Azabicyclo{3,1,0}hexane derivatives used as dopamine receptor d3 modulators

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of azabicyclo{3,1,0}hexane of general formula (I) or pharmaceutically acceptable salts thereof (values of radicals are given in the claim), synthesis method thereof, intermediate compounds, a pharmaceutical composition and use of the novel compounds in therapy as dopamine receptor D3 modulators, for example, for treating drug dependence or as antipsychotic agents.

EFFECT: improved properties of the derivatives.

34 cl, 122 ex

 

The present invention relates to new compounds, methods for their preparation, intermediate compounds used for their production, pharmaceutical compositions containing them and their use in the treatment as modulators of dopamine receptor D3.

In WO 2002/40471 (SmithKline Beecham) discloses some benzazepine with activity against dopamine receptor D3.

Found a new class of compounds with affinity in relation to the dopamine receptors, in particular receptor D3. These compounds are potentially applicable for the treatment of conditions that are favorable modulation, in particular antagonism/inhibition, receptor D3for example, for the treatment of drug dependence, or as antipsychotics.

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

or its salt,

where in the formula

G is chosen from the group consisting of phenyl, pyridyl, benzothiazolyl, indazole;

p is an integer from 0 to 5;

- R1chosen independently from the group consisting of halogen, hydroxy, cyano, C1-4-alkyl, halogen-C1-4-alkyl, C1-4-alkoxy, Halonen-C1-4-alkoxy, C1-4alkanoyl; or R1corresponds to the group R5;

- R2the submitted is a hydrogen or C 1-4-alkyl;

- R3represents a C1-4-alkyl;

- R4represents a hydrogen or phenyl group, heterocyclyl group, 5 - or 6-membered heteroaromatic group, or 8-11 membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, cyano, C1-4-alkyl, halogen-C1-4-alkyl, C1-4-alkoxy, C1-4alkanoyl;

- R5is a fragment selected from the group consisting of isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazolinone, teinila, thiazolyl, pyridyl, 2-pyrrolidinone, such group optionally substituted by one or two substituents selected from among halogen, cyano, C1-4-alkyl, halogen-C1-4-alkyl, C1-4-alkoxy, C1-4alkanoyl;

and when R1represents chlorine, and R is equal to 1, then R1is not in position on the relationship with the rest of the molecule; and when R1corresponds to R5, p is equal to 1.

It is assumed that due to the presence of condensed cyclopropane compounds of formula (I) have the position of Vice "CIS" (both groups associated with the bicyclic system are in the same plane such bicyclic system).

In another embodiment of the present invented the e refers to compounds of the formula (I)', the corresponding compounds of formula (I) with the location of the "CIS", which is characterized by a distinct gap between links

where G, p, R1, R2, R3, R4and R5have the values specified above for compounds of formula (I).

It should be borne in mind that the compounds of formula (I)' have at least two chiral centres, namely in positions 1 and 5 in 3-azabicyclo[3.1.0]hexane of the molecule. In effect fixed zespolony compounds can exist as two stereoisomers are enantiomers relative to the chiral centers in cyclopropane. You should also bear in mind that like the majority of biologically active molecules, the biological activity level of the individual stereoisomers of a given molecule may vary. In addition, the scope of the invention includes the individual stereoisomers (diastereoisomers and enantiomers) and their mixtures, including racemic mixtures, and others that demonstrate appropriate biological activity in connection with the procedures described in this description.

In the compounds of formula (I)' there are at least two chiral centers in cyclopropanol parts, as shown below (distinct clearance between the bonds means the "CIS"configuration).

When G depict is to place a 2-peregrinae derived,

configuration is (1R,5R) due to priorities

item Cana-Ingold-Prelog.

In another embodiment the present invention relates to compounds of formula (IA), which correspond to stereochemical isomers of compounds of formula (I)', enriched in configuration (1S,5R) or (1R,5R)

where G, p, R1, R2, R3, R4and R5have the values specified above for compounds of formula (I)or their pharmaceutically acceptable salts.

In the context of the present invention assumes that a stereochemical isomer enriched in configuration (1S,5R) or (1R,5R) of the formula (IA)correspond, in one embodiment, at least 90% EE (E.E.). In another embodiment the isomers correspond to at least 95% EE In another embodiment the isomers correspond to at least 99% EE

In another embodiment the present invention relates to a stereochemical isomer enriched in configuration (1S,5R), which include

- 5-[5-({3-[(1R,5S)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine -enantiomer 2;

- 5-[5-({3-[(1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine -enantiomer 1;

- 5-[5-({3-[(1R,5S)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-METHYLPHENOL the - enantiomer 1;

- (1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane -enantiomer 2;

- (1R,5S)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane -enantiomer 2;

- 1-[5-[(1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone -enantiomer 2;

- 2-methyl-5-[(1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole -enantiomer 2; or their pharmaceutically acceptable salts.

The term "5 - or 6-membered heteroaromatic group" refers to a monocyclic 5 - or 6-membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms, for example, 1-3 heteroatoms selected from the atoms O, N and S. When the group contains 2-4 heteroatoms can be selected from the atoms O, N and S, and the remaining heteroatoms may be atoms N. Examples of 5 - or 6-membered heteroaromatic group are pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolin, thiazolyl, furyl, thienyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

The term "C1-4-alkyl" refers to alkyl group with one to four carbon atoms in the all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. The term "n-C1-4-alkyl" refers to linear alcelam with the above values.

The term "C1-4-alkoxy" refers to a linear or branched alkoxy(or "alkyloxy")group with one to four carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term "halogen" and its abbreviation "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). When the term "halogen" is used in front of another group, it indicates that the group is substituted by one, two, three or four halogen atoms. For example, the term "halogen-C1-4-alkyl" refers to groups such as trifluoromethyl, bromacil, cryptochromes and other groups formed from C1-4-alkyl groups, with the values specified above; and the term "halogen-C1-4-alkoxy" refers to groups such as triptoreline, bromoethoxy, cryptochromes and other groups formed from C1-4-alkoxygroup with the values specified above.

The term "8-11 membered bicyclic group" refers to a diatomic cyclic system containing generally 8, 9, 10 or 11 carbon atoms, where 1, 2, 3, 4 or 5 carbon atoms optionally replaced by heteroatoms, selected independently from among the atoms O, S and N. Term is n includes bicyclic systems, where both cycles are aromatic, and also bicyclic system, where one cycle is a partially or fully saturated. Examples 8 to 11-membered bicyclic groups, where both cycles are aromatic, include indenyl, naphthyl and azulene. Examples 8 to 11-membered bicyclic groups containing 1, 2, 3, 4 or 5 heteroatoms, in which both cycles are aromatic, include 6N-thieno[2,3-b]pyrrolyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[5,1-b][1,3]thiazolyl, [1,3]thiazolo[3,2-b][1,2,3]triazolyl, indolyl, isoindolyl, indazoles, benzimidazoles, for example, benzimidazol-2-yl, benzoxazolyl, for example, benzoxazol-2-yl, benzisoxazol, benzothiazolyl, benzisothiazole, benzothiazyl, benzofuranyl, naphthyridine, hinely, honokalani, hintline, cinnoline and ethanolic. Examples 8 to 11-membered bicyclic groups containing 1, 2, 3, 4 or 5 heteroatoms, in which one of the cycles is partially or fully saturated, include dihydrobenzofuranyl, indanyl, tetrahydronaphtyl, indolinyl, isoindolyl, tetrahydroisoquinoline, tetrahydroquinoline, benzoxazines and benzodazepines.

The term "heterocyclyl" refers to 5 - or 6-membered monocyclic or 8-11 membered bicyclic group, where 1, 2, 3, 4 or 5 carbon atoms are replaced by heteroatoms selected, independently, from the atoms O, S and N and which is partially or fully nasy the military. Examples of "heterocyclyl", which is a fully saturated 5 - or 6-membered saturated cycle include pyrrolidinyl, imidazolidinyl, pyrazolidine, isothiazolin, thiazolyl, tetrahydrofuranyl, DIOXOLANYL, piperidinyl, piperazinil, morpholinyl, thiomorpholine, tetrahydrothieno, dioxane, tetrahydro-2H-pyranyl and dithienyl. Examples of "heterocyclyl" groups, which are partially saturated 5 - or 6-membered saturated cycles include oxazoline, isoxazoline, imidazolines, pyrazolines, 1,2,3,6-tetrahydropyridine and 3,6-dihydro-2H-pyranyl. Examples of "heterocyclyl" groups, which are fully saturated 8-11 membered diatomic cycles include decahydroquinoline, octahydro-2H-1,4-benzoxazine, octahydro-1H-cyclopent[b]pyridinyl. Examples of "heterocyclyl" groups, which are partially saturated 8 to 11-membered diatomic cycles include 2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and 2,3,4,5-tetrahydro-1H-3-benzazepines.

Any of these groups can join the rest of the molecule in any suitable position.

Used in this description, the term "salt" refers to any salt of the compound of the present invention, obtained with an inorganic or organic acid or base salts included four is divided ammonium bases and internal salts. Physiologically acceptable salts, in particular, suitable for use in medical applications because of their greater water solubility relative to the parent compounds. Such salt should contain physiologically acceptable anion or cation. Suitable physiologically acceptable salts of the compounds of the present invention include acid additive salts formed with inorganic acids such as chloromethane, Hydrobromic, iodomethane, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids such as tartaric, acetic, triperoxonane, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, camphorsulfonate, sotynova, mucus, gentisic, isonicotinoyl, sugar, glucuronic, Voronova, glutamic, ascorbic, Anthranilic, salicylic, phenylacetic, almond, albanova (AMOVA), methansulfonate, econsultancy, Pantothenic, stearic, Sultanova, alginic, galacturonic and arylsulfonate, for example, benzolsulfonat and p-toluensulfonate, acids; primary additive salts formed with alkali metals and alkaline earth metals and organic bases such as N,N-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, atlend the amine, meglumine (N-methylglucamine), lysine and procaine; and an internal salt. Salts with physiologically acceptable anion or cation are included in the scope of the invention as intermediate compounds applicable for obtaining physiologically acceptable salts and/or for use not for therapeutic purposes, for example, situations in vitro.

In one embodiment R1represents halogen, cyano, acetyl, trifluoromethyl, triptoreline.

In one embodiment R2represents hydrogen. In another embodiment R2represents a C1-4-alkyl (e.g. methyl).

In one embodiment R5represents a group selected from isoxazolyl, 2-pyrrolidinone, 1,1-dioxido-2-isothiazolinone, which is optionally substituted by one or two substituents selected from halogen, cyano, C1-2-alkyl (e.g. methyl), halogen-C1-2-alkyl (for example, trifloromethyl)1-2-alkoxy (e.g. methoxy), C1-2alkanoyl (for example, acetyl).

Accordingly, R1represents bromine, fluorine, triptoreline, cyano, hydroxy, chlorine, methoxy, tert-butyl, trifluoromethyl.

Accordingly, R2represents isoxazolyl, 2-pyrrolidinyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazoline, 2-thienyl, 2-pyridyl, 2-thiazolyl.

In one embodiment p is 1 or 2.

In another embodiment R Rav is n 0.

In one embodiment R4can be an optionally substituted phenyl (e.g. phenyl, 4-triptoreline, 3,4-differenl), optionally substituted bicyclic group, such as chinoline (for example, 2-methylinosine, 8-fluoro-2-methylinosine), optionally substituted pyranyl (for example, 4-tetrahydro-2H-pyranyl), optionally substituted pyridinyl (for example, 3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl, 2-methyl-6-trifluoromethyl-3-pyridinyl), optionally substituted pyrazolyl (for example, 5-chloro-1-methyl-1H-pyrazole-4-yl, 1-methyl-3-trifluoromethyl-1H-pyrazole-4-yl, 1,5-dimethyl-1H-pyrazole-4-yl), optionally substituted pyrimidyl (for example, 5-pyrimidinyl), optionally substituted pyridazinyl (for example, 4-pyridazinyl), optionally substituted pyrazinyl (for example, 5-methyl-2-pyrazinyl), optionally substituted furanyl (for example, 3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), optionally substituted thienyl (for example, 5-chloro-2-thienyl), optionally substituted oxazolyl (for example, 4-methyl-1,3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), optionally substituted isoxazolyl (for example, 3-methyl-5-isoxazolyl), optionally substituted thiazolyl (for example, 2,4-dimethyl-1,3-thiazol-5-yl), optionally substituted triazolyl (for example, 1-methyl-1H-1,2,3-triazole-4-yl).

In one embodiment R3represents methyl.

<> One embodiment relates to the compound of formula (IB) or salts thereof, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IB) in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule.

Examples R4include optionally substituted phenyl (e.g. phenyl, 4-triptoreline, 3,4-differenl), optionally substituted bicyclic group, such as chinoline (for example, 2-methylinosine, 8-fluoro-2-methylpyridyl), optionally substituted pyranyl (for example, 4-tetrahydro-2H-pyranyl), optionally substituted pyridinyl (for example, 3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl, 2-methyl-6-trifluoromethyl-3-pyridinyl), optionally substituted pyrazolyl (for example, 5-chloro-1-methyl-1H-pyrazole-4-yl, 1-methyl-3-trichromatic-1H-pyrazole-Il, 1,5-dimethyl-1H-pyrazole-4-yl), optionally substituted pyrimidyl (for example, 5-pyrimidinyl), optionally substituted pyridazinyl (for example, 4-pyridazinyl), optionally substituted pyrazinyl (for example, 5-methyl-2-pyrazinyl), optionally substituted furanyl (for example, 3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), optionally substituted thienyl (for example, 5-chloro-2-thienyl), optionally substituted oxazolyl (for example, 4-methyl-1,3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), optionally substituted isoxazolyl (for example, 3-methyl-5-isoxazolyl), optionally substituted thiazolyl (for example, 2,4-dimethyl-1,3-thiazol-5-yl), optionally substituted triazolyl (for example, 1-methyl-1H-1,2,3-triazole-4-yl).

Another embodiment relates to the compound of formula (IC) or its salt, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IC) in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and to the GDS R 1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule. Examples R4are the groups given above for the compounds (IB).

Another embodiment relates to the compound of formula (ID) or its salt, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (ID) in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule.

Examples R4are the groups given above for the compounds (IB).

Another embodiment relates to the compound of formula (IE) or its salt, where G is a 2-pyridyl or 3-pyridyl, and R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IE) in one embodiment of G which correspond to a 2-pyridyl (connection (IE 1), and in another embodiment of the 3-pyridyl (connection (IE2)), as illustrated below

In the formula (IE), (IE1) and (IE2in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule.

Examples R4are the groups given above for the compounds (IB).

Another embodiment relates to the compound of formula (IF) or its salts, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IF) in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, guy is Roxie, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule.

Examples R4are the groups given above for the compounds (IB).

The strategy for determining the absolute configuration of the compounds of the present invention includes as a first stage receiving chiral intermediate (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

(preparative example 18) using as a decomposing agent (S)-(+)-acetylindole acid.

The absolute configuration of a number of compounds, such chiral intermediate compound known from the literature, see J. Med. Chem., 1981, 24(5), 481-90. For some compounds, disclosed in this reference, the absolute configuration established conventional x-ray analysis of the single crystal.

Among such compounds disclosed is 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane.

The absolute configuration of the optical isomers of the compounds of the present invention set using the comparative analysis method VCD (vibrational circular dichroism) and OR (pricescope rotation).

The configuration (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane established by comparing its experimental VCD spectrum and the observed specific rotation with ab initio calculated data obtained for (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (see preparative example 48) as the reference sample.

Determination of the absolute configuration specified in the connection header is confirmed by x-ray structure of the single crystal obtained for the salt crystal (S)-(+)-acetylindole acid (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane. As the analysis based on the known configuration (S)-(+)-acetylindole acid, and the analysis based on the effects of anomalous dispersion confirms the definition mentioned in the title compound (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

For those compounds that were subjected to detailed analysis (VCD; OR included in the experimental data), revealed a General correlation between the absolute configuration of 3-azabicyclo[3.1.0]hexane group and measured the activity of binding to the dopamine receptor D3 for each pair of enantiomers. For the other compounds of the present invention, where the stereoisomers were evaluated separately, the absolute configuration was established on the basis of reasonable assumptions specialist in the art, i.e. the absolute to which the end has been evaluated, based on the measured activity of binding to the dopamine receptor D3 for both enantiomers and comparison with data for those compounds that were subjected to detailed analysis.

Chiral molecules show vibrational circular dichroism (VCD). Vibrational circular dichroism (VCD) is a different interaction of chiral molecules with infrared radiation with left and right circular polarization during oscillatory perturbations.

Range VCD chiral molecule depends on its three-dimensional structure. Most importantly, VCD spectrum of chiral molecules is a sensitive function of its absolute configuration and, in the case of flexible molecules, its conformation. Therefore, in principle, VCD allows to determine the structure of chiral molecules. VCD spectra were first measured in the 1970-ies. Further devices for measuring VCD was strictly designed taking into account the spectral range and sensitivity. Currently, the VCD spectra of liquids and solutions can be measured in most parts of the fundamental infrared (IR) spectral region (v ≥ 650 cm-1) with high sensitivity at an acceptable resolution (1-5 cm-1using devices as VCD c scattering and Fourier transform (FT). Recently available commercial devices FT VCD, which greatly expanded the availability of the special the TRS VCD.

The use of VCD as a reliable method of determining the absolute configuration of chiral molecules is now fully recognized (see, for example, Shan R.D. et al., Curr. Opin. Drug Disc. Dev., 2001, 4:764-774; T.B. Freedman et al., Helv. Chim. Acta, 2002, 85:years 1160 to 1165; Dyatkin A.B. et al., Chirality, 2002, 14:215-219; Solladie'-Cavallo, A., Balaz. M. et al., Tetrahedron Assym., 2001, 12:2605-2611; L.A. Nafie et al., Circular dichroism, principles and applications, 2nded., New York, John Wiley & Sons, 2000, p.97-131; L.A. Nafie et al., in B. Yan, Gremlish H-U., editors, Infrared and Raman spectroscopy of biological materials, New York, Marcel Dekker, 2001, p.15-54; P.L. Polavarapu et al., J. Anal. Chem., 2000, 366:727-734; Stephens, P.J. et al., Chirality, 2000, 12:172-179; Solladie'-A. Cavallo et al., Eur. J. Org. chem., 2002:1788-1796).

The method involves comparing the observed IR and VCD spectra with calculations of spectra for a specific configuration and gives information about the absolute configuration and conformation in solution.

Taking into account the experimental spectrum of chiral molecules, absolute configuration and/or the conformation of which is unknown and must be determined, the General procedure is as follows: 1) determine all possible patterns; 2) predict the spectra of such structures, and 3) the predicted spectra are compared with the experimental spectrum. The correct structure will give a range, consistent with experiment; the incorrect structure will give spectra that are at odds with experiment.

VCD spectra always measured simultaneously with the oscillating unpolarized absorption spectra of the texts ("infrared (IR) spectra"), and two vibrational spectrum together give more information than one VCD spectrum. In addition, vibrational unpolarized absorption spectra automatically predict simultaneously with VCD spectra.

For definitions of ab initio VCD spectra and unpolarized IR calculated using the program package Gaussian 98.

When synthesize chiral molecules (or, if it is a natural product, isolated), their optical rotation is usually measured at the same frequency or at a small number of discrete frequencies in the visible spectrum or near ultraviolet region. Often specific rotation measured at the same frequency - the frequency of the line D sodium ([α]D). Used frequencies which lie below the threshold of absorption of electrons, i.e. they are in the "bandwidth" of the spectrum. Optical rotation is a reflection of the enantiomeric excess (ei) of the sample and the absolute configuration (AC) of the predominant enantiomer.

When there is optical rotation at the given frequency for 100% of ei measured optical rotation at the same frequency enables us to determine the ei sample. The definition of ei is the main application of discrete frequencies, the optical rotation in the region of the transmission spectrum. In principle it is also possible to determine the AC predominant enantiomer, if it is unknown. However, the definition speakers from optionschoose requires algorithm, easily predict optical rotation of molecules of unknown speakers, and proposed several methodologies for predicting discrete frequency, the optical rotation in the region of the transmission spectrum (E.L. Eliel, S.H. Wilen, Stereochemistry of organic compounds, New York, John Wiley & Sons, 1994, Chapter 13).

More recently, developments in the field of density functional theory ab initio (DFT) has radically improved the accuracy of calculation of the optical rotation. In the first time it became possible easy getting the ACE of optical rotation.

To establish ab initio OR use the Dalton Quantum Chemistry.

Other embodiments of the present invention are the compounds of formula (IB)', (IC)', (ID),' (IF)', which respectively correspond to stereochemical isomers of compounds of formula (IB), (IC), (ID) and (IF)as defined above, enriched in configuration (1S,5R).

The compounds of formula (IE)' correspond to stereochemical isomers of compounds of formula (IE)as defined above, enriched in configuration (1R,5R) or (1S,5R) depending on the availability of the 2-pyridine series.

One embodiment relates to enriched in configuration (1S,5R) the stereochemical isomer of the formula (IB)or salts thereof, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IB)' in one embodiment R3is the battle methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule.

Examples R4include optionally substituted phenyl (e.g. phenyl, 4-triptoreline, 3,4-differenl), optionally substituted bicyclic group, such as chinoline (for example, 2-methylinosine, 8-fluoro-2-methylpyridyl), optionally substituted pyranyl (for example, 4-tetrahydro-2H-pyranyl), optionally substituted pyridinyl (for example, 3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl, 2-methyl-6-trifluoromethyl-3-pyridinyl), optionally substituted pyrazolyl (for example, 5-chloro-1-methyl-1H-pyrazole-4-yl, 1-methyl-3-trichromatic-1H-pyrazole-4-yl, 1,5-dimethyl-1H-pyrazole-4-yl), optionally substituted pyrimidyl (for example, 5-pyrimidinyl), optionally substituted pyridazinyl (for example, 4-pyridazinyl), optionally substituted pyrazinyl (for example, 5-methyl-2-pyrazinyl), not necessarily Sames the config furanyl (for example, 3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), optionally substituted thienyl (for example, 5-chloro-2-thienyl), optionally substituted oxazolyl (for example, 4-methyl-1,3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), optionally substituted isoxazolyl (for example, 3-methyl-5-isoxazolyl), optionally substituted thiazolyl (for example, 2,4-dimethyl-1,3-thiazol-5-yl), optionally substituted triazolyl (for example, 1-methyl-1H-1,2,3-triazole-4-yl).

Another embodiment relates to enriched in configuration (1S,5R) the stereochemical isomer of the formula (IC)' or its salts, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IC)' in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule. Examples R4are the groups given above for the compounds (IB)'.

Another embodiment relates to enriched in configuration (1S,5R) the stereochemical isomer of the formula (ID)or its salt, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (ID)' in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule. Examples R4are the groups given above for the compounds (IB)'.

Another embodiment relates to enriched in configuration (1S,5R) or configuration (1R,5R) the stereochemical isomer of the formula (IE)or its salt, where G is a 2-pyridyl or 3-pyridyl, and R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IE)' in one embodiment of G corresponds to a 2-pyridyl (compound (IE)1'), and in another embodiment G is equal to the 3-what iridiu (compound (IE) 2'as shown below

Therefore, the configuration varies depending on the type of the pyridine cycle, as described above.

In formulas (IE)', (IE)1') and (IE)2' in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule. Examples R4are the groups given above for the compounds (IB)'.

Another embodiment relates to enriched in configuration (1S,5R) the stereochemical isomer of the formula (IF)or its salts, where R1, p, R3and R4have the meanings specified for formula (I)

In the formula (IF)' in one embodiment R3represents methyl. R4can be a phenyl, heterocyclyl, 5 - or 6-membered heteroaromatic group or a 9-11-membered bicyclic group, any of which is not necessary for escena 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxy, oxo, cyano, nitro, C1-4-alkyl, fluorine-C1-4-alkyl, C1-4-alkoxy, fluorine-C1-4-alkoxy, C1-4alkanoyl; and when R1represents chlorine and R is equal to 1, then R1not present in position relative to the links with the rest of the molecule. Examples R4are the groups given above for the compounds (IB)'.

Some compounds of the invention can form acid additive salts with one or more equivalents of acid. The present invention includes in its scope all possible stoichiometric and non-stoichiometric forms.

Pharmaceutically acceptable salts can be obtained from other salts, including other pharmaceutically acceptable salts of compounds of formula (I) using conventional methods.

Specialists in the field of organic chemistry will be clear that many organic compounds can form complexes with solvents in which they enter into the reaction or from which they precipitate or crystallize. Such complexes are known as "solvate". For example, a complex of water known as "hydrate". The solvate of the compounds of the invention are included in the scope of the invention. The compounds of formula (I) can be easily removed in combination with the solvent molecules Krista is essential or evaporation of an appropriate solvent and to obtain a corresponding solvate.

In addition, in the context of the present invention also includes prodrugs. Used in this description, the term "prodrug" denotes a compound that is converted in the body, for example, by hydrolysis in blood, in its active form that has medical effects. Pharmaceutically acceptable prodrugs described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and in the work of D. Fleisher, S. and H. Ramon Barba, "Improved oral drug delivary: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996), 19(2), 115-130, included in this description as a reference.

Prodrugs are covalently-linked carriers which release the compound of structure (I) in vivo when such prodrug is administered to a patient. Prodrugs, as a rule, receive a modification of the functional groups in such a way that the modifications are cleaved, or by manipulation or in vivo with the formation of the original connection. Prodrugs include, for example, the compounds of this invention, in which the hydroxy, amine or sulfhydryl groups are associated with any group in such a way that when administered to a patient there is a decomposition with formation of hydroxy, amine or sulfhydryl groups. Thus, typical examples of prodrugs include, but are not limited to purecycle the figures) acetates, the formate and benzoate formed on alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). In addition, in the case of carboxylic acid (-COOH) can be used ethers such as methyl esters, ethyl esters and other Esters can be active themselves and/or capable of hydrolysis in vivo in humans. Suitable pharmaceutically acceptable capable of hydrolysis in vivo ester groups include groups that are easily broken down in the human body with the formation of the original acid or a salt thereof.

In addition, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the scope of the present invention.

Specialists in the art it will be clear that when the connection of the invention or the MES may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Suitable protective groups for use in accordance with the present invention are well known to experts in the field of organic synthesis and can be used in the usual way. See, for example, "Protective groups in organic synthesis, by T.W. Greene and P.G.M. Wuts (John Wiley & Sons, 1991), or "Protecting Groups", P.J. Kocienski (Georg Thieme Verlag, 1994). Examples of suitable aminosidine groups include C the protective group of the acyl type (for example, formyl, TRIFLUOROACETYL, acetyl), aromatic protective group of the urethane type (for example, benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic protective group of the urethane type (for example, 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Vos), isopropoxycarbonyl, cyclohexyloxycarbonyl) and protective alkyl group type (for example, benzyl, trityl, chlorotrityl). Examples of suitable kislorodozaschitny groups may include, for example, alkylsilane groups, such as trimethylsilyl or tert-butyldimethylsilyl; simple alkylamine groups, such as tetrahydropyranyl or tert-butyl; or ester groups, such as acetate group.

When you want a specific enantiomer of the compounds of General formula (I)can be obtained, for example, by splitting the corresponding enantiomeric mixture of the compounds of formula (I) using conventional methods. Thus, the desired enantiomer can be obtained from racemic compounds of formula (I) by using procedures chiral HPLC.

The invention also includes compounds labeled with radioisotopes, are identical to the compounds denoted by the formula (I) and other formulas, but which in fact one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or atomic number, usually meeting with the, for example by transferring them in nature. Examples of isotopes that can be introduced into compounds of the invention and their pharmaceutically acceptable salts, are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as2H,3H,11C,13C,14C,15N17O,18O,31P,32P,35S18F,35Cl123I and125I.

Compounds of the present invention and pharmaceutically acceptable salts of such compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are included in the scope of the present invention. Radiolabelled compounds of the present invention, for example, compounds which are introduced such radioisotopes as3H,14C applicable in the analysis of distribution of a drug and/or substrate tissue. Tretirovanie isotope, i.e3H, and the isotope carbon-14, i.e14C, is particularly preferred for the ease of their production and detection. Isotopes11C and18F is particularly applicable when the PET (positron emission tomography), and isotopes125I especially applicable when SPECT (emission computed tomography single photon), applicable at the image acquisition brain. In addition, the substitution of heavier isotopes such as deuterium, i.e2N, may provide certain medical benefits, which is what I result in greater resistance to metabolism, for example, increased half-life in vivo or need a lower dose, and therefore may be preferred in some circumstances. Radiolabelled compounds of formula I and other formulas of this invention can be obtained, as a rule, in the procedure disclosed in the schemes and/or in the examples below, by substituting reagent, its radioisotopes, easily available reagent labeled with radioisotopes.

Some of the groups/substituents included in the present invention can be present in the form of isomers. The present invention includes in its scope all such isomers, including racemates, enantiomers, tautomers and their mixtures. Some substituted heteroaromatic groups included in compounds of formula (I)may exist in one or more tautomeric forms. The present invention includes in its scope all such tautomeric forms, including mixtures.

One embodiment of the present invention refers to compounds with a molecular weight of 800 or less. Another embodiment relates to compounds with a molecular weight of 600 or less. Generally, and without limitation, such compounds may have a higher oral availability and sometimes higher solubility and/or penetration into the brain. Molecular mass in d is nom case denote the mass resolutionvideo compounds in free base form, and excluded molecular weight, which contribute salt adhering, solvent molecules (e.g. water), molecular part of prodrugs, otsepleniya in vivo, etc.

As a rule, the compounds or salts according to the invention should be interpreted in such a way that one of them excluded these connections (if any), which are chemically unstable or themselves or in water, and which are clearly not suitable for pharmaceutical applications in all ways of administration is oral, parenteral or any other. Such compounds are well-known specialists in the field of chemistry. However, activated prodrugs or joints ex vivo, which can turn into the body of a mammal (e.g. human) in the compounds of the invention.

Examples of compounds of the present invention are

- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;

- 5-[5-({3-[(1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine,enantiomer 1;

- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;

- 5-[5-({3-[(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine,enantiomer 2;

- 2-methyl-5-[4-methyl-5-({3-[(1R,5S/1S,5R)-1-Fe the Il-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4H-1,2,4-triazole-3-yl]quinoline;

- 2-methyl-5-[4-methyl-5-({3-[(1S,5R)-1-phenyl-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4H-1,2,4-triazole-3-yl]quinoline,enantiomer 2;

- 5-[5-({3-[(1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;

- 5-[5-({3-[(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine,enantiomer 1;

- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;

- 5-[5-({3-[(1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine,enantiomer 2;

- 4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile;

- 4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenol;

- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(3,4-dichlor the Nile)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(3,4-dichlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 2;

- (1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 2;

- (1R,5S/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- 1-[5-[(1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-[5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-N-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]alanon, enantiomer 1;

- (1S,5R/1R,5S)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1S,5R/1R,5S)-1-(4-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1S,5R/1R,5S)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1S,5R/1R,5S)-1-(3-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(3-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4 is -1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-[3-{[4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- 5-[5-({3-[(1S,5R/1R,5S)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;

- 5-[5-({3-[(1S,5R/1R,5S)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine,enantiomer 1;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane,enantiomer 1;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane,enantiomer 2;

- (1R,5S/1S,5R)-1-(3-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thiopropyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,diastereoisomer 1;

- (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane,diastereoisomer 2;

- (1R,5S/1S,5R)-1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane,enantiomer 2;

- 1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone;

- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-sabillo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- 2-methyl-6-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline;

- 8-fluoro-2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline;

- 2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline;

- (1S,5R)-1-[2-ft is R-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- 1-{4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}-2-pyrrolidinone;

- 5-{5-[(3-{(1R,5S/1S,5R)-1-[4-(1,1-dioxido-2-isothiazolinone)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine;

- (1R,5S/1S,5R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- 1-(2-(metiloksi)-5-{(1R,5S/1S,5R)-3-(3-{[4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;

- 1-[5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(3-PIR is dinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-[5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-(2-hydroxy-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;

- 1-{5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}Etalon;

- 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-[5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone;

- 1-[5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone,enantiomer 1;

- 2-methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- 2-methyl-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole,enantiomer 1 ;

- 2-methyl-6-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- 1-methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1H-indazol;

- 1-methyl-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1H-indazol,enantiomer 1;

- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-1-methyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-1,2,3-triazole-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]exan;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-5-isoxazolyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-pyrazole-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-3-(trifluoromethyl)-1,3-oxazol-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,5-dimethyl-3-furanyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-2-thienyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-ethyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-6-(trifluoromethyl)-3-pyridinyl]-4H1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-c]pyrazole;

- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane,enantiomer 2;

- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-3-{3-{[4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R/1R,5S)-2-methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- (1S,5R/1R,5S)-2-methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- (1S,5R/1R,5S)-2-methyl-5-[3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-3-azabicyclo[3.1.0]Gex-1-yl)-1,3-benzothiazole;

- (1S,5R/1R,5S)-5-[3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole;

- (1S,5R/1R,5S)-2-methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}-1,3-benzothiazole;

- (1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane,enantiomer 1;

- (1R,5S/1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane,enantiomer 2;

- (1R,5S/1S,5R)-1-[4-(metiloksi)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[4-(4-chloro-2-fluoro who enyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-(3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-(2-chloro-4-were)-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[3-chloro-4-(metiloksi)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1R,5S/1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

and their pharmaceutically acceptable salts.

Examples of compounds of the present invention are the following compounds, which can be the teaching methods of the present invention:

- 4-[(1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile;

- 4-[(1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenol;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-tert-butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(3-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- 1-[4-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-[4-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone;

- (1S,5R)--(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- 1-{4-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}-2-pyrrolidinone;

- 5-{5-[(3-{(1S,5R)-1-[4-(1,1-dioxido-2-isothiazolinone)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine;

- 1-(2-(metiloksi)-5-{(1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;

- 1-[5-[(1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-{2-(metiloksi)-5-[(1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-[5-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;

- 1-{2-(metiloksi)-5-[(1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-(2-hydroxy-5-{(1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;

- 1-{5-[(1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}Etalon;

- 1-{2-hydroxy-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 1-{2-hydroxy-5-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-and the]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;

- 2-methyl-6-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-1-methyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-1,2,3-triazole-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-5-isoxazolyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-three is evil-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-pyrazole-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,5-dimethyl-3-furanyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-2-thienyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-ethyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-6-(trifluoromethyl)-3-pyridinyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;

- 5-[5-({3-[(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-c]pyrazole;

- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-IU the Il-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-2-methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- (1S,5R)-2-methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- (1S,5R)-2-methyl-5-(3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;

- (1S,5R)-5-[3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole;

- (1S,5R/1R,5S)-2-methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-yl}-1,3-benzothiazole;

- (1S,5R)-1-[4-(4-chloro-2-forfinal]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-(2-chloro-4-were)-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[3-chloro-4-(metiloksi)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;

- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane and

their pharmaceutically acceptable salts.

The crust is ASEE the invention also relates to a method for obtaining compounds of formula (I) or its salt, the definition of which is given above.

The method of the present invention obtain the compounds of formula (I)in which G represents a phenyl derivative, includes stage

(a) interaction of the compounds of formula (II)

where R1and R have the meanings specified for formula (I)with the compound of the formula (III)

where R2, R3and R4have the meanings specified for formula (I), and X represents a leaving group,

or

(b) in the case of the compounds of formula (I), where p is 1 or 2, the interaction of the compounds of formula (IV)

where R1, R2, R3and R4have the meanings specified for formula (I), R is 0 or 1, and Y represents a halogen, performancecountercategory (for example, tripterocalyx), or Y is a group M selected from a derivative of boron (for example, with the function Bronevoy acid B(OH)2) or metal-containing compounds, such as trialkylamine (for example, SnBu3), zinc halide or magnesium halide, with a compound R1-Y1, where Y1 represents halogen, Y represents a group of M; or when Y is a halogen or performancecountercategory, Y1 is a group M, with values above or bodoro is, that can be activated with a suitable base (for example, Cs2CO3in the presence of a suitable transition metal (e.g., Pd); "leaving group" is a group that mean experts in the field of chemistry, i.e. a group which can be substituted by nucleophilic group, for example, reaction type SN2, SN1 or SNAr;

and further, in the case of method (a) and method (b), optional

(i) removing any(s) protective(s) of the group; and/or

(ii) obtaining salt; and/or

(iii) the conversion of compounds of formula (I) or salts thereof to another compound of formula (I) or its salt.

Method (a) can be performed using conventional methods of obtaining a tertiary amine. Leaving group X can be a halogen, such as chlorine. On the other hand, X can be sulfonyloxy, such as1-4-alkylsulfonate (for example, methanesulfonate) or halogen-C1-4-alkylsulfonate (for example, tripterocalyx); or arylsulfonate, where aryl represents optionally substituted phenyl, optionally substituted 5 - or 6-membered heteroaromatic group or an optionally substituted bicyclic group, such as optionally substituted phenyl, where in each case the optional substituents are one or more1- -alkyl groups, for example, a pair-toluensulfonate. When X represents halogen, the interaction can be performed using a base such as potassium carbonate, in the presence of a source of iodide ion, such as sodium iodide, in a solvent such as N,N-dimethylformamide, at a suitable temperature, for example at 60°C.

The compounds of formula (II) can be obtained by methods well known in the art (see, for example, J. Med. Chem., 1981, 24, 481-490). Typical conditions see below in the present description in preparative examples 1-6 and 15-18. Vzaimoprevrascheny groups R1can be performed according to methodologies well known in the art (for example, demethylation metoxygroup with the formation of the hydroxy-group using as a reagent suitable Lewis acid, such as tribromide boron, in an inert solvent, such as dichloromethane). The following preparative examples 7-11 are additional examples of such interconversions in the presence of a suitable protective group for a secondary amine such as N-TRIFLUOROACETYL.

The interaction of the compounds of formula (IV) with R1-Y1 according to the method (b) can be performed in the presence of a transition metal, for example, palladium catalyst, such as dichloride bis-triphenylphosphine, tetranitropentaerithrite(0) or the complex formed in situ from t is IP(dibenzylideneacetone)diplegia(0) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. When M is a group with the function Bronevoy acid such as B(OH)2the interaction can be performed in an alkaline medium, for example, using an aqueous solution of sodium carbonate, in a suitable solvent, such as dioxane. When M is trialkylsilyl, the interaction can be performed in an inert solvent, such as xylene or dioxane, optionally in the presence of LiCl. When M is a zinc halide or magnesium, the interaction can be performed in an aprotic solvent such as tetrahydrofuran. When M represents hydrogen, which can be activated with a suitable base (for example, Cs2CO3in the presence of a suitable transition metal (such as Pd), the interaction can be performed in an inert solvent, such as dioxane, in the presence of a suitable base, such as Cs2CO3. Deputy Y may be a halogen, such as bromine, or sulfonyloxy, such as tripterocalyx; and Y1 may represent a group M, such as hydrogen, which can be activated with a suitable base (for example, Cs2CO3in the presence of a suitable transition metal (such as Pd).

In one aspect the present invention relates to a method of synthesis for the preparation of compounds of formula (I). The method can generally be implemented to obtain the compounds of formula (IIa), in which the phenyl group is substituted on the pyridine applicable for producing compounds of formula (IE). This method includes the stage

where

stage (a') is the stage of the diazotization of aniline (VII) and subsequent interaction with maleimido with the formation of 3-arylmaleimides (VIII);

stage (b') is the stage of cyclopropylamine (VIII) with the formation of the bicyclic imide (IX);

stage (C') is the stage of recovery imide (IX) to form compounds of the formula (II).

Stage (a') can be done using the methods of implementation of the reaction of Meerwein (for example, in J. Am. Chem. Soc., 1955, 77, 2313, retrieves arylmaleimides using this approach). On the other hand, in many cases, this stage it is convenient to perform procedures, where a mixture of maleimide, the corresponding salts of copper(II), such as anhydrous CuCl2and a suitable organic nitrile, such as tert-butylnitrite, in a compatible solvent such as acetonitrile, slowly add a solution of the compounds of formula (VII). The following is the appropriate time for interaction and appropriate treatment. An example of such a method is preparative example 37.

Stage (b') is to post the hinnon adding a solution of purified compounds of the formula (VIII) or mixtures containing the compound of the formula (VIII)is dissolved in a suitable solvent, such as dimethylsulfoxide, sodium iodide trimethylsulfoxonium in a suitable solvent, such as dimethylsulfoxide, and bases, such as sodium hydride. The addition should provide adequate time for interaction and appropriate treatment. An example of such a method is preparative example 37.

Stage (C') can be carried out using a suitable reducing agent in a compatible solvent, such as borane in tetrahydrofuran or Red-Al® in toluene, at an appropriate temperature, for example, at 65°C in the case of borane as the reducing agent. This is followed by appropriate treatment. An example of such a method is preparative example 38.

In another aspect, the present invention relates to another method of synthesis for the preparation of compounds of formula (II) or, generally, of the formula (XIII). This method includes the stage

where

R1, R and G have the meanings specified for formula (I), R14Q represents a suitable alkoxygroup, PG is a suitable protective group, and Y may be a halogen, such as bromine, or sulfonyloxy, such as tripterocalyx, and includes the following stages:

one hundred is, s (a"), which reaction mix (2,5-dihydro-1H-pyrrol-3-yl)boronate (X) with aromatic halogen or sulfonylacetanilide derivative (XI);

stage (b), which is the reaction cyclopropylamine (XII), followed, if necessary, removing the protective group with the formation of the bicyclic amine (XIII).

Stage (a) can be done using conventional methods, combinations for Suzuki, for example, using tetrakis(triphenylphosphine)palladium(0) as the source of catalytic palladium(0), in the presence of cesium fluoride in a suitable solvent, such as tetrahydrofuran, at a suitable temperature. Suitable (R14Q)2In can be a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, and PG can be a benzyl, introducing the compound of the formula (X)described in Synlett., 2002, 5, 829-831. An example of such a method is preparative example 50.

Stage (b) is the reaction of cyclopropylamine e.g. by using a reagent derived from iodide trimethylsulfoxonium and a suitable base such as sodium hydride, in a compatible solvent, such as dimethylsulfoxide. An example of such a method is preparative example 52. This is followed by a reaction of removing the protective group, such as in preparative example 54.

The connection of the formula (III), mo is but to get the interaction of the compounds of formula (V)

where R3and R4have the values listed in this description previously, with a compound of formula (VI)

L(CHR2)(CH2)2X (VI)

where X has the meanings indicated for formula (I), and L represents a leaving group, for example, bromine atom. Typical conditions of interaction, see described in this description of preparative example 13.

The compounds of formula (I), where R1, R2, R3, R4, G and R have the above values, can be obtained by the coupling of compounds of formula (XIV)

where R1, R2, G and R have the meanings indicated above for formula (I), and X represents a leaving group, with a compound of formula (V)

where R3and R4have the meanings specified in the description above. Typical conditions of interaction, when X represents a chlorine, see example 35 or, on the other hand, in examples 41 to 52.

The compound of formula (XIV), where R1, G and R have the meanings specified for formula (I), X represents a leaving group, and R2represents H (hydrogen), can be obtained by alkylation of compounds of formula (XIII) in the presence of a suitable base such as a tertiary amine, for example, diisopropylethylamine, with propylacetamide derived with two leaving groups is, preferably, the different reactivity, in positions 1 and 3, for example, 1-bromo-3-chloropropane. Typical conditions of interaction of this transformation is given in preparative example 40.

The compound of formula (XIV), where R1, G and R have the meanings specified for formula (I), X represents a leaving group, and R2represents a C1-4-alkyl, can be obtained by the interaction between beta-hydroxyketones, for example, 4-hydroxy-2-butanone, if R2represents methyl, and the compound of the formula (XIII) in the presence of a suitable source of borohydride, such as NaBH(OAc)3with the subsequent conversion of the hydroxyl group into a leaving group by methods known to experts in the art, for example, the influence of thionyl chloride. Typical conditions of interaction for such transformations are given in preparative examples 19 and 20.

The interconversion reaction between compounds of formula (I) and their salts can be accomplished using methods well-known to specialists in this field of technology. Examples are

(i) the conversion of one or more R1from alkoxy (e.g. methoxy), hydroxy,

(ii) the conversion of one or more R1of the hydroxy in sulfonyloxy, such as alkylsulfonate or halogenated.sulphonated, for example, meta is sulfonyloxy or tripterocalyx,

(iii) the conversion of one or more R1from halogen or perftorsilanami in cyano;

and subsequent optional obtaining salts of the compounds of formula (I).

Found that the compounds of formula (I) show affinity in relation to the dopamine receptors, in particular receptor D3and it is expected their applicability in the treatment of painful conditions that require modulation of such receptors, such as psychotic state.

This affinity is typically calculated from the IC50as the concentration of compound required to displace 50% of the radioactive ligand from the receptor, and lead in the form of values of Kicalculated using the following equation:

where L = radioligand and KD= the affinity of radioligand in respect of the receptor (Cheng and Prusoff, Biochem. Pharmacol., 22:3099, 1973).

In the context of the present invention, instead of using pKi Ki (corresponding to the antilogarithm Ki), and compounds of the present invention typically show pKi over 7. In one aspect the present invention relates to compounds of formula (I) pKi from 7 to 8. In another aspect, the present invention relates to compounds of formula (I) pKi from 8 to 9. In another aspect the present invention relates to compounds of formula (I) pKi over 9.

Also found that many compounds forms the crystals (I) have an affinity to dopamine receptors D 3greater than D2. I believe that therapeutic effect of currently available antipsychotic drugs (neuroleptics) is manifested through the blockade of receptors D2; however, it is also believed that this mechanism is responsible for undesirable extrapyramidal side effects (eps)associated with many neuroleptic drugs. It is assumed that the blockade was recently characterized the dopamine receptor D3may cause favorable antipsychotic activity without significant eps (see, for example, Sokoloff et al., Nature, 1990, 347:146-151; and Schwartz et al., Clinical Neuropharmacology, Vol.16, No.4, 295-314, 1993). One embodiment relates to compounds of the present invention with a higher (e.g., ≥10 or ≥100x higher affinity for dopamine receptors (D3than D2(this affinity can be measured using standard methodology, for example, using the cloned dopamine receptors - see in this description). These compounds can accordingly be used as selective modulators of the dopamine receptor D3.

From the localization of receptors D3you can also imagine that the compounds can also be used for the treatment of substance abuse, which, as expected, involved receptors D3(see, for example, Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples is the aka substance abuse are alcohol abuse, cocaine, heroin and nicotine. Other conditions that can be treated with these compounds include dyskinetic disorders such as Parkinson's disease, caused by neuroleptics parkinsonism, and late dyskinesia; depression; anxiety, deterioration of cognitive abilities, including memory disorders such as Alzheimer's disease, eating disorders, sexual dysfunction, sleep disorders, vomiting, disorders of movement, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, disorders of circadian rhythm disorders of motor function of the stomach, for example, IBS.

The compounds of formula (I) can be used to ensure all aspects of drug dependence, including withdrawal from abuse of drugs such as alcohol, cocaine, opiates, nicotine, benzodiazepines, and inhibition of tolerance caused by opioids. In addition, the compounds of formula (I) and their pharmaceutically acceptable salt and solvate can be used to mitigate the bias, and therefore they will be applicable in the treatment of addiction to medicines. Addiction to drugs can be defined as incentive motivation to self-appointed psychotic active substance that has been consumed previously. Three main facto is and participate in the development and maintenance of addiction to drugs: (1) frustration due to the cancellation of the medicinal product may act as a negative power, leading to addiction; (2) the environmental stimuli associated with drug effects may become gradually stronger (sensitization) when dealing with desire and passion and (3) knowledge (memory) on the ability of drugs to enhance a pleasant effect and to facilitate the depressed state at the time of cancellation. Addiction may be responsible for the difficulties faced by individuals during withdrawal from abuse of drugs, and therefore makes a significant contribution to the development and maintenance of drug dependence.

The compounds of formula (I) have potential use as antipsychotic drugs, for example, in the treatment of schizophrenia, schizoaffective disorder, psychotic depression, mania, paranoid and delusional disorders. In addition, they can be used as an additional therapeutic measures in Parkinson's disease, in particular, with such compounds as L-DOPA, and possibly dopaminergic agonists, to reduce the side effects experienced when using this kind of treatment for a long period of time (for example, see Schwartz et al., Brain Res. Reviews, 1998, 26, 236-242).

In the context of the present invention the terms that describe the indications used in this description, are classified by the Diagnostic and Statistical Manual of Mental Disorders, 4 thEdition published by the American Psychiatric Association (DSM-IV), and/or International Classification of Diseases, 10thEdition (ICD-10). Different subtypes of the disorders listed herein, are considered part of the present invention. The number in parentheses after the following diseases are related to classification indexes in the DSM-IV.

In the context of the present invention, the term "psychotic disorder" includes

schizophrenia including the subtypes paranoid type (295.30), disorganizational type (295.10), catatonic type (295.20), unspecified type (295.90) and residual type (195.60); disorder schizophrenic form (295.40); schizoaffective disorder (295.70)including the subtypes bipolar type and depressive type; delusion disorder (297.1)including the subtypes type of erotomania, the type of greatness that type of jealousy, the type of persecution, somatic type, mixed type and unspecified type; brief psychotic disorder (298.8); shared (shared) psychotic disorder (297.3); psychotic disorder due to General health, including the subtypes with bredli and with hallucinations; caused by substances psychotic disorder including the subtypes with bredli (293.81) and with hallucinations (293.82); and psychotic disorder without other definition (298.9).

In the context of the present invention, the term "disorder associated the second substance" includes

associated with substance disorders, including disorders due to the use of substances, such as dependence on the substance, the addiction to the substance, and substance abuse; caused by substances disorders, such as intoxication, cancellation substances caused by substance delirium caused by substance persistent dementia caused by substance persistent amnestic disorder-induced psychotic disorder substance-induced substance mood disorder induced substance, anxiety disorder induced substance sexual dysfunction caused by substance a sleep disorder and hallucinogene persistent disorder of perception"freeze frames"); alcohol-related disorders such as alcohol dependence (303.90), alcohol abuse (305.00), alcohol intoxication (303.00), the abolition of alcohol (291.81), alcohol intoxication delirium, delirium abolition of alcohol, alcohol-induced persistent dementia, alcohol-induced persistent amnestic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and is associated with alcohol disorder without other definition (291.9); disorders associated with what amfetamina (or similar to amphetamine substances), such as amphetamine dependence (304.40), methamphetamine abuse (305.70), amphetamine intoxication (292.89), the abolition of amphetamine (292.0), delirium amphetamine intoxication caused by amphetamine psychotic disorder caused by amphetamine mood disorder caused by amphetamine anxiety disorder caused by amphetamine sexual dysfunction caused by amphetamine sleep disorder and is associated with amphetamine disorder without other definition (292.9); disorders associated with caffeine, such as caffeine intoxication (305.90), caused by caffeine anxiety disorder, caused by caffeine sleep disorder and associated with caffeine disorder without other definitions (292.9); disorders associated with hemp, such as the dependence on cannabis (304.30), the abuse of cannabis (305.20), delirium cannabis intoxication caused hemp psychotic disorder caused by cannabis anxiety disorder and is associated with hemp disorder without other definition (292.9); disorders associated with cocaine, such as cocaine dependence (304.20), cocaine abuse (305.60), cocaine intoxication (292.89), the syndrome of cocaine (292.0), delirium due to cocaine intoxication, cocaine related psychotic disorder caused by cocaine mood disturbance caused by cocaine anxiety disorder, cocaine related sexual dysfunction caused by cocaine sleep disorder and is associated with a cocaine disorder without other definition (292.9); related disorders hallucinogen, such as hallucinogenia dependence (304.50), abuse hallucinogen (305.30), hallucinogenia intoxication (292.89), a persistent disorder of perception because of hallucinogen ("snapshots") (292.89), delirium due to hallucinogenic intoxication-induced psychotic disorder hallucinogen-induced hallucinogen mood disturbance caused by hallucinogen anxiety disorder and is associated with hallucinogen disorder without other definition (292.9); disorders associated with aspirator, such as dependence on aspirate (304.60), abuse aspirator (305.90), aspirata intoxication (292.89), delirium due to aspirate intoxication caused by aspirator persistent dementia caused by aspirator psychotic disorder caused by aspirator mood disturbance caused by aspirator anxiety disorder and is associated with aspirator disorder without other definition (292.9); disorders associated with nicotine, such as nicotine dependence (305.1), symptoms of nicotine withdrawal (292.0) and associated with nicotine disorder without other definition (292.9); disorders associated with opioid is mi, such as opioid dependence (304.00), abuse of opioids (305.50), opioid intoxication (292.89), the syndrome of opioid (292.0), delirium due to opioid toxicity caused by opioid psychotic disorder caused by opioid disorders of mood-induced sexual dysfunction opioid-induced opioid disorder of sleep and associated with opioid use disorder without other definition (292.9); disorders associated with phencyclidine (or Felicidade), such as felicianova dependence (304.60), abuse feliciana (305.90), felicianova intoxication (292.89), the delirium of for fencelineecology intoxication caused by Feliciano psychotic disorder caused by Feliciano mood disturbance caused by Feliciano anxiety disorder and is associated with felicities disorder without other definition (292.9); disorders associated with sedatives, hypnotics or sedatives such as dependence sedative, hypnotic or sedative (304.10), abuse sedative, hypnotic or sedative (305.40), intoxication sedative, hypnotic or sedative (292.89), withdrawal sedative, hypnotic or sedative (292.0), delirium due to the hypnotic or sedative medium spans the VA, called sedative, hypnotic or sedative persistent dementia caused sedative, hypnotic or sedative persistent amnestic disorder caused sedative, hypnotic or sedative psychotic disorder, caused by the sedative, tranquilliser or sedative mood disturbance caused by the sedative, tranquilliser or sedative anxiety disorder caused sedative, hypnotic or sedative sexual dysfunction caused sedative, hypnotic or sedative sleep disorder and is associated with sedative, hypnotic or sedative disorder without other definition (292.9); disorders associated with several substances, such as dependence on several substances (304.80); and other (or unknown) disorders associated with substances such as anabolic steroids, nitrate aspirates and dinitrogen oxide.

Therefore, in another aspect, the present invention relates to a method of treating a condition for which a favorable modulation (in particular, antagonism/inhibition) dopamine receptors (especially receptors D3), including the introduction of a mammal (e.g. human)in need, an effective amount of a compound of formu the uly (I) or its pharmaceutically (i.e. the physiologically) acceptable salts. Such conditions include, in particular, psychosis/psychotic conditions such as schizophrenia, and substance abuse.

The invention also relates to the use of compounds of formula (I) or its pharmaceutically acceptable salt for a medicinal product for the treatment of a condition in a mammal, for which a favorable modulation (in particular, antagonism/inhibition) dopamine receptors (especially receptors D3).

The invention also relates to the compound of formula (I) or its pharmaceutically acceptable salt for use for the treatment of a condition in a mammal, for which a favorable modulation (in particular, antagonism/inhibition) dopamine receptors (especially receptors D3).

The invention also relates to the compound of formula (I) or its pharmaceutically acceptable salt, used to treat conditions in mlekopitayushchie, in which the modulation ( in particular, antagonism/inhibition) dopamine receptor is favorable.

In one embodiment of the antagonists of D3according to the invention are used to treat psychoses such as schizophrenia, or substance abuse treatment.

Thus, in another aspect the present invention relates to a method of treating a psychotic condition (for example, sizofrenik is) or substance abuse, includes introduction to the mammal (e.g. human)in need, an effective amount of the compounds of formula (I)as defined in the present description, or its pharmaceutically acceptable salt.

The invention also relates to the use of compounds of formula (I) or its pharmaceutically acceptable salt for a medicinal product for the treatment of psychotic States (for example, schizophrenia or substance abuse in a mammal.

The invention also relates to the compound of formula (I) or its pharmaceutically acceptable salt for use for the treatment of psychotic States (for example, schizophrenia or substance abuse in a mammal.

The invention also relates to the compound of formula (I) or its pharmaceutically acceptable salt for use as an active therapeutic agents for the treatment of a mammal, for example, for use in treating any of the conditions described in this description.

"Treatment" includes preventing, when it is relevant(nd) condition(s).

In the case of application in medicine, the compounds of the present invention, as a rule, impose a standard pharmaceutical composition. Therefore, the present invention relates in another aspect to a pharmaceutical composition containing the compound of formula (I) or agopermalink (i.e. physiologically acceptable salt and pharmaceutically (i.e. physiologically) acceptable carrier. The pharmaceutical composition may be a composition for use in the treatment of any of the States described in this specification.

The compounds of formula (I) can be entered in any suitable way, for example, by the method of oral, parenteral (e.g. intravenous), transbukkalno, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptable salts which are active when administered orally, can be entered into the composition of the liquid or solid compositions, for example syrups, suspensions or emulsions, tablets, capsules and patches.

Liquid preparation, as a rule, will constitute a suspension or solution of the compound or its pharmaceutically acceptable salt in a suitable () liquid () carrier(s), for example, in an aqueous solvent such as water, ethanol or glycerine, or nonaqueous solvent, such as glycol or oil. The preparation may also contain suspendisse substance, preservative, corrigent or dye.

Composition in the form of tablets can be obtained using any(s) pharmaceutical(s) carrier(s), usually used(s) to obtain terdigitata. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

Composition in the form of a capsule can be obtained using conventional procedures encapsulate. For example, using standard media you can obtain granules containing the active ingredient, and then filled hard gelatin capsule; on the other hand, it is possible to obtain a dispersion or suspension with the use of any(s) normal(s) pharmaceutical(s) carrier(s), for example, water-soluble gums, cellulose, silicates or oils and then fill in the dispersion or suspension soft gelatin capsule.

Typical parenteral composition is a solution or suspension of the compound or its pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. On the other hand, the solution can be lyophilisate and then restore suitable solvent just before the introduction.

Compositions for nasal injection can be conveniently obtained in the form of aerosols, drops, gels and powders. Aerosol preparations typically contain a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or nonaqueous rastvoritelei, as a rule, present in an amount of one or more doses in a sterile form in a sealed container, which can take the form of a cartridge or replaceable cartridge for use with the spray device. On the other hand, a tightly closed container may be a unitary dispenser, such as a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve designed for removal of tank contents in a single use. When the dosage form contains an aerosol dispenser, it will contain the propellant, which may be a compressed gas such as compressed air, or an organic propellant such as perchloromethyl hydrocarbon. Aerosol dosage forms can also take the form of a pump spray.

Compositions suitable for transbukkalno and sublingual administration, include tablets, pellets and tablets, where the active ingredient forms a composition with a carrier, such as sugar and Arabian gum, tragakant or gelatin and glycerin.

Compositions for rectal injection usually in the form of suppositories containing the usual basis for suppositories, such as cocoa butter.

Compositions suitable for transdermal administration, include ointments, gels and patches.

In one embodiment of the songs which I is a standard dosage form, such as a tablet, capsule or ampoule.

Each standard dosage form for oral administration includes, for example, from 1 to 250 mg (and for parenteral administration contains, for example, from 0.1 to 25 mg) of compounds of formula (I) or its pharmaceutically acceptable salt in relation to the free base.

Pharmaceutically acceptable compounds of the invention typically will be implemented under the scheme of daily intake of medicinal product (for an adult patient)of, for example, in oral doses from 1 mg to 500 mg, for example, from 10 mg to 400 mg, for example, from 10 mg to 250 mg, or an intravenous, subcutaneous or intramuscular dose of between 0.1 mg to 100 mg, for example, from 0.1 mg to 50 mg, for example, from 1 to 25 mg, of the compounds of formula (I) or its pharmaceutically acceptable salt in relation to the free base, moreover, the compound is administered 1-4 times per day. Appropriate introduction of compounds during long-term therapy, for example, in the course of a week or longer.

Methods of biological testing

Functionality and inherent activity of the compounds of this invention can be measured as described hereinafter scintillation approximate analysis of GTPγS (GTPγS-SPA). Cells used in the study are cells of the Chinese hamster ovary (Cho).

Cell line

CHO_D2

CHO_D3

The cell membrane receive the following clicks the zoom. Cellular precipitation resuspended in 10 volumes of 50 mm HEPES, 1 mm add, pH 7.4 using KOH. The next day in the buffer directly before receiving buffer for homogenization add the following proteases:

10-6M leupeptin (Sigma L2884) - 5000 x initial = 5 mg/ml in buffer;

25 µg/ml bactracin (Sigma W) - 1000 x initial = 25 mg/ml in buffer;

1 mm PMSF - 1000 x initial = 17 mg/ml in 100% ethanol;

2 × 10-6M pastina A - 1000 x initial = 2 mm in 100% DMSO.

Cells are homogenized inclusions 2 × 15 seconds in 1-l glass Glass Warning in the camera class biological hazards. The resulting suspension is centrifuged at 500 g for 20 min (Beckman centrifuge T21, 1550 rpm). The supernatant extract 25-ml pipette, dispense aliquots in pre-chilled centrifuge tubes and centrifuged at 48000 g for planting in the sediment cell membranes (Beckman T1270: 23000rpm for 30 min). Received at 48000 g sediment resuspended in the buffer for homogenization (4 of primary cell sediment). Received at 48000 g sediment resuspended circular spins for 5 seconds and homogenized in the homogenizer of downs 10-15 times. The drug is distributed in aliquots of the appropriate size (200-1000 ál) into polypropylene tubes and stored at -80°C. the protein Content in the membrane preparations appreciate the analysis of proteins by Bradford.

Konechnaya concentration of the drug in the analysis of 3 μm, and curve 11 points perform a serial dilution of 1:4 in 100% DMSO using a Biomek FX. The test drug in the amount of 1% of the total analytical mixture (TAV) add in a completely white 384-well analytical tablets. Add 50% TAV pre-associated (within 90 min at 4°C) membranes, 5 mg/ml, and agglutinin-polystyrene granules c wheat germ for scintillation approximate analysis (RPNQ0260, Amersham), 0.25 mg/well, 20 mm HEPES, pH 7.4, 100 mm NaCl, 10 mm MgCl2, 60 μg/ml saponin and 30 μm GDP. The third additive is a 20% TAV or buffer format (agonist) or final concentration in the analysis of the EU80agonist of quinelorane buffer for analysis (format antagonist). The analysis begins by adding 29% TAV GTPγ[35S] to a final concentration of 0.38 nm (37 MBq/ml, 1160 CI/mmol, Amersham). After all additions analytical tablets centrifuged for 1 min at 1000 rpm shall count on a Viewlux, filter 613/55 for 5 min in a period of 2-6 hours after the last addition.

Effect of test drugs on the basis of network size EU50using interactive selection curve using the least squares method presented in the table as RES50(i.e.-logEC50). The ratio between the maximum impact test l the drug money and the maximum effect of a full agonist of quinelorane gives the size of the actual activity (IA) (i.e. IA = 1 for full agonist, IA < 1 for partial agonist). The fpKi values of the test drug is calculated from the IC50obtained in the experiment format antagonist, using equations Chang and Prusoff (Prusoff) fKi = IC50/1+([A]/EC50), where [A] represents the concentration of the agonist 5-HT in the analysis, and the EU50represents the value of the EU505-HT, obtained in the same experiment. fpKi is defined as-logfKi.

Compounds of the invention listed above have pKi values in the range of 7.0 to 10.5 at the dopamine D3 receptor. Results for pKi evaluated only with an accuracy of about ±0.3 to 0.5.

Compounds of the invention listed above have a selectivity relative to D2, greater than 30.

Examples

Further, the invention is illustrated by examples, which are not restrictive. Preparative examples 1-5 are carried out by analogy with the synthesis method described in J. Med. Chem., 1981, 24, 481-490.

All temperatures are given in °C. Infrared spectra obtained by the instrument FT-IR. Compounds analyzed by direct injection of the sample, dissolved in acetonitrile, in the mass spectrometer, operating in the mode of ionization positive dispersion of electrons (ES+). Proton nuclear magnetic resonance spectrum (1H-NMR) recorded at 400 MHz, chemical shifts are given in ppm nicholases the field (d) from Me 4Si, used as internal standard, and lead as singlets (s), broadened singlets (Ushs), doublets (d), doublets of doublets (DD), triplets (t), quartets (K) or multiplets (m).

Experimental spectra of vibrational circular dichroism (VCD) is obtained using the spectrometer ChiralIRTM VCD, operating in the frequency range 2000-800 cm-1. Spectra receive at room temperature (23°C) using a sealed transparent cuvette with Windows of barium fluoride and a length of 100 microns (the scan time varies from 60 to 120 minutes on the isomer). Solutions of samples typically get by dissolving 10 mg of each enantiomer in 100 μl of deuterochloroform (CDCl3). For institutions ab initio calculated VCD spectra and unpolarized IR using the software package 1 Gaussian 98.

Optical rotation was measured using a polarimeter (Perkin Elmer model 241)operating at 589 nm (sodium source). The measurements were carried out using 1-decimeter microcell, thermostated at 23°C. Concentrations are typically 10 mg/ml (=0,01). For institutions OR ab initio using the Dalton Quantum Chemistry.

Column chromatography carried out on silica gel (Merck AG, Darmstaadt, Germany). In the text the following abbreviations are used: NBS = N-bromosuccinimide, varid = "Red-Al®", HOBt = 1-hydroxybenzotriazole,EtOAc = ethyl acetate, Et2O = diethyl ether, DMF = N,N'-dimethylformamide, Meon = methanol, TFA = triperoxonane acid, THF = tetrahydrofuran, IPA = isopropanol, tea = triethylamine, DCC = 1,3-dicyclohexylcarbodiimide, SCX = strong cation-exchanger, TLC refers to thin layer chromatography on plates of silica, and dried refers to a solution dried over anhydrous sodium sulfate, r.t. (RT) refers to room temperature, Rt = retention time, DMSO = dimethyl sulfoxide.

Preparative example 1. Methylprop(4-methoxyphenyl)acetate

To a mixture of methyl-4-methoxyphenylacetate (20 g, 0.11 mol) and NBS (0.11 mol) in CCl4(0.2 l) add 3 drops of 48% HBr and the resulting mixture is refluxed for 8 hours. The cooled solution is filtered through a layer of silica gel, the filtrate is evaporated in vacuum and obtain 29 g named in the title compounds as a pale yellow oil, which was used in the next stage without additional purification.

NMR (1H, CDCl3): δ of 7.3 (d, 2H), 6,8 (d, 2H), 5,1 (s, 1H), and 3.8 (s, 3H), 3,5 (s, 3H).

Preparative example 2. Dimethyl-1-(4-methoxyphenyl)-1,2-cyclopropanedicarboxylic

To the NaH suspension (4.4 g, 60% in mineral oil) in anhydrous Et2O (0.3 l) under stirring at 0°C for 30 min add methanol (10.3 ml), and then a solution of the floor is built in preparative example 1 prosteradlo ether methylprop(4-methoxyphenyl)acetate (29 g) in methyl acrylate (19,8 ml) (in the examples, where come from ethylvinylacetate derived, using ethanol and ethyl acetate, respectively) and methanol (3 ml). The mixture is stirred at 25°C for 24 h and then unreacted NaH decompose 3 ml of methanol. Add water (75 ml), the organic phase is separated, dried over Na2SO4and filtered. Volatile matter is evaporated in vacuum and get 31,5 g named in the title compound in the form of oils, which are used in the subsequent stage without further purification.

NMR (1H, CDCl3): δ of 7.3 (d, 2H), 6,8 (d, 2H), of 3.77 (s, 3H), of 3.73 (s, 3H), of 3.64 (s, 3H), 2,18 (DD, 1H), 2,05 (DD, 1H), 1,46 (DD, 1H). MS (m/z): 265,4 [MH]+.

Preparative example 3. 1-(4-Methoxyphenyl)-1,2-cyclopropanecarbonyl acid

A mixture of diapir obtained in preparative example 2 (31,5 g) and KOH (13.5 g) in a mixture of EtOH:H2O, 1:1 (240 ml), refluxed for 6 hours and then concentrated to half of its original volume. The aqueous solution is extracted with Et2O, cooled on ice and then acidified with 25 ml of 12 n HCl. The white crystalline reaction product is collected by filtration and dried in vacuum and obtain 12.8 g named the title compound (total yield calculated for methylprop(4-methoxyphenyl)acetate 50%).

NMR (1H, DMSO): δ 12,5 (Ushs, 2H), 7,25 (d, 2H), 6,85 (d, 2H), and 3.7 (s, 3H), 2,0 (DD, 1H), 1,85 (DD, 1H), 1,38 (DD, 1H). MS (m/z): 235,0 [M-H]-.

Preparative example 4. (1R,5S/1S,5R)-1-[4-(Methoxy)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione

A mixture of 12.8 g of decollate obtained in preparative example 3, and 6.5 g of urea in 300 ml of m-xylene is refluxed for 8 hours and then concentrated to dryness in vacuo. The crude substance is purified column chromatography (AcOEt:cyclohexane= 1(?):10 - 4:6) and get 5.5 g named the title compound (yield = 46%).

MS (m/z): 218,1 [MH]+.

Preparative example 5. (1R,5S/1S,5R)-1-[4-(Methoxy)phenyl]-3-azabicyclo[3.1.0]hexane

To a suspension of 5.5 g of imide obtained in preparative example 4, in 170 ml of toluene under stirring in nitrogen atmosphere gradually add 45 ml of Vitrea (3.4 M in toluene). The resulting solution was stirred at the boil under reflux for 2 hours. To the cooled solution was carefully added aqueous NaOH solution (10 M, 40 ml) and the organic layer was washed with two portions of water and dried over Na2SO4. The resulting solution is filtered, the filtrate evaporated in vacuum and obtain 4.8 g named the title compound (yield = 100%).

NMR (1H, CDCl3): δ 7,10 (d, 2H), PC 6.82 (d, 2H), of 3.77 (s, 3H), 3,35 are 2.98 (m, 4H), 2,58 (DD, 1H), 0,87 (DD, 1H), 0,78 (DD, 1H), NHnot watching. MS (m/z): 190,1 [MH]+.

Preparative example 6. (1R,5S/1S,5R)-1-(4-Bromophenyl)-3-azabicyclo[can

To 20 ml of 1 M solution NR3-tetrahydrofuran with stirring at 0°C in an atmosphere of nitrogen was slowly added a solution of 1.32 g (5 mmol) of (1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione, obtained by analogy with the preparative example 4 in 20 ml of dry tetrahydrofuran. The resulting solution was stirred at room temperature for 15 min and then warm on a steam bath for 1 hour. Then the solution is cooled in an ice bath, carefully add 2.5 ml of 6 M HCl, and the solvent is removed in vacuum. The remaining substance is combined with 12.5 ml of 5 M NaOH solution and the mixture extracted with ether. The ether extract is washed twice with water, dried over Na2SO4and filtered and obtain 1.19 g named the title compound (yield = 100%).

NMR (1H, CDCl3): δ to 7.35 (d, 2H), 7,02 (d, 2H), 3.25 to 2,96 (m, 4H), and 1.63 (DD, 1H), 1.55V (DD, 1H), 1,30 (DD, 1H), NHnot watching. MS (m/z): 238,1 [MH]+, 1Br.

Preparative example 7. (1R,5S/1S,5R)-4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile

To a solution of 4-[3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile (280 mg, obtained by the method similar to that described in preparative example 5) and triethylamine (0.25 ml) in dichloromethane (15 ml) at 0°C. add anhydride triperoxonane acid (0,21 ml). The reaction mixture is left to warm to room tempera is URS 2 hours then washed with a saturated solution of NaHCO3organic layer is dried and evaporated and get 269 mg specified in the connection header.

MS (m/z): 281,2 [MH]+.

Preparative example 8. (1R,5S/1S,5R)-4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]benzaldehyde

A mixture of 4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile (283 mg), Ni-Al alloy (450 mg), formic acid (3.9 ml) and water (1.1 ml) was stirred at 80°C for 3 hours. The reaction mixture is cooled to room temperature and filtered. The filtrate is extracted with ethyl acetate, the organic phase is washed with a solution of NaHCO3, dried over Na2SO4and evaporated in vacuum and obtain 195 mg named the title compound as a yellow oil.

MS (m/z): 284,2 [MH]+.

Preparative example 9. The oxime (1R,5S/1S,5R)-4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]benzaldehyde

To a solution of 4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]benzaldehyde (195 mg) in 5 ml of pyridine added hydroxylamine hydrochloride (57,5 mg) and the mixture is stirred for 3 hours at room temperature. The solvent is evaporated, the crude substance was dissolved in ethyl acetate, the organic phase is washed with 10% solution of Na2CO3and brine, dried over Na2SO4and evaporated in vacuum and get 225 mg's name is in the title compound as a yellow oil.

MS (m/z): 299,2 [MH]+.

Preparative example 10. (1R,5S/1S,5R)-4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]-N-hydroxybenzotriazole

To a solution of oxime of 4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]benzaldehyde (0.69 mmol) in 3.5 ml of dimethylformamide at 0°C was added parts of N-chlorosuccinimide (97 mg). After stirring for 1.5 h at 40°C. the solvent is evaporated. The crude reaction product is dissolved in a mixture of diethyl ether/dichloromethane (4/1), the organic phase is washed with water, dried over Na2SO4and concentrated in vacuo and obtain 243 mg named the title compound as a brown oil.

Preparative example 11. (1R,5S/1S,5R)-1-[4-(5-Methyl-3-isoxazolyl)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane

To a solution of 4-[3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]-N-hydroxybenzodioxaborole (0.69 mmol) in 6 ml of chloroform added triethylamine (0,24 ml) and 2-chloropropene (0,29 ml) and the reaction mixture stirred for 18 h at room temperature. The solution is washed with water, dried over Na2SO4and volatiles evaporated in vacuo. The crude substance is purified column chromatography (AcOEt:cyclohexane = 1:10 - 4:6) and receive 180 mg specified in the connection header.

MS (m/z): 337,2 [MH]+.

The drug is wny example 12. (1R,5S/1S,5R)-1-[4-(5-Methyl-3-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane

A mixture of 1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane (0.54 mmol) and K2CO3(296 mg) in methanol (5 ml) and water (5 ml) is stirred for 4 hours at 50°C. the Solvent is evaporated in vacuum and the reaction product is treated with a mixture of dichloromethane/isopropanol, 1/1 and filtered. The filtrate is dried over Na2SO4volatile matter is evaporated in vacuum and get 105 mg named the title compound (yield = 81%).

MS (m/z): 241,2 [MH]+.

Preparative example 13. 5-{5-[(3-Chloropropyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine

To 4-methyl-5-(2-methyl-5-chinoline)-2,4-dihydro-3H-1,2,4-triazole-3-tion (3.6 g, obtained by the method similar to that described in WO 200240471) in ethanol (60 ml)containing 1-bromo-3-chloropropane (2.0 ml)is cautiously added with stirring sodium hydride (0,60 g, 60% in vaseline). The mixture is refluxed for 45 minutes Volatiles evaporated in vacuo and the residue is subjected to column chromatography (gradient EtOAc-acetone). Thus obtained substance are planted from hot EtOAc (20 ml), adding petroleum ether (40-60, 50 ml), cooled and collected by filtration, and get named in the title compound as a colourless kristallicheskoj the substance (2.1 g).

NMR (1H, CDCl3): δ 8,18 (d, 1H), 8,12 (d, 1H), 7,76 (t, 1H), 7,55 (d, 1H), 7,30 (d, 1H, in), 3.75 (t, 2H), 3,50 (t, 2H), 3,40 (s, 3H), was 2.76 (s, 3H), is 2.37 (m, 2H).

Preparative example 14. 3-[(3-Chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole

Ethyl-2-chloroacetoacetate (1 parts by weight; 1 EQ., 1000 g) is treated with formamide (0,68 ABC; approx. 2.8 EQ.) and the resulting warm solution at 120°C. After 5 hours the mixture is cooled to room temperature and kept in a nitrogen atmosphere over night. The mixture is treated with NaOH (3 M, 6 ABC, the reaction is moderately exothermic) and stirred at room temperature for 4 hours. Add ethyl acetate 6 OBC) and the phases are separated. The organic layer is discarded, while the aqueous layer was acidified with conc. (32%) hydrochloric acid to pH 2 (approx. 2,0 OBC). Starts accumulating sediment. The suspension is treated with AcOEt (8 OBC) and vigorously stirred until then, until all the precipitate has dissolved. The aqueous phase is twice extracted with AcOEt (each time for about 6.) and the combined organic layers are subjected to distillation to a small volume (in small volume again see suspension). Add a fresh portion of AcOEt (8 OBC) and the mixture evaporated to dryness. Collected solid is placed in an oven at 40°C. overnight under reduced pressure and get 4-methyl-1,3-oxazol-5-carboxylic acid (498 g, 64.5 per cent).

The resulting substance (498 g, 1 MASC.) dissolved in dry tetrahydrofuran (5 OBC) in nitrogen atmosphere while cooling to 0°C. Add portions DCC (1,62 parts by weight, 1 EQ.), and then HOBt (1,07 parts by weight, 1 EQ.). The mixture is heated to 25±2°C and stirred for 30 minutes Then add 4-methyl-3-thiosemicarbazide (0,83 parts by weight, 1 EQ.) and the mixture is stirred for 2 hours at 25±2°C. the Mixture is filtered and the filter residue is washed with a fresh portion of tetrahydrofuran (1 OBC) and dried on the filter for several hours. The filter residue is suspended in 1 M aqueous NaOH solution (13 OBC) and heat at 70°C for 30 minutes At the end of this time the mixture is cooled to 25±2°C and the solid is removed by filtration. The filter residue is washed with 1 M aqueous NaOH solution (10 OBS). United uterine solution is cooled to 0°C and acidified with up to approx. pH 5 with HCl (aqueous solution; 16%; note: while adding HCl maintain the temperature below +10°C). Suspendirovanie the reaction product is removed by filtration and washed with water (2×3 OBC). The filter residue is dried at 40°C for 18 h in high vacuum and receive a 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-tion (in its corresponding tautomeric form; 290 g, 37%).

In nitrogen atmosphere NaOEt (21% solution in EtOH, 2,08 ABC, 1.1 EQ.) added to EtOH (20 ABC). Add in one 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-tion (in its corresponding tautomeric form; 290 g, 1 parts by weight) and the resulting mixture was stirred at 25±2 is With as long until you get a clear solution. Then add 1-bromo-3-chloropropane (0,54 ABC, 1.1 EQ.) and the solution stirred at 40°C for 24 h and then cooled to 25°C. After filtering, add water (20 ABC) and ethanol phase is removed by distillation in vacuum (internal temperature of ~40°C). The mixture is extracted with EtOAc (41 ABC). The aqueous layer was removed and the organic phase is evaporated to dryness. Add dichloromethane (4 OBC). The organic solution was purified on a short column of silica gel (18 parts by weight of silicon dioxide) with elution EtOAc (200 OBC) and get named in the title compound in the form of a solid foamy substance (267,64 g, 66%).

NMR (1H, CDCl3): δ of 7.90 (s, 1H), 3,70 (s, 5H), 3,40 (t, 2H), 2,52 (s, 3H), 2,30 (m, 2H).

Preparative example 15. 3-[4-(Trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione

At room temperature under vigorous stirring, a mixture of hydrochloric acid (37%, 285 ml) and water (190 ml) is added to 4-(trifluoromethyl)aniline (150 g, 116 ml) and the resulting precipitate is stirred for another 30 minutes. The temperature is reduced to 0°C and to the suspension with stirring, add dropwise a solution of sodium nitrite (70,6 g) in 180 ml of water. Upon completion of the diazotization get a transparent yellow solution. At 0°C is added dropwise a solution of maleimide (180 g) in acetone (1.1 l) and then the pH of the solution was adjusted to 3-3 .5 by adding sodium acetate. For when thou with vigorous stirring chloride copper(II) (18,8 g). After a few minutes starts to separate gas (visible foaming). The reaction mixture was stirred at 0°C for 1 hour and overnight at room temperature.

The acetone is removed in vacuo, the residue is filtered off and dried overnight in a vacuum and get named in the title compound (155 g) as light brown solid (yield = 63%).

MS (m/z): 242,2 [MH]+.

Preparative example 16. (1R,5S/1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione

To a solution of iodide trimethylsulfoxonium (219 g) in DMSO (anhydrous, 2 l) with stirring in small portions, add the crushed sodium hydroxide (40 g). The resulting mixture was stirred at room temperature for 1.5 hour.

Then add dropwise a solution of 3-[4-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione (preparative example 15, 120 g) in DMSO (anhydrous, 0.5 l) and the resulting mixture was stirred at room temperature for 20 minutes. Then lower the temperature to 0°C and gradually add NH4Cl (saturated aqueous solution, 2 l), then Et2O (1 l). After separation of the phases the aqueous layer re-extracted with Et2O (3×1 l). The combined organic layers washed with brine (2×1 l) and then dried over Na2SO4. Evaporation of solvent gives a light brown solid prophetic the creation, which are suspended in 1 l of dichloromethane and 1 l of cyclohexane. The mixture is stirred at room temperature for 45 minutes and then filtered and receive named the title compound (116 g) as a white solid (yield = 71%).

MS (m/z): 256,1 [MH]+.

Preparative example 17. (1R,5S/1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Borane (1m solution in tetrahydrofuran, 1.4 l) is loaded into a 5-l reactor under nitrogen atmosphere and cooled to 0°C. Then, with vigorous stirring, add dropwise a solution of (1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione (preparative example 16, 101 g) in tetrahydrofuran (anhydrous, 1 l), while constantly maintaining the temperature below 5°C, and control the allocation of gas. After adding the resulting mixture was stirred at 0°C for 1 hour and then at room temperature overnight.

The mixture is then cooled to 0°C and add methanol (200 ml), and then gently hydrochloric acid (6 M solution, 0.8 l), controlling greenhouse gas emissions. Then the tetrahydrofuran is removed in vacuo, the residue is cooled to 0°C and add sodium hydroxide (5 M solution) to achieve a pH of 9-10. The aqueous layer was extracted with Et2O (3×1 l). Removal of solvent in vacuo gives named the title compound (140 g) as a white colorless oil.

M is (m/z): to 228.1 [MH] +.

Preparative example 18. (1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1R,5S/1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 17, 140 g) in 1.4 l of tetrahydrofuran with stirring in parts (S)-(+)-almond acid (94 g). The resulting mixture was stirred at room temperature for 2 h before formation of a white precipitate. The mixture is then heated to a temperature of education phlegmy, stirred for 45 minutes and then slowly cooled down to room temperature. White solid is collected by filtration and dried in vacuum. The substance is recrystallized 4 times from tetrahydrofuran (10 volumes) and gain of 32.5 g of a white solid. Then the resulting substance is suspended in a solution of sodium hydroxide (1 M, 400 ml) and Et2O (400 ml) and everything is stirred at room temperature until complete dissolution. After separation of the phases the aqueous layer is again extracted with Et2O (3 × 250 ml). The combined organic layers washed with sodium hydroxide solution (1 M, 3 × 200 ml) and then dried over Na2SO4. Evaporation of the solvent in vacuo gives named the title compound (19 g) as a white solid (yield = 37%).

The absolute configuration of the optical isomers install using sravnitel the data analyses VCD (vibrational circular dichroism) and OR (optical rotation).

The configuration specified in the connection header set, comparing the experimental VCD spectrum and the observed specific rotation data obtained for the (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (see preparative example 48) as the reference sample. The establishment of the absolute configuration specified in the connection header is confirmed by x-ray structure of the single crystal obtained for the salt crystal (S)-(+)-almond acid (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane. Both the analysis based on the known configuration (S)-(+)-almond acid and based on the phenomenon of anomalous dispersion confirm the definition mentioned in the title compounds as representing the (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

NMR (1H, CDCl3): δ 7,51 (d, 2H), 7,25 (d, 2H), 3,20 (d, 1H), 3,0-3,1 (m, 3H), 1.69 in (m, 1H), of 0.8-1.0 (m, 2H), NHnot watching. MS (m/z): to 228.1 [MH]+.

Analytical chromatography

Column: chiralcel OD, 10 μm, 250 × 4.6 mm;

mobile phase: n-hexane; isopropanol + 0.1% Isopropylamine;

gradient: isocratic 2%;

a flow rate of 1 ml/min;

the interval of wavelengths of UV 200-400 nm;

the analysis time 25 min;

the hold time. (min)% a/a
16,5 0,4(1R,5S)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
21,799,6named in the header of the connection.

Specific optical rotation [α]D = -10° (CDCI3, T=20°C, C = 0.004 g/0.8 ml).

Preparative example 19. 3-{(1S,5R)-1-[4-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}-1-butanol

To a suspension of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 18, 100 mg) in tetrahydrofuran (1.1 ml) is added 4-hydroxy-2-butanone (0.66 mmol), acetic acid (0.66 mmol) and NaBH(OAc)3(0.88 mmol). The mixture is stirred at room temperature for 2 hours. After adding NaOH (1 M) the solvent is removed in vacuum, the residue is dissolved in ethyl acetate and the organic layer was washed with H2O and dried over Na2SO4. The solution was concentrated in vacuo and get 130 mg named in the title compound, which was used without further purification.

MS (m/z): 300 [MH]+.

Preparative example 20. (1S,5R)-3-(3-Chloro-1-methylpropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of 3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}-1-butanol (preparative example 19, 130 mg) in chloroform (4 ml) add tional arid (0.87 mmol) and the mixture is stirred at room temperature for 6 hours. After adding NaOH (1 M) is added dichloromethane and the organic layer washed with brine and dried over Na2SO4. The solution was concentrated in vacuo, the crude reaction product is purified flash chromatography (ethyl acetate:cyclohexane = 5:95) and obtain 106 mg specified in the connection header.

MS (m/z): 318 [MH]+.

Preparative example 21. 1-{5-[(1S,5R/1R,5S)-3-Azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl}alanon

Named the title compound is obtained in yield 32 mg of 1-[4-(metiloksi)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane (94 mg) as described in preparative example 34.

MS (m/z): 232 [MH]+. HPLC: condition 1, Rt = 3,393 minutes

Preparative example 22. (1S,5R/1R,5S)-1-(4-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 230 mg of commercially available methyl-4-chlorophenylacetic (1 g, 5.5 mmol), following the methods described in preparative examples 1, 2, 3, 4, 6.

MS (m/z): 194 [MH]+.

Preparative example 23. (1S,5R/1R,5S)-1-(4-Forfinal)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 160 mg of commercially available methyl-4-pertenecerte (1 g, 6 mmol), following the methods described in preparative examples 1, 2, 3, 4, 6.

MS (m/z): 178 [MH]+.

Ven is an operational example 24. (1S,5R/1R,5S)-1-(3-Chlorophenyl)-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from the output of 1.25 g of commercially available methyl-3-chlorophenylacetic (5 g, 27 mmol), following the methods described in preparative examples 1, 2, 3, 4, 5.

MS (m/z): 194 [MH]+. HPLC: condition 1, Rt = 3,469 minutes

Preparative example 25. (1S,5R/1R,5S)-1-(3-Forfinal)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield of 1.97 g of commercially available methyl-3-pertenecerte (5 g, 29.7 mmol), following the methods described in preparative examples 1, 2, 3, 4, 5.

MS (m/z): 178 [MH]+.

Preparative example 26. (1S,5R/1R,5S)-1-[3-(Metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 1.2 g of commercially available methyl-3-methoxyphenylacetate (5 g, 27.7 mmol), following the methods described in preparative examples 1, 2, 3, 4, 5.

MS (m/z): 190 [MH]+. HPLC: condition 1, Rt = 3,219 minutes

Preparative example 27. (1S,5R/1R,5S)-1-[2-Methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 71 mg of commercially available 2-methyl-4-(trifluoromethyl)aniline (1 g, 5.7 mmol), following the methods described in preparative examples 15, 16 and 17.

MS (m/z): 242 [MH]+.

Preparative example 28. Methylprop{4-[(trifluoromethyl)oxy]phenyl}acetate

To a solution of 4-triftormetilfullerenov acid (5 g, 23 mmol) in carbon tetrachloride at 0°C add oxalicacid (25 mmol) and two drops of DMF. After stirring the solution at room temperature for 1 hour add NBS (25 mmol) and few drops of 48% HBr and the mixture is refluxed for 4 hours. The solution is cooled, add Meon (5 ml) and the mixture is stirred at room temperature for 1 hour. After filtration through a layer of silica gel, the filtrate is evaporated in vacuum and obtain 7.2 g named the title compound as a yellow foam, which was used in the next stage without additional purification.

MS (m/z): 314 [MH]+.

Preparative example 29. (1S,5R/1R,5S)-1-{4-[(Trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from the output of 1.2 g of methyl-3-cryptomaterial (preparative example M, 23 mmol), following the methods described in preparative examples 2, 3, 4, 5.

MS (m/z): 244 [MH]+. HPLC: condition 1, Rt = 3,942 minutes

Preparative example 30. (1S,5R/1R,5S)-1-[3-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named in the header with the Association get with the release of 1.5 g of commercially available 3-triftormetilfullerenov acid (5 g, 24.5 mmol), following the methods described in the preparative examples, 28, 2, 3, 4, 5.

MS (m/z): 228 [MH]+. HPLC: condition 1, Rt = 3,665 minutes

Preparative example 31. (1S,5R/1R,5S)-1-(3-Bromophenyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 1.6 g of commercially available 3-bromoferrocene acid (5 g, 23.2 mmol), following the methods described in the preparative examples, 28, 2, 3, 4, 6.

MS (m/z): 239 [MH]+. HPLC: condition 1, Rt = 3,528 minutes

Preparative example 32. (1S,5R)1-(4-Bromophenyl)-3-azabicyclo[3.1.0]hexane

To a solution of (1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (preparative example 6, of 3.96 g) in 80 ml of IPA was added parts of (S)-(+)-acetylindole acid (3,22 g). The resulting mixture was stirred at room temperature for 2 hours until a white precipitate is formed. The mixture is then heated to a temperature of education phlegmy, stirred for 45 minutes and then slowly cooled down to room temperature. White solid is collected by filtration and dried in vacuum. The resulting material is recrystallized 4 times from IPA (10 volumes), and obtain 2.3 g of a white solid.

Then the resulting substance is suspended in a solution of sodium hydroxide (1 M, 400 ml) and Et2O (400 ml), and the whole was stirred at room temperature until complete R is stvorenie. After separation of the phases the aqueous layer is again extracted with Et2O (3 × 250 ml). The combined organic layers washed with sodium hydroxide solution (1 M, 3 × 200 ml) and then dried over Na2SO4. Evaporation of the solvent in vacuo gives named the title compound (1.24 g) as a white solid.

The absolute configuration of the optical isomers is set as described in preparative example 18.

The establishment of the absolute configuration specified in the connection header is confirmed by x-ray structure of the single crystal obtained for the salt crystal (S)-(+)-O-acetylindole acid (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane. Both the analysis based on the known configuration (S)-(+)-acetylindole acid and based on the phenomenon of anomalous dispersion confirm the definition mentioned in the title compounds as representing the (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane.

NMR (1H, CDCl3): δ the 7.43 (d, 2H), to 7.09 (d, 2H), 3,25 (d, 1H), 3.15 in (m, 2H), 3,06 (d, 1H), 1,71 (m, 1H), 0,95 (DD, 1H), 0,89 (t, 1H), NHnot watching.

MS (m/z): 239 [MH]+.

Analytical chromatography

Column: chiralcel OD 5 μm, 250 × 4.6 mm;

mobile phase: n-hexane; isopropanol + 0.1% Isopropylamine;

gradient: isocratic 2%;

a flow rate of 1 ml/min;

the interval of wavelengths of UV 200-400 nm;

the analysis time 25 min;

BP is me hold. 22,3 min, purity >99% a/a;

specific optical rotation [α]D= -86° (CDCl3, T = 20°C, c = 0,0053 g/0.8 ml).

Preparative example 33. (1R,5S/1S,5R)-1-[2-(Trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 53 mg of commercially available methyl[2-(trifluoromethyl)phenyl]acetate (944 mg), following the methods described in preparative examples 1, 2, 3, 4, and 5.

MS (m/z): 228 [MH]+.

Preparative example 34. 1-[4-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]alanon

To a mixture of AlCl3(2 EQ.) and 1,2-dichloroethane (anhydrous, 9 ml) at 0°C. add acetylchloride (of 1.05 EQ.). The reaction mixture was stirred at 0°C for 15 min, and add a solution of 1-[3-(metiloksi)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane (1.1 g, obtained by the method similar to that described in preparative example 7, from 1-[3-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane) in 1,2-dichloroethane (anhydrous, 9 ml). The reaction mixture was stirred at RT for 1.5 hour. Add HCl (1 M, 4 ml)and then water (20 ml) and the mixture extracted with dichloromethane. The organic layer was washed with saturated aqueous NaHCO3and dried over Na2SO4. The solution is filtered and the filtrate concentrated in vacuo. The crude reaction product is purified flash chromatography (cyclohexane:EtOAc, 6:) and receive 593 mg containing protective group of the amine as a colorless liquid. Dissolve 143 mg containing protective group of the amine in the mixture Meon:N2About (3 ml : 3 ml) and added To the2CO3(4 equiv.) stirring the mixture at 50°C for 2.5 hours. The reaction mixture is extracted with dichloromethane and the organic layer was washed with saturated aqueous NaHCO3and dried over Na2SO4. The solution is filtered, the filtrate was concentrated in vacuo and get named in the title compound as a white solid (88 mg).

MS (m/z): 232 [MH]+.

HPLC: conditions 1

Analytical HPLC

Column: Supelcosil ABZ+Plus, 33 × 4.6 mm, 3 μm;

mobile phase: A - H2O + 0.1% HCOOH, CH3CN;

gradient: 0% () for 1 min, from 0% (C) up to 95% (C) for 5 min, 95% (B) for 2 min;

a flow rate of 1 ml/min;

the wavelength of UV 285 nm, band width of 130 nm;

mass interval 100-1000 amu;

ionization ES+;

Rt2,971 minutes

Preparative example 35. 1-[4-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone

Named the title compound is obtained using Propionaldehyde instead of acetylchloride with yield 106 mg of 147 mg of the amine protective group received (705 mg) of 1-[3-(metiloksi)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane (1.07 g)as described in preparative example 34.

MS (m/z): 246 [MH]+.

The HPLC conditions 1.

Rt 3,249 minutes

Preparative example 36. 1(1R,5S/1S,5R)-[2-Fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from the output 112 mg of 2-fluoro-5-(trifluoromethyl)aniline (1,09 g), following the procedures described in preparative examples 37 and 6.

NMR (1H, CDCl3): δ was 7.45 (m, 2H), and 7.1 (m, 1H), 3,2 (m, 2H), 3,05 (m, 2H), 1,7 (m, 1H), 0,95 (m, 1H), and 0.9 (m, 1H), NHnot watching. MS (m/z): 246[MH]+.

Preparative example 37. 1(1R,5S/1S,5R)-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione

To the suspension of maleimide (1.7 equiv.) anhydrous CuCl2(1.2 equiv.) and tert-butylnitrite (1.5 EQ.) in CH3CN (35 ml) at 0°C is added dropwise a solution of 2-fluoro-4-(trifluoromethyl)aniline (16.3 g) in CH3CN (6.5 ml). The reaction mixture was stirred at room temperature for 1 hour and add HCl (10% aqueous, 196 ml). The mixture is extracted with EtOAc, the organic layer was washed with saturated aqueous NaCl and dried over Na2SO4. The solution is filtered and the filtrate concentrated in vacuo. Analysis by NMR of the crude mixture shows a mixture of 1:4 adduct hydrochloride areleaving of maleimide (component a) and unreacted maleimide (component b).

The solution of this crude reaction product in DMSO (140 ml) is added dropwise to the previously obtained solution of iodide of trimet sulfoxide (2 EQ. relative to the component And with the addition of 2 EQ. relative to the component) in anhydrous DMSO (412 ml)to which was added in portions NaH (3 EQ. relative to the component And with the addition of 2 EQ. relative to the component). The reaction mixture was stirred for 30 min and add Asón (2 equiv.) and then the water. The reaction mixture was extracted with Et2O and then EtOAc, the combined organic layers washed with saturated aqueous NaCl and dried over Na2SO4. The solution is filtered and the filtrate concentrated in vacuo. The resulting crude reaction product is treated with water and then with cyclohexane and get named in the title compound as light brown solid (5,98 g).

NMR (1H, CDCl3): δ 7,55 of 7.3 (m, 3H), of 2.8 and 2.7 (m, 1H), 2,1 (m, 1H), 2.0 (m, 1H), NH not observed. MS (m/z): 274[MH]+.

Preparative example 38. (1R,5S/1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-she (2.6 g) in anhydrous tetrahydrofuran (56 ml) at 0°C type NR3in tetrahydrofuran (1 M, 4 EQ.). The reaction mixture was stirred at 65°C for 24 h, cooled to RT and add Meon as long as you do not stop the gas. The solvent is removed in vacuo, add Meon (200 ml), add n-toluensulfonate acid is (3 equiv.) the reaction mixture was stirred at 65°C for 6 h, cooled to room temperature and add a saturated solution of K2CO3(1.7 EQ.). The mixture is extracted with dichloromethane, the organic layer was washed with saturated aqueous NaCl and dried over Na2SO4. The solution is filtered, the filtrate was concentrated in vacuo and get named in the title compound as a colourless oil (2.1 g).

NMR (1H, CDCl3): δ of 7.2 to 7.4 (m, 3H), 3,2 (m, 2H), 3,1 (m, 2H), 1.8 m (m, 1H), 0,8 (m, 2H), NHnot watching. MS (m/z): 246[MH]+.

Preparative example 39. (1S,5R)-1-[2-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (4.4 g) in CH3CN (44 ml) was added with stirring in parts (1R)-(-)-10-camphorsulfonic acid (4,19 g). The resulting mixture was stirred at room temperature for 20 min prior to the formation of a white precipitate. The mixture is then heated to a temperature of education phlegmy, stirred for 45 minutes and then slowly cooled down to room temperature. White solid is collected by filtration and dried in vacuum. The resulting substance 2 times recrystallized from CH3CN (25 ml per g solids) and gain of 1.57 g of a white solid.

Then this substance is suspended in a solution of hydro is sid sodium (1 M, 1.1 EQ.) and dichloromethane (100 ml) and stirred at room temperature until complete dissolution. After separation of the phases the aqueous layer is again extracted with dichloromethane. The combined organic layers washed with sodium hydroxide solution and then dried over Na2SO4. Evaporation of the solvent in vacuo gives named the title compound (874 mg) as colorless liquid.

Analytical chromatography

Column: chiralcel OD, 10 μm, 250 × 4.6 mm;

mobile phase: n-hexane; isopropanol + 0.1% Isopropylamine;

gradient: isocratic 2%;

the flow rate 0.8 ml/min;

the interval of wavelengths of UV 200-400 nm.

Analysis

The hold time. (min)% a/a
17,18>99,5 (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

Preparative example 40. (1S,5R)-3-(3-Chlorpropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (1,00 g) in dry tetrahydrofuran (5 ml) add diisopropylethylamine (2.4 ml) and 1-bromo-3-chloropropane (3,7 ml) and the resulting mixture is refluxed for 3 hours. After cooling to room temperature the mixture razbam Aut with ethyl acetate (30 ml), twice washed with saturated aqueous NH4Cl (20 ml) and once with saturated aqueous NaHCO3(20 ml), dried over anhydrous Na2SO4and concentrate under reduced pressure. The crude reaction product is purified by chromatography on silica gel with elution with a mixture of cyclohexane/EtOAc, 7:3 and get named in the title compound as a colorless oil (1.26 g).

NMR (1H, CDCl3): δ 7,50 (d, 2H), 7,19 (d, 2H)and 3.59 (t, 2H), 3.33 and (d, 1H), 3,09 (d, 1H), 2,58 (m, 2H), 2,66 (DD, 1H), 2,46 (DD, 1H), 1,92 (m, 2H), 1,74 (m, 1H), 1,67 (t, 1H), 0,81 (DD, 1H). MS (m/z): 304 [MH]+.

Preparative example 41. (1S,5R)-3-(3-Chlorpropyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (300 mg) in dry tetrahydrofuran (3 ml) add diisopropylethylamine (0,65 ml) and 1-bromo-3-chloropropane (1,01 ml) and the resulting mixture is refluxed for 3 hours. After cooling to room temperature the mixture is diluted with ethyl acetate (15 ml), washed twice with a saturated aqueous solution of NH4Cl (10 ml) and once with saturated aqueous NaHCO3(10 ml), dried over anhydrous Na2SO4and concentrate under reduced pressure. The crude reaction product is purified by chromatography (silica gel) by elution with a mixture of cyclohexane/EtOAc, 6:4 and named the title compound as a yellow oil (345 mg).

NMR (1H, CDCl3): δ of 7.24 (d, 2H), 7,16 (t, 1H), 3,51 (t, 2H), 3,18 (DD, 1H), 3,03 (d, 1H), 2,54 (t, 2H), 2,48 (DD, 1H), 2,37 (d, 1H)and 1.83 (m, 2H), 1.69 in (m, 1H), 1,34 (t, 1H), 0,70 (DD, 1H). MS (m/z): 322 [MH]+.

Preparative example 42. (1R,5S/1S,5R)-1-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 338 mg of 3-fluoro-4-(trichromatic)aniline (2 g), following the procedures described for preparative examples 37 and 6.

NMR (1H, CDCl3): δ 7.5 (m, 1H), 6,9 (m, 2H), 3,3-3,0 (m, 4H), 1,7 (m, 1H), 0,95 (m, 2H), NHnot watching. MS (m/z): 246 [MH]+.

Preparative example 43. (1R,5S/1S,5R)-1-[4-(Metiloksi)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane

Named in the title compound obtained as a colorless oil with a yield of 1.80 g (95%) of (1R,5S/1S,5R)-1-[4-(methoxy)phenyl]-3-azabicyclo[3.1.0]hexane (1.25 g) by the method similar to that described in preparative example 7.

MS (m/z): 286 [MH]+.

Preparative example 44. 1-{2-(Metiloksi)-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon and 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}alanon

To a suspension of AlCl3(12.6 mmol) in dry 1,2-dichloroethane (16 ml) at 0°C. add acetylchloride (6.6 mmol) and the mixture is stirred at the same temperature for 15 minutes Then dobavlaut a solution of (1R,5S/1S,5R)-1-[4-(metiloksi)phenyl]-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]hexane (1,81 g, 6.3 mmol) in 1,2-dichloroethane (16 ml). The reaction mixture was stirred at 0°C for 15 min and overnight at room temperature. Then add 1 M hydrochloric acid and the mixture extracted with dichloromethane. The organic phase is washed with 5% solution of NaHCO3and water, dried over Na2SO4and concentrated in vacuo. Two reaction product is shared by flash chromatography (cyclohexane/ethyl acetate from 95/5 to 80/29) and receive 965 mg of 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone (48%) and 266 mg of 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone (18%) as yellow oils.

MS (m/z): 328 [MH]+, 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon; 312 [M-H]-, 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon.

Preparative example 45. 1-[5-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]alanon

Named in the title compound obtained as a colorless oil with a yield of 624 mg (91%) of 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone (965 mg) by the method similar to that described in preparative example 12.

MS (m/z): 232 [MH]+.

Preparative example 46. 1-{5-[(1R,5S/1S,5R)-3-Azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}alanon

.

Named in the title compound obtained as a colorless oil with a yield 151 mg (82%) of 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(TRIFLUOROACETYL)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone (266 mg) by the method similar to that described in preparative example 12.

MS (m/z): 216 [MH]+.

Preparative example 47. (1S,5R/1R,5S)-1-(4-Bromophenyl)-3-(3-chlorpropyl)-3-azabicyclo[3.1.0]hexane

To a solution of racemic (1S,5R/1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (0.12 g) in dry tetrahydrofuran (2 ml) add diisopropylethylamine (0,22 ml) and 1-bromo-3-chloropropane (0,062 ml) and the resulting mixture is refluxed for 3 hours. After cooling to room temperature the solvent is removed in vacuo and the resulting crude oil was dissolved in dichloromethane (10 ml). Then the resulting solution was washed twice with a saturated aqueous solution of NH4Cl (5 ml), dried over anhydrous Na2SO4and concentrate under reduced pressure. The crude reaction product is purified by passing the sample through the cartridge with 2 g of silica (Varian) with elution with a gradient from cyclohexane to a mixture of cyclohexane/EtOAc, 7:3, and get named in the title compound as a colorless oil (0.10 g).

NMR (1H, DMSO): δ was 7.45 (d, 2H), 7,10 (d, 2H), the 3.65 (t, 2H), 3,30 (d, 1H), 3.00 and (d, 1H), to 2.55 (t, 2H), 2,45 (m, 1H), 2.40 a (DD, 1H), of 1.85 (m, 2H), 1,80 (m, 1H), 1,30 (t, 1H), 0,70 (m, 1H). MS (m/z): 34, 316, 318 [MH]+.

Preparative example 48. (1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane

Crude named the title compound is obtained in yield of 0.36 g of commercially available 3,4-dichlorophenylamino (1 g, of 4.57 mmol), following the methods described in preparative examples 1, 2, 3, 4, 6.

Named in the title compound share and receive separate the enantiomers by preparative chromatography using a chiral column chiralcel AD, 10 μm, 250 × 21 mm, eluent A - n-hexane; isopropanol + 0.1% Isopropylamine; gradient isocratic 2% b, flow rate 7 ml/min; UV detection at 200-400 nm. Given the retention times obtained using analytical HPLC using a chiral column chiralcel AD, 5 μm, 250 × 4.6 mm, eluent A - n-hexane; isopropanol + 0.1% Isopropylamine; gradient isocratic 2% b, flow rate 1.2 ml/min, UV detection at 200-400 nm.

The enantiomer of 1 - (1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane extract from the racemate (60 mg) with a yield of 20 mg in the form of a white solid. Rt = 41 minutes

Enantiomer of 2 - (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane extract from the racemate (60 mg) to yield 28 mg as a white solid. Rt = 43,4 minutes

The absolute configuration of (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane set using analyses ab initio VCD and ab iniio'OR.

Specific optical rotation (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane [α]D= -67,9° (CDCl3, T = 20°C, c ≈ 0.01 g/ml).

NMR (1H, CDCl3): δ to 7.35 (d, 1H), 7,27 (s, 1H), 7,02 (DD, 1H), 3,25 (d, 1H), 3,13 (ushm, 2H), 3,06 (d, 1H), 1,71 (m, 1H), 0,93 (m, 2H), NHnot watching. MS (m/z): 228 [MH]+.

Preparative example 49. 1-(Phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrol

Get diazepinonelor, following the procedure described in J. Org. Chem., 1984, 49, 945-947. 2-[(1Z)-3-Chloro-1-(chloromethyl)-1-propen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (previously described in Tetrahedron Lett., 1993, 34, 4827-4828) receive, following the General procedure described in Tetrahedron Lett., 1989, 30, 2929, using 1,4-dichloro-2-butyne. Then carry out a further transformation of the thus obtained substance, following the procedure described in Synlett, 2002, 5, 829-831. The last mentioned procedure is modified in that the selection named in the header of the reaction product reaches the extraction (not distilled) solution of crude product of the reaction of acetonitrile with cyclohexane and get named in the title compound (containing ~10 mol.% benzylamino) after evaporation of volatile substances from the cyclohexane phase.

Preparative example 50. 2-[1-(Phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-5-(trifluoromethyl)pyridine

To a solution of 2-bromo-5-(trifluoromethyl)pyridine (4,42 mmol) in dry tetrahydrofuran (45 ml) at room temperature was added 1-(phenylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole (3.4 mmol), tetrakis(triphenylphosphine)palladium(0) (0,196 mmol) and cesium fluoride (13,2 mmol). The resulting mixture was stirred at 80°C for 1.5 hours. After cooling, the solvent is evaporated under reduced pressure and the residue treated with dichloromethane (25 ml) and sodium hydroxide solution (15 ml, 1 M). The organic phase is evaporated under reduced pressure. The crude reaction product is purified column chromatography on silica gel (AcOEt:cyclohexane = 1:10 - 4:6) and obtain 0.33 g named the title compound (yield = 24%).

NMR (1H, CDCl3): δ of 9.8 (s, 1H), a 7.85 (DD, 1H), 7.5 to about 7.2 (m, 6H), 6,7 (s, 1H), 3,95 (m, 2H), 3,9 (s, 2H, in), 3.75 (m, 2H). MS (m/z): 305 [MH]+.

Preparative example 51. 2-[1-(Phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-6-(trifluoromethyl)pyridine

2-[1-(Phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-6-(trifluoromethyl)pyridine get a way similar to that described in preparative example 50, in the amount of 0.56 g (yield = 42%) as oil.

NMR (1H, CDCl3): δ of 7.7 (t, 1H), a 7.85 (DD, 1H), and 7.4 to 7.1 (m, 6H), 6,5 (s, 1H), 3,90 (sushi, 2H), and 3.8 (s, 2H), 3,6 (m, 2H). MS (m/z): 305 [MH]+.

Preparative example 52. 3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo]hexane

To a suspension of sodium hydride (83 g) and iodide trimethylsulfoxonium (0,46 g) is added dropwise DMSO (anhydrous, 3 ml) (gas evolution). The resulting mixture was stirred at room temperature for 0.5 hours. At room temperature add a solution of 2-[1-(phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]-5-(trifluoromethyl)-2-pyridine (330 mg) in DMSO (anhydrous, 6 ml). After 1 hour, add a saturated solution of ammonium chloride (4 ml) and the mixture extracted with dichloromethane (2 × 10 ml). From the organic phase under reduced pressure to evaporate volatile components, the residue is loaded into a SCX column and elute Meon, and then Meon/NH3, 0,25 M Fraction, erwerbende solution of methanol/ammonia, concentrated under reduced pressure and obtain 0.31 g named the title compound (yield = 89%).

NMR (1H, CDCl3): δ 8,78 (s, 1H), 8,03 (DD, 1H), 7,32 (m, 5H), 7,25 (m, 1H), 3,66 (DD, 2H), 3,25 (d, 1H), 2,96 (d, 1H), 2,80 (d, 1H), 2,46 (sushi, 1H), 2,05 (kV, 1 H), was 1.58 (m, 1H), 1,22 (m, 1H). MS (m/z):317 [MH]+.

Preparative example 53. 3-(Phenylmethyl)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

3-(Phenylmethyl)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane receive in the form of oil by the method similar to that described in preparative example 52 (0,46 g, 79%).

NMR (1H, CDCl3): δ of 7.7 (t, 1H), and 7.4 (d, 1H), 7,35 (m, 5H), 7,2 (d, 1H), and 3.7 (s, 2H), 3,4 (d, 1H), 3,1 (who, 1H), 2,85 (d, 1H), to 2.55 (m, 1H), 2,1 (m, 1H), 1,7 (m, 1H), 1,3 (m, 1H). MS (m/z): 317 [MH]+.

Preparative example 54. 1-[5-(Trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane dissolved in ethanol (15 ml), add hydrochloric acid (3 M, from 0.76 ml), and then in an inert atmosphere of 10%, wt./wt., Pd/C (120 mg). After 20 hours in an atmosphere of hydrogen (1 ATM), the mixture is filtered. The solvent is removed under reduced pressure. Add a saturated solution of sodium bicarbonate (10 ml), the mixture is extracted with diethyl ether (2 × 10 ml) and, after evaporation of volatile substances get named in the title compound (0.14 g, 81%).

NMR (1H, DMSO-d6): δ of 8.7 (s, 1H), and 7.8 (d, 1H), 7,15 (d, 1H), 3,4-3,2 (DD, 2H), 3,1 (m, 2H), 2.05 is (m, 1H), 1,4 (m, 1H), 1,05 (t, 1H).

Preparative example 55. 2-Fluoro-4-[1-(phenylmethyl)-2,5-dihydro-1H-pyrrol-3-yl]benzonitrile

Named the title compound is obtained by way similar to that described in preparative example 50, in the amount of 0.44 g (yield = 31%) as oil.

NMR (1H, CDCl3): δ at 7.55 (t, 1H), and 7.4 to 7.2 (m, 5H), 7,2 (d, 1H), and 7.1 (d, 1H), 6,4 (Ushs, 1H), 3,9 (s, 2H), and 3.8 (m, 2H, in), 3.75 (m, 2H), MS (m/z): 279 [MH]+.

Preparative example 56. 2-Fluoro-4-[3-(phenylmethyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile

Named in the title is Obedinenie get way similar to that described in preparative example 52, in the amount of 0.39 g (yield = 84%) as oil.

NMR (1H, CDCl3): δ 7,41 (t,1H), 7,25-to 7.15 (m, 5H), 6,85 is 6.8 (DD, 2H), 3,64 of 3.56 (DD, 2H), 3,19 (DD, 1H), 3,01 (DD, 1H), 2,53 (DD, 1H), 2,47 (DD, 1H), 1,73 (kV, 1H), 1,67 (m, 1H), 0,81 (m, 1H). MS (m/z): 293 [MH]+.

Preparative example 57. 1-[3-Fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of dihydrochloride {[4-(3-azabicyclo[3.1.0]Gex-1-yl)-2-forfinal]methyl}amine, which is obtained by a method similar to that described in preparative example 54, on the basis of 1.1 mol of 2-fluoro-4-[3-(phenylmethyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile, and used without additional purification at room temperature for 5 min is added dropwise a solution of 2,5-bis(metiloksi)tetrahydrofuran (2,53 mmol) and H2SO4(4.4 mol) in methanol/tetrahydrofuran (anhydrous, 1/1, 5 ml). After maturation over night at room temperature gradually add a saturated solution of NaHCO3and extraction 2 × 15 ml dichloromethane followed by purification preparative HPLC to give 14 mg named the title compound as oil (yield = 5%).

NMR (1H, CDCl3): δ 6,88-PC 6.82 (m, 3H), 6,67 (t, 2H), 6,14 (t, 2H), 5,04 (s, 2H), 3,21 (d, 1H), 3,1 (d, 1H), 3,09 (d, 1H), 3,01 (d, 1H), 1,67 (m, 1H), 0,88 (m, 2H). MS (m/z): 257 [MH]+.

Preparative example 58. (1R,5S)/1S,5R)-3-(3-Chlorpropyl)-1-[6-(trifluoromethyl)-3-PIR is dinyl]-3-azabicyclo[3.1.0]hexane

Named in the title compound obtained as a colorless oil with a yield of 522 mg (84%) of (1R,5S)/1S,5R)-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane (584 mg) by the method similar to that described in preparative example 40.

NMR (1H, CDCl3): δ of 8.47 (s, 1H), 7,55 (m, 2H)and 3.59 (t, 2H), 3.33 and (d, 1H), 3,09 (d, 1H), and 2.6 (m, 3H), 2,52 (DD, 1H), 1,92 (m, 2H), 1,78 (m, 1H), 0,85 (m, 1H), 0,81 (DD, 1H). MS (m/z): 305 [MH]+.

Preparative example 59. 5-[(1R,5S)/1S,5R)-3-(3-Chlorpropyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazol

Named in the title compound obtained as a colorless oil with a yield 480 mg (84%) of 5-[(1R,5S)/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole (374 mg) by the method similar to that described in preparative example 40.

NMR (1H, CDCl3): δ of 7.70 (m, 2H), 7,11 (d, 1H)and 3.59 (t, 2H), 3,38 (d, 1H), 3,09 (d, 1H), and 2.8 (s, 3H), of 2.66 (m, 3H), 2,53 (DD, 1H), 1,95 (m, 2H), 1,74 (m, 1H), 1,44 (t, 1H), or 0.83 (DD, 1H). MS (m/z): 307 [MH]+.

Preparative example 60. 1-(1R,5S)/1S,5R)-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione

To the suspension of maleimide (1.8 equiv.) anhydrous CuCl2(1.2 equiv.) and tert-butylnitrite (1.5 EQ.) in CH3CN (5 ml) at 0°C is added dropwise a solution of 3-fluoro-5-(trifluoromethyl)aniline (2.2 g) in CH3CN (4 ml). The reaction mixture was stirred at room temperature for 2 hours and relax the Ute HCl (6 M aqueous solution, 30 ml). The mixture is extracted with EtOAc and the organic layer dried over Na2SO4. The solution is filtered and the filtrate concentrated in vacuo. The residue is treated with water, filtered and dried in vacuum. A solution of the obtained crude product of the reaction in DMSO (10 ml) is added dropwise to the previously obtained solution of iodide trimethylsulfoxonium (2 EQ.) in anhydrous DMSO (20 ml)to which was added in portions NaH (15 EQ.). The reaction mixture was stirred for 30 min and add water and then a saturated solution of NH4Cl (to pH 6.5). The reaction mixture was extracted with Et2O, and the combined organic layers washed with saturated aqueous NaCl and dried over Na2SO4. The solution is filtered and the filtrate concentrated in vacuo. The resulting crude reaction product is treated with cyclohexane and get named in the title compound as a pale green solid (1,02 g).

NMR (1H, CDCl3): δ 7,4-7,20 (m, 3H), 2,85 is 2.75 (m, 1H), 2.0 (m, 1H), of 1.85 (m, 1H), NHnot watching. MS (m/z): 274[MH]+.

Preparative example 61. (1R,5S)/1S,5R)-1-[3-Fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 650 mg of (1R,5S)/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane-2,4-dione following the procedure described in preparative example 38.

NMR (sup> 1H, CDCl3): δ 7,05-7,40 (m, 3H)r3,1-3,3 (m, 4H), 1,7 (m, 1H), and 0.9 (m, 2H), NHnot watching. MS (m/z): 246 [MH]+.

Preparative example 62. (1R,5S)/1S,5R)-1-[2-Fluoro-3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from the output 947 mg of 2-fluoro-3-(trifluoromethyl)aniline (3 g), following the procedures described in preparative examples 60 and 38.

NMR (1H, CDCl3): δ to 7.2 (m, 2H), 6,9 (m, 1H), 3,0-2,7 (m, 4H), 1,6 (m, 1H), 0,7 (m, 2H). MS (m/z): 246 [MH]+.

Preparative example 63. (1R,5S)/1S,5R)-1-[4-(Metiloksi)-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 430 mg of 4-(metiloksi)-5-(trifluoromethyl)aniline (2.2 g), following the procedures described in preparative examples 60 and 38.

NMR (1H, CDCl3): δ between 7.4 and 7.3 (m, 2H), 6,9 (m, 1H), 3,9 (s, 3H), 3,2-3,0 (m, 4H), and 1.9 (s, 1H), 1,65 (m, 1H), 0,8 (m, 2H). MS (m/z): 258 [MH]+.

Preparative example 64. (1R,5S)/1S,5R)-1-(4-Chloro-2-forfinal)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 360 mg of 4-chloro-2-foronline (1,87 g), following the procedures described in preparative examples 60 and 38.

NMR (1H, CDCl3): δ a 7.2 to 7.0 (m, 3H), 3,2-3,0 (m, 4H), 2,0 (s, 1H), 1,75 (m, 1H), 0,8 (m, 2H). MS (m/z): 212 [MH]+.

Preparative example 65. (1R,5S)/1S,5R)-1-{3-[(Trifluoromethyl)oxy]enyl}-3-azabicyclo[3.1.0]hexane

.

Named the title compound is obtained in yield 600 mg of 3-triftormetilfosfinov (2.65 g), following the procedures described in preparative examples 60 and 38.

NMR (1H, CDCl3): δ 7.3 to 7 (m, 4H), 3,3-3,0 (m, 4H), 1.8 m (s, 1H), 1,75 (m, 1H), 0,95 (m, 2H). MS (m/z): 212 [MH]+.

Preparative example 66. (1R,5S)/1S,5R)-1-(2-Fluoro-4-were)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 148 mg of 2-fluoro-4-methylaniline (2,18 g), following the procedures described in preparative examples 60 and 38.

NMR (1H, CDCl3): δ to 7.2 (m, 1H), 6,85 (m, 2H), 3,2-a 2.9 (m, 4H), of 2.25 (s, 3H), of 1.75 (s, 1H), 1,65 (m, 1H), and 0.9 (m, 2H). MS (m/z): 192 [MH]+.

Preparative example 67. (1R,5S)/1S,5R)-1-[3-Chloro-4-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained in yield 60 mg of 2-chloro-4-methylaniline (2,36 g), following the procedures described in preparative examples 60 and 38.

NMR (1H, CDCl3): δ 7,15-7 (m, 2H), 6,85 (m, 1H), 3,85 (s, 3H), of 3.2 and 2.9 (m, 4H), 1,8-1,6 (m, 2H), 0.75 in (m, 2H). MS (m/z): 224 [MH]+.

Preparative example 68. (1R,5S)/1S,5R)-1,1-Dimethylethyl-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of (1R,5S)/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (preparative example 6, 1.3 g) in dichloromethane (20 ml) at premesis the research Institute at room temperature is added triethylamine (0,99 ml) and bis(1,1-dimethylethyl)dicarbonate. Stirring is continued for 6 hours, then the reaction mixture was concentrated in vacuo and the crude reaction product is treated with diethyl ether and water. The organic phase is washed with a saturated solution of ammonium chloride, dried over sodium sulfate, the solvent is evaporated in vacuum and get the crude reaction product, which is purified by chromatography on silica gel (cyclohexane/EtOAc, 9/1) and get named in the title compound (1.68 g, 91%).

MS (m/z): 282,1 [MH-C4H8]+, 1Br.

Preparative example 69. (1R,5S)/1S,5R)-1,1-Dimethylethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

To a solution of (1R,5S)/1S,5R)-1,1-dimethylethyl-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2 g) in DMF (30 ml) under stirring at RT sequentially add bispinatus Debora (2.25 g), potassium acetate (1.75 g) and PdCl2(dppf) (0.15 g). The reaction mixture is warm at 85°C for 1.5 h, poured into water and extracted twice with diethyl ether and the organic phase is washed with brine and dried over sodium sulfate. The solvent is evaporated in vacuo, the crude reaction product is purified by chromatography on silica gel (cyclohexane/EtOAc, 9/1) and get named in the title compound as a white solid (2.1 g, 92%).

MS (m/z): 330,3 [MH-C4H8]+, 1Br.

Pre is artigny example 70. (1R,5S)/1S,5R)-1,1-Dimethylethyl-1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

Named in the title compound obtained as white solid with a yield of 94% of (1R,5S)/1S,5R)-1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane (7,4 g) by the method similar to that described in preparative example 68.

MS (m/z): 282,1 [MH-C4H8]+, 1Br.

Preparative example 71. (1R,5S)/1S,5R)-1,1-Dimethylethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

Named in the title compound obtained as white solid with a yield of 84% of (1R,5S)/1S,5R)-1,1-dimethylethyl-1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.5 g) by the method similar to that described in preparative example 69.

MS (m/z): 330,3 [MH-C4H8]+, 1Br.

Preparative example 72. (1R,5S)/1S,5R)-1-[4-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1R,5S)/1S,5R)-1,1-dimethylethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.3 g) in tetrahydrofuran (12 ml) under stirring at RT and under nitrogen atmosphere successively added 5-bromo-2,4-dimethyl-1,3-thiazole (0,22 g), cesium fluoride (0,47 g) and tetrakis(triphenylphosphine)palladium(0) (0.06 g). The reaction mixture is warm at 80°C for 4 hours and p is storytell is evaporated in vacuum. The crude reaction product is treated with diethyl ether and saturated aqueous ammonium chloride, the organic phase is washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude reaction product is purified by chromatography on silica gel (cyclohexane/EtOAc, 8/1). Then the purified product was dissolved in CH2Cl2(10 ml) and add triperoxonane acid (4 ml). After 2 hours the reaction mixture was treated with solid sodium carbonate and the solvent is evaporated. The residue is treated with solid sodium carbonate and the solvent is evaporated. The residue is treated with water and extracted with CH2Cl2, the organic phase is washed with brine, dried over sodium sulfate and evaporated and get named in the title compound (0.1 g, 34%).

MS (m/z): 271,2 [MH]+.

Preparative example 73. (1R,5S)/1S,5R)-1-{4-[6-(Trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from the output 60% manner similar to that described in preparative example 72 (using 2-bromo-6-(trifluoromethyl)pyridine).

MS (m/z): 305,3 [MH]+.

Preparative example 74. (1R,5S)/1S,5R)-1-[4-(3,5-Dimethyl-4-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1R,5S)/1S,5R)-1,1-dimethylethyl-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane-3-carb is celata (0,37 g) in toluene (5 ml) and ethanol (2 ml) under stirring at RT under nitrogen atmosphere successively added (3,5-dimethyl-4-isoxazolyl)baronova acid (0.25 g), tetrakis(triphenylphosphine)palladium(0) (0.03 g) and a saturated solution of potassium carbonate (2 ml). The reaction mixture is warm at 88°C for 2 h and the solvents evaporated in vacuo. The crude reaction product is treated with diethyl ether and water, the organic phase is washed with brine, dried over sodium sulfate, concentrated in vacuo and extracted twice with ether. The solvent is evaporated and the crude reaction product is purified by chromatography on silica gel (cyclohexane/EtOAc, 8/1). Then the purified product was dissolved in CH2Cl2(10 ml) and add triperoxonane acid (4 ml). After 3 hours the reaction mixture was treated with solid sodium carbonate and the solvent is evaporated. The residue is treated with water and extracted with CH2Cl2, the organic phase is washed with brine, dried over sodium sulfate and evaporated and get named in the title compound (0.12 g, 45%).

MS (m/z): 255,2 [MH]+.

Preparative example 75. (1R,5S)/1S,5R)-1-[3-(2,4-Dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from output 50% way similar to that described in preparative example 72, using (1R,5S)/1S,5R)-1,1-dimethylethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate compound 4).

MS (m/z): 271,3 [MH]+.

Preparative example 76. (1R,5S)/1S,5R)-1-[3-(5-Methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named in the title compound are obtained from the output 55% way similar to that described in preparative example 72, using (1R,5S)/1S,5R)-1,1-dimethylethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (intermediate compound 4).

MS (m/z): 256,2 [MH]+.

Preparative example 77. 5-(2,4-Dimethyl-1,3-oxazol-5-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-tion

In a nitrogen atmosphere at room temperature dissolve 2,4-dimethyl-1,3-oxazol-5-carboxylic acid (0.8 g), N-methylhydrosiloxane (0.6 g), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,09 g), HOBt (0,038 g) and triethylamine (0,86 ml) in dry DMF (15 ml). The mixture is stirred overnight and then the DMF is removed under vacuum. Add a solution of NaOH (0.75 M, 10 ml) and the mixture is warm at 80°C for 3 hours. The reaction mixture was cooled to 0°C and acidified with up to approx. pH 5 with HCl (aqueous, 37%). The suspended product is removed by filtration, washing with water (2 × 3 ml). The filter residue is dried at room temperature over night under vacuum and get named in the title compound in a mixture of 3:2 with 2,4-dimethyl-1,3-oxazol-5-carboxylic acid in the form of a solid foam material (0.68 g, o is d 57%).

NMR (1H, CDCl3): δ of 3.80 (s, 3H), 2,60 (s, 3H), 2.40 a (s, 3H), NH/CHnot watching.

Preparative example 78. 3-[(3-Chloropropyl)thio]-5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole

The mixture of reaction products from preparative example 77 is suspended in EtOH (10 ml). Added NaOEt (21% solution in EtOH, to 1.14 ml), and then 1-bromo-3-chloropropane (0,41 ml), the solution stirred at 90°C for 45 min and then cooled to 25°C. Add acetic acid (0.1 EQ.) and then the solvent is removed in vacuum. The solid is purified column chromatography on silica gel with elution with a mixture of cyclohexane/EtOAc and get named in the title compound in the form of a solid foam material (0,44 g, yield 54%).

NMR (1H, CDCl3): δ 3,70 (t+s, 5H), to 3.35 (t, 2H), 2,50 (s, 3H), and 2.4 (s, 3H), 2,30 (m, 2H). MS (m/z): 287 [MH]+.

Example 1. Hydrochloride 5-[5-({3-[(1R,5S)/1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine

A mixture of (1R,5S)/1S,5R)-1-[4-(methoxy)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 5, 42 mg), 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine (0.26 mmol), Na2CO3(0.44 mmol) and NaI (0.22 mmol) in DMF (anhydrous, 0.4 ml) by warming at 60°C for 24 hours. After removal of the solvent in vacuo the residue is dissolved in ethyl acetate and organizations the practical layer was washed with saturated aqueous NaHCO 3and dried over Na2SO4. The resulting solution is filtered and the filtrate concentrated in vacuo. The crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane) and obtain 65 mg of the free base named in the connection header. To a solution of the obtained substances in dichloromethane (0.2 ml) is added 0.14 mmol of HCl (1 M solution in Et2O), the solvent is evaporated in vacuum, thus obtained substance is treated with Et2O, and get 69 mg named the title compound as a white slaborastvorimogo solids (yield 59%).

[Procedure can similarly be adapted for other combinations of 1-substituted 3-azabicyclo[3.0.1]hexanol and 3-substituted 5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazoles. You can use an equivalent molar quantity To a2CO3instead of Na2CO3.]

NMR (1H, DMSO): δ 10,57 (Ushs, 1H), 8,28 (Ushs, 1H), and 8.2 (d, 1H), 7,94 (t, 1H), 7,82 (d, 1H), 7,56 (d, 1H), 7,25 (d, 2H), 6,91 (d, 2H), 4,01 (DD, 1H), 3,7 (m, 1H), 3,74 (s, 3H), 3,6-3,2 (m, 6H), 3,42 (s, 3H), 2,75 (s, 3H), 2,24 (Quint, 2H), 2,08 (Quint, 1H), 1,62/1,05 (t/t, 2H). MS (m/z): 486,3 [MH]+.

The compound obtained in example 1 divide to get an individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column with a Chiralpack AD-H, 25 × 2.1 cm, eluent CO2containing 20% mixture (ethanol + 0.1% isopr is panola), flow rate 25 ml/min, P 194 bar, T 35°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column with a Chiralpack AD-H, 25 × 0,46 cm, eluent CO2containing 20% mixture (ethanol + 0.1% isopropanol), flow rate 2.5 ml/min, P 194 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (60 mg) as a white solid with a yield 15 mg (yield = 27%). Rt = 39,2 minutes

Enantiomer 2 extract from the racemate (60 mg) as a white solid with a yield 17 mg (yield = 30%). Rt = 43,4 minutes

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 2. Hydrochloride 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to that described in example 1 to yield 39 mg as a white slaborastvorimogo solid (yield = 40%).

NMR (1H, DMSO): δ 10,28 (Ushs,1H), 8,16 (DD, 2H), 7,89 (DD, 1H), 7,76 (d, 1H), 7,55 (d, 2H), 7,49 (d, 1H), 7,28 (d, 2H), 4,06 (ushm, 1H), of 3.77 (ushm, 1H), 3,6 (ushm, 2H), 3,44 (s, 3H), 3,5-3,2 (ushm, 4H), 2,71 (s, 3H), 2.23 to (m, 3H), 1,58/1.14 in (t/m, 2H). MS (m/z): 534,1 [MH]+, 1Br.

The compound obtained in example 2, parts for the floor is placed the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralcel OJ-H, 25 × 2.1 cm, eluent CO2containing 12% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 196 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralcel OJ-H, 25 × 0,46 cm, eluent CO2containing 10% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 196 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (39 mg) as hydrochloride salt as a white solid with a yield of 7 mg Rt = 56,8 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (39 mg) as hydrochloride salt as a white solid with a yield of 7 mg Rt = 62,5 min. Purity >99% a/a on UV.

The absolute configuration of the enantiomers of 1 set using comparative analyses VCD and comparative analyses OR of the corresponding free base, representing 5-[5-({3-[(1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine. As a benchmark, using (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (see preparative example 48).

The absolute configuration of the enantiomers of 2 set as described for the enantiomer 1, as represents 5-[5-({3-[(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine.

Enantiomer 1: specific optical rotation of the corresponding free base [α]D= +47° (CHCl3, T = 20°C, c = of 0.066 g/ml).

Enantiomer 2: specific optical rotation of the corresponding free base [α]D= -42o(CHCl3, T = 20°C, c = 0,065 g/ml).

Enantiomer 2 shows fpKi (D3) > 1 log unit higher than the enantiomer 1.

Example 3. Hydrochloride of 2-methyl-5-[4-methyl-5-({3-[(1R,5S/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4H-1,2,4-triazole-3-yl]quinoline

Named the title compound is obtained from (1R,5S)/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to that described in example 1 to yield 74 mg as a white slaborastvorimogo solid (yield = 40%).

NMR (1H, DMSO): δ 10,4 (Ushs,1H), 8.3 (the Ushs, 1H), and 8.2 (d, 1H), 7,9 (t, 1H), and 7.8 (d, 1H), 7,6 (USD, 1H), between 7.4 and 7.3 (m, 5H), 4,0-3,5 (m/m, 2H), 3,7-of 3.45 (m, 2H), 3,5-3,3 (m, 7H), by 2.73 (s, 3H), 2,3 (m, 3H), 1,60, 1,1 (t,t, 2H). MS (m/z): 456,3 [MH]+.

The compound obtained in example 3, parts for receiving the individual enantiomers method prepreparation HPLC using a chiral column Chiralcel OD, 10 μm, 250 × 20 mm, eluent A - n-hexane; - isopropanol gradient isocratic 35% b, flow rate 7 ml/min, UV detection at 200-400 nm, CD 230 nm. Given the retention times obtained using analytical HPLC using a chiral column Chiralcel OD, 5 MK is, 250 × 4.6 mm, eluent A - n-hexane; - isopropanol gradient isocratic 25% b, flow rate 1 ml/min, UV detection at 200-400 nm.

Enantiomer 1 extract from the racemate (60 mg) as a white solid with a yield 15 mg (yield = 27%). Rt = 39,2 minutes

Enantiomer 2 extract from the racemate (60 mg) as a white solid with a yield 17 mg (yield = 30%). Rt = 43,4 minutes

Enantiomer 2 shows fpKi (D3) > 1 log unit higher than the enantiomer 1.

Example 4. Hydrochloride 5-[5-({3-[(1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (50 mg) by the method similar to that described in example 1, with a yield of 65 mg as a white slaborastvorimogo solid (yield = 52%).

NMR (1H, DMSO): δ 10,6 (s, 1H), 8,32 (Ushs, 1H), 8,21 (d, 1H), of 7.96 (d, 1H), to 7.84 (d, 1H), 7,66 (d, 1H), to 7.61 (d, 1H), and 7.6 (d, 1H), 7,31 (DD, 1H), 4,06 (m, 2H), 3,74 (m, 2H), 3,7-3,2 (m, 4H), to 3.36 (s, 3H), was 2.76 (s, 3H), of 2.25 (m, 4H), 1.69 in (m, 1H), 1,2 (m, 1H). MS (m/z): 524,3 [MH]+, 2Cl.

The compound obtained in example 4 divide to get an individual enantiomers method prepreparation supercritical fluid chromatography (Gilson), as described in example 1.

Enantiomer 1 extract from the racemate (56 mg) as a white solid with a yield 19 mg (yield = 36%). Rt = 26,9 minutes

The absolute is cosy configuration enantiomer 1 set using comparative analyses VCD and comparative analyses OR of the corresponding free base, represents 5-[5-({3-[(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine. As a benchmark, using (1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (see preparative example 48).

The absolute configuration of the enantiomers of 2 set as described for the enantiomer 1, as represents 5-[5-({3-[(1R,5S)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine.

Enantiomer 1: specific optical rotation of the corresponding free base [α]D=-38,4° (CDCl3, T = 20°C, c = 0,010 g/ml).

Enantiomer 2 extract from the racemate (56 mg) as a white solid with a yield 14 mg (yield = 26%). Rt = 31,4 minutes

Enantiomer 2: specific optical rotation of the corresponding free base [α]D= +34,4° (CDCl3, T = 20°C, c = 0,010 g/ml).

Enantiomer 1 shows fpKi (D3) > 0,61 log units higher than the enantiomer 2.

Example 5. Hydrochloride 5-[5-({3-[(1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]hexane (29 mg) by the method similar to that described in example 1, with 38 mg as a white slaborastvorimogo solid (yield = 51%).

YAM is ( 1H, DMSO): δ 10,16 (Ushs,1H), 8,15 (DD, 2H), 7,89 (t, 1H), 7,76 (d, 1H), 7,49 (d, 1H), was 7.36 (d, 2H), 7.23 percent (d, 2H), of 4.05 (DD, 1H), of 3.77 (DD, 1H), to 3.58 (m, 2H), 3,44 (s, 3H), 2,7 (ushm, 4H), of 2.34 (s, 3H), 2,23 (t, 2H), 2,15 (t, 1H)and 1.51 (t, 1H), 1.27mm (s, 9H), 1.14 in (m, 1H). MS (m/z): 512,4 [MH]+.

The compound obtained in example 5, parts for receiving the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson), as described in example 1, but using a pressure of 200 bar instead of bar 194.

Enantiomer 1 extract from the racemate (23 mg) as a white solid with a yield of 6.5 mg (yield = 30%). Rt = 7,0 minutes

Enantiomer 2 extract from the racemate (23 mg) as a white solid with a yield of 5 mg (yield = 23%). Rt = 7,8 minutes

Enantiomer 2 shows fpKi (D3) > of 0.9 log units higher than the enantiomer 1.

Example 6. Hydrochloride 4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-cyanophenyl)-3-azabicyclo[3.1.0]hexane (25 mg) by the method similar to that described in example 1, to yield 19 mg in the form of a white slaborastvorimogo solid (yield = 27%).

NMR (1H, DMSO): δ 10,45 (Ushs, 1H), compared to 8.26 (USD, 1H), 8,17 (d, 1H), to 7.93 (t, 1H), 7,8 (d/d, 3H), 7.5 (d, 1H), 7,46 (d, 2H), 4.09 to (d, 1H), 3,76 (d, 1H), to 3.67 (t, 1H), 3,6-3,2 (ushm, 5H), of 3.43 (s, 3H), by 2.73 (s, 3H)that was 2.34 (m, 1H), 2,25 (Quint, 2H), 1,71/1,22 (dt, 2H).

Example 7. Hydrochlorid-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenol

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-hydroxyphenyl)-3-azabicyclo[3.1.0]hexane (38 mg) by the method similar to that described in example 1, with a yield of 10 mg in the form of a white slaborastvorimogo solid (yield = 11%).

NMR (1H, DMSO): δ 10,17 (Ushs, 1H), and 9.4 (s,1H), 8,15 (USD, 2H), 7,89 (d, 1H), of 7.75 (d, 1H), of 7.48 (d, 1H), 7,12 (d, 2H), 6.73 x (d, 2H), 3,98 (DD, 1H), 3,74 (m, 1H), 3,5 (ushm, 2H), 3,44 (s, 3H), 3,5-3,2 (ushm, 4H), 2,7 (s, 3H), 2,22 (asquint, 2H), 2,03 (m, 1H), 1,46/1,03 (DM, 2H). MS (m/z): 486,2 [MH]+.

Example 8. Hydrochloride (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S)/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to that described in example 1 with a yield of 75 mg in the form of a white slaborastvorimogo solid (yield = 70%).

NMR (1H, DMSO): δ 10,46 (Ushs, 1H), 8,58 (s, 1H), and 7.4 to 7.2 (m, 5H), Android 4.04 (DD, 1H), to 3.73 (m, 1H), and 3.7 (s, 3H), 3,7-3,4 (m, 2H), 3,4-3,2 (m+t, 4H), 2,39 (s, 3H), 2,17 (m, 3H), 1,64, 1,1 (2T, 2H).

Example 9. Hydrochloride (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to that described in example 1, with vyhoda the 24 mg as a white slaborastvorimogo solid (yield = 28%).

NMR (1H, DMSO): δ 10,29 (Ushs, 1H), 8,58 (s, 1H), 7,55 (DD, 2H), 7,27 (DD, 2H), a 4.03 (DD, 1H), of 3.73 (DD, 1H), and 3.7(s, 3H), 3,55 (m, 2H), 3,5-3,2/or 3.28 (m+t, 4H), 2,39 (s, 3H), 2,19 (m, 3H), 1,59/1,12 (2T, 2H). MS (m/z): 474,1 [MH]+.

The compound obtained in example 9, divide to get an individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralcel AS-H, 25 × 2.1 cm, eluent CO2containing 11% of the mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 192 bar, T 36°C, UV detection at 220 nm, loop 2 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 10% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 199 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (138 mg) as hydrochloride salt as a white solid with a yield 59 mg Rt = 22,2 min. Purity >99%, a/a on UV.

Enantiomer 2 extract from the racemate (138 mg) as hydrochloride salt as a white solid with a yield of 50 mg Rt = 30,8 min. Purity >99%, a/a on UV.

The absolute configuration of the enantiomers of 1 set using comparative analyses VCD and comparative analyses OR of the corresponding free base, which represents the (1S,5R)-1-(4-bromo is enyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane. As a benchmark, using (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (compare preparative example 32).

The absolute configuration of the enantiomers of 2 set as described for the enantiomer 1, as representing the (1R,5S)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.

Enantiomer 1: specific optical rotation of the corresponding free base [α]D= -51° (CHCl3, T = 20°C, c = 0,00913 g/ml).

Enantiomer 2: specific optical rotation of the corresponding free base [α]D= +27° (CHCl3, T = 20°C, c = 0,0113 g/ml).

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 10. Hydrochloride (1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to that described in example 1 to yield 52 mg of a white slaborastvorimogo solid (yield = 57%).

NMR (1H CD3OD): δ 8,4 (s, 1H), 7,42 (d, 2H), 7,28 (d, 2H), 4,11 (d, 1H), 3,88 (d, 1H), and 3.8 (s, 3H), of 3.65 (m, 2H), 3.43 points (t, 2H), 3,39 (t, 2H), 2,47 (s, 3H), to 2.29 (m, 2H), of 2.21 (m, 1H), 1,44 (m, 1H), 1,33 (s, 9H), 1,3 (m, 1H). MS (m/z): 452,3 [MH]+.

Example 11. Hydrochloride (1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-(3-{[4-methyl--(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (50 mg) by the method similar to that described in example 1, with a yield of 35 mg in the form of a white slaborastvorimogo solid (yield = 32%).

NMR (1H, DMSO): δ 10,11 (Suss, 1H), 8,58 (s, 1H), 7,6 (d+d, 2H), 6,29 (DD, 1H), 4.04 the/3,74 (DD, 2H), and 3.7 (s, 3H), 3,6-3,2 (m, 4H), of 3.28 (t, 2H), 2,39 (s, 3H), 2.26 and (Quint, 1H), 2,15 (Quint, 2H), 1,53/1,2 (2T, 2H). MS (m/z): 464,1 [MH]+, 2Cl.

The compound obtained in example 11, separated for individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 8% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 194 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 8% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 190 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (29 mg) as hydrochloride salt as a white solid with a yield of 12.5 mg. Rt = 38,0 min. Purity 98.6% of a/a in the UV.

Enantiomer 2 extract from the racemate (29 mg) as a hydrochloride salt in the form of the aircraft the CSO solids with a yield of 12.5 mg Rt = 40,8 min. Purity 98.6% of a/a in the UV.

Enantiomer 1 shows fpKi (D3) > of 0.5 log units higher than the enantiomer 2.

Example 12. Hydrochloride (1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S)/1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to that described in example 1, with 38 mg as a white slaborastvorimogo solid (yield = 39%).

NMR (1H, DMSO): δ 10,18 (Ushs, 1H), 8,58 (s, 1H), 7,24 (d, 2H), 6,91 (d, 2H), 3,97 (DD, 1H), 3,74 (s, 3H), and 3.7 (s, 3H), and 3.7 (m, 1H), 3,6-3,2 (m, 4H), of 3.27 (t, 2H), 2,39 (s, 3H), of 2.15 (Quint, 2H), 2,07 (Quint, 1H), 1,49/1,05 (2T, 2H). MS (m/z): to 426.2 [MH]+.

The compound obtained in example 12, parts for receiving the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 9% mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 192 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 8% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P br, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (30 mg) as hydrochloride salt as a white solid with a yield of 5 mg Rt = 28,7 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (30 mg) as hydrochloride salt as a white solid with a yield of 12.5 mg. Rt = 36,4 min. Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 13. Hydrochloride (1R,5S/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S)/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane (55 mg) by the method similar to that described in example 1, with a yield of 30 mg in the form of a white slaborastvorimogo solid (yield = 25%).

NMR (1H CD3OD): δ of 8.37 (s, 1H), and 7.8 (d, 2H), 7,43 (d, 2H), 6,55 (s, 1H), 4,16/3,88 (2D, 2H), of 3.78 (s, 3H), and 3.7 (m, 2H), 3,48-3,4 (2T, 4H), 2,48 (s, 3H), of 2.45 (s, 3H), to 2.29 (m, 3H), 1,51/1,37 (2T, 2H). MS (m/z): 477,2 [MH]+.

Example 14. (1S,5R)-3-(3-{[4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

A mixture of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 18, 10.4 g), 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (preparative the first example 14, 15.0 g), K2CO3(7.5 g) and NaI (8,23 g) in DMF (anhydrous, 100 ml) and heat at 60°C for 15 hours. The mixture is then cooled to room temperature and diluted with Et2O (250 ml) and water (200 ml). After separation of the phases the aqueous layer is again extracted with Et2O (2 × 200 ml). The combined organic layers washed with water (2 × 150 ml) and then dried over Na2SO4. After evaporation of the solvent in vacuum the crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane), and obtain 16.5 g of free yellow solid. Thus obtained substance is treated with Et2O and get named in the title compound (13 g) as a white solid (yield 61%).

Establishing the configuration specified in the connection header is based on the facts of two types: the fact that it is derived from (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (known configuration, see preparative example 14), and comparison with spectroscopy data obtained for the (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane. Bands in the spectrum VCD named in the title of the joints coincide with the corresponding bands in the spectrum of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.0.1]hexane, in addition, a specific direction of rotation is the same for both connections.

NMR (1H, CDCl3): δ 7,89 (m, 1H), 7,49 (d, 2H), and 7.8 (d, 2H), to 3.67 (s, 3H), and 3.31 (m, 2H), 3,30 (d, 1H), 3,09 (d, 1H), 2,61 (m, 2H), 2,56 (d, 1H), 2,5 (s, 3H), of 2.45 (d, 1H), of 1.97 (m, 2H), 1,73 (m, 1H), 1,47 (t, 1H), 0,8 (DD, 1H). MS (m/z): 464 [MH]+.

Example 15. Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

To a solution of (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (example 14, 9 g) in Et2O (anhydrous, 135 ml) under nitrogen atmosphere is added dropwise chloroethanol acid (1 M solution in Et2O, and 19.4 ml). The resulting suspension is stirred at room temperature for 2 hours. Then the solid is filtered off, washed with Et2O and dried in vacuum over night and get named in the title compound (8,9 g) in the form of not-quite-white solid (yield = 92%).

NMR (1H, DMSO): δ 10,16 (Ushs, 1H), 8,58 (s, 1H), 7,72 (d, 2H), 7,51 (d, 2H), 4,1 (DD, 1H), 3,78 (DD, 1H), 3,70 (s, 3H), 3,66 (m, 2H), 3,29 (t, 2H), 2,5 (ushm, 2H), 2,39 (s, 3H), 2,33 (Quint, 2H), 2,19 (m, 1H), 1,62/1,23 (t/t, 2H). MS (m/z): 464 [MH]+.

Example 16. Hydrochloride (1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

A mixture of (1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 38, 700 mg, 2.8 mmol), 3-[(3-CHL is propyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (preparative example 14, 3.4 mmol), Na2CO3(3.4 mmol) and NaI (3.4 mmol) in DMF (anhydrous, 6 ml) and heat at 60°C for 24 hours. After removal of the solvent in vacuo the residue is dissolved in ethyl acetate and the organic layer was washed with saturated aqueous NaHCO3and dried over Na2SO4. The resulting solution is filtered and the filtrate concentrated in vacuo. The crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane) and obtain 503 mg of the free base named in the connection header.

NMR (1H, CDCl3): δ 7,89 (s, 1H), 7,32 to 7.2 (m, 3H), 3,70 (s, 3H), 3,30 (t, 2H), 3,26 (DD, 1H), 3,10 (DD, 1H), 2,60 (t, 2H), 2,52 (DD, 1H), of 2.51 (s, 3H), 2,43 (DD, 1H), was 1.94 (m, 2H), 1,74 (m, 1H), 1,40 (t, 1H), 0,76 (DD, 1H). MS (m/z): RUB 482.2 [MH]+.

Named in the title compound obtained as a white solid following the method described in example 15.

NMR (1H, DMSO): δ 10,28 (Ushs, 1H), 8,58 (s, 1H), 7,73 (d, 1H), 7,6 (m, 2H), 4/3,57 (d/m, 2H), 3,79 (d, 1H), 3,69 (s, 3H), 3,5-3,2 (susm, 1H), 3.27 to (t, 2H), 2,5 (m, 2H), 2,4 (m, 1H), of 2.38 (s, 3H), and 2.14 (Quint, 2H), 1,62/1,16 (2T, 2H). MS (m/z): 481[MH]+.

The compound obtained in example 16, divide to get an individual enantiomers method prepreparation HPLC using a chiral column Chiralpak AD, 10 μm, 250 x 21 mm, eluent A - n-hexane; isopropanol + 0.1% Isopropylamine, gradient isocratic 9%, flow rate 7 ml/min, UV detection at 200-400 nm. Given the times derivan what I get using analytical HPLC using a chiral column Chiralpak AD-H, 5 μm, 250 × 4.6 mm, eluent A - n-hexane; - isopropanol gradient isocratic 15% b, flow rate 0.8 ml/min, UV detection at 200-400 nm.

Enantiomer 1 extract in the form of a white solid, Rt = 15,4 minutes

Enantiomer 2 is extracted in the form of a white solid, Rt = 16,3 minutes

Enantiomer 2 shows fpKi (D3) > 1 log unit higher than the enantiomer 1.

Example 17. Hydrochloride (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Get (1R,5S/1S,5R)-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane ways, similar to that described in preparative examples 15, 16 and 17. From the obtained substances get named in the title compound as a white slaborastvorimogo solids, following the methods described in examples 14 and 15.

NMR (1H, DMSO) δ 10,5 (Ushs, 1H), 8,58 (s, 1H), 7,7-7.5 (m, 4H), 4.09 to (m, 1H), 3,8-3,2 (m, 8H), 3,29 (t, 2H), 2,39 (s, 3H), 2,3 (m, 1H), 2,18 (m, 2H), 1,68 (t, 1H), 1,21 (t, 1H). MS (m/z): 464 [MH]+.

The compound obtained in example 17, parts for receiving the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 25 × 0,46 cm, eluent CO2containing 10% mixture (ethanol + 0.1% isopropanol), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm, loop 1 mlparena the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 25 x 0,46 cm, eluent CO2containing 10% mixture (ethanol + 0.1% isopropanol), flow rate 22 ml/min, P 190 bar, T 36°C, UV detection at 220 nm.

Enantiomer 1 extract in the form of a white solid, Rt = 17,6 minutes

Enantiomer 2 is extracted in the form of a white solid, Rt = 18,4 min

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 18. Hydrochloride (1R,5S/1S,5R)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Get (1R,5S/1S,5R)-[4-fluoro-3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane ways, similar to that described in preparative examples 15, 16 and 17. From the obtained substances get named in the title compound as a white slaborastvorimogo solids, following the methods described in examples 14 and 15.

NMR (1H, DMSO): δ 10,2 (Ushs, 1H), 8,58 (s, 1H), 7,75 (DM, 1H), 7,72 (m, 1H), 7,53 (t, 1H), 4,06 (DD, 1H), 3,74 (DD, 1H), and 3.7 (s, 3H), 3,6 (m, 2H), 3,4 (m, 2H), or 3.28 (t, 2H), 2,39 (s, 3H), and 2.26 (m, 1H), 2,18 (m, 2H), and 1.54 (t, 1H), 1,22 (DD, 1H). MS (m/z): 481 [MH]+.

Example 19. Hydrochloride of 1-[5-[(1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone

Named the title compound is obtained from (1R,5S/1S,5R)-[5-(3-azabicyclo[3.1.0]Gex-1-yl)-2-(metiloksi)the dryer is l]ethanone (32 mg), similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield of 25 mg

NMR (1H, DMSO): δ 10,31 (Ushs, 1H), 8,58 (s, 1H), 7,52 (d, 1H), 7,49 (DD, 1H), 7,16 (d, 1H), 3,98 (DD, 1H), with 3.89 (s, 3H), and 3.7 (m, 4H), 3,6-3,2 (ushm, 4H), of 3.27 (t, 2H), 2,5 (m, 3H), 2,39 10 (s, 3H), of 2.15 (Quint, 2H), of 2.09 (Quint, 1H), 1,54-1,08 (2T, 2H). MS (m/z): 468 [MH]+.

The compound obtained in example 19, separated for individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 15% mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 196 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 15% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 190 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield 14 mg Rt = 12,5 min Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 16 mg, Rt = 16,8 min. Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2

Example 20. Hydrochloride (1S,5R/1R,5S)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane (58 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield of 99 mg

NMR (1H, DMSO): δ to 9.93 (Ushs, 1H), 8,58 (s, 1H), 7,42 (d, 2H), 7,33 (d, 2H), Android 4.04 (DD, 1H, in), 3.75 (DD, 1H), and 3.7 (s, 3H), 3,5 (m, 2H), 3,3 (ushm, 4H), 2,39 (s, 3H), 2,2 (m, 1H), 2,15 (m, 2H), 1,47-1,14 (2T, 2H). MS (m/z): 431 [MH]+.

The compound obtained in example 20 is divided to obtain the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 15% mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 192 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 15% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 190 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with the output of the m 17 mg. Rt = 7,8 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield 17 mg, Rt = 9,7 min. Purity >99% a/a on UV.

The absolute configuration of the enantiomers of 1 set using comparative analyses VCD and comparative analyses OR of the corresponding free base, which represents the (1S,5R)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane. As a benchmark, using 5-[5-({3-[(1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine (compare with example 2).

The absolute configuration of the enantiomers of 2 set as described for the enantiomer 1, as representing the (1R,5S)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane.

Enantiomer 1: specific optical rotation of the corresponding free base [α]D= -25° (CHCl3, T = 20°C, c = 0,0066 g/ml).

Enantiomer 2: specific optical rotation of the corresponding free base [α]D= +29° (CHCl3, T = 20°C, c = 0,0068 g/ml).

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 21. Hydrochloride (1S,5R/1R,5S)-1-(4-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]GE is Sana

Named the title compound is obtained from (1R,5S/1S,5R)-1-(4-forfinal)-3-azabicyclo[3.1.0]hexane (49 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield of 78 mg

NMR (1H, DMSO): δ 10,06 (Ushs, 1H), 8,58 (s, 1H), was 7.36 (DD, 2H), 7,19 (t, 2H), was 4.02 (DD, 1H), 3,74 (DD, 1H), and 3.7 (s, 3H), 3,55 (m, 2H), 3,5-3,2 (ushm, 4H), 2,39 (s, 3H), of 2.15 (m, 3H), 1,49-1,1 (2T, 2H). MS (m/z): 414 [MH]+.

The compound obtained in example 21, is divided to obtain the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 7% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 196 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 6% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 190 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield 14 mg Rt = 26,2 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with output is om 16 mg, Rt = 32,4 min. Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 22. Hydrochloride (1S,5R/1R,5S)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-(3-chlorophenyl)-3-azabicyclo[3.1.0]hexane (116 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 184 mg.

NMR (1H, DMSO): δ 9,88 (Ushs, 1H), 8,58 (s, 1H), 7,43 (d, 1H), and 7.4 to 7.2 (m, 3H), 4,06 (DD, 1H, in), 3.75 (DD, 1H), and 3.7 (s, 3H), 3,62-3,54 (t/m, 2H), 3,5-3,3 (ushm, 4H), 2,39 (s, 3H), of 2.25 (m, 1H), 2,15 (m, 2H), 1,46-1,19 (2m, 2H). MS (m/z): 431 [MH]+.

The compound obtained in example 22 and separated to obtain individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 25 × 0,46 cm, eluent CO2containing 15% mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 192 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Berger) using a chiral column Chiralpak AD-H, 25 × 0,46 cm, eluent CO2containing 15% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV-det the Ktsia at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield 14 mg Rt = 26,2 min. Purity 100% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 16 mg, Rt = 32,0 min. Purity 100% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 23. Hydrochloride (1S,5R/1R,5S)-1-(3-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-(3-forfinal)-3-azabicyclo[3.1.0]hexane (116 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 150 mg

NMR (1H, DMSO): δ of 10.21 (Ushs, 1H), 8,58 (d, 1H), and 7.4 (m, 1H), a 7.2 to 7.0 (m, 3H), a 4.03 (DD, 1H, in), 3.75 (DD, 1H), and 3.7 (s, 3H), 3,61 (t/m, 1H), 3,52 (m, 1H), 3,3 (m, 2H), or 3.28 (t, 2H), of 2.38 (s, 3H), of 2.25 (m, 1H), of 2.16 (m, 2H), 1,57-1,17 (t/m, 2H). MS (m/z): 414 [MH]+.

The compound obtained in example 23, parts for receiving the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 7% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 192 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention time for ucaut using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 x 0,46 cm, eluent CO2containing 6% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 190 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 12 mg Rt = 24,6 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 14.5 mg, Rt = 26,0 min Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 24. Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-(3-methoxyphenyl)-3-azabicyclo[3.1.0]hexane (116 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 140 mg.

NMR (1H, DMSO): δ 10,16 (Ushs, 1H), 8,58 (d, 1H), 7,26 (DD, 1H), 6,85 (m, 3H), a 4.03 (DD, 1H), of 3.77 (s, 3H), and 3.72 (DD, 1H), and 3.7 (s, 3H), 3,6-3,3 (ushm, 4H), 3,28 (t/m, 2H), 2,39 (s, 3H), 2,18 (m, 3H), 1,53-1,1 (t/m, 2H). MS (m/z): 426 [MH]+.

The compound obtained in example 24, parts for receiving the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralcel OJ-H, 25 × 2.1 cm, eluent CO2containing 13 a mixture of (2-propanol + 0.1% Isopropylamine), the flow rate of 22 ml/min, P 200 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Berger) using a chiral column Chiralcel OJ-H, 25 × 0,46 cm, eluent CO2containing 13% of a mixture of (2-propanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 13.5 mg Rt = 24,2 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 13.5 mg, Rt = 26,8 min. Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 25. Hydrochloride (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (preparative example 32, 30 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 33 mg.

NMR (1H CD3OD): δ rate of 7.54 (d, 2H), 7,28 (d, 2H), 4,08 (m, 3H), 3,8-3,6 (m, 2H), and 3.72 (s, 3H), of 3.65 (m, 3H), 3,47 (t, 2H), 3,3 (m, 3H), of 2.25 (m, 3H), of 1.93 (m, 4H), 1,48 is 1.34 (2m, 2H). MS (m/z): 478 [MH]+.

Example 26. Guide chlorid (1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (preparative example 32, 30 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 36 mg.

NMR (1H CD3OD): δ of 7.96 (m, 4H), 7,54 (d, 2H), 7,29 (m, 2H), 4,14 (d, 1H), 3,90 (m, 1H, in), 3.75 (s, 3H), 3,66 (m, 2H), 3,50 (m, 2H), 3.43 points (t, 2H), 2,30 (m, 3H), 1,50 (m, 1H), 1,34 (t, 1H). MS (m/z): 578 [MH]+.

Example 27. Hydrochloride (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (preparative example 32, 30 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield 49 mg

NMR (1H CD3OD): δ 8,97 (m, 1H), 8,82 (m, 1H), 8,31 (m, 1H), to 7.75 (m, 1H), 7,53 (d, 2H), 7,29 (m, 2H), 4,15 (d, 1H), 3,90 (d, 1H, in), 3.75 (s, 3H), to 3.67 (m, 2H), 3,50 (m, 2H), 3,42 (t, 2H), to 2.29 (m, 3H)and 1.51 (m, 1H), of 1.34 (t, 1H). MS (m/z): 471 [MH]+.

Example 28. Hydrochloride (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.0.1]hexane (preparative example 32, 30 mg) by the method similar to that described in the ore 1, in the form of a white slaborastvorimogo solids with a yield of 26 mg

NMR (1H CD3OD): δ 7,72 (m, 1H), 7,55 (m, 4H), 7,28 (d, 2H), 4,13 (d, 1H), 3,89 (d, 1H), and 3.7 (s, 3H), of 3.64 (m, 2H), 3.43 points (t, 2H), 3,38 (m, 2H), to 2.29 (m, 3H), of 1.48 (m, 1H), 1,34 (t, 1H). MS (m/z): 506 [MH]+.

Example 29. The hydrochloride of 6-[5-({3-[(1S,5R/1R,5S)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine

Named the title compound is obtained from (1R,5S/1S,5R)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane (87 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 110 mg.

NMR (1H CD3OD): δ of 8.95 (d,1H), 8,39 (d, 1H), 8,28 (t, 1H), 8,13 (d, 1H), of 7.96 (d, 1H), 7,37 (m, 4H), 4,17 (d, 1H), 3,93 (d, 1H), 3,71 (m, 2H), 3,62 (s, 3H), 3,5 (2m, 4H), 3.04 from (s, 3H), is 2.37 (m, 2H), and 2.27 (m, 1H), of 1.55 (m, 1H), 1,31 (m, 1H). MS (m/z): 490 [MH]+.

The compound obtained in example 29, separated for individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 25 × 0,46 cm, eluent CO2containing 25% mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 199 bar, T 36°C, UV detection at 220 nm, loop 1 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Berger) using a chiral column Chiralpak AD-H, 25 × 0.6 cm, eluent CO2containing 25% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 13.5 mg Rt = 24,3 minimum Purity of 87.6% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 5 mg, Rt = 26,5 min. Purity 100% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 30. Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane (205 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 246 mg.

NMR (1H, DMSO): δ 10,33 (Ushs, 1H), 8,58 (s, 1H), 7,43 (d, 2H), was 7.36 (d, 2H), Android 4.04 (DD, 1H), of 3.73 (DD, 1H), and 3.7 (s, 3H), 3,6-3,2 (ushm, 6H), 2,39 (s, 3H), 2,2 (m, 3H), 1,61-1,16 (2T, 2H). MS (m/z): 480 [MH]+.

The compound obtained in example 30, divide to get an individual enantiomers method prepreparation HPLC using a chiral column with Chirapak AS-H, 25 × 2 cm, eluent A - n-hexane; - isopropanol gradient isocratic 15%, vol./about., the flow rate of 7 ml/which in UV detection at 220 nm. Given the retention times obtained using chiral column Chiralcel OD, 25 x 0,46 cm, eluent A - n-hexane; - isopropanol gradient isocratic 10%, vol./about., a flow rate of 1 ml/min, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 15 mg Rt = 28,3 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (40 mg) as hydrochloride salt as a white solid with a yield of 16 mg Rt = 50,6 min. Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 31. Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (71,5 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 46 mg.

NMR (1H, DMSO): δ of 10.25 (Ushs, 1H), 8,58 (s, 1H), 7,6 (m, 3H), 3,97 to 3.7 (DD/m, 2H), 3,79/3,4 (DD/m, 2H), 3,69 (s, 3H), of 3.27 (t, 2H), 2,5 (m, 2H), 2,48 (s, 3H), of 2.38 (s, 3H), 2,2 (m, 1H), 2,13 (Quint, 2H), 1,61-1,01 (2T, 2H). MS (m/z): 478 [MH]+.

Example 32. Not used

Example 33. Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}is ropyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane (100 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 72 mg.

NMR (1n, DMSO): δ 10,15 (Ushs, 1H), 7,44 (d, 2H), was 7.36 (d, 2H), 4.04 the (ushm, 1H), 3,94 (DM, 2H), of 3.73 (ushm, 1H), 3,55 (s, 3H), 3,6-3,3 (ushm, 6H), up 3.22 (t, 2H), 3,13 (t, 1H), 2,23 (t, 1H), 2,,21 (m, 2H), 1,9-1,7 (m, 4H), 1,63-1,16 (2T, 2H). MS (m/z): 483 [MN]+.

The compound obtained in example 33, parts for receiving the individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AS-H, 25 × 2.1 cm, eluent CO2containing 8% of a mixture of (2-propanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 200 bar, T 36°C, UV detection at 220 nm. Given the retention times obtained using analytical supercritical fluid chromatography (Berger) using a chiral column Chiralpak AS-H, 25 × 0,46 cm, eluent CO2containing 8% of a mixture of (2-propanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (65 mg) as hydrochloride salt as a white solid with a yield of 15 mg Rt = 23,2 min. Purity 100% a/a on UV.

Enantiomer 2 extract from the racemate (65 mg) as a hydrochloride salt in the ideal of a white solid with a yield of 12 mg, Rt = 24,6 min. Purity 100% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 34. Hydrochloride (1R,5S/1S,5R)-1-(3-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-(3-bromophenyl)-3-azabicyclo[3.1.0]hexane (140 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield 23 mg, and cleaning free base named in the title compound of preparative HPLC using a column X-Terra MS C18, 5 μm, 100 × 19 mm, eluent a to H2O + 0.1% of TFA; CH3CN + 0.1% of TFA, gradient 10% (C) for 1 min, from 10% (B) 35% (C) for 12 min, flow rate of 17 ml/min, UV detection at 200-400 nm. Given the retention times obtained using column X-Terra MS C18, 5 μm, 50 × 4.6 mm, eluent a to H2O + 0.1% of TFA; CH3CN + 0.1% of TFA, gradient isocratic 25%, vol./about., a flow rate of 1 ml/min, UV detection at 200-400 nm. Rt = 6,26 min. Purity 96.4%of, and/or by UV.

NMR (1H, DMSO): δ 9,9 (Ushs, 1H), 8,58 (s, 1H), EUR 7.57 (s, 1H), 7,47 (m, 1H), and 7.3 (m, 2H), Android 4.04 (m, 1H, in), 3.75 (DD, 1H), 3,7-3,2 (m, 6H), and 3.7 (s, 3H), 2,39 (s, 3H), of 2.23 (m, 1H), 2,15 (m, 2H), 1,47 (t, 1H), 1,2 (t, 1H). MS (m/z): 512 [MH]+.

Example 35. Hydrochloride (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)Fe is Il]-3-azabicyclo[3.1.0]hexane

A mixture of (1S,5R)-(3-chloro-1-methylpropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.0.1]hexane (preparative example 20, 105 mg), 4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.43 mmol), tea (0.46 mmol) and NaI (0.43 mmol) in DMF (anhydrous, 1.6 ml) heat at 60°C for 12 hours. After removal of the solvent in vacuo the residue is dissolved in ethyl acetate and the organic layer was washed with H2O and dried over Na2SO4. The resulting solution was concentrated in vacuo, treated with cyclohexane and filtered and receive 125 mg free base named in the connection header. To a solution of the obtained substances in dichloromethane (0.2 ml) is added 0.34 mmol HCl (1 M solution in Et2O), the solvent is evaporated in vacuum, the substance thus obtained, is treated with Et2O and get 105 mg named the title compound as a white slaborastvorimogo solids.

MS (m/z): 478 [MH]+.

The compound obtained in example 35, separated for individual diastereoisomers method prepreparation HPLC using a chiral column with Chirapak AD, 25 × 2 cm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 15%, vol./about., the flow rate 7 ml/min, UV detection in the range of 220-400 nm. Given the retention times obtained using chiral the column with Chirapak AD-H, 25 x 0,46 cm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 17%, vol./about., a flow rate of 1 ml/min, UV detection in the range of 220-400 nm.

Diastereoisomer 1 is extracted from a mixture of diastereoisomers (105 mg) as hydrochloride salt as a white solid with a yield of 30 mg Rt = 17,9 min. Purity 99.4% of a/a in the UV.

NMR (1H, DMSO): δ 10,33 (Ushs, 1H), 8,58 (s, 1H), 7,71 (d, 2H), 7,53 (d, 2H), 4,07 (DD, 1H), 3,78 (DD, 1H), and 3.7 (s, 3H), and 3.7 (m, 1H), 3,56 (Ushs, 2H), 3,4 (m, 1H), 3,18 (m, 1H), and 2.4 (s, 3H), 2,4-2,3 (m, 1H), 2.26 and-is 2.09 (m, 2H), 1,72 (m, 1H), of 1.42 (d, 3H), 1,2 (m, 1H). MS (m/z): 478 [MH]+.

Diastereoisomer 2 is extracted from a mixture of diastereoisomers (105 mg) as hydrochloride salt as a white solid with a yield 46 mg Rt = 21,2 min. Purity >99% a/a on UV.

NMR (1H, DMSO): δ 10,26 (Ushs, 1H), 8,58 (s, 1H), 7.7 (d, 2H), 7,51 (d, 2H), 4,14 (DD, 1H), 3,8-3,6 (m, 3H), and 3.7 (s, 3H), 3,53 (Ushs, 1H), 3,4 (m, 1H), 3,18 (m, 1H), of 2.38 (s, 3H), 2,4-of 2.25 (m, 2H), 2,1 (m, 1H)that was 1.69 (m, 1H), 1.39 in (d, 3H), 1,2 (m, 1H). MS (m/z): 478 [MH]+.

Example 36. Hydrochloride (1R,5S/1S,5R)-1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from 1(1R,5S/1S,5R)-[2-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (109 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 144 mg.

NMR (1H CD3OD): δ to 8.41 (s,1H), 7,8 (m, 1H), 7,74 (m, 1H), 7,39 (t, 1H), 4,13 (d, 1H), 3,95 (d, 1H), 3,81 (s, 3H), of 3.73 (USD, 1H), 3,54 (d, 1H), 3,48 (m, 2H), 3,41 (m, 2H), 2,48 (s, 3H), 2,39 (m, 1H), 2,28 (kV, 2H), 1,58 (m, 1H), 1,35 (m, 1H). MS (m/z): 482 [MH]+.

The compound obtained in example 36, divide to get an individual enantiomers method prepreparation HPLC using a chiral column with Chirapak AS-H, 25 × 2 cm, eluent A - n-hexane; isopropanol + 0.1% Isopropylamine, gradient isocratic 10%, vol./about., the flow rate 7 ml/min, UV detection at 220 nm. Given the retention times obtained using analytical supercritical fluid chromatography (Berger) using a chiral column Chiralpak AD-H, 25 × 0,46 cm, eluent CO2containing 7% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (138 mg) as hydrochloride salt as a white solid with a yield of 48 mg. Rt = 21,2 min. Purity 100% a/a on UV.

Enantiomer 2 extract from the racemate (138 mg) as hydrochloride salt as a white solid with a yield 46 mg Rt = 22,7 minimum Purity of 99% a/a on UV.

Enantiomer 2 shows fpKi (D3) > 1 log unit higher than the enantiomer 1.

Example 37. Hydrochloride of 1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone

Named C is the head of the compound is obtained from 1-[4-[(1S,5R/1R,5S)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone (87 mg), similar to that described in example 1, in the form of a white slaborastvorimogo solids to yield 70 mg

NMR (1N, CDCl3the respective free base: δ 8.0 a (s, 1H), 7.7 (d, 1H), 6,7-6,8 (m, 2H), 3,9 (s, 3H), and 3.7 (s, 3H), at 3.35 (m, 4H), 3,1 (d, 1H), and 2.6 (m, 3H), by 2.55 (s, 3H), of 2.5 (s, 3H), of 2.45 (m, 1H), 2.0 (m, 2H), of 1.75 (m, 1H), 0,8 (m, 1H). MS (m/z): 468 [MH]+.

Example 38. Hydrochloride of 1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone

Named the title compound is obtained from 1-[(1S,5R/1R,5S)-3-azabicyclo[3.1.0]Gex-1-yl)-2-(metiloksi)phenyl]-1-propanone (106 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield of 75 mg

NMR (1N, CDCl3) free base: δ is 7.9 (s, 1H), 6,65 (d, 1H), 6,7 (m, 2H), 3,9 (s, 3H), and 3.7 (s, 3H), at 3.35 (m, 3H), 3,1 (d, 1H), 2,9 (m, 2H), and 2.6 (m, 3H), of 2.5 (s, 3H), of 2.45 (m, 1H), 2.0 (m, 2H), 1.8 m (m, 1H), 1,1 (m, 3H), 0.8 a (m, 1H). MS (m/z): 482 [MH]+.

Example 39. Hydrochloride (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (53 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solid ve is estva with the release of 7 mg.

NMR (1H, DMSO): δ 10,48 (Ushs, 1H), 8,55 (s, 1H), 7,9-to 7.6 (m, 4H), 3,9-3,1 (ushm, 8H), 3,68 (s, 3H), of 2.36 (s, 3H), 2.13 in (m, 2H), of 1.66 (m, 1H), 1,2 (m, 1H), 1,1 (m, 1H). MS (m/z): 464[MH]+.

Example 40. Hydrochloride (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

The free base is named in the title compound is obtained from (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane. A mixture of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 39, 727 mg of 2.97 mmol), 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (preparative example 14, 3.6 mmol), K2CO3(3.6 mmol) and NaI (2,97 mmol) in anhydrous DMF warm at 60°C for 24 hours. After removal of the solvent in vacuo the residue is dissolved in ethyl acetate and the organic layer was washed with saturated aqueous NaHCO3and dried over Na2SO4. The resulting solution is filtered and the filtrate concentrated in vacuo. The crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane) and receive 940 mg of the free base named in the connection header.

Free base (886 mg) is transformed into the hydrochloride salt (847 mg) according to the method described in example 1. Named in the title compound obtained as white Tverdov the matter. Analytical chiral HPLC confirms that the product is identical to the enantiomer 2 obtained in example 16.

Data of NMR and MS consistent with the data shown in example 16.

Absolute configuration named in the header of the connection is confirmed with the use of comparative analyses VCD and comparative analyses OR of the corresponding free base, which represents the (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane. As a benchmark, using (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (see example 14).

Specific optical rotation of the corresponding free base [α]D= -42° (CDCl3, T = 25°C, c = 0.005 g/0.8 ml).

Examples 41 to 52

To a solution of the appropriate 3-thio-5-aryl-1,2,4-triazole (obtained by the method similar to that described in preparative example 13, 0,131 mmol) in dry acetonitrile (2 ml) is added 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory polystyrene (90 mg, 2.2 mmol/g) and the mixture was shaken for 30 minutes at room temperature. Add (1S,5R)-3-(3-chlorpropyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (40 mg) and the mixture was shaken at 70°C for three hours. After the cooling gap is placed a mixture of the resin is removed by filtration, washed with methanol (2 ml) and then remove the solvent under reduced pressure. Do the cleaning using maxnamelen HPLC using a column Waters XTerra Prep MS C18, 10 μm, 30 × 150 mm, using the conditions specified in the table.

Postrain
TimeStream%%
Preview mode040 ml/min991
140 ml/min991
Working mode040 ml/min991
1040 ml/min7525
14,540 ml/min1090
1540 ml/min0100
040 ml/min0100
0,245 ml/min0100
1,545 ml/min0100
240 ml/min0100
A = N2O + 0.1% of formic acid
B = ACN + 0.1% of formic acid

Then the solvent is removed under reduced pressure, and obtain the corresponding compound in the form of salts of formate. The residues dissolved in methanol (1 ml) and loaded into cartridges SCX SPE (1 g), washed with methanol (3 ml) and elute with 2 M solution of ammonia in methanol (3 ml), and then the solvent is removed under reduced pressure. The residues dissolved in dichloromethane (1 ml), add 1.0 M solution of HCl in diethyl ether (0,131 mmol), then the solvent is removed under reduced pressure and receive the products of the reactions of compounds in the form of hydrochloride, summarized in table 1.

Conditions analytical chromatography

Column X-Terra MS C18, 5 mm, 50 x 4.6 mm;

mobile phase: a - rest. NH4HCO3,10 mm, pH 10; CH3CN;

gradient: 10% (B) for 1 min, from 10% (B) 95% (C) for 12 min, 95% (B) for 3 min;

a flow rate of 1 ml/min;

the interval of wavelengths of UV 210-350 nm;

the mass range between 100 and 900 amu;

ionization ES+.

Table 1
Etc.The name and formulaR (min)Analytical data
41Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
9,35NMR (1H, DMSO): δ 10,84 (Ushs, HCl), 8,77 (DD, 1H), 8,19 (USD, 1H), 7,71 (d, 2H), 7,66 (m, 1H), 7,51 (d, 2H), 4,08 (DD, 1H), ca and 3.8 (s, 3H), 3,8-3,3 (m, 7H), of 2.54 (s, 3H), 2,30 (m, 1H), 2,22 (m, 2H)and 1.83 (m,1H), of 1.20 (m, 1H).
NMR (19F, DMSO): δ -60,8.
MS (m/z): 474 [MH]+.
42Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
8,84NMR (1H, DMSO): δ 10,24 (Ushs, HCl), of 9.56 (m, 1H), 9,39 (m, 1H), 8,01 (s, 1H), to 7.64 (m, 2H), 7,44 (m, 2H), 4,08 (m, 1H), 3,68 (s, 3H), to 3.58 (ushm, 1H), 3,7-3,3 (m, 6H), and 2.26 (m, 1H), 2,1 (m, 2H), 1,58 (t, 1H), 1.14 in (t, 1H).
MS (m/z): 461 [MH]+.
43Hydrochloride (1S,5R)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
9,27MS (m/z): 477 [MH]+
44Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
8,92MS (m/z): 461 [MH]+
45Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
of 10.72NMR (1H, DMSO): δ 10,56 (Ushs, HCl), a 7.85 (d, 1H), 7,71 (d, 2H), 7,51 (d, 2H), only 6.64 (d, 1H), 4,08 (DD, 1H, in), 3.75 (DD, 1H), 3,71 (s, 3H), 3,7-3,3 (m, 4H), of 3.27 (t, 2H), 2,31 (m, 1H), 2,28 (s, 3H), 2,18 (m, 2H), 1,74 (t, 1H), 1,21 (t, 1H).
MS (m/z): 463 [MH]+.
46Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
for 9.47 MS (m/z): 474 [MH]+
47Hydrochloride (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
9,79MS (m/z): 494 [MH]+
48Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
10,15NMR (1H, DMSO): δ 10,41 (Ushs, HCl), 9,11 (Ushs, 1H), 8,63 (Ushs, 1H), 7,66 (d, 2H), 7,44 (d, 2H), was 4.02 (DD, 1H), 3,83 (s, 3H), 3,68 (d, 1H), 3,6-3,2 (m, 6H), of 2.54 (s, 3H), of 2.25 (m, 1H), and 2.14 (m, 2H), 1,65 (m, 1H), 1,14 (m,1H).
MS (m/z): 475 [MH]+.
49Hydrochloride (1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
9,15MS (m/z): 467 [MH]+
50Hydrochloride of 2-methyl-6-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline
10,17I have R 1H, DMSO): δ 10,41 (Ushs, HCl), 8,67 (Ushs, 1H), of 8.47 (s, 1H), and 8.2 (s, 2H), 7,72 (m, 1H), 7,68 (m, 2H), 7,49 (m, 2H), 4,07 (m, 1H), 3,74 (DD, 1H), and 3.72 (s, 3H), of 3.64 (DD, 1H), 3,51 (m, 1H), 3,3 (m, 4H), 2,81 (, 3H), 2,28 (m, 1H), 2,19 (m, 2H), 1,72 (t, 1H), 1,19 (t, 1H).
MS (m/z): 524 [MH]+.
51Hydrochloride 8-fluoro-2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline
10,14MS (m/z): 542 [MH]+.
52Hydrochloride of 2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline
10,12MS (m/z): 524 [MH]+.

Examples 53-58

To a solution of the appropriate 3-thio-5-aryl-1,2,4-triazole (0,124 mmol) in dry acetonitrile (2 ml) is added 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory polystyrene (85 mg, 2.2 mmol/g) and the mixture was shaken for 30 minutes at room temperature, then add (1S,5R)-3-(3-chlorpropyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (40 mg) and the mixture was shaken at 50°C during the night. After cooling the mixture, the resin is removed by filtration, washed with methanol (2 ml) and the ATEM remove the solvent under reduced pressure. Do the cleaning using maxnamelen HPLC.

Conditions of preparative chromatography (prep. HPLC 6 of 6 connections)

Column X-Terra MS C18, 5 mm, 100 × 19 mm;

mobile phase: a - rest. NH4HCO3, 10 mm, pH 10; CH3CN;

gradient: 30% (B) for 1 min, from 30% (C) up to 95% (B) in 9 min, 95% (B) for 3 min;

the flow rate of 17 ml/min;

the interval of wavelengths of UV 210-350 nm;

the mass range between 100 and 900 amu;

ionization ES+.

Then the solvent is removed under reduced pressure and get a connection in the form of free bases. The residues dissolved in dichloromethane (2 ml), add 1.0 M solution of HCl in diethyl ether (0,124 mmol), then the solvent is removed under reduced pressure and receive the products of the reactions of compounds in the form of hydrochloride, summarized in table 2.

Conditions analytical chromatography

Column X-Terra MS C18, 5 mm, 50 × 4.6 mm;

mobile phase: a - rest. NH4HCO3, 10 mm, pH 10; CH3CN;

gradient: 30% (B) for 1 min, from 30% (C) up to 95% (B) in 9 min, 95% (B) for 3 min;

a flow rate of 1 ml/min;

the interval of wavelengths of UV 210-350 nm;

the mass range between 100 and 900 amu;

ionization ES+.

Analytical data
Table 2
Etc.The name and formulaR (min)
53Hydrochloride (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane
to 6.58NMR (1H, DMSO): δ at 10.64 (Ushs, HCl), 8,72 (DD, 1H), with 8.05 (d, 1H), 7,73 (d, 1H), to 7.67 (t, 1H), 7.62mm (d, 1H), 7,56 (DD, 1H), 4,01 (d, 1H), 3,79 (d, 1H), 3,7-3,3 (m, 5H), 3,5-3,3 (2 x t, 4H), 2.57 m (s, 3H), 2,46 (m, 1H), 2,18 (m, 2H), 1,73 (t, 1H)and 1.15 (t, 1H).
MS (m/z): 492 [MH
54Hydrochloride (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane
6,09NMR (1H, DMSO): δ 10,66 (Ushs, HCl), 9,63 (m, 1H), for 9.47 (DD, 1H), 8,09 (DD, 1H), 7,73 (d, 1H), to 7.67 (t, 1H), 7.62mm (d, 1H), 3,99 (d, 1H), 3,78 (d, 1H, in), 3.75 (s, 3H), 3,7-3,4 (m, 2H), 3,32 (m, 4H), of 2.36 (m, 1H), 2,17 (m, 2H), 1,74 (t, 1H), 1.14 in (t, 1H). MS (m/z): 479 [MH
55Hydrochloride (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane
6,22NMR (1H, DMSO): δ of 10.05 (Ushs, HCl), 9,38 (s, 1H), 9,19 (s, 2H), 7,74 (d, 1H), to 7.67 (t, 1H), 7.62mm (d, 1H), was 4.02 (USD, 1H), 3,81 (USD, 1H), 3,69 (t, 3H), to 3.58 (m, 1H), 3,5-3,2 (m, 5H), of 2.38 (m, 1H, of 2.16 (m, 2H), 1.55V (t, 1H), 1,17 (t, 1H).
MS (m/z): 479 [MH]+.
56Hydrochloride (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane
7,17NMR (1H, DMSO): δ 10,45 (Ushs, HCl), 7,73 (d, 1H), to 7.67 (t, 1H), 7.62mm (d, 1H), 4,01 (d, 1H), 3,79 (d, 1H), 3,6-3,3 (m, 5H), 3,5-3,3 (t, 2H), or 3.28 (t, 2H), 2,70 (s, 3H), is 2.37 (m, 1H), 2,34 (s, 3H), of 2.16 (m, 2H), 1,67 (t, 1H), 1.55V (t, 1H).
MS (m/z):512 [MH]+
57Hydrochloride (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane
7,7NMR (1H, DMSO): δ 10,23 (Ushs, HCl), 9,17 (s, 1H), to 8.70 (s, 1H), 7,73 (d, 1H), to 7.67 (t, 1H), to 7.61 (d, 1H), 4,01 (d, 1H), with 3.89 (s, 3H), and 3.8 (d, 1H), 3,6-3,3 (m,2H), 3,5-3,2 (ushm, 4H), 2,61 (s, 3H), is 2.37 (m, 1H), of 2.16 (m, 2H), 1.61 of (t, 1H), 1,16 (t, 1H).
MS (m/z): 493 [MH
58Hydrochloride (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane
8,92NMR (1H, DMSO): δ at 10.64 (Ushs, HCl), 7,98 (d, 2H), 7,95 (d, 2H), 7,73 (d, 1H), of 7.70 (t, 1H), to 7.61 (d, 1H), 4.00 points (d, 1H), 3,79 (d 1H), to 3.67 (s, 3H), 3,55 (d, 1H), 3.45 points (d, 1H), 3,34 (ushm, 2H), 3,29 (t, 2H), 2,35 (m, 1H), 2,17 (m, 2H), 1,73 (t, 1H), 1.14 in (t, 1H).
MS (m/z): 545 [MH

Example 59. Hydrochloride of 1-{4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}-2-pyrrolidinone

In the tube Slinka load 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine (EUR. example 2; 0.15 g), 2-pyrrolidinone (32 mg), Tris(dibenzylideneacetone)dipalladium(0) (6 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (130 mg) and 1,4-dioxane (2 ml). Tube Slinka tightly closed with a Teflon screw cap and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture is cooled to room temperature, diluted with dichloromethane (10 ml), filtered and concentrated in vacuo. The crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane) and receive 60 mg of free base named in the connection header. To a solution of the obtained substances in dichloromethane (0.4 ml) is added HCl (0,11 ml, 1 M solution in Et2O), the solvent is evaporated in vacuum, the substance thus obtained, is treated with Et2O and get 64 mg named the title compound as a white solid.

NMR (1H, DMSO: δ 10,48 (Ushs, 1H), 8,24 (USD, 1H), 8,18 (d, 1H), to 7.93 (t, 1H), 7,81 (d, 1H), 7.62mm (d, 2H), 7,54 (d, 1H), 7,31 (d, 2H), Android 4.04 (DD, 1H), 3,82 (t, 2H), 3,76 (DD, 1H), 3,70/3,10 (ushm, 8H), of 3.45 (s, 3H), 2,74 (s, 3H), of 2.25 (m, 2H), 2,16 (m, 1H), 2,07 (m, 2H), 1,63/1,10 (t/t, 2H). MS (m/z): 539 [MH]+.

Example 60. Hydrochloride 5-{5-[(3-{(1R,5S/1S,5R)-1-[4-(1,1-dioxido-2-isothiazolinone)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine

In the tube Slinka load 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine (EUR. example 2; 0.15 g), 1,1-dioxide isothiazolinone (46 mg), Tris(dibenzylideneacetone)dipalladium(0) (6 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10 mg), cesium carbonate (130 mg) and 1,4-dioxane (2 ml). Tube Slinka tightly closed with a Teflon screw cap and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture is cooled to room temperature, diluted with dichloromethane (10 ml), filtered and concentrated in vacuo. The crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane) and receive 50 mg of free base named in the connection header. To a solution of the obtained substances in dichloromethane (0.3 ml) is added HCl (0,087 ml, 1 M solution in Et2O), the solvent is evaporated in vacuum, the substance thus obtained, is treated with Et2O and produces the t 52 mg named the title compound as a white solid.

NMR (1H, DMSO): δ 10,57 (Ushs, 1H), 8,27 (USD, 1H), 8,19 (d, 1H), 7,94 (t, 1H), 7,82 (d, 1H), 7,55 (d, 1H), 7,32 (d, 2H), 7,18 (d, 2H), a 4.03 (DD, 1H), and 3.72 (m, 3H), 3,60/3,20 (ushm, 8H), of 3.45 (s, 3H), of 2.75 (s, 3H), 2,41 (m, 2H, in), 2.25 (m, 2H), and 2.14 (m, 1H), 1,66/1,10 (t/m, 2H). MS (m/z): 575 [MH]+.

Example 61. Hydrochloride (1R,5S/1S,5R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (338 mg) by the method similar to that described in example 1 to yield 247 mg

NMR (1H CD3OD): δ 8,4 (s, 1H), 7,55 (t, 1H), 7,37 (d, 1H), 7,32 (d, 1H), 4.2V (d, 1H), 3,91 (d, 1H), 3,81 (s, 3H), 3,76 (d, 1H), to 3.67 (d, 1H), 3,51 (t, 2H), 3.43 points (t, 2H), 2,47 (s, 3H), 2,41 (m, 1H), 2,31 (m, 2H,), to 1.61 (t, 1H), 1,45 (t, 1H). MS (m/z): 496 [MH]+.

The compound obtained in example 61, share to get an individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 25 × 2.1 cm, eluent CO2containing 12% of a mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 194 bar, T 36°C, UV detection at 220 nm. Given the retention times obtained using analytical supercritical fluid chromatography (Berger) using a chiral column Chiralpak AD-H, 25 x 0,46 cm, eluent CO2containing 10% of the mixture is (ethanol + 0.1% Isopropylamine), the flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (100 mg) as hydrochloride salt as a white solid with a yield 42 mg Rt = 27,1 min. Purity 100% a/a on UV.

Enantiomer 2 extract from the racemate (100 mg) as hydrochloride salt as a white solid with a yield 34 mg, Rt = 31,0 min. Purity 100% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 2 log units higher than the enantiomer 2.

Example 62. Hydrochloride of 1-(2-(metiloksi)-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)ethanone

Named in the title compound obtained as white solid with the yield 51 mg (yield = 60%) by the method similar to that described in example 1 from 1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone (35 mg) and 3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (60 mg, obtained by the method similar to that described in preparative example 13).

NMR (1H, CDCl3, free base): δ 7,80-of 7.70 (m, 4H), to 7.50 (s, 1H), 7,27-7,20 (m, 1H), 6,85 (d, 1H), 3,86 (s, 3H), 3,62 (s, 3H), 3,40-3,24 (m, 3H), 3.15 in (d, 1H), 2,58 (s, 3H), 2,65 is 2.55 (m, 2H), 2,54 at 2.45 (m, 2H), 2,10-1,90 (Quint, 2H,), 1,65-of 1.57(m, 1H), 1,35 (m, 1H), 0.75 in (m, 1H). MS (m/z):531 [MH]+.

Example 63. Hydrochloride of 1-[5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(meth is Loxy)phenyl]ethanone

Named in the title compound obtained as white solid with the yield 40 mg (yield = 50%) by the method similar to that described in example 1 from 1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone (35 mg) and 3-[(3-chloropropyl)thio]-5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole (54 mg, obtained by the method similar to that described in preparative example 13).

NMR (1H, CDCl3, free base): δ 7,56-7,19 (m, 5H), at 6.84 (d, 1H), 3,86 (s, 3H), 3,62 (s, 3H), 3,38-3,24 (m, 3H), 3,10 (d, 1H), 2,58 (s, 3H), 2,65-to 2.42 (m, 4H), 2,10-1,90 (Quint, 2H), 1,65-of 1.57(m, 1H), 1,35 (m, 1H), 0.75 in (m, 1H). MS (m/z): 499 [MH]+.

Example 64. Hydrochloride of 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone

Named in the title compound obtained as yellow solid with a yield 32 mg (yield = 42%) by the method similar to that described in example 1 from 1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone (35 mg) and 3-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}pyridine (48 mg, obtained by the method similar to that described in preparative example 13).

NMR (1H, CDCl3, free base): δ 8,87 (s, 1H), to 8.70 (d, 1H), 8.0 a (d, 1H), of 7.48 (s, 1H), 7,43 (m, 1H), 7.23 percent (m, 1H), at 6.84 (d, 1H), 3,86 (s, 3H), 3,62 (s, 3H), 3,40-of 3.25 (m, 3H), 3,10 (d, 1H), 2,58 (s, 3H), 2,67-to 2.42 (m, 4H), 2,10-1,90 (Quint, 2H), 1,65-of 1.57(m, 1H), 1,35 (m, 1H), 0.75 in (m, 1H. MS (m/z): 464 [MH]+.

Example 65. Hydrochloride of 1-[5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone

Named in the title compound obtained as yellow solid with a yield of 50 mg (yield = 60%) by the method similar to that described in example 1 from 1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone (35 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine (60 mg).

NMR (1H, CDCl3, free base): δ 10,38 (Ushs,1H), and 8.2 (m, 2H), to $ 7.91 (t, 1H), 7,78 (d, 1H), 7.5 (m, 3H), 7,17 (d, 1H), was 4.02 (d, 1H), with 3.89 (s, 3H), 3,74 (DD, 1H), 3,6-3,2 (m, 6H), of 3.45 (s, 3H), of 2.72 (s, 3H), of 2.5 (s, 3H), 2.23 to (Quint, 2H), 2,11 (Quint, 1H), 1.57 in (t, 1H), 1,1 (t, 1H). MS (m/z): 528 [MH]+.

Example 66. Hydrochloride of 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone

Named in the title compound obtained as white solid with a yield of 24 mg (yield = 32%) by the method similar to that described in example 1 from 1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]ethanone (35 mg) and 3-[(3-chloropropyl)thio]-4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole (50 mg, obtained by the method similar to that described in preparative example 13).

NMR (1H, CDCl3freely the base): δ 7,49 (s, 1H), 7,24 (m, 1H), 6,85 (d, 1H), 4,14-of 4.05 (m, 2H), 3,86 (s, 3H), 3,62 (s, 3H), 3,57 is 3.40 (m, 2H), 3,29 is 3.15 (m, 3H), 3,05 (d, 1H), 2,82-2,95 (m, 1H), 2,63-to 2.40 (m, 4H), 2,58 (s, 3H), 2,15-to 1.77 (m, 6H), 1,62 (m, 1H), 1,32 (m, 1H), 0,70 (m, 1H). MS (m/z); 471 [MH]+.

Example 67. Hydrochloride of 1-(2-hydroxy-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)ethanone

Named in the title compound obtained as white solid with a yield of 35 mg (yield = 33%) by the method similar to that described in example 1 from 1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}of ethanone (43 mg) and 3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole (80 mg, obtained by the method similar to that described in preparative example 13).

NMR (1H, CDCl3, free base): δ 12,2 (s, 1H), 7,80-of 7.70 (m, 4H), to 7.50 (s, 1H), 7,30 (m, 5 1H), to 6.88 (d, 1H), 3,86 (s, 3H), 3,40-of 3.25 (m, 3H), 3,10 (d, 1H), 2,58 (s, 3H), 2,65 to 2.35 (m, 4H), 2,0 (Quint, 2H), 1,58 (m, 1H), 1,35 (m, 1H), 0,70 (m, 1H). MS (m/z): 517 [MH]+.

Example 68. Hydrochloride of 1-{5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}of ethanone

Named in the title compound obtained as white solid with the yield 27 mg (yield = 29%) by the method similar to that described in example 1 from 1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}of ethanone (40 mg) and 3-[(3-what labrafil)thio]-5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole (67 mg, obtained by the method similar to that described in preparative example 13).

NMR (1H, DMSO): δ 11,82 (s,1H), 10,26 (Ushs, 1H), a 7.85 (m, 1H), 7,76 (d, 1H), to 7.67 (m, 1H), to 7.61 (m, 1H), 7,51 (DD, 1H), 6,97 (d, 1H), was 4.02 (DD, 1H), 3,74 (DD, 1H), to 3.64 (s, 3H), 3,55 (m, 2H), 3,3 (m, 4H), 2,67 (, 3H), of 2.15 (m, 3H), of 1.52 (t, 1H), 1,13 (t, 1H). MS (m/z): 485 [MH]+.

Example 69. Hydrochloride of 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone

Named in the title compound obtained as white solid with the yield 36 mg (yield = 43%) by the method similar to that described in example 1 from 1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}of ethanone (38 mg) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (57 mg).

NMR (1H, CDCl3, free base): δ 12,2 (s, 1H), 7,88 (s, 1H), 7,50 (s, 1H), 7,24 (m, 1H), return of 6.58 (d, 1H), 3,68 (s, 3H), 3,32 (m, 3H), 3,10 (d, 1H), 2,58-2,47 (m, 4H), 2,58 (s, 3H), 2,47 (s, 3H), 2.0 (m, 2H), 1,62 (m, 1H), 1,35 (m, 1H), 0,68 (m, 1H). MS (m/z): 454 [MH]+.

Example 70. Hydrochloride of 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}of ethanone

Named in the title compound obtained as yellow solid with a yield of 24 mg (yield = 32%) by the method similar to that described in example 1 from 1-{5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-Ki is roxiprin}of ethanone (30 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine (55 mg).

NMR (1H, CDCl3, free base): δ 12,1 (s, 1H), 8,10 (DD, 2H), to 7.67 (t, 1H), 7,50 (m, 2H), 7.23 percent (m, 2H), 6,85 (d, 1H), 3.45 points is 3.23 (m, 3H), 3,40 (s, 3H), is 3.08 (d, 1H), to 2.67 (s, 3H), 2,65-to 2.41 (m, 4H), to 2.55 (s, 3H), 2,02 (m, 2H)that was 1.58 (m, 1H), 1,32 (m, 1H), 0,64 (m, 1H). MS (m/z): 514 [MH]+.

Example 71. Hydrochloride of 1-[5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone

Named in the title compound obtained as white solid with the yield 51 mg (yield = 47%) by the method similar to that described in example 1 from 1-[5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone (52 mg, obtained in a manner analogous to the methods described in preparative examples 43-45) and 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (69 mg).

NMR (1H, DMSO): δ 10,24 (Ushs, 1H), charged 8.52 (m, 1H), 7,42 (d, 1H), 7,40 (DD, 1H), was 7.08 (d, 1H), 3,93 (DD, 1H), 3,81 (s, 3H), to 3.67 (DD, 1H), to 3.64 (s, 3H), of 3.48 (m, 2H), or 3.28 (m, 2H), up 3.22 (t, 2H), 2,86 (q, 2H), 2,33 (, 3H), 2,1 (m, 2H), 2,03 (m, 1H), 1,48 (t, 1H), 1,0 (t, 1H), was 1.04 (t, 3H). MS (m/z): 482 [MH]+.

Named in the title compound separated for individual enantiomers method prepreparation HPLC using a chiral column Chiralpak AS-H, 5 μm, 250 x 21 mm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 40% b, flow rate 7 ml/min, UV detection at 200-400 nm. Given the times hold the cation is obtained using analytical HPLC using a chiral column Chiralpak AS-H, 5 µm, 250 x 4.6 mm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 40% b, flow rate 0.8 ml/min, UV detection at 200-400 nm.

Enantiomer 1 extract from the racemate (66 mg) as a white solid with a yield of 10 mg (yield = 30%). Rt = 17.2 in minutes

Enantiomer 2 extract from the racemate (66 mg) as a white solid with a yield of 10 mg (yield = 30%). Rt = 19,1 minutes

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 72. Hydrochloride of 2-methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole

Get 5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazol of the dihydrochloride of 2-methyl-1,3-benzothiazol-5-amine in a manner analogous to the methods described in preparative examples 15, 16 and 17. From the obtained substances get named in the title compound as a yellow solid, following the methods described in examples 14 and 15.

NMR (1H, DMSO): δ 10,54 (Ushs, 1H), 8,58 (m, 1H), 8.0 a (d, 1H), 7,9 (d, 1H), 7,34 (DD, 1H), 10 4,0 (DD, 1H, in), 3.75 (DD, 1H), 3,70 (s, 3H), of 3.65 (m, 1H), only 3.57 (m, 1H), 3,35 (m, 2H), 3,30 (t, 2H), and 2.8 (s, 3H), 2,39 (s, 3H), and 2.27 (m, 1H), 2,19 (m, 2H), 1,7 (t, 1H), 1,19 (t, 1H). MS (m/z): 467 [MH]+.

Named in the title compound separated for individual enantiomers method prepreparation HPLC using a chiral column with Chralpak AS-H, 5 μm, 250 × 21 mm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 13%, flow rate 7 ml/min, UV detection at 200-400 nm. Given the retention times obtained using analytical HPLC using a chiral column Chiralpak AS-H, 5 μm, 250 x 4.6 mm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 13%, flow rate 1 ml/min, UV detection at 200-400 nm.

Enantiomer 1 extract from the racemate (55 mg) as a white solid with a yield 17 mg (yield = 62%). Rt = 17,1 minutes

Enantiomer 2 extract from the racemate (55 mg) as a white solid with a yield 18 mg (yield = 65%). Rt = 19,3 minutes

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 73. Hydrochloride of 2-methyl-6-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole

Get 6-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole 2-methyl-1,3-benzothiazol-6-amine in a manner analogous to the methods described in preparative examples 15, 16 and 5. From the obtained substances get named in the title compound as a yellow solid, following the methods described in examples 14 and 15.

NMR (1H CD3OD): δ 8,39 (s,1H), 7,98 (d, 1H), 7,89 (d, 1H), and 7.5 (DD, 1H), 4,19 (d, 1H), 3,92 (d, 1H), and 3.8 (s, 3H), and 3.72 (d, 2H), 3,52 (t, 2H), 3,42 (t, H), to 2.85 (s, 3H), 2,47 (s, 3H), 2,31 (m, 3H), and 1.54 (t, 1H), 1,41 (t, 1H). MS (m/z): 467 [MN]+.

Example 74. Hydrochloride of 1-methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1H-indazole

Get 5-[(1R,5S/1S,5R)-3-azabicyclo[3.1.0]Gex-1-yl]-1-methyl-1H-indazol of 1-methyl-1H-indazol-5-amine in a manner analogous to the methods described in preparative examples 15, 16 and 5. From the obtained substances get named in the title compound as a yellow solid, following the methods described in examples 14 and 15.

NMR (1H, DMSO): δ 10,4 (Ushs,1H), 8,58 (m, 1H), 8,01 (s, 1H), of 7.70 (d, 1H), 7,63 (d, 1H), 7,39 (DD, 1H), of 4.05 (m, 1H), Android 4.04 (s, 3H), of 3.75 (d, 1H), 3,70 (s, 3H)and 3.59 (m, 2H), 3,39 (t, 2H), 3,26 (t, 2H), 2,39 (, 3H), 2,18 (m, 3H), 1.61 of (t, 1H), 1.14 in (t, 1H). MS (m/z): 450 [MH]+.

Named in the title compound separated for individual enantiomers method prepreparation SFC (Gilson) using a chiral column Chiralpak AS-H, 250 × 21 mm, modifier: ethanol + 0.1% Isopropylamine 12%, flow rate 22 ml/min, P 200 bar, T 36°C, UV detection at 220 nm. Given the retention times obtained using analytical SFC (Berger) using a chiral column Chiralpak AS-H, 5 μm, 250 × 4.6 mm, modifier: ethanol + 0.1% Isopropylamine 12%, flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (80 is g) as a white solid with a yield 25 mg (yield = 62%). Rt = 19,5 minutes

Enantiomer 2 extract from the racemate (80 mg) as a white solid with a yield 28 mg (yield = 70%). Rt = 22,8 minutes

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 75. Hydrochloride (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane

Get (1R,5S/1S,5R)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane 6-(trifluoromethyl)-3-pyridylamine in a manner analogous to the methods described in preparative examples 37 and 5. From the obtained substances get named in the title compound as a yellow solid, following the methods described in examples 14 and 15.

NMR (1H, DMSO): δ 10,46 (Ushs, 1H), 8,73 (Ushs, 1H), 8,58 (m, 1H), and 8.0 (DD, 1H), of 7.90 (d, 1H), 4,12 (m, 1H), 3,78 (d, 1H), 3,70 (s, 3H), and 3.7 (m, 1H), 3,54 (m, 1H), 3,39 (t, 2H), 3,29 (s, 2H), 2,39 (m, 3H), 2,47 (m, 1H), 2,18 (m, 2H), 1,71 (m, 1H), 1,33 (m, 1H). NMR (19F, DMSO): δ -66,2 (C). MS (m/z): 465 [MH]+.

Examples 76-94

To a solution of the appropriate 3-thio-5-aryl-1,2,4-triazole (obtained by the method similar to that described in preparative example 13, 0,063 mmol) in dry acetonitrile (2 ml) is added 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-datafactory polystyrene (43 mg, 2.2 mmol/g), and the mixture was shaken for 1 hour at room temperature, then add the (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-chlorpropyl)-3-azabicyclo[3.1.0]hexane (20 mg) and the mixture was shaken at 70°C for 3.5 hours. After cooling the mixture, the resin is removed by filtration, washed with dichloromethane (2 ml) and methanol (2 ml) and the collected liquid phase is evaporated under reduced pressure. There are two isomers due to S - and N-alkylation, and the main isomer is the desired S-alkilirovanny isomer. The obtained isomers share using maxnamelen HPLC using a column Waters XTerra Prep MS C18, 10 μm, 30 × 150 mm, using the conditions specified in the table.

TimeStream%%
Preview mode040 ml/min991
140 ml/min991
Working mode040 ml/min991
1040 ml/min7525
14,50 ml/min 1090
1540 ml/min0100
Postrain040 ml/min0100
0,245 ml/min0100
1,545 ml/min0100
240 ml/min0100

A = N2O + 0.1% of formic acid

B = acetonitrile + 0.1% of formic acid

Then the solvent is removed under reduced pressure and get mentioned in the headers of connection in the form of salts of formate.

In the case of examples 93 and 94 isomers share flash chromatography on silica gel. S-Alkylated isomers is dissolved in dry diethyl ether and cooled at 0°C. Gradually add 1,2 EQ. HCl (1.0 M solution in diethyl ether). The obtained precipitated precipitated substance is decanted, washed with pentane and filtered, and receive the products of reactions in the form with which it hydrochloridw.

Conditions analytical chromatography

Examples 76-90

ColumnX Terra MS C18, 5 μm, 50 × 4.6 mm
The mobile phaseA: H2O+0.1% of TFA; B: CH3CN+0.1% of TFA
Gradient10% (C) for 1 min, from 10% (In) to 90% (C) for 12 min, 90% (C) Within 3 min
The flow velocity1 ml/min
The interval of wavelengths UV200-400 nm
The mass rangeBetween 100 and 900 amu
IonizationES+

Example 91

ColumnX Terra MS C18, 5 μm, 50 × 4.6 mm
The mobile phaseA: H2O+0.2% HCOOH; B: CH3CN+0.2% HCOOH
Gradient10% (C) for 1 min, from 10% (B) 95% (C) for 12 min, 95% (B) for 3 min
The flow velocity1 ml/min
The interval of wavelengths UV210-400 nm
The mass rangeBetween 100 and 900 amu
IonizationES+

Example 93

Analytical columnBOND SB C18, 50 mm; i.d. 4.6 mm; 1,8 µm
The mobile phaseAcetam., 5 mm/acetonitrile+0.1% of formic acid
Gradient97/3 > 36/64, vol./about., for 3.5 min, > 0/100, vol./about., for 3.5 min
The flow velocity2 ml/min
DetectionDAD, 210-350 nm
MSES+
Retention time2,42 min
[M+H]+484/486 (picture 1Br)
Analysis98,17%, a/a (using DAD)

Example 94

Analytical columnBOND SB C18, 50 mm; i.d. 4.6 mm; 1,8 µm
The mobile phaseAcetam., 5 mm/acetonitrile+0.1% of formic acid
Gradient97/3 > 36/64, vol./about., for 3.5 min, > 0/100, vol./about., for 3.5 min
The flow velocity2 ml/min
DetectionDAD, 210-350 nm
MSES+
Retention timeto 3.02 min
[M+H]+552/554 (picture 1Br)
Analysis99,51%, a/a (using DAD)

Example 96. Hydrochloride 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from 1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane manner similar to that described in example 1, in the form of a white slaborastvorimogo solid (70 mg, 45%).

NMR (corresponding to the free base,1N CD3OD): δ 8,71 (s, 1H), to 7.93 (s, 1H), 7,78 (DD, 1H), 7,15 (d, 1H), and 3.72 (s, 3H), 3,41 (d, 1H), on 3.36 (t, 2H), 3,13 (d, 1H), 2,8 (d, 1H), 2,68 (m, 2H), 2,54 (s, 3H), 2,48 (DD, 1H), 2,04 (m, 3H), 1,6 (m, 1H), of 1.26 (DD, 1H). MS (m/z 465 [MH] +.

The compound obtained in example 96, share to get an individual enantiomers method prepreparation HPLC using a chiral column with Chirapak AD-H, 5 μm, 250 × 4.6 mm, eluent A - n-hexane; ethanol + 0.1% Isopropylamine, gradient isocratic 30%, vol./about., the flow rate 6 ml/min, UV detection at 270 nm. Given the retention times obtained using chiral column with Chirapak AD-H, 5 μm, 250 × 4.6 mm, eluent A - n-hexane; ethanol, gradient isocratic 30%, vol./about., the flow rate 0.8 ml/min, UV detection at 200-400 nm.

Enantiomer 1 extract from the racemate (70 mg) as hydrochloride salt as a white solid with a yield 18 mg Rt = KZT 19.09 minimum Purity of 100% and/and UV.

Enantiomer 2 extract from the racemate (70 mg) as hydrochloride salt as a white solid with a yield 18 mg Rt = 21,6 minimum Purity of 99% and/and UV.

Enantiomer 2 shows fpKi (D3) > 1 log unit higher than the enantiomer 1.

Example 97. The dihydrochloride of 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane

3-(Phenylmethyl)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane (0,19 mmol) dissolved in 1,2-dichloroethane (1 ml) and add 1-chloramination (0.21 mmol). After two cycles of exposure of microwave frequencies (5 min at 12°C and 10 min at 140°C) the solvent is removed under reduced pressure. Add methanol (2 ml) and the solution is exposed to microwave cycle (10 min, 120°C). The solvent is removed under reduced pressure and obtain 47 mg of the intermediate compound that is used without additional purification process and a method similar to that described in example 1, and get named in the title compound (5 mg, 5%) as a white slaborastvorimogo substances.

NMR (1H CD3OD): δ scored 8.38 (s, 1H), to 7.99 (DD, 1H), to 7.67 (DD, 1H), of 7.48 (DD, 1H), 4,18 (d, 1H), 4,06 (d, 1H), 3,88 (d, 1H), 3,79 (s, 3H), 3,63 (DD, 1H), 3,50 (m, 2H), 3,41 (t, 2H), 2.49 USD (m, 1H), 2,44 (s, 3H), 2,31 (m, 2H,), was 1.69 (m, 1H), 1,65 (DD, 1H). MS (m/z): 465 [MH]+.

Example 98. Hydrochloride (1R,5S/1S,5R)-1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from 1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 57) in the manner similar to that described in example 1, in the form of a white slaborastvorimogo solid (5.4 mg, yield = 19%).

NMR (formate salt) (1N, CDCl3): δ 7,9 (s, 1H), 6,8 (m, 4H), of 6.65 (s, 2H), x 6.15 (s, 2H), of 5.05 (s, 2H), 3,66 (s, 3H), 3,4 (d, 1H), 3,25 (t, 2H), 3,2 (d, 1H), 2,75 (t, 2H), and 2.6 (d, 1H), to 2.55 (m, 1H), 2,5 (s, 3H), 2.0 (m, 2H)and 1.7 (m, 1H), 1,45 (t, 1H), 0,8 (m, 1H); acid proton not observed. MS (hydrochloride salt) (m/z): 475 [MH]+.

Examples 99-104

With the unity of examples 99-104 derived from (1R,5S/1S,5R)-3-(3-chlorpropyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane (40 mg) by the method similar to the methods described in the examples 53-58, white slabogorchichny solids.

ExampleThe name and formulaR
(min)
Analytical data
99Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane
of 5.82MS (m/z): 477 [MH]+
100Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane
of 5.05NMR (1H, DMSO): δ 9,11 (d, 1H), 8,76 (DD, 1H), 8,73 (Ushs, 1H), 8,08 (d, 1H), 8,01 (USD, 1H), 7,83 (d, 1H), 4,25 (d, 1H), 3,95 (d, 1H), 3,81 (s, 3H), 3,79 (d, 1H), 3,71 (DD, 1H), 3,54 (t, 2H), 3.45 points (t, 2H), 2,89 (, 3H), 2,46 (m, 1H), 2,33 (m, 2H),1.69 in (DD, 1H), 1,47 (t, 1H). Acid proton not observed. MS (m/z): 476 [MH]+.
101Hydrochloride (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[31.0]hexane
4,82MS (m/z): 476 [MH]+
102Hydrochloride (1S,5R/1R,5S)-3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane
6,27MS (m/z): 461 [MH]+
103Hydrochloride (1S,5R/1R,5S)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane
of 5.40MS (m/z): 496 [MH]+
104Hydrochloride (1S,5R/1R,5S)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexaneof 7.36MS (m/z): 528 [MH]+

Examples 105-109

Connection examples 105-109 obtained from 5-[(1R,5S/1S,5R)-3-(3-chlorpropyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole (40 mg) in a manner analogous to the methods describe the figures in the examples 53-58, white slabogorchichny solids.

ExampleThe name and formulaR (min)Analytical data
105Hydrochloride (1S,5R/1R,5S)-2-methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazoleof 5.83MS (m/z): 478 [MN]+
106Hydrochloride (1S,5R/1R,5S)-2-methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole5,04MS (m/z): 477 [MN]+

107Hydrochloride (1S,5R/1R,5S)-2-methyl-5-(3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-3-azabicyclo[3.1.0]Gex-1-yl)-1,3-benzothiazole
6,28 MS (m/z): 462 [MH]+
108Hydrochloride (1S,5R/1R,5S)-5-[3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole
5,35MS (m/z): 497 [MH]+
109Hydrochloride (1S,5R/1R,5S)-2-methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}-1,3-benzothiazole
the 7.43NMR (1H, DMSO): δ 7,98-8,03 (m, 4H), of 7.97 (d, 1H), 7,89 (s, 1H), 7,45 (d, 1H), 4.2V (d, 1H), 3,91 (d, 1H), of 3.78 (s, 3H), of 3.73 (d, 2H), 3,49 (m, 4H), 2,88 (s, 3H), of 2.36 (m, 3H), 1,6 (t, 1H), 1,37 (t, 1H). MS (m/z): 530 [MH]+.

Example 110. Hydrochloride (1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (400 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with the release of 383 mg (yield = 46%).

NMR (1H CD3OD): δ 8,46 (s, 1H), 7,54 (Ushs, 1H), 7,47 (USD, 1H), 7,41 (USD, 1H), 4,19 (d, 1H), 3,09 (d, 1H), a 3.87 (s, 3H), 3,71 (m, 2H), 3,51 (t, 2H), 3.46 in(t, 2H), 2.49 USD (s, 3H), 2,33 (m, 3H), 1,67 (m, 1H), 1.39 in (m, 1H). MS (m/z): 482 [MH]+.

Hydrochloride (1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane share for individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralcel AD-H, 25 × 2.1 cm, eluent CO2containing 9% mixture (ethanol + 0.1% Isopropylamine), flow rate 22 ml/min, P 192 bar, T 36°C, UV detection at 220 nm, loop 2 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 25 × 0,46 cm, eluent CO2containing 10% mixture (ethanol + 0.1% Isopropylamine), flow rate 2.5 ml/min, P 180 bar, T 35°C, UV detection at 220 nm.

Enantiomer 1 extract from the racemate (100 mg) as hydrochloride salt as a white solid with a yield of 19.4 mg Rt = 12,6 min. Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (100 mg) as hydrochloride salt as a white solid with a yield of 18.3 mg, Rt = 14,7 min. Purity >99% a/a on UV.

Enantiomer 1 shows fpKi (D3) > 1 log unit higher than the enantiomer 2.

Example 111. Hydrochloride (1R,5S/1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)asabis the CLO[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (400 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with the release of 349 mg (yield = 45%).

NMR (1H CD3OD): δ 8,46 (s, 1H), 7,75-the 7.65 (m, 2H), 7,38 (m, 1H), 4,1 (d, 1H), 3,93 (d, 1H), of 3.78 (s, 3H), 3,71 (d, 1H), 3,54 (d, 1H), 3,48 (t, 2H), 3,38 (t, 2H), of 2.45 (s, 3H), 2,36 10 (m, 1H, in), 2.25 (m, 2H), and 1.54 (m, 1H), 1,34 (m, 1H). MS (m/z): 481 [MH]+.

Hydrochloride (1R,5S/1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane share for individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 250 × 4.6 mm, eluent n-hexane/ethanol, 88/12 (isocratic), flow rate 1 ml/min, P 200-400 bar, T 36°C, UV detection at 200-400 nm, loop 2 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 250 × 4.6 mm, eluent n-hexane/ethanol, 88/12 (isocratic), flow rate 1 ml/min, P 200-400 bar, T 36°C, UV detection at 200-400 nm.

Enantiomer 1 extract from the racemate (98 mg) as hydrochloride salt as a white solid with a yield of 37 mg. Rt = 20,4 minimum Purity of 98.5%, a/a on UV.

Enantiomer 2 extract from the racemate (98 mg) as hydrochloride salt as a white solid with a yield of 35 mg, Rt = 23,0 minimum Purity of 99.5% a/a on UV.

Enantiomer 2 shows fpKi (D3) > 1 log unit higher than the enantiomer 1.

Example 112. Hydrochloride (1R,5S/1S,5R)-1-[4-(metiloksi)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[4-(metiloksi)-5-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (430 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with access 658 mg (yield = 76%).

NMR (1H CD3OD): δ of 8.37 (c, 1H), EUR 7.57 (m, 2H), 717 (d, 1H) x 3.9 (m, 4H), 3, 77 (s, 3H), 3,74 (m, 1H), 3,65-3,30 (m, 6H), is 2.44 (s, 3H), of 2.21 (m, 2H), 2.13 in (m, 1H), USD 1.43 (t, 1H), 1,24 (m, 1H). MS (m/z): 494 [MH]+.

Hydrochloride (1R,5S/1S,5R)-1-[4-(metiloksi)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane share for individual enantiomers method prepreparation supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 250 × 4,6 mm, eluent n-hexane/ethanol + 0.1% Isopropylamine, 70/30 (isocratic), the flow rate ml/min, UV detection at 270 nm, loop 2 ml. Shows the retention times obtained using analytical supercritical fluid chromatography (Gilson) using a chiral column Chiralpak AD-H, 250 × 4.6 mm, eluent n-hexane/ethanol 70/30 (isocratic), flow rate 0.8 ml/min, UV detection at 200-400 nm.

Enantiomer 1 extract from the racemate (100 mg) as hydrochloride salt as a white solid with a yield of 18.3 mg Rt = 15,5 min Purity >99% a/a on UV.

Enantiomer 2 extract from the racemate (100 mg) as hydrochloride salt as a white solid with a yield of 22.2 mg, Rt = 17,5 min Purity >99% a/a on UV.

Enantiomer 2 shows fpKi (D3) > 2 log units higher than the enantiomer 1.

Example 113. Hydrochloride (1R,5S/1S,5R)-1-[4-(4-chloro-2-forfinal]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane

Named the title compound is obtained from (1R,5S/1S,5R)-1-[4-chloro-2-forfinal]-3-azabicyclo[3.1.0]hexane (130 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 112 mg

NMR (1H CD3OD): δ of 8.27 (s, 1H), and 7.3 (t, 1H), and 7.1 (m, 2H), 3,95 (d, 1H), and 3.8 (d, 1H), to 3.67 (s, 3H), of 3.56 (DD, 1H), 3,4-3,2 (m, 5H), was 2.34 (s, 3H), of 2.15 (m, 3H), 1,4 (t, 1H), 1,18 (t, 1H). MS (m/z): 448 [MH]+.

Example 114. Hydrochloride (1R,5S/1S,5R)-1-[3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl-1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from 1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane (150 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids exit 160 mg

NMR (1H CD3OD): δ to 8.41 (s, 1H), 7,49 (t, 1H), and 7.3 (s, 1H), 7,37 (d, 1H), 7,24 (m, 1H), 4,17 (d, 1H), 3,9 (d, 1H), and 3.8 (s, 3H), of 3.69 (d, 2H), 3,51 (t, 2H), 3,42 (t, 2H), 2,47 (s, 3H), 2,3 (m, 3H), 1.57 in (DD, 1H), of 1.36 (t, 1H). MS (m/z): 480 [MH]+.

Example 115. Hydrochloride (1R,5S/1S,5R)-1-(2-fluoro-4-were)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from 1-(2-fluoro-4-were)-3-azabicyclo[3.1.0]hexane (148 mg) by the method similar to that described in example 1, in the form of a white slaborastvorimogo solids with a yield of 60 mg

NMR (1H CD3OD): δ 8, 39 (s, 1H), 7,26 (t, 1H), 7,01 (m, 2H), 3,93 (m, 1H), of 3.77 (m, 4H), 3,61 (m, 1H), 3,41-to 3.38 (m, 5H), 2,47 (s, 3H), of 2.36 (s, 3H), of 2.23 (m, 2H), 2, 19 (m, 1H), 1,45 (t, 1H), 1,21 (t, 1H). MS (m/z): 428 [MH]+.

Example 116. Hydrochloride (1R,5S/1S,5R)-1-[3-chloro-4-(metiloksi)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained from 1-[3-chloro-4-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane (60 mg) in a manner similar to described in the example 1, in the form of a white slaborastvorimogo solids with a yield of 56 mg

NMR (1H CD3OD): δ 8,4 (s, 1H), 7,35 (m, 1H ), and 7.1 (m, 2H), 4,01 (m, 1H), with 3.89 (m, 4H), and 3.8 (s, 3H), 3,6-3,3 (m, 6H), 2,47 (s, 3H), of 2.23 (m, 2H), 2,19 (m, 1H), 1,4 (m, 1H), 1,2 (m, 1H). MS (m/z): 460 [MH]+.

Example 117. Hydrochloride (1R,5S/1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

A mixture of (1R,5S/1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexane (70 mg), 3-[(3-chloropropyl)thio]-4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole (85 mg), potassium carbonate (43 mg), Na2CO3and sodium iodide (45 mg) in anhydrous DMF (0.6 ml) and heat at 60°C for 24 hours. After removal of the solvent in vacuo the residue is dissolved in ethyl acetate and the organic phase is washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The crude reaction product is purified flash chromatography (dichloromethane to 10% Meon in dichloromethane) and obtain 65 mg of the free base named in the connection header. To a solution of the obtained substances in dichloromethane (1 ml) is added HCl (1 M solution in Et2O, 0,13 ml), the solvent is evaporated in vacuum, thus obtained substance is treated with Et2O and get 69 mg named the title compound as a white solid washes the VA (yield 50%).

NMR (1H, DMSO): δ accounted for 10.39 (Ushs, 1H), 8,56 (s, 1H), 7,39 (d, 2H), 7,35 (d, 2H), was 4.02 (m, 1H), and 3.72 (m, 1H), 3,68 (s, 3H), 3,60 (t, 1H), 3,51 (ushm, 1H), 3.27 to (m, 4H), 2,60 (s, 3H), is 2.37 (s, 3H), of 2.35 (s, 3H), 2,19 (m, 1H), 2,16 (m, 2H), 1,62 (m, 1H)and 1.15 (m, 1H). MS (m/z): 507,2 [MH]+.

Example 118. Hydrochloride (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained by way similar to that described in example 117 (using (1R,5S/1S,5R)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane), in the form of a white solid with a yield of 55%.

NMR (1H, CDCl3): δ 10,44 (Ushs, 1H), 8,56 (s, 1H), 8,29 (d, 1H), 8,17 (t, 1H), 8,09 (d, 2H), 25 to 7.84 (d, 1H), 7,43 (d, 2H), 4,08 (m, 1H, in), 3.75 (m, 1H), 3,68 (s, 3H), of 3.64 (t, 1H), 3,53 (ushm, 1H), or 3.28 (m, 4H), is 2.37 (s, 3H), and 2.27 (m, 1H), 2,17 (m, 2H), by 1.68 (m, 1H), 1,17 (m, 1H). MS (m/z): 541,2 [MH]+.

Example 119. Hydrochloride (1R,5S/1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained by way similar to that described in example 117 (using (1R,5S/1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-azabicyclo[3.1.0]hexane), in the form of a white solid with a yield of 53%.

NMR (1H, CDCl3): δ 10,53 (ush, 1H), 8,58 (s, 1H), 7,43 (d, 1H), 7,28-7,38 (m, 3H), 4,07 (DD, 1H), 3,7 (DD, 1H), 3,70 (s, 3H), 3,61 (t, 1H), 3,53 (m, 1H), 3,34 (m, 2H), 3,29 (t, 2H), 2,64 (s, 3H), 2,39 (s, 3H), by 2.73 (s, 3H), of 2.23 (m, 1H), measuring 2.20 (m, 2H), 1,68 (t, 1H), 1,16 (t, 1H). MS (m/z): 507,1 [MH]+.

Example 120. Hydrochloride (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained by way similar to that described in example 117 (using (1R,5S/1S,5R)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane), in the form of a white solid in 51%yield.

NMR (1H, CDCl3): δ 10,44 (ush, 1H), 8,58 (s, 1H), 7,49 (d, 1H), 7,45 (dt, 1H), 7,37 (t, 2H), 7,18 (dt, 1H), at 6.84 (t, 1H), 4,08 (DD, 1H), 3,76 (DD, 1H), 3,70 (s, 3H), 3,62 (t, 1H), 3,54 (TM, 1H), or 3.28 (t, 4H), 2,48 (s, 3H), 2,39 (s, 3H), 2,24 (m, 1H), 2,19 (t, 2H), 1,65 (t, 1H), 1,16 (t, 1H). MS (m/z): 472.0 M. [MH]+.

Example 121. Hydrochloride (1R,5S/1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane

Named the title compound is obtained by way similar to that described in example 117 (using (1R,5S/1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-azabicyclo[3.1.0]hexane), in the form of a white solid with a yield of 55%.

MS (m/z): 491,2 [MH]+.

Example 122. Hydrochloride (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-oxazol-5-yl)]-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azab the cyclo[3.1.0]hexane

A mixture of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (preparative example 18, 60 mg), 3-[(3-chloropropyl)thio]-5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole (preparative example 78, 78 mg), 2-tert-Butylimino-2-diethylamino-1,3-dimethylpyridine-1,3,2-diazaphospholidine on polystyrene (2.2 to mmol/g, 140 mg) and a catalytic amount of NaI in dry acetonitrile (3 ml) and heat at 70°C for 4 h and then overnight at 55°C. the Resin is removed by filtration and washed with acetonitrile (2 × 3 ml). Remove the solvent in vacuo, the remaining solid is dissolved in dry DMF (0.5 ml) and add 3-[(3-chloropropyl)thio]-5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole (preparative example 78, 60 mg), and then potassium carbonate (118 mg). The resulting suspension is warm at 60°C over night. At room temperature add a saturated solution of sodium bicarbonate (4 ml) and the suspension extracted with DCM (2 × 6 ml). The resulting solution was loaded into a SCX column and elute Meon, and then 0.25 M solution Meon/NH3. The resulting material purified preparative HPLC and then converted into the hydrochloride by following the method described in example 15, and get named in the title compound as a white slaborastvorimogo solid (37 mg, yield 27%).

NMR (1H, DMSO): δ 10,38 (ush, 1H), 7,71 (d, 1H), to 7.64 (t, 1H), to 7.59 (d, 1H), 3,98 (USD, 1H), 3,76 (OSD, 1), the 3.65 (s, 3H), 3,54 (ush, 1H), 3,44 (Ust, 1H), 3,31 (ush, 2H), 3,24 (t, 2H), 2,47 (s, 3H), 2,35 (m, 1H), to 2.29 (s, 3H), 2,11 (m, 2H), and 1.63 (t, 1H), 1,13 (t, 1H). MS (m/z): 496 [MH]+.

All publications, including patents and patent applications, without limitation, cited in this specification, are included as reference as if each individual publication was specifically separately listed as incorporated by reference into this application in its entirety.

It should be borne in mind that the present invention covers all combinations of particular groups described in the description above.

Application, who are part of this description and claims, may be used as the basis for priority in respect of any subsequent application. The formula of the invention, a subsequent application may be directed to any sign or combination of signs described in this application. It can refer to a product, composition, method or use, and may include, as examples and without limitation, the claims, below.

1. Derived azabicyclo[3.1.0]hexane General formula (I)

or its pharmaceutically acceptable salt, where
G denotes phenyl, optionally substituted by R1;
R1chosen independently from the group consisting of halogen, hydroxy, cyano, C1-4-alkyl, halogen-C1-4-Ala is La, With1-4-alkoxy, Halonen-C1-4-alkoxy, C1-4alkanoyl; or R1corresponds to the group R5;
R5is a fragment selected from the group consisting of isoxazolyl, one or twice substituted C1-4-alkyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazolinone, teinila, substituted C1-4-alkyl, thiazolyl, double-substituted C1-4-alkyl, pyridyl, substituted single or double-halogen-C1-4-alkyl, or 2-pyrrolidinone;
or G means pyridyl, benzothiazolyl or indazoles, and R1means1-4-alkyl or halogen-C1-4-alkyl, and p is 1;
R1represents hydrogen or C1-4-alkyl;
R3represents a C1-4-alkyl;
R4represents a hydrogen or phenyl group, optionally one or twice substituted by halogen With1-4-alkyl or halogen; chinoline, substituted with halogen or1-4-alkyl; oxazolyl, substituted halogen-From1-4-alkyl or C1-4-alkyl; thieno[2,3-C]pyrazolyl, substituted halogen-From1-4-alkyl or C1-4-alkyl; tetrahydropyranyl; pyridinyl, optionally one or twice substituted by halogen With1-4-alkyl or C1-4-alkyl; pyridazinyl; pyrazolyl, one or twice substituted by halogen, C1-4-alkyl, halogen-C1-4-alkyl; pyrimidine is l; furanyl, one or twice substituted C1-4-alkyl; thiazolyl, substituted double-C1-4-alkyl; pyrazinyl, substituted C1-4-alkyl; triazolyl, substituted C1-4-alkyl; isoxazolyl, substituted C1-4-alkyl; thienyl, substituted with halogen;
p means an integer from 0 to 2;
and when R1represents chlorine and p is 1, then R1is not in the ortho-position relative to the connection with the rest of the molecule; and when R1corresponds to R5, p is equal to 1.

2. The compound of formula I' according to claim 1

or its pharmaceutically acceptable salt,
where G, p, R1, R2, R3, R4and R5have the meanings indicated in claim 1.

3. The compound according to claim 1, where R1represents bromine, fluorine, triptoreline, cyano, hydroxy, chlorine, methoxy, tert-butyl, trifluoromethyl; and R5represents isoxazolyl, one or twice substituted C1-4-alkyl, 2-pyrrolidinyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazoline, 2-thienyl, substituted C1-4-alkyl, 2-pyridyl, substituted single or double-halogen-C1-4-alkyl, 2-thiazolyl, double-substituted C1-4-alkyl.

4. The compound according to claim 1, where p is 1 or 2.

5. The compound according to claim 1, where R2represents hydrogen.

6. The compound according to claim 1, where R4represents not necessarily alseny phenyl, substituted chinoline, optionally substituted pyridinyl, substituted pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, substituted furanyl, substituted thienyl, substituted oxazolyl, substituted isoxazolyl, substituted thiazolyl, substituted triazolyl.

7. The compound of formula (IB)

or its pharmaceutically acceptable salt,
where R1, p, R3and R4have the values listed in any one of claims 1 to 6.

8. The compound of formula (IC)

or its pharmaceutically acceptable salt,
where R1means1-4-alkyl;
p is 1;
R3means1-4-alkyl;
R4means oxazolyl, substituted C1-4-alkyl.

9. The compound of formula (ID)

or its pharmaceutically acceptable salt,
where R1means C1-4-alkyl;
p is 1;
R3means1-4-alkyl;
R4means oxazolyl, substituted C1-4-alkyl.

10. The compound of formula (IE)

or its pharmaceutically acceptable salt, where
G represents 2-pyridyl or 3-pyridyl,
R1means halogen-From1-4-alkyl;
p is 1;
R3means1-4-alkyl;
R4means phenyl, optionally substituted by halogen With1-4-alkyl, oxazolyl, single or double-C is displaced C 1-4-alkyl, pyrazinyl, pyridinyl or thiazolyl, substituted C1-4-alkyl.

11. The compound of formula (IF)

or its pharmaceutically acceptable salt, where
R1means1-4-alkyl;
p is 1;
R3means1-4-alkyl;
R4means phenyl, oxazolyl, pyrazinyl, pyridinyl or thiazolyl, optionally substituted C1-4-alkyl or halogen-C1-4-alkyl.

12. Stereochemical isomer enriched in configuration (1S,5R) of the formula (IA)

or its pharmaceutically acceptable salt, where
G is chosen from the group consisting of phenyl, pyridyl, benzothiazolyl, indazole;
p is an integer from 0 to 5;
R1chosen independently from the group consisting of halogen, hydroxy, cyano, C1-4-alkyl, halogen-C1-4-alkyl, C1-4-alkoxy, halogen-C1-4-alkoxy, C1-4alkanoyl; or R1corresponds to the group R5;
R2represents hydrogen or C1-4-alkyl;
R3represents a C1-4-alkyl;
R4represents a hydrogen or phenyl group, heterocyclyl group, 5 - or 6-membered heteroaromatic group, or 8-11 membered bicyclic group, any of which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of Gal which the gene cyano, C1-4-alkyl, halogen-C1-4-alkyl, C1-4-alkoxy, C1-4alkanoyl;
R5is a fragment selected from the group consisting of isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxido-2-isothiazolinone, teinila, thiazolyl, pyridyl, 2-pyrrolidinone, such group optionally substituted by one or two substituents selected from halogen, cyano, C1-4-alkyl, halogen-C1-4-alkyl, C1-4-alkoxy, C1-4alkanoyl;
and when R1represents chlorine and p is 1, then R1is not in the ortho-position relative to the connection with the rest of the molecule; and when R1corresponds to R5, p is equal to 1.

13. Stereochemical isomer enriched in configuration (1S,5R) formula (IB)'

or its pharmaceutically acceptable salt, where
R1, p, R3and R4have the values listed in any one of claims 1 to 6.

14. Stereochemical isomer enriched in configuration (1S,5R) formula (IC)'

or its pharmaceutically acceptable salt, where R1, p, R3and R4have the values listed in any one of claims 1 to 6.

15. Stereochemical isomer enriched in configuration (1S,5R) formula (ID)'

or its pharmaceutically acceptable salt, where
R1, p, R3and R4they are the only values specified in any one of claims 1 to 6.

16. Stereochemical isomer enriched in configuration (1S,5R) or (1R,5R) formula (IE)'

or its pharmaceutically acceptable salt, where
G represents 2-pyridyl or 3-pyridyl, and R1, p, R3and R4have the values listed in any one of claims 1 to 6.

17. Stereochemical isomer enriched in configuration (1S,5R) formula (IF)'

or its pharmaceutically acceptable salt, where
R1, p, R3and R4have the values listed in any one of claims 1 to 6.

18. Stereochemical isomer enriched in configuration (1R,5S)selected from the group that includes
- 5-[5-({3-[(1R,5S)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 2;
- 5-[5-({3-[(1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 1;
- 5-[5-({3-[(1R,5S)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 1;
- (1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, enantiomer 2;
- (1R,5S)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 2;
1-[5-[(1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,triazol-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone, enantiomer 2;
- 2-methyl-5-[(1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole, enantiomer 2; or its pharmaceutically acceptable salt.

19. The compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt, selected from the group which includes
- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;
- 5-[5-({3-[(1S,5R)-1-(4-methoxyphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 1;
- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;
- 5-[5-({3-[(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 2;
- 2-methyl-5-[4-methyl-5-({3-[(1R,5S/1S,5R)-1-phenyl-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4H-1,2,4-triazole-3-yl]quinoline;
- 2-methyl-5-[4-methyl-5-({3-[(1S,5R)-1-phenyl-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4H-1,2,4-triazole-3-yl]quinoline, enantiomer 2;
- 5-[5-({3-[(1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;
5-[5-({3-[(1S,5R)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 1;
- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;br/> - 5-[5-({3-[(1S,5R)-1-(4-tert-butylphenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 2;
- 4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile;
- 4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenol;
- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1R,5S/1S,5R)-1-(4-tert-butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(3,4-dichlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(3,4-dichlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 2;
- (1R,5S/1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-methoxyphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 2;
- (1R,5S/1S,5R)-1-[4-(5-methyl-3-isoxazolyl)f the Nile]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1,0]hexane;
- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- 1-[5-[(1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-[5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]alanon, enantiomer 1;
- (1S,5R/1R,5S)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-chlorophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1S,5R/1R,5S)-1-(4-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}PDEC is l)-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1S,5R/1R,5S)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo [3,1 .0]hexane;
- (1S,5R)-1-(3-chlorophenyl)-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1S,5R/1R,5S)-1-(3-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(3-forfinal)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(metiloksi)phenyl]-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-[3-{[4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- 5-[5-({3-[(1S,5R/1R,5S)-1-(4-chlorophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine;
- 5-[5-({3-[(1S,5R/1R,5S)-1-(4-chlorophenyl)-3-sabicic what about[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-2-methylinosine, enantiomer 1;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane, enantiomer 1;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane, enantiomer 2;
- (1R,5S/1S,5R)-1-(3-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, diastereoisomer 1;
- (1S,5R)-3-(1-methyl-3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane, diastereoisomer 2;
- (1R,5S/1S,5R)-1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azab the cyclo[3.1.0]hexane;
- (1S,5R)-1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane, enantiomer 2;
- 1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-[4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone;
- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- 2-methyl-6-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline;
- 8-fluoro-2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline;
- 2-methyl-5-{4-methyl-5-[(3-{(1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4H-1,2,4-triazole-3-yl}quinoline;
- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- 1-{4-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}-2-pyrrolidinone;
- 5-{5-[(3-{(1R,5S/1S,5R)-1-[4-(1,1-dioxido-2-isothiazolinone)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine;
- (1R,5S/1S,5R)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-methyl-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- 1-(2-(metiloksi)-5-{(1R,5S/1S,5R)-3-(3-{[4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;
- 1-[5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-[5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-{2-(metiloksi)-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-(2-hydroxy-5-{(1R,5S/1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;
- 1-{5-[(1R,5S/1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}Etalon;
- 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-{2-hydroxy-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-[5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone;
- 1-[5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone, enantiomer 1;
- 2-methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- 2-methyl-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole, enantiomer 1;
- 2-methyl-6-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,1,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- 1-methyl-5-[(1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1H-indazol;
- 1-methyl-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-lH-indazol, enantiomer 1;
- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-pyrid sinil)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-1-methyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-1,2,3-triazole-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-pyrimidinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-5-isoxazolyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo [3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-pyrazole-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-3-(trifluoromethyl)-1,3-oxazol-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-pyridi who yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,5-dimethyl-3-furanyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-2-thienyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-(3-{[4-ethyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo [3.1.0]hexane;
- (1R,5S/1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-6-(trifluoromethyl)-3-pyridinyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- 5-[5-({3-[(1R,5S/1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-C]pyrazole;
- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R)-1-[5-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane, enantiomer 2;
- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R/1S,5S)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-PI is idini]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-{3-{[4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R/1R,5S)-2-methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- (1S,5R/1R,5S)-2-methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- (1S,5R/1R,5S)-2-methyl-5-[3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-3-azabicyclo[3.1.0]Gex-1-yl)-1,3-benzothiazole;
- (1S,5R/1R,5S)-5-[3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole;
- (1S,5R/1R,5S)-2-methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}-1,3-benzothiazole;
- (1R,5S/1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-the l]thio}propyl)azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[3-fluoro-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane, enantiomer 1;
- (1R,5S/1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1,0]hexane;
- (1S,5R)-1-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane, enantiomer 2;
- (1R,5S/1S,5R)-1-[4-(metiloksi)-5-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[4-(4-chloro-2-forfinal]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-(3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-(2-chloro-4-were)-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[3-chloro-4-(metiloksi)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[3-(2,4-dime the Il-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1R,5S/1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

20. The compound according to any one of claims 1 to 17 or its pharmaceutically acceptable salt, selected from the group which includes
- 4-[(1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]benzonitrile;
- 4-[(1S,5R)-3-(3-{[4-methyl-5-(2-methylinosine-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenol;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-phenyl-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-tert-butylphenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[4-(5-methyl-3-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-meth is l-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(3-bromophenyl)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- 1-[4-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-[4-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]-1-propanone;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane;
- 1-{4-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}-2-pyrrolidinone;
- 5-{5-[(3-{(1S,5R)-1-[4-(1,1-dioxido-2-isothiazolinone)phenyl]-3-azabicyclo[3.1.0]Gex-3-yl}propyl)thio]-4-methyl-4H-1,2,4-triazole-3-yl}-2-methylinosine;
- 1-(2-(metiloksi)-5-{(1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;
- 1-[5-[(1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-{2-(metiloksi)-5-[(1S,5R)-3-(3-{[4-methyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-[5-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-(metiloksi)phenyl]Etalon;
- 1-{2-(metiloksi)-5-[(1S,5R)-3-(3-{[4-methyl-5-(tetrahydro-2H-Piran-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabi is yclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-(2-hydroxy-5-{(1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}phenyl)Etalon;
- 1-{5-[(1S,5R)-3-(3-{[5-(3,4-differenl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-hydroxyphenyl}Etalon;
- 1-{2-hydroxy-5-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 1-{2-hydroxy-5-[(1S,5R)-3-(3-{[4-methyl-5-(2-methyl-5-chinoline)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]phenyl}Etalon;
- 2-methyl-6-[(1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(4-pyridazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-1-methyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-1,2,3-triazole-4-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(1,5-dimethyl-1H-pyrazole-4-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-what rimidine)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-furanyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-5-isoxazolyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(1-methyl-1H-pyrazole-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(5-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-methyl-5-(3-methyl-2-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(2,5-dimethyl-3-furanyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[5-(5-chloro-2-thienyl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(4-bromophenyl)-3-(3-{[4-ethyl-5-(3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S5R)-1-(4-bromophenyl)-3-[3-({4-methyl-5-[2-methyl-6-(trifluoromethyl)-3-pyridinyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]hexane;
- 5-[5-({3-[(1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]Gex-3-yl]propyl}thio)-4-methyl-4H-1,2,4-triazole-3-yl]-1-methyl-3-(trifluoromethyl)-1H-thieno[2,3-C]pyrazole;
- 3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-(1R,5R)-1-[6-(trifluoromethyl)-2-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[3-fluoro-4-(1H-pyrrol-1-ylmethyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(2-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-1-[6-(trifluoromethyl)-3-pyridinyl]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-2-methyl-5-[3-(3-{[4-methyl-5-(5-methyl-2-pyrazinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- (1S,5R)-2-methyl-5-[3-(3-{[4-methyl-5-(6-methyl-3-pyridinyl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-AZ is bicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- (1S,5R)-2-methyl-5-(3-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazole-3-yl)thio]propyl}-3-azabicyclo[3.1.0]Gex-1-yl]-1,3-benzothiazole;
- (1S,5R)-5-[3-(3-{[5-(2,4-dimethyl-1,3-thiazol-5-yl)-4-methyl-4H-1.2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]Gex-1-yl]-2-methyl-1,3-benzothiazole;
- (1S,5R/1R,5S)-2-methyl-5-{3-[3-({4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole-3-yl}thio)propyl]-3-azabicyclo[3.1.0]Gex-1-yl}-1,3-benzothiazole;
- (1S,5R)-1-[4-(4-chloro-2-forfinal]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{3-[(trifluoromethyl)oxy]phenyl}-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-(2-chloro-4-were)-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[3-chloro-4-(metiloksi)phenyl]-3-(2-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[4-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-{4-[6-(trifluoromethyl)-2-pyridinyl]phenyl}-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[3-(2,4-dimethyl-1,3-thiazol-5-yl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[3-(5-methyl-2-thienyl)Fe is Il]-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-1-[4-(3,5-dimethyl-4-isoxazolyl)phenyl]-3-(3-{[4-methyl-5-(4-methyl-1,3-oxazol-5-yl)-4H-1,2,4-triazole-3-yl]thio}propyl)-3-azabicyclo[3.1.0]hexane;
- (1S,5R)-3-(3-{[5-(2,4-dimethyl-1,3-oxazol-5-yl)-4-methyl-4H-1,2,4-triazole-3-yl]thio}propyl)-1-[2-fluoro-4-(trifloromethyl)phenyl]-3-azabicyclo[3.1.0]hexane.

21. A method of obtaining a compound according to claim 1, which includes stages of interaction of the compounds of formula (XIV)

where R1, R2, G and R have the meanings indicated in claim 1 and X represents a leaving group, with a compound of formula (V)

where R3and R4have the meanings indicated in claim 1.

22. The method of treatment of a condition for which a favorable modulation of dopamine receptor D3includes introduction to the mammal (e.g. human)in need, an effective amount of a compound according to any one of claims 1 to 20.

23. The method according to item 22, where the state is psychosis, or psychotic, or substance abuse.

24. The method according to item 23, where the state is substance abuse.

25. The method according to item 23, where the psychotic condition is schizophrenia.

26. The use of compounds according to any one of claims 1 to 20 for receiving medicines to treat the condition in a mammal, for which a favorable modulation of dopamine receptor D3.

27. Use p, where the state of one who by psychosis, or psychotic condition, or substance abuse.

28. Use item 27) where the state is substance abuse.

29. The application of item 27, where the psychotic condition is schizophrenia.

30. The compound according to claim 1 for use in therapy.

31. The compound according to claim 1 for use for the treatment of a condition in a mammal, for which a favorable modulation of dopamine receptor D3.

32. The compound according to claim 1 for use for the treatment of psychosis, or psychotic condition, or treatment for substance.

33. The compound according to claim 1 for use in the treatment of schizophrenia.

34. Pharmaceutical composition having a modulating action on the dopamine receptor D3containing the compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where R is a group selected from: i) hydrogen; ii) phenyl and iii) thiophenyl; Z is a substituted or unsubstituted [1,3,4]thiadiazol-2-yl group, R1 is selected from: i) hydrogen; ii) straight C1-C6alkyl; iii) C6 or C10 aryl; iv) C(O)OR5; and v) 2-methylthiazol-4-yl; R5 denotes a straight or branched C1-C6alkyl; and index x equals 0 or 1. The invention also relates to use of compounds of formula (I) to prepare a medicinal agent having human protein tyrosine phosphatase beta (HPTP-β) inhibiting action and use in treatment.

EFFECT: compounds can be used as human protein tyrosine phosphatase beta inhibitors.

11 cl, 1 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof. In formula (I) Y is C-R4 and Z is CH; or Y is C-R4 and Z is N; or Y is N and Z is CH; R1 is a 5- or 6-member ring of formula (II) or (III): R2 is H, C1-C7-alkyl; R3 is phenyl, pyrazolyl, isoxazolyl, pyridinyl, pyrimidinyl or pyrazinyl, which can possibly be substituted with one, two or three substitutes selected from a group consisting of: CN, CI, F, Br, CF3, CHF2, C1-C7-alkyl, -O-C1-C7-alkyl, -(CH2)m-Rc, -O-CH2F, -O-CHF2, -O-CF3, -S(O)2-Rd; R4 is H, C1-C7-alkyl; R5 is H, CI, F, Br, CN, CF3, CHF2, C1-C7-alkyl, -C3-C6-cycloalkyl, -(CH2)m-Re or -(CO)-NRiRj; R6 is C1-C7-alkyl; R7 is H, CI, F, CN or C1-C7-alkyl; Rc is -OH; Rd is C1-C7-alkyl; Re is -CH2F, -CHF2, -CF3, CN, C1-C7-alkoxy; Ri, Rj independently denote H or C1-C7-alkyl; m equals 1-4. The invention also relates to a medicinal agent having mGluR5a receptor antagonist properties, containing one or more of the disclosed compounds as an active component.

EFFECT: high efficiency of the medicinal agent.

24 cl, 208 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

FIELD: chemistry.

SUBSTANCE: compound of formula (I) has antiviral activity toward the human cytomegalovirus (HCMV) or some other representative of the Herpes virida group. In formula (I)

, R1 is a group of formula , where * denotes the point of bonding to a carbonyl group, R3 denotes a pyridyl which can be substituted with a substitute independently selected from a group comprising C1-C6alkyl or a cyano group, R5 and R6 independently denote hydrogen, R2 denotes a phenyl which can be substituted with a substitute selected from a group comprising a trifluoromethoxy group, a difluoromethoxy group and a monofluoromethoxy group, A is a group of formula

or , where * denotes the point of bonding to the carbonyl group, # denotes the point of bonding to the nitrogen atom of urea, R7 denotes C1-C6alkyl which can be substituted with a substitute selected from a group comprising C3-C6cycloalkyl, R8 and R9 independently denote hydrogen, halogen or C1-C6alkyl. The invention also relates to a method of producing a compound of formula (I) from a compound of formula , a method of producing a compound of formula (V), a medicinal agent containing the disclosed compound, use of the compound in preparing a medicinal agent and a method of fighting viral infections, among them human cytomegalovirus (HCMV) or some other representative of the Herpes viridae group.

EFFECT: high antiviral activity.

9 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: formula (I) compound has antibacterial activity and can be used as a medicinal agent. In formula ,

R1 is hydrogen, halogen, C1-4alkyl; R2 is selected from hydrogen, halogen, C1-4alkyl; R3 is selected from hydrogen, halogen, cyano, C1-4alkyl; W is -N(R6)-; X is a single bond; ring A is an unsaturated or partially saturated ring containing 5-6 atoms, one or two of which are independently selected from nitrogen and sulphur; or an unsaturated or partially saturated bicyclic ring containing 9-10 atoms, one, two or three of which are selected from nitrogen and sulphur; R4 and R5 are substitutes on a carbon atom and are independently selected from a halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, formyl, hydroxy iminomethyl, C1-4alkoxyminomethyl, C1-4alkyl, C1-4alkoxy, C1-4alkanoyl, C1-4alkoxy)carbamoyl, N-(C1-4alkyl)-N-(C1-4alkoxy)carbamoyl, C1-4alkylS(O)a, where a equals 0-2, C1-4alkoxycarbonyl, C1-4alkoxycarbonylamino, C1-4alkylsulphonylamino, (saturated or unsaturated carbocycle containing 3-7 atoms)-R10- or (saturated, partially saturated or unsaturated ring containing 5-6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R11-; where R4 and R5 can independently and optionally substituted at the carbon atom with one or more R12; R6 is hydrogen; n equals 1-4; where values of R4 can be identical or different; m equals 0-4; where values of R5 can be identical or different; R12 is selected from azido, halogen, cyano, hydroxy, amino, carboxy, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-4alkoxy, C1-4alkanoyl, N-(C1-4alkyl)amino, N,N-(C1-4alkyl)2amino, C1-4alkylS(O)a, where a equals 0-2, (saturated or unsaturated cabocycle containing 3-7 atoms)-R14- or (saturated, partially saturated or unsaturated ring containing 5 or 6 atoms, one or two of which are selected from nitrogen, oxygen and sulphur)-R15-; where R12 can independently and optionally be substituted at the carbon atom with one or more R9; R10, R11, R14 and R15 are independently selected from a single bond, -C(O)-, -N(R19)C(O)- or -C(O)N(R20)-; where R19 and R20 are independently selected from hydrogen or C1-4alkyl; R16 is selected from halogen, cyano, hydroxy, carboxy, methyl and methoxy. The invention also relates to a pharmaceutical composition, having antibacterial activity, containing the disclosed compound as an active ingredient, use of the disclosed compound to prepare a medicinal agent and a method of producing the compound of formula (I).

EFFECT: high activity of the compounds.

22 cl, 52 tbl, 721 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention describes compounds of formula I: formula I or its pharmaceutically acceptable salt, where the radical values R3, R4, R2, X1, X2, R1 are such as presented in claim 1. Also, the invention describes a pharmaceutical composition exhibiting a Tec-family kinase inhibitor activity and based on the compounds of formula I, a method of Tec-family kinase activity inhibition, and a method of producing the compound of formula I.

EFFECT: produced and described new compounds which are effective as Tec-family (eg, Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase inhibitors, and acceptable compositions are applicable for treatment or prevention of some diseases, disorders or conditions including but not limited, autoimmune, inflammatory, proliferative or hyperproliferative, or immunologically mediated diseases.

50 cl, 18 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

in modification 11, characterised by the following spectral data in the near infrared region [cm-1]: 4086, 4228, 4418, 4457, 4634, 4905, 5846, 5911, 6026, 6081, 6582, as well as to the amorphous form of this compound, characterised by the following spectral data in the near infrared region [cm-1]: 4006, 4081, 4224, 4307, 4403, 4634, 4875, 5193, 5865, 6017, 6073, 6696, 7028, 8452, 8873.

EFFECT: novel polymorphous and amorphous form of compounds of formula I is obtained, having high solubility compared to the existing modification.

6 cl, 7 ex, 8 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically acceptable salts thereof, which have receptor tyrosine kinase type I inhibiting properties and can be used in treating hyperproliferative disorders in mammals. In general formula

,

A is O or S; G is N; B is a 6-member aryl or 5-6-member heteroaryl ring containing a sulphur atom as a heteroatom; E is

, , , , , X is N or CH; D1, D2 and D3 independently denote N or CR19; D4 and D5 independently denote N or CR19 and D6 is O, S or NR20, where at least one of D4 and D5 is CR19; D7, D8, D9 and D10 independently denote N or CR19, where at least one of D7, D8, D9 and D10 is N; R1 is H or C1-C6 alkyl; each R2 independently denotes halogen, cyano, nitro etc, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, -SR18, -OR15, -C(O)R15, -C(O)OR15, -NR14C(O)OR18, -OC(O)R15, -NR14SO2R18, -SO2NR15R14, -NR14C(O)R15, -C(O)NR15R14, -NR15C(O)NR15R14, -NR13C(NCN)NR15R14, -NR15R14, C1-C12alkyl, C2-C12 alkenyl, alkynyl, saturated or partially unsaturated C3-C10cycloalkyl, C3-C10cycloalkyl-C1-C12alkyl, -S(O)p(C1-C6alkyl), -S(O)p(CR13R14)q-phenyl, phenyl, phenyl-C1-3-alkyl, 5-6-member heteroaryl, 5-6-member heteroaryl-C1-C3-alkyl, saturated or partially unsaturated 3-8-member heterocyclyl, 5-6-member heterocyclyl-C1-C3-alkyl, -O(CR13R14)q-phenyl, NR15(CR13R14)q-phenyl, O(CR13R14)q-(5-6-member heteroaryl), NR13(CR13R14)q-(5-6-member heteroaryl, -O(CR13R14)q-(3-8-member heterocyclyl) or -NR15(CR13R14)q-3-8-member heterocyclyl), each R3 denotes Z, where Z is selected from and , W is O or S; W2 is O or S;V is CR8R9, R8b is H or C1-C6alkyl; each of R6, R8, R8a and R9 independently denotes hydrogen, trifluoromethyl, C1-C12alkyl etc.

EFFECT: improved properties and high efficiency of using the compounds.

25 cl, 13 dwg, 1 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 3,4-dihydrobenzoxazine compounds of general formula [1] (where X denotes a nitrogen atom or CR3; R1 denotes a hydrogen atom or a halogen atom; R2 denotes a C1-6alkoxy group which can be substituted with 1-5 identical or different substitutes selected from a halogen atom and a hydroxyl group; and R3 denotes a halogen atom. However, R1 denotes a halogen atom when X denotes CR3). Said compounds are effective when treating diseases where activity of vanilloid receptors subtype 1 (VR1) is involved, e.g. pain.

EFFECT: more efficient use of pharmaceutical compositions based on said compounds, more effective treatment or pain killing.

19 cl, 4 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where R3 has any

of the formulae , where R1 is selected from

,

where each R2 independently denotes hydrogen, halogen, C1-C8alkyl, C1-C8alkoxy- C1-C8alkyl, C1-C8alkoxy; R4 denotes a five- or six-member monocyclic ring system, having two heteroatoms selected from O, N and S, such as pyrazinyl, isoxazole or thiazolyl, each of which can be optionally substituted with one or more of the following substitutes: C1-C8alkyl or C1-C8alkoxy; R5 and R6 independently denote hydrogen or C1-C8alkyl; R7 and R8 together form a cyclopentyl ring; R9 independently denotes C1-C8alkyl; R9a independently denotes C1-C8alkylcarbonyl or phenylcarbonyl; R10 denotes hydrogen; R11 independently denotes C1-C8alkyl or C1-C8alkoxy; R12 denotes hydrogen or -COOR17; R13 independently denotes hydrogen, phenyl and a 6-member heteroaryl containing one heteroatom selected from N; R17 denotes hydrogen; R23 denotes (a) C1-C8alkyl, phenyl, a 5-member heteroaryl containing 1-2 heteroatoms selected from S and N, where any phenyl or heteroaryl residue is optionally substituted with a halogen, C1-C8alkyl or C1-C8alkoxy; R24 denotes C1-C8alkyl; R27 denotes H, C1-C8alkyl, C1-C8alkoxy, O-phenyl, S-phenyl; R29 denotes -(CH2)w-COOR17; where w=0; R31 denotes hydrogen; and pharmaceutically acceptable salts thereof. The invention also relates to a method of producing the disclosed compounds, a pharmaceutical composition, having dual acting ATI and ETA receptor antagonist properties, containing the disclosed compound as an active component, use of the compound in preparing a medicinal agent and methods of treating arterial hypertension.

EFFECT: high effectiveness of the compounds.

8 cl, 1 dwg, 39 ex

Heterocompound // 2425832

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or pharmaceutically acceptable salt thereof, where symbols assume the following values; ring denotes

or , X denotes a single bond, -CH2-, -NR3-, -O-, -S-, R1 denotes a halogen; phenyl; pyridyl; (C3-C8)cycloalkyl; or (C1-C6) alkyl or (C2-C6) alkenyl, each of which can contain a halogen, -CONH2, phenyl or (C3-C8)cycloalkyl as a substitute, R2 denotes CN, -O-(C1-C6)alkyl, -C(=O)H, halogen; or (C1-C6)alkyl, which can be substituted with a halogen or -OH, R3 can form morpholino or 1-pyrrolidinyl together with R1 and nitrogen, and when X denotes a single bond, R1 and R2 can jointly form a 5-member ring and additionally contain -(C1-C6)alkyl as a substitute, R4 denotes the following ring: , , , , , , , , , , or , where any one of the bonds in the ring is linked to an oxazole ring, R5 denotes -H, (C1-C6)alkyl, which can be substituted by not less than one group selected from: -C(=O)NRXRY, -NHRX and -ORX- (C2-C6)alkenyl-; -C(=O)H; -C(=O)NRXRY, RX and RY can be identical or different and denote -H; or (C1-C6)alkyl. The invention also relates to a pharmaceutical composition based on said compounds, having SlP1 agonist activity.

EFFECT: compounds and compositions can be used in medicine for preventing and treating rejection during organ transplant, bone marrow or tissue transplant and autoimmune diseases.

16 cl, 84 tbl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazole derivatives of general formula I

and pharmaceutically acceptable salts thereof, where n equals 1 or 2, m equals 0, 1 or 2, A contains in the ring a group selected from -CR1=, -CR2=, -CR3=, -CR4= and -CR5=, where 0 or 1 in these groups is replaced with N, R1, R2, R3, R4 and R5 are independently selected from a group comprising hydrogen, hydroxy, halogen, cyano, cyano(C1-C6)alkyl, C4-C6 heterocycloalkyl-C0-alkyl, where the said heterocycloalkyl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, C5heteroaryl-(C0-C4)alkyl, where the said heteroaryl contains 1-4 heteroatoms selected from nitrogen atoms, -XSO2R11, -XSO2NR11R12, -XSO2NR11C(O)R12, -XC(NR11)NR11OR12, -XCR11=NOR12, -XC(O)R11, -XC(O)OR11, -XNR11R12, -XC(O)NR11R12, -XOC(O)NR11R12, -XNR11C(O)NR11R12, -XNR11XOR12; -XN(XOR12)2, -XNR11XC(O)OR12 -XNR11XNR11C(O)R12 -XNR11XNR11R12, -XNR11C(O)R12, where each X is independently selected from a group comprising a chemical bond and C1-C4alkylene, each R11 is selected from a group comprising hydrogen and C1-C6alkyl, and R12 is selected from a group comprising hydrogen, C1-C6alkyl and phenyl, or R11 and R12 together with a nitrogen atom to which R11 and R12 are bonded form C6heterocycloalkyl. Said heteroaryl or heterocycloalkyl in R1, R2, R3, R4 or R5 optionally contains one substitute selected from a group comprising hydroxyl, cyano, C1-C6alkyl, hydroxyl(C1-C6)alkyl and carboxy, R6 and R7 independently denote hydrogen, R8 is selected from a group comprising C1-C6alkyl, halogen(C1-C3)alkyl, -CH2OR8a and -COOR8a or two R8 groups bonded to different carbon atoms, together form a (C1-C2)alkyl bridge, or two R8a groups bonded to one carbon atom form a (C3-C8)cycloalkyl group, where R8a is selected from a group comprising hydrogen and C1-C6alkyl, R9 is selected from a group comprising phenyl and C6heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, and C9heteroaryl, where the said heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen atoms, where the said phenyl or heteroaryl in R9 is optionally substituted with 1-2 substitutes independently selected from a group comprising halogen, cyano, hydroxy, C1-C3alkyl, halogen(C1-C3)alkyl, hydroxy(C1-C3)alkyl, -C(O)R13, -C(O)NR13R14, where each of R13 and R14 is independently selected from a group comprising hydrogen and C1-C6alkyl, R10 denotes hydrogen, Y and Z are independently selected from a group comprising CR20 and N, where R20 denotes hydrogen, provided that compounds of formula I do not include compounds of formula II, which are described in claim 1, and provided that compounds of formula I do not include compounds which are: 1-(4-fluorophenyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)piperazine, 1- ((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(4-(trifluoromethyl)-(pyridin-2- yl)piperazine, 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-(trifluoromethyl)-(pyridin-2-yl)piperazine and 1-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-4-(5-fluoropyridin-2-yl)piperazine. The invention also relates to specific compounds obtained.

EFFECT: novel pyrazole derivatives which can be used in treating diseases or disorders which are mediated by disrupted activation of the said compound are obtained.

8 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where the dotted line in the 6-member nitrogen-containing ring Z of formula (I) (said ring Z consists of ring atoms numbered 1 to 6) indicates that a double bond is either present in the 3,4-position of the ring Z of formula (I), or a double bond is absent in ring Z of formula (I); and where the double bond may be present in the 3,4-position of the ring Z of formula (I); or: the double may be absent in ring Z of formula (I) if: i) X denotes N or N+-O-, or ii) V denotes -O-CH2-Q-, or iii) W denotes para-substituted phenyl or para-substituted pyridinyl, and V denotes pyrrolidinyl of formula:

X denotes CH, N, or N+-O-; W denotes para-substituted phenyl or para-substituted pyridinyl; V denotes -O-CH2-Q-, where Q is bonded with a group U of formula (I), or V denotes pyrrolidinyl of formula:

U denotes mono-, di-, tri- or tetra-substituted aryl, where the substitutes are independently selected from C1-7-alkyl and halogen; Q denotes a five-member heteroaryl with two or three heteroatoms independently selected from O and N; R1 denotes C1-7-alkyl or cycloalky; R2 denotes halogen or C1-7-alkyl; R3 denotes halogen or hydrogen; R4 denotes C1-7-alkyl-O-(CH2)0-4-CH2-; R'R"N-(CH2)0-4-CH2-, where R' and R" are independently selected from a group consisting of hydrogen, C1-7-alkyl (optionally substituted with one-three fluorine atoms), cyclopropyl (optionally substituted with one-three fluorine atoms), cyclopropyl- C1-7-alkyl (optionally substituted with one-three fluorine atoms) and -C(=O)-R"', where R'" denotes C1-4-alkyl, C1-4-alkoxy, -CH2-CF3, or cyclopropyl; or R12NH-C(=O)·(O)0-1-(CH2)0-4-, where R12 denotes C1-4-alkyl or cyclopropyl; and n equals 0; and salts thereof. The invention also relates to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having inhibiting effect on renin.

21 cl, 112 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and salts thereof (I), where T is a tetrazolyl group which is not substituted or substituted with [C1-C8]alkyl; L1 denotes (CR1R2)n-, where n equals 1, 2, 3 or 4; R1 and R2 denote hydrogen; L2 denotes a direct bond; A is selected from a group comprising A2, A8 and A20 , where Z1, Z2, Z3 and Z4 are independently selected from a group comprising hydrogen, -NR5R6, -N(R5)C(=O)R6, -N(R5)C(=O)OR6, -N(R5)C(=O)NR6R7, -N(R5)C(=S)NR6R7; Q is selected from a group comprising , where X1, X2 and X3 are independently selected from a group comprising hydrogen, halogen, [C1-C8]alkyl, phenyl or phenyl which is substituted by 1-5 halogen atoms; R5-R7 are independently selected from a group comprising hydrogen, [C1-C8]alkyl, [C1-C8]halogenalkyl, [C2-C8]alkenyl, [C3-C6]cycloalkyl, phenyl and phenyl [C1-C8]alkyl.

EFFECT: invention also relates to a fungicide composition containing an active ingredient in form of an effective amount of the disclosed compound, use of the disclosed compound or fungicide composition thereof for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops and a method for treatment or prophylactic control of phytopathogenic fungi of plants or agricultural crops.

14 cl, 3 tbl, 12 ex

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