RU2588137C2 - Novel triazole compounds - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula (I), pharmaceutically acceptable salts and esters. Compounds of formula (I) have affinity and selectivity for GABA A α5 receptor. In formula

X is N or CH; R¹, R² - C1-C7-alkyl, phenyl substituted by 1 halogen, wherein one of substituents R¹ and R² is an alkyl group; R³ - haloC1-C7-alkyl, nitro, -C(O) R⁴, -C(O) NR⁵R⁶; R⁴ - C1-C7-alkyl, hydroxy, C1-C7-alkoxy; R⁵ - hydrogen, C1-C7-alkyl, haloC1-C7 alkyl hydroxyC1-C7-alkyl, -(CH₂)_n-C3-C8 cycloalkyl, - (CH₂)_n- (4-6 membered heterocycloalkyl with 1 heteroatom selected from O), wherein heterocycloalkyl is optionally substituted with one C1-C7-alkyl group; n is an integer ranging from 0 to 1; R⁶ - hydrogen, C1-C7-alkyl; or R⁵ and R⁶ together with nitrogen to which they are attached form a bicyclic 7-membered heterocycloalkyl with additional heteroatom selected from O, 6-membered heterocycloalkyl with additional heteroatom selected from O, S, wherein heterocycloalkyl is optionally substituted by one or more oxo groups. Invention also relates to a pharmaceutical composition comprising a compound of invention in an effective amount, to a method for treating or preventing diseases associated with GABA A α5 receptor, use of compounds for preparation of medicaments and use of compounds for treating or preventing diseases associated with GABA A α5 receptor.

EFFECT: technical result is obtaining novel compounds having affinity and selectivity for GABA A α5 receptor.

23 cl, 1 tbl, 53 ex

Description

The present invention relates to 1,2,3-triazole-imidazole compounds having affinity and selectivity for the GABA A α5 receptor, their production, pharmaceutical compositions containing these compounds, and their use as medicaments.

The present invention relates to compounds of the formula (I)

where X, R ¹ , R ² and R ³ are the substituents described below, including in the claims, as well as pharmaceutically acceptable salts and esters of these compounds.

Receptors for the main inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: 1) GABA A receptors, which are members of the superfamily of ligand-dependent ion channels, and 2) GABA B receptors, which belong to the class of receptors conjugated to G proteins. The GABA A receptor complex is a membrane-bound, heteropentameric protein polymer that consists primarily of α, β and γ subunits. Currently, a total of 21 GABA A receptor subunits have been cloned and sequenced. Three types of subunits (α, β, and γ) are required to create recombinant GABA A receptors that best mimic the biochemical, electrophysiological, and pharmacological functions of natural GABA A receptors derived from mammalian brain cells. There is strong evidence that the binding site to benzodiazepine lies between the α and γ subunits. As a recombinant GABA A receptor, α1β2γ2 is used, which exhibits numerous effects characteristic of subtypes of the classical benzodiazepine type I receptor, while other recombinant GABA A receptors α2β2γ2, α3β2γ2 and α5β2γ2 are ion channels and are called BzR II RM McKernan, PJ Whiting, in Recombinant Cell Surface Receptors: Focal Point for Therapeutic Intervention, MJ Browne (Ed.) (1997) Chapter 8: 155-173, RG Landes Co., Austin, TX).

As shown by McNamara and Skelton (Psychobiology (1993) 21: 101-108), the inverse agonist of the β-CCM benzodiazepine receptor agonist enhances the spatial learning ability of the Morris water labyrinth test. However, β-CCM and other traditional inverse agonists of the benzodiazepine receptor cause seizures or provoke them, which prevents their use in humans as means of stimulating cognitive abilities. In addition, these compounds are not selective for the subunits of the GABA A receptor, while the partially or completely inverse agonist of the α5 subunit of the GABA A receptor has almost no activity against the α1 and / or α2 and / or α3 binding sites of the GABA A receptor, can be used as a drug stimulating cognitive abilities, while it does not cause seizures, or this side effect is weakly expressed. In addition, you can use GABA A α5 inverse agonists that are active against α1 and / or α2 and / or α3 binding sites of the GABA A receptor, but which are functionally selective for subunits containing α5 binding site. However, inverse agonists that are selective for GABA A α5 subunits and which show little activity on GABA A α1, α2 and α3 receptor binding sites are preferred.

There is evidence in the literature that there is a relationship between the GABA A α5 subunits and the treatment of various diseases of the central nervous system (Neuroscience Letts. (2005) 381: 108-13, Neuropsychobiology (2001) 43 (3): 141-44, Amer. J. Med. Genetics (2004) 131B: 51-9, Autism (2007) 11 (2): 135-47, Investigacion Clinica (2007) 48: 529-41, Nature Neuroscience (2007) 10: 411-13, Neuroscience Letts. (2008) 433: 22-7; Cell (2008) 135: 549-60).

The objectives of the present invention are the compounds of formula (I) and their pharmaceutically acceptable salts and esters, the preparation of the above compounds, drugs containing these compounds and their manufacture, as well as the use of the above compounds for the treatment or prevention of diseases associated with GABA A α5 . The compounds of the present invention are preferably inverse agonists of GABA A α5.

The compounds of the present invention and their pharmaceutically acceptable salts and esters have high affinity and selectivity for the GABA A α5 receptor and can be used, alone or in combination with other drugs, as cognitive stimulants, or for treatment or prevention acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory impairment, schizophrenia, positive, negative and / or cognitive symptoms, those with schizophrenia, bipolar disorder, autism, Down syndrome, type I neurofibromatosis, sleep disturbances, amyotrophic lateral sclerosis (ALS), AIDS dementia, psychoactive substance disorder, anxiety disorder, generalized anxiety disorder, panic attacks, b obsessive-compulsive disorders, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficiency disorders, mul Tiinfarction dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, multiple sclerosis (MS), acute meningitis, fetal alcohol syndrome, and attention disorders.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as is commonly understood by one of the skilled in the art to which this invention belongs. Suitable methods and materials are described below, while methods and materials similar or equivalent to those described below in this application can also be used to apply or test the invention.

All publications, patent applications, patents, and other documents mentioned in this application are incorporated into the text of the application by reference.

Unless otherwise agreed, the application is written using terminology based on the IUPAC systematic nomenclature.

Any open valency of a carbon, oxygen, sulfur or nitrogen atom in the structures presented in this application means a hydrogen atom, unless otherwise indicated.

The definitions described in this application apply regardless of whether the terms are used individually or in combination. It is contemplated that the definitions described herein can be supplemented so that these combinations are chemically appropriate, for example, “heterocycloalkyl-aryl,” “haloalkyl-heteroaryl,” “aryl-alkyl-heterocycloalkyl,” or “alkoxy-alkyl” . The last member of the combination is a radical that is replaced by other members of this combination in the reverse order.

When the number of substituents is indicated, the term “one or more” refers to the range from one to the maximum possible number of substituents, i.e. implies replacement by other functional groups of one hydrogen atom or all hydrogen atoms.

The term “possible” or “possible” means that the described event or circumstance following this term may occur, but does not necessarily occur, and that the description contains examples when the event or circumstance occurs, and cases in which the event or circumstance does not occur.

The term “substituent” means an atom or group of atoms replacing a hydrogen atom of a parent molecule.

The term “substituted” means that a particular group carries one or more substituents. If a group may have several substituents, and the variety of possible substituents is quite large, then the substituents are chosen independently from each other, and there is no need to choose the same substituents. The term “unsubstituted” means that a particular group does not bear any substituents. The term “optionally substituted” means that said group is unsubstituted or substituted by one or more substituents independently selected from a group of possible substituents. When indicating the number of substituents, the term “one or more” means from one to the maximum possible number of substituents, i.e. one or all hydrogen atoms are replaced.

The terms “compound (s) of the present invention” and “compound (s) of the present invention” refer to compounds of the formula (I) as well as stereoisomers, tautomers, solvates and salts of these compounds (for example, pharmaceutically acceptable salts).

It should be borne in mind that the functional groups of the compounds of the present invention can be modified in order to obtain derivatives that are capable of being converted into the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives that are capable of forming the parent compounds of the present invention in vivo are also included in the scope of the present invention.

The term "pharmaceutically acceptable esters" means derivatives of the compounds of the present invention in which the carboxyl group is converted to an ester group in which the carboxyl group is designated as -C (O) O-. Methyl, ethyl, methoxymethyl, methylthiomethyl, and pivaloyloxymethyl esters are examples of such suitable esters. In addition, the term "pharmaceutically acceptable esters" encompasses derivatives of the compounds of the present invention in which the hydroxyl groups are converted to the corresponding esters with inorganic or organic acids such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, or p-toluenesulfonic acid, and which are not toxic to living organisms.

The term "pharmaceutically acceptable salts" means salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts.

The term “pharmaceutically acceptable acid addition salt” means pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and also with organic acids selected from aliphatic , cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, glycol eic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid , cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

The term “pharmaceutically acceptable base addition salt” means those pharmaceutically acceptable salts which are formed with organic or inorganic bases. Suitable inorganic bases forming such salts include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum hydroxides. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, novocaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethyl piperidine and polyamine polymers.

The term "solvate" means crystalline formations containing stoichiometric or non-stoichiometric amounts of solvent included in the crystal lattice. If the solvent included in the crystal is water, then the solvate formed in this case is called hydrate. If the solvent included in the crystal is an alcohol, then the solvate formed in this case is called an alcoholate.

The terms “halo”, “halogen”, and “halogen” are used interchangeably herein to mean fluorine, chlorine, bromine, or iodine atoms. In particular, halo means fluorine and chlorine atoms, most often fluorine.

The term “alkyl” means a monovalent, linear or branched saturated hydrocarbon group containing from 1 to 12 carbon atoms, in particular from 1 to 7 carbon atoms, in particular from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In particular, methyl, isopropyl, isobutyl and tert-butyl, and especially methyl and isopropyl, are used as alkyl.

The term “alkoxy” means a group of the formula —O — R ′ in which R ′ is an alkyl group. Examples of alkoxy radicals include methoxyl, ethoxyl, isopropoxyl and tert-butoxyl groups. In particular, a methoxy group is used as the alkoxyl group.

The term “haloalkyl” means an alkyl group in which at least one of the hydrogen atoms of the alkyl group is substituted by the same or different halogen atoms, in particular fluorine atoms. Examples of the haloalkyl group include monofluoro, difluoro or trifluoromethyl, ethyl or propyl, for example 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl or trifluoromethyl. The term “perhaloalkyl” means an alkyl group, wherein all of the hydrogen atoms of the alkyl group are substituted with the same or different halogen atoms. A specific example of a haloalkyl grappa is trifluoromethyl.

The term “hydroxyalkyl” means an alkyl group in which at least one of the hydrogen atoms of the alkyl group is substituted by a hydroxyl group. Examples of the hydroxyalkyl group include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1 -hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl or 2- (hydroxymethyl) -3-hydroxypropyl. Specific examples of the hydroxyalkyl group include hydroxyisobutyl and hydroxytret-butyl, in particular 2-hydroxy-2-methylpropyl and 1-hydroxy-2-methylpropan-2-yl, and in particular 1-hydroxy-2-methylpropan-2-yl.

The term "cycloalkyl" means a monovalent saturated monocyclic or bicyclic hydrocarbon group containing from 3 to 10 carbon atoms closed in a ring, in particular a monovalent saturated monocyclic hydrocarbon group containing from 3 to 8 carbon atoms closed in a ring. A bicyclic group means a group consisting of two saturated carbon rings having one or more common carbon atoms. In particular, cycloalkyl groups are monocyclic. Examples of monocyclic cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Examples of binocyclic cycloalkyl groups are bicyclo [2.2.1] heptyl, or bicyclo [2.2.2] octyl. A particular example of a cycloalkyl group is cyclopropyl.

The term “cycloalkylalkyl” means an alkyl group in which at least one of the hydrogen atoms of the alkyl group is substituted by a cycloalkyl group. Examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylpropyl and cyclopentylbutyl. A particular example of a cycloalkylalkyl group is cyclopropylmethyl.

The term “heterocycloalkyl” means a monovalent saturated or partially unsaturated mono- or bicyclic ring system containing from 4 to 9 atoms, closed in a ring, which includes 1, 2 or 3 heteroatoms selected from N, O and S, with the rest the atoms that make up the ring are carbon atoms. A bicyclic group means a group consisting of two rings having two common ring atoms, i.e. the bridge separating the two rings is either one single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl groups include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo [3.2.1] octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1] octyl, 9-aza-bicyclo [3.3.1] nonyl, 3- oxa-9-aza-bicyclo [3.3.1] nonyl or 3-thia-9-aza-bicyclo [3.3.1] nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuryl, imidazolinyl, dihydrooxazolyl, tetrahydropyridinyl or dihydropyranyl. Heterocycloalkyl groups may be further substituted as described herein, in particular, they may be substituted with one or more alkyl or oxo groups. Specific examples of heterocycloalkyl groups are morpholinyl, oxetanyl, tetrahydropyranyl, thiomorpholinyl and 2-oxa-6-aza-spiro [3,3] hept-6-yl, in particular morpholinyl, 3-methyloxetan-3-yl, tetrahydropyran-4- il, 1,1-dioxo-1,6-thiomorpholin-4-yl, and 2-oxa-6-aza-spiro [3,3] hept-6-yl. Most often, examples of heterocycloalkyl groups are 3-methyl-oxetan-3-yl, tetrahydropyran-4-yl and 2-oxa-6-aza-spiro [3,3] hept-6-yl.

The term "aromatic" corresponds to the traditional notion of aromaticity, as defined in the literature, in particular, in IUPAC - Compendium of Chemical Terminology, 2nd, A. D. McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).

The term “aryl” means a monovalent aromatic carbocyclic mono- or bicyclic ring system consisting of 6-10 carbon atoms closed in a ring. Examples of aryl residues include phenyl and naphthyl. A particular example of an aryl group is phenyl.

The term “aryloxy” means a group of the formula —O — R ′ in which R ′ is an aryl group. An example of an aryloxy group is a phenoxy group.

The term “heteroaryl” means a monovalent aromatic heterocyclic mono- or bicyclic ring system containing from 5 to 12 atoms closed in a ring, of which 1, 2, 3 or 4 atoms are heteroatoms selected from N, O and S, with the rest the atoms that make up the ring are carbon atoms. Examples of heteroaryl residues include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl azole, isazole, diazole, diazole, diazole, diazole, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, puranyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinazolinyl.

The term “oxo” means a divalent oxygen atom = O.

The term "active pharmaceutical ingredient" (or "API") means a compound that is part of a pharmaceutical composition that has a specific biological activity.

The term "pharmaceutically acceptable" means a property of a material that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, suitable for veterinary medicine as well as for pharmaceutical use in humans.

The term "pharmaceutically acceptable excipient" means any ingredient that does not have any therapeutic activity and is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants, or lubricants used in the manufacture of pharmaceutical products.

The term "pharmaceutical composition" (or "composition") means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable excipients, which is intended for administration to mammals, for example, to a person who needs it.

The term “agonist” means a compound that enhances the activity of another compound or receptor binding site, as defined, for example, on page 35 in Goodman and Gilman’s "The Pharmacological Basis of Therapeutics, 7th ed.", Macmillan Publ. Company, Canada, 1985. A “full agonist” causes complete receptor activation, while a “partial agonist” causes not complete receptor activation, even when it occupies the entire receptor population. An “inverse agonist” produces an effect opposite to that of an agonist, even though it attaches to the same receptor binding site.

The term "inhibition constant" (Ki) means the absolute affinity of binding of a particular inhibitor to the receptor. It is measured by competitive binding analysis and is equal to the concentration at which a particular inhibitor binds to 50% of the receptor molecules in the absence of competing ligands (e.g., radioligands). Ki values can be converted logarithmically to pKi values (-log Ki), which show an exponential increase in inhibitor efficiency with increasing constant values.

The term “therapeutically effective amount” means an amount of a compound of the present invention that, when administered to a patient (i) treats or prevents a particular disease, condition or disorder, (ii) alleviates, improves or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or slows down the onset of one or more symptoms of a particular disease, condition or disorder described herein. The therapeutically effective amount varies depending on the compound, stage of the disease,

which needs to be treated, the severity of the disease or the type of disease that needs to be treated, the age and relative health status of the patient, the method and nature of the administration of the drug, the opinion of the attending medical or veterinarian, and other factors.

The term “treating” or “treating” a disease state includes 1) preventing this disease state, i.e. the development of clinical symptoms of the disease state does not occur in a patient who may be exposed to the disease or predisposed to the disease, but still does not feel or show symptoms of the disease, 2) suppression of the disease state, i.e. the development of the state of the disease or its clinical symptoms stops, or 3) the elimination of the state of the disease, i.e. there is a temporary or permanent regression of the disease or its clinical symptoms.

The term "patient" means vertebrates. In some embodiments, the vertebrates are mammals. Mammals include non-human primates such as chimpanzees, anthropoids and other monkeys, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, laboratory animals, including rodents such as rats, mice, and guinea pigs. In some embodiments, the mammals are humans. The term patient does not mean a specific age or gender.

DETAILED DESCRIPTION OF THE INVENTION

In particular, the present invention relates to compounds of the formula (I)

Where

X N or CH; R ¹ , R ² alkyl, aryl, possibly substituted with 1 or 2 halo or heteroaryl groups, possibly substituted with 1 or 2 halo, where one of the substituents R ¹ and R ² is an alkyl group; R ³ halo, alkyl, haloalkyl, hydroxyalkyl, cyano, nitro, —C (O) R ⁴ , —C (O) NR ⁵ R ⁶ ; R ⁴ hydrogen, alkyl, aryl, hydroxy, alkoxy or aryloxy; R ⁵ hydrogen, alkyl, haloalkyl, hydroxyalkyl, - (CH ₂ ) _n -cycloalkyl, - (CH ₂ ) _n- heterocycloalkyl, - (CH ₂ ) _n- aryl, - (CH ₂ ) _n- heteroaryl, - (CH ₂ ) _m —NR ⁷ R ⁸ , - (CH ₂ ) _m —OR ⁹ where cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, or oxo group; n an integer in the range from 0 to 6; m an integer in the range from 2 to 6; R ⁶ , R ⁷ , R ⁸ , R ⁹ independently of one another, hydrogen, alkyl or aryl; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form heterocycloalkyl, or heteroaryl, where heterocycloalkyl and heteroaryl are optionally substituted with one or more halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxy, or oxo group;

as well as pharmaceutically acceptable salts and esters of these compounds.

Certain embodiments of the present invention are compounds of formula (I) and pharmaceutically acceptable salts and esters of these compounds.

In addition, it should be noted that any implementation option related to a specific residue X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , n, or m, as described herein can be used in combination with other embodiments related to another residue X, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , n, or m, as described in this application.

One of the options for implementing the present invention relates to compounds of formula (I), in which

X N or CH; R ¹ , R ² alkyl, or aryl, optionally substituted with 1 halo, wherein one of the substituents R ¹ and R ² is an alkyl group; R ³ haloalkyl, nitro, -C (O) R ⁴ , -C (O) NR ⁵ R ⁶ ; R ⁴ alkyl, hydroxy, or alkoxy; R ⁵ hydrogen, alkyl, hydroxyalkyl, - (CH ₂ ) _n -cycloalkyl, or - (CH ₂ ) _n -heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one alkyl group; n an integer in the range from 0 to 1; R ⁶ hydrogen; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form heterocycloalkyl, which is optionally substituted by one or more oxo groups;

as well as pharmaceutically acceptable salts and esters of these compounds.

One embodiment of the present invention relates to compounds of formula (Ia)

where R ¹ , R ² and R ³ are the substituents described in this application.

One embodiment of the present invention relates to compounds of formula (Ib)

where R ¹ , R ² and R ³ are the substituents described in this application.

In one embodiment of the present invention, X is N.

In one embodiment of the present invention, X is CH.

In one embodiment of the present invention, one of the substituents R ¹ and R ² is an alkyl group, and the other substituent is an aryl group optionally substituted with one halo.

In one embodiment of the present invention, one of the substituents R ¹ and R ² is a methyl group, and the other substituent is a phenyl group optionally substituted with one fluorine or chlorine atom.

In one embodiment of the present invention, one of the substituents R ¹ and R ² is a methyl group, and the other substituent is a phenyl group substituted with one fluorine atom.

In one embodiment of the present invention, R ¹ is an alkyl group, and R ² is an aryl group substituted with one halo.

In one embodiment of the present invention, R ¹ is a methyl group, and R ² is a phenyl group substituted with one fluorine atom.

In one embodiment of the present invention, R ² is an alkyl group, and R ¹ is an aryl group substituted with one halo.

In one embodiment of the present invention, R ² is a methyl group, and R ¹ is a phenyl group substituted with one fluorine atom.

In one embodiment of the present invention, R ³ is a haloalkyl group, nitro, —C (O) R ⁴ , or —C (O) NR ⁵ R ⁶ .

In one embodiment of the present invention, R ³ is a trifluoromethyl group, nitro, —C (O) R ⁴ , or —C (O) NR ⁵ R ⁶ .

In one embodiment of the present invention, R ³ is a trifluoromethyl group.

In one embodiment of the present invention, R ³ is —C (O) NR ⁵ R ⁶ .

In one embodiment of the present invention, R ⁴ is an alkyl, hydroxyl, or alkoxyl group.

In one embodiment of the present invention, R ⁴ is a methyl, hydroxyl, or methoxy group.

In one embodiment of the present invention, R ⁵ is a hydrogen atom, an alkyl, hydroxyalkyl, - (CH ₂ ) _n -cycloalkyl, or - (CH ₂ ) _n -heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with one alkyl group.

In one embodiment of the present invention, R ⁵ is a hydrogen atom, an isopropyl, isobutyl group, a substituted hydroxyl, tert-butyl group, a substituted hydroxyl, cyclopropyl, cyclopropylmethyl, morpholinyl, tetrahydropyranyl or oxetanyl group substituted with a methyl group.

In one embodiment of the present invention, R ⁵ is an isopropyl, tert-butyl group substituted by a hydroxyl, cyclopropyl, tetrahydropyranyl, or oxetanyl group substituted by a methyl group.

In one embodiment of the present invention, R ⁶ is a hydrogen atom.

In one embodiment of the present invention, R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form a heterocycloalkyl that is optionally substituted with one or more oxo groups.

In one embodiment of the present invention, R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form 1,1-dioxo-1,6-thiomorpholin-4-yl or 2-oxa-6-aza-spiro [ 3.3] hept-6-yl.

In one embodiment of the present invention, R ⁵ and R ^6, together with the nitrogen atom to which they are attached, form 2-oxa-6-aza-spiro [3.3] hept-6-yl.

One of the options for implementing the present invention relates to compounds of formula (I), which are described in the examples as individual compounds, as well as pharmaceutically acceptable salts and esters of these compounds. In addition, the substituents given in the specific examples described below, each individually represents a specific embodiment of the present invention.

The compounds of formula (I) of the present invention are selected from the group consisting of:

1- (4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone;

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid methyl ester;

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl benzamide;

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) -benzamide;

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) benzamide;

(4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) - (2-oxa- 6-aza-spiro [3.3] hept-6-yl) methanone;

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzamide;

4- (2-Fluorophenyl) -1-methyl-5- (1- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole;

4- (2-Fluorophenyl) -1-methyl-5- (1- (4-nitrophenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole;

1- (4- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) phenyl) ethanone;

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl nicotinamide;

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide;

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) -nicotinamide;

(6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} pyridin-3-yl) - ( 2-oxa-6-aza-spiro [3.3] hept-6-yl) methanone;

2- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine;

6- (4- (4- (4-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

Methyl 6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate;

6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;

6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

Methyl 6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (tetrahydro-2H-pyran -4-yl) nicotinamide;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (2-hydroxy-2 methylpropyl) nicotinamide;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

(6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide;

N-Cyclopropyl-6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

2- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -5- (trifluoromethyl) pyridine;

1- (4-Fluorophenyl) -4-methyl-5- [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl] -1H- [1,2,3] triazole;

1- (4- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone;

Methyl 4- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) benzoate;

2- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine;

Methyl 6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;

6- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;

(6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide;

N-Cyclopropyl-6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;

(1,1-dioxo-1,6-thiomorpholin-4-yl) - (6- {4- [3- (4-fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4- yl] -imidazol-1-yl} -pyridin-3-yl) methanone;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide;

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (tetrahydro-2H-pyran -4-yl) nicotinamide;

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide;

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

(6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide;

N-Cyclopropyl-6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

N- (Cyclopropylmethyl) -6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

and pharmaceutically acceptable salts and esters of these compounds.

The compounds of formula (I) of the present invention are selected from the group consisting of:

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl benzamide;

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl nicotinamide;

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) -nicotinamide;

(6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} pyridin-3-yl) - ( 2-oxa-6-aza-spiro [3.3] hept-6-yl) methanone;

2- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;

6- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;

(6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide;

N-Cyclopropyl-6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;

and pharmaceutically acceptable salts and esters of these compounds.

The present invention also relates to a method for producing compounds of formula (I) described herein, including a reaction between a compound of formula (II)

and a compound of formula (III)

where X, R ¹ , R ² and R ³ are the substituents described in this application, and Y is a fluorine or chlorine atom.

The present invention also relates to compounds of formula (I) described above, which can be obtained using the above method.

Compounds of formula (I) can be prepared using the following standard methods, described below, wherein X, R ¹ , R ^2, and R ³ are substituents described above and in the claims, unless otherwise indicated.

According to scheme 1, the compound according to formula (1) can be treated with Cu (I) I, sodium azide and a compound according to formula IR ² in the presence of ascorbic acid to form a compound according to formula (2). The compounds of formula (2) can be treated with a strong base such as BuLi, in a suitable solvent such as DME, at low temperatures, for example, in the range from -75 ° C to -35 ° C, and then reacted with CuCN in the presence of LiCl in a suitable solvent such as THF, at -75 ° C, and then reacted with acetyl chloride to form the compound according to formula (3). Then the compounds of formula 3 can be treated with bromine in a suitable solvent, for example, chloroform and acetic acid to form a compound of formula (4). Further, the reaction of the compound according to formula (4) with formamide in the presence of water when heated, for example, under traditional heating or microwave heating at 140 ° C, gives the product according to formula (5).

In addition, according to Scheme 2, compounds of formula (6) can be reacted with compounds of formula (7) to form compounds of formula (8) which, when treated with a base such as potassium hydroxide, in a suitable solvent such as methanol, form compounds according to the formula (2).

According to scheme 3, the compound according to formula (5) can react with the compound according to formula (9) in the presence of potassium carbonate, in a suitable solvent such as DMF, at elevated temperatures, for example in the range from + 80 ° C to + 160 ° C, with the formation of the compounds of formula (I), where Y is a fluorine or chlorine atom.

According to scheme 4, the compounds of formula (I), where R ³ is - C (O) NR ⁵ R ⁶ , can be obtained using standard methods from the compounds of formula (I), where R ³ is —C (O) ) R ⁴ .

Since the preparation of compounds of formula (I) is not described in the examples, these compounds, as well as all intermediates, can be prepared according to similar methods or according to the methods described above. The starting materials are commercially available, known to those skilled in the art, or can be prepared using methods known to those skilled in the art or similar methods.

The present invention also relates to compounds of formula (I) described above, which can be obtained using the method described above.

BuLi = n-butyllithium

CDI = 1,1'-carbonyldiimidazole

DCM = Dichloromethane

DIPEA = N, N-diisopropylethylamine (Hunig base)

DMF = dimethylformamide

DME = dimethoxyethane

EDAC = 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

HOBt = hydroxybenzotriazole

hv = high vacuum

on = during the night

r.t. = room temperature

TBD = 1,5,7-triazabicyclo [4.4.0] dec-5-ene

TBTU = O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate

THF = tetrahydrofuran

Another embodiment is pharmaceutical compositions or drugs containing the compounds of the present invention and a therapeutically inert carrier, diluent or excipient, as well as methods by which such compositions and drugs can be prepared using the compounds of the present invention.

Compositions are prepared, dosed and administered in accordance with the requirements of medical practice. Factors taken into account in this context include the particular disease to be treated, the specific mammal to be treated, the clinical condition of the particular patient, the cause of the disease, the place of drug delivery, route of administration, route of administration, and other factors known to doctors.

The compounds of the present invention can be administered by any suitable means, including oral, local (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and if required for topical treatment, intracranial administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention can be administered in any convenient form, for example, in the form of tablets, powder, capsules, solutions, spray solutions, suspensions, syrups, spray, suppositories, gels, emulsions, plasters, etc. Such compositions may include components conventional for pharmaceutical preparations, for example, diluents, carriers, pH modifiers, preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffers, deodorants, antioxidants, and other active substances. They may also include other therapeutically significant substances.

A typical preparation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel N.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al., Remington. The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago. The preparations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavorings, diluents and other known additives to create a high-quality drug (i.e., a compound of the present invention or a pharmaceutical composition based thereon) or to aid in the manufacture of stve pharmaceutical product (i.e., medicament).

Dosages for the compounds of the present invention that can be administered can vary within wide limits and, of course, will be set in accordance with individual requirements in each case. In general, in the case of oral administration, the daily dose of the compound of the general formula (I) is from about 0.1 to 1000 mg per person, although the upper limit can also be exceeded if necessary.

An example of a suitable oral dosage form is a tablet containing about 100-500 mg of the compound of the present invention with the addition of anhydrous lactose in an amount of about 90-30 mg, about 5-40 mg of croscarmellose sodium, about 5-30 mg of polyvinylpyrrolidone (PVP) K30, and approximately 1-10 mg of magnesium stearate. Powder substances are mixed first, and then a PVP solution is added to them with stirring. The resulting composition can be dried, formed into granules, mixed with magnesium stearate and compressed into tablets using conventional equipment.

An example of an aerosol preparation is a preparation prepared by dissolving a compound of the present invention, for example 10-100 mg, in a suitable buffer solution, for example, phosphate buffer, with the addition of substances that regulate the osmotic pressure, for example, salts such as sodium chloride. The resulting solution can be filtered, for example, using a filter with a pore size of 0.2 μm, to remove impurities and impurities.

As described above, the original compounds of the present invention and their pharmaceutically acceptable salts and esters possess valuable pharmacological properties and are ligands for GABA A α5 receptors. The compounds of the present invention can also be used, either alone or in combination with other drugs, for the treatment or prevention of diseases that are regulated by ligands for GABA A receptors containing the α5 subunit. These diseases, without limiting the scope of the present invention, include acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory impairment, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, Down syndrome, type I neurofibromatosis, sleep disturbance, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, psychoactive substance-related mental disorders, anxiety disorder, generalized carbohydrate disorder, panic attacks, delusional disorder, obsessive-compulsive disorder, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficiency disorders, multi-infarct dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, syndrome attention deficit hyperactivity disorder, neuropathic pain, stroke, multiple sclerosis (MS), acute meningitis, fetal alcohol syndrome, attention disorders and the need for cognitive abilities.

The present invention also relates to pharmaceutical compositions comprising a compound described above and a pharmaceutically acceptable excipient.

The present invention also includes compounds described above, which are therapeutically active substances.

The present invention also includes the compounds described above, which are therapeutically active substances and are used to treat or prevent diseases associated with the GABA A α5 receptor.

The present invention also includes the compounds described above, which are therapeutically active substances and are used to treat or prevent diseases such as acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory disorders, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, Down syndrome, type I neurofibromatosis, sleep disturbance, amyotrophic lateral sclerosis (ALS), dementia caused by PID, psychoactive substance disorder, anxiety disorder, generalized anxiety disorder, panic attacks, delusional disorder, obsessive-compulsive disorder, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficits, multi-infarction dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit hyperactivity disorder, neuropathic pain, insulin m, multiple sclerosis (MS), acute meningitis, fetal alcohol syndrome, attention disorder, or used as a means of stimulating the cognitive abilities.

The present invention also includes the compounds described above which are used to treat or prevent diseases such as acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory impairment, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia , bipolar disorder, autism, Down syndrome, type I neurofibromatosis, sleep disturbance, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, psychiatric disorders active substances, anxiety disorder, generalized anxiety disorder, panic attacks, delusional disorder, obsessive-compulsive disorders, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficiency disorders, multi-infarction dementia, mood disorders, depression , neuropsychiatric disorders, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke and attention disorders, or are used as as a means of stimulating cognitive abilities.

In another embodiment, the present invention relates to a method for the treatment or prevention of diseases associated with the GABA A α5 receptor.

In another embodiment, the present invention relates to a method for treating or preventing diseases such as acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory impairment, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, type I neurofibromatosis, sleep disturbance, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, psychoactive substances amy, anxiety disorder, generalized anxiety disorder, panic attacks, delusional disorder, obsessive-compulsive disorder, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficiency disorders, multi-infarction dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, multiple sclerosis (MS), acute meningitis, fetal alcohol ndrom, attention disorder, or a method of stimulation of the cognitive abilities, which method comprises administering a compound described above to a human being or animal.

The present invention also includes the use of the compounds described above for the treatment or prevention of diseases associated with the GABA A α5 receptor.

The present invention also includes the use of the compounds described above for the treatment or prevention of diseases such as acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory impairment, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorders, autism, Down syndrome, type I neurofibromatosis, sleep disturbance, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, psychoactive psychiatric disorders substances, anxiety disorder, generalized anxiety disorder, panic attacks, delusional disorder, obsessive-compulsive disorders, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome, cognitive deficits, multi-infarction dementia, mood disorders, depression , neuropsychiatric disorders, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, multiple sclerosis (MS), acute meningitis, fetal al ogolny syndrome, attention disorders, or for the stimulation of cognitive abilities.

The present invention also includes the use of the compounds described above for the manufacture of drugs that are used to treat or prevent diseases associated with the GABA A α5 receptor, such as acute and / or chronic neurological diseases, cognitive disorders, Alzheimer's disease, memory impairment, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, bipolar disorder, autism, Down syndrome, type I neurofibromatosis, sleep disturbance, amyotrophic b fetal sclerosis (ALS), AIDS-related dementia, psychoactive substance-related mental disorders, anxiety disorder, generalized anxiety disorder, panic attacks, delusional disorder, obsessive-compulsive disorder, acute stress, drug addiction, movement disorders, Parkinson's disease, restless legs syndrome , cognitive deficits, multi-infarct dementia, mood disorders, depression, neuropsychiatric disorders, psychosis, attention deficit disorder and hyper ktivnosti, neuropathic pain, stroke, multiple sclerosis (MS), acute meningitis, fetal alcohol syndrome, attention disorders, or for the preparation of medicaments stimulating the cognitive abilities. Such medications include one of the compounds described above.

In particular, the present invention relates to the use of the compounds described above for the treatment, prophylaxis and / or development of CNS conditions caused by defects of the nervous system that lead to excessive GABAergic inhibition in the cerebral cortex and hippocampus, while the CNS state results from cognitive deficiency in Down syndrome, with autism, with type I neurofibromatosis, or after a stroke.

Specific embodiments of the present invention include the treatment or prevention of cognitive impairment, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, Down syndrome, and type I neurofibromatosis.

One embodiment of the present invention includes the treatment or prevention of Alzheimer's disease.

One embodiment of the present invention includes the treatment or prophylaxis of Down syndrome.

One embodiment of the present invention includes the treatment or prevention of type I neurofibromatosis.

The present invention is fully disclosed in the following examples. However, these examples in no way limit the scope of the present invention.

Example 1:

1- (4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone

a) 4- (4-Fluorophenyl) -1-methyl-1H- [1,2,3] triazole

The reaction mixture was divided into 24 tubes of 1.00 g (8.32 mmol) each. A mixture of 1-ethynyl-4-fluorobenzene (24.0 g, 200 mmol), sodium azide (14.41 g, 222 mmol), iodomethane (14.93 ml, 240 mmol), copper (I) iodide (8.03 g, 42 mmol) and the sodium salt of L - (+) - ascorbic acid (7.84 g, 40 mmol) in water (240 ml) was heated at 75 ° C for 10 hours. The mixture was diluted with dichloromethane (25 ml) and filtered . The aqueous layer of the filtrate was extracted with dichloromethane, and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 5% methanol in dichloromethane) to give the title compound (20.3 g, 57%) as a white solid after recrystallization from ethyl acetate-heptane. MS: m / e = 178.1 [M + H] ⁺ .

b) 1- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] ethanone

To a suspension of 4- (4-fluorophenyl) -1-methyl-1H- [1,2,3] triazole (3.54 g, 20.0 mmol) in DME (52 ml) was added dropwise n-BuLi (1.6 M in hexane, 15.0 ml, 24.0 mmol) at - 75 ° C. This mixture was heated to −35 ° C, and then stirred at −35 ° C for 1 h. The reaction mixture was again cooled to −78 ° C, and a light green suspension containing CuCN was quickly added at the same temperature (1.79 g, 20.0 mmol) and LiCl (1.70 g, 40.0 mmol) in THF (26 ml). After 1 h, the mixture was heated to -35 ° C, and acetyl chloride (7.10 ml, 100.0 mmol) was added dropwise at the same temperature. Then the reaction mixture was stirred at room temperature for 2 hours, then it was carefully poured into an aqueous saturated sodium carbonate solution (150 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (2.2 g, 50%) as a yellow oil. MS: m / e = 220.3 [M + H] ⁺ .

c) 2-Bromo-1- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] ethanone

A solution of 1- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] ethanone (4.02 g, 18.34 mmol) was diluted in chloroform (18 ml ) and acetic acid (0.36 ml) were heated under reflux to a boil, then a solution of bromine (1.04 ml, 20.17 mmol) in chloroform (9 ml) was added dropwise over 10 minutes, after 1 h was added bromine (0.10 ml, 2.02 mmol) and refluxed for 1 h. After cooling to room temperature, the mixture was poured into a vessel in an ice bath, then the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (3.48 g, 50%) as a light red solid. MS: m / e = 298.1 / 300.1 [M + H] ⁺ .

d) 4-4-Fluorophenyl) -5-1H-imidazol-4-yl) -1-methyl-1H- [1,2,3] triazole

Suspension of 2-bromo-1- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] ethanone (3.44 g, 11.54 mmol) in formamide (11.04 ml, 276.94 mmol) and water (1.25 ml, 69.24 mmol) were heated in the microwave to 140 ° C for 3 hours. After cooling to room temperature, the mixture was poured into HCl (1H, 150 ml) and then the mixture was extracted with ethyl acetate. The aqueous phase was made alkaline with NaOH (6H) and then extracted twice with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification by trituration (ethyl acetate) was carried out to give the title compound (1.29 g, 46%) as a light brown solid. MS: m / e = 244.2 [M + H] ⁺ .

e) 1- (4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl) phenyl) ethanone

A mixture of 4- (4-Fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H- [1,2,3] triazole (73 mg, 0.30 mmol), 4-fluoroacetophenone (37 μl, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) in DMF (1.5 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 16 hours. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (51 g, 47%) as an off-white solid after recrystallization from ethyl acetate. MS: m / e = 362.2 [M + H] ⁺ .

Example 2

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid methyl ester

e) 1- (4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone

A mixture of 4- (4-Fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H- [1,2,3] triazole (486 mg, 2.00 mmol), methyl 4-fluorobenzoate ( 308 mg, 2.00 mmol) and potassium carbonate (553 mg, 4.00 mmol) in DMF (10 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 16 hours. After cooling to room temperature, the mixture it was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (399 mg, 53%) as a white solid. MS: m / e = 378.4 [M + H] ⁺ .

Example 3

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl benzamide

a) 4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid

A solution of lithium hydroxide monohydrate (85 mg, 2.01 mmol) in water (2.5 ml) was added dropwise to a suspension of 4- {4- [5- (4-fluorophenyl) -3-methyl-3H- [1] methyl ester , 2,3] triazol-4-yl] imidazol-1-yl} -benzoic acid (380 mg, 1.01 mmol) in THF (2.5 ml) and methanol (0.5 ml). The reaction mixture was stirred at room temperature for 1 h and then evaporated, and the residue was dissolved in water acidified with HCl (1H), the resulting precipitate was filtered to give the title compound (315 mg, 86%) as a white solid. MS: m / e = 362.3 [MH] ^- .

b) 4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropylbenzamide

To a solution of 4- {4- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid (75 mg, 0 , 21 mmol) and TBTU (73 mg, 0.23 mmol) in DMF (0.8 ml) were added DIPEA (177 μl, 1.03 mmol). Then, isopropylamine (19 μl, 0.23 mmol) was added, the mixture was stirred at room temperature under argon for 1 h. The mixture was then evaporated and purification was carried out by chromatography (silica gel, from 0 to 100% ethyl acetate in heptane, then from 0 to 10% methanol in dichloromethane) to give the title compound (57 mg, 68%) as a white solid. MS: m / e = 405.4 [M + H] ⁺ .

Example 4

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) -benzamide

4- {4- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid (75 mg, 0.21 mmol) was converted according to the procedure described in example 3b, with 4-aminotetrahydropyran instead of isopropylamine, to give the title compound (73 mg, 79%) as a white solid. MS: m / e = 447.3 [M + H] ⁺ .

Example 5

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) benzamide

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid (75 mg, 0.21 mmol) was converted according to the procedure described in Example 3b, using 3-methyl-3-oxetanamine instead of isopropylamine, to give the title compound (57 mg, 64%) as a white solid after trituration from ethyl acetate. MS: m / e = 433.4 [M + H] ⁺ .

Example 6

(4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) - (2-oxa- 6-aza-spiro [3.3] hept-6-yl) methanone

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid (75 mg, 0.21 mmol) was converted according to the procedure described in example 3b, using 2-oxa-6-azonia-spiro [3,3] heptane oxalate instead of isopropylamine, to give the compound (53 mg, 58%) indicated in the title, as white solid after trituration from ethyl acetate. MS: m / e = 445.4 [M + H] ⁺ .

Example 7

4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzamide

To a solution of 4- {4- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid (76 mg, 0.209 mmol) CDI (41 mg, 0.251 mmol) was added to DMF (2 ml), the resulting mixture was stirred at 60 ° C for 1 h. After cooling to room temperature, ammonium hydroxide (330 μl, 2.09 mmol) was added, the reaction mixture stirred for 1 h and then evaporated. Purification was performed by crystallization to give the compound (64 mg, 84%) indicated in the title as a white solid. MS: m / e = 363.2 [M + H] ⁺ .

Example 8

4- (2-Fluorophenyl) -1-methyl-5- (1- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole

a) 4- (2-fluorophenyl) -1-methyl-1H-1,2,3-triazole

Solution A was prepared from 1-ethynyl-2-fluorobenzene (4.2 g, 35 mmol) and iodomethane (5.96 g, 42 mmol) in acetonitrile (94 ml), and solution B was prepared from sodium azide (2.73 g , 42 mmol) and copper (I) iodide (1.33 g, 6.99 mmol) in water (100 ml). The reaction was carried out in a Uniqsis FlowSyn apparatus at 150 ° C and at a pressure of 100 psi with a flow rate of 1.0 ml / min. and a retention time of 1.5 minutes for each solution of A and B. The eluate was collected in an aqueous solution of ammonium hydroxide (25%), after which the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (1.5 g, 24%) as a light yellow solid. MS: m / e = 178.3 [M + H] ⁺ .

b) 1- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone

4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazole (5.0 g, 28.2 mmol) instead of 4- (4-fluorophenyl) -1-methyl-1H- [1,2,3] triazole was converted according to the procedure described in example 1b, to give the compound (3.33 g, 54%) indicated in the title, which was obtained as a colorless liquid after purification by chromatography (silica gel, from 0 to 50% ethyl acetate in heptane). MS: m / e = 220.2 [M + H] ⁺ .

c) 2-Bromo-1- (4- (2-fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone

1- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone (2.1 g, 9.58 mmol) instead of 1- [5- (4- Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] ethanone was converted according to the procedure described in example 1c to give the compound (2.01 g, 70%) indicated in the title which was obtained as a whitish solid after purification by chromatography (silica gel, 10 to 60% ethyl acetate in heptane). MS: m / e = 378.0 / 380.0 [M + H] ⁺ .

d) 4- (2-FluoroPhenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole

2-Bromo-1- (4- (2-fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone (1.0 g, 3.35 mmol) instead of 2-bromo- 1- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] ethanone was converted according to the procedure described in example 1d, to give the compound (814 mg, 49% ) indicated in the title, which was obtained as a white solid after purification by chromatography (silica gel, ethyl acetate). MS: m / e = 244.2 [M + H] ⁺ .

e) 4- (2-Fluorophenyl) -1-methyl-5- (1- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole

Mixture of 4- (2-fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol), 4-fluorobenzotrifluoride (73 μl , 0.58 mmol) and potassium carbonate (83 mg, 0.58 mmol) in DMF (2.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 16 hours. After cooling to room temperature, the mixture it was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 5% methanol in dichloromethane) to give the title compound (87 mg, 78%) as an off-white solid. MS: m / e = 388.2 [M + H] ⁺ .

Example 9

4- (2-Fluorophenyl) -1-methyl-5- (1- (4-nitrophenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole

4- (2-Fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol) was converted according to the procedure described in the example 8e using 1-fluoro-4-nitrobenzene instead of 4-fluorobenzotrifluoride to give the title compound (100 mg, 95%) as a yellow solid. MS: m / e = 365.1 [M + H] ⁺ .

Example 10

1- (4- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) phenyl) ethanone

4- (2-Fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole (70 mg, 0.29 mmol) was converted according to the procedure described in Example 8e, using 4'-fluoroacetophenone instead of 4-fluorobenzotrifluoride to give the title compound (85 mg, 82%) as an off-white solid. MS: m / e = 362.2 [M + H] ⁺ .

Example 11

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl nicotinamide

a) 6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -nicotinic acid methyl ester

A mixture of 4- (4-fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H- [1,2,3] triazole (82 mg, 0.34 mmol), methyl 6-chloronicotinate ( 58 mg, 0.34 mmol) and potassium carbonate (93 mg, 0.67 mmol) in DMF (1.7 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 16 hours. After cooling to room temperature at temperature, the mixture was poured into HCl (1H) and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (70 mg, 55%) as an off-white solid. MS: m / e = 379.2 [M + H] ⁺ .

b) 6- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-ylmethoxy] nicotinic acid

A solution of lithium hydroxide monohydrate (85 mg, 2.01 mmol) in water (2.5 ml) was added dropwise to a suspension of 6- {4- [5- (4-fluorophenyl) -3-methyl-3H- [1] methyl ester , 2,3] triazol-4-yl] imidazol-1-yl} -nicotinic acid (381 mg, 1.01 mmol) in THF (2.5 ml). The reaction mixture was stirred at room temperature for 1 h and then evaporated, and the residue was dissolved in water acidified with HCl (1H), the resulting precipitate was filtered to give the title compound (349 mg, 95%) as an off-white solid. MS: m / e = 363.3 [MH] ^- .

c) 6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl nicotinamide

To a solution of 6- [5- (4-fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-ylmethoxy] nicotinic acid (30 mg, 0.08 mmol) and TBTU (29 mg, 0.09 mmol) in DMF (0.2 ml) was added DIPEA (70 μl, 0.41 mmol). Then, isopropylamine (8 μl, 0.09 mmol) was added, the mixture was stirred at room temperature under argon for 1 h. The mixture was then evaporated and purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (19 mg, 97%) as a white solid. MS: m / e = 406.4 [M + H] ⁺ .

Example 12

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide

6- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-ylmethoxy] nicotinic acid (109 mg, 0.30 mmol) was converted according to the procedure described in the example 11 s, using 4-aminotetrahydropyran instead of isopropylamine, to give the title compound (70 mg, 52%) as a white solid after trituration from a mixture of methanol and water. MS: m / e = 448.2 [M + H] ⁺ .

Example 13

6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) -nicotinamide

6- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-ylmethoxy] nicotinic acid (109 mg, 0.30 mmol) was converted according to the procedure described in the example 11 s, using 3-methyl-3-oxetanamine instead of isopropylamine, to give the title compound (66 mg, 51%) as an off-white solid after recrystallization from ethyl acetate-heptane. MS: m / e = 434.3 [M + H] ⁺ .

Example 14

(6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} pyridin-3-yl) - ( 2-oxa-6-aza-spiro [3.3] hept-6-yl) methanone

6- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-ylmethoxy] nicotinic acid (109 mg, 0.30 mmol) was converted according to the procedure described in the example 11c using 2-oxa-6-azonia-spiro [3.3] heptane oxalate instead of isopropylamine to give the title compound (55 mg, 41%) as a light yellow solid. MS: m / e = 446.2 [M + H] ⁺ .

Example 15

2- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine

Mixture of 4- (4-Fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H- [1,2,3] triazole (36 mg, 0.15 mmol), 2-chloro-5 (trifluoromethyl) pyridine (27 mg, 0.15 mmol) and potassium carbonate (41 mg, 0.3 mmol) in DMF (0.6 ml) were stirred under argon atmosphere in a sealed flask and heated at 120 ° C for 16 h After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (48 mg, 84%) as a white solid. MS: m / e = 389.2 [M + H] ⁺ .

Example 16

6- (4- (4- (4-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

To a solution of 6- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-ylmethoxy] nicotinic acid (100 mg, 0.274 mmol) in DMF (3 ml) was added CDI (54 mg, 0.329 mmol), the resulting mixture was stirred at 60 ° C for 1 h. After cooling to room temperature, ammonium hydroxide (430 μl, 2.74 mmol) was added, the reaction mixture was stirred for 1 h, and then evaporated. Purification was performed by chromatography (silica gel, 0 to 5% methanol in dichloromethane) to give the title compound (64 mg, 64%) as a white solid. MS: m / e = 364.1 [M + H] ⁺ .

Example 17

Methyl 6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate

a) 4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazole

Solution A was prepared from 1-chloro-2-ethynylbenzene (6.69 g, 49 mmol) and iodomethane (8.35 g, 58.8 mmol) in acetonitrile (40.4 ml), and solution B was prepared from sodium salt L - (+) - ascorbic acid (1.73 g, 9.8 mmol) and sodium azide (3.5 g, 53.9 mmol) in water (50 ml), water: acetonitrile (1: 1, 100 ml) . Copper (I) iodide was placed on the surface of molecular sieves and a dicalite filter. The reaction was carried out in a Uniqsis FlowSyn apparatus at 120 ° C and at a pressure of 100 psi with a flow rate of 0.25 ml / min. and a retention time of 4 minutes for each solution A and B. The eluate was collected in an aqueous solution of ammonium hydroxide (25%), after which the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (2.4 g, 25%) as a light brown solid. MS: m / e = 194.1 [M + H] ⁺ .

b) 1- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone

To a suspension of 4- (2-chlorophenyl) -1-methyl-1H-1,2,3-triazole (2.0 g, 10.3 mmol) in DME (30 ml) n-BuLi (1.6 M in hexane, 7.75 ml, 12.4 mmol) at - 75 ° C. This mixture was heated to −35 ° C, and then stirred at −35 ° C for 1 h. The reaction mixture was again cooled to −78 ° C, and a light green suspension containing CuCN (925 mg, 10.3 mmol) and LiCl (876 mg, 20.7 mmol) in THF (15 ml). After 1 h, the mixture was heated to −35 ° C., and acetyl chloride (3.67 ml, 51.6 mmol) was added dropwise at the same temperature. Then the reaction mixture was stirred at room temperature for 3 hours, after which it was carefully poured into an aqueous saturated sodium carbonate solution (75 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (1.06 g, 44%) as a yellow oil. MS: m / e = 236.1 [M + H] ⁺ .

c) 2-Bromo-1- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone

A solution of 1- (4- (2-chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone (1.02 g, 4.33 mmol) was diluted in chloroform (7 ml) and acetic acid (0.136 ml) was heated to reflux under reflux, then a solution of bromine (0.234 ml, 4.54 mmol) in chloroform (3 ml) was added dropwise over 10 min, bromine (0.09 ml) was added after 1 h , 1.73 mmol) in chloroform (2 ml) and refluxed for 1 h. After cooling to room temperature, the mixture was poured into a container of ice water, then the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (988 mg, 73%) as an off-white solid. MS: m / e = 313.9 / 315.9 [M + H] ⁺ .

d) 4- (2-Chlorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole

Suspension of 2-bromo-1- (4- (2-chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) ethanone (0.86 g, 2.73 mmol) in formamide (2 , 62 ml, 65.6 mmol) and water (0.296 ml, 16.4 mmol) were heated in the microwave to 140 ° C for 3 hours. After cooling to room temperature, the mixture was poured into HCl (1H, 20 ml), and then the mixture was extracted with ethyl acetate. The aqueous phase was made alkaline with NaOH (6H) and then extracted twice with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, ethyl acetate) to obtain the title compound (360 mg, 51%) as an off-white solid. MS: m / e = 260.0 [M + H] ⁺ .

e) Methyl 6- (4- (4- (2-chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate

Mixture of 4- (2-fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole (322 mg, 1.24 mmol), methyl 6-chloronicotinate (213 mg, 1.24 mmol) and potassium carbonate (343 mg, 2.48 mmol) in DMF (7 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 3 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 30 to 100% ethyl acetate in heptane) to give the title compound (370 mg, 76%) as a white solid. MS: m / e = 395.1 [M + H] ⁺ .

Example 18

6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

a) 6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid

A solution of lithium hydroxide monohydrate (75 mg, 1.77 mmol) in water (3.5 ml) was added dropwise to a suspension of methyl 6- (4- (4- (2-chlorophenyl) -1-methyl-1H-1,2 , 3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate (349 mg, 0.884 mmol) in THF (7 ml) and methanol (1 ml). The reaction mixture was stirred at room temperature for 1 h, and then evaporated, and the residue was dissolved in water acidified with HCl (1H), the resulting precipitate was filtered to give the title compound (320 mg, 95%) as a white solid. MS: m / e = 379.3 [MH] ^- .

c) 6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

To a solution of 6- (4- (4- (2-chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.194 mmol) and TBTU (69 mg, 0.214 mmol) in DMF (2.0 ml) were added DIPEA (170 μl, 0.972 mmol). Then isopropylamine (19 μl, 0.214 mmol) was added, the mixture was stirred at room temperature in argon atmosphere for 2 hours. The mixture was then evaporated and purification was performed by chromatography (silica gel, 50 to 100% ethyl acetate in heptane) to give a compound, indicated in the title (52 mg, 63%) as a white solid. MS: m / e = 422.1 [M + H] ⁺ .

Example 19

6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

To a solution of 6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.194 mmol) CDI (38 mg, 0.233 mmol) was added to DMF (3 ml), the resulting mixture was stirred at 60 ° C for 1 h. After cooling to room temperature, ammonium hydroxide (305 μl, 1.94 mmol) was added, the reaction mixture stirred for 1 h and then evaporated. Purification was performed by chromatography (reverse phase HPLC) to give the title compound (54 mg, 73%) as a white foam. MS: m / e = 380.1 [M + H] ⁺ .

Example 20

Methyl 6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate

A mixture of 4- (2-fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole (233 mg, 0.958 mmol), methyl 6-chloronicotinate (164 mg, 0.988 mmol) and potassium carbonate (265 mg, 1.92 mmol) in DMF (5.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 3 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 50 to 100% ethyl acetate in heptane) to give the title compound (303 mg, 79%) as a white solid. MS: m / e = 379.2 [M + H] ⁺ .

Example 21

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid

A solution of lithium hydroxide monohydrate (63 mg, 1.49 mmol) in water (3.0 ml) was added dropwise to a suspension of methyl 6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2 , 3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate (282 mg, 0.745 mmol) in THF (6.0 ml) and methanol (1 ml). The reaction mixture was stirred at room temperature for 1.5 hours and then evaporated, and the residue was dissolved in water acidified with HCl (1H), the resulting precipitate was filtered to give the title compound (244 mg, 90%) as a white solid substances. MS: m / e = 363.3 [MH] ^-

Example 22

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (tetrahydro-2H-pyran -4-yl) nicotinamide

To a solution of 6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (75 mg, 0.194 mmol) and TBTU (73 mg, 0.226 mmol) in DMF (2.0 ml) were added DIPEA (180 μl, 1.03 mmol). Then 4-aminotetrahydropyran (24 μl, 0.226 mmol) was added, the mixture was stirred at room temperature under argon for 30 minutes. The mixture was then evaporated and purified by chromatography (reverse phase HPLC) to give the title compound (71 mg, 77%) as a white solid. MS: m / e = 448.2 [M + H] ⁺ .

Example 23

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (75 mg, 0.194 mmol) was converted as described in Example 22 using isopropylamine instead of 4-aminotetrahydropyran, to give the title compound (51 mg, 61%) as a whitish foam. MS: m / e = 406.3 [M + H] ⁺ .

Example 24

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (2-hydroxy-2 methylpropyl) nicotinamide

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (75 mg, 0.194 mmol) was converted, as described in example 22, with 2-amino-2-methylpropan-1-ol instead of 4-aminotetrahydropyran, to give the title compound (77 mg, 86%) as a whitish foam. MS: m / e = 436.3 [M + H] ⁺ .

Example 25

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

To a solution of 6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (69 mg, 0.189 mmol) CDI (37 mg, 0.227 mmol) was added to DMF (3 ml), the resulting mixture was stirred at 60 ° C for 1 h. After cooling to room temperature, ammonium hydroxide (300 μl, 1.9 mmol) was added, the reaction mixture stirred for 1 h and then evaporated. Purification was performed by chromatography (reverse phase HPLC) to give the title compound (56 mg, 81%) as a white foam. MS: m / e = 364.1 [M + H] ⁺ .

Example 26

(6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (69 mg, 0.189 mmol) was converted, as described in Example 22, with 2-oxa-6-azonia-spiro [3.3] heptane oxalate instead of 4-aminotetrahydropyran, to give the title compound (40 mg, 47%) as a whitish foam. MS: m / e = 446.2 [M + H] ⁺ .

Example 27

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (69 mg, 0.189 mmol) was converted as described in Example 22 using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran to give the title compound (61 mg, 74%) as a whitish foam obtained by purification by chromatography (silica gel. 0 to 10% methanol in dichloromethane). MS: m / e = 434.3 [M + H] ⁺ .

Example 28

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (69 mg, 0.189 mmol) was converted, as described in example 22, with 4-aminomorpholine instead of 4-aminotetrahydropyran, to give the title compound (59 mg, 70%) as a whitish foam obtained by purification by chromatography (silica gel. 0 to 10% methanol in dichloromethane). MS: m / e = 449.2 [M + H] ⁺ .

Example 29

N-Cyclopropyl-6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (69 mg, 0.189 mmol) was converted according to the procedure described in example 22, with cyclopropylamine instead of 4-aminotetrahydropyran, to give the title compound (43 mg, 56%) as a white foam. MS: m / e = 404.4 [M + H] ⁺ .

Example 30

2- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -5- (trifluoromethyl) pyridine

Mixture of 4- (2-fluorophenyl) -5- (1H-imidazol-4-yl) -1-methyl-1H-1,2,3-triazole (70 mg, 0.288 mmol), 2-chloro-5- (trifluoromethyl ) pyridine (53 mg, 0.288 mmol) and potassium carbonate (80 mg, 0.576 mmol) in DMF (2.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 3 hours. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 5% methanol in dichloromethane) to give the title compound (85 mg, 76%) as an off-white solid. MS: m / e = 389.2 [M + H] ⁺ .

Example 31

1- (4-Fluorophenyl) -4-methyl-5- [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl] -1H- [1,2,3] triazole

a) 1-Azido-4-fluorobenzene

Prepared by analogy with J. Org. Chem. (1989) 54: 5938-5945. To a solution of sulfuric acid (40 ml) and trifluoroacetic acid (200 ml), 4-fluoroaniline (22.1 ml, 0.23 mol) was added dropwise. Then, a sodium nitrite solution (20.6 g, 0.3 mol) of the inlet (200 ml) was added over 30 minutes at 15-18 ° C while cooling to 0 ° C. The resulting solution was stirred for 30 minutes on ice. Then a solution of sodium azide (25.42 g, 0.39 mol) in water (150 ml) was added dropwise over 30 minutes. The mixture foamed and the temperature rose to 10 ° C while cooling in an ice bath. The reaction mixture was stirred without cooling for 1 h, then was extracted with diethyl ether. The combined organic layers were washed with water twice. Then, the combined organic layers were diluted with saturated aqueous sodium carbonate (500 ml) until the pH of the mixture became alkaline. The organic phase was separated and washed with brine, and then extracted again with diethyl ether. The organic layers were dried over sodium sulfate and evaporated at 40 ° C, at a pressure of at least 50 mbar (at a lower pressure, the product itself is distilled) to give the title compound (30.42 g, 96%) as a brown liquid.

b) 1- [3- (4-Fluorophenyl) -5-methyl-4,5-dihydro-3H- [1,2,3] triazol-4-yl] piperidine

Prepared by analogy with EP 0433842 A2. A mixture of 1-azido-4-fluorobenzene (2.80 g, 20 mmol) and 1- (1-propenyl) piperidine (18%, 14.2 g, 20 mmol) was first mixed on ice (slightly exothermic reaction at the beginning) and then at room temperature for 144 hours in the dark. Hexane was then added to the brown solutions, a precipitate formed which was filtered off, washed with hexane and dried in hv to give the title compound (1.1 g) as a light pink solid. The filtrate was evaporated and purified by chromatography (silica gel, 10 to 50% ethyl acetate in heptane) to give the title compound (4.34 g) as a light yellow solid. Total yield (5.44 g, 98%). MS: m / e = 263.1 [M + H] ⁺ .

c) 1- (4-Fluorophenyl) -4-methyl-1H- [1,2,3] triazole

Prepared by analogy with EP 0433842 A2. A mixture of 1- [3- (4-fluorophenyl) -5-methyl-4,5-dihydro-3H- [1,2,3] triazol-4-yl] piperidine (1.15 g, 0.004 mol) and hydroxide potassium in MeOH (2H, 29.2 ml, 58 mmol) was refluxed for 6 hours, then cooled to room temperature. The mixture was then poured into water and extracted with diethyl ether, after which the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (555 mg) as a white solid. The filtrate was evaporated and purified by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (41 mg, 79%) as an off-white solid. Total yield (596 mg, 77%). MS: m / e = 178.1 [M + H] ⁺ .

d) 1- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] ethanone

To a suspension of 1- (4-fluorophenyl) -4-methyl-1H- [1,2,3] triazole (4 g, 23 mmol) in DME (114 ml) n-BuLi (1.6 M in hexane) was added dropwise. , 17.0 ml, 27 mmol) at - 75 ° C. This mixture was heated to -35 ° C, and then stirred at -35 ° C for 1 h. The reaction mixture was again cooled to -78 ° C, and a light green suspension containing CuCN (2.03) was quickly added at the same temperature. g, 23 mmol) and LiCl (1.92 g, 45 mmol) in THF (32 ml). After 1 h, the mixture was heated to −35 ° C., and acetyl chloride (8.02 ml, 113.0 mmol) was added dropwise at the same temperature. The reaction mixture was then stirred at room temperature for 2 hours, then it was carefully poured into an aqueous saturated sodium carbonate solution (160 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, dichloromethane) to give the title compound (3.63 g, 69%) as an off-white solid. MS: m / e = 220.3 [M + H] ⁺ .

e) 2-Bromo-1- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] ethanone

A solution of 1- [3- (4-fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] ethanone (3.62 g, 17 mmol) was diluted in chloroform (28 ml) and acetic acid (0.5 ml) was heated under reflux to a boil, then a solution of bromine (0.89 ml, 17 mmol) in chloroform (9 ml) was added and refluxed for 2 hours. After cooling to room temperature the mixture was poured into a vessel in an ice bath, then the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (3.34 g, 68%) as an off-white solid. MS: m / e = 298.3 / 300.2 [M + H] ⁺ .

f) 1- (4-Fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H- [1,2,3] triazole

The reaction was repeated three times. Suspension of 2-bromo-1- [3- (4-fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] ethanone (1.03 g, 3.0 mmol) in formamide (3.3 ml, 81 mmol) and water (0.37 ml, 20 mmol) were heated in a microwave oven to 140 ° C for 3 h. After cooling to room temperature, the reaction mixture was poured into HCl (1H, 150 ml), and then the mixture was extracted with ethyl acetate. The aqueous phase was made alkaline with NaOH (6H) and then extracted twice with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated to give the title compound (1.54 g, 62%) in the form of a light brown solid. MS: m / e = 244.3 [M + H] ⁺ .

g) 1- (4-Fluorophenyl) -4-methyl-5- [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl] -1H- [1,2,3] triazole

A mixture of 1- (4-fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H- [1,2,3] triazole (100 mg, 0.411 mmol), 4-fluorobenzotrifluoride (105 μl, 0.822 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 48 hours. After cooling to room temperature, the mixture was poured with HCl ( 1H) and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (68 mg, 43%) as an off-white solid. MS: m / e = 388.2 [M + H] ⁺ .

Example 32

1- (4- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone

A mixture of 1- (4-fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H- [1,2,3] triazole (100 mg, 0.411 mmol), 4-fluoroacetophenone (51 μl, 0.411 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 48 h. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (79 mg, 53%) as an off-white solid. MS: m / e = 362.3 [M + H] ⁺ .

Example 33

Methyl 4- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) benzoate

a) 1-Azido-2-fluorobenzene

Following the procedure described in Example 31a, 2-fluoroaniline (5.0 g, 45 mmol) was converted to 4-fluoroaniline to the title compound (6.28 g, 99%), which was obtained as a brown liquid.

b) 1- (1- (2-Fluorophenyl) -4-methyl-4,5-dihydro-1H-1,2,3-triazol-5-yl) piperidine

According to the procedure described in example 31b, 1-azido-2-fluorobenzene (2.8 g, 20 mmol), instead of 1-azido-4-fluorobenzene, was converted to the title compound (4.87 g, 93% ), which was obtained as a brown solid. MS: m / e = 263.2 [M + H] ⁺ .

c) 1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazole

According to the procedure described in example 31c, 1- (1- (2-fluorophenyl) -4-methyl-4,5-dihydro-1H-1,2,3-triazol-5-yl) piperidine (1.32 g, 5.32 mmol) instead of 1- [3- (4-fluorophenyl) -5-methyl-4,5-dihydro-3H- [1,2,3] triazol-4-yl] piperidine was converted to the compound indicated in the title (616 mg, 65%), which was obtained as a colorless liquid. MS: m / e = 178.1 [M + H] ⁺ .

d) 1- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) ethanone

To a suspension of 1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazole (2.43 g, 13.7 mmol) in DME (40 ml) n-BuLi (1.6 M in hexane, 10.3 ml, 16.5 mmol) at - 75 ° C. This mixture was heated to −35 ° C, and then stirred at −35 ° C for 1 h. The reaction mixture was again cooled to −78 ° C, and a light green suspension containing CuCN was rapidly added at the same temperature and with stirring ( 1.23 g, 13.7 mmol) and LiCl (1.16 g, 27.4 mmol) in THF (20 ml). After 1 h, the mixture was heated to −35 ° C., and acetyl chloride (4.88 ml, 68.6 mmol) was added dropwise at the same temperature. Then the reaction mixture was stirred at room temperature for 2 hours, then it was carefully poured into an aqueous saturated sodium carbonate solution (100 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (1.69 g, 56%) as a light yellow oil. MS: m / e = 220.2 [M + H] ⁺ .

e) 2-Bromo-1- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) ethanone

A solution of 1- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) ethanone (1.66 g, 7.57 mmol) was diluted in chloroform (12 ml) and acetic acid (0.24 ml), was heated under reflux to a boil, then a solution of bromine (0.41 ml, 7.95 mmol) in chloroform (5 ml) was added, refluxed for 2 hours, after which it was added bromine (0.12 ml, 2.27 mmol) in chloroform (2 ml) and boiled under reflux for another 30 minutes. After cooling to room temperature, the mixture was poured into a vessel in an ice bath, then the mixture was extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 60% ethyl acetate in heptane) to give the title compound (1.54 g, 64%) as an off-white solid. MS: m / e = 298.1 / 300.0 [M + H] ⁺ .

f) 1- (2-Fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H-1,2,3-triazole

The reaction was repeated three times. Suspension of 2-bromo-1- [1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) ethanone (750 mg, 2.4 mmol) in formamide (2,3 ml, 57.6 mmol) and water (0.26 ml, 14.4 mmol) were heated in the microwave to 140 ° C for 3 hours. After cooling to room temperature, the reaction mixture was poured into HCl (1H, 150 ml), and then the mixture was extracted with ethyl acetate. The aqueous phase was made alkaline with NaOH (6H), then extracted twice with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, ethyl acetate) to obtain the title compound (597 mg, 50%) as a light yellow solid. MS: m / e = 244.2 [M + H] ⁺ .

g) Methyl 4- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) benzoate

Mixture of 1- (2-fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H-1,2,3-triazole (290 mg, 1.19 mmol), methyl 4-fluorobenzoate (184 mg, 1.19 mmol) and potassium carbonate (330 mg, 2.38 mmol) in DMF (6.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 2 hours. After cooling to room temperature the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (8 mg, 2%) as an off-white solid. MS: m / e = 378.3 [M + H] ⁺ .

Example 34

2- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine

Mixture of 1- (4-Fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H- [1,2,3] triazole (100 mg, 0.411 mmol), 2-chloro-5 (trifluoromethyl ) pyridine (75 mg, 0.411 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 48 hours. After cooling to at room temperature, the mixture was poured into water, the resulting precipitate was filtered off and purified by chromatography (silica gel, 0 to 100% ethyl acetate in heptane) to give the title compound (98 mg, 60%) as a white solid. MS: m / e = 389.2 [M + H] ⁺ .

Example 35

Methyl 6- (4- (1- (4-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate

A mixture of 1- (4-fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H- [1,2,3] triazole (500 mg, 2.06 mmol), methyl 6-chloronicotinate ( 353 mg, 2.06 mmol) and potassium carbonate (568 mg, 4.11 mmol) in DMF (10 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 16 hours. After cooling to room temperature, the mixture poured into water (150 ml), the resulting precipitate was filtered off and dried to give the title compound (300 mg, 39%) as a light brown solid. MS: m / e = 379.3 [M + H] ⁺ .

Example 36

6- (4- (1- (4-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

a) 6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid

A solution of lithium hydroxide monohydrate (62 mg, 1.46 mmol) in water (2.8 ml) was added dropwise to a suspension of methyl 6- (4- (1- (4-fluorophenyl) -4-methyl-1H-1, 2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate (277 mg, 0.732 mmol) in THF (4.8 ml) and methanol (1 ml). Then the reaction mixture was stirred at room temperature for 1 h, and then evaporated, and the residue was dissolved in water acidified with HCl (1H), the resulting precipitate was filtered off to obtain the title compound (245 mg, 92%) as light brown solid. MS: m / e = 363.2 [MH] ^- .

b) 6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

To a solution of 6- (4- (1- (4-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (56 mg, 0.154 mmol) and TBTU (55 mg, 0.169 mmol) in DMF (2.0 ml) were added DIPEA (131 μl, 0.769 mmol). Then, isopropylamine (15 μl, 0.169 mmol) was added, the mixture was stirred at room temperature in argon atmosphere for 1 h. Then the mixture was evaporated and purification was carried out by chromatography (silica gel, 50 to 100% ethyl acetate in heptane) to give a compound, indicated in the title (47 mg, 75%) as a white solid. MS: m / e = 406.4 [M + H] ⁺ .

Example 37

6- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (56 mg, 0.154 mmol) was converted according to the procedure described in example 22 using 4-aminotetrahydropyran instead of isopropylamine to give the title compound (52 mg, 76%) as an off-white solid. MS: m / e = 448.3 [M + H] ⁺ .

Example 38

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (56 mg, 0.154 mmol) was converted according to the procedure described in example 36b using 3-methyloxetan-3-amine instead of isopropylamine to give the title compound (57 mg, 86%) as an off-white solid. MS: m / e = 434.3 [M + H] ⁺ .

Example 39

(6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (56 mg, 0.154 mmol) was converted according to the procedure described in example 36b using 2-oxa-6-azonia-spiro [3.3] heptane oxalate instead of isopropylamine to give the title compound (29 mg, 42%), which was obtained as whitish solid after recrystallization from a mixture of ethyl acetate-hexane. MS: m / e = 446.2 [M + H] ⁺ .

Example 40

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

To a solution of 6- (4- (1- (4-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (70 mg, 0.192 mmol) CDI (38 mg, 0.231 mmol) was added to DMF (2 ml), the resulting mixture was stirred at 60 ° C for 1 h. After cooling to room temperature, ammonium hydroxide (300 μl, 1.92 mmol) was added, the reaction mixture stirred for 16 hours and then evaporated. Purification was performed by chromatography (silica gel, 50 to 100% ethyl acetate in heptane) to give the title compound (61 mg, 87%) as an off-white solid. MS: m / e = 364.3 [M + H] ⁺ .

Example 41

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropyl) nicotinamide

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (65 mg, 0.178 mmol) was converted according to the procedure described in example 36b, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to give the title compound (61 mg, 79%) as a white solid. MS: m / e = 436.2 [M + H] ⁺ .

Example 42

N-Cyclopropyl-6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (65 mg, 0.178 mmol) was converted according to the procedure described in example 36b, using cyclopropylamine instead of isopropylamine, to give the title compound (27 mg, 38%) as an off-white solid. MS: m / e = 404.2 [M + H] ⁺ .

Example 43

6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

a) Methyl-6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate

A mixture of 1- (2-fluorophenyl) -5- (1H-imidazol-4-yl) -4-methyl-1H-1,2,3-triazole (268 mg, 1.1 mmol), methyl-6-chloronicotinate ( 190 mg, 1.1 mmol) and potassium carbonate (305 mg, 2.2 mmol) in DMF (6.0 ml) were stirred under argon in a sealed flask and heated at 120 ° C for 2 hours. After cooling to room temperature at a temperature, the mixture was poured into water and extracted with ethyl acetate, and the combined extracts were washed with water, brine, dried over sodium sulfate, filtered and evaporated. Purification was performed by chromatography (silica gel, 10 to 100% ethyl acetate in heptane) to give the title compound (120 mg, 29%) as an off-white solid. MS: m / e = 379.2 [M + H] ⁺ .

b) 6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid

A solution of lithium hydroxide monohydrate (29 mg, 0.671 mmol) in water (1.3 ml) was added dropwise to a suspension of methyl 6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2, 3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate (127 mg, 0.336 mmol) in THF (5 ml) and methanol (1 ml). Then the reaction mixture was stirred at room temperature for 1 h, after which it was evaporated, and the residue was dissolved in water acidified with HCl (1H), the resulting precipitate was filtered off to obtain the title compound (108 mg, 88%) as white solid matter. MS: m / e = 363.3 [MH] ^- .

c) 6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide

To a solution of 6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (46 mg, 0.126 mmol) and TBTU (45 mg, 0.139 mmol) in DMF (2.0 ml) were added DIPEA (110 μl, 0.631 mmol). Then isopropylamine (12 μl, 0.139 mmol) was added, the mixture was stirred at room temperature under argon for 2 hours. The mixture was then evaporated and purification was carried out by chromatography (silica gel, 50 to 100% ethyl acetate in heptane) to give a compound, indicated in the title (34 mg, 66%) as a white foam. MS: m / e = 406.3 [M + H] ⁺ .

Example 44

(1,1-dioxo-1,6-thiomorpholin-4-yl) - (6- {4- [3- (4-fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4- yl] -imidazol-1-yl} -pyridin-3-yl) methanone

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (65 mg, 0.178 mmol) was converted according to the procedure described in example 36b using thiomorpholine-1,1-dioxide instead of isopropylamine to give the title compound (32 mg, 37%), which was obtained as a white foam after purification by chromatography ( reverse phase HPLC). MS: m / e = 482.3 [M + H] ⁺ .

Example 45

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide

6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (65 mg, 0.178 mmol) was converted according to the procedure described in example 36b using 4-aminomorpholine instead of isopropylamine to give the title compound (49 mg, 61%), which was obtained as a white solid after recrystallization from ethyl acetate-heptane. MS: m / e = 449.2 [M + H] ⁺ .

Example 46

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (tetrahydro-2H-pyran -4-yl) nicotinamide

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (46 mg, 0.126 mmol) was converted according to the procedure described in example 43 s, using 4-aminotetrahydropyran instead of isopropylamine to give the title compound (59 mg, 70%), which was obtained as a white foam after purification by chromatography (silica gel. 0 to 10% methanol in dichloromethane). MS: m / e = 448.2 [M + H] ⁺ .

Example 47

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) was converted according to the procedure described in example 43c using 2-amino-2-methylpropan-1-ol instead of isopropylamine to give the title compound (56 mg, 63%), which was obtained as a white foam after purification using chromatography (reverse phase HPLC, then silica gel, ethyl acetate). MS: m / e = 436.2 [M + H] +.

Example 48

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

To a solution of 6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) CDI (40 mg, 0.244 mmol) was added to DMF (3 ml), the resulting mixture was stirred at 60 ° C for 1 h. After cooling to room temperature, ammonium hydroxide (320 μl, 2.03 mmol) was added, the reaction mixture stirred for 30 minutes and then evaporated. Purification was performed by chromatography (reverse phase HPLC) to give the title compound (58 mg, 74%) as a white solid. MS: m / e = 364.1 [M + H] ⁺ .

Example 49

(6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) was converted according to the procedure described in example 43 s using 2-oxa-6-azonia-spiro [3.3] heptane oxalate instead of isopropylamine to give the title compound (50 mg, 55%), which was obtained as white solid after purification by chromatography (reverse phase HPLC). MS: m / e = 446.2 [M + H] ⁺ .

Example 50

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) was converted according to the procedure described in example 43c using methyl-3-oxetanamine instead of isopropylamine to give the title compound (70 mg, 80%), which was obtained as a white foam after purification by chromatography (reverse phase HPLC). MS: m / e = 434.3 [M + H] ⁺ .

Example 51

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) was converted according to the procedure described in example 43 s using 4-aminomorpholine instead of isopropylamine to give the title compound (56 mg, 62%), which was obtained as a white foam after purification by chromatography (reverse phase HPLC, then silica gel, ethyl acetate). MS: m / e = 449.2 [M + H] ⁺ .

Example 52

N-Cyclopropyl-6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) was converted according to the procedure described in example 43 s using cyclopropylamine instead of isopropylamine to give the title compound (42 mg, 51%), which was obtained as a white foam after purification by chromatography (reverse phase HPLC, then silica gel, ethyl acetate). MS: m / e = 404.4 [M + H] ⁺ .

Example 53

N- (Cyclopropylmethyl) -6- (4- (1- (2-fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide

6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid (74 mg, 0.203 mmol) was converted according to the procedure described in example 43c using aminomethylcyclopropane instead of isopropylamine to give the title compound (40 mg, 47%), which was obtained as a white foam after purification by chromatography (reverse phase HPLC). MS: m / e = 418.3 [M + H] ⁺ .

Biochemical analysis

The ability of the compounds of the present invention to bind to subtypes of the GABA A receptor was determined using a competitive binding reaction of [ ³ H] flumazenil (85 Ci / mmol; Roche) with HEK293 cells that express rat receptors (stable transfection) or human (transient transfection) of α1β2 / 3γ2, α2β3γ2, α3β3γ2 and α5β3γ2.

Membrane Production

The cell pellet was suspended in Krebs-tris buffer (4.8 mM KCl, 1.2 mM CaCl ₂ , 1.2 mM MgCl ₂ , 120 mM NaCl, 15 mM Tris; pH 7.5; binding assay buffer), homogenized with using a polytron for about 20 seconds on ice and centrifuged for 60 minutes. at 4 ° C (50,000 g; Sorvall, rotor: SM24 = 20,000 rpm). The cell pellet was resuspended in Krebs-tris buffer and homogenized with a polytron for approximately 15 seconds on ice. Then, the protein concentration was measured (Bradford method, Bio-Rad), 1 ml aliquots were prepared, and they were frozen at -80 ° C.

Radioligand Binding Assay

The radioligand binding assay was carried out in a volume of 200 ml (96-well plates) containing 100 ml of cell membranes, [3H] flumazenil at a concentration of 1 nM for α1, α2, α3 subunits and 0.5 nm for α5 subunits, and the analyzed compound in a concentration in the range of 10-10 ^-3 × 10 ^-6 M. Nonspecific binding was determined using 10 ^-5 M diazepam, while it usually amounted to less than 5% of the total binding. Analyzed samples were incubated until equilibrium for 1 hour at 4 ° C and collected on Packard GF / C filters using Packard harvester filtration and washed with ice rinse buffer (50 mM Tris; pH 7.5). After the filters were dried, the radioactivity retained on them was measured using a liquid scintillation counter.

Data processing

K _i values were calculated using Excel-Fit (Microsoft), and are the average of the two definitions.

Compounds from the above examples were analyzed according to the procedure described above, and, in particular, it was found that these compounds have a K _i value for displacing the [ ³ H] flumazenil from the α5 subunit of the GABA A rat receptor of 100 nM or less. One embodiment includes compounds with K _i of 35 nM or less. In one embodiment, the compounds of the present invention selectively bind to the α5 subunit relative to the α1, α2 and α3 subunits.

The most representative analysis results obtained according to the procedure described above for measuring the affinity of binding to HEK293 cells expressing human receptors (h) are presented in table 1 below.

Table 1. The affinity of binding to HEK293 cells expressing human receptors (h), for the examples presented in this application. Example hKi (GABA Aa5) Example hKi (GABA Aa5) Example hKi (GABA Aa5) one 27,2 19 66,2 37 25.9 2 41.2 twenty 16,2 38 9.6 3 21.1 21 86 39 35.8 four 36.6 22 43.3 40 12.6 5 23.8 23 54.9 41 20.8 6 51.3 24 21.3 42 3.2 7 18.8 25 19.3 43 15.1 8 84.3 26 66.5 44 29th 9 76.3 27 16.1 45 69,4 10 29.6 28 32,4 46 49 eleven 14.7 29th 9.5 47 51.7 12 33 thirty 65 48 17.8 13 14.6 31 49.2 49 90 fourteen 37.6 32 25.9 fifty 17.9 fifteen 82,2 33 34.5 51 50,5 16 12.1 34 45.6 52 10.9 17 68.8 35 26.3 53 32,7 eighteen 75.1 36 6.2

Claims (23)

1. The compound of formula (I)

Where
X N or CH; R ¹ , R ² C1-C7 alkyl, phenyl substituted with 1 halogen, where one of the substituents R ¹ and R ² is an alkyl group; R ³ halo C1-C7 alkyl, nitro, -C (O) R ⁴ , -C (O) NR ⁵ R ⁶ ; R ⁴ C1-C7 alkyl, hydroxy, C1-C7 alkoxy; R ⁵ hydrogen, C1-C7 alkyl, halo C1-C7 alkyl, hydroxy C1-C7 alkyl, - (CH ₂ ) _n -C3-C8 cycloalkyl, - (CH ₂ ) _n - (4-6 membered heterocycloalkyl with 1 heteroatom selected from O), wherein the heterocycloalkyl is optionally substituted with one C1-C7 alkyl group; n an integer in the range from 0 to 1; R ⁶ hydrogen, C1-C7 alkyl; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a bicyclic 7-membered heterocycloalkyl with an additional heteroatom selected from O, a 6-membered heterocycloalkyl with an additional heteroatom selected from O, S, where the heterocycloalkyl is optionally substituted with one or more oxo groups;
as well as pharmaceutically acceptable salts and esters of these compounds. 2. The compounds of claim 1, wherein
X N or CH; R ¹ , R ² C1-C7 alkyl, or phenyl optionally substituted with 1 halogen, wherein one of the substituents R ¹ and R ² is a C1-C7 alkyl group; R ³ halo C1-C7 alkyl, nitro, -C (O) R ⁴ , -C (O) NR ⁵ R ⁶ ; R ⁴ C1-C7 alkyl, hydroxy, or C1-C7 alkoxy; R ⁵ hydrogen, C1-C7 alkyl, hydroxyC1-C7 alkyl, - (CH ₂ ) _n -C3-C8 cycloalkyl, or - (CH ₂ ) _n - (4-6 membered heterocycloalkyl with 1 heteroatom selected from O) wherein heterocycloalkyl is optionally substituted with one C1-C7 alkyl group; n an integer in the range from 0 to 1; R ⁶ hydrogen; or R ⁵ and R ⁶ together with the nitrogen to which they are attached form a bicyclic 7-membered heterocycloalkyl with an additional heteroatom selected from O, a 6-membered heterocycloalkyl with an additional heteroatom selected from O, S which is optionally substituted with one or more oxo groups;
as well as pharmaceutically acceptable salts and esters of these compounds. 3. The compounds according to claim 1, in which X is N. 4. The compounds according to claim 1, in which one of the substituents R ¹ and R ² is a C1-C7 alkyl group, and the other Deputy is a phenyl group, possibly substituted by one halogen. 5. The compounds according to claim 1, in which R ¹ is a methyl group, and R ² is a phenyl group substituted by one fluorine atom. 6. The compounds according to claim 1, in which R ² is a methyl group, and R ¹ is a phenyl group substituted with one fluorine atom. 7. The compounds according to claim 1, in which R ³ is a haloCl-C7 alkyl or nitro group, —C (O) R ⁴ , or —C (O) NR ⁵ R ⁶ . 8. The compounds according to claim 1, in which R ³ is —C (O) NR ⁵ R ⁶ . 9. The compounds of claim 1, wherein R ⁴ is a C1-C7 alkyl, hydroxyl, or C1-C7 alkoxy group. 10. The compounds according to claim 1, in which R ⁴ is a methyl, hydroxyl, or methoxy group. 11. The compounds according to claim 1, in which R ⁵ is a hydrogen atom, C1-C7-alkyl, hydroxyC1-C7-alkyl, - (CH ₂ ) _n -C3-C8-cycloalkyl, or - (CH ₂ ) _n - ( A 4-6 membered heterocycloalkyl group with 1 heteroatom selected from O), wherein the heterocycloalkyl group is optionally substituted with one C1-C7 alkyl group. 12. The compounds of claim 1, wherein R5 is a hydrogen atom, an isopropyl, isobutyl group substituted by hydroxyl, a tert-butyl group substituted by hydroxyl, cyclopropyl, cyclopropylmethyl, morpholinyl, tetrahydropyranyl or oxetanyl group substituted by methyl. 13. The compounds according to claim 1, in which R ⁶ is a hydrogen atom. 14. The compounds according to claim 1, in which R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form a bicyclic 7-membered heterocycloalkyl with an additional heteroatom selected from O, a 6-membered heterocycloalkyl with an additional heteroatom selected from O , S, which is optionally substituted by one or more oxo groups. 15. The compounds according to claim 1, in which R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form 1,1-dioxo-1,6-thiomorpholin-4-yl or 2-oxa-6-aza spiro [3.3] hept-6-yl. 16. The compounds according to claim 1, selected from the group consisting of:
1- (4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone;
4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzoic acid methyl ester;
4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl benzamide;
4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) -benzamide;
4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) benzamide;
(4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) - (2-oxa- 6-aza-spiro [3.3] hept-6-yl) methanone;
4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} benzamide;
4- (2-Fluorophenyl) -1-methyl-5- (1- (4- (trifluoromethyl) phenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole;
4- (2-Fluorophenyl) -1-methyl-5- (1- (4-nitrophenyl) -1H-imidazol-4-yl) -1H-1,2,3-triazole;
1- (4- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) phenyl) ethanone;
6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl nicotinamide;
6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide;
6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) -nicotinamide;
(6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} pyridin-3-yl) - ( 2-oxa-6-aza-spiro [3.3] hept-6-yl) methanone;
2- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine;
6- (4- (4- (4-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
Methyl 6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate;
6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;
6- (4- (4- (2-Chlorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
Methyl 6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinic acid;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (tetrahydro-2H-pyran -4-yl) nicotinamide;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (2-hydroxy-2 methylpropyl) nicotinamide;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
(6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;
6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide;
N-Cyclopropyl-6- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
2- (4- (4- (2-Fluorophenyl) -1-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -5- (trifluoromethyl) pyridine;
1- (4-Fluorophenyl) -4-methyl-5- [1- (4-trifluoromethyl-phenyl) -1H-imidazol-4-yl] -1H- [1,2,3] triazole;
1- (4- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} phenyl) ethanone;
Methyl 4- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) benzoate;
2- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine;
Methyl 6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinate;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;
6- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;
(6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide;
N-Cyclopropyl-6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;
(1,1-dioxo-1,6-thiomorpholin-4-yl) - (6- {4- [3- (4-fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4- yl] -imidazol-1-yl} -pyridin-3-yl) methanone;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide;
6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (tetrahydro-2H-pyran -4-yl) nicotinamide;
6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide;
6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
(6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;
6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;
6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-morpholinonicotinamide;
N-Cyclopropyl-6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
N- (Cyclopropylmethyl) -6- (4- (1- (2-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
and pharmaceutically acceptable salts and esters of these compounds. 17. The compounds according to claim 1, selected from the group consisting of:
4- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl benzamide;
6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N-isopropyl nicotinamide;
6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (3-methyl-oxetan- 3-yl) -nicotinamide;
(6- {4- [5- (4-Fluorophenyl) -3-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} pyridin-3-yl) - ( 2-oxa-6-aza-spiro [3.3] hept-6-yl) methanone;
2- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -5-trifluoromethyl-pyridine;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N-isopropylnicotinamide;
6- {4- [3- (4-Fluorophenyl) -5-methyl-3H- [1,2,3] triazol-4-yl] imidazol-1-yl} -N- (tetrahydropyran-4-yl) nicotinamide;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (3-methyloxetan-3 -yl) nicotinamide;
(6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) pyridin-3-yl) (2 -oxa-6-azaspiro [3.3] heptan-6-yl) methanone;
6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) -N- (1-hydroxy-2 methylpropan-2-yl) nicotinamide;
N-Cyclopropyl-6- (4- (1- (4-Fluorophenyl) -4-methyl-1H-1,2,3-triazol-5-yl) -1H-imidazol-1-yl) nicotinamide;
and pharmaceutically acceptable salts and esters of these compounds. 18. Compounds according to any one of claims 1 to 17, having affinity and selectivity for the GABA A α5 receptor. 19. Compounds according to any one of claims 1 to 17 for the treatment or prevention of diseases associated with the GABA A α5 receptor. 20. Pharmaceutical compositions exhibiting binding activity against the GABA A α5 receptor, comprising a compound according to any one of claims 1-17 in an effective amount and a pharmaceutically acceptable excipient. 21. A method of treating or preventing diseases associated with the GABA A α5 receptor, the method comprising administering a compound according to any one of claims 1-17 to a human or animal. 22. The use of compounds according to any one of claims 1 to 17 for the preparation of medicines having affinity and selectivity for GABA A α5 receptor. 23. The use of compounds according to any one of claims 1 to 17 for the treatment or prevention of diseases associated with the GABA A α5 receptor.