Condensed triazolamines as p2x7 modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

 

The present invention relates to compounds suitable for treatment of diseases associated with purinergic receptors RH, and more preferably to the modulators RH7applicable for the treatment of autoimmune and inflammatory diseases.

Purinergic receptors RH are activated with ATP (adenosine triphosphate) ionotropic receptors, including 7 subtypes. Subtype RH receptor (also known as P2Z receptor) is a managed ligands receptor ion channel found in mastocyte, peripheral macrophages, lymphocytes, erythrocytes, fibroblasts and epidermal Langerhans cells. Activation of the receptor RH in such cells of the immune system leads to the secretion of interleukin-1-beta. (Solle et al. J. Biol. Chemistry 276, 125-132, (2001)). Receptor RH also found in microglia, Schwann cells and astrocytes in the Central nervous system (Donnelly-Roberts et al., Br. J. Pharmacol. 151, 571-579 (2007)).

It is shown that antagonists RH block mediated through RH the secretion of IL-1-beta and mediated through RH the flow of cations (Stokes et al., Br. J. Pharmacol. 149, 880-887 (2006)). In mice that are missing the receptor RH, no inflammatory and neuropathic hypersensitivity in relation to mechanical and thermal effects (Chessell et al., Pain 114, 386-396 (2005)). Thus, it is proposed shall be presumed, what RH involved in inflammatory reactions (Ferrari et al., J. Immunol. 176, 3877-3883 (2006)) and in the emergence and persistence of chronic pain (Honore et al., J. Pharmacol. Ex. Ther. 319, 1376-1385 (2006b)).

Thus, modulators of receptor RH can be used to treat pathological conditions such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, hypersensitivity of the respiratory tract, septic shock, glomerulonephritis, irritable bowel syndrome, diabetes, and Crohn's disease. Modulators RH may also be applicable for the treatment of pain, including chronic pain, neuropathic pain and pain associated with inflammatory processes and degenerative pathological conditions.

Therefore, the necessary compounds that act as modulators of receptors RH, including antagonists of the receptor RH, as well as the necessary methods of treatment of diseases, pathological conditions and disorders mediated through RH. The present invention satisfies these and other needs.

The present invention relates to compounds of formula I

or their pharmaceutically acceptable salts, in which:

R1means:

optionally substituted phenyl or optionally substituted heteroaryl;

R2means:

optionally substituted phenyl;

optionally substituted heteroaryl or optionally substituted C3-C6-cycloalkyl;

R3means:

hydrogen or

C1-C6-alkyl;

X denotes: -O-; -NRa-; -S(O)m - or-CRbRcwhere m is from 0 to 2; Randdenotes hydrogen, C1-C6-alkyl or C1-C6-alkylsulphonyl; and each Rband Rcindependently denotes hydrogen or C1-C6-alkyl; or Rband Rctogether with the atom to which they are attached, may form a carbocyclic ring, which optionally contains oxygen as a ring atom; and

Y indicates: -O-; -NRd-; -S(O)nor CReRf-where n is from 0 to 2, and each Rd, Reand Rfindependently denotes hydrogen or C1-C6-alkyl.

The present invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds and methods of producing these compounds.

Definition

Unless otherwise stated, in this application, including the description and the claims, the following terms have the following meanings. It should be noted that when used in the application and in the claims, the singular number also include the plural forms unless the context clearly after the duty to regulate otherwise.

"Alkyl" means the monovalent linear or branched saturated hydrocarbon fragment containing only atoms of carbon and hydrogen, containing from 1 to 12 carbon atoms. "Lower alkyl" means alkyl group containing from 1 to 6 carbon atoms, i.e., C1-C6-alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc.,

"Alkenyl" means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one double bond, for example ethynyl, propenyl etc.

"Quinil" means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one triple bond, such as ethinyl, PROPYNYL, etc.,

"Alkylene" means a linear saturated divalent hydrocarbon radical containing from 1 to 6 carbon atoms, or a branched saturated divalent hydrocarbon radical containing from 3 to 6 carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropene, BU the ilen, pentile etc.

"Alkoxygroup" and "alkyloxy"that can be used interchangeably, mean a fragment of the formula-OR, where R denotes the alkyl fragment, defined in the present invention. Examples of alkoxygroup include, but are not limited to, a methoxy group, ethoxypropan, isopropoxy etc.

"Alkoxyalkyl" means a fragment of the formula Ra-O-Rb-, in which Radenotes alkyl and Rbdenotes alkylene defined in the present invention. Typical alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl and 1-(2-methoxyethyl)-3-methoxypropyl.

"Alkoxyalkyl" means a group of the formula-O-R-R', where R denotes alkylene and R' denotes alkoxygroup defined in the present invention.

"Alkylaryl" means a fragment of the formula-C(O)-R, in which R denotes an alkyl, as defined in the present invention.

"Alkoxycarbonyl" means a group of the formula-C(O)-R, where R denotes alkoxygroup defined in the present invention.

"Alkylcarboxylic" means a group of the formula R-C(O)-R, where R denotes alkylene and R' denotes an alkyl, as defined in the present invention.

"Alkoxycarbonyl" means a group of the formula R-C(O)-R', where R Ref is the em alkylene and R' denotes alkoxygroup, defined in this invention.

"Alkoxycarbonylmethyl" means a group of the formula-O-R-C(O)-R', where R denotes alkylene and R' denotes alkoxygroup defined in the present invention.

"Hydroxycarbonylmethyl" means a group of the formula-O-R-C(O) -, in which R denotes alkylene defined in the present invention.

"Alkylaminocarbonyl" means a group of the formula-O-R-C(O)-other', in which R denotes alkylene and R' denotes an alkyl, as defined in the present invention.

"Dialkylaminomethylcalix" means a group of the formula-O-R-C(O)-NR'r R”, where R denotes alkylene and R' and R” represent alkyl, as defined in the present invention.

"Alkylaminocarbonyl" means a group of the formula-O-R-other', in which R denotes alkylene and R' denotes an alkyl, as defined in the present invention.

"Dialkylaminoalkyl" means a group of the formula-O-R-R NR'r”, where R denotes alkylene and R' and R” represent alkyl, as defined in the present invention.

"Alkylsulfonyl" means a fragment of the formula-SO2-R, in which R denotes an alkyl, as defined in the present invention.

"Alkylsulfonyl" means a fragment of the formula-R'-SO2-R”in which R' denotes alkylene and R” denotes an alkyl, as defined in the present invention.

"Alkylsulfonyl the group" means a group of the formula-O-R-SO 2-R', where R denotes alkylene and R' denotes an alkyl, as defined in the present invention.

"Amino group" means a fragment of the formula-NRR'where each R and R' independently denotes hydrogen or alkyl, as defined in the present invention. Thus, the "amino group" includes "alkylamino" (where one of R and R' denotes alkyl and the other represents hydrogen) and "dialkylamino" (where both R and R' denote alkyl).

"Aminocarbonyl" means a group of the formula-C(O)-R, in which R stands for an amino group, defined in the present invention.

"Alkoxyamino" means a fragment of the formula-NR-OR'in which R denotes hydrogen or alkyl and R' denotes an alkyl, as defined in the present invention.

"Alkylsulfanyl" means a fragment of the formula-SR, in which R denotes an alkyl, as defined in the present invention.

"Aminoalkyl" means a group-R-R'in which R' denotes an amino group and R denotes alkylene defined in the present invention. "Aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl, etc., Amine fragment "aminoalkyl" can be 1 or 2 times substituted by alkyl with education "acylaminoalkyl" and "dialkylaminoalkyl" respectively. "Acylaminoalkyl" includes methylaminomethyl, methylaminomethyl, methylaminopropyl, ethylaminomethyl etc. "Dialkylaminoalkyl" includes di is ethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-acylaminoacyl etc.

"Aminoalkoxide" means the group-OR-R'in which R' denotes an amino group and R denotes alkylene defined in the present invention.

"Alkylsulfonamides group" means a fragment of the formula-NR'r SO2-R, in which R represents alkyl and R' denotes hydrogen or alkyl.

"Aminocarbonylmethyl" or "carbamylethyl" means a group of the formula R-O-C(O)-NR'r R", where R denotes alkylene and each R', R" independently represents hydrogen or alkyl, as defined in the present invention.

"Alkylalkoxy" means a group of the formula-O-R-R', where R denotes alkylene and R' denotes quinil defined in the present invention.

"Aryl" means a monovalent cyclic aromatic hydrocarbon fragment containing mono-, bi - or tricyclic aromatic ring. Aryl group optionally may be substituted as defined in the present invention. Examples of aryl fragments include, but are not limited to, phenyl, naphthyl, tenantry, fluorenyl, indenyl, pentalene, azulene, acidifier, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfone, diphenylethylene, benzodioxane, benzofuranyl, benzodioxolyl, benzopyranyl, benzoxazines, benzoxazinones, benzopyrene the sludge, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity, etc. including their partially hydrogenated derivatives, each of which optionally is substituted.

"Arylalkyl and aralkyl"that can be used interchangeably, mean a radical RaRbin which Rameans alkylenes group, and Rbdenotes aryl group defined in the present invention; for example, examples of arylalkyl are phenylalkyl, such as benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl etc.

"Arylsulfonyl" means a group of the formula-SO2-R, in which R stands for an aryl, as defined in the present invention.

"Alloctype" means a group of the formula-O-R, in which R stands for an aryl, as defined in the present invention.

"Arylalkylamine" means a group of the formula-O-R-R', where R denotes alkylene and R' denotes an aryl defined in the present invention.

"Carboxypropyl" or "hydroxycarbonyl"that can be used interchangeably, mean a group of the formula-C(O)-HE.

"Cianelli" means a fragment of the formula-R'-R”in which R' denotes alkylene defined in the present invention, and R” denotes a cyano or nitrile.

"Cycloalkyl" means a monovalent saturated carbocyclic shall ragment, includes mono - or bicyclic ring. Preferred cycloalkyl is unsubstituted or substituted by alkyl. Cycloalkyl optionally may contain one or more substituents, each Deputy independently means a hydroxy-group, alkyl, alkoxygroup, halogen, halogenated, amino group, monoalkylamines or dialkylamines, unless specifically stated otherwise. Examples cycloalkyl fragments include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc., including partially unsaturated derivatives (cycloalkenyl).

"Cycloalkenyl" means a fragment of the formula-R'-R”in which R' denotes alkylene and R” denotes cycloalkyl defined in the present invention.

"Cycloalkylcarbonyl" means a group of the formula-O-R-R', where R denotes alkylene and R' denotes cycloalkyl defined in the present invention.

"Heteroalkyl" means an alkyl radical, as defined in the present invention, in which 1, 2 or 3 hydrogen atoms replaced by the Deputy, is independently selected from the group comprising-ORa, -NRbRcand-S(O)nRd(where n is a whole number equal to from 0 to 2), and it should be understood that the position of the joining heteroalkyl radical is a carbon atom, where R” denotes hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently of one another denote hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; and, if n is 0, Rddenotes hydrogen, alkyl, cycloalkyl or cycloalkenyl, and, if n is 1 or 2, Rddenotes alkyl, cycloalkyl, cycloalkenyl, amino group, allmenalp, monoalkylamines or dialkylamines. Typical examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxypropyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminoethanol etc.

"Heteroaryl" means a monocyclic or bicyclic radical, containing from 5 to 12 ring atoms, containing at least one aromatic ring containing 1, 2 or 3 ring heteroatoms selected from the group comprising N, O or S and the remaining ring atoms are C, and it should be understood that the position of the joining heteroaryl radical is an aromatic ring. Heteroaryl ring optionally may be substituted as defined in the present is m invention. Examples of heteroaryl fragments include, but are not limited to, optionally substituted imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothiazyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, chinoline, ethenolysis, benzofuran, benzothiophene, benzothiophene, benzimidazole, benzoxazole, benzoxadiazole, benzothiazolyl, benzotriazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, honokalani, purinol, hintline, hemolysins, naphthyridine, pteridine, carbazole, azepine, diazepine, acridine etc., including their partially hydrogenated derivatives, each of which optionally is substituted.

"Heteroaromatic" or "heteroaryl" means a group of the formula-R-R', where R denotes alkylene and R' denotes heteroaryl defined in the present invention.

"Heteroarylboronic" means a group of the formula-SO2-R, where R denotes heteroaryl defined in the present invention.

"Heteroanalogues" means a group of the formula-O-R, where R denotes heteroaryl defined in the present invention.

" Heteroarylboronic " means a group of the formula-O-R-R', where R denotes alkylene and R' denotes heteroaryl defined in the present and the finding.

The terms "halogen" and "halide", which can be used interchangeably, mean Deputy fluorine, chlorine, bromine or iodine.

"Halogenated" means an alkyl, as defined in the present invention, in which one or more hydrogen atoms replaced by identical or different halogen atoms. Examples of halogenation include-CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g.,- CF3), etc.

"Halogenlampe" means a fragment of the formula-OR, where R denotes allogeneically fragment, defined in the present invention. Typical halogenlampe is dipterocarp.

"Heterocyclimamines" means a saturated ring, in which at least one ring element is N, NH or N-alkyl, and the remaining atoms form a cycle alkylenes group.

"Heterocyclyl" means a monovalent saturated fragment containing from 1 to 3 rings containing 1, 2, 3 or 4 heteroatom (selected from the group comprising nitrogen, oxygen and sulfur). Heterocyclyl ring optionally may be substituted as defined in the present invention. Examples heterocyclyl fragments include, but are not limited to, optionally substituted piperidinyl, piperazinil, homopiperazine, azepine, pyrrolidinyl, pyrazolidine, and edutainer, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones, hinokitiol, chinoline, ethenolysis, benzimidazolyl, thiadiazolidine, benzothiazolyl, benzoapyrene, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiomorpholine, themorphological, themorphological, dihydroquinoline, dihydroisoquinoline, tetrahydroquinoline, tetrahydroisoquinoline etc.

"Geterotsiklicheskikh" means a fragment of the formula R-R', where R denotes alkylene and R' denotes heterocyclyl defined in the present invention.

"Geterotsiklicheskikh" means a fragment of the formula-OR, where R denotes heterocyclyl defined in the present invention.

"Geterotsiklicheskikh" means a fragment of the formula-OR-R', where R denotes alkylene and R' denotes heterocyclyl defined in the present invention.

"Hydroxyalkoxy" means a fragment of the formula-OR, where R denotes hydroxyalkyl defined in the present invention. Typical hydroxyalkoxy include, for example, 3-methoxy-2-hydroxypropyl and 3-hydroxy-2-methoxypropyl.

"Hydroxyalkoxy" means a fragment of the formula ROR', where R denotes alkylene and R' denotes hydroxyalkyl defined in this image the shadow, and R or R' or both substituted by a hydroxy-group.

"Hydroxyethylamino" means a fragment of the formula-NR-R'in which R denotes hydrogen or alkyl and R' denotes hydroxyalkyl defined in the present invention.

"Hydroxyethylaminomethyl" means a fragment of the formula-R-NR'-R”, where R denotes alkylene, R' denotes hydrogen or alkyl and R” denotes hydroxyalkyl defined in the present invention.

"Hydroxycarbonylmethyl" or "carboxylic" means a group of the formula-R-(CO)-OH, in which R denotes alkylene defined in the present invention.

"Hydroxycarbonylmethyl" means a group of the formula-O-R-C(O) -, in which R denotes alkylene defined in the present invention.

"Hydroxyethylacrylate" or "hydroxyanthranilate" means a group of the formula R-C(O)-O-R-OH, in which each R denotes alkylene and they may be the same or different.

"Hydroxyalkyl" means alkyl fragment, defined in the present invention, substituted by one or more, preferably one, two or three hydroxy groups, provided that one and the same carbon atom does not contain more than one hydroxy-group. Typical examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-ethylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl

"Hydroxycyclohexyl" means cycloalkyl fragment, defined in the present invention, in which 1, 2 or 3 hydrogen atoms in cycloalkyl radical is replaced by a hydroxy-group. Typical examples include, but are not limited to, 2-, 3 - or 4-hydroxycyclohexyl etc.

"Alkoxyalkyl and hydroxyethoxyethyl"that can be used interchangeably, mean alkyl, as defined in the present invention, which is substituted at least once by a hydroxy-group, and at least once alkoxygroup. Thus, alkoxyalkyl and hydroxyethoxyethyl" include, for example, 2-hydroxy-3-methoxypropan-1-yl, etc.,

"Urea group" or "Areena group" means a group of the formula-NR'-C(O)-NR”R"', where each R', R” and R"' independently represents hydrogen or alkyl.

"Carbamate" refers to the group of the formula-O-C(O)-NR'r R”where each R' and R” independently represents hydrogen or alkyl.

"Carboxypropyl" means a group of the formula-O-C(O)-HE.

"Sulfonamidnuyu group" means a group of the formula-SO2-R NR'r”where each R', R” and R"' independently represents hydrogen or alkyl.

"Not necessarily C is displaced", when used for "aryl", phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" means an aryl, phenyl, heteroaryl, cycloalkyl or heterocyclyl, which optionally contains independently selected 1-4 substituent, preferably 1 or 2 substituent selected from the group comprising alkyl, cycloalkyl, cycloalkenyl, heteroalkyl, hydroxyalkyl, halogen, the nitro-group, a cyano, a hydroxy-group, alkoxygroup, amino group, allmenalp, monoalkylamines, dialkylamines, halogenated, halogenlampe, heteroalkyl, -COR, -SO2R (where R denotes hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R”)n-COOR (where n is a whole number equal to from 0 to 5, R' and R” independently represent hydrogen or alkyl, and R denotes hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl) or(CR'R”)n-CONRaRb(where n is a whole number equal to from 0 to 5, R' and R" independently represent hydrogen or alkyl, and Raand Rbindependently of one another denote hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl). Some preferred optional substituents for "aryl", phenyl", "heteroaryl" "cycloalkyl" or "heterocyclyl" include alkyl, halogen, halogenated, alkoxygroup, cyano, amino group and alkylsulfonyl. More preferred substituents is Vlada methyl, fluorine, chlorine, trifluoromethyl, methoxy group, amino group and methanesulfonyl.

"Useplease group" means a group, usually associated with the concept in synthetic organic chemistry, i.e., an atom or group samanyudu under conditions of substitution reactions. Examples useplease groups include, but are not limited to, halogen, alkane - or areincorporated, such as methanesulfonamido, econsultancy, thiomethyl group, benzolsulfonate, tailorshop and taylortype, dialogeventhandlerupp, optionally substituted benzyloxy, isopropylacetate, alloctype etc.

"Modulator" means a molecule that interacts with the target. Interactions include, but are not limited to, agonistic, antagonistic, etc., defined in the present invention.

"Optional" or "optional" means that the subsequent described event or circumstance may but should not be pursued and that the description includes instances where the event or circumstance is and when it is not.

"Disease" and "pathological condition" means any disease, condition, symptom, disorder, or symptom.

"Inert organic solvent" or "inert solvent is" means, the solvent is inert under the conditions described his participation reactions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc., Unless otherwise noted, the solvents used in the reactions described in the present invention are inert solvents.

"Pharmaceutically acceptable" means suitable for preparing pharmaceutical compositions, generally safe, non-toxic and biologically and in other respects not junk, and includes acceptable for veterinary use and for use in pharmaceuticals intended for people.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, as defined in the present invention, and which have the necessary pharmacological activity of the parent compound. Such salts include:

- salt accession with acids, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and so on; or educated organicheskoi acids, such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonate acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluensulfonate acid, trimethylarsine acid and so on; or

salts formed with an acidic proton contained in the initial connection, replaced by a metal ion, for example an alkali metal ion, alkali earth metal ion or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Preferred pharmaceutically acceptable salts are salts derived from acetic acid, hydrochloric acid, sulfuric acid, methanol the background acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

It should be understood that all references to pharmaceutically acceptable salts include the form with the accession of solvent (solvate and crystalline forms (polymorphic form)defined in the present invention, the same salt accession acid.

"Protective group" or "protecting group" means a group which selectively blocks one reaction site in a multifunctional compound, so that a chemical reaction can be performed selectively at another unprotected reactive center such as this is usually accomplished by synthetic chemistry. Some methods proposed in the present invention, based on the use of protective groups for blocking of the reactive nitrogen atoms and/or oxygen contained in the reagents. For example, the term "protective group of the amino group and the protective group of a nitrogen atom" as used in the present invention are equivalent and refer to organic groups intended to protect nitrogen atom from joining adverse reactions during the synthesis. Examples of protective groups for the nitrogen atom include, but are not limited to, trifluoracetyl, acetamide, benzyl (Bn), benzyloxy manilow (carbobenzoxy, CBZ), p-methoxybenzylideneamino, p-nitrobenzisoxazole, tert-butyloxycarbonyl (BOC), etc., Specialist in the art should know how to choose a group that is easily removed and can withstand the ongoing reaction.

"Solvate" means a form with the accession of solvent, which contain a stoichiometric or non-stoichiometric amount of solvent. Some compounds in the crystalline solid state have a tendency to capture solvent molecules in a fixed molar ratio, thereby forming a MES. If water is the solvent, then the resulting MES is a hydrate, and if the solvent is alcohol, the resulting MES is an alcoholate. Hydrates are formed by combining one or more water molecules with one of the substances in which water is retained in the form of molecules, as H2Oh, this combination can lead to the formation of one or more hydrates.

"Subject" means a mammal, and memleketim. Mammals mean any representative of the class Mammalia, including, but not limited to, humans; primates, non-humans, such as chimpanzees and other apes and monkeys; farm animals, such as large the cattle, horses, sheep, goats and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and Guinea pigs, etc. are Examples of memleketim include, but are not limited to, birds, etc., the Term "subject" does not imply a particular age and gender.

"Arthritis" means diseases or pathological conditions, which are affecting the joints of the body, and the pain associated with such affected joints. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis and gouty arthritis.

"Pain" includes, but is not limited to, inflammatory pain; operating pain; visceral pain; tooth pain; premenstrual pain, Central pain, pain caused by burns; migraine or severe attacks of headache with periodic relapses; pain when nerve damage; pain neuritis; neuralgia; pain in case of poisoning; pain in ischemic lesion, pain in interstitial cystitis; pain in cancer; pain, viral, parasitic or bacterial infection, post-traumatic pain or pain associated with irritable bowel syndrome.

"Therapeutically effective amount" means an amount of compound that when administered to a subject for treatment of a pathological condition is DOS is enough for treatment of this pathological condition. "Therapeutically effective amount" will vary depending on the compound undergoing treatment of a pathological condition, the severity at treatment of a pathological condition, the age and relative health of the subject, the route and form of administration, the decision of the attending physician or practitioner veterinarian and other factors.

The terms defined above and defined in the present invention as applied to a variable include an indication of the broad definition of the variable, as well as preferred, more preferred and most preferred definitions, if any.

Treatment of a pathological condition includes:

(i) preventing a pathologic condition, i.e., preventing the development of clinical symptoms of the pathological condition in the subject, which may be a pathological condition or who are predisposed to it, but which are not felt or not you experience symptoms of a pathological condition,

(ii) suppression of pathological conditions, i.e., the suspension of development of the pathological condition or its clinical symptoms, or

(iii) curing pathological conditions, i.e., the provision of temporary or permanent elimination of the pathological condition or its clinical symptoms.

The terms "treatment", "bringing in the touch" and "introduction to reaction with respect to chemical reactions mean adding or mixing two or more reagents under appropriate conditions to obtain the specified and/or required product. It should be understood that the reaction that leads to a specific and/or desired product, does not necessarily lead to him directly based on the combination of two reagents that were added initially, i.e., can be one or more intermediates which are formed in the mixture and which ultimately lead to the formation of the specified and/or the desired product.

Nomenclature and structure

Generally, the nomenclature used in this application is based on AUTONOM™ v.4.0, a computer system of the Beilstein Institute for the generation of systematic nomenclature IUPAC (international Union of pure and applied chemistry). Chemical structure presented in the present invention, was obtained with the use of the software ISIS (version 2.2. All free valency of carbon atom, oxygen, sulfur or nitrogen in the structures shown in the present invention, indicate the presence of a hydrogen atom, unless specified otherwise. If nitrogen-containing heteroaryl ring is represented as containing a nitrogen atom with the free valence, and the heteroaryl ring is given variables, such as Ra, Rbor Rcsuch variables can be linked to a nitrogen atom containing a free valency, or attached to it. If the structure there is the duty to regulate chiral center, but for chiral center is not specific stoichiometric configuration, both enantiomers associated with this chiral center, describes this structure. If the structure presented in this invention can exist in several tautomeric forms, all such tautomers are described by this structure.

All patents and publications mentioned in the present invention, in its entirety is included in the present invention by reference.

Compounds according to the present invention

The present invention relates to compounds of formula I

or their pharmaceutically acceptable salts, in which:

R1means:

optionally substituted phenyl or optionally substituted heteroaryl;

R2means:

optionally substituted phenyl;

optionally substituted heteroaryl or

optionally substituted C3-C6-cycloalkyl;

R3means:

hydrogen or

C1-C6-alkyl;

X denotes: -O-; -NRa-; -S(O)m - or-CRbRcwhere m is from 0 to 2; Radenotes hydrogen, C1-C6-alkyl or C1-C6-alkylsulphonyl; and each Rband Rcindependently denotes hydrogen or C1-C6-alkyl; or Rband Rctogether with the atom to the what the mu they are attached, may form a carbocyclic ring, which optionally contains oxygen as a ring atom; and

Y indicates: -O-; -NRd-; -S(O)n - or-CReRf-where n is from 0 to 2, and each Rd, Reand Rfindependently denotes hydrogen or C1-C6-alkyl.

In some embodiments, the implementation of formula I, R3denotes hydrogen.

In some embodiments, the implementation of formula I, R3represents C1-C6-alkyl.

In some embodiments, the implementation of formula I, R3denotes methyl.

In some embodiments, the implementation of formula I, R1denotes a substituted phenyl.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2, 3 or 4, preferably 1, 2 or 3 substituent, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; C1-C6-alkylsulfanyl; C1-C6-alkylsulfanyl; phenylsulfonyl, in which the phenyl fragment optionally substituted C1-C6-alkyl; a cyano; hydroxy-group; C1-C6-alkylsulphonyl; aminocarbonyl; C1-C6-alkoxycarbonyl; C1-C6-alkoxycarbonyl the-C 1-C6-alkoxygroup; hydroxycarbonyl; hydroxycarbonyl-C1-C6-alkoxygroup; C1-C6-alkylaminocarbonyl-C1-C6-alkoxygroup; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylamino-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkoxygroup; amino group; amino-C1-C6-alkyl, C1-C6alkenyl; C1-C6-quinil; morpholinyl; morpholinyl-C1-C6-alkyl; piperazinil; piperidinyloxy; aminocarbonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxyamino-C1-C6-alkyl; hydroxy-(C1-C6-alkylamino-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarboxylic-C1-C6-alkyl, C1-C6-alkylaminocarbonyl; C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkylaminocarbonyl-C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl; hydroxycarbonyl-C1-C6-alkyl or nitro-group; a 5 - or 6-membered Goethe is auril, selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which optionally is substituted; or two adjacent substituent may form a C1-C2-alkylenedioxy or halogen-C1-C2-alkylenedioxy.

In the variants of implementation of the formula I, in which R denotes a phenyl substituted one or two times C1-C6-alkyl, C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from the group comprising: C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl; hydroxy-(C1-C6-alkoxy-C1-C6-alkyl; halogen, halogen-C1-C6-alkyl; hydroxy-(C1-C6-alkoxygroup; C1-C6-alkoxy-C1-C6-alkoxygroup or oxoprop is.

In the variants of implementation of the formula I, in which R1denotes phenyl, substituted one or two times C1-C6-alkyl, C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from the group comprising: C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl; hydroxy-(C1-C6-alkoxy-C1-C6-alkyl; halogen, halogen-C1-C6-alkyl; hydroxy-(C1-C6-alkoxygroup; C1-C6-alkoxy-C1-C6-alkoxygroup or oxoprop, or R1denotes chinoline; ethenolysis; honokalani; phthalazines; indolyl or indazole; each of which is optionally substituted by one or two groups independently selected from C1-C6-alkyl; halogen; C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl; halogen and carbonyl group.

In the variants of implementation of the formula I, in which R1denotes phenyl, Sames the config once or twice C 1-C6-alkyl, C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl; hydroxy-(C1-C6-alkoxy-C1-C6-alkyl, halogen, halogen-C1-C6-alkyl or carbonyl group.

In the variants of implementation of the formula I, in which R1denotes phenyl, substituted one or two times C1-C6-alkyl, C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl; halogen, or is cogroup.

In the variants of implementation of the formula I, in which R1denotes phenyl, substituted one or two times C1-C6-alkyl, C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from pyrazolyl and pyridazinyl, each of which is optionally substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl; halogen or carbonyl group.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2, 3 or 4, preferably 1, 2 or 3 substituent, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; cryptometer; methanesulfonyl; methanesulfonyl; methanesulfonyl; toluensulfonyl; cyano; acetyl; aminocarbonyl; methoxycarbonyl; ethoxycarbonylmethoxy; carboxypropyl; hydroxycarbonylmethyl; methylaminoacetaldehyde; methoxyethoxy; hydroxyethoxy; methylaminoacetaldehyde; methanesulfonylaminoethyl; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; the amino group or a nitro-group; morpholinyl; N,N-dimethylaminocarbonylmethyl; boc-piperazinil; N-(2-methoxyethyl)-N-meth is luminometer; N,N-dimethylaminomethyl; aminomethyl; boc-aminomethyl; methylcarbamoylmethyl; N,N-di-(2-hydroxyethyl)-aminomethyl; morpholinylmethyl; 2-hydroxy-1-hydroxymethylene; methylaminoethanol; piperidinyloxy; tert-butoxycarbonylmethyl; N,N-dimethylaminocarbonylmethyl; n-propyl; isopropyl; hydroxycarbonylmethyl; hydroxypropoxy; 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which optionally is substituted; or two adjacent substituent can form methylenedioxy, Ethylenedioxy or diftormetilirovaniya.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2, 3 or 4, preferably 1, 2 or 3 substituent, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; cyano; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1 -C6-alkyl; hydroxy-(C1-C6-alkylamino; C1-C2-alkylenedioxy; C3-C6-cycloalkyl-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which optionally is substituted.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2, 3 or 4, preferably 1, 2 or 3 substituent, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy; Ethylenedioxy; pyrrol-1-yl; 2-hydroxy-5-methylpyrazole-3-yl; 2-methyltetrazol-5-yl; 1,5-dimethylpyrazol-3-Il; pyrazole-3-yl; 5-methylpyridin-2-yl; 1-(2-hydroxypropyl)-5-methylpyrazole-3-yl; 2-isobutylthiazole-3-yl; 1-methyltetrazol-5-yl; 6-methylpyridin-3-yl; pyrazole-1-yl; 2-methylpyrazole-3-yl; 5-aripirazole-3-yl; 4,5-dimethylpyrazol-3-yl; 3,5-dioxo-4-5-dihydro[1,2,4]triazine-2-yl; 5-ethyl-1H-pyrazole-3-yl; 1,5-dimethyl-1H-pyrazole-3-yl; 1-((R)-2,3-dihydroxypropyl)-5-methyl-1H-pyrazole-3-yl; 2,5-dimethyl-2H-pyrazole-3-yl; 5-methyl-1H-[1,2,4]triazole-3-yl; 1,5-dim the Teal-1H-[1,2,4]triazole-3-yl; 3-methylisoxazol-5-yl; 3-methyl-[1,2,4]triazole-1-yl; 4-methyl-[1,2,3]triazole-1-yl; 4-methylpyrazole-1-yl; 5-methyl-[1,3,4]oxadiazol-2-yl; 2-propylpyrazole-3-yl; 4,5-dimethyl-[1,2,4]triazole-3-yl; 2-oxoacridine-3-ylmethyl; 4-methyl-3,5-dioxo-4,5-dihydro-[1,2,4]triazine-2-yl; 5-methylpyrazole-3-yl; 4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-[1,2,4]triazine-2-yl or 5-methylisoxazol-3-yl.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2, 3 or 4, preferably 1, 2 or 3 substituent, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy; Ethylenedioxy; pyrrol-1-yl; 2-hydroxy-5-methylpyrazole-3-yl; 2-methyltetrazol-5-yl; 1,5-dimethylpyrazol-3-Il; pyrazole-3-yl; 5-methylpyridin-2-yl; 1-(2-hydroxypropyl)-5-methylpyrazole-3-yl; 2-isobutylthiazole-3-yl; 1-methyltetrazol-5-yl; 6-methylpyridin-3-yl; pyrazole-1-yl; 2-methylpyrazole-3-yl; 5-aripirazole-3-yl; 4,5-dimethylpyrazol-3-yl; 3,5-dioxo-4-5-dihydro[1,2,4]triazine-2-yl; 5-ethyl-1H-pyrazole-3-yl; 1,5-dimethyl-1H-pyrazole-3-yl; 1-((R)-2,3-dihydroxypropyl)-5-methyl-1H-pyrazole-3-yl; 2,5-dimethyl-2H-pyrazole-3-yl; 5-methyl-1H-[1,2,4]triazole-3-yl; 1,5-dimethyl-1H-[1,2,4]triazole-3-yl; 3-methylisoxazol-5-Il 3-methyl-[1,2,4]triazole-1-yl; 4-methyl-[1,2,3]triazole-1-yl; 4-methylpyrazole-1-yl; 5-methyl-[1,3,4]oxadiazol-2-yl; 2-propylpyrazole-3-yl; 4,5-dimethyl-[1,2,4]triazole-3-yl; 2-oxoacridine-3-ylmethyl; 4-methyl-3,5-dioxo-4,5-dihydro-[1,2,4]triazine-2-yl; 5-methylpyrazole-3-yl; 4-(2-hydroxyethyl)-3,5-dioxo-4,5-dihydro-[1,2,4]triazine-2-yl or 5-methylisoxazol-3-yl.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2, 3 or 4, preferably 1, 2 or 3 substituent, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl; 5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl; 5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl; 3-oxo-2-methyl-2H-pyridazin-4-yl or 3-oxo-2H-pyridazin-5-yl.

In some embodiments, the implementation of formula I, R1denotes phenyl, substituted in position 2 by halogen or C1-C6-alkyl, and optionally containing one or two deputies, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C -alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; cyano; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl; hydroxy-(C1-C6-alkylamino; C1-C2-alkylenedioxy or C3-C6-cycloalkyl-C1-C6-alkoxygroup.

In some embodiments, the implementation of formula I, R1denotes phenyl, substituted in position 2 by halogen or C1-C6-alkyl, and optionally containing one or two deputies, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; cyano; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl; hydroxy-(C1-C6-alkylamino; C1-C2-alkylenedioxy; C3-C6-cycloalkyl-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; piraso the sludge; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl and carbonyl group.

In some embodiments, the implementation of formula I, R1denotes phenyl, substituted in position 2 C1-C6-alkyl or halogen, and optionally containing one or two deputies, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; cyano; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl; hydroxy-(C1-C6-alkylamino; C1-C2-alkylenedioxy or C3-C6-cycloalkyl-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidine is; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl and carbonyl group.

In some embodiments, the implementation of formula I, R1denotes phenyl, which is:

in position 2 substituted with stands or halogen;

in position 3 optionally substituted with halogen or C1-C6-alkoxygroup; and

in position 4 substituted C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl and carbonyl group.

In some embodiments, the implementation of formula I, R1denotes phenyl, which is:

in position 2 substituted with stands or halogen;

in position 3 optionally substituted with halogen or C1-C6-alkoxygroup; and

in position 4 substituted C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxy what upoi; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl; 5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl; 5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl; 3-oxo-2-methyl-2H-pyridazin-4-yl or 3-oxo-2H-pyridazin-5-yl.

In some embodiments, the implementation of formula I, R1denotes phenyl, containing two or three deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; dipterocarp; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy or Ethylenedioxy.

In some embodiments, the implementation of formula I, R1denotes phenyl, containing two or three deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; methyl and methoxy group.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2 or 3 substituent, each of which is independently selected from the group comprising fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl or cyclopropylmethoxy.

In some embodiments, the implementation of whom ormula I, R1denotes phenyl, substituted in position 2 C1-C6-alkyl or halogen, and optionally containing one or two deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; dipterocarp; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy or Ethylenedioxy.

In some embodiments, the implementation of formula I, R1denotes phenyl, substituted in position 2 stands, and optionally containing one or two deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; dipterocarp; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy or Ethylenedioxy.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-acid; 2-bromo-4-chloro-5-methoxyphenyl; 2-bromo-4-fluoro-5-methoxyphenyl; 2,4-dichloro-5-methoxyphenyl; 2-bromo-5-methoxy-4-triptoreline; 2-bromo-4,5-dichlorophenyl; 2-bromo-4-chloro-5-itfinal; 2-bromo-4-chloro-5-triptoreline; 2-bromo-5-methoxy-4-were; 2-isopropyl-4,5-acid; 2-bromo-4-chloro-5-methanesulfonyl; 2-bromo-4-chloro-5-methanesulfonyl; 2-bromo-4-chloro-5-meth is sulfanilyl; 2-bromo-4-chloro-5-forfinal; 2-bromo-5-methoxyphenyl; 2-bromo-5-methoxy-4-ethoxycarbonylphenyl; 2-bromo-4-chloro-5-hydroxyphenyl; 2-bromo-4-chloro-5-(methylaminoquinoline)phenyl; 2-methyl-4,5-acid; 2-bromo-4-chloro-5-ethoxycarbonylphenyl; 2-bromo-4-methanesulfonyl-5-methoxyphenyl; 2-bromo-4-methyl-5-methoxyphenyl; 2-bromo-4-chloro-5-(ethoxycarbonylmethoxy)-phenyl; 2-bromo-4-chloro-5-(hydroxycarbonylmethyl)phenyl; 2-bromo-4-chloro-5-(2-methoxyethoxy)phenyl; 4,5-acid; 2-fluoro-4-chloro-5-methoxyphenyl; 2-bromo-4-methoxycarbonyl-5-methoxyphenyl; 6 bromobenzo[1,3]dioxol-5-yl; 2-bromo-4-chloro-5-(2 hydroxyethoxy)phenyl; 2-bromo-4-deformedarse-5-methoxyphenyl; 5-methoxy-4-were; 2-bromo-4-chloro-5-(2-methylamino-ethoxy)phenyl; 2-bromo-4-cyano-5-were; 2-fluoro-4-methyl-5-methoxyphenyl; 2-bromo-4-chloro-5-acetylphenyl; 5-methoxy-2-were; 2-bromo-4-chloro-5-(3-methanesulfonamide)phenyl; 2-bromo-5-methoxy-4-(tert-butoxycarbonyl)-phenyl; 5-methanesulfonyl-2-methoxyphenyl; 2-bromo-4-chloro-5-(1-hydroxyethyl)-phenyl; 2-fluoro-5-(2-hydroxyethoxy)-4-were; 2-bromo-5-methoxy-4-aminocarbonylmethyl; 6-bromo-2,2-debtorrent[1,3]dioxol-5-yl; 2,6-differenl; 2-bromo-4-cyano-5-methoxyphenyl; 2,5-acid; 3-methoxycarbonyl-2-were; 3-methoxyphenyl; 4-methoxyphenyl; 2,4-acid; 4-chloro-5-methoxyphenyl; 4-fluoro-5-methoxyphenyl; 2-bromo-4-methyl-5-(tert-butoxycarbonyl)phenyl; 3,4,5-trimethoxyphenyl; 2-bromo-4,6-differenl; 2-the Teal-4,5-acid; 2-bromo-4-methoxyphenyl; 4-chloro-5-(2-hydroxyethoxy)-2-were; 3-methoxycarbonyl-2-were; 2,5-dimetilfenil; 2-bromo-5-methoxyphenyl, 2,3-dimetilfenil; 2-bromo-4-chloro-5-hydroxymethylene; 2-bromo-3, 5dimethylphenyl; 4-methoxy-2-were; 2,4-dimetilfenil; 2-iodine-4,5-acid; 2-chloro-4,5-acid; 7-bromo-2,3-dihydrobenzo[1,4]dioxin-6-yl; 4,5-dimethoxy-2-triptoreline; 2-bromo-5-ethoxy-4-methoxyphenyl; 2-bromo-4-ethoxy-5-methoxyphenyl; 2-bromo-5-cyclopropylmethoxy-4-methoxyphenyl; 2-bromo-4-cyclopropylmethoxy-5-methoxyphenyl; 2-cyano-4,5-acid; 2-bromo-5-deformedarse-4-methoxyphenyl; 2-bromo-4,5-bis-deformational; 2-bromo-4-fluoro-5-(2-methoxyethoxy)phenyl; 2-bromo-4-fluoro-5-(2-hydroxyethoxy)phenyl; 4-fluoro-4,5-acid; 2,4-dimetilfenil; 3, 5dimethylphenyl; 4,5-dimethoxy-2-morpholine-4-ylphenyl; 3-methoxy-2-were; 2,3-acid; 4-fluoro-5-(2-hydroxyethoxy)-2-were; 4-chloro-4-(3-hydroxypropyl)-2-were; 2-dimethylamino-4,5-acid; 4-chloro-5-hydroxymethyl-2-were; 2-bromo-4-trifloromethyl; 2-bromo-4-chloro-5-dimethylaminoethyl-methoxyphenyl; 4-chloro-5-{[(2-methoxyethyl)methylamino]methyl}-2-were; 5-(tert-butoxycarbonylamino)-2-methyl-4-chlorophenyl; 5-aminomethyl-4-chloro-2-were; 4-chloro-2-methyl-5-(methylcarbamoyl)phenyl; 5-{[bis-(2-hydroxyethyl)amino]methyl}-4-chloro-2-were; 4-chloro-2-methyl-5-morpholine-4-ylmethylene; 3-METI is phenyl; 4-chloro-5-(2-hydroxyethyl)-2-were; 2-bromo-3,4-atlanticcity (7-bromo-2,3-dihydrobenzo[1,4]-dioxin-6-yl)); 3-chloro-2-were; 3-hydroxymethyl-2-were; 2-methyl-3-methylaminoethanol; 4-chloro-2-methyl-5-(piperidine-4-yloxy)phenyl; 2-methyl-3-(tert-butoxycarbonylmethyl)phenyl; 3-(2-hydroxyethyl)-2-were; 4,5-debtor-2-were; 2-bromo-4,5-differenl; 3,4-dimetilfenil; 2-chloro-3-were; 2-bromo-4-(2-hydroxyethyl)phenyl; 2-bromo-4-isopropylphenyl; 3-fluoro-2-were; 2-bromo-5-(2-hydroxyethoxy)-4-were; 2-(2-hydroxyethyl)-4,5-acid; 4-chloro-5-dimethylaminomethyl-2-were; 2-ethylphenyl; 2-propylphenyl; 5-methoxy-2,3-dimetilfenil and 3-(hydroxycarbonylmethyl)-2-were.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-acid; 2-bromo-4-chloro-5-methoxyphenyl; 2-bromo-4-fluoro-5-methoxyphenyl; 2,4-dichloro-5-methoxyphenyl; 2-bromo-5-methoxy-4-triptoreline; 2-bromo-4,5-dichlorophenyl; 2-bromo-4-chloro-5-itfinal; 2-bromo-4-chloro-5-triptoreline; 2-bromo-5-methoxy-4-were; 2-isopropyl-4,5-acid; 2-bromo-4-chloro-5-methanesulfonyl; 2-bromo-4-chloro-5-methanesulfonyl; 2-bromo-4-chloro-5-methanesulfonyl; 2-bromo-4-chloro-5-forfinal; 2-bromo-5-methoxyphenyl; 2-bromo-5-methoxy-4-ethoxycarbonylphenyl; 2-bromo-4-chloro-5-hydroxyphenyl; 2-bromo-4-chloro-5-(methylaminoquinoline)phenyl; 2-methyl-4,5-acid; 2-bromo-4-chloro-5-marks carbonitrile; 2-bromo-4-methanesulfonyl-5-methoxyphenyl; 2-bromo-4-methyl-5-methoxyphenyl; 2-bromo-4-chloro-5-(ethoxycarbonylmethoxy)-phenyl; 2-bromo-4-chloro-5-(hydroxycarbonylmethyl)phenyl; 2-bromo-4-chloro-5-(2-methoxyethoxy)phenyl; 4,5-acid; 2-fluoro-4-chloro-5-methoxyphenyl; 2-bromo-4-methoxycarbonyl-5-methoxyphenyl; 6 bromobenzo[1,3]dioxol-5-yl; 2-bromo-4-chloro-5-(2-hydroxyethoxy)phenyl; 2-bromo-4-deformedarse-5-methoxyphenyl;5-methoxy-4-were; 2-bromo-4-chloro-5-(2-methylenedioxy)-phenyl; 2-bromo-4-cyano-5-were; 2-fluoro-4-methyl-5-methoxyphenyl; 2-bromo-4-chloro-5-acetylphenyl; 5-methoxy-2-were; 2-bromo-4-chloro-5-(3-methanesulfonamide)phenyl; 2-bromo-5-methoxy-4-(tert-butoxycarbonyl)-phenyl; 5-methanesulfonyl-2-methoxyphenyl; 2-bromo-4-chloro-5-(1-hydroxyethyl)-phenyl; 2-fluoro-5-(2-hydroxyethoxy)-4-were; 2-bromo-5-methoxy-4-aminocarbonylmethyl; 6-bromo-2,2-debtorrent[1,3]dioxol-5-yl; 2,6-differenl; 2-bromo-4-cyano-5-methoxyphenyl; 2,5-acid; 3-methoxycarbonyl-2-were; 3-methoxyphenyl; 4-methoxyphenyl; 2,4-acid; 4-chloro-5-methoxyphenyl; 4-fluoro-5-methoxyphenyl; 2-bromo-4-methyl-5-(tert-butoxycarbonyl)phenyl; 3,4,5-trimethoxyphenyl; 2-bromo-4,6-differenl; 2-ethyl-4,5-acid; 2-bromo-4-methoxyphenyl; 4-chloro-5-(2-hydroxyethoxy)-2-were; 3-methoxycarbonyl-2-were; 2,5-dimetilfenil; 2-bromo-5-methoxyphenyl, 2,3-dimetilfenil; 2-bromo-4-chloro-5-hydroxymethylene; 2-bromo-3, 5dimethylphenyl;4-methoxy-2-were or 2,4-dimetilfenil.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-acid; 2-bromo-4-chloro-5-methoxyphenyl; 2-bromo-4-fluoro-5-methoxyphenyl; 2-bromo-5-methoxy-4-were; 2-methyl-4,5-acid; 2-bromo-4-chloro-5-(2-methoxyethanol; 2-bromo-4-chloro-5-(2-hydroxyethylene; 2-bromo-4-deformedarse-5-methoxyphenyl; 2,5-acid; 2-ethyl-4,5-acid; 2-methyl-5-(2-hydroxyethoxy)-4-chlorophenyl; 2,5-dimetilfenil; 2-bromo-5-methoxyphenyl or 2-bromo-4,5-dimetilfenil.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-acid; 2-bromo-4-chloro-5-methoxyphenyl; 2-bromo-4-fluoro-5-methoxyphenyl; 2-bromo-5-methoxy-4-were; 4,5-dimethoxy-2-were; 2-bromo-4,5-methylenedioxyphenyl (6 bromobenzo[1,3]dioxol-5-yl); 2-bromo-4-chloro-5-(2-hydroxyethoxy)phenyl; 2-bromo-4-deformedarse-5-methoxyphenyl; 5-methoxy-2-were; 2-bromo-4-chloro-5-(1-hydroxyethyl)phenyl; 2-bromo-4-chloro-5-((S)-1-hydroxyethyl)phenyl; 2-ethyl-4,5-acid; 2-bromo-4-methoxyphenyl; 4-chloro-5-(2-hydroxyethoxy)-2-were; 2,5-dimetilfenil; 2-bromo-5-methoxyphenyl, 2,3-dimetilfenil; 2-bromo-4-chloro-5-hydroxymethylene; 2-bromo-3, 5dimethylphenyl; 2,4-dimetilfenil; 3-methoxy-2-were; 4-fluoro-5-(2-hydroxyethoxy)-2-were; 4-chloro-5-(3-hydroxypropoxy)-2-were; 4-chloro-5-hydroxymethyl-2-were; 5-{[bis-(2-hydroxyethyl)amino]methyl}-4-chloro-2-were; 4-chloro-5-(2-hydroxyethyl)-2-METI is phenyl; 2-bromo-4,5-atlanticcity (7-bromo-2,3-dihydrobenzo[1,4]dioxin-6-yl); 3-chloro-2-were; 3-hydroxymethyl-2-were-or 3-(2-hydroxyethyl)-2-were.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-acid; 4,5-dimethoxy-2-were; 4-chloro-5-(2-hydroxyethoxy)-2-methylphenyl; 2-methyl-5-(5-methyl-1H-pyrazole-3-yl)phenyl; 2-methyl-5-(4-methylpyrazole-1-yl)phenyl; 2-methyl-5-[5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl]phenyl; 2-methyl-5-[5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl]phenyl; 2-methyl-5-[5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl]phenyl; 2-methyl-5-[5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl]phenyl; 2-methyl-5-(6-oxo-1-methylpyridin-5-yl)phenyl; 2-chloro-5-[5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl]phenyl; 2-methyl-5-(6-oxo-1H-pyridazin-3-yl)phenyl; 2-methyl-5-(6-oxo-1H-pyridazin-5-yl)phenyl or 2-methyl-4-[4-((R)-2-hydroxy-3-methoxypropyl)-2H-[1,2,4]triazine-3,5-Dion]-ylphenyl.

In some embodiments, the implementation of formula I, R1denotes 4-chloro-5-(2-hydroxyethoxy)-2-were.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-(5-methyl-1H-pyrazole-3-yl)phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-(4-methylpyrazole-1-yl)phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-[5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl]phenyl.

In some variants of the implementation of the formula I, R1refers to 2-methyl-5-[5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl]phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-[5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl] phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-[5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl]phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-(6-oxo-1-methylpyridin-5-yl)phenyl.

In some embodiments, the implementation of formula I, R1denotes 2-chloro-5-[5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl]phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-(6-oxo-1H-pyridazin-3-yl)phenyl.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-(6-oxo-1H-pyridazin-5-yl)phenyl.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-acid.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4-chloro-5-methoxyphenyl.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4-fluoro-5-methoxyphenyl.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-5-methoxy-4-were.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-4,5-acid.

In some embodiments, Khujand the exercise of formula I, R1denotes 2-bromo-4-chloro-5-(2-methoxyethanol.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4-chloro-5-(2-hydroxyethylene.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4-deformedarse-5-methoxyphenyl.

In some embodiments, the implementation of formula I, R1denotes a 2,5-acid.

In some embodiments, the implementation of formula I, R1refers to 2-ethyl-4,5-acid.

In some embodiments, the implementation of formula I, R1refers to 2-methyl-5-(2-hydroxyethoxy)-4-chlorophenyl.

In some embodiments, the implementation of formula I, R1denotes a 2,5-dimetilfenil.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-5-methoxyphenyl.

In some embodiments, the implementation of formula I, R1denotes 2-bromo-4,5-dimetilfenil.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2 or 3 substituent, each of which is independently selected from the group comprising C1-C6-alkyl, C1-C6-alkoxygroup; halogen; hydroxy-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; p is rimidine; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from the group comprising oxoprop; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2 or 3 substituent, each of which is independently selected from the group comprising C1-C6-alkyl, C1-C6-alkoxygroup; halogen; hydroxy-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from the group comprising oxoprop; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2 or 3 substituent, each of the which is independently selected from the group including C1-C6-alkyl, C1-C6-alkoxygroup; halogen; hydroxy-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from the group comprising: oxoprop; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of formula I, R1denotes phenyl containing 1, 2 or 3 substituent, each of which is independently selected from the group comprising methyl, methoxy group, chlorine; bromine; 2-hydroxyethoxy; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 4,5-dimethyl-4H-[1,2,4]triazole-3-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl; 2H-pyrazole-3-yl; 1-((R)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 4-((R)-2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 6-oxo-6N-pyridazin-1-yl; 3-methyl-6-oxo-bn-pyridazin-1-yl; 6-oxo-1,6-dihydropyridin-2-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 1-((S)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 2-ethyl-3-oxo-2,3-dihydropyridin-4-yl); 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 6-oxo-,6-dihydropyridin-3-yl; 2-((R)-2-hydroxy-3-methoxypropyl)-3-oxo-2,3-dihydropyridin-4-yl; 2-oxopyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidine-1 -; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxypyridazine-3-yl or 2,6-dioxo-3,6-dihydro-2H-pyrimidine-1-Il.

In some embodiments, the implementation of formula I, R1denotes phenyl, substituted:

in position 2: C1-C6-alkyl or halogen;

in position 4: hydrogen; C1-C6-alkoxygroup or halogen; and

in position 5: C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of formula I, R1denotes phenyl, substituted:

in position 2: the stands; halogen or bromine;

in position 4: hydrogen; methoxy group or chlorine; and position 5: a methoxy group; hydroxyethoxy; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 4,5-dimethyl-4H-[1,2,4]triazole-3-yl); 2-methyl-3-oxo-2,3-Digue is dropyridine-4-yl; 2H-pyrazole-3-yl; 1-((R)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 4-((R)-2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 6-oxo-6N-pyridazin-1-yl; 3-methyl-6-oxo-6N-pyridazin-1-yl; 6-oxo-1,6-dihydropyridin-2-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 1-((S)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 2-ethyl-3-oxo-2,3-dihydropyridin-4-yl); 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 6-oxo-1,6-dihydropyridin-3-yl; 2-((R)-2-hydroxy-3-methoxypropyl)-3-oxo-2,3-dihydropyridin-4-yl; 2-oxopyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridine-1-yl; 6-methoxypyridazine-3-yl or 2,6-dioxo-3,6-dihydro-2H-pyrimidine-1-yl.

In some embodiments, the implementation of formula I, R1denotes optionally substituted heteroaryl.

In some embodiments, the implementation of formula I, R1denotes chinoline; ethenolysis; honokalani; phthalazines; indolyl or indazole;

each of which is optionally substituted 1 or 2 groups independently selected from C1-C6-alkyl; halogen; C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl; halogen and carbonyl group.

In some embodiments, the implementation of formula I, R1denotes chinoline; ethenolysis; phthalazines; Jn is oil or indazole; each of which is optionally substituted by one or two groups independently selected from C1-C6-alkyl; halogen; hydroxy-C1-C6-alkyl; halogen and carbonyl group.

In some embodiments, the implementation of formula I, R1means: chinoline; ethenolysis or indazole; each of which is substituted 1 or 2 groups independently selected from the group comprising: C1-C6-alkyl; hydroxy-(C1-C6-alkyl and oxoprop.

In some embodiments, the implementation of formula I, R1means: 6-methylinosine-5-yl; 2,6-dimethylaniline-5-yl; 6-methyl-2-oxo-1,2-dihydroquinoline-5 -; 5-ethyl-2-methylinosine-6-yl; 1-(2-hydroxyethyl)-5-methyl-1H-indazol-6-yl; 1,5-dimethyl-1H-indazol-6-yl; 2-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl or 2-methyl-1-oxo-1,2-dihydroisoquinoline-5-yl.

In some embodiments, the implementation of formula I, R1denotes 5-atelinae-6-yl; 7-atelinae-6-yl; 6-methylinosine-5-yl; quinoline-5-yl; 2-methylinosine-5-yl; 7-chloro-2-(2-hydroxy-1-methylethyl)-1-oxo-2,3-dihydroindol-4-yl; 2-oxo-6-methyl-1H-quinoline-5-yl;

In some embodiments, the implementation of formula I, R2denotes optionally substituted phenyl.

In some embodiments, the implementation of formula I, R2denotes phenyl, optionally containing 1, 2, 3, or 4 substituent, each of which is independently selected from the group comprising Gal the gene; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; C1-C6-alkylsulfanyl; C1-C6-alkylsulfanyl; phenylsulfonyl, in which the phenyl fragment optionally substituted C1-C6-alkyl; a cyano; hydroxy-group; C1-C6-alkylsulphonyl; aminocarbonyl; C1-C6-alkoxycarbonyl; C1-C6-alkoxycarbonyl-C1-C6-alkoxygroup; hydroxycarbonyl; hydroxycarbonyl-C1-C6-alkoxygroup; C1-C6-alkylaminocarbonyl-C1-C6-alkoxygroup; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylamino-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkoxygroup; amino group; amino-C1-C6-alkyl, C1-C6alkenyl; C1-C6-quinil; morpholinyl; morpholinyl-C1-C6-alkyl; piperazinil; piperidinyloxy; aminocarbonyl-C1-C6-alkoxygroup; C1-C6-alkoxyamino-C1-C6-alkyl; hydroxy-(C1-C6-alkylamino-C1-C6-al is the sludge; C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarboxylic-C1-C6-alkyl, C1-C6-alkylaminocarbonyl; C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkylaminocarbonyl-C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl; hydroxycarbonyl-C1-C6-alkyl or nitro-group; or two adjacent substituent may form a C1-C2-alkylenedioxy or halogen-C1-C2-alkylenedioxy.

In some embodiments, the implementation of formula I, R2denotes phenyl, optionally containing one or two deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; methanesulfonyl; methanesulfonyl; toluensulfonyl; cyano; acetyl; aminocarbonyl; methoxycarbonyl; ethoxycarbonylmethoxy; carboxypropyl; hydroxycarbonylmethyl; methylaminoacetaldehyde; methoxyethoxy; hydroxyethoxy; methylaminoacetaldehyde; methanesulfonylaminoethyl; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; the amino group or a nitro-group; or two adjacent substituent can form methylenedioxy the PU, Ethylenedioxy or diftormetilirovaniya.

In some embodiments, the implementation of formula I, R2denotes phenyl containing one or two deputies, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; cyano; alkoxyalkyl; hydroxyalkoxy; alkoxycarbonyl-alkoxygroup; hydroxyalkyl or C3-C6-cycloalkyl-C1-C6-alkoxygroup.

In some embodiments, the implementation of formula I, R2denotes phenyl, optionally containing one or two deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl or cyclopropylmethoxy.

In some embodiments, the implementation of formula I, R2denotes phenyl containing one or two deputies, each of which is independently selected from the group comprising fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; cyano; methoxyethoxy; hydroxyethoxy the group; hydroxymethyl; hydroxyethyl or cyclopropylmethoxy.

In some embodiments, the implementation of formula I, R2denotes phenyl containing one or two deputies, each of which is independently selected from the group comprising halogen; methyl; methoxy group; trifluoromethyl; dipterocarp; cyano or methanesulfonyl.

In some embodiments, the implementation of formula I, R2denotes phenyl containing one or two deputies, each of which is independently selected from the group comprising: fluoro; chloro; methyl; methoxy group or cyano.

In some embodiments, the implementation of formula I, R2denotes phenyl, optionally substituted once or twice by halogen.

In some embodiments, the implementation of formula I, R2denotes phenyl substituted once or twice by fluorine.

In some embodiments, the implementation of formula I, R2denotes phenyl; 4-forfinal; 3-forfinal; 2-forfinal; 2-chlorophenyl; 3,4-differenl; 3,5-differenl; 3-were; 4-were-or 3-cyanophenyl.

In some embodiments, the implementation of formula I, R2denotes phenyl; 4-forfinal; 3-forfinal; 2-forfinal; 2-chlorophenyl; 3,4-differenl or 3.5 differenl.

In some embodiments, the implementation of formula I, R2denotes 4-forfinal or 3-forfinal.

In some embodiments, the implementation of the formula is I, R2denotes 4-forfinal.

In some embodiments, the implementation of formula I, R2denotes 3-forfinal.

In some embodiments, the implementation of formula I, R2denotes 3,4-differenl.

In some embodiments, the implementation of formula I, R2denotes optionally substituted C3-C6-cycloalkyl.

In some embodiments, the implementation of formula I, R2represents C3-C6-cycloalkyl, optionally substituted with halogen.

In some embodiments, the implementation of formula I, R2refers to cyclohexyl.

In some embodiments, the implementation of formula I, R2denotes cyclohexyl, optionally substituted 1 or 2 times by halogen.

In some embodiments, the implementation of formula I, R2denotes cyclohexyl, optionally substituted 1 or 2 times by fluorine.

In some embodiments, the implementation of formula I, X is-O-.

In some embodiments, the implementation of formula I, X is-NRa-.

In some embodiments, the implementation of formula I, X is-S(O)m-.

In some embodiments, the implementation of formula I, X is-CRbRc-.

In some embodiments, the implementation of formula I, X represents-CH2-.

In some embodiments, the implementation of formula I, m is 0.

In some embodiments, the implementation of formula I, m is 1./p>

In some embodiments, the implementation of formula I, m is 2.

In some embodiments, the implementation of formula I, Radenotes hydrogen.

In some embodiments, the implementation of formula I, Rarepresents C1-C6-alkyl.

In some embodiments, the implementation of formula I, Rarepresents C1-C6-alkylsulphonyl.

In some embodiments, the implementation of formula I, Radenotes methyl.

In some embodiments, the implementation of formula I, Radenotes acetyl.

In some embodiments, the implementation of formula I, Radenotes hydrogen.

In some embodiments, the implementation of formula I, Rarepresents C1-C6-alkyl.

In some embodiments, the implementation of formula I, Y represents-O-.

In some embodiments, the implementation of formula I, Y represents-NRd-.

In some embodiments, the implementation of formula I, Y represents-S(O)n-.

In some embodiments, the implementation of formula I, Y represents-CRdRe.

In some embodiments, the implementation of formula I, Rddenotes hydrogen.

In some embodiments, the implementation of formula I, Rdrepresents C1-C6-alkyl.

In some embodiments, the implementation of formula I, Redenotes hydrogen.

In some embodiments, the implementation of formula I, Rerepresents C1-C6 -alkyl.

In some embodiments, the implementation of formula I, Rfdenotes hydrogen.

In some embodiments, the implementation of formula I, Rfrepresents C1-C6-alkyl.

In some embodiments, the implementation of formula I, n is 0.

In some embodiments, the implementation of formula I, n is 1.

In some embodiments, the implementation of formula I, n is 2.

In some embodiments, the implementation is more preferable if the compounds of formula I can be described by formula II

in which:

p is from 0 to 3;

each R5independently represents: halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl or cyano;

each R6, R7, R8, R9and R10independently represents: hydrogen; halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; C1-C6-alkylsulfanyl; C1-C6-alkylsulfanyl; phenylsulfonyl, in which the phenyl fragment optionally substituted C1-C6-alkyl; a cyano; hydroxy-group; C1-C6-alkylsulphonyl; aminocarbonyl; C1-C6-alcox is carbonyl; C1-C6-alkoxycarbonyl-C1-C6-alkoxygroup; hydroxycarbonyl; hydroxycarbonyl-C1-C6-alkoxygroup; C1-C6-alkylaminocarbonyl-C1-C6-alkoxygroup; C1-C6-alkoxy-C1-C6-alkoxygroup; hydroxy-C1-C6-alkoxygroup; C1-C6-alkylamino-C1-C6-alkoxygroup; C1-C6-alkylsulfonyl-C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C3-C6-cycloalkyl-C1-C6-alkoxygroup; amino group; amino-C1-C6-alkyl, C1-C6alkenyl; C1-C6-quinil; morpholinyl; morpholinyl-C1-C6-alkyl; piperazinil; piperidinyloxy; aminocarbonyl-C1-C6-alkoxygroup; C1-C6-alkoxyamino-C1-C6-alkyl; hydroxy-(C1-C6-alkylamino-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarboxylic-C1-C6-alkyl, C1-C6-alkylaminocarbonyl; C1-C6-alkoxycarbonyl-C1-C6-alkyl, C1-C6-alkylaminocarbonyl-C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl; hydroxycarbonyl-C1-C6-alkyl or nitro-group; or two adjacent substituent may OBR is to use C 1-C2-alkylenedioxy; halogen-(C1-C2-alkylenedioxy; or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which optionally is substituted;

and the values of X and Rdare as defined in the present invention for formula I.

In some embodiments, the implementation of formula II, more preferably, if the connection proposed in the present invention, may be described by formula IIA or formula II

;

in which the values of X, p, R5, R6, R7, R8, R9R10and Rdare as defined in the present invention.

In some embodiments, the communication proposed in the present invention are described by formula IIa.

In some embodiments, the communication proposed in the present invention are described by formula IIb.

In some embodiments of any of formulas II, IIa and IIb at least one of R6, R7, R8, R9and R10does not denote hydrogen.

In some embodiments, the exercise of any of the of oral II, IIa and IIb at least two of R6, R7, R8, R9and R10not denote hydrogen.

In some embodiments of any of formulas II, IIa and IIb at least three of R6, R7, R8, R9and R10not denote hydrogen.

In some embodiments of any of formulas II, IIa and IIb, each R6, R7, R8, R9and R10independently represents hydrogen; fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; cryptometer; methanesulfonyl; methane sulfonyl; methanesulfonyl; toluensulfonyl; cyano; acetyl; aminocarbonyl; methoxycarbonyl; ethoxycarbonylmethoxy; carboxypropyl; hydroxycarbonylmethyl; methylaminoacetaldehyde; methoxyethoxy; hydroxyethoxy; methylaminoacetaldehyde; methanesulfonylaminoethyl; hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; the amino group or a nitro-group; morpholinyl; N,N-dimethylaminocarbonylmethyl; boc-piperazinil; N-(2-methoxyethyl)-N-methylaminomethyl; N,N-dimethylaminomethyl; aminomethyl; boc-aminomethyl;methylcarbamoylmethyl; N,N-di-(2-hydroxyethyl)-aminomethyl; morpholinylmethyl; 2-hydroxy-1-hydroxymethylene; methylaminoethanol; piperidinyloxy; tert-butoxycarbonylmethyl; N,N-dimethylaminoethyl ethyl; n-propyl; isopropyl; hydroxycarbonylmethyl; hydroxypropoxy; 5 - or 6-membered heteroaryl selected from the group comprising: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which optionally is substituted; or two adjacent substituent can form methylenedioxy, Ethylenedioxy or diftormetilirovaniya.

In some embodiments of any of formulas II, IIa and IIb two of R6, R7, R8, R9and R10denote hydrogen, and each of the remaining R6, R7, R8, R9and R10independently represents hydrogen; fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy or Ethylenedioxy.

In some embodiments of any of formulas II, IIa and IIb two of R6, R7, R8, R9and R10denote hydrogen, and each of the remaining R6, R7, R8, R9and R10independently represents fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy is the Rupp; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy or Ethylenedioxy.

In some embodiments of any of formulas II, IIa and IIb two of R6, R7, R8, R9and R10denote hydrogen, and each of the remaining R6, R7, R8, R9and R10independently represents hydrogen; fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; dipterocarp; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; methylendioxy or Ethylenedioxy.

In some embodiments of any of formulas II, IIa and IIb two of R6, R7, R8, R9and R10denote hydrogen, and each of the remaining R6, R7, R8, R9and R10independently represents hydrogen; fluorine; chlorine; bromine; methyl and methoxy group.

In some embodiments of any of formulas II, IIa and IIb, R6denotes halogen or methyl, R10denotes hydrogen, one of R7, R8and R9denotes hydrogen and the remaining of R7, R8and R9all independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxym the Thiel; hydroxyethyl and hydroxypropoxy.

In some embodiments of any of formulas II, IIa and IIb R6denotes halogen or methyl, R10denotes hydrogen, two of R7, R8and R9denotes hydrogen and the remaining of R7, R8and R9selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl and hydroxypropoxy.

In some embodiments of any of formulas II, IIa and IIb, each R6, R7, R8, R9and R10independently represents hydrogen; halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; cyano; alkoxyalkyl; hydroxyalkoxy; alkoxycarbonylmethyl; hydroxyalkyl or C3-C6-cycloalkyl-C1-C6-alkoxygroup.

In some embodiments of any of formulas II, IIa and IIb, each R6, R7, R8, R9and R10independently represents hydrogen; fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; IU is exitonerror; hydroxyethoxy; hydroxymethyl or hydroxyethyl.

In some embodiments of any of formulas II, IIa and IIb, each R6, R7, R8, R9and R10independently represents hydrogen; fluorine; chlorine; bromine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl or cyclopropylmethoxy.

In some embodiments of any of formulas II, IIa and IIb, R7and R10denote hydrogen.

In some embodiments of any of formulas II, IIa and IIb, R7, R8and R10denote hydrogen.

In some embodiments of any of formulas II, IIa and IIb, R6denotes hydrogen; halogen or C1-C6-alkyl.

In some embodiments of any of formulas II, IIa and IIb, R6denotes halogen or C1-C6-alkyl.

In some embodiments of any of formulas II, IIa and IIb, R6denotes halogen or methyl.

In some embodiments of any of formulas II, IIa and IIb, R6denotes bromine, chlorine or methyl.

In some embodiments of any of formulas II, IIa and IIb, R6denotes bromine or methyl.

In some embodiments of any of formulas II, IIa and IIb, R6denotes methyl.

In some of the options which the exercise of any of formulas II, IIa and IIb, R8denotes hydrogen; a methoxy group; halogen; methyl or dipterocarp.

In some embodiments of any of formulas II, IIa and IIb, R8denotes hydrogen, methoxy group or halogen.

In some embodiments of any of formulas II, IIa and IIb, R8denotes hydrogen.

In some embodiments of any of formulas II, IIa and IIb, R9denotes a methoxy group; hydrogen; 2-hydroxyethoxy; 2-methoxyethoxy; 1-hydroxyethyl or cyclopropylmethyl.

In some embodiments of any of formulas II, IIa and IIb, R9denotes a methoxy group; hydrogen; 2-hydroxyethoxy; 2-methoxyethoxy; 1-hydroxyethyl; cyclopropylmethyl or 5 - or 6-membered heteroaryl selected from the group comprising: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments of any of formulas II, IIa and IIb, R9denotes a methoxy group; 2-hydroxyethoxy or 5 - or 6-membered heteroaryl selected from the group comprising: pyrrolyl; pyrazolyl triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl; halogen; C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments of any of formulas II, IIa and IIb, R9denotes a methoxy group; 2-hydroxyethoxy or 5 - or 6-membered heteroaryl selected from pyrazolyl and pyridazinyl where this pyrazolyl and pyridazinyl optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, halogen or hydroxy-C1-C6-alkyl.

In some embodiments of any of formulas II, IIa and IIb, R9denotes a methoxy group; 2-hydroxyethoxy; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl; 5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl; 5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl; 6-oxo-1-methylpyridin-5-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 6-oxo-1H-pyridazin-3-yl or 6-oxo-1H-pyridazin-5-yl.

In some embodiments of any of formulas II, IIa and IIb, R9denotes a methoxy group; 2-hydroxyethoxy; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-the l; 4,5-dimethyl-4H-[1,2,4]triazole-3-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl; 2H-pyrazole-3-yl; 1-((R)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 4-((R)-2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-Il; 6-oxo-6N-pyridazin-1-yl; 3-methyl-6-oxo-6N-pyridazin-1-yl; 6-oxo-1,6-dihydropyridin-2-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 1-((S)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 2-ethyl-3-oxo-2,3-dihydropyridin-4-yl); 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 6-oxo-1,6-dihydropyridin-3-yl; 2-((R)-2-hydroxy-3-methoxypropyl)-3-oxo-2,3-dihydropyridin-4-yl; 2-oxopyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidine-1 -; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxypyridazine-3-yl; 2,6-dioxo-3,b-dihydro-2H-pyrimidine-1-yl or 4-((R)-2-hydroxy-3-methoxypropyl)-2H-[1,2,4]triazine-3,5-dione]-1-yl.

In some embodiments of any of formulas II, IIa and IIb, p is 0, 1 or 2.

In some embodiments of any of formulas II, IIa and IIb, p is 1 or 2.

In some embodiments of any of formulas II, IIa and IIb, p is 1.

In some embodiments of any of formulas II, IIa and IIb, each R11independently denotes a halogen; C1-C6-alkyl or C1-C6-alkoxygroup.

In some embodiments of any of formulas II, IIa and IIb, each R11illegal is isimo denotes fluorine or methyl.

In some embodiments of any of formulas II, IIa and IIb, R11denotes halogen.

In some embodiments of any of formulas II, IIa and IIb, R11denotes fluorine.

In some embodiments of any of formulas II, IIa and IIb p is 1 and R11denotes halogen.

In some embodiments of any of formulas II, IIa and IIb p is 1 or 2 and R11denotes halogen.

In some embodiments of any of formulas II, IIa and IIb p is 1 and R11denotes a 3-halo or 4-halogen.

In some embodiments of any of formulas II, IIa and IIb p is 1 and R11denotes fluorine.

In some embodiments of any of formulas II, IIa and IIb p is 1 and R11denotes 3-fluoro or 4-fluoro.

In some embodiments of any of formulas II, IIa and IIb p is 1 and R11denotes 4-fluoro.

In some embodiments, the implementation is more preferable if the compounds of formula I can be described by formula III

in which X, R5, R6, R8and R9are as defined in the present invention.

In some embodiments, the implementation of formula III is more preferable if the compounds proposed in the present invention, may be described by formula IIIa or formula IIIb

;

in which X, R5, R6, R7and R8are as defined in the present invention.

In some embodiments, the communication proposed in the present invention are described by formula IIIa.

In some embodiments, the communication proposed in the present invention are described by formula IIIb.

In some embodiments of any of formulas III, IIIa and IIIb, R6denotes halogen; methyl or ethyl.

In some embodiments of any of formulas III, IIIa and IIIb, R6denotes methyl.

In some embodiments of any of formulas III, IIIa and IIIb, R6denotes ethyl.

In some embodiments of any of formulas III, IIIa and IIIb, R6denotes bromine.

In some embodiments of any of formulas III, IIIa and IIIb, each R8and R9independently represents fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; trifluoromethyl; dipterocarp; methanesulfonyl; cyano; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl or hydroxypropoxy.

In some embodiments of any of formulas III, IIIa and IIIb, R8denotes hydrogen; a methoxy group; halogen; methyl or dipterocarp.

In some embodiments, the implementation of the of any of formulas III, IIIa and IIIb, R8denotes hydrogen, methoxy group or halogen.

In some embodiments of any of formulas III, IIIa and IIIb, R8denotes hydrogen.

In some embodiments of any of formulas III, IIIa and IIIb, R8denotes a methoxy group.

In some embodiments of any of formulas III, IIIa and IIIb, R8denotes chlorine.

In some embodiments of any of formulas III, IIIa and IIIb, R8denotes fluorine.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes a methoxy group; 2-hydroxyethoxy; 2-methoxyethoxy; 1-hydroxyethyl or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes a methoxy group; 2-hydroxyethoxy or 5 - or 6-membered heteroaryl selected from the group comprising: pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl each of which is optionally substituted 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes a methoxy group.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes 2-hydroxyethoxy.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes 2-methoxyethoxy.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes 1-hydroxyethyl.

In some embodiments of any of formulas III, IIIa and IIIb, R9denotes a 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl or hydroxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9means pyrrolyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; With1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6the alkyl or hydroxy-C 1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9means pyrazolyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9means triazolyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl; CC1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9represents pyridinyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9denotes pyrimidinyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; Hydra is XI-C 1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9denotes pyrazinyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9denotes pyridazinyl, optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9denotes triazinyl, each optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9represents 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 4,5-dimethyl-4H-[1,2,4]triazole-3-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl; 2H-pee the azole-3-yl; 1-((R)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 4-((R)-2-hydroxy-3-methoxypropyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 6-oxo-bn-pyridazin-1-yl; 3-methyl-6-oxo-6N-pyridazin-1-yl; 6-oxo-1,6-dihydropyridin-2-yl; 2-methyl-3-oxo-2,3-dihydropyridin-4-yl); 4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazine-2-yl; 1-((S)-2-hydroxy-3-methoxypropyl)-5-methyl-1H-pyrazole-3-yl; 2-ethyl-3-oxo-2,3-dihydropyridin-4-yl); 1-methyl-6-oxo-1,6-dihydropyridin-3-yl; 6-oxo-1,6-dihydropyridin-3-yl; 2-((R)-2-hydroxy-3-methoxypropyl)-3-oxo-2,3-dihydropyridin-4-yl; 2-oxopyrrolidin-1-yl; 2,4-dioxo-3,4-dihydro-2H-pyrimidine-1 -; 3-methyl-2-oxo-2H-pyridin-1-yl; 2-oxo-2H-pyridin-1-yl; 6-methoxypyridazine-3-yl; 2,6-dioxo-3,6-dihydro-2H-pyrimidine-1-yl or 4-((R)-2-hydroxy-3-methoxypropyl)-2H-[1,2,4]triazine-3,5-dione]-1-yl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9denotes a methoxy group; 2-hydroxyethoxy or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl, each of which is optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl; halogen; C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl or hydroxy-C1-C6-alkoxy-C1-C6-alkyl.

In some embodiments, Khujand the exercise of, in any of formulas III, IIIa and IIIb, R9denotes a methoxy group; 2-hydroxyethoxy or 5 - or 6-membered heteroaryl selected from the group comprising pyrazolyl and pyridazinyl where this pyrazolyl and pyridazinyl optionally substituted by 1, 2 or 3 groups independently selected from a carbonyl group; C1-C6-alkyl, halogen or hydroxy-C1-C6-alkyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R9denotes a methoxy group; 2-hydroxyethoxy; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl; 5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl; 5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl; 6-oxo-1-methylpyridin-5-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 6-oxo-1H-pyridazin-3-yl or 6-oxo-1H-pyridazin-5-yl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R6denotes bromine or methyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R6denotes a methoxy group; 2-hydroxyethoxy; 2-methoxyethoxy or 1-hydroxyethyl.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R11denotes halogen.

In some embodiments, the implementation of any of formulas III, IIIa and IIIb, R11denotes fluorine.

If any of R1 , R2, R3, R4, R5, R6, R7, R8, R9, Ra, Rb, Rc, Rdor Redenotes alkyl or contains an alkyl fragment, such alkyl is preferably ness. alkyl, i.e., C1-C6-alkyl, and in many cases implementation of C1-C4-alkyl.

The present invention also relates to methods for treating diseases or pathological conditions mediated by receptor RH7or otherwise associated with, which includes an introduction to the needy in this subject compounds proposed in the present invention, in an effective amount.

The present invention also relates to methods of treatment of inflammatory, respiratory pathological condition or diabetes, which includes an introduction to the needy in this subject compounds proposed in the present invention, in an effective amount together with the inhibitor RH in an effective amount.

The disease may be an inflammatory disease, such as arthritis, and more preferably rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, hypersensitivity of the respiratory tract, septic shock, glomerulonephritis, irritable bowel syndrome and Crohn's disease.

Ill the of can be a pain, such as inflammatory pain; operating pain; visceral pain; tooth pain; premenstrual pain, Central pain, pain caused by burns; migraine or severe attacks of headache with periodic relapses; pain when nerve damage; pain neuritis; neuralgia; pain in case of poisoning; pain in ischemic lesion, pain in interstitial cystitis; pain in cancer; pain, viral, parasitic or bacterial infection, post-traumatic pain or pain associated with irritable bowel syndrome.

The disease can be respiratory disturbance, such as chronic obstructive pulmonary disease (COPD), asthma or bronchospasm, or gastrointestinal (LCD) violation, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hepatic colic and other hepatic disorders, renal colic, diarrhea-dominant IBS, the pain associated with stretching of the LCD.

The disease can be diabetes.

The present invention also relates to the use of compounds proposed in the present invention, for preparing a medicinal product intended for the treatment of inflammatory diseases such as arthritis, and more preferably rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive dis is evanie lungs, hypersensitivity of the respiratory tract, septic shock, glomerulonephritis, irritable bowel syndrome and Crohn's disease.

The present invention also relates to the use of compounds proposed in the present invention, for preparing a medicinal product intended for the treatment of respiratory disorders such as chronic obstructive pulmonary disease (COPD), asthma or bronchospasm, or gastrointestinal (LCD) disorders, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hepatic colic and other hepatic disorders, renal colic, diarrhea-dominant IBS, the pain associated with stretching of the LCD.

The present invention also relates to the use of compounds proposed in the present invention, for preparing a medicinal product intended for the treatment of inflammatory disorders.

The present invention also relates to the use of compounds proposed in the present invention, for the treatment of inflammatory diseases such as arthritis, and more preferably rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, hypersensitivity of the respiratory tract, septic shock, glomerulonephritis, irritable bowel syndrome and disease CROs is A.

Typical compounds obtained by the methods proposed in the present invention, are shown in table 1.

TABLE 1

No.StructureName (Autonom)M+HpIC50
1(2-Bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)Amin4307,25
2(5-Atelinae-6-yl)-[5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl]amine3887,52
3(7-Atelinae-6-yl)-[5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl]amine3886,875
4(4,5-Dimethoxy-2-were)-[(S)-5-(-forfinal)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl]-amine 3837,98
5(2-Bromo-4,5-acid)-[5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine4507,775

No.StructureName (Autonom)M+HpIC50
62-{2-Chloro-5-[5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]-triazolo[4,3-a]pyridine-3-ylamino]-4-methylphenoxy}-ethanol4186,99
7(2-Bromo-4,5-acid) (7,7'-spiration-deoxy-5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)Amin4886,2
8(5-Atelinae-6-yl)-[(S)-5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]p is ridin-3-yl]amine 3887,693
9(5-Atelinae-6-yl)-[(R)-5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl]amine3885,17
10(2-Bromo-4,5-acid)-[5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-thiazin-3-yl]amine4667,625
11(6-Methylinosine-5-yl)-((R)-5-phenyl-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-yl)Amin3587,442

449
No.StructureName (Autonom)M+HpIC50
12(2-Bromo-4,5-acid)-[(S)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]amine450 5,1167
13(2-Bromo-4,5-acid)-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine450of 7.75
14[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-[2-methyl-5-(5-methyl-1H-pyrazole-3-yl)phenyl]amine405a 7.62
152-{2-Chloro-5-[(S)-5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]-triazolo[4,3-a]pyridine-3-ylamino]-4-methylphenoxy}-ethanol4177,133
16(2-Bromo-4,5-acid)-[5-(4-forfinal)-7-oxo-5,6,7,8-tetrahydro-7λ4-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine4827,4167
17(2-Bromo-4,5-acid)-[5-(4-forfinal)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-amine7,3267

No.StructureName (Autonom)M+HpIC50
18(4,5-Dimethoxy-2-were)-[5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine4017,58
19(4,5-Dimethoxy-2-were)-[5-(4-forfinal)-7,7-dioxo-5,6,7,8-tetrahydro-7λ6-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine433of 6.96
20[5-(3-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-quinoline-5-ylamine3626,987
212-{2-Chloro-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}ethanol420 to 7.59
22[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-[2-methyl-5-(4-methylpyrazole-1-yl)phenyl]amine4057,855
23(4,5-Dimethoxy-2-were)-[5-(4-forfinal)-5-methyl-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine3996,9

/tr>
No.StructureName (Autonom)M+HpIC50
241-[3-(2-Bromo-4,5-dimethoxyaniline)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-alanon4916,945
25[5-(3-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-(6-methylinosine-5-yl)Amin3767,735
26(2-Bromo-4,5-acid)-[5-(4-forfinal)-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]amine463to 7.32
27[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-(2-methylinosine-5-yl)Amin3766,76
287-Chloro-4-[5-(3-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-2-((R)-2-hydroxy-1-methylethyl)-2,3-dihydroindol-1-he4595,625
292-{2-Chloro-5-[5-(3-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]oxazin-3-ylamino]-4-methylphenoxy}ethanol4207,13

No.StructureName (Autonom)M+HIC 50
302-(3-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-5-methylpyrazole-1-yl)ethanol4497,735
31(R)-1-(3-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-5-methylpyrazole-1-yl)-propan-2-ol4637,45
32(R)-3-(3-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-5-methylpyrazole-1-yl)-propane-1,2-diol4797,5475
33(R)-1-(3-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-5-methylpyrazole-1-yl)-3-methoxypropan-2-ol4937,56
34(S)-1-(3-{3-[(R)-5-(4-FPO is phenyl)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-5-methylpyrazole-1-yl)-propan-2-ol 4637,4

No.StructureName (Autonom)M+HpIC50
35(S)-3-(3-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-5-methylpyrazole-1-yl)-propane-1,2-diol4797,755
36[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-(6-methylinosine-5-yl)Amin3767,87
374-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-2-methyl-2H-pyridazin-3-one4337,865
385-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-6-m is Teal-1 H-quinoline-2-he 3927,46
392-{6-[(R)-5-(4-Forfinal)-5,b-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-5-methylindol-1-yl}-ethanol4097,605
402-(3-{4-Chloro-3-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-phenyl}-5-methyl-pyrazole-1-yl)ethanol4707,54

No.StructureName (Autonom)M+HpIC50
416-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-2H-pyridazin-3-one4197,665
425-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo [3,4-C][1,4]-oxazin-3-ylamino]-2H-ftal the Zin-1-he 3796,135
434-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-2H-pyridazin-3-one4198,28
442-{2-Chloro-5-[(R)-5-(3-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-methylphenoxy}-ethanol4207,6
452-{2-Chloro-5-[(S)-5-(3-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-methylphenoxy}-ethanol420
462-{2-Chloro-5-[(R)-5-(4-forfinal)-5,b-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-thiazin-3-ylamino]-4-methylphenoxy}-ethanol436

No.StructureName (Autonom) M+HpIC50
472-{2-Chloro-5-[(5R,7R)-5-(4-forfinal)-7-oxo-5,6,7,8-tetrahydro-7λ*4*-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-ylamino]-4-methylphenoxy}ethanol4527,705
486-Bromo-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-2H-phthalazine-1-he458EUR 7.57
494-{4-Bromo-3-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-phenyl}-2H-pyridazin-3-one4848,2
502-{2-Chloro-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-Ramapo]-4-were}-2H-pyridazin-3-one4547,17
514-{3-[(R)-5-(4-Forfinal)-5,6-dihydr is-8H-[1,2,4]-triazolo[3,4-C][1,4]-thiazin-3-ylamino]-4-were}-2-methyl-2H-pyridazin-3-one 4498,16

No.StructureName (Autonom)M+HpIC50
524-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-2-(2-hydroxyethyl)-2H-pyridazin-3-one4638,09
534-{4-[(R)-5-(4-Forfinal)-7,7-dioxo-5,6,7,8-tetrahydro-7λ6-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-ylamino]-3-were}-2-methyl-2H-pyridazin-3-one481
541-{4-Bromo-3-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-phenyl}tetrahydro-pyrimidine-2-he4887,325
554-{4-Fluoro-3-[(R)-5-(4-forfinal)-5,6-dihydr is-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-phenyl}-2-methyl-2H-pyridazin-3-one 437to $ 8.035
562-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-4-methyl-2H-[1,2,4]-triazine-3,5-dione484

No.StructureName (Autonom)M+HpIC50
573-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-c][1,4]-oxazin-3-ylamino]-4-were}-1-methyl-1H-pyridine-2-he432
582-{3-Fluoro-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-2H-pyridazin-3-one437
592-{2-Fluoro-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin--ylamino]-4-were}-2H-pyridazin-3-one 437
604-Ethyl-2-{3-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-2H-[1,2,4]triazine-3,5-dione464
611-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-1H-pyridine-2-he418

No.StructureName (Autonom)M+HpIC50
622-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-C][1,4]-oxazin-3-ylamino]-4-were}-4-((R)-2-hydroxy-3-methoxypropyl)-2H-[1,2,4]triazine-3,5-dione524
634-{3-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]-triazolo[3,4-is][1,4]-thiazin-3-ylamino]-4-were}-2H-pyridazin-3-one 435
644-{3-[(R)-5-(4-Forfinal)-7-oxo-5,6,7,8-tetrahydro-7λ4-[1,2,4]triazolo-[3,4-C] [1,4]-thiazin-3-ylamino]-4-methyl-phenyl}-2H-pyridazin-3-one451
654-{3-[(R)-5-(4-Forfinal)-7-oxo-5,6,7,8-tetrahydro-7λ4-[1,2,4]triazolo-[3,4-C] [1,4]thiazin-3-ylamino]-4-methyl-phenyl}-2-methyl-2H-pyridazin-3-one465
664-{3-[(S)-5-(4-Forfinal)-5,6,7,8-tetrahydro-[1,2,4]-triazolo[4,3-a]-pyridine-3-ylamino]-4-were}-2H-pyridazin-3-one417

Synthesis

Connections proposed in the present invention, can be obtained using a variety of methodologies presented in the illustrative schemes of synthesis reactions described below.

Source materials and reagents used in obtaining these compounds, typically purchase from suppliers such as Aldrich Chemical Co., or get them by the techniques known to experts in the Noah engineering procedures described in the literature, such as Fieser and Fieser''s Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd''s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following scheme of reactions of synthesis are merely illustrations of some methods that can synthesize compounds proposed in the present invention, and in these schemes reactions of synthesis it is possible to make various changes, which should offer the specialist in the art based on the disclosure contained in this application.

Source materials and intermediate products for the synthesis reactions, if necessary, can be extracted and cleaned by conventional methods, including, but not limited to, filtration, distillation, crystallization, chromatography, etc., Such substances can be characterized using conventional means, including determination of the physical characteristics and obtaining spectral data.

Unless otherwise stated, the reactions described in the present invention, preferably in an inert atmosphere at atmospheric pressure and in the temperature range from about -78 to about 150°C., more preferably from about 0 to about 125°C., and most preferably and conveniently at a temperature close to the room temperature (or ambient temperature), for example, primer is at 20°C.

The following diagram And illustrates one method of synthesis of specific compounds of formula I in which Z denotes useplease group, and X, R1, R2and R3are as defined in the present invention.

In stage 1 scheme a heterocyclic ketone is treated with pentasulfide phosphorus and receive appropriate tionb. In stage 2, heterocyclisationbenter into the reaction of S-alkylation with an alkylating reagent RZ and get tiomincin the form of a salt with useplease group z On stage 3 tiomincenter into reaction with aridsemiariddand get semicarbazonee. Aridsemiariddcan be obtained by processing the corresponding arylamine with phosgene or phenylcarbamates, then with hydrazine as described in the following experimental examples. Stage 4 semicarbazoneeenter in the cyclization reaction in the presence of dichlorotriphenylphosphorane and receive triazolefthat is a compound of formula I proposed in the present invention.

There are many options the methodology presented in scheme A, and they should be obvious to a person skilled in the art. Specific details of obtaining compounds proposed in the present invention, described in given the nom lower section, devoted to examples.

Application

Connections proposed in the present invention, applicable to the treatment of a wide range of inflammatory diseases and pathological conditions, such as arthritis, including, but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and observed in children with chronic arthritis, osteoarthritis, gouty arthritis and other arthritic pathological condition. Connections proposed in the present invention should be applicable for the treatment of lung disorders or inflammation of the lungs, including respiratory distress syndrome in adults, pulmonary sarcoidosis, asthma, silicosis, and chronic inflammatory disease of the lungs.

It is also assumed that the compounds proposed in the present invention, can be used as analgesics in the treatment of diseases and pathological conditions involving pain, resulting from a variety of reasons, including, but not limited to, inflammatory pain, such as pain associated with arthritis (including rheumatoid arthritis and osteoarthritis), operational pain, visceral pain, dental pain, premenstrual pain, Central pain, pain due to burns, migraine or severe attacks of headache with the periods of the practical relapses, pain, nerve damage, pain, neuritis, neuralgia, pain caused by poisoning, pain with ischemic lesions, pain in interstitial cystitis, pain and cancer pain, pain caused by viral, parasitic or bacterial infection, post-traumatic pain (including fractures and sports injuries) and the pain associated with functional bowel disorders such as irritable bowel syndrome.

In addition, the compounds proposed in the present invention, applicable for the treatment of respiratory disorders, including chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, etc.,

In addition, the compounds proposed in the present invention, applicable to the treatment of gastrointestinal disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), hepatic colic and other hepatic disorders, renal colic, diarrhea-dominant IBS, the pain associated with stretching LCD, etc.

Connections proposed in the present invention are also applicable for the treatment of muscular sclerosis and diabetes.

Introduction and pharmaceutical composition

The present invention includes pharmaceutical compositions containing at least one connection proposed in the present invention, or individual isomers, racemic or prizemistuyu a mixture of isomers or its farmaci is almost acceptable salt or MES together with at least one pharmaceutically acceptable carrier and optionally other therapeutic and/or prophylactic ingredients.

Usually connections proposed in the present invention, is administered in therapeutically effective amounts via any of the accepted route of administration of drugs that provide similar effects. Suitable dose ranges are usually 1-500 mg, preferably 1-100 mg per day and most preferably 1-30 mg / day depending on many factors such as the severity of treated disease, the age and relative health of the subject, the activity of the used connection path and shape of the sign, which directed the introduction, and the preference and experience of the practitioner. Specialist with General training in the art in the treatment of such diseases without undue experimentation and based on personal preparation and disclosure of this application must be able to determine a therapeutically effective amount of the compounds proposed in this invention for treatment of this disease.

Usually connections proposed in the present invention can be typed into the form of pharmaceutical preparations, including preparations suitable for oral (including transbukkalno and sublingual), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, vnutriarterialno is inoe, vnutriobolochechnoe, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred route of administration is generally oral with suitable daily dosing regime, which can be selected in accordance with the severity of the disease.

The connection or connections proposed in the present invention, together with one or more conventional excipients, carriers or diluents can be made in the form of pharmaceutical compositions and single dosage forms. Pharmaceutical compositions and single dosage forms may include conventional ingredients in conventional amounts with or without adding additional active compounds or active ingredients and one-time dosage forms may contain any suitable effective amount of the active ingredient corresponding to the applicable daily dosing range. The pharmaceutical compositions can be used in the form of solids, such as tablets or filled capsules, semi-liquid substances, powders, compositions prolonged action, or in the form of liquids, such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration; or in the form of suppositories for rectal or in the original introduction; or in the form of sterile injectable solutions intended for parenteral administration. Drugs, containing approximately one (1) milligram of active ingredient or, more broadly, from about 0.01 to about one hundred (100) milligrams per tablet, respectively, are suitable typical single dosage forms.

Connections proposed in the present invention, can be prepared in the form of various dosage forms intended for oral administration. Pharmaceutical compositions and dosage forms as an active ingredient may include a connection or connections proposed in the present invention, or their pharmaceutically acceptable salts. Pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, pills, suppositories and dispergirujutsja granules. A solid carrier can be one or more substances which may also act as diluents, flavoring substances, solubilization, lubricants, suspendida substances, binders, preservatives, substances, providing raspadaemost tablets, or kapsulirujushchej material. In powders, the carrier is usually a powdered solid substance that forms a mixture with concistently the active component. In tablets, the active component generally in suitable proportions mixed with carrier having the necessary binding capacity, and pressed into the desired shape and size. Preferably, if the powders and tablets contain from about one (1) to about seventy (70) percent of the active compounds. Suitable carrier materials include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc. is Understood that the term "drug" includes a composition of active compounds with kapsulirujushchej material as the carrier with the formation of capsules in which the active ingredient with the carriers, or without them, is surrounded by media that is associated with it. Similarly, enabled wafers and cakes. Tablets, powders, capsules, pills, wafers and cakes can be a solid form suitable for oral administration.

Other forms suitable for oral administration include liquid forms of drugs, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended for carried out shortly before the introduction of the transformations in liquid form preparations, Emulsions can be prepared in solutions, for example, in aqueous solutions of propylene glycol, or they may contain emulsifying agents, such as lecithin, servicemanual or gum acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickening agents. Aqueous suspensions can be prepared by dispersing finely ground active ingredient in water containing a viscous substance such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose and other well-known suspendresume substances. Solid form preparations include solutions, suspensions and emulsions, and in addition to the active component may contain colorants, flavors, stabilizers, buffer substances, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, etc.,

Connections proposed in the present invention, can be prepared for parenteral administration (e.g. by injection, such as injection loading dose of the substance or continuous infusion) and may be prepared in the form of a single dosage form in ampoules, pre-filled syringes intended for infusion containers of small volume or containing plural the creation of the dose containers with an added preservative. The composition can be in such forms as suspensions, solutions or emulsions in oily or aqueous solvents, for example in the form of solutions in an aqueous solution of polyethylene glycol. Examples of oil and nonaqueous carriers, diluents, solvents and excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and is suitable for injection of organic esters (for example, etiloleat) and they can include forming compositions of substances, such as preserving, wetting, emulsifying or suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic allocation of sterile solid or by lyophilization from solution, for pre-application recovery using a suitable diluent, such as sterile pyrogen-free water.

Connections proposed in the present invention, it is possible to prepare for the local introduction of the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be prepared in water or oil based by the addition of suitable thickening and/or gelling agents. Lotions can be prepared in water or oil based and they also usually contain Odie is or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickening agents, or coloring agents. Drugs applicable for local introduction into the oral cavity include the pellet containing the active tool in giving a taste basis, usually sucrose, gum acacia or tragacanth gum; lozenges contain the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum acacia; and means for mouthwash contain the active ingredient in a suitable liquid carrier.

Connections proposed in the present invention, can be prepared for administration in the form of suppositories. First melt the low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, and the active ingredient is uniformly dispersed, for example, by stirring. The molten homogeneous mixture is then poured into forms appropriate size, allow it to cool and harden.

Connections proposed in the present invention, it is possible to prepare for vaginal administration. Suitable are pessaries, tampons, creams, gels, pastes, foams or aerosol preparations containing, in addition to the active ingredient such carriers which are known in the art.

Connections proposed in the present invention, can be prepared for nasal introduction is. The solution or suspension is injected directly into the nasal cavity by conventional means, such as a dropper, pipette or spray. The preparations can be prepared as a single dose or in mnogochasovoj form. In the latter case, use a dropper or pipette, this can be done by injecting the patient with a suitable predetermined volume of solution or suspension. In the case of spraying can be done, for example, by using a metering spray pump.

Connections proposed in the present invention, can be prepared for administration in the form of aerosol, especially in the respiratory tract and including vnutripuzarnoe introduction. The connection typically has particles of small size, such as about five (5) microns or less. Particles of this size can be obtained by methods known in the art, for example by micronisation. The active ingredient comes in the package under pressure with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Aerosol usually may also contain a surfactant such as lecithin. The dose of the drug can be controlled using a metering valve. Alternatively, the active ingredients which may be supplied as a dry powder, for example a powder mix of the compound with a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). Powdered media will form a gel in the nasal cavity. The powdered composition may be supplied as a single dose, for example, capsules or cartridges, for example, gelatin or blister packs from which the powder can be entered using the inhaler.

If necessary, the preparations can be prepared with intersolubility coating, suitable for prolonged or controlled introduction of the active ingredient. For example, the compounds proposed in the present invention, can be placed in the device for percutaneous or subcutaneous drug delivery. Such devices delivery are preferred when it is necessary prolonged action of the connection and when it is crucial to patient compliance with the treatment regimen. System for percutaneous delivery containing compounds, often attached to the adhesive to the skin of the solid substrate. Required connection can also be combined with means increasing permeability, such as azone (1-dodecylsulfate-2-one). Delivery system with prolonged action enter PADCO what about in the subdermal layer surgically or by injection. Subcutaneous implant contains a compound encapsulated in a soluble in the lipid membrane, such as silicone rubber, or a biologically decomposable polymer, such as polylactic acid.

Preferably, the pharmaceutical preparations consisted of a single dosage form. In such form the preparation is divided into single doses containing appropriate quantities of the active component. Single dosage form can be a packaged preparation, the package contains a specific quantity of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. Single dosage form can be a capsule, tablet, wafer or toffee or it can represent an appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their composition are described in the publication Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. Typical pharmaceutical preparations containing the compound proposed in the present invention, is described below.

EXAMPLES

Below, the method and examples are provided to the specialist in the art could understand and implement the present invention. They should not be considered limiting the volume of the present invention, as merely illustrative and typical.

Unless otherwise indicated, all temperatures, including the melting temperature (i.e., tpl.)given in degrees Celsius (°C). It should be understood that the reaction that leads to a specific and/or desired product, does not necessarily lead to him directly based on the combination of two reagents that were added initially, i.e., can be one or more intermediates which are formed in the mixture and which ultimately lead to the formation of the specified and/or the desired product. In the syntheses and examples can use the following abbreviations.

ABBREVIATIONS

BETBDMS2 bromoethoxy-tert-butyldimethylsilyl
DBU1,8-diazabicyclo[5.4.0]undec-7-EN
DHMdichloromethane/methylene chloride
DIPEAdiisopropylethylamine (base Chunga)
DME1,2-dimethoxyethane (glyme)
DMFN,N-dimethylformamide
DMF·DMA dimethylacetal N,N-dimethylformamide
DMSOthe sulfoxide
DMAP4-dimethylaminopyridine
dppf1,1'-bis(diphenylphosphino)ferrocene
EDCI1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
EtOActhe ethyl acetate
EtOHethanol
GCgas chromatography
GATAO-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylpropylenediamine
GMFAhexamethylphosphoramide
HOAcacetic acid
HOBtN-hydroxybenzotriazole
HPLChigh performance liquid chromatography
IPSisopropyl alcohol
BEYPBCpinacoline ether and is propenylboronic acid
MJPBKm-chloroperbenzoic acid
MeCNacetonitrile
NMMN-methylmorpholin
NMPN-methylpyrrolidinone
Pd2(dba)3Tris(dibenzylideneacetone)dipalladium(0)
TBAFTetra-n-butylammonium
tBDMSICltert-butyldimethylsilyloxy
The teathe triethylamine
TFKtriperoxonane acid
THFtetrahydrofuran
GAVEdiisopropylamide lithium
TBDMStert-butyldimethylsilyloxy
thosethin-layer chromatography
Xantphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Synthesis of 1

(R)-3-(4-Forfinal)--[1,2,4]triazole-1-yl-3,6-dihydro-2H-[1,41 oxazin

The methodology used in this synthesis is presented in figure C.

Stage 1: (R)-5-(4-Forfinal)-morpholine-3-one

With stirring to a mixture of NaH (1.1 g, 45,7 mmole) and THF (30 ml) in an atmosphere of N3 at room temperature was added dropwise a solution of (R)-2-amino-2-(4-forfinal)-ethanol (5.0 g, to 32.2 mmole) in THF (50 ml). The reaction mixture was stirred at room temperature for 30 min, then was cooled to 0°C. was added dropwise a solution of ethylchloride (4.0 g, 33 mmole) in THF (30 ml) and the reaction mixture was stirred at 0°C for 30 min, then stirred at room temperature for 2 hours the Reaction mixture was concentrated under reduced pressure and to the residue was added water (50 ml). the pH of the resulting mixture was brought up to equal to approximately 6.5 by adding 1 M aqueous HCl and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallize from diethyl ether and received 2,87 g (R)-5-(4-forfinal)-morpholine-3-one. The mother liquor obtained after the recrystallization was concentrated and purified via chromatography (50-70% ethyl acetate in hexano) and received additional 1.0 g of (R)-5-(4-forfinal)-morpholine-3-one.

Stage 2: (R)-3-(4-Forfinal)-5-[1,2,4]triazole-1-yl-3,6-digit what-2H-[1,4]oxazin

A solution of 20 g (0,1025 mol) R-5-(4-forfinal)-morpholine-3-one, 71 g (of 1.03 mol) of 1,2,4-triazole and 86 ml of 0.615 mole) of triethylamine in 480 ml of acetonitrile was stirred and cooled in a bath of ice water. Within 20 min was added dropwise a solution of 19 ml (0,205 mole) of phosphorus oxychloride in 20 ml of acetonitrile, keeping the temperature below 30°C. Then the reaction mixture is boiled under reflux for 1.5 hours the Mixture was cooled to room temperature and was added 35 ml of 0.25 mol) of triethylamine, and then 400 ml of ethyl acetate. The mixture was filtered and concentrated under reduced pressure. The residue was subjected to distribution between 400 ml of ethyl acetate and 80 ml of 10% sodium bicarbonate solution containing 25 ml of a saturated solution of sodium chloride. The organic phase was dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was dissolved in 60 ml of ethyl acetate; this solution was passed through a layer containing 300 ml of neutral aluminum oxide, which is a suspension in a mixture of 50% ethyl acetate-hexane. Then the alumina was suirable with 500 ml of ethyl acetate. The eluate was concentrated under reduced pressure. The residue was recrystallize from ethyl ether and received 17,84 g (R)-3-(4-forfinal)-5-[1,2,4]triazole-1-yl-3,6-dihydro-2H-[1,4]oxazine, tpl.=165-167.

Synthesis of 2

(R)-3-(3-Forfinal)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazin

The methods of the ICA, used in this synthesis is presented in figure C.

Stage 1: (R)-5-(3-Forfinal)-morpholine-3-one

With stirring to a mixture of NaH (900 mg, 37.5 mmole) and THF (25 ml) in an atmosphere of N3 at room temperature was added dropwise a solution of (R)-2-amino-2-(3-forfinal)-ethanol (4.0 g of 26.4 mmole) in THF (25 ml). The reaction mixture was stirred at room temperature for 30 min, then was cooled to 0°C. was added dropwise a solution of ethylchloride (of 3.31 g, 27 mmol) in THF (10 ml) and the reaction mixture was stirred at 0°C for 25 min, then stirred at room temperature for 2 hours the Reaction mixture was concentrated under reduced pressure and the residue was subjected to distribution between ethyl acetate and a mixture of brine and water part 1:1. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was recrystallize from diethyl ether and received 1.73 g (34%) of (R)-5-(3-forfinal)-morpholine-3-OHB. tpl.=119-121°C.

Stage 2: (R)-5-(3-Forfinal)-morpholine-3-tion

Under stirring at room temperature to a suspension P4Sio (6.0 g, a 13.4 mmole) and Na2CO3(1.42 g, a 13.4 mmole) in THF (40 ml) was slowly added a solution of (R)-5-(3-forfinal)-morpholine-3-one (2.16 g, 11.1 mmole) in THF (30 ml). The mixture was stirred at room temperature for 2 h and then the reaction OST nawiliwili by adding 10% aqueous solution of Na 2PO4(50 ml). The mixture was stirred for another 5 min and then were extracted with a mixture of ethyl acetate and diethyl ether composition of 1:1. The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographically through silica gel using a solvent mixture of 15-30% ethyl acetate/hexane in gradient mode and obtained 1.84 g (78%) of (R)-5-(3-forfinal)-morpholine-3-thione in the form of a white solid, tpl.=124-125°C.

Stage 3: (R)-3-(3-Forfinal)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazin

At room temperature to a solution of (R)-5-(3-forfinal)-morpholine-3-thione (128 mg, and 0.61 mmole) in methylene chloride (5 ml) in an atmosphere of N2added metalcraft (0.2 ml, or 1.77 mmole). The reaction mixture was stirred at room temperature for 30 min, then concentrated under reduced pressure and obtained crude (R)-3-(3-forfinal)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]oxazin as triflate, which was directly used without further purification.

Synthesis of 3

3-(4-Forfinal)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazin

The methodology used in this synthesis is presented in figure D.

Step 1: tert-Butyl ether [1-(4-forfinal)-2-hydroxyethyl]-carbamino acid

Under stirring at room temperature to dissolve the 2-amino-2-(4-forfinal)-ethanol (15,4 g, 99,2 mmole) in THF (150 ml) was added di-tert-BUTYLCARBAMATE (23 g, 105 mmol), followed by tea (14 ml, 101 mmol). The reaction mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The residue was subjected to distribution between saturated aqueous sodium bicarbonate and ethyl acetate and the organic phase was separated, washed with saturated aqueous sodium bicarbonate, dried over MgSO4, filtered and concentrated under reduced pressure and got 25,0 g (98%) of tert-butyl methyl ether [1-(4-forfinal)-2-hydroxyethyl]-carbamino acid, tpl.=85-86°C.

Step 2: tert-Butyl ether [1-(4-forfinal)-2-Jodeci]-carbamino acid

At room temperature to a solution of triphenylmethylchloride (1,53 g, 5,85 mmole) in methylene chloride was added iodine (1,481 g, 5,85 mmole). The mixture was stirred for 15 min, then was added imidazole (663 mg, 9,74 mmole). The mixture was stirred for another 15 min, then was added tert-butyl ether [1-(4-forfinal)-2-hydroxyethyl]-carbamino acid (1.0 g, 3.9 mmole). The mixture was boiled under reflux for 2 h, then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was subjected to distribution between ethyl acetate and saturated aqueous sodium thiosulfate. Organic saitgali, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographically through silicon dioxide (5-10% ethyl acetate/hexane) and received 820 mg (58%) of tert-butyl methyl ether [1-(4-forfinal)-2-Jodeci]-carbamino acid, tpl.=138-139°C.

Stage 3: Methyl ester [2-tert-butoxycarbonylamino-2-(4-forfinal)-ethylsulfinyl]-acetic acid

A mixture of tert-butyl methyl ether [1-(4-forfinal)-2-Jodeci]-carbamino acid (3.88 g, 10.6 mmole), methyl ester mercaptohexanol acid (1.24 g, an 11.7 mmole) and potassium carbonate (12,21 g, 18 mmol) in acetone (100 ml) under stirring boiled under reflux for 90 minutes and Then the mixture was cooled and concentrated under reduced pressure. The residue was subjected to distribution between water and ethyl acetate and the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallize from hexanol and got to 3.34 g of methyl ester [2-tert-butoxycarbonylamino-2-(4-forfinal)-ethylsulfinyl]-acetic acid, tpl.=61-62°C.

Stage 4: 5-(4-Forfinal)-thiomorpholine-3-one

A solution of methyl ester [2-tert-butoxycarbonylamino-2-(4-forfinal)-ethylsulfinyl]-acetic acid (3,23 g, 9.4 mmole) in triperoxonane acid (10 ml) was stirred at 50°C for 10 hours Then RA the solution was concentrated under reduced pressure and the residue was subjected to distribution between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure and obtained 2.0 g of 5-(4-forfinal)-thiomorpholine-3-it, tpl.=111-112°C.

Stage 5: 5-(4-Forfinal)-thiomorpholine-3-tion

A mixture of pentasulfide phosphorus (5,12 g, 11.5 mmole) and sodium carbonate (1.22 g, 11.5 mmole) in THF (30 ml) was stirred at room temperature. Was slowly added a solution of 5-(4-forfinal)-thiomorpholine-3-one (2.0 g, 9.5 mmole) in THF (25 ml) and the mixture was stirred at room temperature for 90 minutes the Mixture was diluted with 10% aqueous solution of Na3PO4(40 ml) and stirred at room temperature for 5 minutes the Mixture was extracted with a mixture of ethyl acetate and diethyl ether composition 1:4 and the organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the residue using a layer of silicon dioxide (15-20% ethyl acetate/hexane) gave 1,36 g of 5-(4-forfinal)-thiomorpholine-3-thione, tpl.=107-108°C.

Step 6: 3-(4-Forfinal)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]thiazin

At room temperature to a solution of 5-(4-forfinal)-thiomorpholine-3-thione (710 mg, 3.2 mmole) in THF (20 ml) was added methyliodide (1.1 ml, 16.7 mmole). The mixture was stirred in the dark at room temperature for 18 h, then concentrated under reduced pressure and obtained crude 3-(4-forfinal)-5-ethylsulfanyl-3,6-dihydro-2H-[1,4]thiazin as hydroiodide, which is directly used without further purification.

Synthesis of 4

[6-Phenylpiperidine-(2Z)-ilidene]hydrazine

The methodology used in this synthesis is presented in figure E.

Step 1: Benzyl ether (3-hydroxy-1-phenylpropyl)-carbamino acid

Under stirring at room temperature to a solution of 3-amino-3-phenylpropane-1-ol (36 mmol) in a mixture of EtOAc (60 ml) and aqueous sodium carbonate solution (70 ml of a 1.5 M solution) was added benzylchloride (40 mmol). The reaction mixture was stirred at room temperature for 2 h and then the layers were separated. The organic layer is washed with 5% aqueous HCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting oil was chromatographically (10-60% EtOAc in hexano) and obtained 4.7 g (46%) of the benzyl ether (3-hydroxy-1-phenylpropyl)-carbamino acid as a colourless oil.

Step 2: Benzyl ether (4-oxo-1-phenylbutyl)-carbamino acid

Under stirring at -50°C. to a solution of oxalicacid (1.6 ml, 18.2 mmole) in methylene chloride (20 ml) was added dropwise a solution of DMSO (2,84 g of 36.4 mmole). The resulting mixture was stirred at -50°C for 15 min and the solution was added benzyl ester (3-hydroxy-1-phenylpropyl)-carbamino acid (4.7 g, 16,53 mmole) in methylene chloride (35 ml). The mixture was stirred the ri -50°C for 15 min, then was added tea (11.5 ml, 82,7 mmole). The mixture was stirred at -50°C for 5 min, then stirred at room temperature for 30 minutes, the Reaction mixture was washed with 5% aqueous HCl solution, dried over MgSO4, filtered and concentrated under reduced pressure and obtained 4.7 g (100%) of the benzyl ether (4-oxo-1-phenylbutyl)-carbamino acid in the form of a pale yellow oil.

Stage 3: Methyl ester of 4-benzyloxycarbonylamino-4-phenylalkanoic acid

Under stirring at room temperature to a suspension of LiCl (0.84 g, and 19.8 mmole) in dry acetonitrile (50 ml) was added trimethylphosphate (4 ml, 24,75 mmole). The resulting mixture was stirred for 5 min, then was added tea (2.76 ml of 19.8 mmole). The reaction mixture was stirred for 10 min and then was added a solution of benzyl ether (4-oxo-1-phenylbutyl)-carbamino acid with 16.5 mmole) in acetonitrile (15 ml). The reaction mixture was stirred at room temperature for 18 h, then diluted with diethyl ether and saturated aqueous NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure and the obtained oil was chromatographically (5-40% EtOAc in hexano) and got to 4.41 g (79%) of methyl ester of 4-benzyloxycarbonylamino-4-phenylalkanoic acid in the form of a colourless oil is.

Stage 4: 6-Phenylpiperidine-2-he

Methyl ester of 4-benzyloxycarbonylamino-4-phenylalkanoic acid was dissolved in EtOH (30 ml) was added 10% palladium on activated carbon (1.1 g). The mixture was stirred in hydrogen atmosphere at a pressure equal to 45 pounds-force/inch (3,1 bar)at room temperature for 22 h at 65°C for 4 h the Mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was recrystallize from a mixture of methanol, diethyl ether and hexanol and received 1.85 g (81%) 6-phenylpiperidine-2-it is in the form of colorless crystals.

Stage 5: [6-Phenylpiperidine-(2Z)-ilidene]-hydrazine

With stirring to a solution of 6-phenylpiperidine-2-she (0.35 g, 2 mmole) in methylene chloride (1 ml) under nitrogen atmosphere at 0°C was added metalcraft (0,23 ml, 2 mmole). The reaction mixture was stirred at room temperature for 3 h, then under stirring at 0°C was added to a solution of anhydrous hydrazine (0.5 ml) in methanol (1 ml). The mixture was stirred at room temperature for 3.5 h, then was poured into a mixture of methylene chloride and diethyl ether composition of 1:1. The mixture was washed with 1.5 M aqueous solution of sodium carbonate, dried over anhydrous potassium carbonate, filtered and concentrated under reduced pressure and obtained 0.34 g (90%) [6-phenylpiperidine-(2Z)-ilidene]-hydrazine in the form of a colorless oil.

[6-(4-Forfinal)-piperidine-(Z)-ilidene]-hydrazine was obtained in the same way.

Synthesis of 5

[6-(4-Forfinal)-1H-pyrazin-(2Z)-ilidene]hydrazine

The methodology used in this synthesis is presented in figure F.

Stage 1: 2-Chloro-6-(4-forfinal)-pyrazin

A mixture of 2,6-dichloropyrazine (2,75 g, and 18.3 mmole), 4-ftorhinolonovy acid (2.3 g, of 16.5 mmole) and tetrakis(triphenylphosphine)palladium (0.1 g) in dioxane (50 ml) was stirred at 60°C for 1 h the Mixture was cooled and subjected distribution between water and diethyl ether. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallize from diethyl ether and methanol, and was obtained 1.2 g of 2-chloro-6-(4-forfinal)-pyrazine.

Stage 2: [6-(4-Forfinal)-1H-pyrazin-(2Z)-ilidene]-hydrazine

A mixture of 2-chloro-6-(4-forfinal)-pyrazine (1.0 g, 4.7 mmole) and anhydrous hydrazine (1.5 ml, 47 mmol) in dioxane (20 ml) was boiled under reflux for 2 h, then cooled and diluted with cold water. The precipitate was collected by filtration, washed with cold water and dried and got 0,85 g [6-(4-forfinal)-1H-pyrazin-(2Z)-ilidene]-hydrazine.

Synthesis of 6

5-[2-(tert-Butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine-formation

The methodology used in this synthesis is presented in figure G.

Stage 1: 5-Amino-2-chlorophenol

To dissolve the 2-chloro-5-NITROPHENOL (20,0 g, 115,2 mmole) in ethanol (150 ml) and water (150 ml) was added iron powder (32,2 g, 576,2 mmole) and ammonium chloride (32.1 g, 599,3 mmole). The mixture was boiled under reflux for 2 h, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the residue via flash chromatography (hexane:EtOAc/9:1) gave 5-amino-2-chlorophenol (15,85 g, 96%) as a white solid.

Stage 2: 5-Amino-4-bromo-2-chlorophenol

To a solution of 5-amino-2-chlorophenol (15,85 g, 110,4 mmole) in dichloromethane (300 ml) and Meon (150 ml) was added tetrabutylammonium (58,6 g, 121,4 mmole). The mixture was stirred at room temperature for 20 min and then subjected distribution between saturated aqueous Na2SO3and Et2O. the Organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue via flash chromatography (hexane:EtOAc/7:3) gave 5-amino-4-bromo-2-chlorophenol (of 4.38 g, 18%) as a white solid.

Stage 3: 2-Bromo-5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chlorpheniramine

To a solution of 5-amino-4-bromo-2-chlorophenol (0,338 g, 1.52 mmole) in NMP (5 ml) was added cesium carbonate (0,644 g, 1.97 mmole), sodium iodide (0,228 g, 1.52 mmole) and 2-bromoethoxy-tert-butyldimethylsilyl (0,424 g, 1.97 mmole). The mixture of heat and at 100°C for 2 h, then cooled to room temperature. Added water and the mixture was extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue via flash chromatography (hexane:EtOAc/8:2) gave 2-bromo-5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chlorpheniramine (worn : 0.505 g, 78%) as a white solid.

Stage 4: 5-[2-(tert-Butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine

To a solution of 2-bromo-4-chloro-5 (2-dimethyl-tert-butylsilane)-acetanilide (6.5 g, 17,07 mmole) in a mixture of dioxane (120 ml)-water (12 ml) in an atmosphere of Ar was added potassium carbonate (7,08 g, 51,2 mmole), trimethylboroxine (2,408 ml, 17,07 mmole) and PdCl2(dppf)-CH2Cl2(KZT 1,394 g, 1,707 mmole). The mixture was heated at 110°C for 20 h, then cooled to room temperature and filtered through celite. Added water and EtOAc and the organic layer was separated, washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using flash chromatography (0 to 20% EtOAc in hexano and received 3,66 g of 5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine in the form of a white solid. Recrystallization from EtOAc gave 2.35 g of white crystals.

Stage 5: 5-[2-(tert-Butyldimethylsilyloxy and)-ethoxy]-4-chloro-2-methylphenylethylamine

Phosgene (6 ml, 2 M solution in toluene, 12 mmol) was diluted in diethyl ether (75 ml) and the mixture was stirred at 0°C. Under stirring to the solution was added dropwise a solution of 5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine (3.0 g, 9.5 mmole) and tea (4 ml, 28.6 mmole) in diethyl ether (60 ml). The mixture was stirred at 0°C for 15 min and then filtered directly into a solution of anhydrous hydrazine (98%) in EtOH (50 ml)which was stirred at room temperature. The mixture was stirred at room temperature for 20 min, then concentrated under reduced pressure. The residue was subjected to distribution between water and EtOAc and the organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure and obtained 3.4 g(96%) 5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylhydrazine in the form of a white solid, tpl.=136-137°C.

Synthesis of 7

1-[2-(tert-Butyldimethylsilyloxy')-ethyl]-5-methyl-1H-indazol-6-elementaryaged

The methodology used in this synthesis is presented in figure N.

Stage 1: 5-Methyl-6-nitro-1H-indazol

2,4-Dimethyl-5-nitroaniline (1,662 g, 10.00 mmole) was dissolved in glacial acetic acid (100 ml) and the mixture was cooled to 0°C. was Added a solution of sodium nitrite (1 EQ., 690 mg) in water (2 ml), supports the I temperature below 25°C. Stirring was continued for 3 h and the mixture was filtered. The filtrate was kept at room temperature for 3 days, then concentrated under reduced pressure. The residue was diluted with water and the resulting mixture is vigorously stirred. The solid product was collected by filtration, thoroughly washed with cold water and dried. The product was purified using flash chromatography (99:1 dichloromethane/methanol) and received 1,030 g (58,1%) 5-methyl-6-nitro-1H-indazole in the form of solids.

Stage 2: 1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-6-nitro-1H-indazol

5-Methyl-6-nitro-1H-indazole (354 mg, 2.0 mmole) was dissolved in DMF (10 ml) and the mixture under stirring was cooled to 0°C. was added dropwise hexamethyldisilazane lithium (2.2 ml of 1.0 M solution in toluene). The mixture was stirred for 5 min and then was added (2-bromoethoxy)-tert-butyldimethylsilyl (0,52 ml, 2.4 mmole). The mixture was stirred at 0°C for 30 min, then her under stirring for 4 h, allowed to warm to room temperature. The reaction was stopped by the buffer solution having a pH equal to 2, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified using flash chromatography (gradient mode, from 9:1 to 4:1 hexane/ethyl acetate) and poluchili mg(50,7%) 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole in the form of a white powder.

Stage 3: 1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine

1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-6-nitro-1H-indazole (335 mg, 1.00 mmole) was dissolved in 30 ml of a mixture of ethanol and water part 1:1. To this mixture was added ammonium chloride (108 mg) and iron powder (108 mg). Then the mixture was stirred while boiling under reflux for 2 h, then cooled and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified using flash chromatography (95:5 dichloromethane/methanol) and received 240 mg(78,7%) 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine in the form of a yellowish-brown solid.

Stage 4: 1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-elementaryaged

With stirring, a solution of phosgene (0.5 ml 2M solution in toluene) in diethyl ether (5 ml) was cooled to 0°C. To this solution under stirring was added dropwise a solution of 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine (150 mg, of 0.49 mmole) and tea (0.5 ml, of 3.57 mmole) in diethyl ether (10 ml). The mixture was stirred at 0°C for 10 min and then filtered directly into a solution of anhydrous hydrazine (9%) in EtOH (5 ml), which was stirred at room temperature. Reactio the ing the mixture was stirred for 10 min, then was concentrated under reduced pressure. The residue was subjected to distribution between water and EtOAc and the organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure and received 150 mg of 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1 H-indazol-6-elementaryaged.

Synthesis of 8

2-Bromo-4,5-dimethoxybenzamide

The methodology used in this synthesis is presented in figure I.

Stage 1: 2-Bromo-4,5-dimethoxyaniline

According to the method described in the publication JACS 1996, 118, 1028-1030, 4-aminouracil (a 3.06 g, 20,0 mmole) at room temperature was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml). Added tetrabutylammonium (1.15 equiv., 11,09 g) and the mixture was stirred for 20 minutes the Mixture was extracted with saturated aqueous sodium sulfite. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified using flash chromatography (gradient mode from 10:1 to 7:3 hexane/ethyl acetate) and obtained 2-bromo-4,5-dimethoxyaniline 1,403 g (30%) yellow oil.

Stage 2: 2-Bromo-4,5-dimethoxybenzamide

According to the method described in stage 4 synthesis of 7, 2-bromo-4,5-dimethoxyaniline was treated with phosgene and then with hydrazine and received 2-bromo-4,5-dimethoxy nonsaturated.

Synthesis of 9

6-Amino-5-ethylenebisstearamide

The methodology used in this synthesis is presented in figure J.

Stage 1: 6-amino-5-atelinae

To a mixture of 183 mg (0.22 mmole) of Pd(dppf)Cl2·CH2Cl2and of 4.38 g (13,44 mmole) Ssss in 13 ml of DMF in an argon atmosphere was added a solution of 500 mg (2,24 mmole) of 6-amino-5-brainline (sold by the firm ACES Pharma Product List). Added triethylborane in hexano (2,91 ml of 1.0 M solution) and the reaction mixture was heated at 50°C for 22 h, then was poured into 50 ml of water and was extracted with diethyl ether. The combined ether layers washed with saturated aqueous NaHCO3and brine, dried over MgSO4, filtered and concentrated under reduced pressure and the obtained oil. The oil was purified by chromatography on silica gel with elution with a mixture of 0-50% EtOAc/hexane and received 386 mg (65,8%) 6-amino-5-ethylenamine in the form of a colorless oil. MS (mass spectrometry) (IER (electrospray ionization): m/z 173,2 (M+H).

Stage 2: 6-Amino-5-ethylenebisstearamide

6-Amino-5-ethylenebisstearamide was obtained by treatment of 6-amino-5-ethylenamine with phosgene and then with hydrazine as described above in the synthesis of 7, and was obtained 2-bromo-4,5-dimethoxybenzamide.

Synthesis of 10

2-Methyl-5-(5-methyl-2H-pyrazole-3-yl)phenylenediacetic

The methodology used is this synthesis, presented in scheme K.

Stage 1: 5-Methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole

A solution of 1-(4-methyl-3-nitrophenyl)-ethanone and (1,1-dimethoxymethyl)-dimethylamine in DMF was heated at 90°C for 3 h, then cooled to room temperature. The solvent was removed under reduced pressure and the residue was dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixture was cooled to 0°C and at 0°C was added hydrazinehydrate (5 ml). The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure. The residue was purified using flash chromatography (0 to 30% EtOAc in hexano) and was obtained 8.5 g of 5-methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole in the form of a yellowish solid, which was recrystallized from EtOAc and got to 8.2 g of a yellow powdery substance.

Stage 2: 2-Methyl-5-(5-methyl-2H-pyrazole-3-yl)phenylamine

5-Methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole (8,2 g) was dissolved in ethanol and was added palladium (10%) on charcoal. The mixture was first made at atmospheric pressure of hydrogen supplied from a container at room temperature for 5 hours the Mixture was filtered and the filtrate was concentrated under reduced pressure and received 414 mg of the crude 2-methyl-5-(5-methyl-2H-pyrazole-3-yl)phenylamine as a white solid, which was directly used without further clear the I.

Stage 3: 2-Methyl-5-(5-methyl-2H-pyrazole-3-yl)phenylenediacetic

2-Methyl-5-(5-methyl-2H-pyrazole-3-yl)phenylenediacetic was obtained from 2-methyl-5-(5-methyl-2H-pyrazole-3-yl)phenylamine according to the procedure described above in stage 4 synthesis of 7.

Synthesis of 11

5-{1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-pyrazole-3-yl}-2-methylphenylethylamine

The methodology used in this synthesis is presented in figure L.

Stage 1; 1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole

A solution of 5-methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole, 2-bromoethoxy-tert-butyldimethylsilyl, Cs2CO3and NaI in NMP was heated in a microwave oven at 100°C for 1 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (0 to 30% EtOAc in hexano) and received 867 mg of 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole in the form of oil, which also contained 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-3-methyl-5-(4-methyl-3-nitrophenyl)-1H-pyrazole as a product that is present in a small number.

Stage 2: 5-{1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-shall irsol-3-yl}-2-methylphenylamine

1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitrophenyl)-1H-pyrazole (867 mg) was dissolved in ethanol and was added palladium (10%) on charcoal. The mixture was first made at atmospheric pressure of hydrogen supplied from a container at room temperature for 5 hours the Mixture was filtered and the filtrate was concentrated under reduced pressure and obtained the crude 5-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-pyrazole-3-yl}-2-methylphenylamine in the form of a white solid, which was directly used without further purification.

Stage 3: 5-{1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-pyrazole-3-yl}-2-methylphenylethylamine

5-{1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-pyrazole-3-yl}-2-methylphenylamine turned in the appropriate formation by treatment with phosgene and then with hydrazine as described above in stage 4 synthesis of 7.

Synthesis of 12

(2-Bromo-4,5-acid)-amide (S)-2-(4-forfinal)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid

The synthesis technique used in this example are shown in the diagram M

Stage 1: 2-Bromo-4,5-dimethoxyaniline

According to the method described in the publication JACS 1996, 775, 1028-1030, 4-aminouracil (a 3.06 g, 20,0 mmole) at room temperature was dissolved in a mixture of dichloromethane (80 ml) and methanol (40 ml). Added Tetra is etilamphetamine (1.15 equiv., 11,09 g) and the mixture was stirred for 20 minutes the Mixture was extracted with saturated aqueous sodium sulfite. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified using flash chromatography (gradient mode from 10:1 to 7:3 hexane/ethyl acetate) and obtained 2-bromo-4,5-dimethoxyaniline 1,403 g (30%) yellow oil.

Stage 2: 1-Bromo-2-isocyanato-4,5-dimethoxybenzene

2-Bromo-4,5-dimethoxyaniline (464 mg, 2.0 mmole) at room temperature was dissolved in 10 ml of toluene. Added DMAP (1 EQ., 245 mg) and pyridine (1.3 EQ., 0,22 ml), followed by phosgene (1,33 EQ., of 1.33 ml of 20% solution in toluene). The mixture was heated at 90°C for 4 h After cooling, the mixture was filtered and the filtrate was concentrated in vacuo and obtained 1-bromo-2-isocyanato-4,5-dimethoxybenzene (542 mg, quantitative yield) as a light brown oil.

Example 1

2-{2-Chloro-5-[((R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino]-4-methylphenoxy}ethanol

The methodology used in this synthesis is presented in figure N.

Stage 1: (R)-5-(4-Forfinal)-morpholine-3-yl-{5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine}semicarbazone

A mixture of 5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylhydrazine (1.0 g, 2.7 mmole) and (R)-3-(4-forfinal)-5[1,2,4]triazole-1-yl-3,6-dihydro-2H-[1,4]oxazine (1.31 g, 5.3 mmole) in THF (25 ml) was stirred at room temperature for 1 h the Solvent was removed under reduced pressure and the residue was chromatographically through silicon dioxide (35-50% EtOAc/hexane) and got to 1.15 g (77%) of (R)-5-(4-forfinal)-morpholine-3-yl-{5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine}semicarbazone.

Step 2: {5-[2-(tert-Butyldimethylsilyloxy)-ethoxy]-4-chloro-2-were}-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine

A mixture of (R)-5-(4-forfinal)-morpholine-3-yl-{5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-methylphenylamine}semicarbazone (1.0 g, 1.8 mmole), tea (1.5 ml, of 10.72 mmole) and dichlorotriphenylphosphorane (1,33 g, 4 mmole) in acetonitrile (30 ml) was boiled under reflux for 30 min, then cooled and concentrated under reduced pressure. The residue was chromatographically through silica (50-100% EtOAc/hexane) and received 790 mg(82%) {5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-were}-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine, tpl.=141-142°C.

Stage 3: 2-{2-Chloro-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino]-4-methylphenoxy}-ethanol

Under stirring at room temperature to a solution of {5-[2-(tert-butyldimethylsilyloxy)-ethoxy]-4-chloro-2-were}-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-is mine(700 mg, 1,31 mmole) in Meon (20 ml) was added 6 N. aqueous solution of HCl (1.5 ml). The mixture was stirred at room temperature for 10 min and then concentrated to dryness under reduced pressure. The residue was subjected to distribution between saturated aqueous sodium carbonate solution and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographically through silica gel (MeOH/CH2Cl2/NH4OH 5%/74,75%/0,25%) and received 520 mg (95%) of 2-{2-chloro-5-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino]-4-methylphenoxy}-ethanol, tpl.=161-162°C., MS (M+N)=420.

Additional compounds obtained by the above method, are shown in table 1.

Example 2

[(R)-5-(3-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]quinoline-5-ylamine

The methodology used in this synthesis is presented in figure O.

Stage 1: 5-(3-Forfinal)-morpholine-3-yl-(5-aminoquinoline)semicarbazone

Under stirring at room temperature to a solution of (R)-3-(3-forfinal)-5-methylsulfanyl-3,6-dihydro-2H-[1,4]axisinternet (about 230 mg, 0.6 mmole, obtained in synthesis 2) in THF (3 ml) was added 5-aminobenzeneboronic (140 mg, 0.7 mmole, obtained from commercially available 5-aminoquinoline (Aldrich A79205)). The reaction mixture per Merivale at room temperature for 5.5 h, then was concentrated under reduced pressure. The residue was subjected to distribution between saturated aqueous sodium carbonate and ethyl acetate and the organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographically through silica gel (3% Meon in CHCl3) and received 150 mg of 5-(3-forfinal)-morpholine-3-yl-(5-aminoquinoline)semicarbazone in the form of a white solid.

Stage 2: [(R)-5-(3-Forfinal)-5,b-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-quinoline-5-ylamine

Under stirring at room temperature to a mixture of 5-(3-forfinal)-morpholine-3-yl-(5-aminoquinoline)semicarbazone (150 mg, 0.4 mmole) and tea (0.3 ml, 2 mmole) in acetonitrile (15 ml) was added dichlorotriphenylphosphorane (290 mg, of 0.87 mmole). The mixture was boiled under reflux for 2 h, then added an additional quantity of tea (0.2 ml, was 1.43 mmole) and dichlorotriphenylphosphorane (150 mg, 0.45 mmole). The mixture was boiled under reflux for a further 1 h, then cooled and concentrated under reduced pressure. The residue was subjected to distribution between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographically through silica gel (5% Meon in chloroform) and poluchili,6 mg of [(R)-5-(3-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]quinoline-5-Ilumina the form of a foamed substance, MS (M+N)=362.

Additional compounds obtained by the above method, are shown in table 1.

Example 3

2-{6-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino-5-methylindol-1-yl}ethanol

The methodology used in this synthesis is presented in figure R.

Stage 1: (R)-5-(4-Forfinal)-morpholine-3-yl-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine}semicarbazone

A solution of 1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-elementaryaged (150 mg, at 0.42 mmole) and (R)-3-(4-forfinal)-5-[1,2,4]triazole-1-yl-3,6-dihydro-2H-[1,4]oxazine (150 mg, and 0.61 mmole) in THF (5 ml) was stirred at room temperature for 1 h was Added (R)-3-(4-forfinal)-5-[1,2,4]triazole-1-yl-3,6-dihydro-2H-[1,4]oxazin (25 mg, 0.1 mmole) and the mixture was stirred at room temperature for 18 hours the Solvent was removed under reduced pressure and the residue was chromatographically through silica gel (35-50% EtOAc/hexane) and received 120 mg (53%) of (R)-5-(4-forfinal)-morpholine-3-yl-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-ylamine}semicarbazone.

Step 2: {1-[2-(tert-Butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine

A mixture of (R)-5-(4-forfinal)-morpholine-3-yl-{1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-Il is in}semicarbazone (120 mg, 0.22 mmole), tea (0.25 ml, to 1.79 mmole) and dichlorotriphenylphosphorane (180 mg, 0.54 mmole) in acetonitrile (3 ml) was boiled under reflux for 20 min, then cooled and concentrated under reduced pressure. The residue was chromatographically through silica gel with elution with 3% Meon in chloroform and received 110 mg(96%) {1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine.

Stage 3: 2-{6-[(R)-5-(4-Forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino]-5-methylindol-1-yl}-ethanol

Under stirring at room temperature to a solution of {1-[2-(tert-butyldimethylsilyloxy)-ethyl]-5-methyl-1H-indazol-6-yl}-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-yl]-amine (110 mg, of 0.21 mmole) in Meon (5 ml) was added 6 N. aqueous solution of HCl (0.5 ml). The mixture was stirred at room temperature for 15 min and then concentrated under reduced pressure. The residue was recrystallize from a mixture of Meon/EtOAc/diethyl ether and received 70 mg of 2-{6-[(R)-5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]oxazin-3-ylamino]-5-methylindol-1-yl}-ethanol, tpl.=215-217°C., MS (M+N)=409.

Additional compounds obtained by the above method, are shown in table 1.

Example 4

(4,5-Dimethoxy-2-were)-[5-(4-forfinal)-7,7-dioxo-5,6,7,8-tetrahydro-7-lambda*6*-[1.2 L]t is Iesolo[3,4-C][1,4]thiazin-3-yl]amine

The methodology used in this synthesis is presented in figure Q.

Stage 1: 5-(4-Forfinal)-thiomorpholine-3-yl-(4,5-dimethoxy-2-methylphenylamine)semicarbazone

Under stirring at room temperature to a solution of 3-(4-forfinal)-5-methylsulfanyl-3,b-dihydro-2H-[1,4]desiginated (3,12 mmole) in dry THF (30 ml) was added 4,5-dimethoxy-2-methylphenylethylamine (710 mg, 3,15 mmole). The reaction mixture was stirred at room temperature for 2 h, then was diluted with EtOAc and washed with saturated aqueous sodium carbonate. The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographically through silica gel with elution with 20% Meon in chloroform and got 860 mg (66%) of 5-(4-forfinal)-thiomorpholine-3-yl-(4,5-dimethoxy-2-methylphenylamine)semicarbazone in the form of a white solid, tpl.=161-162°C.

Stage 2: (4,5-Dimethoxy-2-were)-[5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine

A solution of 5-(4-forfinal)-thiomorpholine-3-yl-(4,5-dimethoxy-2-methylphenylamine)semicarbazone (100 mg, 0.24 mmole), dichlorotriphenylphosphorane (177 mg, of 0.53 mmole) and tea (0.15 ml) in acetonitrile (6 ml) was stirred in an atmosphere of N2at 85°C for 30 minutes the Solution was cooled and concentrated under reduced pressure. OS is atok was chromatographically through silica gel (2% Meon in chloroform) and received 73 mg (4,5-dimethoxy-2-were)-[5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-Aminov the form of a yellowish-brown solid, tpl.=165-166°C., MS (M+H)=401.

Stage 3: (4,5-Dimethoxy-2-were)-[5-(4-forfinal)-7,7-dioxo-5,6,7,8-tetrahydro-7-lambda*6*-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine

To a mixture of (4,5-dimethoxy-2-were)-[5-(4-forfinal)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine (60 mg, 0.15 mmole) and 95% formic acid (1.0 ml) was added hydrogen peroxide (0.1 ml 30% aqueous solution). The mixture was stirred at room temperature for 1 h, then was added hydrogen peroxide (0.1 ml 30% aqueous solution). The mixture was stirred for another 1 h, then concentrated under reduced pressure. The residue was subjected to distribution between water and 10% aqueous sodium carbonate solution. The organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographically through silica gel (4% Meon in chloroform) and received 34 mg(52%) (4,5-dimethoxy-2-were)-[5-(4-forfinal)-7,7-dioxo-5,b,7,8-tetrahydro-7-lambda*6*-[1,2,4]triazolo[3,4-C][1,4]thiazin-3-yl]-amine as a yellowish brown solid, tpl.=226-227 OF°C, MS (M+N)=433.

Example 5

(2-Bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3-a]pyridine-3-yl')Amin

The methodology used in this synthesis is presented in figure R.

Stage 1: [6-Phenylpiperidine-(2Z)-ilidene]-2-bromo-4,5-dimethoxyphenylethylamine

PR is stirring to a solution of [6-phenylpiperidine-(2)-ilidene]-hydrazine (0.34 g, 1.8 mmole) in dry THF (8 ml) was added 1-bromo-2-isocyanato-4,5-dimethoxybenzene (0.52 g, 2 mmole). The reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The residue was chromatographically (2% methanol in chloroform) and received 0,43 g (48%) of [6-phenylpiperidine-(2Z)-ilidene]-2-bromo-4,5-dimethoxyphenylacetone in the form of a colorless foam substance.

Stage 2: (2-Bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-amine

With stirring to a mixture of [6-phenylpiperidine-(2Z)-ilidene]-2-bromo-4,5-dimethoxyphenylacetone (0.2 g, 0.45 mmole) in 1,2-dibromotetrachloroethane (0.16 g, 0.5 mmole) at 0°C was added tributylphosphine (0.25 ml, 1 mmol), then tea (of 0.56 ml, 2 mmole). The reaction mixture was stirred at room temperature for 90 min, then concentrated under reduced pressure. The residue was chromatographically (hexane (25-50%) in EtOAc) and received a colorless resinous substance. Recrystallization from diethyl ether and ethyl acetate gave 28 mg of (2-bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-amine as a white crystalline solid, MS (M+N)=430.

Additional compounds obtained by the above method, are shown in table 1.

Example 6

(2-Bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo-[4,3 a]pyrazin-3-yl)Amin

The methodology used in this synthesis is presented in figure S.

Stage 1: [6-(4-Forfinal)-1H-pyrazin-(2Z)-ilidene]-2-bromo-4,5-dimethoxyphenylethylamine

A mixture of [6-(4-forfinal)-1H-pyrazin-(2Z)-ilidene]-hydrazine (0,85 g, 4.2 mmole) and 1-bromo-2-isocyanato-4,5-dimethoxybenzene (1.0 g, 4.2 mmole) in THF (40 ml) was stirred at room temperature for 1 h, then concentrated under reduced pressure. The residue was recrystallize from a mixture of EtOAc/hexane and obtained 1.7 g of [6-(4-forfinal)-1H-pyrazin-(2Z)-ilidene]-2-bromo-4,5-dimethoxyphenylacetone.

Stage 2: (2-Bromo-4,5-acid)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine

[6-(4-Forfinal)-1H-pyrazin-(2Z)-ilidene]-2-bromo-4,5-dimethoxyphenylethylamine (1.7 g, 3.7 mmole), 1,2-dibromotetrachloroethane (1.3 g, 4 mmole) and tributylphosphine (2.1 ml, 8.1 mmole) under nitrogen atmosphere was added to a mixture of acetonitrile (35 ml), dichloromethane (35 ml), THF (40 ml) and tea (2.1 ml). The reaction mixture was stirred at room temperature for 30 min, then the reaction was stopped by adding saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was recrystallize from EtOAc and was obtained 1.1 g of (2-bromo-4,5-acid)-(5-phenyl-[1,2,4]triazole,3-a]pyrazin-3-yl)-amine.

Stage 3: (2-Bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine

Under stirring to a suspension of (2-bromo-4,5-acid)-(5-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine (0.2 g, 3.7 mmole) in a mixture of THF (20 ml) and TFA (1 ml) at 0°C was added borohydride sodium (20 mg, 4.0 mmole). The reaction mixture was stirred at room temperature for 15 min, then the reaction was stopped by adding 10% aqueous HCl. The resulting mixture was boiled under reflux for 10 min, then cooled and podslushivaet by adding 1M aqueous solution of NaOH. The mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure and obtained 0.18 g (2-bromo-4,5-acid)-(5-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-amine, MS (M+N)=431.

Example 7

Drugs

Pharmaceutical preparations intended for delivery in different ways, prepared as described in the following tables. "Active ingredient" or "active compound" as used in the tables denotes one or more compounds of formula I.

Composition for oral administration

Ingredientwt./wt.%
The active ingredient20,0%
Lactose79,5%
Magnesium stearate0,5%

The ingredients are mixed and dosed in capsules containing approximately 100 mg each; one capsule contains approximately full daily dose. Composition for oral administration

Ingredientwt./wt.%
The active ingredient20,0%
Magnesium stearate0,5%
Sodium salt croscarmellose2,0%
Lactose76,5%
PVP (polyvinylpyrrolidone)1,0%

The ingredients are combined and granularit solvent, such as methanol. Then the composition is dried and formed into tablets (containing about 20 mg of active compound) using the appropriate teletrauma machine.

Composition for oral administration

Ingredient Number
Active connection1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Flavoringa 0.035 ml
Dyes0.5 mg
Distilled waterhow much you want to 100 ml

The ingredients are mixed to obtain a suspension for oral administration.

The composition for parenteral administration

Ingredientwt./wt.%
The active ingredient0.25 g
Ingredientwt./wt.%
Sodium chloridehow many is required to obtain isotonic
Water for injection100 ml

The active ingredient is dissolved in a portion of water for injection. Then with stirring, add the amount of sodium chloride, sufficient to obtain an isotonic solution. The solution is brought to the required mass by adding the remaining water for injection, filtered through a membrane filter with a pore size of 0.2 μm and packaged under sterile conditions.

Composition for suppositories

Ingredientwt./wt.%
The active ingredient1,0%
Polyethylene glycol 100074,5%
Polyethylene glycol 400024,5%

Ingredients melted in a mixture with each other and stirred on the steam bath and poured into molds containing full weight, equal to 2.5, the Composition for local use

Phrases who are you g
Active connection0,2-2
Span 602
Tween 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
BGA (bottled hydroxyanisol)0,01
Waterhow much you want to 100 ml

All the ingredients except water are combined and heated with stirring to about 60°C. Then, with vigorous stirring, add the amount of water, heated to approximately 60°C, sufficient to emulsify the ingredients, and then add the amount of water required to bring the mass up to about 100 g

Nasal compositions for spraying

As compositions for nasal spray are also several water suspensions containing approximately 0.025 to 0.5% of active compound. The compositions optionally contain inactive ingredients, is such as, for example, microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, etc., For pH control, you can add hydrochloric acid. Nasal compositions for spraying can be delivered using the dosing nasal spray pump, usually delivering approximately 50-100 μl of the composition for a single inclusion. Typical dosing regime is 2-4 spray every 4 to 12 hours

Example 8

The study of the flow of calcium into cells (FLIPR)

Preparation of compound and reagent

The original solutions of compounds were prepared from powders as 10 mm solutions in DMSO. These solutions were kept at RT for 2 weeks required for these experiments, with the aim of preventing freezing-thawing initial solutions in DMSO. The original solutions in DMSO were added to the appropriate buffer for analysis at a concentration equal to 10 μm, and then serially diluted and received solutions with final concentrations are investigated. During this process never occurred in the formation of a visible precipitate. Aqueous solutions of the compounds, as well as ATP (Sigma A7699) and Bz-ATP (benzoylmethyl-ATP) (Sigma B6396) were prepared fresh on each day of the experiment.

Cell culture: 1321N1-hP2X7and HEK293-rP2X7

The 1321N1 cells stably expressing full-size gene RH7che is ovecka (1321N1-hP2X 7), and HEK293 cells, stably expressing the full-size gene RH7rats (HEK293-rP2X7), received from the company Roche Cell Culture Facility. Cells 1321N1-hP2X7were grown in modified according to the method of Dulbecco environment Needle (MDSI) with a high content of glucose with the addition of 10% FBS (fetal bovine serum) and 250 μg/ml G418. Cells HEK293-rP2X7were grown in MDSI/F-12 with the addition of 10% FBS, 1 mm CaCl2, 2 mm MgCl2, 2 mm L-glutamine and 500 μg/ml G418. The cells were divided in such a way that the merger never exceeded 70%.

The flow of calcium into cells (FLIPR)

The day before the experiment, cells 1321N1-HP2X7or HEK293-rP2X7suspended in a mixture containing calcium SFF (phosphate buffered saline) + versen and washed by centrifugation with not containing calcium SFF removal of versene. Cells re-suspended in the culture medium at a density component of 2.5×105cells/ml, and were sown in 96-hole tablets with black walls and a transparent bottom (50,000 cells/well) for about 18 h before the experiments on the study of the flow of calcium into the cells.

On the day of the experiment, the tablets were washed with FLIPR buffer (containing calcium and magnesium balanced salt Hanks solution (HBSS) supplemented with 10 mm Hepes (N-2-hydroxyethylpiperazine-N-2-econsultancy acid), 2 mm probenecid and 2 mm calcium chloride) using a 96-channel device for washing tablets BIO-TEK, and incubated with 2 mm dye Fluo-3 at 37°C for 1 h Then the dye was removed by washing tablets and the cells were allowed to come into equilibrium with the antagonist or diluent (FLIPR buffer) at room temperature for 20 minutes Agonist (100 μm Bz-ATP final concentration for hP2X7; 5 μm Bz-ATP final concentration for rP2X7) added online with FLIPR and measurement of fluorescence was performed with a 1-second intervals for 60 s, and then at 3-second intervals for a further 4 minutes (just over 5 minutes). In conclusion, I added 5 µm ionomycin and the maximum value of the fluorescence excited with Bz-ATP, normalized to the maximum fluorescence excited by ionomycin.

Example 9

The study of the allocation of IL-1β in whole human blood

Preparation of compound and reagent

10 mm Initial solutions of compounds in DMSO (Sigma D2650) received and used freshly prepared or after storage at -20°C. the Corresponding (200×) serial dilution of the compounds were carried out in DMSO, sugarsweetened from 1 to 20 (10×) phosphate buffered saline, Dulbecco (SFFD; Mediatech Inc., 21-030) so that the final concentration of DMSO in the blood always was 0.5%.

30 mm ATP (Sigma A7699) was prepared immediately before use in 50 mm HEPES (Gibco 15630) and 1 M sodium hydroxide solution the pH value is brought to 7.2.

Blood donors

Don the market for human blood did not take drugs and have limited the consumption of alcohol or caffeine for at least 24 h before blood collection. Blood was collected in containing the heparin-sodium vacuum tubes and used the same day.

The method of analysis

Set OptEIA Human IL-1β ELISA forming coating buffer OptEIA, the diluent for analysis and a set of TMB substrate reagent used in this study were purchased from a company BD Pharmingen. The blood was diluted in the ratio 1:1 using SFF Dulbecco added LPS (LPS) (Escherichia Coli 0127:B8, Sigma L3129) to a final concentration of 25 ng/ml, and incubated at 37°C for 2 hours 48 ál of This premirovanii using FSC blood was added to 6 μl of 10× compound in a mixture of 5% DMSO/SF the corresponding well 96-well polypropylene plate. The blood and the connection was mixed and incubated at 37°C for 30 minutes To a mixture premirovany using FSC blood + connection was added 6 μl of 30 mm ATP, thoroughly mixed, and incubated at 37°C for another 30 minutes In each well were added to 96 μl of buffer for analysis by ELISA and the plate was centrifuged at 4°C and 1200 rpm for 10 minutes the Supernatant was removed and investigated the levels of IL-1β using a set of OptiEIA in accordance with the manufacturer's instructions (before conducting the study, the serum can be frozen at -2°C). The values of the IC50was calculated using the software XLfit.

Example 10

Study of asthma and lung function in vivo

Mice BALb/cJ were immunized according to standard immunization Protocol. Briefly, the method consists in the following: mice (group 8) were immunized with ovalbumin (OVA; 10 µg) aluminum oxide injected intraperitoneally on days 0 and 14. Then the mice were injected aerosol of OVA (5%) at day 21 and 22. Animals were injected with diluent (oral) or connection proposed in the present invention (100 mg/kg, orally), all starting with 20 day.

Lung function was assessed at day 23 using system VASO by measuring parameter values PenH after the introduction of the aerosol with methacholine. Then mice were killed and at the end of the study were collected plasma samples.

Although the present invention is described with specific embodiments, specialists in the art should understand that can be made various changes and may be replaced by equivalents without deviating from the true nature and scope of the present invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, stage or stages of the way to the objective nature and scope of the present invention. It is implied that all such modifications are included in the scope of the attached claims.

1. The compound of the formula I

or it is pharmaceutically acceptable salt,
in which:
R1denotes phenyl, substituted one or two times C1-C6-alkyl, C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; this heteroaryl optionally may be substituted by one or two groups independently selected from the group comprising C1-C6-alkyl, C1-C6-alkoxygroup; hydroxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl; hydroxy-(C1-C6-alkoxy-C1-C6-alkyl; halogen, halogen-C1-C6-alkyl; hydroxy-(C1-C6-alkoxygroup; C1-C6-alkoxy-C1-C6-alkoxygroup or oxoprop;
R2denotes phenyl substituted once or twice by the Deputy, each of which is independently selected from the group comprising halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl; nitrile; alkoxyalkyl; hydroxyalkoxy; alkoxycarbonylmethyl; hydroxyalkyl or3-C6 -cycloalkyl-C1-C6-alkoxygroup;
R3denotes hydrogen or C1-C6-alkyl;
X represents-O-; -NRa-; -S(O)mor CRbRcwhere m is from 0 to 2;
Radenotes hydrogen, C1-C6-alkyl or C1-C6-alkylsulphonyl;
Rband Rcdenote hydrogen or Rband Rctogether with the atom to which they are attached, may form a 5-membered cycle, optionally containing two atoms of oxygen; and
Y represents-NRc-where Rcdenotes hydrogen or C1-C6-alkyl.

2. Connection on p. 1, in which R3denotes hydrogen.

3. Connection on p. 1, in which R1denotes phenyl, substituted one or two times C1-C6-alkyl, C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxygroup or halogen and one 5 - or 6-membered heteroaryl selected from pyrazolyl and pyridazinyl, each of which is optionally substituted by one or two groups independently selected from C1-C6-alkyl; hydroxy-(C1-C6-alkyl; halogen or carbonyl group.

4. Connection on p. 1, in which R1denotes phenyl substituted once or twice by the Deputy, each of which is independently selected from the group comprising fluorine; chlorine; bromine; iodine; methyl; ethyl; methoxy group; ethoxypropan; Tr is vermeil; dipterocarp; methanesulfonyl; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; hydroxypropoxy; and once 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl; 5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl; 5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl; 3-oxo-2-methyl-2H-pyridazin-4-yl or 3-oxo-2H-pyridazin-5-yl.

5. Connection on p. 1, in which R1denotes phenyl,
in position 2 substituted with stands or halogen;
in position 3 optionally substituted with halogen or C1-C6-alkoxygroup; and
in position 4 substituted C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxygroup or 5 - or 6-membered heteroaryl selected from the group comprising pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazole; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl or triazinyl; and heteroaryl may be substituted by one or two groups independently selected from C1-C6-alkyl, hydroxy-C1-C6-alkyl and carbonyl group.

6. Connection on p. 1, in which R1denotes phenyl,
in position 2 substituted with stands or halogen;
in position 3 optionally substituted halog the nom or C 1-C6-alkoxygroup; and
in position 4 substituted C1-C6-alkoxygroup, hydroxy-C1-C6-alkoxygroup; 5-methyl-1H-pyrazole-3-yl; 4-methylpyrazole-1-yl; 5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl; 5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl; 5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl; 5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl; 3-oxo-2-methyl-2H-pyridazin-4-yl or 3-oxo-2H-pyridazin-5-yl.

7. Connection on p. 1, in which R1denotes 2-bromo-4,5-acid; 4,5-dimethoxy-2-were; 4-chloro-5-(2-hydroxyethoxy)-2-were; 2-methyl-5-(5-methyl-1H-pyrazole-3-yl)phenyl; 2-methyl-5-(4-methylpyrazole-1-yl)phenyl; 2-methyl-5-[5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl]phenyl; 2-methyl-5-[5-methyl-1-(2-hydroxypropyl)pyrazole-3-yl]phenyl; 2-methyl-5-[5-methyl-1-(1,2-dihydroxypropyl)pyrazole-3-yl]phenyl; 2-methyl-5-[5-methyl-1-(3-methoxy-2-hydroxypropyl)pyrazole-3-yl]phenyl; 2-methyl-5-(6-oxo-1-methylpyridin-5-yl)phenyl; 2-chloro-5-[5-methyl-1-(2-hydroxyethyl)pyrazole-3-yl]phenyl; 2-methyl-5-(6-oxo-1H-pyridazin-3-yl)phenyl or 2-methyl-5-(6-oxo-1H-pyridazin-5-yl)phenyl.

8. Connection on p. 1, in which R2denotes phenyl substituted once or twice by fluorine.

9. Connection on p. 1, in which X represents-O-.

10. Connection on p. 1, in which X represents-NRa-.

11. Connection on p. 1, in which X represents-S(O)m-.

12. Connection on p. 1, to the torus X denotes-CHR b-.

13. Connection under item 1 or 12, in which Rbdenotes hydrogen.

14. Connection on p. 1 of formula II

in which:
p is from 0 to 3;
each R5independently represents: halogen; C1-C6-alkyl, C1-C6-alkoxygroup; halogen-(C1-C6-alkyl; halogen-(C1-C6-alkoxygroup; C1-C6-alkylsulfonyl or nitrile;
R7and R10represent hydrogen;
R6denotes halogen or methyl;
R8denotes hydrogen, methoxy group or halogen;
R9denotes a methoxy group; 2-hydroxyethoxy or 5 - or 6-membered heteroaryl selected from pyrazolyl and pyridazinyl, which is optional substituted with one or two groups independently selected from a carbonyl group; C1-C6-alkyl, halogen or hydroxy-C1-C6-alkyl;
and the values of X and Rcare as specified in paragraph 1.

15. Connection on p. 14 formula III

in which X, R5, R6, R8and R9are as specified in paragraph 14.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical industry and represents a compound having a structure according to formula I:

,

compositions containing the compounds of the above formula applicable to stimulate neurogenesis and/or inhibition of neuron degeneration.

EFFECT: invention may be used in treating diseases and conditions characterised by neuron loss and lower neurogenesis, including Alzheimer's disease, stroke, traumatic brain injury, traumatic nerve injury and depression.

8 cl, 2 tbl, 2 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to method of labelling paired helical filaments (PHF), which includes interaction of PHF with compound and detection of said compound presence, where compound has formula , in which -R- stands for , -Q- is selected from: -NHC(O)-, -N=N-, -CH=CH-; -P is selected from: ; -T is selected from: ; X represents N or CH; -W1-6, -G1-4, -P1-5 are such as given in the invention formula. Invention also relates to method of labelling aggregated tau-protein, which includes interaction of aggregated molecules of tau-protein with compounds and detection of said compound presence, and to compounds of formula , in which values of substituents are such as given in the invention formula.

EFFECT: formula compounds as labels of tau-protein and paired helical filaments (PHF).

28 cl, 5 dwg, 225 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bicyclic heterocyclic compounds of formula (I), which can be applied in prevention or treatment of abnormal or pathological condition, mediated by FGFR kinase, such as cancer. In formula compound, (i) in case when R1 and R2 independently represent hydrogen or C3-8cycloalkyl; A is group Aa, which represents aromatic group, representing phenyl; R3 represents hydrogen or C1-6alkyl; R4 represents group R4a, which represents amino, halogen, C1-6alkyl, -X-R5, phenyl or aromatic heterocyclic group, where said heterocyclic group represents 5- or 6-membered heterocyclyl group and contains 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen or sulphur, where said phenyl or said heterocyclyl group can be optionally substituted with one or two Rb groups; or (ii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ab, which represents aromatic 5-membered heterocyclic group; R3 represents hydrogen or C1-6alkyl; R4 is group R4a, which represents halogen; or (iii) when R1 represents hydrogen and R2 represents C1-6alkyl or halogenC1-6alkyl; A is group Ac, which represents aromatic 6-membered heterocyclic group, containing one nitrogen atom as heteroatom; R3 represents hydrogen or C1-6alkyl; R4 is group R4b, which represents halogen, C1-6alkyl, -X-R5 or aromatic heterocyclic group, containing 1, 2 or 3 heteroatoms, independently selected from nitrogen, oxygen and sulphur. Other values of radicals are given in the invention formula.

EFFECT: obtaining novel derivatives of bicyclic heterocyclic compounds.

21 cl, 7 tbl, 250 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula or , where Ar1 represents phenyl group, optionally substituted with one or several identical or non-identical halogen atoms; R1 represents hydrogen atom; R4, R5, R6a, R6b represent hydrogen atoms; Y, Z independently represent linear C1-4 alkylene group, optionally substituted with one linear C1-4 alkyl group; Ar2 stands for condensed with benzene 5-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, substituted with one linear C1-4 alkyl group, or derivative of 5- or 6-membered heterocyclic ring, containing one nitrogen atom and one sulphur atom, condensed with heteroaromatic 6-memebered ring, containing one or two nitrogen atoms, substituted with one linear C1-4 alkyl group, linear C1-4 alkoxygroup or group -NR7R8, where R7 and R8 independently stand for hydrogen atom, linear or branched C1-4 alkyl group, or R7 and R8 together with nitrogen atom form group of general formula , where R2, R3 represent linear C1-4 alkyl groups, A stands for group -CHR12, oxygen atom or group -NR9, where R12 and R9 stand for hydrogen atom or linear C1-4 alkyl group, m has value 1 or 2, n has value 1 or 2, o has value 0 or 1, p has value 0 or 1, Q stands for group -O-, group -N--H or group -N--CO-R10, where R10 stands for linear C1-4 alkyl group or -NH-R11 group, where R11 represents linear C1-4 alkyl group; and to their salts. Invention also relates to methods of obtaining therein and to based on them pharmaceutical composition, possessing antagonistic activity with respect to receptor CCR3.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions, which can be applied in medicine for obtaining medication, intended for treating asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory intestinal diseases, ulcerous colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis or HIV-infection and AIDS-associated diseases.

14 cl, 3 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted 7,8-dicyanopyrimido[2,1-b][1,3]benzothiazoles of general formula (I)

where a R=CH3, R1=C6H5; b R=CH3, R1=4-CH3OC6H4; c R=CH3, R1=2-thienyl; d R=C6H5, R1=4-CH3OC6H4. The method is carried out by reacting 4-bromo-5-nitrophthalonitrile with esters of 2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acids in the presence of triethylamine, which is used as a deprotonating agent. The reaction takes place at temperature of 18…35°C and molar ratio of reactants (1):(2):(TEA)=1:1:2, for 12-30 hours in dimethylformamide solution. Further, the reaction mass is diluted with water, the water being in tenfold excess, at temperature T=0…25°C; the tarry residue released is decanted from the aqueous layer and recrystallised from alcohol; the precipitate of the end product is filtered and dried on air.

EFFECT: synthesis of compounds which are used as precursors for producing phthalocyanines.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I, including stereoisomers, geometric isomers, tautomers or pharmaceutically acceptable salts thereof: where Z1 is CR1; Z2 is CR2; Z3 is CR3 or N; Z4 is CR4 or N; where (i) X1 is N and X2 is S or (iv) X1 is S and X2 is CR7; R1, R2, R3, R4 and R7 are independently selected from H, F, Cl, Br, I, -CN, -CH2OR10, -(C1-C12 alkylene)NR10R11, -(C1-C12 alkylene)NR12C(=O)R10, -CO2R10, -C(=O)N(R10)OR11, -NR10R11, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)OR11, -C(=O)NR10(C1-C12 alkylene)NR10C(=O)R11, -C(=O)NR10(C1-C12 alkylene)R11, -C(=O)NR10(C1-C12 alkylene)R10, -C(=NR10)NR10R11, -NR12C(=O)R10, -NR12C(=O)OR11, -NR12C(-O)NR10R11, -NR12C(=O)(C1-C12 alkylene)NR10R11, NR12(C=O)C1-C12 alkylene)NR11(C=O)R12, -C≡CR10, C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-6 ring atoms, where 1-4 ring atoms are nitrogen atoms, and phenyl, where the heteroaryl and phenyl are optionally substituted with one or two groups selected from -CH2OH, -(CH2)2OH, -CH2CO2H, -CN, -CH2NH2, -(CH2)2N(CH3)2, -CH3, -CO2H, -CH2CO2CH3, -NH2 and -S(O)2CH3; A is selected from -C(=O)NR5R6, -C(=S)NR5R6, phenyl and C1-C20 heteroaryl, said heteroaryl being an unsaturated carbocyclic residue containing 5-10 ring atoms, 1-4 of which are heteroatoms selected from nitrogen, oxygen or sulphur, C1-C20 heteroaryl and phenyl are optionally substituted with one or three groups independently selected from C1-C12 alkyl, -(C1-C12 alkylene)NR10R11, -CH3, oxo, -CO2CH3, -NH2, 1-methylpiperid-4-yl, isopropyl, isobutyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, benzoimidazolyl, benzyl and phenyl, where the alkyl, benzoimidazolyl and phenyl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, -CF3, -CH2OH, -CH3, -C(=O)NHCH3, -NH2, -OH, -OCH3, -CH2OCH3, -C(=O)N(CH3)2, -N(CH3)2, -C(CH3)2OH, -CH(CH3)2, -CH2(1H-1,2,4-triazol-5-yl) and C(=O)4-methylpiperazin-1-yl; R5 is selected from C1-C12 alkyl, optionally substituted with one group independently selected -NH2, -NHCOCH3 and -OH; R6 is selected from pyridinyl and phenyl, each optionally substituted with one or two groups independently selected from F, Cl, Br, I, -CN, -CF3, -C(=O)NR10R11, -C(=O)NR10(C1-C12 alkylene)NR10R11 and -C(=O)NR10R11; R10, R11 and R12 are independently selected from H, C1-C12 alkyl, C1-C12 alkylene-phenyl, cyclopentyl, pyridinyl and imidazolyl, where C1-C12 alkyl, cyclopentyl are optionally substituted with one or two groups independently selected from -CH2OH, -N(CH3)2, -NHCOCH3, -OH and -S(O)2CH3; or R10 and R11 together with a nitrogen atom to which they are bonded form a C5-C6 heterocyclic ring containing one or two heteroatoms selected from nitrogen and oxygen, or pyrazolyl, optionally substituted with one or two groups independently selected -CH3, -NH2, -N(CH3)2; -OH and oxo. The invention also relates to a pharmaceutical composition having PI3K inhibiting activity based on said compounds.

EFFECT: obtaining novel compounds which can be used in medicine for treating cancer.

25 cl, 5 dwg, 2 tbl, 331 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene citrate salt. The invention also refers to pharmaceutical compositions containing the above citrate, and methods for using citrate in treating several conditions.

EFFECT: what is prepared is the new 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene salt and the pharmaceutical compositions on the basis thereof which can find application in medicine for treating a proliferative disorder.

17 cl, 30 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula [I]: or their pharmacologically acceptable salts, wherein R1 is C1-6 alkyl; R2 is C1-6 alkoxy; m and n mean 1; W means N; the ring A represents fragments of formula , or that can be substituted; X1 is a single bond, C1-6 alkylene group or -C(O)NR3-, wherein R3 is hydrogen, C1-6 alkyl or phenyl; and the ring B represents fragments of formula [5]-[11]: that can be substituted, and a pharmaceutical composition containing them.

EFFECT: new compounds possess activity inhibiting the amyloid beta production, and are effective as a therapeutic agent for treating an Aβ-caused disease, such as Alzheimer disease or Down syndrome.

10 cl, 48 tbl, 399 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula (I), where R1 represents alkoxygroup; U, V and W each represents CH or one of U, V and W represents N, and each other represents CH; A represents CH2 or O; G represents CH=CH-E, where E represents phenyl group, mono- or di-substituted with halogen, or G represents group of one of the formulas given below , , where Z represents CH or N, Q represents O or S and K represents O or S; or salt of such compound. In addition, invention also relates to pharmaceutical composition based on formula (I) compound for prevention or treatment of bacterial infection, as well as to application of claimed compounds for obtaining medication for prevention or treatment of bacterial infection.

EFFECT: novel compounds, which can be applied in treatment of bacterial infection, are obtained and described.

23 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of nucleoside derivatives - 1,2,5-oxadiazoles of general structural formula I where R1 and R2 are selected from phenylsulphonyl, substituted with one or more halogen atoms, nitro groups, carboxy groups, alkyl halides, CH3, OCH3, OCF3; X is selected from N or N→O; or R1 and R2 form a group, where R', R", R'" and R'''' are independently selected from hydrogen; halogens; nitro groups, hydroxy group, carboxy group, CH3; CH2Br; OCH3; phenylsulphonyl; phenylthio group; or the following groups: R' and R" can also be merged into one of the following common rings for inhibiting human immunodeficiency virus (HIV) replication. The invention also relates to a pharmaceutical composition based on compounds of formula I and a method of inhibiting HIV-1 subtypes A and B integrase, including forms which are resistant to raltegravir.

EFFECT: detecting novel activity in compounds of formula I, which can be used in medicine as HIV replication inhibitors.

3 cl, 5 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a 2,4-diamino-1,3,5-triazine derivative of general formula I, having protein kinase inhibitor properties, use thereof and a pharmaceutical composition based thereon. In general formula I Y is CH2, CHR', O, S, S(O) or S(O)2; X1, X2, X3 are independently selected from a CH groups or N; R1 is a C1-8 aliphatic group, C3-8 cycloalkyl, C6-10 aryl, ethylene-dioxyphenyl, methylene dioxyphenyl, pyridyl, each of which is optimally substituted with one or more identical or different groups R"; R' is hydrogen, OH, halogen, such as F, Cl, Br, I, or carboxyl or carboxamide, optimally N-substituted with (C1-6)alkyl, or cyano or halo(C1-8)alkyl, (C1-8)alkoxy, piperidinyl, optimally substituted with methyl; R" is R' or RD; R21, R22, R23, R24 are independently selected from groups F, Cl, Br, I, CN, (C1-16)alkyl; furthermore, R21 and R22 and/or R23 and R24 can be combined and represent one oxo (=O) group or together with a carbon atom can form a spirocycle containing 3 to 7 carbon atoms; furthermore, R21 and R24 together with two carbon atoms can form an aliphatic or aromatic ring containing 4 to 8 atoms, optionally substituted with one or more groups R'; RD is an oxo group =O or =S.

EFFECT: invention can be used to treat autoimmune or cancerous diseases, rheumatoid arthritis and non-Hodgkin lymphoma.

13 cl, 12 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a number of bicyclic nitroimidazole-replaced phenyloxazolydinones of the following structural formula (I):

,

containing nitroimidazole circle, or to its pharmaceutically acceptable salt; where R1 represents hydrogen, (C1-C6)alkyl or aryl; n is equal to 0, 1 or 2; X1 and X2 independently represent H, CF3, CI, OCF3 or F; G represents -OH, triazole or -NHCOR2; R2 represents (C1-C6)alkyl, cycloalkyl or aryl; and L represents a bond or a linker group chosen from any combination 2-3 of the following groups: 1) (C1-C6)alkylene, 2) (C3-C8)cycloalkylene, 3) arylene, arylene-replaced CN, ore arylene-replaced F, 4) group chosen from the group consisting of

,

where R10 represents H, CF3, hydroxyl, amino, alkyl, alkylamino, alkoxy or aryl, and R13 represents H, hydroxyl, amino, alkyl, alkyl amino, alkoxy or aryl, or R13 in combination with nitroimidazole circle can form spiral-shaped structure, 5) -C(=O)-, 6) -O-, 7) -S(O)n-, in which n is equal to 0.1 or 2, 8) -N(R3)-, 9) -C(R4)=C(R5)-, R3 represents hydrogen, (C1-C6) alkyl or aryl, and R4 and R5 represent hydrogen, (C1-C6) alkyl or aryl, or R4 and R5 can be combined together so that they can form a bond. Besides, the invention refers to pharmaceutical composition for treatment of bacterial infection based on compounds of formula I, as well as to a bacterial infection treatment method.

EFFECT: invention describes new compounds that have antibacterial activity against a line of wild type and stable lines of pathogenic microorganisms, and as a result, are suitable for prevention, control and treatment of a number of human and mammal bacterial infections caused by these pathogenic microorganisms such as bacillus Kochii.

15 cl, 93 ex, 1 tbl, 22 dwg

FIELD: biotechnologies.

SUBSTANCE: invention refers to derivatives of oxazolopyrimidine in any of their stereoisomeric forms, or in the form of a mixture of stereoisomeric forms specified in Claim 1.

EFFECT: oxazolopyrimidine derivatives having agonistic activity in relation to Edg-1 receptor.

5 tbl, 319 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel heterocyclic nitrogen- and oxygen-containing compounds having insecticidal activity. In formulae (A) (B) (C) (D) R1 is a 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/ or sulphur atom, a halogen-substituted 5- or 6-member heterocyclic ring containing a nitrogen, oxygen and/or sulphur atom, a substituted or unsubstituted phenyl, where the substitutes are one or more groups selected from a group consisting of halogen atoms, C1-4 halogen alkyl or C1-4 chloroalkoxyl; R5, R6, R7, R8 and R9 are H, saturated or unsaturated C1-4 alkyl, halogen atom, saturated or unsaturated C1-4 alkoxyl, saturated C1-4 halogenalkoxyl, C1-4 alkylcarbonyl, C1-8 alkyl ester, C1-4 alkylsulphonyl, phenyl, benzyl or trifluoromethane sulphonyl ether group; Y is nitro, cyano, trifluoromethyl, trifluoroacetyl or trifluoromethylsuphonyl. Values of radicals R, R2-R4 are given in the claim.

EFFECT: invention also relates to an agrochemical composition containing said compounds, use of the agrochemical composition in pest control and a method of producing said compounds.

12 cl, 7 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

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