alkylhalogenide: 4-methoxybenzylidene

Example 179 (compound 179)

1-{2-[2-(3-chlorophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 479,9 (MH+); RT=8,81 min; purity (UV)=98.6%of the

Alkylhalogenide: 1-bromo-2-(3-chlorophenyl)ethane

Example 180 (compound 180)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(5-methylhexanoic)phenyl]alanon

LC/MS (METHOD A): m/z 440 (MH+); RT=RS 9.69 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-5-methylhexan

Example 181 (compound 181)

1-[2-(2-cyclohexylmethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): m/z 452 (MH+); RT=9,92 min; purity (UV)=97,7%

Alkylhalogenide: (2-bromacil)cyclohexane

Example 182 (compound 182)

ethyl ester 5-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}pentanol acid

LC/MS (METHOD A): m/z 470 (MH+); RT=8,11 min; purity (UV)=100%

Alkylhalogenide: ethyl ester of 4-bromopentanoate acid

Example 183 (compound 183)

1-[2-(3-benzyloxypropionic)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): m/z 490 (MH+); RT=8,64 min; purity (UV)=97,5%

Alkylhalogenide: (3-bromopropionyl)benzene

Example 184 (compound 184)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

1H-NMR(DMSO-d6) δ=8,64 (2H, s), to 7.67-7,58 (2H, m), 7,37 (1H, ears is .c), 6,98 (1H, d), 4,79 (2H, s), to 4.62 (2H, s), 3,90 (3H, s), of 3.80 (3H, s).

Alkylhalogenide: 2-chloracetamide

Example 185 (compound 185)

2-(2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)isoindole-1,3-dione

1H-NMR(CDCl3) δ=at 8.36 (2H, s), 7,74 (2H, m), 7,60 (3H, m), of 6.75 (1H, d), to 4.52 (2H, t), 4,48 (2H, s), is 4.21 (2H, t), 3,91 (3H, s), 3,83 (3H, s).

Alkylhalogenide: 2-(2-bromacil)isoindole-1,3-dione

Example 186 (compound 186)

2-(3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}propyl)isoindole-1,3-dione

1H-NMR(CDCl3) δ=8,48 (2H, s), 7,81 (2H, m), of 7.70 (2H, m), to 7.59 (1H, d), of 6.75 (1H, d), of 4.67 (2H, s), or 4.31 (2H, t), of 3.96 (2H, t), 3,93 (3H, s)to 3.89 (3H, s), is 2.30 (2H, m).

Alkylhalogenide: 2-(3-bromopropyl)isoindole-1,3-dione

Example 187 (compound 187)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-methylacetamide

1H-NMR(CDCl3) δ=charged 8.52 (2H, s), 7,75-to 7.64 (2H, m), 6,79 (1H, d), of 4.67 (2H, s), 4,60 (2H, s), of 3.96 (3H, s), a 3.87 (3H, s), of 2.86 (3H, d).

Alkylhalogenide: 2-chloro-N-methylacetamide

Example 305 (compound 305)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-ethylacetamide

1H-NMR(DMSO-d6) δ=8,64 (2H, s), 8,18 (1H, users), to 7.61 (1H, d), of 6.99 (1H, d), of 4.77 (2H, s), to 4.62 (2H, s), 3,91 (3H, s), with 3.79 (3H, s)and 3.15 (2H, m), a 1.01 (3H, t).

Alkylhalogenide: 2-chloro-N-ethylacetamide

The General procedure for obtaining compounds of formula Ii or Ij, where R2is above a certain value:

2-(3,5-dichloropyridine-4-yl)-1-(3-hydroxy-2,4-methoxyphenyl)alanon (0.035 mmol) of example 2 (Ii) or 1-(2-allyloxy-3-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (0.035 mmol) of example 3 (Ij) was dissolved in dry 3-pentanone (0.4 ml). Added solid K2CO3(0,052 mmol), then 0,052 mmol of allylbromide or iodide, dissolved in 3-pentanone (0.1 ml). In case you were synthesized was added KI (0.5 EQ.). The reaction mixture was heated at 70°C for 18 hours. The samples were filtered, and the solvent was removed in vacuum. Pure compounds were obtained, re-dissolving the reaction mixture in DMSO, followed by purification standard preparative HPLC.

Using this procedure, received the following connections:

Example 188 (compound 188)

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2,4-acid), alanon

LC/MS (METHOD B): (m/z 370 (MH+); RT=4,45 min; purity (UV)=100%

Alkylhalogenide: iodata

Example 189 (compound 189)

1-(3-cyclopropylmethoxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 396,1 (MH+); RT=4,78 min; purity (UV)=100%

Alkylhalogenide: bromelicola

Example 190 (compound 190)

1-(2-allyloxy-3-but-3-enyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B: (m/z) 422,1 (MH+); RT=5,27 min; purity (UV)=100%

Alkylhalogenide: 4-brombach-1-ene

Example 191 (with the unity 191)

1-(3-but-3-enyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 396,3 (MH+); RT=8,39 minutes; (UV) purity=94,0%

Alkylhalogenide: 4-brombach-1-ene

Example 192 (compound 192)

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-propoxyphenyl)alanon

LC/MS (METHOD A): (m/z) 384,3 (MH+); RT=8,42 min; purity (UV)=100%

Alkylhalogenide: 1-iodata

Example 193 (compound 193)

1-(3-allyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 382,3 (MH+); RT=8,01 min; purity (UV)=100%

Alkylhalogenide: allylbromide

Example 194 (compound 194)

2-(3,5-dichloropyridine-4-yl)-1-[2,4-dimethoxy-3-(4-methylpent-3-enyloxy)phenyl]alanon

LC/MS (METHOD A): (m/z) 424,3 (MH+); RT=8,99 min; purity (UV)=100%

Alkylhalogenide: 5-bromo-2-methylpent-2-EN

Example 195 (compound No. 195)

2-(3,5-dichloropyridine-4-yl)-1-[3-(2-hydroxyethoxy)-2,4-acid]alanon

LC/MS (METHOD A): (m/z) 386,3 (MH+); RT=6,21 min; purity (UV)=70,5%

Alkylhalogenide: 2-codetel

Example 196 (compound 196)

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-penetrometer)alanon

LC/MS (METHOD A): (m/z) 446,2 (MH+); RT=8,71 minutes; (UV) purity=82,0%

Alkylhalogenide: 2-phenyl-1-bromatan

Example 197 (compound 197)

1-(3-benzyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 432,2 (MH+); RT=8,49 min; purity (UV)=96,3%

Alkylhalogenide: benzylbromide

Example 198 (link is 198)

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-Penta-2-tyloxapol)alanon

LC/MS (METHOD A): (m/z) 410,3 (MH+); RT=8,67 minutes; (UV) purity=91,9%

Alkylhalogenide: 1-bronet-2-EN

Example 199 (compound 199)

2-(3,5-dichloropyridine-4-yl)-1-[2,4-dimethoxy-3-(2-methoxyethoxy)phenyl]alanon

LC/MS (METHOD A): (m/z) 400,3 (MH+); RT=7,34 min; purity (UV)=of 91.6%

Alkylhalogenide: 1-bromo-2-methoxyethane

Example 200 (compound 200)

1-(3-but-2-ynyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD A): (m/z) 394,3 (MH+); RT=7,81 min; purity (UV)=100%

Alkylhalogenide: 1-brombach-2-in

Example 201 (compound 201)

2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-prop-2-injectively)alanon

LC/MS (METHOD A): (m/z) 380,2 (MH+); RT=7,44 min; purity (UV)=100%

Alkylhalogenide: 3-bromopropyl

Example 4/example 273 (compound 504)

{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid

2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-methoxyphenyl)alanon (1,37 g, 4.1 mmol) of example 1 was dissolved in dry NMP (50 ml). Added ethylbromoacetate (660 μl, 6.1 mmol), then K2CO3(830 mg, 6.1 mmol)and the reaction mixture was stirred at ambient temperature overnight. Was added water (500 ml), and the product was extracted with EtOAc (2×250 ml). The combined organic phases were washed with water (250 ml), brine (250 ml) and vysushila and over MgSO4. The solvent was removed in vacuo, and the resulting pure product was subjected to standard chromatography on silica gel, obtaining the ethyl ester of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid in the form of a solid white color. The output of 990 mg (78%). The compound was re-dissolved by heating in a mixture of MeOH-water (1:1, 200 ml). Added LiOH (490 mg, 12 mmol, 5 equiv.) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was acidified to pH=1 by addition of 1 N. HCl (15 ml) and was extracted with EtOAc (2×250 ml). The combined organic phases are washed with brine (250 ml) and dried overMgSO4. The solvent was removed in vacuum, obtaining {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid in the form of a solid white color.

1H-NMR(CDCl3) δ=charged 8.52 (2H, s), 7,76 (1H, d), for 6.81 (1H, d), is 4.85 (2H, s), of 4.66 (2H, s)to 3.99 (3H, s), 3,88 (3H, s). The yield of 0.85 g (92%).

The General procedure for obtaining compounds of formula Ik, where R9and R12have the values defined here:

{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (0,037 mmol) of example 4 was dissolved in dry DMF (0.25 ml). Added a primary or secondary amine (0.045 mmol)dissolved in DMF (0.05 ml)and then HATU (0.045 mmol), Rast is Genny in DMF (0,050 ml). The reaction mixture was left at ambient temperature for 48 hours. The pure compound was obtained by purification of the standard preparative HPLC.

Using this procedure, received the following connections:

Example 202 (compound 202)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-oxo-2-pyrrolidin-1 ylethoxy)phenyl]alanon

1H-NMR(CDCl3) δ=of 8.47 (2H, s), to 7.64 (1H, d), 6,76 (1H, d), to 4.92 (2H, s), 4,88 (2H, s), of 3.94 (3H, s)to 3.89 (3H, s), 3,53 (2H, t), 3,39 (2H, t), to 1.98 (2H, m)to 1.86 (2H, m).

Amin: pyrrolidin

Example 203 (compound 203)

N-benzyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

1H-NMR(CDCl3) δ=8,49 (2H, s)to 8.12 (1H, users), 7,66 (1H, d), 7,29-7,20 (5H, m), 6,77 (1H, d), 4.72 in (2H, s)4,55 (2H, s), 4,50 (2H, d), of 3.95 (3H, s), 3,81 (3H, s).

Amin: benzylamine

Example 204 (compound 204)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-morpholine-4-yl-2-oksidoksi)phenyl]alanon

1H-NMR(CDCl3) δ=8,48 (2H, s), 7,63 (1H, d), is 6.78 (1H, d), 4,96 (2H, s), 4,80 (2H, s), of 3.94 (3H, s)to 3.89 (3H, s), 3.72 points-3,61 (6H, m), 3,54 is-3.45 (2H, m).

Amin: morpholine

Example 205 (compound 205)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-phenylacetamide

1H-NMR(CDCl3) δ=becomes 9.97 (1H, users), and 8.50 (2H, s), of 7.75 (1H, d), to 7.59 (2H, d), 7,25 (2H, t), 7,07 (1H, t), for 6.81 (1H, d), 4,80 (2H, s)and 4.65 (2H, s)to 3.99 (3H, s)to 3.89 (3H, s).

Amin: aniline

Example 206 (compound 206)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenol is si}-N-methyl-N-phenylacetamide

1H-NMR(CDCl3) δ=8,48 (2H, s), to 7.59 (1H, d), 7,45-to 7.32 (3H, m), 7,25-7,19 (2H, m), 6,70 (1H, d), a 4.83 (2H, s), and 4.68 (2H, s), 3,90 (3H, s), of 3.77 (3H, s), of 3.32 (3H, s).

Amine: N-methylaniline

Example 207 (compound 207)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-hydroxy-3-methylbutyl)ndimethylacetamide

LC/MS (METHOD A): m/z 485 (MH+); RT=of 5.89 min; purity (UV)=100%

Amin: 3-hydroxy-3-methylbutylamine

Example 208 (compound 208)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD A): m/z 441 (MH+); RT=of 6.71 min; purity (UV)=89,3%

1H-NMR(CDCl3) δ=8,51 (2H, s), 7,79 (1H, users), to 7.67 (1H, d), is 6.78 (1H, d), of 4.67 (2H, s), 4,60 (2H, s), of 3.97 (3H, s), a 3.87 (3H, s), with 3.27 (2H, q), of 1.50 (2H, m)of 0.87 (3H, t).

Amine: n-Propylamine

Example 209 (compound 209)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-isopropylacetate

LC/MS (METHOD A): m/z 441 (MH+); RT=6,72 min; purity (UV)=87,7%

1H-NMR(DMSO-d6) δ=8,64 (2H, s), 8,01 (1H, d), the 7.65 (1H, d), of 6.99 (1H, d), of 4.77 (2H, s), br4.61 (2H, s), 3,91 (4H, m), of 3.80 (3H, s), was 1.04 (6H, d).

Amin: Isopropylamine

Example 210 (compound 210)

N-butyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): (m/z) 455 (MH+); RT=7,09 minutes; (UV) purity=100%

Amin: butylamine

Example 211 (compound 211)

N-cyclopentyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): (m/z) 466,9 (MH+); RT=7,19 min; purity UV)=100%

Amin: cyclopentylamine

Example 212 (compound 212)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methylbutyl)ndimethylacetamide

LC/MS (METHOD A): m/z 469 (MH+); RT=7,42 min; purity (UV)=100%

Amin: 3-methylbutylamine

Example 213 (compound 213)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-methoxybenzyl)ndimethylacetamide

1H-NMR (DMSO-d6) δ=8,67 (1H, t)8,64 (2H, s), to 7.61 (1H, d), to 7.15 (2H, d), of 6.99 (1H, d), of 6.75 (2H, d), and 4.75 (2H, s), 4,70 (2H, s), 4.26 deaths (2H, d), 3,90 (3H, s), 3,76 (3H, s), 3,70 (3H, s)

Amine: 4-methoxybenzylamine

Example 214 (compound 214)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2,2-dimethylpropyl)ndimethylacetamide

LC/MS (METHOD A): m/z 469 (MH+); RT=7,44 min; purity (UV)=100%

Amin: 2.2-dimethylpropionic

Example 215 (compound 215)

N-cyclohexyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): (m/z) 481 (MH+); RT=7,52 min; purity (UV)=100%

Amin: cyclohexylamin

Example 216 (compound 216)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methoxybenzyl)ndimethylacetamide

1H-NMR(DMSO-d6) δ=8,72 (1H, t), 8,63 (2H, s), 7,60 (1H, d), 7,12 (1H, t), of 6.99 (1H, d), 6,83-6,74 (3H, m), and 4.75 (2H, s), to 4.73 (2H, s), 4,30 (2H, d), 3,90 (3H, s), of 3.78 (3H, s), of 3.69 (3H, s).

Amin: 3-methoxybenzylamine

Example 217 (compound 217)

N-cycloheptyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): m/z 495 (MH+); RT=784 minutes; purity (UV)=92,2%

Amin: cycloheptylamine

Example 218 (compound 218)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methoxybenzyl)ndimethylacetamide

1H-NMR(DMSO-d6) δ=8,64 (2H, s), and 8.50 (1H, t), a 7.62 (1H, d), 7,19 (1H, t), 7,12 (1H, d), of 6.99 (1H, d), 6,93 (1H, d), 6,76 (1H, t), 4,78 (2H, s), 4,74 (2H, s), or 4.31 (2H, d), 3,91 (3H, s), with 3.79 (3H, s), 3,76 (3H, s).

Amin: 2-methoxybenzylamine

Example 219 (compound 219)

N-cyclohexylmethyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): m/z 495 (MH+); RT=7,86 min; purity (UV)=100%

Amin: cyclohexylethylamine

Example 220 (compound 220)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxyethyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) byr442.9 (MH+); RT=5,41 min; purity (UV)=100%

Amin: 2-hydroxyethylamine

Example 221 (compound 221)

(R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(1-phenylethyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 502,9 (MH+); RT=7,37 min; purity (UV)=100%

Amin: (R)-1-phenylethylamine

Example 222 (compound 222)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-hydroxypropyl)ndimethylacetamide

LC/MS (METHOD A): m/z 457 (MH+); RT=5,51 min; purity (UV)=100%

Amin: 3-hydroxypropylamino

Example 223 (compound 223)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methoxyethyl)ndimethylacetamide

LC/MS (METHOD A): m/z 457 (MH+); RT=6,12 min; purity (UV)=100%

Amin 2-methoxyethylamine

Example 224 (compound 224)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-dimethylaminoethyl)ndimethylacetamide

LC/MS (METHOD A): m/z 470 (MH+); RT=4.26 deaths / min; purity (UV)=100%

Amin: 2-diethylaminoethylamine

Example 225 (compound 225)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-dimethylaminopropyl)ndimethylacetamide

LC/MS (METHOD A): m/z 484 (MH+); RT=4,29 min; purity (UV)=100%

Amin: 3-dimethylaminopropylamine

Example 226 (compound 226)

(S)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(1-phenylethyl)ndimethylacetamide

LC/MS (METHOD A): m/z 503 (MH+); RT=7,39 min; purity (UV)=100%

Amine: (S)-1-phenylethylamine

Example 227 (compound 227)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-isopropoxyphenyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 498,9 (MH+); RT=6,89 min; purity (UV)=100%

Amin: 3-isopropoxypropylamine

Example 228 (compound 228)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-furan-2-ylmethylene

LC/MS (METHOD A): (m/z) 478,9 (MH+); RT=6,74 min; purity (UV)=100%

Amin: furan-2-ylmethylamino

Example 229 (compound 229)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-2-ylmethylene

LC/MS (METHOD A): m/z 490 (MH+); RT=5.17 to min; purity (UV)=100%

Amin: pyridine-2-ylmethylamino

Example 230 (compound 230)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-3-ilma is ylacetamide

LC/MS (METHOD A): m/z 490 (MH+); RT=4,62 min; purity (UV)=100%

Amin: pyridine-3-ylmethylamino

Example 231 (compound 231)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-phenoxyethyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 518,9 (MH+); RT=7,19 min; purity (UV)=98,3%

Amin: 2-phenoxyethylamine

Example 232 (232 connection)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-4-ylmethylene

LC/MS (METHOD A): m/z 490 (MH+); RT=4,46 min; purity (UV)=100%

Amin: pyridine-4-ylmethylamino

Example 233 (compound 233)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-active compounds)ndimethylacetamide

LC/MS (METHOD A): m/z 517 (MH+); RT=7,71 min; purity (UV)=96.8%of the

Amine: 4-ethylbenzylamine

Example 234 (compound 234)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3,5-diferensial)ndimethylacetamide

LC/MS (METHOD A): (m/z) 524,9 (MH+); RT=7,27 min; purity (UV)=95.3%of the

Amin: 3,5-differentiatin

Example 235 (compound 235)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2,3-diferensial)ndimethylacetamide

LC/MS (METHOD A): (m/z) 524,9 (MH+); RT=7,22 min; purity (UV)=100%

Amin: 2,3-differentiatin

Example 236 (compound 236)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-2-retil)ndimethylacetamide

LC/MS (METHOD A): (m/z) 503,9 (MH+); RT=4,54 min; purity (UV)=100%

Amin: 2-pyridine-2-ylethylamine

Example 237 (compound 237)

2-{6-[2-(3,5-is chlorpyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methylbenzyl)ndimethylacetamide

LC/MS (METHOD A): m/z 503 (MH+); RT=7,37 min; purity (UV)=100%

Amin: 2-methylbenzylamine

Example 238 (compound 238)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-terbisil)ndimethylacetamide

LC/MS (METHOD A): (m/z) 506,9 (MH+); RT=7,14 min; purity (UV)=100%

Amin: 3-forbindelsen

Example 239 (compound 239)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methylbenzyl)ndimethylacetamide

LC/MS (METHOD A): m/z 503 (MH+); RT=7,39 min; purity (UV)=100%

Amin: 3-methylbenzylamine

Example 240 (compound 240)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-methylbenzyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 502,9 (MH+); RT=7,39 min; purity (UV)=100%

Amine: 4-methylbenzylamine

Example 241 (compound 241)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-ventilated

LC/MS (METHOD A): m/z 503 (MH+); RT=7,29 min; purity (UV)=100%

Amin: 2-phenylethylamine

Example 242 (compound 242)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-4-retil)ndimethylacetamide

1H-NMR(DMSO-d6) δ=8,65 (2H, s), 8,44 (2H, d), with 8.33 (1H, t), 7,60 (1H, d), 7,30 (2H, d), of 6.99 (1H, d), 4,74 (2H, s), to 4.62 (2H, s), 3,90 (3H, in), 3.75 (3H, s), 3,44 (2H, q), of 2.81 (2H, t).

Amin: 2-pyridine-4-ylethylamine

Example 243 (compound 243)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-phenylpropyl)ndimethylacetamide

LC/MS (METHOD A): m/z 517 (MH+); RT=7,56 min; purity (UV)=100%

Amin: 3-Hairdryer shall Propylamine

Example 244 (compound 244)

N-(2-Chlorobenzyl)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): (m/z) 522,9 (MH+); RT=7,46 min; purity (UV)=100%

Amin: 2-chlorobenzylamino

Example 245 (compound 245)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-piperidine-1-retil)ndimethylacetamide

LC/MS (METHOD A): m/z 510 (MH+); RT=4,46 min; purity (UV)=92,5%

Amin: 2-piperidine-1-ylethylamine

Example 246 (compound 246)

N-(3-Chlorobenzyl)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): (m/z) 522,8 (MH+); RT=7,46 min; purity (UV)=100%

Amin: 3-chlorobenzylamino

Example 247 (compound 247)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-morpholine-4-retil)ndimethylacetamide

LC/MS (METHOD A): m/z 512 (MH+); RT=or 4.31 min; purity (UV)=98,1%

Amin: 2-morpholine-4-ylethylamine

Example 248 (compound 248)

N-(4-Chlorobenzyl)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): (m/z) 522,9 (MH+); RT=7,49 min; purity (UV)=98,7%

Amine: 4-chlorobenzylamino

Example 249 (compound 249)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-3-retil)ndimethylacetamide

LC/MS (METHOD A): m/z 504 (MH+); RT=4,47 min; purity (UV)=100%

Amin: 2-pyridine-3-ylethylamine

Example 250 (compound 250)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyrrolidin-1-retil)ndimethylacetamide

W is/MS (METHOD A): m/z 496 (MH+); RT=4,37 min; purity (UV)=100%

Amin: 2-pyrrolidin-1-ylethylamine

Example 251 (compound 251)

N-(2-acetylamino)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): m/z 484 (MH+); RT=5,31 min; purity (UV)=100%

Amin: 2-acetaminolhen

Example 252 (compound 252)

(R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 518,9 (MH+); RT=6,47 min; purity (UV)=73,4%

Amin: (R)-2-hydroxy-2-phenylethylamine

Example 253 (compound 253)

(S)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide

LC/MS (METHOD A): m/z 519 (MH+); RT=6,47 min; purity (UV)=73,8%

Amine: (S)-2-hydroxy-2-phenylethylamine

Example 254 (compound 254)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-thiophene-2-ylmethylene

LC/MS (METHOD A): (m/z) 494,9 (MH+); RT=6,97 min; purity (UV)=100%

Amin: thiophene-2-ylmethylamino

Example 255 (compound 255)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-[3-(2-oxopyrrolidin-1-yl)propyl]ndimethylacetamide

LC/MS (METHOD A): m/z 524 (MH+); RT=5,66 min; purity (UV)=95,7%

Amin: 3-(2-oxopyrrolidin-1-yl)Propylamine

Example 256 (compound 256)

(2R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxyine-1-yl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 530,8 (MH+); RT=6,62 min; purity (UV)=90.4%of the

Amin: (2R)-2-HYDR shall xiandan-1-ylamine

Example 257 (compound 257)

N-cycloheptylmethyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

LC/MS (METHOD A): m/z 509 (MH+); RT=8,19 min; purity (UV)=100%

Amin: cycloheptylmethyl

Example 258 (compound 258)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-[2-(2-hydroxyethoxy)ethyl]ndimethylacetamide

LC/MS (METHOD A): m/z 487 (MH+); RT=5,41 min; purity (UV)=100%

Amine: 2-(2-hydroxyethoxy)ethylamine

Example 259 (compound 259)

2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-dimethylaminomethyl)ndimethylacetamide

LC/MS (METHOD A): (m/z) 497,9 (MH+); RT=4,36 min; purity (UV)=100%

Amine: 4-dimethylaminobutyric

Example obtain 5 (compound 505)

associated with the resin 2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon

2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon (530 mg, 1.6 mmol) of example for the preparation of 3 was dissolved in dry NMP (5 ml)was added K2CO3(210 mg, 1.5 mmol)and then methyl bromide-Wang resin (560 mg, L=1,45 mmol/g, 0.81 mmol). The reaction mixture was stirred in a vortex at ambient temperature over night. The resin was filtered and washed with a mixture of MeOH:water (4:1, 3×10 ml), NMP (3×25 ml), MeOH (3×25 ml), dry THF (5×25 ml) and dried in vacuum, obtaining 760 mg associated with resin 2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone.

General the procedure for obtaining compounds of formula Im, in which R2is above a certain value:

Associated with the resin 2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon (90 mg, L=1.07 mmol/g, 0.1 mmol) sample receiving 5 were treated with 1 ml of the stock solution R2-OH (0.5 mmol) andPBu3(0.5 mmol), cooled to 0°C and then was treated with 0.5 ml of stock solution TBAD (0.5 mmol). After 3 hours at ambient temperature the reaction mixture was filtered and added to 1 ml of the stock solution R2-OH (0.5 mmol) andPBu3(0.5 mmol). After cooling to 0°C was added 0.5 ml of stock solution TBAD (0.5 mmol). The reaction mixture was stirred in a vortex at ambient temperature over night. The resin washed with THF (5×3 ml) and DCE (5×3 ml). The cleavage products was carried out by adding a stock solution of DCE-TN-TIS (90:10:1, 1 ml). After 30 minutes, splitting the solution was replaced with 1 ml fresh off solution. After an additional 30 minutes United splitting the solution was evaporated in vacuum. Pure compounds were obtained, re-dissolving the reaction mixture in DMSO, followed by purification standard preparative HPLC.

Using this procedure, received the following connections:

Example 260 (compound 260)

1-(3-cyclopentyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 396 (MH+); RT=4,84 min. purity (UV)=100%

Alcohol: Cyclopentanol

Example 261 (compound 261)

1-(3-cyclopropylmethoxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 382,1 (MH+); RT=4,36 min; purity (UV)=100%

Alcohol: cyclopropylmethoxy alcohol

Example 262 (compound 262)

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2-hydroxy-4-methoxyphenyl)alanon

2-(3,5-dichloropyridine-4-yl)-1-(2,3-dihydroxy-4-methoxyphenyl)alanon (450 mg, 1.4 mmol) of example for the preparation of 3 was dissolved in dry DMF (10 ml). Added K2CO3(566 mg, 4.1 mmol), then ethyliodide (442 μl, 5.5 mmol). The reaction mixture was stirred at ambient temperature overnight. Was added water (10 ml)and the organic products were extracted with EtOAc (2×25 ml). The combined organic phases were washed with water (10 ml) and brine (10 ml) and then dried overMgSO4. The solvent was removed in vacuo, and the resulting pure product was subjected to standard chromatography on silica gel, receiving 2-(3,5-dichloropyridine-4-yl)-1-(2,3-diethoxy-4-methoxyphenyl)Etalon in the form of a solid white color. Yield 220 mg (42%). This compound was re-dissolved in DCM (1 ml) in an argon atmosphere.When the ambient temperature was slowly added BCl3(0,97 ml of 1 M solution in DCM). After 2 hours was slowly added to EtOH (2 ml). The solvent was removed in vacuum, and receiving the hydrated pure product was subjected to standard chromatography on silica gel, getting 2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2-hydroxy-4-methoxyphenyl)Etalon in the form of a solid white color.

1H-NMR(DMSO-d6) δ=11,36 (1H, s), 8,67 (2H, s), 7,88 (1H, d), 6,77 (1H, d), 4,80 (2H, s), of 3.96 (2H, square), 3,91 (3H, s)of 1.26 (3H, t). Yield 100 mg (49%).

General procedure for preparing compounds of the formula In which R3(R3≠hydrogen) has the values defined above:

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2-hydroxy-4-methoxyphenyl)Etalon example 263 (12 mg, 0,034 mmol) was dissolved in dry DMSO (0.25 ml). Was added an aqueous solution of K2CO3(0,025 ml of 2 M), then 1.5 EQ. allylbromide or iodide, dissolved in a 0,025 ml of DMSO. The reaction mixture was left at ambient temperature for 48 hours. The pure compound was obtained by purification of the standard preparative HPLC.

Using this procedure, received the following connections:

Example 263 (compound 263)

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-4-methoxy-2-penetrometer)alanon

1H-NMR(CDCl3) δ=of 8.47 (2H, s), to 7.61 (1H, d), 7,26 (4H, m), 7,10 (1H, t), of 6.75 (1H, d), of 4.49 (2H, t), 4,43 (2H, s)to 4.01 (2H, square), 3,91 (3H, s), 3,17 (2H, t), of 1.35 (3H, t).

Alkylhalogenide: 2-bromo-1-Penilaian

Example 264 (compound 264)

1-[2-(5-cyclopropyl[1,3,4]thiadiazole-2-ylethoxy)-3-ethoxy-4-methoxyphenyl]-2-(3,5-dichloropyridine-4-yl)alanon

1H-NMR(CDCl3) δ=of 8.47 (2H, s), to 7.61 (1H, d), for 6.81 (1H, d), 5,64(2H, C)4,56 (2H, s), is 4.15 (2H, square), of 3.95 (3H, s), 2,39 (1H, m)of 1.41 (3H, t), 1.56 to a 1.11 (4H, m).

Alkylhalogenide: 2-chloromethyl-5-cyclopropyl[1,3,4]thiadiazole

Example 265 (compound 265)

benzyl ether of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2-ethoxy-3-methoxyphenoxy}acetic acid

1H-NMR(DMSO-d6) δ=8,62 (2H, s), 7,51 (1H, d), to 7.32 (5H, m), of 6.96 (1H, d), 5,19 (2H, s), 4,74 (2H, s), 3,98 (2H, square), 3,88 (3H, s)of 1.27 (3H, t).

Alkylhalogenide: benzyl ether of 2-bromoxynil acid

Example 266 (compound 266)

1-(3-allyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon

1-(2,3-bis-allyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)Etalon example 6 (3,9 g of 9.55 mmol) was dissolved in MeOH (96 ml) and cooled to 0°C in an argon atmosphere. Was added Pd(PPh3)4(110 mg, 0,0955 mmol), then K2CO3(1.3 g, of 9.55 mmol). The cooling bath was removed and the reaction mixture was stirred for 3 hours and then was evaporated in vacuum. The crude product was re-dissolved in EtOAc (100 ml) and washed twiceNH4Cl (feast upon., 50 ml). The organic phase was dried overNa2SO4and was evaporated in vacuo, and purified flash chromatography using a gradient of toluene and 2%EtOAc as eluent. 1-(3-allyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)Etalon received in the form of a solid white color.

1H-NMR(CDCl3) δ=1,90 (1H, C)8,53 (2H, s), to 7.68 (1H, d), to 6.58 (1H, d), 6,10 (1H, m), 5,26 (2H, m), of 4.66 (2H, s), 4,59 (2H, d), of 3.96 (3H, s). Yield 2.2 g (64%).

The General procedure for obtaining compounds of formula Io, in which R3(R3≠hydrogen) has the above specified values:

2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2-hydroxy-4-methoxyphenyl)Etalon example 263 (12 mg, 0,034 mmol) was dissolved in dry DMSO (0.25 ml). Was added an aqueous solution of K2CO3(0,025 ml of 2 M), then 1.5 EQ. allylbromide or iodide, dissolved in a 0,025 ml of DMSO. The reaction mixture was left at ambient temperature for 48 hours. The pure compound was obtained by purification of the standard preparative HPLC.

Using this procedure, received the following connections:

Example 267 (compound 267)

2-{2-allyloxy-6-[2-(3,5-dichloropyridine-4-yl)acetyl]-3-methoxyphenoxy}benzonitrile

LC/MS (METHOD B): (m/z) 383,2 (MH+); RT=4,72 min; purity (UV)=100%

Alkylhalogenide: 2-chloromethylbenzene

Example 268 (compound 268)

1-(3-allyloxy-4-methoxy-2-penetrometer)-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 472,3 (MH+); RT=5,32 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-Penilaian

Example 269 (compound 269)

1-{3-allyloxy-2-[2-(4-forfinal)ethoxy]-4-methoxyphenyl}-2-(3,5-dichloropyridine-4-yl)alanon

LC/MS (METHOD B): (m/z) 490,2 (MH+); RT=5,26 min; purity (UV)=100%

Alkylhalogenide: 1-bromo-2-(4-ftoh the Nile)ethane

The General procedure for obtaining compounds of formula Ip, in which R3is above a certain value:

1-(2-alkoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)Etalon previous examples (0,021 mmol) was dissolved in dry DCM (0.25 ml). Added methyltrioxorhenium (0,105 mmol), then the hydroperoxide (0,042 mmol)and the reaction mixture was stirred at ambient temperature overnight. AddedMnO2(0,063 mmol). After 2 minutes the reaction mixture was filtered and the reaction mixture was evaporated in vacuum. The crude product was re-dissolved in DMSO (0.4 ml). The pure compound was obtained by purification of the standard preparative HPLC.

Using this procedure, received the following connections:

Example 270 (compound 270)

N-benzyl-2-{6-[2-(3,5-dichloro-1-oxypyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide

1H-NMR(CDCl3) δ=8,15 (2H, s), 8,10 (1H, users), a 7.62 (1H, d), 7,30 (5H, m), 6,76 (1H, d), 4.72 in (2H, s), 4,50 (2H, d), to 4.46 (2H, s), of 3.95 (3H, s), of 3.80 (3H, s).

Used N-benzyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide example 203 as source material.

Example 271 (compound 271)

2-(3,5-Dichloro-1-oxypyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)alanon

1H-NMR(CDCl3) δ=8,13 (2H, s), to 7.61 (1H, d), 7,26 (5H, m), of 6.75 (1H, d), and 4.40 (2H, t), 4,30 (2H, s), 3,93 (3H, s), with 3.79 (3H, s), 3,17 (2H, t).

And the used 2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)Etalon example 112 as the source material.

Example 272 (compound 272)

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}alanon

1H-NMR(CDCl3) δ=8,19 (2H, s), to 7.61 (1H, d), 7,26 (2H, t), to 6.95 (2H, t), of 6.75 (1H, d), of 4.44 (2H, t), 4,34 (2H, s), 3,93 (3H, s), of 3.77 (3H, s), 3, 14 (2H, t).

Used 2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon example 129 as a source material.

Example 274 (compound 274)

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(1-oxypyridine-4-yl)ethoxy]phenyl}alanon

1H-NMR(DMSO-d6) δ=8,62 (2H, s), 8,11 (2H, d), 7,54 (1H, d), 7,39 (2H, d), 6,97 (1H, d), to 4.41 (4H, m), 3,88 (3H, s)to 3.67 (3H, s), 3,11 (2H, t).

Used the example of 100 as the starting material.

Example 275 (compound 275)

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-(2-hydroxy-3,4-acid), alanon

1H-NMR(DMSO-d6) δ=11,20 (1H, users), 8,64 (2H, s), to 7.84 (1H, d), 6,77 (1H, d), 4,70 (2H, users), 3,91 (3H, s), and 3.72 (3H, s).

Used 2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon of example 1 as starting material.

Example 276 (compound 276)

4-(2-{6-[2-(3,5-dichloro-1-oxypyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)benzonitrile

1H-NMR(DMSO-d6) δ=8,61 (2H, s), 7,73 (2H, d), at 7.55 (3H, m), of 6.96 (1H, d), of 4.45 (2H, t), 4,20 (2H, s), 3,88 (3H, s), 3,66 (3H, s), up 3.22 (2H, t).

Used the example of 100 as the starting material.

The General procedure for obtaining the connection is with the formula Iq in which R3(R3≠hydrogen) has the above specified values:

2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon of example 1 (1.5 mmol) or 2-(3,5-dichloro-1-oxypyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon example 274 (1.5 mmol),PBu3(1.5 mmol) and R3-OH (1.0 mmol) was dissolved in argon atmosphere in dry benzene (10 ml). The reaction mixture was cooled to 0°C and then was treated ADDP (1.5 mmol). After 0.5 hours the reaction mixture was heated to ambient temperature and was stirred overnight. Added dekalim, and the reaction mixture was evaporated in vacuo, and purified flash chromatography using a gradient of petroleum ether and EtOAc as eluent.

Using this procedure, received the following connections:

Example 277 (compound 277)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-4-ylethoxy)phenyl]alanon

1H-NMR(DMSO-d6) δ=8,63 (2H, s), 8,44 (2H, d), 7,53 (1H, d), 7,37 (2H, d), 6,97 (1H, d), 4,46 (4H, m), 3,88 (3H, s), 3,66 (3H, s)and 3.15 (2H, t).

R3-OH: 2-pyridine-4-retinol

Example 278 (compound 278)

4-(2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)benzonitrile

1H-NMR(DMSO-d6) δ=8,63 (2H, s), of 7.70 (2H, d), at 7.55 (3H, m), 6,97 (1H, d), 4,47 (2H, t), 4,30 (2H, s)to 3.89 (3H, s), 3,68 (3H, s), 3,23 (2H, t).

R3HE: 4-(2-hydroxyethyl)benzonitrile obtained from 2-(4-bromphen the l)ethanol according to

Example 279 (compound 279)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-2-ylethoxy)phenyl]alanon

1H-NMR(DMSO-d6) δ=8,62 (2H, s), to 8.41 (1H, t), the 7.65 (1H, t), to 7.50 (1H, d), 7,38 (1H, d), 7,10 (1H, m), to 6.95 (1H, d), br4.61 (2H, t), of 4.38 (2H, s), 3,88 (3H, s), and 3.72 (3H, s), or 3.28 (2H, t).

R3HE: 2-pyridine-2-retinol

Example 280 (compound 280)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-3-ylethoxy)phenyl]alanon

1H-NMR(DMSO-d6) δ=8,64 (2H, s), 8,55 (1H, s), a 8.34 (1H, d), to 7.77 (1H, d), 7,53 (1H, d), 7,28 (1H, m), 6,97 (1H, d), 4,47 (2H, s), 4,43 (2H, t), 3,88 (3H, s)to 3.64 (3H, s)and 3.15 (2H, t).

R3HE: 2-pyridine-3-retinol

Example 281 (compound 281)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-methanesulfonyl)ethoxy]-3,4-acid}alanon

(CDCl3) δ=8,50 (2H, s), to 7.59 (3H, m), 7,49 (2H, d), is 6.78 (1H, d), 4,48 (4H, m), 3,93 (3H, s), 3,74 (3H, s), 3,24 (2H, t), 2,63 (3H, s).

R3-OH: 2-(4-methanesulfonyl)ethanol obtained by oxidation of 2-(4-methylsulfinylphenyl)of ethanol and 1.5 EQ. MCPBA in DCM at ambient temperature overnight.

1H-NMR (CDCl3) δ=7,88 (2H, d), was 7.45 (2H, d), to 3.92 (2H, t), totaling 3.04 (3H, s), of 2.97 (2H, t), of 1.70 (1H, users).

LC/MS (METHOD B): (m/z 185 (MH+); RT=1,27 minutes

Example 282 (compound 282)

2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-methanesulfonyl)ethoxy]-3,4-acid}alanon

1H-NMR(CDCl3) δ=8,50 (2H, s), 7,88 (2H, d), to 7.59 (1H, d), 7,53 (2H, d), 6,77 (1H, d), 4,51 (2H, s), of 4.49 (2H, t), 3,93 (3H, s), and 3.72 (3H, s), with 3.27 (2H, t), 2,98 (3H, s).

R3 -OH: 2-(4-methanesulfonyl)ethanol obtained by oxidation of 2-(4-methylsulfinylphenyl)of ethanol and 1.5 EQ. MCPBA in DCM at ambient temperature overnight.

1H-NMR (CDCl3) δ=to 7.59 (2H, d), 7,40 (2H, d), 3,90 (2H, t)to 2.94 (2H, t), of 2.72 (3H, s), of 1.85 (1H, users).

LC/MS (METHOD B): (m/z 201 (MH+); RT=1,48 minutes

Example 283 (compound 283)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(1-phenylpropoxy)phenyl]alanon

1H-NMR (DMSO-d6) δ=8,65 (2H, s), 7,34 (6H, m), 6,85 (1H, d), of 5.48 (1H, t), 4,63 (2H, s), 3,85 (3H, s), and 3.72 (3H, s), and 2.14 (1H, m), of 1.95 (1H, m)to 0.88 (3H, t).

R3-OH: 1-phenylpropane-1-ol

Example 284 (compound 284)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-phenylpropoxy)phenyl]alanon

1H-NMR(DMSO-d6) δ=8,62 (2H, s), 7,51 (1H, d), 7,35 (2H, d), 7.23 percent (2H, t), 7,06 (IH7t), to 6.95 (1H, d), 4,33 (4H, m), 3,88 (3H, s), of 3.69 (3H, s)to 3.33 (1H, m)to 1.37 (3H, d).

R3-OH: 2-phenylpropane-1-ol

Example 285 (compound 285)

2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(1-methyl-2-phenylethane)phenyl]alanon

1H-NMR(DMSO-d6) δ=8,66 (2H, s), 7,46 (1H, d), 7,28 (4H, d), 7,17 (1H, m), 6,93 (1H, d), 4,94 (1H, m), 4,60 (2H, m), 3,88 (3H, s)to 3.58 (3H, s), to 3.02 (2H, m)of 1.18 (3H, d).

R3Is IT: 1-phenylpropane-2-ol

An example of obtaining 6 (compound 506):

Methyl-2,3,4-trimethoxybenzoic acid (25,7 g, 114 mmol) in argon atmosphere was dissolved in DCM (25 ml).Was added dropwise BCl3(133 ml of 1 M solution in DCM, 133 mmol), and Rea is operating and the mixture was left at ambient temperature for 2 hours. Added EtOH (200 ml)and the reaction mixture was stirred for 2 hours. The precipitate was filtered and Perekrest. from a mixture of EtOAc-petroleum ether, receiving 6 g (25%) of the methyl ester of 2-hydroxy-3,4-dimethoxybenzoic acid in the form of a solid white color.

1H-NMR(CDCl3) δ=10,90 (1H, s), to 7.59 (1H, d), 6.48 in (1H, d), 3,93 (3H, s)to 3.92 (3H, s)to 3.89 (3H, s).

Methyl ester of 2-hydroxy-3,4-dimethoxybenzoic acid (6 g, of 28.2 mmol) was re-dissolved in NMP (35 ml) and was treated with tert-butylbromide (42,4 mmol) andK2CO3(42,4 mmol). The reaction mixture was heated at 50°C during the night. The reaction mixture was poured into water (300 ml). Organic products were extracted with EtOAc (2×100 ml)and the combined organic phases are washed with NaCl (feast upon., 100 ml). The organic phase was dried over Na2SO4was evaporated in vacuo, and purified flash chromatography using a gradient of EtOAc in heptane as eluent, obtaining methyl ester 2-tert-butoxycarbonylamino-3,4-dimethoxybenzoic acid (compound 506a) in the form of a colorless oil.

1H-NMR(CDCl3) δ=7,58 (1H, d), of 6.71 (1H, d), 4,56 (2H, s), 3,90 (3H, s), a 3.87 (3H, s), 3,86 (3H, s)of 1.50 (9H, s). Output 8,19 g (89%).

Methyl ester 2-tert-butoxycarbonylamino-3,4-dimethoxybenzoic acid (8,19 g, a 25.1 mmol) was dissolved in DCM (50 ml) and treated with triethylsilane (4 ml, 25,1 mmol) and TN (9,66 ml, output reached 125.5 mmol). The reaction is ionic and the mixture was left overnight. The reaction mixture was evaporated in vacuo, re-dissolved in toluene (200 ml) and evaporated to dryness. This procedure was repeated three times, getting the methyl ester of 2-carboxymethoxy-3,4-dimethoxybenzoic acid (compound 506b) in the form of a solid white color.

1H-NMR(CDCl3) δ=12,6 (1H, users), of 7.75 (1H, d), of 6.73 (1H, d), 4,84 (2H, s), of 3.95 (3H, s)to 3.92 (3H, s), 3,85 (3H, s). The yield of 6.71 g (99%).

Methyl ester 2-carboxymethoxy-3,4-dimethoxybenzoic acid (of 6.71 g of 24.8 mmol) was dissolved in dry DMF (130 ml) in an argon atmosphere. Added Propylamine (4,1 ml of 49.8 mmol)and then HATU (11,32 g, to 29.8 mmol)and the reaction mixture was left overnight. The solvent is evaporated in vacuum and the crude mixture was re-dissolved in EtOAc (150 ml). The organic phase was washed with an aqueous solutionCaCl2(2×50 ml), water (2×50 ml) and brine (50 ml). The organic phase was dried overNa2SO4was evaporated in vacuo, and purified flash chromatography using a gradient of EtOAc in heptane as eluent. Methyl ester of 3,4-dimethoxy-2-propylbromoacetate acid (compound 506c) received in the form of a solid white color.

1H-NMR(CDCl3) δ=of 8.47 (1H, users), 7,71 (1H, d), 6,70 (1H, d), 4,69 (2H, s), 3,93 (3H, s), a 3.87 (3H, s), 3,83 (3H, s)to 3.33 (2H, square), of 1.64 (2H, m), 0,99 (3H, t). Output to 6.67 g (86%).

The General procedure for obtaining compounds of formula Ir, in which Ar and Hetr matter, defined above:

Methyl ester of 3,4-Dimethoxy-2-propylbromoacetate acid (28 mg, 0.09 mmol)obtained in example receive 6, and the connection Ar-Me or HetAr-Me (1.2 EQ., see below) was dissolved in dry THF (1 ml) in an argon atmosphere. The mixture was cooled to 0° and treated dropwise LiHMDS (0,273 ml of 1 M solution). The reaction mixture was heated to ambient temperature and left overnight. The reaction was stopped NH4Cl (feast upon., 2 ml)and the organic products were extracted with EtOAc (2×2 ml). The combined organic phases are washed with NaCl (feast upon., 2 ml). The organic phase was dried overNa2SO4was evaporated in vacuo and re-dissolved in MeOH (0,350 ml), then was purified by standard HPLC purification.

Using this procedure, received the following connections:

Example 286 (compound 286)

2-{6-[2-(6-chloropyrazine-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 408,4 (MH+); RT=3,33 min; purity (UV)=91%

HetAr-IU: 2-chloro-6-methylpyrazine

Example 287 (compound 287)

2-{6-[2-(3-bromopyrazine-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) of 454.3 (MH+); RT=3,26 min; purity (UV)=86%

HetAr-IU: 2-bromo-3-methylpyrazine

Example 288 (compound 288)

2-{6-[2-(2,6-dichlorophenyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

1H-NMR(CDCl3) δ=7,84 (1H, ears is .c), to 7.68 (1H, d), 7,34 (2H, d), 7,19 (1H, t), 6,77 (1H, d), of 4.66 (2H, s), 4,60 (2H, s), of 3.95 (3H, s), 3,86 (3H, s)of 3.25 (2H, square), to 1.48 (2H, m)0,86 (3H, t).

Ar-Me: 1,3-dichloro-2-methylbenzo

Example 289 (compound 289)

2-[2,3-dimethoxy-6-(2-pyridin-4-ylacetic)phenoxy]-N-propylacetamide

1H-NMR(DMSO-d6) δ=8,49 (2H, users), 8,15 (1H, t), of 7.55 (1H, d), from 7.24 (2H, d), to 6.95 (1H, d), 4,56 (2H, s), of 4.44 (2H, s), 3,88 (3H, s), of 3.77 (3H, s)to 3.09 (2H, square), of 1.42 (2H, m), 0,81 (3H, t).

HetAr-IU: 4-methylpyridin

Example 290 (compound 290)

2-[2,3-dimethoxy-6-(2-quinoline-4-ylacetic)phenoxy]-N-propylacetamide

LC/MS (METHOD B): (m/z) 423,4 (MH+); RT=at 2.45 min; purity (UV)=100%

HetAr-IU: 4-methylinosine

Example 291 (compound 291)

2-[2,3-dimethoxy-6-(2-pyrazin-2-ylacetic)phenoxy]-N-propylacetamide

LC/MS (METHOD B): (m/z) 374,1 (MH+); RT=2,58 min; purity (UV)=81%

HetAr-IU: 2-methylpyrazine

Example 292 (compound 292)

2-{6-[2-(3-bromopyridin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 453,07 (MH+); RT=3,13 min; purity (UV)=100%

HetAr-IU: 3-bromo-4-methylpyridin

Example 293 (compound 293)

2-{6-[2-(3,5-dibromopyridin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 531,0 (MH+); RT=3,68 min; purity (UV)=100%

HetAr-IU: 3,5-dibromo-4-methylpyridin

Example 294 (compound 294)

2-{6-[2-(6-chloropyrimidine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 408,3 (MH+); RT=3,19 and 3,79 minutes (probably ketone and enol isomer); clear is that (UV)=100%

HetAr-IU: 4-chloro-6-methylpyrimidin

Example 295 (compound 295)

2-{6-[2-(4-chloropyridin-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 407,4 (MH+); RT=3,50 min; purity (UV)=100%

HetAr-IU: 4-chloro-2-methylpyridin

Example 296 (compound 296)

2-{6-[2-(2-chloropyridin-3-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 407,4 (MH+); RT=3,26 min; purity (UV)=100%

HetAr-IU: 2-chloro-3-methylpyridin

Example 297 (compound 297)

2-{2,3-dimethoxy-6-[2-(2-methoxypyridine-4-yl)acetyl]phenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 403,3 (MH+); RT=3,24 min; purity (UV)=100%

HetAr-IU: 2-methoxy-4-methylpyridin

Example 298 (compound 298)

2-{6-[2-(2-cyano-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide

LC/MS (METHOD B): (m/z) 398,4 (MH+); RT=3,23 min; purity (UV)=94%

HetAr-IU: 4-methylpyridin-2-carbonitril

Example 299 (compound 299)

2-[2,3-dimethoxy-6-(2-pyridazin-3-ylacetic)phenoxy]-N-propylacetamide

LC/MS (METHOD B): (m/z) 374,2 (MH+); RT=2,39 min; purity (UV)=90%

HetAr-IU: 3-methylpyridazin

Example 300 (compound 300)

2-(2-tert-butylamino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}alanon

2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon obtained in example 272, was converted into 2-(2-tert-butylamino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ATOC and]-3,4-acid}Etalon according to the procedure described in J. Org. Chem. (2007), 72, 4554-57. Pure 2-(2-tert-butylamino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon received standard HPLC purification.

LC/MS (METHOD B): (m/z) 535,2 (MH+); RT=6,21 min; purity (UV)=100%

Example 301 (compound 301)

2-(2-amino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}alanon

2-(2-tert-butylamino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon obtained in example 300 (16.5 mg, 0,0308 mmol), triethylsilane (2 EQ.) and TN (0.1 ml) in dichloroethane (0.2 ml) was heated to 50°C for 24 hours. The crude mixture was evaporated in vacuo, re-dissolved in dichloroethane (1 ml) and washedNaHCO3(feast upon., 2×0.5 ml). The organic phase was dried overNa2SO4and the solvent evaporated in vacuum. Pure 2-(2-amino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon got flash chromatography using a gradient of MeOH in dichloromethane as eluent.

LC/MS (METHOD B): (m/z) 479,3 (MH+); RT=4,53 min; purity (UV)=100%

Example 302 (compound 302)

2-(3,5-dichloropyridine-4-yl)-1-(4-ethoxy-3-methoxy-2-penetrometer)alanon

2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)Etalon obtained in example 112 (89,3 mg, 0.1 mmol)was treated with piperidine (0.8 ml) and water,32 ml). The yellow suspension was heated at 90°C for 54 hours. The solvent is evaporated in vacuum. The crude mixture was treated withNH4Cl (feast upon., 1 ml)and the organic products were extracted with EtOAc (3×2 ml). The combined organic phases were dried overNa2SO4and evaporated in vacuum. Cleaning method flash chromatography using a gradient of EtOAc in toluene as eluent, was obtained 2-(3,5-dichloropyridine-4-yl)-1-(4-hydroxy-3-methoxy-2-penetrometer)Etalon in the form of a solid white color. The output of 8.6 mg (20%). 2-(3,5-dichloropyridine-4-yl)-1-(4-hydroxy-3-methoxy-2-penetrometer)alanon (5,5 mg of 0.013 mmol) was dissolved in DMSO (0.45 ml) and treatedK2CO3is 0.019 ml of 1 M aqueous solution), then ethyliodide is 0.019 ml of 1 M solution in DMSO). The reaction mixture was left at ambient temperature for 48 hours and were purified by standard HPLC purification. 2-(3,5-dichloropyridine-4-yl)-1-(4-ethoxy-3-methoxy-2-penetrometer)Etalon received in the form of a colorless solid. Output 3.2 mg (36%).

1H-NMR(CDCl3) δ=8,48 (2H, s), to 7.59 (1H, d), 7,27 (4H, m), 7,11 (1H, t), of 6.73 (1H, d), 4,48 (4H, m), 4,14 (2H, square), of 3.78 (3H, s)3,18 (2H, t), for 1.49 (3H, t).

Example 303

Test PDE4

Human recombinant PDE4 (Gene bank access number NM_006203) were incubated for 1 hour, respectively, with the test compound in concentrations up to 10 μm, with camp (1×10-5

The results were calculated as the molar concentration causing 50%-th inhibition of cleavage of the substrate in comparison with the control samples, and expressed as-log IC50(M).

It was shown that the compounds 101, 103, 104, 106-148, 150-155, 157-206, 208-234, 236-241, 243, 244, 246, 248, 249, 251,-258, 260-272, 274-5, 277-285, 287-290, 292-293, 296, 301 and 302 are effective inhibitors of s-log IC50(M) above 6.

Example 304

Release TNF

Mononuclear cells of peripheral blood (PBMC) were separated from leucocytes films. The blood was mixed with saline in the ratio of 1:1, and PBMC were separated using Lymphoprep tubesTM (Nycomed, Norway). PBMC suspended in RPMI1640 with 2% fetal calf serum (FCS), pen/strep and 2 mm L-glutamine at a concentration of 5×105cells/ml the Cells were pre-incubated for 30 minutes with the test compounds in 96-well tablets for tissue culture and stimulated for 18 hours with lipopolysaccharide (1 mg/ml (Sigma). The level of TNF-α was measured in the supernatant culture using enzyme-linked immunosorbent assays, using primary and secondary biotinylated antibodies from R&D systems. The results were expressed as values pIC50calculated from inhibition curves using as positive controls secretion in LPS-stimulated wells as negative controls secretion in restimulating cells.

It was shown that the compounds 101, 104, 106-138, 140-148, 150-153, 155, 157, 161-164, 168, 170, 171, 176, 177, 182-186, 188-190, 193, 202-206, 208-241, 243, 244, 246, 248, 249, 251-258, 260-275, 277-282, 284, 285, 288-290, 292, and 293 are effective inhibitors of s-log IC50(M) above 6.

1. The compound according to formula I

in which X1X2X3X4and X5independently from each other represent CH or N;
or X3X4and X5independently of one another denote-CH - or N, and X1and X2independently of one another denote C and are part of an additional 6-membered aromatic ring;
in which R1denotes methyl or ethyl, or R1denotes hydrogen;
R2denotes methyl, ethyl, propyl, tert-butoxycarbonylmethyl, allyl, deformity, ethylbenzene, methylbenzol, butenyl, hydroxyethyl, tolyl, pentenyl, methoxyethyl, butenyl, propylene, methylcarbonate, cyclopentyl, each of which may be substituted by one or more identical or different substituents, vibrancies R 5; or R2denotes hydrogen;
R3denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, halogenated, hydroxyalkyl, geteroseksualen, alkylaryl, arylalkyl, alkylalkoxysilane, alkylcarboxylic or alkoxyalkyl, each of which may be substituted by one or more identical or different substituents selected from R6; or R3denotes hydrogen, -CH2-C(O)-heteroseksualci or-CH2-C(O)NR9-R12;
R5denotes methyl, tert-butoxy, ethynyl, cyclopropyl, propenyl, phenyl, butenyl, PROPYNYL, methylhydroxy, ethinyl, allyl, ethyl or methoxy, each of which may be substituted by one or more identical or different substituents selected from R7or R5denotes hydrogen, oxo, chloro, fluoro or hydroxy;
R6denotes alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, aryloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, arylcarbamoyl, hydroxy, alkylsulphonyl, alkylcarboxylic or amino, each of which may be substituted by one or more identical or different substituents selected from R8; or R6denotes hydrogen, oxo, GoLoG is h, cyano or nitro;
R8denotes methyl, ethyl, propyl, butyl, phenyl, cyclopropyl, ethoxy, methoxy, allyl, ethynyl, etoxycarbonyl, hydroxy, naphthyl, cyclohexyl, methoxycarbonyl, phenoxy, isopropoxy, -NH2, methylamine, pyrrolidinyl, morpholinyl, methylsulphonyl, methylsulfinyl, cycloheptyl, cyclopentyl, hydroxymethyl, hydroxyethyl, dimethylamino, furanyl, pyridyl, tolyl, piperidinyl, acetyl, thiophenyl, cycloheptyl, each of which may be substituted by one or more identical or different substituents selected from R10or R8denotes hydrogen, oxo, chlorine, bromine, fluorine, cyano or trifluoromethyl;
R9denotes hydrogen, alkyl, halogenated or hydroxyalkyl;
R10denotes hydrogen, alkyl, oxo, hydroxy, halogen, carboxy, amino, alkoxy, halogenated or hydroxyalkyl;
R11represents one or more identical or different substituents selected from hydrogen, halogen, cyano, amino, alkyl, methylsulfinyl, methylsulfonyl, amino, cyano, or alkoxy;
R12denotes alkylaryl, arylalkyl, carboxy, alkyl, alkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, aryloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, hydroxy, alquiler is of IMT, arylcarbamoyl, alkylcarboxylic or amino, each of which may be substituted by one or more identical or different substituents selected from R8or R12denotes hydrogen;
provided that R1, R2and R3can not be the stands;
provided that when R2and R3both denote hydrogen, R1may not be the stands or hydrogen;
provided that when R1denotes methyl or hydrogen, R2denotes methyl, and R3denotes hydrogen, then ring B cannot be phenyl;
and its pharmaceutically acceptable salts or N-oxides.

2. The compound according to claim 1, in which the ring is a pyridyl, pyrazinyl, hinely, pyrimidinyl or pyridazinyl, if necessary substituted by one or more identical or different substituents selected from fluorine, chlorine, bromine, cyano, methoxy, -NH2or C1-4amino.

3. The compound according to claim 1, in which ring B, if necessary substituted R11represents a 2-(6-chloropyrazine), 2-pyrazinyl, 4-(3-bromopyridin), 4-(3,5-dibromopyridin), 4-(6-chloropyrimidine), 2-(4-chloropyridin), 3-(2-chloropyridin), 4-(2-methoxyphenyl), 4-(2-cyanopyridyl), 3-pyridazines, 4-(2-tert-butylamino-3,5-dichloropyridine), 4-(2-amino-3,5-dichloropyridine), 4-(3,5-dichloropyridine), 2-(3-bromopyrazine), 4-pyridyl, 4-chinolin or 4-(3,5-dichloro-1-OK who piridyl).

4. The connection of claim 1, wherein formula I represents a General formula Iz,

in which X3represents-CH - or n

5. The compound according to claim 1, in which R3denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxyethyl, butenyl, pentenyl, allyl, butenyl, benzyl, methylbenzol, ethylbenzene, ethylpyridine, tolyl, toluoyl, propylbenzoyl, Meilahti, eternity, methylcarbonate, methylcarbonate, methoxyethyl, methoxypropyl, each of which may be substituted by one or more identical or different substituents selected from R6and specified substituent R6may be substituted by one or more identical or different substituents selected from R8or R3denotes hydrogen, -CH2-C(O)-heteroseksualci or-CH2-C(O)NR9-Rl2.

6. The compound according to claim 1, in which R6means ethynyl, methyl, tert-butoxy, isoxazolyl, methoxy, PROPYNYL, butenyl, phenyl, pyridyl, benzoxazolyl, thiazolyl, [1,3,4]thiadiazolyl, [1,2,4]oxadiazolyl, 2,3-dihydro-1H-isoindolyl, ethoxy, thiophenyl, propyl, ethyl, butyl, pentyl, allyl, isopropoxy, isopropyl, naphthyl, cyclohexyl, hydroxy, cyclopentyl, phenoxy, tolyl, toluoyl, benzoyl, carbonylation, ethylbenzene, chipolini, -NH2, etoxycarbonyl, methoxycarbonyl, carbarnoyl, isoindole, methylamine, PIR is aidil, morpholinyl, methylsulphonyl, methylsulfinyl, butylamine, Propylamine, ethylamine, cycloheptyl, hydroxyethyl, hydroxypropyl, indanyl or ethoxyethyl, each of which may be substituted by one or more identical or different substituents selected from R8or R6denotes hydrogen, oxo, fluorine, chlorine or cyano.

7. The compound according to claim 1, in which R9denotes hydrogen, methyl or ethyl.

8. The compound according to claim 1, in which R10denotes hydrogen, oxo, methyl, hydroxy, fluorine, cyano, chlorine or methoxy.

9. The compound according to claim 1, in which R3denotes-CH2-C(O)NH-R12, -CH2-C(O)NH-heteroseksualci, -CH2CH2-phenyl-R6or-CH2-phenyl-R6.

10. The compound according to claim 1, in which R2and/or R3denotes-CH2COOH, methyl, hydrogen, allyl, ethyl, tert-butoxycarbonylmethyl, deformity, 3-methyl-5-methylisoxazole, 2-methoxyethane, 2-butyn, 2-methyl-2-butene, 2-depilated, benzyl, 2-methyl-1,3-benzoxazole, 4-methyl-2-methylthiazole, 2-methyl-5-cyclopropyl[1,3,4]thiadiazole, 3-methyl[1,2,4]oxadiazol, ethyl acetate, 4-(chlorophenyl)ethane, 5-chloro-2-methylthiophene, tenoxicam(4th were)ethane, 3-phenylpropane, (3-methoxyphenyl)ethane, (4-methoxyphenyl)ethane, (3-bromophenyl)ethane, (2-methoxyphenyl)ethane, (4-forfinal)ethane, (2-forfinal)ethane, (3,4-acid)ethane, benzoylacetate, isopropylacetate, methyl ester 3-methylbenzo the Oh of the acid, 3-methylbutane, 1-hexyl, buta-1-ene, Penta-1-ene, 1-propyl, 1-butyl, 2-methylpropan, ethyl ester butyric acid, 4-methylbenzyl, 3-Chlorobenzyl, propoxyphenol, 1-(4-methoxyphenyl)Etalon, 4-methylbenzonitrile, 2-methylnaphthalene, 1-pentyl, methylcyclohexane, 3-methylbenzonitrile, 1 ethoxy-4-chlorobenzene, 2-ethylbutane, 2-hydroxyethane, methyl ester 4-methylbenzoic acid, 1-naphthalene-2-ylatason, 2.5-dimethoxypyridine, 1-p-tolylamino, 4-tormentil, 2-tormentil, 5-trifloromethyl, 5-cryptomaterial, 3-fluoro-5-trifloromethyl, 1-(2-methoxyphenyl)Etalon, 1-(2,4-dimetilfenil)Etalon, 4-Chlorobenzyl, 2-deformational, 4-isopropylbenzyl, 2-fluoro-6-trifloromethyl, 2,3-debtor-4-methylbenzyl, 2-methylbenzyl, 3-methylbenzyl, Penta-2-ene, 6-methyl-2-methylinosine, 2-Chlorobenzyl, 3-methoxybenzyl, 4-methoxybenzyl, (3-chlorophenyl)ethane, 5-methylhexan, ethylcyclohexane, ethyl ether of pentanol acid (propoxymethyl)benzene, ndimethylacetamide, 2-utilizando-1,3-dione, 2-prepolitical-1,3-dione, N-methylacetamide, methylcyclopropane, buta-1-ene, 4-albut-1-ene, 2-methylpent-2-ene, ethanol, 2-methoxyethane, but-2-ine, propyne, acetate, 1-pyrrolidin-1-ylatason, N-benzylacetone, 1-morpholine-4-ylatason, N-phenylacetamide, N-methyl-N-phenylacetamide, N-(3-hydroxy-3-methylbutyl)ndimethylacetamide, N-n-propylacetamide, N-ethylacetamide, N-isopropylacrylamide, N-butylacetamide, N-cyclopentylacetic, N-(3-methylbutyl)ndimethylacetamide, N-(4-methoxy shall ensil)ndimethylacetamide, N-(2,2-dimethylpropyl)ndimethylacetamide, N-cyclohexylmaleimide, N-(3-methoxybenzyl)ndimethylacetamide, N-cycloheptylamine, N-(2-methoxybenzyl)ndimethylacetamide, N-cyclohexylmaleimide, N-(2-hydroxyethyl)ndimethylacetamide, N-(1-phenylethyl)ndimethylacetamide, N-(3-hydroxypropyl)ndimethylacetamide, N-(2-methoxyethyl)ndimethylacetamide, N-(2-dimethylaminoethyl)ndimethylacetamide, N-(3-dimethylaminopropyl)ndimethylacetamide, N-(1-phenylethyl)the ndimethylacetamide, N-(3-isopropoxyphenyl)ndimethylacetamide, N-furan-2-ylmethylene, N-pyridine-2-ylmethylene, N-pyridine-3-ylmethylene, N-(2-phenoxyethyl)ndimethylacetamide, N-pyridine-4-ylmethylene, N-(4-active compounds)ndimethylacetamide, N-(3,5-diferensial)ndimethylacetamide, N-(2,3-diferensial)ndimethylacetamide, N-(2-pyridin-2-retil)ndimethylacetamide, N-(2-methylbenzyl)ndimethylacetamide N-(3-terbisil)ndimethylacetamide, N-(3-methylbenzyl)ndimethylacetamide, N-(4-methylbenzyl)ndimethylacetamide, N-ventilated, N-(2-pyridin-4-retil)ndimethylacetamide, N-(3-phenylpropyl)ndimethylacetamide, N-(2-Chlorobenzyl)ndimethylacetamide, N-(2-piperidine-1-retil)ndimethylacetamide, N-(3-Chlorobenzyl)ndimethylacetamide, N-(2-morpholine-4-retil)ndimethylacetamide, N-(4-chlorbenzyl)ndimethylacetamide, N-(2-pyridin-3-retil)ndimethylacetamide, N-(2-pyrrolidin-1-retil)ndimethylacetamide, N-(2-acetylamino)ndimethylacetamide, (R)-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide, (S)-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide, N-thiophene-2-ylmethylene, N-[3-(2-oxopyrrolidin-1-yl)propyl]the ndimethylacetamide, N-(2-hydroxyine-1-yl)ndimethylacetamide, N-cycloheptylamine, N-[2-(2-hydroxyethoxy)ethyl]ndimethylacetamide, N-(4-dimethylaminomethyl)ndimethylacetamide, cyclopentane, cyclopropylmethyl is, Penilaian, benzyl ester acetic acid, 2-methylbenzonitrile, 2-(1-oxypyridine-4-yl)ethane, (4-pyridyl)ethane, (3-pyridyl)ethane, (2-pyridyl)ethane, (4-benzonitrile)ethane, (4-methylsulfinylphenyl)ethane, (4-methylsulfinylphenyl)ethane, 1-phenylpropane, 2-phenylpropane or 1-methyl-2-Penilaian.

11. The compound according to claim 1, in which R8denotes methyl.

12. Connection by claim 11, in which R12denotes alkyl, cycloalkyl, hydroxyalkyl, aryl, arylalkyl, alkylcarboxylic, each of which may be substituted by one or more identical or different substituents selected from alkyl, cycloalkyl, alkoxy, geterotsiklicheskie, heteroaryl, aryloxy, amino, hydroxy, halogen, hydroxy, each of which may be substituted by oxo or hydroxyl, or R12denotes hydrogen.

13. The compound according to claim 1 with a molecular weight less than 800 Da.

14. The compound according to claim 1, selected from the following compounds:
2-(3,5-dichloropyridine-4-yl)-1-(2-hydroxy-3,4-acid), Etalon (compound 101),
2-(3,5-dichloropyridine-4-yl)-1-(3-hydroxy-2,4-acid), Etalon (compound 102),
1-(2-allyloxy-3-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 103),
2-(3,5-dichloropyridine-4-yl)-1-(2,3-diethoxy-4-methoxyphenyl)alanon (compound 104),
tert-butyl ether {2-tert-butoxycarbonylamino-6-[2-(3,5-dichloropyridine-4-yl)acetyl]-3-methoxyphenoxy}acetic acid (with the Association 105),
1-(2,3-bis-allyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 106),
1-(2,3-bis-deformedarse-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 107),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(5-methylisoxazol-3-ylethoxy)phenyl]alanon (compound 108),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methoxyethoxy)phenyl]alanon (compound 109),
1-(2-but-2-ynyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 110),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbut-2-enyloxy)phenyl]alanon (compound 111),
2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)alanon (compound 112),
1-(2-benzyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 113),
1-(2-allyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 114),
1-[2-(benzoxazol-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 115),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylthiazole-4-ylethoxy)phenyl]alanon (compound 116),
1-[2-(5-cyclopropyl[1,3,4]thiadiazole-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 117),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-([1,2,4]oxadiazol-3-ylethoxy)phenyl]alanon (compound 118),
ethyl ester {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 119),
1-{2-[2-(4-chlorophenyl)ethoxy]-3,4-acid}-2-(3,5-di is lipiridy-4-yl)alanon (compound 120),
1-[2-(5-chlorothiophene-2-ylethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 121),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-phenoxyethoxy)phenyl]alanon (compound 122),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-p-thailatex)phenyl]alanon (compound 123),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-phenylpropoxy)phenyl]alanon (compound 124),
2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(3-methoxyphenyl)ethoxy]phenyl}Etalon (compound 125),
2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(4-methoxyphenyl)ethoxy]phenyl}Etalon (compound 126),
1-{2-[2-(3-bromophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (compound 127),
2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(2-methoxyphenyl)ethoxy]phenyl}Etalon (compound 128),
2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 129),
2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2-forfinal)ethoxy]-3,4-acid}Etalon (compound 130),
2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(3,4-acid), ethoxy]-3,4-acid}Etalon (compound 131),
benzyl ether of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 132),
isopropyl ether {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 133),
methyl ester of 3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzoic acid (connect the tion 134),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbutoxy)phenyl]alanon (compound 135),
2-(3,5-dichloropyridine-4-yl)-1-(2-hexyloxy-3,4-acid), Etalon (compound 136),
1-(2-but-3-enyloxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 137),
2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-Penta-4-tyloxapol)alanon (compound 138),
2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-propoxyphenyl)alanon (compound 139),
1-(2-butoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 140),
2-(3,5-dichloropyridine-4-yl)-1-(2-isobutoxy-3,4-acid), Etalon (compound 141),
ethyl ester of 4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3, dimethoxyphenoxy}butyric acid (compound 142),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(4-methylbenzylamino)phenyl]alanon (compound 143),
1-[2-(3-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 144),
2-(3,5-dichlorides-4-yl)-1-[3,4-dimethoxy-2-(3-phenoxypropane)phenyl]alanon (compound 145),
2-(3,5-dichloropyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(4-methoxyphenyl)-2-oksidoksi]phenyl}Etalon (compound 146),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile (compound 147),
4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile (compound 148),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(naphthalene-2-ylethoxy)phenyl]alanon (compound 149),
2-(3,5-Dich herperidin-4-yl)-1-(3,4-dimethoxy-2-pentyloxide)alanon (compound 150),
1-(2-cyclohexylmethoxy-3,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 151),
3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzonitrile (compound 152),
1-{2-[2-(4-chlorphenoxy)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (compound 153),
2-(3,5-dichloropyridine-4-yl)-1-[2-(2-ethylbutane)-3,4-acid]alanon (compound 154),
2-(3,5-dichloropyridine-4-yl)-1-[2-(2-hydroxyethoxy)-3,4-acid]alanon (compound 155),
methyl ester of 4-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}benzoic acid (compound 156),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-naphthalene-2-yl-2-oksidoksi)phenyl]alanon (compound 157),
2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2,5-acid)-2-oksidoksi]-3,4-acid}Etalon (compound 158),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-oxo-2-p-thailatex)phenyl]alanon (compound 159),
2-(3,5-dichloropyridine-4-yl)-1-[2-(4-forbindelse)-3,4-acid]alanon (compound 160),
2-(3,5-dichloropyridine-4-yl)-1-[2-(2-forbindelse)-3,4-acid]alanon (compound 161),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-triftormetilfosfinov)phenyl]alanon (compound 162),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-cryptomaterial)phenyl]alanon (compound 163),
2-(3,5-dichloropyridine-4-yl)-1-[2-(3-fluoro-5-triftormetilfosfinov)-3,4-acid]alanon (compound 164),
2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(2,4-dimetilfenil)-2-oksidoksi]-3,4-acid}Etalon (compound 166),
1-[2-(4-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 167),
2-(3,5-dichloropyridine-4-yl)-1-[2-(2-differentoccasions)-3,4-acid]alanon (compound 168),
2-(3,5-dichloropyridine-4-yl)-1-[2-(4-isopropylbenzylamine)-3,4-acid]alanon (compound 169),
2-(3,5-dichloropyridine-4-yl)-1-[2-(2-fluoro-6-triftormetilfosfinov)-3,4-acid]alanon (compound 170),
2-(3,5-dichloropyridine-4-yl)-1-[2-(2,3-debtor-4-methylbenzoate)-3,4-acid]alanon (compound 171),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylbenzylamino)phenyl]alanon (compound 172),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methylbenzylamino)phenyl]alanon (compound 173),
2-(3,5-dichloropyridine-4-yl)-1-(3,4-dimethoxy-2-Penta-2-tyloxapol)alanon (compound 174),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-methylinosine-6-ylethoxy)phenyl]alanon (compound 175),
1-[2-(2-chlorobenzoyloxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 176),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(3-methoxybenzyloxy)phenyl]alanon (compound 177),
2-(3,5-dichlorides-4-yl)-1-[3,4-dimethoxy-2-(4-methoxybenzyloxy)phenyl]alanon (compound 178),
1-{2-[2-(3-chlorophenyl)ethoxy]-3,4-acid}-2-(3,5-dichloropyridine-4-yl)alanon (compound 179),
2-(3,5-dichloropyridine-4-yl-1-[3,4-dimethoxy-2-(5-methylhexanoic)phenyl]alanon (compound 180),
1-[2-(2-cyclohexylmethoxy)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 181),
ethyl ester 5-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3, dimethoxyphenoxy}pentanol acid (compound 182),
1-[2-(3-benzyloxypropionic)-3,4-acid]-2-(3,5-dichloropyridine-4-yl)alanon (compound 183),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 184),
2-(2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy)ethyl)isoindole-1,3-dione (compound 185),
2-(3-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}propyl)isoindole-1,3-dione (compound 186),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-methylacetamide (compound 187),
2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2,4-acid), Etalon (compound 188),
1-(3-cyclopropylmethoxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 189),
1-(2-allyloxy-3-but-3-enyloxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 190),
1-(3-but-3-enyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 191),
2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-propoxyphenyl)alanon (compound 192),
1-(3-allyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 193),
2-(3,5-dichloropyridine-4-yl)-1-[2,4-dimethoxy-3-(4-methylpent-3-enyloxy)phenyl]alanon (compound 194),
2-(3,5-dichloropyridine-4-yl)-1-[3-(2-hydroxyethoxy)-2,4-acid]alanon (the connection is giving 195),
2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-penetrometer)alanon (compound 196),
1-(3-benzyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 197),
2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-Penta-2-tyloxapol)alanon (compound 198),
2-(3,5-dichloropyridine-4-yl)-1-[2,4-dimethoxy-3-(2-methoxyethoxy)phenyl]alanon (compound 199),
1-(3-but-2-ynyloxy-2,4-acid)-2-(3,5-dichloropyridine-4-yl)alanon (compound 200),
2-(3,5-dichloropyridine-4-yl)-1-(2,4-dimethoxy-3-prop-2-injectively)alanon (compound 201),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-oxo-2-pyrrolidin-1 ylethoxy)phenyl]alanon (compound 202),
N-benzyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 203),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-morpholine-4 Il-2-oksidoksi)phenyl]alanon (compound 204),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-phenylacetamide (compound 205),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-methyl-N-phenylacetamide (compound 206),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-hydroxy-3-methylbutyl)ndimethylacetamide (compound 207),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 208),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-isopropylacetate (compound 209),
N-butyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenol is si}ndimethylacetamide (compound 210),
N-cyclopentyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 211),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methylbutyl)ndimethylacetamide (compound 212),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-methoxybenzyl)ndimethylacetamide (compound 213),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2,2-dimethylpropyl)ndimethylacetamide (compound 214),
N-cyclohexyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 215),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methoxybenzyl)ndimethylacetamide (compound 216),
N-cycloheptyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 217),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methoxybenzyl)ndimethylacetamide (compound 218),
N-cyclohexylmethyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 219),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxyethyl)ndimethylacetamide (compound 220),
(R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(1-phenylethyl)ndimethylacetamide (compound 221),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-hydroxypropyl)ndimethylacetamide (compound 222),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methoxyethyl)ndimethylacetamide (compound 223),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-Dimitar is iproxy}-N-(2-dimethylaminoethyl)ndimethylacetamide (compound 224),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-dimethylaminopropyl)ndimethylacetamide (compound 225),
(S)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(1-phenylethyl)ndimethylacetamide (compound 226),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-isopropoxyphenyl)ndimethylacetamide (compound 227),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-furan-2-ylmethylene (compound 228),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-pyridine-2-ylmethylene (compound 229),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-3-ylmethylene (compound 230),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-phenoxyethyl)ndimethylacetamide (compound 231),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-pyridin-4-ylmethylene (compound 232),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-active compounds)ndimethylacetamide (compound 233),
2-(6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3,5-diferensial)ndimethylacetamide (compound 234),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2,3-diferensial)ndimethylacetamide (compound 235),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-2-retil)ndimethylacetamide (compound 236),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-methylbenzyl)ndimethylacetamide (compound 237),
2-{6-[2-(3,5-dichloropyridine-4-yl)is cetil]-2,3-dimethoxyphenoxy}-N-(3-terbisil)ndimethylacetamide (compound 238),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-methylbenzyl)ndimethylacetamide (compound 239),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-methylbenzyl)ndimethylacetamide (compound 240),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-ventilated (compound 241),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyridin-4-ilotel)ndimethylacetamide (compound 242),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(3-phenylpropyl)ndimethylacetamide (compound 243),
N-(2-Chlorobenzyl)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 244),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-piperidine-1-retil)ndimethylacetamide (compound 245),
N-(3-Chlorobenzyl)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 246),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-morpholine-4-retil)ndimethylacetamide (compound 247),
N-(4-Chlorobenzyl)-2-(6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 248),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy)-N-(2-pyridin-3-retil)ndimethylacetamide (compound 249),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-pyrrolidin-1-retil)ndimethylacetamide (compound 250),
N-(2-acetylamino)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 251),
(R)-2-{6-[2-(3,5-dichloropyridine-4-yl)aceti is]-2,3-dimethoxyphenoxy}-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide (compound 252),
(S)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxy-2-phenylethyl)ndimethylacetamide (compound 253),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-thiophene-2-ylmethylene (compound 254),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-[3-(2-oxopyrrolidin-1-yl)propyl]ndimethylacetamide (compound 255),
(2R)-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(2-hydroxyine-1-yl)ndimethylacetamide (compound 256),
N-cycloheptylmethyl-2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 257),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-[2-(2-hydroxyethoxy)ethyl]ndimethylacetamide (compound 258),
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-(4-dimethylaminomethyl)ndimethylacetamide (compound 259),
1-(3-cyclopentyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 260),
1-(3-cyclopropylmethoxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 261),
2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-2-hydroxy-4-methoxyphenyl)alanon (compound 262),
2-(3,5-dichloropyridine-4-yl)-1-(3-ethoxy-4-methoxy-2-penetrometer)alanon (compound 263),
1-[2-(5-cyclopropyl[1,3,4]thiadiazole-2-ylethoxy)-3-ethoxy-4-methoxyphenyl]-2-(3,5-dichloropyridine-4-yl)alanon (compound 264),
benzyl ether of {6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2-ethoxy-3-methoxyphenoxy}acetic acid (compound 265), 1-(3-allyloxy-2-hydroxy-4-methoxyphenyl)-2-(3,5-dichloropyridine-4-yl)alanon (compound 266),
2-{2-allyloxy-6-[2-(3,5-dichloropyridine-4-yl)acetyl]-3-methoxyphenoxy}benzonitrile (compound 267),
1-(3-allyloxy-4-methoxy-2-penetrometer)-2-(3,5-dichloropyridine-4-yl)alanon (compound 268),
1-{3-allyloxy-2-[2-(4-forfinal)ethoxy]-4-methoxyphenyl}-2-(3,5-dichloropyridine-4-yl)alanon (compound 269),
N-benzyl-2-{6-[2-(3,5-dichloro-1-oxypyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ndimethylacetamide (compound 270),
2-(3,5-dichloro-1-oxypyridine-4-yl)-1-(3,4-dimethoxy-2-penetrometer)alanon (compound 271),
2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 272),
2-(3,5-dichloro-1-oxypyridine-4-yl)-1-{3,4-dimethoxy-2-[2-(1-oxypyridine-4-yl)ethoxy]phenyl}Etalon (compound 274),
2-(3,5-dichloro-1-oxypyridine-4-yl)-1-(2-hydroxy-3,4-dimethoxyphenyl)alanon (compound 275),
4-(2-{6-[2-(3,5-dichloro-1-oxypyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)benzonitrile (compound 276),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-4-ylethoxy)phenyl]alanon (compound 277),
4-(2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}ethyl)benzonitrile (compound 278),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-2-ylethoxy)phenyl]alanon (compound 279),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-pyridin-3-ylethoxy)phenyl]alanon (compound 280),
2-(3,5-dichloropyridine-yl)-1-{2-[2-(4-methanesulfonyl)ethoxy]-3,4-acid}Etalon (compound 281),
2-(3,5-dichloropyridine-4-yl)-1-{2-[2-(4-methanesulfonyl)ethoxy]-3,4-acid}Etalon (compound 282),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(1-phenylpropoxy)phenyl]alanon (compound 283),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(2-phenylpropoxy)phenyl]alanon (compound 284),
2-(3,5-dichloropyridine-4-yl)-1-[3,4-dimethoxy-2-(1-methyl-2-phenylethane)phenyl]alanon (compound 285),
2-{6-[2-(6-chloropyrazine-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 286),
2-{6-[2-(3-bromopyrazine-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 287),
2-{6-[2-(2,6-dichlorophenyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 288),
2-[2,3-dimethoxy-6-(2-pyridin-4-ylacetic)phenoxy]-N-propylacetamide (compound 289),
2-[2,3-dimethoxy-6-(2-quinoline-4-ylacetic)phenoxy]-N-propylacetamide (compound 290),
2-[2,3-dimethoxy-6-(2-pyrazin-2-ylacetic)phenoxy]-N-propylacetamide (compound 291),
2-{6-[2-(3-bromopyridin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 292),
2-{6-[2-(3,5-dibromopyridin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 293),
2-{6-[2-(6-chloropyrimidine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 294),
2-{6-[2-(4-chloropyridin-2-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 295),
2-{6-[2-(2-chloropyridin-3-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 296),
2-{2,3-dimethoxy-6-[2-(2-IU is oxypyridine-4-yl)acetyl]phenoxy}-N-propylacetamide (compound 297),
2-{6-[2-(2-cyanovirin-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 298),
2-[2,3-dimethoxy-6-(2-pyridazin-3-ylacetic)phenoxy]-N-propylacetamide (compound 299),
2-(2-tert-butylamino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 300),
2-(2-amino-3,5-dichloropyridine-4-yl)-1-{2-[2-(4-forfinal)ethoxy]-3,4-acid}Etalon (compound 301),
2-(3,5-dichloropyridine-4-yl)-1-(4-ethoxy-3-methoxy-2-penetrometer)alanon (compound 302),
{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}acetic acid (compound 504), or
2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-ethylacetamide (compound 305),
and its pharmaceutically acceptable salts or N-oxides.

15. The compound according to claim 1, which represents 2-{6-[2-(3,5-dichloropyridine-4-yl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (compound 208).

16. The compound according to claim 1 for use in the treatment of skin diseases.

17. Pharmaceutical composition for use in skin diseases containing a compound according to claim 1 together with a pharmaceutically acceptable base or excipient or pharmaceutically acceptable carrier (s).

18. The use of compounds according to formula I

in which X1X2X3X4and X5independently from each other represent CH or N;
or X34and X5independently of one another denote-CH - or N, and X1and X2independently of one another denote C and are part of an additional 6-membered aromatic ring;
in which R1denotes methyl or ethyl, or R1denotes hydrogen;
R2denotes methyl, ethyl, propyl, tert-butoxycarbonylmethyl, allyl, deformity, ethylbenzene, methylbenzol, butenyl, hydroxyethyl, tolyl, pentenyl, methoxyethyl, butynyl, PROPYNYL, methylcarbonate, cyclopentyl, each of which may be substituted by one or more identical or different substituents selected from R5; or R2denotes hydrogen;
R3denotes alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, halogenated, hydroxyalkyl, geteroseksualen, alkylaryl, arylalkyl, alkylalkoxysilane, alkylcarboxylic or alkoxyalkyl, each of which may be substituted by one or more identical or different substituents selected from R6; or R3denotes hydrogen, -CH2-C(O)-heteroseksualci or-CH2-C(O)NR9-R12;
R5denotes methyl, tert-butoxy, ethynyl, cyclopropyl, propenyl, phenyl, butenyl, PROPYNYL, methylhydroxy, ethinyl, allyl, ethyl or methoxy, each of which may be substituted by one or more identical or different substituents, selected the C R 7or R5denotes hydrogen, oxo, chloro, fluoro or hydroxy;
R6denotes alkylaryl, carboxy, alkyl, alkenyl, cycloalkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, aryloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, arylcarbamoyl, hydroxy, alkylsulphonyl, alkylcarboxylic or amino, each of which may be substituted by one or more identical or different substituents selected from R8; or R6denotes hydrogen, oxo, halogen, cyano or nitro;
R8denotes methyl, ethyl, propyl, butyl, phenyl, cyclopropyl, ethoxy, methoxy, allyl, ethynyl, etoxycarbonyl, hydroxy, naphthyl, cyclohexyl, methoxycarbonyl, phenoxy, isopropoxy, -NH2, methylamine, pyrrolidinyl, morpholinyl, methylsulphonyl, methylsulfinyl, cycloheptyl, cyclopentyl, hydroxymethyl, hydroxyethyl, dimethylamino, furanyl, pyridyl, tolyl, piperidinyl, acetyl, thiophenyl, cycloheptyl, each of which may be substituted by one or more identical or different substituents selected from R10or R8denotes hydrogen, oxo, chlorine, bromine, fluorine, cyano or trifluoromethyl;
R9denotes hydrogen, alkyl, halogenated or hydroxyalkyl;
R10means at the location, alkyl, oxo, hydroxy, halogen, carboxy, amino, alkoxy, halogenated or hydroxyalkyl;
R11represents one or more identical or different substituents selected from hydrogen, halogen, cyano, amino, alkyl, methylsulfinyl, methylsulfonyl, amino, cyano, or alkoxy;
R12denotes alkylaryl, arylalkyl, carboxy, alkyl, alkenyl, quinil, halogenated, cycloalkyl, cycloalkenyl, carbarnoyl, hydroxyalkyl, aryloxy, alkoxycarbonyl, alkoxycarbonyl, alkoxy, alkoxyalkyl, aryl, heterocyclic ring, aminocarbonyl, alkylthio, alkylcarboxylic, hydroxy, alkylsulphonyl, arylcarbamoyl, alkylcarboxylic or amino, each of which may be substituted by one or more identical or different substituents selected from R8or R12denotes hydrogen;
provided that R1, R2and R3can not be the stands;
provided that when R2and R3both denote hydrogen, R1may not be the stands or hydrogen;
and its pharmaceutically acceptable salts or N-oxides in getting medicines to prevent, treat or alleviate skin diseases or conditions, or acute or chronic disorders associated with skin wounds.

19. Use p, in which a skin disease or condition selected from the group consisting of proliferative and inflammatory skin disorders, psoriasis, cancer, inflammation of the skin, alopecia, skin atrophy induced by steroids skin atrophy, skin ageing, photo-induced skin aging, acne, dermatitis, atopic dermatitis, seborrheic dermatitis, contact dermatitis, urticaria, pruritus and eczema.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

EFFECT: obtaining compounds, which are alpha-adrenergic agonists.

3 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described macrocyclic phenylcarbamates of formula (I), wherein A represents -C(=O)OR1 or -C(=O)-NH-SO2-R2, wherein R1 represents hydrogen or C1-C6alkyl; R2 represetns C3-7cycloalkyl, phenyl, thiazolyl or pyridyl each of which is optionally substituted by one or more substituted specified in C1-6alkyl, C1-6alkoxy, trifluoromethyl and halogen; X represents N or CH; E represents NR5; R5 represents hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl or C3-7cycloalkyl; n is equal to 4 or 5; wherein a dash line -----, adjoining the fragment -(CH2)n-, represents a double bond; and wherein the dash line in a five-merous cycle including X, represents a single bond, and R7 represents hydrogen; R8 is such as specified in the patent claim, or N-oxide thereof, a pharmaceutically acceptable additive salt or a pharmaceutically acceptable solvate possessing antiviral activity, and used as HCV inhibitors; as well as pharmaceutical compositions containing the above compounds as an active ingredient.

EFFECT: preparing the pharmaceutically acceptable additive salt or pharmaceutically acceptable solvate possessing antiviral activity.

10 cl, 23 ex, 1 tbl

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole- 2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, where R means hydrogen; R1 means phenyl, substituted with 1, 2 or 3 substitutes, each of them is independently selected from a group containing halogen, cyano, C1-4alkyl, perfluoroC1-4alkyl and perfluoroC1-4alkoxy; R2 means hydrogen or C1-4alkyl; R3 means hydrogen, trifluoromethyl or cyano; X means N or CR4, where R4 is trifluoromethyl. Also the invention relates to a pharmaceutical composition containing compounds of the formula as an active ingredient. The following derivatives are presented: derivatives of [1-(benzyl)piperydine-4-yl]-([1,3,4]thiadiazole-2-yl)amine and [1-(benzyl)piperydine-4-yl]-(thiazole-2-yl)amine of the formula (I) representing quick-dissociating antagonists of dopamine 2 receptors and used as medicinal agents for treatment or prevention of central nervous system.

EFFECT: improved properties of compounds.

7 cl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosubstituted pyrazolon azo derivatives of formula

or pharmaceutically acceptable salts thereof, intermediate compounds of formula ,

as well as methods for production thereof, a pharmaceutical composition containing a compound of formula (II), and use thereof as a therapeutic agent, which is a thrombopoietin (TPO) mimetic, as well as use thereof as agonists of the thrombopoietin receptor. Values of substitutes in formulae (I) and (IA) are given in the claim.

EFFECT: obtaining bicyclosubstituted pyrazolon azo derivatives.

12 cl, 58 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclic 5-nitropyridin-2-yl-thioalkenyl-4-dithiocarbamate derivatives of general formula (I) or pharmaceutically acceptable acid- or base addition salts thereof. The compounds have antifungal activity even in case of deep, subcutaneous and surface mycoses in humans, caused by strains (including those resistant to existing drugs) of mycosis causative agents. In general formula , R denotes nitro, cyano, halide-substituted C1-C6 alkyl group, n=1, 2 or 3. The invention also relates to use of compounds of formula (I), a method of producing said compounds, a pharmaceutical composition and a method for treatment using said compounds.

EFFECT: improved method.

12 cl, 2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I), stereoisomers, trans- and cis-isomers, racemates or pharmaceutically acceptable salts thereof, having modulating activity on histamine H3-receptors. In formula (I) m equals 0; one of R1 and R2 is selected from a group which includes hydrogen, C1-10alkoxycarbonyl, amido-, carboxy-, C3-8cycloalkyl, halogen, -NRARB, (NRARB)carbonyl, or a group of formula -L2-R6; the other of R1 and R2 is selected from a group which includes hydrogen, halogen; each of R3a and R3b is independently selected from a group which includes hydrogen; each of R4 and R5 is independently selected from a group which includes C1-10alkyl and C1-10hydroxyalkyl; or R4 and R5, taken together with a nitrogen atom to which each is bonded, form a heteroaromatic ring of the type (a) or (b), where Q1 is O or C; Q2 is -N(R20)-; R20 is selected from a group which includes hydrogen and C1-10alkoxycarbonyl; each of p1 and p2 is independently equal to 1, 2 or 3; each of q1, q2, q3, q4 and q5 are independently equal to 0, 1 or 2; and wherein each carbon atom in the ring is substituted with hydrogen or 0, 1 or 2 substitutes, independently selected from a group which includes hydrogen, hydroxy group, fluorine, C1-10alkyl, C1-10hydroxyalkyl and C1-10fluoroalkyl; R6 is a phenyl, heterocycle or heterocycloC1-4alkyl, wherein the heterocycle is a 4-6-member aromatic or non-aromatic ring which contains 1 or 2 heteroatoms independently selected from N, O and S, optionally condensed with a benzene ring, wherein the phenyl or heterocycle can be unsubstituted or optionally substituted with one or more substitutes independently selected from a group which includes C1-4alkoxy, C1-4alkyl, cyano, halogen and oxo-; L is a bond or C1-4alkylene; L2 is a bond, C1-4alkylene, -C(=O)-, -SO2N(R14a)-, -N(R14a)SO2-, -C(O)N(R14a)-, -N(Rl4a)C(O)- or -N(R15)-; R10 is selected from a group which includes hydrogen; R14a is selected from a group which includes hydrogen; R15 is selected from a group which includes hydrogen; and RA and RB are independently selected from a group which includes hydrogen, C1-10alkyl, C1-10acyl, C1-4halogenalkyl, C1-10alkoxycarbonyl, C3-8cycloalkyl and C3-8cycloalkylcarbonyl. The invention also relates to a pharmaceutical composition which contains compounds of formula (I), a method for selective modulation of effects of histamine H3-receptors, use of said compounds in producing a medicament for treating a condition or disorder modulated by histamine H3-receptors, as well as specific compounds of formula (I).

EFFECT: improved properties of compounds.

18 cl, 2 tbl, 154 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: application describes prodrugs being 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}thio)-4-[4-(2-hydroxyethoxy)-phenyl]pyridine-3,5-dicarbonitryl derivatives, and a method for preparing them.

EFFECT: invention can find application in treating and/or preventing cardiovascular diseases.

8 cl, 4 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds, which represent (4,5-dihydrooxazol-2-yl)-(5,6,7,8-tetrahydroquinoxylan-5-yl)-amino and (4,5-dihydrooxazol-2-yl(-(5,6,7,8-tetrahydroquinolin-5-yl)-amino or their pharmaceutically acceptable salt. Said compounds are applied in methods of intraocular pressure reduction and treatment of pain in mammals who require it.

EFFECT: obtaining compounds, which are alpha-adrenergic agonists.

3 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: disclosed is a compound having chemical formula or a salt thereof, where: Ar is an optionally substituted heteroaryl; R1 in each case is independently selected from a group which includes halogen, lower alkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, monoalkylamino, dialkylamino, -O-R5, -N(R5)-R6 and -N(R5)-C(X)-R7; m equals 0 or 1; n equals 0, 1 or 2; R2 is hydrogen or a halogen; L2 is -S(O)2-; R3 is a lower alkyl, optionally substituted with fluorine, C3-6 cycloalkyl, optionally substituted with a lower alkyl, a 5- or 6-member nitrogen-containing heterocycloalkyl, optionally substituted with one or more substitutes selected from fluorine, lower alkyl, fluorine-substituted lower alkyl, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio or fluorine-substituted lower alkylthio, aryl, optionally substituted with a halogen, lower alkyl, optionally substituted with a halogen or lower alkoxy, optionally substituted with a halogen, or a heteroaryl, optionally substituted with a halogen or a lower alkyl; L1 is selected from a group which includes -O-, -C(R12R13)-X-, -X-C(R12R13)-, -C(R12R13)-N(R11)-, -(R11)-C(R12R13)-, -C(X)-N(R11)-, -N(R11)-C(X)-; X is O; R11 is hydrogen; R4 is hydrogen or a lower alkyl; R5 and R6 in each case are independently selected from a group which includes hydrogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, where each is optionally substituted with one or more substitutes selected from fluorine, lower alkoxy, fluorine-substituted lower alkoxy, lower alkylthio, fluorine-substituted lower alkylthio, monoalkylamino, dialkylamino; R7 in each case is independently selected from a group which includes lower alkyl; where the terms "lower alkyl", "lower alkoxy", "lower alkylthio", "monoalkylamino", "dialkylamino", "cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", are as described in the claim. The invention also discloses a pharmaceutical composition for treating Raf kinase mediated diseases which is based on a compound of formula I; use of the compound of formula I to produce a medicinal agent is also disclosed.

EFFECT: novel compound which can be useful in treating diseases and conditions associated with aberrant activity of protein kinases is obtained and described.

9 cl, 13 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to novel 3-(trinitromethyl-ONN-azoxy)-4-nitraminofurazans of general formula I . In formula I, R is Me, or . The invention also relates to methods of producing compounds of formula I.

EFFECT: obtaining compounds which can be used as oxidants for rocket fuel and explosive compositions.

3 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula III which possess the properties of JAK pathway inhibitors and JAK-kinase inhibitors. In formula III: X is specified in a group consisting of C1-C10alkyl, amino, halogen, carboxyl, carboxylic acid ester, C2alkynyl, substituted tri-C1-C6alkylsilyl; R represents hydrogen; the cycle A is specified in a group consisting of C6aryl, bicycloheptene, five-and sis-member mono- or 10-member bicyclic heteroaryl including 1 to 3 heteroatoms specified in a group of heteroatoms, including N, O or S, and five- or six-member mono- or 10-member bicyclic heterocycle, including 1 to 2 heteroatoms specified in a group of heteroatoms, including N or O; p means 0, 1, 2 or 3; each of R2 is independently specified in a group consisting of C1-C6alkyl, C1-C4alkyl substituted by 1 to 3 substitutes. The other substitute and radical values are specified in the patent claim.

EFFECT: compounds may be used in preparing a therapeutic agent for T-cell mediated autoimmune disease, for treating or preventing allograft rejection in a recipient, for treating or preventing a type IV hypersensitivity reactions, which includes administering the above agent containing the compound according to cl 1-11, in an amount effective to treat the autoimmune disease or the allograft rejection or the type IV hypersensitivity.

23 cl, 7 dwg, 12 tbl, 43 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely to new 1,2-dihydroquinoline derivatives of general formula , or to a pharmaceutically acceptable salt thereof, wherein R1 represents a lower alkyl group; R2 represents a hydrogen atom; each of R3 and R4 represents a lower alkyl group; R5 represents a lower alkyl group; R6 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group; X represents -CO-, -C(O)NR8 - or -S(O)2-; each of R7 and/or R8 may be identical or different, and represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl group, a phenyl or naphthyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a lower alkoxy group, a phenoxy group; provided R7 and/or R8 represent a lower alkyl group, a lower alkoxy group, the mentioned lower alkyl group and lower alkoxy group may contain one or three groups specified in a halogen atom, a phenyl group, an unsubstituted monocyclic 6-member heterocyclyl with one heteroatom specified in a nitrogen atom, and 5 carbon atoms in a cycle, a lower alkoxy group, and -NRaRb as a substitute (substitutes); provided R7 and/or R8 represent a phenyl group, a saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, a phenoxy group, the mentioned phenyl group, saturated or unsaturated monocyclic 5- or 6-member heterocyclyl with one or two heteroatoms specified in nitrogen, oxygen and sulphur atoms, and 3-5 carbon atoms in a cycle, phenoxy group may contain one or two groups specified in a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a phenyl group, a hydroxyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, -NRaRb, a nitro group and a cyano group as a substitute (substitutes); Ra and Rb may be identical or different, and each of them represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group; Y represents a lower alkylene group; Z represents an oxygen atom; p is equal to 2, provided p is equal to 2, R6 may be identical or different. The invention also relates to a pharmaceutical composition and a glucocorticoid receptor modulator of the compound of formula (1).

EFFECT: there are produced new 1,2-dihydroquinoline derivatives possessing glucocorticoid receptor binding activity.

7 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrrol derivatives of formula (1): or a pharmaceutically acceptable salt thereof wherein the values A, R1-R3, n are specified in clause 1 of the patent claim.

EFFECT: compounds (1) inhibit activity against the interleukin IL-6 production that allows using them both in pharmaceutical compositions, and in a prophylactic drug for ocular inflammatory disease.

23 cl, 2 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-hydroxylsulphonamide derivatives of formula or , where R1 is H; R2 is H; n is 0; b is an integer in the range of 1-4; R3, R4, R5, R6 and R7 are independently selected from H, halogen, carboxyl, carboxyl ester selected from a group including -C(O)O-morpholino, -C(O)O-C1-C8alkyl and -C(O)O-substituted C1-C8alkyl, where the substitute is morpholino; acylamino, which is a -C(O)NRaRb group, where Ra and Rb are independently C1-C8alkyl, or Ra and Rb together with a nitrogen atom to which they are bonded form morpholino; and sulphonylamino, which is a SO2NR2 group, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; R8 is selected from halogen and carbonylamino, selected from a -CONH-substituted C1-C8alkyl, where the substitute is morpholino; and -CONR2, where two groups R, together with a nitrogen atom to which they are bonded, form morpholino; C is a heteroaromatic ring which contains cyclic fragments Q9, Q10, Q11, Q12, Q13 and Q14, which are independently selected from C, CH and S, under the condition that at least one of the fragments Q9, Q10, Q11, Q12, Q13 and Q14 is S. The invention also relates to a method of modulating nitroxyl levels, a method of treating diseases which respond to treatment with nitroxyl, a treatment set and a pharmaceutical composition containing compounds of formula (I) or (III).

EFFECT: compounds of formula (I) or (III) for treating diseases which respond to treatment with nitroxyl.

20 cl, 5 ex, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula (I) X=N or C-R3; R1 stands for proton, saturated or unsaturated linear alkoxy radical, which has 2-5 carbon atoms; cycloalkyloxy radical, which has to 6 carbon atoms, saturated linear alkylmercapto radical, which has 1-3 carbon atoms; amino radical, having 1-10 carbon atoms, selected from saturated or unsaturated linear mono- or dialkylamino radical, or cycloalkylamino radical, cyclic amino radical, and each of cyclic groups can be substituted with 1-2 metal groups, or benzylaminogroup; R2 represents proton, saturated or unsaturated, linear alkyl radical, which has 1-5 carbon atoms, or cyclic aliphatic radical, which has to 6 carbon atoms, trifluoromethyl, stiryl or methylmercaptogroup; R3 stands for trifluoromethyl, formyl, acetyl, nitro, benzoyl, cyanogroup or alkoxycarbonyl sunstituent, which has 1-3 carbon atoms in alkoxygroup.

EFFECT: obtaining novel 2-nitroheterylthiocyanates of general formula (I), or their pharmaceutically acceptable additive salts with acids or bases, probably in crystalline form, possessing activity with respect to strains of fungi, causative agents of fungal infections, their application for treatment of fungal infections, as well as obtaining based on them pharmaceutical composition.

8 cl, 3 tbl, 25 ex

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