Benzimidazole and indole derivatives as selective 5-ht6 and/or 5-ht2a receptor antagonists

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole and indole derivatives or pharmaceutically acceptable salts of general formula 1, where m assumes values from 0 to 2; n equals 1, X denotes: -NRa-; -CRbRc-; or -C(O)-; where: Ra is hydrogen or C1-6alkyl; Rb is hydrogen or C1-6alkyl; Rc is hydrogen, C1-6alkyl, hydroxy; or Ar denotes: phenyl, possibly substituted with 1-2 halogens; or isoxazole, possibly substituted with C1-6alkyl; R1 is a group of formula p assumes values from 1 to 3; Y denotes: -O-; -NRd-; or -CReRf-; where Rd, Re and Rf each independently denotes hydrogen or C1-6alkyl; each R2 independently denotes: halogen; C1-6alkyl; R3 and R4 each independently denotes hydrogen or C1-6alkyl; R5 and R6 each independently denotes; and R7 and R8 each independently denotes hydrogen or C1-6alkyl; or one of R7 and R8 and one of R5 and R6 together with atoms to which they are bonded can form a 4-6-member ring; or one of R7 and R8 together with Rd and atoms to which they are bonded can form a 6-7-member ring; or one of R7 and R8 and one of Re and Rf together with atoms to which they are bonded can form a 5-6-member ring. The invention also relates to a pharmaceutical composition based on compounds of formula I-VI and use of the compounds of formula I-VI.

EFFECT: obtaining novel benzimidazole and indole derivatives with selective 5-and/or 6-HT2A receptor antagonist properties.

27 cl, 1 tbl, 13 ex

 

This invention relates to compounds substituted benzimidazolone and dihydroindolone corresponding to compositions and methods for their use as therapeutic agents, and methods for their preparation.

According to the proposed invention the compounds of formula I:

or their pharmaceutically acceptable salt,

where:

m has a value from 0 to 3;

n is 1 or 2;

X represents:

-NRa-;

-O-;

-S-;

-CRbRc-; or

-C(O)-;

where:

Rarepresents hydrogen or alkyl;

Rbrepresents hydrogen, fluorine or alkyl;

Rcrepresents hydrogen, fluorine, alkyl, hydroxy; or alkoxy; or

Rband Rctogether form oxo; or

Rband Rctogether with the atom to which they are attached, may form a three to six-membered possibly substituted cycle which may include heteroatom selected from O, N and S;

Ar represents:

possibly substituted aryl; or

possibly substituted heteroaryl;

R1represents a group of the formula;

p has a value from 1 to 4;

Y represents:

-O-;

-NRd-; or

-CReRf;

where Rd, Reand Rfeach independently represents ogorodili alkyl;

each R2represents independently:

halogeno;

alkyl;

halogenoalkane;

halogenoalkane;

alkoxy;

heteroalkyl;

cyano;

-(CH2)q-S(O)r-Rg;

-(CH2)q-C(=O)-NRhRi;

-(CH2)q-SO2-NRhRi;

-(CH2)q-N(Rj)-C(=O)-Rkor

-(CH2)q-C(=O)-Rk;

where:

q is 0 or 1;

r has a value from 0 to 2; and

Rg, Rh, Riand Rjeach independently represents hydrogen or alkyl, and

Rkrepresents hydrogen, alkyl, alkoxy or hydroxy;

R3and R4each independently represents hydrogen or alkyl;

R5and R6each independently represents hydrogen or alkyl; and

R7and R8each independently represents hydrogen or alkyl; or

R7and R8together with the nitrogen to which they are attached, may form a four-semicolony possibly substituted cycle which possibly includes an additional heteroatom selected from O, N and S; or

one of R7and R8and one of R5and R6together with the atoms to which they are attached, may form a four-semicolony possibly substituted cycle which may include additional the heteroatom, selected from O, N and S; or

one of R7and R8together with Rdand the atoms to which they are attached, may form a four-semicolony possibly substituted cycle which possibly includes an additional heteroatom selected from O, N and S;

or

one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, may form a four-semicolony cycle, which possibly includes an additional heteroatom selected from O, N and S.

According to the invention proposed compositions containing the said compounds, methods of using the above-mentioned compounds, and methods for producing the aforementioned compounds.

Steps 5-hydroxytryptamine (5-HT) as the major modulatory neurotransmitter in the brain is mediated by several families of receptors called 5-NT, 5-HT2, 5-NT3, 5-NT, 5-NT, 5-MT and 5-MT. Based on the high level of mRNA of the receptor 5-NT in the brain found that the receptor 5-NT may play a role in the pathology and treatment of disorders of the Central nervous system. In particular, 5-HT2-selective 5-NT-selective ligands identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, apil PSIA, obsessive-compulsive disorder, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic attacks, akathisia, attention deficit disorder and hyperactivity disorder (ADHD), attention deficit disorder (add), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal cord injury and/or head injury such as hydrocephalus. Also expect that such compounds will be useful in the treatment of some gastrointestinal (LCD) disorders such as functional bowel disorder. See, for example, B.L.Roth et al., J. Pharmacol. Exp.Ther., 1994, 268, 1403-14120, D.R.Sibley et al., Mol. Pharmacol., 1993, 43, 320-327, A.J.Sleight et al., Neurotransmission, 1995, 11, 1-5, and .J.Sleight et al., Serotonin ID Research Alert, 1997, 2(3), 115-8.

Although there have been proposed some of the modulators 5-MT and 5-NTA continues to exist a need for compounds that are useful for modulating receptor 5-NT, receptor 5-NTA or both receptors.

In the invention proposed connection benzimidazolone and dihydroindolone, corresponding compositions, methods of their use as therapeutic agents, and methods for their preparation.

All publications cited herein, are included here p is lnom volume by reference.

Unless otherwise stated, the following terms used in this application, including the description and the claims, have the definitions given below. It should be noted that, as they are used in the description and the attached claims, the singular number include the corresponding plural, unless the context clearly indicated otherwise.

"Agonist" refers to a compound that enhances the activity of other compounds or receptor site.

"Alkyl" means a monovalent normal or branched saturated hydrocarbon group, consisting solely of carbon atoms and hydrogen atoms, having from one to twelve carbon atoms. "Lower alkyl" refers to alkyl group of carbon atoms in the amount of from one to six (i.e. "C1-C6alkyl"). Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc.

"Alkylene" means normal saturated divalent hydrocarbon radical of carbon atoms in the amount of from one to six or branched saturated divalent hydrocarbon radical of carbon atoms in an amount of from three to six, for example: methylene, ethylene, 2,2-dimethyl-ethylene, propylene, 2-methylpropene, butylene, pentile etc.

Albaniles" means normal unsaturated divalent hydrocarbon radical of carbon atoms in number from two to six or branched unsaturated divalent hydrocarbon radical of carbon atoms in the amount of from three to six, for example: ethenylene (-CH=CH-), 2,2-di-methyladenine, propylen, 2-methylpropenyl, butylen, penttinen etc.

"Alkoxy" means a group of the formula-OR, where R represents an alkyl group, as defined here. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, isopropoxy etc.

"Aminoethoxy" means the group-ORR', where R' represents amino and R is alkylene. Examples of aminoethoxy include aminoethoxy, 2-aminopropoxy, 3 aminopropoxy and the like. Grouping amino "aminoethoxy" may be substituted once or twice by alkyl with education "acylaminoalkyl and dialkylaminoalkyl" respectively. "Acylaminoalkyl" includes methylaminorex, methylaminopropane, ethyleneoxy etc. "Dialkylaminoalkyl" includes dimethylaminoethoxy, dimethylaminopropoxy, N-methyl-N-ethyleneoxy etc.

"Antagonist" refers to a compound that reduces or prevents the action of another connection or receptor site.

"Aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of mono-, bi - or tricyclic aromatic ring. The aryl group may be substituted as defined here. Examples of aryl groups include, but are not Ogre is nicely them: phenyl, naphthyl, naphthalenyl, tenantry, fluorenyl, indenyl, pentalene, azulene, acidifier, diphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfide, diphenylsulfone, diphenylethylene, benzodioxane, benzofuranyl, benzodioxolyl, benzopyranyl, benzoxazines, benzoxazinones, benzoperylene, benzofurazanyl, benzopyranyl, benzomorphans, methylenedioxyphenyl, atlanticcity and the like, including partially hydrogenated derivatives.

"Allen" means a divalent aryl radical, where the aryl is as defined here. "Allen" includes, for example, ortho-, meta - and para-phenylene (1,2-phenylene, 1,3-phenylene and 1,4-phenylene, respectively), which may be substituted, as defined here.

"Arylalkyl and aralkyl"that can be used interchangeably, mean a radical RaRbwhere Rarepresents a group of alkylene and Rbrepresents an aryl group, as defined herein; benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, etc. are examples of arylalkyl.

"Cycloalkyl" means a saturated carbocyclic group consisting of a mono - or bicyclic rings. Cycloalkyl can be possibly substituted by one or more than one Deputy, where each Deputy independently represents hydroxy, alkyl, alkoxy, halogen is, halogenoalkane, amino, monoalkylamines or dialkylamino, unless specifically stated otherwise. Examples of the groups cycloalkyl include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, including partially unsaturated derivatives, such as cyclohexenyl, cyclopentenyl etc.

"Cycloalkenyl" means a group of the formula-R'-R", where R' is alkylene and R" represents cycloalkyl, as defined here.

"Heteroalkyl" means an alkyl radical, as defined here, where one, two or three hydrogen atoms replaced by Deputy, is independently selected from the group consisting of-ORa, -NRbRcand-S(O)nRd(where n is an integer from 0 to 2), with the understanding that the attachment point heteroalkyl radical passes through a carbon atom, where Rarepresents hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; Rband Rcindependently of one another represent hydrogen, acyl, alkyl, cycloalkyl or cycloalkenyl; and when n is 0, Rdrepresents hydrogen, alkyl, cycloalkyl or cycloalkenyl, and when n is 1 or 2, Rdrepresents alkyl, cycloalkyl, cycloalkenyl, amino, acylamino, monoalkylamines or dialkylamino. Representative examples include, but are not limited the s they are: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylation, 2,3-dihydroxy propyl, 1-hydroxymethylation, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-amino-ethyl, 3-aminopropyl, 2-methylsulfonylmethyl, aminocarbonylmethyl, aminosulfonyl, aminosulfonyl, methylaminoethanol, methylaminomethyl, methylaminomethyl-propyl, etc.

"Heteroaryl" means a monocyclic or bicyclic monovalent radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S, the remaining ring atoms are C, with the understanding that the attachment point heteroaryl radical will be on an aromatic ring. Heteroaryl ring can be substituted, as defined here. Examples of heteroaryl groups include, but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothiazyl, thiophenyl, furanyl, pyranyl, pyridyl, pyridinyl, pyridil, pyrrolyl, pyrazolyl, pyrimidyl, chinoline, ethenolysis, benzofuran, benzothiophene, benzothiophene, benzimidazole, benzoxazole, benzoxadiazole, benzothiazolyl, benzotriazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl honokalani, purinol, hintline, hemolysins, naphthyridine, pteridine, carbazole, azepine, diazepine, acridine and the like, including partially hydrogenated derivatives.

"Heteroaryl" means a divalent heteroaryl radical, where heteroaryl is such as defined here. "Heteroaryl" may be substituted as defined here. "Heteroaryl" includes, for example, indoline, pyrimidinyl etc.

The terms "halogen" and "halogen", which can be used interchangeably, refer to the Deputy fluorine, chlorine, bromine or iodine.

"Halogenated" means an alkyl, as defined here, in which one or more than one hydrogen atom is substituted by an identical or different halogen atoms. Examples of halogenoalkanes include-CH2Cl, -CH2CF3, -CH2Cl3, perfluoroalkyl (for example-CF3and so on

"Heterocyclimamines" means a saturated ring, where at least one ring atom is a N, NH or N-alkyl, and the remaining ring atoms form a group alkylen.

"Heterocyclyl" means a monovalent saturated group consisting of rings in the amount of from one to three, with one, two, three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). Ring heterocyclyl may be substituted, as defined here. Por the measures groups heterocyclyl include, but not limited to: azetidinol, piperidinyl, piperazinil, homopiperazine, azepine, pyrrolidinyl, pyrazolidine, imidazoline, imidazolidine, pyridinyl. pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidine, morpholine, thiazolidine, isothiazolinones, hinokitiol, chinoline, ethenolysis, benzimidazolyl, diazolidinyl, benzothiazolyl, benzoapyrene, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, thiomorpholine, thiomorpholine-sulfoxide, themorphological, dihydroquinoline, dihydroisoquinoline, tetrahydroquinoline, tetrahydroisoquinoline and the like, including partially unsaturated derivatives.

"Heterocyclic" means the group-OR, where R is heterocyclyl. "Heterocyclic" includes, for example, azetidinone, pyrrolidinyloxy, piperidinyloxy, azaindole etc.

"Geterotsiklicheskikh" means the group-ORR', where R' represents heterocyclyl and R represents alkylene. Examples of geterotsiklicheskikh include acetanilides, pyrrolidinyloxy, piperidinyloxy, acetanilides, pyrrolidinyloxy, piperidinyloxy etc.

"Maybe substituted", when used in combination with "aryl", "arilena", "phenyl", "phenylene", "heteroaryl", "heteroatom" or "heterocyclyl"means aryl, Allen, phenyl, f is Nilin, heteroaryl, heteroaryl or heterocyclyl, which may independently substituted by substituents in the amount of from one to four, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkenyl, heteroalkyl, hydroxyalkyl, heteroalkyl, heteroatomic, halogeno, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di alkylamino, halogenoalkane, halogenoalkane, -COR (where R represents hydrogen, alkyl, phenyl or phenylalkyl), -(CR'R")n-COOR (where n is an integer from 0 to 5, R' and R" independently represent hydrogen or alkyl, and R represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl) or(CR'R") -CONRaRb(where n is an integer from 0 to 5, R' and R" independently represent hydrogen or alkyl, and Raand Rbrepresent independently from each other hydrogen, alkyl, cycloalkyl, cycloalkenyl, phenyl or phenylalkyl.

"Leaving group" means a group with a value common related in the chemistry of organic synthesis, i.e. an atom or a group substitutable in terms of substitution reactions. Examples of leaving groups include, but are not limited to, halogen, alkane - or arensulfonic, such as methanesulfonate, econsultancy, thiomethyl, benzosulfimide, that is iloxi, titilate, dehalogenation, possibly substituted benzyloxy, isopropoxy, acyloxy etc.

"Modulator" means a molecule that interacts with the target. These interactions include, but are not limited to, agonistic, antagonistic, and the like, as defined here.

"Probable" or "possible" means that the subsequent described event or circumstance may not necessarily occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

"A painful condition" means any disease, condition, symptom or indication.

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

"Pharmaceutically acceptable" means suitable for the manufacture of pharmaceutical competitievly generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary and medical pharmaceutical applications.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable, as defined here, and which possess the desired pharmacological activity of the parent compound. Such salts include:

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

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

Preferred pharmaceutically acceptable salts are salts formed from acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium.

It should be clear that all references to pharmaceutically acceptable salts include forms accession solvent (solvate) or crystal forms (polymorphs)as defined here, the same salt accession acid.

"Protective group" or "protecting group" means a group which selectively blocks one reactive site in a multifunctional compound, so that a chemical reaction can be performed selectively at another unprotected reactive site within the meaning of generally accepted associated with it in synthetic chemistry. Some of the means according to this invention is based on the protective groups for blocking of the reactive nitrogen atoms and/or oxygen, present in the reagents. For example, the terms "amino-protecting group, and nitrogen-protecting group" is used here interchangeably and refer to organic groups intended to protect nitrogen atom against undesirable reactions during synthetic procedures. Examples of nitrogen protecting groups include, but are not limited to, TRIFLUOROACETYL, acetamido, benzyl (EAP), benzyloxycarbonyl (carbobenzoxy, CBZ), para-methoxybenzeneboronic, para-nitrobenzenesulfonyl, tert-butoxycarbonyl (VOS) and other Specialists in the art should know how to select a group for ease of removal and the ability to withstand subsequent reactions.

"Solvate" means the form of accession of the solvent, which contain either stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to capture a fixed molar fraction of solvent molecules in the crystalline solid state, forming, thus, MES. If the solvent is water, formed MES is a hydrate, when the solvent is alcohol, educated MES represents an anion. Hydrates are formed by combining one or more than one water molecule with one of the substances in which the water retains its molecular state is in the form of H 2Oh, and this combination is capable of forming one or more than one hydrate.

"Subject" means a mammal and not mammals. Mammals mean any member of the class Mammalia, including, but not limited to: humans; primates, not representing a person, such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and Guinea pigs; and the like. Examples of mammals include, but are not limited to: birds and the like. The term "subject" does not denote a particular age or gender.

"Therapeutically effective amount" means an amount of compound that when administered to a subject to treat painful conditions is sufficient for the implementation of such treatment of a pathological state. "Therapeutically effective amount" will vary depending on the compound, the disease condition to be treated, the severity of the disease to be treated, the age and relative health of the subject, the route and form of administration, the opinion of the attending physician or veterinarian, and other factors.

The terms defined above" and "defined here is, when they refer to variables include by reference the broad definition of this variable, as well as preferred, more preferred and most preferred definitions, if any.

"Treating" or "treatment" of the disease condition includes:

(i) preventing the disease condition, i.e. when you do not allow clinical symptoms of painful conditions develop in a subject that may be exposed to or predisposed to this painful condition, but have yet to experience or do not show symptoms of this painful condition.

(ii) inhibiting the disease condition, i.e. when to stop the development of this painful condition or its clinical symptoms, or

(iii) relief of painful conditions, that is when provide temporary or permanent regression of this painful condition or its clinical symptoms.

The terms "treatment", "bringing into contact" and "interaction"when they refer to a chemical reaction, means adding or mixing two or more than two reagents in suitable conditions for the receipt and/or the desired product. It should be clear that the reaction, which gives the specified and/or the desired product may not necessarily be the result of the unification of the two reagents, which the s were the source added, there may be one or more than one intermediate compound, which is formed in the mixture, which, ultimately, leads to the formation of the specified and/or the desired product.

In General, the nomenclature used in this application is based on AUTONOM™ v.4.0, the computerized system Beilstein Institute for education IUPAC systematic nomenclature. For convenience, the IUPAC numbering of the provisions of the representative benzimidazolinone and dihydroindolone compounds described herein are illustrated by the formula:

where the 1-position is substituted by arylalkyl or heteroallyl, as described below.

Chemical structure shown here were obtained using ISIS® version 2.2. Any open valence, appearing on the carbon atom, oxygen or nitrogen in the bodies here indicates the presence of a hydrogen atom. When in the structure of the chiral center is present, but not shown a specific enantiomer, it should be understood that this structure covers both enantiomers of this chiral center.

According to the proposed invention the compounds of formula I:

or their pharmaceutically acceptable salt,

where:

m has a value from 0 to 3;

n is 1 or 2;

X represents:

-NRa-;

-O-

-S-;

-CRbRsup> c-; or

-C(O)-;

where:

Rarepresents hydrogen or alkyl;

Rbrepresents hydrogen, fluorine or alkyl;

Rcrepresents hydrogen, fluorine, alkyl, hydroxy; or alkoxy; or

Rband Rctogether form oxo; or

Rband Rctogether with the atom to which they are attached, may form a three to six-membered cycle, which may include heteroatom selected from O, N and S;

Ar represents:

possibly substituted aryl; or

possibly substituted heteroaryl;

R1represents a group of the formula;

p has a value from 1 to 4;

Y represents:

-O-;

-NRd-; or

-CReRf-;

where Rd, Reand Rfeach independently represents hydrogen or alkyl; each

R2represents independently:

halogeno;

alkyl;

halogenoalkane;

halogenoalkane;

alkoxy;

heteroalkyl;

cyano;

-(CH2)q-S(O)r-Rg;

-(CH2)q-C(=O)-NRhRi;

-(CH2)q-SO2-NRhRi;

-(CH2)q-N(Rj)-C(=O)-Rkor

-(CH2)q-C(=O)-Rk;

where:

q is 0 or 1;

r has a value from 0 to 2; and

Rg, Rh, Riand Rjeach is th independently represents hydrogen or

alkyl, and Rkrepresents hydrogen, alkyl, alkoxy or hydroxy;

R3and R4each independently represents hydrogen or alkyl;

R5and R6each independently represents hydrogen or alkyl; and

R7and R8each independently represents hydrogen or alkyl; or

R7and R8together with the nitrogen to which they are attached, can

to form a four-semicolony possibly substituted cycle which possibly includes an additional heteroatom selected from O, N and S; or

one of R7and R8and one of R5and R6together with the atoms to which they are attached, may form a four-semicolony cycle, which possibly includes an additional heteroatom selected from O, N and S; or

one of R7and R8together with Rdand the atoms to which they are attached, may form a four-semicolony possibly substituted cycle which possibly includes an additional heteroatom selected from O, N and S; or

one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, may form a four-semicolony possibly substituted cycle which possibly includes an additional heteroatom selected from O, N and S.

It should be clear that the volume on the frame of the invention includes not only the different isomers, which can be, but also a diverse mixture of isomers that can be formed. In addition, the scope of the present invention also encompasses a solvate, and salts of compounds of formula I.

In many embodiments of formula I, n is set to 1.

In many embodiments of formula I, R3and R4represent hydrogen.

In many embodiments of formula I, p is set to 2 or 3.

In some embodiments of formula I, Ar represents a possibly substituted aryl, such as a possibly substituted phenyl or possibly substituted naphthyl, such as, for example, phenyl or naphthyl, possibly substituted independently with one, two, three or four times a Deputy halogeno, alkyl, halogenated, halogenoalkane, alkoxy, heteroalkyl, cyano, nitro, amino (including alkylamino, dialkylamino), -(CH2)q-S(O)r-Rg; -(CH2)q-C(=O)-NRhRi; -(CH2)q-SO2-NRhRi; -(CH2)q-N(Rj)-C(=O)-Rkor -(CH2)q-C(=O)-Rk; where q is 0 or 1, r has a value from O to 2, Rg, Rh, Riand Rjeach independently represents hydrogen or alkyl, and Rkrepresents hydrogen, alkyl, alkoxy or hydroxy. More preferably Ar represents a possibly substituted phenyl.

In other embodiments of formula I, Ar, not only is em a possibly substituted heteroaryl. Preferred heteroaryl includes pyridinyl, pyrimidinyl, thienyl, furanyl, pirolli, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, quinoline and isoquinoline, and more preferably pyridinyl, pyrimidinyl, thienyl and furanyl.

In some embodiments of formula I, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula I, m is set to 0.

In some embodiments of formula I, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula I, m is 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In many embodiments of the compounds according to the invention can be represented by formula II:

where:

s has a value from 1 to 4;

each R9represents independently:

halogeno;

alkyl;

halogenoalkane;

halogenoalkane;

alkoxy;

heteroalkyl;

cyano;

-(CH2)q-S(O)r-Rg;

-(CH2)q-C(=O)-NRhRi;

-(CH2)q-SO2-NRhRi;

-(CH2)q-N(Rj)-C(=O)-Rkor

-(CH2)q-C(=O)-Rk;

where:

q is 0 or 1;

r has a value from 0 is about 2; and

Rg, Rh, Riand Rjeach independently represents hydrogen or alkyl, and Rkrepresents hydrogen, alkyl, alkoxy or hydroxy; and

m, p, X, Y, R2, R3, R4, R5, R6, R7and R8are as defined here.

In some embodiments of formula I or formula II, X represents-NRa-.

In some embodiments of formula I or formula II, X represents-O-.

In some embodiments of formula I or formula II, X represents-CRbRc-.

In some embodiments of formula I or formula II, X represents-C(O)-;

In some embodiments of formula I or formula II, Y is-O-.

In some embodiments of formula I or formula II, Y is-NRd-.

In some embodiments of formula I or formula II, Y is-CReRf-.

In some embodiments of formula I or formula II, m is 0 or 1.

In some embodiments of formula I or formula II, R3and R4represent hydrogen.

In some embodiments of formula I or formula II, R3and R4represent alkyl, preferably methyl.

In some embodiments of formula I or formula II one of R3and R4represents hydrogen and the other represents alkyl, preference is sustained fashion methyl.

In some embodiments of formula I or formula II, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula I or formula II, m is 0.

In some embodiments of formula I or formula II, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula I or formula II, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formula I or formula II, where X represents a-NRa-, Rarepresents hydrogen. In other embodiments of formula I or formula II, where X represents a-NRa-, Rarepresents alkyl, preferably methyl.

In some embodiments of formula I or formula II, where X is a

-CRbRc-, Rband Rcrepresent hydrogen.

In other embodiments of formula I or formula II, where X is a

-CRbRc-, Rband Rcrepresent alkyl, preferably methyl.

In still other embodiments of formula I or formula II, where X is a

-CRbRc-one of Rband Rcrepresents hydrogen and the other represents alkyl, p is edocfile methyl.

In still other embodiments of formula I or formula II, where X is a

-CRbRc-one of Rband Rcrepresents alkyl, preferably methyl and the other represents hydroxy.

In other embodiments of formula I or formula II, where X is a

-CRbRc-, Rband Rctogether with the atom to which they are attached, form a three to six-membered cycle, which may include heteroatom selected from O, N and S, and which may be substituted by alkyl. Preferably in such wooloweyah Rband Rctogether with the atom to which they are attached, form a three - or four-membered carbocyclic ring which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, and R3and R4each independently represents hydrogen or methyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4represent hydrogen, and Y represents-O-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, Y represents-O-, and R5and R6represent hydrogen.

In some the embodiments of formula I or formula II, n is 1, p has the value 2, R3and R4each independently represents hydrogen or methyl, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4represent hydrogen, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4represent hydrogen, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, Y is-NRd-and one of R7and R8together with Rdthe atoms, to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4represent hydrogen, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may mo is et to be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, and R3and R4each independently represents hydrogen or methyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents water is od or methyl, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some of the which embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, and X represents-NRa-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents Soboh is-NR a-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are also dinani, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4represent hydrogen, X represents-NRa-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which is neither attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and X represents-NRa-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4every illegal is ASIMO represents hydrogen or methyl, X represents-NRa-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents bodoro is or methyl, X represents-NRa-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-NRa-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4every illegal the performance represents hydrogen or methyl, X represents-NRa-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, and X represents-CRbRc-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which, perhaps, can the t to be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which, who is one, may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-CReRf-and one of R7and R8and one of Reand R together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and X represents-CRbRc-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II n has a 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y is-NRa-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a signature is a group of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-CRbRc-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be amaden-alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, and X represents-O-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, and Y is-NRd-.

In some embodiments, f is rmula I or formula II, n is 1, p has the value 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or metrodora, X represents-O-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, R is meant the e 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and X represents-O-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3 3and R4each independently represents hydrogen or methyl, X represents-O-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or is ormula II n has a value of 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y is-NRa-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II n has a value is s 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-O-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, and X represents-C(O)-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents in the location or methyl, X represents-C(O)-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y is-NRd-and one of R7and R8and one of R5and R6together with the atoms to which they are connec the us, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-CReRf-, and R5, R6, Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which the output they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, R is set to 2, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, and X represents-C(O)-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, and Y is-O-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-O-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents FDS is th hydrogen or methyl, X represents-C(O)-, Y represents-O-, and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, and Y is-NRd-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y is-NRd-, and R5and R6represent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y is-NRa-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X, not only is no a-C(O)-, Y is-NRd-and one of R7and R8together with Rdand the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, and Y is-CReRf-.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-CReRf-, and R5, R6Reand Rfrepresent hydrogen.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X represents-C(O)-, Y represents-CReRf-and one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I or formula II, n is 1, p has a value of 3, R3and R4each independently represents hydrogen or methyl, X pre is is-C(O)-, Y represents-CReRf-and one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a four-semicolony cycle, which may be substituted by alkyl.

In some embodiments of formula I, R1is azetidine, pyrrolidine, piperazinil, piperidinyl, azepine, diazetidine, diazepines, aminoethoxy, azetidinone, pyrrolidinyloxy, piperidinyloxy, azaindole, azetidinone, pyrrolidinyloxy, piperidinyloxy, asainlolita or aminoalkyl.

In some embodiments of formula I, R1represents piperazinil, piperidinyl or pyrrolidinyl.

In some embodiments of formula I, R1represents a group of the formula:

;;;;

;;;;

;;;or

where R7, R8, R10, R11, R12and R13each independently represents hydrogen or alkyl. Preferably in such voploshena R10, R11, Rsup> 12and R13represent hydrogen.

In some embodiments of the compounds according to the invention can be represented by formula III:

where:

Y represents N or CH;

t is 1 or 2;

u has a value of from 1 to 3;

R10, R11, R12and R13each independently represents hydrogen or alkyl; and

m, s, X, R2, R3, R4, R5, R6, R7, R8and R9are as defined here.

In some embodiments of formula III, X is-NRa-.

In some embodiments of formula III, X represents-O-.

In some embodiments of formula III, X is-CRbRc-.

In some embodiments of formula III, X represents-C(O)-;

In some embodiments of formula III, Y is-NRd-.

In some embodiments of formula III, Y is-CRf-.

In some embodiments of formula III, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula III, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula III, m is 0.

In some embodiments of formula III, m is 1 and R2represents fluorine or chlorine.

In some wapl is the use of the formula III, m is set to 2 and each R 2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formula III, R3and R4represent hydrogen. In some embodiments of formula III, R3and R4represent alkyl, preferably methyl.

In some embodiments of formula III, one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula III, where X represents a-NRa-, Rarepresents hydrogen. In other embodiments of formula III, where X represents a-NRa-, Rarepresents alkyl, preferably methyl.

In some embodiments of formula III, where X represents-CRbRc-, Rband Rcrepresent hydrogen.

In other embodiments of formula III, where X represents-CRbRc-, Rband Rcrepresent alkyl, preferably methyl.

In still other embodiments of formula III, where X represents-CRbRc-one of Rband Rcrepresents hydrogen and the other represents alkyl, preferably methyl.

In still other embodiments of formula III, where X represents-CRbRc-one of Rband Rcrepresents the t of an alkyl, preferably methyl and the other represents hydroxy.

In other embodiments of formula III, where X represents-CRbRc-, Rband Rctogether with the atom to which they are attached, form a three to six-membered cycle, which may include heteroatom selected from O, N and S. Preferably, in such embodiments, Rband Rctogether with the atom to which they are attached, form a three - or four-membered carbocyclic ring.

In some embodiments of formula III, Y is-CH-.

In some embodiments of formula III, Y is-N-.

In some embodiments of formula III, Y is-CH-, u has a value of 2, and t has a value of 2.

In some embodiments of formula III, Y is-CH-, and has the value 1 and t has a value of 2.

In some embodiments of formula III, Y is-N-, and has the value 2 and t has a value of 2.

In some embodiments of formula III, Y is-N-, and has the value 2 and t has a value of 3.

In some embodiments of formula III, R8represents hydrogen.

In some embodiments of formula III, R10, R11, R12and R13represent hydrogen.

In some embodiments of formula III compounds according to the invention can be represented by formula IIIa:

where Y represents N or CH and m, s, t, u, Y, R2, R3, R4, R8, R9, R10, R11, R12, R13and R8are as defined here.

In some embodiments of formula IIIa R3represents hydrogen.

In some embodiments of formula IIIa R8represents hydrogen.

In some embodiments of formula IIIa Y is-CH-.

In some embodiments of formula IIIa Y is-N-.

In some embodiments of formula IIIa t is 1 and u has a value of 2.

In some embodiments of formula IIIa t is set to 2 and u has a value of 2.

In some embodiments of formula IIIa t is set to 2 and u has a value of 3.

In some embodiments of formula IIIA, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula IIIa R8represents hydrogen.

In some embodiments of formula IIIa R10, R11, R12and R13represent hydrogen.

In some embodiments of formula IIIa, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula IIIa, m is set to 0.

In some embodiments of formula IIIa, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula IIIa m has a signature is a group of 2 and each R 2represents independently fluorine or chlorine in position 5 and 6 benzimidazolinone cyclic system.

In some embodiments of formula IIIa R3and R4represent hydrogen.

In some embodiments of formula IIIa R3and R4represent alkyl, preferably methyl.

In some embodiments of formula IIIa is one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In other embodiments of formula III compounds according to the invention can be represented by formula IIIb:

where Y represents N or CH and m, s, t, u, Y, R2, R3. R4, R8, R9, R10, R11, R12, R13, Rband Rcare as defined here.

In some embodiments of formula IIIb Rband Rcrepresent hydrogen.

In some embodiments of formula IIIb Rband Rcrepresent alkyl, preferably methyl.

In some embodiments of formula IIIb one of Rband Rcrepresents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula IIIb one of Rband Rcrepresents hydrogen or alkyl and the other represents hydroxyl.

In some embodiments of formula III, R band Rctogether form oxo.

In some embodiments of formula IIIb Y is-CH-.

In some embodiments of formula IIIb Y is-N-.

In some embodiments of formula IIIb t is 1 and u has a value of 2.

In some embodiments of formula IIIb t is set to 2 and u has a value of 2.

In some embodiments of formula IIIb t is set to 2 and u has a value of 3.

In some embodiments of formula IIIb, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula IIIb R8represents hydrogen.

In some embodiments of formula IIIb R10, R11, R12and R13represent hydrogen.

In some embodiments of formula IIIb, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula IIIb, m is 0.

In some embodiments of formula IIIb, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula IIIb, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 dihydroindolone cyclic system.

In some embodiments of formula IIIb R3and R4represent hydrogen.

In some embodiments of formula IIIb R3and R4represent alkyl, predpochtitelno methyl.

In some embodiments of formula IIIb one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of the compounds according to the invention can be represented by formula IV:

where:

p has the value 2 or 3; and

m, s, X, Y, R2, R3, R4, R5, R6, R7, R8and R9are as defined here.

In some embodiments of formula IV, X represents-NRa-.

In some embodiments of formula IV, X represents-O-.

In some embodiments of formula IV, X represents-CRbRc-.

In some embodiments of formula IV, X represents-C(O)-;

In some embodiments of formula IV, Y is-NRd-.

In some embodiments of formula IV, Y is-CReRf-.

In some embodiments of formula IV, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula IV, where X represents a-NRa-, Rarepresents hydrogen. In other embodiments of formula IV, where X represents a-NRa-, Rarepresents alkyl, preferably methyl.

In some embodiments of formula IV, where X represents-CRbRc-, Rband Rcrepresent the FDS is th hydrogen.

In other embodiments of formula IV, where X represents-CRbRc-, Rband Rcrepresent alkyl, preferably methyl.

In still other embodiments of formula IV, where X represents-CRbRc-one of Rband Rcrepresents hydrogen and the other represents alkyl, preferably methyl.

In still other embodiments of formula IV, where X represents-CRbRc-one of Rband Rcrepresents alkyl, preferably methyl and the other represents hydroxy.

In other embodiments of formula IV, where X represents-CRbRc-, Rband Rctogether with the atom to which they are attached, form a three to six-membered cycle, which may include heteroatom selected from O, N and S. Preferably, in such embodiments, Rband Rctogether with the atom to which they are attached, form a three - or four-membered carbocyclic ring.

In some embodiments of formula IV, Y is-CH2-.

In some embodiments of formula IV, Y is-NH-.

In some embodiments of formula IV, Y is-O-.

In some embodiments of formula IV, R is set to 2.

In some embodiments of formula IV, R is set to 3.

In some embodiments of formula IV, Y is the fight About, p represents 2, and one of R7and R8represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula IV, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula IV, m is set to 0.

In some embodiments of formula IV, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula IV, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formula IV, R3and R4represent hydrogen.

In some embodiments of formula IV, R3and R4represent alkyl, preferably methyl.

In some embodiments of formula IV, one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula IV compounds according to the invention can be represented by formula IVa:

where p has a value of 2 or 3 and m, s, p, R2, R3, R4, R7, R8, R9and Raare as defined here.

In some embodiments of formula IVa Rais the Wallpaper hydrogen.

In some embodiments of formula IVa one of R7and R8represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula IVa m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula IVa m has a value of 0.

In some embodiments of formula IVa m has a value of 1 and R2represents fluorine or chlorine.

In some embodiments of formula IVa m has the value 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolinone cyclic system.

In some embodiments of formula IVa R3and R4represent hydrogen.

In some embodiments of formula IVa R3and R4represent alkyl, preferably methyl.

In some embodiments of formula IVa one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In other embodiments of formula IV compounds according to the invention can be represented by formula IVb:

where p has a value of 2 or 3 and m, s, p, R2, R3, R4, R7, R8, R9and Raare as defined here.

In some embodiments of formula IVb Rband Rcrepresent the Wallpaper hydrogen.

In some embodiments of formula IVb Rband Rctogether form oxo.

In some embodiments of formula IVb one of R7and R8represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula IVb m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula IVb m has a value of 0.

In some embodiments of formula IVb m has a value of 1 and R2represents fluorine or chlorine.

In some embodiments of formula IVb m has the value 2 and each R2represents independently fluorine or chlorine in position 5 and 6 dihydroindolone cyclic system.

In some embodiments of formula IVb R3and R4represent hydrogen.

In some embodiments of formula IVb R3and R4represent alkyl, preferably methyl.

In some embodiments of formula IVb one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of the compounds according to the invention can be represented by the formula V:

where m, s, t, u, X, Y, R2, R3, R4, R8, R9, R10, R11, R12and R13are as defined here

In some embodiments of formula V, X represents-NRa-.

In some embodiments of formula V, X represents-O-.

In some embodiments of formula V, X represents-CRbRc-.

In some embodiments of formula V, X represents-C(O)-;

In some embodiments of formula V, Y is-NRd-.

In some embodiments of formula V, Y is-CReRf-.

In some embodiments of formula V, Y is-O-.

In some embodiments of formula V, R10, R11, R12and R13represent hydrogen.

In some embodiments of formula V, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula V, R3and R4represent hydrogen.

In some embodiments of formula V, R3and R4represent alkyl, preferably methyl.

In some embodiments of formula V, one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula V, where X represents-NRa-, Rarepresents hydrogen. In other embodiments of formula V, where X represents-NRa-, Rarepresents alkyl, preferably methyl.

In some embodiments of formula V, where X is present is employed, a-CR bRc-, Rband Rcrepresent hydrogen.

In other embodiments of formula V, where X represents-CRbRc-, Rband Rcrepresent alkyl, preferably methyl.

In still other embodiments of formula V, where X represents-CRbRc-one of Rband Rcrepresents hydrogen and the other represents alkyl, preferably methyl.

In still other embodiments of formula V, where X represents-CRbRc-one of Rband Rcrepresents alkyl, preferably methyl and the other represents hydroxy.

In other embodiments of formula V, where X represents-CRbRc-, Rband Rctogether with the atom to which they are attached, form a three to six-membered cycle, which may include heteroatom selected from O, N and S. Preferably, in such embodiments, Rband Rctogether with the atom to which they are attached, form a three - or four-membered carbocyclic ring.

In some embodiments of formula V, R8represents hydrogen.

In some embodiments of formula V, Y is-O-, t is set to 2 and u has a value of 2.

In some embodiments of formula V, Y is-O-, t is 1 and u has a value of 2.

In some embodiments Faure the uly V Y represents-O-, t is 1 and u is 1.

In some embodiments of formula V, Y is-O-, t is set to 2 and u has a value of 3.

In some embodiments of formula V, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula V, m is set to 0.

In some embodiments of formula V, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula V, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formula V compounds according to the invention can be represented by formula Va:

where m, s, t, u, X, R2, R3, R4, R8, R9, R10, R11, R12, R13and Raare as defined here.

In some embodiments of formula Va R8represents hydrogen.

In some embodiments of formula Va R8represents hydrogen.

In some embodiments of formula Va R10, R11, R12and R13represent hydrogen.

In some embodiments of formula Va m is 0 or 1 and s has a value of 0,1 or 2.

In some embodiments of formula Va t is 1 and u is the meet is 1.

In some embodiments of formula Va t is 1 and u has a value of 2.

In some embodiments of formula Va t has the value 2 and u has a value of 2.

In some embodiments of formula Va t has the value 2 and u has a value of 3.

In some embodiments of formula Va m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula Va m has a value of 0.

In some embodiments of formula Va m has a value of 1 and R2represents fluorine or chlorine.

In some embodiments of formula Va m has the value 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolinone cyclic system.

In some embodiments of formula Va R3and R4represent hydrogen.

In some embodiments of formula Va R3and R4represent alkyl, preferably methyl.

In some embodiments of formula Va is one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula V compounds according to the invention can be represented by formula Vb:

where m, s, t, u, X, R2, R3, R4, R8, R9, R10, R11, R12, R13, Rband Rcare Campidano here.

In some embodiments of formula Vb, Rband Rcrepresent hydrogen.

In some embodiments of formula Vb, Rband Rctogether form oxo.

In some embodiments of formula Vb, R8represents hydrogen.

In some embodiments of formula Vb, R10, R11, R12and R13represent hydrogen.

In some embodiments of formula Vb, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula Vb, t is 1 and u is 1.

In some embodiments of formula Vb, t is 1 and u has a value of 2.

In some embodiments of formula Vb t is set to 2 and u has a value of 2.

In some embodiments of formula Vb t is set to 2 and u has a value of 3.

In some embodiments of formula Vb, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula Vb, m has a value of 0.

In some embodiments of formula Vb, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula Vb m has the value 2 and each R2represents independently fluorine or chlorine in position 5 and 6 dihydroindolone cyclic system.

In some embodiments of formula Vb, R3and R4represent hydrogen.

In some embodied eniah formula Vb, R 3and R4represent alkyl, preferably methyl.

In some embodiments of formula Vb one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of the compounds according to the invention can be represented by formula VI:

where

t has a value from 1 to 3;

u has a value of from 0 to 3; and

m, s, X, Y, R2, R3, R4, R8, R9, R10, R11, R12and R13are as defined here.

In some embodiments of formula VI, X represents-NRa-.

In some embodiments of formula VI, X represents-O-.

In some embodiments of formula VI, X represents-CRbRc-.

In some embodiments of formula VI, X represents-C(O)-;

In some embodiments of formula VI, Y is-NRd-.

In some embodiments of formula VI, Y is-CReRf-.

In some embodiments of formula VI, Y is-O-.

In some embodiments of formula VI, R10, R11, R12and R13represent hydrogen.

In some embodiments of formula VI, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula VI, R3and R4represent water is od. In some embodiments of formula VI, R3and R4represent alkyl, preferably methyl.

In some embodiments of formula VI, one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula VI, where X represents a-NRa-, Rarepresents hydrogen. In other embodiments of formula VI, where X represents a-NRa-, Rarepresents alkyl, preferably methyl.

In some embodiments of formula VI, where X represents-CRbRc-, Rband Rcrepresent hydrogen.

In other embodiments of formula VI, where X represents-CRbRc-, Rband Rcrepresent alkyl, preferably methyl.

In still other embodiments of formula VI, where X represents-CRbRc-one of Rband Rcrepresents hydrogen and the other represents alkyl, preferably methyl.

In still other embodiments of formula VI, where X represents-CRbRc-one of Rband Rcrepresents alkyl, preferably methyl and the other represents hydroxy.

In other embodiments of formula VI, where X represents-CRbRc-, Rband Rctogether with the atom to which they are attached, is brisout three to six-membered cycle, which probably includes a heteroatom selected from O, N and S.

Preferably in such embodiments, Rband Rctogether with the atom to which they are attached, form a three - or four-membered carbocyclic ring.

In some embodiments of formula VI, R8represents hydrogen.

In some embodiments of formula VI, Y is-O-, t is set to 2 and u has a value of 2.

In some embodiments of formula VI, Y is-O-, t is 1 and u has a value of 2.

In some embodiments of formula VI, Y is-O-, t is 1 and u is 1.

In some embodiments of formula VI, Y is-O-, t is set to 2 and u has a value of 3.

In some embodiments of formula VI, Y is-O-, t is set to 2 and u has a value of 0.

In some embodiments of formula VI, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula VI, m has a value of 0.

In some embodiments of formula VI, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula VI, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

Some in the lewinian formula VI compounds according to the invention can be represented by formula VIa:

where m, s, t, u, X, R2, R3, R4, R8, R9, R10, R11, R12, R13and Raare as defined here.

In some embodiments of formula VIa Rarepresents hydrogen.

In some embodiments of formula VIa R8represents hydrogen.

In some embodiments of formula VIa R10, R11, R12and R13represent hydrogen.

In some embodiments of formula VIa m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula VIa t is 1 and u is 1.

In some embodiments of formula VIa t is 1 and u has a value of 2.

In some embodiments of formula VIa t has the value 2 and u has a value of 2.

In some embodiments of formula VIa t has the value 2 and u has a value of 3.

In some embodiments of formula VIa m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula VIa m has a value of 0.

In some embodiments of formula VIa m has a value of 1 and R2represents fluorine or chlorine.

In some embodiments of formula VIa m has the value 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolinone cyclic system.

In some of the which embodiments of formula VIa R 3and R4represent hydrogen.

In some embodiments of formula VIa R3and R4represent alkyl, preferably methyl.

In some embodiments of formula VIa one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula VI compounds according to the invention can be represented by formula VIb:

where m, s, t, u, R2, R3, R4, R8, R9, R10, R11, R12, R13, Rband Rcare as defined here.

In some embodiments of formula VIb Rband Rcrepresent hydrogen.

In some embodiments of formula Vb, Rband Rctogether form oxo.

In some embodiments of formula VIb R10, R11, R12and R13represent hydrogen.

In some embodiments of formula VIa R8represents hydrogen.

In some embodiments of formula VIb, m is 0 or 1 and s is 0, 1 or 2.

In some embodiments of formula VIb t is 1 and u is 1.

In some embodiments of formula VIb t is 1 and u has a value of 2.

In some embodiments of formula VIb t is set to 2 and u has a value of 2.

In some embodiments of formula VIb t has the value 2 and u has a value of 3.

In some embodiments of formula VIb, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula VIb, m is set to 0.

In some embodiments of formula VIb, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula VIb, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 dihydroindolone cyclic system.

In some embodiments of formula VIb R3and R4represent hydrogen.

In some embodiments of formula VIb R3and R4represent alkyl, preferably methyl.

In some embodiments of formula VIb one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of the compounds according to the invention can be represented by formula VII:

where:

Y is-N - or-CH -;

m, s, X, R2, R3, R4, R8and R9are as defined here.

In some embodiments of formula VII, X represents NH.

In some embodiments of formula VII, X represents CH2.

In some embodiments of formula VII, X is=O.

In some embodiments of formulas is VII m is 0 or 1 and R 2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula VII, m has a value of 0.

In some embodiments of formula VII, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula VII, m has a value of 2, and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formula VII, s is 0, 1 or 2 and R9represents halogeno.

In some embodiments of formula VII, R3and R4represent hydrogen.

In some embodiments of formula VII, R3and R4represent alkyl, preferably methyl.

In some embodiments of formula VII, one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula VII, Y is-N-. In some embodiments of formula VII, Y is-CH-.

In some embodiments of formula VII, the compounds according to the invention can be represented by the formula VIIa:

where:

Y is-N - or-CH -, and

m, s, R2, R3, R4, R8and R9are as defined here.

In some embodiments of formula VIIam is 0 or 1 and R 2represents halogen, preferably fluorine or chlorine.

In some embodiments of formulas VIIa m has a value of 0.

In some embodiments of formulas VIIa m has a value of 1 and R2represents fluorine or chlorine.

In some embodiments of formulas VIIa m has the value 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formulas VIIa s is 0, 1 or 2 and R9represents halogeno.

In some embodiments of formulas VIIa R8represents hydrogen.

In some embodiments of formulas VIIa R8represents methyl.

In some embodiments of formulas VIIa R3and R4represent hydrogen.

In some embodiments of formulas VIIa R3and R4represent alkyl, preferably methyl.

In some embodiments of formulas VIIa one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula VII, Y is-N-.

In some embodiments of formula VII, Y is-CH-.

In some embodiments of formula VII, the compounds according to the invention can be represented by formula VIIb:

where:

Y before the hat is-N - or-CH -, and m, s, R2, R3, R4, R8and R9are as defined here.

In some embodiments of formula VIIb, m is 0 or 1 and R2represents halogen, preferably fluorine or chlorine.

In some embodiments of formula VIIb, m is 0.

In some embodiments of formula VIIb, m is 1 and R2represents fluorine or chlorine.

In some embodiments of formula VIIb, m is set to 2 and each R2represents independently fluorine or chlorine in position 5 and 6 benzimidazolone or dihydroindolone cyclic system.

In some embodiments of formula VIIb s is 0, 1 or 2 and R9represents halogeno.

In some embodiments of formula VIIb R8represents hydrogen.

In some embodiments of formula VIIb R8represents methyl.

In some embodiments of formula VIIb R3and R4represent hydrogen.

In some embodiments of formula VIIb R3and R4represent alkyl, preferably methyl.

In some embodiments of formula VIIb one of R3and R4represents hydrogen and the other represents alkyl, preferably methyl.

In some embodiments of formula VII, Y is-N-.

In some embodiments of formula VII, Y is-CH.

When any one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, Ra, Rb, Rc, Rd, Re,

Rf, Rg, Rh, Ri, Rjand Rkhere is an alkyl or contains an alkyl group, such alkyl represents preferably lower alkyl, that is, With1-C6alkyl, and more preferably1-C4alkyl.

Given as examples of compounds according to this invention shown in Table 1 together with the melting temperature or the data of mass spectrometry M+N, and examples of the preparation (described below) for each connection. The melting temperature specified for the respective cleaners containing hydrochloride salts, if not marked otherwise.

Table 1
No.StructureName (Autonom)TPL °C/M+N
11-Benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he>300°C
2 1-Benzyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he253,5-254,8°C
31-Benzyl-3-methyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he203,8-205,1°C

No.StructureName (Autonom)TPL °C / M+N
44-(Azetidin-3-ylethoxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he210,0 is 216.6°C
51-Benzyl-4-(3-dimethylamino-propoxy)-1,3-dihydro-benzimidazole-2-he186,5-189,5°C
61-Benzyl-4-(pyrrolidin-3-ylethoxy)-1,3-dihydro-benzimidazole-2-he226,0-228,9°C
71-B is nil-4-(piperidine-4-yloxy)-1,3-dihydro-benzimidazole-2-he 260,9-263,3°C
84-(Azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he181,0-184,0°C

No.StructureName (Autonom)TPL °C / M+N
9(R)-1-Benzyl-4-(pyrrolidin-2-ylethoxy)-1,3-dihydro-benzimidazole-2-he239,5-241,8°C
101-Benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-heto 284.6-285,9°C
111-Benzyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he241,0-242,3°C
121-(3-Fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he>300°C

No.StructureName (Autonom)TPL °C / M+N
131-(3-Fluoro-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione247,8-248,1°C
144-[1,4]Diazepan-1-yl-1-(3-fluoro-benzyl)-1H-indole-2,3-dione354
151-(3-Fluoro-benzyl)-3,3-dimethyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he354
161-(3-fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-indol-2-he213,2-213,9°C
171-(3-Fluoro-benzyl)-3-hydroxy-3-methyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he208,4-209,8°C

No.Structures the Name (Autonom)TPL °C / M+N
184-[1,4]Diazepan-1-yl-1-(3-fluoro-benzyl)-1,3-dihydro-indol-2-he178,3-181,5°C
191-(3-Fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-indol-2-heto 221.1-223,7°C
201-Benzyl-6-chloro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he188.0-190,1°C. (TFA salt)
211-Benzyl-6-fluoro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he316
221-(2-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he251,7-252,5°C

No.StructureThe UNESCO is (Autonom) TPL °C/M+N
231-(2-Chloro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he248,4-249,7°C
241-(3-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he219,9-br220.6°C
251-(3-Chloro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he213,8-214,5°C
261-(2,3-debtor-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he238,8-241,6°C
271-Benzyl-4-(2-methylamino-ethyl)-1,3-dihydro-benzimidazole-2-he282

No.StructureName (Autonom) TPL °C / M+N
281-Benzyl-6-fluoro-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he>300°C
291-(3-Fluoro-benzyl)-6-fluoro-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he>300°C
301-(4-Fluoro-benzyl)-6-fluoro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he271,3-271,9°C
311-(4-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he250,9-251,9°C
321-Benzyl-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-he256,9-257,3°C

No.StructureName (Autonom)TPL °C / M+N
331-Benzyl-6-fluoro-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-heof 267.8-269,9°C
341-(3-Fluoro-benzyl)-6-fluoro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he312
351-(3-Fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he>300°C
361-(3-Fluoro-benzyl)-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-he177,6-179,3°C
371-Benzyl-6-methyl-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he>300°C

No.StructureName (Autonom)TPL °C / M+N
38 1-(2,3-debtor-benzyl)-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-he238,0-240,8 "
391-(3-Fluoro-benzyl)-6-methyl-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he340
406-Fluoro-1-(3-fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he>300°C
41(S)-1-(1-Phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he323

No.StructureName (Autonom)TPL °C / M+N
42(R)-1-(1-Phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he323
437-Chloro-1-(3-fluoro-b is nil)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he 361
445-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he361
451-Benzyl-3-methyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he323

No.StructureName (Autonom)TPL °C/M+N
465,6-debtor-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he363
471-(1-Methyl-1-phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he337
481-[1-(3-Fluoro-phenyl)-ethyl]-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he341
491-(2,3-debtor-benzyl)-6-fluoro-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he363

No.StructureName (Autonom)TPL °C/M+N
506-Fluoro-1-(5-methyl-isoxazol-3-ylmethyl)-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-he331
511-(2,3-debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he345
526-Fluoro-1-(1-methyl-1-phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he355
531-(3-Fluoro-benzyl)-4-pyrrolidin-3-yl-1,3-dihydro-indol-2-he311

No.StructureName (Autonom)TPL °C / M+N
541-(2,3-debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione358
551-(2-Fluoro-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione232,1-234,3°C
561-(2,3-debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he>300°C
571-(3,4-debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione265,7-267,2°C

No.StructureName (Autonom)TPL °C / M+N
581-(3,5-debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione 270,3-273,0
591-(3,5-debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he>300°C
601-(3,4-debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he>300°C
611-(3-Chloro-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione249,1-251,7°C

No.StructureName (Autonom)TPL °C / M+N
621-(2,5-debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione227,9-230,1°C
631-(2-Fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he261,7-263,0°C
64 1-(3-Chloro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he276,1-277,0°C
655-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he360

No.StructureName (Autonom)TPL °C/M+N
667-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he273,4-275,0°C
675,7-dichloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he394

In another aspect of the present invention proposed a composition comprising a therapeutically effective amount of at least one of the compounds of formula I and a pharmaceutically acceptable carrier.

In another aspect according to the invention, a method for treating diseases of the Central nervous system (CNS) of a subject, wherein the subject BBO is Yat therapeutically effective amount of compounds of formula I. The disease may include, for example, psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, syndrome disorders of attention, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease.

In another aspect according to this invention a method of treatment of the disease zheludochno-intestinal tract of the subject, wherein the subject is administered a therapeutically effective amount of the compounds of formula (I).

In another aspect of the invention, a method for obtaining compounds of formula (I).

Synthesis

Compounds according to this invention can be obtained by different methods depicted in the illustrative schemes reactions of synthesis, shown and described below.

Source materials and reagents used to obtain these compounds, in General or are commercially available, for example, from vendors such as Aldrich Chemical Co., or are obtained using methods known to experts in this field, following the procedures set forth in such sources as Fieser & Fieser''s Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Road's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 with additions; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following scheme of reactions of synthesis are only illustrative of some methods by which the s can be synthesized compounds according to the invention, and in respect of these schemes reactions of synthesis can be made of various modifications, which the specialist can offer, taking into account the description of the invention.

Source materials and intermediate compounds in the schemes of synthesis reactions can be isolated and purified if desired using conventional techniques, including, but neornithes them: filtration, distillation, crystallization, chromatography and the like, Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless otherwise specified herein described reaction is preferably carried out in an inert atmosphere at atmospheric pressure and the reaction temperature from about

-78°C to about 150°C., more preferably from about 0°to about 125°C., and most preferably and conveniently at about room temperature (or ambient temperature), for example about 20°C.

In scheme a below illustrates one method of synthesis, suitable for producing compounds according to the invention, where m, n, p, Y, R2, R3, R4, R6, R7and R8are as defined here. Numerous ways of synthesis, leading to benzimidazolone, and they can be used to obtain the desired compounds, the technique with the Scheme And is provided only as an example. oncrete examples of implementation techniques in the Diagram And described below in the "Examples"section.

SCHEME AND

In stage 1 Scheme And deformirovanie and treated with the amine b with connection C. In this reaction, Y can be O or NRd. The reaction of stage 1 can be performed in the presence of potassium carbonate or other weak base in a polar solvent. When one of R7and R8or they both represent hydrogen, you can use an appropriate strategy to protect/unprotect the amino group, followed by removing the protecting after stage 4 below. The group of fluorine in the compound and may in some embodiments be replaced by other leaving groups.

In stage 2, the reaction aralkylamines carried out by treating compound with aralkylamines d with obtaining aralkylamines E. Ar can be aryl or heteroaryl, as noted above. In many embodiments, the compound d may be benzylamino. This reaction can also be carried out in the presence of potassium carbonate or similar soft base in a polar solvent.

The restoration carried out in stage 3, to restore the nitro-group of compounds e and to obtain the aniline f. At this stage, can be used mild reducing agent, such as dithionite sodium, proton polar solvent.

In stage 4 the crystallization is carried out by treating the aniline is connected to the I f with phosgene or an equivalent of phosgene with getting benzimidazolone q. Benzimidazolinone connection q is a compound of formula I according to the invention.

There are many variations of the methods proposed in the Scheme And that are easily understood by a specialist. In one such variation, the compound b can for simplicity be replaced by the connection of the formula HY-PG, where PG is a protective group. After the completion of stage 4 saitou group you can delete and enter groupby alkylation. In another embodiment, it is possible to carry out the additional step of alkylation for doing alkyl group in position 3 of compound q. When one of R7and R8represents hydrogen, a subsequent stage of the alkylation can be carried out for the introduction of alkyl instead of R7and R8.

In scheme B below offered another way of synthesis of compounds according to the invention, where m, n, p, Y, R2, R3, R4, R6, R7and R8are as defined here.

SCHEME B

In stage 1 scheme B indole h is subjected to N-alkylation by reacting with an alkylating agent i with producing 1-substituted indelaware connection i. At the stage 2 compound i is treated with the amine b with connection with. the Group X can represent O or NRdas outlined above. The presence of potassium carbonate or other weak is the first base in a polar solvent can facilitate the reaction in stage 2. When one of R7and R8or they both represent hydrogen, you can use an appropriate strategy to protect/unprotect the amino group, followed by removing the protection.

At stage 3 of indole k are bromirovanii by treatment with N-bromosuccinimide or other source of bromine (not shown) to obtain 3-bromoindole I. Bromoindole I then subjected to oxidation in stage 4 with obtaining dihydroindolone m. The connection m is a compound of formula I according to the invention.

Diagram illustrates a method of obtaining compounds of formula I, where R1represents pyrrolidinyl group. The diagram In L is a leaving group such as bromine or other halogen, and the variables m, n, X, R2, R3, R4, R6, R7, R8, R10and R11are as defined here.

SCHEMA

In stage 1 of the Scheme In connection n is subjected to interaction with petrovanovoy acid on obtaining pyrrolyl-substituted compounds p. Connection p then hydronaut to obtain pyrrolidinyl-substituted compounds g. Compound g is a compound of formula I according to the invention. In embodiments, where R8represents hydrogen, in the method of Scheme b may be used appropriate methods of protection and unprotect.

Over continue details of preparing compounds of formula I described in the "Examples" section below.

Applicability

Compounds according to the invention have a selective affinity (affinity) to the receptors 5-HT, including receptor 5-HT6, 5-HT2Aor both of the receptor, and expect that as such they are useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, eating disorders such as anorexia, bulimia and obesity, panic attacks, akathisia, syndrome disorders of attention hyperactivity disorder (ADHD)syndrome disorders (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Also expect that such compounds will be useful in the treatment of some LCD (gastrointestinal) disorders such as functional disorder of the bowel and irritable bowel syndrome.

Testing

The pharmacology of the compounds of this invention were determined using methods known in the art. Methods in vitro to determine the affinity of the test compounds to the receptor the 5-NT and the receptor 5-NTA in the analysis of the binding of radioactive ligand and functional analyses described below.

Introduction and Pharmaceutical compositions

The present invention includes pharmaceutical compositions containing at least one compound of the present invention, or individual isomers, racemic or not racemic mixture of isomers, or pharmaceutically acceptable salt or MES together with at least one pharmaceutically acceptable carrier and, possibly, other therapeutic and/or prophylactic ingredients.

As a rule, the compounds of the present invention is administered in therapeutically effective amounts via any of the accepted modes of introduction for agents that serve similar applications. Suitable dosage intervals are typically 1-500 mg, preferably 1-100 mg per day and most preferably 1-30 mg / day, depending on various factors such as the severity of the disease to be treated, the age and relative health of the subject, the effectiveness of the connection path and form of administration, indication, which is the introduction, as well as the preferences and experience of the attending physician. Ordinary specialist in the field of treatment of such diseases will be able without undue experimentation, relying on their own knowledge and description of the present invention, to establish a therapeutically effective the th number of compounds of the present invention for this disease.

As a rule, the compounds of the present invention will be introduced in the form of pharmaceutical preparations, including suitable for oral (including transbukkalno and sublingual), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred method of administration is generally oral with common mode daily dosage, which can be adjusted according to the degree of destruction.

The compound or compounds of the present invention together with one or more conventional adjuvant, carrier or diluent may be put into the form of pharmaceutical compositions and standard dosage forms. Pharmaceutical compositions and standard dosage forms may comprise conventional ingredients in conventional proportions, with an additional active compounds or substances, or without them, and a standard dosage forms may contain any suitable effective amount of the active ingredient, is proportional to the intended interval daily dosage, which should be applied. The pharmaceutical composition can be used is in the form of solids, such as tablets or filled capsules, semi-solid substances, powders, sustained release formulations release or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Drugs, containing approximately one (1) milligram of active ingredient or, more broadly, from about 0.01 to about one hundred (100) milligrams per tablet, are accordingly suitable representative standard dosage forms.

Compounds of the present invention can be included in the preparations in a wide variety of dosage forms for oral administration. Pharmaceutical compositions and dosage forms may contain a compound or compounds of the present invention, or their pharmaceutically acceptable salts as the active ingredient. Pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid dosage forms include powders, tablets, pills, capsules, starch wafers, suppositories, and dispersible granules. A solid carrier can be one or more than one substance, which may also act as a diluent, origimage agent, a solubilizer, a lubricating agent, a suspending agent, a coupling agent, preservative, raising agent for tablets or encapsulating material. In powders, the carrier is, as a rule, finely powdered solid substance which is a mixture with finely ground active ingredient. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and pressed to the desired shape and size. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compounds. Suitable carrier materials include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. The term "drug" shall include the preparation of the active compound with encapsulating material as a carrier, forming a capsule in which the active ingredient with the carrier or without carriers, is surrounded by carrier, which is in conjunction with him. In this way enabled starch wafers and cakes. Tablets, powders, capsules, pills, starch wafers and cakes can be used as solid forms suitable for p is moralnego introduction.

Other forms suitable for oral administration include liquid preparations of forms, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended for the rapid transformation before applying the medication liquid form. The emulsion can be prepared in solutions, for example aqueous solutions of propylene glycol, or they may contain emulsifying agents such as lecithin, servicemanual or Arabian gum. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing finely ground active component in water with viscous substance, such as natural or synthetic polymers, resins, methylcellulose, sodium carboxymethyl cellulose and other well-known suspendresume agents. Drugs liquid forms include solutions, suspensions and emulsions can contain, in addition to the active component, colorants, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

Preparations of the compounds of the present invention can be prepared for parenteral administration (e.g. the, by injection, for example bolus injection or continuous infusion)and may be presented in the form of a standard dose vials, prefilled syringes, infusion of a small volume or in containers of multiple doses with added preservative. These compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous media such as solutions in aqueous polyethylene glycol. Examples of oil or non-aqueous carriers, diluents, solvents or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and injectable organic esters (for example, etiloleat) and may contain agents for drugs, such as preserving, moisturizing, emulsifying or suspendida, stabilizing and/or dispersing agents. Alternative active ingredient may be in powder form, obtained by aseptic selection of sterile solid or by lyophilization from solution, for recovery before applying in a suitable solvent, such as sterile pyrogen-free water.

Preparations of the compounds of the present invention can be prepared for the local introduction of the epidermis as ointments, creams or lotions, or as a transdermal patch. Preparations in the form of ointments and cremo who can cook, for example, with an aqueous or oily base with the addition of suitable thickening and/or gelling agent. Preparations in the form of lotions can be prepared with water or oil based, and they will generally also contain one or more than one emulsifying agent, stabilizing agent, dispersing agent, suspendisse agent, thickening agent or coloring agent. Drugs suitable for local administration in the mouth include pellet containing the active agents in a corrective basis, usually sucrose and Arabian gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and Arabian gum; and gargle for mouth, containing the active ingredient in a suitable liquid carrier.

Preparations of the compounds of the present invention can be prepared for administration in the form of suppositories. Low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted and homogeneous dispersed active component, for example, by stirring. Then, this molten homogeneous mixture is poured into molds of suitable size, is allowed to cool and harden.

Preparations of the compounds of the present invention can be prepared for vaginal administration. Fit will be pessaries, tampons, creams, gels, pastes, foams or sprays, the content is the following in addition to the active ingredient such carriers, which are known in the art as suitable.

Preparations of the compounds of the present invention can be prepared for nasal administration. Solutions or suspensions contribute directly to the nasal cavity by conventional means, such as a dropper, pipette or spray. These drugs can be presented in the form of single or multiple doses. In the latter case, a dropper or pipette, this can be achieved by introducing the patient corresponding predetermined volume of solution or suspension. In the case of a spray, this may be achieved, for example, by means of measuring the spray.

Preparations of the compounds of the present invention can be prepared for aerosol administration, particularly in the respiratory tract and including intranasal administration. The connection should generally have a small particle size, for example of the order of five (5) microns or less. This particle size can be obtained by methods known in the art, for example by grinding in micron colloidal mill. The active ingredient is presented in a sealed container with a suitable propellant such as a chlorofluorocarbon (CFC), for example, DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, any carbon dioxide or other suitable gas. Aerosol can for Udo the STV also contain surfactant, such as lecithin. The dose can be adjusted using a measuring valve. Alternative active ingredients can be represented in the form of a dry powder, for example a powder mix of the compound in a suitable powder base, such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). This powdered media will form a gel in the nasal cavity. This powder composition may be presented in the form of a standard dose of, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder can be entered using the inhaler.

When desirable, the preparations can be prepared with intersolubility coatings adapted for the introduction of a prolonged or controlled release of the active ingredient. For example, the preparations of the compounds of the present invention can be prepared in devices for percutaneous or subcutaneous drug delivery. These delivery systems have the advantage when you need prolonged release the connection, and when the patient's compliance regime and regimen is a critical factor. Connection systems for percutaneous delivery is often attached to a solid carrier, adhesive to the skin. An interesting connection can is about to merge with the amplifier permeability, for example, Azone (1-dodecylsulfate-2-one). Delivery system, sustained release of injected under the skin in the subcutaneous layer by surgery or injections. Subcutaneous implants encapsulate the fat-soluble compound in the membrane, such as silicone rubber, or a biologically erodible polymer, such as polylactic acid.

The pharmaceutical preparations are preferably in a standard dosage forms. In such form the preparation is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Standard dosage form can be a very capsule, tablet, starch wafer or wafer, or it may represent the appropriate number of any of these in packaged form.

Other suitable pharmaceutically carriers and their preparations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E.W.Martin, Mack Publishing Company, 19thedition, Easton, Pennsylvania. Representative pharmaceutical preparations containing the compound of the present invention, described below in the Examples.

EXAMPLES

Following cooking iprimary given, to give the specialist in the art to more clearly understand and implement the invention. They should not be construed as limiting the scope of invention, but only as his illustration.

Example 1

1-Benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he

The synthesis procedure described in this example was carried out according to the method shown in the diagram,

SCHEME G

Stage 1

4-(3-fluoro-2-nitro-Phenyl)-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of piperazine-1-carboxylic acid tert-butyl ether (0,204 g, 1.1 mmol) in 1 ml of dimethyl sulfoxide was added potassium carbonate (0,303 g, 2.2 mmol), and then 1.3-debtor-2-nitro-benzene (strength of 0.159 g, 1 mmol). The solution was stirred for 30 min at room temperature, and then diluted with 50 ml of ethyl ether. The organic phase is washed three times with 50 ml of water and once with 50 ml brine, dried over sodium sulfate, and concentrated in vacuum to obtain 0,314 g (0,965 mmol, 96,5%) of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow oil. MS: 226 (M-BOC+H)+.

Stage 2

4-(3-Benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl methyl ether

4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ether (0,300 g, 0,923 mmol) and benzylamine (0,110 ml, 1,015 mmol) were combined in 1 ml of DMSO with potassium carbonate (0,318 g 2,308 mmol)and heated the reaction mixture to 120°C for 2 h, the Reaction mixture was poured into 100 g of a mixture of ice water and was extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed twice with 50 ml water, once with 50 ml brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified flash chromatography (1% to 15% ethyl acetate in hexano) obtaining 0,208 g (0.50 mmol, 54%) of 4-(3-benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: 413 (M+N)+.

Stage 3

4-(2-Amino-3-benzylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl methyl ether

A solution of 4-(3-benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ether (0,200 g, 0,485 mmol) in 5 ml of ethanol was added to a solution of dithionite sodium (0.565 g, 3,245 mmol) in 10 ml of water, and the reaction mixture was heated to 100°C. the Mixture was stirred for 5 min, cooled to room temperature, and concentrated in vacuo to remove ethanol. A yellow solid precipitated and was filtered and dried under vacuum for 18 h to obtain 0,173 g (0.45 mmol, 90%) of 4-(2-amino-3-benzylamino-phenyl)-piperazine-1-carboxylic KIS is the notes tert-butyl ether. MS: 383 (M+N)+.

Stage 4

4-(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-piperazine-1-carboxylic acid srat-butyl methyl ether

To a solution of 4-(2-amino-3-benzylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ether (0,176 g, 0,459 mmol) in 1 ml dichloromethane was added 1 ml of 2 M aqueous sodium carbonate. To stir the solution for five minutes dropwise added phosgene (0,261 ml of 1.93 M solution in toluene, 0,504 mmol). Stirring is continued for 2 hours, during which the formed fine white precipitate. The solid was filtered and dried under a stream of nitrogen to obtain 0,112 g of 4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in the form of a fine white powder. MS: 409 (M+N)+.

Stage 5

1-Benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-he

To a solution of 0,112 g of 4-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of ethyl acetate and 5 ml of ethanol was added 3 ml of 2 M ethanolic hydrogen chloride. The resulting solution was boiled under reflux for one hour, when it cools, the precipitated solid precipitate. The solid was filtered and dried overnight under vacuum to obtain 82 mg of the hydrochloride of 1-ensil-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it. MS: 309 (M+N)+.

Similarly, but using 1-methylpiperazine in stage 1 instead of piperazine-1-carboxylic acid tert-butyl ether, and lowering stage 5, was obtained 1-benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it. MS: 323 (M+N)+.

Example 2

4-(Azetidin-3-ylethoxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme D.

SCHEME D

Stage 1

1-Benzyloxy-3-fluoro-2-nitro-benzene

To a suspension of sodium hydride (1,522 g, 38,06 mmol) in anhydrous DMF (150 ml) at room temperature dropwise over 10 min was added benzyl alcohol (3,44 ml, 33.3 mmol) and stirring continued for a further 10 minutes To the reaction mixture in one portion was added 2,6-diplomarbeit (5,046 g, 31,72 mmol). The reaction mixture was stirred for one hour and was added 100 ml of water and 100 ml of ethyl acetate. The layers were separated and the aqueous layer was extracted with 75 ml of ethyl acetate. The combined organic layers were washed with 100 ml water and 100 ml of brine, dried over sodium sulfate and concentrated in vacuum. The obtained residue was purified flash chromatography (from 6% to 35% ethyl acetate in hexano) obtaining 6,818 g (27.6 mmol, 87%) of 1-benzyloxy-3-fluoro-2-nitro-benzene in the IDA yellow oil. MS: 248 (M+N)+.

Similarly, using (2-hydroxy-ethyl)-methyl-carbamino acid tert-butyl ester instead of benzyl alcohol was obtained [2-(3-fluoro-2-nitro-phenoxy)-ethyl]-methyl-carbamino acid tert-butyl ether. MS: 215(M-BOC+H)+.

Stage 2

Benzyl-(3-benzyloxy-2-nitro-phenyl)-amine

Potassium carbonate (5,71 g, up 41.4 mmol) was added to a solution of 1-benzyloxy-3-fluoro-2-nitro-benzene (6,818 g, 27.6 mmol) and benzylamine (3,32 ml, 30,34 mmol) in tetrahydrofuran, and the resulting suspension was heated to 110°C for 2 hours After cooling to room temperature the mixture was poured into a mixture of 1 liter of ice water and was extracted twice with 150 ml of ethyl acetate and twice with 75 ml of dichloromethane. The combined organic fractions were dried over sodium sulfate and concentrated in vacuum in the presence of 25 g of silica gel. Pre-loaded silica gel was subjected to flash chromatography (from 8% to 35% ethyl acetate in hexano) obtaining 8,118 g (24,28 mmol, 88%) of benzyl-(3-benzyloxy-2-nitro-phenyl)-amine as an orange solid. MS: 335 (M+N)+.

Similarly, starting from [2-(3-fluoro-2-nitro-phenoxy)-ethyl]-methyl-carbamino acid tert-butyl ester, was obtained [2-(3-Benzylamino-2-nitro-phenoxy)-ethyl]-methyl-carbamino acid tert-butyl ether. MS: 302 (M-BOC+H)+.

<> Stage 3

N*1*-Benzyl-3-benzyloxy-benzene-1,2-diamine

A solution of benzyl-(3-benzyloxy-2-nitro-phenyl)-amine (8,116 g, a 24.3 mmol) in 500 ml of ethanol was added to a solution of thiosulfate sodium (29.0 g, 162,8 mmol) in 350 ml of water at 100°C under stirring. The reaction mixture was heated for 30 min at this temperature and then cooled and concentrated in vacuum. Whitish solid matter deposited in the sediment, filtered and dried overnight under a stream of nitrogen to obtain 6,77 g (22,24 mmol, 91.5 per cent) N*1*-Benzyl-3-benzyloxy-benzene-1,2-diamine. MS: 305 (M+N)+.

Similarly, starting from [2-(3-benzylamino-2-nitro-phenoxy)-ethyl]-methyl-carbamino acid tert-butyl ester, was obtained [2-(2-amino-3-benzylamino-phenoxy)-ethyl]-methyl-carbamino acid tert-butyl ether. MS: 372 (M+N)+.

Stage 4

1-Benzyl-4-benzyloxy-1,3-dihydro-benzimidazole-2-he

To a solution of N*1*-benzyl-3-benzyloxy-benzene-1,2-diamine (4,60 g, 15,11 mmol) in 100 ml dichloromethane at 0°C was added triethylamine (4,201 ml, 30,22 mmol), after which the portions was added triphosgene (1,57 g of 5.29 mmol). The resulting solution was stirred for 2 h at 0°C. the Reaction mixture was allowed to warm to room temperature and then added to 200 ml of water. The organic phase was separated, washed with 100 ml of 10% aqueous HCl, 100 masimango aqueous sodium bicarbonate and 100 ml of salt solution, dried over sodium sulfate, and concentrated in vacuum to obtain 4,60 g (13,92 mmol, 92%) 1-benzyl-4-benzyloxy-1,3-dihydro-benzimidazole-2-it is in the form of a yellow-brown solid. MS: 331 (M+N)+.

Similarly, starting from [2-(2-amino-3-benzylamino-phenoxy)-ethyl]-methyl-carbamino acid tert-butyl ester, was obtained [2-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ether. MS: 398 (M+N)+.

Stage 5

1-Benzyl-4-hydroxy-1,3-dihydro-benzimidazole-2-he

To a solution of 1-benzyl-4-benzyloxy-1,3-dihydro-benzimidazole-2-it (0,875 g of 2.64 mmol) in 100 ml 1:1 ethyl acetate:THF was added palladium hydroxide (0,270 mg, 1,923 mmol). The reaction mixture was purged with gaseous hydrogen at 1 ATA, left mixed at room temperature for 2 h, and then filtered through celite. The filtrate was concentrated in vacuum to obtain 640 mg (2,64 mmol quantitatively) 1-benzyl-4-hydroxy-1,3-dihydro-benzimidazole-2-it is in the form of a white solid. MS: 241 (M+N)+.

Stage 6

3-(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-intoximeter)-azetidin-1-carboxylic acid tert-butyl methyl ether

To a solution of 1-benzyl-4-hydroxy-1,3-dihydro-benzimidazole-2-it (0,100 g, 0,417 mmol) and 3-hydroxymethyl-azetidine-1-carb is new acid tert-butyl ether (0,078 g, 0,417 mmol) in 0.5 ml anhydrous THF under nitrogen was added dropwise triphenylphosphine (0,109 g, 0,417 mmol) and diisopropylethylamine (0,082 ml, 0,417 mmol). The reaction mixture was stirred for 24 h, concentrated in vacuo and was purified preparative TLC (3% methanol in dichloromethane) to give 57 mg (0.14 mmol, 33.6%), and 3-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-intoximeter)-azetidin-1-carboxylic acid tert-butyl ester as a clear oil. MS: 410 (M+H)+.

Stage 7

4-(Azetidin-3-ylethoxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he

3-(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-intoximeter)-azetidin-1-carboxylic acid tert-butyl ether in the amount of 57 mg (0.14 mmol) was dissolved in 0.5 ml of ethanol and combined with 0.5 ml of 2 N. ethanolic hydrogen chloride and boiled under reflux for 30 minutes White solid, which precipitated upon cooling, was filtered and dried under vacuum for 18 h to obtain 23 mg of the hydrochloride of 4-(azetidin-3-ylethoxy)-1-benzyl-1,3-dihydro-benzimidazole-2-it is in the form of a white solid, TPL: 210,0 is 216.6°C. MS: 310 (M+N)+.

The following compounds were prepared similarly using the appropriate aminoplast or N-BOC protected amerosport:

1-Benzyl-4-(3-dimethylamino-propoxy)-1,3-dihydro-benzimidazole-2-it, TPL: 186,5189,5°C (HCl salt). MS: 326 (M+N)+;

1-Benzyl-4-(pyrrolidin-3-ylethoxy)-1,3-dihydro-benzimidazole-2-he (racemic), TPL: 226,0-228,9°C (HCl salt). MS: 324 (M+N)+;

1-Benzyl-4-(piperidine-4-yloxy)-1,3-dihydro-benzimidazole-2-it, TPL: 260,9-263,3°C (HCl salt). MS: 324 (M+N)+; and

(R)-1-Benzyl-4-(pyrrolidin-2-ylethoxy)-1,3-dihydro-benzimidazole-2-it, TPL: 239,5-241,8°C (HCl salt). MS: 324 (M+N)+.

Example 3

4-(Azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme E.

SCHEME E

Stage 1

4-(1-Benzhydryl-azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he

To a suspension of 1-benzyl-4-hydroxy-1,3-dihydro-benzimidazole-2-it (0.104 g g 0,433 mmol) and 1-benzhydryl-azetidin-3-ol (0,114 g, 0,477 mmol) in 0.5 ml anhydrous THF was added triphenylphosphine (0.125 g, 0,477 mmol) and diisopropylethylamine (0,093 ml, 0,477 mmol). The reaction mixture is boiled under reflux for 2 h, then concentrated in vacuo and was purified preparative TLC (2% methanol in dichloromethane) to give 78 mg (0,17 mmol, 39.5 per cent) of 4-(1-benzhydryl-azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-it is in the form of a yellow glass. MS: 462 (M+N)+.

Stage 2

4-(Azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he

4-(1-Benzhydryl-azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-he (78 mg, 0,17 mmol) was dissolved in 0.33 ml of dichloroethane and cooled to 0°C under nitrogen. Was added dropwise α-chloroethyl chloroformate (0,018 ml, 0,164 mmol)and the solution boiled under reflux for 2 h, concentrated in vacuo and dissolved in 20 ml of methanol. This solution was boiled under reflux for one hour, concentrated in vacuo and dissolved in 75 ml of dichloromethane, and the resulting solution was washed with 75 ml of 2 M aqueous potassium carbonate and 75 ml of water. The organic phase was dried over sodium sulfate, concentrated in vacuo, and purified flash chromatography (3% methanol in dichloromethane) to give 42 mg (0.14 mmol, 82%) of 4-(azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-it is in the form of a clear oil. MS: 296 (M+N)+. The corresponding hydrochloride salt obtained by recrystallization from EtOH/HCl, had a melting point 181,0-184,0°C.

Example 4

1-Benzyl-3-methyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme J.

SCHEME W

Stage 1

[2-(1-Benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl methyl ether

[2-(1-is ensil-2-oxo-2,3-dihydro-1H-benzimidazole-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ether, used in this example was prepared according to the method with stages 1-4 of Example 2, but replacing benzyl alcohol in stage 1 (2-hydroxy-ethyl)-methyl-carbamino acid tert-butyl ether.

To a solution of [2-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ether (0,100 g, 0,252 mmol) in 2 ml of anhydrous N,N-dimethylformamide was added sodium hydride (11 mg, 60%dispersion in mineral oil) under nitrogen. This suspension was stirred at room temperature for 10 min and then one portion was added methyliodide (0,018 ml, 0,277 mmol). Stirring was continued for one hour and the reaction mixture was added to 150 ml of water and was extracted twice with 75 ml of ethyl acetate. The combined organic fraction was washed with 100 ml of brine, dried over sodium sulfate and concentrated in vacuum. The residue was purified flash chromatography (from 18% to 28% ethyl acetate in hexane) to give 92 mg (0,223 mmol, 88,5%) [2-(1-benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ester as a clear oil. MS: 412(M+H)+.

Stage 2

1-Benzyl-3-methyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-he

[2-(1-Benzyl-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yloxy)-ethyl]-methyl-carbamino is islote tert-butyl ester (92 mg, 0,223 mmol) was dissolved in 1 ml of ethanol and combined with 0.5 ml of 2 N. ethanolic HCl, and the resulting solution was boiled under reflux for 30 minutes While cooling was observed a white precipitate. The solid is filtered and dried for 18 h under vacuum to obtain 47 mg of the hydrochloride of 1-benzyl-3-methyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it. TPL: 203,8-205,1°C. MS: 312 (M+N)+.

Similarly, according to the above procedure, but omitting the stage 1, was prepared 1-benzyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it. TPL: amounts to 188.7-191,3°C (HCl salt), MS: 298 (M+N)+.

Example 5

1-Benzyl-4-(2-methylamino-ethyl]-1,3-dihydro-benzimidazole-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme 3.

SCHEME 3

Stage 1

1-(2,2-dimethoxy-ethyl)-2,3-dinitro-benzene

To a solution of 2,3-dinitrotoluene (3,02 g of 16.6 mmol) in 25 ml DMF was added dimethylformamide, dimethylacetal (6,0 ml of 5.4 g, 45 mmol)and the solution was placed in a 140°C and was stirred for 16 hours the Solvent was removed under reduced pressure to obtain a dark red solid mass.

The crude enamine was dissolved in 40 ml Meon and was added to 4.0 ml of chlorotrimethylsilane (3.4 g, and 31.7 mmol). The solution was brought to boiling in the presence of a reverse refrigerator and premesis is whether for 16 h at boiling under reflux. The solvent was removed under reduced pressure, and the crude material was directly subjected to chromatography to obtain 1-(2,2-dimethoxy-ethyl)-2,3-dinitro-benzene (1.85 g, 44%).1H NMR (CDCl3) δ 2,96 (2H, d, J=5,2 Hz), the 3.35 (6H, s), of 4.49 (1H, t, J=5,2 Hz), 7,60 (apparent t, 1H, J=8,0 Hz), 7,76 (d, 1H, J=6,5 Hz), with 8.05 (dd, 1H, J=1,3, 8,0).

Stage 2

3-(2,2-dimethoxy-ethyl)-benzene-1,2-diamine

1-(2,2-dimethoxy-ethyl)-2,3-dinitro-benzene (1.85 g, 7.19 mmol) was dissolved in 20 ml Meon and added 90 mg of 10% by weight Pd/C. the Mixture was stirred for 1 at H2within 14 h at room temperature. The mixture was filtered through celite and purified chromatography to obtain 3-(2,2-dimethoxy-ethyl)-benzene-1,2-diamine (1.04 g, 73%).1H NMR (Dl3) δ 2,87 (2H, d, J=Hz 5,3), 3,37 (6H, s), 4,50 (1H, t, J=Hz 5,3), 7,60 (6,62-6,66, m, 3H).

Stage 3

4-{2,2-dimethoxy-ethyl)-1,3-dihydro-benzimidazole-2-he

3-(2,2-dimethoxy-ethyl)-benzene-1,2-diamine (1,03 g of 5.26 mmol) was dissolved in THF and added carbonyldiimidazole (935 mg, 5,77 mmol). The mixture was stirred at K.T. within 18 hours the Solvent was removed and the crude material was subjected to chromatography to obtain 4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzimidazole-2-it is in the form of a colorless solid (440 mg, 38%).1H NMR (CDCl3) δ 3,03 (2H, d, J=5,2 Hz), 3,40 (6H, s), 4,58 (1H, t, J=5,2 Hz), 6,86-6,89 (m, 1H), of 6.96-7,02 (m, 2H), 9,29 (br s, 1H), 10,28 (br s, 1H). MS: 221 (M-H)-.

Study the 4

1-Benzyl-4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzimidazole-2-he

4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzimidazole-2-he (435 mg, a 1.96 mmol) was dissolved together with benzylbromide (335 mg, a 1.96 mmol) in 10 ml of anhydrous DMF. Added tert-piperonyl potassium (1.0 M in THF, 2.2 ml, 2.2 mmol). The reaction mixture was stirred at room temperature for 90 min and then was divided between ether and water. The organic phase is washed with saline and dried over Na2SO4. After filtration and removal of solvent under reduced pressure the crude material was subjected to chromatography to obtain 1-benzyl-4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzimidazole-2-it (100 mg, 16%).1H NMR (CDCl3) δ of 3.00 (2H, d, J=5,0 Hz), 3,40 (6H, s). 4,55 (1H, t, J=5,0 Hz), 6.75 in (d, 1H, J=7.5 Hz), 6,84-to 6.95 (m, 2H), 7.23 percent-to 7.35 (m, 5H), 8.95 (br s, 1H).13C (CDCl3) δ 36,9, 44,9, 54,4, 105,6, 107,5, 118,8, 121,7, 124,0, 127,9, 128,0, 129,1, 129,2, 130,8, 136,7.

Stage 5

(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-acetaldehyde

(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-acetaldehyde (90 mg, 0.29 mmol) was dissolved in acetone and was added p-toluensulfonate acid (10 mg). The mixture was stirred for 2 h and then was divided between ethyl acetate and water. After washing with saturated sodium bicarbonate solution, water and brine the organic layer was dried over Na 2SO4filtered, and concentrated to obtain 1-benzyl-4-(2-hydroxy-ethyl)-1,3-dihydro-benzimidazole-2-she (80 mg, Quant.).1H NMR (CDCl3) δ a-3.84 (d, 2H, J=2,1 Hz), is 5.06 (s, 2H), 6,80-7,02 (M, 3H), 7,20-7,33 (m, 5H), 9,78 (t, 1H, J=2,0 Hz)and 10.7 (br s, 1H). MS: 265 (M-H)-.

Stage 6

1-Benzyl-4-[2-(benzyl-methyl-amino)-ethyl]-1,3-dihydro-benzimidazole-2-he

To a solution of 1-benzyl-4-(2-hydroxy-ethyl)-1,3-dihydro-benzimidazole-2-she (53 mg) and benzylmethylamine (29 mg) in 1.0 ml of methylene chloride was added borohydride triacetoxy sodium (51 mg). After 1 hour the reaction mixture was extinguished with water and separated with methylene chloride. The crude material was washed with saline, dried with sodium sulfate and concentrated to obtain 79 mg of 1-benzyl-4-[2-(benzyl-methyl-amino)-ethyl]-1,3-dihydro-benzimidazole-2-it. MS: 372 (M+N)-.

Stage 7

[2-(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-etil-methyl-carbamino acid tert-butyl methyl ether

1-Benzyl-4-[2-(benzyl-methyl-amino)-ethyl]-1,3-dihydro-benzimidazole-2-he (79 mg) was dissolved in 3 ml of 1:1 mixture of tetrahydrofuran and ethanol and then added Pd(OH)2. The mixture was shook at 45 psi (about 310 kPa, or 3 at) H2within 24 h before to filter the catalyst and to remove the solvent. The crude material pererestorani in 2 ml of tetrahydrofuran was added di-the pet-butylboronic (131 mg). After 16 h the reaction mixture was directly purified chromatographically to obtain 31 mg of [2-(1-benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-ethyl]-methyl-carbamino acid tert-butyl ester, MS: 382 (M+N)-.

Stage 8

1-Benzyl-4-(2-methylamino-ethyl)-1,3-dihydro-benzimidazole-2-he

[2-(1-Benzyl-2-oxo-2,3-dihydro-1H-benzimidazole-4-yl)-ethyl]-methyl-carbamino acid tert-butyl ester (31 mg) was dissolved in 2.0 ml of tetrahydrofuran was added 100 μl of 2.0 N. HCl/EtOH. The solution was heated on the steam bath for 30 min and then cooling slowly added diethyl ether to obtain 10 mg of the hydrochloride of 1-benzyl-4-(2-methylamino-ethyl)-1,3-dihydro-benzimidazole-2-it is in the form unpainted powder. MS: 282 (M+N)-.

Example 6

1-(3-Fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme I.

SCHEME AND

Stage 1

4-Bromo-1-(3-Fluoro-benzyl)-1H-indole

A solution of 4-bromoindole (3,91 g) in 25 ml tO was mixed with KOH (924 mg) for one hour. The solvent was removed under reduced pressure and was replaced by 75 ml of acetone. To this solution was added 3-ftorangidridy, and the mixture was stirred at room temperature for 30 min, and then the asili water. Added ethyl acetate, and the layers were separated. After drying with sodium sulfate the organic phase was concentrated and 4-bromo-1-(3-fluoro-benzyl)-1H-indole (4.12 g) was isolated by column chromatography. MS: 305 (M+N)+.

Stage 2

4-[1-(3-Fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 4-bromo-1-(3-fluoro-benzyl)-1H-indole (750 mg, 25 mmol) in tert-butanol was added BOC-piperidine (470 mg, 26 mmol), DICYCLOHEXYL-(2',4',6'-triisopropyl-biphenyl-2-yl)-Foshan (60 mg), potassium carbonate (862 mg) and Tris(dibenzylideneacetone)dipalladium (23 mg). The mixture was heated with delegacia and was stirred for 14 h, the Reaction mixture was cooled and extinguished by adding water, and the resulting mixture was extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude material was purified column chromatography to obtain 510 mg of 4-[1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: 410 (M+N)+.

Stage 3

4-[3-Bromo-1-(3-fluoro-benzyl)-1H-indol-4-yl-piperazine-1-carboxylic acid tert-butyl methyl ether

To a solution of 4-[1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (360 mg) in 5 ml of CH2Cl2at 0°C N-bromosuccinimide (160 mg). After 30 min was added water and the layers were separated. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified column chromatography to obtain 4-[3-bromo-1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. 263 mg. MS: 488, 490 (M+N)+; 510, 512 (M+Na).

Stage 4

4-[1-(3-Fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

4-[3-Bromo-1-(3-fluoro-benzyl)-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (273 mg) was dissolved in 3 ml of 2-methoxyethanol and added 85%phosphoric acid (575 ml). The dark solution was heated to 140°C and was stirred for 16 hours the next day, the mixture was made basic with the help of 1.0 N. NaOH was added Et2O. the Organic layer was separated, washed with brine and dried over sodium sulfate. After filtration and removal of solvent the crude material was collected in 3 ml THF was added di-tert-BUTYLCARBAMATE (218 mg). The mixture was stirred for 24 h at room temperature, after which the mixture was fractionally between water and ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified column chromatography with the teachings 115 mg of 4-[1-(3-fluoro-benzyl)-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS: 326 (M-BOC+H)+.

Stage 5

1-(3-Fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-he

4-[1-(3-Fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (115 mg) was dissolved in 2 ml tO and added 500 μl of 2.0 N. HCl/EtOH. The solution was heated with delegacia on the steam bath for 30 min and then cooled to room temperature. Was slowly added diethyl ether to knocked out of the hydrochloride of 1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it. MS: 326 (M+N)+.

Example 7

1-(3-Fluoro-benzyl)-3,3-dimethyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme K.

SCHEME TO

Stage 1

4-[1-(3-Fluoro-benzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

4-[1-(3-Fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (350 mg) was dissolved in 4 ml DMF was added 60%NaH (60 mg). After stirring for 30 min was added methyliodide (1.0 ml), the reaction vessel was closed tightly and the mixture was left to mix for 16 h at room temperature. The reaction is extinguished by water was added ethyl acetate. The layers were separated, and the organization is practical phase was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography to obtain 300 mg of 4-[1-(3-fluoro-benzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester, MS: 454 (M+N)+.

Stage 2

1-(3-Fluoro-benzyl)-3,3-dimethyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he

4-[1-(3-Fluoro-benzyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (260 mg) was dissolved in 3 ml tO and added 0.5 ml of 2.0 N. HCl/EtOH. After heating for 30 min with delegacia, the solution was cooled and was added diethyl ether to precipitate 1-(3-fluoro-benzyl)-3,3-dimethyl-4-piperazine-1-yl-1,3-dihydro-indol-2-hydrochloride (121 mg). MS: 354 (M+N)+.

Example 8

1-(3-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-indol-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme L.

SCHEME L

Stage 1

[2-(1H-Indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl methyl ether

To a cooled (0°C.) solution of 4-hydroxyindole (2,92 g) and (2-hydroxy-ethyl)-methyl-carbamino acid tert-butyl ester (3.50 g) in 100 ml THF was added h3(5.8 g), and then dropwise within 10 min was added diisopropylcarbodiimide (4.44 g). After 16 h the reaction mixture was processed as usual and the crude oil was purified chromatographically to obtain 4.1 g of [2-(1H-indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ester. MS: 313 (M+Na)+.

Stage 2

{2-[1-(3-Fluoro-benzyl)-1H-indol-4-yloxy]-ethyl}-methyl-carbamino acid tert-butyl methyl ether

[2-(1H-Indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ester was treated with NaOH/EtOH, and then added 3-florantyrone, as described above in Stage 1 of Example 5, to obtain {2-[1-(3-fluoro-benzyl)-1 H-indol-4-yloxy]-ethyl}-methyl-carbamino acid tert-butyl ester. MS: 299 (M-BOC+H)+.

Stage 3

[2-(1-Benzyl-3-bromo-1H-indol-4-yloxy)-ethyl}-methyl-carbamino acid tert-butyl methyl ether

{2-[1-(3-Fluoro-benzyl)-1H-indol-4-yloxy]-ethyl}-methyl-carbamino acid tert-butyl ester was treated with N-bromosuccinimide using the method from step 3 of Example 6 to obtain [2-(1-benzyl-3-bromo-1H-indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ether.

Stage 4

[2-(1-Benzyl-2-oxo-2,3-dihydro-1H-indol-4-yloxy)-etil-methyl-carbamino acid tert-butyl methyl ether

[2-(1-Benzyl-3-bromo-1H-indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ester was treated with phosphoric acid using the procedure from step 4 PR is a measure 6 to obtain [2-(1-benzyl-2-oxo-2,3-dihydro-1H-indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ether.

Stage 5

1-Benzyl-4-(2-methylamino-ethoxy)-1,3-dihydro-indol-2-he

With (1-benzyl-2-oxo-2,3-dihydro-1 H-indol-4-yloxy)-ethyl]-methyl-carbamino acid tert-butyl ester was removed protection using the procedure from step 5 of Example 6 to obtain 1-benzyl-4-(2-methylamino-ethoxy)-1,3-dihydro-indol-2-it, MS: 297 (M+N)+.

Example 9

1-(3-Fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-indol-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme M

SCHEME M

Stage 1

4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione

4-Bromo-1H-indole-2,3-dione (6,38 g) was dissolved in 100 ml of DMF and, at 0°C, and the portions was added 60%NaH (1,32 g). The mixture was stirred for 20 min, and then added 3-florantyrone. The solution was stirred for approximately 30 min, extinguished with water, and was fractionally between water and diethyl ether. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to get 9,18 g of 4-bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione, which was sufficiently pure for use in the next stage 2. MS: 385 (M+N)+.

Stage 2

4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl methyl ether

4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione (167 mg) was dissolved in 2.5 ml of dioxane was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (154 mg), and then the complex [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) with dichloromethane (1:1) (24 mg) and2CO3(138 mg). The reaction mixture was heated up to 80°C for 18 h and then cooled and concentrated under reduced pressure. The obtained residue was purified chromatography to obtain 4-[1-(3-fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester. MS: 337 (M-BOC+H)+.

Stage 3

4-[1-(3-Fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperidine-1-carboxylic acid tert-butyl methyl ether

4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (930 mg) was dissolved in 17 ml of hydrazine and 17 ml of ethanol, and the solution was heated at 110°C for 16 hours the Reaction mixture was cooled and was fractionally between water and ethyl acetate, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified chromatographically to obtain 146 mg of 4-[1-(3-fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperidine-1-carboxylic acid tert-butyl ester. MS: 423 (M-N)- .

Stage 4

1-(3-Fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-indol-2-he

4-[1-(3-fluoro-benzyl)-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (146 mg) was shot protection, as described in stage 5 of Example 6, to obtain the hydrochloride of 1-(3-fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-indol-2-it is in the form of a white powder. MS: 325 (M+N)+.

Example 10

1-(3-Fluoro-benzyl)-3-hydroxy-3-methyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme N.

SCHEME N

Stage 1

4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

4-Bromo-1-(3-fluoro-benzyl)-1H-indole-2,3-dione (3,05 g) was dissolved in 45 ml of tert-butanol was added BOC-piperazine (2,04 g), PD2(db)3(164 mg), DICYCLOHEXYL-(2',4',6'-triisopropyl-biphenyl-2-yl)-Foshan (217 mg) and potassium carbonate (1.84 g). The mixture was stirred at 120°C for 4 h and then cooled to room temperature. The mixture was fractionally between ethyl acetate and water, and the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified chromatographically with the receipt of 1.80 g of 4-[1-(3-fluoro-benzyl)-2,3-dioxo-2,3-Digi the ro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: 340 (M-BOC+H)+.

Stage 2

4-[1-(3-Fluoro-benzyl)-3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl methyl ether

4-[1-(3-Fluoro-benzyl)-2,3-dioxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (330 mg) was dissolved in 4 ml of THF and cooled to -78°C before adding 1.6 M metallice in hexano (800 μl). The solution was stirred and was heated to room temperature, then was stirred for one hour at room temperature. The reaction was suppressed by addition of water and was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified column chromatography to obtain 315 mg of 4-[1-(3-fluoro-benzyl)-3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS: 356 (M-BOC+H)+.

Stage 3

1-(3-Fluoro-benzyl)-3-hydroxy-3-methyl-4-piperazine-1-yl-1,3-dihydro-indol-2-he

4-[1-(3-fluoro-benzyl)-3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-4-yl]-piperazine-1-carboxylic acid tert-butyl ester was removed protection as described for stage 5 of Example 1, to obtain 1-(3-fluoro-benzyl)-3-hydroxy-3-methyl-4-piperazine-1-yl-1,3-dihydro-indol-2-she (201 mg). MS: 356 (M+N)+.

Example 11

1-Benzyl-4-PI is Raiden-3-yl-1,3-dihydro-benzimidazole-2-he

The synthesis procedure described in this example was carried out according to the method shown in scheme O.

SCHEME ABOUT

Stage 1

1-Bromo-3-fluoro-2-nitro-benzene

To a suspension tetrahydrate sodium perborate (135,374 g, 886,4 mmol) in 500 ml of acetic acid at 55°C was added dropwise a solution of 2-bromo-6-fluoro-phenylamine (33,685 g, 177,271 mmol) in 70 ml of acetic acid for 1 hour. The reaction mixture was stirred at 55°C for additional 3 h, then was cooled to 0°C in an ice bath. Insoluble materials were removed by filtration through a plug of celite, which was washed with 100 ml of acetic acid. Combined fractions of acetic acid was added to 3 l of a mixture of ice water under stirring to obtain waxy solid, which was removed by filtration. The crude solid was dissolved in 250 ml ethyl acetate, washed three times with 200 ml of 10%aqueous hydrogen chloride, 200 ml of saturated sodium bicarbonate and 100 ml of saline solution. The solution was concentrated in vacuum to obtain 11,51 g of 1-bromo-3-fluoro-2-nitro-benzene in the form of a red oil,1H NMR (CDCl3, 300 MHz) δ: 7,26 (m, 1H), 7,38 (m, 1H), 7,49 (m, 1H)

Stage 2

Benzyl-(3-bromo-2-nitro-phenyl)-amine

Potassium carbonate (2.58 g, 18,73 mmol) was added to a solution of 1-br is m-3-fluoro-2-nitro-benzene (of 2.06 g, 9,36 mmol) and benzylamine (1.13 ml, 9,364 mmol)and the resulting suspension was stirred at room temperature for 18 hours the Reaction mixture was poured into 500 ml of a mixture of ice water and was extracted four times with 100 ml of ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated in vacuum to obtain an oil, which was purified by recrystallization from 75 ml heated with delegacia ethanol with 3 ml of water. Filtering gathered to 1.83 g of benzyl-(3-bromo-2-nitro-phenyl)-amine in the form of a thin red needle-shaped crystals. MS: 308, 309 (M+N)+.

Stage 3

N-1-Benzyl-3-bromo-benzene-1,2-diamine

A solution of benzyl-(3-bromo-2-nitro-phenyl)-amine (0,503 g 1,638 mmol) in 35 ml of ethanol was added to a solution of thiosulfate sodium (1,91 g, 10,97 mmol) in 50 ml of water at 100°C under stirring. The reaction mixture was heated for 30 min at this temperature, and then concentrated in vacuo to remove ethanol. Oil, which was formed in the resulting aqueous solution was extracted twice with 100 ml dichloromethane. The combined organic fractions were dried over sodium sulfate, and then purified flash chromatography (gradient from 2 to 10% ethyl acetate in hexano) obtaining 0,327 g N-1-benzyl-3-bromo-benzene-1,2-diamine as a red oil. MS: 278, 279 (M+N)+.

Stage 4

3-Benzyl-bromo-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl methyl ether

A solution of N-benzyl-3-bromo-benzene-1,2-diamine (0,483 g 1,742 mmol) in 20 ml dichloromethane was cooled to 0°C under nitrogen. Was added di-tert-BUTYLCARBAMATE (1,899 g 8,712 mmol)and then 4-dimethylaminopyridine (10 mg, 0,087 mmol)and the reaction mixture was stirred for one hour and allowed to warm to room temperature. The reaction mixture was concentrated in the presence of 0.5 g of silica gel, and subjected to flash chromatography (gradient from 1 to 10% ethyl acetate in hexano) obtaining 0,580 g 3-benzyl-7-bromo-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester as a white solid. MS: 304, 305 (M+N)+.

Stage 5

3-Benzyl-2-oxo-7-(1-triisopropylsilyl-1H-pyrrol-3-yl)-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl methyl ether

To 10 ml of a 9:1 mixture dimethoxyethane/water was added 3-benzyl-7-bromo-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ether (0,719 g 1,783 mmol), 3-bornyl-1-triisopropylsilyl-1H-pyrrole (0,476 g 1,783 mmol), the complex [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) with dichloromethane (1:1) (69,7 mg, 0,089 mmol) and cesium carbonate (0,697 g, 2,139 mmol). The resulting suspension was purged under vacuum with argon and was heated to 85°C for 1 hour. The reaction mixture was added to 100 ml of a mixture of 1:1 water/ethyl acetate and the organic layer from elali. The combined organic fractions were washed with 100 ml water and 100 ml of brine and dried over sodium sulfate. Concentration in vacuo gave a crude solid, which was purified flash chromatography (gradient from 0 to 10% ethyl acetate in hexano) obtaining 0,750 g 3-benzyl-2-oxo-7-(1-triisopropylsilyl-1H-pyrrol-3-yl)-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester as a white solid. MS: 446 (M-BOC+H)+.

Stage 6

3-Benzyl-7-(1-tert-butoxycarbonyl-1H-pyrrol-3-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid luet-butyl methyl ether

To a solution of 3-benzyl-2-oxo-7-(1-triisopropylsilyl-1H-pyrrol-3-yl)-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ether (0,768 g of 1.40 mmol) in 30 ml of 1,4-dioxane is added dropwise within 5 min was added tetrabutylammonium fluoride (1,548 ml of 1 M solution in tetrahydrofuran, 1,548 mmol). The reaction mixture was stirred for 45 min and then added to 200 ml of 1:1 mixture of water/ethyl acetate. The layers were separated and the aqueous layer was extracted twice with 100 ml of ethyl acetate. The combined organic fractions were dried over sodium sulfate and concentrated in vacuo, and purified flash chromatography (gradient from 20 to 40% ethyl acetate in hexano) obtaining 0,447 g of the crude 3-benzyl-2-oxo-7-(1H-Pirro is-3-yl)-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester. This material was dissolved in 7 ml of tetrahydrofuran and cooled to 0°C under nitrogen. To this solution was added di-tert-BUTYLCARBAMATE (0,752 g of 3.45 mmol) and 4-dimethylaminopyridine (14 mg, 0,115 mmol) and stirring was continued for one hour so that the reaction mixture was allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified flash chromatography (gradient from 1 to 10% ethyl acetate in hexano) obtaining 0,550 g 3-benzyl-7-(1-tert-butoxycarbonyl-1H-pyrrol-3-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester, MS: 490 (M+N)+.

Stage 7

3-Benzyl-7-(1-tert-butoxycarbonyl-pyrrolidin-3-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl methyl ether

In the vessel Parra, through which was passed a stream of nitrogen, was added 5%dispersion of platinum on coal (15 mg), and then a solution of 3-benzyl-7-(1-tert-butoxycarbonyl-1H-pyrrol-3-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ether (0,150 g, 0,307 mmol) in 10 ml of methanol. The vessel Parra under vacuum was purged with hydrogen at atmospheric pressure and was stirred for 95 hours, the Reaction mixture was then under vacuum was purged with nitrogen, filtered through a plug of celite to remove the catalyst and concentrated in vacuum. The obtained residue was purified flash XP is matography (gradient from 5% to 10% ethyl acetate in hexano) to obtain 80 mg of racemic 3-benzyl-7-(1-tert-butoxycarbonyl-pyrrolidin-3-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester in the form of a transparent oil. MS: 516 (M+Na)+.

Stage 8

1-Benzyl-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-he

A solution of 3-benzyl-7-(1-tert-butoxycarbonyl-pyrrolidin-3-yl)-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid tert-butyl ester (80 mg, 0,273 mmol) in 5 ml of ethanol was heated under reflux was added 2 N. ethanolic hydrogen chloride (0.5 ml). The reaction mixture is boiled under reflux for 45 min, then was slowly added ether (2 ml). The solid precipitate was formed upon cooling and was removed by filtration to obtain 40 mg of the hydrochloride of 1-benzyl-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-it is in the form of a yellow-brown solid. MS: 294 (M+N)+.

Example 12

Recipes

Pharmaceutical preparations for delivery in different ways is prepared, as shown in the Table below. "Active ingredient" or "active compound"as used in these Tables, means one or more than one compounds of formula I.

Composition for oral administration

Magnesium stearate
Ingredient% wt./wt.
The active ingredient20,0%
Lactose79,5%
0,5%

The ingredients are mixed and distributed in capsules containing approximately 100 mg each; one capsule would be close to the total daily dosage.

Composition for oral administration

Ingredient% wt./wt.
The active ingredient20,0%
Magnesium stearate0,5%
Nitrocresols2,0%
Lactose76,5%
PVP (polyvinylpyrrolidone)1,0%

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

Composition for oral administration

IngredientNumber
Active connection1.0 g
Fumaric acid is the 0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Corrigenta 0.035 ml
Dyes0.5 mg
Distilled waterq.s. to 100 ml

The ingredients are mixed before formation of a suspension for oral administration.

Parenteral drug

Ingredient% wt./wt.
The active ingredient0.25 g
Sodium chlorideq.s. to obtain isotonicity
Water for injection100 ml

Active ing event dissolved in parts of water for injection. Then add a sufficient quantity of sodium chloride under stirring, to make the solution isotonic. The weight of the solution, bring the remaining water for injection, filtered through a filter with a membrane of 0.2 μm and packaged under sterile conditions.

The drug is in the form of a suppository

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

The ingredients are melted together, mixed in a steam bath and poured into molds containing the total mass of 2.5,

Local drug

IngredientsGrams
Active connection0,2-2
Span 602
Tween 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Waterq.s. 100

All the ingredients except water are combined and heated to about 60°C under stirring. Then add a sufficient quantity of water at about 60°C With vigorous stirring to emulsify the ingredients, and then add water as needed (q.s.) approximately 100 g

Nasal spray drugs

Some water suspension containing approximately 0.025 to 0.5 percent of the active compounds are prepared in the form of nasal spray products. These drugs may contain inactive ingredients, such as, for example, microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, and the like. Hydrochloric acid can be added to regulate pH. Nasal spray drugs can be delivered via a volumetric pump for nasal aerosols, typically delivering 50-100 microliters of drug action. The typical dosage is 2-4 injection every 4 to 12 hours.

Example 13

Studies of the binding of radioactive ligand

This example illustrates the study the project for the binding of radioactive ligand in vitro compound of formula I.

Binding activity of compounds of this invention in vitro was determined as described below. Dual-determining affinity ligand 5-HT6conducted by competition for the binding of [3H]LSD in cell membranes isolated from cells NECK, stably expressing the recombinant human receptor 5-HT6. Dual-determining affinity ligand 5-HT2Aconducted by competition for the binding of [3H]ketanserina (3-(2-(4-(4-perbenzoic)piperidino)ethyl)-2,4(1H,3H)-chineselanguage) in cell membranes isolated from cells Cho-K1, stably expressing the recombinant human receptor 5-HT2A. Membrane preparations were prepared from cell lines of SOME 293 method described Monsma et al., Molecular Pharmacology, Vol.43 pp.320-327 (1993), and from cell lines Cho-K1, as described Bonhaus et al., Br J Pharmacol. Jun; 115 (4): 622-8 (1995).

To assess the affinity of the receptor 5-HT6all determinations were performed in the analytical buffer containing 50 mm Tris-HCl, 10 mm MgSO4, 0.5 mm EDTA, 1 mm ascorbic acid, pH 7.4, at 37°C in a reaction volume of 250 microliters. To assess the affinity of the receptor 5-HT2Aall determinations were performed in the analytical buffer containing 50 mm Tris-HCl, 5 mm ascorbic acid, 4 mm CaCl2, pH 7.4 at 32°C in a reaction volume of 250 microliters.

Analytical tubes containing [3H]LSD and [ H]ketanserin (5 nm), the competing ligand, and the membranes were incubated in a water bath with swing for 75 min at 37°C (for 5-HT6) or 60 min at 32°C (for 5-HT2A), was filtered on tablets Packard GF-B (pre-soaked with 0.3% PEI)using a 96-well harvester cells Packard, and washed 3 times in chilled ice 50 mm Tris-HCl. Associated [3H]LSD and [3H]ketanserin was defined as the number of radioactive counts per minute using a counter Packard TopCount.

The displacement of [3H]LSD and [3H]ketanserina of binding sites was quantified by subtracting the concentration data - link 4-parameter logistic equation:

where Hill is the hill coefficient, [ligand] is the concentration of competing radioactive ligand and IC50represents the concentration of radioactive ligand, producing premaxillae specific binding of the radioactive ligand. Window-specific binding is the difference between Umah and basal parameters.

Using the techniques of this Example, the compounds of formula I were tested and found that they are selective antagonists of 5-HT6selective antagonists of 5-HT2Aor by both. For example, the compound 1-(3,4-debtor be the ZIL)-4-piperazine-1-yl-1,3-dihydro-indol-2-he exhibited a pKi of approximately 9,48 for receptor 5-HT 2A.

The test results are shown in table 2.

Table 2
No.pKi 5-HT6No.pKi 5-HT6
109,4439,48
188,1458,73
208,57479,46
258,91538,3
299,38549,11
328,5764of 9.21
409,2668,59

Although the present invention is described with reference to specific embodiments, specialists in the art it should be clear that h is about can be made various changes, and equivalents may be substituted, without departing from the true nature and scope of the invention. In addition, can be done many modifications to adapt to the particular situation, the substance of a particular composition, method, stage or stages of the method in relation to the objective of the essence and scope of the present invention. It is implied that all such modifications are within the scope of the attached claims.

1. The compound of formula I:

or its pharmaceutically acceptable salt,
where m has a value from 0 to 2;
n has a value of 1;
X represents:
-NRa-;
-CRbRc-; or
-C(O)-;
where Rarepresents hydrogen or C1-6alkyl;
Rbrepresents hydrogen or C1-6alkyl;
Rcrepresents hydrogen, C1-6alkyl, hydroxy;
or
Ar represents:
phenyl, possibly substituted by 1-2 halogen; or
isoxazol possibly substituted C1-6by alkyl;
R1represents a group of the formula
p has a value from 1 to 3;
Y represents:
-O-;
-NRd-; or
-CReRf-;
where Rd, Reand Rfeach independently represents hydrogen or C1-6alkyl;
each R2represents independently:
halogeno; C1-6alkyl;
R3and R4each independently represents hydrogen or C1-6alkyl;
R5and R6each independently represents hydrogen; and
R7and R8each independently represents hydrogen or C1-6alkyl; or one of R7and R8and one of R5and R6together with the atoms to which they are attached, may form a four-to six-membered cycle; or one of R7and R8together with Rdand the atoms to which they are attached, may form a six-semicolony cycle; or
one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, may form a five or six-membered cycle.

2. The compound according to claim 1, where R3and R4represent hydrogen.

3. The compound according to claim 1, where AG represents a possibly substituted by 1-2 halogen phenyl.

4. The compound according to claim 1, where m is 0 or 1.

5. The compound according to claim 1, where p has a value of 2.

6. The compound according to claim 5, where Y represents-O-.

7. The connection according to claim 6, where one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four to six-membered cycle.

8. The compound according to claim 5, where Y is-NRd-.

9. The connection of claim 8, where one of R7and R8together with Rdand the atoms which they are attached, form a six-semicolony cycle.

10. The compound according to claim 2, where p has a value of 3.

11. The connection of claim 10, where Y represents-O-.

12. Connection claim 11, where one of R7and R8and one of R5and R6together with the atoms to which they are attached, form a four to six-membered cycle.

13. The compound according to claim 5, where Y represents-CReRf-.

14. The connection indicated in paragraph 13, where one of R7and R8and one of Reand Rftogether with the atoms to which they are attached, form a five or six-membered cycle.

15. The compound according to claim 1, where R1is pyrrolidinyl, piperazinil, piperidinyl, diazepines, piperidinyloxy or pyrrolidinyloxy.

16. The compound according to claim 1, where:
R1is:
;;;
;;;;
;;;or

R7, R8, R10, R11, R12and R13each independently represents hydrogen or C1-6alkyl.

17. Connection P16, where R10, R11, R12and R13represent hydrogen.

18. The compound according to claim 1, where the specified compound has the formula II:
;
where s has a value from 1 to 2;
each R9is an independent halogeno; and
m, p, X, Y, R2, R3, R4, R5, R6, R7and R8are as set forth in claim 1.

19. The compound according to claim 1, where the specified compound has the formula III:

where t and u each independently has a value from 1 to 3;
R10, R11, R12and R13each independently represents hydrogen or C1-6alkyl;
m, s, X, Y, R2, R3, R4, R8and R9are as set forth in p.

20. The compound according to claim 1, where the specified compound has the formula IV:

where p has a value of 2 or 3; and
m, s, X, Y, R2, R3, R4, R7, R8and R9are as set forth in p.

21. The compound according to claim 1, where the specified compound has the formula V:
;
where t and u each independently has a value from 1 to 3;
R10, R11, R12and R13each independently represents hydrogen or C1-6alkyl; and
m, s, X, Y, R2, R3, R4, R8and R9are as set forth in p.

22. The connection according to claim 19, where the aforementioned compound has the formula VI:
;
where t has a value from 1 to 3;
u has a value of from 0 to 3;
R10, R11, R12and R13each independently represents hydrogen or C1-6alkyl;and
m, s, X, Y, R2, R3, R4, R8and R9are as set forth in p.

23. The compound according to claim 1, where the specified connection is selected:
1-Benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-3-methyl-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
4-(Azetidin-3-ylethoxy)-1-benzyl-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-(3-dimethylamino-propoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-(pyrrolidin-3-ylethoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-(piperidine-4-yloxy)-1,3-dihydro-benzimidazole-2-it,
4-(Azetidin-3-yloxy)-1-benzyl-1,3-dihydro-benzimidazole-2-it,
(R)-1-Benzyl-4-(pyrrolidin-2-ylethoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3-fluoro-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione,
4-[1,4]Diazepan-1-yl-1-(3-fluoro-benzyl)-1H-indole-2,3-dione,
1-(3-Fluoro-benzyl)-3,3-dimethyl-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3-fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-indol-2-it,
1-(3-fluoro-benzyl)-3-hydroxy--methyl-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
4-[1,4]Diazepan-1-yl-1-(3-fluoro-benzyl)-1,3-dihydro-indol-2-it,
1-(3-Fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-indol-2-it,
1-Benzyl-6-chloro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-6-fluoro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(2-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(2-Chloro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(3-Chloro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(2,3-debtor-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-(2-methylamino-ethyl)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-6-fluoro-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-6-fluoro-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-(4-Fluoro-benzyl)-6-fluoro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(4-Fluoro-benzyl)-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-6-fluoro-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-6-fluoro-4-(2-methylamino-ethoxy)-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-6-methyl-4-piperidine-4-yl-1,3-dihydro-benzimidazole--she,
1-(2,3-debtor-benzyl)-4-pyrrolidin-3-yl-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-6-methyl-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-it,
6-Fluoro-1-(3-fluoro-benzyl)-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-it,
(S)-1-(1-Phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
(R)-1-(1-Phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
7-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
5-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-Benzyl-3-methyl-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
5,6-Debtor-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-(1-Methyl-1-phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-[1-(3-Fluoro-phenyl)-ethyl]-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-(2,3-Debtor-benzyl)-6-fluoro-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
6-Fluoro-1-(5-methyl-isoxazol-3-ylmethyl)-4-piperidine-4-yl-1,3-dihydro-benzimidazole-2-it,
1-(2,3-Debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
6-Fluoro-1-(1-methyl-1-phenyl-ethyl)-4-piperazine-1-yl-1,3-dihydro-benzimidazole-2-it,
1-(3-Fluoro-benzyl)-4-pyrrolidin-3-yl-1,3-dihydro-indol-2-it,
1-(2,3-Debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione,
1-(2-Fluoro-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione,
1-(2,3-Debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3,4-Debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione,
1-(3,5-Debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3,4-Debtor-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3-Chloro-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione,
1-(2,5-Debtor-benzyl)-4-piperazine-1-yl-1H-indole-2,3-dione,
1-(2-Fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
1-(3-Chloro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
5-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it,
7-Chloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it
5,7-Dichloro-1-(3-fluoro-benzyl)-4-piperazine-1-yl-1,3-dihydro-indol-2-it.

24. The compound of formula I-VI according to any one of claims 1 to 23, with activity selective receptor antagonist 5-HT6and(or) 6-HT2Aand its pharmaceutically acceptable salts for use in the treatment or prevention of the relevant diseases.

25. Pharmaceutical composition having activity of selective receptor antagonist 5-HT6and / or 5-HT2Acontaining the compound according to any one of claims 1 to 23 in a mixture with a pharmaceutically acceptable carrier.

26. The use of the compounds of formula I-VI according to any one of claims 1 to 23, as well as its pharmaceutically acceptable salts for the manufacture of drugs for the treatment of diseases of the Central nervous system.

27. Use p, where disease of the Central nervous system selected from the group consisting of psychoses, schizophrenia, mania the social depression, neurological disorders, memory disorders, syndrome disorders of attention, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, disorders associated with eating, and Huntington's disease.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel substituted imidazole compounds of formula I where values of radicals are given in description, as well as to their based on them pharmaceutical compositions.

EFFECT: formula I compounds, as well as their salts, esters and compositions based on them possess ability to inhibit protein of kinesin spindle (KSP) and can be used for treatment of cancer diseases.

40 cl, 15 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) where: R1 denotes C1-C10alkyl, C3-C10cycloalkyl; R3 denotes H, halide; R4 denotes a 6-member monocyclic heteroaryl containing 1-2 nitrogen atoms, one of which can be oxidised, optionally substituted with a halide; n ranges from 0 to 3; provided that R1 denotes C3-C10cycloalkyl and/or R4 denotes a 6-member monocyclic heteroaryl optionally substituted with a halide and containing 2 ring N heteroatoms, one of which can be oxidised or pharmaceutically acceptable salt thereof.

EFFECT: obtaining peptidyl deformylase (PDF) inhibiting compounds.

12 cl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of general formula (I-B), where values of radicals are described in formula of invention, or to its pharmaceutically acceptable salts, which possess activity of inhibiting cholesterol ester transfer protein, due to which said compounds or salts can be used for prevention and/or treatment of arteriosclerotic diseases, hyperlipemia or dislipidemia or similar diseases.

EFFECT: obtaining pharmaceutical compositions for prevention and treatment of arteriosclerosis, as well as application of formula I-B compounds for manufacturing of medication.

15 cl, 36 tbl, 252 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolidinium derivatives of formula I

in enantiomer form or pharmaceutically acceptable salt thereof, where R1 and R3 each independently denotes cyclopentyl, cyclohexyl, phenyl; R2 denotes OH; R4 denotes C1-C4alkyl; R5 denotes C1alkyl, substituted with a CO-NH-R6 group; R6 denotes a 5-member unsaturated heterocyclic group containing one N atom and one O atom in the ring, a 6-member heterocyclic group containing two N atoms in the ring.

EFFECT: compounds can inhibit binding of aceylcholine with M3 muscarinic receptors, which facilitates their use in a pharmaceutical composition.

6 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I

, where R1 is selected from a group comprising hydrogen, lower alkyl, lower hydroxyl, lower alkoxyalkyl, lower halogenalkyl, lower cyanoalkyl; unsubstituted or substituted phenyl; lower phenylalkyl, where the phenyl ring can be unsubstituted or substituted; and heteroaryl, selected from pyridyl and pyrimidinyl; R2 denotes hydrogen or halogen; G denotes a group selected from

, where m equals, 0, 1; R3 is selected from lower alkyl, cycloalkyl and lower cycloalkylalkyl; n equals 0, 1; R4 denotes lower alkyl, as well as pharmaceutical compositions.

EFFECT: said compounds are used to treat or prevent diseases associated with histaminase receptor modulation.

19 cl, 1 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of cis-2,4,5-triarylimidazoline of general formula I and pharmaceutically acceptable salts thereof, where X1 is selected from a group comprising lower alkoxy; X2 and X3 are independently selected from a group comprising hydrogen, halogen, cyano, lower alkyl, lower alkoxy, piperidinyl, -NX4X5, -SO2NX4X5, -C(O)NX4X5, -C(O)X6, -SOX6, -SO2X6, -NC(O)-lower alkoxy, -C≡C-X7, provided that both X2 and X3 do not denote hydrogen, lower alkyl or lower alkoxy, provided that when X2 or X3 denote hydrogen, the other does not denote lower alkyl, lower alkoxy or halogen, provided that when X2 denotes -HX4X5, X3 does not denote hydrogen, X2 and X3 together can form a ring selected from 5-7-member unsaturated rings which can contain three heteroatoms selected from S, N and O, X4 and X5 are independently selected from a group comprising hydrogen, lower alkyl, lower alkoxy, lower alkyl, substituted by a lower alkoxy, -SO2-lower alkyl, -C(O)piperazinyl-3-one; X6 is selected from a group comprising lower alkyl, morpholine, piperidine, pyrrolidine; X7 is selected from a group comprising hydrogen, lower alkyl, trifluoromethyl; Y1 and Y2 are independently selected from a group comprising halogen; R is selected from a group comprising lower alkoxy, piperidinyl substituted with a five-member heterocyclic ring which contains one nitrogen heteroatom, piperidinyl substituted with a hydroxy, -CH2OH or -C(O)NH2, piperazinyl substituted with one or two R1 [1,4]diazepanyl, substituted R1, R1 can denote one or two substitutes selected from a group comprising oxo, lower alkyl substituted with one R2, -C(O)R3, -SO2-lower alkyl, -SO2-five-memer heterocyclyl, which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl; R2 is selected from a group comprising -SO2-lower alkyl, hydroxy, lower alkoxy, -NH-SO2-lower alkyl, -cyano, -C(O)R4; R3 is selected from a group comprising a five-member heterocyclyl which is selected from isoxazolyl, dimethylisoxazolyl, pyrrolidinyl, pyrrolyl, thiophenyl, imidazolyl, thiazolyl, thiazolidinyl, imidazolidinyl, lower alkyl, lower alkenyl, lower alkyl substituted with a six-member heterocyclyl selected from piperidinyl, piperazinyl, 3-oxopiperazinyl, morpholinyl, C3-cycloalkyl; R4 is selected from a group comprising hydroxy, morpholine, piperidine, 4-acetylpiperazinyl, -NR5R6; R5 and R6 are independently selected from a group comprising hydrogen, lower alkyl, lower alkyl substituted with lower alkoxy or cyano, lower alkoxy and C3-cycloalkyl. The invention also relates to a pharmaceutical composition based on the formula I compound, use of the formula I compound in preparing a medicinal agent and a method for synthesis of the formula I compound.

EFFECT: novel derivatives of cis-2,4,5-triarylimidazoline of general formula I are obtained, which can be used to treat diseases, based on reaction of the MDM2 protein with p53-like protein, particularly as anticancer agent.

54 cl, 412 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel AMPA receptor antagonists - 1H-quinazoline-2,4-dione derivatives, selected from the group: N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,4]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,3]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; (2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)amide ethanesulphonic acid; N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-thiomorpholin-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide and N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide and physiologically acceptable salts thereof.

EFFECT: compounds can be used in treating such diseases as epilepsy and schizophrenia.

9 cl, 106 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula: or to its pharmaceutically acceptable salt, where: Ar2 represents phenyl or pyridyl, each of which is substituted by 0-4 substituents, independently selected from R2; X and Z represent N; Y represents CRX; D represents N; F represents N, CH or carbon, substituted by substituent, representing R1 or R10; Rx in each case is independently selected from hydrogen, halogen, C1-C4alkyl, amino, cyano and mono- or di-(C1-C4alkyl)amino; R1 represents 0-3 substituents, independently selected from: (a) halogen, cyano and nitro; (b) groups of formula -Q-M-Ry; R10 represents one substituent, selected from: (a) groups of formula -Q-M-Ry; so that R10 is not hydroxy, amino or unsubstituted group, selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, C1-C6aloxy, C2-C6alkyl, ether, C2-C6alkanoyl, C3-C6alcanone, C1-C6halogenalkyl, C1-C6halogenoalkoxy, mono- or di-(C1-C6alkyl)amino, C1-C6alkylsulfonyl, mono- or di-(C1-C6alkyl)aminosulfonyl or mono- or di-(C1-C6alkyl)aminocarbonyl; each Q is independently selected from C0-C4alkylene; each M is independently absent or is selected from O, C(=O), OC(=O), C(=O)O, S(O)m, N(RZ), C(=O)N(Rz), C(=NH)N(Rz), N(Rz)C(=O), N(Rz)C(=NH), N(Rz)S(O)m, S(O)mN(Rz) and N[S(O)mRz]S(O)m, where m equals 2; and Rz in each case is independently selected from hydrogen, C1-C8alkyl and groups, which taken together with Ry, form possibly substituted (4-7)-member heterocycle; and each Ry independently represents hydrogen, C1-C8halogenalkyl, C1-C8alkyl, C2-C8alkenyl, (C3-C8carbocycle)C0-C4alkyl, ((4-7)-member heterocycle)C0-C4alkyl or taken together with Rz forms (4-7) member heterocycle, where each alkyl, carbocycle and heterocycle is substituted by 0-4 substituents, independently selected from hydroxy, halogen, amino, cyano, nitro, -COOH, aminocarbonyl, aminosulfonyl, C1-C6alkyl, C3-C7cecloalkyl, C2-C6alkyl ether, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C8alkoxy, C1-C8hydroxyalkyl, mono- and di-(C1-C6alkyl)aminocarbonyl, mono- and di-(C1-C6alkyl)aminosulfonyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkanoylamino and phenyl; so that Ry is not hydrogen, if Q represents C0alkyl and M is absent; each R2: (a) is independently selected from (1) hydroxyl, amino, cyano, halogen, -COOH, nitro and (2) C1-C6alkyl, (C3-C8cycloalkyl)C0-C4alkyl, C1-C6halogenalkyl; R3 is selected from: (1) hydrogen; (2) C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl; and (3) groups of formula: where L represents C0-C6alkylene; R5 and R6: (a) are independently selected from C1-C12alkyl, (C3-C8cycloalkyl)C0-C4alkyl; or (b) are combined with formation of (4-6)-member heterocycle, containing one or two heteroatoms independently selected from O and N; and where each of (2) and (3) is substituted by 0-4 substituents, independently selected from: C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl, each of which is substituted by 0-4 secondary substituents, independently selected from hydroxy, C1-C4alkyl and C1-C4alkoxy; and R4 represents 0-2 substituents, independently selected from C1-C3alkyl.

EFFECT: claimed are pharmaceutical compositions for modulation of capsaicin receptor activity and methods of applying said compounds for treatment of such disorders as pain, itch, cough, hiccup, urinary incontinence or obesity.

65 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 4-aminocarbonylpyrimidine of formula (I).

EFFECT: invention is applicable as P2Y12 receptor antagonists for treatment and/or prevention of diseases or disease states of peripheral vessels, as well as vessels, supplying internal organs, vessels of liver and kidneys, in treatment and/or prevention of cardiovascular and cerebrovascular diseases and states, associated with aggregation of platelets, including thrombosis in humans and mammals.

26 cl, 500 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel amide derivatives of general formula [1] in any of versions (A) or (B), or its pharmaceutically acceptable salt, which possess properties of tyrosinkinase BCR-ABL inhibitor. Amide derivative of general formula [1] represents compound: , where according to Version (A) R1 represents any of the following groups (1)-(3): (1) -) -CH2-R11 [R11 represents saturated 4-6 member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom, which is substituted by group selected from group, consisting of oxo, -CH2-R111 (R111 represents saturated 5-member nitrogen-containing heterocyclic group), saturated 5-member nitrogen-containing heterocyclic group, aminomethyl, monoalkylaminomethyl, dialkylaminomethyl and (5-methyl-2-oxo-1,3-Dioxol-4-yl)methyl, and in addition, can be substituted by 1 or 2 similar or different substituents, selected from group, consisting of (C1-C4)alkyl, (C1-C4 alkoxycarbonyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, amino, carbamoyl], (2) -O-R12 [R12 represents saturated 4-6-member nitrogen-containing heterocyclic group]; and (3) - CH=R13 [R13 represents saturated 4-6-member nitrogen-containing heterocyclic group, which can contain additional nitrogen atom, and which can be substituted by 1-3 similar or different substituents, selected from group, consisting of oxo, (C1-C4)alkyl]; R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy and carbamoyl; R3 represents hydrogen, halogen; Het1 represents any of groups with the following chemical formulae [4] and [6]: [4] [6] [19] [10] Het2 represents pyridyl or pyrimidinyl. According to Version (B) R1 represents -CH2-R14 [R14 represents saturated 4-6-member nitrogen-containing heterocyclic group, optionally containing additional nitrogen atom; saturated 5-6-member nitrogen-containing heterocyclic group, which can be substituted by 1-3 similar groups, selected from (C1-C4)alkyl] R2 represents (C1-C4)alkyl, halogen, halogen(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkoxycarbonyl, (C1-C4)acyl, amino, mono(C1-C4)alkylamino, di(C1-C4)alkylamino, nitro, carbamoyl, mono(C1-C4)alkylcarbamoyl, di(C1-C4)alkylcarbamoyl or cyano; R3 represents hydrogen or halogen; Het1 represents any of groups with the following chemical formulas [9] and [10], Het2 represents pyridyl.

EFFECT: invention can be applied for treatment of chronic myeloleukosis, acute lymphoblastic leukosis and acute myeloblastic leukosis.

6 cl, 89 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof, having CRP receptor antagonist activity. In formula (I) R1 denotes C3-C8 alkyl, optionally substituted with hydroxyl; phenyl optionally substituted with 1-3 substitutes selected from halogen, nitro, amino, hydroxyl, C1-C4 alkoxy, C1-C4 alkyl, optionally substituted with hydroxyl or C1-C4 alkylamino; naphthyl; C-bonded 5-6-member heteroaryl with 1-2 heteroatoms selected from S, N or O, optionally substituted with C1-C4 alkyl, C1-C4 alkoxy or acetyl; N-bonded 5-member heteroaryl with 1-2 heteroatoms selected from N, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl or phenyl; R2 denotes phenyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, halogenC1-C4alkyl, C1-C4 alkoxy, halogenC1-C4alkoxy, halogen, hydroxy, di(C1-C4 alkyl)amino or di(C1-C4 alkyl)aminocarbonyl; or a heterocyclic group which is pyridyl, optionally substituted with 1-3 substitutes selected from C1-C4 alkyl, C1-C4 alkoxy or di(C1-C4 alkyl)amino; X denotes -NR3-, where R3 denotes C1-C4 alkyl, optionally substituted with hydroxyl, carboxyl or C1-C4 alkoxycarbonyl; Y1 denotes CR3a, where R3a denotes hydrogen, halogen, cyano, hydroxy, C1-C4 alkyl, optionally substituted with hydroxyl or halogen, C1-C4 alkoxy optionally substituted with halogen; Y2 denotes CR3b, where R3b denotes hydrogen or halogen; Y3 denotes N or CR3c, where R3c denotes hydrogen; and Z denotes O or -NR4-, where R4 denotes hydrogen.

EFFECT: invention also pertains to a method of producing compounds of formula (I), a pharmaceutical composition, an inhibiting method, CRF receptor antagonists and use thereof to prepare a medicinal agent.

25 cl, 9 tbl, 163 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

Chemical compounds // 2405780

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I): , in which: R1 and R2 are independently specified from hydrogen, C1-6alkyl, C1-6alkoxy and cyclopropyl; X1, X2 and X3 independently represent =N- or =CR10; R3 and R10 are independently specified from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl, C1-6alkyl, N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkoxycarbonyl; R4 represents hydrogen; R5 and R6 are independently specified from hydrogen, hydroxy and C1-6alkyl where R5 and R6 independently can be optionally substituted in carbon atom with one or more R16 where R16 represents hydroxy; A represents a single link or C1-2alkylene; where specified C1-2alkylene can be optionally substituted with one or more R18; the ring C represents a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms in which at least one atom can be specified from nitrogen, sulphur or oxygen which can be linked with carbon or nitrogen atom where the -CH2- group can be optionally substituted with -C(O)- and ring sulphur atom can be optionally oxidised to produce S-oxide; R7 is specified from halogen and C1-6alkyl where R7 can be optionally substituted in carbon atom with halogen; n is equal to 0.1 or 2; where R7 values can be equal or different; and R18 is independently specified from halogen and hydroxy; or its pharmaceutically acceptable salt. Also the invention refers to their pharmaceutical compositions and methods for preparation and application thereof for cancer treatment.

EFFECT: preparation of new compounds which can find application for cancer treatment.

23 cl, 96 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel potassium or hydrazinium salts of 4-dinitromethyl-1,2,3-triazoles of general formulae V-VIII: V, VI VII, VIII, where Kat+ =K+ (V,VII), NH2NH3+ (VI;VIII).

EFFECT: higher herbicidal activity.

1 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrrole derivatives of formula (I): , where R1 denotes hydrogen; R2 denotes adamantine which is unsubstituted or substituted with a hydroxy group or halogen; R3 denotes trifluoromethyl, pyrazole, triazole, piperidine, pyrrolidine, hydroxymethylpiperidine, benzylpiperazine, hydroxypyrrolidine, tert-butylpyrrolidine, hydroxyethylpiperazine, hydroxypiperidine or thiomorpholyl group; R4 denotes cyclopropyl, tert-butyl, -CH(CH3)2CH2OH, methyl, -CF3 or -(CH2)nCF3 group, where n equals 1 or 2; R5 denotes hydrogen or lower alkyl which is unsubstituted or substituted with a halogen, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds and pharmaceutical compositions containing said compounds can inhibit 11β-hydroxysteroid dehydrogenase of the form 1 (11-BETA-HSD-1) and can be used to treat diseases such as type II sugar diabetes type and metabolic syndrome.

17 cl, 99 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein R means dihydrosubstituted C2-C6alkyl group, and Cy represents spiro[4.5]dec-6-yl, spiro[2.5]oct-4-yl, spiro[3.5]non-5-yl, 3,3-dimethylbicyclo[2.2.1]hept-2-yl or 1-spiro(bicyclo[2.2.1]heptane-2,1'-cyclopropane)-3-yl-group. Said compounds act as nociceptive receptor antagonists, and are applied e.g. as agents improving acceptability of narcotic analgesics, relieving narcotic analgesic dependence or narcomania; as an analgesic intensifier; antiobesity agents or appetite suppressants; agents for treating decreasing cognition and senile dementia /amnesia; agents for treating developing cognition disorder; therapeutic agents in schizophrenia; agents for treating neurodegenerative diseases; antidepressants or therapeutic agents in affective disorder; therapeutic or prophylactic agents in diabetes insipidus; therapeutic or prophylactic agents in polyuria; and therapeutic agents in hypotension and similar.

EFFECT: preparation of the compounds acting as nociceptive receptor antagonists.

11 cl, 5 ex, 3 tbl

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