Heterocyclic compounds having affinity to muscarine receptors

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

 

The scope of the invention

The present invention relates to new heterocyclic compounds having an affinity for muscarinic receptors, pharmaceutical compositions containing these compounds and to the use of these compounds for obtaining a medicinal product for the treatment, mitigation or prevention of diseases and conditions mediated by muscarinic receptors.

Prior art

Muscarinic cholinergic receptors mediate the action of the neurotransmitter acetylcholine in the Central and peripheral nervous systems. Muscarinic receptors contain five different subtypes, designated as muscarinic M1, M2, M3, M4 and M5 receptors. Each subtype has a specific distribution in the Central and peripheral nervous systems. The M1 receptor is predominantly expressed in the cerebral cortex and is involved in the regulation of higher cognitive functions; M2 receptor represents the predominant subtype found in the heart and is involved in the regulation of heart rate; M3 receptor is widely expressed in many peripheral tissues and is involved in the stimulation of the gastrointestinal tract and urinary tract, as well as sweating and salivation; M4 receptor presence is there in the brain and may be involved in motor function and antipsychotic actions; M5 receptor is localized in the brain and may be involved in joining the connection and in the development of psychotic conditions such as schizophrenia. In view of the key physiological roles allocated to each of the subtypes of muscarinic receptors, extensive efforts have been made to develop new compounds exhibiting selective agonistic or antagonistic properties (see, for example, EP 0296721; EP 0316718; Sauerberg, P. et al., J. Med. Chem., 1992, Vol. 35, No. 22, 2274-2283; Ward, J.S. et al., 1992, J. Med. Chem., Vol. 35, No. 22, 4011-4019; US 5,527,813; Zlotos, D.P. et al., Exp. Opin. Ther. Patents, Vol. 9, No. 8, 1999, 1029-1053; Plate, R., et al., Bioorg. Med. Chem. 4 (1996), 227-237; Plate, R. et al., Bioorg. Med. Chem. 8 (2000), 449-454; Del Guidice, M.R. et al., Arch. Pharm. Med. Chem. 2003, 336, 143-154).

Well-known examples of preferential agonist M1/M4 muscarinic receptors is thiadiazoline connection xanomeline, which in preclinical studies has a desirable profile, however, in clinical studies showing adverse side effects (see, for example, review Eglen, R., Progress in Medicinal Chemistry, 2005, 43, p.105-136 and U.S. patent No. 5376668), which seems to be associated with the activity, mediated by M2 receptors (e.g., effects on heart rate). In addition, xanomeline has relatively low in vitro metabolic stability. Related xanomeline compounds also are disclosed in U.S. patent 5527813. One is to representative compounds exhibit adverse side effects, which seems to be associated with the activity, mediated by the M2 and M3 receptors (e.g., impacts, respectively, on heart rate and salivation).

Although further research on the development of therapeutics that have a selective M1/M4 profile, still not received a promising tool. There is therefore a need for new selective compounds with desired properties.

Description of the invention

Currently, it was found that the heterocyclic compounds of formula (I)

where the heterocycle contains two double bonds, which may be present in several positions, shown by the dotted lines (---);

- heterocycle contains two heteroatoms,

W represents N or NH;

- Y is CH, O or NH, where

if Y is O, X1represents CH and X2represents the balance of C-Z-R2 or C-R3, where Z represents NH, O or S; and

if Y represents CH or NH, then one of X1and X2represents CH or N and the other represents the balance of C-Z-R2 or C-R3, where Z represents NH or S;

-R1 is selected from the structures (a), (b) and (c):

(b)and;

- R2 is selected from (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from halogen, hydroxy, cyano, oxo, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenylamine, (C1-C6)alkanity, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy, phenylthio, where the phenyl group is optionally substituted with halogen; or

- R2 represents a non-branched (C2-C8)alkyl, substituted in the position of the symbol Za - group compound of the formula (Ia)

,

where if X1represents CH or N, X1a represents CH or N and X2a represents a-Za-, or

if X1is a C-Z-R2, X1a is a C-Za and X2a represents CH or N; and symbols Wa, Ya and Za, and the substituent R1a have the same meaning as previously defined for the symbols W, Y and Z and the substituent R1, and are not independently selected, pricemay of symbols Wa, Ya and Za and the substituent R1a represent, respectively, the symbols and substituents, identical symbols W, Y and Z and the substituent R1 in another part of the structure of formula (I);

- R3 is selected from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from halogen, hydroxy, cyano, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenylamine, (C1-C6)alkanity, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, 5-membered unsaturated heterocycle, optionally substituted with halogen, phenyl, phenyloxy, phenylthio, where the phenyl group is optionally substituted with halogen; or their pharmaceutically acceptable salt, solvate or hydrate,

show affinity for muscarinic receptors, in particular to M1 and/or M4 receptors, exerting a modulating, in particular (partial) agonistic action on muscarinic receptors. In addition, the compounds of the present invention are higher in vitro metabolic stability than the connection xanomeline prior art.

Compounds according to the invention can be used for the treatment, relief and prevention of diseases and conditions mediated muskarinove and receptors. Preferred compounds are agonists of the M1 and M4 receptors and can be used in the treatment of diseases and conditions mediated by muscarinic M1/M4 receptor, such as, but not limited to, Alzheimer's disease, cognitive impairment, disease, Sjogren's syndrome, schizophrenia, and for pain. In particular, the compounds of the present invention can be used for the treatment, mitigation or prevention of cognitive impairment and psychotic disorders.

In one embodiment of the invention the compounds have the formula (I), where R2 is selected from (C1-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from halogen, hydroxy, cyano, oxo, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenylamine, (C1-C6)alkanity, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy, phenylthio, where the phenyl group is optionally substituted with halogen. Preferably, R2 is selected from (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)quinil, not necessarily independently samemanner is one or more substituents, selected from halogen, hydroxy, cyano, oxo, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, tetrahydrofuranyl and phenyl, where the phenyl group is optionally substituted with halogen. Especially preferred compounds of formula (I), where R2 is selected from (C1-C8)alkyl, (C2-C8)alkenyl, optionally substituted by one or more substituents selected from halogen or (C1-C6)alkoxy.

In addition, in one embodiment of the invention R3 is selected from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally substituted Deputy selected from (C5-C7)cycloalkyl or phenyl, where the phenyl group is optionally substituted with halogen.

In yet another embodiment of the invention R1 has the structure (a) or (b), in particular (a).

In another embodiment, the compounds have the formula (I), where W represents N and Y represents NH, in particular, when X1represents CH and X2represents the balance of C-Z-R2 or C-R3, and Z represents O or S, and preferably, X2represents the balance of C-Z-R2. Z preferably represents S.

In yet another embodiment, Y is O and Z is a small town in which to place an O or S, and preferably, Z represents S.

The term "halogen" refers to fluorine-, chlorine-, bromine - or iodine. Preferred is a fluorine-.

The term "(1-C10)alkyl" means a branched or unbranched alkyl group having 1-10 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, n-pentyl, sec-pentyl, hexyl, octyl. In particular, residue C-Z-R2, where Z represents O or S, n-pentyl is the preferred alkyl group. Preferred alkyl groups substituted with R2 represent ethoxyethyl, when Z represents O or S, and -(CH2)3CF3when Z represents S.

The term "(1-C6)alkoxy" means alkoxygroup having 1-6 carbon atoms, where the alkyl fragment is as defined above. The term "(1-C6)alkylthio" has a similar meaning. The term "(1-C4)alkoxy(C1-C4)alkoxy" means (C1-C4)alkoxygroup, the alkyl part of which is in turn substituted (C1-C4)alkoxy.

The term "(2-C8)alkenyl" means a branched or unbranched alkenylphenol group having 2-8 carbon atoms, where the double bond (connection) can be present in different parts of the group, for example vinyl, allyl, butenyl, n-pentenyl, second-pentenyl, hexenyl, chenil etc. In the remainder of the C-Z-R2, where Z represents O or S, Alchemilla group is a 4-pentenyl and preferred substituted Alchemilla group represents 4,4-deverbal-3-enyl.

The term "(1-C6)alkenylacyl" means alkenylacyl having 1-6 carbon atoms, where Alchemilla part is as defined above. The term "(1-C6)alkanity" has a similar meaning.

The term "(2-C8)quinil" means a branched or unbranched alkylamino group having 2-8 carbon atoms, where the triple bond (connection) can be present in different parts of the group, such as ethinyl, propargyl, 1-butynyl, 2-butynyl etc.

The term "(5-C7)cycloalkyl" means a cyclic alkyl group having 5-7 carbon atoms, thus, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term "5-membered unsaturated heterocycle" in the definition of R2 means a heterocycle containing 5 atoms, where at least one atom is a heteroatom selected from C, N and S, and the other atoms are carbon atoms, where the heterocycle, in addition, at least contains one double bond. Examples are furazilina and pyrrolidine group. With reference to substituents, the term "independently" means that the deputies could the t to be the same or different from each other.

Compounds according to the invention can suitably be obtained by methods available in this area, and as illustrated in the experimental section of the present description. To obtain the compounds according to the invention were discovered certain new and useful intermediate compounds.

Thus, another variant embodiment of the invention is a heterocyclic compound of the formula (II)

,

where the heterocycle contains two double bonds, which may be present in several positions, shown by the dotted lines (---);

- heterocycle contains two heteroatoms,

and W represents N, NH or N-2-(trimethylsilyl)ethoxymethyl;

- Y* represents CH, O, N, or NR4, where R4 is selected from H, 2-(trimethylsilyl)ethoxymethyl, -SO2N(CH3)2and-SO2phenyl; where

if Y* represents O, X1* represents CH and X2* represents the balance of C-Z*R2* or C-R3*, where Z* represents NH, O or S; and

if Y* is a CH or NH, then one of X1* and X2* represents CH or H and the other represents the balance of C-Z*R2* or C-R3*, where Z* represents NH or S;

-R2* is selected from (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)quinil not necessarily independent Sames the frame by one or more substituents, selected from halogen, hydroxy, cyano, oxo, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenylamine, (C1-C6)alkanity, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, 5-membered unsaturated heterocycle (optionally substituted with halogen), phenyl, phenyloxy or phenylthio, where the phenyl group is optionally substituted with halogen;

or

-R2* is a non-branched (C2-C8)alkyl, substituted in position symbol Z*a group of Deputy groups of the formula (IIa)

,

where if X1* represents CH or N, X1*a represents CH or N, and X2*a is a C-Z*a-, or

if X1* is a C-Z*R2*X1*a is a C-Z*a-and X2*a represents CH or N; and

the symbols W*a, Y*a and Z*a have the same meaning as previously defined for characters W*, Y* and Z*, and they are not independently selected, each of the symbols W*a, Y*a and Z*a represents respectively the symbols identical to W*, Y* and Z* in another part of the structure of formula (II); and

-R3* is selected from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from halogen, guy is Roxie, cyano, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkenylamine, (C1-C6)alkanity, (C1-C4)alkoxy(C1-C4)alkoxy, (C5-C7)cycloalkyl, 5-membered unsaturated heterocycle, optionally substituted with halogen, phenyl, phenyloxy, phenylthio, where the phenyl group is optionally substituted with halogen,

moreover, this connection can be used to obtain compounds of formula (I), where R1 has the structure (a). The preferred type of substitution in the compound of formula (II) corresponds to the preferred type of substitution of the compounds of formula (I).

Also another variant implementation of the present invention is a heterocyclic compound of the formula (III)

,

where R5 represents H and R6 represents Br,

or R5 represents-Si(CH3)3and R6 represents Br or-Si(CH3)3,

moreover, this connection can be used to obtain compounds of formula (I), where R1 has the structure (a).

Compounds of the present invention may contain one or more asymmetric centers and thus can occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric the s centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently receive two optical isomers and it is intended that all possible optical isomers and diastereoisomers in mixtures and as pure or partially purified compounds are included in claims of the present invention. It is implied that the present invention covers all such isomeric forms of these compounds. Independent synthesis of these diastereomers or their chromatographic separations may be achieved as known in this field as disclosed in the present description with appropriate modification of the methodology. Their absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates which optionally derivatized reagent containing an asymmetric center is known absolute configuration. If desired, racemic mixtures of compounds can be separated, so that there were separate enantiomers. The separation can be carried out by methods well known in the field, such as the connection of racemic mixtures of compounds in enantiomerically pure compound for education diastereomeric mixture, followed by the separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

Connections can usestat as polymorphs and in a form intended for inclusion in the present invention. In addition, the compounds may form a solvate with water (i.e. hydrates) or common organic solvents, and it is assumed that such a solvate is also covered by the scope of the invention.

Labeled with isotopes of the compound of formula (I) or its pharmaceutically acceptable salts, including the compounds of formula (I)labeled with isotopes, subject to identify PET (positron emission tomography) or SPECT (single photon emission computed tomography), also fall under the scope of the invention. The same applies to compounds of formula (I)labeled with [13C]-, [14C]-, [3H]-, [18F]-, [125I], or other isotopically enriched atoms, suitable for labeling of receptors, or studies of metabolism.

The term "pharmaceutically acceptable salt" refers to those salts which are, within sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are suitable from the point of view of the ratio benefit/risk. Pharmaceutically acceptable salts are well known in this field. They can be obtained in situ during the final isolation and purification of the compounds according to the invention, or separately by their interaction with pharmaceutically acceptable non-toxic based is s or acids, including inorganic or organic bases and inorganic or organic acids.

Compounds according to the invention can be administered orally or parenterally. The exact dose scheme and the introduction of these compounds and their compositions will depend on the biological activity of the compound, the age, body weight and sex of the patient, the needs of a specific subject, which is injected drug, the degree of destruction or the needs and opinions of healthcare workers. In General, parenteral administration requires lower dosages than other routes of administration that are more dependent on adsorption. However, dosages for men are preferably from 0.001 to 10 mg per 1 kg of body weight, preferably from 0.01 to 1 mg per kg of body weight. In General, enteral and parenteral dosage will be in the range from 0.1 to 1000 mg per day total quantity of active ingredients.

Medicines made with the compounds of the present invention, can also be used as adjuvant in the treatment. In this case, the drug is injected in the combined treatment with other compounds used in the treatment of such pathological conditions. In this respect also discusses pharmaceutical combination preparations containing at least one shall Obedinenie of the present invention and, at least one other pharmacologically active substance.

After mixing with pharmaceutically acceptable excipients, for example, as described in the standard reference "Remington, The Science and Practice of Pharmacy" (21stedition, Lippincott Williams & Wilkins, 2005, see especially Part 5: Pharmaceutical Manufacturing), connections can pressoffice in solid dosage forms such as pills or tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids compounds may also be used in the form of a solution, suspension or emulsion.

For the manufacture of dosage forms such as tablets, provides for the use of conventional additives such as fillers, colorants, polymeric binder, and the like. In General, may be any pharmaceutically acceptable additive which does not interfere with the function of active connections.

Suitable carrier materials that can be entered for the connection according to the invention, include, for example, lactose, starch, cellulose derivatives and the like or mixtures thereof, used in the right quantities. Compositions for intravenous administration can, for example, be a solution of the compounds according to the invention in sterile isotonic aqueous buffer. If necessary, intravenous compositions can on the part, for example, solubilizing agents, stabilizing agents and/or local anesthetic to relieve pain at the injection site.

The pharmaceutical compositions according to the invention may be formulated for any route of administration, and must contain at least one compound according to the present invention and its pharmaceutically acceptable salts with any pharmaceutically acceptable ingredient, excipient, carrier, adjuvant or excipient.

By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with other ingredients of the composition and is not harmful to their recipient.

In one embodiment, the invention provides a pharmaceutical package or kit containing one or more containers filled with one or more pharmaceutical compositions according to the invention. With such container(s) can be various written materials such as instructions for use and a notice in the form prescribed by a governmental Agency regulating the manufacture, use and sale of pharmaceutical products, and the notice reflects approval by the Agency of manufacture, use or sale for use in human or veterinary medicine.

Yet other definitions, all technical and scientific Ter the ins, used in the present description, have the same meaning, which is usually understandable to the average person skilled in the art to which this invention. Although the implementation or testing of the present invention can be used in the methods and materials similar or equivalent to those described in this application, this document describes appropriate methods and materials. All publications, patent applications, patents, and other references mentioned in the present description, fully incorporated into it by reference. In case of contradiction is the advantage of the present description, including definitions.

The following examples are intended only to further a more detailed illustration of the invention and, therefore, these examples in no way should be seen as constricting or limiting the scope of invention.

EXAMPLES

1. Materials and methods

Spectranuclear magnetic resonance(1H NMR and13With NMR, ART) were determined in the indicated solvent using the instrument Bruker ARX 400 (1H: 400 MHz,13C: 100 MHz) at 300 K, unless otherwise indicated. Experiments19F NMR and13With NMR was carried out on the spectrometer Varian Inova 500, operating at 11,74 T (499,9 MHz to1N; 125,7 MHz to13With; at 50.7 MHz, 470,4 MHz to19F)using the 5 mm wavelength sensor is CA. The spectra were determined in deuterated chloroform or dichloromethane, obtained from Cambridge Isotope Laboratories Ltd. Chemical shifts (δ) are presented in ppm in the lower field from tetramethylsilane (1H, 13C) or CC13F (19F). Constant connection J is represented in Hz. The shape of the peaks in the NMR spectra are indicated by the symbols q (Quartet), “dq” (double Quartet), t (triplet), dt (double triplet), d (doublet), dd (double doublet), s (singlet), bs” (broadened singlet) and m (multiplet). The signals of the NH and OH were identified after mixing the sample with a drop of D2O.

Flash chromatographyrefers to the cleaning with the indicated eluent and silica gel (Acros silica gel: 0,030-0.075 mm or silica gel Merck 60: 0,040-0,063 mm).

Chromatography on a columnwere performed using silica gel 60 (0,063-0,200 mm, Merck).

The melting pointregistered on the apparatus for determining the melting point of the Büchi B-545.

Mass spectra(MS) were recorded on a device Macromass QTOF-2 using the software MassLynx for receiving and reconstructing the data. Made accurate mass measurements quasimolecular ion [M+H]+. Accurate measurement of the mass was performed using a spectrometer JEOL JMS-SX/SX 102 A Tandem Mass Spectrometer using fast atom bombardment (FAB). Used force resolution 10000 (definition 10% decrease) for FAB mass Spectro is etrie with high resolution.

All reactionsincluding moisture sensitive compounds or conditions, were carried out in an anhydrous nitrogen atmosphere.

The reaction was controlled by the use ofthin-layer chromatography(TLC) is covered with a silicon oxide plastic plates (pre-coated with silica gel Merck 60 F254) with the indicated eluent.

Spots were visualized by UV light (254 nm) or I2.

The attenuation coefficientswas determined by spectrophotometer HP 8453 UV-visible spectrum.

Analytical high performance liquid chromatography (HPLC)performed on a C18 column (Interstill ODS-3, particle size 3 mm; 4.6 mm, 50 mm)using the following gradient elution: linear gradient from 5% to 95% aqueous CH3CN containing 0.04% of HCO2H for 2 min at 2.0 ml/min, the Products were detected at λ=254 nm.

Liquid chromatography - mass spectrometry (LC-MS), method A.

System LC-MS consists of 2 Micronesia Perkin Elmer series 200. The pumps are connected to each other blending mixer 50 ál, the United auto sampler Gilson 215. The method is as follows:

StageThe total timeFlow (ml/min)A (%)In (%)
0 02000955
11,820000100
22,520000100
32,72000955
43,02000955

A = 100% water with 0.025% HCOOH and 10 mmol of NH4HCOOO pH ±3.

In = 100% ACN with 0.025% HCOOH.

Automatic sampler has an injection loop with a capacity of 2 ml. Automatic sampler is connected with the column Waters Atlantis C18 30*4.6 mm with particle size of 3 μm. Column thermostated in a column thermostat Perkin Elmer series 200 at 40°C. the Column is connected with UV-counter, Perkin Elmer series 200 flow-through cuvette of 2.7 mm. The wavelength set at 254 nm. UV meter is connected to a mass spectrometer (Sciex API 150EX. The mass spectrometer has the following options:

Range scan: 150-900 a.m.u.; polarity: positive; type of scan: profile; Q1: UNIT; step size: 0,10 a.m.u.; time for scan: 0,500 sec; NEB: 10; CUR: 10; IS: 5200; TEM: 325; DF: 30; FP: 225 and EP: 10.

The light scattering detector is connected with a Sciex API 150. The light scattering detector is a Sedere Sedex 55, operating at 50°C and 3 bars N2.

Full system connected G3.

Liquid chromatography - Mass spectrometry (LC-MS)method C.

System LC-MS consists of devices Agilent 1100 series, consisting of the following components:

- Degasser G1379A

Binary pump G1312A

The method is as follows:

StageTotal time (min)Flow (ml/min)A (%)In (%)
001,0298
110,51,0982
218,01,0982
318,11,02 98
424,01,0298

A: Acetonitrile with 0.1% HCOOH or acetonitrile with 10 mm NH3.

In: Water with 0.1% HCOOH or water with 10 mm NH3.

Automatic sampler is connected with the column Bond Extend C18 150×4.6 mm with 3.5 µm particles.

Column thermostated in a column thermostat G1316A Colcomm at 35°C.

The column is connected to the detector from the series diodes G1315B DAD. The range of wavelengths is selected from 220 to 320 nm. UV meter is connected to a mass spectrometer MSD G1946D mode electronic sputtering.

The mass spectrometer has the following options:

10 l/min
Range scan:100-800 amu
Polarity:positive and negative
Mode:Scan
Step size:0,20
Cycle time:1,04 s
% Cycle time:50%
The drying gas:nitrogen
The gas flow:
Gas temperature:300°C
The spray pressure30 psi
Capillary voltage:3000

The detector Allitech ELSD 2000 is connected in parallel with MSD. The stream is divided after DAD.

ELSD has the following options:

The drying gas:nitrogen
The gas flow:1.5 l/min
The tube temperature drift:39°C
Drummer:enabled

2. Abbreviations

n-BuLin-utility
t-BuOHtert-butanol
dbadibenzylideneacetone
DCMdichloromethane
DMFN,N'-dimethylformamide
DMF-DMAN,N'-dimethylformamide-dimethylacetal
DMSOthe sulfoxide
EtOHethanol
Et2Osimple diethyl ether
ggram(s)
hhour(s)
IUmethyl
Melmethyliodide
MeOHmethanol
mgmilligram(s)
Minminute(s)
Mlmilliliter(s)
m.p., mpthe melting point or melting range
NBSN-bromosuccinimide
NISN-jodatime
PEsimple petroleum ether
Rtretention time (LC/MS)
SEM-CI(2-hermeticity)trimethylsilane
TBAF fluoride tetrabutylammonium
THFtetrahydrofuran

3. General aspects of synthesis

Different routes of synthesis for the preparation of compounds of the present invention, illustrated in formula I, is described and can be easily obtained from open source materials. For more General information about the chemistry of pyrazole, imidazole and isoxazol can be found, for example, in J.A. Joule, K. Mills and G.F. Smith, "Heterocyclic Chemistry", third edition, Stanley Thornes (Publishers) Ltd., Cheltenham,1998. More information on addition and subsequent removal of protective groups in organic synthesis can be found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, Inc., New York,1999.

The choice of a particular method depends on such factors as the compatibility of functional groups with a reagent used, the use of protective groups, catalysts, activating and connecting reactants and final structural characteristics present in the final output connection.

In the example of the General procedure (scheme 1) hydrochloride nicotinanilide (1) becomes N-methyl-N-methoxime (2) in the presence of a base and interacts with hexyllithium (J. Med. Chem., 35,1992, 2392-2406) to obtain 1-pyridine-3-ingatan-1-it (3).

Easy-α-methyltyrosine compound 3 (J. Org. Chem., 71,2006, 538-2541) gave 2-methylene-1-pyridine-3-ingatan-1-he (4), which interacted with hydrazine (Synthesis,1989, 320-321) to obtain 1-(4-pentyl-3-pyridin-3-yl-4,5-dihydropyrazol-1-yl)ethanone (5). Oxidation of 2-pyrazoline in the pyrazole can be carried out using methods well known to specialists in this field. Specific conditions are activated MnO2in dichloroethane (ER) to obtain compound 6, the protective group was removed in the basic conditions to obtain compound 7. The derived 3-(4-pentyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (9) was obtained from compound 8 by quaternization of pyridine part of CH3I and the restoration of the corresponding pyridinium salt NaBH4(Arch. Pharm. Med. Chem., 336,2003, 143-154).

Scheme 1

In another example, General procedure (scheme 2) public pyridine-3-ilocana acid (10) is transformed into a derivative of N-methyl-N-methoxyamine (12), which interacts with BiuLi to obtain 1-pyridine-3-elexan-2-it (13). Treatment of compound 13 N,N-dimethylformaldehyde gave enamin (14), which becomes pyrazole (15). Synthesis of 3-(4-butyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (16) is illustrated in scheme 2, in accordance with consisting of two steps by the sequence shown in scheme 1.

Scheme 2

In another example, the General procedure (scheme 3) 3-(4-bromo-1H-pyrazole-3-yl)pyridine (20A) or iodine-analog (20V) (Bioorganic & Medicinal Chemistry, 4,1996, 227-237) is used as the precursor for the synthesis of compounds of General formula I. Delity derived (Bioorganic & Medicinal Chemistry, 8,2000, 2317-2335) connection 20A received in milligrammes range by deprotonation of pyrazole-NH and exchange of bromine-lithium (2.1 EQ. n-BuLi, THF, -78°C, 2 h), captures a disulfide (e.g., methyldichlorosilane), giving 3-(4-methylsulfanyl-1H-pyrazole-3-yl)pyridine 21A, which was converted into a derivative 1,2,5,6-tetrahydro-1-methylpyridine 22A, in accordance with consisting of two steps by the sequence shown in scheme 1.

The production of anions in the ortho-position of the aromatic systems used in the synthetic procedures described in the present application carried out in accordance with the overall strategy of synthesis, known as the directed ortho-metallation (DOM). Within the specified area with this purpose, we studied the number of functional groups, known as group directed metallation (DMG).

Dimethylsulfone group as group directed metallation (DMG) in N1-position of dimethylamide 3-pyridin-3-alprazol-1-sulfonic acid (23) allows litrovaya 5th position and thereby its function is ment (Chem. Ber., 124,1991, 1639-1650). 5-Li-derived compound 23 obtained in milligrammes range α-metallation (1.0 in EQ. t-BuLi, THF, -78°C, 1 h), captures (J. Org. Chem., 64,1999, 5366-5370) disulfide (e.g., 1-butyldiethanolamine) to obtain dimethylamide 5-butylsulfonyl-3-pyridin-3-alprazol-1-sulfonic acid 24, which was deprotection (25) and transformed into derived 1,2,5,6-tetrahydro-1-methylpyridine 26, in accordance with consisting of two steps by the sequence shown in scheme 1.

Scheme 3

Another synthetic route for producing compounds of the present invention, illustrated in formula I, is described in scheme 4. Introduction 2-(trimethylsilyl)ethoxymethyl group (SEM) as a protective group (Tetrahedron Letters, 39,1998, 5171-5174) gave a mixture of compounds 27A and 27B. The subsequent exchange of the bromine-lithium (1.1 EQ. n-BuLi, THF, -78°C, 1 h), and the interaction of this 4-lithium derivative 27A/B with S8leads to the formation of an intermediate compound linearities (J. Org. Chem., 69,2004, 3236-3239) 3-pyridin-3-yl-1-(2-trimethylsilylethynyl)-1H-pyrazole-4-thiol. This intermediate compound was grasped by 4-bromo-1,1,1-tricornutum to obtain a mixture of compounds 28A and 28C. Subsequent removal of the protective group SEM resulted in obtaining the target compound 3-[4-(4,4,4-tricorbuy sulfanyl)-1H-pyrazole-3-yl]pyridine 21B, which was converted into a derivative 1,2,5,6-tetrahydro-1-methylpyridine 22V, in accordance with consisting of two steps by the sequence shown in scheme 1.

Scheme 4

In another aspect of 3-(4-iodine-1H-pyrazole-3-yl)pyridine (20V, scheme 5) is used as a starting material for the compounds of the present invention, illustrated in formula I. 4-citipointe protected SEM derived 29A/B, obtained as well as the corresponding compounds 27A/B (scheme 4), interacted with trimethylboron with subsequent oxidation by hydrogen peroxide in situ (J. Heterocyclic Chem., 31,1994, 1377-1380) to obtain the corresponding 3-pyridin-3-yl-1-(2-trimethylsilyl-1-ethoxymethyl)-1H-pyrazole-4-ol (30, one isomer). Alkylation of 4-hydroxy 30 can be carried out using methods well known in the field, for example, the interaction of compound 30 with K2CO3in DMF in the presence of various (aryl)alkylhalogenide, for example (3-bromopropyl)benzene, to form a compound 31A (one isomer). Subsequent removal of the group SEM led to 3-[4-(3-phenylpropoxy)-1H-pyrazole-3-yl]pyridine (32A), which was converted into a derivative 1,2,5,6-tetrahydro-1-methylpyridine 33A, in accordance with consisting of two steps by the sequence shown is Oh scheme 1.

Scheme 5

Scheme 6 illustrates two alternative ways to obtain 3-(4-alkoxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine connections.

A mixture of public protected SEM pyrazoles 29A/B was converted into a mixture 34A/B effective consisting of two stages in the sequence described in scheme 1 (quaternization of pyridine part of CH3I and the restoration of the corresponding pyridinium salt NaBH4).

Reported methods of education links With About (for example, J. Am. Chem. Soc., 123,2001, 10770). More precisely, the effective transformation of primary alcohols analogue 4-iterate (34A/B) can be achieved using the methodology catalyzed by CuI/1,10-phenanthroline transverse compounds (Organic Letters, 4,2002, 973-978). Subsequent removal of the protecting connection 35A (one isomer) gave 3-(4-hexyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (33B).

In alternative sequences of synthesis (scheme 6) bond formation C-O can be achieved using the above methodology catalyzed by CuI/1,10-phenanthroline cross-linked compounds, to generate compound 31G. The synthesis of compounds 33G was illustrated in scheme 6, in accordance with the procedures illustrated in scheme 5.

Scheme 6

One aspect of the invention, relative to the tsya to derived bis-3-(4-alkylsulfanyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (for example, connection 22S, scheme 7), which are associated with muscarinic receptors and can activate (J. Med. Chem., 44,2001, 4563-4576). Introduction phenylsulfonyl as a protective group (from 20A) was performed selectively to a region for generating 3-(1-phenylsulfonyl-4-bromo-1H-pyrazol-3-yl)pyridine (36A of 20A).

Cross-connection of aliphatic and aromatic thiols and approach formulated above can oposredovanie catalytic system Pd2(dba)3/Xanthos in xylene, boiling under reflux, to obtain the corresponding simple arolovich thioesters (Organic Letters, 6,2004, 4587-4590, Tetrahedron, 61,2005, 5253-5259).

Using this methodology, compound 36A was converted into a protected derivative 37 bis-alkylsulfonate. Removal of N1-phenylsulfonyl can be accomplished using methods well known to specialists in this field, for example an optional interaction connection 37 with potassium hydroxide in diethylene glycol in the presence of hydrazine. The quaternization (bis)pyridine part of CH3I and the restoration of the corresponding salt (bis)pyridinium NaBH4gave a derivative of pyrazole 22P.

Scheme 7 illustrates an alternative method of obtaining derivatives of 3-(4-alkylsulfanyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine, which can be used for the Intesa compounds, presented in figure 3 and 4 (respectively, 22A and 22B), and the main feature is the availability of the parent thiol.

Scheme 7

Another illustration of obtaining compounds of formula I of the present invention is shown in scheme 8.

Direct nitration (Chem. Ber., 88,1955, 1577) derived 19 pyrazole gave 3-(4-nitro-1H-pyrazole-3-yl)pyridine (38), which was restored in the corresponding 3-pyridin-3-yl-1H-pyrazole-4-ylamine (39) and interacted with the acid chloride, for example by butyrylcholine, for the formation of amide (40). Subsequent conversion into a derivative 41 1,2,5,6-tetrahydro-1-methylpyridine was conducted in accordance with consisting of two steps by the sequence shown in scheme 1. Subsequent recovery amide LiAIH4generates butyl-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-yl]amine (42).

Scheme 8

Scheme 9 illustrates the preparation of derivatives of 3-(4-quinil (and alkenyl)-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine in the form of compounds of formula I.

3-(1-phenylsulfonyl-4-bromo-1H-pyrazole-3-yl)pyridine (36A, scheme 7) or iodine - similar 36V (scheme 9) are excellent substrates for connections Sonogashira with integral acetylene (Tetrahedron Letters, 38,1997, 7835-7838, Eur. J. Org. Chem.,2006, 3283-3307). Catalysis PdCl2(PPH3)2in the Pris is under CuI (surplus Et 3N, DMF, 80°C, 2 h), and (for example) Gex-1-in generates the connection 43A. Subsequent withdrawal of protection (in accordance with scheme 7) with subsequent consisting of two steps by the sequence shown in scheme 1, gave 3-(4-Gex-1-inyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (45A).

The amount and reactivity of compound 36A (or 36V) further illustrated by the reactions of compounds Suzuki-Miyaura (for example) with alkenylboronic acids. Catalysis of Pd(OAc)2and effective S-Phos in the presence of K3PO4and (for example) (E)-HEXEN-1-elborno acid (J. Am. Chem. Soc., 127,2005, 4685-4696) gave alkenyl 46A. Subsequent withdrawal of protection from subsequent consisting of two steps by the sequence shown in scheme 1, gave 3-(4-Gex-1-enyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (47A).

Scheme 9

In another aspect of 3-(4-iodine-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (48, Bioorganic & Medicinal Chemistry 8,2000, 449-454) is used as starting material for compounds of formula I of the present invention (scheme 10).

Referring to scheme 3, deleteoperation (Bioorganic & Medicinal Chemistry 8,2000, 2317-2335) 48, (2.1 EQ. n-Buli, THF, -78°C, 2 h) was captured by a disulfide (e.g., 1-butyldisulfide) to obtain the corresponding 3-(4-butylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane 49A.

Scheme 10 illustrates an alternative - n is also common - the method of obtaining derivatives of 3-(4-alkylsulfanyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane. Thus, the connection 48 may be converted by catalytic system Pd2(dba)3/Xanthos (similar to figure 7, but in DMF at 120°C), giving the corresponding simple arrowy tiefer 49B in one stage without protection.

A mixture of public protected SEM pyrazoles 50 (one isomer) was turned into a mixture of 51 methodology, cross-connection, catalyzed by CuI/1,10-phenanthroline as described in scheme 6, but using different terms. Subsequent removal of the protection 51A gives the corresponding 3-(4-butoxy-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane 52A.

Scheme 10

Another illustration of obtaining compounds of formula I of the present invention is shown in scheme 11.

Public 1-azabicyclo[3.2.1]octane-6-he (53), (J. Med. Chem., 36,1993, 683-689) were grown in 6-(1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]-6-ol (55) similarly effective including two stage sequence (Bioorganic & Medicinal Chemistry, 8,2000, 449-454). Attempts to improve the yield of the dehydration of alcohol (55)carried out by acylation (56) (Heterocycles, 24,1986, 971-977) and subsequent elimination of heat (185°C), gave the expected endo-1-azabicyclo[3.2.1] derivative (58). Yoginirohini (Bioorganic & Medicinal Chemistry, 4,1996, 227-237) and the introduction of pentane-1-thiol kataliticheski the th system Pd 2(dba)3/Xanthos (in accordance with scheme 7) gave endo-6-(4-intercultural-1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (60A).

Scheme 11

Figure 12 shows another illustration of obtaining compounds of formula I of the present invention.

Produced 3-pyridinethione (61) becomes chlorhydroxide derived (US 2004/0157900), which is converted into oxide nicotinanilide (Tetrahedron 61,2005, 4363-4371) “in situ” and interacts with 1,2-bis-trimethylsilylethynyl (Chem. Ber., 107,1974, 3717-3722) to obtain 1,3-dipolar cycloaddition product 3-(4,5-bis-trimethylsilyloxy-3-yl)pyridine (62). Caused by halogen ipso disilylgermane led to the derivatization of 4-bromo-5-trimethylsilyl (63). Subsequent disilylgermane NH4OH (Chem. Ber., 112,1979, 2829-2836) generates 3-(4-bromination-3-yl)pyridine (64).

Derivatives isoxazolidine 62, 63 and 64 represent new connections in and of themselves are variants of implementation of the present invention.

Introduction (for example) butane-1-thiol in connection 64 catalytic system Pd2(dba)3/Xanthos (in accordance with schemes 7, 10 and 11) gave 3-(4-butylsulfonyl-3-yl)pyridine (65A). The quaternization of pyridine part of the mainly sophisticated dimethyl ether sulfuric acid and recovering the corresponding the soup pyridinium salt NaBH 4generates the corresponding 3-(4-butylsulfonyl-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (66A).

Scheme 12

Scheme 13 illustrates the preparation of derivatives of 3-(4-quinil (and alkenyl)isoxazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine as compounds of formula I.

3-(4-bromination-3-yl)pyridine (64) is an excellent substrate for connection Sonogashira with (end) acetylene using similar methodology described in scheme 9.

Subsequent conversion of these etkinlik derivatives (scheme 13, for example, 69A) using the conditions of quaternization and recovery described in scheme 12, gave the corresponding derivatives of 3-(4-alkylresorcinol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (example 70A).

The amount and reactivity of compounds 64 further illustrated by the reactions of compounds Suzuki-Miyaura (for example) with alkenylboronic acids, using the methodology described in scheme 9. Subsequent conversion of these alkenyl derivatives (scheme 13, for example, 67A) using the conditions of quaternization and recovery described in scheme 12, gave the corresponding derivatives of 3-(4-alkenylsilanes-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (example 68A).

Scheme 13

Obtaining compounds f is rmula I of the present invention are shown below in figure 14.

3-trimethylindolenine (71) (Eur. J. Org. Chem.,2002, 2126), obtained from 3-bromopyridine using the methodology Knochel (Angew. Chem., Int. Ed., 39,2000, 4414-4435), connected in Stille conditions (toluene, 120°C, PdCl2(PPH3)2with 4,5-dibromo-1-(2-trimethylsilylethynyl)-1H-imidazole (72) (Tetrahedron Letters, 39,1998, 5171-5174) to obtain 3-[5-bromo-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]pyridine (73). Introduction (for example) pentane-1-thiol catalytic system Pd2(dba)3/Xanthos (in accordance with the scheme 12) gave the corresponding derivative of 5-interculturalisation (A). The quaternization of pyridine part (CH3I) and the recovery of the corresponding pyridinium salt NaBH4(75A) with subsequent removal of the group SEM 3-[5-intercultural-3H-imidazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine (76A).

Alternative transformation A in 76A, removing protection V (scheme 14, the connection 77), followed by quaternization and recovery generates the desired 3-[5-hexylsilane-3H-imidazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine (V).

Scheme 14

4. The synthesis of certain compounds

N-methoxy-N-nicotine amide(compound 2, scheme 1)

Hydrochloride nicotinanilide (compound 1) (10 g, 56 mmol) and 6,28 g N,O-dimethylhydroxylamine HCl (72,8 mmol) were combined in 200 ml of dichloromethane. To this the th mixture was added 18,14 ml of pyridine (15 min at 0°C). The reaction mixture is subsequently stirred for 4 hours at room temperature. The reaction mixture was concentrated in vacuum. The obtained residue was collected in dichloromethane and N2About (0°C), washed with 2N NaOH solution followed by washing with brine, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (Meon/triethylamine 97/3) gave compound 2 as an oil (6,92 g, 74%).1H-NMR (200 MHz, CDCl3): δ 8,96 (d, J=2 Hz, 1H), 8,69 (d, J=5 Hz, 2 Hz, 1H), 8,04 (dt, J=8 Hz, 2 Hz, 1H), 7,41-7,32 (m, 1H), of 3.56 (s, 3H), 3,40 (s, 3H). (TLC Meon/triethylamine Rf0,19).

1-pyridine-3-ingatan-1-he (compound 3, scheme 1)

To a solution of anhydrous THF (15 ml)containing the compound 2 (1.0 g, of 6.02 mmol) was added dropwise is 3.08 ml (7,66 mmol) hexolite (2.5 M in hexane) at -78°C in an atmosphere of N2. After adding the resulting solution was stirred for 30 minutes at -78°C. the Mixture was allowed to warm to ambient temperature and poured into a solution of NH4Cl (10 g/50 ml of N2O, 0°C). Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1:1) to obtain compound 3 as an oil (0,91 g, 78%).1H-NMR (200 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), 8,78 (d, J=5 Hz, 2 is C, 1H), 8,24 (dt, J=8 Hz, 2 Hz, 1H), 7,47-7,37 (m, 1H), 2,99 (t, J=7 Hz, 2H), 1,84-of 1.65 (m, 2H), 1,47-1,25 (m, 6H), 0,90 (ushort, J=7 Hz, 3H).

2-methylene-1-pyridine-3-ingatan-1-he (compound 4, scheme 1)

To 1 g (5.2 mmol) of compound 3 dissolved in 10 ml Meon, was added 0.1 ml of piperidine, 0.1 ml of acetic acid and 3 ml of an aqueous solution of formaldehyde (37% formaldehyde in water). The mixture was heated at the boil under reflux for 48 hours.

The mixture was cooled and concentrated in vacuum. Added ethyl acetate and the organic layer washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain compound 4 in the form of oil (of 1.05 g, 95%).1H-NMR (200 MHz, CDCl3): δ to 8.94 (d, J=2 Hz, 1H), 8,76 (d, J=5 Hz, 2 Hz, 1H), with 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7,46-7,35 (m, 1H), 5,94 (s, 1H), 5,64 (s, 1H), 2,48 (ushort, J=7 Hz, 2H), 1.60-to 1,25 (m, 6H), 0,99-of 0.82 (m, 3H).

1-(4-pentyl-3-pyridin-3-yl-4,5-dihydropyrazol-1-yl)alanon (compound 5, scheme 1)

Compound 4 (3,37 g of 16.6 mmol) and of 5.89 ml of hydrazine hydrate is added dissolved in 50 ml of acetic acid and was heated at the boil under reflux for 1.5 hours. The mixture was cooled and concentrated in vacuum. Added ethyl acetate and the organic layer washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash games is-chromatography (simple ether/ethyl acetate 1/1) to obtain compound 5 (amorphous, of 2.92 g, 68%).1H-NMR (600 MHz, D6DMSO): δ of 8.92 (d, J=2 Hz, 1H), 8,67-8,64 (m, 1H), 8,07 (userd, J=8 Hz, 1H), 7,39 was 7.36 (m, 1H), Android 4.04 (t, J=10 Hz, 1H), 3.96 points (DD, J=10 Hz, J=5 Hz, 1H), 3,67-3,61 (m, 1H), 2.40 a (s, 3H), 1,76 was 1.69 (m, 1H), 1,50-of 1.42 (m, 1H), 1,39-1,22 (m, 6H), 0,87 (ushort, J=7 Hz, 3H).

3-(4-pentyl-1H-pyrazole-3-yl)pyridine (compound 7, scheme 1)

Compound 5 (0.9 g, 3,47 mmol) and a 3.01 g MnO2(10 EQ.) combined in dichloroethane (100 ml) and warmed with boiling under reflux for 2 hours (Dean Stark). Added additional MnO2(8,02 g) and the mixture is boiled under reflux for a further 12 hours. The mixture was cooled, filtered and the filtrate was thoroughly washed with dichloromethane/isopropyl alcohol (1/1). The mixture was concentrated in vacuo to obtain the product of oxidation (6) (TLC in ethyl acetate Rf0,20), contaminated with some starting material (5) (TLC in ethyl acetate Rf0,27), and already deacetylating product (7) (TLC in ethyl acetate Rf0,12). This mixture (0.64 g) was used in the next stage without further purification.

The above material was dissolved in 5 ml EtOH and 5 ml of 2N NaOH, and the reaction mixture is boiled under reflux for 4 hours. The mixture was cooled and concentrated in vacuum. Added ethyl acetate and the organic layer washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chrome is cografya (ethyl acetate) to obtain compound (7) as an oil (344 mg, 1.6 mmol, 46% (total)).1H-NMR (200 MHz, CDCl3): δ 8,88 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 7,92 (dt, J=8 Hz, 2 Hz, 1H), 7,47 (users, 1H), 7,38-7,33 (m, 1H), 2,62 (t, J=7 Hz, 2H), 1,64-of 1.55 (m, 2H), 1,36 of 1.28 (m, 6H), 0,85 (ushort, J=7 Hz:3H).

3-(4-pentyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 9, scheme 1)

Logmean (0,08 ml, 1.28 mmol) was added to a solution of compound 7 (130 mg, 0.6 mmol) in acetone (10 ml). After heating for 12 hours the reaction mixture was cooled and the precipitated crystals were filtered off, washed simple diethyl ether and dried to obtain compound 8. To a cooled (-30°C.) suspension of this derived pyridinium iodide (8) in the Meon (15 ml) in small portions was added sodium borohydride (90 mg, 2.4 mmol). The mixture was allowed to warm to ambient temperature and was poured into a saturated solution of NH4Cl (0°C). The solvent is (partially) removed under reduced pressure. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (Meon/ethylamine 97/3) to obtain compound 9 (amorphous, 63 mg, 45% (total)).1H-NMR (200 MHz, CDCl3): δ 7,35 (users, 1H), 6,07-6,00 (users, 1H), 3.33 and is 3.25 (m, 2H), 2,64 to 2.35 (m, 6H), of 2.45 (s, 3H), 1,68 of 1.50 (m, 2H), 1,41 of 1.28 (m, 4H), 0,90 (ushort, J=7 Hz, 3H).

N-methoxy-N-methyl-2-pyridi the-3-ylacetamide (compound 12, scheme 2)

To a solution of anhydrous dichloromethane (200 ml)containing compound 10 (15,35 g, to 88.4 mmol)was added 14,93 ml (163,3 mmol) oxalicacid and a few drops of DMF. The mixture is gently boiled under reflux in an atmosphere of N2. The mixture was cooled and concentrated, re-dissolved in dichloromethane and concentrated. The residue was dissolved in 200 ml of anhydrous dichloromethane and added 11,09 g (113,7 mmol) N,O-dimethylhydroxylamine HCl. To this mixture (0°C) was added by 2.73 ml of pyridine (15 minutes). The reaction mixture is subsequently stirred for 4 hours at room temperature. The reaction mixture was concentrated in vacuum. Then the obtained residue was collected in dichloromethane and N2About (0°C), washed with 2N NaOH solution followed by washing with brine, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (ethyl acetate) gave compound 12 in the form of an oil (5.2 g, 33%).1H-NMR (400 MHz, CDCl3): δ 8,53-8,49 (m, 2H), 7,66 (userd, J=8 Hz, 1H), 7,29-7,24 (m, 1H), 3,78 (s, 2H), 3,68 (s, 3H), 3,20 (s, 3H).

1-pyridine-3-elexan-2-on (compound 13, scheme 2)

To a solution of anhydrous THF (15 ml)containing the compound 12 (1.0 g, 5.5 mmol)was added dropwise 2.6 ml (6.5 mmol) of n-Buli (2.5 M in hexane) at -50°C in an atmosphere of N2. After adding the resulting solution was stirred for 30 minutes at -60°C. the Mixture gave perhaps the th to warm to ambient temperature and poured into a solution of NH 4Cl (10 g/50 ml of N2O, 0°C). Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain compound 13 in the form of an oil (0.21 g, 25%).1H-NMR (400 MHz, CDCl3): δ of 8.50 (DD, J=5 Hz, 2 Hz, 1H), 8,45 (d, J=2 Hz, 1H), 7,54 (dt, J=8 Hz, J=2 Hz, 1H), 7,29-7,24 (m, 1H), 3,70 (s, 2H), 2,50 (t, J=7 Hz, 2H), 1,62-of 1.53 (m, 2H), 1,34-1,24 (m, 2H), 0,9 (ushort, J=7 Hz, 3H).

1-dimethylamino-2-pyridin-3-ilhat-1-EN-3-one (compound 14, scheme 2)

A solution of 13 (2.0 g, 11 mmol) and DMFDMA (2.5 ml, 14.6 mmol) in dry t-BuOH was heated under reflux for 18 hours in an atmosphere of N2. The solution was allowed to acquire room temperature and subsequently concentrated in a vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain compound 14 in the form of oil (1.85 g, 62%).1H-NMR (400 MHz, CDCl3): δ 8,51 (DD, J=5 Hz, 2 Hz, 1H), 8,45 (d, J=2 Hz, 1H), 7,66 (s, 1H), 7,53 (dt, J=8 Hz, J=2 Hz, 1H), 7,28-7,24 (m, 1H), 2,72 (users, 6H), of 2.20 (t, J=7 Hz, 2H), 1,54 of 1.46 (m, 2H), 1,26-of 1.16 (m, 2H), 0,9 (ushort, J=7 Hz, 3H).

3-(4-butyl-1H-pyrazole-3-yl)pyridine (compound 15, scheme 2)

Compound 14 (0.95 g, 4 mmol) and 0.46 ml of hydrazine hydrate is added (9.4 mmol) was dissolved in anhydrous ethanol (25 ml) and was heated at the boil under reflux for 2 hours. The mixture was cooled and concentrated in vacuo the resulting residue was purified flash chromatography (ethyl acetate) to obtain compound 15 (amorphous, 0.7 g, 85%).1H-NMR (200 MHz, CDCl3): δ 8,65 (d, J=2 Hz, 1H), charged 8.52 (DD, J=5 Hz, 2 Hz, 1H), 7,72-to 7.67 (m, 2H), 7,35-7,31 (m, 1H), 2,82 (t, J=7 Hz, 2H), 1.70 to of 1.62 (m, 2H), 1,42-of 1.33 (m, 2H), 0,9 (ushort, J=7 Hz, 3H).

3-(4-butyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 16, scheme 2)

Logmean (0.9 ml, 14 mmol) was added to a solution of compound 15 (600 mg, 3 mmol) in acetone (50 ml). After heating for 12 hours the reaction mixture was cooled and the precipitated crystals were filtered off, washed simple diethyl ether and dried to obtain the corresponding derivative of pyridinium iodide. To a cooled (-30°C.) suspension of this derived pyridinium iodide in the Meon (100 ml) in small portions was added sodium borohydride (0.5 g, to 18.9 mmol). The mixture was allowed to warm to ambient temperature and was poured into a saturated solution of NH4Cl (0°C). The solvent is (partially) removed under reduced pressure. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (Meon/triethylamine 97/3) to obtain specified in the connection header 16 (amorphous, 500 mg, 70% (total)).1H-NMR (400 MHz, CDCl3): δ 7,40 (users, 1H), 5,78-5,74 (users, 1H), 3.15 and was 3.05 (m, 2H), 2,71 (ushort, J=7 Hz, 2H), has 2.56 (t, J=6 Hz, 2H), 2,43 (s, 3H), 2,38 of-2.32 (m, 2H), 1,68 is 1.60 (m, 2H), 1,43-of 1.36 (m, H), of 0.96 (t, J=7 Hz, 3H).

3-(4-methylsulfanyl-1H-pyrazole-3-yl)pyridine (compound 21A, scheme 3)

To a solution of anhydrous THF (150 ml)containing compound 20A (3.0 g, a 13.4 mmol, obtained in accordance with Bioorganic & Medicinal Chemistry, 4,1996, 227-237)was added dropwise 2.1 EQ. n-BuLi (11.2 ml, 2.5 M in hexane) at -78°C in an atmosphere of N2. After adding the resulting solution was stirred for 2 hours at -78°C. At this temperature, was added 1.1 EQ. methyldichlorosilane (1,33 ml) and the resulting solution was stirred for 1 hour at -78°C and subsequently allowed to warm to ambient temperature overnight. The mixture is then extinguished with saturated solution of NH4Cl at 0°C and concentrated in vacuum. Added ethyl acetate and the organic layer washed with 5% NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (ethyl acetate) gave compound 21A (oil, 1,71 g, 67%).1H-NMR (200 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8,28 (dt, J=8 Hz, 2 Hz, 1H), of 7.70 (s, 1H), 7,42-7,33 (m, 1H), of 2.38 (s, 3H).

3-(4-methylsulfanyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 22, scheme 3)

2.5 EQ. iodomethane (1.39 ml, 22,37 mmol) was added to a solution of 21A (1,71 g of 8.95 mmol) in acetone (100 ml)and the mixture was stirred for 18 hours. Precipitated crystals were filtered off, washed with diethyl simple e is Il and dried to obtain the corresponding derivative of pyridinium iodide. To refrigerated

(-30°C) suspension of this derived pyridinium iodide in the Meon (100 ml) in small portions was added sodium borohydride (1.35 g, 35.5 mmol). The mixture was allowed to warm to ambient temperature and was poured into a saturated solution of NH4Cl (0°C). The solvent is (partially) removed under reduced pressure. Added ethyl acetate and the organic layer was washed concentrated NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (Meon) to obtain specified in the title compound 22A (solid, 1.39 g, 74% (total)), mp 131, 5mm°C. LCMS (method A); Rt= 0,96 min, ([M+H]+= 210).1H-NMR (400 MHz, CDCl3): δ 7,52 (s, 1H), 6,56-6,46 (users, 1H), 3,40-to 3.36 (m, 2H), 2,62 (ushort, J=6 Hz, 2H), 2,46 (s, 3H), 2,45-of 2.38 (m, 2H), 2,30 (s, 3H).

3-[4-(4,4,4-trifloromethyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (compound 22B, scheme 4)

60% suspension of NaH in mineral oil (0.54 g, 13,64 mmol) was added to a solution of anhydrous THF (100 ml)containing compound 20A (2,79, 12.4 mmol) in an atmosphere of N2. The resulting mixture was stirred for 2 hours at room temperature and subsequently treated 13,64 mmol (2,41 ml) (2-hermeticity)trimethylsilane (SEM-Cl). The resulting mixture was stirred for 18 hours at room temperature. To the mixture was added utilized the t and the organic layer was washed three times with saturated solution of NaHCO 3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain a mixture 27A (main component) and 27B in the form of oil (3,19 g, 73%). Thoroughly adjustable cleaning flash chromatography (simple diethyl ether/PE 1/1) gave compound 27B, and the subsequent connection 27A. Compound 27B (oil).1H-NMR (400 MHz, CDCl3): δ to 9.15 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), to 8.20 (dt, J=8 Hz, 2 Hz, 1H), 7,71 (s, 1H), 7,38-7,34 (m, 1H), 5,44 (s, 2H), to 3.64 (t, J=8 Hz, 2H), 0,94 (ushort, J=8 Hz, 2H), 0,02 (s, 9H). Compound 27A (oil).1H-NMR (400 MHz, CDCl3): δ of 8.90 (d, J=2 Hz, 1H), up 8.75 (DD, J=5 Hz, 2 Hz, 1H), of 7.96 (dt, J=8 Hz, 2 Hz, 1H), 7,63 (s, 1H), 7,47-7,42 (m, 1H), of 5.34 (s, 2H), 3,70 (t, J=8 Hz, 2H), 0,92 (ushort, J=8 Hz, 2H), 0,02 (s, 9H). Analyses NOESYPHSW and HMBCGP used to confirm both connections.

To a solution of anhydrous THF (50 ml)containing a mixture of 27 A/B (0,92 g, 2.6 mmol)was added dropwise to 1.14 ml (1.1 EQ.) n-BuLi (2.5 M in hexane) (-78°C in an atmosphere of N2). After adding the resulting solution was stirred for 60 minutes at -78°C. At this temperature was added sulfur powder (2.6 mmol, 0.083 g) and the reaction mixture was stirred for another 2 hours (-78°C). The reaction was monitored by thin-layer chromatography. After addition of 4-bromo-1,1,1-triptorelin (1.1 EQ., 0.54 ml) the mixture was allowed to warm to ambient temperature (during the night) and in lively in a saturated solution of NH 4Cl (0°C). The solvent is (partially) removed under reduced pressure. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1)) to obtain a mixture of (mainly) 28A and 28B genotype (oil, (0,49 g, 45%).1H-NMR (described data 28A, 400 MHz, CDCl3): δ 8,80 (d, J=2 Hz, 1H), 8,70 (DD, J=5 Hz, 2 Hz, 1H), of 7.96 (dt, J=8 Hz, 2 Hz, 1H), 7,68 (s, 1H), of 7.48-the 7.43 (m, 1H), to 5.35 (s, 2H), 3.72 points ushort, J=8 Hz, 2H), 2,58 (t, J=7 Hz, 2H), 2,10-of 1.97 (m, 2H), 1,71-to 1.59 (m, 2H), 0,93 (ushort, J=8 Hz, 2H), 0,00 (s, 9H).

To a solution of anhydrous THF (20 ml)containing a mixture of 28A/B (0,49 g, 1.18 mmol)was added 3,54 ml (3.0 equiv.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (simple diethyl ether) to obtain 3-[4-(4,4,4-trifloromethyl)-1H-pyrazole-3-yl]pyridine (21B) (oil (0.32 g, 95%).1H-NMR (400 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), 8,28 (dt, J=8 Hz, 2 Hz, 1H), 7,73 (s, 1H), 7,42-7,37 (m, 1H), 2,61 (t, J=7 Hz, 2H), 2,19-of 2.08 (m, 2H), 1,75-of 1.65 (m, 2H).

Connect the tion 21B (0.3 g, for 1.49 mmol) was converted into compound 22B, using the methodology described for the conversion of 21A to 22A. Output 0,131 g (amorphous, 72%). LCMS (method A); Rt: 1,64 min, ([M+H]+= 306).1H-NMR (400 MHz, CDCl3): δ EUR 7.57 (s, 1H), 6,67-6,60 (users, 1H), 3,43-3,39 (m, 2H), 2.71 to 2,62 (m, 4H), 2.49 USD (s, 3H), 2,48 is 2.43 (m, 2H), 2,28-2,19 (m, 2H), 1,81 is 1.75 (m, 2H).

bis-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-yl)-2-sulfanilate]methane (compound 22 ° C, 7)

60% dispersion of NaH in mineral oil (0.73 g, and 18.3 mmol) was added to a solution of anhydrous THF (100 ml)containing compound 20A (3,71 g of 16.6 mmol) in an atmosphere of N2. The resulting mixture was stirred for 2 hours at room temperature and then processed to 18.3 mmol (2,33 ml) phenylsulfonylacetate. The resulting mixture was stirred for 18 hours at room temperature. To the mixture was added ethyl acetate and the organic layer was washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether) to obtain 3-(1-phenylsulfonyl-4-bromo-1H-pyrazole-3-yl)pyridine (36A) (TLC in ethyl acetate Rf0,7) (amorphous, 5.34 g, 89%).1H-NMR (400 MHz, CDCl3): δ 9,1 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), 8,24 (s, 1H), 8,16 (dt, J=8 Hz, 2 Hz, 1H), 8,10-with 8.05 (m, 2H), 7,70 (ushort, J=7 Hz, 2H), 7,62-7,56 (m, 2H), 7,39-7,34 (m, 1H).

To a degassed solution of xylene (20 ml), kept Adamu connection 36 (0.7 g, 1.92 mmol)was added to 0.45 EQ. (of 0.12 ml, 0.86 mmol) of pentane-1,5-dithiol and 0.5 EQ. To2CO3(0,137 g, 0.96 mmol). The resulting mixture was stirred for another 2 hours in an atmosphere of N2. Consistently added 0,192 mmol Pd2(dba)3(176 mg) and 0.384 mmol of Xanthos (222 mg). After adding the resulting solution was boiled under reflux with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (ethyl acetate) to obtain compound 37 in the form of oil (0,46 g, 68%) (TLC in ethyl acetate Rf0,29).

Compound 37 (0,46 g of 0.65 mmol), 0.7 g of KOH and 1 ml of NH2NH2•H2O United in diethylene glycol (10 ml) and warmed by boiling under reflux for 1 hour in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in the Meon. Filtration through a 5 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (ethyl acetate) gave bis-[3-pyridin-3-yl-1H-pyrazole-4-yl)-2-sulfanilate]methane as devoid of protection similar compounds 37 (amorphous, 0,23 g, 83%).1H-NMR (400 MHz, CDCl3): δ to 9.15 (d, J=2 Hz, 2H), to 8.57 (DD, J=5 Hz, 2 Hz, 2H), 8,31 (dt, J=8 Hz, 2 Hz, 2H), 7,66 (s, 2H), was 7.36-to 7.32 (m, 2H), 2,50-to 2.42 (m, 4H), 1,34-of 1.26 (m, 6H).

Devoid of protection similar compounds 37 (0,23 g, 0.54 mmol) was converted into the Conn is out at 22 ° C using the methodology described for the conversion of compounds 21A to 22A. Yield 0.2 g (oil, 80%), LCMS (method A); Rt: 1,66 min, ([M+H]+= 459).1H-NMR (400 MHz, CDCl3): δ 7.50 for (s, 2H), 6,92-6,85 (users, 2H), 3,90-of 3.80 (m, 4H), 3,07 (ushort, J=7 Hz, 4H), 2,77 (s, 6H), 2,66-of 2.54 (m, 8H), 1,54 was 1.43 (m, 6H).

3-(4-ethylsulfanyl-1H-pyrazole-3-yl)pyridine (compound 21D)

Connection 21D received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using ethyldimethylamine as disulfide and 3-(4-bromo-1H-pyrazole-3-yl)pyridine (compound 20A).

Yield: 76% (oil). LCMS (method A); Rt: 1,56 min, ([M+H]+= 206).1H-NMR (200 MHz, CDCl3): δ 9,11 (d, J=2 Hz, 1H), 8,64 (DD, J=5 Hz, 2 Hz, 1H), 8,18 (dt, J=8 Hz, 2 Hz, 1H), 7,71 (s, 1H), 7,39-7,35 (m, 1H), 2,64 (kV, J=7 Hz, 2H), 1.26 in (t, J=7 Hz, 3H).

3-(4-ethylsulfanyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 22D)

Connection 22D received from the connection 21D in accordance with the procedure described for the synthesis of compound 2A (from 21A) (see scheme 3). Yield: 73% (solid), mp 95-97°C . LCMS (method A); Rt: 1,15 min, ([M+H]+= 224).1H-NMR (mixture of rotational isomers (3/1), described the main, 400 MHz, CDCl3): δ 7,53 (s, 1H), 6,55-6,46 (users, 1H), 3,40-3,37 (m, 2H), 2,67-2,60 (m, 4H), to 2.46 (s, 3H), 2,43-of 2.36 (m, 2H), 1,19 (3H).

3-(4-propylsulfonyl-1H-pyrazole-3-yl)pyridine (compound E)

Connection 22E received in accordance with the procedure described for the synthesis of compounds 2A, ISOE is isua (see scheme 3) 1-propylsulfonyl as disulfide and 3-(4-bromo-1H-pyrazole-3-yl)pyridine (compound 20A) (flash chromatography in ethyl acetate/simple diethyl ether 5/1).

Yield: 76% (oil).1H-NMR (200 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,68 (s, 1H), 7,39-7,35 (m, 1H), has 2.56 (t, J=7 Hz, 2H), 1,54 was 1.43 (m, 2H), of 0.90 (t, J=7 Hz, 3H).

3-(4-propylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 22E)

Connection 22E received from the connection A in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 77% (solid), mp 111°C . LCMS (method A); Rt: 1,39 min, ([M+H]+= 238).1H-NMR (mixture of rotational isomers (8/1), described the main, 400 MHz, CDCl3): δ at 7.55 (s, 1H), 6,61-6,55 (users, 1H), 3,43-3,39 (m, 2H), 2,68-2,60 (m, 4H), 2,48 (s, 3H), 2,46-2,39 (m, 2H), 1,58 (DQC., J=7 Hz, 7 Hz, 2H), and 0.98 (t, J=7 Hz, 3H).

3-(4-butylsulfonyl-1H-pyrazole-3-yl)pyridine (compound 21F)

Connection 21F received in accordance with the procedure described for the synthesis of compound 22A (see scheme 3)using 1-butyldisulfide as disulfide and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20A) (flash chromatography in ethyl acetate/simple diethyl ether 3/1).

Output: 18,4% (oil).1H-NMR (200 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,68 (s, 1H), 7,39-7,34 (m, 1H), 2,58 (t, J=7 Hz, 2H), 1,48-of 1.40 (m, 2H), 1,3-1,25 (m, 2H), of 0.90 (t, J=7 Hz, 3H).

3-(4-butylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 22F)

Connection 22F was obtained from compound 21F according to the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 73% (amorphous substance). The compound was subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated. Recrystallization from EtOH/ethyl acetate gave a solid (free base/fumaric acid 1/1), mp 120-121°C. LCMS (method A); Rt: 1,16 min, ([M+H]+= 252).

3-(4-intercultural-1H-pyrazole-3-yl)pyridine (compound 21G)

Connection 21G received in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3)using 1-intellisharpen as disulfide and 3-(4-bromo-1H-pyrazole-3-yl)pyridine (compound 20A).

Yield: 71% (oil).1H-NMR (400 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8,32 (dt, J=8 Hz, 2 Hz, 1H), 7,66 (s, 1H), 7,39-7,34 (m, 1H), 2.57 m (t, J=7 Hz, 2H), 1,48-of 1.41 (m, 2H), 1.30 and to 1.14 (m, 4H), 0,81 (t, J=7 Hz, 3H).

3-(4-intercultural-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 22G)

Connection 22G received from the connection 21G in accordance with the procedure described for the synthesis of compound 22A (see scheme 3). Yield: 77% (solid). mp 100-101°C. LCMS (method A); Rt: 1,67 min, ([M+H]+= 266).1H-NMR (400 MHz, CDCl3): δ 7,51 (s, 1H), 6,56-6,47 (ush the D.C, 1H), 3,40-to 3.36 (m, 2H), 2,65 at 2.59 (m, 4H), of 2.45 (s, 3H), 2,44-of 2.38 (m, 2H), 1.57 in to 1.47 (m, 4H), 1,39-1,24 (m, 4H), to 0.88 (t, J=7 Hz, 3H).

3-(4-hexylsilane-1H-pyrazole-3-yl)pyridine (compound 21H)

Connection 21H received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 1-heksildiantipirilmetan as disulfide and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B).

Yield: 37% (oil).1H-NMR (400 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), to 8.62 (DD, J=5 Hz, 2 Hz, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), of 7.70 (s, 1H), 7,40-7,35 (m, 1H), 2,59 (t, J=7 Hz, 2H), 1,50-of 1.42 (m, 2H), 1,34 by 1.12 (m, 6H), 0,81 (t, J=7 Hz, 3H).

3-(4-hexylsilane-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 22H)

Connection 22H received from the connection 21H in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 49% (amorphous substance). LCMS (method A); Rt: 1,81 min, ([M+H]+= 280).1H-NMR (400 MHz, CDCl3): δ 7,51 (s, 1H), 6,60-6,50 (users, 1H), 3,40-to 3.36 (m, 2H), 2,65 at 2.59 (m, 4H), of 2.45 (s, 3H), 2,44-of 2.38 (m, 2H), 1.56 to to 1.48 (m, 2H), 1,39 is 1.20 (m, 6H) to 0.88 (t, J=7 Hz, 3H).

3-[4-(3-phenylpropylamine)-1H-pyrazole-3-yl]pyridine (compound 21I)

Connection 21I received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 3-phenylpropionitrile-3-propylbenzoyl as disulfide (obtained in accordance with the methodology described in Tetrahedron Letters, 42, 2001, 6741-6743) and 3-(4-bromo-1H-pyrazole-3-elpidina (compound 20A). (flash chromatography (ethyl acetate)). Output: 22% (oil).1H-NMR (400 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), to 8.62 (DD, J=5 Hz, 2 Hz, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,69 (s, 1H), 7,40 and 7.36 (m, 1H), 7,24 (ushort, J=7 Hz, 2H), 7,17 (ushort, J=7 Hz, 1H),? 7.04 baby mortality (userd, J=7 Hz, 2H), 2,65-to 2.57 (m, 4H), of 1.84 and 1.75 (m, 2H).

3-[4-(3-phenylpropylamine)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (compound 22I)

Connection 22I was obtained from compound 21I in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 59% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ 7,51 (s, 1H), 7,30-7,22 (m, 2H), 7,21 for 7.12 (m, 3H), 6,66-6,46 (users, 1H), 3,39-to 3.34 (m, 2H), 2,70 is 2.55 (m, 6H), is 2.44 (s, 3H), 2,43-of 2.36 (m, 2H), 1,89 and 1.80 (m, 2H).

3-[4-(4,4-deverbal-3-animalfunny)-1H-pyrazole-3-yl]pyridine (compound 21J)

Connection 21J received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 4-(4,4-deverbal-3-tillicoultry)-1,1-deverbal-1-ene as a disulfide (Tetrahedron Letters, 42,2001, 6741-6743) and 3-(4-bromo-1H-pyrazole-3-yl)pyridine (compound 20A) (flash chromatography (ethyl acetate)). Yield: 58% (oil).1H-NMR (400 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), to 8.62 (DD, J=5 Hz, 2 Hz, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,72 (s, 1H), 7,42 and 7.36 (m, 1H), 4,19-4,06 (m, 1H), 2,59 (t, J=7 Hz, 2H), 2,18-of 2.09 (m, 2H).

3-[4-(4,4-deverbal-3-animalfunny)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (compound 22J)

Connection 22J received from the connection 21H is accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 90% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ rate of 7.54 (s, 1H), 6,68-6,44 (users, 1H), 4,27-to 4.15 (m, 1H), 3,40-to 3.36 (m, 2H), 2,66-2,60 (m, 4H), 2,47 (s, 3H), 2,45-of 2.38 (m, 2H), 2,22 with 2.14 (m, 2H).

3-[4-(3-phenylalanyl)-1H-pyrazole-3-yl]pyridine (compound 21K)

Connection 21K received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 3-generallydesigned-3-allevents as disulfide (Tetrahedron Letters, 42,2001, 6741-6743) and 3-(4-bromo-1H-pyrazole-3-yl)pyridine (compound 20A) (flash chromatography (ethyl acetate)). Output: 22% (oil). (TLC ethyl acetate Rf0,45).

3-[4-(3-phenylalanyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (connection 22K)

Connection 22K received from the connection 21K in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 72% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ 7,52 (s, 1H), 7,30-to 7.18 (m, 5H), 6,70-6,20 (users, 1H), 6,20-6,07 (m, 2H), 3,37 (d, J=7 Hz, 2H), 3.33 and of 3.28 (m, 2H), 2,54 (ushort, J=7 Hz, 2H), 2.40 a (s, 3H), 2,39-of 2.30 (m, 2H).

3-[4-(Penta-4-animalfunny)-1H-pyrazole-3-yl]pyridine (compound 21L)

Connection 21L received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 5-Penta-4-initialpayment-1-ene as a disulfide (Tetrahedron Letters, 42,2001, 6741-6743) and 3-(4-iodine-1H-pyrazole-3-yl)pyrid is on (compound 20B) (flash chromatography (ethyl acetate)). Yield: 28% (oil). LCMS (method A); Rt: 2,21 min, ([M+H]+= 246).1H-NMR (400 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), to 8.62 (DD, J=5 Hz, 2 Hz, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,71 (s, 1H), 7,41-7,35 (m, 1H), 5,73-5,59 (m, 2H), equal to 4.97-4,89 (m, 2H), 2,59 (t, J=7 Hz, 2H), 2,10-2,03 (m, 2H), 1,61-and 1.54 (m, 2H).

3-[4-(Penta-4-animalfunny)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (compound 22L)

Connection 22L received from the connection 21L in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 61% (amorphous substance). LCMS (method A); Rt: 1,84 min, ([M+H]+= 264).1H-NMR (400 MHz, CDCl3): δ 7,52 (s, 1H), 6,70-6,40 (users, 1H), 5,81-of 5.68 (m, 1H), 5,04-4,94 (m, 2H), 3,40-to 3.36 (m, 2H), 2,66-to 2.57 (m, 4H), of 2.45 (s, 3H), 2,45-is 2.37 (m, 2H), 2,17-of 2.09 (m, 2H), 1,66 is 1.58 (m, 2H).

3-[4-(furan-2-elmersolver)-1H-pyrazole-3-yl]pyridine (compound 21M)

Connection 21M received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using departuredate and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B) (flash chromatography (ethyl acetate)). Yield: 54% (oil).1H-NMR (200 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), 8,59 (DD, J=5 Hz, 2 Hz, 1H), to 8.20 (dt, J=8 Hz, 2 Hz, 1H), 7,54 (s, 1H), 7,38-7,32 (m, 1H), 7,21-7,19 (m, 1H), 6,16-6,12 (m, 1H), 5,88 of 5.84 (m, 1H, in), 3.75 (s, 2H).

3-[4-(furan-2-elmersolver)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (connection 22M)

Connection 22M received from the connection 21M in accordance with the procedure described for sin is ESA compound 22A (see scheme 3).

Yield: 65% (amorphous substance). LCMS (method A); Rt: 1,04 min, ([M+H]+= 276).1H-NMR (200 MHz, CDCl3): δ was 7.36 (s, 1H), 7,33-7,31 (m, 1H), 6,38-6,26 (users, 1H), 6,24-of 6.20 (m, 1H), 5,93-5,90 (m, 1H), 3,78 (s, 2H), 3,30-up 3.22 (m, 2H), 2,60 (ushort, J=7 Hz, 2H), 2,44 (s, 3H), 2,41 is 2.33 (m, 2H).

3-(4-benzylmethyl-1H-pyrazole-3-yl)pyridine (compound 21N)

Connection 21N received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using dibenzyltoluene and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B) (flash chromatography (ethyl acetate)). Yield: 33% (oil).1H-NMR (400 MHz, CDCl3): δ 9,0 (d, J=2 Hz, 1H), 8,58 (DD, J=5 Hz, 2 Hz, 1H), 8,10 (dt, J=8 Hz, 2 Hz, 1H), 7,43 (s, 1H), 7,33-7,28 (m, 1H), 7,17-7,11 (m, 3H), 7,02-of 6.96 (m, 2H), and 3.72 (s, 2H).

3-(4-benzylmethyl)-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 22N)

Connection 22N received from the connection 21N in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 48% (amorphous substance). LCMS (method A); Rt: 1,55 min, ([M+H]+= 286). Connection 22N were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated.1H-NMR (600 MHz, D6DMSO): δ 7,63 (s, 1H), 7,28 (t, J=7 Hz, 2H), 7,28 (t, J=7 Hz, 2H), 7,24 (ushort, J=7 Hz, 1H), 7,17 (userd, J=7 Hz, 2H), 6,82-6,79 (users, 1H), 6,66 (s, 2H), 4,28 (userd, J=15 Hz, 1H), of 4.05 (DD, J=16 Hz, 6 Hz, 2H,), 3,86-of 3.80 (m, 1H), 3,55-to 3.50 (m, 1H), 3,18-3,10 (m, 1H), equal to 2.94 and 2.93 (2×s, 3H), 2,68 is 2.46 (m, 2H).

3-[4-(2-ethoxyethylene is)-1H-pyrazole-3-yl]pyridine (compound 21O)

Connection 21O received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 1-ethoxy-2-(2-amoxicillan)ethane as disulfide (Tetrahedron Letters, 42,2001, 6741-6743) and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B) (flash chromatography (ethyl acetate)). Yield: 28% (oil). LCMS (method A); Rt: 2,21 min, ([M+H]+= 246).1H-NMR (400 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), to 8.62 (DD, J=5 Hz, 2 Hz, 1H), 8,33 (dt, J=8 Hz, 2 Hz, 1H), of 7.75 (s, 1H), 7,41 and 7.36 (m, 1H), 3.46 in (t, J=7 Hz, 2H), 3,38 (kV, J=7 Hz, 2H), 2,78 (t, J=7 Hz, 2H), 1.14 in (t, J=7 Hz, 3H).

3-[4-(2-amoxicillan)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (connection 22O)

Connection 22O received from the connection 21O in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 63% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ 7,56 (s, 1H), 6,70-6,50 (users, 1H), 3,55-of 3.43 (m, 4H), 3,40-to 3.36 (m, 2H), of 2.81 (t, J=7 Hz, 2H), 2,61 (ushort, J=7 Hz, 2H), 2,46 (s, 3H), 2,44-of 2.38 (m, 2H), of 1.18 (t, J=7 Hz, 3H).

3-{4-[2-(2-methoxyethoxy)ethylsulfanyl]-1H-pyrazole-3-yl}pyridine (compound 21P)

Connection 21P received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 1-methoxy-2-{2-[2-((2-methoxyethoxy)tildesley]ethoxy}ethane as disulfide (Tetrahedron Letters, 42, 2001, 6741-6743) and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B) (flash chromatography (ethyl acetate)). Output: 3% (oil). 1H-NMR (400 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), 8,58 (DD, J=5 Hz, 2 Hz, 1H), 8,35 (dt, J=8 Hz, 2 Hz, 1H), 7,78 (s, 1H), 7,39-7,32 (m, 1H), 3,51-3,44 (m, 6H), to 3.34 (s, 3H), 2,78 (t, J=7 Hz, 2H).

3-{4-[2-(2-methoxyethoxy)ethylsulfanyl]-1H-pyrazole-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine (connection 22P)

Connection 22P received from the connection 21P in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 33% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ EUR 7.57 (s, 1H), 6,74-6,69 (users, 1H), 3,59-3,51 (m, 8H), to 3.38 (s, 3H), and 2.83 (t, J=7 Hz, 2H), 2,77 (ushort, J=7 Hz, 2H), by 2.55 (s, 3H), 2,52 at 2.45 (m, 2H).

3-(4-arylsulfonyl-1H-pyrazole-3-yl)pyridine (compound 21Q)

Connection 21Q received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 3-arildisulfuri as disulfide and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B). (flash chromatography (ethyl acetate)). Yield: 27% (oil).1H-NMR (200 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8,29 (dt, J=8 Hz, 2 Hz, 1H), of 7.70 (s, 1H), 7,40 and 7.36 (m, 1H), 5,77-to 5.66 (m, 1H), 4,94 (userid, J=11 Hz, 1 Hz, 1H), a 4.83 (userid, J=17 Hz, 1 Hz, 1H), 3,19 (userd, J=8 Hz, 2H).

3-(4-arylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 22Q)

Connection 22Q received from the connection 21Q in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 17% (amorphous substance).1H-NMR (200 MHz, CDl 3): δ 7,52 (s, 1H), 6,62-6,48 (users, 1H), of 5.84-5,74 (m, 1H), 4,98 (userid, J=11 Hz, 1 Hz, 1H), 4,90 (userid, J=17 Hz, 1 Hz, 1H), 4,00-3,95 (m, 2H), 3,23 (userd, J=8 Hz, 2H), 2,61 (ushort, J=7 Hz, 2H), 2,46 (s, sH), 2,44-2,39 (m, 2H).

3-(3-pyridin-3-yl-1H-pyrazole-4-ylsulphonyl)propionitrile (connection 21R)

Connection 21R received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 3-(2-cyanoethylidene)propionitrile as disulfide and 3-(4-iodine-1H-pyrazole-3-yl)pyridine (compound 20B) (flash chromatography (ethyl acetate)). Yield: 62% (oil).1H-NMR (200 MHz, CDCl3): δ 9,20 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8,33 (dt, J=8 Hz, 2 Hz, 1H), 7,82 (s, 1H), 7,43-7,37 (m, 1H), was 2.76 (t, J=7 Hz, 2H), 2,45 (t, J=7 Hz, 2H).

3-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-ylsulphonyl]propionitrile (connection 22R)

Connection 22R received from the connection 21R in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Output: 8% (amorphous substance).1H-NMR (200 MHz, CDCl3): δ 7,58 (s, 1H), 6,60-6,50 (users, 1H), 3,40-to 3.36 (m, 2H), and 2.79 (t, J=7 Hz, 2H), 2,66 (ushort, J=7 Hz, 2H), 2,50 (t, J=7 Hz, 2H), 2,47 (s, 3H), 2,45-of 2.38 (m, 2H).

3-[4-(3-methylbutanoyl)-1H-pyrazole-3-yl]pyridine (compound 21S)

Connection 21S received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 3-methyl-1-(3-methylbutyronitrile)butane as disulfide and 3-(4-iodine-1H-pyrazole-3-yl)is iridin (compound 20B) (flash chromatography (ethyl acetate)). Yield: 39% (oil).1H-NMR (200 MHz, CDCl3): δ 9,18 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), 8,35 (dt, J=8 Hz, 2 Hz, 1H), 7,78 (s, 1H), 7,39-7,35 (m, 1H), 2,60 (t, J=7 Hz, 2H), 1,65-of 1.57 (m, 1H), 1,42-of 1.33 (m, 2H), 0,81 (d, J=7 Hz, 6H).

3-[4-(3-methylbutanoyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (connection 22S)

Connection 22S received from the connection 21S in accordance with the procedure described for the synthesis of compound 22A (from 21A) (see scheme 3).

Yield: 73% (amorphous substance).1H-NMR (200 MHz, CDCl3): δ 7.5 (a s, 1H), 6,60-6,48 (users, 1H), 3,40-to 3.36 (m, 2H), 2,66 at 2.59 (m, 4H), of 2.45 (s, 3H), 2,44-2,39 (m, 2H), 1,72-of 1.62 (m, 1H), 1,45-of 1.39 (m, 2H), 0,86 (d, J=7 Hz, 6H).

Dimethylamide 3-pyridin-3-alprazol-1-sulfonic acid (compound 23, scheme 3)

Compound 19 (3.0 g, of 20.7 mmol) and 2,22 ml phenylsulfonylacetate (20,7 mmol) were combined in pyridine (100 ml) and was stirred for 18 hours while boiling under reflux. The reaction mixture was concentrated in vacuum. The residue was collected in ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (simple diethyl ether/PE 2/1) to obtain compound 23 (amorphous substance, 2.86 g, 55%).1H-NMR (200 MHz, CDCl3) δ 9,1 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,16 (dt, J=8 Hz, 2 Hz, 1H), with 8.05 (d, J=3 Hz, 1H), 7,39-7,34 (m, 1H), 6.75 in (d, J=3 Hz, 1H), to 3.02 (s, 6H).

Dimethylamide 5-butylal the Nile-3-pyridin-3-alprazol-1-sulfonic acid (compound 24, scheme 3)

To a solution of anhydrous THF (50 ml)containing compound 24 (1.0 g, 4 mmol)was added dropwise 1 EQ. n-BuLi (2.35 ml, 1.7 M in pentane) at -78°C in an atmosphere of N2. After adding the resulting solution was stirred for 1 hour at -78°C. At this temperature, was added 1.1 EQ. 1-butyldiethanolamine (0,79 ml) and the resulting solution was stirred for 1 hour at -78°C and then allowed to warm to ambient temperature overnight. The mixture is then extinguished with saturated solution of NH4Cl at 0°C and concentrated in vacuum. Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (simple diethyl ether/PE 5:1) to ethyl acetate/simple diethyl ether 1/1) gave compound 24 (oil, 0,93 g, 70%).1H-NMR (200 MHz, CDCl3) δ 9,1 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,15 (dt, J=8 Hz, 2 Hz, 1H), 7,39-7,34 (m, 1H), 6,50 (s, 1H), to 3.02 (s, 6H), to 3.02 (t, J=7 Hz, 2H), 1,82-to 1.67 (m, 2H), 1.60-to of 1.42 (m, 2H), 0,97 (t, J=7 Hz, 3H).

3-(5-butylsulfonyl-1H-pyrazole-3-yl)pyridine (compound 25, scheme 3)

Compound 24 (0,92 g, a 2.71 mmol) was dissolved in 50 ml of n-BuOH. To this solution was added 2 g of KOH dissolved in 50 ml of N2Oh, and the reaction mixture was stirred for 18 hours at room temperature in an atmosphere of N2. The reaction mixture was concentrated in HAC is the mind. The obtained residue was collected in ethyl acetate, washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (simple diethyl ether/PE 4/1) gave compound 25 (amorphous substance of 0.44 g, 70%). TLC in ethyl acetate Rf0,34).

3-(5-butylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 26, scheme 3)

Compound 26 was obtained according to the procedure described for the synthesis of compound 22A (from 21A).

Yield: 70% (amorphous substance).1H-NMR (200 MHz, CDCl3) δ 6,27 (s, 1H), 6.22 per 6,18 (users, 1H), 3,31-of 3.27 (m, 2H), 2,82 (t, J=7 Hz, 2H), 2,58 (ushort, J=7 Hz, 2H), 2,44 (s, 3H), 2,39 of-2.32 (m, 2H), 1,62-and 1.54 (m, 2H), 1,44 to 1.37 (m, 2H), 0,86 (t, J=7 Hz, 3H).

3-[4-(3-phenylpropoxy)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (compound 33A, scheme 5)

60% dispersion of NaH in mineral oil (3 g, 1.1 EQ.) was added to a solution of anhydrous THF (100 ml)containing compound 20B (18,36 g, 68,74 mmol) in an atmosphere of N2. The resulting mixture was stirred for 2 hours at room temperature and then treated 13,37 ml (1.1 EQ.) (2-hermeticity)trimethylsilane (SEM-CI). The resulting mixture was stirred for 18 hours at room temperature. To the mixture was added ethyl acetate and the organic layer was washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. Received OS is atok was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain (variable) mixture of 29A and 29B in the form of oil (23,09 g, 83%).1H-NMR (400 MHz, CDCl3): NMR much like NMR mixture 27A/B (see scheme 4), presents the main isomer (mainly 29A): δ to 9.15 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), 8,17 (dt, J=8 Hz, 2 Hz, 1H), 7,74 (s, 1H), 7,39-7,34 (m, 1H), 5,46 (s, 2H), 3,71-3,62 (m, 4H, both isomers), 0,98-0,84 (m, 4H, both isomers), 0,02 (both isomers, Si(CH3)3).

To a solution of anhydrous THF (250 ml)containing a mixture of compounds 29A/B (10 g, 25 mmol)was added dropwise to 10.5 ml (1.1 EQ.) n-BuLi (2.5 M in hexane) (-78°C in an atmosphere of N2). After adding the resulting solution was stirred for 60 minutes at -78°C. At this temperature was added trimethylboron (3 EQ., 8,50 ml) (dropwise within 15 minutes) and the reaction mixture was stirred for 2 hours at -78°C. Then the reaction mixture was allowed to warm to ambient temperature (during the night).

The temperature of the reaction mixture has been compressed to -10°C and was added 2.2 ml (1.5 EQ.) of acetic acid. Subsequently was added dropwise 1.1 EQ. 30% solution of N2About2(2,93 ml) while maintaining the temperature at the level <-5°C. the Mixture was allowed to warm to ambient temperature and stirred for another 4 hours. To the reaction mixture were added 10 ml of N2Oh, and then ethyl acetate (500 ml). The organic layer is washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. Polucen the th residue was purified flash chromatography (simple diethyl ether with subsequent exposure to ethyl acetate) to obtain 3-pyridin-3-yl-1-(2-trimethylsilyl-1-ethoxymethyl)-1H-pyrazole-4-ol (30) in the form (variable) mixture protected SEM isomers of the product (amorphous substance, 2.9 g, 40%).1H-NMR (400 MHz, CDCl3the mixture of isomers ~1/1); δ which 9.22 and 8,90 (2×users, 1H), of 8.47-8,18 (m, 2H), 7,45-7,34 (m, 1H), was 7.36 and 7,31 (2×s, 1H), are 5.36 and 5.35 (2×s, 2H), 3,74 at 3.69 and 3,64-3,59 (2×m, 2H), 0,99-of 0.90 (m, 2H), 0.02 and 0.01 to (2×s, 9H).

To a solution of anhydrous DMF (50 ml)containing compound 30 (2,03 g, 6,98 mmol), was added 1.5 EQ. To2CO3(1.45 g) and the mixture was stirred for 1 hour in an atmosphere of N2. After adding 3-bromopropylate (1.1 EQ., 1,17 ml) the resulting solution was stirred for 18 hours at 45°C and allowed to reach ambient temperature. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (simple diethyl ether) to obtain compound 31A in the form of a mixture of isomers SEM (oil, 1.92 g, 67%).1H-NMR (400 MHz, CDCl3presented main isomer): δ 8,96 (d, J=2 Hz, 1H), 8,61 (DD, J=5 Hz, 2 Hz, 1H), with 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7,42-7,39 (m, 1H), 7,39 (s, 1H), 7,30-7,14 (m, 5H), lower than the 5.37 (s, 2H), 3,98 (t, J=7 Hz, 2H), 3,74 at 3.69 (m, 2H,), is 2.74 (t, J=7 Hz, 2H), 2,10-2,02 (m, 2H), and 0.98 to 0.92 (m, 2H), of 0.01 (s, 9H).

To a solution of anhydrous THF (50 ml)containing compound 31A (1,93 g, 4,71 mmol)was added 14,16 ml (3.0 equiv.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and the eat was concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain the desired compound 3-[4-(3-phenylpropoxy)-1H-pyrazole-3-yl]pyridine (32A) (oil, 1,32 g, 73%).1H-NMR (400 MHz, CDCl3): δ to 9.15 (d, J=2 Hz, 1H), 8,54 (DD, J=5 Hz, 2 Hz, 1H), 8,24 (dt, J=8 Hz, 2 Hz, 1H), 7,35-7,31 (m, 1H), 7,30-7,25 (m, 2H), 7,22-7,17 (m, 3H), of 3.96 (t, J=7 Hz, 2H), and 2.83 (t, J=7 Hz, 2H), 2,19-2,11 (m, 2H).

Compound 32A (0.3 g, 1,49 mmol) was converted into compound indicated in the title compound 3-[4-(3-phenylpropoxy)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (33A), using the methodology described for the conversion of compounds 21A to 22A (see scheme 3).

Yield: 70% (amorphous substance, 72%). LCMS (method A); Rt: 1,52 min, ([M+H]+= 298).1H-NMR (400 MHz, CDCl3): δ 7,31-7,25 (m, 2H), 7,22-7,17 (m, 3H), 7,16-7,11 (users, 1H), 6,62-6,44 (users, 1H), a 3.87 (t, J=7 Hz, 2H), 3,41-to 3.36 (m, 2H), and 2.79 (t, J=7 Hz, 2H), 2,58 (t, J=7 Hz, 2H), 2,44 (s, 3H), 2,42 to 2.35 (m, 2H), 2,11-2,04 (m, 2H).

3-(4-hexyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 33B, scheme 6)

Compound 29A/B was converted into 3-(4-iodine-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 34A/B), using the methodology described for the conversion of 21A to 22A (see scheme 3).

Yield: 47% (amorphous compound). LCMS (pic is b (A); Rt: 2,66 min, ([M+H]+= 420) and Rt: 2,74 min, ([M+H]+= 420).

A mixture of compound 34A/B (0.75 g, to 1.79 mmol), CuI (34 mg, 0,179 mmol), Cs2CO3(1.18 g, 3.58 mmol), 1,10-phenanthroline (0.07 g, 0,358 mmol) and 1-hexanol (5 ml, 40 mmol) was heated at 140°C for 18 hours (in air atmosphere).

The mixture was cooled to room temperature. Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/PE 1:1) to obtain compound 35A in the form of an oil (0.24 g, 34%). LCMS (method A); Rt: 2,50 min, ([M+H]+= 394). (TLC ethyl acetate/PE 1/1, Rf0,07).

To a solution of anhydrous THF (20 ml)containing a mixture of compound 35A (0.24 g, 0.6 mmol), was added of 1.52 ml (2.5 EQ.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/MeOH (1/1)) to obtain the heading compound 33B (oil, 0.12 g, 75%). LCMS (method A); Rt: 1,99 min, ([M+H]+= 264).

Compound 33B was subjected to interaction is 1 EQ. fumaric acid in EtOH and concentrated (amorphous substance).1H-NMR (600 MHz, D6DMSO): δ 7,50 (users, 1H), return of 6.58 (s, 2H), 6,50 (users, 1H), 3,88 (t, J=7 Hz, 2H), 3,75 (users, 2H), 3,02 (ushort, J=7 Hz, 2H), 2,69 (s, 3H), 2,48-to 2.42 (m, 2H), 1,75-to 1.67 (m, 2H), 1,45-to 1.38 (m, 2H), 1,36 of 1.28 (m, 4H), 0,89 (t, J=7 Hz, 3H).

3-(4-Butylochka-1H-pyrazole-3-yl)pyridine (compound 32C)

Connection 32C received in accordance with the procedure described for the synthesis of compound 32A (see scheme 5) using 1-bromobutane as alkylhalogenide and 3-pyridin-3-yl-1-(2-trimethylsilyl-1-ethoxymethyl)-1H-pyrazole-4-ol (30).

Processing and flash chromatography (ethyl acetate/simple diethyl ether 1/1) gave compound 31 s 30% Yield (oil).1H-NMR (presents the main isomer, 400 MHz, CDCl3): δ 8,9 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), with 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7,42 (s, 1H), 7,41-7,37 (m, 1H), lower than the 5.37 (s, 2H), 3,98 (t, J=7 Hz, 2H), 3,74-3,68 (m, 2H), 1,74-of 1.66 (m, 2H), 1,49-of 1.39 (m, 2H), to 0.92 (t, J=7 Hz, 3H), of 0.02 (s, 9H).

Filmed protection mixture SEM-isomers (TBAF/THF) to obtain 3-(4-Butylochka-1H-pyrazole-3-yl)pyridine (32C).

Yield: 70% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,53 (DD, J=5 Hz, 2 Hz, 1H), 8,23 (dt, J=8 Hz, 2 Hz, 1H), 7,35-7,31 (m, 1H), 7,30 (s, 1H), of 3.77 (t, J=7 Hz, 2H), 1,84-to 1.77 (m, 2H), 1.57 in to 1.47 (m, 2H), and 0.98 (t, J=7 Hz, 3H).

3-(4-Butylochka-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 33)

Connection 32C turned specified in the title compound (33), using the methodologists who, described for the conversion of compounds 21A to 22A (see scheme 3).

Yield: 77% (amorphous substance). LCMS (method A); Rt: 1,48 min, ([M+H]+= 236).1H-NMR (400 MHz, CDCl3): δ 7,19 (users, 1H), 6,52-6.42 per (users, 1H), 3,88 (t, J=7 Hz, 2H), 3,38-to 3.34 (m, 2H), 2.57 m (t, J=7 Hz, 2H), 2,44 (s, 3H), 2,41-of 2.36 (m, 2H), 1,79-1,71 (m, 2H), 1,53 was 1.43 (m, 2H), 0,97 (t, J=7 Hz, 3H).

3-(4-but-3-enyloxy-1H-pyrazole-3-yl)pyridine (compound 32D)

Connection 32D received in accordance with the procedure described for the synthesis of compound 32A (see scheme 5) using 4-brombach-1-ene as alkylhalogenide and 3-pyridin-3-yl-1-(2-trimethylsilyl-1-ethoxymethyl)-1H-pyrazole-4-ol (30).

Processing and flash chromatography (simple diethyl ether) gave compound 31D. Exit 41% (oil, TLC simple diethyl ether Rf0,37), which were later removed protection (TBAF/THF) to obtain 3-(4-but-3-enyloxy-1H-pyrazole-3-yl)pyridine (32D).

Yield: 75% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ to 9.15 (d, J=2 Hz, 1H), 8,58 (DD, J=5 Hz, 2 Hz, 1H), 8,24 (dt, J=8 Hz, 2 Hz, 1H), 7,35-7,30 (m, 1H), 7,32 (s, 1H), 5,96-to 5.85 (m, 1H), 5,22-5,11 (m, 2H), was 4.02 (t, J=7 Hz, 2H), 2,62 is 2.55 (m, 2H).

3-(4-but-3-enyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 33D)

Connection 32D turned specified in the header connection (33D), using the methodology described for the conversion of compounds 21A to 22A (see scheme 3).

Yield: 94% (amorphous substance). LCMS (method A); Rt: 1,33 min, ([M+] += 234).1H-NMR (400 MHz, CDCl3): δ 7,20 (users, 1H), 6,60-6.42 per (users, 1H), 5,94-of 5.83 (m, 1H), 5,19 is 5.07 (m, 2H), 3,94 (t, J=7 Hz, 2H), 3,38-to 3.33 (m, 2H), 2,59-of 2.50 (m, 4H), of 2.44 (s, 3H), 2,41-of 2.36 (m, 2H).

3-(4-heptyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection E)

A mixture of compound 34A/B (0.75 g, to 1.79 mmol) (see scheme 6), CuI (34 mg, 0,179 mmol), Cs2CO3(1.18 g, 3.58 mmol), 1,10-phenanthroline (0.07 g, 0,358 mmol) and 1-heptanol (5 ml) was heated at 140°C for 18 hours (in air atmosphere).

The mixture was cooled to room temperature. Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/PE 1/1) to obtain compound E (p similar 35A, scheme 6) in the form of oil (0,22 g, 30%). LCMS (method A); Rt: 2,60 min, ([M+H]+= 408).

To a solution of anhydrous THF (20 ml)containing a mixture of compounds E (0,22 g, 0.54 mmol)was added to 1.35 ml (2.5 EQ.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (utilized the t/MeOH (1/1)) to obtain specified in the connection header E (oil, 0.08 g, 53%). LCMS (method A); Rt: 2,23 min, ([M+H]+= 278).

Connection E were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (amorphous substance).1H-NMR (600 MHz, D6DMSO): δ 7,37 (users, 1H), return of 6.58 (s, 2H), to 6.43 (users, 1H), 3,84 (t, J=7 Hz, 2H), 3,51 (users, 2H), 2,77 (ushort, J=7 Hz, 2H), 2,52 (s, 3H), 2,39 is 2.33 (m, 2H), 1,72-of 1.66 (m, 2H), 1,45-1,22 (m, 8H), of 0.87 (t, J=7 Hz, 3H).

3-(4-Penta-4-enyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 33F)

A mixture of compound 34A/B (0.75 g, to 1.79 mmol) (see scheme 6), CuI (34 mg, 0,179 mmol), Cs2CO3(1.18 g, 3.58 mmol), 1,10-phenanthroline (0.07 g, 0,358 mmol) and Penta-4-EN-1-ol (5 ml) was heated at 140°C for 18 hours (in air atmosphere).

The mixture was cooled to room temperature. Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/PE 1:1) to obtain compound 35F (Penta-4-enjoy similar 35A, scheme 6) in the form of oil (0,41 g, 60%). LCMS (method A); Rt: 2,33 min, ([M+H]+= 378).

To a solution of anhydrous THF (20 ml)containing a mixture of compounds 35F (0,22 g, 0.54 mmol)was added to 1.35 ml (2.5 EQ.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the content of inorganic fillers layer was washed with a concentrated solution of NaHCO 3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/MeOH (1/1)) to obtain specified in the connection header 33F (oil, 0.08 g, 53%). LCMS (method A); Rt: 1,83 min, ([M+H]+= 248).

Connection 33F were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (amorphous substance).1H-NMR (600 MHz, D6DMSO): δ 7,38 (users, 1H), 6,56 (C 2H 5), 6,48-6,44 (m, 1H), 5,88-5,80 (m, 1H), 5,06-of 4.95 (m, 2H), 3,86 (t, J=7 Hz, 2H), 3,60 (users, 2H), 2,86 (ushort, J=7 Hz, 2H), 2,58 (s, 3H), 2,42-is 2.37 (m, 2H), 2,20-of 2.15 (m, 2H,)and 1.83-1.77 in (m, 2H).

3-(4-pentyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 33G, scheme 6)

A mixture of compound 29A/B (1.0 g, 2.49 mmol) (see scheme 5), CuI (0.05 g, 0,249 mmol), Cs2CO3(1,62 g, to 4.98 mmol), 1,10-phenanthroline (0.09 g, 0,498 mmol) and pentanol (7 ml) was heated at 140°C for 18 hours (in air atmosphere).

The mixture was cooled to room temperature. Added ethyl acetate and the organic layer washed with 5% solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/PE 1:2) to obtain compound 31G in the form of an oil (0.24 g, 27%). LCMS (method A); Rt: was 2.76 min, ([M+H]+= 362).1H-NMR (400 MHz, mixture of isomers, CDCl3): δ 9,25 and of 8.90 (d, J=2 Hz, 1H), 8,61 and charged 8.52 (DD, J=5 Hz, 2 Hz, 1H), 8,28 and of 8.06 (dt, J=8 Hz, 2 Hz, 1H), 7.3 and 7,29 (s, 1H), 7,41-7,37 and 7.35-7,31 (m, 1H), 5,39 and lower than the 5.37 (s, 2H), 4,0-to 3.92 (m, 2H), 3,71 and of 3.60 (ushort, J=7 Hz, 2H), 1,88-1,80 and 1.76-1.69 in (m, 2H), 1,52-1,25 (m, 6H), 0,97-of 0.90 (m, 3H).

To a solution of anhydrous THF (25 ml)containing compound 31G (0,23 g to 0.63 mmol)was added to 1.59 ml (2.5 EQ.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain 3-(4-pentyloxy-1H-pyrazole-3-yl)pyridine 32G (oil, 0.14 g, 95%). LCMS (method A); Rt: 2,27 min, ([M+H]+= 232).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,53 (DD, J=5 Hz, 2 Hz, 1H), 8,23 (dt, J=8 Hz, 2 Hz, 1H), was 7.36-7,29 (m, 2H), 3.96 points (ushort, J=7 Hz, 2H), 1,87-of 1.78 (m, 2H), 1,51 is 1.34 (m, 6H), were 0.94 (t, J=7 Hz, 3H).

The connection is made in accordance to the title compound (33 G) using the methodology described for the termination of the connections 21A to 22A (see scheme 3).

Yield: 85% (amorphous substance). LCMS (method A); Rt: 1,83 min, ([M+H]+= 250).1H-NMR (400 MHz, CDCl3): δ 7,19 (users, 1H), 6,54-6,50 (users, 1H), 3,88 (t, J=7 Hz, 2H), 3,40-to 3.36 (m, 2H), 2,59 (t, J=7 Hz, 2H), of 2.45 (s, 3H), 2,43-is 2.37 (m, 2H), 1,81 is 1.75 (m, 2H), 1,46 is 1.34 (m, 4H), of 0.93 (t, J=7 Hz, 3H).

Butyl-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-yl]amine (soy is inania 42, scheme 8)

To the concentrated solution (10 ml) H2SO4containing compound 19 (0,725 g, 5 mmol)was added dropwise a mixture of 5 ml of H2SO4and 5 ml of HNO3at -10°C in an atmosphere of N2. After adding the resulting solution was stirred for 3 hours at room temperature. The mixture was poured into ice and then adding 2 N NaOH. Added ethyl acetate and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain compound 38 in the form of oil (or 0.57 g, 60%).1H-NMR (200 MHz, CDCl3and D6DMSO 1/1): δ 8,9 (d, J=2 Hz, 1H), 8,7 (d, J=5 Hz, 2 Hz, 1H), with 8.05 (dt, J=8 Hz, 2 Hz, 1H), 7,60 (s, 1H), of 7.48-7,40 (m, 1H).

Compound 38 (of 0.37 g, 1.9 mmol) was dissolved in Meon (containing Pd(OH)2/C (0.03 g)). The hydrogenation was carried out within 3 hours (1 ATM) at room temperature. The reaction mixture was filtered, washed with ethyl acetate/Meon (1/1) and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate followed by the addition of ethyl acetate/Meon 1/1) Dublin obtain compound 39 in the form of oil (0,29 g, 95%).1H-NMR (200 MHz, CDCl3and D6DMSO 1/1): δ 9,05 (d, J=2 Hz, 1H), 8,51 (d, J=5 Hz, 2 Hz, 1H), 8,09 (dt, J=8 Hz, 2 Hz, 1H), 7,43 (s, 1H), 7,37-7,32 (m, 1H).

To a solution of anhydrous CH3CN (15 ml)containing a mixture of compound 39 (0.21 g, 1 mmol) and 0.27 ml (1.5 EQ.) of triethylamine, was added to 0.14 ml butyrylcholine in the atmosphere N2. After adding the resulting solution was stirred for 3 hours at room temperature and subsequently concentrated in a vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain N-(3-pyridin-3-yl-1H-pyrazole)butyramide 40 (oil, 0,19 g, 77%). (TLC ethyl acetate Rf0,16).

Compound 40 was converted into compound 41 using the methodology described for the conversion of compounds 21A to 22A (see scheme 3).

Yield: 65% (amorphous substance). LCMS (method A); Rt: 0,73 min, ([M+H]+= 249).1H-NMR (600 MHz, CDCl3): δ 8,4 (users, 1H), 7.5 (users, 1H), 6,0-5,96 (m, 1H), 3.27 to (users, 2H), 2.63 in (t, J=7 Hz, 2H), 2,43 (s, 3H), 2,43-is 2.37 (m, 2H), 2,32 (t, J=7 Hz, 2H), 1,76 is 1.70 (m, 2H), and 0.98 (t, J=7 Hz, 3H).

To a solution of anhydrous THF (25 ml)containing compound 41 (0.27 g, of 1.09 mmol), was added 0.04 g (1.0 EQ.) LiAlH4in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and allowed to warm to ambient temperature. To the reaction mixture was added 0.04 ml of N2About followed by the addition of 0.08 ml of 2N NaOH and 0.04 ml of N2O. the mixture was warmed for 10 minutes (60°C), the cooling gap is Ali to room temperature and filtered. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate/MeOH 1/1) to obtain specified in the connection header 42 (oil, 0.21 g, 95%). LCMS (method A); Rt: 1,05 min, ([M+H]+= 235).1H-NMR (600 MHz, CDCl3): δ 7,1 (users, 1H), 6,17-6,14 (m, 1H), 3,4-3,37 (m, 2H), 2,99 (t, J=7 Hz, 2H), 2,64 (t, J=7 Hz, 2H), 2,48 (s, 3H), 2,47-to 2.42 (m, 2H), 1,66-to 1.60 (m, 2H), 1,47-of 1.40 (m, 2H), 0,97 (t, J=7 Hz, 3H).

3-(4-Gex-1-inyl-1H-pyrazole-3-yl)pyridine (compound 44A, scheme 9)

Compound 20B (10,49 g, and 38.6 mmol) was converted into 3-(1-phenylsulfonyl-4-iodine-1H-pyrazole-3-yl)pyridine (36V) using the methodology described for the conversion of compounds 20A 36A (see diagram 7). Output: 11,65 g (amorphous substance, 74%). (TLC simple diethyl ether Rf0,4).1H-NMR (400 MHz, CDCl3): δ 9,05 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), of 8.27 (s, 1H), 8,12 (dt, J=8 Hz, 2 Hz, 1H), 8,10-of 8.06 (m, 2H), 7,73-to 7.67 (m, 1H), 7,58 (ushort, J=7 Hz, 2H), 7,39-7,34 (m, 1H).

It triethylamine (10 ml) and DMF (4 ml)containing the compound 36V (0.97 g, 2.36 mmol), was added 3 EQ. Gex-1-in (0,81 ml). The resulting mixture was stirred for another 2 hours in an atmosphere of N2. Sequentially added 10% mol CuI (45 mg), 5% mol PdCl2(PPH3)2(83 mg) and 18% mol PPH3(111 mg). After adding the resulting solution was warmed at 70°C in accordance with is their 18 hours in an atmosphere of N 2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE (1/1)) to obtain 3-(1-phenylsulfonyl-4-Gex-1-inyl-1H-pyrazole-3-yl)pyridine (43A) in the form of oil (0.66 g, 77%).1H-NMR (400 MHz, CDCl3): δ 9.5 to 9,2 (users, 1H), 8,8-8,4 (users, 1H), 8.34 per (userd, J=8 Hz, 1H), 8,21 (s, 1H), 8,08-of 8.04 (m, 2H), to 7.67 (ushort, J=7 Hz, 1H), EUR 7.57 (ushort, J=7 Hz, 2H), 7,41-7,32 (users, 1H), 2,42 (t, J=7 Hz, 2H), 1,62-of 1.53 (m, 2H), 1,49-of 1.39 (m, 2H), of 0.93 (t, J=7 Hz, 3H).

Compound 43A (0.66 g, is 1.81 mmol), 1.3 g of KOH and 2 ml of NH2NH2·H2O United in diethylene glycol (20 ml) and warmed by boiling under reflux for 1 hour in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in the Meon. Filtration through 25 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (ethyl acetate) gave specified in the header connection 44A. The yield of 0.37 g (90%).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), at 8.60 (DD, J=5 Hz, 2 Hz, 1H), 8.34 per (dt, J=8 Hz, 2 Hz, 1H), 7,73 (s, 1H), 7,39-7,34 (m, 1H), 2,43 (t, J=7 Hz, 2H), 1,64-of 1.56 (m, 2H), 1,52-of 1.42 (m, 2H), were 0.94 (t, J=7 Hz, 3H).

3-(4-Gex-1-inyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 45A, scheme 9)

Compound 44A was made in connection 45A to use the cation methodology, described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 90% (amorphous substance). LCMS (method A); Rt: 1,79 min, ([M+H]+= 244).1H-NMR (400 MHz, CDCl3): δ EUR 7.57 (s, 1H), 6,78-6,66 (users, 1H), 3,42-to 3.38 (m, 2H), 2,59 (ushort, J=7 Hz, 2H), of 2.45 (s, 3H), 2,44-is 2.37 (m, 2H), 1,62 was 1.43 (m, 4H), were 0.94 (t, J=7 Hz, 3H).

3-(4-hept-1-inyl-1H-pyrazole-3-yl)pyridine (compound V)

Connection W received in accordance with the procedure described for the synthesis of compound 44A (see scheme 9)using hept-1-in and 3-(1-phenylsulfonyl-4-bromo-1H-pyrazole-3-yl)pyridine (36A). (flash chromatography with a simple diethyl ether) to obtain 3-(1-phenylsulfonyl-4-hept-1-inyl-1H-pyrazole-3-yl)pyridine (V) in the form of an oil (90%).1H-NMR (400 MHz, CDCl3): δ 9,25 (users, 1H), 8,6 (users, 1H), 8.34 per (userd, J=8 Hz, 1H), 8,21 (s, 1H), 8,06 (userd, J=8 Hz, 2H), to 7.67 (ushort, J=7 Hz, 1H), EUR 7.57 (ushort, J=7 Hz, 2H), was 7.36-7,30 (m, 1H), 2,42 (t, J=7 Hz, 2H), 1,63-of 1.55 (m, 2H,), 1,44 of 1.28 (m, 4H), to 0.89 (t, J=7 Hz, 3H). Connection W made in connection W using the methodology described for the conversion of compound 43A 44A in (see diagram 9). Yield: 98% (oil).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,59 (DD, J=5 Hz, 2 Hz, 1H), of 8.37 (dt, J=8 Hz, 2 Hz, 1H), 7,72 (s, 1H), 7,38-7,33 (m, 1H), 2,42 (t, J=7 Hz, 2H), 1,65-of 1.57 (m, 2H), 1,46-of 1.30 (m, 4H), of 0.90 (t, J=7 Hz, 3H).

3-(4-hept-1-inyl-1H-pyrazole-3-yl)-1,2,5 .6-tetrahydro-1-methylpyridine (connection B)

Connection W made in connection W using the methodology described for pravr the communication connection 21A to 22A (see scheme 3). Yield: 44% (amorphous substance). LCMS (method A); Rt: 1,84 min, ([M+H]+= 258).1H-NMR (400 MHz, CDCl3): δ EUR 7.57 (s, 1H), 6,78-6,66 (users, 1H), 3,42-to 3.38 (m, 2H), 2,59 (ushort, J=7 Hz, 2H), of 2.45 (s, 3H), 2,44-is 2.37 (m, 2H), 1,62 was 1.43 (m, 4H), were 0.94 (t, J=7 Hz, 3H).

3-(4-non-1-inyl-1H-pyrazole-3-yl)pyridine (compound C)

Connection IS received in accordance with the procedure described for the synthesis of compound 44A (see figure 9), using non-1-in and 3-(1-phenylsulfonyl-4-iodine-1H-pyrazole-3-yl)pyridine (36V). (flash chromatography with a simple diethyl ether/PE 1/1) to obtain 3-(1-phenylsulfonyl-4-non-1-inyl-1H-pyrazole-3-yl)pyridine (and 43C) in the form of oil (80%). (TLC simple diethyl ether Rf0,44).

Connection and 43C made in connection S using the methodology described for the conversion of compound 43A 44A in (see diagram 9). Yield: 78% (oil).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,61 (DD, J=5 Hz, 2 Hz, 1H), 8,35 (dt, J=8 Hz, 2 Hz, 1H), 7,73 (s, 1H), 7,39-7,34 (m, 1H), 2,42 (t, J=7 Hz, 2H), 1,65-of 1.56 (m, 2H), 1,47-to 1.38 (m, 2H), 1,37-1,22 (m, 6H), of 0.90 (t, J=7 Hz, 3H).

3-(4-non-1-inyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 45C)

Connection IS made in connection 45C, using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 79% (amorphous substance). LCMS (method A); Rt: 2,17 min, ([M+H]+= 286).1H-NMR (400 MHz, CDCl3): δ EUR 7.57 (s, 1H), 6,74-6,69 (users, 1H), 3,40-to 3.36 (m, 2H), 2,58 (ushort, J=7 Hz, 2H), 2,44 (s, H), 2,43-of 2.36 (m, 2H), 1,63-of 1.55 (m, 2H), 1,48-of 1.39 (m, 2H), 1,36 is 1.23 (m, 6H), to 0.89 (t, J=7 Hz, 3H).

3-[4-(5-finalment-1-inyl)-1H-pyrazole-3-yl]pyridine (compound 44D)

Connection IS received in accordance with the procedure described for the synthesis of compound 44A (see figure 9), using the Penta-4-universal and 3-(1-phenylsulfonyl-4-iodine-1H-pyrazole-3-yl)pyridine (36V). (flash chromatography with a simple diethyl ether/PE (1/1)) to obtain 3-[1-phenylsulfonyl-4-(5-finalment-1-inyl)-1H-pyrazole-3-yl]pyridine (43D) in the form of oil (80%).1H-NMR (400 MHz, CDCl3): δ 9,3 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,33 (dt, J=8 Hz, 2 Hz, 1H), they were 8.22 (s, 1H), 8,09-with 8.05 (m, 2H), 7,68 (ushort, J=8 Hz, 1H), EUR 7.57 (ushort, J=8 Hz, 2H), 7,35-7,25 (m, 3H), 7,21-to 7.15 (m, 3H), 2,74 (t, J=7 Hz, 2H), 2,42 (t, J=7 Hz, 2H), 1,96-to 1.87 (m, 2H). (TLC simple diethyl ether Rf0,56).

Connection 43D made in connection 44D, using the methodology described for the conversion of compound 43A 44A in (see diagram 9). Yield: 86% (oil).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,35 (dt, J=8 Hz, 2 Hz, 1H), 7,74 (s, 1H), 7,40-7,17 (m, 6H), 2,77 (t, J=7 Hz, 2H), 2,44 (t, J=7 Hz, 2H), 1,99-1,89 (m, 2H).

3-[4-(5-finalment-1-inyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (compound 45D)

Connection 44D made in connection 45D, using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 95% (amorphous substance). LCMS (method A); Rt: 1,99 min, ([M+H]+= 306).1H-NMR (400 MHz, CDCl3): δ 7,58 (who, 1H), 7,31-to 7.18 (m, 5H), 6,79-6.73 x (users, 1H), 3.43 points is 3.40 (m, 2H), 2,78 (t, J=7 Hz, 2H), 2,60 (ushort, J=7 Hz, 2H), 2,45-is 2.37 (m, 7H), 1,95-to 1.87 (m, 2H).

3-[4-(5-cyclohexylidene-1-inyl)-1H-pyrazole-3-yl]pyridine (compound 44TH)

Connection 44TH received in accordance with the procedure described for the synthesis of compound 44A (see figure 9), using the Penta-4-vinylcyclohexane and 3-(1-phenylsulfonyl-4-iodine-1H-pyrazole-3-yl)pyridine (36V). (flash chromatography with a simple diethyl ether/PE 1/1) to obtain 3-[1-phenylsulfonyl-4-(5-cyclohexylidene-1-inyl)-1H-pyrazole-3-yl]pyridine (43TH) in the form of an oil (90%).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,33 (dt, J=8 Hz, 2 Hz, 1H), 8,21 (s, 1H), 8,08-of 8.04 (m, 2H), 7,68 (ushort, J=8 Hz, 1H), EUR 7.57 (ushort, J=8 Hz, 2H), 7,35-7,31 (m, 1H), of 2.38 (t, J=7 Hz, 2H), 1,72-of 1.55 (m, 6H), 1,31-1,10 (m, 7H), of 0.95 to 0.8 (m, 2H).

Connection 43TH made in connection 44TH using the methodology described for the conversion of compound 43A 44A in (see diagram 9). Yield: 94% (oil).1H-NMR (400 MHz, CDCl3): δ a 9.25 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,35 (dt, J=8 Hz, 2 Hz, 1H), 7,72 (s, 1H), 7,39-7,34 (m, 1H), 2.40 a (t, J=7 Hz, 2H), 1,73-of 1.57 (m, 6H), 1,35-1,10 (m, 7H), of 0.93 and 0.75 (m, 2H).

3-[4-(5-cyclohexylidene-1-inyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine (connection E)

Connection 44TH made in connection E using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 90% (amorphous substance). LCMS (method A); Rf: 2,28 min, ([M+H]+= 312),1 H-NMR (400 MHz, CDCl3): δ EUR 7.57 (s, 1H), 6,76-of 6.71 (users, 1H), 3,41-3,37 (m, 2H), 2,59 (ushort, J=7 Hz, 2H), 2,45 to 2.35 (m, 7H), 1,75-of 1.55 (m, 6H), 1,35-1,10 (m, 7H), 0,94-0,8 (m, 2H).

3-(4-Gex-1-enyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 47A, scheme 9)

To toluene (20 ml)containing 36A (0,67 g of 1.84 mmol) (see scheme 7), was added 1.5 EQ. (E)-HEXEN-1-elborno acid (0.35 g). The resulting mixture was stirred for 2 hours in an atmosphere of N2. Sequentially added 2 EQ. To3RHO4(0,78 g), 4% mol Pd(OAc)2(16.5 mg) and 8% mol S-Phos (60,4 mg). After adding the resulting solution was warmed at 90°C for 18 hours in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(1-phenylsulfonyl-4-Gex-1-enyl-1H-pyrazole-3-yl)pyridine (46A) in the form of oil (0,38 g, 61%).1H-NMR (400 MHz, CDCl3): δ 8,8 (d, J=2 Hz, 1H), 8,6 (DD, J=5 Hz, 2 Hz, 1H), 8,15 (s, 1H), 8,10-with 8.05 (m, 2H), 7,94 (dt, J=8 Hz, 2 Hz, 1H), 7,70-to 7.64 (m, 1H), 7,56 (ushort, J=8 Hz, 2H), 7,37-7,33 (m, 1H), to 6.19-of 6.02 (m, 1H), the 2.2 and 2.13 (m, 2H), 1,45-of 1.29 (m, 4H), of 0.90 (t, J=7 Hz, 3H).

Compound 46A (0.34 g, 0.97 mmol), 0.7 g of KOH and 1 ml of NH2NH2·H2O United in diethylene glycol (10 ml) and warmed by boiling under reflux for 1 cha is in the atmosphere N 2. The mixture was cooled, concentrated and re-dissolved in the Meon. Filtration through 25 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (ethyl acetate) gave 3-(4-Gex-1-enyl-1H-pyrazole-3-yl)pyridine (devoid of protection similar 46A). Yield 0.18 g (86%). (TLC simple diethyl ether Rf0,18).

3-(4-Gex-1-enyl-1H-pyrazole-3-yl)pyridine was converted to the specified in the title compound 47A, using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 50% (amorphous substance). LCMS (method A); Rt: 2,30 min, ([M+H]+= 246).1H-NMR (400 MHz, CDCl3): δ to 7.59 (s, 1H), 6.22 per (userd, J=16 Hz, 1H), 6,03 is 5.98 (users, 1H), 5,98-5,88 (m, 1H), 3,26-is 3.21 (m, 2H), 2.63 in (ushort, J=7 Hz, 2H), 2,44 (s, 3H), 2,43-of 2.36 (m, 2H), 2,19-2,11 (m, 2H), 1,46-of 1.29 (m, 4H), of 0.91 (t, J=7 Hz, 3H).

3-{4-[2-(3-forfinal)vinyl]-1H-pyrazole-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine (compound 47B)

To toluene (20 ml)containing 36A (0,48 g of 1.32 mmol) (see scheme 7), was added 1.5 EQ. (E)-2-(3-forfinal)vinylboronic acid (0.33 g). The resulting mixture was stirred for 2 hours in an atmosphere of N2. Sequentially added 2 EQ. To3RHO4(0.56 g), 4% mol Pd(OAc)2(8,8 mg) and 8% mol S-Phos (32 mg). After adding the resulting solution was warmed at 90°C for 18 hours in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed three times on Ishenim solution of NaHCO 3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(1-phenylsulfonyl-4-[2-(3-forfinal)vinyl]-1H-pyrazole-3-yl)pyridine (V) in the form of an oil (0.39 g, 73%).1H-NMR (400 MHz, CDCl3): δ cent to 8.85 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), at 8.36 (s, 1H), 8,13-8,08 (m, 2H), 7,95 (dt, J=8 Hz, 2 Hz, 1H), 7,72-to 7.67 (m, 1H), 7,58 (ushort, J=8 Hz, 2H), 7,41-7,37 (m, 1H), 7,33-7,27 (m, 1H), 7,16 (userd, J=7 Hz, 1H), 7,12-7,07 (m, 1H), 7,0-6,94 (m, 1H), 6,92 (d, J=16 Hz, 1H), PC 6.82 (d, J=16 Hz, 1H).

Connection V (1.06 g, 2,62 mmol), 1.3 g of KOH and 2 ml of NH2NH2·H2O United in diethylene glycol (25 ml) and warmed by boiling under reflux for 1 hour in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in the Meon. Filtration through 25 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (ethyl acetate) gave 3-{4-[2-(3-forfinal)vinyl]-1H-pyrazole-3-yl}pyridine (devoid of protection similar 46B). The yield of 0.42 g (60,4%).1H-NMR (400 MHz, CDCl3): δ cent to 8.85 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), 7.95 is-of 7.90 (m, 2H), 7,45-7,41 (m, 1H), 7,32-7,27 (m, 1H), 7,20-7,16 (m, 1H), 7,14-to 7.09 (m, 1H), 6,99 (d, J=16 Hz, 1H), of 6.96-6,86 (m, 2H).

3-{4-[2-(3-forfinal)vinyl]-1H-pyrazole-3-yl}pyridine was converted to the specified in the title compound 47B, using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 67% (amorphous substance). LCMS (SPO is about A); Rt: 1,79 min, ([M+H]+= 284).1H-NMR (400 MHz, CDCl3): δ for 7.78 (s, 1H), 7,31-7,25 (m, 1H), 7,20-7,10 (m, 2H), 7,0-to 6.88 (m, 2H), for 6.81 (d, J=16 Hz, 1H), 6,07-6,01 (m, 1H), 3.33 and is 3.25 (m, 2H), 2,69 (ushort, J=7 Hz, 2H), 2,50-to 2.42 (m, 5H).

3-(4-Oct-1-enyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 47S)

To toluene (20 ml)containing 36A (of 0.91 g, 2.5 mmol) (see scheme 7), was added 1.5 EQ. (E)-octene-1-elborno acid (0,59 g). The resulting mixture was stirred for 2 hours in an atmosphere of N2. Sequentially added 2 EQ. To3RHO4(1.06 g), 4% mol Pd(OAc)2(of 22.4 mg) and 8% mol S-Phos (82 mg). After adding the resulting solution was warmed at 90°C for 18 hours in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(1-phenylsulfonyl-4-Oct-1-enyl-1H-pyrazole-3-yl)pyridine (S) in the form of an oil (0.31 g, 32%).1H-NMR (400 MHz, CDCl3): δ cent to 8.85 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), 8,15 (s, 1H), 8,08-with 8.05 (m, 2H), to 7.93 (dt, J=8 Hz, 2 Hz, 1H), 7,69-to 7.64 (m, 1H), to 7.59-7,52 (m, 2H), 7,37-7,33 (m, 1H), to 6.19 (d, J=16 Hz, 1H), 6,10-6,03 (m, 1H), 2,19-2,12 (m, 2H), 1,45 to 1.37 (m, 2H), 1,36 is 1.23 (m, 6H), of 0.90 (t, J=7 Hz, 3H).

Connection S (0.35 g, 0.89 mmol), 0.7 g of KOH and 1 ml of NH2NH2·H2O United in diethylene glycol (10 ml) Corp. and the Wali boiling under reflux for 1 hour in an atmosphere of N 2. The mixture was cooled, concentrated and re-dissolved in the Meon. Filtration through 25 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (ethyl acetate) gave 3-(4-Oct-1-enyl-1H-pyrazole-3-yl)pyridine (devoid of protection similar S). Output 0,19 g (95%).1H-NMR (400 MHz, CDCl3): δ cent to 8.85 (d, J=2 Hz, 1H), 8,65 (DD, J=5 Hz, 2 Hz, 1H), to $ 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7,71 (s, 1H), 7,41 and 7.36 (m, 1H), 6,27 (d, J=16 Hz, 1H), 6,07 is 5.98 (m, 1H), 2,19-2,12 (m, 2H), 1,46-to 1.38 (m, 2H), 1,37 is 1.23 (m, 6H), to 0.89 (t, J=7 Hz, 3H).

3-(4-Oct-1-enyl-1H-pyrazole-3-yl)pyridine was converted to the specified header connection 47S, using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 95% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ 7,58 (s, 1H), 6,24 (userd, J=16 Hz, 1H), 6,07-of 6.02 (m, 1H), 5,98-of 5.89 (m, 1H), 3,29-of 3.25 (m, 2H), 2.63 in (ushort, J=7 Hz, 2H), 2,46 (s, 3H), 2,44-of 2.38 (m, 2H), 2,18-2,12 (m, 2H), 1,46-to 1.38 (m, 2H), 1,38-1,24 (m, 6H), of 0.91 (t, J=7 Hz, 3H).

3-(4-butylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 49A, scheme 10)

To a solution of anhydrous THF (150 ml)containing compound 48 (0.5 g, of 1.65 mmol, obtained in accordance with Bioorganic & Medicinal Chemistry, 8,2000, 449-454 was added dropwise 2.1 EQ. n-BuLi (1.39 ml, 2.5 M in hexane) at -78°C in an atmosphere of N2. After adding the resulting solution was stirred for 1.5 hours at -78°C. At this temperature, was added 1.1 EQ. ethyldimethylamine (0.35 ml) and the resulting solution AC is stirred for 1 hour at -78°C and subsequently allowed to warm to ambient temperature overnight. The mixture is then extinguished with saturated solution of NH4Cl at 0°C and concentrated in vacuum. Added ethyl acetate and the organic layer was washed with 2 N NaOH, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (MeOH) gave specified in the title compound 49A (amorphous compound, 0.15 g, 35%). Connection 49A was subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (solid), mp 162-164°C. LCMS (method A); Rt: 1,62 min, ([M+H]+= 266).1H-NMR (400 MHz, D6DMSO): 7,83 (s, 1H), gold 6.43 (s, 2H), 3,60-3,39 (m, 3H), 3.25 to about 3.00 (m, 4H), 2,58 (ushort, J=7 Hz, 2H), 2,10-2,05 (m, 1H), 1,98 of-1.83 (m, 2H), 1,78 by 1.68 (m, 1H), 1,48-of 1.30 (m, 4H), from 0.84 (t, J=7 Hz, 3H).

3-(4-intercultural-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 49B, scheme 10)

Compound 48 (2.50 g; 8.25 mmol), K2CO3(1,82 g; 13,2 mmol) and pentane-1-thiol (1,53 ml, 12.4 mmol) was dissolved in 30 ml of DMF and the solution was degirolami for 45 minutes with argon. To this solution was added Pd2(dba)3(755 mg; 0.83 mmol) and Xanthos (953 mg of 1.65 mmol). After the addition the reaction mixture was heated to 120°C and was stirred for 20 hours in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in MeOH. Filtration through 25 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (EtOH) gave specified in the title compound 49B in the form of a Mac is. Yield 395 mg (17%). Compound 49B was subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (solid), mp 142-145°C.1H-NMR (600 MHz, D6DMSO): δ 7,83 (s, 1H), 6.48 in (s, 2H), to 3.58-3,51 (m, 1H), 3,48-to 3.41 (m, 2H), 3.25 to 3.15 in (m, 3H), 3,11-3,03 (m, 1H), 2,61 of $ 2.53 (m, 2H), 2,11-to 2.06 (m, 1H), 1,97-of 1.85 (m, 2H), 1.77 in was 1.69 (m, 1H), 1,59-of 1.52 (m, 1H), 1,48-of 1.41 (m, 2H), 1,34-1,22 (m, 4H), or 0.83 (t, J=7 Hz, 3H).

3-(4-methylsulfanyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound C)

Compound 48 (2.50 g; 8.25 mmol) (see scheme 10) was dissolved in 30 ml of DMF and the solution was degirolami for 45 minutes with argon. To this solution was added NaSMe (867 mg, 12.4 mmol), Pd2(dba)3(755 mg; 0.83 mmol) and Xanthos (953 mg of 1.65 mmol). After the addition the reaction mixture was heated to 120°C and was stirred for 20 hours in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in MeOH. Filtration through 25 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (EtOH) gave compound C (oil). Crystallization from simple diethyl ether gave specified in the header connection (solid), TPL 145-147°C. Yield: 290 mg (16%).1H-NMR (600 MHz, D6DMSO): δ of 7.70 (s, 1H), 3,21-of 3.12 (m, 1H), 3,10-a 3.01 (m, 2H), 2,92-to 2.85 (m, 1H), 2,81-by 2.73 (m, 2H), 2,68-2,61 (m, 1H), of 2.21 (s, 3H), 1,81-of 1.78 (m, 1H), 1,68-of 1.55 (m, 3H), 1,25-of 1.18 (m, 1H).

3-(4-ethylsulfanyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 49D)

Compound 49D got in accordance is with the procedure described for the synthesis of compound 49B (see diagram 10) using ethanthiol as a reagent. Subsequent purification with flash chromatography (EtOH to EtOH/triethylamine 99/1) gave compound 49D.

Yield: 30% (oil).1H-NMR (600 MHz, D6DMSO): δ of 7.69 (s, 1H), 3,16-2,99 (m, 3H), 2,92-2,84 (m, 1H), 2,80-a 2.71 (m, 2H), 2,67-2,60 (m, 1H), 2,56 is 2.51 (m, 2H), 1,78 is 1.75 (m, 1H), 1,66-and 1.54 (m, 3H), 1,25-of 1.18 (m, 1H), only 1.08 (t, J=7 Hz, 3H).

3-(4-propylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 49E)

Connection 49E received in accordance with the procedure described for the synthesis of compound 49B (see diagram 10) using propane-1-thiol as a reagent. Subsequent purification with flash chromatography (EtOH to EtOH/triethylamine 99/1) gave compound 49E.

Output: 25% (amorphous substance).1H-NMR (600 MHz, D6DMSO): δ 7,72-to 7.64 (users, 1H), 3,16-2,99 (m, 3H), 2,93-2,84 (m, 1H), 2,80-a 2.71 (m, 2H), 2,67-2,60 (m, 1H), 2,54-2,48 (m, 2H + MSO), of 1.78 and 1.75 (m, 1H), 1,66-and 1.54 (m, 3H), 1,47-of 1.40 (m, 2H), 1,25-of 1.18 (m, 1H), 0,90 (t, J=7 Hz, 3H).

3-(4-hexylsilane-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 49F)

Connection 49F received in accordance with the procedure described for the synthesis of compound 49B (see diagram 10) using hexane-1-thiol as a reagent. Subsequent purification with flash chromatography (EtOH) gave compound 49F.

Output: 25% (oil). Connection 49F were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (solid), mp 130°is. 1H-NMR (600 MHz, D6DMSO): δ 7,81 (s, 1H), 6,46 (s, 2H), 3,55-to 3.49 (m, 1H), 3,45-3,39 (m, 2H), 3,22-3,13 (m, 3H), is 3.08-to 3.02 (m, 1H), 2,60-2,52 (m, 2H), 2,09-2,05 (m, 1H), 1,95 of-1.83 (m, 2H), 1,75 by 1.68 (m, 1H), 1,57-is 1.51 (m, 1H), 1,46-of 1.40 (m,2H), 1,35-of 1.29 (m, 2H), 1,27-1,17 (m, 4H), or 0.83 (t, J=7 Hz, 3H).

3-(4-penicillanic-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 49G)

Connection 49G received in accordance with the procedure described for the synthesis of compound 49B (see diagram 10) using 3-phenyl-1-propanethiol as a reagent. Subsequent purification with flash chromatography (EtOH) gave compound 49G.

Yield: 11% (oil). Connection 49G were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (amorphous substance).1H-NMR (600 MHz, D6DMSO): δ 7,86 (s, 1H), 7,26 (t, J=8 Hz, 2H), 7,19-7,14 (m, 3H), of 6.49 (s, 2H), 3,56-to 3.50 (m, 1H), 3.46 in-3,39 (m, 2H), 3,24-3,14 (m, 3H), 3,10-3,03 (m, 1H), 2,66 (t, J=7 Hz, 2H), 2,60 of $ 2.53 (m, 2H), 2,03-2,00 (users, 1H), 1,94-to 1.82 (m, 2H), 1.77 in by 1.68 (m, 3H), 1.56 to 1,50 (m, 1H).

3-[4-(3-methylbutanoyl)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane (compound 49H)

Connection 49H received in accordance with the procedure described for the synthesis of compound 49B (see diagram 10) using 3-methyl-1-butanethiol as a reagent. Subsequent purification with flash chromatography (EtOH) gave compound 49H.

Output: 20% (oil). Connection 49H were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (solid) mp 157-159°C.1H-NMR (600 MHz, D6DMSO): δ 7,83 (who, 1H), 6,47 (s, 2H), 3,56-to 3.50 (m, 1H), 3.46 in is 3.40 (m, 2H), 3,24 is 3.15 (m, 3H), 3,09-3,03 (m, 1H), 2,58 (t, J=7 Hz, 2H), 2,09 e 2.06 (users, 1H), 1,96-of 1.84 (m, 2H), 1,76 by 1.68 (m, 1H), 1,67-to 1.59 (m, 1H), 1,58-of 1.52 (m, 1H), 1,38-of 1.30 (m, 2H), or 0.83 (d, J=7 Hz, 6H).

3-[4-(4,4-deverbal-3-animalfunny)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane (compound 49I)

Connection 49I received in accordance with the procedure described for the synthesis of compound 21A (see scheme 3)using 3-phenylpropionitrile-3-propylbenzoyl as disulfide obtained in accordance with the methodology described in Tetrahedron Letters, 42,2001, 6741-6743) and 3-(4-iodine-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 48, see diagram 10). The cleaning conditions were as follows: preparative HPLC (system CHSLCPO2), column: Inertsil ODS-3, 8 μm. Eluent 10%/90% CH3CN/H2O + HCOOH, 50 ml/min, LCMS (method A): Rt: 1,16 min, ([M+H]+= 300). Output: 4,5% (oil).1H-NMR (600 MHz, CDCl3): δ 7,63 (s, 1H), 4,24 and 4.17 (DDT, J=7 Hz, 26 Hz, 3 Hz, 1H), 3,91-a-3.84 (m, 1H), 3,51-3,37 (m, 3H), 3,32-3,19 (m, 2H), 3,12-3,03 (m, 1H), 2.57 m (t, J=7 Hz, 2H), 2,23-of 2.15 (m, 3H), 2,12 is 2.01 (m, 1H), 2,01-1,89 (m, 2H), 1,61-is 1.51 (m, 1H).

3-(4-butoxy-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 52A, scheme 10)

60% dispersion of NaH in mineral oil (1.5 g, 38 mmol) was added to a solution of anhydrous THF (300 ml)containing 3-(4-iodine-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound 48, 9.6 g, and 31.7 mmol) in an atmosphere of N2. The resulting mixture was stirred for 2 hours at room temperature to a solution of the Oia solids. The reaction mixture was sequentially treated 38.4 mmol (6,74 ml) 2-chloretocsitiodiasole (SEM-CI). The resulting mixture was stirred for 20 hours at room temperature. Due to the partial quaternization of the desired product (50) was added TBAF (1 M solution in THF, 45 ml, 45 mmol) and the mixture was stirred for 20 hours at room temperature. To the mixture was added ethyl acetate and the organic layer was washed with 2 N NaOH solution followed by washing with brine, dried (Na2SO4), filtered and concentrated to obtain 3-[4-iodine-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane (50). Yield: 11.6 g, to 26.7 mmol, 84%. LCMS (method C); Rt: 3,11 min, ([M+H]+= 434).

A mixture of compound 50 (2.5 g, 5,77 mmol), CuI (1,37 g, 7.19 mmol), Cs2CO3(3,90 g, 12 mmol), 1,10-phenanthroline (2,60 g, 14.4 mmol) and butanol (25 ml) was heated at 150°C for 4 hours in a microwave oven.

The mixture was cooled to room temperature. Added ethyl acetate and the organic layer was washed with 2 N NaOH solution, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (gradient of EtOH to EtOH/triethylamine 300/1), and then the second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) to obtain compound 51A in the form of oil (0.33 g, 15%). LCMS (method C); Rt: 3,27 min, ([M+H]+= 380).

Crestore anhydrous THF (5 ml), containing compound 51A (0.33 g, 0.86 mmol), was added 3.5 ml of TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was stirred for 20 hours at room temperature and subsequently concentrated in a vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (gradient of EtOH to EtOH/triethylamine 97/3), followed by purification preparative HPLC: Prewash (system CHSLCPO2), column: Inertsil ODS-3, 8 μm. Eluent 10%/90% CH3CN/H2O + HCOOH, 50 ml/min, to obtain the specified connection 52A (oil, 0.1 g, 45%). LCMS (method A): Rt: 1,0 min, ([M+H]+= 250).1H-NMR (600 MHz, D6DMSO + a few drops HCOOH): δ 8,63 (s, ~1H), 7,2 (s, 1H), 3,99-3,93 (m, 1H), 3,85 (t, J=7 Hz, 2H), 3,54-3,26 (m, 5H), 3,19-of 3.12 (m, 1H), 2,36 of-2.32 (m, 1H), 2,12-of 1.95 (m, 3H), 1,76 is 1.70 (m, 2H), 1,67-to 1.60 (m, 1H), 1,50-of 1.42 (m, 2H), and 0.98 (t, J=7 Hz, 3H).

3-(4-propoxy-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound V)

Connection W received in accordance with the procedure described for the synthesis of compound 52A (see figure 10), using propanol and 3-[4-iodine-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane (50). Processing and flash chromatography (gradient of EtOH to EtOH/triethylamine 300/1), and then the second flash chromatography (EtOH/ethyl acetate/triethylamine 25/5/1) gave compound 51B report in the form of oil (14%). LCMS (method C); Rt: 7,15 min, ([M+H]+= 366). In the next shot the protection connection 51A (TBAF/THF) and was purified flash chromatography (gradient of EtOH to EtOH/triethylamine 97/3), followed by purification preparative TLC (CH3CN/H2O) to obtain specified in the connection header W in the form of oil (51%). LCMS (method A); Rt: 0,91 min, ([M+H]+= 236).1H-NMR (600 MHz, D6DMSO): δ 7,34 (s, 1H), 3,74 (t, J=7 Hz, 2H), 3,24-3,19 (m, 1H), 3,03-2,96 (m, 1H), 2,92-2,87 (m, 1H), 2,86-to 2.74 (m, 3H), 2,69-2,62 (m, 1H), 1,88-of 1.84 (m, 1H), 1,67-of 1.55 (m, 5H), 1,26-1,20 (m, 1H), to 0.92 (t, J=7 Hz, 3H).

3-(4-pentyloxy-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane (compound C)

Connection IS received in accordance with the procedure described for the synthesis of compound 52A (see figure 10), using pentanol (25 ml) and 3-[4-iodine-1-(2-trimethylsilylethynyl)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane (50), (2 g, 4.61 mmol). Processing and flash chromatography (gradient of EtOH to EtOH/triethylamine 300/1), and then the second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) gave compound IS in the form of oil (0,46 g, 15%). LCMS (method C); Rt: 3,30 min, ([M+H]+= 394).

To a solution of protected SEM pyrazole S ones (0.46 g, 1.2 mmol) in EtOH (5 ml) was added HCl (4 M in dioxane, 1 ml, 4 mmol) and the reaction mixture was stirred at 75°C for 20 hours. Subsequent purification with flash chromatography (gradient of EtOH to EtOH/triethylamine 97/3), followed by purification preparative HPLC: Prep the LC system (CHSLCPO2), column: Inertsil ODS-3, 8 μm. Eluent 10%/90% CH3CN/H2O + HCOOH, 50 ml/min, gave specified in the header connection S (oil, 60 mg, 19%).1H-NMR (600 MHz, D6DMSO + a few drops HCOOH): δ 8,65 (s, ~1H), 7,2 (s, 1H), 3.96 points-3,90 (m, 1H), 3,84 (t, J=7 Hz, 2H), 3,54-of 3.46 (m, 1H), 3,45-3,26 (m, 4H), 3,19-of 3.12 (m, 1H), 2,36 of-2.32 (m, 1H), 2,12-of 1.95 (m, 3H), 1,79-of 1.74 (m, 2H), 1,67-to 1.60 (m, 1H), 1,45-of 1.35 (m, 4H), of 0.95 (t, J=7 Hz, 3H).

Exo-6-(1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]]Octan-6-ol (compound 55, scheme 11)

Suspension of Propylenediamine (14,62 g, 114 mmol) and t-BuOK (14,92 g, 133 mmol) in 350 ml of anhydrous THF was stirred for 1 hour at -10°C in an atmosphere of N2. Then was added a suspension of 1-azabicyclo[3.2.1]octane-6-she (53, J. Med. Chem., 36,1993, 683-689) (11,92 g, 95 mmol) in 100 ml THF and the resulting homogeneous reaction mixture was stirred for 2 hours at 0°C. the mixture is Then extinguished aqueous solution of acetic acid at 0°C and concentrated in vacuum. Added ethyl acetate and the organic layer was washed with 2 N NaOH, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (dichloromethane/MeOH/NH4OH 93/7/0,5) gave 6-(3,3-diethoxypropane-1-inyl)-1-azabicyclo[3.2.1]Octan-6-ol (54) in the form of oil (20,87 g, 86%). LCMS (method A); Rt: 1,18 min, ([M+H]+= 254).1H-NMR (400 MHz, CDCl3): δ 5,28 (s, 1H), 3,74-the 3.65 (m, 2H), 3,61-to 3.52 (m, 2H), 3.45 points (d, J=13 Hz, 1H), 3,12 totaling 3.04 (m, 1H), 3,0-2,82 (m, 4H), 2,22-to 2.18 (m, 1H), 2,17-2,02 (m, 1H), 1,98-1,89 (m, 1H), 1,71-to 1.61 (m, 1H), 1,39-of 1.30 (m, 1H), 1,22 (t, J7 Hz, 6H).

Compound 54 (15,39 g of 60.7 mmol) and 7,02 g of hydrazine dihydrochloride were combined in EtOH/H2O (3/2, 250 ml) and warmed by boiling under reflux for 18 hours in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in the Meon. To the reaction mixture were added Amberlyte IRA-95 (basically) and subsequently stirred for 18 hours at room temperature. The mixture was filtered, concentrated and re-dissolved in the Meon. Filtering through 100 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) gave specified in the title compound 55 (amorphous substance). Output 8,45 g (72%).1H-NMR (600 MHz, D6DMSO + a few drops of CF3COOH): δ of 7.70 (d, J=2 Hz, 1H), 6.42 per (d, J=2 Hz, 1H), 4,24-4,20 (m, 1H), 3,41-of 3.31 (m, 4H), 3.25 to is 3.21 (m, 1H), 2,45-to 2.42 (m, 1H), 2.40 a-2,30 (m, 1H), 2,10-2,04 (m, 1H), 1,74-of 1.64 (m, 2H), methodology represented DEPT, HSQC, COSY, HMBC, ROESY and NOESY (methods NMR spectroscopy).

Endo-6-(1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (compound 58, scheme 11)

Compound 55 (7,83 g, 41 mmol) and 9,81 ml (120 mmol) of pyridine were combined in benzene (150 ml). Was added acetic anhydride (11,48 ml, 120 mmol) and the reaction mixture was warmed to 40°C for 72 hours in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in Mahon. Filtering through 100 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) to give compound 56 (amorphous substance, 9.6 g ~ 100%).LCMS (method A); Rt: 0,98 min, ([M+H]+= 236), which was used without further purification.

Compound 56 (1.2 g, 5.1 mmol) was heated (in pure form) at 200°C for 5 min under reduced pressure (23 mbar) and then cooled to room temperature. Purification with flash chromatography (dichloromethane/MeOH/NH4OH 85/15/1) gave 6-(1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]Oct-6-ene (57) in the form of oil (0,49 g, 49%). LCMS (method A); Rt: 1,27 min, ([M+H]+= 176).1H-NMR (400 MHz, CDCl3): δ 7,56 (d, J=2 Hz, 1H), gold 6.43 (s, 1H), 6,36 (d, J=2 Hz, 1H), 3,50 is-3.45 (m, 1H), 3,06-of 2.97 (m, 1H), 2,93 (d, J=10 Hz, 1H), 2,86-and 2.79 (m, 2H), 2.06 to of 1.93 (m, 1H), 1,78-1,72 (m, 1H), 1,49-of 1.41 (m, 1H).

Compound 57 (3,84 g, 21.9 mmol)and 6.9 g of ammonium formate (110 mmol) and 20% Pd(OH)2/C (340 mg) were combined in MeOH (150 ml) and warmed by boiling under reflux for 1 hour. The mixture was cooled, filtered, concentrated and re-dissolved in the Meon. Filtration through 40 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) and subsequent purification with flash chromatography (MeOH/triethylamine 90/3) to give endo-6-(1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (58) (amorphous substance, 2.8 g, 73%). LCMS (method A); Rt: 0,80 min, ([M+H]+= 178).1H-NMR (600 MHz, D6DMSO/CDCl3(1/1)): δ rate of 7.54 (d, J=2 Hz, 1H), 6,16 (d, J=2 Hz, 1H), 3,98-to 3.92 (m, 1H), 3,90-a-3.84 (m, 1H), 3,82-of 3.77 (m, 1H), 3,53-of 3.48 (m, 1H), 3,32-3,24 (m, 3H), 2,82-2,77 (m, 1H), 2,03-of 1.94 (m, 1H), 1,68 is 1.60 (m, 1H), 1,58-of 1.52 (m, 1H), 1,51 to 1.47 (m, 1H), methodology represented DEPT, HSQC, COSY, HMBC, ROESY and NOEY.

Endo-6-(4-intercultural--1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (compound 60A, scheme 11)

To a solution of 58 (1,49 g to 8.41 mmol) in anhydrous DMF (60 ml), at -10°C was added 2,68 g (of 10.93 mmol) N-jodatime. The reaction mixture was stirred for 2 hours at -10°C and 1 hour at room temperature. The solvent is (partially) removed under reduced pressure. Added the Meon and the resulting reaction mixture was filtered through 120 g SCX-2 (MeOH followed by the addition of 1 N NH3/MeOH) to obtain endo-6-(4-iodine-1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (59) (amorphous substance, 1.73 g, 67%). LCMS (method A); Rt: 1,25 min, ([M+H]+= 304).1H-NMR (600 MHz, D6DMSO + CF3COOH): δ 7,72 (s, 1H), 4,08-a 4.03 (m, 1H), 3,80 of 3.75 (m, 1H), of 3.73-3,68 (m, 1H), 3,50 is-3.45 (m, 1H), 3,34-of 3.25 (m, 3H), 3.04 from to 3.0 (m, 1H), 2,24 with 2.14 (m, 1H), 1,64-of 1.57 (m, 1H), 1,50-of 1.42 (m, 1H), 1,22-1,17 (m, 1H)used methods represented DEPT, HSQC, COSY, HMBC, ROESY and NOESY.

Compound 59 (0.50 g; of 1.65 mmol), K2CO3(0.3 g; 2.14 mmol) and pentane-1-thiol (0,26 ml of 2.06 mmol) was dissolved in 20 ml of xylene/DMF (9/1) and the solution was degirolami for 45 minutes with argon. To this solution was added Pd2(dba)3(150 mg; 0,165 mmol) and Xanthos (190 mg; 0.33 mmol). After the addition the reaction mixture was heated to 130°C and was stirred for 20 hours in an atmosphere of N2. The mixture was cooled, concentrated and re-dissolved in MeOH. Filtering through 75 g SCX-2 (MeOH followed EXT is the relation 1 N NH 3/MeOH) and subsequent purification with flash chromatography (MeOH/triethylamine (97/3)) gave specified in the title compound 60A in the form of oil. Yield 150 mg (32%). Connection 60A were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated (amorphous substance).

LCMS (method A); Rt: 1,39 min, ([M+H]+= 280).1H-NMR (600 MHz, D6DMSO): δ a 7.85 (s, 1H), gold 6.43 (s, 2H), 3,80-3,70 (m, 2H), 3,63-to 3.58 (m, 1H), 3,28-up 3.22 (m, 1H), 3,20-3,19 (m, 3H), 2,82-2,78 (m, 1H), 2,63 is 2.55 (m, 2H), 2,12 is 2.01 (m, 1H), 1,65-of 1.56 (m, 1H), 1,50-of 1.44 (m, 2H), 1,37-to 1.15 (m, 6H), of 0.85 (t, J=7 Hz, 3H).

Endo-6-(4-butylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (compound 60)

Compound 60 was obtained according to the procedure described for the synthesis of compound 60A (see figure 11), using butane-1-thiol and endo-6-(4-iodine-1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane (50). Connection 60V were subjected to interaction with 1 EQ. fumaric acid in EtOH and concentrated. Yield: 49% (amorphous substance). LCMS (method A); Rt: 1,71 min, ([M+H]+= 266).1H-NMR (600 MHz, D6DMSO): δ 7,80 (s, 1H), 6,46 (s, 2H), 3,94-to 3.89 (m, 1H), 3,86-3,81 (m, 1H), 3,79-3,74 (m, 1H), 3.45 points-to 3.41 (m, 1H), 3,31-up 3.22 (m, 3H), 2,93-2,89 (m, 1H), 2,62 is 2.55 (m, 2H), 2.21 are 2,11 (m, 1H), 1,66-to 1.59 (m, 1H), 1,49-to 1.42 (m, 2H), 1,40-of 1.33 (m, 2H), 1,26-1,20 (m, 2H), 0,86 (t, J=7 Hz, 3H).

3-(4-bromination-3-yl)pyridine (compound 64, scheme 12)

To a solution of anhydrous THF (250 ml)containing 3-pyridinoline (61) (18,87 g 154,7 mmol)was added 20,57 g (1.0 EQ.) N-chlorosuccinimide. After adding the floor, the military solution was stirred for 18 hours at 65°C. Then the temperature of the reaction mixture was lowered to -30°C and was added 1,2-bis-trimethylsilylmethyl (26,4 g, 170,4 mmol), followed by the addition of triethylamine (2 EQ., 42 ml, drip), maintaining the temperature <-25°C. After stirring for a further 30 minutes the mixture was allowed to warm to ambient temperature, diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(4,5-bis-trimethylsilyloxy-3-yl)pyridine (62) in the form of oil (of 4.45 g, 17%).1H-NMR (400 MHz, CDCl3): δ to 8.70 (DD, J=5 Hz, 2 Hz, 1H), 8,68 (d, J=2 Hz, 1H), 7,76 (dt, J=8 Hz, 2 Hz, 1H), 7,41-7,37 (m, 1H), and 0.46 (s, 9H), of 0.11 (s, 9H).

To a solution of anhydrous CCl4(80 ml)containing compound 62 (4,45 g of 15.4 mmol), was added (1.1 EQ., the 1.04 ml) Br2. After adding the resulting solution was stirred for 18 hours at 40°C. the Reaction mixture was cooled and concentrated in vacuum. Added ethyl acetate and the organic layer was washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (simple diethyl ether) gave 3-(4-bromo-5-trimethylsilyloxy-3-yl)pyridine (63) in the form of an oil (4.5 g, ~100%).1H-NMR (400 MHz, CDCl3): δ remaining 9.08 (d, J=2 Hz, 1H), 8,73 (DD, J=5Hz, 2 Hz, 1H), 8,14 (dt, J=8 Hz, 2 Hz, 1H), 7,46-7,41 (m, 1H), and 0.40 (s, 9H).

To a solution of EtOH (20 ml)containing compound 63 (4.5 g, to 15.4 mmol), was added 5 ml of 25% NH4OH. After adding the resulting solution was stirred for 10 minutes at room temperature. The reaction mixture was concentrated in vacuum. Added ethyl acetate and the organic layer was washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. Purification with flash chromatography (simple diethyl ether) gave specified in the header connection (64) in the form of oil (2.76 g, 82%). (TLC simple diethyl ether Rf0,4).1H-NMR (400 MHz, CDCl3): δ 9,14 (d, J=2 Hz, 1H), 8,76 (DD, J=5 Hz, 2 Hz, 1H), 8,58 (s, 1H), 8,19 (dt, J=8 Hz, 2 Hz, 1H), of 7.48-the 7.43 (m, 1H).

3-(4-butylsulfonyl-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 66A, scheme 12)

To a degassed solution of dioxane (40 ml)containing compound 64 (1.0 g, of 4.44 mmol), was added 1.2 EQ. (of 0.62 ml) butane-1-thiol and 2 EQ. triethylamine (1,52 ml). The resulting mixture was stirred for another 2 hours in an atmosphere of N2. Consistently added 2.5% mmol Pd2(dba)3(100 mg) and 5% mmol of Xanthos (128 mg). After adding the resulting solution was stirred for 18 hours at 95°C in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with saturated solution of NaHO 3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether) to obtain 3-(4-butylsulfonyl-3-yl)-pyridine (65A) in the form of an oil (0.26 g, 25%) (TLC simple diethyl ether Rf0,54).1H-NMR (400 MHz, CDCl3): δ 9,24 (d, J=2 Hz, 1H), 8,72 (DD, J=5 Hz, 2 Hz, 1H), 8,49 (s, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,45-7,41 (m, 1H), 2,61 (t, J=7 Hz, 2H), 1,52 was 1.43 (m, 2H), 1,39-of 1.29 (m, 2H), or 0.83 (t, J=7 Hz, 3H).

1 EQ. complex dimethyl ester of sulfuric acid (about 0.14 ml, 1.5 mmol) was added to a solution of 65A (0.35 g, 1.5 mmol) in acetone (20 ml) and the mixture was stirred for 18 hours at room temperature. Precipitated crystals were filtered, thoroughly washed simple diethyl ether and dried to obtain the corresponding derivative complex nanometrology ether sulfuric acid pyridinium. To a cooled (-30°C.) suspension of this compound in the Meon (25 ml) in small portions was added sodium borohydride (0.17 g, 4.5 mmol). The mixture was allowed to warm to ambient temperature and was poured into a saturated solution of NH4Cl (0°C). The solvent is (partially) removed under reduced pressure. Added ethyl acetate and the organic layer was washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (Meon) to receive the Deposit specified in the title compound 66A (amorphous substance, 1,09 g, 73% (total)). LCMS (method A); Rt: 1,58 min, ([M+H]+= 253).1H-NMR (600 MHz, CDCl3): δ 8,23 (s, 1H), 7,06? 7.04 baby mortality (m, 1H), 3,40-to 3.38 (m, 2H), 2,68 (t, J=7 Hz, 2H), 2,59 (t, J=7 Hz, 2H), 2,48-to 2.42 (m, 5H), 1,57-is 1.51 (m, 2H), 1,44 to 1.37 (m, 2H), of 0.90 (t, J=7 Hz, 3H).

3-(4-vexillological-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection B)

To a degassed solution of dioxane (30 ml)containing compound 64 (0.6 g, of 2.66 mmol) (see scheme 12), was added 1.2 EQ. (of 0.62 ml) hexane-1-thiol and 2 EQ. triethylamine (0,92 ml). The resulting mixture was stirred for another 2 hours in an atmosphere of N2. Consistently added 2.5% mmol Pd2(dba)3(61 mg) and 5% mmol of Xanthos (77 mg). After adding the resulting solution was stirred for 18 hours at 95°C in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether) to obtain 3-(4-vexillological-3-yl)pyridine (V) in the form of an oil (0.25 g, 37%)1H-NMR (400 MHz, CDCl3): δ 9,24 (d, J=2 Hz, 1H), 8,73 (DD, J=5 Hz, 2 Hz, 1H), 8,49 (s, 1H), 8,31 (dt, J=8 Hz, 2 Hz, 1H), 7,45-7,41 (m, 1H), 2,61 (t, J=7 Hz, 2H), 1,52 was 1.43 (m, 2H), 1,35-of 1.13 (m, 6H), of 0.85 (t, J=7 Hz, 3H).

1 EQ. complex dimethyl ester of sulfuric acid (0,09 ml, 0.95 mmol) was added to a solution of 65A (0.25 g, 0.95 mmol) in Aceto is e (20 ml) and the mixture was stirred for 18 hours at room temperature. Precipitated crystals were filtered, thoroughly washed simple diethyl ether and dried to obtain the corresponding derivative complex nanometrology ether sulfuric acid pyridinium. To a cooled (-30°C.) suspension of this compound in the Meon (25 ml) in small portions was added sodium borohydride (0,144 g, 4 EQ.). The mixture was allowed to warm to ambient temperature and was poured into a saturated solution of NH4Cl (0°C). The solvent is (partially) removed under reduced pressure. Added ethyl acetate and the organic layer was washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (Meon) to obtain specified in the connection header W (amorphous substance, to 0.72 g, 65% (total)). LCMS (method A); Rt: 1,92 min, ([M+H]+= 281).1H-NMR (400 MHz, CDCl3): δ 8,23 (s, 1H), 7,06? 7.04 baby mortality (m, 1H), 3,40-to 3.38 (m, 2H), to 2.67 (t, J=7 Hz, 2H), 2,59 (t, J=7 Hz, 2H), 2,48-to 2.42 (m, 5H), 1,59-is 1.51 (m, 2H), 1.41 to to 1.21 (m, 6H), of 0.85 (t, J=7 Hz, 3H).

3-(4-Gex-1-telesocial-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 68A, scheme 13)

To anhydrous THF (30 ml)containing compound 64 (0.64 g, 2,84 mmol), was added 1.5 EQ. (E)-HEXEN-1-elborno acid (0.55 g). The resulting mixture was stirred for 2 hours in an atmosphere of N2. Sequentially added 2 EQ. To3RHO4(1.2 g), 2% mol PdOAc) 2(13 mg) and 4% mol S-Phos (47 mg). After adding the resulting solution was warmed at 65°C for 18 hours in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(4-Gex-1-telesocial-3-yl)pyridine (compound 67A) in the form of oil (0,47 g, 69%).1H-NMR (400 MHz, CDCl3): δ 8,9 (d, J=2 Hz, 1H), 8,72 (DD, J=5 Hz, 2 Hz, 1H), 8,49 (s, 1H), 8.0 a (dt, J=8 Hz, 2 Hz, 1H), 7,45-7,41 (m, 1H), 6,11 of 5.99 (m, 2H), 2,22 with 2.14 (m, 2H), 1,46-of 1.29 (m, 4H), of 0.91 (t, J=7 Hz, 3H).

3-(4-Gex-1-enyl-1H-pyrazole-3-yl)pyridine (67A) was converted into the specified header connection 68A, using the methodology described for the conversion of compound 65A 66A in (see diagram 12). Yield: 95% (amorphous substance). LCMS (method A); Rt: 1,68 min, ([M+H]+= 247).1H-NMR (400 MHz, CDCl3): δ of 8.28 (s, 1H), 6,36-6,30 (m, 1H), 6,09-to 5.93 (m, 2H), 3.46 in-to 3.41 (m, 2H), 2,70 (t, J=7 Hz, 2H), 2,52 (s, 3H), of 2.51 at 2.45 (m, 2H), 2.21 are to 2.14 (m, 2H), 1,47 to 1.31 (m, 4H), to 0.92 (t, J=7 Hz, 3H).

3-(4-Oct-1-telesocial-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection B)

To anhydrous THF (20 ml)containing compound 64 (0,49 g, 2,17 mmol) (see scheme 13), was added 1.5 EQ. (E)-octene-1-elborno acid (0.51 g). The resulting mixture was stirred for 2 hours in an atmosphere of N2. Consistently we use the 2 EQ. To3RHO4(0,92 g), 2% mol Pd(OAc)2(10 mg) and 4% mol S-Phos (36 mg). After adding the resulting solution was warmed at 65°C for 18 hours in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(4-Oct-1-telesocial-3-yl)pyridine (compound V) in the form of oil (0,19 g, 34%).1H-NMR (400 MHz, CDCl3): δ 8,9 (d, J=2 Hz, 1H), 8,72 (DD, J=5 Hz, 2 Hz, 1H), 8,49 (s, 1H), 7,9 (dt, J=8 Hz, 2 Hz, 1H), 7,45-7,40 (m, 1H), 6,11 of 5.99 (m, 2H), 2.21 are to 2.13 (m, 2H), 1,46-to 1.38 (m, 2H), 1,37-to 1.21 (m, 6H), of 0.91 (t, J=7 Hz, 3H).

3-(4-Oct-1-enyl-1H-pyrazole-3-yl)pyridine (V) was converted into the specified header connection V using the methodology described for the conversion of compound 65A 66A in (see diagram 12). Yield: 54% (amorphous substance). LCMS (method A); Rt: 2.0V min, ([M+H]+= 275).1H-NMR (400 MHz, CDCl3): δ of 8.28 (s, 1H), 6,32-6,27 (m, 1H), 6,09-to 5.93 (m, 2H), 3,37-to 3.33 (m, 2H), 2,61 (t, J=7 Hz, 2H), of 2.45 (s, 3H), 2,44-2,39 (m, 2H), 2,20-2,12 (m, 2H), 1,48-to 1.38 (m, 2H), 1,37-of 1.24 (m, 6H), of 0.85 (t, J=7 Hz, 3H).

3-(4-hept-1-inalization-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (compound 70A, scheme 13)

To anhydrous THF (20 ml)containing compound 64 (1.08 g, 4.8 mmol), was added 1.5 EQ. hept-1-vinyltrimethylsilane (1,21 g), 3 EQ. KOAc (1,41 g) and 1 EQ. TBAF (1.0 M in THF). Received the th mixture was stirred for another 2 hours in an atmosphere of N 2. Sequentially added 10% mol Pd(OAc)2(108 mg) and 20% mol PPH3(251 mg). After adding the resulting solution was warmed at 90°C for 18 hours in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-(4-hept-1-inalization-3-yl)pyridine (69A) in the form of an oil (0.34 g, 30%).1H-NMR (400 MHz, CDCl3): δ 9,3 (d, J=2 Hz, 1H), 8,7 (DD, J=5 Hz, 2 Hz, 1H), 8,58 (s, 1H), 8.34 per (dt, J=8 Hz, 2 Hz, 1H), 7,44-7,39 (m, 1H), 2,42 (t, J=7 Hz, 2H), 1,65-of 1.57 (m, 2H), 1,45-of 1.29 (m, 4H), of 0.91 (t, J=7 Hz, 3H).

3-(4-hept-1-inyl-1H-pyrazole-3-yl)pyridine (69A) was converted into the specified header connection 70A, using the methodology described for the conversion of compound 65A 66A in (see diagram 12). Yield: 50% (amorphous substance). LCMS (method A); Rt: 1,78 min, ([M+H]+= 259).1H-NMR (400 MHz, CDCl3): δ of 8.40 (s, 1H), 7.18 in-7,13 (m, 1H), 3,41-to 3.36 (m, 2H), 2,59 (t, J=7 Hz, 2H), of 2.45 (s, 3H), 2,45-of 2.38 (m, 2H), 1,64-1,55-2,12 (m, 2H), 1,46-of 1.30 (m, 4H), of 0.91 (t, J=7 Hz, 3H).

3-[5-bromo-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]pyridine (compound 73, scheme 14)

To anhydrous THF (100 ml)containing 3-bromopyridin (3,29 g, 20,82 mmol), was added 1.2 EQ. iPrMgCl (12,49 ml, 2M in THF) and the resulting mixture was stirred for 2 hours in atmospheres the N 2(10°C). Then added 1.2 EQ. (CH3)3SnCl, and the reaction mixture was stirred for 18 hours at room temperature (in the atmosphere N2). The reaction mixture was extinguished with saturated solution of NH4Cl, diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether/PE 1/1) to obtain 3-trimethylethylenediamine (71) (3,32 g, 66%). LCMS (method A); Rt: 2,09 min, ([M+H]+= 242).1H-NMR (400 MHz, CDCl3): δ 8,62 (users, 1H), charged 8.52 (DD, J=5 Hz, 2 Hz, 1H), 7,76 (dt, J=8 Hz, 2 Hz, 1H), 7,25-7,21 (m, 1H), 0,33 (s, 9H), with a concomitant Sn when 0,41 0,27.

To a solution of compound 71 (0,82 g, 3.4 mmol) in anhydrous toluene (50 ml) was added to 0.9 EQ. (1.10 g) of 4,5-dibromo-1-(2-trimethylsilylethynyl)-1H-imidazole (compound 72, LCMS (method A); Rt: 3,60 min, ([M+H]+= 357)), and the resulting mixture was stirred for 2 hours in an atmosphere of N2(room temperature). To this reaction mixture was added 10% mol PdCl2(PPH3)2(240 mg). After addition the temperature was raised to 100°C and the resulting solution was stirred for 18 hours in an atmosphere of N2. The reaction mixture was cooled, diluted with ethyl acetate, washed three times with saturated solution of NaHCO3, dried (Na2SO4), filtered and the end of what was tarawali. The obtained residue was purified flash chromatography (simple diethyl ether followed by ethyl acetate) to obtain 3-[5-bromo-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]pyridine (73) in the form of oil (385 mg, 36%). LCMS (method A); Rt: 3,40 min, ([M+H]+= 355).1H-NMR (400 MHz, CDCl3and HMBC): δ 8,79 (d, J=2 Hz, 1H), 8,66 (DD, J=5 Hz, 2 Hz, 1H), to $ 7.91 (dt, J=8 Hz, 2 Hz, 1H), 7,66 (s, 1H), 7,44-7,40 (m, 1H), 5,17 (s, 2H), 3,56-to 3.50 (m, 2H), were 0.94-0.87 (m, 2H), 0,0 (s, 9H).

3-(5-intercultural-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection 76A, scheme 14)

To a degassed solution of xylene (100 ml)containing compound 73 (1,82 g, 5,16 mmol)was added to 1.25 equiv. (0,80 ml) pentane-1-thiol and 1.25 equiv. To2CO3(0.8 g). The resulting mixture was stirred for another 2 hours in an atmosphere of N2. Sequentially added 10% mol Pd2(dba)3(470 mg) and 20% mol of Xanthos (600 mg). After adding the resulting solution was stirred for 18 hours at 130°C in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether followed by ethyl acetate) to obtain 3-[5-intercultural-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]pyridine (A) in the form of oil (530 mg, 30%) and IP is the same material (73, 380 mg, 21%).1H-NMR (400 MHz, CDCl3): δ 9,38 (d, J=2 Hz, 1H), 8,53 (DD, J=5 Hz, 2 Hz, 1H), 8,42 (dt, J=8 Hz, 2 Hz, 1H), 7,82 (s, 1H), 7,35-7,30 (m, 1H), 5,43 (s, 2H), 3,59-of 3.54 (m, 2H), 2,66 (t, J=7 Hz, 2H), 1,47-to 1.38 (m, 2H), 1,28-1,10 (m, 4H), 0,96-0,89 (m, 2H), 0,80 (t, J=7 Hz, 3H), 0,0 (s, 9H).

3-[5-intercultural-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]pyridine (A) was converted into 3-[5-intercultural-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine (75A), using the methodology described for the conversion of compounds 21A to 22A (see scheme 3). Yield: 75% (amorphous substance).1H-NMR (400 MHz, CDCl3): δ 7,68 (s, 1H), 6.75 in-of 6.71 (m, 1H), lower than the 5.37 (s, 2H), 3,54-of 3.46 (m, 4H), to 2.67 (t, J=7 Hz, 2H), 2.57 m (t, J=6 Hz, 2H), 2,46 (s, 3H), 2,44-of 2.38 (m, 2H), 1,55 of 1.46 (m, 2H), 1,37-1,24 (m, 4H), 0,94-0,85 (m, 5H), 0,0 (s, 9H).

To a solution of anhydrous THF (20 ml)containing the compound 75A (0,42 g, 1.06 mmol)was added 3,18 ml (3 EQ.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (Meon) followed by further purification on (25 g) SCX-2 (MeOH followed by exposure to 1 N NH3/MeOH) to obtain the heading compound 76A (oil, 0.2 g, 73%). LCMS (method A);R t: 1,0 min, ([M+H]+= 266).1H-NMR (400 MHz, CDCl3): δ rate of 7.54 (s, 1H), 6,36 of 6.31 (m, 1H), 3,49-of 3.46 (m, 2H), 2,75 (t, J=7 Hz, 2H), 2,64 (t, J=6 Hz, 2H), 2,47 (s, 3H), 2,43-of 2.38 (m, 2H), 1,55-1,49 (m, 2H), 1,35 is 1.23 (m, 4H), of 0.85 (t, J=7 Hz, 3H).

3-(5-hexylsilane-3H-imidazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (connection V, scheme 14).

To a degassed solution of xylene (30 ml)containing compound 73 (0.6 g, 1.70 mmol) was added to 1.25 equiv. (0,30 ml) hexane-1-thiol and 1.25 equiv. To2CO3(0.29 grams). The resulting mixture was stirred for another 2 hours in an atmosphere of N2. Sequentially added 10% mol Pd2(dba)3(160 mg) and 20% mol of Xanthos (200 mg). After adding the resulting solution was stirred for 18 hours at 130°C in an atmosphere of N2. After cooling to room temperature the mixture was diluted with ethyl acetate, washed with saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The obtained residue was purified flash chromatography (simple diethyl ether) to obtain 3-[5-hexylsilane-3-(2-trimethylsilylethynyl)-3H-imidazol-4-yl]pyridine (V) in the form of an oil (120 mg, 18%) and starting material (73, 380 mg).1H-NMR (400 MHz, CDCl3): δ 9,38 (d, J=2 Hz, 1H), 8,53 (DD, J=5 Hz, 2 Hz, 1H), 8,42 (dt, J=8 Hz, 2 Hz, 1H), 7,82 (s, 1H), 7,35-7,30 (m, 1H), 5,43 (s, 2H), 3,59-of 3.54 (m, 2H), 2,66 (t, J=7 Hz, 2H), 1,46 to 1.37 (m, 2H), 1,28-of 1.06 (m, 8H), 0,96-0,89 (m, 2H), 0,80 (t, J=7 Hz, 3H), 0,0 (s, 9H).

To a solution of anhydrous THF (30 ml), terashima connection V (0.29 grams, to 0.74 mmol), was added 2.2 ml (3 EQ.) TBAF (1.0 M in THF) in an atmosphere of N2. After adding the resulting solution was boiled under reflux for 18 hours and then concentrated in vacuum. Added ethyl acetate and the organic layer was washed with a concentrated solution of NaHCO3, dried (Na2SO4), filtered and concentrated in vacuum. The obtained residue was purified flash chromatography (ethyl acetate) to obtain 3-(5-hexylsilane-3H-imidazol-4-yl)pyridine (77) in oil (0.14 g, 71%).1H-NMR (400 MHz, CDCl3): δ 9,25 (users, 1H), 8,53 (DD, J=5 Hz, 2 Hz, 1H), 8,42-8,35 (m, 1H), 7,78 (s, 1H), 7,38-7,34 (m, 1H), 2,79-2,69 (m, 2H), 1,53-of 1.44 (m, 2H), 1,33-of 1.09 (m, 6H), to 0.80 (t, J=7 Hz, 3H).

3-(5-hexylsilane-3H-imidazol-4-yl)pyridine (77) were converted into listed at the beginning of the connection, using the methodology described for the conversion of compounds 21A to 22A (see scheme 3) (however, the quaternization was carried out at room temperature with a small excess of CH3I). Yield: 70% (oil). LCMS (method A); Rt: 1,21 min, ([M+H]+= 280).1H-NMR (400 MHz, CDCl3): δ 7,53 (s, 1H), 6,40-of 6.29 (m, 1H), 3.45 points-to 3.41 (m, 2H), 2,79-of 2.72 (m, 2H), 2,59 (t, J=6 Hz, 2H), of 2.45 (s, 3H), 2,41-is 2.37 (m, 2H), 1,55-1,49 (m, 2H), 1,38 to 1.31 (m, 2H), 1.30 and 1,19 (m, 4H), of 0.85 (t, J=7 Hz, 3H).

5. Pharmacological tests

(I) an Analytical method for screening ligands of muscarinic receptors (In vitro; functional analysis)

The test substance

Join RA is tarali in DMSO (10 mm) and diluted in analytical buffer up to the tested concentration. Initial testing was carried out at 1 μm to identify active compounds antagonistic action type (PI, percentage of inhibition relative to the reference agonist and blank samples >30%), and active compounds agonistic action type (PS, the percentage of stimulation relative to the reference agonist and blank samples >30%), testing continued at lower concentrations 10-fold dilutions: 0,1 µm, 0.01 µm, etc.

GPCR-A-MA-ACH M3
Analytical parameters: Target, Type, Fabric
AnalysisTargetViewFabric
Muscarine M1GPCR-A-MA-ACH M1PeopleCells Chinese hamster ovary
Muscarine M1GPCR-A-MA-ACH M1RabbitThe ductus deferens (the stimulation field)
Muscarine M2GPCR-A-MA-ACH M2Guinea pigThe left atrium (electrical stimulation)
Muscarine M3Guinea pigThe ileum
Muscarin M4GPCR-A-MA-ACH M4PeopleCells Chinese hamster ovary

Analytical parameters: the Ligand (Kd (coeeficient dissociation), Concentration), Nonspecific binding (Concentration)
AnalysisThe reference agonistLigand TC50(nm)The concentration of L ligand (nm)Reference antagonistReaction
Muscarine M1Acetylcholine0,8100
(agonistic type)
3
(antagonistically type)
pirenzepineCa2+-FLIPR Fluorometry
Muscarine M1McN-A-3432503000
(agonistic type)
1000
(antagonistically type)
pirenzepine Inhibition of contraction in the form of twitching
Muscarine M2Carbachol1503000
(agonistic type)
1000
(antagonistically type)
methoctramineNegative inotropic effect
Muscarine M3Carbachol1253000
(agonistic type)
1000
(antagonistically type)
4-DAMPReduction
Muscarin M4Oxotremorine4010000
(agonistic type)
10000
(antagonistically type)
pirenzepineLuminescence Ca2+-aquarina

Analytical parameters: Method, Bibliography
AnalysisMethod (see below)Bibliography (see below)
Muscarine M1analysis of cell-basedSur et al. (2003)
Muscarine M1insulated bodyEltze (1988)
Muscarine M2insulated bodyEglen et al. (1988)
Muscarine M3insulated bodyClague et al. (1985)
Muscarin M4analysis of cell-basedStables et al. (1997)

ANALYTICAL PROCEDURES AND CALCULATIONS

Analytical procedures

Tests on isolated organs, agonistic action type

On the cloth was affected by the maximum concentration of the corresponding reference agonist to confirm reactivity and to obtain control of the reaction. After a thorough wash and restore the original status of the tissue was affected by the test compounds or the same agonist. Analyses M1 and M2 receptors compounds were left in contact with the tissues until then, until there was obtained a stable reaction, or a maximum of 15 minutes When tested several concentrations, were added cumulatively. In the analysis of M3 receptors compounds were left in contact with the tissue for a time sufficient to obtain the maximum reaction or Maxi the mind for 10 min, then washed away. When tested several concentrations, were added sequentially via a 40-minute intervals. When they got the reaction, such agonistic corresponding to the reference antagonist was tested against the highest concentration of compounds to confirm the participation of the studied receptors in this response.

Tests on isolated organs, antagonistic action type:

On the cloth was affected by a submaximal concentration of the corresponding reference agonist to get the control response. Analyses M1 and M2 receptors under test compounds and reference compounds were added after stabilization caused by the agonist response, then left in contact with the tissues until then, until there was obtained a stable effect, or within a maximum of 15 minutes When tested several concentrations were added cumulatively. In the analysis of M3 receptors under test compounds or reference antagonist was added for 30 minutes before re-exposure to agonist, which was added in 40-minute intervals. The inhibition induced by agonists of the response caused by the connection, if it occurred, indicated antagonistic activity against the studied receptors. Each compound was tested in three assays for the detection of agonistic and antagonist the practical activity in one or more concentrations in three separate tissues. In each analysis the reference agonist and antagonist were tested at several concentrations in three separate tissues to obtain curves of the concentration - response.

CELLULAR ANALYSES

Cells were incubated with the compound and measured the response.

Answer and calculation results

Tests on isolated organs:

The measured parameters were the maximum change in amplitude of contractions induced by electrical stimulation (tests M1 and M2 receptors) or voltage (analysis of M3 receptors) due to caused by each compound reduction. The results are expressed as percentage of the control reaction caused by the agonist. Values AS reference agonist (concentration that causes a reaction, which is half the maximum) and the IC50 value of the reference antagonist (concentration causing half-maximal inhibition of the reaction caused by the agonist) was calculated by linear regression analysis of their curves of reaction from concentration.

CELLULAR ANALYSES

The results are expressed as percentage values of the reference agonist and blank samples in the presence of test compounds, the percentage stimulation for agonistic activity type; for antagonistic activity type (test compound in the presence of the reference agonist) in the form p is acenta inhibition. Values AS (concentration causing a half-maximal stimulation of control values), the IC50 values (concentration causing a half-maximal inhibition of control values) was determined by analysis of nonlinear regression curves of reaction from concentration using the curve fitting equation of the Hill.

Bibliography

(II) an Analytical method for screening ligands of muscarinic receptors

(In vitro; the analysis of binding with the receptor)

The test substance

Compounds were dissolved in DMSO (10 mm) and diluted in analytical buffer up to the tested concentration. Initial testing was carried out at 10 μm; for the active connection (PI, percentage of inhibition relative to the total and nonspecific binding >40%) testing continued at lower concentrations 10-fold dilutions: 1 µm, 0.1 µm, etc.

Analytical parameters: Target, Type, Fabric
AnalysisTargetViewFabric
Muscarin M nonselectiveGPCR-A-MA-M ACH RatThe cerebral cortex
Muscarine M1GPCR-A-MA-ACH M1PeopleCells Cho (Chinese hamster ovary)
Muscarine M2GPCR-A-MA-ACH M2PeopleCells Cho (Chinese hamster ovary)
Muscarine M3GPCR-A-MA-ACH M3PeopleCells Cho (Chinese hamster ovary)
Muscarin M4GPCR-A-MA-ACH M4PeopleCells Cho (Chinese hamster ovary)

Analytical parameters: the Ligand (Kd, Concentration), Nonspecific binding (Concentration)
AnalysisThe ligandKd ligand (nm)The concentration of L ligand (nm)Not specifically bind the connectionThe concentration of nonspecific binding (μm)
Muscarin M nonselective3H-QNB0,010,05Atropine1 micron
Muscarine M13H-pirenzepine132Atropine1 micron
Muscarine M23H-AFDX3844,32Atropine1 micron
Muscarine M33H-4DAMP0,50,2Atropine1 micron
Muscarin M43H-oxotremorine4,56Atropine1 micron
Muscarin M43H-4DAMPof 0.3320,2Atropine1 micron

Analytical pairs of the m: Method, Bibliography
AnalysisConditions of incubation period/temperatureBibliography (see below)
Muscarin M nonselective120 min/22°CRichards (1990)
Muscarine M160 min/22°CDörje et al. (1991)
Muscarine M260 min/22°CDörje et al. (1991)
Muscarine M360 min/22°CPeralta et al. (1987)
Muscarin M430 min/25°CDörje et al. (1991)
Muscarin M460 min/22°CDörje et al. (1991)

ANALYTICAL PROCEDURES AND CALCULATIONS

Analytical procedures

After incubation, the connection with the preparation of receptors ("Fabric") and ligand at a specified time and at a specified temperature was rapidly filtered under vacuum through glass fiber filters; the filters were carefully washed in ice-cold buffer using a collector cells. Associated radioactivity was measured by scintillation treatment tip can is this using liquid scintillation mixture.

Answer and calculation results

The results were expressed as a percentage of the total binding of the ligand and the percentage of nonspecific binding on the concentration of the tested compounds (two repetitions); the curve of concentration - offset value of IC50 was determined by analysis of nonlinear regression using curve fitting the Hill equation. The inhibition constants (Ki) was calculated according to the equation of Cheng-Prushoff Ki=IC50/(1+L/Kd), where L represents the concentration of radioligand in the analysis, and Kd is the affinity of radioligand to the receptor. The results were expressed as mean values pKi ± SD (standard deviation)of at least 2 separate experiments; i.e. drop-down values (±1 std (standard deviation) average value) and inconsistencies were excluded. Made the conclusion that compounds with no affinity at concentrations of 10 μm and above are "inactive" and are denoted pKi "<5,0".

Bibliography

Determination of metabolic stability(in vitro)

Used the method in accordance with the procedures described DI, L. et al., Journal of Biomolecular Screening, Vol. 8, No. 4, 453-462 (2003).

6. PHARMACOLOGICAL DATA(see table 1-3)

Table 3
Stability in human liver homogenate/selected compounds
Connectiont ½ (minutes)
22V52
22G50
22J129
22L56
22O245
33F230
33G56
Xanomeline (standard)17

1. Heterocyclic compound of the formula (I)

where X2represents the balance of C-Z-R2 or C-R3, where Z represents NH or S;
- R1 is selected from the structures (a), (b) and (C)

- R2 is selected from (C1-C10)alkyl, (C1-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents, vibrancies halogen, cyano, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkoxy, purile and phenyl, where the phenyl group is optionally substituted with halogen; or
- R2 represents a non-branched (C2-C8)alkyl substituted by a group

where R1a represents the aforementioned group of formula (a);
- R3 is selected from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from (C5-C7) cycloalkyl and phenyl, where the phenyl group is optionally substituted with halogen;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where R2 is selected from (C1-C10) alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from halogen, cyano, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkoxy, purile and phenyl, where the phenyl group is optionally substituted with halogen.

3. The compound according to claim 2, where R2 is selected from (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)quinil, optionally independently substituted by one or more substituents selected from halogen, cyano, (C1-C6)is laksi, (C1-C4)alkoxy(C1-C4)alkoxy, tetrahydrofuranyl and phenyl, where the phenyl group is optionally substituted with halogen.

4. The compound according to claim 3, where R2 is selected from (C1-C8)alkyl, (C2-C6)alkenyl, optionally substituted by one or more halogen or (C1-C6)alkoxy.

5. The compound according to claim 1, where R3 is selected from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally substituted Deputy selected from (C5-C7)cycloalkyl or phenyl, where the phenyl group is optionally substituted with halogen.

6. The compound according to claim 1, where R1 has the structure (a).

7. The connection according to claim 6, where Z represents S.

8. A compound selected from
3-(4-pentyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-butyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-butylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(furan-2-elmersolver)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-butylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-(4-benzylmethyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(4,4,4-trifloromethyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
N-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-yl]butyramide,
3-(4-methylsulfanyl-1H-pyrazole-3-and the)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-propylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
butyl-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-yl]amine,
3-(4-intercultural-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-ethylsulfanyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-Butylochka-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-arylsulfonyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-ylsulphonyl]propionitrile,
3-[4-(3-methylbutanoyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(3-phenylpropoxy)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-hexylsilane-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-but-3-enyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-Gex-1-enyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-hept-1-inspirator-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-ethylsulfanyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
endo-6-(4-butylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane
3-(4-propylsulfonyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-(4-non-1-inyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-Gex-1-inyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-{4-[2-(3-forfinal)vinyl]-1H-pyrazole-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(5-cyclohexylidene-1-inyl)-1H-pyrazole-3-the l]-1,2,5,6-tetrahydro-1-methylpyridine,
bis-[3-(1-methyl-1,2,5,6-tetrahydropyridine-3-yl)-1H-pyrazole-4-yl]-2-sulfanilate]methane,
3-[4-(5-finalment-1-inyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-Oct-1-enyl-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(3-phenylpropylamine)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(4,4-deverbal-3-animalfunny)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(3-phenylalanyl)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-hexylsilane-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-(4-intercultural-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-[4-(3-methylbutanoyl)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane
3-(4-hexyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-pentyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-methylsulfanyl-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-[4-Penta-4-animalfunny)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-[4-(2-amoxicillan)-1H-pyrazole-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-heptyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-Penta-4-enyloxy-1H-pyrazole-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine,
3-(4-penicillanic-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-(4-pentyloxy-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-(4-butoxy-1H-pyrazole-3-yl)-1-azabicyclo[2.2.2]octane
3-(4-propoxy-1H-pyrazole-3-yl)-1-Isabel the lo[2.2.2]octane
3-[4-(4,4-deverbal-3-animalfunny)-1H-pyrazole-3-yl]-1-azabicyclo[2.2.2]octane
3-{4-[2-(2-methoxyethoxy)ethylsulfanyl]-1H-pyrazole-3-yl}-1,2,5,6-tetrahydro-1-methylpyridine, and
endo-6-(4-intercultural-1H-pyrazole-3-yl)-1-azabicyclo[3.2.1]octane
or their pharmaceutically acceptable salts.

9. The pharmaceutical composition intended for the treatment, mitigation or prevention of diseases and conditions mediated by muscarinic receptors, selected from Alzheimer's disease, cognitive impairment, disease, Sjogren's syndrome, schizophrenia, and for pain relief, containing the compound according to any one of claims 1 to 8 and a pharmaceutically acceptable auxiliary ingredients.

10. The use of compounds according to any one of claims 1 to 8 to obtain drugs for treatment, mitigation or prevention of diseases and conditions mediated by muscarinic receptors, selected from Alzheimer's disease, cognitive impairment, disease, Sjogren's syndrome, schizophrenia, and for pain relief.

11. The use of claim 10, where the muscarinic receptor is a M1 and/or M4.

12. The use of claim 10 or 11, where diseases and conditions represent a cognitive disorder, and schizophrenia.

13. Heterocyclic compound of the formula (II)

where X2* is a C-Z*R2* or C-R3*;
where Z* represents NH or S;
R* is selected from (C 1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)quinil, optionally independently substituted by one or more substituents selected from halogen, cyano, (C1-C6)alkoxy, (C1-C4)alkoxy(C1-C4)alkoxy, purile and phenyl, where the phenyl group is optionally substituted with halogen; or
- R2* is a non-branched (C2-C8)alkyl substituted by a group

where R1a represents the aforementioned group of formula (a),
defined in claim 1;
-R3* is selected from (C4-C10)alkyl, (C2-C10)alkenyl and (C2-C10)quinil, optionally independently substituted by one or more substituents selected from (C5-C7)cycloalkyl and phenyl, where the phenyl group is optionally substituted with halogen,
provided that the connection represents 2,6-debtor-N-(3-pyridin-3-yl-1H-pyrazole-4-yl) benzamide and N-(3-pyridin-3-yl-1H-pyrazole-4-yl)acetamide", she excluded.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: invention refers to the compound of formula(I) or to is salt where R1 is -H or C1-6 alkyl; R2 is bridged aza-ring chosen out of group including formula and where ring hydrogen atom in bridged aza-ring may be substituted by one or several groups of R22; m, n and p have respective values 1 or 2; r has the value 0 or 1; R21 is C1-6 alkyl, -C1-6 alkyl-O-phenyl or -C1-6 alkyl-phenyl; R22 is C1-6 alkyl-cycloalkyl or -C1-6 alkyl-phenyl; R2 is thienyl, phenyl, pyridyl, pyranzinyl, thiazolyl or pyrazolyl, each of which can be substituted by one or several R31; R31 is the halogen, -OH, -CN, -CF3, C1-6 alkyl or -O-C1-6 alkyl; ring A is the group consisting of thiophene, thiazole, isothiazole, thidiazole, oxazole, isooxazole, cyclohexan, norboran, benzothiophene and 5,6-dihydro-4H-cyclopentathiophene, each of which can be substituted by the group chosen out of the group consisting out of one or several RA1; where RA1 is a halogen, -CN, -NH2, C1-6 alkyl, -O-C1-6 alkyl, CONH2, - HN-C1-6 alkyl, -HN-C1-6 alkyl-O-C1-6 alkyl-phenyl, -HN-C1-6 alkyl-phenyl or -HN-C1-6 alkyl-OH where C1-6 alkyl can be substituted with one or several halogen atoms; V is -NH- or -O-; W is -(CH2)q-; q has the value 0.1 or 2; X is the counteranion and is an ordinary bond; on condition when in case ring A is cyclohexane, R3 is phenyl which can be replaced with one or several R31. The invention also refers to pharmaceutical composition that has antagonistic effect on muscarine receptor M3, on the basis of said compound.

EFFECT: production of new compound and pharmaceutical composition on its basis, which can be applied in the medicine as an active substance for preventive and/or therapeutic drug for treatment of inflammatory diseases such as chronic obstructive pulmonary disease (COPD), asthma and the like.

14 cl, 60 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described is a method of producing 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide by reacting 1-azabicyclo[2.2.2]oct-3(R)yl ether of 2-hydroxy-2,2-dithien-2-ylacetic acid and 3-phenoxypropyl bromide, where the reaction takes place in a solvent or mixtures of solvents, having boiling point ranging from 50 to 210°C and selected from a group comprising ketones and cyclic ethers, preferably in acetone, dioxane and tetrahydrofuran.

EFFECT: efficient method of obtaining the compounds.

12 cl, 8 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing (R)- quinuclidin-3-yl 6-((3S,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate or salt thereof, involving: 1) converting a compound which is 4-amino-3-methoxypiperidine-1-carboxylate to a salt; 2) converting the ethyl 4-amino-3-methoxypiperidine-1-carboxylate salt into ethyl 4-(diphenylamine)-3-methoxypiperidine-1-carboxylate 3) treating ethyl 4-(diphenylamino)-3-methoxypiperidine-1-carboxylate with hydroxide or hydride of an alkali metal to obtain 3-methoxy-N,N-diphenylpiperidine-4-amine 4) obtainijng a chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine by bringing 3-methoxy-N,N-diphenylpiperidine-4-amine into contact with a chiral splitting agent and extracting the obtained chiral salt of the cis-isomer of 3-methoxy-N,N-diphenylpiperidine-4-amine; optional recrystalisation of product 4; converting product 4 or 5 to a base to obtain product 4 or 5 in form of a free base; 7) bringing product 6 into contact with ethyl 6-bromohexanoate to obtain ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 8) esterification of ethyl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate using (R)-quinuclidin-3-ol with a Lewis acid to obtain (R)- quinuclidin-3-yl 6-((3S,4R)-4-(diphenylamine)-3-methoxypiperidin-1-yl)hexanoate 9) removing protection from the 4-amine group of product 8 to obtain (R- quinuclidin-3-yl 6- [(3S,4R)-4-amino-3-methoxypiperidin-1-yl)hexanoate; 10) acylation of product 9 4-amino-5-chloro-2-methoxybenzoic acid to obtain (R)- quinuclidin-3-yl 6-((38,4R)-4-(4-amino-5-chloro-2-methoxybenzamide)-3-methoxypiperidin-1-yl)hexanoate; 11) optional conversion of product 10 into a salt.

EFFECT: method increases output of the end product and reduces content of impurities.

7 cl, 3 ex, 6 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula I where X1-X4 each independently represent CR1, B represents -C(O)-O- or -C(O)-NH-CH2-, Y represents S or NH, R1 represents H, C1-C4alkoxy, unsubstituted or substituted by once or several times with F, or Het, and Het stands for heterocyclic group, fully saturated, partly saturated or fully unsaturated, containing in cycle 5-10 atoms, of which at least one atom represents N, O or S, unsubstituted or substituted once or several times with C1-C8alkyl, or to its pharmaceutically acceptable salt.

EFFECT: obtaining pharmaceutical composition for selective activation/stimulation of nicotine receptors α7 on the basis of said compound, as well as to their application for treatment of patient, suffering from psychotic disease, neurodegenerative disease, including cholinergic system dysfunction and/or condition of memory failure and/or failure of cognitive abilities.

52 cl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I in which A denotes X denotes O; R denotes H; R1 denotes OH, CN, a nitro group, NH2, NR2CSR8, NR2CONR2R9, NR2C SNR2R9, NR2SO2R10, NR2CONR6R7, NR2CSNR6R7, NR2R9, SO2R10, SOR10, alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 2-6 carbon atoms, alkynyl containing 2-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group in each case is unsubstituted or substituted with Ar or He, cycloalkenyl containing 5-8 carbon atoms, alkoxy group containing 1-4 carbon atoms, cycloalkoxy group containing 3-7 carbon atoms, cycloalkylalkoxy group containing 4-7 carbon atoms, fluorinated alkoxy group containing 1-4 carbon atoms, fluorinated hydroxyalkyl containing 1-4 carbon atoms, hydroxyalkoxy group containing 2-4 carbon atoms, an ordinary hydroxyalkoxy group containing 2-4 carbon atoms, monoalkylamino group containing 1-4 carbon atoms, dialkylamine group, where each alkyl group independently contains 1-4 carbon atoms, alkoxycarbonyl containing 2-6 carbon atoms, Het or OAr; R2 denotes H, alkyl containing 1-4 carbon atom, cycloalkyl containing 3-7 carbon atoms, and cycloalkyl alkyl containing 4-7 carbon atoms; R6 and R7 independently denote H, alkyl containing 1-4 carbon atoms, cycloalkyl containing 3-7 carbon atoms, or cycloalkylalkyl containing 4-7 carbon atoms, or R6 and R7 together denote an alkylene group containing 4-6 carbon atoms, which forms a ring with an N atom; R8 denotes alkyl containing 1-4 carbon atoms, fluorinated alkyl containing 1-4 carbon atoms, alkenyl containing 3-6 carbon atoms, alkynyl containing 3-6 carbon atoms, where each alkyl, fluorinated alkyl, alkenyl or alkynyl group is unsubstituted or substituted with Ar, cycloalkyl containing 3-7 carbon atoms, or Het; R9 denotes Ar or Het; R10 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar, or NR6R7; Ar denotes an aryl group containing 6-10 carbon atoms, which is unsubstituted or substituted once or several times with an alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, halogen, cyano group or combinations thereof; and Het denotes dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, isoxazolinyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl or naphthyridinyl, which is unsubstituted or substituted once or several times with halogen, aryl containing 6-10 carbon atoms, which is optionally substituted with alkyl containing 1-8 carbon atoms, alkoxy group containing 1-8 carbon atoms, oxo group, -CXR11 or combinations thereof, or R11 denotes alkyl containing 1-4 carbon atoms which is unsubstituted or substituted with Ar or Het; or pharmaceutically acceptable salts thereof, where formula IA is attached to the rest of the bonding molecule in the 3, 4 or 7 positions. The invention also relates to a pharmaceutical composition and to use of compounds in any of claims 1-37.

EFFECT: obtaining novel biologically active compounds, having nicotinic acetylcholine receptor subtype α7 ligand activity.

59 cl, 316 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I

in form of a salt, where R1 and R2 each independently denotes phenyl, where one or both R1 and R2 are substituted in one, two or three positions by the following groups: halogen, C1-C8alkyl or C1-C8alkoxy, and R3 is hydroxy, or R1 and R2 each denotes an unsubstituted phenyl, and R is hydrogen, C1-C8alkyl, C1-C8alkoxy or C1-C8alkylthio, or R1 is C3-C8cycloalkyl and R2 is phenyl or a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes oxygen and sulphur, and R3 is hydroxy, or -CR1R2R3 denotes 9-hydroxy- 9H-fluoren-9-yl or 9-hydroxy-9H-xanthen-9-yl, and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, optionally substituted with phenyl, or R1 and R2 each denotes an unsubstituted phenyl, and R3 is hydroxy and R4 is C1-C8alkyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen and R6 is 5-methyl-3-isoxazolyl or R1 and R2 each denote unsubstituted phenyl, and R3 is hydroxy and R4 is 1-ethyl substituted in one, two or three positions by a -CO-N(R5)R6 group, where R5 is hydrogen, R6 is a 5-member heterocycle containing at least one heteroatom in the ring selected from a group which includes nitrogen and oxygen, provided that the formula I compound is not (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrazin-2-ylcarbamoylmethy)-1-azoniumbicyclo[2.2.2]octane, (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide or (R)-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azoniumbicyclo [2.2.2]octane bromide. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-8, as well as to methods for synthesis of formula I compounds.

EFFECT: obtaining new biologically active compounds which have M3 muscarinic receptor mediated activity.

14 cl, 254 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat diseases mediated by the nicotinic acetylcholine receptor, such as derangement of memory. In general formulae , and A is an indazolyl, benzothiazolyl or isobenzothiazolyl group which corresponds to structural formulae a) to c) respectively or X is O; R1 is H, F, Cl, Br, I, cycloalkyl containing 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; ; R2 is H; R3 is H; R4 is H, F, Cl, Br, I, cycloalkyl which contains 3-7 carbon atoms, alkoxy which contains 1-4 carbon atoms, fluorinated alkoxy which contains 1-4 carbon atoms, Ar or Het; R5 is H; Ar is an aryl group containing 6 carbon atoms which is unsubstituted or substituted once or several times with halogen; and Het is a 5- or 6-member heteroaromatic group containing a heteroatom in the ring which is selected from N, O and S, or a 6-member saturated heterocyclic group which contains a heteroatom in the ring which is selected from N and O; and their pharmaceutically acceptable salts, where, if the said compound has formula I, the indazolyl group of group A is bonded through its 3rd, 4th or 7th position, the benzothiazole group of group A is bonded through the 4th or 7th position, the isobenzothiazole group of group A is bonded through the 3rd, 4th or 7th position.

EFFECT: obtaining compounds with properties of nicotinic acetylcholine receptor (nAChR) ligands, and pharmaceutical compositions based on the said compounds.

53 cl, 95 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula , where B represents a hydrogen atom or a group selected from -R1, -OR1, hydroxy, - O(CO)R1, cyano and non-aromatic heterocycle which is a saturated or unsaturated C3-C10carbocyclic ring in which one or more carbon atoms, preferably 1 or 2 carbon atoms, are substituted with oxygen atoms as heteroatoms, where R1 is selected from a group containing hydrogen atoms, C1-C8alkyl, C2-C8alkenyl and C3-C8cycloalkyl, where the alkyl group is unsubstituted or substituted with one or more substitutes selected from halogen atoms and C1-C4alkyl, and where the alkenyl group is unsubstituted or substituted with one or more substitutes selected from C1-C4alkyl, n equals an integer from 0 to 4, A is selected from a group containing -CH2-, -CH=CR3-, -CR3=CH-, -CR3R4-, -O-, -CO-, -O-(CH2)2-O-, where R3 and R4 each independently represents a hydrogen atom or C1-C8alkyl, m equals an integer from 0 to 8, p equals 2, and the bicyclic azonium ring contains a substitute on position 3, including all possible configurations of asymmetrical centres, D is selected from a group containing: or where R5 is selected from a group containing phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, R6 is selected from a group containing 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, C3-C8cycloalkyl, C1-C8alkyl, C2-C8alkenyl and phenylethyl, R7 represents a hydrogen atom or a group selected from hydroxyl, hydroxymethyl and methyl, Q represents a single bond or a group selected from -CH2-, -CH2CH2-, -O-, -O-CH2-, equals an integer from 0 to 3, X represents a pharmaceutically acceptable anion of mono- or polybasic acid, under the condition that the B-(CH2)n-A-(CH2)m- group does not represent a straight C1-4alkyl and that the following compounds are excluded: 1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo[2.2.2]octane and 1-carboxymethyl-3-(2-hydroxy-2,2-dithiophen-2-ylacetoxy)-1-azoniumbicyclo [2.2.2]octane. The invention also relates to a method of producing formula (I) compounds, to a pharmaceutical composition, to use of compounds in any of paragraphs 1-14, as well as a combined product.

EFFECT: obtaining novel biologically active compounds with antagonistic activity towards muscarine receptors M3.

21 cl, 64 ex

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

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: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): , where: R1 is selected from -ORa, -C(O)NRaRb, -NHS(O)2Rc, -C(O)ORa; A means C1-4alkylenyl; R2 means C3-12cycloalkyl or C6-10aryl which is optionally substituted by one -ORa, one or two halogen atoms, one or two C1-3alkyls substituted by two or three halogen atoms; or one, two, three or four C1-3alkyls; G means C1-4alkylenyl; R3 is selected from hydrogen, -C(O)R4, -C(O)NHR5, -S(O)2Rc and -S(O)2NRaRb; R4 means C3-6cycloalkyl or C1-6alkyl, C3-6cycloalkyl is optionally substituted by one -ORa, and C1-6alkyl is optionally substituted by one or two substitutes selected from -ORa, -C(O)ORa, -S(O)2R6, -C(O)NRaRb, -NRaRb, -CN, C3-6cycloalkyl and phenyl; or by one -D-(CH2)j-R7 where D means , j is equal to 1, n is equal to 1 or 2; R6 means C1-3alkyl optionally substituted by R7; R7 means -C(O)ORa; R5 means C1-6alkyl, benzo[1.3]dioxole or -(CH2)q-phenyl; where phenyl is optionally substituted by one or two substitutes selected from halogen, -ORa, C1-3alkiyl and C1-3alkoxy where C1-3alkyl and C1-3alkoxy optionally substituted by 2 or 3 halogen atoms, and q is equal to 0, 1; Ra and Rb independently mean hydrogen or C1-4alkyl; and Rc means C1-3alkyl; provided when R2 means phenyl substituted in position 4, R3 is not -C(O)R4 where R4 means C1-4alkyl substituted by C(O)ORa; to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, to a method of preparing the compound of formula (I), to compounds of formula (II), (III), to application of the compounds on any claim 1-14, to a method of analysing a biological system or a sample containing a mu-opioid receptor, and also to a method of treating a mammal suffering a disease caused by mu-opioid receptor activity.

EFFECT: production of the new biologically active compounds exhibiting mu-opioid receptor antagonist activity.

26 cl, 204 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new tartrate salts of (1R,2R,3S,5S)-2-methoxymethyl-3-(3,4-difluorophenyl)-8-azabicyclo[3.2.1]octane, such as L-tartrate monohydrates and anhydrates.

EFFECT: application as inhibitors of monoamine neurotransmitter reuptake.

8 cl, 8 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 8-ethyl-6,7-fullero[60]-3-oxa-8-azabicyclo[3.2.1]octane of the general formula (1): . Method involves interaction of fullerene[60] with N-ethylmorpholine in the mole ratio fullerene-C60 : N-ethylmorpholine = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% with respect to fullerene[60], in toluene medium as a solvent at temperature ˜20°C for 18-30 h. The yield of the end product is 73-90%. Synthesized compound can be used as chelating agent, sorbent, biologically active compound and in creature of novel materials with desired electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry.

SUBSTANCE: claimed method includes reaction of C60-fullerene with dipiperidine methane in presence of Cp2TiCl2 as catalyst in toluene medium at room temperature (approximately 20°C) for 15-25 hours. Yield of target product is 70-90 %. Compound of present invention is useful as chelating agent, sorbent, biologically active compound and for production of new materials with desired electronic, magnetic and optical properties. .

EFFECT: new compound; method of increased yield and selectivity.

1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

The invention relates to 2-substituted 4,5-dailyedition General formula (I), where R1- 4-pyridyl; R2- phenyl, naphthas-1-yl or naphthas-2-yl, which optionally can contain up to 5 substituents selected from halogen; R3is hydrogen; R4- pyridyl, optionally substituted with halogen or amino group

The invention relates to new derivatives of 8-azabicyclo[3.2.1]Octan-3-methanamine in the form of pure geometric-isomers of General formula I, where U represents the formula (A) or (B) in which V is hydrogen or halogen, (C1-C3)alkyl group or one or two (C1-C3)alkoxygroup, W and X each represents either two oxygen atom or the oxygen atom and the group CH2or the group CH2and the oxygen atom or the oxygen atom and the group WITH n = 0 or 1, R is through the band when U denotes the formula (a), or hydrogen or (C1-C3)alkyl, when U denotes the formula (I), Y represents one or more atoms or a group comprising hydrogen, halogen and t

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula I wherein the substitutes A, B, B', Q and R1-R5 in formula I are specified as follows: A and B' are one of the following groups: (i) (R6)N(CH2)n, wherein n is 0 or 1; (ii) (CH2)n, wherein n is 0, 1 or 2; (iii) C(O)(CH2)n, wherein n is 0 or 1; or provided each of A and B' represents nitrogen, together they can form a bivalent radical of formula: -(CH2)s-X1-(CH2)t- (a), wherein each s and t is independently 1 or 2, and X1 represents (CH2)n, wherein n is 0 or 1; B is one of the following groups: (i) (R6)N; (ii) oxygen; (iii) C=δ, wherein δ represents oxygen or sulphur; (iv) C(R6)=C(R7); each R6 and R7 independently represent hydrogen, C1-4-alkyl; R1 is specified in the following groups: (i) phenyl group substituted by one or more substitute such as: - halogen specified in F, CI, Br or I, or alkyl1 group; aryl1 or heteroaryl group1; cyano, NH-alkyl1, N(alkyl1)(alkyl1) and amino; - NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl group, or (ii) pyridinyl group which can be substituted by one substitute, such as halogen specified in I, F, Cl or Br; alkyl1 group; aryl1 group; cyano, NH-alkyl1, N(alkyl1)(alkyl1), and amino; -NHCO-R or NHCOO-R, or COO-R, or CONH-R, wherein R represents hydrogen or alkyl1 group; each R2, R3, R4 and R5 are independently specified in hydrogen or linear or branched alkyl group containing 1 to 10 carbon atoms; Q is specified in the following groups: (i) alkyl1; (ii) aryl1; (iii) heteroaryl1. The compounds of formula (I) are used for preparing a drug showing the c-kit inhibitor properties and aiming at treating a disease specified in neoplastic, allergic, inflammatory and autoimmune diseases.

EFFECT: use of oxazole derivatives as tyrosine kinase inhibitors.

13 cl, 1 tbl, 31 ex

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