Cyclopropylamide derivatives as n3-histamine receptor modulators

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclopropylamine derivatives of formula: or its pharmaceutically acceptable salt, wherein: one of R1 and R2 means a group of formula -L2-R6a-L3-R6b; the other of R1 and R2 means H, C1-10alkyl, C1-10alkoxy, halogen, CN; each R3, R3a R3b independently means H, C1-6alkyl, trifluoromethyl, C1-10alkoxy, CN; R4 and R5 taken together with a nitrogen atom whereto each attached form a non-aromatic cycle of formula: R7, R8, R9 and R10 each H, C1-10alkyl; R6a means cyanophenyl, phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepanyl, azetidinyl, azetidin-2-onyl, pyridazin-3(2H)-onyl, pyridin-2(1H)-onyl, pyrimidin-2(1H)-onyl, pyrrolidin-2-onyl, benzothiazolyl wherein the pyridinyl and pyrimidinyl groups optionally contain 1-3 substitutes specified in a group consisting of C1-10alkyl and C1-10alkoxy; R6b means H; L means - [C(R16)(R17)]k; L2 means a bond, C2-10alkylene, -O-, -C(=O)-, -NH-, -N(R16)C(=O), -C(=O)N(R16) and -N(C1-6alkyl)-;L3 means a bond; R15 means H, C1-6alkyl, C1-6alkoxycarbonyl, amido and formyl R16 , R17 in each specific case means H, C1-6alkyl; Rx and Ry in each specific case independently mean H, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, fluorine, diC1-6alkylamino; k is equal to 1, 2 or 3; m is equal to 2.

EFFECT: compounds show H3 receptor inhibitory activity that makes them applicable in a pharmaceutical composition.

10 cl, 7 dwg, 44 ex

 

The scope of the invention

The invention relates to compounds of cyclopropylamine, compositions containing such compounds, methods of producing such compounds and methods of treating conditions and disorders using such compounds and compositions.

Description related technologies

Histamine is a well-known modulator of neuronal activity. In the literature it is reported that at least four types of histamine receptors, usually referred to as histamine-1, histamine-2, histamine-3 and histamine-4. Suppose that the class of histamine receptors, known as 3-histamine receptors, plays a role in neurotransmission in the Central nervous system.

Histamine-3 receptor (H3) was first characterized pharmacologically in histaminergic nerve terminals (Nature, 302: 832-837 (1983)), where it regulates the release of neurotransmitters in the Central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract. It is believed that H3receptors are presynaptic in histaminergic nerve endings and also in neurons, with another activity, such as adrenergic, cholinergic, serotonergic and dopaminergic activity. The existence of H3receptors p is doridoidea the development of selective agonists and antagonists of H 3receptor (Nature, 327: 117-123 (1987); Leurs and Timmerman, ed. "The History of H3Receptor: a Target for New Drugs," Elsevier (1998)). Activity on H3the receptors can be modified or adjusted by introducing ligands H3-receptors. The ligands can exhibit antagonist, inverse agonist, agonistic or partial agonistic activity. For example, H3receptors linked to conditions and disorders related to memory and learning processes, neurological processes, cardiovascular function and regulation of blood sugar, among other systemic activities. Although there are different classes of compounds demonstrating activity by modulating the H3receptors, it would be useful to obtain additional compounds that demonstrate activity in H3the receptors that could be included in pharmaceutical compositions useful for therapeutic methods.

The INVENTION

The invention relates to cyclopropylamine and, more specifically, bicyclic and tricyclics-substituted derivatives of cyclopropylamine. Thus, one aspect of the invention relates to compounds of formula (I):

or their pharmaceutically acceptable salt, complex ether, amide or prodrug,

where one of R1and R2appears the t group of the formula-L 2-R6a-L3-R6b; one of R1and R2selected from a hydrogen atom, alkyl, alkoxy, halogen, cyano, dialkoxy;

R3, R3aand R3beach independently selected from the group consisting of hydrogen atom, alkyl, triptoreline, triptoreline, alkoxy, halogen, cyano, dialkoxy;

R4and R5each independently selected from alkyl, foralkyl, hydroxyalkyl, alkoxyalkyl and cycloalkyl, or R4and R5taken together with the nitrogen atom to which each is attached, form a nonaromatic cycle formula:

or

R7, R8, R9and R10in each case each independently selected from a hydrogen atom, hydroxyalkyl, foralkyl, cycloalkyl and alkyl;

R11, R12, R13and R14each independently selected from a hydrogen atom, hydroxyalkyl, alkyl and foralkyl;

R6aselected from a 5 to 6-membered heteroaryl cycle, cyanophenyl, (8-12)-membered bicyclic heteroaryl cycle and (4-12)-membered heterocyclic system;

R6bselected from a hydrogen atom, a 5 to 6-membered heteroaryl cycle, aryl cycle (8-12)-membered bicyclic heteroaryl system and (4-12)-membered heterocyclic system;

Q is selected from O and S;

L denotes -[C(R16)(R17)]k;

L2selected from communication, alkylene, -O-, -C(=O)-, -S-, -NH-, -N(R16)C(=O)-, -C(=O)N(R16and-N(alkyl)-;

L3selected from communication, alkylene, -O-, -C(=O)-, -S-, -N(R16)C(=O)-, -C(=O)N(R16and-N(R15)-;

R15selected from a hydrogen atom, alkyl, acyl, alkoxycarbonyl, amido, and formyl;

R16and R17in each case independently selected from a hydrogen atom and alkyl;

Rxand Ryin each case independently selected from a hydrogen atom, hydroxy, alkyl, alkoxy, alkylamino, fluorine, dialkylamino;

k is 1, 2 or 3; and

m is an integer from 1 to 5.

Another aspect of the invention relates to pharmaceutical compositions containing the compounds according to the invention. Such compositions can be entered according to the method according to the invention usually as part of a therapeutic schema for the treatment or prevention of conditions and disorders associated with the activity of H3-receptors.

Another aspect of the invention relates to a method of selective modulation of the activity of H3-receptors. The method is useful for the treatment or prevention of conditions and disorders associated with modulation of H3receptors in mammals. More specifically, the method is useful for the treatment or prevention of conditions and disorders associated with memory and learning processes, neurological processes, cardiovascular function and mass is th body. Therefore, the compounds and compositions according to the invention are useful as medicines for the treatment or prevention of diseases modulated H3-receptors.

It also examines the methods for producing compounds according to the invention.

Here, the following describes compounds, compositions containing these compounds, methods of obtaining these compounds and methods of treatment or prevention of conditions and disorders by administration of a data connection.

DETAILED description of the INVENTION

Definition of terms

Some of the terminology used in the description, are assumed to refer to the following definitions, as described in detail below.

Used herein, the term "acyl" means an alkyl group as defined here, is attached to the original molecular fragment through a carbonyl group, which is defined here. Typical examples of acyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopent.

Used herein, the term "acyloxy" denotes an acyl group as defined here, is attached to the original molecular fragment through an oxygen atom. Typical examples of acyloxy include, but are not limited to, atomic charges, propionyloxy, isobutyryloxy.

We use here the terminology is "alkenyl" denotes a linear or branched hydrocarbon, containing from 2 to 10 carbon atoms, preferably 2, 3, 4, 5 or 6 carbon atoms, and containing at least one double bond in the carbon-carbon that is formed by removing two hydrogen atoms. Typical examples of alkenyl include, but are not limited to, ethynyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-Heptene and 3-decenyl.

Used herein, the term "alkoxy" denotes an alkyl group as defined here, is attached to the original molecular fragment through an oxygen atom. Typical examples of alkoxygroup include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy.

Used herein, the term "alkoxyalkyl" means alkoxygroup, which is defined here, attached to the original molecular fragment through another alkoxygroup, which is defined here. Typical examples of alkoxyalkyl include, but are not limited to, tert-butoxyethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, ethoxyethoxy.

Used herein, the term "alkoxyalkyl" means alkoxygroup, which is defined here, attached to the original molecular fragment through an alkyl group, which is defined here. Typical examples of alkoxyalkyl include, but are not limited to, tert-butoxy the Tyl, 2-ethoxyethyl, 2-methoxyethyl and ethoxymethyl.

Used herein, the term "alkoxycarbonyl denotes alkoxygroup, which is defined here, attached to the original molecular fragment through a carbonyl group, which is defined here. Typical examples of alkoxycarbonyl include, but are not limited to this, methoxycarbonyl, etoxycarbonyl and tert-butoxycarbonyl.

Used herein, the term "alkoxyimino" means alkoxygroup, which is defined here, attached to the original molecular fragment through aminogroup, which is defined here. Typical examples of alkoxyimino include, but are not limited to this, ethoxy(imino)methyl and methoxy(imino)methyl.

Used herein, the term "alkoxycarbonyl" means alkoxygroup, which is defined here, attached to the original molecular fragment through sulfonyloxy group, which is defined here. Typical examples alkoxycarbonyl include, but are not limited to this, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.

Used herein, the term "alkyl" denotes a linear or branched hydrocarbon containing from 1 to 10 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. Typical examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-etylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

Used herein, the term "alkylamino" refers to an alkyl group as defined here, is attached to the original molecular fragment through the NH group. Typical examples of alkylamino include, but are not limited to this, methylamino, ethylamino, isopropylamino, butylamino.

Used herein, the term "alkylaryl" refers to an alkyl group as defined here, is attached to the original molecular fragment through a carbonyl group, which is defined here. Typical examples of alkylcarboxylic include, but are not limited to this, methylcarbamyl, ethylcarboxyl, isopropylcarbonate, n-propylboronic and the like.

The term "alkylene" denotes a divalent group derived linear or branched hydrocarbon having from 1 to 10 carbon atoms. Typical examples of alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

Used herein, the term "alkylsulfonyl" means an alkyl group as defined here, is attached to the original molecular fragment through sulfonyloxy group is, which is defined here. Typical examples alkylsulfonyl include, but are not limited to this, methylsulphonyl and ethylsulfonyl.

Used herein, the term "quinil" denotes a linear or branched hydrocarbon group containing from 2 to 10 carbon atoms, preferably 2, 3, 4 or 5 carbon atoms, and having at least one triple bond of carbon-carbon. Typical examples of quinil include, but are not limited to this, acetylenyl, 1-PROPYNYL, 2-PROPYNYL, 3-butynyl, 2-pentenyl and 1-butynyl.

Used herein, the term "amido" denotes amino, alkylamino or dialkylamino attached to the original molecular fragment through a carbonyl group, which is defined here. Typical examples of aminogroup include, but are not limited to this, aminocarbonyl, methylaminomethyl, dimethylaminoethyl and ethylmethylamino.

Used herein, the term "amino" denotes the group-NH2.

Used herein, the term "aryl" denotes a monocyclic aromatic hydrocarbon cyclic system. Typical examples of aryl include, but are not limited to, phenyl.

Aryl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, Ala xianfei, of alkyl, alkylsulphonyl, alkylsulfonyl, quinil, amido, carboxy, cyano, cycloalkylcarbonyl, formyl, halogenoalkane, halogenoalkane, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, dialkoxy, NRARBand (NRARB)sulfonyl.

Used herein, the term "arylalkyl" denotes an aryl group as defined here, is attached to the original molecular fragment through an alkyl group, which is defined here. Typical examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

Used herein, the term "carbonyl" refers to a group-C(=O)-.

Used herein, the term "carboxy" refers to a group-CO2H, which can be protected as ester group-CO2-alkyl.

Used herein, the term "cyano" refers to the group-CN.

Used herein, the term "cyanophenyl" refers to the group-CN, attached to the original molecular fragment via a phenyl group, including, but not limited to, 4-cyanophenyl, 3-cyanophenyl and 2-cyanophenyl.

Used herein, the term "cycloalkyl" denotes a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Cycloalkyl group is about the invention are substituted by 0, 1, 2, 3 or 4 substituents selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkyl, quinil, amido, carboxy, cyano, Ethylenedioxy, formyl, halogenoalkane, halogenoalkane, halogen, hydroxy, hydroxyalkyl, methylenedioxy, oxo, dialkoxy and-NRARB.

Used herein, the term "cycloalkylcarbonyl" means cycloalkyl group, which is defined here, attached to the original molecular fragment through a carbonyl group, which is defined here. Typical examples of cycloalkylcarbonyl include, but are not limited to this, cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl and cyclohexylcarbonyl.

Used herein, the term "dialkylamino" denotes two independent alkyl groups that are defined here, is attached to the original molecular fragment through the nitrogen atom. Typical examples of dialkylamino include, but are not limited to, dimethylamino, diethylamino, ethylmethylamino, butylmethylamine.

Used herein, the term "fluorine" means-F.

Used herein, the term "feralcode" means, at least one alkyl fluoride group, which is defined here, attached to the original molecular fragment through an oxygen group, which is defined here. Typical is haunted examples of foralkyl include, but is not limited to this, triptoreline (CF3O), deformedarse (CHF2O).

Used herein, the term "foralkyl" denotes at least one fluorine atom, which is defined here, attached to the original molecular fragment through an alkyl group, which is defined here. Typical examples of foralkyl include, but are not limited to this, vermeil, deformity, trifluoromethyl, pentafluoroethyl and 2,2,2-triptorelin.

Used herein, the term "formyl" refers to the group-C(O)H.

Used herein, the term "halo" or "halogen" refers to Cl, Br, I or F.

Used herein, the term "halogenoalkane" means at least one halogen, as defined here, is attached to the original molecular fragment through alkoxygroup, which is defined here. Typical examples of halogenlamp include, but are not limited to, 2-floratone, triptoreline, pentaverate.

Used herein, the term "halogenated" means at least one halogen, as defined here, is attached to the original molecular fragment through an alkyl group, which is defined here. Typical examples of halogenoalkane include, but are not limited to, chloromethyl, 2-foretel, trifluoromethyl, pentafluoroethyl and 2-chloro-3-terpencil.

Used herein, the term "heteroaryl" means aromati is a mini-cycle, containing one or more heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur, or tautomer. Such cyclic systems may be monocyclic or bicyclic, as described hereafter. Heteroaryl loops attached to the original molecular fragment or to the L2or L3where L2and L3defined in formula (I)via a carbon atom or a nitrogen atom.

Used here, the expression "monocyclic heteroaryl" or "5 - or 6-membered heteroaryl cycle" refers to 5 - or 6-membered aromatic cycles containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen atoms, oxygen, or sulfur, or their tautomers. Examples of such cycles include, but are not limited to, a cycle in which one carbon atom is substituted by an atom of O or S; one, two or three N atoms, arranged in a suitable manner, to obtain an aromatic cycle or a cycle in which two carbon atoms in the cycle replaced by one atom of O or S and one atom of n Such cycles may include, but are not limited to this, six-membered aromatic cycles, where one to four of the ring carbon atoms is replaced by nitrogen atoms, five-membered cycles containing ring sulfur atoms, oxygen or nitrogen; five-membered cycles containing one to four nitrogen atoms; and five-membered cycles containing an oxygen atom and the sulfur and from one to three nitrogen atoms. Typical examples 5 to 6-membered heteroaryl cycles include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolin, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl and [1,2,4]triazolyl.

Used here, the expression "bicyclic heteroaryl or(8-12)-membered bicyclic heteroaryl system" refers to 8-, 9-, 10-, 11 -, or 12-membered bicyclic aromatic system containing at least 3 double bonds, which ring atoms include one or more heteroatoms independently selected from oxygen atom, sulfur and nitrogen. Representative examples of bicyclic heteroaryl systems include indolyl, benzothiazyl, benzofuranyl, indazoles, benzimidazoles, benzothiazoles, benzoxazoles, benzothiazoles, benzisoxazole, chinoline, ethenolysis, hintline, honokalani, phthalazine, pteridine, purinol, naphthyridine, cinnoline, thieno[2,3-d]imidazole, thieno[3,2-b]pyridinyl and pyrrolopyrimidine.

Heteroaryl groups according to the invention, monocyclic or bicyclic, can be replaced by hydrogen or optionally substituted by one or more substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxycarbonyl, alkyl, alkylsulphonyl, alkylsulfonyl, amido, carboxy, cyano, cycloalkyl, feralcode, formyl, halogenoalkane, halogenoalkane, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, -NRARBand (NRARB)carbonyl. Monocyclic heteroaryl or 5 - or 6-membered heteroaryl cycles are substituted by 0, 1, 2, 3, 4, or 5 substituents. Bicyclic heteroaryl or (8-12)-membered bicyclic heteroaryl systems are replaced 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents. Heteroaryl groups of the present invention may be present as tautomers.

Used here, the expression "heterocyclic system" and "heterocycle" refers to (4-12)-membered monocyclic or bicyclic system containing one, two, three, four or five heteroatoms, independently selected from the group comprising atoms of nitrogen, oxygen and sulfur, and also containing at least one carbon atom is connected to four other atoms or one carbon atom replaced by exography and attached to two other atoms. Four - and five-membered cycles can have zero or one double bond. Six-membered ring may have zero, one or two double bonds. Seven - and eight-membered cycles can have zero, one, two or three DV is inih communication. Non-aromatic heterocyclic group according to the invention can be attached via a carbon atom or a nitrogen atom. Non-aromatic heterocyclic group may be present in tautomeric form. Typical examples of nitrogen-containing heterocycles include, but are not limited to this, azepane, azetidine, aziridine, atacanli, dihydropyridines, dihydropyridines, dihydropyrimidines, morpholinyl, piperazinil, piperidinyl, pyrrolidinyl, pyrrolyl, dihydrothiazolo, dihydropyridines and thiomorpholine. Typical examples of non-aromatic heterocycles, not containing nitrogen include, but are not limited to this, dioxane, dithienyl, tetrahydrofuryl, dihydropyran, tetrahydropyranyl and [1,3]DIOXOLANYL.

The heterocycles of the invention are substituted with hydrogen, or optionally substituted 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkyl, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, arylalkyl, arylalkanolamine, carboxy, cyano, formyl, halogenoalkane, halogenoalkane, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, dialkoxy, -NRARBand (NRARB)sulfonyl.

Additional examples of heterocycles include, but are not limited to this, azetidin-2-it, azepin-2-the n, isoindoline-1,3-dione, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-he, pyridazin-3(2H)-he pyridine-2(1H)-he pyrimidine-2(1H)-he pyrimidine-2,4(1H,3H)-dione, pyrrolidin-2-it, benzo[d]thiazol-2(3H)-he pyridin-4(1H)-he, imidazolidin-2-it, 1H-imidazole-2(3H)-he, piperidine-2-it, tetrahydropyrimidin-2(1H) -, 1H-benzo[d]imidazol-2(3H)-he [1,2,4]thiadiazolyl, [1,2,5]thiadiazolyl, [1,3,4]thiadiazines, [1,2,4]oxadiazolyl, [1,2,5]oxadiazolyl, [1,3,4]oxadiazine and 1.5-dihydrobenzo[b][1,4]diazepin-2-IMT.

Used herein, the term "hydroxy" refers to the group-OH.

Used herein, the term "hydroxyalkyl" means at least one hydroxy-group, which is defined here, attached to the original molecular fragment through an alkyl group, which is defined here. Typical examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-methyl-2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxybutyl and 2-ethyl-4-hydroxyethyl.

Used herein, the expression "hydroxy-protective group" means a Deputy, which protects hydroxyl groups against undesirable interactions during the methods of synthesis. Examples of hydroxy-protecting groups include, but are not limited to this, methoxymethyl, benzoyloxymethyl, 2-methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyl, triphenylmethyl, 2,2,2-trichloroethyl, tert-butyl, trimethylsilyl, tre is-butyldimethylsilyl, tert-butyldiphenylsilyl, metronatural, acetonide, benzylidene acetal, cyclic complex orthoepy, methoxymethyl, cyclic carbonates and cyclic boronate. Hydroxy-protective group attached to the hydroxyl groups by reaction of a compound that contains the hydroxy-group, with a base, such as triethylamine, and a reagent selected from alkylhalogenide, alkylacrylate, trialkylsilanes, trialkylsilyl, iridiumsatellite or alkylphosphonate, CH2I2or a complex ester of dihalogenoalkane, for example, methyliodide, benzimidazol, triethylcitrate, acetylchloride, benzylchloride or dimethylcarbonate. The protective group can also be attached to the hydroxy-group by reaction of a compound that contains the hydroxy-group, with acid and alkylates.

The term "imino", which is defined here, refers to the group-C(=NH)-.

Used herein, the term "mercapto" refers to the group-SH.

Used herein, the term "-NRARB" indicates two groups of RAand RBthat are attached to the original molecular fragment through the nitrogen atom. RAand RBindependently selected from a hydrogen atom, alkyl, acyl and formyl. Typical examples-NRARBinclude, but are not limited to, amino, dimethylamino, meilani is about, acetylamino, acetylecholine.

Used herein, the term "(NRARB)alkyl" refers to a group-NRARBas defined here, is attached to the original molecular fragment through an alkyl group, which is defined here. Typical examples (NRARB)alkyl include, but are not limited to, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(amino)ethyl, 2-(ethylmethylamino)ethyl and the like.

Used herein, the term "(NRARB)carbonyl" refers to the group - NRARBas defined here, is attached to the original molecular fragment through a carbonyl group, which is defined here. Typical examples (NRARB)carbonyl include, but are not limited to this, aminocarbonyl, (methylamino)carbonyl, (dimethylamino)carbonyl, (ethylmethylamino)carbonyl and the like.

Used herein, the term "(NRARB)sulfonyl" refers to the group-NRARBas defined here, is attached to the original molecular fragment through sulfonyloxy group, which is defined here. Typical examples (NRARB)sulfonyl include, but are not limited to this, aminosulfonyl, (methylamino)sulfonyl, (dimethylamino)sulfonyl and (ethylmethylamino)sulfonyl.

Used herein, the term "nitro" refers to the group-NO2.

Used is here, the expression "nitrogen-protective group" means a group designed to protect the nitrogen atom against undesirable interactions during the methods of synthesis. Nitrogen protecting groups include carbamates, amides, N-benzyl derivatives and imine derivatives. The preferred nitrogen-protective groups are acetyl, benzoyl, benzyl, benzyloxycarbonyl (Cbz), formyl, phenylsulfonyl, pivaloyl, t-butoxycarbonyl (Boc), tert-butylacetyl, TRIFLUOROACETYL and triphenylmethyl (trityl). The nitrogen protective group attached to a primary or secondary amino groups by reaction of a compound that contains an amino group, with a base, such as triethylamine, and a reagent selected from alkylhalogenide, alkylacrylate, dialkylamino anhydride, for example, represented by the formula (alkyl-O)2C=O, dietilovogo anhydride, for example, represented by the formula (aryl-O)2C=O, allhelgona, alkylphosphonate or alkylsulfonate, arylsulfonate or halogen-CON(alkyl)2for example, acetylchloride, benzoyl chloride, benzylbromide, benzyloxycarbonylamino, formilitary, phenylsulfonylacetate, pivaloyloxy, (tert-butyl-O-C=O)2O, triftoratsetatov anhydride and triphenylmethylchloride.

Used herein, the term "oxo" refers to (=About). Used herein, the term "sulfonyl" denotes the group-S(O)2-. Used herein, the term "is jalkotzy" denotes an alkyl group, defined here, is attached to the original molecular fragment through a sulfur atom. Typical examples of dialkoxy include, but are not limited to, methylthio, ethylthio, propylthio.

Used herein, the term "antagonist" includes and describes compounds that prevent the activation of receptors only agonist H3receptors, such as histamine, and also includes compounds known as "inverse agonists". Inverse agonists are compounds that not only prevents activation of the receptor by the agonist H3receptors, such as histamine, but also inhibit the native activity of H3-receptors.

Compounds of the invention

Compounds of the invention can have the formula (I)described above.

In the compounds of formula (I) one of R1and R2denotes a group of the formula-L2-R6a-L3-R6b. Another group of R1and R2selected from a hydrogen atom, alkyl, alkoxy, halogen, cyano, dialkoxy. Preferably, if R1indicates an L2-R6a-L3-R6band R2selected from a hydrogen atom, alkyl, alkoxy, halogen, cyano, dialkoxy. If one of R1and R2indicates an L2-R6a-L3-R6bthen the other preferably denotes a hydrogen atom.

L2selected from communication, is skilene, -O-, -C(=O)-, -S-, -NH-, -N(R16)C(=O)-, -C(=O)N(R16and-N(alkyl)-. Preferably, if L2means a connection.

L3selected from communication, alkylene, -O-, -C(=O)-, -S-, -N(R16)C(=O)-, -C(=O)N(R16and-N(R15)-, where R15selected from a hydrogen atom, alkyl, acyl, alkoxycarbonyl, amido, and formyl. Preferably, if L3means a connection.

R6aselected from a 5 to 6-membered heteroaryl cycle, cyanophenyl, (8-12)-membered bicyclic heteroaryl cycle and (4-12)-membered heterocyclic system. (5-6)-Membered heteroaryl cycle (8-12)-membered bicyclic heteroaryl system and (4-12)-membered heterocyclic system for R6amay be substituted or unsubstituted.

R6bselected from a hydrogen atom, a 5 to 6-membered heteroaryl cycle, aryl cycle (8-12)-membered bicyclic heteroaryl system and (4-12)-membered heterocyclic system. (5-6)-Membered heteroaryl cycle, aryl cycle, 8-12 membered bicyclic heteroaryl system and (4-12)-membered heterocyclic system for R6bmay be substituted or unsubstituted.

Specific examples of 5 to 6-membered heteroaryl cycles, suitable for R6aand R6binclude , but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolin, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrazolyl, [1,2,3]thiadiazolyl, [1,2,3]oxadiazolyl, thiazolyl, thienyl, [1,2,3]triazinyl, [1,2,4]triazinyl, [1,3,5]triazinyl, [1,2,3]triazolyl and [1,2,4]triazolyl. Preferred 5 to 6-membered heteroaryl cycles are, for example, pyrimidinyl, pyridinyl and pyrazolyl. Each of the 5 to 6-membered heteroaryl cycles independently is unsubstituted or substituted by substituents, which are described, for example, in the examples or definitions.

Examples (8-12)-membered bicyclic heteroaryl systems suitable for R6aand R6binclude, but are not limited to, indolyl, benzothiazyl, benzofuranyl, indazoles, benzimidazoles, benzothiazoles, benzoxazoles, benzothiazoles, benzisoxazole, chinoline, ethenolysis, hintline, honokalani, phthalazine, pteridine, purinol, naphthyridine, cinnoline, thieno[2,3-d]imidazole, thieno[3,2-b]pyridinyl and pyrrolopyrimidine. Preferred (8-12)-membered bicyclic heteroaryl systems are, for example, benzothiazolyl and thieno[3,2-b]pyridinyl. Each of (8-12)-membered bicyclic heteroaryl systems is independently unsubstituted or substituted with substituents that are described here, for example, in the examples or definitions.

Examples (4-12)-membered heterocyclic systems, suitable for R6aand R6binclude , but are not limited to this, azepane, azetidine, aired the Nile, asomani, dihydropyridines, dihydropyridines, dihydropyrimidines, morpholinyl, piperazinil, piperidinyl, pyrrolidinyl, pyrrolyl, dihydrothiazolo, dihydropyridines, thiomorpholine, dioxane, dithienyl, tetrahydrofuryl, dihydropyran, tetrahydropyranyl, [1,3]DIOXOLANYL, azetidin-2-IMT, azepin-2-IMT, isoindoline-1,3-dionyl, (Z)-1H-benzo[e][1,4]diazepin-5(4H)-IMT, pyridazin-3(2H)-IMT, pyridine-2(1H)-IMT, pyrimidine-2(1H)-IMT, pyrimidine-2,4(1H,3H)-dionyl, pyrrolidin-2-IMT, benzo[d]thiazol-2(3H)-IMT, pyridin-4(1H)-IMT, imidazolidin-2-IMT, 1H-imidazol-2(3H)-IMT, piperidine-2-IMT, tetrahydropyrimidin-2(1H)-IMT, [1,2,4]thiadiazolyl, [1,2,5]thiadiazolyl, [1,3,4]thiadiazines, [1,2,4]oxadiazolyl, [1,2,5]oxadiazolyl, [1,3,4]oxadiazine and 1H-benzo[d]imidazol-2(3H)-IMT.

Preferred (4-12)-membered heterocyclic systems are azetidin-2-IMT, azepin-2-IMT, pyridazin-3(2H)-IMT, pyrrolidin-2-IMT and piperidine-2-IMT. Each of heterocyclic systems independently is unsubstituted or substituted by substituents, which are described, for example, in the examples or definitions.

In one preferred embodiment, the group R1indicates an L2-R6a-L3-R6bwhere L2denotes a bond; R6bdenotes a hydrogen atom; L3denotes a bond; R6aselected from 5 - or 6-membered heteroaryl cycle; and R 2, R3, R3a, R3b, R4, R5and L are as described herein above.

In another preferred embodiment, the group R1represents - L2-R6a-L3-R6bwhere L2denotes a bond; R6bdenotes a hydrogen atom; L3denotes a bond; R6aselected from (8-12)-membered bicyclic heteroaryl system; and R2, R3, R3a, R3b, R4, R5and L are as described herein above.

In another preferred embodiment, the group R1represents - L2-R6a-L3-R6bwhere L2denotes a bond; R6bdenotes a hydrogen atom; L3denotes a bond; R6aselected from (4-12)-membered heterocyclic system; and R2, R3, R3a, R3b, R4, R5and L are as described herein above.

In another preferred embodiment, the group R1represents - L2-R6a-L3-R6bwhere L2denotes a bond; R6bdenotes a hydrogen atom; L3denotes a bond; R6adenotes pyridazin-3(2H)-IMT; and R2, R3, R3a, R3b, R4, R5and L are as described herein above.

Each of R3, R3aand R3bindependently selected from the group comprising a hydrogen atom, alkyl, triptorelin, three is torelax, alkoxy, halogen, cyano, dialkoxy. Preferably, if R3, R3aand R3brepresent hydrogen atoms, or one of R3, R3aand R3bdenotes halogen and the others are hydrogen atoms. The preferred halogen is fluorine. R4and R5each independently selected from the group comprising alkyl, foralkyl, hydroxyalkyl, alkoxyalkyl and cycloalkyl. Alternative, R4and R5taken together with the nitrogen atom to which each is attached, form a nonaromatic cycle formula

or

R7, R8, R9and R10each independently selected from a hydrogen atom, hydroxyalkyl, foralkyl, cycloalkyl and alkyl.

Rxand Ryin each case, independently selected from the group comprising a hydrogen atom, hydroxy, hydroxyalkyl, alkyl, alkoxy, alkylamino, fluorine, dialkylamino.

Preferably, if at least one carbon atom in the group of formula (a) is replaced, though any one of R7, R8, R9and R10or one of Rxand Rydifferent from the hydrogen atom. Preferred substituents for R7, R8, R9and R10if they exist, are hydroxyalkyl, foralkyl or alkyl. More specifically, the preferred alkylen the th group is methyl. Preferred substituents for Rxand Ryif they exist, are alkyl, fluorine or hydroxy.

Group of formula (a) are preferred for R4and R5if they together form a non-aromatic cycle. The preferred group for R4and R5if they are together with the nitrogen atom to which each is attached, form a group of formula (a)is (2R)-methylpyrrolidine or (2S)-methylpyrrolidine.

R11, R12, R13and R14each independently selected from a hydrogen atom, hydroxyalkyl, alkyl and foralkyl. Preferably, if at least three substituent selected from R11, R12, R13and R14represent hydrogen atoms.

Q is selected from O and S. Preferred atom for Q is an oxygen atom.

The preferred group for R4and R5if they are together with the nitrogen atom to which each is attached, form a group of formula (b)is morpholinyl.

The variable m is an integer from 1 to 5.

L denotes -[C(R16)(R17)]kwhere R16and R17in each case independently selected from a hydrogen atom and alkyl, and k is 1, 2 or 3. Preferably, if k is 1 or 2.

One option relates to compounds of the formula (II)

where L, R1, R2, R3, R3a, R3b , R4and R5are as described above.

In one preferred embodiment, compounds according to the invention of the formula (II), R1represents-L2-R6a-L3-R6bwhere L2denotes a bond; R6bdenotes a hydrogen atom; L3denotes a bond; R6aselected from 5 - or 6-membered heteroaryl cycle or (4-12)-membered heterocyclic system; R4and R5taken together with the nitrogen atom to which each is attached, form a (4-8)membered nonaromatic cycle represented by the formula (a), and R2, R3, R3a, R3band L are as described above.

Another option relates to compounds of the formula (III)

where L, R1, R2, R3, R3a, R3b, R4and R5are as described above.

In one preferred embodiment, compounds according to the invention of the formula (III), R1represents-L2-R6a-L3-R6bwhere L2denotes a bond; R6bdenotes a hydrogen atom; L3denotes a bond; R6aselected from 5 - or 6-membered heteroaryl cycle, or (4-12)-membered heterocyclic system; R4and R5taken together with the nitrogen atom to which each is attached, form a (4-8)membered nonaromatic cycle, presents what armoloy (a), and R2, R3, R3a, R3band L are as described above.

Specific examples of the compounds included, as expected, in the scope of the invention, include, but are not limited to, the following connections:

4'-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-{(1S,2S)-2-[(2-methylpyrrolidine-1-yl)methyl]cyclopropyl}-1,1'-biphenyl-4-carbonitrile;

5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2,6-dimethyl-3-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine;

2-methoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine;

5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]m is Teal}cyclopropyl)phenyl]pyrimidine;

2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he;

2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he;

2-methyl-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1,3-benzothiazole;

1,3,5-trimethyl-4-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1H-pyrazole;

2,6-dimethyl-3-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine;

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine-5-amine;

4'-((1R,2S)-2-{2-[(2R)-2-methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-[(TRANS)-2-(2-pyrrolidin-1-retil)cyclopropyl]-1,1'-biphenyl-4-carbonitrile;

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxamide;

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]isonicotinamide;

2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he;

1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]piperidine-2-he;

1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}of Cyclops who drank)phenyl]azepin-2-he;

1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-he;

1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-he;

1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-he;

1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azepin-2-he;

1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]piperidine-2-he;

1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-he;

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]ndimethylacetamide and

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1H-1,2,4-triazole-3-carboxamide.

The following compounds can be obtained according to methods described here and schemes:

5-(pyrrolidin-1-ylcarbonyl)-2-{4-[(TRANS)-2-(2-pyrrolidin-1-ileti}cyclopropyl]phenyl}pyridine;

4'-{(1S,2R)-2-[2-(2-methylpyrrolidine-1-yl)ethyl]cyclopropyl}-1,1'-biphenyl-4-carbonitrile;

4'-((1S,2R)-2-{2-[(3R)-3-hydroxypyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-((1S,2R)-2-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;

4'-[(1S,2R)-2-(2-azepin-1-ileti}cyclopropyl]-1,1'-biphenyl-4-carbonitrile and

4'-[(1S,2R)-2-(2-morpholine-4-ileti}cyclopropyl]-1,1'-biphenyl-4-carbonitrile.

The preferred options are compounds selected from the following:

2-methoxy-5-[4-((1S,2S)-2{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;

2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he, or their salts.

Another preferred variant relates to the compound 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-it or its salt.

Compounds according to the invention represent, according to the 5,01 ACD/ChemSketch (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or according to the nomenclature of the ACD; differently, the compounds denoted using ChemDraw (Cambridgesoft). The practice of naming chemical compounds based on the structures, and the establishment of chemical structures from data chemical names well known to the average expert in the field.

Compounds according to the invention can exist as stereoisomers, where there are asymmetric or chiral centers. These stereoisomers are "R" or "S" isomers depending on the configuration of substituents around the chiral carbon atom. Used here, the symbols "R" and "S" represent the configuration defined in the recommendations of the IUPAC 1974 for section E, Fundamental stereochemistry in Pure Appl. Chem., 1976, 45: 13-30. The invention addresses the various stereoisomers and mixtures thereof, and they are specifically included in the scope of this invention. The stereoisomers including the up enantiomers and diastereoisomers and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds according to the invention can be obtained synthetically from commercially available starting materials that contain asymmetric or chiral centers or by receiving racemic mixture, followed by separation, which is well known to the average person skilled in the art. These separations are illustrated by (1) joining a mixture of enantiomers to a chiral auxiliary agent, separating the resulting mixture of diastereomers by means of recrystallization or chromatography, and an optional release of the optically pure product from the auxiliary agent, as described by Furniss, Hannaford, Smith, and Tatchell, "Vogel''s Textbook of Practical Organic Chemistry", 5th edition (1989), Longman Scientific &Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) ways fractionated recrystallization.

Compounds according to the invention can exist as CIS - or TRANS-isomers, where the substituents in the loop can be attached so that they are on the same side of cycle (CIS) relative to each other or on opposite sides of the loop relative to each other (TRANS). For example, CYCLOBUTANE and cyclohexane can be present as CIS - or TRANS-configuration and may be present as a single isomer of the mixture of CIS - and TRANS-isomers. Individual CIS - or TRANS-isomers of the compounds according to the invention can be obtained synthetically from commercially available starting materials using selective organic transformations, or to receive individual isomeric forms by purification of the mixture of CIS - and TRANS-isomers. Such methods are well known to the average person skilled in the art and may include separation of the isomers by means of recrystallization or chromatography.

It should be understood that the compounds according to the invention may have tautomeric forms, and geometric isomers, and that they also form an aspect of the invention. It is also understood that the compounds according to the invention can exist as isomers, where the atoms can have different mass, such as hydrogen, deuterium and tritium, or12C,11C and13C, or19F and18F.

Methods for obtaining compounds of the invention

Compounds according to the invention can be better understood in connection with the following synthetic schemes and methods that illustrate the ways in which you can get a data connection.

In the descriptions of the following schemes and examples used the following abbreviation: Ac is acetyl; atm - atmospheric; AIBN - 2,2'-azobis(2-methylpropionitrile); BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; Boc - butyloxycarbonyl; Bu is butyl; dba - dibenzylideneacetone; DBU is 1,8-diazabicyclo[5,4,0]undec-7-ene; DHM - dichloromethane; DIBAL-H - diisobutylaluminium; DMAP is 4-(N,N-dimethylamino)pyridine; DME is 1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO is dimethylsulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; EDTA - ethylenediaminetetraacetic acid; Et is ethyl; EtOH is ethanol; EtOAc is ethyl acetate; HPLC - high performance liquid chromatography; IPA - isopropyl alcohol; IPAC or IPAc - isopropylacetate; LDA - sitedisability; NBS is N-bromosuccinimide; NIS is N-jodatime; Me is methyl; MeOH - methanol; Ms - methanesulfonyl; MTBE tert-butyl methyl ether; Pd, palladium; Ph is phenyl; tBu is tert-butyl; TE-buffer - combined buffer Tris and EDTA; TEA is triethylamine; TFA - triperoxonane acid; THF - tetrahydrofuran; Tris - 2-amino-2-hydroxymethyl-1,3-propandiol and Ts - couple-toluensulfonyl; K.T. - "room temperature" or ambient temperature, respectively, of 15-40°C. as identifiers available in descriptions of the compounds presented in the literature or available commercially, you can use CAS; CAS numbers are identification numbers assigned to the connection service Chemical Abstracts Service of the American Chemical Society and is well known to the average expert in the field.

Compounds according to this invention can be obtained by various synthetic methods. Typical methods shown in schemes 1-7, but are not limited to this.

Scheme 1/p>

Compounds of formulas (13) and (14), where R3, R3a, R3b, R4and R5such as defined in formula (I), R1indicates an L2-R6a-L3-R6band R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, where L2denotes a bond, -N(H), -N(alkyl), -O - or-S-, and R6a, L3and R6bsuch as defined in formula (I)can be obtained as described in scheme 1. Esters of formula (1), where R denotes lower alkyl and X is Cl, Br, I or triflate purchased or obtained using methodologies well known to the average person skilled in the art, can be recovered using a reducing agent such as DIBAL, but is not limited to this, and getting allyl alcohols of the formula (2). Allyl alcohols of the formula (2) can be converted to cyclopropylamine alcohols of formulas (5) and (6), following the methodology of work A. Charette, J.Org. Chem. 1998. Cyclopropylamine alcohols of formulas (5) and (6) can oxidize through interaction, known as oxidation in Turn, using this agent as DMSO and oxalicacid, but is not limited to this, and getting the aldehydes of the formula (7) and (8). References describing this methodology can be found in the following work: Tidwell, Thomas T. Organic Reactions (New York) (1990), 39, 297-572 and cited in this article the links. The aldehydes of the formulae (7) and (8) can be processed restore the representatives, such as Lamborgini sodium or triacetoxyborohydride sodium, but not limited to, in the presence of an amine of the formula (9), through interaction, known as reductive amination, with the preparation of amines of the formulas (10) and (11) respectively. References that describe this methodology can be found in the following works: M. D. Bomann, etc., J. Org. Chem., 60: 5995-5960 (1995); A. E. Moormann and others, Synth. Commun., 23: 789-795 (1993) and A. Pelter and others, J. Chem. Soc, PT I, 4: 717-720 (1984); A.F. Abdel-Magid, etc., J. Org. Chem. 1996, 61, 3849-3862.

You can use the Suzuki reaction for the conversion of amines of the formulas (10) and (11), respectively, in the compounds of formulas (13) and (14), where R3, R3a, R3b, R4, R5such as defined in formula (I), R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R1indicates an L2-R6a-L3-R6bwhere L2denotes a bond, and R6a, L3and R6bsuch as defined in formula (I). On the Suzuki reaction can be performed interaction of amines of the formula (13) and (14), where X denotes triplet, I, Br or Cl, with baronowie acids or baronowie esters of the formula (12), where R101denotes a hydrogen atom or alkyl, a metal catalyst, such as (but not limited to) palladium diacetate or Pd(PPh3)4not necessarily with the addition of Pd-ligand, such as 2-(dicyclohexylphosphino)beef is nil or Tris(2-furyl)phosphine, and grounds, such as (but not limited to) water 0,2M K3PO4or sodium carbonate.

Differently, instead Baranovich acids or esters of the formula (12) can be used in the Suzuki reaction pinacolborane reagents, such as (but not limited to) the reagents represented by the formula (12a). References that describe the preparation and use of such reagents suitable methodology the Suzuki reaction can be found in the following work: N. Miyaura and other, Chem. Rev. 95: 2457 (1995) and the references cited in this article.

There are many aryl, heteroaryl and heterocyclic Baranovich acids and esters Baranovich acids, which are commercially available or which can be obtained, as described in the scientific literature of synthetic organic chemistry. Examples of reagents in the form of Baranovich acids and esters Baranovich acids for the synthesis of compounds of formula (I) are the reagents below in table 1 and the following description, but is not limited to this.

Table 1
Examples of reagents in the form of Baranovich acids and esters Baranovich acids
Boranova acid and esters Baranovich acidsCommercial source, Chemical Abstracts Number (CAS #) Il the literary reference
2 pyrimidine-5-baronova acidCAS #373384-19-1
2-methoxypyridine-5-baronova acidFrontier Scientific, Inc., Logan, UT, USA
1H-pyrimidine-2,4-Dion-5-baronova acidSpecs, Fleminglaan, the Netherlands CAS #70523-22-7; Schinazi, Raymond F.; Prusoff, William H., Synthesis of 5-(dihydroxyaryl)-2'-deoxyuridine and related boron-containing pyrimidines, Journal of Organic Chemistry (1985), 50(6), 841-7.
pyridine-3-baronova acidCAS #1692-25-7, Frontier Scientific, Inc., Logan, UT, USA
2,4-dimethoxypyrimidine-5-baronova acidCAS #89641-18-9, Frontier Scientific, Inc., Logan, UT, USA
2-methoxy-5-pyridineboronic acidDigital Specialty Chemicals, Dublin, NH; CAS #163105-89-3; New stable when stored halogen and alkoxy-substituted pyridylboron acids and their reactions of cross-linking by Suzuki with getting heteroarylboronic, Parry, Paul R.; Bryce, Martin R.; Tarbit, Brian, Department of Chemistry, Synthesis (2003), (7), 1035-1038; Functional pyridylboron acids and their reactions of cross-linking by Suzuki with obtaining new heteroarylboronic, Parry, Paul R.; Wang, Changsheng; Batsanov, Andrei S.; Bryce, Martin R.; Tarbit, Brian, Journal of Organic Chemistry (2002), 67(21), 7541-7543.
pyrimidine-5-baronova acidCAS #109299-78-7, S. Gronowitz and others, "On the synthesis of various thienyl and selenitireducens", Chem. Scr. 26(2): 305-309 (1986).
pinacolone ether pyrimidine-5-Bronevoy acidUmemoto and others, Angew. Chem. Int. Ed. 40(14): 2620-2622 (2001).
hydrate 2-methylpyridin-5-Bronevoy acidSYNCHEM OHG Heinrich-Plett-Strassse 40; Kassel, D-34132; Germany; CAS #659742-21-9
2H-Piran, 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)CAS # 287944-16-5; Murata, Miki; Oyama, Takashi; Watanabe, Shinji; Masuda, Yuzuru, Synthesis alkenylboronic via palladium-catalyzed bilirubine of alkenylsilanes (or iodine) pinacolborane. Synthesis (2000), (6), 778-780.
3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethylethylamine ether 1(2H)pyridylcarbinol-howl acidCAS # 286961-14-6; Multipurpose synthesis of 4-arylmethylidene via palladium-mediated cross-linking by Suzuki with cyclic vinylboronate, Eastwood, Paul R., Discovery Chemistry, Aventis Pharma, Essex, UK., Tetrahedron Letters (2000), 41(19), 3705-3708.
(5-cyano-3-pyridinyl)-baronova acidCAS #497147-93-0; Chemstep Institut du PIN - University Bordeaux 1 351 cours de la liberation Talence Cedex, 33450 France

Boranova acids is or esters Baranovich acids of formulas (12) and (12a) can be obtained from the corresponding halides or triflates, either through (1) metallocene with organolithium agent followed by the addition of alkylborane or pinacolborane, or (2) cross-linking with the same reagent as bis(pinacolato)LIBOR (CAS #73183-34-3), but is not limited to this.

References that describe first the methodology can be found in the following works: B. T. O'neill, and others, Organic Letters, 2: 4201 (2000); M. D. Sindkhedkar and others, Tetrahedron, 57: 2991 (2001); W. C. Black, etc., J. Med. Chem., 42: 1274 (1999); R. L. Letsinger, etc., J. Amer. Chem. Soc, 81: 498-501 (1959) and F. I. Carroll, and others, J. Med. Chem., 44: 2229-2237 (2001). References that describe the second methodology, can be found in the following papers: T. Ishiyama and others, Tetrahedron, 57: 9813-9816 (2001); T. Ishiyama, etc., J. Org. Chem., 60: 7508-7510(1995); and Takagi and others, Tetrahedron Letters, 43: 5649-5651 (2002).

Another way to get Baranovich acids and esters Baranovich acids includes the interaction described by O. Baudoin, etc., J. Org. Chem., 65: 9268-9271 (2000), which interact aryl and heteroaryl halides or triflates with dialkylanilines, such as pinacolborane, in the presence of triethylamine and palladium(II) acetate in dioxane.

Differently, using other methods of interaction, such as the combination of style, it is possible to obtain the compounds of formulas (13) and (14), where R3, R3a, R3b, R4and R5such as defined in formula (I), R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R1additional the et-L 2-R6a-L3-R6b,where L2denotes a bond, and R6a, L3and R6bsuch as defined in formula (I), respectively, of the amines of the formulas (10) and (11), processing them organomanganese formula (R102)3SnR1where R102denotes alkyl or aryl, in the presence of a palladium source such as Tris(dibenzylidineacetone)dipalladium (CAS # 52409-22-0) or palladium diacetate, and a ligand such as tri(2-furyl)phosphine (CAS # 5518-52-5) or triphenylarsine. Communication is usually carried out in a solvent such as DMF at a temperature of from about 25 to 150°C. Such methods are described, for example, in the works of J. K. Stille, Angew. Chem. Int. Ed. 25: 508 (1986) and T. N. Mitchell, Synthesis, 803 (1992).

Though many stannane available commercially or described in the literature, which describes the reaction of a combination of the still, where the compounds of formulas (10) and (11) can be transformed into compounds of formulas (13) and (14) respectively, you can also get new stannane of aryl halides, aritifical, heteroarylboronic and heteroallele interaction with hexadecyldimethylamine formula ((R102)3Sn)2where R102denotes alkyl or aryl, in the presence of a palladium source, such Pd(Ph3P)4. Examples of sexualteledyne include, but are not limited to this, hexamethyldisilane (CAS # 661-69-8). Such methods are described, for is example, in the works Krische and others, Helvetica Chimica Acta 81(11): 1909-1920 (1998) and Benaglia and others, Tetrahedron Letters 38: 4737-4740 (1997).

You can spend the interaction of these reagents with (10) and (11) to obtain the compounds of formulas (13) and (14) respectively in terms of style, as described, or, for example, under the conditions described in A. F. Littke and others, J. of Amer. Chem. Soc. 124: 6343-6348 (2002).

Compounds of formulas (13) and (14), where R3, R3a, R3b, R4, R5such as defined in formula (I), R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R1indicates an L2-R6a-L3-R6bwhere L3and R6bsuch as defined in formula (I), L2denotes a bond, and R6adenotes a nitrogen-containing heteroaryl or heterocyclic system associated with the source part through the nitrogen, can be obtained by heating compounds of formulas (10) and (11) respectively, with heteroaryl or heterocyclic system of the formula H-R6aL3R6bwhere H denotes a hydrogen atom on the nitrogen atom, in the presence of such grounds as tert-butyl sodium or cesium carbonate (but not limited to, a metal catalyst, such as copper metal or CuI, palladium diacetate (but not limited to) and optionally a ligand, such as BINAP or three-tert-butylphosphine (but not limited to). The interaction can be rastvoritele, such as dioxane, toluene or pyridine (but not limited to). References that describe these methods can be found in the following works: J. Hartwig and others, Angew. Chem. Int. Ed. 37: 2046-2067 (1998); J. P. Wolfe and others, Ace. Chem. Res., 13: 805-818 (1998); M. Sugahara, etc., Chem. Pharm. Bull., 45: 719-721 (1997); J. P. Wolfe and others, J. Org. Chem., 65: 1158-1174 (2000); F. Y. Kwong and others, Org. Lett., 4: 581-584 (2002); A. Klapars, etc., J. Amer. Chem. Soc, 123: 7727-7729 (2001); B. H.Yang, etc., J. were obtained. Chem., 576: 125-146 (1999) and A. Kiyomori and others, Tet. Lett., 40: 2657-2640 (1999).

Compounds of formulas (13) and (14), where R3, R3a, R3b, R4, R5such as defined in formula (I), R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R1indicates an L2-R6a-L3-R6bwhere L2represents-NH - or-N(alkyl)-, and R6a, R6band L3such as defined for the compounds of formula (I)can be obtained by heating compounds of formulas (10) and (11) respectively, with the compound of the formula H2N-R6a-L3-R6bor HN(alkyl)-R6a-L3-R6bwith a base , such as tert-butyl sodium or cesium carbonate (but not limited to), in the presence of a metal catalyst such as metallic copper or CuI, palladium diacetate (but not limited to), and also optionally with a ligand such as BINAP or three-tert-butylphosphine (but not limited to). The interaction can be performed in a solvent, Taco is as dioxane, toluene or pyridine. References that describe these methodologies can be found in the following works: J. Hartwig and others, Angew. Chem. Int. Ed., 37: 2046-2067 (1998); J. P. Wolfe and others, Ace. Chem. Res., 13: 805-818 (1998); J. P. Wolfe and others, J. Org. Chem., 65: 1158-1174 (2000); F. Y. Kwong and others, Org. Lett., 4:581-584(2002); and B. H.Yang, etc., J. were obtained. Chem., 576: 125-146 (1999).

Compounds of formulas (13) and (14), where R3, R3a, R3b, R4and R5such as defined by formula (I), R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R1indicates an L2-R6a-L3-R6bwhere L2denotes oxygen, and R6a, L3band R6bsuch as defined in formula (I)can be obtained by heating compounds of formulas (10) and (11) respectively, with the compound of the formula HOR6a-L3-R6busing a base such as sodium hydride (but not limited to), in a solvent such as toluene or N,N-dimethylformamide, in the presence of metal catalyst such as CuI or palladium diacetate. References that describe these methodologies can be found in the following works: J. Hartwig and others, Angew. Chem. Int. Ed., 37: 2046-2067 (1998); K. E. Torraca, etc., J. Amer. Chem. Soc, 123: 10770-10771 (2001); S. Kuwabe etc., J. Amer. Chem. Soc, 123: 12202-12206 (2001); K. E. Toracca, etc., J. Am. Chem. Soc, 122: 12907-12908 (2000); R. Olivera and others, Tet. Lett, 41:4353-4356 (2000); J.-F. Marcoux, etc., J. Am. Chem. Soc, 119: 10539-10540 (1997); A. Aranyos, etc., J. Amer. Chem. Soc, 121: 4369-4378 (1999); T. Satoh and others, Bull. Chem. Soc. Jpn., 71: 2239-2246 (1998); J. F. Hartwg, Tetrahedron Lett., 38: 2239-2246 (1997); M. Palucki, etc., J. Amer. Chem. Soc, 119: 3395-3396 (1997); N. Hagaetal, J. Org. Chem., 61: 735-745 (1996); R. Bates and others, J. Org. Chem., 47: 4374-4376 (1982); T. Yamamoto and others, Can. J. Chem., 61: 86-91 (1983); A. Aranyos, etc., J. Amer. Chem. Soc, 121: 4369-4378 (1999); and E. Baston and others, Synth. Commun., 28: 2725-2730 (1998).

Compounds of formulas (13) and (14), where R3, R3a, R3b, R4and R5such as defined in formula (I), R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R1indicates an L2-R6a-L3-R6bwhere L2denotes a sulfur atom, and R6a, L3and R6bsuch as defined for the compounds of formula (I)can be obtained by heating compounds of formulas (10) and (11) respectively, with the compound of the formula HSR6a-L3-R6bin the presence of a base, with a metal catalyst such as CuI or palladium diacetate, or without it, in a solvent such as dimethylformamide or toluene. References that describe these methodologies can be found in the following papers: G. Y. Li and others, J. Org. Chem., 66: 8677-8681 (2001); Y. Wang and others, Bioorg. Med. Chem. Lett., 11: 891-894 (2001); G. Liu and others, J. Med. Chem., 44: 1202-1210 (2001); G. Y. Li and others, Angew. Chem. Int. Ed., 40: 1513-1516 (2001); U. Schopfer and others, Tetrahedron, 57: 3069-3074 (2001); C. Palomo, etc., Tet. Lett., 41: 1283-1286 (2000); A. Pelter and others, Tet. Lett., 42: 8391-8394 (2001); W. Lee and others, J. Org. Chem., 66: 474-480 (2001) and A. Toshimitsu, etc., Het. Chem., 12: 392-397 (2001).

Scheme 2

Similarly, compounds of formulas (24) and (25), where 3, R3a, R3b, R4and R5such as defined in formula (I), R1denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, and R2indicates an L2-R6a-L3-R6bwhere L2denotes a bond, -N(H), -N(alkyl), -O - or-S-, and R6a, L3and R6bsuch as defined in formula (I)can be obtained as described in scheme 2, compounds of formula (15), where R denotes lower alkyl, X denotes Cl, Br, I or triflate, using the reaction conditions indicated in scheme 1, except that for the Suzuki reactions using Bronevoy acid or esters of the formula (23) instead of the compounds of the formula (12) and pinacolborane reagents of formula (23a) instead of (12a) and use organostannic formula (R102)3SnR2instead of (R102)3SnR1for a combination of the sill. References that describe the methodology of the Suzuki reaction, can be found in the following work: N. Miyaura and other, Chem. Rev. 95: 2457(1995) and cited in this article references.

Scheme 3

Compounds of the formulas (32) and (33), where R3, R3a, R3b, R4, R5such as defined in formula (I); R1indicates an L2-R6a-L3-R6band R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, where L 2denotes a bond, -N(H), -N(alkyl), -O - or-S -, and R6a, L3and R6bsuch as defined in formula (I)can be obtained as described in scheme 3. The aldehydes of the formulae (24) and (25)obtained in the reaction conditions, the appropriate reaction scheme 1, from esters of formula (1), where R denotes lower alkyl, can be treated with methyltriphenylphosphonium in the presence of a base, such as tert-butyl potassium (but not limited to, obtaining alkenes of formula (26) and (27) respectively. Links related to this method can be found in the works: JohnsonYlide Chemistry, Academic Press: New York, 1966, and Hopps, H. B.; Biel, J. H. Aldrichimica Acta (1969), 2(2), 3-6. Alkenes of formula (26) and (27) can be converted to alcohols of formulas (28) and (29), through a sequence of interactions, known as hydroporinae-oxidation. The alcohols of formulas (28) and (29) can be processed by such agent as triplet-anhydride, taillored or methylchloride (but not limited to), in the presence of a base such as potassium carbonate (but not limited to, receiving respectively triplet, toilet or mesilate. Received triplet, toilet or mesilate can be treated with the amine of formula (9), optionally in the presence of a base such as potassium carbonate or sodium carbonate (but not limited to, receiving amines of the formulas (30) and (31) respectively. Compounds of the formulas (30) and (31) can conversion shall be in the amines of the formulas (32) and (33) respectively, using the reaction conditions described in scheme 1.

Scheme 4

Similarly, compounds of the formulas (42) and (43), where R3, R3a, R3b, R4, R5such as defined in formula (I); R2indicates an L2-R6a-L3-R6band R1denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy, where L2denotes a bond, -N(H), -N(alkyl), -O - or-S -, and R6a, L3and R6bsuch as defined in formula (I)can be obtained as described in scheme 4. Esters of the formula (15), where R denotes lower alkyl, X is Br, Cl or I, can be converted to amines of the formulas (42) and (43), using the reaction conditions described in scheme 3, except that for the Suzuki reaction using Bronevoy acid or esters of the formula (23) instead of the compounds of the formula (12) and pinacolborane reagents of formula (23a) instead of (12a) and except that they use organostannic formula (R102)3SnR2instead of (R102)3SnR1for a combination of the sill.

Scheme 5

Compounds of the formulas (46) and (47), where R3, R3a, R3b, R4, R5such as defined in formula (I); R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy; and R1about the means-L 2-R6a-L3-R6bwhere L2denotes a bond, -N(H), -N(alkyl), -O - or-S -, and R6a, L3and R6bsuch as defined in formula (I)can be obtained as described in scheme 5. Esters of formula (1), where R denotes lower alkyl, X is Br, Cl or I, can be converted to alcohols of formulas (28) and (29) according to scheme 3. The alcohols of formulas (28) and (29) can oxidize, through interaction, known as oxidation in Turn, this agent as DMSO and oxalicacid (but not limited to), in the presence of a base, such as triethylamine, to obtain the aldehydes of the formulae (44) and (45). The aldehydes of the formulae (44) and (45) can be converted to amines of the formulas (46) and (47), respectively, using the reaction conditions described in scheme 3, and converting the compounds of formulas (24) and (25) into compounds of the formulas (32) and (33).

Scheme 6

Similarly, compounds of formulas (50) and (51), where R3, R3a, R3b, R4, R5such as defined in formula (I); R1denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy; and R2indicates an L2-R6a-L3-R6bwhere L2denotes a bond, -N(H), -N(alkyl), -O - or-S-, and R6a, L3and R6bsuch as defined in formula (I)can be obtained as described in scheme 6. Esters of the formula (15), where R denotes lower alkyl, X Ref is em Br, Cl or I, can be converted to alcohols of formulas (38) and (39) as described in scheme 4. The alcohols of formulas (38) and (39) can oxidize through interaction, known as oxidation in Turn, this agent as DMSO and oxalicacid (but not limited to), with aldehydes of the formulae (48) and (49) respectively. The aldehydes of the formulae (48) and (49) can be converted to amines of the formulas (50) and (51) respectively, using the reaction conditions described in scheme 4, and converting the compounds of formulas (38) and (39) into compounds of the formulas (42) and (43).

Scheme 7

Esters of formula (1), where X is I, Br, Cl or hydroxy; R represents lower alkyl; R3, R3aand R3bsuch as defined in formula (I); and R2denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy; you can buy or receive, as described in scheme 7. The halides of the formula (52), where Y represents I, Br or triflate (obtained by treating phenol with triglycerides), you can handle the acrylate in the presence of a palladium source, such as dichlorobis(triphenylphosphine)palladium(II) (CAS# 13965-03-2), or Tris(dibenzylideneacetone)dipalladium (CAS# 52409-22-0), or palladium diacetate, and a ligand such as tri(2-furyl)phosphine (CAS # 5518-52-5) or triphenylphosphine, in a solvent such as DMF, at 25-150°C, receiving esters of the formula (1).

Different esters f is rmula (1) can be obtained through substituted benzaldehyde formula (53) by the Wittig reaction, which is well known to experts in the field of organic synthesis. References that describe these methods can be found in the following works: S. Li and others, Chemische Berichte, 123: 1441-1442 (1990); T. Kauffmann and others, Tetrahedron Lett, 22: 5031-5034 (1981).

Similarly, esters of the formula (15), where X is I, Br, Cl, or hydroxyl; R is lower alkyl; R3, R3aand R3bsuch as defined in formula (I); and R1denotes a hydrogen atom, alkyl, alkoxy, halogen, cyano or dialkoxy; you can buy or receive, as described in scheme 7.

Compounds and intermediate products according to the invention it is possible to allocate and clear ways, well known to experts in the field of organic synthesis. Well-known examples of methods for isolation and purification of compounds can include (but are not limited to, chromatography on a solid carrier, such as silica gel, aluminum oxide or silicon dioxide derivative alkylsilane groups, the recrystallization at high or low temperature with optional pre-treatment with activated carbon, thin-layer chromatography, distillation under different pressures, sublimation in vacuum and friction, as described, for example, in "Vogel''s Textbook of Practical Organic Chemistry", 5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essex CM20 2JE, England.

Compounds according to the invention have, at least, one of the n basic nitrogen, through which you can get the desired salt of the compound during processing of acid compounds. Examples of acids suitable for this interaction include (but is not limited tartaric acid, lactic acid, succinic acid, as well as almond, atrractive, methansulfonate, econsultancy, toluensulfonate, naphthalenesulfonate, benzosulfimide, coal, fumaric, maleic, gluconic, acetic, propionic, salicylic, hydrochloric, Hydrobromic, phosphoric, sulfuric, citric or hydroxybutiric acid, camphorsulfonic, Apple, phenylacetic acid, aspartic, glutamic and the like.

Compositions of the invention

The invention also relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula (I) in combination with a pharmaceutically acceptable carrier. The compositions contain compounds according to the invention is prepared by adding one or more non-toxic pharmaceutically acceptable carriers. It is possible to prepare pharmaceutical compositions for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.

Used herein, the expression "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid will fill the l, the diluent, encapsulating material or auxiliary agent of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragakant; malt; gelatin; talc; cocoa butter and waxes for suppositories; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters, for example etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; water, not containing pyrogens; isotonic saline; ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and colouring agents, agents regulating the release, covering agents, sweeteners, flavoring agents and fragrances, preservatives and antioxidants can also be present in the composition at the discretion of the specialist in the field of preparation of pharmaceutical preparations.

The pharmaceutical compositions according to this invention, you can enter humans and other mammals orally, rectally, parenterally, intracisternally, intrawaginalno, intraperitoneally, topically (in the form of powders, ointments or drops), transbukkalno or by oral or nasal spray. Used herein, the term "parenteral" refers to introduction methods, which include intravenous, intramuscular, intraperitoneal, vnutrigrudne, subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injections contain pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for recovery in the form of sterile solutions or dispersions for injection. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like and suitable mixtures), vegetable oils (e.g. olive oil) and organic esters for injection, such as etiloleat, or their suitable mixtures. Suitable fluidity of the composition can be maintained, for example, using a coating such as lecithin, maintaining the required particle size in the case of dispersions, and by using SAS.

These compositions the AI can also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. To prevent the action of microorganisms using various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. Also, it may be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the pharmaceutical forms for injection can be performed using agents that slow the absorption such as aluminum monostearate and gelatin.

In some cases, to prolong the action of drugs is often desirable to slow the absorption of drugs after subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor water solubility. Then the absorption rate of the drug depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Differently, delayed absorption of parenteral entered the dosage form reaches through dissolution or suspendirovanie drugs in the oil filler.

In addition to the active compounds of the suspension may contain suspendresume agents, for example ethoxylated isostearyl alcohols, polyoxyethylene the orbits and complex sorbitane esters, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar, tragakant and mixtures thereof.

If you want and for more effective distribution, the compounds according to the invention can be incorporated in systems with slow release or targeted delivery, such as polymer matrices, liposomes, and microspheres. They can be sterilized, for example, by filtration through filter traps bacteria, or incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile environment for injection immediately before use.

Introduced by injection depo-form is prepared, getting microencapsulation matrix medicines in biorazlagaemykh polymers, such as polylactide-polyglycolide. Depending on the ratio of drug and polymer and the nature of the particular polymer used, you can adjust the speed of release of the drug. Examples of other biorazlagaemykh polymers include poly(complex orthoevra) and poly(anhydrides). Introduced by injection depo-preparations also get through seizure of drugs in liposomes or microemulsions that are compatible with body tissues.

Injectable preparations can be sterilized, for example, by filtration through filter traps bacteria or incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile environment for injection immediately before use.

Injectable preparations, for example introduced by the injection of sterile aqueous or oil suspensions can be prepared according to known methods using suitable dispersing or wetting agents and suspendresume agents. A sterile preparation for injection may also be a sterile solution, suspension or emulsion for injection into non-toxic acceptable for parenteral use diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable fillers and solvents that can be used are water, ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, as a solvent or medium for suspension usually use sterile, non-volatile oils. For this purpose you can use any clean, non-volatile oils, including synthetic mono - or diglycerides. In addition, in preparations for injection use fatty acids such as oleic acid.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, one or more compounds according to the invention are mixed, p is at least with one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or fillers, such as starches, lactose, sucrose, glucose, mannitol, and salicylic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum Arabic; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or starch from tapioca, alginic acid, certain silicates and sodium carbonate; (e) agents, retarding dissolution such as paraffin; f) absorption accelerators such as Quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerylmonostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills dosage form may also comprise buffering agents.

Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using lactose or milk sugar, as well as glycols of high molecular mass.

Solid dosage forms of tablets, pills, capsules fruit is, pills and granules can be obtained with coatings and shells, such as intersolubility coatings and other coatings well known in the field of pharmaceutical preparations. They may not necessarily contain agents that provide opacity, as well as to have a composition in which the active ingredient(s) is released with a delay and only (or preferentially) in a certain part of the intestinal tract. Examples of materials that may be useful for slow release of the active agent can include polymeric substances and waxes.

Compositions for rectal or vaginal injection preferably represent suppositories, which can be obtained by mixing the compounds of this invention with suitable carriers, does not cause irritation, such as cocoa butter, polyethylene glycol or wax for suppositories, which is solid at ambient temperature and liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents, usually is used in this field, for example, water or other solvents, agents that promote dissolution, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, wheat germ oil, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, glycols and sorbitane esters of fatty acids and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavoring agents and fragrances.

Dosage forms for topical or transdermal administration of compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, tools for inhalation or patches. The desired compound according to the invention is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, which may be required. It is also believed that ocular medications, ear drops, eye ointments, powders and solutions are also included in the scope of this invention.

Ointments, pastes, creams and gels may contain, in addition to the active compounds according to this invention the animals and p is Stateline fats, oils, waxes, paraffins, starch, tragakant, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide or mixtures thereof.

Powders and sprays can contain, in addition to the compounds according to this invention lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and powdered polyamide or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorocarbons.

Compounds according to the invention can also be introduced in the form of liposomes. As is well known in this field, liposomes is usually derived from phospholipids or other lipid substances. Liposomes are formed from mono - or multi-layer of hydrated liquid crystals that are dispersed in the aquatic environment. You can use any non-toxic, physiologically acceptable and digestible lipid capable of forming liposomes. These compositions in the form of liposomes may contain in addition to the compounds according to the invention, stabilizers, preservatives and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidylcholine (lecithins), used separately or together.

The method of the formation of liposomes are known in this field. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976), p33 and following.

Dosage forms for the outer application of the compounds according to the invention include powders, sprays, ointments and remedies for inhalation. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants that may be required. It is also believed that eye medication, eye ointments, powders and solutions are also included in the scope of this invention. Also considered liquid aqueous compositions containing the compounds according to the invention.

You can use the compounds according to the invention in the form of pharmaceutically acceptable salts, esters or amides, derivatives of inorganic or organic acids. Used herein, the expression "pharmaceutically acceptable salts, esters and amides" refers to salts of carboxylates, additive salts of amino acids, zwitterions, esters and Amida formula (I), which in part made of the medical report are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, correspond to the reasonable value of benefit/risk and are effective for their intended use.

Used herein, the expression "pharmaceutically acceptable salt" refers to salts that are made within the medical reports are suitable for use in contact with tissues of the people and lower animals without undue toxicity, irritation, allergic response and the like and meet the reasonable value of benefit/risk. Pharmaceutically acceptable salts are well known in this field. Salt can be obtained on site during the final isolation and purification of the compounds according to the invention or separately by interacting functions of the free base with a suitable organic acid.

Typical additive salts of acids include, but are not limited to) acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphorsulfonate, digluconate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic (isetionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, para-toluensulfonate, undecanoate. Preferred salts of the compounds according to the invention are salts of tartrate and hydrochloride.

Examples of acids that can be used for the formation of pharmaceutically acceptable additive salts of acids include inorganic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as y is veleva acid, maleic acid, succinic acid and citric acid.

Additive salts of the bases can be obtained on site during the final isolation and purification of the compounds according to this invention by interacting fragment containing carboxylic acid with a suitable base such as the hydroxide, carbonate or bicarbonate pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, the salts of cations of alkali or alkaline earth metals, such as lithium salts, sodium, potassium, calcium, magnesium and aluminum and the like, and nontoxic Quaternary ammonium salt and amines cations, including ammonium salts of Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other typical organic amines suitable for the formation of additive salts of bases include Ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

You can also quaternization basic nitrogen-containing groups such agents as lower alkylhalogenide, for example methyl-, ethyl-, propyl - and butylchloride, bromides and iodides; diallylsulfide, for example the dimethyl-, diethyl-, dibutil and dimycolate; alkylhalogenide with a length of chain, such Cardell-, lauryl-, myristyl and sterilgarda, bromides and iodides; arylalkylamine, such as benzyl and phenetermine and others. It soluble or dispersible in water or oil products.

Used herein, the expression "pharmaceutically acceptable ester” refers to esters of the compounds according to the invention, which is hydrolyzed in vivo and include compounds that break easily in the human body, leaving the original compound or its salt. Examples of pharmaceutically acceptable, non-toxic esters of the invention include C1-C6alkalemia esters and C5-C7cycloalkyl esters, although preferred are C1-C4alkalemia esters. Esters of compounds of formula (I) can be obtained in the usual way. For example, such esters can be attached to hydroxy groups by reaction of a compound that contains the hydroxy-group, acid and alkalicarbonate acid, such as acetic acid, or with acid and arylcarbamoyl acid, such as benzoic acid. In the case of compounds containing carboxylate group, pharmaceutically acceptable esters derived from compounds containing carboxylate group, by reaction of this compound with a base, so it is to triethylamine, and alkylhalogenide, the alkyl triflate, for example methyliodide, benzimidazol, cyclopenthiazide. They can also be obtained by the interaction of the compounds containing carboxylate group with acid such as hydrochloric acid, and alcohol, such as methanol or ethanol.

Used herein, the expression "pharmaceutically acceptable amide" refers to non-toxic Amida according to the invention, derivatives of ammonia, primary C1-C6alkylamines followed and secondary C1-C6dialkylamino. In the case of secondary amines amine may represent a 5 - or 6-membered heterocycle containing one nitrogen atom. Preferred amides are derivatives of ammonia, primary C1-C3alkylamide and secondary C1-C2dialkylamide. Amides of the compounds of formula (I) can be obtained in the usual way.

Pharmaceutically acceptable amides are obtained from compounds containing primary or secondary amino groups, the interaction of a compound that contains an amino group, with alkylamides, arrangedwith, allelochemical or arylalkenes. In the case of compounds containing carboxylate group, pharmaceutically acceptable esters derived from compounds containing carboxylate group, the interaction of this compound with a base, such as triethylamine, dehydrating agent, such is how dicyclohexylcarbodiimide or carbonyldiimidazole, and alkylamino, dialkylamino, for example, methylamine, diethylamine, piperidine. They can also be obtained by interaction of this compound with an acid, such as sulfuric acid, and alkalicarbonate acid, such as acetic acid, or with acid and arylcarbamoyl acid, such as benzoic acid, dehydrating conditions, for example, with the addition of molecular sieves. The composition may contain the compound according to the invention in the form of pharmaceutically acceptable prodrugs.

Used here, the expression "pharmaceutically acceptable prodrug" or "prodrug" refers to prodrugs of the compounds according to the invention, which in part made of the medical report are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, correspond to the reasonable value of benefit/risk and effective for their intended use. Prodrugs according to the invention can quickly be transformed in vivo into the parent compound of formula (I), for example, by hydrolysis in blood. A comprehensive discussion are given in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), incorporated herein by reference.

The invention considers the FA is matemticas active compounds, synthesized chemically or formed by in vivo biotransformation to compounds of formula (I).

The methods of the invention

The compounds and compositions according to the invention are useful for the treatment and prevention of certain diseases and disorders in humans and animals. An important consequence of the ability of compounds according to the invention to modulate the effects of H3-histamine receptors in the cells is the ability of the compounds described in the invention, to influence physiological processes in humans and animals. Thus, the compounds and compositions described in the invention, are useful for the treatment and prevention of diseases and disorders modulated H3-histamine receptors. Usually the treatment or prevention of such diseases and disorders can be produced through the selective modulation of H3-histamine receptor in a mammal, with the introduction of the compounds or compositions according to the invention, by itself or in combination with another active agent, as part of a therapeutic schema.

Compounds according to the invention, including (but not limited to the compounds mentioned in the examples, possess an affinity for H3-histamine receptors and, therefore, the compounds according to the invention can be useful for the treatment and prevention of such diseases or conditions, as a violation, articulating what Eesa hyperactivity with attention deficit (ADHD), attention deficit disorder, dementia and disease with deficiency of memory, learning, schizophrenia, cognitive deficits in schizophrenia, cognitive deficits and dysfunction in psychiatric disorders, Alzheimer's disease, a small cognitive disturbance, epilepsy, seizures, allergic rhinitis and asthma, motion sickness, vertigo, Meniere's disease, vestibular disorders, vertigo, obesity, diabetes, type II diabetes, syndrome X, syndrome of insulin resistance, metabolic syndrome, pain, including neuropathic pain, neuropathy, sleep disorders, narcolepsy, pathological sleepiness, impaired circadian rhythm, drug abuse, change mood, bipolar violation, depression, obsessive-compulsive violation, Tourette syndrome, Parkinson's disease, and medullary thyroid carcinoma, melanoma and polycystic ovary. The ability of modulators H3-histamine receptors and, consequently, the compounds according to the invention, to prevent or cure such violations demonstrated by the examples found in the following links.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat disorders characterized by hyperactivity with attention deficit (ADHD), and attention deficit disorder, can sell in order to demonstrate the results Cowart and other J. Med. Chem.2005, 48, 38-55; Fox, G. B. and others, "Pharmacological properties of ABT-239: II. Neuropsychological characterization and broad preclinical efficacy for cognitive abilities and in schizophrenia potent and selective antagonist of N3-histamine receptor", the Journal of Pharmacology and Experimental Therapeutics (2005) 313, 176-190; "Effects of ligands GT-2331 N3-histamine receptors and ciproxifan in repeated experiments on the acquisition of avoidance in young spontaneously hypertensive rats," Fox, G. B. and other Behavioural Brain Research (2002), 131 (1,2), 151-161; Yates and other JPET (1999) 289, 1151-1159 "Identification and pharmacological characterization of a series of new 1H-4-substituted-imidazolidine ligands of the histamine receptor H3"; Ligneau, and others the Journal of Pharmacology and Experimental Therapeutics (1998), 287, 658-666; Tozer, M. Expert Opinion Therapeutic Patents (2000) 10, 1045; M. T. Halpern, "GT-2331", Current Opinion in Central and Peripheral Nervous System Investigational Drugs (1999) 1, 524-527; Shaywitz and others, Psychopharmacology, 82: 73-77 (1984); Dumery and Blozovski, Exp. Brain Res., 67: 61-69 (1987); Tedford and others, J. Pharmacol. Exp. Ther., 275: 598-604 1995); Tedford and others, Soc. Neurosci. Abstr, 22:22 (1996); Fox and others, Behav. Brain Res., 131: 151-161 (2002); Glase, S. A., and other "Disorders characterized by hyperactivity with attention deficit: pathophysiology and development of new treatment methods", Annual Reports in Medicinal Chemistry (2002), 37 11-20; Schweitzer, J. B. and Holcomb, H. H. "Investigational drugs for disorders characterized by hyperactivity with attention deficit", Current Opinion in Investigtive Drugs (2002) 3, 1207.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat dementia and disease with deficiency of memory and learning can be demonstrated by the results of the work "Two new and selective nikitabelyh antagonist H3receptor A-304121 and A-317920: II. In vivo behavioral and neuropsychological characteristics" Fox, G. B., and others the Journal of pharmacology and experimental therapeutics (2003 Jun), 305(3), 897-908; "Identification of a new antagonist H3receptors (H3R) with the properties to enhance cognitive ability in rats" Fox, G. B.; Inflammation Research (2003), 52 (Suppl. 1), S31-S32; Bernaerts, P. and others", the Antagonist of the histamine H3typename increases dependent on the dose of the consolidation of memory and draws the amnesia caused by dizocilpine or scopolamine, when a single test for inhibition of avoidance response in mice, Behavioural Brain Research 154 (2004) 211-219; Onodera and other Nauyn-Schmiedebergs Arch. Pharmacol. (1998), 357, 508-513; Prast and other Brain Research (1996) 734, 316-318; Chen et al Brain Research (1999) 839, 186-189 "Effects of histamine on MK-801-induced memory deficit in rats, acting in the radial maze"; Passani and other Central histaminergic system and cognitive ability", Neuroscience and Biobehavioral Reviews (2000) 24, 107-113.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat schizophrenia, cognitive Def the CIT in schizophrenia and cognitive deficits, you can demonstrate the results Fox, G. B. and others, "Pharmacological properties of ABT-239: II. Neuropsychological characterization and broad preclinical efficacy for cognitive abilities and in schizophrenia potent and selective antagonist of N3-histamine receptor", the Journal of Pharmacology and Experimental Therapeutics (2005) 313, 176-190 and "Strengthening predisposing inhibition of fear in mice antagonists H3receptors by theoperation and ciproxifan" Browman, Kaitlin E., and others, Behavioural Brain Research (2004), 153(1), 69-76; "Blockade of H3receptors by theoperation improves cognitive ability in rats without causing motor excitation"; Komater, V. A. and others Psychopharmacology (Berlin, Germany) (2003), 167(4), 363-372; AA Rodrigues, FP Jansen, Leurs R, H Timmerman and GD Prell "Interaction of clozapine with H3-histamine receptor in the rat brain" British Journal of Pharmacology (1995), 114(8), pp. 1523-1524; Passani and other Central histaminergic system and cognitive ability" Neuroscience and Biobehavioral Reviews (2000) 24, 107-113; Morriset, S. and others "Atypical antipsychotics increase histamine metabolism in the brain through blockade of the receptors 5-hydroxytryptamine 2A" Journal of Pharmacology and Experimental Therapeutics (1999) 288, 590-596.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat dysfunction in psychiatric disorders, disease, Alzhei the EPA and a small cognitive impairment can be demonstrated by the results Meguro, etc. Pharmacology, Biochemistry and Behavior (1995) 50 (3), 321-325; Esbenshade, T. and others "Pharmacological and behavioral properties of A-349821, selective and potent human antagonist N3-histamine receptor," Biochemical Pharmacology 68 (2004) 933-945; Huang, Y.-W. and others, "Effect of the antagonist of the histamine H3closedprofit on induced by MK-801 deficit in spatial memory in rats, Sprague-Dawley, which is assessed in experiments with a radial maze", Behavioural Brain Research 151 (2004) 287-293; Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78; P. Panula and others, Neuroscience (1997) 82, 993-997; Haas and others, Behav. Brain Res. (1995) 66, 41-44; De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986), 283, 193-198; Kamei and others, Psychopharmacology, 10 (1990) 102, p. 312-318; Kamei and Sakata, Jpn. J. Pharmacol. (1991), 57, 437-482; Schwartz and others, Psychopharmacology, The Fourth Generation of Progress. Bloom and Kupfer (eds). Raven Press, New York, (1995) 397 and Wada and others, Trends in Neurosci. (1991) 14, p. 415.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat epilepsy and seizures can be demonstrated by the results: Harada, C, etc. "Inhibitory effect of jodieproffit, selective antagonist of the histamine H3on the seizures caused by kindling almond complex brain," Brain Research Bulletin (2004) 63: 143-146; and Yokoyama and others, Eur. J. Pharmacol. (1993) 234: 129-133; Yokoyama and others European Journal of Pharmacology (1994) 260: 23; Yokoyama and linuma, CNS Drugs (1996) 5: 321; Vohora, Life Sciences (2000) 66: 297-301; Onodera, etc., Prog. Neurobiol. (1994) 42: 685; Chen, Z. and others "Headlight is Ekologicheskie effects carcinine on histaminergic neurons in the brain," British Journal of Pharmacology (2004) 143, 573-580; R. Leurs, R.C. Vollinga and H. Timmerman, "the medicinal chemistry and therapeutic potential of ligands of N3-histamine receptor", Progress in Drug Research (1995) 45: 170-165; Leurs and Timmerman, Prog. Drug Res. (1992) 39: 127; H. Yokoyama and K. linuma "Histamine and seizures: implications for the treatment of epilepsy", CNS Drugs, 5(5): 321-330 (1995) and K. Hurukami, H. Yokoyama, K. Onodera, K. linuma and T. Watanabe, "AQ-0145, a newly developed antagonist of histamine H3reduces sensitivity to seizures are electrically induced convulsions in mice", Meth. Find. Exp. Clin. Pharmacol., 17(C):70-73 (1995); Yawata and other "Role histaminergic neurons in the development of epileptic seizures in EL mice," Molecular Brain Research 132 (2004) 13-17.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat allergic rhinitis and asthma, can be demonstrated by the results McLeod, R.L., Mingo, G.G., Herczku, C, DeGennaro-Culver, F., Kreutner, W., Egan, R.W., Hey, J.A., "a Combined blockade of histamine receptors (H1and H3makes removing the swelling of the nose in an experimental model of swelling of the nose", Am. J. Rhinol. (1999a) 13: 391-399; McLeod, Robbie L; Egan, Robert W.; Cuss, Francis M.; Bolser, Donald C; Hey, John A. (Allergy, Schering-Plough Research Institute, Kenilworth, NJ, USA.) Progress in the study of the respiratory tract (2001), 31 (New Drugs for Asthma, Allergy and COPD): 133-136; A. Delaunois, A. and others, "Modulation of acetylcholine, capsaicin and substance P affects N3-histamine receptors in selected perfoirmance rabbit lung" European Jounal of Pharmacology (1995) 277: 243-250; Dimitriadou and other "Functional relationship between mast cells and C-sensitive nerve fibers identified through the modulation of the histamine H3receptors in the lungs and spleen of rats", Clinical Science (1994), 87: 151-163.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat motion sickness, vertigo, Meniere's disease, vestibular disorders, vertigo, can be demonstrated by the results: Pan, and other, Methods and Findings in Clinical Pharmacology (1998), 20(9), 771-777; O'neill and others, Methods and Findings in Clinical Pharmacology (1999) 21(4), 285-289; and R. Leurs, R.C. Vollinga and H. Timmerman "medicinal chemistry and therapeutic potential of ligands of N3-histamine receptor", Progress in Drug Research (1995), 45: 170-165; Lozada and other "Flexibility expression and binding of H3-histamine receptors in the vestibular nuclei after labyrinthectomy in rats", BioMedCentral Neuroscience 2004, 5:32.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat obesity, diabetes, type II diabetes, syndrome X, syndrome of insulin resistance and metabolic syndrome can be demonstrated by the results: Hancock, A. A. "Effects against obesity A-331440, new neiedzilinasos antagonist N3-histamine receptors", European Journal of Pharmacology (2004) 487, 183 - 197; Hancock, A. A. and others "Histamine antagonists H 3in models of obesity," Inflamm. res. (2004) 53, Supplement 1 S47-S48;and E. Itoh, M. Fujimiay and A. Inui, "Typename, the antagonist of N3-histamine receptor strongly suppresses induced peptide YY food consumption in rats," Biol. Psych. (1999) 45(4): 475-481; S.I. Yates and others, "Effects of a new antagonist N3-histamine receptor GT-2394 on food consumption and weight increase in rats, Sprague-Dawley", Abstracts, Society for Neuroscience, 102, 10:219 (November, 2000); and C. Bjenning, and other "Perifericheskie input ciproxifan elevates hypothalamic histamine and effectively reduces food intake in rats Sprague Dawley", Abstracts, International Sendai Histamine Symposium, Sendai, Japan, #P39 (November, 2000); Sakata T, etc. "Hypothalamic neuronal histamine modulates unlimited food rats", Brain research (1990 Dec 24), 537(1-2), 303-6.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat pain, including neuropathic pain, and neuropathy, can be demonstrated by the results: Malmberg-Aiello, Petra; Lamberti, Claudia; Ghelardini, Carla; Giotti, Alberto; Bartolini, Alessandro. British Journal of Pharmacology (1994), 111(4), 1269-1279; Hriscu, Anisoara; Gherase, Florenta; Pavelescu, M.; Hriscu, E. "an Experimental evaluation of the analgesic efficacy of some antihistamines as proof of involvement histaminergic receptors in pain, Farmacia, (2001), 49(2), 23-30, 76.

The ability of compounds according to the invention, including (but not limited to the ü this connection, specified in the examples, to treat sleep disorders, including narcolepsy and pathological sleepiness and impaired circadian rhythm, can be demonstrated by the results: Barbier, A. J. and others "promoting Strong revival effect of JNJ-5207852, new H3antagonist-based diamine", British Journal of Pharmacology (2004) 1-13; Monti and others, Neuropsychopharmacology. (1996) 15, 31-35; Lin and others, Brain Res. (1990) 523: 325-330; Monti, and others, Neuropsychopharmacology. (1996) 15: 31-35; Ligneau, and others, Journal of Pharmacology and Experimental Therapeutics (1998), 287, 658-666; Sakai and others, Life Sci. (1991) 48: 2397-2404; Mazurkiewicz-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol., (1989) 67: 75-78; P. Panula and others, Neuroscience (1998)44, 465-481; Wada and others, Trends in Neuroscience (1991) 14: 415; Monti and others, Eur. J. Pharmacol. (1991), 205: 283; Dvorak, C, etc. "4-Phenoxypyridine: potent, conformationally restricted, nakedsoldier antagonists histamine H3" Journal of Medicinal Chemistry (2005) 48, 2229-2238.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat drug abuse. Amphetamine is a drug stimulant for men. It and similar drugs stimulate locomotor activity in animals and found that the H3antagonist of topermit suppresses locomotor stimulation induced by amphetamine; therefore, H3-antagonists, apparently, are useful for the treatment of abuse of drugs that can be demonstrated by the results: Clapham J.; Kilpatrick, G. J. "Typename, a selective antagonist of N3-histamine receptors, reduces stimulant-induced locomotor activity in mice", European journal of pharmacology (1994), 259(2), 107-14.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat mood swings, bipolar violation, depression, obsessive-compulsive disorder, and Tourette syndrome can be demonstrated by the results: Lamberti, and others, British Journal of Pharmacology (1998) 123, 1331-1336; Perez-Garcia C, etc., Psychopharmacology (Berlin) (1999) 142(2): 215-20.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat Parkinson's disease (a disease in which patients have a deficit in the ability to initiate movement, and the brain of patients have low levels of dopamine) can be demonstrated by the results: Sanchez-Lemus, E. and others, "Activation of N3-histamine receptors inhibits induced by the dopamine receptor D1the cAMP accumulation in slices of the striatum of rats," Neuroscience Letters (2004) 364, p. 179-184; Sakai and others, Life Sci. (1991) 48, 2397-2404; Fox, G. B. and others, "Pharmacological properties of ABT-239: II. Neuropsychological characterization and broad preclinical efficacy for cognitive abilities and in schizophrenia potent and selective antagonist of N3-stamenova receptor", Journal of Pharmacology and Experimental Therapeutics, 313: 176-190, 2005; Chen, Z. and others "Pharmacological effects carcinine on histaminergic neurons in the brain", British Journal of Pharmacology (2004) 143, 573-580.

The ability of compounds according to the invention, including (but not limited to the compounds mentioned in the examples, to treat medullary carcinoma of the thyroid, melanoma, polycystic ovary can be demonstrated by the results of the work: Polish Med. Sci. Mon. (1998) 4(5): 747; Adam Szelag "the Role of histamine H3receptors in the proliferation of neoplastic cells in vitro", Med. Sci. Monitor (1998) 4(5): 747-755; and C.H. Fitzsimons and other "signaling histamine receptors in epidermal tumor cell lines with H-ras gene changes, Inflammation Res. (1998) 47 (Suppl 1): S50-S51.

Compounds according to the invention is particularly useful for the treatment and prevention of conditions or disorders that affect hyperactivity with attention deficit, Alzheimer's disease or dementia. Compounds according to the invention is particularly useful for the treatment and prevention of conditions or disorders that affect schizophrenia or cognitive deficits in schizophrenia. Compounds according to the invention is particularly useful for the treatment and prevention of conditions or disorders that affect narcolepsy, insomnia, allergic rhinitis, asthma, or obesity.

The actual dose levels of active ingredients in the pharmaceutical composition is provided according to this invention can be varied so to get the number of active compound(s)that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage depends on the activity of the particular compound, the route of administration, the severity of the subject to treatment condition, condition of the patient being treated, and his previous medical history. However, the competence of the specialist in this area to start the dosage of the compounds at levels below the level required to achieve the desired therapeutic effect and gradually increase the dosage to achieve the desired effect.

Applying the above or other treatments, can be used therapeutically effective amount of one of the compounds according to the invention in pure form or in the form of a pharmaceutically acceptable salt, complex, ester, amide or prodrug, if such forms exist. In other words, the connection can be introduced in the form of pharmaceutical compositions containing interesting connection in combination with one or more pharmaceutically acceptable carriers. The expression "therapeutically effective amount" of the compounds according to the invention refers to the amount of the compound sufficient to treat disorders in reasonable proportion Paul is a/the risk applicable to any method of treatment. However, it is clear that the total daily amount of the compounds and compositions according to the invention is determined by the attending physician made within the medical conclusion. The specific therapeutically effective dose level for any particular patient depends on many factors, including the subject of the treatment of the violation and the severity of the disorder; activity of the specific compound; the specific composition; the age, body weight, General health, sex, and food of the patient; the time of administration, route of administration, and rate of excretion of the specific compound; the duration of the treatment; drugs used in combination or simultaneously with the compound; and like factors well known in medical practice. For example, in this area it is advisable to start the dosage of the compounds at levels below the level required to achieve the desired therapeutic effect and gradually increase the dose to achieve the desired effect.

For the treatment or prevention of disease total daily dose of the compounds according to this invention, administered to a human or lower animal may range from about 0.001 to 30 mg/kg of body weight. For oral administration is preferred can be up to the s from about 0.001 to 1 mg/kg of body weight. If required, an effective daily dose can be divided into multiple doses for administration; therefore, compositions for single doses may contain such amounts or shares that make up the daily dose.

Compounds and methods according to the invention will be better understood by reference to the following examples which are given for illustration and not to limit the scope of the invention.

EXAMPLES

Example 1

4'-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 1A

TRANS-3-(4-bromophenyl)prop-2-EN-1-ol

To a solution of ethyl TRANS-4-bromocinnamic (8 ml, of 42.6 mmol) in anhydrous dichloromethane (150 ml) in an atmosphere of N2add drop by drop diisobutylaluminium in dichloromethane (128 ml, 1M, 128 mmol) at -78°C. After addition the mixture allowed to warm from -78°C to -30°C for two hours. The mixture is then cooled back to -78°C and add water 1H. HCl until acidic (pH 2). The organic layer is separated and the aqueous layer was extracted with dichloromethane. The combined organic layers dried with MgSO4, filtered and concentrated under reduced pressure, obtaining specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 1.44 (t, J=6 Hz, 1H), 4,32 (t, J=4.5 Hz, 2H), 6,37 (dt, J=16.5 Hz, J=6 Hz, 1H), to 6.57 (dt, J =15 Hz, J =3 Hz, 1H), 7,25 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 214 (M+H)+.

Example 1B

(1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol

Specified in the header of the compound obtained by the method described in the work of A.B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96)using TRANS-3-(4-bromophenyl)prop-2-EN-1-ol (the product of example 1A) instead of 3-phenyl-prop-2-EN-1-ol.

1H NMR (300 MHz, CDCl3): δ 0,92-1,0 (m, 2H), of 1.45 to 1.48 (m, 2H), 1,76-of 1.85 (m, 1H), 3,61 (d, J=7.5 Hz, 2H), 6,95 (d, J=9 Hz, 2H), 7,37 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 228 (M+H)+.

Example 1C

(1S,2S)-2-(4-Bromophenyl)cyclopropanecarboxaldehyde

DMSO (0.8 ml, 3 EQ.) add drop by drop to a solution of oxalicacid (of 0.48 ml) in anhydrous dichloromethane (50 ml) in an atmosphere of N2at -78°C. Then add drop by drop a solution of (1S,2S)-[2-(4-bromophenyl)cyclopropyl]methanol (product from example 1B, 823 mg) in dichloromethane (20 ml) at -78°C. Continue stirring at this temperature for 30 min, then add triethylamine (2 ml, 4 EQ.) and take bath with dry ice. After stirring for 1 hour the mixture was treated with saturated aqueous NH4Cl. The mixture is extracted with diethyl ether twice. The combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified through chromatography with hexane through a silica gel padding and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ to 1.48 (m, 1H), 1,65 (dt, J=9 Hz, J=6 Hz, 1H), 2,15 (m, 1H), 2.57 m (m, 1H), 6,98 (d,J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H), 9,46 (d, J=4.5 Hz, 1H). MS (DCI-NH3) m/z 226 (M+H)+.

Example 1D

1-[(1S,2S)-2-(4-Bromophenyl)cyclopropylmethyl]-2(S)-methylpyrrolidine

A solution of (1S,2S)-2-(4-bromophenyl)cyclopropanecarboxaldehyde (product of example 1C, 820 mg of 3.64 mmol) and salt (S)-2-methylpyrrolidine and tartaric acid (1.12 g, to 4.73 mmol) in ethanol (30 ml) is treated with lamborghini.com sodium (345 mg, 5.46 mmol). The mixture is stirred at room temperature for two hours. The mixture is alkalinized to pH 10-12, using NaOH (10%), and distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers are dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified on silica gel, elwira 1-2% methanol (containing 10% concentrated NH4OH) in dichloromethane and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 0.87 to 0.92(m, 1H), 0,97-1,02 (m, 1H), 1,16 (d, J=6 Hz, 2H), 1,22 (m, 1H), 1,39-1,49(m, 1H), 1,73-of 1.81 (m, 3H), 2.0 (m, 2H), 2,36 (kV, J=6 Hz, 1H), 2,45 (m, 1H), 3,13 (DD, J=12 Hz, J=6 Hz, 1H)at 3.25 (m, 1H), 7,00 (d, J=6 Hz, 2H), 7,37 (d, J=6 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

(S)-2-methylpyrrolidine and its salts are available commercially from a number of sources, including: (S)-2-methylpyrrolidine (registration number 59335-84-1 according to Chemical abstracts) from Sigma-Aldrich Chemical Company, P. O. Box 14508 St. Louis, MO, 63178 USA and (S)-2-methylpyrrolidine hydrochloride (registration number 17450074-4 according to Chemical abstracts) from AstaTech, Inc. Keystone Business Park 2525 Pearl Buck Road Bristol, PA, 19007 USA. Methods of obtaining (S)-2-methylpyrrolidine method enantioselective recrystallization from tartaric acid is described, for example, Sakurai and others Cristal Growth & Design (2006) vol. 6(7) pages 1606-1610. Salt (S)-2-methylpyrrolidine and L-tartaric acid (313 g) is recrystallized from a mixture of 4.8 l of ethanol and 1.2 l of methanol, heated to 60°C, and allowed to cool to precipitate the salt (S)-2-methylpyrrolidine and L-tartaric acid.

Example 1E

4'-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

To a solution of 1-[(1S,2S)-2-(4-bromophenyl)cyclopropylmethyl]-2(S)-methylpyrrolidine (product of example 1D, 50 mg, 0,17 mmol) in isopropyl alcohol (4 ml) under nitrogen atmosphere add 4-cyanoaniline acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 mmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture is heated at 90°C for 5 h, cooled to ambient temperature and distributed between ethyl acetate (25 ml) and H2O (10 ml). The separated organic layer was washed with a saturated solution of salt, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographic on silica gel, elwira 3% methanol (containing 10% concentrated NH4OH) in dichloromethane and receiving specified in the header of the connection.

1H NMR (300 MHz, CD3OD): δ 1,01 (m, 1H), 1,13 (m, 1H), 1,25 (d, J6 Hz, 3H), of 1.36 (m, 1H), and 1.54 (m, 1H), 1,89 (m, 3H), 2,11 (m, 1H), 2,30 (m, 1H), 2,65 (m, 1H), and 2.79 (m, 1H), 3.27 to (DD, J=12 Hz, J=6 Hz, 1H), 3,40 (m, 1H), 7,22 (d, J=9 Hz, 2H), to 7.59 (d, J=6 Hz, 2H), for 7.78 (s, 4H). MS (DCI-NH3) m/z 317 (M+H)+.

Example 2

4'-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 2A

1-[2-(4-Bromophenyl)-(1S,2S)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine

Specified in the header connection receive, using the method described in example 1D, using (R)-2-methylpyrrolidine instead of (S)-2-methylpyrrolidine.

1H NMR (300 MHz, CD3OD): δ 0,92(m, 1H), 0,99 (m, 1H), 1,13 (d, J=6 Hz, 3H), 1,24 (m, 1H), USD 1.43(m, 1H), 1.77 in(m, 3H), of 1.98 (m, 2H), 2,13 (DD, J=12 Hz, J=6 Hz, 1H), 2,30 (kV, J=9 Hz, 1H), 2,41 (m, 1H), equal to 2.94 (DD, J=12 Hz, J=6 Hz, 1H), 3,25 (m, 1H), 7,00 (d, J=9 Hz, 2H), was 7.36 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

(R)-2-methylpyrrolidine and its salts are available commercially from a number of sources, including (R)-2-methylpyrrolidine (registration number 41720-98-3 according to Chemical abstracts) from Sigma-Aldrich Chemical Company, P. O. Box 14508 St. Louis, MO, 63178 USA and (R)-2-methylpyrrolidine hydrochloride (registration number 135324-85-5 according to Chemical abstracts) from AstaTech, Inc. Keystone Business Park 2525 Pearl Buck Road Bristol, PA, 19007 USA. Methods of obtaining (R)-2-methylpyrrolidine method enantioselective recrystallization from tartaric acid is described, for example, in the works: Sakurai, and other Crystal Growth & Design (2006) vol. 6(7) pages 1606-1610 and Pu and other Organic Process Research &Development 2005, 9, 45-50.

Example 2B

4'-((1S,2S)-2-{[(2R)-2-metalpro the one-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Specified in the header of the get connection using the procedure described in example 1E using 1-[2-(4-bromophenyl)-(1S,2S)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine (the product from example 2A) instead of 1-[(1S,2S)-2-(4-bromophenyl)cyclopropylmethyl]-2(S)-methylpyrrolidine (product of 1D).

1H NMR (300 MHz, CD3OD): δ 0,92(m, 1H), 0,99 (m, 1H), 1,13 (d, J=6 Hz, 2H), 1,24 (m, 1H), USD 1.43(m, 1H), 1.77 in(m, 3H), of 1.98 (m, 2H), 2,13 (DD, J=12 Hz, J=6 Hz, 1H), 2,30 (kV, J=9 Hz, 1H), 2,41 (m, 1H), equal to 2.94 (DD, J=12 Hz, J=6 Hz, 1H), 3,25 (m, 1H), 7,00 (d, J=9 Hz, 2H), was 7.36 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 3

4'-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 3A

(1R,2R)-2-(4-Bromophenyl)cyclopropyl]methanol

Specified in the header of the compound obtained by the method described in the work of A.B. Charette and H.Lebel (Organic Synthesis, 1998, 76, 86-96)using TRANS-3-(4-bromophenyl)prop-2-EN-1-ol (the product from example 1A) instead of 3-phenylprop-2-EN-1-ol.

1H NMR (300 MHz, CDCl3): δ 0,92-1,0 (m, 2H), of 1.45 to 1.48 (m, 2H), 1,76-of 1.85 (m, 1H), 3,61 (d, J=7.5 Hz, 2H), 6,95 (d, J=9 Hz, 2H), 7,37 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 228 (M+H)+.

Example 3B

(1R,2R)-2-(4-Bromophenyl)cyclopropanecarboxaldehyde

DMSO (0.8 ml, 3 EQ.) add drop by drop to a solution of oxalicacid (of 0.48 ml) in anhydrous dichloromethane (50 ml) in an atmosphere of N2at -78°C. Then add drop by drop a solution of (1R,2R)-[2-(4-bromophenyl)cyclopropyl]methanol (product of example 3A, 823 mg) is dichloromethane (20 ml) at -78°C. Continue stirring at this temperature for 30 min, then add triethylamine (2 ml, 4 EQ.) and take bath with dry ice. After stirring for 1 hour the mixture was treated with saturated aqueous NH4Cl. The mixture is extracted with diethyl ether. The combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified through chromatography with hexane through a silica gel padding and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ to 1.48 (m, 1H), 1,65 (dt, J=9 Hz, J=6 Hz, 1H), 2,15 (m, 1H), 2.57 m (m, 1H), 6,98 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H), 9,46 (d, J=4.5 Hz, 1H). MS (DCI-NH3) m/z 226 (M+H)+.

Example 3C

1-[2-(4-Bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine

A solution of (1R,2R)-2-(4-bromophenyl)cyclopropanecarboxaldehyde (product of example 3B, 600 mg, or 2.67 mmol) and salt (R)-2-methylpyrrolidine and tartaric acid (0,82 g, 3,47 mmol) in ethanol (30 ml) is treated with lamborghini.com sodium (252 mg, 4 mmol). The mixture is stirred at room temperature for two hours. The mixture was quenched with HCl (1N), then alkalinized to pH 10-12, using NaOH (10%), and distributed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers are dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified on silica gel with 2% methanol (containing 10% concentrated NH 4OH) in dichloromethane, getting listed at the beginning of the connection.

1H NMR (300 MHz, CD3OD): δ 0,89 (m, 1H), and 0.98 (m, 1H), 1,14 (d, J=6 Hz, 2H), 1,19 (m, 1H),USD 1.43 (m, 1H), 1,75 (m, 3H), of 1.95 (m, 2H), 2,30 (kV, J=9 Hz, 1H), 2,37 (m, 1H), 3,14 (DD, J=12 Hz, J=6 Hz, 1H), up 3.22 (m, 1H), 7,00 (d, J=9 Hz, 2H), was 7.36 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 3D

4'-((1R,2R)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl|cyclopropyl)-1,1'-biphenyl-4-carbonitrile

To a solution of 1-[2-(4-bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine (product of example 3C, 50 mg, 0,17 mmol) in isopropyl alcohol (4 ml) is added under nitrogen atmosphere 4-cyanoaniline acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 mmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture is heated to 90°C for 5 h, cooled to ambient temperature and distributed between ethyl acetate (25 ml) and H2O (10 ml). The organic extract was washed with a saturated solution of salt, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographic on silica gel, elwira methanol (containing 10% concentrated NH4OH) in dichloromethane and receiving specified in the header of the connection.

1H NMR (300 MHz, CD3OD): δ 1,08 (m, 1H), 1,19 (m, 1H), 1,32 (d, J=6 Hz, 3H), of 1.42 (m, 1H), and 1.63 (m, 1H), 1,99 (m, 3H), of 2.20 (m, 1H), 2,65 (m, 1H), equal to 2.94 (m, 1H), of 3.07 (m, 1H), 3,34 (DD, J=9 Hz, J=6 Hz, 1H), 3,51 (m, 1H), 7,24 (d, J=9 Hz, 2H), 7,60 (d, J=6 Hz, 2H), 7,78 (s, 4H). MS (DCI-NH3) m/z 317 (M+H) +.

Example 4

4'-((1R,2R)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 4A

1-[2-(4-Bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methylpyrrolidine

Specified in the header of the get connection using the procedure described in example 3C using salt (S)-2-methylpyrrolidine and tartaric acid instead of salt (R)-2-methylpyrrolidine and tartaric acid.

1H NMR (300 MHz, CD3OD): δ 0,93 (m, 1H), 0,99 (m, 1H), 1,13 (d, J=6 Hz, 3H), 1,24 (m, 1H), 1,44 (m, 1H), 1,76 (m, 3H), of 1.98 (m, 1H), and 2.14 (DD, J=12 Hz, J=6 Hz, 1H), 2,32 (kV, J=9 Hz, 1H), 2,43 (m, 1H), equal to 2.94 (DD, J=12 Hz, J=6 Hz, 1H), 3,26 (m, 1H), 7,00 (d, J=9 Hz, 2H), was 7.36 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 4B

4'-((1R,2R)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Specified in the header of the get connection using the procedure described in example 3D, using 1-[2-(4-bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methylpyrrolidine (the product from example 4A) instead of 1-[2-(4-bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2R)-2-methylpyrrolidine (product from example 3C).

1H NMR (300 MHz, CD3OD): δ 1,22 (m, 2H), 1,42 (d, J=6 Hz, 3H), of 1.53 (m, 1H), 1,76 (m, 1H), 2,08 (m, 3H), 2,31 (m, 1H), 3,09 (DD, J=12 Hz, J=6 Hz, 1H), 3,23 (m, 1H), 3,39 (DD, J=12 Hz, J=6 Hz, 1H), 3,50 (m, 1H), 3,67 (m, 1H), 7,27 (d, J=9 Hz, 2H), to 7.61 (d, J=6 Hz, 2H), 7,78 (s, 4H). MS (DCI-NH3) m/z 317 (M+H)+.

Example 5

4'-((1S,2S)-2-[(2-Methylpyrrolidine-1-yl)methyl]cyclopropyl)-1,1'-biphenyl-4-carb is nitrile

Example 5A

1-[2-(4-Bromophenyl)-(1S,2S)-cyclopropylmethyl]-2-methylpyrrolidine

Specified in the header connection receive, using the method described in example 1D, using racemic 2-methylpyrrolidine instead of (S)-2-methylpyrrolidine.

1H NMR (300 MHz, CDCl3): δ of 0.87 to 0.92(m, 1H), 0,97-1,02 (m, 1H), 1,16 (d, J=6 Hz, 2H), 1,22 (m, 1H), 1,39-1,49(m, 1H), 1,73-of 1.81 (m, 3H), 2.0 (m, 2H), 2,36 (kV, J=6 Hz, 1H), 2,45 (m, 1H), 3,13 (DD, J=12 Hz, J=6 Hz, 1H)at 3.25 (m, 1H), 7,00 (d, J=6 Hz, 2H), 7,37 (d, J=6 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 5B

4'-((1S,2S)-2-[(2-Methylpyrrolidine-1-yl)methyl]cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Specified in the header of the get connection using the procedure described in example 1E using 1-[2-(4-bromophenyl)-(1S,2S)-cyclopropylmethyl]-2-methylpyrrolidine (the product from example 5A) instead of 1-[(1S,2S)-2-(4-bromophenyl)cyclopropylmethyl]-2(S)-methylpyrrolidine (product from example 1D).

1H NMR(300 MHz, CD3OD): δ 0,98 (m, 1H), 1,1 (m, 1H), 1,20 (d, J=6 Hz, 2H), 1,34 (m, 1H), 1,49(m, 1H), of 1.84 (m, 3H), of 2.06 (m, 2H), of 2.51 (m, 1H), 2,61 (m, 1H), 3,06 (DD, J=12 Hz, J=6 Hz, 0,5H), up 3.22 (DD, J=12 Hz, J=6 Hz, 0,5H), to 3.34 (m, 1H), 7,22 (DD, J=12 Hz, J=6 Hz, 2H), to 7.59 (d, J=9 Hz, 2H), to 7.77 (s, 4H). MS (DCI-NH3) m/z 317(M+H)+.

Example 6

5-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 1E using 5-pyrimidinemethanol acid instead of 4-cyan is phenylboronic acid.

1H NMR (300 MHz, CD3OD): δ 0,96 (m, 1H), 1,09 (m, 1H), 1,16 (d, J=6 Hz, 3H), 1,31 (m, 1H), 1,44 (m, 1H), 1,76 (m, 2H), to 1.86(m, 1H), 1,99 (m, 2H), 2,35 (m, 1H), 2,41 (m, 1H), 3,29 (DD, J=12 Hz, J=6 Hz, 1H), to 3.58 (m, 1H), 7,26 (DD, J=12 Hz, J=6 Hz, 2H), 7,60 (d, J=9 Hz, 2H), to 7.77 (s, 4H). MS (DCI-NH3) m/z 317 (M+H)+.

Example 7

2-Methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 1E using 2-methoxy-5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 0,94 (m, 1H), of 1.05 (m, 1H)and 1.15 (d, J=6 Hz, 3H), 1.26 in (m, 1H), USD 1.43 (m, 1H), 1.77 in(m, 3H), of 1.94 (m, 2H), 2,32 (m, 2H), 3,21 (m, 2H), Android 4.04 (s, 1H), 7,21 (d, J=9 Hz, 2H), 7,52 (d, J=9 Hz, 2H), 8,78 (s, 2H). MS (DCI-NH3) m/z 324 (M+H)+.

Example 8

2,6-Dimethyl-3-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine

Specified in the header of the get connection using the procedure described in example 2B, using 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (obtained according to the method described in J. Org. Chem. 67: 7541-7543(2002)) instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ of 0.95 (m, 1H), 1.06 a (m, 1H), 1,16 (d, J=6 Hz, 3H), of 1.33 (m, 1H), 1,47 (m, 1H), 1,80(m, 3H), 2,00 (m, 1H), measuring 2.20 (DD, J=12 Hz, J=6 Hz, 1H), 2,37 (m, 2H), 2,41 (s, 3H), 2,48 (m, 1H), 2,52 (s, 3H), and 3.0 (DD, J=12 Hz, J=6 Hz, 1H), 7,19 (m, 5H), 7,51 (d, J=9 Hz, 1H). MS (DCI-NH3) m/z 321 (M+H)+.

Example 9

2-Methoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine

Specified in the header of the get connection using the procedure described in example 2B, using 2-methoxy-5-pyridineboronic acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1,21 (m, 2H), 1,45 (d, J=6 Hz, 3H), 1,50 (m, 1H), 1,76 (m, 1H), 2,00 (m, 3H), of 2.34 (m, 1H), 3,14 (DD, J=12 Hz, J=6 Hz, 1H), 3.27 to (m, 1H), 3,44 (DD, J=12 Hz, J=6 Hz, 1H), 3,54 (m, 1H), to 3.73(m, 1H), 3,95 (s, 3H), to 6.88 (d, J=9 Hz, 1H), 7,21 (d, J=9 Hz, 2H), 7,51 (d, J=9 Hz, 2H), to 7.93 (DD, J=12 Hz, J=6 Hz, 1H), with 8.33 (d, J=3 Hz, 1H). MS (DCI-NH3) m/z 323 (M+H)+.

Example 10

5-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 2B, using a 5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1.26 in (m, 2H), 1,45 (d, J=6 Hz, 3H), and 1.56 (m, 1H), 1,76 (m, 1H), 2,09 (m, 3H), 2,35 (m, 1H), 3,12 (DD, J=12 Hz, J=6 Hz, 1H), 3,26 (m, 1H), 3.46 in (DD, J=12 Hz, J=6 Hz, 1H), 3,55 (m, 1H), to 3.73 (m, 1H), 7,32 (d, J=9 Hz, 2H), 7,66 (d, J=9 Hz, 2H), 9,04 (s, 2H), 9,12 (s, 1H). MS (DCI-NH3) m/z 317

Example 11

5-[4-((1R,2R)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 4B using 5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3 OD): δ 1,09 (m, 1H), 1,17 (m, 1H), 1,29 (d, J=6 Hz, 3H), of 1.45 (m, 1H), 1,61 (m, 1H), 1,95(m, 3H), of 2.16 (m, 1H), 2,66 (DD, J=12 Hz, J=6 Hz, 1H), 2,79 (kV, J=9 Hz, 1H), 2,99 (m, 1H), 3,20 (DD, J=12 Hz, J=6 Hz, 1H), 3,49 (m, 1H), 7,29 (d, J=9 Hz, 2H), 7,63 (d, J=9 Hz, 2H), 9,03 (s, 2H), 9,10 (s, 1H). MS (DCI-NH3) m/z 317(M+H)+.

Example 12

5-[4-((1R,2R)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 3D, using a 5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1.00 each (m, 1H), 1,11 (m, 1H), 1,21 (d, J=6 Hz, 3H), of 1.34 (m, 1H)and 1.51 (m, 1H), equal to 1.82 (m, 2H), 1,90 (m, 1H), 2,08 (m, 1H), 2,18 (m, 1H), 2,53 (kV, J= 9 Hz, 1H), 2,62 (m, 1H), 3,23 (DD, J=12 Hz, J=6 Hz, 1H), 3,34 (m, 1H), 7,27 (d, J=9 Hz, 2H), 7.62mm (d, J=9 Hz, 2H), 9,03 (s, 2H), 9,10 (s, 1H). MS (DCI-NH3) m/z 317(M+H)+.

Example 13

2,4-Dimethoxy-5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 4B using 2,6-dimethoxy-5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ of 1.03 (m, 1H), 1,11 (m, 1H), 1.27mm (d, J=6 Hz, 3H), 1.39 in (m, 1H), 1,59 (m, 1H), 1.93 and (m, 3H), of 2.15 (m, 1H), 2,58 (DD, J=12 Hz, J=6 Hz, 1H), 2,73 (kV, J=9 Hz, 1H), 2.91 in (m, 1H), 3.15 in (DD, J=12 Hz, J=6 Hz, 1H), of 3.45 (m, 1H), a 4.03 (s, 6H), 7,16 (d, J=9 Hz, 2H), 7,40 (d, J=9 Hz, 2H), by 8.22 (s, 1H). MS (DCI-NH3) m/z 354 (M+H)+.

Example 14

2,4-Dimethoxy-5-[4-((1R,2R)-2-{[(2R)-2-IU is iparralde-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 3D, using 2,6-dimethoxy-5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1.04 million (m, 1H)and 1.15 (m, 1H), 1,31 (d, J=6 Hz, 3H), 1,38 (m, 1H), 1,62 (m, 1H), 1,97 (m, 3H), 2,18 (m, 1H), 2.57 m (DD, J=12 Hz, J=6 Hz, 1H), 2,87 (kV, J=9 Hz, 1H), to 3.02 (m, 1H), 3,34 (DD, J=12 Hz, J=6 Hz, 1H), 3,50 (m, 1H), a 4.03 (s, 6H), 7,16 (d, J=9 Hz, 2H), 7,41 (d, J=9 Hz, 2H), by 8.22 (s, 1H). MS (DCI-NH3) m/z 354 (M+H)+.

Example 15

2,4-Dimethoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 2B, using 2,6-dimethoxy-5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1.04 million (m, 1H), 1,12 (m, 1H), 1,28 (d, J=6 Hz, 3H), 1.39 in (m, 1H), 1,60 (m, 1H), was 1.94 (m, 3H), of 2.15 (m, 1H), 2,65 (DD, J=12 Hz, J=6 Hz, 1H), 2,78 (kV, J=9 Hz, 1H), 2,98 (m, 1H), 3,17 (DD, J=12 Hz, J=6 Hz, 1H), 3,47 (m, 1H), a 4.03 (s, 6H), 7,17 (d, J=9 Hz, 2H), 7,41 (d, J=9 Hz, 2H), by 8.22 (s, 1H). MS (DCI-NH3) m/z 354 (M+H)+.

Example 16

2,4-Dimethoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 1E using 2,6-dimethoxy-5-pyrimidinemethanol acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1.04 million (m, 1H), 1,12 (m, 1H), 1,28 d, J=6 Hz, 3H), 1.39 in (m, 1H), 1,60 (m, 1H), was 1.94(m, 3H), of 2.15 (m, 1H), 2,65 (DD, J=12 Hz, J=6 Hz, 1H), 2,78 (kV, J= 9 Hz, 1H), 2,98 (m, 1H), 3,17 (DD, J=12 Hz, J=6 Hz, 1H), 3,47 (m, 1H), a 4.03 (s, 6H), 7,17 (d, J=9 Hz, 2H), 7,41 (d, J=9 Hz, 2H), by 8.22 (s, 1H). MS (DCI-NH3) m/z 354 (M+H)+.

Example 17

2-[4-((1R,2R)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

A solution of the product from example 4A (47 mg, 0.16 mmol; 1-[2-(4-bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methylpyrrolidine), 3(2H)-pyridazinone (CAS # 504-30-3, 20 mg, 0.2 mmol), copper iodide (1.5 mg, 0,008 mmol), N,N'-TRANS-dimethylcyclohexane-1,2-diamine (2.3 mg, to 0.016 mmol) and potassium phosphate (75 mg, 0.35 mmol) in a mixture toluene and isopropanol (4 ml, 1:1) is heated at 110°C in vials with screw cap for 16 hours. The mixture is cooled to ambient temperature, treated with H2O and extracted with ethyl acetate (2×25 ml). The organic layer is separated, washed with saturated salt solution and dried with magnesium sulfate. After filtration the organic layer is concentrated under reduced pressure and the resulting oil purified on silica gel 1-3% methanol (containing 10% concentrated NH4OH) in dichloromethane, getting listed at the beginning of the connection.

1H NMR (300 MHz, CD3OD): δ 1,07 (m, 1H), 1.14 in (m, 1H), 1,26 (d, J=6 Hz, 3H), of 1.40 (m, 1H), 1,58 (m, 1H), 1,90 (m, 3H), 2.13 in (m, 1H), 2,58 (m, 1H), 2,70 (kV, J=9 Hz, 1H), 2,89 (m, 1H), 3,14 (DD, J=12 Hz, J=6 Hz, 1H), 3,44 (m, 1H), 7,07 (d, J=9 Hz, 1H), 7,24 (d, J=9 Hz, 2H), 7,44 (d, J=9 Hz, 2H), 7,47 (m, 1H), 8,03 (who, 1H). MS (DCI-NH3) m/z 310 (M+H)+.

Example 18

2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

Specified in the header of the get connection using the procedure described in example 17, using as starting material the product of example 1D 1-[(1S,2S)-2-(4-bromophenyl)cyclopropylmethyl]-2(S)-methylpyrrolidine instead of 1-[2-(4-bromophenyl)-(1R,2R)-cyclopropylmethyl]-(2S)-2-methylpyrrolidine.

1H NMR (300 MHz, CD3OD): δ 0,97 (m, 1H), 1,13 (m, 1H), 1,23 (d, J=6 Hz, 3H), of 1.34 (m, 1H)and 1.51 (m, 1H), of 1.85(m, 3H), 1.93 and (m, 1H), 2,01 (m, 1H), 2,68 (kV, J=9 Hz, 1H), 2,85 (m, 1H), is 3.08 (m, 1H), 3,23 (m, 1H), 7,07 (d, J=9 Hz, 1H), 7,22 (d, J=9 Hz, 2H), 7,44 (d, J=9 Hz, 2H), 7,47 (m, 1H), 8,03 (m, 1H). MS (DCI-NH3) m/z 310(M+H)+.

Example 19

N-[4-((1S,2S)-2-([(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1H-1,2,4-triazole-3-carboxamide

Specified in the header of the get connection using the procedure described in example 34G, using 1H-1,2,4-triazole-3-carboxamide instead pyridazin-3(2H)-it.

1H NMR (300 MHz, CD3OD): δ 1,11-of 1.18 (m, 1H), 1,22 of 1.28 (m, 1H), 1,38 (d, J=6 Hz, 3H), 1,47-of 1.53 (m, 1H), 1,67-of 1.74 (m, 1H), 2,01-of 2.15 (m, 3H), 2,24 to 2.35 (m, 1H), 2.91 in-2,99 (m, 1H), 3,13 is 3.23 (m, 1H), 3.33 and-of 3.43 (m, 2H), 3,60-3,68 (m, 1H), 7,34 (d, J=9 Hz, 2H), 7,79 (d, J=9 Hz, 2H), 9,05 (s, 1H). MS (DCI-NH3) m/z 326 (M+H)+.

Example 20

2-Methyl-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1,3-benzothiazole

Example 20A

2-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxa Golan-2-yl)benzothiazole

A solution of 5-bromo-2-methylbenzothiazole (2 g, 8,8 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.7 g, 10.6 mmol; CAS 73183-34-3), potassium acetate (3.1 g, and 31.7 mmol) and complex Pd(dppf)2Cl2-dichloromethane (1:1) (360 mg, 0.51 mmol) in anhydrous tetrahydrofuran (70 ml) under nitrogen atmosphere heated at the boil under reflux overnight. After cooling to ambient temperature the mixture is filtered through diatomaceous earth and washed with ethyl acetate. The filtrate is washed with water and saturated salt solution, dried (MgSO4), filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel, elwira 10% ethyl acetate in hexane and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 1.37 (s, 12H), 2,84 (s, 3H), of 7.75 (d, J=9 Hz, 1H), 7,82 (d, J=9 Hz, 1H), scored 8.38 (s, 1H); (DHI/ NH3) m/z 276 (M+H)+.

Example 20B

2-Methyl-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1,3-benzothiazole

Specified in the header of the get connection using the procedure described in example 1E using the product from example 20A instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 1,01 (m, 1H), 1.14 in (m, 1H), 1,26 (d, J=6 Hz, 3H), of 1.35 (m, 1H), 1.55V (m, 1H), 1.91 a (m, 3H), 2,12 (m, 1H), 2,34 (m, 1H), to 2.67 (m, 1H), 2,75 (m, 1H), 2,85 (s, 3H), 3,26 (m, 2H), 3,41 (m, 1H), 7,21 (d, J=9 Hz, 2H), 7,60 (d, J=9 Hz, 2H), 7,65 (DD, J=9 Hz, J=3 Hz, 1H), of 7.96 (d, J=6 Hz, 1H), of 8.06 (d, J=3 Hz, 1H). MS (DCI-N 3) m/z 362 (M+H)+.

Example 21

1,3,5-Trimethyl-4-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1H-pyrazole

Specified in the header of the get connection using the procedure described in example 1E using 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (CAS # 844891-04-9) instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 0,99 (m, 1H), 1,07 (m, 1H), 1,22 (d, J=6 Hz, 3H), of 1.29 (m, 1H)and 1.51 (m, 1H), 1,86 (m, 3H), of 2.08 (m, 1H), 2,15 (s, 3H), 2,18 (m, 1H), of 2.21 (s, 3H), of 2.56 (m, 1H), 2,65 (m, 1H), 3,24 (m, 1H), to 3.38 (m, 1H), 7,14 (s, 4H). MS (DCI-NH3) m/z 324 (M+H)+.

Example 22

2,6-Dimethyl-3-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine

Specified in the header of the get connection using the procedure described in example 1E using 2,6-dimethylpyridin-3-Bronevoy acid instead of 4-cyanophenylacetic acid.

1H NMR (300 MHz, CD3OD): δ 0,97(m, 1H), 1,09 (m, 1H), 1,22 (d, J=6 Hz, 3H), 1,32 (m, 1H)and 1.51 (m, 1H), 1,86 (m, 3H), 2,07 (m, 1H), 2,18 (m, 1H), 2,41 (s, 3H), 2,52 (s, 3H), by 2.55 (m, 1H), 2,62 (m, 1H), 3,25 (m, 1H), 3,37 (m, 1H), 7,19 (m, 5H), 7,49 (d, J=9 Hz, 1H). MS (DCI-NH3) m/z 321 (M+H)+.

Example 23

5-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine

Specified in the header of the get connection using the procedure described in example 1E using pyrimidine-3-Bronevoy acid instead of 4-cyanophenylacetic acid.

1H NMR(300 MHz, CD3OD): δ 0,96(m, 1H), 1,1 (m, 1H), 1,16 (d, J=6 Hz, 3H), 1,31 (m, 1H), 1,45 (m, 1H), 1.77 in (m, 2H), to 1.86 (m, 1H), 2.0 (m, 2H), 2,4 (m, 2H), 3,18 (m, 1H), 3.27 to (m, 1H), 7,26 (d, J=9 Hz, 2H), 7.62mm (d, J=9 Hz, 2H), 9,03 (s, 2H), which is 9.09 (s, 1H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 24

N-isobutyl-N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]amine

Example 24A

4-(2-[(2S)-2-Methylpyrrolidine-1-ylmethyl]-(1S,2S)-cyclopropyl}phenylamine

A solution of the product from example 1D (640 mg, to 2.18 mmol, 1-[(1S,2S)-2-(4-bromophenyl)cyclopropylmethyl]-2(S)-methylpyrrolidine), lithium bis(trimethylsilyl)amide (560 mg), Pd2(dba)3(100 mg) and P(t-Bu)3(10% in hexane, 530 mg) in toluene (3 ml) is heated in a microwave reactor at 160°C for 40 minutes the Mixture is diluted with dichloromethane and H2O and distribute. The aqueous layer was extracted with DHM and the organic layers combined, dried and concentrated, getting brownish residue, which was purified on silica gel, elwira 3% methanol (containing 10% concentrated NH4OH) in dichloromethane and receiving specified in the header of the connection.

1H NMR (300 MHz, CD3OD): δ 0,73(m, 1H), 0,85 (m, 1H), 1,07 (m, 1H), 1,13 (d, J=6 Hz, 3H), of 1.41 (m, 1H), and 1.63 (m, 1H), 1,76 (m, 3H), 2.0 (m, 1H), 2,28 (m, 2H), 3,12 (m, 1H), 3.27 to (m, 1H), 6,65 (d, J=9 Hz, 2H), 6,83 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 231 (M+H)+.

Example 24B

N-isobutyl-N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]amine

A solution of the product from example 24A (35 mg,0.15 mmol, 4-{2-[(2S)-2-methylpyrrolidine-1-ylmethyl]-(1S,2S)-cyclopropyl}phenylamine and 2-methylpropionamidine (20 ml, 0.23 mmol) in ethanol (8 ml) was treated with borane-pyridine (30 ml) at room temperature and stirred for 16 hours. The mixture is concentrated and the residue purified on silica gel, elwira 3% methanol (containing 10% concentrated NH4OH) in dichloromethane and receiving specified in the header of the connection.

1H NMR (300 MHz, CD3OD): δ 0,82 (m, 1H), 0,94 (m, 1H), 0,95 (d, J=9 Hz, 6H), 1,17 (m, 1H), 1,26 (d, J=6 Hz, 3H), 1.57 in (m, 1H), 1,76 (m, 2H), 1,90 (m, 3H), 2.13 in (m, 1H), 2,37 (m, 1H), 2,75 (m, 1H), 2,84 (m, 3H), 3,23 (m, 1H), of 3.45 (m, 1H), 6,56 (d, J=9 Hz, 2H), 6,86 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 287 (M+H)+.

Example 25

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine-5-amine

A solution of the product from example 24A (300 mg, 1.3 mmol, 4-{2-[(2S)-2-methylpyrrolidine-1-ylmethyl]-(1S,2S)-cyclopropyl}phenylamine), 5-bromopyrimidine (311 mg, of 1.95 mmol), Tris(dibenzylideneacetone)dipalladium(0)·chloroform (40 mg), Cs2CO3(1 g) and 1,1'-bis(diphenylphosphino)ferrocene (65 mg) in anhydrous dioxane (8 ml) is heated to 110°C for 48 hours. The mixture is cooled to room temperature, diluted with EtOAc and washed with water and saturated salt solution. The organic layer is dried (MgSO4), filtered, concentrated under reduced pressure and purified on silica gel, elwira 3% methanol (containing 10% concentrated in the NH 4OH) in dichloromethane and receiving specified in the header of the connection.

1H NMR (300 MHz, CD3OD): δ 0,84 (m, 1H), 0,96 (m, 1H), 1,14 (d, J=6 Hz, 3H), 1,20 (m, 1H), USD 1.43 (m, 1H), 1,75 (m, 3H), of 1.88 (m, 1H), 2,01 (m, 1H), 2,28 (m, 1H), 2,35 (m, 1H), 3,14 (m, 1H), 3,26 (m, 1H), was 7.08 (s, 4H), 8,44 (s, 2H), 8,51 (s, 1H). MS (DCI-NH3) m/z 309 (M+H)+.

Example 26

4'-((1R,2S)-2-(2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 26A

3-(4-Bromophenyl)prop-2-EN-1-ol

To a solution of ethyl TRANS-4-bromocinnamic [CAS 24393-53-1] (8 ml, of 42.6 mmol) in anhydrous dichloromethane (150 ml) in an atmosphere of N2add drop by drop diisobutylaluminium in dichloromethane (128 ml, 1M, 128 mmol) at -78°C. After addition the mixture allowed to warm from -78°C to -30°C for two hours. The mixture is then cooled back to -78°C and add water 1H. HCl. The organic layer is separated, dried using MgSO4, filtered and concentrated under reduced pressure, obtaining specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 1.44 (t, J=6 Hz, 1H), 4,32 (t, J=4.5 Hz, 2H), 6,37 (dt, J=16.5 Hz, J=6 Hz, 1H), to 6.57 (dt, J=15 Hz, J=3 Hz, 1H), 7,25 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 214 (M+H)+.

Example 26B

Bis-dimethylamide 2-butyl-[1,3,2]dioxaborolan-(S,S)-4,5-dicarboxylic acid

2-(Buta-1-yl)tetrahydro-4H-1,3,6,2-dioxaborolan [CAS 92527-13-4] is obtained from n-butylboronic acid and 2-(2-hydroxyethylamino)ethanol [CAS 111-42-2], it is reported to work in Organic Synthesis, 1998, 76, 86-96. This dioxaborolan (3 g, 17.5 mmol) and (2S,3S)-2,3-dihydroxy-N,N,N',N'-tetramethylbutylamine [CAS 63126-52-3] (4,65 g) dissolved in anhydrous dichloromethane (95 ml) in an atmosphere of N2. Add a saturated solution of salt (30 ml). The resulting mixture was stirred at room temperature for 1 hour. Two layers are separated and the aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers washed with saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of oil.

1H NMR (300 MHz, CDCl3): δ of 0.82 to 0.9 (m, 5H), 1,25-1,45 (m, 4H), 2,98 (s, 6H), 3,2 (s, 6H), 5,52 (s, 2H). MS (DCI-NH3) m/z 271 (M+H)+.

Example -26 C

(1R,2R)-[2-(4-Bromophenyl)cyclopropyl]methanol

To a -10°C solution of dimethoxyethane (1.2 ml, 2 EQ.) in anhydrous dichloromethane (30 ml) in an atmosphere of N2add one drop of diethylzinc (12 ml, 1M in dichloromethane), and then add drop by drop diameter (1.8 ml) for 15 min, keeping the temperature below

-5°C. the Mixture is stirred for another 10 min after adding at -10°C, then add a solution of dioxaborolan from example 26B (1.8 g in 5 ml dichloromethane) for 6 min at -5°C. Then add drop by drop a solution of alkene from example 26A (1 g in 5 ml dichloromethane). The cooling bath is removed and the mixture is stirred over night. The mixture was quenched by adding saturated aqueous NH4Cl and 10% aqueous HCl. the mixture is twice extracted with ether. The combined organic extracts treated with an aqueous 2n. NaOH (40 ml) and 30% aqueous H2O2(5 ml) and then stirred for 5 minutes Then the separated organic layer is washed sequentially with 10% aqueous HCl, water Na2S2O3, aqueous NaHCO3and a saturated solution of salt. The organic layer is dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue is purified on silica gel, elwira a mixture of hexane/ethyl acetate 4:1 and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0,92-1,0 (m, 2H), of 1.45 to 1.48 (m, 2H), 1,76-of 1.85 (m, 1H), 3,61 (d, J=7.5 Hz, 2H), 6,95 (d, J=9 Hz, 2H), 7,37 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 228 (M+H)+.

Example 26D

(1R,2R)-2-(4-Bromophenyl)cyclopropanecarboxaldehyde

DMSO (0.8 ml, 3 EQ.) add drop by drop to a solution of oxalicacid (of 0.48 ml) in anhydrous dichloromethane (50 ml) in an atmosphere of N2at -78°C. Then add drop by drop a solution of the alcohol from example -26 C (823 mg) in dichloromethane (20 ml) at -78°C. Stirring at this temperature continued for 30 min, then add triethylamine (2 ml, 4 EQ.) and remove bath with dry ice. After stirring for 1 hour the mixture was treated with saturated aqueous NH4Cl. The mixture is extracted with ether. The combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified elwira what Aksana through the packing of silica gel and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ to 1.48 (m, 1H), 1,65 (dt, J=9 Hz, J=6 Hz, 1H), 2,15 (m, 1H), 2.57 m (m, 1H), 6,98 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H), 9,46 (d, J=4.5 Hz, 1H). MS (DCI-NH3) m/z 226 (M+H)+.

Example 26E

1-Bromo-4-[(1R,2S)-2-vinylcyclopropyl]benzene

A solution of the aldehyde from example 26D (500 mg, 2.22 mmol) and methyltriphenylphosphonium iodide [CAS 2065-66-9] (1,17 g) in anhydrous dichloromethane (50 ml) stirred at 0°C in an atmosphere of N2. Add to this chilled mixture of tert-butyl potassium (340 mg). Take a bath with ice and the mixture is stirred at room temperature for one hour. The mixture is quenched with saturated aqueous NH4Cl. The mixture is extracted with dichloromethane and the combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified on silica gel with hexane, getting listed at the beginning of the connection.

1H NMR (300 MHz, CDCl3): δ 1.1 to 1.2 (m, 2H), 1.6 to 1.7 (m, 1H), 1,84-of 1.92 (m, 1H), of 5.05 (DDD, J=34 Hz, J=9 Hz, J=1 Hz, 1H), 5,52 (DDD, J=18 Hz, J=10 Hz, J=9 Hz, 1H), 6,95 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 224 (M+H)+.

Example 26F

2-[(1S,2R)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

To a solution of alkene from example 26E (2.25 g, 10 mmol) in anhydrous THF (50 ml) in an atmosphere of N2add borane-THF (13 ml, 1M) at 0°C. the Mixture is stirred at room temperature for two hours, then cooled to 0°C. Add water rest the R of hydrogen peroxide (35%, 3.5 ml), take a bath with ice, the mixture is allowed to warm to room temperature and continue stirring for 10 minutes the Mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified on silica gel with hexane/ethyl acetate 4:1, receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 0.8 to 0.92 (m, 2H), 1,02-1,1 (m, 1H), 1,46 (s, 1H), 1.6 to 1.7 (m, 2H, in), 3.75 (t, J=6 Hz, 2H), 6,9 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 241 (M+H)+.

Example 26G

4'-[(1R,2S)-2-(2-Hydroxyethyl}cycloprop-1-yl] - biphenyl-4-carbonitrile

A solution of the product of example 26F (1.2 g, 5 mmol), 4-cyanophenylacetic acid [CAS 126747-14-6] (1,46 g, 2 equiv.) Pd(PPh3)2Cl2(350 mg) and Cs2CO3(6.5 g) in isopropanol (80 ml) in an atmosphere of N2stirred at the boil under reflux overnight. The mixture is distributed between ethyl acetate and H2O. the Organic layer was washed with saturated aqueous Na2CO3and then a saturated solution of salt. Then the organic layer is dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue purified by chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 4:1 and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl 3): δ 0,85-of 1.03 (m,2H), 1,12-1,2 (m, 1H), of 1.65 to 1.7 (m, 3H), of 3.78 (t, J=6 Hz, 2H), 7,15 (d, J=9 Hz, 2H), of 7.48 (d, J=9 Hz, 2H), 7,68 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 264 (M+H)+.

Example 26H

2-[(1S,2R)-2-(4'-Cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid

To a solution of the product of example 26G (560 mg, 2,13 mmol) and methanesulfonamide (to 0.22 ml, 1.2 EQ.) in dichloromethane (10 ml) in an atmosphere of N2add triethylamine (0,42 ml, 1.4 EQ.) at 0°C. the Mixture is stirred at room temperature for 5 hours. The mixture is treated with H2O and the organic layer was washed with saturated salt solution, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue purified by chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 4:1 and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0.9 to a 1.08 (m, 2H), 1.18 to 2,02 (m, 2H), 3.0 a (s, 3H), 4,35 (t, J=6 Hz, 2H), 7,15 (d, J=9 Hz, 2H), of 7.48 (d, J=9 Hz, 2H), 7,68 (kV, J=9 Hz, 2H). MS (DCI-NH3) m/z 342 (M+H)+.

Example 26I

4'-((1R,2S)-2-{2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

To a solution of nelfinavir example 26H (500 mg, about 1.47 mmol) and potassium carbonate (0,446 g, 3,24 mmol) in DMF (10 ml) is added (R)-2-methylpyrrolidine hydrogen bromide [CAS 117607-13-3] (300 mg, is 1.81 mmol). The mixture is stirred at 50°C during the night. The mixture is distributed between ethyl acetate and H2O. the Organic layer p is washed with saturated salt solution, dried (MgSO4) and concentrated in vacuo. The resulting residue is purified by chromatography on silica gel, elwira a mixture of MeOH/EtOAc/CH2Cl27,5/between 20/70 and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3, free base): δ 0,85-0,9 (m, 1H), 1,03-1,0 (m, 1H), 1,14 (d, J=Hz, 3H), 1,4-2,4 (m, 11H), 2,9 (m, 1H), 3.15 and is 3.23 (m, 1H), 7,15 (d, J=9 Hz, 2H), 7,47 (d, J=9 Hz, 2H), 7,66 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 331,2 (M+H)+.

Elemental analysis: calculated for C23H26N2·C4H6O61,25 H2O (g L-tartaric acid): C, 64,46; H, 6,91; N, to 5.57; found: C, 64,46; H, 6,91; N, 5,57.

Example 27

(2R)-1-{2-[(1S,2R)-2-(4-Bromophenyl)cyclopropyl]ethyl}-2-methylpyrrolidine

Example 27A

2-[2-(4-Bromophenyl)cyclopropyl]ethyl ester

(1S,2R)-methanesulfonic acid

The alcohol from example 26F 2-[(1S,2R)-2-(4-bromophenyl)cycloprop-1-

yl]ethanol is converted into 2-[2-(4-bromophenyl)cyclopropyl]ethyl ester (1S,2R)-methanesulfonic acid according to the methods described in example 26H.

Example 27B

(2R)-1-{2-[(1S,2R)-2-(4-Bromophenyl)cyclopropyl]ethyl}-2-methylpyrrolidine

Specified in the header connection receive according to the methods described in example 26I, using the product from example 27A 2-[2-(4-bromophenyl)cyclopropyl]ethyl ester (1R,2R)-methanesulfonic acid instead of the product from example 26H.

1H NMR (300 MHz, CDCl3free OS is Finance): δ 0,75-0,9 (m, 2H), 0,97 of-1.04 (m, 1H)and 1.15 (d, J=Hz, 3H), 1,5-of 1.65 (m, 8H), of 1.85 to 2.35 (m, 3H), 2,85-2,95 (m, 1H), 3,12-3,20 (m, 1H), 6,9 (d, J=9 Hz, 2H), 7,33 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 310 (M+H)+.

Example 28

4'-((1S,2R)-2-{2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cycloprop-1-yl)-1,1'-biphenyl-4-carbonitrile

Example 28A

Bis-dimethylamide 2-butyl-[1,3,2]dioxaborolan-(R,R)-4,5-dicarboxylic acid

2-(Buta-1-yl)tetrahydro-4H-1,3,6,2-dioxaborolan [CAS 92527-13-4] (3 g, 17.5 mmol), obtained from n-butylboronic acid and 2-(2-hydroxyethylamino)ethanol [CAS 111-42-2], as reported in the work of Organic Synthesis, 1998, 76, 86-96, and (2R,3R)-2,3-dihydroxy-N,N,N',N'-tetramethylbutylamine [CAS 26549-65-5] (9,85 g) dissolved in anhydrous dichloromethane (160 ml) atmosphere N2. Add a saturated solution of salt (25 ml). The resulting mixture was stirred at room temperature for about 16 hours. Two layers are separated and the aqueous layer was extracted with dichloromethane. The combined organic layers washed with 50 ml of saturated salt solution, dried over MgSO4, filtered and concentrated in vacuo, obtaining mentioned in the title compound in the form of oil.

Example 28B

(1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol

To the solution at -10°C dimethoxyethane (5,2 ml) in anhydrous dichloromethane (200 ml) in an atmosphere of N2add one drop of diethylzinc (62,6 ml, 1M in dichloromethane), and then add drop by drop diameter (10.1 ml), maintaining t is mperature below -5°C. After the addition the mixture is stirred for another 10 min at -10°C, then add a solution of dioxaborolane (bis-dimethylamide 2-butyl-[1,3,2]dioxaborolan-(R,R)-4,5-dicarboxylic acid) (8.8 g in 40 ml dichloromethane) at -5°C. Then add drop by drop a solution of alkene from example 26A (3-(4-bromophenyl)prop-2-1-ol, 5,3 g in 50 ml of dichloromethane). The cooling bath is removed and the mixture is stirred over night. The mixture was quenched by adding saturated aqueous NH4Cl and 10% aqueous HCl. This mixture is twice extracted with ether. The combined organic extracts treated with an aqueous 2n. NaOH (250 ml) and 30% aqueous H2O2(35 ml) and then stirred for 5 minutes Then the organic layer is washed sequentially with 10% aqueous HCl, water Na2S2O3, aqueous NaHCO3and a saturated solution of salt. The organic layer is dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue is purified on silica gel, elwira a mixture of hexane/ethyl acetate and receiving specified in the header of the connection.

Example 28C

(1S,2S)-2-(4-Bromophenyl)cyclopropanecarboxaldehyde

DMSO (3 EQ.) add drop by drop to a solution of oxalicacid in anhydrous dichloromethane in the atmosphere N2at -78°C. Then add drop by drop a solution of the alcohol from example 28B ((1S,2S)-[2-(4-bromophenyl)cyclopropyl]methanol) in dichloromethane at -78°C. Continue stirring at this temperature for 30 min, the eat added triethylamine (4 EQ.) and remove bath with dry ice. After stirring for 1 hour the mixture was treated with saturated aqueous NH4Cl. The mixture is extracted with ether. The combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified elwira hexane through a silica gel padding and receiving specified in the header of the connection.

Example 28D

1-Bromo-4-[(1S,2R)-2-vinylcyclopropyl]benzene

A solution of the aldehyde from example 28C [(1S,2S)-2-(4-bromophenyl)cyclopropanecarboxaldehyde] and methyltriphenylphosphonium iodide [CAS 2065-66-9] in anhydrous dichloromethane was stirred at 0°C in an atmosphere of N2. Add to this chilled mixture of tert-butyl potassium. Bath ice is removed and the mixture is stirred at room temperature for one hour. The mixture is quenched with saturated aqueous NH4Cl. Extracted with a mixture of dichloromethane and the combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified on silica gel with hexane, getting listed at the beginning of the connection.

Example 28E

2-[(1R,2S)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

To a solution of alkene from example 28D (1-bromo-4-[(1S,2R)-2 - vinylcyclopropyl]benzene) in anhydrous THF (50 ml) in an atmosphere of N2add borane-THF at 0°C. the Mixture is stirred at room temperature for two hours and then ohlord the Ute to 0°C. Add an aqueous solution of hydrogen peroxide (30%), bath with ice is removed and the mixture allowed to warm to room temperature with continuous stirring for 10 minutes the Mixture was quenched with saturated aqueous NH4Cl and extracted with ether. The combined organic extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure. The residue is purified on silica gel with hexane/ethyl acetate 4:1 and receiving specified in the header of the connection.

Example 28F

4'-[(1S,2R)-2-(2-Hydroxyethyl)cycloprop-1-yl] - biphenyl-4-carbonitrile

A solution of the product of example 28E (2-[(1R,2S)-2-(4-bromophenyl)cycloprop-1-yl]ethanol)4-cyanophenylacetic acid [CAS 126747-14-6] (2 equiv.) Pd(PPh3)2Cl2and Cs2CO3in isopropanol in an atmosphere of N2stirred at the boil under reflux overnight. The mixture is distributed between ethyl acetate and H2O. the Organic layer was washed with saturated aqueous NaHCO3and then a saturated solution of salt. Then the organic layer is dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue purified by chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 4:1 and receiving specified in the header of the connection.

Example 28G

2-[(1R,2S)-2-(4'-Cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid

To a solution of the product of example 28F (4'-[(1S,2R)-2-(2-hydroxyethyl}cycloprop-1-yl] - biphenyl-4-carbonitrile) and methanesulfonamide (1.2 EQ.) in dichloromethane in the atmosphere N 2add triethylamine (1.4 EQ.) at 0°C. the Mixture is stirred at room temperature overnight and then treated with H2O. the Separated organic layer was washed with a saturated solution of salt, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the resulting residue purified by chromatography on silica gel, elwira a mixture of hexane/ethyl acetate 4:1 and receiving specified in the header of the connection.

Example 28H

4'-((1S,2R)-2-{2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

To a solution of nelfinavir example 28G 2-[(1R,2S)-2-(4'-cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid and potassium carbonate in DMF add (R)-2-methylpyrrolidine hydrogen bromide [CAS 117607-13-3]. The mixture is stirred at 50°C during the night. The mixture is distributed between ethyl acetate and H2O. the Organic layer was washed with a saturated solution of salt, dried (MgSO4) and concentrated in vacuo. The resulting residue is purified by chromatography on silica gel, elwira a mixture of MeOH/EtOAc/CH2Cl27,5/between 20/70 and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3, free base): δ 0.88 to 1.0 in (m, 2H), 1,18 (d, J=6 Hz, 3H), 1,4-2,4 (m, 11H), 2,9 (m, 1H), 3.15 and is 3.23 (m, 1H), 7,15 (d, J=9 Hz, 2H), 7,47 (d, J=9 Hz, 2H), 7,66 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 331,2 (M+H)+.

Elemental analysis: calculated for C23H26N2 4H6O6·1,25 H2O (g L-tartaric acid): C, 64,46; H, 6,91; N, to 5.57; found: C, 64,46; H, 6,91; N, 5,57.

Example 29

4'-((1R,2S)-2-{2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 29A

3-(4-Bromophenyl)-N-methoxy-N-methylacrylamide

The solution oxalicacid in dichloromethane (2M, 100 ml, 200 mmol) is added drop by drop to a stirred solution of TRANS-4-bromcresol acid [CAS 1200-07-3] (25,0 g, 110 mmol) and DMF (0.5 ml) in dichloromethane (300 ml) at 0°C in an atmosphere of dry nitrogen. Nitrogen piping and the cooling bath removed and the mixture is stirred at room temperature until gas evolution stops. Volatiles are removed under reduced pressure and the residue re-dissolved in dichloromethane (200 ml). The resulting solution is added drop by drop to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (21,5 g, 220 mmol) and triethylamine (61,4 ml, 440 mmol) in dichloromethane (150 ml) at 0°C. after addition the cooling bath is removed and the mixture is stirred over night at room temperature. Insoluble material is removed by filtration and concentrate the filtrate under reduced pressure. The residue is distributed between ethyl acetate and aqueous 10% citric acid. The organic layer is washed successively aqueous 10% citric acid, aqueous 3n. sodium hydroxide and a saturated solution of the m salt. Then an ethyl acetate solution is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified by the method of column chromatography (hexane/ethyl acetate 65:35), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 3.31 (s, 3H), 3,76 (s, 3H), 7,02 (d, J=15 Hz, 1H), 7,43 (d, J=9 Hz, 2H), 7,51 (d, J=9 Hz, 2H), to 7.67 (d, J=9 Hz, 1H). MS (DCI-NH3) m/z 270 (M+H)+m/z 287 (M+NH4)+.

Example 29B

N-Methoxy-N-methylamide 2-(4-bromophenyl)-TRANS-cyclopropanecarboxylic acid (racemic)

Stir the solution trimethylsulfoxonium (26,78 g, 119 mmol) in DMSO (100 ml) at 0°C is treated with sodium hydride (60% oil dispersion, of 4.57 g, 114 mmol), in small pieces. When you are finished adding bath with ice is removed and the mixture is stirred at room temperature for 45 minutes the Solution alkinoos intermediate product from example 29A (26,85 g, 99 mmol) in DMSO (100 ml) is added drop by drop to the mixture and continue stirring over night. The mixture is diluted with saturated aqueous ammonium chloride and the mixture extracted with diethyl ether (4×100 ml). The combined extracts dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure, getting the oil cleanse method column chromatography (hexane/ethyl acetate 70:30) to obtain specified in the connection header.

1H NMR (300 is Hz, CDCl3): δ of 1.23 to 1.31 (m, 1H), 1.60-to a rate of 1.67 (m, 1H), 2,32-to 2.42 (m, 1H), 2,42-of 2.50 (m, 1H), 3,23 (s, 3H), of 3.69 (s, 3H), 7,00 (d, J=9 Hz, 2H), 7,39 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 284 (M+H)+m/z 301 (M+NH4)+.

Example 29C

2-(4-Bromophenyl)-TRANS-cyclopropanecarbonyl acid (racemic)

A solution of the product from example 29B (24.3 g, 86 mmol) and of potassium tert-butylate (80,8 g, 684 mmol) in diethyl ether (900 ml) and water (10 ml) was stirred at room temperature for three days. Then the mixture is slowly acidified by adding concentrated hydrochloric acid. The ether layer is washed with saturated salt solution and the acidic aqueous layer is extracted with ethyl acetate (2×100 ml). The ether layer and an ethyl acetate extracts are combined, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure, obtaining specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 1,33-of 1.42 (m, 1H), 1,63-1,71 (m, 1H), 1,84 is 1.91 (m, 1H), of 2.51-2,60 (m, 1H), 6,98 (d, J=9 Hz, 2H), 7,41 (d, J=9 Hz, 2H), 11,08 (sh, 1H). MS (DCI-NH3) m/z 258 (M+NH4)+.

Example 29D

[(1R,2R)-2-(4-Bromophenyl)cyclopropyl)-((1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5.2.1.01,5]Dec-4-yl))methanon and [(1S,2S)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo - 3λ6-thia-4-azatricyclo[5.2.1.01,5]Dec-4-yl)}metano

Mix a solution of racemic TRANS-cyclopropene intermediate what about the product of example 29C (20.5 g, 85 mmol) in DMF (100 ml) is treated with 1,1'-carbonyl diimidazol (15.2 g, 94 mmol) in dry nitrogen atmosphere. The mixture is stirred at 40°C for 1 hour and then added (1S)-(-)-2,10-camphorsultam ([CAS 94594-90-8], catalog number Aldrich 29,835-2) (25,82 g, 120 mmol) and DBU (12,7 ml, 85 mmol). The mixture is stirred at 40°C for 6 h and then at room temperature overnight. The mixture is distributed between ethyl acetate and aqueous 2n. the hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate and then with saturated salt solution. Next, the ethyl acetate solution is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and purify the residue by the method of column chromatography (hexane/dichloromethane/isopropanol 90:5:5). Drying in a high vacuum gives a mixture of diastereomers. The diastereomers separated through chromatography on a chiral column (Chiralcel OJ ®, hexane/ethanol 90:10). First eluruumis the diastereoisomer (retention time: about 11.8 min) identify by x-ray crystallography, as with S,S-absolute configuration at cyclopropyl carbon atoms. For aliremove later diastereoisomer (retention time of 19 min) set R,R absolute configuration at cyclopropyl carbon atoms.

Eluruumis the first diastereoisomer (S,S-cyclopropyl), [(1S,2S)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λsup> 6-thia-4-azatricyclo[5.2.1.01,5]Dec-4-yl)}meanon:

1H NMR (300 MHz, CDCl3): δ 0,97 (s, 3H), of 1.17 (s, 3H), of 1.30 to 1.47 (m, 3H), 1,61 was 1.69 (m, 1H), 1,83 of 1.99 (m, 3H), 2,01-2,19 (m, 2H), 2,53-2,61 (m, 1H), 2,63-a 2.71 (m, 1H), 3,42 of 3.56 (m, 2H), 3,86-to 3.92 (m, 1H), 7,10 (d, J=9 Hz, 2H), 7,40 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 455 (M+NH4)+.

Eluruumis later diastereoisomer (R,R-cyclopropyl), [(1R,2R)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5.2.1.01,5]Dec-4-yl)}meanon:

1H NMR (300 MHz, CDCl3): δ 0,98 (s, 3H), of 1.20 (s, 3H), 1,29 to 1.47 (m, 3H), 1,1,73 of-1.83 (m, 1H), 1,83 is 2.00 (m, 3H), 2.00 in to 2.18 (m, 2H), 2,46 at 2.59 (m, 2H), 3,39 of 3.56 (m, 2H), 3,86-4,96 (m, 1H), to 7.09 (d, J=9 Hz, 2H), 7,39 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 455 (M+NH4)+.

Example 29E

(1R,2R)-2-(Bromophenyl)cyclopropanecarboxaldehyde

The solution aliremove later R,R-diastereoisomer ([(1R,2R)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5,2,1,01,5]Dec-4-yl)}meanon), described in example 29D (5,2 g, up 11,86 mmol), in dichloromethane (100 ml) is stirred in a dry nitrogen atmosphere at -78°C. To the mixture add one drop of 1M solution diisobutylaluminium hydride in dichloromethane (26,1 ml of 26.1 mmol). Upon completion of the addition the mixture was stirred at -78°C for 3 hours. Then add one drop of methanol (27 ml) at -78°C. Bath with dry ice replace the bath with ice water and add saturated aqueous ammonium chloride to absorb the mixture. After 10 min Nera the soluble material is removed by filtration and the organic layer is separated, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure, obtaining a colorless oil, which was purified by the method of column chromatography (hexane/ethyl acetate 9:1). The fractions containing the product are combined and concentrated under reduced pressure, obtaining specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 1,45-of 1.57 (m, 1H), 1.70 to of 1.78 (m, 1H), 2,11-2,19 (m, 1H), 2,55-2,63 (m, 1H), 6,99 (d, J=9 Hz, 2H), 7,42 (d, J=9 Hz, 2H), 9,35 (d, J=4.5 Hz, 1H). MS (DCI-NH3) m/z 225 (M+H)+, m/z 242 (M+NH4)+.

Example 29F

1-Bromo-4-[(1R,2S)-2-vinylcyclopropyl-1-yl]benzene

The intermediate aldehyde from example 29E (2.35 g, 10,44 mmol) is converted into an alkene by the methods described in example 26E, followed by chromatography (100% hexane)to give specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 1,07-1,19 (m, 2H), 1.60-to 1,71 (m, 1H), 1,83 is 1.91 (m, 1H), 4,91 is equal to 4.97 (m, 1H), of 5.05-5,14 (m, 1H), the 5.45 5,59 (m, 1H), 6,93 (d, J=9 Hz, 2H), was 7.36 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 241 (M+NH4)+.

Example 29G

2-[(1S,2R)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

Intermediate alkene from example 29F (1.64 g, 7,35 mmol) is converted into alcohol by way of example 26F, followed by chromatography (hexane/ethyl acetate 7:3), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0,96-of 0.79 (m, 2H), and 1.00-1.14 in (m, 1H), 1,54 to 1.76 (m, 3H), 4,91 is equal to 4.97 (m, 1H), 3,76 (t, J=6 Hz, 2H), 6,92 (d, J=9 Hz, 2H), 7,35 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 28 (M+NH 4)+.

Example 29H

4'-[(1R,2S)-2-(2-Hydroxyethyl}cycloprop-1-yl] - biphenyl-4-carbonitrile

Intermediate Bromphenol example 29G (0,83 g, 3,44 mmol) is converted into an intermediate biphenyl way of example 26G, but when the total interaction time of 45 min, followed by chromatography (hexane/ethyl acetate 7:3), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0,87-of 0.95 (m, 1H), 0,97 of-1.04 (m, 1H), 1,11-1,24 (m, 1H), 1,61-to 1.79 (m, 3H), 3,79 (t, J=6 Hz, 2H), 7,15 (d, J=9 Hz, 2H), of 7.48 (d, J=9 Hz, 2H), to 7.67 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 281 (M+NH4)+.

Example 29I

2-[(1S,2R)-2-(4'-Cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid

The intermediate alcohol of example 29H (0.31 g, 1.18 mmol) is converted into an intermediate mesilate way of example 26H, getting listed at the beginning of the connection.

1H NMR (300 MHz, CDCl3): δ 0,89-to 0.96 (m, 1H), 1.00 and-a 1.08 (m, 1H), 1,13-1,24 (m, 1H), 1,76-of 1.93 (m, 3H), 2,98 (s, 3H), 4,35 (t, J=6 Hz, 2H), 7,16 (d, J=9 Hz, 2H), 7,49 (d, J=9 Hz, 2H), 7,68 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 359 (M+NH4)+.

Example 29J

4'-((1R,2S)-2-{2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Intermediate mesilate example 29I (0,37 g at 1.08 mmol) is converted into the end product by way of example 26I. Get listed in the title compound after column chromatography (dichloromethane/methanol/ammonium hydroxide 95:5:traces). At asanee in the title compound was dissolved in methanol. To this stirred solution was added a solution of one equivalent of L-tartaric acid in methanol. After stirring for 15 minutes the solution is concentrated to half volume and treated with ethyl ether, causing crystallization specified in the connection header in the form of monosol L-tartaric acid.

1H NMR (300 MHz, CD3OD, salt L-tartaric acid): δ 0,93-1,10 (m,2H), 1,13-1,24 (m, 1H), 1,44 (d, J=6 Hz, 3H), 1,71-of 1.85 (m, 2H), 1.85 to 1,99 (m, 2H), 2,02-of 2.15 (m, 2H), 2,25-2,49 (m, 1H), 3,06-3,19 (m, 2H), 3,41 of 3.56 (m, 2H), 3,59-and 3.72 (m, 1H), 4,39 (s, 2H), 7,21 (d, J=9 Hz, 2H), 7,58 (d, J=9 Hz, 2H), to 7.77 (s, 4H). MS (DCI-NH3) m/z 331.

Example 30

4'-((1S,2R)-2-{2-[(2R)-2-Methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile

Example 30A

(1S,2S)-2-(4-Bromophenyl)cyclopropanecarboxaldehyde

The solution aliremove first S,S-diastereoisomer ([(1S,2S)-2-(4-bromophenyl)cyclopropyl]-{(1S,5R,7R)-(10,10-dimethyl-3,3-dioxo-3λ6-thia-4-azatricyclo[5,2,1,01,5]Dec-4-yl)}meanon), described in example 29D, in dichloromethane is stirred in a dry nitrogen atmosphere at -78°C. To the mixture add one drop of 1M solution of diisobutylaluminium in dichloromethane. Upon completion of the addition the mixture was stirred at -78°C for 3 hours. Then add one drop of methanol at -78°C. Then replace the bath with a dry ice bath with ice water and add saturated aqueous ammonium chloride to absorb the mixture. After 10 min, the insoluble material is dilaut by filtration and the organic layer is separated, dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified by the method of column chromatography (hexane/ethyl acetate 9:1). The fractions containing the product are combined and concentrated under reduced pressure, obtaining specified in the header of the connection.Example 30B

1-Bromo-4-[(1S,2R)-2-vinylcyclopropyl-1-yl]benzene

The product from example 30A affect the conditions described in example 26E, followed by chromatography (100% hexane)to give specified in the header of the connection.

Example 30C

2-[(1R,2S)-2-(4-Bromophenyl)cycloprop-1-yl]ethanol

The product of example 30B affect the conditions described in example 26F, followed by chromatography (hexane/ethyl acetate 7:3), receiving specified in the header of the connection.

Example 30D

4'-[(1S,2R)-2-(2-hydroxyethyl)cycloprop-1-yl] - biphenyl-4-carbonitrile

The product of example 30C affect the conditions described in example 26G, followed by chromatography (hexane/ethyl acetate 7:3), receiving specified in the header of the connection.

Example 30E

2-[(1R,2S)-2-(4'-cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid

The product of example 30D affect the conditions described in example 26H, getting listed at the beginning of the connection.

Example 30F

4'-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-bi is enyl-4-carbonitril

The product from example 30E (2-[(1R,2S)-2-(4'-cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid, 0.40 g, 1,17 mmol) is then converted into 4'-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile according to the method described in example 29J. Column chromatography (dichloromethane/methanol/ammonium hydroxide 96:4:traces) gives specified in the header connection. Specified in the title compound was dissolved in ethyl ether and bubbled solution of anhydrous gaseous HCl, getting hydrochloride salt specified in the title compound, which crystallized from methanol/ethyl ether.

1H NMR (300 MHz, CD3OD, hydrochloride salt): δ 0.95 to-1,12 (m, 2H), 1,14-1,24 (m, 1H), 1,45 (d, J=6 Hz, 3H), 1,66-of 1.81 (m, 1H), 1,81-of 1.93 (m, 3H), 2.00 in 2,17 (m, 2H), 2,27-to 2.41 (m, 1H), 3,07-3,26 (m, 2H), 3.43 points of 3.56 (m, 2H), 3,64 of 3.75 (m, 1H), 7,21 (d, J=9 Hz, 2H), 7,58 (d, J=9 Hz, 2H), to 7.77 (s, 4H). MS (DCI-NH3) m/z 331 (M+H)+.

Example 31

4'-[(TRANS)-2-(2-Pyrrolidin-1-retil)cyclopropyl]-1,1'-biphenyl-4-carbonitrile

Example 31A

tert-Butyl(but-3-enyloxy)dimethylsilane

Stir the solution at 0°C homeprofessional alcohol (10 g, 0.14 mol) and tert-butyldimethylsilyl (21,5 g, 0.14 mol) in dichloromethane (50 ml) is treated with triethylamine (22,8 ml, has 0.168 mol). Then the mixture is stirred over night at room temperature. The mixture is washed with water and the organic layer is dried (MgSO4and altroot. The filtrate is concentrated under reduced pressure and the residue purified by chromatography (hexane/ethyl acetate 95:5), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 0.08 (s, 6H), of 0.90 (s, 9H), to 1.96 (t, J=3 Hz, 1H), 2,41 (dt, J=6 Hz, J=3 Hz, 2H, in), 3.75 (d, J=6 Hz, 2H).

Example 31B

Tert-butultimately-(4-tributylstannyl-3-enyloxy)silane

A solution of the product of example 31A (1.08 g, by 5.87 mmol), hydride three-(n-butyl)tin (1,43 ml, 5,31 mmol) and AlBN (catalyst) in benzene (10 ml) was stirred at 80°C for 3 hours. Volatiles are removed under reduced pressure, obtaining mentioned in the title compound as a colourless oil (> 95% of E-isomer).

1H NMR (300 MHz, CDCl3): δ of 0.05 (s, 6H), 0,80-0,98 (m, 15H), of 0.90 (s, 9H), 1,23-to 1.38 (m, 6H), 1,42-of 1.53 (m, 6H), 2,34-to 2.40 (m, 2H), 3,66 (d, J=6 Hz, 2H), 5,94 is 5.98 (m, 2H).

Example 31C

4'-[4-(Tert-butultimately-silyloxy)buta-1-enyl]biphenyl-4-carbonitrile

A solution of the product of example 31B (4,95 g, 10.4 mmol), 4'-cyanobiphenyl (3.1 g, 9,48 mmol, obtained from 4'-hydroxybiphenyl-4-carbonitrile standard methods) and Pd(PPh3)2Cl2(of 0.332 g, 0.47 mmol) in DMF (20 ml) was stirred at 80°C during the night. The mixture is cooled to room temperature and distributed between ethyl acetate and water. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified methodology the column chromatography is 97.5:2.5 to hexane/ethyl acetate), getting listed at the beginning of the connection.

1H NMR (300 MHz, CDCl3): δ of 0.07 (s, 6H), of 0.91 (s, 9H), 2,46 (kV, J=6 Hz, 2H, in), 3.75 (t, J=6 Hz, 2H), 6,32 (d, J=16 Hz, 1H), 6.48 in (d, J=16 Hz, 1H), 7,44 (d, J=9 Hz, 2H), 7,54 (d, J=9 Hz, 2H), 7,65-7,74 (m, 4H). MS (DCI-NH3) m/z 364 (M+H)+m/z 359 (M+NH4)+.

Example 31D

TRANS-4'{2-[2-(tert-butyldimethylsilyloxy)ethyl]cyclopropyl}-biphenyl-4-carbonitrile (racemic)

Conduct the reaction education cyclopropanol ring according to the method described in Tetrahedron Letters 1998, 39, 8621-8624. Stir the solution diethylzinc (1M in hexane, to 4.1 ml, 4.1 mmol) in dichloromethane (10 ml) cooled to 0°C. To the cold mixture is added drop by drop a solution triperoxonane acid (of 0.32 ml, 4.1 mmol) in dichloromethane (2 ml). Continue stirring at 0°C for 20 min and then to the cold mixture is added drop by drop a solution diiodomethane (0.4 ml, 4.9 mmol) in dichloromethane (2 ml). After 20 min, add to the mixture a solution of the product of example 31C (0.6 g, of 1.65 mmol) in dichloromethane (5 ml) and bath with ice removed. The mixture is stirred at room temperature for 3 hours, diluted with 0,1N. aqueous HCl and extracted with hexane. The crude product is purified by the method of preparative thin-layer chromatography (hexane/ethyl acetate 97:3), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0,04 (s, 3H), of 0.05 (s, 3H), from 0.84 to 0.97 (m, 2H), 0,89 (s, 3H), 1.56 to about 1.75 (m, 3H), 3,74 (t, J=6 Hz, 2H), 7,14 (d, J=9 Hz, 2H), of 7.48 (d, J=9 Hz, 2H), 7,65 (d, J=9 Hz, 2H), 7,71 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 378 (M+H)+m/z 359 (M+NH4)+.

Example 31E

TRANS-4'-{2-[2-(tert-butyldimethylsilyloxy)ethyl]cyclopropyl}-biphenyl-4-carbonitrile (racemic)

1M solution of tetrabutylammonium fluoride in THF (3.1 ml, 3.1 mmol) are added to stir at room temperature to a solution of the product of example 31D (0,585 g, 1.55 mmol) in THF (5 ml). The mixture is stirred for 2 hours, distributed between ethyl acetate and water. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified by the method of column chromatography (hexane/ethyl acetate 65:35), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ of 0.87 to 0.97 (m, 1H), 0,97-of 1.05 (m, 1H), 1,12-to 1.21 (m, 1H), 1,64-to 1.79 (m, 2H), 3,76-a-3.84 (m, 2H), 7,15 (d, J=9 Hz, 2H), of 7.48 (d, J=9 Hz, 2H), 7,68 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 281 (M+H)+.

Example 31F

TRANS-2-[2-(4'-cyanobiphenyl-4-yl)cyclopropyl]ethyl ester methanesulfonic acid (racemic)

The triethylamine (of 0.18 ml, 1,29 mmol) are added to stir at room temperature to a solution of the product of example 31E (0.24 g, of 0.91 mmol) and methanesulfonamide (0,092 ml, 1,19 mmol) in dichloromethane (10 ml). After stirring for 30 min the mixture was washed with water. The organic layer is dried (MgSO4) and filtered. The filtrate is concentrated p and reduced pressure, receiving raw connection specified in the header.

1H NMR (300 MHz, CDCl3): δ 0,89-to 0.96 (m, 1H), 1,01-1,08 (m, 1H), 1,13-of 1.23 (m, 1H), 1,76 of-1.83 (m, 1H), 1,83-of 1.93 (m, 2H), 2,99 (s, 3H), 4,35 (t, J=6 Hz, 2H), 7,16 (d, J=9 Hz, 2H), 7,49 (d, J=9 Hz, 2H), 7,68 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 359 (M+NH4)+.

Example 31G

4'-[(TRANS)-2-(2-pyrrolidin-1-retil)cyclopropyl]-1,1'-biphenyl-4-carbonitrile

A solution of the product of example 31F (0,054 g, 0,158 mmol) in pyrrolidine (5 ml) stirred at the boil under reflux overnight. Volatiles are removed under reduced pressure and the residue purified by the method of column chromatography (dichloromethane/methanol 95:5), receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0,84-of 0.91 (m, 1H), 0,92-1,0 (m, 1H), of 1.05 to 1.16 (m, 1H), of 1.5-1.9 (m, 8H), 2,48 is 2.75 (m, 5H), 7,14 (d, J=9 Hz, 2H), of 7.48 (d, J=9 Hz, 2H), 7,65 (kV, J=9 Hz, 4H). MS (DCI-NH3) m/z 317 (M+H)+.

Example 32

N-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxamide

Example 32A

4-((1S,2S)-2-(((S)-2-Methylpyrrolidine-1-yl)methyl)cyclopropyl)aniline

A solution of the product from example 1D (1,72 g of 5.85 mmol), lithium bis(trimethylsilyl)amide (1.51 g, 8,78 mmol), Pd2(dba)3(268 mg, 0.29 mmol) and tri-tert-butylphosphine (1.42 g, 10% in hexane, 0,702 mmol) in anhydrous toluene (10 ml) is heated to 120°C in a sealed tube for 16 hours. The mixture is cooled on the ambient temperature, treated with HCl (1M) and extracted with ethyl acetate (2×75 ml). The organic layers are combined washed with H2O and saturated salt solution and dried with magnesium sulfate. After filtration the organic layer is concentrated under reduced pressure and the resulting oil purified on silica gel 1-3% methanol (containing 10% concentrated NH4OH) in dichloromethane, getting listed at the beginning of the connection.

1H NMR (300 MHz, CD3OD): δ 0.70 to 0.76 to (m, 1H), 0,82-0,88 (m, 1H), 1,13 (d, J=6 Hz, 3H), 1,03-1,11 (m, 1H), of 1.35 to 1.48 (m, 1H), 1.60-to of 1.66 (m, 1H), 1,69-to 1.87 (m, 3H), 1,92-2,04 (m, 1H), and 2.27(DD, J=12 Hz, J=Hz,1H), 2,32-2,40 m, 1H), 3,12 (DD, J=12 Hz, J=3 Hz, 1H), 3,23-3,29 (m, 1H), only 6.64 (d, J=9 Hz, 2H), at 6.84 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 231 (M+H)+.

Example 32B

N-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxamide

A solution of the product from example 32A (50 mg, 0.22 mmol) 5-(trifluoromethyl)thieno[3,2-b]pyridine-6-carboxylic acid (110 mg, 0.44 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (55 mg, 0.28 mmol) in DHM (10 ml) is treated with triethylamine (0,061 ml, 0.44 mmol) and stirred at ambient temperature for 16 hours. The mixture is concentrated under reduced pressure and the residue purified on silica gel 1-3% methanol (containing 10% concentrated NH4OH) in dichloromethane, getting listed at the beginning of the connection.

1H NMR (300 MHz, CD3 OD): δ 0,86-of 1.92 (m, 1H), 0,99-of 1.05 (m, 1H), 1,17 (d, J=6 Hz, 3H), 1,20-of 1.29 (m, 1H), 1,42-of 1.52 (m, 1H), 1,73 of-1.83 (m, 3H), 1,94-of 2.08 (m, 2H), 2,32 is 2.51 (m, 2H), 3,17 (DD, J=12 Hz, J=3 Hz, 1H), 3,26-3,30 (m, 1H), 7,10 (d, J=9 Hz, 1H), 7,55 (d, J=9 Hz, 2H), of 7.70 (d, J=6 Hz, 2H), 8,30 (d, J=6 Hz, 1H), total of 8.74 (s, 1H). MS (DCI-NH3) m/z 460 (M+H)+.

Example 33

N-(4-[(1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl]phenyl)isonicotinamide

A solution of the product from example 32A (50 mg, 0.22 mmol), hydrochloride of isonicotinohydrazide (62 mg, 0.31 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in DHM (10 ml) is treated with triethylamine (of 0.12 ml, 0.86 mmol) and stirred at ambient temperature for 16 hours. The mixture is concentrated under reduced pressure and the residue purified on silica gel 1-3% methanol (containing 10% concentrated NH4OH) in dichloromethane, getting listed at the beginning of the connection.

1H NMR (300 MHz, CD3OD): δ 1.04 million-1,10 (m, 1H), 1,16-of 1.23 (m, 1H), 1,39 (d, J=6 Hz, 3H), 1,37-of 1.42 (m, 1H), from 1.66-1.77 in (m, 1H), 2,01-of 2.08 (m, 3H), 2,25-of 2.36 (m, 1H), equal to 2.94 (DD, J=6 Hz, J=3 Hz, 1H), 3.15 and 3.21-in (m, 1H), 3,40 (DD, J=6 Hz, J=3 Hz, 1H), 3,61-3,70 (m, 1H), 7,16 (d, J=9 Hz, 1H), 7,63 (d, J=9 Hz, 2H), 7,86 (d, J=6 Hz, 2H), 8,73 (d, J=3 Hz, 1H), 8,03 (m, 1H). MS (DCI-NH3) m/z 336 (M+H)+.

Example 34

2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

Example 34A

(E)-3-(4-Bromophenyl)prop-2-EN-1-ol

To a solution of (E)-ethyl 3-(4-bromophenyl)acrylate (25 g, 96 mmol) in DHM (300 ml), cooled to -78°C in the atmosphere and the PTA add one drop of DIBAL-H (240 ml 1M in DHM, 240 mmol) in about 20 minutes, the Mixture was stirred at -78°C for 2 hours. Then take bath with dry ice. The reaction mixture was diluted with DHM (500 ml), quenched with HCl (1N.) and distributed between the phases. The combined organic phases are washed with H2O, dried and concentrated under reduced pressure, obtaining specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ was 1.43 (t, J=6 Hz, 1H), 4,32 (t, J=4.5 Hz, 2H), 6,37 (dt, J=16.5 Hz, J=6 Hz, 1H), to 6.57 (d, J =15 Hz, 1H), 7,25 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 214 (M+H)+.

Example 34B

2-Butyl-1,3,6,2-dioxaborolan

To a solution of 2,2'-isunderline (26,12 g, 246 mmol) in DHM (250 ml) and ether (500 ml) add ad-butylboronic acid (25.4 g, 242 mmol) and molecular sieves (3A, 4-6 mesh, 65 g). The solution was stirred at ambient temperature for 2 hours. The mixture is filtered, and concentrate the filtrate under reduced pressure. The obtained white solid is recrystallized from a mixture of DGM/ether, receiving white crystals specified in the header of the product.

1H NMR (300 MHz, CDCl3): δ 0,47 (t, J=9 Hz, 2H), from 0.88 (t, J=6 Hz, 3H), of 1.20 to 1.37 (m, 4H), 2,82 (broad, 2H), 3,24 (broad, 2H), 3,95 (broad, 4H), 4,27 (broad, 1H). MS (DCI-NH3) m/z 172 (M+H)+.

Example 34C

(4R,5R)-2-Butyl-N4,N4,N5,N5-tetramethyl-1,3,2-dioxaborolan-4,5-dicarboxamide

A solution of the product from example 34B (31,3 g, 183 mmol) and (2R,3R)-2,3-dihydrox the-N1,N1,N4,N4-tetramethylbutylamine (31 g, 149 mmol) in DHM (600 ml) is treated with a saturated salt solution (120 ml) and stirred at ambient temperature for 30 minutes the Organic layer was separated and the aqueous layer was extracted with additional DHM. The organic layers are combined and washed with saturated salt solution (700 ml), dried with MgSO4and concentrate under reduced pressure, obtaining specified in the header of the product.

1H NMR (300 MHz, CDCl3): δ 0,83-of 0.90 (m, 6H), 1.26 in-1.42 are (m, 5H), 2,98 (s, 6H), 3,20 (s, 6H). MS (DCI-NH3) m/z 205 (M+H)+.

Example 34D

(1S,2S)-[2-(4-Bromophenyl)cyclopropyl]methanol

A solution of DME (24,39 ml, 235 mmol) in DHM (700 ml) under nitrogen atmosphere cooled to -10°C and add diethylzinc (235 ml, 1M in hexane, 235 mmol) for 5-10 min, and then diameter or 37.9 ml, 469 mmol). Within 5-10 minutes add the product of example 34C (33,0 g, 122 mmol) in 100 ml DHM. During the addition the temperature is maintained within the range of -5° to -10°C. Add one drop of the product of example 34A (E)-3-(4-bromophenyl)prop-2-EN-1-ol (20 g, 94 mmol) in DHM (150 ml) and the reaction mixture stirred at ambient temperature for 16 hours. The mixture is quenched with saturated aqueous NH4Cl (300 ml), HCl (1N., 480 ml) and diluted with ether (900 ml). The organic layer is separated. The aqueous layer was extracted with additional ether. The organic layers are combined and treated with NaOH (2n., 880 ml). To a solution of dobavlyayte drop of H 2O2(30%, 136 ml) while cooling the reaction mixture in a bath with ice. The solution is stirred for 5-10 minutes the Organic layer is separated, washed with HCl (1N.), saturated aqueous Na2S2O3saturated aqueous NaHCO3and saturated salt solution, dried and concentrated. The remainder chromatographic on silica gel, elwira a mixture of EtOAc/hexane 5-15% and receiving specified in the header of the connection.

1H NMR (300 MHz, CDCl3): δ 0,92-1,0 (m, 2H), of 1.45 to 1.48 (m, 2H), 1,76-of 1.85 (m, 1H), 3,61 (d, J=7.5 Hz, 2H), 6,95 (d, J=9 Hz, 2H), 7,37 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 228(M+H)+, (ee 94%).

Example 34E

(1S,2S)-2-(4-Bromophenyl)cyclopropanecarboxaldehyde

To a solution of oxalicacid (17,50 ml, 2M in DHM, 35,0 mmol) in DHM (150 ml), cooled to -78°C under nitrogen atmosphere add one drop of DMSO (equal to 4.97 ml, 70,0 mmol), and then add drop by drop a solution of the product of example 34D ((1S,2S)-2-(4-bromophenyl)cyclopropyl)methanol (5.3g, 23,34 mmol) in DHM (100 ml). The mixture is stirred 30 min at -78°C. the mixture is Then treated with triethylamine (13,01 ml, 93 mmol) and increase the reaction temperature to the ambient temperature. The mixture is partitioned between DJM (400 ml) and H2O (400 ml). The organic layer was separated, washed with water, dried and concentrated under reduced pressure, obtaining specified in the header of the product.

1H NMR (300 MHz, CDCl3): δ to 1.48 (m, 1H), 1,65 (dt, J=9 Hz, J=6 Hz, 1H), 2,15 (m, 1H), 2.57 m (m, 1H),6,98 (d, J=9 Hz, 2H), 7,45 (d, J=9 Hz, 2H), 9,46 (d, J=4.5 Hz, 1H). MS (DCI-NH3) m/z 226 (M+H)+.

Example 34F

1-{[(1S,2S)-2-(4-Bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine

A solution of the product of example 34E (1S,2S)-2-(4-bromophenyl)cyclopropanecarboxaldehyde (5.7 g, to 25.3 mmol) in DHM (20 ml) and MeOH (300 ml) is treated with (S)-2-methylpyrrolidine (8,94 g, 38,0 mmol) at ambient temperature and the mixture is stirred for 5-10 minutes and Then the mixture is cooled to 0°C and add drop by drop a solution of NaCNBH3(of 2.51 g, 38,0 mmol) in MeOH (50 ml). After the addition the temperature of the reaction mixture was raised to room temperature and stirred the mixture overnight. The reaction mixture was treated with NaOH (1N.) to alkaline pH, extracted three times DHM (500 ml ×3), dried and concentrated under reduced pressure. The crude product is loaded into a column of silica gel and elute with 1 to 3% methanol (containing 10% concentrated NH4OH) in dichloromethane, receiving specified in the header of the product.

1H NMR (300 MHz, CDCl3): δ of 0.87 to 0.92(m, 1H), 0,97-1,02 (m, 1H), 1,16 (d, J=6 Hz, 2H), 1,22 (m, 1H), 1,39-1,49(171, 1H), 1,73-of 1.81 (m, 3H), 2.0 (m, 2H), 2,36 (kV, J=6 Hz, 1H), 2,45 (m, 1H), 3,13 (DD, J=12 Hz, J=6 Hz, 1H)at 3.25 (m, 1H), 7,00 (d, J=6 Hz, 2H), 7,37 (d, J=6 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 34G

2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

A solution of the product from example 34F 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl is]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0,340 mmol), pyridazin-3(2H)-she (52,3 mg, 0,544 mmol), N1,N2-dimethylated-1,2-diamine (0,088 ml, 0,816 mmol) and copper iodide(I) (78 mg, 0,408 mmol) in pyridine (2 ml) in a nitrogen atmosphere in a sealed ampoule is heated on an oil bath to 135°C for 16 hours. The reaction mixture is cooled and diluted with DHM (10 ml), filtered through diatomaceous earth and washed DHM. The filtrate is washed successively H2O, 28-30% NH4OH (10 ml ×2) and H2O, dried with MgSO4and concentrate under reduced pressure. The remainder chromatographic on silica gel, elwira a mixture of concentrated NH4OH/MeOH/DHM (0,4/4/96) and getting listed at the beginning of the connection.

1H NMR (300 MHz, CD3OD): δ of 0.90 to 0.97 (m, 1H), 1,03-of 1.09 (m, 1H)and 1.15 (d, J=6 Hz, 3H), of 1.23 and 1.33 (m, 1H), 1,39-1,49 (m, 1H), 1,70-1,80 (m, 2H), 1,82-2,05 (m, 3H), 2.26 and-to 2.42 (m, 2H), and 3.16 (DD, J=12 Hz, J=6 Hz, 1H), 3,21 of 3.28 (m, 1H), 7,07 (d, J=6 Hz, 2H), 7,21 (DD, J=6 Hz, J= 1.5 Hz, 2H), 7,43 (d, J=6 Hz, 2H), 7,47 (DD, J=9 Hz, J=3 Hz, 1H), 8,02 (DD, J=6 Hz, J=1.5 Hz, 1H). MS (DCI-NH3) m/z 310 (M+H)+.

Example 34H

2-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-(2R,3R)-2,3-dihydroxysuccinic

A solution of the product from example 34G ( 3.25 g, 10.5 mmol) in methanol (20 ml) is treated with L-tartaric acid (1,577 g, 10.5 mmol) and stirred at ambient temperature for 1 hour. The mixture is concentrated under reduced pressure and the resulting solid is recrystallized from a mixture of isopro the silt alcohol/acetone, getting listed in the title compound in the form of L-tartrate.

1H NMR (300 MHz, CD3OD): δ 1,12-1,19 (m, 1H), 1,23-of 1.30 (m, 1H), USD 1.43 (d, J=6 Hz, 3H), 1,47-of 1.56 (m, 1H), 1,72-of 1.81 (m, 1H), 2,02-2,19 (m, 3H), 2,28-2,39 (m, 1H), 3.04 from-3,11 (m, 1H), 3,43-3,55 (m, 2H), 3,64 of 3.75 (m, 1H), to 4.38 (with, 2H), was 7.08 (DD, J=6 Hz, J=2 Hz, 1H), 7,28 (d, J=6 Hz, 2H), 7,44 is 7.50 (m, 3H), 8,03 (m, 1H). MS (DCI-NH3) m/z 310 (M+H)+.

Elemental analysis: calculated for C23H29N3O7: C, 60,12; 6,36; N, 9,14; found: 60,07; USD 5.76; N, 8,82.

Example 35

2-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

Example 35A

(R)-1-(((1S,2S)-2-(4-bromophenyl)cyclopropyl)methyl)-2-methylpyrrolidine

Specified in the header of the get connection using the procedure described in example 34F, using (R)-2-methylpyrrolidine instead of (S)-2-methylpyrrolidine.

1H NMR (300 MHz, CDCl3): δ from 0.88 to 0.94(m, 1H), 0,95-1,02 (m, 1H), 1,12 (d, J=6 Hz, 2H), 1,19-of 1.29 (m, 1H), 1,37-1,49 (m, 1H), 1,71-of 1.81 (m, 3H), 1.93 and-2,05 (m, 1H), 2,12 (DD, J 12 Hz, J=6 Hz, 1H), 2,29 (kV, J=6 Hz, 1H), 2,36-of 2.45 (m, 1H), 2,93 (DD, J=12 Hz, J=6 Hz, 1H), 3,25 (m, 1H), 7,00 (d, J=6 Hz, 2H), 7,37 (d, J=6 Hz, 2H). MS (DCI-NH3) m/z 294 (M+H)+.

Example 35B

2-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-he

Specified in the header of the get connection using the procedure described in example 34G, using the product from example 35A instead of the product from example 34F 1-{[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-which of ethylpyrrolidin.

1H NMR (300 MHz, CD3OD): δ of 0.94-0.98 (m, 1H), 1,05-1,09 (m, 1H), 1,13 (d, J=3 Hz, 3H), 1.30 and of 1.36 (m, 1H), 1,4-of 1.48 (m, 1H), 1,72-of 1.81 (m, 2H), 1,84-of 1.88 (m, 1H), 2,16 (DD, J=6 Hz, J=3 Hz, 1H), 2,31 (kV, J=6 Hz, 1H), 2,41 at 2.45 (m, 1H), 2,94-2,98 (kV, J=3 Hz, 1H), 3.25 to be 3.29 (m, 1H), 7,07 (d, J=6 Hz, 2H), 7,21 (d, J=6 Hz, 2H), 7,41 (d, J=6 Hz, 2H), 7,46 (DD, J=6 Hz, J=3 Hz, 1H), 8,02-8,03 (m, 1H). MS (DCI-NH3) m/z 310 (M+H)+.

Example 36

1-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]piperidine-2-he

Specified in the header of the get connection using the procedure described in example 34G, using piperidine-2-he instead pyridazin-3(2H)-it and using the product from example 35A instead of the product from example 34F.

1H NMR (300 MHz, CD3OD): δ 1,08-to 1.21 (m, 2H), 1,39 (d, J=6 Hz, 3H), USD 1.43 to 1.48 (m, 1H), 1,68-of 1.78 (m, 1H), 1,92 is 1.96 (m, 3H), 2,01-of 2.08 (m, 3H), 2.23 to to 2.35 (m, 1H), 2,50 (t, J=6 Hz, 2H), 3,03 (DD, J=12 Hz, J=6 Hz, 1H), 3,13-3,22 (m, 1H), 3,32-to 3.36 (m, 1H), 3,39-3,47 (m, 1H), to 3.58-to 3.67 (m, 3H), 7,17 (d, J=3 Hz, 4H). MS (DCI-NH3) m/z 313(M+H)+.

Example 37

1-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azepin-2-he

Specified in the header of the get connection using the procedure described in example 35B using azepin-2-he instead pyridazin-3(2H)-it and using the product from example 35A instead of the product from example 34F.

1H NMR (300 MHz, CD3OD): δ 1,02-1,08 (m, 1H), 1,13-1,19 (m, 1H), 1,36 (d, J=6 Hz, 3H), 1,35-to 1.38 (m, 1H), 1,64-1,71 (m, 1H), 1,84 (broad, 6H), 1,97-2,05 (m, 3H), 2,21 of-2.32 (m, 1H), 2,67-a 2.71 (m, 2H), 2,78-to 2.85 (m, 1H), 3,05-3,15 (m, 1H), 3,23 of 3.28 (m, 1H), 3,35-3,41 (who, 1H), 3,54-3,63 (m, 1H), 3.75 to of 3.78 (m, 1H), 7,13 (d, J=3 Hz, 4H). MS (DCI-NH3) m/z 327 (M+H)+.

Example 38

1-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-he

Specified in the header of the get connection using the procedure described in example 35B using pyrrolidin-2-he instead pyridazin-3(2H)-it and using the product from example 35A instead of the product from example 34F.

1H NMR (300 MHz, CD3OD): δ 0,89-to 0.96 (m, 1H), 1,01-1,08 (m, 1H), 1,22 (d, J=6 Hz, 3H), between 1.25-1.30 (m, 1H), 1,48-of 1.55 (m, 1H), 1,8-1,89 (m, 4H), 2,03-of 2.27 (m, 4H), to 2.57 (t, J=6 Hz, 2H), 2,65-to 2.74 (m, 1H), up 3.22 (q, J=6 Hz, 1H), 3.33 and is 3.40 (m, 1H), 3,89 (t, J=6 Hz, 2H), 7,10 (d, J=9 Hz, 2H), 7,46 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 299.

Example 39

1-[4-((1S,2S)-2-{[(2R)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-he

Specified in the header of the get connection using the procedure described in example 35B using azetidin-2-he instead pyridazin-3(2H)-it and using the product from example 35A instead of the product from example 34F.

1H NMR (300 MHz, CD3OD): δ 0,98 of-1.04 (m, 1H), 1,08-1,15 (m, 1H), 1,34 (d, J=6 Hz, 3H), of 1.35 (m, 1H), 1,59-1,72 (m, 1H), 1,94-2,04 (m, 3H), 2,18-to 2.29 (m, 1H), 2,75 (kV, J=6 Hz, 1H), 2,98-of 3.07 (m, 1H), is 3.08 (t, J=6 Hz, 2H), 3,16-3,26 (m, 1H), 3,32-to 3.36 (m, 1H), 3,52-3,62 (m, 1H), 3,65 (t, J=6 Hz, 2H), 7,11 (d, J=9 Hz, 2H), 7,30 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 299 (M+H)+.

Example 40

1-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-he

Specified in the header of the connection get PR is changing methodology, described in example 34G, using azetidin-2-he instead pyridazin-3(2H)-it.

1H NMR (300 MHz, CD3OD): δ 0,97-1,03 (m, 1H), 1,08-to 1.14 (m, 1H), 1,33 (d, J=6 Hz, 3H), of 1.35 (m, 1H), 1,60 by 1.68 (m, 1H), 1,94-2,04 (m, 3H), 2,17-to 2.29 (m, 1H), 2,71 (kV, J=6 Hz, 1H), 2,96-3,03 (m, 1H), is 3.08 (t, J=6 Hz, 2H), 3,13-up 3.22 (m, 1H), 3,51-3,59 (m, 1H), 3,66 (t, J=6 Hz, 2H), 7,11 (d, J=9 Hz, 2H), 7,30 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 285 (M+H)+.

Example 41

1-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azepin-2-he

Specified in the header of the get connection using the procedure described in example 34G, and using azepin-2-he instead pyridazin-3(2H)-it.

1H NMR (300 MHz, CD3OD): δ 0,98-1,05 (m, 1H), 1,09 is 1.16 (m, 1H), 1,32 (d, J=6 Hz, 3H), 1,36-of 1.39 (m, 1H), 1,59 was 1.69 (m, 1H)and 1.83 (broad, 6H), 1,94-2,0 (m, 3H), 2,16-of 2.27 (m, 1H), 2,61-a 2.71 (m, 2H), 2,90 are 2.98 (m, 1H), 3,07-3,14 (m, 1H), 3,32-3,37 (m, 1H), 3,48-to 3.58 (m, 1H), 3.75 to of 3.78 (m, 1H), 7,13 (d, J=3 Hz, 4H). MS (DCI-NH3) m/z 327 (M+H)+.

Example 42

1-[4-((1S,2S)-2-{[(2S)-2-Methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]piperidine-2-he

Specified in the header of the get connection using the procedure described in example 34G, and using piperidine-2-he instead pyridazin-3(2H)-it.

1H NMR (300 MHz, CD3OD): δ 0,97-1,03 (m, 1H), 1,08-1,15 (m, 1H), 1,30 (d, J=6 Hz, 3H), 1,31-to 1.38 (m, 1H), 1.56 to to 1.63 (m, 1H), 1,92 of 1.99 (m, 3H), 2,14-of 2.24 (m, 3H), 2.49 USD (t, J=6 Hz, 2H), 2,52 at 2.59 (m, 1H), 2,81-2,90 (m, 1H), 2,96 totaling 3.04 (m, 1H), 3,44-of 3.54 (m, 1H), 3,61-the 3.65 (m, 2H), 7,17 (d, J=3 Hz, 4H). MS (DCI-NH3) m/z 313 (M+N)+.

Example 43

1-[4-((1S,2S)-2-{[(2S)-2-methyl who irreligion-1-yl]methyl}cyclopropyl)phenyl]pyrrolidin-2-he

Specified in the header of the get connection using the procedure described in example 34G, and using pyrrolidin-2-he instead pyridazin-3(2H)-it.

1H NMR (300 MHz, CD3OD): δ 0,99-of 1.05 (m, 1H), 1,10-of 1.16 (m, 1H), 1,34 (d, J=6 Hz, 3H), 1,35-1,40 (m, 1H), 1,59-1,71 (m, 1H), 1,95-2,04 (m, 3H), 2,12-of 2.27 (m, 3H), 2,58 (t, J=6 Hz, 2H), 2,67 was 2.76 (m, 1H), 3,02 (kV, J=6 Hz, 1H), 3,15-up 3.22 (m, 1H), 3,31-3,37 (m, 1H), 3,51-3,59 (m, 1H), 3,89 (t, J=6 Hz, 2H), 7,13 (d, J=9 Hz, 2H), 7,49 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 299 (M+H)+.

Example 44

N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]ndimethylacetamide

Specified in the header of the get connection using the procedure described in example 34G, and using the ndimethylacetamide instead pyridazin-3(2H)-it.

1H NMR (300 MHz, CD3OD): δ 0,98 of-1.04 (m, 1H), 1,09 is 1.16 (m, 1H), 1,36 (d, J=6 Hz, 3H), 1,29-of 1.40 (m, 1H), 1,61-of 1.74 (m, 1H), 1,94-to 2.06 (m, 3H), 2,10 (s, 3H), 2,20 of-2.32 (m, 1H), 2.77-to 2,84 (m, 1H), 3.04 from-3,14 (m, 1H), 3,21-of 3.27 (m, 1H), 3.33 and-3,39 (m, 1H), 3,55-3,63 (m, 1H), 7,06 (d, J=9 Hz, 2H), 7,44 (d, J=9 Hz, 2H). MS (DCI-NH3) m/z 273 (M+H)+.

Determination of biological activity

To determine the effectiveness of typical compounds according to this invention as ligands N3-histamine receptors (ligands H3receptors), conduct the following tests according to previously described methods (Euporean Journal of Pharmacology, 188: 219-227 (1990); Journal of Pharmacology and Experimental Therapeutics, 275:598-604 (1995); Journal of Pharmacology and Experimental Therapeutics, 276:1009-1015 (1996); and Biochemical Pharmacology, 22:3099-3108 (1973)).

Briefly speaking, d is genesereth the cerebral cortex of male rats Sprague-Dawley (1 g tissue/10 ml buffer) in a buffer of 50 mm Tris-HCl/5 mm EDTA, containing a cocktail of protease inhibitors (Calbiochem)using the set of transmitter station at 20500 rpm Homogenates centrifuged for 20 min at 40000g. The supernatant is decanted and precipitation weighed. The precipitate is re-suspended using a homogenizer transmitter station, in 40 ml of buffer 50 mm Tris-HCl/5 mm EDTA with protease inhibitors and centrifuged for 20 min at 40000g. Membrane residue re-suspended in 6,25 volumes (per gram wet weight of sediment) buffer 50 mm Tris-HCl/5 mm EDTA with protease inhibitors and aliquots, quickly frozen in liquid N2and stored at -70°C until use in research. Cortical membranes of rats (12 mg wet weight/tube) and incubated with (3H)-N-α-methylhistamine (~0,6 nm) antagonists H3receptors or without them in the total incubation volume of 0.5 ml of a buffer of 50 mm Tris-HCl/5 mm EDTA (pH of 7.7). The compounds are dissolved in DMSO, receiving a 20 mm solution and performed serial dilutions, and then added to the incubation mixture before incubation studies adding membranes. To determine nonspecific binding use of typename (3 μm). Incubation to assess binding carried out for 30 min at 25°C and stopped by adding 2 ml of chilled on ice buffer 50 mm Tris-HCl (pH 7,7) and conducting filtration through a plate impregnated with 0.3% polyethylenimine Unifilter (Packard). These filters 4 times p is washed with 2 ml of chilled on ice buffer 50 mm Tris-HCl and dried for 1 hour. The radioactivity determined using techniques using liquid scintillation counter. The results of analyzing, applying transformations hill, and determine the values of Kiusing the equation of Chen-Prusoff.

Alternatively, use cortical membranes of rats as a source of N3-histamine receptors are also suitable membranes derived from cells expressing the receptor H3. For this purpose, rat H3-histamine receptors that have been cloned and expressed in cells, and subsequently conduct research on competitive binding according to methods described previously (see: Esbenshade and others the Journal of Pharmacology and Experimental Therapeutics, vol. 313: 165-175, 2005; Esbenshade, etc., Biochemical Pharmacology, vol. 68 (2004) 933-945; Krueger and others the Journal of Pharmacology and Experimental Therapeutics, vol. 314: 271-281, 2005.) Membranes obtained from C6 cells or HEK293 expressing rat H3-histamine receptors, by homogenization on ice in TE-buffer (50 mm Tris-HCl buffer, pH of 7.4, containing 5 mm EDTA) 1 mm benzamidine, 2 μg/ml Aprotinin, 1 μg/ml leupeptin and 1 μg/ml of pepstatin. The homogenate was centrifuged at 40000g for 20 min at 4°C. This step is repeated and the resulting residue re-suspended in TE-buffer. Aliquots frozen at -70°C until the right moment. The day of the test membrane was thawed and diluted with TE-Butera is.

Membrane preparations are incubated with [3H]-N-α-methylhistamine (0.5 to 1.0 nm) in the presence or absence of increasing concentrations of ligands with the aim of competitive binding of H3-receptors. Incubation with the purpose of linking is carried out in final volume of 0.5 ml TE-buffer at 25°C and stopped after 30 minutes To determine nonspecific binding use of typename (30 μm). All binding assays are terminated by filtration under vacuum through filters pre-soaked polyethylenimine (0,3%), Unifilter (Perkin Elmer Life Sciences) or Whatman GF/B, with subsequent brief three-fold washing with 2 ml of chilled on ice TE-buffer. Related radioactive label is determined using a liquid scintillation counter. For all radio-define research of the competitive binding values IC50and the slope of the hill through conversion hill and pKithe values determined by the equation of Chen-Prusoff.

Generally, typical compounds according to the invention exhibit binding capacity (ability to bind) in the above-described studies of approximately from 0.05 to 1000 nm. Preferred compounds according to the invention bind H3-histamine receptors and the binding capacity of from about 0.05 to 250 nm. More preferred compounds according to the invention bind H3-histamines is e receptors and the binding capacity of from about 0.05 to 10 nm.

In addition to the utility of in vitro methods for the characterization of H3-binding ability of compounds there are animal models of human diseases that demonstrate the usefulness of the compounds according to the invention for the treatment of human diseases.

One animal model of human disease ADHD (hyperactivity with attention deficit and related disorders attention in humans is the test for inhibition of avoidance response in young SHR rats (young spontaneously hypertensive rats strain). This model is also referred to as differently as PAR-model (reaction passive avoidance). The methodology and usefulness of this test is described in the literature, for example, in the works: Komater, V. A. and others Psychopharmacology (Berlin, Germany) (2003), 167(4), 363-372; "Two new and selective nikitabelyh antagonist H3receptor A-304121 and A-317920: II. In vivo behavioral and neuropsychological characteristics", Fox, G. B., and others, Journal of Pharmacology and Experimental Therapeutics (2003), 305(3), 897-908; Cowart and others J. Med. Chem. 2005, 48, 38-55; Fox, G. B. and others, "Pharmacological properties of ABT-239: II. Neuropsychological characterization and broad preclinical efficacy for cognitive abilities and in schizophrenia potent and selective antagonist of the histamine H3-receptor", the Journal of Pharmacology and Experimental Therapeutics (2005) 313, 176-190; "Effects of ligands of the histamine H3receptors GT-2331 and ciproxifan for purchase is the acquisition of avoidance when the repetition in young spontaneously hypertensive rats", Fox, G. B. and other Behavioural Brain Research (2002), 131 (1,2), 151-161. Typical compounds are active in research on this model, and the preferred compounds according to the invention is active in research on this model at doses in the range of about 0.001 to 3 mg/kg of body weight.

Compounds according to the invention are ligands H3-histamine receptors, which modulate the function H3-histamine receptors. Connections can be inverse agonists, which inhibit the basal activity of the receptor, or they can be antagonists, which block the action of receptor-activating agonists.

It is clear that the foregoing detailed description and accompanying examples are merely illustrative and are not limitations on the scope of the invention, which is defined exclusively by the attached claims and their equivalents. Specialists in this field will clear various changes and modifications of the disclosed variants. You can make such changes and modifications, including without limitation, changes and modifications relating to the chemical structures, substituents, derivatives, intermediates, products syntheses, drugs or methods, or any combination of such changes and modifications on the application of the invention, without deviating from the essence and scope.

1. Sedimentary:

or its pharmaceutically acceptable salt, where
one of R1and R2denotes a group of the formula-L2-R6A-L3-R6b;
the other of R1and R2selected from the group consisting of a hydrogen atom, a C1-10of alkyl, C1-10alkoxy, halogen and cyano;
R3, R3aand R3beach independently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, trifloromethyl,1-10alkoxy, halogen and cyano;
R4and R5taken together with the nitrogen atom to which each is attached,
form a nonaromatic cycle formula:

R7, R8, R9and R10in each case each independently selected from the group consisting of a hydrogen atom and C1-10of alkyl;
R6ais cyanophenyl or a ring selected from the group consisting of phenyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, [1,2,3]triazolyl, [1,2,4]triazolyl, azepane, azetidine, azetidin-2-onila, pyridazin-3(2H)-onila, pyridine-2(1H)-onila, pyrimidine-2(1H)-onila, pyrrolidin-2-onila and benzothiazolyl where pyridinoline and pyrimidinyl group optionally contain 1-3 substituents selected from the group consisting of C1-10the alkyl and C1-10alkoxy;
R6brepresents a hydrogen atom;
L denotes -[C(R16 )(R17)]k;
L2selected from the group consisting of ties, With2-10alkylene, -O-, -S(=O)-, -NH-, -N(R16)C(=O)-, -C(=O)N(R16and-N(C1-6alkyl)-;
L3that is the link;
R16and R17in each case, independently selected from the group consisting of a hydrogen atom and C1-6of alkyl;
Rxand Ryin each case, independently selected from the group consisting of a hydrogen atom, a C1-6of alkyl, C1-6alkoxy, C1-6alkylamino, fluorine and dis1-6alkylamino;
k is 1, 2 or 3; and
m is 2.

2. The compound according to claim 1, in which R4and R5taken together with the nitrogen atom to which each is attached, form a (2R)-methylpyrrolidinone cycle or (2S)-methylpyrrolidinone cycle.

3. The compound according to claim 1, where the compound has the formula

where L, R1, R2, R3, R3a, R3b, R4, R5each defined in claim 1.

4. The compound according to claim 1, where the compound has the formula

where L, R1, R2, R3, R3a, R3b, R4and R5each of these, as described in claim 1.

5. The compound according to claim 1, in which R1indicates an L2-R6a-L3-R6band R6adenotes pyridazin-3(2H)-IMT.

6. The compound according to claim 1, selected from the group consisting of:
4'-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}Cyclops is sawdust)-1,1'-biphenyl-4-carbonitrile;
4'-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;
4'-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;
4'-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;
4'-{(1S,2S)-2-[(2-methylpyrrolidine-1-yl)methyl]cyclopropyl}-1,1'-biphenyl-4-carbonitrile;
5-[4-((1S,2S)-2-{[(28)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2,6-dimethyl-3-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine;
2-methoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine;
5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2,4-dimethoxy-5-[4-((1R,2R)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2,4-dimethoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine;
2-[4-((1R,2R)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-she;
2-[4-((IS,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]m is Teal}cyclopropyl)phenyl]pyridazin-3(2H)-it;
1,3,5-trimethyl-4-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1H-pyrazole;
2,6-dimethyl-3-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridine;
N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine-5-amine;
4'-((1R,2S)-2-{2-[(2R)-2-methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;
4'-((1S,2R)-2-{2-[(2R)-2-methylpyrrolidine-1-yl]ethyl}cyclopropyl)-1,1'-biphenyl-4-carbonitrile;
4'-[(TRANS)-2-(2-pyrrolidin-1-ileti}cyclopropyl]-1,1'-biphenyl-4 carbonitrile;
N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]isonicotinamide;
2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-she;
1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azepin-2-it;
1-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-it;
1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azetidin-2-it;
1-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]azepin-2-it; and
N-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]-1H-1,2,4-triazole-3-carboxamide.

7. A compound selected from the group consisting of: 2-methoxy-5-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyrimidine; 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-it 2-[4-((1S,2S)-2-{[(2R)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]p is ridazin-3(2H)-it, or its pharmaceutically acceptable salt.

8. The compound which is 2-[4-((1S,2S)-2-{[(2S)-2-methylpyrrolidine-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one or its pharmaceutically acceptable salt.

9. The pharmaceutical composition inhibiting the activity of H3receptors containing a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

10. A method of inhibiting the activity of H3receptor, comprising introducing an effective amount of a compound according to claim 1 in need of such treatment to the mammal.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, where R1 denotes C1-C8-alkylaminocarbonyl, which is optionally substituted with a 5- or 6-member heterocyclic ring containing 3-4 ring heteroatoms selected from a group consisting of oxygen, nitrogen and sulphur, where the ring can be optionally substituted with C1-C8-alkyl or C1-C8-alkoxy group ; R2 denotes C1-C3-alkyl or a halogen; one of R3 and R4 denotes R6, and the other denotes R7; R5 denotes hydrogen or halogen; R6 denotes hydrogen, hydroxy group amino group, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxy, -OR8 or C1-C8-halogenalkyl; R7 denotes hydrogen, OR11, halogen, carboxy, -SO2R8, cyanogroup or C1-C8-halogenalkyl, or when R4 denotes R7, then R7 can also denote -NR12 R13 ; R8 R11 independently denote C1-C8-alkyl or C3-C8-cycloalkyl, which can be optionally substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group or di-C1-C8-alkyl)amino group; any R9 denotes C1-C8-alkyl or C3-C8-cycloalkyl, which can optionally be substituted with hydroxy group, C1-C8-alkoxy group, nitrile, amino group, C1-C8-alkylamino group, di(C1-C8-alkyl)amino group or a 5- or 6-member heterocyclic ring containing one or two ring heteroatoms selected from a group consisting of oxygen and nitrogen, where the ring can optionally be substituted with C1-C8-alkyl, and R10 denotes hydrogen or C1-C8-alkyl; or R9 and R10 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which can contain one or two additional nitrogen heteroatoms, where the ring can be optionally substituted with C1-C8-alkyl; any R12 denotes C1-C8-alkyl or C3-C8-cycloalkyl which can be optionally substituted with di(C1-C8-alkyl)aminogroup, and R13 denotes hydrogen or C1-C8-alkyl; or R12 and R13 together with a nitrogen atom with which they are bonded form a 5- or 6-member heterocyclic ring which contains one or two additional nitrogen heteroatoms, where the ring can optionally be substituted with C1-C8-alkyl.

EFFECT: possibility of using the compounds to produce a pharmaceutical agent for treating diseases mediated by phosphatidylinositol-3 kinase.

6 cl, 3 tbl, 181 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oxazolidinone derivatives of formula (I) or pharmaceutically acceptable salts thereof, synthesis method thereof and pharmaceutical compositions containing said derivatives which are used as an antibiotic. Oxazolidinone derivatives, where R1 and R1' independently denote hydrogen or fluorine; R2 denotes -OR7, fluorine, monophosphate or metal phosphate; and R7 denotes hydrogen, C1-3alkyl or an acylated amino acid group, where the amino acid is alanine, glycine, proline, proline, isoleucine, leucine, phenylalanine, β-alanine or valine; R3 denotes hydrogen, a C1-4alkyl group which is unsubstituted or substituted cyano, , -(CH2)m-OR7 (m equals 0, 1, 2, 3, 4) or a ketone group. Oxazolidinone derivatives of formula (I) have antibacterial activity against different human and animal pathogens.

EFFECT: oxazolidinone derivatives, having inhibiting activity towards a wide range of bacteria and having low toxicity.

27 cl, 4 tbl, 73 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I): or to any of its stereoisomers, or to any mixture of their stereoisomers, or to their pharmaceutically acceptable salts where Ra, Rb and Rc independently represent hydrogen, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, arylalkyl, formyl or alkylcarbonyl; Rd represents a heteroaryl group; where said heteroaryl group means a 5-6-member aromatic heterocyclic group which contains one or two heteroatoms in the ring structure, specified from nitrogen (N) or sulphur (S) and where the heteroaryl group is optionally substituted with one or more substitutes independently specified from the group including: halogeno, hydrazino and alkoxy. Also the invention refers to a pharmaceutical composition, the application of a chemical compound under any of cl. 1-6, as well as to a method of GABAa-receptor complex modulation in the central nervous system.

EFFECT: preparation of the new biologically active compounds exhibiting gamma-amino-butyric acid (GABAa) receptor complex modulating activity in the central nervous system.

11 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula , wherein: R1 means phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms and wherein said phenyl, 6-member heteroaryl is optionally substituted by one R7; R2 means phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms and wherein each of said phenyl or 6-member heteroaryl is optionally substituted by one R7; R3 means halogen R7 independently means halogen, OR8, phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms wherein any phenyl or heteroaryl can be optionally substituted by one R14; R14 means halogen, OR8; R8 independently means C1-6alkyl; m is equal to 1; in the form of a free base or its pharmaceutically acceptable salt, and to their pharmaceutically acceptable salt.

EFFECT: compounds possess BACE inhibitory activity.

8 cl, 6 tbl, 136 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenyl methanone derivatives of the formula I: where R1 denote -OR1, heterocycle such as morpholinyl, pyrrolidinyl, tetrahydropyranyl, phenyl, heteoaryl such as pyrazolyl, which are not substituted or substituted with C1-6alkyl, halogen; R1 denote C1-6alkyl, C1-6alkyl substituted with halogen, or denotes a -(CH2)0-saturated C3-6cycloalkyl; R2 denotes -S(O)2-C1-6alkyl, -S(O)2NH-C1-6alkyl, NO2 or CN; R3 denotes pyridinyl, substituted with C1-6alkyl, substituted with halogen, or phenyl which is not substituted or substituted with one to three substitutes selected from a group consisting of C1-6alkyl, C1-6alkoxy, CN, NO2, halogen, C1-6alkyl, substituted with halogen, C1-6alkoxy, substituted with halogen, phenyl, sulphonamide; X denotes -CH2-, -NH-, -CH2O- or -OCH2-; n denotes 1, 2; m denotes 1, 2; o denotes 1 or 1; and pharmaceutically acceptable acid addition salt thereof.

EFFECT: compounds have glycine reuptake inhibition which enables their use to prepare a pharmaceutical composition.

9 cl, 2 tbl, 40 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole derivatives of formula any isomers thereof or any mixture of isomers thereof or a pharmaceutically acceptable salt, where R is -(CR'R")n-Rc, where Rc is C1-6-alkyl, R' is hydrogen or C1-6-alkyl, and R" is hydroxy; n equals 1; X is N; and Y, Z and W is CRd, where each Rd is hydrogen; Ro is halogen. The invention also relates to a pharmaceutical composition containing a compound of formula I, use of the compound of formula I and a GABAA-receptor complex modulating method.

EFFECT: obtaining novel benzimidazole derivatives which are sensitive to GABAA-receptor complex modulation.

8 cl, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzimidazole derivatives of formula

and pharmaceutically acceptable salts and esters thereof, where R1 denotes C1-10alkyl, lower alkoxy group-lower alkyl, lower alkoxy group-carbonyl-lower alkyl, C3-6cycloalkyl, C3-6cycloalkyl-lower alkyl, phenyl, phenyl-lower alkyl, di(phenyl)-lower alkyl, heterocyclyl, such as piperidinyl, tetrahydropyranyl, 2-oxo-pyrrolidinyl-lower alkyl, where the cycloalkyl, phenyl or heterocyclyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, lower alkoxy group, lower alkoxy group-carbonyl, morpholinyl, formylamino group and halogen; R2 denotes hydrogen or lower alkyl; R3 denotes lower alkyl, C3-6cycloalkyl, partially unsaturated cyclohexyl, phenyl, phenyl-lower alkyl, pyridinyl, benzodioxolyl, tetrahydropyranyl, where the phenyl group is optionally substituted with 1-2 substitutes independently selected from a group comprising a halogen, lower alkyl, lower alkoxy group, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2; R4 denotes: a) heteroaryl which is an aromatic 5-6-member monocyclic ring or a 9-10-member bicyclic ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and/or sulphur, which is optionally substituted with 1-2 substitutes independently selected from a group comprising lower alkyl, phenyl, lower alkoxy group, -N(lower alkyl)2, oxo group, NH2, halogen, cyano group and morpholinyl; b) unsubstituted naphthyl, naphthyl or phenyl, which are substituted with 1-3 substitutes independently selected from a group comprising halogen, hydroxy group, NH2, CN, hydroxy-lower alkyl, lower alkoxy group, lower alkyl-carbonyl, lower alkoxy group-carbonyl, sulphamoyl, di-lower alkyl-sulphamoyl, lower alkyl-sulphonyl, thiophenyl, pyrazolyl, thiadiazolyl, imidazolyl, triazolyl, tetrazolyl, 2-oxopyrrolidinyl, lower alkyl, fluoro-lower alkyl, fluoro-lower alkoxy group, N(lower alkyl)2, carbamoyl, lower alkenyl, benzoyl, phenoxy group and phenyl which is optionally substituted with 1-2 substitutes independently selected from halogen and fluoro-lower alkyl; or c) if R3 denotes cycloalkyl and R1 denotes cycloalkyl, then R4 can also denote phenyl; R5, R6, R7 and R8 independently denote H, halogen, lower alkoxy group or lower alkyl, or R6 and R7, which are bonded to each other, form a 6-member aromatic carbocyclic ring together with carbon atoms to which they are bonded; provided that the compound of formula (I) is not selected from a group comprising butylamide 2-[2-(2-chlorophenyl)benzoimidazol-1-yl]-4-methylpentanoic acid and 2-(2-benzo[1,3]dioxol-5-ylbenzoimidazol-1-yl)-N-benzyl-butyric acid amide. The invention also relates to a pharmaceutical composition based on the formula I compound.

EFFECT: novel benzimidazole derivatives which are useful as farnesoid X receptor antagonists are obtained.

30 cl, 379 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic electroluminescent devices based on compounds of formula

where Y, Z is selected from N, P, P=O, C=O, O, S, S=O and SO2; Ar1, Ar2, Ar3 are selected from benzene, naphthaline, anthracene, phenanthrene, pyridine, pyrene or thiophene, optionally substituted with R1; Ar4, Ar5, Ar6, Ar7 are selected from benzene, naphthaline, anthracene, phenanthrene, pyridine, pyrene, thiophene, triphenylamine, diphenyl-1-naphthylamine, diphenyl-2-naphthylamine, phenyldi(1-naphthyl)amine, phenyldi(2-naphthyl)amine or spirobifluorene, optionally substituted with R1; E is a single bond, N(R1), O, S or C(R1)2; R1 denotes H, F, CN, alkyl, where the CH2 can be substituted with -R2C=CR2 -, -C=C-, -O- or -S-, and H can be substituted with F, optionally substituted aryl or heteroaryl, where R1 can form a ring with each other; R2 denotes H, aliphatic or aromatic hydrocarbon; X1, X4, X2, X3 are selected from C(R1)2, C=O, C=NR1, O, S, S=O, SO2, N(R1), P(R1), P(=O)R1, C(R1)2-C(R1)2, C(R1)2-C(R1)2-C(R1)2, C(R1)2-O and C(R1)2-O-C(R1)2; n, o, p, q, r and t are equal to 0 or 1; s = 1.

EFFECT: obtaining novel compounds - emission layer dopants, and novel electroluminescent devices based on said compounds which emit a blue colour.

18 cl, 91 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula which exhibits an inhibiting action on protein kinases A and B. In the compounds of formula (I), A represents a saturated hydrocarbon binding group containing 1 to 7 carbon atom where the binding group includes a chain of the maximum length 5 atoms located between R1 and NR2R3, and a chain of the maximum length 4 atoms located between E and NR2R3 where one of carbon atoms in the binding group can be optionally substituted by an oxygen or nitrogen atom; and where the carbon atoms of the binding group A can optionally have one or more substitutes selected from oxo, fluorine and hydroxy provided the hydroxy group if any is not located on a carbon α-atom in relation to the NR2R3 group and provided the oxo group if any is located on the carbon α-atom in relation to the NR2R3; E represents a phenyl or pyridine group; R1 represents a C6-10aryl or pyridyl group which is not substituted or substituted with 1 or 2 substitutes specified in the patent claim; and R2, R3, R4 and R5 have the values specified in the points of the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing said compounds, to methods of making the compounds and their application as cancer drugs.

29 cl, 1 tbl, 108 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing a compound of general formula I where R1 denotes a radical of formula II: where R2 is a protective tetrazole group which is a novel intermediate compound when producing losartan - 2-n-butyl-4-chloro-5-hydroxymethyl-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4]methyl}-imidazole, and a method of producing losartan based on compound I by reducing the formyl group and then adding a chlorine atom to the imidazole ring and removing the protective R2 group.

EFFECT: method ensures high output of the end product from available starting and intermediate compounds on an industrial scale.

9 cl

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: chemistry.

SUBSTANCE: invention relates to a method of producing candesartan or a protected form of candesartan, candesartan salt or candesartan ester using a catalyst or several catalysts preferably containing one or more transition metals, and one or more of the following solvents: tetrahydrofuran (THF), THF/NMP (N-methylpyrrolidone), Et2O, DME (dimethoxy ethane), benzene, toluene, involving the following steps: (a) supply and reaction of a compound of formula (I), where R denotes hydrogen, unsubstituted or substituted alkyl or aryl radical, preferably methyl or (cyclohexyloxycarbonyloxy)ethyl, Y1 denotes a group capable of a coupling reaction into which Y2 comes in to form a C-C bond, with a compound of formula (II), having group Y2, where R1 is selected from a group comprising hydrogen, tert. Butyl and triphenylmethyl, preferably triphenylmethyl, to form candesartan, a protected form of candesartan or candesartan ester or candesartan cilexetil or some other candesartan ester, where (i) Y1 denotes B(OR4)2, where each of the radicals R4 independently denotes hydrogen, alkyl, aryl or alkylaryl, preferably hydrogen, and Y2 denotes a halogen, preferably bromine, or (and) Y denotes a halogen, preferably bromine,and Y2 denotes B(OR4)2, where each of radicals R4 independently denotes hydrogen, alkyl, aryl or alkylaryl, preferably hydrogen, and if necessary, (b) conversion to candesartan, candesartan cilexetil or salt.

.

EFFECT: novel method for producing candesartan with high output.

24 cl, 3 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula , wherein: R1 means phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms and wherein said phenyl, 6-member heteroaryl is optionally substituted by one R7; R2 means phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms and wherein each of said phenyl or 6-member heteroaryl is optionally substituted by one R7; R3 means halogen R7 independently means halogen, OR8, phenyl, 6-member heteroaryl containing one or two atoms N as heteroatoms wherein any phenyl or heteroaryl can be optionally substituted by one R14; R14 means halogen, OR8; R8 independently means C1-6alkyl; m is equal to 1; in the form of a free base or its pharmaceutically acceptable salt, and to their pharmaceutically acceptable salt.

EFFECT: compounds possess BACE inhibitory activity.

8 cl, 6 tbl, 136 ex

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