Method for treatment allergy by using substituted pyrazoles

FIELD: organic chemistry, medicine, allergology.

SUBSTANCE: invention relates to a method for treatment of allergy by administration to patient the therapeutically effective dose of a pharmaceutical composition comprising compound of the formula (I) . Invention provides the enhanced effectiveness of treatment.

EFFECT: improved treatment method.

7 cl, 3 dwg, 49 ex

 

The scope of the invention

This invention relates to the use of substituted pyrazoles for the treatment of allergic diseases.

Background of invention

Atopic Allergy affects at least 20% of the population in developed countries and includes a wide range of IgE-mediated diseases such as hay fever, asthma, atopic dermatitis and food allergies. The impact on the subject of allergies, relevant allergens leads to cross-linking of allergen-specific IgE connection with fat cells, initiating the degranulation and the release of proinflammatory mediators, such as histamine and eicosanoids that cause a reaction welfare-and-signal in the skin test. Usually, for this early response followed by long late reaction, in which inflammatory cells, particularly eosinophils and activated T-2 CD4 T cells, are involved in the location allergic effect. Inflammatory cytokines, such as IL-4 and IL-5, both produced by TH-2 cells, important for the production of IgE by b-cells and eosinophilia, respectively. It was shown that immunotherapy, targeted to CD4 T cells, is effective to reduce the production of IgE, activation of Pro-inflammatory cells and release of inflammatory mediators.

Leche is of allergies at the present time, focused on CD4 T cells, has mixed success. To reduce the sensitivity using allergenic extracts or vaccine is effective in the case of many allergens such as insect bites Hymenoptera, which can cause life-threatening allergic reactions. The mechanism may be induction of tolerance in T-cells, or transformation TN-2 TN-1. However, such treatment requires prolonged treatment, frequent doctor visits and pre-stabilization with the use of other drugs and is associated with some degree of pain and rare deaths. Alternatively, immunosuppressive drugs such as steroids, which effectively stabilize the beginning allergic response, often associated with serious side effects.

Activation of CD4 T cells is a major factor in initiating and maintaining allergic reactions. The allergens are absorbed by specialized antigen-presenting cells (APCs)such as dendritic cells and b cells. Protein allergens pass through endosomal and lysosomal system, where they are destroyed by various proteases. Such peptide fragments bound molecules MHC class II on the cell surface are heteros who trimeric complexes, consisting of two transmembrane glycoprotein chains (α and β), which form a connecting support for the third component of the peptide from amino acids 11-20. The complex antigen-a molecule MHC class II is recognized by CD4 T-cells and leads to activation of T cells. Activated T-cells, in turn, activates several other components of the immune system such as b cells and macrophages, which are key to the response of the body against pathogens, but also lead to Allergy symptoms.

Molecules of class II, like other transmembrane proteins, are moved in the endoplasmic network (ER) after synthesis, where they are associated with a third protein, the invariant chain (Ii). Invariant chain molecule is a transmembrane protein type II, which serves as the class II-specific companion, promoting the release of complexes of class II-Ii of the ER and does not allow binding of class II molecules with peptides and deployed proteins in the ER and the secretory pathway. Tselenapravlennoi motif in the cytoplasmic tail of Ii sends complexes of class II-Ii of the secretory pathway in endosomal system.

Before molecules MHC class II can be an antigen, Ii must be removed by a number of proteases that otscheplaut Ii. End Ii peptide fragments, called class II-associated invariant is Anya peptides (CLIP), take the place of the peptide binding to class II molecules and in most cases not spontaneously released. CLIP protects the connecting area of class II from clotting during intracellular transport, and after the second destruction in endosomal system. The binding of antigenic peptides generated from endocytotic proteins, requires a free and already open binding site. Consequently, the CLIP must be released at a time when an open binding site stabilized to give the ability to bind to other peptides. Leucocytes antigen human-DM ("HLA-DM") mediates both such functions promotora thus the binding of antigenic peptides. After binding of peptides to class II molecules are transported to the cell surface through a path that is mostly not known.

Taking the above into account, the inhibition of proteolysis of invariant chain will prevent deleting Ii from connecting zone class II, which, in turn, will specifically block the binding of antigen molecules MHC class II.

Cathepsin S (CatS) is cysteinate expressed in lymphatic tissues. CatS mediates proteolysis of invariant chain, which is a prerequisite for peptide loading of class II molecules (Riese et al. (1996) Immunity 4:357). CatS has 50-60% homology with KATEP the ins L and K, but it differs from them in that it has a broad pH optimum, which is extended in the alkaline pH region. CatS modulates antigen demonstration in animal models, and inhibitors are effective in models of asthma (Riese et al. (1998) J.Clin.Invest. 101:2351). Cathepsin S-deficient mice have impaired ability to present exogenous proteins by professional antigen-presenting cells (Nakagawa et al (1999) Immunity 10:207; Shi et al. (1999) Immunity 10:197).

It is assumed that compounds that inhibit the proteolytic activity of cathepsin S may find use for the treatment of chronic autoimmune diseases, including, but not limited to, lupus and rheumatoid arthritis; and are potentially useful for modulating the immune response to tissue transplantation. Methods of modulating autoimmunity using an agent that modulates the activity of cathepsin S, for example, proteolysis of Ii chain, as well as methods of treatment of a subject having an autoimmune disease, assessment methods of treatment for its ability to modulate the immune response described in WO 99/58153.

Connection, in some way similar to the compounds of the present invention, are described in the following references.

Winters and others ((Winters G., Sala, A., Barone D., Baldoli E. J.Med.Chem., 1985, 28, 934-940; Singh, P., Sharma R.C., Quant. Struct. -Act. Relat. 1990, 9, 29-32; Winters, G., Sala, A., Barone D. in U.S. patent 4500525 (1985)) was described by bizik the practical pyrazoles shown below type. Deputy R never contains a heterocyclic ring, and these molecules does not prescribe any inhibitory activity against protease; they are described as modulators α1-adrenergic receptors.

Shutske, etc. described below bicyclic pyrazoles. In their system the pyridine ring is aromatic (Shutske G.M., Kapples K.J., Tomer J.D. U.S. Patent 5264576 (1993)). Another link belongs to R, which is the linker for heterocycle, the claims indicates only R=hydrogen. Compounds are mentioned as inhibitors of serotonin reuptake.

The compound 2-[4-[4-(3-methyl-5-phenyl-1H-pyrazole-1-yl)butyl]-1-piperazinil]pyrimidine known from EP-382637, which describes the pyrimidines with anxiolytic properties. This compound and its analogues are additionally described in EP-502786 as cardiovascular agents and agents in respect of the Central nervous system. Pharmaceutical drugs such compounds are described in EP-655248 for use in the treatment of gastric secretion and as antiulcer agents. In WO 9721439 described medicines such compounds for the treatment of obsessive-compulsive disorders, apnea (apnea) during sleep, sexual disorders, vomiting and motion sickness.

is soedineniya 5-methyl-3-phenyl-1-[4-(4-phenyl-1-piperazinil)butyl]-1H-indazole and 5-bromo-3-(2-chlorophenyl)-1-[4-(4-phenyl-1-piperazinil)butyl]-1H-indazol, in particular cleaners containing hydrochloride salt, is known from WO-9853940 and SA:314528, where data and similar compounds are described as inhibitors of the kinase in the first link, and as having affinity to benzodiazepine receptors in the last link.

Summary of the invention

The object of the present invention is the use of inhibitors of cathepsin S for the treatment of allergic diseases, including, but not limited to, atopic Allergy. Examples of allergic disorders include hay fever, asthma, atopic dermatitis and food allergies. Allergens include dust, pollen, mold and pet allergies or pet hair.

In one aspect the present invention relates to a method of treatment of a subject suffering from allergic diseases, particularly atopic allergic diseases, which includes the introduction of a specified subject a therapeutically effective amount of a pharmaceutical composition comprising an inhibitor of cathepsin S.

In another aspect, the present invention relates to a method of treatment of a subject suffering from IgE-mediated allergic diseases, particularly atopic allergic painful condition, which includes the introduction of a specified subject therapeutically effective amounts of the pharmaceutical composition, including the inhibitor of cathepsin S.

In the third aspect of the invention relates to the use of or applying to obtain a drug inhibitor of cathepsin S for the treatment of allergic diseases, more particularly for the treatment of IgE-mediated allergic diseases, more particularly for the treatment of hay fever, asthma, atopic dermatitis or food allergies. The invention also relates to anti-allergic pharmaceutical compositions comprising as active ingredient an effective amount of an inhibitor of cathepsin S and a pharmaceutically acceptable carrier. The active ingredient can be introduced into the composition of the medicinal product in any way that is appropriate to specific allergic diseases, including aerosol, oral and local drugs and medicines slow release.

The present invention relates to the treatment of allergic diseases with the use of one or more compounds which can be represented by the formula (I):

where

R1represents hydrogen, azido, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, C2-5alkenyl, cyano, nitro, R7R8N2-8acyl, R9OC=O, R10R11NC=O or R10R11NSO2or R1taken together with W, as described below;

R2represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, C2-5alkenyl,1-5halogenated, cyano, or R48R49N;

alternative, R1and R2can be taken together with education optionally substituted 5-7-membered carbocyclic or heterocyclic ring, this ring may be unsaturated or aromatic;

each R3and R4independently represents hydrogen or C1-5alkyl;

each R5and R6independently represents hydrogen, C1-5alkyl, C2-5alkenyl,1-5alkoxy, C1-5alkylthio, halogen, or 4-7-membered carbocyclic or heterocyclyl;

alternative, R5and R6can be taken together with education optionally substituted 5-7-membered carbocyclic or heterocyclic ring, this ring may be unsaturated or aromatic, and optionally may be substituted by one to three substituents, independently selected from halogen, cyano, amino, nitro, R40, R40O-, R40S-, R40O(C1-5alkylen), R40O(C=O)-, R40(C=O)-, R40(C=S)-, R40(C=O)O-, R40O(C=O)(C=O)-, R40SO2, Other62(C=NH)-, other62SO2and other62(C=O)-;

R40represents H, C1-5alkyl, C2-5alkenyl, Anil, benzyl, phenethyl,1-5heterocyclyl, (C1-5heterocyclyl)1-5alkylene, amino or mono - or di(C1-5alkyl)amino, or R58OR59-where R58represents H, C1-5alkyl, C2-5alkenyl, phenyl, benzyl, phenethyl,1-5heterocyclyl or (C1-5heterocyclyl)1-6alkylene, and R59represents a C1-5alkylene, phenylene, or divalent1-5heterocyclyl; and

R62can represent N in addition to the values for R40;

R7represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, naphthyl,1-5heterocyclyl,2-8acyl, aroyl, R27OC=O, R28R29NC=O, R27SO, R27SO2or R28R29NSO2;

R8represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl or1-5heterocyclyl;

alternative, R7and R8can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

R9represents a C1-5alkyl, phenyl, naphthyl or1-5heterocyclyl;

R21represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, naphthyl,1-5heterocyclyl,2-8acyl, aroyl, R30OC=O, R31, R 32NC=O, R30SO, R30SO2or R31R32NSO2;

R22represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl or1-5heterocyclyl;

alternative, R21and R22can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

each R23, R26, R27, R30, R33, R44, R45and R50represents a C1-5alkyl, phenyl, naphthyl or1-5heterocyclyl;

R24represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, naphthyl,1-5heterocyclyl,2-8acyl, aroyl, R33OC=O, R34R35NC=O, R33SO, R33SO2or R34R35NSO2;

R25represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl or1-5heterocyclyl;

alternative, R24and R25can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

each R10and R11independently represents hydrogen, C1-5alkyl, C2-5alkenyl, phenyl or1-5heterocyclyl;

alternative, R10and R11

each R28, R29, R31, R32, R34, R35, R46, R51and R52independently represents hydrogen, C1-5alkyl, phenyl or1-5heterocyclyl;

alternative, R28and R29, R31and R32,R34and R35, R46and R47orR51and R52independentlycan be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

n is 1 or 2;

G represents a C3-6alkerdeel or3-6alcander, optionally substituted hydroxy, halogen, C1-5the alkyl, C1-5alkoxy, oxo, hydroxyimino, CO2R60, R60R61NCO2, (L)-C1-4alkylene, (L)-C1-5alkoxy, N3or [(L)-C1-5alkylene]amino;

each R60and R61independently represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, benzyl, phenethyl or1-5heterocyclyl;

alternative, R60and R61can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

L t is made by an amino, mono - or di-C1-5alkylamino, pyrrolidinyl, morpholinyl, piperidinyl, homopiperazine or piperazinil, where available ring nitrogen atoms can be optionally substituted C1-5by alkyl, benzyl,2-5the acyl, C1-5alkylsulfonyl or1-5alkoxycarbonyl;

X represents nitrogen or R12C;

Y represents nitrogen or R13C;

Z represents nitrogen or R14C;

R12represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, C2-5alkenyl, cyano, nitro, R21R22N, C2-8acyl, C1-5halogenated,1-5heterocyclyl, (C1-5heterocyclyl)1-5alkylene, R23OC=O, R23O(C=O)NH-, R23SO, R22NHCO-,, R22NH(C=O)NH-, R23(C1-4alkylen)NHCO-, R23SO2or R23SO2NH-;

R13represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, C2-5alkenyl, cyano, nitro, R42R43N, C2-8acyl, C1-5halogenated,1-5heterocyclyl, (C1-5heterocyclyl)1-5alkylen R44OC=O, R44O(C=O)NH-, R44SO, R43NHCO-, R43NH(C=O)NH-, R44(C1-4alkylen)NHCO-, R44SO2or R44SO2NH-;

R14represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, C2-5alkenyl, cyano, nitro, R24 R25N, C2-8acyl, C1-5halogenated,1-5heterocyclyl, (C1-5heterocyclyl)1-5alkylen R26OC=O, R26O(C=O)NH-, R26SO, R25NHCO-, R25NH(C=O)NH-, R26(C1-4alkylen)NHCO-, R26SO2or R26SO2NH-;

alternative, R12and R13or R12and R2orR13and R14can be taken together with education optionally substituted 5-6-membered carbocyclic or heterocyclic ring, this ring may be unsaturated or aromatic;

Ar represents a monocyclic or bicyclic aryl or heteroaryl ring, optionally substituted by 1-3 substituents selected from halogen, C1-5alkoxy, C1-5of alkyl, C2-5alkenyl, cyano, azido, nitro, R15R16N, R17SO2, R17S, R17SO, R17O(C=O), R15R16NC=O1-5halogenoalkane,1-5halogenoalkane,1-5allogenicity and C1-5alkylthio;

R15represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, benzyl, C1-5heterocyclyl,2-8acyl, aroyl, R53OC=O, R54R55NC=O, R53S, R53SO, R53SO2or R54R55NSO2;

R16represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, benzyl what I 1-5heterocyclyl;

alternative, R15and R16can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

each R17and R53represents a C1-5alkyl, phenyl or1-5heterocyclyl;

each R54and R55independently represents hydrogen, C1-5alkyl, C2-5alkenyl, phenyl, benzyl or1-5heterocyclyl;

alternative, R54and R55can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

W represents the SO2, C=O, CHR20or a covalent bond; or W and R1taken together with 6-membered ring, to which both are attached, form one of the two following formulas:

where Xandrepresents O, S or N; and Xbrepresents O, S or SO2;

R20represents hydrogen, C1-5alkyl, phenyl, benzyl, naphthyl or1-5heterocyclyl;

R42represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, naphthyl,1-5heterocyclyl,2-8acyl, Arai is, R45OC=O, R46R47NC=O, R45SO, R45SO2or R46R47NSO2;

R43represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl or1-5heterocyclyl;

alternative, R42and R43can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

R44represents a C1-5alkyl, C2-5alkenyl, phenyl, naphthyl or1-5heterocyclyl;

R48represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl, naphthyl,1-5heterocyclyl,2-8acyl, aroyl, R50OC=O, R51R52NC=O, R50SO, R50SO2or R51R52NSO2;

R49represents hydrogen, C1-5alkyl, C3-5alkenyl, phenyl or1-5heterocyclyl;

alternative, R48and R49can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic; and

where each of the above hydrocarbon or heteroplastic groups, unless otherwise specified, and, in addition to any specific substituents, optionally and independently substituted by 1-3 substituents, chosen is different from methyl, halogenmethyl, hydroxymethyl, halogen, hydroxy, amino, nitro, cyano, C1-5of alkyl, C1-5alkoxy, -COOH, C2-6acyl, [di(C1-4alkyl)amino]2-5alkylene, [di(C1-4alkyl)amino]2-5alkyl-NH-CO - and C1-5halogenoalkane;

or its pharmaceutically acceptable salt, amide or ether complex, including their stereoisomeric form.

The described compounds are inhibitors of the proteolytic activity of human cathepsin S with high affinity binding. For use in medicine may be desirable to obtain pharmaceutically acceptable salts of compounds of formula (I).

Some compounds of the present invention can have one stereogenic atom and can exist as two enantiomers. Some compounds of the present invention can have two or more stereogenic atoms and, optionally, can exist as diastereomers. Professionals in this field should be understood that all such stereoisomers and mixtures thereof in any ratio included in the scope of the present invention.

Another aspect of the present invention relates to pharmaceutical anti-allergic composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. An additional variant embodiment of the invention is a JV is a way to obtain anti-allergic pharmaceutical composition, includes mixing the compounds described above, with a suitable pharmaceutically acceptable carrier.

The invention also covers pharmaceutical compositions comprising more than one compound of formula (I) and compositions comprising the compound of formula (I) and the other pharmaceutically active agent.

Another object of the invention is a method of treating allergic diseases or conditions mediated by the enzyme cathepsin S, in need thereof of a subject, comprising administration to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above. With the introduction of more than one active agent is a therapeutically effective amount may be a jointly effective amount. These compounds inhibit protease activity of human cathepsin S, an enzyme involved in the immune response. In preferred embodiments, the implementation of the inhibition of cathepsin S is selective. As such described compounds and compositions can be used for prevention, inhibition or treatment of allergic diseases such as atopic allergic diseases.

Additional features and advantages of the invention will be apparent and the following detailed description and examples, and appended claims.

Brief description of drawings

Figure 1 shows the inhibition of proliferative responses of T-cells of two types-dust mite, Der p and Der f. The upper chart, figa: Curve breeding for purified RUMS from an allergic donor under cultivation with titrated doses of allergenic extracts prepared from Der p and Der f, within seven days. Proliferation of T cells was evaluated in points by measuring implementation3H-thymidine for 18 hours at the end of cultivation. The lower chart, figw: the Effect of titrated doses of LHVS on the proliferative response of T cells to extracts of dust mites.

Figure 2 shows the inhibition of proliferative responses of T cells to ragweed, but not ConA, using LHVS. The upper chart, figa: Curve breeding for purified RUMS from an allergic donor under cultivation with titrated doses of allergenic extracts prepared from short Ragweed and giant Ragweed within seven days. Proliferation of T cells was evaluated in points by measuring implementation3H-thymidine for 18 hours at the end of cultivation. The lower chart, figw: the Effect of titrated doses of LHVS on the proliferative response of T cells to extracts of ambrosia.

Figure 3 shows the inhibition of proliferative responses of T-cle is OK man on Der f, but not Con A, two inhibitors of cathepsin S, the compounds of example 11 (figa) and example 36 (pigv). Purified RUMS from an allergic donor were cultured with extracts of allergens prepared from Der f in the presence of titrated doses of these compounds within seven days. Proliferation of T cells was evaluated in points by measuring implementation3H-thymidine for 18 hours at the end of cultivation.

Detailed description of the invention

The purpose of the present invention was to determine, does inhibition of cathepsin S in the presence of certain antigens in the human system. According to the invention, it is now established that inhibitors of cathepsin S block the presence of several crude allergenic extracts in humans in the analysis of ex vivo, confirming, thus, the usefulness of inhibitors of cathepsin S for the treatment of allergic diseases.

Block Ii decomposition should reduce the presence of antigen to CD4 T cells and disrupt the normal immune response. Inhibitor of cathepsin S has a specific influence on the activation of CD4 T cells, thereby limiting the degree of concomitant immunomodulary, unwanted side effects of corticosteroid therapy.

When using inhibitors of cathepsin S in accordance with the methods of the present and the gaining of immunological component allergic reactions can be blocked to varying degrees, having the advantage compared to modern therapy which greater selectivity, and low or reduced side effects, or both. The present invention is based in part on the discovery of the fact that inhibitors of cathepsin S may block the presence of untreated allergenic extracts from human ex vivo analysis. This ex vivo system closely mimics the process that occurs throughout the body, when antigens enter the circulatory system and represented by antigen-presenting cells, which, in turn, activate CD4 T cells. In the case of treatment of a subject an inhibitor or metabolite will also be present in the blood, as in the analysis of ex vivo.

The object of the invention is the treatment of allergic diseases with the use of pyrazole compounds of formula (I).

A. Terms

The following terms used in the description are defined below.

"Alkyl" includes optionally substituted linear or branched hydrocarbon having at least one remote hydrogen with the formation of radical groups. Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl, isopentyl, sec-pentyl, hexyl, heptyl, octyl and the like. Alkyl includes cycloalkyl, such as cyclopropyl, cyclobutyl, the Cyclops is Teal, and cyclohexyl.

"Alkenyl" includes optionally substituted linear and branched hydrocarbon radicals, as defined above, having at least one carbon-carbon double bond (sp2). Alkenyl include ethynyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), Isopropenyl (or 1-methylvinyl), but-1-enyl, but-2-enyl, butadienyl, pentenyl, hexa-2,4-dienyl and the like. Hydrocarbon radicals, with the combination of double bond and triple connections, such as 2-penten-4-inyl included in this description to define alkinyl. Alkenyl includes cycloalkenyl. CIS - and TRANS - or (E)- and (Z)forms are included in this invention.

"Quinil" includes optionally substituted linear and branched hydrocarbon radicals, as defined above, having at least one carbon-carbon triple bond (sp). Alkinyl include ethinyl, propinyl, butinyl and pentenyl. Hydrocarbon radicals, with the combination of double bond and triple connections, such as 2-penten-4-inyl included in this description to define alkinyl. Quinil does not include cycloalkenyl.

"Alkoxy" includes optionally substituted linear or branched alkyl group with a terminal oxygen, alkyl linking group with the remainder of the molecule. Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentox and such is haunted. "Aminoalkyl", "thioalkyl" and sulfonylated" similar CNS group, with the terminal oxygen atom in the alkoxy substituted respectively for the NH (or NR), S and SO2. Heteroalkyl includes alkoxy, aminoalkyl, thioalkyl and the like.

"Aryl" includes phenyl, naphthyl, biphenylyl, tetrahydronaphthyl and the like, each of which optionally can be substituted. Aryl also includes arylalkyl groups such as benzyl, phenethyl and phenylpropyl. Aryl includes ring system containing optionally substituted 6-membered carbocyclic aromatic ring, this system can be bicyclic, bridged and/or condensed. The system may include rings that are aromatic or partially or completely saturated. Examples of ring systems include indenyl, pentalene, 1,4-dihydronaphtho, indanyl, benzimidazolyl, benzothiophene, indolyl, benzofuranyl, ethenolysis and the like.

"Heterocyclyl" includes optionally substituted aromatic and non-aromatic rings having carbon atoms and at least one heteroatom (O, S, N) or heteroatomic fragment (SO2, CO, CONH, COO) in the ring. Unless stated otherwise, the heterocyclic radical can have a valence, linking it with the rest of the molecule through a carbon atom, for example, 3-furyl or 2-imidazolyl, or through Goethe what oatom, for example, N-piperidyl or 1-pyrazolyl. Preferably monocyclic heterocyclyl contains from 4 to 7 ring atoms, or from 5 to 6 ring atoms; the ring can be from 1 to 5 heteroatoms or heteroatomic fragments and preferably from 1 to 3. Heterocyclyl may be saturated, unsaturated, aromatic (e.g., heteroaryl), non-aromatic or condensed.

Heterocyclyl also includes condensed, for example bicyclic ring, such as optionally condensed with an optionally substituted carbocyclic or heterocyclic five - or six-membered aromatic ring. For example, "heteroaryl" includes optionally substituted six-membered heteroaromatic ring containing 1, 2 or 3 nitrogen atom, condensed with an optionally substituted five - or six-membered carbocyclic or heterocyclic aromatic ring. Specified heterocyclic five - or six-membered aromatic ring condensed with the specified five - or six-membered aromatic ring may contain 1, 2 or 3 nitrogen atom, when it is a six-membered ring, or 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulphur, when it is five-membered ring.

Examples heterocyclyl include thiazolyl, furyl, pyranyl, isobenzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, isot azolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolyl, indazoles, purinol, hinely, furutani, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, piperidyl, piperazinil, indolinyl and morpholinyl. For example, the preferred heterocyclyl or heterocyclic radicals include morpholinyl, piperazinil, pyrrolidinyl, pyridyl, cyclohexylamino, cycloheptylamine and, more preferably, piperidyl.

Examples illustrating heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, benzothiazyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl.

"Acyl" refers to a carbonyl relates or an atom of hydrogen (i.e. formyl group) or optionally substituted alkyl or alkenylphenol chain, or heterocyclyl.

"Halo" or "halogen" includes fluorine, chlorine, bromine and iodine, and preferred as the substituent chlorine or bromine.

"Alcander" or "alkylene" represents a linear or branched optionally substituted divalent alkanoyl radical such as, for example, methylene, ethylene, propylene, butylene, pentile or hexylen.

"Alcander" represents, as described above, linear or branched optionally substituted divalent and is kenawy radical, such as, for example, propylen, butylen, penttinen or hexarelin. In these radicals, the carbon atom linking the nitrogen, preferably should not be unsaturated.

"Aroyl" refers to a carbonyl group linked with optionally substituted aryl or heteroaryl group, where the aryl or heteroaryl have the above values. In particular, benzoyl represents phenylcarbinol.

As defined herein, two radicals together with the atom(s)to which they are attached, can form an optionally substituted 4-7-, 5-7 or 5-6-membered carbocyclic or heterocyclic ring, this ring may be saturated, unsaturated or aromatic. These rings can be as defined above in the section "Summary of the invention". Specific examples of such rings such as shown in the next section.

"Pharmaceutically acceptable salts, esters and amides" include carboxylate salts (e.g., With1-8alkyl, cycloalkyl, aryl, heteroaryl or nonaromatic heterocyclic), amino acid additive salts, esters and amides, which have the proper ratio of benefit/risk, are pharmacologically effective and suitable for contact with the tissues of patients without excessive toxicity, irritation, or CTE is Noah allergic reactions. Examples of salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate and laurylsulphate. These may include cations of the alkali metal and alkaline earth metal such as sodium, potassium, calcium and magnesium, as well as non-toxic ammonium cations, Quaternary ammonium and amine, such as tetraethylammonium, methylamine, trimethylamine and ethylamine. See, for example, the publication S.M.Berge et al., "Pharmaceutical Salts (Pharmaceutical salts)", J.Pharm.Sci., 1977, 66:1-19, included in this description by reference. Examples of pharmaceutically acceptable amides of the invention include amides which are derived from ammonia, primary1-6alkylamines followed and secondary di(C1-6alkyl)amines. Secondary amines include 5 - or 6-membered heterocyclic or heteroaromatic ring group containing at least one nitrogen atom and optionally 1 or 2 additional heteroatoms. Preferred amides derived from ammonia, With1-3alkyl primary amines or di(C1-2alkyl)amines. Examples of pharmaceutically acceptable esters of the invention include1-7alkalemia,5-7cycloalkyl, phenyl and phenyl(C1-6 )alkalemia esters. Preferred esters include methyl esters.

"Patient" or "subject" includes mammals, such as humans and animals (dogs, cats, horses, rats, rabbits, mice, primates, non-human)in need of observation, experiment, treatment or prevention in connection with the appropriate disease or disease state. Preferably, the patient or subject is a human.

"Composition" includes a product containing certain ingredients in certain amounts, as well as any product obtained directly or indirectly with the combination of certain ingredients in certain amounts.

"Therapeutically effective amount" or "effective amount" refers to an amount of active compound or pharmaceutical agent that causes the biological or medical response system tissue, animal or human, required for a researcher, veterinarian, physician, or other Clinician, which includes alleviation of the symptoms of diseases or disorders, being treated with.

Referring to the various radicals in this description and the claims, it is necessary to make three General observations. The first remark concerns the valence. For all hydrocarbon radicals, whether they feast upon nymi, unsaturated or aromatic, and are they or are not cyclic, linear or branched, and similarly in respect of all heterocyclic radicals, each radical includes substituted radicals and monovalent, divalent and multivalent radicals, as defined in the claims. The context will indicate that the Deputy is alkylene or hydrocarbon radical, which removed at least two hydrogen atoms (divalent) or removed a greater number of hydrogen atoms (polyvalent). Examples of the divalent radical linking the two parts of the molecule, G is the formula (I), which connects the two rings.

Secondly, it should be understood that the radicals or structural fragments as defined herein, include substituted radicals or structural fragments. Hydrocarbons include monovalent radicals containing carbon and hydrogen, such as alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl (either aromatic or unsaturated), and the corresponding divalent radicals, such as alkylene, albaniles, phenylene and the like. GetProperty include monovalent and divalent radicals containing carbon, hydrogen and at least one heteroatom. Examples of monovalent heterogenous include acyl, acyloxy, ALCO is ciazil, heterocyclyl, heteroaryl, aroyl, benzoyl, dialkylamino, hydroxyalkyl and the like. Using "alkyl" as an example, it should be understood that "alkyl" includes substituted alkyl having one or more substituents, such as, for example, from 1 to 5, 1 to 3, from 2 to 4 substituents. The substituents may be the same (dihydroxy, dimethyl), similar (Harper) or different (chlorbenzyl or aminomethylpyridine). Examples of substituted alkyl include halogenated (such as vermeil, chloromethyl, deformity, perchloromethyl, 2-bromacil, performer and 3-itselemental), hydroxyalkyl (such as hydroxymethyl, hydroxyethyl, 2-hydroxypropyl, aminoalkyl (such as aminomethyl, 2-amino-ethyl, 3-aminopropyl, and 2-aminopropyl), nitroalkyl, alkylaryl and the like. Di(C1-6alkyl)amino group includes an independently selected alkyl groups with education, for example, methylpropylamine, isopropylethylene, in addition to dialkylamino groups with two identical alkyl groups, such as dimethylamino or diethylamino.

Third, refers only stable compounds. For example, when there R NR'r" group, and R can represent alkenylphenol group, the double bond is removed, at least one carbon from the nitrogen atom, to prevent the formation of enamine. Similarly, when the dotted line represents the Wallpaper optional sp 2communication if it is missing, then enabled(s) corresponding atom(s) of hydrogen.

Preferred substituents for Ar include methyl, methoxy, vermeil, deformity, performer (trifluoromethyl), 1-foretel, 2-foretel, ethoxy, fluorine, chlorine and bromine, and especially methyl, bromine, chlorine, performer, performatce, methoxy and fluorine. Preferred examples of the substituted Ar or Ar1are 4-substituted and 3,4-disubstituted phenyl. Compounds according to the invention is additionally described in the next section.

C. Connections

The object of the invention is the use of compounds of formula (I)as described above under "Summary of the invention for the treatment of allergic diseases.

Preferred compounds include those in which:

(a) R1represents hydrogen, halogen, C1-5alkoxy, hydroxy, C1-5alkyl, cyano, nitro, R7R8N2-8acyl or R10R11NSO2;

(b) R1represents halogen, cyano, nitro, R7R8N or R10R11NSO2;

(c) R2represents hydrogen;

(d) each R3and R4independently represents hydrogen or C1-3alkyl;

(e) one of R3and R4represents hydrogen;

(f) each R3and R4represents hydrogen;

(g) one of R5R 6represents hydrogen and the other is a 5-7-membered carbocyclic or heterocyclyl, optionally substituted;

(h) R5and R6taken together form a six-membered heterocyclyl;

(i) R5and R6taken together form pyridinyl, pyrimidinyl or piperazinil, optionally N-substituted by a group R40O(C=O)(C=O)-, R40SO2, R40NHCO2, R40(C=O)- or R40N(C=O)-;

(j) each R7, R8, R21, R22, R24, R25independently represents hydrogen or C1-5alkyl; or, independently, each of R7and R8, R21and R22andR24and R25can be taken together with education optionally substituted 4-7-membered heterocyclic ring, this ring may be saturated, unsaturated or aromatic;

(k) at least one of R7and R8, R21and R22andR24and R25taken together, represents morpholinyl, piperidinyl or pyrrolidinyl;

(l) each R9, R23, R26and R27independently represents hydrogen or C1-5alkyl;

(m) G is a C3-4alcander, optionally substituted hydroxy, (L)-C1-5alkyloxy - or [(L)-C1-5alkylene]amino;

(n) G is a C3alcander, optional substituted the initial hydroxy, (L)-C1-5alkyloxy - or [(L)-C1-5alkylene]amino;

(a) X represents nitrogen;

(R) Y represents CR13;

(q) Z represents CR14;

(r) X represents CH;

(s) R12represents hydrogen, R22O(C=O)NH-, R22NH(C=O)NH-, R22SO2NH-; R23SO or R23SO2and R13represents hydrogen, R43O(C=O)NH-, R43NH(C=O)NH-, R43SO2NH-, R44SO or R44SO2;

(t) R14represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, nitro, R25O(C=O)NH-, R25NH(C=O)NH-, R25SO2NH - or R24R25N;

(u) R14is a halogen, R25O(C=O)NH-, R25NH(C=O)NH-, R25SO2NH - or R24R25N; Ar represents a monocyclic ring, optionally substituted with 1-2 substituents selected independently from halogen, C1-5of alkyl, cyano, nitro R15R16N, CF3and OCF3;

(v) Ar represents a six-membered ring, substituted by 1-2 substituents selected independently from halogen, CF3and OCF3specified Deputy or deputies are in the 4-position or at the 3 - and 4-positions, respectively;

(w) W is a SO2C=O or CHR20;

(x) W is a covalent bond;

(y) W and R1taken together, have four the Ulu (I)(a);

(z) W and R1taken together have the formula (I)(b);

(aa) one of R3and R4represents hydrogen; Ar represents a monocyclic ring, optionally substituted with 1-2 substituents selected independently from halogen, C1-5of alkyl, cyano, nitro R15R16N, CF3and OCF3; R12represents hydrogen, R23SO or R23SO2; R13represents hydrogen, R44SO or R44SO2; R14represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, nitro or R24R25N; and G represents a C3-4alcander, optionally substituted hydroxy, C1-3alkyl, (L)-C1-5alkyloxy or [(L)-C1-5alkylene]amino;

(bb) each R3and R4represents hydrogen; Ar represents a six-membered ring, optionally substituted with 1-2 substituents selected independently from halogen, C1-5of alkyl, cyano, nitro, R15R16N, CF3and OCF3; R12represents hydrogen, R23SO or R23SO2; R13represents hydrogen, R44SO or R44SO2; R14represents hydrogen, halogen, C1-5alkoxy, C1-5alkyl, cyano, nitro or R24R25N; and G represents a C3alcander, optionally substituted hydroxy, ()-C 1-5alkyloxy - or [(L)-C1-5alkylamino-;

(SS) Ar represents phenyl;

(dd) a combination of the above values.

Especially preferred compounds include in this description and in the examples, such as

1-[4-(2-amino-6-chlorophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol; 1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]-3-metalmachine; 1-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]-3-metalmachine; methyl ester of 3-amino-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzoic acid; 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenylamine and 1-[2-(4-{3-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)-3-chlorophenyl]-3-metalmachine; amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; methyl ester [3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-1-the l]propyl}piperazine-1-yl)phenyl]carbamino acid; amide 1-[3-(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)propyl]-3-(4-bromophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; methyl ester of 2-(4-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl]piperazine-1-yl)-3-nitrobenzoic acid; 1-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol; 2-(4-{2-hydroxy-3-[3-(4-itfeel)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzonitrile; amide 3-(4-bromophenyl)-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; 2-(4-{3-[5-acetyl-3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile; 2-(4-{3-[3-(4-chloro-3-were)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile; 1-(3-(4-chloro-3-were)-1-{3-[4-(2,4-dimetilfenil)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)Etalon; 1-{3-[4-(3,5-dichloropyridine-4-yl)piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine; 2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo-[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzonitrile; N-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydrate the azolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]methanesulfonamide; amide 3-(3,4-dichlorophenyl)-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid; amide 3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid.

In addition, preferred compounds include those in which Ar is selected from 4-trifloromethyl, 4-bromophenyl, 4-chlorphenyl, 4-chloro-3-methylphenyl and 3,4-dichlorophenyl.

More preferred compounds include compounds described in examples 19, 27 and 33.

Related compounds

The invention relates to these compounds and closely related pharmaceutically acceptable forms of the described compounds, such as their salts, esters, amides, acid, hydrate or solvate form; hidden or protected forms and racemic mixtures or enantiomeric or optically pure form. Related compounds also include compounds according to the invention, which has been modified to detect, for example, labeled with the isotope18F for use as a probe in positron emission tomography (PET) or single photon emission computed tomography (SPECT).

The invention also includes the described compounds having one or more functional groups (e.g. hydroxyl, amino or carboxyl), hidden protective groups. With the Autry, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rded., (1999), John Wiley & Sons, NY. Some of these hidden or protected compounds are pharmaceutically acceptable; others are useful as intermediate compounds. Disclosed in the description of the synthetic intermediates and methods and their minor modification is also included in the scope of the invention.

Protective groups for hydroxy

Protection of the hydroxyl group includes methyl ethers, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, and Silovye ethers.

Replaced by a simple methyl esters

Examples of substituted simple methyl esters include methoxymethyl, methylthiomethyl, tert-butyldimethylsilyl, (phenyldimethylsilane)methoxymethane, benzyloxycarbonyl, p-methoxybenzyloxy, (4 methoxyphenoxy)methyl, guilleray, tert-butoxymethyl, 4-interracially, sroximity, 2-methoxyethoxymethyl, 2,2,2-tricloracetatului, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetradecane, tetrahydropyranyloxy, 1-methoxycyclohexyl, 4-methoxyacetanilide, 4-methoxycarbonylpropionyl, S,S, dioxido 4-methoxycarbonylpropionyl, 1-[(2-chloro-4-ethyl)phenyl]-4-methoxypiperidine-4-silt, 1,4-dioxane-2-silt, tetrahydropyranyloxy, tetrahydropyranyloxy and 2,3,3A,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-mechanosensory-2-silt.

Replaced by a simple ethyl esters

Examples of substituted ethyl simple esters include 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethoxy, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-perately, 2,2,2-trichlorethylene, 2-trimethylsilylethynyl, 2-(phenylseleno)ethyl, tert-butyl, allyl, p-hlorfenilovy, p-methoxyphenacyl, 2,4-dinitrophenolate and benzyl.

Replaced by the simple benzyl esters

Examples of substituted simple benzyl esters include n-methoxybenzyloxy, 3,4-dimethoxybenzoyl, nitrobenzyloxy, p-nitrobenzyloxy, p-halogenosilanes, 2,6-dichlorobenzoyl, p-cyanobenzyl, p-phenylbenzyl, 2 - and 4-picolylamine, N-oxide, 3-methyl-2-picalilly, diphenylmethylene, p,p'-dinitrobenzonitrile, 5-dibenzosuberyl, triphenylmethane, α-afterdepolarisations, p-methoxyphenylethylamine, di(p-methoxyphenyl)fenilmetilovy, three(p-methoxyphenyl)methyl, 4-(4'-bromination)penultimately, 4,4'4"-Tris(4,5-dichlorophenolindophenol)methyl, 4,4',4"-Tris(levonogestrel)methyl, 4,4'4"-Tris(benzyloxyphenyl)methyl, 3-(imidazol-1-ylmethyl)bis(4,4"-acid)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrene is metalowy, 9-antilogy, 9-(9-phenyl)xantanovy, 9-(9-phenyl-10-oxo)antilogy, 1,3-benzodithiol-2-silt and S,S-dioxido benzisothiazolinone.

Silovye ethers

Examples cyrilovich ethers include trimethylsilyloxy, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, citilinkproperty, dimethylhexylamine, tert-butyldimethylsilyloxy, tert-butyldiphenylsilyl, tribenzylamine, three-p-csillery, triphenylsilanol, diphenylmethylsilane and tert-butylperoxyisopropyl.

Esters

In addition to simple esters of hydroxyl group can be protected in the form of ester. Examples of esters include formate, benzoylformate, acetate, CHLOROACETATE, dichloroacetate, trichloroacetate, triptorelin, methoxyacetate, triphenylmethane, phenoxyacetyl, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate, adamantoyl, crotonate, 4-methoxytrityl, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoic (mezitt).

Carbonates

Examples of the carbonaceous protective groups include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)-ethyl, 2-(phenylsulfonyl)ethyl, 2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, the-nitrobenzyl, S-benzoylthiourea, 4-ethoxy-1-naphthyl and methyldithiocarbamate.

Group auxiliary cleavage

Examples of auxiliary groups include removal of 2-iodobenzoate, 4-azidomethyl, 4-nitro-4-methylpentanoate, (dibromomethyl)benzoate, 2-formylbenzenesulfonic, 2-(methylthiomethyl)ethylcarbonate, 4-(methylthiomethyl)butyrate and 2-(methylthiomethyl)benzoate.

Mixed esters

Examples of mixed esters include 2,6-dichloro-4-methylphenoxyacetic, 2,6-dichloro-4-(1,1,3,3-TETRAMETHYLBUTYL)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, jordivericat, isobutyrate, mononuclear, (E)-2-methyl-2-butenoate (throat), o-(methoxycarbonyl)benzoate, p-P-benzoate, α-aftout, nitrate, alkyl N,N,N',N'-tetramethylpiperidine, N-phenylcarbamate, Borat, and dimethylphosphinic 2,4-dinitrobenzenesulfonic.

The sulfonates

Examples of sulfonates include sulfate, methanesulfonate (mesilate), bansilalpet and toilet.

Protective groups for amino

Protective groups for amino groups include carbamates, amides and special-NH protective groups.

Examples of carbamates include methyl and ethylcarbamate, substituted ethylcarbamate, carbamates auxiliary cleavage, carbamates protolytic cleavage of the derived type urea and mixed carbamates.

Carbamates

Examples of methyl - and ethylcarbamate include the methyl and ethyl, 9-fluorenylmethyl, 9-(2-sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl,2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydromyrcenol)]methyl, and 4-methoxyphenacyl.

Substituted ethyl

Examples of the substituted ethylcarbamate include 2,2,2-trichloroethyl, 2-trimethylsilylmethyl, 2-phenylethyl, 1-(1-substituted)-1-methylethyl, 1,1-dimethyl-2-halogenated, 1,1-dimethyl-2,2-dibromoethyl, 1,1-dimethyl-2,2,2-trichloroethyl, 1-methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-tert-butylphenyl)-1-methylethyl, 2-(2'- and 4'-pyridyl)ethyl, 2-(N,N-dicyclohexylcarbodimide)ethyl, tert-butyl, 1-substituted, vinyl, allyl, 1-isotropically, cinnamyl, 4-nitrocinnamyl, 8-chinolin, N-hydroxypiperidine, acidity, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-Chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfonylbenzoyl, 9-antimetal and diphenylmethyl.

Group auxiliary cleavage

Examples of auxiliary groups include removal of 2-methylthioethyl, 2-methylsulfonylamino, 2-(p-toluensulfonyl)ethyl, [2-(1,3-dithienyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophene, 2-phosphonoethyl, 2-triphenylphosphite, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxymethyl, p-(dihydroxyaryl)benzyl, 5-benzisoxazoles and 2-(trifluoromethyl)-6-homonymity.

Group protolytic cleavage

Examples of groups protolytic cleavage include m-nitrophenyl, 3,5-dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nor is roventil and phenyl(o-nitrophenyl)methyl.

Derivative type urea

Examples of derived type urea include phenothiazinyl-(10)-carbonyl derivative, N'-p-toluensulfonate and N'-phenylenecarbonyl.

Mixed carbamates

Examples of mixed carbamates include tert-amyl, S-benzelstierna, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzoic, diisopropylate, 2,2-dimethoxyaniline, o-(N,N-dimethylcarbamate)benzyl, 1,1-dimethyl-3-(N,N-dimethylcarbamate)propyl, 1,1-dimethylpropyl, di(2-pyridyl)methyl, 2-furylmethyl, 2-Iodate, isobornyl, isobutyl, isonicotinic, p-(p'-methoxyphenylazo)benzyl, 1-methylcyclobutene, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1-(3,5-acid)ethyl, 1-methyl-1-(p-phenylazophenyl)ethyl, 1-methyl-1-phenylethyl, 1-methyl-1-(4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-tert-butylphenyl, 4-(ammonium)benzyl and 2,4,6-trimethylbenzyl.

Examples of amides include:

Amides

N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-TRIFLUOROACETYL, N-phenylacetyl, N-3-phenylpropionyl, N-Picolines, N-3-pyridinecarboxamide, N-benzoylferrocene derivative, N-benzoyl, N-p-vinylbenzyl.

Group auxiliary cleavage

N-o-nitrophenylacetic, N-o-nitrophenoxyacetic, N-acetoacetyl, (N'-databasemaximumpoolsize)acetyl, N-3-(p-hydroxyphenyl)propionyl, N-3-(o-neath openil)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylethanone)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyl, N-o-nitrocinnamyl, N-acetylmethionate derivative, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl and 4,5-diphenyl-3-oxazoline-2-it.

Cyclic kidnie derivatives

N-phthalimide, N-datasection, N-2,3-diphenylmethyl, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethylcyclopentadienyl adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-it, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-it 1-substituted 3,5-dinitro-4-pyridinyl.

Special NH-protective group

Examples of special NH-protective groups include

N-alkyl and N-aryl amines,

N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropionyl, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary ammonium salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorene, N-2,7-dichloro-9-fluorenylmethyl, N-ferrocenylmethyl and N-2-picolylamine N'-oxide.

Imino-derivatives

N-1,1-dimethyltrimethylene, N-benzyliden, N-p-methoxybenzylidene, N-diphenylmethylene, N-[(2-pyridyl)mesityl]methylene and N-(N',N'-dimethylaminomethylene).

Protection for the carbonyl group

Acyclic acetals and ketals

Examples of acyclic acetals and ketals include dimethyl, bis(2,2,2-trichlorethyl), dibenzyl, bis(-nitrobenzyl) and diacetyl.

Cyclic acetals and ketals

Examples of cyclic acetals and ketals include 1,3-dioxans, 5-methylene-1,3-dioxane, 5,5-dibromo-1,3-dioxane, 5-(2-pyridyl)-1,3-dioxane, 1,3-dioxolane, 4-methyl bromide-1,3-dioxolane, 4-(3-butenyl)-1,3-dioxolane, 4-phenyl-1,3-dioxolane, 4-(2-nitrophenyl)-1,3-dioxolane, 4,5-dimethoxymethyl-1,3-dioxolane, o,O'-phenyleneoxy and 1,5-dihydro-3H-2,4-benzo-doxepin.

Acyclic dithioacetals and ketals

Examples of acyclic dithioacetals and ketals include S,S'-dimethyl -, S,S'-diethyl -, S,S'-dipropyl, S,S'-dibutil, S,S'-dipentyl, S,S'-diphenyl, S,S'-dibenzyl and S,S'-diacetyl.

Cyclic dithioacetals and ketals

Examples of cyclic dithioacetals and ketals include 1,3-dition, 1,3-ditiolan and 1,5-dihydro-3H-2,4-benzodiapine

Acyclic monotically and ketals

Examples of acyclic monotically and ketals include O-(trimethylsilyl)-S-alkyl, O-methyl-S-alkyl or-S-phenyl and O-methyl-S-2-(methylthio)ethyl.

Cyclic monotically and ketals

Examples of cyclic monotically and ketals include 1,3-oxathiolane.

Mixed derivatives

O-substituted cyanhydrin

Examples of O-substituted cyanhydrin include O-acetyl, trimethylsilyl, 1-ethoxyethyl and O-tetrahydropyranyl.

Substituted hydrazones

Examples of substituted hydrazones include N,N-dimethyl, 2,4-dinitrophenyl.

Aksinya derivatives

Examples of Zimnij derivatives include O-methyl, O-benzyl and O-phenylthiomethyl.

Emini

Substituted methylene derivatives, cyclic derivatives.

Examples of substituted methylene and cyclic derivatives include oxazolidine, 1-methyl-2-(1'-hydroxyalkyl)imidazoles, N,N'-dimethylimidazolidine, 2,3-dihydro-1,3-benzothiazole, adducts of diethylamine and complex bis(2,6-di-tert-butyl-4-methoxyphenoxy) methylamine (MAD).

Protection for the carboxyl group

Esters

Substituted methyl esters

Examples of substituted methyl esters include 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyloxy, tetrahydropyranyloxy, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxyethanol, finally, p-prominately, α-methylbenzylamine, p-methoxybenzyloxy, carboxamidates and N-phthalimidomethyl.

2-Substituted ethyl esters

Examples of 2-substituted ethyl esters include 2,2,2-trichlorethylene, 2-halogenations, ω-chloralkali, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 1,3-dithienyl-2-methyl, 2-(p-nitrobenzylidene)ethyl, 2-(p-toluensulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenethyl, tert-butyl, cyclopentyloxy, cyclohexyloxy, allyl, 3-butene-1 silt, 4-(trimethylsilyl)-2-butene-1-ILO is th, cinnamony, α-methylcinnamic, phenyl, p-(methylmercapto)phenyl and benzyl.

Substituted benzyl esters

Examples of substituted benzyl esters include triphenylmethane, diphenylmethylene, bis(o-nitrophenyl)methyl, 9-antimetropia, 2-(9,10-dioxo)antimotility, 5-dibenzosuberyl, 1-pyrenylethynyl, 2-(trifluoromethyl)-6-chromidotilapia, 2,4,6-trimethylbenzyl, p-bromobenzoyl, nitrobenzyloxy, p-nitrobenzyloxy, p-methoxybenzyloxy, 2,6-dimethoxybenzoyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzoate, peperonity, 4-picalilly and n-P-benzyl.

Silovye esters

Examples cyrilovich esters include trimethylsilyloxy, triethylsilyl, tert-butyldimethylsilyloxy, ISO-propyltrimethoxysilane, phenyldimethylsilane and di-tert-butylmethacrylate.

Activated esters

Examples of activated esters include thiols.

Mixed derivatives

Examples of mixed derivatives include oksazolov, 2-alkyl-1,3-oxazoline, 4-alkyl-5-oxo-1,3-oxazolidine, 5-alkyl-4-oxo-1,3-dioxolane, complex ortho-ester, a phenyl group and a set of pentaaminocobalt(III).

Staniloae esters

Examples stanilova esters include triethylsilane and tri-n-butylstannyl.

Amides and hydrazides

Amides

the reamers amides include N,N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydropteridine, o-nitroanilide, N-7-nitroindole, N-8-nitro-1,2,3,4-tetrahydroquinolin and p-P-benzosulfimide.

The hydrazides

Examples of hydrazides include N-phenyl and N,N'-aminobutiramida hydrazides.

C. Synthesis

Compounds of the present invention can be obtained using conventional synthetic organic chemistry and the use of a matrix or combinatorial methods in accordance with the following schemes 1-11 and illustrations, are described in detail in examples 1-24. An ordinary person skilled in the art will be able to modify and adapt described in this description of the methodology for obtaining the described compounds.

D. preparative form and introduction

These compounds inhibit the proteolytic activity of human cathepsin S and is therefore useful as medicines especially in the treatment of patients suffering from Aller the systematic diseases or conditions, modulated or regulated by the inhibition of the activity of cathepsin S.

The object of the invention is a method of treatment of a subject with allergic disease, mediated by cathepsin S, which includes an introduction to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention. The invention also relates to a method for inhibiting the activity of cathepsin S in entity, which includes an introduction to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of the invention.

Whereas inhibitory effect on the proteolytic activity of human cathepsin S, the compounds of the present invention can be formulated into various pharmaceutical forms for administration. To obtain such pharmaceutical compositions an effective amount of a specific compound in the form of a base or an acid additive salt as the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier.

The media can have a wide range of forms depending on the form of preparation desired for administration. Such pharmaceutical compositions are preferably in the form of standard dosage forms, preferably suitable for oral administration or arenteralne injection. For example, upon receipt of the compositions in the form of an oral formulation of the dosage form can be any of the usual pharmaceutical media. They include water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricating agents, binding agents, loosening agents and the like in the case of powders, pills, capsules and tablets. Given the ease of administration, tablets and capsules are preferred standard oral dosage form, and in this case, you typically use solid pharmaceutical carriers. For parenteral compositions, the carrier will usually include sterile water, at least for the most part, although there may be other ingredients, for example, facilitate solubility. For example, can be obtained solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Can also be obtained suspension for injection, in this case, you can use the appropriate liquid carriers, suspendresume agents and the like. In the compositions suitable for subcutaneous administration, the carrier optionally includes the agent, usilivaya the permeability, and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor quantities, these additives do not cause significant adverse effects on the skin. Such additives may facilitate the introduction into the skin and/or may be useful to obtain the desired compositions. Such compositions can be administered in various ways, for example, in the form of a percutaneous patch, by applying the spot, in the form of ointment. Acid additive salts of compounds of formula I, thanks to their increased water solubility over the corresponding basic form are more appropriate for obtaining water compositions.

Especially, it is preferable to formulate the above pharmaceutical composition in the form of a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form, as used herein, refers to physically discrete units suitable as unit doses, each unit contains a predetermined quantity of active ingredient calculated to provide the desired therapeutic action, together with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including scored tablets or coated tablets), capsules the crystals, pills, sachets, wafers, injectable solutions or suspensions, tea spoons, table spoons and the like and their individual components.

Pharmaceutically acceptable acid additive salts include therapeutically active non-toxic acid additive salt form, which are capable of forming the described connections. The latter can usually be obtained by processing the basic form of a suitable acid. Suitable acids include, for example, inorganic acid, such as halogen acids, for example hydrochloric or Hydrobromic acid; sulfuric, nitric, phosphoric and the like; or organic acids, such as acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, palm and the like. The term "additive salt" also includes a solvate, which are described compounds and their salts are able to form. Such a solvate, for example, represent the hydrates, the alcoholate and the like. On the contrary, the salt form may be converted upon treatment with alkali in the form of a free base.

Stereoisomeric forms include all possible nomernye form, which may be the compounds of formula (I). If not marked or not specified other, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, the compounds include all diastereomers and enantiomers of basic molecular structure. More specifically, stereogenic centers may have the (R)- or (S)-configuration; substituents at bivalent cyclic saturated radicals may have either the CIS - or TRANS-configuration. The invention includes a stereochemical isomeric forms of the described compounds, including diastereoisomeric, as well as mixtures thereof in any proportion. Described compounds can also exist in tautomeric forms. It is implied that although these forms it is not clear from the above and the following formulas, they are included in the scope of the present invention.

Specialists in the treatment of diseases or conditions mediated by the enzyme cathepsin S can easily determine the effective daily amount from the following test results and other information. It is generally assumed that a therapeutically effective dose will be from about 0.001 mg/kg to 5 mg/kg body weight, more preferably from 0.01 mg/kg to 0.5 mg/kg of body weight. May be appropriate to carry out the introduction of a therapeutically effective dose in the form of two, three, four, or is more podos through suitable intervals during the day. These padosi can be obtained in a standard dosage forms, for example, containing from 0.05 mg to 250 mg, and, in particular, from 0.5 to 50 mg of the active ingredient at a standard dosage form. Examples include 2 mg, 4 mg, 7 mg, 10 mg, 15 mg, 25 mg and 35 mg dosage forms. Compounds according to the invention can also be obtained in the form of compositions with delayed release or formulations for subcutaneous injection or transdermal patches. Described compounds can also be formulated in the form of spray or other compositions for inhalation or local injection.

The exact dose and frequency of administration depends on the particular used the compounds of formula (I), a specific medical condition being treated, the severity of the disease being treated, the age, weight and General physical condition of the particular patient, and other medications that can be taken by a patient, as is well known to specialists in this field. Moreover, it is clear that the effective daily amount may be reduced or increased depending on the response of the patient being treated, and/or depending on the evaluation of the physician prescribing the compounds of the present invention. The ranges of effective daily amounts noted in this description, hence the nutrient, only as an indication.

The following section includes detailed information related to the acquisition, characteristics and application of the described compounds.

E. Examples

EXAMPLE 1

1-(3-(4-Chlorophenyl)-1-{3-[4-(2-forfinal)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)alanon

A. 1-[3-(4-Chlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

To a mixed solution of 50 g (0.35 mol) of N-acetyl-4-piperidone and 31 g (0.35 mol) of the research in benzene (350 ml) was added a catalytic amount (˜0.25 g) p-toluensulfonate acid. The mixture was boiled under reflux for 10 hours with a trap Dean-stark. The solvent was removed under reduced pressure, obtaining a brown oil. The crude product was diluted in CH2Cl2(175 ml) and was added to 50.0 ml (0.35 mol) Et3N. the Mixture was cooled to 0°C and slowly added over 1 hour via an addition funnel a solution of 45.0 ml (0.35 mol) of 4-chlorobenzoyl chloride in CH2Cl2(50 ml). The mixture was left to warm to room temperature and was stirred overnight. The reaction mixture was then diluted 1H. HCl (150 ml) and stirred intensively for 3 hours. The aqueous layer was extracted with CH2Cl2(3×250 ml) and the combined extracts were dried over Na2SO4and the solvent was removed under reduced on the no. The crude oil was diluted with EtOH (350 ml) and cooled to 0°C. To this stirred solution was slowly added 33,0 ml (1.06 mol) of hydrazine and the mixture was left to warm to room temperature and was stirred overnight, during this time he formed a white precipitate. The volume of the reaction mixture was reduced to ˜150 ml) was added to a mixture of EtOAc (750 ml). The suspension was intensively stirred for 2 hours and filtered, then washed with EtOAc (2×200 ml) and dried in vacuum, obtaining 41,4 g (42% in 3 stages) pale yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3. Mass spectrum (elektrorazpredelenie), m/z calculated for C14H14ClN3O [M+H]+276,08 found 276,0,1H NMR (400 MHz, CDCl3, mixture of amide rotamers): the 7.65 (d, J=8,4 Hz, 2H), to 7.64 (d, J=9,3 Hz, 2H), 7,58 (d, J=10.5 Hz, 2H), 7,55 (d, J=8.5 Hz, 2H), 4,94 (s, 2H), 4,78 (s, 2H), 4,08 (t, J=5,9 Hz, 2H), 3,90 (t, J=5.8 Hz, 2H), to 3.02 (t, J=5.8 Hz, 2H), 2,96 (t, J=5,9 Hz, 2H), a 2.36 (s, 3H), 2,31 (s, 3H).

B. 1-[3-(4-Chlorophenyl)-1-(3-chlorpropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

Cs2CO3(2.66 g, 8.2 mmol) was added to a solution of 1-[3-(4-chloro-phenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (1.0 g, 5.4 mmol) in DMF (10 ml) and was stirred for 15 minutes. Was added 1-bromo-3-chloropropane (1.28 g, 8.2 mmol) and was stirred in an atmosphere of N2at room temperature for 36 hours. To the reaction mixture was added to the ode (50 ml) and was stirred for 5 minutes. The product precipitated. The water part decantation and was added to the residue water and again decantation. Semi-solid substance was placed in CH2Cl2and was passed through a short layer of SiO2(5% MeOH/EtOAc)to give 1.06 g (83%) of a pale yellow semi-solid substances. Mass spectrum (elektrorazpredelenie): exact mass calculated for C17H19Cl2N3O, 351,09; m/z found, 352,0 [M+H]+.1H NMR (500 MHz, CDCl3mixture 1:1 rotamers): 7,60 (d, J=8,3 Hz, 1H), 7,53 (d, J=8,3 Hz, 1H), 7,40 (d, J=8,3 Hz, 1H), was 7.36 (d, J=8,3 Hz, 1H), 4,77 (s, 1H), br4.61 (s, 1H), 4,20 (t, J=6.2 Hz, 2H), 3,94 (t, J=5.8 Hz, 1H), 3,76 (t, J=5.8 Hz, 1H), 3,52 (kV, J=6,1 Hz, 2H), 2,84 (t, J=5.5 Hz, 1H), 2,77 (t, J=5.6 Hz, 1H), 2.37 (sextet, J=6,1 Hz, 2 H), of 2.21 (s, 1.5 H)of 2.16 (s, 1.5 H).

C. 1-(3-(4-Chlorophenyl)-1-{3-[4-(2-forfinal)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)alanon

1-[3-(4-Chlorophenyl)-1-(3-chlorpropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (0,053 g, 0.15 mmol) was dissolved in CH3CN (0.5 ml) and the solution was added 1-(2-forfinal)piperazine (0,053 g, 0.30 mmol) in CH3CN (0.5 ml) followed by addition of K2CO3(0,031 g, 0.22 mmol) and Bu4NI (0,018 g, 0.05 mmol). The mixture was stirred at room temperature for 7 days. Preparative TLC (silica, 5% MeOH/EtOAc) gave 30 mg (41%) specified in the connection header. Mass spectrum (elektrorazpredelenie): exact mass calculated for C27H31ClFN5O 495,22; m/z found, 496,3 [M+H +.1H NMR (500 MHz, CDCl3mixture 1:1 rotamers): 7,60 (d, J=8,3 Hz, 1H), 7,54 (d, J=8,3 Hz, 1H), 7,39 (d, J=8,3 Hz, 1H), 7,35 (d, J=8,3 Hz, 1H), 7,06-of 6.90 (m, 4H), of 4.77 (s, 1H), 4,60 (s, 1H), 4,10 (t, J=6,8 Hz, 2H), 3,92 (t, J=5.7 Hz, 1H), 3,74 (t, J=5.7 Hz, 1H), is 3.08 (user. s, 4H), and 2.83 (t, J=5.6 Hz, 1H), 2,77 (t, J=5.7 Hz, 1H), 2,58 (user. s, 4H), 2,41-of 2.38 (m, 2H), 2,19 (s, 1,5H), 2.13 and (C, 1,5H), 2,10-2,07 (m, 2H).

EXAMPLE 2

1-{3-(4-Chlorophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}alanon

A. 1-[3-(4-Chlorophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

To a stirred solution of 1.00 g (3.63 mmol) of 1-[3-(4-chlorophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone and to 2.85 ml (36,3 mmol) of epichlorohydrin was added to 1.30 g (3,99 mmol) of solid Cs2CO3,The reaction mixture was stirred for 48 hours and the solvent was removed under reduced pressure. The residue was then diluted with H2O (50 ml) and EtOAc (50 ml). The layers were separated and the organic layer washed with H2O (25 ml) and saturated salt solution (25 ml), dried over Na2SO4and the solvent was removed under reduced pressure. Purification with flash chromatography (silica, 0-15% acetone/CH2Cl2) gave 0,72 g (60%) of a white solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,5. Mass spectrum (elektrorazpredelenie): m/z calculated for C17H18ClN3O2[M+H]+,332,11, found 332,0,1H NMR (400 MHz, CDCl3, mixture of amide rotamers): 7,60 (d, J=8.6 Hz, 2H), 7,54 (d, J=8,4 Hz, 2H), 7,40 (d, J=8.6 Hz, 2H), was 7.36 (d, J=8,4 Hz, 2H), 4,80 and 4.73 (A and B of AB Quartet, Jab=to 15.8 Hz, 2H), 4,60 (s, 2H), 4,47 (DD, J=15,3, 2.5 Hz, 1H), 4,42 (DD, J=15,0, 2.7 Hz, 1H), 4,11 (DD, J=5,3, 2.5 Hz, 1H), 4,08 (DD, J=5,1, 3.3 Hz, 1H), 3,99-of 3.85 (m, 2H), of 3.73 (dt, J=5,9, 1.8 Hz, 2H), 3,37 (m, 2H), 2,87 is 2.80 (m, 3H), 2,80-2,69 (m, 3H), 2,53 (DD, J=4,7, 2.5 Hz, 1H), 2,48 (DD, J=4,6, 2,6, 1H), 2,19 (s, 3H), of 2.15 (s, 3H).

B. 1-{3-(4-Chlorophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}alanon

A solution of 1-[3-(4-chlorophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]-ethanone (0.8 g, 2,42 mmol) in CH2Cl2(12 ml) was treated with ytterbium triflate(III) (0.15 g, 0.24 mmol) and 1-(0-tolyl)-piperazine (0.51 g, 2,90 mmol) at 25°C. the Reaction mixture was stirred for 24 hours and diluted with EtOAc (100 ml) and H2O (50 ml). The organic layer was separated, washed with H2O (2×50 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 5% MeOH/CH2Cl2) gave 1.08 g (88%) of target compound, a white powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,38. Mass spectrum (elektrorazpredelenie): m/z 508,3 ([M+H]+C28H34ClN5O2calculated 507,2).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,60 and 7,37 (AB system, Jab=8,8 Hz, 2H), 7,54 and 7,40 (AB system, Jab=8,8 Hz, 2H), 7.18 in-7,14 (m, 2H, 7,00-6,97 (m, 2H), 4,85 and 4.73 (AB system, Jab=15,5 Hz, 1H), to 4.62 (s, 1H), 4,20-4,11 (m, 2H), 4,06-4,01 (m, 1H), 3,88-3,70 (m, 2H), 2,97-2,87 (m, 6H), 2,85 is 2.75 (m, 2H), 2,65 is 2.55 (m, 2H), of 2.51-2,48 (m, 2H), to 2.29 (s, 3H), of 2.21 (s, 1,5H), 2,17 (s, 1,5H).

EXAMPLE 3

1-{3-(4-Chlorophenyl)-1-[2-methoxy-3-(4-o-tailpipes-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}alanon

Mix a solution of 1-{3-(4-chlorophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}ethanone (25 mg, 0.05 mmol) in THF (0.2 ml) was treated with NaH (1,42 mg, 0.06 mmol) at 25°C. After 20 minutes was added modesty methyl (3,7 ml, 0.06 mmol) and the reaction mixture was stirred additionally for 2 hours. Preparative TLC (silica, 5% MeOH/CH2Cl2) gave to 14.6 mg (56%) of a colorless film. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,38. Mass spectrum (elektrorazpredelenie): m/z 522,2 ([M+H]+C29H36CIN5About2calculated 521,3).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,62 and 7,37 (AB system, Jab=8,8 Hz, 2H), 7,55 and 7,40 (AB system, Jab=8,8 Hz, 2H), 7.18 in-7,14 (m, 2H), 7,02-to 6.95 (m, 2H), 4,82, and of 4.75 (AB system, Jab=15,5 Hz, 1H), to 4.62 (s, 1H), 4,30-of 4.25 (m, 1H), 4.09 to to 3.73 (m, 4H), 3,29 (s, 1,5H), 3.27 to (C, 1,5H), 2.93 which is 2.55 (m, 12H), is 2.30 (s, 3H), of 2.21 (s, 1,5H), of 2.16 (s, 1,5H).

EXAMPLE 4

1-[1-{2-Hydroxy-3-[4-(2-hydroxyphenyl)piperazine-1-yl]propyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4-c]pyridine-5-yl]alanon

A. 1-[3-(4-Itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

Into a flask equipped with a trap Dean-stark download N-acetyl-4-piperidone (27,29 g, 137 mmol), piperidine (16.5 ml, 129 mmol), p-toluensulfonate acid (0.5 g) and benzene (150 ml). The mixture was heated to 125°C. After 8 hours the mixture was left to cool and was concentrated in vacuum, obtaining the corresponding enamine (35 g). Within 2 hours was added dropwise to a solution of the enamine (11,0 g, approximately 41 mmol) in CH2Cl2(80 ml) at 0°C a solution of p-identilied (9.28 are g, 34.8 mmol) in CH2Cl2(40 ml). The mixture was then left to warm to room temperature and stirred additionally for 17 hours. The solution was treated with 1H. HCl (200 ml) and stirred intensively for 5 hours. The layers were separated and the aqueous layer was extracted with CH2Cl2(3×150 ml). The combined extracts were dried over Na2SO4and concentrated. The residue was dissolved in EtOH (200 ml) and was treated with NH2NH2(16.0 ml, 51 mmol). The mixture was stirred for 17 hours and was added H2O (300 ml). The precipitate was collected by filtration and dried in the air, getting 8,82 g (59%) of 1-[3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone, suitable for use without additional purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3. Mass spectrum (El the spray): m/z calculated for C 14H15IN3O [M+H]+368,03 found 368,0.1H NMR (CD3OD/CDCl3, 500 MHz, mixture of amide rotamers): 7,72 (d, J=8,2 Hz, 2H), 7,69 (d, J=8,3 Hz, 2H), 7,24 (d, J=8,2 Hz, 2H), 7,20 (d, J=8,3 Hz, 2H), 4,69 (s, 2H), 4,56 (s, 2H), 3,83 (t, J=6.0 Hz, 2H), 3,69 (t, J=5.8 Hz, 2H), and 2.79 (t, J=5.7 Hz, 2H), 2,72 (t, J=5.8 Hz, 2H), 2.13 and (s, 3H), of 2.08 (s, 3H).

B. 1-[3-(4-Itfeel)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

Cs2CO3(1.30 grams, to 4.01 mmol) was added to a solution of 1-[3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (1,34 g, 3.65 mmol) and epichlorohydrin (2,85 ml of 36.4 mmol) in DMF (10.0 ml). The mixture was stirred for 17 hours, then was distributed between EtOAc (400 ml) and a saturated solution of NaHCO3(150 ml). Containing NaHCO3layer was extracted with EtOAc (2×150 ml). The combined extracts were washed H2O (2×150 ml), saturated salt solution (150 ml), dried over Na2SO4and concentrated. The residue was purified column chromatography (silica, 10% to 25% acetone/CH2Cl2)to give 890 mg (58%) specified in the connection header. HPLC, tR=of 5.53 min (Conditions inverted phases: HP 1100 LCMS, Phenomenex luna 2,1×150 mm column, 60% MeOH/H2O (with 0.5% AcOH) to 90%MeOH/H2O (with 0.5% AcOH), keeping the initial conditions for 2 minutes, then brought to the final conditions for 5 minutes). Mass spectrum (elektrorazpredelenie), m/z calculated for C17H18IN3O2N [M+Na] +445,04 found 445,95,1H NMR (CDCl3, 500 MHz, mixture of amide rotamers): 7,76 (d, J=8,3 Hz, 2H), of 7.75 (d, J=8,3 Hz, 2H), 7,42 (d, J=8,2 Hz, 2H), 7,35 (d, J=8,2 Hz, 2H), 4,80 and 4.73 (A and B of AB Quartet, Jab=15.6 Hz, 2H), 4,60 (s, 2H), 4,84 (DD, J=15,1, and 2.1 Hz, 1H), 4,42 (DD, J=15,0, and 2.1 Hz, 1H), 4,11 (t, J=5,0 Hz, 1H), 4,08 (t, J=5.0 Hz, 1H), 3,98-a 3.87 (m, 2H), 3,74 (m, 2H), 3,34 (m, 2H), 2,87-of 2.72 (m, 6H), 2,52 (DD, J=4,6, and 2.6 Hz, 1H), 2,48 (DD, J=4,5, 2,6, 1H), measuring 2.20 (s, 3H), and 2.14 (s, 3H).

C. 1-[1-{2-Hydroxy-3-[4-(2-hydroxyphenyl)piperazine-1-yl]-propyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

1-[3-(4-Itfeel)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (62 mg, 0.15 mmol) and 4-(2-hydroxyphenyl)piperazine (34 mg, 0,19 mmol) were combined in CH2Cl2(0.5 ml) and the solution was treated with Yb(OTf)3·H2O (44 mg, 0,071 mmol). The mixture was shaken for 72 hours, then diluted with CH2Cl2(1 ml). Purification preparative TLC (silica, 10% MeOH/CH2Cl2) gave 45 mg (51%) not quite white powder. TLC (silica, 8% MeOH/CH2Cl2): Rf=0,2. Mass spectrum (elektrorazpredelenie): m/z calculated for C27H33IN5O3[M+H]+602,15 found 602,2.1H NMR (CDCl3, 500 MHz, mixture of amide rotamers): 7,76 (d, J=8.6 Hz, 1H), 7,72 (d, J=8.6 Hz, 1H), 7,42 (d, J=8.5 Hz, 1H), 7,34 (d, J=8.5 Hz, 1H), 7,14 (m, 1H), 7,80 (t, J=7.7 Hz, 1H), 6,94 (d, J=8,1 Hz, 1H), 6,86 (t, J=7.7 Hz, 1H), of 4.83 and 4.72 in (A and B of AB Quartet, Jab=15.6 Hz, 1H), br4.61 (s, 1H), 4,22-to 4.15 (m, 2H), was 4.02 (m, 2H), 3,88 (m, 1H), 3,76 (m, 3H) 3,00-2,49 (m, 11H), of 2.20 (s, 1,5H), of 2.15 (s, 1,5H).

EXAMPLE 5

1-[1-[2-Hydroxy-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A. 1-[3-(4-Triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of N-acetyl-4-piperidone (2,82 g, 20 mmol), research (1,93 ml, 22 mmol) and p-toluensulfonate acid (5 mg) in benzene (8.5 ml) was boiled under reflux for 8 hours with the device, Dean-stark. The solvent was removed and the residue was dissolved in CH2Cl2(20 ml). Was added triethylamine (3.1 ml) and p-cryptomathematical (3,27 ml, 22 mmol) in CH2Cl2(4 ml) was added dropwise to the solution at 0°C. the Reaction mixture was stirred at 25°C for 24 hours and diluted with aqueous HCl (5%, 25 ml). After stirring for 30 minutes, the organic layer was separated, washed with H2O (20 ml), dried (Na2SO4) and concentrated. The residue was dissolved in EtOH (95%, 18 ml) and treated at 0°C hydrazine (2,9 ml, 60 mmol). The mixture was stirred at 25°C for 3 hours and added H2O (4 ml). The most volatile components were removed and the residue was extracted with CH2Cl2(50 ml). The organic layer was separated, washed with H2O (20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 5% MeOH/H 2Cl2) gave 5.1 g (83%) of white powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,30. Mass spectrum (elektrorazpredelenie): m/z 332,0 ([M+Na]+C15H14F3N3O calculated 309,1).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,73-to 7.67 (m, 4H), 4,85 (s, 1,2H), and 4.68 (s, 0,8H), of 3.96 (t, J=4.5 Hz, 0,8H), of 3.78 (t, J=4.5 Hz, 1,2H), 2,89 (t, J=4.5 Hz, 1,2H), and 2.83 (t, J=4.5 Hz, 0,8H), of 2.23 (s, 1,8H), to 2.18 (s, 1,2H).

B. 1-[1-Oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 1-[3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (2.4 g, to 7.77 mmol) in DMF (15 ml) was treated with cesium carbonate (of 5.05 g of 15.5 mmol) and epichlorohydrin (6,1 ml, with 77.7 mmol) at 25°C and was stirred for 24 hours before dilution with EtOAc (100 ml) and H2O (50 ml). The organic layer was separated, washed with H2O (2×50 ml), saturated salt solution (50 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10% acetone/CH2Cl2) gave 2.30 g (81%) of white powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,35. Mass spectrum (elektrorazpredelenie): m/z 388,0 ([M+Na]+C18H18F3N3O2calculated 365,1.1H NMR (CDCl3, 400 MHz, mixture of two rotamers): to 7.77 and 7,63 (AB system, Jab=8,2 Hz, 2H), 7,71 and to 7.67 (AB system, Jab=8,4 Hz, 2H), 4,82, and was 4.76 (AB system, Jab=15,5 Hz, 1,2H), 4,5 (s, 0,8H), 4,45 is 4.35 (m, 1H), 4,08-was 4.02 (m, 1H), 3,92-of 3.80 (m, 1H), 3,70-3,63 (m, 1H), 3,30 (m, 1H), 2,80-to 2.67 (m, 3H), 2,48-to 2.42 (m, 1H), 2,13 (s, 1,3H), 2,08(s, 1,7H).

C. 1-[1-[2-Hydroxy-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon.

A solution of 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (1,16 g, 3,20 mmol) in CH2Cl2(15 ml) was treated with ytterbium triflate(III) (0.40 g, 0.64 mmol) and 1-(O-tolyl)piperazine (0.84 g, 4.77 mmol) at 25°C and was stirred for 48 hours before dilution CH2Cl2(100 ml) and H2O (50 ml). The organic layer was separated, washed with H2O (2×50 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 5% MeOH/CH2Cl2) gave 1.54 g (89%) of white powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,35. Mass spectrum (elektrorazpredelenie): m/z USD 542.3 ([M+H]+C29H34F3N5O2calculated to 541.3).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,82 and the 7.65 (AB system, Jab=8,2 Hz, 2H), 7,72 and to 7.68 (AB system, Jab=8,4 Hz, 2H), 7.18 in-6,97 (m, 4H), 4,88 and was 4.76 (AB system, Jab=16 Hz, 0,9H)and 4.65 (s, 1,1H), 4,23-4,12 (m, 2H), 4,08-4,00 (m, 2H), 3,88-3,70 (m, 2H), 3,02-to 2.85 (m, 6H), 2,85 is 2.75 (m, 2H), 2,65 is 2.55 (m, 2H), 2,53 at 2.45 (m, 2H), to 2.29 (s, 3H), of 2.21 (s, 1,8H), 2,17 (, 1,2H).

EXAMPLE 6

2-(4-{3-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydro irazola[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile

A solution of 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (0.84 g, 2,30 mmol) in CH2Cl2(10 ml) was treated with ytterbium triflate(III) (0,29 g, 0.46 mmol) and 1-(2-cyanophenyl)piperazine (0.75 g, 3.5 mmol) at 25°C and was stirred for 48 hours before dilution CH2Cl2(100 ml) and H2O (50 ml). The organic layer was separated, washed with H2O (2×50 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 5% MeOH/CH2Cl2) gave to 1.15 g (90%) of light yellow crystals. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,30. Mass spectrum (elektrorazpredelenie): m/z 553,3 ([M+H]+C29H31F3N6O2calculated 552,3).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,82 and to 7.68 (AB system, Jab=8,2 Hz, 2H), 7,76 and 7,72 (AB system, Jab=8,4 Hz, 2H), 7,60-of 7.48 (m, 2H), 7,05-7,00 (m, 2H), 4,90, and 4,78 (AB system, Jab=16 Hz, 1H), 4,69 (s, 1H), 4,30-3,71 (m, 6H), of 3.25 (m, 4H), 3,02 is 2.75 (m, 4H), 2,70-to 2.65 (m, 2H), 2,60 of $ 2.53 (m, 2H), 2,23 (s, 1.5 H)to 2.18 (s, 1,5H).

EXAMPLE 7

1-[3-(3,4-Dichlorophenyl)pyrazole-1-yl]-3-(4-o-tailpipes-1-yl)propan-2-ol.

A. 3-(3,4-Dichlorophenyl)-1-oxiranylmethyl-1H-pyrazole

Stir a solution of 3-(3,4-dichlorophenyl)pyrazole (300 mg, 1.4 mmol) in DMF (5 ml) was treated with cesium carbonate (550 mg, was 1.69 mmol) and epichlorohydrin (1.1 ml, 14.0 mmol) pikantnoi temperature for 18 hours. The crude reaction mixture is then distributed between EtOAc (50 ml) and water (35 ml). The aqueous phase was additionally extracted (2×50 ml) and the combined organic layers were washed with saturated salt solution, dried (Na2SO4), filtered and concentrated under reduced pressure, obtaining the crude product. Purification of column chromatography (silica, 25% EtOAc/hexane) give 308 mg (82%) specified in the connection header.1NMR (400 MHz, CDCl3): 7,83 (d, J=2 Hz, 1H), 7,54 (DD, J=2,8 Hz, 1H), 7,44 (d, J=2 Hz, 1H), 7,38 (d, J=8 Hz, 1H), 6.48 in (d, J=2 Hz, 1H), 4,45 (DD, J=3, 9.7 Hz, 1H), 4,12 (DD, J=6, 15 Hz, 1H), and 3.31 (m, 1H), 2,81 (DD, J=4,0, 4.6 Hz, 1H), 2,47 (DD, J=2,6, a 4.7 Hz, 1H).

C. 1-[3-(3,4-Dichlorophenyl)pyrazole-1-yl]-3-(4-o-tailpipes-1-yl)propan-2-ol

A solution of 3-(3,4-dichlorophenyl)-1-oxiranylmethyl-1H-pyrazole (30 mg, 0.11 mmol) and 1-(2-were)piperazine (22 mg, 0.12 mmol) in EtOH (1 ml) was heated at 80°C during the night. Removal of solvent and purification of column chromatography (silica, 0-5% acetone/CH2Cl2) gave 35 mg (70%) specified in the connection header.1H NMR (400 MHz, CDCl3): 7,89 (d, J=2 Hz, 1H), to 7.61 (DD, J=2, 8.7 Hz, 1H), EUR 7.57 (d, J=2 Hz, 1H), 7,45 (d, J=8,4 Hz, 1H), 7,16 (m, 2H), 6,99 (m, 2H), is 6.54 (d, J=2.3 Hz, 1H), or 4.31 (m, 1H), 4,18 (m, 2H), 2,93 (m, 4H), 2,60 (m, 2H), 2,47 (m, 3H), 2,88 (s, 3H).

EXAMPLE 8

1-[1-[2-(2-Piperazine-1-yl-ethylamino)-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-14,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A. 1-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tailpipes-1-yl)propan-2-he

A solution of DMSO (3.55 ml, 50 mmol) in CH2Cl2(7 ml) was treated with oxalylamino (2,90 ml, 33 mmol) at -78°C and was stirred for 30 minutes. Then was slowly added a solution of 1-[1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (1.8 g, 3.3 mmol) in CH2Cl2(7 ml) and the reaction mixture was stirred additionally for 30 minutes before quenching with triethylamine (18,4 ml, 132 mmol). The reaction mixture was slowly heated to 25°C and diluted with EtOAc (50 ml) and saturated NaHCO3(30 ml). The organic layer was separated, washed with H2O (2×50 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 2-5% MeOH/CH2Cl2) gave 1.50 g (83%) of light yellow powder. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,35. Mass spectrum (elektrorazpredelenie): m/z 540,3 ([M+H]+C29H32F3N5O2calculated to 539.3).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,78 and 7.62 (AB system, Jab=8,2 Hz, 2H), 7,70 and to 7.64 (AB system, Jab=8,4 Hz, 2H), 7.18 in-to 6.95 (m, 4H), 5,10 (s, 1H), 5,07 (s, 1H), 4,84 (s, 1H), and 4.68 (s, 1H), 3.96 points (t, J=4.4 Hz, 1H), 3,78 (t, J=4.4 Hz, 1H), 3,47 (s, 4H), to 3.34 (s, 2H), 2,74-to 2.65 (m, 6H), to 2.29 (s, 3H), 2,20 (C, 1,5H), 2,17 (s, 1,5H).

B. 1-[1-[2-(2-what piperazin-1 ylethylamine-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon.

A solution of 1-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-3-(4-o-tailpipes-1-yl)propan-2-she (54 mg, 0.1 mmol) in 1,2-dichloroethane (0.5 ml) was treated with 1-(2-amino-ethyl) - piperazine (26 μl, 0.2 mmol) and glacial acetic acid (34 μl, 0.6 mmol) at 25°C and was stirred within 30 minutes. Added triacetoxyborohydride sodium (63,6 mg, 0.3 mmol) and the reaction mixture was stirred additionally for 4 hours, after which extinguished CH2Cl2(5 ml) and saturated NaHCO3(5 ml). The organic layer was separated, washed with H2O (2×5 ml), dried over Na2SO4and concentrated. Preparative TLC (silica, 10% MeOH/CH2Cl2gave 22 mg (35%) light yellow film. TLC (10% MeOH/CH2Cl2): Rf=0,2. Mass spectrum (elektrorazpredelenie): m/z 653,3 ([M+H]+C35H47F3N8O calculated 652,4).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,78-of 7.60 (m, 4H), 7.18 in-PC 6.82 (m, 4H), 4,88-4,30 (m, 2H), 4,23-3,90 (m, 2H), 3,85-3,70 (m, 2H), 3,22-to 2.85 (m, 10H), 2,85-2,30 (m, 15H), is 2.30 (s, 3H), of 2.21 (s, 1,5H), 2,17 (s, 1,5H).

EXAMPLE 9

tert-Butyl ester 1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl)-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

A. tert-Butyl ether 3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

p-Toluensulfonate acid (0055 g, 0.29 mmol) and morpholine (4,76 ml, 54 mmol) was added to a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (10.3 g, 52 mmol) in benzene (22 ml). The reaction mixture was heated in a flask equipped with a reflux condenser and a trap Dean-stark boiling under reflux for 20 hours. The reaction mixture was cooled and concentrated in vacuum, obtaining the enamine, which was used without further purification. The enamine was dissolved in CH2Cl2(60 ml) and cooled to 0°C. was Added triethylamine (8,67 ml, 62 mmol), followed by adding dropwise 4-iodobenzoyl chloride (13.8 g, 52 mmol)dissolved in CH2Cl2(10 ml). The reaction mixture was left to warm to room temperature and was stirred for 72 hours. The reaction mixture was poured into water (200 ml) and CH2Cl2layer was separated, dried (Na2SO4) and concentrated. The oil obtained was placed in EtOH (200 ml) and treated with hydrazine (4,88 ml, 155 mmol) at 0°C. the Reaction mixture was left to warm to room temperature and was stirred for 17 hours. The mixture was concentrated and the resulting material was washed with EtOAc, getting 9,52 g (43%) of white solids. TLC (silica, 10% acetone/CH2Cl2): Rf=0,18. Mass spectrum (elektrorazpredelenie): m/z 426,0 (426,1 calculated for C17H20IN3O2[M+H]+).1H the Mr (400 MHz, CDCl3): 7,74 (user. s, 2H), 7,31 (user. d, J=8.0 Hz, 2H), 4,63 (user. s, 2H), of 3.73 (user. s, 2H), 2,77 (user. s, 2H), 1,49 (s, 9H).

B. tert-Butyl ether 3-(4-itfeel)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

The cesium carbonate (1.84 g, the 5.65 mmol) was added to a solution of epichlorohydrin (3,68 ml, 47,05 mmol) and tert-butyl methyl ether 3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (2.0 g, 4,71 mmol) in DMF (10 ml). The reaction mixture was left to mix for 24 hours, then distributed between aqueous NaHCO3and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and saturated salt solution, dried (Na2SO4) and concentrated. Purification of column chromatography (silica, 0-10% acetone/CH2Cl2) gave of 2.26 g (69%) of white foam substance. TLC (silica, 10% acetone/CH2Cl2): Rf=0,44. Mass spectrum (elektrorazpredelenie): m/z 482,0 (482,1 calculated for C20H24IN3O3, [M+H]+).1H NMR (400 MHz, CDCl3): 7,60 (user. s, 2H), 7,28 (user. d, J=8,2 Hz, 2H), 4,48 (user. s, 2H), 4,32 (user. d, J=14,8 Hz, 1H), 3,99 (DD, J=15,0, a 5.4 Hz, 1H), 3,61 (user. s, 1H), 3,26-3,20 (m, 1H), 2,72 (t, J=4.4 Hz, 1H), 2,65-of 2.58 (m, 2H), 2.40 a (user. s, 1H), of 1.36 (s, 9H).

C. tert-Butyl ester 1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid.

Hydrate triftoratsetata ytterbium (III) (0,193 g, 0,311 mmol) and 1-(2-cyanophenyl)piperazine (0,292 g, 1.56 mmol) was dissolved in CH2Cl2(2 ml) was added to a solution of tert-butyl methyl ether 3-(4-itfeel)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid in CH2Cl2(5 ml). The reaction mixture was left to mix for 48 hours at 25°C. Purification with flash chromatography (silica, 0-15% acetone/CH2Cl2) give 392 mg (56%) of a white foam substance. TLC (silica, 10% acetone/CH2Cl2): Rf=0,41. Mass spectrum (elektrorazpredelenie): m/z 669,2 (669,2 calculated for C31H37IN6O3[M+H]+).1H NMR (400 MHz, CDCl3): 7,73 (user. s, 2H), 7,58-7,56 (m, 1H), 7,52-of 7.48 (m, 1H), 7,39 (user. d, J=7,1 Hz, 2H),? 7.04 baby mortality-7,00 (m, 2H), 4,60 (user. s, 2H), 4,06-Android 4.04 (m, 2H), 4,06-Android 4.04 (m, 1H), 3,76-3,70 (m, 2H), 3,26 (user. s, 4H), 2,84-of 2.38 (m, 7H), 1.56 to 1,53 (m, 2H), to 1.48(s,9H).

EXAMPLE 10

Amide 1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

A. 2-(4-{2-Hydroxy-3-[3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzonitrile.

Triperoxonane acid (3 ml) was added to a solution of tert-butyl ester 1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carbon is Oh acid (0,402 g, 0,601 mmol) in CH2Cl2(3 ml) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, then diluted with EtOAc. The organic layer is washed with aqueous NaHCO3and saturated salt solution, dried (Na2SO4) and concentrated, obtaining Amin (0,342 g, 100%) as a yellowish foam substance. TLC (silica, 10% acetone/CH2Cl2): Rf=0,14. Mass spectrum (elektrorazpredelenie): m/z 569,2 (569,1, calculated for C26H29IN6O, [M+H]+).1H NMR (400 MHz, CDCl3:CD3OD(6:1)): 7,73 (d, J=8.6 Hz, 2H), 7,56 (DD, J=7,6, 1.8 Hz, 1H), 7,52 (t, J=8.0 Hz, 1H), 7,25 (d, J=8.6 Hz, 2H), to 7.09 (t, J=7,6 Hz, 1H), 7,02 (DD, J=8,4 Hz, 1H), 4,43 is 4.36 (m, 1H), or 4.31 (s, 2H), 4,21 (DD, J=14,1, and 4.5 Hz, 1H), 4,11 (DD, J=14,5, 6.3 Hz, 1H), 3,54-to 3.49 (m, 2H), 3,40-3,24 (m, 8H), 3,18-of 3.06 (m, 3H), 3,03-2,95 (m, 3H).

B. Amide 1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid.

Diisopropylethylamine (mean HDI of 0.531 ml, was 3.05 mmol), DMAP (5 mg) and trimethylsilyltriflate (0,413 ml of 3.05 mmol) was added to a solution of 2-(4-{2-hydroxy-3-[3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzonitrile in pyridine (3 ml) and CH2Cl2(6 ml). The reaction mixture was stirred for 20 hours, then distributed between aqueous NaHCO3and CH2Cl2. Containing CH2Cl2layer was washed with saturated salt solution, dried (Na2SO4 ) and concentrated. The obtained product was dissolved in CH2Cl2(5 ml) and was treated with 21 wt.% ethoxide sodium in EtOH (0.5 ml) for 3 hours. The reaction mixture was washed with saturated salt solution, dried (Na2SO4) and concentrated. Purification of column chromatography (silica, 0-10% MeOH/CH2Cl2) gave 290 mg (78%) specified in the connection header. HPLC (reversed phase), tR=4,21 minutes Mass spectrum (elektrorazpredelenie): m/z 612,2 (612,5 calculated for C27H30IN7About2M++H).1H NMR (400 MHz, CDCl3): 7,73 (d, J=8.6 Hz, 2H), EUR 7.57 (DD, J=7,6, and 1.6 Hz, 1H), 7,50 (t, J=7.8 Hz, 1H), was 7.36 (d, J=8.6 Hz, 2H), 7,05 (t, J=7,6 Hz, 1H), 7,00 (d, J=8,4 Hz, 1H), with 4.64 (user. s, 2H), 4,57 (user. s, 2H), 4,30 (user. s, 1H), 4,20 (DD, J=14,1, 3.3 Hz, 1H), 4,06 (DD, J=14,1, 6.3 Hz, 1H), 3,82-the 3.65 (m, 2H), 3,29-3,20 (m, 4H), 3.04 from is 2.80 (m, 6H), 2,68 (user. s, 2H).

EXAMPLE 11

1-[5-Carbarnoyl-3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-1-ylmethyl]-2-[4-(2-cyanophenyl)piperazine-1-yl]ethyl ester carbamino acid

Specified in the title compound (13 mg, 3%) was obtained with 1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid as described in example 10. Mass spectrum (elektrorazpredelenie): m/z 655,2 (655,2 calculated for C28H31IN8About3, [M+H]+). HPLC (reversed phase): t R=6,29 min1H NMR (400 MHz, CDCl3): of 7.69 (d, J=8.1 Hz, 2H), 7,50 (d, J=7,52, 1H), 7,43 (t, J=8,1 Hz, 1H), 7,31 (d, J=8.1 Hz, 2H), of 6.96 (t, J=9.0 Hz, 2H), with 4.64 (user. s, 2H), 4,08 (d, J=16,8 Hz, 2H), 3.96 points (DD, J=14,0, and 6.6 Hz, 1H), 3,80 at 3.69 (m, 2H), 3,10-2,80 (m, 4H), 2,66 (user. s, 2H), 2,50 (user. s, 2H).

EXAMPLE 12

1-{3-(3-Amino-4-chlorophenyl)-1-[2-hydroxy-3-(4-o-tolyl-piperazine-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}alanon

A. 1-[3-(4-Chloro-3-nitrophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

Into a flask equipped with a trap Dean-stark download N-acetyl-4-piperidone (27,29 g, 137 mmol), piperidine (16.5 ml, 129 mmol), p-toluensulfonate acid (0.5 g) and benzene (150 ml). The mixture was heated to 125°C. After 8 hours the mixture was left to cool and was concentrated in vacuum, obtaining the corresponding enamine (35 g). The solution of the enamine (a 3.87 g, 20.0 mmol) in dichloromethane (24 ml) was treated with triethylamine (3,07 ml of 22.0 mmol) and 4-chloro-3-nitrobenzoyl chloride (4,84 g of 22.0 mmol). The reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 16 hours. To the reaction mixture was added hydrazine (of 1.88 ml, 60 mmol). This solution was stirred at room temperature for additional 16 hours. The solvents were removed under reduced pressure. To the residue for the formation of the suspension was added ethyl acetate (100 ml). This suspension was filtered and dried, the floor is tea 6.4 g (100%) yellow solid. Mass spectrum (elektrorazpredelenie): m/z 321,0 (321,0 calculated for C14H13ClN4O3, [M+H]+).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 8,10-of 8.00 (m, 3H), of 4.90 (s, 0,8H), is 4.85 (s, 1,2H), 3.96 points (m, 2H), 2.95 and (m, 2H), measuring 2.20 (s,3H).

B. 1-[3-(4-Chloro-3-nitrophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon.

A solution of 1-[3-(4-chloro-3-nitrophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (6.4 g, 20.0 mmol) in DMF (60 ml) was treated with cesium carbonate (13,0 g, 40 mmol) and epichlorohydrin (15.6 ml, 200.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for additional 24 hours before being diluted with ethyl acetate (350 ml) and water (50 ml). The organic layer was separated, washed with water (2×50 ml), saturated salt solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography (silica, 10% acetone/CH2Cl2)to give 7.5 g (83%) of light yellow powder. Mass spectrum (elektrorazpredelenie): m/z 377,0 (377,0 calculated for C17H17ClN4O4, [M+H]+).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 8,15-with 8.05 (m, 1H), 7,75-the 7.65 (m, 1H), 7,55 was 7.45 (m, 1H), 4.80 to the 4.65 (m, 1,2H), 4,60 (s, 0,8H), 4,45 is 4.35 (m, 1H), 4,08-was 4.02 (m, 1H), 3,92-of 3.80 (m, 1H), 3,70-3,63 (m, 1H), 3,30-3,20 (m, 1H), 2,90-to 2.67 (m, 3H), 2,55-2,48 (m, 1H), 2,15 (s, 1,7H), 2,10 (s, 1,3H).

C. 1-{3-(4-Chloro-3-nitrophenyl)-1-[2-hydroxy-3-(4-o-tollip perazin-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}alanon

A solution of 1-[3-(4-chloro-3-nitrophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (0,754 g, 2.0 mmol) in dichloromethane (10 ml) was treated with ytterbium triflate(III) (0.25 g, 0.40 mmol) and 1-(2-were)piperazine (0,705 g, 4.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours and was diluted with dichloromethane (100 ml) and water (50 ml). The organic layer was separated, washed with water (2×50 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified column chromatography (silica, 5% MeOH/CH2Cl2), receiving 0,98 g (90%) of the desired product as a pale yellow solid. Mass spectrum (elektrorazpredelenie): m/z 553,2 (553,2 calculated for C28H33ClN6O4, [M+H]+).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 8,25-of 8.15 (m, 1H), 7,75-of 7.70 (m, 1H), 7,63-of 7.55 (m, 1H), 7,20-7,10(m, 2H), 7,05-to 6.95 (m, 2H), 4,90-4,70 (m, 1H)and 4.65 (s, 1H), 4,30-to 4.15 (m, 2H), 4,10-3,70 (m, 4H), 3.00 and-to 2.40 (m, 12H), 2,20(, 3H), of 2.15 (s, 1,5H), 2,10 (s, 1,5H).

D. 1-{3-[3-Amino-4-chlorophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}Etalon.

To Hydrosulphite solution of sodium (1.28 g, 7,3 mmol) in 30 ml of water was added 1-{3-(4-chloro-3-nitrophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl}Etalon (810 mg, 1.5 mmol) in 15 ml THF. The reaction mixture plumage is shivali at room temperature for 5 minutes. The color of the solution changed from light yellow to colorless. A solution of hydrogen chloride (1N., 10 ml) was added to the reaction mixture. This solution was stirred at room temperature for 30 minutes and treated with a saturated solution of sodium bicarbonate until then, until the solution pH reached a value of from 7 to 8. The product was extracted with dichloromethane (3×80 ml). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure, obtaining the remainder. This residue was purified column chromatography (silica, 5-20% MeOH/CH2Cl2), getting 644 mg (84,1%) specified in the connection header. Mass spectrum (elektrorazpredelenie): m/z 523,3 (523,3 calculated for C28H35ClN6O2, [M+H]+).1H NMR (CDCl3, 400 MHz, mixture of two rotamers): 7,30-6,70 (m, 7H), 4.80 to 4,60 (m, 1H), 4,55 (s, 1H), 4,20-of 4.05 (m, 4H), 3.95 to 3,90 (m, 2H), 3,80-of 3.60 (m, 2H), 2,90-of 2.30 (m, 9H), of 2.20 (s, 3H), of 2.15 (s, 1,5H), 2,10 (s, 1,5H).

EXAMPLE 13

(R)-1-(3-(4-Bromophenyl)-1-{3-[4-(5-chloro-2-were)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)Etalon.

A. (2S)-1-tert-Butyldimethylsilyloxy.

To a cooled to 0°C to a solution of R-(+)-glycidol (3.88 g, a 52.4 mmol) in CH2Cl2(100 ml) was added tert-BUTYLCARBAMATE (9,41 g of 62.4 mmol), then Et3N (13,5 ml, to 96.8 mmol). The solution was left to heat the sterile until 23° C under stirring for 17 hours. Received a pink solution was diluted with Et2O (250 ml) and stirred additionally for 30 minutes. The solution was distributed between Et2O (800 ml) and saturated aqueous NaHCO3(200 ml). Containing Et2O layer was washed saturated aqueous NaHCO3(250 ml), H2O (3 × 200 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrated. Purification of the residue column chromatography (silica, 5-10% Et2O/hexane) gave 8,21 g (84%) specified in the connection header. TLC (silica, 10% Et2About/hexane): Rf=0,5.1H NMR (CDCl3, 400 MHz): 3,85 (DD, J=11,9, and 3.2 Hz, 1H), 3,66 (DD, J=11,9, and 4.8 Hz, 1H), 3,09 (m, 1H), 2,77 (DD, J=5,0, 4,2 Hz, 1H), 2,64 (DD, J=5,2, 2.7 Hz, 1H), from 0.90 (s, 9H), and 0.08 (s, 3H), of 0.07 (s, 3H).

B. 1-[3-(4-Bromophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

Into a flask equipped with a trap Dean-stark download N-acetyl-4-piperidone (100,1 g, 709 mmol), piperidine (68 ml, 779 mmol), p-TsOH (3.7 g) and benzene (500 ml). The mixture was heated to 125°C. After 17 hours the mixture was left to cool and divide into two portions. To a cooled to 0°C the solution of the enamine (approximately 355 mmol) in CH2Cl2(320 ml) for 15 hours was added dropwise a solution of p-bromobenzoyl chloride (70,0 g, 319 mmol) in CH2Cl2(400 ml). The mixture was then left to warm to 23°C and stirred EXT is niteline for 5 hours The solution was treated with 1H. HCl (500 ml) and was intensively stirred for 1.5 hours. The layers were separated and the aqueous layer was extracted with CH2Cl2(2×300 ml). The combined extracts washed with saturated aqueous NaHCO3(300 ml), H2O (300 ml), saturated salt solution (300 ml), dried over Na2SO4and concentrated. The residue was dissolved in MeOH (300 ml) and was treated with NH2NH2(50,0 ml of 1.59 mol). The mixture was stirred for 17 hours, after which the precipitate was collected by filtration and dried in the air, receiving 52 g (50%) specified in the title compound, which was suitable for use without additional purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3. Mass spectrum (elektrorazpredelenie): m/z calculated for C14H1679BrN3O [M+H]+, 320,04 found 320.1H NMR (CD3OD/CDCl3, 400 MHz, mixture of amide rotamers): 7,53 and 7.35 (A and B system AA'BB', J=8.5 Hz, 2H), 7,51 and 7,39 (A and B system AA'BB', J=8.6 Hz, 2H), 4.72 in (s, 2H), 4,58 (s, 2H), 3,85 (t, J=5,9 Hz, 2H), 3,71 (t, J=5.8 Hz, 2H), of 2.81 (t, J=5.8 Hz, 2H), 2,74 (t, J=5.8 Hz, 2H), 2,16 (s, 3H), 2,11 (s, 3H).

C. (S)-1-[3-(4-Bromophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of KHMDS in toluene (0.5 M, and 3.7 ml of 1.85 mmol) was added to a 0°C to a solution of 1-[3-bromophenyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone (492 mg, 1.54 mmol) in DMF (4.0 ml). The mixture was stirred those which begins 1 hour, then added by syringe (2S)-1-tert-butyldimethylsilyloxy (870 mg, to 4.62 mmol). The mixture was stirred additionally for 48 hours and was distributed between EtOAc (300 ml) and saturated aqueous NaHCO3(100 ml). The aqueous layer was extracted with EtOAc (2×100 ml). The combined extracts were washed H2O (2×100 ml), saturated salt solution (100 ml), dried over Na2SO4and concentrated. The residue was dissolved in MeOH (50 ml) and was treated with CSA (97 mg). The mixture was stirred for 17 hours and then concentrated to dryness. The residue is suspended in MeC(OMe)3(50 ml) and stirred additionally for 17 hours. The mixture was diluted with EtOAc (400 ml) and washed with saturated aqueous NaHCO3(50 ml), H2O (2×50 ml), saturated salt solution (50 ml), dried over Na2SO4and concentrated. The crude complex orthoepy was dissolved in CH2Cl2(5 ml), cooled to 0°C and treated AcBr (of 0.18 ml, 2.4 mmol). The mixture was left to warm with stirring for 4 hours before treatment, as described above. The crude obtained acetylmuramic was dissolved in MeOH (50 ml)was treated with K2CO3(207 mg, 1.50 mmol) and was stirred for 4 hours. The reaction mixture was diluted with EtOAc (400 ml) and washed with saturated aqueous NH4Cl (100 ml). Containing EtOAc layer was washed H2O (2×100 ml), saturated salt solution 100 ml), dried over Na2SO4and concentrated. The crude product was purified column chromatography (silica, 10-40% acetone/CH2Cl2)to give 158 mg (27%) specified in the connection header. Analysis of chiral HPLC (Daicel OD, 0,5% Et2NH/MeOH) showed >95% optical purity. HPLC (reversed phase): tR=4,90 minutes Mass spectrum (elektrorazpredelenie): m/z calculated for C17H1979BrN3O2[M++H], 376,07 found 376,0.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 7,47 (l with a small splitting (partial fuzzy), J=8.5 Hz, 2H), 7,44 (m, 4H), 7,38 (d with a small splitting, J=8.5 Hz, 2H), 4,71 and with 4.64 (A and B of AB Quartet, Jab=15.7 Hz, 2H), 4,51 (s, 2H), 4,39 (DD, J=15,1, 2.5 Hz, 1H), 4,34 (DD, J=15,0, 2,9 Hz, 1H), was 4.02 (DD, J=5,2, 3,9 Hz, 1H), 3,98 (DD, J=5,3, and 3.7 Hz, 1H), 3,83 (m, 2H), to 3.64 (m, 2H), 3,25 (user. m, 2H), 2,80-2,60 (m, 6H), 2,46 (DD, J=4,6, and 2.6 Hz, 1H), of 2.38 (DD, J=4,6, and 2.6 Hz, 1H), 2,10 (s, 3H), of 2.06 (s, 3H).

D. (R)-1-(3-(4-Bromophenyl)-1-{3-[4-(5-chloro-2-were)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)Etalon.

(S)-1-[3-(4-Bromophenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon (37 mg, 0.98 mmol) and 4-(2-methyl-5-chlorophenyl)piperazine (36 mg, 0,17 mmol) were combined in EtOH (0.4 ml) and heated to 70°C. After 18 hours the mixture was left to cool, was diluted in CH2Cl2and was purified preparative TLC (silica, 8% MeOH/CH2Cl2), receiving 35 mg, 61%) specified in the connection header. HPLC (reversed phase): tR=to 4.41 min Mass spectrum (elektrorazpredelenie): m/z calculated for C28H3435Cl79BrN6O2[M++H], 586,16 found 586,2,1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): 7,56 (d (partial fuzzy), J=8.5 Hz, 2H), 7,53 (s, 4H), of 7.48 (d, J=8.5 Hz, 2H), 7,08 (user. d, J=8.5 Hz, 1H), 6,95 (m, 2H), 4,85 and 4.73 (A and B of AB Quartet, Jab=15.6 Hz, 1H), to 4.62 (s, 1H), 4,20 (m, 2H), Android 4.04 (m, 2H), 3,90-3,71 (m, 2H), 2,92 of $ 2.53 (m, 11H), of 2.21 (s, 1,5H), of 2.16 (s, 1,5H).

EXAMPLE 14

2-(4-{3-[5-Acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-forproper}piperazine-1-yl)benzonitrile.

A solution of 2-(4-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile (150 mg, 0.27 mmol) in CH2Cl2(1 ml) was treated with DAST (Et2NSF3, 7 µl of 0.60 mmol) at -78°C. the Reaction mixture was slowly heated to 25°C for 1 hour and then up to 60°C for an additional 2 hours. Preparative TLC (silica, 5% MeOH/CH2Cl2) gave 75 mg (50%) specified in the title compound as a pale yellow powder. TLC (5% MeOH/CH2Cl2): Rf=0,28. Mass spectrum (elektrorazpredelenie): m/z 555,2 ([M+H]+C29H30F4N6O calculated 554,2).1H NMR(CDCl3, 400 MHz, mixture of two rotamers): 7,71 and to 7.59 (AB system, Jab=8,2 Hz, 2H), 7,66 and 7.62 (AB system, Jab=8,4 Hz, 2H), 7,50-7,38 (m, 2H), of 6.96-6,92 (m, 2H), 5,01 (PD, J=49,0, 3.0 Hz, 1H), 4,77 and 4.73 (AB system, Jab=15.7 Hz, 1,1H), 4,59 (s, 0,9H), to 4.41-4,18 (m, 2H), 3.95 to of 3.80 (m, 1H), 3,69 (DD, J=5,5, 5,5 Hz, 1H), 3,18 (m, 4H), 2,83-to 2.65 (m, 8H), and 2.14 (s, 1,6H), 2,10 (s, 1,4H).

EXAMPLE 15

Methyl ether (3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)octoxynol acid

A. 4-Chloro-3-methylbenzoate

To a suspension 52,55 g (0.31 mol) of 4-chloro-3-methylbenzoic acid in CH2Cl2(1.2 l) with DMF (1 ml) at 0°C in an atmosphere of N2with gas output, barotrauma after 2,5h. the sodium hydroxide solution was added 29,56 ml (0,339 mol) of oxalicacid. The mixture was left to warm to room temperature for 3 hours. The reaction mixture was concentrated and used further in crude form.

C. tert-Butyl ether 3-(4-chloro-3-were)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

To a stirred solution of 55.8 g (0.28 mol) of tert-butyl methyl ether 4-oxopiperidin-1-carboxylic acid and 25.7 g (0.29 mol) of the research in benzene (125 ml) was added a catalytic amount (˜0.25 g) p-toluensulfonate acid. The mixture was boiled under reflux for 10 hours with a trap Dean-stark. The solvent was removed under reduced pressure, obtaining a brown oil. accidenly product was diluted in CH 2Cl2(400 ml) was added 46,83 ml (0.34 mol) Et3N. the Mixture was cooled to 0°C and slowly added via addition funnel over 2 hours a solution of 4-chloro-3-methylbenzonitrile (0.35 mol) in CH2Cl2(200 ml). The reaction mixture was poured into water (400 ml) and CH2Cl2layer was separated, dried (Na2SO4) and concentrated. The oil obtained was placed in EtOH (400 ml) and was treated with 35 ml of hydrazine at 0°C. the Reaction mixture was left to warm to room temperature and was stirred for 17 hours, during this time was the formation of a white precipitate. The volume of the reaction mixture was reduced to ˜150 ml) was added Et2O (750 ml). The suspension was intensively stirred for 2 hours and filtered, then washed with Et2O (2×200 ml) and dried in vacuum, obtaining 50,74 g (52% in 3 stages) tert-butyl ether 3-(4-chloro-3-were)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid as a pale orange solid. Mass spectrum (elektrorazpredelenie): exact mass calculated for C18H22ClN3About2, 347,1; m/z found, 348,1 [M+H]+.1H NMR (400 MHz, CDCl3): 7,26-the 7.43 (m, 4H)and 4.65 (user. s, 2H), of 3.73 (user. s, 2H), 2,77 (user. s, 2H), 2,34 (s, 3H), 1,49 (s, 9H).

C. tert-Butyl ether 3-(4-chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

K R is the target tert-butyl ester 3-(4-chloro-3-were)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (18,26 g, 53 mmol) and epichlorohydrin (41,12 ml, 526 mmol) in DMF (100 ml) was added cesium carbonate (20,56 g, 63 mmol). The reaction mixture was left to mix for 72 hours, diluted with EtOAc (200 ml) and washed with saturated solution of NaHCO3and a saturated solution of salt. The organic layer was dried over Na2SO4concentrated and was purified column chromatography (silica, 20% acetone/CH2Cl2)to give tert-butyl ether 3-(4-chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (12.0 g, 57%). TLC (silica, 20% acetone/CH2Cl2): Rf=0,68. Mass spectrum (elektrorazpredelenie) m/z 491,2 (491,2 calculated for C27H31ClN6O, [M+H]+).1H NMR (400 MHz, CDCl3): of 7.55 (s, 1H), was 7.36 (m, 2H), br4.61 (m, 2H), to 4.38-4,47 (m, 1H), 4,11 (DD, J=14,3, 5.7 Hz, 1H), 3,67-with 3.79 (m, 2H), 3,34 (m, 1H), and 2.83 (t, J=4.5 Hz, 1H), 2,75 (m, 2H), of 2.51 (m, 1H), 2,41 (s, 3H), of 1.48 (s, 9H).

D. tert-Butyl ether 3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

tert-Butyl ether 3-(4-chloro-3-were)-1-oxiranylmethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (5,33 g, 13,2 mmol) and 1-(2-cyanophenyl)piperazine (2,97 g, 15,86 mmol) was partially dissolved in EtOH (50 ml) and triethylamine (2 ml). The reaction mixture was heated at 80°C for 18 hours. The mixture was concentrated and was purified in the column chromatography (silica, 20% acetone/CH2Cl2)to give tert-butyl ether 3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (6,51 g, 83%) as a yellow solid. TLC (silica, 20% acetone/CH2Cl2): Rf=0,35. Mass spectrum (elektrorazpredelenie): m/z 591.3 (591,3 calculated for C32H39ClN6O3, [M+H]+).

E. 2-(4-{3-[3-(4-Chloro-3-were)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile

tert-Butyl ether 3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (1.26 g, 2,13 mmol) was dissolved in triperoxonane acid (3 ml) and CH2Cl2(3 ml) and left to mix for 2 hours. The reaction mixture was concentrated, was placed in EtOAc (50 ml) and washed with aqueous solution of NaHCO3(2×25 ml). Containing EtOAc layer was dried over Na2SO4and concentrated, obtaining 2-(4-{3-[3-(4-chloro-3-were)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile (of 1.05 g, 99%) as a yellow foam substance. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,27. Mass spectrum (elektrorazpredelenie): m/z 491,2 (491,2 calculated for C27H31ClN6O, [M+H]+).1H NMR (400 MHz, CDCl3):9,8 (user. s, 1H), 7,55 (d, J=7,6 Hz, 1H), 7,50 (t, J=8,2 Hz, 1H), 7,38 (s, 1H), 7,31 (d, J=8,2 Hz, 1H), 7,20 (d, J=8,2 Hz, 1H), 7,11 (t, J=8,2 Hz, 1H), 6,98 (d, J=8,2 Hz, 1H), 4,56 (user. s, 1H), 4,12-4,32 (m, 4H), 2,98-3,51 (m, 13 H), to 2.35 (s, 3H).

F. Methyl ether (3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)octoxynol acid

2-(4-{3-[3-(4-Chloro-3-were)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl)piperazine-1-yl)benzonitrile (58 mg, the amount of 0.118 mmol) was dissolved in CH2Cl2(0,59 ml) and treated with METHYLCHLOROSILANE (16 mg, 0,129 mmol). The reaction mixture was left to mix for 18 hours at room temperature. Column chromatography (silica, 2-10% MeOH/CH2Cl2) gave methyl ether (3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)octoxynol acid (54 mg, 79%) as a white solid. Mass spectrum (elektrorazpredelenie): m/z 577,3 (577,2 calculated for C30H33ClN6About4, [M+H]+).1H NMR (400 MHz, CDCl3): 7,32 to 7.62 (m, 5H), 7,14 (t, J=7,6 Hz, 1H), 7,05 (d, J=8,2 Hz, 1H), 4,59-4,80 (m, 3H), 4,12-to 4.28 (m, 2H), 3,92 (s, 3H), 3,78-3,86 (m, 2H), 3,44-of 3.60 (m, 5H), 3.15 and is 3.40 (m, 4H), 2,83 was 3.05 (m, 2H), 2,41 (s, 3H).

EXAMPLE 16

5-Methanesulfonyl-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

A.1-Methanesulfonamido-4-one

Potassium carbonate (324 g, 2340 mmol) was added to a solution of the hydrochloride monohydrate of 4-piperidone (90 g, 586 mmol) in chloroform (300 ml) and water (300 ml). The suspension was cooled to 0°C and treated with methylsulfonylamino (136 ml, 1760 mol), adding dropwise within 1 hour (observed gas evolution). The reaction mixture was left to shake things up within 72 hours and distributed between CH2Cl2(500 ml) and saturated aqueous NaHCO3(500 ml). The aqueous layer was extracted with CH2Cl2(3×200 ml). The organic layer was washed with 1% KHSO4(250 ml), dried (Na2SO4) and concentrated, obtaining 90,5 g (87%) of white solids. Mass spectrum (elektrorazpredelenie): exact mass calculated for C6H11NO3S, 177,1; m/z found, 178,1 [M+H]+. HPLC (reversed phase): tR=2,19 min1H NMR (400 MHz, CDCl3): of 3.60 (t, J=6.5 Hz, 4H), 2,89 (s, 3H), at 2.59 (t, J=6.3 Hz, 4H).

B. 5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

p-Toluensulfonate acid (of 1.34 g, 7.0 mmol) and morpholine (25,83 ml, 296 mmol) was added to a solution of 1-methanesulfonyl-piperidine-4-it (50.0 g, 282 mmol) in benzene (282 ml). The reaction mixture was heated in a flask equipped with a reflux condenser and a trap Dean-stark boiling under reflux for 15 hours. The reaction mixture was cooled and koncentrirane and in vacuum, getting an enamine, which was used without further purification. The enamine was dissolved in CH2Cl2(200 ml) and cooled to 0°C. were added triethylamine (47,2 ml, 339 mmol), followed by adding dropwise 4-triftormetilfullerenov (42,3 ml, 285 mmol)dissolved in CH2Cl2(82 ml). The reaction mixture was left to warm to room temperature and was stirred for 20 hours. The reaction mixture was washed for 1H. aqueous HCl (250 ml) containing CH2Cl2layer was separated, dried (Na2SO4) and concentrated. The oil obtained was placed in EtOH (300 ml) and treated with hydrazine (by 44.3 ml of 1.41 mol) at 0°C. the Reaction mixture was left to warm to room temperature and was stirred for 24 hours. The mixture was concentrated and the resulting solid was filtered, washing EtOH, and dried in vacuum, obtaining 70 g (72%) 5-methanesulfonyl-3-(4-triptoreline-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine as a white solid. Mass spectrum (elektrorazpredelenie): exact mass calculated for C14H14F3N3O2S, 345,0; m/z found, 346,0 [M+H]+. HPLC (reversed phase): tR=6,33 min1H NMR (400 MHz, CDCl3): 7,72 (s, 4H), 4,58 (s, 2H), 3,69 (t, J=5.7 Hz, 2H), 2,99 (t, J=5.7 Hz, 2H), 2,92 (s, 3H).

C. 3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]prop is n-1-ol

Cs2CO3(33,74 g to 103.5 mmol) was added to a solution of 5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (29,8 g, 86,3 mmol) in anhydrous DMF (70 ml) and was stirred for 25 minutes. Was added 3-bromo-1-propanol (8.6 ml of 13.2 g of 94.9 mmol) and was stirred in an atmosphere of N2at room temperature for 18 hours. To the reaction mixture were added water (500 ml) and was stirred for 5 minutes. Precipitated precipitated substance was filtered and washed with water (4×100 ml) and dried by freeze-drying. The crude compound (31.0 g) was placed in anhydrous DMF (65 ml)was added Cs2CO3(33,74 g to 103.5 mmol) and was stirred for 10 minutes. Was added 3-bromo-1-propanol (8.6 ml of 13.2 g of 94.9 mmol) and MeOH (6.0 ml of 4.75 g, 148 mmol) and stirring was continued in an atmosphere of N2at room temperature for 15 hours. To the reaction mixture were added water (500 ml) and was stirred for 10 minutes. Precipitated precipitated substance was filtered and washed with water (3×100 ml). The filter cake was dissolved in CH2Cl2(200 ml) and washed with saturated salt solution (50 ml), dried (Na2SO4) and concentrated. The solid is triturated with Et2O (200 ml), was filtered off, washed with Et2O and dried, obtaining 16.0 g of the target compound. The mother liquor was chromatographically (silica, 0-10% acetone/EtAc), receiving additional 3.0 g specified in the connection header. The total yield was 54.6%. Mass spectrum (elektrorazpredelenie): calculated for C17H20F3N3About3S, 403,12; m/z found, 404,0 [M+H]+, 426,0 [M+Na]+.1H NMR (400 MHz, CDCl3): 7,71 (d, J=8,2 Hz, 2H), 7,66 (d, J=8.5 Hz, 2H), 4,55 (s, 2H), 4,23 (t, J=6.5 Hz, 2H), 3,70-3,63 (m, 4H), 2,90 (s, 3H), 2,90 (t, J=5,1 Hz, 2H), 2,62 (t, J=5,9 Hz, 1H), 2.06 to (kV, J=6,1 Hz, 2H).

D. 3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]Propionaldehyde.

Periodinane dessa-Martin (Dess-Martin) (3,45 g, 8.2 mmol) was added to a solution of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propan-1-ol (3.0 g, 7.4 mmol) in CH2Cl2(20 ml) at 0°C in an atmosphere of N2. After 15 minutes the reaction mixture was left to warm to room temperature and stirred for another 1.5 hours. The reaction mixture was diluted with Et2O (60 ml) and slowly added 20% aqueous NaHCO3(35 ml). Then added Na2S2O3and stirred at room temperature for 30 minutes. The layers were separated and the aqueous portion was extracted with Et2O (2×30 ml). The combined organic extracts were washed with saturated salt solution, dried (Na2SO4) and concentrated. Liquid chromatography medium pressure (SJH) (1-10% MeOH/CH2Cl2) gave 2,53 g Zell is on aldehyde with 85% yield. Mass spectrum (elektrorazpredelenie): calculated for C17H18F3N3O3S, 401,11; m/z found, 402,1 [M+H], of 434.1 [M+MeOH+H].1H NMR (400 MHz, CDCl3): 9,82 (s, 1H), 7,63 (d, J=8,4 Hz, 2H), 7,58 (d, J=8,4 Hz, 2H), and 4.68 (s, 2H), 4,25 (t, J=6,1 Hz, 2H), 3,63 (t, J=5.8 Hz, 4H), 3,14 (t, J=6,1 Hz, 2H), 2,92 (t, J=5.8 Hz, 2H), of 2.81 (s, 3H).

E. 5-Methanesulfonyl-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]Propionaldehyde (to 0.060 g, 0.15 mmol) and 1-(2-nitrophenyl)piperazine (0,032 g, of) 0.157 mmol) in CH2Cl2(0.5 ml), was added ice AcOH (8,5 μl, 0.15 mmol) and was stirred for 15 minutes at room temperature. Added NaBH(OAc)3level (0.041 g, 0,19 mmol) and stirred under nitrogen atmosphere overnight. Then was added a saturated solution of NaHCO3(0.5 ml) and was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2(0.5 ml). SGH-purification (silica, 2-15% MeOH/CH2Cl2) gave the desired product as a white solid (0,063 g, 71%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0,67. Mass spectrum (elektrorazpredelenie): exact mass calculated for C27H31F3N6O4S, 592,21; m/z found, 593,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,80 (DD, J=1,6, 8,2 Hz, 1H), 7.7 (d, J=8,3 Hz, 2H), of 7.70 (d, J=8,3 Hz, 2H), 7,52 (DDD, J=1,6, 7,3, 8,3 Hz, 1H), 7,19 (DD, J=1,2, 8,3 Hz, 1H), to 7.09 (m, 1H), 4,59 (s, 2H), 4,17 (t, J=6.9 Hz, 2H), 3,71 (t, J=5.8 Hz, 2H), 3,13 (user. t, J=4.8 Hz, 4H), 2,96 (t, J=5.6 Hz, 2H), 2.95 and (s, 3H), 2,66 (user. t, J=4.4 Hz, 4H), of 2.51 (t, J=7,0 Hz, 2H), 2,17 (kV, J=6,9 Hz, 2H).

EXAMPLE 17

1-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]urea

A. tert-Butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid

To a stirred solution of 1,2-dichloro-3-nitrobenzene (0.96 g, 5.0 mmol) and tert-butyl methyl ether piperazine-1-carboxylic acid (0,93 g, 5.0 mmol) in acetonitrile (5 ml) was added K2CO3(to 1.38 g, 10 mmol). The mixture was boiled under reflux for 48 hours. The solvent was removed under reduced pressure. The crude substance was distributed between EtOAc (100 ml) and H2O (20 ml). The organic layer was washed H2O (2×20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10-20% EtOAc/hexane) gave tert-butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid (1.2 g, 70%). TLC (silica, 20% EtOAc/hexane): Rf=0,45. Mass spectrum (elektrorazpredelenie): exact mass calculated for C15H20ClN3O4, 341,1; m/z found, 364,1 [M+Na]+.1H NMR (400 MHz, CDCl3): 7,56 (DD, J=8,2, and 1.4 Hz, 1H), 7,0 (DD, J=8,2, and 1.4 Hz, 1H), 7,13 (t, J=8,2 Hz, 1H), 3,38 of 3.56 (m, 4H), 3,06 (m, 4H), to 1.48 (s, 9H).

B. 1-(2-chloro-6-nitrophenyl)piperazine

tert-Butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid (1,87 g vs. 5.47 mmol) was dissolved in triperoxonane acid (5.0 ml) and CH2Cl2(5.0 ml) and left to mix for 2 hours. The reaction mixture was concentrated, diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4concentrated and was purified column chromatography (silica, 100% CH2Cl2)to give 1-(2-chloro-6-nitrophenyl)piperazine (1.26 g, 95%). Mass spectrum (elektrorazpredelenie): exact mass calculated for C10H12ClN3O2, 241,1; m/z found, 242,1 [M+H]+.1H NMR (400 MHz, CDCl3): rate of 7.54 (DD, J=8,2, 1,6 Hz, 1H), 7,49 (DD, J=8,2, 1,6 Hz, 1H), 7,10 (t, J=8,2 Hz, 1H), is 3.08 (user. s, 4H), 2,99 (user. s, 4H), 2,07-2,12 (m, 1H).

C. 1-{3-[4-(2-Chloro-6-nitrophenyl)piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]Propionaldehyde (0.5 g, 1.25 mmol) and 1-(2-chloro-6-nitrophenyl)piperazine (0,301 g, 1.25 mmol) in CH2Cl2(6 ml) was added sodium sulfate (0,354 g of 2.50 mmol) and triacetoxyborohydride sodium (0,396 g of 1.87 mmol). The mixture was left to mix in to the room temperature during the night. The mixture was diluted with CH2Cl2and washed with water. Containing CH2Cl2layer was dried over Na2SO4and the solvent was removed under reduced pressure. The residue was purified column chromatography (silica, 10% acetone/CH2Cl2)to give 1-{3-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-1,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0,380 g, 49%). Mass spectrum (elektrorazpredelenie): exact mass calculated for C27H30ClF3N6O4S, 626,2; m/z found, 627,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,73 (d, J=8,2 Hz, 2H), 7,66 (d, J=8,2 Hz, 2H), 7,54 (DD, J=8,2, 1.2 Hz, 1H), 7,49 (DD, J=8,2, 1.2 Hz, 1H), 7,10 (t, J=8,2 Hz, 1H), 4,58 (s, 2H), 4,13 (t, J=6.5 Hz, 2H), 3,71 (t, J=5,9 Hz, 2H), 3,01-3,11 (m, 4H), 2.95 points (t, J=5,9 Hz, 2H), 2,92 (s, 3H), 2,42 of $ 2.53 (m, 4H), 2.40 a (t, J=6.5 Hz, 2H), 2,12 (kV, J=6,5 Hz, 2H).

D. 3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenylamine

To a stirred solution of 1-{3-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0,153 g, 0,244 mmol) in EtOH (2,44 ml) was added zinc dust (0,80 mg, 1,22 mmol) and was slowly added acetic acid (0,70 ml). After 15 minutes, the yellow solution became colorless and the excess zinc dust was filtered through a layer of celite. The filtrate was concentrated and the residue was purified is kolonochnoi chromatography (silicon dioxide, 0-10% MeOH/CH2Cl2)to give 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenylamine (0,146 g, 100%). Mass spectrum (elektrorazpredelenie): exact mass calculated for C27H32ClF3N6About2S 596,2; m/z found, 597,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,73 (d, J=8,2 Hz, 2H), 7,66 (d, J=8,2 Hz, 2H), to 6.88 (t, J=8,2 Hz, 1H). 6,63 (t, J=7,6 Hz, 2H), 4,55 (s, 2H), 4,36 (s, 2H), 4,15 (t, J=6.5 Hz, 2H), 3,60-3,70 (m, 4H), of 2.97 (t, J=5.3 Hz, 2H), 2,90 (s, 3H), and 2.83 (d, J=10,8 Hz, 2H), 2,74 (d, J=11.5 Hz, 2H), 2,37 (t, J=6.6 Hz, 2H,), 2,11-of 2.20 (m, 4H).

E. 1-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]urea

To a stirred solution of 3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenylamine (0,062 g, 0.104 g mmol) in CH2Cl2(0,52 ml) was added trimethylsilyltriflate (0,017 ml, 0.125 mmol). The reaction mixture was left to mix for 48 hours at room temperature. The reaction was not completed, therefore, additionally added is 0.017 ml (0.125 mmol) trimethylsilyltriflate and the reaction mixture was heated at 45°C for 10 hours. Column chromatography (silica, 3 to 10% MeOH/CH2Cl2) gave 1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-1-and the]propyl}piperazine-1-yl)phenyl]urea (0.015 g, 22%). Mass spectrum (elektrorazpredelenie): exact mass calculated for C28H33ClF3N7O3S, 639,2; m/z found, 640,2 [M+H]+.1H NMR (400 MHz, CDCl3): compared to 8.26 (user. s, 1H), with 8.05 (d, J=8,2 Hz, 1H), 7,73 (d, J=8,2 Hz, 2H), 7,66 (d, J=8,2 Hz, 2H), to 7.09 (t, J=8,2 Hz, 1H), 6,92 (d, J=8,2 Hz, 1H)and 4.65 (s, 2H), 4,55 (s, 2H), 4,15 (t, J=6,7 Hz, 2H), 3,65-to 3.73 (m, 4H), 2,96 (t, J=5.6 Hz, 2H), 2,87 of 2.92 (m, 2H), 2.91 in (s, 3H), 2,70 (d, J=11,4 Hz, 2H), 2.40 a (t, J=6,7 Hz, 2H), 2,09-2,22 (m, 4H).

EXAMPLE 18

Amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-sulfonic acid

A. tert-Butyl ether 3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

To a stirred solution of 500 g (2.51 mol) of tert-butoxycarbonyl-4-piperidone and 87.1 g (was 2.76 mol) of the research in benzene (1.25 l) was added a catalytic amount (˜0.25 g) p-TsOH. The mixture was boiled under reflux for 36 hours with trap Dean-stark. Half of the solvent was removed under reduced pressure and the resulting solution was cooled and filtered. Then the filtrate was concentrated, obtaining 630 g (94%) of an orange-red oil. The enamine was divided and 320 g (1,19 mol) was diluted in CH2Cl2(1.0 l) was added 165,0 ml (1,19 mol) Et3N. the Mixture was cooled to 0°C and slowly added using a dropping funnel over 1 hour of RA is creative 225 g (1,08 mol) of 4-triftormetilfullerenov in CH 2Cl2(0.5 l). The mixture was left to warm to room temperature and was stirred overnight. The reaction mixture was then diluted 1H. HCl (450 ml) and stirred intensively for 3 hours. The aqueous layer was extracted with CH2Cl2(3×500 ml) and the combined extracts were dried over Na2SO4and the solvent was removed under reduced pressure. The crude oil was diluted with EtOH (1 l) and cooled to 0°C. To this stirred solution was slowly added 115 g (3,57 mol) of hydrazine and the mixture was left to warm to room temperature and was stirred overnight, during this time he formed a white precipitate. The volume of the reaction mixture was reduced to ˜500 ml and cooled. The precipitate was collected, getting 285 g (72% of enamine) of a white solid.1H NMR (400 MHz, CDCl3): 7,63-of 7.55 (m, 4H), 4,58 (user. s, 2H), 3,69-3,62 (user. m, 2H), 2,74 of 2.68 (user. m, 2H), 1,47 (s, 9H).

B. tert-Butyl ester 1-(2-methoxycarbonylethyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

tert-Butyl ether 3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (1.85 g, 5,04 mmol) and methyl acrylate (0,50 ml, 5.6 mmol) were combined in toluene (30 ml) and was heated to 75°C. the resulting mixture was treated with t-BuONa (100 mg) and heating was continued for 48 hours. The mixture was left to cool and distributed between EtOc (300 ml) and NaHCO 3(75 ml). The aqueous layer was extracted with EtOAc (3×75 ml). The combined extracts were dried over Na2SO4and concentrated. Column chromatography (silica, 30 to 60% EtOAc/hexane) give 343 mg (15%) specified in the connection header. TLC (silica, 50% EtOAc/hexane): Rf=0,4. Mass spectrum (elektrorazpredelenie): m/z calculated for C22H27F3N3O4[M++H] 454,20 found 454,1,1H NMR (CDCl3, 400 MHz): 7,75 (user. d, J=8.1 Hz, 2H), to 7.64 (user. s, 2H), 4,63 (user. s, 2H), 4,30 (t, J=6.6 Hz, 2H), 3,75 (user. s, 2H), 3,68 (s, 3H), 2,98 (t, J=6.6 Hz, 2H), 2,79 (user. t, J=5.6 Hz, 2H), to 1.48 (s, 9H).

C. tert-Butyl ester 1-(3-hydroxypropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

A solution of LiBH4(26 mg, 1.2 mmol) in THF (0.5 ml) was added to a cooled to 0°C to a solution of tert-butyl ester 1-(2-methoxycarbonylethyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (317 mg, 0.70 mmol) in THF (4.0 ml). The mixture was stirred for 5 minutes, then further added LiBH4(15 mg) and stirring continued for 17 hours. The mixture was distributed between EtOAc (80 ml) and saturated aqueous NaHCO3(20 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The combined extracts were dried over Na2SO4and concentrated. Column chromatography (silica, 0-8% MeOH/CH Cl2) give 268 mg (95%) specified in the connection header. HPLC (reversed phase), tR=6,82 minutes Mass spectrum (elektrorazpredelenie): m/z calculated for C21H26F3N3O3[M++Na] 448,18 found 448,10,1H NMR (CDCl3, 400 MHz): 7,73 (user. d, J=8,2 Hz, 2H), 7,65 (user. s, 2H), with 4.64 (user. s, 2H), 4,21 (t, J=6.4 Hz, 2H), 3,76 (user. s, 2H), 3,66 (t, J=5.7 Hz, 2H), 2,73 (user. t, J=5.4 Hz, 2H), 2,04 (kV, J=6,1, 2H), to 1.48 (s, 9H).

D. tert-Butyl ester 1-(3-oxopropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

Periodinane dessa-Martin (1,43 g, to 3.36 mmol) was added in portions to a stirred solution of tert-butyl ester 1-(3-hydroxypropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (1.30 grams, of 3.05 mmol) in CH2Cl2(15 ml) at 0°C in an atmosphere of N2. Then the reaction mixture was stirred at 0°C for 15 minutes and left to warm to room temperature. After stirring at room temperature for 1.5 hours the reaction mixture was diluted with Et2O (50 ml) and was slowly added to a saturated solution of NaHCO3(15 ml) (Caution! The evolution of gas). Then added Na2S2O3.5H2O (5.31g, with 21.4 mmol) and was stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with Et2O (2×30 ml). The combined extracts p is washed with saturated salt solution, dried (Na2SO4) and concentrated. SCH (1-10% MeOH/CH2Cl2) gave the aldehyde yield of 79% (1,02 g). TLC (silica, 10% MeOH/CH2Cl2): Rf=0,67. Mass spectrum (elektrorazpredelenie) calculated for C21H24F3N3O3, 424,2 ([M+H]+), m/z found, 424,2,1H NMR (400 MHz, CDCl3): 9,82 (s, 1H), 7,65 (user. d, J=8.0 Hz, 2H), 7,54 (user. s, 2H), 4.53-in (s, 2H), 4,21 (t, J=6.2 Hz, 2H), 3,68 (user. s, 2H), 3.04 from (t, J=6.2 Hz, 2H), 2,70 (t, J=5.6 Hz, 2H), 1.39 in(s, 9H).

E. tert-Butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid

To a stirred solution of 0.96 g (5.0 mmol) of 1,2-dichloro-3-nitrobenzene and 0,93 g (5.0 mmol, 1 equiv.) 1-tert-butyloxycarbonyl in acetonitrile (5 ml) was added to 1.38 g (10 mmol, 2 equiv.) K2CO3. The mixture was boiled under reflux for 48 hours. The solvent was removed under reduced pressure. The crude product was distributed between EtOAc (100 ml) and 20 ml of H2O. the Organic layer was washed H2O (2×20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10-20% EtOAc/hexane) gave 1.2 g (70%) of tert-butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid. TLC (silica, 20% EtOAc/hexane): Rf=0,45.1H NMR (400 MHz, CDCl3): 7,56 (DD, J=8,2, and 1.4 Hz, 1H), 7,50 (DD, J=8,2, and 1.4 Hz, 1H), 7,13 (t, J=8,2 Hz, 1H), 3,56-to 3.38 (m, 4H), 3,10-3,00 (m, 4H), to 1.48 (s, 9H).

F. tert-Butyl E. the Il-1-{3-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

tert-Butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid (940 mg, of 2.75 mmol) in 10 ml of CH2Cl2was treated with 5 ml triperoxonane acid and stirred at 25°C for 1 hour. Volatile components were then removed. The residue was placed in CH2Cl2(60 ml) and KOH (4h., 20 ml). The organic layer was separated, dried over Na2SO4and concentrated. The yellow oil was dissolved in CH2Cl2and added to 996 mg (2,35 mmol) tert-butyl ester 1-(3-oxopropyl)-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid. The yellow solution was treated with glacial acetic acid (0.8 ml, 6 EQ.) and was stirred at 25°C for 1 hour. Added NaBH(OAc)3(1.5 g, 7.05 mmol) and stirred under nitrogen atmosphere for 2 hours. Then was added a saturated solution of NaHCO3(20 ml)was stirred for 30 minutes and the layers were separated. The organic extract was washed with saturated salt solution, dried over Na2SO4and concentrated under reduced pressure. Column chromatography (silica, 2-5% MeOH/CH2Cl2) gave tert-butyl ester 1-{3-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid as a white solid (1.40 g, 92%). TLC (silica, 5% MeOH/CH2Cl2): Rf=0,3. Mass when ECTR (elektrorazpredelenie): exact mass, calculated for C31H36ClF3N6About4, 648,24; m/z found 649,3 [M+H]+.1H NMR (400 MHz, CDCl3): of 7.69 (d, J=8,2 Hz, 1H), 7,60 is 7.50 (m, 1H), 7,45-7,37 (m, 4H), 7,02 (t, J=8,2 Hz, 1H), 4,58 (user. s, 2H), Android 4.04 (t, J=6,7 Hz, 2H), of 3.73-the 3.65 (m, 2H), 3,05-2,95 (m, 4H), 2,71 (t, J=5.6 Hz, 2H), 2,50 to 2.35 (m, 4H), 2,30 (t, J=6,8 Hz, 2H), 2.05 is-of 1.95 (m,2H), of 1.41 (s, 9H).

G. 1-{3-[4-(2-Amino-6-chlorophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

A solution of 360 mg (0,56 mmol) tert-butyl ester 1-{3-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid in 4 ml of MeOH was treated with 182 mg (5 EQ.) zinc dust and glacial acetic acid (1.57 in ml, 50 EQ.) at 25°C. the Reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then filtered through a layer of celite and focused, getting a thick oil. The residue was placed in CH2Cl2(50 ml) and a saturated solution of NaHCO3(20 ml). The organic layer was separated, washed with H2About (2×10 ml), dried over Na2SO4and concentrated, obtaining tert-butyl ester 1-{3-[4-(2-amino-6-chlorophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,3. Mass spectrum (elektrorazpredelenie): exact mass calculated for C31 H38ClF3N6O2, 618,27; m/z found, 619,3 [M+H]+.

H. tert-Butyl ester 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7--tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

A solution of tert-butyl ester 1-{3-[4-(2-amino-6-chlorophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid (257 mg, 0.42 mmol) in 4 ml of CH2Cl2handle 32 l (0.42 mmol, 1.0 EQ.) methanesulfonanilide and 116 l (0.83 mmol, 2 EQ.) of triethylamine and the reaction mixture was stirred at 25°C for 1 hour. Added EtOAc (40 ml) and a saturated solution of NaHCO3(20 ml). The organic layer was separated and washed with H2O (20 ml), saturated salt solution (20 ml), dried over Na2SO4and concentrated, obtaining the crude tert-butyl ester 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0,3. Mass spectrum (elektrorazpredelenie): exact mass calculated for C32H40ClF3N6O4S, 696,25; m/z found, 697,2 [M+H]+.

I. Amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-tert-butoxycarbonyl is about acid

A solution of 97 mg (0.14 mmol) of tert-butyl ester 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid in 3 ml of CH2Cl2was treated with 1.5 ml triperoxonane acid. The reaction mixture was stirred at 25°C for 1 hour, then remove all volatile components. To this crude substance in 0.5 ml of CH2Cl2was added dropwise a pre-mixed solution chlorosulfonylisocyanate (18 μl, 0,209 mmol) and 2-methyl-2-propanol (20 µl, 0,209 mmol) in CH2Cl2(0,150 ml). The reaction mixture was allowed to mix at 25°C during the night. Preparative TLC (silica, 2-10% MeOH/CH2Cl2) gave specified in the title compound (84 mg, 78%). TLC (silica, 10% MeOH/CH2Cl2): Rf=0,3. Mass spectrum (elektrorazpredelenie): exact mass calculated for C32H41ClF3N7O6S2, 775,22; m/z found, 776,2 [M+H]+

J. Amide 1-{3-[4-(2-Chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-sulfonic acid

Amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-tert-butoxycarbonylamino acid (84 mg, 0.11 mmol) was dissolved in three is terukuni acid (0.75 ml) and CH 2Cl2(0.75 ml). The reaction mixture was allowed to mix at 25°C for 2 hours. Removing volatile components in a stream of nitrogen gave amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-sulfonic acid with a quantitative yield in the form of a salt triperoxonane acid. Mass spectrum (elektrorazpredelenie): exact mass calculated for C27H33ClF3N4S2, 675,17; m/z found, 676,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,73 and 7,63 (AB system, J=8,2 Hz, 4H), 7,37 (d, J=7.8 Hz, 1H), 7,13 (t, J=7.8 Hz, 1H),? 7.04 baby mortality (d, J=7.8 Hz, 1H), 4,32 (s, 2H), 4,20 (t, J=6.3 Hz, 2H), a 3.87-of 3.80 (m, 2H), 3,80 of 3.75 (m, 4H), 3,70 is 3.25 (m, 7H), 3,00 is 2.75 (m, 4H), 2,25-of 2.15 (m, 2H).

EXAMPLE 19

N-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]methanesulfonamide

A. 5-Methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (10.0 g, 29,0 mmol) and epichlorohydrin (24 ml, 307 mmol) was not mixed in DMF (150 ml)containing Cs2CO3(10.4 g, 31.9 per mmol). After stirring at room temperature for 4 days, the mixture was evaporated, put in EtOAc and washed with water. Organic cha is to be dried (MgSO 4) and was evaporated, obtaining a light yellow solid. Column chromatography (silica, 5% acetone/CH2Cl2) gave 4.1 g (35%) of white solids. TLC (silica, 5% acetone/CH2Cl2): Rf=0,28. Mass spectrum (elektrorazpredelenie): exact mass calculated for C17H18F3N3O3S, 401,10; m/z found, 402,1 [M+H]+.1H NMR (400 MHz, CDCl3): to 7.84 (d, J=8,3 Hz, 2H), 7,79 (d, J=8,3 Hz, 2H), 4,70-to 4.62 (m, 3H), 4,25 (d, J=5.4 Hz, 1H), 3,90-3,70 (m, 2H), 3,47 (m, 1H), 3,10-2,9 (m, 6H), 2,65-2,60 (m, 1H).

B. tert-Butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid

To a stirred solution of 0.96 g (5.0 mmol) of 1,2-dichloro-3-nitrobenzene and 0,93 g (5.0 mmol, 1 EQ.) 1-tert-butyloxycarbonyl in acetonitrile (5 ml) was added to 1.38 g (10 mmol, 2 EQ.) K2CO3. The mixture was boiled under reflux for 48 hours. The solvent was removed under reduced pressure. The crude product was distributed between EtOAc (100 ml) and 20 ml of H2O. the Organic layer was washed H2O (2×20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10-20% EtOAc/hexane) gave 1.2 g (70%) of tert-butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid. TLC (silica, 20% EtOAc/hexane): Rf=0,45.1H NMR (400 MHz, CDCl3): 7,56 (DD, J=8,2, and 1.4 Hz, 1H), 7,50 (DD, J=8,2, and 1.4 Hz, 1H), 7,13 (t, J=8,2 Hz,1H), 3,56-to 3.38 (m, 4H), 3,10-3,00 (m, 4H), to 1.48 (s, 9H).

C. tert-Butyl ester 4-(2-amino-6-chlorophenyl)piperazine-1-carboxylic acid

A solution of 342 mg (1 mmol) of tert-butyl ester 4-(2-chloro-6-nitrophenyl)piperazine-1-carboxylic acid in 5.0 ml of MeOH was treated with 630 mg (10 mmol, 10 EQ.) of ammonium formate and a catalytic amount of 10% Pd-C (34 mg). The reaction mixture was stirred at 65°C for 30 minutes. The reaction mixture was then filtered through a layer of celite and concentrated, obtaining a yellow solid. TLC (silica, 5% acetone/CH2Cl2): Rf=0,40. Mass spectrum (elektrorazpredelenie): exact mass calculated for C15H22ClN3O2, 311,14; m/z found, 312,1 [M+H]+.

D. tert-Butyl ester 4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-carboxylic acid

tert-Butyl ester 4-(2-amino-6-chlorophenyl)piperazine-1-carboxylic acid (163 mg, of 0.53 mmol) in CH2Cl2handle 62 l (0.80 mmol, 1.5 EQ.) methanesulfonanilide and 148 l (1.06 mmol, 2 EQ.) of triethylamine and the reaction mixture was stirred at 25°C for 1 hour. Added EtOAc (40 ml) and a saturated solution of NaHCO3(20 ml). The organic layer was separated and washed with H2O (20 ml), saturated salt solution (20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 0-5% acetone/CH2Cl2) gave 145 mg (70%) of tert-b is delovogo ester 4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-carboxylic acid. TLC (silica, 5% acetone/CH2Cl2): Rf=0,35. Mass spectrum (elektrorazpredelenie): exact mass calculated for C16H24ClN3O4S, 389,12; m/z found, 388,1 (negative).1H NMR (400 MHz, CDCl3): 7,41 (DD, J=8,2, 1,6 Hz, 1H), 7,11 (t, J=8,2 Hz, 1H), 6,99 (DD, J=8,2, 1,6 Hz, 1H), 4,25-3,91 (m, 2H), 3,66-to 3.52 (m, 2H), 3,01 (s, 3H), 3,01-2,84 (m, 2H), 2,70-of 2.56 (m, 2H), 2,55 is 2.43 (m, 2H), of 1.44 (s, 9H).

E. N-[3-Chloro-2-(4-(2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]methanesulfonamide

tert-Butyl ester 4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-carboxylic acid (145 mg, and 0.37 mmol) was dissolved in 3 ml of CH2Cl2and was treated with 1.5 ml triperoxonane acid. The reaction mixture was stirred at 25°C for 1 hour, then remove all volatile components. The solid was treated with CH2Cl2(20 ml) and aqueous KOH (4h., 10 ml). The organic layer was separated, dried over Na2SO4and concentrated. Crude oil (90 mg) was dissolved in absolute EtOH (1.0 ml) and was treated with 96 mg (0.24 mmol) of 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture is boiled under reflux at 85°C for 3 hours and then the solvent was removed. Column chromatography (silica, 0-5% MeOH/CH2Cl2) Dawa is and 138 mg (20% over 4 steps) of N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]methanesulfonamide. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,45. Mass spectrum (elektrorazpredelenie): exact mass calculated for C28H34ClF3N6O5S2, 690,17; m/z found, 691,2 [M+H]+.1H NMR (400 MHz, CDCl3): of 8.28 (s, 1H), 7,65 and to 7.59 (AB system, J=8,4 Hz, 4H), of 7.36 (d, J=8,1 Hz, 1H), 7,07 (t, J=8,2 Hz, 1H), 6,95 (d, J=8,2 Hz, 1H), 4,54-of 4.44 (m, 2H), 4,21-of 3.94 (m, 3H), of 3.77-to 3.52 (m, 4H), to 3.41 (m, 2H), 2,96 (s, 3H), of 2.81 (s, 3H), 3,05-by 2.73 (m, 4H), 2,66-of 2.20 (m, 4H).

EXAMPLE 20

1-[4-(2,6-Dinitrophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol

A. tert-Butyl ester 4-(2,6-dinitrophenyl)piperazine-1-carboxylic acid

To a stirred solution of 1.01 g (5.0 mmol) 1-chloro-2,6-dinitrobenzene and 0,93 g (5.0 mmol) 1-tert-butyloxycarbonyl in acetonitrile (5 ml) was added to 1.38 g (10 mmol) of K2CO3,The mixture was boiled under reflux for 48 hours. The solvent was removed under reduced pressure. The crude product was distributed between EtOAc (100 ml) and 20 ml of H2O. the Organic layer was washed H2O (2×20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10-20% EtOAc/hexane) to give 1.31 g of tert-butyl methyl ether (85%) of 4-(2,6-dinitrophenyl)piperazine-1-carboxylic acid. TLC (silica, 20% EtOAc/hexane): Rf=0,35.1H NMR (400 MHz, CDCl 3): of 7.75 (d, J=8,2 Hz, 2H), 7,25 (t, J=8,2 Hz, 1H), 3,30 (m, 4H), 2.95 and (m, 2H), of 1.44 (s, 9H).

B. 1-[4-(2,6-Dinitrophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol

tert-Butyl ester 4-(2,6-dinitrophenyl)piperazine-1-carboxylic acid (220 mg, to 0.63 mmol) was dissolved in 5.0 ml of CH2Cl2and was treated with 3.0 ml triperoxonane acid. The reaction mixture was stirred at 25°C for 1 hour, then remove all volatile components. The solid was treated with CH2Cl2(20 ml) and aqueous KOH (4 N, 10 ml). The organic layer was separated, dried over Na2SO4and concentrated. Crude oil (67 mg) was dissolved in absolute EtOH (1.2 ml) and was treated with 141 mg (0.35 mmol, 1.3 EQ.) 5-methanesulfonyl-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. The reaction mixture is boiled under reflux at 85°C for 3 hours and then the solvent was removed. Purification of column chromatography (silica, 10-20% acetone/CH2Cl2) gave 150 mg (85%) of 1-[4-(2,6-dinitrophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol. TLC (silica, 10% acetone/CH2Cl2): Rf=0,3. Mass spectrum (elektrorazpredelenie): exact mass calculated for C27H30F3N7O7S, 63,19; m/z found, 654,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,71 (d, J=8,2 Hz, 2H), of 7.64 and 7,58 (AB system, J=8,4 Hz, 4H), 7,20 (t, J=8,2 Hz, 1H), of 4.54 (s, 2H), 4,29-4,12 (m, 2H), 3,66 (t, J=5.3 Hz, 2H), 3,70-2,95 (m, 9H), 2.91 in (s, 3H), 2,67 of-2.32 (m, 4H).

EXAMPLE 21

Methyl ester of 2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)-3-methanesulfonylaminoethyl acid.

A. tert-Butyl ester 4-(2-methoxycarbonyl-6-nitrophenyl)piperazine-1-carboxylic acid

To mix the solution 736 mg and 2.83 mmol) ethyl 2-bromo-3-nitrobenzoate and 579 mg (3.1 mmol, 1.1 EQ.) 1-tert-butyloxycarbonyl in n-butanol (6 ml) was added 330 mg (3.1 mmol, 1.1 EQ.) Na2CO3. The mixture was boiled under reflux for 4 hours. The solvent was removed under reduced pressure. The crude product was distributed between EtOAc (100 ml) and 20 ml of H2O. the Organic layer was washed H2O (2×20 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10-20% EtOAc/hexane) gave 744 mg (72%) of tert-butyl ester 4-(2-methoxycarbonyl-6-nitrophenyl)piperazine-1-carboxylic acid. TLC (silica, 20% EtOAc/hexane): Rf=0,5.1H NMR (400 MHz, CDCl3): to 7.67 (DD, J=8,2, and 1.4 Hz, 1H), 7.62mm (DD, J=8,2, and 1.4 Hz, 1H), 7,16 (t, J=8,2 Hz, 1H), 3,86 (s, 3H), 3,44-to 3.36 (m, 4H), 3,03-2,95 (m, 4H), to 1.48 (s, 9H).

B. Methyl e is Il-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)-3-methanesulfonylaminoethyl acid

A solution of 1.0 g (2,73 mmol) tert-butyl ester 4-(2-methoxycarbonyl-6-nitrophenyl)piperazine-1-carboxylic acid in 18 ml of MeOH was treated 893 mg (13.7 mmol, 5 EQ.) zinc dust and glacial acetic acid (8 ml). The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was then filtered through a layer of celite and focused, getting a thick oil. The residue was placed in EtOAc (200 ml) and a saturated solution of NaHCO3(100 ml). The organic layer was separated, washed with H2O (2×50 ml), dried over Na2SO4and concentrated. Column chromatography (silica, 10-30% EtOAc/hexane) gave the desired amine (844 mg, 92%). Amine (42 mg, 0.13 mmol) in CH2Cl2(0.5 ml) was treated with a 9.7 μl (0.13 mmol, 1.0 EQ.) methanesulfonanilide and 34,9 μl (0.25 mmol, 2 EQ.) of triethylamine and the reaction mixture was stirred at 25°C for 1 hour. Added EtOAc (20 ml) and a saturated solution of NaHCO3(10 ml). The organic layer was separated and washed with H2O (10 ml), saturated salt solution (20 ml), dried over Na2SO4and concentrated. The crude oil was dissolved in 2 ml of CH2Cl2and was treated with 0.5 ml triperoxonane acid. The reaction mixture was stirred at 25°C for 1 hour before removing all volatile components. The crude oil was dissolved in absolute EtOH (1.0 ml) and was treated with 40 mg (0.1 mmol) 5-metasul who were radioactive-1-oxiranylmethyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine and 200 μl of triethylamine. The reaction mixture is boiled under reflux at 85°C for 4 hours and then the solvent was removed. Preparative TLC (silica, 7% MeOH/CH2Cl2) gave 35 mg (49% for 3 stages) specified in the connection header. TLC (silica, 5% MeOH/CH2Cl2): Rf=0,30. Mass spectrum (elektrorazpredelenie): exact mass calculated for C30H37F3N6O7S2, 714,21; m/z found, 715,2 [M+H]+.1H NMR (400 MHz, CDCl3): 8,11 (s, 1H), 7,74-to 7.59 (m, 5H), 7,30 (d, J=8,1 Hz, 1H), 7,21 (t, J=8,2 Hz, 1H), 4,62 figure-4.49 (m, 2H), 4,25-3,99 (m, 3H), 3,90 (s, 3H), 3,80 is 3.57 (m, 3H), 3,53-of 3.27 (m, 2H), 3,14-2,78 (m, 4H), 3,05 (s, 3H), of 2.86 (s, 3H), was 2.76-to 2.65 (m, 2H), 2,61-of 2.20 (m, 4H).

EXAMPLE 22

1-{3-[4-(1,1-Dioxo-1H-1,6-benzo[d]isothiazol-3-yl)piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine.

A. 3-Piperazine-1-yl-benzo[d]isothiazol 1,1-dioxide

POCl3(of 10.2 ml, 109,2 mmol) was added to the saccharin (5.0 g, 27,3 mmol) and was heated at 120°C for 20 hours. Excess reagent was removed using a rotary evaporator and to the residue was added water (50 ml) for sediment. The solid was filtered, washed with water (2×20 ml) and dried. Part of the above crude material (2.0 g, for 9.95 mmol) and piperazine (4,28 g, 49,75 mmol) were placed in dioxane (10 ml) and heated at 100°C within 24 hours. Re clonney the mixture was left to cool to room temperature and poured into ice-cold water (50 g) and neutralized by adding 10%aqueous NaOH. The mixture was extracted with CH2Cl2(3×25 ml) and the combined organic extracts were washed with saturated salt solution, dried (Na2SO4) and concentrated. SCH (silica, 5-20% MeOH/CH2Cl2) computes the derived piperazinil (0.07 g, 4.2 per cent). Mass spectrum (elektrorazpredelenie): exact mass calculated for C11H13N3O2S, 251,07; m/z found, 252,1 [M+H]+.1H NMR (400 MHz, CDCl3): 7,72 (DD, J=0,8, 7,4 Hz, 1H), to 7.64 (d, J=7.8 Hz, 1H), 7,49 (dt, J=0,8, 7,4 Hz, 1H), 7,43 (dt, J=1,2, 7,8 Hz, 1H), 3,80 (s, 4H), 2,85 (user. t, J=5.0 Hz, 4H), 2,07 (user. s, 1H).13C NMR (100 MHz, CDCl3): 160,8, 145,3, 133,3, 133,0, 128,5, 125,9, 123,2, 49,8, 46,3.

B. 1-{3-[4-(1,1-Dioxo-1H-1,6-benzo[d]isothiazol-3-yl-piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

To a stirred solution of 3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]Propionaldehyde (0,040 g, 0.13 mmol) and 1,1-dioxide 3-piperazine-1-yl-benzo[d]isothiazole (0,050 g, 0.21 mmol) in CH2Cl2(0.5 ml) was added ice AcOH (12 μl, 0.21 mmol) and was stirred for 15 minutes at room temperature. Added NaBH(OAc)3(0,058 g, 0.27 mmol) and stirred under nitrogen atmosphere overnight. Then was added a saturated solution of NaHCO3(0.5 ml) and was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2(5 ml). SCH (silicon dioxide, 2-15% MeOH/CH2Cl2) gave the desired product as a white solid (0,048 g, 76%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0,50. Mass spectrum (elektrorazpredelenie): exact mass calculated for C28H31F3N6O4S2, 636,18; m/z found, 637,2 [M+H]+.1H NMR (400 MHz, CDCl3): 7,94 (DD, J=0,8 and 7.6 Hz, 1H), 7,86 (d, J=7.8 Hz, 1H), of 7.75 (d, J=8,3 Hz, 2H), 7,73-7,63 (m, 2H), 7,68 (d, J=8,3 Hz, 2H), 4,57 (s, 2H), 4,17 (t, J=6.9 Hz, 2H), 4.04 the (user. s, 4H), of 3.69 (t, J=5.7 Hz, 2H), equal to 2.94 (s, 3H), of 2.92 (t, J=6.2 Hz, 2H), 2,62 (t, J=5.0 Hz, 4H), 2,44 (t, J=6.6 Hz, 2H), 2,13 (kV, J=6,6 Hz, 2H).

EXAMPLE 23

1-[1-{3-[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A. 6-Chloro-2-piperazine-1-yl-benzothiazole

To a stirred solution of 1.07 g (5,24 mmol) 2,6-dichlorobenzothiazole in dry DMF (25 ml) was added 2.4 g of potassium carbonate (15.7 mmol) and 0.5 g of piperazine (5.8 mmol). The mixture was stirred at room temperature for 4 hours. When the reaction was completed, the reaction mixture was distributed between EtOAc (150 ml) and water (50 ml) and separated. The aqueous layer was extracted with EtOAC (2×100 ml). The combined organic layers were then washed with water (2×25 ml), saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure, obtaining of 1.33 g (100%) CE is avago product as a white solid. Mass spectrum (elektrorazpredelenie): exact mass calculated for C11H12ClN3S, 253,04; m/z found, 254,0 [M+H]+.

B. 1-[1-{3-[4-(6-Chlorobenzothiazole-2-yl)piperazine-1-yl]-2-hydroxypropyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

To a stirred solution of 144 mg (0,39 mmol) 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone in 4 ml of EtOH was added 100 mg (0,39 mmol) 6-chloro-2-piperazine-1-yl-benzothiazole. The solution was heated at 60°C during the night. The solvent was then removed using rotary evaporation and the crude product was purified column chromatography (silica, 0-10% MeOH/EtOAc)to give 220 mg (90%) of white solids. Mass spectrum (elektrorazpredelenie): exact mass calculated for C29H30ClF3N6O2S: 618,18; m/z found, 619,2 [M+H]+. HPLC (reversed phase 40-90%): tR=8,27 min1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): of 7.70 (d, J=8.34 per Hz, 1H), 7.62mm (m, 2H), EUR 7.57 (d, J=8,59 Hz, 1H), of 7.48 (d, J=2,53 Hz, 1H), was 7.36 (d, J=8,59 Hz, 1H), 7,16 (DD, J=8,59, of 2.53 Hz, 1H), 4,80, and 4,68 (A and B of AB Quartet, J=15,92 Hz, 1H), 4,58 (s, 1H), 4,18-4,08 (m, 2H), 4,01-to 3.89 (m, 2H), 3,85-of 3.60 (m, 2H), 3,59-3,47 (m, 4H), 2,94 is 2.75 (m, 2H), 2,72-2,62 (m, 2H), 2,55-2,47 (m, 2H), 2,46-2,39 (m, 2H), 2.13 and (C, 1,5H), 2,08 (s, 1,5H).

EXAMPLE 24

1-[1-[3-(4-Benzo[d]isoxazol-3-yl-piperazine-1-yl)-2-hydroxypropyl]-3-(4-trifluoromethyl who enyl)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A. tert-Butyl ether 4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid

To a stirred solution of 100 mg (of 0.65 mmol) 3-chloro-1,2-benzisoxazole in pyridine (1 ml) was added 145 mg of tert-butyl methyl ether piperazine-1-yl-carboxylic acid (0.78 mmol) and 0.18 ml of DBU (0.78 mmol). The mixture was stirred at 100°C overnight, then was distributed between EtOAC (50 ml) and water (20 ml) and separated. The aqueous layer was extracted with EtOAC (2×30 ml). The combined organic layers were then washed with water (25 ml), saturated salt solution, dried over Na2SO4and the solvent was removed under reduced pressure, obtaining the crude product. Purification of column chromatography (silica, 60-100%CH2Cl2/hexane) gave 82 mg (42%) of the desired product as a pale yellow solid. Mass spectrum (elektrorazpredelenie): exact mass calculated for C16H21N3O3, 303,16; m/z found, to 326.1 [M+Na]+.1H NMR (CDCl3, 400 MHz): to 7.68 (dt, J=8,02, and 0.98 Hz, 1H), 7,52-7,44 (m, 2H), 7,24 (DDD, J=8,42, 6,46, of 1.57 Hz, 1H), 3,66-3,61 (m, 4H), 3,56-to 3.49 (m, 4H), for 1.49 (s, 9H).

B. 1-[1-[3-(4-Benzo[d]isoxazol-3-yl-piperazine-1-yl)-2-hydroxypropyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]alanon

A solution of 82 mg (0.27 mmol) of tert-butyl methyl ether 4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid in 2 ml of CH2Cl2processed triperoxonane acid is (0.5 ml) at room temperature over night. The solvent was then removed and the crude product was dissolved in EtOH and stirred over 100 mg of sodium bicarbonate for 1 hour, the solid is then filtered, and the filtrate was concentrated. The crude piperazine was then dissolved in 4 ml of EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl]ethanone. The solution was heated at 60°C during the night. The solvent was then removed using a rotary evaporator and the crude product was purified column chromatography (silica, 0-10% MeOH/EtOAc)to give 105 mg (68%) of white solids. Mass spectrum (elektrorazpredelenie), exact mass calculated for C29H31F3N6O3, 568,24; m/z found, 569,2 [M+H]+.1H NMR (CDCl3, 400 MHz, mixture of amide rotamers): to 7.77 (d, J=to 8.41 Hz, 1H), 7,69 (m, 2H), to 7.67 to 7.62 (m, 2H), 7,50-7,44 (m, 1H), 7,45-7,42 (m, 1H), 7.23 percent-to 7.18 (m, 1H), 4,93 (user. m, 1H), 4,87 and 4,75 (A and B of AB Quartet, J=15,65 Hz, 1H)and 4.65 (user. s, 1H), 4,27-to 4.15 (m, 2,3H), 4.09 to 3,95 (m, 1,7H), 3,91-3,82 (m, 0,7H), 3,81-3,66 (m, 1,3H), 3,62-to 3.49 (m, 4H), 3,01-to 2.85 (m, 1,5H), 2,85-to 2.74 (m, 2,5H), 2.71 to 2,60 (m, 2H), 2,58 at 2.45 (m, 2H), 2,20 (C, 1,5H), of 2.15 (s, 1,5H).

EXAMPLE 25

1-[4-(2-Amino-6-chlorophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol

EXAMPLE 26

1-[3-Chloro-2-(4-{3-[5-methanesulfonyl the-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]-3-metalmachine

EXAMPLE 27

1-[3-Chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]-3-metalmachine

EXAMPLE 28

Methyl ester of 3-amino-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzoic acid

EXAMPLE 29

3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenylamine.

EXAMPLE 30

1-[2-(4-{3-[3-(4-Bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)-3-chlorophenyl]-3-metalmachine.

EXAMPLE 31

Amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

EXAMPLE 32

Methyl ester [3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]carbamino acid

EXAMPLE 33

Amide 1-[3-(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)propyl]-3-(4-bromophenyl)-1,4,6,7-Tetra is droperidol[4,3-c]pyridine-5-carboxylic acid

EXAMPLE 34

Methyl ester of 2-(4-{3-[6-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)-3-nitrobenzoic acid

EXAMPLE 35

1-[4-(2-Chloro-6-nitrophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propane-2-ol

EXAMPLE 36

2-(4-{2-Hydroxy-3-[3-(4-itfeel)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzonitrile.

EXAMPLE 37

Amide 3-(4-bromophenyl)-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

EXAMPLE 38

2-(4-{3-[5-Acetyl-3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile

EXAMPLE 39

2-(4-{3-[3-(4-Chloro-3-were)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile

EXAMPLE 40

1-(3-(4-Chloro-3-were)-1-{3-[4-(2,4-dimetilfenil)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-yl)alanon

EXAMPLE 41

1-{3-[4-(3,5-Declarer the DIN-4-yl)piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine

EXAMPLE 42

2-(4-{3-[5-Methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)benzonitrile

EXAMPLE 43

N-[3-Chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-1-yl]propyl}piperazine-1-yl)phenyl]methanesulfonamide

EXAMPLE 44

Amide 3-(3,4-dichlorophenyl)-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

EXAMPLE 45

Amide 3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl}-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylic acid

EXAMPLE 46

Analysis of inhibition of cathepsin S

Recombinant cathepsin S man (CatS) expressed in baculovirus system and purified in a single stage using columns with dipropylacetate. 10 l gave ˜700 mg CatS, and N-terminal sequencing (determining the primary structure of the protein) confirmed the identity. The analysis was carried out in 100 mm solution of sodium acetate pH 5.0, containing 1 mm DTT and 100 mm NaCl. The substrate for analysis was a

(Aedens)EKARVLAEAA(Dabcyl)K-amide

Kmfor the substrate is about 5 μm, but the presence of substrate inhibition impedes kineticist the th analysis. At 20 microns of the substrate, the speed of the analysis is linear in the range of 1-8 ng CatS in 100 ál of reaction mixture. When using 2 ng/well CatS producing the product is linear and gives ˜7-fold amplified signal after 20 minutes when only 20%loss of the substrate. Initial tests conducted by stopping the reaction after 20 minutes in 0.1% SDS, and then measure the fluorescence. For other analyses of the measured every minute for 20 minutes. Speed calculated by the slope of the ascending and hence calculate the percentage of inhibition (see below, tables 1 and 2)

Table 1
EXAMPLEIC50(µm)
10,89
21,22
30,84
40,51
50,36
60,30
76,60
80,89
91,14
100,05
110,03
120,98
130,77
140,25
150,12
160,06
170,08
180,14
190,06
200,17
210,07
222,15
231,10
240,47

Table 2
EXAMPLEIC50(µm)
250,04
260,04
270,04
280,07
290,07
300,08
310,10
320,10
330,10
340,11
350,12
360,12
370,12
380,12
390,13
400,13
410,13
420,13
430,13
440,13
450,13

EXAMPLE 47

Ex vivo inhibition of allergic response inhibit the AMI cathepsin S.

The following analysis shows that inhibitors of cathepsin S block the response of T-cells on untreated aldergrove extracts.

Materials and methods

Reagents: Glitserinovoye untreated aldergrove extracts of household dust mites (Dermataphagoides pteronyssinus, Dermataphagoides farinae) and ragweed [Ambrosia trifida (ciganska), Ambrosia artemisiifolia (short)] were obtained from Hollister-Stier Laboratories (Minneapolis, MN). Of concanavalin a (ConA) was obtained from Calbiochem (La Jolla, CA).

The donors. All allergic donors were pre-screened for their specific allergies using RAST tests. Haploid types of HLA class II these donors was determined using PCR.

Cell culture. Menagerie cells in human peripheral blood (PBMC) were purified from blood samples from allergic donors using a gradient of Ficoll-Hypaque followed by rinsing phosphate buffered saline solution. RVMS cultured in three or duplicate sequence at the rate of 0.5 to 1.0×106cells/well together with titrated doses allergenic extracts in the presence or in the absence of a known inhibitor of cathepsin S, LHVS (morpholinoethyl-leucine-Homo-phenylalanine-vinylsulphonyl) (Palmer et al. (1995), J.Med.Chem. 38:3193 and Riese et al. (1996), Immunity 4:357). Originally prepared serially diluted original solution LHVS in 100% DMSO, and the ZAT is diluted in the ratio of 1:15 to 40% by hydroxypropylcellulose (HPCD). Three microliters of LHVS in HPCD was added in RVMS culture (200 μl/well) After 6 days of cultivation was added 1 mccu/well3H-thymidine (TdR). After 18 hours the cells were collected using a Filtermate Harvester (Packard) and counted introduction3H-TdR on a Topcount (Packard).

Inhibition of proliferative responses of T cells to home dust mites

About 10% of the majority of the population are allergic to household dust mites (HDM) Dermatophagoides, while Dermataphagoides pteronyssinus (Der p) and D. Farinae (Der f) are the two main species present in different proportions in most countries. The main clinical manifestations are asthma and chronic rhinitis (runny nose).

Effect of inhibition of cathepsin S to activate the HDM allergen-specific CD4 T-cells was tested in ex vivo analysis of the proliferation of T-cells. Cultivation RVMS with crude extracts or Der p or Der f resulted in strong proliferation (figa). This proliferation consisted primarily of allergen-specific CD4 T cells. When the activity of cathepsin S was blocked by a specific inhibitor of cathepsin S LHVS (see Riese et al. (1996), Immunity 4:357), proliferation is significantly inhibited (pigv). Inhibition of LHVS was specific in relation to responses induced by HDM extracts, since the proliferative response the cells, induced by ConA, pan-T cell mitogen, was not mentioned. Furthermore, this inhibition was observed for all four investigated HDM-allergic donors regardless of various haploid types of HLA class II DR4; DR7, 15; DR11, 15 and Dr4,11).

This system is very similar to the situation in vivo. Allergic subject will be exposed to the crude mixture of allergens that will lead to the proliferation of T-cells and the allergic response. The observation of inhibition of activated CD4 T cells under the influence of an inhibitor of cathepsin S shows that such inhibitors may be effective in the treatment of generalized population of patients who are prone to allergies to household dust mites.

Inhibition of proliferative responses of T cells to the ambrosia

About 10% of the U.S. population suffer from allergies to pollen of ragweed, which leads to the fact that it is one of the most important allergens from the point of view of clinical disease. The pollen allergens are a major cause gain runny nose (rhinitis) and asthma in this population.

The effect of inhibition of cathepsin S on the activation of allergen-specific to the development of CD4 T-cells was investigated in ex vivo analysis of the proliferation of T-cells. Cultivation RVMS with crude extracts of both short and giant ragweed in the of Odilo to strong proliferation (figa). This proliferation consisted primarily of allergen-specific CD4 T-cells. When the activity of cathepsin S was blocked by a specific inhibitor of cathepsin S LHVS (see Riese et al. (1996), Immunity 4:357), proliferation is significantly inhibited (pigv). Inhibition of LHVS was specific in relation to responses induced by ragweed, since the proliferative response of T-cells induced by ConA, pan-T cell mitogen, was not mentioned. Furthermore, this inhibition was observed for the two investigated allergic to ragweed donors regardless of various haploid types of HLA class II (DR7, 15 and Dr4,11).

A similar experiment was performed using two additional CatS inhibitors, compounds of the above example 11 and example 36, with the results shown in figa and figv respectively.

This system is very similar to the situation in vivo. Allergic subject will be exposed to the crude mixture of allergens that will lead to the proliferation of T-cells and the allergic response. The observation of inhibition of activated CD4 T cells under the influence of an inhibitor of cathepsin S shows that such inhibitors may be effective in the treatment of generalized population of patients who are prone to allergies to ragweed.

Example 48

The observation of inhibition of ka is epsin S in human blood

The effect of in vivo administration of inhibitors of cathepsin S in a series of clinical trials can be observed by measuring the accumulation of intermediate products of the decomposition of the invariant chain (Ii), for example, p10Ii fragment in the blood of subjects receiving a dose of the substance. After the introduction of the inhibitor of cathepsin within a certain period of time, for example, from 0.01 to 50 mg/kg/day for creating blood concentrations in the range from 1 nm to 10 μm for 16-30 hours, blood is taken and purified leukocytes (WBC), for example, using red blood cell lysis or by using gradient centrifugation of Ficoll-Hypaque. Then get a whole cell lysates of cells and analyze them using Western blot analysis or ELISA analysis. For Western blotting analysis of cell lysates initially separated on SDS-PAGE gels. After transfer to nitrocellulose membrane Ii and intermediate products of its decomposition, including R can be detected using mouse mAb against Ii, for example, Pin1.1, or rabbit polyclonal antibodies specific against C-terminal fragment R or against full fragment R. For ELISA analysis, it is possible to use a pair of antibodies against Ii, including Pin1.1 and polyclonal antibody rabbit or mouse monoclonal antibody specific against R. The same analysis can also be used to nabludenia.esli inhibitors of cathepsin S in vivo in animal studies, for example, in monkeys, dogs, pigs, rabbits, Guinea pigs and rodents.

In this example RUMS from human blood were incubated with an inhibitor of cathepsin S, LHVS (morpholinoethyl-leucine-Homo-phenylalanine-vinylsulphonyl, also called N-[(1S)-3-methyl-1-[[[(1S,2E)-1-(2-phenylethyl)-3-(phenylsulfonyl)-2-propenyl]amino]carbonyl]butyl]-4-morpholinylcarbonyl. This compound is described in U.S. patent 5976858 and in the publication of Palmer et al. (1995), J.Med.Chem. 38:3193 and Riese et al. (1996), Immunity 4:357. After incubation for 24 hours the specimens were examined using standard protocols SDS-PAGE, transferred to nitrocellulose membrane and probed with an antibody that recognizes the invariant chain, including R fragment. In the presence of LHVS were observed R fragment representing the block formed by the decomposition of Ii by inhibiting cathepsin S.

EXAMPLE 49

The observation in vivo inhibition of allergic response inhibitors of cathepsin S

To demonstrate the efficacy of inhibitors of cathepsin S in the suppression of allergic responses in vivo allergic volunteers were injected with a dose of inhibitors of cathepsin at the levels at which inhibited the degradation of the invariant chain. The allergen is injected subcutaneously and the size of skin reactions determine after 15 minutes, 6 hours and 24 hours. Skin biopsy performed 2 hours. Immediate well-being-and-signal response is not mediated T-cell response, and it was not expected that it will be affected by the inhibitors of cathepsin S, whereas induration (hardening) in the late phase (visible after 6 hours, more pronounced after 24 hours) is characterized by the activation and infiltration of CD4 T-cells and eosinophils) and should also be inhibited by introduction of inhibitors of cathepsin S. a Skin biopsy is used to determine the cellular composition of induration and suggest that treated with an inhibitor of cathepsin S subjects have fewer attendees of activated CD4 T cells compared to placebo-treated entities.

Links to these techniques is given in Eberlein-Konig et al. (1999) Clin.Exp.Allergy 29: 1641-1647 and Gaga et al. (1991) J.Immunol. 147:816-822.

As a control experiment will be used prednisone and cyclosporine A. Prednisone will inhibit both immediate response and the response in the late phase, while cyclosporine And will only inhibit the response in the late phase.

F. Other embodiments of the inventions

Distinguishing features and advantages of the invention are obvious to an ordinary person skilled in the art. Based on this description, including a Brief summary of the invention", a detailed description of the background of invention, p is emery and claims, an ordinary person skilled in the art will be able to make modifications and adaptations to different conditions and applications. Such other embodiments of the invention are also included in the scope of this invention.

1. The method of treatment of a subject with allergic disease, which comprises administration to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I)

where R1selected from the group comprising benzisothiazole, 1,1-dioxopentanoate, benzothiazolyl, optionally substituted by a chlorine atom, benzisoxazoles and six-membered aromatic carbocyclic or nitrogen-containing ring which may be substituted by at least one of the group comprising Cl, F, CH3HE, CN, NO2, NH2, -NH-C(O)-NH2, -SO2, -NH-C(O)-NH-CH3-C(O)O-CH3, -NH-SO2-CH3,-NH-C(O)O-CH3;

R2selected from the group comprising HE, " co3piperazineethanol, -O-C(O)-NH2, F;

n=0 or 1;

m=1 or 2;

R3and R4independently mean hydrogen or R3and R4together with the pyrazol ring form a nitrogen-containing unsaturated or saturated six-membered heterocyclic ring which may be substituted on the nitrogen atom by the group-C(O)R 5, -SO2-CH3or-SO2-NH2where

R5means of CH3, -O-(CH3)3, NH2, -CO(O)-CH3;

Ar means six-membered aromatic ring which may be substituted by one or more substituents selected from H, C1, NH2CH3, I, CF3,

or its pharmaceutically acceptable salt.

2. The method according to claim 1, where AG represents phenyl.

3. The method according to claim 1, where the specified connection choose from:

1-[4-(2-amino-6-chlorophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl]propane-2-ol;

1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl]propyl} piperazine-1-yl)phenyl]-3-metallocene;

1-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]propyl} piperazine-1-yl)phenyl]-3-metallocene;

methyl ester 3-amino-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]propyl} piperazine-1-yl) benzoic acid;

3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl]propyl} piperazine-1-yl)phenylamine;

1-[2-(4-{3-[3-(4-bromophenyl)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]-2-hydroxypropyl} piperazine-1-yl)-3-chlorophenyl]-3-metallocene;

and amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl) piperazine-1-yl]propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-carboxylic acid.

4. The method according to claim 1, where the specified connection choose from:

methyl ester [3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]-pyridine-1-yl]propyl} piperazine-1-yl)phenyl]carbamino acids;

amide 1-[3-(4-benzo[d]isothiazol-3-yl-piperazine-1-yl)propyl]-3-(4-bromophenyl)-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-carboxylic acid;

methyl ester of 2-(4-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]-pyridine-1-yl]-2-hydroxypropyl]piperazine-1-yl)-3-nitrobenzoic acids;

1-[4-(2-chloro-6-nitrophenyl)piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl] propane-2-ol;

2-(4-{2-hydroxy-3-[3-(4-itfeel)-5-methanesulfonyl-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl] propyl} piperazine-1 - yl) benzonitrile;

amide 3-(4-bromophenyl)-1-{3-[4-(2-nitrophenyl) piperazine-1-yl] propyl}-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-carboxylic acid;

2-(4-{3-[5-acetyl-3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]-2 - hydroxypropyl]piperazine-1-yl) benzonitrile;

2-(4-{3-[3-(4-chloro-3-were)-5-methanesulfonyl-4, 5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]-2-g is droxidopa} piperazine-1-yl) benzonitrile;

1-(3-(4-chloro-3-were)-1-{3-[4(2,4-dimetilfenil)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl) ethanone;

1-{3-[4-(3,5-dichloropyridine-4-yl)piperazine-1-yl]propyl]-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-C]pyridine;

2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]propyl} piperazine-1-yl)benzonitrile;

N-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl] propyl} piperazine-1-yl)phenyl]methanesulfonamide;

amide 3-(3,4-dichlorophenyl)-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]-propyl}-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-carboxylic acid;

and amide 3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl)piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-carboxylic acid.

5. The method according to claim 1, where the specified connection choose from:

1-(3-(4-chlorophenyl)-1-{3-[4-(2-forfinal)piperazine-1-yl]propyl}-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl)ethanone;

1-(3-(4-chlorophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl) propyl]-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-yl)ethanone;

1-(3-(4-chlorophenyl)-1-[2-methoxy-3-(4-o-tailpipes-1-yl) propyl]-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl)ethanone;

1-[1-{2-hydroxy-3-[4-(2-hydroxyphenyl)piperazine-1-yl]propyl}-3-(4-shall adrenal)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-yl]ethanone;

1-[1-[2-hydroxy-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl]ethanone;

2-(4-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl]-2-hydroxypropyl}piperazine-1-yl)benzonitrile;

1-[3-(3,4 - dichlorophenyl) pyrazole-1-yl]-3-(4-o-tailpipes-1-yl)propan-2-ol;

1-[1-[2-(2-piperazine-1-yl-ethylamino)-3-(4-o-tailpipes-1-yl)propyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-yl] ethanone;

tert-butyl ester 1-{3-[4-(2-cyanophenyl) piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-carboxylic acid;

amide 1-{3-[4-(2-cyanophenyl) piperazine-1-yl]-2-hydroxypropyl}-3-(4-itfeel)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-carboxylic acid;

1-[5-carbarnoyl-3-(4-itfeel)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridine-1-ylmethyl]-2-[4-(2-cyanophenyl) piperazine-1-yl] ethyl ester carbamino acids;

1-{3-(3-amino-4-chlorophenyl)-1-[2-hydroxy-3-(4-o-tailpipes-1-yl) propyl]-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl}ethanone;

(R)-1-(3-(4-bromophenyl)-1-{3-[4-(5-chloro-2-were)piperazine-1-yl]-2-hydroxypropyl)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-yl)ethanone;

2-(4-{3-[5-acetyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl]-2-forproper] piperazine-1-yl) benzene the Rila;

methyl ester (3-(4-chloro-3-were)-1-{3-[4-(2-cyanophenyl) piperazine-1-yl]-2-hydroxypropyl}-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl) octoxynol acids;

5-methanesulfonyl-1-{3-[4-(2-nitrophenyl)piperazine-1-yl]propyl}-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H pyrazolo [4,3-C] pyridine;

1-[3-chloro-2-(4-{3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl] propyl} piperazine-1-yl)phenyl] urea;

amide 1-{3-[4-(2-chloro-6-methanesulfonylaminoethyl) piperazine-1-yl]-propyl}-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-sulfonic acid;

N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl] propyl} piperazine-1-yl) phenyl] methanesulfonamide;

1-[4-(2,6-dinitrophenyl) piperazine-1-yl]-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl]propane-2-ol;

methyl ester of 2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C] pyridin-1-yl] propyl} piperazine-1-yl)-3-methanesulfonylaminoethyl acids;

1-{3-[4-(1,1-dioxo-1H-1,6-benzo[d] isothiazol-3-yl) piperazine-1-yl]propyl}-5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydro-1H-pyrazolo [4,3-C] pyridine;

1-[1-{3-[4-(6-chlorobenzothiazole-2-yl) piperazine-1-yl]-2-hydroxypropyl}-3-4-triptoreline)-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl]ethanone; and

1-[1-[3-(4-benzo [d]isoxazol-3-yl-piperazine-1-yl)-2-hydroxypropyl]-3-(4-triptoreline)-1,4,6,7-tetrahydropyrazolo [4,3-C] pyridine-5-yl]ethanone.

6. The method according to claim 1, where the specified connection choose from:

N-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]-pyridine-1-yl]propyl}piperazine-1-yl) phenyl] methanesulfonamide;

amide 1-[3-(4-benzo [d]isothiazol-3-yl-piperazine-1-yl) propyl]-3-(4-bromophenyl)-1,4,6,7-tetrahydropyrazolo [4,3-C]pyridine-5-carboxylic acid; and

1-[3-chloro-2-(4-{2-hydroxy-3-[5-methanesulfonyl-3-(4-triptoreline)-4,5,6,7-tetrahydropyrazolo [4,3-C]pyridin-1-yl]propyl} piperazine-1-yl) phenyl]-3-metalmachine.

7. The method according to claim 1, where the specified pharmaceutical composition obtained when the amount of dose, appropriate for the treatment of allergic diseases.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivative of triazaspiro[5.5]undecane of the formula (I): wherein R1 means compound of the formula (1): or (2): wherein G represents a bond, (C1-C4)-alkylene, (C2-C4)-alkenylene or -CO-; ring A represents: (1) C5-10-membered mono- or bicarbocyclic ring or (2) 5-10-membered mono- or bicyclic heterocycle comprising 1-2 nitrogen atoms and/or 1-2 oxygen atoms; substitute R6 means the following values: (1) (C1-C4)-alkyl, (2) halogen atom, (3) nitrile group, (4) trifluoromethyl group and others; R2 represents: (1) (C1-C4)-alkyl, (2) (C2-C4)alkynyl or (3) (C1-C4)-alkyl substituted with a substitute represented in claim 1 of the invention claim; each R3 and R4 represents independently: (1) hydrogen atom, (2) (C1-C4)-alkyl or (3) (C1-C4)-alkyl substituted with 1-2 substituted taken among: (a) Cyc 2 and (b) hydroxy-group (wherein Cyc 2 represents (1) C5-6-membered monocarbocyclic ring or (2) 5-6-membered monocyclic heterocycle comprising 1-2 nitrogen atoms and/or one oxygen atom), or R3 and R4 form in common group of the formula: wherein R26 represents (C1-C4)-alkyl or Cyc 2; R5 represents hydrogen atom or (C1-C4)-alkyl, its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to pharmaceutical composition inhibiting HIV, regulator of chemokine/chemokine receptor and agent used in treatment and prophylaxis of some diseases, such as inflammatory diseases, asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis and other diseases that comprise as an active component above described compound of the formula (I) or its quaternary ammonium salt, its N-oxide or its nontoxic salt. Also, invention relates to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane or its pharmaceutically acceptable salt and pharmaceutical composition based on thereof, and to (3R)-1-butyl-2,5-dioxo-3-((1R)-1-hydroxy-1-cyclohexylmethyl)-9-(4-(4-carboxyphenyloxy)phenylmethyl)-1,4,9-triazaspiro[5.5]undecane hydrochloride and pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of derivative and composition.

16 cl, 32 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of triazaspiro[5,5]undecane of the formula (I):

wherein values of radicals R1-R5 are given in the invention claim, ort o their quaternary ammonium salts, N-oxides or nontoxic salts. Proposed compounds possess inhibitory and regulating activity with respect to chemokine/chemokine receptors and can be useful in prophylaxis and treatment of different inflammatory diseases, such as asthma, atopic dermatitis, nettle rash, allergic diseases, nephritis, hepatitis, arthritis or proliferative arthritis and other similar diseases. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I).

EFFECT: improved control method, valuable medicinal properties of compounds.

9 cl, 5 sch, 36 tbl, 70 ex

FIELD: medicine.

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EFFECT: higher efficiency of application.

5 cl, 3 ex, 2 tbl

FIELD: medicine, allergology, toxins, pharmacy.

SUBSTANCE: invention relates to recombinant allergens of insect venom and to specific methods for their preparing, in particular, antigen 5 of wasp venom allergen. Recombinant antigen 5 is prepared in bacterial cells as insoluble aggregates followed by their denaturation and transfer to a soluble monomeric allergen. Transfer is carried out by dialysis using acid buffer solution (pH = 3.5-6.5) that can comprise guanidine hydrochloride, or by using a cysteine-containing solvent. Based on describes methods the practically pure recombinant antigen 5 of wasp venom allergen is isolated and used in pharmaceutical composition for hyposensibilization of body to wasp venom allergen. Invention provides preparing protein with reduced reaction capability JgE owing to it can be used in immunotherapy in treatment of allergy.

EFFECT: improved preparing method, valuable properties of allergen.

8 cl, 1 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

FIELD: pharmaceutical industry.

SUBSTANCE: composition contains steroid as active principle, in particular 11-β,16-α,17-α,21-tetrahydroxy-9-α-fluoro-1,4-pregnadiene-3,20-dione or pharmaceutically acceptable salt thereof and special-destination additives including microcrystalline cellulose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

3 cl, 1 tbl

Antiallergic drug // 2253451

FIELD: pharmaceutical industry.

SUBSTANCE: drug composition includes antihistamine agent as active principle, in particular 1-(p-chlorophenyl)-1-(pyrid-2-yl)-3-N,N-dimethylpropylamine or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier including microcrystalline cellulose, lactose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

6 cl, 5 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new pyranoindazoles of the formula (1): wherein R1 and R2 are chosen independently from hydrogen atom or alkyl group; R3 and R4 represent independently hydrogen atom or alkyl group; R5, R6 and R7 mean hydrogen atom; R8 and R9 mean hydrogen atom, hydroxyl, alkoxy-group, -NR10R11, -OC(=O)NR1R2, -OC(=O)-(C1-C4)-alkyl or alkylthiol; R10 and R11 mean hydrogen atom; A means -(CH2)n, C=O; B means a simple or double bond; n = 0-2; Y means nitrogen atom (N); X means carbon atom C; dotted line means the corresponding simple or double bond. Also, invention relates to a pharmaceutical composition based on compounds of the formula (1), to a method for regulating normal or enhanced intraocular pressure, method for treatment of glaucoma and method for blocking or binding serotonine receptors. Invention provides preparing new pyranoindazoles possessing the valuable pharmaceutical effect.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 4 tbl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

The invention relates to new tricyclic pyrazole derivative or its pharmaceutically acceptable salt

The invention relates to new 2H-[1]benzothiophene[4,3,2-cd]indazols, the pharmaceutical compositions based on them, methods of treatment of tumors when using these compounds and methods for treating cancer in mammals when using pharmaceutical compositions based benzopyranones

The invention relates to 3-substituted derivatives of 3H-2,3-benzodiazepine, method of production thereof and to pharmaceutical compositions based on them

FIELD: medicine, pediatric gastroenterology.

SUBSTANCE: the present innovation deals with selecting children with functional dyspepsia at helicobacteriosis for the purpose to carry out anti-helicobacter therapy. So, one should detect the following signs in a child: hypertrophic gastropathy in gastric antral department, relapses of dyspepsia symptoms during 1 yr and more, despite treatment by applying antacids and anti-secretory preparations, inheritance on ulcerous disease, previously observed erosions in gastroduodenal area; and in case of any of the above-mentioned signs in a child it is necessary to fulfill anti-helicobacter therapy, and in case of the absence of the above-mentioned signs this therapy should not be carried out. This innovation provides differentiated approach to therapy, it, also, enables to avoid groundless medicinal loading upon a child and decrease financial expenses for the treatment.

EFFECT: higher efficiency of individualization.

4 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of urea of the formula (I): wherein A means heteroaryl that is taken among the group that comprises: and wherein radicals B, R1 and R2 have values given in description. These compound possess capacity to inhibit activity of enzyme RAF kinase and to inhibit growth of tumor cells. Also, invention relates to a method for inhibition of activity of RAF kinase in mammal body and to pharmaceutical compositions based on compounds of the formula (I). Invention provides preparing new derivatives of urea possessing valuable pharmaceutical properties.

EFFECT: improved method for inhibition, valuable properties of compounds and composition.

25 cl, 6 tbl

FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)

. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.

EFFECT: improved method for treatment.

9 cl, 2 tbl, 2 dwg, 40 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

Drug // 2229882
The invention relates to a new combination drug, which can be used as a means of protecting the person from the early transient incapacitation and edema of the primary reaction to radiation
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