Derivatives of 5- or 6-substituted benzimidazoles as inhibitors of respiratory syncytial virus replication

FIELD: medicine.

SUBSTANCE: invention relates to derivatives of 5- or 6-substituted benzimidazoles, being inhibitory active as regards replication of respiratory syncytial viruses and having formula (I), wherein Q is R6a, piperidinyl, substituted with R6; G is methylene; R1 is piridyl, substituted with 2 substitutes, chosen from hydroxy, C1-6alkyl; one of R2a and R2b is cyano-C2-6alkenyl, Ar3C1-6alkyl, Het-C1-6alkyl, N(R8aR8b)C1-6alkyl, Ar3C2-6alkenyl, Ar3-amino-C1-6alkyl, Het-amino-C1-6alkyl, Het-C1-6alkyl-amino-C1-6alkyl, Ar3tioC1-6alkyl, Ar3amino-carbonyl, Het-amino-carbonyl, Ar3(CH2)ncarbonyl-amino, Het-(CH2)ncarbonyl-amino; and the other of R2a and R2b represents hydrogen; R3 represents hydrogen or C1-6alkyl; in the case when R2a represents hydrogen, R3 represents hydrogen; in the case when R2b represents hydrogen, R3 represents hydrogen or C1-6alkyl; R5 represents hydrogen; R6 represents C1-6alkyl, optionally substituted with one or two substitutes, each of which is independently chosen from group consisting of NR7aR7b, Ar2, hydroxy, amino-carbonyl, amino-sulphonyl; R6a is C1-6alkyl, substituted with one or two substitutes, each of which is independently chosen from group consisting of Ar2, hydroxy or heterocyclic, chosen from a group consisting of piperidinyl, piperazinyl; R7a represents hydrogen; R7b represents hydrogen; R8a represents Ar3, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy C1-6alkyl, cyanoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl, amino-carbonyl C1-6alkyl, carboxylC1-6alkyl; R8b represents Ar3, C1-6alkyl, hydroxyC1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl; each independently represents 1; Ar1 represents phenyl; Ar2 represents phenyl or phenyl substituted with one C1-6alkyl-oxy; Ar3 represents phenyl, naphtalenyl, 1,2,3,4-tetra-hydro- naphtalenyl or indanyl, wherein said phenyl, naphtyl, 1,2,3,4- tetra-hydro- naphtalenyl or indanyl can be optionally and each individually substituted with one or more, for example, 2 or 3 substitutes chosen from group consisting of halogen, hydroxy-, mercapto- cyano-, C1-6alkyl, C2-6alkinyl, Ar3 , hydroxy-C1-6alkyl, CF3, cyano-C1-6alkyl, amino-carbonyl, C1-6alkyl-oxy, C1-6alkyltio, Ar1-oxy, Ar1-amino, amino-sulphonyl, amino-carbonylC1-6alkyl, C1-4alkyl-carbonyl, C1-4alkyl-carbonyl-amino and C1-4alko-oxy-carbonyl; Het represents heterocycle chosen from phuranyl, imidazolyl, morpholinyl, piridyl, quinolene, iso-quinolene, each of said heterocycles can be optionally substituted with hydroxyl-Sibalkyl, as well as to acid additional salt thereof and stereo-chemical isomeric forms. In addition, the invention relates to pharmaceutical composition on the basis of compound of formula I and to application of compound of formula I and for production of medicinal preparation.

EFFECT: new derivatives of benzimidazole having useful biological properties.

22 cl, 6 tbl, 18 ex

 

The present invention relates to derivatives of 5 - or 6-substituted benzimidazole having antiviral activity, in particular having inhibitory activity against the replication of the respiratory syncytial virus (RSV). It relates also to a method for their production and to their containing compositions.

Human RSV or respiratory syncytial virus is a major RNA virus member of the family Paramyxoviridae, subfamily pneumoviridae along with bovine RSV virus. Human RSV is responsible for a number of respiratory diseases in people of all ages all over the world. It is a major cause of lower respiratory disease in infants and children. More than half of infants are infected with RSV in the first year of life and almost all in their first two years of life. Infection in young children may cause lung damage that persists for years and can lead to chronic lung disease in later life (chronic wheezing, asthma). Older children and adults often fall ill a common cold after RSV infection. In old age such disposition rises again, and RSV entails a number of outbreaks of pneumonia, which in old age lead to significant mortality.

Infection with this virus subgroup does not protect against subsequent deg. of infection is of RSV isolate from the same subgroup in the following the winter season. Thus, the re-infection with RSV is common, despite the fact that there are only two subtypes, A and B.

Currently only three medications are recommended for use against RSV infection. The first is Riboflavin, a nucleoside analogue, providing aerosol treatment for severe RSV infection in hospitalized children. The aerosol route of administration, toxicity (risk of teratogenicity), cost and significant fluctuations in the efficiency limit its application. Two other drugs, RespiGam® and palivizumab, using polyclonal and monoclonal antibodies intended for preventive use.

Other attempts to create a safe and effective RSV vaccine so far has failed. Inactivated vaccines can protect against the disease and in practice in some cases exacerbate the disease upon subsequent infection. With limited success has been used attenuated vaccine. Obviously, there is a need for effective, non-toxic and easy to use medication against RSV replication.

Previously benzimidazole and imidazopyridine as inhibitors of replication of RSV have been disclosed in WO 01/00611, WO 01/00612 and WO 01/00615.

Several series benzimidazolyl and imidazopyridines of piperidino disclosed in the patent is, patent applications and publications Janssen Pharmaceutica N.V. as compounds with antigistaminnami properties. See, for example, EP-A-5318, EP-A-99139, EP-A-145037, WO-92/01687, F. Janssens et al. in Journal of Medicinal Chemistry, Am. Chem. Soc, Vol. 28, no. 12, pp. 1934-1943 (1985).

The present invention relates to inhibitors of replication of RSV, which can be represented by the formula (I):

to their proletarienne forms, N-oxides, salts of accession, Quaternary amines, metal complexes and stereochemical isomeric forms, where

Q is Ar2, R6apyrrolidinyl, substituted R6piperidinyl, substituted R6or homopiperazine, substituted R6;

G represents a simple bond or a C1-10alcander, optionally substituted by one or more substituents individually selected from the group consisting of hydroxy, C1-6alkyloxy, Ar1With1-6alkyloxy,1-6alkylthio, Ar1With1-6alkylthio, HO(-CH2-CH2-O)n-With1-6alkyloxy(-CH2-CH2-O)n- Ar1With1-6alkyloxy(-CH2-CH2-O)n-;

R1is Ar1or monocyclic or bicyclic a heterocycle selected from piperidinyl, piperazinil, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, tetrahydrofuranyl, teinila, pyrrolyl, thiazolyl, oxazolyl, imide who was solila, isothiazoline, pyrazolyl, isoxazolyl, oxadiazolyl, chinoline, khinoksalinona, benzofuranyl, benzothiazyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, iridoviridae, naphthyridine, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl, 2,3-dihydro-1,4-like[2,3-b]pyridyl or a radical of the formula

where each of the aforementioned monocyclic or bicyclic heterocycles may be optionally substituted 1 or where possible more, such as 2, 3, 4 or 5 substituents individually selected from the group of substituents consisting of halogen, hydroxy, amino, cyano, carboxyl,1-6of alkyl, C1-6alkyloxy,1-6alkylthio,1-6alkalosis1-6of alkyl, Ar1, Ar1With1-6of alkyl, Ar1With1-6alkyloxy, hydroxys1-6of alkyl, mono - or di(C1-6alkyl)amino, mono - or di(C1-6alkyl)amino1-6of alkyl, polyhalogen1-6of alkyl, C1-6alkylcarboxylic,1-6alkyl-SO2-NR4a-, Ar1-SO2-NR4A-With1-6allyloxycarbonyl, -C(=O)-NR4AR4b, HO(-CH2-CH2-O)n-, halogen(-CH2-CH2-O)n-With1-6alkyloxy(-CH2-CH2-O)n-, Ar1With1-6alkyloxy(-CH2-CH2-O)nand MES is - and di(C 1-6alkyl)amino(-CH2-CH2-O)n;

one of R2aand R2bis tsianos1-6alkyl, tsianos2-6alkenyl, Ar3With1-6alkyl, Ar3(OH)1-6alkyl, Het-C1-6alkyl, N(R8aR8b)1-6alkyl, Ar3C2-6alkenyl, Het-C2-6alkenyl, Ar3aminos1-6alkyl, Het-amino1-6alkyl, Het-C1-6alkylamino1-6alkyl, Ar3tios1-6alkyl, Het-tios1-6alkyl, Ar3sulfonic1-6alkyl, Het-sulfonyl1-6alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl, Ar3carbylamine, Het-carbylamine, Ar3(CH2)ncarbylamine, Het-(CH2)ncarbylamine or Ar3(CH2)namino; and

the other of R2Aand R2brepresents hydrogen;

in that case, if R2ais hydrogen, then R3represents hydrogen;

in that case, if R2bis hydrogen, then R3represents hydrogen or C1-6alkyl;

R4aand R4bmay be the same or may differ from each other, and each independently represents hydrogen or C1-6alkyl; or

R4aand R4btaken together may form a bivalent radical of the formula -(CH2)swhere s represents 4 Il is 5;

R5represents hydrogen or C1-6alkyl;

R6represents hydrogen or C1-6alkyl, optionally substituted by one or more substituents, each independently selected from the group consisting of trifloromethyl, NR7aR7bC3-7cycloalkyl, Ar2, hydroxy, C1-4alkoxy, C1-4alkylthio, Ar2-hydroxy-, Ar2tio, Ar2(CH2)nhydroxy, Ar2(CH2)nthio, hydroxycarbonyl, aminocarbonyl,1-4alkylcarboxylic, Ar2carbonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, C1-4alkoxycarbonyl(CH2)nhydroxy, mono - or di(C1-4alkyl)aminocarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrole, imidazolyl, triazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane, pyridyl and tetrahydropyridine, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl;

R6ais1-6alkyl, substituted the ne or more substituents, each of which is independently selected from the group consisting of trifloromethyl, NR7aR7bC3-7cycloalkyl, Ar2, hydroxy, C1-4alkoxy, C1-4alkylthio, Ar2-hydroxy-, Ar2tio, Ar2(CH2)nhydroxy, Ar2(CH2)nthio, hydroxycarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, C1-4alkoxycarbonyl(CH2)nhydroxy, mono - or di(C1-4alkyl)aminocarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or heterocycle selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrole, imidazolyl, triazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane, pyridyl and tetrahydropyridine, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl;

R7arepresents hydrogen, C1-6alkyl, formyl or1-6alkylsulphonyl;

R7brepresents hydrogen, C1-6alkyl, formyl or1-6alkylsulphonyl;

R8ais Ar3With1-6 alkyl, hydroxys1-6alkyl, C1-6alkoxyl1-6alkyl, tsianos1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, Ar3With1-6alkyl, Het-C1-6alkyl, aminocarbonyl-C1-6alkyl, carboxyls1-6alkyl;

R8bis Ar3With1-6alkyl, hydroxys1-6alkyl, C1-6alkoxyl1-6alkyl, tsianos1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, Ar3With1-6alkyl, Het-C1-6alkyl;

each n independently is 1, 2, 3 or 4;

each m independently is 1 or 2;

each p independently represents 1 or 2;

Ar1represents phenyl or phenyl substituted 1 or more, such as 2, 3 or 4 substituents selected from halogen, hydroxy, C1-6of alkyl, hydroxys1-6of alkyl, polyhalogen1-6of alkyl, and C1-6alkyloxy;

Ar2represents phenyl or phenyl substituted 1 or more, such as 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C1-6of alkyl, hydroxys1-6of alkyl, polyhalogen1-6of alkyl, amino1-6of alkyl, C1-6alkyloxy, aminosulfonyl, aminocarbonyl, hydroxycarbonyl,1-4alkylsulphonyl, mono - or di(C1-4alkyl)amino, mono - or di(C1-4alkyl)aminocarb the Nile, mono - or di(C1-4alkyl)aminosulfonyl, mono - or di(C1-4alkyl)amino1-4the alkyl and C1-4alkoxycarbonyl;

Ar3represents phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalene or indanyl where specified phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene or indanyl may optionally and each individually be substituted with one or more, for example, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, mercapto, amino, cyano, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Ar1hydraxis1-6of alkyl, polyhalogen1-6of alkyl, amino1-6of alkyl, tsianos1-6of alkyl, aminocarbonyl,1-6alkyloxy,1-6alkylthio, Ar1is hydroxy, Ar1-thio, Ar1-amino, aminosulfonyl, aminocarbonyl1-6of alkyl, hydroxycarbonyl1-6of alkyl, hydroxycarbonyl, C1-4alkylsulphonyl, mono - or di(C1-4alkyl)amino, mono - or di(C1-4alkyl)aminocarbonyl, mono - or di(C1-4alkyl)aminosulfonyl, mono - or di(C1-4alkyl)amino1-6of alkyl, C1-4alkylcarboxylic and C1-4alkoxycarbonyl;

Het represents a heterocycle selected from tetrahydrofuranyl, tetrahydrothieno, dioxane, dioxolane, pyrrolidinyl, pyrrolidinone, furanyl, teinila, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isotis is Lila, pyrazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, piperidinyl, homopiperazine, piperazinil, morpholinyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, tetrahydropyranyl, chinoline, izochinolina, benzodioxane, benzodioxole, indolinyl, indolyl, each of these heterocycles may be optionally substituted by oxo, amino, Ar1C1-4the alkyl, amino1-4the alkyl, hydroxys1-6the alkyl, Ar1C1-4the alkyl, mono - or di(C1-6alkyl)amino1-6the alkyl, mono - or di(C1-6alkyl)amino, or two C1-4alkyl radicals.

The present invention also relates to the use of compounds of formula (I), or its proletarienne forms, N-oxide, salt of accession, Quaternary amine, metal and its stereochemical isomeric forms, for the preparation of pharmaceuticals for inhibition of RSV replication. Or the present invention relates to a method of inhibiting RSV replication in warm-blooded animals, and this method includes the introduction of an effective amount of the compounds of formula (I), or its proletarienne forms, N-oxide, salt of accession, Quaternary amine, metal and stereochemical isomeric form.

In the following aspect, the present invention relates to new compounds of the formula (I), also the as to methods of producing these compounds.

In the present description and the claims the term “proletarienne form” means the pharmacologically acceptable derivatives, for example esters and amides, such that, as a result of biotransformation derived, represent the active drug as defined for compounds of formula (I). The reference to Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8thed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15), in which we are talking in General about proletarienne forms included as references. Proletarienne forms are characterized by good solubility in water and biouswoyaemosti and easily converted into the active inhibitors in vivo.

Assume that the terms “C1-10alcander, optionally substituted by one or more substituents” and “C1-6alkyl, optionally substituted by one or more substituents”, for example, as used in the definition of G and, respectively, R6or R6ainclude C1-10alkadiene or C1-6alkyl radicals containing two or more substituents, for example, two, three, four, five or six substituents, in particular, two or three Vice, especially two Deputy. Upper limit on the number of substituents is determined by the number of hydrogen atoms that can be replaced, as well as the General properties of the substituents, for example, about what yamam, moreover, these characteristics allow experts to define the specified upper limits.

As used in the description, the term ”polyhalogen1-6alkyl” as a group or part of a group, for example, in polyhalogen1-6alkyloxy, means mono - or polyhalogen substituted C1-6alkyl, in particular C1-6alkyl, substituted one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl with one or more fluorine atoms, for example, deformity, trifluoromethyl, triptorelin. Also included perftools1-6alkyl groups, which are C1-6alkyl group in which all hydrogen atoms are replaced by fluorine atoms, for example, pentaverate. In that case, if more than one halogen atom attached to an alkyl group in the definition of polyhalogen1-4of alkyl, halogen atoms may be the same or different.

Each of the monocyclic or bicyclic heterocycles in the definition of R1may be optionally substituted 1 or, if possible, more substituents, for example, 2, 3, 4, or 5 substituents. In particular, these heterocycles may be optionally substituted by not more than 4, not more than 3, no more than 2 substituents, or 1 substituent.

Each Ar1or Ar2may represent the n is substituted phenyl or phenyl, substituted by 1 or more substituents, for example, 5 or 4 substituents, or preferably not more than 3 substituents, or not more than 2 substituents, or by one Deputy. Ar3represents phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalene or indanyl, each of which may optionally be substituted by one or more substituents, for example, 5 or 4 substituents or, preferably, not more than 3 substituents, or not more than two substituents or one Deputy.

Preferably, hydroxys1-6alkyl group, when she is Deputy of the oxygen atom or nitrogen atom, represented hydraxis2-6alkyl group in which the hydroxyl group and the oxygen atoms or nitrogen were separated by at least two carbon atoms.

R6or R6Amay present With1-6alkyl, substituted by one or more substituents selected from NR7aR7b, hydroxy, C1-4alkoxy, C1-4alkylthio, Ar2-hydroxy-, Ar2tio, Ar2(CH2)nhydroxy, Ar2(CH2)nthio, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, C1-4alkoxycarbonyl(CH2)nhydroxy, mono - and di(C1-4alkyl)aminocarbonyl. In this case, C1-6the site alkyl which preferably contains, at least two carbon atoms (i.e. is2-6alkyl), and these substituents are not substituted at the carbon atom linked to the nitrogen in Q.

The term "C1-4alkyl" as a group or part of a group that is used in the description, defines an unbranched or branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl and the like; C2-4alkyl as a group or part of a group defines an unbranched or branched saturated hydrocarbon radicals containing from 2 to 4 carbon atoms, such as ethyl, propyl, 1-methylethyl, butyl and the like; C1-6alkyl as a group or part of a group defines an unbranched or branched saturated hydrocarbon radicals containing from 1 to 6 carbon atoms such as the groups defined for C1-4the alkyl and penttila, hexyl, 2-methylbutyl etc.

The term "C2-6alkenyl" as a group or part of a group that is used in the description, defines an unbranched or branched saturated hydrocarbon radicals containing at least one double bond and preferably containing one double bond, and further containing from 2 to 6 carbon atoms, for example, ethynyl, propenyl, butene-1-yl, butene-2-yl, penten-1-yl, penten-2-yl, HEXEN-1-yl, HEXEN-2-yl, HEXEN-3-yl, 2-methylbutan-1-silt, etc.

C-7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

C2-5alcander represents a divalent unbranched or branched saturated hydrocarbon radicals containing from 2 to 5 carbon atoms, for example, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl etc.; C1-4alcander represents a divalent unbranched or branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol etc.; C1-6alcander includes C1-4alcander and its higher homologues containing from 5 to 6 carbon atoms, such as, for example, 1,5-pentanediyl, 1,6-hexandiol etc.; C1-10alcander includes C1-6alcander and its higher homologues containing 7 to 10 carbon atoms, such as, for example, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decandiol etc.

Used in the description of the fragment (=O) forms a carbonyl fragment when attached to a carbon atom, sulfoxide fragment when attached to a sulfur atom, and sulfanilic fragment, if two of these fragments are attached to the sulfur atom. Group (=N-OH) forms hydroxyamine fragment when attached to a carbon atom.

The term "halogen" unites fluorine, chlorine, bromine and iodine.

SL what needs to be noted, that the provisions of the radicals on any piece of molecules used in the above definitions, may be located on this fragment anywhere, unless it is chemically stable.

Radicals used in variable definitions, include all possible isomers, unless otherwise noted. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1 pencil, 2-pentyl and 3-pentyl.

If any variable occurs more than one time in any constituent parts, each determined independently.

The terms “compounds of formula (I)or compounds of the present invention” or a similar term used in the description, assume that they include compounds of General formula (I), their proletarienne forms, N-oxides, salts of accession, Quaternary amines, metal complexes and stereochemical isomeric form. An interesting subgroup of compounds of formula (I) or any of its subgroups are N-oxides, salts and all stereoisomeric forms of the compounds of formula (I).

Note that some of the compounds of formula (I) may contain one or more centers of chirality and exist as a stereochemical isomeric form.

The term "stereochemical isomeric forms, as indicated in the description, defines all possible compounds consisting of the same atoms connected in the same consequences of the successive links, but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.

If there are no other indications or references, the chemical designation of compounds comprises a mixture of all possible stereochemical isomeric forms, which may have the specified connection. This mixture may contain all of the diastereomers and/or enantiomers basic molecular structure of the compounds. All stereochemical isomeric forms of the compounds of the present invention in pure form or in mixture with each other included in the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates, as indicated in the description, are defined as isomers, containing no other enantiomeric or diastereoisomeric forms of the same basic molecular structure of the compounds or intermediates. In particular, the term ”stereoisomer pure” refers to compounds or intermediate compounds, characterized by a stereoisomeric excess of at least 80% (i.e. at least 90% of one isomer and a maximum of 10% of the other possible isomers) not more than stereoisomeric excess of 100% (i.e. 100% of one isomer and no other isomers), more preferably to compounds or intermediate compounds, the characteristics of erisugusest stereoisomeric excess of 90% to 100%, even more preferably with a stereoisomeric excess of from 94% to 100% and most preferably from stereoisomeric excess of from 97% to 100%. The terms “enantiomerically pure” and “diastereomers clean” should be understood in the same way, but to consider the enantiomeric excess and diastereomeric excess, respectively.

Pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained using well-known specialists of the procedure. For example, the enantiomers can be separated from each other, using selective crystallization of their diastereomeric salts with optically active acids or bases. Examples include tartaric acid, dibenzoyltartaric acid, ditawarkannya acid and campostoma acid. In another embodiment, the enantiomers can be separated using chromatographic techniques with chiral stationary phases. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction proceeds in a stereospecific. Preferably, if you want to get specific stereoisomer, to synthesize the specified connection using stereospecific method of receipt. These methods benefit is about to use with enantiomerically pure raw materials.

Diastereomeric the racemates of the formula (I) can be obtained separately by conventional means. It is advantageous to use appropriate physical separation methods such as selective crystallization and chromatography, for example, column chromatography.

For some compounds of formula (I), their proletarienne forms, N-oxides, salts, Quaternary amines, or metal complexes and intermediates used for their production, not experimentally determined absolute stereochemical configuration. Specialists can determine the absolute configuration of these compounds using methods known in the art, for example, x-ray diffraction.

The present invention also includes all isotopes of the atoms forming the structure of the considered compounds. Isotopes are atoms with the same atomic number but different mass number. As an example (but without limitation) you can specify the isotopes of hydrogen include tritium and deuterium.

Isotopes of carbon include13C and14C.

For therapeutic use suitable salts of the compounds of formula (I), in which the counterion is pharmaceutically acceptable. However, salts of acids and bases, which are pharmaceutically unacceptable salts may also find application, for example, when Paul the treatment or purification of pharmaceutically acceptable compounds. All salts, regardless of whether they are pharmaceutically acceptable or not included in the scope of the present invention.

Mean pharmaceutically acceptable salt accession of acids and bases, as indicated in the description, include therapeutically active non-toxic form of salts accession of acids and bases, which are capable of forming compounds of formula (I). Pharmaceutically acceptable salt accession acids can be obtained by treating the appropriate acid. Suitable acids include, for example, inorganic acid, such as halogen acids, e.g. hydrochloric or Hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids, for example, acetic, propanoic, hydroxilase, lactic, pyruvic, oxalic (i.e. ethicality), malonic, succinic (i.e. butanedioate), maleic, fumaric, malic (i.e. hydroxybutyrate), tartaric, citric, methansulfonate, econsultancy, benzosulfimide, p-toluensulfonate, reklamowe, salicylic, p-aminosalicylic, pambou, etc. acids.

Conversely, these salt forms can be converted by processing the corresponding base in the form of a free base.

The compounds of formula (I)containing acidic protons, can changepriority in the form of their non-toxic salts of joining metals or amines, processing appropriate organic and inorganic bases. The appropriate form of the salts of the bases include, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium and the like, salts of organic bases, for example, salt, benzathine, N-methyl-D-glucamine, geranamine, and salts of amino acids, such as arginine, lysine, etc.

The term "salt accession"used in the description, also includes a solvate, which can form compounds of formula (I)and their salts. These are solvate, for example, hydrates, alcoholate, etc.

The term "Quaternary amine"as used in the description, defines the Quaternary ammonium salts that can form the compounds of formula (I), the reaction of the basic nitrogen compounds of formula (I) and the corresponding quaternized agent, for example, optionally substituted alkylhalogenide, helgaleena or arylalkylamine, for example, under the conditions or benzylidene. You can use other reagents with easy atmasamyama groups, for example, alkylarylsulfonate, alkylarylsulfonate and alkyl-p-toluensulfonate. The Quaternary amine nitrogen is positively charged. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, triptorelin and acetate. Selected counterion which you can enter, using ion-exchange resins.

Assume that the N-oxide forms of the compounds of the present invention include compounds of formula (I)in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

It should be noted that the compounds of formula (I) can have the property of binding metals, chelation, complexation, and can therefore exist in the form complexes with metals or Metallistov. Such metilirovannye derivatives of compounds of formula (I) should be included in the scope of the present invention.

Some of the compounds of formula (I) may exist in their tautomeric form. While these details are not specified in the above formulas, they are also included in the scope of the present invention.

It is implied that any specified in the description of the subgroup of compounds of formula (I) also includes proletarienne forms, N-oxides, salts of accession, Quaternary amines, metal complexes and stereochemical isomeric forms of these subgroups of compounds of formula (I).

One of the variants of the present invention relates to compounds of the formula (I-a):

where Q, R5, G, R1and R2bhave the values listed above in the definitions of formula (I), or for any of the subgroups specified in the description of compounds.

Another option infusion is his invention relates to compounds of the formula (I-b):

where Q, R5, G, R1, R2Aand R3have the values listed above in the definitions for compounds of formula (I), or the values specified for any of the subgroups defined in the description of the compounds.

One of the specific variants of the present invention relates to compounds of the formula (I-a-1):

where Q, R5, G, and R1have the values listed above in the definitions for compounds of formula (I), or the values specified for any of the subgroups defined in the description of the compounds; and

Alk represents a C1-6alcander;

R8cis specified for R8avalues and may also represent hydrogen;

R9, R10, R11independently of one another have the same values as defined for the substituents at Ar3that are specified in the definitions for compounds of formula (I) or any of the subgroups defined in the description of the compounds.

Another particular variant of the present invention relates to compounds of the formula (I-b-1):

where Q, R5, G, R1and R3have the values listed above in the definitions for compounds of formula (I), or the values specified for any of the subgroups defined in the description of the compounds of formula (I); and

Alk represents a C1-6alcander;

R8chas is shown for R 8avalues and may also represent hydrogen;

R9, R10, R11independently of one another have the same values as defined for the substituents at Ar3that are specified in the definitions for compounds of formula (I) or any of the subgroups defined in the description of the compounds.

Another variant of the present invention relates to compounds of the formula (I-c):

where t, G, R1, R2a, R2b, R3, R5and R6have the values listed above in the definitions for compounds of formula (I), or the values specified for any of the subgroups defined in the description of the compounds.

Another variant of the present invention relates to compounds of the formula (I-d):

where t, R5, R6, G, R1and R2bhave the above values or values that are specified for any of the subgroups defined in the description of the compounds.

Another variant of the present invention relates to compounds of the formula (I-e):

where t, R5, R6, G, R1, R2Aand R3have the above values or values that are specified for any of the subgroups defined in the description of the compounds.

Other options include compounds of formula (I-c), (I-d) or (I-e), where t is 2, i.e. compounds of formula

where Q, t, R5, G, R1, R2A, R2b, R3have the above values or values that are specified for any of the subgroups defined in the description of the compounds.

Another variant of the present invention relates to compounds of the formula (I-d-2):

where R5, R6, G, and R1have the above values or values that are specified for any of the subgroups defined in the description of the compounds; and

t represents 1, 2 or 3; preferably t is 2;

Alk represents a C1-6alcander;

R8cis specified for R8avalues and may also represent hydrogen;

R9, R10, R11independently of one another have the same values as defined for the substituents at Ar3that are specified in the definitions for compounds of formula (I) or any of the subgroups defined in the description of the compounds.

Another variant of the present invention relates to compounds of the formula (I-e):

where R5, R6, G, R1and R3have the above values, or values that are specified for any of the subgroups defined in the description of the compounds; and

t represents 1, 2 or 3; preferably t is 2;

R8cis specified for R8avalues, and also may present the identification of hydrogen;

R9, R10, R11independently of one another have the same values as defined for the substituents at Ar3that are specified in the definitions for compounds of formula (I) or any of the subgroups defined in the description of the compounds.

Other preferred subgroups are those in which Alk represents ethylene or methylene, more preferably in which Alk represents methylene.

In (I-a-1), (I-b-1), (I-d-2) or (I-e-2) R8cpreferably represents hydrogen, hydroxys1-6alkyl, aminocarbonyl1-6alkyl.

In (I-a-1), (I-b-1), (I-d-2) or (I-e-2):

(a) R9, R10, R11preferably and independently of one another represent hydrogen, halogen, hydroxy, mercapto, amino, cyano, C1-6alkyl, C2-6alkenyl, C2-6quinil, Ar1hydraxis1-6alkyl, CF3aminos1-6alkyl, tsianos1-6alkyl, aminocarbonyl,1-6alkyloxy,1-6alkylthio, Ar1is hydroxy, Ar1-thio, Ar1-amino, aminosulfonyl, aminocarbonyl1-6alkyl, hydroxycarbonyl1-6alkyl, hydroxycarbonyl, C1-4alkylsulphonyl,1-4alkylcarboxylic or1-4alkoxycarbonyl; or

(b) R9, R10, R11more preferably and independently of one another represent hydrogen, halogen, hydroxy, mercapto, cyano, C1-6alkyl, C2-6Elke the sludge, C2-6quinil, Ar1hydraxis1-6alkyl, CF3aminos1-6alkyl, tsianos1-6alkyl, aminocarbonyl,1-6alkyloxy,1-6alkylthio, Ar1is hydroxy, Ar1-thio, Ar1-amino, aminosulfonyl, aminocarbonyl1-6alkyl, hydroxycarbonyl1-6alkyl, C1-4alkylsulphonyl,1-4alkylcarboxylic or C1-4alkoxycarbonyl; or

(c) R9, R10, R11more preferably and independently of one another represent halogen, C1-6alkyl or hydraxis1-6alkyl; or

(d) R9, R10more preferable are indicated in (a), (b) or (c) values, and R11represents hydrogen; or

(e) R9, R10more preferably and independently of one another represent C1-6alkyl or hydraxis1-6alkyl; and R11represents hydrogen; or

(f) R9, R10even more preferably represent From1-6alkyl, and R11represents hydrogen; or

(g) R9is1-6alkyl, R10is hydraxis1-6alkyl, and R11represents hydrogen.

It should be understood that imply that the above specified subgroups of compounds of formula (I-a), (I-b), etc. as well as any other specific in the description of the subgroups include any proletarienne forms, N-oxides, salts also the organisations, Quaternary amines, metal complexes and stereochemical isomeric forms of such compounds.

Particular subgroups of compounds of formula (I) are those compounds of formula (I)or any subgroup defined in the description of compounds of formula (I)in which G represents C1-10alcander, especially, where G is methylene.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where

(a) R1differs from Ar1; or where

(b) R1is Ar1or monocyclic heterocycle, which is specified in the definitions for compounds of formula (I) or any of their subgroups.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I) or compounds of any of the defined in the description of the subgroups of compounds of formula (I), where

(c) R1represents pyridyl, optionally substituted by 1 or 2 substituents, independently selected from the group consisting of halogen, hydroxy, amino, cyano, carboxyl,1-6of alkyl, C1-6alkyloxy,1-6alkylthio,1-6alkalosis1-6of alkyl, Ar1, Ar1With1-6of alkyl, Ar1With1-6alkyloxy, hydroxys1-6of alkyl, mono - or di(C1-6alkyl)amino, mono - or di(C1-6alkyl)amine is 1-6of alkyl, polyhalogen1-6of alkyl, C1-6alkylcarboxylic,1-6alkyl-SO2-NR4a-, Ar1-SO2-NR4a-With1-6allyloxycarbonyl, -C(=O)-NR4aR4b, HO(-CH2-CH2-O)n-, halogen(-CH2-CH2-O)n-With1-6alkyloxy(-CH2-CH2-O)n-, Ar1With1-6alkyloxy(-CH2-CH2-O)nand mono - or di(C1-6alkyl)amino(-CH2-CH2-O)n-; or especially

(d) R1represents pyridyl, substituted by 1 or 2 substituents, independently selected from the group consisting of hydroxy, C1-6of alkyl, halogen, C1-6alkyloxy, Ar1With1-6alkyloxy and (C1-6alkyloxy)1-6alkyloxy; preferably, where

(e) R1represents pyridyl, substituted by 1 or 2 substituents, independently selected from the group consisting of hydroxy, C1-6of alkyl, halogen and C1-6alkyloxy; or where

(f) R1represents pyridyl, substituted by 1 or 2 substituents, independently selected from the group consisting of hydroxy and C1-6of alkyl; more preferably, where

(g) R1represents pyridyl, substituted hydroxy and C1-6by alkyl; or more preferably, where

(h) R1represents pyridyl, substituted hydroxy and stands; or where

(i) R1is 3-hydroxy-6-methylpiperid-2-the l

Further options include such compounds of formula (I) or any subgroup of compounds of formula (I), where

(j) R1is Ar1chinoline, benzimidazolyl, a radical of the formula

pyrazinyl, or pyridyl; or where

(k) R1is Ar1chinoline, benzimidazolyl or a radical of formula (c-4), where m is 2, pyrazinyl or pyridyl;

where each of the radicals in (j) and (k) may be optionally substituted by the substituents listed in the definition of compounds of formula (I), and, in particular, pyridyl may be substituted as specified above in (a)-(i); or more specifically, where

(l) R1is Ar1chinoline, benzimidazolyl or a radical of formula (c-4), where m is 2, pyrazinyl or pyridyl, where each of these radicals may be optionally substituted with one, two or three radicals selected from the group consisting of halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy, Ar1With1-6alkyloxy, (C1-6alkyloxy)1-6alkyloxy; or, more specifically, where

(m) R1is Ar1chinoline, benzimidazolyl or a radical of formula (c-4), where m is 2, pyrazinyl or pyridyl, where each of these radicals may be optionally substituted with one, two or three radicals selected from the group consisting of halogen is, hydroxy, C1-6of alkyl, C1-6alkyloxy, benzyloxy; or more specifically, where

(n) R1represents phenyl, optionally substituted one, two or three radicals selected from the group consisting of halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy; chinoline; radical (c-4), where m is 2, optionally substituted by up to two radicals, selected from C1-6of alkyl; benzimidazolyl, optionally substituted C1-6by alkyl; pyridyl, optionally substituted by one or two radicals selected from hydroxy, halogen, C1-6of alkyl, benzyloxy and C1-6alkyloxy; pyrazinyl, optionally substituted by not more than three radicals selected from C1-6of alkyl; or pyridyl, substituted or optionally substituted as described in (a)-(i); or where

(o) R1represents phenyl, optionally substituted by one or two radicals selected from the group consisting of halogen, hydroxy, C1-6of alkyl, C1-6alkyloxy;

(p) R1is chinoline;

(q) R1represents the radical (c-4), where m is 2, optionally substituted by up to two radicals, selected from C1-6of alkyl;

(r) R1is benzimidazolyl, optionally substituted C1-6by alkyl; pyridyl, optionally substituted by one or two happy the Kalami selected from hydroxy, halogen, benzyloxy and C1-6alkyloxy,

(s) R1is pyrazinyl, optionally substituted by not more than three radicals selected from C1-6the alkyl.

Preferred subgroups of compounds of formula (I)or any subgroup of compounds of formula (I)are those in which G represents a simple bond or a methylene and R1is specified in (a)-(s) values. Further preferred are the compounds of formula (I) or any of the specific in the description of the subgroups, where G represents a simple bond, and R1represents the radical (C-4), in particular where m is 2, optionally substituted by not more than two radicals selected from C1-6the alkyl. Hereinafter, preferred are the compounds of formula (I), or any of the specific in the description of the subgroups, or where G is methylene, and R1is specified in (a)-(s) values, but different from the radical (C-4).

A particular variant of the present invention relates to compounds of formula (I) or any of the specific in the description of the subgroups of compounds of formula (I), where

(a) one of R2aand R2bchoose from tsianos1-6of alkyl, tsianos1-6alkenyl, AG3C1-6of alkyl, (AG3)(IT)C1-6of alkyl, Het-C1-6of alkyl, N(R8aR8b) C1-6of alkyl, AG3C2-6alkenyl, Het-C2-6al is Anila, AG3aminos1-6of alkyl, Het-amino1-6of alkyl, Het-C1-6alkylamino1-6of alkyl, AG3tios1-6of alkyl, Het-tios1-6of alkyl, Ar3sulfonic1-6of alkyl, Het-sulfonyl1-6of alkyl, AG3aminocarbonyl, Het-aminocarbonyl, AG3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl, AG3carbylamine, Ar3(CH2)namino; and the other of R2aand R2brepresents hydrogen; or

(b) one of R2aand R2bchoose from tsianos1-6of alkyl, tsianos2-6alkenyl, AG3C1-6of alkyl, (Ar3)(IT)C1-6of alkyl, Het-C1-6of alkyl, N(R8aR8b)C1-6of alkyl, AG3C2-6alkenyl, Ar3aminos1-6of alkyl, Het-amino1-6of alkyl, Het-C1-6alkylamino1-6of alkyl, Ar3tios1-6of alkyl, AG3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl, Ar3carbylamine, Ar3(CH2)namino; and the other of R2aand R2brepresents hydrogen; or

(c) one of R2aand R2bchoose from tsianos1-6of alkyl, Ar3With1-6of alkyl, Het-C1-6of alkyl, N(R8aR8b)C1-6of alkyl, Ar3C2-6alkenyl, Ar3aminos1-6of alkyl, Het-amino1-6of alkyl, Het-C1-6alkylamino1-6/sub> of alkyl, Ar3tios1-6of alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl,

Het-(CH2)naminocarbonyl; and the other of R2aand R2brepresents hydrogen; or

(d) one of R2aand R2bchoose from tsianos1-6of alkyl, Ar3C1-6of alkyl, Het-C1-6of alkyl, N(R8aR8b)C1-6of alkyl, Ar3With2-6alkenyl, Ar3aminos1-6of alkyl, Het-amino1-6of alkyl, Ar3aminocarbonyl; and the other of R2aand R2brepresents hydrogen; or

(e) one of R2aand R2bchoose from Ar3C1-6of alkyl, N(R8aR8b)C1-6alkenyl, Ar3aminos1-6of alkyl; and the other of R2aand R2brepresents hydrogen; or

(f) one of R2aand R2bselected from N(R8aR8b)C1-6of alkyl, Ar3aminos1-6of alkyl; and the other of R2aand R2bis hydrogen; and for any of (a)-(f)

in that case, if R2ais hydrogen, then R3represents hydrogen;

in that case, if R2bis hydrogen, then R3represents hydrogen or C1-6alkyl; or preferably then R3represents hydrogen.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I) or any defined in opisanie.php compounds of formula (I), where R5represents hydrogen.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where Q is Ar2.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where Q is R6a.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where Q represents pyrrolidinyl, substituted R6piperidinyl, substituted R6or homopiperazine, substituted R6; in particular, where Q represents piperidinyl, substituted R6. Preferably, the group R6was substituted at the nitrogen atom of the specified pyrrolidinyl, piperidinyl or homopiperazine. More preferably, the specified pyrrolidinyl, piperidinyl or homopiperazine was associated with-N(R5)-a slice through the 3-strong communication, or, in particular, through 4-ilen connection.

An interesting subgroup of compounds are those compounds of formula (I) or any defined in the description of sub-groups, where Q is R6awhere

(a) R6ais1-6alkyl, substituted two Deputy what stitely or preferably, one Deputy, each of which is independently selected from the group consisting of trifloromethyl, NR7aR7b, Ar2, hydroxy, C1-6alkoxy, Ar2(CH2)nhydroxy, hydroxycarbonyl, aminocarbonyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane and pyridyl, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl; or in particular, where

(b) R6ais1-6alkyl, substituted by one, and, optionally, another Deputy who represents hydroxy, where specified by the Deputy is trifluoromethyl, NR7aR7b, Ar2, hydroxy, C1-4alkoxy, Ar2(CH2)nhydroxy, hydroxycarbonyl, aminocarbonyl,1-4alkylsulphonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, mono - or di(C 1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane and pyridyl, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl; or further, in particular,

(c) R6ais1-6alkyl, substituted NR7aR7b, Ar2, hydroxy, C1-4alkoxy, hydroxy-carbonyl, aminocarbonyl, aminosulfonyl1-4alkylcarboxylic, Ar2carbonyl, C1-4alkoxycarbonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, where each of these heterocycles may be optionally substituted by oxo or one or two C1-6alkyl radicals; or further, in particular,

(d) R6ais1-6alkyl, substituted NR7aR7b, Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperid the Nile, homopiperazine, piperazinil, where each of these heterocycles may be optionally substituted by oxo or one or two C1-6alkyl radicals; or further, in particular,

(e) R6ais1-6alkyl, substituted Ar2or hydroxy, or C1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, piperazinil, where each of these heterocycles may be optionally substituted by one or two1-6alkyl radicals; or preferably

(f) R6ais1-6alkyl, substituted Ar2or hydroxy, or C1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted dis1-6alkyloxyaryl, pyrrolidinium, piperidinium, piperazinil, 4-C1-6alkylpiperazine; or preferably

(g) R6ais1-6alkyl, substituted Ar2or hydroxy, or C1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted piperidinium or piperazinil; or more preferably

(h) R6ais1-6alkyl, substituted Ar2or1-6alkyl, substituted piperidinium or piperazinil.

Preferably, in (a)-(h) in the previous section radika the s pyrrolidinyl, piperidinyl, homopiperazine or piperazinil were connected by its nitrogen atom with C1-6the alkyl, whom they are alternates.

Other specific subgroups of compounds of formula (I) are those compounds of formula (I), or any specific in the description of the subgroups of compounds of formula (I), where Q represents pyrrolidinyl, substituted R6piperidinyl, substituted R6or homopiperazine, substituted R6; where

(a) R6represents hydrogen or C1-6alkyl, optionally substituted with two substituents or, preferably, one Deputy, each of which is independently selected from the group consisting of trifloromethyl, NR7aR7b, Ar2, hydroxy, C1-6alkoxy, Ar2(CH2)nhydroxy, hydroxycarbonyl, aminocarbonyl,1-6alkylcarboxylic,1-6alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl,1-4alkylcarboxylic, Ar2carbonyloxy, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane and pyridyl, where each of these heterocycles may be optionally substituted by one or two radicals is AMI, selected from oxo and C1-6of alkyl; or, in particular,

(b) R6represents hydrogen or C1-6alkyl, optionally substituted with one substituent and optionally with another Deputy, who represents hydroxy, where specified by the Deputy is trifluoromethyl, NR7aR7b, Ar2, hydroxy, C1-4alkoxy, Ar2(CH2)nhydroxy, hydroxy-carbonyl, aminocarbonyl,1-4alkylsulphonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl,1-4alkylcarboxylic, Ar2carbonyloxy, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane and pyridyl, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl; or further, in particular,

(c) R6represents hydrogen or C1-6alkyl, optionally substituted NR7aR7b, Ar2, hydroxy, C1-4alkoxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl, C1-4alkoxycarbonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted Goethe what ollom, selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, where each of these heterocycles may be optionally substituted by oxo or one or two C1-6alkyl radicals; or further, in particular,

(d) R6represents hydrogen or C1-6alkyl, optionally substituted NR7aR7b, Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, where each of these heterocycles may be optionally substituted by oxo or one or two C1-6alkyl radicals; or further, in particular, where

(e) R6represents hydrogen or C1-6alkyl, optionally substituted Ar2, hydroxy, aminocarbonyl or aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, piperazinil, where each of these heterocycles may be optionally substituted by one or two1-6alkyl radicals; or preferably

(f) R6represents hydrogen or C1-6alkyl, the optional samewe the tion Ar 2, hydroxy, amino-carbonyl, aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted pyrrolidinium, piperidinium, piperazinil, 4-C1-6alkylpiperazine; or preferably

(g) R6represents hydrogen or C1-6alkyl, optionally substituted Ar2, hydroxy, aminocarbonyl or aminosulfonyl; or preferably

(h) R6represents hydrogen or C1-6alkyl, substituted Ar2or1-6alkyl, substituted piperidinium or piperazinil; or

(i) R6is1-6alkyl.

Preferably, in (a)-(h) in the previous section radicals pyrrolidinyl, piperidinyl, homopiperazine or piperazinil were connected by its nitrogen atom with C1-6the alkyl, whom they are alternates.

The following specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where R7aand R7brepresent hydrogen or C1-6alkyl, or, preferably, where R7aand R7brepresent hydrogen.

The following specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where

(a) R8apresented AET Ar 3With1-6alkyl, hydroxys1-6alkyl, C1-6alkoxyl1-6alkyl, tsianos1-6alkyl, amino1-6alkyl, mono - or di(C1-6alkyl)amino1-6alkyl, Ar3With1-6alkyl, Het-C1-6alkyl, aminocarbonyl1-6alkyl, carboxyls1-6alkyl; and R8bis Ar3; or

(b) R8ais Ar3With1-6alkyl, hydroxys1-6alkyl, Ar3With1-6alkyl, Het-C1-6alkyl, aminocarbonyl1-6alkyl; and R8bis Ar3; or

(c) R8ais hydraxis1-6alkyl, aminocarbonyl1-6alkyl; and R8bis Ar3; or

(d) R8ais Ar3and R8bis Ar3; or

(e) R8ais1-6alkyl, hydroxys1-6alkyl, Ar3With1-6alkyl, Het-C1-6alkyl, aminocarbonyl1-6alkyl; and R8bis1-6alkyl, hydroxys1-6alkyl, Ar3With1-6alkyl, Het-C1-6alkyl.

In particular, Ar1represents phenyl or phenyl substituted with 1, 2, 3 substituents 1 or 2 substituents selected from those specified in the definition of the compounds of formula (I) or any of their sub-groups.

In the group of the compounds of formula (I) or any subgroup of compounds of formula (I):

(a) Ar1preferably represents phenyl or FeNi is, substituted for not more than 3 substituents, or not more than 2 substituents, or with one assistant, selected from halogen, hydroxy, C1-6of alkyl, hydroxys1-6of alkyl, trifloromethyl and C1-6alkyloxy;

(b) Ar1more preferably represents phenyl or phenyl substituted by not more than 3 substituents, or not more than 2 substituents, or with one assistant, selected from halogen, hydroxy, C1-6the alkyl and C1-6alkyloxy;

(c) Ar1more preferably represents phenyl or phenyl substituted by not more than 3 substituents, or not more than 2 substituents, or with one assistant, selected from halogen and C1-6the alkyl.

In particular, Ar2represents phenyl or phenyl substituted with 1, 2, 3 substituents 1 or 2 substituents selected from the group consisting of those listed in the definition of the compounds of formula (I) or any of their sub-groups.

The following specific subgroups of compounds of formula (I) are those compounds of formula (I), or any specific in the description of the subgroups of compounds of formula (I), where Ar2is specified for Ar1values.

The following specific subgroups of compounds of formula (I) are those compounds of formula (I) or any specific in the description of the subgroups of compounds of formula (I), where Ar3represents phenyl, in which talini, 1,2,3,4-tetrahydronaphthalene or indanyl, or, preferably, where Ar3represents phenyl, naphthalenyl or indanyl; where specified phenyl may optionally and each individually be substituted with one or more, for example, 2, 3 or 4 substituents selected from the group consisting of substituents at Ar3in the definitions of the compounds (I).

The following specific subgroups of compounds of formula (I) are those compounds of formula (I), or any specific in the description of the subgroups of compounds of formula (I), where

(a) Ar3represents phenyl, optionally substituted one, two or three substituents selected from halogen, hydroxy, mercapto, amino, cyano, C1-6of alkyl, C2-6alkenyl, C2-6the quinil, Ar1hydraxis1-6of alkyl, CF3aminos1-6of alkyl, tsianos1-6of alkyl, aminocarbonyl,1-6alkyloxy,1-6alkylthio, Ar1is hydroxy, Ar1-thio, Ar1-amino, aminosulfonyl, aminocarbonyl1-6of alkyl, hydroxycarbonyl1-6of alkyl, hydroxycarbonyl,1-4alkylcarboxylic,1-4alkylcarboxylic or C1-4alkoxycarbonyl; or where

(b) Ar3represents phenyl, optionally substituted one, two or three substituents selected from halogen, hydroxy, mercapto, cyano, C1-6of alkyl, C2-6alkenyl, C2-6Ala the Nile, Ar1hydraxis1-6of alkyl, CF3aminos1-6of alkyl, tsianos1-6of alkyl, aminocarbonyl,1-6alkyloxy,1-6alkylthio, Ar1is hydroxy, Ar1-thio, Ar1-amino, aminosulfonyl, aminocarbonyl1-6of alkyl, hydroxycarbonyl1-6of alkyl, C1-4alkylsulphonyl, C1-4alkylcarboxylic or C1-4alkoxycarbonyl; or where

(c) Ar3represents phenyl, optionally substituted one, two or three substituents selected from halogen, C1-6the alkyl or hydraxis1-6of alkyl; or

(d) Ar3is phenyl substituted one, two or three substituents selected from halogen, C1-6the alkyl or hydraxis1-6of alkyl; or

(e) Ar3represents phenyl, optionally substituted one, two or three substituents selected from halogen, C1-6the alkyl or hydraxis1-6of alkyl; or

(f) Ar3is phenyl substituted one, two or three substituents selected from halogen, C1-6the alkyl or hydraxis1-6of alkyl; or

(g) Ar3represents phenyl, substituted with one or two substituents selected from halogen, C1-6the alkyl or hydraxis1-6of alkyl; or

(h) Ar3represents phenyl, optionally substituted by one or two substituents selected from C1-6 the alkyl or hydraxis1-6the alkyl.

In particular, Ar3is specified for Ar2values, more preferably Ar3is specified for Ar1values.

The following specific subgroups of compounds of formula (I) are those compounds of formula (I), or any specific in the description of the subgroups of compounds of formula (I), where

(a) Het represents tetrahydrofuranyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, isothiazolin, pyrazolyl, isoxazolyl, piperidinyl, homopiperazine, piperazinil, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydropyranyl, chinoline, ethenolysis, benzodioxane, benzodioxole, indolinyl, indolyl, which may optionally be substituted by oxo, amino, Ar1C1-4the alkyl, amino1-4the alkyl, hydroxys1-6the alkyl, Ar1With1-4the alkyl, mono - or di(C1-6alkyl)amino1-6the alkyl, mono - or di(C1-6alkyl)amino, (hydraxis1-6alkyl)amino, and optionally further one or two With1-4alkyl radicals; or

(b) Het is tetrahydrofuranyl, furanyl, thienyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, piperidinyl, homopiperazine, piperazinil, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, tetrahydropyranyl, chinoline, ethenolysis, benzodioxane, benzodioxole, indolinyl indolyl, which may be optionally substituted by oxo, amino, Ar1With1-4the alkyl, amino1-4the alkyl, hydroxys1-6the alkyl, and optionally further one or two With1-4alkyl radicals; or

(c) Het represents furanyl, thienyl, imidazolyl, pyrazolyl, isoxazolyl, morpholinyl, pyrimidinyl, benzodioxolyl, chinoline, indolinyl, which may be optionally substituted hydraxis1-6the alkyl or one or two C1-4alkyl radicals; or

(d) Het represents furanyl, thienyl, imidazolyl, pyrazolyl, isoxazolyl, morpholinyl, pyrimidinyl, benzodioxolyl, chinoline, indolinyl, which may be optionally substituted hydraxis1-6the alkyl or one or two C1-4alkyl radicals; or

(e) Het is furanyl, imidazolyl, morpholinyl, benzodioxolyl, chinoline, indolinyl, which may be optionally substituted hydraxis1-6the alkyl or one or two C1-4alkyl radicals; or

(f) Het represents morpholinyl, which may be optionally substituted by one or two1-4alkyl radicals; or

(e) Het is morpholinyl.

The preferred compounds are the compounds listed in tables 1-5, especially in connection rooms 1-77, 138, 143-165 and 171-177.

The compounds of formula (I) or any of their podgroup is s can be obtained in accordance with the following schemes reactions

In these schemes, Q, G, R1, R2a, R2b, R3and R5have the meanings given above for compounds of formula (I) or any of their subgroups. W represents a corresponding tsepliaeva group, preferably chlorine or bromine. The reaction shown in the scheme, are usually in a suitable solvent, e.g. an ether, for example, THF, halogenated hydrocarbon, e.g. dichloromethane, l3, toluene, in a polar aprotic solvent such as DMF, DMSO, DMA, etc.

The compounds of formula (I), where Q is pyrrolidino, piperidinyl or homopiperazine group, substituted R6that is different from hydrogen, i.e. R6Athat is represented by formula (I-c-1), can be obtained in accordance with the following reaction scheme.

In this diagram, G, t, R1, R2a, R2b, R3, R5have the meanings given above for compounds of formula (I) or any of their subgroups. W represents a corresponding tsepliaeva group, preferably chlorine or bromine. The reaction shown in the scheme, can be maintained in a suitable solvent, e.g. an ether, for example, THF, halogenated hydrocarbon, e.g. dichloromethane, CHCl3, toluene, in a polar aprotic solvent, such as the MOF, DMSO, DMA, etc. you Can add the base to bind the acid that is released during the reaction. Optionally, you can add certain catalysts, for example, salts of iodine (e.g., KI). The intermediate compound (IV) can also be converted into compounds (I-c-1), using the reaction of reductive N-alkylation, based on the aldehyde or ketone R6b=O(V-a), where R6bhas the same values that R6Aprovided that it is less than one hydrogen. This reaction reductive alkylation is carried out in a suitable solvent, for example, in alcohol, using hydrogen in the presence of a metal catalyst, for example, Pd or NaB3CN.

Some of the compounds of formula (I) can also be derived from precursor compounds of the formula (I), using the reaction conversion of the respective functional groups.

The precursor compounds of the formula (I), for example, are those where R2aor R2bsubmit C1-6alkoxycarbonyl or1-6alkyl, substituted C1-6alkoxycarbonyl, which can be restored, for example, using LiAl4to the corresponding compounds of formula (I), where R2aor R2bare hydraxis1-6alkyl. The last group can oxidize, using a mild oxidant, to the aldehyde group, for example, using Mno2 , from which you can derive, using amines, for example, in the process of rehabilitation amination, to the corresponding mono(derived From1-6the alkyl)amines. The latter can be alkilirovanii or areleaving to alkylamines followed, where R2Aor R2bcorrespond to the formula-Alk-NR8AR8b. Alternative precursor compounds of the formula (I), where R2Aor R2bare hydraxis1-6alkyl, can be converted into the corresponding Halogens1-6alkyl compounds, for example, treating with a suitable halogenation agent such as SOCl2moreover , the compounds obtained are then subjected to interaction with the amine or amine derivative. This sequence of reactions illustrated in the following schemes, in which R12is1-6alkyl radical, preferably methyl or ethyl. This sequence of reactions can be performed on the basis of (VII-a) or (VII-b) separately, but can also be carried out using the compound (VII-a and VII-b), and then separate the products of the reaction or at the end of the sequence of reactions, or at an intermediate stage.

Or on the basis of (VII-b)

The precursor compounds of the formula (I), where R2aor R2brepresent al is digid, can be converted into the corresponding compounds where R2aor R2bare replaced With2-6alkenyl (I-g-1) or (I-g-2), using the Wittig reaction or the reaction of the Wittig-Horner. In the first case, use the reagent type reagent Wittig, such as triphenylphosphine in a suitable reaction inert solvent such as ether, on the basis of triphenylphosphine and derived halogen. The reaction of the Wittig-Horner carried out using phosphonate, for example, a reagent of the formula di(C1-6alkyloxy)-P(=O)-CH2-CH2-CN in the presence of a base, preferably a strong base, in an aprotic organic solvent. Compounds where R2aor R2bare replaced With2-6alkenyl that you can restore the corresponding compounds where R2aor R2bare replaced With2-6alkyl (I-i-1) or (I-i-2), for example, using hydrogen in the presence of a catalyst of a noble metal such as Pd/C. Cyano, in turn, can be restored to the appropriate methylaminopropyl (-CH2-NH2using hydrogen in the presence of a catalyst, such as Raney Nickel, in a suitable solvent, for example, in a mixture of methanol/ammonia. As a result of the reaction receive the compound (I-j-1) and (I-j-2), which can be monoalkylated or dialkylamino, obtaining the compound (I-k), (I-k-2) and (I-l-1), (I-1-2). These alkylation reaction can be carried out using the reaction of reductive alkylation using an aldehyde or ketone in the presence of hydrogen and catalyst (receiving monoalkyl derivatives) or by using appropriately substituted alkylhalogenide (receiving mono - or valkirye derivatives). These reactions are presented in the following diagrams reactions. In these schemes, R2A-1represents CN, Ar3or Het, Alk1is4-6alkadiene radicals (which are the same as C1-6alcander, but contains 4-6 carbon atoms), R8aand R8bhave the values listed in the description and the claims, but preferably they differ from Ar3.

You can also obtain derivative compounds of formula (I), where R2aor R2brepresent the aldehyde or1-6alkyl, substituted keto or aldehyde, using the reaction of the Grignard type, for the introduction of aryl or alkyl groups.

An additional aspect n the present invention relates to the fact that some of the compounds identified as precursors of compounds of formula (I)are new compounds.

In particular, the compounds of formula (VII-a), (VII-b), (VIII-a), (VIII-b), (IX-a), (IX-b), (I-f-1), (I-f-2), (I-g-1), (I-g-2), where G, R1, R2a, R2b, R3, R5, R8a, R8b, R12have the meanings given above for compounds of formula (I) or any of their subgroups, and where Q represents pyrrolidinyl, piperidinyl or homopiperazine, substituted at its nitrogen atom of the radical R6that is1-6alkyl, optionally substituted by one or more, preferably one or two, substituents, each of which is independently selected from the group consisting of trifloromethyl, C3-7cycloalkyl, Ar2, hydroxy, C1-4alkoxy, C1-4alkylthio, Ar2is hydroxy, Ar2tio, Ar2(CH2)nhydroxy, Ar2(CH2)nthio, hydroxycarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, Ar2(CH2)ncarbonyloxy, C1-4alkoxycarbonyl(CH2)nhydroxy, mono - or di(C1-4alkyl)aminocarbonyl, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4Ala is l)aminosulfonyl or heterocycle, selected from the group consisting of pyrrolidinyl, pyrrolyl, dihydropyrrole, imidazolyl, triazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane, pyridyl and tetrahydropyridine, where each of these heterocycles may be optionally substituted by one or two substituents selected from oxo or1-6of alkyl; and where the specified R6may be represented by R6bas well as the form of their pharmaceutically acceptable salts and their possible stereoisomeric forms are new connections.

Of particular interest are any of a group of new compounds defined in the previous section, where

(a) R6bis1-6alkyl, optionally substituted with two substituents or, preferably, one Deputy, each of which is independently selected from the group consisting of trifloromethyl, Ar2, hydroxy, C1-4alkoxy, Ar2(CH2)nhydroxy, hydroxycarbonyl, aminocarbonyl, C1-4alkylsulphonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidine is La, homopiperazine, piperazinil, DIOXOLANYL, dioxane and pyridyl, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl; or, in particular, where

(b) R6bis1-6alkyl, optionally substituted with one substituent and, optionally, another Deputy who represents hydroxy, where specified by the Deputy is trifluoromethyl, Ar2, hydroxy, C1-4alkoxy, Ar2(CH2)nhydroxy, hydroxycarbonyl, aminocarbonyl,1-4alkylsulphonyl, C1-4alkoxycarbonyl, Ar2(CH2)ncarbonyl, aminocarbonyl, C1-4alkylcarboxylic, Ar2carbonyloxy, mono - or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, mono - or di(C1-4alkyl)aminosulfonyl or a heterocycle selected from the group consisting of pyrrolidinyl, imidazolyl, piperidinyl, homopiperazine, piperazinil, DIOXOLANYL, dioxane and pyridyl, where each of these heterocycles may be optionally substituted by one or two radicals selected from oxo and C1-6of alkyl; or further, in particular,

(c) R6bis1-6alkyl, optionally substituted Ar2, hydroxy, C1-4alkoxy, hydroxy-carbonyl, aminocarbonyl, aminosulfonyl, C1-4Ala is sikabonyi, or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, where each of these heterocycles may be optionally substituted by oxo or one or two C1-6alkyl radicals; or further, in particular,

(d) R6bis1-6alkyl, optionally substituted Ar2, hydroxy, hydroxycarbonyl, aminocarbonyl, aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, homopiperazine, piperazinil, where each of these heterocycles may be optionally substituted by oxo or one or two C1-6alkyl radicals; or further, in particular,

(e) R6bis1-6alkyl, optionally substituted Ar2, hydroxy, aminocarbonyl or aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted heterocycle selected from DIOXOLANYL, pyrrolidinyl, piperidinyl, piperazinil, where each of these heterocycles may be optionally substituted by one or two1-6alkyl radicals; or preferably

(f) R6bthe stand is made With 1-6alkyl, optionally substituted Ar2, hydroxy, aminocarbonyl, aminosulfonyl or1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted pyrrolidinium, piperidinium, piperazinil, 4-C1-6alkylpiperazine; or preferably

(g) R6bis1-6alkyl, optionally substituted Ar2, hydroxy, aminocarbonyl or aminosulfonyl; or preferably

(h) R6bis1-6alkyl.

Preferably, in (a)-(h) in the previous section radicals pyrrolidinyl, piperidinyl, homopiperazine or piperazinil were bound by their nitrogen atoms with C1-6the alkyl, substituents which they are.

In addition, it was found that these compounds possess anti-viral properties, in particular, possess inhibitory activity against RSV. Of particular interest are compounds of formula (VII-a), (VII-b), (VIII-a) and (VIII-b), where Q is 4-piperidinyl in which the nitrogen of the ring substituted by the radical R6that is1-6alkyl, as well as their form pharmaceutically acceptable salts and their possible stereoisomeric forms. The terms “form pharmaceutically acceptable salts and stereoisomeric forms”used in the description have the meanings indicated in the description.

In addition, the connection is of oral (VII-a), (VII-b), (VIII-a), (VIII-b), (IX-a), (IX-b), (I-f-1), (I-f-2), (I-g-1), (I-g-2), where G, R1, R2a, R2b, R3, R5, R8a, R8band R12have the values listed in the definitions for compounds of formula (I) or any of their subgroups, and where Q represents R6bthat has the values listed in the previous section, as well as their form pharmaceutically acceptable salts and their possible stereoisomeric forms, are new compounds. In addition, it was found that the compounds possess anti-viral properties, in particular, possess inhibitory activity against RSV.

Of particular interest are such compounds mentioned in the previous section, where G, R1, R2A, R2b, R3, R5, R8aand R8bare as defined in any of the subgroups specified in this description and in the claims. Preferred are those new connections mentioned in the previous section, where G represents C1-6alcander, more preferably where G is methylene; and/or where R2A, R2b, R3, R5- all represent hydrogen; and/or R1represents pyridyl, substituted as defined in the description and in the claims, in particular, R1is pyridyl, substituted with one or two substituents selected from C of alkyl and hydroxy.

The compounds of formula (I) can be transformed into each other using well-known specialists reaction conversion of functional groups, including those disclosed in the description.

The nitro group can be restored to the amino groups, which can then be alkilirovanii to the mono - or dialkylamino, or allievate to arylcarboxamide or alkylcarboxylic, etc. groups. Ceanography can be restored to aminomethylbenzoic groups, which can then be modified.

A number of intermediate compounds, which are used to obtain the compounds of formula (I)are known compounds or are analogs of known compounds which can be obtained in accordance with modifications known in the art methods, which can easily exercise specialists. Several ways to obtain the intermediate compounds are presented in more detail.

In the first stage, diaminobenzoic (VI) cyclist using urea, in a suitable solvent, for example xylene, getting benzimidazole (VII). The last turn in the benzimidazole derivative (VIII), where W is tsepliaeva group, as defined above, in particular, using the reaction of (VII) with an appropriate halogenation agent, such as POCl3and the resulting intermediate compound (VIII) evaluation of Gaut interaction with the amine derivative (IX) to obtain the intermediate compound (II).

The same sequence of reactions can be used for other intermediates. For example, intermediate compounds of formula (IV) can be obtained by interaction of intermediate compounds (IX) with an amine (X), where Q is pyrrolidino, piperidinyl or homopiperazine group, where the nitrogen is substituted by a protective group, receiving predecessors (IV), which can be converted into intermediate compounds (IV), removing the protective group. Suitable for this purpose, protective groups include allyloxycarbonyl groups, such as methoxy - or etoxycarbonyl that can be removed using a base, or benzyl or benzyloxycarbonyl group that can be removed using hydrogen in the presence of a catalyst.

The compounds of formula (I) can be converted into the corresponding N-oxide forms, using well-known specialists of the procedure for the conversion of trivalent nitrogen into its N-oxide form. The above reaction of N-oxidation can be accomplished by the interaction of the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metal or alkaline earth metal, e.g. sodium peroxide, potassium peroxide; suitable organic perox the water may include peroxyacids, such as, for example, peroxybenzoyl acid or halogen-substituted peroxybenzoyl acid, for example, 3-chloroperoxybenzoic acid, phenoxyalkanoic acid, for example, peroxyoctanoic acid, alkylhydroperoxide, for example, tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

Pure stereochemical isomeric forms of the compounds of formula (I) can be obtained by applying known in the art treatments. The diastereomers can be separated using physical methods such as selective crystallization and chromatographic techniques, for example, the distribution in countercurrent, liquid chromatography, etc.

The compounds of formula (I)obtained disclosed above methods usually represent racemic mixtures of enantiomers which can be separated using well-known specialists of ways. Racemic compounds of the formula (I), which are sufficiently basic or acidic, can be transformed into the form of the corresponding diastereomeric salts using reaction with a suitable chiral acids, respectively chiral bases. Specified form diastereomeric the Oli then exhale, for example, using selective or fractional crystallization, and separated from it enantiomers, using an alkali or acid. An alternative method of separating the enantiomeric forms of the compounds of formula (I) include liquid chromatography, in particular liquid chromatography using a chiral stationary phase. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction proceeds in a stereospecific. Preferably, if you want to get specific stereoisomer, to synthesize the specified connection using stereospecific methods of production. In these ways it is advantageous to use enantiomerically pure starting materials.

In the following aspect the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula (I)as defined in the description, or compounds of any of the subgroups of compounds of formula (I)as defined in the description, and pharmaceutically acceptable carrier. A therapeutically effective amount in this context is the number, which is enough for preventive action against, or to stabilize or to attenuate viral infection and cha is in the surrounding area, RSV viral infection in an infected subject, or a subject who is at risk of being infected. In another aspect the present invention relates to a method for producing a pharmaceutical composition, as defined in the description, which includes a thorough mixing of the pharmaceutically acceptable carrier with a therapeutically effective amount of the compounds of formula (I)as defined in the description, or compounds of any of the subgroups of compounds of formula (I)as defined in the description.

Therefore, compounds of the present invention or any subgroup can be prepared in various pharmaceutical forms in accordance with the purposes of the introduction. Suitable compositions can specify all compositions usually employed for systematic drug. To prepare the pharmaceutical compositions of the present invention an effective amount of a particular compound, optionally in salt form attached, or in the form of complex metal as the active ingredient together in a homogeneous mixture with a pharmaceutically acceptable carrier, and the specified media may take various forms depending on the need to accept a form of the drug. Preferably, these pharmaceutical compositions were in a unit dose form suitable, in particular, for peroral the tion, rectal, percutaneous injection or parenteral injection. For example, in the preparation of compositions in dose form for oral administration, you can use any of the usual pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers, for example, starches, sugars, kaolin, lubricating agents, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to the simplicity of the introduction of tablets and capsules represent the most convenient forms for a single dose for oral administration, and in these cases, obviously, use solid pharmaceutical carriers. For compositions for parenteral administration the carrier typically includes sterile water, at least in the most part, although there may be other ingredients, for example, agents that promote solubility. You can, for example, to prepare solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. You can also prepare a suspension for injection, and in this case, you can use liquid media, suspendresume agents, etc. also Included are solid form preparations to is that you need to turn just before the introduction of drugs in liquid form. In compositions intended for percutaneous administration, the carrier optionally includes increasing permeability of the agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in small proportions, and these additives should not adversely impact on the skin.

Compounds of the present invention can also enter via oral inhalation or insufflation, using the methods and compositions that experts use for such purposes. So, usually compounds of the present invention can enter into the lungs in the form of solutions, suspensions or dry powders, and preferred solutions. Any system designed for the delivery of solutions, suspensions or dry powders with oral inhalation or insufflation, suitable for administration of the compounds of the present invention.

Thus, the present invention also provides a pharmaceutical composition adapted for administration via inhalation or insufflation through the mouth, which include a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably the compounds of the present invention using the inhalation solution in doses of sprays or aerosols.

It is particularly convenient to create the above pharmaceutical composition in unit dose form is for ease of administration and uniformity of dosage. In the same sense as it is used in the description, the term "unit dose form" refers to physically discrete units suitable as unit doses, each unit contains a certain amount of active ingredient calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored tablets and pills in the shell), capsules, pills, suppositories, sachets of powder, pills, solutions or suspensions for injection, etc. and their separate parts.

The compounds of formula (I) exhibit antiviral properties. Viral infections that can be treated using compounds and methods of the present invention include infections that are excited ortho - and paramyxoviruses and, in particular, human and bovine respiratory syncytial virus (RSV). A series of compounds of the present invention is active against mutant strains of RSV. In addition, many compounds of the present invention exhibit favorable pharmacokinetic profile and possess attractive properties, from the point of view of bioavailability, including reasonable length of time half-life, AUC and peak values, and the absence of adverse events, for example, not enough fast the first manifestation and the delay in the tissues.

In vitro antiviral activity against RSV compounds of the present invention are tested using the test as disclosed in the experimental part of the description, and it can also be demonstrated using the analysis of the recovery of the virus. In vivo antiviral activity against RSV compounds of the present invention can be demonstrated in the test model, using cotton rats, as disclosed Wyde et al. (Antiviral Research (1998), 38, 31-42).

Thanks antiviral properties, especially anti-RSV characteristics of the compounds of formula (I) or any subgroup, proletarienne forms, N-oxides, salts of accession, Quaternary amines, metal complexes and stereochemical isomeric form can be used to treat individuals with a viral infection, particularly with RSV infection, and also for the prophylaxis of these infections. In General, compounds of the present invention can be used for the treatment of warm-blooded animals infected with viruses, especially respiratory syncytial virus.

Compounds of the present invention or any subgroup can therefore be used as medicines. Such use as a medicine or method of treatment comprises the systemic introduction of infected with a virus to a subject, or a subject susceptible to viral infections, amount, effective to combat the conditions associated with viral infection, especially RSV infection.

The present invention also relates to the use of compounds of the present invention or any subgroup for the preparation of medicaments for the treatment or prophylaxis of viral infections, especially RSV infection.

In addition, the present invention relates to a method of treating warm-blooded animals infected with a virus or at risk of HIV infection, especially RSV, and this method includes the introduction of antiviral effective amount of the compounds of formula (I)as defined in the description, or compounds of any of the subgroups of compounds of formula (I)as defined in the description.

It is generally assumed that antiviral effective daily amounts should be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be convenient to introduce the required dose in the form of two, three, four or more fractions of doses at appropriate intervals throughout the day. These shares doses can be prepared in the form of a unit dose forms, for example, containing from 1 to 1000 mg, in particular from 5 to 200 mg of active ingredient in a unit dose form.

The exact size of the dose and frequency of injection depends on specifically used the compounds of formula (I)subject to treat a specific condition, is Aresti subject to treatment condition, age, weight, sex, extent of disorder and General physical condition of the particular patient, as well as other medications that the patient can't take that well known in the art. Moreover, it is clear that the effective daily amount can be reduced or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compound of the present invention. Therefore, the intervals effective daily amounts shown above are only Advisory.

In addition, it is possible to use, as is common in medicine, a combination of another antiviral agent and the compounds of formula (I). Therefore, the present invention relates also to a product containing (a) compound of formula (I), and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of viral infections. Various drugs can be combined in one preparation together with pharmaceutically acceptable carriers. For example, the compounds of the present invention can be combined with beta-interferon or alpha-tumor necrosis factor for the treatment or prevention of RSV infections.

EXAMPLES

The following examples are intended to illustrate altoadige of the invention, but the invention is not limited. The terms "connection 1, connection 2", etc. used in these examples correspond to the same numbers of compounds in tables.

Compounds identified using LC/MS in the following components:

LCT:ionization electrospray in a positive mode, scanning with between 100 and 900 at. unit of mass; Xterra MS C18 (Waters, Milford, MA) 5 μm, a 3.9×150 mm); flow rate 1 ml/min Using two mobile phases (mobile phase A: 85% 6.5 mm ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mm ammonium acetate + 80% acetonitrile) to implement a gradient elution from 100% a for 3 min to 100% B in 5 min, 100% B for 6 min to 100% A for 3 min, and balance again 100% a for 3 min).

ZQ:ionization electrospray, both in positive and in negative (pulse) mode, scanning from 100 to 1000 at. unit of mass; Xterra RP C18 (Waters, Milford, MA) 5 μm, a 3.9×150 mm); flow rate 1 ml/min Using two mobile phases (mobile phase A: 85% 6.5 mm ammonium acetate + 15% acetonitrile; mobile phase B: 20% 6.5 mm ammonium acetate + 80% acetonitrile) to perform gradient elution with 100% a for 3 min to 100% B in 5 min, 100% B for 6 min to 100% A for 3 min, and balance again 100% a for 3 min).

Example 1

Scheme A

The mixture ofa-1(0,166 mol) and urea (0,99 mol) in xylene (300 ml) stirred at the boil under reflux for 12 hours. The reaction mixture is cooled to room temperature. The precipitate is filtered off, washed with xylene and diisopropyl ether and then dried, obtaining 32 g of intermediate compounda-2(93%, tplate: >260°C).

The mixture ofa-2(0,073 mol) in POCl3(150 ml) was stirred at 100°C. Concentrated HCl (about 1.5 ml) was carefully added dropwise to dissolve thea-2. The mixture was stirred at 120°C for 6 hours. The solvent is evaporated to dryness. The residue is placed in a mixture of N2About/ice, alkalinized K2CO3(powder) and extracted with a mixture of ethyl acetate + 10% methanol. The organic layer emit, dried over MgSO4), filtered and the solvent is evaporated to dryness, obtaining 13.5 g of the intermediate compounda-3(83%, Tplate: 178°C).

The mixture ofa-3(0,051 mmol) anda-4(0,056 mol) was stirred at 160°C for 2 hours. The residue is placed in a mixture of CH2Cl3/H2O and alkalinized with 10% solution of K2CO3in the water. The organic layer emit, dried over MgSO4), filtered and the solvent is evaporated to dryness. The residue is purified using a chromatographic column with silica gel (eluent: CH2Cl2/methanol/NH4OH 95/5/0,5). Pure fractions are collected and the solvent is evaporated, receiving and 15.3 g of intermediate compounda-5(79%).

The mixture ofa-5(0,0396 mol),a-6(0,059 mol) and K2CO3(0,1584 mol) in H 3CN (180 ml) is stirred and refluxed for 12 hours. The solvent is evaporated to dryness. The residue is placed in CH2Cl2. The organic layer was washed with H2O, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (20 g) is purified using a chromatographic column with silica gel (eluent: toluene/2-propanol/NH4HE 85/15/1; 20-45 μm). Two fractions are collected and the solvent is evaporated, getting to 5.3 g of fraction 1 (27%) and 6.3 g of fraction 2 (32%). Fraction 1 twice crystallized from a mixture of 2-propanone/CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 4.9 g of the intermediate compounda-7(25%, tplate: 179°C). Fraction 2 is crystallized from a mixture of 2-propanone/CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 5.5 g of the intermediate compounda-8(28%, tplate: 238°C).

LiAlH4(0,009 mol) is added in portions to a mixture ofa-7(of 0.003 mol) in tetrahydrofuran (60 ml) at 5°C in a stream of N2. The reaction mixture was stirred at 5°C for 1 hour and then at room temperature for 12 hours. Carefully add ethyl acetate and H2O, and the aqueous layer was saturated with K2CO3(powder). The organic layer emit, dried over MgSO4) and then filtered on celite. The resulting filtrate is evaporated to dryness, obtaining 1.3 g of the intermediate compounda-9(97%). Neo is ewenny the product is used directly in the next reaction stage.

The intermediate connectiona-10get a similar way, opened for intermediate connectiona-9.

The mixture ofa-9(0,0028 mol) and Pd/C 10% (2.5 g) in CH3OH (40 ml) hydronaut at 40°C for 12 h under a pressure of 8 bar, and then filter on celite. Celite is washed with a solution of a mixture of CH3OH/tetrahydrofuran (50/50). The resulting filtrate is evaporated to dryness, obtaining 1.8 g of intermediate compounda-11(95%, tplate: 260°C).

HCHO 37% in water (0,0098 mol), NaBH3CN (0,0059 mol), then CH3CO2H (2 ml) is added at room temperature to a mixture ofa-11(0,0049 mol) in CH3CN (50 ml). The resulting mixture was stirred at room temperature for 12 hours. The solvent is evaporated to dryness. The residue is placed in ethanol (30 ml) and add 5 HCl solution in 2-propanol (4 ml). The mixture is stirred at 80°C for 8 hours. The solvent is evaporated to dryness. The residue is placed in CH2Cl2/K2CO310%. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is crystallized from a mixture of CH3OH/2-propanone/CH3CN. The precipitate is filtered off and dried, obtaining of 1.65 ga-12(88%). Part of this fraction (0.15 g) is crystallized from a mixture of CH3OH/2-propanone. The precipitate is filtered off and dried (tplate: 165°C).

SOCl2(2.1 ml) is added dropwise to a mixture ofa-12(0,0018 mol) in CH2Cl2 (20 ml) at 5°C. The mixture was stirred at 5°C for 1 hour, then at room temperature for 12 hours. The solvent is evaporated to dryness, obtaining 0,93 g of intermediate compounda-13(100%). The crude product is used directly in the next reaction stage.

The mixture ofa-13(0,0003 mol),a-14(of 0.0005 mol) and K2CO3(0,0019 mol) in dimethylformamide (30 ml) was stirred at 80°C for 4 h and poured into H2O. the Aqueous layer was saturated with K2CO3and extracted with a mixture of CH2Cl2/CH3OH. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.25 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 90/10/1; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.05 g, 24%) crystallized from a mixture of 2-propanone/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0,042 g connectiona-15(20%, connection1, tplate 201°C).

Example 2

Scheme B

The mixture ofb-1(0,0028 mol) and MnO2(2.5 g) in CH2Cl2(40 ml) was stirred at room temperature for 12 h and then filtered over celite. Celite was washed with CH2Cl2. The resulting filtrate is evaporated to dryness. The residue is placed in 2-propanone.

The precipitate is filtered off and the shat, receiving 0.75 g of the intermediate compoundb-2(69%, tplate: 250°C).

Option 1:The mixture ofb-2(0.0001 mol), 3,5-dichloraniline (0.0001 mol), BH3CN on solid media (0.0001 mol) and CH3CO2H (2 drops) in CH3OH (4 ml) was stirred at room temperature for 24 hours. The solution is filtered. The resulting filtrate is evaporated to dryness. The residue is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 87/12/1,5; 5 μm). Pure fractions are collected and the solvent is evaporated, getting 0,026 g of 2-[6-[(3,5-dichlorophenylamino)methyl]-2-(1-methylpiperidin-4-ylamino)benzoimidazol-1-ylmethyl]-6-methyl-3-ol (38%, compound 2).

Option 2:b-2(of 0.0005 mol), NaBH3CN (0,0006 mol) and then CH3CO2H (0.2 ml) is added at room temperature to a mixture of 3-methylaniline (0,0006 mol) in CH3CN (20 ml). The mixture is stirred at room temperature for 12 hours. Type H2O. the Mixture is saturated with K2CO3(powder) and extracted with CH2Cl2/CH3HE. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.3 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/triethylamine; 90/10/0,1; 5 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.17 g, 68%) crystallized from sm is si CH 3OH/2-propanone/diisopropyl ether. The precipitate is filtered off and dried, obtaining of 0.13 g of 2-[6-[(1-ethylidene-3-methylpentan-2,4-diarylamino)methyl]-2-(1-methylpiperidin-4-ylamino)benzoimidazol-1-ylmethyl]-6-methylpyridin-3-ol (52%, the connection9, tplate 141°C).

Example 3

Scheme C

The mixture ofc-1(0,0018 mol), 2-methylthiophenol (0.002 mol) and K2CO3(0,0077 mol) in CH3CN (70 ml) was stirred at 50°C for 12 hours. The solvent is evaporated to dryness. The residue is placed in H2O. the Mixture was extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.55 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 88/12/2; 15-40 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.35 g, 39%) crystallized from a mixture of CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0.32 g of 6-methyl-2-[2-(1-methylpiperidin-4-ylamino)-6-m-tolylsulfochloride-1-ylmethyl]pyridine-3-ol (compound93, tplate: 202°C).

Example 4

Scheme D

In scheme D R is defined as Ar3, Het1, Het1(CH2)nor Het1(CH2)n.

The intermediate connectiond-2(tplate: 262°C) on ucaut same way, opened for intermediate connectiona-11. The intermediate connectiond-3get a similar way, opened for intermediate connectiona-12.

The mixture ofd-3(0,0003 mol) in 3 BC HCl solution in water (30 ml) was stirred at 80°C for 12 hours. The solvent is evaporated. The residue is dried, receiving 0.18 g of the intermediate compoundd-4. The crude product is used directly in the next reaction stage.

The mixture ofd-4(0,0003 mol), 2-methylaniline (of 0.0005 mol)of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (of 0.0005 mol) and 1-hydroxybenzotriazole (of 0.0005 mol) in CH2Cl2(20 ml) was stirred at room temperature for 24 hours. Add a 10% solution of K2CO3in the water. The aqueous layer was saturated with K2CO3(powder). The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.2 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 80/20/1; 10 μm). Pure fractions are collected and the solvent is evaporated. Get 0,29 g (14%). This fraction is placed in diisopropyl ether, and then in a mixture of CH3OH/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0,007 g m-tolylamino 3-(3-hydroxy-6-methylpyridin-2-ylmethyl)-2-(1-methylpiperidin-4-ylamino)-3H-benzoimidazol-5-carboxylic acid (4%, connect the s 116, tplate: 172°C).

Example 5

Scheme E

The mixture ofe-1(0,0524 mol) ande-2(0,1048 mol) was stirred at 120°C in a Parr apparatus for 10 h, then placed in H2O and extracted with ethyl acetate. Selected organic layer is purified by short open chromatographic column with silica gel (eluent: CH2Cl2/methanol 96/4). The fractions containing the product are collected and the solvent is evaporated to dryness, obtaining of 7.7 g of intermediate compounde-3(44%).

The mixture ofe-3(0,0312 mol),e-4(0,0343 mol) and K2CO3(0,1092 mol) in dimethylformamide (100 ml) was stirred at 70°C for 24 hours. Then add H2O. the Mixture was extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (12.2 g) is purified using a chromatographic column with silica gel (eluent: toluene/isopropanol/NH4OH 90/10/0,5; 15-40 μm). Two fractions are collected and the solvent is evaporated, receiving 4 g of intermediate compounde-5(28%) and 5.4 g of intermediate compounde-6(38%).

e-5(0,0088 mol) is added in portions to a 48% solution of HBr in water (40 ml). The mixture is slowly brought to 70°C and then stirred for 12 hours. The precipitate is filtered, washed with CH3CN and sushi is so The residue (4.6 g, 80%) is placed in the H2O and alkalinized K2CO3(powder). The precipitate is filtered and then washed with ethanol. The resulting filtrate is evaporated, receiving 3 g of intermediate compounde-7(52%). In a similar way, gete-8.

HCHO 37% in H2O (0,0152 mol), then NaBH3CN (0,0091 mol) is added at room temperature to a mixture ofe-7(0,0075 mol) in CH3CN (100 ml). Acetic acid (3.5 ml) is added slowly at room temperature. The mixture is stirred at room temperature for 12 h and poured into H2O. the Aqueous layer was saturated with K2CO3(powder). The mixture is extracted with a mixture of ethyl acetate/CH3OH. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness, obtaining 2.6 g of the intermediate compounde-9(87%). In a similar way we obtain ae-10.

The mixture ofe-9(0,0065 mol) and Raney Nickel (2.6 g) in CH3OH (100 ml) hydronaut at room temperature for 1 hour under a pressure of 3 bars and then filtered on celite. Celite was washed with CH3OH. The resulting filtrate is evaporated. The residue (2.2 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/14/1; 15-40 μm). Pure fractions are collected and the solvent is evaporated, receiving of 0.85 g of intermediate compoundf-11(35%). Similarly produces the t e-12.

The mixture ofe-11(0,000125 mol) and 3-methylbenzoic acid (0,00025 mol) in CH2Cl2(4 ml) was stirred at room temperature. Add 1-hydroxybenzotriazole (0,00025 mol) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,00025 mol). The reaction mixture was stirred at room temperature for 12 hours. The solution is concentrated and added 10% solution of NaHC3in water (2 ml) and CH3OH (2 ml). The mixture is stirred and refluxed for 4 hours. Then CH3OH removed under reduced pressure and the resulting solution was extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 90/10/0,5; 15-40 μm). Pure fractions are collected and the solvent is evaporated, obtaining 0.04 g of N-[3-(3-hydroxy-6-methylpyridin-2-ylmethyl)-2-(1-methylpiperidin-4-ylamino)-3H-benzoimidazol-5-yl]-3-methylbenzamide (60%, compound 65). In a similar way we obtain N-[1-(3-hydroxy-6-methylpyridin-2-ylmethyl)-2-(1-methylpiperidin-4-ylamino)-1H-benzoimidazol-5-yl]-3-methylbenzamide (0,028 g (42% yield, compound 78).

Example 6

Scheme F

The mixture off-1(of 0.0005 mol), 3-methylbenzaldehyde (0,0006 mol), BH3CN solid but is the (0,0006 mol) and acetic acid (8 drops) in CH 3OH (10 ml) was stirred at room temperature for 24 hours. Solid media is filtered off and washed with CH3OH. The resulting filtrate is evaporated. The remainder (0,53 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0,5 to 89/10/1; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.11 g) is crystallized from a mixture of CH3OH/diisopropyl ether. The precipitate is isolated and dried, obtaining 0,072 g connectionf-2i.e. 6-methyl-2-[6-(3-methylbenzylamino)-2-(1-methylpiperidin-4-ylamino)benzoimidazol-1-ylmethyl]pyridine-3-ol (28%, compound 28, tplate: 240°C).

Example 7

Scheme G

The mixture ofg-1(0,0079 mol),g-2(0,0095 mol) and triethylamine (0,0118 mol) in dimethylformamide (60 ml) was stirred at 80°C for 12 hours. The solvent is evaporated to dryness. The residue is placed in a mixture of CH2Cl2/H2O. the Organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (7 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 90/10/0,5; 15-40 μm). Pure fractions are collected and the solvent is evaporated, obtaining 1.2 g of the intermediate compoundg-3(30%).

The mixture ofg-3(0,0023 mol) and Mno2(2.4 g) in CH2Cl2(80 ml) is stirred pikantnoi temperature for 12 h and then filtered over celite. Celite was washed with N2O. the resulting filtrate is evaporated to dryness. The residue (1.2 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0,1; 35-70 μm).

Pure fractions are collected and the solvent is evaporated, obtaining 0.8 g of intermediate compoundg-4(67%).

Determenirovana (0,0023 mol) are added to a mixture of NaH (0,0047 mol) in tetrahydrofuran (20 ml) at 5°C in a stream of N2. The mixture was stirred at 5°C for 30 minutes added dropwise a solution ofg-4(0,0007 mol) in tetrahydrofuran (10 ml). The mixture was stirred at 5°C for 1 hour and then stirred at room temperature for 12 hours. Type H2O. the Mixture was extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is crystallized from a mixture of CH3OH/2-propanone. The precipitate is filtered off and dried, obtaining 0.24 g of the intermediate compoundg-5(52%).

The mixture ofg-5(0.0001 mol) in 5 BC HCl solution in 2-propanol (0.5 ml) and 2-propanol (5 ml) was stirred at 60°C for 4 h and then cooled to room temperature. The precipitate is filtered, washed with a mixture of 2-propanol/isopropyl ether and dried, obtaining 0,058 g cleaners containing hydrochloride salt of 2-{2-[1-(2-amino-ethyl)piperidine-4-ylamino]-6-stilbenoids-1-ylmethyl}-6-methylpyridin-3-ol, (g-6; connection 14, 63%, 3,69 HCl + 3,03 H2O, Tplate: >260°C).

The mixture ofg-5(is 0.0002 mol) and Pd/C 10% (0.03 g) in CH3OH (10 ml) and tetrahydrofuran (10 ml) hydronaut at room temperature for 4 hours under a pressure of 2 bars and then filtered on celite. Celite was washed with H2O. the resulting filtrate is evaporated to dryness, obtaining 0.14 g of the intermediate compoundg-7(100%). This product is used directly in the next reaction stage.

The mixture ofg-7(is 0.0002 mol) in 5 BC HCl solution in 2-propanol (1.4 ml) and 2-propanol (15 ml) was stirred at 60°C for 4 h and then cooled to room temperature. The precipitate is filtered, washed with a mixture of 2-propanol/isopropyl ether and dried, obtaining was 0.138 gg-8, cleaners containing hydrochloride salt of 2-{2-[1-(2-amino-ethyl)piperidine-4-ylamino]-6-penicillintylenol-1-ylmethyl}-6-methylpyridin-3-ol (87%, 3,62 HCl + 2,41 H2O connection 140, tplate: 181°C).

Example 8

Scheme N

The mixture ofh-1(0,0027 mol), ethylbromoacetate (0,0032 mol) and triethylamine (0,004 mol) in dimethylformamide (40 ml) was stirred at 50°C for 1 hour, poured into ice water and extracted three times CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is placed in a mixture of 2-propanone/diisopropyl ether. The precipitate is filtered, prom is live H 2O and dried, obtaining 1 g of the intermediate compoundh-2(82%).

The intermediate connectionh-3get a similar way, opened to obtaing-4.

CH3CO2H (0.2 ml) is added at room temperature to a mixture ofh-3(of 0.0004 mol), 3-methylaniline (of 0.0005 mol) and NaBH3CN (of 0.0005 mol) in CH3CN (20 ml). The resulting mixture was stirred at room temperature for 6 hours. Add CH3CO2H (0.2 ml). The mixture is stirred at room temperature for 12 hours. The solvent is evaporated to dryness. The residue is placed in a mixture of CH2Cl2/K2CO310%. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness, obtaining 0,22 g of the intermediate compoundh-4(100%). The specified product is used directly in the next reaction stage.

LiAlH4(0,0008 mol) are added to a mixture ofh-4(of 0.0004 mol) in tetrahydrofuran (20 ml) at 5°C in a stream of N2. The mixture was stirred at 5°C for 1 hour, then brought to room temperature and stirred for 4 hours. Add the minimum number of H2O and then CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0,22 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4 OH 85/15/1; 15-40 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.1 g, 50%) is crystallized from a mixture of CH3OH/CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0.08 g of 2-[2-[1-(2-hydroxyethyl)piperidine-4-ylamino]-6-(m-trilaminate)benzoimidazol-1-ylmethyl]-6-methylpyridin-3-ol (40%, the connection145, tplate: 137°C).

Example 9

Scheme I

The mixture ofi-1(0,0185 mol) in ethanol (60 ml) and H2SO436 N. (5 ml) is stirred and refluxed for 24 hours. The solvent is evaporated to dryness. The residue is placed in CH2Cl2. The organic layer was washed with a 10% solution of K2CO3in water, dried (over MgS4), filtered and the solvent is evaporated to dryness, obtaining 3.2 g of intermediate compoundi-2(89%).

The intermediate connectioni-3get the same way, opened for intermediate connectiona-2. The intermediate connectioni-4get the same way, opened for intermediate connectiona-3. The intermediate connectioni-5get a manner analogous to the method of obtaining the intermediatea-5.

The mixture ofi-5(0,0048 mol), 2-chloromethyl-6-methyl-3-pyridinol (0,0058 mol) and K2CO3(0,0192 mol) in dimethylformamide (0 ml) was stirred at room temperature for 12 h, poured into ice water and extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (3.4 g) is purified using a chromatographic column with silica gel (eluent: toluene/2-propanol/NH4OH 83/16/1; 15-35 μm). Two fractions are collected and the solvent is evaporated, obtaining 0.9 g of the intermediate compoundi-6(37%) and 0.78 g of intermediate compoundi-7(32%).

The intermediate connectioni-8get the same way, opened for intermediate connectiona-9. The intermediate connectioni-9get the same way, opened for intermediate connectiona-11. The intermediate connectioni-10(tplate: 221°C) are obtained in a manner analogous to the way opened for intermediate connectionh-2. The intermediate connectioni-11get the same way, opened for intermediate connectionh-3. The intermediate connectioni-12(tplate: 143°C) are obtained in a manner analogous to the way opened for intermediate connectionh-4.

2-[2-[1-(2-hydroxyethyl)piperidine-4-ylamino]-4-methyl-6-(m-trilaminate)benzoimidazol-1-ylmethyl]-6-methylpyridin-3-ol (i-13connection 168, tplate: 123°C) are obtained in a manner analogous to the way opened for the connectionh-5.

the example 10

Scheme J

The intermediate connectionj-2get the same way, opened for intermediate connectionh-3.

Dieticiansupervised (0,0052 mol) are added to a mixture of NaH (0,0105 mol) in tetrahydrofuran (30 ml) at 5°C in a stream of N2. The mixture was stirred at 5°C for 30 minutes Then add a solution ofj-2(0,0017 mol) in tetrahydrofuran (20 ml). The mixture was stirred at 5°C for 1 hour and then stirred at room temperature for 12 hours. Type H2O. the Mixture was extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0,1; 70-200 μm). Pure fractions are collected and the solvent is evaporated, gaining 0.7 g of intermediate compoundj-3(84%).

The mixture ofj-3(0,0014 mol) and Pd/C 10% (0.25 g) in CH3OH (35 ml) hydronaut at 40°C for 6 hours under a pressure of 8 bar, and then cooled to room temperature and filtered on celite. The resulting filtrate is evaporated to dryness, receiving 0.3 g of the intermediate compoundj-4(52%).

The intermediate connectionj-5get the same way, opened for intermediate connectionh-2. The intermediate link is j-6(tplate: 207°C) are obtained in a manner analogous to the way opened for intermediate connectioni-13.

The mixture ofj-6(0,0003 mol) and Raney Nickel (0.2 g) in a saturated solution of NH3in CH3OH (25 ml) hydronaut at room temperature for 1 hour and then filtered on celite. The resulting filtrate is evaporated to dryness. The residue (0,22 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 80/20/2; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.083 g, 49%) dissolved in a mixture of ethanol/2-propanone and converted into the salt of hydrochloric acid. The precipitate is filtered off and dried. The residue is crystallized from diisopropyl ether. The precipitate is filtered off and dried, obtaining 0.08 g of the hydrochloride of 2-{6-(3-aminopropyl)-2-[1-(2-hydroxyethyl)piperidine-4-ylamino]benzoimidazol-1-ylmethyl}-6-methylpyridin-3-ol (salt). (36%, 3,6 HCl, the connection157, tplate: 185°C).

Example 11

Scheme K

Mix k-1 (0,0019 mol), 3-chloropropanesulfonyl (0,0022 mol) and triethylamine (0,0028 mol) in dimethylformamide (50 ml) was stirred at 70°C for 48 h, poured into ice water, saturated with K2CO3(powder) and extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated douhet (1.5 g) clear, using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/2; 15-40 μm). Pure fractions are collected and the solvent is evaporated, getting 0,336 g of intermediate compoundk-2(36%).

The mixture ofk-2(0,0007 mol) and MnO2(1 g) in CH2Cl2(30 ml) was stirred at room temperature for 6 hours and then filtered on celite. Celite was washed with H2O. the Solvent from the resulting filtrate is evaporated to dryness, obtaining 0.33 g of intermediate compoundk-3(100%). The product obtained is used directly in the next reaction stage.

CH3CO2H (0.2 ml) is added at room temperature to a mixture ofk-3(of 0.0004 mol), 3,5-dimethylaniline (of 0.0005 mol) and NaBH3CN (of 0.0005 mol) in CH3CN (20 ml). The mixture is stirred at room temperature for 30 minutes Add CH3CO2H (0.2 ml). The mixture is stirred at room temperature for 12 hours. The solvent is evaporated to dryness. The residue is placed in CH2Cl2. The organic layer was washed with a 10% solution of K2CO3in water, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.26 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 90/10/1; 5 μm). Pure fractions are collected and the solvent is evaporated, getting 0.09 g (32%). This fra is of crystallized from a mixture of CH 3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0.083 g of amide 2-{4-[6-[(3,5-dimethylphenylamine)methyl]-1-(3-hydroxy-6-methylpyridin-2-ylmethyl)-1H-benzoimidazol-2-ylamino]piperidine-1-yl}econsultancy acid (30%, compound 147, tplate: 142°C).

Example 12

Scheme L

The intermediate connectionl-2(tplate: 210°C) are obtained in a manner analogous to the way opened for intermediate connectionk-2. The intermediate connectionl-3get the same way, opened for intermediate connectionk-3. The intermediate connectionl-4get the same way, opened for the connectionk-4.

The mixture ofl-4(0,0003 mol) in 7 N. solution of NH3in CH3OH (15 ml) was stirred at 80°C for 12 hours. The solvent is evaporated to dryness. The residue (0.21 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/14/1; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0,057 g, 30%) crystallized from a mixture of 2-propanone/CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0.05 g of 2-{4-[6-[(3,5-dimethylphenylamine)methyl]-1-(3-hydroxy-6-methylpyridin-2-ylmethyl)-1H-benzoimidazol-2-ylamino]piperidine-1-yl}ndimethylacetamide (26%, the connection , tplate: 206°C).

Example 13

Scheme M

The mixture ofm-1(is 0.0002 mol) in tetrahydrofuran (30 ml) is cooled to 5°C in a stream of N2. Add LiAlH4(0,0007 mol). The mixture was stirred at 5°C for 1 hour and then stirred at room temperature for 1 hour. Add the minimum number of N2O. Add CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.16 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/1; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0,073 g, 53%) crystallized from a mixture of 2-propanone/CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0,064 g of 2-{6-[(3,5-dimethylphenylamine)methyl]-2-[1-(2-hydroxyethyl)piperidine-4-ylamino]benzoimidazol-1-ylmethyl}-6-methylpyridin-3-ol (m-2, 46%, the connection149, tplate: 144°C).

Example 14

Scheme N

The mixture ofn-1(0,022 mol) and N-(propylamino)piperidine (0,0207 mol) was stirred at 140°C for 1 hour and then placed in a mixture of CH2Cl2/CH3OH. The organic layer was washed with K2CO310%, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is purified ISOE is isua chromatographic column with silica gel (eluent: CH 2Cl2/CH3OH/NH4OH 92/8/1; 70-200 μm). Pure fractions are collected and the solvent is evaporated, obtaining 2.2 g of the intermediate compoundn-2(30%).

The mixture ofn-2(0,0066 mol),n-3(0,0073 mol) and K2CO3(0.02 mol) in dimethylformamide (25 ml) was stirred at room temperature for 24 hours, poured into H2O and extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue is placed in a mixture of CH3CN/diisopropyl ether. The precipitate is filtered, washed with H2O and dried, obtaining 1.8 g of the mixture of intermediate compoundsn-4andn-5(61%).

LiAlH4(0.012 mol) is added in portions to a mixture ofn-4(0.002 mol) andn-5(0.002 mol) in tetrahydrofuran (60 ml) at 5°C in a stream of N2. The mixture was stirred at 5°C for 1 hour, then at room temperature for 12 hours. Add the minimum number of N2O. Add a solution of CH2Cl2/CH3OH (90/10). The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (1,65 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 80/20/3; 15-40 μm). Two fractions are collected and the solvent is evaporated, receiving 0.35 g of fraction 1 and 0,049 g of fraction 2. Fraction 1 is crystallized from a mixture of 2-propanone/diisopropyl levy ether. The precipitate is filtered off and dried, obtaining O,33 g of intermediate compoundn-6(19%, tplate: 220°C). Fraction 2 is crystallized from a mixture of 2-propanone/diisopropyl ether. The precipitate is filtered off and dried, obtaining of 0.43 g of intermediate compoundn-7(26%, tplate: 146°C).

The mixture ofn-6(0,0006 mol) and MnO2(0.5 g) in CH2Cl2(30 ml) was stirred at room temperature for 12 h and then filtered over celite. Celite was washed with H2O. the resulting filtrate is evaporated to dryness, obtaining 0.26 g of the intermediate compoundn-8(100%). The compound obtained is used directly in the next reaction stage.

CH3CO2H (0.3 ml) are added to a mixture ofn-8(0,0006 mol), 3,5-dimethylaniline (0,0007 mol) and NaBH3CN (0,0007 mol) in CH3CN (30 ml). The mixture is stirred at room temperature for 30 minutes Add CH3CO2H (0.3 ml). The mixture is stirred at room temperature for 24 hours. The solvent is evaporated to dryness. The residue is placed in a mixture of 2-propanone/5 n HCl/ethanol. The mixture is stirred at 80°C for 12 hours. The solvent is evaporated to dryness. The mixture is extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.39 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH 4OH 90/10/0,5; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0,119 g, 59%) are placed in a mixture of CH3CN/diisopropyl ether. The precipitate is filtered off and dried, obtaining 0.17 g of 2-[6-[(3,5-dimethylphenylamine)methyl]-2-(3-piperidine-1-ylpropionic)benzoimidazol-1-ylmethyl]-6-methylpyridin-3-ol (n-9, 53%, the connection 170, tplate: 161°C).

Example 15

Scheme About

2-{6-[(3,5-dimethylphenylamine)methyl]-2-[3-(4-methylpiperidin-1-yl)propylamino]benzoimidazol-1-ylmethyl}-6-methylpyridin-3-ol (compound171, tplate: 150°C) and intermediate connections get the same way, opened for connectionn-9.

Example 16

Scheme P

The intermediate connectionp-9(tplate: 212°C) are obtained in a manner analogous to the way opened for the connectionn-9.

The mixture ofp-9(of 0.0004 mol) in 3 BC HCl solution in water (20 ml) and tetrahydrofuran (20 ml) was stirred at room temperature for 6 hours, alkalinized K2CO3(powder) and extracted with CH2Cl2. The organic layer emit, dried (over MgS4), filtered and the solvent is evaporated to dryness. The residue (0.25 g) is purified using a chromatographic column with silica gel (eluent: CH2Cl2/CH3(OH/NH 4OH 92/8/0,5; 10 μm). Pure fractions are collected and the solvent is evaporated. The residue (0.17 g, 92%) crystallized from a mixture of CH3CN/diisopropyl ether. The precipitate is filtered off and dried, getting to 0.127 g of 3-[6-[(3,5-dimethylphenylamine)methyl]-1-(3-hydroxy-6-methylpyridin-2-ylmethyl)-1H-benzoimidazol-2-ylamino]propane-1,2-diol (p-10, 69%, the connection172, tplate: 128°C).

Example 17

Scheme Q

2-{6-[(3,5-dimethylphenylamine)methyl]-2-[2-(4-methoxyphenyl)ethylamino]benzoimidazol-1-ylmethyl}-6-methylpyridin-3-ol (compound 187, tplate: 178°C) and intermediate connections get the same way, opened for connectionn-9.

The following tables list compounds that receive in accordance with any of the examples above.

Table 1

Table 2A

Table 2b

Table 3

Table 4

Table 5

Example 18:In vitro screening against activityagainst respiratory syncytial virus

The percentage protection against cytopathology caused by viruses (antiviral activity or EC50), which is reached by the test compounds, and their cytotoxicity (CC50), both calculated on the basis of the curves dose-response. The selectivity of antiviral action is represented by the coefficient of selectivity (SI), calculated by dividing CC50(dose cytotoxicity for 50% of cells) on EC50(antiviral activity to 50% of the cells). In the tables in the above experimental part lists the categories belongs to each of the obtained compounds: compounds that belong to the category of activity "A"have the meanings pEC50(-log EC50if expressed in molar units), equal to or greater than 7. Compounds belonging to the category of activity "B"have the value of pEC50between 6 and 7. Compounds belonging to the category of activity, have the value of pEC50equal to or less than 6.

Automated colorise the historical analyses on the basis of tetrazole used to determine the values of EC 50and CC50for the test compounds. Flat-bottomed 96-well plastic microtiter tablets fill 180 µl minimum eagle medium, supplemented with 5% FCS (0% for FLU) and 20 mm Hepes buffer. Then the original solutions (7,8 × final test concentration) connection type by volume of 45 ál of a series of holes (three of a kind) in order to provide simultaneous assessment of their effect on virus-infected cells and simulation infected cells. Perform five fivefold dilutions directly in microtiter tablets using the robot system. Not processed by the virus controls and control HeLa cells included in each test. Approximately 100 TCID50respiratory syncytial virus add in two of the three series in a volume of 50 μl. The same volume of medium added to the third row to determine the cytotoxicity of the compounds at the same concentrations as were used to determine the antiviral activity. After two hours of incubation to all wells add a suspension of HeLa cells (4×105cells/ml) in a volume of 50 μl. The culture is incubated at 37°C in an atmosphere of 5% CO2. 7 days after infection spectrophotometric determine the cytotoxicity and antiviral activity. To each well of microtiter tablet add 25 ál of MTT solution (3-(4,5-dimethyl shall eazol-2-yl)-2,5-diphenyltetrazolium). Tablets incubated further at 37°C for 2 h, then the medium is removed from each Cup. The solubilization of the crystals formazan provide by adding 100 ál of 2-propanol. Complete dissolution of crystals formazan reach once the tablet is placed on a flatbed shaker for 10 minutes. And finally, read the absorption, using an eight-channel computer-controlled photometer (Multiskan MCC, Flow Laboratories) at two wavelengths (540 and 690 nm). The absorption measured at 690 nm, automatically subtracted from the absorption at 540 nm, in order to exclude the effects of non-specific absorption.

1. The compound of formula (I):

Sol connection and stereochemical isomeric forms,
where Q represents R6apiperidinyl, substituted R6;
G is methylene;
R1is pyridyl, substituted with 2 substituents selected from hydroxy, C1-6of alkyl;
one of R2aand R2bis tsianos2-6alkenyl, AG3C1-6alkyl, Het-C1-6alkyl, N(R8aR8b)1-6alkyl, AG3With1-6alkenyl, AG3aminos1-6alkyl, Het-amino1-6alkyl, Het-C1-6alkylamino1-6alkyl, Ar3tios1-6alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, AG3(CH2)ncarbylamine, Het-(CH2)ncarbylamine; and the other of R2a/sup> and R2brepresents hydrogen;
R3represents hydrogen or C1-6alkyl;
in that case, if R2ais hydrogen, then R3represents hydrogen;
in that case, if R2bis hydrogen, then R3represents hydrogen or C1-6alkyl;
R5represents hydrogen;
R6represents C1-6alkyl, optionally substituted by one or two substituents, each of which is independently selected from the group consisting of NR7aR7b, Ar2, hydroxy, aminocarbonyl, aminosulfonyl;
R6arepresents C1-6alkyl, substituted by one or two substituents, each of which is independently selected from the group consisting of Ar2, hydroxy or heterocycle selected from the group consisting of piperidinyl, piperazinil;
R7arepresents hydrogen;
R7brepresents hydrogen;
R8ais Ar3With1-6alkyl, hydroxys1-6alkyl, C1-6alkoxy, C1-6alkyl, tsianos1-6alkyl, di(C1-6alkyl)amino1-6alkyl, AG3C1-6alkyl, HetC1-6alkyl, aminocarbonyl1-6alkyl, carboxyls1-6alkyl;
R8bis Ar3C1-6alkyl, hydroxys1-6alkyl, Ar3C1-6alkyl, HetC1-6alkyl;
each n independently is 1;
Ar1present which allows phenyl;
AG2represents phenyl or phenyl substituted by one C1-6alkyloxy;
Ar3represents phenyl, naphthalenyl, 1,2,3,4-tetrahydronaphthalene or indanyl where specified phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene or indanyl may optionally and each individually be substituted with one or more, for example, 2 or 3 substituents selected from the group consisting of halogen, hydroxy, mercapto, cyano, C1-6of alkyl, C2-6the quinil, Ar1hydraxis1-6of alkyl, CF3tsianos1-6of alkyl, aminocarbonyl, C1-6alkyloxy, C1-6alkylthio, AG1is hydroxy, AG1-amino, aminosulfonyl, aminocarbonyl1-6of alkyl, C1-4alkylcarboxylic,1-4alkylcarboxylic and C1-4alkoxycarbonyl;
Het represents a heterocycle selected from furanyl, imidazolyl, morpholinyl, pyridyl, chinoline, izochinolina, each of these heterocycles may be optionally substituted hydraxis1-6the alkyl.

2. The compound according to claim 1, where the compound has formula (I-a-1):

where Q, R5, G, and R1have claimed in claim 1 values; and
Alk represents a C1-6alcander;
R8chas the same values as specified for R8Aas claimed in claim 1, and may also represent hydrogen;
R9, R10, R11independently from the Ruga have the same values what is mentioned for the substituents at AG3as claimed in claim 1.

3. The compound according to claim 1, where the compound has formula (I-b-1):

where Q, R5, G, and R1have claimed in claim 1 values; and
Alk represents a C1-6alcander;
R8chas the same values as specified for R8aas claimed in claim 1, and may also represent hydrogen;
R9, R10, R11independently from each other are the same values that you specify for the substituents at AG3as claimed in claim 1.

4. The compound according to claim 1, where the compound has formula (I-c):

where t=2, G, R1, R2aR2b, R3, R5and R6have claimed in claim 1 values.

5. The compound according to claim 1, where the compound has formula (I-d-2):

where t=2, R5, R6, G, and R1have claimed in claim 1 values; and
Alk represents a C1-6alcander;
R8chas the same values as specified for R8aas claimed in claim 1, and may also represent hydrogen;
R9, R10, R11independently from each other are the same values that you specify for the substituents at AG3as claimed in claim 1.

6. The compound according to claim 1, where the compound has formula (I-e-2):

where t=2, R5, R6, G, and R1have claimed in claim 1 values; and
Alk performance is made by C 1-6alcander;
R8chas the same values as specified for R8Aas claimed in claim 1, and may also represent hydrogen;
R9, R10, R11independently from each other are the same values that you specify for the substituents at AG3as claimed in claim 1.

7. The compound according to claim 1, where one of R2aand R2bchoose from tsianos2-6alkenyl, AG3C1-6of alkyl, Het-C1-6of alkyl, N(R8aR8b)C1-6alkyl, AG3C2-6alkenyl, AG3aminos1-6of alkyl, Het-amino1-6of alkyl, Het-C1-6alkylamino1-6of alkyl, AG3tios1-6of alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, Ar3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl, Ar3carbylamine; and the other of R2aand R2brepresents hydrogen.

8. The compound according to claim 1, where one of R2aand R2bchoose from Ar3C1-6of alkyl, Het-C1-6of alkyl, N(R8aR8b)C1-6of alkyl, AG3C2-6alkenyl, Ar3aminos1-6of alkyl, Het-amino1-6of alkyl, Het-C1-6alkylamino1-6of alkyl, Ar3tios1-6of alkyl, Ar3aminocarbonyl, Het-aminocarbonyl, AG3(CH2)naminocarbonyl, Het-(CH2)naminocarbonyl; and the other of R2aand R2brepresents hydrogen.

9. The compound according to claim 1, where one of R 2aand R2bselected from N(R8aR8b)C1-6of alkyl, Ar3aminos1-6of alkyl; and the other of R2aand R2brepresents hydrogen.

10. The compound according to claim 1, where
in that case, if R2ais hydrogen, then R3represents hydrogen;
in that case, if R2bis hydrogen, then R3represents hydrogen or C1-6alkyl.

11. The compound according to claim 1, where Q is R6awhere R6arepresents C1-6alkyl, substituted by one or two substituents, each of which is independently selected from the group consisting of AG2, hydroxy or heterocycle selected from piperidinyl and piperazinil.

12. The compound according to claim 1, where Q is R6awhere R6ais1-6alkyl, substituted Ar2or hydroxy, or C1-6alkyl, substituted two hydroxyadamantane or1-6alkyl, substituted piperidinium, piperazinil.

13. The compound according to claim 1, where Q represents piperidinyl, substituted R6where R6represents C1-6alkyl, optionally substituted by one or two substituents, each of which is independently selected from the group consisting of NR7aR7b, Ar2, hydroxy, aminocarbonyl, aminosulfonyl.

14. The compound according to claim 1, where Q represents piperidinyl, substituted R6where R6represents the t 1-6alkyl, optionally substituted NR7aR7b, Ar2, hydroxy, aminocarbonyl, aminosulfonyl, or C1-6alkyl, substituted two hydroxyadamantane.

15. The compound according to claim 1, where Q represents piperidinyl, substituted R6where R6represents C1-6alkyl, substituted AG2.

16. The connection indicated in paragraph 13, where Q represents piperidinyl, substituted R6.

17. The compound according to claim 1, where R8ais AG3C1-6alkyl, hydroxys1-6alkyl, C1-6alkoxyl1-6alkyl, tsianos1-6alkyl, di(C1-6alkyl)amino-C1-6alkyl, Ar3C1-6alkyl, Het-C1-6alkyl, aminocarbonyl1-6alkyl, carboxyls1-6alkyl; and R8bis AG3.

18. The compound according to claim 1, where R8arepresents C1-6alkyl, hydroxys1-6alkyl, AG3C1-6alkyl, Het-C1-6alkyl, aminocarbonyl-C1-6alkyl; and R8brepresents C1-6alkyl, hydroxys1-6alkyl, Ar3C1-6alkyl, Het-C1-6alkyl.

19. The compound according to claim 1, where AG3represents phenyl, optionally substituted with two or three substituents selected from halogen, hydroxy, mercapto, cyano, C1-6of alkyl, C2-6the quinil, AG1hydraxis1-6of alkyl, CF3tsianos1-6of alkyl, aminocarbonyl, C1-6alkyloxy, C1-6 alkylthio, AG1is hydroxy, AG1-amino, aminosulfonyl, aminocarbonyl1-6of alkyl, C1-6alkylcarboxylic,1-4alkylcarboxylic or C1-4alkoxycarbonyl.

20. The compound according to claim 1, where AG3represents phenyl, substituted with two or three substituents selected from halogen, C1-6the alkyl or hydraxis1-6the alkyl.

21. The pharmaceutical composition intended for the treatment of infections caused by respiratory syncytial virus (RSV), including pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 20.

22. The use of compounds according to any one of claims 1 to 20 to obtain drugs for inhibition of RSV replication.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new a compound of formula I or formula II, or to its pharmaceutically acceptable salts, I II, where X is S; R1 is H or C1-C6alkyl; R2 is NR5R6; R3 is aryl, substituted with a halogen; R4 is H; R5 is H; R6 is H; R7 is CH2NR8R9 where R8 is H, C1-C10alkyl, C3-C8cycloalkyl, aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), heterocycle(C1-C6alkyl), heterocycle(C2-C6alkenyl), hydroxyl(C1-C6alkyl), hydroxyl(C2-C6alkyl), C1-C6alkoxycarbonyl, aryl(C1-C6alkoxy)carbonyl, carbamoyl(C1-C6alkyl); where the above mentioned aryl is an aromatic ring and is not substituted or substituted with one to three substituting groups, each of which, independently from the others, is chosen from: methylenedioxy, hydroxy, C1-C6-alkoxy, halogen, C1-C6alkyl, trifluoromethyl, trifluoromethoxy, NO2, NH2, NH(C1-C6alkyl), N(C1-C6alkyl)2, NH-acyl, N(C1-C6alkyl)-acyl, hydroxy(C1-C6alkyl), dihydroxy(C1-C6alkyl), CN, C(=O)O(C1-C6alkyl), phenyl, phenyl(C1-C6alkyl), phenyl(C1-C6alkenyl), phenoxy and phenyl(C1-C6alkoxy), R9 is H, C1-C10alkyl, heterocycle(C1-C6alkyl) or heterocycle(C2-C6alkenyl); where the above mentioned heterocycle represents a 5-member saturated monocyclic ring system, consisting of carbon atoms, as well as heteroatoms, chosen from a group comprising N, O, and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes NO2, aryl(C1-C6alkyl), arylsulphonyl; or R8 and R9 together with nitrogen, to which they are bonded, form a heterocycle, which represents a 5 - 7-member saturated monocyclic ring system, consisting of carbon atoms, as well as one to three heteroatoms, chosen from a group comprising N, O and S, which can be unsubstituted or have one to three substituting groups, independently chosen from a list which includes C1-C6alkoxy, hydroxy, C1-C6alkyl, C2-C6-alkenyl, C(=O)O(C1-C6alkyl), C(=O)NH2, C(=O)NH(C1-C6alkyl), C(=O)N(C1-C6-alkyl)2, hydroxy(C1-C6alkyl), dihydroxy(C2-C6alkyl), aryl, aryl(C1-C6alkyl), aryl(C2-C6alkenyl), aryl(C1-C6alkoxy) and pyrimidin-2-yl; and m equals 0. The invention also relates to a pharmaceutical composition, as well as to use of formula I or formula II compounds.

EFFECT: obtaining new biologically active compounds, with inhibitory properties towards casein kinase 1ε.

32 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to N-substituted aniline and diphenylamine analogues, chosen from 3,4-bisdifluoromethoxy-(3-carboxyphenyl)-N-(5-(2-chloropyridinylmethyl))-aniline, 3,4-bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(3-(2-chloropyridylmethyl))-aniline, 3,4 - bisdifluoromethoxy - N-(3-carboxyphenyl) - N-(4-(3,5-dimethylisoxazolylmethyl)) aniline, 3 - cyclopentyloxy - 4-methoxy - N-(3-aminocarbonylphenyl) - N-(3-pyridylmethyl) aniline and other compounds given in paragraph 1 of the formula of invention and to their pharmaceutically acceptable salts as inhibitors of PDE4 enzyme.

EFFECT: compounds can be used for treating and preventing diseases caused by activity of the PDE4 enzyme.

15 cl, 8 dwg, 58 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the new compounds of general formula (II) , whereat values R1, R2, X, R11, R12, R18, R19, m, n are displayed in claim 1 of the formula.

EFFECT: compounds display agonistic and antagonistic activity which allows to propose their usage in pharmaceutical compositions for treatment of diseases and distresses connected with histamine H3 receptor.

38 cl, 80 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, medicine.

SUBSTANCE: invention refers to the triheterocylic compounds of formula (Ia) and their pharmaceutically acceptable salts used as growth inhibitors of the cancer or tumor cells, to the preparation method and pharmaceutical compositions thereof, to the treatment method used aforesaid compounds as well as to the intermediates of formula (II) the to the method of its preparation. In general formulas (Ia) and

, Q1 is -N(R1)-; Q2 is -C(R3)-; Q3 is -C(R5)-; Q4 is -C(R9)-; R1 is -Ym(Ra), where -Ra is -H, -OH, -C(O)R14, -O-C(O)R14, -C(O)N(R14)2, -C(O)OR14, -OS(O)2ONa-; R2 is -H; R3, R4 and R5 independently are -Ym(Rb), where Rb is -H, halogen, -C1-C8 alkyl, -O-(C1-C8 alkyl) or -OR14, -at condition that if value m of radical Ym(Rb) is equal 0, then R5 is not H; R6 is -H; R7 is -Ym-(RC), where -RC is -O-(C1-C8 alkyl) or -NH(phenyl), R8 is -Ym(Rd), where - Rd is -H, -OH, R9, R10, R11, R12 and R13 independently are -Ym(Re), where Re is -H, halogen, 5-6-membered heterocycle containing 2 heteroatoms selected from N or O, -OR14, or -O-C(O)OR14; every R14 independently is -H, -C1-C8 alkyl, -phenyl, 5-6-membered heterocycle containing one heteroatom being S; every Y independently is -C1-C8 alkylene-; every m independently is equal 0 or 1.

EFFECT: claimed compounds can find application for treatment of different cancer species.

41 cl, 4 tbl, 4 dwg, 8 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention refers to the new substituted dihydroquinazolines of formula (I) and to their pharmaceutically acceptable salts having antiviral properties. In general formula (I) , Ar is phenyl group which can be mono-, di- or trisubstituted. The substituting group are independently selected from the group including C1-6 alkyl-, C1-6 alkoxy-, trifluoromethyl groups and halogen atoms or two substituting groups together with linked carbon atoms form 1,3-dioxolane; R1 is hydrogen atom, amine group, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R2 is hydrogen atom, C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; R3 is C1-6 alkyl group, C1-6 alkoxy group, C1-6 alkylthiol group, cyanic group, halogen atoms, nitro group or trifluoromethyl group; or one of the radicals R1, R2 and R3 is hydrogen atom and two others together with linked carbon atoms form cyclopentane or cyclohexane ring, R4 is hydrogen atom or C1-6 alkyl group, R5 is hydrogen atom or alkyl group, R6 is carboxyl, aminocarbonyl, alkoxycarbonyl groups, halogen atoms, cyanic or hydroxyl groups, R7 is hydrogen atom or halogen atoms and R8 is hydrogen atom or halogen atoms, its pharmaceutically acceptable salts.

EFFECT: claimed compounds can find application for treatment and prevention of diseases and as antiviral agents.

21 cl, 3 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new nitroxide compounds with formula I: where one of A, B and D represents N-O and others represent CR6; R1 represents alkyl, containing 1 to 4 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; R2 represents alkyl, containing 1 to 12 carbon atoms, which is branched or straight and which is unsubstituted or substituted once or several times with a halogen; cycloalkylalkylk, containing 3 to 10 carbon atoms, which is unsubstituted or substituted once or several times with oxo, aryl, containing 6 to 14 carbon atoms, which is unsubstituted or substituted once or several times with OCF3; or a heterocyclic group, which is saturated, partially saturated or unsaturated, with 5 to 10 atoms in the ring, where at least 1 atom in the ring is an atom of N, O, or S; R3 represents cycloalkyl, containing 3 to 10 carbon atoms, which is unsubstituted once or several times with oxo, aryl, containing from 6 to 14 carbon atoms or which is unsubstituted or substituted once or several times with OCF3; or heteroaryl, with 5 to 10 atoms in the ring, in which at least 1 atom in the ring is a heteroatom; R represents H or alkyl, containing 1 to 4 carbon atoms. The invention also relates to pharmaceutically used salts of these compounds, pharmaceutical compositions containing these compounds, method of inhibiting PDE4 enzyme and to methods treatment using these compounds.

EFFECT: new compounds with useful biological properties.

62 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of formula 1: where R1 stands for cycloalkyl containing 3 to 10 carbon atoms, R2 stands for alkyl containing 1 to 4 carbon atoms, R3 stands for pyridylmethyl, R4 stands for phenyl unsubstituted or substituted with carboxy-, cyanogroup or alkoxycarbonyl; or to its pharmaceutically acceptable salts provided the specified compounds is not 4-(2-chlor-4-methoxyphenyl)-5-methyl-2-[N-(1-propylindazole-6-yl)-N-propylamino]thiazole where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures, or to compounds of formula II: where R3 stands for hydrogen or pyridylmethyl, R4 stands for hydrogen or phenyl unsubstituted or substituted with carboxy-, cyanogroup, alkoxycarbonyl, tetrazole-5-yl or phenylsulphonyl aminocarbonyl; R7 stands for alkoxygroup containing 1 to 4 carbon atoms being branched or nonbranched; R8 stands for -CO-C1-4- alkyl or dioxanyl, and at least one of R3 and R4 is different from hydrogen, or to its pharmaceutically acceptable salts where optically active compound can be in the form of one of its separated enantiomers or their mixtures, including racemic mixtures. Additionally, the invention refers to pharmaceutical enzyme PDE4, based on compounds of formula I and II and to their application for producing medical products for enzyme PDE4 inhibition in treatment of various diseases.

EFFECT: compound improvement.

35 cl, 11 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or its pharmaceutically acceptable salts: , where R1 is phenyl group optionally substituted by substitutes selected out of halogen atom, -O-C1-6-alkyl; or R1 is phenyl condensed with aromatic or non-aromatic 5-7-member ring where the ring can optionally include up to three heteroatoms selected independently out of N, O and S; R2 is hydrogen, -O-C1-6-alkyl, -C1-6-alkyl or halogen atom; R3 is C1-6-alkyl, -(CH2)P-NO2, -(CH2)p-NR4R5, -(CH2)P-CONHOH, -(CH2)p-CN, -(CH2)P-CO2H, -(CH2)p-CO2R4, -(CH2)P-CONR4R5, -(CH2)p-OR4, -(CH2)p-NHCOR4 or -(CH2)p-NHSO2R4; R4 and R5 are independently hydrogen or C1-6-alkyl; p is 0, 1, 2, 3 or 4; X is C1-10-alkylene group; one of A1 and A2 is nitrogen atom, while the other is NR7; and R7 is hydrogen atom or OH-group. Also invention concerns pharmaceutical composition, method of TGF-β and/or activine signal transit route inhibition, method of reduction of excessive exocellular matrix accumulation for mammals, method of tumour cell metastasis inhibition for mammals, method of treatment of cancer neoplasm caused by TGF-β superexpression by TGF-β signal transit route inhibition for mammals, method of disease treatment, and method of thrombosis inhibition for mammals.

EFFECT: new compounds with useful biological properties.

16 cl, 19 ex, 2 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: in new compounds with formula (I): (I) A is absent or represents (CH2)2; L is CH or N; M is NR1, O, S, S(O) or S(O)2; R1 is C1-6alkyl, substituted with phenyl {which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3}; phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, CF3, C1-4alkylthio}, S(O)2R, S(O)2NR6R7, C(O)R8; R2 is phenyl (which is possibly substituted with halogen, CN or C1-4halogenalkyl), thienyl or halogenthienyl; R3 is hydrogen or methyl; Rb is hydrogen or C1-3alkyl; R4 is a five- or six-member heterocycle, containing at least one carbon atom, one to four nitrogen atoms and, possibly, one oxygen or sulphur atom, where the carbon atom in the said heterocycle R4 is possibly substituted with oxo, C1-6alkyl [which is possibly substituted with halogen, OH, C1-4alkoxy, S(C1-4alkyl) group or piperidinyl {which it self is possibly substituted with benzene [which is possibly substituted with a S(O)2(C1-4alkyl) group], C(O)(C1-4alkoxy) group, C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) [where alkyl is possibly substituted with fluoro]}], C3-6cycloalkyl, CN, C(O)NH2, C(O)NH(phenylC1-2alkyl) group, phenyl [which is possibly substituted with a S(O)2(C1-4alkyl) group] or benzyl [which is possibly substituted with a S(O)2(C1-4alkyl) group]; if possible, the nitrogen atom in the said heterocycle R4 is substituted with C1-6alkyl [which is possibly substituted with C1-4alkoxy, S(O)(C1-4alkyl) group, S(O)2(C1-4alkyl), C(O)(C1-4alkoxy), CONH2, CONH(C1-4alkyl), CON(C1-4alkyl)2, phenyl{which is possibly substituted with C1-4alkyl, C1-4alkoxy, S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}, piperidinyl {which is possibly substituted with a S(O)(C1-4alkyl) group or S(O)2(C1-4alkyl)}], C3-6cycloalkyl, CO(C1-4alkyl) group [which is possibly substituted with a halogen], S(O)2(C1-4alkyl) group [which is possibly substituted with fluorine], COO(C1-6alkyl) group, phenyl [which is possibly substituted with a S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group]; - under the condition that the nitrogen atom in the said heterocycle R4 is substituted with an alky group, the said alkyl does not have C1-4alkoxy, S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) substitute on the carbon atom, bonded to the nitrogen atom in the said heterocycle R4; - five- or six-member heterocyle R4 is possibly condensed with cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring; ring carbon atoms in the said condensed cyclohexane, piperadine, benzole, pyridine, pyridazine, pyrimidine or pyrazine ring are possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy, CF3, S(C1-4alkyl), S(O)(C1-4alkyl) or S(O)2(C1-4alkyl) group; and the nitrogen atom of the condensed piperidine ring is possibly substituted with C1-4alkyl [which is possibly substituted with oxo, halogen, OH, C1-4alkoxy, C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl) group, C(O)N(C1-4alkyl)2 group, C(O)(C1-4alkyl)group [where alkyl is possibly substituted with C1-4alkoxy or halogen], benzene [which is possibly substituted with S(O)(C1-4alkyl) or S(O)2(C1-4alkyl)], C(O)(C1-4alkoxy), C(O)NH2, C(O)NH(C1-4alkyl), C(O)N(C1-4alkyl)2 or S(O)2(C1-4alkyl) group [where alkyl is possibly substituted with fluoro]; R5 is C1-6alkyl [which is possibly substituted with a halogen (for example fluoro), C1-4alkoxy, phenyl {which itself is possibly substituted with a halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with a halogen or C1-6alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with a S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R8 is hydrogen, C1-4alkyl [which is possibly substituted with halogen (for example fluro), C1-4alkoxy, phenyl{which itself is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}], C3-7cycloalkyl (which is possibly substituted with halogen or C1-4alkyl), piranyl, phenyl {which is possibly substituted with halogen, C1-4alkyl, C1-4alkoxy}, or a 5- or 6-member saturated nitrogen-containing heterocyclic ring {which is possibly substituted with S(O)2(C1-4alkyl) or C(O)(C1-4alkyl) group}; R6 and R7 are bonded, forming a 5- or 6-member ring which is possibly substituted with C1-4alkyl; R9 and R10 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts. The invention also relates to a method of obtaining compounds in paragraph 1, to a method of modulating activity of CCR5 receptor, as well as to a pharmaceutical composition.

EFFECT: obtaining new biologically active compounds with modulating effect towards CCR5 receptor.

15 cl, 29 ex, 12 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula IId and their pharmacologically acceptable salts. In formula IId M represents -CH- or -N-; R2c bonded with carbon atom of 5-member ring and is selected from hydrogen and methyl; R2d is bonded with carbon atom from 6-member ring and selected from hydrogen and fluorine; one of R2a and R2b represents methoxy, and other is Q1X1, where X1 represents -O-, and values of other radicals are given in formula IId, to pharmaceutical composition, inhibiting antiogenesis and/or reducing vessel permeability, which contains as active component compound of formula IId, to application of invention compounds for preparation of medication and to compounds of 7-benzyloxy-4(4-fluorine-2-methylindol-5-iloxy)-6-methoxyquinazoline and 4-(4-fluorine-2- methylindol -5-yloxy)-7-hydroxy-6-methoxyquinazo-line.

EFFECT: development of effective method of obtaining quinazoline compounds.

12 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to quinazolene derivatives of formula (I) and pharmaceutically acceptable salts of salt for slowing down cancer cells growth, as well as to method of obtaining compound and pharmaceutical composition based on them. Compounds can be applied for treatment of cancer diseases in which growth of cancer cells is induced by epithelial growth factor. In general formula (I) R1 represents hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylamino, C1-6dialkylamino, C1-6alkyltio, 2-((Nmethyl-(2-hydroxyethyl)amino)mathyl)vinyl, phenoxy, phenyl, dimethylaminoethoxymethyl, methoxyethoxymethyl, 4-methylpiperazinylmethyl, ethoxycarbonyl, benzamino, cyclopentenyl, 2-(4-methylpiperazinylmethyl)vinyl, methanesulphonylethylaminomethyl, methoxyethylaminomethyl, 2-(methanesulphonylethylaminomethyl)vinyl or 5-member heteroaryl, containing 1-2 heteroatoms selected from N, O or S, which are optionally substituted with X; R2 represents hydrogen or C1-6alkyl; R3 represents C1-6alkyl or C1-6dialkylamino C1-6alkyl; Y represents -(CR11R12)-, phenyl or 5-member heteroaryl, containing one sulphur atom, R11 and R12, each independently represent hydrogen, halogen, hydroxy, carboxyC1-3alkyl, C1-6alkyl, C1-6alkoxy, C1-6alkyltio, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkanoyl, C1-6alkoxycarbonyl, phenyl; optionally are condensed with each other with formation of 3-member non-aromatic ring, or R11 or R12 can be condensed with R2 with formation together with carbon and nitrogen, to which they are bonded, of 4-6-member non-aromatic ring, optionally containing additional sulphur heteroatom; R4 represents hydrogen, halogen, C1-6alkoxy, ethylsulphanyl, cyclopropylmethoxy, cyclopentyloxy, or C1-6alkylamino, optionally substituted with R13, where R13 represents halogen, trifuoromethyl, C1-6alkoxy, 4-methylpiperidinylmethoxy, N,N-dimethylamino or 6-member heteroaryl, containing 1-2 heteroatoms selected from N and O; R5 represents hydrohen or C1-3alkyl; R6 represents R14, phenyl, 1-phenylethyl, 3-ethenylphenyl, 1-penta-2,4-dienyl-1N-indasol-5-yl, imidasol or 9-member heteroaryl, containing 1-2 nitrogen atoms, optionally substituted with substituent R15, where R14 and R15, each independently represent hydrogen, halogen, C1-6alkyl, or phenyl, benzyl, 10-member heteroarylC1-6alkyl, containing one nitrogen atom, benzyloxy, 6-member heteroarylC1-6alkoxy, containing one nitrogen atom, 6-member heteroaryloxy, containing one nitrogen atom, phenylcarbamoyl, optionally substituted with R16, where R16 represents halogen, nitro, C1-6alkyl, or C1-6alkoxy; n equals integer number within the range from 1 to 4; p equals 0 or 1; X represents halogen, nitro, cyano, trifluoromethyl, C1-6alkyl, C1-6alkoxy, C1-6dialkylamino, C1-6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkyloxycarbonyl, C1-6alkanoyl, phenyl or 5-6-member heteroaryl, containing 1-2 heteroatoms selected from N and O; where heteroaryl represents heteroaromatic or non-aromatic group.

EFFECT: obtaining quinazoline derivatives and pharmaceutically acceptable salts of salts for slowing down growth of cancer cells.

11 cl, 7 dwg, 5 tbl, 225 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: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns novel bicyclic imidazol derivatives of the general formula I , where: W is CH or N; R is selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl and substituted (C3-C10)cycloalkyl; Z is selected out of group including a) -C(=O)OR7, where R7 is selected out of group including hydrogen and alkyl; b) -C(=O)NR8R9, where R8 and R9 are independently selected out of group including hydrogen, alkyl, aryl, substituted aryl, heterocyclic group, or alternatively R8 and R9 form heterocyclic group or substituted heterocyclic group, together with nitrogen atom linked to them; c) tetrazolyl; HET is condensed 6,6-bicycle maintained by condensed link of any two 6-member cycles selected out of aryl, cycloalkyl, cycloalkenyl, heterocyclic or heteroaryl cycles optionally substituted by (Y)q; on the condition that at least one 6-member cycle in bicycle is heterocyclic or heteroaryl; each Y is independently selected out of group including halogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, (C3-C10)cycloalkyl, substituted (C3-C10)cycloalkyl, heterocyclic group, substituted heterocyclic group, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -CO2R7, -NR14R15, -NHNR14R15, -C(=O)NR14R15, -OR14, -SR14; where R7 is as defined above, and each of R14 and R15 is independently selected out of group including hydrogen, (C1-C10)alkyl, substituted (C1-C10)alkyl, aryl, substituted aryl; n is integer equal to 0, 1 or 2; q is integer equal to 1, 2 or 3; where heterocyclic group relates to substituted or non-substituted group with 1 ring or several condensed rings including 1 to 10 carbon atoms and 1 to 2 heteroatoms selected out of group including nitrogen, sulfur and oxygen, inside the ring including optionally 1 to 2 exocarbonyl groups; and pharmaceutically accepted salts or tautomers. Additionally, invention concerns compounds of general formulae II-VIII

and pharmaceutical composition based on compounds of the general formulae I- VIII, XI and XII, and treatment method for mammal virus infection partially mediated by a virus of Flaviviridae virus family, using claimed pharmaceutical composition.

EFFECT: obtaining new compounds, with useful biological effect.

82 cl, 9 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula (I): , where R1 is -COOH or -(CH2)n-R14; R2 is or , where X is -CH or -N; each of R3, R4, R5 and R6 is selected out of group including -H, -(lower) alkyl, -N(CH3)2, -O-(lower) alkene, -(lower) alcoxy, or where R5 and R6 are substitutes in adjoining carbon atoms in ring, R5 and R6 optionally form 5- or 6-member saturated carbocyclic ring together with adjoining carbon atoms, R14 is unsaturated 5-member substituted or non-substituted heterocyclic ring including 1 to 4 heteroatoms selected out of N, O and S, n is 0 or 1, or their pharmaceutically acceptable salts or complex ethers. Invention also concerns pharmaceutical composition.

EFFECT: obtaining new bioactive compounds and pharmaceutical composition based on them, with inhibition effect on glutamine fructose-6-phosphate amidotransferase (GFAT).

16 cl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydrochinoline derivatives represented by general formula , where t is equal 0, 1 or 2; each R independently represents H, alkyl, alkenyl or cycloalkyl; n is equal 0; R is selected from group, consisting of H, alkyl, halogenalkyl, cycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5 or group - Racycloalkyl, and where R2 is not substituted with amine or alkylamine; each R4 independently represents halogen; m is equal 0, 1 or 2; each R5 independently represents H, alkyl, alkenyl, alkinyl, cycloalkyl; p is equal 0 or 1; y represents -NR10-, -O-, -S-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, -RaHetRaN(R10)2, -HetRaAy or -HetRaHet; each Ra independently represents alkylene, possibly suibstituted with one or more than one alkyl or hydroxyl, cycloalkylene, possibly substituted with one or more than one alkyl or hydroxyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl or -Ra-cycloalkyl; each Ay independently represents possibly substituted phenyl or naphtyl group; each Het independently represents possibly substituted 3-12-member mono- or polycyclic heterocyclyl group, containing as heteroatoms N, or 5-7-member possibly substituted heteroaryl group, containing as heteroatom N; or its pharmaceutically acceptable salts or ethers. Also described are methods of obtaining compounds of formula (I-G).

EFFECT: obtained are novel compounds, which demonstrate protective against HIV-infection effect on target-cells by means of specific binding with chemokine receptor and which influence binding of natural ligand or chemokine with target-cell receptor, such as CXCR4 and/or CCR5.

54 cl, 2 tbl, 90 ex

FIELD: chemistry.

SUBSTANCE: there is disclosed N-hydroxyformamide compound of formula (I) or its pharmaceutically acceptable salt where ring B represents phenyl, pyridinyl or pyrimidinyl; R2 represents the group chosen from C1-6alkyl, phenyl or naphthyl where the specified group is substituted with one or more fluoro group; n is equal to 1, 2 or 3; and R1 represents tetrahydropyranyl, 2-pyrimidinyl-CH2CH2-, 2-pyrimidinyl-CH2CH2CH2-, SF-2-pyrimidinyl-CH2CH2-, C1-6alkyl or phenyl.

EFFECT: compounds are metalloproteinase inhibitors.

6 cl, 8 ex

FIELD: medicine.

SUBSTANCE: compounds of the present invention have inhibiting effect on tyrosineprotein kinase. In formula I (I) (Ia), Z means radical of formula Ia; each several R1, R2, R3 independently of each other means hydrogen, C1-C7alkyl, halogen-C1-C7alkyl, C1-C7alkoxy, halogen-C1-C7alkoxy, halogen, 5 or 6-membered rich heterocyclil containing 1 or 2 heteroatoms selected from group comprising N and O and at least one of R1, R2 and R3 is piperidil, piperedil-C1-C7alkyl, C1-C7alkylpiperazinyl or C1-C7-alkylpiperazinyl-C1-C7alkyl; R4 means amino or C1-C7alkylamino.

EFFECT: improved effectiveness.

8 cl, 17 tbl, 168 ex

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