Derivatives of 5-member heterocycles as kinase p38 inhibitors

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

 

The scope of the invention

The present invention relates to derivatives of 5-membered heterocycles, including derivatives of pyrazole and imidazole, which show efficacy in the inhibition of cytokines. The present invention also relates to using such compounds for treating conditions associated with kinase activity 38α and β, as well as kinase R.

Background of invention

Many cytokines involved in the response of the inflammatory response, including IL-1, IL6, IL-8 and TNF-α. Excessive production of cytokines, such as IL-1 and TNF-α has been observed for a number of diseases, including colitis, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxic shock, osteoporosis, Alzheimer's disease, and congestive heart failure (Henry and others, Drugs Fut., 24, cc.1345-1354 (1999); Salituro, etc., Curr. Med. Chem., 6, cc.807-823 (1999)). Clinical trials showed the effectiveness of the protein antagonists of cytokines in the treatment of chronic inflammatory diseases, such as, for example, monoclonal antibodies to TNF-α (Remicade, Rankin and others, Br. J. Rheumatol., 34, cc.334-342 (1995)) and soluble hybrid protein receptor-Fc TNF-α (etanercept) (Moreland and others, 25 Ann. Intern. Med., 130, cc.478-486 (1999)).

The biosynthesis of TNF-α occurs in many cell types in response to an external stimulus, such as, for example, mitogen, infection or trauma. Important mediators producerof is of TNF-α are mitogen-activated proteins, kinase (MAP) and, above all, kinase R. These kinases are activated in response to various stress factors, including, without limitation, provocatively cytokines, endotoxin, ultraviolet irradiation and osmotic shock. To activate R want to dual phosphorylation at earlier stages metabolic pathway kinases aluminum maker MAP (MKK3 and MCC) for residues of threonine and tyrosine in the fragment Thr-Gly-Tyr contained in the isoenzymes R.

Known 4 isoforms of the kinase R, i.e. 38α, 38β, 38γ and 38δ. α - and β-Isoforms are expressed in inflammatory cells and are the main modulators of the production of TNF-α. Inhibition of enzymes 38α and β in cells results in decreased expression of TNF-α. It is established that the introduction of inhibitors 38α and β when tested in animal models with inflammatory diseases such inhibitors have shown efficacy in the treatment of these diseases. In this regard, enzymes R play an important role in inflammatory processes mediated by IL-1 and TNF-α (see, for example, US patents№№6277989, 6130235, 6147080, 5945418, 6251914, 5977103, 5658903, 5932576 and 6087496 and international applications for patents WO 00/56738, WO 01/27089. WO 01/34605, WO 00/12497, WO 00/56738, WO 00/12497 and WO 00/12074, US patents No. 6376527, 6316466 and 6444696 and international applications for patents WO 99/57101, WO 02/40486, WO 03/032970, WO 03/033482, WO 03/032971, WO 03/032986, WO 03/032980, WO 03/032987, WO 03/033483, WO 03/033457 and WO 03/032972.

Thus, there is a need to develop inhibitors of kinases R, including kinase RA and p38b, to treat, prevent or ameliorate one or more symptoms of diseases and disorders associated with the activity of the kinase R.

Summary of the invention

The present invention provides compounds, compositions and methods to treat, prevent or ameliorate one or more symptoms of conditions associated with kinase activity R. In one embodiment, the compounds used in the compositions and methods of the present invention are derivatives of pyrazole or imidazole. In another embodiment, derivatives of pyrazole or imidazole are used as inhibitors of kinases, including kinases 38α and 38β.

In one embodiment provides compounds of formula

or their pharmaceutically acceptable derivatives, where:

R1means hydrogen, acyl, or-P(O)(OH)2;

R2means hydrogen, halogen, optionally substituted alkyl, alkylthio, alkylsulfonyl, alkylsulfonyl, optionally substituted alkoxy, optionally substituted, heterocyclic or alkylamino;

G means aryl, aralkyl, cycloalkyl, heteroaryl, heteroalkyl or heterocyclyl, optionally condensed with a phenyl ring, and substituted groups R3and 4provided that the heterocyclic ring is attached to a carbonyl group through a carbon atom in the cycle or G means OR83or NR80R81;

In means aryl or heteroaryl;

With mean 5-membered heteroaryl ring containing one or two heteroatoms in the loop;

D means heteroaryl, optionally substituted heteroaryl or-C(O)NR80R81;

each R80and R81independently means hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;

R83means hydrogen, alkyl, cycloalkyl, heteroaryl or optionally substituted heteroaryl;

R3choose from a group including:

(a) amino, alkylamino or dialkylamino,

(b) acylamino,

(C) optionally substituted heterocyclyl,

(d) optionally substituted aryl or heteroaryl,

(e) heteroalkyl,

(e) heteroalkyl,

(g) heteroalkyl,

(C) heterologic,

(and) heteroalkyl,

(K) optionally substituted geterotsiklicheskikh,

(l) optionally substituted heterocyclisation,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh or heterocyclics,

(o) optionally substituted by heterocyclisation,

(p) optionally is substituted by geterotsiklicheskikh the sludge

(p) geterofullereny;

(s) -NHSO2R6where R6means alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh;

(t) -NHSO2NR7R8where R7and R8independently of one another denote hydrogen, alkyl or heteroalkyl;

(y) -Y-(alkylene)-R9where Y represents a simple bond, -O-, -NH - or-S(O)n(where n denotes a Prime number from 0 to 2) and R9means halogen, cyano, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -COOH, -COR10, -COOR11, -CONR12R13, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where R10means alkyl or optionally substituted heterocycle, R11means alkyl, a R12, R13, R14, R15, R16, R17, R18and R19independently of one another denote hydrogen, alkyl or heteroalkyl;

(f) -C(=NR20)(NR21R22), where R20, R21and R22independently mean hydrogen, alkyl or hydroxy, or R20and R21together denote -(CH2)nwhere n is 2 or 3, and R22means hydrogen, alkyl;

(x) -NHC(X)NR23R24where X is-O - or-S-, and R23and R24independently of one another denote hydrogen, alkyl or heteroalkyl;

(C) -CONR5 R26where R25and R26independently mean hydrogen, alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh, or R25and R26together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclyl;

(h) -S(O)nR27where n denotes a Prime number from 0 to 2 and R27means alkyl, heteroalkyl, optionally substituted geterotsiklicheskikh or-NR28R29where R28and R29independently of one another denote hydrogen, alkyl or heteroalkyl;

(W) cycloalkenyl, cycloalkenyl and cycloalkylcarbonyl, all of these groups optionally substituted by alkyl groups, halogen, hydroxy or amino;

(y) alluminare or heterooligomerization;

(e) Z-alkylene-NR30R31or Z-alkylene-OR32where Z denotes-NH-, -N((ness.)alkyl) -, or-O-, and R30, R31and R32independently of one another denote hydrogen, alkyl or heteroalkyl;

(h) -OC(O)-alkylene-CO2H or-OC(O)-NR'r R" (where R' and R" independently denote hydrogen or alkyl),

(I) heteroelement or heteroarylboronic,

(AA) hydrogen

(BB) halogen,

(BB) pseudohalogen,

(gg) hydroxy,

(DD) optionally substituted alkoxy,

(it) C(L)R40where L is O, S or NR55; R40means hydrogen, optionally substituted alkyl, neoba is consequently replaced by alkenyl, optionally substituted quinil, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted of heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halogen, pseudohalogen, OR55, SR55, NR57R58or SiR52R53R54where R52, R53and R54choose, as described in the following paragraphs (i) or (ii): (i) R52, R53and R54each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55and NR62R63; or (ii) any two of R52, R53and R54together form alkylene, albaniles, akinyan, heteroalkyl, while others choose, as described in paragraph (i); R55means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R56means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55or NR64R65where R64and R65each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR66or NR62R63or R64and R65together form alkylene, albaniles, akinyan, heteroalkyl, where R66means hydrogen, alkyl, alkene is l, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R57and R58choose, as described in the following paragraphs (i) or (ii): (i) R57and R58each independently mean hydrogen, optionally substituted alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55, NR67R68or C(L)R69where R67and R68each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl, or both Deputy together form alkylene, albaniles, akinyan, heteroalkyl and R69means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR70or NR62R63where R70means alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or (ii) R57and R58together form alkylene, albaniles, akinyan, heteroalkyl or alkylenediamines; R62and R63each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or R62and R63together form alkylene, albaniles, akinyan, heteroalkyl, and

(ii) optionally substituted alkyl;

R4selected from the group including

(a) hydrogen,

(b) halogen,

(b) alkyl,

p> (g) alkoxy and

(d) hydroxy;

R5selected from the group including

(a) hydrogen,

(b) halogen,

(b) alkyl,

(d) halogenated,

(e) thioalkyl,

(e) hydroxy,

(g) amino,

(C) alkylamino,

(and) dialkylamino,

(K) heteroalkyl,

(l) optionally substituted heterocycle,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh,

(o) alkylsulfonyl,

(p) aminosulfonyl, monoalkylamines or dialkylaminoalkyl,

(R) heteroatomic and

(C) carboxy;

R6selected from the group including

(a) hydrogen,

(b) halogen,

(C) alkyl and

(g) alkoxy.

In the present invention are also pharmaceutical compositions containing the compound of the present invention, in combination with a pharmaceutically acceptable carrier.

In the present invention are also ways to treat, prevent or ameliorate one or more symptoms of diseases in mammals mediated by cytokines, and the methods include administration to a mammal in need of such treatment, the compounds of formula I. Diseases and disorders that can be treated, to prevent or reduce the symptoms include but are not limited to, chronic inflammatory diseases, inflammation of the intestine is, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxic shock, osteoporosis, Alzheimer's disease and congestive heart failure.

In the present invention are also ways to prevent or suppress the inflammatory response using the compounds and compositions of the present invention.

In another embodiment provides methods of inhibiting kinases R, including kinase 38α and 38β, using the compounds and compositions of the present invention.

There are also articles containing packaging material, a compound or composition according to the present invention, intended to treat, prevent or ameliorate one or more symptoms of diseases or disorders mediated by kinase R and labels, which indicated that the compound or composition is used to treat, prevent or ameliorate one or more symptoms of diseases or disorders mediated by kinase R.

Detailed description of preferred embodiments of the invention

A. Definitions

If not stated otherwise, all technical and scientific terms used in this context, have common values adopted in the technical field to which the invention relates (of the invention). All patents, applications for the grant of a patent, published for the Cai and publications the sequence of the gene Bank, databases, websites and other published materials that are referenced by the authors in the description of the present invention, unless specified otherwise, are fully included in the scope of the present invention as references. If there are many meanings for these terms, the preferred values defined in the description section. If you mention the URL or use other such identifier or address, it should be understood that such identifiers can change and particular information on the Internet may appear to be missing, but similar information can be found on the Internet. In addition, references to these identifiers indicate the availability and prevalence of such information.

Used in this context, the term 38α means the enzyme described in the work of Han and others, Biochim. Biophys. Acta 1265(2-3):224-7 (1995). Used in this context, the term 38β means the enzyme described in the work of Jiang and others, J. Biol. Chem. 271(30): 17920-6 (1996). Used in this context, the term 38γ means the enzyme described in the work of Li and others, Biochem. Biophys. Res. Commun. 228:334-340 (1996). Used in this context, the term 38δ means the enzyme described in the work of Wang and others, J. Biol. Chem. 272(38):23668-74 (1997).

Used in this invention pharmaceutical is Ki acceptable derivatives of compounds include their salts, esters, esters of enols, simple enol esters, acetals, ketals, orthoepy, hemiacetals, policital, acid, base, solvate, hydrate or prodrug. Such derivatives can be obtained by known methods for such modification. The compounds can enter the animal or human, they are pharmaceutically active or are prodrugs and do not show significant toxicity. Pharmaceutically acceptable salts include, without limitation, salts of amines, such as, without limitation, N,N'-dibenziletilendiaminom, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyethylamine, Ethylenediamine, N-methylglucamine, procaine, N-benzylpenicillin, 1-pair-of chlorbenzyl-2-pyrrolidin-1'-iletilmesinden, diethylamine and other bonds alkylamines, piperazine and Tris(hydroxymethyl)aminomethane; alkali metal salts, such as, without limitation, sodium and potassium; salts of alkaline-earth metals such as without limitation, barium, calcium and magnesium; salts of transition metals, such as, without limitation, zinc, and salts of other metals, such as, without limitation, sodium phosphate and disodium phosphate, and include, without limitation, nitrates, borates, methansulfonate, bansilalpet, toluols lithonate, inorganic salts, such as, without limitation, hydrochloride, hydrobromide, hydroiodide and sulfates; and salts of organic acids, such as, but not limited to, acetates, triptoreline, oxalates, benzoate, salicylates, maleate, lactates, malaty, tartratami, citrates, ascorbates, succinate, butyrate, valerate and fumarate. Also use zwitterion (internal) salt. In some embodiments, the salt form of the compounds have a high dissolution rate and oral bioavailability. Pharmaceutically acceptable esters include, without limitation, alkalemia, alkenilovyh, alkinilovymi, arrouye, heteroaryl, Arakelova, heteroalkyl, cycloalkyl and heterocyclyl esters of acids, including, without limitation, carboxylic acid, phosphoric acid, phosphinic acid, sulfonic acid, sulfinate acid and boranova acid. Pharmaceutically acceptable ethers of enols include, but are not limited to, derivatives of formula C=C(OR)where R denotes hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable esters of the enol include, without limitation, derivatives of compounds of the formula C=C(OC(O)R), where R is hydrogen, alkyl, alkene is l, quinil, aryl, heteroaryl, aralkyl, heteroalkyl, cycloalkyl or heterocyclyl. Pharmaceutically acceptable solvate and hydrates are complexes of the compounds with one or more molecules of solvent or water, or from 1 to about 100, or from 1 to about 10, or from 1 to about 2, 3 or 4 molecules of solvent or water.

The term ”alkyl” means a linear saturated monovalent hydrocarbon radical containing from 1 to 6 carbon atoms, or branched saturated monovalent hydrocarbon radical containing from 3 to 6 carbon atoms, for example methyl, ethyl, propyl, 2-propyl, pentyl etc.

The term ”cycloalkyl” means a saturated or partially unsaturated non-aromatic cyclic hydrocarbon ring system, preferably containing from 1 to 3 rings and 3 to 7 carbon atoms in the ring, which may mean the condensed system with C3-C7carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and substituted. ”Substituted cycloalkyl” is substituted by one or more alkyl or substituted alkyl groups as described above, or one or more groups described above as alkyl substituents. The term ”(ness.)cycloalkyl” means nezametno is saturated or unsaturated non-aromatic cyclic hydrocarbon ring system, containing from 3 to 5 carbon atoms.

The term ”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, propylene, 2-methylpropene, pentile etc.

The term ”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.

The term ”albaniles” means a linear divalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one double bond, such as ethenylene, propylen etc.

The term ”quinil” means a linear monovalent hydrocarbon radical containing from 2 to 6 carbon atoms, or a branched divalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one triple bond, such as ethinyl, PROPYNYL and the like

The term ”akinyan” means a linear divalent hydrocarbon radical containing from 2 D. what 6 carbon atoms, or branched monovalent hydrocarbon radical containing from 3 to 6 carbon atoms containing at least one triple bond, such as ethynylene, propylen etc.

The term ”alkoxy” means a radical-OR where R is alkyl, as described above, for example methoxy, ethoxy, propoxy, 2-propoxy, etc.

The term ”acyl” means a radical-C(O)R, where R is alkyl or halogenated, for example acetyl, TRIFLUOROACETYL, etc.

The term ”acylamino” means the radical-NRC(O)R', where R is hydrogen or alkyl, and R' represents an alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh, for example acetylamino, 2-amino-2-methylpropionamide etc.

The term ”halogen” means fluorine, chlorine, bromine or iodine, mainly fluorine and chlorine.

The term ”halogenated” means alkyl substituted by one or more identical or different halogen atoms, such as-CH2Cl-CF3, -CH2CF3, -CH2CCl3etc.

The term ”aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical containing from 6 to 10 atoms in the ring, for example phenyl, 1-naphthyl, 2-naphthyl, and other Aryl ring optionally condensed 5-, 6 - or 7-membered monocyclic saturated ring, optionally containing 1 or 2 heteroatoms that are independently selected from the group comprising acidic the rod, the nitrogen or sulfur, with the remaining atoms in the cycle are carbon atoms, and 1 or 2 carbon atoms optionally replaced by a carbonyl group. Examples of aryl radicals, condensed with other rings, include, but are not limited to, 2,3-dihydrobenzo[1,4]dioxane, chroman, isochroman, 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran, benzo[1,3]dioxol, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, 2,3-dihydro-1H-indole, 2,3-dihydro-1H-isoindole, benzimidazole-2-it, 3H-benzoxazol-2-it, etc.

The term ”heteroaryl” means a monovalent monocyclic or bicyclic aromatic radical containing from 5 to 10 atoms in the ring, while containing 1, 2 or 3 heteroatoms in the ring which are selected from N, O or S, with the remaining atoms in the cycle means a carbon atom. This term also includes radicals where the heteroatom in the ring oxidized or quaternity, such as, for example, forming an N-oxide or a Quaternary salt. Typical examples include, without limitation, thienyl, benzothiazyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, chinoline, honokalani, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolyl, benzisoxazole, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridinyl, 4-pyridinyl, N-alkyl-2-pyridones, pyrazinyl, pyridazinyl, pyrimidinyl and with the corresponding N-oxides (e.g., pyridyl N-oxide, chinoline N-oxide), and their Quaternary salts, etc.

The term ”heterocycle or heterocyclyl” means a non-aromatic cyclic radical containing from 3 to 8 atoms in the cycle, in which 1 or 2 cyclic atoms are heteroatoms selected from N, O or S(O)n(n means an integer from 0 to 2), with the remaining atoms in cyclotrichium carbon, and 1 or 2 carbon atoms optionally replaced by a carbonyl group. This term also includes radicals, in which the nitrogen atom in the ring is oxidized or quaternity, such as, for example, forming an N-oxide or a Quaternary salt. Typical examples include, without limitation, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophene, piperidine, morpholine, piperazine derivatives, pyrrolidine, oxiranyl, dioxane, 1,3-dioxolane, 2,2-dimethyl-1,3-DIOXOLANYL, sulfolane, 2-oxazolidinyl, 2-imidazolidinyl, S,S, diocletianopolis etc.

The term ”heterocyclimamines” means a saturated monovalent cyclic group containing 4 to 8 atoms in the cycle, in which at least 1 atom in the cycle means N and optionally contains one additional cyclic atom selected from N or O, with the remaining atoms in the cycle mean C. the Term includes groups such as pyrrolidino, piperidino, morpholino, piperazine derivatives, etc.

The term ”optional samewe the hydrated alkyl, alkenyl, quinil, alkoxy or cycloalkyl” means an alkyl group, alkenyl, quinil, alkoxy or cycloalkyl, as described above, which are optionally independently substituted by 1 or 2 substituents selected from the group comprising alkyl, phenyl, benzyl, halogenated, heteroalkyl, halogen, cyano, heterocyclyl, acyl, -OR (where R is hydrogen or alkyl), -NRR' (where R and R' independently are selected from the group including hydrogen, acyl or alkyl, which is optionally substituted by the groups hydroxy, alkoxy, cyano, halogen or heterocyclyl), -NHCOR (where R is alkyl, which is optionally substituted by the groups hydroxy, alkoxy, cyano, halogen or heterocyclyl), -NRS(O)nR' (where R is hydrogen or alkyl, n means an integer from 0 to 2; and R' represents hydrogen, alkyl or heteroalkyl, and optionally substituted by hydroxy groups, alkoxy, cyano, halogen or heterocyclyl), -NRS(O)nNR'r R" (where R is hydrogen or alkyl, n means an integer from 0 to 2; and R' and R" independently means hydrogen, alkyl or heteroalkyl, are not substituted by the groups hydroxy, alkoxy, cyano, halogen or heterocyclyl), -S(O)nR (where n denotes an integer from 0 to 2; and R means hydrogen, alkyl or heteroalkyl, and optionally substituted by hydroxy groups, alkoxy, cyano, halogen or heterocyclyl), -S(O)nNRR' (where n denotes an integer from 0 to 2 and R and R' independently of the means hydrogen, alkyl or heteroalkyl and optionally substituted by hydroxy groups, alkoxy, cyano, halogen or heterocyclyl), -COOR, -(alkylene)COOR (where R is hydrogen or alkyl), -CONR'R or -(alkylene)CONR'R" (where R' and R" independently denote hydrogen or alkyl or together with the nitrogen atom to which they are attached, form a heterocyclic ring).

The term ”optionally substituted aryl, heteroaryl or heterocyclyl” means aryl, heteroaryl or heterocyclyl ring, as described above, which is optionally independently substituted by 1 or 2 substituents selected from the group comprising alkyl, phenyl, benzyl, halogenated, heteroalkyl, halogen, cyano, acyl, -OR (where R is hydrogen or alkyl), -NRR' (where R and R' independently are selected from the group including hydrogen, acyl or alkyl), -NHCOR (where R is alkyl), -NRS(O)nR' (where R is hydrogen or alkyl, n means an integer from 0 to 2 and R' denotes hydrogen, alkyl or heteroalkyl), -NRS(O)nNR'r R" (where R is hydrogen or alkyl, n denotes a Prime number from 0 to 2 and R' and R" independently denote hydrogen, alkyl or heteroalkyl), -S(O)nR (where n denotes an integer from 0 to 2 and R means hydrogen, alkyl or heteroalkyl), -S(O)nNRR' (where n denotes an integer from 0 to 2 and R and R' independently denote hydrogen, alkyl or heteroalkyl), -COOR, -(alkylene)COOR (where R is hydrogen or alkyl), -CONR'R or -(Ala is flax)CONR'R" (where R' and R" independently denote hydrogen or alkyl).

The term ”heteroalkyl” means an alkyl radical, as defined above, containing 1, 2 or 3 substituent, which is selected from-NRaRb, -ORcwhere Ra, Rband Rcindependently of one another denote hydrogen, alkyl or acyl, or Raand Rbtogether form a group of heterocyclimamines. Typical examples include, without limitation, hydroxymethyl, acetoxymethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, 2-methoxyethyl, 2-amino-ethyl, 2-dimethylaminoethyl, 2-acetamidomethyl, 3-[pyrrolidin-1-yl]ethyl etc.

The term ”heteroalkyl” means alkanniny radical, as defined above, containing 1 or 2 substituent, which is selected from-NRaRb, -ORcor-S(O)nRdwhere Ra, Rband Rcindependently of one another denote hydrogen or alkyl, Rdmeans alkyl or-NRR' (where R and R' independently of one another denote hydrogen or alkyl). Typical examples include, without limitation, 3-hydroxy-1-propenyl, 3-aminopropan-1-enyl, 2-aminoanthracene, 2-methylsulfonylamino etc.

The term ”heteroalkyl” means alkynylaryl radical, as defined above, containing 1 or 2 substituent, which is selected from-NRaRb, -ORc, -S(O)nRdor-S(O)nNRR' (where R and R' independently of one another denote hydrogen or alkyl), where Ra, R band Rcindependently of one another denote hydrogen or alkyl and Rdmeans alkyl, and n means an integer from 0 to 2. Typical examples include, without limitation, 3-hydroxy-1-PROPYNYL, 3-dimethylaminopropan-1-inyl etc.

The term ”heteroatomic” means a radical-OR where R means heteroalkyl group as defined above, for example, 2-hydroxyethoxy, 3 hydroxypropoxy, 2,3-dihydroxypropane, 2-aminoethoxy etc.

The term ”heteroalkyl” means a radical-NRaRbwhere Rameans hydrogen or alkyl, and Rbmeans heteroalkyl group as defined above, for example 2-hydroxyethylamino, 3 dimethylaminopropylamine etc.

The term ”optionally substituted geterotsiklicheskikh” means a radical-RaRbwhere Rameans alkylenes group, a Rboptionally substituted heterocyclyl group, as defined above, for example 2-(morpholine-4-yl)ethyl, 3-(piperidine-1-yl)-2-methylpropyl etc.

The term ”optionally substituted heterocyclisation” means a radical-RaRbwhere Rameans alkynylamino group, and Rboptionally substituted heterocyclyl group, as defined above, for example 3-(morpholine-4-yl)prop-1-enyl, 3-(piperidine-1-yl)prop-1-enyl, 3-(4-methylpiperazin-1-yl)prop-1-enyl etc.

The term ”optional someseni geterotsiklicheskikh” means a radical-R aRbwhere Rameans alkylamino group, and Rboptionally substituted heterocyclyl group, as defined above, for example 3-(morpholine-4-yl)prop-1-inyl, 3-(piperidine-1-yl)prop-1-inyl etc.

The term ”optionally substituted, geterotsiklicheskikh” means a radical-OR where R is optionally substituted heterocyclyl group, as defined above, for example 2-(morpholine-4-yl)ethoxy, 3-(piperazine-1-yl)propoxy, 2-[2-oxopyrrolidin-1-yl]ethoxy etc.

The term ”optionally substituted, heterocyclisation” means a radical-NRaRbwhere Rameans hydrogen or alkyl, and Rboptionally substituted heterocyclisation group, as defined above, for example 2-(pyrrolidin-2-yl)ethylamino, 3-(piperidine-1-yl)propylamino etc.

The term ”optionally substituted, heteroaromatic” means the radical-O-Rawhere Rameans heteroalkyl radical, for example 2-(pyridin-3-yl)ethoxy, 2-[3(2H)-pyridazin-1-yl]ethoxy etc.

The term ”optional” means that sequentially described event or circumstance may occur or do not occur and that the description includes instances where the event or circumstance occurs or does not occur. For example, the term ”aryl group optionally mono - or disubstituted by alkyl group”means an alkyl group in outstay or missing, and the description includes instances when the aryl group is mono - or tizamidine alkyl group, and when heterocycla the group is not substituted by an alkyl group.

The term ”aminosidine group” means those organic groups intended to protect nitrogen atoms against undesirable reactions during the synthesis process, for example benzyl, antioxygenic (CBZ), tert-butoxycarbonyl (BOC), TRIFLUOROACETYL, etc.

In the present invention is selected only such groups and their substituents, which form a sustainable residues and compounds, as is well known to specialists in this field of technology. It should also be understood that the chemical groups described in this context, are substituted or unsubstituted, branched or unbranched, depending on each specific case.

In the present invention includes all stereoisomers of the compounds in the form of mixtures thereof, in pure form or in almost pure form. Definition of the compounds of the present invention includes all possible stereoisomers and their mixtures. In the present invention included racemic form of the individual optical isomers, characterized by a specific activity. Racemic forms separated by physical methods, such as, for example, fractional crystallization, separation or crystallization diastereomers the x derivatives or separation by chromatography on a chiral column. Individual optical isomers is obtained from the racemate by standard techniques, such as, for example, the formation of salts with optically active acid followed by crystallization.

Compounds of the present invention can also include their prodrugs. Any compound that is converted in vivo into the bioactive agent is called a prodrug. In the art there are known various forms of prodrugs. Examples of such prodrugs, see, for example, in the works:

a) Design of Prodrugs, edited by .Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited .Widder, and others (Acamedic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and .Bundgaard, Chapter 5 ”Design and Application of Prodrugs,” .Bundgaard, c.113-191 (1991), and

in) .Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992),

each of which is included in the description by reference.

Used in this context, the term ”treatment” means any method, according to which one or more symptoms of diseases or disorders weakened or otherwise changed for the better. The term ”treatment” also includes any pharmaceutical use of the compounds and compositions of the present invention, such as use for the treatment of diseases or disorders mediated by kinase R, or diseases and disorders associated with the activity of the kinase R, including kinase 38α and 38β.

Used on nom context, the term ”reduce the symptoms of a particular disease with the introduction of specific compounds or specific pharmaceutical composition” means any decrease in the intensity of symptoms, permanent or temporary, lasting or transient that occurs when the action or due to the introduction of the composition.

Used in this context, the term ”IC50” means the amount, concentration or dosage of a specific investigational compound that causes 50% inhibition of a maximal response, such as modulation of the activity of the kinase 38α, which is determined by a special method of analysis.

B. Connection

Data analysis the activity of the kinase R, including kinase 38α and 38β suggests that the compounds of the present invention are active. In one embodiment, the invention includes compounds of the present invention characterized by formula I

or their pharmaceutically acceptable derivatives, where:

R1means hydrogen, acyl, or-P(O)(OH)2;

R2means hydrogen, halogen, alkyl or alkylthio;

And means aryl, heteroaryl or heterocyclic ring, optionally condensed with a phenyl cycle, provided that the heterocyclic ring is attached to a carbonyl group through a carbon atom in the cycle;

In means aryl or heteroaryl;

With mean 5-membered heteroaryl containing one or two heteroatoms in the loop;

D means heteroaryl, optionally substituted heteros is aryl or-C(O)NR 80R81where R80and R81independently mean hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;

R3choose from a group including:

(a) amino, alkylamino or dialkylamino,

(b) acylamino,

(C) optionally substituted heterocyclyl,

(d) optionally substituted aryl or heteroaryl,

(e) heteroalkyl,

(e) heteroalkyl,

(g) heteroalkyl,

(C) heterologic,

(and) heteroalkyl,

(K) optionally substituted geterotsiklicheskikh,

(l) optionally substituted heterocyclisation,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh or heterocyclics,

(o) optionally substituted by heterocyclisation,

(p) optionally substituted geterotsiklicheskikh,

(p) geterofullereny,

(s) -NHSO2R6where R6means alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh,

(t) -NHSO2NR7R8where R7and R8independently of one another denote hydrogen, alkyl or heteroalkyl,

(y) -Y-(alkylene)-R9where Y represents a simple bond, -O-, -NH - or-S(O)n- (where n denotes an integer from 0 to 2), R9means halogen, cyano, optionally substituted aryl, optionally substituted the initial heteroaryl, optionally substituted heterocyclyl, -COOH, -COR10, -COOR11, -CONR12R13, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where R10means alkyl or optionally substituted heterocyclyl, R11means alkyl, and R12, R13, R14, R15, R16, R17, R18and R19independently of one another denote hydrogen, alkyl or heteroalkyl,

(f) -C(=NR20)(NR21R22), where R20, R21and R22independently mean hydrogen, alkyl or hydroxy, or R20and R21together denote -(CH2)n-where n is 2 or 3, and R22means hydrogen or alkyl,

(x) -NHC(X)NR23R24where X is-O - or-S-, and R23and R24independently of one another denote hydrogen, alkyl or heteroalkyl,

(C) -CONR25R26where R25and R26independently mean hydrogen, alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh, or R25and R26together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring,

(h) -S(O)nR27where n means an integer from 0 to 2, or R27means alkyl, heteroalkyl, optionally substituted geterotsiklicheskikh or-NR28R29where R28and R29the independent is on from each other denote hydrogen, alkyl or heteroalkyl,

(W) cycloalkenyl, cycloalkenyl and cycloalkylcarbonyl, all optionally substituted by alkyl groups, halogen, hydroxy or amino,

(y) alluminare or heteroarylboronic,

(e) Z-alkylene-NR30R31or Z-alkylene-OR32where Z denotes-NH-, -N((ness.)alkyl) -, or-O-, and R30, R31and R32independently of one another denote hydrogen, alkyl or heteroalkyl,

(h) -OC(O)-alkylene-CO2H or-OC(O)-NR'r R” (where R' and R” independently denote hydrogen or alkyl),

(I) heteroelement or heteroarylboronic;

(AA) hydrogen

(BB) halogen,

(BB) pseudohalogen,

(gg) hydroxy,

(DD) optionally substituted alkoxy,

(it) C(L)R40where L is O, S or NR55, R40means hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted of heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halogen, pseudohalogen, OR55, SR55, NR57R58or SiR52R53R54; where R52, R53and R54choose, as described in the following paragraphs (I) or (ii): (I) R52, R53and R54each independently mean hydrogen, and the keel, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55or NR62R63or (ii) any two of R52, R53and R54together form alkylene, albaniles, akinyan, heteroalkyl, while others choose, as described in paragraph (I); R55means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R56means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55or NR64R65where R64and R65each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR66or NR62R63or R64and R65together form alkylene, albaniles, akinyan, heteroalkyl, where R66means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R57and R58choose, as described in the following paragraphs (I) or (ii): (I) R57and R58each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55, NR67R68or C(L)R69where R67and R68each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl, or these replace the Fort worth together form alkylene, albaniles, akinyan, heteroalkyl, and R69means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR70or NR62R63where R70means alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or (ii) R57and R58together form alkylene, albaniles, akinyan, heteroalkyl; R62and R63each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or R62and R63together form alkylene, albaniles, akinyan, heteroalkyl, and

(ii) optionally substituted alkyl,

R4selected from the group including

(a) hydrogen,

(b) halogen,

(b) alkyl,

(g) alkoxy and

(d) hydroxy,

R5selected from the group including

(a) hydrogen,

(b) halogen,

(b) alkyl,

(d) halogenated,

(e) thioalkyl,

(e) hydroxy,

(g) amino,

(C) alkylamino,

(and) dialkylamino,

(K) heteroalkyl,

(l) optionally substituted heterocycle,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh,

(o) alkylsulfonyl,

(p) aminosulfonyl, monoalkylamines or dialkylaminoalkyl,

(R) heteroatomic and

(C) carboxy;

R6choose from a group, Lucaya

(a) hydrogen,

(b) halogen,

(C) alkyl and

(g) alkoxy.

In one embodiment, the second means a 5-membered heteroaryl ring containing in cycle 1 or 2 heteroatoms. In another embodiment, To select from a group comprising pyrazole, imidazole, pyrrole, thiazole, isothiazol, oxazol, isoxazol, furan and thiophene. In another embodiment, by means of a pyrazole or imidazole. In yet another embodiment With means imidazole. In one embodiment, the second means pyrazole.

1. Derivatives of pyrazole

In one embodiment of the present invention With means pyrazol ring, and the invention includes compounds characterized by formula II

or their pharmaceutically-acceptable derivatives, which featured the substituents defined in this context.

In this embodiment, the hydrogen of the NH group in the ring is replaced by one of the substituents shown in the structure (for example, -C(O)-(A)(R3)(R4), -R2or-B(D)(R6R5)).

In another embodiment, the present invention includes compounds characterized by formula III

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In one embodiment, the present invention includes compounds characterized by the formula IV

or farm citiesi acceptable derivatives, in which these substituents are defined in this context.

In another embodiment, the present invention includes compounds characterized by the formula V

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In one embodiment, the present invention includes compounds characterized by the formula Va

or their pharmaceutically acceptable derivatives, where A, D, R3, R4and R6defined in this context.

2. Imidazole derivatives

In another embodiment, the present invention includes compounds of the imidazole of formula VI

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In this embodiment, the hydrogen of the NH group in the loop is replaced by one of the substituents shown in the structure (for example, -C(O)-A(R3)(R4), -R2or(D)(R6)(R5)).

In another embodiment, the invention includes compounds characterized by formula VII

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

In yet another embodiment, the invention includes compounds, characterizational VIII

or their pharmaceutically acceptable derivatives, in which these substituents are defined in this context.

3. Other embodiments of the present invention

In other embodiments, use of compounds characterized shown above formulas, or their pharmaceutically acceptable derivatives, where R1means hydrogen. In one embodiment, R2means hydrogen or (ness.)alkyl. In another embodiment, R2means hydrogen.

In another embodiment, G means OR83or NR80R81. In another embodiment, R83means alkyl or cycloalkyl. In one embodiment, R83means alkyl. In another embodiment, R83means ethyl. In another embodiment, R80and R81each independently mean hydrogen or cycloalkyl. In one embodiment, R80and R81each independently means hydrogen, alkyl or cycloalkyl. In another embodiment, R80and R81each independently mean hydrogen or cyclohexyl. In one embodiment, the G means NH2or NH (cyclohexyl).

In another embodiment, G denotes aryl, heteroaryl, cycloalkyl, heterocyclyl or heterocyclic ring, optionally condensed with a phenyl ring, and substituted groups R3and R4provided that the heterocyclic ring attached to the carbonyl group is e through the carbon atom in the cycle. In one embodiment, the G means phenyl, cyclohexyl, cyclopentyl or benzyl and substituted groups R3and R4. In another embodiment, G means phenyl and substituted groups R3and R4.

In one embodiment, a represents aryl ring. In another embodiment a represents a phenyl ring.

In one embodiment, the means In the aryl ring. In another embodiment, means In the phenyl ring.

In one embodiment, D is-C(O)NR80R81. In another embodiment, R80and R81each independently mean hydrogen, cycloalkyl or alkoxy. In one embodiment, R80means hydrogen. In another embodiment, R81means cycloalkyl or alkoxy. In one embodiment, R81means3-C6cycloalkyl or C1-C6alkoxy. In another embodiment, R81means cyclopropyl or methoxy.

In one embodiment, D is optionally substituted heteroaryl. In another embodiment, D is optionally substituted triazolyl. In one embodiment, the D means 1,2,4-triazole-3-yl.

In another embodiment, R3means hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R40, halogen, pseudohalogen or or41where L is O, S or NR55, R40means hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optional the nutrient substituted aryl, optionally substituted heteroaryl, optionally substituted of heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R56, halogen, pseudohalogen, OR55, SR55, NR57R58or SiR52R53R54, R41means hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted of heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, C(L)R59, NR60R61or SiR52R53R54where R52, R53and R54choose, as described in the following paragraphs (i) or (ii): (i) R52, R53and R54each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55or NR62R63; or (ii) any two of R52, R53and R54together form alkylene, albaniles, akinyan, heteroalkyl, while others choose, as described in paragraph (i); R55means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R56means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55or NR64 R65where R64and R65each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR66or NR62R63or R64and R65together form alkylene, albaniles, akinyan, heteroalkyl, where R66means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl; R57and R58choose, as described in the following paragraphs (i) or (ii): (i) R57and R58each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55, NR67R68or C(L)R69where R67and R68each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl or heterocyclyl, or these substituents together form alkylene, albaniles, akinyan, heteroalkyl and R69means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR70or NR62R63where R70means alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or (ii), R57and R58together form alkylene, albaniles, akinyan, heteroalkyl; R59means hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, hetero is iklil, OR70or NR62R63; R60and R61each independently mean hydrogen, alkyl, alkenyl, quinil, aritmetikore, heteroaryl, cycloalkyl, heterocyclyl or C(L)R71; where R71means alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, OR55or NR62R63; R60and R61together form alkylene, albaniles, akinyan, heteroalkyl; R62and R63each independently mean hydrogen, alkyl, alkenyl, quinil, aryl, heteroaryl, heteroaryl, cycloalkyl, heterocyclyl, or R62and R63together form alkylene, albaniles, akinyan, heteroalkyl.

In one embodiment, R3means hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R40, halogen or or41. In another embodiment, R3means hydrogen, optionally substituted heterocyclyl, optionally substituted alkyl, C(L)R40, iodine, chlorine or or41. In one embodiment, R3means hydrogen, optionally substituted DIOXOLANYL, optionally substituted methyl, C(L)R40, iodine, chlorine or or41. In another embodiment, R3means hydrogen, 2-DIOXOLANYL, optionally substituted methyl, C(O)R40, iodine, chlorine or or41. In one embodiment, R3means hydrogen, 2-DIOXOLANYL, optionally substituted methyl, What About, iodine, chlorine or or41. In another embodiment, R3means hydrogen.

In one embodiment, R3means optionally substituted methyl. In another embodiment, R3means methyl, which is optionally substituted by groups heterocyclyl, hydroxy, aralkylamines or heterocyclisation. In one embodiment, R3means N-morpholinylmethyl, hydroxymethyl, N-(2-(3-chlorophenyl)-1-ethyl)aminomethyl, N-(2-morpholinyl-1-ethyl)aminomethyl or 4-piperidinylmethyl.

In another embodiment, And means Acting In one embodiment, R40means hydrogen, optionally substituted alkyl or cycloalkyl. In another embodiment, R40means hydrogen or alkyl. In one embodiment, R40means hydrogen.

In another embodiment, R41means hydrogen or optionally substituted alkyl. In another embodiment, R41means hydrogen or alkyl, which is optionally substituted by groups heterocyclyl, aryl, dialkylamino, halogen or hydroxy. In one embodiment, R41means hydrogen or C1-C3alkyl, which is optionally substituted by groups heterocyclyl, phenyl, dialkylamino, halogen or hydroxy. In another embodiment, R41means hydrogen, 2-(N-morpholinyl)ETH-1-yl, benzyl, 2-(N,N-di-(2-hydroxy-1-ethyl)amino)-1-ethyl, 2-bromo-1-ethyl, 2,2-dioxolane-4-ylmethyl, 2-(4-methylpiperazin-1-yl)-1-ethyl or 2,3-dihydroxy-1-propyl. In one embodiment, R41who appoints (S)-2,3-dihydroxy-1-propyl.

In another embodiment, R4means hydrogen. In one embodiment, R5means alkyl. In another embodiment, R5means methyl. In one embodiment, R6means hydrogen.

In another embodiment, use of the compounds characterized shown above formulas, including formulas I-VIII, or their pharmaceutically acceptable derivatives, where:

R1means hydrogen, acyl, or-P(O)(OH)2;

R2means hydrogen, halogen, alkyl or alkylthio;

And means aryl, heteroaryl or heterocyclic ring, optionally condensed with a phenyl ring, provided that the heterocyclic ring is attached to a carbonyl group through a carbon atom in the cycle;

In means aryl or heteroaryl;

D means heteroaryl, optionally substituted heteroaryl or-C(O)NR80R81; where R80and R81independently mean hydrogen, alkyl, cycloalkyl, alkoxy, hydroxy, heteroaryl or optionally substituted heteroaryl;

R3choose from a group including:

(a) amino, alkylamino or dialkylamino,

(b) acylamino,

(C) optionally substituted heterocyclyl,

(d) optionally substituted aryl or heteroaryl,

(e) heteroalkyl,

(e) heteroalkyl,

(g) heteroalkyl,

(C) heterologic,

(and) heteroalkyl,

(K) optionally substituted hetero is EliLilly,

(l) optionally substituted heterocyclisation,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh or heterocyclics,

(o) optionally substituted by heterocyclisation,

(p) optionally substituted geterotsiklicheskikh,

(p) geterofullereny,

(s) -NHSO2R6where R6means alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh,

(t) -NHSO2NR7R8where R7and R8independently of one another denote hydrogen, alkyl or heteroalkyl,

(y) -Y-(alkylene)-R9where Y represents a simple bond, -O-, -NH - or-S(O)n- (where n denotes an integer from 0 to 2) and R9means cyano, optionally substituted heteroaryl, -COOH, -COR10, -COOR11, -CONR12R13, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where R10means alkyl or optionally substituted heterocyclyl, R11means alkyl and R12, R13, R14, R15, R16, R17, R18and R19independently of one another denote hydrogen, alkyl or heteroalkyl,

(f) -C(=NR20)(NR21R22), where R20, R21and R22independently mean hydrogen, alkyl or hydroxy, or R20and R21together imply (CH 2)n-where n is 2 or 3, and R22means hydrogen or alkyl,

(x) -NHC(X)NR23R24where X is-O - or-S-, and R23and R24independently of one another denote hydrogen, alkyl or heteroalkyl,

(C) -CONR25R26where R25and R26independently mean hydrogen, alkyl heteroalkyl or optionally substituted geterotsiklicheskikh, or R25and R26together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring

(h) -S(O)nR27where n means an integer from 0 to 2, or R27means alkyl, heteroalkyl, optionally substituted geterotsiklicheskikh or-NR28R29where R28and R29independently of one another denote hydrogen, alkyl or heteroalkyl,

(W) cycloalkenyl, cycloalkenyl and cycloalkylcarbonyl, all optionally substituted by alkyl groups, halogen, hydroxy or amino,

(y) alluminare or heteroarylboronic,

(e) Z-alkylene-NR30R31or Z-alkylene-OR32where Z denotes-NH-, -N((ness.)alkyl) -, or-O-, and R30, R31and R32independently of one another denote hydrogen, alkyl or heteroalkyl,

(h) -OC(O)-alkylene-CO2H or-OC(O)-NR'r R" (where R' and R" independently denote hydrogen or alkyl), and

(I) heteroelement or heteroarylboronic;

R4in baraut from the group including

(a) hydrogen,

(b) halogen,

(b) alkyl,

(g) alkoxy and

(d) hydroxy,

R5selected from the group including

(a) hydrogen,

(b) halogen,

(b) alkyl,

(d) halogenated,

(e) thioalkyl,

(e) hydroxy,

(g) amino,

(C) alkylamino,

(and) dialkylamino,

(K) heteroalkyl,

(l) optionally substituted heterocycle,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh,

(o) alkylsulfonyl,

(p) aminosulfonyl, monoalkylamines or dialkylaminoalkyl,

(R) heteroatomic and

(C) carboxy.

R6selected from the group including

(a) hydrogen,

(b) halogen,

(C) alkyl and

(d) alkoxy;

their prodrugs, individual isomers, mixtures of isomers and pharmaceutically acceptable salts.

In another embodiment provides compounds where:

R1means hydrogen or acyl,

R2means hydrogen or alkyl,

A represents aryl or heteroaryl ring.

In one embodiment provides compounds where:

R1means hydrogen, acyl, or-P(O)(OH)2;

R2means hydrogen, halogen, alkyl or alkylthio;

And means aryl, heteroaryl or heterocyclyl, optionally condensed with a phenyl ring, provided that the heterocyclic ring also is dinino to a carbonyl group through a carbon atom in the cycle;

In means aryl or heteroaryl;

R3choose from a group including:

(a) amino,

(b) acylamino,

(C) optionally substituted heterocycle,

(d) heteroaryl, optionally substituted with substituents, which are selected from the group comprising halogen, alkyl or alkoxy,

(e) heteroalkyl,

(e) heteroalkyl,

(g) heteroalkyl,

(C) heterologic,

(and) heteroalkyl,

(K) optionally substituted geterotsiklicheskikh,

(l) optionally substituted heterocyclisation,

(m) optionally substituted geterotsiklicheskikh,

(h) optionally substituted by geterotsiklicheskikh,

(o) optionally substituted by heterocyclisation,

(p) optionally substituted geterotsiklicheskikh,

(p) geterofullereny,

(s) -NHSO2R6where R6means alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh,

(t) -NHSO2NR7R8where R7and R8independently of one another denote hydrogen, alkyl or heteroalkyl,

(y) -Y-(alkylene)-R9where Y represents a simple bond, -O-, -NH - or-S(O)n- (where n is an integer from 0 to 2) and R9means cyano, heteroaryl, -COOH, -COR10, -COOR11, -CONR12R13, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where 10means alkyl or optionally substituted heterocycle, R11means alkyl, a R12, R13, R14, R15, R16, R17, R18and R19independently of one another denote hydrogen, alkyl or heteroalkyl,

(f) -C(=NR20)(NR21R22), where R20, R21and R22independently mean hydrogen, alkyl or hydroxy, or R20and R21together denote -(CH2)nwhere n is 2 or 3, and R22means hydrogen or alkyl,

(x) -NHC(X)NR23R24where X is-O - or-S-, and R23and R24independently of one another denotes hydrogen, alkyl or heteroalkyl,

(C) -CONR25R26where R25and R26independently mean hydrogen, alkyl, heteroalkyl or optionally substituted geterotsiklicheskikh, or R25and R26together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring,

(h) -S(O)nR, where n is an integer from 0 to 2, and R27means alkyl, heteroalkyl, optionally substituted geterotsiklicheskikh, or-NR28R29where R28and R29independently of one another denote hydrogen, alkyl or heteroalkyl,

R4selected from the group including

(a) hydrogen,

(b) halogen,

(C) alkyl and

(d) alkoxy;

R5selected from the group including

(the) hydrogen

(b) halogen,

(b) alkyl,

(d) halogenated,

(e) thioalkyl,

(e) hydroxy,

(g) amino,

(C) alkylamino,

(and) dialkylamino,

(K) heteroalkyl,

(l) optionally substituted heterocycle,

(m) optionally substituted geterotsiklicheskikh and

(h) optionally substituted by geterotsiklicheskikh.

R6selected from the group including

(a) hydrogen,

(b) halogen,

(C) alkyl and

(g) alkoxy.

In another embodiment provides compounds where R3means

(a) optionally substituted heterocyclyl,

(b) aryl or heteroaryl, both optional zameshannye substituents, which are selected from the group comprising halogen, alkyl, amino, alkoxy, carboxy, (ness.)alkoxycarbonyl, SO2R' (where R' is alkyl) or-O2NHR'R" (where R' and R" independently denote hydrogen or alkyl),

(C) heteroalkyl,

(g) heteroalkyl,

(d) heteroalkyl,

(e) heterologic,

(g) optionally substituted geterotsiklicheskikh or heterocyclics,

(C) optionally substituted heterocyclisation,

(I) optionally substituted geterotsiklicheskikh,

(K) optionally substituted by geterotsiklicheskikh,

(l) optionally substituted by heterocyclisation,

(m) optionally substituted geterotsiklicheskikh,

(n) -Y(alkylene)-R9where Y means simply the link, -O-, -NH - and R9means optionally substituted heteroaryl, -CONR12R, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where R12, R13, R14, R15, R16, R17, R18and R19independently from each other mean heteroalkyl, hydrogen, alkyl or heteroalkyl,

(o) cycloalkenyl, cycloalkenyl and cycloalkylcarbonyl, all optionally substituted by alkyl groups, halogen, hydroxy or amino,

(p) alluminare or heteroarylboronic or

(R) Z-alkylene-NR30R31where Z denotes-NH-, -N(alkyl) -, or-O-, and R30and R31independently of one another denote hydrogen, alkyl or heteroalkyl.

In another embodiment provides compounds where R1and R2mean hydrogen, and means phenyl. In an additional embodiment provides compounds where R4means hydrogen, a R5means halogen or alkyl. In another embodiment provides compounds where R5means chlorine, fluorine or methyl, and R6means hydrogen, chlorine, fluorine, methyl or methoxy. In one embodiment provides compounds where R3means optionally substituted heteroaryl.

In another embodiment provides compounds where R3means pyridin-2-yl, pyridin-3-yl, pyridine-4-yl, N-oxidability-2-yl, N-oxidability-Il, N-oxidability-4-yl or pyridone-2-yl, all optionally substituted. In another embodiment provides compounds where R3is in position 3. In another embodiment provides compounds where R5means 4-F or 2-IU, and R6means hydrogen. In one embodiment provides compounds where R3optionally substituted phenyl group.

In an additional embodiment provides compounds where R3mean 3-sulfamoylbenzoyl, 3-methylsulfinylphenyl, 3-carboxyphenyl or 3-ethoxycarbonylphenyl. In another embodiment provides compounds where R5means 4-F, and R6means hydrogen.

In another embodiment provides compounds where R3means

(a) heteroalkyl,

(b) heterologic,

(C) heteroalkyl,

(g) optionally substituted geterotsiklicheskikh,

(d) optionally substituted by geterotsiklicheskikh,

(e) optionally substituted by heterocyclisation,

(W) -Y-(alkylene)-R9where Y represents a simple bond, -O - or-NH - and R9means optionally substituted heteroaryl, -CONR12R13, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where R12, R13, R14, R15, R16, R17, R18and R19independently of one another denote hydrogen, alkyl or heteroalkyl, or

<> (C) Z-alkylene-NR30R31where Z denotes-NH-, -N(alkyl) -, or-O-, and R30and R31independently of one another denote hydrogen, alkyl or heteroalkyl.

In another embodiment provides compounds where R3means heteroalkyl. In another embodiment provides compounds where R3is in position 3 and it is chosen from the group comprising 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminomethyl, 2-diethylaminoethylamine, 3 dimethylaminopropylamine, hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl or 3-hydroxybutyl. In one embodiment provides compounds where R5mean 2-F, a R6means 4-F.

In another embodiment provides compounds where R5means 2 is Me and R6means hydrogen. In an additional embodiment provides compounds where R9means heteroatomic or heteroalkyl. In one embodiment provides compounds where R3is in position 3 and it is chosen from the group comprising 3-dimethylaminopropoxy, 2-dimethylaminoethoxy, 2-hydroxyethoxy, 2,3-dihydroxypropane, 2-diethylaminoethylamine and 3 dimethylaminopropylamine.

In another embodiment provides compounds where R3means optionally substituted geterotsiklicheskikh, optionally substituted, geterotsiklicheskikh or optionally substituted heterocyclyl the laminitis. In one embodiment provides compounds where R3is in position 3 and it is chosen from the group comprising 3-(morpholine-4-yl)propoxy, 2-(morpholine-4-yl)ethoxy, 2-(2-oxopyrrolidin-1-yl)ethoxy, 3-(morpholine-4-yl)propyl, 2-(morpholine-4-yl)ethyl, 4-(morpholine-4-yl)butyl, 3-(morpholine-4-yl)propylamino, 2-(morpholine-4-yl)ethylamino, 4-hydroxypiperidine, 2-(S,S-diocletianopolis-4-yl)ethyl, 3-(S,S-diocletianopolis-4-yl)propyl and N-methylpiperazine.

In yet another embodiment provides compounds where R3means-Y-(alkylene)-R9where Y represents a simple bond, -O - or-NH - and R9means optionally substituted heteroaryl, -CONR12R13, -SO2R14, -SO2NR15R16, -NHSO2R17or-NHSO2NR18R19where R12, R13, R14, R15, R16, R17, R18and R19independently of one another denote hydrogen, alkyl or heteroalkyl. In yet another embodiment provides compounds where Y represents a simple bond, and R9means-SO2R14or-SO2NR15R16.

In another embodiment provides compounds where R3mean 5-methylsulfonylmethyl or sulfanilate.

In one embodiment, the compounds are selected from the group consisting of 5-amino-1-(4-forfinal)-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole, 5-amino-1-(2,4-differenl)-4-[3-(3-morpholine-ylpropyl)benzoyl]pyrazole, 5-amino-4-(3-aminobenzoyl)-1-(4-forfinal)pyrazole, 5-amino-1-(4-forfinal)-4-[3-(3-morpholine-4-ylpropyl)benzoyl]pyrazole, 5-amino-4-[3-(2-aminosulfonyl)benzoyl]-1-(4-forfinal)pyrazole, 5-amino-4-(3-acetylaminobenzoic)-1-phenylpyrazole, 5-amino-4-[3-(2-amino-ethyl)benzyl]-1-(4-forfinal)pyrazole, 5-amino-1-(4-forfinal)-4-[3-(3-morpholine-4-ylpropionic)benzoyl]pyrazole, 5-amino-4-[3-(2-aminosulfonyl)benzoyl]-1-(4-forfinal)pyrazole and 5-amino-1-(4-forfinal)-4-(3-pyridin-3-aventyl)pyrazole.

In another embodiment the compounds are selected from the group consisting of 5-amino-1-(2-were)-4-[3-pyridin-3-yl)benzoyl]pyrazole, 5-amino-1-(2-were)-4-[3-(N-oxidability-3-yl)benzoyl]pyrazole, 5-amino-4-[3-(2,3-dihydroxypropane)benzoyl]-1-(4-forfinal)pyrazole, 5-amino-4-[3-(1,2-dihydroxyethyl)benzoyl]-1-(4-forfinal)pyrazole, 5-amino-1-(4-forfinal)-4-[3-(sulfamoylbenzoyl]pyrazole, 5-amino-1-(4-forfinal)-4-[3-(3-hydroxy-3-methylbutyl)benzoyl]pyrazole, 5-amino-1-(4-forfinal)-4-[3-(2-(1-hydroxycyclopent)ethyl)benzoyl]pyrazole, 5-amino-4-[3-(2-methylsulfonylamino)benzoyl]-1-(4-forfinal)pyrazole and 5-amino-1-(2,4-differenl)-4-[3-(2-hydroxyarylalkyl)benzoyl]pyrazole.

In one embodiment, the compound is chosen from the group comprising 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-methoxy-4-methylbenzamide, 3-(5-amino-4-benzoimidazol-1-yl)-N-methoxy-4-methylbenzamide, 3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid -(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-4-methylbenzoic acid, 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, {5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]-1H-pyrazole-4-yl}phenylmethanone, 3-[5-amino-4-(3-[1,3]dioxolane-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-hydroxymethylbenzene)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-{5-amino-4-[3-(4-methylpiperazin-1-ylmethyl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-morpholine-4-iletilmistir)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-morpholine-4-iletilmistir)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide and 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide.

In another embodiment the compounds are selected from the group comprising 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-methoxy-4-methylbenzamide, 3-(5-amino-4-benzoimidazol-1-yl)-N-methoxy-4-methylbenzamide, 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, {5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)-phenyl]-1H-pyrazole-4-yl}eileanan, 3-[5-amino-4-(3-[1,3]dioxolane-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-hydroxymethylbenzene)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-{5-amino-4-[3-(4-methylpiperazin-1-ylmethyl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-morpholine-4-iletilmistir)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-morpholine-4-iletilmistir)-pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, 3-[5-amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide or 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide.

In another embodiment the compounds are selected from the group including

3-{5-amino-4-[3-(2-dimethylaminoethanol)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(5-chlorothiophene-2-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-hydrazinobenzothiazole)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-cyclohexylcarbodiimide-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-phenylacetylamino-1-yl)-N-cyclopropyl-4-methylbenzamide,

-[5-amino-4-(tetrahydropyran-4-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-ethylcarboxylate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide and

3-[5-amino-4-(3-isopropylcarbamate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide.

In yet another embodiment the compounds are selected from the group including

ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methyl-1H-pyrazole-4-carboxylic acid,

ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,

3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-hydrazinobenzothiazole)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

benzylated 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,

3-(5-amino-4-cyclohexanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide and

cyclohexylamin 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid.

In another embodiment the compounds are selected from the group including:

amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid,

amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methanesulfonyl-1H-pyrazole-4-carboxylic acid,

ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid,

ethyl ester of 5-amino-3-[(3-chlorobenzylamino)methoxy]--(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,

3-[5-amino-4-benzoyl-3-(piperidine-4-yloxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoyl-3-methanesulfonamido-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide,

ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-(2-hydroxyethoxy)-1H-pyrazole-4-carboxylic acid,

tert-butyl ester 4-[5-amino-4-benzoyl-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-3-yloxy]piperidine-

1-carboxylic acid,

3-(5-amino-4-benzoyl-3-methylsulfonylbenzoyl-1-yl)-N-cyclopropyl-4-methylbenzamide and

3-[5-amino-4-benzoyl-3-(2-methoxyethoxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide.

In another embodiment the compounds are selected from the group including:

3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-methoxy-4-methylbenzamide,

3-(5-amino-4-benzoimidazol-1-yl)-N-methoxy-4-methylbenzamide,

3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid,

3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-4-methylbenzoic acid,

3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

{5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]-1H-pyrazole-4-yl}phenylmethanone,

3-[5-amino-4-(3-[1,3]dioxolane-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-qi is sapropel-4-methylbenzamide,

3-[5-amino-4-(3-hydroxymethylbenzene)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-{5-amino-4-[3-(4-methylpiperazin-1-ylmethyl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-morpholine-4-iletilmistir)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-{5-amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-cyclohexylcarbodiimide-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-phenylacetylamino-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-isopropylcarbamate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-{5-amino-4-[3-(2-dimethylaminoethanol)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-ethylcarboxylate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-methylcarbamoylmethyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(3-cyclopropanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-and the Ino-4-(3-cyclopentanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-{5-amino-4-[3-(morpholine-4-carbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,

3-{5-amino-4-[3-(cyclopropanecarbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-(tetrahydropyran-4-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoyl-3-ethoxypyrazine-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-benzoyl-3-(2-methoxyethoxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-[5-amino-4-benzoyl-3-(2-benzyloxyethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

tert-butyl ester 4-[5-amino-4-benzoyl-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-3-yloxy]piperidine-1-

carboxylic acid,

triptorelin 3-[5-amino-4-benzoyl-3-(piperidine-4-yloxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoyl-3-methylsulfonylbenzoyl-1-yl)-N-cyclopropyl-4-methylbenzamide,

3-(5-amino-4-benzoyl-3-methanesulfonamido-1-yl)-N-cyclopropyl-4-methylbenzamide,

amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid,

amide 5-Amino-1-(5-cyclopropanecarbonyl-2-were)-3-methanesulfonyl-1H-pyrazole-4-carboxylic acid and

ethyl ester of 5-Amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid.

Century With ntes connections

In the present invention it is also proposed a method of obtaining the compounds of formula (I), and this method includes the following stages:

(i) the interaction of 2-keto-3-phenylaminopyrimidine formula 1:

with a hydrazine of formula 2

where R3, R4, R5and R6defined above, by the connection of the formula (I), where R1means hydrogen, or

(ii) the interaction of 2-keto-3-phenylaminopyrimidine formula 3

where Z signifies hydroxy, nitro or halogen and R4defined above, with a hydrazine of formula 2, you get a compound of formula 4

with the subsequent conversion of the group Z in the desired group R3while getting the connection formula (I), where R1means hydrogen;

(iii) an optional modification of any of the groups R1, R3, R', R5or R6;

(iv) optional conversion of the compounds of formula (I)obtained in stage (i), (ii) or (iii)described above, into the corresponding acid additive salt by acidification;

(v) optional conversion of the compounds of formula (I)obtained in stage (i), (ii) or (iii)described above, into the corresponding free base by treatment with base and

(vi) an optional section is of a mixture of stereoisomers of the compounds of formula (I), obtained at stages (i)to(v)described above, thus receive individual stereoisomer.

In the present invention it is also proposed a method of obtaining the compounds of formula I, which includes the interaction of the compounds of formula 5

where R5and R6defined above, L denotes a leaving group in the reaction conditions ORGANOMETALLIC substitution, which includes but not limited to halogen, pseudohalogen, aryloxy, perforations, N-alkoxyamino, including N-methoxyamino,

with an ORGANOMETALLIC reagent of the formula

where R3and R4defined above, and M indicates a metal atom, including, without limitation, alkali metal, alkaline earth metal and a transition metal, such as Li, K and Mg, you get a compound of formula (I), where R1means hydrogen,

(ii) an optional modification of any of the groups R1, R3, R4, R5or R6;

(iii) optional conversion of the compounds of formula (I)obtained in stage (i) or (ii)described above, into the corresponding acid additive salt by acidification;

(iv) optional conversion of the compounds of formula (I)obtained in stage (i) or (ii)described above, into the corresponding free base by treatment basis is a W, and optional separation of a mixture of stereoisomers of the compounds of formula (I)obtained in stage (i) or (iv)described above, thus receive individual stereoisomer.

Described in this connection are presented as examples, and they can be obtained by known methods, in the same way as described in the present invention, using known methods of chemical synthesis, including methods similar to those described in the Examples section below.

Proposed in the present invention compounds are usually obtained in the following schemes, as well as by known methods. Additional methods of synthesis are described, for example, in US patents No. 6376527, 6316466 and 6444696 and in international application number WO 99/57101, all of which are included in the present invention by reference.

In addition to these documents, the present invention presents the following examples of ways (without limitation) obtaining compounds of the present invention (see below scheme 1-8).

As intermediate compounds according to the present invention using amines attached to the aryl or heteroaryl ring system. There are many methods of obtaining such intermediate compounds. Several ways to obtain the amines used to produce compounds of the present invention, showing the and schemes 1-7.

Substituted anilines of type (II)used in the present invention, obtained from a commercial preparation of 3-amino-4-methylbenzoic acid as shown in scheme 1, using methods similar to that described in international application number WO 02/40486. The amino group in the structure of aniline is protected by a Boc group. This is followed by a condensation with methylamine in the presence of condensing agents EDC and HOBt. The Boc group is removed using HCl in dioxane, and thus receive the desired substituted aniline of type (II) as hydrochloride.

Scheme 1

Substituted anilines of type (III)used in the present invention, obtained from a commercial preparation of 3-amino-4-methylbenzoic acid as shown in scheme 2. After condensation with cyclopropylamine in the presence of a condensing agent EDC receive aniline of type (III).

Scheme 2

Substituted anilines of type (IV)used in the present invention, obtained from a commercial preparation of 4-methyl-3-nitrobenzoic acid as shown in scheme 3, using methods similar to that described in international application number WO 03/033482. After condensation of the acid with tert-butoxycarbonylmethyl in the presence of a condensing agent HBTU and HOBt get protected acylhydrazides. After removal of the protective groups in the presence of the FU and condensation with triethylorthoformate get oxadiazolidine nitrotoluene. After hydrogenation of nitro groups get the desired aniline of type (IV).

Scheme 3

Substituted anilines of type (V)used in the present invention, obtained from a commercial preparation of 4-methyl-3-nitrobenzamide, as shown in figure 4, using the methods described in the work of Han and others J. Med. Chem., 41, 2019-2028 (1998). Specified arylcarboxamide condense with diethylacetal N,N-dimethylformamide. This is followed by reaction with hydrazine in acetic acid, while getting triazolylmethyl nitrotoluene. After hydrogenation of nitro groups get the desired aniline type (V).

Scheme 4

Substituted anilines of type (VI)used in the present invention, obtained from a commercial preparation of methyl ester of 4-iodobenzoyl acid as shown in scheme 5. After nitration of aromatic precursor, followed by reduction of the nitro aniline get. This is followed by a condensation with amenitiesalarm in the presence of a catalyst based on palladium, followed by disilylgermane and saponification, thus receive the desired ethynylpyridine the aminobenzoic acid. By condensation with methoxamine in the presence of a condensing agent EDC get the desired aniline (VI). See, for example, Eur. J. Org. Chem; 4607 (2001).

Scheme 5

In another embodiment, the substituted aniline of type (VI)used in the present invention, is obtained from 4-amino-3-nitrobenzoic acid as shown in scheme 6. After substitution reactions of diazogroup on iodine using diazonium salts with subsequent esterification with methanol to obtain methyl ester of 4-iodine-3-nitrobenzoic acid. The nitrogroup restore SnCl2will get the desired aniline. This is followed by a condensation with amenitiesalarm in the presence of a catalyst based on palladium, followed by disilylgermane and saponification, thus receive ethynylpyridine the aminobenzoic acid. By condensation with methoxamine in the presence of a condensing agent EDC get the desired aniline (VI). See, for example, Eur. J. Org. Chem., 4607 (2001).

Scheme 6

As shown in figure 7, the substituted anilines of type (VII)used in the present invention, is obtained from the intermediate methyl ester 4-itrinternet acids, which are synthesized as shown in scheme 6. This is followed by a condensation with vinyltrimethylsilane using a catalyst based on palladium, and subsequent merger of the vinylcarbene to the resulting styrene double bond, thus receive cyclopropylmethyl methyl ether nitrobenzoic acid. After the restoration of the nitro group followed the introduction is by protective groups are Boc and saponification get protected 3-amino-4-cyclopropylbenzene acid. After condensation with alkoxyamine in the presence of a condensing agent EDC get the desired aniline (VII). See, for example, international application no WO 02/092087 and WO 02/40486.

Scheme 7

As intermediate compounds according to the present invention using hydrazines attached to the aryl or heteroaryl ring system. There are many methods of obtaining such intermediate compounds. An example of such a method of obtaining some of the hydrazines used in the present invention, is shown in scheme 8.

Arylhydrazines type (VIII)used in the present invention, is obtained from the hydrochloride of 3-amino-N-methoxy-4-methylbenzamide, which is produced according to the methods described in international application number WO 02/40486. After the formation of the salt of aryldiazonium and its subsequent recovery SnCl2get the desired hydrazine type (VIII).

As shown in scheme 8, arylhydrazines type (IX)used in the present invention, is obtained from 3-amino-N-cyclopropyl-4-methylbenzamide, which is produced according to the methods shown in scheme 2. After the formation of the salt of aryldiazonium and its subsequent recovery SnCl2get the desired hydrazine type (IX).

Similarly you can get other hydrazines of the amines shown above in schemes 1-7.

Scheme 8

As shown in scheme 9, Acrylonitrile type (X)used in the present invention, is obtained from kilowog ether and acetonitrile. Acetonitrile is treated with diisopropylamide lithium in THF at -78°C, then add arrowy ether, thus receive the appropriate allolactose. The obtained intermediate compound is introduced into reaction with N,N'-diphenylformamidine in a solvent such as toluene at the boiling temperature of the solvent, thus receive the corresponding Acrylonitrile type (X).

Scheme 9

As shown in scheme 10, aminopyrazole type (XI)used in the present invention, derived from Acrylonitrile type (X), which is produced according to the methods shown in scheme 9, and hydrazines such as hydrazine type (VIII) and (IX), which is obtained by the methods shown in scheme 8. Acrylonitrile and hydrazine are heated at a temperature of from 60 to 100°C. in a solvent such as DMF or ethanol, thus receive the desired aminopyrazole type (XI).

Scheme 10

As shown in scheme 11, aminopyrazole type (XIII)used in the present invention, derived from Acrylonitrile type (XII), which is produced during the processing of Acrylonitrile type (X)obtained by the methods shown in scheme 9, sodium hydride and the disulfide angle of the ode with subsequent processing iodomethane, and hydrazines such as hydrazine type (VIII) and (IX), which is obtained by the methods shown in scheme 8. Acrylonitrile and hydrazine are heated at a temperature of from 60 to 100°C. in a solvent such as DMF or ethanol, thus receive the desired aminopyrazole type (XIII).

Scheme 11

As shown in figure 12, aminopyrazole type (XIV)used in the present invention, derived from Acrylonitrile type (XII), which is produced according to the methods shown in scheme 11, and hydrazines such as hydrazine type (VIII) and (IX), which is obtained by the methods shown in scheme 8. When processing the obtained intermediate compound (XII) an alcoholic solution of alkoxide followed by heating at a temperature of from 60 to 100°C. in the presence of hydrazine in a solvent such as DMF or ethanol, receive required aminopyrazole type (XIII).

Scheme 12

As shown in scheme 13, aminoimidazole type (XV)used in the present invention, derived from substituted anilines of type (III), which is obtained by the methods shown in scheme 2. Aniline is heated in triethylorthoformate. After removal of the solvent in vacuo the product is introduced into reaction with para-toluensulfonate of aminomalononitrile and sodium acetate in acetic acid, while the receive intermediate derived aminoglucosides the La. After the interaction of this intermediate compound with a Grignard reagent receive aminoimidazole type (XV).

Scheme 13

Proposed in the present invention compounds derived from hydrazines, attached to the aryl or heteroaryl ring system, using the methods described in US patents No. 6316466, 6376527 and 6444696.

Additional methods of synthesis used in the synthesis of compounds of the present invention, are described in the following scientific journals, which are included in the description of the invention as links:

1. J. Heterocyclic Chem. 17, 631 (1980)

2. Tetrahedron 55(48), 13703 (1999)

3. European Patent No. EP 0713876

4. Chemische Berichte 126(10), 2317 (1993)

5. Journal of Organic Chem. 58(24), 6620 (1993)

6. Tetrahedron Letters 35, 3239 (1973)

7. Journal of Chemical Research, Synopses 1, 2 (1997)

8. Boletin de la Sociedad Quimica del Peru 53(3), 150 (1987)

9. Journal of the Chemical Society, Chemical Communications 2, 35 (1973)

10. Comptes Rendus des Seances de l'academie des Sciences, Series C: Sciences Chimiques 274(20), 1703 (1972)

In the present invention are also compounds that are obtained using the method described in the present invention.

, The Formulations of the pharmaceutical compositions

In the present invention it is also proposed pharmaceutical composition comprising compounds of the present invention. The composition is used, for example, as a drug. The composition with the contains, for example, pharmaceutically acceptable excipient or carrier. The composition or drug of the present invention are used to treat, prevent or ameliorate one or more symptoms of diseases or disorders mediated by kinase R, including inflammatory diseases.

Thus, the present invention offers a pharmaceutical composition intended for the treatment of conditions associated with kinase R, including state-mediated TNF-α, IL-1 and/or IL-8, as described above. The compositions contain other therapeutic agents as described in this context, and get them, for example, using conventional solid or liquid carriers or diluents, as well as pharmaceutical additives of a type depends on the method of administration (for example, fillers, binders, preservatives, stabilizers, flavors, etc.), by known methods.

Compounds of the present invention is administered by any means suitable for this condition is intended to ensure that depend on specific interactions with the binding site or on the number of injected drugs. Local injection is usually used in the treatment of skin diseases and systemic treatment usually use in the treatment of cancer or a precancerous condition is, they may use other methods of drug delivery. For example, the compounds administered orally, in the form of tablets, capsules, granules, powders or liquid compositions, including syrups, local way in the form of solutions, suspensions, gels or ointments, sublingual method; transbukkalno way, parenteral way in the form of subcutaneous, intravenous, intramuscular, vnutrigrudne injection or infusion (e.g., using a sterile aqueous or nonaqueous solutions or suspensions for injection), nazalnam way in the form of aerosols for inhalation, local way in the form of creams or ointments, rectal way in the form of suppositories, or in the form of liposomes. The composition is administered in the form of standard dosage forms containing non-toxic pharmaceutically acceptable carriers or diluents. The compound is administered in a form suitable for immediate or sustained release. Immediate or extended release is achieved with the use of suitable pharmaceutical compositions or primarily, in case of prolonged release using tools such as subcutaneous implants or osmotic pumps. Examples of compositions for the local introduction include local media, such as PLASTIBASE® (gel mineral oil polyethylene).

P is emery compositions for oral administration include suspensions, which contain, for example, microcrystalline cellulose as a filler, alginic acid or sodium alginate as a suspending agent, methylcellulose as a thickener, and sweeteners or flavoring agents, known to experts in the art; tablets for immediate release, which contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, fillers, dezintegriruetsja agents, thinners and oil, well-known specialists in this field of technology. Compounds of the present invention is injected oral, sublingual and/or transbukkalno way, for example, with the use of tablets obtained by molding, extrusion or lyophilization. Typical compositions include dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. These compositions also include macromolecular fillers such as cellulose (AVICEL®) or polyethylene glycol (PEG); fillers to increase the adhesion of the mucous membranes, such as hydroxypropylcellulose (GOC), hypromellose (HPMC), sodium carboxymethyl cellulose (NCMC) and/or copolymer of maleic anhydride (e.g., GANTREZ®), and agents controls the respective vysvobojdenie medicines such as a copolymer of polyacrylic acid (e.g., CARBOPOL 934®). To simplify the production and use of the compositions in them add the oil, glidant, flavorings, colorants and stabilizers.

Typical compositions for nasal injection in the form of an aerosol or inhalation include solutions that contain, for example, benzyl alcohol or other suitable preservatives, absorption accelerators to speed up absorption and/or for increasing the bioavailability and/or other solubilization or dispersing agents known to specialists in this field of technology.

Typical compositions for parenteral administration include solutions or suspensions for injection, which include, for example, suitable non-toxic parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, ringer's solution, isotonic sodium chloride or other suitable dispersing or wetting and suspendresume agents, including synthetic mono - or diglycerides, and fatty acids, including oleic acid.

Typical compositions for rectal injection include suppositories, which contain, for example, suitable not cause irritating excipients such as cocoa butter, synthetic esters of glycerides or polyethylene glycols, which are solid at ordinary who's temperatures and melt and/or dissolve in the rectum to release the drug.

An effective amount of the compounds of the present invention is defined by experts in the field of technology and the typical dose for a mammal is from about 0.05 to 100 mg/kg of body weight of the active ingredient per day, which is administered once or in several separate doses, for example, from 1 to 4 times per day. It should be understood that the number of individual doses and frequency of administration for each subject varies and depends on many factors, including the activity of the used compounds, metabolic stability and validity of the connection, the age, body weight, General health, sex and diet of the subject, the mode and time of administration, rate of excretion, combination with other drugs and the severity of the particular disease. Subjects in need of treatment include animals, especially mammals, such as humans and domestic animals, such as dogs, cats, horses, etc. Thus, the term ”patient”used in this context, includes all subjects, especially mammals, including humans, suffering from a disease associated with different levels of enzyme R.

In one embodiment, the present invention also offers a method of obtaining medicines, which involves mixing the compounds according to the present izopet is in pharmaceutically acceptable excipients and processing the mixture in the prepared herbal form.

D. Methods of using compounds and compositions.

In another embodiment, compounds of the present invention are used to treat, prevent or ameliorate one or more symptoms of inflammatory diseases. In one embodiment, the compounds of the present invention is used to produce medicines for the treatment or prevention of inflammatory diseases.

Compounds of the present invention are selective inhibitors of the kinase activity R and first of all isoforms 38α and 38β. In this regard, the compounds of the present invention is used to treat conditions associated with kinase activity R. Such conditions include diseases in which the level of cytokines is modulated in response to intracellular signal involving R, first of all diseases that are associated with excess biogas produced cytokines IL-1, IL-4, IL-8 and TNF-α. The present invention provides methods of treating diseases with the introduction of the compounds of the present invention, which inhibits the kinase activity R. In the present invention are also methods of suppression or suspension of the development of diseases or disorders with the introduction of the compounds of the present invention. The methods of the present invention can be used to the exclusion or partial reduction of intense the particular symptoms of the disease or condition and/or for attenuating, reduce the intensity or exclusion of diseases or disorders and/or symptoms. The term ”inhibition of kinase R-38α/β” means the inhibition of the kinase 38α and 38β. Thus, the value of the IC50for inhibition of kinase R-38α/β means that the connection is characterized by the efficiency of inhibition of at least one or both kinases 38α and 38β.

Since the compounds of the present invention are active as inhibitors of the kinase R-38α/β, their use for treating conditions mediated R, including, without limitation, inflammatory diseases, autoimmune diseases, increased fragility of bone, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases and viral infections.

More preferably the specific condition or disease, for treating the compounds of the present invention, include, without limitation, pancreatitis (acute or chronic), asthma, allergies, respiratory distress syndrome in adults, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, lupus erythematosus, scleroderma, chronic thyroiditis, graves disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune Nate is opinio, thrombocytopenia, atopic dermatitis, chronic active hepatitis, bulbospinal palsy, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft versus host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, degeneration of muscle tissue, total exhaustion, psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, rubella, acute synovitis, pancreatitis, mediated basophilic islets of Langerhans, disease, characterized by multiple infiltration of neutrophils, rheumatoid spondylitis, gouty arthritis and other arteriopathies conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, sarcoidosis lungs, bone resorption, allograft rejection, fever, and muscle pain caused by infectious disease, exhaustion, caused by infectious disease, the formation of keloid zone, scarring, ulcerative colitis, paresis, influenza, osteoporosis, osteoarthritis and disease of the bone associated with the formation of multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, metstaticescoy melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and bacterial dysentery, b is Alzheimer's disease, Parkinson's disease, cerebral ischemia or neurodegenerative disease caused by traumatic injury, angiogenic diseases, including solid tumors, revascularization in eye tissues and infantile hemangioma, viral diseases including acute hepatitis (including hepatitis a, hepatitis b and hepatitis C, human immunodeficiency virus (HIV), retinitis caused by cytomegalovirus, acquired immunodeficiency syndrome (AIDS), severe acute respiratory syndrome (SARS), AIDS-associated complex, or malignant disease and herpes, stroke, myocardial ischemia, ischemia in myocardial infarction, hypoxia bodies, vascular hyperplasia, cardiac or renal reperfusion injury, thrombosis, cardiac hypertrophy, platelet aggregation caused by thrombin, endotoxemia and/or toxic shock syndrome, and conditions associated with the action of prostaglandin-endoperoxide-2.

Inhibitors R of the present invention inhibit the expression of inducible Pro-inflammatory proteins such as prostaglandin-endoperoxide-2 (PGHS-2), which is also referred to as cyclooxygenase-2 (SOH-2). In this regard, state, mediated R include swelling, lack of sensitivity to pain, fever and pain, such as neuromuscular pain, headache, pain that accompanies cancer ill the tion, dental pain and arthritis pain. Compounds of the present invention is also used for the treatment of viral diseases in animals, such as lentivirinae infection, including, without limitation, virus infectious anemia in horses or retroviral infection, including human immunodeficiency virus feline, human immunodeficiency virus family bullish and human immunodeficiency virus family dog. The terms ”state associated with R or diseases or disorders associated with R”used in this context, combine all of the States described above, and any other conditions associated with kinase activity n.

Thus, the present invention provides methods of treatment for these conditions, including an introduction to the subject in need of such treatment, an effective amount of at least one compound of the present invention or its pharmaceutically acceptable derivative. Methods of treating conditions associated with kinase activity R include the introduction of the compounds of the present invention alone or in combination with other suitable therapeutic agents intended for treatment of these conditions. Examples of such other therapeutic agents include corticosteroids, rolipram, calphostin, CSAID, 4-substituted, imidazo[1,2-A]cinoxacin is, described in US patent No. 4200750 and work S.Ceccarelli and others European Journal of Medicinal Chemistry, 33, 943-955 (1998), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants, and inhibitors of translocation to the nuclei of cells, such as desoxypeganine (DSG), non-steroidal anti-inflammatory drug (NSAID)such as ibuprofen, celecoxib and rofecoksib, steroids, such as prednisone and dexamethasone, antiviral agents such as abacavir, antiproliferative agents, such as methotrexate, Leflunomide, FK506 (tacrolimus, prograf), cytotoxic drug tools such as azathioprine and cyclophosphamide, inhibitors of TNF-α, such as tenidap, antibodies against TNF or soluble TNF receptor, and rapamycin (sirolimus or rapamune) or their derivatives.

The above other therapeutic agents, when used in combination with the compounds of the present invention is administered, for example, in the quantities listed in the directory Physicians' Desk Reference (PDR) or as defined by experts in the field of technology. According to the methods described in the present invention, such other therapeutic agent is administered before administration of the compounds of the present invention, simultaneously with, or after their introduction.

The following examples are intended only to illustrate embodiments of the present invention and not about rancimat its volume, as defined in the claims. Abbreviations used in examples are described below. Compounds described in the examples identified by the number of sample and the stage in which they were received (e.g., ”1A” means specified in the header of the compound obtained in example 1, stage A), or only the number of the example in which the connection is specified in the header (for example, ”2” means the connection specified in the header of example 2).

Reduction

Ph = phenyl

Bz = benzyl

t-Bu = tert-butyl

Me = methyl

Et = ethyl

Pr = propyl

Iso-P or i-Pr = isopropyl

Meon = methanol

EtOH = ethanol

EtOAc = ethyl acetate

Boc = tert-butyloxycarbonyl

CBZ = carbobenzoxy, or carbobenzoxy, or benzyloxycarbonyl

DHM or CH2Cl2= dichloromethane

EDC = 1,2-dichloroethane

DMF = dimethylformamide

DMSO = dimethyl sulfoxide

TFU = triperoxonane acid

THF = tetrahydrofuran

HATU = O-(7-Asobancaria-1-yl-N,N,N',N'-tetramethylrhodamine hexaphosphate

KOH = potassium hydroxide

To2CO3= potassium carbonate

POCl3= oxychloride phosphorus

KQtBu = tert-piperonyl potassium

EDC or EDCl = hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DIPEA = diisopropylethylamine

HOBt = hydrate of 1-hydroxybenzotriazole

m-SRV = meta-chloroperbenzoic acid

NaH = sodium hydride

NaOH = hydro is led sodium

Na2S2O3= sodium thiosulfate

Na2SO4= sodium sulfate

Pd = palladium

Pd/C = palladium on coal

min = minute(you)

l = liter

ml = ml

μl = microliter

g = gram(s)

mg = milligram(s)

mol = mol

mmol = millimoles(and)

the mEq. = milliequivalent

CT = room temperature

V.U. = retention time on the column GHUR (min)

General methods. Mass spectra were obtained using a mass spectrometer Thermo Finnigan LCQ Duo Ion Trap. Examples: ”GHUR (gradient within 6 min)” refers to column Keystone 18 Beta Basic, the rate of elution of 0.4 ml/min, eluent: a linear gradient within 6 min (original solvent %B=0, final solvent %B=100), solvent A: acetonitrile + 0.025% of TFU; solvent B=N2O + 0.025% OF TFU. ”GHUR (gradient over 4 min)” refers to column Keystone 18 Beta Basic, the rate of elution of 0.5 ml/min, eluent: a linear gradient over 4 min (original solvent %B = 0, final solvent %B=100), solvent A: acetonitrile+0.025% of TFU; solvent B=H2O + 0.025% OF TFU.

Example 1

Obtain 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-methoxy-4-methylbenzamide

A. 3-Hydrazino-N-methoxy-4-methylbenzamide

To a solution of 3-amino-N-methoxy-4-methylbenzamide 1 (102 mg, of 0.56 mmole, obtaining described in the application WO 02/40486 A2, p.66) in the e (5 ml) under stirring at 0°C. was added conc. HCl (5 ml) and sodium nitrite (43 mg, of 0.62 mmole). The reaction mixture was stirred at 0°C for 40 min, then was added a solution of tin chloride (II) (241 mg, of 1.27 mmole) in conc. HCl (1 ml) and the mixture was stirred for 1 h, then kept at -20°C for 20 h and was heated up to CT with further concentrated to a solid white color. The solid is triturated in ethanol, filtered and the filtrate was concentrated, it was received 3 hydrazino-N-methoxy-4-methylbenzamide 2 (486 mg) as a solid white color in the form of a mixture with salts of tin and ethanol, the product was used without further purification. GHUR (gradient within 6 min): V.U. 0,78 min MS: m/z 195,9 [M+H]+.

B. 3-[5-Amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-methoxy-4-methylbenzamide

In a mixed solution of 3-hydrazino-N-methoxy-4-methylbenzamide 2 (116 mg, calculated to 0.14 mmole) in EtOH (10 ml) was added 2-(3-iodobenzoyl)-3-phenylenediacrylate 3 (59 mg, of 0.14 mmole, obtaining described in application No. WO 02/57101 A1, p.84) and the resulting mixture was heated in a bath (at a temperature of 65-70°C) for 4 h, then was added another portion of 3-hydrazino-N-methoxy-4-methylbenzamide 2 (80 mg, of 0.11 mmole) and the mixture was heated at the same temperature for 27 hours the Mixture was cooled to room temperature, concentrated and re-dissolved in EtOAc, then washed with water and brine, dried over Na2/sub> SO4and concentrated, to receive the crude semi-solid substance. Then the mixture was purified Express chromatography (eluent: EtOAc/hexane, 1:1), remove impurities, and then elution with 100% EtOAc received 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-methoxy-4-methylbenzamide 4 (38 mg, 0.08 mmole, 55%) as a solid off-white color. GHUR (gradient within 6 min): V.U. 3,49 min MS: m/z 476,96 [M+H]+.

1H-NMR (300 MHz, CD3OD): δ 8,10 (s, 1H), 7,95 (d, J 8,0, 1H), 7,88 (d, J 8.0 in. 1H), 7,82 (m, 2H), 7,78 (s, 1H), 7,58 (d, J 8,0, 1H), 7,33 (t, J 7,8, 1H), 5,02 (s, 3H), of 2.33 (s, 3H).

13C-NMR (125 MHz, DMSO-d6): δ 189,3, 154,3, 143,5, 143,3, 142,0, 138,3, 137,4, 133,5, 132,9, 132,0, 130,4, 128,8, 128,4, 104,8, 95,4, 64,8, 18,2.

Example 2

Obtain 3-(5-amino-4-benzoimidazol-1-yl)-N-methoxy-4-methylbenzamide

In mix a solution of 3-amino-N-methoxy-4-methylbenzamide 1 (104 mg, of 0.58 mmole) in water (2 ml) at 0°C. was added conc. HCl (2 ml), then was added sodium nitrite (44 mg, 0,63 mmole). The reaction mixture was stirred at 0°C for 40 min, then was added a solution of tin chloride (II) (245 mg, of 1.30 mmole) in conc. HCl (1 ml) and the resulting mixture was stirred for 40 min, then kept at -20°C for 20 h and then the mixture was heated to room temperature and concentrated, when it received a solid white color. The solid is triturated in ethanol, the solid substance was removed and added to 2-benzoyl-3-phenylenediacrylate 5 (144 mg, of 0.58 mmole, obtaining described in article Grothaus, J. Am. Chem. Soc., 58, 1334 (1936)and the mixture was heated on the steam bath (at a temperature of 65-70°C) for 16 hours the Mixture was cooled to room temperature, concentrated and purified Express chromatography (eluent: EtOAc/hexane, 1:1), remove impurities, and then elution with 100% EtOAc received 3-(5-amino-4-benzoimidazol-1-yl)-N-methoxy-4-methylbenzamide 6 in the form of a solid off-white color (41 mg, 0.12 mmole, 28%). GHUR (gradient over 4 min): V.U. 1,93 min MS: m/z 351,1 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ 11,88 (s, 1H, NH), 7,803 (m, 4H), 7,56 (m, 4H), 7,01 (s, 2H, NH2), of 3.32 (s, 3H), 2,162 (s, 3H).

13C-NMR (125 MHz, DMSO-d6): δ 187,6, 151,9, 141,2, 139,7, 139,6, 135,7, 131,4, 131,2, 130,9, 128,5, 128,1, 127,8, 126,4, 102,6, 63,2, 17,2.

Example 3

Obtain 3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid

A. Hydrochloride 3-hydrazino-4-methylbenzoic acid

In mix a solution of 3-amino-4-methylbenzoic acid 1 (5,64 g, and 31.2 mmole, 1.0 EQ.) in 100 ml of dioxane and 100 ml of water at 0°C was added 100 ml conc. HCl was then added in portions sodium nitrite (2,82 g, 40.9 mmole, 1.1 EQ.) in the form of solids within 45 min with suitable speed to ensure a satisfactory rate of gas emission and the level of foaming, it was obtained a clear solution brown. Anhydrous holdem the reed tin (II) (15.62 wide g 83,7 mmole, of 2.25 EQ.) was dissolved in conc. HCl (25 ml) and was added into the solution dropwise approximately 25 ml) at 0°C. After 1 h the precipitate was filtered and washed with dioxane and then dried in vacuum, to receive hydrochloride 3-hydrazino-4-methylbenzoic acid 2 as a solid yellow-brown (to 4.98 g, 66%). GHUR (gradient over 4 min): V.U. 0,97 min MS: m/z 167 [M+H]+.

1H-NMR δ (300 MHz, DMSO-d6) there is a 10.03 (s, 1H, COOH), 7,89 (s, 1H), 7,51 (s, 1H), 7,27 (d, J 8,0, 1H), 3,38 (s, 3H, NHNH2), of 2.23 (s, 3H).

B. 3-(5-Amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid

In the mixed solution of the hydrochloride of 3-hydrazino-4-methylbenzoic acid 2 (242 mg, 1,19 mmole, 1.0 EQ.) in 25 ml of ethanol was added 2-benzoyl-3-phenylenediacrylate 4 (296 mg, 1,19 mmole, 1.0 EQ., obtaining described in article Grothasu, Davis, J. Am. Chem. Soc., 58, 1334 (1936)) and triethylamine (161 μl, 1,19 mmole, 1.0 EQ.) and the mixture was heated to 65°C. All solids had dissolved when the temperature reached 65°C. After 3 h according to LC-MS was defined by the complete consumption of hydrazine. The solid was filtered, it was obtained 3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid 5 (95 mg, 25%) as a solid beige color. GHUR (gradient over 4 min): V.U. 2,10 min MS: m/z 322 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ to 7.99 (d, J 7,6, 1H), 7,81 (s, 2H), 7,78 (s, 1H), EUR 7.57 (m, 4H), 7,02 (s, 2H, NH2), to 2.18 (s, 3H).

12C-NMR(75 MHz, DMSO-d6): δ 187,6, 166,3, 152,0, 141,3, 141,2, 139,6, 135,9, 131,6, 131,2, 130,1, 129,8, 128,6, 127,8, 102,6, 17,4.

Example 4

Obtain 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide

In mix a solution of 3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid 5 (example 3, 700 mg, 2.18 mmole, 1.0 EQ.) in 30 ml of DMF was added EDCI (855 mg, 4.35 mmole, 2.0 EQ.), HOBt (589 mg, 4.35 mmole, 2.0 EQ.) and diisopropylethylamine (1,59 ml, 8,71 mmole, 4.0 EQ.) and the solution was stirred for 15 min at room temperature, then added cyclopropylamine (302 μl, 4.35 mmole, 2.0 EQ.) and the reaction mixture was stirred for 1 h the Mixture was diluted with EtOAc (300 ml), washed with water (2×25 ml) and brine (25 ml), dried (Na2SO4) and concentrated. The product was purified rapid chromatography on silica gel (eluent: EtOAc/Meon, 8:2), when it received the product in the form of a brown oil. Then the product was purified by rubbing in a mixture (EtOAc/hexane/CH2Cl2, 1:1:1) and dried in vacuum, it was obtained 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide 6 (387 mg, 50%) as white powder. GHUR (gradient over 4 min): V.U. 2,11 min MS: m/z 361 [M+H]+.

1H-NMR (300 MHz, CD3OD): δ a 7.92 (d, J 7,6, 1H), 7,81 (m, 4H), 7,54 (m, 4H), 2,85 (m, 1H), 2,22 (s, 3H), 0,80 (d, J 5,7, 2H), 0,63 (s, 2H).

13C-NMR (75 MHz, CD3OD): δ 191,2, 170,1, 153,8, 143,3, 142,0, 141,1, 136,9, 134,8, 132,9, 132,7, 130,1, 129,7, 12,2, 128,1, 104,8, 24,1, 17,7, 6,6.

Example 5

Obtain 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-4-methylbenzoic acid

In the mixed solution of the hydrochloride of 3-hydrazino-4-methylbenzoic acid 1 (example 3A, 314 mg, and 1.54 mmole, 1.0 EQ.) in 50 ml of ethanol and 5 ml of methanol was added 2-(3-iodobenzoyl)-3-phenylenediacrylate 2 (579 mg, and 1.54 mmole, obtaining described in application No. WO 02/57101 A1, p.84). The mixture was heated at 75°C for 18 hours the precipitate was collected on a glass Frit and washed with ethanol, was obtained 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-4-methylbenzoic acid 3 (153 mg, 22%) as a solid white color. MS: m/z 448 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ to 2.18 (s, 3H), 7,05 (.s, 2H), 7,34 (dd, J1=J27,7 Hz), 7,58 (d, J 8.1 Hz, 1H), 7,78 (s, 1H), 7,81 (m, 2H), 7,94 (m, 1H), 7,98 (m, 1H), 8,03 (m, 1H).

Example 6

Obtain 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-(N'-tert-Butoxycarbonylamino)-methylbenzoic acid

Hydrochloride 3-hydrazino-4-methylbenzoic acid 1 (example 3A, 13 g, 64.5 mmole) was dissolved in dioxane (200 ml) and N2O (100 ml)was added aqueous NaOH (5,16 g NaOH in 100 ml of N2Oh, 2×64.5 mmole), then immediately added (BOC)2O (15.5 g, 1,1×6.5 mmole). The reaction mixture was stirred at room temperature for 2 h and was concentrated on a rotary evaporator. Then add H2O and CH2Cl2(containing the Meon) was added with stirring a strong ion-exchange resin in the H+form to neutralize the mixture to pH<2, the resin was filtered and washed with CH2Cl2and Meon. The aqueous layer was washed with two portions of CH2Cl2(with the addition of a small amount Meon). The combined organic layers were dried over Na2SO4(with the addition of a small amount of EtOAc). After filtration and concentration was obtained 3-(N'-tert-butoxycarbonylamino)-4-methylbenzoic acid 4 (16 g, 94%) as a solid white color.

1H-NMR (300 MHz, CDCl3): δ to 1.48 (s, 9H), and 2.27 (s, 3H), USD 5.76 (s, 1H), 7,14 (d, J 7.7 Hz, 1H), 7,56 (d, J 7.7 Hz, 1H), to 7.61 (s, 1H).

B. tert-Butyl ether N'-(5-cyclopropanecarbonyl-2-were)hydrazinecarboxamide acid

3-(N'-tert-Butoxycarbonylamino)-4-methylbenzoic acid 4 (14 g, 52,6 mmole) was dissolved in DMF (250 ml), was added EDCI (20 g, 105,2 mmole) and HOBt (16 g, 105,2 mmole). The mixture was stirred at room temperature for 30 min, was added cyclopropylamine (7,4 ml, 105,2 mmole)was then added DIPEA (37 ml, 4×52,6 mmole). The reaction mixture was stirred at room temperature for 18 hours After concentrating the reaction mixture in vacuo the e was added N 2O. Then the mixture was extracted with three portions of CH2Cl2. The organic layer was washed with an aqueous solution of NaCl. After drying over Na2SO4, filtration and concentration was obtained a solid white color. The crude product was dissolved in CH2Cl2/MeOH and then purified column chromatography on a column of silica gel (eluent: CH2Cl2/EtOAc, gradient from 2:1 to 1:1), it was obtained the desired product, which was purified by recrystallization from EtOAc/CH2Cl2obtained solid is washed with EtOAc and was obtained tert-butyl ether N'-(5-cyclopropanecarbonyl-2-were)hydrazinecarboxamide acid 5 (11 g, 69%).

1H-NMR (300 MHz, CDCl3): δ of 0.58 (m, 2H), 0,84 (m, 2H), to 1.48 (s, 9H), of 2.23 (s, 3H), 2,87 (m, 1H), 5,69 (.s, 1H), 6,17 (.s, 1H), 6,39 (.s, 1H), of 7.70 (m, 2H), 7,32 (s, 1H).

Century Triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide

tert-Butyl ether N'-(5-cyclopropanecarbonyl-2-were)hydrazinecarboxamide acid 5 was dissolved in a mixture of CH2Cl2/TFU (2:1)containing 2% N2Oh, and the mixture was stirred at room temperature for 3 hours After concentration in vacuo received a syrup, which was added CH2Cl2and toluene, concentrated in vacuo, to receive Triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide 6 (100%) as a solid off-white color is. MS: m/z 206 [M+H]+.

1H-NMR (300 MHz, D2O): δ of 0.68 (m, 2H), 0.88 to (m, 2H), 2,31 (s, 3H), and 2.79 (m, 1H), 7,31 (s, 1H), was 7.36 (.s, 2H).

Year 3-[5-Amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

In a mixed solution of triptoreline N-cyclopropyl-3-hydrazino-4-methylbenzamide 6 (648 mg, of 1.74 mmole, 1.0 EQ.) in 2 ml of ethanol was added 2-(3-iodobenzoyl)-3-phenylenediacrylate 2 (550 mg, of 1.74 mmole, obtaining described in the application No. WO 02/57101 A1, p.84) and DIEA (0,50 ml, 2.9 mmole). The mixture was heated at 160°C for 40 min in a microwave reactor, then the mixture was concentrated in vacuum. The crude product was purified column chromatography on a column of silica gel (eluent: EtOAc/hexane, gradient from 1:1 to 2:1), was obtained 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 7 (589 mg, 70%) as a solid white color. MS: m/z 497 [M+H]+.

1H-NMR (300 MHz, CDCl3): δ 0,60 (m, 2H), 0,86 (m, 2H), 2,24 (s, 3H), 2,87 (m, 1H), 5,81 (user, 2H), 6.35mm (.s, 1H), 7,25 (dd, J1=J27,8 Hz, 1H), 7,45 (d, J 8.1 Hz, 1H), 7,69 (d, J 1.7 Hz, 1H), 7,80 (m, 3H), 7,89 (m, 1H), 8,00 (s, 1H).

Example 7

Receive {5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]-1H-pyrazole-4-yl}phenylmethanone

A. N-Dimethylaminomethylene-4-methyl-3-nitrobenzamide

4-Methyl-3-nitrobenzamide 1 (10 g, 56 mmol) suspended in 80 ml of dimethylacetal N,N-di is malformed and then was heated at 95°C for 2 hours The resulting red solution with stirring, cooled to room temperature. After another 2 h, the precipitate red was collected on a glass Frit and washed with three portions Et2O, it was obtained N-dimethylaminomethylene-4-methyl-3-nitrobenzamide 2 (8.7 g, 66%) as a solid red color. GHUR (gradient over 4 min): V.U. 1,76 min MS: m/z 236,0 [M+H]+.

B. 3-(4-Methyl-3-nitrophenyl)-4H-[1.2.4]triazole

To a solution of N-dimethylaminomethylene-4-methyl-3-nitrobenzamide 2 (8.6 g, 37 mmol) in 250 ml of acetic acid was added dropwise anhydrous hydrazine (4,7 ml, 180 ml). The resulting solution was light orange color was heated at 95°C for 1.5 h, then cooled and stirred at room temperature for 18 hours Acetic acid was removed in vacuo and the residue was distributed between H2O and EtOAc. The organic layer was washed with two portions of saturated solution of NaHCO3, then was dried over MgSO4. After filtration and concentration in vacuo, the residue triturated in warm EtOAc and the resulting solid off-white color was collected on a glass Frit, was obtained 3-(4-methyl-3-nitrophenyl)-4H-[1,2,4]triazole 3 (5.8 g, 77%). GHUR (gradient over 4 min): V.U. 1,82 min MS: m/z 205,1 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ 8,57 (user, 1H), 8,46 (s, 1H), 8,12 (d, J 7,9, 1H), 7,56 (d, J 7,9, 1H), 2,5 (s, 3H).

13C-NMR (125 MHz, DMSO-d6): δ 149,1, 133,5, 130,1, 121,3, 19,5.

Century 2-Methyl-5-(4H-[1.2.4]triazole-3-yl)phenylamine

3-(4-Methyl-3-nitrophenyl)-4H-[1,2,4]triazole 3 (5.75 g, 28.2 mmole) suspended in 220 ml of ethanol and 2.35 ml (approximately 28.2 mmole) of concentrated aqueous HCl. Then carefully added under nitrogen atmosphere to 900 mg of 10% palladium on charcoal (dry) and the mixture was passed hydrogen gas for 5 min using a cylinder attached to the syringe needle. Then the reaction mixture was stirred in an atmosphere of hydrogen gas (balloon) at room temperature for 5 hours the Catalyst was removed by filtration through a thin layer of celite. The filtrate was concentrated in vacuo and the residue was neutralized with saturated solution of NaHCO3. The mixture was extracted with six portions of EtOAc and the combined organic layers were dried over MgSO4. After filtration and concentration in vacuo the residue was recrystallized from EtOAc, was obtained 2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenylamine 4 (4.5 g, 92%) as a solid off-white color. GHUR (gradient over 4 min): V.U. 0,79 min MS: m/z 175,2 [M+H]+.

1H-NMR (300 MHz, Meon-d3): δ 8,10 (.s, 1H), 7,54 (s, 1H), 7,29 (m, 2H), 7,15(d, J 7,6, 2H), of 2.23(s, 3H).

, [2-Methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]hydrazine

To a solution of 2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenylamine 4 (200 mg, 1.15 mmole) in di is the Xan (5 ml) and water (5 ml) was added conc. HCl (10 ml) at 0°C, then added sodium nitrite (87 mg, of 1.26 mmole). The reaction mixture was stirred at 0°C for 40 min, then was added dropwise a solution of tin chloride (II) (481 mg, at 2.59 mmole) in conc. HCl (1 ml). The mixture was stirred at 0°C for 2 h, to receive the precipitated solid white. The solid was filtered and identified as [2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]hydrazine 5 (261 mg)which was used without further purification. GHUR (gradient over 4 min): V.U. 0,71 min MS: m/z 190,1 [M+H]+.

D. {5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]-1H-pyrazole-4-yl}phenylmethanone

In a mixed solution of [2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]hydrazine 5 (261 mg, calculated 1.15 mmole) in EtOH (25 ml) was added 2-benzoyl-3-phenylenediacrylate 6 (285 mg, 1.15 mmole, obtaining described in article Grothaus, J. Am. Chem. Soc., 58, 1334 (1936)and the mixture was heated at 65-70°C for 12-16 h, and then cooled to room temperature and concentrated, to receive the crude product. Then the mixture was purified Express chromatography (eluent: EtOAc/hexane, 1:1), to receive {5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]-1H-pyrazole-4-yl}phenylmethanone 7 (21 mg, and 0.09 mmole, 8%) as a solid white color. GHUR (gradient over 4 min): V.U. 1,89 min MS: m/z 345,2 [M+H]+.

1H-NMR (500 MHz, DMSO-d6): δ of 8.40 (d, 1H), 8,24 (.s, 1H), 8,14 (s, 1 H)to 8.12 (d, 2H),7,34 (.s, 2H), 7,92-a 7.85 (m, 4H), 2.49 USD (s, 3H).

13C-NMR (500 MHz, DMSO-d6): δ 152,9, 142,2, 140,5, 137,1, 132,7 132,2, 129,4, 128,8, 127,6, 126,0, 103,6, 18,1.

Example 8

Obtain 3-[5-amino-4-(3-[1,3]dioxolane-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. Methyl ester 3-[1,3]dioxolane-2-eventing acid

A mixture of methyl ester of 3-formylbenzoate acid 1 (6,09 g that 37.2 mmole), ethylene glycol (2,28 ml, 40.9 mmole) and monohydrate para-toluensulfonate acid (0,78 g, 4.09 to mmole) was heated under reflux using a nozzle Dean-stark during the night. Analysis by TLC showed complete consumption of starting material. The reaction mixture was poured into a cooled aqueous NaHCO3and EtOAc. The organic layer was separated and dried over Na2SO4, then was filtered and concentrated, to receive the crude product, which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 8:1), to receive the desired methyl ester 3-[1,3]dioxolane-2-eventing acid 2 (6,41 g, 83%) as a colourless oil.

1H-NMR (300 MHz, CDCl3): δ to 3.92 (s, 3H), 4,01 (m, 2H), 4,13 (m, 2H), to 5.85 (s, 1H), 7.46 (dd, J1=J27.7 Hz, 1H), 7,68 (dt, J17.7 Hz, J21.2 Hz, 1H), with 8.05 (dt, J17.7 Hz, J21.5 Hz, 1H), 8,16 (dd, J1=J21.5 Hz, 1H).

B. 3-(3-[1,3]Dioxolane-2-ylphenyl)--oxopropionate

In a mixture of acetonitrile (1.90 ml of 36.4 mmole) in THF (60 ml) was added LDA (1.8 M in THF, 33.9 ml) at -78°C. After stirring the mixture at -78°C for 20 min was added to one portion of the methyl ester of 3-[1,3]dioxolane-2-eventing acid 2 (6,06 g of 29.1 mmole) in THF (20 ml). The mixture was stirred at -78°C for 1.5 h, then was heated to 0°C and was stirred for 1 h at the same temperature. The reaction was stopped by the addition of saturated NH4Cl. The mixture was extracted with three portions of EtOAc. The organic layers were combined and dried over Na2SO4. After filtration and concentration under vacuum was obtained residue, which was purified by chromatography on silica gel (eluent: CH2Cl2then CH2Cl2/ethyl acetate, 20:1), to receive the desired 3-(3-[1,3]dioxolane-2-ylphenyl)-2-oxopropionate 3 (5,71 g, 96%) as a solid white color.

1H-NMR (300 MHz, CDCl3): δ 4,12 (m, 6H), 5,86 (s, 1H), 7,55 (dd, J1=J27.7 Hz, 1H), to 7.77 (d, J 7.7 Hz, 1 H), 7,92 (d, J 7.7 Hz, 1H), 8,01 (s, 1H).

Century 2-(3-[1,3]Dioxolane-2-aventyl)-3-phenylenediacrylate

A mixture of 3-(3-[1,3]dioxolane-2-ylphenyl)-2-oxopropanenitrile 3 (of 3.07 g, 15.0 mmol) and N,N'-diphenylformamidine (4,10 g, 21 mmol) in toluene was heated under reflux for 18 hours After concentration in vacuo was obtained residue, which was purified by chromatography on silica gel (eluent: hexane/EtOAc, gradient from 3:1 is about 2:1, then 1:1), to receive the desired 2-(3-[1,3]dioxolane-2-aventyl)-3-phenylenediacrylate 4 (3.88 g, 81%) as a solid yellow color.

1H-NMR (300 MHz, CDCl3): δ 4,12 (m, 4H), of 5.92 (s, 1H), 7,26 (m, 4H), 7,47 (m, 3H), of 7.65 (d, J 7.7 Hz, 1H), 7,94 (dt, J17.7 Hz, J21.3 Hz, 1H), with 8.05 (m, 2H).

Year 3-[5-amino-4-(3-[1,3]dioxolane-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A mixture of 2-(3-[1,3]dioxolane-2-aventyl)-3-phenylaminopyrimidine 4 (0.20 g, of 0.62 mmole), triptoreline N-cyclopropyl-3-hydrazino-4-methylbenzamide 8 (example 6B, 0.20 g, of 0.62 mmole) and DIEA (0.5 ml) in DMF (3 ml) was heated at 160°C for 40 min in a microwave reactor. Then the mixture was cooled to room temperature and concentrated. The obtained residue was purified by chromatography on silica gel (eluent: hexane/EtOAc, gradient from 1:4 to 100% EtOAc), to receive the desired 3-[5-amino-4-(3-[1,3]dioxolane-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 5 (0.26 g, 100%) as a solid orange color. MS: m/z 433,2 [M+H]+.

1H-NMR (300 MHz, CDCl3): δ 0,60 (m, 2H), 0,86 (m, 2H), 2,24 (s, 3H), 2,87 (m, 1H), 4,11 (m, 4H), to 5.85 (m, 3H), 6,51 (.s, 1H), 7,43 (d, J 8.0 Hz, 1H), 7,45 (dd, J1=J2a 7.6 Hz; 1H) of 7.70 (m, 2H), 7,82 (m, 3H), 7,95 (s, 1H), 8,00 (s, 1H).

Example 9

Obtain 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A mixture of 3-[5-amino-4-(3-[1,3]dioxolane-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 5 (example 8, 1,14 g, 2.6 mmole) suspended in water Asón (10 ml, 1.5 M in N2About). Was added dropwise an ice Asón until a clear solution is formed. The reaction mixture was stirred at room temperature overnight. After evaporation of the solvent under reduced pressure, the obtained residue was added toluene and EtOAc, the mixture was again concentrated, to receive the crude product, which was purified by chromatography on silica gel (eluent: hexane/EtOAc, 1:4), and received the desired 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 6 (0,91 g, 89%) as a solid yellow foam. MS: m/z 389,1 [M+H]+.

1H-NMR (300 MHz, CDCl3): δ 0,61 (m, 2H), 0,85 (dd, J16,9 Hz, J2of 12.4 Hz, 2H), of 2.25 (s, 3H), 2,87 (m, 1H), 5,95 (.s, 2H), 6,57 (.s, 1H), 7,44 (d, J 8.0 Hz, 1H), to 7.67 for 7.78 (m, 4H), 8,07 (s, 1H), of 8.09 (d, J 1.3 Hz, 1H), 8,31 (s, 1H), 10,12 (s, 1H).

Example 10

Obtain 3-[5-amino-4-(3-hydroxymethylbenzene)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

In a mixture of 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 6 (38 mg, 0,098 mmole) in methanol (3 ml) was added NaBH4(11 mg, of 0.29 mmole). The reaction mixture was stirred at room temperature for 1 h the Reaction was stopped by addition of an aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and neymann the m NaCl. Then the organic layer was dried over Na2SO4was filtered and concentrated, thus obtained residue, which was purified by chromatography on silica gel (eluent: hexane/EtOAc, 1:4), and received the desired 3-[5-amino-4-(3-hydroxymethylbenzene)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 7 (22 mg, 58%) as a solid white color. MS: m/z 391,2 [M+H]+.

1H-NMR (300 MHz, CDCl3): δ of 0.56 (m, 2H), 0,82 (m, 2H), 2,22 (s, 3H), 2,82 (m, 1H), and 4.75 (s, 2H), 5,91 (.s, 2H), 6.75 in (.s, 1H), 7,49 (m, 3H), 7,76 (m, 4H), to 7.99 (s, 1H).

Example 11

Obtain 3-{5-amino-4-[3-(4-methylpiperazin-1-ylmethyl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

In a mixture of 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 6 (example 9, 1.0 EQ.) 1-methylpiperazine (1,09 EQ.) in a mixture of equal amounts of 1,2-dichloroethane and dichloromethane was added Asón (0.96 equiv.) then add triacetoxyborohydride sodium (1.5 EQ.). The reaction mixture was stirred at room temperature for 2 hours the Reaction was stopped by addition of an aqueous NaOH and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. Then the organic layer was dried over Na2SO4was filtered and concentrated, thus obtained residue, which was purified by chromatography on silica gel (eluent: CH2Cl2/methanol, 9:1, then C 2Cl2/Meon/NH3H2O 9:1:0.05) and received the product (67%). MS: m/z 473,3 [M+H]+.

1H-NMR (300 MHz, CDCl3): δ 0,61 (m, 2H), 0,86 (m, 2H), and 2.26 (s, 3H), of 2.30 (s, 3H), 2,52 (.s, 8H), 2,90 (m, 1H), 3,60 (s, 2H), by 5.87 (.s, 1H), 6.30-in (.s, 2H), 7,45 (m, 3H), of 7.70 (m, 2H), 7,83 (m, 3H).

Example 12

Obtain 3-[5-amino-4-(3-morpholine-4-iletilmistir)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

Connection receive in the same way as described in example 11, but replacing 1-methylpiperidine on morpholine, thus receive the product (45%). MS: m/z 460,2 [M+H]+.

1H-NMR (300 MHz, CDCl3): δ 0,61 (m, 2H), 0,87 (m, 2H), and 2.26 (s, 3H), of 2.25 (s, 3H), 2.49 USD (m, 4H). 2,90 (m, 1H)and 3.59 (s, 2H), and 3.72 (t, J 4.4 Hz, 2H), 5,85 (.s, 2H), 6.35mm (.s, 1H), 7,45 (m, 3H), 7,71 (m, 2H), 7,83 (m, 3H).

Example 13

Obtain 3-{5-amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

A. Ethyl ester 3-(2-morpholine-4-ylethoxy)benzoic acid

To a solution of ethyl-3-hydroxybenzoate 1 (of 3.32 g, 20 mmol), hydrochloride of 4-(2-chloroethyl)of the research (to 5.58 g, 30 mmol) and 18-crown-6 (20 mg) in DMF (100 ml) was added potassium carbonate (6.2 g, 45 mmol). The mixture was stirred at 100°C for 20 hours the Solvent was removed in vacuum and the residue suspended in ethyl acetate. The organic layer was washed with saturated solution of NaHCO3, ZAT is saline and dried over sodium sulfate. The solvent was evaporated, the thus obtained product of the ethyl ester of 3-(2-morpholine-4-ylethoxy)benzoic acid 2 (5,3 g, 95%) as oil is light yellow in color. GHUR (gradient over 4 min): V.U. 1,47 min MS: m/z 280,2 [M+H]+.

B. 3-[3-(2-Morpholine-4-ylethoxy)phenyl]-3-oxopropionate

Diisopropylamide lithium (16.4 ml, and 29.6 mmole, 1.8 M solution in heptane/tetrahydrofuran/ethylbenzene) was added dropwise under nitrogen atmosphere to a solution of acetonitrile (1.2 g, up 29.6 mmole) in dry tetrahydrofuran (20 ml) at -78°C. After stirring the reaction mixture for 30 min was added dropwise a solution of ethyl ester of 3-(2-morpholine-4-ylethoxy)benzoic acid 2 (5.5 g, 19.7 mmole) in dry tetrahydrofuran (20 ml) and stirred at -78°C for 1 h, then added water, the aqueous layer was separated and acidified with diluted hydrochloric acid to pH 7. The product was extracted with ethyl acetate. The organic layer was washed with saline and then dried over sodium sulfate. The solvent was removed in vacuum, it was obtained 3-[3-(2-morpholine-4-ylethoxy)phenyl]-3-oxopropionate 3 (4.8 g) in the form of oil is light yellow in color. GHUR (gradient over 4 min): V.U. 1,11 min MS: m/z 275,2 [M+H]+.

Century 2-[3-(2-Morpholine-4-ylethoxy)benzoyl]-3-phenylenediacrylate

A mixture of 3-[3-(2-morpholine-4-ylethoxy)phenyl]-3-oxopropanenitrile 3 (4.8 g, of 17.5 mmole) and N,N-diphenylformamidine (1.2 g, 24.5 mmole) in dry the toluene (100 ml) was heated at 110 C for 3 h in nitrogen atmosphere. The solvent was removed and the oily residue was purified by chromatography on a column of silica gel (eluent: gradient from 100% EtOAc to EtOAc/MeOH/Et3N, 100:10:1), was obtained 2-[3-(2-morpholine-4-ylethoxy)benzoyl]-3-phenylenediacrylate 4 (3.1 g, 47%) as a solid light yellow color. GHUR (gradient over 4 min): V.U. 2,04 min MS: m/z 378,2 [M+H]+.

Year 3-{5-Amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-4-methylbenzoic acid

2-[3-(2-Morpholine-4-ylethoxy)benzoyl]-3-phenylenediacrylate 4 (189 mg, 0.5 mmole) and the hydrochloride of 3-hydrazino-4-methylbenzoic acid 7 (example 3A, 152 mg, 0.75 mmole) suspended in N,N-dimethylformamide (5 ml) and was heated at 160°C in a microwave reactor for 30 minutes the Solvent was evaporated and the residue was purified by chromatography on a column (eluent: EtOAc~Meon), received the product, 3-{5-amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-4-methylbenzoic acid 5 (200 mg) in the form of a solid of light yellow color. GHUR (gradient over 4 min): V.U. 1,60 min MS: m/z 451,2 [M+H]+.

D. 3-{5-Amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

A mixture of 3-{5-amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-4-methylbenzoic acid 5 (400 mg, to 0.89 mmole), cyclopropylamine (0,89 mmole), EDCI (340 mg, of 1.78 mmole), HOBt (272 mg, of 1.78 mmole) and diisopropylethylamine (459 mg, of 3.56 mmole) in dry N,N-DIMET formamide (10 ml) was stirred at room temperature for 18 hours The solvent was evaporated, the residue suspended in EtOAc and washed with water, saturated solution of NaHCO3and a salt solution. The organic layer was dried over sodium sulfate. After purification by chromatography on a column (eluent: EtOAc/MeOH/Et3N, 100:10:1) received the product 3-{5-amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide 6 (45 mg, 10%) as a solid light yellow color. GHUR (gradient over 4 min): V.U. 1,69 min MS: m/z 490,24 [M+H]+.

Example 14

Obtain 3-[5-amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. Ethyl ester 3-benzyloxybenzyl acid

To2CO3(6.9 g, 50 mmol) and 18-crown-6 was added to a solution of ethyl ester of 3-hydroxybenzoic acid 1 (of 8.3 g, 50 mmol) in acetone (100 ml) and the mixture was stirred at room temperature for 18 hours, the Solid was filtered, the filtrate was concentrated in vacuum, it was received ethyl ester 3-benzyloxybenzyl acid 2 as a colorless liquid.

B. 3-(3-Benzyloxyphenyl)-3-oxopropionate

LDA (1.8 M, 100 mmol, 56 ml) was added to a solution of acetonitrile (4.1 g, 100 mmol) in THF (100 ml, dry) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 30 minutes Then a solution of ethyl what about the ether 3-benzyloxybenzyl acid 2 in 50 ml of anhydrous THF was added dropwise into the reaction mixture. The mixture was stirred at -78°C for 1 h, then added water, the organic layer was separated, the aqueous layer was acidified with hydrochloric acid to pH~2 and was extracted with EtOAc. Layers of THF and EtOAc were combined and washed with water and brine, dried over Na2SO4. The solvent was removed in vacuum and the solid residue triturated in Et2O and dried in vacuum, to receive the desired product, 3-(3-benzyloxyphenyl)-3-oxopropionate 3 (11,0 g, 87%), in the form of a solid light brown color.

Century 2-(3-Benzyloxybenzyl)-3-dimethylaminoacetonitrile

Dimethylacetal N,N-dimethylformamide (10 ml) was added to a solution of 3-(3-benzyloxyphenyl)-3-oxopropanenitrile 3 (2.5 g, 10 mmol) in DMF (20 ml, dry) and the mixture was stirred at 100°C for 3 hours the Solvent was removed and the residue was purified by chromatography on a column of silica gel (eluent: EtOAc), it was obtained the desired product, 2-(3-benzyloxybenzyl)-3-dimethylaminoacetonitrile 4 (2.6 g, 90%), in the form of solid light yellow color.

Year 3-[5-Amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

2-(3-Benzyloxybenzyl)-3-dimethylaminoacetonitrile 4 (147 mg, 0.5 mmole) and triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide 8 (example 6 In, 240 mg, 0.75 mmole) was dissolved in DMF (5 ml) and was heated at 160°C in a microwave reactor for 30 minutes the Solvent was removed and the residue is ciali chromatography on a column (eluent: EtOAc/hexane, 3:1), it was obtained the desired product, 3-[5-amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 6 (120 mg, 52%), in the form of a solid of light yellow color.

Example 15

Obtain 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

3-[5-Amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 6 (200 mg, 0.43 mmole) was dissolved in Meon (10 ml), was added the catalyst, 10% palladium on charcoal (dry) and was stirred in an atmosphere of hydrogen for 2 hours the Catalyst was removed by filtration, the solvent was removed in vacuum, to receive the desired product, 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 7 (140 mg, 87%), in the form of a solid of light yellow color.

Example 16

Obtain 3-[5-amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 2-(4-Methylbenzoyl)-3-phenylenediacrylate

A mixture of 4-toluoyltartaric 1 (4.0 g, 25 mmol) and N,N-diphenylformamidine (4.9 g, 25 mmol) in dry toluene (50 ml) was heated at 85°C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature and was added 170 ml of hexane. After stirring the mixture at room temperature for 5 min was formed who I yellow precipitate. The solid substance was collected in a flask with a glass filter and washed with hexane, it was obtained pure 2-(4-methylbenzoyl)-3-phenylenediacrylate 2 (4.5 g, 68%).

1H-NMR (300 MHz, CDCl3): δ of 8.04 (d, J 13,0, 1H), 7,86 (d, J 7,9, 2H), 7,42 (t, J 7,4, 1H), 7,28-7,25 (m, 3H), 7,19 (d, J 7,6, 1H), 2,41 (s, 3H).

B. 3-[5-Amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A mixture of 2-(4-methylbenzoyl)-3-phenylaminopyrimidine 2 (205 mg, 0,78 mmole), triptoreline N-cyclopropyl-3-hydrazino-4-methylbenzamide 7 (example 6B, 250 mg, 0,78 mmole) and Diisopropylamine (0,14 ml to 0.78 mmole) in 8 ml of ethanol was heated at 65°C for 18 hours the Solvent was removed and the residue was purified by chromatography on a column of silica gel (eluent: EtOAc/hexane, gradient from 1:3 to 3:1). Then the product was purified by rubbing in Et2O, it was obtained 3-[5-amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 3 (64 mg, 22%) as a solid white color. GHUR (gradient over 4 min): V.U. of 2.26 min MS: m/z 375,2 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ 8,51 (d, J 4,0, 1H), to 7.93 (d, J 8,0, 1H), 8,51 (d, J 4,0, 1H), 7,83 (.s, 1H), 7,82 (s, 1H), of 7.70 (d, J 7,9, 2H), 7,53 (d, J 8,0, 1H), 7,35 (d, J 7,9, 2H), 6,95 (.s, 2H), 2,86 (m, 1H), 2.40 a (s, 3H), 2,14 (s, 3H), of 0.68 (m, 2H), 0,56 (m, 2H).

13C-NMR (300 MHz, DMSO-d6): δ 187,4, 166,0, 151,9, 141,3, 141,1, 139,2, 136,9, 135,6, 133,0, 131,2, 129,1, 128,3, 128,0, 126,5, 102,6, 23,1, 21,0, 17,2, 5,6.

Example 17

Obtain 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzene is and

A. 3-(5-Amino-4-cyanomelana-1-yl)-N-cyclopropyl-4-methylbenzamide

A mixture of 3-amino-N-cyclopropyl-4-methylbenzamide 1 (380 mg, 2.0 mmole) in 2.0 ml of triethylorthoformate was stirred in a microwave reactor at 120°C for 20 minutes the Solvent was removed under reduced pressure. The residue was dissolved in 5 ml of acetic acid and then added para-toluensulfonate of aminomalononitrile (506 mg, 2.0 mmole) and sodium acetate (164 mg, 2.0 mmole). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with 20 ml of water and then added aqueous NaOH to pH 8. The resulting mixture was extracted with EtOAc (3×50 ml). The combined organic layers were washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered and concentrated in vacuum. The residue was purified by chromatography on a column of silica gel (eluent: methylene chloride/methanol, 10:1), was obtained 3-(5-amino-4-cyanomelana-1-yl]-N-cyclopropyl-4-methylbenzamide 3 (170 mg, 30%) as a colourless solid. GHUR (gradient over 4 min): V.U. 1,39 min MS: m/z 282 [M+H]+.

B. 3-(5-Amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide

To a solution of 3-(5-amino-4-cyanomelana-1-yl)-N-cyclopropyl-4-methylbenzamide 3 (of 56.4 mg, 0.2 mmole) in dry THF (10 ml) was added phenylmagnesium (1 M, 1 ml) at room temperature is round in nitrogen atmosphere. After 1 h the solution was added HCl (3 N., 10 ml) and the mixture was stirred over night. The solution was neutralized by adding aqueous NaOH. The mixture was extracted with ethyl acetate (2×100 ml), washed with water and dried over Na2SO4. After evaporation of the solvent the residue was purified by the method GHUR, it was obtained 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide (56 mg, 78%) as a solid white color. IHMS (gradient over 4 min): V.U. 2,07 min MS: m/z 316,17 [M+H]+.

Example 18

Obtain 3-(5-amino-4-cyclohexylcarbodiimide-1-yl)-N-cyclopropyl-4-methylbenzamide

The compound was obtained by the same way as described in example 17, but replacing phenylmagnesium on cyclohexylmaleimide. GHUR (gradient 10-90 for 4 min): V.U. 2,01 min MS: m/z 367,29 [M+H]+.

Example 19

Obtain 3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 17, but replacing phenylmagnesium on cyclopentylamine. GHUR (gradient 10-90 for 4 min): V.U. 1,92 min MS: m/z 353,22 [M+H]+.

Example 20

Obtain 3-(5-amino-4-phenylacetylamino-1-yl)-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as opisanoj example 17, but the replacement phenylmagnesium on benzylmagnesium. GHUR (gradient 10-90 for 4 min): V.U. 2,14 min MS: m/z 375,20 [M+H]+.

Example 21

Obtain 3-[5-amino-4-(3-isopropylcarbamate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-[amino-1-(5-cyclopropanecarbonyl-2-were)-1H-imidazole-4-carbonyl]benzoic acid

To a solution of tert-butyl methyl ether 3-iodobenzoyl acid (4.6 g) in THF (20 ml) was added cyclohexylaniline (2 M in THF, 8.5 ml) in an atmosphere of N2at -40°C. the solution Temperature was maintained at -40°C to 0°C for 20 min, it was added 3-(5-amino-4-cyanomelana-1-yl)-N-cyclopropyl-4-methylbenzamide and the reaction was carried out at room temperature for 1 h Then was added HCl (4 M, 10 ml) and the mixture was heated at a temperature from 40°C to 45°C during the night. The mixture was neutralized with a solution To a2CO3and was extracted with EtOAc (2×100 ml), the combined organic layers were dried over Na2SO4and concentrated. After purification of the crude product by chromatography on a column (eluent: EtOAc/Meon, 6:1) was obtained the desired product (0,46 g).

B. 3-[5-Amino-4-(3-isopropylcarbamate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A solution of acid 4 (160 mg), EDCl (90 mg) and N-hydroxysuccinimide (53 mg) in DMF (2 ml) was kept at room te is the temperature during the night, was added water (12 ml), the solution was extracted with EtOAc (2×15 ml) and dried over Na2SO4. After evaporation of the solvent was obtained residue, to which was added EtOAc (4 ml) and 2-Propylamine (1.2 EQ.). The reaction was carried out at room temperature for 1 h, then the reaction mixture was concentrated and the crude product was purified by chromatography on a column, to receive the desired product (80%). GHUR (gradient over 4 min): V.U. 2,00 min MS: m/z 446,19 [M+H]+.

Example 22

Obtain 3-{5-amino-4-[3-(2-dimethylaminoethanol)benzoyl]imidazol-1-yl)-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, but replacing Isopropylamine 2-diethylaminoethylamine. GHUR (gradient 10-90 for 4 min): V.U. 2,18 min MS: m/z 475,15 [M+H]+.

Example 23

Obtain 3-[5-amino-4-(3-ethylcarboxylate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, but replacing Isopropylamine for ethylamine. GHUR (gradient 10-90 for 4 min): V.U. 1,70 min MS: m/z 432,18 [M+H]+.

Example 24

Obtain 3-[5-amino-4-(3-methylcarbamoylmethyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, n is the replacement Isopropylamine on methylamine. GHUR (gradient 10-90 for 4 min): V.U. 1,61 min MS: m/z 418,15 [M+H]+.

Example 25

Obtain 3-[5-amino-4-(3-cyclopropanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, but replacing Isopropylamine on cyclopropylamine. GHUR (gradient 10-90 for 4 min): V.U. 1,74 min MS: m/z 444,14 [M+H]+.

Example 26

Obtain 3-[5-amino-4-(3-cyclopentanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, but replacing Isopropylamine on cyclopentylamine. GHUR (gradient 10-90 for 4 min): V.U. 1,95 min MS: m/z 472,24 [M+H]+.

Example 27

Obtain 3-{5-amino-4-[3-(morpholine-4-carbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, but replacing Isopropylamine for morpholine. GHUR (gradient 10-90 for 4 min): V.U. 1,67 min MS: m/z 474,17 [M+H]+.

Example 28

Obtain 3-{5-amino-4-[3-(cyclopropanecarbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide

The compound was obtained in the same way as described in example 21, but replacing Isopropylamine on cyclopropylmethyl the amine. GHUR (gradient 10-90 for 4 min): V.U. to 1.86 min MS: m/z 458,23 [M+H]+.

Example 29

Obtain 3-[5-amino-4-(tetrahydropyran-4-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 4-Bromotetradecane

Tetrahydro-4H-Piran-4-ol (1.0 g, 10 mmol), chetyrehhloristy carbon (3.6 g, 11 mmol) and triphenylphosphine (3.1 g, 12 mmol) was dissolved in CH2Cl2(25 ml) and stirred at room temperature overnight. The crude reaction mixture was concentrated, then purified rapid chromatography on silica gel (eluent: EtOAc/hexane, 1:20), when it received the product (1.4 g, 87%) as a colourless oil.

B. 3-[5-Amino-4-(tetrahydropyran-4-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A solution of 4-bromotetradecane (of 0.82 g, 5 mmol) in dry THF (10 ml) was added dropwise to a suspension of magnesium (132 mg, 5.5 mmole) and iodine (25 mg) in dry THF (20 ml) at 50°C in an atmosphere of N2. After addition of the reagents, the mixture was stirred for 30 min at 50°C, then cooled to room temperature. In the reaction mixture was added a solution of 3-(5-amino-4-cyanomelana-1-yl)-N-cyclopropyl-4-methylbenzamide (90 mg, of 0.32 mmole) in THF (10 ml) and the mixture was stirred at room temperature for 3 h, then the reaction was stopped by addition of HCl (2 BC) and the mixture was stirred at ControlTemplate during the night. To the solution was added saturated aqueous K2CO3to pH~8 and was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4and concentrated. The crude product was purified by chromatography on a column of silica gel (eluent: EtOAc~EtOAc/Meon/Et3N, 100:10:1), to receive the product (35 mg, 30%) as a solid beige color. GHUR (gradient over 4 min): V.U. 3,05 min MS: m/z 369,18 [M+H]+.

Example 30

Obtain 3-(5-amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide

A. 3-Benzoyl-3,3-bis-methylsulfonylmethane

In a mixed solution of benzoylacetonitrile 1 (7.50 g, 51,7 mmole) in THF (100 ml) at 0°C was added dry sodium hydride (2,61 g, 103 mmol). The resulting suspension was stirred at 0°C for 45 min, then was added carbon disulfide (2,39 ml, 54,8 mmole). The reaction mixture was stirred at room temperature for 2 hours the resulting red solution was cooled to 0°C was added itmean (6.75 ml, 109 mmol). The mixture was stirred at room temperature for 18 hours the Solvent was removed in vacuum. The residue was diluted with ether and washed with saline. The aqueous layer was extracted with two portions of ether. The combined organic layers were washed with two portions of 5 sodium thiosulfate and then with saline. The organic layer was dried over MgSO4was filtered and concentrated, to receive 3-benzoyl-3,3-bis-methylsulfonylmethane 2 in the form of a yellow powder (9.5 g, 74%). The product was used in the next stage without further purification.

B. 3-(5-Amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide

Sodium (317 mg, of 13.8 mmole) was added to methanol (10 ml) at 0°C. After consumption of the entire quantity of sodium resulting solution of sodium methylate at 0°C was added a mixed solution of 3-benzoyl-3,3-bis-methylsulfonylmethane 2 (3.12 g, 12.5 mmole) in dioxane (30 ml). The reaction mixture was heated to room temperature and then was heated at 80°C for 3 hours the resulting solution was dark red color was cooled to room temperature and added to a solution of trifter acetate N-cyclopropyl-3-hydrazino-4-methylbenzamide (4,00 g, 12.5 mmole) and diisopropylethylamine (2,18 ml, 12.5 mmole) in dioxane (15 ml). The mixture was heated at 85°C for another 6 h the Solvent was removed in vacuo, the residue was diluted with saturated solution of NaHCO3and was extracted with three portions of EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified rapid chromatography on silica gel (eluent: EtOAc/hexane, EtOAc gradient from 75% to 90%) and recrystallized from EtOAc, got treba the range of 3-(5-amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide 3 (950 mg, 19%) as a solid white color. GHUR (gradient 10-90 for 4 min): V.U. 2,33 min MS: m/z 391,2 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ of 8.50 (d, J 3,4, 1H), to $ 7.91 (d, J 7,9, 1H), a 7.85 (s, 1H), to 7.61 (d, J 6,9, 2H), 7,41 to 7.62 (m, 4H), 7,00 (.s, 2 H), 3,66 (s, 3H), 2,87 (m, 1H), measuring 2.20 (s, 3H), 0.70 to (m, 2H), 0,85 (m, 2 H).

13C-NMR (125 MHz, DMSO-d6): δ 188,1, 166,0, 159,5, 152,8, 140,1, 139,5, 135,5, 132,9, 131,1, 130,6, 128,1, 128,0, 127,4, 126,8, 91,0, 55,2, 23,0, 15,1, 5,6.

Example 31

Obtain 3-(5-amino-4-benzoyl-3-ethoxypyrazine-1-yl)-N-cyclopropyl-4-methylbenzamide

Ethanol (0,47 ml, 8.0 mmole) was added to a suspension of dry sodium hydride (41 mg, 1.6 mmole) in dioxane (2 ml). The mixture was stirred at room temperature for 10 min, was added 2-benzoyl-3,3-bis-methylsulfonylmethane 2 (0.20 g, 0.80 mmole) and the mixture was stirred at 85°C. for 2.5 hours the Mixture was cooled to room temperature, was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0.26 g, to 0.80 mmole) and the reaction mixture was heated at 85°C for another 3 hours, the Solvents were removed in vacuo, the residue was diluted with saturated solution of NaHCO3and was extracted with three portions of EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified rapid chromatography on silica gel (eluent: EtOAc/hexane, EtOAc gradient from 75% to 85%). Then the product was purified by washing with a mild mixture of tOAc and hexane, this got the desired 3-(5-amino-4-benzoyl-3-ethoxypyrazine-1-yl)-N-cyclopropyl-4-methylbenzamide 4 (27 mg, 8.3 per cent) in the form of a solid white color. GHUR (gradient 10-90 for 4 min): V.U. 2,37 min MS: m/z 405,2 [M+H]+.

1H-NMR (300 MHz, DMSO-d6): δ 8,49 (d, J 4,0, 1H), of 7.90 (d, J 8,0, 1H), a 7.85 (s, 1H), 7.62mm (d, J 7,1, 2H), 7,50 (d, J a 7.5, 2H), 7,41 was 7.45 (m, 2H), 6,99 (.s, 2H), 4.05 (q, J 7,0, 2H), 2,87 (m, 1H), 2,19 (s, 3H), of 1.09 (t, J 7,0, 3H), is 0.69 (m, 2H), EUR 0.58 (m, 2H).

13C-NMR (125 MHz, DMSO-d6): δ 188,2, 166,0, 158,9, 152,6, 140,0, 139,5, 135,5, 132,9, 131,1, 130,6, 128,1, 127,2, 126,7, 91,2, 63,4, 23,0, 17,3, 14,2, 5,6.

Example 32

Obtain 3-[5-amino-4-benzoyl-3-(2-methoxyethoxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

Dry sodium hydride (21 mg, from 0.84 mmole) was added to a solution of 2-methoxyethanol (0.63 ml, 8.0 mmole) in dioxane (2 ml) at 0°C. the Mixture was stirred at room temperature for 30 min, was added 2-benzoyl-3,3-bis-methylsulfonylmethane 2 (0.20 g, to 0.80 mmole) and the mixture was stirred at 85°C for 4 h the Mixture was cooled to room temperature, was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0.26 g, 0,80 mmole), then added diisopropylethylamine (0,14 ml of 0.80 mmole) and the reaction mixture was heated at 85°C for 11 h, the Solvents were removed in vacuo, the residue was diluted with saturated solution of NaHCO3and was extracted with three portions of EtOAc. Unite the military organic layers were dried over MgSO 4, filtered and concentrated. The crude product was purified rapid chromatography on silica gel (eluent: EtOAc/hexane, EtOAc gradient from 70% to 90%). Then the product was purified by washing with a mild mixture of EtOAc and hexane, to receive the desired 3-[5-amino-4-benzoyl-3-(2-methoxyethoxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 5 (60 mg, 17%) as a solid white color. GHUR (gradient 10-90 for 4 min): V.U. 2,17 min MS: m/z 435,2 [M+H].+

1H-NMR (500 MHz, DMSO-d6): δ of 8.47 (s, 1H), 7,89 (d, J 7,9, 1H), 7,83 (s, 1H), to 7.64 (d, J 7,4, 2H), 7,49 (d, J 7,7, 2H), 7,40-the 7.43 (m, 2H), 6,99 (.s, 2H), 4,12 (m, 2 H), 3,42 (m, 2H), 3,12 (s, 3H), of 2.86 (m, 1H), 2,07 (s, 3H), is 0.69 (m, 2H), 0,56 (m, 2H).

Example 33

Obtain 3-[5-amino-4-benzoyl-3-(2-benzyloxyethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of 2-benzyloxyethanol (1.1 ml, 8.0 mmole) in dioxane (2 ml) at 0°C was added dry sodium hydride (21 mg, from 0.84 mmole). The resulting reaction mixture was stirred at room temperature for 35 minutes and Then was added 2-benzoyl-3,3-bis-methylsulfonylmethane 2 (0.20 g, 0,80 mmole), the reaction mixture was stirred at a temperature of 80°C for 2.5 h and cooled to room temperature, was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0.26 g, to 0.80 mmole) and the reaction mixture was heated at 80°C for additional 8.5 hours After cooling, re klonoa mixture to room temperature the solvent was removed in vacuum. The obtained residue was diluted with saturated solution of NaHCO3and three times was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified Express chromatography (SiO2, eluent: gradient of EtOAc/hexane, 60% to 85%). The obtained product was purified by washing with warm EtOAc, to receive the desired 3-[5-amino-4-benzoyl-3-(2-benzyloxyethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 6 in the form of a solid off-white color (74 mg, 18%). GHUR: (gradient 10-90% for 4 min), V.U. to 2.57 min MS: m/z 511,2

[M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ 8,49 (d, J 4.0 Hz, 1H), of 7.90 (d, J 8.0 Hz, 1H), a 7.85 (s, 1H), 7,66 (d, J 7,1 Hz, 2H), 7,49 (m, 2H), 7,27-7,40 (m, 5H), 7,22 (d, J 6,7 Hz, 2H), 7,02 (.s, 2H), 4,34 (s, 2H), 4,19 (m, 2H), only 3.57 (m, 2H), 2,87 (m, 1H), 2,17 (s, 3H), is 0.69 (m, 2H), 0,59 (m, 2H).

Example 34

Obtain tert-butyl ester 4-[5-amino-4-benzoyl-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-3-yloxy]piperidine-

1-carboxylic acid

To a solution of tert-butyl methyl ether 4-hydroxypiperidine-1-carboxylic acid 7 (0.565 g, of 2.81 mmole) in dioxane (2 ml) at 0°C was added dry sodium hydride (41.0 mg, 1,60 mmole). The resulting reaction mixture was stirred at room temperature for 45 minutes Then add 2-benzoyl-3,3-bis-methylsulfonylmethane 2 (0.20 g, 0.80 mmol who), the reaction mixture was stirred at 65°C for 4 h and cooled to room temperature, was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0.26 g, to 0.80 mmole) and the reaction mixture was heated at 80°C for another 3 hours After cooling the reaction mixture to room temperature the solvent was removed in vacuum. The obtained residue was diluted with saturated solution of NaHCO3and three times was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified Express chromatography (SiO2, eluent: gradient of EtOAc/hexane, from 65% to 85%). The obtained product was purified by washing with warm EtOAc, to receive the desired tert-butyl ester 4-[5-amino-4-benzoyl-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-3-yloxy]piperidine-

1-carboxylic acid 8 in the form of a solid off-white color (70 mg, 16%). GHUR: (gradient 10-90% for 4 min), V.U. 2,63 min MS: m/z 559,9 [M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ 8,49 (d, J 3.6 Hz, 1H), of 7.90 (d, J 8.1 Hz, 1H), to 7.84 (s, 1H), to 7.59 (d, J 7.7 Hz, 2H), 7,40-7,51 (m, 4H), 6,99 (.s, 2H), and 4.75 (m, 1H), 3,18 (m, 2H), 2,99 (m, 2H), 2,87 (m, 1H), 2,19 (s, 3H), by 1.68 (m, 2H), USD 1.43 (m, 2H), of 1.37 (s, 9H), of 0.71 (m, 2H), EUR 0.58 (m, 2H).

Example 35

Getting trifenatate 3-[5-amino-4-benzoyl-3-(piperidine-4-yloxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

In Rast is the PR tert-butyl ester 4-[5-amino-4-benzoyl-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-3-yloxy]piperidine-

1-carboxylic acid 8 (5.0 mg, 0,0089 mmole) in dichloromethane (2.0 ml) was added triperoxonane acid (0.5 ml). The resulting reaction mixture was stirred at room temperature for 3 hours the Volatile components were removed in vacuum and the residue was washed with ether and a small amount of EtOAc, when required triptorelin 3-[5-amino-4-benzoyl-3-(piperidine-4-yloxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide 9 in the form of a solid white color (3.0 mg, 59%). GHUR: (gradient 10-90% for 4 min), V.U. a 1.75 min MS: m/z 460,1 [M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ of 8.50 (d, J 4.0 Hz, 1H), 8,33 (.s, 2H), of 7.90 (d, J 8.0 Hz, 1H), 7,83 (s, 1H), 7.62mm (d, J 7.0 Hz, 2H), 7,44-7,52 (m, 4H), 7,03 (.s, 2H), 4,82 (m, 1H), 2,97 (m, 2H), 2,85 (m, 1H), 2,73 (m, 2H), and 2.27 (s, 3H), at 1.91 (m, 2H), 1,73 (m, 2H), 0,71 (m, 2H), or 0.57 (m, 2H).

Example 36

Obtain 3-(5-amino-4-benzoyl-3-methylsulfonylbenzoyl-1-yl)-N-cyclopropyl-4-methylbenzamide

In a solution of benzoyl-3,3-bis-methylsulfonylmethane 2 (0,218 g, 0,874 mmole) in ethanol (5 ml) was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0,243 g, 0,874 mmole) and diisopropylethylamine (0,152 ml, 0,874 mmole). The resulting mixture was heated at 65°C for 18 h, then cooled to room temperature and the solvent was removed in vacuum. The obtained residue was diluted with saturated solution of NaHCO3and three times extra is believed EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified Express chromatography (SiO2, eluent: gradient of EtOAc/hexane, from 65% to 100%). The obtained product was purified by washing with warm EtOAc and hexane, to receive the desired 3-(5-amino-4-benzoyl-3-methylsulfonylbenzoyl-1-yl)-N-cyclopropyl-4-methylbenzamide 10 in the form of a solid off-white color (57 mg, 16%). GHUR: (gradient 10-90% for 4 min), V.U. 2,34 min MS: m/z 407,1

[M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ of 8.50 (d, J 4.0 Hz, 1H), to 7.93 (dd, J 1,2, 7.9 Hz, 1H), 7,86 (s, 1H), 7,45-EUR 7.57 (m, 6H), 6,85 (.s, 2H), 2,88 (m, 1H), of 2.23 (s, 3H), of 2.18 (s, 3H), is 0.69 (m, 2H), EUR 0.58 (m, 2H).

13With NMR (DMSO-d6, 125 MHz) δ 189,3, 165,9, 152,8, 148,0, 140,4, 139,3, 135,4, 132,9, 131,2, 130,6, 128,4, 128.1, 127,2, 126,6, 102,0, 23,0, 17,3, 13,4, 5,6.

Example 37

Obtain 3-(5-amino-4-benzoyl-3-methanesulfonamido-1-yl)-N-cyclopropyl-4-methylbenzamide

To a suspension of 3-(5-amino-4-benzoyl-3-methylsulfonylbenzoyl-1-yl)-N-cyclopropyl-4-methylbenzamide 10 (40 mg, 0,098 mmole) in dichloromethane (1 ml) was added 3-chloroperoxybenzoic acid (70-75%, 53 mg, 0.22 mmole). The resulting solution was stirred at room temperature for 2 h, and then kept at 4°C over night. When heated to room temperature in the solution was observed precipitation. Solid jamestonbellajo color was collected on the Frit and washed with dichloromethane and ether, this got the desired 3-(5-amino-4-benzoyl-3-methanesulfonamido-1-yl)-N-cyclopropyl-4-methylbenzamide 11 (27 mg, 63%). GHUR: (gradient 10-90% for 4 min), V.U. 1,98 min MS: m/z 439,08 [M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ 8,53 (d, J 3,7 Hz, 1H), of 7.97 (d, J 8.1 Hz, 1H), 7,92 (s, 1H), 7,76 (d, J 7.2 Hz, 1H), of 7.48-to 7.64 (m, 5H), 6.30-in (.s, 2H), 3,29 (s, 3H), 2,88 (m, 1H), 2,17 (s, 3H), is 0.69 (m, 2H), EUR 0.58 (m, 2H).

Example 38

Getting amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid

To a solution of 2-cyano-3,3-bis-methylsulfonylamino 12 (100 mg, 0,574 mmole) in ethanol (5 ml) was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0,183 g, 0,574 mmole) and diisopropylethylamine (0.100 ml, 0,574 mmole). The resulting mixture was heated at 65°C for 18 h, then cooled to room temperature and the solvent was removed in vacuum. In the obtained residue was added EtOAc, it was observed precipitation. The solid was collected on a Frit and washed with EtOAc and ether, to receive the desired amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid 13. GHUR: (gradient 10-90% for 4 min), V.U. 1,98 min MS: m/z 439,08 [M+H]+.

1H NMR (DMSO-d6, 500 MHz) δ of 8.47 (d, J 3,7 Hz, 1H), of 7.90 (d. J 7.9 Hz, 1H), 7,78 (s, 1H), 7,49 (d, J 8.0 Hz, 1H), for 6.81 (.s, 2H), 6.30-in s, 2H), 2,86 (m, 1H), of 2.45 (s, 3H), 2,11 (s, 3H), of 0.68 (m, 2H), or 0.57 (m, 2H).

Example 39

Getting amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methanesulfonyl-1H-pyrazole-4-carboxylic acid

To a suspension of amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid 13 (100 mg, 0,289 mmole) in dichloromethane (3 ml) was added 3-chloroperoxybenzoic acid (70-75%, 157 mg, 0,637 mmole). The obtained clear solution was stirred at room temperature for 16 h, and then was added a saturated solution of NaHCO3and the reaction mixture was intensively stirred for minutes the resulting suspension was filtered on a porous filter and the obtained solid substance was three times washed N2About three times with ether, it was obtained the desired amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methanesulfonyl-1H-pyrazole-4-carboxylic acid 14 in the form of a solid white (87 mg, 80%). GHUR: (gradient 10-90% for 4 min), V.U. of 1.66 min MS: m/z 378,1 [M+H]+.

1H NMR (DMSO-d6, 500 MHz) δ 8,49 (s, 1H), 7,95 (d, J 7,6 Hz, 1H), 7,83 (s, 1H), 7,53 (d, J 7.8 Hz, 1H), 7,46 (.s, 2H), 6,74 (.s, 2H), 3,40 (s, 3H), 2,84 (m, 1H), 2,09 (s, 3H), of 0.68 (m, 2H). of 0.55 (m, 2H).

Example 40

Obtaining the ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid

In the solution of the ethyl ester of 2-cyano-3,3-bis-methylsulfonylamino acid 15 (78,0 mg, 0,359 mmole) in ethanol (3 ml) was added triptorelin N-cyclopropyl-3-hydrazino-4-methylbenzamide (0,100 g, 0,313 mmole) and diisopropylethylamine (0,0626 ml, 0,359 mmole). The resulting mixture was heated at 65°C for 2 h, then cooled to room temperature and the solvent was removed in vacuum. In the obtained residue was added EtOAc and ether, it was observed precipitation. The solid was collected on a Frit and washed with EtOAc and ether, to receive the desired ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid 16 in the form of a solid white (80 mg, 59%). GHUR: (gradient 10-90% for 4 min), V.U. 2,18 min MS: m/z 375,1 [M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ of 8.47 (d, J 3,7 Hz, 1H), of 7.90 (d, J 7.9 Hz, 1H), 7,78 (s, 1H), 7,49 (d, J 8.0 Hz, 1H), for 6.81 (.s, 2H), 6.30-in (s, 2H), 2,86 (m, 1H), of 2.45 (s, 3H), 2,11 (s, 3H), of 0.68 (m, 2H), or 0.57 (m, 2H). GHUR: (gradient 10-90% for 4 min), V.U. 1,66 minutes MS m/z 378,1 [M+H]+.

1H NMR (DMSO-d6, 300 MHz) δ of 8.50 (d, J 2.6 Hz, 1H), 7,92 (dd, J 7,9 Hz, 1H), 7,81 (s, 1H), 7,51 (d, J 7.9 Hz, 1H), 6,24 (.s, 2H), 4,22 (q, J 6.6 Hz, 2H), 2,88 (m, 1H), 2,35 (s, 3H), and 2.14 (s, 3H), of 1.29 (t, J 6,7 Hz, 3H), 0,72 (m, 2H), EUR 0.58 (m, 2H).

13With NMR (DMSO-d6125 MHz) δ 166,0, 163,1, 151,8, 148,5, 139,4, 135,8, 132,9, 131,1, 128,2, 126,7, 91,3, 58,9, 23,0, 17,2, 14,4, 12,3, 5,6.

Example 41

Poluchenie-[5-amino-4-(3-chlorobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 2-(3-Chlorobenzoyl)-3-phenylenediacrylate

A solution of 3-chlorobenzalmalononitrile (476 mg, of 2.66 mmole, 1.0 EQ.) and diphenylformamidine (522 mg, of 2.66 mmole, 1.0 EQ.) in 25 ml of toluene was stirred at room temperature for 2 h, and then was heated at 100°C during the night. The resulting solution was cooled and diluted with hexane. The obtained solid was filtered and dried, it was obtained the desired product (566 mg, 75%). GHUR: (gradient 10-95% a for 4 min), V.U. 2,97 min MS: m/z 283,2 [M+H]+.

1H NMR (CDCl3) δ of 8.06 (d, J 13,2 Hz, 1H), a 7.85 (m, 2H), 7,46 (m, 4H), 7,27 (m, 4H).

B. 3-[5-Amino-4-(3-chlorobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A solution of 2-(3-chlorobenzoyl)-3-phenylaminopyrimidine (63 mg, 0.22 mmole, 1.0 EQ.), trifenatate N-cyclopropyl-3-hydrazino-4-methylbenzamide (72 mg, 0.22 mmole, EV.) triethylamine (31 μl, 0.22 mmole, 1.0 EQ.) in 10 ml of ethanol was heated at 65°C for 20 hours After cooling, the reaction mixture was concentrated and the residue was purified rapid chromatography on silica gel to remove by-products (eluent:hexane/ethyl acetate, 7:3), and then to highlight specified in the connection header (eluent:ethyl acetate/hexane, 3:2) in a solid brown color (33 mg, 38%). GHUR: (gradient 10-95% a for 4 min), V.U. 2,35 min MS: m/z 395,1 [M+H]+.

1H NMR (CD3OD) δ a 7.92 (dd, J 2, Hz, 1H), to 7.77 (m, 4H), at 7.55 (m, 3H), 2,85 (m, 1H), of 2.23 (s, 3H), 0,80 (d, J 5.5 Hz, 2H), 0,63 (d, J 2.0 Hz, 2H).

13With NMR (CD3OD) δ 187,1, 168,1, 151,9, 141,0, 140,9, 140,0, 134,9, 133,8, 132,8, 130,9, 130,5, 129,4, 128,1, 127,0, 126,1, 125,6, 102,6, 22,1, 15,7, 4,6.

Example 42

Obtain 3-[5-amino-4-(3-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 41, but the replacement 3-chlorobenzalmalononitrile 3-methylbenzonitrile. GHUR: (gradient 10-95% a for 4 min), V.U. of 2.27 min MS: m/z 375,16 [M+H]+.

1H NMR (CD3OD) δ a 7.92 (d, J 7.0 Hz, 1H), 7,83 (s, 1H), 7,80 (s, 1H), EUR 7.57 (m, 3H), 7,42 (m, 2H), 2,85 (septet, J 3.6 Hz, 1H), of 2.45 (s, 3H), of 2.23 (s, 3H), 0,80 (d, J 5.4 Hz, 2H), 0.64 in (s, 2H).

Example 43

Obtain 3-[5-amino-4-(2-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 41, but the replacement 3-chlorobenzalmalononitrile 2-methylbenzonitrile. GHUR: (gradient 10-90% for 4 min), V.U. of 2.21 min MS: m/z 375,15 [M+H]+.

Example 44

Obtain 3-[5-amino-4-(2-methoxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 41, but the replacement 3-chlorobenzalmalononitrile 2-methoxyphenylacetonitrile. GHUR: (gradient 10-90% for 4 min), vo 2,03 minutes MS: m/z 391,16 [M+H]+.

Example 45

Obtain 3-[5-amino-4-(4-chlorbenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 41, but the replacement 3-chlorobenzalmalononitrile 3-methylbenzonitrile. GHUR: (gradient 10-90% for 4 min), V.U. 1,65 min MS: m/z 394,2 [M+H]+.

Example 46

Obtain 3-[5-amino-4-(2-chlorobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 2-(2-Chlorobenzoyl)-3-phenylenediacrylate

A solution of 2-chlorobenzalmalononitrile (1.0 g, 5.6 mmole, 1.0 EQ.) and diphenylformamidine (1.10 g, 5.6 mmole, 1.0 EQ.) in 50 ml of toluene was heated at 85°C during the night. The heating source was removed, while the desired product slowly precipitated from the solution. The obtained solid was filtered and dried, it was obtained the desired product (826 mg, 52%). GHUR: (gradient 10-90% for 4 min), V.U. 3,13 min MS: m/z 283,2 [M+H]+.

B. 3-[5-Amino-4-(2-chlorobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A solution of 2-(2-chlorobenzoyl)-3-phenylaminopyrimidine (93 mg, of 0.33 mmole, 1.0 EQ.), trifenatate N-cyclopropyl-3-hydrazino-4-methylbenzamide (104 mg, of 0.33 mmole, 1 EQ.) triethylamine (31 μl, 0.22 mmole, 1.0 EQ.) in 20 ml of ethanol was heated at 60°C for 48 hours, After cooling the reaction mixture the concentration of Aravali and the residue was dissolved in minimum amount of ethyl acetate, added 100 ml of diethyl ether, the precipitate was filtered and dried, it was obtained the desired product (50 mg, 39%). GHUR: (gradient 10-90% for 4 min), V.U. of 2.51 min MS: m/z 395,1 [M+H]+.

1H NMR (DMSO) δ of 8.50 (d, J 3.8 Hz, 1H), to 7.93 (d, J 8.0 Hz, 1H), to 7.84 (s, 1H), EUR 7.57 (m, 5H), 7,32 (s, 1H), 7.01 (s, 2H), 3,37 (m, 2H), 2,86 (m, 1H), and 2.14 (s, 3H), of 1.09 (t, 2H), of 0.68 (m, 2H), EUR 0.58 (m, 2H).

Example 47

Obtain 3-[5-amino-4-(3-methoxybenzoyl)pyrazole-1-yl]-4,N-cyclopropyl-4-methylbenzamide

A. 3-Methoxyphenylacetonitrile

To a solution of ethyl ester of 3-methoxybenzoic acid (3,05 ml of 18.6 mmole, 1.0 EQ.) and acetonitrile (1,19 ml, 22.9 mmole, of 1.23 EQ.) in 5 ml of THF at -50°C in an atmosphere of N2when mixing tube was added a freshly prepared solution of LDA (diisopropylamino, 5,3 ml, 38,0 mmole, 2,04 EQ. and 2.5 M n-utility in hexane, 15,25 ml, 38,0 mmole, 2,04 EQ.). The reaction mixture was stirred at the same temperature for 3 h, and then warmed up to 0°C for 1 h the Reaction was stopped by adding 10 ml of a saturated solution of NH4Cl and the reaction mixture was heated to room temperature. The resulting mixture was extracted with EtOAc, the organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified Express XP is matography on silica gel, when it received the product in a solid off-white color.

B. 2-(3-Methoxybenzoyl)-3-phenylenediacrylate

A solution of 3-methoxyphenylacetonitrile (1.20 g, 68.5 mmole, 1.0 EQ.) and diphenylformamidine (1,34 g, 68.5 mmole, 1.0 EQ.) in 25 ml of toluene was stirred at room temperature for 2 h, and then was heated at 100°C during the night. The resulting solution was cooled and diluted with hexane. The obtained solid was filtered and dried, it was obtained the desired product. GHUR: (gradient 10-90% for 4 min), V.U. 3,05 min MS: m/z 279,2 [M+H]+.

Century 3-[5-Amino-4-(3-methoxybenzoyl)pyrazole-1-yl]-4-methylbenzoic acid

A solution of 2-(3-chlorobenzoyl)-3-phenylaminopyrimidine (63 mg, 0.22 mmole, 1.0 EQ.), hydrochloride 3-hydrazino-4-methylbenzoic acid (72 mg, 0.22 mmole, 1 EQ.) triethylamine (31 μl, 0.22 mmole, 1.0 EQ.) in 10 ml of ethanol was heated at 65°C for 20 hours After cooling, the reaction mixture was concentrated and the residue was purified rapid chromatography on silica gel to remove by-products (eluent:hexane/ethyl acetate, 7:3), and then to highlight specified in the connection header (eluent:ethyl acetate/hexane, 3:2) in a solid brown color (15 mg, 32%). GHUR: (gradient 10-90% for 4 min), V.U. 2,13 min MS: m/z 352,2 [M+H]+.

Year 3-[5-Amino-4-(3-methoxybenzoyl)pyrazole-1-yl]-4,N-methylbenzamide

In plants the EOS 3-[5-amino-4-(3-methoxybenzoyl)pyrazole-1-yl]-4-methylbenzoic acid (50 mg, of 0.14 mmole, 1.0 EQ.) in 10 ml of DMF under stirring was added EDCI (41 mg, of 0.21 mmole, 1.5 EQ.), HOBt (29 mg, 1.5 mmole, 2.0 EQ.) and diisopropylethylamine (55 mg, 0.43 mmole, 3.0 EQ.), the solution was stirred at room temperature for 15 min, then was added methylamine hydrochloride (13 mg, 0,19 mmole, 1.5 EQ.) and the reaction mixture was stirred for 1 h the reaction mixture was diluted with EtOAc (300 ml) and washed with water (2×25 ml), brine (25 ml), dried (Na2SO4) and concentrated. The residue was purified rapid chromatography on silica gel, thus received the product (15 mg, 32%) as a solid brown color. GHUR: (gradient 10-90% for 4 min), V.U. of 1.97 min MS: m/z 365,2 [M+H]+.

Example 48

Obtaining the ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

A. Ethyl ester of 5-amino-1-(5-carboxy-2-were)-1H-pyrazole-4-carboxylic acid

In the solution of hydrochloride of 3-hydrazino-4-methylbenzoic acid (example 3A, 478 mg, a 2.36 mmole, 1.0 EQ.) in 20 ml of ethanol was added ethyl(ethoxymethylene)cyanoacrylate (399 mg, a 2.36 mmole, 1.0 EQ.) and triethylamine (329 μl, a 2.36 mmole, 1.0 EQ.), the resulting mixture with stirring, they were heated at 65°C for 5 hours After keeping at room temperature over night added another United porci the hydrochloride of 3-hydrazino-4-methylbenzoic acid (159 mg, 0,78 mmole, 0.3 EQ.) triethylamine (110 μl, 0,78 mmole, 0.3 equiv.) was heated for 2.5 hours the mixture was cooled to room temperature and concentrated. The crude residue was purified rapid chromatography on silica gel to remove by-products (eluent: hexane/EtOAc, 7:3 to 1:1), and then to highlight specified in the connection header (eluent: EtOAc to EtOAc/Meon, 9:1) in a solid brown color (464 mg, 68%). GHUR: (gradient 10-95% a for 4 min), V.U. of 1.87 min MS: m/z 290,1 [M+H]+.

1H NMR (CD3OD) δ 8,08 (d, J 7.0 Hz, 1H), to 7.93 (s, 1H), 7,76 (s, 1H), 7,54 (d, J 8.0 Hz, 1H), 4,29 (q, J 7,1 Hz, 2H), 2,19 (s, 3H), of 1.35 (d, J 7,1 Hz, 3H).

13With NMR (CD3OD) δ 166,5, 163,8, 150,4, 141,7, 139,9, 135,3, 130,8, 129,5, 128,6, 93,8, 58,8, 15,8, 12,9.

B. Ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

A solution of ethyl ester of 5-amino-1-(5-carboxy-2-were)-1H-pyrazole-4-carboxylic acid (47 mg, 0.16 mmole, 1.0 EQ.), EDCl (62 mg, of 0.32 mmole, 2.0 EQ.), HOBt (44 mg, of 0.32 mmole, 2.0 EQ.) and diisopropylethylamine (119 μl, of 0.32 mmole, 2.0 EQ.) in DMF (5 ml) was stirred at RT for 15 min, then was added cyclopropylamine (23 μl, of 0.32 mmole, 2.0 EQ.). After stirring overnight the solution was diluted with EtOAc and water, the organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The crude residue was purified Express-chromatography the th on silica gel (eluent: EtOAc/hexane, 8:2), when it received the product as a colourless oil (42 mg, 79%). GHUR: (gradient 10-95% a for 4 min), V.U. 1,84 min MS: m/z 329,09 [M+H]+.

1H NMR (CD3OD) δ of 7.96 (s, 1H, NH), 7,88 (d, J 7.9 Hz, 1H), 7,78 (s, 1H), of 7.75 (s, 1H), 7,50 (d, J 8.0 Hz, 1H), 4,28 (q, J 7,1 Hz, 2H), and 2.83 (m, 1H), 2,16 (s, 3H), of 1.35 (d, J 7.0 Hz, 3H), 0,78 (dd, J 12,3, 7,0 Hz, 2H), 0,63 (dd, J 7,0, 4.5 Hz, 2H).

13With NMR (CD3OD) δ 170,1, 165,8, 152,3, 142,1, 141,8, 137,2, 134,6, 132,8, 130,0, 128,2, 128,1, 95,8, 60,8, 24,1, 17,6, 14,9, 6,6.

Example 49

Obtaining the ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methyl-1H-pyrazole-4-carboxylic acid

A. Ethyl ester of 5-amino-1-(5-carboxy-2-were)-3-methyl-1H-pyrazole-4-carboxylic acid

In the solution of hydrochloride of 3-hydrazino-4-methylbenzoic acid (example 3A, 353 mg of 1.74 mmole, 1.0 EQ.) in 15 ml of ethanol was added ethyl ester of 2-cyano-3-taxibot-2-ene acid (obtained as described in article Xia and others, J. Med. Chem., 40, 4372, (1997), 319 mg, 1,746 mmole, 1.0 EQ.) and triethylamine (242 μl, of 1.74 mmole, 1.0 EQ.), the resulting mixture with stirring, they were heated at 65°C over night. The mixture was cooled to room temperature and concentrated. The crude residue was purified rapid chromatography on silica gel (causing CH2Cl2), then fill the column and removal of by-products used eluent: hexane/EtOAc, 6:4, and then to separate the product (eluent: EtOAc/hexane, 8:2 EtOAc/EON, 8:2) in a solid brown color (464 mg, 68%). GHUR: (gradient 10-95% a for 4 min), V.U. of 1.97 min MS: m/z 304,1 [M+H]+.

B. Ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methyl-1H-pyrazole-4-carboxylic acid

A solution of ethyl ester of 5-amino-1-(5-carboxy-2-were)-3-methyl-1H-pyrazole-4-carboxylic acid (150 mg, of 0.49 mmole, 1.0 EQ.), EDCl (190 mg, of 0.98 mmole, 2.0 EQ.), HOBt (134 mg, and 0.98 mmole, 2.0 EQ.) and diisopropylethylamine (362 μl, and 0.98 mmole, 2.0 EQ.) in DMF (5 ml) was stirred at RT for 15 min, then was added cyclopropylamine (68 μl, and 0.98 mmole, 2.0 EQ.). After stirring overnight the solution was diluted with EtOAc and water, the organic layer was washed with water (2 times) and brine, dried (Na2SO4) and concentrated. The crude residue was purified rapid chromatography on silica gel (eluent: gradient from EtOAc/hexane, 3:2 to 100% EtOAc), received the product in a solid white color (29 mg, 17%). GHUR: (gradient 10-95% a for 4 min), V.U. of 1.97 min MS: m/z 343 [M+H]+.

1H NMR (CD3OD) δ 7,87 (d, J 7,1 Hz, 1H), 7,76 (s, 1H), 7,50 (d, J 8.0 Hz, 1H), 4,29 (q, J 7.0 Hz, 2H), 2,84 (m, 1H), 2,34 (s, 3H), of 2.18 (s, 3H), of 1.36 (t, J 7.0 Hz, 3H), of 0.79 (d, J 5.5 Hz, 2H), and 0.62 (s, 2H).

13With NMR (CD3OD) δ 168,1, 164,4, 151,3, 149,8, 140,1, 135,2, 132,6, 130,7, 127,9, 126,3, 92,0, 58,6, 22,1, 15,7, 12,9, 12,6, 4,6.

Example 50

Obtaining the ethyl ester of 5-amino-3-[(3-chlorobenzylamino)methoxy]-1-(5-cyclopropyl carbamoyl-2-were)-1H-pyrazole-4-carboxylic acid

A. Ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-(2-hydroxyethoxy)-1H-pyrazole-4-carboxylic acid

A solution of ethyl ester cyano[1,3]dioxolane-2-ylideneamino acid (obtained as described in article Neidlein and Kikelj, Synthesis, 981, (1988, 266 mg of 1.45 mmole, 1.0 EQ.), trifenatate N-cyclopropyl-3-hydrazino-4-methylbenzamide (example 6C, 463 mg of 1.45 mmole, 1.0 EQ.) triethylamine (405 μl, 2.9 mmole, 2.0 EQ.) in 20 ml of ethanol was heated at 65°C over night. After cooling to room temperature the reaction mixture was concentrated and the residue was purified rapid chromatography on silica gel (eluent: gradient from hexane/EtOAc, 1:1 to 100% EtOAc), it was obtained the desired compound in the form of solid yellow-brown (350 mg, 62%). GHUR: (gradient 10-95% a for 4 min), V.U. 1,59 min MS: m/z 389,06 [M+H]+.

1H NMR (CD3OD) δ 7,87 (d, J 7.9 Hz, 1H), 7,78 (s, 1H), 7,49 (d, J 7.8 Hz, 1H), 4,29 (dd, J 14,9, 6,9 Hz, 2H), 4,19 (d, J 4.3 Hz, 2H), 3,84 (d, J 4,4, Hz, 2H), 2,84 (m, 1H), 2,22 (s, 3H), of 1.35 (t, J 7,3 Hz, 3H), 0,81 (d, J 5.3 Hz, 2H), 0,63 (s, 2H).

B. Ethyl ester of 5-amino-3-carboxymethoxy-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

To a solution of alcohol 50A (48 mg, 0.12 mmole, 1.0 EQ.) in 5 ml of acetonitrile under stirring was added 2,2',6,6'-tetramethylpiperidinyloxy (TEMPO) (rolled the practical number) and the resulting solution was heated to 35°C. Then was added dropwise sodium chlorite (17 mg, 0.24 mmole, 2.0 EQ.) in water (2 ml) and aqueous sodium hypochlorite solution diluted to 2% (1 ml) and heating was continued for 24 h, the solution was painted a bright orange color. The reaction mixture was cooled to CT and was diluted with water, then the reaction was stopped by 1 M Na2SO3and the mixture was stirred for 30 min, washed with EtOAc, and the pH of the aqueous layer was brought from 8 to 2 by adding 3 M HCl and was extracted with CH2Cl2. Extracts CH2Cl2was dried and concentrated, when it received the product in a solid yellow color. GHUR: (gradient 10-95% a for 4 min), V.U. 1,70 min MS: m/z 403,02 [M+H]+.

1H NMR (CD2OD) δ 7,83 (d, J 7.9 Hz, 1H), 7,52 (s, 1H), 7,46 (d, J 7.9 Hz, 1H), to 4.73 (s, 2H), 4,19 (q, J 7,1 Hz, 2H), 2,84 (m, 1H), 2,18 (s, 3H), of 1.31 (t, J 7.0 Hz, 3H), 0,78 (d, J 6,1 Hz, 2H), and 0.62 (s, 2H).

13With NMR (CD3OD) δ 171,1, 170,2, 168,4, 163,6, 159,7, 151,3, 140,5, 135,2, 132,5, 130,7, 127,6, 126,2, 80,9, 59,6, 58,7, 22,1, 15,8, 12,5, 4,6.

C. Ethyl ester of 5-amino-3-[(3-chlorobenzylamino)methoxy]-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

In the acid solution 50V (28 mg, 0.7 mmole, 1.0 EQ.), EDCl (32 mg, 0.17-mmole, 2.4 equiv.) HOBt (22 mg, 0.16 mmole, 2.4 EQ.) in DMF (3.0 ml) at room temperature was added 3-chlorobenzylamino (18 μl, 0.07 mmole, 1.0 EQ.) and the resulting mixture was stirred over night. Then the reaction mixture is diluted with EtOAc, washed with water (2 times), brine, dried (Na2SO4) and concentrated. The residue was purified rapid chromatography on silica gel (eluent: EtOAc/hexane, 9:1), to receive the product as colourless oil (16 mg, 44%). GHUR: (gradient 10-95% a for 4 min), V.U. 2,34 min MS: m/z 525,99 [M+H]+.

1H NMR (CD3OD) δ a 7.85 (d, J 7.9 Hz, 1H), 7,56 (s, 1H), 7,47 (d, J 8.0 Hz, 1H), 7,25 (m, 3H), to 4.73 (s, 2H), of 4.45 (s, 2H), 4,25 (q, J 7.0 Hz, 2H), 2,84 (m, 1H), 2,17 (s, 3H), of 1.27 (t, J 7.0 Hz, 3H), 0,80 (dd, J 12,3, 6,7 Hz, 2H,), and 0.62 (d, J 2.2 Hz, 2H).

13With NMR (CD3OD) δ 168,9, 168,3, 163,4, 159,6, 151,1, 140,3, 140,1, 135,2, 133,6, 132,6, 130,8, 129,1, 127,7, 126,6, 126,4, 125,0, 66,3, 58,8, 41,1, 22,1, 15,9, 12,9, 4,6.

Example 51

Obtain 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide

A. Hydrochloride 3-hydrazino-4-methylbenzoic acid

A solution of 3-amino-4-methylbenzoic acid 1 (100 g, of 0.66 mol, 1.0 EQ.) in water (1,78 l) was cooled to a temperature of 0-5°C. using an ice water. At the same temperature was sequentially added conc. HCl (1,78 l) and sodium nitrite (68,5 g 0,99 mol, 1.5 EQ.), the resulting reaction mixture was stirred at 0-5°C for 1 h At the same temperature was added chloride dihydrate tin (II) (336 g, 1,488 mole, of 2.25 EQ.) in conc. HCl (540 ml) and the mixture was stirred for 2 hours resulting solid substance was filtered and washed with water (3×500 ml), dried in vacuum at 25-30 is C for 15 h, it was obtained the crude material (110 g), which was dissolved in ethanol (1 l) and stirred at 70°C for 1 h, the resulting material was filtered while hot, washed with ethanol (50 ml) and dried in the air, it was given a clean hydrazine 2 (60 g, 45%) as a solid off-white color.

B. 3-(5-Amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid

In a solution of hydrazine 2 (59 g of 0.29 mol, 1.0 EQ.) in ethanol (4.5 l) under stirring was added compound 3 (65 g, 0,262 mol, 0.9 EQ., obtained as described in article Grothasu Davis, J. Am. Chem. Soc., 58, 1334 (1936)), and triethylamine (29 g, 0,29 mol, 1.0 EQ.), the resulting mixture was heated at 65°C. the Resulting homogeneous mixture was stirred at 65°C for 4 h, and the product precipitated. The solid was filtered while hot and dried, to receive acid 4 (45 g, 53%) as a solid crystalline substances off-white color. GHUR: (column Waters C18 X-Terra, 5 μm, 4.6 mm×250 mm, the rate of elution of 1.0 ml/min, eluent: 0.1% tea in N2O/acetonitrile, 40:60, for 30 min), V.U. 2,12 min, purity 96.6 percent. Data1H NMR (DMSO-d6, 400 MHz), see example 3.

Century 3-(5-Amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide

In a solution of acid 4 (46 g, 0,143 mol, 1.0 EQ.) in DMF (1.9 l) with stirring was added EDCl (57,5 g, 0,299 mole, 2,09 equiv.) HOBt (41,4 g, 0,306 mole, 2,14 EQ.) and diisopropylethylamine (76,6 is, of 0.59 mol, 4,15 equiv.) the resulting solution was stirred at room temperature for 20 min Then the solution was cooled to 15-20°C., was added cyclopropylamine (20.6 g, of 0.36 mol, of 2.51 EQ.) and stirred at room temperature. The course of the reaction was controlled by TLC. Because after 14 h the reaction was not completed, was added another portion of cyclopropylamine (9,36 g 0,16 mol, to 1.14 EQ.) and was stirred for another 2 h, the DMF was removed under reduced pressure at 50-55°C. To the residue was added EtOAc (1 l) and water (500 ml), the mixture was stirred for 10 min, were extracted and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×250 ml). The combined organic layers were washed with sodium bicarbonate (2×500 ml) and brine (2×500 ml), dried over anhydrous sodium sulfate and concentrated. To the residue was added EtOAc/dichloromethane/hexane (50 ml:50 ml:50 ml), the mixture was stirred for 10 min and filtered, to receive a product from 34.1 g, 65.7 per cent) in the form of a crystalline solid off-white color. GHUR: (column Waters C18 X-Terra, 5 μm, 4.6 mm×250 mm, the rate of elution of 1.0 ml/min, eluent: 0.1% of TFU in N2O/acetonitrile, 50:50, for 30 min), V.U. of 5.53 min, purity of 99.3%. MC: m/z 360 [M]+.1H NMR (DMSO-d6, 400 MHz), see example 4.

Example 52

Obtain 3-[5-amino-4-(3-cyanobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (110 mg, of 0.23 mmole) in DMF (5 ml) was added CuCN (40 mg, 0.45 mmole) and tetrakis(triphenylphosphine)palladium (catalytic amount), the resulting mixture was heated at 100°C in an atmosphere of N2throughout the night. The solvent was removed and the residue suspended in EtOAc, solid matter was filtered, the filtrate washed with water, brine, dried over Na2SO4and concentrated. The crude product was purified by chromatography on a column of silica gel (eluent: EtOAc). The product was obtained in a solid beige color (30 mg, 34%). GHUR: (gradient 10-90% for 4 min), V.U. 2,02 min MS: m/z 386,13 [M+H]+.

Example 53

Obtain 3-[5-amino-4-(3-[1,3,4]oxadiazol-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-[5-Amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carbonyl]benzoic acid

To a solution of 3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (900 mg) in CH3CN (25 ml) was added NaH2PO4(55 mg in 2 ml water) and H2O2(1.3 g, 30% solution in water), and then at 10° was added dropwise an aqueous solution of NaClO2(365 mg). The resulting mixture was stirred at the same temperature for 4 h, then was added to the Na 2SO3. The solvent was removed and the residue was dissolved in EtOAc, the organic layer was washed with water and brine, then concentrated. The crude product was purified by chromatography on a column of silica gel (eluent: gradient from EtOAc to EtOAc/AcOH, 100:1), to receive the desired intermediate compound in the form of a beige foam (345 mg, 37%).

B. 3-[5-Amino-4-(3-hydrazinobenzothiazole)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

Compound 53A (50 mg, 0.12 mmole), tert-butyl, carbazate (33 mg, 0.24 mmole), EDCl (46 mg, 0.24 mmole), HOBt (37 mg, 0.24 mmole) was dissolved in dry DMF (5 ml) and stirred at room temperature overnight. The solvent was removed and the residue was dissolved in EtOAc, the organic layer was washed with water, aqueous solution With2CO3and brine, dried over Na2SO4. Then added TFU/EDC (5 ml, 1:1) and stirred at room temperature for 30 minutes the Solvent was removed and the residue was dissolved in EtOAc, washed with an aqueous solution To a2CO3and dried over Na2SO4. The solvent was removed, while received In connection in the form of a solid beige color (45 mg, 88%).

Century 3-[5-Amino-4-(3-[1,3,4]oxadiazol-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of compound V in the Meon (2 ml) was added triethylorthoformate (2 ml) and the resulting mixture was stirred at whom atoi temperature during the night. The solvent was removed and the residue was dissolved in 1,4-dioxane was then added 5 drops of 4 M HCl solution in dioxane and the mixture was heated in a microwave reactor at 120°C for 30 minutes the Solvent was removed and the residue was dissolved in EtOAc, the organic layer was washed with water and brine, the crude product was purified preparative TLC (eluent: EtOAc/MeOH, 95:5), when it received the product in a solid beige color (25 mg, 63%). GHUR: (gradient 10-90% for 4 min), V.U. 1,81 min MS: m/z 429,13 [M+H]+.

Example 54

Obtain 3-{5-amino-4-[3-(5-methyl[1,3,4]oxadiazol-2-yl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 53, but the replacement triethylorthoformate on trimethylacetate. GHUR: (gradient 10-90% for 4 min), V.U. 1,84 min MS: m/z 443,15 [M+H]+.

Example 55

Obtain 3-{5-amino-4-[3-(pyrrolidin-1-carbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 21, but replacing Isopropylamine on pyrrolidin. GHUR: (gradient 10-90% for 4 min), V.U. 1,93 min MS: m/z 458,2 [M+H]+.

Example 56

Obtain 3-[5-amino-4-(3-cyclopropanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 21, but replacing Isopropylamine on cyclopropylamine. GHUR: (gradient 10-90% for 4 min), V.U. 1,74 min MS: m/z 444,14 [M+H]+.

Example 57

Obtain 3-[5-amino-4-(3-carbamoylmethyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 21, but replacing Isopropylamine to ammonia. GHUR: (gradient 10-90% for 4 min), V.U. 1,51 min MS: m/z 404,2 [M+H]+.

Example 58

Obtain 3-[5-amino-4-(3-isopropylcarbamate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 21B, but replacing 3-[5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-imidazole-4-carbonyl]benzoic acid 3-[5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carbonyl]benzoic acid. GHUR: (gradient 10-90% for 4 min), V.U. 1,89 min MS: m/z 446,2 [M+H]+.

Examples 59-69 (in Russian)

The compounds shown in the following examples was obtained in the same way as described in example 58, but the replacement Isopropylamine to the corresponding amine.

Examples 70-75

Compounds shown in shown the following examples, received in the same way as described in example 11, but replacing 1-methylpiperazine to the corresponding amine.

Examples 76-93

The compounds shown in the following examples was obtained in the same way as described in example 17, but replacing phenylmagnesium to the corresponding Grignard reagent.

Example 94

Obtain 3-(5-amino-4-benzoyl-2-Mei-1-yl)-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 17, but replacing triethylorthoformate on triethylorthoformate. GHUR: (gradient 10-90% for 4 min), V.U. 1,56 min MS: m/z 375 [M+H]+.

Example 95

Obtain 3-(5-amino-4-benzoyl-2-propylimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 17, but replacing triethylorthoformate on triethylorthoformate. GHUR: (gradient 10-90% for 4 min), V.U. 2,14 min MS: m/z 403 [M+H]+.

Example 96

Obtain 3-[5-amino-4-(3-carbamoyloximes)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. {3-[5-Amino-1-(5-cyclopropyl carbamoyl-2-were)-1H-pyrazole-4-carbonyl]phenoxy}acetic acid

To a solution of 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (400 mg, of 1.06 mmole) and tert-BUTYLCARBAMATE (319 mg, 2.12 mmole) in DMF (20 ml) under stirring was added To the2CO3(292 mg, 2.12 mmole) and the resulting mixture was heated at 100°C during the night. The solvent was removed and the residue suspended in EtOAc, washed with water, brine, dried over Na2SO4and concentrated. The crude product was purified by chromatography on a column of silica gel (eluent: EtOAc/hexane, 3:1), to receive a product in the form of oil is light yellow in color (140 mg, 27%).

B. {3-[5-Amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carbonyl]phenoxy}acetic acid

Oil (180 mg, 0.37 mmole), obtained at the last stage, was dissolved in DHM (5 ml), was added TFU (5 ml) and at room temperature was stirred overnight. Volatile organic components were removed, was added toluene, and then deleted it in a vacuum, when it received the product in a solid white color (140 mg, 88%).

Century 3-[5-Amino-4-(3-carbamoyloximes)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of intermediate compound obtained in the previous phase, in THF (5 ml) was added SOCl2(1 ml) and the mixture was stirred at room temperature for 2 h the Volatile components were removed, then added NH3(0.5 M process is in dioxane) and the resulting mixture was stirred at room temperature for 30 minutes The solvent was removed and the residue was purified preparative TLC (eluent: EtOAc/MeOH/Et3N, 100:10:1)and then preparative GHUR, when it received the product in a solid beige color (4.2 mg, 10%). GHUR: (gradient 10-90% for 4 min), V.U. 1,78 min MS: m/z 434,14 [M+H]+.

Examples 97-105

The compounds shown in the following examples was obtained in the same way as described in example 96, but the replacement of ammonia to the corresponding amine.

Example 106

Obtain 3-[5-amino-4-(3-pyrazin-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of 3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (130 mg, of 0.27 mmole) and 2-tributyltinchloride (119 mg, of 0.32 mmole) in DMF (2 ml) under stirring was added tetrakis(triphenylphosphine)palladium (catalytic amount) and the resulting mixture was heated in a microwave reactor at 160°C for 15 minutes the Solvent was removed and the residue was dissolved in EtOAc. The organic layers were washed with water, brine and concentrated. The crude material was purified preparative GHUR, to receive the desired product in the form of a solid beige color (6.2 mg, 5%). GHUR: (gradient 10-90% for 4 min), V.U. 2,12 min MS: m/z 439,19 [M+H]+.

Example 107

Obtain 3-[5-amino-4-(pyridin-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 106, but replacing 2-tributyltinchloride 2-tributylstannyl.

GHUR: (gradient 10-90% for 4 min), V.U. 1,94 min MS: m/z 438,26 [M+H]+.

Example 108

Obtain 3-[5-amino-4-(pyridine-2-carbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-(5-Amino-4-canoperate-1-yl)-N-cyclopropyl-4-methylbenzamide

In the solution trifenatate N-cyclopropyl-3-hydrazino-4-methylbenzamide (8,45 g of 26.5 mmole) and 2-ethoxymethylenemalononitrile (3.2 g, of 26.5 mmole) in EtOH (100 ml) was added DIPEA (3.4 g, about 26.5 mmole) and stirred at 65°C for 3 hours the Solvent was removed and the residue suspended in EtOAc (~100 ml), then the resulting suspension was added water. The solid was filtered, the filtrate washed with water, brine, dried over Na2SO4concentrated and purified by chromatography on a column of silica gel (eluent: EtOAc), the filtrate and the fractions obtained after chromatography, combined, received the product in a solid beige color (7,1 g, 96%).

B. 3-[5-Amino-4-(pyridine-2-carbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of 2-iodopyridine (of 1.03 g, 5 mmol) in THF (15 ml) at -20°C was added dropwise cyclohexylaniline (5 ml, 2.0 to the solution in Et 2O). The mixture was stirred at the same temperature for 20 min, then was added 3-(5-amino-4-canoperate-1-yl)-N-cyclopropyl-4-methylbenzamide (140 mg, 0.5 mmole) and continued stirring at room temperature over night. The reaction was stopped by addition of an aqueous solution To a2CO3obtained mixture was extracted with EtOAc and the organic layers were washed with water and brine. After purification by chromatography on a column of silica gel (eluent: EtOAc) received the product in a solid white color (60 mg, 33%). GHUR: (gradient 10-90% for 4 min), V.U. 2,09 min MS: m/z 362,20 [M+H]+.

Example 109

Obtain 3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 17B, but replacing 3-(5-amino-4-cyanomelana-1-yl)-N-cyclopropyl-4-methylbenzamide 3-[5-amino-4-(3-cyanobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide and phenylmagnesium on cyclopentylamine. GHUR: (gradient 10-90% for 4 min), V.U. of 2.54 min MS: m/z 353,19 [M+H]+.

Examples 110-126

The compounds shown in the following examples was obtained in the same way as described in example 109, but the replacement cyclopentylamine to the corresponding Grignard reagent.

Example 127

Obtain 3-{5-amino-4-[3-([1,3,4]oxadiazol-2-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

A. 3-[5-Amino-4-(3-hydrazinobenzothiazole)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

Connection 97A (300 mg, to 0.69 mmole), tert-BUTYLCARBAMATE (182 mg, to 1.38 mmole), EDCl (263 mg, to 1.38 mmole) and HOBt (211 mg, to 1.38 mmole) was dissolved in dry DMF (10 ml) and stirred at room temperature for 2 hours the Solvent was removed, the residue was dissolved in EtOAc, washed with water, aqueous solution With2CO3, brine and dried over Na2SO4. To the mixture was added TFU/EDC (5 ml, 1:1) and stirred at room temperature for 30 minutes the Solvent was removed, the residue was dissolved in EtOAc, washed with an aqueous solution To a2CO3and dried over Na2SO4. The crude residue was purified by chromatography on a column of silica gel (eluent: EtOAc/MeOH, 10:1), it was obtained the desired compound in the form of solid white (88 mg, 28%).

B. 3-{5-Amino-4-[3-([1,3,4]oxadiazol-2-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

To a solution of compound 52 (48 mg, of 0.11 mmole) in Meon (3 ml) was added triethylorthoformate (3 ml) and the resulting mixture was stirred at room temperature for the eyes. The solvent was removed, the solid residue was dissolved in 1,4-dioxane was added 5 drops of HCl in dioxane (4 M) and the mixture was heated in a microwave reactor at 120°C for 30 minutes the Solvent was removed, the residue was dissolved in EtOAc, washed with water and brine. The crude product was purified preparative GHUR, when it received the product in a solid white color (3,3 mg, 6.7 per cent). GHUR: (gradient 10-90% for 4 min), V.U. 2,07 min MS: m/z 459,13 [M+H]+.

Example 128

Receive (2-methylcyclohexyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

A. 5-Amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

A solution of ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid (1.0 g, see example 44), LiOH (1.2 g) in water/ethanol (15 ml:20 ml) was heated at 50°C during the night. The solution was neutralized with diluted HCl (2 M) and was extracted with ethyl acetate (2×200 ml), dried over Na2SO4. The solvent was evaporated under reduced pressure, then added ethyl acetate and diethyl ether. The obtained solid substance-was filtered, it was obtained the desired 3-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid (0.8 g, yield 88%).

B. (2-methylcyclo exil)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

A solution of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCl (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was kept at room temperature for 24 h, was added water (4 ml) and the solution was extracted with ethyl acetate (2×3 ml). The organic phase is washed with water (3 ml), dried over Na2SO4and was evaporated. The residue was purified on a plate for preparative TLC, to receive the desired (2-methylcyclohexyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid (19 mg, 70%). GHUR: (gradient over 4 min), V.U. 2,34 min MS: m/z 396,31 [M+H]+.

Example 129-156

The compounds shown in the following examples was obtained in the same way as described in example 128, but replacing 2-methylcyclohexylamine to the corresponding amine.

Example 157

Receiving (2,2-dimethylpropyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

The specified connection was obtained in the same way as described in example 128, but the replacement Isopropylamine on neopentylene. GHUR: (gradient 10-90% for 4 min), V.U. 2,19 min MS: m/z 370,32 [M+H]+.

Example 158

Obtain (1-ethylpyrrolidin-2-ylmethyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

The specified connection was obtained in the same way as described in example 128, but the replacement Isopropylamine 2-(aminomethyl)-1-ethylpyrrolidin. GHUR: (gradient 10-90% for 4 min), V.U. 1,41 min MS: m/z 411,25 [M+H]+.

Example 159

Receive (2-pyrrolidin-1-retil)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

The specified connection was obtained in the same way as described in example 128, but the replacement Isopropylamine 1-(2-amino-ethyl)pyrrolidin. GHUR: (gradient 10-90% for 4 min), V.U. of 1.34 min MS: m/z 397,22 [M+H]+.

Example 160

Getting cyclohexylethylamine 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid

The specified connection was obtained in the same way as described in example 57, but the replacement Isopropylamine N-methylcyclohexylamine. GHUR: (gradient 10-90% for 4 min), V.U. 2,37 min MS: m/z 396,3 [M+H]+.

Example 161

Obtain 3-[5-amino-4-(3-cyanobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-[5-Amino-4-(3-iodobenzoyl)pyrazole-1-yl]-4-methylbenzene Ki is a lot

In a solution of hydrazine 2 (32,5 g, 0,160 mol, 1.0 EQ.) in ethanol (3.6 l) under stirring was added compound 1 (60 g, 0,160 mol, 1.0 EQ.), obtained, as described in the application WO 02/57101 A1, p.84, and triethylamine (16.56 g, 0,16 mol, 1.0 EQ.), the resulting mixture was heated to 65°C. All solids were dissolved at 65°C. After cooling, the solid was filtered, received acid 3 (22 g, 30%) as a solid light brown color. GHUR: (column Waters C18 X-Terra, 5 μm, 4.6 mm×250 mm, the rate of elution of 1.0 ml/min, eluent: 0.1% tea in N2O/acetonitrile, 40:60, for 30 min), V.U. 6,74 min, purity 95.2 per cent.

B. 3-[5-Amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

In a solution of acid 3 (21 g, 0,0469 mol, 1.0 EQ.) in DMF (30 ml) was added EDCl (17 g, 0,0886 mol, 2.0 EQ.), HOBt (12,6 g, 0,0939 mol, 2.0 EQ.) and diisopropylethylamine (24.2 g, 0,18 mol, 4.0 EQ.), the resulting solution was stirred at room temperature for 15 min, then was added cyclopropylamine (10.7 g, 0,0939 mol, 2.0 EQ.) and the reaction mixture was stirred for 1 h the mixture was added water and was extracted with EtOAc (1 l), washed with water (2×200 ml) and brine (200 ml), dried over anhydrous sodium sulfate and concentrated. The product was purified rapid chromatography on silica gel (eluent: EtOAc/hexane, 8:2), when it received the product in the form of a brown oil. For further purification the product triturated in isopropyl ether (1 l) and dried in vacuum, when this was received amide 4 (12 g, 50%) as a solid off-white color.

Century 3-[5-Amino-4-(3-cyanobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

In the iodide solution 4 (7,4 g 0,015 mol, 1.0 EQ.) in N,N-dimethylformamide (25 ml) in an atmosphere of n2added copper cyanide. The resulting suspension was heated under reflux for 1 h the Completion of the reaction was controlled by TLC. Heating was stopped and the reaction mixture was cooled to 80°C. the Reaction was stopped by adding ice-cold water (15 ml), 25% aqueous ammonia (15 ml) and ethyl acetate (50 ml). The mixture was filtered to remove solids from the filtrate was separated organic layer was washed with water, saturated salt solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude material was dried at 60°C in high vacuum, then purified by column (eluent: ethyl acetate), to receive the product (3 g, 51%) as a solid off-white color. GHUR: (column Waters C18 X-Terra, 5 μm, 4.6 mm×250 mm, the rate of elution of 1.0 ml/min, eluent: 0.1% tea in N2O/acetonitrile, 70:30, for 30 min), V.U. 23,70 min, purity of 99.4%.

1H NMR (400 MHz, CDCl3) δ 8,10 (t, J 2.9 Hz, 1H), of 8.06 (t, J 2.7 Hz, 1H), 8,04 (m, 1H), 7,85 (t, J 2.5 Hz, 1H), 7,83 (m, 1H), 7,81 (d, J 1.8 Hz, 1H), 7,95 (d, J 1.6 Hz, 1H), 7,37 (s, 1H), 7,65 (t, J 7.8 Hz, 1H), 7,45 (d, J 8.0 Hz, 1H), 6,41 (s, 1H), 5,94 (s, 2H), 2,88 (m, 1H), 2,24 (s, 3H), 0,86 (d, J of 6.9 and 6.1 Hz, 2H), and 0.61 (m, 2H).

13With NMR (400 MHz, CDCl3) δ 186,6, 167,2, 151,5, 141,3, 140,7, 140,3, 135,1, 134,5, 134,0, 132,2, 131,8, 129,5, 128,7, 126,2, 118,1, 113,0, 103,7, 30,9, 23,2, 17,7, 6,8.

Example 162

Obtain 3-[5-amino-4-(3-pyrazin-2-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A. 3-[5-Amino-4-(3-bromobenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

To a solution of 3-bromo-1-iodobenzoyl (2,82 g) in THF (20 ml) at -40°C in an atmosphere of N2added cyclohexylaniline (2 M solution in THF, 6 ml). The solution was kept at a temperature from -40°C to 0°C for 20 min, then was added 3-(5-amino-4-cyanomelana-1-yl)-N-cyclopropyl-4-methylbenzamide (0.18 g) and the reaction mixture was stirred at RT for 1 h Then was added HCl (4 M, 20 ml) and the mixture was stirred at RT for 2 days. The mixture was neutralized with a solution To a2CO3and was extracted with EtOAc (2×100 ml), the combined organic layers were dried over Na2SO4and concentrated. The crude product was purified by chromatography on a column (eluent: EtOAc), it was obtained the desired product (0.15 g, 54%). GHUR: (gradient 10-90% for 4 min), V.U. of 1.85 min MS: m/z 438,10, 441,07 [M+H]+.

B. 3-[5-Amino-4-(3-pyrazin-2-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

A solution of 3-[5-amino-4-(3-bromobenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide (60 mg), 2-tributyltin is ispirazione (120 μl) and tetrakis(triphenylphosphine)palladium (0) (30 mg) in 1,4-dioxane (0.8 ml) was heated in a microwave reactor at 160°C for 25 min, then added water (3 ml) and the mixture was extracted with ethyl acetate (2×4 ml), the solvent was evaporated and the residue was purified preparative TLC (eluent: EtOAc/Meon, 10:1), it was obtained the desired product (38 mg, 63%). GHUR: (gradient 10-90% for 4 min), V.U. 2,18 min MS: m/z 439,27 [M+H]+.

Example 163

Obtain 3-[5-amino-4-(3-pyrimidine-5-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 162, but replacing 2-tributyltinchloride 4-tributylstannyl. GHUR: (gradient 10-90% for 4 min), V.U. 1,93 min MS: m/z 439,19 [M+H]+.

Example 164

Obtain 3-[5-amino-4-(3-pyridin-2-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 162, but replacing 2-tributyltinchloride 2-tributylstannyl. GHUR: (gradient 10-90% for 4 min), V.U. 2,04 min MS: m/z 438,25 [M+H]+.

Example 165

Obtain 3-[5-amino-4-(3-pyrimidine-2-aventyl)imidazol-1-yl-1-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 162, but replacing 2-tributyltinchloride 2-tributylstannyl. GHUR: (gradient 10-90% for 4 min), V.U. 2,49 min MS: m/z 439,2 [M+H] +.

Example 166

Obtaining 5-amino-1-(5-cyclopropanecarbonyl-2-were)-4-methylsulfonylbenzoyl-1H-imidazole

A solution of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-4-methylsulfonylbenzoyl-1H-imidazole (64 mg) and oxone (242 mg) in water/methanol (2 ml:2 ml) was kept at room temperature for 2 hours Then the solution was evaporated and added THF/Meon (2 ml:2 ml). The resulting mixture was heated to dissolve the solids and filtered. The filtrate was concentrated under reduced pressure and the residue was purified preparative GHUR, when it received the product (1.6 mg). GHUR: (gradient 10-90% for 4 min), V.U. 1,90 min MS: m/z 439,15 [M+H]+.

Example 167

Obtaining 5-amino-1-(5-cyclopropanecarbonyl-2-were)-4-[3-(5-methyl)oxadiazol-3-aventyl]-1H-imidazole

A mixture of N-hydroxy-3-iodobenzylamine (1.31 g), acetic anhydride (1 ml) and a catalytic amount of para-toluensulfonate acid was heated in acetic acid (10 ml) at 90°C for 6 hours, the Solvent was evaporated, added water and methanol (1:1, 100 ml). The precipitate was filtered, it was obtained the desired product (1.1 g).

To a solution of 3-(3-itfeel)-5-metronidazole (0,286 g) in THF (15 ml) in an atmosphere of N2added cyclopentylamine (2 M, 1.1 ml) at -20°C, ZAT is gradually raised the temperature for approximately 20 min to 5-10°C., was added 5-amino-1-(5-cyclopropanecarbonyl-2-were)-4-cyanomelana (96 mg) and the reaction mixture was stirred at room temperature for 0.5 h and Then added dilute HCl (4 M, 12 ml) and the reaction mixture was heated at 60°C for 3 hours After distribution in water and ethyl acetate, the final product was purified by chromatography on a column (eluent: ethyl acetate/hexane, 1:1). GHUR: (gradient 10-90% for 4 min), V.U. 2,03 min MS: m/z 443,20 [M+H]+.

Example 168

Obtain 3-(5-amino-4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide

A. 3-{5-Amino-4-[3-(2-bromoethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

To a solution of 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (472 mg, of 1.26 mmole) in dry THF (20 ml) at 0°C was added 2-bromoethanol (785 mg, 6.3 mmole), PPh3(1.3 g, 5,04 mmole) and diethylazodicarboxylate (877 mg, 5,04 mmole), the mixture was stirred at room temperature for 72 hours To the mixture was added an aqueous solution of NH4Cl, then the THF layer was separated. The aqueous layer was extracted with EtOAc. The combined organic phases are washed with salt solution, was purified preparative GHUR, when it received the product in a solid white color (360 mg, 59%).). GHUR: (gradient 10-90% for 4 min), V.U. 2,72 minutes MS: m/z 483,14/485,09 [M+H]+.

B. 3-(5-Amino-4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}pyrazole-1-yl)-]-N-cyclopropyl-4-methylbenzamide

To a suspension of 3-{5-amino-4-[3-(2-bromoethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide (24 mg, 0.05 mmole) in EtOH (1 ml) was added 1-methylpiperazine (100 mg, 1 mmol), the mixture was stirred at 80°C during the night. The solvent was removed, the residue was dissolved in EtOAc, washed with water, dried over Na2SO4. The solvent was removed, it was obtained the desired product as a colorless oil (18 mg, 72%). GHUR: (gradient 10-90% for 4 min), V.U. 1,33 min MS: m/z 503,29 [M+H]+.

Example 169

Obtain 3-[5-amino-4-(3-{2-[bis-(2-hydroxyethyl)amino]ethoxy}benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 168, but replacing 1-methylpiperazine 2-[bis-(2-hydroxyethyl)amino]ethanol. GHUR: (gradient 10-90% for 4 min), V.U. 1,39 min MS: m/z 508,24 [M+H]+.

Example 170

Obtain 3-{5-amino-4-[3-(2-dimethylaminoethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

The specified connection was obtained in the same way as described in example 168, but replacing 1-methylpiperazine 2-dimethylaminoethanol. GHUR: (gradient 10-90% for 4 min), V.U. 1,59 min MS: m/z 448,22 [M+H]+.

Example 171

Obtain 3-{5-amino-4-[3-(2,3-dihydroxypropane)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

A. 3-{5-Amino-4-[3-(2,2-dimethyl[1,3]dioxolane-4-ylethoxy)benzoyl]pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide

To a solution of 3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (75 mg, 0.2 mmole) and 4-chloromethyl-2,2-dimethyl[1,3]dioxolane (36 mg, 0.24 mmole) in DMF (4 ml) under stirring was added To the2CO3and the resulting mixture was stirred at 150°C in a microwave reactor for 2 h the Solvent was removed, the residue was dissolved in EtOAc, washed with water, brine, dried over Na2SO4and concentrated. The residue was purified by chromatography on a column (eluent: EtOAc/hexane, 3:1), thus received this product as a colorless oil (18 mg, 18%). GHUR: (gradient over 4 min), V.U. to 2.57 min MS: m/z 491,11 [M+H]+.

B. 3-{5-Amino-4-[3-(2,3-dihydroxypropane)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

Connection A (10 mg) was dissolved in SPLA (1 ml), was added 0.5 ml of water and the resulting mixture was stirred at 50°C during the night. The solvent was removed, the residue was purified preparative TLC (eluent: EtOAc), to receive a product in the form of oil is light yellow in color (4,1 mg, 45%). GHUR: (gradient 10-90% for 4 min), V.U. 1,73 min MS: m/z 451,21 [M+H]+ .

Example 172

Obtain 3-(5-amino-4-{3-[2-(4-chlorphenoxy)ethoxy]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide

To a solution of 3-{5-amino-4-[3-(2-bromoethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide (24 mg, 0.05 mmole) and 4-chlorophenol (128 mg, 1 mmol) in DMF (1 ml) was added To a2CO3(138 mg, 1 mmol) and the resulting mixture was stirred at 100°C for 2 hours Then the mixture was cooled and the solid was filtered. The filtrate was concentrated and was purified preparative GHUR, when it received the product in a solid beige color (10 mg, 38%). GHUR: (gradient 10-90% for 4 min), V.U. 2,77 min MS: m/z 531,21 [M+H]+.

Example 173

Obtain 3-{5-amino-4-[3-(4H-[1,2,4]triazole-3-yl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide

To a solution of 3-[5-amino-4-(3-carbamoylmethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide (120 mg)in DMF (2 ml) under stirring was added dimethylacetal N,N-dimethylformamide (5 ml) and the resulting solution was stirred at 80°C during the night. The solvent was removed, the residue was dissolved in Asón (5 ml), was added hydrazine monohydrate (3 ml) and the resulting mixture was stirred at 90°C during the night. The solution was acidified with hydrochloric acid to pH~1 and stirred at 80 the With during the night. The solvent was removed, the residue resuspendable in EtOAc, then washed with an aqueous solution To a2CO3, water, brine and concentrated. The crude product was purified by chromatography on a column of silica gel (eluent: EtOAc), received the product in a solid white color (65 mg, 51%). GHUR: (gradient 10-90% for 4 min), V.U. 1,58 min MS: m/z 428,18 [M+H]+.

Example 174

Obtain 3-{5-amino-4-[3-(4H-[1,2,4]triazole-3-yl)benzoyl]imidazol-1-yl} -N-cyclopropyl-4-methylbenzamide

The specified connection was obtained as described in example 173, but replacing 3-[5-amino-4-(3-carbamoylmethyl)pyrazole-1-yl]-1-cyclopropyl-4-methylbenzamide 3-[5-amino-4-(3-carbamoylmethyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide. GHUR (gradient, 10% to 90% for 4 min), V.U. was 1.58 min; MS: m/z 428,24 [M+H]+.

Example 175

The ability of the compounds of the present invention to inhibit the synthesis or activity of cytokines was assessed using the following methods of analysis in vitro.

Getting kinases R

The cDNA preparations 38α and β person received when cloning by PCR. cDNA of α - and β-isoforms were subcloned into the plasmid DEST2 (firm Gateway, In Vitrogen). A hybrid protein His6-p38 expressed in E. coli and was isolated from bacterial lysates by affinity chromatography using Ni+2-NTA-agarose. Protein Hissub> 6-p38 was activated by incubation in the presence of an active kinase MCC. Active kinase R separated from MCC affinity chromatography. Constitutive active MCC received by the method described in Raingeaud, etc. Mol. Cell. Biol., 1247-1255 (1996).

The production of TNF-α in cells RVMS stimulated lipolysaccharide (LPS)

Heparinized whole human blood was obtained from healthy volunteers. Mononuclear cells periferiinoi blood (RVMS) were isolated from whole human blood centrifugation in density gradient Accu-paque and resuspendable at a concentration of 5×106/ml in the medium for analysis (RPMI medium containing 10% fetal bovine serum). 175 μl of cell Suspension were incubated in the presence of 10 µl of the tested compound in 4% DMSO) in 96-well tablets for the cultivation of tissues for 30 min at RT. Then the cell suspension was added 15 μl of LPS (original solution 13,33 ng/ml) and the plate incubated for 18 h at 37°C in a humid atmosphere containing 5% CO2. After incubation the culture medium was collected and stored at -20°C.

Cells TNR-1 (TIB-202, ATCC) were washed and resuspendable at a concentration of 1×105/ml in the medium for analysis (RPMI medium containing 3% fetal bovine serum). 175 μl of cell Suspension were incubated in the presence of 10 µl of the tested compound in 4% DMSO) in 96-well tablets d is I the cultivation of tissues for 30 min at RT. The cell suspension was added 15 μl of LPS (original solution 13,33 ng/ml) and the plate incubated for 18 h at 37°C in a humid atmosphere containing 5% CO2. After incubation the culture medium was collected and stored at -20°C.

The concentration of TNF-α in the medium was quantified using a standard set for the ELISA, BioSource International, Camarillo, CA). The concentration of TNF-α and the value of the IC50the investigated compounds (the concentration at which the observed inhibition by 50% the production of TNF-α, LPS stimulated) was calculated using a logistic equation with four parameters (SigmaPlot, SPSS, Inc.).

Analysis of kinase 38α

The activity of the kinase 38α was determined by the amount of released ATP in the studied reactions in the oxidation of NADH, which occurs by condensation of pyruvate kinase and lactatedehydrogenase. The analysis was performed in 384-well tablets used for research by means of UV-spectroscopy. The final volume in the wells was 25 μl, which is obtained when the addition of 2.5 μl of a solution of the compound in 10% DMSO and 17.5 μl of buffer solution for analysis and 5 μl of ATP. Buffer solution for analysis contains the following reagents that add to the final concentration required for analysis: 25 mm HEPES, 20 mm 2-glycerol, pH of 7.6, 10 mm MgCl2, 0.1 mm of orthovanadate sodium, 0.5 mm phosphoenol is iravati, 0.12 mm NADH, 3.1 mg/ml LDH, to 6.67 mg/ml pyruvate kinase, 0.25 mm substrate peptide, 2 mm DTT, 0.005% of Tween 80 and 20 nm kinase 38α firm Upstate. The compounds pre-incubated in the presence of kinase 38α for 60 min and the reaction was initiated by addition of ATP at a final concentration of 0.15 mm. The reaction rate was determined at 340 nm on a SpectraMax spectrophotometer to read the tablet for 10 min at 37°C. the Data on inhibition were analyzed by nonlinear regression using the least squares method using the SigmaPlot application.

The production of TNF-α in mice, stimulated lipolysaccharide (LPS)

Mice (female Balb/C, age 6-8 weeks, the company Taconic Labs; no 8 animals per group (n=8)was injected intraperitoneal lipopolysaccharide (LPS, 50 ng/kg E. coli strain 0111:B4, firm Sigma), suspended with sterile saline. After 90 min, the mice were euthanized in an atmosphere of CO2/About2and taking samples of blood. In the obtained serum was determined by the content of TNF-α using a commercial kit for ELISA according to the manufacturer's instructions (BioSource International). The compounds were administered orally through different periods of time prior to the introduction of LPS. Compounds were introduced in the form of compounds or solutions in the presence of different media or solubilizing agents.

Results

All the compounds obtained in the examples are showing a lot of activity is ü as inhibitors of the kinase R according to the above analyses. Inhibitory activity of some compounds of the present invention in relation kinase R presented in the table below. The value of the IC50in relation kinase R, marked with ”+++”means the activity of <1 μm, the sign ”++” - from 1.0 to 10 μm, and ”+” - >10 μm.

ExampleIC50in relation kinase 38α
1+++
2+++
3++
4+++
5++
6+++
7+++
8+++
9+++
10+++
18+++
29+++
30+++
33+++
34+++
48+++
49+++
50+++
52+++
53+++
76+++
87+++
128+++
129+++
135+++
148+++
171+++

Since modifications of the variants of the present invention appear obvious to a person skilled in the art, the claimed subject and scope of the invention defined in the attached claims.

1. The compound of the formula:

or its pharmaceutically acceptable salt,
where R1means hydrogen;
R2means hydrogen, alkyl, alkylthio, alkylsulfonyl, optionally substituted alkoxy, in which the Deputy is chosen from-OR, where R isone alkyl; 3 chlorobenzylidenemalononitrile, or R2means optionally replaced by a-COOR, piperidinyloxy, where R represents alkyl;
G denotes phenyl, pyridyl, cyclohexyl, cyclopentyl, tetrahydropyranyl or benzyl is substituted by groups R3and R4provided that peregrinae ring attached to a carbonyl group through a carbon atom in the cycle, or G means OR83or NR80R81;
In means phenyl;
By means of a ring of pyrazole or imidazole of the formula

oraccordingly,
where high connection associated with G-C(=0), low communication associated with the ring, and medium links associated with R1NH;
D means triazolyl or-C(O)NR80xR81xwhere R80xand R81xmean hydrogen, alkoxy or cycloalkyl, including the one ring of 3-7 carbon atoms;
each R80and R81independently means hydrogen, alkyl, cycloalkyl, which means a saturated non-aromatic cyclic hydrocarbon system containing 1-2 rings and from three to seven carbon atoms in the ring, where cycloalkyl may be optionally condensed with a benzene ring, and which is unsubstituted or substituted by one or two substituents, independently selected from alkyl, 1-ethynylcyclohexanol, methoxybenzyl, benzyl, 3-Chlorobenzyl, qi is lipantil, 2,4-dichlorobenzyl, cyclohexylmethyl, 3,4-dichlorobenzyl, 3-trifloromethyl, tormentil, N-ethyl-2-pyrrolidinyl, methylbenzyl, pyridylmethyl, morpholinylmethyl, 1-cyclohexylethyl, 1-phenylethyl or 2-pyrrolidinyl; or R80and
R81together form optionally substituted by one or two alkilani4-C5-alkylen;
R83means hydrogen or alkyl, or cycloalkyl, which is a saturated non-aromatic hydrocarbon ring containing from three to seven carbon atoms;
R3choose from a group including:
(b) optionally substituted heterocyclyl where heterocyclyl means cyclic non-aromatic radical containing 5-6 ring atoms in which one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, where the substituents can be one or two substituent independently selected from alkyl;
(c) optionally substituted heteroaryl, which represents a monocyclic radical containing 5 to 6 ring atoms, where one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, where the substituents can be one or two substituent independently selected from alkyl;
(d) optionally substituted geterotsiklicheskikh where heterocyclisation cyclic non-aromatic radical, containing 5-6 ring atoms in which one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, where substituents can be two substituent independently selected from alkyl;
(f) -Y-(alkylene)-R9where Y represents-O-, and R9means optionally substituted by alkyl heterocyclyl containing 5-6 ring atoms in which one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, oxadiazolyl, -COOH, -COOR11or-CONR12R13where R11means alkyl, and R12and R13each independently of one another denote hydrogen or alkyl;
(g) -CONR25R26where R25and R26independently mean hydrogen or alkyl, or R25and R26together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, morpholine or piperazine;
(h) hydrogen;
(i) halogen;
(j) cyano;
(k) hydroxy;
(1) alkoxy, optionally substituted by one Deputy, selected from phenyl, -CONR'R", where R' and R" together form pyrrolidine, piperazine or morpholine, NRR', where R and R' are independently selected from hydrogen and alkyl, optionally substituted hydroxy, and-OR, where R is hydrogen or alkyl;
(m) C(L)R40where L is O; R40means hydrogen, OR55or NR57R58, where the R 55means hydrogen or alkyl, R57and R58each independently mean hydrogen, cycloalkyl containing one ring of 3-7 carbon atoms, alkyl, substituted dialkylamino, di(hydroxyalkyl)amino or above cycloalkyl;
(n) alkyl or hydroxyalkyl;
(o) 2-(4-methylpiperazin-1-yl)-2-oksidoksi, 2-(3-aminopyrrolidine-1-yl)-2-oksidoksi, 2-(3-methylaminopropyl-1-yl)-2-oksidoksi, [(1H-benzoimidazol-2-ylmethyl)carbarnoyl]methoxy, [2-(2-benzyloxy-5-chlorophenyl)ethylcarbamate]methoxy, [2-(5-chloro-2-hydroxyphenyl)ethylcarbamate]methoxy, 2-(3,5-dimethylpiperidin-1-yl)-2-oksidoksi or 4 chlorophenoxyacetic;
(R) cyclopropane;
(q) methylthio; and
(r) methylsulphonyl;
R4choose from a group that includes
(a) hydrogen;
(b) halogen;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
or R3and R4which are the substituents of adjacent atoms in the cycle, together form alkylenedioxy;
R5means hydrogen;
R6choose from a group that includes
(a) hydrogen; and
(b) alkyl;
or the connection is a
3-(5-amino-4-{3-[(3-chlorobenzylamino)methyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{[2-(3-chlorophenyl)ethylamino]methyl}benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[4-(3-chlorophenyl)piperazine-1-ylmethyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino--(3-{[2-(2-benzyloxy-5-chlorophenyl)ethylamino]-methyl}benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[(2-morpholine-4-ylethylamine)methyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[(3-morpholine-4-ylpropionic)methyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-vinyloxyethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
phenylamide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid,
3-[5-amino-4-(3-Ioganson)pyrazole-1-yl]-4-methylbenzoic acid,
3-[5-amino-4-benzoyl-3-(2-benzyloxyethyl)pyrazole-1-yl]N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(2-dimethylaminoethanol)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide, or
tert-butyl ether {3-[5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-imidazole-4-carbonyl]phenoxy}acetic acid, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where G means OR83or NR80R81.

3. The compound according to claim 1, where R80and R81each independently mean hydrogen, cyclohexyl, 2-methylcyclohexyl, 3-pentyl, bicyclo[2.2.1]heptyl, 1-ethynylcyclohexanol, methoxybenzyl, benzyl, cyclopropyl, 3-Chlorobenzyl, cyclopentyl, 2,4-dichlorobenzyl, cyclohexylmethyl, 3,4-dichlorobenzyl, 4-methylcyclohexyl, 3-trifloromethyl, 4-tert-butylcyclohexyl, neopentyl, tormentil, N-ethyl-2-pyrrolidinyl, methylbenzyl, pyridine the sludge, morpholinylmethyl, 1-cyclohexylethyl, 1-phenylethyl or 2-pyrrolidinyl.

4. The compound according to claim 1, where G denotes NH2or NH(diclohexal).

5. The compound according to claim 1, where G denotes phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl substituted by groups R3and R4.

6. The compound according to claim 1, where G denotes phenyl, substituted groups R3and R4.

7. The compound according to claim 1 of formula III:

which corresponds to the formula given in claim 1, or its pharmaceutically acceptable salt, where a corresponds to G, and means phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl.

8. The compound according to claim 1 of formula VII:

which corresponds to the formula given in claim 1, or its pharmaceutically acceptable salt, where a corresponds to G, and means phenyl, pyridyl, cyclohexyl, cyclopentyl or benzyl.

9. The compound according to claim 1, where R2means hydrogen or (ness.)alkyl.

10. The compound according to claim 1, where R2means hydrogen, methyl, n-propyl or 3-chlorobenzylidenemalononitrile.

11. The connection according to claim 7, where a represents phenyl.

12. The connection according to claim 7, where the means phenyl.

13. The connection according to claim 7, where D means 1,2,4-triazole-3-yl.

14. The connection according to claim 7, where R3means cyano.

15. The compound according to claim 1, where R3means hydrogen, DIOXOLANYL, pyrimidinyl, pyridyl, pyrazine is, cyano, oxadiazolyl, triazolyl, methylthio or methanesulfonyl.

16. The connection according to claim 7, where R3means N-morpholinylmethyl, hydroxymethyl, N-(2-(3-chlorophenyl)-1-ethyl)aminomethyl, N-(2-morpholinyl-1-ethyl)aminomethyl, (3 chlorobenzylamino)methyl, 4-(3-chlorophenyl)piperazine-1-ylmethyl, [2-(2-benzyloxy-5-chlorophenyl)ethylamino]methyl, (3-morpholine-4-ylpropionic)methyl, carbamoylmethyl, 2-(4-methylpiperazin-1-yl)-2-oksidoksi, 2-oxo-2-piperazine-1-ylethoxy, 2-(3-aminopyrrolidine-1-yl)-2-oksidoksi, 2-(3-methylaminopropyl-1-yl)-2-oksidoksi, 2-(3,5-dimethylpiperazine-1-yl)-2-oksidoksi, 2-morpholine-4-yl-2-oksidoksi, [(1H-benzoimidazol-2-ylmethyl)carbarnoyl]methoxy, [2-(2-benzyloxy-5-chlorophenyl)ethylcarbitol]methoxy, [2-(5-chloro-2-hydroxyphenyl)ethylcarbamate]methoxy or 4-piperidinylmethyl.

17. The connection according to claim 7, where R4means hydrogen.

18. The compound according to claim 1, which has one of the following formulas III or VII, respectively,
or
in which a represents G in the formula given in claim 1, and where
R1means hydrogen;
R2means hydrogen, alkyl or alkylthio;
And means phenyl;
In means phenyl;
D means triazolyl or-C(O)NR80xR81xwhere R80xand R81xmean hydrogen, alkoxy or cycloalkyl, including the one ring of 3-7 carbon atoms;
R3selected from the group including:
(b) optionally substituted heterocyclyl where heterocyclyl means cyclic non-aromatic radical containing 5-6 ring atoms in which one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, where the substituents can be one or two substituent independently selected from alkyl;
(c) optionally substituted heteroaryl, which represents a monocyclic radical containing 5 to 6 ring atoms, where one, two or three ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, where the substituents can be one or two substituent independently selected from alkyl;
(d) optionally substituted geterotsiklicheskikh where heterocyclyl means cyclic non-aromatic radical containing 5-6 ring atoms in which one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms are atoms, where substituents can be two substituent independently selected from alkyl;
(f) -Y-(alkylene)-R9where Y represents-O-, and R9means optionally substituted by alkyl heterocyclyl containing 5-6 ring atoms in which one or two ring atoms are heteroatoms selected from N and O, and the remaining atoms is the tsya atoms, oxadiazolyl, -COOH, -COOR11or-CONR12R13where R11means alkyl, and R12and R13each independently of one another denote hydrogen or alkyl;
(g) -CONR25R26where R25and R26independently mean hydrogen or alkyl, or R25and R26together with the nitrogen atom to which they are attached, form pyrrolidine, piperidine, morpholine or piperazine;
(h) hydrogen;
(j) cyano;
R4choose from a group that includes
(a) hydrogen;
(b) halogen;
(c) alkyl;
(d) alkoxy; and
(e) hydroxy;
R5means hydrogen;
R6choose from a group that includes
(a) hydrogen; and
(b) alkyl;
or its pharmaceutically acceptable salt.

19. Connection p, where R1and R2mean hydrogen, and means phenyl.

20. The connection according to claim 7, where R3is in position 3.

21. The connection according to claim 7, where R3is in position 3 and it is chosen from the group comprising hydroxymethyl, 1,2-dihydroxyethyl, 3-hydroxy-3-methyl-1-butyl or 3-hydroxybutyl.

22. The compound according to claim 1, which is selected from the group including
3-[5-amino-4-(3-Ioganson)pyrazole-1-yl]-N-methoxy-4-methylbenzamide,
3-(5-amino-4-benzoimidazol-1-yl)-N-methoxy-4-methylbenzamide,
3-(5-amino-4-benzoimidazol-1-yl)-4-methylbenzoic acid,
3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-and benzoyl)pyrazole-1-yl]-4-methylbenzoic acid,
3-[5-amino-4-(3-iodobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
{5-amino-1-[2-methyl-5-(4H-[1,2,4]triazole-3-yl)phenyl]-1H-pyrazole-4-yl}phenylmethanone,
3-[5-amino-4-(3-[1,3]dioxolane-2-yl-benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-formylbenzoate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-hydroxymethylbenzene)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(4-methylpiperazin-1-ylmethyl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-morpholine-4-iletilmistir)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(2-morpholine-4-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-benzyloxybenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-hydroxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide, and
3-(5-amino-4-benzoimidazol-1-yl)-]-N-cyclopropyl-4-methylbenzamide.

Any according to claim 7, which is 3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide.

24. The compound according to claim 1, which is selected from the group including
3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-cyclohexylcarbodiimide-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzene is,
3-(5-amino-4-phenylacetylamino-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-isopropylcarbamate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-ethylcarboxylate)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-methylcarbamoylmethyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyclopropanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyclopentanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(morpholine-4-carbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(cyclopropanecarbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(tetrahydropyran-4-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-benzoyl-3-ethoxypyrazine-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-benzoyl-3-(2-methoxyethoxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-benzoyl-3-(2-benzyloxyethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
tert-butyl ester 4-[5-amino-4-benzoyl-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-3-yloxy]piperidine-1-carboxylic acid,
3-[5-amino-4-benzoyl-3-(piperidine-4-yloxy)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-benzoyl-3-methylsulfanyl pyrazol-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-benzoyl-3-methanesulfonamido-1-yl)-N-cyclopropyl-4-methylbenzamide,
amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1 H-pyrazole-4-carboxylic acid,
amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methanesulfonyl-1 H-pyrazole-4-carboxylic acid,
ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid,
3-[5-amino-4-(3-chlorobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(2-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(2-methoxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-chlorbenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(2-chlorobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-methoxybenzoyl)pyrazole-1-yl]-4-N-cyclopropyl-4-methylbenzamide,
ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
ethyl ester of 5-amino-1-(5-cyclopropanecarbonyl-2-were)-3-methyl-1H-pyrazole-4-carboxylic acid,
ethyl ester of 5-amino-3-[(3-chlorobenzylamino)methoxy]-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-(5-amino-4-benzoimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyanobenzoyl)pyrazole-1-the l]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-[1,3,4]oxadiazol-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(5-methyl[1,3,4]oxadiazol-2-yl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(pyrrolidin-1-carbonyl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyclopropanecarbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-carbamoylmethyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-isopropylcarbamate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-methylcarbamoylmethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-cyclopropanecarbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-carbamoylmethyl)-pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(piperazine-1-carbonyl)-benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-dimethylcarbamoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(cyclopropanecarbonyl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-ethylcarboxylate)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-methylcarbamoylmethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyclopentanecarbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-isopropylcarbamate)pyrazol-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyclopropanecarbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[(3-chlorobenzylamino)methyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{[2-(3-chlorophenyl)ethylamino]methyl}benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[4-(3-chlorophenyl)piperazine-1-ylmethyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{[2-(2-benzyloxy-5-chlorophenyl)ethylamino]-methyl}benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[(2-morpholine-4-ylethylamine)methyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[(3-morpholine-4-ylpropionic)methyl]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(pyridine-2-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(2-methylbenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,4-differentail)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-perbenzoic)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,4-dichlorobenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-methoxybenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-perbenzoic)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,5-dichlorobenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-methoxybenzoyl)imidazol-1-yl]-N-cyclopropa the-4-methylbenzamide,
tert-butyl ester 3-[5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-imidazole-4-carbonyl]benzoic acid
3-[5-amino-4-(3,5-differentail)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(benzo[1,3]dioxol-5-carbonyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-chlorbenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,4-dimethoxybenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-benzyloxybenzyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-fluoro-3-methylbenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-chlorobenzoyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-benzoyl-2-Mei-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-benzoyl-2-propylimidazol-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-carbamoyloximes)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[2-(4-methylpiperazin-1-yl)-2-oksidoksi]benzoyl}-pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(2-oxo-2-piperazine-1-ylethoxy)benzoyl]-pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[2-(3-aminopyrrolidine-1-yl)-2-oksidoksi]-benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[2-(3-methylaminopropyl-1-yl)-2-oksidoksi]-benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[2-(3,5-dimethylpiperazine-1-yl)2-oksidoksi]-benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(2-morpholine-4-yl-2-oksidoksi)benzoyl]-pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{[(1H-benzoimidazol-2-ylmethyl)carbarnoyl]-methoxy}benzoyl)-pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{[2-(2-benzyloxy-5-chlorophenyl)ethylcarbamate]-methoxy}benzoyl)-pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{[2-(5-chloro-2-hydroxyphenyl)ethylcarbamate]-methoxy}benzoyl)-pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-pyrazin-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-pyridin-2-aventyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(pyridine-2-carbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-cyclopentanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(benzo[1,3]dioxol-5-carbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(2-perbenzoic)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-ethoxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-methoxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-cyclopropanecarbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-methoxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,4-dimethoxybenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-methylsulfonylbenzoyl)pyrazole-1-yl]-N-ecoprofile-4-methylbenzamide,
3-[5-amino-4-(3-methylsulfonylbenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-perbenzoic)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-perbenzoic)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,4-differentail)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3,5-differentail)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-fluoro-3-methylbenzyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(4-perbenzoic)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-cyclohexanecarbonyl-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-vinyloxyethyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-([1,3,4]oxadiazol-2-ylethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
(2-methylcyclohexyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
phenylamide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(1-ethylpropyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1 H-pyrazole-4-carboxylic acid,
bicyclo[2.2.1]hept-2-alamid 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(1-ethynylcyclohexanol)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-[5-amino-4-(2,5-dimethylpyridin-1-carbonyl)pyrazole-1-yl]--cyclopropyl-4-methylbenzamide,
4-methoxybenzylamine 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
indan-1-alamid 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
benzylated 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-[5-amino-4-(piperidine-1-carbonyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
cyclohexylamin 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
cyclopropylamino 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-chlorobenzylamino 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
cyclopentolate 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
2,4-dichloraniline 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
cyclohexylethylamine 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3,4-dichloraniline 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(4-methylcyclohexyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-triptoreline 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(4-tert-butylcyclohexyl)amide 5-amino-1-(5-cyclopropa the carbarnoyl-2-were)-1H-pyrazole-4-carboxylic acid,
(2.2-dimethylpropyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-methoxybenzylamine 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
4-forbindelse 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(1-ethylpyrrolidin-2-ylmethyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
2-methylbenzylamine 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(pyridine-2-ylmethyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(2-morpholine-4-retil)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(1-cyclohexylethyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(1-phenylethyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(2.2-dimethylpropyl)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
(2-pyrrolidin-1-retil)amide 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
cyclohexylethylamine 5-amino-1-(5-cyclopropanecarbonyl-2-were)-1H-pyrazole-4-carboxylic acid,
3-[5-amino-4-(3-cyanobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-feast of the zine-2-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-pyrimidine-5-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-pyridin-2-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-pyrimidine-2-aventyl)imidazol-1-yl]-N-cyclopropyl-4-methylbenzamide,
5-amino-1-(5-cyclopropanecarbonyl-2-were)-4-methylsulfonylbenzoyl-1H-imidazole,
5-amino-1-(5-cyclopropanecarbonyl-2-were)-4-[3-(5-methyl)oxadiazol-3-aventyl]-1H-imidazole,
3-(5-amino-4-{3-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-[5-amino-4-(3-{2-[bis-(2-hydroxyethyl)amino]ethoxy}benzoyl)pyrazole-1-yl]-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(2-dimethylaminoethoxy)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(2,3-dihydroxypropane)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide,
3-(5-amino-4-{3-[2-(4-chlorphenoxy)ethoxy]benzoyl}pyrazole-1-yl)-N-cyclopropyl-4-methylbenzamide,
3-{5-amino-4-[3-(4H-[1,2,4]triazole-3-yl)benzoyl]pyrazole-1-yl}-N-cyclopropyl-4-methylbenzamide, and
3-{5-amino-4-[3-(4H-[1,2,4]triazole-3-yl)benzoyl]imidazol-1-yl}-N-cyclopropyl-4-methylbenzamide,
or its pharmaceutically acceptable salt.

25. The connection according to claim 7, which is 3-(5-amino-4-benzoyl-3-methoxybutanol-1-yl)-N-cyclopropyl-4-methylbenzamide.

26. The connection according to claim 7, which is 3-[5-amino-4-(3-cyanobenzoyl)pyrazole-1-yl]-N-cyclopropyl-4-ethylbenzamide.

27. The pharmaceutical composition inhibiting the kinase R comprising the compound according to claim 7 or 26 and a pharmaceutically acceptable carrier.

28. The pharmaceutical composition according to item 27, received for introduction in the form of a single dosage form.

29. The connection according to claim 7 or 26, intended to treat, prevent or reduce the intensity of one or more symptoms mediated by kinase R disease or condition.

30. The use of compounds according to claim 7 or 26 for obtaining a medicinal product intended to treat, prevent or reduce the intensity of one or more symptoms mediated by kinase R disease or condition.

31. The method of induction response cytokine response, where the response cytokine response induce by using kinase activity R, including introduction to the subject in need this, the compounds according to claim 7 or 26.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds with general formula (I), where W is oxygen or sulphur; X1 and X3 are independently hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy and X4 is hydrogen, Y is in position (N2) or (N3); when Y is in position (N2), Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; when Y is in position (N3), Y is phenyl, pyridinyl or pyrimidinyl, where phenyl is optionally substituted with one or more atoms or groups selected from halogen, C1-C5 alkyl, C1-C6-alkoxy; the bond in position C4-C5 is a single or double bond; R1 and R2 each independently represent phenyl and C1-C6-alkyl, where at least one of R1 and R2 represents C1-C6-alkyl; or R1 and R2 together with the nitrogen atom to which they are bonded form a cyclic group containing from 4 to 7 links and a nitrogen atom and possibly another heteroatom, such as nitrogen or oxygen, possibly substituted with one or more C1-C6-alkyl groups; or to their pharmaceutically acceptable salts. The invention also relates to methods of producing the proposed compounds with formula (I), and specifically to compounds with formulae (Ia) and (Ib), in which X1, X3, X3, X4 and Y are as described in general formula (I). The invention also relates to intermediate compounds of synthesis of formula (I) compounds - compounds with formulae (Va) and (Vb). In formula (Va) X1, X3 and X4 represent hydrogen; X2 is hydrogen, halogen or C1-C6-alkoxy and Y is C1-C6-alkyl, C1-C6-fluoroalkyl, phenyl, pyridinyl or pyrazinyl; where phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. In formula (Vb) X1 and X3 represent hydrogen or C1-C6-alkoxy; X2 is hydrogen, halogen, C1-C6-alkyl or C1-C6-alkoxy, X4 is hydrogen; Y is phenyl, pyridinyl or pyrmidinyl; phenyl is possibly substituted with one or more atoms or groups selected from halogen, C1-C6-alkyl, C1-C6-alkoxy. The invention also relates to a medicinal agent based on a formula (I) compound or its pharmaceutically acceptable salt for preventing and treating pathologies where peripheral type benzodiazepine receptors take part. The invention also relates to use of formula (I) compounds in preparing the said medicinal agent and to a pharmaceutical composition for preventing and treating pathologies in which peripheral type benzodiazepine receptors take part.

EFFECT: new compounds have useful biological activity.

11 cl, 3 tbl, 6 ex

.

FIELD: chemistry.

SUBSTANCE: present invention relates to a quinazoline compound of formula or its pharmaceutically acceptable salts, used as inhibitors of potential-dependant sodium and calcium channels, where R1, R2, R3, R5a, R5, y and x are defined in the formula of invention. The invention also relates to a pharmaceutical composition containing the disclosed compound and to methods of inhibiting one or more of NaV1.2, NaV1.3, NaV1.8, or CaV2.2.

EFFECT: 4-aminoquinazoline antagonists of selective sodium and calcium ion channels.

17 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula compounds, as well as their pharmaceutically acceptable salts, a pharmaceutical composition based on them, with inhibitory activity towards phosphorylation of protein Tau, and to methods of producing said compounds. In formula (I), R5 is aryl, aryl(C1-C6)alkyl; R6 is halogen; R3 is (C1-C6)alkyl, possibly substituted with substitutes selected from halogen, OH, NH2, azetidine; or monocyclic aryl or heteroaryl, such as thiophene or pyridine, possibly substituted with substitutes selected from NO2, CN, (C1-C6)alkoxy, (C1-C6)alkyl; or CONR1R2, SO2Ra, C(=NH)R1b, COOR1c; R1, R2 independently represent a hydrogen atom, possibly substituted with one halogen atom, (C1-C6)alkyl, moncyclic aryl or monocyclic 5- or 6-member heteroaryl containing 1 or 2 heteroatoms, such as S, O, N, possibly substituted with one or more substitutes selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxyl, trifluoromethyl, N(CH3)2; or R1 and R2 can form a 5- or 6-member ring which optionally contains a heteroatom such as N; R1a is aryl, possibly substituted with (C1-C6)alkoxy; R1b is (C1-C6)alkyl, possibly substituted aryl or 6-member heteroaryl, containing 1 or 2 N atoms, where the substitute is (C1-C6)alkoxyl; R1c is (C1-C6)alkyl, (C2-C6)alkenyl; and their pharmaceutically acceptable salts.

EFFECT: aminoindazole derivatives as kinase inhibitor.

8 cl, 44 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: invention is related to compounds with common formulae I , III , IV and V , value of radicals such as given in formula of invention. Also suggested invention is related to pharmaceutical composition in the basis of above-mentioned compounds, to their use, and also to method of frequent urination treatment, enuresis and increased activity of urinary bladder.

EFFECT: increased efficiency of diseases treatment, in particular for treatment of frequent urination and enuresis, increased activity of urinary bladder and pain.

16 cl, 406 ex, 73 tbl

V:

FIELD: medicine.

SUBSTANCE: there are described derivatives of 1,3,4-oxadiazol-2-one of formula I and their pharmaceutically acceptable salts wherein ARYL represents phenyl which can have one substitute chosen from halogen; W represents chain or (CH2)m where m designates an integer 1 to 4; Z represents -O(CH2)n-, -(CH2)n-Y-(CH2)n- where Y designates O, n independently means an integer 1 to 5; X represents O or S; R1 represents C1-6 alkyl; R2 represents substituted phenyl where substitutes are chosen from the group including C1-6alkyl, C1-4perfluoralkyl. There are also described pharmaceutical composition, and method of treating a disease in mammal wherein said disease can be modulated by PPAR-delta receptor binding activity.

EFFECT: compounds possess agonist or antagonist activity with respect to PPAR-delta receptor.

9 cl, 2 tbl, 34 ex

Amide derivatives // 2375352

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula I, to its pharmaceutically acceptable salts exhibiting properties of inhibitors of cytokine production, such as TNF (tumour necrosis factor) and various members of interleukins (IL) family, and properties of kinase inhibitors, particularly p38α kinase. The invention also concerns methods for producing; pharmaceutical compositions and application thereof for making the medicines for treating diseases affected by the compound of the invention with specified activity. In formula I , m represents 0, 1 or 2; R1 represents halogeno, hydroxy, (1-6C) alkyl, (1-6C)alkoxy, (2-6C)alkenyl, (2-6C) alkinyl, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, amino-(2-6C) alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, N-(1-6C)alkylcarbamoyl - (1-6C)alkoxy, di[(1-6C) alkyl]amino-(1-6C)alkyl, hydroxy-(2-6C)alkylamino, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyloxy and heterocyclyl-(1-6C)alkoxy and wherein any heteroaryl or heterocyclyl group in substitute representing R1, can probably have 1 or 2 substitutes chosen from hydroxy, halogeno, (1-6C) alkyl, (2-6C)alkinyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-6C)alkyl, (1-6C)alkoxycarbonyl, (2-6C) alkanoyl, halogen-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, carboxy- (1-6C)alkyl and methylsulphonyl and wherein any said substitute representing R1 which contains group CH2 attached to 2 carbon atoms, or group CH3 attached to carbon or nitrogen atom, can probably have with each specified group CH2 or CH3, one or two substitutes chosen from halogeno, hydroxy, amino, triflouromethyl, oxo, carboxy, acetamido, (1-6C)alkyl, (3-6C)cycloalkyl, (1-6C)alkoxy, (1-6C)alkyamino, di-[(1-6C)alkyl]amino, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, halogen-(1-6C)alkyl, (1-6C)alkoxycarbonyl, carbamoyl, N, N-di-[(1-6)alkyl]carbamoyl, (1-6C)alkylsulphonyl, heteroaryl, heteroaryl-(1-6)alkyl and heterocyclyloxy and wherein any heterocyclyl group in substitute representing R1, can probably have 1 oxo-subsitute; R2 represents trifluoromethyl or (1-6C)alkyl; R3 represents hydrogen or (1-6C)alkyl; and R4 represents (3-6C)cycloalkyl, and R4 can be optionally substituted with one or more substitutes chosen from (1-6C)alkyl; and wherein heteroaryl represents aromatic 5- or 6-merous monocyclic ring containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur; heterocyclyl represents saturated 3-10-merous monocyclic or bicyclic ring, each containing one or two heteroatoms chosen from oxygen, nitrogen and sulphur.

EFFECT: improved efficiency.

24 cl, 16 tbl, 66 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, chemical technology, biology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (11): wherein X2 represents a leaving group; R3 and R4 represent substitutes chosen independently from group consisting of hydrogen atom, aromatic group and aliphatic group, or taken in common -NR3R4 form 4-11-membered aliphatic ring, but R3 and R4 can't means hydrogen atom simultaneously. Method involves interaction of compound of the formula (10): wherein X1 represents a leaving group with amine of the formula (3): (HNR3R4) in the presence of Lewis acid and a non-nucleophilic base and wherein groups X1 and X2 are similar. Compounds of the formula (11) can be used in treatment of anomalous growth of cells.

EFFECT: improved method of synthesis, valuable biological property of compound.

14 cl, 5 sch, 2 ex

FIELD: chemistry.

SUBSTANCE: proposed phosphodiesterase 4 inhibitors are characterised by formulae II, III, V, VI, where X is CH or N; L is a single bond, -(CH2)nCONH-, -(CH2)nCON(CH2CH3)-, (CH2)nSO2, (CH2)nCO2 or alkylene, optionally substituted oxo or hydroxy; n assumes values from 0 to 3; R1 is optionally substituted alkyl; R3 - H, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted phenyl, phenylalkyl, heterocyclyl, heterocyclylalkyl or cycloalkylalkyl; R4 and R5 represent alkyl; R6 - cycloalkyl, R7 is H; R8 is H, carboxy, alkoxycarbonyl, -CO-alkyl, optionally substituted alkyl.

EFFECT: new phosphodiesterase 4 inhibitors have improved properties.

55 cl, 30 ex

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